JP2001294572A - Novel sulfonyl derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a novel sulfonyl derivative, salts thereof and solvates thereof that have strong FXa-inhibitory action, manifests promptly, sufficiently and sustainingly anti-thrombogenic effect with reduced side effects and are useful as excellent anticoagulant drugs. SOLUTION: This invention release to a compound represented by the general formula (I): Q1-Q2-T1-Q3-SO2-QA (I) (wherein Q1 is a saturated or unsaturated bicyclic condensed ring group which may be substituted or a saturated or unsaturated tricyclic condensed ring group which may be substituted; Q2 is a single bond, oxygen atom, sulfur atom, a straight or branched chain 1-6C alkylene, and the like; QA is an aryl-alkenyl which may be substituted, a heteroarylalkenyl which may be substituted, and the like; T1 denotes carbonyl group, or the like), the salts thereof and the solvates thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel orally administrable compound (sulfonyl derivative) which inhibits activated blood coagulation factor X (hereinafter abbreviated as FXa) and exhibits a potent anticoagulant effect. The present invention relates to a salt or a blood coagulation inhibitor containing them as an active ingredient, or a prophylactic and / or therapeutic agent for thrombus or embolus.

[0002]

BACKGROUND OF THE INVENTION Unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Barger's disease, deep vein thrombosis,
Generalized intravascular coagulation, thrombus formation after prosthetic valve replacement, reocclusion after revascularization, and thrombus formation during extracorporeal circulation, because enhanced blood coagulation is one of the important factors, and There is a need for an excellent anticoagulant which is excellent in drug activity, is persistent, has a low risk of bleeding, has few side effects, and has a sufficient effect immediately by oral administration (Thrombosis Research, Thrombosis Research, 68).
Vol., Pp. 507-512, 1992).

Studies of anticoagulants based on various mechanisms of action suggest that FXa inhibitors may be excellent anticoagulants. The blood coagulation system is a series of reactions in which a large amount of thrombin is produced through an amplification process by a multi-step enzymatic reaction to produce insoluble fibrin. In endogenous systems, after a multi-step reaction following activation of the contact factor,
Activated Factor VIII activates Factor X on the phospholipid membrane in the presence of activated Factor VIII, calcium ions. In the exogenous system, activated factor VII activates factor X in the presence of tissue factor. That is, activation of factor X to FXa in the coagulation system is an essential reaction for thrombin generation. Activated X in both systems
Factor (FXa) limits the degradation of prothrombin to produce thrombin. The generated thrombin activates upstream clotting factors, so that thrombin generation is further amplified. As described above, the coagulation system higher than FXa is an endogenous system,
Since the system is divided into extrinsic systems, inhibition of a coagulation enzyme higher than FXa cannot sufficiently suppress the production of FXa, resulting in the production of thrombin. In addition, since the coagulation system is a self-amplification reaction, suppression of the coagulation system can be achieved more efficiently by inhibiting FXa positioned higher than inhibiting generated thrombin (Thrombosis Research; Thrombosis Research).
ch. 15, Vol. 617-629, 1979).

Another advantage of the FXa inhibitor is that there is a large discrepancy between the effective dose in the thrombus model and the dose that prolongs the bleeding time in the experimental bleeding model. Is considered to be an anticoagulant with a low risk of bleeding.

[0005] Various compounds have been reported as FXa inhibitors. In general, antithrombin III and antithrombin III-dependent pentasaccharide, etc., are prothrombinase conjugates that play a practical role in thrombus formation in vivo. (Thrombosis Research; Thrombosis Research)
ch, 68, 507-512, 1992,
Journal of ClinicalInvestment; Journal of ClinicalInve
stigation, Vol. 71, pp. 1383-1389, 1983, Mebio; Mebio, August, 92-
P. 97), and shows no efficacy with oral administration.
Chick anticoagulant peptide (TAP) isolated from blood-sucking animals such as mites and leeches (Science; S
science, 248, 593-596, 19
90 years. ) And antistasin (AST) (Journal of Biological Chemistry; Journal)
al of Biological Chemistr
y, 263, 10162-10167, 198
8 years) also inhibits FXa and exhibits antithrombotic effects from venous thrombotic models to arterial thrombotic models, but these are high molecular peptides and are ineffective by oral administration. From this perspective,
Development of small FXa inhibitors that directly inhibit coagulation factors in an antithrombin III-independent manner has been carried out.

[0006]

DISCLOSURE OF THE INVENTION The present invention relates to a novel sulfonyl derivative as an excellent anticoagulant, which has a strong FXa inhibitory effect and has sufficient side effects to obtain a sufficient and sustained antithrombotic effect promptly by oral administration. , Their salts and their solvates.

[0007]

Means for Solving the Problems In view of the above-mentioned circumstances, the present inventors have intensively studied the synthesis and pharmacological action of a novel anti-FXa inhibitor, and as a result, have found that a novel sulfonyl derivative,
The salt or a solvate thereof shows a strong FXa inhibitory action and a strong anticoagulant action, and also inhibits FXa strongly and rapidly and continuously even in oral administration, and shows a strong anticoagulant action and antithrombotic action and is safe. Thus, the present invention was found to be useful as a preventive and therapeutic agent for various diseases caused by thrombus and embolism, and completed the present invention.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to a compound represented by the following general formula (I), a salt thereof and a solvate thereof.

Formula (I) Q ¹ -Q ² -T ¹ -Q ³ -SO ₂ -Q ^A (I) wherein Q ¹ is a saturated or unsaturated bicyclic compound which may have a substituent. Or a saturated or unsaturated tricyclic fused ring group which may have a substituent.

Q ² represents a single bond, an oxygen atom, a sulfur atom, a linear or branched alkylene group having 1 to 6 carbon atoms, a linear or branched alkenylene group having 2 to 6 carbon atoms, A chain or branched alkynylene group having 2 to 6 carbon atoms, a group -N (R ¹ ) -CO- (wherein R ¹ represents a hydrogen atom or an alkyl group), a group -N (R ² ) - (in CH ₂₎ m-(group, R ² is a hydrogen atom or an alkyl group, m
Represents an integer of 0 to 6. ) Or group

[0011]

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(This group may have a substituent 2
A saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group,
A divalent saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, or a divalent saturated or unsaturated bicyclic fused ring group which may have a substituent. I do. ← C indicates that the carbon atom of this group is bonded to Q ¹ . ).

Q ³ represents any of the following groups.

[0014]

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(In these groups, R ³ , R ⁴ , R ⁵ , R ⁶ , R
^When the carbon atom to which R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ are attached is not adjacent to a nitrogen atom, each independently represents a hydrogen atom,
Hydroxyl group, alkyl group, alkoxyl group, alkoxyalkyl group, alkoxyalkyloxy group, hydroxyalkyl group, hydroxyalkyloxy group, hydroxyalkylcarbonyl group, hydroxyalkylsulfonyl group,
Formyl group, formylalkyl group, formylalkylcarbonyl group, formylalkylsulfonyl group, alkylcarbonyl group, alkylsulfonyl group, alkylcarbonylalkyl group, alkylsulfonylalkyl group, carboxyl group, carboxyalkyl group, carboxyalkyloxy group, carboxyalkylcarbonyl group Carboxyalkylsulfonyl group, carboxyalkylcarbonylalkyl group, carboxyalkylsulfonylalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkyloxy group, alkoxycarbonylalkylcarbonyl group, alkoxycarbonylalkylsulfonyl group, one substituent Or an amino group which may have two, one substituent or Aminoalkyl group, which may have one or two substituents on the amino group, aminoalkylcarbonyl group, which may have one or two substituents on the amino group One or two substituents on the amino group
Aminocarbonylcarbonyloxy group, which may have one or two substituents on the amino group, aminocarbonylalkyl which may have one or two substituents on the amino group An aminocarbonylalkyloxy group, which may have one or two substituents on the amino group, an alkylsulfonylaminocarbonylalkyl group, which may have one substituent on the amino group, a substituent on the amino group An arylsulfonylaminocarbonylalkyl group, which may have one, an aminosulfonylalkyl group, a cyanoalkyl group, which may have one or two substituents on the amino group, and one substituent on the amino group There are also alkoxyalkylaminocarbonylalkyl groups, alkyl Carbonyloxy group or a group A ¹ -B ^1, - (the radical, A ¹ is also have also 5- to 6-membered cyclic hydrocarbon group or a substituent of the saturated or unsaturated having a substituent saturation Or unsaturated 5
Means a 6-membered heterocyclic group. B ¹ is a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a group -O
-C ₁ -C ₆ alkylene group, a group -COO-C _{1 ~C 6} alkylene group, a group -NHCO- or a group -NHCO-C _{1 ~C 6}
Means an alkylene group. ).

Further, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R
^When the carbon atom to which ¹⁰ and R ¹¹ are attached is adjacent to a nitrogen atom, each independently represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, a hydroxyalkylcarbonyl group,
Hydroxyalkylsulfonyl, formyl, formylalkyl, formylalkylcarbonyl, formylalkylsulfonyl, alkylcarbonyl, alkylsulfonyl, alkylcarbonylalkyl, alkylsulfonylalkyl, carboxyl, carboxyalkyl, carboxyalkylcarbonyl Group, carboxyalkylsulfonyl group, carboxyalkylcarbonylalkyl group, carboxyalkylsulfonylalkyl group, alkoxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylcarbonyl group, alkoxycarbonylalkylsulfonyl group, substituent on amino group part An aminoalkyl group which may have one or two Pieces or two also aminoalkyl group having a substituent at the amino group moiety 1
Aminocarbonyl group which may have one or two,
An aminocarbonylalkyl group which may have one or two substituents on the amino group, an alkylsulfonylaminocarbonylalkyl group which may have one substituent on the amino group, and one substituent on the amino group An arylsulfonylaminocarbonylalkyl group which may have one or two substituents in the amino group, an aminosulfonylalkyl group, a cyanoalkyl group, or an alkoxy which may have one substituent in the amino group An alkylaminocarbonylalkyl group, an alkylcarbonyloxyalkyl group, or a group A ² -B ^2-
(Wherein, A ² is a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent. B ² represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a group —O—C ₁ -C ₆ alkylene group, a group —COO—C ₁ -C ₆ alkylene group, a group —NH.
CO— or a group —NHCO—C ₁ -C ₆ alkylene group. ).

Further, R ³ and R ⁴ , R ⁵ and R ⁶ , R ⁷
And R ⁸ , R ¹⁰ and R ¹¹ may have a substituent together with the carbon atoms constituting the ring, or may have a saturated or unsaturated 5- to 7-membered cyclic hydrocarbon group or a substituent. It may mean a saturated or unsaturated 5- to 7-membered heterocyclic group,

R ⁹ and R ¹² are each independently a hydrogen atom, an alkyl group, a hydroxyalkyl group, a hydroxyalkylcarbonyl group, a hydroxyalkylsulfonyl group, an alkoxyl group, an alkoxyalkyl group, an alkoxyalkylcarbonyl group, an alkoxyalkylsulfonyl group. , Formyl group, formylalkyl group, formylalkylcarbonyl group, formylalkylsulfonyl group, alkylcarbonyl group, alkylcarbonylalkyl group,
Alkylsulfonyl group, alkylsulfonylalkyl group, carboxyalkyl group, carboxyalkylcarbonyl group, carboxyalkylsulfonyl group, carboxyalkylcarbonylalkyl group, carboxyalkylsulfonylalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylcarbonyl group, An alkoxycarbonylalkylsulfonyl group, an amino group which may have one or two substituents, an aminoalkyl group which may have one or two substituents on the amino group, one substituent on the amino group Or an aminoalkyloxy group which may have two, an aminoalkylcarbonyl group which may have one or two substituents on the amino group, and one substituent on the amino group Or two or more aminoalkyloxycarbonyl groups, one or two substituents on the amino group, and one or two substituents on the amino group An aminocarbonylalkyl group, an aminocarbonyloxyalkyl group which may have one or two substituents on the amino group, an alkylsulfonylaminocarbonylalkyl group which may have one substituent on the amino group, an amino group An arylsulfonylaminocarbonylalkyl group which may have one substituent,
An aminosulfonylalkyl group, a cyanoalkyl group, which may have one or two substituents on the amino group part;
It means an alkoxyalkylaminocarbonylalkyl group or an alkylcarbonyloxyalkyl group which may have one substituent in the amino group part.

R ⁹ is a saturated or unsaturated 5 which may have a substituent together with a carbon atom constituting a ring together with R ⁷ or R ⁸ and a nitrogen atom to which R ⁹ is bonded.
It may mean a 7 to 7 membered heterocyclic group.

R ¹² is a saturated or unsaturated 5- to 7-membered which may have a substituent, together with R ¹⁰ or a carbon atom constituting a ring together with R ¹¹ and a nitrogen atom to which R ¹² is bonded. May mean a heterocyclic group.

A, b, d, e and g each independently represent an integer of 0 or 1. c represents an integer of 0 to 3. f, h and i each independently represent an integer of 1 to 3. However, the sum of a, b and c means an integer of 2 or 3, the sum of d and e means an integer of 0 or 1, and the sum of f, g and h means an integer of 3 to 5. .

Q ^A represents an arylalkenyl group which may have a substituent, a heteroarylalkenyl group which may have a substituent, a saturated or unsaturated bicyclic fused ring group which may have a substituent, A saturated or unsaturated tricyclic fused ring group which may have a group, a group Ar-C
(H) = N- (wherein Ar represents an aryl group which may have a substituent) or group Het-C (H) =
N- (in the group, Het means a heteroaryl group which may have a substituent).

T ¹ represents a carbonyl group, a group —CH (R ¹³ ) — (wherein R ¹³ represents a hydrogen atom, an alkyl group, a hydroxyalkyl group which may be protected with a hydroxyl group, an alkoxyalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an aryl group, an aralkyl group, refers to a heteroaryl group, also aminoalkyl group having a heteroarylalkyl group or an amino group moiety in a substituent (protecting group).) group -C (= NOR ¹⁴ )-Or group -C (= N-NH
R ^{14 ′} ) — wherein R ¹⁴ and R ^{14 ′} each represent a hydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an amino group part. Means an aminoalkyl group which may have a substituent.) A salt thereof, and a solvate thereof.

Hereinafter, the substituents in the sulfonyl derivative of the present invention represented by the general formula (I) will be described. <About Group Q ^A > The group Q ^A is an arylalkenyl group which may have a substituent, a heteroarylalkenyl group which may have a substituent, or a saturated or unsaturated bicyclic condensation which may have a substituent. A cyclic group, a saturated or unsaturated tricyclic fused ring group which may have a substituent, a group A
r-C (H) = N- (wherein, Ar represents an aryl group which may have a substituent) or a group Het-C
(H) = N- (wherein Het means a heteroaryl group which may have a substituent).

In the group Q ^A , the arylalkenyl group which may have a substituent means a group composed of an aryl group and a linear, branched or cyclic alkenylene group having 2 to 6 carbon atoms. Examples of the aryl group include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. Examples of the arylalkenyl group include a phenylethenyl group.

The heteroarylalkenyl group which may have a substituent means a group composed of a heteroaryl group and a linear, branched or cyclic alkenylene group having 2 to 6 carbon atoms. A heteroaryl group means an aromatic monovalent group containing at least one heteroatom, for example,
Examples include a pyridyl group, a furyl group, and a thienyl group. As the heteroarylalkenyl group, for example,
And a pyridylethenyl group.

A saturated or unsaturated bicyclic fused ring group which may have a substituent or a saturated or unsaturated tricyclic fused ring group may be a saturated or unsaturated pentacyclic group which may have a substituent. A 6-membered cyclic hydrocarbon group condensed,
Saturated or unsaturated 5 to 5 which may have a substituent
A 6-membered cyclic hydrocarbon group condensed with a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, or a saturated or unsaturated 5-6 group which may have a substituent. A fused heterocyclic group.

Examples of the saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group include, for example, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl and the like. Can be mentioned. When there are a plurality of structural isomers such as a cyclopentenyl group, they are all included.

The saturated or unsaturated 5- or 6-membered heterocyclic group is a cyclic group containing at least one hetero atom, and examples of the hetero atom include an oxygen atom, a nitrogen atom and a sulfur atom. it can. Examples of the saturated or unsaturated 5- to 6-membered heterocyclic group include, for example, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, oxa Triazolyl group, thiadiazolyl group, furazanyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, oxazinyl group, oxadiazinyl group, morpholinyl group, thiazinyl group, thiadiazinyl group, thiomorpholinyl group, tetrazolyl group, Examples thereof include a triazolyl group and a triazinyl group. When there are a plurality of structural isomers such as a pyranyl group, they are all included.

Therefore, for example,
Examples include an indenyl group, an indanyl group, a naphthyl group, a tetrahydronaphthyl group, an anthryl group, and a phenanthryl group. Examples thereof include a benzofuranyl group, a benzothienyl group, an indolyl group, an indolinyl group, a quinolyl group, a benzodiazinyl group, a tetrahydroisoquinolyl group, a benzothiazolyl group, a tetrahydrobenzothiazolyl group, and an isoindolyl group. As those, naphthyridinyl group, tetrahydrothienopyridyl group, tetrahydrothiazolopyridyl group, tetrahydropyridopyridyl group, thiazolopyridazinyl group, tetrahydrothiazolopyridazinyl group, pyrrolopyridyl group, tetrahydropyrrolopyridyl group, Dihydropyridoquinazolyl group, pyridopyrimidinyl group, tetrahydropyridopyrimidinyl group, pyranothiazolyl group, dihydropyranothiazolyl group, flopyridyl group, tetrahydrofuropyridyl group, oxazolopyridyl group, tetrahydrooxazolopyridyl group, oxazolopyri Dazinyl group,
Examples thereof include a tetrahydrooxazolopyridazinyl group.

The aryl group in the group Ar-C (H) = N- (wherein Ar represents an aryl group which may have a substituent) has the same meaning as described above. The group Ar-C (H) = N- means a group composed of a phenyl group which may have a substituent and a group -C (H) = N-.

Further, a group Het-C (H) = N- (in the group,
Het means a heteroaryl group which may have a substituent. The heteroaryl group in ()) means the same as described above, and includes the group Het-C
(H) = N- means a group composed of a pyridyl group which may have a substituent and a group Het-C (H) = N-, and the like.

An arylalkenyl group, a heteroarylalkenyl group, a saturated or unsaturated bicyclic fused ring group,
Saturated or unsaturated tricyclic fused ring group, group Ar-C
(H) = N- and the group Het-C (H) = N- may each have 1 to 2 substituents, and the substituents include a hydroxyl group, a fluorine atom, a chlorine atom, a bromine atom, and an iodine. A halogen atom such as an atom, a halogenomethyl group substituted with 1 to 3 halogen atoms, an amino group, a cyano group, an aminomethyl group, an amidino group, a hydroxyamidino group, a linear, branched or cyclic carbon atom To 6 alkyl groups (e.g., methyl group, ethyl group, etc.), linear, branched or cyclic C1-C6 alkoxyl groups (e.g., methoxyl group, ethoxyl group, etc.), linear, branched A branched or cyclic C 2-7 alkoxycarbonylamidino group (for example, methoxycarbonylamidino group,
An ethoxycarbonylamidino group, etc., a linear, branched or cyclic alkenyl group having 2 to 6 carbon atoms (for example,
A vinyl group, an allyl group, etc.), a linear, branched or cyclic alkynyl group having 2 to 6 carbon atoms (eg, an ethynyl group, a propynyl group, etc.), a linear, branched or cyclic carbon number of 2 And alkoxycarbonyl groups (e.g., methoxycarbonyl group, ethoxycarbonyl group, etc.) and aminocarbonyl group.

The group Q ^A more specifically represents any of the following groups.

[0035]

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[0036]

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[0037]

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The substituents in these groups will be described below. Base

[0039]

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R in^FifteenIs hydrogen atom, hydroxyl group, nitro
Group, cyano group, halogen atom, alkyl group, hydroxy
Sialkyl group, alkoxyl group, alkoxyalkyl
Group, carboxyl group, carboxyalkyl group, alkyl
Carbonyl group, alkoxycarbonyl group, alkoxyca
Rubonylalkyl group, alkylcarbonyloxy group, or
Or group A^Three-B^Three-(In the group, A^ThreeRepresents one substituent or
May have two amino groups or substituents
A saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group;
Or a saturated or unsaturated 5 which may have a substituent.
Means a 6-membered heterocyclic group. B ^ThreeIs a single bond, carbo
Nyl group, alkylene group, carbonylalkyl group, carbo
Nilalkyloxy group or alkylenecarbonyl
It means a xy group. ).

[0041] In R ^15, examples of the halogen atom, fluorine atom include chlorine atom, a bromine atom and an iodine atom.

The alkyl group means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, an isopropyl group and a cyclopropyl group.

The hydroxyalkyl group means a group consisting of a hydroxyl group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. Examples of the alkylene group include a methylene group, an ethylene group and a trimethylene group. , Propylene group,
Cyclohexylene groups and the like can be mentioned. Examples of the hydroxyalkyl group include a hydroxymethyl group,
Examples thereof include a hydroxyethyl group.

The alkoxyl group means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms and an oxygen atom, and includes, for example, a methoxyl group, an ethoxyl group,
An isopropoxyl group can be exemplified.

The alkoxyalkyl group is a group consisting of a linear, branched or cyclic C1-C6 alkoxyl group and a linear, branched or cyclic C1-C6 alkylene group. Means, for example, a methoxymethyl group,
Examples thereof include a methoxyethyl group and an ethoxymethyl group.

The carboxyalkyl group means a group consisting of a carboxyl group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms, such as carboxymethyl group and carboxyethyl group. be able to.

The alkylcarbonyl group means a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms and a carbonyl group, such as a methylcarbonyl group and an ethylcarbonyl group. be able to.

The alkoxycarbonyl group means a linear, branched or cyclic C1-C6 alkoxyl group and a carbonyl group, such as a methoxycarbonyl group and an ethoxycarbonyl group. be able to.

The alkoxycarbonylalkyl group includes a linear, branched or cyclic C 2-7 alkoxycarbonyl group and a linear, branched or cyclic C 1-7 alkoxycarbonyl group.
6 means an alkylene group, and examples thereof include a methoxycarbonylethyl group and an ethoxycarbonylmethyl group.

The alkylcarbonyloxy group is a straight-chain,
It means a group composed of a branched or cyclic alkylcarbonyl group having 2 to 7 carbon atoms and an oxygen atom, and examples thereof include a methylcarbonyloxy group, an ethylcarbonyloxy group, and an isopropylcarbonyloxy group.

In the group A ³ -B ^3- , A ³ represents one substituent.
Or two or more amino groups, a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, or a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent. A heterocyclic group is meant.

Therefore, when A ³ represents an amino group which may have one or two substituents, B ³ represents a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group or an alkylenecarbonyl group. Since it means an oxy group, the group A ³ -B ^3-
Represents, for example, a group or the like shown in the following group (A).

Group (A): an amino group which may have one or two substituents, an aminocarbonyl group which may have one or two substituents on the amino group part, and a substituent on the amino group part An aminoalkyl group which may have one or two, an aminocarbonylalkyl group which may have one or two substituents on the amino group part,
An aminocarbonylalkyloxy group which may have one or two substituents on the amino group, an aminoalkylcarbonyl group which may have one or two substituents on the amino group, and a substituent on the amino group An aminoalkylcarbonyloxy group which may have one or two;

Hereinafter, the groups shown in the group (A) will be described.

The aminocarbonyl group which may have one or two substituents in the amino group part means a group constituted by an amino group which may have one or two substituents and a carbonyl group.

An aminoalkyl group which may have one or two substituents in the amino group part is different from an amino group which may have one or two substituents in a linear, branched or cyclic carbon group. It means a group composed of an alkylene group of formulas 1 to 6, and examples of the aminoalkyl group include an aminomethyl group and an aminoethyl group.

The aminocarbonylalkyl group which may have one or two substituents in the amino group part is the same as the above-mentioned aminocarbonyl group which may have a substituent and which has a straight, branched or cyclic number of carbon atoms. It means a group composed of an alkylene group of 1 to 6, and examples of the aminocarbonylalkyl group include an aminocarbonylmethyl group and an aminocarbonylethyl group.

The aminocarbonylalkyloxy group which may have one or two substituents in the amino group part means a group consisting of the above-mentioned aminocarbonylalkyl group which may have a substituent and an oxygen atom. And the aminocarbonylalkyloxy group means, for example, an aminocarbonylmethoxyl group and an aminocarbonylethoxyl group.

The aminoalkylcarbonyl group which may have one or two substituents in the amino group part means a group consisting of an aminoalkyl group which may have a substituent and a carbonyl group described above. Examples of the alkylcarbonyl group include, for example, an aminomethylcarbonyl group,
An aminoethylcarbonyl group and the like can be mentioned. The aminoalkylcarbonyloxy group which may have one or two substituents in the amino group part means a group consisting of the above-mentioned aminoalkylcarbonyl group which may have a substituent and an oxygen atom, Examples of the carbonyloxy group include an aminomethylcarbonyloxy group and an aminoethylcarbonyloxy group.

Examples of the substituent which can be substituted on the amino group (part) include those of the following group (1).

Group (1): alkyl, alkenyl, halogenoalkyl, halogenoalkenyl, hydroxyalkyl, hydroxyalkylcarbonyl, hydroxyalkylsulfonyl, alkoxyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxyalkyl Sulfonyl group, formyl group, formylalkyl group, formylalkylcarbonyl group, formylalkylsulfonyl group, alkylcarbonyl group, alkylcarbonylalkyl group, alkylsulfonyl group, alkylsulfonylalkyl group, carboxyalkyl group, carboxyalkylcarbonyl group, carboxyalkylsulfonyl Group, carboxyalkylcarbonylalkyl group,
Carboxyalkyl alkylsulfonyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, an alkoxycarbonylalkyl group, alkoxycarbonyl alkylsulfonyl, trifluoromethylsulfonyl oxyalkenyl group, and group a ³ -b ³ -
(In the group, a ³ represents one to three substituents selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an alkoxyl group, an alkyl group, a cyano group, a nitro group, a carboxyl group, an alkoxycarbonyl group and an aminocarbonyl group. .b ³ is a single bond which means 5-6 membered heterocyclic group also saturated or 5- to 6-membered cyclic hydrocarbon group or a saturated or unsaturated unsaturated having pieces, carbonyl group, an alkylene group, A carbonylalkyl group, a carbonylalkyloxy group, an alkylenecarbonyloxy group, an alkyleneaminocarbonyl group, an alkyleneaminocarbonylalkyl group, an alkyleneaminosulfonyl group or an alkyleneaminosulfonylalkyl group).

Here, the substituent in the group (1) which can be substituted for the amino group (part) will be described.

The alkyl group means a linear, branched or cyclic one having 1 to 6 carbon atoms. For example, a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group and the like can be mentioned.

The alkenyl group means a linear, branched or cyclic alkenyl group having 2 to 6 carbon atoms, and examples thereof include a vinyl group and an allyl group.

The halogenoalkyl group means a group consisting of a halogen atom and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms, for example, chloromethyl group,
A bromoethyl group and the like can be mentioned.

The halogenoalkenyl group means a group consisting of a halogen atom and a linear or branched alkenylene group having 2 to 6 carbon atoms, for example, a chlorovinyl group,
Bromoallyl group and the like can be mentioned. The position of the double bond is not particularly limited.

The hydroxyalkyl group means a group consisting of a hydroxyl group and a linear, branched or cyclic alkylene group having 2 to 6 carbon atoms, such as a hydroxyethyl group and a hydroxypropyl group. Can be.

The hydroxyalkylcarbonyl group means a group composed of the above-mentioned hydroxyalkyl group and carbonyl group, and examples thereof include a hydroxymethylcarbonyl group and a hydroxyethylcarbonyl group.

The hydroxyalkylsulfonyl group means a group composed of the above-mentioned hydroxyalkyl group and sulfonyl group, and examples thereof include a hydroxymethylsulfonyl group and a hydroxyethylsulfonyl group.

The alkoxyl group means a linear, branched or cyclic C1-C6 group. For example, a methoxyl group, an ethoxyl group and the like can be mentioned.

The alkoxyalkyl group is a group consisting of a linear, branched or cyclic C1-C6 alkoxyl group and a linear, branched or cyclic C2-C6 alkylene group. And examples thereof include a methoxyethyl group, an ethoxyethyl group, and a methoxypropyl group.

The alkoxyalkylcarbonyl group means a group composed of the above-mentioned alkoxyalkyl group and carbonyl group, and examples thereof include a methoxyethylcarbonyl group and an ethoxymethylcarbonyl group.

The alkoxyalkylsulfonyl group means a group composed of the above-described alkoxyalkyl group and sulfonyl group, and examples thereof include a methoxymethylsulfonyl group and an ethoxymethylsulfonyl group.

The formylalkyl group means a group consisting of a formyl group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. Examples thereof include a formylmethyl group and a formylethyl group. Can be mentioned.

The formylalkylcarbonyl group means a group composed of the above-mentioned formylalkyl group and carbonyl group, and examples thereof include a formylmethylcarbonyl group and a formylethylcarbonyl group.

The formylalkylsulfonyl group means a group composed of the above-mentioned formylalkyl group and sulfonyl group, and examples thereof include a formylmethylsulfonyl group and a formylethylsulfonyl group.

The alkylcarbonyl group means a group consisting of a straight-chain, branched or cyclic alkyl group having 1 to 6 carbon atoms and a carbonyl group. Examples thereof include a methylcarbonyl group and an ethylcarbonyl group. be able to.

The alkylcarbonylalkyl group means a group composed of the above-mentioned alkylcarbonyl group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms.
For example, a methylcarbonylmethyl group, an ethylcarbonylmethyl group and the like can be mentioned.

The alkylsulfonyl group means a group composed of the above-mentioned alkyl group and sulfonyl group, and examples thereof include a methylsulfonyl group and an ethylsulfonyl group.

The alkylsulfonylalkyl group means a group comprising the above-mentioned alkylsulfonyl group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms.
For example, a methylsulfonylmethyl group, an ethylsulfonylmethyl group and the like can be mentioned.

The carboxyalkyl group means a group composed of a carboxyl group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. For example, a carboxymethyl group, a carboxyethyl group and the like can be mentioned.

The carboxyalkylcarbonyl group means a group composed of the above-mentioned carboxyalkyl group and carbonyl group, and examples thereof include a carboxymethylcarbonyl group and a carboxyethylcarbonyl group.

The carboxyalkylsulfonyl group means a group composed of the carboxyalkyl group and the sulfonyl group, and examples thereof include a carboxymethylsulfonyl group and a carboxyethylsulfonyl group.

The carboxyalkylcarbonylalkyl group is the same as the carboxyalkylcarbonyl group described above,
It means a group composed of a branched or cyclic alkylene group having 1 to 6 carbon atoms, and examples thereof include a carboxymethylcarbonylmethyl group and a carboxyethylcarbonylmethyl group.

The carboxyalkylsulfonylalkyl group is linear with the carboxyalkylsulfonyl group described above,
It means a group composed of a branched or cyclic alkylene group having 1 to 6 carbon atoms, and examples thereof include a carboxymethylsulfonylmethyl group and a carboxyethylsulfonylmethyl group.

The alkoxycarbonyl group means a linear, branched or cyclic C1-C6 alkoxy group and a carbonyl group. For example, a methoxycarbonyl group, an ethoxycarbonyl group and the like can be mentioned.

The alkoxycarbonylalkyl group means a group composed of the above-mentioned alkoxycarbonyl group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. For example, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, etc. can be mentioned.

The alkoxycarbonylalkylcarbonyl group means a group composed of the above-mentioned alkoxycarbonylalkyl group and carbonyl group, for example, methoxycarbonylethylcarbonyl group, ethoxycarbonylmethylcarbonyl group and the like.

The alkoxycarbonylalkylsulfonyl group means a group composed of the above-mentioned alkoxycarbonylalkyl group and sulfonyl group, for example, methoxycarbonylethylsulfonyl group, ethoxycarbonylmethylsulfonyl group and the like.

The trifluoromethylsulfonyloxyalkenyl group means a group consisting of a trifluoromethylsulfonyloxy group and a linear or branched alkenylene group having 2 to 6 carbon atoms. Oxyvinyl groups, trifluoromethylsulfonyloxyallyl groups and the like can be mentioned.

In the groups a ³ -b ^3- , a ³ is a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent such as a halogen atom, or a saturated or unsaturated 5- or 6-membered hydrocarbon group. Wherein the saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group is, for example, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl Group, cyclohexadienyl group and phenyl group. When there are a plurality of structural isomers such as a cyclopentenyl group, they are all included.

The saturated or unsaturated 5- or 6-membered heterocyclic group is a cyclic group containing at least one hetero atom, and examples of the hetero atom include an oxygen atom, a nitrogen atom and a sulfur atom. it can. Examples of the saturated or unsaturated 5- to 6-membered heterocyclic group include, for example, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, oxa Triazolyl group, thiadiazolyl group, furazanyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, oxazinyl group, oxadiazinyl group, morpholinyl group, thiazinyl group, thiadiazinyl group, thiomorpholinyl group, tetrazolyl group, Examples thereof include a triazolyl group and a triazinyl group. When there are a plurality of structural isomers such as a pyranyl group, they are all included.

B ³ is a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a carbonylalkyloxy group, an alkylenecarbonyloxy group, an alkyleneaminocarbonyl group, an alkyleneaminocarbonylalkyl group, an alkyleneaminosulfonyl group or an alkyleneaminosulfonylalkyl group Wherein the alkylene group is a linear, branched or cyclic C 1
~ 6.

The carbonylalkyl group means a group consisting of a carbonyl group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. Examples of the carbonylalkyl group include a carbonylmethyl group and a carbonylethyl group. Can be mentioned.

The carbonylalkyloxy group means a group composed of the above-mentioned carbonylalkyl group and an oxygen atom, and examples thereof include a carbonylmethoxy group and a carbonylethoxy group.

The alkylenecarbonyloxy group means a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms, a carbonyl group and an oxygen atom, and is, for example, a methylenecarbonyloxy group, an ethylene group. Examples thereof include a carbonyloxy group.

The alkyleneaminocarbonyl group means a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms, an imino group and a carbonyl group. Examples thereof include a methyleneaminocarbonyl group and an ethylene group. Examples include an aminocarbonyl group.

The alkyleneaminocarbonylalkyl group means a group composed of the above-mentioned alkyleneaminocarbonyl group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. For example, methyleneaminocarbonylmethyl And an ethyleneaminocarbonylmethyl group.

The alkyleneaminosulfonyl group means a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms, an imino group and a sulfonyl group,
For example, a methyleneaminosulfonyl group, an ethyleneaminosulfonyl group and the like can be mentioned.

The alkyleneaminosulfonylalkyl group means a group consisting of the above-mentioned alkyleneaminosulfonyl group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. Examples thereof include an aminosulfonylmethyl group and an ethyleneaminosulfonylmethyl group.

[0102] substituent which may be substituted with a heterocyclic group of 5- to 6-membered also cyclic hydrocarbon group or a saturated or unsaturated having a 5-6 membered substituted groups, saturated or unsaturated as a ³ above The group will be explained. The halogen atom, the alkoxyl group, the alkyl group, the alkoxycarbonyl group and the aminocarbonyl group mean the same as those described above.

As the group a ³ -b ^3- , there are various groups depending on the combination of a ³ and b ³ , and examples thereof include the following groups.

A saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent A saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and a carbonyl group Constituent group, saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent and alkylene group, or saturated or unsaturated 5- or 6-membered which may have a substituent A group consisting of a heterocyclic group and a carbonylalkyl group, a group consisting of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, and a carbonylalkyloxy group, A group comprising a saturated or unsaturated 5- or 6-membered heterocyclic group and an alkylenecarbonyloxy group which may have a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent When A group comprising a alkyleneaminocarbonylalkyl group and a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, which may have a substituent; A group consisting of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group and an alkyleneaminosulfonyl group; and a saturated or unsaturated 5- or 6-membered heterocyclic group and a alkylene which may have a substituent. A group comprising an aminosulfonylalkyl group;

The substituents which can be substituted on the amino group (part) include those of the following group (2) in addition to those of the above group (1).

Group (2): an amino group which may have one or two substituents selected from the group (1), and one amino group having one substituent selected from the group (1) Alternatively, an aminoalkyl group which may have two, an aminocarbonyl group which may have one or two substituents selected from the above group (1) in the amino group part, and the above group (1) in the amino group part An aminocarbonylalkyl group which may have one or two substituents selected from the group consisting of: an aminocarbonylalkylcarbonyl group which may have one or two substituents selected from the above group (1) in the amino group portion; The above group (1) in the amino group portion
An aminocarbonylalkylsulfonyl group which may have one or two substituents selected from the group consisting of: an aminoalkylcarbonyl group which may have one or two substituents selected from the above group (1) in the amino group part; An aminosulfonyl group which may have one or two substituents selected from the above group (1) in the amino group part, and one or two substituents selected from the above group (1) in the amino group part. An aminoalkylsulfonylalkyl group which may have one or two substituents selected from the above group (1) in the amino group part, and an aminoalkylsulfonylalkyl group which may have one or two substituents in the amino group part. An aminosulfonylalkylcarbonyl group which may have one or two substituents selected from the group consisting of La substituents selected one or two
An aminosulfonylalkylsulfonyl group which may have one

The substituents of the group (2) will be described below.

The aminoalkyl group in this group (2),
The aminocarbonyl group, aminocarbonylalkyl group and aminoalkylcarbonyl group mean the same as those described above.

The aminoalkyl group which may have a substituent in the amino group part is the same as the amino group which may have a substituent described above and which is linear, branched or cyclic having 2 to 6 carbon atoms. It means a group composed of an alkylene group, and examples of the aminoalkyl group include an aminoethyl group and an aminopropyl group.

The aminocarbonylalkylcarbonyl group which may have a substituent in the amino group part means a group composed of an aminocarbonylalkyl group which may have a substituent and a carbonyl group as described above. Examples of the carbonylalkylcarbonyl group include an aminocarbonylmethylcarbonyl group and an aminocarbonylethylcarbonyl group.

The aminocarbonylalkylsulfonyl group which may have a substituent in the amino group part means a group composed of an aminocarbonylalkyl group which may have a substituent and a sulfonyl group which have been described above. Examples of the carbonylalkylsulfonyl group include an aminocarbonylmethylsulfonyl group and an aminocarbonylethylsulfonyl group.

The aminosulfonyl group which may have a substituent in the amino group means a group constituted by an amino group which may have a substituent and a sulfonyl group as described above.

The aminosulfonylalkyl group which may have a substituent in the amino group moiety is the same as the above-mentioned aminosulfonyl group which may have a substituent and which is linear, branched or cyclic having 1 to 6 carbon atoms. It means a group composed of an alkylene group, and examples of the aminosulfonylalkyl group include an aminosulfonylmethyl group and an aminosulfonylethyl group.

The aminoalkylsulfonyl group which may have a substituent in the amino group means a group consisting of an aminoalkyl group which may have a substituent and a sulfonyl group as described above, and an aminoalkylsulfonyl group. Examples of the group include an aminomethylsulfonyl group and an aminoethylsulfonyl group.

The aminosulfonylalkylcarbonyl group which may have a substituent in the amino group means a group consisting of the aminosulfonylalkyl group which may have a substituent and the carbonyl group described above. Examples of the carbonyl group include an aminosulfonylmethylcarbonyl group and an aminosulfonylethylcarbonyl group.

The aminosulfonylalkylsulfonyl group which may have a substituent in the amino group part means a group comprising the above-mentioned aminosulfonylalkyl group which may have a substituent and a sulfonyl group. Examples of the sulfonyl group include an aminosulfonylmethylsulfonyl group and an aminosulfonylethylsulfonyl group.

A ³ also means a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, wherein a saturated or unsaturated 5- or 5-membered cyclic hydrocarbon group is also preferred. Examples of the 6-membered cyclic hydrocarbon group include a cyclopentyl group, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexyl group, a cyclohexenyl group, a cyclohexadienyl group, and a phenyl group. When there are a plurality of structural isomers such as a cyclopentenyl group, they are all included.

A saturated or unsaturated 5- or 6-membered heterocyclic group is a cyclic group containing at least one heteroatom,
Examples of the hetero atom include an oxygen atom, a nitrogen atom and a sulfur atom. As the saturated or unsaturated 5- or 6-membered heterocyclic group, for example, a furyl group, a pyrrolyl group,
Thienyl group, pyrazolyl group, imidazolyl group, pyrazolinyl group, oxazolyl group, oxazolinyl group, thiazolyl group, thiazolinyl group, oxatriazolyl group, thiadiazolyl group, furazanyl group, pyranyl group, pyridyl group,
Pyridazinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, oxazinyl group, oxadiazinyl group,
Examples include a morpholinyl group, a thiadinyl group, a thiadiazinyl group, a thiomorpholinyl group, a tetrazolyl group, a triazolyl group, and a triazinyl group. When there are a plurality of structural isomers such as a pyranyl group, they are all included.

When A ³ represents a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, B ³ represents a single bond, a carbonyl group, an alkylene group or a carbonyl group. Since it means an alkyl group, a carbonylalkyloxy group or an alkylenecarbonyloxy group, the group A ³ -B ³ -is, for example, the following group (B)
And the like.

Group (B): a saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group or heterocyclic group which may have a substituent, and a saturated or unsaturated 5 to 6-membered which may have a substituent. A group consisting of a 5-membered cyclic hydrocarbon group or a heterocyclic group and a carbonyl group, a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or a heterocyclic group which may have a substituent and an alkylene group; A saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group or a heterocyclic group, a carbonyl and an alkylene group, which may have a substituent, and a saturated group which may have a substituent. Or a group composed of an unsaturated 5 to 6-membered cyclic hydrocarbon group or heterocyclic group, a carbonyl group, an alkylene group, and an oxygen atom,
Saturated or unsaturated 5-6 which may have a substituent
A group comprising a 6-membered cyclic hydrocarbon group or a heterocyclic group, an alkylene group and a carbonyl group, a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or a heterocyclic group which may have a substituent; A group comprising an alkylene group, a carbonyl group and an oxygen atom.

The groups shown in the group (B) will be described below.

In the group consisting of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a heterocyclic group and a carbonyl group, a cyclic hydrocarbon group and a carbonyl group are included. Examples of the group include a cyclopentylcarbonyl group and a phenylcarbonyl group. Examples of the group composed of a heterocyclic group and a carbonyl group include a furylcarbonyl group, a thienylcarbonyl group, and a pyridylcarbonyl group.

In the group consisting of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a heterocyclic group and an alkylene group, it comprises a cyclic hydrocarbon group and an alkylene group. The group means a group composed of the above-mentioned cyclic hydrocarbon group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms, and examples thereof include a cyclohexylmethyl group and a benzyl group. Can be. Further, the group composed of a heterocyclic group and an alkylene group means a group composed of the above-described heterocyclic group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. Examples thereof include a furylmethyl group, a thienylethyl group, and a pyridylpropyl group.

In the group consisting of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a heterocyclic group, a carbonyl group and an alkylene group, a cyclic hydrocarbon group and a carbonyl group The group consisting of an alkylene group means a group consisting of the above-mentioned cyclic hydrocarbon group, a carbonyl group, and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms. Examples thereof include a pentadienylcarbonylmethyl group and a phenylcarbonylethyl group. Further, the group consisting of a heterocyclic group, a carbonyl group, and an alkylene group refers to the above-described heterocyclic group, a carbonyl group, and a linear, branched, or cyclic alkylene group having 1 to 6 carbon atoms. It means a constituent group, and examples thereof include a furylcarbonylmethyl group, a thienylcarbonylethyl group, and a pyridylcarbonylpropyl group.

A cyclic hydrocarbon group of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a group consisting of a heterocyclic group, a carbonyl group, an alkylene group and an oxygen atom. The group consisting of a carbonyl group, an alkylene group and an oxygen atom means a group consisting of the above-mentioned cyclic hydrocarbon group, a group consisting of a carbonyl group and an alkylene group, and a group consisting of an oxygen atom, for example, cyclopentylcarbonylmethoxy. And a phenylcarbonylethoxy group. Further, the group consisting of a heterocyclic group, a carbonyl group, an alkylene group and an oxygen atom means a group consisting of the above-described heterocyclic group, a group consisting of a carbonyl group and an alkylene group, and a group consisting of an oxygen atom. However, examples thereof include a furylcarbonylmethoxy group, a thienylcarbonylethoxy group, and a pyridylcarbonylpropoxy group.

In the group consisting of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or a heterocyclic group which may have a substituent, an alkylene group and a carbonyl group, a cyclic hydrocarbon group and an alkylene group The group composed of a carbonyl group means a group composed of a group composed of the above-described cyclic hydrocarbon group and alkylene group and a group composed of a carbonyl group, such as a cyclohexylmethylcarbonyl group and a phenylethylcarbonyl group. be able to. Further, the group consisting of a heterocyclic group, an alkylene group and a carbonyl group means a group consisting of a group consisting of the above-described heterocyclic group and alkylene group and a carbonyl group, for example, furylmethyl Examples thereof include a carbonyl group, a thienylethylcarbonyl group, and a pyridylpropylcarbonyl group.

A cyclic hydrocarbon group of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a group consisting of a heterocyclic group, an alkylene group, a carbonyl group and an oxygen atom. The group consisting of an alkylene group, a carbonyl group, and an oxygen atom means a group consisting of the above-mentioned cyclic hydrocarbon group, a group consisting of an alkylene group and a carbonyl group, and a group consisting of an oxygen atom, for example, cyclohexadienyl. Examples thereof include a methylcarbonyloxy group and a phenylethylcarbonyloxy group. Further, the group consisting of a heterocyclic group, an alkylene group, a carbonyl group, and an oxygen atom means a group consisting of a group consisting of the above-described heterocyclic group, alkylene group, carbonyl group, and an oxygen atom. Examples thereof include a furylmethylcarbonyloxy group, a thienylethylcarbonyloxy group, and a pyridylpropylcarbonyloxy group.

The substituents which can be substituted on the saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group include the following groups (3).
The number of substituents that can be substituted is 1 to 3.

Group (3): hydroxyl, alkyl, alkoxyl, hydroxyalkyl, alkoxyalkyl, halogen, cyano, nitro, carboxyl, alkoxycarbonyl, formyl, heteroaryl, heteroarylalkyl Group, alkylimino group, amidino group, guanidino group, amino (hydroxyimino) alkyl group, amino (alkoxyimino) alkyl group, amino (aryloxyimino) alkyl group, amino having one or two substituents Group, an aminocarbonyl group which may have one or two substituents on the amino group part, an aminocarbonylalkyl group which may have one or two substituents on the amino group part, a substituent on the amino group part Aminocarbo which may have one or two Le alkyloxy group, also aminoalkyl groups having one or two substituents on the amino moiety, one substituent group on the amino moiety, or 2
Aminoalkyloxy group, which may have one or two substituents on the amino group, aminoalkylcarbonyl which may have one or two substituents on the amino group An oxy group, and an oxygen atom.

The saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or heterocyclic group in group (3) is described below.
The substituents that can be substituted will be described.

An alkyl group, an alkoxyl group, a hydroxyalkyl group, an alkoxyalkyl group, a halogen atom, an alkoxycarbonyl group, an aminocarbonyl group which may have one or two substituents on the amino group, and a substituent on the amino group An aminoalkyl group which may have one or two, an aminocarbonylalkyl group which may have one or two substituents on the amino group part,
An aminocarbonylalkyloxy group which may have one or two substituents on the amino group, an aminoalkylcarbonyl group which may have one or two substituents on the amino group, and a substituent on the amino group The aminoalkylcarbonyloxy group which may have one or two has the same meaning as described above.

The heteroaryl group means an aromatic monovalent group containing at least one heteroatom, and examples thereof include a pyridyl group, a furyl group and a thienyl group.

The heteroarylalkyl group is the same as the above-mentioned heteroaryl group in the form of a linear, branched or cyclic C 1 -C 1.
And 6 means an alkylene group, for example,
Examples thereof include a pyridylmethyl group, a furylethyl group, and a thienylmethyl group.

The alkylimino group means a divalent group consisting of a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms and a nitrogen atom.
An ethylimino group and the like can be mentioned.

An amino (hydroxyimino) alkyl group means a group in which an amino group and a hydroxyimino group are bonded to the same carbon atom of a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, For example, an amino (hydroxyimino) methyl group, an amino (hydroxyimino) ethyl group and the like can be mentioned.

An amino (alkoxyimino) alkyl group means a group in which an amino group and an alkoxyimino group are bonded to the same carbon atom of a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms. Here, the alkoxyimino group means a divalent group composed of the alkoxyl group and the imino group described above. Examples of the amino (alkoxyimino) alkyl group include an amino (methoxyimino) methyl group and an amino (ethoxyimino) methyl group.

An amino (aryloxyimino) alkyl group means a group in which an amino group and an aryloxyimino group are bonded to the same carbon atom of a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms. I do. Here, the aryloxyimino group means a divalent group composed of an aryl group and an imino group. Here, examples of the aryl group include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. Examples of the amino (aryloxyimino) alkyl group include an amino (phenoxyimino) methyl group and an amino (naphthyloxyimino) methyl group.

The aminoalkyloxy group, which may have one or two substituents on the amino group, is different from an amino group having a substituent in the form of a straight-chain, branched or cyclic C2-C6 amino group.
Means an alkylene group and an oxygen atom, and examples of the aminoalkyloxy group include an aminoethyloxy group and an aminopropyloxy group. Examples of the group which can be substituted on the amino group include the same groups as described above.

In addition, the oxygen atom can be a substituent,
The case of a cyclic hydrocarbon group is a case of a keto compound. In the case of a heterocyclic group or a bicyclic or tricyclic fused ring group, an oxygen atom is bonded to a nitrogen atom or a sulfur atom constituting a ring to form an N-oxide or an S-oxide. , And a keto compound.

In the present invention, R ¹⁵ is R ¹⁶ or R ^{16
In the} case where it does not mean an alkylene group or an alkenylene group having 1 to 3 carbon atoms together with ¹⁷ , R ¹⁵ represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, a group A ³ -B ³
-Is preferred.

In R ¹⁶ and R ¹⁷ , examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The alkyl group means a linear, branched or cyclic alkyl group having 1 to 8 carbon atoms. Examples thereof include a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group, a heptyl group and an octyl group. And the like.

The hydroxyalkyl group means a group consisting of a hydroxyl group and a linear, branched or cyclic alkylene group having 1 to 8 carbon atoms. Examples thereof include a hydroxymethyl group and a hydroxyethyl group. it can.

The alkoxyalkyl group means a group consisting of the above-mentioned alkyl group, an oxygen atom and a linear, branched or cyclic alkylene group having 1 to 8 carbon atoms, such as a methoxymethyl group, Examples thereof include a methoxyethyl group and an ethoxymethyl group.

Incidentally, R ¹⁶ or R ¹⁷ together with R ¹⁵ may mean an alkylene group or an alkenylene group having 1 to 3 carbon atoms.

[0145]

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However, the following groups and the like are meant.

[0147]

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Or

[0149]

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[0150] In the present invention, the R ¹⁶ or R ^17, R ¹⁵
And R ¹⁶ and R ¹⁷ are preferably a hydrogen atom or an alkyl group when they do not mean an alkylene group or an alkenylene group having 1 to 3 carbon atoms.

In the present invention, R ¹⁵ and R ¹⁶ or R ¹⁷
Are preferably an alkylene group or an alkenylene group having 1 to 3 carbon atoms.

R ¹⁸ and R ¹⁹ are each independently a hydrogen atom, a hydroxyl group, a halogen atom, a halogenoalkyl group, an alkyl group, an alkoxyl group, an alkenyl group, an alkynyl group which may be substituted by an alkylsilyl group as a protecting group, a trifluoromethyl group, a cyano group, an amino group, an aminoalkyl group, alkylaminoalkyl group, amidino group, means a hydroxyamidino group or an alkoxycarbonyl amidino group (with R ¹⁸ and R ¹⁹ are simultaneously hydrogen atoms is Absent.).

In R ¹⁸ and R ¹⁹ , a halogen atom,
A halogenoalkyl group, an alkyl group, an alkoxyl group, an alkenyl group, and an aminoalkyl group mean the same as those described above.

The alkylaminoalkyl group means an aminoalkyl group in which one or two linear, branched or cyclic alkyl groups are substituted with an amino group. Examples thereof include a methylaminomethyl group and an ethylmethyl group. Examples include an aminomethyl group.

An alkynyl group which may be substituted by an alkylsilyl group as a protecting group may be substituted by an alkylsilyl group such as a trimethylsilyl group, a triethylsilyl group, a tertiary butyldimethylsilyl group or a dimethylphenylsilyl group. Means some alkynyl groups.

In the present invention, R ¹⁸ and R ¹⁹ are preferably a halogen atom and an alkynyl group, particularly preferably a chlorine atom, a bromine atom and an ethynyl group.

Group

[0158]

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X ³ represents a nitrogen atom or a group ＣC (R ¹⁰⁰ ) — (wherein R ¹⁰⁰ is a hydrogen atom, a halogen atom, an alkyl group, an alkoxycarbonyl group, an aralkyloxycarbonylalkyl group, an alkoxycarbonylalkyl group, A nitro group, an amino group which may have a protecting group, or an aminoalkyl group which may have a protecting group at the amino group part).

The halogen atom, the alkyl group, the alkoxycarbonyl group, the aryloxycarbonylalkyl group, the alkoxycarbonylalkyl group, and the aryloxycarbonylalkyl group in R ¹⁰⁰ are the same as those described above. An amino group which may have a protecting group or an aminoalkyl group which may have a protecting group at the amino group part means an amino group or an aminoalkyl group which may have a commonly known protecting group.

X ⁴ is an oxygen atom, a sulfur atom or a group —N (R ¹⁰¹ ) — (wherein R ¹⁰¹ is a hydrogen atom, an alkyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, an alkoxycarbonylalkyl group, an alkylsulfonyl group Or an arylsulfonyl group).

[0162] in R ^101, an alkyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, an alkoxycarbonylalkyl group, an alkylsulfonyl group and arylsulfonyl group means the same ones described earlier.

[0163] X ⁵ and X ⁸ are each independently a nitrogen atom or a group -C (R ¹⁰²⁾ - (. In groups, R ¹⁰² is to mean a hydrogen atom or a halogen atom) means, in the R ^102, The halogen atom means the same as described above.

X ⁶ and X ⁷ are each independently a nitrogen atom or a group —C (R ¹⁰³ ) — (wherein R ¹⁰³ is a hydrogen atom, a hydroxyl group, a halogen atom,
A halogenoalkyl group, an alkyl group, an alkoxyl group, an alkenyl group, an alkynyl group which may be substituted by an alkylsilyl group as a protecting group, a cyano group, an amino group, an aminoalkyl group, an alkylaminoalkyl group, an amidino group,
It means a hydroxyamidino group or an alkoxycarbonylamidino group. ).

In [0165] R ^103, halogen atom, halogenoalkyl group, an alkyl group, an alkoxyl group, an alkenyl group, an alkynyl group which alkylsilyl group is also replaced as a protecting group, aminoalkyl group, alkylaminoalkyl group, an alkoxycarbonyl amidinophenyl The group means the same as described above.

Group

[0167]

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As described below,

[0169]

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[0170]

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[0171]

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[In the above groups, R ¹⁰¹ and R ¹⁰³ are the same as described above. R ^{103 ′} has the same meaning as R ¹⁰³ . Is preferable.

Here, R¹⁰¹As a hydrogen atom
preferable. Also, R¹⁰³And R^{103 '}Either of
Is a halogen atom, an alkynyl group, an amidino group, a hydro
A xyamidino group or an alkoxycarbonylamidino group
Are preferred, among which a halogen atom, an ethynyl group,
Amidino group, hydroxyamidino group, methoxy carbonyl
Luamidino groups are particularly preferred.

Group

[0175]

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[0176] in, X ⁹ and X ¹² are each independently a nitrogen atom or a group -C (R ¹⁰⁴⁾ - (. In groups, R ¹⁰⁴ is to mean a hydrogen atom or a halogen atom) means, R ¹⁰⁴ Means the same as those described above.

X ¹⁰ and X ¹¹ are each independently a nitrogen atom or a group —C (R ¹⁰⁵ ) — (wherein R ¹⁰⁵ is a hydrogen atom, a hydroxyl group, a halogen atom,
A halogenoalkyl group, an alkyl group, an alkoxyl group, an alkenyl group, an alkynyl group which may be substituted by an alkylsilyl group as a protecting group, a cyano group, an amino group, an aminoalkyl group, an alkylaminoalkyl group, an amidino group,
It means a hydroxyamidino group or an alkoxycarbonylamidino group. ).

In R ¹⁰⁵ , a halogen atom, a halogenoalkyl group, an alkyl group, an alkoxyl group, an alkenyl group, an alkynyl group, an aminoalkyl group, an alkylaminoalkyl group, an alkoxycarbonylamidino group which may be substituted by an alkylsilyl group as a protective group. The group means the same as described above.

Group

[0180]

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As follows,

[0182]

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[Wherein, R ¹⁰⁵ is the same as defined above. R ^{105 ′} is R
Means the same as ¹⁰⁵ . Are preferred.

Here, one of R ¹⁰⁵ and R ^{105 ′} is preferably a halogen atom, an alkynyl group, an amidino group, a hydroxyamidino group or an alkoxycarbonylamidino group, and particularly preferably a halogen atom, an ethynyl group or an amidino group. , A hydroxyamidino group and a methoxycarbonylamidino group are particularly preferred.

<Regarding Group Q ¹ > Q ¹ represents a saturated or unsaturated bicyclic fused ring group which may have a substituent or a saturated or unsaturated tricyclic fused ring group which may have a substituent. It means a ring group.

[0186] tricyclic fused ring group also saturated or unsaturated having a bicyclic fused ring group or a substituent a saturated or unsaturated sometimes have a substituent, in terms of group Q ^A Means the same as those described, more specifically, a condensed saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, and a saturated group which may have a substituent. Or a condensed unsaturated 5- or 6-membered cyclic hydrocarbon group and a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, or a saturated or unsaturated It means that an unsaturated 5- to 6-membered heterocyclic group is condensed. For example, examples thereof include an indenyl group, an indanyl group, a naphthyl group, a tetrahydronaphthyl group, an anthryl group, and a phenanthryl group. As for
Examples include a benzofuranyl group, an indolyl group, an indolinyl group, a quinolyl group, a benzodiazinyl group, a tetrahydroisoquinolyl group, a benzothiazolyl group, a tetrahydrobenzothiazolyl group, and an isoindolyl group.
As those, naphthyridinyl group, tetrahydrothienopyridyl group, tetrahydrothiazolopyridyl group, tetrahydropyridopyridyl group, thiazolopyridazinyl group, tetrahydrothiazolopyridazinyl group, pyrrolopyridyl group, tetrahydropyrrolopyridyl group, Dihydropyridoquinazolyl group, pyridopyrimidinyl group, tetrahydropyridopyrimidinyl group, pyranothiazolyl group, dihydropyranothiazolyl group, flopyridyl group, tetrahydrofuropyridyl group, oxazolopyridyl group, tetrahydrooxazolopyridyl group, oxazolopyri Examples thereof include a dazinyl group and a tetrahydrooxazolopyridazinyl group.

A saturated or unsaturated bicyclic fused ring group,
Examples of the substituent which can be substituted on the saturated or unsaturated tricyclic fused ring group include those of the following group (4). The number of substituents that can be substituted is 1 to 7.

Group (4): hydroxyl group, alkyl group, alkenyl group, halogenoalkyl group, halogenoalkenyl group, alkoxyl group, hydroxyalkyl group, alkoxyalkyl group, halogen atom, cyano group, nitro group, carboxyl group, alkoxycarbonyl group , Formyl group, heteroaryl group, heteroarylalkyl group, alkylimino group, amidino group, guanidino group, amino (hydroxyimino) alkyl group, amino (alkoxyimino) alkyl group, amino (aryloxyimino) alkyl group,
A hydroxyimino group, an alkoxyimino group, an aminoimino group which may have one or two substituents on the amino group, an amino group which may have one or two substituents, and a Aminocarbonyl group which may have one or two substituents, aminocarbonylalkyl group which may have one or two substituents in the amino group part, amino group which may have one or two substituents in the amino group part A carbonylalkyloxy group, an aminoalkyl group which may have one or two substituents on the amino group,
Or two aminoalkyloxy groups, one or two substituents on the amino group, an aminoalkylcarbonyl group, one or two substituents on the amino group Aminoalkylcarbonyloxy group, oxygen atom, trifluoromethylsulfonyloxy group, trifluoromethylsulfonyloxyalkenyl group, boric acid group (-B (O
H ₂ )) having one to three substituents selected from the group consisting of halogen atoms, hydroxyl groups, amino groups, alkoxyl groups, alkyl groups, cyano groups, nitro groups, carboxyl groups, alkoxycarbonyl groups and aminocarbonyl groups. A saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group, and a halogen atom, a hydroxyl group, an amino group, an alkoxyl group, an alkyl group, a cyano group, a nitro group, a carboxyl group, an alkoxycarbonyl group and an aminocarbonyl group. A saturated or unsaturated 5- or 6-membered heterocyclic group which may have 1 to 3 substituents selected from the group consisting of:

As for the substituent of this group (4), the group Q ^A
Means the same as those described in groups (1) to (3).

In the present invention, Q ¹ represents a thienopyridyl group which may have a substituent, a tetrahydrothienopyridyl group which may have a substituent, a thiazolopyridyl group which may have a substituent, or a substituent. Tetrahydrothiazolopyridyl group which may have a substituent, thiazolopyridazinyl group which may have a substituent, tetrahydrothiazolopyridazinyl group which may have a substituent, pyranothiazolyl group which may have a substituent , A dihydropyranothiazolyl group which may have a substituent, a floppyridyl group which may have a substituent, a tetrahydrofuropyridyl group which may have a substituent, an oxazolopyridyl group which may have a substituent, A tetrahydrooxazolopyridyl group which may have a group, an Sa Zorro pyridazinyl group, is also tetrahydropyran oxazolone pyridazinylamino group may have a substituent group.

<Regarding Group Q ² > Group Q ² is a single bond, an oxygen atom, a sulfur atom, a linear or branched alkylene group having 1 to 6 carbon atoms, a linear or branched alkylene group having 2 carbon atoms. Alkenylene group, linear or branched C 2-6
An alkynylene group, a group -N (R ¹ ) -CO- (wherein R ¹ represents a hydrogen atom or an alkyl group), a group -N (R ² )-(CH ₂ ) m- (in the group, R ² represents a hydrogen atom or an alkyl group;
Represents an integer of 0 to 6. ) Or group

[0192]

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(This group may have a substituent.
A saturated or unsaturated 5- to 6-membered cyclic hydrocarbon group,
A divalent saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, or a divalent saturated or unsaturated bicyclic fused ring group which may have a substituent. I do. ← C indicates that the carbon atom of this group is bonded to Q ¹ . ).

In the group Q ² , examples of the linear or branched alkylene group having 1 to 6 carbon atoms include methylene, ethylene, trimethylene, propylene, tetramethylene, butylene, pentamethylene and the like. And a hexamethylene group.

Examples of the linear or branched alkenylene group having 2 to 6 carbon atoms include a vinylene group, a propenylene group, a butenylene group and a pentenylene group. The position of the double bond is not particularly limited.

Examples of the linear or branched alkynylene group having 2 to 6 carbon atoms include a propynylene group, a butynylene group, a pentynylene group and a hexynylene group.

Group

[0198]

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This group means a divalent saturated or unsaturated 5- or 6-membered cyclic group which may contain one or more hetero atoms which may have a substituent. It represents a bond between the carbon atom of the group and Q ¹ and includes, for example, a cyclohexylene group, a cyclohexenylene group, a phenylene group, a pyrroldiyl group, a thiendiyl group and the like.

The group —N (R ¹ ) —CO— and the group —N
The alkyl group of R ¹ and R ² in (R ² ) — (CH ₂ ) m— means a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, for example, a methyl group , An ethyl group, an isopropyl group, and a cyclopropyl group. As the group —N (R ¹ ) —CO—, a group ← N
(R ¹ ) -CO- (← indicates a bond between a nitrogen atom of this group and Q ¹ ), and a group -N (R ² )-(CH ₂ )
As m-, a group ← N (R ² ) — (CH ₂ ) m- (← indicates a bond between a nitrogen atom of this group and Q ¹ ) is preferable.

In the present invention, Q ² is preferably a single bond, a carbonyl group, a phenylene group, a cyclohexylene group or a cyclohexenylene group.

[0202] <for group Q ^3> R ³ as a substituent group in ^{Q 3, R 4, R 5} , R 6, R 7, R 8, R 10, and R ^{1 1}
In the alkyl group, alkoxyl group, alkoxyalkyl group, hydroxyalkyl group, hydroxyalkyloxy group, hydroxyalkylcarbonyl group, hydroxyalkylsulfonyl group, formylalkyl group, formylalkylcarbonyl group, formylalkylsulfonyl group, alkylcarbonyl group, alkyl Sulfonyl group, alkylcarbonylalkyl group, alkylsulfonylalkyl group, carboxyalkyl group, carboxyalkylcarbonyl group, carboxyalkylsulfonyl group, carboxyalkylcarbonylalkyl group, carboxyalkylsulfonylalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonyl Alkylcarbonyl group, alkoxycarbonylalkylsulfonyl group, Also amino group may have one or two groups, one of the substituents on the amino moiety, or 2
An aminoalkyl group, which may have one or two substituents on the amino group, and one or two substituents on the amino group.
An aminoalkylcarbonyl group, which may have one or two substituents in the amino group, an aminocarbonyl, which may have one or two substituents in the amino group Group, an aminocarbonylalkyl group which may have one or two substituents on the amino group part, and an aminocarbonylalkyloxy group which may have one or two substituents on the amino group part may be represented by the group Q Means the same as those described for ^R15 in section ^A.

The alkoxyalkyloxy group means a group composed of the above-described alkoxyalkyl group and an oxygen atom, and examples thereof include a methoxymethyloxy group, a methoxyethyloxy group and an ethoxymethyloxy group. .

The carboxyalkyloxy group means a group composed of the carboxyalkyl group and an oxygen atom, and examples thereof include a carboxymethoxyl group and a carboxyethoxyl group.

The alkoxycarbonylalkyloxy group means a group composed of the above-described alkoxycarbonylalkyl group and an oxygen atom, and examples thereof include a methoxycarbonylethyloxy group and an ethoxycarbonylethyloxy group. .

The alkylsulfonylaminocarbonylalkyl group, which may have one substituent in the amino group, is the above-mentioned alkylsulfonyl group, an imino group, which may have one substituent, a carbonyl group, and a straight chain. It means a group composed of a branched or cyclic alkylene group having 1 to 6 carbon atoms, such as a methylsulfonylaminocarbonylmethyl group.

The arylsulfonylaminocarbonylalkyl group, which may have one substituent in the amino group part, is an aryl group, a sulfonyl group, an imino group, which may have one substituent, a carbonyl group, and a straight chain. It means a group composed of a branched or cyclic alkylene group having 1 to 6 carbon atoms, such as a phenylsulfonylaminocarbonylmethyl group.

An aminosulfonylalkyl group which may have one or two substituents in the amino group part means an amino group and a sulfonyl group which may have one or two substituents and a linear or branched amino group. Or cyclic carbon number 1
It means a group composed of six alkylene groups, and examples thereof include an aminosulfonylmethyl group.

The cyanoalkyl group means a group composed of a cyano group and a linear, branched or cyclic alkylene group having 1 to 6 carbon atoms.

The alkoxyalkylaminocarbonylalkyl group, which may have one substituent in the amino group, includes the above-mentioned alkoxyalkyl group, an imino group, which may have one substituent, and a carbonyl group. Means an ethoxymethylaminocarbonylmethyl group.

The alkylcarbonyloxyalkyl group includes the above-mentioned alkylcarbonyl group, an oxygen atom and a straight chain,
It means a group composed of a branched or cyclic alkylene group having 1 to 6 carbon atoms, such as a methylcarbonyloxyethyl group.

In the group A ¹ -B ^1- , A ¹ is a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent. Means a 6-membered heterocyclic group, wherein
Examples of the saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group include a cyclopentyl group, a cyclopentenyl group,
Examples thereof include a cyclopentadienyl group, a cyclohexyl group, a cyclohexenyl group, a cyclohexadienyl group, and a phenyl group. When there are a plurality of structural isomers such as a cyclopentenyl group, they are all included.

The saturated or unsaturated 5- or 6-membered heterocyclic group is a cyclic group containing at least one hetero atom, and examples of the hetero atom include an oxygen atom, a nitrogen atom and a sulfur atom. it can. Examples of the saturated or unsaturated 5- to 6-membered heterocyclic group include, for example, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, oxa Triazolyl group, thiadiazolyl group, furazanyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, oxazinyl group, oxadiazinyl group, morpholinyl group, thiazinyl group, thiadiazinyl group, thiomorpholinyl group, tetrazolyl group, Examples thereof include a triazolyl group and a triazinyl group. When there are a plurality of structural isomers such as a pyranyl group, they are all included.

B ¹ is a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a group —O—C ₁ -C ₆ alkylene group, a group —COO—C ₁ -C ₆ alkylene group, a group —NHC
O— or the group —NHCO—C ₁ -C ₆ alkylene group.

Examples of the group A ¹ -B ¹ -include the following groups. It is composed of a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, and a carbonyl group. And a group comprising a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent and an alkylene group.

Further, R ³ and R ⁴ , R ⁵ and R ⁶ , R ⁷
And R ⁸ , R ¹⁰ and R ¹¹ may have a substituent together with the carbon atoms constituting the ring, or may have a saturated or unsaturated 5- to 7-membered cyclic hydrocarbon group or a substituent. A saturated or unsaturated 5- to 7-membered heterocyclic group is meant, wherein a saturated or unsaturated 5
Examples of the 7- to 7-membered cyclic hydrocarbon group include a cyclopentyl group, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexyl group, a cyclohexenyl group, a cyclohexadienyl group, and a phenyl group. When there are a plurality of structural isomers such as a cyclopentenyl group, they are all included.

The saturated or unsaturated 5- to 7-membered heterocyclic group is a cyclic group containing at least one hetero atom, and examples of the hetero atom include an oxygen atom, a nitrogen atom and a sulfur atom. it can. Examples of the saturated or unsaturated 5- or 6-membered heterocyclic group include, for example, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, and thiazolinyl groups. , An oxatriazolyl group,
Thiadiazolyl, furazanyl, pyranyl, pyridyl, pyridazinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxazinyl, oxadiazinyl, morpholinyl, thiazinyl, thiadiazinyl, thiomorpholinyl, tetrazolyl, triazolyl and triazinyl And the like. When there are multiple structural isomers such as a pyranyl group,
They are all included.

Q^ThreeR as a substituent in⁹And R¹²
An alkyl group, a hydroxyalkyl group, an alcohol
Xyl group, hydroxyalkylcarbonyl group, hydroxy
Silalkylsulfonyl group, alkoxyalkyl group,
Coxyalkylcarbonyl group, alkoxyalkylsul
Honyl group, formylalkyl group, formylalkylcal
Bonyl, formylalkylsulfonyl, alkyl
Rubonyl group, alkylsulfonyl group, alkyl carbonyl
Alkyl group, alkylsulfonylalkyl group, carbo
Xyalkylcarbonyl group, carboxyalkylsulfo
Nil group, carboxyalkylcarbonylalkyl group,
Ruboxyalkylsulfonylalkyl group, alkoxyca
Rubonyl group, alkoxycarbonylalkyl group, alcohol
Xycarbonylalkylcarbonyl group, alkoxycar
A bonylalkylsulfonyl group, one or two substituents
Amino group that may have a substituent on the amino group part
An aminoalkyl group which may have one or two,
The amino group may have one or two substituents
Substituting a substituent on a certain aminoalkyloxy group or amino group
Aminoalkyl carbs that may have one or two
One or two substituents on the bonyl or amino group
Aminoalkyloxycarbonyl group,
The amino group may have one or two substituents.
Aminocarbonyl group, no substituent at the amino group
Or aminocarbonylalkyl which may have two
Having one or two substituents on the group and the amino group
The aminocarbonyloxyalkyl group, which may be
Base Q ^AMeans the same as described in section
I do.

In the group A ² -B ^2- , A ² is a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent or a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent. Means a 6-membered heterocyclic group, wherein
Examples of the saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group include a cyclopentyl group, a cyclopentenyl group,
Examples thereof include a cyclopentadienyl group, a cyclohexyl group, a cyclohexenyl group, a cyclohexadienyl group, and a phenyl group. When there are a plurality of structural isomers such as a cyclopentenyl group, they are all included.

The saturated or unsaturated 5- or 6-membered heterocyclic group is a cyclic group containing at least one hetero atom, and examples of the hetero atom include an oxygen atom, a nitrogen atom and a sulfur atom. it can. Examples of the saturated or unsaturated 5- to 6-membered heterocyclic group include, for example, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, oxa Triazolyl group, thiadiazolyl group, furazanyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, oxazinyl group, oxadiazinyl group, morpholinyl group, thiazinyl group, thiadiazinyl group, thiomorpholinyl group, tetrazolyl group, Examples thereof include a triazolyl group and a triazinyl group. When there are a plurality of structural isomers such as a pyranyl group, they are all included.

B ² is a single bond, a carbonyl group, an alkylene group, a carbonylalkyl group, a group —O—C ₁ -C ₆ alkylene group, a group —COO—C ₁ -C ₆ alkylene group, a group —NHC
O— or the group —NHCO—C ₁ -C ₆ alkylene group.

Examples of the group A ² -B ² -include the following groups. It is composed of a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, a saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent and a carbonyl group. And a group comprising a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent and an alkylene group.

R ⁹ and R ⁷ , R ⁹ and R ⁸ , R ¹²
And R ¹⁰ , R ¹² and R ¹¹ are a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent, together with a carbon atom constituting the ring and a nitrogen atom to which R ⁹ or R ¹² is bonded. Here, a saturated or unsaturated 5- to 7-membered heterocyclic group is a cyclic group containing at least one nitrogen atom, and may further contain another atom. Examples of the hetero atom include an oxygen atom, a nitrogen atom and a sulfur atom. Examples of the saturated or unsaturated 5- to 6-membered heterocyclic group include, for example, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyrazolinyl, oxazolyl, oxazolinyl, thiazolyl, thiazolinyl, oxa Triazolyl group, thiadiazolyl group, furazanyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrrolidinyl group, piperazinyl group, piperidinyl group, oxazinyl group, oxadiazinyl group, morpholinyl group, thiazinyl group, thiadiazinyl group, thiomorpholinyl group, triazolyl group and And a triazinyl group. When there are a plurality of structural isomers such as a pyranyl group, they are all included.

In the present invention, Q ³ is

[0225]

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(In these groups, R ³ , R ⁴ , R ⁵ , R ⁶ , R
^{7, R 8, R 9,} R 10, R 11, R 12, a, b, c, d,
e, f, g, h and i are the same as above. ), And among them, Q ³ represents a group

[0227]

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Wherein R ³ , R ⁴ , a, b and c are as defined above. R ³ and R ⁴ are each independently a hydrogen atom, a hydroxyalkyl group, a cyanoalkyl group, a carboxyl group carboxyalkyl group, an alkoxycarbonyl group, an alkoxycarbonylalkyl group, a carboxyalkylaminocarbonyl group, a carboxyalkylamino Carbonylalkyl group, alkoxycarbonylalkylaminocarbonyl group, alkoxycarbonylalkylaminocarbonylamino group, carbamoyl group, monoalkylcarbamoyl group, dialkylcarbamoyl group, carbamoylalkyl group, monoalkylcarbamoylalkyl group, dialkylcarbamoylalkyl group, morpholinylcarbonyl Group, morpholinylcarbonylalkyl group, tetrazolylaminocarbonyl group, tetrazolylaminocarbonylalkyl Group, tetrazolylalkyl group, tetrazolylalkylaminocarbonyl group, tetrazolylalkylaminocarbonylalkyl group, aminoalkyl group which may have one or two substituents in the amino group, alkylaminosulfonylalkyl group ,
An oxopyrrolidinylalkyl group, an oxopiperidinylalkyl group, or an oxooxazolidinylalkyl group, wherein a means 0, b means 0, and c means 2 is more preferable. .

<Regarding Group T ¹ > T ¹ is a carbonyl group, a group —CH (R ¹³ ) — (R ¹³ is a hydrogen atom, an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, An aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group, or an aminoalkyl group which may have a substituent in the amino group part.) Group —C (＝ NOR ¹⁴ ) — or group —C (＝ N -NH
R ^{14 ′} ) — wherein R ¹⁴ and R ^{14 ′} each represent a hydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or an amino group part. Means an aminoalkyl group which may have a substituent.)

Here, the alkyl, carboxyalkyl, alkoxycarbonyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, and amino groups in R ¹³ , R ^14, and R ^{14 ′} have a substituent. it aminoalkyl group which is also means the same as those described in group Q ^a. In the present invention, a carbonyl group is preferable as T ¹ .

The compound represented by the general formula (1) of the present invention may have optical isomers or stereoisomers derived from an incorrect carbon atom.
Both stereoisomers and mixtures thereof are included in the present invention.

The salt of the compound represented by the general formula (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and specific examples thereof include hydrochloride, hydrobromide, and iodine. Mineral acid salts such as hydride, phosphate, nitrate and sulfate, organic sulfonic acid salts such as benzoate, methanesulfonic acid salt, 2-hydroxyethanesulfonic acid salt and p-toluenesulfonic acid salt, and acetic acid Salt, propanoate,
Oxalate, malonate, succinate, glutarate,
Organic carboxylate salts such as adipate, tartrate, maleate, malate and mandelate can be mentioned. The solvate is not particularly limited as long as it is a pharmaceutically acceptable salt, and specific examples include hydrates and ethanol solvates.

Preferred examples of the compound represented by formula (1) of the present invention will be described below.

1-[[(6RS) -6-aminomethyl-
5,6,7,8-tetrahydronaphthalen-2-yl]
Carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine 1-[[(6RS) -6-aminomethyl-5,6,7,
8-tetrahydronaphthalen-2-yl] methyl] -4
-[(6-chloronaphthalen-2-yl) sulfonyl]
Piperazine 1-[[((2RS) -6-aminomethyl-1,2,3,
4-tetrahydronaphthalen-2-yl] methyl] -4
-[(6-chloronaphthalen-2-yl) sulfonyl]
Piperazine 1-[[((2RS) -6-aminomethyl-1,2,3,
4-tetrahydronaphthalen-2-yl] carbonyl]
-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine 1-[(7-aminomethylnaphthalen-2-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl)
Sulfonyl] piperazine

1-[(7-aminomethylnaphthalene-2
-Yl) methyl] -4-[(6-chloronaphthalene-2
-Yl) sulfonyl] piperazine 1-[(6-aminomethylnaphthalen-2-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl)
Sulfonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(isoquinolin-7-yl) carbonyl]
Piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(quinolyl-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[( 4-Hydroxyquinolin-2-yl) carbonyl] piperazine

1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(8-hydroxyquinoline-
7-yl) carbonyl] piperazine 1-[(benzimidazol-5-yl) carbonyl]-
4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine 1-[(benzimidazol-5-yl) carbonyl]-
4-[(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(thiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 1-[(E) -4-chlorostyrylsulfonyl] -4-
[(Thiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl] piperazine 1 -[(6-chloronaphthalen-2-yl) sulfonyl] -4- [trans-3- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propenoyl] piperazine 1 -[(6-Chloronaphthalen-2-yl) sulfonyl] -4- [3- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propionyl]
Piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [3- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propyl] piperazine 1 -[(6-chloronaphthalen-2-yl) sulfonyl] -4- [N-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl] carbamoyl] piperazine

1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] piperazine 4 -[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-1-[(4,5,6
7-tetrahydrothieno [3,2-c] pyridine-2-
Yl) carbonyl] piperazine 2-carboxy-4-[(6-chloronaphthalene-2-
Yl) sulfonyl] -1-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-aminohydroxyiminomethyl-
4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [N- (4 5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbamoyl
Piperazine

1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [N-methyl-N- (4,5
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl) carbamoyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[5- (1-pyrrolin-2-yl) -4,
5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl] carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-aminohydroxyiminomethyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine 1-[(5-carbamoyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(6- Chloronaphthalen-2-yl)
Sulfonyl] piperazine

1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[5- (1-pyrroline-2-
Yl) -4,5,6,7-tetrahydrothiazolo [5
4-c] pyridin-2-yl] carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-formyl-4,5,6,7-tetrahydrothiazolo [5 , 4-c] Pyridin-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5
5-dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridinium iodide

2-[[4-[(6-chloronaphthalene-
2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine N-oxide 2-carbamoyl-4-[(6 -Chloronaphthalene-2
-Yl) sulfonyl] -1-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine 2-carbamoyl-4-[(6-chloronaphthalene-2
-Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[5- (2-hydroxyethyl ) -4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[5- (pyridine- 2-yl) methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl] carbonyl] piperazine

1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[5- (pyridin-3-yl) methyl-4,5,6,7-tetrahydrothiazolo [5,4- c] pyridin-2-yl] carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[[5- (pyridin-4-yl) methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl] carbonyl] piperazine 1-[(E) -4-chlorostyrylsulfonyl] -4-
[(4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 1-[(E) -4-chlorostyrylsulfonyl] -4-
[5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine (3S) -3-[(6-chloronaphthalen-2-yl)
Sulfonamido] -1-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl] pyrrolidine

(3S) -3-[(6-chloronaphthalen-2-yl) sulfonamido] -1-[(4,5,6
7-tetrahydrothieno [3,2-c] pyridine-2-
Yl) carbonyl] pyrrolidine (3S) -1-[(6-chloronaphthalen-2-yl)
Sulfonyl] -3-[[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl]
Amino] pyrrolidine (3S) -3-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonylamino] -1-[(6-chloronaphthalen-2-yl ) Sulfonyl] pyrrolidine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] homo Piperazine 4-[(6-chloronaphthalen-2-yl) sulfonamido] -1-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] piperidine

1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(6-aminohydroxyiminomethylbenzofuran-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) ) Sulfonyl] -4-[(5-aminohydroxyiminomethylbenzothien-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(1,2,3 4-tetrahydroisoquinolin-6-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl )) Carbonyl] piperazine 6-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbo Nil] -2,
2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide

1-[(5-chloroindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(6-
Methyl-4,5,6,7-tetrahydrothieno [2,3
-C] pyridin-2-yl) carbonyl] piperazine 1-[(5-chlorobenzo [b] furan-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] furan-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

1-[(5-chlorobenzo [b] thiene-
2-yl) sulfonyl] -4-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5 , 6,7,8-Tetrahydro-1,6
-Naphthyridin-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin- 2-yl) carbonyl]
Piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydro-1H-
Pyrrolo [3,2-c] pyridin-2-yl) carbonyl] piperazine

1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,
7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-ethyl-4,5 , 6,7-Tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(1-methyl- 4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(1 , 5-Dimethyl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine-2
-Yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6-methyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine-2 -Yl) carbonyl] piperazine

1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(3-hydroxy-6-methyl-4,5,6,7-tetrahydrofuro [2,3-c]
Pyridin-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-methyl-3-hydroxy-4,5,
6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-methyl-4 , 5,6,7-Tetrahydrooxazolo [4,5-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) −1 − [(4
5-dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2,6-bis (carbamoylmethyl) -4-[(5-chloroindole- 2-yl) sulfonyl] -1-
[(4,5-Dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

Cis-2,6-bis (carbamoylmethyl) -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4,5-dimethyl-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 4-[(5-chloroisoindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 2- [4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide 4-[( 6-chloronaphthalen-2-yl) sulfonyl] -2-[(N-methyl) carbamoyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chloronaphthalen-2-yl) sulfonyl] -1 -[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine

N-[[4-[(6-chloronaphthalene-
2-yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl]
Carbonyl] glycine ethyl ester 4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2 -Yl) carbonyl] -2- [N- (morpholin-4-yl) carbamoyl] piperazine N '-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine-2
-Yl] carbonyl] hydrazinoacetic acid ethyl ester 4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c ] Pyridin-2-yl) carbonyl] -2- [N-[[(morpholin-4-yl) carbonyl] methyl] carbamoyl] piperazine 4-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] carbonyl]
Morpholine

4-[(6-chloronaphthalen-2-yl) sulfonyl] -2- (ethoxycarbonyl) -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine [4-[(6-chloronaphthalen-2-yl) sulfonyl]- 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] acetic acid methyl ester 2-[[N- ( tert-butoxy) amino] carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c ] Pyridin-2-yl)
Carbonyl] piperazine [4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2- Yl) carbonyl] piperazin-2-yl] acetamide 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-[(N-isopropyl) carbamoyl] -1
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine

4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-[[(piperidin-1-yl)
Carbonyl] methyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-[[N- (2-methoxybenzyl) )] Carbamoyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-[[N- (2-methoxyethyl)] carbamoyl] -1-[(5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine) 4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-carboxylic acid N '-[[4-[(6-chloronaphthalen-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] carbonyl]
Hydrazinoacetic acid

4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2-[[N- (tetrahydropyran-2-yloxy)] carbamoyl] piperazine 4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-hydrooxamate 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-[[ N- (2-hydroxybenzyl)] carbamoyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1- [ (6-Bromonaphthalen-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] Perazine 1-[(7-amidinonaphthalen-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl ] Piperazine

1-[(6-Amidinonaphthalen-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[7- [N- (Methoxycarbonyl) amidino] naphthalen-2-yl] sulfonyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]- 4-[[6- [N- (methoxycarbonyl) amidino] naphthalen-2-yl] sulfonyl] piperazine 1-[(7-[(amino) (hydroxyimino) methyl] naphthalen-2-yl) sulfonyl] -4 − [(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-[(amino) (hydroxyimino) methyl] naphthalene-2- Yl) sulfonyl] -4-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

1-[(6-ethynylnaphthalen-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 1-[(5-bromoindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine -2-yl) carbonyl] piperazine 1-[(5-amidinoindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl) carbonyl] piperazine 1-[(6-amidinoindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c ] Pirizi N-2-yl) carbonyl] piperazine

1-[[5-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl]-
4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[[6-[(amino) (hydroxyimino) methyl ] Indol-2-yl] sulfonyl] -4-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] -4-[[5- (N-methoxycarbonylamidino) indol-2-yl] sulfonyl] piperazine 1-[(5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxycarbonyl) amidino] indol-2-yl] sulfonyl] piperazine 1-[( 5-amidinobenzo [b] thien-2-yl)
Sulfonyl] -4-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

1-[(6-amidinobenzo [b] thien-2-yl) sulfonyl] -4-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[[5-[(amino) (hydroxyimino) methyl] benzo [b] thien-2-yl ] Sulfonyl] -4
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine 1-[[6-[(amino) (hydroxyimino) methyl] benzo [b] thien-2-yl] sulfonyl] -4
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[5- [N- (methoxycarbonyl) amidino ] Benzo [b] thien-2-yl] sulfonyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4 -[[6- [N- (methoxycarbonyl) amidino] benzo [b] thien-2-yl] sulfonyl] piperazine

4-[(5-amidinoisoindole-2
-Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] isoindol-2-yl] sulfonyl] -1 −
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[[5- [N- (methoxycarbonyl) amidino]
Isoindol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine -1-yl] carbonyl] -5-
Methylthiazolo [5,4-c] pyridinium iodide 2-[[4-[(5-chloroindol-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5-
Methylthiazolo [5,4-c] pyridinium iodide

2-[[4-[(5-bromoindole-
2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide 2-[[4-[(5-ethynylindol-2-yl)
Sulfonyl] piperazin-1-yl] carbonyl] -5
-Methylthiazolo [5,4-c] pyridinium iodide 2-[[2- (carbamoyl) -4-[(5-chloroindol-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5-methylthiazolo [ 5,4-c]
Pyridinium iodide 2-[[2- (carbamoylmethyl) -4-[(5-chloroindol-2-yl) sulfonyl] piperazine-
1-yl] carbonyl] -5-methylthiazolo [5,4
-C] pyridinium iodide 2-[[2,6-bis (carbamoylmethyl) -4-
[(5-Chloroindol-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide

2-[[2-[[(tetrazol-5-ylmethyl) amino] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazine-1-
Yl] carbonyl] -5-methylthiazolo [5,4-
c] Pyridinium iodide 2-[[2- [2- (tetrazol-5-yl) ethyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5- Methylthiazolo [5,4-c] pyridinium iodide 2-[[2-[(morpholin-4-ylcarbonyl) methyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazin-1-yl] Carbonyl] -5-
Methylthiazolo [5,4-c] pyridinium iodide 4-[(5-chloroindol-2-yl) sulfonyl] -2- (carbamoylmethyl) -1-[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4 -C] pyridin-2-yl) carbonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2-[[(tetrazol-5-
Yl) amino] carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine -2-yl) carbonyl] -2-[[(tetrazol-5-ylmethyl)
Amino] carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2 -Yl) carbonyl] -2-[[(tetrazol-5-ylamino)
Carbonyl] methyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2 -Yl) carbonyl] -2-[[[(tetrazol-5-ylmethyl) amino] carbonyl] methyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4 , 5,6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (tetrazol-5-ylmethyl) piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2- [2- (tetrazol-5
-Yl) ethyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoylmethyl) -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2 -[(Morpholin-4-ylcarbonyl) methyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine4- [(5-ethynylindole-
2-yl) sulfonyl] -2-[(morpholin-4-ylcarbonyl) methyl] -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-ethynylisoindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(5-chloroisoindole-2-
Yl) sulfonyl] -2- (N-methylcarbamoyl)
-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2- (carbamoylmethyl) -4-[(5-chloro Isoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] piperazine 2- (carbamoylmethyl) -4-[(5-ethynylisoindol-2-yl) sulfonyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroisoindol-2-yl) sulfonyl] -2- (N-methylcarbamoylmethyl) -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroisoindol-2-yl) sulfonyl]- 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazine

4-[(5-chloroisoindole-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholine-4-
Ylcarbonyl) methyl] piperazine 4-[(5-bromoisoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine -2-yl) carbonyl] -2- (morpholinocarbonylmethyl) piperazine 4-[(5-ethynylisoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl)
Carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydro Oxazolo [4,5-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(4
5-dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoylmethyl) -1-[(4,5-dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (morpholinocarbonylmethyl) -1-
[(4,5-Dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -2- (morpholinocarbonylmethyl) -1-
[(4,5-Dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-bromoindol-2-yl) sulfonyl] -2- (morpholinocarbonylmethyl) -1-
[(4,5-dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2,6-bis (carbamoylmethyl) -4-[(5 -Chloroindol-2-yl) sulfonyl] -1-
[(4,5-Dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(5-ethynylindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl)-
1-[(4,5-Dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2,6-bis (carbamoylmethyl) -1- [ (4,5
-Dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4
-[(5-ethynylindol-2-yl) sulfonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[[(ethoxycarbonylmethyl) aminocarbonyl] methyl] -1-[( 4,5-dimethyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[[(ethoxycarbonylmethyl) Aminocarbonyl] methyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[[(carboxoxymethyl) amino Carbonyl] methyl] -1-[(4,5-dimethyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -2-[[(carboxymethyl) aminocarbonyl] methyl] -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4,5-dimethyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[[[(tetrazol-5-yl) methyl] aminocarbonyl] methyl] piperazine 4- [(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]- 2-[[[(tetrazol-5-yl) methyl] aminocarbonyl] methyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4,5-dimethyl-4,5, 6, - tetrahydrophthalic thiazolo [5,4-c] pyridin-2-yl) carbonyl] -2 - [(tetrazol-5-yl)
Methyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1--1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2- Yl) carbonyl] -2-[(tetrazol-5-yl) methyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4,5-dimethyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (tetrazol-5-yl) ethyl] piperazine 4-[(5-chloroindole-2 -Yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (tetrazol-5 -Yl) ethyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4,5-dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl) carbonyl] -2-[(2-oxopyrrolidine-1
-Yl) methyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2-[(2-oxopyrrolidin-1-yl)
Methyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4,5-dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2 -Yl) carbonyl] -2- [2- (2-oxopyrrolidin-1-yl) ethyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2- [2- (2-oxopyrrolidin-1-yl) ethyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[(4-hydroxy-2- Oxopyrrolidin-1-yl) methyl] -1-[(4,5-dimethyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[(4-hydroxy-2-oxopyrrolidin-1-yl) methyl] -1-[(5 -Methyl-4,5
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- [2- (4-hydroxy-2 -Oxopyrrolidin-1-yl) ethyl] -1-[(4,5-dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- [2- (4-hydroxy-2-oxopyrrolidin-1-yl) ethyl] -1 -[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4,5-dimethyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(2,5-dioxopyrrolidin-1-yl) methyl] piperazine 4-[(5- Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(2 , 5-Dioxopyrrolidine-1-
Yl) methyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4,5-dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine -2-yl) carbonyl] -2- [2- (2,5-dioxopyrrolidin-1-yl) ethyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (2,5-dioxopyrrolidine-
1-yl) ethyl] piperazine 2,6-bis [2- (4-hydroxy-2-oxopyrrolidin-1-yl) ethyl] -4-[(5-chloroindol-2-yl) sulfonyl] -1- [(4,5-dimethyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine

2,6-bis [2- (2-oxopyrrolidin-1-yl) ethyl] -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4,5-dimethyl- 4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 2,6-bis [2- (tetrazol-5-yl) ethyl] -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4 , 5-Dimethyl-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 2,6-bis [(tetrazol-5-yl) methyl]-
4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4,5-dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) Carbonyl] piperazine 2,6-bis [(N-methylcarbamoyl) methyl]-
4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4,5-dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) Carbonyl] piperazine 2,6-bis [(2,5-dioxopyrrolidin-1-yl) methyl] -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4,5-dimethyl −4
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

2,6-bis [2- (2,5-dioxopyrrolidin-1-yl) ethyl] -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4,5 −
Dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(7-amidinonaphthalen-2-yl) sulfonyl] -1-[(5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-carboxylic acid 4-[(6-amidinonaphthalen-2-yl) sulfonyl] -1-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-carboxylic acid 1-[(5-methyl-4 , 5,6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[7- [N- (methoxycarbonyl) amidino] naphthalen-2-yl] sulfonyl] pipera 2-Carboxylic acid 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (Methoxycarbonyl) amidino] naphthalen-2-yl] sulfonyl] piperazine-2-carboxylic acid

4-[(7-[(amino) (hydroxyimino) methyl] naphthalen-2-yl) sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-carboxylic acid 4-[(6-[(amino) (Hydroxyimino) methyl] naphthalen-2-yl) sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-carboxylic acid 4-[(5-amidinoindol-2-yl) sulfonyl] -1-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-carboxylic acid 4-[(6-amidinoindole- 2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-carboxylic acid 4- [ [5-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-carboxylic acid

4-[[6-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-carboxylic acid 1-[(5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[5- [N- (methoxycarbonyl) amidino] indol-2-yl] sulfonyl] piperazine- 2-carboxylic acid 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxy Carbonyl) amidino] indol-2-yl] sulfonyl] piperazine-2-carboxylate 4-[(5-amidinobenzo [b] thien-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-carboxylic acid 4-[(6-amidinobenzo [b] thien-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-carboxylic acid

1-[[5-[(amino) (hydroxyimino) methyl] benzo [b] thien-2-yl] sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothia Zolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-carboxylic acid 4-[[6-[(amino) (hydroxyimino) methyl] benzo [b] thien-2-yl] sulfonyl] -1
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine-2-carboxylic acid 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[5- [N- (Methoxycarbonyl) amidino] benzo [b] thien-2-yl] sulfonyl] piperazine-2-carboxylic acid 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl) carbonyl] -4-[[6- (N-methoxycarbonylamidino) benzo [b] thien-2-yl] sulfonyl] piperazine-2-carboxylic acid 4-[(5-amidinoisoindole- 2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine-2-carboxylic acid

4-[[5-[(amino) (hydroxyimino) methyl] isoindol-2-yl] sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-c] Pyridin-2-yl) carbonyl] piperazine-2-carboxylic acid 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl ) Carbonyl] -4-[[5- [N- (methoxycarbonyl) amidino] isoindol-2-yl] sulfonyl] piperazine-2-carboxylic acid 4-[(7-amidinonaphthalen-2-yl) sulfonyl]- 2- (ethoxycarbonyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 4-[(6-amidinonaphthalen-2-yl) sulfonyl] -2- (ethoxycarbonyl) -1-[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 2- (ethoxycarbonyl) -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -4-[[7- [N
-(Methoxycarbonyl) amidino] naphthalene-2-
Yl] sulfonyl] piperazine

2- (ethoxycarbonyl) -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4
-[[6- [N- (methoxycarbonyl) amidino] naphthalen-2-yl] sulfonyl] piperazine 4-[(7-[(amino) (hydroxyimino) methyl] naphthalen-2-yl) sulfonyl] -2- (Ethoxycarbonyl) -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 4-[(6-[(amino) (hydroxyimino) methyl] naphthalen-2-yl) sulfonyl] -2- (ethoxycarbonyl) -1-[(5-methyl-4,5, 6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 4-[(5-amidinoindol-2-yl) sulfonyl] -2- (ethoxycarbonyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4
-C] pyridin-2-yl) carbonyl] piperazine 4-[(6-amidinoindol-2-yl) sulfonyl] -2- (ethoxycarbonyl) -1-[(5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] piperazine

4-[[5-[(Amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl]-
2- (ethoxycarbonyl) -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine 4-[[6-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl] -2- (ethoxycarbonyl) -1-[(5-methyl-4 , 5,6
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 2- (ethoxycarbonyl) -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -4-[[5- [N
-(Methoxycarbonyl) amidino] indole-2-
Yl] sulfonyl] piperazine 2- (ethoxycarbonyl) -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -4-[[6- [N
-(Methoxycarbonyl) amidino] indole-2-
Yl] sulfonyl] piperazine 4-[(5-amidinobenzo [b] thien-2-yl)
Sulfonyl] -2- (ethoxycarbonyl) -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(6-amidinobenzo [b] thien-2-yl) sulfonyl] -2- (ethoxycarbonyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] benzo [b] thien-2-yl] sulfonyl] -2
-(Ethoxycarbonyl) -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[[6-[(amino) (hydroxyimino) methyl] benzo [b] thien-2-yl ] Sulfonyl] -2
-(Ethoxycarbonyl) -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2- (ethoxycarbonyl) -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -4-[[5- [N
-(Methoxycarbonyl) amidino] benzo [b] thien-2-yl] sulfonyl] piperazine 2- (ethoxycarbonyl) -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -4-[[6- [N
-(Methoxycarbonyl) amidino] benzo [b] thien-2-yl] sulfonyl] piperazine

4-[(5-amidinoisoindole-2
-Yl) sulfonyl] -2- (ethoxycarbonyl)-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl ] Isoindol-2-yl] sulfonyl] -2-
(Ethoxycarbonyl) -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2- (ethoxycarbonyl) -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -4-[[5- [N
-(Methoxycarbonyl) amidino] isoindole-
2-yl] sulfonyl] piperazine 4-[(7-amidinonaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine -2-yl) carbonyl] -2-[(tetrazol-5-yl) methyl]
Piperazine 4-[(6-amidinonaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl ] -2-[(tetrazol-5-yl) methyl]
Piperazine

1-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxycarbonyl) ) Amidino] naphthalen-2-yl] sulfonyl] -2-[(tetrazol-5-yl) methyl] piperazine 4-[(6-[(amino) (hydroxyimino) methyl] naphthalen-2-yl) sulfonyl]- 1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[(Tetrazol-5-yl) methyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] -2-[(tetrazol-5-yl) methyl]
Piperazine 4-[(5-amidinoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl ] -2-[(tetrazol-5-yl) methyl]
Piperazine 4-[(6-amidinoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl ] -2-[(tetrazol-5-yl) methyl]
Piperazine

4-[[5-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(tetrazol-5-yl) methyl] piperazine 4- [[6-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[(Tetrazol-5-yl) methyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4- [ [5- (N-methoxycarbonylamidino) indol-2-yl] sulfonyl] -2-[(tetrazol-5-yl) methyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothia Zolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxycarbonyl) amidino] indol-2-yl] sulfonyl] -2-
[(Tetrazol-5-yl) methyl] piperazine 4-[(5-amidinobenzo [b] thien-2-yl)
Sulfonyl] -4-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(tetrazol-5-yl)
Methyl] piperazine

4-[[5-[(amino) (hydroxyimino) methyl] benzo [b] thien-2-yl] sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothia Zolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(tetrazol-5-yl) methyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] -4-[[5- [N- (methoxycarbonyl) amidino] benzo [b] thien-2-yl] sulfonyl]-
2-[(tetrazol-5-yl) methyl] piperazine 4-[(5-amidinoisoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl)
Carbonyl] -2-[(tetrazol-5-yl) methyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] isoindol-2-yl] sulfonyl] -1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]-
2-[(tetrazol-5-yl) methyl] piperazine 4-[[5- [N- (methoxycarbonyl) amidino]
Isoindol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[(Tetrazol-5-yl) methyl] piperazine

2-[[4-[(6-chloronaphthalene-
2-yl) sulfonyl] -2-[(tetrazol-5-
Yl) methyl] piperazin-1-yl] carbonyl]-
5-methylthiazolo [5,4-c] pyridinium iodide 2-[[4-[(5-chloroindol-2-yl) sulfonyl] -2-[(tetrazol-5-yl) methyl] piperazin-1-yl ] Carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide 4-[(7-amidinonaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (tetrazol-5-yl) ethyl] piperazine 4-[(6-amidinonaphthalen-2-yl) sulfonyl] -1 -[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (tetrazol-5-yl) ethyl] pipera 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxycarbonyl) amidino ] Naphthalen-2-yl] sulfonyl] -2- [2
-(Tetrazol-5-yl) ethyl] piperazine

4-[(6-[(amino) (hydroxyimino) methyl] naphthalen-2-yl) sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (tetrazol-5-yl) ethyl]
Piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl ] -2- [2- (Tetrazol-5-yl) ethyl] piperazine 4-[(5-amidinoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (tetrazol-5-yl) ethyl] piperazine 4-[(6-amidinoindol-2-yl) sulfonyl] -1 -[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (tetrazol-5-yl) ethyl] piperazine 4 − [[5- [(Amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[2- (tetrazol-5-yl) ethyl] piperazine

4-[[6-[(Amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (tetrazol-5-yl) ethyl]
Piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[5- (N-methoxycarbonylamidino) indole -2-yl] sulfonyl] -2- [2-
(Tetrazol-5-yl) ethyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6 -[N- (methoxycarbonyl) amidino] indol-2-yl] sulfonyl] -2- [2
-(Tetrazol-5-yl) ethyl] piperazine 4-[(5-amidinobenzo [b] thien-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (tetrazol-5-yl) ethyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] Benzo [b] thien-2-yl] sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (tetrazol-5-yl) ethyl]
Piperazine

1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[5- [N- (methoxycarbonyl) ) Amidino] benzo [b] thien-2-yl]
Sulfonyl] -2- [2- (tetrazol-5-yl)
Ethyl] piperazine 4-[(5-amidinoisoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2- Ill)
Carbonyl] -2- [2- (tetrazol-5-yl)
Ethyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] isoindol-2-yl] sulfonyl] -1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]-
2- [2- (tetrazol-5-yl) ethyl] piperazine 4-[[5- [N- (methoxycarbonyl) amidino]
Isoindol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[2- (tetrazol-5-yl) ethyl] piperazine 2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -2- [2- (tetrazol-5-yl) ethyl] piperazine 1 -Yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide

2-[[4-[(5-chloroindole-
2-yl) sulfonyl] -2- [2- (tetrazole-
5-yl) ethyl] piperazin 1-yl] carbonyl]
-5-methylthiazolo [5,4-c] pyridinium iodide 4-[(7-amidinonaphthalen-2-yl) sulfonyl] -1-[(6-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] -2- [N-[(tetrazol-5-yl) methyl] carbamoyl] piperazine 4-[(6-amidinonaphthalen-2-yl) sulfonyl] -1 -[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [N-[(tetrazol-5-yl) methyl] carbamoyl ] Piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxycarbonyl) Amidino ] Naphthalen-2-yl] sulfonyl] -2- [N
-[(Tetrazol-5-yl) methyl] carbamoyl] piperazine 4-[(6-[(amino) (hydroxyimino) methyl] naphthalen-2-yl) sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[N-[(tetrazol-5-yl) methyl] carbamoyl] piperazine

4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2- [N-[(tetrazole-
5-yl) methyl] carbamoyl] piperazine 4-[(5-amidinoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c ] Pyridin-2-yl) carbonyl] -2- [N-[(tetrazol-5-yl) methyl] carbamoyl] piperazine 4-[(6-amidinoindol-2-yl) sulfonyl] -1-[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [N-[(tetrazol-5-yl) methyl] carbamoyl] piperazine 4- [ [5-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[N-[(tetrazol-5-yl) methyl] carbamoyl] piperazine 4-[[6-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[N-[(tetrazol-5-yl) methyl] carbamoyl] piperazine

1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[5- (N-methoxycarbonylamidino ) Indol-2-yl] sulfonyl]-
2- [N-[(tetrazol-5-yl) methyl] carbamoyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) Carbonyl] -4-[[6- [N- (methoxycarbonyl) amidino] indol-2-yl] sulfonyl] -2- [N
-[(Tetrazol-5-yl) methyl] carbamoyl] piperazine 4-[(5-amidinobenzo [b] thien-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [N-[(tetrazol-5-
Yl) methyl] carbamoyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] benzo [b] thien-2-yl] sulfonyl] -1
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
-2- [N-[(tetrazol-5-yl) methyl] carbamoyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl ) Carbonyl] -4-[[5- [N- (methoxycarbonyl) amidino] benzo [b] thien-2-yl] sulfonyl]
-2- [N-[(tetrazol-5-yl) methyl] carbamoyl] piperazine

4-[(5-amidinoisoindole-2
-Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [N-[(tetrazol-5-yl) methyl] carbamoyl] piperazine 4-[[5-[(amino ) (Hydroxyimino) methyl] isoindol-2-yl] sulfonyl] -1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]-
2- [N-[(tetrazol-5-yl) methyl] carbamoyl] piperazine 4-[[5- [N- (methoxycarbonyl) amidino]
Isoindol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[N-[(tetrazol-5-yl) methyl] carbamoyl] piperazine 2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -2- [N-[(tetrazol-5-yl)
Methyl] carbamoyl] piperazin 1-yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide 2-[[4-[(5-chloroindol-2-yl) sulfonyl] -2- [N- [(Tetrazol-5-yl)
Methyl] carbamoyl] piperazin 1-yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide

4-[(7-amidinonaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2- [N-[(tetrazole-
5-yl) methyl] carbamoylmethyl] piperazine 4-[(6-amidinonaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4- c] pyridin-2-yl) carbonyl] -2- [N-[(tetrazol-5-yl) methyl] carbamoylmethyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxycarbonyl) amidino] naphthalen-2-yl] sulfonyl] -2- [N
-[(Tetrazol-5-yl) methyl] carbamoylmethyl] piperazine 4-[(6-[(amino) (hydroxyimino) methyl] naphthalen-2-yl) sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[N-[(tetrazol-5-yl) methyl] carbamoylmethyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [N-[(tetrazol-5-yl) methyl] carbamoylmethyl] piperazine

4-[(5-amidinoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2- [N-[(tetrazole-
5-yl) methyl] carbamoylmethyl] piperazine 4-[(6-amidinoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4- c] pyridin-2-yl) carbonyl] -2- [N-[(tetrazol-5-yl) methyl] carbamoylmethyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] indole-2- Yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[N-[(tetrazol-5-yl) methyl] carbamoylmethyl] piperazine 4-[[6-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[N-[(tetrazol-5-yl) methyl] carbamoylmethyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) Carbonyl] -4-[[5- (N-methoxycarbonylamidino) indol-2-yl] sulfonyl] -2- [N-
[(Tetrazol-5-yl) methyl] carbamoylmethyl] piperazine

1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxycarbonyl) ) Amidino] indol-2-yl] sulfonyl] -2- [N-[(tetrazol-5-yl) methyl] carbamoylmethyl] piperazine 4-[(5-amidinobenzo [b] thien-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [N-[(tetrazol-5-
Yl) methyl] carbamoylmethyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] benzo [b] thien-2-yl] sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [N-[(tetrazol-5-yl) methyl] Carbamoylmethyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[5- [N- (methoxy Carbonyl) amidino] benzo [b] thien-2-yl] sulfonyl]
-2- [N-[(tetrazol-5-yl) methyl] carbamoylmethyl] piperazine 4-[(5-amidinoisoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] -2- [N-[(tetrazol-5-yl) methyl] carbamoylmethyl] piperazine

4-[[5-[(amino) (hydroxyimino) methyl] isoindol-2-yl] sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-c] Pyridin-2-yl) carbonyl] -2- [N-[(tetrazol-5-yl) methyl] carbamoylmethyl] piperazine 4-[[5- [N- (methoxycarbonyl) amidino]
Isoindol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[N-[(tetrazol-5-yl) methyl] carbamoylmethyl] piperazine 2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -2- [N-[(tetrazol-5-yl )
Methyl] carbamoylmethyl] piperazin 1-yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide 2-[[4-[(5-chloroindol-2-yl) sulfonyl] -2- [N -[(Tetrazol-5-yl)
Methyl] carbamoylmethyl] piperazin 1-yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide 4-[(7-amidinonaphthalen-2-yl) sulfonyl] -2- (ethoxycarbonylmethyl)- 1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(6-amidinonaphthalen-2-yl) sulfonyl] -2- (ethoxycarbonylmethyl)
-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2- (ethoxycarbonylmethyl) -1-[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] -4-[[6-
[N- (methoxycarbonyl) amidino] naphthalene-
2-yl] sulfonyl] piperazine 4-[(6-[(amino) (hydroxyimino) methyl] naphthalen-2-yl) sulfonyl] -2- (ethoxycarbonylmethyl) -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -2- (ethoxycarbonylmethyl) -1 − [(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-amidinoindol-2-yl) sulfonyl] -2- (ethoxy Carbonylmethyl) -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(6-amidinoindol-2-yl) sulfonyl] -2- (ethoxycarbonylmethyl)
-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[[5-[(amino) (hydroxyimino) Methyl] indol-2-yl] sulfonyl] -2- (ethoxycarbonylmethyl) -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[[6-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl]- 2- (ethoxycarbonylmethyl) -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c ] Pyridin-2-yl) carbonyl] -2- (ethoxycarbonylmethyl) -4-[[5
-(N-methoxycarbonylamidino) indole-2
-Yl] sulfonyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (ethoxycarbonylmethyl) -4 − [[6
-[N- (methoxycarbonyl) amidino] indol-2-yl] sulfonyl] piperazine

4-[(5-amidinobenzo [b] thien-2-yl) sulfonyl] -2- (ethoxycarbonylmethyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] benzo [b] thien-2-yl] sulfonyl] -2
-(Ethoxycarbonylmethyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (ethoxy Carbonylmethyl) -4-[[5
-[N- (methoxycarbonyl) amidino] benzo [b] thien-2-yl] sulfonyl] piperazine 4-[(5-amidinoisoindol-2-yl) sulfonyl] -2- (ethoxycarbonylmethyl) -1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] iso Indole-2-yl] sulfonyl] -2-
(Ethoxycarbonylmethyl) -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine

2- (ethoxycarbonylmethyl) -4-
[[5- [N- (methoxycarbonyl) amidino] isoindol-2-yl] sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] piperazine 2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -2- (ethoxycarbonylmethyl) piperazin-1-yl] carbonyl] -5- Methylthiazolo [5,4-c] pyridinium iodide 2-[[4-[(5-chloroindol-2-yl) sulfonyl] -2- (ethoxycarbonylmethyl) piperazin-1-yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide 4-[(7-amidinonaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4- c] pyridin-2-yl) carbonyl] piperazine-2-acetic acid 4-[(6-amidinonaphthalen-2-yl) sulfonyl] -1-[(5-methyl- , 5,6,7-tetrahydronaphthalene thiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-acetic acid

1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxycarbonyl) ) Amidino] naphthalen-2-yl] sulfonyl] piperazine-2-acetic acid 4-[(6-[(amino) (hydroxyimino) methyl] naphthalen-2-yl) sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-acetic acid 4-[(5-ethynylindol-2-yl) sulfonyl]- 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-acetic acid 4-[(5-amidinoindole-2- Yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-acetic acid 4-[(6- Amidinoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-acetic acid

4-[[5-[(Amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-acetic acid 4-[[6-[(amino) ( [Hydroxyimino) methyl] indol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-acetic acid 1-[(5-methyl-4,5,6,7- Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[5- (N-methoxycarbonylamidino) indol-2-yl] sulfonyl] piperazine-
2-acetic acid 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxycarbonyl ) Amidino] indol-2-yl] sulfonyl] piperazine-2-acetic acid 4-[(5-amidinobenzo [b] thien-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-acetic acid

4-[[5-[(Amino) (hydroxyimino) methyl] benzo [b] thien-2-yl] sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothia Zolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine-2-acetic acid 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[5- [N -(Methoxycarbonyl) amidino] benzo [b] thien-2-yl] sulfonyl]
Piperazine-2-acetic acid 4-[(5-amidinoisoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazine-2-acetic acid 4-[[5-
[(Amino) (hydroxyimino) methyl] isoindol-2-yl] sulfonyl] -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine-2-acetic acid 4-[[5- [N- (methoxycarbonyl) amidino]
Isoindol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-acetic acid

2-[[2- (carboxymethyl) -4-
[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide 2-[[2- (carboxymethyl) -4-[( 5-chloroindol-2-yl) sulfonyl] piperazine-1
-Yl] carbonyl] -5-methylthiazolo [5,4-
c] pyridinium iodide 4-[(7-amidinonaphthalen-2-yl) sulfonyl] -2-[(N-methylcarbamoyl) methyl] -1
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine 4-[(6-amidinonaphthalen-2-yl) sulfonyl] -2-[(N-methylcarbamoyl) methyl] -1
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine 2-[(N-methylcarbamoyl) methyl] -1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]-
4-[[6- [N- (methoxycarbonyl) amidino]
Naphthalen-2-yl] sulfonyl] piperazine

4-[(6-[(amino) (hydroxyimino) methyl] naphthalen-2-yl) sulfonyl]-
2-[(N-methylcarbamoyl) methyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -2 -[(N-methylcarbamoyl) methyl] -1
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine 4-[(5-amidinoindol-2-yl) sulfonyl] -2-[(N-methylcarbamoyl) methyl] -1
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine 4-[(6-amidinoindol-2-yl) sulfonyl] -2-[(N-methylcarbamoyl) methyl] -1
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine 4-[[5-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl] -2-[(N
-Methylcarbamoyl) methyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine

4-[[6-[(Amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl]-
2-[(N-methylcarbamoyl) methyl] -1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydro Thiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(N-methylcarbamoyl) methyl] -4
-[[5- (N-methoxycarbonylamidino) indol-2-yl] sulfonyl] piperazine 2-[(N-methylcarbamoyl) methyl] -1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]-
4-[[6- [N- (methoxycarbonyl) amidino]
Indole-2-yl] sulfonyl] piperazine 4-[(5-amidinobenzo [b] thien-2-yl)
Sulfonyl] -2-[(N-methylcarbamoyl) methyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] benzo [b] thien-2-yl] sulfonyl]-
2-[(N-methylcarbamoyl) methyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

2-[(N-methylcarbamoyl) methyl] 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4 -[[5- [N- (methoxycarbonyl) amidino] benzo [b] thien-2-yl] sulfonyl] piperazine 4-[(5-amidinoisoindol-2-yl) sulfonyl] -2-[(N- Methylcarbamoyl) methyl]
-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[[5-[(amino) (hydroxyimino) Methyl] isoindol-2-yl] sulfonyl] -2-
[(N-methylcarbamoyl) methyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine 2-[(N-methylcarbamoyl) methyl] -4-
[[5- [N- (methoxycarbonyl) amidino] isoindol-2-yl] sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] piperazine 2-[[2-[(N-methylcarbamoyl) methyl]-
4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide

2-[[2-[(N-methylcarbamoyl) methyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazin-1-yl] carbonyl]
-5-methylthiazolo [5,4-c] pyridinium iodide 4-[(7-amidinonaphthalen-2-yl) sulfonyl] -2-[[N- (ethoxycarbonylmethyl) carbamoyl] methyl] -4-[( 5-methyl-4,5
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-amidinonaphthalen-2-yl) sulfonyl] -2-[[N- (ethoxycarbonylmethyl) Carbamoyl] methyl] -4-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[[N- (ethoxycarbonylmethyl) carbamoyl] methyl] -1-[(5-methyl-4,5 , 6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxycarbonyl) amidino] naphthalen-2-yl] sulfonyl] piperazine 4-[(6- [ (Amino) (hydroxyimino) methyl] naphthalen-2-yl) sulfonyl] -2-[[N
-(Ethoxycarbonylmethyl) carbamoyl] methyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(5-ethynylindol-2-yl) sulfonyl] -2-[[N- (ethoxycarbonylmethyl) carbamoyl] methyl] -1-[(5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 4-[(5-amidinoindol-2-yl) sulfonyl] -2-[[N- (ethoxycarbonylmethyl) carbamoyl] methyl] -1-[(5-methyl −4,5
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-amidinoindol-2-yl) sulfonyl] -2-[[N- (ethoxycarbonylmethyl) Carbamoyl] methyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl] -2- [[N
-(Ethoxycarbonylmethyl) carbamoyl] methyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[[ 6-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl] -2-[[N
-(Ethoxycarbonylmethyl) carbamoyl] methyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

2-[[N- (ethoxycarbonylmethyl) carbamoyl] methyl] -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -4-[[5- (N
-Methoxycarbonylamidino) indol-2-yl] sulfonyl] piperazine 2-[[N- (ethoxycarbonylmethyl) carbamoyl] methyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxycarbonyl) amidino] indol-2-yl] sulfonyl] piperazine 4-[(5-amidino Benzo [b] thien-2-yl)
Sulfonyl] -2-[[N- (ethoxycarbonylmethyl) carbamoyl] methyl] -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] benzo [b] thien-2-yl] sulfonyl] -2
-[[N- (ethoxycarbonylmethyl) carbamoyl] methyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[[N- (ethoxycarbonylmethyl) carbamoyl] methyl] -1-[(5-methyl-4,5,6,7 −
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[5- [N- (methoxycarbonyl) amidino] benzo [b] thien-2-yl] sulfonyl] piperazine

4-[(5-amidinoisoindole-2
-Yl) sulfonyl] -2-[[N- (ethoxycarbonylmethyl) carbamoyl] methyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] isoindol-2-yl] sulfonyl] -2-
[[N- (ethoxycarbonylmethyl) carbamoyl]
Methyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine 2-[[N- (ethoxycarbonylmethyl) carbamoyl] methyl] -4-[[5- [N- (methoxycarbonyl) amidino] isoindol-2-yl] sulfonyl] -1-[(5- Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -2 -[[N- (ethoxycarbonylmethyl) carbamoyl] methyl] piperazin-1-yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide 4-[(7-amidinonaphthalen-2-yl) sulfonyl ] -2-[[N- (carboxymethyl) carbamoyl] methyl] -4-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(6-amidinonaphthalen-2-yl) sulfonyl] -2-[[N- (carboxymethyl)
Carbamoyl] methyl] -4-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[[N- (carboxymethyl) carbamoyl] methyl] -1-[(5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxycarbonyl)
Amidino] naphthalen-2-yl] sulfonyl] piperazine 4-[(6-[(amino) (hydroxyimino) methyl] naphthalen-2-yl) sulfonyl] -2-[[N
-(Carboxymethyl) carbamoyl] methyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[[N- (carboxymethyl) carbamoyl] methyl] -4- [(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4 -[(5-amidinoindol-2-yl) sulfonyl] -2-[[N- (carboxymethyl) carbamoyl] methyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(6-amidinoindol-2-yl) sulfonyl] -2-[[N- (carboxymethyl)
Carbamoyl] methyl] -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl]- 2-[[N
-(Carboxymethyl) carbamoyl] methyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[[6-[(amino) (hydroxyimino) methyl] indole -2-yl] sulfonyl] -2-[[N
-(Carboxymethyl) carbamoyl] methyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[[N- (carboxymethyl) carbamoyl] methyl] -1- [(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[5- (N-methoxycarbonylamidino) indole-2- Yl] sulfonyl] piperazine 2-[[N- (carboxymethyl) carbamoyl] methyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2- Yl) carbonyl] -4-[[6- [N- (methoxycarbonyl)
Amidino] indol-2-yl] sulfonyl] piperazine

4-[(5-amidinobenzo [b] thien-2-yl) sulfonyl] -2-[[N- (carboxymethyl) carbamoyl] methyl] -1-[(5-methyl-4,5, 6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] benzo [b] thien-2-yl] sulfonyl] -2
-[[N- (carboxymethyl) carbamoyl] methyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2 -[[N- (carboxymethyl) carbamoyl] methyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4 -[[5- [N- (methoxycarbonyl)
Amidino] benzo [b] thien-2-yl] sulfonyl] piperazine 4-[(5-amidinoisoindol-2-yl) sulfonyl] -2-[[N- (carboxymethyl) carbamoyl] methyl] -1- [ (5-methyl-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] isoindol-2-yl] sulfonyl] -2-
[[N- (carboxymethyl) carbamoyl] methyl]
-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

2-[[N- (carboxymethyl) carbamoyl] methyl] -4-[[5- [N- (methoxycarbonyl) amidino] isoindol-2-yl] sulfonyl] -1-[(5-methyl -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[[2-[[N- (carboxymethyl) carbamoyl] methyl] -4- [ (6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl]
-5-methylthiazolo [5,4-c] pyridinium iodide 2-[[2-[[N- (carboxymethyl) carbamoyl] methyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazine- 1-yl] carbonyl]
-5-methylthiazolo [5,4-c] pyridinium iodide 4-[(7-amidinonaphthalen-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 4-[(6-amidinonaphthalen-2-yl) sulfonyl] -4-[( 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine

1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxycarbonyl) ) Amidino] naphthalen-2-yl] sulfonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 4-[(6-[(amino) (hydroxyimino) methyl] naphthalen-2-yl) sulfonyl ] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[(Morpholin-4-yl) carbonylmethyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 4-[(5-amidinoindol-2-yl) sulfonyl] -1-[( 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 4-[( 6-amidinoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [ Morpholin-4-yl) carbonyl methyl] piperazine

4-[[5-[(Amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 4-[[6-[(amino) (hydroxyimino) methyl] indol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[(Morpholin-4-yl) carbonylmethyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4 -[[5- (N-methoxycarbonylamidino) indol-2-yl] sulfonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 1-[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- [N- (methoxycarbonyl) amidino] indol-2-yl] sulfonyl] -2-
[(Morpholin-4-yl) carbonylmethyl] piperazine 4-[(5-amidinobenzo [b] thien-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-yl)
Carbonylmethyl] piperazine

4-[[5-[(amino) (hydroxyimino) methyl] benzo [b] thien-2-yl] sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothia Zolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 1-[(5-methyl-4,5,6,7-tetrahydrothia Zolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[5- [N- (methoxycarbonyl) amidino] benzo [b] thien-2-yl] sulfonyl]-
2-[(morpholin-4-yl) carbonylmethyl]
Piperazine 4-[(5-amidinoisoindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 4-[[5-[(amino) (hydroxyimino) methyl] isoindol-2-yl] sulfonyl] -1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]-
2-[(morpholin-4-yl) carbonylmethyl]
Piperazine 4-[[5- [N- (methoxycarbonyl) amidino]
Isoindol-2-yl] sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[(Morpholin-4-yl) carbonylmethyl] piperazine

2-[[4-[(6-chloronaphthalene-
2-yl) sulfonyl] -2-[(morpholin-4-
Yl) carbonylmethyl] piperazin-1-yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide 2-[[4-[(5-chloroindol-2-yl) sulfonyl] -2- [ (Morpholin-4-yl) carbonylmethyl] piperazin-1-yl] carbonyl] -5
-Methylthiazolo [5,4-c] pyridinium iodide 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4-cyano-5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2- [2- (2,5-dioxopyrrolidin-1-yl) ethyl] piperazine 1-[(4-carbamoyl-5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2- [2- (2,5-dioxopyrrolidin-1-yl) ethyl] piperazine 4-[(5-chloro Indole-2-yl) sulfonyl] -1-[(4-dimethylamino-5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (2,5-
Dioxopyrrolidin-1-yl) ethyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4-cyano-5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -2- [2- (tetrazol-5-yl) ethyl] piperazine 1-[(4-carbamoyl-5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2- [2- (tetrazol-5-yl) ethyl] piperazine 4-[(5-chloroindol-2-yl) Sulfonyl] -1-[(4-dimethylamino-5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (tetrazol-5-yl) ethyl] piperazine 4-[(5-chloroindole-2 -Yl) sulfonyl] -1-[(4-cyano-5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2-[[[[(ethoxycarbonyl) methyl] amino] carbonyl] methyl] piperazine 1-[(4-carbamoyl-5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2-[[[[(ethoxycarbonyl) methyl] amino] carbonyl] methyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4-dimethylamino-5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] -2-
[[[[(Ethoxycarbonyl) methyl] amino] carbonyl] methyl] piperazine 2-[[[(carboxymethyl) amino] carbonyl]
Methyl] -4-[(5-chloroindol-2-yl)
Sulfonyl] -1-[(4-cyano-5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(4-carbamoyl-5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2-[[[(carboxymethyl) amino] carbonyl] methyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazine 2-[[[(carboxymethyl) amino] carbonyl ]
Methyl] -4-[(5-chloroindol-2-yl)
Sulfonyl] -1-[(4-dimethylamino-5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1- [7-[(dimethylamino) methyl] benzothiazol-2-yl) carbonyl] -2 -(N-methylcarbamoyl) piperazine

4-[(5-Chloroindol-2-yl) sulfonyl] -1- [7-[(dimethylaminomethyl) methyl] thiazolo [5,4-c] pyridin-2-yl) carbonyl] -2 -(N-methylcarbamoyl) piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1- [7-[(dimethylamino) methyl] -4,
5,6,7-tetrahydrobenzothiazol-2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1- [7-
[(Morpholin-4-yl) methyl] benzothiazol-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1- [6-
(Morpholin-4-yl) -4,5,6,7-tetrahydrobenzothiazol-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl ) -1- [7-
(Piperidin-1-yl) benzothiazol-2-yl) carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl)-
1- [6- (piperidin-1-yl) -4,5,6,7
-Tetrahydrobenzothiazol-2-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(2-methyl-4,5,6,7-
Tetrahydropyrrolo [3,4-c] pyridin-5-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5-methyl-4,5,6 , 7-
Tetrahydropyrrolo [3,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(2-methyl-4,5,6 , 7-
Tetrahydropyrrolo [3,4-c] pyridin-5-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-
Tetrahydropyrrolo [3,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -1-[(5-methoxy-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-[(morpholin-4- Ylcarbonyl) methyl] -1-[(5-sulfo-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(5
-Sulfo-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2 -[[(Morpholin-4-yl) carbonyl] methyl] -1-[(4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[( 6-ethynylbenzo [b] thien-2-yl)
Sulfonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] -1-[(4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -1-[(5,6-dimethyl-
4,5,6,7-tetrahydrothiazolo [4,5-d]
Pyridazin-2-yl) carbonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazin 4-[(6-ethynylbenzo [b] thien-2-yl)
Sulfonyl] -1-[(5,6-dimethyl-4,5,
6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -2-[[(morpholine-
4-yl) carbonyl] methyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [4,5-d] Pyridazin-2-yl) carbonyl] piperazine 1-[(6-ethynylbenzo [b] thien-2-yl)
Sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) Sulfonyl] -4-[(5,6-dimethyl-4,5,6,
7-tetrahydrothiazolo [4,5-d] pyridazine-
2-yl) carbonyl] piperazine

1-[(5,6-dimethyl-4,5,6
7-tetrahydrothiazolo [4,5-d] pyridazine-
2-yl) carbonyl] -4-[(6-ethynylbenzo [b] thien-2-yl) sulfonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (N -Methylcarbamoyl) -1-
[(4,5,6,7-tetrahydrothiazolo [4,5-
d] pyridazin-2-yl) carbonyl] piperazine 4-[(6-ethynylbenzo [b] thien-2-yl)
Sulfonyl] -2- (N-methylcarbamoyl) -1-
[(4,5,6,7-tetrahydrothiazolo [4,5-
d] pyridazin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5,6-dimethyl-4,5,6,
7-tetrahydrothiazolo [4,5-d] pyridazine-
2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine 1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) Carbonyl] -4-[(6-ethynylbenzo [b] thien-2-yl) sulfonyl] -2- (N-methylcarbamoyl) piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] -4-[(4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl ] Piperazine 2-[(N, N-dimethylcarbamoyl) methyl] -4
-[(6-ethynylbenzo [b] thien-2-yl) sulfonyl] -1-[(4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl)
Methyl] -1-[(5,6-dimethyl-4,5,6,7
-Tetrahydrothiazolo [4,5-d] pyridazine-2
-Yl) carbonyl] piperazine 2-[(N, N-dimethylcarbamoyl) methyl] -1
-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(6-ethynylbenzo [b] thien-
2-yl) sulfonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(4
5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine

2- (2-cyanoethyl) -4-[(6-
Ethynylbenzo [b] thien-2-yl) sulfonyl]
-1-[(4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(5,
6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 2- (2-cyanoethyl) -4-[(6-ethynylbenzo [b] Thien-2-yl) sulfonyl] -1-
[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl ) Sulfonyl] -1-[(5-hydroxy-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] -2- (N-methylcarbamoyl)
Piperazine 4-[(6-ethynylbenzo [b] thien-2-yl)
Sulfonyl] -1-[(5-hydroxy-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2- (N-methylcarbamoyl) piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -1-[(5-hydroxy-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine 4-[(6-ethynylbenzo [b] thien-2-yl)
Sulfonyl] -1-[(5-hydroxy-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5-hydroxy-4 , 5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 1-[(6-ethynylbenzo [b] thien-2-yl)
Sulfonyl] -4-[(5-hydroxy-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(5-
Hydroxy-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

2- (2-cyanoethyl) -4-[(6-
Ethynylbenzo [b] thien-2-yl) sulfonyl]
-1-[(5-hydroxy-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2- Yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl)
Methyl] -1-[(5-hydroxy-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[[(morpholin-4-yl)
Carbonyl] methyl] piperazine 2-[(N, N-dimethylcarbamoyl) methyl] -4
-[(6-ethynylbenzo [b] thien-2-yl) sulfonyl] -1-[(5-hydroxy-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] -1-[(4,5,6, 7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(6-ethynylbenzo [b] thien-2-yl)
Sulfonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] -1-[(4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl)
Carbonyl] piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -1-[(5,6-dimethyl-
4,5,6,7-tetrahydrooxazolo [4,5-
d] pyridazin-2-yl) carbonyl] -2-
[[(Morpholin-4-yl) carbonyl] methyl] piperazine 4-[(6-ethynylbenzo [b] thien-2-yl)
Sulfonyl] -1-[(5,6-dimethyl-4,5,
6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine 1-[(6-chlorobenzo [b] thiene -2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 1-[(6-ethynylbenzo [b] Thien-2-yl)
Sulfonyl] -4-[(4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) Sulfonyl] -4-[(5,6-dimethyl-4,5,6
7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine

1-[(5,6-dimethyl-4,5,6
7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(6-ethynylbenzo [b] thien-2-yl) sulfonyl] piperazine 4-[(6-chlorobenzo [b ] Thien-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-
[(4,5,6,7-tetrahydrooxazolo [4,5
-D] pyridazin-2-yl) carbonyl] piperazine 4-[(6-ethynylbenzo [b] thien-2-yl)
Sulfonyl] -2- (N-methylcarbamoyl) -1-
[(4,5,6,7-tetrahydrooxazolo [4,5
-D] pyridazin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5,6-dimethyl-4,5,6,
7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine 1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxa Zolo [4,5-d] pyridazin-2-yl)
Carbonyl] -4-[(6-ethynylbenzo [b] thien-2-yl) sulfonyl] -2- (N-methylcarbamoyl) piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] -4-[(4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl ] Piperazine 2-[(N, N-dimethylcarbamoyl) methyl] -4
-[(6-ethynylbenzo [b] thien-2-yl) sulfonyl] -1-[(4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl)
Methyl] -1-[(5,6-dimethyl-4,5,6,7
-Tetrahydrooxazolo [4,5-d] pyridazine-
2-yl) carbonyl] piperazine 2-[(N, N-dimethylcarbamoyl) methyl] -1
-[(5,6-Dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(6-ethynylbenzo [b] thien-2 -Yl) sulfonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(4,
5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine

2- (2-cyanoethyl) -4-[(6-
Ethynylbenzo [b] thien-2-yl) sulfonyl]
-1-[(4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(5,
6-dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl
Piperazine 2- (2-cyanoethyl) -4-[(6-ethynylbenzo [b] thien-2-yl) sulfonyl] -1-
[(5,6-Dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl ) Sulfonyl] -1-[(5-hydroxy-4,5.6.7)
-Tetrahydrooxazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2- (N-methylcarbamoyl) piperazine 4-[(6-ethynylbenzo [b] thien-2-yl)
Sulfonyl] -1-[(5-hydroxy-4,5.6.
7-tetrahydrooxazolo [5,4-c] pyridine-
2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -1-[(5-hydroxy-
4,5,6,7-tetrahydrooxazolo [5,4-
c] pyridin-2-yl) carbonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine 4-[(6-ethynylbenzo [b] thien-2-yl)
Sulfonyl] -1-[(5-hydroxy-4,5,6,
7-tetrahydrooxazolo [5,4-c] pyridine-
2-yl) carbonyl] -2-[[(morpholin-4-
Yl) carbonyl] methyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5-hydroxy-4,5,6,7
-Tetrahydrooxazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 1-[(6-ethynylbenzo [b] thien-2-yl)
Sulfonyl] -4-[(5-hydroxy-4,5,6,
7-tetrahydrooxazolo [5,4-c] pyridine-
2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(5-
Hydroxy-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

2- (2-cyanoethyl) -4-[(6-
Ethynylbenzo [b] thien-2-yl) sulfonyl]
-1-[(5-hydroxy-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2- Yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl)
Methyl] -1-[(5-hydroxy-4,5,6,7-
Tetrahydrooxazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 2-[(N, N-dimethylcarbamoyl) methyl] -4
-[(6-ethynylbenzo [b] thien-2-yl) sulfonyl] -1-[(5-hydroxy-4,5,6,7
-Tetrahydrooxazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5,6-dihydrobenzo [f] isoquinolin-8-yl) carbonyl] piperazine1-
[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5,6-dihydropyrido [4,3-
f] Quinazolin-3-yl) carbonyl] piperazine

8-[[1-[(6-chlorobenzo [b]
Thien-2-yl) sulfonyl] piperazin-4-yl] carbonyl] -5,6-dihydrobenzo [f] isoquinoline N-oxide 3-[[1-[(6-chlorobenzo [b] thien-2-
Yl) sulfonyl] piperazin-4-yl] carbonyl] -5,6-dihydropyrido [4,3-f] quinazoline N-oxide 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4- [(5-Methanesulfonyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-methanesulfonyl −4,5
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-methanesulfonyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (morpholin-4-ylcarbonylmethyl) piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2- (2-cyanoethyl)-
1-[(5-methanesulfonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [4,5-c] pyridine- 2-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5-methanesulfonyl-4,5,
6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-methanesulfonyl −4,5
6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-methanesulfonyl-4,5,
6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (morpholine-4-
Ylcarbonylmethyl) piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2- (2-cyanoethyl)-
1-[(5-methanesulfonyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2- Yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-5-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2- Yl) sulfonyl] -4-[(4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-5-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2- Yl) sulfonyl] -4-[(2-dimethylamino-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-5-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-methyl- 5-oxo-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholine-
4-yl) carbonylmethyl] piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -1-[(5-methyl-6-oxo-4,5,6,7-tetrahydrooxazolo [5
4-c] pyridin-2-yl) carbonyl] -2-
[(Morpholin-4-yl) carbonylmethyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(6-oxo-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1 -[(6-oxo-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 1- [(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(6-chlorobenzo [b] thien-2-yl) sulfoni ] -2- (N-methylcarbamoyl) piperazine 1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[( 6-ethynylbenzo [b] thien-2-
Yl) sulfonyl] -2- (N-methylcarbamoyl)
Piperazine

1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(6-chlorobenzo [b] thien- 2-yl) sulfonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine 1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine -2-yl) carbonyl] -4-[(6-ethynylbenzo [b] thien-2-
Yl) sulfonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine 1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2 -Yl) carbonyl] -4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazine 1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c ] Pyridin-2-yl) carbonyl] -4-[(6-ethynylbenzo [b] thien-2-
Yl) sulfonyl] piperazine 1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(6-chlorobenzo [b] Thien-2-yl) sulfonyl] -2- (2-cyanoethyl) piperazine

1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) -4-
[(6-ethynylbenzo [b] thien-2-yl) sulfonyl] piperazine 1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) Carbonyl] -4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] piperazine 1-[(5-amino-4,5,6, 7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(N, N-dimethylcarbamoyl) methyl] -4-[(6-ethynylbenzo [b] thien-2-
Yl) sulfonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(2-methyl-4,5,6,7-tetrahydropyrrolo [3,4-c] pyridine-5- Yl) carbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydropyrrolo [3,4-c] pyridine-2- Yl) carbonyl] piperazine

1-[(5-chloroindol-2-yl) sulfonyl] -4-[(2-methyl-4,5,
6,7-tetrahydropyrrolo [3,4-c] pyridine-
5-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,6 , 7-Tetrahydropyrrolo [3,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(2-Methyl-4,5,6,7-tetrahydropyrrolo [3,4-c] pyridin-5-yl) carbonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydropyrrolo [3,4-c] pyridin-5-yl) carbonyl] piperazine 1-[(5-ethynylindole -2-yl) sulfonyl] -4-[(2-methyl-4,5,6,7-tetrahydropyrrolo [3,4-c] pyridin-5-yl) carbonyl] -2-[(morpholine-4- Ilcarbonyl)
Methyl] piperazine

1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,
6,7-tetrahydropyrrolo [3,4-c] pyridine-
2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methoxy-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl ] -1-[(5-Methoxy-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[(morpholin-4-ylcarbonyl) methyl] -1- [ (5-sulfo-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2 -(2-cyanoethyl) -1-[(5-sulfo-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] -piperazine

4-[(5-ethynylindol-2-yl) sulfonyl] -2-[(morpholin-4-ylcarbonyl) methyl] -1-[(5-sulfo-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -piperazine 2- (2-cyanoethyl) -4-[(5-ethynylindol-2-yl) sulfonyl] -1- [(5-sulfo-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[[(morpholin-4-yl) carbonyl]
Methyl] -1-[(4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl]- 2-[[(morpholin-4-yl) carbonyl]
Methyl] -1-[(4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl]- 1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -2-[[(morpholin-4-yl)
Carbonyl] methyl] piperazine

1-[(5,6-dimethyl-4,5,6
7-tetrahydrothiazolo [4,5-d] pyridazine-
2-yl) carbonyl] -4-[(5-ethynylindol-2-yl) sulfonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine 1-[(5-chloroindol-2- Yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl ] -4-[(4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4 -[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 1-[(5,6-dimethyl-4,5, 6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(5-ethynylindol-2-yl) sulfonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl)-
1-[(4,5,6,7-tetrahydrothiazolo [4,
5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(4,
5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5,6-dimethyl -4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine 1-[(5,6-dimethyl-4,5 , 6,7-Tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(5-ethynylindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) piperazine 4 -[(5-Chloroindol-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] -1-[(4,5,6,7-tetrahydrothiazolo [4,5-d ] Ridajin 2-yl) carbonyl] piperazine

2-[(N, N-dimethylcarbamoyl)
Methyl] -4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] -1-[(5,6-dimethyl-4,5,6,7-tetrahydrothia Zolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 2-[(N, N-dimethylcarbamoyl) methyl] -1
-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(5-ethynylindol-2-yl) sulfonyl ] Piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(4,5
6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 2- (2-cyanoethyl) -4-[(5-ethynylindol-2-yl) sulfonyl] -1- [ (4,5
6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-
[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 2- (2-cyanoethyl) -1-[(5,6 -Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-
d] pyridazin-2-yl) carbonyl] -4-[(5
-Ethynylindol-2-yl) sulfonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-hydroxy-4,5,6,7-tetrahydrothiazolo [5,4 -C] pyridin-2-yl)
Carbonyl] -2- (N-methylcarbamoyl) piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-hydroxy-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl)
Carbonyl] -2- (N-methylcarbamoyl) piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-hydroxy-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl)
Carbonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine

4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-hydroxy-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[[(morpholine-4
-Yl) carbonyl] methyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(6-hydroxy-4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl)
Carbonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(5-hydroxy-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl )
Carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(5-hydroxy-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] piperazine 2- (2-cyanoethyl) -4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-hydroxy-4,5,6, 7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] piperazine

4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] -1-[(5-hydroxy-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[(N, N-dimethylcarbamoyl) methyl] -4
-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-hydroxy-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine 1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(5-chloroindol-2-yl ) Sulfonyl] -2- (N-methylcarbamoyl) piperazine 1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4- [(5-ethynylindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) piperazine 1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine -2-yl) carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine

1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(5-ethynylindole-
2-yl) sulfonyl] -2-[[(morpholin-4-
Yl) carbonyl] methyl] piperazine 1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(5-chloroindole -2-yl) sulfonyl] piperazine 1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(5-ethynyl Indole-2-yl) sulfonyl] piperazine 1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(5- Chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) piperazine 1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) Carbonyl] -2- (2-cyanoethyl) -4-[(5-ethynylindol-2-yl) sulfonyl] piperazine

1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(5-chloroindole-2
-Yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] piperazine 1-[(5-amino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2- Yl) carbonyl] -2-[(N, N-dimethylcarbamoyl) methyl] -4-[(5-ethynylindol-2-yl) sulfonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[[(morpholin-4-yl) carbonyl]
Methyl] -1-[(4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl]- 2-[[(morpholin-4-yl) carbonyl]
Methyl] -1-[(4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl]- 1-[(5,6-Dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazine-2-
Yl) carbonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine

1-[(5,6-dimethyl-4,5,6
7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(5-ethynylindol-2-yl) sulfonyl] -2-[[(morpholin-4-yl) carbonyl] Methyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl]
Piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl]
Piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazine-2-
Yl) carbonyl] piperazine 1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl)
Carbonyl] -4-[(5-ethynylindole-2-
Yl) sulfonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl)-
1-[(4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -2- ( N-methylcarbamoyl) -1-[(4,
5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5,6-dimethyl -4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazine-2-
Yl) carbonyl] -2- (N-methylcarbamoyl)
Piperazine 1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl)
Carbonyl] -4-[(5-ethynylindole-2-
Yl) sulfonyl] -2- (N-methylcarbamoyl)
Piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] -1-[(4,5,6,7-tetrahydrooxazolo [4,5 -D] pyridazin-2-yl) carbonyl]
Piperazine

2-[(N, N-dimethylcarbamoyl)
Methyl] -4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl)
Carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] -1-[(5,6-dimethyl-4,5,6,7 -Tetrahydrooxazolo [4,5-d] pyridazine-2-
Yl) carbonyl] piperazine 2-[(N, N-dimethylcarbamoyl) methyl] -1
-[(5,6-Dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(5-ethynylindol-2-yl) sulfonyl ] Piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(4,5
6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 2- (2-cyanoethyl) -4-[(5-ethynylindol-2-yl) sulfonyl] -1- [ (4,5
6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-
[(5,6-Dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 2- (2-cyanoethyl) -1-[(5,6 -Dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-
d] pyridazin-2-yl) carbonyl] -4-[(5
-Ethynylindol-2-yl) sulfonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-hydroxy-4,5.6.7-tetrahydrooxazolo [5,4 -C] pyridin-2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-hydroxy-4,5.6 0.7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1- [ (5-hydroxy-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[[(morpholin-4-yl)
Carbonyl] methyl] piperazine

4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-hydroxy-4,5,
6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[[(morpholine-
4-yl) carbonyl] methyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(5-hydroxy-4,5,6,7-tetrahydrooxazolo [5,4-c ] Pyridin-2-yl) carbonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(5-hydroxy-4,5,6,7-tetrahydrooxazolo [5,4- c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(5-hydroxy-4,5,6,7 -Tetrahydrooxazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine 2- (2-cyanoethyl) -4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-hydroxy-4,5,6 , 7-Tetrahydrooxazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] -1-[(5-hydroxy-4,5,
6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[(N, N-dimethylcarbamoyl) methyl] -4
-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-hydroxy-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(5,6-dihydrobenzo [f] isoquinolin-8-yl) carbonyl] piperazine 1-[(5,6-dihydrobenzo [f ] Isoquinoline-
8-yl) carbonyl] -4-[(5-ethynylindol-2-yl) sulfonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(5,6-dihydropyrido [4 , 3-f]
Quinazolin-3-yl) carbonyl] piperazine

1-[(5,6-dihydropyrido [4,3
-F] quinazolin-3-yl) carbonyl] -4-
[(5-ethynylindol-2-yl) sulfonyl]
Piperazine 8-[[1-[(5-chloroindol-2-yl) sulfonyl] piperazin-4-yl] carbonyl] -5
6-dihydrobenzo [f] isoquinoline N-oxide 8-[[1-[(5-ethynylindol-2-yl)
Sulfonyl] piperazin-4-yl] carbonyl]-
5,6-dihydrobenzo [f] isoquinoline N-oxide 3-[[1-[(5-chloroindol-2-yl) sulfonyl] piperazin-4-yl] carbonyl] -5
6-dihydropyrido [4,3-f] quinazoline N-oxide 3-[[1-[(5-ethynylindol-2-yl)]
Sulfonyl] piperazin-4-yl] carbonyl]-
5,6-dihydropyrido [4,3-f] quinazoline N-
Oxide

1-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrooxazolo [4,5-c] pyridine-
2-yl) carbonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [4,5-c] pyridine -2-yl) carbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(6-oxo-4,5,6,7-tetrahydrobenzothiazol-2-yl) carbonyl] Piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(6-hydroxyimino-4,5,6,7
-Tetrahydrobenzothiazol-2-yl) carbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(6-hydroxy-4,5,6,7-tetrahydrobenzothiazole-2- Yl) carbonyl] piperazine

1-[(5-chloroindol-2-yl) sulfonyl] -4-[(6-ethylenedioxy-
4,5,6,7-tetrahydrobenzothiazole-2-
Yl) carbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] furan-2-yl) carbonyl ] Piperazine 1-[(6-acetoxy-4,5,6,7-tetrahydrobenzothiazol-2-yl) carbonyl] -4-
[(5-chloroindol-2-yl) sulfonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(6-methoxy-4,5,6,7-tetrahydrobenzothiazole- 2-yl) carbonyl] piperazine 1-[(6-amino-4,5,6,7-tetrahydrobenzothiazol-2-yl) carbonyl] -4-[(5
-Chloroindol-2-yl) sulfonyl] piperazine

1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(6-dimethylamino-4,
5,6,7-tetrahydrobenzothiazol-2-yl) carbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[[6- (pyrrolidin-1-yl) -4,
5,6,7-tetrahydrobenzothiazol-2-yl] carbonyl] piperazine 1-[(6-acetylamino-1-4,5,6,7-tetrahydrobenzothiazol-2-yl) carbonyl]
-4-[(5-Chloroindol-2-yl) sulfonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(6-oxo-4,5,6,7-tetrahydro Benzothiazol-2-yl) carbonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(6-hydroxyimino-4,5,6,7
-Tetrahydrobenzothiazol-2-yl) carbonyl] piperazine

1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(6-hydroxy-4,5,
6,7-tetrahydrobenzothiazol-2-yl) carbonyl] piperazine 1-[(6-ethylenedioxy-4,5,6,7-tetrahydrobenzothiazol-2-yl) carbonyl]-
4-[(5-ethynylindol-2-yl) sulfonyl] piperazine 1-[(6-acetoxy-4,5,6,7-tetrahydrobenzothiazol-2-yl) carbonyl] -4-
[(5-ethynylindol-2-yl) sulfonyl]
Piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(6-methoxy-4,5,6,7-tetrahydrobenzothiazol-2-yl) carbonyl] piperazine 1-[(6- Amino-4,5,6,7-tetrahydrobenzothiazol-2-yl) carbonyl] -4-[(5
-Ethynylindol-2-yl) sulfonyl] piperazine

1-[(6-dimethylamino-4,5,
6,7-tetrahydrobenzothiazol-2-yl) carbonyl] -4-[(5-ethynylindol-2-yl) sulfonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -1- [ [6- (pyrrolidine-1-yl) -4,
5,6,7-tetrahydrobenzothiazol-2-yl] carbonyl] piperazine 1-[(6-acetylamino-1-4,5,6,7-tetrahydrobenzothiazol-2-yl) carbonyl]
-4-[(5-Ethynylindol-2-yl) sulfonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-6-oxo-4,5,6 ,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-6-oxo-4, 5,6
7-tetrahydrooxazolo [5,4-c] pyridine-
2-yl) carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -2-[(morpholin-4-yl) carbonylmethyl] -1-[(6-oxo-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[(morpholin-4-yl) carbonylmethyl] -1-[(6-oxo-4,5,6, 7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydro Thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(4-methyl-4,5,6,7-tetrahydro Thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(thieno [3,2-b] pyridin-2-yl ) Carbonyl] piperazine

2-[[4-[(5-chloroindole-
2-yl) sulfonyl] piperazin-1-yl] carbonyl] thieno [3,2-b] pyridine N-oxide 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(4,5, 6,7-tetrahydrothieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(4-methyl-4,5, 6,7-tetrahydrothieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(thieno [3,2-b] Pyridin-2-yl) carbonyl] piperazine 2-[[4-[(5-ethynylindol-2-yl)
Sulfonyl] piperazin-1-yl] carbonyl] thieno [3,2-b] pyridine N-oxide

4-[(5-chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-
[(4,5,6,7-tetrahydrothieno [3,2-
b] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(4-methyl-4,5,6,7 -Tetrahydrothieno [3,2-b]
Pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(thieno [3,2-b] pyridin-2-yl ) Carbonyl] piperazine 2-[[4-[(5-chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) piperazine-1
-Yl] carbonyl] thieno [3,2-b] pyridine
N-oxide 4-[(5-ethynylindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(4,5
6,7-tetrahydrothieno [3,2-b] pyridine-
2-yl) carbonyl] piperazine

4-[(5-ethynylindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-
[(4-Methyl-4,5,6,7-tetrahydrothieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 2-[[4-[(5-ethynylindol-2-yl)
Sulfonyl] -2- (cyanoethyl) piperazine-1-
Yl] carbonyl] thieno [3,2-b] pyridine N
-Oxide 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4, -c] pyridin-5-yl) carbonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4, -c] pyridin-5-yl) carbonyl] piperazine

1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrooxazolo [5,4, -c] pyridin-5-yl)
Carbonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrooxazolo [5,4, -c] pyridin-5-yl) carbonyl]
Piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(2-dimethylamino-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-5-yl) carbonyl] piperazine 1-[(2-dimethylamino-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-5- Yl) carbonyl] -4-[(5-ethynylindol-2-yl) sulfonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(5-methylsulfonyl4,5,6 , 7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methylsulfonyl 4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine 4-[(5-ethynylindol-2-yl) sulfonyl]- 1-[(5-methylsulfonyl4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (morpholin-4-ylcarbonylmethyl) piperazine 2- (2-cyanoethyl) -4-[(5-ethynylindole-2- Yl) sulfonyl] -1-[(5-methylsulfonyl4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(5-chloroindole-2 -Yl) sulfonyl] -4-[(5-methylsulfonyl4,5,6,7-
Tetrahydrooxazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methylsulfonyl4,5,6,7-
Tetrahydrooxazolo [5,4-c] pyridine-2-
Yl) carbonyl] -2- (N-methylcarbamoyl)
Piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methylsulfonyl4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (morpholine-
4-ylcarbonylmethyl) piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(5-methylsulfonyl4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(5-methylsulfonyl4,5,6,7-
Tetrahydrooxazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(5-
Methylsulfonyl 4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl
Piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methylsulfonyl4,5,6,7-
Tetrahydrooxazolo [5,4-c] pyridine-2-
Yl) carbonyl] -2- (morpholin-4-ylcarbonylmethyl) piperazine

2- (2-cyanoethyl) -4-[(5-
Ethynylindol-2-yl) sulfonyl] -1-
[(5-Methylsulfonyl4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl ] -1-[(5-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (2-oxo-pyrrolidine-1 -Yl) ethyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c ] Pyridin-2-yl) carbonyl] -2- [2- (2-oxo-1,3-
Oxazolan-3-yl) ethyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] -2- [2- (2-oxo-pyrrolidin-1-yl) ethyl] piperazine 4-[(5-chlorobenzo [b] thien-2-yl) sulfonyl] -2- [2-[(coumarin-7-yl) oxy] ethyl] -1-[(6-methyl-4,5,5,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2- [2-[(coumarin-7
-Yl) oxy] ethyl] -1-[(5-methyl-4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- [2- [ (Cyclopropylcarbonyl) amino] ethyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chlorobenzo [b] thien-2-yl) sulfonyl] -2- [2-[(cyclo Propylcarbonyl) amino] ethyl] -1-[(6-methyl-4,5,
5,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-[[(cyclopropylcarbonyl ) Amino] methyl] -1-[(5-methyl-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-[[(cyclopropylcarbonyl) amino] methyl] -1-[(5-methyl-4,5, 6,7
-Tetrahydrooxazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2- (2-cyanoethyl)-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl ) Sulfonyl] -2- (2-cyanoethyl) -1-[(5-
Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chlorobenzo [b] thien-2-yl) sulfonyl] -2- [(N-cyanomethyl-N-methylcarbamoyl) methyl] -1-[(6-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-[(N-cyanomethyl- N-methylcarbamoyl) methyl] -1-[(5-methyl-4,5,
6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2- (3-butynyl) -4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl]- 4-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine

2- (3-butynyl) -4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-
[(5-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-[[N- (2-hydroxyethyl)
Carbamoyl] methyl] -4-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-[[N- (2-hydroxyethyl)
Carbamoyl] methyl] -4-[(5-methyl-4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[[N, N-bis- (2-hydroxyethyl) carbamoyl] methyl] -1-[( 6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine 2-[[N, N-bis- (2-hydroxyethyl) carbamoyl] methyl] -1-[(6-chlorobenzo [b] thien-2-yl) Sulfonyl] -4-[(5-
Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

1-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2-[[N- (2-methoxyethyl) carbamoyl] methyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-[[N- (2-methoxyethyl) carbamoyl] methyl] -4- [ (5-methyl-4,5,
6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[[N, N-bis- (2-methoxyethyl) carbamoyl] methyl] -1-[(6- Chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine 2-[[N, N-bis- (2-methoxyethyl) carbamoyl] methyl] -1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4 -[(5-methyl-
4,5,6,7-tetrahydrooxazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-[[N- (2-hydroxyethyl)
-N-methylcarbamoyl] methyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2-[[N- (2-hydroxyethyl) -N-methylcarbamoyl] methyl] -1
-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[[N-benzyl-N- (2-hydroxyethyl) Carbamoyl] methyl] -4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[[N-benzyl-N- (2-hydroxyethyl) carbamoyl] methyl] -4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chlorobenzo [b] thien-2-yl) sulfonyl] -1 -[(6-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2-[(morpholin-4-
Yl) carbonyl] ethyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- [2- (dimethylaminocarbonyl)
Ethyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2-[(pyrrolidin-1-yl) carbonyl] ethyl] piperazine 2- [2- (amino Sulfonyl) ethyl] -4-[(6
-Chlorobenzo [b] thien-2-yl) sulfonyl]
-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2- Yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2-[(morpholine- 4-
Yl) sulfonyl] ethyl] piperazine 2- [2-[(t-butoxycarbonylamino) sulfonyl] ethyl] -4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5- Methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine 2- [2-[(n-butoxycarbonylamino) sulfonyl] ethyl] -4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[( 5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2- [2- (ethoxycarbonylamino) sulfonyl] ethyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 2- [2- (acetylamino) sulfonyl] ethyl]-
4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl ) Carbonyl] piperazine 2- (aminosulfonylmethyl) -4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl ] -1-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-yl)
Sulfonylmethyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine -2-yl) carbonyl] -2-[(pyrrolidin-1-yl) sulfonylmethyl] piperazine

2-[(t-butoxycarbonylamino)
Sulfonylmethyl] -4-[(6-chlorobenzo [b]
Thien-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 2-[(n-butoxycarbonylamino) sulfonylmethyl] -4-[(6-chlorobenzo [b] thien-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-[(ethoxycarbonylamino) Sulfonylmethyl] -1-[(5-methyl-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 2-[(acetylamino) sulfonylmethyl] -4-
[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl ] Piperazine 2- [3-[(4H-5-acetoxy-4-oxo) pyran-2-yl] propyl] -4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1- [ (5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2- [3-[(4H-5-hydroxy-4-oxo) pyran-2-yl] propyl]
-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2- Yl) sulfonyl] -2- [3-[(4H-5-methoxy-4-
Oxo) pyran-2-yl] propyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine N-methyl-N-[[4-[(6-chlorobenzo [b]
Thien-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine-2
-Yl] acetyl] methanesulfonamide N-[[4-[(6-chlorobenzo [b] thien-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] acetyl] benzenesulfonamide N- [2- [4-[(6-chlorobenzo [b] thiene) −
2-yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl]
Ethyl] trifluoromethanesulfonamide

N-methyl-N- [2- [4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazin-2-yl] ethyl] trifluoromethanesulfonamide N-[[4-[(6-chlorobenzo [b] thien-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] acetyl] -N'-methanesulfonylhydrazine 4-[(6-chlorobenzo [b] thien-2 -Yl) sulfonyl] -2- [2- (2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)
Ethyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- [2- (2,5-dihydro-5-oxo-4H-1,2,4-oxadiazole- 3-yl)
Ethyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien- 2-yl) sulfonyl] -2- [2- (2-oxo-3H-1,2,2
3,5-oxathiadiazol-4-yl) ethyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2- [2- (2-oxo-3
H-1,2,3,5-oxathiadiazol-4-yl) ethyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrooxazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- [2- (2,5-dihydro-5-oxo-4H-1,2,4-thiadiazole- 3-yl) ethyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [ b] thien-2-yl) sulfonyl] -2- [2- (2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl) ethyl] -1-[(5- Methyl-4,5,6,7-tetrahydrooxaazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- [2- (2,5-dihydro- - thioxo-4H-1,2,4-oxadiazol-3-yl) ethyl] -1 - [(5-methyl-4,5,6,7
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- [2- (2,5-dihydro- 5-thioxo-4H-1,2,4-oxadiazol-3-yl) ethyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrooxaazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2- [2- (2-oxo-1,
3-oxazolan-3-yl) ethyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4 -C] pyridin-2-yl) carbonyl] -2- [2- (2-oxo-1,3-oxazolan-3-yl) ethyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (2-oxo-1,3- Oxazolan-3-yl) ethyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c ] Pyridin-2-yl) carbo ] -2- [2- (2-oxopyrrolidin-1-yl) ethyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6, 7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2- (2-oxopyrrolidin-1-yl) ethyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -2- [2-[(coumarin-7-yl) oxy] ethyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- [2-[(coumarin-7- Yl) oxy] ethyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- [2-[(cyclopropylcarbonyl) amino] ethyl] -1-[(5-methyl-4,5,6,7 −
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- [2-[(cyclopropylcarbonyl) amino] ethyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrooxazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[[(cyclopropylcarbonyl) amino]
Methyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -2-[[(cyclopropylcarbonyl) amino] methyl] -1-[(5-methyl-4,5,
6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2- [2- (aminosulfonyl) ethyl] -4-[(5
-Chloroindol-2-yl) sulfonyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1 -[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2-[(morpholin-4-yl) sulfonyl] ethyl] Piperazine 2- [2-[(t-butoxycarbonylamino) sulfonyl] ethyl] -4-[(5-chloroindole-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2- [2-[(n-butoxycarbonylamino) sulfonyl] ethyl] -4-[(5-chloroindole- 2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -2- [2- (ethoxycarbonylamino) sulfonyl] ethyl] -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine 2- [2- (acetylamino) sulfonyl] ethyl]-
4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] Piperazine 2- [2- (aminosulfonyl) ethyl] -4-[(5
-Ethynylindol-2-yl) sulfonyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -1 -[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2-[(morpholin-4-yl) sulfonyl] ethyl] Piperazine 2- [2-[(t-butoxycarbonylamino) sulfonyl] ethyl] -4-[(5-ethynylindole-2
-Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

2- [2-[(n-butoxycarbonylamino) sulfonyl] ethyl] -4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 2- [2- (ethoxycarbonylamino) sulfonyl]
Ethyl] -4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 2- [2- (acetylamino) sulfonyl] ethyl]-
4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] Piperazine 2- (aminosulfonylmethyl) -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5, 4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-yl) sulfonylmethyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2-[(pyrrolidin-1-yl) sulfonylmethyl] piperazine 2-[(t-butoxycarbonylamino) sulfonylmethyl] -4-[(5-chloroindol-2-yl) sulfonyl]- 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[(n-butoxycarbonylamino) sulfonylmethyl] -4 -[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[(ethoxycarbonylamino) sulfonylmethyl] -1-[(5-methyl-4,5, , 7-tetrahydronaphthyl thiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine 2-[(acetylamino) sulfonylmethyl] -4-
[(5-Chloroindol-2-yl) sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

2- (aminosulfonylmethyl) -4-
[(5-ethynylindol-2-yl) sulfonyl]
-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl ] -1-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-yl) sulfonylmethyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(pyrrolidin-1-yl) sulfonylmethyl] piperazine 2-[(t-butoxycarbonylamino) sulfonylmethyl] -4-[(5-ethynylindol-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[(n-butoxycarbonylamino) sulfonylmethyl] -4-[(5-ethynylindol-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

2-[(ethoxycarbonylamino) sulfonylmethyl] -4-[(5-ethynylindole-2
-Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-[(acetylamino) sulfonylmethyl] -4-
[(5-ethynylindol-2-yl) sulfonyl]
-1-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2- [3-[(4H-5-acetoxy-4) -Oxo) pyran-2-yl] propyl] -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5, 4-
c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- [3-[(4H-5-hydroxy-4-oxo) pyran-2-yl] Propyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- [3-[(4H-5-methoxy-4-oxo) pyran-2-yl] Propyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine

N-[[4-[(5-chloroindole-
2-yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl]
Acetyl] -N-methylmethanesulfonamide N-[[4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] acetyl] benzenesulfonamide N- [2- [4-[(5-chloroindol-2-yl) sulfonyl] -1-[( 5-methyl-4,5,6
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazin-2-yl] ethyl]
Trifluoromethanesulfonamide N- [2- [4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazin-2-yl] ethyl]
-N-methyltrifluoromethanesulfonamide N-[[4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] acetyl]-
N'-methanesulfonylhydrazine

2- [3-[(4H-5-acetoxy-4)
-Oxo) pyran-2-yl] propyl] -4-[(5
-Ethynylindol-2-yl) sulfonyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -2 -[3-[(4H-5-hydroxy-4-oxo) pyran-2-yl] propyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -2- [3-[(4H-5-methoxy-4-oxo) pyran-2-yl] Propyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine N-methyl-N-[[4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl]
Acetyl] methanesulfonamide N-[[4-[(5-ethynylindol-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] acetyl] benzenesulfonamide

N- [2- [4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazin-2-yl] ethyl] trifluoromethanesulfonamide N- [2- [4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl- 4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazin-2-yl] ethyl]
-N-methyltrifluoromethanesulfonamide N-[[4-[(5-ethynylindol-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] acetyl]-
N'-methanesulfonylhydrazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- [2- (2,5-dihydro-5-oxo-4
H-1,2,4-oxadiazol-3-yl) ethyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl ) Carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -2- [2- (2,5-dihydro-5-oxo-4
H-1,2,4-oxadiazol-3-yl) ethyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl ) Carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -2- [2- (2,5-dihydro-5
-Oxo-4H-1,2,4-oxadiazole-3-
Yl) ethyl] -1-[(5-methyl-4,5,6,7
-Tetrahydrooxazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -2- [2- (2,5-dihydro-5-oxo-4
H-1,2,4-oxadiazol-3-yl) ethyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl ) Carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2- Yl) carbonyl] -2- [2- (2-oxo-3H-1,2,
3,5-oxathiadiazol-4-yl) ethyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] -2- [2- (2-oxo-3H-1,2,2,
3,5-oxathiadiazol-4-yl) ethyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [ 5,4-c] pyridin-2-yl) carbonyl] -2- [2- (2-oxo-3H-1,2,2,
3,5-oxathiadiazol-4-yl) ethyl] piperazine

4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrooxazolo [5,4-c] pyridine-
2-yl) carbonyl] -2- [2- (2-oxo-3
H-1,2,3,5-oxathiadiazol-4-yl) ethyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- [2- (2,5-dihydro-5- Oxo-4
H-1,2,4-thiadiazol-3-yl) ethyl]
-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2- [2- (2,5-dihydro-5- Oxo-4H-
1,2,4-thiadiazol-3-yl) ethyl] -4
-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- [2- (2,5-dihydro-5-oxo-4
H-1,2,4-thiadiazol-3-yl) ethyl]
-1-[(5-methyl-4,5,6,7-tetrahydrooxaazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2- [2- (2,5-dihydro-5- Oxo-4H-
1,2,4-thiadiazol-3-yl) ethyl] -4
-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxaazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -2- [2- (2,5-dihydro-5
-Thioxo-4H-1,2,4-oxadiazole-3
-Yl) ethyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 2- [2- (2,5-dihydro-5-thioxo-4H-
1,2,4-oxadiazol-3-yl) ethyl]-
4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] Piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- [2- (2,5-dihydro-5-thioxo-
4H-1,2,4-oxadiazol-3-yl) ethyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxaazolo [5,4-c] pyridin-2-yl )
Carbonyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -2- [2- (2,5-dihydro-5-thioxo-
4H-1,2,4-oxadiazol-3-yl) ethyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxaazolo [5,4-c] pyridin-2-yl )
Carbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -2-[[N- (2-hydroxyethyl) carbamoyl] methyl] -4-[(5-methyl-4,5,6,
7-tetrahydrooxazolo [5,4-c] pyridine-
2-yl) carbonyl] piperazine

2-[[N, N-bis- (2-hydroxyethyl) carbamoyl] methyl] -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine 2-[[N, N-bis- (2-hydroxyethyl) carbamoyl] methyl] -4-[(5-chloroindol-2-yl) sulfonyl]- 1-[(5-methyl-4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[[N- (2- [Methoxyethyl) carbamoyl] methyl] -4-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[[N- (2-methoxyethyl) carbamoyl] methyl ] -4-[(5-methyl-4,5,6,7-
Tetrahydrooxazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 2-[[N, N-bis- (2-methoxyethyl) carbamoyl] methyl] -4-[(5-chloroindole-2
-Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

2-[[N, N-bis- (2-methoxyethyl) carbamoyl] methyl] -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4, 5,6,7-tetrahydrooxazolo [5,4
-C] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[[N- (2-hydroxyethyl) -N-
Methylcarbamoyl] methyl] -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[[N- (2-hydroxyethyl) -N-
Methylcarbamoyl] methyl] -1-[(5-methyl-
4,5,6,7-tetrahydrooxazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 2-[[N-benzyl-N- (2-hydroxyethyl) carbamoyl] methyl] -4-[(5-chloroindol-2-yl) sulfonyl] -1- [(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine 2-[[N-benzyl-N- (2-hydroxyethyl) carbamoyl] methyl] -4-[(5-chloroindol-2-yl) sulfonyl] -1- [(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine

4-[(5-Chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2 -[(N-cyanomethyl-N-methylcarbamoyl) methyl] -1-[(5-methyl-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2-[(N-cyanomethyl-N-methylcarbamoyl) methyl] -1-[(5-methyl-4,5,6 , 7
-Tetrahydrooxazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2- [2-[(morpholin-4-yl) carbonyl] ethyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- [2- (dimethylaminocarbonyl) Ethyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2- [2-[(pyrrolidine-1
-Yl) carbonyl] ethyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl) carbonyl] -2- [2-[(morpholin-4-yl) carbonyl] ethyl] piperazine 4-[(5-ethynylindol-2-yl) sulfonyl] -2- [2- (dimethylamino Carbonyl) ethyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-ethynylindole-2 -Yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- [2-[(pyrrolidin- - yl) carbonyl] ethyl] piperazine 2- (3-butynyl) -4 - [(5-chloro-indol-2-yl) sulfonyl] -4 - [(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

2- (3-butynyl) -4-[(5-chloroindol-2-yl) sulfonyl] -4-[(5-
Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chloro-3-hydroxybenzo [b] thien-2-yl) Sulfonyl] -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(6-chloro-3-hydroxybenzo [b] thien-2-yl) sulfonyl] -1- [ (5-methyl-
4,5,6,7-tetrahydrooxazolo [5,4-
c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(6-chloro-3-hydroxybenzo [b] thien-2-yl) sulfonyl] -1 -[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazine 4-[(6-chloro-3-hydroxybenzo [b] thien-2-yl) sulfonyl] -1-[(5 -Methyl-
4,5,6,7-tetrahydrooxazolo [5,4-
c] pyridin-2-yl) carbonyl] -2- (N, N
-Dimethylcarbamoylmethyl) piperazine

4-[(6-Chloro-3-hydroxybenzo [b] thien-2-yl) sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-(2-cyanoethyl) piperazine 4-[(6-chloro-3-hydroxybenzo [b] thien-2-yl) sulfonyl] -1-[(5-methyl-
4,5,6,7-tetrahydrooxazolo [5,4-
c] pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) piperazine 4-[(3-acetyl-6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-methyl- 4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholine-
4-ylcarbonyl) methyl] piperazine 4-[(3-acetyl-6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(3-acetyl-6-chlorobenzo [B] thien-2-yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazine

4-[(3-acetyl-6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-(N, N-dimethylcarbamoylmethyl) piperazine 4-[(3-acetyl-6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) piperazine 4-[(3-acetyl-6-chlorobenzo [b] thien-2 -Yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) piperazine 4-[(6-chloro-3- (hydroxymethyl) cibenzo [b ] Thien-2-yl) sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[(Morpholin-4-ylcarbonyl) methyl] piperazine 4-[(6-chloro-3- (hydroxymethyl) benzo [b] thien-2-yl) sulfonyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[(Morpholin-4-ylcarbonyl) methyl] piperazine

4-[(6-Chloro-3- (hydroxymethyl) benzo [b] thien-2-yl) sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazine 4- [ (6-Chloro-3- (hydroxymethyl) benzo [b] thien-2-yl) sulfonyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-(N, N-dimethylcarbamoylmethyl) piperazine 4-[(6-chloro-3- (hydroxymethyl) benzo [b] thien-2-yl) sulfonyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] -2- (2
-Cyanoethyl) piperazine 4-[(6-chloro-3- (hydroxymethyl) benzo [b] thien-2-yl) sulfonyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-(2-cyanoethyl) piperazine 4-[(6-chloro-3- (N, N-dimethylaminomethyl) benzo [b] thien-2-yl) sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine

4-[(6-Chloro-3- (N, N-dimethylaminomethyl) benzo [b] thien-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7 -Tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(6-chloro-3- (N, N-dimethyl) Aminomethyl) benzo [b] thien-2-yl) sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazine 4- [ (6-Chloro-3- (N, N-dimethylaminomethyl) benzo [b] thien-2-yl) sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazine 4- [ (6-Chloro-3- (N, N-dimethylaminomethyl) benzo [b] thien-2-yl) sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) piperazine 4-[(6-chloro -3- (N, N-dimethylaminomethyl) benzo [b] thien-2-yl) sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) piperazine

4-[(6-Chloro-3- (cyanomethyl) cybenzo [b] thien-2-yl) sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4 -[(6-Chloro-3- (cyanomethyl) benzo [b] thien-2-yl) sulfonyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[(Morpholin-4-ylcarbonyl) methyl] piperazine 4-[(6-chloro-3- (cyanomethyl) benzo [b] thien-2-yl) sulfonyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] -2-
(N, N-dimethylcarbamoylmethyl) piperazine 4-[(6-chloro-3- (cyanomethyl) benzo [b] thien-2-yl) sulfonyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-(N, N-dimethylcarbamoylmethyl) piperazine 4-[(6-chloro-3- (cyanomethyl) benzo [b] thien-2-yl) sulfonyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] -2- (2
-Cyanoethyl) piperazine

4-[(6-Chloro-3- (cyanomethyl) benzo [b] thien-2-yl) sulfonyl] -1
-[(5-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) piperazine 4-[(6-chloro- 3- (carbamoylmethyl) cybenzo [b] thien-2-yl) sulfonyl] -1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]-
2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(6-chloro-3- (carbamoylmethyl) benzo [b] thien-2-yl) sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[(Morpholin-4-ylcarbonyl) methyl] piperazine 4-[(6-chloro-3- (carbamoylmethyl) benzo [b] thien-2-yl) sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-(N, N-dimethylcarbamoylmethyl) piperazine 4-[(6-chloro-3- (carbamoylmethyl) benzo [b] thien-2-yl) sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-(N, N-dimethylcarbamoylmethyl) piperazine

4-[(6-Chloro-3- (carbamoylmethyl) benzo [b] thien-2-yl) sulfonyl]
-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) piperazine 4-[(6- Chloro-3- (carbamoylmethyl) benzo [b] thien-2-yl) sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-(2-cyanoethyl) piperazine 4-[(5-chloro-3-hydroxyindole-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholine-4
-Ylcarbonyl) methyl] piperazine 4-[(5-chloro-3-hydroxyindole-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholine-4-
Ylcarbonyl) methyl] piperazine 4-[(5-chloro-3-hydroxyindole-2-
Yl) sulfonyl] -1-[(5-hydroxymethyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine

1-[(5-Chloro-3-hydroxyindol-2-yl) sulfonyl] -4-[(5-hydroxymethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl) carbonyl] piperazine 4-[(5-chloro-3-hydroxyindole-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazine 4-[(5-chloro-3-hydroxyindole-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazine 4-[(5-chloro-3-hydroxyindole-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) piperazine 4-[(5-chloro-3-hydroxyindole-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (2-cyanoethyl)
Piperazine

4-[(3-acetyl-5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-
4,5,6,7-tetrahydrooxazolo [5,4-
c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(3-acetyl-5-chloroindol-2-yl) sulfonyl] -1-[(5 -Methyl-4,5,6
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(3-acetyl-5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4, 5,6
7-tetrahydrooxazolo [5,4-c] pyridine-
2-yl) carbonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazine 4-[(3-acetyl-5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5 , 6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazine 4-[(3-acetyl-5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5, 6,
7-tetrahydrooxazolo [5,4-c] pyridine-
2-yl) carbonyl] -2- (2-cyanoethyl) piperazine

4-[(3-acetyl-5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) piperazine 4-[(5-chloro-3- (hydroxymethyl) indol-2-yl) sulfonyl] -1-[(5-methyl-
4,5,6,7-tetrahydrooxazolo [5,4-
c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(5-chloro-3- (hydroxymethyl) indol-2-yl) sulfonyl] -1- [(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(5-chloro-3- (hydroxymethyl) indol-2-yl) sulfonyl] -1-[( 5-methyl-
4,5,6,7-tetrahydrooxazolo [5,4-
c] pyridin-2-yl) carbonyl] -2- (N, N
-Dimethylcarbamoylmethyl) piperazine 4-[(5-chloro-3- (hydroxymethyl) indol-2-yl) sulfonyl] -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazine

4-[(5-Chloro-3- (hydroxymethyl) indol-2-yl) sulfonyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl]
-2- (2-cyanoethyl) piperazine 4-[(5-chloro-3- (hydroxymethyl) indol-2-yl) sulfonyl] -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) piperazine 4-[(5-chloro-3- (N, N-dimethylaminomethyl) indol-2-yl) sulfonyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl]
-2-[(morpholin-4-ylcarbonyl) methyl]
Piperazine 4-[(5-chloro-3- (N, N-dimethylaminomethyl) indol-2-yl) sulfonyl] -1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]-
2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(5-chloro-3- (N, N-dimethylaminomethyl) indol-2-yl) sulfonyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl]
-2- (N, N-dimethylcarbamoylmethyl) piperazine

4-[(5-chloro-3- (N, N-dimethylaminomethyl) indol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazine 4-[(5-chloro-3- (N, N-dimethylaminomethyl) indole-2 -Yl) sulfonyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl]
-2- (2-cyanoethyl) piperazine 4-[(5-chloro-3- (N, N-dimethylaminomethyl) indol-2-yl) sulfonyl] -1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]-
2- (2-cyanoethyl) piperazine 4-[(5-chloro-3- (cyanomethyl) indol-2-yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(5-chloro-3- ( Cyanomethyl) indol-2-yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholine-
4-ylcarbonyl) methyl] piperazine

4-[(5-chloro-3- (cyanomethyl) indol-2-yl) sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-(N, N-dimethylcarbamoylmethyl) piperazine 4-[(5-chloro-3- (cyanomethyl) indol-2-yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazine 4-[(5-chloro-3- (cyanomethyl) Indole-2-yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) piperazine 4-[(5-chloro-3- (cyanomethyl) indole-2- Yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) piperazine 4-[(5-chloro-3- (carbamoylmethyl) indole-2 -Yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-
c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-ylcarbonyl) methyl] piperazine

4-[(5-Chloro-3- (carbamoylmethyl) indol-2-yl) sulfonyl] -1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]-
2-[(morpholin-4-ylcarbonyl) methyl] piperazine 4-[(5-chloro-3- (carbamoylmethyl) indol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6 , 7-Tetrahydrooxazolo [5,4-
c] pyridin-2-yl) carbonyl] -2- (N, N
-Dimethylcarbamoylmethyl) piperazine 4-[(5-chloro-3- (carbamoylmethyl) indol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-
c] pyridin-2-yl) carbonyl] -2- (N, N
-Dimethylcarbamoylmethyl) piperazine 4-[(5-chloro-3- (carbamoylmethyl) indol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5 , 4-
c] pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) piperazine 4-[(5-chloro-3- (carbamoylmethyl) indol-2-yl) sulfonyl] -1-[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] -2- (2-cyanoethyl) piperazine

4-[(5-Chloro-1-hydroxyindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 4-[(5-chloro-1-hydroxyindole-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholine-4
-Yl) carbonylmethyl] piperazine 4-[(5-chloro-1-methoxyindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 4-[(5-chloro-1-methoxyindol-2-yl) sulfonyl] -1-[(5-methyl-4, 5,6
7-tetrahydrooxazolo [5,4-c] pyridine-
2-yl) carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 4- [4-[(6-chloro-1-hydroxyindol-2-yl) sulfonyl] -1-[(5- Methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholine-
4-yl) carbonylmethyl] piperazine

4- [4-[(6-Chloro-1-hydroxyindol-2-yl) sulfonyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2
-[(Morpholin-4-yl) carbonylmethyl] piperazine 4- [4-[(6-chloro-1-methoxyindole-
2-yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholine-
4-yl) carbonylmethyl] piperazine 4- [4-[(6-chloro-1-methoxyindole-
2-yl) sulfonyl] -1-[(5-methyl-4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[(morpholin-4-yl) carbonylmethyl] piperazine 1-[(6-chloro-1-hydroxy Indole-2-
Yl) sulfonyl] -4-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-chloro-1-hydroxyindole-2-
Yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine

1-[(6-Chloro-1-hydroxyindol-2-yl) sulfonyl] -4-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4
5-d] pyridazin-2-yl) carbonyl] piperazine 1-[(6-chloro-1-hydroxyindole-2-
Yl) sulfonyl] -4-[(5,6-dimethyl-4,
5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 1-[(6-chloro-1-hydroxyindole-2-
Yl) sulfonyl] -4-[(6-hydroxy-4,
5,6,7-tetrahydrobenzo [d] thiazole-2
-Yl) carbonyl] piperazine 1-[(6-chloro-1-hydroxyindole-2-
Yl) sulfonyl] -4-[(6,7-dihydro-4H
-Pyrano [4,3-d] thiazol-2-yl) carbonyl] piperazine 1-[(6-chloro-1-hydroxyindole-2-
Yl) sulfonyl] -4-[(thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine

2-[[4-[(6-Chloro-1-hydroxyindol-2-yl) sulfonyl] piperazine-
1-yl] carbonyl] thieno [3,2-b] pyridine N-oxide 1-[(6-chloro-1-hydroxyindole-2-
Yl) sulfonyl] -4-[(oxazolo [4,5-
b] pyridin-2-yl) carbonyl] piperazine 2-[[4-[(6-chloro-1-hydroxyindol-2-yl) sulfonyl] piperazin-1-yl] carbonyl] oxazolo [4,5-b] pyridine N-oxide 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(oxazolo [4,5-b] pyridine-2
-Yl) carbonyl] piperazine 2-[[4-[(5-chloroindol-2-yl) sulfonyl] piperazin-1-yl] carbonyl] oxazolo [4,5-b] pyridine N-oxide

1-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -4-[(oxazolo [4,5
-B] pyridin-2-yl) carbonyl] piperazine 2-[[4-[(6-chlorobenzo [b] thien-2-
Yl) sulfonyl] piperazin-1-yl] carbonyl] oxazolo [4,5-b] pyridine N-oxide 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(oxazolo [4,5- b] pyridine-2
-Yl) carbonyl] piperazine 2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] oxazolo [4,5-b] pyridine N-oxide 1-[(5 -Bromoindol-2-yl) sulfonyl] -4-[(oxazolo [4,5-b] pyridine-2
-Yl) carbonyl] piperazine

2-[[4-[(5-bromoindole-
2-yl) sulfonyl] piperazin-1-yl] carbonyl] oxazolo [4,5-b] pyridine N-oxide 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(oxazolo [4 5-b] pyridine-2
-Yl) carbonyl] piperazine 2-[[4-[(5-ethynylindol-2-yl)
Sulfonyl] piperazin-1-yl] carbonyl] oxazolo [4,5-b] pyridine N-oxide 4-[(5-chloroindol-2-yl) sulfonyl] -2- (N, N-dimethylcarbamoylmethyl)-
1-[(oxazolo [4,5-b] pyridin-2-yl) carbonyl] piperazine 2-[[4-[(5-chloroindol-2-yl) sulfonyl] -2- (N, N-dimethylcarbamoyl Methyl) piperazin-1-yl] carbonyl] oxazolo [4,5-b] pyridine N-oxide

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2- (N, N-dimethylcarbamoylmethyl) -1-[(oxazolo [4,5-b]
Pyridin-2-yl) carbonyl] piperazine 2-[[4-[(6-chlorobenzo [b] thien-2-
Yl) sulfonyl] -2- (N, N-dimethylcarbamoylmethyl) piperazin-1-yl] carbonyl] oxazolo [4,5-b] pyridine N-oxide 2- (N, N-dimethylcarbamoylmethyl) -4-
[(5-ethynylindol-2-yl) sulfonyl]
-1-[(oxazolo [4,5-b] pyridin-2-yl) carbonyl] piperazine 2-[[2- (N, N-dimethylcarbamoylmethyl)
-4-[(5-Ethynylindol-2-yl) sulfonyl] piperazin-1-yl] carbonyl] oxazolo [4,5-b] pyridine N-oxide 4-[(6-chlorobenzo [b] thien-2- Yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl)
Methyl] -1-[(6-hydroxy-4,5,6,7-
Tetrahydrobenzo [d] thiazol-2-yl) carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5,6-dimethyl-4,
5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -2- [2- (imidazol-1-yl) ethyl] piperazine 4-[(6-chlorobenzo [b] Thien-2-yl) sulfonyl] -1-[(5,6-dimethyl-4,5,6,
7-tetrahydrothiazolo [4,5-d] pyridazine-
2-yl) carbonyl] -2- [2- (imidazole-
1-yl) ethyl] piperazine 4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d ] Pyridazin-2-yl) carbonyl] -2- [2- (imidazol-1-yl) ethyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(6,7-dihydro -4H-pyrano [4,
3-d] thiazol-2-yl) carbonyl] -2-
(Methylcarbamoyl) piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4,3-d] thiazol-2-yl) Carbonyl]-
2- (methylcarbamoyl) piperazine

4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-
Pyrano [4,3-d] thiazol-2-yl) carbonyl] -2- (methylcarbamoyl) piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(6,7-dihydro- 4H-pyrano [4
3-d] thiazol-2-yl) carbonyl] -2-
(2-morpholinoethyl) piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4
3-d] thiazol-2-yl) carbonyl] -2-
[2- (Imidazol-1-yl) ethyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4,3- d] thiazol-2-yl) carbonyl]-
2- [2- (imidazol-1-yl) ethyl] piperazine 4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4
3-d] thiazol-2-yl) carbonyl] -2-
[2- (Imidazol-1-yl) ethyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-
Pyrano [4,3-d] thiazol-2-yl) carbonyl] -2- [2- (1H-1,2,4-triazole-
1-yl) ethyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4,3-d] thiazole-2- Yl) carbonyl]-
2- [2- (1H-1,2,4-triazol-1-yl) ethyl] piperazine 4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(6,7-dihydro-4H -Pyrano [4,
3-d] thiazol-2-yl) carbonyl] -2-
[2- (1H-1,2,4-triazol-1-yl)
Ethyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4
3-d] thiazol-2-yl) carbonyl] -2-
[2- (1H-1,2,3,4-tetrazol-1-yl) ethyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(6,7- Dihydro-4H-pyrano [4,3-d] thiazol-2-yl) carbonyl]-
2- [2- (1H-1,2,3,4-tetrazole-1
-Yl) ethyl] piperazine

4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-
Pyrano [4,3-d] thiazol-2-yl) carbonyl] -2- [2- (1H-1,2,3,4-tetrazol-1-yl) ethyl] piperazine 4-[(5-chloroindole -2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4
3-d] thiazol-2-yl) carbonyl] -2-
[2- (2H-1,2,3,4-tetrazol-2-yl) ethyl] piperazine 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(6,7- Dihydro-4H-pyrano [4,3-d] thiazol-2-yl) carbonyl]-
2- [2- (2H-1,2,3,4-tetrazole-2
-Yl) ethyl] piperazine 4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4
3-d] thiazol-2-yl) carbonyl] -2-
[2- (2H-1,2,3,4-tetrazol-2-yl) ethyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1- [ (6,7-dihydro-4H-pyrano [4,3-d] thiazole-2-
Yl) carbonyl] piperazine

4-[(5-chloroindol-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-
Pyrano [4,3-d] thiazol-2-yl) carbonyl] -2- [2- (2H-1,2,3,4-tetrazol-5-yl) ethyl] piperazine 1-[(6-chlorobenzo [ b] thien-2-yl) sulfonyl] -4-[(thieno [3,2-b] pyridine-
2-yl) carbonyl] piperazine 2- [4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazin-1-yl] carbonyl]
Thieno [3,2-b] pyridine N-oxide 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 2 -[4-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] thieno [3,2-b] pyridine N-oxide

1-[(6-ethynylindol-2-yl) sulfonyl] -4-[(thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 2- [4-[(6-ethynyl) Indole-2-yl) sulfonyl] piperazin-1-yl] carbonyl] thieno [3,2-b] pyridine N-oxide 1-[(6-ethynylbenzo [b] thien-2-yl)
Sulfonyl] -4-[(thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 2- [4-[(6-ethynylbenzo [b] thien-2-
Yl) sulfonyl] piperazin-1-yl] carbonyl] thieno [3,2-b] pyridine N-oxide 1-[(6-ethynylnaphthalen-2-yl) sulfonyl] -4-[(thieno [3,2- b] pyridin-2-yl) carbonyl] piperazine

2- [4-[(6-ethynylnaphthalene-
2-yl) sulfonyl] piperazin-1-yl] carbonyl] thieno [3,2-b] pyridine N-oxide 4-[(6-chlorindol-2-yl) sulfonyl] -2- (N, N-dimethyl Carbamoyl) methyl-
1-[(thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 2- [4-[(6-chlorindol-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl ) Methyl] piperazin-1-yl] carbonyl] thieno [3,2-b] pyridine N-oxide 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (N, N-dimethyl Carbamoyl) methyl-1-[(thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 2- [4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- [ (N, N-dimethylcarbamoyl) methyl] piperazin-1-yl] carbonyl] thieno [3,2-b] pyridine N-oxide

4-[(6-Chlornaphthalen-2-yl) sulfonyl] -2- (N, N-dimethylcarbamoyl) methyl-1-[(thieno [3,2-b] pyridine-
2-yl) carbonyl] piperazine 2- [4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] piperazin-1-yl] carbonyl] thieno [3 , 2-b] pyridine N-oxide 4-[(6-chlorindol-2-yl) sulfonyl] -2-[(pyrrolidin-1-yl) carbonylmethyl] -1-[(thieno [3,2-b ] Pyridin-2-yl) carbonyl] piperazine 2- [4-[(6-chlorindol-2-yl) sulfonyl] -2-[(pyrrolidin-1-yl) carbonylmethyl] piperazin-1-yl] carbonyl] Thieno [3,2-b] pyridine N-oxide 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-[(pyrrolidin-1-yl) ca Bonirumechiru] -1 - [(thieno [3,2-b] pyridine -
2-yl) carbonyl] piperazine

2- [4-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -2-[(pyrrolidine-
1-yl) carbonylmethyl] piperazin-1-yl]
Carbonyl] thieno [3,2-b] pyridine N-oxide 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-[(pyrrolidin-1-yl) carbonylmethyl] -1-[(thieno [ 3,2-b] pyridin-2-yl) carbonyl] piperazine 2- [4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-[(pyrrolidin-1-yl) carbonylmethyl] piperazine-1 -Yl] carbonyl] thieno [3,2-b] pyridine N-oxide 4-[(6-chlorindol-2-yl) sulfonyl] -2- (2-hydroxyethyl) -1-[(thieno [3 2-b] pyridin-2-yl) carbonyl] piperazine 2- [4-[(6-chlorindol-2-yl) sulfonyl] -2- (2-hydroxyethyl) piperazine-
1-yl] carbonyl] thieno [3,2-b] pyridine N-oxide

4-[(6-Chlorobenzo [b] thiene-
2-yl) sulfonyl] -2- (2-hydroxyethyl) -1-[(thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 2- [4-[(6-chlorobenzo [b] Thien-2-yl) sulfonyl] -2- (2-hydroxyethyl) piperazin-1-yl] carbonyl] thieno [3,2-b]
Pyridine N-oxide 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2- (2-hydroxyethyl) -1-[(thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 2- [4-[(6-chloronaphthalen-2-yl) sulfonyl] -2- (2-hydroxyethyl) piperazine-
1-yl] carbonyl] thieno [3,2-b] pyridine N-oxide 4-[(6-chloroindol-2-yl) sulfonyl] -2- (2-hydroxymethyl) -1-[(thieno [3 , 2-b] pyridin-2-yl) carbonyl] piperazine

2- [4-[(6-Chlorindole-2
-Yl) sulfonyl] -2- (2-hydroxymethyl)
Piperazin-1-yl] carbonyl] thieno [3,2-
b] pyridine N-oxide 4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (2-hydroxymethyl) -1-
[(Thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 2- [4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (2-hydroxymethyl) piperazine -1-yl] carbonyl] thieno [3,2-b]
Pyridine N-oxide 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2- (2-hydroxymethyl) -1-[(thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine 2- [4-[(6-chloronaphthalen-2-yl) sulfonyl] -2- (2-hydroxymethyl) piperazine-
1-yl] carbonyl] thieno [3,2-b] pyridine N-oxide

1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(6,7-dihydro-4-H
-Pyrano [3,4-d] imidazolo-2-yl) carbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(6,7-dihydro-4-H-pyrano [ 4,3-d] Imidazolo-2-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(6,7-dihydro-4-H-pyrano [ 3,4-d] Imidazolo-2-yl) carbonyl]
Piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(6,7-dihydro-4-H-pyrano [4,3-d] imidazolo-2-yl) carbonyl]
Piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6,7-dihydro-4-H-pyrano [3,4-d] imidazolo-2-yl) carbonyl] piperazine

1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(6,7-dihydro-4-H
-Pyrano [4,3-d] imidazolo-2-yl) carbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(4-oxo-3,4-dihydrothieno [3, 2-d] pyrimidin-2-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(4-oxo-3,4-dihydrothieno [3,2- d] pyrimidin-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4-oxo-3,4-dihydrothieno [3,2-d] pyrimidin-2 -Yl) carbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(2,3, -dihydro-1-H-thieno [2,3-b] [1,4] Oxazi N-6-yl) carbonyl] piperazine

1-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -4-[(2,3, -dihydro-1-H-thieno [2,3-b] [1,4] oxazin-6-yl) carbonyl] piperazine 1-[(6- Chloronaphthalen-2-yl) sulfonyl] -4-[(2,3, -dihydro-1-H-thieno [2,3-b] [1,4] oxazin-6-yl) carbonyl] piperazine 1- [ (5-Chloroindol-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [4,5-b] pyridin-2-yl) carbonyl] piperazine 1-[(6- Chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [4,5-b] pyridin-2-yl) carbonyl] piperazine 1-[(6- Chloronaphthalen-2-yl) sulfonyl ] -4-[(4,5,6,7-tetrahydrothiazolo [4,5-b] pyridin-2-yl) carbonyl] piperazine

1-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -4-[(5,6-dimethyl-
4,5,6,7-tetrahydrooxazolo [4,5-
d] pyridazin-2-yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo [4 , 5-d] pyridazine-2-
Yl) carbonyl] piperazine 1-[(5-bromoindol-2-yl) sulfonyl] -4-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazine -2-
Yl) carbonyl] piperazine 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazine -2-
Yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (N, N-dimethylcarbamoylmethyl)-
1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl)
Carbonyl] piperazine

4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2- (N, N-dimethylcarbamoylmethyl) -1-[(5,6-dimethyl-4,
5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 2- (N, N-dimethylcarbamoylmethyl) -4-
[(5-ethynylindol-2-yl) sulfonyl]
-1-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [b] thien- 2-yl) sulfonyl] -1-[(5,6-dimethyl-4,5,
6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl] -2- [2- (tetrazol-1-yl) ethyl] piperazine 4-[(6-chlorobenzo [b] thien- 2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(5
6-dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazin-2-yl) carbonyl
Piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[[6- (pyrrolidin-1-yl) -4,
5,6,7-tetrahydrobenzo [d] thiazole-2
-Yl] carbonyl] piperazine

1-[(6-Amino-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazine 1 -[(5-chloroindol-2-yl) sulfonyl] -1-[(6-N-formylamino-4,5,6,
7-tetrahydrobenzo [d] thiazol-2-yl)
Carbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -1-[(6-sulfonamido-4,5,6,7-
Tetrahydrobenzo [d] thiazol-2-yl) carbonyl] piperazine

In the present invention, not only the above compounds but also salts of the above compounds and solvates thereof can be mentioned as preferable ones.

The method for producing the compound (sulfonyl derivative) represented by the general formula (I) of the present invention will be described below.

The compound of the present invention represented by the general formula (I),
The salts and their solvates can be produced by a combination of known general chemical production methods. Representative synthetic methods are described below.

In the synthesis of the sulfonyl derivative of the present invention, when it is necessary to protect a substituent such as a nitrogen atom, a hydroxyl group, a carboxyl group, etc., it is generally known that the substituent can be removed when necessary. These protective groups may be protected when necessary by a general organic chemistry method shown in the following production method. In addition, raw materials necessary for synthesizing the sulfonyl derivative of the present invention can be obtained by a general synthesis method of organic chemistry, and typical production methods of the raw materials are shown in Reference Examples. Further, the raw material of the sulfonyl derivative of the present invention can be synthesized by applying the method exemplified in Reference Example.

The following describes the protecting groups for the substituent such as a nitrogen atom, a hydroxyl group and a carboxyl group and the method for deprotection.

Examples of a suitable protecting group for a nitrogen atom in an amino group or an alkylamino group include a common acyl-type protecting group,
That is, an alkanoyl group such as an acetyl group, or an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a tertiary butoxycarbonyl group, or a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, a para (ortho) nitrobenzyloxycarbonyl Suitable are arylmethoxycarbonyl, benzyl, arylmethyl such as triphenylmethyl or aroyl such as benzoyl. The method of deprotection of these protecting groups depends on the chemical properties of the protecting groups employed. For example, in acyl-type protecting groups such as alkanoyl, alkoxycarbonyl or aroyl, lithium hydroxide, sodium hydroxide or It can be hydrolyzed and deprotected by using a suitable base such as an alkali metal hydroxide such as potassium hydroxide.

A substituted methoxycarbonyl-type protecting group such as a tertiary butoxycarbonyl group or a paramethoxybenzyloxycarbonyl group may be a suitable acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid , Trifluoromethanesulfonic acid or a combination of these acids. Further, arylmethoxycarbonyl groups such as benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group and para (ortho) nitrobenzyloxycarbonyl group and arylmethyl groups such as benzyl group are removed by hydrogenolysis using a palladium carbon catalyst. be able to. The benzyl group can be converted to a nitrogen-hydrogen bond by removing the benzyl group by birch reduction using sodium metal in liquid ammonia. The triphenylmethyl group can be removed by a suitable acid such as formic acid, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids. In addition, it can be removed by birch reduction using metallic sodium in liquid ammonia, and can also be removed by hydrogenolysis using a palladium carbon catalyst.

As the other amino-protecting group, a primary amino group can be protected as a phthaloyl group.
It can be removed with hydrazine, dimethylaminopropylamine and the like. The nitrogen atom of indole can be protected with a phenylsulfonyl group, a toluenesulfonyl group, an acetyl group, a trifluoroacetyl group or the like, and a suitable one such as an alkali metal hydroxide such as sodium hydroxide, lithium hydroxide or potassium hydroxide. By using a suitable base, it can be hydrolyzed and deprotected.

Suitable protective groups for hydroxyl groups include acyl-type protective groups and ether-type protective groups. Suitable acyl-type protecting groups are alkanoyl groups such as acetyl group and aroyl groups such as benzoyl group, and ether-type protecting groups are arylmethyl groups such as benzyl group and silyl ether groups such as tert-butyldimethylsilyl group. Methoxymethyl group, tetrahydropyranyl group and the like. Removal of these protecting groups will depend on the chemical nature of the protecting group employed. For example, acyl groups such as alkanoyl and aroyl groups can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide. The arylmethyl-type protecting group can be removed by hydrogenolysis using a palladium carbon catalyst, and a silyl group such as a tertiary butyldimethylsilyl group can be removed by a hydrofluoride such as tetrabutylammonium fluoride. Further, a methoxymethyl group, a tetrahydropyranyl group and the like can be removed with acetic acid, hydrochloric acid or the like. The hydroxyl group substituted by an aryl group can be protected by a methyl group and can be removed by a Lewis acid such as aluminum chloride, boron tribromide, phosphorus tribromide, trimethylsilyl iodide, hydrogen bromide, or the like.

The carboxyl group can be protected by esterification. Methyl and ethyl esters are hydrolyzed with an appropriate base such as lithium hydroxide, sodium hydroxide and alkali metal hydroxide such as potassium hydroxide, and tertiary butyl esters are treated with trifluoroacetic acid or hydrochloric acid. The tertiary butyl group can be removed. In the case of an arylmethyl group type ester such as a benzyl group, the arylmethyl group can be removed by hydrogenolysis using a palladium carbon catalyst.

As the protecting group for acetylene, an alkylsilyl group such as a trimethylsilyl group, a tert-butyldimethylsilyl group, and a tert-butyldiphenylsilyl group can be used. Deprotection can be carried out using a suitable base such as an alkali metal oxide or a hydrofluoric acid such as tetrabutylammonium fluoride or hydrogen fluoride pyridine.

[Production method-1] Compound represented by general formula (Ia) Q ¹ -Q ² -T ¹ -Q ^3a (Ia) wherein Q ¹ , Q ² and T ¹ are the same as above. Q ^3a means any of the following groups.

[0453]

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(In the group, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , a, b, c, d, e, f,
g, h and i are the same as above. )] ^Wherein the nitrogen atom of Q ^3a is a sulfonic acid halide represented by the general formula (IIa): Halo-SO ₂ -Q ^A (IIa) wherein Q ^A is the same as defined above. Halo is chlorine, bromine,
It means a halogen atom such as iodine. To obtain a sulfonyl derivative represented by the general formula (I): Q ¹ -Q ² -T ¹ -Q ³ -SO ₂ -Q ^A (I) wherein Q ¹ , Q ² , Q ³ , Q ^A and T ¹ are the same as above. ].

<Synthesis of Compound Represented by General Formula (Ia)> The compound represented by the general formula (Ia) can be synthesized by a series of operations according to known techniques.

For example, a compound represented by the general formula (IIIa) Q ^3b -H (IIIa) [Q ^3b means any of the following groups, which can be synthesized by a known method or by applying a known method.

[0457]

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(R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , a, b, c, d, e, f,
g, h and i are the same as above. R ²¹ represents a general nitrogen protecting group such as a tertiary butoxycarbonyl group, a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, a paranitrobenzyloxycarbonyl group, and a benzyl group. )], An activated carboxylic acid Q ¹ -Q ^2b -COOH (IVa) represented by the following general formulas (IVa) to (IVd), wherein a nitrogen atom to which a hydrogen atom of Q ^3b is bonded can be synthesized by a known technique. ^{) Q 1 -N (R 20)} - (CH 2) m1-COOH (IVb) Q 1 -O- (CH 2) m1-COOH (IVc) Q 1 -S- (CH 2) m1-COOH (IVd) [In the above formula, Q ¹ is the same as above. R ²⁰ represents a linear or branched alkylalkylene group or a general nitrogen protecting group such as a tertiary butoxycarbonyl group, a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, a paranitrobenzyloxycarbonyl group, or a benzyl group. means. Q ^2b is a single bond, linear or branched carbon number 1
To 6 alkylene groups, linear or branched carbon number 2
To 6 alkenylene groups, linear or branched alkynylene groups having 2 to 6 carbon atoms, or

[0459]

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(This group has the same meaning as described above.) m1 represents an integer of 1 to 6. ] The general formula acylated (Ib) compounds ^{Q 1 -Q 2 -T 1 -Q 3b} (Ib) [ wherein represented ^{by, Q 1, Q 2, Q} 3b and T ¹ are as defined above. ] Can be synthesized.

[0461] Further, Q ^3b when the nitrogen atom of Q ^3b of the compound represented by the general formula (IIIa) is a nitrogen atom to form an amide bond, the compound represented by the general formula (IIIa)
Is converted to a compound represented by the following general formulas (Va) to (Vd): Q ¹ -Q ^2b -CHL ¹ R ¹³ (Va) Q ¹ -N (R ²⁰ )-(CH ₂ ) m ¹ -CHL ¹ in ^{R 13 (Vb) Q 1 -O-} (CH 2) m1-CHL 1 R 13 (Vc) Q 1 -S- (CH 2) m1-CHL 1 R 13 (Vd) [ the above equation, Q ^1, Q ^2b , R ¹³ , R ²⁰ and m1 are the same as described above. L ¹ means a leaving group frequently used in organic chemistry such as chlorine, bromine, iodine, a methylsulfonyloxy group, and a paratoluenesulfonyloxy group. ], The compounds represented by the general formula (Ib) can be synthesized.

When the nitrogen atom of Q ^3b of the compound represented by the general formula (IIIa) is a primary or secondary amine, a carbonyl compound Q ^1- represented by the following general formulas (VIa) to (VId) ^{Q 2b -C (= O) R} 13 (VIa) Q 1 -N (R 20) - (CH 2) m1-C (= O) R 13 (VIb) Q 1 -O- (CH 2) m1-C (= O) R ¹³ (VIc) Q ¹ -S- (CH ₂ ) m 1 -C (ＲO) R ¹³ (VId) wherein Q ¹ , Q ^2b , R ¹³ , R ²⁰ and m 1 are Same as And a reductive alkylation reaction for forming and reducing an imine, a compound represented by the general formula (IIIa) and a reagent such as phosgene, triphosgene, 1,1′-carbonyldiimidazole, and the following which can be synthesized by application of known techniques: Compounds having a primary amine represented by the general formulas (VIIa) to (VIId) or a secondary amine represented by the general formula (VIIe) Q ¹ -Q ^2b -NH ₂ (VIIa) Q ¹ -N (R ²⁰ )-(CH _{2) m2-NH 2 (VIIb} ) Q 1 -O- (CH 2) m2-NH 2 (VIIc) Q 1 -S- (CH 2) m2-NH 2 (VIId)

[0463]

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[In the above formula, Q ¹ , Q ^2b and R ²⁰ are the same as above. m2 represents an integer of 2 to 6. Base

[0465]

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Represents a 5- or 6-membered heterocyclic group which may have a substituent. )] To form a urea derivative, or an isocyanate derivative or an isocyanate formed from a carboxylic acid represented by any of formulas (IVa) to (IVd) to an amine represented by formula (IIIa) The general formula (I)
The compounds represented by b) can be produced.

In the compound represented by formula (Ib), the structure of Q ¹ has a halogen atom or an aryl group substituted with a trifluoromethanesulfonyloxy group, or a halogen atom or an alkenyl group substituted with a trifluoromethanesulfonyloxy group. In this case, a coupling reaction can be performed with an aryl compound substituted with a boric acid group using a transition metal catalyst.

If an alkenyl group or an alkenyl group substituted with a boric acid group is present in the structure of Q ¹ of the compound represented by the formula (Ib), a halogen atom or a trifluoromethanesulfonyloxy group is substituted with a transition metal catalyst. It is possible to couple with an aryl group.

Similarly, when the compound represented by the formula (Ib) has an aryl group substituted with a boric acid group in the structure of Q ¹ , the aryl compound substituted with a halogen atom or a trifluoromethanesulfonyloxy group or a halogen atom or it can be substituted alkenyl compound a coupling reaction of a trifluoromethanesulfonyloxy group, a substituted aryl group a halogen atom or a trifluoromethanesulfonyloxy group in the structure for Q ¹ of the compound represented by the general formula (Ib) If so, the alkenyl compound can be coupled with a transition metal catalyst to obtain compounds represented by the general formula (Ib).
The compound represented by the general formula (Ib) thus obtained can be deprotected if necessary when the nitrogen atom of Q ^3b is protected, so that the compound represented by the general formula (Ia) can be obtained. can get.

For example, as an appropriate activated product of the carboxylic acids represented by the general formulas (IVa) to (IVd), the carboxylic acids represented by the general formulas (IVa) to (IVd) Mixed acid anhydride, such as obtained by reacting with formic acid ester to obtain an anhydride,
Activated esters obtained by reacting with acid halides such as acyl chlorides prepared using acid halides such as thionyl chloride, phenols such as paranitrophenol, pentafluorophenyl-trifluoroacetate, etc. -Hydroxybenztriazole or an active ester obtained by reacting with N-hydroxysuccinimide, usually 1-benzotriazolyloxy- (pyrrolidino) -phosphonium hexafluorophosphite as used for peptide synthesis of amino acids;
N, N'-dicyclohexylcarbodiimide or N
Reaction product with-(3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, reaction product with diethyl cyanophosphonate (salting method), triphenylphosphine and 2,2'-dipyridyl disulfide Reaction products (Mukoyama method).

The activated product of the carboxylic acid thus obtained and the compound represented by the general formula (IIIa) or a salt thereof are usually added to an inert solvent in the presence of a suitable base at 78 ° C. to 150 ° C. under zero temperature. To give a compound represented by the general formula (Ib).

Specific bases include, for example, alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride. Organic metal bases represented by carbonates, alkoxides, hydroxides or hydrides, alkyllithiums such as n-butyllithium, dialkylaminolithiums such as lithium diisopropylamide, lithium bis (trimethylsilyl) amides Organic metal bases of bissilylamine, or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine,
Diisopropylethylamine, diazabicyclo [5.
4.0] organic bases such as undec-7-ene (DBU).

As an inert solvent, dichloromethane,
Alkyl halide solvents such as chloroform and carbon tetrachloride; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane; aromatic solvents such as benzene and toluene; N, N-dimethylformamide; Amide-based solvents such as dimethylacetamide and N-methylpyrrolidin-2-one; and in addition to these, if appropriate, sulfoxide-based solvents such as dimethylsulfoxide and sulfolane; and ketone-based solvents such as acetone and methylethylketone. it can.

The Q of the compound represented by the formula (IIIa)
^When the nitrogen atom of ^{3b is} a nitrogen atom forming an amide bond, the compound represented by any of formulas (Va) to (Vd) and an appropriate base are used in an inert solvent in an inert solvent at a temperature of 78 ° C to 150 ° C under zero.
To alkylate the nitrogen atom and obtain a compound of the general formula (I
The compound represented by b) can be obtained. Specific bases include, for example, alkoxides of alkali metals or alkaline earth metals such as sodium ethoxide, potassium butoxide, sodium hydride, potassium hydride, or hydrides, or alkyllithiums such as n-butyllithium, Organometallic bases typified by dialkylaminolithiums such as lithium diisopropylamide, bissilylamines such as lithium bis (trimethylsilyl) amide, or diazabicyclo [5.4.0] undec-7-ene (DBU) )) And the like.

As the inert solvent, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, and amide solvents such as N, N-dimethylformamide are preferable.

For example, when the nitrogen atom of Q ^3b of the compound represented by the formula (IIIa) is a primary or secondary amine, it is usually in an inert solvent, if necessary, an organic acid such as acetic acid, hydrochloric acid or the like. In the presence of a mineral acid or a Lewis acid such as aluminum chloride at a temperature of 20 ° C. to 150 ° C. under zero temperature.
Forming an imine with the carbonyl compounds represented by Ia) to (VId), and forming the imine in an inert solvent in a borohydride reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride; Alternatively, the compound represented by the general formula (Ib) can be obtained by hydrogenating at 10 ° C. to 110 ° C. with a catalytic reduction catalyst such as a palladium carbon catalyst.

Examples of the inert solvent include halogenated carbons such as dichloromethane, chloroform and carbon tetrachloride; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane; benzene solvents such as toluene;
Amide solvents such as N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidin-2-one are preferred.

The Q of the compound represented by the formula (IIIa)
^When the nitrogen atom of ^3b is a primary or secondary amine, a compound having a primary amine represented by the general formulas (VIIa) to (VIId) or a secondary amine represented by the general formula (VIIe) and phosgene, triphosgene or 1, Urea derivatives can be derived using reactants of reagents such as 1'-carbonyldiimidazole. The reaction is carried out using a reagent such as phosgene, triphosgene, 1,1'-carbonyldiimidazole, a primary amine represented by the general formulas (VIIa) to (VIId) or a secondary amine represented by the general formula (VIIe) and a general formula (IIIa). The urea derivative can be synthesized by reacting the compound of the above formula in an inert solvent in the presence of a base, if necessary.

Examples of the inert solvent include halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and the like.
Ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane; benzene solvents such as toluene; amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidin-2-one Can be mentioned. Preferred are dichloromethane, tetrahitrofuran and toluene.

As the base, for example, sodium carbonate,
Potassium carbonate, sodium hydroxide, alkali metal or alkaline earth metal carbonates such as potassium hydroxide,
Hydroxide or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,
N-methylmorpholine, diisopropylethylamine,
Diazabicyclo [5.4.0] undec-7-ene (D
Organic bases such as BU). The reaction may be carried out at a temperature of 70 ° C to 110 ° C below zero.

The Q of the compound represented by the formula (IIIa)
^When the nitrogen atom of ^3b is a primary or secondary amine, the compound represented by the general formula (Ib) is
It can also be obtained by reacting the compound represented by Ia) with an isocyanate derivative in an inert solvent at a temperature of 20 ° C to 100 ° C under zero.

The isocyanate derivative has the general formula (IV)
a) carboxylic acid represented by a) in an inert solvent such as tetrahydrofuran, chloroform or toluene at a temperature of 20 ° C.
From 110 ° C. to an acid halide with an acid halide such as thionyl chloride or oxalyl chloride, and then reacted with sodium azide in an inert solvent such as tetrahydrofuran, chloroform or toluene at 0 ° C. to 80 ° C. Thereafter, the mixture is heated at 20 ° C. to 100 ° C., the carboxylic acid represented by the general formula (IVa) is mixed with a chloroformate such as isobutyl chloroformate in an inert solvent such as tetrahydrofuran, chloroform or toluene. A mixed acid anhydride by reacting at 110 ° C. to 110 ° C., reacting with sodium azide in the range of 0 ° C. to 80 ° C., and then heating at 20 ° C. to 100 ° C.
Alternatively, a carboxylic acid represented by the general formula (IVa) is converted to hydrazide via an ester in an inert solvent such as tetrahydrofuran, chloroform or toluene at a temperature of 20 ° C. to 110 ° C., and further reacted with nitrous acid or an alkyl ester thereof to obtain an acyl azide. And heating in a solvent such as chloroform, dichloroethane, toluene, xylene, N, N-dimethylformamide at 20 ° C. to 150 ° C.

The carboxylic acid represented by the general formula (IVa) is reacted with diphenylphosphoryl azide at 10 ° C. to 140 ° C. in an inert solvent such as chloroform, tetrahydrofuran, toluene, N, N-dimethylformamide in the presence of a base such as triethylamine. The compound represented by the general formula (Ib) can also be produced by reacting within the range described above and then reacting with the amine represented by the general formula (IIIa).

In the compound represented by formula (Ib), the structure of Q ¹ has a halogen atom or an aryl group substituted with a trifluoromethanesulfonyloxy group, or a halogen atom or an alkenyl group substituted with a trifluoromethanesulfonyloxy group. In that case, benzene-water,
In a two-phase solvent such as toluene-water, an amide solvent such as N, N-dimethylformamide, or an ether solvent such as tetrahydrofuran or dimethoxyethane, if necessary,
Sodium carbonate, sodium hydroxide, potassium hydroxide,
Using a transition metal catalyst such as tetrakis (triphenylphosphine) palladium (0) in the presence of barium hydroxide, potassium phosphate, cesium carbonate, cesium fluoride and the like,
The coupling reaction can be carried out at 20 to 150 ° C. for 0.5 to 120 hours with the aryl derivative having a substituted boric acid group.

If an alkenyl group or an alkenyl group substituted with a boric acid group is present in the structure of Q ¹ of the compound represented by the formula (Ib), a transition metal catalyst such as palladium acetate is used. Alternatively, in the presence of cesium fluoride or the like, an aryl group substituted with a halogen atom or a trifluoromethanesulfonyloxy group and an amide solvent such as N, N-dimethylformamide at 20 ° C. to 1 ° C.
The coupling reaction can be performed at 50 ° C. for 0.5 to 120 hours. Similarly, when the compound represented by the formula (Ib) has an aryl group substituted with a boric acid group in the structure of Q ¹ , a halogen atom, an aryl derivative substituted with a trifluoromethanesulfonyloxy group, a halogen atom, trifluoromethane It can be substituted alkenyl derivative and the coupling reaction of the sulfonyl group, if there is substituted the aryl group a halogen atom or a trifluoromethanesulfonyloxy group in the structure for Q ¹ of the compound, using the alkenyl compound and a transition metal catalyst To obtain the compounds represented by the general formula (Ib).

When the nitrogen atom of Q ^3b of the compound represented by the general formula (Ib) thus obtained is protected,
The compound represented by the general formula (Ia) can be obtained by deprotecting as required.

<Synthesis of Compound Represented by General Formula (IIa)> The sulfonic acid halide represented by the general formula (IIa) can be synthesized by a known method or by applying a known method. Hereinafter, a general synthesis method will be described.

Among the sulfonic acid halides represented by the general formula (IIa), those represented by the general formula (IIa-1a)

[0489]

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[Wherein R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ ,
X ¹ , X ² and Halo are the same as described above. The sulfonic acid halide represented by the general formula (IIa-1b)

[0490]

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[Wherein R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ ,
X ¹ and X ² are the same as above. Halogenation of a sulfonic acid represented by the general formula (IIa-1c):

[0493]

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[Wherein R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ ,
X ¹ and X ² are the same as above. Various methods that have been reported so far, such as the chlorosulfonylation of unsaturated bonds represented by the formula (The Chemistry of Sulfonic Acids Esters and
their Derivatives, Edited by S. Patai and Z. Rapp
oport, 1991 John Wiley & Sons Ltd).

For example, a sulfonic acid represented by the general formula (IIa-1b) is reacted with a thionyl halide at a temperature of 0 ° C. to 150 ° C. in the presence of N, N-dimethylformamide.
By reacting for 0.5 to 24 hours, a sulfonic acid halide represented by the general formula (IIa-1a) can be synthesized. At this time, the reaction system may be diluted with an inert solvent such as dichloromethane, chloroform, carbon tetrachloride, N-methylpyrrolidin-2-one, dimethylsulfoxide, and sulfolane.

In addition, the compound represented by the general formula (IIa-
By reacting the compound represented by 1c) with thionyl halide or chlorosulfonic acid in an inert solvent such as N, N-dimethylformamide at a temperature of 0 ° C. to 150 ° C. for 0.5 to 24 hours, (IIa-
The sulfonic acid halide represented by 1a) can be synthesized.

Also, among the sulfonic acid halides represented by the general formula (IIa), those represented by the general formula (IIa-2a)

[0498]

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Wherein X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and Halo are the same as described above. The sulfonic acid halide represented by the general formula (IIa-2b)

[0500]

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[Wherein X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ and X ⁸ are the same as above. A method of reacting a condensed heterocyclic ring represented by the formula (1) with a base and then with sulfur dioxide, followed by a reaction with a halogenating agent (for example, JP-A-60
JP-A-204760, JP-A-62-116575, JP-A-4-128266), or by applying them.

For example, a condensed heterocyclic ring represented by the general formula (IIa-2b) is converted to an ether-type inert solvent in a solvent at a temperature below 78 ° C.
At 0 ° C to 0 ° C and then at 78 ° C below
To 0 ° C., and then reacted with a halogenating agent at 50 ° C. to 50 ° C. in an inert solvent of an alkyl halide type at a temperature of 50 ° C. to 50 ° C. to give a compound of the general formula (IIa-2)
The compound of b) is obtained. Specific bases include, for example,
Alkali metal or alkaline earth metal alkoxides or hydrides such as sodium ethoxide, potassium butoxide, sodium hydride, potassium hydride, or hydrides, or alkyl lithiums such as n-butyllithium, t-butyllithium, lithium diisopropylamide Organic metal bases such as dialkylaminolithium, and organic metal bases of bissilylamine such as lithium bis (trimethylsilyl) amide. Examples of ether type inert solvents include diethyl ether, tetrahydrofuran, , 2-dimethoxyethane, dioxane and the like. As the halogenating agent, chlorine, bromine, phosphorus pentachloride, thionyl chloride, N-chlorosuccinimide or N-bromosuccinimide is preferable, and as the halogenated alkyl type inert solvent, dichloromethane, chloroform, tetrachloroethane and the like are preferable.

Also, among the compounds represented by the general formula (IIa-2a), those represented by the general formula (IIa-2c)

[0504]

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[Wherein R ¹⁰¹ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and Halo are the same as described above. The compound represented by the general formula (IIa-2d)

[0506]

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[Wherein R ¹⁰¹ , X ⁵ , X ⁶ , X ⁷ and X ⁸
Is the same as above. In water or a mixed solvent of water and an organic carboxylic acid such as acetic acid at 0 ° C to 30 ° C.
By reacting a halogen such as chlorine gas at 10 ° C. for 10 minutes to 6 hours, a corresponding sulfonyl chloride is formed.

The reaction of the compound represented by the general formula (IIa-2d) with a halogen, if necessary, is usually carried out using water or 10 to 90% by using a Lewis acid such as ferric chloride as a catalyst.
In acetic acid aqueous solution at 0 ° C. to 20 ° C., and chlorine gas is used as halogen.

<Reaction between the compound represented by the general formula (Ia) and the compound represented by the general formula (IIa)> The compound represented by the general formula (Ia) synthesized by the above-described method or the like is usually converted into an appropriate compound. By reacting the sulfonic acid halide represented by the general formula (IIa) synthesized by the above-described method or the like with a base in the presence of a base at 78 ° C. to 150 ° C. in an inert solvent under zero, the compound represented by the general formula (I) A compound can be obtained.

The obtained compound represented by the general formula (I) can be subjected to removal of a protecting group and chemical conversion of a substituent, if necessary.

Examples of specific bases include, for example, alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride. Organic metal bases represented by carbonates, alkoxides, hydroxides or hydrides, alkyllithiums such as n-butyllithium, dialkylaminolithiums such as lithium diisopropylamide, lithium bis (trimethylsilyl) amides Organometallic bases such as bissilylamine, or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec , And the like organic bases such as 7-ene (DBU).

As the inert solvent, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2
-Dimethoxyethane, dioxane, toluene, N, N-
Examples thereof include dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide, sulfolane, and a mixed solvent thereof.

[Production method-1- (1)] When the nitrogen atom of Q ^3a in the general formula (Ia) to be sulfonylated is a primary or secondary amine, sodium carbonate and potassium carbonate are used as bases. Alkali metal or alkaline earth metal carbonates, hydroxides, or pyridine, 2,6-lutidine, such as sodium hydroxide, potassium hydroxide,
Organic bases such as collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU), and the like are suitable. In addition to the active solvent, alcohol solvents such as water, ethanol and butanol, and ester solvents such as ethyl acetate can also be used.

[Production method-1- (2)] When the nitrogen atom of Q ^3a in the general formula (Ia) to be sulfonylated is a nitrogen atom constituting an amide group, the base may be, for example, sodium Alkyl or alkaline earth metal alkoxides such as ethoxide, potassium butoxide, sodium hydride, potassium hydride, or hydrides, or alkyllithium such as n-butyllithium, dialkylaminolithium such as lithium diisopropylamide. A representative organometallic base, an organometallic base of bissilylamine such as lithium bis (trimethylsilylamide), or diazabicyclo [5.4.
0] Organic bases such as undec-7-ene (DBU). Examples of the inert solvent include tetrahydrofuran, 1,2-dimethoxyethane, dioxane, N, N-dimethylformamide and the like. 〓

[Production method-2] General formula (VIIIa) Q ^3a -SO ₂ -Q ^A (VIIIa) wherein Q ^3a and Q ^A are the same as described above. The nitrogen atom of Q ^3a of the compound represented by], reported conventionally obtained by or chemically general methods are, carboxylic acids or their represented by the following general formula (IVa) ~ (IVd) A method for producing a sulfonyl derivative (I) by acylation with an activated product.

Q ¹ -Q ² -COOH (IVa) Q ¹ -Q ^2b -COOH (IVa) Q ¹ -N (R ²⁰ )-(CH ₂ ) m ¹ -COOH (IVb) Q ¹ -O- (CH ₂ ) in ^{m1-COOH (IVc) Q 1} -S- (CH 2) m1-COOH (IVd) [ the ^{formula, Q 1, Q 2, Q} 2b, Q a, R 20 and m1 are as defined above. ]

The compound represented by formula (VIIIa) can be synthesized by various methods. less than,
Some synthetic methods are shown.

<< Synthesis Method of Compound Represented by General Formula (VIIIa) >><Synthesis of Compound Represented by General Formula (VIIIa-1a)> Among the compounds represented by the general formula (VIIIa), general formula (VIIIa) -1a)

[0519]

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[Wherein R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ ,
X ¹ , X ² and Q ^3a are the same as described above. ] Can be synthesized as follows.

That is, the compound represented by the general formula (IIIa) Q ^3b -H (IIIa) wherein Q ^3b is the same as described above. A nitrogen atom of a primary or secondary amine or amide in an inert solvent in the presence of a suitable base, by reacting a compound of the formula (IIa-1a)

[0522]

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[Wherein R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ ,
X ¹ , X ² and Halo are the same as described above. By sulfonylation at a temperature of 78 ° C to 150 ° C below zero, to give a compound of the general formula (VIIIa-1b)

[0524]

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[Wherein R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ ,
X ¹ , X ² and Q ^3b are the same as above. ] Can be obtained.

Specific examples of the base include alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride. Organic metal bases represented by carbonates, alkoxides, hydroxides or hydrides, alkyllithiums such as n-butyllithium, dialkylaminolithiums such as lithium diisopropylamide, lithium bis (trimethylsilyl) amides Organic metal bases of bissilylamine, or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine,
Diisopropylethylamine, diazabicyclo [5.
4.0] organic bases such as undec-7-ene (DBU).

As the inert solvent, dichloromethane,
Chloroform, carbon tetrachloride, tetrahydrofuran, 1,
2-dimethoxyethane, dioxane, toluene, N, N
-Dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide, sulfolane, acetone and the like.

The thus obtained general formula (VIII)
If the nitrogen atom of Q ^{3b in} the compound represented by a-1b) is protected, deprotection is performed as necessary to obtain a compound represented by the general formula (VIIIa-1a).

The compound represented by the general formula (VIIIa-1a) can be obtained by removing the nitrogen protecting group of the compound represented by the general formula (VIIIa-1c) obtained by the following method by an appropriate method. can get.

[0530]

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[In the formula, R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , X ¹ and X ² are the same as described above. R ²² is a hydrogen atom, an alkyl group,
A hydroxy group protected with a methoxymethyl group or a tetrahydropyranyl group, a hydroxyalkyl group protected with a methoxymethyl group or a tetrahydropyranyl group, an alkoxyl group, an alkoxyalkyl group, a dialkoxyalkyl group, a dialkylamino group, Monoalkylamino, dialkylaminoalkyl, aminoalkyl protected with a tert-butoxycarbonyl group, monoalkylaminoalkyl, dialkylaminocarbonyl, dialkylaminocarbonylalkyl , A dialkylaminoalkyloxy group, a monoalkylaminoalkyloxy group in which an amino group is protected by a tertiary butoxycarbonyl group, or a dialkylaminocarbonylalkyloxy group. Q ^3c represents any of the following groups.

[0532]

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(In the group, when the carbon atom bonded to R ²³ , R ²⁴ , R ²⁵ and R ²⁶ is not adjacent to the nitrogen atom, each independently represents a hydrogen atom, an alkyl group, a methoxymethyl group or a tetrahydropyranyl group. A hydroxy group protected with a group or the like, a hydroxyalkyl group protected with a methoxymethyl group or a tetrahydropyranyl group, or the like, an alkoxyl group, an alkoxyalkyl group, a dialkoxyalkyl group,
Dialkylamino group, monoalkylamino group protected with tertiary butoxycarbonyl group, monoalkylaminoalkyl group, monoalkylaminoalkyl group protected with tertiary butoxycarbonyl group, dialkylaminocarbonyl group , A dialkylaminocarbonylalkyl group, a dialkylaminoalkyloxy group, a monoalkylaminoalkyloxy group in which an amino group is protected by a tertiary butoxycarbonyl group, or a dialkylaminocarbonylalkyloxy group.

When the carbon atom bonded to R ²³ , R ²⁴ , R ²⁵ and R ²⁶ is adjacent to the nitrogen atom, each of them independently represents a hydroxyl group with a hydrogen atom, an alkyl group, a methoxymethyl group or a tetrahydropyranyl group. A protected hydroxyalkyl group, an alkoxyalkyl group, a dialkoxyalkyl group, a dialkylaminoalkyl group, a monoalkylaminoalkyl group protected with an amino group by a tertiary butoxycarbonyl group, a dialkylaminocarbonyl group, a dialkylaminocarbonylalkyl group, Or a dialkylaminoalkyloxy group or the like.

Further, R ²³ and R ²⁴ , R ²⁵ and R ²⁶ may together have a saturated or unsaturated 5- to 7-membered cyclic hydrocarbon or a substituent which may have a substituent. R ²⁷ may be a saturated or unsaturated 5- to 7-membered heterocyclic group, and R ²⁷ may be an alkyl group, a hydroxyalkyl group protected with a hydroxyl group, a hydroxyalkylcarbonyl group protected with a hydroxyl group, or a hydroxyalkyl group protected with a hydroxyl group. Sulfonyl group, alkoxyalkyl group, alkoxyalkylcarbonyl group, alkoxyalkylsulfonyl group, alkylcarbonyl group, alkylcarbonylalkyl group, alkylsulfonyl group, alkylsulfonylalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylcarbonyl group, Alkoki A cyclocarbonylalkylsulfonyl group,
It means a monoalkylaminoalkyl group, a dialkylaminocarbonyl group, a dialkylaminocarbonylalkyl group or the like in which an amino group is protected by a dialkylaminoalkyl group, a tertiary butoxycarbonyl group. R ²⁵ and R ²⁷ or R ²⁶ and R ²⁷ together may mean a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent.

R ²⁸ represents a protecting group for a nitrogen atom such as a tertiary butoxycarbonyl group, a benzyl group or a triphenylmethyl group. j and k represent an integer of 0 or 1. l means an integer of 1 to 3. Here, the sum of k and l means an integer of 1 to 4. )]

General formula (IIIb) Q ^3c -H (IIIb) obtained by a known method or its application [wherein Q ^3c is as defined above. The amino compound represented by the formula (IXa) in the presence of a suitable base,

[0538]

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[Wherein R ¹⁷ and Q ^3c are the same as defined above. ]
In an inert solvent in the presence of a suitable base, a sulfonamide represented by the general formula (XIa)

[0540]

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[In the formula, R ¹⁶ , R ¹⁸ , R ¹⁹ , R ²² , X ¹ and X ² are the same as described above. With a carbonyl compound represented by the formula (XIIa):

[0542]

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[Wherein R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²² ,
Q ^3c , X ¹ and X ² are the same as above. And converting the alcohol of the alcohol represented by the general formula (XIIa) to a methanesulfonyloxy group or the like in the presence of an appropriate base, or phosphorus halide or triphenylphosphine / tetrahalogen Leaving group by a method of converting to a halogen atom by carbon fluoride,
By removing methanesulfonic acid or hydrogen halide in the presence of an appropriate base, the compound represented by the general formula (VIIIa-
The compound represented by 1c) can be obtained.

An amino compound obtained by a known method represented by the general formula (IIIb) or its application is converted into an optionally substituted alkyl sulfonic acid halide in an inert solvent in the presence of a suitable base. 78 ° C to 150 ° C
To give a sulfonamide compound represented by the general formula (IXa).

As the base, for example, sodium carbonate,
Alkali metal or alkaline earth metal carbonates such as potassium carbonate, or pyridine, 2,6-lutidine,
Organic bases such as collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine and diazabicyclo [5.4.0] undec-7-ene (DBU) can be mentioned.

Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl Pyrrolidin-2-one and the like can be mentioned, and dimethyl sulfoxide, sulfolane, acetone and the like can also be used depending on the kind of base used.

The sulfonamide represented by the formula (IXa) is reacted with the compound represented by the formula (XI) in an inert solvent in the presence of a suitable base.
a) a carbonyl compound represented by a) and
By reacting at ° C, an alcohol compound represented by the general formula (XIIa) can be obtained.

Examples of the base include a hydride of an alkali metal or an alkaline earth metal such as sodium ethoxide, potassium butoxide, sodium hydride and potassium hydride, or an alkyl lithium such as n-butyl lithium, lithium bis Examples thereof include organic metal bases of bissilylamine such as (trimethylsilyl) amide, and organic metal bases represented by dialkylaminolithium such as lithium diisopropylamide. Inert solvents include tetrahydrofuran,
Examples thereof include 2-dimethoxyethane and dioxane.

The hydroxyl group of the alcohol represented by the general formula (XIIa) may be converted, if necessary, to an alkali metal or alkaline earth metal carbonate such as sodium carbonate or potassium carbonate, or pyridine, 2,6-lutidine, collidine,
4-dimethylaminopyridine, triethylamine, N-
Methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DB
In a solvent such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene and N, N-dimethylformamide in the presence of a suitable base such as an organic base such as U)
At 0 ° C to 110 ° C, it is treated with a phosphorus halide such as phosphorus pentachloride or a triphenylphosphine-halogen complex such as triphenylphosphine dibromide to form a halide. By removing, for example, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidine-2- on,
In dimethyl sulfoxide, sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, alkali metal or alkaline earth metal carbonate such as potassium hydride, alkoxide, hydroxide Or hydride, or an organometallic base represented by an alkyllithium such as n-butyllithium, a dialkylamine such as lithium bis (trimethylsilyl) amide, a dialkylaminolithium such as lithium diisopropylamide, or Pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7
Treatment with an organic base such as ene (DBU) at a temperature of 78 ° C. to 150 ° C. below zero gives a compound of the general formula (VIIIa-
The compound of 1c) is obtained.

Further, the hydroxyl group of the alcohol represented by the general formula (XIIa) is converted to an alkali metal or alkaline earth metal carbonate such as sodium carbonate or potassium carbonate, or pyridine, 2,6-lutidine, collidine,
-Dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU)
In a solvent such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide in the presence of a suitable base such as an organic base.
At 0 ° C. to 110 ° C., treatment with an alkyl or aryl sulfonic acid chloride such as methane sulfonic acid chloride to obtain an alkyl or aryl sulfonic acid ester derivative, under more basic conditions than the obtained alkyl or aryl sulfonic acid ester derivative, The compound represented by the general formula (VIIIa-1c) can be obtained by removing the alkyl or aryl sulfonic acid.

That is, for example, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, N
-Alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride in methylpyrrolidin-2-one and dimethyl sulfoxide Carbonates, alkoxides, hydroxides or hydrides, or alkyllithiums such as n-butyllithium, organometallic bases of bissilylamines such as lithium bis (trimethylsilyl) amide, dialkylaminolithiums such as lithium diisopropylamide Or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] By treatment with 0.99 ° C. from minus 78 ° C. with an organic base such as Ndeku-7-ene (DBU), to give a compound represented by the general formula (VIIIa-1c).

Further, the compound represented by the general formula (VIIIa-1c) can be obtained by converting the sulfonamide represented by the general formula (IXa) with a silyl halide such as trimethylsilyl chloride in an inert solvent in the presence of a suitable base. The compound can also be obtained by reacting the compound with a carbonyl compound represented by the general formula (XIa) in an inert solvent in the presence of a base, followed by treatment under acidic to basic aqueous conditions (Peterson reaction) ).

That is, the sulfonamide represented by the general formula (IXa) was converted to sodium ethoxide, potassium butoxide, hydrogen in a solvent such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane at a temperature of 78 ° C. to 110 ° C. Hydrides of alkali metals or alkaline earth metals such as sodium hydride and potassium hydride, or organometallic bases of alkyllithium such as n-butyllithium, bissilylamine such as lithium bis (trimethylsilyl) amide, lithium diisopropyl A silyl compound is formed with an alkylsilyl chloride such as trimethylsilyl chloride in the presence of an organic metal base represented by dialkylaminolithium such as an amide, and then condensed with a carbonyl compound represented by the general formula (XIa) under the same conditions. By treating the acid in basic aqueous conditions, to give a compound represented by the general formula (VIIIa-1c).

The protecting group for the nitrogen atom of the compound represented by the formula (VIIIa-1c) can be removed by a commonly used method. That is, in the case of a tertiary butoxycarbonyl group, a suitable acid, for example, acetic acid,
It can be removed by hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids. In addition, an arylmethyl group such as a benzyl group can be removed by hydrogenolysis using a palladium carbon catalyst, and a triphenylmethyl group can be formed by a suitable acid such as formic acid, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like. , Trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids. Further, the triphenylmethyl group can be removed by birch reduction using metallic sodium in liquid ammonia, and can also be removed by hydrogenolysis using a palladium carbon catalyst.
-1c) can be obtained.

<Synthesis of Compound Represented by Formula (VIIIa-2a)> Of the compounds represented by Formula (VIIIa), the compound represented by Formula (VIIIa-2a)

[0556]

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[Wherein X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and Q ^3a are the same as above. ] Can be synthesized by the following method.

That is, the compound represented by the general formula (IIIa) Q ^3b -H (IIIa) wherein Q ^3b is the same as described above. A sulfonic acid halide represented by the general formula (IIa-2a) in an inert solvent, in the presence of a suitable base, in the presence of a suitable base,

[0559]

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[In the formula, X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and Halo are the same as described above. 78 degrees below zero to 15
By sulfonylation at 0 degree, the compound represented by the general formula (VIII)
The compound represented by a-2b) can be obtained.

[0561]

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[Wherein X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and Q ^3b are the same as described above. ]

Specific bases include, for example, alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride and potassium hydride. Organic metal bases represented by carbonates, alkoxides, hydroxides or hydrides, alkyllithiums such as n-butyllithium, dialkylaminolithiums such as lithium diisopropylamide; bis such as lithium bis (trimethylsilyl) amide Organometallic bases of silylamine, or pyridine,
2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.
0] Organic bases such as undec-7-ene (DBU).

As the inert solvent, dichloromethane,
Chloroform, carbon tetrachloride, tetrahydrofuran, 1,
2-dimethoxyethane, dioxane, toluene, N, N
-Dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide, sulfolane, acetone and the like.

The compound of the general formula (VIII) thus obtained
If the nitrogen atom of Q3b of the compound represented by a-2b) is protected, the compound is represented by the general formula (VIIIa-2a) by deprotection if necessary.

The compound represented by the general formula (VIIIa-2a) can be obtained by the following production method.
The compound represented by the following general formula (VIIIa-2c) can be obtained by removing the nitrogen-protecting group of Q3d by an appropriate method as necessary.

[0567]

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[Wherein X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ and X ⁸ are the same as above. Q ^3d represents any of the following groups.

[0569]

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(In the group, R ³⁰ , R ³¹ , R ³² and R ³³ are
When the carbon atom bonded to R ³⁰ , R ³¹ , R ³² and R ³³ is not adjacent to the nitrogen atom, each independently represents a hydrogen atom,
Hydroxyl group protected with an alkyl group, hydroxyl group methoxymethyl group or tetrahydropyranyl group, hydroxyalkyl group hydroxyalkyl group protected with a methoxymethyl group or tetrahydropyranyl group, alkoxyl group, alkoxyalkyl group, dialkoxyalkyl group , A dialkylamino group, a monoalkylamino group protected with an amino group by a tertiary butoxycarbonyl group, a dialkylaminoalkyl group, a monoalkylaminoalkyl group protected with an amino group by a tertiary butoxycarbonyl group, dialkylaminocarbonyl Group, dialkylaminocarbonylalkyl group, dialkylaminoalkyloxy group, monoalkylaminoalkyloxy group in which amino group is protected by tertiary butoxycarbonyl group, amino group in tertiary butoxycarbonyl group Protected monoalkylamino aminocarbonyl alkyloxy group, dialkylaminocarbonylalkyl group, a dialkylaminoalkyl group,
Monoalkylaminoalkyloxy, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, carbamoylalkyl, monoalkylcarbamoylalkyl, dialkylcarbamoylalkyl, pyrrolidinocarbonyl, pyrrolidinocarbonylalkyl Piperidinocarbonyl group piperidinocarbonylalkyl group morpholinocarbonyl group morpholinocarbonylalkyl group or dialkylaminocarbonylalkyloxy group.

When the carbon atom bonded to R ³⁰ , R ³¹ , R ³² and R ³³ is adjacent to the nitrogen atom, each of them independently forms a hydroxyl group with a hydrogen atom, an alkyl group, a methoxymethyl group or a tetrahydropyranyl group. A protected hydroxyalkyl group, an alkoxyalkyl group, a dialkoxyalkyl group, a dialkylaminoalkyl group, a monoalkylaminoalkyl group protected with an amino group by a tertiary butoxycarbonyl group, a dialkylaminocarbonyl group, a dialkylaminocarbonylalkyl group, Carbamoyl group monoalkylcarbamoyl group carbamoylalkyl group monoalkylcarbamoylalkyl group pyrrolidinocarbonyl group pyrrolidinocarbonylalkyl piperidinocarbonyl group piperidinocarbonylalkyl group morpholinocarbonyl group morpholino Means Ruboniruarukiru group or dialkylamino alkyloxyalkyl group.

Also, R ³⁰ and R ³¹ , R ³² and R ³³ may together have a saturated or unsaturated 5- to 7-membered cyclic hydrocarbon or a substituent which may have a substituent. R ³⁴ may mean a saturated or unsaturated 5- to 7-membered heterocyclic group, and R ³⁴ represents an alkyl group, a hydroxyalkyl group protected with a hydroxyl group, a hydroxyalkylcarbonyl group protected with a hydroxyl group, a hydroxyalkyl group protected with a hydroxyl group. Sulfonyl group, alkoxyalkyl group, alkoxyalkylcarbonyl group, alkoxyalkylsulfonyl group, alkylcarbonyl group, alkylcarbonylalkyl group, alkylsulfonyl group, alkylsulfonylalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylcarbonyl group, Alkoki A cyclocarbonylalkylsulfonyl group,
It means a monoalkylaminoalkyl group, a dialkylaminocarbonyl group, a dialkylaminocarbonylalkyl group or the like in which an amino group is protected by a dialkylaminoalkyl group, a tertiary butoxycarbonyl group. R ³² and R ³⁴ or R ³³ and R ³⁴ together may mean a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent.

R ³⁵ represents a general protecting group for a nitrogen atom such as a tertiary butoxycarbonyl group, a benzyl group or a triphenylmethyl group. j and k represent an integer of 0 or 1. l means an integer of 1 to 3. Where k
And l mean an integer from 1 to 4. )]

General formula (IIIc) Q ^3d -H (IIIc) obtained by a known method or its application [wherein Q ^3d is the same as defined above. The amino compound represented by the general formula (IIa-)
2e)

[0575]

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[Wherein X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ and X ⁸ are the same as above. And a thiol of a condensed heterocyclic ring represented by the general formula (VIIIa-2)
d)

[0577]

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[Wherein X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and Q ^3d are the same as defined above. ] Can be obtained.

The compound represented by the general formula (VIIIa-2c) can be obtained by oxidizing the obtained compound represented by the general formula (VIIIa-2d) in an inert solvent in the presence of a suitable base.

An amino compound obtained by a known method represented by the general formula (IIIc) or its application is converted into a compound represented by the general formula (IIa-II) in water, alcohols, dioxane or a mixed solvent thereof in the presence of a suitable base and an oxidizing agent. 2
The compound represented by the general formula (VIIIa-2d) can be obtained by reacting the thiol represented by e) at a temperature of 10 ° C. to 50 ° C. below zero.

As the base, for example, sodium carbonate,
Potassium carbonate, sodium hydroxide, alkali metal or alkaline earth metal carbonates such as potassium hydroxide,
Hydroxides and the like can be given. Examples of the oxidizing agent include oxygen, chlorine, bromine, iodine, and hypochlorous acid.
The obtained compound represented by the general formula (VIIIa-2d) is treated with an inorganic base such as potassium permanganate or hydrogen peroxide in water, alcohol or a mixed solvent thereof at 30 to 60 ° C. in the presence of a suitable base. By reacting with an oxidizing agent or an organic oxidizing agent such as 3-chloroperbenzoic acid, a compound represented by the general formula (VIIIa-2c) is obtained.

The protecting group for the nitrogen atom of the compound represented by the formula (VIIIa-2c) can be removed by a commonly used method. That is, in the case of a tertiary butoxycarbonyl group, a suitable acid, for example, acetic acid,
It can be removed by hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids. In addition, an arylmethyl group such as a benzyl group can be removed by hydrogenolysis using a palladium carbon catalyst, and a triphenylmethyl group can be formed by a suitable acid such as formic acid, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like. , Trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids. Further, an arylmethyl group such as a benzyl group can be removed by birch reduction using metallic sodium in liquid ammonia, and can also be removed by hydrogenolysis using a palladium carbon catalyst, and represented by the general formula (VIIIa-2a). The compounds shown can be obtained.

Also, among the compounds represented by the general formula (VIIIa-2a), those represented by the general formula (VIIIa-2e)

[0584]

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[Wherein X ⁵ , X ⁶ , X ⁷ , X ⁸ , R ¹⁰¹ and Q ^3a are the same as described above. The compound represented by the general formula (VIIIa-2) obtained by the production method described below
It can also be obtained by removing the protecting group for the nitrogen of ^Q3d of the compound represented by f).

That is, the general formula (IIIc) Q ^3d -H (IIIc) obtained by a known method or its application, wherein Q ^3d is the same as described above. With the general formula (IIa-2c)

[0587]

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[Wherein X ⁵ , X ⁶ , X ⁷ , X ⁸ , R ¹⁰¹ and Halo are the same as described above. By reacting with an acid halide represented by the general formula (VIIIa-2f):

[0589]

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[Wherein X ⁵ , X ⁶ , X ⁷ , X ⁸ , R ¹⁰¹ and Q ^3d are the same as described above. ] Can be obtained.

The compound represented by the general formula (IIa-2d) is treated with water or a mixed solvent of water and an organic carboxylic acid such as acetic acid at 0 ° C. to 30 ° C. with 10 halogens such as chlorine gas.
The reaction is carried out for minutes to 6 hours to produce the corresponding sulfonyl chloride. The compound represented by the general formula (VIIIa-2f) can be obtained by adding the produced sulfonyl chloride to an amino compound represented by the general formula (IIIc) dissolved in an appropriate solvent at 50 to 40 ° C. under zero temperature. .

The reaction of the compound represented by the general formula (IIa-2d) with a halogen is carried out, if necessary, by using a Lewis acid such as ferric chloride as a catalyst, usually in water or a 10-90% aqueous acetic acid solution. C. to 20.degree. C., and chlorine gas is used as halogen. The resulting acid chloride (IIa
-2c) reacts with an amine represented by the general formula (IIIc) in an alcohol solvent such as water and ethanol, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane and dioxane, a halogen solvent such as dichloromethane and chloroform, and acetone. The reaction is carried out in a solvent such as described above or a mixed solvent thereof at a temperature of 20 ° C. to 50 ° C. in the presence of a base, if necessary, to obtain a compound represented by the general formula (VIIIa-2f). As the base, for example, sodium carbonate, potassium carbonate, sodium hydroxide, alkali metal or alkaline earth metal carbonates such as potassium hydroxide, hydroxides, or pyridine,
2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.
0] Organic bases such as undec-7-ene (DBU).

The protecting group for the nitrogen atom of the compound represented by the formula (VIIIa-2f) can be removed by a commonly used method. That is, in the case of a tertiary butoxycarbonyl group, a suitable acid, for example, acetic acid,
It can be removed by hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids. In addition, an arylmethyl group such as a benzyl group can be removed by hydrogenolysis using a palladium carbon catalyst, and a triphenylmethyl group can be formed by a suitable acid such as formic acid, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like. , Trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids. Further, an arylmethyl group such as a benzyl group can be removed by birch reduction using metallic sodium in liquid ammonia, and can also be removed by hydrogenolysis using a palladium carbon catalyst, and represented by the general formula (VIIIa-2e). The compounds shown can be obtained.

<Synthesis of Compound Represented by Formula (VIIIa-3a)> Of the compounds represented by Formula (VIIIa), the compounds represented by Formula (VIIIa-3a)

[0595]

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[Wherein X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , Q ^3a ,
w and z are the same as above. The compound represented by the general formula (VIIIa) obtained by the production method described below
-3b)

[0597]

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[Wherein X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , Q ^3d ,
w and z are the same as above. Q3d of the compound of the formula
Can be obtained by removing the nitrogen protecting group.

That is, the general formula (IIIc) Q ^3d -H (IIIc) wherein Q ^3d is as defined above. The amino compound represented by] presence of an appropriate base, in a solvent inert, chlorosulfonyl isocyanate of the general formula obtained from alcohol _{(XIII) Cl-SO 2 -NHCOOR} 60 (XIII) [R 60 is a third A group that can be easily removed, such as a tertiary butyl group, a benzyl group, a paramethoxybenzyl group, or a paranitrobenzyl group. By reacting a compound represented by, general formula _{^{(XIV) Q 3d -SO 2 -NHCOOR}} 60 (XIV) [ wherein, R ⁶⁰ and Q ^3d are as defined above. ] Can be synthesized.

The protecting group on the nitrogen atom of the compound represented by the general formula (XIV) is removed to obtain a compound of the general formula (XV) Q ^3d -SO ₂ -NH ₂ (XV) wherein Q ^3d is the same as defined above. . The compound represented by the formula (IIa-3a) is reacted with the obtained compound (XV) in an inert solvent in the presence of a suitable base.

[0601]

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[Wherein X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , w and z are the same as above. L ² and L ³ each independently represent a leaving group frequently used in organic chemistry such as chlorine, bromine, iodine, a methylsulfonyloxy group, and a paratoluenesulfonyloxy group. The compound represented by the general formula (VIIIa-3b) can be synthesized by reacting the compound represented by the general formula (VIIIa-3b).

Formulas (IIIc) and (XIII)
In the reaction, as a base, for example, sodium carbonate, potassium carbonate or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,
N-methylmorpholine, diisopropylethylamine,
Diazabicyclo [5.4.0] undec-7-ene (D
Organic bases such as BU) can be used. Examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, and dioxane; halogen solvents such as dichloromethane and chloroform; benzene;
The reaction is carried out in a solvent such as toluene or acetone or a mixed solvent thereof at a temperature below 70 ° C. to 100 ° C. by the general formula (XIV)
Can be synthesized.

The removal of the protecting group on the nitrogen atom of the compound represented by the general formula (XIV) can be carried out by using a suitable acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, in the case of a tertiary butoxycarbonyl group. It can be removed by phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids. Also, an arylmethyl group such as a benzyloxycarbonyl group, a paranitrobenzyloxycarbonyl group or a paramethoxybenzyloxycarbonyl group can be removed by hydrogenolysis using a palladium carbon catalyst. Is a suitable acid such as acetic acid, hydrochloric acid,
The compound can be removed by hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids to obtain the compound represented by the general formula (XV).

The reaction between the compound represented by the general formula (XV) and the compound represented by the general formula (IIa-3a) is carried out by an alcohol solvent such as ethanol, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, and dichloromethane. , A solvent such as acetone, a solvent such as acetone, N, N-dimethylformamide, N-methylpyrrolidin-2-one, acetamide or a mixed solvent thereof in the presence of a base, under zero.
C. to 150.degree. C. to obtain the compound represented by the general formula (VIII-3b). Examples of the base include sodium carbonate, potassium carbonate, sodium hydride, potassium hydride or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5. 4.0] Undec-7
Organic bases such as -ene (DBU).

The protecting group for the nitrogen atom of the compound represented by the formula (VIII-3b) can be removed by a commonly used method. That is, in the case of a tertiary butoxycarbonyl group, it can be removed with an appropriate acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids. it can. In addition, an arylmethyl group such as a benzyl group can be removed by hydrogenolysis using a palladium carbon catalyst, and a triphenylmethyl group can be formed by a suitable acid such as formic acid, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like. , Trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids. Further, an arylmethyl group such as a benzyl group can be removed by birch reduction using metallic sodium in liquid ammonia, and can also be removed by hydrogenolysis using a palladium carbon catalyst, and represented by the general formula (VIII-3a). The compounds shown can be obtained.

<< Reaction between Compounds Represented by General Formulas (IVa) to (IVd) and Compounds Represented by General Formula (VIIIa) >> For example, the carboxylic acids represented by the general formulas (IVa) to (IVd) As the active substance, a compound represented by the general formula (I)
Reacting the carboxylic acids of Va) to (IVd) with a chloroformate such as isobutyl chloroformate,
Mixed acid anhydrides obtained by forming anhydrides, acid halides such as acyl chlorides produced using inorganic acid halides such as thionyl chloride, phenols such as paranitrophenol, pentafluorophenyl- Active esters reacted with trifluoroacetate, active esters reacted with N-hydroxybenztriazole or N-hydroxysuccinimide, N, N'-dicyclohexylcarbodiimide or N- (3 -Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, reaction product with diethyl cyanophosphonate (salting method), triphenylphosphine and 2,2 '
-Reaction products with dipyridyl disulfide (Mukoyama method)
And the like.

The activated carboxylic acid thus obtained is reacted with the compound represented by the general formula (VIIIa) in an inert solvent in the presence of an appropriate base at 78 ° C. to 150 ° C. under zero temperature. Thereby, the sulfonyl derivative represented by the general formula (I) can be obtained.

As the base, for example, sodium carbonate,
Alkali metal or alkaline earth metal carbonates, alkoxides, hydroxides or hydrides, such as potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, or n -Organometallic bases represented by alkyllithium such as butyllithium, dialkylaminolithium such as lithium diisopropylamide,
Organometallic bases of bissilylamines such as lithium bis (trimethylsilyl) amide, or pyridine, 2,6
-Lutidine, collidine, 4-dimethylaminopyridine,
Organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, and diazabicyclo [5.4.0] undec-7-ene (DBU) can be given.

As the inert solvent, dichloromethane,
Chloroform, carbon tetrachloride, tetrahydrofuran, 1,
2-dimethoxyethane, dioxane, toluene, N, N
-Dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide, sulfolane and the like.

[Production method-2- (1)] General formula (VIIIa) to be acylated Q ^3a -SO ₂ -Q ^A (VIIIa) [wherein Q ^3a and Q ^A are as defined above. When the nitrogen atom of Q ^{3a in} the compound of formula (I) is a primary or secondary amine, the base may be an alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide. Carbonates, hydroxides,
Or an organic base such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU). Suitable solvents include alcoholic solvents such as ethanol and butanol and ester solvents such as ethyl acetate in addition to inert solvents.

[Production method-2- (2)] General formula (VIIIa) to be acylated Q ^3a -SO ₂ -Q ^A (VIIIa) wherein Q ^3a and Q ^A are as defined above. When the nitrogen atom of Q ^{3a in} the compound of formula (I) is a nitrogen atom forming an amide bond, the base may be, for example, an alkali metal such as sodium ethoxide, potassium butoxide, sodium hydride, potassium hydride or the like. Alkaline earth metal alkoxides or hydrides, alkylmetals such as n-butyllithium, organometallic bases typified by dialkylaminolithiums such as lithium diisopropylamide, bissilyls such as lithium bis (trimethylsilyl) amide Amine organometallic bases,
Or an organic base such as diazabicyclo [5.4.0] undec-7-ene (DBU). Examples of the inert solvent include tetrahydrofuran, 1,2-dimethoxyethane, dioxane, N, N-
Dimethylformamide and the like are preferred.

[Production Method-3] General Formula (VIIIa) Q ^3a -SO ₂ -Q ^A (VIIIa) wherein Q ^3a and Q ^A are the same as described above. In the case where the nitrogen atom of Q ^3a of the compound represented by formula (I) is a nitrogen atom constituting an amide, the nitrogen atom of the compound represented by formula (VIIIa) is represented by the following formulas (Va) to (Vd) Compound Q ¹ -Q ^2b -CHL ¹ R ¹³ (Va) Q ¹ -N (R ²⁰ )-(CH ₂ ) m ¹ -CHL ¹ R ¹³ (Vb) Q ¹ -O- (CH ₂ ) m ¹ -CHL ¹ R ¹³ (Vc) Q ¹ -S- (CH ₂ ) m ¹ -CHL ¹ R ¹³ (Vd) [wherein Q ¹ , Q ^2b , R ¹³ , R ²⁰ , m1 and L ¹ are the same as above. To produce the sulfonyl derivative of the present invention.

When the nitrogen atom of Q ^3a of the compound represented by the general formula (VIIIa) is a nitrogen atom of an amide bond, the nitrogen atom of Q ^3a of the compound represented by the general formula (VIIIa) is replaced by a compound represented by the general formula (Va) By alkylating with the compound represented by (Vd), the sulfonyl derivative represented by the general formula (I) can be synthesized. That is, a compound represented by the general formula (VIIIa)
In an inert solvent, at a temperature of 78 ° C to 150 ° C, the general formula (V
Compounds represented by a) to (Vd) and 0.5 to 12 hours
The reaction is carried out for 0 hour to alkylate a nitrogen atom to obtain a sulfonyl derivative represented by the general formula (I).

Examples of the base include alkoxides of alkali metals or alkaline earth metals such as sodium ethoxide, potassium butoxide, sodium hydride and potassium hydride, or hydrides, or alkyllithiums such as n-butyllithium; Organometallic base represented by dialkylaminolithium such as lithium diisopropylamide, lithium bis (trimethylsilyl)
Organometallic bases of bissilylamines such as amides, or organic bases such as diazabicyclo [5.4.0] undec-7-ene (DBU) can be mentioned.
As the inert solvent, tetrahydrofuran, 1,2-
Dimethoxyethane, toluene, dioxane, N, N-dimethylformamide and the like are preferred.

[Production Method-4] General Formula (VIIIa) Q ^3a -SO ₂ -Q ^A (VIIIa) wherein Q ^3a and Q ^A are the same as described above. When the nitrogen atom of Q ^3a of the compound represented by the formula (I) is a primary or secondary amine, a carbonyl compound represented by the following formulas (VIa) to (VId) Q ¹ -Q ^2b -C (ＣO) ^{R 13 (VIa) Q 1 -N} (R 20) - (CH 2) m1-C (= O) R 13 (VIb) Q 1 -O- (CH 2) m1-C (= O) R 13 (VIc ) Q ¹ -S- (CH ₂ ) m 1 -C (＝ O) R ¹³ (VId) [wherein Q ¹ , Q ^2b , R ¹³ , R ²⁰ and m1 are the same as above. To form a sulfonyl derivative (I).

When the nitrogen atom of Q ^{3a in} the compound represented by the formula (VIIIa) is an amine, the compound represented by the formula (VIIIa)
a) a compound represented by general formula (VIa) to (VId)
The carbonyl compound represented by, usually in an inert solvent,
If necessary, imine is formed in the presence of an organic acid such as acetic acid, a mineral acid such as hydrochloric acid, or a Lewis acid such as aluminum chloride at a temperature of 20 ° C. to 150 ° C. for 0.5 to 120 hours under zero. In an inert solvent, sodium borohydride, sodium cyanoborohydride, sodium borohydride reducing agents such as sodium triacetoxyborohydride,
Alternatively, the sulfonyl derivative represented by the general formula (I) can be obtained by hydrogenating with a catalytic reduction catalyst such as a palladium carbon catalyst at 10 ° C to 110 ° C for 0.5 hours to 120 hours.

As the inert solvent, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2
-Dimethoxyethane, dioxane, toluene, N, N-
Dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulfoxide, sulfolane and the like are preferred.

[Production method-5] General formula (VIIIa) Q ^3a -SO ₂ -Q ^A (VIIIa) wherein Q ^3a and Q ^A are the same as above. When Q ^{3a of the} compound represented by the formula (I) is a primary or secondary amine, the compound represented by the formula (VIIIa) is converted to a compound represented by the formula (VIIa) to (VIIa) using a reagent such as phosgene, triphosgene or carbonyldiimidazole. Compound having a primary amine represented by VIId) or a secondary amine represented by general formula (VIIe) Q ¹ -Q ^2b -NH ₂ (VIIa) Q ¹ -N (R ²⁰ )-(CH ₂ ) m ₂ -NH ₂ ^{(VIIb) Q 1 -O- (CH} 2) m2-NH 2 (VIIc) Q 1 -S- (CH 2) m2-NH 2 (VIId)

[0620]

Embedded image

[Wherein Q ¹ , Q ^2b , R ²⁰ , m2 and a group

[0622]

Embedded image

Is the same as above. A reaction to form a urea derivative.

If Q ^{3a of the} compound represented by the formula (VIIIa) is an amine, the compounds represented by the formulas (VIIa) to (VII)
d) reacting a primary or secondary amine compound represented by the general formula (VIIe) with a reagent such as phosgene, triphosgene, 1,1'-carbonyldiimidazole to form a urea derivative of the general formula (I) It is possible to lead to the sulfonyl derivatives of the invention represented.

The reaction was carried out with phosgene, triphosgene, 1,1 '
-Reagents such as carbonyldiimidazole have the general formula (V
Compounds having a primary amine represented by IIa) to (VIId) or a secondary amine represented by the general formula (VIIe) and a compound represented by the general formula (VIIIa) are added, if necessary, to an inert solvent in the presence of a base. Can be synthesized by sequentially reacting. Examples of the inert solvent include dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, toluene, N, N-dimethylformamide, N, N
-Dimethylacetamide, N-methylpyrrolidine-2-
On, dimethyl sulfoxide, sulfolane and the like can be mentioned, and preferred are dichloromethane, tetrahydrofuran and toluene.

As the base, for example, sodium carbonate,
Potassium carbonate, sodium hydroxide, alkali metal or alkaline earth metal carbonates such as potassium hydroxide,
Hydroxide or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine,
N-methylmorpholine, diisopropylethylamine,
Diazabicyclo [5.4.0] undec-7-ene (D
Organic bases such as BU) may be mentioned, and the reaction may be carried out at a temperature of 70 ° C to 110 ° C below zero.

[Production Method-6] General Formula (VIIIa) Q ^3a -SO ₂ -Q ^A (VIIIa) wherein Q ^3a and Q ^A are the same as above. When the nitrogen atom of Q ^{3a in} the compound of formula (I) is a primary or secondary amine, a known isocyanate derivative (Q ¹ -Q ^2b -N =
C = O) wherein Q ¹ and Q ^2b are the same as above. Or a carboxylic acid represented by the general formulas (IVa) to (IVd): Q ¹ -Q ^2b -COOH (IVa) Q ¹ -N (R ²⁰ )-(CH ₂ ) m 1 -COOH (IVb) Q ¹ -O- (CH ₂₎ in ^{m1-COOH (IVc) Q 1} -S- (CH 2) m1-COOH (IVd) [ the ^{formula, Q 1, Q 2b, R} 20 and m1 are as defined above. The isocyanate produced from the formula (VI)
By reacting with the amine shown in IIa),
A method for producing a sulfonyl derivative represented by the general formula (I) having a urea group.

When Q ^{3a of the} compound represented by the general formula (VIIIa) is an amine, the sulfonyl derivative represented by the general formula (I) may be a compound represented by the general formula (VIIIa) or a known isocyanate derivative In an inert solvent at a temperature of 20 ° C. to 100 ° C. for 0.5 to 120 hours.

The isocyanate derivative has the general formula (IV)
It can also be synthesized from the carboxylic acids represented by a) to (IVd). That is, the general formulas (IVa) to (IVd)
Is converted into an acid halide with thionyl chloride or oxalyl chloride, etc., in an inert solvent,
A method of reacting with sodium azide at a temperature in the range of 0 ° C. to 60 ° C. and then heating the mixed acid anhydride by reacting a carboxylic acid represented by the general formula (IVa) with a chloroformate such as isobutyl chloroformate And reacting with sodium azide and then heating, or a method of general formula (IVa) ~
(IVd) in an inert solvent such as tetrahydrofuran, chloroform or toluene,
At 20 ° C to 110 ° C below zero, it is converted to hydrazide via ester, and further reacted with nitrous acid or its alkyl ester to obtain acyl azide. And by heating at 150 ° C.

The carboxylic acids represented by the general formulas (IVa) to (IVd) are reacted with diphenylphosphoryl azide in an inert solvent in the presence of a base such as triethylamine at 10 ° C. to 10 ° C.
The sulfonyl derivative represented by the general formula (I) can also be produced by reacting at 0 ° C. and then reacting with an amine represented by the general formula (VIIIa).

[Production method-7] General formula (Ia) to be sulfonylated Q ¹ -Q ² -T ¹ -Q ^3a (Ia) wherein Q ¹ , Q ² , Q ^3a and T ¹ are as defined above. the same. When the nitrogen atom of Q ^{3a in} the compound represented by formula (I) is a primary or secondary amine, a compound represented by the general formula (XIII) obtained from chlorosulfonyl isocyanate and an alcohol in an inert solvent in the presence of a suitable base: ^{_{) Cl-SO 2 -NHCOOR 60 (}} XIII) [ wherein, R ⁶⁰ is as defined above. By reacting the compound represented by the general formula (XVI): Q ¹ -Q ² -T ¹ -Q ³ -SO ₂ -NHCOOR ⁶⁰ (XVI) [wherein Q ¹ , Q ² , Q ³ , R ⁶⁰ and T ¹ are as defined above. ] Can be synthesized.

The protective group on the nitrogen atom of the compound represented by the formula (XVI) is removed to give a compound of the formula (XVII) Q ¹ -Q ² -T ¹ -Q ³ -SO ₂ -NH ₂ (XVII) Wherein Q ¹ , Q ² , Q ³ and T ¹ are the same as above. The compound of the formula (XVII) is obtained in the presence of a suitable base in an inert solvent,
General formula (IIa-3a)

[0633]

Embedded image

[Wherein X ⁹ , X ¹⁰ , X ¹¹ , X ¹² , L ² , L
³ , w and z are the same as above. The compound represented by the following general formula (I-3a) can be synthesized from the compounds represented by the general formula (I).

[0635]

Embedded image

[Wherein Q ¹ , Q ² , Q ³ , T ¹ , X ⁹ ,
X ¹⁰ , X ¹¹ , X ¹² , w and z are the same as described above. ]

In the reaction between the compound represented by the general formula (Ia) and the compound represented by the general formula (XIII), as a base, for example, sodium carbonate, potassium carbonate or pyridine, 2,6-lutidine, collidine, 4-pyridine Organic bases such as dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, and diazabicyclo [5.4.0] undec-7-ene (DBU) can be used. As a solvent, diethyl ether, tetrahydrofuran, dimethoxy The reaction is carried out in an ether solvent such as ethane or dioxane, a halogen solvent such as dichloromethane or chloroform, a solvent such as benzene, toluene or acetone, or a mixed solvent thereof at a temperature of 70 ° C. to 100 ° C., and represented by the general formula (XVI). Compounds can be synthesized.

The removal of the protecting group on the nitrogen atom of the compound represented by the formula (XVI) may be carried out by using a suitable acid such as acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, It can be removed by phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids. Also, an arylmethyl group such as a benzyloxycarbonyl group, a paranitrobenzyloxycarbonyl group or a paramethoxybenzyloxycarbonyl group can be removed by hydrogenolysis using a palladium carbon catalyst. Is a suitable acid such as acetic acid, hydrochloric acid,
The compound can be removed by hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids to obtain a compound represented by the general formula (XVII).

The reaction between the compound represented by the general formula (XVII) and the compound represented by the general formula (IIa-3a) is carried out by an alcohol solvent such as ethanol, an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, and dichloromethane. In a solvent such as chloroform, a solvent such as chloroform, a solvent such as acetone, N, N-dimethylformamide, N-methylpyrrolidin-2-one, acetamide or a mixed solvent thereof in the presence of a base at 20 ° C to 150 ° C under zero temperature; Among the compounds represented by the general formula (I), the compound represented by the general formula (I-3a) can be obtained. Examples of the base include sodium carbonate, potassium carbonate, or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7.
Organic bases such as -ene (DBU).

The compound represented by the formula (I-3a) can be subjected to removal of a protecting group by a general method, if necessary.

[0641] [Production method -8] by coupling reaction using a transition metal catalyst, general formula ^{(I) Q 1 -Q 2 -T} 1 -Q 3 -SO 2 -Q A (I) [ In formula (I), Q ¹ , Q ² , Q ³ , Q ^A and T ¹ are the same as above. A method for synthesizing a sulfonyl derivative represented by the formula:

In the structure of Q ¹ of the sulfonyl derivative represented by the formula (I), a halogen atom or a trifluoromethanesulfonyloxy-substituted aryl group or a halogen atom or a trifluoromethanesulfonyloxy-substituted alkenyl group is present. In this case, a transition metal catalyst can be used to carry out a coupling reaction with an aryl compound substituted with a boric acid group.

If an alkenyl group is present in the structure of Q ¹ of the sulfonyl derivative represented by the formula (I), the sulfonyl derivative can be coupled to a halogen atom or a substituted aryl group of a trifluoromethanesulfonyloxy group using a transition metal catalyst. It is possible.

Similarly, when the structure of Q ¹ of the sulfonyl derivative represented by the general formula (I) includes an aryl group substituted with a boric acid group, an aryl compound or a halogen atom substituted with a halogen atom or a trifluoromethanesulfonyloxy group Alternatively, a coupling reaction with an alkenyl compound having a substituted trifluoromethanesulfonyloxy group can be performed.

If the structure of Q ¹ of the sulfonyl derivative represented by the formula (I) contains a halogen atom or an aryl group substituted with a trifluoromethanesulfonyloxy group,
The sulfonyl derivative represented by the general formula (I) can be obtained by coupling with an alkenyl compound using a transition metal catalyst. The thus obtained sulfonyl derivative represented by the general formula (I) may be deprotected if necessary.

In the structure of Q ¹ of the sulfonyl derivative represented by the general formula (I), a halogen atom or an aryl group substituted with a trifluoromethanesulfonyloxy group, or a halogen atom or an alkenyl group substituted with a trifluoromethanesulfonyloxy group is present. In such a case, sodium carbonate, sodium hydroxide, and water are used in a two-phase solvent such as benzene-water and toluene-water, an amide solvent such as N, N-dimethylformamide, and an ether solvent such as tetrahydrofuran and dimethoxyethane. In the presence of a base such as barium oxide, potassium phosphate or cesium carbonate or a neutral salt such as cesium fluoride, a transition metal catalyst such as tetrakis (triphenylphosphine) palladium (0) is used.
The coupling reaction can be carried out at 0 to 150 ° C for 0.5 to 120 hours with the aryl derivative having a substituted boric acid group.

When the structure of Q ¹ of the sulfonyl derivative represented by the formula (I) includes an aryl group substituted with a boric acid group, similarly, a halogen atom or an aryl compound substituted with a trifluoromethanesulfonyloxy group, halogen The coupling reaction can be carried out with an atom or a substituted alkenyl derivative of a trifluoromethanesulfonyloxy group.

If an alkenyl group or an alkenyl group substituted with a boric acid group is present in the structure of Q ¹ of the sulfonyl derivative represented by the general formula (I), an appropriate base may be used by using a transition metal catalyst such as palladium acetate. Under an amide solvent such as N, N-dimethylformamide, a coupling reaction with an aryl group substituted with a halogen atom or a trifluoromethanesulfonyloxy group is carried out at a temperature of 20 to 150 ° C. for 0.5 to 120 hours. it can.

Similarly, when the structure of Q ¹ of the sulfonyl derivative represented by the general formula (I) includes an aryl group substituted with a boric acid group, a halogen atom, an aryl derivative substituted with a trifluoromethanesulfonyloxy group, a halogen atom And a coupling reaction with an alkenyl derivative having a substituted trifluoromethanesulfonyloxy group.

[0650] If general formula substituted aryl group a halogen atom or a trifluoromethanesulfonyloxy group in the structure for Q ¹ of the sulfonyl derivative represented by the formula (I) is present, coupled using alkenyl compound and a transition metal catalyst, It is possible to obtain a sulfonyl derivative represented by the general formula (I). The sulfonyl derivative represented by the general formula (I) thus obtained can be deprotected, if necessary, to obtain a sulfonyl derivative represented by the general formula (I) in which a substituent is converted.

[Production method-9] Production method of thioamide-type sulfonamide derivative, amide oxime-type sulfonamide and hydrazono-type sulfonamide General formula (I) Q ¹ -Q ² -T ¹ -Q ³ -SO ₂ -Q ^A (I) wherein Q ¹ , Q ² , Q ³ , Q ⁴ and T ¹ are the same as above. Wherein T ¹ -Q ^{3 of the} sulfonyl derivative represented by

[0652]

Embedded image

[Wherein R ³ , R ⁴ , R ⁷ , R ⁸ and R ⁹ are the same as described above. n means an integer of 1 or 2. p is 1
From 3 to 3. q means an integer of 0 to 3. Here, the sum of p and q means an integer of 3 or 4. And Q ¹ , Q ² , Q in the general formula (I)
^{In the} case where no substituent having an amine, an alkylamine, an amide, a hydroxyl group or a carboxylic acid group is present on R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ and the substituents which can be substituted for them in the general formula (I) ) In an inert solvent to diphosphorus pentasulfide or Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-
Diphosphetane-2,4-disulfide) below 30 ° C
To 150 ° C, if necessary in an inert solvent, from 0 ° C to 1
By reacting at 20 ° C., a thioamide-type sulfonamide derivative (I) is obtained. Examples of inert solvents include dichloromethane, chloroform, alkyl halide solvents such as carbon tetrachloride, tetrahydrofuran,
Examples include ether solvents such as 1,2-dimethoxyethane and dioxane, aromatic solvents such as benzene and toluene, and mixed solvents thereof.

The obtained thioamide-type sulfonamide derivative was treated with hydroxylamine, optionally substituted alkoxyamine, hydrazine or optionally substituted hydrazine or a salt thereof, if necessary, with mercuric chloride. In the presence of a mercury catalyst such as (II) or the like, a temperature of 30 ° C. to 15 ° C.
The sulfonamide derivative represented by the general formula (I) can be obtained by reacting at 0 ° C., if necessary, in an appropriate solvent at 0 ° to 120 °. Examples of the solvent include alcohol solvents such as ethanol, alkyl halide solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, and aromatic solvents such as benzene and toluene. And a mixed solvent thereof.

Further, a halogenating agent such as phosphorus oxychloride or phosphorus pentachloride or an alkylating agent such as Meerbain reagent is added to the sulfonyl derivative represented by the general formula (I).
30 ° C to 140 ° C below zero, if necessary, for example, at 0 ° C in a halogen-based solvent which is an inert solvent such as chloroform.
To imino chloride or imino ether in an inert solvent at 0 ° C. to 80 ° C., preferably 20 ° C.
The sulfonyl derivative represented by the general formula (I) can be obtained by reacting hydroxylamine or an optionally substituted alkoxyamine or a salt thereof at a temperature of from 60 ° C to 60 ° C in the presence of a base catalyst if necessary. .

As the inert solvent, dichloromethane,
Examples include alkyl halide solvents such as chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane, and aromatic solvents such as benzene and toluene. Is preferred. Examples of the base include alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride, alkoxides, and hydroxides. Metal hydride, or an organometallic base represented by alkyllithium such as n-butyllithium, dialkylaminolithium such as lithium diisopropylamide, an organometallic base of bissilylamine such as lithium bis (trimethylsilyl) amide, Or an organic such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU). Or the like can be given to the group.

[Production Process-10] N-Oxidation In the sulfonyl derivative represented by the general formula (I),
¹, Q^Two, Q^Three, Q^A, T ¹Or a replacement
A heterocyclic aromatic ring containing a nitrogen atom, an aliphatic 3
When there is a secondary amine, the sulfonium represented by the general formula (I)
Water derivatives such as water and acetic acid, benzene, toluene,
Benzene solvents such as xylene, tetrahydrofuran,
Ether solvents such as dimethoxyethane,
Halogen such as dichloromethane, chloroform and carbon tetrachloride
Hydrogen peroxide, metachloroperbenzoate in alkyl fluoride solvents
Acid or peracid such as tert-butyl hydroperoxide
At 40 to 60 ° C below 0.5 hours to 12 hours.
React for 0 hours, preferably at 20 ° C to 20 ° C below zero
Thus, an N-oxide derivative represented by the general formula (I)
A sulfonyl derivative can be obtained.

[Production Method-11] Quaternization of nitrogen atom In the sulfonyl derivative represented by the general formula (I),
¹, Q^Two, Q^Three, Q^A, T ¹Or a replacement
Heterocyclic aromatic ring containing a nitrogen atom on the substituent, aliphatic tertiary
When an amine is present, a sulfonyl represented by the general formula (I)
Derivatives include 1,2-dimethoxyethane, dioxane, etc.
Ether solvents, aromatic solvents such as benzene and toluene
Solvent, N, N-dimethylformamide, N, N-dimethyl
Luacetamide, N-methylpyrrolidin-2-one, etc.
Amide solvents such as dimethyl sulfoxide and sulfolane
In any sulfoxide solvent, methyl iodide, ethyl iodide
Alkyl halides such as below 10 ° C to 150 ° C
C., preferably from 0 ° C. to 80 ° C.,
Sulfonyl derivative represented by general formula (I) of a primary amino compound
Get.

[Production Method-12] Sulfoxidation and Sulfonation [0658] In the sulfonyl derivative represented by the general formula (I),
When a heterocyclic ring containing a sulfur atom or an aliphatic thioether is present on Q ¹ , Q ² , Q ³ , Q ^A , T ¹ or a substituent capable of substituting thereon, the sulfonyl group represented by the general formula (I) The derivative is peroxide-oxidized in a solvent such as water and acetic acid, a benzene-based solvent such as benzene, toluene and xylene, an ether-based solvent such as tetrahydrofuran and dimethoxyethane, or an alkyl-based solvent such as dichloromethane, chloroform and carbon tetrachloride. Peroxide, such as hydrogen, metachloroperbenzoic acid, or tert-butyl hydroperoxide, at a temperature below 40 ° C to 60 ° C for 0.5 hours to 12 hours.
The reaction is carried out for 0 hour, preferably at a temperature of 20 ° C. to 20 ° C. below zero, so that sulfoxide or sulfone of the general formula (I)
Can be obtained.

[Production Method-13] Amidination-1 In the sulfonyl derivative represented by the general formula (I),
¹, Q^Two, Q^Three, Q^A, T ¹Or a replacement
When there is a nitrile group on the substituent,
This can be converted to an amidino group by a standard method. example
For example, the sulfonyl derivative represented by the general formula (I)
Then, an aliphatic ether-based solvent such as diethyl ether,
Alkyl halides such as chloroform and dichloromethane
Solvents, aprotic solvents such as benzene, or mixtures thereof
Existence of hydrogen halide such as hydrogen chloride and hydrogen bromide
At present, an equivalent to a large excess of methanol, ethanol, and propane
Alcohol having 1 to 4 carbon atoms, such as, for example,
Operate at 60 ° C for 3 hours to 120 hours.
And the resulting iminoether form is ethanol,
Alcohols having 1 to 4 carbon atoms such as ropanol, diethyl
Aliphatic ether solvents such as ether, chloroform, etc.
Aprotic, such as alkyl halide solvents and benzene
Solvent, N, N-dimethylformamide, dimethylsulfo
In a solvent such as oxide or a mixed solvent of these,
, A monoalkylamine which may have a substituent or
Is a dialkylamine which may have a substituent or
These carbonates and acetates at a temperature below 10 ° C to 140 ° C,
0.5 to 200 hours, preferably in ethanol
The reaction is carried out at 8 ° C to 30 ° C below zero for 10 hours to 96 hours.
Thus, the compound represented by the general formula (I) having an amidino group
Can be obtained.

[Production Method-14] Amidination-2 In the sulfonyl derivative represented by the general formula (I),
¹, Q^Two, Q^Three, Q^A, T ¹Or a replacement
When there is a primary or secondary amino group on the substituent,
This is converted to a substituted amidino group by the general methods used.
Can be exchanged. For example, the sulfonium represented by the general formula (I)
Of ethyl ether-based compounds such as diethyl ether
Medium, chloroform, dichloromethane, etc.
Aprotic solvents such as
Amide compound in a mixed solvent of, if necessary, in the presence of a base catalyst
Or iminoate synthesized from nitrile compounds
, Imino chloride or their salts and below 10 ° C
At 140 ° C. for 0.5 to 200 hours, preferably 0 to 200 hours.
Reaction at 10 ° C to 80 ° C for 10 to 96 hours
By the formula, a compound represented by the general formula (I) having an amidino group
A rufonyl derivative can be obtained. As a base, charcoal
Sodium acid, potassium carbonate, sodium hydroxide, hydroxy acid
Alkali metals or alkaline earths such as potassium iodide
Metal carbonate, hydroxide, or pyridine, 2,6-le
Thidine, collidine, 4-dimethylaminopyridine, tri
Ethylamine, N-methylmorpholine, diisopropyl
Ethylamine, diazabicyclo [5.4.0] undec
Organic bases such as -7-ene (DBU) may be mentioned.
it can.

[Production Method-15] N-Nitrilation In the sulfonyl derivative represented by the general formula (I),
¹, Q^Two, Q^Three, Q^A, T ¹Or a replacement
When there is a primary or secondary amine on the substituent,
This can be cyanated by the general methods used.

For example, a sulfonyl derivative represented by the general formula (I) is prepared by heating a sulfonyl derivative represented by the general formula (I) in an alcoholic solvent such as methanol, ethanol and propanol in the presence of a salt such as sodium acetate and a base at a temperature below 10 ° C. By reacting cyanogen bromide at 110 ° C., preferably from 0 ° C. to 60 ° C., a sulfonyl derivative represented by the general formula (I) having a nitrile group on a nitrogen atom can be obtained. Examples of the base include carbonates and hydroxides of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide, and pyridine, 2,6-lutidine, collidine, and 4-dimethylamino. Organic bases such as pyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU) can be mentioned.

[Production Method-16] Amidoximation, carboxamido-O-alkyloxy
In the sulfonyl derivative represented by the general formula (I),
¹, Q^Two, Q^Three, Q^A, T ¹Or a replacement
When there is a nitrile group on the substituent,
By an amidoxime group, carboxamide-
It can be converted to an O-alkyl oxime group.

For example, a sulfonyl derivative represented by the general formula (I) is converted into an alcoholic solvent such as methanol, ethanol and propanol, an etheric solvent such as diethyl ether and tetrahydrofuran, chloroform, In a halogenated hydrocarbon such as dichloromethane, an aprotic solvent such as toluene, an amide solvent such as N, N-dimethylformamide, a solvent such as dimethyl sulfoxide, or a mixed solvent thereof, a temperature of 10 ° C. to 110 ° C. below zero, preferably 0 ° C
To 60 ° C., if necessary, in the presence of a base catalyst, by reacting hydroxylamine or an optionally substituted alkoxyamine or a salt thereof to obtain a general formula having an amidoxime group or a carboxamide-O-alkyloxime group. The sulfonyl derivative represented by (I) can be obtained. As the base, sodium carbonate, potassium carbonate, sodium hydroxide, alkali metal or alkaline earth metal carbonates such as potassium hydroxide, hydroxides, or pyridine, 2,6-lutidine, collidine,
4-dimethylaminopyridine, triethylamine, N-
Methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DB
Organic bases such as U) can be mentioned.

[Production method-17] Guanidination [0666] In the sulfonyl derivative represented by the general formula (I),
¹, Q^Two, Q^Three, Q^A, T ¹Or a replacement
When there is a primary or secondary amino group on the substituent,
Substitute or unsubstitute it according to the general method used
Can be converted to a guanidino group.

For example, a sulfonyl derivative represented by the general formula (I) having a primary or secondary amino group is converted into an aliphatic ether solvent such as diethyl ether, a halogenated hydrocarbon such as chloroform or dichloromethane, In an aprotic solvent such as benzene or a mixed solvent thereof, if necessary, in the presence of a base catalyst, using N, N′-ditert-butoxycarbonylthiourea and N, N′-dicyclohexylcarbodiimide as condensing agents, at a temperature below 10 ° C. 0.5 hours to 200 hours at 140 ° C., preferably 10 ° C. at 0 ° C. to 80 ° C.
After reacting for from 96 hours to 96 hours, the usual tertiary butoxycarbonyl group is removed to obtain a sulfonyl derivative represented by the general formula (I), which is a guanidino compound. As the base, sodium carbonate, potassium carbonate,
Alkali metal or alkaline earth metal carbonates such as sodium hydroxide and potassium hydroxide, hydroxides, or pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropyl Organic bases such as ethylamine and diazabicyclo [5.4.0] undec-7-ene (DBU) can be mentioned.

[Production method-18] Removal of protecting group for nitrogen atom In the sulfonyl derivative represented by the general formula (I),
¹, Q^Two, Q^Three, Q^A, T ¹Or a replacement
On the substituent, an acylamino group, an alkoxycarbonylamino
Water, lower alcohols or tetra
Lithium hydroxide in drofuran or a mixture of these solvents
Like sodium, potassium or sodium hydroxide
From 0 ° C to 80 ° C, with the use of alkali metal hydroxide as a base
Hydrolysis can give an amino compound. Also third
Butoxycarbonyl group or paramethoxybenzyl
Bonding of acyl-type protecting group such as oxycarbonyl group
Nitrogen atoms are used in water, alcoholic solvents such as methanol,
Halogen such as chloromethane, chloroform, carbon tetrachloride
Alkylated solvent, tetrahydrofuran, 1,2-di
Ether solvents such as methoxyethane and dioxane;
Suitable acids in aromatic solvents such as toluene and toluene
For example, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoro
Acetic acid, trifluoromethanesulfonic acid or these
Between 0 ° C and 80 ° C depending on the combination of acids
Removal of acyl-type protecting groups and conversion to nitrogen-hydrogen bond
it can.

Also, a benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, para (ortho)
A nitrogen atom to which an arylmethoxycarbonyl group such as a nitrobenzyloxycarbonyl group is bonded is water, an alcohol solvent such as methanol or ethanol, an ester solvent such as ethyl acetate, an ether solvent such as diethyl ether or tetrahydrofuran, acetic acid, N , N-dimethylformamide or a mixed solvent thereof by hydrogenolysis using a palladium carbon catalyst to remove these arylmethoxycarbonyl groups from the nitrogen atom,
It can be converted to a nitrogen-hydrogen bond. A nitrogen atom to which a silyl protecting group such as a trimethylsilyl group or a tert-butyldimethylsilyl group is bonded is a halogenated alkyl solvent such as dichloromethane, chloroform or carbon tetrachloride, or an ether based solvent such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane. By reacting a hydrofluoric acid salt such as hydrochloric acid or tetrabutylammonium fluoride at 0 ° C. to 80 ° C. in an aromatic solvent such as a solvent, benzene and toluene,
By removing the silyl group from the nitrogen atom, it can be converted to a nitrogen-hydrogen bond. At the nitrogen atom to which the benzyl group is bonded, the benzyl group is subjected to catalytic reduction using a palladium carbon catalyst or the like in a solvent such as ethanol, tetrahydrofuran, or acetic acid at 0 ° C to 80 ° C, or Birch reduction using liquid sodium in liquid ammonia. It can be removed and converted to a nitrogen-hydrogen bond. At the nitrogen atom to which the triphenylmethyl group is bonded, triethanolamine is reduced by catalytic reduction using a palladium carbon catalyst or the like in a solvent such as ethanol, tetrahydrofuran, or acetic acid at 0 ° C to 80 ° C, or Birch reduction using liquid metal sodium in liquid ammonia. The phenylmethyl group can be removed and converted to a nitrogen-hydrogen bond. Removal of the triphenylmethyl group at 0 ° C. to 80 ° C. with a suitable acid such as formic acid, acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid or a combination of these acids. To convert to a nitrogen-hydrogen bond.

[Production Method-19] Ester Hydrolysis In the sulfonyl derivative represented by the general formula (I),
¹, Q^Two, Q^Three, Q^A, T ¹Or a replacement
When there is an alkoxycarbonyl group on the substituent,
Lithium and sodium hydroxide for
Alkali metal hydroxides such as thorium and potassium hydroxide
It can be hydrolyzed with any suitable base and converted to a carboxylic acid.
You. The tertiary butyl ester is trifluoroacetic acid.
Alternatively, the tertiary butyl group is removed by treatment with hydrochloric acid.
Arylmethyl group type esters such as benzyl group
Ant by hydrogenolysis using a palladium carbon catalyst
The carboxylic acid can be obtained by removing the methyl group
You. Potassium conversion of ester groups to carboxylic acid residues
It can also be performed using trimethylsilanolate.

[Production Method-20] represented by general formula (I)
In the sulfonyl derivative, Q¹, Q^Two, Q^Three, Q^A, T
¹Alternatively, an acyloxy group may be
Group, arylmethyloxy group, silyl ether group,
When there is a toxicoxy group or a tetrahydropyranyl group,
Acyl groups such as alkanoyl and aroyl are hydroxyl
Lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.
Hydrolysis with a suitable base such as alkali metal hydroxide
Or the presence of ammonia, methylamine, etc.
Can also be removed by reacting
You. Arylmethyl-type protecting group uses palladium carbon catalyst
Tertiary butyric acid
Silyl ether groups such as
Hydrofluoric acid such as butyl ammonium fluoride
Can be removed. In addition, methoxymethyl group, tetrahydropi
Ranyl groups and the like can be removed with acetic acid, hydrochloric acid or the like.

[Production method-21] represented by the general formula (I)
In the sulfonyl derivative, Q¹, Q^Two, Q^Three, Q^A, T
¹Alternatively, an amino group is
In some cases, commonly used acyl halides, carbohydrates
It can be acylated by a method using an activated acid.
Alkylation by reductive alkylation
be able to. In addition, sulfo chloride
Nylation, isocyanate or carboxylic acid
Urea derivative by reacting
To produce a sulfonyl derivative represented by the general formula (I)
it can.

[Production Method-22] represented by general formula (I)
In the sulfonyl derivative, Q¹, Q^Two, Q^Three, Q^A, T
¹Alternatively, a carboxy group may be
When a carboxyl group is present,
Carbamoyl by the reactive ester method, mixed acid anhydride method, etc.
Group, alkylcarbamoyl group, dialkylcarbamoyl
Can be converted to hydroxyl group and aldehyde group by reduction
it can. The converted hydroxyl or aldehyde group is usually
Further ether bond by applying the organic chemical method of
Formation, conversion to amino group, conversion to alkylamino group
Functional group conversion can be performed. Also, carboxyl
After converting the group to an ester directly or by a usual method,
Or mixed acid anhydride, then reduced and converted to alcohol
You can also.

[Production Method-23] Formation of Phenol In the sulfonyl derivative represented by the general formula (I),
¹, Q^Two, Q^Three, Q^A, T ¹Or a replacement
When there is a methoxy group substituted with an aryl group on the substituent
Include dichloromethane, chloroform, carbon tetrachloride, etc.
Alkyl halide solvents, benzene solvents such as toluene
Aluminum chloride at 78 ° C to 110 ° C in a medium
Lewis acids such as phosphorus bromide, boron tribromide, or halogen
Below zero in alkylated or ethereal solvents
From iodide to trimethylsilyl at 78 ° C to 110 ° C
The methyl group can be removed and converted to a hydroxyl group.

[Production method-24] Conversion of halogen atom to alkynyl group: Compound represented by general formula (I), general formula (VIIIa)
A compound represented by general formula (VIIIa-1b), a compound represented by (VIIIa-1c),
A compound represented by the general formula (VIIIa-2a), a compound represented by the general formula (VIIIa-2b),
IIa-2c), a compound represented by the general formula (VIIIa)
-D), a compound represented by the general formula (VIIIa-2)
e) a compound represented by the general formula (VIIIa-3a), or a compound represented by the general formula (VIIIa-3b)
When chlorine, bromine, or iodine is substituted on the aromatic ring of the compound represented by the formula, the compound can be converted to an acetylene group by reacting the compound with a silylacetylene compound in the presence of a transition metal catalyst.

The reaction is carried out by reacting a compound represented by the general formula (I) in which an aromatic ring is substituted with chlorine, bromine or iodine, or a compound represented by the general formula (VII):
Compounds represented by Ia), general formula (VIIIa-1b)
A compound represented by the general formula (VIIIa-1c), a compound represented by the general formula (VIIIa-2a), a compound represented by the general formula (VIIIa-2b),
A compound represented by the general formula (VIIIa-2c), a compound represented by the general formula (VIIIa-2d),
IIa-2e), a compound represented by the general formula (VIIIa)
-3a) or a compound of the general formula (VIII)
a-3b) and a silylacetylene such as trimethylsilylacetylene, if necessary, in the presence of a suitable base such as triethylamine or pyridine, in the presence of a benzene-based solvent such as toluene, or an ether-based solvent such as tetrahydrofuran;
Chlorine by reacting with amides such as N, N-dimethylformamide or a mixed solvent thereof with palladium acetate and triphenylphosphine in a temperature range from 20 ° C. to 150 ° C. for 0.5 to 120 hours. Bromine and iodine can be converted to silylacetylene groups.

The obtained silylacetylene compound is mixed with an alcoholic solvent such as methanol, an ethereal solvent such as tetrahydrofuran, water, or a mixed solvent thereof at 0 ° C. with a base such as potassium carbonate, potassium hydrogencarbonate or sodium hydroxide. By treating at ~ 80 ° C, silyl groups can be removed.

[Production Method-25] Conversion of halogen atom to nitrile group Compound represented by general formula (I), general formula (VIIIa)
A compound represented by the general formula (VIIIa-1b), a compound represented by the general formula (VIIIa-1c), a compound represented by the general formula (VIIIa-2a),
A compound represented by the general formula (VIIIa-2b), a compound represented by the general formula (VIIIa-2c), a compound represented by the general formula (VI
IIa-2d), a compound represented by the general formula (VIIIa)
-E), a compound represented by the general formula (VIIIa-3)
a) a compound represented by the general formula (VIIIa-
When the aromatic ring of the compound represented by 3b) is substituted with chlorine, bromine or iodine, it can be converted to a nitrile group by reacting with zinc cyanide in the presence of a transition metal catalyst. The reaction is carried out using a compound represented by the general formula (I) in which an aromatic ring is substituted with chlorine, bromine or iodine, or a compound represented by the general formula (VIIIa):
A compound represented by the general formula (VIIIa-1b), a compound represented by the general formula (VIIIa-1c), a compound represented by the general formula (VIIIa-2a),
A compound represented by the general formula (VIIIa-2b), a compound represented by the general formula (VIIIa-2c), a compound represented by the general formula (VI
IIa-2d), a compound represented by the general formula (VIIIa)
-E), a compound represented by the general formula (VIIIa-3)
a) a compound represented by the general formula (VIIIa-
3b) a compound represented by formula (3) and zinc cyanide, if necessary, in the presence of a suitable base such as triethylamine or pyridine, in the presence of a benzene solvent such as toluene, an ether solvent such as tetrahydrofuran, or an amide solvent such as N, N-dimethylformamide; Alternatively, the mixture is reacted with a transition metal catalyst such as tetrakis (triphenylphosphine) palladium (0) in a mixed solvent thereof at a temperature in the range of 20 ° C. to 150 ° C. for 0.5 to 120 hours to obtain chlorine, bromine, iodine. Can be converted to a nitrile group.

[Production Method-26] Conversion of halogen atom to trifluoromethyl group Compound represented by general formula (I), general formula (VIIIa)
A compound represented by the general formula (VIIIa-1b), a compound represented by the general formula (VIIIa-1c), a compound represented by the general formula (VIIIa-2a),
A compound represented by the general formula (VIIIa-2b), a compound represented by the general formula (VIIIa-2c), a compound represented by the general formula (VI
IIa-2d), a compound represented by the general formula (VIIIa)
-E), a compound represented by the general formula (VIIIa-3)
a) a compound represented by the general formula (VIIIa-
When chlorine, bromine, or iodine is substituted for the compound represented by the compound represented by 3b), chlorine, bromine, or the like is reacted by reacting a trifluoromethylation reagent in the presence of a metal catalyst.
Iodine can be converted to a nitrile group. A compound represented by the general formula (I) substituted with chlorine, bromine or iodine;
A compound represented by the general formula (VIIIa-1):
b), a compound represented by the general formula (VIIIa-1c), a compound represented by the general formula (VIIIa-2a), a compound represented by the general formula (VIIIa-2b), a general formula (VIIIa-2c) A compound represented by the general formula (VIIIa-2d), a compound represented by the general formula (VIIIa-2e), a compound represented by the general formula (VI
IIa-3a) or a compound of the general formula (V
IIIa-3b) and a trifluoromethylating reagent such as methyl 2,2-difluoro-2- (fluorosulfonyl) acetate in the presence of a metal catalyst such as copper iodide, a benzene-based solvent such as toluene, tetrahydrofuran, etc. Of chlorine, bromine, and iodine in trifluoromethyl by reacting at 0 ° C. to 150 ° C. for 0.5 to 120 hours in an ether-based solvent, an amide-based solvent such as N, N-dimethylformamide, or a mixed solvent thereof. Can be converted to a base.

[Production Method-27] Conversion of Nitrile Group to Tetrazole Group In the case where the compound represented by the general formula (I) is substituted with a nitrile group, the compound is represented by a benzene-based solvent such as benzene or toluene.
In the presence of trimethylaluminum or di-n-butyltin oxide, a compound represented by the general formula (I) is reacted with sodium azide or trimethylsilyl azide at 0 ° C to 170 ° C to obtain a compound represented by the general formula (III) having a tetrazole group: The compound represented by I) can be obtained.

[Production method-28] Conversion of amidino group to alkoxycarbonylamidino group When an amidino group is present in the compound represented by the formula (I), an alkyl halide solvent such as dichloromethane or chloroform, N, N Amide solvents such as dimethylformamide, in ether solvents such as tetrahydrofuran,
By reacting an acid chloride such as alkyl chlorocarbonate or a reagent such as alkyl p-nitrobenzyl carbonate at a temperature of 78 ° C. to 100 ° C. in the presence of a base, the compound is represented by the general formula (I) having an alkoxycarbonylamidino group. A compound can be obtained.

Examples of the base include sodium carbonate, potassium carbonate, pyridine, 2,6-lutidine, 4-dimethylaminopyridine, diazabicyclo [5.4.0] undec-7-ene (DBU) and the like. .

[Production method-29] represented by the general formula (I)
In the sulfonyl derivative, Q¹, Q^Two, Q^Three, Q^A, T
¹Or a primary or
When a secondary amine is present, the
Can be roxylated. For example, a sulfone represented by the general formula (I)
The honyl derivative is converted to benzene, toluene, xylene, etc.
Benzene solvent, tetrahydrofuran, dimethoxyethane
Ether solvents such as
In alkyl halide solvents such as roform and carbon tetrachloride
Peroxides such as metachloroperbenzoic acid at 60 ℃ below zero
At 80 ° C. for 0.5 to 120 hours, preferably zero
By reacting at 20 ° C to 40 ° C below, water of nitrogen atom
An oxidized sulfonyl derivative can be obtained.

Further, for example, a sulfonyl derivative represented by the general formula (I) is converted to a benzene-based solvent such as benzene, toluene, or xylene; an ether-based solvent such as dimethoxyethane; In an alkyl halide solvent, a peroxide such as benzoyl peroxide is reacted at a temperature of 60 ° C to 80 ° C under a temperature of 0.5 to 120 hours, preferably at a temperature of 20 ° C to 40 ° C under the temperature of zero, to thereby obtain a nitrogen atom. A benzoyloxylated sulfonyl derivative can be obtained, and the benzoyloxylated sulfonyl derivative of a nitrogen atom is hydrolyzed by the method described in [Production Method-19] to give a hydroxylated sulfonyl derivative of a nitrogen atom. Derivatives can be obtained.

The compounds (sulfonyl derivatives) of the present invention represented by the general formula (I), salts thereof and solvates thereof have a specific and excellent FXa inhibitory activity, and are effective in inhibiting blood coagulation, It is useful as an agent for preventing and / or treating emboli.

The sulfonyl derivative of the present invention exerts its effects even when administered orally, and can be administered either orally or parenterally. The dose of the sulfonyl derivative of the present invention may be appropriately increased or decreased depending on the condition, age, body weight, etc. of the patient. Generally, in the case of oral administration, 1 to 1 per adult
000 mg / day, preferably 5-300 mg / day may be administered. The dosage form is not particularly limited,
Examples include tablets, capsules, powders, granules, suspensions, syrups, dry syrups and the like. These can be produced by a known formulation technique together with usual additives such as excipients, lubricants and binders.

In the case of parenteral administration, the dosage form is not particularly limited, and examples thereof include ointments, plasters, injections, suppositories and the like. When administered as an injection, 0.1-100 mg / adult per adult
Daily, preferably 0.5 to 30 mg / day may be injected subcutaneously, intravenously or intravenously.

[0688]

The compound (sulfonyl derivative) represented by the general formula (I) of the present invention exhibits an anticoagulant effect based on an excellent FXa inhibitory effect. Accordingly, the sulfonyl derivative of the present invention does not act on platelets at all, and various diseases caused by thrombus and embolism, such as cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism, Burger disease, deep vein thrombosis, Generalized intravascular coagulation syndrome, thrombus formation after artificial valve replacement, reocclusion after revascularization, thrombus formation during extracorporeal circulation,
Blood coagulation at the time of blood collection can be treated or prevented.

Hereinafter, the sulfonyl derivative of the present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited thereto.

[0690]

EXAMPLES The sulfonyl derivative of the present invention and a method for producing the same will be specifically described below. The starting compounds for the sulfonyl derivative of the present invention also include novel compounds, and these compounds and their production methods will be described as reference examples.

In the production of the compound, silica gel column chromatography was performed using Merck silica gel 60 or silica gel for Yamazen medium pressure liquid chromatography as a carrier.

Also, nuclear magnetic resonance spectrum (NMR)
Used tetramethylsilane as an internal standard.

Reference Example 1 1-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride and trifluoroacetate tert-butyl 1-piperazinecarboxylate (856 mg) were dissolved in dichloromethane (20 ml), and triethylamine was dissolved. (0.77 ml), 6-chloro-
2-Naphthylsulfonyl chloride (WO96 / 100
22) (1.20 g) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue.
Washed with 1N hydrochloric acid. The extracted organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in saturated hydrochloric acid ethanol (10 ml), concentrated under reduced pressure, and the residue was washed with ethyl acetate to give the hydrochloride of the title compound (1.62 g, quant.) As a colorless solid. ¹ H NMR (DMSO-d ₆ ) δ 3.1-3.4 (8
H, m), 7.75 (1H, dd, J = 8.8, 2.0
Hz), 7.86 (1H, dd, J = 8.8, 1.5H)
z), 8.22 (1H, d, J = 8.8 Hz), 8.2
6-8.32 (2H, m), 8.56 (1H, s),
8.63 (2H, brs). MS (FAB) m / z 311 [(M + H) ⁺ , C
l ³⁵ ], 313 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 14 H 15 ClN 2 O} 2 S · HCl · 0.1H 2
As O: Calcd: C, 48.17; H, 4.68; Cl, 20.
31; N, 8.03; S, 9.19. Analytical values: C, 47.91; H, 4.68; Cl, 20.
41; N, 7.80; S, 9.21. Further, treatment with trifluoroacetic acid instead of saturated ethanol with hydrochloric acid was performed to obtain a trifluoroacetic acid salt. Elemental analysis: C ₁₄ H ₁₅ ClN ₂ O ₂ S.CF ₃ CO ₂ H Calculated: C, 45.24; H, 3.80; Cl, 8.3
5; F, 13.42; N, 6.59; S, 7.55. Analytical values: C, 44.84; H, 3.80; Cl, 8.2.
7; F, 13.72; N, 6.29; S, 7.50.

Reference Example 2 1-[(E) -4-Chlorostyrylsulfonyl) piperazine hydrochloride By the same reaction as in Reference Example 1, tert-butyl 1-
The title compound was obtained using piperazine carboxylate and (E) -4-chlorostyrylsulfonyl chloride (WO96 / 1022) as starting materials. ¹ H NMR (DMSO-d ₆ ) δ 3.20 (4H, br
s), 3.33-3.38 (4H, m), 7.47.
(2H, s), 7.53 (1H, d, J = 8.8H
z), 7.82 (1H, d, J = 8.8 Hz). Elemental _{analysis: C 12 H 15 ClN 2 O} 2 S · HCl Calculated: C, 44.59; H, 4.99 ; Cl, 21.
94; N, 8.67; S, 9.92. Analytical values: C, 44.42; H, 4.78; Cl, 21.
83; N, 8.68; S, 9.87.

Reference Example 3 4-tert-butoxycarbonyl-1-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazine 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine under ice cooling. (517 mg), 6-chloro-2-naphthylsulfonyl chloride (WO96 / 10
022) (588 mg) in dichloromethane (18 ml)
And dissolved in diisopropylethylamine (0.59 m
l) was added and the mixture was stirred at room temperature for 63 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (688 mg, 71%). ¹ H NMR (CDCl ₃ ) δ 1.05 (3H, t, J =
7.1 Hz), 1.38 (9H, s), 2.80-4.
70 (9H, m), 7.55 (1H, dd, J = 8.
6, 2.2 Hz), 7.77 (1H, dd, J = 8.
6, 1.7 Hz), 7.85-7.90 (3H, m),
8.33 (1H, s). MS (FAB) m / z 483 [(M + H) ⁺ , C
l ³⁵ ], 485 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 4 1-[(6-Chloronaphthalen-2-yl) sulfonyl] homopiperazine hydrochloride Homopiperazine (5 g) was dissolved in tetrahydrofuran (100 ml) at room temperature to give 2- (tert-butoxycarbonyloxyimino). ) -2-Phenylacetonitrile (12.3 g) was added slowly and stirred for 3 hours. After completion of the reaction, the solvent was distilled off and the residue was subjected to silica gel column chromatography (10 to 20% methanol-dichloromethane).
Then, ethanolic 1N hydrochloric acid was added, the solvent was distilled off, and ethanol was added to solidify the powder.
g) was obtained. Using this, the title compound was obtained in the same reaction as in Reference Example 1. ¹ H NMR (DMSO-d ₆ ) δ 2.00 (2H, br
s), 3.10-3.30 (4H, m), 3.30-
3.50 (2H, m), 3.55-3.65 (2H,
m), 7.72 (1H, d, J = 8.8 Hz), 7.8
9 (1H, d, J = 8.3 Hz), 8.17 (1H,
d, J = 8.8 Hz), 8.22-8.28 (2H,
m), 8.56 (1H, s), 9.29 (2H, br)
s). MS (FAB) m / z 325 (M + H) ⁺ . Elemental _{analysis: C 15 H 17 ClN 2 O} 2 S · HCl Calculated: C, 49.89; H, 5.02 ; N, 7.7
5; Cl, 19.63. Analytical values: C, 49.94; H, 5.05; N, 7.4.
7; Cl, 19.65.

Reference Example 5 (2RS) -2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonyl-1,2,2
3,4-tetrahydronaphthalene (2RS) -6-methoxycarbonyl-2-toluenesulfonyloxymethyl-1,2,3,4-tetrahydronaphthalene (2.56 g) was added to dimethylformamide (2
5 ml), sodium azide (0.92 g) was added, and the mixture was stirred at an external temperature of about 50 ° C. for 14 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, and dried over sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in tetrahydrofuran (35 ml), and triphenylphosphine (1.82 g) was added.
Stir for 1 hour. After adding about 28% aqueous ammonia (15 ml) and stirring for 3 hours, the reaction solution was concentrated under reduced pressure and extracted with ether, and diluted hydrochloric acid was added to make it acidic, and the aqueous layer was separated. A diluted aqueous sodium hydroxide solution was added to the mixture to make it alkaline, and the mixture was extracted with dichloromethane. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in dichloromethane (15 ml), and di-tert-butyl was added under ice cooling.
A dichloromethane solution (5 ml of dichloromethane) of dicarbonate (1.80 g) was added, and the mixture was stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by a silica gel column (silica gel 30 g, dichloromethane-dichloromethane: methanol = 50: 1), and recrystallized from a mixed solvent of n-hexane and ethyl acetate to give colorless crystals ( 1.56 g, 71%). ¹ H NMR (CDCl ₃ ) δ 1.40-1.60 (1
H, m), 1.46 (9H, s), 1.90-2.10
(2H, m), 2.50 (1H, dd, J = 17.1,
10.7Hz), 2.70-3.00 (3H, m),
3.10-3.30 (2H, m), 3.89 (3H,
s), 4.68 (1H, br), 7.12 (1H, d,
J = 7.8 Hz), 7.70-7.80 (2H, m). Elemental analysis: as C ₁₈ H ₂₅ NO ₄ Calculated: C, 67.69; H, 7.89; N, 4.3
9. Analytical values: C, 67.78; H, 7.61; N, 4.1.
2.

Reference Example 6 1-[[(6RS) -6- (N-tert-butoxycarbonylaminomethyl) -5,6,7,8-tetrahydronaphthalen-2-yl] carbonyl] -4-[(6 −
Chloronaphthalen-2-yl) sulfonyl] piperazine (2RS) -2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonyl-1,2,2
3,4-tetrahydronaphthalene (0.14 g) was dissolved in tetrahydrofuran (5 ml), 1N sodium hydroxide (0.50 ml) was added, and the mixture was stirred at room temperature for 3 days and at an external temperature of about 50 ° C. for 20 hours. Further, 1N sodium hydroxide (0.40 ml) was added and the mixture was added at an external temperature of about 50 ° C.
Stirred for days. After the reaction solution was concentrated under reduced pressure, dichloromethane and dilute hydrochloric acid were added to separate the organic layer, which was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. N,
Dissolve in N-dimethylformamide (5 ml) and add 1-
[(6-Chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (0.19 g), N-methylmorpholine (0.05 ml), 1- (3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (86. 0m
g), 1-hydroxybenzotriazole (71.0 m
g) was added and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and washed with water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (dichloromethane to dichloromethane).
Purification with dichloromethane: methanol = 100: 1) gave a colorless oil (0.23 g, 86%). ¹ H NMR (CDCl ₃ ) δ 1.30-1.60 (1
H, m), 1.45 (9H, s), 1.80-2.00
(2H, m), 2.43 (1H, dd, J = 16.6,
10.7Hz), 2.70-2.90 (3H, m),
3.00-3.20 (6H, m), 3.50-3.90
(4H, br), 4.69 (1H, br), 6.90-
7.10 (3H, m), 7.59 (1H, dd, J =
8.8, 2.0 Hz), 7.75 (1H, dd, J =
8.8, 2.0 Hz), 7.90-8.00 (3H,
m), 8.30 (1H, s). MS (FAB) m / z 598 [(M + H) ⁺ , C
l ³⁵ ], 600 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 7 (2RS) -2- (N-tert-butoxycarbonylaminomethyl) -6-hydroxymethyl-1,2,3
4-tetrahydronaphthalene (2RS) -2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonyl-1,2,2
3,4-Tetrahydronaphthalene (0.47 g) was dissolved in dichloromethane (10 ml), and diisobutylaluminum hydride (0.95 M hexane solution, 3.60 ml) was added dropwise at an external temperature of -78 ° C. At 90
Stirred for minutes. Methanol was added to the reaction solution, the temperature was raised to room temperature, insolubles were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. After diluting with dichloromethane, washing with water and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain colorless crystals (0.1%). 31g,
72%). A part thereof was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain colorless crystals. ¹ H NMR (CDCl ₃ ) δ 1.40-1.60 (1
H, m), 1.46 (9H, s), 1.60-1.70.
(1H, m), 1.90-2.00 (2H, m), 2.
45 (1H, dd, J = 16.6, 10.7 Hz),
2.70-2.90 (3H, m), 3.10-3.30
(2H, m), 4.62 (2H, d, J = 5.9H
z), 4.67 (1H, br), 7.00-7.20.
(3H, m). Elemental analysis: Calculated _{C 17 H 25 NO 3: C} , 70.07; H, 8.65; N, 4.8
1. Analytical values: C, 70.21; H, 8.49; N, 4.7.
5.

Reference Example 8 1-[[(6RS) -6- (N-tert-butoxycarbonylaminomethyl) -5,6,7,8-tetrahydronaphthalen-2-yl] methyl] -4-[(6 -Chloronaphthalen-2-yl) sulfonyl] piperazine (2RS) -2- (N-tert-butoxycarbonylaminomethyl) -6-hydroxymethyl-1,2,3,
4-Tetrahydronaphthalene (0.19 g) was dissolved in dichloromethane (5 ml), and pyridinium chlorochromate (0.17 g) was added. After stirring at room temperature for 2 hours, the reaction solution was directly subjected to silica gel column chromatography (hexane: acetic acid). Purification with ethyl (4: 1) gave a colorless solid (0.16 g). This is dichloromethane (8m
1) and dissolved in 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine trifluoroacetate (0.1.
24g), triethylamine (80.0 μl) and sodium triacetoxyborohydride (0.17 g) were added, and the mixture was stirred at room temperature under an argon gas atmosphere for 16 hours. An aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was diluted with dichloromethane, and the organic layer was separated. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3:
Purified in 1) to give a colorless candy (0.33 g, 86%)
I got ¹ H NMR (CDCl ₃ ) δ 1.30-1.50 (1
H, m), 1.44 (9H, s), 1.80-2.00
(2H, m), 2.40 (1H, m), 2.51 (4
H, br), 2.60-2.90 (3H, m), 3.0.
9 (6H, br), 3.39 (2H, s), 4.67
(1H, br), 6.90-7.00 (3H, m),
7.56 (1H, d, J = 8.8 Hz), 7.77 (1
H, d, J = 8.8 Hz), 7.80-8.00 (3
H, m), 8.28 (1H, s). MS (FAB) m / z 584 [(M + H) ⁺ , C
l ³⁵ ], 586 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 9 (2RS) -2- (tert-butyldimethylsilyloxymethyl) -6-methoxycarbonyl-1,2,3
4-tetrahydronaphthalene (2RS) -2-hydroxymethyl-6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene (1.71 g) was added to N, N-dimethylformamide (5 m
l), imidazole (0.81 g) under ice cooling, t
tert-butyldimethylsilyl chloride (1.81
g) was added and the mixture was stirred at room temperature for 14 hours. After methanol was added to the reaction solution, the mixture was concentrated under reduced pressure and diluted with ethyl acetate. After washing with water, drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to give a pale yellow solid (2.20 g, 85%). %). ¹ H NMR (CDCl ₃ ) δ 0.06 (6H, s),
0.91 (9H, s), 1.40-1.60 (1H,
m), 1.90-2.10 (2H, m), 2.53 (1
H, dd, J = 17.1, 10.3 Hz), 2.80-
3.00 (3H, m), 3.58 (2H, d, J = 5.
9 Hz), 3.89 (3H, s), 7.14 (1H,
d, J = 7.8 Hz), 7.70-7.80 (2H,
m). MS (FAB) m / z 335 (M + H) ^<+> .

Reference Example 10 (2RS) -2- (tert-Butyldimethylsilyloxymethyl) -6-hydroxymethyl-1,2,3,4
-Tetrahydronaphthalene In the same manner as in Reference Example 7, the title compound was obtained using (2RS) -2- (tert-butyldimethylsilyloxymethyl) -6-methoxycarbonyl-1,2,3,4-tetrahydronaphthalene as a raw material. . ¹ H NMR (CDCl ₃ ) δ 0.07 (6H, s),
0.91 (9H, s), 1.30-1.50 (1H,
m), 1.50-1.60 (1H, m), 1.90-
2.10 (2H, m), 2.48 (1H, m), 2.7
0-2.90 (3H, m), 3.58 (2H, m),
4.62 (2H, d, J = 5.9 Hz), 7.09 (3
H, m). MS (FAB) m / z 307 (M + H) ^<+> .

Reference Example 11 (2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2- (tert-butyldimethylsilyloxymethyl) -1,2,3,4-tetrahydronaphthalene (2RS) -2 -(Tert-butyldimethylsilyloxymethyl) -6-hydroxymethyl-1,2,3,4
-Tetrahydronaphthalene (1.00 g) was dissolved in dichloromethane (10 ml) and triethylamine (0.5
ml) was added and the mixture was cooled with ice. A dichloromethane solution (1 ml of dichloromethane) of methanesulfonyl chloride (0.39 g) was added, and the mixture was stirred at room temperature for 9 hours, washed with water, and dried over anhydrous sodium sulfate. The title compound (1.1) was obtained in the same manner as in Reference Example 5 using the residue obtained by evaporating the solvent under reduced pressure.
0 g, 83%). ¹ H NMR (CDCl ₃ ) δ 0.06 (6H, s),
0.91 (9H, s), 1.40-1.60 (1H,
m), 1.46 (9H, s), 1.90-2.00 (2
H, m), 2.45 (1H, m), 2.70-2.90
(3H, m), 3.57 (2H, m), 4.24 (2
H, m), 4.76 (1H, br), 7.00-7.1.
0 (3H, m). MS (FAB) m / z 406 (M + H) ^<+> .

Reference Example 12 (2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2-hydroxymethyl-1,2,3
4-tetrahydronaphthalene (2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2- (tert-butyldimethylsilyloxymethyl) -1,2,3,4-tetrahydronaphthalene (1.09 g) was added to tetrahydrofuran. (10m
l), tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 4.0 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure,
The mixture was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 2: 1) to obtain a colorless solid (0.77 g,
98%). A part thereof was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain colorless crystals. ¹ H NMR (CDCl ₃ ) δ 1.40-1.60 (2
H, m), 1.46 (9H, s), 1.90-2.10
(2H, m), 2.48 (1H, dd, J = 16.6,
10.7Hz), 2.70-3.00 (3H, m),
3.6-3.7 (2H, m), 4.24 (2H, d, J
= 5.4 Hz), 4.78 (1H, br), 7.00-
7.10 (3H, m). Elemental analysis: Calculated _{C 17 H 25 NO 3: C} , 70.07; H, 8.65; N, 4.8
1. Analytical values: C, 70.02; H, 8.61; N, 4.4.
6.

Reference Example 13 1-[[(2RS) -6- (N-tert-butoxycarbonylaminomethyl) -1,2,3,4-tetrahydronaphthalen-2-yl] methyl] -4-[(6 -Chloronaphthalen-2-yl) sulfonyl] piperazine (2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2-hydroxymethyl-1,2,3,
4-tetrahydronaphthalene (0.17 g) was dissolved in dichloromethane (5 ml), and N-methylmorpholine N
-Oxide (0.13 g), molecular sieves
4A (activated powder, 0.18 g) was added, and ruthenium tetroxide tetrapropylammonium salt (10 m
g) was added and the mixture was stirred at room temperature for 1 hour. Ether was added to the reaction solution to remove insolubles by celite filtration, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane) to obtain an aldehyde compound, which was used in the same reaction as in Reference Example 8 to give
The title compound (0.14 g, 41%) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.20-1.40 (1
H, m), 1.44 (9H, s), 1.80-2.00
(2H, m), 2.20-2.40 (3H, m), 2.
50-2.60 (4H, m), 2.60-2.80 (3
H, m), 3.11 (4H, m), 4.20 (2H,
d, J = 5.4 Hz), 4.79 (1H, br), 6.
94 (3H, m), 7.57 (1H, dd, J = 8.
8, 1.5 Hz), 7.79 (1H, dd, J = 8.
8, 1.5 Hz), 7.90-8.00 (3H, m),
8.31 (1H, s). MS (FAB) m / z 584 [(M + H) ⁺ , C
l ³⁵ ], 586 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 14 1-[[(2RS) -6- (N-tert-butoxycarbonylaminomethyl) -1,2,3,4-tetrahydronaphthalen-2-yl] carbonyl] -4-[(6 −
Chloronaphthalen-2-yl) sulfonyl] piperazine (2RS) -6- (N-tert-butoxycarbonylaminomethyl) -2-hydroxymethyl-1,2,3,
4-tetrahydronaphthalene (0.21 g) was added to carbon tetrachloride (2 ml), acetonitrile (2 ml), and water (3 m
l), sodium periodate (0.48 g),
Ruthenium trichloride hydrate (4 mg) was added, and the mixture was stirred for 90 minutes. The reaction solution was diluted with dichloromethane, and the organic layer was separated and dried over anhydrous sodium sulfate.
Ether was added to the residue obtained by evaporating the solvent under reduced pressure,
The insoluble material was removed by filtration, and the filtrate was distilled off under reduced pressure. The title compound (0.11 g, 25%) was obtained by the same reaction as in Reference Example 12 using the obtained carboxylic acid compound. ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
1.70-2.00 (2H, m), 2.60-2.90
(4H, m), 2.95 (1H, m), 3.11 (4
H, m), 3.64 (2H, m), 3.76 (2H,
m), 4.22 (2H, d, J = 5.4 Hz), 4.8
2 (1H, br), 6.90-7.10 (3H, m),
7.59 (1H, d, J = 8.8 Hz), 7.77 (1
H, d, J = 8.8 Hz), 7.90-8.00 (3
H, m), 8.31 (1H, s). MS (FD) m / z597 ( M + Cl 35), 599
(M ⁺ , Cl ³⁷ ).

Reference Example 15 2- (N-tert-butoxycarbonylaminomethyl) -7-methoxycarbonylnaphthalene In the same reaction as in Reference Example 11, 2-hydroxymethyl-7-methoxycarbonylnaphthalene (1.01 g) was used as a starting material. To give the title compound. ¹ H NMR (CDCl ₃ ) δ 1.49 (9H, s),
3.98 (3H, s), 4.50 (2H, d, J = 5.
4Hz), 4.99 (1H, br), 7.53 (1H,
d, J = 8.3 Hz), 7.80-7.90 (3H,
m), 8.04 (1H, dd, J = 8.3, 1.0H
z), 8.57 (1H, s). Elemental analysis: As C ₁₈ H ₂₁ NO ₄ Calculated: C, 68.55; H, 6.71; N, 4.4
4. Analytical values: C, 68.54; H, 6.70; N, 4.4.
6.

Reference Example 16 1-[[7- (N-tert-butoxycarbonylaminomethyl) naphthalen-2-yl] carbonyl] -4-
[(6-Chloronaphthalen-2-yl) sulfonyl] piperazine In the same manner as in Reference Example 6, the title compound was obtained using 2- (N-tert-butoxycarbonylaminomethyl) -7-methoxycarbonylnaphthalene as a raw material. ¹ H NMR (CDCl ₃ ) δ 1.46 (9H, s),
3.12 (4H, br), 3.50-4.00 (4H,
br), 4.45 (2H, d, J = 5.9 Hz), 5.
01 (1H, br), 7.34 (1H, d, J = 7.8)
Hz), 7.45 (1H, d, J = 8.3 Hz), 7.
50-7.60 (1H, m), 7.66 (1H, s),
7.70-7.80 (4H, m), 7.90-8.00
(3H, m), 8.30 (1H, s). MS (FAB) m / z 594 [(M + H) ⁺ , C
l ³⁵ ], 596 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 17 1-[[7- (N-tert-butoxycarbonylaminomethyl) naphthalen-2-yl] methyl] -4-
[(6-Chloronaphthalen-2-yl) sulfonyl] piperazine Using 2- (N-tert-butoxycarbonylaminomethyl) -7-methoxycarbonylnaphthalene as a starting material, the title compound was obtained by the same reaction as in Reference Examples 7 and 13. The compound was obtained. ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s),
2.50-2.70 (4H, m), 3.10 (4H, b
r), 3.61 (2H, s), 4.44 (2H, d, J
= 5.4 Hz), 4.92 (1H, br), 7.30-
7.40 (2H, m), 7.50-7.70 (3H,
m), 7.70-7.90 (3H, m), 7.90-
8.00 (3H, m), 8.29 (1H, s). MS (FAB) m / z 580 [(M + H) ⁺ , C
l ³⁵ ], 582 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 18 2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonylnaphthalene 2,6-naphthalenedicarboxylate dimethyl (2.00
g) was suspended in a mixed solvent of tetrahydrofuran (40 ml) and methanol (8 ml), sodium borohydride (0.98 g) was added under ice cooling, and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction solution, and the mixture was concentrated under reduced pressure. Ethyl acetate and diluted hydrochloric acid were added to separate an organic layer. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was adsorbed on silica gel (13 g) and purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain colorless crystals (1. (23 g, 70%), and the title compound was obtained by the same reaction as in Reference Example 11. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
3.98 (3H, s), 4.50 (2H, d, J = 5.
4Hz), 4.99 (1H, br), 7.47 (1H,
d, J = 8.3 Hz), 7.75 (1H, s), 7.8
4 (1H, d, J = 8.8 Hz), 7.92 (1H,
d, J = 8.8 Hz), 8.06 (1H, d, J = 8.
3Hz), 8.58 (1H, s). Elemental analysis: As C ₁₈ H ₂₁ NO ₄ Calculated: C, 68.55; H, 6.71; N, 4.4
4. Analytical values: C, 68.93; H, 6.70; N, 4.2.
9.

Reference Example 19 Methyl 5-benzimidazolecarboxylate hydrochloride Under ice-cooling, thionyl chloride (2.
After dropwise addition of 5-benzimidazolecarboxylic acid (5.00 g), the mixture was refluxed for 5 hours. The reaction solution was distilled off under reduced pressure, and the residue was pulverized in ether and collected by filtration to obtain colorless crystals (6.36 g, 97%). ¹ H NMR (DMSO-d ₆ ) δ 3.93 (3H,
s), 7.96 (1H, d, J = 8.8 Hz), 8.1.
2 (1H, d, J = 8.8 Hz), 8.40 (1H,
s), 9.66 (1H, s). Elemental analysis: C ₉ H ₈ N ₂ O ₂ .HCl Calculated: C, 50.84; H, 4.27; N, 13.1
7; Cl, 16.67. Analytical values: C, 50.64; H, 4.22; N, 13.1
2: Cl, 16.59.

Reference Example 20 Methyl N-triphenylmethyl-5-benzimidazolecarboxylate Methyl 5-benzimidazolecarboxylate hydrochloride (1.00 g) was suspended in dichloromethane (15 ml), and triethylamine (1.50 ml) was added. Triphenylmethyl chloride (1.50 g) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give a yellow solid. As a result, the title compound (2.10 g, quant.) Was obtained. ¹ H NMR (CDCl ₃ ) δ 3.75 (2H, s),
3.89 (1H, s), 6.49 (1 / 3H, d, J =
8.8 Hz), 7.1-7.4 (16H, m), 7.6
6. 1 (ＨH, dd, J = 8.8, 1.5 Hz);
78 (2 / 3H, d, J = 8.8 Hz), 7.87 (2
/ 3H, dd, J = 8.8, 1.5 Hz), 7.96
(1 / 3H, s), 8.02 (2 / 3H, s). MS (FAB) m / z 419 (M + H) ^<+> .

Reference Example 21 Thiazolo [5,4-c] pyridine-2-carboxylic acid sodium salt ethyl thiazolo [5,4-c] pyridine-2-carboxylate (J. Heterocyclic Chem., 2)
7,563,1990) (0.61 g) was dissolved in tetrahydrofuran (12 ml), a 1 N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 30 minutes. It was used for the next reaction without purification. ¹ H NMR (DMSO-d ₆ ) δ 7.95 (1H, d,
J = 5.9 Hz), 8.57 (1H, d, J = 5.9H)
z), 9.27 (1H, s).

Reference Example 22 1-[(5-tert-butoxycarbonyl-4,5,
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl) methyl] -4-[(6-chloronaphthalene-
2-yl) sulfonyl] piperazine By the same reaction as in Reference Example 8, 5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine (WO94 / 215)
99), 1-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as a starting material to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s),
2.53-2.62 (4H, m), 2.72 (2H, b
rs), 3.10 (4H, br s), 3.59 (2
H, s), 3.66 (2H, br s), 4.38 (2
H, s), 6.54 (1H, s), 7.57 (1H, d
d, J = 8.8, 2.0 Hz), 7.76 (1H, d
d, J = 8.8, 2.0 Hz), 7.87-7.94
(3H.m), 8.29 (1H, s). MS (FAB) m / z 562 [(M + H) ⁺ , C
l ³⁵ ], 564 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 23 3- (5-tert-butoxycarbonyl-4,5,
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl) propionic acid Under ice cooling, sodium hydride (approximately 60%, 126 mg) was added to tetrahydrofuran (10 ml) and stirred for 5 minutes, and then ethyl diethylphosphonoacetate (0.42 ml).
Was added dropwise and the mixture was stirred under ice cooling for 30 minutes. 5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine (WO94 /
(2599) (360 mg) in tetrahydrofuran (10 ml of tetrahydrofuran) was added dropwise, and the mixture was stirred under ice cooling for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added.
Washed with water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5:
1) to give a yellow oil (515 mg, quan)
t. ) Got. This oil (1.38 g, 4.09 mm)
ol) in methanol (40 ml), 10% palladium on carbon (0.20 g) was added thereto, and the mixture was subjected to catalytic reduction under normal pressure for 1 hour. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give a pale yellow oil (1). .41 g, quant.).

This oil (1.38 g, 4.07 mmol)
1) was dissolved in tetrahydrofuran (15 ml), ethanol (10 ml) and 1N aqueous sodium hydroxide solution (8 ml) were added, and the mixture was heated under reflux for 30 minutes. 1 in the reaction solution
The organic layer was separated by adding normal hydrochloric acid and ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (1.28 g, quant.) As a colorless oily substance. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
2.70 (2H, t, J = 7.3 Hz), 2.76 (2
H, br s), 3.09 (2H, t, J = 7.3H)
z), 3.70 (2H, s), 4.40 (2H, s),
6.51 (1H, s). MS (FD) m / z 311M ⁺ .

Reference Example 24 (E) -3- (5-tert-Butoxycarbonyl-)
4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) acrylic acid In the reaction shown in Reference Example 23, a hydrolysis reaction was carried out without carrying out catalytic reduction to give the title compound. Obtained. ¹ H NMR (CDCl ₃ ) δ 1.49 (9H, s),
2.85 (2H, brs), 3.73 (2H, brs)
s), 4.47 (2H, s), 6.12 (1H, d, J
= 15.4 Hz), 6.98 (1H, s), 7.77
(1H, d, J = 15.4 Hz). MS (FD) m / z 309 M ⁺ .

Reference Example 25 1-[(E) -3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-
c] pyridin-2-yl) propenoyl] -4-[(6
-Chloronaphthalen-2-yl) sulfonyl] piperazine By the same reaction as in Reference Example 6, (E) -3- (5-te
rt-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) acrylic acid, 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride The title compound was obtained as starting material. ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s),
2.80 (2H, brs), 3.12 (4H, t, J
= 4.9 Hz), 3.46-3.86 (6H, m),
4.41 (2H, s), 6.39 (1H, d, J = 1
5.1Hz), 6.83 (1H, s), 7.55-7.
78 (3H, m), 7.89-7.92 (3H, m),
8.30 (1H, s). MS (FD) m / z 601 (M ⁺ , Cl ³⁵ ), 603
(M ⁺ , Cl ³⁷ ).

Reference Example 26 1- [3- (5-tert-butoxycarbonyl-4,
5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propionyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine 3- (5-tert-butoxycarbonyl- 4,5,
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl) propionic acid (445 mg) was dissolved in tetrahydrofuran (10 ml), and N-methylmorpholine (170 μl) and isobutyl chloroformate (2
10 μl) were sequentially added dropwise. After stirring at −20 ° C. for 10 minutes, 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (607 mg) previously dissolved in dichloromethane (10 ml) was added. -2
After stirring at 0 ° C. for 10 minutes, the reaction solution was heated to room temperature. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in dichloroethane, and 1N hydrochloric acid, saturated sodium hydrogen carbonate,
After washing with saturated saline and drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 2:
Purification in 1) afforded the title compound (625 mg, 72%). ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s),
2.53 (2H, t, J = 7.5 Hz), 2.68 (2
H, brs), 2.99-3.10 (6H, m),
3.51-3.55 (2H, m), 3.64 (2H, b
rs), 3.72-3.77 (2H, m), 4.34.
(2H, s), 6.43 (1H, s), 7.59 (1
H, dd, J = 8.8, 2.0 Hz), 7.74 (1
H, dd, J = 8.8, 2.0 Hz), 7.88-7.
94 (3H, m), 8.30 (1H, s). MS (FAB) m / z 604 [(M + H) ⁺ , C
l ³⁵ ], 606 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 27 3- (5-tert-butoxycarbonyl-4,5,
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl) propanal ethyl 3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propionate obtained in Reference Example 102 ( 1.68 g) was dissolved in dichloromethane (100 ml), stirred at -78 ° C for 10 minutes, and then diisobutylaluminum hydride (0.98 M hexane solution, 7.5).
0 ml) was slowly added dropwise. After stirring at −78 ° C. for 10 minutes, methanol (50 ml) was added and the temperature was raised to room temperature. The reaction solution was concentrated under reduced pressure, dichloromethane and a saturated aqueous solution of ammonium chloride were added to the residue, and the mixture was filtered through celite. The organic layer was separated from the filtrate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (935 mg,
55%). ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
2.76 (2H, brs), 2.81 (2H, t, J
= 7.3 Hz), 3.09 (2H, t, J = 7.3H)
z), 3.69 (2H, brs), 4.39 (2H,
s), 6.49 (1H, s), 9.81 (1H, s). MS (FD) m / z 295 M ^<+> .

Reference Example 28 1- [3- (5-tert-butoxycarbonyl-4,
5,6,7-Tetrahydrothieno [3,2-c] pyridin-2-yl) propyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine By the same reaction as in Reference Example 8, 3 -(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propanal,
The title compound was obtained using 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as a raw material. ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s),
1.69-1.79 (2H, m), 2.36 (2H,
t, J = 7.3 Hz), 2.49-2.54 (4H,
m), 2.65-2.75 (4H, m), 3.10 (4
H, br s), 3.67 (2H, br s), 4.3
7 (2H, s), 6.39 (1H, s), 7.57 (1
H, dd, J = 8.8, 2.0 Hz), 7.78 (1
H, dd, J = 8.8, 2.0 Hz), 7.88-7.
95 (3H, m), 8.30 (1H, s). MS (FD) m / z 589 (M +, Cl 35), 591
(M ⁺ , Cl ³⁷ ).

Reference Example 29 2-aminomethyl-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c]
Pyridine 5-tert-butoxycarbonyl-2-hydroxymethyl-4,5,6,7-tetrahydrothieno [3,2-
c] pyridine (WO94 / 21599) (2.10 g)
Was dissolved in tetrahydrofuran (100 ml), triphenylphosphine (2.66 g) and phthalimide (1.15 g) were added, and then diethyl azodicarboxylate (1.28 ml) was added dropwise, followed by stirring at room temperature for 5 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain a colorless solid. This is ethanol (40m
1), hydrazine hydrate (0.39 ml) was added, and the mixture was heated under reflux for 5 hours. After the precipitated solid was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane-dichloromethane: methanol = 25: 1) to give the title compound (44).
8 mg, 21%). ¹ H NMR (DMSO-d ₆ ) δ 1.42 (9H,
s), 2.72 (2H, m), 3.60 (2H, m),
3.80 (2H, s), 4.32 (2H, s), 6.6
4 (1H, s). MS (FD) m / z 268 M ⁺ .

Reference Example 30 1- [N-[(5-tert-butoxycarbonyl-
4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl] carbamoyl] -4-
[(6-chloronaphthalen-2-yl) sulfonyl] piperazine 5-tert-butoxycarbonyl-2-aminomethyl-4,5,6,7-tetrahydrothieno [3,2-c]
Pyridine (150 mg) was added to tetrahydrofuran (100
carbonyldiimidazole (136 mg) was added under ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in toluene (50 ml). Triethylamine (0.23 ml) under ice-cooling,
1-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (356 mg) was added, and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 1).
The title compound (303 mg, 89%) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.46 (9H, s),
2.70 (2H, brs), 3.07 (4H, t, J
= 4.9 Hz), 3.48 (4H, t, J = 4.9H)
z), 3.66 (2H, brs), 4.36 (2H,
brs), 4.39 (2H, d, J = 5.4 Hz),
4.69 (1H, t, J = 5.4 Hz), 6.58 (1
H, s), 7.58 (1H, dd, J = 8.8, 2.0
Hz), 7.74 (1H, dd, J = 8.8, 2.0H)
z), 7.87-7.93 (3H, m), 8.30 (1
H, s). MS (FD) m / z 604 (M +, Cl 35), 606
(M ⁺ , Cl ³⁷ ).

Reference Example 31 1-[(5-tert-butoxycarbonyl-4,5,
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine Similarly to Reference Example 6, 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3, 2-c]
Pyridine-2-carboxylic acid (WO94 / 21599),
The title compound was obtained using 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as a raw material. ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s),
2.79 (2H, brs), 3.12 (4H, t, J
= 4.9 Hz), 3.68 (2H, brs), 3.8
4 (4H, t, J = 4.9 Hz), 4.42 (2H, b
rs), 6.91 (1H, s), 7.59 (1H, d
d, J = 8.8, 2.0 Hz), 7.75 (1H, d
d, J = 8.8, 2.0 Hz), 7.90-7.97
(3H, m), 8.30 (1H, s). MS (FD) m / z 575 (M +, Cl 35), 577
(M ⁺ , Cl ³⁷ ).

Reference Example 32 1-[(5-tert-butoxycarbonyl-4,5,
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazine As in Reference Example 6, 5-tert-butoxycarbonyl-4,5,6,7- Tetrahydrothieno [3,2-c]
Pyridine-2-carboxylic acid (WO94 / 21599),
1-[(6-chloronaphthalen-2-yl) sulfonyl] -3-ethoxycarbonylpiperazine (WO96 /
10022) as a starting material to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 1.32 (3H, t, J =
7.3 Hz), 1.47 (9H, s), 2.35-2.
46 (1H, m), 2.55-2.64 (1H, m),
2.80 (2H, brs), 3.15-3.20 (1
H, m), 3.69 (2H, brs), 3.75-
3.85 (1H, m), 4.12 (2H, q, J = 7.
3Hz), 4.20-4.36 (2H, m), 4.39
-4.48 (3H, m), 6.96 (1H, s), 7.
59 (1H, dd, J = 8.8, 2.0 Hz), 7.7
5 (1H, dd, J = 8.8, 2.0 Hz) 7.88-
7.94 (3H, m), 8.32 (1H, s). MS (FAB) m / z 648 [(M + H) ⁺ , C
l ³⁵ ], 650 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 33 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(5-cyano-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2 -Yl) carbonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl Piperazine hydrochloride (195 mg), triethylamine (0.2 ml) and sodium acetate (118 mg) were suspended in ethanol, and cyanogen bromide (114 mg) was added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, dichloromethane was added to the residue, and the mixture was washed with water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain the title compound (51 mg, 28%). ¹ H NMR (CDC
_{l 3) δ2.93-2.98 (2H, m} ), 3.11-
3.14 (4H, m), 3.49-3.55 (2H,
m), 3.81-3.84 (4H, m), 4.29 (2
H, s), 6.89 (1H, s), 7.59 (1H, d
d, J = 8.8, 2.0 Hz), 7.75 (1H, d
d, J = 8.8, 2.0 Hz), 7.90-7.94
(3H, m), 8.30 (1H, s). MS (FAB) m / z 501 [(M + H) ⁺ , C
l ³⁵ ], 503 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 34 1- [N- (5-tert-butoxycarbonyl-4,
5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbamoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine 5-tert-butoxycarbonyl-4,5 , 6,7-
Tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid (WO94 / 21599) (283 mg) was dissolved in benzene (10 ml), and triethylamine (0.1
4 ml), diphenylphosphoryl azide (0.21 m
g) was added and the mixture was heated under reflux for 2 hours. After cooling the reaction solution to room temperature, 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (347 mg),
Triethylamine (0.28 ml) was added, and the mixture was refluxed overnight. After the reaction solution was cooled to room temperature, dichloromethane and a 3N aqueous solution of sodium hydroxide were added to extract an organic layer. After the extracted organic layer was washed with 0.5N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 2: 1),
The title compound (284 mg, 48%) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
2.65 (2H, brs), 3.10 (4H, t, J
= 4.9 Hz), 3.57 (4H, t, J = 4.9H)
z), 3.64 (2H, br s), 4.27 (2H,
s), 6.15 (1H, br s), 7.58 (1H,
dd, J = 8.8, 2.0 Hz), 7.73 (1H, d
d, J = 8.8, 2.0 Hz), 7.87-7.93
(3H, m), 8.28 (1H, s). MS (FAB) m / z 591 [(M + H) ⁺ , C
l ³⁵ ], 593 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 35 1- [N- (5-tert-butoxycarbonyl-4,
5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) -N-methylcarbamoyl] -4-
[(6-Chloronaphthalen-2-yl) sulfonyl] piperazine 1- [N- (5-tert-butoxycarbonyl-4,
5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbamoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine (147
mg) was dissolved in N, N-dimethylformamide (10 ml), 60% oily sodium hydride (22 mg) was added, and the mixture was stirred at room temperature for 30 minutes. After adding methyl iodide (0.023 ml) to the reaction solution and stirring at room temperature for 90 minutes, the reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the obtained residue.
After washing with water and saturated saline, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2:
Purification according to 1) gave the title compound (43 mg). ¹ H NMR (CDCl ₃ ) δ 1.49 (9H, s),
2.63 (2H, brs), 3.01 (4H, t, J
= 4.9 Hz), 3.13 (3H, s), 3.40 (4
H, t, J = 4.9 Hz), 3.67 (2H, br)
s), 4.31 (2H, s), 6.21 (1H, br)
s), 7.58 (1H, dd, J = 8.8, 2.0H
z), 7.72 (1H, dd, J = 8.8, 2.0H
z), 7.88-7.95 (3H, m), 8.27 (1
H, s). MS (FAB) m / z 605 [(M + H) ⁺ , C
l ³⁵ ], 607 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 36 1-[(6-tert-butoxycarbonyl-4,5,
6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine 6-tert- Butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridine-2-carboxylic acid (WO94 / 2159)
9) Using 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as the starting material, the title compound was obtained. ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s),
2.84 (2H, brs), 3.19 (4H, br)
3.72 (2H, t, J = 5.4 Hz), 3.87 (2
H, br s), 4.54 (2H, s), 4.63 (2
H, br s), 7.57 (1H, dd, J = 8.8,
2.0 Hz), 7.76 (1H, dd, J = 8.8,
2.0 Hz), 7.87-7.94 (3H, m), 8.
30 (1H, s) MS (FAB) m / z 577 [(M + H) ⁺ , C
l ³⁵ ], 579 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 37 1-[(5-tert-butoxycarbonyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazine 5-tert-butoxycarbonyl −4,5,6,7−
Tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid (WO94 / 21599) (742 mg), 1
-[(6-chloronaphthalen-2-yl) sulfonyl]
-3-ethoxycarbonylpiperazine hydrochloride (WO9
6/10022) (1.00 g), benzotriazol-1-yl-oxy-tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP: registered trademark) (1.50 g) in N, N-dimethylformamide (30 ml). Dissolve and add triethylamine (0.40
ml) was added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the title compound (505 mg, 30%). ¹ H NMR (CDCl ₃ ) δ1.24-1.37 (3
H, m), 1.47 (9H, s), 2.45-2.60.
(1H, m), 2.62-2.71 (1H, m), 2.
75-2.90 (2H, m), 3.65-3.94 (3
H, m), 4.19-4.31 (2H, m), 4.45
-4.72 (4H, m), 5.35 (1 / 2H, br)
s), 5.71-5.77 (1 / 2H, m), 6.72.
(1H, brs), 7.58 (1H, dd, J = 8.
8, 2.0 Hz), 7.77 (1H, dd, J = 8.
8, 2.0 Hz), 7.88-7.92 (3H, m),
8.33 (1H, s) MS (FAB) m / z 649 [(M + H) ⁺ , C
l ³⁵ ], 651 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 38 1-[(5-tert-butoxycarbonyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-carbamoyl-4-
[(6-Chloronaphthalen-2-yl) sulfonyl] piperazine 1-[(5-tert-butoxycarbonyl-4,5,
6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazine (487 mg) was added to tetrahydrofuran ( 5
ml), methanol (5 ml) and 1N aqueous sodium hydroxide solution (3 ml) were added, and the mixture was stirred at room temperature for 4 hours. After adjusting the pH to 1 to 2 by adding 1 N hydrochloric acid, ethyl acetate was added to separate an organic layer. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (5 ml).
At 0 ° C, N-methylmorpholine (0.09 ml) and isobutyl chloroformate (0.11 ml) were added dropwise. After stirring at −20 ° C. for 10 minutes, an ammonia-dichloromethane solution (0.50 ml) was added. After stirring at −20 ° C. for 10 minutes, ethanolic 1N hydrochloric acid (10 ml) was added, and the reaction solution was heated to room temperature. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in dichloroethane and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane to dichloromethane: methanol = 100: 1) to give the title compound (317 m
g, 68%). ¹ H NMR (DMSO-d ₆ ) δ 1.41 (9H,
s), 2.39-2.86 (4H, m), 3.60-
3.80 (4H, m), 4.25-4.34 (1H,
m), 4.36-4.34 (1 / 2H, m), 4.62
(2H, brs), 4.97 (1 / 2H, br)
s), 5.44-5.52 (1 / 2H, m), 6.19.
(1 / 2H, brs), 7.30-7.39 (1H,
m), 7.63-7.85 (3H, m), 8.15 (1
H, d, J = 8.8 Hz), 8.20-8.29 (2
H, m), 8.48 (1H, s). MS (FAB) m / z 620 [(M + H) ⁺ , C
l ³⁵ ], 622 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 39 1-[(5-tert-butoxycarbonyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(E) -4-chlorostyrylsulfonyl] piperazine 5-tert-butoxycarbonyl as in Reference Example 6. -4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridine-2-carboxylic acid (WO94 / 2159)
9), 1-[(E) -4-chlorostyrylsulfonyl)
The title compound was obtained using piperazine hydrochloride as a raw material. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
2.87 (2H, brs), 3.31 (4H, m),
3.75 (2H, brs), 3.90 (2H, brs)
s), 4.57 (2H, br s), 4.68 (2H, brs).
s), 6.64 (1H, d, J = 15.6 Hz), 7.
28-7.35 (5H, m). MS (FAB) m / z 553 [(M + H) ⁺ , C
l ³⁵ ], 555 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 40 (3S) -3-Amino-1-tert-butoxycarbonylpyrrolidine By the same reaction as in Reference Example 5, (3R) -1-tert was obtained.
The title compound was obtained using -butoxycarbonyl-3-methanesulfonyloxypyrrolidine (1.50 g) as a raw material. ¹ H NMR (CDCl ₃ ) δ 1.46 (9H, s)
98-2.11 (2H, m) 2.95-3.10 (1
H, m), 3.26-3.60 (4H, m). MS (FAB) m / z 187 (M + H) ⁺ .

Reference Example 41 (3S) -3-[(6-chloronaphthalen-2-yl)
Sulfonamido] pyrrolidine trifluoroacetate (3S) -3-amino-
The title compound was obtained using 1-tert-butoxycarbonylpyrrolidine as a raw material. ¹ H NMR (DMSO-d ₆ ) δ 1.69-1.80
(1H, m), 1.88-1.99 (1H, m), 2.
95-3.28 (4H, m), 3.75-3.84 (1
H, m), 7.71 (1H, m), 7.91 (1H,
m), 8.10-8.30 (4H, m), 8.53 (1
H, s), 8.91 (1H, br s), 9.06 (1
H, brs).

Reference Example 42 (3S) -1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c]
Pyridin-2-yl) methyl] -3-[(6-chloronaphthalen-2-yl) sulfonamido] pyrrolidine By the same reaction as in Reference Example 8, 5-tert-butoxycarbonyl-2-formyl-4,5, 6,7-tetrahydrothieno [3,2-c] pyridine (WO 94/21
599), (3S) -3-[(6-chloronaphthalene-
2-yl) Sulfonamido] pyrrolidine The title compound was obtained using trifluoroacetate as a raw material. ¹ H NMR (CDCl ₃ ) δ 1.49 (9H, s),
1.52-1.63 (1H, m), 2.03--2.12.
(1H, m), 2.19-2.27 (1H, m), 2.
35-2.54 (2H, m), 2.73-2.85 (3
H, m), 3.59 (1H, d, J = 13.9 Hz),
3.66 (1H, d, J = 13.9 Hz), 3.70
(2H, brs), 3.88-3.95 (1H,
m), 4.39 (2H, s), 4.99 (1 / 2H,
s), 5.02 (1 / 2H, s), 6.49 (1H,
s), 7.55 (1H, dd, J = 8.8, 2.0H
z), 7.82-7.90 (4H, m), 8.40 (1
H, s). MS (FD) m / z 561 (M +, Cl 35), 563
(M +, Cl ³⁷ ).

Reference Example 43 (3S) -1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c]
Pyridin-2-yl) carbonyl] -3-[(6-chloronaphthalen-2-yl) sulfonamido] pyrrolidine Similar to Reference Example 6, 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c]
Pyridine-2-carboxylic acid (WO94 / 21599),
(3S) -3-[(6-chloronaphthalen-2-yl)
Sulfonamide] pyrrolidine The starting compound was obtained using trifluoroacetate as a raw material. ¹ H NMR (CDCl ₃ ) δ 1.50 (9H, s),
1.80-2.08 (2H, m), 2.75 (2H, b
rs), 3.48-3.87 (6H, m), 3.88.
-4.05 (1H, m), 4.37 (2H, br)
s), 6.09 (1H, br s), 7.05-7.1.
5 (1H, m), 7.55 (1H, dd, J = 8.8,
1.5 Hz), 7.79-7.91 (4H, m), 8.
41 (1H, s). MS (FAB) m / z 576 [(M + H) ⁺ , C
l ³⁵ ], 578 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 44 (3S) -3-Amino-1-[(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidine (3R) -1-tert-butoxycarbonyl-3-methanesulfonyloxypyrrolidine was converted to trifluoro After dissolving in acetic acid, the mixture was concentrated under reduced pressure, and diethyl ether was added to remove the supernatant. Using the obtained residue, a crude product of a sulfonamide compound was obtained in the same reaction as in Reference Example 1, and the title compound was obtained by azidation and reduction in the same manner as in Reference Example 5. ¹ H NMR (DMSO-d ₆ ) δ1.38-1.53
(3H, m), 1.72-1.83 (1H, m), 2.
81-2.89 (1H, m), 3.20-3.39 (4
H, m), 7.69 (1H, dd, J = 8.8, 1.9)
Hz), 7.87 (1H, d, J = 8.8 Hz), 8.
12 (1H, d, J = 8.8 Hz), 8.21 (1H,
s), 8.26 (1H, d, J = 8.8 Hz), 8.3
9 (1H, s). MS (FAB) m / z 311 [(M + H) ⁺ , C
l ³⁵ ], 313 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 45 (3S) -3-[[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-
c] pyridin-2-yl) methyl] amino] -1-
[(6-Chloronaphthalen-2-yl) sulfonyl] pyrrolidine By the same reaction as in Reference Example 8, 5-tert-butoxycarbonyl-2-formyl-4,5,6,7-tetrahydrothieno [3,2-c ] Pyridine (WO94 / 215)
99), The title compound was obtained using (3S) -3-amino-1-[(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidine as a starting material. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
1.60-1.69 (1H, m), 1.95-2.05
(1H, m), 2.72 (2H, brs), 3.11
(1H, dd, J = 10.3, 4.4 Hz), 3.30
-3.46 (4H, m), 3.68 (2H, br)
s), 3.72 (2H, s), 4.36 (2H, s),
6.44 (1H, s), 7.56 (1H, dd, J =
8.8, 2.0 Hz), 7.86-7.91 (4H,
m), 8.36 (1H, s). MS (FD) m / z 561 (M +, Cl 35), 563
(M ⁺ , Cl ³⁷ ).

Reference Example 46 (3S) -3-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c]
Pyridin-2-yl) carbonylamino] -1-[(6
-Chloronaphthalen-2-yl) sulfonyl] pyrrolidine In the same manner as in Reference Example 5, 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c]
Pyridine-2-carboxylic acid (WO94 / 21599),
The title compound was obtained using (3S) -3-amino-1-[(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidine as a starting material. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
1.90-2.00 (1H, m), 2.11-2.22
(1H, m), 2.80 (2H, brs), 3.32
-3.42 (1H, m), 3.44-3.57 (3H,
m), 3.71 (2H, brs), 4.38 (2H,
d, J = 1.5 Hz), 4.40-4.49 (1H,
m), 5.80-5.87 (1H, m), 6.96 (1
H, s), 7.54 (1H, dd, J = 8.8, 1.5
Hz), 7.83-7.89 (3H, m), 7.90
(1H, d, J = 8.8 Hz), 8.37 (1H,
s). MS (FD) m / z 576 [(M + H) ⁺ , C
l ³⁵ ], 578 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 47 1-[(5-tert-butoxycarbonyl-4,5,
6,7-tetrahydrothieno [3,2-c] pyridine-
2-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine As in Reference Example 6, 5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3 , 2-c]
Pyridine-2-carboxylic acid (WO94 / 21599),
The title compound was obtained using 1-[(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine hydrochloride as a raw material. ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s),
2.01 (2H, brs), 2.78 (2H, brs)
s), 3.37-3.54 (4H, m), 3.68 (2
H, br s), 3.78 (2H, t, J = 6.1H)
z), 3.86 (2H, t, J = 6.1 Hz), 4.3
9 (2H, s), 6.88 (1H, brs), 7.5
5 (1H, dd, J = 8.8, 2.0 Hz), 7.75
−7.80 (1H, m), 7.83-7.90 (3H,
m), 8.33 (1H, s). MS (FD) m / z 589 (M +, Cl 35), 591
(M ⁺ , Cl ³⁷ ).

Reference Example 48 4-benzylamino-1-tert-butoxycarbonylpiperidine 1-tert-butoxycarbonyl-4-piperidone (7.00 g) was dissolved in dichloromethane (500 ml), and benzylamine (4.03 ml) was dissolved. Sodium triacetoxyborohydride (11.91 g) was added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (7.46).
g, 76%). ¹ H NMR (CDCl ₃ ) δ1.24-1.37 (2
H, m), 1.45 (9H, s), 1.80-1.9.
0 (2H, m), 2.62-2.70 (1H, m),
2.75-2.85 (1H, m), 2.98-3.07
(1H, m), 3.78-3.90 (3H, m), 3.
95-4.10 (1H, m), 7.21-7.34 (5
H, m). MS (FD) m / z 290 M ⁺

Reference Example 49 4-Amino-1-tert-butoxycarbonylpiperidine acetate 4-benzylamino-1-tert-butoxycarbonylpiperidine (4.04 g) was added to methanol (2 ml),
It was dissolved in acetic acid (30 ml), 10% palladium carbon (containing about 50% water, 3.06 g) was added, and catalytic reduction was performed at medium pressure (3 atm) overnight. After removing the catalyst by filtration, the filtrate was distilled off under reduced pressure, and the obtained residue was solidified in ethyl acetate to obtain the title compound (2.23 g, 57%). ¹ H NMR (DMSO-d ₆ ) δ 1.10-1.23
(2H, m), 1.39 (9H, s), 1.69-1.
77 (2H, m), 1.80 (3H, s), 2.50
(2H, s), 2.67-2.88 (2H, m), 3.
80-3.90 (1H, m). MS (FAB) m / z 201 (M + H) + Elemental _{analysis: C 10 H 20 N 2 O} 2 · CH 3 CO 2 H Calculated: C, 53.16; H, 9.37 ; N, 10.3
3. Analytical values: C, 53.51; H, 9.10; N, 9.9.
3.

Reference Example 50 4-[(6-Chloronaphthalen-2-yl) sulfonamido] piperidine trifluoroacetate As in Reference Example 1, 4-amino-1-tert-butoxycarbonylpiperidine acetate, 6- The title compound was obtained using chloro-2-naphthylsulfonyl chloride as a raw material. ¹ H NMR (DMSO-d ₆ ) δ1.47-1.60
(2H, m), 1.68-1.78 (2H, m), 2.
81-2.95 (2H, m), 3.10-3.20 (2
H, m), 3.29-3.40 (1H, m), 7.70
(1H, dd, J = 8.8, 2.0 Hz), 7.91
(1H, dd, J = 8.8, 2.0 Hz), 8.11-
8.15 (2H, m), 8.21 (1H, s), 8.3
1 (1H, brs), 8.50 (1H, s), 8.55
(1H, brs). MS (FAB) m / z 325 [(M + H) ⁺ , C
l ³⁵ ], 327 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 51 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(6-cyanobenzofuran-2-yl) carbonyl] piperazine By the same reaction as in Reference Example 6, 6-cyano Benzofuran-2-carboxylic acid, 1-[(6-chloronaphthalene-2
-Yl) sulfonyl] piperazine hydrochloride as a starting material to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 3.21 (4H, s),
3.95 (4H, s), 7.32 (1H, d, J = 1.
0 Hz), 7.55 (1H, dd, J = 8.3, 1.0
Hz), 7.59 (1H, dd, J = 8.8, 2.0H)
z), 7.72 (1H, d, J = 8.3 Hz), 7.7
7 (1H, dd, J = 8.8, 2.0 Hz), 7.81
(1H, s), 7.88-7.95 (3H, m), 8.
32 (1H, s). MS (FAB) m / z 480 [(M + H) ⁺ , C
l ³⁵ ], 482 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 52 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(5-cyanobenzothien-2-yl) carbonyl] piperazine Cyanobenzothien-2-carboxylic acid, 1-[(6-chloronaphthalene-2
-Yl) sulfonyl] piperazine hydrochloride as a starting material to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 3.18 (4H, s),
3.89 (4H, s), 7.43 (1H, d, J = 2.
0 Hz), 7.60 (1H, d, J = 8.8 Hz),
7.73-7.80 (2H, m), 7.85-7,95
(4H, m), 8.10 (1H, s), 8.32 (1
H, s). MS (FAB) m / z 496 [(M + H) ⁺ , C
l ³⁵ ], 498 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 53 6-Methoxy-3,4-dihydroisoquinoline 3-methoxyphenethylamine (75.0 g) was dissolved in tetrahydrofuran (100 ml).
0 ml) and acetic anhydride (108 ml), and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added, the organic layer was separated, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in benzene (200 ml).
40 ml) was added dropwise. After stirring at 70 ° C. for 15 minutes, 2N hydrochloric acid was added after adding ice, and the mixture was stirred for 1 hour under ice cooling. The aqueous layer was separated, neutralized by adding potassium carbonate, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane to dichloromethane: methanol = 100: 1) to obtain the title compound (13.5 g, 17%). ¹ H NMR (CDCl ₃ ) δ 2.72 (2H, t, J =
7.3 Hz), 3.72 (2H, t, J = 7.3H)
z), 3.83 (3H, s), 6.68 (1H, d, J
= 2.4 Hz), 6.79 (1H, dd, J = 8.3,
2.4 Hz), 7.22 (1H, d, J = 8.3H)
z), 8.25 (1H, s). MS (FAB) m / z 162 (M + H) ⁺ .

Reference Example 54 6-methoxy-1,2,3,4-tetrahydroisoquinoline 6-methoxy-3,4-dihydroisoquinoline (10.
4 g) in methanol (100 ml) and water (10 g).
ml) and then sodium borohydride (6.1
0 g) was added and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure, the residue was dissolved in dichloromethane, washed with water,
The separated organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane to dichloromethane: methanol = 100: 15) to give the title compound (7.95).
g, 76%). ¹ H NMR (CDCl ₃ ) δ 2.79 (2H, t, J =
5.9 Hz), 3.12 (2H, t, J = 5.9H)
z), 3.76 (3H, s), 3.96 (2H, s),
6.62 (1H, s), 6.70 (1H, dd, J =
8.3, 2.4 Hz), 6.92 (1H, d, J = 8.
3 Hz). MS (FAB) m / z 164 (M + H) ^<+> .

Reference Example 55 6-Hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride 6-methoxy-1,2,3,4-tetrahydroisoquinoline (7.75 g) was added to dimethyl sulfide (20 ml).
, Aluminum chloride (19.0 g) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. Dichloromethane and dilute hydrochloric acid were added to separate the aqueous layer, and the mixture was made weakly alkaline with a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane.
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in saturated ethanol (100 ml), and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the precipitated solid was separated. Filter and collect the title compound (7.91 g,
90%). ¹ H NMR (DMSO-d ₆ ) δ 3.06 (2H, t,
J = 5.9 Hz), 3.43 (2H, m), 4.25
(2H, s), 6.76 (1H, d, J = 2.0H
z), 6.83 (1H, dd, J = 8.3, 2.0H
z), 7.15 (1H, d, J = 8.3 Hz), 9.7
1 (3H.brs). MS (FAB) m / z 150 (M + H) ⁺ .

Reference Example 56 2-tert-butoxycarbonyl-6-hydroxy 1,2,3,4-tetrahydroisoquinoline 6-hydroxy 1,2,3,4-tetrahydroisoquinoline hydrochloride (7.87 g) was added to methanol (100 ml).
l), triethylamine (4.67 ml),
Di-tert-butyl dicarbonate (13.95
g) was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, washed with 1 N hydrochloric acid, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 3: 1).
To give the title compound (9.96 g, 94%). ¹ H NMR (CDCl ₃ ) δ 1.49 (9H, s),
2.75 (2H, t, J = 5.9 Hz), 3.61 (2
H, t, J = 5.9 Hz), 4.48 (2H, s),
6.25 (1H, brs), 6.64 (1H, d, J
= 2.4 Hz), 6.70 (1H, brs), 6.9
3 (1H, d, J = 7.8 Hz).

Reference Example 57 2-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydroisoquinoline 2-tert-butoxycarbonyl-6-hydroxy1,2,3,4-tetrahydroisoquinoline (9.96
g) was dissolved in pyridine (100 ml), trifluorosulfonic anhydride (8.10 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1-6: 1) to give the title compound (1).
(3.47 g, 88%) as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 1.49 (9H, s),
2.87 (2H, t, J = 5.9 Hz), 3.66 (2
H, t, J = 5.9 Hz), 4.59 (2H, s),
7.06 (1H, brs), 7.08 (1H, d, J
= 8.3 Hz), 7.17 (1H, d, J = 8.3H)
z). Elemental _{analysis: C 15 H 18 F 3 NO} 5 S Calculated: C, 47.24; H, 4.76 ; F, 14.9
4; N, 3.67; S, 8.41. Analytical values: C, 47.34; H, 4.72; F, 15.2
5; N, 3.42; S, 8.65.

Reference Example 58 2-tert-Butoxycarbonyl-6-methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline 2-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-1,2,3,4- Tetrahydroisoquinoline (1.34 g) was added to methanol (50 m
l), triethylamine (0.73 ml), palladium (II) acetate (40 mg), 1,3- (diphenylphosphino) propane (145 mg) were added, and the mixture was stirred at 70 ° C. overnight under a stream of carbon monoxide. did. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to obtain the title compound (665 mg, 65%). ¹ H NMR (CDCl ₃ ) δ 1.50 (9H, s),
2.88 (2H, m), 3.66 (2H, brs),
3.91 (3H, s), 4.62 (2H, s), 7.1
7 (1H, d, J = 7.8 Hz), 7.83 (1H,
s), 7.84 (1H, d, J = 7.8 Hz).

Reference Example 59 1-[(2-tert-butoxycarbonyl-1,2,2,
3,4-tetrahydroisoquinolin-6-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine As in Reference Example 2, 2-tert-butoxycarbonyl-6-methoxycarbonyl-1 , 2,3,4-tetrahydroisoquinoline, 1-[(6-chloronaphthalene-2
-Yl) sulfonyl] piperazine hydrochloride as a starting material to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
2.76 (2H, t, J = 5.4 Hz), 3.09 (4
H, br), 3.60 (2H, t, J = 5.4 Hz),
3.77 (4H, br), 4.52 (2H, s), 7.
12-7.25 (3H, m), 7.59 (1H, dd,
J = 8.8, 2.0 Hz), 7.75 (1H, dd, J
= 8.8, 2.0 Hz), 7.88-7.95 (3H,
m), 8.30 (1H.s). MS (FAB) m / z 570 [(M + H) ⁺ , C
l ³⁵ ], 572 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 60 (3RS) -3-Amino-1-tert-butoxycarbonylpyrrolidine Under ice cooling, 3-aminopyrrolidine (0.54 g) was dissolved in methanol (30 ml), and diisopropylethylamine (720 μl) was added. -(Tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (0.
84 g), and the mixture was gradually heated to room temperature and stirred for 11 hours. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane-5% methanol-dichloromethane) to give the title compound (0.5%).
9g, 94%). ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
2.0-2.3 (2H, m), 3.1-4.0 (5H,
m).

Reference Example 61 (3RS) -1-tert-butoxycarbonyl-3-
[(6-Chloronaphthalen-2-yl) sulfonamido] pyrrolidine In the same manner as in Reference Example 1, (3RS) -3-amino-1-te
The title compound was obtained using rt-butoxycarbonylpyrrolidine as a raw material. ¹ H NMR (CDCl ₃ ) δ 1.37 (9H, s),
1.60-2.10 (2H, m), 3.00-3.50
(4H, m), 3.88 (1H, br), 4.96 (1
H, br), 7.50-7.60 (1H, m), 7.8.
0-7.90 (4H, m), 8.43 (1H, s). MS (FAB) m / z 411 [(M + H) ⁺ , C
l ³⁵ ], 413 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 62 1,4-Dibenzyl-2-methoxycarbonylmethylpiperazine N, N′-dibenzylethylenediamine (12 ml) and triethylamine (12 ml) were dissolved in toluene (250 ml).
ml), methyl 3-bromocrotonate (7.0 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 24 hours. Further, triethylamine (2.0 ml) was added, and
After stirring for an hour, insolubles were removed by filtration, and the filtrate was distilled off under reduced pressure. 10% hydrochloric acid (300 ml) was added to the obtained residue, and the precipitated crystals were removed by filtration. Ethyl acetate was added to the filtrate, and the aqueous layer was separated.
Potassium carbonate was added to make it alkaline. Ethyl acetate was added thereto, the organic layer was separated, washed with saturated saline, dried over anhydrous potassium carbonate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (1
(0.7 g, 62%). ¹ H NMR (CDCl ₃ ) δ 2.30-2.70 (8
H, m), 3.11 (1H, brs), 3.40-
3.80 (4H, m), 3.60 (3H, s), 7.2
0-7.40 (10H, m). MS (FAB) m / z 339 (M + H) ^<+> .

Reference Example 63 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -3-methoxycarbonylmethylpiperazine 1,4-Dibenzyl-2-methoxycarbonylmethylpiperazine (2.04 g) was treated with acetic acid (40 ml). Dissolved in
10% palladium on carbon (about 50% water content, 2.00
g) was added, and catalytic reduction was performed at room temperature under 4 atm for 4 hours. The catalyst was removed by filtration, and the filtrate was evaporated under reduced pressure. Dichloromethane and a saturated aqueous solution of potassium carbonate were added to the residue, and the precipitated insoluble material was removed by filtration. The organic layer was separated. After washing with a saturated saline solution, the solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was treated with dichloromethane (30
ml), 6-chloro-2-naphthylsulfonyl chloride (782 mg) was added, the mixture was stirred at 0 ° C for 2 hours, and triethylamine (410 µl) was added, and the mixture was further stirred at 0 ° C for 3 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane to 3%
Purification with methanol-dichloromethane) gave the title compound (759 mg, 33%). ¹ H NMR (CDCl ₃ ) δ 1.71 (1 H, br
s), 2.15 to 2.55 (4H, m), 2.90-
3.05 (2H, m), 3.15-3.25 (1H,
m), 3.60-3.70 (5H, m), 7.55-
7.60 (1H, m), 7.75-7.80 (1H,
m), 7.85-7.95 (3H, m), 8.30 (1
H, s). MS (FAB) m / z 383 [(M + H) ⁺ , C
l ³⁵ ], 385 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 64 1-benzenesulfonyl-6-chloroindole A solution of 6-chloroindole (777 mg) in tetrahydrofuran (25 ml) was added at -78 ° C with n-butyllithium (1.61 M hexane solution, 3.34 ml). In addition,
The temperature was raised to -40 ° C in one hour. The reaction solution was again cooled to -78 ° C.
Then, benzenesulfonyl chloride (867 μl) was added, and the temperature was raised to room temperature in 3 hours. Add water to the reaction mixture,
Extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (silica gel 40).
g, hexane: ethyl acetate = 5: 7), and the obtained white solid was recrystallized from ethanol to give the title compound (826 mg, 55%) as a white solid. ¹ H NMR (CDCl ₃ ) δ 6.64 (1H, d, J =
3.9 Hz), 7.21 (1H, dd, J = 8.3)
1.2Hz), 7.42-7.60 (5H, m), 7.
88 (2H, d, J = 7.3 Hz), 8.03 (1H,
s). Elemental analysis: C ₁₄ H ₁₀ ClNO ₂ S Calculated: C, 57.63; H, 3.45 ; Cl, 12.
15; N, 4.80; S, 10.99. Analytical values: C, 57.48; H, 3.75; Cl, 12.
34; N, 4.87; S, 10.87.

The compounds shown in Reference Examples 65 to 66 were synthesized in the same manner as in Reference Example 64.

Reference Example 65 1-benzenesulfonyl-5-chloroindole ¹ H-NMR (CDCl ₃ ) δ 6.61 (1H, d, J =
3.9 Hz), 7.26 (1H, dd, J = 8.3)
2.0Hz), 7.45 (2H, t, J = 7.3H)
z), 7.50 (1H, d, J = 2.0 Hz), 7.5
6 (1H, m), 7.59 (1H, d, J = 3.9H)
z), 7.86 (2H, m), 7.92 (1H, d, J
= 8.3 Hz). Elemental analysis: C ₁₄ H ₁₀ ClNO ₂ S Calculated: C, 57.63; H, 3.45 ; Cl, 12.
15; N, 4.80; S, 10.99. Analytical values: C, 57.82; H, 3.58; Cl, 11.
91; N, 4.79; S, 10.92.

Reference Example 66 1-benzenesulfonyl-5-bromoindole ¹ H NMR (CDCl ₃ ) δ 6.60 (1H, d, J =
3.7 Hz), 7.42 (1H, dd, J = 8.8,
2.0Hz), 7.45 (2H, t, J = 8.8H)
z), 7.55 (1H, d, J = 8.8 Hz), 7.5
7 (1H, d, J = 3.7 Hz), 7.73 (1H,
d, J = 2.0 Hz), 7.86 (2H, d, J = 8.
8 Hz), 7.87 (1 H, d, J = 8.8 Hz). Elemental analysis: C ₁₄ H ₁₀ BrNO ₂ S Calculated: C, 50.01; H, 3.00; N, 4.1
7; Br, 23.77; S, 9.54. Analytical values: C, 49.96; H, 2.97; N, 4.0.
2; Br, 23.90; S, 9.53.

Reference Example 67 1-benzenesulfonyl-5-trimethylsilylethynylindole 1-benzenesulfonyl-5-bromoindole (1.
50 g) and triphenylphosphine (351 mg) were dissolved in tetrahydrofuran (7.00 ml), and triethylamine (2.00 ml), N, N-dimethylformamide (7.00 ml), trimethylsilylacetylene (945 μl), and acetic acid were dissolved at room temperature. Palladium (100m
g) was added and the mixture was heated under reflux for 5 hours. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction solution, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 to 10: 1) to give the title compound (935 mg, 59%) as a white solid. ¹ H NMR (CDCl ₃ ) δ 0.24 (9H, s),
6.62 (1H, d, J = 3.9 Hz), 7.42 (1
H, dd, J = 8.8, 1.5 Hz), 7.44 (2
H, t, J = 7.8 Hz), 7.52 (1H, d, J =
7.8 Hz), 7.56 (1H, d, J = 3.9H)
z), 7.66 (1H, d, J = 1.5 Hz), 7.8
5 (2H, d, J = 7.8 Hz), 7.92 (1H,
d, J = 8.8 Hz). MS (FAB) m / z 354 (M + H +).

Reference Example 68 5-Chloro-1-ethylindole 5-Chloroindole (1.52 g) was added to benzene (10
ml) and a 50% aqueous sodium hydroxide solution (10%).
ml), tetrabutylammonium bromide (161
mg) and bromoethane (1.64 g).
Stirred for 0 hours. After adding a saturated aqueous solution of ammonium chloride to the reaction solution, water and dichloromethane were added, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 20) to give the title compound (1.68 g, 93%) as colorless crystals. As obtained. ¹ H NMR (CDCl ₃ ) δ 1.46 (3H, t, J =
7.3 Hz), 4.16 (2H, q, J = 7.3H)
z), 6.43 (1H, d, J = 2.4 Hz), 7.1
4 (1H, d, J = 2.4 Hz), 7.15 (1H,
d, J = 8.3 Hz), 7.26 (1H, J = 8.3H)
z), 7.59 (1H, s). MS (EI) m / z 179 (M +, Cl 35), 181
(M ⁺ , Cl ³⁷ ).

Reference Example 69 1-benzenesulfonyl-6-chloroindole-2-sulfonyl chloride 1-benzenesulfonyl-6-chloroindole (77
7 mg) in ether (12 ml) at -78 ° C.
tert-butyl lithium (1.56 M pentane solution,
(1.78 ml) was added dropwise, and the temperature was raised to 0 ° C. in 30 minutes.
After stirring for 1 hour, the reaction mixture was cooled again to −78 ° C., sulfur dioxide was introduced, the temperature was raised to room temperature in 1 hour, and the mixture was stirred for 1 hour. After the reaction solution was concentrated under reduced pressure, hexane was added and the mixture was again concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane, and N-chlorosuccinimide (390 mg) was added at 0 ° C.
Was added and the temperature was raised to room temperature in 1 hour, followed by stirring for 30 minutes.
Dichloromethane and water were added to the reaction solution, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from methanol to give the title compound (857 mg, 79 mg) as a white solid. %). _{^{1 H NMR (CDCl 3) δ7.39}} (1H, dd, J
= 8.3, 1.6 Hz), 7.48-7.67 (4H,
m), 7.68 (1H, s), 8.08 (2H, d, J
= 7.3 Hz), 8.35 (1H, s). Elemental _{analysis: C 14 H 9 ClNO 4 S} 2 Calculated: C, 43.09; H, 2.32 ; Cl, 18.
17; N, 3.59; S, 16.43. Analytical values: C, 43.32; H, 2.67; Cl, 18.
25; N, 3.64; S, 16.22.

The compounds shown in Reference Examples 70 to 77 were synthesized in the same manner as in Reference Example 69.

[0765] Reference Example 70 chloride 1-benzenesulfonyl-indol-2-sulfonyl _{^{1 H NMR (CDCl 3) δ7.40}} (1H, t, J =
7.6 Hz), 7.45-7.53 (2H, m), 7.
57-7.67 (2H, m), 7.69 (1H, d, J
= 7.8 Hz), 7.73 (1H, s), 8.08 (2
H, d, J = 7.3 Hz), 8.31 (1H, d, J =
8.8 Hz). MS (EI) m / z 355 M ⁺ . Elemental _{analysis: C 14 H 10 ClNO 4 S} 2 Calculated: C, 47.26; H, 2.83 ; Cl, 9.9
6; N, 3.94; S, 18.02. Analytical values: C, 47.33; H, 3.08; Cl, 10.
04; N, 3.98; S, 18.18.

[0766] Reference Example 71 chloride 1-benzenesulfonyl-5-chloroindole-2-sulfonyl _{^{1 H NMR (CDCl 3) δ7.46-7.54}} (2
H, m), 7.58 (1H, dd, J = 9.3, 2.0)
Hz), 7.63 (1H, t, J = 7.3 Hz), 7.
64 (1H, s), 7.67 (1H, d, J = 2.0H
z), 8.06 (2H, d, J = 7.3 Hz), 8.2
6 (1H, d, J = 9.3 Hz). MS (EI) m / z 291 (M +, Cl 35), 293
(M ⁺ , Cl ³⁷ ). Elemental _{analysis: C 14 H 9 Cl 2 NO} 4 S 2 Calculated: C, 43.09; H, 2.32 ; Cl, 18.
27; N, 3.59; S, 16.43. Analytical values: C, 42.98; H, 2.51; Cl, 18.
36; N, 3.59; S, 16.47.

Reference Example 72 5-Chloro-1-ethylindole-2-sulfonyl chloride ¹ H NMR (CDCl ₃ ) δ 1.52 (3H, t, J =
7.3 Hz), 4.59 (2H, q, J = 7.3H)
z), 7.36 (1H, s), 7.39 (1H, d, J
= 8.8 Hz), 7.45 (1H, dd, J = 8.8,
2.0Hz), 7.73 (1H, d, J = 2.0H)
z). MS (EI) m / z 277 (M +, Cl 35), 279
(M ⁺ , Cl ³⁷ ).

[0768] Reference Example 73 chloride 1-benzenesulfonyl-5-trimethylsilyl-ethynyl-indole-2-sulfonyl _{^{1 H NMR (CDCl 3) δ0.26}} (9H, s),
7.48 (2H, t, J = 7.8 Hz), 6.61 (1
H, t, J = 7.8 Hz), 7.65 (1H, s),
7.69 (1H, dd, J = 8.8, 1.5 Hz),
7.79 (1H, d, J = 1.5 Hz), 8.04 (2
H, d, J = 7.8 Hz), 8.24 (1H, d, J =
8.8 Hz). MS (FAB) m / z 452 [(M + H) ⁺ , C
l ³⁵ ], 454 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 74 5-chlorobenzo [b] furan-2-sulfonyl chloride ¹ H NMR (CDCl ₃ ) δ 7.57 (1H, dd, J)
= 8.8, 2.0 Hz), 7.59 (1H, s), 7.
61 (1H, d, J = 8.8 Hz), 7.76 (1H,
d, J = 2.0 Hz). MS (EI) m / z 250 (M +, Cl 35), 252
(M ⁺ , Cl ³⁷ ). Elemental _{analysis: C 8 H 4 Cl 2 O} 3 S Calculated: C, 38.27; H, 1.61 ; Cl, 28.
24; S, 12.77. Analytical values: C, 38.33; H, 1.71; Cl, 28.
16; S, 12.57.

Reference Example 75 6-Chlorobenzo [b] furan-2-sulfonyl chloride ¹ H NMR (CDCl ₃ ) δ 7.43 (1H, dd, J)
= 8.8, 2.0 Hz), 7.62 (1H, s), 7.
69 (1H, s), 7.70 (1H, d, J = 8.8H)
z). MS (EI) m / z 250 (M +, Cl 35), 252
(M ⁺ , Cl ³⁷ ). Elemental _{analysis: C 8 H 4 Cl 2 O} 3 S Calculated: C, 38.27; H, 1.61 ; Cl, 28.
24; S, 12.77. Analytical values: C, 38.31; H, 1.60; Cl, 28.
34; S, 12.60.

Reference Example 76 5-Chlorobenzo [b] thien-2-sulfonyl chloride ¹ H NMR (CDCl ₃ ) δ 7.57 (1H, dd, J)
= 8.8, 2.0 Hz), 7.85 (1H, d, J =
8.8 Hz), 7.96 (1H, d, J = 2.0H)
z), 8.08 (1H.s). MS (FD) m / z 266 (M +, Cl 35), 268
(M ⁺ , Cl ³⁷ ).

Reference Example 77 6-Chlorobenzo [b] thien-2-sulfonyl chloride ¹ H NMR (CDCl ₃ ) δ 7.51 (1H, dd, J)
= 8.3, 1.5 Hz), 7.90 (1H, d, J =
8.3 Hz), 7.92 (1H, s), 8.11 (1
H, s). MS (FAB) m / z 266 [(M + H) ⁺ , C
l ³⁵ ], 268 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 78 1-tert-butoxycarbonyl-4-[(1-benzenesulfonyl-5-chloroindol-2-yl) sulfonyl] piperazine 1-benzenesulfonyl-5-chloroindole-2-sulfonyl (4 Tert-butyl 1-piperazinecarboxylate (2.21 g) and triethylamine (1.65 ml) were added to a dichloromethane solution (.41 g) of dichloromethane (75 ml) under ice cooling, followed by stirring at room temperature for 3 hours. After completion of the reaction, water and dichloromethane were added, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 20) to give the title compound (3.63 g, 60%) as colorless crystals. ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
3.35-3.42 (4H, br), 3.50-3.5
5 (4H, br), 7.40-7.48 (4H, m),
7.53-7.58 (2H, m), 8.00-8.05
(2H, m), 8.23 (1H, d, J = 8.8H
z).

The compounds shown in Reference Examples 79 to 82 were synthesized in the same manner as in Reference Example 78.

Reference Example 79 1-tert-butoxycarbonyl-4-[(1-benzenesulfonylindol-2-yl) sulfonyl] piperazine ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
3.34-3.44 (4H, br), 3.48-3.5
6 (4H, br), 7.33 (1H, t, J = 7.3H)
z), 7.36-7.45 (2H, m), 7.47-
7.61 (4H, m), 8.04 (2H, d, J = 7.
3 Hz), 8.29 (1H, d, J = 8.8 Hz). MS (EI) m / z 505 M ⁺ .

Reference Example 80 1-tert-butoxycarbonyl-4-[(5-chloro-1-ethylindol-2-yl) sulfonyl] piperazine ¹ H NMR (CDCl ₃ ) δ 1.41 (3H, t, J =
7.3 Hz), 1.43 (9H, s), 3.16-3.
23 (4H, m), 3.48-3.55 (4H, m),
4.45 (2H, q, J = 7.3 Hz), 7.03 (1
H, s), 7.32-7.34 (2H, m), 7.66.
(1H, d, J = 2.0 Hz). MS (EI) m / z 427 (M +, Cl 35), 429
(M ⁺ , Cl ³⁷ ).

Reference Example 81 1-tert-butoxycarbonyl-4-[(1-benzenesulfonyl-5-chloroindol-2-yl) sulfonyl] homopiperazine ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s) ,
1.98-2.17 (2H, m), 3.42-3.57
(8H, m), 7.28 (1H, s), 7.41-7.
46 (3H, m), 7.53-7.57 (2H, m),
8.05 (2H, d, J = 7.3 Hz), 8.20 (1
H, d, J = 9.3 Hz). MS (FAB) m / z 554 [(M + H) ⁺ , C
l ³⁵ ], 556 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 82 cis-1-[(1-benzenesulfonyl-5-chloroindol-2-yl) sulfonyl] -3,5-dimethylpiperazine ¹ H NMR (CDCl ₃ ) δ 1.07 (6H, d, J =
6.4 Hz), 2.45-2.55 (2H, m), 2.
95-3.05 (2H, m), 3.75-3.80 (2
H, m), 7.35-7.50 (4H, m), 7.50
−7.60 (2H, m), 8.00 to 8.05 (2H,
m), 8.22 (1H, d, J = 9.3 Hz) MS (FAB) m / z 468 [(M + H) ⁺ , C
l ³⁵ ], 470 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 83 3-ethoxycarbonyl-1-[(1-benzenesulfonyl-5-chloroindol-2-yl) sulfonyl]
Saturated hydrochloric acid ethanol solution was added to piperazine tert-butyl 1- (3-ethoxycarbonyl) piperazinecarboxylate (3.97 g), and the mixture was stirred for 30 minutes. After evaporating the solvent under reduced pressure, the residue was suspended in dichloromethane (200 ml), and 1-benzenesulfonyl-5-chloroindole-2 chloride was added.
-Sulfonyl (6.00 g) and triethylamine (6.
40 ml) and stirred at room temperature for 3 hours. Water and dichloromethane were added, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 20) to give the title compound (4.44).
g, 56%) as colorless crystals. ¹ H NMR (CDCl ₃ ) δ 1.24 (3H, t, J =
6.8 Hz), 2.87-2.95 (1H, m), 3.
11-3.28 (3H, m), 3.57-3.66 (2
H, m), 3.91-3.98 (1H, m), 4.17
(2H, q, J = 6.8 Hz), 7.38-7.48
(4H, m), 7.55-7.59 (2H, m), 8.
03 (2H, d, J = 7.8 Hz), 8.21 (1H,
d, J = 9.3 Hz). MS (EI) m / z 511 (M +, Cl 35), 513
(M ⁺ , Cl ³⁷ ) ⁺ .

Reference Example 84 1-tert-butoxycarbonyl-4-[(5-chloroindol-2-yl) sulfonyl] piperazine 1-tert-butoxycarbonyl-4-[(1-benzenesulfonyl-5-chloroindole- 2-Nyl) sulfonyl] piperazine (4.84 g) was added with a 0.5 N sodium hydroxide methanol solution (20 ml), and the mixture was stirred at room temperature for 1 hour. After adding an aqueous saturated ammonium chloride solution under ice-cooling, water and dichloromethane were added, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 20).
The title compound (3.33 g, 93%) was obtained as a colorless powder. ¹ H NMR (CDCl ₃ ) δ 1.40 (9H, s),
3.05-3.14 (4H, m), 3.48-3.57
(4H, m), 6,96 (1H, d, J = 2.0H
z), 7.33 (1H, dd, J = 8.8, 2.0H
z), 7.38 (1H, d, J = 8.8 Hz), 7.6
7 (1H, d, J = 2.0 Hz), 8.78 (1H, b
r). MS (FAB) m / z 400 [(M + H) ⁺ , C
l ³⁵ ], 402 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 85 1-[(5-Chloroindol-2-yl) sulfonyl] -3-methoxycarbonylpiperazine The title compound was synthesized in the same manner as in Reference Example 84. ¹ H NMR (CDCl ₃ ) δ 2.70-2.82 (1
H, m), 2.84-2.97 (2H, m), 3.06
-3.16 (1H, m), 3.37-3.46 (1H,
m), 3.61 (1H, dd, J = 8.3, 3.4H)
z), 3.69-3.80 (1H, m), 3.75 (3
H, s), 6.98 (1H, s), 7.32 (1H, d
d, J = 8.8, 2.0 Hz), 7.38 (1H, d,
J = 8.8 Hz), 7.67 (1H, s), 8.80
(1H, s). MS (EI) m / z 357 (M +, Cl 35), 359
(M ⁺ , Cl ³⁷ ) ⁺ .

Reference Example 86 3- (N-methylcarbamoyl) -1-[(5-chloroindol-2-yl) sulfonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -3-methoxy Carbonyl piperazine (480m
g) was dissolved in tetrahydrofuran (25 ml).
A 2N methanol solution of sodium hydroxide (7 ml) and water (2 ml) were added, and the mixture was stirred at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure. The obtained yellow amorphous (520 m
g) was dissolved in N, N-dimethylformamide (60 ml) and 1-hydroxybenzotriazole (1
8.1 mg), 1- (3-dimethylaminopropyl)-
3-Ethylcarbodiimide hydrochloride (334 mg), methylamine hydrochloride (90.5 mg) and N-methylmorpholine (271 mg) were added, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, water and ethyl acetate were added, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methanol: dichloromethane = 1: 5).
Purification by 0) afforded the title compound (140 mg, 29%) as a brown amorphous solid. ¹ H NMR (DMSO-d ₆ ) δ 2.39-2.52
(2H, m), 2.64 (3H, d, J = 3.9H
z), 2.18-2.30 (1H, m), 2.94-
3.00 (1H, m), 3.20-3.37 (2H,
m), 3.57-3.66 (1H, m), 6.90-
6.95 (1H, br), 7.22-7.27 (1H,
br), 7.44-7.49 (1H, m), 7.66-
7.78 (2H, m), 8.04-8.17 (3H,
m), 12.24 (1H, m).

Reference Example 87 1-[(5-Chloroindol-2-yl) sulfonyl] piperazine hydrochloride 1-tert-butoxycarbonyl-4-[(1-benzenesulfonyl-5-chloroindol-2-yl) sulfonyl ] Piperazine (3.63 g) was added to methanol (1
00 ml), and thereto was added a 0.2 N sodium hydroxide methanol solution (100 ml) under ice cooling, followed by stirring at room temperature for 12 hours. After adding a saturated aqueous solution of ammonium chloride under ice-cooling, water and dichloromethane were added, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the precipitated solid was collected by filtration, dissolved in saturated hydrochloric ethanol, and stirred for 30 minutes. The solvent was distilled off under reduced pressure and dried under reduced pressure to obtain the title compound (1.25 g, 54%) as a colorless powder. ¹ H NMR (DMSO-d ₆ ) δ 3.25-3.43
(8H, br), 7.46 (1H, d, J = 8.8H)
z), 7.64 (1H, d, J = 8.8), 7.93
(1H, s), 9.33 (1H, br), 12.70
(1H, br). MS (EI) m / z 298 (M +, Cl 35), 300
(M ⁺ , Cl ³⁷ ). Elemental _{analysis: C 12 H 14 ClN 3 O} 2 S · HCl · 0.5H 2
As O: Calcd: C, 41.75; H, 4.67; Cl, 20.
54; N, 12.17; S, 9.29. Analytical values: C, 41.78; H, 4.98; Cl, 20.
40; N, 11.88; S, 9.34.

Reference Example 88 1-tert-Butoxycarbonyl-4-[(5-chloro-1-methylindol-2-yl) sulfonyl] piperazine Sodium hydride (oil-approximately 60%, 50.3 mg) was added with petroleum ether. After washing twice, tetrahydrofuran (10 m
l), and a solution of 1-tert-butoxycarbonyl-4-[(5-chloroindol-2-yl) sulfonyl] piperazine (457 mg) in tetrahydrofuran (10 ml of tetrahydrofuran) was added thereto under ice-cooling.
Stirred for minutes. After adding iodomethane (179 mg) under ice-cooling, the mixture was heated to room temperature and stirred for 85 hours. Water and diethyl ether were added, the organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 50) to give the title compound (27
0 mg, 57%) as a colorless powder. ¹ H NMR (CDCl ₃ ) δ 1.42 (9H, s),
3.14-3.21 (4H, m), 3.48-3.55
(4H, m), 3.96 (3H, s), 7.06 (1
H, s), 7.31 (1H, d, J = 9.3 Hz),
7.36 (1H, dd, J = 9.3, 2.0 Hz),
7.66 (1H, d, J = 2.0 Hz). MS (FAB) m / z 413 [(M + H) ⁺ , C
l ³⁵ ], 415 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 89 1-tert-butoxycarbonyl-4-[(5-chloro-1-ethoxycarbonylmethylindol-2-yl) sulfonyl] piperazine The title compound was synthesized in the same manner as in Reference Example 88. ¹ H NMR (CDCl ₃ ) δ 1.27 (3H, t, J =
7.3 Hz), 1.43 (9H, s), 3.10-3.
19 (4H, m), 3.45-3.53 (4H, m),
4.22 (2H, q, J = 7.3 Hz), 5.15 (2
H, s), 7.15 (1H, s), 7.17 (1H,
d, J = 8.8 Hz), 7.26 (1H, s), 7.3
6 (1H, dd, J = 8.8, 2.0 Hz), 7.68
(1H, d, J = 2.0 Hz). MS (FAB) m / z 485 [(M + H) ⁺ , C
l ³⁵ ], 487 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 90 6-Chloro-2-mercaptobenzothiazole A solution of p-chloroaniline (5.70 g) in acetic acid (7 ml of acetic acid) was added to 30 ml of disulfur dichloride (25.0 ml) under ice-cooling.
Then, the mixture was stirred at room temperature for 3 hours and at about 80 ° C. for 3 hours. Benzene (50 ml) was added to the reaction solution, and green crystals were collected by filtration and washed with benzene. Put this in ice water (5
After stirring for 1 hour, the mixture was made alkaline with a 6N aqueous sodium hydroxide solution, and sodium hydrogen carbonate (6 g) was further added, followed by stirring at 100 ° C. for 1 hour. Activated carbon was added to the reaction solution, and the mixture was filtered through celite. Carbon disulfide (2.70 ml) was added to the filtrate, and the mixture was heated at about 50 ° C and stirred for 1.5 hours. After cooling to room temperature, the colorless powder precipitated by acidification with 1N hydrochloric acid was collected by filtration, dried and dried to give the title compound (1.
(30 g, 14%). ¹ H NMR (DMSO-d ₆ ) δ 7.28 (1H, d,
J = 8.3 Hz), 7.45 (1H, dd, J = 8.
3.2.0 Hz), 7.86 (1H, d, J = 2.0H)
z). MS (FAB) m / z 202 [(M + H) ⁺ , C
l ³⁵ ], 204 [(M + H) ⁺ , Cl ³⁷ ]. Elemental analysis: C ₇ H ₄ ClNS ₂ Calculated: C, 41.68; H, 2.00 ; Cl, 17.
58; N, 6.94; S, 31.80. Analysis: C, 41.64; H, 2.13; Cl, 17.
83; N, 6.94; S, 31.70.

Reference Example 91 1-tert-butoxycarbonyl-4-[(5-chlorobenzothiazol-2-yl) sulfenyl] piperazine At room temperature, tert-butyl 1-piperazinecarboxylate (5.58 g), 5-chloro -2-mercaptobenzothiazole (1.21 g) and sodium hydroxide (0.48 g) are dissolved in water (25 ml), and an aqueous solution containing iodine (1.53 g) and potassium iodide (1.65 g) (25 ml) ) Was slowly added dropwise. The precipitated colorless crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (1.1 g, 48%). ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
3.24 (4H, brs), 3.58 (4H, brs)
s), 7.26 (1H, m), 7.70 (1H, d, J
= 8.3 Hz), 7.81 (1H, s). MS (FAB) m / z 386 [(M + H) ⁺ , C
l ³⁵ ], 388 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 92 1-tert-butoxycarbonyl-4-[(6-chlorobenzothiazol-2-yl) sulfenyl] piperazine The title compound was synthesized in the same manner as in Reference Example 91. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
3.24 (4H, brs), 3.58 (4H, brs)
s), 7.37 (1H, dd, J = 8.8, 2.0H
z), 7.73 (1H, d, J = 8.8 Hz), 7.7
7 (1H, d, J = 2.0 Hz). MS (FAB) m / z 386 [(M + H) ⁺ , C
l ³⁵ ], 388 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 93 1-tert-butoxycarbonyl-4-[(5-chlorobenzothiazol-2-yl) sulfonyl] piperazine 1-tert-butoxycarbonyl-4-at room temperature
[(5-Chlorobenzothiazol-2-yl) sulfenyl] piperazine (1.10 g), potassium carbonate (1.
30 g) was suspended in a mixed solvent of ethanol (30 ml) and water (10 ml), and ethanol (25 ml) of 3-chloroperbenzoic acid (2.11 g) was added dropwise at 0 ° C., followed by heating to room temperature and 24 hours. Stirred. The organic layer was separated by adding sodium thiosulfate and ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane to 2% methanol-dichloromethane). The title compound (29
(3 mg, 25%). ¹ H NMR (CDCl ₃ ) δ 1.43 (9H, s),
3.35-3.43 (4H, m), 3.51-3.58
(4H, m), 7.55 (1H, dd, J = 8.8,
1.5 Hz), 7.90 (1H, d, J = 8.8H)
z), 8.18 (1H, d, J = 1.5 Hz). MS (FAB) m / z 418 [(M + H) ⁺ , C
l ³⁵ ], 420 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 94 1-tert-Butoxycarbonyl-4-[(6-chlorobenzothiazol-2-yl) sulfonyl] piperazine The title compound was synthesized in the same manner as in Reference Example 93. ¹ H NMR (CDCl ₃ ) δ 1.43 (9H, s),
3.35-3.43 (4H, m), 3.50-3.58
(4H, m), 7.59 (1H, dd, J = 8.8,
2.0Hz), 7.97 (1H, d, J = 2.0H)
z), 8.10 (1H, d, J = 8.8 Hz). MS (FAB) m / z 418 [(M + H) ⁺ , C
l ³⁵ ], 420 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 95 1-[(5-chlorobenzothiazol-2-yl) sulfonyl] piperazine hydrochloride 1-tert-butoxycarbonyl-4-[(5
-Chlorobenzothiazol-2-yl) sulfonyl] piperazine (293 mg) in dichloromethane (10 ml)
, And the mixture was added with saturated ethanol (10 ml), stirred for 30 minutes, and the solvent was distilled off under reduced pressure. Ethyl acetate was added and the colorless powder was collected by filtration to give the title compound (165 mg, 66
%). ¹ H NMR (DMSO-d ₆ ) δ 3.23 (4H, br
s), 3.56 (4H, br s), 7.78 (1
H, dd, J = 8.8, 2.0 Hz), 8.39-8.
43 (2H, m). MS (FAB) m / z 318 [(M + H) ⁺ , C
l ³⁵ ], 320 [(M + H) ⁺ , Cl ³⁷ ].

The compounds shown in Reference Examples 96 to 100 were synthesized in the same manner as in Reference Example 95.

Reference Example 96 1-[(6-Chlorobenzothiazol-2-yl) sulfonyl] piperazine hydrochloride ¹ H NMR (DMSO-d ₆ ) δ 3.21-3.27
(4H, m), 3.52-3.57 (4H, m), 7.
79 (1H, dd, J = 8.8, 2.0 Hz), 8.2
8 (1H, d, J = 8.8 Hz), 8.53 (1H,
d, J = 2.0 Hz). MS (FAB) m / z 318 [(M + H) ⁺ , C
l ³⁵ ], 320 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 11 H 12 ClN 3 O} 2 S 2 · 1.05HCl ·
0.5 H ₂ O Calculated: C, 36.19; H, 3.88;
91; N, 11.51; S, 17.57. Analytical values: C, 36.19; H, 4.10; Cl, 20.
08; N, 11.50; S, 17.19.

Reference Example 97 1-[(5-Chlorobenzo [b] furan-2-yl) sulfonyl] piperazine hydrochloride ¹ H NMR (DMSO-d ₆ ) δ 3.20 (4H, b
r), 3.45 (4H, br), 7.62 (1H, d,
J = 8.8 Hz), 7.76 (1H, s), 7.85
(1H, d, J = 8.8 Hz), 7.96 (1H,
s), 9.41 (1H, br). MS (FAB) m / z 301 [(M + H) ⁺ , C
l ³⁵ ], 303 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 12 H 13 ClN 2 O} 3 S · HCl · 0.1H 2
For O: C, 42.51; H, 4.22; Cl, 20.
91; N, 8.26; S, 9.46. Analytical values: C, 42.38; H, 4.33; Cl, 20.
92; N, 8.18; S, 9.58.

Reference Example 98 1-[(6-Chlorobenzo [b] furan-2-yl) sulfonyl] piperazine hydrochloride ¹ H NMR (DMSO-d ₆ ) δ 3.20 (4H, t,
J = 4.9 Hz), 3.42 (4H, t, J = 4.9H)
z), 7.51 (1H, d, J = 7.8 Hz), 7.8
2 (1H, s), 7.89 (1H, d, J = 7.8H
z), 9.18 (1H, br). MS (FAB) m / z 301 [(M + H) ⁺ , C
l ³⁵ ], 303 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 12 H 13 ClN 2 O} 3 S · HCl · 0.5H 2
As O: Calcd: C, 41.63; H, 4.37; Cl, 20.
48; N, 8.09; S, 9.26. Analytical values: C, 41.54; H, 4.32; Cl, 20.
49; N, 7.90; S, 9.07.

Reference Example 99 1-[(5-Chlorobenzo [b] thien-2-yl) sulfonyl] piperazine hydrochloride ¹ H NMR (DMSO-d ₆ ) δ 3.20-3.50
(8H, m), 7.64 (1H, dd, J = 8.8,
2.0 Hz), 8.12 (1H, s), 8.20 (1
H, s), 8.23 (1H, d, J = 8.8 Hz),
9.22 (2H, brs). MS (FAB) m / z 317 [(M + H) ⁺ , C
l ³⁵ ], 319 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 12 H 13 ClN 2 O} 2 S 2 · HCl · 1.6H 2
As O: Calcd: C, 37.72; H, 4.54; Cl, 18.
56; N, 7.33; S, 16.78. Analytical values: C, 37.56; H, 4.67; Cl, 18.
72; N, 7.17; S, 16.56.

Reference Example 100 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] piperazine hydrochloride ¹ H NMR (DMSO-d ₆ ) δ 3.20-3.38
(8H, m), 7.59 (1H, dd, J = 8.8,
2.0 Hz), 8.10 (1H, d, J = 8.8H)
z), 8.16 (1H, s), 8.36 (1H, d, J
= 8.8 Hz), 9.29 (2H, brs). MS (FAB) m / z 317 [(M + H) ⁺ , C
l ³⁵ ], 319 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 12 H 13 ClN 2 O} 2 S 2 · HCl Calculated: C, 40.80; H, 3.99 ; Cl, 20.
07; N, 7.93; S, 18.15. Analytical values: C, 40.64; H, 4.04; Cl, 20.
06; N, 7.90; S, 17.91.

Reference Example 101 1-tert-butoxycarbonyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl]- 3- [Ethoxycarbonyl] piperazine hydrochloride (WO96 / 10022) (43.0 g) was dissolved in methanol (1000 ml), and triethylamine (17.
1 ml), di-tert-butyl dicarbonate (2
7.0 g) and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was washed with 1N hydrochloric acid. The extracted organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
8: 1) to give the title compound (46.0 g, 93%).
Was obtained as a colorless solid. ¹ H NMR (CDCl ₃ ) δ1.24-1.32 (3
H, m), 1.33-1.50 (9H, m), 2.37.
(1H, m), 2.54 (1H, d, J = 10.7H
z), 3.15-3.41 (1H, m), 3.68-
4.08 (2H, m), 4.10-4.39 (3H,
m), 4.62 (1 / 2H, brs), 4.82 (1
/ 2H, brs), 7.58 (1H, dd, J = 8.
8, 2.0 Hz), 7.75 (1H, dd, J = 8.
8, 2.0 Hz), 7.87-7.94 (3H, m),
8.31 (1H, d, J = 2.0 Hz). MS (FAB) m / z 483 [(M + H) ⁺ , C
l ³⁵ ], 485 [(M + H) ⁺ , Cl ³⁷ ]. Elemental analysis: C ₂₂ H ₂₇ ClNO ₆ S Calculated: C, 54.71; H, 5.63 ; Cl, 7.3
4; N, 5.80; S, 6.64. Analytical values: C, 54.89; H, 5.42; Cl, 7.1.
5; N, 5.76; S, 6.24.

Reference Example 102 1-tert-butoxycarbonyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine-2
-Carboxylic acid 1-tert-butoxycarbonyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazine (23.0 g) was dissolved in tetrahydrofuran (40 ml), ethanol (40 ml),
A 3N aqueous sodium hydroxide solution (30 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was acidified with 1N hydrochloric acid, and then ethyl acetate was added to separate the organic layer, followed by drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the precipitated solid was collected by filtration to obtain the title compound (23.8 g, quant.) As a colorless solid. ¹ H NMR (CDCl ₃ ) δ 2.41 (1 H, m),
2.59 (1H, m), 3.15-3.38 (1H,
m), 3.70-4.08 (2H, m), 4.20-
4.39 (1H, m), 4.72 (1 / 2H, br)
s), 4.91 (1 / 2H, br s), 7.58 (1
H, dd, J = 8.8, J = 2.0 Hz), 7.76
(1H, dd, J = 8.8, 2.0 Hz), 7.87−
7.95 (3H, m), 8.34 (1H, s). MS (FAB) m / z 455 [(M + H) ⁺ , C
l ³⁵ ], 457 [(M + H) ⁺ , Cl ³⁷ ]. Elemental analysis: as C ₂₀ H ₂₃ ClNO ₆ S Calculated: C, 52.80; H, 5.10; Cl, 7.7
9; N, 6.16; S, 7.05. Analytical values: C, 52.62; H, 5.00; Cl, 7.7.
5; N, 6.22; S, 6.83.

Reference Example 103 1-tert-butoxycarbonyl-2-carboxymethyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine 1-[(6-chloronaphthalen-2-yl) sulfonyl]- Using 3- [methoxycarbonylmethyl] piperazine as a raw material, the title compound was obtained in the same manner as in Reference Examples 101 and 102. ¹ H NMR (DMSO-d ₆ ) δ 1.38 (9H,
s), 2.32 (1H, dt, J = 12.2, 3.4H)
z), 2.48 (1H, dd, J = 12.2, 3.4H)
z), 2.61 (1H, dd, J = 15.6, 5.9H
z), 2.86 (1H, dd, J = 15.6, 8.3H
z), 3.13 (1H, s), 3.68 (3H, s),
3.74-4.08 (3H, m), 7.58 (1H, d
d, J = 8.8, 2.0 Hz), 7.74 (1H, d
d, J = 8.8, 2.0 Hz), 7.89-7.94
(3H, m), 8.29 (1H, s). MS (FAB) m / z 469 [(M + H) ⁺ , C
l ³⁵ ], 471 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 22 H 27 ClN 2 O} 7 S Calculated: C, 54.71; H, 5.63 ; Cl, 7.3
4; N, 5.80; S, 6.64. Analytical values: C, 54.74; H, 5.69; Cl, 7.3.
4; N, 5.84; S, 6.62.

Reference Example 104 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine 5-ethoxycarbonyl-4,
5,6,7-Tetrahydrothiazolo [5,4-c] pyridine (WO94 / 21599) (21.0 g) was dissolved in anhydrous tetrahydrofuran (500 ml), and a solution of lithium aluminum humanide in tetrahydrofuran (1) was added under ice cooling. .0M, 200 ml) and stirred at room temperature for 2 hours. Water (7 ml) was slowly added to the reaction solution to stop the reaction, and then a 1N aqueous potassium hydroxide solution (7 ml) and anhydrous magnesium sulfate were sequentially added. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure, and the resulting residue was distilled under reduced pressure (1.
Purification by 5 mmHg, boiling point 82-85 ° C) gave the title compound (6.10 g, 40%) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 2.52 (3H, s),
2.83 (2H, t, J = 5.9 Hz), 2.98 (2
H, t, J = 5.9 Hz) 3.70 (2H, s);
87 (2H, brs), 8.63 (1H, s). MS (FAB) m / z 155 [(M + H) ^<+ >].

Reference Example 105 Lithium 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid 5-methyl-4,5,6,7-tetrahydrothia Zolo [5,4-c] pyridine (6.43 g) was dissolved in anhydrous tetrahydrofuran (200 ml), and n-hexane solution of n-butyllithium (1.47 M,
34.00 ml) was added dropwise, and the mixture was stirred at the same temperature for 40 minutes, and then carbon dioxide gas was blown for 1 hour. The temperature was raised to room temperature, and the reaction solution was concentrated under reduced pressure to give the title compound (9.42 g, qu).
ant. ) Was obtained as a light brown foamy solid. ¹ H NMR (DMSO-d ₆ ) δ 2.37 (3H,
s), 2.64-2.77 (4H, m), 3.54 (2
H, s). MS (FAB) m / z 199 (M + H) ^<+> .

Reference Example 106 N-[[1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-3-yl] carbonyl] glycine ethyl ester trifluoroacetate 1-tert-butoxycarbonyl-4- [ (6-Chloronaphthalen-2-yl) sulfonyl] piperazine-2
-Using a carboxylic acid as a raw material, an amide bond was formed by the same reaction as in Reference Example 6, and then the protecting group was removed using trifluoroacetic acid to obtain the title compound. ¹ H NMR (DMSO-d ₆ ) δ 1.20 (3H, t,
J = 7.3 Hz), 2.47-2.82 (2H, m),
3.14-3.28 (1H, m), 3.30-3.39
(1H, m), 3.72-3.79 (1H, m), 3.
95, (2H, d, J = 5.9 Hz), 4.08-4.
18 (3H, m), 4.20 (1H, dd, J = 11.
2,3.4 Hz), 7.75 (1H, dd, J = 8.
8, 2.0 Hz), 7.84 (1H, d, J = 8.8H)
z), 8.23 (1H, d, J = 8.8 Hz), 8.2
8 (1H, s), 8.30 (1H, d, J = 8.8H)
z), 8.55 (1H, s), 9.29 (1H, t, J
= 5.9 Hz). MS (FAB) m / z 440 [(M + H) ⁺ , C
l ³⁵ ], 442 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 107 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -3-[[(morpholin-4-yl) carbonyl]
Methyl] piperazine hydrochloride 1-tert-butoxycarbonyl-2-carboxymethyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine and morpholine were used as starting materials to form an amide bond by the same reaction as in Reference Example 6. After formation, the protecting group was removed as in Reference Example 1 to give the title compound. ¹ H NMR (DMSO-d ₆ ) δ 2.65-2.91
(4H, m), 3.10-3.22 (1H, m), 3.
30-3.82 (12H, m), 7.74 (1H, d,
J = 8.8 Hz), 7.84 (1H, d, J = 8.8H)
z), 8.20 (1H, d, J = 8.8 Hz), 8.2
2-8.31 (2H, m), 8.55 (1H, s),
9.18 (1H, brs), 9.32 (1H, brs)
s). MS (FAB) m / z 438 [(M + H) ⁺ , C
l ³⁵ ], 440 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 108 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -3- [N- (morpholin-4-yl) carbamoyl] piperazine trifluoroacetate The title compound was prepared in the same manner as in Reference Example 106. Obtained. ¹ H NMR (DMSO-d ₆ at 100 ° C.) δ2.
59-3.97 (13H, m), 4.00-4.12
(1H.m), 4.38-4.50 (1H.m),
7.68 (1H, dd, J = 8.8, 2.4 Hz),
7.84 (1H, d, J = 8.8 Hz), 8.15 (1
H, d, J = 8.8 Hz), 8.18 (1H, s),
8.22 (1H, d, J = 8.8 Hz), 8.48 (1
H, s), 9.18 (1H, br s). MS (FAB) m / z 439 [(M + H) ⁺ , C
l ³⁵ ], 441 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 109 N [[1-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-3-yl] carbonyl] hydrazinoacetic acid ethyl ester hydrochloride The title compound was obtained in the same manner as in Reference Example 106. ¹ H NMR (DMSO-d ₆ ) δ 1.20-1.24
(3H, m), 2.55-2.90 (2H, m), 3.
00-3.20 (1H, m), 3.30-3.38 (1
H, m), 3.53-3.87 (3H, m), 3.94.
-4.19 (3H, m), 4.27 (1 / 2H, d, J
= 9.8 Hz), 4.54-4.63 (1 / 2H,
m), 4.95 (1H, brs), 7.75 (1H,
dd, J = 8.8, 2.0 Hz), 7.84-7.95
(1H, m), 8.19-8.32 (3H, m), 8.
56 (1H, s), 8.80-9.00 (1H, m),
9.78-10.20 (1H, m). MS (FAB) m / z 455 [(M + H) ⁺ , C
l ³⁵ ], 457 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 110 4- (aminoacetyl) morpholine hydrochloride N-tert-butoxycarbonylglycine (2.00
g), morpholine (1.00 ml), 1-hydroxybenzotriazole monohydrate (1.74 g), 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.84 g) was converted to N, N-dimethyl Dissolved in formamide (100 ml) and allowed to stir at room temperature overnight. After the reaction solution was concentrated under reduced pressure, it was diluted with dichloromethane and washed with water,
Dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain a colorless foam. This is dichloromethane (2m
1), saturated ethanol (10 ml) was added thereto, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was dried under reduced pressure to give the title compound (1.80 g, quant.) As a pale yellow foam. _{^{1 H NMR (DMSO-d 6}} ) 3.39 (2H, t, J
= 4.5 Hz), 3.48 (2H, t, J = 4.5H)
z), 3.52-3.63 (4H, m), 3.77-
3.90 (2H, m), 8.32 (3H, brs). MS (FAB) m / z 145 (M + H) ^<+> .

Reference Example 111 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -3- [N-[[(morpholin-4-yl) carbonyl] methyl] carbamoyl] piperazine hydrochloride Same as Reference Example 106 The title compound was obtained. ¹ H NMR (DMSO-d ₆ ) δ 2.67 (1H, d,
J = 11.2 Hz), 2.79 (1H, d, J = 11.
2Hz), 3.09-3.18 (1H, m), 3.17
-3.30 (1H, m), 3.42 (1H, d, J = 1
3.2Hz), 3.45-3.74 (8H, m), 3.
82 (1H, d, J = 12.2 Hz), 4.10-4.
30 (4H, m), 7.86 (1H, d, J = 8.8H)
z), 7.95 (1H, d, J = 8.8 Hz), 8.3
2 (1H, d, J = 8.8 Hz), 8.40 (1H,
s), 8.41 (1H, d, J = 8.8 Hz), 8.6
7 (1H, d, J = 8.8 Hz), 8.93 (1H, b
rs), 9.12 (1H, d, J = 4.9 Hz), 1
0.03 (1H, brs). MS (FAB) m / z 481 [(M + H) ⁺ , C
l ³⁵ ], 483 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 112 1-benzyl-4-tert-butoxycarbonylpiperazine tert-butyl 1-piperazinecarboxylate (2.50 g) was dissolved in acetonitrile (80 ml), and benzyl bromide (1.59 ml) was added under ice cooling. And triethylamine (1.87 ml) were added dropwise, and the mixture was stirred at room temperature for 90 minutes. After evaporating the solvent under reduced pressure, distilled water and dichloromethane were added, the organic layer was separated, and washed with saturated saline.
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 20-1: 5) to give the title compound (3.12 g, 84%). ) Was obtained as a colorless powder. ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
2.38 (4H, t, J = 4.9 Hz), 3.42 (4
H, t, J = 4.8 Hz), 3.51 (2H, s),
7.25-7.29 (1H, m), 7.30-7.33
(4H, m). MS (EI) m / z 276 M <^+> .

Reference Example 113 1-Benzylpiperazine hydrochloride To 1-benzyl-4-tert-butoxycarbonylpiperazine (3.12 g) was added saturated hydrochloric acid ethanol, the mixture was stirred at room temperature for 90 minutes, and the solvent was distilled off under reduced pressure and dried. This afforded the title compound (2.73 g, 97%) as a white powder. ¹ H NMR (DMSO-d ₆ ) δ 3.05-3.67
(9H, m), 4.38 (2H, br), 7.35-
7.70 (5H, m), 9.61 (1H, br). MS
(EI) m / z 176 M ⁺ . Elemental analysis: as C ₁₁ H ₁₆ N ₂ .2HCl.0.2 H ₂ O Calculated: C, 52.27; H, 7.34; Cl, 28.
05; N, 11.27. Analytical values: C, 52.04; H, 7.36; Cl, 27.
89; N, 11.24.

Reference Example 114 1-Benzyl-4-sulfamoylpiperazine chlorosulfonyl isocyanate (0.35 ml) was dissolved in dichloromethane (5 ml), and tert-butanol (0.21 ml) was added dropwise under ice cooling. Stirred for minutes. This was added dropwise to a dichloromethane solution (20 ml of dichloromethane) of 1-benzylpiperazine dihydrochloride (0.25 g) under ice cooling, and then triethylamine (0.2 ml) was added.
8 ml) and stirred for 30 minutes under ice-cooling.
Stirred for hours. Distilled water and dichloromethane were added, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methanol: dichloromethane = 1: 50 to 1:
25), 1-benzyl- [4- (N-tert)
-Butoxycarbonyl) sulfamoyl] piperazine was obtained as a colorless powder. To this was added saturated hydrochloric acid ethanol, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate and dichloromethane were added.
The organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (0.26 g, quant.).
Was obtained as a colorless powder. ¹ H NMR (CDCl ₃ ) δ 2.58 (4H, t, J =
4.9 Hz), 3.22 (4H, t, J = 4.9H)
z), 3.56 (2H, s), 4.33 (2H, b
r), 7.27-7.36 (5H, m). MS (EI) m / z 255 M ⁺ .

Reference Example 115 3,4-bis (bromomethyl) -1-chlorobenzene 1-chloro-3,4-dimethylbenzene (20.0 m
l) was dissolved in acetonitrile (500 ml), N-bromosuccinimide (53.0 g) and azoisobutyronitrile (1.20 g) were added, and the mixture was heated under reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure, dichloromethane was added to the obtained residue, the precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane) to give the title compound (41.5 g, 93%) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 4.59 (2H, s),
4.61 (2H, s), 7.27-7.36 (3H,
m). MS (EI) m / z 295 M ^<+> .

Reference Example 116 1-benzyl-4-[(5-chloroisoindole-2
-Yl) sulfonyl] piperazine 1-benzyl-4-sulfamoylpiperazine (251
mg) in ethanol (5 ml) and 3,4-bis (bromomethyl) -1-chlorobenzene (293 mg).
And potassium carbonate (204 mg) were added, and the mixture was refluxed for 3 and a half hours. After cooling, the precipitate was removed by filtration, and the filtrate was distilled off under reduced pressure.
100) to give the title compound (222 mg, 58%)
I got ¹ H NMR (CDCl ₃ ) δ2.37-2.58 (4
H, m), 3.24-3.41 (4H, m), 3.53
(2H, s), 4.64 (4H, m), 7.13-7.
34 (8H, m). MS (FAB) m / z 392 [(M + H) ⁺ , C
l ³⁵ ], 394 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 117 1-[(5-Chloroisoindole-2-yl) sulfonyl] piperazine 1-benzyl-4-[(5-chloroisoindole-2
-Yl) sulfonyl] piperazine (222 mg),
To a 2-dichloroethane solution (20 ml) was added 1-chloroethyl chloroformate (81 mg) under ice-cooling, and the mixture was stirred for 15 minutes, and further heated under reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure, dry methanol was added to the residue obtained, and the mixture was refluxed for 11 hours. After cooling, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethanol: dichloromethane = 1: 50 to 1:10),
The title compound (120 mg, 70%) was obtained. ¹ H NMR (CDCl ₃ ) δ 2.96 (4H, t, J =
4.4Hz), 3.09-3.22 (1H, br),
3.30 (4H, t, J = 4.4 Hz), 4.65 (4
H, m), 7.14-7.35 (3H, m). MS (FAB) m / z 302 [(M + H) ⁺ , C
l ³⁵ ], 304 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 118 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2-[(N-methyl) carbamoyl] piperazine trifluoroacetate 1-tert-butoxycarbonyl-4-[(6- Chloronaphthalen-2-yl) sulfonyl] piperazine-2
-The carboxylic acid was reacted with methylamine by the same reaction as in Reference Example 6 to form an amide bond, and then the protecting group was removed using trifluoroacetic acid to obtain the title compound. ¹ H NMR (DMSO-d ₆ ) δ 2.54-2.65
(2H, m), 2.67 (3H, d, J = 3.9H
z), 3.12-3.22 (1H, m), 3.33 (1
H, d, J = 13.2 Hz), 3.70 (1H, d, J)
= 12.2 Hz), 4.04, (2H, d, J = 8.8)
Hz), 7.75 (1H, dd, J = 8.8, 2.0H)
z), 7.87 (1H, d, J = 8.8 Hz), 8.2
0 (1H, d, J = 8.8 Hz), 8.27 (1H,
s), 8.29 (1H, d, J = 8.8 Hz), 8.5
8 (1H, s), 8.70 (1H, d, J = 4.4H)
z), 9.06 (1H, brs). MS (FAB) m / z 440 [(M + H) ⁺ , C
l ³⁵ ], 442 [(M + H) ⁺ , Cl ³⁷ ].

The compounds of Reference Examples 119 to 124 were synthesized in the same manner as in Reference Example 118.

Reference Example 119 4-[[1-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-3-yl] carbonyl] morpholine trifluoroacetate ¹ H NMR (DMSO-d ₆ ) δ 2.49 −2.58
(1H, m), 2.64-2.75 (1H, m), 3.
09-3.81 (11H, m), 3.93 (1H, d,
J = 12.2 Hz), 4.76 (1H, dd, J = 1)
0.7, 2.4 Hz), 7.75 (1H, d, J = 8.
8Hz), 7.90 (1H, d, J = 8.8Hz),
8.21 (1H, d, J = 8.8 Hz), 8.27 (1
H, s), 8.29 (1H.d, J = 8.8 Hz),
8.58 (1H, s), 9.15 (1H, br s). MS (FAB) m / z 440 [(M + H) ⁺ , C
l ³⁵ ], 442 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 120 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -3-[(N-tert-butoxy) carbonyl]
Piperazine trifluoroacetate ¹ H NMR (DMSO-d ₆ ) δ2.58-2.70
(2H, m), 3.14-3.23 (1H, m), 3.
30-3.40 (1H, m), 3.64 (1H, d, J
= 12.2 Hz), 3.97 (1H, d, J = 12.2)
Hz), 4.05 (1H, dd, J = 10.2, 3.4)
Hz), 7.74 (1H, dd, J = 8.8, 2.0H)
z), 7.87 (1H, d, J = 8.8 Hz), 8.2
1 (1H, d, J = 8.8 Hz), 8.27 (1H,
d, J = 2.0 Hz), 8.29 (1H, d, J = 8.
8Hz), 8.57 (1H, s), 11.24 (1H,
s). MS (FAB) m / z 426 [(M + H) ⁺ ,
Cl ³⁵ ], 428 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 121 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -3-[(N-isopropyl) carbamoyl] piperazine hydrochloride ¹ H NMR (DMSO-d ₆ ) δ 1.05-1. 18
(6H, m), 2.60-2.77 (2H, m), 3.
08-3.16 (1H, m), 3.30-3.41 (1
H, m), 3.67 (1H, d, J = 12.2 Hz),
3.80-3.90 (1H, m), 4.99 (2H,
d, J = 7.8 Hz), 7.74 (1H, dd, J =
8.8, 2.0 Hz), 7.87 (1H, dd, J =
8.8, 1.5 Hz), 8.22 (1H, d, J = 8.
8Hz), 8.28 (1H, s), 8.31 (1H,
d, J = 8.8 Hz), 8.58 (1H, s), 8.7
4 (1H, d, J = 7.3 Hz). MS (FAB) m / z 396 [(M + H) ⁺ , C
l ³⁵ ], 398 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 122 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -3-[[(piperidin-1-yl) carbonyl]
Methyl] piperazine hydrochloride ¹ H NMR (DMSO-d ₆ ) δ1.45-1.90
(8H, m), 2.78 (1H, d, J = 16.1H)
z), 3.08-3.20 (1H, m), 3.20-
3.60 (7H, m), 3.68-3.92 (3H,
m), 7.58 (1H, d, J = 8.8 Hz), 7.7
1 (1H, d, J = 8.8 Hz), 7.85-7.98
(3H, m), 8.31 (1H, s), 9.09 (1
H, br s), 11.32 (1H, br s). MS (FAB) m / z 436 [(M + H) ⁺ , C
l ³⁵ ], 438 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 123 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -3-[[N- (2-methoxybenzyl)] carbamoyl] piperazine hydrochloride ¹ H NMR (DMSO-d ₆ ) δ2 .69 (1H, t,
J = 11.2 Hz), 2.72-2.30 (1H,
m), 3.08-3.16 (1H, m), 3.31-
3.37 (1H, m), 3.68 (1H, d, J = 1)
2.2 Hz), 4.05 (1H, d, J = 12.2H)
z), 4.14 (1H, dd, J = 10.3, 3.4H
z), 4.29 (1H, d, J = 5.4 Hz), 6.9
3 (1H, t, J = 7.3 Hz), 7.02 (1H,
d, J = 7.8 Hz), 7.24 (1H, d, J = 7.
3Hz), 7.29 (1H, t, J = 7.8Hz),
7.77 (1H, dd, J = 8.8, 2.0 Hz),
7.88 (1H, d, J = 8.8 Hz), 8.23 (1
H, d, J = 8.8 Hz), 8.30 (1H, s),
8.32 (1H, d, J = 8.8 Hz), 8.59 (1
H, s), 9.17 (1H, t, J = 5.4 Hz). MS (FAB) m / z 474 [(M + H) ⁺ , C
l ³⁵ ], 476 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 124 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2-[[N- (2-methoxyityl)] carbamoyl] piperazine ¹ H NMR (DMSO-d ₆ ) δ2.54 -2.75
(2H, m), 3.02-3.51 (7H, m), 3.
70 (1H, d, J = 12.2 Hz), 7.75 (1
H, d, J = 8.8 Hz), 7.87 (1H, d, J =
8.8 Hz), 8.22 (1H, d, J = 8.8H)
z), 8.28 (1H, s), 8.31 (1H, d, J
= 8.8 Hz), 8.58 (1H, s), 8.97 (1
H, t, J = 5.4 Hz), 10.01 (1H, br)
s). MS (FAB) m / z 412 [(M + H) ⁺ , C
l ³⁵ ], 414 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 125 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -3- [carbamoylmethyl] piperazine hydrochloride 1-tert-butoxycarbonyl-2-carboxymethyl-4-[(6-chloro Naphthalen-2-yl) sulfonyl] piperazine (800 mg) was dissolved in N, N-dimethylformamide (20 ml), and pyridine (0.
85 ml), ammonium bicarbonate (417 mg) and ditert-butoxycarbonate (1.15 g) were added, and the mixture was stirred at room temperature for 7 hours. After the reaction solution was concentrated under reduced pressure, dichloromethane was added to the residue, and the mixture was washed once each with 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and after adding ethanolic saturated hydrochloric acid (30 ml) to the residue, the solution was concentrated under reduced pressure. The precipitated solid was removed by filtration while washing with ethanol, and the filtrate was concentrated under reduced pressure. The residue was crystallized in methanol to give the title compound (426 mg) as a colorless solid. IR (KBr) cm ^-1 3185,2917,268
4,2607,1677,1342,1299,117
0,1155,1135,755,692,578. ¹ H NMR (DMSO-d ₆ ) δ2.58-2.65
(1H, m), 2.72-2.83 (1H, m), 3.
12-3.21 (1H, m), 3.30-3.48 (3
H, m), 3.55-3.81 (1H, m), 7.21.
(1H, br s), 7.66 (1H, br s),
7.73 (1H, dd, J = 8.8, 2.0 Hz),
7.85 (1H, d, J = 8.8 Hz), 8.20 (1
H, d, J = 8.8 Hz), 8.26 (1H, s),
8.29 (1H, d, J = 8.8 Hz), 8.56 (1
H, s), 9.02-9.23 (2H, m). MS (FAB) m / z 368 [(M + H) ⁺ , C
l ³⁵ ], 370 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 126 1- (3-Furyl) -2-nitroethylene 3-furaldehyde (10.0 g) in ethanol (20
Nitromethane (6.37 g) was added to the solution at room temperature, and a 10 N aqueous sodium hydroxide solution (1
1.0 ml) was added dropwise and stirred for 1 hour. 1 reaction mixture
The mixture was poured into a 5% aqueous hydrochloric acid solution (500 ml), and the resulting precipitate was collected by filtration and dried to give the title compound (8.0) as a pale yellow powder.
1 g). ¹ H NMR (CDCl ₃ ) δ 6.57 (1 H, d, J =
2.0 Hz), 7.39 (1H, d, J = 13.4H)
z), 7.52 (1H, brs), 7.83 (1H,
br s), 7.94 (1H, d, J = 13.4H)
z).

Reference Example 127 2- (t-Butoxycarbonylamino) -1- (3-furyl) ethane Lithium aluminum hydride (2.20 g) was suspended in tetrahydrofuran (170 ml), and 1- (3
A solution of (furyl) -2-nitroethylene (8.00 g) in tetrahydrofuran (80 ml) was added dropwise at room temperature over 2 hours, and the mixture was stirred for 30 minutes. The reaction solution was cooled to 0 ° C., ethyl acetate (50 ml) was added dropwise, water (10 ml) was added dropwise, and the mixture was stirred for 30 minutes while gradually raising the temperature. After filtration through celite using ethyl acetate and concentration of the filtrate, the obtained residue was dissolved in methylene chloride (200 ml), di-t-butyl dicarbonate (12.6 g) was added at room temperature, and the mixture was stirred for 1 hour. did. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (silica gel 400 g, hexane: ethyl acetate = 15: 1 → 8: 1) to give the title compound (4. 3
0 g). ¹ H NMR (CDCl ₃ ) δ 1.44 (9H, s),
2.61 (2H, t, J = 6.8 Hz), 3.25 −
3.37 (2H, m), 4.57 (1H, brs),
6.29 (1H, s), 7.26 (1H, s), 7.3
7 (1H, s).

Reference Example 128 6- (t-Butoxycarbonyl) -4,5,6,7-tetrahydrofuro [2,3-c] pyridine 2- (t-butoxycarbonylamino) -1- (3-furyl) Ethane (2.20 g) in toluene (300 ml)
Paraformaldehyde (625 mg) and p-toluenesulfonic acid (49.5 mg) were added to the solution.
The mixture was heated under reflux for 2 hours while being dehydrated using a Stark. After cooling to room temperature, a saturated aqueous solution of sodium hydrogen carbonate (200 ml) and ethyl acetate (200 ml) were added to the reaction solution,
The layers were separated, and the aqueous layer was extracted with ethyl acetate (100 ml).
The organic layers were combined, washed with saturated saline (100 ml),
After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel 100 g, hexane: ethyl acetate = 15: 1 → 10:
Purify using 1) to give the title compound (1.
04g). IR (KBr) cm ^-1 : 3145, 3005, 297
6,2925,2862,1695,1448,141
9,1365,1279,1228,1165,112
4,912,895,758. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
2.52 (2H, brs), 3.63 (2H, brs)
s), 4.44 (2H, s), 6.25 (1H, s),
7.29 (1H, s). MS (FAB) m / z 224 [(M + H +], 168
[(M + H-isobutene (56)) ⁺ ]. Calculated _{HRMS M + H (C 12 H} 18 NO 3): 224.1287 Analysis Value: 224.1299

Reference Example 129 6-Methyl-4,5,6,7-tetrahydrofuro [2,
3-c] pyridine 6- (t-butoxycarbonyl) -4,5,6,7-tetrahydrofuro [2,3-c] pyridine (1.05 g)
To the mixture was added a saturated methanol solution of hydrochloric acid (30 ml) at room temperature, and the mixture was stirred for 2 hours, and the reaction solution was concentrated to give a residue. This residue was suspended in methylene chloride (20 ml), methanol (20 ml) and triethylamine (1.31 m
l), acetic acid (810 μl), formaldehyde (37%
Aqueous solution, 610 μl) and sodium triacetoxyborohydride (1.51 g) were added at room temperature and stirred for 1 hour. Add a saturated sodium bicarbonate solution (100
ml) and methylene chloride (20 ml) were added and the mixture was separated, and the aqueous layer was extracted with methylene chloride (3 × 10 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue is subjected to silica gel column chromatography (silica gel 50 g, methylene chloride: acetone =
1: 1 → 1: 2 → methylene chloride: methanol = 10:
Purification using 1) gave the title compound (434 mg) as a colorless, transparent oil. ¹ H NMR (CDCl ₃ ) δ 2.48 (3H, s),
2.56 (2H, t, J = 5.6 Hz), 2.67 (2
H, t, J = 5.6 Hz), 3.48 (2H, s),
6.23 (1H, d, J = 2.0 Hz), 7.25 (1
H, s).

Reference Example 130 3-Aminoacrylaldehyde isoxazole (5.00 g) in methanol (100 g)
ml) solution at room temperature with Raney nickel (Nikko Chemical R-1)
00) (about 1.0 g), and added under a hydrogen atmosphere (3.05).
-2.65 kg / cm ² ) and stirred for 3 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated to give a residue. The residue was reprecipitated with a chloroform-hexane system to give the title compound (4.91 g, 69.1 mm) as a yellow solid.
ol, 95%). ¹ H NMR (CDCl ₃ ) δ 4.60-5.20 (2
H, br), 5.45 (1H, dd, J = 12.7,
8.3 Hz), 7.15 (1H, d, J = 12.7H)
z), 9.18 (1H, d, J = 8.3 Hz). ¹ H NMR (CD ₃ OD) δ 5.55 (1 H, dd, J
= 12.2, 9.3 Hz), 7.59 (1H, d, J =
12.2 Hz), 8.98 (1H, d, J = 9.3H)
z).

Reference Example 131 6- (t-Butoxycarbonyl) -5,6,7,8-tetrahydro-1,6-naphthyridine 1-benzyl-4-piperidone (3.80 g) and 3-
Aminoacrylaldehyde (2.10 g) and triethylamine (1.50 ml) and pyridinium acetate (30.
0 mg) and heated and stirred at 120 ° C. After 22 hours, the reaction mixture was allowed to cool to room temperature, and the resulting brown caramel-like substance was dissolved in a 3N aqueous solution of hydrochloric acid.
x 50 ml). To this aqueous layer was added a saturated aqueous sodium carbonate solution (50 ml), and then chloroform (3 ×
60 ml). After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue. The residue was distilled (0.90 mmHg, 145-150 ° C),
6-benzyl-5,6, as a pale yellow transparent oily substance
About 3: 2 mixture (1.98 g) of 7,8-tetrahydro-1,6-naphthyridine and 1-benzyl-4-piperidone as a raw material was obtained.

This mixture was dissolved in acetic acid (25 ml),
10% palladium-carbon (500 mg) was added, and the mixture was vigorously stirred at 50 to 60 ° C. under a hydrogen atmosphere (about 1 atm). After 2 hours, the reaction mixture was allowed to cool, filtered, and the filtrate was concentrated to give 5,6,6 as a colorless transparent oily substance.
A residue containing 7,8-tetrahydro-1,6-naphthyridine was obtained. This residue was dissolved in toluene (20 ml),
40% aqueous sodium hydroxide solution (30 ml) and di-t
-Butyl dicarbonate (3.20 g, 14.7 mmol
l) was added at room temperature. After stirring for 10 minutes, water (30 m
l) and toluene (20 ml) were added and the mixture was separated, and the aqueous layer was extracted with toluene (30 ml). The organic layers were combined, washed with saturated saline (50 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The residue was subjected to silica gel column chromatography (silica gel 50 g,
Purification using methylene chloride: ethyl acetate = 5: 1 → 3: 1) gave the title compound (98) as a colorless transparent oil.
1 mg). IR (KBr) cm ^-1 : 2974, 1693, 157
7, 1454, 1419, 1392, 1365, 128
8,1259,1241,1228,1161,111
9,1097,989,930,881,862,78
9,768,737. ¹ H NMR (CDCl ₃ ) δ 1.50 (9H, s),
3.01 (2H, t, J = 5.9 Hz), 3.76 (2
H, t, J = 5.9 Hz), 4.59 (2H, s),
7.13 (1H, dd, J = 7.8, 4.9 Hz),
7.41 (1H, d, J = 7.8 Hz), 8.43 (1
H, d, J = 4.9 Hz). MS (FAB) m / z 235 [(M + H) ⁺ ], 17
9 [(M + H) ⁺ -isobutene (56)].

Reference Example 132 6- (t-Butoxycarbonyl) -5,6,7,8-tetrahydro-1,6-naphthyridine-1-oxide 6- (t-butoxycarbonyl) -5,6,7,8 To a solution of -tetrahydro-1,6-naphthyridine (1.72 g) in methylene chloride (40 ml) was added metachloroperbenzoic acid (3.80 g) at 0 ° C, and the mixture was stirred. 30 minutes later,
Dimethyl sulfide (1.62 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium hydrogen carbonate (150 ml) and methylene chloride (30 ml) were added to the reaction mixture, and the mixture was separated.
30 ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue. This residue was subjected to silica gel column chromatography (silica gel 100 g, methylene chloride: methanol = 20: 1 →
10: 1) to give the title compound (1.80 g, 7.19 mmol, 98) as a colorless transparent oil.
%). IR (KBr) cm ^-1 : 2976, 2929, 286
0,1697,1431,1365,1263,124
0,1167,1115,1028,910,771. ¹ H NMR (CDCl ₃ ) δ 1.49 (9H, s),
3.05 (2H, t, J = 5.9 Hz), 3.75 (2
H, t, J = 5.9 Hz), 4.59 (2H, s),
7.04 (1H, d, J = 8.8 Hz), 7.14 (1
H, dd, J = 8.8, 5.9 Hz), 8.18 (1
H, d, J = 5.9 Hz).

Reference Example 133 6- (t-Butoxycarbonyl) -2-cyano-5
6,7,8-Tetrahydro-1,6-naphthyridine 6- (t-butoxycarbonyl) -5,6,7,8-tetrahydro-1,6-naphthyridine-1-oxide (7
Trimethylsilyl cyanide (610 ml) was added to a solution of 60 mg) in methylene chloride (15 ml) at room temperature, and the mixture was stirred for 5 minutes. Then, N, N-dimethylcarbamyl chloride (420 ml) was added to the reaction mixture, and the mixture was stirred for 41 hours. A saturated aqueous solution of sodium hydrogen carbonate (50 ml) and chloroform (30 ml) were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with chloroform (30 ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue. This residue was subjected to silica gel column chromatography (silica gel 50 g, methylene chloride: ethyl acetate = 6:
(1 → 2: 1) to give the title compound (697 mg) as a white solid. The white solid was recrystallized from a hexane-methylene chloride system to obtain colorless needle crystals. IR (KBr) cm ^-1 : 2978, 2933, 223
5,1693,1685,1572,1477,145
8,1415,1365,1267,1238,116
9, 1161, 1124, 1097, 935, 839,
768. ¹ H NMR (CDCl ₃ ) δ 1.50 (9H, s),
3.05 (2H, t, J = 5.9 Hz), 3.77 (2
H, t, J = 5.9 Hz), 4.67 (2H, s),
7.54 (2H, s). MS (FAB) m / z 260 [(M + H) ⁺ ], 20
4 [(M + H) ⁺ -isobutene (56)]. Elemental _{analysis: C 14 H 17 N 3 O} 2 Calculated: C, 64.85; H, 6.61 ; N, 16.2
0. Analytical values: C, 64.89; H, 6.60; N, 16.5.
7.

Reference Example 134 6- (t-butoxycarbonyl) -2-methoxycarbonyl-5,6,7,8-tetrahydro-1,6-naphthyridine 6- (t-butoxycarbonyl) -2-cyano-5
Concentrated hydrochloric acid (40 ml) was added to methanol (40 ml) of 6,7,8-tetrahydro-1,6-naphthyridine (1.25 g) at room temperature, and the mixture was stirred at 100 ° C. for 3 hours.
After allowing this reaction mixture to cool to room temperature, stirred tetrahydrofuran (150 ml) and sodium carbonate (40 g)
Di-t-butyl dicarbonate (1.58 g, 7.23 mmol) was slowly added to the aqueous solution (250 ml) at room temperature. After stirring for 30 minutes, water (200 m
1) was added and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (100 ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue. The residue is subjected to silica gel column chromatography (silica gel 100).
g, methylene chloride: ethyl acetate = 3: 1 → 1: 1) to give the title compound (95%) as a colorless oil.
5 mg). ¹ H NMR (CDCl ₃ ) δ 1.50 (9H, s),
3.12 (2H, t, J = 5.9 Hz), 3.77 (2
H, t, J = 5.9 Hz), 4.00 (3H, s),
4.67 (2H, s), 7.57 (1H, d, J = 8.
1 Hz), 7.98 (1 H, d, J = 8.1 Hz).

Reference Example 135 6- (t-butoxycarbonyl) -2-[[4- (chloronaphthalen-2-yl) sulfonyl] piperazine-1
-Yl] carbonyl] -5,6,7,8-tetrahydro-1,6-naphthyridine 6- (t-butoxycarbonyl) -2-methoxycarbonyl-5,6,7,8-tetrahydro-1,6-naphthyridine (955 mg) in tetrahydrofuran (20 m
l) To the solution was added a 3N-sodium hydroxide aqueous solution (20 ml) at room temperature, and after stirring for 2 hours, ammonium sulfate (16.0 g) was added to the reaction solution. Concentrated hydrochloric acid was added to pH 4, and chloroform (2 x 20 ml) was added. ). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 6- (t-butoxycarbonyl)-as a white solid.
The residue (874 mg) of 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylic acid was obtained. In a solution of the residue in N, N-dimethylformamide (40 ml), methylene chloride (40 ml) and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (1.42 g) were dissolved. 1- (dimethylaminopropyl) -3-ethylcarbodiimide (785 m
g) and 1-hydroxybenzotriazole (555 m
g) and diisopropylethylamine (1.71 ml) was added at 0 ° C. After stirring at room temperature overnight, a 10% aqueous citric acid solution (200 ml) and methylene chloride (100 ml) were added to the reaction solution, and the mixture was separated. The organic layer was extracted with methylene chloride (50 ml). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (silica gel 100).
g, methylene chloride: acetone = 10: 1 → 5: 1), and the resulting white solid was reprecipitated with a methylene chloride-methanol-water system, collected by filtration, washed with water to give a white solid. The title compound (1.44 g) was obtained. IR (KBr) cm ^-1 : 2978, 2924, 284
6,1697,1637,1577,1479,145
4,1432,1365,1340,1238,116
6,733,577. ¹ H NMR (CDCl ₃ ) δ 1.50 (9H, s),
2.92 (2H, t, J = 5.7 Hz), 3.11 (2
H, brt, J = 4.4 Hz), 3.23 (2H, b
rt, J = 4.4 Hz), 3.74 (2H, t, J =
5.7 Hz), 3.78 (2H, brt, J = 4.4)
Hz), 3.90 (2H, brt, J = 4.4H)
z), 4.59 (2H, s), 7.42 (1H, br)
d, J = 7.8 Hz), 7.47 (1H, br d, J
= 7.8 Hz), 7.58 (1H, dd, J = 2.0,
8.8 Hz), 7.77 (1H, dd, J = 2.0,
8.5Hz), 7.90 (1H, d, J = 2.0H)
z), 7.92-7.95 (2H, m), 8.30 (1
H, brs). MS (FAB) m / z 571 [(M + H) ⁺ , C
l ³⁵ ], 515 [(M + H) ⁺ -isobutene
(56), Cl ³⁵ ]. Elemental analysis: C ₂₈ H ₃₁ ClN ₄ O ₅ S Calculated: C, 58.89; H, 5.47; N, 9.8
1; Cl, 6.21; S, 5.61. Analytical values: C, 58.59; H, 5.61; N, 9.8.
4; Cl, 6.53; S, 5.66.

Reference Example 136 2- (t-butoxycarbonylamino) -3- (t-butyldiphenylsilyloxy) propanol N- (t-butoxycarbonyl) -L-serine methyl ester (13.8 g) N, N Imidazole (6.4) in a solution of dimethylformamide (140 ml) at room temperature.
3 g) was added thereto, and t-butyldiphenylsilyl chloride (19.7 ml) was added at 0 ° C., followed by stirring at room temperature for 39 hours. Ethyl acetate (200 ml) and water (60
0 ml), and the mixture was separated. The aqueous layer was separated with ethyl acetate (100 m
Extracted in l). The organic layers are combined and saturated saline (100
ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. This residue was purified without purification, using tetrahydrofuran (100 ml) and methanol (10 ml).
0 ml), and sodium borohydride (7.20 g) was gradually added at 0 ° C. After stirring at 0 ° C. for 2 hours and at room temperature for 1 hour, the reaction mixture was mixed with ethyl acetate (1%).
00 ml), saturated aqueous ammonium chloride solution (300 m
l) and water (300 ml) were added and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (100 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue.
The residue is subjected to silica gel column chromatography (silica gel 500 g, hexane: ethyl acetate = 10: 1 →
Purification using 1: 1) gave the title compound (24.9 g,) as a white solid. ¹ H NMR (CDCl ₃ ) δ 1.07 (9H, s),
1.44 (9H, s), 2.39 (1H, br s),
3.63-3.85 (5H, m), 5.07 (1H, b
rs), 7.35-7.48 (6H, m), 7.60.
-7.67 (4H, m).

Reference Example 137 2- (t-butoxycarbonylamino) -3- (t-butyldiphenylsilyloxy) propanal 2- (t-butoxycarbonylamino) -3- (t-butyldiphenylsilyloxy) propanol ( 3.03
g) in methylene chloride (100 ml) at room temperature was added with Dess-Martin periodinane (3.60 g).
Minutes. A saturated aqueous sodium hydrogen carbonate solution (50 ml) and a 10% aqueous sodium sulfite solution (50 ml) were added to the reaction mixture.
ml) and the mixture was separated. The aqueous layer was separated with diethyl ether (50 m
Extracted in l). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (silica gel 150 g, hexane: ethyl acetate = 4: 1 → 3: 1) to be colorless and transparent. The title compound (2.97 g) was obtained as an oil. ¹ H NMR (CDCl ₃ ) δ 1.03 (9H, s),
1.46 (9H, s), 3.93 (1H, dd, J =
3.9, 10.3 Hz), 4.18 (1H, d, J =
2.9, 10.3 Hz), 4.27-4.35 (1H,
m), 5.33-5.43 (1H, m), 7.32-
7.48 (6H, m), 7.55-7.63 (4H,
m), 9.66 (1H, s).

Reference Example 138 1,5-bis (t-butoxycarbonyl) -2- (t-
Butyldiphenylsilyloxy) methyl-4,5,6
To a solution of 7-tetrahydro-1H-pyrrolo [3,2-c] pyridine diisopropylamine (2.35 ml) in tetrahydrofuran (40 ml) was added n-butyllithium (1.66 N hexane solution, 9.20 ml) at 0 ° C. 30
A solution of N- (t-butoxycarbonyl) -4-piperidone (2.77 g) in tetrahydrofuran (10 ml) was added at −78 ° C. to the reaction solution stirred for 1.5 minutes, followed by stirring for 1.5 hours. A solution of 2- (t-butoxycarbonylamino) -3- (t-butyldiphenylsilyloxy) propanal (2.97 g) in tetrahydrofuran (10 ml) cooled to -78 ° C was added dropwise to the reaction solution, and then gradually raised. Warm 1
Stir for 3 hours. Water (150 ml) and diethyl ether (350 ml) were added for liquid separation, and the aqueous layer was extracted with diethyl ether (100 ml). Combine the organic layers and add water (1
After washing with saturated saline (3 × 100 ml) and drying over anhydrous sodium sulfate, the residue obtained by concentration under reduced pressure was dissolved in methylene chloride (20 ml), and concentrated hydrochloric acid was added dropwise to adjust the pH to 5. Stir for 1 hour. Further, concentrated hydrochloric acid was added dropwise to adjust the pH to 4, and after stirring for 1 hour, a saturated aqueous solution of sodium hydrogencarbonate (50 ml) and methylene chloride (20 ml) were added.
ml), and the mixture is separated. The aqueous layer is separated with diethyl ether (2 × 5
0 ml). The combined organic layers were combined with a saturated saline solution (5
After washing with anhydrous sodium sulfate and concentrating under reduced pressure, the residue obtained was purified using silica gel column chromatography (silica gel 150 g, hexane: ethyl acetate = 8: 1 → 4: 1), The title compound (2.20 g) was obtained as a colorless and transparent caramel-like substance. IR
(KBr) cm ^-1 : 2931, 2856, 1738, ¹
697, 1473, 1427, 1392, 1367, 1
350,1331,1232,1167,1144,1
109, 1066, 822, 739. ¹ H NMR (CDCl ₃ ) δ 1.08 (9H, s),
1.43 (9H, s), 1.49 (9H, s), 2.8
9 (2H, br s), 3.64 (2H, br s),
4.32 (2H, s), 4.85 (2H, brs),
6.12 (1H, s), 7.30-7.48 (6H,
m), 7.60-7.75 (4H, m). MS (FAB / m-NBA / NaCl) m / z 613
[(M + Na) ⁺ ].

Reference Example 139 1,5-bis (t-butoxycarbonyl) -2-hydroxymethyl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine 1,5-bis ( t-butoxycarbonyl) -2- (t-
Butyldiphenylsilyloxy) methyl-4,5,6
To a pyridine (20 ml) solution of 7-tetrahydro-1H-pyrrolo [3,2-c] pyridine (2.10 g) was added a hydrogen fluoride-pyridine mixture (5.0 ml) at 0 ° C.
Stirred at room temperature for 1 hour. The reaction solution was poured into stirred ethyl acetate (50 ml) and iced water (300 ml), separated, and the aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layers were combined with a saturated aqueous sodium hydrogen carbonate solution (100 m
1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (silica gel 150 g, hexane: ethyl acetate =
3: 1) to give the title compound (882 mg) as a colorless and transparent caramel-like substance. IR (KBr) cm ^-1 : 3432, 2976, 293
1,1736,1695,1419,1365,135
0,1323,1234,1167,1144,110
5,754. ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s),
1.60 (9H, s), 2.85 (2H, br s),
3.45-3.70 (1H, br), 3.64 (2H,
br s), 4.29 (2H, s), 4.59 (2H,
d, J = 7.3 Hz), 6.01 (1H, s). MS (FAB / m-NBA / NaCl) m / z 375
[(M + Na) ⁺ ].

Reference Example 140 1,5-bis (t-butoxycarbonyl) -2-formyl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine 1,5-bis (t -Butoxycarbonyl) -2-hydroxymethyl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine (14.0 mg) in methylene chloride (2.0 ml) at room temperature. -Martin
Periodinane (34.0 mg) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (10 ml), 10%
An aqueous sodium thiosulfate solution (10 ml) and a saturated aqueous sodium hydrogen carbonate solution (10 ml) were added, and the mixture was separated. The aqueous layer was extracted with ethyl acetate (10 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative silica gel thin-layer chromatography (hexane: ethyl acetate = 2: 1) to give a colorless, transparent caramel. The title compound (9.8 mg) was obtained as a substance. IR (KBr) cm ^-1 : 2976, 2933, 174
1,1697,1660,1479,1413,136
7, 1346, 1298, 1281, 1234, 116
5,1146,1103,895,850,768. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
1.63 (9H, s), 2.96 (2H, brt, J
= 5.4 Hz), 3.68 (2H, brt, J = 5.
4Hz), 4.37 (2H, s), 6.97 (1H,
s), 10.14 (1H, br s). MS (FAB / m-NBA) m / z 351 [(M +
H) ⁺ ], 295 [(M + H-isobutene (5
6)) ⁺ ], 239 [(M + H-2xisobuten)
e (56)) ⁺ ].

Reference Example 141 1,5-bis (t-butoxycarbonyl) -2-[[4
-[(6-chloronaphthalen-2-yl) sulfonyl]
Piperazin-1-yl] carbonyl] -4,5,6,7
-Tetrahydro-1H-pyrrolo [3,2-c] pyridine 1,5-bis (t-butoxycarbonyl) -2-formyl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] To a solution of pyridine (44.0 mg) in t-butanol (2.0 ml) was added 2-methyl-2 at room temperature.
-Butene (150 μl) and sodium chlorite (10
2 mg) and a solution of sodium dihydrogen phosphate (135 mg) in water (6.0 ml) were added. After stirring for 21 hours, diethyl ether (10 ml) and water (10 ml) were added to the reaction solution, ammonium sulfate was added until saturation, and the mixture was separated and extracted with diethyl ether (10 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1,5-bis (t-butoxycarbonyl) -4,5,6,7-tetrahydro-1H-pyrrolo [3,3 as a white foam. 2-c] Pyridine-2-carboxylic acid residue was obtained. N, N-dimethylformamide of this residue (2.0
ml) solution with methylene chloride (2.0 ml) and 1-
[(6-Chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (55.0 mg) was dissolved in
-(Dimethylaminopropyl) -3-ethylcarbodiimide (30.5 mg) and 1-hydroxybenzotriazole (21.5 mg) were added, and diisopropylethylamine (67.0 µl) was added at 0 ° C. After stirring at room temperature overnight, a 10% aqueous citric acid solution (10 ml) was added to the reaction mixture.
And methylene chloride (10 ml) were added and the mixture was separated, and the organic layer was extracted with methylene chloride (10 ml). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified using preparative silica gel thin-layer chromatography (methylene chloride: acetone = 10: 1) to obtain a white color. The solid was reprecipitated with a methylene chloride-methanol-water system, collected by filtration and washed with water to obtain the title compound (50.0 mg) as a colorless and transparent caramel-like substance. IR (KBr) cm ^-1 : 2981,929,286
0,1743,1693,1647,1456,142
1,1367,1348,1325,1279,123
6,1165,1103,955,945,729. ¹ H NMR (CDCl ₃ ) δ 1.32 (9H, s),
1.46 (9H, s), 2.83 (2H, brt, J
= 5.6 Hz), 3.04 (2H, br), 3.17.
(2H, br), 3.55 (2H, br), 3.62
(2H, brt, J = 5.6 Hz), 3.82 (2
H, br), 4.25 (2H, s), 5.94 (1H,
s), 7.59 (1H, dd, J = 2.0, 8.8H)
z), 7.76 (1H, dd, J = 1.7, 8.5H
z), 7.87-7.98 (3H, m), 8.30 (1
H, brs). MS (FAB / m-NBA / NaCl) m / z 681
[(M + Na) ⁺ ], 581 [(M + Na-Boc (1
00)) ⁺ ], 525 [(M + Na-Boc (100)
-Isobutene (56)) ⁺ ].

Reference Example 142 6-Bromobenzo [b] thiophene 6-Bromobenzothien-2-carboxylic acid (14 g) and copper powder (874 mg) were added to quinoline (45 ml).
The mixture was heated and stirred at an oil temperature of 220 ° C. for 2 hours. After cooling, ether was added, and the copper powder was removed by filtration. The filtrate was washed with a 1N aqueous hydrochloric acid solution and then with a 1N aqueous sodium hydroxide solution.
Finally, it was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane),
The title compound (5.56 g) was obtained as a pale yellow solid. In addition, a raw material (3.15 g) was recovered. ¹ H NMR (CDCl ₃ ) δ 7.29 (1 H, d, J =
5.4 Hz), 7.42 (1H, d, J = 5.4H)
z), 7.46 (1H, dd, J = 8.3, 1.5H
z), 7.67 (1H, d, J = 8.3, Hz), 8.
01 (1H, d, J = 1.5 Hz). MS (EI) m / z 214 [M ⁺ , 81Br], 21
2 [M ⁺ , 79Br].

Reference Example 143 6-Trimethylsilylethynylbenzo [b] thiophene 6-Bromobenzo [b] thiophene (2.13 g) was dissolved in tetrahydrofuran (15 ml), and triphenylphosphine (787 mg) and triethylamine (40 m
l), N, N-dimethylformamide (15 ml), trimethylsilylacetylene (1.47 g), and palladium acetate (225 mg) were added, and the mixture was refluxed for 5 hours. After cooling down,
The mixture was diluted with methylene chloride (150 ml) and washed with water (twice) and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane only) to give the title compound (1.38).
g) was obtained. ¹ H NMR (CDCl ₃ ) δ 0.27 (9H, s),
7.30 (1H, d, J = 5.7 Hz), 7.44 (1
H, dd, J = 8.3, 1.0 Hz), 7.49 (1
H, d, J = 5.7 Hz), 7.73 (1H, d, J =
8.3 Hz), 8.00 (1H, s). MS (EI) m / z 230 M ⁺ .

Reference Example 144 6-Trimethylsilylethynylbenzo [b] thien-2-sulfonyl chloride 6-Trimethylsilylethynylbenzo [b] thiophene (408 mg) was dissolved in dry diethyl ether (10 ml). Cool to -78 ° C,
Tert-butyllithium (1.54 mol n-pentane solution, 1.15 ml) was added dropwise, the temperature was raised to 0 ° C. over 30 minutes, and the mixture was further stirred for 1 hour. Here again the solution-
After cooling to 78 ° C., sulfur dioxide gas was introduced. After the temperature was raised to room temperature over 1 hour, the mixture was stirred for 1 hour. After sufficient volatilization of the dissolved unreacted sulfur dioxide gas, the solvent was distilled off under reduced pressure. Hexane (20 ml) was added, and the insoluble precipitate was collected by filtration and washed with hexane. This is methylene chloride (10m
After cooling to 0 ° C., N-chlorosuccinimide (248 mg) was added, and the mixture was stirred for 30 minutes, warmed to room temperature, and further stirred for 1 hour. After water was added and the layers were separated, the aqueous layer was extracted with methylene chloride (5 times with 10 ml). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (498 mg) as a pale yellow solid. ¹ H NMR (CDCl ₃ ) δ 0.28 (9H, s),
7.58 (1H, dd, J = 8.3, 1.5 Hz),
7.89 (1H, d, J = 8.3 Hz), 8.02 (1
H, s), 8.10 (1H, s). MS (EI) m / z 328 M ⁺ .

Reference Example 145 1-[(6-Trimethylsilylethynylbenzo [b] thien-2-yl) sulfonyl] -3- (N-methylcarbamoyl) piperazine 1,4-dibenzyl-2- (N-methylcarbamoyl)
Piperazine (437 mg) was dissolved in methanol (15 ml), and palladium hydroxide (22 mg) and concentrated hydrochloric acid (0.
22 ml), hydrogen gas was introduced (1 atm), and the mixture was stirred at room temperature for 1 hour. Triethylamine (0.9ml)
After adding, palladium was removed by filtration and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride, triethylamine (0.5 ml) was added, and 6-trimethylsilylethynylbenzo [b] thien-2-sulfonyl chloride (399 m
g) was added under ice-cooling, and the mixture was returned to room temperature and stirred for 20 hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogencarbonate (twice), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol: methylene chloride = 1: 19). Title compound as a pale yellow solid (462 mg)
I got ¹ H NMR (CDCl ₃ ) δ 0.28 (9H, s),
1.52 (1H, brs), 2.57-2.66 (2
H, m), 2.80, 2.79 (total 3H, e
achs), 2.97 (1H, dt, J = 3.3, 1
1.5 Hz), 3.09 (1H, dt, J = 13.2,
3.1 Hz), 3.51 (1H, dd, J = 9.8,
3.4 Hz), 3.59 (1H, dd, J = 11.7,
0.98 Hz), 3.92 (1H, dd, J = 11.
7, 2.4 Hz), 6.56-6.57 (1H, m),
7.52 (1H, dd, J = 8.3, 0.98 Hz),
7.77 (1H, s), 7.82 (1H, d, J = 8.
3 Hz), 7.97 (1H, s). MS (FAB) m / z 436 (M + H) ^<+> .

Reference Example 146 1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- (methoxycarbonylmethyl) piperazine. To a solution of 1- (tert-butoxycarbonyl) -3- (3-methoxycarbonylmethyl) piperazine (5.03 g) in ethanol (50 ml) was added a saturated hydrochloric acid ethanol solution (20 ml), and the mixture was stirred for 30 minutes. After evaporating the solvent under reduced pressure, a methylene chloride solution (200 ml) was obtained. At room temperature, 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (7.64 g) and triethylamine (9.5 ml) were added, and the mixture was stirred at room temperature for 4 hours. Distilled water and methylene chloride were added, the aqueous layer was extracted three times, and the combined organic layers were dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methanol: methylene chloride =
1:50) to give the title compound (4.97)
g) was obtained as a colorless oil. MS (FAB +) m / z 512 [(M + H) ⁺ , Cl
³⁵ ], 514 [(M + H) ⁺ , Cl ³⁷ ]. ¹ H NMR (CDCl ₃ ) δ 2.15-2.30 (1
H, br), 2.34-2.49 (2H, m), 2.7.
2-2.76 (1H, m), 2.90-3.22 (3
H, m), 3.17-3.25 (1H, m), 3.67
(3H, s), 3.71-3.77 (2H, m), 7.
39-7.47 (4H, m), 7.52-7.58 (2
H, m), 8.02 (2H, d, J = 7.8 Hz),
8.23 (1H, d, J = 9.3 Hz).

Reference Example 147 1- (tert-butoxycarbonyl) -4-[(5-
Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -2- (methoxycarbonylmethyl)
Piperazine. To a solution of 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- (methoxycarbonylmethyl) piperazine (2.00 g) in ethanol (250 ml) at room temperature was added di-tert-butyl dicarbonate. (3.91 g) was added and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, diethyl ether was added, and the precipitated crystals were collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (2.01).
g) was obtained as a colorless solid. MS (FAB +) m / z 612 [(M + H) ⁺ , Cl
³⁵ ], 614 [(M + H) ⁺ , Cl ³⁷ ]. ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
2.45-2.54 (1H, m), 2.74-2.86
(1H, m), 2.92-3.03 (1H, m), 3.
07-3.27 (1H, m), 3.37 (3H, s),
3.67-3.77 (2H, m), 3.94-4.06
(2H, m), 4.52-4.67 (1H, m), 7.
38-7.49 (4H, m), 7.57-7.60 (2
H, m), 8.03 (2H, d, J = 6.8 Hz),
8.23 (1H, d, J = 9.3 Hz).

Reference Example 148 1- (tert-butoxycarbonyl) -4-[(5-
Chloroindol-2-yl) sulfonyl] -2-
[[(Morpholin-4-yl)] carbonyl] methyl]
Piperazine 1- (tert-butoxycarbonyl) -4-[(5-
Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -2- (methoxycarbonylmethyl)
A solution of piperazine (1.0 g) in 1,4-dioxane (1
(00 ml), a 1N aqueous sodium hydroxide solution (4.9 ml) was added at room temperature, and the mixture was heated to 80 ° C. and stirred for 6 hours. After adding a saturated ammonium chloride aqueous solution under ice-cooling to make the reaction solution neutral, distilled water was added, the aqueous layer was extracted four times with methylene chloride, and the combined organic layers were dried over anhydrous sodium sulfate. Distilled off. The obtained residue was dried under reduced pressure to obtain a methylene chloride solution (150 ml). At room temperature, 1-hydroxybenzotriazole (0.24
g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.41 g), morpholine (0.16 g), and N-methylmorpholine (0.4 g).
1g) and stirred at room temperature for 12 hours. Distilled water was added, the aqueous layer was extracted three times with methylene chloride, and the combined organic layers were washed four times with distilled water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methanol: methylene chloride = 1: 50) to give the title compound (0.71 g) as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 1.41 (9H, s),
2.23-2.30 (3H, m), 3.34-3.84
(12H, m), 3.91-4.12 (1H, m),
4.49-4.64 (1H, m), 6.98 (1H,
s), 7.27-7.33 (1H, m), 7.37 (1
H, d, J = 8.8 Hz), 7.66 (1H, s). MS (FAB +) m / z 527 [(M + H) ⁺ , Cl
³⁵ ], 529 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 149 1- (tert-butoxycarbonyl) -2- (carbamoylmethyl) -4-[(5-chloroindole-2-
Yl) sulfonyl] piperazine 1- (tert-butoxycarbonyl) -4-[(5-
Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -2- (methoxycarbonylmethyl)
To a solution of piperazine (800 mg) in 1,4-dioxane (100 ml) was added a 1N aqueous sodium hydroxide solution (3.9 ml) at room temperature, and the mixture was heated to 80 ° C. and stirred for 13 hours. After adding a saturated ammonium chloride aqueous solution under ice-cooling to make the reaction solution neutral, distilled water and methylene chloride are added, the aqueous layer is extracted four times with methylene chloride, and the combined organic layers are dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was dried under reduced pressure overnight to give an N, N'-dimethylformamide solution (50 ml). Add this at room temperature
rt-butyl dicarbonate (856 mg, 3.92
mmol), pyridine (259 mg), and ammonium hydrogencarbonate (233 mg), and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in methylene chloride, and hexane and diethyl ether were added to solidify. This was collected by filtration, washed with hexane, and dried under reduced pressure to give the title compound (502 mg) as a colorless solid. MS (FAB +) m / z 457 [(M + H) ⁺ , Cl
³⁵ ], 459 [(M + H) ⁺ , Cl ³⁷ ]. ¹ H NMR (CDCl ₃ ) δ 0.88 (1 H, t, J =
6.4 Hz), 1.24 to 1.33 (1H, m), 1.
35-1.44 (1H, m), 1.46 (9H, s),
2.32-2.59 (2H, m), 2.88-3.18
(2H, m), 3.69-3.88 (1H, m), 3.
91-4.16 (1H, m), 4.35-4.82 (1
H, m), 5.91-6.60 (1H, m), 6.97
(1H, s), 7.26-7.29 (1H, m), 7.
41 (1H, d, J = 8.8 Hz), 7.66 (1H,
s).

Reference Example 150 1,4-dibenzyl-2-ethenylpiperazine. A solution of 1,4-dibenzyl-2- (ethoxycarbonyl) piperazine (6.76 g) in methylene chloride (250 m
l) was cooled to -78 ° C, and then diisobutylaluminum hydride (39 mol / l of a 1.0 mol / l hexane solution) was added.
l) was added dropwise, and the mixture was stirred at -78 ° C for 2 hours. A saturated ammonium chloride aqueous solution and methylene chloride were added, the aqueous layer was extracted three times, and the combined organic layers were washed with distilled water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was used in the next reaction without purification. After cooling a solution of methyltriphenylphosphonium iodide (8.07 g) in tetrahydrofuran (150 ml) to -78 ° C, n-butyllithium (13.14 m in 1.52 mol hexane solution) was added.
l) was added dropwise, and the mixture was stirred at -78 ° C for 2 hours. To this, the tetrahydrofuran solution of the above residue was added dropwise. -78
The temperature was raised from 0 ° C. to 0 ° C. with stirring for 4 hours, and a saturated aqueous ammonium chloride solution was added to stop the reaction. Diethyl ether was added, the aqueous layer was extracted three times, and the combined organic layers were washed with saturated saline and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (methanol: methylene chloride =
1:50) to give the title compound (3.22 g) as a pale yellow oil. MS (EI) m / z 292M ⁺ . ¹ H NMR (CDCl ₃ ) δ 2.07-2.22 (3
H, m), 2.62-2.76 (3H, m), 2.89.
-2.97 (1H, m), 3.07 (1H, d, J = 1
3.2Hz), 3.43-3.56 (2H, m), 4.
04 (1H, d, J = 13.2 Hz), 5.15-5.
32 (2H, m), 5.77-5.88 (1H, m),
7.20-7.33 (10H, m).

Reference Example 151 2-ethylpiperazine hydrochloride 1,4-dibenzyl-2-ethenylpiperazine (10.
To a 9 g) ethanol solution (600 ml) was added concentrated hydrochloric acid (6 ml) and palladium hydroxide (1.1 g) at room temperature.
The mixture was stirred under a hydrogen atmosphere at 1 atm for 12 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was solidified from methylene chloride-diethyl ether, and washed with diethyl ether. By drying this under reduced pressure,
The title compound (6.516 g) was obtained as a brown solid. MS (EI) m / z 114 M ⁺ . ¹ H NMR (DMSO-d ₆ ) δ 0.95 (3H, t,
J = 7.8 Hz), 1.56-1.79 (2H, m),
2.95-3.07 (1H, m), 3.15-3.54
(6H, m), 9.75 (4H, br).

Reference Example 152 1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- (ethyl) piperazine. To a methylene chloride solution (700 ml) of 2-ethylpiperazine hydrochloride (5.00 g) was added 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (7.1).
4g) and triethylamine (11.16 ml) were added, and the mixture was stirred at room temperature for 3 hours. Distilled water and methylene chloride were added, and the aqueous layer was extracted three times. The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methanol:
Methylene chloride = 1: 100) to give the title compound (5.86 g) as a pale yellow oil. MS (EI) m / z 468 (M +, Cl 35), 470
(M ⁺ , Cl ³⁷ ). ¹ H NMR (CDCl ₃ ) δ 0.94 (3H, t, J =
7.8 Hz), 1.33-1.46 (2H, m), 2.
53-2.62 (1H, m), 2.56-2.74 (1
H, m), 2.87-3.07 (3H, m), 3.75
-3.83 (2H, m), 7.38 (1H, s), 7.
40-7.47 (3H, m), 7.53-7.57 (2
H, m), 8.00-8.05 (2H, m), 8.22.
(1H, d, J = 8.8 Hz).

Reference Example 153 1-[(5-Chloroindol-2-yl) sulfonyl] -3- (ethyl) piperazine. A solution of 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- (ethyl) piperazine (3.78 g) in 1,4-dioxane (200 m
To 1), a 1N aqueous sodium hydroxide solution (16 ml) was added, and the mixture was stirred at 80 ° C. for 11.5 hours. A saturated aqueous ammonium chloride solution was added, distilled water and ethyl acetate were added, the aqueous layer was extracted three times, the combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methanol: methylene chloride = 1: 100), and crystallized from tetrahydrofuran-diethyl ether to give the title compound (2.
54 g) were obtained. ¹ H NMR (CDCl ₃ ) δ 0.92 (3H, t, J =
7.8 Hz), 1.25-1.42 (2H, m), 2.
09 (1H, t, J = 1.3 Hz), 2.47 (1H,
dt, J = 11.2, 2.9 Hz), 2.63-2.7
2 (1H, m), 2.92 (1H, dt, J = 17.
2,2.9 Hz), 3.00-3.07 (1H, m),
3.60-3.70 (2H, m), 6.95 (1H,
s), 7.30 (1H, dd, J = 8.8, 1.9H)
z), 7.37 (1H, d, J = 8.8 Hz), 7.6
7 (1H, d, J = 1.9 Hz), 8.98 (1H, b
r).

Reference Example 154 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -3- (ethyl) piperazine. To a methylene chloride solution (30 ml) of 2-ethylpiperazine hydrochloride (307 mg) was added (6-chlorobenzo [b] thien-2-yl) sulfonyl chloride (438 mg) and triethylamine (498 mg).
Stir for 6 hours. Distilled water and methylene chloride were added, and the aqueous layer was extracted three times. The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methanol: methylene chloride = 1: 20) to give the title compound (255 mg) as a pale-yellow oil. MS (FAB) m / z 345 [(M + H) ⁺ , C
l ³⁵ ], 347 [(M + H) ⁺ , Cl ³⁷ ]. ¹ H NMR (CDCl ₃ ) δ 0.95 (3H, t, J =
7.8 Hz), 1.24 to 1.46 (2H, m), 2.
16 (1H, t, J = 10.7 Hz), 2.54 (1
H, td, J = 11.2, 2.9 Hz), 2.65−
2.75 (1H, m), 2.95 (1H, td, J = 1
1.2, 2.9 Hz), 3.04-3.10 (1H,
m), 3.65-3.72 (2H, m), 7.43 (1
H, dd, J = 8.8, 2.0 Hz), 7.75 (1
H, s), 7.81 (1H, d, J = 8.8 Hz),
7.86 (1H, s).

Reference Example 155 1,4-Dibenzyl-2- (2-methyl-1-propenyl) piperazine 1,4-Dibenzyl-2-ethoxycarbonylpiperazine (19.57 g) in methylene chloride (400 ml)
After cooling to −78 ° C., diisobutylaluminum hydride (121.7 ml of a 0.95 mol hexane solution) was added dropwise, and the mixture was stirred at −78 ° C. for 2.5 hours. A saturated ammonium chloride aqueous solution and methylene chloride were added, the aqueous layer was extracted three times, and the combined organic layers were washed with distilled water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was used in the next reaction without purification. After cooling a solution of isopropyltriphenylphosphonium iodide (25.0 g) in tetrahydrofuran (300 ml) to -78 ° C, n-
Butyl lithium (1.53 mol hexane solution 37.
8 ml) was added dropwise, and the mixture was stirred at -78 ° C for 30 minutes. A solution of the above residue in tetrahydrofuran was added dropwise. -78
The temperature was gradually raised at ° C., and the mixture was stirred overnight. A saturated aqueous ammonium chloride solution was added to stop the reaction. Add ethyl acetate,
The aqueous layer was extracted three times, and the combined organic layers were washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 20) to give the title compound (6.0 g) as a pale-yellow oil. MS (EI) m / z 320 M ⁺ . ¹ H NMR (CDCl ₃ ) δ 0.88 (3H, s),
0.91 (3H, s), 2.00 (1H, t, J = 1
0.7 Hz), 2.04-2.21 (2H, m), 2.
64-2.72 (3H, m), 3.00-3.18 (2
H, m), 3.40-3.55 (2H, m), 4.06
(1H, d, J = 13.7 Hz), 5.13 (1H,
d, J = 8.8 Hz), 7.16-7.45 (10H,
m).

Reference Example 156 2- (2-Methylpropyl) piperazine hydrochloride 1,4-dibenzyl-2- (2-methyl-1-propenyl) piperazine (5.2 g) in ethanol solution (300 g)
concentrated hydrochloric acid (3 ml) and palladium hydroxide (683 mg) were added to the mixture at room temperature, and the mixture was stirred under a hydrogen atmosphere at 1 atm for 2 hours. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from methylene chloride-hexane and washed with diethyl ether. This was dried under reduced pressure to give the title compound (2.95) as a brown solid.
g) was obtained. MS (EI) m / z 143 M ⁺ . ¹ H NMR (DMSO-d ₆ ) δ 0.86-1.30
(1H, m), 1.73 (3H, s), 1.76 (3
H, s), 3.10-3.47 (7H, m), 4.36.
−4.45 (1H, m), 5.18 (1H, d, J =
9.3 Hz).

Reference Example 157 1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- (2-methylpropyl) piperazine 2- (2-methylpropyl) piperazine hydrochloride (1. 5
0 g) in methylene chloride solution (150 ml).
-Chloro-1-phenylsulfonylindole-2-sulfonyl (2.72 g) and triethylamine (2.
91 ml) and stirred at room temperature for 13 hours. Distilled water,
Methylene chloride was added, the aqueous layer was extracted three times, and the combined organic layers were washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methanol: methylene chloride = 1: 20) to give the title compound (2.69 g) as a brown oil. MS (FAB) m / z 496 [(M + H) ⁺ , C
l ³⁵ ], 498 [(M + H) ⁺ , Cl ³⁷ ]. ¹ H NMR (CDCl ₃ ) δ 0.89 (1 H, t, J =
5.9 Hz), 1.50-1.52 (1H, m), 2.
70-2.79 (1H, m), 2.90-3.12 (3
H, m), 3.55-3.83 (3H, m), 5.02.
(1H, d, J = 8.3 Hz), 7.35-7.48
(4H, m), 7.51-7.58 (2H, m), 8.
02 (2H, d, J = 8.3 Hz), 8.22 (1H,
d, J = 8.8 Hz).

Reference Example 158 1-[(5-Chloroindol-2-yl) sulfonyl] -3- (2-methylpropyl) piperazine. 1,4-Dioxane- of 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- (2-methylpropyl) piperazine (2.57 g)
A 1N aqueous sodium hydroxide solution (10.4 ml) was added to the distilled water mixed solution (100-10 ml), and the mixture was stirred at 80 ° C. for 3 days. After terminating the reaction with saturated ammonium chloride, distilled water and ethyl acetate were added, the aqueous layer was extracted three times, the combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methanol: methylene chloride = 1: 5).
0) to give the title compound (0.93 g) as a brown oil. MS (FAB) m / z 356 [(M + H) ⁺ , C
l ³⁵ ], 358 [(M + H) ⁺ , Cl ³⁷ ]. ¹ H NMR (CDCl ₃ ) δ 0.78-1.30 (2
H, m), 1.69 (3H, s), 1.70 (3H,
s), 1.63-1.80 (1H, m), 2.39-
2.55 (1H, m), 2.90-3.07 (2H,
m), 3.48-3.70 (3H, m), 4.90 (1
H, d, J = 8.3 Hz), 6.92-6.99 (1
H, m), 7.31 (1H, dd, J = 8.8, 2.0
Hz), 7.36 (1H, d, J = 8.8 Hz), 7.
65-7.69 (1H, m), 8.72 (1H, b
r).

Reference Example 159 1- (tert-butoxycarbonyl) -4-[(6-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine 6-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt (293 mg) N, N -Dimethylformamide (10
1)-(tert-butoxycarbonyl) piperazine (294 mg), 1-hydroxybenzotriazole monohydrate (214 mg) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3 ml).
03 mg) was added at room temperature. After stirring for 38 hours, methylene chloride (20 ml) and water (200 ml) were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with methylene chloride (3 × 10 ml). The organic layers were combined, washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methylene chloride: acetone =
2: 1) to give the title compound (300 mg) as a pale yellow caramel. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
2.51 (3H, s), 2.83, (2H, t, J =
5.7 Hz), 2.94 (2H, t, J = 5.7H)
z), 3.53 (4H, t, J = 5.2 Hz), 3.7
1 (2H, s), 3.75 (2H, br s), 4.3
8 (2H, brs). MS (FAB) m / z 367 (M + H) ^<+> , 311
(M-isobutene + H) ⁺ , 267 (M-Bo
c + H) ⁺ .

Reference Example 160 Thiazolo [4,5-c] pyridine 3- (tert-butoxyamino) -4-mercaptopyridine (9.20 g) was dissolved in formic acid (60 ml).
The mixture was refluxed for 4 hours. The reaction solution was concentrated under reduced pressure, and a 5 N aqueous potassium hydroxide solution (100 ml) was added to the residue, followed by extraction with ether. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and the precipitated solid was collected by filtration to give the title compound as a colorless solid (3.97 g). ¹ H NMR (CDCl ₃ ) δ 7.93 (1 H, d, J =
5.4 Hz), 8.60 (1H, d, J = 5.4H)
z), 9.07 (1H, s), 9.46 (1H, s).

Reference Example 161 5-Methyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridine Thiazolo [4,5-c] pyridine (700 mg) was added to N,
After dissolving in N-dimethylformamide (80 ml) and adding methyl iodide (0.65 ml), the mixture was heated and stirred at 80 ° C. for 4 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in water (100 ml), sodium borohydride (583 mg) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of potassium carbonate was added to the reaction solution, and the mixture was extracted with ether. After the extracted organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (methylene chloride: methanol = 25:
Purification according to 1) gave the title compound (596 mg) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 2.52 (3H, s),
2.77 (2H, t, J = 5.4 Hz), 2.92 −
3.00 (2H, m), 3.69 (2H, t, J = 2.
0 Hz), 8.61 (1H, s). MS (FAB) m / z 155 (M + H) ^<+> .

Reference Example 162 Lithium 5-methyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridine-2-carboxylic acid 5-methyl-4,5,6,7-tetrahydrothia Zolo [4,5-c] pyridine (583 mg) was dissolved in anhydrous tetrahydrofuran (10 ml), and a hexane solution of n-butyllithium (1.54 M, 2.70 m) was added at -78 ° C.
l) was added dropwise, and the mixture was stirred for 10 minutes.
The mixture was stirred for 0 minutes. After cooling the reaction solution to −78 ° C., carbon dioxide gas was blown therein for 15 minutes, and the temperature was raised to room temperature. The reaction solution was concentrated under reduced pressure to obtain the title compound (820 mg) as a pale brown foamy solid. ¹ H NMR (DMSO-d ₆ ) δ 2.38 (3H,
s), 2.64 (2H, brs), 2.80 (2H, b
rs), 3.44 (2H, br s). MS (FD) m / z 199 (M + H) ^<+> .

Reference Example 163 Lithium thiazolo [4,5-c] pyridine-2-carboxylate Prepared in the same manner as in Reference Example 162. ¹ H NMR (DMSO-d ₆ ) δ 8.07 (1H, d,
J = 5.4 Hz), 8.48 (1H, d, J = 5.4H)
z), 9.22 (1H, s).

Reference Example 164 5-Isopropyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridine Prepared in the same manner as in Reference Example 161. ¹ H NMR (CDCl ₃ ) δ 1.16 (6H, d, J =
6.8 Hz), 2.80-2.92 (4H, m), 2.
95-3.03 (1H, m), 3.83 (2H, t, J
= 2.0 Hz), 8.60 (1H, s). MS (FAB) m / z 183 (M + H) ⁺ .

Reference Example 165 Lithium 5-isopropyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridine-2-carboxylate Synthesized in the same manner as in Reference Example 162. ¹ H NMR (DMSO-d ₆ ) δ 0.92-1.10
(6H, m), 2.72 (4H, s) 2.83-2.9
8 (1H, m), 3.55 (2H, s). MS (FAB) m / z 227 (M + H) ^<+> .

Reference Example 166 1-Benzoyl-3-bromo-2-methyl-4-piperidone Copper cyanide (197 mg) was added to diethyl ether (50 m).
1), and a diethyl ether solution of methyllithium (1.10 mol, 4.00 ml) was added dropwise at -78 ° C, and the temperature was raised to 0 ° C. The reaction was allowed to stir for 10 minutes and cooled again to -78 ° C. N-benzoylazacyclohex-2-en-4-one (400 mg) (Can.
Chem. , 1981, 3136-3140) in diethyl ether (5 ml) was added dropwise at -78 ° C, and the mixture was stirred for 30 minutes. Trimethylsilyl chloride (0.
After dropwise addition of 53 ml, 4.20 mmol), the temperature was raised to room temperature. After a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, the mixture was extracted with ethyl acetate. The extracted organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was dissolved in acetone (10 ml), and sodium acetate (135 mg) was added under ice-cooling.
Water (2 ml), N-bromosuccinimide (292 m
g) was added and the mixture was stirred at room temperature overnight. To the reaction solution was added a 2 mol aqueous solution of sodium thiosulfate (10 ml), and the mixture was stirred for 30 minutes. Then, ethyl acetate was added, and the organic layer was separated. The extracted organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue is subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 3).
To give the title compound (240 mg) as a yellow oil. ¹ H NMR (CDCl ₃ ) δ 1.39 (3H, d, J =
7.3 Hz), 2.20-2.40 (1H, m), 2.
65 (1H, brs), 3.18-3.58 (2H,
m), 4.01 (1H, brs), 4.15-4.6.
2 (1 / 2H, m), 4.80-5.28 (1 / 2H,
m), 7.40-7.55 (5H, m). MS (FAB) m / z 296 (M ⁺ , Br ⁷⁹ ), 29
8 (M ⁺ , Br ⁸¹ ).

Reference Example 167 5-benzoyl-4-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine 1-benzoyl-2-methyl-3-bromo-4-piperidone (240 mg) ) Was dissolved in butanol (20 ml), thioformamide (160 mg) was added, and the mixture was stirred at 100 ° C. for 2.5 hours. The reaction solution was cooled to room temperature, filtered through celite, and the filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
1: 2) to give the title compound (56 mg) as a yellow oil. ¹ H NMR (CDCl ₃ ) δ 1.39 (3H, d, J =
5.6 Hz), 2.88-3.10 (2H, m), 3.
41 (1H, brs), 3.94 (1H, brs),
5.97 (1H, brs), 7.38-7.48 (5
H, m), 8.70 (1H, s). MS (FAB) m / z 259 (M + H) ^<+> .

Reference Example 168 5-tert-butoxycarbonyl-4-methyl-4,
5,6,7-Tetrahydrothiazolo [5,4-c] pyridine Sodium hydride (60% oily, 270 mg) was added to butanol (70 ml) under ice cooling and stirred for 30 minutes. The reaction solution was added with 5-benzoyl-4-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine (240 m
g) Butanol solution (5 ml) was added and heated under reflux for 4 days. Water (5 ml) was added to the reaction solution, and the mixture was heated under reflux for 30 minutes, cooled to room temperature, added with di-t-butyl dicarbonate (883 mg), and stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure, 3N hydrochloric acid (10 ml) and ethyl acetate were added to the residue, and the mixture was partitioned, and the organic layer was separated. After the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off, the residue was subjected to silica gel column chromatography (ethyl acetate:
Purification by hexane = 1: 4) gave the title compound (168).
mg) as a yellow oil. ¹ H NMR (CDCl ₃ ) δ 1.46 (3H, d, J =
5.6 Hz), 1.49 (9H, s), 2.85-2.
92 (2H, m), 3.10 (1H, m), 4.27-
4.50 (1H, m), 5.23-5.52 (1H,
m), 8.65 (1H, s). MS (FAB) m / z 255 (M + H) ^<+> .

Reference Example 169 5- (tert-butoxycarbonyl) -4-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Lithium pyridine-2-carboxylate Synthesized in the same manner as in Reference Example 162. _{^{1 H NMR (DMSO-d 6}} ) δ1.38-1.40
(3H, m), 1.43 (9H, s), 2.60-2.
82 (2H, m), 3.11 (1H, brs), 4.
15 (1H, brs), 5, 10-5.32 (1H,
m). MS (FAB) m / z 298 M ⁺ .

Reference Example 170 (5-tert-butyldimethylsilyloxy-4 chloride)
-Oxo-4H-pyran-2-yl) methyl kojic acid (5.00 g) in methylene chloride (300 ml)
In N, N-dimethylformamide (0.03
ml) and thionyl chloride (3.08 ml) were added under ice-cooling, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (600 ml), and triethylamine (19.51 ml), N, N-dimethylaminopyridine (0.20 g), and tert-butyldimethylsilyl chloride (7.95 g) were added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and the mixture was washed sequentially with a 0.3 N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and then the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give the title compound (6.10).
g) was obtained as a light brown oil. ¹ H NMR (CDCl ₃ ) δ 0.23 (6H, s),
0.95 (9H, s), 4.30 (2H, s), 6.4
3 (1H, s), 7.67 (1H, s). MS (FAB) m / z 275 (M + H) ^<+> .

Reference Example 171 [(5-tert-butyldimethylsilyloxy-4-
Oxo-4H-pyran-2-yl) methyl] amine (5-tert-butyldimethylsilyloxy-4 chloride)
-Oxo-4H-pyran-2-yl) methyl (2.00
g) was dissolved in N, N-dimethylformamide (20 ml), sodium azide (1.00 g) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed once with water and once with a saturated saline solution. The extracted organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is methanol (100 ml)
And 10% palladium on carbon (50% wet w
/ W, 800 mg) and stirred overnight under a normal pressure hydrogen stream. The reaction solution was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to give the title compound (29).
0 mg) as a colorless oil. ¹ H NMR (CDCl ₃ ) d 0.23 (6H, s),
0.95 (9H, s), 3.68 (2H, s), 6.3
5 (1H, s), 7.64 (1H, s). MS (FAB) m / z 256 (M + H) ^<+> .

Reference Example 172 1- (tert-butoxycarbonyl) -2- [N-
[(5-tert-butyldimethylsilyloxy-4-
Oxo-4H-pyran-2-yl) methyl] carbamoyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazine It was synthesized by the same reaction as in Reference Example 62. ¹ H NMR (DMSO-d ₆ ) δ 0.15 (6H,
s), 0.91 (9H, s), 1.30 (9H, br)
s), 2.34-2.44 (1H, m), 2.56-
2.71 (1H, m), 3.19-3.46 (1H,
m), 3.55-3.68 (1H, m), 3.77-
3.94 (1H, m), 4.03-4.32 (3H,
m), 4.50-4.69 (1H, m), 6.22 (1
H, brs), 7.00 (1H, s), 7.32 (1
H, dd, J = 8.8, 2.0 Hz), 7.49 (1
H, d, J = 8.8 Hz), 7.79 (1H, d, J =
2.0 Hz), 8.12 (1H, s), 8.66 (1
H, br s), 12.43 (1H, s). MS (FA
B) m / z 681 [(M + H) ⁺ , Cl ³⁵ ], 683
[(M + H) ⁺ , Cl ³⁷ ].

Reference Example 173 1- (tert-butoxycarbonyl) -4-[(5-
Chloroindol-2-yl) sulfonyl] -2- [N
-[(5-hydroxy-4-oxo-4H-pyran-2
-Yl) methyl] carbamoyl] piperazine 1- (tert-butoxycarbonyl) -2- [N-
[(5-tert-butyldimethylsilyloxy-4-
Oxo-4H-pyran-2-yl) methyl] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazine (570 mg) was dissolved in tetrahydrofuran (10 ml), and tetrabutylammonium fluoride 1 2.0M tetrahydrofuran solution (8.3
7 ml), and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 3) to give the title compound (475 mg) as a pale-yellow foam. ¹ H NMR (DMSO-d ₆ ) δ 1.31 (9H, br
s), 2.30-2.86 (2H, m), 3.12-
3.19 (1H, m), 3.52-3.68 (1H,
m), 3.80-3.94 (1H, m), 4.00-
4.30 (3H, m), 4.51-4.69 (1H,
m), 6.23 (1H, brs), 7.00 (1H,
s), 7.32 (1H, dd, J = 8.8, 2.0H)
z), 7.49 (1H, d, J = 8.8 Hz), 7.7
9 (1H, d, J = 2.0 Hz), 8.01 (1H, d, J = 2.0 Hz)
s), 8.68 (1H, br s), 12.44 (1
H, br s) MS (FAB) m / z 567 [(M +
H) ⁺ , Cl ³⁵ ], 569 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 174 2- [N-[(5-acetoxy-4-oxo-4H-
Pyran-2-yl) methyl] carbamoyl] -1- (t
ert-butoxycarbonyl) -4-[(5-chloroindol-2-yl) sulfonyl] piperazine 1- (tert-butoxycarbonyl) -4-[(5-
Chloroindol-2-yl) sulfonyl] -2- [N
-[(5-hydroxy-4-oxo-4H-pyran-2
-Yl) methyl] carbamoyl] piperazine (411m
g) was dissolved in acetonitrile (10 ml) and acetic anhydride (0.075 ml) triethylamine (0.11 m
l) was added and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and the mixture was washed successively with 0.2 N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and the organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (methylene chloride: methanol = 50: 50).
Purification according to 5) gave the title compound (256 mg) as a colorless foam. ¹ H NMR (DMSO-d ₆ ) δ 1.32 (9H, br
s), 2.25 (3H, s), 2.31-2.70
(2H, m), 3.00 (1H, brs), 3.63
(1H, br s), 3.86 (1H, br s),
4.01-4.33 (3H, m), 4.52-4.70
(1H, m), 6.30 (1H, brs), 7.01
(1H, s), 7.32 (1H, dd, J = 8.8,
2.0Hz), 7.49 (1H, d, J = 8.8H)
z), 7.79 (1H, d, J = 2.0 Hz), 8.4
5. (1H, s), 8.72 (1H, brs),
44 (1H, s). MS (FAB) m / z 609 [(M + H) ⁺ , C
l ³⁵ ], 611 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 175 3- [N-[(5-acetoxy-4-oxo-4H-pyran-2-yl) methyl] carbamoyl] -1-[(5
-Chloroindol-2-yl) sulfonyl] piperazine trifluoroacetate 2- [N-[(5-acetoxy-4-oxo-4H-pyran-2-yl) methyl] carbamoyl] -1- (te
The title compound was obtained by treating rt-butoxycarbonyl) -4-[(5-chloroindol-2-yl) sulfonyl] piperazine with trifluoroacetic acid (5 ml) in methylene chloride (5 ml) and drying under reduced pressure. (224m
g) was obtained. ¹ H NMR (DMSO-d ₆ ) δ 2.26 (3H,
s), 2.57-2.72 (2H, m), 3.14-
3.23 (1H, m), 3.39 (1H, d, J = 1
1.7Hz), 3.65 (1H, d, J = 11.7H)
z), 4.03-4.09 (1H, m), 4.17-
4.26 (1H, m), 4.34-4.42 (1H,
m), 6.46 (1H, s), 7.12 (1H, s),
7.36 (1H, dd, J = 8.8, 2.0 Hz),
7.52 (1H, d, J = 8.8 Hz), 7.82 (1
H, d, J = 2.0 Hz), 8.50 (1H, s),
9.42 (1H, brs), 12.57 (1H, s). MS (FAB) m / z 509 [(M + H) ⁺ , C
l ³⁵ ], 511 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 176 N-[[1-[(5-chloroindol-2-yl) sulfonyl] piperazin-3-yl] acetyl] methanesulfonamide trifluoroacetate 1- (tert-butoxycarbonyl) -2 -[(Carboxy) methyl] -4-[(5-chloroindole-2
-Yl) sulfonyl] piperazine (772 mg) was dissolved in tetrahydrofuran (5 ml), carbonyldiimidazole (820 mg) was added, and the mixture was heated under reflux for 1 hour. After the reaction solution was cooled to room temperature, methanesulfonamide (322 mg) and 1,8-diazabicyclo [5.
4.0] -7-undecene (0.50 ml) was added and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was 1 N
An aqueous hydrochloric acid solution was added. After removing the supernatant, the precipitate was washed with water and dried to obtain a colorless foam. This was dissolved in methylene chloride (10 ml), trifluoroacetic acid (10 ml) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the resulting precipitate was collected by filtration to give the title compound (863 mg) as a colorless solid. ¹ H NMR (DMSO-d ₆ ) δ 2.53-2.74
(3H, m), 3.25 (3H, s), 3.43-3.
50 (2H, m), 3.61-3.80 (4H, m),
7.10 (1H, s), 7.34 (1H, dd, J =
8.8, 2.0 Hz), 7.50 (1H, d, J = 8.
8 Hz), 7.80 (1H, d, J = 2.0 Hz), 1
2.58 (1H, s). MS (FAB) m / z 435 [(M + H) ⁺ , C
l ³⁵ ], 437 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 177 1- (tert-butoxycarbonyl) -4-[(6-
Chlorobenzo [b] thien-2-yl) sulfonyl]-
2- (ethoxycarbonyl) piperazine 2-ethoxycarbonylpiperazine acetate (2.08
g) was dissolved in methylene chloride (200 ml), triethylamine (3.63 ml) was added, and the mixture was stirred at room temperature overnight. 6-Chlorobenzo [b] thiene-2 chloride was added to the reaction mixture.
-Sulfonyl (2.00 g) in methylene chloride (20
ml) was slowly added dropwise over 2 hours. After the reaction solution was stirred at room temperature for 30 minutes, ditert-butyl dicarbonate (3.27 g) was added, and the mixture was stirred at room temperature overnight.
The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution. The extracted organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give the title compound (2.26 g) as a pale-yellow foam. ¹ H NMR (CDCl ₃ ) δ 1.30 (3H, t, J =
7.3 Hz), 1.36-1.49 (9H, m), 2.
52 (1H, td, J = 11.7, 3.4 Hz);
66-2.77 (1H, m), 3.20-3.42 (1
H, m), 3.68-3.82 (1H, m), 3.87.
-4.08 (1H, m), 4.17-4.40 (1H,
m), 4.68 (1 / 2H, brs), 4.87 (1
/ 2H, brs), 7.43 (1H, dd, J = 8.
3.2.0 Hz), 7.77 (1H, s), 7.82
(1H, d, J = 8.3 Hz), 7.86 (1H.
d, J = 2.0 Hz). MS (FAB) m / z 489 [(M + H) ⁺ , C
l ³⁵ ], 491 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 178 1- (tert-butoxycarbonyl) -4-[(6-
Chlorobenzo [b] thien-2-yl) sulfonyl] piperazine-2-carboxylic acid 1- (tert-butoxycarbonyl) -4-[(6-
Chlorobenzo [b] thien-2-yl) sulfonyl]-
2- (ethoxycarbonyl) piperazine (2.25 g)
Was dissolved in tetrahydrofuran (10 ml), and ethanol (20 ml) and a 3N aqueous sodium hydroxide solution (3
ml) and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and a 1N aqueous hydrochloric acid solution was added to the residue to adjust the pH to 1 to 2. Then, ethyl acetate was added and the organic layer was separated. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the precipitated solid was collected by filtration to obtain the title compound (2.17 g) as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 1.44 (9H, s),
2.54 (1H, td, J = 11.7, 3.4 Hz),
2.69-2.79 (1H, m), 3.20-3.44
(1H, m), 3.70-3.84 (1H, m), 3.
89-4.12 (1H, m), 4.30-4.41 (1
H, m), 4.78 (1 / 2H, brs), 4.98
(1 / 2H, brs), 7.45 (1H, dd, J =
8.3, 2.0 Hz), 7.79 (1H, s), 7.8
3 (1H, d, J = 8.3 Hz), 7.88 (1H.
d, J = 2.0 Hz). MS (FAB) m / z 461 [(M + H) ⁺ , C
l ³⁵ ], 463 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 179 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -3-[(N-methyl) carbamoyl] piperazine hydrochloride 1- (tert-butoxycarbonyl) -4- [ (6-
Chlorobenzo [b] thien-2-yl) sulfonyl] piperazine-2-carboxylic acid (691 mg), N-methylamine hydrochloride (111 mg), 1-hydroxybenzotriazole monohydrate (230 mg), hydrochloric acid 1- (3 −
Dimethylaminopropyl) -3-ethylcarbodiimide (345 mg) was added to N, N-dimethylformamide (50
ml) and triethylamine (0.23 ml)
Was added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 1) to obtain a pale yellow foam. This was dissolved in a saturated hydrochloric acid / ethanol solution (10 ml), and the reaction solution was concentrated under reduced pressure. The precipitated solid was collected by filtration while washing with ethyl acetate to give the title compound (468 mg) as a colorless solid. ¹ H NMR (DMSO-d ₆ ) δ 2.67 (3H, d,
J = 4.4 Hz), 2.77 (1H, t, J = 11.2)
Hz), 2.87 (1H, t, J = 11.2 Hz),
3.15-3.25 (1H, m), 3.32-3.40
(1H, m), 3.70 (1H, d, J = 12.7H
z), 3.98-4.03 (1H, m), 4.07-
4.15 (1H, m), 7.62 (1H, dd, J =
8.8, 2.0 Hz), 8.11 (1H, d, J = 8.
8Hz), 8.22 (1H, s), 8.40 (1H,
d, J = 2.0 Hz), 8.80 (1H, d, J = 4.
4 Hz). MS (FAB) m / z 374 [(M + H) ⁺ , C
l ³⁵ ], 376 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 180 (Piperazin-1-yl) acetic acid ethyl ester hydrochloride 1- (tert-butoxycarbonyl) piperazine (9
42 mg) in N, N-dimethylformamide (50 m
l), triethylamine (1.40 ml) was added, and then bromoacetic acid ethyl ester (1.13 m
l) was added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain a colorless foam. After being dissolved in a saturated hydrochloric acid-ethanol solution (10 ml), the reaction solution was concentrated under reduced pressure. The precipitated solid was collected by filtration while washing with ethyl acetate, and the title compound (841 m
g) was obtained as a colorless solid. ¹ H NMR (DMSO-d ₆ ) δ 1.24 (3H, t,
J = 7.3 Hz), 3.36 (8H, brs), 4.
08 (2H, brs), 4.18 (2H, q, J =
7.3 Hz), 9.73 (2H, brs). MS (FAB) m / z 173 (M + H) ^<+> .

Reference Example 181 [4-[[1-[(6-chloronaphthalen-2-yl)]
Sulfonyl] piperazin-3-yl] carbonyl] piperazin-1-yl] acetic acid ethyl ester hydrochloride The title compound was synthesized by the same reaction as in Reference Example 179. ¹ H NMR (DMSO-d ₆ ) δ 1.26 (3H,
t, J = 7.3 Hz), 2.51-2.78 (1H,
m), 2.90-4.32 (17H, m), 4.79
(1H, brs), 7.76 (1H, dd, J = 8.
8, 2.0 Hz), 7.90 (1H, d, J = 8.8H)
z), 8.22 (1H, d, J = 8.8 Hz), 8.2
9 (1H, s), 8.32 (1H, d, J = 8.8H)
z), 8.63 (1H, s), 8.90 (1H, br)
s). MS (FAB) m / z 509 [(M + H) ⁺ , C
l ³⁵ ], 511 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 182 5-[[[[[1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-3-yl] carbonyl]
Amino] methyl] tetrazole trifluoroacetate The title compound was synthesized by the same reaction as in Reference Example 179. ¹ H NMR (DMSO-d ₆ ) δ 2.53-2.68
(2H, m), 3.15-3.23 (1H, m), 3.
30-3.37 (1H, m), 3.68-3.76 (1
H, m), 4.12-4.20 (2H, m), 4.65
-4.68 (2H, m), 7.76 (1H, dd, J =
8.8, 2.0 Hz), 7.86 (1H, dd, J =
8.8, 2.0 Hz), 8.26 (1H, d, J = 8.
8 Hz), 8.30-8.34 (2H, m), 8.56
(1H, s), 9.51-9.59 (1H, m). MS (FAB) m / z 435 [(M + H) ⁺ , C
l ³⁵ ], 437 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 183 [1- (tert-butoxycarbonyl) -4-[(6
-Chloronaphthalen-2-yl) sulfonyl] piperazin-2-yl] acetic acid hydrazinamide 1- [1- (tert-butoxycarbonyl) -4-
[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-2-yl] acetic acid (1.11 g) was dissolved in tetrahydrofuran (20 ml) and N-methylmorpholine (0.26 ml) was added at -20 ° C. Isobutyl formate (0.31 ml) was sequentially added dropwise. After stirring at −20 ° C. for 10 minutes, hydrazine hydrate (690 ml) was added. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed once each with a 1N aqueous hydrochloric acid solution, saturated sodium hydrogen carbonate, and saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [methylene chloride: methanol = 100: 0 to 100: 1] to give the title compound (513 mg) as colorless. Obtained as a foam. ¹ H NMR (DMSO-d ₆ ) δ 1.31 (9H,
s), 2.14-2.38 (3H, m), 3.00-
3.12 (1H, m), 3.57-3.68 (2H,
m), 3.83-3.90 (1H, m), 4.16 (2
H, br s), 4.51 (1H, br s), 7.7.
0 (1H, dd, J = 8.8, 2.0 Hz), 7.78
(1H, d, J = 8.8 Hz), 8.15 (1H, d,
J = 8.8 Hz), 8.23 (1H, s), 8.25
(1H, d, J = 8.8 Hz), 8.47 (1H,
s), 9.08 (1H, s). MS (FAB) m / z 483 [(M + H) ⁺ , C
l ³⁵ ], 485 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 184 2-[[1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-3-yl] methyl] -2,3-
Dihydro-2-oxo-1,3,4-oxadiazole trifluoroacetate [1- (tert-butoxycarbonyl) -4-[(6
-Chloronaphthalen-2-yl) sulfonyl] piperazin-2-yl] acetic acid hydrazinamide (505 mg)
Was dissolved in tetrahydrofuran (2 ml), carbonyldiimidazole (102 mg) and triethylamine (0.14 ml) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and the mixture was washed once with a 1N aqueous hydrochloric acid solution, once with water and once with a saturated saline solution. The extracted organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methylene chloride: methanol = 10).
0: 0 to 100: 1) to give a colorless foam. This was dissolved in methylene chloride (2 ml), trifluoroacetic acid (5 ml) was added, and the mixture was stirred at room temperature for 1 minute. The reaction solution was concentrated under reduced pressure, the residue was washed with diethyl ether, and the deposited precipitate was collected by filtration to give the title compound (412).
mg) as a colorless foam. ¹ H NMR (DMSO-d ₆ ) δ 2.60-2.79
(2H, m), 2.85 (1H, dd, J = 16.1,
6.8 Hz), 3.03 (1H, dd, J = 16.1,
6.8 Hz), 3.20 (1H, d, J = 10.2H)
z), 3.43 (1H, d, J = 12.7 Hz);
71 (1H, d, J = 11.2 Hz), 3.90 (1
H, d, J = 11.2 Hz), 7.74 (1H, dd,
J = 8.8, 2.0 Hz), 7.86 (1H, dd, J)
= 8.8, 2.0 Hz), 8.21 (1H, d, J =
8.8 Hz), 8.27 (1 H, s), 8.28 (1
H, d, J = 8.8 Hz), 8.55 (1H, s), 1
2.30 (1H, s). MS (FAB) m / z 409 [(M + H) ⁺ , C
l ³⁵ ], 411 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 185 1- (tert-butoxycarbonyl) -4-[(6-
Chloronaphthalen-2-yl) sulfonyl] -2- (2
-Hydroxylethyl) piperazine 1- [1- (tert-butoxycarbonyl) -4-
[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-2-yl] acetic acid (2.00 g) was dissolved in tetrahydrofuran (100 ml), and N-methylmorpholine (0.51 ml) was added at -20 ° C. Isobutyl acid (0.64 ml) was sequentially added dropwise. After stirring at −20 ° C. for 10 minutes, sodium borohydride (483 m
g) and methanol (20 ml) were sequentially added and stirred for 10 minutes. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed once each with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methylene chloride: methanol = 100: 0-100:
Purification according to 3) gave the title compound (1.75 g) as a colorless foam. ¹ H NMR (CDCl ₃ ) δ 1.40 (9H, s),
1.72-1.85 (1H, m), 2.08-2.18
(1H, m), 2.33 (1H, dt, J = 11.7,
3.4 Hz), 2.50-2.59 (1H, m),
07 (1H, dt, J = 3.4, 12.7 Hz);
25-3.42 (1H, m), 3.60-3.78 (3
H, m), 3.90-3.98 (1H, m), 4.37.
-4.44 (1H, m), 7.58 (1H, dd, J =
8.8, 2.0 Hz), 7.74 (1H, dd, J =
8.8, 2.0 Hz), 7.88-7.95 (3H,
m), 8.29 (1H, s). MS (FAB) m / z 455 [(M + H) ⁺ , C
l ³⁵ ], 457 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 186 2- (2-bromoethyl) -1- (tert-butoxycarbonyl) -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine 1- (tert-butoxycarbonyl) -4- [(6-
Chloronaphthalen-2-yl) sulfonyl] -2- (2
-Hydroxylethyl) piperazine (1.00 g) was dissolved in methylene chloride (50 ml) and carbon tetrabromide (1.
46 g) and triphenylphosphine (1.15 g) were added, and the mixture was stirred at room temperature for 30 minutes. After a saturated aqueous solution of sodium sulfite was added to the reaction solution, the organic layer was separated. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [hexane: ethyl acetate = 10: 1 to 6: 1].
The title compound (990 mg) was obtained as a colorless foam. ¹ H NMR (CDCl ₃ ) δ 1.41 (9H, s),
2.20-2.41 (3H, m), 2.44 (1H, d
d, J = 12.2, 3.9 Hz), 3.04-3.15
(1H, m), 3.43 (1H, brs), 3.68
(1H, d, J = 12.2 Hz), 3.77 (1H,
d, J = 10.7 Hz), 3.95-4.15 (1H,
m), 4.46 (1H, brs), 7.58 (1H,
dd, J = 8.8, 2.0 Hz), 7.74 (1H, d
d, J = 8.8, 2.0 Hz), 7.87-7.94
(3H, m), 8.29 (1H, s). MS (FAB) m / z 518 [(M + H) ⁺ , C
l ³⁵ ], 520 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 187 1- (tert-butoxycarbonyl) -4-[(6-
Chloronaphthalen-2-yl) sulfonyl] -2- (2
-Cyanoethyl) piperazine 2- (2-bromoethyl) -1- (tert-butoxycarbonyl) -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine (980 mg) was added to N, N-
It was dissolved in dimethylformamide (20 ml), sodium cyanide (102 mg) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue.
Washed once with water and once with saturated saline. The extracted organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (842 mg) as a colorless foam. ¹ H NMR (CDCl ₃ ) δ 1.41 (9H, s),
1.92-2.03 (1H, m), 2.21-2.44
(4H, m), 2.48 (1H, dd, J = 11.7,
3.9 Hz), 3.13 (1H, brs), 3.68
(1H, d, J = 11.7 Hz), 3.77 (1H,
d, J = 11.7 Hz), 4.09 (1H, br)
s), 4.38 (1H, br s), 7.58 (1H,
dd, J = 8.8, 2.0 Hz), 7.73 (1H, d
d, J = 8.8, 2.0 Hz), 7.88-7.95
(3H, m), 8.29 (1H, s). MS (FAB) m / z 464 [(M + H) ⁺ , C
l ³⁵ ], 466 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 188 5- [2- [1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-3-yl] ethyl] tetrazole 1- (tert-butoxycarbonyl) -4-[(6 −
Chloronaphthalen-2-yl) sulfonyl] -2- (2
-Cyanoethyl) piperazine (529 mg) was added to N, N-
Dissolve in dimethylformamide (1.5 ml), ammonium chloride (588 mg), sodium azide (74
1 mg), and the mixture was heated and stirred at 100 ° C. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed once with water and once with a saturated saline solution. The extracted organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 50: 1) to obtain a colorless foam. This was dissolved in methylene chloride (5 ml), trifluoroacetic acid (5 ml) was added, and the mixture was stirred at room temperature for 1 minute.
The reaction solution was concentrated under reduced pressure, and the deposited precipitate was washed with diethyl ether and collected by filtration to give the title compound (141 mg) as a colorless solid. ¹ H NMR (DMSO-d ₆ ) δ 1.95-2.08
(2H, m), 2.45-2.70 (2H, m), 2.
98-3.22 (3H, m), 3.35-3.51 (2
H, m), 3.62-3.88 (2H, m),. 7.7
5 (1H, d, J = 8.8 Hz), 7.88 (1H,
d, J = 8.8 Hz), 8.20 (1H, d, J = 8.
8Hz), 8.27 (1H, s), 8.29 (1H,
d, J = 8.8 Hz), 8.56 (1H, s). MS (FAB) m / z 407 [(M + H) ⁺ , C
l ³⁵ ], 409 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 189 1- (tert-butoxycarbonyl) -4-[(5-
Chloroindol-2-yl) sulfonyl] -2-
[(N-methylcarbamoyl) methyl] piperazine Synthesized in the same manner as in Example 79. ¹ H NMR (CDCl ₃ ) δ 1.40 (9H, s),
2.34-2.45 (1H, br), 2.50-2.6
3 (1H, br), 2.63-2.80 (2H, b
r), 2.83 (3H, d, J = 4.6 Hz), 2.9
8-3.10 (1H, m), 3.65-4.15 (3
H, br), 4.62 (1H, brs), 6.05-
6.25 (1H, br), 6.97 (1H, d, J =
1.7Hz), 7.29 (1H, dd, J = 8.8,
1.7Hz), 7.40 (1H, d, J = 8.8H)
z), 7.66 (1H, d, J = 1.7 Hz). MS (FAB) m / z 471 [(M + H) ⁺ , C
l ³⁵ ], 473 [(M + H) ⁺ , Cl ³⁷ ]

Reference Example 190 1- (tert-butoxycarbonyl) -4-[(5-
Chloroidol-2-yl) sulfonyl] -2-[[N
-(Tetrahydrofurfuryl) carbamoyl] methyl]
Piperazine Synthesized in the same manner as in Example 79. ¹ H NMR (CDCl ₃ ) δ 1.42 (9H, s),
1.50-1.70 (1H, m), 1.85-2.10
(3H, m), 2.25-2.35 (1H, br),
2.50-2.85 (3H, br), 2.89-3.2
0 (2H, m), 3.25-3.50 (1H, br),
3.55-4.17 (6H, m), 4.57 (1H, b
rs), 6.29 (1H, brs), 6.90-
6.97 (1H, m), 7.21-7.38 (2H,
m), 7.60-7.68 (1H, m). MS (FA
B) m / z 541 [(M + H) ⁺ , Cl ³⁵ ], 543
[(M + H) ⁺ , Cl ³⁷ ]

Reference Example 191 4-Ethoxycarbonylthiazole formamide (100 ml) was stirred under ice-cooling, and diphosphorus pentasulfide (27.48 g) was added as a solid. Stirred overnight at room temperature. Water (200 ml) was added, followed by extraction with diethyl ether (8 × 200 ml), and the collected organic layer was washed with saturated saline. After drying over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure to obtain thioformamide (35.8 g) as a yellow oil. To this oil was added ethyl pyruvate (20.0 g) with stirring. Ethanol (100 ml) was added to the reaction mixture, and then ethyl bromide pyruvate (45.04 g) was further added, followed by stirring at room temperature for 3 hours. The solvent was distilled off under reduced pressure, methylene chloride was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (42.73 g) as a brown oil. ¹ H NMR (CDCl ₃ ) δ 1.43 (3H, t, J =
7.3 Hz), 4.45 (2H, q, J = 7.3H)
z), 8.26 (1H, d, J = 2.0 Hz), 8.8
6 (1H, d, J = 2.0 Hz). MS (EI) m / z 157 M ⁺ .

Reference Example 192 4-Formylthiazole 4-Ethoxycarbonylthiazole (15.2 g) was dissolved in dry tetrahydrofuran (150 ml), and -78 was added.
Cooled to ° C. Diisobutylaluminum hydride (0.95 mol hexane solution, 102 ml) was added dropwise thereto, and the mixture was stirred at -78 ° C for 1 hour. Methanol (20
ml), and the mixture was heated to room temperature and filtered through Celite. The precipitate was washed with tetrahydrofuran and ethyl acetate,
Further, the precipitate was added to a saturated aqueous solution of ammonium chloride and extracted with methylene chloride. The organic layers were combined, and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride, washed with brine, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure,
The title compound (7.37 g) was obtained as a yellow solid. ¹ H NMR (CDCl ₃ ) δ 8.27 (1 H, d, J =
2.0Hz), 8.92 (1H, d, J = 2.0H)
z), 10.15 (1H, s). MS (EI) m / z 113 M ⁺ .

Reference Example 193 4- (2-Nitro-1-propenyl) thiazole 4-formylthiazole (10.9 g) was dissolved in isopropyl alcohol (100 ml), and potassium fluoride (280 mg) and nitromethane (14.46 g) were added. In addition, the mixture was stirred at 60-65 ° C for 2 hours, and then stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified with benzene (50
acetic anhydride (12.29 g) and 4- (dimethylamino) pyridine (588 mg) were added thereto, and the mixture was refluxed slowly for 2 hours. The solvent was distilled off under reduced pressure, methylene chloride was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (hexane: ethyl acetate = 1: 1) gave the title compound (8.73 g) as bright yellow crystals. ¹ H NMR (CDCl ₃ ) δ 2.78 (3H, d, J =
0.5 Hz), 7.68 (1H, d, J = 2.0H)
z), 8.03 (1H, m), 8.92 (1H, d, J
= 2.0 Hz). MS (EI) m / z 170 M ⁺ .

Reference Example 194 4- [2- [N- (tert-butoxycarbonyl) amino] propyl] thiazole Lithium aluminum hydride (2.41 g) was added to dried tetrahydrofuran (50 ml) under ice-cooling.
To this suspension was added dropwise a solution of 4- (2-nitro-1-propenyl) thiazole (10.8 g) in dry tetrahydrofuran (90 ml). After stirring at the same temperature for 40 minutes, sodium sulfate decahydrate (15 g) was added.
Minutes. The mixture was filtered through celite, and the organic matter was extracted from the precipitate with hot methanol. The organic layers were combined and the solvent was distilled off under reduced pressure. To the residue were added methylene chloride (50 ml), sodium carbonate (3.4 g), and di-tert-butyl dicarbonate (13.86 g), and the mixture was stirred at room temperature for 2 hours. After washing with water, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography (Φ
4 × 20 cm, hexane: ethyl acetate = 3: 1 → 3:
2) to give the title compound (2.86) as a brown oil.
g) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.13, 1.16 (to
tal 3H, deach, J = 6.6, 6.4H
z), 1.42 (9H, s), 2.91-3.09 (2
H, m), 4.00-4.11 (1H, m), 5.03
−5.08 (1H, m), 7.05-7.10 (1H,
m), 8.75-8.77 (1H, m). MS (FA
B) m / z 243 (M + H) ⁺ .

Reference Example 195 5- (tert-butoxycarbonyl) -6-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridine 4- [2- [N- (t-butoxycarbonyl) amino]
Propyl] thiazole (1.07 g) in ethanol (2
6%) and paraformaldehyde (2.94 g of 90%), 1N hydrochloric acid ethanol solution (13 ml)
Was added, and the mixture was placed in a sealed tube and stirred at 100 ° C. for 28 hours. On the way, the operation of cooling to room temperature, loosening the lid, and lowering the internal pressure of the sealed tube was performed several times. Thereafter, the solvent was distilled off under reduced pressure, and methylene chloride (18 ml), triethylamine (2.6 ml),
Di-tert-butyl dicarbonate (1.45 g) was added, and the mixture was stirred at room temperature for 3 hours. After washing with water, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by column chromatography (hexane: ethyl acetate = 4: 1) using silica gel as a carrier gave the title compound (625 mg) as a pale yellow solid. ¹ H NMR (CD
Cl ₃ ) δ 1.15 (3H, d, J = 6.8 Hz),
1.49 (9H, s), 2.77 (1H, d, J = 1
6.6 Hz), 3.09-3.14 (1H, m), 4.
21 (1H, d, J = 16.8 Hz), 4.84 (1
H, br s), 5.06 (1H, br s), 8.6
9 (1H, s). MS (FAB) m / z 255 (M + H) ^<+> .

Reference Example 196 4-Formyl-2- (trans-β-styryl) oxazole 4-ethoxycarbonyl-2- (trans-β-styryl) oxazole (8.57 g) (J. Org. Ch)
em. 1996, 61, 6496-6497) in methylene chloride (80 ml) at −78 ° C. with diisobutylaluminum hydride (1.0 molar hexane solution, 6 ml).
6.0 ml) was added dropwise. After stirring for 15 minutes, methanol (11 ml) was added dropwise and the temperature was raised to room temperature in 1 hour. The reaction mixture was filtered through celite, and the obtained paste was dissolved in ethyl acetate (200 ml) and a saturated aqueous solution of ammonium chloride (200 ml). After liquid separation, the aqueous layer was extracted with methylene chloride (2 × 100 ml). The organic layers were combined, washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and saturated saline (100 ml), combined with the filtrate at the time of celite filtration, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue. . The obtained residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 5: 1 → methylene chloride: methanol = 10: 1),
The title compound (5.86 g) was obtained as colorless needle crystals. ¹ H NMR (CDCl ₃ ) δ 6.96 (1 H, d, J =
16.6 Hz), 7.35-7.45 (3H, m),
7.56 (2H, d, J = 6.4 Hz), 7.67 (1
H, d, J = 16.6 Hz), 8.26 (1H, s),
9.98 (1H, s). MS (FAB) m / z 200 (M + H) ⁺ .

Reference Example 197 2- (trans-β-styryl) -4-vinyloxazole (methyl) triphenylphosphonium bromide (8.16)
g, 22.8 mmol) in tetrahydrofuran (80 m
l) Add n-butyllithium (1.54
Hexane solution, 14.2 ml) was added dropwise at room temperature.
Minutes. The reaction mixture was cooled again to 0 ° C., a solution of 4-formyl-2- (trans-β-styryl) oxazole (3.64 g) in tetrahydrofuran (20 ml) was added, and the temperature was raised to room temperature. After stirring for 2 hours, water (200 m
l) and ethyl acetate (100 ml) were added and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (50 ml). The organic layers were combined, washed with saturated saline (100 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 1) to give the title compound (2.84 g) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) δ 5.33 (1H, dd, J
= 10.7, 1.5 Hz), 5.98 (1H, dd, J)
= 17.6, 1.5 Hz), 6.56 (1H, dd, J)
= 17.6, 10.7 Hz), 6.95 (1H, d, J)
= 16.6 Hz), 7.31-7.42 (3H, m),
7.49-7.56 (4H, m). MS (FAB) m / z 198 (M + H) ^<+> .

Reference Example 198 4- (2-hydroxyethyl) -2- (trans-β
-Styryl) oxazole 2- (trans-β-styryl) -4-vinyloxazole (13.0 g) in tetrahydrofuran (500 m
l) Add 9-borabicyclo [3.3.
1] Nonane (0.5 mol tetrahydrofuran solution, 1
58 ml) and stirred at room temperature for 15 hours. Water (10 ml), 3N aqueous sodium hydroxide solution (80 ml) and aqueous hydrogen peroxide (80 ml) were sequentially added dropwise to the reaction mixture at 0 ° C., and the mixture was stirred at room temperature for 6 hours. Add water (6
(00 ml) and ethyl acetate (200 ml), and the mixture was separated. The aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined, washed with saturated saline (200 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1 → ethyl acetate only).
And purified as a colorless solid using the title compound (14.1).
g) was obtained. ¹ H NMR (CDCl ₃ ) δ 2.69 (1 H, br
s), 2.80 (2H, t, J = 5.6 Hz), 3.9
0-3.97 (2H, m), 6.91 (1H, d, J =
16.6 Hz), 7.30-7.42 (4H, m),
7.43-7.56 (3H, m). MS (FAB) m / z 216 (M + H) ⁺ .

Reference Example 199 N- [2- [2- (trans-β-styryl) oxazol-4-yl] ethyl] phthalimide 4- (2-hydroxyethyl) -2- (trans-β
-Styryl) oxazole (292 mg) in tetrahydrofuran (15 ml) was treated with phthalimide (200 m
g), triphenylphosphine (357 mg) and diethyl azodicarboxylate (214 μl) were added at room temperature,
Stir for 4 hours. The solvent of the reaction mixture was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (447 mg) as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 2.98 (2H, t, J =
7.2 Hz), 4.03 (2H, t, J = 7.2H)
z), 6.88 (1H, d, J = 16.6 Hz), 7.
28-7.45 (5H, m), 7.48 (2H, d, J
= 7.3 Hz), 7.71 (2H, dd, J = 5.4,
2.9 Hz), 7.84 (2H, dd, J = 5.4,
2.9 Hz). MS (FAB) m / z 345 (M + H) ^<+> .

Reference Example 200 4- [2- (tert-butoxycarbonylamino) ethyl] -2- (trans-β-styryl) oxazole N- [2- [2- (trans-β-styryl) oxazole-4- Yl] ethyl] phthalimide (6.40
g) in ethanol (150 ml)
A hydrate (1.50 ml) was added at room temperature, and the mixture was stirred for 1 hour. Then, hydrazine monohydrate (500 μl) was added again at room temperature, and the mixture was stirred for 2 hours. Add methylene chloride (1
50 ml), saturated aqueous sodium hydrogen carbonate solution (150 m
l) and di-tert-butyl dicarbonate (13.
4 g, 61.4 mmol) at room temperature. After stirring for 30 minutes, the layers were separated, and the aqueous layer was extracted with methylene chloride (50 ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1 →
Purification using 1: 1) gave the title compound (5.06 g) as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
2.75 (2H, t, J = 6.6 Hz), 3.46 (2
H, dt, J = 5.9, 6.6 Hz), 4.92 (1
H, br s), 6.91 (1H, d, J = 16.6H)
z), 7.29-7.45 (4H, m), 7.48 (1
H, d, J = 16.6 Hz), 7.52 (2H, d, J)
= 7.3 Hz). MS (FAB) m / z 315 (M + H) ^<+> .

Reference Example 201 5- (tert-butoxycarbonyl) -2- (tra
ns-β-styryl) -4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine 4- [2- (tert-butoxycarbonylamino) ethyl] -2- (trans-β-styryl) To a solution of oxazole (190 mg) in toluene (15 ml) was added paraformaldehyde (54.5 mg) and p-toluenesulfonic acid (7.2 mg) at room temperature. After heating under reflux for 1 hour, the mixture was allowed to cool, and ethyl acetate (15 ml) was added to the reaction mixture.
And a saturated aqueous solution of sodium hydrogencarbonate (15 ml) were added for liquid separation. After the aqueous layer was extracted with ethyl acetate (10 ml), the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 1 →
2: 1) to give the title compound (153 mg) as a colorless and transparent caramel-like substance. ¹ H NMR (CDCl ₃ ) δ 1.50 (9H, s),
2.67 (2H, brs), 3.73 (2H, brs)
s), 4.55 (2H, s), 6.90 (1H, d, J
= 16.1 Hz), 7.29-7.42 (3H, m),
7.46 (1H, d, J = 16.1 Hz), 7.52
(2H, d, J = 7.3 Hz). MS (FAB) m / z 327 (M + H) ^<+> .

Reference Example 202 5- (tert-butoxycarbonyl) -2-formyl-4,5,6,7-tetrahydrooxazolo [5,4-
c] pyridine 5- (tert-butoxycarbonyl) -2- (tra
ns-β-styryl) -4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine (803 mg) in tetrahydrofuran (16 ml) was mixed with acetone (8.0).
ml), water (4.0 ml), N-methylmorpholine oxide (577 mg) and osmium tetroxide (0.039
Molar aqueous solution, 3.20 ml) at room temperature and stirred overnight. Ethyl acetate (50 ml) and a 10% aqueous sodium thiosulfate solution (50 ml) were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with ethyl acetate (30 ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. To a solution of the obtained residue in tetrahydrofuran (16 ml) were added methanol (8.0 ml), water (8.0 ml), and sodium metaperiodate (790 mg) at room temperature. After stirring for 3 hours, the reaction mixture was added to ethyl acetate (30 m
l) and water (50 ml) were added and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (20 ml). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (50 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 2: 1) to give the title compound (234 mg) as a colorless transparent glassy substance. ¹ H NMR (CDCl ₃ ) δ 1.49 (9H, s),
2.77 (2H, brs), 3.77 (2H, brs)
s), 4.62 (2H, s), 9.70 (1H, s). Since this aldehyde was unstable, it was used immediately for the next reaction.

Reference Example 203 5- (tert-butoxycarbonyl) -2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine. 5- (tert-butoxycarbonyl) -2-formyl-4,5,6,7-tetrahydrooxazolo [5,4-
c] Pyridine (225 mg) in methanol (9.0 m
1) Sodium cyanide (220 mg) and manganese dioxide (780 mg) were added to the solution at room temperature, and the mixture was stirred for 30 minutes and filtered through celite using ethyl acetate. The filtrate was washed with water (50 ml) and saturated saline (50 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2 → 1: 1) to give the title compound (120m) as a colorless transparent glassy substance.
g) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.49 (9H, s),
2.73 (2H, brs), 3.74 (2H, brs)
s), 4.01 (3H, s), 4.59 (2H, s). MS (FAB) m / z 283 (M + H) ^<+> .

Reference Example 204 5- (tert-butoxycarbonyl) -4,5,6
7-tetrahydrooxazolo [5,4-c] pyridine-
Lithium 2-carboxylate 5- (tert-butoxycarbonyl) -2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine (311 mg) solution in tetrahydrofuran (8.0 ml) (2.0 ml) and lithium hydroxide (25.0 mg) were added to the mixture at room temperature, and after stirring for 10 minutes, the solvent was distilled off under reduced pressure to obtain the title compound (280 mg) as a colorless solid. This residue can be used without purification
Used for the next reaction. ¹ H NMR (DMSO-d ₆ ) δ 1.42 (9H,
s), 3.31 (2H, s), 3.60 (2H, d, J
= 5.4 Hz), 4.42 (2H, s).

Reference Example 205 2-methoxycarbonyl-5-methyl-4,5,6,7
-Tetrahydrooxazolo [5,4-c] pyridine 5- (tert-butoxycarbonyl) -2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine (500 mg) chloride Trifluoroacetic acid (15 ml) was added to a methylene (15 ml) solution at room temperature, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure,
Methylene chloride (20 ml), triethylamine (495 μl), acetic acid (205 μl), formalin (230 μl) and sodium triacetoxyborohydride (570 mg) were added to the obtained residue at room temperature. After stirring for 15 minutes, methylene chloride (20 ml) and a saturated aqueous solution of sodium hydrogen carbonate (50 ml) were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with methylene chloride (3 × 20 ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (chloroform: methanol = 20: 1 → 10:
Purification using 1) gave the title compound (257 mg) as a colorless, transparent oil. ¹ H NMR (CDCl ₃ ) δ 2.52 (3H, s),
2.72-2.78 (2H, m), 2.78-2.83
(2H, m), 3.61 (2H, t, J = 1.7H
z), 4.00 (3H, s). MS (FAB) m / z 197 (M + H) ^<+> .

Reference Example 206 1- (tert-Butoxycarbonyl) -4-[(5-
Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2-methoxycarbonyl-5-methyl-4,5,6,7
-Tetrahydrooxazolo [5,4-c] pyridine (2
Water (2.0 ml) and lithium hydroxide (30.0 mg) in a solution of 50 mg) in tetrahydrofuran (8.0 ml).
Was added at room temperature, and after stirring for 10 minutes, the solvent was distilled off under reduced pressure. 1- (tert-Butoxycarbonyl) piperazine (260 mg), 1-hydroxybenzotriazole monohydrate (189 mg) and hydrochloric acid 1 were added to a solution of the obtained residue in N, N-dimethylformamide (4.0 ml).
-(3-Dimethylaminopropyl) -3-ethylcarbodiimide (268 mg) was added at room temperature. After stirring for 63 hours, methylene chloride (20 ml) and a saturated aqueous sodium hydrogen carbonate solution (30 ml) were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with methylene chloride (2 × 10 ml). The combined organic layers were washed with water (150 ml), and the aqueous layer was extracted with methylene chloride (3 × 10 ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methylene chloride: acetone = 1: 1 → 1: 3).
The title compound (359 mg) was obtained as a colorless and transparent caramel-like substance. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
2.51 (3H, s), 2.71 (2H, t, J = 4.
5Hz), 2.79 (2H, t, J = 4.5Hz),
3.51 (4H, t, J = 5.0 Hz), 3.60 (2
H, s), 3.75 (2H, t, J = 5.0 Hz),
4.22 (2H, t, J = 5.0 Hz). MS (FAB) m / z 351 (M + H) ^<+> .

Reference Example 207 6- (tert-butoxycarbonyl) -2-methylthio-5,6,7,8-tetrahydropyrido [4,3-
d] Pyrimidine N, N-dimethylformamide dimethyl acetal (18.6 ml) was added to a solution of 1- (tert-butoxycarbonyl) -4-piperidone (9.30 g) in tetrahydrofuran (40 ml) at room temperature, and the mixture was heated under reflux for 3 days. did. After allowing the reaction mixture to cool to room temperature, it was concentrated under reduced pressure to obtain a residue. To a solution of this residue in ethanol (120 ml) was added methylisothiourea sulfate (19.5 g) and sodium ethoxide (13.2 g) at room temperature, and the mixture was heated under reflux for 5 hours. After cooling, water (700 ml) and ethyl acetate (200 ml) were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined, washed with saturated saline (200 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (methylene chloride: acetone = 20: 1).
→ 15: 1) to give the title compound (1.82 g) as a colorless and transparent caramel-like substance. ¹ H NMR (CDCl ₃ ) δ 1.49 (9H, s),
2.56 (3H, s), 2.89 (2H, t, J = 5.
9Hz), 3.72 (2H, t, J = 5.9Hz),
4.52 (2H, s), 8.27 (1H, s). MS (FAB) m / z 282 (M + H) ⁺ .

Reference Example 208 6- (tert-Butoxycarbonyl) -2-methylsulfonyl-5,6,7,8-tetrahydropyrido [4
3-d] pyrimidine 6- (tert-butoxycarbonyl) -2-methylthio-5,6,7,8-tetrahydropyrido [4,3-
d] Pyrimidine (2.20 g) in methylene chloride (80 m
l) The solution was added at room temperature with metachloroperbenzoic acid (3.37).
g) was added. After stirring for 4 hours, a 10% aqueous sodium thiosulfate solution (100 ml) and a saturated aqueous sodium hydrogen carbonate solution (100 ml) were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with methylene chloride (2 × 50 ml). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue is subjected to silica gel column chromatography (methylene chloride: acetone = 20: 1 → 1).
0: 1) to give the title compound (2.34 g) as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 1.50 (9H, s),
3.10 (2H, t, J = 5.9 Hz), 3.34 (3
H, s), 3.80 (2H, t, J = 5.9 Hz),
4.71 (2H, s), 8.63 (1H, s). MS (FAB) m / z 314 (M + H) ⁺ .

Reference Example 209 6- (tert-butoxycarbonyl) -2-cyano-
5,6,7,8-tetrahydrocyano [4,3-d] pyrimidine 6- (tert-butoxycarbonyl) -2-methylsulfonyl-5,6,7,8-tetrahydropyrido [4
3-d] pyrimidine (330 mg) in methylene chloride (1
0 ml) solution at room temperature was added tetrabutylammonium cyanide (425 mg). After stirring at room temperature for 3 hours,
The solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by silica gel column chromatography (methylene chloride: acetone = 20: 1) to give the title compound (261 mg) as a pale yellow foam. ¹ H NMR (CDCl ₃ ) δ 1.50 (9H, s),
3.02 (2H, t, J = 5.9 Hz), 3.78 (2
H, t, J = 5.9 Hz), 4.68 (2H, s),
8.55 (1H, s). MS (FAB) m / z 261 (M + H) ^<+> .

Reference Example 210 6- (tert-butoxycarbonyl) -2-methoxycarbonyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine 6- (tert-butoxycarbonyl) -2- Cyano
Concentrated hydrochloric acid (5.0 ml) was added to a solution of 5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine (814 mg) in methanol (10 ml) at room temperature, and then 100 ° C.
For 1 hour. After cooling, the reaction mixture was concentrated under reduced pressure.
The obtained residue was dissolved in methylene chloride (15 ml), and triethylamine (2.20 ml) and di-t were added at room temperature.
tert-Butyl dicarbonate (1.03 g) was added. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to obtain a residue. The obtained residue was purified by silica gel column chromatography (methylene chloride: acetone = 6: 1 → 3: 1) to give the title compound (6) as a pale yellow caramel substance.
19 mg). ¹ H NMR (CDCl ₃ ) δ 1.50 (9H, s),
3.10 (2H, t, J = 5.8 Hz), 3.79 (2
H, t, J = 5.8 Hz), 4.06 (3H, s),
4.71 (2H, s), 8.65 (1H, s). MS (FAB) m / z 294 (M + H) ^<+> .

Reference Example 211 1,4-Dibenzyl-2- (formylmethyl) piperazine 1,4-Dibenzyl-2- (2-hydroxyethyl) piperazine (620 mg) was dissolved in methylene chloride (30 ml). Under ice cooling, 4-methylmorpholine N-oxide (281 mg) and tetrapropylammonium perruthenate (141 mg) were added, and the mixture was returned to room temperature after 10 minutes and stirred. After 18 hours, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1) to give the title compound (360 mg) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 2.33-2.82 (8
H, m), 3.13 (1H, brs), 3.34 (1
H, d, J = 13.2 Hz), 3.48 (2H, AB)
q, J = 13.2 Hz), 3.81 (1H, d, J = 1)
3.2Hz), 7.29 (10H, m), 9.81 (1
H, s). MS (FAB) m / z 309 [(M + H) ^<+ >].

Reference Example 212 1,4-Dibenzyl-2- [2- (1-piperidinyl)
[Ethyl] piperazine 1,4-dibenzyl-2- (formylmethyl) piperazine (600 mg) and piperidine (200 mg) were dissolved in methanol (10 ml). After stirring for 30 minutes as it was, the solvent was concentrated under reduced pressure, dissolved again in methanol (10 ml), sodium borohydride (147 mg) was added, and the mixture was stirred. After 5 hours, the solvent was distilled off under reduced pressure, chloroform was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 10: 1 → 5: 1) to give the title compound as a colorless oil. (640 mg). ¹ H NMR (CDCl ₃ ) δ 1.42 (2H, m),
1.57 (4H, m), 1.85 (2H, m), 2.2
2-2.70 (13H, m), 3.22 (1H, d, J
= 13.5 Hz), 3.46 (2H, ABq, J = 1)
3.0Hz), 3.99 (1H, d, J = 13.2H)
z), 7.30 (10H, m). MS (FAB) m / z 378 [(M + H) ^<+ >].

Reference Example 213 1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [2- (1-piperidinyl) ethyl] piperazine 1,4-dibenzyl-2- [2 -(1-piperidinyl)
Ethyl] piperazine (740 mg) and 10% palladium-carbon (100 mg) were added, dissolved in acetic acid (5.0 ml), and stirred under a hydrogen atmosphere at 1 atm. After 20 hours, the palladium was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methylene chloride (10 ml), triethylamine (595 mg) was added, and 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (765 mｍ) was added.
g) was added dropwise over 90 minutes, and stirring was continued at room temperature. After 19 hours, chloroform was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol: isopropylamine = 500: 75: 1) to give the title as a colorless oil. The compound (335 mg) was obtained. ¹ H NMR (CDCl ₃ ) δ1.46-1.86 (8
H, m), 2.50-3.19 (11H, m), 3.7
4 (2H, m), 7.13-7.57 (6H, m),
7.99 (1H, d, J = 9.5 Hz), 8.02 (1
H, d, J = 8.3 Hz), 8.22 (1H, d, J =
9.0 Hz). MS (FAB) m / z 551 [(M + H) ^<+ >].

Reference Example 214 1,4-Dibenzyl-2- [2-[(2-methoxyethyl) amino] ethyl] piperazine The title compound was synthesized in the same manner as in Reference Example 212. ¹ H NMR (CDCl ₃ ) δ 1.84 (2H, m),
2.22 (3H, m), 2.51-2.81 (8H,
m), 3.23 (1H, d, J = 14.4 Hz);
35 (3H, s), 3.41-3.52 (4H, m),
4.02 (1H, d, J = 13.2 Hz), 7.30
(10H, m). MS (FAB) m / z 368 [(M + H) ^<+ >].

Reference Example 215 2- [2- [N- (tert-butoxycarbonyl)-
(2-methoxyethyl) amino] ethyl] -1,4-dibenzyl-piperazine 1,4-dibenzyl-2- [2-[(2-methoxyethyl) amino] ethyl] piperazine (540 mg) and di-tert- Butyl dicarbonate (353 mg) was added, dissolved in methylene chloride (10 ml), triethylamine (223 mg) was added, and the mixture was stirred for 3 days. The reaction is stopped, the solvent is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography (methylene chloride: methanol =
100: 1) to give the title compound (6) as a colorless oil.
10 mg). ¹ H NMR (CDCl ₃ ) δ 1.40 (9H, s),
1.87 (2H, m), 2.21 (3H, m), 2.5
3 (2H, m), 2.68 (2H, m), 3.22-
3.52 (9H, m), 3.29 (3H, s), 4.0
3 (1H, d, J = 13.5 Hz), 7.30 (10
H, m). MS (FAB) m / z 468 [(M + H) ^<+ >].

Reference Example 216 3- [2- [N- (tert-butoxycarbonyl)-
N- (2-methoxyethyl) amino] ethyl] -1-
[(5-Chloro-1-phenylsulfonylindole-
2-yl) sulfonyl] piperazine 2- [2- [N- (tert-butoxycarbonyl)-
(2-Methoxyethyl) amino] ethyl] -1,4-dibenzyl-piperazine (610 mg) and 10% palladium-carbon (100 mg) were added, and methanol (10 ml) was added.
And stirred under a hydrogen atmosphere at 1 atm. Three days later, the palladium was filtered off, and the solvent was concentrated under reduced pressure. The obtained residue was dissolved in methylene chloride (10 ml), triethylamine (390 mg) was added, and 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (503 m) was added.
g) was added dropwise over 30 minutes, and stirring was continued at room temperature. After 22 hours, chloroform was added, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 25: 1).
The title compound (490 mg) was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
1.46-3.76 (15H, m), 3.31 (3H,
s), 7.21-7.56 (6H, m), 8.01 (2
H, d, J = 7.4 Hz), 8.22 (1H, d, J =
9.1 Hz). MS (FAB) m / z 641 [(M + H) ^<+ >].

Reference Example 217 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -3- (2-methylpropyl) piperazine 2- (2-methylpropyl) piperazine hydrochloride (35
3 mg) in methylene chloride solution (30 ml).
-Chlorobenzo [b] thien-2-sulfonyl (438
mg) and triethylamine (498 mg),
Stir at room temperature for 3 hours. Add distilled water and methylene chloride,
The aqueous layer was extracted three times with methylene chloride, the combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methanol: methylene chloride = 1: 100) to give the title compound (363 mg) as a pale-yellow oil. ¹ H NMR (CDCl ₃ ) δ 0.78-0.94 (0.
5H, m), 1.16-1.34 (0.5H, m),
1.40-1.54 (1H, m), 1.70 (3H,
s), 1.71 (3H, s), 2.24 (1H, t, J
= 11.2 Hz), 2.55 (1H, td, J = 11.
2, 3.4 Hz), 2.92-3.08 (2H,
m), 3.52-3.62 (2H, m), 3.65-
3.74 (1H, m), 4.92 (1H, d, J = 8.
3Hz), 7.43 (1H, dd, J = 8.8, 2.0
Hz), 7.74 (1H, s), 7.81 (1H, d,
J = 8.8 Hz), 7.85 (1H, d, J = 2.0H)
z). MS (FAB +) m / z 383 [(M + H) ⁺ , Cl
³⁵ ], 385 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 218 1- (t-butoxycarbonyl) -3,3-dimethylpiperazine 2,2-dimethylpiperazine (460 mg, 4.03 m
mol) (J. Med. Chem., 1995, 38,
4389. ) In methylene chloride solution (5.0 ml)
Tert-butyl dicarbonate (780 μl) was added and stirred for 3 hours. The mixture was diluted with methylene chloride and saturated saline was added to form two layers. After liquid separation, the aqueous layer was extracted with methylene chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The crude product was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to give the title compound (360 mg) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 1.19 (6H, s),
1.46 (9H, s), 2.93 (2H, t, J = 4.
9Hz), 3.23 (2H, s), 3.42-3.48
(2H, br), 3.95-4.01 (1H, s).

Reference Example 219 4- (tert-butoxycarbonyl) -1-[(6-
Chloronaphthalen-2-yl) sulfonyl] -2,2-
Dimethylpiperazine 1- (tert-butoxycarbonyl) -3,3-dimethylpiperazine (125 mg) in methylene chloride (3.0)
triethylamine (90 μl), chloride 6
-Chloronaphthalene-2-sulfonyl (167 mg) was added, and the mixture was stirred at room temperature for 84 hours. After diluting with methylene chloride and adding a saturated aqueous sodium chloride solution to form two layers, the layers were separated, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give the title compound (155 mg) as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 1.31 (6H, s),
1.44 (9H, s), 3.22 (2H, br s),
3.49-3.62 (2H, br), 3.57-3.6
2 (2H, br), 7.56 (1H, dd, J = 8.
8, 2.0 Hz), 7.79 (1H, d, J = 8.8H)
z), 7.86 (1H, s), 7.87-7.92 (3
H, m), 8.36 (1H, s).

Reference Example 220 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -2,2-dimethylpiperazine hydrochloride 4- (tert-butoxycarbonyl) -1-[(6-
Chloronaphthalen-2-yl) sulfonyl] -2,2-
To a methylene chloride solution (0.5 ml) of dimethylpiperazine (140 mg) was added a saturated hydrochloric acid ethanol solution (0.5 m
l) was added and the mixture was stirred at room temperature for 14 hours. Ethanol was added thereto, and hydrochloric acid was sufficiently removed by azeotropic distillation, followed by drying with a vacuum pump to obtain the title compound (119 mg) as a colorless solid. ¹ H NMR (DMSO-d ₆ ) δ 3.17 (4
H, brs), 3.50-3.95 (4H, br),
7.44 (2H, t, J = 3.9 Hz), 7.57 (2
H, d, J = 8.8 Hz), 7.66 (1H, t, J =
3.9 Hz), 7.92 (2H, d, J = 8.8H)
z), 8.36 (1H, d, J = 7.8 Hz), 9.2
1 (2H, d, J = 3.9 Hz). MS (FAB) m / z 339 [(M + H) ⁺ , C
l ³⁵ ], 341 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 221 1,4-bis (tert-butoxycarbonyl) -2-
(2-hydroxyethyl) piperazine 1,4-dibenzyl-2- (2-hydroxyethyl) piperazine (19.2 g) was treated with methanol (200 ml),
It was dissolved in concentrated hydrochloric acid (5.4 ml), and palladium hydroxide (1.02 g) was suspended in this reaction solution. The suspension was then vigorously shaken at room temperature under 1 atmosphere of hydrogen atmosphere for 15.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Methylene chloride (250 ml), methanol (50 ml) and diisopropylethylamine (20.0 ml) were added to the obtained residue to dissolve the residue, and di-tert was added under ice cooling.
-Butyl dicarbonate (27.0 g) was added, and the mixture was stirred at room temperature for 18.5 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 9: 1 → hexane: ethyl acetate = 1: 1), hexane was added to the residue to solidify, and the title compound (1
6.1 g) as a colorless powder. ¹ H NMR (CDCl ₃ ) δ 1.46, 1.48 (18
H, each s), 1.30-1.90 (2H,
m), 2.70-4.40 (10H, m). MS (FAB) m / z 331 (M + H) ^<+> .

Reference Example 222 1,4-bis (tert-butoxycarbonyl) -2-
Formylmethylpiperazine 1,4-bis (tert-butoxycarbonyl) -2-
(2-Hydroxyethyl) piperazine (5.00 g) was dissolved in methylene chloride (150 ml). To this reaction solution were added N-methylmorpholine (2.14 g) and tetra-n-propylammonium perruthenate (0.97 g) under ice-cooling, followed by stirring at room temperature for 17 hours. The reaction solution was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 1: 1).
2: 1) to give the title compound (3.11 g) as a colorless powder. ¹ H NMR (CDCl ₃ ) δ 1.45 (18H, s),
2.50-3.10 (5H, m), 3.70-4.20
(3H, m), 4.66 (1H, br), 9.76 (1
H, s). MS (FAB) m / z 329 (M + H) ^<+> .

Reference Example 223 1,4-bis (tert-butoxycarbonyl) -2-
[3- (thien-2-yl) -2-propenyl] piperazine 1,4-bis (tert-butoxycarbonyl) -2-
Formylmethylpiperazine (1.01 g) was dissolved in tetrahydrofuran (50 ml). Under ice-cooling, a solution of [(thien-2-yl) methyl] phosphonium bromide (1.62 g) in chloroform (100 ml) was added to the reaction solution, and 1,8-diazabicyclo [5.4.0] -7 was further added.
-Undecene (620 µl) was added dropwise, and the mixture was stirred at room temperature for 15 hours. The reaction solution was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 2: 1) to give the title compound (1.13).
g) was obtained as a pale yellow oil. ¹ H NMR (CDCl ₃ ) δ 1.30-1.50 (18
H, m), 2.30-2.50 (1H, m), 2.50
-3.10 (4H, m), 3.40-4.60 (4H,
m), 5.45-6.05 (1H, m), 6.50-
6.65 (1H, m), 6.85-7.30 (3H,
m). MS (FAB) m / z 409 (M + H) ^<+> .

Reference Example 224 1,4-bis (tert-butoxycarbonyl) -2-
[3- (Thien-2-yl) propyl] piperazine 1,4-bis (tert-butoxycarbonyl) -2-
[3- (Thien-2-yl) -2-propenyl] piperazine (1.01 g) was dissolved in methanol (70 ml), and 10% palladium on carbon (50% wee) was added to the reaction mixture.
t, 431 mg) were suspended. This suspension is then
The mixture was vigorously shaken at room temperature under a hydrogen atmosphere at 1 atm for 6 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane:
Ethyl acetate = 9: 1 to 2: 1) to give the title compound (9
75 mg) as a colorless powder. ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
1.46 (9H, s), 1.50-1.80 (4H,
m), 2.70-3.00 (5H, m), 3.80-
4.20 (4H, m), 7.75-7.80 (1H,
m), 7.85-7.95 (1H, m), 7.10 (1
H, d, J = 5.1 Hz). MS (FAB) m / z 411 (M + H) ^<+> .

Reference Example 225 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [3- (thien-2
-Yl) propyl] piperazine The title compound was synthesized in the same manner as in Reference Example 146. ¹ H NMR (CDCl ₃ ) δ1.35-1.80 (4
H, m), 2.55-2.65 (1H, m), 2.75
-3.10 (6H, m), 3.77 (2H, t, J = 1
0.9 Hz), 6.70-6.80 (1H, m), 6.
85-6.95 (1H, m), 7.05-7.15 (1
H, m), 7.35-7.0 (4H, m), 7.50-
7.60 (2H, m), 8.00-8.10 (2H,
m), 8.22 (1H, d, J = 9.3 Hz). MS (FAB) m / z 564 [(M + H) ⁺ , C
l ³⁵ ], 566 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 226 1,4-bis (tert-butoxycarbonyl) -2-
[3- (3,4-Dimethoxyphenyl) -2-propenyl] piperazine The title compound was synthesized in the same manner as in Reference Example 223. ¹ H NMR (CDCl ₃ ) δ 1.40-1.50 (18
H, m), 2.35-3.10 (5H, m), 3.75
-4.30 (10H, m), 5.50-6.05 (1
H, m), 6.30-6.50 (1H, m), 6.75
-6.90 (3H, m). MS (FAB) m / z 463 (M + H) ^<+> .

Reference Example 227 1,4-bis (tert-butoxycarbonyl) -2-
[3- (3,4-Dimethoxyphenyl) propyl] piperazine The title compound was synthesized in the same manner as in Reference Example 224. ¹ H NMR (CDCl ₃ ) δ 1.45 (18H, s),
1.20-1.70 (4H, m), 2.50-3.05
(5H, m), 3.70-4.20 (10H, m),
6.65-6.80 (3H, m). MS (FAB) m / z 465 (M + H) ^<+> .

Reference Example 228 1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [3- (3,4-dimethoxyphenyl) propyl] piperazine A method similar to that of Reference Example 146. Was used to synthesize the title compound. ¹ H NMR (CDCl ₃ ) δ 1.30-1.70 (4
H, m), 2.50-2.65 (3H, m), 2.75
-3.05 (4H, m), 3.70-3.90 (8H,
m), 6.0-6.70 (2H, m), 6.75-6.
80 (1H, m), 7.35-7.50 (4H, m),
7.50-7.60 (2H, m), 8.02 (2H,
d, J = 8.1 Hz), 8.22 (1H, d, J = 9.
0 Hz). MS (FAB) m / z 619 [(M + H) ⁺ , C
l ³⁵ ], 621 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 229 1,4-bis (tert-butoxycarbonyl) -2-
(2-bromoethyl) piperazine 1,4-bis (tert-butoxycarbonyl) -2-
(2-Hydroxyethyl) piperazine (2.01 g) and triphenylphosphine (1.98 g) were dissolved in methylene chloride (70 ml). This reaction solution was added under ice cooling.
Carbon tetrabromide (3.07 g) was added, and the mixture was stirred at room temperature for 2.5 hours. A 10% aqueous sodium thiosulfate solution was added for extraction, and the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography (hexane: ethyl acetate = 4: 1) using silica gel as a carrier to give the title compound (2.
20 g) as a colorless powder. ¹ H NMR (CDCl ₃ ) δ 1.47, 1.48 (18
H, each s), 2.00-2.20 (2H,
m), 2.70-3.00 (3H, m), 3.30-
3.45 (2H, m), 3.80-4.40 (4H,
m).

Reference Example 230 1,4-bis (tert-butoxycarbonyl) -2-
[2-[(Pyrrolidin-1-yl) sulfonyl] ethyl] piperazine Sodium sulfite (1.68 g) was dissolved in water (90 ml). Under ice-cooling, 1,4-bis (tert.
A solution of -butoxycarbonyl) -2- (2-bromoethyl) piperazine (2.20 g) in N, N-dimethylformamide (90 ml) was added, and the mixture was stirred at 50 ° C for 15 hours. The reaction solution was concentrated under reduced pressure. Ethanol was added to the obtained residue, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product (2.98 g) as a colorless paste. Next, this crude product was dissolved in N, N-dimethylformamide (10 ml) and thionyl chloride (40 ml) was added under ice-cooling.
7 μl) was added dropwise, and the mixture was stirred at 0 ° C. for 0.5 hour and at room temperature for 1 hour. The reaction solution was poured into ice water (40 ml) to remove insolubles and dried. The residue was dissolved in methylene chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale yellow oil (524.9 mg). Subsequently, this crude product was dissolved in methylene chloride (10 ml), and diisopropylethylamine (550 μl) and pyrrolidine (220 μl) were added under ice cooling.
l) was added and the mixture was stirred at room temperature for 19 hours. The reaction solution was evaporated under reduced pressure, and the residue was subjected to column chromatography (hexane: ethyl acetate = 1: 1) using silica gel as a carrier to obtain the title compound (122 mg) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) δ 1.47, 1.47 (18
H, each s), 1.85-2.20 (6H,
m), 2.70-3.10 (5H, m), 3.30-
3.40 (4H, m), 3.80-4.30 (4H,
m).

Reference Example 231 1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [2-[(pyrrolidin-1-yl) sulfonyl] ethyl] piperazine Same as Reference Example 146 The title compound was synthesized by the method described above. ¹ H NMR (CDCl ₃ ) δ 1.80-2.00 (6
H, m), 2.60-2.70 (1H, m), 2.80
-3.1 (6H, m), 3.30-3.40 (4H,
m), 3.65-3.85 (2H, m), 7.40-
7.50 (4H, m), 7.50-7.60 (2H,
m), 8.01 (2H, d, J = 7.8 Hz), 8.2
2 (2H, d, J = 8.3 Hz). MS (FAB) m / z 601 [(M + H) ⁺ , C
l ³⁵ ], 603 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 232 6-methyl-4,5,6,7-tetrahydrofuro [2,
3-c] Pyridin-2-carboxylic acid lithium salt The title compound was synthesized in the same manner as in Reference Example 105. _{^{1 H NMR (DMSO-d 6}} ) δ2.30-2.60
(4H, m), 2.35 (3H, s), 3.34 (2
H, s), 6.50 (1H, s).

Reference Example 233 1- (tert-butoxycarbonyl) -4-[(6-
Methyl-4,5,6,7-tetrahydrofuro [2,3-
c] Pyridin-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Reference Example 62. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
2.49 (3H, s), 2.55-2.65 (2H,
m), 2.65-2.75 (2H, m), 3.45-
3.55 (6H, m), 3.76 (4H, brs),
6.86 (1H, s). MS (FAB) m / z 350 (M + H) ⁺ .

Reference Example 234 (4-Chloro-2-methoxyphenyl) methanol 4-chloro-2-methoxyphenylcarboxylic acid (20.
1 g) in tetrahydrofuran (100 ml),
The atmosphere was replaced with argon. A borane-methyl sulfide complex (11.0 ml) was added dropwise to the reaction solution. After the dropwise addition, when the reflux due to the generation of the heat of reaction stopped, the mixture was stirred at room temperature for 2 hours. Under ice cooling, water was added to the reaction solution. Further, ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added for extraction, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to obtain the title compound (17.6 g) as a pale yellow powder. ¹ H NMR (CDCl ₃ ) δ 2.25 (1 H, s),
3.85 (3H, s), 4.63 (2H, s), 6.8
6 (1H, d, J = 1.8 Hz), 6.92 (1H, d
d, J = 8.2, 1.8 Hz), 7.21 (1H, d,
J = 8.2 Hz).

Reference Example 235 4-Chloro-1-formyl-2-methoxybenzene (4-chloro-2-methoxyphenyl) methanol (3.69 g) was dissolved in methylene chloride (80 ml). To the reaction mixture, add molecular sieve 4A under ice cooling.
(4.57 g), N-methylmorpholine (2.81 g)
And tetra-n-propylammonium perruthenate (420 mg) were added, and the mixture was stirred at room temperature for 2.5 hours.
The reaction solution was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 9:
1) to give the title compound (3.07 g) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) δ 3.94 (3H, s),
6.99 (1H, d, J = 2.0 Hz), 7.00-
7.05 (1H, m), 7.77 (1H, d, J = 8.
3 Hz), 10.39 (1H, s).

Reference Example 236 4-chloro-2-methoxystyrene bromide methyltriphenylphosphonium bromide (5.03 g)
Was suspended in tetrahydrofuran (50 ml) and purged with argon. Then, n-butyl lithium (1.5
A 9 molar solution, hexane) (9.80 ml) was added dropwise over 30 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, and a solution of 4-chloro-1-formyl-2-methoxybenzene (2.02 g) in tetrahydrofuran (15 ml) was added dropwise under ice-cooling again. After completion of the dropwise addition, the mixture was stirred at room temperature for 3.5 hours. After completion of the stirring, water was added under ice-cooling, ethyl acetate was added and extracted, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 9:
1) to give the title compound (1.51 g) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) δ 3.83 (3H, s),
5.26 (1H, dd, J = 11.2, 1.5 Hz),
5.70 (1H, dd, J = 17.8, 1.2 Hz),
6.80-7.00 (3H, m), 7.37 (1H,
d, J = 8.3 Hz). MS (FAB) m / z 169 [(M + H) ⁺ , C
l ³⁵ ], 171 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 237 (4-Chloro-2-methoxystyryl) sulfonyl sulfuryl chloride (1.66 ml) was added and the atmosphere was replaced with argon. Then, N, N-dimethylformamide (1.7 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 40 minutes. To this reaction solution was added 4-chloro-2-methoxystyrene (2.0
5 g) and stirred at 90 ° C. for 3 hours. Add ice,
The mixture was extracted with methylene chloride, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (hexane: ethyl acetate = 9: 1) using silica gel as a carrier to obtain the title compound (885 mg) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) δ 3.96 (3H, s),
6.98 (1H, d, J = 2.0 Hz), 7.03 (1
H, dd, J = 8.3, 2.0 Hz), 7.38 (1
H, d, J = 8.3 Hz), 7.50 (1H, d, J =
15.1 Hz), 7.78 (1H, d, J = 15.1H)
z). MS (FAB) m / z 266 [(M + H) ⁺ , Cl ³⁵
+ Cl ³⁵ ].

Reference Example 238 1- (tert-butoxycarbonyl) -4-[(E)
-4-Chloro-2-methoxystyrylsulfonyl] piperazine The title compound was synthesized in the same manner as in Reference Example 78. ¹ H NMR (CDCl ₃ ) δ 1.44 (9H, s),
3.10-3.20 (4H, m), 3.50-3.60
(4H, m), 3.91 (3H, s), 6.82 (1
H, d, J = 15.6 Hz), 6.94 (1H, d, J)
= 2.0 Hz), 6.97 (1H, dd, J = 8.3,
2.0Hz), 7.33 (1H, d, J = 8.3H)
z), 7.56 (1H, d, J = 15.6 Hz). MS (FAB) m / z 416 [(M + H) ⁺ , C
l ³⁵ ], 418 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 239 1- (tert-butoxycarbonyl) -2- [2-
(Tert-butyldiphenylsilyloxy) ethyl]
-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine 1-tert-butoxycarbonyl-4-[(6-chloronaphthalen-2-yl) sulfonyl] -2- (2-hydroxyethyl) piperazine ( 739 mg) and imidazole (226 mg) were dissolved in N, N-dimethylformamide (15 ml), tert-butylchlorodiphenylsilane (0.70 ml) was added under ice cooling, and the mixture was stirred at room temperature for 23 hours. The reaction solution was distilled off under reduced pressure. The resulting residue was extracted by adding methylene chloride and a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was washed with dilute hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Column chromatography of the residue using silica gel as a carrier (hexane: ethyl acetate = 2: 1 to: 2)
To give the title compound (804 mg) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) δ 1.06 (9H, s),
1.31 (9H, s), 1.90-2.00 (2H,
m), 2.20-2.30 (1H, m), 2.30-
2.40 (1H, m), 2.95-3.05 (1H,
m), 3.60-3.80 (4H, m), 3.85-
4.00 (1H, m), 4.35-4.45 (1H,
m), 7.35-7.45 (6H, m), 7.55-
7.60 (1H, m), 7.65-7.75 (5H,
m), 7.85-7.95 (3H, m), 8.26 (1
H, s). MS (FAB) m / z 693 [(M + H) ⁺ , C
l ³⁵ ], 695 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 240 3- [2- (tert-butyldiphenylsilyloxy) ethyl] -1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine 1- (tert-butoxycarbonyl) -2- [ 2-
(Tert-butyldiphenylsilyloxy) ethyl]
4- (6-Chloronaphthalen-2-yl) piperazine (91.2 mg) was dissolved in nitrobenzene (5.0 ml) and stirred at 170-185 * C for 10.5 hours. Silica gel column chromatography (methylene chloride-5
% Methanol-methylene chloride) to give the title compound (4
3 mg) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) δ 1.04 (9H, s),
1.50-1.65 (2H, m), 2.05-2.15
(1H, m), 2.35-2.45 (1H, m), 2.
85-3.00 (3H, m), 3.65-3.75 (4
H, m), 7.35-7.45 (6H, m), 7.55
−7.60 (1H, m), 7.60−7.65 (4H,
m), 7.70-7.80 (1H, m), 7.85-
7.95 (3H, m), 8.28 (1H, s). MS (FAB) m / z 593 [(M + H) ⁺ , C
l ³⁵ ], 595 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 241 2, cis-6-bis (methoxycarbonylmethyl) -4
-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazine and 2, trans-6-bis (methoxycarbonylmethyl) -4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] Piperazine The title compound was synthesized in the same manner as in Reference Example 63. 2, cis-6-bis (methoxycarbonylmethyl) -4
Instrumental data for-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazine ¹ H NMR (CDCl ₃ ) δ 2.15-2.45 (6
H, m), 2.90 (1H, br), 3.25-3.3.
5 (2H, m), 3.65-3.75 (2H, m),
3.70 (6H, s), 7.43 (1H, dd, J =
8.5, 1.7 Hz), 7.75 (1H, s), 7.8
2 (1H, d, J = 8.8 Hz), 7.85-7.90
(1H, m). MS (FAB) m / z 461 [(M + H) ⁺ , C
l ³⁵ ], 463 [(M + H) ⁺ , Cl ³⁷ ].

Instrumental data for 2, trans-6-bis (methoxycarbonylmethyl) -4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazine ¹ H NMR (CDCl ₃ ) δ 2.50-2 .65 (6
H, m), 2.85-2.95 (2H, m), 3.20
-3.25 (2H, m), 3.50-3.55 (2H,
m), 3.70 (6H, s), 7.43 (1H, dd,
J = 8.6, 1.7 Hz), 7.74 (1H, s),
7.82 (1H, d, J = 8.8 Hz), 7.86 (1
H, brs). MS (FAB) m / z 461 [(M + H) ⁺ , C
l ³⁵ ], 463 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 242 1,4-Dibenzyl-2-hydroxymethylpiperazine Lithium aluminum hydride (1.04 g) was suspended in tetrahydrofuran (42 ml). 1
After a suspension of 4-dibenzyl-2-ethoxycarbonylpiperazine (12.5 g) in tetrahydrofuran (300 ml) was added dropwise, the mixture was stirred at room temperature for 89.5 hours. The reaction solution was ice-cooled, and a saturated aqueous sodium sulfate solution and a 3N aqueous sodium hydroxide solution were added. Then, the insoluble matter is removed by filtration,
The solvent was distilled off under reduced pressure. After the residue was dissolved in tetrahydrofuran and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Lithium aluminum hydride (1.5 g) was suspended in tetrahydrofuran (50 ml), and after replacing with argon, the reaction solution was heated to 50 ° C. A solution obtained by dissolving the residue obtained above in tetrahydrofuran (50 ml) was added dropwise to the reaction solution, and the mixture was heated under reflux for 4.5 hours. Lithium aluminum hydride (0.87 g) was added for 4.5 hours,
Further, lithium aluminum hydride (0.87 g) was added, and the mixture was heated under reflux for 4.5 hours. After cooling the reaction solution on ice, a saturated aqueous solution of sodium sulfate and a 3N aqueous solution of sodium hydroxide were added, insolubles were removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (methylene chloride to 5% methanol-methylene chloride) to give the title compound (8.42 g) as a pale red oil. ¹ H NMR (CDCl ₃ ) δ 2.30-2.70 (5
H, m), 2.90-3.00 (1H, m), 3.40
-3.50 (4H, m), 3.58 (1H, d, J = 1)
3.2Hz), 3.90-4.10 (2H, m), 7.
20-7.35 (10H, m). MS (FAB) m / z 297 (M + H) ^<+> .

Reference Example 243 2- (tert-butyldiphenylsilyloxy) methyl-1,4-dibenzylpiperazine 1,4-dibenzyl-2-hydroxymethylpiperazine (1.11 g) and imidazole (347 mg) were added to N, N -Dissolved in dimethylformamide (20 ml). To this reaction solution, tert-butylchlorodiphenylsilane (1.17 ml, 1.24 g) was added under ice cooling.
Stirred at room temperature for 14.5 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. Then the organic layer was washed with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The residue was subjected to column chromatography (hexane: ethyl acetate = 9: 1 → 8: 2) using silica gel as a carrier to obtain the title compound (1.42 g). ¹ H NMR (CDCl ₃ ) δ 0.98 (9 H, s),
2.15-2.30 (3H, m), 2.50-2.55
(1H, m), 2.60-2.70 (2H, m), 2.
80-2.90 (1H, m), 3.24 (1H, d, J
= 13.7 Hz), 3.40-3.50 (2H, m),
3.60-3.70 (1H, m), 3.90-4.00
(2H, m), 7.15-7.45 (16H, m),
7.55-7.65 (4H, m). MS (FAB) m / z 535 (M + H) ^<+> .

Reference Example 244 3- (tert-butyldiphenylsilyloxy) methyl-1- (6-chlorobenzo [b] thien-2-yl)
Piperazine It was synthesized in the same manner as in Reference Example 145. ¹ H NMR (CDCl ₃ ) δ 1.02 (9H, s),
2.30-2.40 (1H, m), 2.45-2.65
(1H, m), 2.90-3.15 (3H, m), 3.
50-3.70 (4H, m), 7.35-7.45 (7
H, m), 7.55-7.65 (4H, m), 7.71.
(1H, s), 7.75-7.85 (2H, m). MS (FAB) m / z 585 [(M + H) ⁺ , C
l ³⁵ ], 587 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 245 1,4-Dibenzyl-2- (2-hydroxyethyl) piperazine The title compound was synthesized in the same manner as in Reference Example 242. ¹ H NMR (CDCl ₃ ) δ 1.80-1.90 (1
H, m), 2.00-2.10 (1H, m), 2.25
-2.35 (2H, m), 2.35-2.45 (1H,
m), 2.45-2.55 (1H, m), 2.60-
2.70 (1H, m), 2.75-2.85 (1H,
m), 2.85-2.95 (1H, m), 3.39 (1
H, d, J = 12.7 Hz), 3.49 (1H, d, J)
= 1.5 Hz), 3.70-3.80 (1H, m),
3.80-3.90 (1H, m), 4.16 (1H,
d, J = 12.7 Hz), 7.20-7.40 (10
H, m).

Reference Example 246 2- [2- (tert-butyldiphenylsilyloxy) ethyl] -1,4-dibenzylpiperazine The title compound was synthesized in the same manner as in Reference Example 243. ¹ H NMR (CDCl ₃ ) δ 0.99 (9H, s),
1.75-1.95 (2H, m), 2.10-2.20
(3H, m), 2.40-2.50 (1H, m), 2.
50-2.65 (3H, m), 3.10-3.20 (1
H, m), 3.30-3.50 (2H, m), 3.60
-3.75 (2H, m), 3.83 (1H, d, J = 1
3.2Hz), 7.15-7.25 (10H, m),
7.25-7.40 (6H, m), 7.55-7.65
(4H, m). MS (FAB) m / z 549 (M + H) ^<+> .

Reference Example 247 3- [2- (tert-butyldiphenylsilyloxy) ethyl] -1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazine The title was obtained in the same manner as in Reference Example 244. Compounds were synthesized. ¹ H NMR (CDCl ₃ ) δ 1.04 (9H, s),
1.50-2.00 (3H, m), 2.20-2.30
(1H, m), 2.50-2.60 (1H, m), 2.
85-3.05 (3H, m), 3.65-3.80 (4
H, m), 7.35-7.45 (7H, m), 7.60.
-7.65 (4H, m), 7.72 (1H, s), 7.
75-7.85 (2H, m). MS (FAB) m / z 599 [(M + H) ⁺ , C
l ³⁵ ], 601 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 248 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -3- (methoxycarbonylmethyl) piperazine The title compound was synthesized in the same manner as in Reference Example 63. ¹ H NMR (CDCl ₃ ) δ 2.30-2.50 (3
H, m), 2.63 (1H, dt, J = 3.4, 11.
0 Hz), 2.90-3.10 (2H, m), 3.20
-3.30 (1H, m), 3.60-3.70 (2H,
m), 3.69 (3H, s), 7.44 (1H, dd,
J = 8.8, 2.0 Hz), 7.75 (1H, s),
7.82 (1H, d, J = 8.3 Hz), 7.85 −
7.90 (1H, m). MS (FAB) m / z 389 [(M + H) ⁺ , C
l ³⁵ ], 391 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 249 2-tert-butoxycarbonylisoindoline-5
Carboxylic acid methyl ester The title compound was synthesized in the same manner as in Reference Example 56. ¹ H NMR (CDCl ₃ ) δ 1.52 (9H, s),
3.92 (3H, s), 4.65-4.72 (2H,
m), 4.73 (2H, s), 7.29 (0.5H,
d, J = 7.8 Hz), 7.34 (0.5 H, d, J =
7.8 Hz), 7.91 (0.5 H, s), 7.96
(1H, s), 7.98 (0.5H, s). MS (FAB) m / z 278 (M + H) ^<+> . Elemental analysis: as C ₁₅ H ₁₉ NO ₄ Calculated: C, 64.97; H, 6.91; N, 5.0
5. Analytical values: C, 64.94; H, 7.13; N, 4.9.
6.

Reference Example 250 2-tert-butoxycarbonylisoindoline-5
Carboxylic acid The title compound was synthesized in the same manner as in Reference Example 102. ¹ H NMR (CDCl ₃ ) δ 1.53 (9H, s),
4.70-4.72 (2H, m), 4.75 (2H,
s), 7.32 (0.5 H, d, J = 7.3 Hz),
7.38 (0.5 H, d, J = 7.3 Hz), 7.97
(0.5H, s), 8.02 (1H, s), 8.04
(0.5H, s). MS (FAB) m / z 264 (M + H) ⁺ . Elemental analysis: as C ₁₄ H ₁₇ NO ₄ Calculated: C, 63.87; H, 6.51; N, 5.3
2. Analytical values: C, 63.79; H, 6.65; N, 5.1.
2.

Reference Example 251 4-tert-butoxycarbonyl-3-carboxymethyl-1-[(5-chloroindol-2-yl) sulfonyl] piperazine 4-tert-butoxycarbonyl-1-[(5-chloro-1 -Phenylsulfonylindol-2-yl) sulfonyl] -3-methoxycarbonylmethylpiperazine (612.1 mg, 1.00 mmol) in tetrahydrofuran (10 ml) was treated with 1N NaOH (6.0 m).
l) and stirred for 6 hours, then dioxane (5.0 m
l) was added and the mixture was stirred at 80 ° C for 5 hours. After returning to room temperature, the reaction solution was neutralized with a saturated ammonium chloride solution and extracted with methylene chloride. The organic phase was washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated to give the title compound (535.2 mg, 98%) as a pale yellow amorphous. IR (KBr) cm ^-1 3700-3200, 2975,
2917, 2857, 1697, 1569, 1506
1445, 1415, 1365, 1162, 1120. ¹ H NMR (DMSO-d ₆ ) δ 1.33 (9H,
s), 2.12-2.25 (1H, m), 2.30-
2.42 (2H, m), 2.35-3.57 (1H,
m), 2.60-2.71 (1H, m), 2.90-
3.02 (1H, m), 3.54-3.65 (1H,
m,), 3.72-3.86 (2H, m), 4.43.
(1H, brs), 6.99 (1H, s), 7.30
(1H, dd, J = 8.8, 1.8 Hz), 7.48
(1H, d, J = 8.8 Hz), 7.75 (1H, d,
J = 1.8 Hz). MS (FAB) m / z 480 (M + Na) ⁺

Reference Example 252 4-tert-butoxycarbonyl-1-[(5-chloroindol-2-yl) sulfonyl] -3- [N-
(2-Hydroxyethyl) carbamoylmethyl-piperazine Ethanolamine (45.8 mg) in methylene chloride (1
0 ml) solution at room temperature with 1-hydroxybenzotriazole (67.6 mg), 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (124.
6 mg), 4-tert-butoxycarbonyl-3-carboxymethyl-1-[(5-chloroindole-2-
Yl) sulfonyl] piperazine (273.0 mg) and N-methylmorpholine (0.083 ml) were added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was treated with methylene chloride (50 m
1), washed with distilled water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1) to give the title compound (248.9 mg) as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 1.40 (9H, s),
2.30-2.90 (3H, m), 3.03-4.15
(7H, m), 4.62-4.71 (1H, m), 6.
56 (1H, brs), 6.95 (1H, s), 7.
28 (1H, dd, J = 8.8, 1.7 Hz), 7.3
7 (1H, d, J = 8.8 Hz), 7.64 (1H,
d, J = 1.7 Hz), 10.10-10.70 (1
H, br m). FAB-MS m / z 502 [(M
+ H) ⁺ , Cl ³⁵ ], 504 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 253 4-[(5-Chloro-1-phenylsulfonyl-indol-2-yl) sulfonyl] -1- (tert-butoxycarbonyl) -2- (2-hydroxyethyl) piperazine 4- (tert) -Butoxycarbonyl) -1-[(5-
Chloro-1-phenylsulfonylindol-2-yl) sulfonyl 1] -3-[(methoxycarbonyl) methyl] piperazine (2.5 g) was added to tetrahydrofuran-
It was dissolved in methanol (10/155 ml), lithium borohydride (135 mg) was added, and the mixture was stirred for 48 hours.
After evaporating the solvent under reduced pressure, water and chloroform were added and partitioned. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 2: 3) to give the title compound (1.84 g) as a colorless oil. ) Got. ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s),
1.60 (2H, m), 2.98-4.42 (9H,
m), 7.42-7.59 (6H, m), 8.01 (1
H, d, J = 1.2 Hz), 8.03 (1H, d, J =
1.2Hz), 8.21 (1H, d, J = 9.3H)
z). MS (FAB) m / z 584 [(M + H) ^<+ >].

Reference Example 254 4-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -1- (tert-butoxycarbonyl) -2- (formylmethyl) piperazine To 100 ml of Nascol, [(5-chloro-1-
Phenylsulfonyl-indol-2-yl) sulfonyl] -1- (tert-butoxycarbonyl) -2-
(2-Hydroxyethyl) piperazine (830 mg) was added and dissolved in methylene chloride (20 ml). Under ice cooling, 4
-Methylmorpholine N-oxide (200 mg), tetrapropyl ammonium perruthenate (100 m
g) was added, and after 20 minutes, the temperature was returned to room temperature and stirred. After 24 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (380 mg) as a colorless oil. Was. ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
2.64 (1H, dd, J = 5.4, 17.4 Hz),
2.95-3.15 (5H, m), 3.72 (1H,
d, J = 13.2 Hz), 3.94 (1H, m), 4,
73 (1H, m), 7.40-7.58 (6H, m),
8.00 (1H, d, J = 1.2 Hz), 8.02 (1
H, d, J = 1.2 Hz), 8.20 (1H, d, J =
9.0 Hz), 9.62 (1H, s).

Reference Example 255 4-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -1- (tert-butoxycarbonyl) -2- [2- (1,4-dioxa-8-
Azaspiro [4,5] decane-8-yl) ethyl] piperazine 4-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -1- (tert-butoxycarbonyl) -2- (formylmethyl) ) Piperazine (440 mg) and 1,4-dioxa-8-azaspiro [4,5] decane (162 mg) were added, and methanol (1 mg) was added.
0 ml). After stirring for 30 minutes, the solvent was concentrated under reduced pressure, dissolved again in methanol (10 ml), and NaBH ₄
(58 mg) was added and stirred. After 14 hours, the reaction was stopped, and the solvent was distilled off under reduced pressure.
And washed with NaHCO _3. After the organic layer was dried over anhydrous MgSO ₄ , the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (AcOEt: hexane =
4: 1) to give the title compound (410 mg) as a colorless amorphous. ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
1.68 (4H, t, J = 6.4 Hz), 1.83-
3.20 (12H, m), 3.61 (1H, m), 3.
94 (4H, s), 4.0-4.25 (2H, m),
7.39-7.58 (6H, m), 8.01 (1H,
d, J = 1.5 Hz), 8.04 (1H, d, J = 1.
0 Hz), 8.22 (1H, d, J = 9.3 Hz). MS (FAB) m / z 709 [(M + H) ^<+ >].

Reference Example 256 4-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -1- (tert-butoxycarbonyl) -2-[(1,3-dioxolan-2-
Yl) methyl] piperazine 4-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -1- (tert-butoxycarbonyl) -2- (formylmethyl) piperazine (440 mg) and ethylene glycol ( 71 mg) in toluene (10 ml), and p-TsOH.H ₂ O
(15 mg) was added and the mixture was heated to 60 ° C. and stirred for 16 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried over anhydrous MgSO ₄ and the solvent was distilled off under reduced pressure to obtain the title compound (460 mg) as a colorless amorphous. ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
1.63 (2H, m), 1.98 (2H, m), 2.4
9-3.95 (3H, m), 3.66-4.13 (8
H, m), 4.78 (1H, t, J = 4.9 Hz),
7.17 (1H, m), 7.42-7.58 (5H,
m), 8.02 (1H, d, J = 1.5 Hz), 8.0
4 (1H, d, J = 1.0 Hz), 8.23 (1H,
d, J = 9.3 Hz). MS (FAB) m / z 626 [(M + H) ^<+ >].

Reference Example 257 1,4-dibenzyl-2-[(1,3-dioxoisoindol-2-yl) methyl] piperazine 1,4-dibenzyl-2- (hydroxymethyl) piperazine (1.51 g) , Phthalimide (0.790 g),
To a solution of triphenylphosphine (1.40 g) in tetrahydrofuran (20 ml) was added a solution of diethyl azodicarboxylate, 40% toluene (2.34 ml) under ice-cooling.
Stirred at room temperature for 6 hours. Further, 1,4-dibenzyl-2- (hydroxymethyl) piperazine (0.87
g), phthalimide (0.486 g), triphenylphosphine (0.81 g), tetrahydrofuran (5 m
l) was added, and a 40% toluene solution of diethyl azodicarboxylate (1.34 ml) was added, followed by stirring at room temperature for 18 hours and a half. Further, phthalimide (0.405 g), diethyl azodicarboxylate, 40% toluene solution (1.1%) were added under ice cooling.
0 ml) and stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography twice using silica gel as a carrier (first time: 3% methanol-methylene chloride, second time: ethyl acetate / hexane = 1/3)
To give a crude product. The crude product was crystallized from hexane-methylene chloride, collected by filtration, and the filtered product was washed with hexane to give the title compound (0.243 g) as a colorless powder. ¹ H NMR (CDCl ₃ ) δ 2.30-2.40 (4
H, m), 2.50-2.60 (1H, m), 2.95
-3.10 (2H, m), 3.40-3.55 (2H,
m), 3.60-3.65 (1H, m), 3.75-
3.80 (1H, m), 3.95-4.05 (1H,
m), 4.15-4.25 (1H, m), 7.10-
7.35 (10H, m), 7.70-7.75 (2H,
m), 7.80-7.85 (2H, m). MS (FAB) m / z 426 (M + H) ⁺ .

Reference Example 258 1-[(5-Chloro-1-phenylsulfonyl) piperazin-2-yl] -3-[(1,4-dioxoisoindol-2-yl) methyl] piperazine 1,4- Concentrated hydrochloric acid (0.25 m) was added to a suspension of dibenzyl-2-[(2-phthalimido) methyl] piperazine (0.529 g, 1.24 mmol) in methanol (30 ml).
l), palladium hydroxide (87 mg, 0.62 mmol)
l) was added, and the mixture was stirred under a hydrogen atmosphere for 2.5 hours. The palladium hydroxide was removed by filtration, washed with methanol and a small amount of triethylamine, and the mother liquor was concentrated under reduced pressure. The obtained 2-[(2
-Phthalimido) methyl] piperazine in methylene chloride (25 ml) was cooled to 0-C and triethylamine (0.5 ml), 1-benzenesulfonyl-5-chloro-2-chlorosulfonylindole (0.437 g,
1.12 mmol), and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 2.5 days. The reaction solution was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash column chromatography (ethyl acetate / n-hexane = 1 / 4-1 / 0) using silica gel as a carrier gave 0.350 g (47%) of the title compound as a colorless amorphous solid. IR (KBr) cm ^-1 2923, 2846, 1772,
1710, 1517, 1467, 1448, 1432,
1388, 1353, 1334, 1295, 1243,
1222, 1186, 1157, 1137, 1112
1089, 1074, 997, 977, 898, 83
5,727,713. ¹ H NMR (CDCl ₃ ) δ 2.77-2.88 (2
H, m), 2.98-3.09 (2H, m), 3.16.
-3.18 (1H, m), 3.69-3.72 (3H,
m), 3.81 (1H, broad d, J = 12.6).
Hz), 7.36 (1H, s), 7.40-7.46
(3H, m), 7.52-7.56 (2H, m), 7.
71-7.74 (2H, m), 7.83-7.86 (2
H, m), 7.99 (2H, dd, J = 1.1, 7.4)
Hz), 8.22 (1H, d, J = 9.2 Hz). MS (FAB) m / z 599 [(M + H) ⁺ , C
l ³⁵ ], 601 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 27 H 23 N 4 O} 6 ClS 2 Calculated: C, 54.13; H, 3.87 ; N, 9.3
5; Cl, 5.92; S, 10.70. Analytical values: C, 53.88; H, 4.09; N, 8.8.
3; Cl, 5.67; S, 10.33.

Reference Example 259 1,4-di (tert-butoxycarbonyl) -2-
[2- (2-Naphthoxy) ethyl] piperazine 1,4-di (tert-butoxycarbonyl) -2-
(2-hydroxyethyl) piperazine (0.330
g, 1 mmol) and b-naphthol (0.144 g, 1
mmol), triphenylphosphine (0.288 g,
1.1 mmol) in tetrahydrofuran (10 ml) was dissolved in diethyl azodicarboxylate (0.175 ml, 1.
1 mmol) and stirred at room temperature for 3 hours. Furthermore, diethyl azodicarboxylate, 40% toluene solution (0.4%)
40 ml, 1.1 mmol) and stirred at room temperature for 2 hours. Flash column chromatography using silica gel as carrier (ethyl acetate / n-hexane = 1 /
By performing purification according to 9-1 / 4), 0.300 g (65%) of the title compound was obtained as a yellow syrup. ¹ H NMR (CDCl ₃ ) δ 1.38 (9H, s),
1.47 (9H, s), 1.99-2.04 (1H,
m), 2.16 (1H, m), 2.82-3.02 (2
H, broad), 4.00-4.12 (6H, broad)
ad m), 4.46 (1H, broad), 7.09
−7.12 (2H, m), 7.29−7.33 (1H,
m), 7.39-7.43 (1H, m), 7.67-
7.75 (3H, m). MS (FAB) m / z 457 (M + H) ^<+> .

Reference Example 260 1-[(5-Chloro-1-phenylsulfonylindole-2-i) sulfonyl] -3- [2- (2-naphthoxy) ethyl] piperazine 1,4-di (tert-butoxycarbonyl) ) -2-
[2- (2-Naphthoxy) ethyl] piperazine (0.2
85 g, 0.624 mmol) of methylene chloride (10 m
l) Trifluoroacetic acid (2 ml) was added to the solution, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure, and
2- [2] by azeotropic distillation three times with methylene chloride
-(2-Naphthoxy) ethyl] piperazine was obtained as a pale yellow powder. The obtained suspension of 2- [2- (2-naphthoxy) ethyl] piperazine in methylene chloride (20 ml) was cooled to 0 ° C, and triethylamine (0.260 ml,
1.86 mmol), 1-benzenesulfonyl-5-chloro-2-chlorosulfonylindole (0.231
g, 0.592 mmol) and stirred at 0 ° C. for 2 hours and at room temperature for 20 室温 hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash column chromatography using silica gel as a carrier (ethyl acetate / n-hexane = 1 / 2-1-1 / 1/0) gave 0.249 g (65%) of the title compound as a colorless amorphous solid. Was. ¹ H NMR (CDCl ₃ ) δ 1.89-1.95 (2
H, m), 2.73-2.79 (1H, m), 2.92
-3.09 (4H, m), 3.79 (1H, broad)
d, J = 10.9 Hz), 3.87 (1H, broa)
dd, J = 12.2 Hz), 4.18 (2H, t, J)
= 6.0 Hz), 7.06-7.10 (2H, m),
7.31-7.35 (1H, m), 7.36 (1H,
s), 7.39-7.48 (5H, m), 7.52-
7.56 (1H, m), 7.69-7.72 (2H,
m), 7.76 (1H, d, J = 8.3 Hz), 8.0
0 (2H, d, J = 7.8 Hz), 8.22 (1H,
d, J = 9.2 Hz). MS (FAB) m / z 610 [(M + H) ⁺ , C
l ³⁵ ], 612 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 261 1,4-di (tert-butoxycarbonyl) -2-
(2-phenoxyethyl) piperazine 1,4-di (tert-butoxycarbonyl) -2-
(2-hydroxyethyl) piperazine (0.660
g, 2 mmol), triphenylphosphine (0.57
7 g, 2.2 mmol) in tetrahydrofuran (10 m
l) A solution of phenol (0.188 g, 2 mmol) in tetrahydrofuran (5 ml) and diethyl azodicarboxylate (0.35 ml, 2.2 mmol) were added to the solution, and the mixture was stirred at room temperature for 4 hours. Flash column chromatography using silica gel as carrier (ethyl acetate / n-
Purification with hexane = 1/4) gave 0.611 g (75%) of the title compound as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 1.38 (9H, s),
1.46 (9H, s), 1.91-1.96 (1H,
m), 2.06-1.12 (1H, m), 2.81-
3.00 (2H, broad), 3.94-3.98
(6H, m), 4.40 (1H, broad), 6.8
6 (2H, d, J = 7.8 Hz), 6.92 (1H, d
d, J = 7.2, 7.2 Hz), 7.23-7.27
(2H, m). MS (FAB) m / z 407 (M + H) ^<+> .

Reference Example 262 1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- (2-phenoxyethyl) piperazine 1,4-di (tert-butoxycarbonyl) -2-
(2-phenoxyethyl) piperazine (0.611 g,
To a solution of 1.50 mmol) in methylene chloride (10 ml) was added trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and azeotroped three times with toluene and three times with methylene chloride to obtain 2- (2-phenoxyethyl) piperazine as a colorless powder. 2 obtained
A suspension of-(2-phenoxyethyl) piperazine in methylene chloride (25 ml) was cooled to 0 ° C, and triethylamine (0.630 ml, 4.5 mmol), 1-benzenesulfonyl-5-chloro-2-chlorosulfonylindole ( (0.556 g, 1.42 mmol) and the mixture was stirred at 0 ° C. for 1.5 hours and at room temperature for 23 hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash column chromatography using silica gel as a carrier (ethyl acetate / n-hexane = 1 / 2-1-1 / 1/0) yielded 0.600 g (71%) of the title compound.
Was obtained as a colorless powder. IR (KBr) cm ^-1 3320, 3016, 2944,
2881, 1594, 1496, 1467, 1444,
1382, 1328, 1240, 1228, 1178,
1160, 1141, 1118, 1087, 1078,
1045, 1031, 960, 835, 813, 74
8,736,725,711. ¹ H NMR (CDCl ₃ ) δ 1.81-1.86 (2
H, m), 2.70-2.76 (1H, m), 2.93
-3.07 (4H, m), 3.76-3.85 (2H,
m), 4.05 (2H, t, J = 5.8 Hz), 6.8
4 (2H, d, J = 7.8 Hz), 6.92-6.96
(1H, m), 7.36 (1H, s), 7.40-7.
45 (4H, m), 7.50-7.56 (3H, m),
8.00 (2H, d, J = 7.5 Hz), 8.22 (1
H, d, J = 9.2 Hz). MS (FAB) m / z 560 [(M + H) ⁺ , C
l ³⁵ ], 562 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 26 H 26 N 3 O} 5 ClS 2 Calculated: C, 55.76; H, 4.68 ; N, 7.5
0; Cl, 6.33; S, 11.45. Analytical values: C, 55.63; H, 4.66; N, 7.4.
3; Cl, 6.42; S, 11.47.

Reference Example 263 1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [2-[(tert
-Butyldiphenylsilyloxy) ethyl] piperazine Concentrated hydrochloric acid in a solution of 2- [2-[[tert-butyl (diphenyl) silyl] oxy] ethyl] -1,4-dibenzylpiperazine (9.95 mmol) in methanol (200 ml). (1.8 ml, 22 mmol) and palladium hydroxide (0.698 g, 5 mmol) were added, and the mixture was stirred under a hydrogen atmosphere for 3.5 hours. The palladium hydroxide was removed by filtration, washed with methanol and a small amount of triethylamine, and the mother liquor was concentrated under reduced pressure. The obtained solution of 2- [2-[[tert-butyl (diphenyl) silyl] oxy] ethyl] piperazine in methylene chloride (200 ml) was cooled to 0 ° C., triethylamine (3.5 ml), 1-benzenesulfonyl-5. -Chloro-2-chlorosulfonylindole (3.
51 g, 9 mmol) and stirred at 0 ° C. for 2.5 hours and at room temperature for 13 hours. The reaction solution was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The aqueous layer was made alkaline with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate.
After drying over sodium sulfate, the mixture was concentrated under reduced pressure. In addition, flash column chromatography using silica gel as a carrier (ethyl acetate / n-hexane = 1 / 2-1 /
Purification according to 1) gives 4.78 g of the title compound.
(66%) as a colorless amorphous solid. ¹ H NMR (CDCl ₃ ) δ 1.01 (9H, s),
1.55-1.61 (2H, m), 2.63-2.68
(1H, m), 2.88-3.01 (4H, m), 3.
73-3.80 (4H, m), 7.33-7.45 (1
0H, m), 7.49-7.56 (2H, m), 7.6
1-7.64 (4H, m), 8.01 (2H, dd, J
= 1.1, 8.4 Hz), 8.22 (1H, d, J =
9.3 Hz). MS (FAB) m / z 722 (M + H) ^<+> .

Reference Example 264 1- (tert-butoxycarbonyl) -2- [2-
(Tert-butyldiphenylsilyloxy) ethyl]
-4-[(1-Phenylsulfonyl-5-chloroindol-2-yl) sulfonyl] piperazine 1-[(1-benzenesulfonyl-5-chloroindol-2-yl) sulfonyl] -3- [2-[( tert
A solution of -butyldiphenylsilyl) oxy] ethyl] piperazine (4.78 g) in methylene chloride (200 ml) was cooled to 0 ° C, triethylamine (0.933 ml) was added, and then ditert-butyl dicarbonate (1.
A solution of 46 g) in methylene chloride (50 ml) was added dropwise over 40 minutes. The mixture was stirred at 0 ° C. for 15 minutes and at room temperature for 15 hours. It was cooled again to 0 ° C and triethylamine (0.9
33 ml, 6.7 mmol) and ditert-butyl dicarbonate (1.46 g, 6.7 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. Further, 4-dimethylaminopyridine (0.108 g, 0.88 mmol) was added, and the mixture was added at room temperature for 3 hours.
Stirred for half an hour. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by flash column chromatography using silica gel as a carrier (ethyl acetate / n-hexane = 1/4) to give the title compound 4.
48 g (82%) were obtained as a colorless amorphous solid. ¹ H NMR (CDCl ₃ ) δ 1.00 (9H, s),
1.38 (9H, s), 1.84-1.92 (2H,
m), 2.86-2.93 (1H, m), 3.02-
3.14 (2H, m), 3.32 (1H, broa
d), 3.58-3.62 (2H, m), 3.92 (2
H, broad d, J = 12.4 Hz), 4.42
(1H, broad), 7.29 (1H, s), 7.3
2-7.43 (10H, m), 7.51-7.58 (5
H, m), 7.99-8.01 (2H, m), 8.17
(1H, d, J = 9.0 Hz). MS (FAB) m / z 822 (M + H) ^<+> .

Reference Example 265 1- (tert-butoxycarbonyl) -4-[(5-
Chloroindol-2-yl) sulfonyl] -2- (2
-Hydroxyethyl) piperazine 4-[(1-benzenesulfonyl-5-chloroindol-2-yl) sulfonyl] -1- (tert-butoxycarbonyl) -2- [2-[(tert-butyldiphenylsilyloxy) ethyl ] Piperazine (4.48
To a solution of g) in tetrahydrofuran (20 ml) was added a solution of tetrabutylammonium fluoride, 1.0 M in tetrahydrofuran (5.5 ml), and the mixture was stirred at room temperature for 3.5 hours.
The reaction solution was concentrated under reduced pressure, and purified by flash column chromatography using silica gel as a carrier (ethyl acetate: hexane = 1 /: 9-1: 0) to give the title compound (0.75 g) as a colorless solid. . ¹ H NMR (DMSO-d ₆ ) δ 1.33 (9H,
s), 1.74-1.77 (2H, m), 2.24-
2.40 (2H, m), 3.04 (1H, m), 3.3
5-3.46 (2H, m), 3.56-3.63 (2
H, m), 3.85-3.88 (1H, broad)
d, J = 13.2 Hz), 4.25 (1H, broa)
d), 4.43 (1H, broad), 6.98 (1
H, d, J = 0.7 Hz), 7.29 (1H, dd, J)
= 1.9, 8.8 Hz), 7.46-7.48 (1H,
m), 7.74 (1H, m). MS (FAB) m / z 444 (M + H) ^<+> .

Reference Example 266 1,4-bis (tert-butoxycarbonyl) -2-
(2-tosyloxyethyl) piperazine 1,4-di (tert-butoxycarbonyl) -2-
(2-hydroxyethyl) piperazine (5.05 g,
15.2 mmol), p-toluenesulfonyl chloride (4.34 g, 22.7 mmol) in methylene chloride (2
00 ml) solution was cooled to 0 ° C and triethylamine (1
(1 ml, 78.9 mmol) was added dropwise. The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1 day. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with 1 N hydrochloric acid, water, and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. Flash column chromatography using silica gel as carrier (ethyl acetate / n-hexane = 1 / 4-1 / 1)
And purified to give 4.82 g of the title compound (6
5%) as a colorless solid. IR (KBr) cm ^-1 2981, 2863, 168
1,1596,1479,1421,1392,136
9,1355,1336,1297,1278,124
5,1232,1187,1174,1135,111
0,1097,1004,970,933,890,8
58,821,765. ¹ H NMR (CDCl ₃ ) δ 1.44 (18H, s),
1.78-1.84 (1H, m), 1.94 (1H, b
load), 2.44 (3H, s), 2.86 (3H,
broad), 3.85 (2H, broad), 3.9
7-4.07 (3H, m), 4.21 (1H, broa
d), 7.33 (2H, d, J = 8.3 Hz), 7.7
7 (2H, d, J = 8.3 Hz). MS (FAB) m / z 485 (M + H) ^<+> . Elemental _{analysis: C 23 H 36 N 2 O} 7 S Calculated: C, 57.00; H, 7.49 ; N, 5.7
8; S, 6.62. Analytical values: C, 57.63; H, 7.64; N, 5.8.
7; S, 6.69.

Reference Example 267 1,4-bis (tert-butoxycarbonyl) -2-
[2- (2-oxo-1,3-oxazolan-3-yl) ethyl] piperazine To a suspension of sodium hydride (60%, 57 mg) in N, N-dimethylformamide (20 ml) was added 2-oxazolidone (0. 122 g) and stirred at 90 ° C. for 1 hour. 1,4-di (tert-butoxycarbonyl) -2
-(2-tosyloxyethyl) piperazine (0.686
A solution of g) in N, N-dimethylformamide (15 ml) was added, and the mixture was stirred at 90 ° C. for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with water and saturated saline,
After drying over magnesium sulfate, the mixture was concentrated under reduced pressure to give the title compound (0.515 g) as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 1.46 (8H, s),
1.47 (10H, s), 1.78-1.85 (2H,
m), 2.81-2.95 (3H, m), 3.39-
3.64 (2H, m), 3.85-4.05 (2H, b
load), 4.00 (2H, broad d, J = 1)
3.4 Hz), 4.09-4.28 (2H, m), 4.
30-4.34 (2H, m). MS (FAB) m / z 400 (M + H) ^<+> .

Reference Example 268 1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [2- (2-oxo-1,3-oxazolan-3-yl) ethyl] piperazine 1,4-di (tert-butoxycarbonyl) -2-
[2- (2-oxo-1,3-oxazolan-3-yl) ethyl] piperazine (0.495 g, 1.23 mm
ol) in methylene chloride (10 ml) was added with trifluoroacetic acid (2 ml) and stirred at room temperature for 5 室温 hours. The reaction solution was concentrated under reduced pressure and azeotroped three times with toluene and three times with methylene chloride to give 2- [2- (2-oxo-1,3
-Oxazolan-3-yl) ethyl] piperazine was obtained as a colorless oil. The obtained 2- [2- (2-oxo-
1,3-oxazolan-3-yl) ethyl] piperazine and triethylamine (0.520 ml, 3.73 mmol)
1) methylene chloride (50 ml) solution was cooled to 0 ° C.
1-benzenesulfonyl-5-chloro-2-chlorosulfonylindole (0.459 g, 1.17 mmol)
And stirred at 0 ° C. for 1 hour and at room temperature for 1 day. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. Flash column chromatography using silica gel as carrier (methanol /
Purification by methylene chloride = 1 / 50-1 / 20-1 / 10) gave 0.222 g of the title compound (32
%) Was obtained as a pale yellow amorphous solid. IR (KBr) cm ^-1 3318, 3120, 306
4,2919,2857,1743,1517,148
2,1448,1434,1386,1351,126
7,1222,1211,1186,1159,113
7, 1112, 1089, 1074, 971, 835,
761, 738, 728, 713. ¹ H NMR (CDCl ₃ ) δ 1.51-1.76 (2
H, m), 2.69-2.74 (1H, m), 2.77
-2.85 (2H, m), 2.96-3.03 (2H,
m), 3.20-3.27 (1H, m), 3.48-
3.55 (2H, m), 3.59-3.69 (2H,
m), 3.83 (1H, broad d, J = 11.7)
Hz), 4.30-4.40 (2H, m), 7.39-
7.46 (4H, m), 7.51-7.57 (2H,
m), 7.99-8.02 (2H, m), 8.22 (1
H, d, J = 9.0 Hz). MS (FAB) m / z 553 [(M + H) ⁺ , C
l ³⁵ ], 555 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 23 H 25 N 4 O} 6 ClS 2 Calculated: C, 49.95; H, 4.56 ; N, 10.1
3; Cl, 6.41; S, 11.60. Analytical values: C, 49.69; H, 4.58; N, 9.9.
2; Cl, 6.52; S, 11.31.

Reference Example 269 4,5-bis (bromomethyl) thiazole 4,5-dimethylthiazole (5.00 g) at room temperature, N
-Bromosuccinimide (15.7 g) and α, α ′
-Azobisisobutyronitrile (362 mg) was dissolved in ethylene dichloride (500 ml), and the mixture was heated under reflux for 1 hour. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel chromatography (hexane: diethyl ether = 1: 4) to obtain the title compound (5.24 g, 44%). ¹ H NMR (CDCl ₃ ) δ 4.64 (2H, s),
4.74 (2H, s), 8.75 (1H, s).

Reference Example 270 5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazine Under ice cooling, 4,5-bis (bromomethyl) thiazole (6
00 mg) and 1,2-dimethylhydrazine dihydrochloride (294 mg) were suspended in ethanol (20 ml), and triethylamine (1.23 ml) was added to the reaction solution at once, followed by stirring at room temperature for 30 minutes and at 50 ° C. for 30 minutes. did. The solvent was distilled off, and silica gel chromatography (5.
% Methanol-methylene chloride) to give the title compound (90 mg, 24%). ¹ H NMR (CDCl ₃ ) δ 2.43 (3H, s),
2.56 (3H, s), 3.92 (2H, s), 4.0
6 (2H, brs), 8.68 (1H, s). MS
(FAB) m / z 170 (M + H) ⁺ .

Reference Example 271 3- (methoxycarbonylmethyl) -1-[[1-phenylsulfonyl-5- (trimethylsilylethynyl) indol-2-yl] sulfonyl] piperazine Reference Example 1
The title compound was synthesized in the same manner as in 52. ¹ H NMR (CDCl ₃ ) δ 0.25 (9H, s),
2.38 (1H, dd, J = 16.2, 8.8 Hz),
2.46 (1H, dd, J = 16.2, 4.2 Hz),
2.76 (1H, dd, J = 12.5, 10.0H
z), 2.91-2.99 (1H, m), 2.99-
3.07 (2H, m), 3.17-3.25 (1H,
m), 3.67 (3H, s), 3.69-3.78 (2
H, m), 7.38-7.44 (3H, m), 7.54.
(1H, t, J = 7.6 Hz), 7.58 (1H, d
d, J = 8.9, 1.6 Hz), 7.68 (1H, d,
J = 1.6 Hz), 7.98-8.02 (2H, m),
8.22 (1H, d, J = 8.9 Hz). MS (FAB) m / z 574 (M + H) ^<+> .

Reference Example 272 1,4-bis (t-butoxycarbonyl) -2- [2-
[(Morpholin-4-yl) sulfonyl] ethyl] piperazine The title compound was synthesized in the same manner as in Reference Example 230. ¹ H NMR (CDCl ₃ ) δ 1.47 (18H, s),
1.95-2.00 (1H, m), 2.10-2.20
(1H, m), 2.70-3.10 (5H, m), 3.
25 (4H, t, J = 4.7 Hz), 3.75 (4H,
t, J = 4.7 Hz), 3.80-4.30 (4H,
m). MS (FAB) m / z 464 (M + H) ^<+> .

Reference Example 273 1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [2-[(morpholin-4-yl) sulfonyl] ethyl] piperazine Same as Reference Example 146 The title compound was synthesized by the method described above. ¹ H NMR (CDCl ₃ ) δ 1.80-1.90 (1
H, m), 1.90-2.00 (1H, m), 2.60
-2.70 (1H, m), 2.80-3.10 (6H,
m), 3.20-3.30 (4H, m), 3.60-
3.85 (6H, m), 7.40-7.50 (4H,
m), 7.50-7.60 (2H, m), 8.00-
8.10 (2H, m), 8.22 (1H, d, J = 9.
1 Hz). MS (FAB) m / z 617 [(M + H) ⁺ , C
l ³⁵ ], 619 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 274 1,4-bis (tert-butoxycarbonyl) -2-
Hydroxymethylpiperazine The title compound was synthesized in the same manner as in Reference Example 221. ¹ H NMR (CDCl ₃ ) δ1.46-1.47 (18
H, m), 2.70-4.400 (10H).

Reference Example 275 1,4-bis (tert-butoxycarbonyl) -2-
The title compound was synthesized in the same manner as in Formylpiperazine Reference Example 222. ¹ H NMR (CDCl ₃ ) δ1.45-1.50 (18
H, m), 2.80-3.00 (1H, m), 3.00
-3.20 (2H, m), 3.70-4.00 (2H,
m), 4.40-4.70 (2H, m), 9.59 (1
H, s). MS (FAB) m / z 315 (M + H) ^<+> .

Reference Example 276 1,4-bis (tert-butoxycarbonyl) -2-
(2-ethoxycarbonylethenyl) piperazine In a 50 ml two-necked flask, sodium hydride (141) was added.
mg, oily 60%) and then replaced with argon. Then, tetrahydrofuran (5 ml) was added, and under ice-cooling, triethylphosphonoacetate (700 μl) was added, and the mixture was stirred at room temperature for 15 minutes. The reaction solution is cooled again, and
A solution of 4-bis (tert-butoxycarbonyl) -2-formylpiperazine (911 mg) in tetrahydrofuran (7 ml) was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the completion of the reaction, water was added to the reaction solution, and ethyl acetate was further added to carry out a liquid separation operation. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to flash column chromatography using silica gel as a carrier (hexane: ethyl acetate =
2: 1) to give the title compound (920 mg, 83%) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) δ 1.20-1.30 (3
H, m), 1.40-1.50 (18H, m), 2.7
5-3.20 (3H, m), 3.80-4.80 (6
H, m), 5.93 (1H, dd, J = 15.9, 2.
0 Hz), 6.82 (1H, dd, J = 15.9, 4.
4 Hz). MS (FAB) m / z 385 (M + H) ^<+> .

Reference Example 277 1,4-bis (tert-butoxycarbonyl) -2-
(2-Ethoxycarbonylethyl) piperazine The title compound was synthesized in the same manner as in Reference Example 223. ¹ H NMR (CDCl ₃ ) δ 1.25 (3H, t, J =
7.1 Hz), 1.46 (9H, s), 1.46 (9
H, s), 1.70-1.85 (1H, m), 1.85
−2.00 (1H, m), 2.20-2.40 (2H,
m), 2.70-3.00 (3H, m), 3.80-
4.20 (6H, m). MS (FAB) m / z 387 (M + H) ^<+> .

Reference Example 278 1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- (2-ethoxycarbonylethyl) piperazine The title compound was synthesized in the same manner as in Reference Example 146. . ¹ H NMR (CDCl ₃ ) δ 1.25 (3H, t, J =
7.2 Hz), 1.30-1.80 (3H, m), 2.
30-2.45 (2H, m), 2.55-2.65 (1
H, m), 2.75-3.05 (4H, m), 3.70
-3.80 (2H, m), 4.11 (2H, q, J =
7.2 Hz), 7.35-7.50 (4H, m), 7.
50-7.60 (2H, m), 8.02 (2H, d, J
= 7.3 Hz), 8.22 (1H, d, J = 9.3H)
z). MS (FAB) m / z 540 [(M + H) ⁺ , C
l ³⁵ ], 542 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 279 1,4-bis (tert-butoxycarbonyl) -2-
An aqueous solution (3.0 m) of (2-cyanoethyl) piperazine potassium cyanide (85.0 mg)
l) is 1,4-bis (t-butoxycarbonyl) -2-
A solution of (2-bromoethyl) piperazine (393 mg) in ethanol (3.0 ml) was added, and the mixture was heated and stirred at 110 ° C for 3 hours. After the ethanol was distilled off under reduced pressure, methylene chloride (100 ml) was added, and the organic layer was washed with distilled water until the aqueous phase became neutral. After washing with saturated brine, drying over anhydrous sodium sulfate and concentration, the residue was subjected to silica gel column chromatography (silica gel 15 g, hexane: ethyl acetate = 2: 1) to give the title compound (145.0 m
g, 43%) as a white solid. ¹ H NMR (CDCl ₃ ) δ 1.47 (12H, s),
1.49 (6H, s), 1.75-1.88 (1H,
m), 1.92-2.10 (1H, m), 2.28-
2.35 (2H, m), 2.70-3.10 (3H,
m), 3.80-4.15 (3H, m), 4.20-
4.30 (1H, m). MS (FAB) m / z 340 (M + H) ^<+> .

Reference Example 280 4-[(1-Phenylsulfonyl-5-chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) piperazine The title compound was synthesized in the same manner as in Reference Example 146. ¹ H NMR (DMSO-d ₆ ) δ 1.65-1.77
(1H, m), 1.78-1.90 (1H, m), 2.
48 (2H, t, J = 7.6 Hz), 2.70 (1H,
dd, J = 12.5, 9.5 Hz), 2.85-3.1
0 (4H, m), 3.62-3.70 (1H, m),
3.75-3.85 (1H, m), 7.40-7.50
(4H, m), 7.55-7.60 (2H, m), 8.
01 (2H, dd, J = 8.6, 1.2 Hz), 8.2
2 (1H, d, J = 9.0 Hz). MS (FAB) m / z 493 [(M + H) ⁺ , C
l ³⁵ ], 495 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 281 2-amino-6,6-ethylenedioxy-4,5,6
7,4-Tetrahydrobenzo [d] thiazole 1,2-cyclohexanedione ethylene ketal (7.80 g) was added to a 200 ml eggplant flask, dissolved in cyclohexane (20 ml), and pyrrolidine (4.35) was added.
ml), p-toluenesulfonic acid monohydrate (48.0 m
g) was added and the mixture was heated to reflux while trapping water with Dean Stark. After 70 minutes, the mixture was cooled to room temperature, the solvent was decanted, and the solvent was concentrated under reduced pressure. The obtained residue was dissolved in methanol (15 ml), and sulfur powder (1.60 g) was added thereto while taking care not to raise the temperature in a water bath. After 15 minutes, a solution of cyanamide (2.10 g) in methanol (10 ml) was added. In minutes. After 14 hours, the residue obtained after distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (silica gel 300 g, methylene chloride: methanol = 1).
00: 5 → 10: 1) to give the title compound (8.89 g) as a dark green solid. ¹ H NMR (CDCl ₃ ) δ 1.96 (2H, t, J =
6.4 Hz), 2.74 (2H, t, J = 6.4H)
z), 2.81 (2H, s), 4.02 (4H, s),
4.77 (2H, brs). MS (FAB) m / z 213 (M + H) ⁺ .

Reference Example 282 2-chloro-6,6-ethylenedioxy-4,5,6
7, -Tetrahydrobenzo [d] thiazole In a 100 ml eggplant flask, copper (II) chloride (760 m
g), dissolved in acetonitrile (10 ml) and cooled in a water bath while tert-butyl nitrite (730 mg)
Was added all at once. After 10 minutes, 2-amino-6,6-ethylenedioxy-4,5,6,7, -tetrahydrobenzo [d] thiazole (1.00 g) was added in about 50 minutes, and the mixture was stirred at room temperature for 1 hour. Then heat to 65 ° C and add 2
Stirring was continued for hours. After adding silica gel (5 g) to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (silica gel 50 g, hexane: ethyl acetate = 3: 1) to give the title compound (860 mg) as a yellow oil. ) Got. ¹ H NMR (CDCl ₃ ) δ 2.00 (2H, t, J =
6.4 Hz), 2.91 (4H, m), 4.03 (4
H, s). MS (FAB) m / z 232 [(M + H) ⁺ , C
l ³⁵ ], 234 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 283 6,6-Ethylenedioxy-4,5,6,7-tetrahydrobenzo [d] thiazole In a 100 ml eggplant flask, 2-chloro-6,6-ethylenedioxy-4,5, 6,7, -Tetrahydrobenzo [d] thiazole (860 mg) was added and methanol (1
0%) and 10% palladium on carbon (100 m
g) and sodium acetate (305 mg) were added, and the mixture was stirred under a hydrogen atmosphere at 4.5 atm. After 17 hours, the solvent was concentrated after filtering palladium, and the obtained residue was subjected to silica gel column chromatography (silica gel 50 g, ethyl acetate: hexane = 1: 1) to give the title compound (720 mg) as a pale yellow oil. I got ¹ H NMR (CDCl ₃ ) δ 2.04 (2H, t, J =
6.8 Hz), 3.03 (4H, m), 4.05 (4
H, s), 8.62 (1H, s). MS (FAB) m / z 198 (M + H) ^<+> .

Reference Example 284 (6,6-ethylenedioxy-4,5,6,7, -tetrahydrobenzo [d] thiazol-2-yl) carboxylic acid lithium salt The title compound was prepared in the same manner as in Reference Example 162. Synthesized. ¹ H NMR (DMSO-d ₆ ) δ 1.94 (2H, t,
J = 6.6 Hz), 3.34-3.44 (4H, m),
3.95 (4H, s).

Reference Example 285 2-amino-6,7-dihydro-4H-pyrano [4,3
-D] Thiazole The title compound was synthesized in the same manner as in Reference Example 281. ¹ H NMR (CDCl ₃ ) δ 2.66-2.70 (2
H, m), 3.97 (2H, t, J = 5.6 Hz),
4.63 (2H, s), 4.94 (2H, br s). MS (FAB) m / z 157 (M + H) ⁺ .

Reference Example 286 2-Chloro-6,7-dihydro-4H-pyrano [4,3
-D] Thiazole The title compound was synthesized in the same manner as in Reference Example 282. ¹ H NMR (CDCl ₃ ) δ 2.85-2.89 (2
H, m), 4.02 (2H, t, J = 5.6 Hz),
4.73 (2H, s). MS (FAB) m / z 175 [(M + H) ⁺ , C
l ³⁵ ], 177 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 287 6,7-Dihydro-4H-pyrano [4,3-d] thiazole The title compound was synthesized in the same manner as in Reference Example 283. ¹ H NMR (CDCl ₃ ) δ 2.97-3.01 (2
H, m), 4.04 (2H, t, J = 5.6 Hz),
4.87 (2H, s), 8.69 (1H, s). MS (FAB) m / z 142 (M + H) ⁺ .

Reference Example 288 Lithium (6,7-dihydro-4H-pyrano [4,3-d] thiazol-2-yl) carboxylate In a 200 ml three-necked flask, 4,5-dihydro-7H-
Pyrano [4,3, d] thiazole (1.14 g) was added, dissolved in ether (30 ml), and cooled to -78 ° C.
6 M butyllithium (6.6 ml) was added and stirred.
After 20 minutes, carbon dioxide gas was introduced, and after about 15 minutes, the introduction was stopped. The reaction solution was returned to room temperature and concentrated under reduced pressure to obtain the title compound (1.65 g) as a colorless amorphous substance. ¹ H NMR (DMSO-d ₆ ) δ 2.83 (2H, t,
J = 5.6 Hz), 3.92 (2H, t, J = 5.6H)
z), 4.73 (2H, s).

Reference Example 289 4-[(5-chloroindol-2-yl) sulfonyl] -2-[[N- (phenylsulfonyl) carbamoyl] methyl] piperazine trifluoroacetate 1-tert-butoxycarbonyl-2- Carboxymethyl-4-[(5-chloroindol-2-yl) sulfonyl] piperazine (1.00 g) was dissolved in tetrahydrofuran (10 ml), carbonyldiimidazole (1.06 g) was added, and the mixture was heated under reflux overnight. After cooling the reaction solution to room temperature, benzenesulfonamide (685 m
g), 1,8-diazabicyclo [5.4.0] -7-undecene (0.64 ml) and carbonyldiimidazole (353 mg) were added, and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, dichloromethane was added to the residue, and the precipitated solid was filtered off. The filtrate was washed sequentially with 1N hydrochloric acid and saturated saline. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Φ3.0 × 10.0 cm, dichloromethane:
Purification by methanol = 100: 1) gave a light brown foam. This was dissolved in dichloromethane (10 ml), trifluoroacetic acid (10 ml) was added, the mixture was stirred at room temperature for 1 minute, and the reaction solution was concentrated under reduced pressure. Diethyl ether was added to the residue, and the resulting precipitate was collected by filtration and filtered to give the title compound (496 m
g, 31%) as a colorless foam. ¹ H NMR (DMSO-d ₆ ) δ 2.60-2.75
(3H, m), 3.10-3.20 (1H, m), 3.
29-3.38 (1H, m), 3.53-3.73 (4
H, m), 7.06 (1H, d, J = 2.0 Hz),
7.34 (1H, dd, J = 8.8, 2.0 Hz),
7.50 (1H, d, J = 8.8 Hz), 7.64 (2
H, t, J = 7.1 Hz), 7.74 (1H, t, J =
7.1 Hz), 7.80 (1H, d, J = 2.0H)
z), 7.93, (2H, d, J = 7.1 Hz), 1
2.53 (1H, s). MS (FAB) m / z 497 [(M + H) ⁺ , C
l ³⁵ ], 499 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 290 1-tert-butoxycarbonyl-4-[(5-chloroindol-2-yl) sulfonyl] -2-[(N-
Methylsulfonylcarbamoyl) methyl] piperazine 1-tert-butoxycarbonyl-2-carboxymethyl-4-[(5-chloroindol-2-yl) sulfonyl] piperazine (1.00 g) was dissolved in tetrahydrofuran (10 ml) and carbonyl was dissolved. Diimidazole (1.06 g) was added and the mixture was heated under reflux overnight. After the reaction solution was cooled to room temperature, methanesulfonamide (415 m
g) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.64 ml) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, dichloromethane was added to the residue, and the mixture was washed successively with 1 N hydrochloric acid and saturated saline. The organic layer was dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure,
The residue was subjected to silica gel column chromatography (Φ3.0
× 10.0 cm, dichloromethane: methanol = 10
0: 1) to give the title compound (518 mg, 44
%) As a colorless foam. ¹ H NMR (DMSO-d ₆ ) δ 1.33 (9H,
s), 2.23-2.60 (3H, m), 2.62-
2.78 (1H, m), 3.05 (1H, brs),
3.21 (3H, s), 3.52-3.70 (2H,
m), 3.84-3.97 (1H, m), 4.56 (1
H, br s), 7.02 (1H, s), 7.32 (1
H, d, J = 8.8 Hz), 7.49 (1H, J = 8.8 Hz).
8 Hz), 7.77 (1H, s), 11.84 (1H,
s), 12.43 (1H, s). MS (FAB) m / z 557 [(M + Na) ⁺ , Cl
³⁵ ], 559 [(M + Na) ⁺ , Cl ³⁷ ].

Reference Example 291 1-[(5-chloroindol-2-yl) sulfonyl] -3-[(N-methyl-N-methylsulfonylcarbamoyl) methyl] piperazine trifluoroacetate 1-tert-butoxycarbonyl- 4-[(5-chloroindol-2-yl) sulfonyl] -2-[(N-
Methylsulfonylcarbamoyl) methyl] piperazine (347 mg) was added to N, N-dimethylformamide (10
sodium bicarbonate (55 mg) and methyl iodide (0.05 ml), and the mixture was stirred at room temperature overnight.
The reaction solution was concentrated under reduced pressure, dichloromethane was added to the residue,
It was sequentially washed once with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (φ1.7 ×
12.0 cm, dichloromethane: methanol = 200:
Purification according to 1) gave a colorless foam. This was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (2 m
After l) was added and the mixture was stirred at room temperature for 1 minute, the reaction solution was concentrated under reduced pressure. Diethyl ether was added to the residue, and the resulting precipitate was collected by filtration to give the title compound (189 mg, 43%) as a colorless foam. ¹ H NMR (DMSO-d ₆ ) δ 2.60-2.80
(2H, m), 3.02-3.11 (2H, m), 3.
16 (3H, s), 3.20-3.30 (1H, m),
3.39 (3H, s), 3.61-3.80 (4H,
m), 7.08 (1H, d, J = 1.5 Hz), 7.3
4 (1H, dd, J = 8.8, 2.2 Hz), 7.50
(1H, J = 8.8 Hz), 7.80 (1H, d, J =
2.2Hz), 12.54 (1H, brs). MS (FAB) m / z 449 [(M + H) ⁺ , C
l ³⁵ ], 451 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 292 N-methanesulfonylhydrazine hydrochloride t-butylcarbazate (2.64 g) was converted to pyridine (3
0 ml), methanesulfonyl chloride (1.62 ml) was added under ice cooling, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and 1N
Washing was sequentially performed with hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate.
After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was solidified with hexane and ethyl acetate to obtain a pale yellow solid. This was dissolved in dichloromethane (20 ml) and saturated hydrochloric acid ethanol (20 ml)
Was added, and the solution was concentrated under reduced pressure. The obtained residue was solidified from ethyl acetate to obtain N-methanesulfonylhydrazine (1.67 g, 57%) as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) δ 3.25 (3H,
s), 9.80 (br s, 9.80). MS (FAB) m / z 111 (M + H) ⁺ .

Reference Example 293 4-[(5-chloroindol-2-yl) sulfonyl] -2-[(2-methylsulfonylhydrazino) carbonylmethyl] -1-[(6-methyl-4,5,6 , 7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine trifluoroacetate 1-tert-butoxycarbonyl-2-carboxymethyl-4-[(5-chloroindol-2-yl) sulfonyl] piperazine (600 mg), N-methanesulfonylhydrazine (192 mg), 1-Hydroxybenzotriazole monohydrate (200 mg) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (301 mg) were dissolved in dichloromethane (20 ml), and triethylamine (0.21 ml) was added. Stirred overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed once with water and saturated saline, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Φ
3.0 × 8.0 cm, dichloromethane: methanol = 5
0: 1) to give a colorless foam. This was dissolved in dichloromethane (2 ml), trifluoroacetic acid (10 ml) was added, the mixture was stirred at room temperature for 1 minute, and the reaction solution was concentrated under reduced pressure. Diethyl ether was added to the residue, and the resulting precipitate was collected by filtration to give the title compound (278 mg, 38%) as a colorless foam. ¹ H NMR (DMSO-d ₆ ) δ 2.51-2.82
(3H, m), 2.96 (3H, s), 3.11-3.
21 (1H, m), 3.31-3.42 (1H, m),
3.60-3.85 (4H, m), 7.07 (1H,
s), 7.34 (1H, dd, J = 8.8, 2.0H)
z), 7.50 (1H, J = 8.8 Hz), 7.80
(1H, s), 9.52 (1H, d, J = 2.7H
z), 10.39 (1H, d, J = 2.7 Hz), 1
2.51-12.57 (1H, m). MS (FAB) m / z 450 [(M + H) ⁺ , C
l ³⁵ ], 452 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 294 1- (tert-butoxycarbonyl) -4-[(5-
Chloroindol-2-yl) sulfonyl] -2-
[(Pyrrolidin-1-ylcarbonyl) methyl] piperazine 1- (3-dimethylaminopropyl- used in Reference Example 6
The title compound was synthesized by a method using 3-ethylcarbodiimide hydrochloride as a condensing agent. ¹ H NMR (CDCl ₃ ) δ 1.41 (9H, s),
1.85-1.97 (2H, m), 1.98-2.18
(2H, m), 2.22-2.35 (1H, m), 2.
50-3.00 (3H, m), 2.97 (1H, dt,
J = 3.4, 13.0 Hz), 3.40-3.60 (4
H, m), 3.64-3.75 (1H, m), 3.80
-4.20 (2H, m), 4.63 (1H, br d,
J = 10.0 Hz), 6.96 (1H, d, J = 1.7)
Hz), 7.27 (1H, dd, J = 9.1, 1.7H)
z), 7.37 (1H, d, J = 9.1 Hz), 7.6
5 (1H, d, J = 1.7 Hz). MS (FAB) m / z 511 [(M + H) ⁺ , C
l ³⁵ ], 513 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 295 2-[(N-benzylcarbamoyl) methyl] -1-
(Tert-butoxycarbonyl) -4-[(5-chloroindol-2-yl) sulfonyl] piperazine 1- (3-dimethylaminopropyl- used in Reference Example 6
The title compound was synthesized by a method using 3-ethylcarbodiimide hydrochloride as a condensing agent. ¹ H NMR (CDCl ₃ ) δ 1.40 (9H, s),
2.35-2.48 (1H, m), 2.50-2.85
(3H, m), 2.95-3.07 (1H, m), 3.
62-3.78 (1H, m), 3.80-4.15 (2
H, m), 4.40-4.50 (2H, m), 4.60
-4.70 (1H, m), 6.93 (1H, s), 7.
20-7.40 (7H, m), 7.64 (1H, s). MS (FAB) m / z 547 [(M + H) ⁺ , C
l ³⁵ ], 549 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 2965 9 (6) -Chloro-2-mercaptobenzimidazole 4-chloro-1,2-phenylenediamine (14.37)
To a mixed solution of g) of ethanol (100 ml) and water (15 ml), carbon disulfide (6.60 ml) and sodium hydroxide (6.330 g) were added, and the mixture was refluxed for 3 hours. Activated carbon (4.0 g) was added to the reaction solution, and the mixture was refluxed for 10 minutes and filtered with suction. Ethanol (100 ml), hot water of about 70 ° C (20
0 ml) to wash the precipitate, and to the obtained filtrate, a mixed solution of acetic acid (9.0 ml) and water (16.0 ml) was added. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (ethyl acetate only), further solidified with acetone-water and ethyl acetate-hexane, and dried to obtain the title compound (9.03 g) as a pale yellow powder. . m. p. > 220 ° C (dec). IR (KBr) cm ^-1 3116, 3084, 3055
2952, 1614, 1512, 1475, 1369,
1323, 1190, 1066. ¹ H NMR (CD ₃ OD) δ 7.15 (2H, s),
7.21 (1H, s). MS (EI) m / z 184
[M ⁺ , Cl ³⁵ ], 186 [M ⁺ , Cl ³⁷ ].

Reference Example 297 1- (tert-butoxycarbonyl) -4-[[5
(6) -Chlorobenzimidazol-2-yl] sulfonyl] piperazine 5 (6) -Chloro-2-mercaptobenzimidazole (1.837 g) was suspended in a 20% aqueous acetic acid solution (60 ml) and chlorinated at 7 ° C. or lower. Gas was bubbled for 70 minutes. The yellow precipitate was collected by filtration and washed with cold water. The obtained yellow solid was treated with 1- (tert-butoxycarbonyl) piperazine (3.905 g) in water (18 ml) and acetone (20 m2).
l), and the mixture was stirred at room temperature for 20 hours. After removing acetone under reduced pressure, the precipitate was collected by filtration and dried to give the title compound (3.16 g) as a pale-yellow powder. m. p. 210-211 ° C. IR (KBr) cm ^-1 3212,2983,1666,
1435, 1367, 1356, 1279, 1176,
1165, 1147, 1138, 974, 949. ¹ H NMR (CDCl ₃ ) δ 1.44 (9H, s),
3.33-3.41 (4H, m), 3.53-3.59
(4H, m), 7.30-7.60 (2H, m), 7.
72-7.88 (1H, m). MS (FAB) m / z 401 [(M + H) ⁺ , C
l ³⁵ ], 403 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 298 1-[[5 (6) -chlorobenzimidazol-2-yl] sulfonyl] piperazine hydrochloride 1- (tert-butoxycarbonyl) -4-[[5
(6) -Chlorobenzimidazol-2-yl] sulfonyl] piperazine (1.406 g) in ethanol (5.
0 ml) and dichloromethane (4.0 ml) mixed solution.
A saturated ethanolic hydrochloric acid solution (5.0 ml) was added, and the mixture was added at room temperature for 4 hours.
Stirred for hours. After concentration under reduced pressure, the crude product was subjected to silica gel column chromatography (dichloromethane: methanol =
20: 1). Further, a 1N ethanol solution of hydrochloric acid (1 ml) was added to the purified compound, concentrated and dried to obtain the title compound (1.19 g) as a hygroscopic colorless amorphous. ¹ H NMR (DMSO-d ₆ ) δ 3.25-3.80
(8H, m), 7.40-7.50 (1H, br),
7.60-7.80 (2H, br), 9.20-9.5
5 (1H, br). MS (FAB) m / z 301 [(M + H) ⁺ , C
l ³⁵ ], 303 [(M + H) ⁺ , Cl ³⁷ ].

Reference Example 299 2-amino-5-tert-butoxycarbonyl-4,
5,6,7-Tetrahydrothiazolo [5,4-c] pyridine 1-tert-butoxycarbonyl-4-piperidone (40.0 g) is dissolved in cyclohexane (80 ml), and p-toluenesulfonic acid monohydrate is dissolved. (191 mg),
Pyrrolidine (17.6 ml) was added, and the mixture was refluxed for 2 hours while being dehydrated with a Dean-Stark trap. The supernatant was taken and concentrated under reduced pressure.
0 ml) and sulfur powder (6.42 g) was added. Under ice-cooling, a methanol solution (10 ml) of cyanamide (8.44 g) was slowly added dropwise, followed by stirring at room temperature for 5 hours. The precipitated solid was collected by filtration and the title compound (31.0 g)
Was obtained as a pale yellow solid. IR (KBr) cm ^-1 3347, 3282, 311
8,3008,2977,2929,2863,274
2,1675,1633,1602,1536,147
3,1452,1419,1380,1365,134
6,1319,1292,1257,1236,117
4,1120. _{^{1 H NMR (DMSO-d 6}} ) 1.41 (9H, s),
2.40-2.46 (2H, m), 3.57 (2H,
t, J = 5.6 Hz), 4.29 (2H, s), 6.7
9 (2H, s). MS (EI) m / z 255 (M ^<+> ).

Reference Example 300 2-bromo-5-tert-butoxycarbonyl-4,
5,6,7-Tetrahydrothiazolo [5,4-c] pyridine Cupric bromide (1.05 g) was suspended in N, N-dimethylformamide, and tert-butyl nitrite (696 l) was added. After adding 2-amino-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine (1.00 g) under ice-cooling,
The reaction solution was heated and stirred at 40 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give the title compound (568 mg) as a yellow solid. ¹ H NMR (CDCl ₃ ) 1.48 (9H, s), 2.
85 (2H, brs), 3.72 (2H, t, J =
5.6 Hz), 4.56 (2H, brs). MS (FAB) m / z 319 (M + H) ^<+> .

Reference Example 301 2-bromo-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridinetrifluoroacetate 2-bromo-5-tert-butoxycarbonyl-4,
5,6,7-Tetrahydrothiazolo [5,4-c] pyridine (890 mg) was dissolved in dichloromethane (2 ml), trifluoroacetic acid (15 ml) was added, and the mixture was stirred at room temperature for 1 minute. The reaction solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the precipitated solid was collected by filtration to give the title compound (867).
mg) as a colorless foamy solid. _{^{1 H NMR (DMSO-d 6}} ) 2.98 (2H, t, J
= 6.1 Hz), 3.72 (2H, t, J = 6.1H)
z), 4.35 (2H, s), 9.53 (2H, br)
s). MS (FAB) m / z 219 (M + H) ^<+> .

Reference Example 302 2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine 2-bromo-4,5,6,7-tetrahydrothiazolo [5 , 4-c] pyridine trifluoroacetate (422 m
g) was suspended in dichloromethane (10 ml), triethylamine (356 l) was added, and the mixture was stirred at room temperature for 15 minutes. Acetic acid (216 l) and formaldehyde aqueous solution (35% solution, 202 l) were added to the reaction solution, and the mixture was stirred at room temperature for 2 minutes. Sodium triacetoxyborohydride (428 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. A 1N aqueous sodium hydroxide solution (10 ml) was added to the reaction solution to carry out a liquid separation operation. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1) to give the title compound (286 m
g) was obtained as a light brown oil. ¹ H NMR (CDCl ₃ ) 2.49 (3H, s), 2.
79 (2H, t, J = 5.8 Hz), 2.88-2.9
3 (2H, m), 3.58 (2H, s). MS (FAB) m / z 233 (M + H) ^<+> .

Reference Example 303 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt 2-bromo-5-methyl-4,5,6, 7-Tetrahydrothiazolo [5,4-c] pyridine (531 mg) was dissolved in anhydrous diethyl ether (20 ml), and n-butyllithium n-hexane solution (1.54 mo) was added at -78 ° C.
(l / l, 1.63 ml) was added dropwise, and the mixture was stirred under ice cooling for 30 minutes. After blowing carbon dioxide gas into the reaction solution at -78 ° C for 1 hour, the temperature was raised to room temperature. The reaction solution was concentrated under reduced pressure to obtain the title compound (523 mg) as a pale brown foamy solid. _{^{1 H NMR (DMSO-d 6}} ) 2.37 (3H, s),
2.64-2.77 (4H, m), 3.54 (2H,
s). MS (FAB) m / z 199 (M + H) ^<+> .

Reference Example 304 4- (tert-Butoxycarbonyl) aminopyridine 4-Aminopyridine (10.0 g) was dissolved in tetrahydrofuran (500 ml), and ditert-butyl dicarbonate (25.5 g) was added. Stirred for minutes. The reaction solution was concentrated under reduced pressure. The precipitated solid was washed with hexane to give the title compound as a colorless solid (16.9 g). 5. ¹ H NMR (CDCl ₃ ) 1.53 (9H, s);
86 (1H, brs), 7.30 (2H, dd, J =
1.5, 4.9 Hz), 8.44 (2H, dd, J =
1.5, 4.9 Hz). MS (FAB) m / z 195 (M + H) ^<+> .

Reference Example 305 4- (tert-butoxycarbonyl) amino-3-mercaptopyridine 4- (tert-butoxycarbonyl) aminopyridine (61.6 g) was added to tetrahydrofuran (2000 ml).
And stirred at -78C for 10 minutes. N-
Butyl lithium in hexane (1.59 mol / l5
00 ml), and the mixture was stirred for 10 minutes.
Stirred for hours. After the reaction solution was cooled to -78 ° C, sulfur powder (12.2 g) was added, and the mixture was heated to room temperature and stirred for 1 hour. Water (1000 ml) was added to the reaction solution to separate it.
3N hydrochloric acid was added to the aqueous layer to adjust the pH to 3 to 4, and then dichloromethane was added to separate the layers. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 2) to give the title compound (33.24 g) as a pale yellow foam. IR (KBr) cm ^-1 1731, 1536, 150
2,1243,1214,1153,1141. _{^{1 H NMR (DMSO-d 6}} ) 1.52 (9H, s),
7.89 (1H, d, J = 6.4 Hz), 7.99 (1
H, d, J = 6.4 Hz), 8.20 (1H, s),
9.91 (1H, brs). MS (FAB) m / z 227 (M + H) ^<+> .

Reference Example 306 Thiazolo [5,4-c] pyridine 4- (tert-butoxycarbonyl) amino-3-mercaptopyridine (33.24 g) was added to formic acid (250 m
1) and heated to reflux for 3 days. The reaction solution was concentrated under reduced pressure, and a 5N aqueous potassium hydroxide solution (100 m
l) and ether were added and the mixture was separated. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 4) to give the title compound as a colorless solid (9.03 g). ¹ H NMR (CDCl ₃ ) 8.05 (1H, d, J =
5.4 Hz), 8.70 (1H, d, J = 5.4H)
z), 9.23 (1H, s), 9.34 (1H, s). MS (FAB) m / z 137 (M + H) ^<+> .

Reference Example 307 5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine Thiazolo [5,4-c] pyridine (1.61 g) was converted to N,
After dissolving in N-dimethylformamide (50 ml) and adding methyl iodide (1.50 ml), the mixture was heated and stirred at 80 ° C. for 4 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol (100 ml), sodium borohydride (1.53 g) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, a saturated aqueous solution of potassium carbonate and ether were added to the residue, and the mixture was separated. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane:
Purification by methanol = 100: 4) gave the title compound (1.28 g) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) 2.52 (3H, s), 2.
83 (2H, t, J = 5.9 Hz), 2.98 (2H,
t, J = 5.9 Hz) 3.70 (2H, s), 3.87
(2H, br s), 8.63 (1H, s). MS (FAB) m / z 155 (M + H) ^<+> .

Example 1 1-[[(6RS) -6-aminomethyl-5,6,7,
8-tetrahydronaphthalen-2-yl] carbonyl]
-4-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride 1-[[(6RS) -6- (N-tert-butoxycarbonylaminomethyl) -5,6,7,8-tetrahydronaphthalene -2-yl] carbonyl] -4-[(6-
Chloronaphthalen-2-yl) sulfonyl] piperazine (0.22 g) was dissolved in saturated ethanol (5 ml) in hydrochloric acid, stirred at room temperature for 90 minutes, and the solvent was distilled off under reduced pressure. Recrystallization from the mixed solvent gave the title compound (0.14 g, 68%). ¹ H NMR (DMSO-d ₆ ) δ1.30-1.50
(1H, m), 1.90-2.10 (2H, m), 2.
40-2.60 (1H, m), 2.60-3.00 (5
H, m), 3.03 (4H, m), 3.40-3.80.
(4H, br), 7.00-7.10 (3H, m),
7.73 (1H, dd, J = 8.8, 2.0 Hz),
7.81 (1H, dd, J = 8.8, 1.5 Hz),
8.05 (3H, br), 8.18 (1H, d, J =
8.3 Hz), 8.20-8.30 (2H, m), 8.
49 (1H, s). MS (FAB) m / z 498 [(M + H) ⁺ , C
l ³⁵ ], 500 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 26 H 28 CIN 3 O} 3 S · HCl · 3 / 2H 2
Calculated as O: C, 55.61; H, 5.74; N, 7.4
8; Cl, 12.63; S, 5.71. Analytical values: C, 55.64; H, 5.53; N, 7.7.
7; Cl, 12.79; S, 5.76.

Example 2 1-[[(6RS) -6-aminomethyl-5,6,7,
8-tetrahydronaphthalen-2-yl] methyl] -4
-[(6-chloronaphthalen-2-yl) sulfonyl]
Piperazine hydrochloride As in Example 1, 1-[[(6RS) -6- (Nt
tert-butoxycarbonylaminomethyl) -5,6
7,8-tetrahydronaphthalen-2-yl] methyl]
The title compound was obtained using -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a starting material. ¹ H NMR (DMSO-d ₆ ) δ1.30-1.50
(1H, m), 2.00-2.10 (2H, m), 2.
40-2.60 (1H, m), 2.60-3.00 (7
H, m), 3.00-3.20 (2H, m), 3.30
-3.50 (2H, m), 3.82 (2H, m), 4.
22 (2H, br), 7.00-7.10 (1H,
m), 7.25 (2H, s), 7.73 (1H, dd,
J = 8.8, 2.4 Hz), 7.81 (1H, dd, J
= 8.8, 1.5 Hz), 8.00-8.40 (6H,
m), 8.52 (1H, s), 11.08 (1H, b
r). MS (FAB) m / z 484 [(M + H) ⁺ , C
l ³⁵ ], 486 [(M + H) ⁺ , Cl ³⁷ ]. Elemental analysis: C ₂₆ H ₃₀ ClN ₃ O ₂ S.2HCl Calculated: C, 56.07; H, 5.79; N, 7.5
4; Cl, 19.10; S, 5.76. Analytical values: C, 56.04; H, 5.79; N, 7.5.
2; Cl, 18.95; S, 5.80.

Example 3 1-[[(2RS) -6-aminomethyl-1,2,3,3
4-tetrahydronaphthalen-2-yl] methyl] -4
-[(6-chloronaphthalen-2-yl) sulfonyl]
Piperazine hydrochloride As in Example 1, 1-[[(2RS) -6- (Nt
ert-butoxycarbonylaminomethyl) -1,2,2
3,4-tetrahydronaphthalen-2-yl] methyl]
The title compound was obtained using -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a starting material. ¹ H NMR (DMSO-d ₆ ) δ1.30-1.50
(1H, m), 2.00-2.20 (1H, m), 2.
20-2.40 (1H, m), 2.40-2.60 (1
H, m), 2.75 (2H, m), 2.90-3.30
(7H, m), 3.60-3.70 (2H, m), 3.
70-4.00 (4H, m), 7.04 (1H, d, J
= 7.8 Hz), 7.10-7.30 (2H, m),
7.74 (1H, m), 7.86 (1H, d, J = 8.
8 Hz), 8.20-8.50 (6H, m), 8.56
(1H, s), 10.69 (1H, br). MS (FAB) m / z 484 [(M + H) ⁺ , C
l ³⁵ ], 486 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 26 H 30 ClN 3 O} 2 S · 2HCl · 1 / 2H
Calculated as ₂ O: C, 55.18; H, 5.88; N, 7.4
2; Cl, 18.79; S, 5.66. Analytical values: C, 55.34; H, 5.70; N, 7.3.
1; Cl, 18.76; S, 5.85.

Example 4 1-[[(2RS) -6-aminomethyl-1,2,3,3
4-tetrahydronaphthalen-2-yl] carbonyl]
-4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride 1-[[(2RS) -6- (N-t) in the same manner as in Example 1.
ert-butoxycarbonylaminomethyl) -1,2,2
The title compound was obtained using 3,4-tetrahydronaphthalen-2-yl] carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a starting material. ¹ H NMR (DMSO-d ₆ ) δ 1.55 (1H,
m), 1.80-1.90 (1H, m), 2.60-
2.90 (4H, m), 2.90-3.10 (5H,
m), 3.50-3.80 (4H, m), 3.90 (2
H, s), 7.05 (1H, d, J = 7.8 Hz),
7.10-7.20 (2H, m), 7.71 (1H,
d, J = 8.8 Hz), 7.82 (1H, d, J = 8.
3 Hz), 8.10-8.40 (6H, m), 8.50
(1H, s). MS (FAB) m / z 498 [(M + H) ⁺ , C
l ³⁵ ], 500 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 26 H 28 ClN 3 O} 3 S · 1.2HCl · 0.
8H ₂ O Calculated: C, 56.15; H, 5.58 ; N, 7.5
5; Cl, 14.02; S, 5.76. Analytical values: C, 55.93; H, 5.22; N, 7.3.
7; Cl, 14.26; S, 5.70.

Example 5 1-[(7-Aminomethylnaphthalen-2-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl)
Sulfonyl] piperazine hydrochloride 1-[[7- (N-tert-butoxycarbonylaminomethyl) naphthalen-2-yl] as in Example 1.
The title compound was obtained using carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a starting material. ¹ H NMR (DMSO-d ₆ ) δ 3.10 (4H, b
r), 3.30-3.90 (4H, br), 4.18
(2H, s), 7.46 (1H, d, J = 8.8H)
z), 7.69 (1H, d, J = 8.8 Hz), 7.7
3 (1H, d, J = 8.8 Hz), 7.83 (1H,
d, J = 8.8 Hz), 7.89 (1H, s), 7.9
0-8.00 (3H, m), 8.19 (1H, d, J =
8.8 Hz), 8.20-8.30 (2H, m), 8.
50 (4H, brs). MS (FAB) m / z 494 [(M + H) ⁺ , C
l ³⁵ ], 496 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 26 H 24 ClN 3 O} 3 S · HCl · 3 / 4H 2
Calculated as O: C, 57.41; H, 4.91; N, 7.7
2; Cl, 13.03; S, 5.89. Analytical values: C, 57.40; H, 4.87; N, 7.7.
1; Cl, 13.09; S, 5.89.

Example 6 1-[(7-Aminomethylnaphthalen-2-yl) methyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride 1-[(7-aminomethylnaphthalen-2-yl) methyl] piperazine hydrochloride [[7- (N-tert-butoxycarbonylaminomethyl) naphthalen-2-yl]
Methyl] -4-[(6-chloronaphthalen-2-yl)
The title compound was obtained using [sulfonyl] piperazine as a raw material. ¹ H NMR (DMSO-d ₆ ) δ 2.92 (2H,
m), 3.22 (2H, m), 3.83 (2H, m),
4.20 (2H, d, J = 5.4 Hz), 4.51 (2
H, br), 7.60-7.90 (4H, m), 7.9.
0-8.40 (7H, m), 8.52 (1H, s),
8.57 (3H, br), 11.52 (1H, br). MS (FAB) m / z 480 [(M + H) ⁺ , C
l ³⁵ ], 482 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 26 H 26 ClN 3 O} 2 S · 2HCl · 1 / 4H
Calculated for ₂ O: C, 56.02; H, 5.15; N, 7.5
4; Cl, 19.08; S, 5.75. Analytical values: C, 55.88; H, 5.45; N, 7.3.
4; Cl, 18.90; S, 5.69.

Example 7 1-[(6-Aminomethylnaphthalen-2-yl) carbonyl] -4-[(6-chloronaphthalen-2-yl)
Sulfonyl] piperazine hydrochloride 2- (N-tert-butoxycarbonylaminomethyl) -6-methoxycarbonylnaphthalene (0.15
g) was dissolved in tetrahydrofuran (5 ml), 1N sodium hydroxide (0.70 ml) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with dichloromethane, and diluted hydrochloric acid was added to separate an organic layer. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was dissolved in N, N-dimethylformamide (5 ml), and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride was used. (0.21 g), N-methylmorpholine (54.0 μl), 1- (3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (9
4.0 mg), 1-hydroxybenzotriazole (7
7.0 mg) and stirred at room temperature for 21 hours. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and washed with water. After drying over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue obtained was purified by silica gel column chromatography (dichloromethane to dichloromethane: methanol = 100: 1), and the same reaction as in Example 1 was carried out to obtain colorless crystals. To give the title compound (77.0 g, 29%). ¹ H NMR (DMSO-d ₆ ) δ 3.09 (4H, b
r), 3.40-3.90 (4H, br), 4.19
(2H, s), 7.47 (1H, d, J = 8.3H
z), 7.66 (1H, d, J = 8.3 Hz), 7.7
3 (1H, d, J = 9.3 Hz), 7.83 (1H,
d, J = 8.8 Hz), 7.90-8.10 (4H,
m), 8.19 (1H, d, J = 8.8 Hz), 8.2
0-8.30 (2H, m), 8.40-8.60 (4
H, m). MS (FAB) m / z 494 [(M + H) ⁺ , C
l ³⁵ ], 496 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 26 H 24 ClN 3 O} 3 S · HCl · 3 / 4H 2
O, 1 / 5Et ₂ O Calculated: C, 57.60; H, 5.14; N, 7.5
2; Cl, 12.69; S, 5.74. Analytical values: C, 57.64; H, 5.10; N, 7.1.
2; Cl, 12.69; S, 5.82.

Example 8 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(isoquinolin-7-yl) carbonyl]
Piperazine hydrochloride methyl 7-isoquinolinecarboxylate (J. Org. Ch)
em. , 38 (21), 3701, 1973) (206
mg) was dissolved in 4N hydrochloric acid, heated under reflux for 4 hours, and the solvent was distilled off under reduced pressure.
-Chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride was used as a starting material, and the title compound (298 mg, 62%) was obtained in the same reaction as in Example 7. ¹ H NMR (DMSO-d ₆ ) δ 2.95-3.25
(4H, m), 3.40-3.60 (2H, m), 3.
70-3.90 (2H, m), 7.73 (1H, dd,
J = 8.8, 2.0 Hz), 7.84 (1H, d, J =
8.8 Hz), 8.05 (1H, d, J = 7.3H)
z), 8.20 (1H, d, J = 8.8 Hz), 8.2
5-8.35 (3H, m), 8.41 (1H, d, J =
6.4 Hz), 8.45 (1 H, s), 8.52 (1
H, s), 8.71 (1H, d, J = 6.4 Hz),
9.79 (1H, s). MS (FAB) m / z 465 [(M + H) ⁺ , C
l ³⁵ ], 467 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 24 H 20 ClN 3 O} 3 S · HCl · 2.2H 2
Calculated as O: C, 53.18; H, 4.72; N, 7.7
5; Cl, 13.08; S, 5.92. Analytical values: C, 53.11; H, 4.70; N, 7.6.
0; Cl, 13.01; S, 6.16.

Example 9 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(quinolyl-2-yl) carbonyl] piperazine hydrochloride

[1017]

Embedded image By a reaction similar to that in Example 7, the title compound was obtained using quinoline-2-carboxylic acid and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as starting materials. ¹ H NMR (DMSO-d ₆ ) δ 3.05 (2H,
m), 3.17 (2H, m), 3.62 (2H, m),
3.83 (2H, m), 7.61 (1H, d, J = 8.
3Hz), 7.60-7.80 (2H, m), 7.80
−7.90 (2H, m), 7.95 (1H, d, J =
8.3 Hz), 8.00 (1H, d, J = 7.3H)
z), 8.18 (1H, d, J = 8.8 Hz), 8.2
0-8.40 (2H, m), 8.43 (1H, d, J =
8.3 Hz), 8.51 (1H, s). Elemental analysis: as C ₂₄ H ₂₀ ClN ₃ O ₃ S Calculated: C, 61.87; H, 4.33; N, 9.0
2; Cl, 7.61; S, 6.88. Analytical values: C, 61.76; H, 4.20; N, 8.7.
3; Cl, 7.65; S, 6.99.

Example 10 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(4-hydroxyquinolin-2-yl) carbonyl] piperazine hydrochloride By the same reaction as in Example 7, 4 -Hydroxyquinoline-2-carboxylic acid, 1-[(6-chloronaphthalene-2
-Yl) sulfonyl] piperazine hydrochloride as a starting material to obtain the title compound. ¹ H NMR (DMSO-d ₆ ) δ 3.00-3.30
(4H, br), 3.53 (2H, br), 3.77
(2H, br), 6.45 (1H, s), 7.48 (1
H, t, J = 7.3 Hz), 7.70-7.90 (4
H, m), 8.10-8.40 (4H, m), 8.52
(1H, s). MS (FAB) m / z 482 [(M + H) ⁺ , C
l ³⁵ ], 484 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 24 H 20 ClN 3 O} 4 S · 9 / 10HCl · 1
_{/ 3CH 3 OH, 3 / 2H} 2 O Calculated: C, 52.90; H, 4.60 ; N, 7.6
1; Cl, 12.19; S, 5.80. Analytical values: C, 53.17; H, 4.59; N, 7.3.
9; Cl, 12.31; S, 6.07.

Example 11 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(8-hydroxyquinolin-7-yl) carbonyl] piperazine hydrochloride -Hydroxyquinoline-7-carboxylic acid, 1-[(6-chloronaphthalene-2
-Yl) sulfonyl] piperazine hydrochloride as a starting material to obtain the title compound. ¹ H NMR (DMSO-d ₆ ) δ 2.90-3.30
(4H, br), 3.35 (2H, br), 3.79
(2H, br), 7.39 (1H, d, J = 8.3H
z), 7.53 (1H, d, J = 8.3 Hz), 7.6
0-7.90 (3H, m), 8.10-8.40 (3
H, m), 8.50 (1H, s), 8.60 (1H,
d, J = 7.8 Hz), 8.96 (1H, d, J = 4.
4 Hz). MS (FAB) m / z 482 [(M + H) ⁺ , C
l ³⁵ ], 484 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 24 H 20 ClN 3 O} 4 S · HCl · CH 3 OH
· 1 / 4H ₂ O Calculated: C, 54.11; H, 4.63 ; N, 7.5
7; Cl, 12.78; S, 5.78. Analytical values: C, 54.40; H, 4.84; N, 7.6.
6; Cl, 13.04; S, 5.99.

Example 12 1-[(benzimidazol-5-yl) carbonyl]-
4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride

[1021]

Embedded image The title compound was obtained by a reaction similar to that of Example 7 using methyl N-triphenylmethyl-5-benzimidazolecarboxylate and 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as starting materials. . ¹ H NMR (DMSO-d ₆ ) δ 3.08 (4H, b
r), 3.30-4.00 (4H, br), 7.48
(1H, d, J = 8.3 Hz), 7.60-7.90
(4H, m), 8.10-8.30 (3H, m), 8.
50 (1H, s), 9.51 (1H, s). MS (FAB) m / z 455 [(M + H) ⁺ , C
l ³⁵ ], 457 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 22 H 19 ClN 4 O} 3 S · HCl · 5 / 4H 2
Calculated as O: C, 51.42; H, 4.41; N, 10.9
0; Cl, 13.80; S, 6.24. Analytical values: C, 51.53; H, 4.40; N, 10.7
1; Cl, 13.61; S, 6.40.

Example 13 1-[(Benzimidazol-5-yl) carbonyl]-
4-[(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine hydrochloride methyl N-triphenylmethyl-5-benzimidazolecarboxylate, 1-[(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine The title compound was obtained by the same reaction as in Example 12 using the hydrochloride as a raw material. ¹ H NMR (DMSO-d ₆ ) δ 1.67 (1H,
m), 1.93 (1H, m), 3.20-3.90 (8
H, m), 7.44 (1 / 2H, m), 7.54 (1 /
2H, m), 7.68 (1H, m), 7.80-8.0
0 (3H, m), 8.10-8.30 (3H, m),
8.49 (1 / 2H, s), 8.55 (1 / 2H,
s), 9.56 and 9.57 (1H, each
s). MS (FAB) m / z 469 [(M + H) ⁺ , C
l ³⁵ ], 471 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 23 H 21 ClN 4 O} 3 S · HCl · 0.3CH
Calculated as ₃ OH.H ₂ O: C, 52.50; H, 4.76; N, 10.5
1; Cl, 13.30; S, 6.01. Analytical values: C, 52.31; H, 4.66; N, 10.5
0; Cl, 13.34; S, 6.01.

Example 14 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(thiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine hydrochloride By the same reaction as in Example 7, thiazolo [5,4-c]
Pyridine-2-carboxylic acid sodium salt, 1-[(6-
The title compound was obtained using chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride as a starting material. ¹ H NMR (DMSO-d ₆ ) δ 3.10-3.30
(4H, m), 3.84 (2H, m), 4.32 (2
H, m), 7.69 (1H, dd, J = 8.8, 2.0
Hz), 7.83 (1H, dd, J = 8.8, 2.0H)
z), 8.10-8.30 (4H, m), 8.51 (1
H, s), 8.79 (1H, d, J = 5.9 Hz),
9.62 (1H, s). MS (FAB) m / z 473 [(M + H) ⁺ , C
l ³⁵ ], 475 [(M + H) ⁺ , Cl ³⁷ ]. Elemental analysis: C ₂₁ H ₁₇ ClN ₄ O ₃ S ₂ .HCl Calculated: C, 49.51; H, 3.56; N, 11.0
0; Cl, 13.92; S, 12.59. Analytical values: C, 49.45; H, 3.71; N, 11.2.
0; Cl, 13.67; S, 12.55.

Example 15 1-[(E) -4-Chlorostyrylsulfonyl] -4-
[(Thiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride By the same reaction as in Example 7, thiazolo [5,4-c]
Pyridine-2-carboxylic acid sodium salt, 1-[(E)
The title compound was obtained using -4-chlorostyrylsulfonyl) piperazine hydrochloride as a raw material. ¹ H NMR (DMSO-d ₆ ) δ 3.30 (4H,
m), 3.87 (2H, m), 4.35 (2H, m),
7.35 (1H, d, J = 15.6 Hz), 7.40 −
7.50 (3H, m), 7.79 (1H, d, J = 8.
3Hz), 8.22 (1H, d, J = 5.9Hz),
8.77 (1H, d, J = 5.9 Hz), 9.59 (1
H, s). MS (FAB) m / z 449 [(M + H) ⁺ , C
l ³⁵ ], 451 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 19 H 17 ClN 4 O} 3 S2 · 1 / 2HCl Calculated: C, 48.85; H, 3.78 ; N, 11.9
9; Cl, 11.38; S, 13.73. Analytical values: C, 49.18; H, 3.80; N, 12.2
0; Cl, 11.05; S, 13.84.

Example 16 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl ] Piperazine hydrochloride 1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,
2-c] pyridin-2-yl) methyl] -4-[(6-
The title compound was obtained using chloronaphthalen-2-yl) sulfonyl] piperazine as a raw material. ¹ H NMR (DMSO-d ₆ ) δ 2.82-2.88
(4H, m), 2.91-2.99 (4H, m), 3.
28-3.36 (2H, m), 3.47-3.55 (4
H, m), 4.02 (2H, brs), 6.58 (1
H, s), 7.71 (1H, dd, J = 8.8, 2.0
Hz), 7.81 (1H, dd, J = 8.8, 2.0H)
z), 7.23-7.28 (3H, m), 8.49 (1
H, s), 9.42 (2H, br s). MS (FAB) m / z 462 [(M + H) ⁺ , C
l ³⁵ ], 464 [(M + H) ⁺ , Cl ³⁷ ].

Example 17 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4- [trans-3- (4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2 -Yl) propenoyl] piperazine hydrochloride By the same reaction as in Example 1, 1- [trans-3-
(5-tert-butoxycarbonyl-4,5,6,7
-Tetrahydrothieno [3,2-c] pyridin-2-yl) propenoyl] -4-[(6-chloronaphthalene-
The title compound was obtained using 2-yl) sulfonyl] piperazine as a starting material. ¹ H NMR (DMSO-d ₆ ) δ 2.95-3.10
(6H, m), 3.32-3.51 (3H, m), 3.
60-3.80 (3H, m), 4.12 (2H, s),
6.75 (1H, d, J = 15.1 Hz), 7.19
(1H, s), 7.50 (1H, d, J = 15.1H)
z), 7.70 (1H, dd, J = 8.8, 2.4H
z), 7.81 (1H, dd, J = 8.8, 2.0H
z), 8.15 (1H, d, J = 8.8 Hz), 8.2
2 (1H, d, J = 2.0 Hz), 8.50 (1H,
s), 9.53 (2H, br s). MS (FAB) m / z 502 [(M + H) ⁺ , C
l ³⁵ ], 504 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 24 H 24 ClN 3 O} 3 S 2 · HCl · 0.5H 2
As O: Calcd: C, 52.65; H, 4.79; Cl, 12.
95; N, 7.67; S, 11.71. Analytical values: C, 52.36; H, 4.88; Cl, 12.
63; N, 8.01; S, 11.39.

Example 18 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4- [3- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl ) Propionyl]
Piperazine hydrochloride 1- [3- (5-ter) by the same reaction as in Example 1.
Starting from t-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propionyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine To give the title compound. ¹ H NMR (DMSO-d ₆ ) δ 2.80-3.60
(16H, m), 4.12 (2H, brs), 7.1
1 (1H, brs), 7.74 (1H, dd, J =
8.8, 2.0 Hz), 7.83 (1H, dd, J =
8.8, 2.0 Hz), 8.20 (1H, s), 8.2
5-8.30 (2H, m), 8.53 (1H, s),
9.67 (2H, brs). MS (FAB) m / z 504 [(M + H) ⁺ , C
l ³⁵ ], 506 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 24 H 26 ClN 3 O} 3 S 2 · 1.2HCl ·
1.3 H ₂ O Calculated: C, 50.46; H, 5.26; Cl, 13.
65; N, 7.36. Analytical values: C, 50.83; H, 5.26; Cl, 13.
43; N, 6.97.

Example 19 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4- [3- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl )) Propyl] piperazine hydrochloride 1- [3- (5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) propyl ] -4-
The title compound was obtained using [(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a starting material. ¹ H NMR (DMSO-d ₆ ) δ 1.90-2.07
(2H, m), 2.72-2.80 (2H, m), 2.
82-3.21 (8H, m), 3.35 (2H, br
s), 3.51 (2H, d, J = 11.5 Hz);
82 (2H, d, J = 11.5 Hz), 4.06 (2
H, s), 6.66 (1H, s), 7.74 (1H, d
d, J = 8.8, 1.5 Hz), 7.85 (1H, d
d, J = 8.8, 1.5 Hz), 8.20 (1H, d,
J = 8.8 Hz), 8.25-8.39 (2H, m),
8.55 (1H, s), 9.50 (2H, brs),
11.26 (1H, brs). MS (FAB) m / z 490 [(M + H) ⁺ , C
l ³⁵ ], 492 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 24 H 28 ClN 3 O} 2 S 2 · 2HCl · 1.6
H ₂ O Calculated: C, 48.71; H, 5.65 ; Cl, 17.
97; N, 7.10; S, 10.84. Analytical values: C, 49.01; H, 5.77; Cl, 17.
62; N, 6.96; S, 10.82.

Example 20 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4- [N-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2- Yl) methyl] carbamoyl] piperazine hydrochloride 1- [N-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2) as in Example 1. The title compound was obtained using -yl) methyl] carbamoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a starting material. _{^{1 H NMR (DMSO-d 6}} ) δ2.78-2.86
(2H, brs), 2.88-2.94 (4H, brs).
m), 3.29-3.35 (2H, m), 3.37-
3.42 (4H, m), 4.03 (2H, brs),
4.19 (2H, d, J = 5.4 Hz), 6.62 (1
H, s), 7.25 (1H, t, J = 5.4 Hz),
7.72 (1H, dd, J = 8.8, 2.0 Hz),
7.82 (1H, dd, J = 8.8, 2.0 Hz),
8.16 (1H, d, J = 8.8 Hz), 8.22-
8.26 (2H, m), 8.50 (1H, s), 9.2
7 (2H, brs). Elemental _{analysis: C 23 H 25 ClN 4 O} 3 S 2 · HCl · 1.3H 2
For O: C, 48.90; H, 5.10; Cl, 12.
55; N, 9.92. Analytical values: C, 49.02; H, 5.20; Cl, 12.
50; N, 9.76.

Example 21 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl ] Piperazine hydrochloride 1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,
2-c] pyridin-2-yl) carbonyl] -4-
The title compound was obtained using [(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a starting material. ¹ H NMR (DMSO-d ₆ ) δ 2.99-3.05
(2H, m), 3.08 (4H, t, J = 4.6H
z), 3.35-3.40 (2H, m), 3.71 (4
H, t, J = 4.6 Hz), 4.11 (2H.s),
7.17 (1H, s), 7.71 (1H, dd, J =
8.8, 2.0 Hz), 7.82 (1H, dd, J =
8.8, 2.0 Hz), 8.22-8.28 (3H,
m), 8.50 (1H, s), 9.38 (2H, br)
s). MS (FAB) m / z 476 [(M + H) ⁺ , C
l ³⁵ ], 478 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 22 H 23 ClN 3 O} 3 S 2 · HCl · 3 / 2H 2
As O: Calcd: C, 48.98; H, 4.86; Cl, 13.
14; N, 7.79; S, 11.89. Analytical values: C, 48.96; H, 4.67; Cl, 13.
21; N, 7.74; S, 11.93.

Example 22 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonyl-1-[(4,5,6,
7-tetrahydrothieno [3,2-c] pyridine-2-
Yl) carbonyl] piperazine hydrochloride By the same reaction as in Example 1, 1-[(5-tert-
Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl]
The title compound was obtained using -4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-ethoxycarbonylpiperazine as a starting material. ¹ H NMR (DMSO-d ₆ ) δ 1.22 (3H, t,
J = 7.0 Hz), 2.38-2.58 (1H, m),
2.65-2.72 (1H, m), 3.04 (2H, b
rs), 3.29-3.43 (3H, m), 3.70.
(1H, brs), 4.01-4.30 (6H,
m), 5.18 (1H, brs), 7.27 (1H,
s), 7.73 (1H, dd, J = 8.8, 2.0H
z), 7.82 (1H, d, J = 8.8 Hz), 8.2
6 (1H, s), 8.29 (1H, s), 8.54 (1
H, s), 9.59 (2H, br s). MS (FAB) m / z 548 [(M + H) ⁺ , C
l ³⁵ ], 550 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 25 H 26 N 3 ClO} 5 S 2 · 1.2HCl ·
0.6 H ₂ O Calculated: C, 49.83; H, 4.75; Cl, 12.
94; N, 6.97; S, 10.64. Analytical values: C, 49.62; H, 4.71; Cl, 13.
30; N, 7.19; S, 10.56.

Example 23 2-Carboxy-4-[(6-chloronaphthalene-2-
Yl) sulfonyl] -1-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] piperazine hydrochloride 4-[(6-chloronaphthalen-2-yl) Sulfonyl] -2-ethoxycarbonyl-1-[(4,5,6,
7-tetrahydrothieno [3,2-c] pyridine-2-
Il) carbonyl] piperazine hydrochloride (95 mg) was dissolved in tetrahydrofuran (1 ml), ethanol (2 ml) and 1 N sodium hydroxide (3 ml) were added, and the mixture was heated under reflux for 30 minutes. 4N hydrochloric acid (2m
l) was added and the resulting precipitate was collected by filtration and the title compound (8) was added.
(3 mg, 90%) as a colorless foam. ¹ H NMR (DMSO-d ₆ ) δ2.30-2.53
(1H, m), 2.58-2.69 (1H, m), 3.
04 (2H, brs), 3.29-3.83 (4H,
m), 4.07-4.32 (4H, m), 4.90-
5.20 (1H, m), 7.03-7.30 (1H,
m), 7.71 (1H, dd, J = 8.8, 2.4H
z), 7.81 (1H, d, J = 8.8 Hz), 8.8
1 (1H, d, J = 8.8 Hz), 8.20-8.29
(2H, m), 8.52 (1H, s), 9.58 (2
H, brs). MS (FAB) m / z 520 [(M + H) ⁺ , C
l ³⁵ ], 522 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 23 H 22 N 3 ClO} 5 S 2 · 1.2HCl ·
0.8 H ₂ O Calculated: C, 47.78; H, 4.32; Cl, 13.
49; N, 7.27; S, 11.09. Analytical values: C, 47.41; H, 4.36; Cl, 13.
81; N, 7.14; S, 11.01.

Example 24 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(5-aminohydroxyiminomethyl-
4,5,6,7-Tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] piperazine In methanol (4 ml), 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4- [(5-cyano-
4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] piperazine (41 m
g) in dichloromethane (dichloromethane 1 ml) was added, hydroxylamine hydrochloride (28 mg) and triethylamine (0.55 ml) were added, and the mixture was stirred at room temperature for 2 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (dichloromethane to dichloromethane: methanol = 100: 3) to obtain the title compound (14 mg, 32%). _{^{1 H NMR (DMSO-d 6}} ) δ2.74-2.79
(2H, m), 3.06 (4H, s), 3.35-3.
38 (2H, m), 3.71 (4H, s), 4.07
(2H, s), 5.32 (2H, s), 7.08 (1
H, s), 7.71 (1H, dd, J = 8.8, 1.6)
Hz), 7.81 (1H, dd, J = 8.8, 1.6H)
z), 8.16 (1H, s), 8.23-8.25 (2
H, m), 8.33 (1H, brs), 8.49 (1
H, s). MS (FAB) m / z 534 [(M + H) ⁺ , C
l ³⁵ ], 536 [(M + H) ⁺ , Cl ³⁷ ].

Example 25 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4- [N- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl ) Carbamoyl]
Piperazine hydrochloride By the same reaction as in Example 1, 1- [N- (5-ter
Starting material of t-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbamoyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine To give the title compound. ¹ H NMR (DMSO-d ₆ ) δ 2.83 (2H, br
s), 2.99 (4H, br s), 3.30 (2
H, br s), 3.54 (4H, br s), 4.0.
0 (2H, s), 6.33 (1H, s), 7.70 (1
H, dd, J = 8.8, 2.0 Hz), 7.82 (1
H, d, J = 8.8 Hz), 8.16 (1H, d, J =
8.8 Hz), 8.22 (1 H, s), 8.26 (1
H, d, J = 8.8 Hz), 8.50 (1H, s),
9.18 (2H, brs), 9.82 (1H, s). MS (FAB) m / z 491 [(M + H) ⁺ , C
l ³⁵ ], 493 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 22 H 23 N 4 ClO} 3 S 2 · HCl · 0.3H 2
As O: Calcd: C, 49.59; H, 4.65; Cl, 13.
31; N, 10.51; S, 12.03. Analytical values: C, 49.32; H, 4.63; Cl, 13.
34; N, 10.81; S, 12.03.

Example 26 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4- [N-methyl-N- (4,5,6,7-tetrahydrothieno [3,2-c] pyridine -2-yl) carbamoyl] piperazine hydrochloride By the same reaction as in Example 1, 1- [N- (5-ter
t-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) -N-methylcarbamoyl] -4-[(6-chloronaphthalene-
The title compound was obtained using 2-yl) sulfonyl] piperazine as a starting material. ¹ H NMR (DMSO-d ₆ ) δ 2.83 (2H, t,
J = 5.4 Hz), 2.97 (4H, brs), 3.
10 (3H, s), 3.28-3.41 (6H, m),
4.00 (2H, s), 6.35 (1H, s), 7.7
2 (1H, dd, J = 8.8, 2.0 Hz), 7.81
(1H, dd, J = 8.8, 2.0 Hz), 8.17
(1H, d, J = 8.8 Hz), 8.23-8.31
(2H, m), 8.50 (1H, s), 9.28 (2
H, brs). MS (FAB) m / z 505 [(M + H) ⁺ , C
l ³⁵ ], 507 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 23 H 25 N 4 ClO} 3 S 2 · 1.1HCl ·
0.5 H ₂ O Calculated: C, 49.85; H, 4.93; Cl, 13.
43; N, 10.11; S, 11.57. Analytical values: C, 49.55; H, 4.92; Cl, 13.
23; N, 10.13; S, 11.83.

Example 27 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[[5- (1-pyrolin-2-yl) -4,
5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl] carbonyl] piperazine hydrochloride 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5 6,7-Tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] piperazine hydrochloride (400 mg) was dissolved in N, N-dimethylformamide (20 ml), and triethylamine (0.16 ml), Methoxypyrroline (464m
g) was added and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, and the resulting precipitate was collected by filtration.
The title compound (411 mg, 88%) was obtained as a pale yellow foamy solid. ¹ H NMR (DMSO-d ₆ ) δ 2.07-2.18
(2H, m), 2.90-3.11 (8H, m), 3.
62 (2H, t, J = 6.8 Hz), 3.72 (4H,
br), 3.80 (2H, t, J = 5.9 Hz);
99 (2H, t, J = 5.9 Hz), 4.62 (1H,
brs), 4.73 (1H, brs), 7.10
(1H, s), 7.50 (1H, s), 7.72 (1
H, dd, J = 8.8, 2.0 Hz), 7.82 (1
H, dd, J = 8.8, 2.0 Hz), 8.18 (1
H, d, J = 8.8 Hz), 8.22-8.28 (2
H, m), 8.51 (1H, s), 10.37 (1H,
br s), 10.53 (1H, br s). MS (FAB) m / z 542 [(M + H) ⁺ , C
l ³⁵ ], 544 [(M + H) ⁺ , Cl ³⁷ ]. Elemental analysis: C ₂₆ H ₂₇ ClN ₄ O ₃ S ₂ .1.3HCl.
0.4 H ₂ O Calculated: C, 52.25; H, 4.91; Cl, 13.
64; N, 9.37; S, 10.73. Analytical values: C, 52.34; H, 5.03; Cl, 13.
56; N, 9.36; S, 10.74.

Example 28 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) Carbonyl] piperazine hydrochloride 1-[(6-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]- 4
-[(6-chloronaphthalen-2-yl) sulfonyl]
The title compound was obtained using piperazine as a raw material. ¹ H NMR (DMSO-d ₆ ) δ 3.01 (2H, t,
J = 5.9 Hz), 3.11 (4H, br), 3.44
(2H, br s), 3.74 (2H, br s),
4.32-4.46 (4H, m), 7.71 (1H, d
d, J = 8.8, 2.0 Hz), 7.83 (1H, d
d, J = 8.8 Hz, 2.0 Hz), 8.15 (1H,
d, J = 8.8 Hz), 8.23 (1H, s), 8.2
6 (1H, d, J = 8.8 Hz), 8.30 (1H, d, J = 8.8 Hz)
s). MS (FAB) m / z 477 [(M + H) ⁺ , C
l ³⁵ ], 479 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 21 H 21 ClN 4 O} 3 S 2 · HCl · 0.2H 2
As O: Calcd: C, 48.78; H, 4.37; Cl, 13.
71; N, 10.84; S, 12.40. Analytical values: C, 48.60; H, 4.50; Cl, 13.
58; N, 10.62; S, 12.29.

Example 29 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(5-aminohydroxyiminomethyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine hydrochloride and 1-[(5-carbamoyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4- [ (6-chloronaphthalene-2
-Yl) sulfonyl] piperazine By the same reaction as in Reference Example 344, Example 24, 1-
[(6-chloronaphthalen-2-yl) sulfonyl]-
4-[(4,5,6,7-tetrahydrothiazolo [5
Starting from 4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-aminohydroxyiminomethyl-4,5, 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl
In addition to obtaining piperazine hydrochloride, 1-[(5-carbamoyl-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] -4-[(6
-Chloronaphthalen-2-yl) sulfonyl] piperazine.

1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(5-aminohydroxyiminomethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazine hydrochloride ¹ H NMR (DMSO-d ₆ ) δ 2.77 (2H, br
s), 3.09 (4H, br), 3.48 (2H,
t, J = 5.4 Hz), 3.73 (2H, brs),
4.30-4.50 (4H, m), 5.61 (1H, b
rs), 7.71 (1H, dd, J = 8.8, 2.0
Hz), 7.82 (1H, dd, J = 8.8 Hz, 2.
0 Hz), 8.15 (1H, d, J = 8.8 Hz),
8.22 (1H, d, J = 1.5 Hz), 8.25 (1
H, d, J = 8.8 Hz), 8.50 (1H, s),
8.53 (1H, brs). MS (FAB) m / z 535 [(M + H) ⁺ , C
l ³⁵ ], 537 [(M + H) ⁺ , Cl ³⁷ ].

1-[(5-carbamoyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine ¹ H NMR (DMSO-d ₆ ) δ 2.75 (2H, br
s), 3.09 (4H, br), 3.63 (2H,
t, J = 5.9 Hz), 3.73 (2H, brs),
4.39 (2H, brs), 4.59 (2H, s),
6.17 (2H, s), 7.70 (1H, dd, J =
8.8, 2.0 Hz), 7.82 (1H, dd, J =
8.8 Hz, 2.0 Hz), 8.14 (1 H, d, J =
8.8 Hz), 8.21 (1H, d, J = 1.5H)
z), 8.25 (1H, d, J = 8.8 Hz), 8.5
0 (1H, s). MS (FAB) m / z 520 [(M + H) ⁺ , C
l ³⁵ ], 522 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 22 H 22 ClN 5 O} 4 S 2 · H 2 O Calculated: C, 49.11; H, 4.50 ; N, 13.0
2. Analytical values: C, 48.98; H, 4.12; N, 12.8.
3.

Example 30 1-[(6-Chloronaphthalen-2-yl) sulfoni
L] -4-[[5- (1-pyrolin-2-yl) -4,
5,6,7-tetrahydrothiazolo [5,4-c] pyri
Zin-2-yl] carbonyl] piperazine hydrochloride 1-[(6-chloronaphthalene-
2-yl) sulfonyl] -4-[(4,5,6,7-te
Trahydrothiazolo [5,4-c] pyridine-2-i
Le) carbonyl] piperazine hydrochloride as a raw material
The title compound was obtained. ¹ 1 H NMR (DMSO-d₆) Δ 2.07-2.15
(2H, m), 2.94-3.16 (8H, m), 3.
63 (2H, t, J = 7.3 Hz), 3.75 (2H, t, J = 7.3 Hz)
br s) 3.90 (2H, br s), 4.39 (2
H, br s), 4.93 (2H, s), 7.70 (1
H, dd, J = 8.8, 2.0 Hz), 7.83 (1
H, dd, J = 8.8 Hz, 2.0 Hz), 8.15
(1H, d, J = 8.8 Hz), 8.22 (1H, d,
J = 2.0 Hz), 8.25 (1H, d, J = 8.8H)
z), 8.50 (1H, s). MS (FAB) m / z 544 [(M + H)⁺, C
l³⁵], 546 [(M + H)⁺, Cl³⁷]. Elemental analysis: C_{twenty five}H₂₆ClN_FiveO_ThreeS_Two・ 1.4 HCl ・ C
H_ThreeAs OH Calcd: C, 49.79; H, 5.05; Cl, 13.
57; N, 11.17; S, 10.23. Analytical values: C, 49.44; H, 4.78; Cl, 13.
63; N, 10.83; S, 10.15.

Example 31 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(5-formyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazine 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(4,5
The title compound was obtained using 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride and formic acid as starting materials. _{^{1 H NMR (DMSO-d 6}} ) δ2.74-2.88
(2H, m), 3.10 (4H, br), 3.31 (2
H, s), 3.66-3.86 (4H, m), 4.64.
-4.73 (2H, m), 7.69 (1H, dd, J =
8.8, 2.0 Hz), 7.82 (1H, dd, J =
8.8, 2.0 Hz), 8.14 (1H, d, J = 8.
8 Hz), 8.15-8.22 (2H, m), 8.24
(1H, d, J = 8.8 Hz), 8.50 (1H,
s). MS (FAB) m / z 505 [(M + H) ⁺ , C
l ³⁵ ], 507 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 22 H 21 ClN 4 O} 4 S 2 · 1 / 5H 2 O Calculated: C, 51.95; H, 4.24 ; Cl, 6.9
7; N, 11.02; S, 12.61. Analytical values: C, 52.18; H, 4.30; Cl, 6.6.
9; N, 10.71; S, 12.21.

Example 32 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazine hydrochloride 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2 -Yl) carbonyl] piperazine hydrochloride (400 mg) in dichloromethane (10
ml) and triethylamine (0.22 m
l), acetic acid (0.05 ml) was added, and the mixture was stirred at room temperature for 5 minutes. Then, a 30% aqueous formaldehyde solution (0.08 ml) and sodium triacetoxyborohydride (264 mg) were added.
Was added and stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After the residue was dissolved in a saturated hydrochloric acid-ethanol solution (1 ml), the reaction solution was concentrated under reduced pressure, and the obtained residue was crystallized from hexane and ethyl acetate to give the title compound (298 m
g, 71%). ¹ H NMR (DMSO-d ₆ ) δ 2.89 (3H,
s), 3.10 (6H, br), 3.32-3.81.
(4H, m), 4.30-4.81 (4H, m), 7.
71 (1H, dd, J = 8.8, 2.0 Hz), 7.8
2 (1H, dd, J = 8.8, 2.0 Hz), 8.15
(1H, d, J = 8.8 Hz), 8.20-8.28
(2H, m), 8.50 (1H, s), 11.28 (1
H, brs). MS (FAB) m / z 491 [(M
+ H) ⁺ , Cl ³⁵ ], 493 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 22 H 23 ClN 4 O} 3 S 2 · HCl · 0.6H 2
For O: C, 49.09; H, 4.72; Cl, 13.
17; N, 10.41; S, 11.91. Analytical values: C, 48.88; H, 4.78; Cl, 13.
26; N, 10.42; S, 12.03.

Example 33 2-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5
5-dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridinium iodide 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-methyl-4 , 5,6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride (200 mg) was treated with N, N-
Dissolved in dimethylformamide (20 ml), methyl iodide (0.05 ml), potassium carbonate (79.0 m
g) was added and the mixture was stirred at 80 ° C. overnight. After the reaction solution was concentrated under reduced pressure, water was added to the residue, and the deposited precipitate was collected by filtration. This was mixed with a dichloromethane / methanol mixed solution (1:
The precipitate was dissolved in 1), ethyl acetate was added, and the resulting precipitate was collected by filtration to give the title compound (144 mg, 56%). ¹ H NMR (DMSO-d ₆ ) δ 3.05-3.23
(12H, m), 3.77 (2H, t, J = 5.9H)
z), 4.40 (2H, brs), 4.79 (2H,
brs), 7.71 (1H, dd, J = 8.8, 2.
0 Hz), 7.83 (1H, dd, J = 8.8, 2.0
Hz), 8.15 (1H, d, J = 8.8 Hz), 8.
20-8.27 (2H, m), 8.52 (1H, s). MS (FD) m / z 505 (M +, Cl 35), 507
(M ⁺ , Cl ³⁷ ). Elemental _{analysis: C 23 H 26 ClIN 4 O} 3 S 2
_{· 1 / 2CH 3 CO 2 CH} 2 CH 3 Calculated: C, 44.35; H, 4.47 ; N, 8.2
8. Analytical values: C, 44.52; H, 4.23; N, 8.0.
1.

Example 34 2-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridine N-oxide 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl) carbonyl] piperazine hydrochloride (400 mg) was suspended in acetone (10 ml), 1N aqueous sodium hydroxide solution (0.38 ml), and 30% aqueous hydrogen peroxide (3.50 m).
After l) was added, the mixture was stirred at room temperature for 8 days. After the reaction solution was concentrated under reduced pressure, the residue was purified by synthetic adsorbent chromatography (Diaion (registered trademark) HP-20, water to water: acetonitrile = 2: 5) to give the title compound (84).
mg, 39%). ¹ H NMR (DMSO-d ₆ ) δ 2.83-2.90
(1H, m), 3.10 (5H, br), 3.20-
3.47 (4H, m), 3.61-3.83 (3H,
m), 4.28-4.50 (3H, m), 4.78-
4.85 (1H, m), 7.69 (1H, dd, J =
8.8, 2.0 Hz), 7.82 (1H, dd, J =
8.8, 2.0 Hz), 8.14 (1H, d, J = 8.
8 Hz), 8.19-8.27 (2H, m), 8.50
(1H, s). MS (FD) m / z 506 (M +, Cl 35), 508
(M ⁺ , Cl ³⁷ ).

Example 35 2-carbamoyl-4-[(6-chloronaphthalene-2
-Yl) sulfonyl] -1-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine trifluoroacetate 1-[(5-t) dissolved in dichloromethane (1 ml)
tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-carbamoyl-4-[(6-chloronaphthalen-2-yl) sulfonyl ] Piperazine (303
After adding trifluoroacetic acid (1 ml), the mixture was concentrated under reduced pressure, and the deposited precipitate was collected by filtration and washed with diethyl ether to obtain the title compound (263 mg, 83%). _{^{1 H NMR (DMSO-d 6}} ) δ2.39-2.70
(2H, m), 2.92-3.06 (2H, m), 3.
42-3.77 (4H, m), 4.25-4.50 (7
/ 2H, m), 4.97 (1 / 2H, brs), 5.
35-5.44 (1 / 2H, m), 6.14 (1/2
H, br s), 7.30-7.39 (1H, m),
7.66-7.73 (2H, m), 7.77-7.82
(1H, m), 8.16 (1H, d, J = 8.8H
z), 8.21-8.28 (2H, m), 8.49 (1
H, s), 9.26 (2H, br s). MS (FA
B) m / z 520 [(M + H) ⁺ , Cl ³⁵ ], 522
[(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 22 H 22 ClN 5 O} 4 S 2 · CF 3 CO 2 H ·
0.6 H ₂ O Calculated: C, 44.29; H, 3.73; Cl, 5.4
0; F, 9.55; N, 10.67; S, 9.77. Analytical values: C, 44.59; H, 3.79; Cl, 5.2.
6; F, 9.54; N, 10.28; S, 9.72.

Example 36 2-carbamoyl-4-[(6-chloronaphthalene-2
-Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride As in Example 32, 2-carbamoyl-4-[(6-
Chloronaphthalen-2-yl) sulfonyl] -1-
[(4,5,6,7-tetrahydrothiazolo [5,4-
c] Pyridin-2-yl) carbonyl] piperazine The title compound was obtained starting from trifluoroacetate. ¹ H NMR (DMSO-d ₆ ) δ2.37-2.70
(2H, m), 2.91 (3H, s), 3.00-3.
78 (6H, m), 4.28-4.77 (7 / 2H,
m), 4.97 (1 / 2H, brs), 5.40-
5.50 (1 / 2H, m), 6.14 (1 / 2H, br)
s), 7.32-7.40 (1H, m), 7.68-
7.75 (2H, m), 7.77-7.83 (1H,
m), 8.15 (1H, d, J = 8.8 Hz), 8.2
1-8.28 (2H, m), 8.49 (1H, s). MS (FAB) m / z 534 [(M + H) ⁺ , C
l ³⁵ ], 536 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 23 H 24 ClN 5 O} 4 S 2 · HCl · 2.5H 2
As O: Calcd: C, 44.88; H, 4.91; Cl, 11.
52; N, 11.38; S, 10.42. Analytical values: C, 44.83; H, 4.89; Cl, 11.
65; N, 11.31; S, 10.46.

Example 37 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[[5- (2-hydroxyethyl) -4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl] piperazine hydrochloride 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride (132 mg) and glyoxylic acid hydrate (82 mg) as starting materials and a reaction similar to that in Example 32. The obtained crude product was treated with tetrahydrofuran (50 m
l), triethylamine (0.22 ml),
Ethyl chloroformate (0.03 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 15 minutes.
g) and water (10 ml) were added, and the mixture was stirred at room temperature for 1 hour.
The reaction solution was concentrated under reduced pressure, diluted with dichloromethane, washed with brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (dichloromethane-dichloromethane: methanol = 100: 3), dissolved in saturated ethanol (1 ml), concentrated under reduced pressure, and concentrated in ethyl acetate. After crushing and washing, the title compound (52 mg, 33%) was obtained. ¹ H NMR (DMSO-d ₆ ) δ 3.11 (4H, br
s), 3.20-3.57 (6H, m), 3.69-
3.87 (4H, m), 4.34-4.82 (4H,
m), 5.38 (1H, brs), 7.71 (1H,
dd, J = 8.8, 2.0 Hz), 7.82 (1H, d
d, J = 8.8 Hz, 2.0 Hz), 8.15 (1H,
d, J = 8.8 Hz), 8.22 (1H, s), 8.2
5 (1H, d, J = 8.8 Hz), 8.50 (1H,
s), 10.48 (1H, br s). MS (FAB) m / z 521 [(M + H) ⁺ , C
l ³⁵ ], 523 [(M + H) ⁺ , Cl ³⁷ ].

By the same reaction as in Example 32, 1-
[(6-chloronaphthalen-2-yl) sulfonyl]-
4-[(4,5,6,7-tetrahydrothiazolo [5
The compounds of Example 38, Example 39, and Example 40 were obtained using 4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride as a raw material.

Example 38 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[[5- (pyridin-2-yl) methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl] carbonyl] piperazine hydrochloride ¹ H NMR (DMSO-d ₆ ) δ 3.07-3.17
(6H, m), 3.63 (2H, t, J = 6.3H
z), 3.74 (2H, brs), 4.39 (2H,
br s), 4.58 (2H, s), 4.61 (2H,
s), 7.50-7.64 (1H, m), 7.67-
7.73 (2H, m), 7.82 (1H, dd, J =
8.8, 1.5 Hz), 7.97 (1H, m), 8.1
5 (1H, d, J = 8.8 Hz), 8.22 (1H,
d, J = 1.5 Hz), 8.25 (1H, d, J = 8.
8Hz), 8.50 (1H, s), 8.69 (1H,
d, J = 4.9 Hz). MS (FAB) m / z 568 [(M + H) ⁺ , C
l ³⁵ ], 570 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 27 H 26 ClN 5 O} 3 S 2 · 2HCl · 0.8
H ₂ O Calculated: C, 49.48; H, 4.55 ; Cl, 16.
23; N, 10.68; S, 9.78. Analytical values: C, 49.72; H, 4.48; Cl, 16;
31; N, 10.86; S, 9.53.

Example 39 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[[5- (pyridin-3-yl) methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl] carbonyl] piperazine hydrochloride ¹ H NMR (DMSO-d ₆ ) δ 3.03-3.37
(6H, m), 3.40-3.81 (4H, m), 3.
74 (2H, brs), 4.40 (2H, brs),
4.50 (2H, s), 4.70 (2H, s), 7.7
0 (1H, dd, J = 8.8, 2.4 Hz), 7.82
(1H, d, J = 8.8 Hz), 8.15 (1H, d,
J = 8.8 Hz), 8.22 (1H, s), 8.25
(1H, d, J = 8.8 Hz), 8.50 (1H,
s), 8.73 (1H, d, J = 7.8 Hz), 8.9
3 (1H, d, J = 4.4 Hz). MS (FAB) m / z 568 [(M + H) ⁺ , C
l ³⁵ ], 570 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 27 H 26 ClN 5 O} 3 S 2 · 2.9HCl ·
4.5 H ₂ O Calculated: C, 42.96; H, 5.06; Cl, 18.
32; N, 9.28. Analytical values: C, 42.97; H, 4.84; Cl, 18.
19; N, 9.23.

Example 40 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[[5- (pyridin-4-yl) methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl] carbonyl] piperazine hydrochloride ¹ H NMR (DMSO-d ₆ ) δ 3.11 (4H, br)
s), 3.19 (2H, br s), 3.64 (2
H, br s), 3.74 (2H, br s), 4.4
1 (2H, brs), 4.49 (2H, s), 4.8
0 (2H, s), 7.69 (1H, dd, J = 8.8,
2.0 Hz), 7.82 (1H, dd, J = 8.8,
2.0 Hz), 8.15 (1H, d, J = 8.8H)
z), 8.21 (1H, d, J = 2.0 Hz), 8.2
5 (1H, d, J = 8.8 Hz), 8.41 (2H,
d, J = 6.3 Hz), 8.50 (1H, s), 9.0
4 (2H, d, J = 6.3 Hz). MS (FAB) m / z 568 [(M + H) ⁺ , C
l ³⁵ ], 570 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 27 H 26 ClN 5 O} 3 S 2 · 2.7HCl ·
6.0 H ₂ O Calculated: C, 41.86; H, 5.30; Cl, 16;
93; N, 9.04; S, 8.28. Analytical values: C, 42.05; H, 4.98; Cl, 16;
92; N, 9.37; S, 8.61.

Example 41 1-[(E) -4-Chlorostyrylsulfonyl] -4-
[(4,5,6,7-tetrahydrothiazolo [5,4-
c] Pyridin-2-yl) carbonyl] piperazine hydrochloride 1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine, as in Example 1. -2-yl) carbonyl] -4
The title compound was obtained using-[(E) -4-chlorostyrylsulfonyl] piperazine as a starting material. ¹ H NMR (DMSO-d ₆ ) δ 3.04 (2H, br
s), 3.23 (4H, br), 3.47 (2H, b
rs), 3.77 (2H, brs), 4.35-
4.50 (2H, m), 7.33 (1H, d, J = 1
5.6 Hz), 7.43 (1H, d, J = 15.6H)
z), 7.49 (1H, d, J = 8.3 Hz), 7.7
9 (1H, d, J = 8.3 Hz), 9.57 (2H, b
rs). MS (FAB) m / z 453 [(M + H) ⁺ , C
l ³⁵ ], 455 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 19 H 21 ClN 4 O} 3 S 2 · HCl · 0.3H 2
As O: Calcd: C, 46.12; H, 4.60; Cl, 14.
33; N, 11.32; S, 12.96. Analytical values: C, 46.42; H, 4.66; Cl, 14.
38; N, 11.02; S, 13.02.

Example 42 1-[(E) -4-Chlorostyrylsulfonyl] -4-
[5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride 1-[(E) -4- The title compound was obtained using chlorostyrylsulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride as a starting material. ¹ H NMR (DMSO-d ₆ ) δ 2.92 (3H,
s), 3.01-3.32 (6H, br), 3.35-
3.88 (4H, m), 4.29-4.84 (4H,
m), 7.33 (1H, d, J = 15.6 Hz), 7.
49 (1H, d, J = 15.6 Hz), 7.49 (1
H, d, J = 8.3 Hz), 7.79 (1H, d, J =
8.3 Hz), 11.31 (1H, brs). MS (FAB) m / z 467 [(M + H) ⁺ , C
l ³⁵ ], 469 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 20 H 23 ClN 4 O} 3 S 2 · HCl · 0.2H 2
As O: Calcd: C, 47.37; H, 4.85; Cl, 13.
98; N, 11.05; S, 12.65. Analytical values: C, 47.30; H, 4.92; Cl, 14.
05; N, 11.03; S, 12.49.

Example 43 (3S) -3-[(6-Chloronaphthalen-2-yl)
Sulfonamide] -1-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl] pyrrolidine hydrochloride As in Example 1, (3S) -1- [ (5-tert-
Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl] -3
The title compound was obtained using-[(6-chloronaphthalen-2-yl) sulfonamido] pyrrolidine as a starting material. [Α] _D = −69.72 ° (25 ° C., c = 1.00, C
H ₃ OH). ¹ H NMR (DMSO-d ₆ at 100 ° C.) δ1.
88-1.89 (1H, m), 2.10-2.25 (1
H, m), 3.02-3.07 (2H, m), 3.10
-3.50 (6H, m), 4.02 (1H, s), 4.
12 (2H, s), 4.45 (2H, s), 7.12
(1H, s), 7.65 (1H, d, J = 8.3H
z), 7.91 (1H, d, J = 8.3 Hz), 8.1
0 (1H, d, J = 8.3 Hz), 8.14 (1H,
s), 8.16 (1H, d, J = 8.3 Hz), 8.1
8 (1H, brs), 8.48 (1H, s), 9.6
5 (2H, brs). MS (FD) m / z 461 (M +, Cl 35), 463
(M ⁺ , Cl ³⁷ ). Elemental _{analysis: C 22 H 24 ClN 3 O} 2 S 2 · 2.1HCl · H 2
Calculated as O: C, 47.47; H, 5.09; Cl, 19.
74; N, 7.55; S, 11.52. Analytical values: C, 47.55; H, 5.13; Cl, 19.
85; N, 7.45; S, 11.48.

Example 44 (3S) -3-[(6-Chloronaphthalen-2-yl)
Sulfonamide] -1-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl] pyrrolidine hydrochloride As in Example 1, (3S) -1- [ (5-tert-
Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl]
The title compound was obtained using -3-[(6-chloronaphthalen-2-yl) sulfonamido] pyrrolidine as a starting material. [Α] _D = −62.70 ° (25 ° C., c = 1.00, C
H ₃ OH) ¹ H NMR (DMSO-d ₆ at 100 ° C.) δ1.
82-1.90 (1H, m), 1.96-2.05 (1
H, m), 3.05 (2H, t, J = 6.0 Hz),
3.42-3.57 (2H, m), 3.60-3.72
(2H, m), 3.84-3.90 (1H, m), 4.
12 (2H, s), 4.45 (2H, s), 7.25
(1H, s), 7.64 (1H, dd, J = 8.3,
1.6 Hz), 7.90 (1H, dd, J = 8.3,
1.6 Hz), 7.97 (1H, d, J = 5.6H)
z), 8.08 (1H, d, J = 8.7 Hz), 8.1
2 (1H, s), 8.14 (1H, d, J = 8.7H
z), 8.47 (1H, s), 9.55 (2H, br)
s). MS (FAB) m / z 476 [(M + H) ⁺ , C
l ³⁵ ], 478 [(M + H) ⁺ , Cl ³⁷ ]. Elemental analysis: as C ₂₂ H ₂₂ ClN ₃ O ₃ S ₂ .HCl Calculated: C, 51.56; H, 4.52; Cl, 13.
84; N, 8.20; S, 12.51. Analytical values: C, 51.25; H, 4.61; Cl, 13.
68; N, 7.98; S, 12.36.

Example 45 (3S) -1-[(6-chloronaphthalen-2-yl)
Sulfonyl] -3-[[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl]
Amino] pyrrolidine hydrochloride As in Example 1, (3S) -3-[[(5-tert
-Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) methyl] amino] -1-[(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidine as a raw material As a result, the title compound was obtained. [Α] _D = + 34.82 ° (25 ° C., c = 1.00, C
H ₃ OH). ¹ H NMR (DMSO-d ₆ ) δ 1.98-2.20
(2H, m), 2.99-3.04 (2H, m), 3.
19-3.26 (1H, m), 3.30-3.50 (3
H, m), 3.61-3.72 (1H, m), 3.52.
-3.60 (1H, m), 4.13 (2H, s), 4.
29 (2H, s), 7.09 (1H, s), 7.71
(1H, dd, J = 8.8, 2.0 Hz), 7.89
(1H, dd, J = 8.8, 2.0 Hz), 8.17
(1H, d, J = 8.8 Hz), 8.25 (1H, d,
J = 2.0 Hz), 8.30 (1H, s), 8.57
(1H, s), 9.55 (2H, brs), 9.7-
10.0 (1H, m). MS (FD) m / z 461 (M +, Cl 35), 463
(M ⁺ , Cl ³⁷ ). Elemental _{analysis: C 22 H 24 ClN 3 O} 2 S 2 · 2HCl · 0.2
H ₂ O Calculated: C, 49.06; H, 4.94 ; Cl, 19.
75; N, 7.80; S, 11.91. Analytical values: C, 48.88; H, 4.97; Cl, 19.
65; N, 7.67; S, 11.84.

Example 46 (3S) -3-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonylamino] -1-[(6-chloronaphthalene- 2-yl) sulfonyl] pyrrolidine hydrochloride (3S) -3-[(5-tert-
Starting from butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonylamino] -1-[(6-chloronaphthalen-2-yl) sulfonyl] pyrrolidine, The title compound was obtained. [Α] _D = + 33.56 ° (25 ° C., c = 1.00, C
H ₃ OH). ¹ H NMR (DMSO-d ₆ ) δ 1.85-1.95
(1H, m), 1.95-2.05 (1H, m), 3.
04 (2H, m), 3.24-3.40 (1H, m),
3.41-3.53 (3H, m), 4.04-4.24
(3H, m), 7.34 (1H, s), 7.67 (1
H, d, J = 8.8 Hz), 7.84 (1H, d, J =
8.8 Hz), 8.03 (1H, d, J = 8.8H)
z), 8.17 (1H, s), 8.22 (1H, d, J
= 8.8 Hz), 8.27 (1H, d, J = 5.7H)
z), 8.50 (1H, s), 9.59 (1H, br)
s), 9.71 (1H, br s). MS (FD) m / z 476 [(M + H) ⁺ , C
l ³⁵ ], 478 [(M + H) ⁺ , Cl ³⁷ ].

Example 47 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) carbonyl ] Homopiperazine hydrochloride In the same manner as in Example 1, 1-[(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,
2-c] pyridin-2-yl) carbonyl] -4-
The title compound was obtained using [(6-chloronaphthalen-2-yl) sulfonyl] homopiperazine as a starting material. ¹ H NMR (DMSO-d ₆ ) δ 1.83 (2H, br
s), 3.04 (2H, t, J = 5.4 Hz);
30-3.59 (6H, m), 3.60-3.88 (4
H, m), 4.14 (2H, s), 7.20 (1H, b
rs), 7.69 (1H, dd, J = 8.8, 2.0
Hz), 7.84 (1H, d, J = 8.8 Hz), 8.
10 (1H, d, J = 8.8 Hz), 8.17-8.2
1 (2H, m), 8.50 (1H, s), 9.57 (2
H, brs). MS (FAB) m / z 490 [(M + H) ⁺ , C
l ³⁵ ], 492 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 23 H 25 ClN 3 O} 3 S 2 · 1.1HCl ·
0.2 H ₂ O Calculated: C, 51.66; H, 4.99; Cl, 13.
92; N, 7.86. Analytical values: C, 51.46; H, 4.61; Cl, 13.
55; N, 8.05.

Example 48 4-[(6-Chloronaphthalen-2-yl) sulfonamido] -1-[(4,5,6,7-tetrahydrothieno [3,2-c] pyridin-2-yl) Carbonyl] piperidine hydrochloride By the same reaction as in Examples 7 and 1, 5-tert
-Butoxycarbonyl-4,5,6,7-tetrahydrothieno [3,2-c] pyridine-2-carboxylic acid (WO
94/21599), 4-[(6-chloronaphthalene-
2-yl) Sulfonamide] piperidine The title compound was obtained using trifluoroacetate as a raw material. ¹ H NMR (DMSO-d ₆ ) δ1.26-1.38
(2H, m), 1.58-1.65 (2H, m), 2.
93-3.13 (4H, m), 3.29-3.40 (3
H, m), 3.90-4.05 (2H, m), 4.11.
(2H, s), 7.16 (1H, s), 7.68 (1
H, dd, J = 8.0, 2.0 Hz), 7.92 (1
H, dd, J = 8.8, 2.0 Hz), 8.07 (1
H, d, J = 7.3 Hz), 8.13 (2H, d, J =
8.8 Hz), 8.20 (1H, d, J = 7.3H)
z), 8.23 (1H, s), 8.51 (1H, s),
9.71 (2H, brs). MS (FAB) m / z 490 [(M + H) ⁺ , C
l ³⁵ ], 492 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 23 H 25 ClN 3 O} 3 S 2 · 2.4HCl · 3
H ₂ O Calculated: C, 43.67; H, 5.32 ; Cl, 19.
05; N, 6.64. Analytical values: C, 43.85; H, 5.10; Cl, 19.
07; N, 6.63.

Example 49 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(6-aminohydroxyiminomethylbenzofuran-2-yl) carbonyl] piperazine [(6-chloronaphthalene-
The title compound was obtained using 2-yl) sulfonyl] -4-[(6-cyanobenzofuran-2-yl) carbonyl] piperazine as a starting material. ¹ H NMR (DMSO-d ₆ ) δ 3.11 (4H,
s), 3.83 (4H, br), 5.90 (2H, br)
s), 7.34 (1H, s), 7.64-7.75
(3H, m), 7.83 (1H, dd, J = 8.8,
2.0 Hz), 7.89 (1H, s), 8.17 (1
H, d, J = 8.8 Hz), 8.23 (1H, d, J =
1.5 Hz), 8.26 (1H, d, J = 8.8H)
z), 8.51 (1H, s), 9.77 (1H, s). MS (FAB) m / z 513 [(M + H) ⁺ , C
l ³⁵ ], 515 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 24 H 21 ClN 4 O} 5 S · 1 / 5H 2 O Calculated: C, 55.80; H, 4.18 ; Cl, 6.8
6; N, 10.70; S, 6.21. Analytical values: C, 55.65; H, 4.25; Cl, 6.8.
1; N, 10.70; S, 6.37.

Example 50 4-[(5-Aminohydroxyiminomethylbenzothien-2-yl) carbonyl] -1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine

[1063]

Embedded image As in Example 24, 1-[(6-chloronaphthalene-
The title compound was obtained using 2-yl) sulfonyl] -4-[(5-cyanobenzothien-2-yl) carbonyl] piperazine as a starting material. ¹ H NMR (DMSO-d ₆ ) δ 3.11 (4H,
s), 3.77 (4H, s), 5.87 (2H, br)
s), 7.67 (1H, s), 7.71 (1H, d, J
= 2.0 Hz), 7.75 (1H, d, J = 8.8H)
z), 7.83 (1H, dd, J = 8.8, 2.0H
z), 7.94 (1H, d, J = 8.8 Hz), 8.1
5 (1H, s), 8.17 (1H, d, J = 8.8H)
z), 8.25 (1H, d, J = 8.8 Hz), 8.2
9 (1H, d, J = 8.3 Hz), 8.50 (1H,
s), 9.68 (1H, s). MS (FAB) m / z 529 [(M + H) ⁺ , C
l ³⁵ ], 531 [(M + H) ⁺ , Cl ³⁷ ]. Elemental analysis: C ₂₄ H ₂₁ N ₄ ClO ₄ S ₂ .0.3H ₂ O Calculated: C, 53.94; H, 4.07; N, 10.4
8. Analytical values: C, 54.22; H, 4.17; N, 10.2
3.

Example 51 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(1,2,3,4-tetrahydroisoquinolin-6-yl) carbonyl] piperazine hydrochloride Example 1 Similarly, 1-[(2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline-6
The title compound was obtained using -yl) carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine as a starting material. ¹ H NMR (DMSO-d ₆ ) δ 2.89-3.29
(4H, m), 3.20-3.83 (8H, m), 4.
25 (2H, s), 7.10-7.25 (3H, m),
7.71 (1H, d, J = 8.3 Hz), 7.81 (1
H, d, J = 8.3 Hz), 8.17 (1H, d, J =
8.8 Hz), 8.15-8.25 (2H, m), 8.
49 (1H.s), 9.54 (2H.brs). MS (FAB) m / z 470 [(M + H) ⁺ , C
l ³⁵ ], 472 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 24 H 24 ClN 3 O} 3 S · HCl · 2.0H 2
As O: Calcd: C, 53.14; H, 5.39; Cl, 13.
07; N, 7.75; S, 5.91. Analytical values: C, 53.43; H, 5.43; Cl, 13.
15; N, 8.07; S, 5.55.

Example 52 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl) carbonyl] piperazine hydrochloride

[1066]

Embedded image By a reaction similar to that in Example 32, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(1,2,2
The title compound was obtained using 3,4-tetrahydroisoquinolin-6-yl) carbonyl] piperazine hydrochloride as a raw material. ¹ H NMR (DMSO-d ₆ ) δ 2.88 (3H,
s), 2.90-3.80 (13H, m), 4.12-
4.56 (1H, m), 7.19 (1H, s), 7.2
0 (2H, d, J = 6.8 Hz), 7.72 (1H, d
d, J = 8.8, 2.0 Hz), 7.81 (1H, d,
J = 8.8 Hz), 8.17 (1H, d, J = 8.8H)
z), 8.24-8.28 (2H, m), 8.49 (1
H. s), 10.93 (1H.br s). MS (FAB) m / z 484 [(M + H) ⁺ , C
l ³⁵ ], 486 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 24 H 24 ClN 3 O} 3 S · HCl · 2.3H 2
As O: Calcd: C, 53.44; H, 5.67; Cl, 12.
62; N, 7.48; S, 5.71. Analytical values: C, 53.71; H, 5.81; Cl, 12.
37; N, 7.26; S, 5.62.

Example 53 6-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -2,
2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide As in Example 33, 1-[(6-chloronaphthalene-
2-yl) sulfonyl] -4-[(2-methyl-1,
2,3,4-Tetrahydroisoquinolin-6-yl) carbonyl] piperazine hydrochloride as a raw material gave the title compound. ¹ H NMR (DMSO-d ₆ ) δ 2.90-3.85
(18H, m), 4.61 (2H, s), 7.19 (1
H, d, J = 7.8 Hz), 7.24 (1H, d, J =
7.8 Hz), 7.28 (1H, s), 7.72 (1
H, dd, J = 8.8, 1.5 Hz), 7.81 (1
H, d, J = 8.8 Hz), 8.17 (1H, d, J =
8.8 Hz), 8.20-8.31 (2H, m), 8.
50 (1H.s). Elemental analysis: C ₂₆ H ₂₉ ClIN ₃ O ₃ S.H ₂ O Calculated: C, 48.49; H, 4.85; N, 6.5
3. Analytical values: C, 48.66; H, 4.96; N, 6.3.
9.

Example 54 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazine hydrochloride 1-[(5-chloroindol-2-yl) sulfonyl] piperazine, lithium 5-methyl-4,5,6,7-tetrahydrothia The title compound was obtained as a brown amorphous starting from zolo [5,4-c] pyridine-2-carboxylate. ¹ H NMR (CDCl ₃ ) δ 2.49 (3H, s),
2.78-2.83 (2H, m), 2.85-2.94
(2H, m), 3.15-3.28 (4H, br),
3.67 (2H, s), 3.82-3.95 (2H, b
r), 4.50-4.65 (2H, br), 6.96.
(1H, d, J = 2.0 Hz), 7.32 (1H, d
d, J = 8.8, 2.0 Hz), 7.36 (1H, d,
J = 8.8 Hz), 7.67 (1H, s), 8.71
(1H, br). MS (FAB) m / z 480 [(M + H) ⁺ , C
l ³⁵ ], 482 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 20 H 22 ClN 5 O} 3 S 2 · HCl · 0.5H 2
As O: Calcd: C, 44.64; H, 4.76; Cl, 13.
18; N, 13.02; S, 11.92. Analytical values: C, 44.69; H, 4.72; Cl, 13.
36; N, 12.76; S, 11.76.

Embodiment 55 to Embodiment 6 as in Embodiment 54
Compound No. 0 was synthesized.

Example 55 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride 1H-NMR (DMSO-d6) δ 2.50-2.63
(3H, m), 2.65-2.74 (2H, m), 2.
92 (3H, s), 3.00-3.14 (2H, m),
3.22-3.42 (2H, m), 3.63-3.78
(2H, m), 4.23-4.29 (1H, m), 4.
35-4.47 (1H, m), 4.64-4.80 (1
H, m), 4.97-5.02 (1 / 2H, m), 5.
45-5.51 (1H, m), 6.13-6.17 (1
/ 2H, m), 7.02 (1H, br), 7.32 (1
H, dd, J = 8.8, 2.0 Hz), 7.47 (1
H, d, J = 8.3 Hz), 7.77 (1H, br),
8.07-8.16 (1H, m), 12.41 (1H,
s). MS (FAB) m / z 537 [(M + H) ⁺ , C
l ³⁵ ], 539 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 22 H 25 ClN 6 O} 4 S 2 · HCl · 1.7H 2
Calculated as O: C, 43.74; H, 4.90; Cl, 11.
74; N, 13.91; S, 10.62. Analytical values: C, 44.02; H, 5.07; Cl, 11.
83; N, 13.59; S, 10.52.

Example 56 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(6-
Methyl-4,5,6,7-tetrahydrothieno [2,3
-C] pyridin-2-yl) carbonyl] piperazine
Hydrochloride

[1072]

Embedded image ¹ H NMR (DMSO-d ₆ ) δ 2.65 (3H, d,
J = 4.5 Hz), 2.85-3.22 (7H, m),
3.22-3.38 (2H, m), 3.66 (1H,
d, J = 12.2 Hz), 3.55-3.68 (2H,
m), 4.17-4.40 (3H, m), 4.55-
4.68 (1H, m), 6.99 (1H, d, J = 2.
0 Hz), 7.27-7.31 (2H, m), 7.48
(1H, d, J = 8.8 Hz), 7.77 (1H, d,
J = 2.0 Hz), 8.09 (1H, brs), 1
0.60 (1H, brs), 12.41 (1H,
s). MS (FAB) m / z 536 [(M + H) ⁺ , C
l ³⁵ ], 538 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 23 H 26 ClN 5 O} 4 S 2 · 1.3HCl ·
0.6H ₂ O · 1.5EtOH Calculated: C, 47.07; H, 5.70; Cl, 12.12.
29; N, 10.56; S, 9.67. Analytical values: C, 46.68; H, 5.63; Cl, 12.
16; N, 10.20; S, 10.06.

Example 57 1-[(5-Chlorobenzo [b] furan-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] ] Pyridin-2-yl) carbonyl] piperazine ¹ H NMR (DMSO-d ₆ ) δ 2.91 (3H,
s), 3.11 (2H, br), 3.25-3.90.
(4H, m), 3.76 (2H, br), 5.35-
4.80 (2H, br), 4.41 (2H, br),
7.46 (1H, d, J = 8.8 Hz), 7.73 (1
H, s), 7.84 (1H, d, J = 8.8 Hz),
7.96 (1H, s), 11.48 (1H, br). MS (FAB) m / z 481 [(M + H) ⁺ , C
l ³⁵ ], 483 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 20 H 21 ClN 4 O} 4 S 2 · 1.1HCl ·
As calculated for 0.3 H ₂ O: C, 45.63; H, 4.35; Cl, 14.
14; N, 10.64; S, 12.18. Analytical values: C, 45.81; H, 4.29; Cl, 13.
93; N, 10.44; S, 12.26.

Example 58 1-[(6-Chlorobenzo [b] furan-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] ] Pyridin-2-yl) carbonyl] piperazine ¹ H NMR (DMSO-d ₆ ) δ 2.91 (3H,
s), 3.00-3.55 (7H, m), 3.60-
3.85 (3H, m), 4.42 (3H, br), 4.
67 (1H, br), 7.46 (1H, d, J = 8.8)
Hz), 7.73 (1H, s), 7.84 (1H, d,
J = 8.8 Hz), 7.96 (1H, s), 11.48
(1H, br). MS (FAB) m / z 481 [(M + H) ⁺ , C
l ³⁵ ], 483 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 20 H 21 ClN 4 O} 4 S 2 · HCl · 0.17
H ₂ O Calculated: C, 46.15; H, 4.33 ; Cl, 13.
62; N, 10.76; S, 12.32. Analytical values: C, 46.45; H, 4.41; Cl, 13.
61; N, 10.58; S, 12.02.

Example 59 1-[(5-Chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] ] Pyridin-2-yl) carbonyl] piperazine hydrochloride ¹ H NMR (DMSO-d ₆ ) δ 2.91 (3H,
s), 2.98-3.90 (10H, m), 4.24-
4.77 (4H, m), 7.60 (1H, d, J = 8.
8Hz), 8.05 (1H, s), 8.10-8.21
(2H, m), 11.72 (1H, br s). MS (FAB) m / z 497 [(M + H) ⁺ , C
l ³⁵ ], 499 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 20 H 21 ClN 4 O} 3 S 3 · HCl · 0.9H 2
As O: Calcd: C, 43.70; H, 4.36; Cl, 12.
90; N, 10.19; S, 17.50. Analytical values: C, 43.82; H, 4.49; Cl, 13.
27; N, 9.86; S, 17.32.

Example 60 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] ] Pyridin-2-yl) carbonyl] piperazine hydrochloride ¹ H NMR (DMSO-d ₆ ) δ 2.91 (3H,
s), 3.02-3.25 (5H, m), 3.32-
3.90 (6H, m), 4.33-4.55 (2H,
m), 4.64-4.75 (1H, m), 7.55 (1
H, dd, J = 8.8, 2.0 Hz), 8.06 (1
H, d, J = 8.8 Hz), 8.09 (1H, s), 1
1.42 (1H, brs). MS (FAB) m / z 497 [(M + H) ⁺ , C
l ³⁵ ], 499 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 20 H 21 ClN 4 O} 3 S 3 · 1.1HCl ·
1.4H ₂ O Calculated: C, 42.71; H, 4.46 ; Cl, 13.
24; N, 9.96; S, 17.11. Analytical values: C, 42.49; H, 4.51; Cl, 13.
01; N, 9.76; S, 16.95.

Example 61 2- [4-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium iodide

[1078]

Embedded image 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(thiazolo [5,4-c] pyridine-2-
Il) carbonyl] piperazine was treated and purified in the same manner as in Example 33 to obtain the title compound. IR (KBr) cm ^-1 3016, 1631, 1450,
1432, 1344, 1328, 1276, 1267,
1162, 1135, 998, 727, 578. ¹ H NMR (DMSO-d ₆ ) δ 3.10-3.23
(4H, m), 3.85 (2H, brs), 4.29
(2H, br s), 4.48 (3H, s), 7.70
(1H, dd, J = 8.8, 2.0 Hz), 7.83
(1H, d, J = 8.8, 2.0 Hz), 8.17 (1
H, d, J = 8.8 Hz), 8.23 (1H, d, J =
2.0Hz), 8.26 (1H, d, J = 8.8H)
z), 8.52 (1H, s), 8.71 (1H, d, J
= 6.8 Hz), 8.98 (1H, d, J = 6.8,
2.0Hz), 9.92 (1H, d, J = 2.0H)
z). MS (FAB) m / z 487 (M ⁺ , Cl ³⁵ ), 48
9 (M ⁺ , Cl ³⁷ ).

Example 62 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2-[(N-methyl) carbamoyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt (616 mg), 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-[(N-methyl) carbamoyl] piperazine trifluoroacetate (1.12 g), 1-hydroxybenzotriazole
Monohydrate (36 mg) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (579 mg) were dissolved in N, N-dimethylformamide (100 ml) and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, dichloromethane was added to the residue, and the mixture was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure,
The residue was subjected to silica gel column chromatography [Φ3.0
× (1.5 + 8) cm, ethyl acetate: methanol = 10
0: 4] to give a colorless foam. This was dissolved in 1N HCl (20 ml) and concentrated under reduced pressure to obtain the title compound (845 mg) as a pale yellow foam. IR (KBr) cm ^-1 3380, 1668, 1623,
1542, 1415, 1342, 1330, 1159,
1135, 1078, 952, 941, 723, 57
8. ¹ H NMR (DMSO-d ₆ ) δ 2.42-2.80
(5H, m), 2.90 (3H, s), 2.95-3.
80 (6H, m), 4.23-4.50 (5 / 2H,
m), 4.60-4.77 (1H, m), 4.98 (1
/ 2H, br s), 5.45-5.55 (1H,
m), 6.15 (1 / 2H, br s), 7.71 (1
H, d, J = 8.8 Hz), 7.78-7.82 (1
H, m), 8.07-8.13 (1H, m), 8.15
(1H, d, J = 8.8 Hz), 8.23 (1H, d, J = 8.8 Hz)
s), 8.25 (1H, d, J = 8.8 Hz), 8.4
9 (1H, s), 11.70-12.00 (1H,
m). MS (FAB) m / z 548 [(M + H) ⁺ , C
l ³⁵ ], 550 [(M + H) ⁺ , Cl ³⁷ ].

Example 63 By a method similar to that in Example 62,
~ The compound of Example 76 was obtained.

Example 63 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine Raw material: 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2 -Lithium carboxylate, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -3-[[(morpholin-4-yl) carbonyl] methyl] piperazine hydrochloride. _{^{1 H NMR (DMSO-d 6}} ) δ2.35-2.83
(2H, m), 2.89 (3H, s), 2.95-3.
88 (18H, m), 4.31-4.45 (3 / 2H,
m), 4.67 (2H, d, J = 15.1 Hz), 5.
03 (0.5H, brs), 5.37 (0.5H,
d, J = 13.7 Hz), 5.79 (1 / 2H, br)
s), 7.70 (1H, dd, J = 8.8, 2.0H
z), 7.81 (1H, d, J = 8.8 Hz), 8.1
5 (1H, d, J = 8.8 Hz), 8.23 (1H,
s), 8.27 (1H, d, J = 8.8 Hz), 8.5
0 (1H, s), 11.50-11.75 (1H,
m). MS (FAB) m / z 618 [(M + H) ⁺ , C
l ³⁵ ], 620 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 28 H 32 ClN 5 O} 5 S 2 · 1.5HCl · 3
H ₂ O Calculated: C, 46.27; H, 5.48 ; Cl, 12.
19; N, 9.63; S, 8.82. Analytical values: C, 46.49; H, 5.20; Cl, 12.
16; N, 9.67; S, 8.88.

Example 64 N-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4- c] pyridin-2-yl) carbonyl] piperazin-2-yl] carbonyl]
Glycine ethyl ester Raw material: 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt, N-[[1-[(6-chloronaphthalene-2) -Yl) sulfonyl] piperazin-3-yl] carbonyl]
Glycine ethyl ester trifluoroacetate. ¹ H NMR (DMSO-d ₆ ) δ 1.17-1.24
(3H, m), 2.38 (3H, s), 2.39-2.
53 (1H, m), 2.58-2.84 (5H, m),
3.20-3.29 (1H, m), 3.54-3.81
(4H, m), 3.90-4.00 (1H, m), 4.
06-4.17 (1H, m), 4.32 (1H, d, J
= 11.7 Hz), 4.47 (1 / 2H, d, J = 1)
3.7 Hz), 5.14 (1 / 2H, s), 5.66
(1 / 2H, d, J = 13.7 Hz), 6.42 (1
H, br s), 7.68 (1H, d, J = 8.3H)
z), 7.79 (1H, d, J = 8.3 Hz), 8.1
2 (1H, dd, J = 8.8, 3.4 Hz), 8.19
(1H, s), 8.23 (1H.d, J = 8.8H
z), 8.48 (1H, s), 8.52 (1 / 2H,
t, J = 5.4 Hz), 8.61 (1 / 2H, t, J =
5.4 Hz). MS (FD) m / z 619 (M +, Cl 35), 621
(M ⁺ , Cl ³⁷ ). Elemental _{analysis: C 27 H 30 ClN 5 O} 6 S 2 ·
Calculated as 0.2 HCl · 0.1 H ₂ O: C, 51.54; H, 4.87; Cl, 6.7
6; N, 11.13; S, 10.19. Analytical values: C, 51.31; H, 4.92; Cl, 6.7.
4; N, 10.92; S, 10.01.

In this reaction, the following compound having an ester bond hydrolyzed was also obtained. N-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2- Yl) carbonyl] piperazin-2-yl] carbonyl]
Glycine ¹ H NMR (DMSO-d ₆ ) δ 2.37 (3H,
s), 2.59-2.83 (6H, m), 3.20-
3.32 (1H, m), 3.52-3.77 (4H,
m), 3.82-3.95 (1H, m), 4.28-
4.35 (1H, m), 4.45 (1 / 2H, d, J =
13.7 Hz), 5.13 (1 / 2H, brs),
5.63 (1 / 2H, d, J = 13.7 Hz), 6.3
6 (1H, brs), 7.69 (1H, d, J = 8.
3Hz), 7.80 (1H, d, J = 8.3Hz),
8.12 (1H, dd, J = 8.8, 3.4 Hz),
8.20 (1H, s), 8.23 (1H.d, J = 8.
8Hz), 8.41 (1 / 2H, t, J = 5.4H)
z), 8.45-8.50 (3 / 2H, m). MS (FD) m / z 592 [(M + H) ⁺ , C
l ³⁵ ], 594 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 27 H 30 ClN 5 O} 6 S 2 · H 2 O Calculated: C, 49.22; H, 4.63 ; Cl, 5.8
1; N, 11.48; S, 10.51. Analytical values: C, 49.11; H, 4.78; Cl, 6.0.
2; N, 11.41; S, 10.25.

Example 65 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2- [N- (morpholin-4-yl) carbamoyl] piperazine hydrochloride Raw material: 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-carboxylic acid lithium salt, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -3- [N- (morpholin-4-yl) carbamoyl] piperazine trifluoroacetate. ¹ H NMR (DMSO-d ₆ at 100 ° C.) δ2.
58-2.84 (8H, m), 2.89 (3H, s),
2.98-3.58 (3H, m), 3.40-3.80
(8H, m), 4.10-4.70 (4H, m), 7.
65 (1H, dd, J = 8.6, 2.4 Hz), 7.7
9 (1H, dd, J = 8.6, 1.2 Hz), 8.09
(1H, d, J = 8.6 Hz), 8.14 (1H, d, J = 8.6 Hz)
s), 8.18 (1 Hd, J = 8.6 Hz), 8.4
2 (1H, s), 8.58 (1H, brs). MS (FAB) m / z 619 [(M + H) ⁺ , C
l ³⁵ ], 621 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 24 H 26 ClN 4 O} 5 S 2 · 1.7HCl ·
1.7 h ₂ O Calculated: C, 45.56; H, 5.11 ; Cl, 13.
45; N, 10.57; S, 8.93. Analytical values: C, 45.35; H, 5.34; Cl, 13.
46; N, 12.01; S, 8.93.

Example 66 N '-[[4-[(6-chloronaphthalen-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] carbonyl]
Hydrazinoacetic acid ethyl ester hydrochloride Raw material: 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt, N ′-[[1-[(6- Chloronaphthalene-2-
Yl) sulfonyl] piperazin-3-yl] carbonyl] hydrazinoacetic acid ethyl ester hydrochloride. ¹ H NMR (DMSO-d ₆ ) δ 1.18-1.28
(3H, m), 2.36 (3H, s), 2.65-2.
85 (5H, m), 3.23-3.28 (1H, m),
3.31 (2H, s), 3.44-3.75 (4H,
m), 4.08-4.24 (3H, m), 4.38 (1
/ 2H, d, J = 13.7 Hz), 5.01 (1/2
H, s), 5.22-5.31 (1H, m), 5.52.
(1 / 2H, d, J = 13.7 Hz), 6.10 (1 /
2H, br s), 7.69 (1H, d, J = 8.8,
2.0 Hz), 7.72-7.80 (1H, m), 7.
72-7.80 (3H, m), 8.47 (1H, s),
9.77-9.85 (1H, m). MS (FAB) m /
z 635 [(M + H) ⁺ , Cl ³⁵ ], 637 [(M +
H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 27 H 31 ClN 6 O} 6 S 2 · 1.6HCl · H 2
For O: C, 45.58; H, 4.90; Cl, 12.
95; N, 11.81; S, 9.01. Analytical values: C, 45.71; H, 5.09; Cl, 12.
83; N, 11.46; S, 8.94.

Example 67 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2- [N-[[(morpholin-4-yl) carbonyl] methyl] carbamoyl] piperazine hydrochloride Raw material: 5-methyl-4,5,6,7-tetrahydrothiazolo [5 4-c] pyridine-2-carboxylic acid lithium salt, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -3- [N-[[(morpholin-4-yl) carbonyl] methyl] carbamoyl] piperazine Hydrochloride. _{^{1 H NMR (DMSO-d 6}} ) δ2.35-2.82
(2H, m), 2.90 (3H, s), 2.95-3.
30 (2H, m), 3.32-3.86 (13H,
m), 4.05-4.20 (1H, m), 4.23-
4.50 (2.5H, m), 4.59-4.70 (1
H, m), 5.15 (0.5H, s), 5.50 (0.
5H, d, J = 12.2 Hz), 6.30 (0.5H,
s), 7.70 (1H, dd, J = 8.8, 2.0H
z), 7.80 (1H, d, J = 8.8 Hz), 8.1
2-8.38 (4H, m), 8.48 (1H, s), 1
1.45-11.75 (1H, m). MS (FAB) m / z 661 [(M + H) ⁺ , C
l ³⁵ ], 663 [(M + H) ⁺ , Cl ³⁷ ]. Elemental analysis: C ₂₉ H ₃₃ ClN ₆ O ₆ S ₂ .HCl.H ₂ O Calculated: C, 48.67; H, 5.07; Cl, 9.9
1; N, 11.74; S, 8.96. Analytical values: C, 48.70; H, 5.03; Cl, 10.
23; N, 11.55; S, 9.32.

Example 68 4-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4- c] pyridin-2-yl) carbonyl] piperazin-2-yl] carbonyl]
Morpholine hydrochloride raw material: 5-methyl-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Lithium carboxylate, 4-[[1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine-3-
Yl] carbonyl] morpholine trifluoroacetate. IR (KBr) cm ^-1 3396, 2919, 2854,
1652, 1623, 1457, 1112, 954, 7
23,578. ¹ H NMR (DMSO-d ₆ ) δ 2.62-2.79
(1H, m), 2.85-3.92 (19H, m),
4.02-4.13 (1 / 2H, m), 4.30-4.
49 (3 / 2H, m), 4.58-4.80 (1H,
m), 5.24-5.46 (1H, m), 6.28-
6.45 (1H, m), 7.71 (1H, dd, J =
8.8, 2.0 Hz), 7.83 (1H, d, J = 8.
8 Hz), 8.12-8.28 (3H, m), 8.53
(1H, s), 11.30-11.80 (1H, m). MS (FAB) m / z 604 [(M + H) ⁺ , C
l ³⁵ ], 606 [(M + H) ⁺ , Cl ³⁷ ].

Example 69 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2- (ethoxycarbonyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-
c] pyridin-2-yl) carbonyl] piperazine Raw material: 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt, 1-[(6- Chloronaphthalen-2-yl) sulfonyl] -3- [ethoxycarbonyl] piperazine. ¹ H NMR (CDCl ₃ ) δ1.25-1.35 (3
H, m), 2.43-2.94 (9H, m), 3.31
(1 / 2H, dt, J = 12.7, 3.4 Hz), 3.
60-3.76 (2.5H, m), 3.83 (1/2)
H, d, J = 11.7 Hz), 3.89 (1 / 2H,
d, J = 11.7 Hz), 4.19-4.30 (2H,
m), 4.42-4.50 (1H, m), 4.55 (1
/ 2H, 14.2 Hz), 5.76 (1 / 2H, 14.2 Hz).
2Hz), 7.57 (1H, dd, J = 8.3, 1.5
Hz), 7.77 (1H, dd, J = 8.3, 1.5H)
z), 7.89-7.94 (3H, m), 8.34 (1
H, s). MS (FAB) m / z 563 [(M + H) ⁺ , C
l ³⁵ ], 565 [(M + H) ⁺ , Cl ³⁷ ].

Example 70 [4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine -2-yl) carbonyl] piperazin-2-yl] acetic acid methyl ester Raw material: 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt, 1 -[(6-chloronaphthalen-2-yl) sulfonyl] -3- [methoxycarbonylmethyl] piperazine. IR (KBr) cm ^-1 2944, 2846, 278
8, 1735, 1619, 1455, 1164. ¹ H NMR (CDCl ₃ ) δ 2.40-2.92 (10
H, m), 3.04 (1H, dd, J = 16.1, 8.
8 Hz), 3.16-3.27 (1 / 2H, m), 3.
42-3.55 (1 / 2H, m), 3.60-3.72
(5H, m), 3.83-3.97 (2H, m), 4.
60 (1 / 2H, d, J = 13.2 Hz), 5.21
(1 / 2H, brs), 5.70 (1 / 2H, d, J
= 13.2 Hz), 6.15 (1 / 2H, brs),
7.57 (1H, dd, J = 8.8, 2.0 Hz),
7.75 (1H, dd, J = 8.8, 2.0 Hz),
7.87-7.95 (3H, m), 8.30 (1H,
s). MS (FAB) m / z 563 [(M + H) ⁺ , C
l ³⁵ ], 565 [(M + H) ⁺ , Cl ³⁷ ].

Example 71 2-[[N- (tert-butoxy) amino] carbonyl] -4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,5 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine trifluoroacetate Raw material: 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt, 1-[(6-chloronaphthalene-2) -Yl) sulfonyl] -3-[(N-tert-butoxy) carbonyl] piperazine trifluoroacetate. IR (KBr) cm ^-1 2979, 1675, 1465,
1199, 1184, 1166, 1135, 721. ¹ H NMR (DMSO-d ₆ ) δ 1.15-1.25
(9H, m), 2.36 (3H, s), 2.37-2.
49 (1H, m), 2.67-2.84 (5H, m),
3.25-3.35 (1H, m), 3.59-3.78
(3H, m), 4.13-4.25 (1H, m), 4.
38 (1H, d, J = 13.2 Hz), 5.01 (1 /
2H, br s), 5.52 (1 / 2H, d, J = 1)
3.2Hz), 5.14 (1 / 2H, s), 6.21
(1 / 2H, brs), 7.69 (1H, dd, J =
8.8, 2.0 Hz), 7.76-7.74 (1H,
m), 8.14 (1H, d, J = 8.8 Hz), 8.2
1 (1H, s), 8.24 (1H.d, J = 8.8H
z), 8.47-8.53 (1H, m), 10.75-
10.78 (1H, m). MS (FAB) m / z 606 [(M + H) ⁺ , C
l ³⁵ ], 608 [(M + H) ⁺ , Cl ³⁷ ].

Example 72 [4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine -2-yl) carbonyl] piperazin-2-yl] acetamide hydrochloride Raw material: lithium 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylate 1 -[(6-chloronaphthalen-2-yl) sulfonyl] -3- [carbamoylmethyl] piperazine hydrochloride. IR (KBr) cm ^-1 1671, 1616, 1465,
1457, 1419, 1332, 1162, 1133
1124,1078,956,701,578. _{^{1 H NMR (DMSO-d 6}} ) δ2.30-2.80
(4H, m), 2.90 (3H, s), 2.93-3.
25 (2H, m), 3.30-3.55 (1H, m),
3.62-3.88 (3H, m), 4.05-4.43
(2.5H, m), 4.60-4.71 (1H, m),
5.05 (0.5H, brs), 5.34 (0.5
H, d, J = 13.2 Hz), 5.69-5.84.
(0.5H, m), 6.82 (0.5H, br s),
6.93 (0.5H, brs), 7.37-7.50
(1H, m), 7.70 (1H, d, J = 8.8H
z), 7.80 (1H, d, J = 8.8 Hz), 8.1
0-8.29 (3H, m), 8.49 (1H, s). MS (FAB) m / z 576 [(M + H) ⁺ , C
l ³⁵ ], 578 [(M + H) ⁺ , Cl ³⁷ ].

Example 73 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2-[(N-isopropyl) carbamoyl] -1
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine hydrochloride Raw material: 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt, 1-[(6-chloronaphthalen-2-yl) sulfonyl ] -3-[(N-isopropyl) carbamoyl]
Piperazine hydrochloride IR (KBr) cm ^-1 2967,2933,1666,
1625, 1542, 1463, 1344, 1332,
1159, 1135, 954, 725, 578. ¹ H
_{NMR (DMSO-d 6) δ1.00-1.10} (6
H, m), 2.50-2.80 (2H, m), 2.91
(3H, s), 2.93-3.50 (4H, m), 3.
60-3.79 (2H, m), 3.82-3.95 (1
H, m), 4.18-4.30 (1H, m), 4.32
-4.50 (1.5H, m), 4.60-4.77 (1
H, m), 4.97 (0.5H, s), 5.03 (0.
5H, d, J = 13.2 Hz), 5.90 (0.5H,
s), 7.70 (1H, d, J = 8.8 Hz), 7.7
9 (1H, d, J = 8.8 Hz), 7.92-8.00
(1H, m), 8.22 (1H, d, J = 8.8H
z), 8.18-8.28 (2H, m), 8.48 (1
H, s). MS (FAB) m / z 576 [(M + H) ⁺ , C
l ³⁵ ], 578 [(M + H) ⁺ , Cl ³⁷ ].

Example 74 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2-[[(piperidin-1-yl) carbonyl]
Methyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine hydrochloride Raw material: 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt, 1-[(6-chloronaphthalen-2-yl) ) Sulfonyl] -3-[[(piperidin-1-yl) carbonyl] methyl] piperazine hydrochloride IR (KBr) cm ^-1 2931, 284, 1623,
1455, 1334, 1159, 1135, 1124
1078, 954, 700, 578. ¹ H NMR (DMSO-d ₆ ) δ 1.20-1.70
(8H, m), 2.35-2.82 (2H, m), 2.
90 (3H, s), 2.95-3.88 (11H,
m), 4.31-4.45 (1.5H, m), 4.62
-4.76 (1H, m), 5.03 (0.5H, br)
s), 5.34 (0.5 H, d, J = 13.2 Hz),
5.70 (0.5H, brs), 7.70 (1H,
d, J = 8.8 Hz), 7.81 (1H, d, J = 8.
8Hz), 8.15 (1H, d, J = 8.8Hz),
8.22 (1H, s), 8.27 (1H, d, J = 8.
8Hz), 8.50 (1H, s). MS (FAB) m / z 616 [(M + H) ⁺ , C
l ³⁵ ], 618 [(M + H) ⁺ , Cl ³⁷ ].

Example 75 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2-[[N- (2-methoxybenzyl)] carbamoyl] -1-[(5-methyl-4,5, 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine hydrochloride Raw material: 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt, 1-[(6-chloronaphthalen-2-yl) ) Sulfonyl] -3-[[N- (2-methoxybenzyl)] carbamoyl] piperazine hydrochloride. ¹ H NMR (DMSO-d ₆ ) δ 2.42-3.54
(9H, m), 3.62-3.85 (5H, m), 4.
12-4.50 (3.5H, m), 4.60-4.77
(1H, m), 5.09 (1 / 2H, brs), 5.
43-5.52 (1 / 2H, m), 6.11-6.19
(1 / 2H, m), 6.85-7.00 (2H, m),
7.16-7.29 (2H, m), 7.72 (1H,
d, J = 10.7 Hz), 7.80-7.86 (1H,
m), 8.16 (1H, d, J = 8.8 Hz), 8.2
2-8.28 (2H, m), 8.50 (1H, s),
8.65-8.72 (1H, m). MS (FAB) m / z 654 [(M + H) ⁺ , C
l ³⁵ ], 656 [(M + H) ⁺ , Cl ³⁷ ].

Example 76 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2-[[N- (2-methoxyethyl)] carbamoyl] -1-[(5-methyl-4,5, 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride Raw material: 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine -2-Carboxylic acid lithium salt, 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2-[[N- (2-methoxyityl)] carbamoyl] piperazine. IR (KBr) cm ^-1 2931, 1544, 1463,
1423, 1344, 1332, 1157, 1133
1078,954,943,723,578. ¹ H N
_{MR (DMSO-d 6) δ2.42-2.82} (2H,
m), 2.92 (3H, s), 2.95-3.79 (1
3H, m), 4.21-4.80 (3.5H, m),
5.02 (1 / 2H, brs), 5.47 (1/2
H, d, J = 12.2 Hz), 6.07 (1 / 2H, b)
rs), 7.70 (1H, dd, J = 8.8, 2.0
Hz), 7.79 (1H, d, J = 8.8 Hz), 8.
13 (1H, d, J = 8.8 Hz), 8.17-8.3
2 (3H, m), 8.48 (1H, s), 11.09-
11.40 (1H, m). MS (FAB) m / z 592 [(M + H) ⁺ , C
l ³⁵ ], 594 [(M + H) ⁺ , Cl ³⁷ ].

Example 77 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazine-2-carboxylic acid 4-[(6-chloronaphthalen-2-yl) sulfonyl] -2- (ethoxycarbonyl) -1-[(5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine (2.08 g) was dissolved in tetrahydrofuran (10 ml), ethanol (20 ml) and a 1N aqueous sodium hydroxide solution (3.70 ml) were added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, water (20 m
l) was added and the resulting precipitate was collected by filtration and the title compound (1.3) was added.
9g) was obtained as a pale yellow foam. IR (KBr) cm ^-1 1731, 1625, 1461,
1346, 1332, 1315, 1159, 1135
1078, 954, 943, 723, 580. ¹ H N
_{MR (DMSO-d 6) δ2.32-3.86} (11
H, m), 4.27 (1H, d, J = 11.7 Hz),
4.35-4.48 (3 / 2H, m), 4.59-4.
78 (1H, m), 5.21 (1 / 2H, m), 5.3
8-5.52 (1 / 2H, m), 6.34-6.47
(1 / 2H, m), 7.71 (1H, dd, J = 8.
8, 2.0 Hz), 7.83 (1H, d, J = 8.8H)
z), 8.16 (1H, d, J = 8.8 Hz), 8.2
3 (1H, s), 8.27 (1H, d, J = 8.8H)
z), 8.53 (1H, s), 11.60-11.90
(1H, m). Elemental _{analysis: C 23 H 23 ClN 4 O} 5 S 2 · 1.3HCl ·
1.5 H ₂ O Calculated: C, 45.33; H, 4.51; Cl, 13.
38; N, 9.19; S, 10.52. Analytical values: C, 45.69; H, 4.55; Cl, 13.
29; N, 9.21; S, 10.21.

Example 78 N '-[[4-[(6-chloronaphthalen-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] carbonyl]
Hydrazinoacetic acid N '-[[4-[(6-chloronaphthalen-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] carbonyl]
Starting from hydrazinoacetic acid ethyl ester hydrochloride,
The title compound was obtained in the same manner as in Example 77. MS (FAB) m / z 607 [(M + H) ⁺ , C
l ³⁵ ], 609 [(M + H) ⁺ , Cl ³⁷ ]. ¹ H NMR (DMSO-d ₆ at 100 ° C.) δ2.
41 (3H, s), 2.65-3.30 (6H, m),
3.37-3.77 (8H, m), 4.16 (1H,
d, J = 12.7 Hz), 7.64 (1H, dd, J =
8.7, 2.4 Hz), 7.78 (1H, dd, J =
8.7, 1.6 Hz), 8.07 (1H, d, J = 8.
7 Hz), 8.11 (1H, d, J = 1.6 Hz),
8.16 (1H, d, J = 8.7 Hz), 8.42 (1
H, s). Elemental analysis: C ₂₅ H ₂₇ ClN ₆ O ₆ S ₂ .2H ₂ O Calculated: C, 46.69; H, 4.86; N, 13.0
7, S, 9.97. Analytical values: C, 46.87; H, 4.86; N, 12.8.
2; S, 9.62.

Example 79 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2-[[N- (tetrahydropyran-2-yloxy)] carbamoyl] piperazine 4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4 , 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine-2-carboxylic acid (141 mg),
2-tetrahydropyranyloxyamine (180m
g), 1-hydroxybenzotriazole monohydrate (1
1 mg), 1- (dimethylaminopropyl) -3-hydrochloride
Ethylcarbodiimide (145 mg) and potassium carbonate (129 mg) were added to N, N-dimethylformamide (20 mg).
ml) and allowed to stir at room temperature overnight. The reaction solution was concentrated under reduced pressure, dichloromethane was added to the residue, and the mixture was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (φ0.7 × 25.0 cm, dichloromethane: methanol = 100: 3) to give the title compound (30
8 mg) as a colorless foam. ¹ H NMR (CDCl ₃ ) δ 1.50-1.89 (6
H, m), 2.45-2.55 (3H, m), 2.72
-3.00 (6H, m), 3.57-3.97 (5H,
m), 4.28 (0.5 H, d, J = 12.2 Hz),
4.35 (0.5H, d, J = 12.2Hz), 4.5
2-4.61 (0.5H, m), 4.92 (0.5H,
s), 5.02 (0.5H, br s), 5.06-
5.10 (0.5H, m), 5.55-5.65 (0.
5H, m), 5.88 (0.5H, brs), 6.21
(0.5H, br s), 7.51-7.58 (1H,
m), 7.77-7.93 (4H, m), 8.35 (1
H, s), 9.61 (0.5H, br s), 10.1
0 (1H, brs). MS (FAB) m / z 634 [(M + H) ⁺ , C
l ³⁵ ], 636 [(M + H) ⁺ , Cl ³⁷ ].

Example 80 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazine-2-carbohydroxamic acid 4-[(6-chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-c] Pyridin-2-yl) carbonyl] -2-[[N- (tetrahydropyran-2-yloxy)] carbamoyl] piperazine (297 mg)
Was dissolved in methanol (10 ml), and 1N hydrochloric acid (10
ml) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was HP-20 (φ1.7 × 20.0 c
m, acetonitrile: water = 1: 5) to give the title compound (65 mg) as a pale yellow foam. ¹ H NMR (CDCl ₃ ) δ 2.32-2.73 (2
H, m), 2.91 (3H, s), 2.97-3.30.
(3H, m), 3.35-3.50 (1H, m), 3.
63-3.76 (2H, m), 4.22-4.48
(2.5H, m), 4.61-4.75 (1H, m),
4.99 (0.5H, s), 5.47 (0.5H, d,
J = 12.2 Hz), 6.24 (0.5 H, s), 7.
70 (1H, d, J = 8.8 Hz), 7.75-7.8
5 (1H, m), 8.15 (1H, d, J = 8.8H
z), 8.23 (1H, s), 8.25 (1H, d, J
= 8.8 Hz), 8.48 (1H, s), 10.26
(1H, br s), 10.97 (1H, br s). MS (FAB) m / z 550 [(M + H) ⁺ , C
l ³⁵ ], 552 [(M + H) ⁺ , Cl ³⁷ ].

Example 81 4-[(6-Chloronaphthalen-2-yl) sulfoni
] -2-[[N- (2-hydroxybenzyl)] cal
Bamoyl] -1-[(5-methyl-4,5,6,7-te
Trahydrothiazolo [5,4-c] pyridine-2-i
L) carbonyl] piperazine 4-[(6-chloronaphthalen-2-yl) sulfoni
] -2-[[N- (2-methoxybenzyl)] carba
Moyl] -1-[(5-methyl-4,5,6,7-tet
Lahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine hydrochloride (195 mg)
Dissolve in dichloromethane (10 ml) and tribro at -78 ° C
Moborane-dichloromethane solution (1.0 M, 2.08 m
l) was added dropwise. The reaction was warmed to room temperature and stirred overnight.
Was. Methanol (2 ml), sodium carbonate
(200 mg) and water (3 ml) were added to extract an organic layer.
Then, it was dried over anhydrous sodium sulfate. Solvent is distilled under reduced pressure
The precipitated solid was collected by filtration while washing with 1N hydrochloric acid.
The title compound (50 mg, 24%) was obtained as a pale yellow solid.
Was. ¹ 1 H NMR (DMSO-d₆) Δ 2.36-2.87
(9H, m), 3.11-3.28 (1H, m), 3.
59-3.80 (3H, m), 4.12-4.45
(3.5H, m), 4.48-4.57 (1 / 2H,
m), 5.08 (1 / 2H, brs), 6.19 (1
/ 2H, br s), 6.63-6.81 (2H,
m), 6.98-7.15 (2H, m), 7.70 (1
H, dd, J = 8.3, 1.5 Hz), 7.78-7.
84 (1H, m), 8.13 (1H, d, J = 8.8H
z), 8.20-8.28 (2H, m), 8.49 (1
H, s), 8.50-8.62 (1H, m), 9.45
(1 / 2H, s), 9.50 (1 / 2H, s). MS (FAB) m / z 640 [(M + H)⁺, C
l³⁵], 642 [(M + H)⁺, Cl³⁷].

Example 82 2-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -6-
Methyl-4,5,6,7-tetrahydrofuro [2,3-
c] pyridine hydrochloride

[1102]

Embedded image 6-methyl-4,5,6,7-tetrahydrofuro [2,
To a solution of 3-c] pyridine (58.1 mg) in tetrahydrofuran (3.2 ml) was added n-butyllithium (1.59 N hexane solution, 320 μl) at −78 ° C., and the mixture was stirred for 1 hour and then cooled to 0 ° C. And stirred for 30 minutes. The reaction solution was cooled again to -78 ° C, and carbon dioxide gas was introduced for 1 hour. After heating to room temperature over 30 minutes, the mixture was concentrated to obtain a residue. N, N-dimethylformamide of this residue (6.0 ml)
To the solution was added 1-[(6-chloronaphthalen-2-yl) sulfonyl] piperazine hydrochloride (177 mg, 510 μl).
mol) and dissolved at room temperature in 1- (dimethylaminopropyl) -3-ethylcarbodiimide (98.0 mg, 5
11 μmol) and 1-hydroxybenzotriazole (69.0 mg, 511 μmol) and diisopropylethylamine (185 μl, 1.06 mm) at 0 ° C.
ol). After stirring at room temperature overnight, methylene chloride (20 ml) and a saturated aqueous solution of sodium hydrogen carbonate (50 ml) were added to the reaction solution, and the mixture was separated.
x 10 ml). Combine the organic layers with water (50m
1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to preparative silica gel thin-layer chromatography (methylene chloride: acetone: methanol = 1).
0: 5: 1), and the obtained white solid was dissolved in a 1N-ethanol solution of hydrochloric acid, concentrated, further added with water and concentrated to give the title compound (74.
7 mg). IR (KBr) cm ^-1 : 3396, 2918, 285
0,2538,1620,1456,1432,134
4,1329,1282,1161,955,941,
729. ¹ H NMR (DMSO-d ₆ ) δ 2.68 (1 H, br
d, J = 15.1 Hz), 2.78-2.92 (1
H, br), 2.85 (3H, s), 3.04 (4H,
brs), 3.26 (1H, brs), 3.52
(1H, br s), 3.72 (4H, br s),
3.20 (1H, br d, J = 15.1 Hz);
43 (1H, br d, J = 15.1 Hz), 6.92
(1H, s), 7.71 (1H, dd, J = 2.0,
8.8 Hz), 7.80 (1H, d, J = 8.8H)
z), 8.15 (1H, d, J = 8.8 Hz), 8.2
3 (1H, s), 8.25 (1H, d, J = 8.8H)
z), 8.48 (1H, s), 11.64 (1H, br)
s). MS (FAB) m / z 474 [(M + H) ⁺ ] Elemental analysis: C ₂₃ H ₂₄ ClN ₃ O ₄ S. 1.1 HCl.
Calculated for 7H ₂ O: C, 50.72; H, 5.27; N, 7.7
1; Cl, 13.67; S, 5.89. Analytical values: C, 50.58; H, 5.39; N, 7.6.
9; Cl, 13.94; S, 5.85.

Example 83 2-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5
6,7,8-tetrahydro-1,6-naphthyridine hydrochloride 6- (t-butoxycarbonyl) -2-[[4- (chloronaphthalen-2-yl) sulfonyl] piperazine-1
-Yl] carbonyl] -5,6,7,8-tetrahydro-1,6-naphthyridine (1.28 g, 2.24 mmol
l) At room temperature, a saturated hydrochloric acid ethanol solution (50 m
1) was added and the mixture was stirred for 20 minutes, and then the reaction solution was concentrated to obtain the title compound (1.26 g) as a white solid. IR (KBr) cm ^-1 : 3396, 2924, 261
5,2544,1957,1655,1610,147
3,1454,1425,1448,1336,128
6,1157,941,731,580. ¹ H NMR (DMSO-d ₆ ) δ 3.02 (2H, br
t, J = 5.3 Hz), 3.05 (2H, t, J =
6.4 Hz), 3.42-3.49 (2H, brm),
3.52 (2H, brt, J = 5.3 Hz), 3.7
5 (2H, brt, J = 5.3 Hz), 4.33 (2
H, brt, J = 5.3 Hz), 7.56 (1H, b
rd, J = 8.3 Hz), 7.89 (1H, d, J =
8.3 Hz), 7.89 (1H, dd, J = 1.5,
8.8 Hz), 7.98 (1H, dd, J = 2.0,
8.8 Hz), 8.34 (1H, d, J = 8.8H)
z), 8.43 (1H, s), 8.44 (1H, d, J
= 8.8 Hz), 8.67 (1H, brs), 9.8
7 (2H, brs). MS (FAB) m / z 471 [(M + H) ⁺ , C
l ³⁵ ]. Elemental _{analysis: C 23 H 23 ClN 4 O} 3 S · 1.9HCl · 0.
9H ₂ O Calculated: C, 49.64; H, 4.84 ; N, 10.0
7; Cl, 18.48; S, 5.76. Analytical values: C, 49.64; H, 4.96; N, 10.0
1; Cl, 18.73; S, 5.93.

Example 84 2-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -6
Methyl-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride

[1105]

Embedded image 2-[[4- (chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5,6,
7,8-tetrahydro-1,6-naphthyridine (174
mg) in methylene chloride (3.5 ml), triethylamine (95.6 μl), acetic acid (58.9 μl), formaldehyde (37% aqueous solution, 42.0 μl), and sodium triacetoxyborohydride (110 mg)
Was added at room temperature and stirred for 15 minutes. A saturated sodium hydrogen carbonate solution (10 ml) and methylene chloride (10
ml), and the mixture is separated. The aqueous layer is separated from methylene chloride (10 ml).
Extracted. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative silica gel thin-layer chromatography (methylene chloride: methanol = 15: 1), and the obtained white solid was dissolved in a 1N-ethanol solution of hydrochloric acid and then concentrated to give the title compound as a white solid. (170 mg). IR (KBr) cm ^-1 : 3359, 2918, 254
4,1655,1641,1475,1431,134
2,1331,1284,1155,953,941,
727,579. ¹ H NMR (DMSO-d ₆ ) δ 3.04 (3H, d,
J = 3.9 Hz), 3.17 (2H, brs);
26 (2H, brs), 3.38-3.65 (2H,
m), 3.68 (2H, brs), 3.39 (2H,
brs), 4.40-4.70 (2H.m), 4.5
7 (2H, brs), 7.57 (1H, d, J = 7.
8 Hz), 7.84-7.92 (2H, m), 7.98
(1H, d, J = 8.8 Hz), 8.33 (1H, d,
J = 8.3 Hz), 8.42 (1H, s), 8.43
(1H, d, J = 8.8 Hz), 8.67 (1H,
s), 11.86 (1H, br s). MS (FAB) m / z 485 [(M + H) ⁺ , C
l ³⁵ ].

Example 85 2-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -4,
5,6,7-tetrahydro-1H-pyrrolo [3,2-
c] pyridine hydrochloride 1,5-bis (t-butoxycarbonyl) -2-[[4
-[(6-chloronaphthalen-2-yl) sulfonyl]
Piperazin-1-yl] carbonyl] -4,5,6,7
To a solution of -tetrahydro-1H-pyrrolo [3,2-c] pyridine (300 mg) at room temperature was added a saturated ethanol solution of hydrochloric acid (25 ml), and the mixture was stirred for 1 hour, and the reaction solution was concentrated.
Further, water was added, and the mixture was concentrated under reduced pressure. To this residue was added a saturated methanol solution of hydrochloric acid (25 ml) at room temperature, and after stirring for 1 hour, the reaction solution was concentrated. Further, water was added, and the mixture was concentrated under reduced pressure to obtain the title compound (200 mg) as a white solid. IR (KBr) cm ^-1 : 3290, 2918, 276
2,2559,1614,1483,1454,138
1,1340,1323,1244,1155,114
7, 1136, 978, 955, 727, 575. ¹ H NMR (DMSO-d ₆ ) δ 2.77 (2H, br
t, J = 5.9 Hz), 3.03 (4H, t, J =
5.3 Hz), 3.30 (2H, brt, J = 5.9)
Hz), 3.73 (4H, brt, J = 5.3H)
z), 3.99 (2H, brs), 6.32 (1H,
d, J = 2.0 Hz), 7.73 (1H, dd, J =
2.0, 8.8 Hz), 7.83 (1H, dd, J =
2.0, 8.8 Hz), 8.17 (1H, d, J = 8.
8Hz), 8.25 (1H, d, J = 2.0Hz),
8.28 (1H, d, J = 8.8 Hz), 8.50 (1
H, brs), 9.07 (2H, br), 11.38.
(1H, br). MS (FAB) m / z 459 [(M + H) ⁺ , C
l ³⁵ ]. Elemental _{analysis: C 22 H 23 ClN 4 O} 3 S · 1.1HCl · 0.
Calculated for 3H ₂ O: C, 52.38; H, 4.94; N, 11.1
1; Cl, 14.76; S, 6.36. Analytical values: C, 52.48; H, 4.92; N, 11.0
7; Cl, 14.48; S, 6.65.

Example 86 2-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -5-
Methyl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine hydrochloride 2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] Carbonyl] -4,
5,6,7-tetrahydro-1H-pyrrolo [3,2-
c] Pyridine hydrochloride (200 mg) was suspended in methylene chloride (4.5 ml) and triethylamine (125 mg) was added.
μl), acetic acid (77.0 μl), formaldehyde (3
7% aqueous solution, 56.1 μl) and sodium triacetoxyborohydride (139 mg) were added at room temperature.
Stir for 5 minutes. A saturated sodium hydrogen carbonate solution (20 ml) and methylene chloride (10 ml) were added to the reaction solution, and the mixture was separated. The aqueous layer was extracted with methylene chloride (2 × 10 ml).
The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue is purified by silica gel column chromatography (silica gel 25 g, methylene chloride: methanol = 10: 1 → 7: 1), and the obtained white solid is dissolved in a 1N ethanol solution of hydrochloric acid, concentrated, and further concentrated in water. And concentrated to give the title compound (133 mg) as a white solid. IR (KBr) cm ^-1 : 3213, 2918, 265
0,2530,1604,1585,1508,149
1,1456,1342,1331,1157,72
7,579. _{^{1 H NMR (DMSO-d 6}} ) δ2.72-2.86
(1H, m), 2.83 (3H, d, J = 4.9H)
z), 2.87-2.99 (1H, m), 3.03 (4
H, brt, J = 4.4 Hz), 3.19-3.31.
(1H, m), 3.46-3.64 (1H, m), 3.
74 (4H, brt, J = 4.4 Hz), 3.97
(1H, dd, J = 7.8, 14.2 Hz), 4.20
(1H, br d, J = 14.2 Hz), 6.32 (1
H, d, J = 2.4 Hz), 7.72 (1H, dd, J)
= 2.4, 8.8 Hz), 7.82 (1H, dd, J =
2.0, 8.8 Hz), 8.16 (1H, d, J = 8.
8Hz), 8.25 (1H, d, J = 2.0Hz),
8.27 (1H, d, J = 8.8 Hz), 8.51 (1
H, brs), 10.84 (1H, brs), 11.
42 (1H, brs). MS (FAB) m / z 473 [(M + H) ⁺ , C
l ³⁵ ]. Elemental _{analysis: C 23 H 25 ClN 4 O} 3 S · 1.3HCl · 0.
7H ₂ O Calculated: C, 51.83; H, 5.24 ; N, 10.5
1; Cl, 15.30; S, 6.02. Analytical values: C, 51.83; H, 5.37; N, 10.3
0; Cl, 15.35; S, 6.09.

Example 87 22-[[4-[(6-Chloronaphthalen-2-yl)]
Sulfonyl] piperazin-1-yl] carbonyl] -5
-Ethyl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine hydrochloride 2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl ] Carbonyl] -4,
5,6,7-tetrahydro-1H-pyrrolo [3,2-
c] Pyridine hydrochloride (149 mg) was suspended in methylene chloride (3.0 ml), and methanol (0.60 m
l), triethylamine (82.5 μl), acetic acid (5
1.0 ml, 891 μmol), acetaldehyde (1
9.5 μl) and sodium triacetoxyborohydride (74.0 mg) were added at room temperature, and the mixture was stirred for 15 minutes. Saturated sodium hydrogen carbonate solution (30 ml)
And methylene chloride (15 ml) were added and the mixture was separated, and the aqueous layer was extracted with methylene chloride (2 × 10 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was subjected to silica gel column chromatography (silica gel 30 g, methylene chloride: methanol = 1).
0: 1), and the obtained white solid was dissolved in a 1N-ethanol solution of hydrochloric acid (10 ml), concentrated, further added with water (30 ml), and concentrated to give the title compound (81.7 mg) as a white solid. ) Got. IR (KBr) cm ^-1 : 3386, 3226, 291
8,2586,1603,1585,1491,145
4,1427,1344,1331,1163,113
6,1078,933,727,579. ¹ H NMR (DMSO-d ₆ ) δ 1.26 (3H, t,
J = 7.3 Hz), 2.72-2.82 (1H, m),
2.86-3.00 (1H, m), 3.02 (4H, b
rs), 3.12-3.64 (6H, m), 3.73.
(4H, brs), 3.96 (1H, dd, J = 7.
8, 14.1 Hz), 4.22 (1H, br d, J =
14.1 Hz), 6.31 (1H, d, J = 2.4H)
z), 7.71 (1H, br d, J = 8.8 Hz),
7.81 (1H, br d, J = 8.8 Hz), 8.1
6 (1H, d, J = 8.8 Hz), 8.23 (1H, b
rs), 8.26 (1H, d, J = 8.8 Hz),
8.50 (1H, brs), 10.39 (1H, brs)
s), 11.40 (1H, br s). MS (FAB) m / z 486 [(M + H) ⁺ , C
l ³⁵ ]. Elemental _{analysis: C 24 H 27 ClN 4 O} 3 S · 1.2HCl · 2.
0H ₂ O Calculated: C, 50.86; H, 5.73 ; N, 9.8
8; Cl, 13.76; S, 5.66. Analytical values: C, 51.11; H, 5.71; N, 9.5.
8; Cl, 13.60; S, 5.66.

Example 88 5- (t-butoxycarbonyl) -2-[[4-[(6
-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine 2-[[4-[(6- Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -4,
5,6,7-tetrahydro-1H-pyrrolo [3,2-
c] Pyridine hydrochloride (780 mg) was suspended in methylene chloride (15 ml), saturated aqueous sodium hydrogen carbonate (15 ml) and di-t-butyl dicarbonate (5 ml).
06 ml) at room temperature and stirred for 1 hour. Water (30 ml) and methylene chloride (30 ml) were added to the reaction solution, the layers were separated, and the aqueous layer was extracted with methylene chloride (2 × 20 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. This residue was subjected to silica gel column chromatography (silica gel 75 g, methylene chloride:
(Acetone = 8: 1 → 2: 1), and the obtained white solid was dissolved in a 1N-ethanol solution of hydrochloric acid, concentrated, further added with water and concentrated to give the title compound (641 mg) as a white solid. Obtained. ¹ H NMR (CDCl ₃ ) δ 1.46 (9H, s),
2.61 (2H, brs), 3.12 (4H, brs)
t, J = 4.9 Hz), 3.66 (2H, brs),
3.90 (4H, brt, J = 4.9 Hz), 4.3
6 (2H, brs), 6.19 (1H, d, J = 2.
0 Hz), 7.57 (1H, dd, J = 1.7, 9.0)
Hz), 7.76 (1H, br d, J = 8.8H)
z), 7.86-7.97 (3H, m), 8.29 (1
H, brs), 9.24 (1H, brs).

Example 89 5- (t-Butoxycarbonyl) -2-[[4-[(6
-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] 1-methyl-4,5,6,
7-tetrahydro-1H-pyrrolo [3,2-c] pyridine 5- (t-butoxycarbonyl) -2-[[4-[(6
-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine (33.
0 mg) N, N-dimethylformamide (15 ml)
The solution was added at 0 ° C. with sodium hydride (60% in o
After stirring for 10 minutes, methyl iodide (4.5 μl) was added, and the mixture was stirred at 0 ° C. for 1 hour.
A saturated aqueous ammonium chloride solution (10 ml), methylene chloride (20 ml), and water (30 ml) were added to the reaction solution, and the mixture was separated. The aqueous layer was extracted with methylene chloride (10 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative silica gel thin-layer chromatography (methylene chloride: acetone = 9: 1) to give the title compound (32.3 mg) as a colorless and transparent caramel-like substance. ¹ H NMR (CDCl ₃ ) δ 1.46 (9H, s),
2.58 (2H, brs), 3.12 (4H, brs)
t, J = 4.5 Hz), 3.50 (3H, s), 3.6
8 (2H, brs), 3.84 (4H, brt, J
= 4.5 Hz), 4.32 (2H, brs), 6.0.
2 (1H, s), 7.58 (1H, dd, J = 2.0,
8.8 Hz), 7.77 (1H, dd, J = 1.7,
8.5Hz), 7.88-7.97 (3H, m), 8.
32 (1H, brs).

Example 90 2-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -1-
Methyl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine hydrochloride 5- (t-butoxycarbonyl) -2-[[4-[(6
-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -1-methyl-4,5,
To 6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine (280 mg) at room temperature was added a saturated ethanolic hydrochloric acid solution (25 ml), and after stirring for 1 hour, the reaction solution was concentrated and further added with water ( 10 ml) and concentrated under reduced pressure to give the title compound (210 mg) as a white solid. IR (KBr) cm ^-1 : 3381, 2918, 274
8,1622,1583,1495,1454,134
2,1331,1248,1163,1136,95
3,935,879,726,579,476. ¹ H NMR (DMSO-d ₆ ) δ 2.81 (2H, br
t, J = 5.6 Hz), 3.05 (4H, br)
s), 3.35 (2H, brt, J = 5.6 Hz),
3.42 (3H, s), 3.69 (4H, br s),
3.97 (2H, brs), 6.18 (1H, s),
7.73 (1H, dd, J = 2.0, 8.8 Hz),
7.83 (1H, dd, J = 2.0, 8.8 Hz),
8.18 (1H, d, J = 8.8 Hz), 8.27 (1
H, br s), 8.28 (1H, d, J = 8.8H)
z), 8.50 (1H, brs), 9.34 (1H,
br d, J = 27.4 Hz). MS (FAB) m / z 473 [(M + H) ⁺ , C
l ³⁵ ]. Elemental _{analysis: C 23 H 25 ClN 4 O} 3 S · 1.4HCl · 1.
2H ₂ O Calculated: C, 50.63; H, 5.32 ; N, 10.2
7; Cl, 15.59; S, 5.88. Analytical values: C, 50.71; H, 5.53; N, 10.1
4; Cl, 15.53; S, 5.90.

Example 91 2-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -1,
5-methyl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine hydrochloride

[1113]

Embedded image 2-[[4-[(6-chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] -1-
Methyl-4,5,6,7-tetrahydro-1H-pyrrolo [3,2-c] pyridine hydrochloride (170 mg) was suspended in methylene chloride (10 ml), and methanol (10 m
l), triethylamine (100 μl), acetic acid (62.
0 μl), formaldehyde (37% aqueous solution, 46.5)
μl) and sodium triacetoxyborohydride (115 mg) were added at room temperature and stirred for 30 minutes. A saturated sodium hydrogen carbonate solution (50 ml) and methylene chloride (30 ml) were added to the reaction solution, and the mixture was separated. The aqueous layer was extracted with methylene chloride (2 × 10 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue. This residue was subjected to silica gel column chromatography (silica gel 30 g, methylene chloride: methanol = 10: 1 →
7: 1), and the obtained white solid was dissolved in a 1N-ethanol solution of hydrochloric acid, concentrated, and further added with water and concentrated to obtain the title compound (162 mg) as a white solid. IR (KBr) cm ^-1 : 3396, 2924, 266
3,2586,1622,1581,1456,134
2,1329,1248,1163,1136,95
5,937,727,579. _{^{1 H NMR (DMSO-d 6}} ) δ2.77-3.00
(5H, m), 3.06 (4H, brs), 3.23
-3.37 (1H, m), 3.43 (3H, s), 3.
55-3.65 (1H, m), 3.69 (4H, br
s), 3.90-4.03 (1H, m), 3.93 (3
H, s), 4.19 (1H, br d, J = 11.7H)
z), 6.18 (1H, s), 7.74 (1H, dd,
J = 2.0, 8.8 Hz), 7.83 (1H, dd, J
= 2.0, 8.8 Hz), 8.18 (1H, d, J =
8.8 Hz), 8.27 (1H, brs), 8.28
(1H, d, J = 8.8 Hz), 8.51 (1H, br
s), 11.00 (1H, brs). MS (FAB) m / z 487 [(M + H) ⁺ , C
l ³⁵ ]. Elemental _{analysis: C 24 H 27 ClN 4 O} 3 S · 1.4HCl · 1.
Calculated for 4H ₂ O: C, 51.18; H, 5.58; N, 9.9
5; Cl, 15.11; S, 5.69. Analytical values: C, 51.09; H, 5.83; N, 9.7.
8; Cl, 15.37; S, 5.79.

Example 92 2- (N-methylcarbamoyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] -4-[(6-
Trimethylsilylethynylbenzo [b] thien-2-yl) sulfonyl] piperazine 3- (N-methylcarbamoyl) -1-[(6-trimethylsilylethynylbenzo [b] thien-2-yl) sulfonyl] piperazine (218 mg) , N-dimethylformamide (5 ml) and 5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt (188 mg), 1
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (240 mg) and 1-hydroxybenzotriazole (68 mg) were added, and the mixture was stirred at room temperature for 30 hours. Dilute the reaction with methylene chloride and wash with water (2
Times) and then washed with saturated sodium bicarbonate,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The obtained residue is subjected to silica gel column chromatography (methanol: methylene chloride = 3: 97 → 5: 95 →
7:93) to give the title compound (90 mg). MS (FAB) m / z 616 (M + H) ^<+> .

Example 93 4-[(6-Ethynylbenzo [b] thien-2-yl)
Sulfonyl] -2- (N-methylcarbamoyl) -1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 2- (N-methylcarbamoyl) -1-[(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] -4-[(6-
Trimethylsilylethynylbenzo [b] thien-2-yl) sulfonyl] piperazine (90 mg) was dissolved in a mixed solvent of tetrahydrofuran (0.5 ml) and methanol (0.5 ml), and 1N aqueous sodium hydroxide solution (0.3 ml) was added. The mixture was stirred at room temperature for 2 hours. After making it weakly acidic with a saturated aqueous ammonium chloride solution, it was made weakly alkaline with a saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with methylene chloride (4 times), and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (methanol: methylene chloride = 1: 9). The same reaction and post-treatment were repeated three times, and they were combined and purified with Sephadex LH-20 (eluted with methanol). The obtained amorphous was dissolved in methylene chloride and added dropwise to hexane to give the title compound (82 mg) as a pale gray solid. ¹ H NMR (CDCl ₃ ) δ 2.49 (3H, s),
2.80-2.90 (10H, m), 3.15-3.1
8 (1H, m), 3.22 (1H, s), 3.53-
3.62 (1H, m), 3.67 (1H, s), 4.4
9 (1H, d, J = 12.2 Hz), 4.65, 5.7
4 (total 1H, each d, J = 13.7H
z), 5.26, 6.18 (total 1H, eac
hs), 6.45, 6.49 (total 1H, e
ach s), 7.54 (1H, d, J = 8.3H)
z), 7.80 (1H, s), 7.82 (1H, d, J
= 8.3 Hz), 7.97 (1H, s). MS (FAB) m / z 544 (M + H) ^<+> .

Example 94 1-[(5-tert-butoxycarbonyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2-[[(morpholin-4-yl) Carbonyl] methyl] piperazine 1- (tert-butoxycarbonyl) -4-[(5-
Chloroindol-2-yl) sulfonyl] -2-
[[(Morpholin-4-yl) carbonyl] methyl] piperazine (930 mg) was dissolved in methylene chloride (5 ml), trifluoroacetic acid (2 ml) was added, and the mixture was added at room temperature.
Minutes. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained is N, N
-Dissolved in dimethylformamide (10 ml),
tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt (695 mg), 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide hydrochloride (506 mg) and 1-hydroxybenzotriazole (119 mg) were added, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride.
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (585 mg) as an orange foamy solid. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
2.58-3.96 (19H, m), 4.60-6.0
2 (4H, m), 6.98 (1H, s), 7.27 (1
H, d, J = 9.0 Hz), 7.38 (1H, d, J =
9.0 Hz), 7.64 (H, s), 10.39 (1
H, s).

Example 95 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methylsulfonyl-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine

[1118]

Embedded image 1-[(5-tert-butoxycarbonyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2-[[(morpholin-4-yl) Carbonyl] methyl] piperazine (585
mg) was dissolved in methylene chloride (5 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution is added, and methylene chloride (N, N
-Dimethylformamide was added thereto), and the organic layer was dried over anhydrous sodium sulfate. A 1N ethanol solution of hydrochloric acid (1 ml) was added, and the solvent was again distilled off under reduced pressure to give a hydrochloride (585 mg,
N, N-dimethylformamide containing 2 molecules).
100 mg of this was added to methylene chloride (3 ml),
Trimethylamine (0.5 ml) and methanesulfonyl chloride (20 mg) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography (methylene chloride: methanol = 9: 1), and the obtained solid was dissolved in methylene chloride and crystallized by adding ether. The title compound (3) as a white solid
4.2 mg). ¹ H NMR (DMSO-d ₆ ) δ 2.33-3.57
(20H, m), 3.72-3.79 (2H, m),
4.38, 5.39 (total 1H, each,
J = 12.2, 13.7 Hz), 4.55 (2H,
s), 5.06, 5.82 (total 1H, eac
h br s), 7.02 (1H, s), 7.30 (1
H, d, J = 8.8 Hz), 7.47 (1H, d, J =
8.8 Hz), 7.76 (1H, s), 12.41 (1
H, s). MS (FAB) m / z 671 (M + H) ^<+>

Example 96 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(4
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine trifluoroacetate 5- (tert-butoxycarbonyl) -4,5,6
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Carboxylic acid (530 mg), 4-[(5-chloronaphthalen-2-yl) sulfonyl] -2-[(N-methyl) carbamoyl] piperazine hydrochloride (527 m
g), 1-hydroxybenzotriazole monohydrate (2
00 mg), 1- (dimethylaminopropyl) -3 hydrochloride
-Ethylcarbodiimide (324 mg) was dissolved in N, N-dimethylformamide (50 ml), and triethylamine (0.18 ml) was added, followed by stirring at room temperature overnight.
The reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and water was added.
After washing once with a saturated saline solution, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 1) to obtain a pale yellow foam (577 mg). This is methylene chloride (3m
l), trifluoroacetic acid (6 ml) was added, and the mixture was concentrated under reduced pressure. The precipitated precipitate was collected by filtration while washing with diethyl ether to obtain the title compound (596 mg) as a colorless foamy solid. ¹ H NMR (DMSO-d ₆ ) δ 2.53-2.62
(3H, m), 2.63-2.74 (1H, m), 2.
90-3.06 (2H, m), 3.12-3.22
(0.5H, m), 3.39-3.59 (1.5H,
s), 3.68-3.77 (1H, m), 4.28 (1
H, d, J = 11.7 Hz), 4.28-4.50
(1.5H, m), 4.97 (0.5H, br s),
5.44 (0.5 H, d, J = 13.2 Hz), 6.1
3 (0.5H, brs), 7.72 (1H, dd, J
= 8.8, 2.0 Hz), 7.80 (1H, d, J =
8.8 Hz), 8.07-8.18 (2H, m), 8.
22-8.27 (2H, m), 8.50 (1H, s),
9.16-9.40 (1H, m). MS (FAB) m / z 534 [(M + H) ⁺ , C
l ³⁵ ], 536 [(M + H) ⁺ , Cl ³⁷ ].

Example 97 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(5-
Methylsulfonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine The title compound was synthesized in the same manner as in Example 95. ¹ H NMR (CDCl ₃ ) δ 2.61-2.87 (1
H, m), 2.88 (6H, brs), 2.89-
3.24 (3H, m), 3.45-3.90 (4H,
m), 4.43-4.60 (3H, m), 4.74,
5.21 (total 1H, each br s),
5.60-6.09 (total 1H, m), 6.3
0, 6.42 (total 1H, brs), 7.5
8 (1H, d, J = 7.6 Hz), 7.80 (1H,
d, J = 9.0 Hz), 7.89-7.91 (3H,
m), 8.35 (1H, s). MS (FAB) m / z 612 (M + H) ^<+> .

Example 98 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-dimethylaminosulfonyl-4,
5,6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine Compounds were synthesized. ¹ H NMR (DMSO-d ₆ ) δ 2.60-3.79
(25H, m), 4.38, 5.37 (total 1
H, each d, J = 13.5, 14.5 Hz),
4.53 (2H, s), 5.04, 5.75 (tota
l 1H, eachbr), 7.02 (1H, s),
7.30 (1H, dd, J = 8.8, 2.0 Hz),
7.47 (1H, d, J = 8.8 Hz), 7.76 (1
H, s), 12.41 (1H, s). MS (FAB) m / z 700 (M + H) ^<+> .

Example 99 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine hydrochloride 1- (tert-butoxycarbonyl) -4-[(5-
Chloroindol-2-yl) sulfonyl] -2-
[[(Morpholin-4-yl)] carbonyl] methyl]
Piperazine (710 mg) in ethanol (50 m
To 1), a saturated hydrochloric acid-ethanol solution (20 ml) was added at room temperature, and the mixture was stirred for 3 hours. After concentrating the reaction solution under reduced pressure, diethyl ether and ethanol were added to precipitate crystals. After being collected by filtration, it was washed with ethanol and dried under reduced pressure. This was made into an N, N-dimethylformamide solution (50 ml), and then 1-hydroxybenzotriazole (68.8 mg) and 1- (3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (11) were added at room temperature.
5.4 mg), 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt (189.0 mg), and N-methylmorpholine (140.5 mg) ) And stirred at room temperature for 19 hours. The reaction solvent was distilled off under reduced pressure, distilled water and ethyl acetate were added, the aqueous layer was extracted three times, and the combined organic layers were washed four times with distilled water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methanol: ethyl acetate = 1: 50).
The purified product was crystallized by adding diethyl ether and methylene chloride, and collected by filtration and washed with diethyl ether. A 1N hydrochloric acid-ethanol solution (0.5 ml) and a small amount of distilled water were added thereto, the solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure under heating at 60 ° C. to give the title compound (187 mg) as a yellow amorphous solid. As obtained. MS (FAB +) m / z 607 [(M + H) ⁺ , Cl
³⁵ ], 609 [(M + H) ⁺ , Cl ³⁷ ] ¹ H-NMR (DMSO-d ₆ ) δ 2.66-2.89
(1H, m), 2.99 (3H, s), 3.03-3.
29 (2H, m), 3.34-3.46 (1H, m),
3.52-3.92 (8H, m), 4.42-4.53
(1.5H, m), 4.73-4.81 (1H, m),
5.10-5.17 (0.5H, m), 5.39-5.
47 (1H, m), 5.82-5.92 (0.5H,
m), 7.12 (1H, br), 7.41 (1H, d
d, J = 2.0, 8.8 Hz), 7.58 (1H, d,
J = 8.8 Hz), 7.87 (1H, br), 12.5
7 (1H, s).

Example 100 2- (carbamoylmethyl) -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-
c] Pyridin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized as in Example 98. MS (FAB +) m / z 537 [(M + H) ⁺ , Cl
³⁵ ], 539 [(M + H) ⁺ , Cl ³⁷ ] ¹ H-NMR (DMSO-d ₆ ) δ 1.00-1.08
(1H, m), 2.65-2.68 (1H, m), 2.
88-2.94 (2H, m), 3.00-3.12 (1
H, m), 3.27-3.46 (3H, m), 3.62.
-3.73 (1H, m), 4.32-4.39 (1H,
m), 5.04-5.37 (1H, m), 6.83-
6.86 (1H, m), 7.01 (1H, s), 7.2
7-7.33 (1H, m), 7.46 (1H, d, J =
8.5 Hz), 7.76 (1H, s), 12.42 (1
H, s).

Example 101 1-[(5-Chloroisoindolin-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine -2-yl) carbonylpiperazine hydrochloride

[1125]

Embedded image The title compound was synthesized in the same manner as in Example 62. MS (FAB +) m / z 482 [(M + H) ⁺ , Cl
³⁵ ], 484 [(M + H) ⁺ , Cl ³⁷ ]. ¹ H NMR (CDCl ₃ ) δ 2.93 (3H, s),
3.08-3.19 (1H, m), 3.28-3.40
(8H, m), 3.40-3.53 (1H, br),
3.68-3.77 (2H, br), 4.28-4.4
6 (2H, m), 4.63-4.65 (4H, m),
7.33 (1H, d, J = 8.3 Hz), 7.37 (1
H, dd, J = 2.0, 8.3 Hz), 7.41 (1
H, s).

Example 102 1-[(5-Ethynylindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazine 1- (tert-butoxycarbonyl) -4-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine (300 mg) in saturated hydrochloric acid in ethanol (8.0 m)
l) was added and the mixture was stirred for 1 hour, and the reaction mixture was concentrated under reduced pressure. N, N-dimethylformamide (8.0) was added to the residue.
ml) and 1-phenylsulfonyl-5-trimethylsilylethynylindole-2-sulfonyl chloride (450
mg) at room temperature followed by diisopropylethylamine (860 μl) at 0 ° C. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to obtain a residue. The obtained residue is subjected to silica gel column chromatography (methylene chloride: acetone: methanol = 30: 10: 1 → 10: 1).
0: 1) to give a colorless caramel-like substance,
4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -1-[(1-phenylsulfonyl-5-trimethylsilylethynylindole- 2-yl) carbonyl]
Piperazine (123 mg) was obtained. This was dissolved in tetrahydrofuran (3.0 ml), and methanol (3.0 ml) was dissolved.
ml) and potassium hydroxide (22.5 mg) were added at room temperature. After stirring for 2 hours, a saturated aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture, and a saturated aqueous solution of sodium hydrogen carbonate (15 ml) and methylene chloride (10 ml) were added.
After l) was added and the mixture was separated, the aqueous layer was extracted with methylene chloride (10 ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative silica gel thin-layer chromatography (methylene chloride: acetone: methanol = 40: 10: 1) to give the title compound (39.4 mg) as a colorless solid. Further, this was dissolved in methylene chloride, methanol and water, concentrated under reduced pressure and dried to obtain the title compound as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 2.49 (3H, s),
2.81, (2H, t, J = 5.5 Hz), 2.90
(2H, t, J = 5.5 Hz), 3.04 (1H,
s), 3.22 (4H, br s), 3.68 (2H,
s), 3.88 (2H, br s), 4.57 (2H,
br s), 7.00 (1H, s), 7.37 (1H,
d, J = 8.6 Hz), 7.47 (1H, dd, J =
8.6, 1.5 Hz), 7.86 (1H, s), 8.8
8 (1H, brs). MS (FAB) m / z 470 (M + H) ^<+> .

Example 103 2- (N-methylcarbamoyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] -4-[(1-
Phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine 4- (tert-butoxycarbonyl) -2- (N-methylcarbamoyl) -1-[(5-methyl-4,5,
To a solution of 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine (410 mg) at room temperature was added a saturated hydrochloric acid methanol solution (20 ml).
After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure. This residue was treated with methylene chloride (15 ml) and 1-phenylsulfonyl-5-trimethylsilylethynylindole-2-chloride.
After adding sulfonyl (450 mg) at room temperature, diisopropylethylamine (590 μl) was added at room temperature. After stirring for 12 hours, diisopropylethylamine (590 μl) was added again at room temperature, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution (50 m
1) and methylene chloride (50 ml) were added and the mixture was separated, and the aqueous layer was extracted with methylene chloride (2 × 20 ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1) to give the title compound (3) as a colorless transparent glassy substance.
89 mg). ¹ H NMR (CDCl ₃ ) δ 0.25 (9H, s),
2.50 (3H, d, J = 8.3 Hz), 2.65 −
3.02 (8H, m), 3.05-3.30 (2H,
m), 3.70 (2H, brs), 4.13 (1H,
d, J = 13.4 Hz), 4.40 (1H, d, J = 1)
3.4 Hz), 4.67 (1 / 2H, d, J = 13.4)
Hz), 5.24 (1 / 2H, brs), 5.66
(1 / 2H, d, J = 14.0 Hz), 6.08 (1 /
2H, brs), 6.39 (1H, brs), 7.4
1 (2H, t, J = 7.7 Hz), 7.47-7.63
(3H, m), 7.71 (1H, s), 8.02 (2
H, d, J = 7.8 Hz), 8.18 (1H, d, J =
8.8 Hz). MS (FAB) m / z 739 (M + H) ^<+> .

Example 104 4-[(5-Ethynylindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine 2- (N-methylcarbamoyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] -4-[(1-
Phenylsulfonyl 5-trimethylsilylethynylindol-2-yl) carbonyl] piperazine (350 m
g) was dissolved in tetrahydrofuran (5.0 ml), and methanol (5.0 ml) and potassium hydroxide (102 ml) were dissolved.
g) was added at room temperature. After stirring for 4 hours, a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and methylene chloride (50 ml) were added to the reaction mixture, and the mixture was separated.
0 ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methylene chloride:
Purification was performed twice using methanol (20: 1) to give the title compound (126 mg) as a colorless solid. Further, this was dissolved in methylene chloride, methanol and water, concentrated under reduced pressure and dried to obtain the above compound as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 2.51 (3H, s),
2.75-3.30 (11H, m), 3.58-3.8
5 (3H, m), 4.50-4.70 (2H, m),
5.25 (1 / 2H, brs), 5.64 (1/2
H, d, J = 11.5 Hz), 6.10 (1 / 2H, b)
rs), 6.53 (1 / 2H, br s), 7.10
(1H, s), 7.43 (2H, s), 7.85 (1
H, s), 10.78 (1H, d, J = 9.5 Hz). MS (FAB) m / z 527 (M + H) ^<+> .

Example 105 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridine- 2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 2.92 (3H,
s), 3.04-3.28 (6H, m), 3.35-
3.90 (4H, m), 4.12-4.70 (4H,
m), 7.69 (1H, dd, J = 8.8, 2.0H
z), 7.82 (1H, dd, J = 8.8, 2.0H
z), 8.14 (1H, d, J = 8.8 Hz), 8.2
1 (1H, s), 8.25 (1H, dd, dd, J =
8.8, 2.0 Hz), 8.50 (1H, s), 11.
27 (1H, brs). MS (FAB) m / z 491 [(M + H) ⁺ , C
l ³⁵ ], 493 [(M + H) ⁺ , Cl ³⁷ ].

Example 106 4-[(5-Chloronaphthalen-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [4
5-c] pyridin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 62. _{^{1 H NMR (DMSO-d 6}} ) δ2.43-2.81
(5H, m), 2.89-2.95 (4H, m), 3.
22-3.80 (6H, m), 4.16-4.65
(2.5H, m), 5.01 (0.5H, s), 5.3
6-5.45 (0.5H, m), 6.06 (0.5H,
br s), 7.00 (1H, s), 7.29 (1H,
d, J = 8.8 Hz), 7.48 (1H, d, J = 8.
8 Hz), 7.75 (1H, s), 11.25-11.
40 (1H, m), 12.43 (1H, s). MS (FAB) m / z 537 [(M + H) ⁺ , C
l ³⁵ ], 539 [(M + H) ⁺ , Cl ³⁷ ].

Example 107 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(5-
Isopropyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 1.31-1.40
(6H, m), 2.38-2.75 (5H, m), 3.
10-3.80 (8H, m), 4.22-4.50
(2.5H, m), 4.97 (1 / 2H, brs),
5.35-5.49 (1 / 2H, m), 6.13 (1 /
4H, brs), 6.19 (1 / 4H, brs),
7.70 (1H, d, J = 8.8 Hz), 7.79 (1
H, d, J = 8.8 Hz), 8.09-8.28 (4
H, m), 8.49 (1H, s), 10.80-11.
34 (1H, m). MS (FAB) m / z 576 [(M + H) ⁺ , C
l ³⁵ ], 578 [(M + H) ⁺ , Cl ³⁷ ].

Example 108 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(thiazolo [5,4-c] pyridin-2-
Yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 3.20 (4H, br
s), 3.84 (2H, br s), 4.35 (2
H, br s), 7.28 (1H, dd, J = 8.8,
2.5 Hz), 7.47 (1H, dd, J = 8.8,
2.0 Hz), 7.74 (1H, d, J = 2.0H)
z), 8.05 (1H, d, J = 5.4 Hz), 8.6
7 (1H, d, J = 5.4 Hz), 9.44 (1H, d, J = 5.4 Hz)
s), 12.41 (1H, s). MS (FAB) m / z 462 [(M + H) ⁺ , C
l ³⁵ ], 464 [(M + H) ⁺ , Cl ³⁷ ].

Example 109 2-[[4-[(5-chloroindole-2-iodide)
Yl) sulfonyl] piperazin-1-yl] carbonyl] -5-methylthiazolo [5,4-c] pyridinium The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 3.14-3.28
(4H, m), 3.86 (2H, brs), 4.29
(2H, br s), 4.49 (3H, s), 7.04
(1H, s), 7.30 (1H, dd, J = 8.8,
2.0 Hz), 7.48 (1H, d, J = 8.8H)
z), 7.76 (1H, s), 8.72 (1H, d, J
= 6.8 Hz), 9.00 (1H, d, J = 6.8H)
z), 9.94 (1H, s), 12.44 (1H, br)
s). MS (FAB) m / z 476,478.

Example 110 1-[(5-tert-Butoxycarbonyl-7-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] -4-[(5-
Chloroindol-2-yl) sulfonyl] -2- (N
-Methylcarbamoyl) piperazine hydrochloride The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 1.38 (3H, d,
J = 6.6 Hz), 1.42 (9H, s), 2.55-
2.80 (5H, m), 3.31 (3H, s), 3.4
6-3.56 (1 / 2H, m), 3.61-3.72
(1H, m), 3.81-3.90 (1H, m), 4.
18-4.29 (2H, m), 4.43-4.48 (1
/ 2H, m), 4.91-5.05 (1H, m), 5,
26-5.45 (1H, m), 6.15-6.25 (2
H, m), 6.98-7.03 (1H, m), 7.26
−7.33 (1H, m), 7.41-7.50 (1H,
m), 7.73-7.80 (1H, m), 8.02-
8.17 (1H, m), 12.40 (1H, s). MS (FAB) m / z 637 [(M + H) ⁺ , C
l ³⁵ ], 639 [(M + H) ⁺ , Cl ³⁷ ].

Example 111 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(4-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] Pyridin-2-yl) carbonyl] piperazine trifluoroacetate The title compound was synthesized in the same manner as in Example 35. ¹ H NMR (DMSO-d ₆ ) δ 1.55 (3H, d,
J = 6.4 Hz), 2.28-2.76 (5H, m),
2.88-3.10 (2H, m), 3.25-3.65
(1H, m), 4.20-4.30 (1H, m), 4.
40-4.50 (1 / 2H, m), 4.83 (1H, b
rs), 4.92-5.02 (1 / 2H, m), 5.
40-5.50 (1 / 2H, m), 6.13 (1/2
H, s), 7.00 (1H, s), 7.30 (1H,
d, J = 8.8 Hz), 7.46 (1H, d, J = 8.
8 Hz), 7.76 (1H, s), 8.06-8.14
(1H, m), 8.93-9.62 (2H, m), 1
2.40 (1H, s). MS (FAB) m / z 537 [(M + H) ⁺ , C
l ³⁵ ], 539 [(M + H) ⁺ , Cl ³⁷ ].

Example 112 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(4,5-dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine hydrochloride

[1137]

Embedded image The title compound was synthesized in the same manner as in Example 32. ¹ H NMR (DMSO-d ₆ ) δ 1.40-1.70
(3H, m), 2.40-2.80 (4H, m), 2.
92 (3H, brs), 3.00-3.25 (2H,
m), 3.40-3.80 (1H, m), 4.19-
4.30 (1H, m), 4.39-4.50 (1/2)
H, m), 4.66-4.82 (1 / 2H, brs),
5.00 (1 / 2H, brs), 5.40-5.55
(1 / 2H, m), 5.73 (1 / 2H, brs),
6.17 (1 / 2H, brs), 7.00 (1H,
s), 7.30 (1H, d, J = 8.8 Hz), 7.4
6 (1H, d, J = 8.8 Hz), 7.76 (1H,
s), 8.05-8.20 (1H, m), 12.41.
(1H, s). MS (EI) m / z 550 (M +, Cl 35), 552
(M ⁺ , Cl ³⁷ ).

Example 113 2- [N-[(5-acetoxy-4-oxo-4H-pyran-2-yl) methyl] carbamoyl] -4-[(5
-Chloroindol-2-yl) sulfonyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ at 100 ° C.) δ2.
22 (3H, s), 2.38 (3H, s), 2.65-
2.89 (8H, m), 3.64 (2H, s), 3.7
0 (1H, d, J = 11.0 Hz), 4.28 (1H,
d, J = 12.4 Hz), 6.30 (1H, s), 6.
98 (1H, s), 7.26 (1H, dd, J = 9.
2,1.8 Hz), 7.46 (1H, d, J = 9.2H)
z), 7.70 (1H, d, J = 1.8 Hz), 8.2
8 (1H, s), 8.51 (1H, s), 12.00
(1H, brs). MS (FAB) m / z 689 [(M + H) ⁺ , C
l ³⁵ ], 691 [(M + H) ⁺ , Cl ³⁷ ].

Example 114 4-[(5-Chloroindol-2-yl) sulfonyl] -2- [N-[(5-hydroxy-4-oxo-4
H-pyran-2-yl) methyl] carbamoyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 23. ¹ H NMR (DMSO-d ₆ at 100 ° C.) δ2.
71-2.84 (1H, m), 2.90 (3H, s),
3.00 (1H, dd, J = 12.2, 4.3 Hz),
3.06-3.28 (4H, m), 3.54 (2H, b
rs), 3.74 (1H, d, J = 12.0 Hz),
4.09-4.28 (4H, m), 4.52 (2H, b
rs), 7.00 (1H, d, J = 1.2 Hz),
7.29 (1H, dd, J = 9.2, 1.8 Hz),
7.50 (1H, d, J = 9.2 Hz), 7.73 (1
H, d, J = 1.8 Hz), 7.91 (1H, s),
8.60 (1H, s), 12.14 (1H, br)
s). MS (FAB) m / z 647 [(M + H) ⁺ , C
l ³⁵ ], 649 [(M + H) ⁺ , Cl ³⁷ ].

Example 115 N-[[4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4- c] Pyridin-2-yl) carbonyl] piperazin-2-yl] acetyl] methanesulfonamide hydrochloride The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 2.61-3.10
(8H, m), 3.15 (3H, s), 3.34-3.
81 (4H.m), 3.90-4.48 (2.5H,
m), 4.60-4.72 (1H, m), 5.10
(0.5H, brs), 5.29-5.39 (0.5
H, m), 5.80-6.00 (0.5H, m), 7.
02 (1H, s), 7.30 (1H, d, J = 8.8H)
z), 7.48 (1H, d, J = 8.8 Hz), 7.7
5 (1H, s), 11.45-11.70 (1H,
m), 11.85-12.00 (1H, m), 12.4
6 (1H, brs). MS (FAB) m / z 615 [(M + H) ⁺ , C
l ³⁵ ], 617 [(M + H) ⁺ , Cl ³⁷ ].

Example 116 N-[[1-[(5-tert-butoxycarbonyl-)
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazine-2
-Yl] acetyl] methanesulfonamide The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 1.40 (9H,
s), 2.62-2.93 (6H, m), 3.09-
3.20 (3H, m), 3.40-3.50 (0.5
H, m), 3.60-3.78 (4.5H, m), 4.
35-4.43 (0.5H, m), 4.61 (2H,
s), 5.07-5.14 (0.5H, m), 5.30.
−5.40 (0.5H, m), 5.90−6.00
(0.5H, m), 7.03 (1H, s), 7.29
(1H, dd, J = 8.8, 2.0 Hz), 7.45
(1H, d, J = 8.8 Hz), 7.74 (1H, d, J = 8.8 Hz)
s), 11.84 (1H, br s), 12.39 (1
H, brs). MS (FAB) m / z 701 [(M + H) ⁺ , C
l ³⁵ ], 703 [(M + H) ⁺ , Cl ³⁷ ].

Example 117 N-[[4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazin-2-yl] acetyl] methanesulfonamide trifluoroacetate The title compound was synthesized in the same manner as in Example 35. ¹ H NMR (DMSO-d ₆ ) δ 2.64-3.04
(6H, m), 3.15 (3H, d, J = 7.1H
z), 3.41-3.53 (2H, m), 3.60-
3.80 (4H, m), 4.35-4.43 (0.5
H, m), 4.44 (2H, s), 5.06-5.12.
(0.5H, m), 5.25-5.35 (0.5H,
m), 5.86 (0.5H, brs), 7.02 (1
H, s), 7.29 (1H, dd, J = 8.8, 2.0
Hz), 7.46 (1H, d, J = 8.8 Hz), 7.
75 (1H, s), 9.25 (2H, brs), 1
1.86 (1H, brs), 12.42 (1H, brs)
s). MS (FAB) m / z 601 [(M + H) ⁺ , C
l ³⁵ ], 603 [(M + H) ⁺ , Cl ³⁷ ].

Example 118 N-[[1-[[5- (1-acetoxyethoxy) carbonyl-4,5,6,7-tetrahydrothiazolo [5
4-c] pyridin-2-yl) carbonyl] -4-
[(5-chloroindol-2-yl) sulfonyl] piperazin-2-yl] acetyl] methanesulfonamide N-[[4-[(5-chloroindol-2-yl) sulfonyl] -1-[(4, 5,6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] acetyl] methanesulfonamide trifluoroacetate (97 mg) is dissolved in ethanol (2 ml). , Triethylamine (0.63m
l,) and 1-acetoxyethyl p-nitrophenyl carbonate (110 mg) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and the mixture was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 50: 1) to give the title compound (50 mg) as a colorless foam. ¹ H NMR (DMSO-d ₆ ) δ 1.42 (3H, br
s), 2.01 (3H, br s), 2.60-2.
90 (6H, m), 3.07-3.16 (3H, m),
3.64-3.80 (4H, m), 4.09-4.12.
(0.5H, m), 4.35-4.41 (0.5H,
m), 4.63-4.77 (2.5H, m), 5.05
-5.11 (0.5H, m), 5.32-5.39
(0.5H, m), 5.89-5.96 (0.5H,
m), 6.62-6.70 (1H, m), 7.02 (1
H, s), 7.29 (1H, d, J = 8.8 Hz),
7.46 (1H, d, J = 8.8 Hz), 7.75 (1
H, s), 11.88 (1H, br s), 12.44.
(1H, brs). MS (FAB) m / z 731 [(M + H) ⁺ , C
l ³⁵ ], 733 [(M + H) ⁺ , Cl ³⁷ ].

Example 119 4-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 2.62 (3H,
s), 2.66-4.49 (13.5H, m), 4.6.
0-4.76 (1H, m), 5.05 (1 / 2H, br)
s), 5.50-5.62 (1 / 2H, m), 6.1.
5-6.27 (1 / 2H, m), 7.57 (1H, d,
J = 8.8 Hz), 8.07 (1H, d, J = 8.8H)
z), 8.08 (1H, s), 8.17 (1 / 2H, b
rs), 8.23 (1 / 2H, brs), 8.37
(1H, s). MS (FAB) m / z 554 [(M + H) ⁺ , C
l ³⁵ ], 556 [(M + H) ⁺ , Cl ³⁷ ].

Example 120 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(thiazolo [4,5-c] pyridine-2-
Yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (CDCl ₃ ) δ 3.27 (4H, br
s), 3.90-4.03 (2H, m), 4.61-
4.73 (2H, m), 7.58 (1H, dd, J =
8.8, 2.0 Hz), 7.79 (1H, dd, J =
8.8, 2.0 Hz), 7.85-8.01 (4H,
m), 8.34 (1H, s), 8.59 (1H, d, J
= 5.4 Hz), 9.35 (1H, d, J = 1.0H)
z). MS (FAB) m / z 473 [(M + H) ⁺ , C
l ³⁵ ], 475 [(M + H) ⁺ , Cl ³⁷ ].

Example 121 2-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl] thiazolo [4,5-c] pyridine N-oxide Same as in Example 34 The title compound was synthesized by the method described above. ¹ H NMR (DMSO-d ₆ ) δ 3.15 (4H, br
s), 3.80 (2H, br s), 4.32 (2
H, br s), 7.70 (1H, dd, J = 8.8,
2.0 Hz), 7.83 (1H, dd, J = 8.8,
2.0 Hz), 8.15 (1H, d, J = 8.8H)
z), 8.18 (1H, d, J = 8.8 Hz), 8.2
2 (1H, s), 8.25 (1H, d, J = 8.8H
z), 8.30 (1H, d, J = 2.0 Hz), 8.3
2 (1H, d, J = 1.5 Hz), 8.51 (1H,
s), 9.03 (1H, d, J = 1.5 Hz). MS (FAB) m / z 489 [(M + H) ⁺ , C
l ³⁵ ], 491 [(M + H) ⁺ , Cl ³⁷ ].

Example 122 2-[[4-[(6-chloronaphthalene-2-iodide)
Yl) sulfonyl] piperazin-1-yl] carbonyl] -5-methylthiazolo [4,5-c] pyridinium The title compound was synthesized in the same manner as in Example 33. ¹ H NMR (DMSO-d ₆ ) δ 3.10-3.25
(4H, m), 3.85 (2H, brs), 4.29
(2H, br s), 4.47 (3H, s), 7.71
(1H, dd, J = 8.8, 2.0 Hz), 7.84
(1H, d, J = 8.8 Hz), 8.17 (1H, d,
J = 8.8 Hz), 8.23 (1H, s), 8.26
(1H, d, J = 8.8 Hz), 8.53 (1H,
s), 8.86 (1H, d, J = 6.8 Hz), 8.9
0 (1H, d, J = 6.8 Hz), 10.03 (1H,
s). MS (FAB) m / z 487, 489.

Example 123 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(thiazolo [4,5-c] pyridin-2-yl) carbonyl ]
Piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ at 100 ° C.) δ2.
61 (3H, d, J = 4.9 Hz), 2.75-2.8
8 (1H, m), 2.98 (1H, dd, J = 12.
7, 4.9 Hz), 3.20-3.80 (1H, m),
4.29 (1H, d, J = 2.7 Hz), 4.90 −
5.48 (1H, m), 7.61 (1H, dd, J =
8.8, 2.0 Hz), 7.79 (1H, brs),
7.81 (1H, dd, J = 8.8, 2.0 Hz),
8.04-8.10 (2H, m), 8.12 (1H,
d, J = 5.4 Hz), 8.15 (1H, d, J = 8.
8 Hz), 8.44 (1H, d, J = 1.0 Hz),
8.56 (1H, d, J = 5.4 Hz), 9.28 (1
H, brs). MS (FAB) m / z 530 [(M + H) ⁺ , C
l ³⁵ ], 532 [(M + H) ⁺ , Cl ³⁷ ].

Example 124 2-[[4-[(6-chloronaphthalene-2-iodide) iodide
Yl) sulfonyl] -2- (N-methylcarbamoyl)
Piperazin-1-yl] carbonyl] -5-methylthiazolo [4,5-c] pyridinium The title compound was synthesized in the same manner as in Example 3. ¹ H NMR (DMSO-d ₆ at 100 ° C.) δ2.
62 (3H, d, J = 4.4 Hz), 2.77-2.8
7 (1H, m), 2.94-3.03 (1H, m),
3.10-3.90 (2H, m), 4.31 (1H,
d, J = 12.7 Hz), 4.50 (3H, s), 4.
85-5.85 (2H, m), 7.64 (1H, dd,
J = 8.8, 2.0 Hz), 7.80 (1H, dd, J
= 8.8, 2.0 Hz), 7.82-7.90 (1H,
m), 8.10 (1H, d, J = 8.8 Hz), 8.1
2 (1H, d, J = 2.0 Hz), 8.17 (1H, d, J = 2.0 Hz)
d, J = 8.8 Hz), 8.45 (1H, s), 8.8
6 (2H, d, J = 1.5 Hz), 9.93 (1H, b
rs). MS (FAB) m / z 544 (M +, Cl 35), 54
6 (M ⁺ , Cl ³⁷ ).

Example 125 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [4
5-c] pyridin-2-yl) carbonyl] piperazine hydrochloride It was synthesized by the same method as the sodium borohydride reduction used in Reference Example 161. ) ¹ H NMR (DMSO-
_{d 6) δ2.41-2.80 (5H, m} ), 3.12-
3.78 (7H, m), 4.15-4.60 (2.5
H, m), 4.97 (0.5H, brs), 5.35
−5.48 (0.5H, m), 6.03 (0.5H, b
rs), 7.70 (1H, dd, J = 8.8, 2.0
Hz), 7.79 (1H, d, J = 8.8 Hz), 8.
06-8.20 (2H, m), 8.22 (1H, s),
8.24 (1H, d, J = 8.8 Hz), 8.48 (1
H, s), 11.20-11.63 (1H, m). MS (FAB) m / z 548 [(M + H) ⁺ , C
l ³⁵ ], 550 [(M + H) ⁺ , Cl ³⁷ ].

Example 126 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5-ethyl-4,5,6,7-tetrahydrothiazolo [4,5-c] pyridine- 2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine hydrochloride The title compound was synthesized in the same manner as in Reference Example 161. ¹ H NMR (DMSO-d ₆ ) δ 1.28-1.40
(3H, m), 2.40-2.79 (5H, m), 3.
10-3.83 (10H, m), 4.15-4.60
(2.5H, m), 4.97 (0.5H, br s),
5.35-5.45 (0.5H, m), 6.05-6.
12 (0.5H, m), 7.70 (1H, dd, J =
8.8, 2.0 Hz), 7.79 (1H, d, J = 8.
8Hz), 8.05-8.17 (2H, m), 8.22
(1H, s), 8.24 (1H, d, J = 8.8H
z), 8.49 (1H, s), 11.01-11.20
(1H, m). MS (FAB) m / z 562 [(M +
H) ⁺ , Cl ³⁵ ], 564 [(M + H) ⁺ , Cl ³⁷ ].

Example 127 [2-[[4-[(6-chloronaphthalen-2-yl)]
Sulfonyl] piperazin-1-yl] carbonyl]-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-5-yl] acetic acid tert-butyl ester 1-[(6-chloronaphthalen-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine -2-yl) carbonyl] piperazine hydrochloride (240 mg) was dissolved in N, N-dimethylformamide (50 ml), and triethylamine (0.28 ml) was added.
Butyl ester (0.14 ml) was added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Φ3.0 × 12.0 cm, hexane: ethyl acetate = 3: 2) to obtain the title compound (207 mg) as a colorless foam. . ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s),
2.86-2.92 (2H, m), 3.00 (2H,
t, J = 5.4 Hz) 3.18 (4H, brs),
3.35 (2H, s), 3.87 (2H, br s),
3.90 (2H, s), 4.55 (2H, br s),
7.57 (1H, dd, J = 8.8, 2.0 Hz),
7.76 (1H, dd, J = 8.8Hz, 2.0H
z), 7.87-7.93 (3H, m), 8.31 (1
H, s). MS (FAB) m / z 591 [(M + H) ⁺ , C
l ³⁵ ], 593 [(M + H) ⁺ , Cl ³⁷ ].

Example 128 [2-[[4-[(6-chloronaphthalen-2-yl)]
Sulfonyl] piperazin-1-yl] carbonyl]-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-5-yl] acetic acid ethyl ester The title compound was synthesized in the same manner as in Example 127. ¹ H NMR (CDCl ₃ ) δ 1.28 (3H, t, J =
7.3 Hz), 2.85-2.95 (2H, m), 2.
97-3.07 (2H, m), 3.18 (4H, br
s), 3.46 (2H, s), 3.87 (2H, br)
s), 3.92 (2H, s), 4.20 (2H, q, J
= 7.3 Hz), 4.55 (2H, brs), 7.57
(1H, d, J = 8.8 Hz), 7.76 (1H, d,
J = 8.8 Hz), 7.82-7.95 (3H, m),
8.31 (1H, s). MS (FAB) m / z 477 [(M + H) ⁺ , C
l ³⁵ ], 479 [(M + H) ⁺ , Cl ³⁷ ].

Example 129 [2-[[4-[(6-chloronaphthalen-2-yl)]
Sulfonyl] piperazin-1-yl] carbonyl]-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-5-yl] acetic acid trifluoroacetate [2-[[4-[(6-chloronaphthalen-2-yl)]
Sulfonyl] piperazin-1-yl] carbonyl]-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-5-yl] acetic acid tert-butyl ester (200 mg) was dissolved in methylene chloride (1 ml),
Trifluoroacetic acid (2 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diethyl ether was added to the residue, and the deposited precipitate was collected by filtration to give the title compound (193).
mg) as a colorless foam. ¹ H NMR (DMSO-d ₆ ) δ 2.96 (2H, br
s), 3.08 (4H, br s), 3.27-3.
96 (6H, m), 4.37 (4H, brs), 7.
70 (1H, dd, J = 8.8, 2.0 Hz), 7.8
2 (1H, d, J = 8.8 Hz), 8.20-8.28
(3H, m), 8.50 (1H, s). MS (FAB)
m / z 535 [(M + H) ⁺ , Cl ³⁵ ], 537
[(M + H) ⁺ , Cl ³⁷ ].

Example 130 N-[[2-[[4- (6-Chloronaphthalen-2-yl) sulfonyl] piperazin-1-yl] carbonyl]
-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-5-yl] acetyl] methanesulfonamide hydrochloride [2-[[4-[(6-chloronaphthalen-2-yl)]
Sulfonyl] piperazin-1-yl] carbonyl]-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-5-yl] acetic acid trifluoroacetate (11
0 mg) was dissolved in tetrahydrofuran (20 ml), carbonyldiimidazole (60 mg) was added, and the mixture was heated under reflux for 1 hour. After the reaction solution was cooled to room temperature, methanesulfonamide (34 mg) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.05 ml) were used.
Was added and stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and the mixture was washed once with water, 0.2N hydrochloric acid, and saturated saline each. The extracted organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 4) to obtain a colorless foam. This was suspended in 1N hydrochloric acid-ethanol solution (1 ml), concentrated under reduced pressure, and azeotroped with water to give the title compound (44 mg) as a pale yellow foam. ¹ H NMR (DMSO-d ₆ ) δ 3.00 (2H, br
s), 3.11 (4H, br s), 3.28 (3
H, s), 3.32-4.06 (6H, m), 4.40.
(4H, brs), 7.70 (1H, dd, J = 8.
8, 2.0 Hz), 7.82 (1H, d, J = 8.8H)
z), 8.14 (1H, d, J = 8.8 Hz), 8.2
2 (1H, s), 8.25 (1H, d, J = 8.8H
z), 8.50 (1H, s). MS (FAB) m / z 612 [(M + H) ⁺ , C
l ³⁵ ], 614 [(M + H) ⁺ , Cl ³⁷ ].

Example 131 [4-[[4-[(6-chloronaphthalen-2-yl)]
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] carbonyl]
Piperazin-1-yl] acetic acid ethyl ester hydrochloride The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ at 100 ° C.) δ1.
26 (3H, t, J = 7.2 Hz), 2.80-3.3
5 (13H, m), 3.44-3.89 (11H,
m), 4.20 (2H, q, J = 7.2 Hz), 4.5
2 (2H, brs), 7.67 (1H, dd, J =
8.8, 1.7 Hz), 7.81 (1H, d, J = 8.
8, 1.7 Hz), 8.11 (1H, d, J = 8.8H)
z), 8.16 (1H, s), 8.19 (1H, d, J
= 8.8 Hz), 8.47 (1H, s). MS (FAB) m / z 689 [(M + H) ⁺ , C
l ³⁵ ], 691 [(M + H) ⁺ , Cl ³⁷ ].

Example 132 [4-[[4-[(6-Chloronaphthalen-2-yl)]
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] carbonyl]
Piperazin-1-yl] acetic acid hydrochloride The title compound was synthesized in the same manner as in Example 23. ¹ H NMR (DMSO-d ₆ at 100 ° C.) δ2.
84-2.93 (5H, m), 3.10-3.34 (7
H, m), 3.45-3.61 (2H, m), 3.70
-4.70 (12H, m), 7.67 (1H, dd, J
= 8.8, 2.0 Hz), 7.81 (1H, d, J =
8.8, 1.7 Hz), 8.11 (1H, d, J = 8.
8Hz), 8.17 (1H, s), 8.20 (1H,
d, J = 8.8 Hz), 8.48 (1H, s). MS (FAB) m / z 661 [(M + H) ⁺ , C
l ³⁵ ], 663 [(M + H) ⁺ , Cl ³⁷ ].

Example 133 N-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4- c] pyridin-2-yl) carbonyl] piperazin-2-yl] carbonyl]
Methanesulfonamide hydrochloride 2-carbamoyl-4-[(6-chloronaphthalene2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-Tetrahydrothiazolo [4,5-c] pyridin-2-yl) carbonyl] piperazine (300 mg) was dissolved in tetrahydrofuran (30 ml), and a 0.5 molar toluene solution of potassium bis (trimethylsilyl) amide (1. 12 ml) and stirred under ice cooling for 10 minutes. Methanesulfonyl chloride (0.04 ml) was added to the reaction solution, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and the mixture was washed once with water and once with a saturated saline solution. The extracted organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 0 to 100: 3) to give a colorless foam. This was suspended in 1N hydrochloric acid (1 ml) and concentrated under reduced pressure to obtain the title compound (96 mg) as a pale yellow foam. _{^{1 H NMR (DMSO-d 6}} ) δ2.73-2.84
(1H, m), 2.90 (6H, s), 3.09-3.
77 (8H, m), 3.99-4.27 (1H, m),
4.39-4.51 (1H, m), 4.69-4.79
(1H, m), 4.99 (1H, s), 7.64-7.
73 (2H, m), 8.06-8.10 (1H, m),
8.12-8.19 (1H, m), 8.44 (1H,
s), 11.41 (1H, br s), 11.52 (1
H, s). MS (FAB) m / z 612 [(M + H) ⁺ , C
l ³⁵ ], 614 [(M + H) ⁺ , Cl ³⁷ ].

Example 134 5- [2- [4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl) carbonyl] piperazin-2-yl] ethyl] tetrazole trifluoroacetate 5-tert-butoxycarbonyl-4,5,6,7-
Lithium salt of tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid (329 mg), 5- [2- [4
-[(6-chloronaphthalen-2-yl) sulfonyl]
Piperazin-2-yl] ethyl] tetrazole trifluoroacetate (295 mg), 1-hydroxybenzotriazole monohydrate (9 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11 mg)
4 mg) in N, N-dimethylformamide (10 ml)
And allowed to stir at room temperature overnight. The reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and the mixture was washed once with water and saturated saline, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methylene chloride: methanol = 25:
Purification according to 2) gave a pale yellow foam (48 mg). This was dissolved in methylene chloride (1 ml), trifluoroacetic acid (1 ml) was added, and the mixture was concentrated under reduced pressure.
The deposited precipitate was collected by filtration while washing with diethyl ether to give the title compound (48 mg) as a colorless solid. ¹ H NMR (DMSO-d ₆ ) δ1.12-1.40
(2H, m), 1.95-3.00 (7H, m), 3.
42-3.47 (1H, m), 3.60-3.88
(2.5H, m), 4.10-4.15 (0.5H, b
rs), 4.38-4.45 (2H, m), 4.67.
-4.80 (1H, m), 5.25-5.31 (0.5
H, m), 5.58-5.65 (0.5H, m), 7.
70 (1H, d, J = 8.8 Hz), 7.82 (1H, d, J = 8.8 Hz)
d, J = 8.8 Hz), 8.14 (1H, d, J = 8.
8 Hz), 8.18-8.26 (2H, m), 8.46
-8.50 (1H, m). MS (FAB) m / z 573 [(M + H) ⁺ , C
l ³⁵ ], 575 [(M + H) ⁺ , Cl ³⁷ ].

Example 135 5- [2- [4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazin-2-yl] ethyl]
Tetrazole The title compound was synthesized in the same manner as in Example 32. ¹ H NMR (DMSO-d ₆ ) δ 1.08-1.40
(2H, m), 1.90-3.84 (15.5H,
m), 4.10 (0.5H, brs), 4.32-
4.43 (0.5H, m), 4.72-4.80 (0.
5H, m), 5.35-5.43 (0.5H, m),
5.69-5.80 (0.5H, m), 7.68 (1
H, dd, J = 8.8, 2.0 Hz). MS (FAB) m / z 587 [(M + H) ⁺ , C
l ³⁵ ], 589 [(M + H) ⁺ , Cl ³⁷ ].

Example 136 5-[[[[4-[(6-chloronaphthalen-2-yl)]
Sulfonyl] -1-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] carbonyl] amino] methyl] tetrazole trifluoroacetate The title compound was synthesized in the same manner as in Example 134. ¹ H NMR (DMSO-d ₆ ) δ 2.63-2.78
(1H, m), 2.85-2.93 (1H, m), 2.
99-3.05 (1H, m), 3.28-3.79 (6
H, m), 4.27-4.34 (1H, m), 4.40.
-4.70 (3.5H, m), 5.13-5.16
(0.5H, m), 5.48-5.56 (0.5H,
m), 6.10-6.13 (0.5H, m), 7.70
(1H, d, J = 8.8 Hz), 7.79 (1H, d,
J = 8.8 Hz), 8.08-8.26 (3H, m),
8.48 (1H, s), 8.89-9.00 (1H,
m). MS (FAB) m / z 602 [(M + H) ⁺ , C
l ³⁵ ], 604 [(M + H) ⁺ , Cl ³⁷ ].

Example 137 5-[[[[4-[(6-chloronaphthalen-2-yl)
Sulfonyl] -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazin-2-yl] carbonyl]
Amino] methyl] tetrazole The title compound was synthesized in the same manner as in Example 32. ¹ H NMR (DMSO-d ₆ ) δ 2.36 (3H,
s), 3.59 (1H, d, J = 12.2 Hz);
65-3.75 (1H, m), 4.16-4.56
(4.5H, m), 5.06 (0.5H, br s),
5.48-5.57 (0.5H, m), 6.20 (0.
5H, brs), 7.67 (1H, dd, J = 8.
8, 2.0 Hz), 7.80 (1H, d, J = 8.8H)
z), 8.05-8.35 (4H, m), 8.49 (1
H, s).

Example 138 5-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazin-2-yl] methyl] -2,3-dihydro-2-oxo-1,3,4-oxadiazole trifluoroacetate The title compound was synthesized by a method similar to that in Example 134. did. _{^{1 H NMR (DMSO-d 6}} ) δ2.38-2.69
(2H, m), 2.92-3.11 (3H, m), 3.
18-3.34 (1H, m), 3.40-3.88 (5
H, m), 4.39-4.47 (2.5H, m), 4.
99 (0.5H, brs), 5.38-5.44
(0.5H, m), 5.72-5.88 (0.5H, b
rs), 7.70 (1H, d, J = 8.8 Hz),
7.81 (1H, d, J = 8.8 Hz), 8.15 (1
H, d, J = 8.8 Hz), 8.22 (1H, s),
8.24 (1H, d, J = 8.8 Hz), 8.50 (1
H, s), 9.23 (2H, br s), 12.03
(0.5H, s), 12.08 (0.5H, s). MS (FAB) m / z 575 [(M + H) ⁺ , C
l ³⁵ ], 577 [(M + H) ⁺ , Cl ³⁷ ].

Example 139 5-[[4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4- c] pyridin-2-yl) carbonyl] piperazin-2-yl] methyl]-
2,3-Dihydro-2-oxo-1,3,4-oxadiazole The title compound was synthesized in the same manner as in Example 32. ¹ H NMR (DMSO-d ₆ ) δ 2.35 (3H,
s), 2.37-2.82 (6H, m), 2.97-
3.36 (2.5H, m), 3.45-3.88 (4.
5H, m), 4.40-4.46 (0.5H, m),
4.98 (0.5H, brs), 5.45-5.55
(0.5H, brs), 5.93 (0.5H, brs)
s), 7.70 (1H, dd, J = 8.8, 2.0H
z), 7.81 (1H, dd, J = 8.8, 2.0H
z), 8.15 (1H, d, J = 8.8 Hz), 8.2
2 (1H, s), 8.24 (1H, d, J = 8.8H
z), 8.50 (1H, s), 11.91-12.10.
(1H, m). MS (FAB) m / z 589 [(M + H) ⁺ , C
l ³⁵ ], 591 [(M + H) ⁺ , Cl ³⁷ ].

Example 140 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[[(morpholin-4-yl) carbonyl]
Methyl] -1-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine hydrochloride The title compound was synthesized in the same manner as in Example 1. ¹ H NMR (DMSO-d ₆ ) δ 2.33-3.85
(19H, m), 4.35-4.50 (2.5H,
m), 5.01-5.08 (0.5H, m), 5.27
-5.37 (0.5H, m), 5.68-5.78
(0.5H, m), 7.03 (1H, s), 7.32
(1H, d, J = 8.8 Hz), 7.48 (1H, d,
J = 8.8 Hz), 7.77 (1H, s), 9.54
(2H, brs), 12.45 (1H, s). MS (FAB) m / z 593 [(M + H) ⁺ , C
l ³⁵ ], 595 [(M + H) ⁺ , Cl ³⁷ ].

Example 141 1-[[5- (1-Acetoxyethoxy) carbonyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine 4-[(5-chloroindol- 2-yl) sulfonyl] -2-[[(morpholin-4-yl) carbonyl]
Methyl] -1-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine hydrochloride (200 mg) was added to ethanol (6 m
l) and diisopropylethylamine (83 μl).
After 1) and 1-acetoxyethyl p-nitrophenyl carbonate (128 mg) were added, the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the mixture was partitioned between methylene chloride and an aqueous solution of sodium hydrogen carbonate. The oil layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated. Purified by silica gel column chromatography (1-2% methanol-methylene chloride). Dissolve in ethyl acetate and crystallize with diethyl ether to give the title compound (100
mg). ¹ H NMR (DMSO-d ₆ ) δ 1.43 (3H, br
s), 2.00-2.03 (3H, m), 2.30-
3.80 (19H, m), 4.35-4.45 (0.5
H, m), 4.61-4.77 (2H, m), 5.01.
−5.08 (0.5H, m), 5.27-5.37
(0.5H, m), 5.71-5.82 (0.5H,
m), 6.65-6.68 (1H, m), 7.01 (1
H, s), 7.30 (1H, d, J = 8.8 Hz),
7.47 (1H, d, J = 8.8 Hz), 7.75 (1
H, s), 12.40 (1H, s). MS (FAB) m / z 723 [(M + H) ⁺ , C
l ³⁵ ], 725 [(M + H) ⁺ , Cl ³⁷ ].

Example 142 1-[[5- (tert-butoxycarbonyl) -4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 1.41 (9H,
s), 2.43-2.85 (5H, m), 3.15-
3.75 (6H, m), 4.20-4.27 (1H,
m), 4.40-4.48 (0.5H, m), 4.60
-4.67 (2H, m), 5.01 (0.5H, s),
5.52-5.57 (0.5H, m), 6.19 (0.
5H, brs), 6.99-7.01 (1H, m),
7.30 (1H, d, J = 8.8 Hz), 7.44-
7.48 (1H, m), 7.76 (1H, s), 8.0
4-8.12 (1H, m), 12.39 (1H, s). MS (FAB) m / z 623 [(M + H) ⁺ , C
l ³⁵ ], 625 [(M + H) ⁺ , Cl ³⁷ ].

Example 143 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(4
5,6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 1. ¹ H NMR (DMSO-d ₆ ) δ 2.43-2.75
(5H, m), 2.95 (1H, brs), 3.02
(1H, brs), 3.15-3.25 (0.5H,
m), 3.38-3.50 (2H, m), 3.50-
3.62 (0.5H, m), 3.63-3.75 (1
H, m), 4.20-4.27 (1H, m), 4.35
-4.50 (2.5H, m), 5.00 (0.5H, b
rs), 5.42-5.53 (0.5H, m), 6.
15 (0.5H, br s), 7.01 (1H, s),
7.30 (1H, d, J = 8.8 Hz), 7.47 (1
H, d, J = 8.8 Hz), 7.77 (1H, s),
8.09-8.14 (1H, m), 9.43 (1H, b
rs), 12.42 (1H, s). MS (FAB) m / z 523 [(M + H) ⁺ , C
l ³⁵ ], 525 [(M + H) ⁺ , Cl ³⁷ ].

Example 144 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-hydroxy-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl)
Carbonyl] -2- (N-methylcarbamoyl) piperazine

[1170]

Embedded image 4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1- at room temperature
[(4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine (2
09mg) and benzoyl peroxide (70%, 138m
g) was dissolved in methylene chloride (25 ml) and heated under reflux for 9 hours. Silica gel column chromatography (4
% Methanol-methylene chloride) to give 1-[(5-benzoyloxy-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] -4-[(5-
Chloroindol-2-yl) sulfonyl] -2- (N
-Methylcarbamoyl) piperazine (190 mg) was obtained. This was dissolved in a mixed solvent of tetrahydrofuran (20 ml) and methanol (20 ml).
Stirred for 0 minutes. The solvent was distilled off, and the mixture was separated with chloroform and water. The oil layer was dried over anhydrous sodium sulfate, and the filtrate was concentrated.
% Methanol-methylene chloride) to give the title compound (19 mg) as a colorless powder. ¹ H NMR (CDCl ₃ ) δ 2.75-3.25 (7
H, m), 3.34 (2H, brs), 3.58-
3.68 (1H, m), 4.05-4.45 (2H, b
r), 4.53-4.73 (2H, m), 5.25
(0.5H, brs), 5.50-5.75 (2.5
H, m), 6.11 (0.5H, brs), 6.50.
(0.5H, s), 7.05 (1H, brs), 7.0.
25-7.32 (1H, m), 7.35-7.45 (1
H, m), 7.64 (1H, s), 10.73 (1H,
s).

Example 145 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(N-methylcarbamoyl) methyl] -1
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine hydrochloride The title compound was synthesized in the same manner as in Example 94. ¹ H NMR (DMSO-d ₆ ) δ2.40-2.85
(7H, m), 2.89 (3H, s), 3.00-3.
30 (3H, br), 3.40-3.82 (4H,
m), 4.30-4.80 (2.5H, br), 5.0
6 (0.5H, brs), 5.26-5.40 (0.
5H, m), 5.81 (0.5H, brs), 7.0
2 (1H, s), 7.31 (1H, d, J = 8.6H)
z), 7.48 (1H, d, J = 8.6 Hz), 7.7
6 (1H, s), 7.89-7.94 (1H, m), 1
1.16 (1H, brs), 12.44 (1H, brs)
s). MS (FAB) m / z 551 [(M + H) ⁺ , C
l ³⁵ ], 553 [(M + H) ⁺ , Cl ³⁷ ].

Example 146 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(methoxycarbonyl) methyl] -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (CDCl ₃ ) δ 2.49 (3H, s),
2.50-2.90 (7H, m), 2.95-3.06
(1H, m), 3.10-3.25 (0.5H, m),
3.35-3.50 (0.5H, m), 3.50-3.
70 (5H, m), 3.70-3.95 (2H, b
r), 4.60-4.64 (0.5H, br), 5.2
2 (0.5H, brs), 5.71-5.75 (0.
5H, m), 6.18 (0.5H, brs), 6.9
6 (1H, s), 7.31 (1H, dd, J = 8.8,
1.7Hz), 7.36 (1H, d, J = 8.8H)
z), 7.65 (1H, d, J = 1.7 Hz), 9.1
5-9.20 (1H, br). MS (FAB) m / z 552 [(M + H) ⁺ , C
l ³⁵ ], 554 [(M + H) ⁺ , Cl ³⁷ ].

Example 147 2- (carboxymethyl) -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(6-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 77. ¹ H NMR (DMSO-d ₆ ) δ 2.38 (3H,
s), 2.40-3.81 (13H, m), 4.36-
4.41 (0.5H, br), 5.01 (0.5H, b)
rs), 5.41-5.44 (0.5H, m), 5.
86 (0.5H, brs), 7.03 (1H, s),
7.31 (1H, dd, J = 8.8, 1.7 Hz),
7.47 (1H, d, J = 8.8 Hz), 7.76 (1
H, d, J = 1.7 Hz), 12.42 (1H, s). MS (FAB) m / z 538 [(M + H) ⁺ , C
l ³⁵ ], 540 [(M + H) ⁺ , Cl ³⁷ ].

Example 148 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[[N-[(1,3-dioxolan-2-yl) methyl] carbamoyl] methyl] -1- [ (5-methyl-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 79. ¹ H NMR (CDCl ₃ ) δ 2.50 (3H, s),
2.51-3.10 (7H, m), 3.30-3.65
(3H, m), 3.68 (2H, s), 3.70-4.
12 (6H, m), 4.46-4.57 (0.5H,
m), 4.90-5.00 (1H, m), 5.10-
5.20 (0.5H, m), 5.55-5.70 (0.
5H, m), 5.87 (0.5H, s), 6.28
(0.5H, s), 6.52 (0.5H, s), 6.9
9 (1H, s), 7.28 (1H, d, J = 8.8H)
z), 7.37 (1H, d, J = 8.8 Hz), 7.6
4 (1H, s), 10.38 (0.5H, br s),
10.62 (0.5H, s). MS (FAB) m / z 623 [(M + H) ⁺ , C
l ³⁵ ], 625 [(M + H) ⁺ , Cl ³⁷ ].

Example 149 1-[[4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4- c] pyridin-2-yl) carbonyl] piperazin-2-yl] acetyl] piperidin-4-one ethylene ketal The title compound was synthesized in the same manner as in Example 79. ¹ H NMR (CDCl ₃ ) δ 1.60 (4H, s),
2.49 (3H, s), 2.55-3.20 (7H,
m), 3.20-3.35 (0.5H, m), 3.50
-3.85 (8H, m), 4.00 (5H, br)
s), 4.12-4.23 (0.5H, m), 4.55
-4.67 (0.5H, m), 4.95-5.07
(0.5H, m), 5.45-5.60 (0.5H,
m), 5.95-6.07 (0.5H, m), 7.00
(1H, s), 7.22-7.31 (1H, m), 7.
37 (1H, d, J = 8.8 Hz), 7.64 (1H,
s), 10.37 (0.5H, br s), 11.14
(0.5H, s). MS (FAB) m / z 663 [(M + H) ⁺ , C
l ³⁵ ], 665 [(M + H) ⁺ , Cl ³⁷ ].

Example 150 4-[(5-chloroindol-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] -1-[(5-methyl-4,5,6, 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 79. ¹ H NMR (DMSO-d ₆ ) δ2.40-2.80
(6H, m), 2.81-3.20 (9H, m), 3.
35-3.85 (5H, m), 4.30-4.80
(2.5H, br), 5.00 (0.5H, br)
s), 5.26-5.40 (0.5H, m), 5.75.
(0.5H, br s), 7.01 (1H, s), 7.
30 (1H, d, J = 8.6 Hz), 7.47 (1H,
d, J = 8.6 Hz), 7.75 (1H, s), 11.
22 (1H, brs), 12.42 (1H, s). MS (FAB) m / z 565 [(M + H) ⁺ , C
l ³⁵ ], 567 [(M + H) ⁺ , Cl ³⁷ ].

Example 151 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[[N- (2,2-diethoxyethyl) carbamoyl] methyl] -1-[(5-methyl- 4,5,
6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 79. ¹ H NMR (CDCl ₃ ) δ 1.15-1.27 (6
H, m), 2.50 (3H, s), 2.55-3.10.
(8H, m), 3.30-3.90 (10H, m),
4.00-4.15 (1H, m), 4.45-4.60
(1.5H, m), 5.12 (0.5H, br s),
5.55-5.70 (0.5H, m), 5.82 (0.
5H, br s), 6.19 (0.5H, br s),
6.59 (0.5H, brs), 7.01 (1H,
s), 7.22-7.31 (1H, m), 7.36 (1
H, d, J = 9.0 Hz), 7.65 (1H, s), 1
0.21 (0.5H, brs), 10.72 (0.5
H, s). MS (FAB) m / z 653 [(M + H) ⁺ , C
l ³⁵ ], 655 [(M + H) ⁺ , Cl ³⁷ ].

Example 152 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2-[[N- (tetrahydrofurfuryl) carbamoyl] methyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 1.40-1.55
(1H, m), 1.65-1.90 (3H, m), 2.
40-2.89 (3H, br), 2.90 (3H, br)
s), 3.00-3.40 (5H, m), 3.41-
3.85 (9H, m), 4.25-4.70 (1.5
H, m), 5.08 (0.5H, brs), 5.26
−5.37 (0.5H, m), 5.83 (0.5H, b)
rs), 7.03 (1H, s), 7.31 (1H,
d, J = 9.0 Hz), 7.48 (1H, d, J = 9.
0 Hz), 7.77 (1H, s), 8.07 (1H, b
rs), 11.00-11.30 (1H, br), 1
2.43 (1H, s). MS (FAB) m / z 621 [(M + H) ⁺ , C
l ³⁵ ], 623 [(M + H) ⁺ , Cl ³⁷ ].

Example 153 1-[[5- (tert-Butoxycarbonylaminosulfonyl) -4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl] -4
-[(5-chloroindol-2-yl) sulfonyl]
-2-[[(morpholin-4-yl) carbonyl] methyl] piperazine tert-butyl alcohol (53 mg) was added to methylene chloride (3 ml), and chlorosulfonyl isocyanate (88 mg) was added while cooling to 0 ° C. Stir for 10 minutes. Here, 4-[(5-chloroindol-2-yl) sulfonyl] -2-[[(morpholin-4-yl)
Carbonyl] methyl] -1-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine (300 mg) and a solution of triethylamine (475 mg) in methylene chloride (3 ml) were added. After stirring at room temperature for 1 hour, water was added to the reaction solution, extracted with methylene chloride, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using silica gel as a carrier (methanol: methylene chloride = 1: 19) to give the title compound (311 mg). Partially preparative silica gel thin layer chromatography (methanol: methylene chloride = 1:
Further purification was performed in 9), and ether was added to obtain the following instrument data as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) δ1.23, 1.24
(Total 9H, each s), 2.33-3.
75 (19H, m), 4.37-5.86 (4H,
m), 7.03 (1H, s), 7.31 (1H, d, J
= 8.8 Hz), 7.47 (1H, d, J = 8.8H)
z), 7.76 (1H, s), 11.21 (1H,
s), 12.42 (1H, s). MS (FAB) m / z 772 (M + H) ⁺

Example 154 1-[[5- (Aminosulfonyl) -4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl] -4-[(5-chloroindole-2
-Yl) sulfonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine 1-[[5- (tert-butoxycarbonylaminosulfonyl) -4,5,6,7-tetrahydrothiazolo [5 , 4-c] pyridin-2-yl] carbonyl] -4
-[(5-chloroindol-2-yl) sulfonyl]
-2-[[(morpholin-4-yl) carbonyl] methyl] piperazine (275 mg) was treated with methylene chloride (3 m
1), trifluoroacetic acid (3 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, a saturated hydrochloric acid-ethanol solution (3 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, methylene chloride and water were added to the residue. After liquid separation, the aqueous layer was extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative silica gel thin-layer chromatography (methanol: methylene chloride = 1: 9). The obtained solid was dissolved in a small amount of methylene chloride, and solidified by adding diethyl ether to obtain the title compound (50 mg) as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) δ 2.33-3.75
(19H, m), 4.35-5.84 (4H, m),
7.01-7.02 (3H, m), 7.31 (1H,
d, J = 8.8 Hz), 7.48 (1H, d, J = 9.
0 Hz), 7.76 (1H, s), 12.41 (1H,
s). MS (FAB) m / z 672 (M + H) ^<+>

Example 155 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[[(morpholin-4-yl) carbonyl]
Methyl] -1- [5-[(phenylsulfonyl) -4,
5,6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl] piperazine The title compound was synthesized in the same manner as in Example 95. ¹ H NMR (DMSO-d ₆ ) δ 2.33-3.74
(19H, m), 4.34-5.71 (4H, m),
7.02 (1H, s), 7.31 (1H, d, J = 8.
6 Hz), 7.47 (1H, d, J = 9.0 Hz),
7.57-7.61 (2H, m), 7.65-7.67
(1H, m), 7.76 (1H, s), 7.80 (2
H, d, J = 7.8 Hz), 12.40 (1H, s).

Example 156 1-[[5- (tert-Butoxycarbonyl) -6-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl] carbonyl] -4-
[(5-Chloroindol-2-yl) sulfonyl]-
2- (N-methylcarbamoyl) piperazine 5- (tert-butoxycarbonyl) -6-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridine (203 mg) was dissolved in diethyl ether (8 ml) dried with a molecular sieve, the atmosphere in the vessel was replaced with argon, and then cooled to -78 ° C. This solution contains n
-Butyl lithium (1.66 mol n-hexane solution,
(506 μl) was added dropwise and stirred at the same temperature for 1.5 hours. Thereafter, the mixture was stirred at the same temperature for 1 hour while blowing carbon dioxide gas into the reaction solution. The temperature was raised to room temperature, the solvent was distilled off under reduced pressure, and crude 5- (tert-butoxycarbonyl) -6-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
A pyridine-2-carboxylic acid lithium salt was obtained. This was used in the next reaction without generation. 3- (N-Methylcarbamoyl) -1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] piperazine (248 mg) was added to N, N-dimethylformamide (4 m
l) and the crude 6- (tert-butoxycarbonyl) -5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt (ca) .550 μmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (144 mg) and 1-hydroxybenzotriazole (34 mg), and the mixture was stirred at room temperature overnight. Methylene chloride was added to the reaction solution, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to flash column chromatography using silica gel as a carrier (hexane: ethyl acetate =
2: 1) to give the title compound (121
mg). ¹ H NMR (CDCl ₃ ) δ 1.12-1.17 (3
H, m), 1.49 (9H, s), 2.62-3.23.
(7H, m), 3.63 (1H, d, J = 12.3H
z), 4.22 (1H, d, J = 17.9 Hz);
55-4.74 (2H, m), 4.83-4.89 (1
H, m), 5.09-5.16 (1H, m), 5.25
-6.49 (2H, m), 7.06 (1H, s), 7.
27-7.30 (2H, m), 7.38-7.42 (1
H, m), 7.64 (1H, s), 10.62-10.
67 (1H, m).

Example 157 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(6-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 1. ¹ H NMR (DMSO-d ₆ ) δ1.39-1.40
(3H, m), 2.33-3.68 (10H, m),
4.21-5.00 (4H, m), 5.44-6.15
(1H, m), 7.01 (1H, s), 7.31 (1
H, dd, J = 8.5, 2.0 Hz), 7.48 (1
H, d, J = 8.5 Hz), 7.77 (1H, s),
8.11-8.14 (1H, m), 9.38-9.75
(2H, m), 12.42 (1H, s).

Example 158 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [5,4-c] Pyridin-2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine hydrochloride 1-[[5- (tert-butoxycarbonyl) -6-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl] carbonyl] -4-
[(5-Chloroindol-2-yl) sulfonyl]-
2- (N-methylcarbamoyl) piperazine (40 m
g) was dissolved in a saturated hydrochloric acid-ethanol solution (2 ml) and stirred at room temperature for 1 hour. Diethyl ether was added to the reaction solution, and precipitation was taken into consideration, followed by washing with diethyl ether. Methylene chloride (7 ml), triethylamine (81
μl) and acetic acid (34 μl). A 30% aqueous formaldehyde solution (21 μl) and sodium triacetoxyborohydride (64 mg) were added thereto,
Stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, methylene chloride was added, and the mixture was washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in a 1N ethanol solution of hydrochloric acid, stirred at room temperature for 5 minutes, and the solvent was distilled off under reduced pressure. The deposited precipitate was collected by filtration and washed with diethyl ether to give the title compound (68 mg) as a white solid. ¹ H NMR (DMSO-d ₆ ) δ 1.32-1.40
(3H, m), 2.33-3.94 (13H, m),
4.23-4.26 (1H, m), 4.44-5.01
(3H, m), 5.50-6.16 (1H, m), 7.
02 (1H, s), 7.31 (1H, dd, J = 8.
8, 2.0 Hz), 7.48 (1H, d, J = 8.8H)
z), 7.77 (1H, s), 8.10-8.16 (1
H, m), 11.15-11.54 (1H, m), 1
2.43 (1H, s).

Example 159 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(4
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine trifluoroacetate 5- (tert-butoxycarbonyl) -2-methoxycarbonyl-4,5,6,7 To a solution of -tetrahydrooxazolo [5,4-c] pyridine (120 mg) in tetrahydrofuran (4.0 ml) was added water (1.0 ml) and lithium hydroxide (18.0 mg) at room temperature, and after stirring for 10 minutes, The solvent was distilled off under reduced pressure. N, N- of the obtained residue
In a dimethylformamide solution, 1-[(6-chloronaphthalen-2-yl) sulfonyl] -3- (N-methylcarbamoyl) piperazine hydrochloride (190 mg), 1-hydroxybenzotriazole monohydrate (11.5 m
g) and 1- (3-dimethylaminopropyl) -3 hydrochloride
-Ethylcarbodiimide (90.0 mg) was added at room temperature. After stirring for 4 hours, methylene chloride (30 m
1) and water (250 ml) were added and the mixture was separated, and the aqueous layer was extracted with methylene chloride (20 ml). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (50 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (silica gel 25 g, methylene chloride: acetone = 5: 1 → 3:
Purification was performed using 1) to obtain a colorless transparent oily substance. To a solution of this material in methylene chloride (4.0 ml) was added trifluoroacetic acid (4.0 ml) at room temperature, and the mixture was stirred for 1 hour.
The reaction mixture was concentrated under reduced pressure, and the obtained residue was reprecipitated with a methylene chloride-methanol-diethyl ether system to obtain the title compound (165 mg) as a pale brown solid. _{^{1 H NMR (DMSO-d 6}} ) δ2.30-2.70
(2H, m), 2.58 (3H, d, J = 3.9H
z), 2.77 (2H, br d, J = 16.1H
z), 3.05-3.60 (3H, m), 3.71 (1
H, br d, J = 11.2 Hz), 4.29 (1H,
br d, J = 11.7 Hz), 4.35-4.50
(2H + 1/2 of 1H, m), 4.96 (1/2
of 1H, brs), 5.05 (1/2 of
1H, br d, J = 13.2 Hz), 5.78 (1 /
2 of 1H, brs), 7.71 (1H, d, J
= 8.3 Hz), 7.73-7.83 (1H, m),
8.00-8.20 (1H, m), 8.15 (1H,
d, J = 8.3 Hz), 8.24 (1H, s), 8.2
5 (1H, d, J = 8.3 Hz), 8.48 (1/2
of 1H, s), 8.49 (1 / 2of 1H,
s), 9.34 (2H, br s). MS (FAB) m / z 518 (M + H) ^<+> .

Example 160 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(5-
Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 32. ¹ H NMR (DMSO-d ₆ ) δ 2.48 (3H,
s), 2.52-2.80 (6H, m), 2.80-
3.00 (3H, m), 3.10 (1/2 of 1
H, t, J = 11.2 Hz), 3.49 (1/2 of)
1H, t, J = 11.2 Hz), 3.54 (2H,
s), 3.78 (1/2 of 1H, br d, J =
10.3 Hz), 3.86 (1/2 of 1H, br)
d, J = 11.2 Hz), 4.45 (1H, t, J =
11.4 Hz), 4.63 (1/2 of 1H, br)
d, J = 12.7 Hz), 5.24 (1/2 of)
1H, s), 5.38 (1/2 of 1H, br)
d, J = 12.7 Hz), 6.12 (1/2 of 1)
H, br s), 6.16 (1/2 of 1H,
s), 6.40 (1/2 of 1H, br s),
7.58 (1H, d, J = 7.8 Hz), 7.80 (1
H, d, J = 7.8 Hz), 7.86-7.96 (3
H, m), 8.34 (1H, s). MS (FAB) m / z 532 (M + H) ⁺ .

Example 161 1-[[5- (tert-butoxycarbonyl) -4,
5,6,7-Tetrahydrooxazolo [5,4-c] pyridin-2-yl] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazine Title by the same method as in Example 62. Compounds were synthesized. ¹ H NMR (CDCl ₃ ) δ 1.46 (9H, s),
2.64 (2H, brs), 3.22 (4H, brs)
s), 3.71 (2H, br s), 3.90 (2H,
brs), 4.42 (2H, brs), 4.53.
(2H, brs), 6.97 (1H, d, J = 2.0)
Hz), 7.33 (1H, dd, J = 8.8, 2.0H)
z), 7.37 (1H, d, J = 8.8 Hz), 7.6
7 (1H, s), 8.71 (1H, br s).

Example 162 1-[[5- (tert-butoxycarbonyl) -4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2-[[(morpholine-4- Yl) carbonyl] methyl] piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s),
2.50-2.70 (2H, m), 2,70-3.20
(2H + 1/2 of 1H, m), 3.38 (1/2
of 1H, t, J = 11.2Hz), 3.50-
3.95 (11H + 1/2 of 1H, m), 3.9
9 (1/2 of 1H, br d, J = 12.7H
z), 4.40-4.60 (1/2 of 1H, b
r), 4.53 (2H, s), 4.64 (1/2 of
1H, br d, J = 13.7 Hz), 5.02 (1
/ 2 of 1H, br s), 5.24 (1/2 o
f 1H, br s), 5.79 (１ ／ of 1
H, brs), 7.00 (1H, s), 7.20-
7.35 (1H, m), 7.38 (1H, d, J = 8.
8 Hz), 7.65 (1/2 of 1H, s), 7.
67 (1/2 of 1H, s), 9.89 (1/2
of 1H, br s), 10.60-11.00 (1
/ 2of 1H, br).

Example 163 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazine hydrochloride 1-[[5- (tert-butoxycarbonyl) -4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazine (10
(0 mg) in methylene chloride (3.0 ml) was added with trifluoroacetic acid (3.0 ml) at room temperature and stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure, and methylene chloride (4.0 ml) and triethylamine (50.0 μm) were added to the obtained residue.
l), acetic acid (21.0 μl), formalin (23.5 μl)
l) and sodium triacetoxyborohydride (5
8.0 mg) was added at room temperature. After stirring for 1 hour, methylene chloride (20 ml) and a saturated aqueous sodium hydrogen carbonate solution (50 ml) were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with methylene chloride (20 ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified using preparative silica gel thin-layer chromatography (chloroform: methanol = 10: 1),
Free form of the title compound as a colorless solid (82.6 mg)
I got To this was added a 1N aqueous hydrochloric acid solution, tetrahydrofuran, and methanol, and the mixture was concentrated under reduced pressure to give the title compound as a colorless solid. ¹ H NMR (DMSO-d ₆ ) δ 2.90 (4H,
s), 3.11 (3H, brs), 3.25-3.75.
(2H, br), 3.35 (2H, s), 3.75 (2
H, br s), 4.16 (2H, br s), 4.2
0-4.75 (2H, br), 7.04 (1H, s),
7.32 (1H, dd, J = 8.8, 1.0 Hz),
7.50 (1H, d, J = 8.8 Hz), 7.78 (1
H, d, J = 1.0 Hz), 11.51 (1H, br)
s), 12.46 (1H, s). MS (FAB) m / z 464 (M + H) ^<+> .

Example 164 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine- 2-yl) carbonyl] -2-[[(morpholin-4-yl) carbonyl] methyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 163. _{^{1 H NMR (DMSO-d 6}} ) δ2.30-2.75
(2H, m), 2.75-3.20 (2H, m), 2.
90 (3H, s), 3.20-3.90 (15H,
m), 4.30-4.45 (1H + 1/2 of 1
H, m), 4.55-4.70 (1H, m), 4.89
(1/2 of 1H, brs), 5.05 (1/2
of 1H, brs), 5.47 (1/2 of
1H, brs), 7.04 (1H, s), 7.29-
7.35 (1H, m), 7.50 (1H, dd, J =
8.8, 2.9 Hz), 7.76-7.80 (1H,
m), 11.45-11.95 (1H, br), 12.
49 (1H, brs). MS (FAB) m / z 591 (M + H) ⁺ .

Example 165 1-[[5- (tert-Butoxycarbonyl) -4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl] carbonyl] -4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazine 5- (tert-butoxy Carbonyl) -4,5,6
7-tetrahydrooxazolo [5,4-c] pyridine-
N, N of lithium 2-carboxylate (70.0 mg)
-1- in dimethylformamide (4.0 ml) solution
[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] piperazine hydrochloride (90.0 mg), 1-hydroxybenzotriazole monohydrate (7.0 mg) and 1- (3-dimethylaminopropyl hydrochloride) -3-Ethylcarbodiimide (64.0 mg) was added at room temperature.
After stirring for 2 days, ethyl acetate (30 ml) and water (500 ml) were added to the reaction mixture, and the mixture was separated.
0 ml). The organic layers were combined, washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative silica gel thin-layer chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (37.9 mg) as a colorless transparent glassy substance. ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s),
2.65 (2H, s), 3.27 (4H, t, J = 5.
0 Hz), 3.70 (2H, s), 3.91 (2H,
s), 4.42 (2H, s), 4.53 (2H, s),
7.45 (1H, dd, J = 8.8, 1.5 Hz),
7.77 (1H, s), 7.81 (1H, d, J = 8.
8 Hz), 7.86 (1H, d, J = 1.5 Hz). MS (FAB) m / z 567 (M + H) ⁺ .

Example 166 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] ] Pyridin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 163. ¹ H NMR (DMSO-d ₆ ) δ 2.90 (3H,
s), 2.94 (1H, brs), 3.10-3.25.
(4H, m), 3.49 (2H, s), 3.64 (1
H, br s), 3.79 (2H, s), 4.21 (2
H, s), 4.39 (1H, br s), 4.60 (1
H, br s), 7.58 (1H, dd, J = 8.8,
2.0 Hz), 8.07 (1H, d, J = 8.8H)
z), 8.10 (1H, s), 8.34 (1H, d, J
= 2.0 Hz), 11.70 (1H, brs). MS (FAB) m / z 481 (M + H) ^<+> .

Example 167 1-[(5-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(1-phenylsulfonyl- 5-trimethylsilylethynylindol-2-yl) sulfonyl]
Piperazine The title compound was synthesized in the same manner as in Example 103. ¹ H NMR (CDCl ₃ ) δ 0.25 (9H, s),
2.51 (3H, s), 2.69 (2H, t, J = 5.
4 Hz), 2.78 (2H, t, J = 5.4 Hz),
3.52 (2H, brs), 3.55 (2H, brs)
s), 3.59 (2H, s), 3.89 (2H, br)
s), 4.41 (2H, br s), 7.42 (2H,
t, J = 7.6 Hz), 7.47 (1H, s), 7.5
5 (1H, t, J = 7.6 Hz), 7.59 (1H, d
d, J = 8.8, 1.7 Hz), 7.69 (1H, d,
J = 1.7 Hz), 8.00 (2H, d, J = 7.6H)
z), 8.22 (1H, d, J = 8.8 Hz).

Example 168 1-[(5-Ethynylindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazine

[1195]

Embedded image The title compound was synthesized in the same manner as in Example 104. ¹ H NMR (CDCl ₃ ) δ 2.48 (3H, s),
2.66 (2H, t, J = 5.4 Hz), 2.75 (2
H, t, J = 5.4 Hz), 3.04 (1H, s),
3.21 (4H, t, J = 4.4 Hz), 3.54 (2
H, s), 3.89 (2H, br s), 4.43 (2
H, br s), 7.00 (1H, s), 7.37 (1
H, d, J = 8.6 Hz), 7.47 (1H, dd, J)
= 8.6, 1.5 Hz), 7.86 (1H, br)
s), 8.85 (1H, br s). MS (FAB / glycerol) m / z 454 (M
+ H) ⁺ .

Example 169 1-[[5- (tert-butoxycarbonyl) -4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2-ethylpiperazine As in Example 165 The title compound was synthesized by the method described above. ¹ H NMR (CDCl ₃ ) δ 0.90 (1/2 of
3H, t, J = 7.1 Hz), 0.96 (1/2 of
3H, t, J = 7.1 Hz), 1.47 (9H,
s), 1.78-2.03 (2H, m), 2.45-
2.73 (4H, m), 3.18 (1/2 of 1
H, t, J = 11.5 Hz), 3.51 (1/2 of)
1H, t, J = 11.5 Hz), 3.60-3.92
(4H, m), 4.52 (2H, s), 4.62 (1 /
2 of 1H, d, J = 13.0 Hz), 4.79
(1/2 of 1H, brs), 5.20 (1/2
of 1H, brs), 5.40 (1/2 of
1H, brs), 6.94 (1H, d, J = 1.5H)
z), 7.31 (1H, dd, J = 8.8, 2.0H
z), 7.37 (1H, d, J = 8.8 Hz), 7.6
6 (1H, d, J = 2.0 Hz), 8.87 (1H, b
rs). MS (FAB) m / z 578 (M + H) ^<+> .

Example 170 4-[(5-Chloroindol-2-yl) sulfonyl] -2-ethyl-1-[(4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine- 2-yl) carbonyl] piperazine trifluoroacetate 1-[[5- (tert-butoxycarbonyl) -4,
Chlorination of 5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2-ethylpiperazine (320 mg) Trifluoroacetic acid (5.0 ml) was added to a methylene (5.0 ml) solution at room temperature to add 1 ml.
Stirred for 0 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (423 mg) as a pale brown solid. ¹ H NMR (DMSO-d ₆ ) δ 0.78 (1/2 o
f 3H, t, J = 6.9 Hz), 0.83 (1/2
of 3H, t, J = 6.9 Hz), 1.47 (9H,
s), 1.65-1.95 (2H, m), 2.30-
2.70 (2H, m), 2.80 (2H, s), 3.1
3 (1/2 of 1H, t, J = 12.7 Hz),
3.37-4.00 (2H + 1/2 of 1H,
m), 3.42 (2H, s), 4.30-4.47 (2
H + 1/2 of 1H, m), 4.60 (1/2 o
f 1H, br s), 4.73 (1/2 of 1
H, d, J = 14.0 Hz), 4.91 (1/2 of)
1H, br s), 8.01 (1H, s), 7.30
(1H, d, J = 8.8 Hz), 7.47 (1H, d,
J = 8.8 Hz), 7.76 (1H, s), 9.36
(2H, br s), 12.42 (1H, s). MS (FAB) m / z 478 (M + H) ^<+> .

Example 171 4-[(5-Chloroindol-2-yl) sulfonyl] -2-ethyl-1-[(5-methyl-4,5,6,
7-tetrahydrooxazolo [5,4-c] pyridine-
2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 32. ¹ H NMR (DMSO-d ₆ ) δ 0.73-0.83
(3H, m), 1.60-1.92 (2H, m), 2.
30-2.70 (2H, m), 2.75-3.03 (2
H, m), 2.89 (3H, s), 3.03-3.53.
(2H + 1/2 of 1H, m), 3.53-3.8.
0 (2H + 1/2 of 1H, m), 4.20-4.
45 (1H + 1/2 of 1H, br), 4.60
(1H + 1 / 2of 1H, brs), 4.76 (1
/ 2 of 1H, d, J = 13.0 Hz), 4.92
(1/2 of 1H, brs), 7.00 (1H,
s), 7.30 (1H, dd, J = 8.8, 2.0H)
z), 7.47 (1H, d, J = 8.8 Hz), 7.7
5 (1H, d, J = 2.0 Hz), 11.57 (1H,
br s), 12.43 (1H, s). MS (FAB) m / z 492 (M + H) ^<+> .

Example 172 1-[[6- (tert-butoxycarbonyl) -5,
6,7,8-Tetrahydropyrido [4,3-d] pyrimidin-2-yl] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazine The title is obtained by the same method as in Example 159. Compounds were synthesized. ¹ H NMR (CDCl ₃ ) δ 1.49 (9H, s),
2.96 (2H, t, J = 5.9 Hz), 3.14 (2
H, t, J = 5.0 Hz), 3.27 (2H, t, J =
5.1Hz), 3.53 (2H, t, J = 5.0H)
z), 3.75 (2H, t, J = 5.9 Hz), 3.9
3 (2H, t, J = 5.1 Hz), 4.62 (2H,
s), 6.96 (1H, s), 7.35 (1H, dd,
J = 8.5, 1.7 Hz), 7.38 (1H, d, J =
8.5Hz), 7.69 (1H, d, J = 1.7H)
z), 8.48 (1H, s), 8.77 (1H, br)
s). MS (FAB) m / z 561 (M + H) ^<+> .

Example 173 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-2-yl) Carbonyl] piperazine trifluoroacetate The title compound was synthesized in the same manner as in Example 170. ¹ H NMR (DMSO-d ₆ ) δ 2.96 (2H, t,
J = 4.5 Hz), 3.03 (2H, t, J = 6.0H)
z), 3.11 (2H, t, J = 4.5 Hz), 3.2
9 (2H, t, J = 4.5 Hz), 3.49 (2H, b
rs), 3.75 (2H, t, J = 4.5 Hz),
4.36 (2H, s), 7.03 (1H, s), 7.3
2 (1H, dd, J = 8.8, 1.7 Hz), 7.49
(1H, d, J = 8.8 Hz), 7.78 (1H, d,
J = 1.7 Hz), 8.70 (1H, s), 9.25
(2H, br s), 12.46 (1H, s). MS (FAB) m / z 461 (M + H) ^<+> .

Example 174 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(6-methyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine- 2-yl) carbonyl] piperazine hydrochloride

[1202]

Embedded image The title compound was synthesized in the same manner as in Example 32. ¹ H NMR (DMSO-d ₆ ) δ 2.92 (3H,
s), 2.98 (2H, brs), 3.06 (1H, b
rs), 3.13 (2H, t, J = 5.0 Hz),
3.28 (1H, brs), 3.32 (2H, t, J
= 5.0 Hz), 3.46 (1H, brs), 3.7
0 (1H, brs), 3.77 (2H, brs),
4.34 (1H, br d, J = 15.4 Hz);
57 (1H, br d, J = 15.4 Hz), 7.04
(1H, d, J = 1.6 Hz), 7.34 (1H, d
d, J = 8.8, 2.0 Hz), 7.62 (1H, d,
J = 8.8 Hz), 7.79 (1 H, d, J = 2.0 H)
z), 8.71 (1H, s), 11.67 (1H, br)
s), 12.50 (1H, d, J = 1.6 Hz). MS (FAB) m / z 475 (M + H) ^<+> .

Example 175 1-[[6- (tert-butoxycarbonyl) -5,
6,7,8-Tetrahydropyrido [4,3-d] pyrimidin-2-yl] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) piperazine The title compound was synthesized in the same manner as in Example 159. ¹ H NMR (CDCl ₃ ) δ 1.49 (１ ／ of
9H, s), 1.50 (1/2 of 9H, s),
2.60-2.72 (1/2 of 1H, m);
85-3.12 (6H, m), 3.12-3.30 (1
H, m), 3.45-3.70 (1H, m), 3.70
-3.90 (2H + 1/2 of 1H, m), 4.3
2 (1/2 of 1H, brs), 4.60-4.
75 (１ ／ of 1H + 2H, m), 4.81 (1 /
2 of 1H, d, J = 12.9 Hz), 5.31-
5.35 (1/2 of 1H, m), 6.68 (1 /
2of 1H, brs), 7.04 (1/2 of
1H, s), 7.07 (1/2 of 1H, s),
7.20-7.35 (1H, m), 7.39 (1 / 2o
f 1H, d, J = 8.8 Hz), 7.40 (1/2)
of 1H, d, J = 8.3 Hz), 7.62 (1/2)
of 1H, s), 7.66 (1/2 of 1H,
s), 7.87 (1/2 of 1H, br s), 1
0.47 (1/2 of 1H, brs), 10.7
0 (1/2 of 1H, brs). MS (FAB) m / z 618 (M + H) ^<+> .

Example 176 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(5
6,7,8-Tetrahydropyrido [4,3-d] pyrimidin-2-yl) carbonyl] piperazine trifluoroacetate The title compound was synthesized in the same manner as in Example 170. ¹ H NMR (DMSO-d ₆ ) δ2.30-2.58
(2H, m), 2.60 (1/2 of 3H, d, J
= 4.4 Hz), 2.64 (1/2 of 3H, d,
J = 4.2 Hz), 2.65-2.75 (1H, m),
3.00 (1/2 of 2H, t, J = 5.4 Hz),
3.06 (1/2 of 2H, t, J = 6.2H
z), 3.29 (1/2 of 1H, brt, J =
11.0 Hz), 3.39 (1/2 of 1H, br)
d, J = 13.5 Hz), 3.50 (2H, br)
s), 3.53-3.80 (1/2 of 1H + 1)
H, m), 4.10-4.30 (1/2 of 1H,
m), 4.35 (1/2 of 2H, s), 4.38
(1/2 of 2H, s), 4.50 (1/2 of 2H, s)
1H, br d, J = 13.5 Hz), 5.05 (1
/ 2 of 1H, brs), 7.00 (1/2 o
f 1H, s), 7.01 (1/2 of 1H,
s), 7.28-7.38 (1H, m), 7.48 (1
/ 2 of 1H, d, J = 8.8 Hz), 7.49
(1/2 of 1H, d, J = 8.8 Hz), 7.7
7 (1/2 of 1H, d, J = 1.7 Hz);
78 (1/2 of 1H, d, J = 1.7 Hz),
7.90-8.03 (1/2 of 1H, m), 8.
07-8.17 (1/2 of 1H, m), 8.69
(1/2 of 1H, s), 8.73 (1/2 of 1H, s)
1H, s), 9.24 (2H, br s), 12.4
3 (1H, s). MS (FAB) m / z 518 (M + H) ^<+> .

Example 177 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(6-
Methyl-5,6,7,8-tetrahydropyrido [4,3
-D] Pyrimidin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 32. ¹ H NMR (DMSO-d ₆ ) δ2.30-2.55
(2H, m), 2.61 (1/2 of 3H, d, J
= 3.5 Hz), 2.65 (1/2 of 3H, d,
J = 4.2 Hz), 2.68-2.77 (1H, m),
2.93 (3H, brs), 2.97-3.18 (1
H, m), 3.20-3.80 (6H, m), 4.04.
-4.65 (3H, m), 5.07 (1/2 of 1
H, br s), 7.00 (1/2 of 1H, d,
J = 1.5 Hz), 7.02 (1/2 of 1H, d,
J = 1.7 Hz), 7.30-7.37 (1H, m),
7.50 (1/2 of 1H, d, J = 8.8H
z), 7.51 (1/2 of 1H, d.J = 8.8H)
z), 7.78 (1/2 of 1H, d, J = 1.7)
Hz), 7.80 (1/2 of 1H, d, J = 2.
0 Hz), 8.05 (1/2 of 1H, br)
s), 8.15 (1/2 of 1H, br d, J =
4.2 Hz), 8.70 (1/2 of 1H, s),
8.74 (1/2 of 1H, s), 11.68 (1
H, br s), 12.48 (1H, s). MS (FA
B) m / z 532 (M + H) ⁺ .

Example 178 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2- [2- (piperidin-1-yl) ethyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 62. _{^{1 H NMR (DMSO-d 6}} ) δ: 1.16-3.79
(26H, m), 4.37-4.45 (1H, m),
4.68-4.75 (2H, m), 5.40-5.47
(1H, m), 7.02 (1H, d, J = 5.1H
z), 7.32 (1H, dd, J = 2.2, 8.8H)
z), 7.49 (1H, d, J = 8.8 Hz), 7.7
7 (1H, s). MS (FAB) m / z 591 [(M + H) ⁺ , C
l ³⁵ ], 593 [(M + H) ⁺ , Cl ³⁷ ].

Example 179 4-[(5-Chloroindol-2-yl) sulfonyl] -2- [2- [N- (2-methoxyethyl) amino] ethyl] -1-[(5-methyl-4 , 5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 2.33-4.77
(21H, m), 3.29 (3H, s), 3.34 (3
H, s), 5.39-5.43 (1H, m), 7.01.
(1H, d, J = 4.4 Hz), 7.30 (1H, d
d, J = 7.8, 2.0 Hz), 7.49 (1H, d,
J = 8.8 Hz), 7.76 (1H, s). MS (FA
B) m / z 581 [(M + H) ⁺ , Cl ³⁵ ], 583
[(M + H) ⁺ , Cl ³⁷ ].

Example 180 1-[[5- (tert-Butoxycarbonyl) -4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2- [2- (piperidin-1 -Yl) ethyl] piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (CDCl ₃ ) δ: 1.48 (9H, s),
1.16-3.79 (23H, m), 4.45-4.5
9 (1H, m), 4.65-4.75 (2H, m),
6.70-6.80 (1H, m), 6.96 (1H,
s), 7.28-7.31 (1H, m), 7.64 (1
H, d, J = 1.7 Hz), 8.02 (1H, s). MS (FAB) m / z 677 (M + H) ^<+>

Example 181 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methylsulfonyl-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] -2- [2- (piperidin-1-yl) ethyl] piperazine The title compound was synthesized in the same manner as in Example 95. ¹ H NMR (CDCl ₃ ) δ: 1.54-3.83 (2
3H, m), 2.89 (3H, s), 4.59 (2H,
s), 4.55-4.84 (1H, m), 5.51-
5.84 (1H, m), 7.00 (1H, d, J = 1
5.0 Hz), 7.27-7.29 (1H, m), 7.
50-7.57 (1H, m), 7.63 (1H, s). MS (FAB) m / z 655 [(M + H) ⁺ , C
l ³⁵ ], 657 [(M + H) ⁺ , Cl ³⁷ ].

Example 182 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2- [3- (thien-2-yl) propyl]
Piperazine hydrochloride 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [3- (thien-2
-Yl) propyl] piperazine (257 mg), 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridine-2-carboxylic acid lithium salt (129
mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (131 mg) and 1-
Hydroxybenzotriazole hydrate (76.4mg)
Was dissolved in N, N-dimethylformamide (15 ml). Further, under ice cooling, diisopropylethylamine (18
0 μl) was added dropwise, and the mixture was stirred at room temperature for 15.5 hours. Methylene chloride and water were added for extraction, and the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (2% methanol-methylene chloride) using silica gel as a carrier. After adding 1N hydrochloric acid-ethanol to form a hydrochloride, methylene chloride-methanol-ether is added to solidify, followed by purification by thin layer chromatography (10% methanol-methylene chloride), and addition of 1N hydrochloric acid-ethanol again. Methylene chloride-methanol-
Ether was added to solidify, collected by filtration, washed with ether and dried to obtain the title compound (62.6 mg) as a colorless powder. ¹ H NMR (DMSO-d ₆ ) δ 1.45-2.00
(4H, m), 2.30-3.80 (11H, m),
4.30-4.80 (3H, m), 5.15-5.65
(1H, m), 6.75-6.85 (1H, m), 6.
85-6.95 (1H, m), 7.01 (1H, s),
7.20-7.35 (2H, m), 7.48 (1H,
d, J = 9.0 Hz), 7.75 (1H, s), 11.
42 (1H, br), 12.44 (1H, s). MS (FAB) m / z 604 [(M + H) ⁺ , C
l ³⁵ ], 606 [(M + H) ⁺ , Cl ³⁷ ].

Example 183 4-[(5-Chloroindol-2-yl) sulfonyl] -2- [3- (3,4-dimethoxyphenyl) propyl] -1-[(5-methyl-4,5, 6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 182. ¹ H NMR (DMSO-d ₆ ) δ 1.40-1.90
(4H, m), 2.40-2.70 (1H, m), 2.
90 (3H, s), 3.00-3.20 (2H, m),
3.30-3.80 (16H, m), 4.30-4.8
0 (3H, m), 5.20-5.60 (1H, m),
6.60-6.70 (1H, m), 6.82 (1H,
d, J = 8.1 Hz), 7.01 (1H, s), 7.2
5-7.35 (1H, m), 7.48 (1H, d, J =
8.8 Hz), 7.70-7.80 (1H, m), 1
1.20-11.50 (1H, br), 12.43 (1
H, s). MS (FAB) m / z 658 [(M + H)
⁺ , Cl ³⁵ ], 660 [(M + H) ⁺ , Cl ³⁷ ].

Example 184 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2- [2-[(pyrrolidin-1-yl) sulfonyl] ethyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 182. ¹ H NMR (DMSO-d ₆ ) δ 1.80-1.90
(4H, m), 2.10-2.30 (2H, m), 2.
40-3.85 (15H, m), 2.90 (3H,
s), 4.30-4.90 (3H, m), 5.30-
5.50 (1H, m), 7.02 (1H, s), 7.2
5-7.35 (1H, m), 7.48 (1H, d, J =
8.8 Hz), 7.76 (1H, s), 11.27 (1
H, br), 12.44 (1H, s). MS (FAB) m / z 641 [(M + H) ⁺ , C
l ³⁵ ], 642 [(M + H) ⁺ , Cl ³⁷ ].

Example 185 1-[(6-Methyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridin-2-yl) carbonyl]-
4-[(1-Phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine The title compound was synthesized in the same manner as in Example 103. ¹ H NMR (CDCl ₃ ) δ 0.25-0.35 (9
H, m), 2.45-2.55 (3H, m), 2.55
-2.65 (2H, m), 2.65-2.75 (2H,
m), 3.45-3.55 (6H, m), 3.85-
3.95 (4H, m), 7.40-7.65 (6H,
m), 7.70-7.75 (1H, m), 8.00-
8.05 (2H, m), 8.20-8.25 (1H,
m). MS (FAB) m / z 665 (M + H) ⁺ .

Example 186 1-[(5-Ethynylindol-2-yl) sulfonyl] -4-[(6-methyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine-2 -Yl) carbonyl] piperazine

[1215]

Embedded image The title compound was synthesized in the same manner as in Example 104. ¹ H NMR (CDCl ₃ ) δ 2.47 (3H, s),
2.50-2.60 (2H, m), 2.65 (2H,
t, J = 5.6 Hz), 3.17 (4H, t, J = 5.
0 Hz), 3.46 (2H, s), 3.90 (4H, b
rs), 6.84 (1H, s), 7.00 (1H,
d, J = 1.0 Hz), 7.35-7.40 (1H,
m), 7.45-7.50 (1H, m), 7.87 (1
H, s), 8.92 (1H, br s). MS (FAB) m / z 453 (M + H) ^<+> .

Example 187 1-[(5-Chloroindol-2-yl) sulfonyl] 4-[(6-methyl-4,5,6,7-tetrahydrofuro [2,3-c] pyridine-2- Yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 2.76 (2H, b
r), 2.89 (3H, s), 3.05-3.10 (2
H, m), 3.35-3.50 (2H, m), 3.74
(4H, br), 4.10-4.60 (2H, m),
6.97 (1H, s), 7.00-7.05 (1H,
m), 7.30-7.35 (1H, m), 7.49 (1
H, d, J = 9.0 Hz), 7.78 (1H, d, J =
2.0 Hz), 10.88 (1H, brs), 12.
45 (1H, s). MS (FAB) m / z 463 [(M + H) ⁺ , C
l ³⁵ ], 465 [(M + H) ⁺ , Cl ³⁷ ].

Example 188 1-[(2-tert-butoxycarbonylisoindolin-5-yl) carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazine Method similar to that in Example 62. Was used to synthesize the title compound. ¹ H NMR (CDCl ₃ ) δ 1.51 (9H, s),
3.13 (4H, brs), 3.72 (4H, brs)
s), 4.60-4.70 (4H, m), 6.96 (1
H, s), 7.18-7.30 (3H, m), 7.31.
7.40 (2H, m), 7.69 (1H, s), 8.
93 (1H, s). MS (FAB) m / z 545
[(M + H) ⁺ , Cl ³⁵ ], 547 [(M + H) ⁺ , Cl
³⁷ ]. Elemental analysis: C ₂₆ H ₂₉ ClN ₄ O ₅ S.H ₂ O Calculated: C, 55.46; H, 5.55; N, 9.9
5. Analytical values: C, 55.69; H, 5.35; N, 9.8.
5.

Example 189 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(isoindoline-5-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 1. m. p. 196-199 ° C (dec). ¹ H NMR (DMSO-d ₆ ) δ 3.08 (4H, br
s), 3.44 (2H, br s), 3.69 (2
H, br s), 4.47 (2H, s), 4.50 (2
H, s), 7.02 (1H, s), 7.30-7.45.
(4H, m), 7.51 (1H, d, J = 8.8H
z), 7.79 (1H, d, J = 2.0 Hz), 9.6
5 (2H, brs), 12.44 (1H, s). MS (FAB) m / z 445 [(M + H) ⁺ , C
l ³⁵ ], 447 [(M + H) ⁺ , Cl ³⁷ ]. Elemental analysis: as C ₂₁ H ₂₁ ClN ₄ O ₃ S Calculated: C, 48.75; H, 5.06; Cl, 13.
70; N, 10.83; S, 6.20. Analytical values: C, 49.06; H, 4.96; Cl, 13.
61; N, 10.63; S, 6.08.

Example 190 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(2-methylisoindolin-5-yl)
Carbonyl] piperazine The title compound was synthesized in the same manner as in Example 32.

[1220]

Embedded image m. p. 175-180 ° C (dec). ¹ H NMR (DMSO-d ₆ ) δ 2.97 (3H, br
s), 3.09 (4H, br s), 3.43 (2
H, br s), 3.68 (2H, br s), 4.5
7 (4H, brs), 7.02 (1H, s), 7.3
0-7.45 (4H, m), 7.51 (1H, d, J =
9.0 Hz), 7.79 (1H, s), 11.58 (1
H, brs), 12.46 (1H, s). MS (FAB) m / z 459 [(M + H) ⁺ , C
l ³⁵ ], 461 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 22 H 23 ClN 4 O} 3 S · 0.95HCl ·
1.6 H ₂ O Calculated: C, 50.58; H, 5.24; Cl, 13.
23; N, 10.72; S, 6.14. Analytical values: C, 50.90; H, 5.46; Cl, 13.
10; N, 10.32; S, 5.97.

Example 191 1-[(5-Chloroindol-2-yl) sulfonyl] -3- [N- (2-hydroxyethyl) carbamoylmethyl-4- (5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonylpiperazine hydrochloride The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 2.30-3.82
(20H, m), 2.90 (3H, s), 4.30-
4.50 (2H, m), 4.50-4.75 (1.5
H, m), 5.00-5.10 (0.5H, m), 5.
28-5.38 (0.5H, m), 5.80-5.90
(0.5H, m), 7.02 (1H, s), 7.31
(1H, d, J = 8.8 Hz), 7.48 (1H, d,
J = 8.8 Hz), 7.76 (1H, s), 7.95 −
8.05 (1H, m), 11.24 (0.5H, m),
11.39 (0.5H, m), 12.43 (1H,
s). FAB-MSm / z 580 [(M + H) ⁺ -H, Cl
³⁵ ], 582 [(M + H) ⁺ -H, Cl ³⁷ ].

Example 192 4-[(5-Chloroindol-2-yl) sulfonyl] -2- [2- (1,4-dioxa-8-azaspiro [4,5] decane-8-yl) ethyl] -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ: 1.79-3.73
(22H, m), 2.89 (3H, s), 3.93 (4
H, s), 4.43-4.75 (2H, m), 5.55.
(1H, m), 7.01 (1H, d, J = 6.1H
z), 7.30 (1H, dd, J = 1.9, 8.8H)
z), 7.49 (1H, d, J = 8.8 Hz), 7.7
6 (1H, s), 12.45 (1H, s). MS (FAB) m / z 649 [(M + H) ⁺ , C
l ³⁵ ], 651 [(M + H) ⁺ , Cl ³⁷ ].

Example 193 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(1,3-dioxolan-2-yl) methyl] -1-[(5-methyl-4,5 , 6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (CDCl ₃ ) δ: 1.77 (2H, m),
2.22 (2H, m), 2.49-3.95 (15H,
m), 4.55-5.03 (3H, m), 5.66 (1
H, m), 6.94 (1H, s), 7.28-7.37.
(2H, m), 7.64 (1H, d, J = 1.7H)
z), 9.34 (1H, s). MS (FAB) m / z 566 [(M + H) ⁺ , C
l ³⁵ ], 568 [(M + H) ⁺ , Cl ³⁷ ].

Example 194 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(2-1,3-dioxoisoindole-
2-yl) methyl] -1-[(5-methyl-4,5,
6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (CDCl ₃ ) δ 2.42-2.45 (3
H, m), 2.55-2.84 (5.5H, m), 3.
31-3.57 (2H, m), 3.70-3.92
(4.5H, m), 4.42-4.51 (1H, m),
4.61 (2 / 3H, broad d, J = 12.7H
z), 5.25 (1 / 3H, broad), 5.82
(1 / 3H, broad), 6.22 (2 / 3H, br)
oad d, J = 9.7 Hz), 6.99 (1H,
s), 7.30-7.38 (2H, m), 7.62-
7.73 (5H, m), 7.79 (2 / 3H, m),
8.97 (1 / 3H, broad). MS (FAB) m / z 639 (M + H) ^<+> .

Example 195 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2- [2- (2-naphthoxy) ethyl] piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (CDCl ₃ ) δ 2.28-2.51 (5
H, m), 2.55-2.60 (2H, m), 2.78
-2.87 (4H, m), 3.26-3.29 (1H,
m), 3.52-3.63 (2H, m), 3.84-
3.87 (2H, m), 4.06-4.19 (2H,
m), 4.61 (2 / 3H, broad d, J = 1)
2.7Hz), 5.16 (1 / 3H, broad),
5.71 (1 / 3H, broad m), 6.22 (2
/ 3H, broad), 6.87-6.94 (2H,
m), 7.09 (1H, broad), 7.22-7.
33 (3H, m), 7.39-7.43 (1H, m),
7.64-7.74 (4H, m), 9.09 (1H, b
load s). MS (FAB) m / z 650 (M + H) ^<+> .

Example 196 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2- (2-phenoxyethyl) piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (CDCl ₃ ) δ 2.26-2.40 (2
H, m), 2.47 (3H, s), 2.55-2.61.
(1H, m), 2.67-2.85 (5H, m), 3.
24-3.30 (1 / 3H, m), 3.48-3.51
(2 / 3H, m), 3.62-3.65 (2H, m),
3.82-4.08 (4H, m), 4.61 (2/3
H, broad d, J = 13.9 Hz), 5.12
(1 / 3H, broad), 5.82 (1 / 3H, br)
oad d, J = 12.9 Hz), 6.18 (2/3)
H, broad), 6.68-6.70 (1H, m),
6.87-6.92 (2H, m), 6.95 (1H,
s), 7.21-7.23 (2H, m), 7.29-
7.35 (2H, m), 7.65 (1H, s), 8.0
2 (1 / 3H, s), 9.03 (2 / 3H, broad
s). MS (FAB) m / z 599 (M ⁺ , Cl ³⁵ ), 60
1 (M ⁺ , Cl ³⁷ ).

Example 197 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (2-hydroxyethyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4
-C] pyridin-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (CDCl ₃ ) δ 1.88-1.94 (2
H, m), 2.48 (3H, s), 2.41-2.62.
(2H, m), 2.75-2.90 (4H, m), 3.
12-3.21 (1H, m), 3.33-3.85 (6
H, m), 4.66 (2 / 3H, broad d, J =
13.7 Hz), 4.88-4.90 (1 / 3H,
m), 5.37-5.40 (2 / 3H, m), 6.18
(1 / 3H, broad d, J = 13.4Hz),
6.91-6.95 (1H, m), 7.29-7.37
(2H, m), 7.65 (1H, s), 9.02 (1
H, broads). MS (FAB) m / z 524 [(M + H) ⁺ , C
l ³⁵ ], 526 [(M + H) ⁺ , Cl ³⁷ ].

Example 198 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2- [2- (2-oxo-1,3-oxazolan-3-ylyl) ethyl] piperazine

[1229]

Embedded image The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (CDCl ₃ ) δ 1.90 (1 H, broa
d), 2.23-2.32 (1H, broad m),
2.48 (3H, s), 2.65 (2H, broad
m), 2.80 (2H, broads), 2.87-
2.89 (2H, broad m), 3.21-3.4
5 (3H, broad m), 3.56 (2H, broad m)
adm), 3.67 (2H, s), 3.76-4.0.
4 (2H, broadm), 4.29-4.41 (2
H, m), 4.62 (2 / 5H, broad d, J =
10.4 Hz), 4.75 (3 / 5H, broad),
4.62 (3 / 5H, broad d, J = 14.6H
z), 5.90 (2 / 5H, broad), 6.97
(1H, s), 7.29 (1H, dd, J = 1.9,
8.7 Hz), 7.41 (1H, broad m),
7.63 (1H, s). MS (FAB) m / z 593 (M + H) ^<+> .

Example 199 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] Pyridazin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 82. ¹ H NMR (DMSO-d ₆ ) δ 2.65 (3H, br
s), 2.76 (3H, br s), 3.13 (4
H, br s), 3.74 (2H, br s), 4.1
0-4.50 (6H, br), 7.03 (1H, d, J
= 1.5 Hz), 7.31 (1H, dd, J = 8.8,
2.0 Hz), 7.48 (1H, d, J = 8.8H)
z), 7.76 (1H, d, J = 2.0 Hz), 12.
42 (1H, brs). MS (FAB) m / z 495 [(M + H) ⁺ , C
l ³⁵ ], 497 [(M + H) ⁺ , Cl ³⁷ ].

Example 200 2-[[(4-tert-butoxycarbonylpiperazin-1-yl) carbonyl] methyl] -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine. The title compound was synthesized in the same manner as in Example 79. ¹ H NMR (CDCl ₃ ) δ 1.49 (9H, s),
2.49 (3H, s), 2.55-3.20 (8H,
m), 3.30-3.85 (12H, m), 3.95-
4.04 (0.5H, m), 4.10-4.18 (0.
5H, m), 4.55-4.67 (0.5H, m),
4.95-5.07 (0.5H, m), 5.55-5.
65 (0.5H, m), 6.00-6.10 (0.5
H, m), 7.00 (1H, s), 7.25-7.31
(1H, m), 7.37 (1H, d, J = 8.8H
z), 7.65 (1H, s). MS (FAB) m / z 706 [(M + H) ⁺ , C
l ³⁵ ], 708 [(M + H) ⁺ , Cl ³⁷ ].

Example 201 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2-[[(piperazin-1-yl) carbonyl] methyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 1. ¹ H NMR (DMSO-d ₆ ) δ 2.50-3.85
(23H, m), 4.30-4.45 (1H, m),
4.60-4.75 (0.5H, m), 5.00-5.
10 (0.5H, m), 5.30-5.40 (0.5
H, m), 5.80-5.95 (0.5H, m), 7.
03 (1H, s), 7.32 (1H, d, J = 8.8H)
z), 7.50 (1H, d, J = 8.8 Hz), 7.7
8 (1H, s), 9.20-9.45 (1H, br),
12.46 (1H, brs). MS (FAB) m / z 606 [(M + H) ⁺ , C
l ³⁵ ], 608 [(M + H) ⁺ , Cl ³⁷ ].

Example 202 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(N-furfurylcarbamoyl) methyl]
-1-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride. The title compound was synthesized in the same manner as in Example 79. ¹ H NMR (DMSO-d ₆ ) δ 2.50-3.50
(13H, m), 3.60-3.85 (2H, m),
4.12-4.50 (3H, m), 4.60-4.75
(0.5H, m), 5.05-5.10 (0.5H,
m), 5.30-5.40 (0.5H, m), 5.78
−5.90 (0.5H, m), 6.17-6.25 (1
H, br), 6.35-6.42 (1H, m), 7.0.
3 (1H, s), 7.31 (1H, d, J = 8.8H)
z), 7.48 (1H, d, J = 8.8 Hz), 7.5
1-7.58 (1H, m), 7.77 (1H, s),
8.41-8.55 (1H, br), 12.44 (1
H, brs). MS (FAB) m / z 617 [(M + H) ⁺ , C
l ³⁵ ], 619 [(M + H) ⁺ , Cl ³⁷ ].

Example 203 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(N-methoxy-N-methylcarbamoyl) methyl] -1-[(5-methyl-4,5, 6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride. The title compound was synthesized in the same manner as in Example 79. ¹ H NMR (DMSO-d ₆ ) δ 2.50-3.83
(20H, m), 4.30-4.80 (2.5H, b
r), 5.07 (0.5H, brs), 5.31-
5.36 (0.5H, br), 5.78 (0.5H, b
rs), 7.03 (1H, s), 7.31 (1H,
d, J = 9.2 Hz), 7.48 (1H, d, J = 9.
2Hz), 7.77 (1H, s), 11.04 (1H,
br s), 12.45 (1H, br s). MS (FAB) m / z 581 [(M + H) ⁺ , C
l ³⁵ ], 583 [(M + H) ⁺ , Cl ³⁷ ].

Example 204 1-[(5-tert-butoxycarbonyl-4,5.
6.7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazine. The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
2.85 (2H, brs), 3.22 (4H, brs)
s), 3.73 (2H, br s), 3.89 (2H, brs).
br s), 4.58 (2H, br s), 4.65.
(2H, br s), 6.97 (1H, s), 7.32
(1H, dd, J = 8.8, 2.0 Hz), 7.37
(1H, d, J = 8.8 Hz), 7.66 (1H, d,
J = 2.0 Hz), 8.72 (1H, s). MS (FAB) m / z 566 [(M + H) ⁺ , C
l ³⁵ ], 568 [(M + H) ⁺ , Cl ³⁷ ].

Example 205 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(4,5.6.7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) Carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 1. ¹ H NMR (DMSO-d ₆ ) δ 3.01 (2H, t,
J = 6.1 Hz), 3.13 (4H, brs);
44 (2H, t, J = 6.1 Hz), 3.75 (2H, t, J = 6.1 Hz)
brs), 4.36 (2H, brs), 4.42
(2H, s), 7.04 (1H, s), 7.31 (1
H, dd, J = 8.8, 2.0 Hz), 7.49 (1
H, d, J = 8.8 Hz), 7.77 (1H, d, J =
2.0 Hz), 9.46 (2H, brs), 12.4
3 (1H, s). MS (FAB) m / z 466 [(M + H) ⁺ , C
l ³⁵ ], 468 [(M + H) ⁺ , Cl ³⁷ ].

Example 206 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(5-hydroxy-4,5.6.7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl)
Carbonyl] piperazine The title compound was synthesized in the same manner as in Example 144. ¹ H NMR (DMSO-d ₆ ) δ 2.70-3.05
(2H, br), 3.05-3.25 (6H, br),
3.65-4.50 (6H, br), 7.03 (1H,
s), 7.30 (1H, dd, J = 8.8, 2.0H)
z), 7.47 (1H, d, J = 8.8 Hz), 7.7
6 (1H, d, J = 2.0 Hz), 8.35 (1H,
s), 12.40 (1H, s). MS (FAB) m / z 482 [(M + H) ⁺ , C
l ³⁵ ], 484 [(M + H) ⁺ , Cl ³⁷ ].

Example 207 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(ethoxycarbonyl) methyl] -1-
[(5-Methylsulfonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1- (tert-butoxycarbonyl) -4-[(5-
Chloroindol-2-yl) sulfonyl] -2-
[(Methoxycarbonyl) methyl] piperazine (1.1
5g) was dissolved in a saturated hydrochloric acid-ethanol solution and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, methylene chloride and a saturated aqueous solution of sodium hydrogen carbonate were added, and the mixture was separated. After that, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. A part (519 m) of the obtained residue (0.97 g)
g) was dissolved in N, N-dimethylformamide (2 ml) and (5-tert-butoxycarbonyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carboxylic acid lithium salt (328 mg),
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (288 mg) and 1-hydroxybenzotriazole (363 mg) were added, and the mixture was stirred at room temperature for 3 days. Methylene chloride and water were added to separate the organic layer, which was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane: ethyl acetate = 1: 1). This was dissolved in a saturated hydrochloric acid-ethanol solution (5 ml) and stirred at room temperature for 1 hour. Add methylene chloride,
After washing with a saturated aqueous solution of sodium hydrogencarbonate and drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (5 ml), methanesulfonyl chloride (105 μl) and triethylamine (0.5 ml) were added, and the mixture was stirred at room temperature for 15 minutes. After washing with water and drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Flash column chromatography on silica gel (methylene chloride: methanol = 4
9: 1) to give the title compound (207 mg). ¹ H NMR (DMSO-d ₆ ) δ 1.07-1.16
(3H, m), 2.67-2.90 (5H, m), 2.
96 (3H, s), 3.20-3.24 (2H, m),
3.53-3.78 (4H, m), 3.95-4.04
(2H, m), 4.39, 5.04 (1H, each
d, J = 14.4, 14.9 Hz), 4.55 (2H,
s), 5.03, 5.95 (1H, each br).
s), 7.03 (1H, s), 7.31 (1H, dd,
J = 8.8, 1.7 Hz), 7.47 (1H, d, J =
8.8 Hz), 7.76 (1H, d, J = 1.7H)
z), 12.41 (1H, s). MS (FAB) m / z 630 (M + H) ⁺

Example 208 2- [Carboxymethyl] -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methylsulfonyl-4,5,6,7-tetrahydrothiazolo [ 5,4-c] pyridin-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 77. ¹ H NMR (DMSO-d ₆ ) δ 2.32-3.74
(14H, m), 4.38, 5.37 (1H, each
d, J = 12.2, 12.4 Hz), 4.54 (2
H, s), 5.00, 5.83 (1H, each br)
s), 7.02 (1H, s), 7.30 (1H, d,
J = 8.8 Hz), 7.47 (1H, d, J = 8.8H)
z), 7.75 (1H, s), 12.51 (1H,
s).

Example 209 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[[N- (methylsulfonyl) carbamoyl] methyl] -1-[(5-methylsulfonyl) -4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl] piperazine 2- [carboxymethyl] -4-[(5-chloroindol-2-yl) sulfonyl] -1- [(5-Methylsulfonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine (115 mg) in tetrahydrofuran (5 ml)
And carbonyldiimidazole (58 mg) was added thereto, followed by heating under reflux for 2 hours. Cool to room temperature, methanesulfonamide (34 mg), 1,8-diazabicyclo [5.
4.0] -7-undecene (55 mg) and 1.5
Stirred for hours. The solvent was distilled off under reduced pressure, the residue was dissolved in methylene chloride, and washed with water, 0.2 N hydrochloric acid, and saturated saline. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative TLC (methylene chloride: methanol = 9: 1). The solvent was evaporated under reduced pressure, and the obtained solid was washed with ether to give the title compound (62 mg) as a colorless solid. ¹ H NMR (DMSO-d ₆ ) δ 2.50-3.56
(15H, m), 3.65-3.77 (2H, m),
4.40, 5.40 (1H, each d, J = 15.
4,11.8 Hz), 4.55 (2H, s), 5.1
0, 5.98 (1H, each br s), 7.04
(1H, s), 7.31 (1H, d, J = 8.8, 2.
0 Hz), 7.47 (1H, d, J = 8.8 Hz),
7.76 (1H, d, J = 2.0 Hz), 11.88
(1H, s), 12.44 (1H, s). MS (FAB) m / z 602 (M + H) ⁺ .

Example 210 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2 -Yl) carbonyl] piperazine 5- (tert-butoxycarbonyl) -4,5,6
7-tetrahydrothiazolo [5,4-c] pyridine-2
1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazine (2.50 g) in a solution of lithium carboxylate (1.89 g) in N, N-dimethylformamide (40 ml), 1-hydroxy Benzotriazole monohydrate (1.20 g) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.7
0 g) was added at room temperature. After stirring for 2 days, ethyl acetate (200 ml) and water (1.0 l) were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with ethyl acetate (2 × 150 ml).
The organic layers were combined, washed with water (1.0 l) and a saturated aqueous solution of sodium hydrogen carbonate (200 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (silica gel 2).
00g, methylene chloride: ethyl acetate = 7: 1 → 1: 1)
And purified as 1-[[5-
(Tert-butoxycarbonyl) -4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl] carbonyl] -4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazine was obtained. Trifluoroacetic acid (15 ml) was added to a solution of the obtained box-form in methylene chloride (15 ml) at room temperature, and after stirring for 10 minutes, the solvent was distilled off under reduced pressure to obtain a residue. Methylene chloride (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (150 ml) were added to the residue, and the layers were separated. The aqueous layer was extracted with methylene chloride (6 × 25 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by silica gel column chromatography (silica gel 100 g, methylene chloride: methanol = 25: 1 → 10: 1) to give the title compound (754 mg) as a pale brown solid. ¹ H NMR (DMSO-d ₆ ) δ 2.67 (2H, t,
J = 5.7 Hz), 2.96 (2H, t, J = 5.7H)
z), 3.18 (4H, t, J = 4.9 Hz), 3.3
1 (1H, s), 3.77 (2H, brs), 3.9
0 (2H, s), 4.44 (2H, brs), 7.5
7 (1H, dd, J = 8.8, 2.0 Hz), 8.05
(1H, d, J = 8.8 Hz), 8.09 (1H,
s), 8.31 (1H, d, J = 2.0 Hz). MS (FAB) m / z 483 (M + H) ⁺ .

Example 211 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -4-[[5- (pyridin-4-yl)-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl] carbonyl] piperazine hydrochloride

[1243]

Embedded image 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine (200 mg) of N, N-dimethylformamide (2.0 ml) was added to 4-bromopyridine (8
7.0 mg) and triethylamine (150 μl) were added at room temperature, and the mixture was heated with stirring at 120 ° C. for 12 hours. After the reaction solution was concentrated, methylene chloride (20 ml), a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and water (50 ml) were added, and the mixture was separated. The aqueous layer was extracted with methylene chloride (4 × 20 ml). After combining the organic layers and drying over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The obtained residue was purified using preparative silica gel thin-layer chromatography (methylene chloride: methanol = 20: 1), and further purified by preparative silica gel thin-layer chromatography (methylene chloride: acetone: methanol = 15: 5: Purification was performed using 1), and this was dissolved in methylene chloride, methanol and 1N hydrochloric acid, concentrated under reduced pressure and dried to obtain the title compound (56.5 mg) as a pale yellow solid. ¹ H NMR (DMSO-d ₆ ) δ 2.97 (2H, t,
J = 5.6 Hz), 3.17 (4H, brs);
77 (2H, brs), 4.05 (2H, t, J =
5.6 Hz), 4.41 (2H, brs), 5.01.
(2H, s), 7.31 (2H, br s), 7.56
(1H, d, J = 8.4 Hz), 8.05 (1H, d,
J = 8.4 Hz), 8.08 (1H, s), 8.30
(2H, s), 8.32 (1H, s), 13.70 (1
H, brs). MS (FAB) m / z 560 (M + H) ⁺ .

Example 212 2- (methoxycarbonylmethyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] -4-[[5-
(Trimethylsilylethynyl) indol-2-yl]
Sulfonyl] piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (CDCl ₃ ) δ 0.26 (9H, s),
2.49 (3H, s), 2.53-2.68 (1H,
m), 2.74 (1H, dd, J = 12.0, 2.7H
z), 2.77-2.83 (3H, m), 2.87 (2
H, brs), 3.00 (1H, dd, J = 15.
8, 8.7 Hz), 3.11-3.26 (1 / 2H, b
r), 3.39-3.54 (1 / 2H, br), 3.5
9-3.67 (5H, m), 3.72-3.96 (2
H, m), 4.61 (1 / 2H, br d, J = 13.
2Hz), 5.22 (1 / 2H, brs), 5.71
(1 / 2H, br d, J = 13.2 Hz), 6.16
(1 / 2H, br s), 6.97 (1H, s), 7.
34 (1H, d, J = 8.6 Hz), 7.43 (1H,
dd, J = 8.6, 1.5 Hz), 7.81 (1H,
s), 9.35 (1H, br d, J = 11.0H
z). MS (FAB) m / z 614 (M + H) ^<+> .

Example 213 4-[(5-Ethynylindol-2-yl) sulfonyl] -2- (methoxycarbonylmethyl) -1-[(5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 104. ¹ H NMR (CDCl ₃ ) δ 2.49 (3H, s),
2.53-2.95 (7H, m), 2.95-3.05
(1H, m), 3.04 (1H, s), 3.20 (1 /
2H, brt, J = 11.6 Hz), 3.46 (1 /
2H, brt, J = 11.6 Hz), 3.59-3.
75 (5H, m), 3.75-3.97 (2H, m),
4.62 (1 / 2H, br d, J = 12.8 Hz),
5.22 (1 / 2H, brs), 5.73 (1/2
H, br d, J = 13.6 Hz), 6.18 (1/2)
H, br s), 7.00 (1H, s), 7.37 (1
H, d, J = 8.6 Hz), 7.45 (1H, dd, J)
= 8.6, 1.2 Hz), 7.85 (1H, s), 9.
28 (1H, brd, J = 13.2 Hz). MS (FAB) m / z 542 (M + H) ^<+> .

Example 214 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2- [2-[(morpholin-4-yl) sulfonyl] ethyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 182. ¹ H NMR (DMSO-d ₆ ) δ 2.10-2.40
(2H, m), 2.50-2.80 (2H, m), 2.
90 (3H, s), 3.00-3.30 (8H, m),
3.30-3.90 (9H, s), 4.30-4.90
(3H, m), 5.30-5.50 (1H, m), 7.
03 (1H, s), 7.31 (1H, dd, J = 8.
8, 1.5 Hz), 7.48 (1H, d, J = 8.8H)
z), 7.76 (1H, d, J = 1.5 Hz), 11.
42 (1H, br), 12.45 (1H, s). MS (FAB) m / z 657 [(M + H) ⁺ , C
l ³⁵ ], 659 [(M + H) ⁺ , Cl ³⁷ ].

Example 215 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (2-ethoxycarbonylethyl) -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (CDCl ₃ ) δ 1.15-1.25 (3
H, m), 1.40-1.80 (1H, m), 2.05
−2.15 (1H, m), 2.25-2.45 (3H,
m), 2.49 (3H, s), 2.50-3.55 (6
H, m), 3.67 (2H, s), 3.70-3.90.
(2H, m), 4.00-4.20 (2H, m), 4.
55-6.10 (2H, m), 6.95 (1H, s),
7.30-7.40 (2H, m), 7.65 (1H,
d, J = 1.6 Hz), 9.03 (1H, br). MS (FAB) m / z 580 [(M + H) ⁺ , C
l ³⁵ ], 582 [(M + H) ⁺ , Cl ³⁷ ].

Example 216 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2-[[2- (morpholin-4-yl) carbonyl] ethyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Reference Example 6. ¹ H NMR (DMSO-d ₆ ) δ 1.85-2.00
(1H, m), 2.05-2.20 (1H, m), 2.
20-2.35 (2H, m), 2.55-2.70 (1
H, m), 2.80-2.95 (4H, m), 3.00
-3.80 (14H, m), 4.25-5.55 (5
H, m), 7.02 (1H, s), 7.30 (1H, d
d, J = 8.8, 2.0 Hz), 7.48 (1H, d,
J = 8.8 Hz), 7.75 (1H, d, J = 2.0H)
z), 11.45 (1H, brs), 12.43 (1
H, s). MS (FAB) m / z 621 [(M + H) ⁺ , C
l ³⁵ ], 623 [(M + H) ⁺ , Cl ³⁷ ].

Example 217 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[[2- (N, N-dimethylaminocarbonyl) ethyl] -1-[(5-methyl-4, 5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Reference Example 6. ¹ H NMR (DMSO-d ₆ ) δ 1.85-2.00
(1H, m), 2.05-2.20 (1H, m), 2.
20-2.35 (2H, m), 2.50-2.65 (1
H, m), 2.70-3.80 (17H, m), 4.3
0-5.55 (4H, m), 7.02 (1H, s),
7.29 (1H, dd, J = 8.8, 2.0 Hz),
7.48 (1H, d, J = 8.8 Hz), 7.75 (1
H, d, J = 2.0 Hz), 11.49 (1H, br)
s), 12.44 (1H, s). MS (FAB) m / z 579 [(M + H) ⁺ , C
l ³⁵ ], 581 [(M + H) ⁺ , Cl ³⁷ ].

Example 218 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [ 5,4-
c] Pyridin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 182. ¹ H-NMR (DMSO-d ₆ ) δ 1.90-2.18
(2H, m), 2.20-2.90 (4H, m), 2.
90 (3H, s), 3.12 (2H, brs),
21-3.82 (6H, m), 4.30-4.85 (2
H, m), 5.31-5.43 (0.5H, m), 5.
55-5.70 (0.5H, m), 7.02 (1H,
d, J = 2.0 Hz), 7.31 (1H, dd, J =
8.9, 2.1 Hz), 7.48 (1H, d, J = 8.
8 Hz), 7.76 (1H, d, J = 1.7 Hz), 1
1.18 (1H, brs), 12.44 (1H, brs)
s). MS (FAB) m / z 533 [(M +
H) ⁺ , Cl ³⁵ ], 535 [(M + H) ⁺ , Cl ³⁷ ].

Example 219 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(6,6-ethylenedioxy-4,5,
6,7-Tetrahydrobenzo [d] thiazol-2-yl) carbonyl] piperazine The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 1.93 (2H, t,
J = 6.6 Hz), 2.73-3.32 (10H,
m), 3.73 (1H, brs), 3.93 (4H,
s), 3.95 (1H, br s), 6.97, 7.0
3 (1H, s), 7.30 (1H, dd, J = 8.8,
2.2Hz), 7.45-7.47 (1H, m), 7.
76 (1H, s). MS (FAB) m / z 523 [(M + H) ⁺ , C
l ³⁵ ], 525 [(M + H) ⁺ , Cl ³⁷ ].

Example 220 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(6-oxo-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl ]
Piperazine

[1253]

Embedded image In a 300 ml eggplant flask, 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(6,6-ethylenedioxy-4,5,6,7-tetrahydrobenzo [d] thiazole-2- Yl) carbonyl] piperazine (740 mg) was added, dissolved in methanol (150 ml), p-toluenesulfonic acid monohydrate (100 mg) was added, and the mixture was heated under reflux. After 16 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel 75 g, ethyl acetate: hexane = 1: 1) to give the title as a pale yellow amorphous solid. The compound (110 mg) was obtained. ¹ H NMR (CDCl ₃ ) δ 2.76 (2H, t, J =
6.8 Hz), 3.18 (2H, t, J = 6.8H)
z), 3.19-3.22 (6H, m), 3.65 (2
H, s), 3.89 (1H, br s), 4.59 (1
H, brs), 6.97 (1H, s), 7.31-
7.39 (2H, m), 7.66 (1H, d, J = 2.
0 Hz). MS (FAB) m / z 479 [(M + H) ⁺ , C
l ³⁵ ], 481 [(M + H) ⁺ , Cl ³⁷ ].

Example 221 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(6,7-dihydro-7H-pyrano [4
3-d] thiazol-2-yl) carbonyl] piperazine

[1255]

Embedded image The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 2.82 (2H, t,
J = 5.6 Hz), 3.12 (4H, t, J = 4.9H)
z) 3.28-3.35 (2H, m), 3.73 (1
H, br s), 3.93 (2H, t, J = 5.6H)
z), 4.39 (1H, brs), 4.79 (2H,
s), 7.03 (1H, s), 7.30 (1H, dd,
J = 8.8, 2.2 Hz), 7.47 (1H, d, J =
8.8 Hz), 7.76 (1H, s). MS (FAB) m / z 467 [(M + H) ⁺ , C
l ³⁵ ], 469 [(M + H) ⁺ , Cl ³⁷ ].

Example 222 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2-[[N- (phenylsulfonyl) carbamoyl] methyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 2.52-3.77
(12H, m), 3.88-4.20 (2H, m),
4.24-4.48 (1.5H, m), 4.52-4.
75 (1H, m), 5.00 (0.5H, m), 5.2
3-5.32 (0.5H, m), 5.57 (0.25
H, brs), 5.79 (0.25H, brs),
6.97 (1H, s), 7.28 (1H, d, J = 8.
8Hz), 7.45 (1H, d, J = 8.8Hz),
7.49-7.53 (1H, m), 7.61 (2H, b
rs), 7.72 (1H, s), 7.85 (2H, b
rs), 11.54-11.98 (1H, m), 1
2.20-12.50 (2H, m). MS (FAB) m
/ Z 677 [(M + H) ⁺ , Cl ³⁵ ], 679 [(M
+ H) ⁺ , Cl ³⁷ ].

Example 223 1-[(5-Chloroindol-2-yl) sulfonyl] -2-[(N-methyl-N-methylsulfonylcarbamoyl) methyl] -4-[(5-methyl-4,5 ,
6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 3.12-4.53
(21H, m), 3.75-3.82 (0.5H,
m), 4.35-4.45 (1H, m), 5.09
(0.5H, brs), 5.32-5.49 (0.5
H, m), 5.85 (0.5H, brs), 7.02
(1H, s), 7.30 (1H, dd, J = 8.8,
2.0 Hz), 7.47 (1H, dd, J = 8.8,
2.0 Hz), 7.75 (1H, s), 12.44 (1
H, brs). MS (FAB) m / z 629 [(M + H) ⁺ , C
l ³⁵ ], 631 [(M + H) ⁺ , Cl ³⁷ ].

Example 224 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(2-methylsulfonylhydrazino) carbonylmethyl] -1-[(5-methyl-4,5,6 , 7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine hydrochloride The title compound was synthesized in the same manner as in Example 62. ¹ H NMR (DMSO-d ₆ ) δ 3.10-4.60
(17H, m), 5.10-5.25 (1.5H,
m), 5.40-5.55 (1H, m), 5.90
(0.5H, brs), 6.11-6.20 (0.5
H, m), 6.74 (0.5H, brs), 7.81
(1H, s), 8.10 (1H, d, J = 8.6H)
z), 8.27 (1H, d, J = 8.6 Hz), 8.5
6 (1H, s), 10.15-10.25 (1H,
m), 11.08 (1H, s), 11.99 (1H,
s), 13.22 (1H, s). MS (FAB) m / z 630 [(M + H) ⁺ , C
l ³⁵ ], 632 [(M + H) ⁺ , Cl ³⁷ ].

Example 225 1-[[5 (6) -chlorobenzimidazol-2-yl] sulfonyl] -4-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 6-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl ) Lithium carboxylate (153 mg) in N, N-dimethylformamide (3.0 ml) was added to 1-[[5 (6) -chlorobenzimidazol-2-yl] sulfonyl] piperazine (25
5 mg), 1-hydroxybenztriazole (11 m
g) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (148 mg) were sequentially added, and the mixture was stirred at room temperature for 28 hours. After the reaction solution was concentrated under reduced pressure, dichloromethane and a saturated aqueous solution of sodium chloride were added to form two layers. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1), then ethanol (2 ml), 1N hydrochloric acid in ethanol (1.5 ml) were added, and the mixture was concentrated and dried to give the title compound (168 mg) as colorless. Obtained as amorphous. IR (KBr) cm ^-1 1622, 1429, 1365,
1279, 1157, 1055, 1005, 970, 9
39,922. ¹ H NMR (DMSO-d ₆ ) δ 2.90 (3H,
s), 3.03-4.00 (10H, br), 4.40.
(3H, brs), 4.63-4.77 (1H, m),
7.40 (1H, dd, J = 8.8, 2.0 Hz),
7.72 (1H, d, J = 8.8 Hz), 7.78 (1
H, s), 11.48-11.65 (1H, brs). MS (FAB) m / z 481 [(M + H) ⁺ , C
l ³⁵ ], 483 [(M + H) ⁺ , Cl ³⁷ ].

Example 226 1-[[6- (tert-butoxycarbonyl) -5,
7-dihydropyrrolo [3,4-d] pyrimidin-2-yl] carbonyl] -4-[(5-chloroindole-2
-Yl) sulfonyl] piperazine 6- (tert-butoxycarbonyl) -5,7-dihydro-2-methoxycarbonylpyrrolo [3,4-d] pyrimidine (317 mg) in tetrahydrofuran (15 m
l) Add water (1 ml) and lithium hydroxide (30.0
mg) at room temperature, and after stirring for 10 minutes, the solvent was distilled off under reduced pressure. 1-[(5-Chloroindole-2) was added to a solution of the obtained residue in N, N-dimethylformamide (10 ml).
-Yl) sulfonyl] piperazine hydrochloride (380 m
g), 1-hydroxybenzotriazole monohydrate (1
53 mg) and 1- (dimethylaminopropyl) -3-
Ethyl carbodiimide hydrochloride (433 mg) was added at room temperature. After stirring for 3 hours, the solution was concentrated, and ethyl acetate and saturated saline were added to the reaction mixture to carry out liquid separation. After the oil layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (5%
(Methanol-methylene chloride). Diethyl ether was added for solidification, and the colorless powder was collected by filtration and dried to give the title compound (495 mg). ¹ H NMR (DMSO-d ₆ ) δ 1.45 (9H,
s), 2.94 (2H, brs), 3.12 (2H, b
rs), 3.30 (2H, br s), 3.76 (2
H, brs), 4.55-4.58 (2H, m),
4.63-4.67 (2H, m), 7.03 (1H,
s), 7.33 (1H, dd, J = 8.8, 2.1H)
z), 7.50 (1H, d, J = 8.8 Hz), 7.7
8 (1H, d, J = 2.1 Hz), 8.75 (1H × 1
/ 2, s), 8.78 (1H x 1/2, s), 12.4
3 (1H, s). MS (FAB) m / z 547 [(M + H) ⁺ , C
l ³⁵ ], 549 [(M + H) ⁺ , Cl ³⁷ ].

[1261] 6- (tert-Butoxycarbonyl) -5,7-dihydro-2-methoxycarbonylpyrrolo [3,4-d] pyrimidine used as a starting material was synthesized by the following method.

[1262] <1-tert-butoxycarbonyl-3
-Pyrrolidone> (3R) in methylene chloride (200ml)
-1-tert-butoxycarbonyl-3-hydroxypyrrolidine (10.0 g), N-methylformolin N
-Oxide (12.5 g) was dissolved, and molecular sieve (MS4A, 5.00 g) and tetrapropylammonium parthenate (0.94 g) were added under ice-cooling.
The mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered through Celite, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1). The title compound (8.65 g) was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ: 1.49 (9H, s),
2.59 (2H, t, J = 7.8 Hz), 3.70 −
3.81 (4H, m).

[1263] <6- (tert-butoxycarbonyl)
-5,7-dihydro-2-methylthiopyrrolo [3,4-
d] pyrimidine> 1- (tert-butoxycarbonyl) -3-pyrrolidone (4.57 g) at room temperature with N, N
-Dimethylformamide dimethyl acetal (30m
l) was added and heated at 140 ° C. for 1 hour. After allowing the reaction mixture to cool to room temperature, it was concentrated under reduced pressure to obtain a residue. Hexane was added to this residue, and the precipitated yellow powder was collected by filtration and dried. This was dissolved in ethanol (100 ml), and methylisothiourea sulfate (9.24 g) and sodium ethoxide (4.52 g) were added to the solution at room temperature, and the mixture was heated under reflux for 24 hours. After allowing to cool, saturated saline and diethyl ether were added to the reaction mixture, and the mixture was separated. The oil layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (1% methanol-methylene chloride). The title compound (1.10 g) was obtained as a pale yellow powder. ¹ H NMR (CDCl ₃ ) δ 1.51 (9H, s),
2.57 (3H, m), 4.15-4.45 (4H,
m), 8.39 (1H × 1/2, s), 8.43 (1H
× 1/2, s). MS (FAB) m / z 268 (M + H) ⁺ .

[1264] <6- (tert-butoxycarbonyl)
-5,7-dihydro-2-methylsulfonylpyrrolo [3,4-d] pyrimidine> 6- (tert-butoxycarbonyl) -5,7-dihydro-2-methylthiopyrrolo [3,4-d] pyrimidine (1 0.08 g) in methylene chloride (20 ml) was added with meta-chloroperbenzoic acid (1.99 g) under ice-cooling. After stirring for 5 hours, a saturated aqueous sodium sulfite solution, a saturated aqueous sodium hydrogen carbonate solution and methylene chloride were added to the reaction mixture, and the mixture was separated. The oil layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. Hexane was added to the obtained residue, and the precipitated colorless powder was collected by filtration and dried to give the title compound (1.09 g). ¹ H NMR (CDCl ₃ ) 1.53 (9H, s), 3.
36 (3H, m), 4.77-4.90 (4H, m),
8.77 (1H × 1/2, s), 8.81 (1H × 1 / s)
2, s). MS (FAB) m / z 300 (M + H) ⁺ .

[1265] <6- (tert-butoxycarbonyl)
-2-cyano-5,7-dihydropyrrolo [3,4-d]
Pyrimidine> 6- (tert-butoxycarbonyl)-
5,7-dihydro-2-methylsulfonylpyrrolo [3,
4-d] pyrimidine (1.05 g) in methylene chloride (3
0 ml) solution at room temperature was added tetrabutylammonium cyanide (1.04 g). After stirring for 1 hour at room temperature,
1N sodium hydroxide was added to carry out liquid separation. The oil layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified using silica gel column chromatography (methylene chloride: acetone = 20: 1) to give the title compound (776 mg) as a colorless powder. ¹ H NMR (CDCl ₃ ) δ 1.52 (9H, s),
4.70-4.85 (4H, m), 8.68-8.77
(1H, m). MS (FAB) m / z 247 (M + H) ^<+> .

<6- (tert-butoxycarbonyl)
-5,7-dihydro-2-methoxycarbonylpyrrolo [3,4-d] pyrimidine> 6- (tert-butoxycarbonyl) -2-cyano-5,7-dihydropyrrolo [3,4-d] pyrimidine (776 mg) ) Was added to a methanol (10 ml) solution at room temperature, and the mixture was stirred at 100 ° C for 1 hour. After cooling, the reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in methanol (10 ml), and triethylamine (2.20 ml) and di-tert-butyl dicarbonate (1.37 g) were added at room temperature.
Was added. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure, and methylene chloride and saturated saline were added to carry out liquid separation. The oil layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a residue.
The obtained residue was purified using silica gel column chromatography (3% methanol-methylene chloride) to give the title compound (317 mg) as a colorless powder. ¹ H NMR (CDCl ₃ ) δ 1.53 (9H, s),
4.09 (3H, s), 4.75-4.85 (4H,
m), 8.81 (1H × 1/2, s), 8.85 (1H
× 1/2, s). MS (FAB) m / z 280 (M + H) ⁺ .

Example 227 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(5,7-dihydropyrrolo [3,4-d]
Pyrimidin-2-yl) carbonyl] piperazine trifluoroacetate 1-[[6- (tert-butoxycarbonyl) -5,
7-dihydropyrrolo [3,4-d] pyrimidin-2-yl] carbonyl] -4-[(5-chloroindole-2
-Yl) sulfonyl] piperazine (450 mg) in methylene chloride (10 ml).
ml) was added at room temperature. After stirring for 1 hour, water was added and the mixture was concentrated under reduced pressure to give the title compound as a pale yellow powder (488 m
g) was obtained. ¹ H NMR (DMSO-d ₆ ) δ 2.95 (2H, t,
J = 4.8 Hz), 3.14 (2H, t, J = 4.8H)
z), 3.31 (2H, t, J = 4.8 Hz), 3.7
8 (2H, t, J = 4.8 Hz), 4.55 (2H,
s), 4.65 (2H, s), 7.04 (1H, d, J
= 1.5 Hz), 7.34 (1H, dd, J = 8.8,
2.1Hz), 7.50 (1H, d, J = 8.8H)
z), 7.79 (1H, d, J = 2.1 Hz), 8.8
5 (1H, s), 9.75 (2H, brs), 12.4
7 (1H, brs). MS (FAB) m / z 447 [(M + H) ⁺ , C
l ³⁵ ], 449 [(M + H) ⁺ , Cl ³⁷ ].

Example 228 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(5,7-dihydro-6-methylpyrrolo [3,4-d] pyrimidin-2-yl) carbonyl] Piperazine hydrochloride

[1269]

Embedded image 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(5,7 dihydropyrrolo [3,4-d] pyrimidin-2-yl) carbonyl] piperazine (564
mg), methylene chloride (5 ml), triethylamine (139 ml), acetic acid (57.5 ml), formalin (64.5 ml) and sodium triacetoxyborohydride (160 mg) were added at room temperature. After stirring for 30 minutes, methylene chloride (10 ml) and a saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture, and the mixture was separated. The aqueous layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel chromatography (5% methanol-methylene chloride), dissolved in 1N aqueous hydrochloric acid-methylene chloride-methanol, and concentrated to give the title compound (201 mg) as a pale yellow solid.
I got ¹ H NMR (DMSO-d ₆ ) δ 2.96 (2H, t,
J = 4.8 Hz), 3.00 (3H, s), 3.13
(2H, t, J = 4.8 Hz), 3.25-3.45
(2H, m), 3.76 (2H, t, J = 4.8H)
z), 4.50-5.00 (4H, br), 7.03
(1H, d, J = 0.73 Hz), 7.32 (1H, d
d, J = 8.8, 1.7 Hz), 7.50 (1H, d,
J = 8.8 Hz), 7.78 (1H, d, J = 1.7H)
z), 8.86 (1H, s), 12.15 (1H, br)
s), 12.47 (1H, br s). MS (FAB) m / z 461 [(M + H) ⁺ , C
l ³⁵ ], 463 [(M + H) ⁺ , Cl ³⁷ ].

Example 229 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(5,6-dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] Pyridazine-2-
Yl) carbonyl] piperazine hydrochloride

[1271]

Embedded image Ethyl 5,6-dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-d] pyridazine-2-carboxylate (207 mg) was added to tetrahydrofuran (15
ml) and water (1 ml), and the mixture was dissolved in lithium hydroxide (24.0 mg) at room temperature and stirred for 15 minutes. The solvent was distilled off under reduced pressure, and 1-[(5-chloroindol-2-yl) sulfonyl] piperazine (275 m
g), 1-hydroxybenzotriazole monohydrate (124 mg), 1- (dimethylaminopropyl) -3
-Ethylcarbodiimide hydrochloride (352 mg) was added and dissolved in N, N-dimethylformamide (10 ml).
Stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, dichloromethane and water were added to the residue, liquid separation was performed, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (4% methanol-dichloromethane) to obtain a colorless foam. This was dissolved in 1N hydrochloric acid (ethanolic) and concentrated. Ethyl acetate was added, and the precipitated colorless powder was collected by filtration and dried to give the title compound (312 mg). ¹ H NMR (DMSO-d ₆ ) δ 2.60-2.85
(6H, br), 3.11 (4H, brs), 3.7
5 (2H, brs), 4.10-4.45 (6H, b
r), 7.03 (1H, d, J = 1.5 Hz), 7.3
1 (1H, dd, J = 8.8, 2.0 Hz), 7.48
(1H, d, J = 8.8 Hz), 7.77 (1H, d,
J = 2.0 Hz), 12.42 (1H, s). MS (FAB) m / z 479 [(M + H) ⁺ , C
l ³⁵ ], 481 [(M + H

[1272] Ethyl 5,6-dimethyl-4,5,6,7-tetrahydrooxazolo [4,5-
d] Pyridazine-2-carboxylate was synthesized by the following method.

[1273] <Ethyl 4,5-bis (bromomethyl)
Oxazole-2-carboxylate> ethyl at room temperature
4,5-dimethyloxazole-2-carboxylate (2.65 g), N-bromosuccinimide (5.58
g) and α, α'-azobisisobutyronitrile (1
29 mg) was dissolved in ethylene dichloride (250 ml) and heated under reflux for 1.5 hours. After completion of the reaction, the solvent was distilled off and the residue was purified by silica gel chromatography (SI40D, hexane: ethyl acetate = 4: 1) to give the title compound (1.
84 g) were obtained. ¹ H NMR (CDCl ₃ ) δ 1.44 (3H, t, J =
7.1 Hz), 4.43 (2H, s), 4.49 (3
H, q, J = 7.1 Hz), 4.55 (2H, s). MS (FAB) m / z 326 (M + H, Br ⁷⁹ an
^{d Br 79) +, 328 (} M + H, Br 79 and B
r ⁸¹ ) ⁺ , 330 (M + H, Br ⁸¹ and B
r ⁸¹ ) ⁺ .

[1274] <Ethyl 5,6-dimethyl-4,5>
6,7-tetrahydrooxazolo [4,5-d] pyridazine-2-carboxylate> room temperature, ethyl 4,5
-Bis (bromomethyl) oxazole-2-carboxylate (920 mg) and 1,2-dimethylhydrazine dihydrochloride (561 mg) in ethanol (20 ml)
And triethylamine (1.96) was added to the reaction mixture.
ml) at once, and the mixture was stirred at room temperature for 4 hours. The layers were separated with methylene chloride and saturated saline, the oil layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. Purification by silica gel chromatography (3% methanol-methylene chloride) gave the title compound (207 mg, pale yellow oil). ¹ H NMR (CDCl ₃ ) δ 1.44 (3H, t, J =
7.1 Hz), 2.44 (3H, s), 2.52 (3
H, s), 3.75 (2H, br s), 3.92 (2
H, br s), 4.47 (2H, q, J = 7.1H)
z). MS (FAB) m / z 226 (M + H) ^<+> .

Example 230 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(5-methoxy-4,5,6,7-tetrahydro [5,4-c] pyridine-2- Yl) carbonyl] piperazine

[1276]

Embedded image Under an argon atmosphere, 5-methoxy-4,5,6,7-tetrahydro [5,4-c] pyridine (96 mg) was dissolved in diethyl ether (2 ml), cooled to -78 ° C, and n-butyllithium (hexane Solution, 1.54mo
1 / l, 403 μl) was added dropwise. The reaction solution was stirred for 15 minutes under ice-cooling, cooled again to -78 ° C, blown with carbon dioxide gas for 1 hour, and then heated to room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude purified product of lithium 5-methoxy-4,5,6,7-tetrahydro [5,4-c] pyridine-2-carboxylate. This was dissolved in dimethylformamide (20 ml), and 1-[(5-chloroindol-2-yl) sulfonyl] piperazine hydrochloride (13
9 mg), 1-hydroxybenzotriazole monohydrate (76.0 mg) and 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (216 mg)
Was added. After stirring at room temperature overnight, the solution was concentrated, methylene chloride and saturated saline were added to the reaction mixture, and the mixture was separated. After the oil layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The obtained residue was purified using silica gel column chromatography (ethyl acetate). Diethyl ether was added for solidification, and the colorless powder was collected by filtration and dried to give the title compound (49 mg). ¹ H NMR (CDCl ₃ ) δ 2.85-3.10 (2
H, br), 3.22 (4H, br s), 3.31.
(2H, br s), 3.58 (3H, s), 3.89
(2H, brs), 4.00-4.40 (2H, b
r), 4.58 (2H, brs), 6.97 (1H,
s), 7.32 (1H, d, J = 8.8 Hz), 7.3
7 (1H, d, J = 8.8 Hz), 7.67 (1H,
s) 8.75 (1H, s). MS (FAB) m / z 496 [(M + H) ⁺ , C
l ³⁵ ], 498 [(M + H) ⁺ , Cl ³⁷ ]. HRMS (FAB) m / z 496.0853 (M +
H) ⁺ (calculated C ₂₀ H ₂₂ ClN ₅ O ₄ S ₂ 496.088
0).

[1277] 5-Methoxy-4,5 used as a raw material
6,7-Tetrahydro [5,4-c] pyridine was synthesized by the following method.

[1278] <4,5,6,7-tetrahydro [5,4
-C] pyridine> 6-tert-butoxycarbonyl-4,5,6,7-tetrahydro [5,4-c] under ice-cooling
Pyridine (6.00 g) was dissolved in methylene chloride (25 ml), trifluoroacetic acid (25 ml) was added, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. The solvent was distilled off, liquid separation was performed with chloroform and a saturated aqueous solution of sodium hydrogen carbonate, the oil layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound (3.23 g, colorless oil). ¹ H NMR (CDCl ₃ ) δ 2.86-2.91 (2
H, m), 3.20 (2H, s), 3.70 (1H,
s), 4.08-4.10 (2H, m), 8.64 (1
H, s). MS (FAB) m / z 141 (M + H) ^<+> .

[1279] <5-benzoyloxy-4,5,6,7
-Tetrahydro [5,4-c] pyridine> 4,5.6.
7-tetrahydro [5,4-c] pyridine (3.23
g) and benzoyl peroxide (purity 70%, 7.97)
g) was dissolved in methylene chloride (200 ml) and heated under reflux for 5 hours. A saturated aqueous sodium hydrogencarbonate solution was added to carry out liquid separation, and the oil layer was dried over anhydrous sodium sulfate. Purification by silica gel chromatography (2% methanol-methylene chloride) gave the title compound (2.30 g). ¹ H NMR (CDCl ₃ ) δ 3.05-3.30 (2
H, br), 3.40-3.90 (2H, br), 4.
40-4.80 (2H, br), 7.42 (2H, t,
J = 8.1 Hz), 7.52-7.62 (1H, m),
7.95 (2H, dd, J = 8.1, 1.5 Hz),
8.73 (1H, s). MS (FAB) m / z 261 (M + H) ^<+> .

<5-Methoxy-4,5,6,7-tetrahydro [5,4-c] pyridine> 5-benzoyloxy-4,5.6.7-tetrahydro [5,4-
c] Pyridine (2.30 g) in tetrahydrofuran (5
0 ml) and methanol (50 ml), and dissolved in a 1 N aqueous sodium hydroxide solution (9.00 m
l) was added and stirred for 10 minutes. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel chromatography (8% methanol-methylene chloride) to obtain a crude product of 5-hydroxy-
4,5.6.7-Tetrahydro [5,4-c] pyridine (1.27 g, colorless glassy solid) was obtained. Subsequently, a crude product of 5-hydroxy-4,5.6.7-tetrahydro [5,4-c] pyridine (156 mg) was dissolved in tetrahydrofuran (10 ml), and the solution was cooled to -78 ° C. Then, potassium bis (trimesylsilyl) amide (0.5 N toluene solution, 2.00 ml) and iodomethane (124 μl) were sequentially added, and the temperature was raised to room temperature over 30 minutes. Water and methylene chloride were added, and the mixture was separated. The oil layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. Silica gel chromatography (3% methanol-
Purification with methylene chloride) gave the title compound (16 mg, a colorless oil). ¹ H NMR (CDCl ₃ ) δ 2.95-3.20 (2
H, br), 3.31 (2H, t, J = 5.9 Hz),
3.61 (3H, s), 4.00-4.50 (2H, b
r), 8.64 (1H, s). MS (FAB) m / z 171 (M + H) ^<+> .

Example 231 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5,6-dimethyl-4,5,6,
7-tetrahydrothiazolo [4,5-d] pyridazine-
2-yl) carbonyl] piperazine hydrochloride

[1282]

Embedded image Trifluoroacetic acid (5 ml) was added to a dichloromethane solution (10 ml) of 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazine (104 mg), and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, the residue was dried under reduced pressure. The obtained trifluoroacetate was added to an N, N-dimethylformamide solution (25 m
1) at room temperature, 1-hydroxybenztriazole (68 mg), 1- (dimethylaminopropyl) -3-
Ethylcarbodiimide hydrochloride (125 mg), 5,6
-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazine-2-carboxylic acid lithium salt (143 mg), and N-methylmorpholine (51
mg) and stirred at room temperature for 11 hours. After the reaction,
The reaction solvent was distilled off under reduced pressure, distilled water (30 ml) and ethyl acetate (50 ml) were added, and the organic layer was separated by liquid separation. The aqueous layer was extracted four times with ethyl acetate, and the combined organic layers were washed four times with distilled water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 3). This purified product (1
39 mg) in 1N hydrochloric acid-ethanol solution (1 ml),
Distilled water (1 ml) was added, the solvent was distilled off under reduced pressure, and the residue was dried under reduced pressure at 60 ° C. overnight to obtain 1-[(6
-Chlorobenzo [b] thien-2-yl) sulfonyl]
-4-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl)
Carbonyl] piperazine was obtained as the hydrochloride salt of a brown amorphous solid. _{^{1 H NMR (DMSO-d 6}} ) 2.69 (3H, s),
2.80 (3H, s), 3.20 (4H, br), 3.
80 (2H, br), 4.30 (2H, br), 4.4
3 (4H, br), 7.57 (1H, d, J = 8.8H)
z), 8.06 (1H, d, J = 8.8 Hz), 8.1
0 (1H, s), 8.31 (1H, s). MS (FAB) m / z 512 [(M + H) ⁺ , C
l ³⁵ ], 514 [(M + H) ⁺ , Cl ³⁷ ].

[1283] The 5,6-dimethyl-4,
5,6,7-Tetrahydrothiazolo [4,5-d] pyridazine-2-carboxylic acid lithium salt was synthesized by the following method.

<4,5-bis (bromomethyl) thiazole> 1,4-dimethylthiazole (20.0 g) of 1,
N-bromosuccinimide (62.9 g) and a, a'-azobis (isobutyronitrile) (1.45 g) were added to a 2-dichloroethane solution (2.0 l) at room temperature, and 10
The mixture was refluxed at 0 ° C. for 2 hours. The solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane: hexane = 2: 1 to dichloromethane) to give 4,5-bis (bromomethyl) thiazole (22.5 g) as a brown oil. As obtained. ¹ H NMR (CDCl ₃ ) 4.64 (2H, s), 4.
74 (2H, s), 8.75 (1H, s).

<5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazine> 4,5
-Bis (bromomethyl) thiazole (22.5 g) in dichloromethane-ethanol mixed solution (500 ml-30
0 ml) at room temperature was added with 1,2-dimethylhydrazine hydrochloride (11.6 g). After cooling to 0 ° C., triethylamine (48 ml) was added dropwise and the mixture was stirred at room temperature for 13 hours. After the reaction was completed, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane: methanol = 50: 1 to 20: 1) to give 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d]. Pyridazine (4.2 g) was obtained as a brown oil. ¹ H NMR (CDCl ₃ ) 2.43 (3H, s);
56 (3H, s), 3.92 (2H, s), 4.06
(2H, br), 8.68 (1H, s).

<5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazine-2-carboxylic acid lithium salt> 5,6-dimethyl-4,5
After cooling a solution of 6,7-tetrahydrothiazolo [4,5-d] pyridazine (4.1 g) in tetrahydrofuran to -78 ° C, n-butyllithium (1.56 mol / ln-
(Hexane solution, 17.6 ml) was added dropwise over 10 minutes. The mixture was stirred at -78 ° C for 4 hours while blowing carbon dioxide gas into the reaction system with a gas inlet tube. After slowly raising the temperature to room temperature over 2 hours, the solvent was distilled off under reduced pressure. Diethyl ether was added to the obtained residue to solidify it, which was collected by filtration. After washing with diethyl ether and drying overnight under reduced pressure, 5,6-dimethyl-4,5,6,7
-Tetrahydrothiazolo [4,5-d] pyridazine-2
-Lithium carboxylate (3.9 g) was obtained as a brown powder. _{^{1 H NMR (DMSO-d 6}} ) 2.28 (3H, s),
2.39 (3H, s), 3.65 (2H, br), 3.
86 (2H, br).

Example 232 (+)-2-N-Methylcarbamoyl-1-[(5-methyl-4,5,6,7-tetrahydro [5,4-c] pyridin-2-yl) carbonyl]- 4-[(5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine (-)-2-N-methylcarbamoyl-4-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine (1.02
g) in N, N-dimethylformamide solution (100 m
1), at room temperature, 1-hydroxybenztriazole (2
50 mg), 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (460 mg), (5-methyl-4,5,6,7-tetrahydro [5,4-c] pyridin-2-yl) carboxylic acid Lithium salt (520m
g) and N-methylmorpholine (370 mg) were added, and the mixture was stirred at room temperature for 26 hours. After completion of the reaction, the reaction solvent was distilled off under reduced pressure, distilled water (100 ml) and ethyl acetate (100 ml) were added, and the organic layer was separated by liquid separation. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed three times with distilled water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 50: 1) to give the title compound (6).
30 mg) as a pale yellow amorphous solid. [A] _D = + 109 (c = 0.51, CH ₂ Cl ₂ ). ¹ H NMR (CDCl ₃ ) 0.26 (9H, s), 2.
51 (3H, s), 2.80-2.98 (4H, m),
2.83 (3H, s), 3.00-3.23 (3H,
m), 3.57-3.80 (3H, m), 4.49-
4.77 (1.5H, m), 5.19-5.28 (0.
5H, m), 5.55-5.68 (0.5H, m),
6.02-6.13 (0.5H, m), 6.45-6.
63 (1H, m), 7.09 (1H, s), 7.34-
7.55 (2H, m), 7.82 (1H, s), 10.
66-10.84 (1H, m). MS (FAB) m / z 599 (M + H) ⁺ .

[1288] (-)-2-N-Methylcarbamoyl-4-[(1-phenylsulfonyl-5-
Trimethylsilylethynylindol-2-yl) sulfonyl] piperazine was synthesized by the following method.

<1,4-bis (tert-butoxycarbonyl) -2-ethoxycarbonylpiperazine>

[1290] 1-tert-butoxycarbonyl-2-
To a solution of ethoxycarbonylpiperazine L-(+)-tartrate (WO9827069) (2.16 g) in dichloromethane (100 ml) was added triethylamine (1.42).
g) and di-tert-butyl dicarbonate (1.53
g) was added and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol = 10: 1) to give 1,4-bis (tert-butoxycarbonyl) -2-ethoxycarbonylpiperazine ( 2.31
g) was obtained as a colorless powder. ¹ H NMR (CDCl ₃ ) 1.28 (3H, t, J =
7.1 Hz), 1.44 (9H, s), 1.48 (4.
5H, s), 1.53 (4.5H, s), 2.69-
2.97 (1H, m), 2.98-3.32 (2H,
m), 3.70-4.08 (2H, m), 4.12-
4.27 (2H, m), 4.44-4.75 (2H,
m).

<1,4-bis (tert-butoxycarbonyl) -2-N-methylcarbamoylpiperazine> 1,4-bis (tert-butoxycarbonyl) -2
Ethoxycarbonylpiperazine (2.31 g) of 1,
To a 4-dioxane solution (16 ml) was added a 1N aqueous sodium hydroxide solution (9.7 ml) at room temperature, and the mixture was stirred at room temperature for 9 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride (20 ml) and dichloromethane (50 ml) were added, and the organic layer was separated by liquid separation. The aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried over sodium sulfate, and the solvent was distilled off under reduced pressure. This crude carboxylic acid was made into a dichloromethane solution (100 ml), and
Hydroxybenzotriazole (0.87 g), 1-
(Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.48 g), methylamine hydrochloride (0.52 g), and N-methylmorpholine (1.3
0 g) was added and the mixture was stirred at room temperature for 26 hours. After the reaction,
The reaction solvent was distilled off under reduced pressure, distilled water (80 ml) was added, and the organic layer was separated by liquid separation. The aqueous layer was extracted three times with dichloromethane, and the combined organic layers were washed three times with distilled water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 50: 50).
By subjecting it to 1), 1,4-bis (tert-butoxycarbonyl) -2-N-methylcarbamoylpiperazine (1.13 g) was obtained as a pale yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 1.46 (9H, s), 1.
48 (9H, s), 2.81 (1.5H, s), 2.8
2 (1.5H, s), 2.89-3.18 (3H,
m), 3.78-3.96 (2H, m), 4.38-
4.63 (2H, m), 5.96-6.13 (1H, b
r).

<129><(-)-2-N-methylcarbamoyl-
4-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine> The above 1,4-bis (tert-butoxycarbonyl) -2-N-methylcarbamoylpiperazine (1.1
To a dichloromethane solution (20 ml) of 3 g) was added trifluoroacetic acid (5 ml) at room temperature, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and 4N hydrochloric acid 1,4-dioxane solution (15 ml) was added to the residue, and the solvent was distilled off under reduced pressure. This was unpurified into a dichloromethane solution (200 ml), and (1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl chloride (2.10 g) and triethylamine (1.55 ml) were added. At 5
Stirred for hours. After completion of the reaction, distilled water (100 ml) was added, and a liquid separation operation was performed to separate an organic layer. The aqueous layer was extracted three times with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 50: 1) to give 2-N-methylcarbamoyl-4-[(1-phenylsulfonyl-5-
Trimethylsilylethynylindol-2-yl) sulfonyl] piperazine (1.05 g) was obtained as a pale yellow amorphous solid. _{[A] D = -49 (c} = 0.51, CH 2 Cl 2). ¹ H NMR (CDCl ₃ ) 0.25 (9H, s), 2.
79 (1.5H, s), 2.80 (1.5H, s),
2.88-2.97 (1H, m), 3.00-3.18
(3H, m), 3.44-3.49 (1H, m), 3.
68-3.75 (1H, m), 3.86-3.93 (1
H, m), 6.59-6.67 (1H, m), 7.40.
(2H, t, J = 7.9 Hz), 7.16 (1H,
s), 7.56 (1H, t, J = 7.9 Hz), 7.5
6 (1H, dd, J = 1.8, 8.8 Hz), 7.66
−7.69 (1H, m), 8.00 (2H, d, J =
7.9 Hz), 8.19 (1H, d, J = 8.8H)
z). MS (FAB) m / z 559 (M + H) ^<+> .

[1293] (5-Methyl-4,5,
Lithium 6,7-tetrahydro [5,4-c] pyridin-2-yl) carboxylate was synthesized by the following method.

<5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine> 5-ethoxycarbonyl-4,5,6,7-tetrahydrothiazolo [5,4-c] ] Pyridine (Reference Example 36) (21.0 g)
Was dissolved in anhydrous tetrahydrofuran (500 ml), a solution of lithium aluminum humanide in tetrahydrofuran (1.0 M, 200 ml) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water (7 ml) was slowly added to the reaction solution,
After stopping the reaction, 1N aqueous potassium hydroxide solution (7
ml) and anhydrous magnesium sulfate were sequentially added. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by distillation under reduced pressure (1.5 mmHg, boiling point: 82-85 ° C) to give the title compound (6.10 g, 40%) as a colorless oil. Obtained as material. ¹ H NMR (CDCl ₃ ) δ 2.52 (3H, s),
2.83 (2H, t, J = 5.9 Hz), 2.98 (2
H, t, J = 5.9 Hz) 3.70 (2H, s);
87 (2H, brs), 8.63 (1H, s). MS (FAB) m / z 155 [(M + H) ^<+ >].

<5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt> 6-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine (6.43 g) was dissolved in anhydrous tetrahydrofuran (200 ml), and an n-hexane solution of n-butyllithium (1.47 M, 34.00 ml) was added dropwise at an external temperature of -78 ° C. After stirring at the same temperature for 40 minutes, carbon dioxide gas was blown in for 1 hour.
The temperature was raised to room temperature, and the reaction solution was concentrated under reduced pressure to obtain the title compound (9.42 g) as a pale brown foamy solid. ¹ H NMR (DMSO-d ₆ ) δ 2.37 (3H,
s), 2.64-2.77 (4H, m), 3.54 (2
H, s). MS (FAB) m / z 199 (M + H) ^<+> .

Example 233 (+)-2-N-Methylcarbamoyl-1-[(5-methyl-4,5,6,7-tetrahydro [5,4-c] pyridin-2-yl) carbonyl]- 4-[(5-ethynylindol-2-yl) sulfonyl] piperazine (+)-2-N-methylcarbamoyl-1-[(5-methyl-4,5,6,7-tetrahydro [5,4-c ] Pyridin-2-yl) carbonyl] -4-[(5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine (600 mg) in tetrahydrofuran-
Potassium hydroxide (140 mg) powder was added to a methanol mixed solution (15 ml-15 ml) at room temperature.
Stir for 2 hours. Saturated ammonium chloride aqueous solution (30m
After l) was added to terminate the reaction, a saturated aqueous sodium hydrogen carbonate solution (30 ml) was added to neutralize the solution. To this was added dichloromethane (100 ml), and the organic layer was separated by liquid separation. The aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (dichloromethane: acetone:
By applying methanol = 100: 100: 3),
The title compound (480 mg) was obtained. [A] _D = + 122 (c = 0.39, CH ₂ Cl ₂ ). ¹ H NMR (CDCl ₃ ) 2.51 (3H, s), 2.
80-2.98 (4H, m), 2.83 (3H, s),
3.00-3.26 (3H, m), 3.02 (1H,
s), 3.55-3.78 (3H, m), 4.46-
4.78 (1.5H, m), 5.19-5.30 (0.
5H, m), 5.56-5.69 (0.5H, m),
6.02-6.16 (0.5H, m), 6.44-6.
64 (1H, m), 7.10 (1H, s), 7.36-
7.53 (2H, m), 7.84 (1H, s), 10.
67-10.88 (1H, m). MS (FAB) m / z 527 (M + H) ^<+> .

Example 234 1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -2-N-methylcarbamoyl- 4-[(6
-Trimethylsilylethynylbenzo [b] thien-2-
Yl) sulfonyl] piperazine 2-N-methylcarbamoyl-4-[(6-trimethylsilylethynylbenzo [b] thien-2-yl) sulfonyl] piperazine (1.13 g) in N, N-dimethylformamide solution (100 ml) At room temperature, 1-hydroxybenzotriazole (350 mg), 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (596 mg), 5,6-dimethyl-4,5,6,7-
Tetrahydrothiazolo [4,5-d] pyridazine-2-
Lithium carboxylate (682 mg) and N-methylmorpholine (524 mg) were added, and the mixture was stirred at room temperature for 21 hours. After completion of the reaction, the reaction solvent was distilled off under reduced pressure, distilled water (100 ml) and ethyl acetate (100 ml) were added, and the organic layer was separated by liquid separation. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed four times with distilled water.
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (dichloromethane: methanol = 100: 1 to 1).
50: 1) to give the title compound (840 m
g) was obtained as a pale yellow amorphous solid. _{^{1 H NMR (CDCl 3) 0.27}} (9H, s), 2.
40 (3H, s), 2.52 (3H, s), 2.67-
2.83 (2H, m), 2.86 (3H, br), 3.
12-3.24 (0.5H, m), 3.48-3.59
(0.5H, m), 3.72-3.91 (3H, m),
4.03 (2H, br), 4.45-4.51 (1H,
m), 4.62-4.70 (0.5H, m), 5.21
−5.30 (0.5H, m), 5.65−5.76
(0.5H, m), 6.10-6.18 (0.5H,
m), 6.30-6.47 (1H, m), 7.51 (1
H, d, J = 8.3 Hz), 7.75-7.82 (2
H, m), 7.95 (1H, s). MS (FAB) m / z 631 (M + H) ^<+> .

[1298] 2-N-Methylcarbamoyl-4-[(6-trimethylsilylethynylbenzo [b] thien-2-yl) sulfonyl] piperazine used as a starting material was synthesized by the following method.

<1,4-Dibenzyl-2- (N-methylcarbamoyl) piperazine> 1,4-Dibenzyl-2-
(Ethoxycarbonyl) piperazine (6 g) was dissolved in ethanol (100 ml), 1N aqueous sodium hydroxide solution (18 ml) was added, and the mixture was heated under reflux. Add 1N aqueous sodium hydroxide solution while monitoring the reaction (total 28 ml)
And heated to reflux for a total of 2 hours and 30 minutes. An equivalent amount of a 1N aqueous hydrochloric acid solution was added thereto for neutralization, and the solvent was distilled off under reduced pressure. Dichloromethane (100 ml) was added to the residue, and the insoluble material was removed by filtration. Then, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4.41) was used.
g), 1-hydroxybenzotriazole monohydrate (2.39 g), methylamine hydrochloride (1.79)
g) and triethylamine (7.4 ml) were added, and the mixture was stirred at room temperature overnight. After the organic layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate only) to obtain the title compound (3.88 g). ¹ H NMR (CDCl ₃ ) δ 2.24-2.37 (3
H, m), 2.59-2.62 (1H, m), 2.73
-2.77 (1H.m), 2.83, 2.84 (3H,
each m), 2.89-2.92 (1H, m),
3.15-3.18 (1H.m), 3.39 (1H,
d, J = 13.4 Hz), 3.48 (2H, s), 3.
75 (1H, d, J = 13.4 Hz), 7.23-7.
34 (11H, m).

<2- (N-methylcarbamoyl) piperazine diacetate> 1,4-Dibenzyl-2- (N-methylcarbamoyl) piperazine (22.8 g) was treated with acetic acid (22.8 g).
00 ml) and 10% palladium on carbon (2.3
g, 50% moisture). After the inside of the reaction vessel was replaced with hydrogen and stirred at room temperature overnight, the catalyst was removed by filtration. The solvent was distilled off under reduced pressure to obtain the diacetate of the title compound (1 as a pale yellow solid).
7.95 g).

<1301><2-N-methylcarbamoyl-4-
[(6-Trimethylsilylethynylbenzo [b] thien-2-yl) sulfonyl] piperazine> 2-N-methylcarbamoylpiperazine acetate solution (1.19 g) in dichloromethane (100 ml) at room temperature was added with (6-trimethylsilylethynylbenzo). [B] Thien-2-yl) sulfonyl chloride (1.51 g) and triethylamine (1.95 ml) were added, and the mixture was stirred at room temperature for 4.5 hours. After completion of the reaction, distilled water (60 ml) was added, and a liquid separation operation was performed to separate an organic layer. The aqueous layer was extracted three times with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 20: 1) to give the title compound (1.16 g).
Was obtained as a pale yellow amorphous solid. _{^{1 H NMR (CDCl 3) 0.28}} (9H, s), 2.
57-2.68 (2H, m), 2.79 (1.5H,
s), 2.80 (1.5H, s), 2.93-3.01
(1H, m), 3.06-3.13 (1H, m), 3.
47-3.53 (1H, m), 3.55-3.63 (1
H, m), 3.87-3.94 (1H, m), 6.50.
−6.63 (1H, br), 7.52 (1H, d, J =
8.3 Hz), 7.77 (1H, s), 7.81 (1
H, d, J = 8.3 Hz), 7.97 (1H, s). MS (FAB) m / z 463 (M + H) ^<+> .

Example 235 1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(6-ethynyl) Benzo [b] thien-2-yl) sulfonyl] -2-N-methylcarbamoylpiperazine

[1303]

Embedded image 1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -2-N-methylcarbamoyl-4-[(6
-Trimethylsilylethynylbenzo [b] thien-2-
Il) sulfonyl] piperazine (815 mg) was treated in the same manner as in Example 233 to give the title compound as a pale-yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 2.40 (3H, s), 2.
52 (3H, s), 2.67-2.83 (2H, m),
2.86 (3H, br), 3.12-3.24 (0.5
H, m), 3.21 (1H, s), 3.45-3.58
(0.5H, m), 3.72-3.89 (3H, m),
4.03 (2H, br), 4.45-4.51 (1H,
m), 4.62-4.70 (0.5H, m), 5.21
−5.30 (0.5H, m), 5.67−5.76
(0.5H, m), 6.08-6.17 (0.5H,
m), 6.28-6.45 (1H, m), 7.54 (1
H, d, J = 8.6 Hz), 7.80 (1H, s),
7.82 (1H, d, J = 8.6 Hz), 7.96 (1
H, s). MS (FAB) m / z 559 (M + H) ^<+> .

Example 236 4-[(5-Chloroindol-2-yl) sulfonyl]
-1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl)
Carbonyl] -2-ethylpiperazine hydrochloride 1-[(5-chloroindol-2-yl) sulfonyl]
To a solution of -3-ethylpiperazine (262 mg) in N, N-dimethylformamide (25 ml) at room temperature was added 1-hydroxybenzotriazole (108 mg), 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (199 mg), 5,6-dimethyl-4,5,6
7-tetrahydrothiazolo [4,5-d] pyridazine-
Lithium 2-carboxylate (228 mg), and N
-Methylmorpholine (81 mg) was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solvent was distilled off under reduced pressure,
Distilled water (30 ml) and ethyl acetate (50 ml) were added, and the organic layer was separated by liquid separation. Aqueous layer with ethyl acetate 3
Extracted twice and the combined organic layers were washed four times with distilled water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by thin-layer chromatography (silica gel, dichloromethane: methanol = 10: 1). To this purified product (114 mg) was added a 1 N aqueous hydrochloric acid solution (0.5 ml) and a dichloromethane-ethanol mixed solution (5 ml-5 ml), and the solvent was distilled off under reduced pressure.
The title compound was obtained as a pale yellow amorphous solid by drying under reduced pressure at 60 ° C. overnight. _{^{1 H NMR (DMSO-d 6}} ) 0.84 (3H, b
r), 2.69 (3H, s), 2.80 (3H, s),
3.07-3.35 (2H, m), 3.60-3.82
(6H, m), 4.18-4.65 (4H, m), 5.
15-5.42 (1H, m), 7.02 (1H, s),
7.30 (1H, dd, J = 2.0, 8.8 Hz),
7.48 (1H, d, J = 8.8 Hz), 8.76 (1
H, d, J = 2.0 Hz). MS (FAB) m / z 523 [(M + H) ⁺ , C
l ³⁵ ], 525 [(M + H) ⁺ , Cl ³⁷ ].

Example 237 (-)-2-N-methylcarbamoyl-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] -4-[(5
-Trimethylsilylethynylindol-2-yl) sulfonyl] piperazine (+)-2-N-methylcarbamoyl-4-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine and 5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] Pyridin-2-carboxylic acid lithium salt was treated in the same manner as in Example 232 to give the title compound as a pale-yellow amorphous solid. _{[A] D = -91 (c} = 0.51, CH 2 Cl 2). ¹ H NMR (CDCl ₃ ) 0.26 (9H, s), 2.
52 (3H, s), 2.70-2.95 (4H, m),
2.83 (3H, s), 3.02-3.28 (3H,
m), 3.60-3.78 (3H, m), 4.48-
4.77 (1.5H, m), 5.17-5.27 (0.
5H, m), 5.54-5.69 (0.5H, m),
6.00-6.10 (0.5H, m), 6.40-6.
57 (1H, m), 7.09 (1H, s), 7.34-
7.55 (2H, m), 7.82 (1H, s), 10.
64-10.78 (1H, m). MS (FAB) m / z 599 (M + H) ⁺ .

The starting material (+)-2-N-methylcarbamoyl-4-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine was shown in Example 232 as (−) -2-
N-methylcarbamoyl-4-[(1-phenylsulfonyl-5-trimethylsilylethynylindole-2-
Yl) sulfonyl] piperazine in the same manner as 1-
It was synthesized from tert-butoxycarbonyl-2-ethoxycarbonylpiperazine D-(-)-tartrate.

Example 238 (-)-2-N-methylcarbamoyl-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] -4-[(5
-Ethynylindol-2-yl) sulfonyl] piperazine (-)-2-N-methylcarbamoyl-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] -4-[(5
-Trimethylsilylethynylindol-2-yl) sulfonyl] piperazine was treated in the same manner as in Example 233 to give the title compound as a colorless amorphous solid. [A] _D = −133 (c = 0.38, CH ₂ Cl ₂ ), −
4.6 (c = 0.53, EtOH). ¹ H NMR (CDCl ₃ ) 2.51 (3H, s), 2.
80-2.98 (4H, m), 2.84 (3H, s),
3.00-3.27 (3H, m), 3.02 (1H,
s), 3.58-3.79 (3H, m), 4.42-
4.77 (1.5H, m), 5.19-5.30 (0.
5H, m), 5.58-5.69 (0.5H, m),
5.99-6.11 (0.5H, m), 6.46-6.
59 (1H, m), 7.11 (1H, s), 7.37-
7.54 (2H, m), 7.85 (1H, s), 10.
68-10.86 (1H, m). MS (ESI) m / z 527 (M + H) ^<+> .

Example 239 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -2- (N, N-dimethylcarbamoyl) methyl-4-[(5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride 1-tert-butoxycarbonyl-4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl]- 2-
To a solution of (N, N-dimethylcarbamoyl) methylpiperazine (200 mg) in ethanol (10 ml) was added a saturated ethanol solution of hydrochloric acid (5 ml), and the mixture was stirred at room temperature for 2.5 hours. After the solvent was distilled off under reduced pressure, the residue was dried under reduced pressure. This was added to an N, N-dimethylformamide solution (40 m
1) and then 1-hydroxybenzotriazole (5
4 mg), 1- (dimethylaminopropyl) -3-ethylcarbodiimide (100 mg), 5-methyl-4,
5,6,7-Tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt (110 mg) and N-methylmorpholine (120 mg) were added, and the mixture was stirred at room temperature for 21 and a half hours. After completion of the reaction, the reaction solvent was distilled off under reduced pressure, and distilled water (30 ml) and ethyl acetate (50 m
1) was added and the organic layer was separated by liquid separation operation. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed three times with distilled water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to thin layer chromatography (silica gel, dichloromethane: methanol = 1).
0: 1) and purified. This purified product (0.11 mm
ol), 1N hydrochloric acid-ethanol solution (2 ml) and dichloromethane (5 ml) were added, and the solvent was distilled off under reduced pressure.
Drying under reduced pressure at 60 ° C. overnight gave the title compound as an off-white amorphous solid. ¹ H NMR (CDCl ₃ ) 2.49 (3H, s), 2.
55-2.70 (2H, m), 2.71-2.83 (3
H, m), 2.85-2.98 (3H, m), 2.93
(3H, s), 3.02 (3H, s), 3.07-3.
30 (1H, m), 3.46-3.74 (2.5H,
m), 3.83-4.09 (1.5H, m), 4.60
-4.69 (0.5H, m), 5.26-5.33
(0.5H, m), 5.67-5.76 (0.5H,
m), 6.06-6.14 (0.5H, m), 7.43
(1H, dd, J = 1.8, 8.8 Hz), 7.76
(1H, s), 7.80 (1H, d, J = 8.8H)
z), 7.85 (1H, d, J = 1.8 Hz). MS (FAB) m / z 582 [(M + H) ⁺ , C
l ³⁵ ], 584 [(M + H) ⁺ , Cl ³⁷ ].

The 1-tert-butoxycarbonyl-4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2- (N, N-dimethylcarbamoyl) methylpiperazine was synthesized by the following method.

<2-methoxycarbonylmethylpiperazine hydrochloride> Concentrated hydrochloric acid aqueous solution (10 ml) was added to an ethanol solution (350 ml) of 1,4-dibenzyl-2-methoxycarbonylmethylpiperazine (15.0 g) at room temperature,
And palladium hydroxide (1.00 g) were added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (10.24 g) as a brown amorphous solid. _{^{1 H NMR (DMSO-d 6}} ) 2.79-2.97 (2
H, m), 3.13-3.36 (4H, m), 3.38
-3.55 (4H, m), 3.67 (3H, s), 3.
80-3.93 (1H, m), 9.60-9.89 (2
H, br).

<1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -3-methoxycarbonylmethylpiperazine> 2-Methoxycarbonylmethylpiperazine hydrochloride (6.87 g) in dichloromethane solution (3
(6-ml) at room temperature, and (6-chlorobenzo [b] thien-2-yl) sulfonyl chloride (9.54 g) and triethylamine (16.6 ml) were added at room temperature.
Stirred for half an hour. After completion of the reaction, distilled water (200 ml) was added, and a liquid separation operation was performed to separate an organic layer. The aqueous layer was extracted three times with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 50: 1) to give the title compound (3.49 g) as a pale-yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 2.28-2.48 (3H,
m), 2.55-2.67 (2H, m), 2.85-
3.08 (2H, m), 3.14-3.27 (1H,
m), 3.59-3.68 (2H, m), 3.69 (3
H, s), 7.43 (1H, dd, J = 2.0, 8.6).
Hz), 7.74 (1H, s), 7.80 (1H, d,
J = 8.6 Hz), 7.85 (1H, d, J = 2.0H)
z). MS (FAB) m / z 389 [(M + H) ⁺ , C
l ³⁵ ], 391 [(M + H) ⁺ , Cl ³⁷ ].

[1312] <1-tert-butoxycarbonyl-4>
-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-methoxycarbonylmethylpiperazine>
1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -3-methoxycarbonylmethylpiperazine (3.46 g) in dichloromethane (100 ml)
In addition, di-tert-butyl dicarbonate (2.
33 g) was added and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, distilled water (100 ml) was added, and the organic layer was separated by liquid separation. The aqueous layer was extracted three times with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (dichloromethane: methanol = 10).
0: 1 to 50: 1) to give the title compound (3.44 g) as a pale yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 1.41 (4.5 H, s),
1.57 (4.5H, s), 2.42-2.54 (1
H, m), 2.55-2.67 (2H, m), 2.79
-2.88 (1H, m), 3.06-3.22 (1H,
br), 3.69 (3H, s), 3.72-3.83.
(2H, m), 3.94-4.10 (1H, br),
4.60-4.76 (1H, br), 7.44 (1H, br)
dd, J = 2.0, 8.8 Hz), 7.51 (1H,
s), 7.81 (1H, d, J = 8.8 Hz), 7.8
6 (1H, d, J = 2.0 Hz). MS (FAB) m / z 489 [(M + H) ⁺ , C
l ³⁵ ], 491 [(M + H) ⁺ , Cl ³⁷ ].

<[1-tert-Butoxycarbonyl-]
4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazin-2-yl] acetic acid> 1-tert
-Butoxycarbonyl-4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-methoxycarbonylmethylpiperazine (3.07 g) in 1,4-
A 1N aqueous sodium hydroxide solution (9.4 ml) was added to the dioxane solution (200 ml) at room temperature, and the mixture was stirred at 80 ° C. for 1 hour. The reaction solvent was distilled off under reduced pressure. A saturated aqueous ammonium chloride solution (50 ml) and dichloromethane (100 ml) were added to the residue, and the organic layer was separated by liquid separation. The aqueous layer was extracted three times with dichloromethane, and the combined organic layers were concentrated under reduced pressure, and solidified with diethyl ether. The solid was collected by filtration and dried under reduced pressure to give the title compound (2.54 g) as a colorless amorphous solid. _{^{1 H NMR (DMSO-d 6}} ) 1.34 (9H, s),
2.45-2.55 (1H, m), 2.57-2.69
(2H, m), 2.85-2.96 (1H, m), 3.
03-3.12 (1H, m), 3.73-3.84 (2
H, m), 3.95-4.16 (1H, m), 4.59
-4.77 (1H, m), 7.45 (1H, d, J =
8.5 Hz), 7.76 (1H, s), 7.82 (1
H, d, J = 8.5 Hz), 7.86 (1H, s). MS (FAB) m / z 475 [(M + H) ⁺ , C
l ³⁵ ], 477 [(M + H) ⁺ , Cl ³⁷ ].

[1314] <1-tert-Butoxycarbonyl-4>
-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (N, N-dimethylcarbamoyl) methylpiperazine> [1-tert-butoxycarbonyl-
4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazin-2-yl] acetic acid (685 mg)
Into an N, N-dimethylformamide solution (35 ml)
At room temperature, 1-hydroxybenzotriazole (195 m
g), 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (331 mg), dimethylamine hydrochloride (176 mg), and N-methylmorpholine (365 mg) were added, and the mixture was stirred at room temperature for 23 hours. After completion of the reaction, the reaction solvent was distilled off under reduced pressure, and distilled water (30 m
1) and ethyl acetate (50 ml) were added, and the organic layer was separated by liquid separation. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed three times with distilled water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 100: 1) to give the title compound (590 mg) as a pale-yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 1.41 (4.5 H, s),
1.57 (4.5H, s), 2.45-2.64 (3
H, m), 2.95 (3H, br), 2.97-3.2
1 (3H, m), 3.03 (3H, s), 3.74-
3.88 (1H, m), 3.94-4.17 (1H,
m), 4.75-4.81 (1H, m), 7.44 (1
H, dd, J = 2.0, 8.8 Hz), 7.74 (1
H, s), 7.81 (1H, d, J = 8.8 Hz),
7.86 (1H, d, J = 2.0 Hz). MS (FAB) m / z 502 [(M + H) ⁺ , C
l ³⁵ ], 504 [(M + H) ⁺ , Cl ³⁷ ].

Example 240 4- [1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5,6-dimethyl-4,
5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazin-2-yl] acetylmorpholine hydrochloride

[1316]

Embedded image 4- [1-tert-butoxycarbonyl-4-[(6
-Chlorobenzo [b] thien-2-yl) sulfonyl]
Piperazin-2-yl] acetylmorpholine in Example 2
Treated in the same manner as in 40, 5,6-dimethyl-4,5,6,
7-tetrahydrothiazolo [4,5-d] pyridazine-
By condensing with a lithium 2-carboxylate,
4- [1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5,6-dimethyl-4,
The hydrochloride salt of 5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazin-2-yl] acetylmorpholine was obtained as a colorless amorphous solid. _{^{1 H NMR (DMSO-d 6}} ) 2.49 (3H, s),
2.51 (3H, s), 2.53-2.81 (4H,
m), 2.89-3.17 (2H, m), 3.22-
3.83 (12H, m), 4.15-4.43 (1.5
H, m), 5.03-5.10 (0.5H, m), 5.
28-5.38 (0.5H, m), 5.72-5.84
(0.5H, m), 7.57 (1H, d, J = 8.8H)
z), 8.05 (1H, d, J = 8.8 Hz), 8.1
0 (1H, s), 8.32 (1H, s). MS (FAB) m / z 544 [(M + H) ⁺ , C
l ³⁵ ], 546 [(M + H) ⁺ , Cl ³⁷ ].

[1312] 4- [1-tert-Butoxycarbonyl-4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazin-2-yl] used as a raw material
Acetylmorpholine was synthesized by the following method.

<4- [1-tert-Butoxycarbonyl-4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazin-2-yl] acetylmorpholine> [1-tert-butoxycarbonyl-4] −
Using [(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazin-2-yl] acetic acid and morpholine (145 mg) as starting materials, 1-ter of Example 239
t-butoxycarbonyl-4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (N, N
-Dimethylcarbamoyl) methylpiperazine was obtained in the same manner as in the synthesis of the title compound (500 mg) as a pale yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 1.41 (4.5 H, s),
1.57 (4.5H, s), 2.44-2.64 (3
H, m), 2.91-3.18 (2H, m), 3.43
-3.86 (10H, m), 3.95-4.17 (1
H, m), 4.76-4.82 (1H, m), 7.44.
(1H, dd, J = 1.7, 8.5 Hz), 7.74
(1H, s), 7.81 (1H, d, J = 8.5H)
z), 7.88 (1H, d, J = 1.7 Hz). MS (FAB) m / z 544 [(M + H) ⁺ , C
l ³⁵ ], 546 [(M + H) ⁺ , Cl ³⁷ ].

Example 241 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5,6-dimethyl-4,5,6,
7-tetrahydrothiazolo [4,5-d] pyridazine-
2-yl) carbonyl] -2- (N, N-dimethylcarbamoyl) methylpiperazine hydrochloride 1-tert by a method similar to that of Example 239.
-Butoxycarbonyl-4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (N, N
-Dimethylcarbamoyl) methylpiperazine and 5,
From 6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazine-carboxylic acid lithium salt, 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4 -[(5,6-dimethyl-4,
5,6,7-Tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -2- (N, N-dimethylcarbamoyl) methylpiperazine hydrochloride was obtained as a colorless amorphous solid. _{^{1 H NMR (DMSO-d 6}} ) 2.52-3.12 (4
H, m), 2.72 (3H, s), 2.80 (3H,
s), 2.92 (3H, s), 2.98 (3H, s),
3.15-3.47 (1H, m), 3.48-4.00
(3H, m), 4.05-4.60 (3.5H, m),
4.90-5.08 (0.5H, m), 5.27-5.
38 (0.5H, m), 5.73-5.85 (0.5
H, m), 7.57 (1H, d, J = 8.0 Hz),
8.05 (1H, d, J = 8.0 Hz), 8.10 (1
H, s), 8.32 (1H, s). MS (ESI) m / z 597 [(M + H) ^<+> , C
l ³⁵ ], 599 [(M + H) ⁺ , Cl ³⁷ ].

Example 242 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5,6-dimethyl-4,5,6,
7-tetrahydrothiazolo [4,5-d] pyridazine-
2-yl) carbonyl] -2-N-methylcarbamoylmethylpiperazine In the same manner as in Example 239, 1-
tert-butoxycarbonyl-4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-N-
Methylcarbamoylmethylpiperazine and 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4
From the lithium salt of 5-d] pyridazine-2-carboxylic acid, 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5,6-dimethyl-4,
5,6,7-Tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -2-N-methylcarbamoylmethylpiperazine was obtained as an off-white amorphous solid. ¹ H NMR (CDCl ₃ ) 2.40 (3H, s), 2.
93 (3H, s), 2.55-2.77 (3H, m),
2.81 (1.5H, s), 2.82 (1.5H, s)
s), 2.87-3.00 (1H, m), 3.14-
3.28 (1H, m), 3.78-4.09 (6H,
m), 4.57-4.68 (0.5H, m), 5.16
−5.30 (0.5H, m), 5.64−5.78
(0.5H, m), 5.89 (1H, br), 6.03
−6.19 (0.5H, m), 7.44 (1H, dd,
J = 2.0, 8.8 Hz), 7.76 (1H, s),
7.80 (1H, d, J = 8.8 Hz), 7.85 (1
H, d, J = 2.0 Hz). MS (ESI) m / z 583 [(M + H) ⁺ , C
l ³⁵ ], 585 [(M + H) ⁺ , Cl ³⁷ ].

[1321] 1-tert-Butoxycarbonyl-4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2-N-methylcarbamoylmethylpiperazine was synthesized by the following method.

<1-tert-Butoxycarbonyl-4>
-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2-N-methylcarbamoylmethylpiperazine> 1-tert-butoxycarbonyl-4-[(6-chlorobenzo [b] thien- 2-yl)
Sulfonyl] -2- (N, N-dimethylcarbamoyl)
[1-tert] in the same manner as in the synthesis of methylpiperazine.
-Butoxycarbonyl-4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazine-2
[-Yl] acetic acid to give the title compound (700 mg) as a pale-yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 1.42 (4.5 H, s),
1.57 (4.5H, s), 2.29-2.63 (2
H, m), 2.67-2.92 (2H, m), 2.81
-2.96 (3H, m), 3.04-3.19 (1H,
m), 3.66-3.86 (2H, m), 3.95-
4.15 (1H, m), 4.62-4.76 (1H,
m), 5.64-5.87 (1H, br), 7.43-
7.50 (1H, m), 7.74 (1H, s), 7.8
1 (1H, d, J = 8.5 Hz), 7.85 (1H,
s). MS (FAB) m / z 488 [(M + H) ⁺ , C
l ³⁵ ], 490 [(M + H) ⁺ , Cl ³⁷ ].

Example 243 2- (N, N-dimethylcarbamoyl) methyl-1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]-
4-[(5-trimethylsilylethynylindole-2
-Yl) sulfonyl] piperazine (optically active substance) (2-N, N-dimethylcarbamoyl) methyl-4-
To a solution of [(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine (optically active substance) (235 mg) in N, N-dimethylformamide (25 ml) was added 1-hydroxybenzotriazole (54 mg) at room temperature. ), 1- (dimethylaminopropyl) -3-ethylcarbodiimide (230 m
g), lithium 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylate (226 mg), and N-methylmorpholine (8
1 mg) and stirred at room temperature for 21 hours. After completion of the reaction, the reaction solvent was distilled off under reduced pressure, distilled water (30 ml),
Ethyl acetate (50 ml) was added, and the organic layer was separated by liquid separation. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed three times with distilled water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 25: 1) to give the title compound (184 mg) as a pale-yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 0.26 (9H, s), 2.
37-3.18 (14H, m), 3.27-3.39
(1H, m), 3.60-3.85 (3H, m), 3.
68 (3H, s), 3.98-4.24 (1H, m),
4.56-4.65 (0.5H, m), 5.03-5.
13 (0.5H, m), 5.51-5.60 (0.5
H, m), 6.04-6.13 (0.5H, m), 7.
02 (1H, s), 7.35 (1H, d, J = 8.5H
z), 7.41 (1H, d, J = 8.5 Hz), 7.8
3 (1H, s), 10.43 (0.5H, br), 1
0.98 (0.5H, br). MS (ESI) m / z 627 (M + H) ^<+> .

The starting material (2-N, N-dimethylcarbamoyl) methyl-4-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine (optically active substance) is synthesized by the following method. did.

<(+)-1-tert-butoxycarbonyl-2-ethoxycarbonylpiperazine> 1-ter
t-butoxycarbonyl-2-ethoxycarbonylpiperazine L-(+)-tartrate (WO9827069)
To a dichloromethane solution (60 ml) of was added saturated sodium bicarbonate to make the solution neutral. To this was added dichloromethane, and the organic layer was separated by liquid separation. The aqueous layer was extracted three times with dichloromethane, and the combined organic layers were dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was dried under reduced pressure to give the title compound (7.6 g) as a colorless oil. [A] _D = + 60 (c = 1.09, EtOH). ¹ H NMR (CDCl ₃ ) 1.28 (3H, t, J =
7.1 Hz), 1.44 (9H, s), 1.48 (4.
5H, s), 2.66-2.77 (1H, m), 2.8
6-3.21 (3H, m), 3.46-3.57 (1
H, m), 3.71-3.89 (1H, m), 4.17.
-4.30 (2H, m), 4.47-4.55 (0.5
H, m), 4.60-4.73 (0.5H, m). MS (ESI) m / z 259 (M + H) ^<+> .

<(+)-1,4-Dibenzyl 2-ethoxycarbonylpiperazine> The above (+)-1-tert-
Trifluoroacetic acid (20 ml) was added to a dichloromethane solution (60 ml) of butoxycarbonyl-2-ethoxycarbonylpiperazine (7.6 g) at room temperature.
Stirred for hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and 4N hydrochloric acid 1,4-dioxane solution (70 ml) was added to the residue. Solidified. After drying this under reduced pressure, the dichloromethane solution (150
benzyl bromide (11.0 g) at 0 ° C.
Triethylamine (13.4 g) was added, and the mixture was stirred at room temperature for 5 hours. Saturated ammonium chloride aqueous solution (100ml)
Was added to stop the reaction, and the organic layer was separated by a liquid separation operation. The aqueous layer was extracted three times with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (dichloromethane: methanol = 100: 0 to 1).
00: 3) to give the title compound (6.3).
g) was obtained as a pale yellow oil. [A] _D = + 57 (c = 1.0, EtOH). ¹ H NMR (CDCl ₃ ) 1.24 (3H, t, J =
7.1 Hz), 1.44 (9H, s), 2.35-2.
77 (3H, m), 3.00-3.14 (1H, m),
3.26-3.35 (1H, m), 3.42 (1H,
d, J = 13.2 Hz), 3.49-3.64 (1H,
m), 3.91 (1H, d, J = 13.2 Hz), 4.
11-4.24 (3H, m), 7.18-7.34 (1
0H, m). MS (ESI) m / z 339 (M + H) ^<+> .

<(+)-1,4-Dibenzyl 2-hydroxymethylpiperazine> A solution of (+)-1,4-dibenzyl-2-ethoxycarbonylpiperazine (6.25 g) in tetrahydrofuran (40 ml) at 0 ° C. Add lithium aluminum hydride (530mg,) and add
For 16 hours. At 0 ° C., a 20% aqueous sodium hydroxide solution (12 ml) was added dropwise to stop the reaction. The reaction solution was filtered through celite, and the solid component was washed with diethyl ether. The filtrate is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography (dichloromethane:
Methanol = 50: 1 to 20: 1) to give the title compound (4.15 g) as a pale yellow oil. [A] _D = + 64 (c = 1.0, EtOH). _{^{1 H NMR (CDCl 3) 2.28-2.54}} (3H,
m), 2.55-2.74 (3H, m), 2.88-
3.03 (1H, m), 3.40-3.52 (3H,
m), 3.54-3.62 (1H, m), 3.76 (1
H, br), 3.98 (1H, d, J = 13.4H)
z), 4.05 (1H, dd, J = 3.0, 11.2H
z), 7.18-7.38 (10H, m). MS (ESI) m / z 297 (M + H) ^<+> .

<(+)-1,4-Dibenzyl 2-chloromethylpiperazine> The above (+)-1,4-dibenzyl 2
-Hydroxymethylpiperazine (4.07 g) in benzene (40 ml) was added at room temperature to thionyl chloride (1.2 m
1). This was stirred at room temperature for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Dichloromethane (4
0 ml) and distilled water (30 ml), and the organic layer was separated by liquid separation. After washing the aqueous layer twice with dichloromethane, the combined organic layers were washed with distilled water until the aqueous layer became neutral. The solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 100: 0 to 50: 1) to give the title compound (0.94 g) as a pale yellow oil. As obtained. [A] _D = + 53 (c = 1.0, EtOH). ¹ H NMR (CDCl ₃ ) 2.31-2.48 (3H,
m), 2.55-2.74 (3H, m), 2.77-
2.87 (1H, m), 3.40-3.55 (3H,
m), 3.66-3.74 (1H, m), 3.83-
3.94 (1H, m), 7.20-7.37 (10H,
m). MS (ESI) m / z 315 (M + H) ^<+> .

<(+)-1,4-Dibenzyl 2-cyanomethylpiperazine> Potassium cyanide (230 mg) was added to distilled water and heated to 80 ° C. to dissolve it. to this,
The above (+)-1,4-dibenzyl 2-chloromethylpiperazine (860 mg) in ethanol solution (5 ml) was added to 8
It was added dropwise at 0 ° C. over 3 minutes. This was slowly cooled to room temperature and then stirred for 5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Dichloromethane (30 ml) and distilled water (20 ml) were added, and the organic layer was separated by a liquid separation operation. After washing the aqueous layer twice with dichloromethane, the combined organic layers were washed twice with distilled water and dried over magnesium sulfate. The solution is concentrated under reduced pressure, and the obtained residue is subjected to silica gel column chromatography (dichloromethane:
Methanol = 50: 1) to give the title compound (730 mg) as a pale yellow oil. [A] _D = +41 (c = 1.04, EtOH). IR (KBr) cm ^-1 3025, 3243, 2814,
2245, 1603, 1495, 1454, 1350,
1138, 1028, 833, 735. ¹ H NMR
_{(CDCl 3) 2.35-2.49 (3H,} m), 2.
52-2.67 (4H, m), 2.83-2.93 (1
H, m), 2.96-3.05 (1H, m), 3.41
-3.54 (3H, m), 3.78 (1H, d, J = 1)
3.2Hz), 7.22-7.37 (10H, m). MS (ESI) m / z 306 (M + H) ⁺ .

[1330] <2- (N, N-dimethylcarbamoyl)
Methyl piperazine hydrochloride (optically active substance)> above (+)
-1,4-dibenzyl 2-cyanomethylpiperazine (4
To 40 mg), concentrated hydrochloric acid was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure.
N-dimethylformamide solution (30 ml), 1-hydroxybenzotriazole (190 mg) at room temperature,
1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (360 mg), dimethylamine hydrochloride (150 mg), and N-methylmorpholine (87
0 mg) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solvent was distilled off under reduced pressure, distilled water (50 ml),
Ethyl acetate (50 ml) was added, and the organic layer was separated by liquid separation. The aqueous layer was extracted four times with ethyl acetate, and the combined organic layers were washed three times with distilled water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was converted into an ethanol solution (40 ml), palladium hydroxide (40 mg), a 1N aqueous hydrochloric acid solution (4 ml) were added, and the mixture was stirred under a hydrogen atmosphere for 6 hours. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethanol (2 ml) and dichloromethane (4 m
l) and diethyl ether (10 ml) were added to solidify, and the solid was collected by filtration and dried under reduced pressure to obtain the title compound (260 mg) as an off-white amorphous solid. _{^{1 H NMR (DMSO-d 6}} ) 2.87 (3H, s),
2.96 (3H, s), 3.03-3.55 (8H,
m), 3.69-3.88 (1H, m), 9.13-1
0.05 (4H, m). MS (ESI) m / z 172 (M + H) ^<+> .

[1331] <2- (N, N-dimethylcarbamoyl)
Methyl-4-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine (optically active substance)> hydrochloride of the above 2- (N, N-dimethylcarbamoyl) methylpiperazine (optically active substance) ) (260 mg) in dichloromethane (50 m
l) at room temperature (1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl chloride (480 mg), and triethylamine (85
0 mg) and stirred at room temperature for 7 hours. After the reaction,
A saturated aqueous solution of ammonium chloride (30 ml) was added, and a liquid separation operation was performed to separate an organic layer. The aqueous layer was extracted three times with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (dichloromethane: methanol = 50: 1) to give the title compound (220 m
g) was obtained as a pale yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 0.26 (9H, s), 2.
34-2.49 (1H, m), 2.95-3.13 (9
H, m), 3.21-3.33 (1H, m), 3.69.
-3.80 (2H, m), 7.36 (3H, m), 7.
52-7.60 (2H, m), 7.68 (1H, s),
7.96-8.04 (2H, m), 8.21 (1H,
d, J = 8.8 Hz). MS (ESI) m / z 587 (M + H) ^<+> .

Example 244 2- (N, N-dimethylcarbamoyl) methyl-4-
[(5-ethynylindol-2-yl) sulfonyl]
-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine (optically active substance) 2- (obtained in Example 243) N, N-dimethylcarbamoyl) methyl-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(5- Trimethylsilylethynylindol-2-yl) sulfonyl] piperazine (one of the optically active substances) (180 mg) in tetrahydrofuran (15 ml) at 0 ° C. was added with tetra-n-butylammonium fluoride (1.0 mol / l tetrahydrofuran solution, .44 ml) and stirred at room temperature for 4 hours. After adding 10% aqueous citric acid solution (20 ml) to stop the reaction, dichloromethane (60 ml) was added and the organic layer was separated by liquid separation. The aqueous layer was extracted three times with dichloromethane, and the combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to thin layer chromatography (silica gel, dichloromethane: methanol = 10: 1) to give dichloromethane,
Ethanol and distilled water were added, and the solvent was distilled off under reduced pressure to give the title compound as a colorless amorphous solid (51 m
g) was obtained. Analysis using an optically active substance separation column Column: Daicel Chemical CHIRALPAK-OD Flow rate: 1.0 ml / min Solvent: n-Hexane: 2-PrOH: Et ₂ NH =
70: 30: 0.5. Retention time: 24.8 minutes (the other optically active substance 35.5)
Min) Optical purity: 92% ee in optical purity based on peak area ratio. ¹ H NMR (CDCl ₃ ) 2.50 (3H, s), 2.
57-3.19 (11H, m), 3.23-3.36
(1H, m), 3.62-3.86 (3H, m), 4.
02-4.28 (1H, m), 4.54-4.68
(0.5H, m), 4.98-5.08 (0.5H,
m), 5.51-5.60 (0.5H, m), 6.02.
−6.13 (0.5H, m), 7.04 (1H, s),
7.37 (1H, d, J = 8.8 Hz), 7.44 (1
H, d, J = 8.8 Hz), 7.85 (1H, s), 1
0.39 (0.5H, br), 11.06 (0.5H,
br). MS (FAB) m / z 555 (M + H) ^<+> .

Example 245 1- [4-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5,6-dimethyl-4,
5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazin-2-yl] acetylpyrrolidine hydrochloride 1- [1-tert-
Butoxycarbonyl-4-[(6-chlorobenzo [b]
Thien-2-yl) sulfonyl] piperazin-2-yl] acetylpyrrolidine and 5,6-dimethyl-4,
The title compound was obtained as a colorless amorphous solid from lithium 5,6,7-tetrahydrothiazolo [4,5-d] pyridazine-2-carboxylate. _{^{1 H NMR (DMSO-d 6}} ) 1.60-1.91 (4
H, m), 2.24-2.58 (1H, m), 2.54
-3.02 (2H, m), 2.71 (3H, s), 2.
82 (3H, s), 3.05-3.95 (10H,
m), 4.12-4.70 (2.5H, m), 5.00
−5.12 (0.5H, m), 5.25-5.37
(0.5H, m), 5.76-5.88 (0.5H,
m), 7.56 (1H, d, J = 8.3 Hz), 8.0
2-8.07 (1H, m), 8.09 (1H, s),
8.37 (1H, s). MS (FAB) m / z 623 [(M + H) ⁺ , C
l ³⁵ ], 625 [(M + H) ⁺ , Cl ³⁷ ].

1- [1-tert-butoxycarbonyl-4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazin-2-yl] used as a raw material
Acetylpyrrolidine was synthesized by the following method.

<1- [1-tert-Butoxycarbonyl-4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazin-2-yl] acetylpyrrolidine> tert-Butoxycarbonyl-4-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (N, N-dimethylcarbamoyl) methylpiperazine was prepared in the same manner as in 1-tert-butoxycarbonyl- 4-[(6-
From chlorobenzo [b] thien-2-yl) sulfonyl] piperazin-2-yl] acetic acid and pyrrolidine, the title compound (830 mg) was obtained as a pale yellow amorphous solid. _{^{1 H NMR (CDCl 3) 1.41}} (9H, s), 1.
88-2.06 (4H, m), 2.08-2.38 (1
H, m), 2.44-2.62 (2H, m), 2.83
-3.27 (2H, m), 3.34-3.63 (4H,
m), 2.66-2.90 (2H, m), 3.90-
4.19 (1H, m), 4.75-4.84 (1H,
m), 7.39-7.44 (1H, m), 7.74 (1
H, s), 7.80 (1H, d, J = 8.5 Hz),
7.85 (1H, s). MS (ESI) m / z 528 (M + H) ^<+> .

Example 246 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -2- (N, N-diethylcarbamoyl) methyl-4-[(5,6-dimethyl-4,5 , 6,7-Tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine hydrochloride In the same manner as in Example 231, 1-tert-butoxycarbonyl-4-[(6-chlorobenzo [ b] thien-2-yl) sulfonyl] -2- (N, N-diethylcarbamoyl) methylpiperazine and 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-
d] lithium pyridazine-2-carboxylate (446
mg) to give the title compound as a colorless amorphous solid. _{^{1 H NMR (DMSO-d 6}} ) 0.88-1.15 (6
H, m), 2.30-2.50 (1H, m), 2.54
-2.89 (2H, m), 2.76 (3H, s), 2.
88 (3H, s), 2.92-3.47 (4H, m),
3.48-3.95 (6H, m), 4.26-4.58
(2.5H, m), 5.04-5.14 (0.5H,
m), 5.28-5.37 (0.5H, m), 5.74
−5.86 (0.5H, m), 7.56 (1H, d, J
= 8.8 Hz), 8.04 (1H, d, J = 8.8H)
z), 8.09 (1H, s), 8.31 (1H, s). MS (ESI) m / z 625 [(M + H) ^<+> , C
l ³⁵ ], 627 [(M + H) ⁺ , Cl ³⁷ ].

[1337] 1-tert-Butoxycarbonyl-4-[(6-chlorobenzo [b] thiene-
2-yl) sulfonyl] -2- (N, N-diethylcarbamoyl) methylpiperazine was synthesized by the following method.

[1338] <1-tert-Butoxycarbonyl-4>
-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -2- (N, N-diethylcarbamoyl) methylpiperazine> 1-tert-butoxycarbonyl-4-[(6- Chlorobenzo [b] thien-2-yl) sulfonyl] -2- (N, N-dimethylcarbamoyl) methylpiperazine was obtained as a pale yellow amorphous solid by the same method. ¹ H NMR (CDCl ₃ ) 1.14 (3H, t, J =
7.1 Hz), 1.21 (3H, t, J = 7.1H)
z), 1.41 (9H, s), 2.03-2.37 (1
H, m), 2.44-2.62 (2H, m), 2.93
-3.22 (2H, m), 3.23-3.53 (4H,
m), 3.70-3.90 (2H, m), 3.93-
4.17 (1H, m), 4.76-4.85 (1H,
m), 7.44 (1H, dd, J = 2.0, 8.8H
z), 7.74 (1H, s), 7.81 (1H, d, J
= 8.8 Hz), 7.86 (1H, d, J = 2.0H)
z). MS (ESI) m / z 530 [(M + H) ⁺ , C
l ³⁵ ], 532 [(M + H) ⁺ , Cl ³⁷ ].

Example 247 (-)-4-[[6-Chlorobenzothien-2-yl]
Sulfonyl] -2- (N, N-dimethylcarbamoyl)
Methyl-1-[(5,6-dimethyl-4,5,6,7-
Tetrahydrothiazolo [4,5-d] pyridazine-2-
Il) carbonyl] piperazine Optically active 1-[[6-chlorobenzothien-2-yl] sulfonyl] -2- (N, N-dimethylcarbamoyl) methylpiperazine (232 mg) in N, N-dimethylformamide (20 ml) ), At room temperature, 1-hydroxybenzotriazole (78 mg), 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (332 mg), 5,6-dimethyl-4,5,6,7-
Tetrahydrothiazolo [4,5-d] pyridazine-2-
Lithium carboxylate (380 mg) and N-methylmorpholine (233 mg) were added, and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, the reaction solvent was distilled off under reduced pressure, distilled water (30 ml) and ethyl acetate (50 ml) were added, and the organic layer was separated by liquid separation. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed three times with distilled water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. By subjecting the obtained residue to thin layer chromatography (dichloromethane: methanol = 10: 1),
The title compound (195 mg) was obtained as a pale yellow amorphous solid. [] ²⁰ _D = -20 (EtOH, c = 0.38) ¹ H NMR (CDCl ₃ ) 2.64-3.12 (14
H, m), 3.14-3.42 (1H, m), 3.54
-4.18 (6H, m), 4.22-4.70 (2.5
H, m), 4.98-5.07 (0.5H, m), 5.
24-5.36 (0.5H, m), 5.73-5.87
(0.5H, m), 7.56 (1H, d, J = 8.6H)
z), 8.04 (1H, d, J = 8.6 Hz), 8.0
9 (1H, s), 8.32 (1H, s). MS (FAB) m / z 597 [(M + H) ⁺ , C
l ³⁵ ], 599 [(M + H) ⁺ , Cl ³⁷ ].

The optically active 1-[[6-
Chlorobenzothien-2-yl] sulfonyl] -2-
(N, N-dimethylcarbamoyl) methylpiperazine was synthesized by the following method.

<134] <1-[[6-Chlorobenzothien-2-
Yl] sulfonyl] -2- (N, N-dimethylcarbamoyl) methylpiperazine (optically active substance)> Example 243
(6-chlorobenzothien-2-yl) sulfonyl chloride (457 m) was added at room temperature to a dichloromethane solution (50 ml) of the optically active 2- (N, N-dimethylcarbamoyl) methylpiperazine hydrochloride (418 mg) used in the above.
g), and triethylamine (865 mg),
Stirred at room temperature for 2 hours. After the completion of the reaction, a saturated aqueous solution of ammonium chloride (20 ml) was added, and a liquid separation operation was performed to separate an organic layer. The aqueous layer was extracted three times with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (dichloromethane: methanol = 20:
1) to give the title compound (133 mg) as a pale yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 2.23-2.34 (1H,
m), 2.37-2.49 (2H, m), 2.63-
2.72 (1H, m), 2.88-3.07 (2H,
m), 2.93 (3H, s), 2.97 (3H, s),
3.21-3.32 (1H, m), 3.56-3.70
(2H, m), 7.43 (1H, dd, J = 1.7,
8.6 Hz), 7.75 (1 H, s), 7.81 (1
H, J = 8.6 Hz), 7.85 (1H, d, J = 1.
7 Hz).

Example 248 1-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (morpholinocarbonylmethyl) -4 −
[(1- (phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine 4- (tert-butoxycarbonyl) -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] -2- (morpholinocarbonylmethyl) piperazine (321 mg)
Was added at room temperature to a methylene chloride (3.0 ml) solution at room temperature, followed by stirring for 10 minutes. The reaction mixture was concentrated under reduced pressure, and 1-phenylsulfonyl-5- chloride was added to a solution of the obtained residue in methylene chloride (15 ml).
Trimethylsilylethynylindole-2-sulfonyl (440 mg) and diisopropylethylamine (45
0 μg) at room temperature and stirred for 4 hours. A saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with methylene chloride (2 × 15 ml).
After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue is subjected to silica gel column chromatography (methylene chloride: acetone =
2: 1 → 1: 1) to give the title compound (325 mg) as a colorless and transparent oil. ¹ H NMR (CDCl ₃ ) δ 0.25 (9H, s),
2.43 (1/2 of 1H, br d, J = 15.4)
Hz), 2.50 (3H, brs), 2.62 (1 /
2 of 1H, br d, J = 15.4 Hz);
70-3.08 (6H, m), 3.08-3.80 (1
2H, m), 3.94 (1/2 of 1H, br)
d, J = 12.8 Hz), 4.02 (1/2 of 1)
H, br d, J = 12.8 Hz), 4.17 (1H,
br d, J = 11.0 Hz), 4.64 (1/2 o)
f 1H, d, J = 13.5 Hz), 5.22 (1/2)
of1H, br d, J = 7.8 Hz), 5.66
(1/2 of 1H, d, J = 13.5 Hz), 5.
96 (1/2 of 1H, brs), 7.40-
7.50 (3H, m), 7.44-7.64 (2H,
m), 7.70 (1H, s), 8.05 (2H, d, J
= 7.8 Hz), 8.18 (1H, d, J = 8.8H)
z). MS (FAB) m / z 809 (M + H) ^<+> . HRMS (FAB) m / z 809.2283 (M +
H) ⁺ (calculated C ₃₇ H ₄₅ N ₆ O ₇ S ₃ Si 809.228
1)

The starting material, 4- (tert-butoxycarbonyl) -1-[(5-methyl-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Il) carbonyl] -2- (morpholinocarbonylmethyl) piperazine was synthesized by the following method.

<1-tert-butoxycarbonyl-3>
-Methoxycarbonylmethylpiperazine> 1,4-dibenzyl-2-methoxycarbonylmethylpiperazine (3
0.4 g) in methanol (800 ml), concentrated hydrochloric acid (15
ml), and palladium hydroxide (1.
5 g) were suspended. The suspension was then vigorously shaken at room temperature under a hydrogen atmosphere for 4.5 hours. After the completion of the reaction (the reaction is terminated by TLC <hexane: ethyl acetate = 4: 1)
>), Triethylamine (31 ml) was added to dissolve the insolubles, and the mixture was slightly concentrated. The catalyst was removed by filtration, and the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Methylene chloride (600 ml) and triethylamine (27.5 ml) were added to the residue.
To give 2- (tert-butoxycarbonylimino) -2-phenylacetonitrile (12.
9g) and stirred at 0 ° C for 3.5 hours. Since the reaction was not completed (the completion of the reaction was confirmed by TLC <5% methanol-methylene chloride> that the raw materials disappeared), 2- (tert-butoxycarbonylimino) -2-phenylacetonitrile (3. 76 g), and the temperature was gradually raised from 0 ° C. to room temperature, followed by stirring for 22 hours. After completion of the stirring, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methylene chloride → 10% methanol-methylene chloride) to give the title compound (9.7).
7g) was obtained as a pale yellow amorphous powder. ¹ H NMR (CDCl ₃ ) δ 1.46 (9H, s),
2.15-3.10 (7H, m), 3.80-4.00
(2H, m).

<4- (tert-butoxycarbonyl)
-2-methoxycarbonylmethyl-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine> 5
-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt (874 mg) and 1- (tert-butoxycarbonyl) -3- (methoxycarbonylmethyl) piperazine (820 mg) in dimethylformamide (10 ml) was added to 1-hydroxybenzotriazole monohydrate (5
15 mg) and 1- (dimethylaminopropyl) -3-
Ethyl carbodiimide hydrochloride (730 mg) was added at room temperature, and the mixture was stirred for 2 days. After concentrating the reaction mixture under reduced pressure, ethyl acetate (50 ml) and water (200 ml) were added to separate the layers, and the aqueous layer was extracted with ethyl acetate (2 × 50 ml). The organic layers were combined, washed with water (300 ml) and a saturated aqueous solution of sodium hydrogen carbonate (100 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by silica gel column chromatography (methylene chloride: acetone = 2: 1 → 1: 1) to give the title compound (908 mg) as a colorless and transparent oil. ¹ H NMR (CDCl ₃ ) δ 1.460 (1/2 of
9H, s), 1.464 (1/2 of 9H,
s), 2.30-3.23 (6H, m), 2.51 (3
H, s), 3.40 (1/2 of 1H, br)
s), 3.55-3.75 (4H, m), 3.696.
(1/2 of 3H, s), 3.703 (1/2 of 3H, s)
3H, s), 3.90 (1/2 of 1H, br)
s), 4.12 (2H, br d, J = 13.2H)
z), 4.48 (1/2 of 1H, d, J = 12.
5 Hz), 5.12 (1/2 of 1H, s), 5.
44 (1/2 of 1H, d, J = 12.5 Hz),
6.01 (1/2 of 1H, s). MS (FAB) m / z 439 (M + H) ^<+> , 383.
(M + Hisobutene) ⁺ . HRMS (FAB) m / z 439.11992 (M +
H) ⁺ (calcd _{C 20 H 31 N 4 O 5} S 439.2015)

<4- (tert-butoxycarbonyl)
-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (morpholinocarbonylmethyl) piperazine> 4- (tert- Butoxycarbonyl) -2-methoxycarbonylmethyl-1-[(5-methyl-4,5,
6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine (235 mg) in tetrahydrofuran (4.0 ml) was treated with water (1.0 m).
l) and lithium hydroxide (13.1 mg) were added at room temperature and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, and morpholine (70.1 μl), 1-hydroxybenzotriazole monohydrate (86.7 mg) and 1- (dimethylaminopropyl) were added to a solution of the obtained residue in dimethylformamide (2.0 ml). ) -3-Ethylcarbodiimide hydrochloride (123 mg) was added at room temperature, and the mixture was stirred for 3 days.
After the reaction mixture was concentrated under reduced pressure, methylene chloride (30 ml) and water (300 ml) were added to separate the layers, and the aqueous layer was extracted with methylene chloride (4 × 30 ml). Combine the organic layers and add water (3
00 ml) and saturated aqueous sodium hydrogen carbonate solution (100
ml) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue is subjected to silica gel column chromatography (methylene chloride: acetone =
Purify with 1: 1 → methylene chloride: methanol = 10: 1) to give the title compound (201 mg) as a colorless and transparent oil.
I got ¹ H NMR (CDCl ₃ ) δ 1.47 (9H, s),
2.20 (1/2 of 1H, brs), 2.40-
3.25 (1/2 of 1H + 6H, m), 2.51
(3H, s), 3.25-3.85 (10H, m),
3.85-4.25 (2H, br), 4.48 (1/2
of 1H, d, J = 15.9 Hz), 5.06 (1
/ 2 of 1H, s), 5.43 (1/2 of 1
H, d, J = 15.9 Hz), 5.93 (1/2 of)
1H, s). MS (FAB) m / z 494 (M + H) ^<+> , 438.
(M + Hisobutene) ⁺ . HRMS (FAB) m / z 494.2443 (M +
H) ⁺ (calcd _{C 23 H 36 N 5 O 5} S 494.2446)

Example 249 4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2- (morpholinocarbonylmethyl) piperazine

[1348]

Embedded image 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (morpholinocarbonylmethyl) -4-
[(1- (phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine (320 mg) in tetrahydrofuran (4.0 ml)
Methanol (4.0 ml) and potassium hydroxide (78.3 mg) were added to the solution at room temperature, and the mixture was stirred for 2 hours. Methylene chloride (20 ml), a saturated aqueous solution of ammonium chloride (5.0 ml) and a saturated aqueous solution of sodium hydrogen carbonate (30 ml) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted with methylene chloride (2 × 10 ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by preparative silica gel thin-layer chromatography (methylene chloride: methanol = 20: 1) to give the title compound (150 mg) as a colorless amorphous solid.
I got ¹ H NMR (CDCl ₃ ) δ 2.48 (3H, br
s), 2.55-3.20 (10H, m), 3.03
(1H, s), 3.25-3.90 (10H, m),
4.01 (1/2 of 1H, br d, J = 11.
2 Hz), 4.14 (1/2 of 1H, br d,
J = 12.2 Hz), 4.61 (1H, br d, J =
12.9 Hz), 5.06 (1/2 of 1H, d,
J = 8.0 Hz), 5.60 (1/2 of 1H, b)
rd, J = 12.9 Hz), 6.06 (1/2 of
1H, br s), 7.03 (1H, s), 7.38
(1H, d, J = 8.7 Hz), 7.42 (1H, d,
J = 8.7 Hz), 7.85 (1H, s), 10.44
(1/2 of 1H, brs), 10.92 (1 /
2of 1H, brs). MS (FAB) m / z 597 (M + H) ^<+> .

Example 250 2- (N, N-dimethylcarbamoylmethyl) -1-
[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]-
4-[(1- (phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine By a method similar to that in Example 248, 4- (tert-butoxycarbonyl) -2- (N, N-dimethylcarbamoyl Methyl) -1-[(5-methyl-4,5,6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine and 1-phenylsulfonyl chloride-5-trimethylsilylethynylindole-
From 2-sulfonyl, the title compound (258 mg) was obtained as a colorless and transparent glassy substance. ¹ H NMR (CDCl ₃ ) δ 0.25 (9H, s),
2.25-2.55 (8H, m), 2.65-3.45
(10H, m), 3.60-3.80 (2H, m),
3.96 (1/2 of 1H, br d, J = 13.
7 Hz), 4.07 (1/2 of 1H, br d,
J = 13.7 Hz), 4.22 (1H, brd, J = 1)
2.5 Hz), 4.65 (1/2 of 1H, br)
d, J = 12.5 Hz), 5.17 (1/2 of 1)
H, br d, J = 9.3 Hz), 5.63 (1/2)
of 1H, br d, J = 13.7 Hz), 5.94
(1/2 of 1H, br d, J = 8.0 Hz),
7.40-7.50 (3H, m), 7.52-7.62
(2H, m), 7.71 (1H, d, J = 1.0H
z), 8.05 (2H, dd, J = 8.8, 1.0H
z), 8.20 (1H, d, J = 8.8 Hz). MS (FAB) m / z 767 (M + H) ^<+> . HRMS (FAB) m / z 767.2164 (M +
H) ⁺ (calcd _{C 35 H 43 N 6 O 6} S 3 Si 767.217
6)

[1350] 4- (tert-Butoxycarbonyl) -2- (N, N-dimethylcarbamoylmethyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5, 4-c] pyridin-2-yl)
Carbonyl] piperazine was synthesized by the following method.

[1351] <4- (tert-butoxycarbonyl)
-2- (N, N-dimethylcarbamoylmethyl) -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine> 4- (tert-butoxycarbonyl) -1 used in Example 248 -[(5-methyl-4,5,6,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] -2- (morpholinocarbonylmethyl) piperazine by the same method as in the synthesis of 4- (te).
colorless than rt-butoxycarbonyl) -2-methoxycarbonylmethyl-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine The title compound (206 mg) was obtained as a clear oil. ¹ H NMR (CDCl ₃ ) δ 1.45 (9H, s),
2.45-2.65 (1H, m), 2.50 (3H,
s), 2.70-3.25 (13H, m), 3.40-
3.60 (1H, m), 3.60-3.80 (2H,
m), 3.80-4.35 (2H, br), 4.48
(1/2 of 1H, d, J = 13.0 Hz), 5.
10 (1/2 of 1H, s), 5.40 (1/2
of 1H, d, J = 11.3 Hz), 5.94 (1 /
2 of 1H, s). MS (FAB) m / z 452
(M + H) ⁺ , 396 (M + Hisobutene) ⁺ . HRMS (FAB) m / z 452.2344 (M +
H) ⁺ (calculated C ₂₁ H ₃₄ N ₅ O ₄ S 452.2332)

Example 251 2- (N, N-dimethylcarbamoylmethyl) -4-
[(5-ethynylindol-2-yl) sulfonyl]
-1-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine In the same manner as in Example 249, 2- (N, N -Dimethylcarbamoylmethyl) -1-[(5-methyl-4,
Colorless than 5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine The title compound (114 mg) was obtained as an amorphous solid. ¹ H NMR (CDCl ₃ ) δ 2.43-3.50 (16
H, m), 2.49 (3H, brs), 3.58-
3.95 (3H, m), 4.05 (1/2 of 1H,
br d, J = 12.4 Hz), 4.19 (1/2 o)
f 1H, brd, J = 12.4 Hz), 4.61 (1
H, br d, J = 12.9 Hz), 5.12 (1/2)
of 1H, d, J = 8.0 Hz), 5.59 (1 /
2 of 1H, br d, J = 14.4 Hz), 6.0.
9 (1/2 of 1H, brs), 7.03 (1H,
s), 7.38 (1H, d, J = 8.8 Hz), 7.4
2 (1H, dd, J = 8.8, 1.3 Hz), 7.85
(1H, s), 10.70 (1/2 of 1H, br)
s), 11.10 (1/2 of 1H, br)
s). MS (FAB) m / z 555 (M + H) ^<+> .

Example 252 2- (N, N-dimethylcarbamoylmethyl) -4-
[(5-ethynylindol-2-yl) sulfonyl]
-1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

[1354]

Embedded image According to a method similar to that in Example 231, 5-methyl-4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridine-2-carboxylic acid lithium salt and 3- (N,
From N-dimethylcarbamoylmethyl) -1-[(5-ethynylindol-2-yl) sulfonyl] piperazine, the title compound was obtained as a colorless amorphous solid. ¹ H NMR (CDCl ₃ ) δ 2.40-3.20 (18
H, m), 3.40 (1/2 of 1H, t, J = 1)
1.5Hz), 3.46-3.60 (1/2 of 1
H + 2H, m), 3.78 (1/2 of 1H, br)
d, J = 12.2 Hz), 3.87 (1/2 of)
1H, br d, J = 11.2 Hz), 4.03 (1 /
3 of 1H, br d, J = 12.2 Hz);
19 (1/2 of 1H, br d, J = 12.7H
z), 4.64 (1/2 of 1H, br d, J =
13.5 Hz), 5.12 (1/2 of 1H, br)
d, J = 11.2 Hz), 5.26 (１ ／ of
1H, br d, J = 14.2 Hz), 5.82 (1 /
2 of 1H, brs), 7.02 (1H, s),
7.39 (1H, d, J = 8.8 Hz), 7.42 (1
H, d, J = 8.8 Hz), 7.84 (1H, s), 1
0.45 (1/2 of 1H, brs), 11.0
0 (1/2 of 1H, brs). MS (FAB) m / z 539 (M + H) ^<+> .

[1355] 5-Methyl-4,5, used as a raw material
Lithium 6,7-tetrahydrooxazolo [5,4-c] pyridine-2-carboxylate was synthesized by the following method.

<5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine-2-carboxylic acid lithium salt> 2-methoxycarbonyl-5-methyl-4,5,6 7-tetrahydrooxazolo [5,4-
c] pyridine (800 mg) in tetrahydrofuran (2
Water (6.0 ml) and lithium hydroxide (99.7 mg) were added to the solution at room temperature and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (825 mg). ¹ H NMR (DMSO-d6) δ 2.37 (3H,
s), 2.47 (2H, t, J = 5.6 Hz), 2.6.
4 (2H, t, J = 5.6 Hz), 3.43 (3H,
s).

[1358] 3- (N, N-Dimethylcarbamoylmethyl) -1-[(5-ethynylindol-2-yl) sulfonyl] piperazine used as a starting material was synthesized by the following method.

1-[(5-ethynylindole-2-
Yl) sulfonyl] -3- (N, N-dimethylcarbamoylmethyl) piperazine> 1-[(1-phenylsulfonyl-5-trimethylsilylethynylindole-2
-Yl) sulfonyl] -3- (methoxycarbonylmethyl) piperazine (0.93 g), lithium hydroxide (1
36 mg) was added to a mixed solvent of methanol (13 ml) and tetrahydrofuran (13 ml), and the mixture was heated under reflux for 45 minutes. Allow to cool, and add N, N-dimethylformamide (15 m
After l) was added, methanol and tetrahydrofuran were distilled off under reduced pressure. Here dimethylamine hydrochloride (23
8 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (621 mg), 1-hydroxybenzotriazole monohydrate (109 mg)
Was added and stirred at room temperature overnight. The solvent was distilled off under reduced pressure using a pump, and dichloromethane and a saturated aqueous solution of sodium hydrogen carbonate were added to carry out liquid separation. The aqueous layer was extracted with dichloromethane, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The same reaction was repeated once more (374 mg of the starting material), and these were combined and flash column chromatography on silica gel (first time;
SI-40B, ethyl acetate: methanol = 9: 1, second time; SI-40A, ethyl acetate: methanol = 17:
Purify twice in 3) to give the title compound (5) as a pale yellow solid.
45 mg). ¹ H NMR (CDCl ₃ ) 2.26-2.43 (3H,
m), 2.61-2.68 (1H, m), 2.87-
2.99 (9H, m), 3.05 (1H, s), 3.1
9-3.25 (1H.m), 3.62-3.64 (1
H, m), 7.00 (1H, s), 7.39 (1H, d
d, J = 8.5, 0.7 Hz), 7.46 (1H, d
d, J = 8.5, 1.2 Hz), 7.87 (1H, br)
s), 9.22 (1H, br s). MS (FAB) m / z 375 (M + H) ^<+> .

Example 253 2- (2-cyanoethyl) -1-[(5-methyl-4,
5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[(5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine 5-methyl-4,5 6,7-tetrahydrooxazolo [5,4-c] pyridine-2-carboxylic acid lithium salt (146 mg) and 3- (2-cyanoethyl) -1-
[(1-Phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine (360 mg) in dimethylformamide (3.0 ml)
1-Hydroxybenzotriazole monohydrate (106 mg) and 1- (dimethylaminopropyl)-
3-Ethylcarbodiimide hydrochloride (150 mg) was added at room temperature, and the mixture was stirred for 3 days. After concentrating the reaction mixture under reduced pressure, methylene chloride (20 ml) and water (100 ml) were added, and the mixture was separated. The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (50 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue is subjected to silica gel column chromatography (methylene chloride:
Purification with acetone = 2: 1 → 1: 1) gave the title compound (267 mg) as a colorless and transparent glass. ¹ H NMR (CDCl ₃ ) δ 0.26 (9H, s),
2.00-2.30 (1H, m), 2.35-2.85
(10H, m), 2.49 (3H, s), 3.18 (1
/ 2 of 1H, t, J = 13.0 Hz), 3.53
(1/2 of 1H, t, J = 13.0 Hz), 3.
55 (2H, s), 3.75 (1/2 of 1H, t,
J = 11.6 Hz), 3.85 (1/2 of 1H,
t, J = 14.2 Hz), 4.71 (1/2 of 1)
H, d, J = 13.6 Hz), 4.99 (1/2 of)
1H, br s), 5.47 (1/2 of 1H,
d, J = 13.4 Hz), 5.73 (1/2 of 1)
H, br s), 6.97 (1H, s), 7.35 (1
H, d, J = 8.8 Hz), 7.46 (1H, dd, J)
= 8.8, 1.5 Hz), 7.82 (1H, s), 8.
96 (1H, brs). MS (FAB) m / z 579 (M + H) ^<+> . HRMS (FAB) m / z 579.2210 (M +
H) ⁺ (calculated C ₂₈ H ₃₅ N ₆ O ₄ SSi 579.221
0)

1- (2-Cyanoethyl) -1-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] used as a raw material
Piperazine was synthesized by the following method.

[1361] <3- (2-cyanoethyl) -1- (1-
(Phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine> 1,
4-bis (tert-butoxycarbonyl) -2- (2
Thioanisole (4.74m) in a solution of -cyanoethyl) piperazine (1.37g) in methylene chloride (20ml).
l), 1,2-ethanedithiol (340 μl) and trifluoroacetic acid (20 ml) were added under ice-cooling,
The mixture was heated and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and diisopropylethylamine (2.81 ml) and 1-phenylsulfonyl-5-trimethylsilylethynylindole-2-sulfonyl chloride (2.2 g) were added to a solution of the obtained residue in methylene chloride (40 ml) at room temperature. And stirred for 5 hours. A saturated aqueous sodium hydrogen carbonate solution (100 ml) was added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with methylene chloride (50 ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by silica gel column chromatography (methylene chloride: acetone = 10: 1 → 3: 1) to give the title compound (4) as a colorless and transparent glassy substance.
94 mg). ¹ H NMR (CDCl ₃ ) δ 0.25 (9H, s),
1.65-1.77 (1H, m), 1.77-1.90
(1H, m), 2.48 (2H, t, J = 7.4H
z), 2.71 (1H, dd, J = 12.5, 9.5H
z), 2.80-3.10 (5H, m), 3.68 (1
H, d, J = 12.5 Hz), 3.80 (1H, d, J)
= 10.5 Hz), 7.41 (2H, t, J = 7.8H)
z), 7.43 (1H, s), 7.55 (1H, t, J
= 7.8 Hz), 7.58 (1H, dd, J = 8.8,
1.5Hz), 7.69 (1H, d, J = 1.5H)
z), 8.00 (2H, d, J = 7.8 Hz), 8.2
1 (1H, d, J = 8.8 Hz). MS (FAB) m / z 555 (M + H) ^<+> . HRMS (FAB) m / z 555.1567 (M +
H) ⁺ (calcd _{C 26 H 31 N 4 O 4} S 2 Si 555.155
6)

Example 254 2- (2-Cyanoethyl) -4-[(5-ethynylindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrooxazolo [ 5,4-
c] pyridin-2-yl) carbonyl] piperazine 2- (2-cyanoethyl) -1- as in Example 233
[(5-Methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridin-2-yl) carbonyl]
-4-[(5-trimethylsilylethynylindole-
2-yl) sulfonyl] piperazine to give the title compound (196 mg) as a colorless amorphous solid. ¹ H NMR (CDCl ₃ ) δ 2.00-2.25 (1
H, m), 2.25-2.90 (9H, m), 2.48
(3H, s), 3.05 (1H, s), 3.17 (1 /
2 of 1H, t, J = 11.8 Hz), 3.45 −
3.65 (1 / 2of 1H, m), 3.54 (2H,
s), 3.75 (1H, t, J = 11.8 Hz), 3.
85 (1H, t, J = 13.1 Hz), 4.71 (1 /
2 of 1H, br d, J = 13.3 Hz), 5.0
0 (1/2 of 1H, brs), 5.46 (1/2
of 1H, br d, J = 13.3 Hz), 5.7
1 (1/2 of 1H, brs), 6.99 (1
H, s), 7.38 (1H, d, J = 8.5 Hz),
7.47 (1H, d, J = 8.5 Hz), 7.85 (1
H, s), 9.29 (1H, br s). MS (FAB) m / z 507 (M + H) ^<+> .

Example 255 4-[(6-Bromonaphthalen-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine 4-tert-butoxycarbonyl-2- (N-methylcarbamoyl) -1-[(5-methyl-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Il) carbonyl] piperazine (169 mg) was dissolved in a 1N hydrochloric acid ethanol solution (5 ml), stirred at room temperature for 30 minutes, and the solvent was distilled off under reduced pressure. N, N-dimethylformamide (5 ml), triethylamine (0.83 ml), and 6-bromo-2-chlorosulfonylnaphthalene (122 mg) were added to the residue, and the mixture was stirred at room temperature overnight. Water was added, extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (methanol: methylene chloride = 1: 9). This was dissolved in a small amount of methylene chloride, and hexane was added to make a powder. This was collected by filtration to give the title compound (93 mg) as a white solid. ¹ H NMR (CDCl ₃ ) δ 2.49 (3H, s),
2.64-3.15 (9H, m), 3.41-3.86
(4H, m), 4.45-4.48 (1H, m), 4.
59-6.12 (2H, m), 6.38 (1H, s),
7.70 (1H, d, J = 8.3 Hz), 7.78-
7.89 (3H, m), 8.08 (1H, s), 8.3
3 (1H, s).

[1364] 4-tert-Butoxycarbonyl-2- (N-methylcarbamoyl) -1-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine was synthesized by the following method.

[1365] <4-tert-butoxycarbonyl-2>
-Ethoxycarbonyl-1-[(5-methyl-4,5,
6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine> In Example 248, 4- (tert-butoxycarbonyl) -2-methoxycarbonylmethyl-1-[(5-methyl −4,5,6
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine in the same manner as in the synthesis of 1-tert-butoxycarbonyl-3-ethoxycarbonylpiperazine and 5-methyl-4,
The title compound (2.13 g, white solid) was obtained from lithium 5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylate. MS (FAB) m / z 439 (M + H ^< + ^> ).

[1366] <4-tert-butoxycarbonyl-2>
-(N-methylcarbamoyl) -1-[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine> 4- (tert-butoxycarbonyl) used in Example 248
Similar to the synthesis of -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (morpholinocarbonylmethyl) piperazine 4-tert-butoxycarbonyl-2-ethoxycarbonyl-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4
-C] pyridin-2-yl) carbonyl] piperazine to give the title compound (630 mg, pale yellow solid). MS (FAB) m / z 442 (M + H ^< + ^> ).

Example 256 4-[(6-ethynylnaphthalen-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine 4-[(6-bromonaphthalen-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine (365 mg) in tetrahydrofuran (1.5 ml) in triethylamine (4.5 ml), dimethylformamide (4.5 ml), trimethylsilylacetylene (134 μl), and palladium acetate ( 14.5mg)
Was added at room temperature. After heating under reflux for 5 hours, the mixture was allowed to cool to room temperature, and methylene chloride (50 ml) and water (50 ml) were added to the reaction mixture.
0 ml), and the mixture was separated. The aqueous layer was separated from methylene chloride (2 × 50).
ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 2- (N
-Methylcarbamoyl) -1-[(5-methyl-4,
5,6,7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -4-[[6- (trimethylsilylethynyl) naphthalen-2-yl] sulfonyl] piperazine was obtained. Methanol (10 ml) and potassium hydroxide (42.5 mg) were added to a solution of the obtained residue in tetrahydrofuran (10 ml) at room temperature. Fifteen
After stirring for one minute, methylene chloride (30 ml), a saturated aqueous solution of ammonium chloride (5.0 ml) and a saturated aqueous solution of sodium hydrogen carbonate (30 ml) were added to the reaction mixture, and the mixture was separated. The aqueous layer was extracted with methylene chloride (2 × 10 ml). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residue. The obtained residue was purified by silica gel column chromatography (methylene chloride: acetone: methanol = 20: 20: 1 → 10: 10: 1) to give the title compound (198 mg) as a colorless amorphous solid. ¹ H NMR (CDCl ₃ ) δ 2.48 (3H, s),
2.58-3.00 (9H, m), 3.13 (1/2
of 1H, t, J = 11.2 Hz), 3.25 (1
H, s), 3.47 (1/2 of 1H, t, J = 1)
1.2Hz), 3.67 (2H, s), 3.70-3.
90 (1H, m), 4.47 (1H, d, J = 12.0
Hz), 4.57 (1/2 of 1H, brd, J
= 16.0 Hz), 5.21 (1/2 of 1H, b)
rs), 5.67 (1/2 of 1H, br d,
J = 12.8 Hz), 6.17 (1/2 of 1H,
brs), 6.38 (1/2 of 1H, br)
s), 6.45 (1/2 of 1H, br s),
7.64 (1H, d, J = 8.3 Hz), 7.78 (1
H, d, J = 8.5 Hz), 7.91 (2H, d, J =
8.3 Hz), 8.06 (1H, s), 8.33 (1
H, s). MS (FAB) m / z 538 (M + H) ^<+> . HRMS (FAB) m / z 538.1575 (M +
H) ⁺ (calcd _{C 26 H 28 N 5 O 4} S 2 538.1583)

Example 257 1- [5- (tert-butoxycarbonyl) -4,
5,6,7-tetrahydro [5,4-c] pyridine-2
-Yl] carbonyl-4-[(5-chloroindole-
2-yl) sulfonyl] -2-[(morpholino) carbonylmethyl] piperazine 1- (tert-butoxycarbonyl) -4- [4-[(5-chloroindol-2-yl) by a method similar to that in Example 239. Sulfonyl] -2-[(morpholino) carbonylmethyl] piperazine and 5-tert-butoxy-4,5,6,7-tetrahydrothiazolo [5
4-c] pyridine-2-carboxylic acid lithium salt,
The title compound (585 mg) as an orange foamy solid
I got ¹ H NMR (CDCl ₃ ) 1.48 (9H, s), 2.
58-3.13, 3.37-3.96 (19H, m),
4.60-4.66, 5.57-5.60 (1H, ea
ch m), 5.07, 6.02 (1H, each b
rs), 6.98 (1H, s), 7.27 (1H,
d, J = 9.0 Hz), 7.38 (1H, d, J = 9.
0 Hz), 7.64 (3H, m), 10.39 (1H,
s). MS (FAB) m / z 693 (M + H) ^<+> .

Example 258 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(morpholino) carbonylmethyl] -1-
[(4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine hydrochloride 1- [5- (tert-butoxycarbonyl) -4,
5,6,7-tetrahydro [5,4-c] pyridine-2
-Yl] carbonyl-4-[(5-chloroindole-
2-yl) sulfonyl] -2-[(morpholino) carbonylmethyl] piperazine (2.03 g) was added to a saturated ethanolic hydrochloric acid solution (5 ml), and the mixture was stirred at room temperature for 1 hour.
The solvent was distilled off under reduced pressure, the residue was dissolved in a small amount of methanol, ether was added thereto, and the resulting precipitate was collected by filtration to obtain the title compound (618 mg) as a pale yellow solid. _{^{1 H NMR (DMSO-d 6}} ) 2.33-3.81 (1
9H, m), 4.36-5.72 (4H, m), 7.0
3 (1H, s), 7.32 (1H, d, J = 9.0H)
z), 7.48 (1H, d, J = 9.0 Hz), 7.7
7. (1H, s), 9.50 (2H, brs), 12.
41 (1H, s).

Example 259 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (morpholinocarbonylmethyl) -1-
[(5-Sulfo-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine sodium salt 4-[(5-chloroindol-2-yl) sulfonyl] -2- (morpholinocarbonylmethyl) -1-
[(4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine (1
37 mg) was dissolved in dichloromethane (3 ml), and triethylamine (250 l) and chlorosulfuric acid (19
l) was added and the mixture was stirred at room temperature for 3 hours. 0.5 N hydrochloric acid was added to the reaction solution, the layers were separated, and the aqueous layer was extracted with dichloromethane. After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to preparative TL
C (5 mm thick, dichloromethane: methanol = 4:
Purified in 1). This was dissolved in methanol, 1N aqueous sodium hydroxide solution (195 l) was added, and the solvent was distilled off under reduced pressure. The same reaction and purification were performed once again (150
mg) and combine them with gel filtration (LH-
20, methanol) to give the title compound (95 mg) as a colorless solid. _{^{1 H NMR (DMSO-d 6}} ) 2.33-3.59 (1
7H, m), 3.74 (2H, d, J = 9.8 Hz),
4.08 (2H, s), 4.38, 5.45 (1H,
d, J = 13.2 Hz), 5.03, 5.89 (1H,
each br s), 7.01 (1H, s), 7.2
9 (1H, d, J = 8.4 Hz), 7.48 (1H,
d, J = 8.4 Hz), 7.75 (1H, s), 12.
40 (1H, brs). MS (FAB) m / z 673 (M + H) ^<+> , 695
(M + Na) ⁺ .

Example 260 4-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -1-[(5,6-dimethyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine hydrochloride

[1372]

Embedded image 5-tert-butoxycarbonyl-6-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridine (Reference Example 195) (240 mg, 0.94 mmol
l) was dried over molecular sieves in ether (10
ml), and the inside of the container was replaced with argon.
Cooled to ° C. To this solution was added n-butyllithium (1.6
6mol / L hexane solution, 596ml, 0.99mm
ol), and the mixture was stirred at the same temperature for 45 minutes. After the temperature was raised to −30 ° C. over 2 hours, the mixture was cooled again to −78 ° C., and stirred for 30 minutes while blowing CO ₂ gas into the reaction solution. The temperature was raised to room temperature, the solvent was distilled off under reduced pressure, and lithium 5-tert-butoxycarbonyl-6-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylate was used. Salt was obtained. Used for the next reaction without formation.
1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -3- [N-methylcarbamoyl] piperazine (352 mg), 5-tert-butoxycarbonyl-6-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid lithium salt (279 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (271 m
g), 1-hydroxybenzotriazole monohydrate (64 mg) was added to N, N-dimethylformamide (8 m
l) and stirred at room temperature for 3 days. Dichloromethane,
Water was added thereto to remove the organic layer, which was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Flash column chromatography using silica gel on the residue (SI-
40B, hexane: ethyl acetate = 1: 1).
The obtained residue (225 mg) was dissolved in a saturated ethanol solution of hydrochloric acid (5 ml) and stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, dichloromethane and a saturated aqueous solution of sodium hydrogen carbonate were added to the residue, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To this, dichloromethane (10 ml) was added, and acetic acid (24 l), 35
% Aqueous formaldehyde (33 l) and sodium triacetoxyborohydride (109 mg) were added at room temperature.
Stirred for 0 minutes. Water was added for liquid separation, and the aqueous layer was extracted with dichloromethane. The organic layer is dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The obtained residue is subjected to flash column chromatography (SI
-40A, dichloromethane: methanol = 19: 1). This was added to a 1N ethanol solution of hydrochloric acid (5 ml)
After stirring at room temperature for 5 minutes, the solvent was distilled off under reduced pressure. The obtained residue was subjected to gel filtration (LH-20, diameter 2 cm).
X 30 cm, methanol) to give the title compound (110 mg) as a pale yellow powdery solid. _{^{1 H NMR (DMSO-d 6}} ) 1.35 (3H, br
s), 2.49-6.20 (18H, m), 7.56.
(1H, dd, J = 8.6, 2.0 Hz), 8.05-
8.07 (2H, m), 8.11-8.16 (1H,
m), 8.31 (1H, d, J = 2.0 Hz), 11.
35-11.80 (1H, m). MS (FAB) m / z 568 (M + H) ^<+>

Example 261 2- (N, N-dimethylcarbamoylmethyl) -1-
[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(5-ethynylindol-2-yl)
Sulfonyl] piperazine 3- (N, N-dimethylcarbamoylmethyl) -1-
[(5-Ethynylindol-2-yl) sulfonyl] piperazine (310 mg), 5,6-dimethyl-
4,5,6,7-tetrahydrothiazolo [4,5-d]
Pyridazine-2-carboxylic acid lithium salt (236m
g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (238 mg), 1-hydroxybenzotriazole monohydrate (56 mg) were dissolved in N, N-dimethylformamide (6 ml), and dissolved at room temperature. Stirred for hours. Dichloromethane and a saturated aqueous solution of sodium hydrogen carbonate were added to carry out liquid separation, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (SI-40B, dichloromethane: methanol = 97:
3 → 19: 1) and purified again by preparative TLC.
(Thickness 2.0 mm, dichloromethane: methanol = 9:
1) to give the title compound as a pale yellow solid (200m
g) was obtained. _{^{1 H NMR (CDCl 3) 2.36-4.19}} (24
H, m), 4.36, 5.58 (1H, each d,
J = 14.2, 13.7 Hz), 5.12, 6.09
(1H, each s), 7.03 (1H, s), 7.
42 (2H, brs), 7.85 (1H, m), 1
0.60, 11.08 (1H, each s). MS (FAB) m / z 570 (M + H) ^<+> .

Example 262 1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(5-ethynyl) Indole-2-yl) sulfonyl] -2- (N-methylcarbamoyl)
Piperazine 1-[(5-Ethynylindol-2-yl) sulfonyl] -3- (N-methylcarbamoyl) piperazine and 5,6-dimethyl-4,5,6,7- by the same method as in Example 232. Tetrahydrothiazolo [4,5-
d] The title compound was obtained as a pale yellow solid from lithium pyridazine-2-carboxylate. _{^{1 H NMR (DMSO-d 6}} ) 2.25-3.51 (1
2H, m), 3.67-3.74 (3H, m), 4.0
0 (2H, brs), 4.01 (1H, s), 4.2
4 (1H, t, J = 12.1 Hz), 4.43-6.1
8 (2H, m), 7.02-7.04 (1H, m),
7.35 (1H, d, J = 8.9 Hz), 7.44 (1
H, d, J = 8.9 Hz), 7.85 (1H, s),
8.05-8.09 (1H, m), 12.38 (1H,
s). MS (FAB) m / z 542 (M + H) ^<+> .

The starting material 1-[(5-ethynylindol-2-yl) sulfonyl] -3- (N-methylcarbamoyl) piperazine was synthesized by the following method.

<1-[(1-Phenylsulfonyl-5-
Trimethylsilylethynylindol-2-yl) sulfonyl] -3- (N-methylcarbamoyl) piperazine> 2- [N-methylcarbamoyl] piperazine (1.
84 g), 1-phenylsulfonyl-5-trimethylsilylethynylindole-2-sulfonyl chloride (3.16 g) and triethylamine (3.9 ml) were added to dichloromethane (30 ml), and the mixture was stirred at room temperature for 3 days. Water was added for liquid separation, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane: methanol = 9:
Purify in 1) to afford the title compound (1.75) as a yellow solid.
g) was obtained. ¹ H NMR (CDCl ₃ ) 0.25 (9H, s), 2.
79, 2.80 (3H, each s), 2.90-
3.17 (4H, m), 3.46-3.49 (1H,
m), 3.72 (1H, d, J = 12.0 Hz), 3.
5. 90 (1H, dd, J = 12.6, 3.3 Hz);
64-6.65 (1H, m), 7.39-7.43 (2
H, m), 7.46 (1H, s), 7.52-7.58.
(2H, m), 7.682-7.686 (1H, m),
8.00 (1H, d, J = 9.0 Hz), 8.20 (1
H, d, J = 9.0 Hz).

1-[(5-ethynylindole-2-
Yl) sulfonyl] -3- (N-methylcarbamoyl) piperazine> 1-[(1-phenylsulfonyl-5
-Trimethylsilylethynylindol-2-yl) sulfonyl] -3- (N-methylcarbamoyl) piperazine (559 mg) and potassium hydroxide (112 mg) were added to methanol (5 ml), and the mixture was stirred at room temperature for 5 hours.
Dichloromethane and water were added for liquid separation, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography on silica gel (SI-40B, dichloromethane: methanol = 9:
Purify in 1) to give the title compound (108
mg). _{^{1 H NMR (DMSO-d 6}} ) 2.33-2.43 (2
H, m), 2.56, 2.57 (3H, each
s), 2.64-2.69 (1H, m), 2.89-
2.92 (1H.m), 3.25-3.30 (3H,
m), 3.51 (1H, dd, J = 11.1, 2.8H
z), 4.03 (1H, s), 7.03 (1H, s),
7.37 (1H, dd, J = 8.5, 1.6 Hz),
7.50 (1H, d, J = 8.5 Hz), 7.81-
7.85 (1H, m), 7.88 (1H, s), 12.
36 (1H, s).

Example 263 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-2-yl ) Carbonyl] piperazine hydrochloride triphosgene (139 mg) was added to dichloromethane (5 m
l) and stirred at −78 ° C. while stirring with 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] piperazine (664 mg) in dichloromethane (15 m
l) was added dropwise and stirred at the same temperature for 1 hour. Here, a dichloromethane solution of triethylamine (141 l) (6 m
l) was added dropwise, and the mixture was stirred at −78 ° C. for 30 minutes. Here, 2,3-dihydro-1H-pyrrolo [3,4-c]
Pyridine (170 mg) in dichloromethane (10 m
l) was added dropwise, and the mixture was stirred while raising the temperature to -20 ° C over 1 hour, and further stirred while raising the temperature to room temperature over 1 hour. Water was added to the reaction solution for liquid separation, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to flash column chromatography (SI
-40C, ethyl acetate: methanol = 23: 2 → 9:
Purified in 1). Of the obtained title compound (202 mg), 55 mg was dissolved in methanol (2 ml), and 1N hydrochloric acid (120 l) was added to form a hydrochloride. The solvent was distilled off under reduced pressure, and the residue was dried in vacuo to give a pale yellow solid. To give the title compound (55 mg). ¹ H NMR (CD ₃ OD) 3.22-3.24 (4H,
m), 3.50-3.52 (4H, m), 4.95 (2
H, s), 5.01 (2H, s), 7.49-7.52.
(1H, m), 7.94-8.00 (3H, m), 8.
06-8.07 (1H, m), 8.71-8.72 (1
H, m), 8.767-8.774 (1H, s). MS (FAB) m / z 463 (M + H) ^<+> .

[1379] 2,3-Dihydro-1H used as a raw material
-Pyrrolo [3,4-c] pyridine was synthesized by the following method.

[1380] <2-benzyl-2,3-dihydro-1H
-Pyrrolo [3,4-c] pyridine> lithium aluminum hydride (2.55 g) in dry ether (150
ml) and stirred at 0 ° C. with stirring in a dry ether solution of ethyl 3,4-pyridinedicarboxylate (10 g) (100 g).
l) was added dropwise. After completion of the dropwise addition, the mixture was heated under reflux for 1 hour, allowed to cool, and then methanol (50 ml) and then a 1N hydrochloric acid ethanol solution (40 ml) were added. The precipitate was removed by celite filtration, and the solvent was distilled off under reduced pressure. Chloroform (50 ml) was added to the residue, and thionyl chloride (20 m
l) was added dropwise over 30 minutes. This was heated and refluxed for 1.5 hours while stirring. After allowing to cool, the mixture was added to a saturated aqueous sodium hydrogen carbonate solution and separated. The aqueous layer was extracted with dichloromethane, the organic layers were combined, washed with a saturated aqueous solution of sodium carbonate, and dried over anhydrous potassium carbonate. The solvent was distilled off under reduced pressure, and dichloromethane (100 ml) was added. Benzylamine (4.8 g) was added thereto, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to carry out liquid separation, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and then flash column chromatography on silica gel (SI-40).
D, dichloromethane: methanol = 9: 1)
The title compound (1.35 g) was obtained as a brown oil. _{^{1 H NMR (CDCl 3) 3.92}} (2H, s), 3.
93 (2H, s), 3.97 (2H, s), 7.14
(1H, d, J = 4.9 Hz), 7.27-7.41
(5H, m), 8.42 (1H, d, J = 4.9H)
z), 8.44 (1H, s). MS (FAB) m / z 211 (M + H) ⁺ .

<2,3-Dihydro-1H-pyrrolo [3,
4-c] pyridine> 2-benzyl-2,3-dihydro-
Dissolve 1H-pyrrolo [3,4-c] pyridine (1.03 g) in methanol (100 ml), add 1N hydrochloric acid (2.5 ml), 10% Pd / C (50% wet) and replace with hydrogen. Then, the mixture was stirred at room temperature for 23 hours. The palladium was removed by filtration and the solvent was dried while neutralizing the acid with potassium carbonate (1.5 g). After evaporating the solvent under reduced pressure, silica gel column chromatography (diameter 4 cm x 7 cm,
Purification with dichloromethane: methanol = 9: 1) gave the title compound (195 mg) as a crude product. ¹ H NMR (CD ₃ OD) 4.21 (2H, s), 4.
24 (2H.s), 7.39 (1H, d, J = 4.8H)
z), 8.36 (1H, d, J = 4.8 Hz), 8.4
7 (1H, s). No NH of the amine was observed.

Example 264 2-[[4-[(6-chlorobenzo [b] thien-2-
Yl) sulfonyl] piperazin-1-yl] carbonyl-2,3-dihydro-1H-pyrrolo [3,4-c] pyridine N-oxide

[1383]

Embedded image 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(2,3-dihydro-1H-pyrrolo [3,4-c] pyridin-2-yl) carbonyl] piperazine (113 mg) ) Was dissolved in dichloromethane (5 ml), m-chloroperbenzoic acid (84 mg,) was added,
Stirred at room temperature for 1 hour. A saturated aqueous sodium sulfite solution was added to the reaction solution, and the mixture was separated.The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure. The residue was purified by preparative TLC (dichloromethane: methanol = 9: 1). The obtained solid was dissolved in dichloromethane, and powdered by adding ether, to obtain the title compound (105 mg) as a white solid. _{^{1 H NMR (DMSO-d 6}} ) 3.10-3.11 (4
H, m), 3.33-3.36 (4H, m), 4.58
(2H, s), 4.61 (2H, s), 7.30 (1
H, d, J = 6.6 Hz), 7.59 (1H, dd, J)
= 8.7, 1.8 Hz), 8.06-8.10 (3H,
m), 8.18 (1H, s), 8.34 (1H, d, J
= 1.8 Hz). MS (FAB) m / z 479 (M + H) ^<+> .

Example 265 4-[(6-Chloronaphthalen-2-yl) sulfonyl] -1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-c] Pyridazin-2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine hydrochloride 1- (6-chloronaphthalen-2-ylsulfonyl) -3- (N-methylcarbamoyl) by a method similar to that in Example 236. Piperazine, and 5,6-dimethyl-4,
The title compound (127 mg) was obtained as a light brown solid from lithium 5,6,7-tetrahydrothiazolo [4,5-d] pyridazine-2-carboxylate (285 mg). ¹ H NMR (CDCl ₃ ) 2.60-4.57 (19
H, m), 5.23-6.52 (2H, m), 7.58
(1H, dd, J = 8.2 Hz), 7.78 (1H,
d, J = 8.2 Hz), 7.92-7.94 (4H,
m), 8.35 (1H, s). MS (FAB) m / z 563 (M + H) ^<+> .

The 1- (6-chloronaphthalen-2-ylsulfonyl) -3- (N-methylcarbamoyl) piperazine used as a starting material was synthesized by the following method.

<1- (6-Chloronaphthalen-2-ylsulfonyl) -3- (N-methylcarbamoyl) piperazine> 2- (N-methylcarbamoyl) piperazine 2
Acetate (1.58 g) was added to dichloromethane (20 ml), and triethylamine (1.6 ml) and 6-chloronaphthalene-2-sulfonyl chloride (1.57 g) were added thereto.
g) was added. After stirring at room temperature for 1 hour, triethylamine (0.83 ml) was added, and the mixture was further stirred for 2.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography using silica gel as a carrier (SI-40C, dichloromethane: methanol = 19: 1) to give the title compound (898 mg) as a white foamy solid. MS (FAB) m / z 368 (M + H) ^<+> .

Example 266 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(N-cyanomethyl-N-methylcarbamoyl) methyl] -1-[(5-methyl-4,5, 6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine hydrochloride N-cyanomethyl-N-methylamine (33.6 mg)
Of 1- (dimethylaminopropyl) -3-ethylcarbodiimide in a dichloromethane (5.0 ml) solution at room temperature.
Hydrochloride (92.0 mg), 2-carboxymethyl-4-
[(5-Chloroindol-2-yl) sulfonyl]-
1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine (215.2 mg), 1-hydroxybenzotriazole (54.0 mg) ) And N-methylmorpholine (0.052 ml) were added, and the mixture was stirred at room temperature for 2 days. The reaction solution was diluted with dichloromethane (50 ml), washed sequentially with distilled water, saturated aqueous sodium hydrogen carbonate, distilled water, and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1). This purified product was dissolved in ethanol (2.0 ml), 1N hydrochloric acid in ethanol (0.50 ml) was added, the mixture was stirred at room temperature for 1 hour, and the solvent was distilled off to give the title compound (181.8 mg,). Obtained as a colorless powder. IR (KBr) cm ^-1 3800-3200, 3114,
2923, 2800-2400, 1650, 1623,
1544, 1502, 1465, 1355, 1159. ¹ H NMR (DMSO-d ₆ ) 2.30-3.82 (1
5H, m), 4.23-4.80 (5.5H, m),
5.00-5.10 (0.5H, m), 5.30-5.
40 (0.5H, m), 5.65-5.85 (0.5
H, m), 7.03 (1H, s), 7.30 (1H, d
d, J = 8.9, 2.1 Hz), 7.47 (1H, d,
J = 8.9 Hz), 7.77 (1H, s), 11.29
(1H, brs), 12.46 (1H, s). MS (FAB) m / z 590 [(M + H) ⁺ , C
l ³⁵ ], 592 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 25 H 28 ClN 7 O} 4 S 2 · The HCl key 0.9H ₂ O
0.3EtOH Calculated: C, 46.83; H, 5.00; Cl, 10.
80; N, 14.93; S, 9.77. Analytical values: C, 47.03; H, 5.26; Cl, 10.
97; N, 14.72; S, 9.80.

Example 267 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(N-cyanomethylcarbamoyl) methyl] -1-[(5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride aminoacetonitrile hydrochloride and 2-carboxymethyl-4-[(5-chloroindol-2-yl) sulfonyl] -1- [(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl)
[Carbonyl] piperazine was obtained in the same manner as in Example 266 to give the title compound (162.1 mg) as a colorless powder. IR (KBr) cm ^-1 3700-2900, 2800-
2400,1671,1619,1542,1504
1465, 1421, 1353, 1159. ¹ H NMR (DMSO-d ₆ ) 2.30-3.82 (1
0H, m), 2.88 (3H, s), 4.00-4.1.
8 (2H, m), 4.30-4.60 (2.5H,
m), 5.00-5.12 (0.5H, m), 5.30
-5.40 (0.5H, m), 5.85-5.95
(0.5H, m), 7.02 (1H, s), 7.31
(1H, d, J = 8.9 Hz), 7.49 (1H, d,
J = 8.9 Hz), 7.76 (1H, s), 8.70 −
8.83 (1H, m), 11.38 (1H, br)
s), 12.43 (1H, s). MS (FAB) m / z 576 [(M + H) ⁺ , C
l ³⁵ ], 578 [(M + H) ⁺ , Cl ³⁷ ]. Elemental analysis: C ₂₄ H ₂₆ ClN ₇ O ₄ S ₂ HCl HCl 1.2 H ₂ O
As calculated: C, 45.45; H, 4.67; Cl, 11.
18; N, 15.46; S, 10.11. Theory C, 45.69; H, 4.97; Cl, 11.3.
9; N, 15.30; S, 10.01.

Example 268 4-[(5-Chloroindol-2-yl) sulfonyl] -2-cyanomethyl-1-[(5-methyl-4,
5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride 4-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -2- The title compound (94.7 mg,) was prepared in the same manner as in Example 236 from cyanomethylpiperazine and lithium 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylate. Was obtained as a yellow amorphous powder. IR (KBr) cm ^-1 3700-3300, 3012
2925, 2854, 2800-2300, 2250,
1623, 1544, 1502, 1463, 1417,
1357, 1160. _{^{1 H NMR (DMSO-d 6}} ) 2.60-2.80 (1
H, m), 2.90 (3H, s), 3.00-3.80.
(10H, m), 4.30-4.80 (2.5H,
m), 5.09 (0.5 H, s), 5.36 (0.5
H, d, J = 14.9 Hz), 6.09 (0.5 H,
s), 7.04 (1H, s), 7.30 (1H, dd,
J = 8.8, 2.0 Hz), 7.48 (1H, d, J =
8.8 Hz), 7.76 (1H, d, J = 2.0H)
z), 11.45 (1H, brs), 12.48 (1
H, brs). MS (FAB) m / z 519 [(M + H) ⁺ , C
l ³⁵ ], 521 [(M + H) ⁺ , Cl ³⁷ ].

The 4-[(5-chloro-1) used as a raw material
-Phenylsulfonylindol-2-yl) sulfonyl] -2-cyanomethylpiperazine was synthesized by the following method.

<2- (methoxycarbonyl) methylpiperazine diacetate> 1,4- (dibenzyl) -2- (methoxycarbonyl) methylpiperazine (10.15 g)
A 10% palladium on carbon catalyst (2.03 g) was suspended in a solution of acetic acid (90 ml) in water, and the suspension was cooled to room temperature under a hydrogen atmosphere at room temperature.
Stirred for hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure and dried to give the title compound (7.39 g) as a white solid.
IR (KBr) cm ^-1 3465, 2899, 2958,
1739, 1658, 657. _{^{1 H NMR (DMSO-d 6}} ) 1.84 (6H, s),
2.20-2.40 (4H, m), 2.50-3.00
(5H, m), 3.59 (3H, s). MS (FAB) m / z 159 (M + H) ^<+> .

<1,4-bis (tert-butoxycarbonyl) -2- (methoxycarbonyl) methylpiperazine> 2- (methoxycarbonyl) methylpiperazine 2
Acetate (7.37 g) in dichloromethane (200 ml)
Triethylamine (11.1 ml) was added to the suspension and 30
Stirred for minutes. Further, di (tert-butyl) dicarbonate (12.14 g) was added, and the mixture was stirred at room temperature for 18 hours. Distilled water (200 ml) was added to the reaction solution, and extracted with dichloromethane. 0.5N hydrochloric acid, distilled water,
The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (silica gel 300 g, hexane: ethyl acetate = 5: 1) to give the title compound (9.35 g) as a colorless waxy solid. ¹ H NMR (CDCl ₃ ) 1.45, 1.46 (18
H, each s), 2.40-2.65 (2H,
m), 2.70-3.10 (3H, m), 3.68 (3
H, s), 3.75-4.15 (3H, m), 4.50
-4.65 (1H, m). MS (FAB) m / z 359 (M + H) ^<+> .

<1,4-bis (tert-butoxycarbonyl) -2-carboxymethylpiperazine> 1,4-
To a solution of bis (tert-butoxycarbonyl) -2- (methoxycarbonyl) methylpiperazine (4.30 g) in tetrahydrofuran (30 ml) was added a 1N aqueous sodium hydroxide solution (20 ml), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, distilled water (30 ml) and 1
Normal hydrochloric acid (25 ml) was added, and the mixture was extracted with dichloromethane. The organic layer was washed with distilled water and saturated saline, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give the title compound (4.
16g) was obtained as a colorless foam. _{^{1 H NMR (DMSO-d 6}} ) 1.39 (18H,
s), 2.20-2.35 (0.5H, m), 2.40
-3.05 (3.5H, m), 3.23 (2H, s),
3.70-3.90 (2.5H, m), 4.33 (0.
5H, m), 12.34 (1H, s). MS (FAB) m / z 345 (M + H) ^<+> , 367
(M + H + Na) ⁺ .

<1,4-bis (tert-butoxycarbonyl) -2-carbamoylmethylpiperazine> 1,4
To a solution of -bis (tert-butoxycarbonyl) -2-carboxymethylpiperazine (1.03 g) in dimethylformamide (10 ml), di (tert-butyl) dicarbonate (1.96 g) and pyridine (0.607 m
l) and ammonium bicarbonate (0.52 g)
The mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, distilled water and dichloromethane were added to the residue, and the mixture was separated. The organic layer was washed sequentially with 0.5N hydrochloric acid, distilled water, saturated aqueous sodium hydrogen carbonate, distilled water, and saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated to dryness under reduced pressure to give the title compound (1.05 g) as a colorless candy. ¹ H NMR (CDCl ₃ ) 1.45, 1.47.1.4
9 (18H, eachs), 2.45-2.60 (2
H, m), 2.75-3.10 (3H, br m),
3.80-4.20 (4H, brm), 4.52 (2
H, brs), 5.20-5.55 (1H, br
m). MS (FAB) m / z 344 (M + H) ^<+> .

<1,4-bis (tert-butoxycarbonyl) -2-cyanomethylpiperazine> 1,4-bis (tert-butoxycarbonyl) -2-carbamoylmethylpiperazine (1.03 g) in dichloromethane (1
Pyridine (1.21 ml) and p-toluenesulfonyl chloride (1.23 g) were added to the solution.
Stirred for days. The reaction solution was diluted with dichloromethane (50 ml) and washed sequentially with distilled water, 1N aqueous sodium hydroxide solution, distilled water, and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
3: 1) to give the title compound (0.81 g) as a colorless waxy solid. IR (KBr) cm ⁻¹ 2981, 933, 2883,
2246, 1693, 1477, 1455, 1423
1402,1168. ¹ H NMR (CDCl ₃ ) 1.49 (18H, s),
2.50-3.15 (6H, brm), 3.80-
4.20 (2.5H, brm), 4.49 (0.5
H, brs). MS (FAB) m / z 326 (M + H) ⁺ .

<4-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -2-cyanomethylpiperazine> 1,4-bis- (tert-butoxycarbonyl) -2-cyanomethylpiperazine ( 34
To a solution of (1.7 mg) in dichloromethane (5.0 ml) were added thioanisole (1.23 ml) and trifluoroacetic acid (5.0 ml) at room temperature, and the mixture was stirred for 1 hour. Solvent and
After the trifluoroacetic acid was distilled off under reduced pressure, the residue was dissolved in dichloromethane (10 ml), and diisopropylethylamine (0.732 ml) and (5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl chloride (491) were added at room temperature. (0.7 mg) and stirred for 3 days. The reaction solution was diluted with methylene chloride (50 ml), washed with distilled water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (dichloromethane: methanol = 2).
0: 1) to give the title compound (183.0 mg) as a pale yellow foam. _{^{1 H NMR (CDCl 3) 2.50-2.56}} (2H,
m), 2.83-3.00 (2H, m), 3.05-
3.28 (3H, m), 3.30-3.50 (0.5
H, m), 3.60-3.70 (1H, m), 3.75
-3.90 (1H, m), 3.95-4.10 (0.5
H, m), 7.40-7.50 (4H, m), 7.50
−7.60 (2H, m), 7.98−8.05 (2H,
m), 8.21 (1H, d, J = 9.0 Hz). MS (FAB) m / z 479 [(M + H) ⁺ , C
l ³⁵ ], 481 [(M + H) ⁺ , Cl ³⁷ ].

Example 269 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (ethoxycarbonyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-
c] pyridin-2-yl) carbonyl] piperazine 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- (ethoxycarbonyl) piperazine and 5-methyl-4,5,6, From the lithium 7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylate, in the same manner as in Example 232,
The title compound was obtained as a yellow powder. ¹ H NMR (CDCl ₃ ) 1.20-1.32 (3H,
m), 2.42-3.35 (9H, m), 3.55-
3.90 (4H, m), 4.15-4.35 (2H,
m), 4.43 (1H, d, J = 12.0 Hz), 4.
56 (0.5 H, d, J = 14.2 Hz), 5.40
(0.5H, s), 5.78 (0.5H, d, J = 1
4.2Hz), 6.79 (0.5H, s), 6.98
(1H, s), 7.29 (1H, dd, J = 8.8,
1.8 Hz), 7.36 (1H, d, J = 8.8H)
z), 7.64 (1H, d, J = 1.8 Hz), 9.1
5-9.25 (1H, m).

Example 270 4-[(5-chloroindol-2-yl) sulfonyl] -2- (ethoxycarbonyl) -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5 , 4-
c] pyridin-2-yl) carbonyl] piperazine hydrochloride 4-[(5-chloroindol-2-yl) sulfonyl] -2- (ethoxycarbonyl) -1-[(5-methyl-4,5,6, 7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine (1
Was dissolved in ethanol (2.0 ml), and 1N hydrochloric acid in ethanol (0.3 ml) was added. After stirring for 10 minutes, the solvent was distilled off to obtain the title compound (90.0 mg) as a pale yellow powder. Was. IR (KBr) cm ^-1 3700-3300, 3106
2952, 2900-2300, 1735, 1629,
1544, 1504, 1465, 1357, 1159. ¹ H NMR (DMSO-d ₆ ) 1.10-1.25 (3
H, m), 2.30-3.80 (10H, m), 2.8
8 (3H, s), 4.10-4.25 (2H, m),
4.30-4.80 (2H, m), 4.42 (0.5
H, d, J = 13.2 Hz), 5.34 (0.5H,
s), 5.44 (0.5 H, d, J = 13.2 Hz),
6.34 (0.5H, s), 7.06 (1H, s),
7.31 (1H, dd, J = 8.8, 2.0 Hz),
7.48 (1H, d, J = 8.8 Hz), 7.77 (1
H, d, J = 2.0 Hz), 11.50 (1H, br)
s), 12.52 (1H, br s). MS (FAB) m / z 552 [(M + H) ⁺ , C
l ³⁵ ], 554 [(M + H) ⁺ , Cl ³⁷ ].

Example 271 2-Carboxy-4-[(5-chloroindole-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -2- (ethoxycarbonyl) -1-[( 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] pyridin-2-yl) carbonyl] piperazine (6
To a solution of 89.3 mg) in tetrahydrofuran (20 ml) was added a 1 N aqueous solution of sodium hydroxide (2.805 ml), and the mixture was stirred at room temperature for 2 days. The reaction solution was neutralized by adding 1 N hydrochloric acid (2.805 ml), and the solvent was distilled off under reduced pressure. The residue was evaporated to dryness to give the title compound (803.5 mg,)
Was obtained as a pale yellow powder. _{^{1 H NMR (DMSO-d 6}} ) 2.30-3.80 (1
2H, m), 4.23 (2H, d, J = 12.0H
z), 4.37 (0.5 H, J = 12.0 Hz), 5.
19 (0.5H, s), 5.48 (0.5H, d, J =
12.0 Hz), 6.40 (0.5 H, s), 7.04
(1H, s), 7.30 (1H, dd, J = 8.8,
2.0Hz), 7.49 (1H, d, J = 8.8H)
z), 7.75 (1H, d, J = 2.0 Hz), 12.
52 (1H, brs). MS (FAB) m / z 524 [(M + H) ⁺ , C
l ³⁵ ], 526 [(M + H) ⁺ , Cl ³⁷ ].

Example 272 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(N-cyanomethyl) carbamoyl] -1
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine hydrochloride 2-carboxy-4-[(5-chloroindole-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine (181.3 m
g) in dichloromethane (10.0 ml) at room temperature.
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (99.5 mg), aminoacetonitrile hydrochloride (32.0 mg), and N-methylmorpholine (0.114 ml) were added, and the mixture was stirred at room temperature for 18 hours. did. Dilute the reaction with dichloromethane (50 ml)
The extract was washed with distilled water, saturated aqueous sodium bicarbonate, distilled water and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1). This purified product was dissolved in ethanol (5.0 ml),
A 1N ethanol solution of hydrochloric acid (0.50 ml) was added, and the mixture was stirred at room temperature for 30 minutes, concentrated and dried to give the title compound (7
7.6 mg) as a colorless powder. IR (KBr) cm ^-1 3700-3200, 3016
2927, 2800-2400, 1731, 1685,
1627, 1542, 1504, 1463, 1355,
1157. _{^{1 H NMR (DMSO-d 6}} ) 2.30-4.80 (1
6.5H, m), 5.15 (0.5H, s), 5.55
(0.5H, d, J = 13.4 Hz), 6.06 (0.
5H, s), 7.01 (1H, d, J = 4.5 Hz),
7.30 (1H, dd, J = 8.72.0 Hz);
47 (1H, dd, J = 8.7, 4.3 Hz), 7.7
7 (1H, s), 11.38 (1H, brs), 1
2.46 (1H, s). MS (FAB) m / z 562 [(M + H) ⁺ -H, C
l ³⁵ ], 564 [(M + H) ⁺ -H, Cl ³⁷ ].

Example 273 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(N-cyanomethyl-N-methyl) carbamoyl] -1-[(5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl)
Carbonyl] piperazine hydrochloride 2-carboxy-4-[(5-chloroindole-2-
Yl) sulfonyl] -1-[(5-methyl-4,5,
The title compound (98.0 mg) was pale orange from 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine and N-methylaminoacetonitrile hydrochloride in the same manner as in Example 272. Obtained as a powder. IR (KBr) cm ^-1 3700-3200, 3116,
3008, 2938, 2869, 2800-2300,
1662, 1627, 1544, 1502, 1463,
1411, 1353, 1157. _{^{1 H NMR (DMSO-d 6}} ) 2.30-4.80 (1
9H, m), 5.25 (0.5H, d, J = 15.2H)
z), 5.43 (0.5H, s), 7.05 (1H,
s), 7.31 (1H, dd, J = 8.82.0H)
z), 7.46 (1H, dd, J = 13.4, 8.8H)
z), 7.76 (1H, s), 11.50-11.70
(1H, brm), 12.52 (1H, s). MS (FAB) m / z 576 [(M + H) ⁺ -H, C
l ³⁵ ], 578 [(M + H) ⁺ -H, Cl ³⁷ ].

Example 274 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(5,6-dimethyl-4,5,6,7-tetrahydrothia Zoro [4,
5-d] pyridazin-2-yl) carbonyl] piperazine hydrochloride 4-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -2- (2-cyanoethyl) piperazine and 5,6-dimethyl −4,5,6
7-tetrahydrothiazolo [4,5-d] pyridazine-
The title compound (235.1 mg,) was obtained as a pale yellow amorphous powder from lithium 2-carboxylate in the same manner as in Example 236. IR (KBr) cm ^-1 3700-3400, 3118,
2965, 2927, 2700-2400, 2246,
1693, 1621, 1546, 1502, 1469,
1355, 1160. _{^{1 H NMR (DMSO-d 6}} ) 1.95-2.12 (1
H, m), 2.20-2.40 (1H, m), 2.45
-2.95 (8H, m), 3.21-4.70 (10.
5H, m), 4.79 (0.5H, s), 5.31
(0.5H, d, J = 14.2 Hz), 5.54 (0.
5H, s), 7.01 (1H, d, J = 1.9 Hz),
7.30 (1H, dd, J = 8.8, 1.9 Hz),
7.48 (1H, d, J = 8.8 Hz), 7.76 (1
H, d, J = 1.9 Hz), 12.46 (1H, br)
s). MS (FAB) m / z 548 [(M + H) ⁺ , C
l ³⁵ ].

Example 275 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] Pyridazin-2-yl) carbonyl] -2-[(morpholinocarbonyl) methyl] piperazine hydrochloride 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- (morpholinocarbonyl) methylpiperazine And 5,6-dimethyl-4,
Example 23 was prepared from lithium 5,6,7-tetrahydrothiazolo [4,5-d] pyridazine-2-carboxylic acid lithium salt.
The title compound (383.3 mg,) was obtained in the same manner as in Example 6.
Was obtained as a pale orange amorphous powder. IR (KBr) cm ^-1 3800-3400, 3116,
2967, 2923, 2859, 1627, 1465,
1450, 1355, 1159. _{^{1 H NMR (DMSO-d 6}} ) 2.30-2.90 (1
0H, m), 2.98-3.20 (1H, m), 3.2
3-3.85 (10H, m), 4.20-4.60
(4.5H, m), 5.05 (0.5H, s), 5.3
0 (0.5H, d, J = 12.7Hz), 5.78
(0.5H, s), 7.02 (1H, d, J = 1.8H)
z), 7.30 (1H, dd, J = 8.81.8H)
z), 7.48 (1H, d, J = 8.8 Hz), 7.7
7 (1H, s), 12.46 (1H, s). MS (FAB) m / z 622 [(M + H) ⁺ , C
l ³⁵ ], 624 [(M + H) ⁺ , Cl ³⁷ ].

The raw material 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl]-
3- (morpholinocarbonyl) methylpiperazine was synthesized by the following method.

<1,4-bis (tert-butoxycarbonyl) -2- (morpholinocarbonyl) methylpiperazine> 1,4-bis (tert-butoxycarbonyl)
2-Carboxymethylpiperazine (2.41 g) in dichloromethane (50 ml) was added to 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide hydrochloride (1.48 g) and morpholine (1.40 ml) were added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with dichloromethane (200 ml) and washed sequentially with distilled water, 0.5N hydrochloric acid, distilled water, saturated aqueous sodium bicarbonate, distilled water, and saturated saline. After drying this solution over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (2.89 g) as a pale yellow foam. ¹ H NMR (CDCl ₃ ) 1.45, 1.46 (18
H, each s), 2.20-3.10 (5H,
m), 3.30-4.15 (11H, m), 4.59
(1H, s). MS (FAB) m / z 414 (M + H) ^<+> .

<3-[(morpholinocarbonyl) methyl] -1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] piperazine> 1,4
To a solution of -bis (tert-butoxycarbonyl) -2- (morpholinocarbonyl) methylpiperazine (0.82 g) in ethanol (10 ml) was added saturated ethanol (3).
0 ml) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was suspended in dichloromethane (20 ml), and diisopropylethylamine (1.40 ml) and
(5-chloro-1-phenylsulfonylindole-2
-Yl) sulfonyl chloride (0.94 g) was added and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with dichloromethane (10
0 ml), and washed sequentially with distilled water, saturated aqueous sodium bicarbonate, distilled water, and saturated saline. After drying over anhydrous sodium sulfate,
The solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography (dichloromethane: methanol = 20: 1).
To give the title compound (0.63 g,) as a pale yellow foam. ¹ H NMR (CDCl ₃ ) 2.30-2.50 (2H,
m), 2.80-3.15 (2H, m), 3.25-
3.35 (1H, m), 3.38-3.80 (9H,
m), 7.38-7.50 (4H, m), 7.52-
7.60 (2H, m), 8.00-8.05 (2H,
m), 8.21 (1H, d, J = 9.0 Hz). MS (FAB) m / z 567 [(M + H) ⁺ , C
l ³⁵ ], 569 [(M + H) ⁺ , Cl ³⁷ ].

Example 276 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-[(5-chloroindole- 2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] piperazine 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3-[(N, N- Dimethylcarbamoyl) methyl] piperazine and 6-ter
t-butyldiphenylsilyloxy-4,5,6,7-
From lithium tetrahydrobenzo [d] thiazole-2-carboxylic acid salt, in the same manner as in Example 232,
The title compound (217.3 mg) was obtained as a brown solid. ¹ H NMR (CDCl ₃ ) 1.02 (9H, s), 1.
80-2.05 (2H, brm), 2.50-3.2
0 (6H, m), 2.89 (3H, s), 2.96 (3
H, s), 3.25-3.42 (1H, m), 3.70
-3.88 (2H, m), 4.00-4.10 (0.5
H, m), 4.15-4.30 (1.5H, m), 4.
55-4.65 (0.5H, m), 5.05-5.15
(1H, m), 5.58 (1H, d, J = 14.4H
z), 5.95-6.20 (0.5H, m), 6.98
(1H, s), 7.25-7.30 (1H, m), 7.
32-7.48 (7H, m), 7.57-7.70 (5
H, m), 10.67, 10.72, 11.14 (1
H, each br s). MS (FAB) m / z 804 [(M + H) ⁺ , C
l ³⁵ ], 806 [(M + H) ⁺ , Cl ³⁷ ].

The starting material 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3-
[(N, N-dimethylcarbamoyl) methyl] piperazine was synthesized by the following method.

<1,4-bis (tert-butoxycarbonyl) -2-[(N, N-dimethylcarbamoyl) methyl] piperazine> [1,4-bis (tert-butoxycarbonylpiperazin-2-yl)] acetic acid (2.90
g) was dissolved in N, N-dimethylformamide (20 ml), dimethylamine hydrochloride (686 mg), 1-hydroxybenzotriazole monohydrate (1.29)
g), 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.26 g) and triethylamine (2.33 ml) were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, dichloromethane and water were added to the residue, liquid separation was performed, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (3.7 × 12 cm, hexane:
Purification by ethyl acetate = 3: 1) gave the title compound (3.
12g, 99%) as a colorless foamy solid. ¹ H NMR (CDCl ₃ ) 1.40-1.50 (18
H, m), 2.29 (1H, brs), 2.67-
3.14 (10H, m), 3.81-4.12 (3H,
m), 4.61 (1H, br s). MS (FAB) m / z 372 (M + H) ^<+> .

<1 [1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3-
[(N, N-dimethylcarbamoyl) methyl] piperazine> 1,4-bis (tert-butoxycarbonyl)-
To a solution of 2- (N, N-dimethylcarbamoyl) methylpiperazine (742.9 mg) in ethanol (10 ml) was added saturated ethanol (20 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and the residue was suspended in dichloromethane (20 ml). To this was added diisopropylethylamine (1.045 ml) and 1-[(5-
Chloro-1-phenylsulfonylindol-2-yl) sulfonyl chloride (936.6 mg) was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with dichloromethane (1
00 ml), washed sequentially with distilled water, saturated aqueous sodium bicarbonate, distilled water and saturated saline, dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (methylene chloride: methanol = 20: 1).
To give the title compound (544.6 mg) as a yellow foam. ¹ H NMR (CDCl ₃ ) 2.15 to 2.60 (4H,
m), 2.91 (3H, s), 2.96 (3H, s),
2.97-3.17 (2H, m), 3.25-3.35
(1H, m), 3.60-3.80 (2H, m), 7.
22 (1H, brs), 7.35-7.48 (4H,
m), 7.53-7.60 (2H, m), 8.01 (2
H, d, J = 7.6 Hz), 8.22 (1H, d, J =
9.0 Hz). MS (FAB) m / z 525 [(M + H) ⁺ , C
l ³⁵ ], 527 [(M + H) ⁺ , Cl ³⁷ ].

The raw material lithium 6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazole-2-carboxylate was synthesized by the following method.

<2-chloro-6-oxo-4,5,6>
7-tetrahydrobenzo [d] thiazole> 300 mL
2-Chloro-6,6-ethylenedioxy-4,5,6,7-tetrahydrobenzo [d] thiazole (Reference Example 282) (5.19 g) was added to an eggplant-shaped flask, and dissolved in methanol (50 mL). And concentrated hydrochloric acid (5 mL) was added, and the mixture was heated under reflux. After 3 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, neutralized with a saturated sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the residue obtained after evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (ethyl acetate: hexane: chloroform = 2: 6: 1) to give the title compound (2.7 g) , A pale yellow solid). ¹ H NMR (CDCl ₃ ) δ: 2.76 (2H, t, J
= 6.8 Hz), 3.13-3.18 (2H, m),
3.56 (2H, s). MS (FAB) m / z 188 [(M + H) ⁺ , C
l ³⁵ ], 190 [(M + H) ⁺ , Cl ³⁷ ].

[1413] <2-chloro-6-hydroxy-4,5,
6,7-tetrahydrobenzo [d] thiazole> 300
2-chloro-6-oxo-4,
5,6,7-Tetrahydrobenzo [d] thiazole (2.7 g) was added, dissolved in methanol (30 mL), sodium borohydride (816 mg) was added, and the mixture was stirred at room temperature. After 1 hour, the reaction was stopped, the solvent was distilled off under reduced pressure, chloroform was added, and the mixture was washed with saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained after evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (2.89 g, colorless oil) ) Got. ¹ H NMR (CDCl ₃ ) δ: 1.91 to 2.08 (2
H, m), 2.72-3.05 (4H, m), 4.23.
-4.28 (1H, m). MS (FAB) m / z 190 [(M + H) ⁺ , C
l ³⁵ ], 192 [(M + H) ⁺ , Cl ³⁷ ].

<2-Chloro-6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazole>
-Chloro-6-hydroxy-4,5,6,7-tetrahydrobenzo [d] thiazole (2.8 g) was added, dissolved in tetrahydrofuran (50 mL), imidazole (1.47 g), tert-butyldiphenylsilyl chloride. (4.35 g) was added and the mixture was stirred at room temperature. After 2 days, the reaction was stopped, the crystals were collected by filtration, the solvent was distilled off under reduced pressure, chloroform was added, and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained after evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (silica gel 100).
g, ethyl acetate: hexane = 1: 8) to give the title compound (6.17 g, colorless oil). ¹ H NMR (CDCl ₃ ) δ: 1.04 (9H, s),
1.82-2.00 (2H, m), 2.58-2.76
(3H, m), 2.88-2.95 (1H, m), 4.
17-4.23 (1H, m), 7.34-7.46 (6
H, m), 7.60-7.68 (4H, m). MS (FAB) m / z 428 [(M + H) ⁺ , C
l ³⁵ ], 430 [(M + H) ⁺ , Cl ³⁷ ].

<6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazole-2-carboxylic acid lithium salt> 2-Chloro-6-tert-butyldiphenyl was placed in a 100 mL three-necked flask. Silyloxy-4,5,6,7-tetrahydrobenzo [d] thiazole (1 g) was added and ether (15 m
L), cooled to -78 ° C and then 1.51 M tert.
-Butyl lithium (2.3 mL) was added and stirred. Further, 1.51 M tert-butyl lithium (1.15 m
After adding L), carbon dioxide gas was bubbled, and the bubbling was stopped after about 15 minutes, the reaction solution was returned to room temperature, and concentrated under reduced pressure to obtain the title compound (quantitative analysis, pale yellow amorphous). ¹ H NMR (DMSO-d ₆ ) δ: 0.99 (9H,
s), 1.83-1.92 (2H, m), 2.56-
2.88 (4H, m), 4.19-4.24 (1H,
m), 7.39-7.70 (10H, m).

Example 277 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] -1-[(6-hydroxy-4,5,6, 7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] piperazine

[1417]

Embedded image 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] piperazine (320.2
mg) in tetrahydrofuran (10 ml)
An ol / l tetrabutylammonium fluoride tetrahydrofuran solution (0.60 ml) was added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, distilled water and dichloromethane were added to the residue, and the mixture was separated. The organic layer was washed with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (silica gel 15).
g, dichloromethane: methanol = 50: 1 → 20:
Purification was performed in 1), and the solvent was distilled off. The residue was solidified with diethyl ether to give the title compound (156.9 mg, 70%) as a colorless powder. IR (KBr) cm ^-1 3388, 3212, 3021
2927, 1627, 1533, 1504, 1459,
1413, 1357, 1307, 1159. _{^{1 H NMR (DMSO-d 6}} ) 1.75-1.93 (2
H, m), 2.30-3.40 (14.5H, m),
3.48-3.62 (0.5H, m), 3.68-3.
82 (2H, m), 4.03 (1H, brs);
38 (0.5 H, d, J = 13.6 Hz), 4.95
(1H, d, J = 3.9 Hz), 5.00 (0.5H,
s), 5.38 (0.5 H, d, J = 13.6 Hz),
5.82 (0.5H, s), 7.02 (1H, s),
7.30 (1H, dd, J = 8.8, 2.0 Hz),
7.46 (1H, d, J = 8.8 Hz), 7.75 (1
H, d, J = 2.0 Hz), 12.41 (1H, s). MS (FAB) m / z 566 [(M + H) ⁺ , C
l ³⁵ ], 568 [(M + H) ⁺ , Cl ³⁷ ].

Example 278 2- [2- (tert-butyldimethylsilyloxy)
Ethyl] -1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-
[(5-Chloroindol-2-yl) sulfonyl] piperazine 3- [2- (tert-butyldiphenylsilyloxy) ethyl] -1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] Piperazine and lithium salt of 1- [6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazole-2-carboxylic acid (332.7 m
g) The title compound (410.6 mg, 82%) was obtained as a brown solid by a method similar to that of Example 232. ¹ H NMR (CDCl ₃ ) 1.02 (18H, each
s), 1.80-2.05 (2H, brm), 2.
30-3.90 (12H, m), 4.05-4.25
(1.5H, m), 4.45-4.60 (1H, m),
5.05-5.15 (0.5H, m), 5.60-5.
70 (0.5H, m), 5.85-6.10 (0.5
H, m), 6.90 (1H, s), 7.27-7.47.
(14H, m), 7.50-7.72 (11H, m),
8.76 (1H, brs). MS (FAB) m / z 1001 (M + H) ⁺ .

The starting material, 3- [2- (tert-butyldiphenylsilyloxy) ethyl] -1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] piperazine, was synthesized by the following method. .

<2- [2- (tert-Butyldiphenylsilyloxy) ethyl] piperazine dihydrochloride>
[2- (tert-Butyldiphenylsilyloxy) ethyl] -1,4-dibenzylpiperazine (8.20 g)
Concentrated methanol (200 ml) in concentrated hydrochloric acid (2.90 ml).
ml) and palladium hydroxide (1.00 g) were added.
The suspension was then vigorously stirred at room temperature under a hydrogen atmosphere for 6 hours. The catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (6.51 g) as a colorless solid. _{^{1 H NMR (DMSO-d 6}} ) 0.96,0.98,
1.01 (9H, eachs), 1.75-1.97
(2H, m), 3.05-3.80 (9H, each)
s), 7.30-7.41 (2H, m), 7.42-
7.53 (4H, m), 7.60-7.72 (4H,
m), 9.86 (2H, brs). MS (FAB) m / z 369 (M + H) ^<+> .

<14 [3- [2- (tert-Butyldiphenylsilyloxy) ethyl] -1-[(5-chloro-1-
Phenylsulfonylindol-2-yl) sulfonyl] piperazine> 2- [2- (tert-butyldiphenylsilyloxy) ethyl] piperazine dihydrochloride (3.
To a solution of 45 g) in dichloromethane (120 ml) was added diisopropylethylamine (5.44 ml), and the mixture was stirred at room temperature for 1 hour, and then (5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl chloride (3.
35 g) of a dichloromethane (80 ml) solution was added dropwise,
Stir at room temperature for 18 hours. After completion of the stirring, distilled water and dichloromethane were added, and the mixture was separated. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1 → 20: 1) to give the title compound (1.59 g, 28%) as a yellow foam. _{^{1 H NMR (CDCl 3) 0.98}} (9H, s), 1.
50-1.75 (2H, m), 2.66 (1H, dd,
J = 12.3, 10.1 Hz), 2.85-3.05
(4H, m), 3.70-3.90 (4H, m), 7.
30-7.48 (11H, m), 7.50-7.58
(2H, m), 7.60-7.66 (3H, m), 8.
01 (2H, dd, J = 8.4, 1.0 Hz), 8.2
1 (1H, d, J = 9.0 Hz). MS (FAB) m / z 722 [(M + H) ⁺ -H, C
l ³⁵ ], 724 [(M + H) ⁺ -H, Cl ³⁷ ].

Example 279 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (2-hydroxyethyl) -1-[(6-hydroxy-4,5,6,7-tetrahydrobenzo [ d]
Thiazol-2-yl) carbonyl] piperazine 2- [2- (tert-butyldimethylsilyloxy)
Ethyl] -1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-
[(5-Chloroindol-2-yl) sulfonyl] piperazine (404.6 mg) in tetrahydrofuran (1
0 ml) solution, a 1 mol / l tetrabutylammonium fluoride tetrahydrofuran solution (1.21 ml) was added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1), and the solvent was distilled off. The residue was solidified with diethyl ether to give the title compound (1
79.5 mg, 85%) as a colorless powder. IR (KBr) cm ^-1 3434, 3025, 2927,
2875, 1608, 1535, 1504, 1461,
1438, 1357, 1159. _{^{1 H NMR (DMSO-d 6}} ) 1.70-2.00 (4
H, m), 2.30-3.30 (7H, m), 3.38
-3.52 (2H, m), 3.60-3.80 (2H,
m), 4.03 (1H, brs), 4.32-4.4.
2 (0.5H, brm), 4.52 (1H, t, J =
5.2Hz), 4.82 (0.5H, brs), 4.9
6 (1H, d, J = 3.7 Hz), 5.25-5.35
(0.5H, m), 5.60 (0.5H, br s),
7.01 (1H, s), 7.31 (1H, dd, J =
8.8, 2.0 Hz), 7.47 (1H, d, J = 8.
8 Hz), 7.76 (1H, d, J = 2.0 Hz), 1
2.39 (1H, s). MS (FAB) m / z 525 [(M + H) ⁺ , C
l ³⁵ ], 527 [(M + H) ⁺ , Cl ³⁷ ].

Example 280 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-[(5-chloroindole- 2-yl) sulfonyl] -2-[(methoxycarbonyl) methyl] piperazine 1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3-[(methoxycarbonyl) methyl] piperazine and 1 -[6-tert-
The title compound was obtained as a brown foam from lithium butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazole-2-carboxylate in the same manner as in Example 232. ¹ H NMR (CDCl ₃ ) 1.02 (9H, s), 1.
80-2.05 (2H, brm), 2.50-3.2
0 (8H, m), 3.10-3.25 (0.5H,
m), 3.30-3.50 (0.5H, m), 3.55
-3.70 (3H, m), 3.75-3.90 (2H,
m), 4.15-4.25 (1H, m), 4.55-
4.70 (0.5H, m), 5.22 (0.5H, br)
s), 5.73 (0.5H, br s), 6.05-
6.20 (0.5H, m), 6.96 (1H, s),
7.27-7.50 (8H, m), 7.57-7.70
(5H, m), 9.11, 9.16 (1H, each
brs). MS (FAB) m / z 791 [(M + H) ⁺ , C
l ³⁵ ], 793 [(M + H) ⁺ , Cl ³⁷ ].

Example 281 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -2- (carboxymethyl) -4- [(5-Chloroindol-2-yl) sulfonyl] piperazine 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4 A 1 N aqueous solution of sodium hydroxide (0.60 ml) was added to a solution of-[(5-chloroindol-2-yl) sulfonyl] -2-[(methoxycarbonyl) methyl] piperazine (180.0 mg) in tetrahydrofuran (5.0 ml). Was added and stirred at room temperature for 2 days. The reaction solution was neutralized by adding a saturated aqueous solution of ammonium chloride, and extracted with dichloromethane. The organic layer was washed with distilled water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (178.1 m
g) was obtained as a pale yellow foam. _{^{1 H NMR (CDCl 3) 0.97}} (9H, s), 1.
70-1.95 (2H, m), 2.30-3.00 (5
H, m), 3.10-3.95 (6H, m), 4.23
(1H, brs), 4.33 (0.5H, br)
s), 4.97 (0.5H, br s), 5.32
(0.5H, brs), 5.76 (0.5H, brs)
s), 7.00 (1H, s), 7.27 (1H, d, J
= 8.6Hz), 7.35-7.50 (8H, m),
7.53 (1H, d, J = 6.8 Hz), 7.60 (1
H, d, J = 6.8 Hz), 12.89 (1H, br)
s). MS (FAB) m / z 777 [(M + H) ⁺ , C
l ³⁵ ], 779 [(M + H) ⁺ , Cl ³⁷ ].

Example 282 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-[(5-chloroindole- 2-yl) sulfonyl] -2- (morpholinocarbonylmethyl) piperazine 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl]- 1-Ethyl-3- (3-dimethylaminopropyl) at room temperature in a solution of 2- (carboxymethyl) -4-[(5-chloroindol-2-yl) sulfonyl] piperazine (175.6 mg) in dichloromethane (10 ml). Carbodiimide hydrochloride (6
6.1 mg), 1-hydroxybenzotriazole (3
1.1 mg) and morpholine (0.060 ml), and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with dichloromethane (50 ml), washed sequentially with distilled water, saturated aqueous sodium hydrogen carbonate, distilled water, and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane: methanol = 4).
0: 1 → 20: 1) to give the title compound (167.9).
mg) as a pale yellow foam. ¹ H NMR (CDCl ₃ ) 1.02 (9H, s), 1.
78-2.05 (2H, brm), 2.50-3.4
0 (7H, m), 3.50-3.85 (7H, m),
3.95-4.05 (0.5H, m), 4.12-4.
30 (2H, m), 4.55-4.68 (0.5H,
m), 4.95-5.03 (0.5H, m), 5.28
−5.35 (0.5H, m), 5.58 (0.5H, b)
rd, J = 14.2 Hz), 5.90-6.20
(0.5H, m), 6.99 (1H, s), 7.27-
7.50 (8H, m), 7.57-7.80 (5H,
m), 10.20 (0.5H, d, J = 23.9H)
z), 10.88 (0.5H, d, J = 14.7H)
z). MS (FAB) m / z 846 [(M + H) ⁺ , C
l ³⁵ ], 848 [(M + H) ⁺ , Cl ³⁷ ].

Example 283 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(6-hydroxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl ] -2- (morpholinocarbonylmethyl) piperazine 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-[(5 -Chloroindol-2-yl) sulfonyl] -2- (morpholinocarbonylmethyl) piperazine to give the title compound as a colorless powder in the same manner as in Example 277. IR (KBr) cm ^-1 3400-3300, 3133,
3021, 923, 1623, 1533, 1457,
1357, 1159. _{^{1 H NMR (DMSO-d 6}} ) 1.70-1.93 (2
H, m), 2.30-3.64 (17H, m), 3.6
8-3.82 (2H, m), 4.01 (1H, br)
s), 4.36 (0.5 H, d, J = 13.3 Hz),
4.94 (1H, d, J = 3.7 Hz), 5.02
(0.5H, s), 5.38 (0.5H, d, J = 1
3.3Hz), 5.75-5.80 (0.5H, br)
m), 7.01 (1H, s), 7.29 (1H, dd,
J = 8.9, 1.8 Hz), 7.45 (1H, d, J =
8.9 Hz), 7.74 (1H, d, J = 1.8H)
z), 12.40 (1H, s). MS (FAB) m / z 608 [(M + H) ⁺ , C
l ³⁵ ], 610 [(M + H) ⁺ , Cl ³⁷ ].

Example 284 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(6-hydroxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl ] -2-[(Methoxycarbonyl) methyl] piperazine 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4- [ The title compound (166.8 mg) was obtained as a colorless powder from (5-chloroindol-2-yl) sulfonyl] -2-[(methoxycarbonyl) methyl] piperazine by the method of Example 277. IR (KBr) cm ^-1 3399,3021,927,
2854, 1735, 1619, 1533, 1506
1159. ¹ H NMR (CDCl ₃ ) 1.95-2.15 (2H,
m), 2.50-3.25 (10H, m), 3.30-
3.95 (5H, m), 4.28 (1H, brs),
4.55-4.65 (0.5H, br m), 5.21
(0.5H, brs), 5.65-5.80 (0.5
H, br m), 6.15 (0.5H, br s),
6.95 (1H, d, J = 1.9 Hz), 7.30 (1
H, dd, J = 8.8, 1.9 Hz), 7.35 (1
H, d, J = 8.8H), 7.64 (1H, d, J =
1.9 Hz), 9.05 (1H, d, J = 15.9H)
z). MS (FAB) m / z 553 [(M + H) ⁺ , C
l ³⁵ ], 553 [(M + H) ⁺ , Cl ³⁷ ]. HRMS (FAB) m / z 553.0988 (M +
H) ⁺ (calculated C ₂₃ H ₂₆ ClN ₄ O ₆ S ₂ 553.098
2).

Example 285 2- (carboxymethyl) -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(6-hydroxy-4,5,6,7-tetrahydrobenzo [d] Thiazol-2-yl) carbonyl] piperazine 2- (carboxymethyl) -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(6-hydroxy-4,5,6,7-tetrahydrobenzo [D] thiazol-2-yl) carbonyl] piperazine (104.1)
mg)) in tetrahydrofuran (5.0 ml), 1N aqueous sodium hydroxide solution (0.40 ml) was added, and the mixture was stirred at room temperature for 18 hours. 1N hydrochloric acid (0.50
ml), distilled water and dichloromethane were added, and the mixture was separated. The organic layer was washed with distilled water and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (63.3 mg) as a colorless powder. IR (KBr) cm ^-1 3297,3023,2927,
1720, 1612, 1533, 1504, 1461,
1357, 1159. ¹ H NMR (DMSO-d ₃ ) 1.75-1.95 (2
H, m), 2.30-3.60 (7H, m), 3.65
-3.80 (4H, m), 4.02 (2H, brs),
4.32-4.45 (0.5H, brm), 4.90
−5.10 (1.5H, brm), 5.35−5.5
0 (0.5H, br m), 5.85 (0.5H, br
s), 7.02 (1H, s), 7.31 (1H, d
d, J = 8.8, 1.8 Hz), 7.47 (1H, d,
J = 8.8H), 7.76 (1H, d, J = 1.8H)
z), 12.43 (1H, s). MS (FAB) m / z 539 [(M + H) ⁺ , C
l ³⁵ ], 541 [(M + H) ⁺ , Cl ³⁷ ]. HRMS (FAB) m / z 539.0828 (M +
H) ⁺ (calculated C ₂₂ H ₂₄ ClN ₄ O ₆ S ₂ 539.082
6).

Example 286 2- [2- (tert-butyldimethylsilyloxy)
Ethyl] -1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-
[(5-Trimethylsilylethynylindol-2-yl) sulfonyl] piperazine 3- [2- (tert-butyldiphenylsilyloxy) ethyl] -1-[(1-phenylsulfonyl-5-
As in Example 232 using trimethylsilylethynylindol-2-yl) sulfonyl] piperazine and lithium 6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazole-2-carboxylate To give the title compound as a pale yellow foam. ¹ H NMR (CDCl ₃ ) 0.27 (9H, s), 1.
03 (18H, eachs), 1.70-2.10 (2
H, br m), 2.25-3.90 (12H, m),
4.05-4.30 (1.5H, m), 4.45-4.
60 (1H, m), 5.00-5.20 (0.5H,
m), 5.60-5.70 (0.5H, m), 5.80
−6.05 (0.5H, m), 6.93 (1H, s),
7.27-7.50 (14H, m), 7.52-7.7
2 (11H, m), 7.83 (1H, s), 8.69
(1H, brs). MS (ESI) m / z 1063 (M + H) ^<+> .

[1430] The 3- [2- (tert-
Butyldiphenylsilyloxy) ethyl] -1-[(1
-Phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine was synthesized by the following method.

[1431] <3- [2- (tert-Butyldiphenylsilyloxy) ethyl] -1-[(1-phenylsulfonyl-5-trimethylsilylethynylindole-2
-Yl) sulfonyl] piperazine> 2- [2- (ter
[t-Butyldiphenylsilyloxy) ethyl] piperazine dihydrochloride (Example 277) (3.05 g) was dissolved in dichloromethane (100 ml) and diisopropylethylamine (4.80 ml). Under ice cooling (1-phenylsulfonyl-5-trimethylsilylethynylindole-
(2-yl) sulfonyl chloride (2.46 g) was added, and the mixture was stirred at room temperature for 15 hours. After completion of the stirring, dichloromethane and water were added to carry out a liquid separation operation, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to flash column chromatography (3% methanol-dichloromethane) using silica gel as a carrier to obtain the title compound (1.12 g). ¹ H NMR (CDCl ₃ ) 0.25 (9H, s), 1.
02 (9H, s), 1.50-1.65 (2H, m),
2.60-2.70 (1H, m), 2.85-3.05
(4H, m), 3.70-3.80 (4H, m), 7.
35-7.45 (9H, m), 7.50-7.60 (2
H, m), 7.60-7.70 (5H, m), 7.95
−8.05 (2H, m), 8.21 (1H, d, J =
8.8 Hz). MS (FAB) m / z 784 (M + H) ^<+> .

143 and 3- (2-hydroxyethyl) -1
-[(1-Phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine (1.09 g) was obtained as a pale yellow foam. ¹ H NMR (CDCl ₃ ) 0.25 (9H, s), 1.
60-1.65 (2H, m), 2.65-2.75 (1
H, m), 2.85-3.00 (2H, m), 3.00
-3.10 (2H, m), 3.70-3.85 (4H,
m), 7.35-7.45 (3H, m), 7.50-
7.60 (2H, m), 7.65-7.70 (1H,
m), 7.95-8.05 (2H, m), 8.22 (1
H, d, J = 8.8 Hz). MS (FAB) m / z 546 (M + H) ^<+> .

Example 287 4-[(5-ethynylindol-2-yl) sulfonyl] -2- (2-hydroxyethyl) -1-[(6-hydroxy-4,5,6,7-tetrahydrobenzo [ d]
Thiazol-2-yl) carbonyl] piperazine 2- [2- (tert-butyldimethylsilyloxy)
Ethyl] -1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-
[(5-trimethylsilylethynylindol-2-yl) sulfonyl] The title compound was obtained as a colorless powder in the same manner as in Example 279 using piperazine. IR (KBr) cm ^-1 3218, 3120, 3025
2925, 2854, 2103, 1612, 1535,
1511, 1461, 1355, 1162. _{^{1 H NMR (DMSO-d 6}} ) 1.70-2.00 (4
H, m), 2.30-3.27 (7H, m), 3.35
-3.52 (2H, m), 3.58-3.80 (2H,
m), 4.03 (1H, brs), 4.32-4.4.
5 (0.5H, brm), 4.53 (1H, t, J =
4.7Hz), 4.82 (0.5H, brs), 4.9
6 (1H, d, J = 3.9 Hz), 5.30-5.40
(0.5H, m), 5.60 (0.5H, br s),
7.04 (1H, s), 7.36 (1H, dd, J =
8.6, 1.5 Hz), 7.45 (1H, d, J = 8.
6Hz), 7.85 (1H, s), 12.40 (1H,
s). MS (ESI) m / z 515 (M + H) ^<+> .

Example 288 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-[(5-chloroindole- 2-yl) sulfonyl] -2- [2- (imidazol-1-yl) ethyl] piperazine 4-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -2- [2- (imidazole -1-yl) ethyl] piperazine (299.4 mg)
Using dimethylformamide and 1- [6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazole-2-carboxylic acid lithium salt in the same manner as in Example 232, the title was obtained. The compound was obtained as a light brown foam. ¹ H NMR (CDCl ₃ ) 1.02 (9H, s), 1.
80-1.90 (1H, m), 1.90-2.05 (1
H, m), 2.10-3.05 (8H, m), 3.10
-4.15 (5H, m), 4.21 (1H, br)
s), 4.64 (0.5H, br d, J = 12.0H)
z), 4.86 (0.5H, s), 5.75 (0.5
H, d, J = 14.2 Hz), 5.85-6.10.
(0.5H, br m), 6.80-7.15 (3H,
m), 7.20-7.50 (8H, m), 7.52-
7.70 (6H, m), 10.10-10.50 (1
H, br m). MS (ESI) m / z 813 (M + H) ^<+> .

The starting material, 4-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl]-
2- [2- (Imidazol-1-yl) ethyl] piperazine was synthesized by the following method.

<1,4-Bis (tert-butoxycarbonyl) -2- [2- (imidazol-1-yl) ethyl] piperazine> of sodium hydride washed with hexane (oil-approximately 60%, 51.7 mg) Imidazole (7 mL) was added to a suspension of tetrahydrofuran (10.0 ml) at 0 ° C.
0.4 mg) and stirred at room temperature for 15 minutes. 1,4-bis (tert-butoxycarbonyl) -2 was added to the solution.
A solution of-(2-bromoethyl) piperazine (393 mg) in tetrahydrofuran (20 ml) was added, and the mixture was heated under reflux for 6 hours. After evaporating the solvent under reduced pressure, distilled water and dichloromethane were added, and the mixture was separated. The organic layer was washed with saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (silica gel 20 g,
Dichloromethane: methanol = 40: 1) to give the title compound (218.5 mg) as a pale brown solid. ¹ H NMR (CDCl ₃ ) 1.46, 1.47 (18
H, each s), 1.85-2.20 (2H, br)
m), 2.70-3.10 (3H, br m), 3.
80-4.20 (6H, m), 6.95 (1H, s),
7.06 (1H, s), 7.49 (1H, s). MS (FAB) m / z 381 (M + H) ^<+> .

<4-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -2- [2
-(Imidazol-1-yl) ethyl] piperazine>
1,4-bis (tert-butoxycarbonyl) -2-
To a solution of [2- (imidazol-1-yl) ethyl] piperazine (0.90 g) in ethanol (10 ml) was added a saturated hydrochloric acid ethanol solution (10 ml) at room temperature, and the mixture was stirred for 30 minutes. The reaction solution was concentrated to dryness under reduced pressure, and the residue was suspended in dichloromethane (10 ml). After adding diisopropylethylamine (2.06 ml) and stirring at room temperature for 30 minutes,
(5-chloro-1-phenylsulfonylindole-2
-Yl) sulfonyl chloride (1.11 g) and 2
Stirred for days. The reaction solution was diluted with dichloromethane (50 ml), washed sequentially with distilled water, saturated aqueous sodium hydrogen carbonate, distilled water, and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (silica gel 50 g, dichloromethane: methanol = 1).
00: 1 → 50: 1 → 20: 1) to give the title compound (0.46 g,) as a yellow foam. _{^{1 H NMR (DMSO-d 6}} ) 1.65-1.77 (1
H, m), 1.78-1.90 (1H, m), 2.48
(2H, t, J = 7.6 Hz), 2.70 (1H, d
d, J = 12.5, 9.5 Hz), 2.85-3.10
(4H, m), 3.62-3.70 (1H, m), 3.
75-3.85 (1H, m), 7.40-7.50 (4
H, m), 7.55-7.60 (2H, m), 8.01.
(2H, dd, J = 8.6, 1.2 Hz), 8.22
(1H, d, J = 9.0 Hz). MS (FAB) m / z 534 [(M + H) ⁺ , C
l ³⁵ ].

Example 289 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(6-hydroxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl ] -2- [2- (Imidazol-1-yl) ethyl]
Piperazine hydrochloride 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-[(5-chloroindol-2-yl ) Sulfonyl] -2- [2- (imidazol-1-yl) ethyl] piperazine (210.0 m
g) in tetrahydrofuran (10 ml)
A mol / l tetrabutylammonium fluoride tetrahydrofuran solution (0.39 ml) was added, and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, distilled water and dichloromethane were added to the residue, and the mixture was separated. The organic layer was washed with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (dichloromethane:
Purified by methanol = 20: 1 → 10: 1). This purified product was dissolved in ethanol (3.0 ml), a 1 N ethanol solution of hydrochloric acid (0.50 ml) was added, and the mixture was stirred for 30 minutes, and then the solvent was distilled off. The residue was solidified with diethyl ether to give the title compound (126.6 mg) as a colorless powder. IR (KBr) cm ^-1 3388, 3106, 2917,
2800-2300, 2246, 1619, 1544,
1504, 1465, 1423, 1355, 1307,
1274, 1230, 1159. _{^{1 H NMR (DMSO-d 6}} ) 1.50-1.95 (4
H, m), 2.15-3.82 (10H, m), 3.9
7-4.10 (1H, m), 4.10-4.30 (2
H, m), 4.47-4.52 (0.5H, m), 4.
68-4.77 (0.5H, m), 5.55-5.67
(0.5H, m), 5.75-5.90 (0.5H,
m), 7.01 (1H, s), 7.29 (1H, dd,
J = 8.8, 2.0 Hz), 7.48 (1H, d, J =
8.8 Hz), 7.60-7.85 (3H, m), 9.
10 (1H, s), 12.47 (1H, s), 14.5
3 (1H, brs). MS (ESI) m / z 575 [(M + H) ^<+> , C
l ³⁵ ], 577 [(M + H) ⁺ , Cl ³⁷ ].

Example 290 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -2-[(N, N-dimethyl Carbamoyl) methyl] -4-[(5-trimethylsilylindol-2-yl) sulfonyl] piperazine 3- [2- (N, N-dimethylcarbamoyl) methyl]
Piperazine-1-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl]-and 1- [6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] The title compound was obtained as a brown solid from the lithium thiazole-2-carboxylate in the same manner as in Example 232. ¹ H NMR (CDCl ₃ ) 0.26 (9H, s), 1.
03 (9H, s), 1.78-2.05 (2H, br
m), 2.55-3.40 (15H, m), 3.68-
3.83 (1H, m), 3.98-4.10 (0.5
H, m), 4.05-4.25 (1.5H, m), 4.
54-4.65 (0.5H, m), 5.02-5.10.
(0.5H, m), 5.50-5.60 (0.5H,
m), 5.95-6.20 (0.5H, m), 7.00
(1H, s), 7.27-7.50 (8H, m), 7.
57-7.70 (4H, m), 8.82 (1H, s). MS (ESI) m / z 866 (M + H) ^<+> .

The raw material 3- [2- (N, N-dimethylcarbamoyl) methyl] -1-[(1-phenylsulfonyl-5-trimethylsilylethynylindole-2-
Il) sulfonyl] piperazine was synthesized by the following method.

<1,4-Dibenzyl-2- (dimethylaminocarbonylmethyl) piperazine> 1,4-Dibenzyl-2- (methoxycarbonylmethyl) piperazine (2
0.1 g) was dissolved in methanol (100 ml), a solution of sodium hydroxide (4.90 g) / water (50 ml) was added, and the mixture was heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, and concentrated hydrochloric acid (10 ml) and water (50 ml) were added to the obtained residue, and methanol was further added to completely dissolve the residue. Purified product (24.6 g)
I got Then, a part (23.7 g) of this crude product
With N, N-dimethylformamide (200 ml) and diisopropylethylamine (30.3 ml, 22.
3g) and dimethylamine hydrochloride (4.73).
g), 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11.0 g) and 1-hydroxybenzotriazole (3.53 g) were added, and the mixture was stirred at room temperature for 66.5 hours. The reaction solution was evaporated under reduced pressure, water and dichloromethane were added to the residue, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane → 1% to 10% methanol-dichloromethane) to obtain the title compound (10.3 g, yellow oil). ¹ H NMR (CDCl ₃ ) 2.35-2.50 (4H,
m), 2.50-2.85 (4H, m), 2.88 (3
H, s), 2.99 (3H, s), 3.35-3.60.
(4H, m), 3.65-3.75 (1H, m), 7.
20-7.40 (10H, m). MS (ESI) m / z 352 (M + H) ^<+> .

<3- (dimethylaminocarbonylmethyl) -1-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl]
Piperazine> 1,4-dibenzyl-2- (dimethylaminocarbonylmethyl) piperazine (5.01 g) was dissolved in methanol (150 ml) and concentrated hydrochloric acid (2.40 ml), and palladium hydroxide (350 mg) was added to the reaction solution. Suspended. The suspension was then vigorously shaken at room temperature under a hydrogen atmosphere for 3.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was treated with dichloromethane (16
0 ml) and triethylamine (8.00 ml, 5.8).
1g) and (1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl chloride (5.18 g) were added under ice-cooling, and the mixture was stirred for 14 hours while gradually warming from 0 ° C to room temperature. Water was added to carry out a liquid separation operation, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane → 2% to 5% methanol-dichloromethane) to obtain the title compound (4.41 g, pale yellow amorphous). ¹ H NMR (CDCl ₃ ) 0.25 (9H, s), 2.
05-2.20 (2H, m), 2.55-2.85 (4
H, m), 2.66 (3H, s), 2.71 (3H,
s), 3.20-3.30 (1H, m), 3.65-
3.75 (2H, m), 7.35-7.45 (3H,
m), 7.50-7.60 (2H, m), 7.65-
7.70 (1H, m), 7.95-8.05 (2H,
m), 8.21 (1H, d, J = 9.0 Hz). MS (ESI) m / z 587 (M + H) ^<+> .

Example 291 4-[(5-ethynylindol-2-yl) sulfonyl] -2-[(N, N-dimethylcarbamoyl) methyl] -1-[(6-hydroxy-4,5,6, 7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] piperazine 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] The title compound was obtained as a colorless powder from 2--2-[(N, N-dimethylcarbamoyl) methyl] -4-[(5-trimethylsilylindol-2-yl) sulfonyl] piperazine in the same manner as in Example 279. IR (KBr) cm ^-1 3434, 3399, 3282,
3120,3021,927,2854,2103,
1627, 1459, 1357, 1162. _{^{1 H NMR (DMSO-d 6}} ) 1.74-1.95 (4
H, m), 2.30-3.65 (15H, m), 3.7
0-3.85 (2H, m), 4.03 (2H, br)
s), 4.35-4.45 (0.5H, brm),
4.95 (1H, d, J = 3.7 Hz), 4.97−
5.10 (0.5H, brm), 5.31-5.45
(0.5H, br m), 5.81 (0.5H, br
s), 7.05 (1H, s), 7.35 (1H, dd,
J = 8.6, 1.3 Hz), 7.44 (1H, d, J =
8.6 Hz), 7.86 (1H, s), 12.42 (1
H, s). MS (FAB) m / z 556 (M + H) ^<+> .

Example 292 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[[N- (2-hydroxyethyl) -N-methylcarbamoyl] methyl] -1-[(5-methyl −
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine hydrochloride N-methylethanolamine and 2-carboxymethyl-4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5, The title compound was obtained as a pale yellow powder in the same manner as in Example 272 using 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine. IR (KBr) 3500-3300, 3114, 292
3,2800-2400,1735,1623,154
4,1502,1465,1355,1159 cm ^-1 . _{^{1 H NMR (DMSO-d 6}} ) 2.30-3.85 (1
8H, m), 2.91 (3H, s), 4.30-4.4
5 (2H, m), 4.50-4.75 (1.5H,
m), 5.00-5.10 (0.5H, m), 5.25
−5.40 (0.5H, m), 5.68-5.80
(0.5H, m), 7.02 (1H, s), 7.30
(1H, dd, J = 8.91.7 Hz), 7.47 (1
H, d, J = 8.9 Hz), 7.77 (1H, s), 1
1.11 (1H, brs), 12.45 (1H, brs)
s). FAB-MSm / z 595 [(M + H) ⁺ , C
l ³⁵ ], 597 [(M + H) ⁺ , Cl ³⁷ ].

Example 293 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[[N-methyl-N- (2-methoxyethyl) carbamoyl] methyl] -1-[(5-methyl −
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine hydrochloride N, O-dimethylethanolamine and 2-carboxymethyl-4-[(5-chloroindol-2-yl)
The title compound was obtained from sulfonyl] -1- [5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine in the same manner as in Example 272 to give the title compound. Obtained as a pale yellow powder. IR (KBr) 3500-3200, 3107, 292
5,2700-2400,1627,1544,150
2,1465,1159 cm ^-1 . _{^{1 H NMR (DMSO-d 6}} ) 2.30-3.82 (2
1H, m), 2.82 (3H, s), 3.21, 3.2
2, 3.23, 3.27 (6H, each s);
30-4.50 (2H, m), 4.55-4.75
(0.5H, m), 5.00-5.10 (0.5H,
m), 5.28-5.38 (0.5H, m), 5.65
−5.75 (0.5H, m), 6.99 (1H, d, J)
= 2.0 Hz), 7.29 (1H, dd, J = 8.8)
2.0 Hz), 7.46 (1H, d, J = 8.8H)
z), 7.75 (1H, s), 11.23 (1H, br)
s), 12.43 (1H, s). FAB-MSm / z 609 [(M + H) ⁺ , C
l ³⁵ ], 611 [(M + H) ⁺ , Cl ³⁷ ].

Example 294 4-[(5-chloroindol-2-yl) sulfonyl] -2- [2- (imidazol-1-yl) ethyl]
-1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine dihydrochloride 4-[(5-chloro-1-phenyl) Sulfonylindol-2-yl) sulfonyl] -2- [2- (imidazol-1-yl) ethyl] piperazine and 5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
From lithium pyridine-2-carboxylate, Example 2
The title compound was obtained as a pale orange powder in the same manner as in 36. IR (KBr) cm ^-1 3388, 3099, 3010,
2952, 2925, 2856, 2800-230
0,1731,1616,1575,1544,146
3,1355,1159. _{^{1 H NMR (DMSO-d 6}} ) 2.15-2.45 (2
H, br m), 2.2.60-2.75 (1H,
m), 2.90 (3H, s), 3.05-3.85 (8
H, br m), 4.10-4.20 (2H, m),
4.30-4.85 (2.5H, m), 5.35-5.
55 (1H, m), 5.65-5.75 (0.5H,
m), 7.02 (1H, s), 7.29 (1H, dd,
J = 8.9, 1.5 Hz), 7.48 (1H, d, J =
8.9 Hz), 7.60-7.90 (3H, m), 9.
02, 9.12 (1H, each s), 12.47
(1H, brs). MS (FAB) m / z 574 [(M + H) ⁺ , C
l ³⁵ ], 576 [(M + H) ⁺ , Cl ³⁷ ]. HRMS (FAB) m / z 574.14664 (M +
H) ⁺ (calculated C ₂₅ H ₂₉ ClN ₇ O ₃ S ₂ 574.146
2).

Example 295 1-[[5-Chloro-1- [2- (trimethylsilyl)]
Ethoxy] indol-2-yl] sulfonyl] -4-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine 1-tert-butoxycarbonyl-4-[(5-methyl-4, 5,6,7-tetrahydrothiazolo [5,4-
To a solution of c] pyridin-2-yl) carbonyl] piperazine (0.154 g, 0.420 mmol) in dioxane (5 ml) was added 4N hydrochloric acid / dioxane (5 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure,
It was azeotroped three times with methanol and three times with ether. Dichloromethane (10 ml) was added to the obtained 1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine, and
After cooling to 0 ° C., triethylamine (2.5 ml),
5-chloro-2-chlorosulfonyl-1- [2-
(Trimethylsilyl) ethoxy] indole (0.64
5 mmol) in dichloromethane (5 ml)
The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1 day. The reaction solution was diluted with water, separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. Flash column chromatography using silica gel as carrier (SI-40A, dichloromethane / methanol = 1 / 0-100 / 1-50)
/ 1-10 / 1) to give the title compound (0.
135 g,) was obtained as a light brown amorphous. ¹ H NMR (CDCl ₃ ) 0.06 (9H, s), 1.
19-1.25 (2H, m), 2.48 (3H, s),
2.78-2.81 (2H, m), 2.87-2.90
(2H, m), 3.29 (2H, broad), 3.3
6 (2H, broad), 3.67 (2H, s), 3.
84 (2H, broad), 4.38-4.42 (2
H, m), 4.50 (2H, broad), 6.88.
(1H, s), 7.34-7.35 (2H, m), 7.
61 (1H, d, J = 0.9 Hz). MS (ESI) m / z 596 [(M + H) ^<+> , C
l ³⁵ ], 598 [(M + H) ⁺ , Cl ³⁷ ].

The starting material 5-chloro-2-chlorosulfonyl-1- [2- (trimethylsilyl) ethoxy] indole was synthesized by the following method.

<5-chloro-1- [2- (trimethylsilyl) ethoxy] -2-oxindole> 5-chloro-2-nitrophenylacetic acid (1.26 gl), platinum-activated carbon (Pt 5%, 38 mg), Dimethyl sulfoxide (0.505 ml) in 95% aqueous ethanol (63 m
l) The suspension was stirred under a hydrogen atmosphere for 5 hours. After filtering the reaction mixture through celite, the filtrate was concentrated under reduced pressure. Water (30 ml) and sulfuric acid (0.75 ml) were added to the residue,
Stirred for hours. The resulting solid was collected by filtration and washed with water to obtain a crude product containing 5-chloro-1-hydroxyoxindole. The obtained crude product and 2- (trimethylsilyl) ethanol (0.575 ml), triphenylphosphine (1.05 g) in dichloromethane (2
0 ml) The suspension was cooled to 0 ° C., diethyl azodicarboxylate (0.630 ml) was added, and the mixture was stirred for 5 hours while gradually returning to room temperature. After concentrating the reaction solution under reduced pressure, flash column chromatography using silica gel as a carrier (SI-40B, ethyl acetate / hexane = 0 / 1-1)
/ 9) to give the title compound (0.235 g)
Was obtained as a colorless flocculent solid. _{^{1 H NMR (CDCl 3) 0.05}} (9H, s), 1.
15-1.19 (2H, m), 3.49 (2H, s),
4.22-4.26 (2H, m), 6.87 (1H,
d, J = 8.3 Hz), 7.21 (1H, broa)
d), 7.26-7.29 (1H, m). MS (FAB) m / z 284 [(M + H) ⁺ , C
l ³⁵ ], 286 [(M + H) ⁺ , Cl ³⁷ ].

<5-chloro-1- [2- (trimethylsilyl) ethoxy] indole> 5-chloro-1- [2-
(Trimethylsilyl) ethoxy] -2-oxindole (0.232 g) in tetrahydrofuran (5 ml) was cooled to −78 ° C., and diisobutylaluminum hydride (0.95 M in hexane, 1.30 ml) was added over 5 minutes. Stir for 1.5 hours. 10% hydrochloric acid (10
ml), and extracted twice with ether. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Silica gel column chromatography (hexane)
The title compound (0.179 g) was obtained as a colorless oil. _{^{1 H NMR (CDCl 3) 0.05}} (9H, s), 1.
13-1.17 (2H, m), 4.25-4.29 (2
H, m), 6.28 (1H, dd, J = 0.9, 3.4).
Hz), 7.17 (1H, dd, J = 1.8, 8.8H)
z), 7.25-7.26 (1H, m), 7.33 (1
H, d, J = 8.8 Hz), 7.54 (1H, d, J =
1.8 Hz). MS (FAB) m / z 268 [(M + H) ⁺ , C
l ³⁵ ], 270 [(M + H) ⁺ , Cl ³⁷ ].

[1451] <5-chloro-2-chlorosulfonyl-1
-[2- (Trimethylsilyl) ethoxy] indole>
A solution of 5-chloro-1- [2- (trimethylsilyl) ethoxy] indole (0.173 g) in tetrahydrofuran (10 ml) was cooled to -78 ° C, and tert-butyllithium (1.54 M solution in pentane, 0.500 m
After l) was added little by little, the temperature was raised to -20 ° C. After cooling again to −78 ° C., sulfur dioxide was introduced over a period of 20 minutes. The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, hexane was added to the residue, and the mixture was concentrated again under reduced pressure. Dichloromethane (10 ml) was added to the residue,
After cooling to 0 ° C, N-chlorosuccinimide (0.1
The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours. Dichloromethane and water were added to the reaction solution, and after separation, the aqueous layer was extracted with dichloromethane. The dichloromethane layers were combined, concentrated under reduced pressure, and then subjected to flash column chromatography (SI-40A, hexane) using silica gel as a carrier to obtain a crude title compound.

The starting material 1-tert-butoxycarbonyl-4-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine is as follows: Was synthesized by the method described above.

[1453] <1-tert-butoxycarbonyl-4>
-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl]
Piperazine> tert-butyl 1-piperazinecarboxylate (0.372 g), 5-methyl-4,5,6,7-
A solution of lithium tetrahydrothiazolo [5,4-c] pyridine-2-carboxylate (0.453 g) and 1-hydroxybenzotriazole (0.270 g) in N, N-dimethylformamide (20 ml) was cooled to 0 ° C. And 1
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.383 g) was added, and the mixture was stirred at 0 ° C for 1 hour and at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure,
The residue was diluted with ethyl acetate and water. After separation, the aqueous layer was extracted with ethyl acetate. Combine the organic layers and wash with saturated brine,
After drying over sodium sulfate, the mixture was concentrated under reduced pressure. Flash column chromatography using silica gel as carrier (SI-40B, methanol / dichloromethane = 1 /
25) to give the title compound (0.338 g)
Was obtained as a light brown solid. ¹ H NMR (CDCl ₃ ) 1.47 (9H, s), 2.
51 (3H, s), 2.81-2.84 (2H, m),
2.92-2.95 (2H, m), 3.50-3.53
(4H, m), 3.70-3.71 (2H, m), 3.
74 (2H, broad), 4.37 (2H, broad)
d). MS (FAB) m / z 367 (M + H) ^<+> .

Example 296 1-[(5-chloro-1-hydroxyindole-2-
Yl) sulfonyl] -4-[(5-methyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine

[1455]

Embedded image 1-[[5-chloro-1- [2- (trimethylsilyl)
Ethoxy] indol-2-yl] sulfonyl] -4-
[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine (0.135 g) in tetrahydrofuran (3 m
l) Add tetrabutylammonium fluoride (1.
(0M tetrahydrofuran solution, 0.230 ml) and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure at room temperature. The residue was diluted with ether, ethyl acetate and water. After separation, the organic layer was washed with saturated saline. After drying over sodium sulfate, the mixture was concentrated under reduced pressure at room temperature. The residue was washed twice with ether and dissolved in ethyl acetate, and then washed three times with water and once with a saturated saline solution. After drying over sodium sulfate, concentrate under reduced pressure,
The residue was washed three times with ether to give the title compound (8
1.7 mg) as a light brown powder. IR (KBr) cm ^-1 3436, 2925, 2856,
2792, 1735, 1623, 1542, 1473,
1450, 1359, 1278, 1247, 1220,
1162,1103,1056,995,943,88
5,850,796,755,711. _{^{1 H NMR (DMSO-d 6}} ) 2.37 (3H, s),
2.71-2.74 (2H, m), 2.78-2.79
(2H, m), 3.33 (4H, broad), 3.6
3. (2H, s), 3.73 (2H, broad), 4.
40 (2H, broad), 6.94 (1H, s),
7.34 (1H, dd, J = 1.9, 8.7 Hz),
7.46 (1H, d, J = 8.7 Hz), 7.74 (1
H, d, J = 1.9 Hz). MS (ESI) m / z 496 [(M + H) ^<+> , C
l ³⁵ ], 498 [(M + H) ⁺ , Cl ³⁷ ].

Example 297 4-[(5-Chloroindol-2-yl) rusphonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2- [2- (2-oxopyrrolidin-1-yl) ethyl] piperazine hydrochloride 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [2- (2-oxopyrrolidin-1-yl) ethyl] piperazine and 5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] The title compound as a pale yellow powder was obtained in the same manner as in Example 236 using lithium pyridine-2-carboxylate. IR (KBr) cm ^-1 3396, 3106, 2925,
2867, 1660, 1619, 1544, 1502
1465, 1355, 1307, 1272, 1230,
1159, 1120, 1095, 1058, 1014
952, 916, 877, 809, 742. _{^{1 H NMR (DMSO-d 6}} ) 1.89-1.92 (4
H, m), 2.12-2.20 (2H, m), 2.92
(3H, s), 3.09-3.19 (5H, m), 3.
41-3.49 (2H, m), 3.69-3.81 (4
H, m), 4.41 (2H, broad), 4.63-
4.72 (2H, m), 4.71 (1H, broa
d), 5.34-5.37 (1H, m), 7.01 (1
H, s), 7.28-7.31 (1H, m), 7.47.
(1H, d, J = 8.7 Hz), 7.75 (1H,
s), 12.42 (1H, s). MS (FAB) m / z 591 [(M + H) ⁺ , C
l ³⁵ ], 593 [(M + H) ⁺ , Cl ³⁷ ].

The 1-[(5-chloro-1) used as a raw material
-Phenylsulfonylindol-2-yl) sulfonyl] -3- [2- (2-oxopyrrolidin-1-yl)
[Ethyl] piperazine was synthesized by the following method.

<1,4-bis (tert-butoxycarbonyl) -2- (2-tosyloxyethyl) piperazine> 1,4-bis (tert-butoxycarbonyl) -2
-(2-hydroxyethyl) piperazine (5.05
g), a solution of p-toluenesulfonyl chloride (4.34 g,) in dichloromethane (200 ml) was cooled to 0 ° C, and triethylamine (11.0 ml) was added dropwise. 1 at 0 ° C
For 1 day at room temperature. The reaction solution was concentrated under reduced pressure,
The residue was diluted with ethyl acetate, washed with 1N hydrochloric acid, water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure.
Flash column chromatography using silica gel as carrier (SI-40D, ethyl acetate / hexane =
(1 / 4-1 / 1) to give the title compound (4.82).
g) was obtained as a colorless solid. IR (KBr) cm ^-1 2981, 2863, 1681,
1596, 1479, 1421, 1392, 1369,
1355, 1336, 1297, 1278, 1245
1232, 1187, 1174, 1135, 1110,
1097, 1004, 970, 933, 890, 85
8,821,765. ¹ H NMR (CDCl ₃ ) 1.44 (18H, s),
1.78-1.84 (1H, m), 1.94 (1H, b
load), 2.44 (3H, s), 2.86 (3H,
broad), 3.85 (2H, broad), 3.9
7-4.07 (3H, m), 4.21 (1H, broa
d), 7.33 (2H, d, J = 8.3 Hz), 7.7
7 (2H, d, J = 8.3 Hz). MS (FAB) m / z 485 (M + H) ^<+> .

<1,4-bis (tert-butoxycarbonyl) -2- [2- (2-oxopyrrolidin-1-yl) ethyl] piperazine> Sodium hydride (60% o
il, 42.0 mg) in tetrahydrofuran (20 m
l) To the suspension was added -pyrrolidone (76.0 l) and N, N-dimethylformamide (20 ml).
Stirred for minutes. 1,4-Bis (tert-butoxycarbonyl) -2- (2-tosyloxyethyl) piperazine (0.484 g) was added, and the mixture was stirred at 50 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (ethyl acetate / hexane = 1/1/1/0) gave the title compound (0.256 g) as a colorless solid. ¹ H NMR (CDCl ₃ ) 1.46 (10H, s),
1.47 (8H, s), 1.74 (2H, broa
d), 1.98-2.06 (2H, m), 2.35-
2.39 (2H, m), 2.77 (1H, broa
d), 2.93 (2H, broad), 3.15 (1
H, broad), 3.29-3.35 (1H, m),
3.44 (2H, broad), 3.89 (2H, br)
oad), 4.02 (2H, broad d, J = 1)
3.4 Hz). MS (FAB) m / z 398 (M + H) ^<+> .

<1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [2
-(2-oxopyrrolidin-1-yl) ethyl] piperazine> 1,4-bis (tert-butoxycarbonyl)
2- [2- (2-oxopyrrolidin-1-yl) ethyl] piperazine (0.256 g) in dichloromethane (1
Trifluoroacetic acid (2 ml) was added to the solution, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure, and azeotroped three times with toluene and three times with dichloromethane to give 2
-[2- (2-oxopyrrolidin-1-yl) ethyl]
Piperazine trifluoroacetate was obtained as a colorless powder. The obtained 2- [2- (2-oxopyrrolidine-1-
Yl) ethyl] piperazine trifluoroacetate and triethylamine (0.270 ml) in dichloromethane (3
0 ml) solution was cooled to 0 ° C., and 5-chloro-2-chlorosulfonyl-1-phenylsulfonylindole (0.
238 g), and the mixture was stirred for 1 day while gradually returning to room temperature. The reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash column chromatography using silica gel as carrier (SI-40B, methanol / dichloromethane =
1 / 50-1 / 20-1 / 10) to give the title compound (0.126 g) as a colorless oil. ¹ H NMR (CDCl ₃ ) 1.47-1.72 (2H,
m), 2.00-2.08 (2H, m), 2.31-
2.45 (2H, m), 2.65-2.80 (3H,
m), 2.96-3.02 (2H, m), 3.07-
3.14 (1H, m), 3.27-3.33 (1H,
m), 3.39-3.45 (1H, m), 3.61-
3.70 (2H, m), 3.80 (1H, d, J = 1)
0.7Hz), 7.37 (1H, s), 7.40-7.
45 (3H, m), 7.51-7.56 (2H, m),
7.99-8.01 (2H, m), 8.21 (1H,
d, J = 9.0 Hz). MS (FAB) m / z 551 [(M + H) ⁺ , C
l ³⁵ ], 553 [(M + H) ⁺ , Cl ³⁷ ].

Example 298 4-[(5-Chloroindol-2-yl) sulfonyl] -2- [2-[(cyclopropylcarbonyl) amino] ethyl] -1-[(5-methyl-4,5, 6,7-
Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [2-[(cyclo The title compound was prepared from lithium propylcarbonyl) amino] ethyl] piperazine and 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid in the same manner as in Example 236. The compound was obtained as a tan amorphous solid. The obtained solid was treated with a 1N ethanol solution of hydrochloric acid and solidified using ethanol-dichloromethane-hexane. IR (KBr) cm ^-1 3085, 3010, 2925,
1619, 1544, 1504, 1465, 1353,
1307, 1270, 1236, 1159, 1122
1097,1060,1045,1018,952,9
35,916,875,809,742. _{^{1 H NMR (DMSO-d 6}} ) 0.62-0.64 (4
H, m), 1.49 (1H, broad), 1.91-
2.02 (3H, m), 2.57 (1H, broa
d), 2.90 (3H, s), 3.06 (4H, bro)
ad), 3.20-3.22 (2H, m), 3.42-
3.56 (2H, m), 4.41 (2H, broa
d), 4.66-4.75 (2H, m), 5.33-
5.67 (1H, m), 7.01 (1H, d, J = 1.
7 Hz), 7.30 (1H, dd, J = 1.9, 8.7)
Hz), 7.49 (1H, d, J = 8.7 Hz), 7.
75 (1H, d, J = 1.7 Hz), 12.45-1
2.47 (1H, m). MS (FAB) m / z 591 [(M + H) ⁺ , C
l ³⁵ ], 593 [(M + H) ⁺ , Cl ³⁷ ].

The 1-[(5-chloro-1) used as a raw material
-Phenylsulfonylindol-2-yl) sulfonyl] -3- [2-[(cyclopropylcarbonyl) amino] ethyl] piperazine was synthesized by the following method.

<2- [2-[(Cyclopropylcarbonyl) amino] ethyl] -1,4-bis (tert-butoxycarbonyl) piperazine> 1,4-bis (tert
-Butoxycarbonyl) -2- (2-tosyloxyethyl) piperazine (0.808 g, 1.66 mmol),
A suspension of sodium azide (0.540 gl) in N, N-dimethylformamide (40 ml) was stirred at 90 ° C. for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water. After separation, the organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. To the obtained solution of 2- (2-azidoethyl) -1,4-bis (tert-butoxycarbonyl) piperazine in methanol (20 ml) was added 10%.
% Palladium on carbon catalyst Wet (62.0 mg)
The mixture was stirred under a hydrogen atmosphere for 4 hours. Further, 10% palladium carbon catalyst Wet (62.0 mg) was added, and the mixture was stirred for 1.5 hours under a hydrogen atmosphere. After filtration, the reaction solution was concentrated under reduced pressure. The obtained 2- (2-aminoethyl) -1,4-bis (tert-butoxycarbonyl) piperazine and cyclopropanecarboxylic acid (0.131 ml), 1-hydroxybenzotriazole (0.228 g) in dichloromethane (25 ml) The solution was cooled to 0 ° C and 1-ethyl-
3- (3-dimethylaminopropyl) carbodiimide
Hydrochloride (0.325 g) was added, and the mixture was stirred for 16 hours while gradually returning to room temperature. The reaction solution is concentrated under reduced pressure, the residue is diluted with ethyl acetate, washed with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (0 .6
54 g) were obtained as a pale yellow amorphous. _{^{1 H NMR (CDCl 3) 0.69-0.73}} (2H,
m), 0.93-0.96 (2H, m), 1.35-
1.42 (1H, m), 1.45 (9H, s), 1.4
8 (9H, s), 1.78-1.84 (1H, m),
2.52 (1H, broad), 2.78 (1H, br)
oad), 2.88-2.95 (2H, m), 3.02.
(1H, broad), 3.85 (3H, broad)
d), 4.04 (1H, broad), 4.21 (1
H, broad), 6.84 (1H, broad).

<1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [2
-[(Cyclopropylcarbonyl) amino] ethyl] piperazine> 2- [2-[(cyclopropylcarbonyl)
[Amino] ethyl] -1,4-bis (tert-butoxycarbonyl) piperazine (0.649 g) was added with 4N hydrochloric acid / dioxane (10 ml), and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure. The obtained 2- [2-
Dichloromethane (25 ml) was added to [(cyclopropylcarbonyl) amino] ethyl] piperazine, cooled to 0 ° C, and triethylamine (0.680 ml), 5-
Chloro-2-chlorosulfonyl-1-phenylsulfonylindole (0.605 g) was added, and the mixture was stirred for 1 day while gradually returning to room temperature. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. Flash column chromatography using silica gel as carrier (column used: SI
-40B, methanol / dichloromethane = 1/20) to give the title compound (0.285 g) as a yellow amorphous solid. _{^{1 H NMR (CDCl 3) 0.69-0.76}} (2H,
m), 0.90-0.95 (2H, m), 1.30-
1.36 (1H, m), 1.49-1.60 (2H,
m), 2.67 (1H, dd, J = 10.1, 12.3)
Hz), 2.76-2.88 (2H, m), 2.94-
3.04 (2H, m), 3.17-3.25 (1H,
m), 3.53-3.61 (1H, m), 3.69-
3.72 (1H, m), 3.83 (1H, d, J = 1
2.4 Hz), 6.14 (1H, broad), 7.3
8 (1H, s), 7.40-7.46 (3H, m),
7.51-7.57 (2H, m), 7.99-8.02
(2H, m), 8.22 (1H, d, J = 9.0H
z). MS (FAB) m / z 551 [(M + H) ⁺ , C
l ³⁵ ], 553 [(M + H) ⁺ , Cl ³⁷ ].

Example 299 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[[(cyclopropylcarbonyl) amino] methyl] -1-[(5-methyl-4,5,6 , 7-Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3-[[( Cyclopropylcarbonyl) amino] methyl] piperazine and 5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] The title compound was obtained as a yellow amorphous solid from the lithium salt of pyridine-2-carboxylic acid in the same manner as in Example 236. IR (KBr) cm ^-1 3247, 3085, 3010,
2923, 2861, 1619, 1544, 1502
1465, 1421, 1355, 1307, 1270,
1197, 1159, 1122, 1095, 1058,
1018, 950, 931, 916, 877, 809,
742. _{^{1 H NMR (DMSO-d 6}} ) 0.39-0.85 (4
H, m), 1.17-1.48 (2H, m), 2.57
-2.71 (1H, m), 2.91 (3H, s), 3.
04-3.32 (4H, m), 3.65-3.80 (4
H, m), 4.29-4.83 (3H, m), 5.32
−5.72 (1H, m), 7.03 (1H, broad)
d, J = 7.5 Hz), 7.30 (1H, broad)
d, J = 6.8 Hz), 7.49 (1H, broad)
d, J = 7.8 Hz), 7.75 (1H, broa)
d), 8.13-8.19 (1H, m), 12.46.
(1H, s). MS (FAB) m / z 577 [(M + H) ⁺ , C
l ³⁵ ], 579 [(M + H) ⁺ , Cl ³⁷ ].

The 1-[(5-chloro-1) used as a raw material
-Phenylsulfonylindol-2-yl) sulfonyl] -3-[[(cyclopropylcarbonyl) amino]
[Methyl] piperazine was synthesized by the following method.

<2- (Aminomethyl) -1,4-dibenzylpiperazine> 2-Cyano-1,4-dibenzylpiperazine (10.4 gl) in tetrahydrofuran (150 g)
ml) solution into lithium aluminum hydride (4.10).
g) was added over 15 minutes, followed by stirring at room temperature for 1.5 hours. Add a small amount of water and sodium sulfate to the reaction solution,
After filtration, concentration of the title compound (1
0.9 g) as a brown oil. ¹ H NMR (CDCl ₃ ) 2.15 to 2.21 (1H,
m), 2.26-2.33 (2H, m), 2.42-
2.47 (1H, m), 2.58-2.61 (1H,
m), 2.69-2.71 (1H, m), 2.74-
2.80 (2H, m), 3.05 (1H, dd, J =
5.6, 13.4 Hz), 3.26 (1H, d, J = 1)
3.4 Hz), 3.44-3.52 (2H, m), 4.
04 (1H, d, J = 13.4 Hz), 7.22-7.
31 (10H, m). MS (FAB) m / z 296 (M + H) ^<+> .

<2-[[(Cyclopropylcarbonyl)
Amino] methyl] -1,4-dibenzylpiperazine> 2
-(Aminomethyl) -1,4-dibenzylpiperazine (0.477 g), cyclopropanecarboxylic acid (0.1
27 ml), 1-hydroxybenzotriazole (0.
217 g) in dichloromethane (10 ml) was cooled to 0 ° C., and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.308 g) was added.
The mixture was stirred at C for 1 hour and at room temperature for 23 hours. The reaction solution is concentrated under reduced pressure, the residue is diluted with ethyl acetate, washed once with a saturated aqueous solution of sodium hydrogen carbonate, twice with water, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.
548 g) as a brown oil. ¹ H NMR (CDCl ₃ ) 0.71-0.73 (2H,
m), 0.92-0.94 (2H, m), 1.30-
1.34 (1H, m), 2.25-2.37 (3H,
m), 2.57-2.59 (1H, m), 2.66-
2.70 (2H, m), 2.80-2.84 (1H,
m), 3.34 (1H, d, J = 13.4 Hz);
39-3.57 (4H, m), 3.96 (1H, d, J
= 13.4 Hz), 6.39 (1H, broad),
7.22-7.37 (10H, m). MS (FAB) m / z 364 (M + H) ^<+> .

<1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3-
[[(Cyclopropylcarbonyl) amino] methyl] piperazine> 2-[[(cyclopropylcarbonyl) amino] methyl] -1,4-dibenzylpiperazine (0.5
36 g) in methanol (25 ml).
3 ml) and palladium hydroxide (52.0 mg) were added,
The mixture was stirred under a hydrogen atmosphere for 3 hours. The palladium hydroxide was removed by filtration, washed with methanol and a small amount of triethylamine, and the mother liquor was concentrated under reduced pressure. The obtained 2-[[(cyclopropylcarbonyl) amino] methyl] piperazine is dissolved in dichloromethane (30 ml), cooled to 0 ° C., then triethylamine (0.6 ml), 5-chloro-2-chlorosulfonyl-1 -Phenylsulfonylindole (0.
544 g), and the mixture was gradually returned to room temperature and stirred for 21 and a half hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash column chromatography using silica gel as a carrier (SI-40B, methanol / dichloromethane = 1/25) gave the title compound (0.
399 g) were obtained as a yellow amorphous solid. IR (KBr) cm ^-1 3396, 3289, 3072,
3008, 2919, 2854, 1652, 1519,
1479, 1448, 1386, 1349, 1224
1186, 1159, 1135, 1112, 1089,
1074, 1020, 998, 941, 833, 72
8,713. ¹ H NMR (CDCl ₃ ) 0.70-0.
75 (2H, m), 0.91-0.96 (2H, m),
1.30-1.36 (1H, m), 2.75-2.80
(1H, m), 2.85-2.92 (1H, m), 2.
95-3.08 (3H, m), 3.25-3.36 (2
H, m), 3.70-3.75 (2H, m), 5.97
(1H, broad), 7.38-7.46 (4H,
m), 7.51-7.57 (2H, m), 7.99-
8.02 (2H, m), 8.21 (1H, d, J = 9.
3 Hz). MS (FAB) m / z 537 [(M + H) ⁺ , C
l ³⁵ ], 539 [(M + H) ⁺ , Cl ³⁷ ].

Example 300 4-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -2- [2-[(coumarin-7-yl) oxy] ethyl] -1-[(5 -Methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine 1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [2-[(coumarin-7-yl) oxy] ethyl] piperazine and 5 -Methyl-4,5,6,7-tetrahydrothiazolo [5,4
-C] The title compound was obtained as a light brown amorphous solid from lithium pyridine-2-carboxylate in the same manner as in Example 232. _{^{1 H NMR (DMSO-d 6}} ) 2.07-2.21 (2
H, m), 2.33-2.51 (2H, m), 2.67
-2.76 (1H, m), 2.90 (3H, s), 3.
10 (3H, broad), 3.40-3.85 (5
H, m), 4.01-4.25 (2H, m), 4.40
-4.96 (1H, m), 5.34-5.85 (1H,
m), 6.26-6.31 (1H, m), 6.69-
7.09 (3H, m), 7.27-7.34 (1H,
m), 7.46-7.53 (1H, m), 7.58-
7.66 (1H, m), 7.74-7.78 (1H,
m), 7.95-8.00 (1H, m), 12.41-
12.56 (1H, m). MS (FAB) m / z 66
8 [(M + H) ⁺ , Cl ³⁵ ], 670 [(M + H) ⁺ , C
l ³⁷ ].

[1471] The starting material, 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl]-
3- [2-[(coumarin-7-yl) oxy] ethyl]
Piperazine was synthesized by the following method.

<1,4-bis (tert-butoxycarbonyl) -2- [2-[(coumarin-7-yl) oxy] ethyl] piperazine> 1,4-bis (tert-butoxycarbonyl) -2- ( 2-hydroxyethyl) piperazine (0.660 g), umbelliferone (0.3
24 g) and triphenylphosphine (0.577 g) in tetrahydrofuran (20 ml) were added with diethyl azodicarboxylate (0.350 ml), and the mixture was stirred at room temperature for 5 hours. After concentrating the reaction solution under reduced pressure, flash column chromatography (SI-
40B, ethyl acetate / hexane = 1/2) to give a mixture (1.22 g) of the title compound and a by-product as a colorless powder. ¹ H NMR (CDCl ₃ ) 1.38 (9H, s), 1.
47 (9H, s), 1.94-1.99 (1H, m),
2.11 to 2.16 (1H, m), 3.01 (2H, b
load), 3.97-4.05 (6H, broad)
m), 4.42 (1H, broad), 6.24 (1
H, d, J = 9.3 Hz), 6.77 (1H, d, J =
2.3 Hz), 6.81 (1H, dd, J = 8.5,
2.3Hz), 7.35 (1H, d, J = 8.5H)
z), 7.62 (1H, d, J = 9.3 Hz). MS (FAB) m / z 474M ⁺ .

[1473] <1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [2
-[(Coumarin-7-yl) oxy] ethyl] piperazine> 1,4-bis (tert-butoxycarbonyl)-
2- [2-[(coumarin-7-yl) oxy] ethyl]
Piperazine (2.00 mmol) in dichloromethane (2
Trifluoroacetic acid (4 ml) was added to the solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue (2- [2-[(coumarin-7-yl) oxy] ethyl] piperazinetrifluoroacetic acid) was azeotroped three times with toluene and three times with dichloromethane to give a colorless powder. As obtained. The obtained residue and a solution of triethylamine in dichloromethane (75 ml) were cooled to 0 ° C.
-Chlorosulfonyl-1-phenylsulfonylindole (0.706 g) was added, and the mixture was stirred at 0 ° C for 1 hour and at room temperature for 1 day. The reaction solution was saturated aqueous sodium hydrogen carbonate,
The extract was washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and the resulting solid was collected by filtration to give the title compound (0.301 g) as a colorless solid. The filtrate was purified by flash column chromatography using silica gel as a carrier (SI-40B, methanol / dichloromethane = 1 / 50-1 / 20) to give the title compound (55.0 mg) as a yellow-white solid. IR (KBr) cm ^-1 3318, 2940, 2896,
1735, 1610, 1506, 1434, 1384,
1349, 1326, 1276, 1228, 1157,
1137, 1120, 1089, 1045, 1029,
995,956,892,835,800,763,7
36,725,711. ¹ H NMR (CDCl ₃ ) 1.81-1.97 (2H,
m), 2.75 (1H, dd, J = 9.9, 12.3H
z), 2.88-3.10 (4H, m), 3.73-
3.76 (1H, m), 3.87 (1H, broad)
d, J = 11.2 Hz), 4.12 (2H, t, J =
5.9 Hz), 6.25 (1H, d, J = 9.5H)
z), 6.78-6.80 (2H, m), 7.33-
7.35 (1H, m), 7.39-7.45 (4H,
m), 7.51-7.57 (2H, m), 7.62 (1
H, d, J = 9.5 Hz), 7.99-8.02 (2
H, m), 8.22 (1H, d, J = 9.0 Hz). MS (FAB) m / z 628 [(M + H) ⁺ , C
l ³⁵ ], 630 [(M + H) ⁺ , Cl ³⁷ ]. Elemental analysis: C ₂₉ H ₂₆ ClN ₃ O ₇ S ₂ 0.1 CH ₂ Cl ₂ Calculated: C, 54.90; H, 4.15; Cl, 6.6
8; N, 6.60; S, 10.07. Analytical values: C, 54.83; H, 4.13; Cl, 6.7.
2; N, 6.54; S, 10.05.

Example 301 4-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -2- [2-[(coumarin-7-yl) oxy] ethyl] 1-[(5- Methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine hydrochloride 4-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -2- [2-[(coumarin-7-yl) oxy] ethyl] 1 -[(5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
Pyridin-2-yl) carbonyl] piperazine was treated in the same manner as in Example 270 to give the title compound. IR (KBr) cm ^-1 3396, 2917, 1727,
1708, 1610, 1554, 1506, 1465,
1403, 1353, 1307, 1280, 1230,
1201, 1157, 1122, 1095, 1058,
1045,1016,995,952,931,91
6,890,835,809,748. Elemental _{analysis: C 31 H 30 ClN 5 O} 6 S 2 1.4HCl1.5
H ₂ O 0.4 hexane Calculated: C, 51.38; H, 5.16; Cl, 10.
90; N, 8.97; S, 8.21. Analytical values: C, 51.49; H, 5.02; Cl, 10.
75; N, 9.02; S, 8.01.

Example 302 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2-[(2-oxo-1,3-oxazolan-3-yl) methyl] piperazine hydrochloride 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3-[(2-oxo-
As in Example 236 from 1,3-oxazolan-3-yl) methyl] piperazine and lithium 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylate The title compound was obtained as a pale yellow solid by the method of (1). IR (KBr) cm ^-1 3118, 2923, 1739,
1621, 1544, 1502, 1465, 1442,
1357, 1309, 1270, 1232, 1160,
1124,1095,1056,1006,956,9
14,877,809,759,742,705. _{^{1 H NMR (DMSO-d 6}} ) 2.66-2.72 (1
H, m), 2.90 (3H, s), 3.03-3.16.
(3H, m), 3.25-3.27 (3H, m), 3.
47-3.54 (2H, m), 3.66-3.82 (5
H, m), 3.94-4.10 (1H, m), 4.21
-4.38 (2H, m), 4.66-4.99 (1H,
m), 5.32-5.77 (1H, m), 7.03 (1
H, s), 7.30 (1H, d, J = 8.8 Hz),
7.50 (1H, d, J = 8.8 Hz), 7.76 (1
H, s), 12.46 (1H, s). MS (FAB) m / z 579 [(M + H) ⁺ , C
l ³⁵ ], 581 [(M + H) ⁺ , Cl ³⁷ ]. HRMS (FAB) m / z 579.1240 (M +
H) ⁺ (calculated C ₂₄ H ₂₈ ClN ₆ O ₅ S ₂ 579.125
1). Elemental _{analysis: C 24 H 28 ClN 6 O} 5 S 2 1HCl1H 2 O0.
Calculated for 5 EtOH: C, 45.73; H, 5.07; N, 12.8
0. Analytical values: C, 45.82; H, 5.19; N, 12.5
7.

The raw material 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl]-
3-[(2-oxo-1,3-oxazolan-3-yl) methyl] piperazine was synthesized by the following method.

<2-[[[(2-Chloroethoxy) carbonyl] amino] methyl] -1,4-dibenzylpiperazine> 2- (Aminomethyl) -1,4-dibenzylpiperazine (0.570 g) Dichloromethane (40ml)
The solution was cooled to 0 ° C, a solution of 2-chloroethyl chloroformate (0.200ml) in dichloromethane (20ml) was added slowly, and the mixture was stirred at 0 ° C for 1 hour. The reaction solution is concentrated under reduced pressure, the residue is diluted with ethyl acetate, washed once with a saturated aqueous solution of sodium hydrogen carbonate, once with water, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (0.795 g). Was obtained as a yellow oil. ¹ H NMR (CDCl ₃ ) 2.24-2.35 (3H,
m), 2.53 (1H, broad), 2.64-2.
66 (2H, m), 2.77-2.80 (1H, m),
3.28-3.35 (2H, m), 3.42-3.55
(3H, m), 3.67 (2H, t, J = 5.6H
z), 3.95 (1H, d, J = 12.9 Hz), 4.
30 (1H, t, J = 5.6 Hz), 5.59 (1H,
broad), 7.21-7.37 (10H, m).

<1,4-Dibenzyl-2-[(2-oxo-1,3-oxazolan-3-yl) methyl] piperazine> N, N-dimethylformamide (10 ml) of sodium hydride (79.0 mg) In the suspension,
[[[(2-Chloroethoxy) carbonyl] amino] methyl] -1,4-dibenzylpiperazine (1.92 mm
ol) in N, N-dimethylformamide (7 ml) was added dropwise over 20 minutes and stirred at room temperature for 1 day.
The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water.
After separation, the organic layer was washed with water and saturated saline. After drying over magnesium sulfate, concentration under reduced pressure gave a crude product of the title compound (0.745 g) as a yellow-brown oil. ¹ H NMR (CDCl ₃ ) 2.32-2.47 (4H,
m), 2.56-2.59 (1H, m), 2.81-
2.89 (2H, m), 3.35-3.45 (4H,
m), 3.50-3.57 (2H, m), 3.69 (1
H, dd, J = 5.0, 14.3 Hz), 3.94 (1
H, d, J = 13.4 Hz), 4.15-4.20 (1
H, m), 7.21-7.30 (10H, m). MS (FAB) m / z 366 (M + H) ^<+> .

<1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3-
[(2-oxo-1,3-oxazolan-3-yl) methyl] piperazine> 1,4-dibenzyl-2-[(2-
Oxo-1,3-oxazolan-3-yl) methyl] piperazine (1.92 mmol) in methanol (30 m
l) Concentrated hydrochloric acid (0.45 ml) and palladium hydroxide (76.0 mg) were added to the solution, and the mixture was stirred under a hydrogen atmosphere for 3.5 hours. The palladium hydroxide was removed by filtration, washed with methanol and a small amount of triethylamine, and the mother liquor was concentrated under reduced pressure. The obtained 2-[(2-oxo-1,3-oxazolan-3-
Yl) methyl] piperazine in dichloromethane (40m
1) and cooled to 0 ° C., then triethylamine (0.9 ml), 5-chloro-2-chlorosulfonyl-
1-Phenylsulfonylindole (0.714 g) was added, the temperature was gradually returned to room temperature, and the mixture was stirred for 20 and a half hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline,
After drying over sodium sulfate, the mixture was concentrated under reduced pressure. Flash column chromatography using silica gel as carrier (SI-40B, methanol / dichloromethane = 1 /
Purification by 25) afforded the title compound (0.427 g) as a pale yellow amorphous solid. IR (KBr) cm ⁻¹ 3451, 915, 2857,
1747, 1583, 1517, 1482, 1448,
1386, 1351, 1268, 1222, 1186
1159, 1137, 1114, 1089, 1074
1047, 1022, 998, 835, 813, 76
1,728,713. ¹ H NMR (CDCl ₃ ) 2.72-2.78 (1H,
m), 2.81-2.87 (1H, m), 2.95-
3.13 (3H, m), 3.17-3.22 (1H,
m), 3.32-3.38 (1H, m), 3.59-
3.71 (3H, m), 3.85 (1H, broad)
d, J = 9.4 Hz), 4.35 (2H, t, J = 8H)
z), 7.39 (1H, s), 7.41-7.47 (3
H, m), 7.54-7.58 (2H, m), 7.99
−8.02 (2H, m), 8.22 (1H, d, J =
9.0 Hz). MS (FAB) m / z 539 [(M + H) ⁺ , C
l ³⁵ ], 541 [(M + H) ⁺ , Cl ³⁷ ].

Example 303 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine- 2-yl) carbonyl] -2-[(2-oxopyrrolidin-1-yl)
Methyl] piperazine hydrochloride 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3-[(2-oxopyrrolidin-1-yl) methyl] piperazine and 5-methyl-4,5 , 6,7-tetrahydrothiazolo [5,4-
c] The title compound as a pale yellow solid was obtained from lithium pyridine-2-carboxylate in the same manner as in Example 236. IR (KBr) cm ^-1 3399, 2925, 1666,
1623, 1544, 1502, 1465, 1421,
1357, 1309, 1272, 1234, 1160,
1128,1097,1060,1020,956,9
16,877,811,740,700. ¹ H NMR (DMSO-d ₆ ) 1.17-1.23 (1
H, m), 1.47-1.93 (2H, m), 2.00
-2.21 (2H, m), 2.67-2.71 (1H,
m), 2.89 (3H, s), 3.03-3.31 (5
H, m), 3.66-3.81 (5H, m), 3.93.
-4.05 (1H, m), 4.15-4.40 (2H,
m), 4.65-4.96 (1H, m), 5.23-
5.80 (1H, m), 7.03 (1H, s), 7.3
0 (1H, d, J = 8.8 Hz), 7.49 (1H,
d, J = 8.8 Hz), 7.76 (1H, s), 12.
47 (1H, broad). MS (FAB) m / z 577 [(M + H) ⁺ , C
l ³⁵ ], 579 [(M + H) ⁺ , Cl ³⁷ ].

[1481] The starting material, 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl]-
3-[(2-oxopyrrolidin-1-yl) methyl] piperazine was synthesized by the following method.

<2-[(4-chlorobutyryl) aminomethyl] -1,4-dibenzylpiperazine> 2- (aminomethyl) -1,4-dibenzylpiperazine (0.669)
A solution of g) in dichloromethane (25 ml) was cooled to 0 ° C, a solution of 4-chlorobutyryl chloride (0.250 ml) in dichloromethane (25 ml) was added dropwise over 15 minutes, and the mixture was stirred at 0 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed once with a saturated aqueous solution of sodium hydrogen carbonate, once with water, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.85%).
1 g) was obtained as a yellow oil. ¹ H NMR (CDCl ₃ ) 2.05-2.10 (2H,
m), 2.24-2.34 (4H, m), 2.41-
2.51 (2H, m), 2.53-2.58 (1H,
m), 2.66-2.69 (1H, m), 2.76 (1
H, broad), 2.85 (1H, broad),
3.40-3.54 (4H, m), 3.58 (2H,
t, J = 6.2 Hz), 3.92-3.95 (1H,
m), 7.23-7.36 (10H, m). MS (FAB) m / z 400 [(M + H) ⁺ , C
l ³⁵ ], 402 [(M + H) ⁺ , Cl ³⁷ ].

<1,4-Dibenzyl-2-[(2-oxopyrrolidin-1-yl) methyl] piperazine> In a suspension of sodium hydride (85.0 mg) in N, N-dimethylformamide (10 ml), 2-[(4-chlorobutyryl) aminomethyl] -1,4-dibenzylpiperazine (0.846 g) of N, N-dimethylformamide (1
0 ml) solution was added dropwise over 1 hour and stirred at room temperature for 17 半 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water. After separation, the organic layer was washed with water and saturated saline. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure to give the title compound (0.704 g) as a brown oil. ¹ H NMR (CDCl ₃ ) 1.85-1.93 (2H,
m), 2.24-2.36 (5H, m), 2.43-
2.57 (2H, m), 2.79-2.84 (2H,
m), 3.26-3.30 (1H, m), 3.36-
3.55 (5H, m), 3.66-3.71 (1H,
m), 3.96 (1H, d, J = 13.6 Hz), 7.
20-7.37 (10H, m). MS (FAB) m / z 364 (M + H) ^<+> .

<1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3-
[(2-oxopyrrolidin-1-yl) methyl] piperazine> 1,4-dibenzyl-2-[(2-oxopyrrolidin-1-yl) methyl] piperazine (0.700 g)
Hydrochloric acid (0.45m
l) and palladium hydroxide (82.0 mg) were added, and the mixture was stirred under a hydrogen atmosphere for 5 1/2 hours. The palladium hydroxide was removed by filtration, washed with methanol and a small amount of triethylamine, and the mother liquor was concentrated under reduced pressure. The obtained 2-[(2-oxopyrrolidin-1-yl) methyl] piperazine is dissolved in dichloromethane (40 ml), cooled to 0 ° C., then triethylamine (0.9 ml), 5-chloro-2-chlorosulfonyl. -1-phenylsulfonylindole (0.703
g,) and stirred at 0 ° C. for 1 hour and at room temperature for 13 半 hours. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure.
Purification by flash column chromatography using silica gel as a carrier (SI-40B, methanol / dichloromethane = 1/25) gave the title compound (0.36
5g) was obtained as a pale yellow oil. _{^{1 H NMR (CDCl 3) 1.99-2.07}} (2H,
m), 2.36-2.40 (2H, m), 2.72 (1
H, dd, J = 9.9, 12.3 Hz), 2.80−
2.86 (1H, m), 2.93-2.99 (1H,
m), 3.02-3.10 (2H, m), 3.12-
3.16 (1H, m), 3.37-3.50 (3H,
m), 3.69 (1H, broad d, J = 12.4).
Hz), 3.80 (1H, broad d, J = 11.
2Hz), 7.36 (1H, s), 7.40-7.46
(3H, m), 7.52-7.57 (2H, m), 7.
98-8.01 (2H, m), 8.21 (1H, d, J
= 9.0 Hz). MS (FAB) m / z 537 [(M + H) ⁺ , C
l ³⁵ ], 539 [(M + H) ⁺ , Cl ³⁷ ].

Example 304 1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridin-2-yl) carbonyl] -4-[(6-trimethylsilyl) Ethynylbenzo [b] thien-2-yl) sulfonyl] piperazine 1- (tert-butoxycarbonyl) -4-[(5
Performed with 6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine and 2-chlorosulfonyl-6-trimethylsilylethynylbenzo [b] thiophene The title compound was obtained as a pale brown powder in the same manner as in Example 295. IR (KBr) cm ^-1 3064, 3029, 2946,
2867, 2771, 1244, 1735, 1625,
1538, 1484, 1471, 1450, 1430,
1349, 1332, 1282, 1249, 1159,
1106,1058,1002,993,939,89
8,856,842,806,757,730. ¹ H NMR (CDCl ₃ ) 0.26 (9H, s), 2.
40 (3H, s), 2.52 (3H, s), 3.28
(4H, broad), 3.83 (2H, broad)
s), 3.91 (2H, broad), 4.01 (2
H, broad), 4.58 (2H, broad),
7.51 (1H, d, J = 8.3 Hz), 7.76 (1
H, s), 7.80 (1H, d, J = 8.3 Hz),
7.96 (1H, s). MS (FAB) m / z 574 (M + H) ^<+> . Elemental analysis: C ₂₅ H ₃₁ N ₅ O ₃ S ₃ Si Calculated: C, 52.33; H, 5.45; N, 12.2
0; S, 16.76. Analytical values: C, 52.25; H, 5.53; N, 12.0
9; S, 16.52.

The raw material 1- (tert-butoxycarbonyl) -4-[(5,6-dimethyl-4,5,6,7
-Tetrahydrothiazolo [4,5-d] pyridazine-2
-Yl) carbonyl] piperazine was synthesized by the following method.

<1- (tert-butoxycarbonyl)
-4-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl)
Carbonyl] piperazine> 5,6-dimethyl-4,5
Title of brown amorphous was obtained from lithium 6,7-tetrahydrothiazolo [4,5-d] pyridazine-2-carboxylate (1.71 g) and 1-tert-butoxycarbonylpiperazine in the same manner as in Example 232. The compound was obtained. ¹ H NMR (CDCl ₃ ) 1.48 (9H, s), 2.
43 (3H, s), 2.55 (3H, s), 3.51-
3.54 (4H, m), 3.75 (2H, broa
d), 3.87 (2H, broads), 4.05
(2H, broad), 4.37 (2H, broad)
d). MS (FAB) m / z 381 M ⁺ .

Example 305 1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridin-2-yl) carbonyl] -4-[(6-ethynyl) Benzo [b] thiene-
2-yl) sulfonyl] piperazine 1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(6- A solution of trimethylsilylethynylbenzo [b] thien-2-yl) sulfonyl] piperazine (0.499 g) in tetrahydrofuran-methanol (1: 1, 20 ml) was mixed with potassium hydroxide (85%,
0.203 g) and stirred at room temperature for 3.5 hours. The reaction solution was diluted with dichloromethane and water. After separation, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. Flash column chromatography using silica gel as carrier (SI-40B, ethyl acetate / methanol = 1 / 0-1)
00/1) to give the title compound (0.330
g) was obtained as a pale yellow powder. IR (KBr) cm ^-1 3272, 3046, 2960,
2910, 2861, 2788, 1731, 1617,
1535, 1486, 1473, 1446, 1359,
1307, 1278, 1160, 1133, 1101,
1058,993,935,865,848,817,
771,727. ¹ H NMR (CDCl ₃ ) 2.40 (3H, s), 2.
52 (3H, s), 3.21 (1H, s), 3.27
(4H, broad), 3.83 (2H, broad)
s), 3.91 (2H, broad), 4.01 (2
H, broad), 4.58 (2H, broad),
7.53-7.55 (1H, m), 7.78 (1H,
s), 7.83 (1H, d, J = 8.5 Hz), 7.9
9 (1H, s). MS (FAB) m / z 502 (M + H) ⁺ .

Example 306 1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(1-phenyl Sulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine 1-tert- (butoxycarbonyl) -4-[(5
Using 6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine and 2-chlorosulfonyl-1-phenylsulfonyl-5-trimethylsilylethynyl indole The title compound was obtained as a pale yellow solid in the same manner as in Example 295. ¹ H NMR (CDCl ₃ ) 0.25 (9H, s), 2.
42 (3H, s), 2.54 (3H, s), 3.53
(4H, broad), 3.84 (2H, broad)
s), 3.88 (2H, broad), 4.04 (2
H, broad), 4.55 (2H, broad),
7.40-7.44 (2H, m), 7.46 (1H,
s), 7.52-7.59 (2H, m), 7.68 (1
H, d, J = 1.4 Hz), 8.00 (2H, d, J =
7.5 Hz), 8.21 (1H, d, J = 9.0H)
z). MS (FAB) m / z 697 (M + H) ^<+> .

Example 307 1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(-5- Ethynylindole-2-
Yl) sulfonyl] piperazine

[1491]

Embedded image 1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(1-phenylsulfonyl-5-trimethylsilylethynyl Indole-2-yl) sulfonyl] piperazine was obtained in the same manner as in Example 305 to give the title compound as a pale-yellow amorphous solid. IR (KBr) cm ^-1 3280, 2921, 2854,
2790, 2103, 1731, 1619, 1536,
1511, 1473, 1450, 1359, 1330,
1309, 1278, 1265, 1162, 1103
1054,1020,995,954,933,89
0,840,815,723. ¹ H NMR (CDCl ₃ ) 2.40 (3H, s), 2.
51 (3H, s), 3.03 (1H, s), 3.22
(4H, broad), 3.82 (2H, broad)
s), 3.87 (2H, broad), 4.00 (2
H, broad), 4.56 (2H, broad),
7.00 (1H, s), 7.37 (1H, d, J = 8.
5 Hz), 7.46 (1H, d, J = 8.5 Hz),
7.85 (1H, s), 8.93 (1H, broa
d). MS (FAB) m / z 485 (M + H) ^<+> .

Example 308 1-[(6-Chloronaphthalen-2-yl) sulfonyl] -4-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] Pyridazin-2-yl) carbonyl] piperazine 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazine-2-carboxylic acid lithium salt and 1-[(6-chloronaphthalene -2-yl) sulfonyl] piperazine to give the title compound as a pale-brown solid in the same manner as in Example 232. IR (KBr) cm ^-1 3430, 3029, 2917,
2854, 1623, 1546, 1477, 1452,
1344, 1330, 1278, 1267, 1238,
1164, 1135, 1103, 1078, 1052
1018,993,954,931,881,844,
811,788,727. _{^{1 H NMR (DMSO-d 6}} ) 2.71 (3H, s),
2.82 (3H, s), 3.10 (4H, broad)
s), 3.75 (2H, broad), 4.33-4.
36 (2H, m), 4.45 (2H, broad),
7.71 (1H, dd, J = 2.0, 8.9 Hz),
7.83 (1H, d, J = 8.5 Hz), 8.16 (1
H, d, J = 8.7 Hz), 8.23-8.27 (2
H, m), 8.51 (1H, s). MS (FAB) m / z 506 [(M + H) ⁺ , C
l ³⁵ ], 508 [(M + H) ⁺ , Cl ³⁷ ]. Elemental _{analysis: C 22 H 24 ClN 5 O} 3 S 2 1.3HCl0.5
H ₂ O 0.1EtOH Calculated: C, 47.02; H, 4.78; Cl, 14.
38, N, 12.35; S, 11.31. Analytical values: C, 47.31; H, 4.98; Cl, 14.
61, N, 12.05; S, 11.10.

Example 309 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine hydrochloride [thieno [3 2-b] pyridin-2-yl] carboxylic acid lithium salt and 1-[(5-chloroindole-
2-yl) sulfonyl] piperazine to give the title compound (269 mg, 55%) as a white powder in the same manner as in Example 236. m. p. > 270 ° C IR (KBr) cm ^-1 3114, 3089, 1628,
1431, 1340, 1281, 1149, 960. ¹ H NMR (DMSO-d ₆ ) 3.11-3.22 (4
H, br), 3.70-3.82 (4H, br), 7.
04 (1H, s), 7.33 (1H, dd, J = 8.
8, 2.0 Hz), 7.51 (1H, d, J = 8.8H)
z), 7.52-7.64 (1H, br), 7.80
(1H, d, J = 2.0 Hz), 7.82-7.88
(1H, m), 8.63-8.87 (1H, br), 1
2.45-12.53 (1H, br). MS (ESI) m / z 461 [(M + H) ^<+> , C
l ³⁵ ], 463 [(M + H) ⁺ , Cl ³⁷ ].

[1494] The raw material [thieno [3,2-b] pyridine-
[2-yl] carboxylic acid lithium salt was synthesized by the following method.

<4,5,6,7-Tetrahydrothieno [3,2-b] pyridine> 4- (tert-butoxycarbonyl) -4,5,6,7-tetrahydrothieno [3,2-b] pyridine (1470 g) in dichloromethane (15.0 ml) was added to trifluoroacetic acid (4.
0 ml) and stirred at room temperature for 6 hours. After dilution with dichloromethane, the mixture was concentrated under reduced pressure. The crude product is subjected to silica gel column chromatography (dichloromethane: methanol = 2
5: 1) to give the title compound (835 mg) as a red oil. ¹ H NMR (CDCl ₃ ) 1.92-2.02 (2H,
m), 2.75 (2H, t, J = 6.3 Hz), 3.2
1-3.27 (2H, m), 6.49 (1H, d, J =
5.4 Hz), 6.95 (1H, d, J = 5.4H)
z).

<Thieno [3,2-b] pyridine> 4
To a solution of 5,6,7-tetrahydrothieno [3,2-b] pyridine (643 mg) in toluene (5.0 ml) was added 1
0% palladium carbon (674 mg) was added, and the mixture was heated under reflux for 4 days. After cooling, palladium carbon was removed by celite filtration, and the filtrate was concentrated under reduced pressure. The crude product is subjected to medium pressure column chromatography (dichloromethane: methanol = 3
5: 1) to give the title compound (411 mg) as a brown oil. ¹ H NMR (CDCl ₃ ) 7.25 (1 H, dd, J =
8.3, 4.7 Hz), 7.56 (1H, d, J = 5.
4 Hz), 7.74 (1H, d, J = 5.4 Hz),
8.19 (1H, d, J = 8.3 Hz), 8.70 (1
H, d, J = 4.7 Hz). ¹³ C NMR (CDCl ₃ ) 155.84, 147.1
0, 132.94, 130.42, 130.30, 12
5.02, 118.48. MS (FAB) m / z 136 (M + H) ^<+> .

<[Thieno [3,2-b] pyridine-2-
Il] carboxylic acid lithium salt> thieno [3,2-b]
To a solution of pyridine (414 mg) in ether (5.0 ml) was added tert-butyllithium (1.51
mol / l hexane solution) (2.30 ml).
After stirring for minutes, carbon dioxide was bubbled in at -78 ° C for 15 minutes. The reaction solution was concentrated under reduced pressure to obtain the title compound (651 mg) as a pale yellow powder. _{^{1 H NMR (DMSO-d 6}} ) 7.28 (1H, dd,
J = 8.1, 4.5 Hz), 7.56 (1H, s),
8.31 (1H, d, J = 8.1 Hz), 8.58 (1
H, dd, J = 4.5 Hz). MS (FAB) m / z 186 (M + H) ⁺ .

Example 310 2-[[4-[(5-Chloroindol-2-yl) sulfonyl] piperazin-1-yl] carbonyl] thieno [3,2-b] pyridine N-oxide

[1499]

Embedded image 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(thieno [3,2-b] pyridin-2-yl) carbonyl] piperazine (94 mg) in dichloromethane (40 ml) and ethanol (2. 0 ml) at 0 ° C. with> 70% metachloroperbenzoic acid (1
57 mg) and stirred at room temperature for 26 hours. 1 in the reaction solution
Excess metachloroperbenzoic acid was reduced using a normal aqueous sodium thiosulfate solution and diluted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by medium pressure column chromatography (dichloromethane: methanol = 35: 1) to give the title compound (90 mg) as a colorless solid. m. p. > 155 ° C (decomposition) IR (KBr) cm ^-1 1627, 1417, 1354,
1240, 1159, 1099, 997, 953. ¹ H NMR (CDCl ₃ ) 3.15-3.35 (4H,
br), 3.70-4.00 (4H, br), 7.01.
(1H, s), 7.20-7.45 (3H, br),
7.67 (1H, s), 7.80 (1H, d, J = 7.
3Hz), 7.93 (1H, s), 8.40-8.60
(1H, br), 10.80-11.00 (1H, b
r). MS (ESI) m / z 477 [(M + H) ⁺ , C
l ³⁵ ], 479 [(M + H) ⁺ , Cl ³⁷ ].

Example 311 4-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -2- (2-cyanoethyl) -1-[(5-
Methyl-4,5,6,7-tetrahydrothiazolo [5,
4-c] pyridin-2-yl) carbonyl] piperazine 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -3- (2-cyanoethyl) piperazine and (5-methyl-4,5, The title compound was obtained as a pale yellow powder by a method similar to that in Example 232 using lithium 6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carboxylate. ¹ H NMR (CDCl ₃ ) 1.70-1.90 (2H,
br), 2.05-2.28 (1H, m), 2.35-
2.56 (3H, m), 2.49 (3H, s), 2.5
9-2.72 (1H, m), 2.73-2.90 (3
H, m), 3.00-3.30 (1H, m), 3.45
-3.58 (0.5H, m), 3.60-3.95
(4.5H, m), 4.67-4.75 (0.5H, b
r), 4.95-5.05 (0.5H, m), 5.77
−5.87 (0.5H, m), 6.09-6.18
(0.5H, m), 7.44 (1H, dd, J = 8.
5,1.7 Hz), 7.76 (1H, s), 7.81
(1H, d, J = 8.5 Hz), 7.85 (1H, d,
J = 1.7 Hz). MS (FAB) m / z 550 [(M + H) ⁺ , C
l ³⁵ ], 552 [(M + H) ⁺ , Cl ³⁷ ].

The raw material 1-[(6-chlorobenzo [b] thien-2-yl) sulfonyl] -3- (2-cyanoethyl) piperazine was synthesized by the following method.

<1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -3- (2-cyanoethyl)
Piperazine> 1,4-bis (tert-butoxycarbonyl) -2- (2-cyanoethyl) piperazine (937
mg) in dichloromethane (4.0 ml), trifluoroacetic acid (3.0 ml) was added, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure, and the residue was diluted with dichloromethane (1
0.0ml) solution and triethylamine (2.0m
l), (6-Chlorobenzo [b] thien-2-yl) sulfonyl chloride (780 mg) was added, and the mixture was stirred at 0 ° C for 3 hours. Dichloromethane and 2N hydrochloric acid were added to the reaction solution to form two layers. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product is subjected to silica gel column chromatography (dichloromethane: methanol = 40:
Purification was performed in 1) to give the title compound (443 mg) as a white powder. IR (KBr) cm ^-1 1589, 1491, 1344
1219, 1155, 1003. ¹ H NMR (CDCl ₃ ) 1.00-1.60 (1H,
br), 1.61-1.73 (1H, m), 1.75-
1.86 (1H, m), 2.30 (1H, t, J = 1
0.5 Hz), 2.47 (2H, t, J = 7.3H)
z), 2.59 (1H, td, J = 10.5, 3.0H
z), 2.89-3.00 (2H, m), 3.04-
3.12 (1H, m), 3.61 (2H, t, J = 7.
3 Hz), 7.44 (1H, dd, J = 8.7, 1.8)
Hz), 7.76 (1H, s), 7.83 (1H, d,
J = 8.7 Hz), 7.86 (1H, d, J = 1.8H)
z). MS (FAB) m / z 370 [(M + H) ⁺ , C
l ³⁵ ], 372 [(M + H) ⁺ , Cl ³⁷ ].

Example 312 1-[[4- (tert-Butoxycarbonyl) -4,
5,6,7-tetrahydrothieno [3,2-b] pyridin-2-yl] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazine [4- (tert-butoxycarbonyl)- 4,5,
6,7-tetrahydrothieno [3,2-b] pyridine-
Example 2 from 2-yl] carboxylic acid and 1-[(5-chloroindol-2-yl) sulfonyl] piperazine
By a method similar to that of 32, the title compound (464 mg) was obtained as a colorless powder. IR (KBr) cm ^-1 2976, 2929, 1697,
1363, 1269, 1161. ¹ H NMR (CDCl ₃ ) 1.50 (9H, s), 1.
93-2.02 (2H, m), 2.77 (2H, t, J
= 6.4 Hz), 3.11-3.17 (4H, m),
3.69-3.74 (2H, m), 3.83-3.89
(4H, m), 6.94 (1H, d, J = 1.5H
z), 7.32 (1H, dd, J = 8.8, 1.7H
z), 7.36 (1H, d, J = 8.8 Hz), 7.6
0-7.90 (1H, br), 7.67 (1H, d, J
= 1.7 Hz), 8.96-9.04 (1H, br). MS (FAB) m / z 565 [(M + H) ⁺ , C
l ³⁵ ], 567 [(M + H) ⁺ , Cl ³⁷ ].

[4- (tert-Butoxycarbonyl) -4,5,6,7-tetrahydrothieno [3,2-b] pyridin-2-yl] carboxylic acid used as a starting material was synthesized by the following method.

<3- (tert-butoxycarbonyl)
Amino-2- (methoxycarbonyl) thiophene> 3-
Methyl aminothiene-2-carboxylate (15.71 g)
-78 ° C in tetrahydrofuran (250 ml) solution
Then, a 0.5 mol / l potassium hexamethyldisilazane toluene solution (400 ml) was added dropwise, and di-tert
-Butyl dicarbonate (22.32 g) was added, and the mixture was stirred at room temperature for 15 hours. After the reaction solution was concentrated, ethyl acetate and 2N hydrochloric acid were added to form two layers, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product is subjected to silica gel column chromatography (hexane: ethyl acetate =
After purification in 20: 1), the residue was solidified from an ethyl acetate-hexane solution to obtain the title compound (20.55 g) as a white powder. m. p. 90-91 ° C. IR (KBr) cm ^-1 3324, 3118, 2979,
1730, 1682, 1587, 1446, 1294,
1261, 1225, 1165, 1095. ¹ H NMR (CDCl ₃ ) 1.52 (9H, s), 3.
87 (3H, s), 7.43 (1H, d, J = 5.4H
z), 7.88 (1H, d, J = 5.4 Hz), 9.3
5 (1H, s). ¹³ C NMR (CDCl ₃ ) 175.31, 164.5
0, 151.93, 145.57, 131.37, 12
1.13, 81.03, 51.77, 28.25. MS
(FAB) m / z 257M ⁺ , 258 (M + H) ⁺ . Elemental analysis: as C ₁₁ H ₁₅ NO ₄ S Calculated: C, 51.35; H, 5.88; N, 5.4
4; S, 12.46. Analytical values: C, 51.39; H, 5.89; N, 5.3.
6; S, 12.46.

<3- (tert-butoxycarbonyl)
Amino-2- (hydroxymethyl) thiophene> 3-
Sodium borohydride (7.85 g) was added to a solution of (tert-butoxycarbonyl) amino-2- (methoxycarbonyl) thiophene (7.933 g) in tetrahydrofuran (40 ml), and methanol (40 ml) was added dropwise at room temperature. For 4 hours. Ether and a saturated aqueous sodium chloride solution were added to the reaction solution to form two layers. The organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound (5.92 g) as a white powder. m. p. 114-117 ° C. IR (KBr) cm ^-1 3411, 3330, 2974,
1695, 1577, 1495, 1394, 1271,
1252, 1163, 995. ¹ H NMR (CDCl ₃ ) 1.51 (9H, s), 2.
95-3.15 (1H, br), 4.66 (1H, d,
J = 6.1 Hz), 6.68-6.74 (1H, b
r), 7.14 (1H, d, J = 5.4 Hz), 7.1
6 (1H, d, J = 5.4 Hz). MS (FAB) m / z 229M ⁺ . Elemental analysis: as C ₁₀ H ₁₅ NO ₃ S Calculated: C, 52.38; H, 6.59; N, 6.1
1: S, 13.98. Analytical values: C, 52.35; H, 6.65; N, 5.9.
3: S, 13.91.

<3- (tert-butoxycarbonyl)
Amino-2-formylthiophene> 3- (tert-butoxycarbonyl) amino-2- (hydroxymethyl)
Thiophene (5.52 g) in dichloromethane (240 m
1) 4-Methylmorpholine N-oxide (4.22 g), molecular sieve 4A powder (4.3)
25 g), and the mixture was stirred at room temperature for 15 minutes. Then, tetrapropylammonium pearl tenate (212 mg) was added, and the mixture was stirred at room temperature for 20 hours. Dichloromethane and a 1N aqueous solution of sodium sulfite were added to the reaction solution to form two layers. The organic layer was washed with a saturated aqueous solution of sodium chloride and an aqueous solution of copper sulfate, dried over sodium sulfate, and concentrated under reduced pressure. The crude product is subjected to silica gel column chromatography (hexane: ethyl acetate =
20: 1) to give the title compound (4.40 g) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) 1.53 (9H, s), 7.
66 (1H, d, J = 5.3 Hz), 7.94 (1H,
d, J = 5.3 Hz), 9.67 (1H, s), 9.7
7-9.85 (1H, br). ¹³ C NMR (CDCl ₃ ) 183.35, 151.9
1,145.42,135.80,121.78,11
9.31, 81.40, 28.14. MS (FAB) m / z 227M ⁺ , 228 (M +
H) ⁺ .

<1509> Ethyl (E) -3- [3- (tert-
(Butoxycarbonyl) aminothien-2-yl] acrylate> ethyl diethylphosphonoacetate (3.800 m
l) in tetrahydrofuran (25 ml)
Sodium hydride (oily) (800 mg) was added at 0 ^{° C.} , and the mixture was stirred for 10 minutes. The reaction solution was added with 3- (tert-butoxycarbonyl) amino-2-formylthiophene (4.0).
07g) in tetrahydrofuran (10.0 ml) was added and stirred at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture to form two layers. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product is subjected to silica gel column chromatography (hexane: ethyl acetate = 20: 1).
The title compound (4.972 g) was obtained as a pale yellow solid. m. p. 85-86 ° C. IR (KBr) cm ^-1 3338, 2985, 1709,
1699, 1624, 1558, 1491, 1267,
1248, 1161, 960. ¹ H NMR (CDCl ₃ ) 1.33 (3H, t, J =
7.1 Hz), 1.53 (9H, s), 4.25 (2
H, q, J = 7.1 Hz), 6.13 (1H, d, J =
15.4 Hz), 6.76-6.83 (1H, br),
7.28 (1H, d, J = 5.6 Hz), 7.50-
7.57 (1H, br), 7.72 (1H, dd, J =
15.3, 0.7 Hz). MS (FAB) m / z 297M ⁺ , 298 (M +
H) ⁺ . Elemental analysis: C ₁₄ H ₁₉ NO ₄ S Calculated: C, 56.55; H, 6.44 ; N, 4.7
1: S, 10.78. Analytical values: C, 56.61; H, 6.51; N, 4.5.
9; S, 10.84.

<Ethyl 3- [3- (tert-butoxycarbonyl) aminothien-2-yl] propionate> Ethyl (E) -3- [3- (tert-butoxycarbonyl) aminothien-2-yl] acrylate (4.
87 g) in ethanol (40 ml) was added with 10% palladium on carbon (1066 mg), and hydrogenated at room temperature in the presence of hydrogen.
Stirred for days. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (4.84 g) as a colorless oil. ¹ H NMR (CDCl ₃ ) 1.24 (2H, t, J =
7.1 Hz), 1.52 (9H, s), 2.65 (2
H, t, J = 6.6 Hz), 2.99 (2H, t, J =
6.6 Hz), 4.13 (2H, q, J = 7.1H)
z), 7.06 (1H, d, J = 5.4 Hz), 7.1
5-7.33 (2H, br).

<3- (tert-butoxycarbonyl)
Amino-2- (3-hydroxypropyl) thiophene>
Ethyl 3- [3- (tert-butoxycarbonyl) aminothien-2-yl] propionate (2.87 g)
Was added to a solution of methanol (4.0 ml) and sodium borohydride (1.62) in a tetrahydrofuran (20 ml) solution.
g) was added and the mixture was heated under reflux for 4 hours. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture to form two layers. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (silicagel 160 cm).
³ ; hexane: ethyl acetate = 4: 1) to give the title compound (2.467 g) as a colorless oil. ¹ H NMR (CDCl ₃ ) 1.50 (9H, s), 1.
82-1.91 (2H, m), 1.98-2.23 (1
H, br), 2.85 (2H, t, J = 6.8 Hz),
2.58-3.65 (2H, m), 6.95-7.03
(1H, br), 7.05 (1H, d, J = 5.4H)
z), 7.19-7.29 (1H, br). ¹³ C NMR (CDCl ₃ ) 153.63, 132.6
5,127.96,123.86,121.10,6
0.33, 33.00, 28.38, 22.12, 1
4,24. MS (FAB) m / z 258 (M + H) ^<+> .

<3- [3-[(tert-Butoxycarbonyl) amino] thien-2-yl] propylmethanesulfonate> 3- (tert-butoxycarbonyl) amino-2- (3-hydroxypropyl) thiophene (1 .46 g) in pyridine (4.0 ml) at 0 ° C.
Then, methanesulfonyl chloride (500 l) was added thereto, and the mixture was stirred at room temperature for 5.5 hours. Ice and ethyl acetate were added to the reaction solution, and the mixture was stirred for 10 minutes, and 2N hydrochloric acid was added to form two layers. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (1.75 g) as a colorless oil. ¹ H NMR (CDCl ₃ ) 1.50 (9H, s), 2.
05-2.12 (2H, m), 2.86 (2H, t, J
= 7.1 Hz), 3.02 (3H, s), 4.24 (2
H, t, J = 6.0 Hz), 6.21-6.30 (1
H, br), 7.07 (1H, d, J = 5.4 Hz),
7.18-7.26 (1H, br). MS (FAB) m / z 335M ⁺ , 336 (M +
H) ⁺ .

<4- (tert-butoxycarbonyl)
-4,5,6,7-tetrahydrothieno [3,2-b]
Pyridine> 3- [3-[(tert-butoxycarbonyl) amino] thien-2-yl] propylmethanesulfonate (1.39 g) in tetrahydrofuran (20.0
ml) solution at −78 ° C. with n-butyllithium (1.
54 mol / l hexane solution) (3.0 ml)
Stir at room temperature for 21 hours. Saturated ammonium chloride and ethyl acetate were added to the reaction solution to form two layers. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1),
The title compound (874 mg) was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) 1.50 (9H, s), 1.
94-2.03 (2H, m), 2.80 (2H, t, J
= 6.5 Hz), 3.72-3.77 (2H, m),
7.00 (1H, d, J = 5.4 Hz), 7.27−
7.80 (1H, br). MS (FAB) m / z 239M ⁺ , 240 (M +
H) ⁺ .

<[4- (tert-Butoxycarbonyl) -4,5,6,7-tetrahydrothieno [3,2-
b] pyridin-2-yl] carboxylic acid> 4- (tert
-Butoxycarbonyl) -4,5,6,7-tetrahydrothieno [3,2-b] pyridine (948 mg) in tetrahydrofuran (30.0 ml) at −78 ° C. was added with n-butyllithium (1.50 mol / l). (hexane solution) (3.20 ml) was added, and carbon dioxide was blown in at -78 ° C for 1.5 hours. 2N hydrochloric acid and ethyl acetate were added to the reaction solution to form two layers. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to give the title compound (400 mg) as a white solid. IR (KBr) cm ^-1 3159, 2974, 2941,
1709, 1653, 1464, 1389, 1194
1161, 1126. ¹ H NMR (CDCl ₃ ) 1.56 (9H, s), 1.
97-2.06 (2H, m), 2.85 (2H, t, J
= 6.5 Hz), 3.74-3.79 (2H, m),
8.10-8.50 (1H, br). MS (FAB) m / z 283M +, 284 (M +
H) ⁺ . Elemental analysis: as C ₁₃ H ₁₇ NO ₄ S Calculated: C, 55.11; H, 6.05; N, 4.9
4; S, 11.32. Analytical values: C, 55.27; H, 6.16; N, 4.8.
5; S, 11.20.

Example 313 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothieno [3,2-b] pyridin-2-yl) carbonyl ] Piperazine hydrochloride 1-[[4- (tert-butoxycarbonyl) -4,
5,6,7-tetrahydrothieno [3,2-b] pyridin-2-yl] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] piperazine (437 m
To a solution of g) in ethanol (4.0 ml) was added a saturated hydrochloric acid ethanol solution (4.0 ml), and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to obtain the title compound (375 mg) as a pale yellow powder. m. p. > 150 ° C (decomposition). IR (KBr) cm ^-1 3114, 2924, 2864,
1618, 1435, 1354, 1157, 1099,
953. _{^{1 H NMR (DMSO-d 6}} ) 2.01-2.10 (2
H, m), 2.82 (2H, t, J = 6.2 Hz),
3.10-3.16 (4H, m), 3.30-3.38
(2H, m), 3.69-3.76 (4H, m), 7.
23 (1H, s), 7.30 (1H, dd, J = 8.
8, 2.0 Hz), 7.50 (1H, d, J = 8.8H)
z), 7.75 (1H, d, J = 1.7 Hz), 12.
45 (1H, s). MS (FAB) m / z 465 [(M + H) ⁺ , C
l ³⁵ ], 467 [(M + H) ⁺ , Cl ³⁷ ].

Example 314 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(4-methyl-4,5,6,7-tetrahydrothieno [3,2-b] pyridine-2 -Yl) carbonyl] piperazine hydrochloride 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothieno [3,2-b] pyridin-2-yl ) Carbonyl] piperazine (234 mg) in 1,2-dichloroethane (4.
0 ml) suspension in 90% paraformaldehyde (92 ml).
mg), triacetoxy sodium borohydride (288
mg) and stirred at room temperature for 25 hours. A saturated aqueous solution of sodium hydrogen carbonate and dichloromethane were added to the reaction solution to form two layers. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by medium pressure column chromatography (dichloromethane: methanol = 30: 1), and then dichloromethane (5.0 m
l) and dissolved in ethanol (5.0 ml), 1N hydrochloric acid in ethanol (1.0 ml) was added, and the mixture was concentrated under reduced pressure. The obtained oil was concentrated under reduced pressure from a mixed solution of dichloromethane and ethyl acetate to give the title compound (115 mg) as a pale-yellow powder. m. p. > 144 ° C (decomposition). IR (KBr) cm ^-1 2923, 2864, 1732,
1620, 1460, 1433, 1358, 1277,
1261, 1159, 1099, 953. _{^{1 H NMR (DMSO-d 6}} ) 2.00-2.08 (2
H, m), 2.74 (2H, t, J = 6.0 Hz),
2.90 (3H, s), 3.05-3.20 (6H, b
r), 3.65-3.78 (4H, br), 7.03
(1H, s), 7.30 (1H, s), 7.32 (1
H, dd, J = 8.8, 2.0 Hz), 7.51 (1
H, d, J = 8.8 Hz), 7.78 (1H, s), 1
2.48 (1H, s). MS (FAB) m / z 479 [(M + H) ⁺ , C
l ³⁵ ].

Example 315 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) -1-[(4
5,6,7-tetrahydrothieno [3,2-b] pyridin-2-yl) carbonyl] piperazine hydrochloride

[1517]

Embedded image 3- (N-methylcarbamoyl) -1-[(5-chloroindol-2-yl) sulfonyl] piperazine (19
8 mg) of N, N-dimethylformamide (4.0 m
l) Add [4- (tert-butoxycarbonyl)
-4,5,6,7-tetrahydrothieno [3,2-b]
Pyridin-2-yl] carboxylic acid (173 mg) triethylamine (84 l), 1-hydroxybenztriazole monohydrate (85 mg), 1-ethyl-3- (3-
(Dimethylaminopropyl) carbodiimide monohydrochloride (122 mg) was added, and the mixture was stirred at room temperature for 3 days. Dichloromethane and 2N hydrochloric acid were added to the reaction solution to form two layers. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 30: 1),
1-[[4- (tert-butoxycarbonyl) -4,
5,6,7-tetrahydrothieno [3,2-b] pyridin-2-yl] carbonyl] -4-[(5-chloroindol-2-yl) sulfonyl] -2- (N-methylcarbamoyl) piperazine ( 107 mg) as a pale yellow powder. To a mixed solution of the obtained pale yellow powder (107 mg) in dichloromethane (6.0 ml) and ethanol (6.0 ml) was added a saturated ethanol solution of hydrochloric acid (8.0 ml), and the mixture was stirred at room temperature for 1 hour, and then ethyl acetate was added and concentrated under reduced pressure. Thus, the title compound (101 mg) was obtained as a white powder. IR (KBr) cm ^-1 1633, 1485, 1435,
1358, 1306, 1265, 1230, 1157,
953. ¹ H NMR (CD ₃ OD) 2.07-2.23 (2H,
m), 2.55-2.80 (2H, m), 2.78 (3
H, s), 2.92 (2H, t, J = 5.9 Hz),
3.30-3.50 (2.5H, m), 3.55-3.
70 (0.5H, m), 3.72-3.81 (2H, b
r), 4.20-4.45 (1.5H, br), 4.9
7-5.17 (0.5H, br), 7.01 (1H,
s), 7.28 (1H, dd, J = 8.8, 2.0H
z), 7.45 (1H, d, J = 8.8 Hz), 7.6
9 (1H, d, J = 2.0 Hz), 7.70-7.83
(1H, br). MS (ESI) m / z 522 [(M + H) ⁺ , C
l ³⁵ ].

Example 316 4-[(5-Chloro-1-phenylsulfonylindol-2-yl) rufonyl] -2-[(morpholinocarbonyl) methyl] -1-[[4,5,6,7-tetrahydro Thieno [3,2-b] pyridin-2-yl] carbonyl] piperazine [4- (tert-butoxycarbonyl) -4,5.
6,7-tetrahydrothieno [3,2-b] pyridine-
To a solution of 2-yl] carboxylic acid (202 mg) in tetrahydrofuran (5.0 ml) was added 95% thionyl chloride (20%).
0l) was added and refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was made into a tetrahydrofuran (7.0 ml) solution.
[(-Chloro-1-phenylsulfonylindole-2
-Yl) ruphonyl] -3-[(morpholinocarbonyl)
[Methyl] piperazine (244 mg) and triethylamine (100 l) were sequentially added, and the mixture was stirred at room temperature for 18 hours. Dichloromethane and 2N hydrochloric acid were added to the reaction solution to form two layers. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel medium pressure column chromatography (dichloromethane: methanol = 30: 1) to give the title compound (115 mg) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) 1.91-2.02 (2H,
m), 2.46-2.58 (1H, br), 2.72
(2H, t, J = 6.3 Hz), 2.85-3.80
(14H, m), 3.85-3.96 (1H, br),
4.02-4.10 (1H, br), 4.15-4.4
0 (1H, br), 4.45-4.70 (1H, b
r), 5.03-5.18 (1H, br), 7.06
(1H, s), 7.42-7.51 (4H, m), 7.
55-7.63 (2H, m), 8.05 (2H, d, J
= 7.3 Hz), 8.20 (1H, d, J = 9.3H)
z). MS (ESI) m / z 732 [(M + H) ⁺ , C
l ³⁵ ], 734 [(M + H) ⁺ , Cl ³⁷ ]. HRMS (EI) calcd _{C 32 H 34 ClN 5 O 7} S 3: 73
1.1309. Analytical value 731.1288.

Example 317 4-[(5-Chloroindol-2-yl) sulfonyl] -2-[(morpholinocarbonyl) methyl] -1-
[[4,5,6,7-tetrahydrothieno [3,2-
b] pyridin-2-yl] carbonyl] piperazine hydrochloride 4-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -2- (morpholinocarbonyl) methyl-1-[[4,5, To a solution of 6,7-tetrahydrothieno [3,2-b] pyridin-2-yl] carbonyl] piperazine (115 mg) in 1,4-dioxane (4.0 ml), a 1 N aqueous sodium hydroxide solution (0.60 ml). Was added and stirred at room temperature for 7 hours. Dichloromethane and a saturated aqueous solution of ammonium chloride were added to the reaction solution to form two layers. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by medium pressure column chromatography (dichloromethane: methanol = 30: 1), and then purified with dichloromethane (0.1%).
50 ml) and ethanol (2.0 ml), 1N hydrochloric acid in ethanol (1.0 ml) was added, and the mixture was concentrated under reduced pressure to give the title compound (102 mg) as a white powder. IR (KBr) cm ^-1 1631, 1437, 1354,
1232, 1157, 1115, 957. _{^{1 H NMR (DMSO-d 6}} ) 1.90-2.07 (2
H, br), 2.55-4.08 (19H, br),
4.30-4.50 (1H, br), 4.55-4.7
5 (1H, br), 4.85-5.05 (1H, b
r), 7.02 (1H, s), 7.32 (1H, d, J
= 8.4 Hz), 7.49 (1H, d, J = 8.4H)
z), 7.55-7.80 (1H, br), 7.77
(1H, s), 12.48 (1H, s). MS (FAB) m / z 592 [(M + H) ⁺ , C
l ³⁵ ], 594 [(M + H) ⁺ , Cl ³⁷ ].

Example 318 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[[6- (N, N-dimethylamino) -4,
5,6,7-tetrahydrobenzo [d] thiazole-2
-Yl] carbonyl] piperazine

[1521]

Embedded image [6- (N, N-dimethylamino) -4,5,6,7-
Lithium tetrahydrobenzo [d] thiazol-2-yl] carboxylate and 1-[(5-chloroindol-2-yl) sulfonyl] piperazine (210 mg)
From the title compound (80) in the same manner as in Example 232.
mg, a colorless solid). ¹ H NMR (CDCl ₃ ) δ 1.75-1.80 (1
H, m), 2.13-2.16 (1H, m), 2.36
(6H, s), 2.75-3.20 (11H, m),
3.87 (1H, brs), 4.57 (1H, brs)
s), 6.96 (1H, s), 7.30-7.37 (2
H, m), 7.67 (1H, dd, J = 5.2, 1.7)
Hz). MS (FAB) m / z 508 [(M + H) ⁺ , C
l ³⁵ ], 510 [(M + H) ⁺ , Cl ³⁷ ].

The lithium [6- (N, N-dimethylamino) -4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl] carboxylate used as a starting material was synthesized by the following method.

<2-Chloro-6- (N, N-dimethylamino) -4,5,6,7-tetrahydrobenzo [d] thiazole> 2-chloro-6-oxo-4,5,6,7-
Tetrahydrobenzo [d] thiazole (2.0 g) was dissolved in methanol (100 mL), and ammonium acetate (8.2 g) and sodium cyanoborohydride (4.0) were dissolved.
g) was added and heated under reflux. After 20 hours, the reaction was stopped, hydrochloric acid was added to destroy excess sodium cyanoborohydride, the solvent was distilled off under reduced pressure, made alkaline with a 1N sodium hydroxide solution, and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a pale yellow oil. This oily substance was treated with methanol (50 m
L) and dissolved in an aqueous formaldehyde solution (4.29)
g) and sodium cyanoborohydride (3.49 g) were added and the mixture was stirred at room temperature. After 12 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, methylene chloride was added, the mixture was washed with a saturated sodium hydrogen carbonate solution, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methylene chloride: methanol =
10: 1) to give the title compound (740 mg, pale yellow oil). ¹ H NMR (CDCl ₃ ) δ: 1.71-1.78 (1
H, m), 2.10-2.19 (1H, m), 2.35
(6H, s), 2.66-2.94 (5H, m). MS (FAB) m / z 217 [(M + H) ⁺ , C
l ³⁵ ], 219 [(M + H) ⁺ , Cl ³⁷ ].

[1524] <[6- (N, N-dimethylamino)-
4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl] carboxylic acid lithium salt> 2-chloro-6
-(N, N-dimethylamino) -4,5,6,7-tetrahydrobenzo [d] thiazole (750 mg) is dissolved in ether (15 mL), and cooled to -78 ° C, and then 1.5M.
Tert-butyllithium (3.5 mL) was added and stirred. After 20 minutes, carbon dioxide gas was bubbled, and after about 15 minutes, the bubbling was stopped. The reaction solution was heated to room temperature and concentrated under reduced pressure to obtain the title compound (100%, pale yellow amorphous). ¹ H NMR (DMSO-d ₆ ) δ: 1.75-1.78
(1H, m), 1.98-2.07 (1H, m), 2.
50 (6H, s), 2.64-2.88 (5H, m).

Example 319 1-[(6,7-Dihydro-4H-pyrano [4,3-
d] thiazol-2-yl) carbonyl] -2-[(4
-Methylpiperazin-1-yl) carbonylmethyl]-
4-[[5- (2-Trimethylsillethynyl) indol-2-yl] sulfonyl] piperazine lithium salt of 6,7-dihydro-4H-pyrano [4,3-d] thiazole-2-carboxylic acid (130 mg) and From 3-[(4-methylpiperazin-1-yl) carbonylmethyl] -1-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine, by the same method as in Example 232,
The title compound (150 mg, pale yellow amorphous) was obtained. ¹ H NMR (CDCl ₆ ) δ 0.27 (9H, s),
2.34-3.83 (22H, m), 4.02-4.0
4 (2H, m), 4.85 (2H, s), 7.04 (1
H, s), 7.35-7.43 (2H, m), 7.84.
(1H, s).

[1525] 3-[(4-Methylpiperazin-1-yl) carbonylmethyl] -1-[(1-
[Phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine was synthesized by the following method.

<1,4-di (tert-butoxycarbonyl) -2-[(4-methylpiperazin-1-yl) carbonylmethyl] piperazine> 2-carboxymethyl-
1,4-Di (tert-butoxycarbonyl) piperazine (1 g) was dissolved in methylene chloride (30 mL), and N-
Methyl piperazine (325 L), 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide hydrochloride (8
35 mg), 1-hydroxybenzotriazole (59
0 mg) and N-methylmorpholine (880 mg), and the mixture was stirred at room temperature. After 40 hours, the reaction was stopped, and the organic layer was washed with a saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 20: 1) to give the title compound (1.16 g, pale yellow oil). ¹ H NMR (CDCl ₃ ) δ 1.44 (9H, s),
1.46 (9H, s), 2.29-4.05 (19H,
m), 4.60 (1H, br s). MS (FAB) m / z 427 (M + H) ^<+> .

<3-[(4-Methylpiperazin-1-yl) carbonylmethyl] -1-[(1-phenylsulfonyl-5-trimethylsilylethynylindole-2-
Yl) sulfonyl] piperazine> 1,4-di (tert
-Butoxycarbonyl) -2-[(4-methylpiperazin-1-yl) carbonylmethyl] piperazine (1.1
6 g) was dissolved in methylene chloride (50 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred for 2 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in methylene chloride (50 mL). ) And stirred at room temperature. After 3 days, the reaction was stopped, washed with a saturated sodium hydrogen carbonate solution, and then the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 20: 1) to give the title compound (1.
73 g, pale yellow oil) was obtained. ¹ H NMR (DMSO-d ₆ ) δ 0.02 (9H,
s), 1.97-3.89 (20H, m), 7.27-
7.50 (6H, m), 7.62-7.97 (3H,
m). MS (FAB) m / z 642 (M + H) ^<+> .

Example 320 1-[(6,7-Dihydro-4H-pyrano [4,3-
d] thiazol-2-yl) carbonyl] -4-[(5
-Ethynylindol-2-yl) sulfonyl] -2-
[(4-Methylpiperazin-1-yl) carbonylmethyl] piperazine

[1530]

Embedded image 1-[(6,7-dihydro-4H-pyrano [4,3-
d] thiazol-2-yl) carbonyl] -2-[(4
-Methylpiperazin-1-yl) carbonylmethyl]-
4-[[5- (2-Trimethylsilleethynyl) indol-2-yl] sulfonyl] piperazine (150 m
g) was added and dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (340 L) was added, and the mixture was stirred at room temperature. After 7 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, methylene chloride was added, and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (silica gel 15 g, methylene chloride: methanol = 10: 1).
The title compound (110 mg, colorless amorphous) was obtained. ¹ H NMR (CDCl ₃ ) δ 2.15-3.81 (23
H, m), 3.97-4.03 (2H, m), 4.84.
(2H, s), 7.04 (1H, s), 7.37-7.
43 (2H, m), 7.85 (1H, s). MS (FAB) m / z 597 (M + H) ^<+> .

Example 321 4-[(6-Chlorobenzo [d] thien-2-yl) sulfonyl] -1-[[6- (N, N-dimethylamino)
-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl] carbonyl] -2-[(N, N-dimethylcarbamoyl) methyl] piperazine hydrochloride [6- (N, N-dimethylamino) −4,5,6,7−
Lithium tetrahydrobenzo [d] thiazol-2-yl] carboxylate and 1-[(6-chlorobenzo [d] thien-2-yl) sulfonyl] -3-[(N,
[N-dimethylcarbamoyl) methyl] piperazine and the title compound (120
mg, pale yellow solid). ¹ H NMR (CDCl ₆ ) δ 1.75-1.80 (1
H, m), 2.12 to 2.15 (1H, m), 2.35
(6H, s), 2.38-4.04 (14H, m),
2.93 (3H, s), 3.02 (3H, s), 7.4
3 (1H, dd, J = 8.3, 1.7 Hz), 7.75
(1H, s), 7.80 (1H, d, J = 8.5H)
z), 7.85 (1H, s). MS (FAB) m / z 610 [(M + H) ⁺ , C
l ³⁵ ], 612 [(M + H) ⁺ , Cl ³⁷ ].

[1335] 1-[(6-Chlorobenzo [d] thien-2-yl) sulfonyl] -3-
[(N, N-dimethylcarbamoyl) methyl] piperazine was synthesized by the following method.

<1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -3- (N, N-dimethylcarbamoyl) methylpiperazine> 1,4-dibenzyl-
2- (Dimethylaminocarbonylmethyl) piperazine (5.22 g) was dissolved in methanol (150 mL) and concentrated hydrochloric acid (2.50 mL), and palladium hydroxide (356 mg) was suspended in this reaction solution. The suspension was then vigorously shaken at room temperature under a hydrogen atmosphere for 7.5 hours. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was distilled off under reduced pressure. The obtained residue was added with dichloromethane (160 ml), triethylamine (8.40 mL, 6.10 g) and (6-chlorobenzo [b] thien-2-yl) sulfonyl chloride (2.85 g) under ice-cooling. 13.5
After stirring for an additional hour, (6-chlorobenzo [b] thiene-
(2-yl) sulfonyl chloride (0.39 g) was added, and the mixture was stirred at room temperature for 2.5 hours. After completion of the stirring, water was added to carry out a liquid separation operation, and the organic layer was dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure. The residue was subjected to medium pressure column chromatography (3% methanol-dichloromethane) to obtain the title compound (4.65 g, pale yellow amorphous). ¹ H NMR (CDCl ₃ ) 2.25-2.35 (1H,
m), 2.35-2.40 (2H, m), 2.60-
3.05 (4H, m), 2.93 (3H, s), 2.9
6 (3H, s 3.20-3.30 (1H, m), 3.5
5-3.65 (2H, m), 7.42 (1H, dd, J
= 8.5, 2.0 Hz), 7.74 (1H, s), 7.
81 (1H, d, J = 8.8 Hz), 7.84-7.8
6 (1H, m). MS (ESI) m / z 402 (M + H) ^<+> .

Example 322 1-[(6-tert-Butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-[(5-chloroindole- 2-yl) sulfonyl] piperazine 6-tert-butyldiphenylsilyloxy-4,
5,6,7-tetrahydrobenzo [d] thiazole-2
-The title compound (colorless solid) was obtained from lithium carboxylate and 1-[(5-chloroindol-2-yl) sulfonyl] piperazine in the same manner as in Example 232. ¹ H NMR (CDCl ₃ ) δ 1.02 (9H, s),
1.81-2.01 (2H, m), 2.62-2.99
(6H, m), 3.19-3.21 (4H, m), 3.
87 (1H, br s), 3.93 (4H, s), 4.
19-4.23 (1H, m), 4.57 (1H, br)
s), 6.95 (1H, d, J = 1.0 Hz), 7.2
9-7.69 (13H, m). MS (FAB) m / z 719 [(M + H) ⁺ , C
l ³⁵ ], 721 [(M + H) ⁺ , Cl ³⁷ ].

Example 323 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(6-hydroxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl ] Piperazine 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-[(5-chloroindol-2-yl) The title compound (160 mg, pale yellow solid) was obtained from [sulfonyl] piperazine in the same manner as in Example 277. ¹ H NMR (DMSO-d ₆ ) δ 1.89-2.03
(2H, m), 2.73-3.11 (6H, m), 3.
21-3.31 (4H, m), 3.83 (1H, br)
s), 4.16-4.20 (1H, m), 4.45 (1
H, br s), 6.99 (1H, s), 7.26 (1
H, dd, J = 8.8, 2.2 Hz), 7.43 (1
H, d, J = 8.8 Hz), 7.66 (1H, s). MS (FAB) m / z 481 [(M + H) ⁺ , C
l ³⁵ ], 483 [(M + H) ⁺ , Cl ³⁷ ].

Example 324 4-[(5-tert-butoxycarbonyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -1-[(6-chlorobenzo [d] thien-2-yl) sulfonyl] piperazine (5-tert-butoxycarbonyl- 4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Il) lithium salt of carboxylic acid (415 mg) and 1
The title compound (light yellow solid) was obtained from-[(6-chlorobenzo [d] thien-2-yl) sulfonyl] piperazine in the same manner as in Example 232. ¹ H NMR (CDCl ₃ ) δ 1.48 (9H, s),
2.86-4.65 (14H, m), 7.43 (1H,
dd, J = 8.6, 2.0 Hz), 7.76 (1H,
s), 7.80 (1H, d, J = 8.6 Hz), 7.8
4 (1H, s). MS (FAB) m / z 583 [(M + H) ⁺ , C
l ³⁵ ], 585 [(M + H) ⁺ , Cl ³⁷ ].

Example 325 1-[(6-Chlorobenzo [d] thien-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine-2 -Yl) carbonyl] piperazine 4-[(5-tert-butoxycarbonyl-4,5,
6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] -1-[(6-chlorobenzo [d] thien-2-yl) sulfonyl] piperazine (4
50 mg) and dissolved in methylene chloride (10 mL).
Saturated ethanol (2 mL) was added and the mixture was stirred at room temperature. After 1 hour, the reaction was stopped, methylene chloride was added, and the mixture was washed with a saturated sodium hydrogen carbonate solution and a 1N sodium hydroxide solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 10: 1) to give the title compound (290 mg, pale yellow solid). ¹ H NMR (DMSO-d ₆ ) δ 2.67-3.58
(12H, m), 3.78 (1H, brs), 4.4
4 (1H, brs), 7.55-7.58 (1H,
m), 8.05 (1H, d, J = 8.8 Hz), 8.0
9 (1H, s), 8.31 (1H, s). MS (FAB) m / z 483 [(M + H) ⁺ , C
l ³⁵ ], 485 [(M + H) ⁺ , Cl ³⁷ ].

Example 326 1-[(6-Chlorobenzo [b] thien-2-yl) sulfonyl] -4-[(5-hydroxy-4,5,6,7
-Tetrahydrothiazolo [5,4-c] pyridine-2-
Yl) carbonyl] piperazine

[1539]

Embedded image 1-[(6-chlorobenzo [d] thien-2-yl) sulfonyl] -4-[(4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine (290 mg) in methylene chloride (30 m
L), benzoyl peroxide (230 mg) was added, and the mixture was stirred at room temperature. After 17 hours, the reaction was stopped, the excess reagent was broken with a sodium sulfite solution, washed with water, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 50: 1),
The obtained residue was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), 1N sodium hydroxide solution was added, and the mixture was stirred for 15 minutes. The reaction was stopped, the solvent was distilled off under reduced pressure, methylene chloride was added, and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 100: 1) to give the title compound (80 mg, pale yellow solid). ¹ H NMR (DMSO-d ₆ ) δ 2.67-3.32
(12H, m), 3.78 (1H, brs), 4.4
4 (1H, brs), 7.55-7.58 (1H,
m), 8.05 (1H, d, J = 8.8 Hz), 8.0
9 (1H, s), 8.31 (1H, s). MS (FAB) m / z 499 [(M + H) ⁺ , C
l ³⁵ ], 501 [(M + H) ⁺ , Cl ³⁷ ].

Example 327 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(6-hydroxyimino-4,5,6,7
-Tetrahydrobenzo [d] thiazol-2-yl) carbonyl] piperazine

[1541]

Embedded image 1-[(5-Chloroindol-2-yl) sulfonyl] -4- [6-oxo-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] piperazine (220 mg) in methanol (7 mL) and 1,4-dioxane (2 mL), and dissolved in hydroxyamine hydrochloride (39 mg) and sodium acetate (70 mg).
Was dissolved in water (1 mL), and the mixture was stirred at 60 ° C. After 6 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, water was added, the mixture was extracted with methylene chloride, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 50: 1) to give the title compound (10
0 mg, a pale yellow solid). ¹ H NMR (CD ₃ OD) δ: 2.64 (2H, t, J
= 6.6 Hz), 2.90-2.94 (2H, m),
3.19-3.22 (6H, m), 3.83 (1H, b
rs), 3.86 (2H, s), 4.46 (1H, b
rs), 7.01 (1H, s), 7.27 (1H, d
d, J = 8.8, 2.0 Hz), 7.45 (1H, d,
J = 8.8 Hz), 7.69 (1H, d, J = 1.7H)
z). MS (FAB) m / z 494 [(M + H) ⁺ , C
l ³⁵ ], 496 [(M + H) ⁺ , Cl ³⁷ ].

Example 328 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[[6- (pyrrolidin-1-yl) -4,
5,6,7-tetrahydrobenzo [d] thiazole-2
-Yl] carbonyl] piperazine hydrochloride 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(6-oxo-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl ) Carbonyl]
Piperazine (200 mg) was dissolved in 1,2-dichloroethane (5 mL), and pyrrolidine (55 L) and acetic acid (4
0L), sodium triacetoxyborohydride (13 L
3 mg) and stirred at room temperature. After 24 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, a saturated sodium hydrogencarbonate solution was added, the mixture was extracted with methylene chloride, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methylene chloride: methanol = 50: 1) to obtain a pale yellow solid. This was dissolved in 1N hydrochloric acid ethanol (5 mL), and the solvent was distilled off to give the title compound (11) as a hydrochloride.
5 mg, a pale yellow solid) was obtained. ¹ H NMR (CD ₃ OD) δ: 1.99-2.11 (4
H, m), 2.45-2.48 (2H, m), 2.86
-3.96 (16H, m), 4.44 (1H, br)
s), 6.99 (1H, s), 7.27 (1H, dd,
J = 8.8, 2.2 Hz), 7.44 (1H, d, J =
8.8 Hz), 7.67 (1H, d, J = 2.0H)
z). MS (FAB) m / z 534 [(M + H) ⁺ , C
l ³⁵ ], 536 [(M + H) ⁺ , Cl ³⁷ ].

Example 329 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4
3-d] thiazol-2-yl) carbonyl] -2-
(N, N-dimethylcarbamoyl) methylpiperazine lithium salt of 6,7-dihydro-4H-pyrano [4,3-d] thiazole-2-carboxylic acid and 1-[(5-chloro-1-phenylsulfonylindole-2) -Ill)
Sulfonyl] -3- (N, N-dimethylcarbamoyl)
The title compound (light yellow solid) was obtained from methyl piperazine in the same manner as in Example 232. ¹ H NMR (CDCl ₃ ) 2.72-3.51 (16
H, m), 3.79-3.82 (1H, m), 4.02.
-4.10 (2H, m), 4.12-4.20 (1H,
m), 4.84 (2H, s), 6.99 (1H, s),
7.29-7.32 (1H, m), 7.37 (1H,
d, J = 9.0 Hz), 7.64 (1H, s). MS (FAB) m / z 552 [(M + H) ⁺ , C
l ³⁵ ], 554 [(M + H) ⁺ , Cl ³⁷ ].

Example 330 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(6-methoxymethoxy-4,5,6,7
-Tetrahydrobenzo [d] thiazol-2-yl) carbonyl] piperazine (1) and 1-[(5-chloro-1-methoxymethylindol-2-yl) sulfonyl] -4-[(6-methoxymethoxy-4) , 5,6,7
-Tetrahydrobenzo [d] thiazol-2-yl) carbonyl] piperazine (2) 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(6-hydroxyxy-4,5,6,7 −
Tetrahydrobenzo [d] thiazol-2-yl) carbonyl] piperazine (180 mg) was treated with methylene chloride (6
mL) and 1,4-dioxane (4 mL), methoxymethyl chloride (70 L) and diisopropylethylamine (0.2 mL) were added, and the mixture was stirred at room temperature. After 24 hours, the solvent was distilled off under reduced pressure, chloroform was added, and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methylene chloride: methanol = 10: 1).
The title compound (1) (50 mg, colorless solid) and the title compound (2) (80 mg, colorless solid) were obtained. Title compound (1) ¹ H NMR (CDCl ₃ ) δ 1.99-2.04 (2
H, m), 2.80-3.15 (6H, m), 3.33.
-3.37 (7H, m), 3.86 (1H, brs),
4.25-4.30 (1H, m), 4.54 (1H, b
rs), 5.73 (2H, s), 7.12 (1H,
s), 7.37 (1H, dd, J = 8.8, 2.2H
z), 7.48 (1H, d, J = 8.8 Hz), 7.6
6 (1H, s). MS (FAB) m / z 525 [(M + H) ⁺ , C
l ³⁵ ], 527 [(M + H) ⁺ , Cl ³⁷ ]. Title compound (2) ¹ H NMR (CDCl ₃ ) δ 2.04-2.07 (2
H, m), 2.76-3.19 (6H, m), 3.31.
-3.37 (7H, m), 3.37 (3H, s), 3.
86 (1H, brs), 4.11-4.15 (1H,
m), 4.54 (1H, brs), 4.70 (1H,
d, J = 6.8 Hz), 4.74 (1H, d, J = 6.
8Hz), 5.73 (2H, s), 7.12 (1H,
s), 7.36 (1H, dd, J = 8.8, 2.0H
z), 7.47 (1H, d, J = 8.8 Hz), 7.6
6 (1H, s). MS (FAB) m / z 569 [(M + H) ⁺ , C
l ³⁵ ], 571 [(M + H) ⁺ , Cl ³⁷ ].

Example 331 1-[(6,7-Dihydro-4H-pyrano [4,3-
d] thiazol-2-yl) carbonyl] -4-[(5
-Trimethylsilylethynylindol-2-yl) sulfonyl] piperazine 6,7-dihydro-4H-pyrano [4,3-d] thiazole-2-carboxylic acid lithium salt and 1-[(1-phenylsulfonyl-5-trimethylsilylethynyl) Indole-2-yl) sulfonyl] piperazine and the title compound (110 mg,
(Light yellow amorphous) was obtained. ¹ H NMR (DMSO-d ₆ ) δ 0.22 (9H,
s), 2.85-2.90 (2H, m), 3.26-
3.31 (6H, m), 3.81 (1H, brs),
3.94-4.03 (2H, m), 4.44 (1H, b
rs), 4.80-4.83 (2H, m), 6.98.
(1H, s), 7.33-7.47 (2H, m), 7.
79 (1H, s).

The 1-[(1-phenylsulfonyl-5-trimethylsilylethynylindole-
2-yl) sulfonyl] piperazine was synthesized by the following method.

<1 [-[(1-Phenylsulfonyl-5-
Trimethylsilylethynylindol-2-yl) sulfonyl] piperazine> piperazine (13.4 g) was dissolved in dichloromethane (300 mL), and (1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl chloride (100 mL) was dissolved under ice-cooling. 250mg)
Was added, and the mixture was stirred for 23 hours while gradually warming from 0 ° C. to room temperature. After completion of the stirring, the reaction solution was ice-cooled, and the precipitated crystals were removed by filtration. Water was added to the filtrate to carry out a liquid separation operation. Distilled off under. The residue is subjected to medium pressure column chromatography (S
I-40D, 3% methanol-dichloromethane) to give the title compound (2.17 g, pale yellow amorphous). ¹ H NMR (CDCl ₃ ) 0.25 (9H, s), 2.
90-3.00 (4H, m), 3.35-3.45 (4
H, m), 7.35-7.45 (3H, m), 7.50.
−7.60 (2H, m), 7.65-7.70 (1H,
m), 7.95-8.05 (2H, m), 8.22 (1
H, d, J = 8.8 Hz). MS (ESI) m / z 502 (M + H) ⁺ .

Example 332 1-[(6,7-Dihydro-4H-pyrano [4,3-
d] thiazol-2-yl) carbonyl] -4-[(5
-Ethynylindol-2-yl) sulfonyl] piperazine 1-[(6,7-dihydro-4H-pyrano [4,3-
d] thiazol-2-yl) carbonyl] -4-[(5
-Trimethylsilylethynylindol-2-yl) sulfonyl] piperazine (110 mg) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), and powdered potassium hydroxide (24 mg) was added, followed by stirring at room temperature. After the solvent was distilled off under reduced pressure, chloroform was added, and the mixture was washed with a saturated ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ethyl acetate:
Hexane = 1: 1) to give the title compound (65 mg, colorless solid). ¹ H NMR (CDCl ₃ ) δ 2.89-2.91 (2
H, m), 3.04-3.23 (7H, m), 3.89.
(1H, br s), 4.02 (2H, t, J = 4.6)
Hz), 4.59 (1H, brs), 4.83 (2
H, s), 7.00 (1H, s), 7.34-7.49.
(2H, m), 7.86 (1H, s), 8.90 (1
H, s). MS (FAB) m / z 457 (M + H) ^<+> .

Example 333 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-[(5-trimethylsilylethynylindole -2-yl) sulfonyl] piperazine 6-t-butyldiphenylsilyloxy-4,5,6
7-Tetrahydrobenzo [d] thiazole-2-carboxylic acid lithium salt and 1-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine were obtained in the same manner as in Example 232 to give the title compound ( (Light yellow amorphous) was obtained. ¹ H NMR (CDCl ₃ ) δ 0.26 (9H, s),
1.02 (9H, s), 1.82 to 2.01 (2H,
m), 2.62-3.21 (10H, m), 3.87
(1H, brs), 4.20-4.22 (1H, brs)
m), 4.57 (1H, brs), 6.98 (1H,
s), 7.30-7.67 (12H, m), 7.82.
(1H, s), 8.79 (1H, s).

Example 334 1-[(5-ethynylindol-2-yl) sulfonyl] -4-[(6-hydroxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl ] Piperazine 1-[(6-tert-butyldiphenylsilyloxy-4,5,6,7-tetrahydrobenzo [d] thiazol-2-yl) carbonyl] -4-[(5-trimethylsilylethynylindol-2-yl) ) Sulfonyl] piperazine to give the title compound (60 mg, colorless solid) in the same manner as in Example 320. ¹ H NMR (CD ₃ OD) δ 1.89-2.02 (2
H, m), 2.72-3.22 (11H, m), 3.8
1 (1H, brs), 4.14-4.19 (1H, brs)
m), 4.43 (1H, brs), 7.03 (1H,
s), 7.36-7.44 (2H, m), 7.82 (1
H, s). MS (FAB) m / z 471 (M + H) ^<+> .

Example 335 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4
3-d] thiazol-2-yl) carbonyl] -2-methoxycarbonylmethylpiperazine 6,7-dihydro-4H-pyrano [4,3-d] thiazole-2-carboxylic acid lithium salt and 1-[(1- Phenylsulfonyl-5-chloroindol-2-yl)
The title compound (light yellow amorphous) was obtained from [sulfonyl] -3-methoxycarbonylmethylpiperazine in the same manner as in Example 232. ¹ H NMR (CDCl ₃ ) δ2.59-3.20 (9
H, m), 3.65-3.95 (5H, m), 4.01.
(2H, t, J = 5.6 Hz), 4.83 (2H,
s), 6.96 (1H, s), 7.30-7.38 (2
H, m), 7.65 (1H, s), 9.08-9.13
(1H, m). MS (FAB) m / z 539 [(M + H) ⁺ , C
l ³⁵ ], 541 [(M + H) ⁺ , Cl ³⁷ ].

Example 336 2-Carboxymethyl-4-[(5-chloroindol-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4,3-d] thiazole-2 -Ill)
Carbonyl] piperazine 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4
3-d] thiazol-2-yl) carbonyl] -2-methoxycarbonylmethylpiperazine (110 mg) was dissolved in tetrahydrofuran (2 mL) and methanol (5 mL), 1N sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature. did. After 5 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, 1N hydrochloric acid was added, the mixture was extracted with methylene chloride, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (275 mg, pale yellow). Yellow amorphous). ¹ H NMR (CDCl ₃ ) δ2.59-3.23 (9
H, m), 3.75-4.00 (4H, m), 4.81
(2H, s), 6.95 (1H, s), 7.25-7.
27 (1H, m), 7.36 (1H, d, J = 8.8H
z), 7.62 (1H, s), 9.82-9.98 (1
H, m). MS (FAB) m / z 525 [(M + H) ⁺ , C
l ³⁵ ], 527 [(M + H) ⁺ , Cl ³⁷ ].

Example 337 4-[(5-chloroindol-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4
3-d] thiazol-2-yl) carbonyl] -2-
[[N- (methylsulfonyl) carbamoyl] methyl]
Piperazine 2-carboxymethyl-4-[(5-chloroindol-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4,3-d] thiazol-2-yl)
Carbonyl] piperazine (275 mg) was added, dissolved in tetrahydrofuran (10 mL), 1,1′-carbonylbis-1H-imidazole (255 mg) was added, and the mixture was heated under reflux. One hour later, the reaction solution was cooled to room temperature, methanesulfonamide (100 mg) and 1,8-diazacyclo [5,4,0] unde-7-cene (160 L) were added, and the mixture was stirred at room temperature. After 15 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, 1N hydrochloric acid was added, the mixture was extracted with methylene chloride, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, methylene chloride: methanol = 10: 1),
The title compound (190 mg, a colorless solid) was obtained. ¹ H NMR (CDCl ₃ ) δ 2.61-3.26 (12
H, m), 3.78-3.99 (4H, m), 4.77.
-4.81 (2H, m), 6.93 (1H, s), 7.
22-7.35 (2H, m), 7.62 (1H, s). MS (FAB) m / z 602 [(M + H) ⁺ , C
l ³⁵ ], 604 [(M + H) ⁺ , Cl ³⁷ ].

Example 338 1-[(6,7-Dihydro-4H-pyrano [4,3-
d] thiazol-2-yl) carbonyl] -2- (N,
N-dimethylcarbamoyl) methyl-4-[(5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine lithium salt of 6,7-dihydro-4H-pyrano [4,3-d] thiazole-2-carboxylic acid and 3 − (N, N−
Example 232 from dimethylcarbamoyl) methyl-1-[[1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl] sulfonyl] piperazine.
By the same method as in the above, the title compound (420 mg, pale yellow amorphous) was obtained. ¹ H NMR (CDCl ₃ ) δ 0.26 (9H, s),
2.57-3.05 (9H, m), 2.89 (3H,
s), 2.96 (3H, s), 3.76-4.21 (4
H, m), 4.84 (2H, s), 7.02 (1H,
s), 7.35-7.43 (2H, m), 7.82 (1
H, s), 8.02 (1H, s). MS (FAB) m / z 614 (M + H) ^<+> .

Example 339 1-[(6,7-Dihydro-4H-pyrano [4,3-
d] thiazol-2-yl) carbonyl] -2- (N,
N-dimethylcarbamoyl) methyl-4-[(5-ethynylindol-2-yl) sulfonyl] piperazine 1-[(6,7-dihydro-4H-pyrano [4,3-
d] thiazol-2-yl) carbonyl] -2- (N,
The title compound (250 mg, colorless amorphous) was obtained from N-dimethylcarbamoyl) methyl-4-[(5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine in the same manner as in Example 332. ¹ H NMR (CDCl ₃ ) δ 2.69-3.36 (16
H, m), 3.76-4.22 (4H, m), 4.84.
(2H, s), 7.04 (1H, s), 7.37-7.
52 (2H, m), 7.85 (1H, s). MS (FAB) m / z 542 (M + H) ^<+> .

Example 340 4-[(6-Chlorobenzo [d] thien-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4,3-d] thiazol-2-yl ) Carbonyl]-
2-methoxycarbonylmethylpiperazine 6,7-dihydro-4H-pyrano [4,3-d] thiazole-2-carboxylic acid lithium salt and 1-[(6-chlorobenzo [d] thien-2-yl) sulfonyl]- 3
Example 23 from -methoxycarbonylmethylpiperazine
The title compound (320 mg, pale yellow amorphous) was obtained in the same manner as in 2. ¹ H NMR (CDCl ₃ ) δ 2.67-3.24 (9
H, m), 3.64-3.69 (3H, m), 3.91
-3.97 (2H, m), 4.02 (2H, t, J =
5.9 Hz), 4.84 (2H, s), 7.44 (1
H, dd, J = 8.5, 2.0 Hz), 7.77 (1
H, s), 7.81 (1H, d, J = 8.5 Hz),
7.85 (1H, s). MS (FAB) m / z 556 [(M + H) ⁺ , C
l ³⁵ ], 558 [(M + H) ⁺ , Cl ³⁷ ].

Example 341 2-carboxymethyl-4-[(6-chlorobenzo [d] thien-2-yl) sulfonyl] -1-[(6
7-dihydro-4H-pyrano [4,3-d] thiazol-2-yl) carbonyl] piperazine 4-[(6-chlorobenzo [d] thien-2-yl) sulfonyl] -1-[(6,7- Dihydro-4H-pyrano [4,3-d] thiazol-2-yl) carbonyl]-
Example 3 from 2-methoxycarbonylmethylpiperazine
By the same reaction as in 36, the title compound (light yellow amorphous)
I got ¹ H NMR (CDCl ₃ ) δ 2.65-3.51 (9
H, m), 3.87-3.90 (2H, m), 4.02
(2H, t, J = 5.5 Hz), 4.84 (2H, t, J = 5.5 Hz)
s), 7.44 (1H, dd, J = 8.6, 1.5H)
z), 7.78 (1H, s), 7.81 (1H, d, J
= 8.6 Hz), 7.85 (1H, s). MS (FAB) m / z 542 [(M + H) ⁺ , C
l ³⁵ ], 544 [(M + H) ⁺ , Cl ³⁷ ].

Example 342 4-[(6-Chlorobenzo [d] thien-2-yl) sulfonyl] -1-[(6,7-dihydro-4H-pyrano [4,3-d] thiazol-2-yl ) Carbonyl]-
2-[(N, N-dimethylcarbamoyl) methyl] piperazine 2-carboxymethyl-4-[(6-chlorobenzo [d] thien-2-yl) sulfonyl] -1-[(6
The title compound (light yellow amorphous) was obtained by the same reaction as in Example 266 using 7-dihydro-4H-pyrano [4,3-d] thiazol-2-yl) carbonyl] piperazine and dimethylamine hydrochloride. Was. ¹ H NMR (CDCl ₃ ) δ 2.53-3.27 (9
H, m), 2.93 (3H, s), 3.02 (3H,
s), 3.91-4.04 (4H, m), 4.83 (2
H, s), 7.43 (1H, dd, J = 8.6, 1.7)
Hz), 7.76 (1H, s), 7.80 (1H, d,
J = 8.6 Hz), 7.85 (1H, s). MS (FAB) m / z 569 [(M + H) ⁺ , C
l ³⁵ ], 571 [(M + H) ⁺ , Cl ³⁷ ].

Example 343 1-[[6- (N, N-dimethylamino) -4,5,
6,7-tetrahydrobenzo [d] thiazol-2-yl] carbonyl] -2- (N, N-dimethylcarbamoyl) methyl-4-[(5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine [6- (N, N-dimethylamino) -4,5,6,7-
Lithium tetrahydrobenzo [d] thiazol-2-yl] carboxylate and 3- (N, N-dimethylcarbamoyl) methyl-1-[(1-phenylsulfonyl-
5-trimethylsilylethynylindol-2-yl)
The title compound (170 mg, pale yellow amorphous) was obtained in the same manner as in Example 232 using [sulfonyl] piperazine. ¹ H NMR (CDCl ₃ ) δ 0.26 (9H, s),
1.75-2.13 (2H, m), 2.37 (9H,
s), 2.49-4.22 (20H, m), 7.02.
(1H, s), 7.36-7.42 (2H, m), 7.
83 (1H, s). MS (FAB) m / z 655 (M + H) ^<+> .

Example 344 4-[(5-ethynylindol-2-yl) sulfonyl] -1-[[6- (N, N-dimethylamino) -4,
5,6,7-tetrahydrobenzo [d] thiazole-2
-Yl] carbonyl] -2- (N, N-dimethylcarbamoyl) methylpiperazine 1-[[6- (N, N-dimethylamino) -4,5,
Example from 6,7-tetrahydrobenzo [d] thiazol-2-yl] carbonyl] -2- (N, N-dimethylcarbamoyl) methylpi-4-[(5-trimethylsilylethynylindol-2-yl) sulfonyl] perazine Title compound (colorless, amorphous) by a method similar to 320.
I got ¹ H NMR (CDCl ₃ ) δ 1.74-1.75 (1
H, m), 2.12 to 2.18 (1H, m), 2.35
(6H, s), 2.59-3.33 (19H, m),
3.73-3.78 (1H, m), 4.20-4.23
(1H, m), 7.00 (1H, s), 7.36-7.
44 (2H, m), 7.86 (1H, s). MS (FAB) m / z 583 (M + H) ⁺ .

Example 345 2- [2- (benzyloxycarbonylaminosulfonyl) ethyl] -4-[(5-chloroindol-2-yl) sulfonyl] -1-[(5-methyl-4,5,6 ,
7-tetrahydrothiazolo [5,4-c] pyridine-2
-Yl) carbonyl] piperazine 3- [2- (benzyloxycarbonylaminosulfonyl) ethyl] -1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] piperazine and 5-methyl-4,5 The title compound was obtained as a colorless amorphous powder in the same manner as in Example 232 using lithium salt of 6,6,7-tetrahydrothiazolo [5,4-c] pyridine-2-carboxylic acid. _{^{1 H NMR (DMSO-d 6}} ) 1.95-2.10 (1
H, m), 2.20-2.70 (4H, m), 2.75
-2.90 (5H, m), 3.00-3.80 (8H,
m), 4.35-4.45, 4.75-4.85 (1
H, reach m), 4.95-5.05 (2H,
m), 5.35-5.45, 5.60-5.70 (1
H, reach m), 7.01 (1H, s), 7.30.
−7.40 (6H, m), 7.47 (1H, d, J =
8.8 Hz), 7.75 (1 H, s), 12.38 (1
H, s). MS (FAB) m / z 721 [(M + H) ⁺ , C
l ³⁵ ], 723 [(M + H) ⁺ , Cl ³⁷ ].

[1562] 3- [2- (benzyloxycarbonylaminosulfonyl) ethyl] -1-
[(5-Chloro-1-phenylsulfonylindole-
2-yl) sulfonyl] piperazine was synthesized by the following method.

<1,4-bis (tert-butoxycarbonyl) -2- [2- (chlorosulfonyl) ethyl] piperazine> Sodium sulfite (4.57 g) was added to water (10
0 ml). Under ice cooling, 2-bromoethyl 1,4-bis (tert-butoxycarbonyl) was added to the reaction mixture.
A solution of piperazine (5.92 g) in N, N-dimethylformamide (200 ml) was added, and the mixture was added at 50 ° C. for 11 hours.
The mixture was stirred at 0 for 8 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethanol (150 ml) was added to the obtained residue, the insolubles were removed by filtration, and the filtrate was distilled off under reduced pressure to obtain a crude purified product of sodium sulfate (6.17 g) as a colorless paste. Then, a part (1.02 g) of this crude product
Was dissolved in N, N-dimethylformamide (10 ml) in a 100 ml eggplant flask, and thionyl chloride (215 l) was added dropwise to the reaction mixture under ice cooling, followed by stirring at room temperature for 1 hour. After completion of the stirring, the reaction solution was poured into ice water (40 ml), and the insoluble matter was collected by filtration and dried. The residue was dissolved in dichloromethane, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (166 mg) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) 1.48 (18H, s),
2.10-2.20 (1H, m), 2.25-2.45
(1H, m), 2.70-3.10 (3H, m), 3.
50-3.60 (1H, m), 3.65-4.15 (4
H, m), 4.20-4.40 (1H, m).

<2- [2- (Aminosulfonyl) ethyl] -1,4-bis (tert-butoxycarbonyl)
Piperazine> dichloromethane (50 ml) and aqueous ammonia (50 ml) were mixed and separated, and the organic layer was dried over anhydrous sodium sulfate to prepare ammonia-dichloromethane. 1,4-bis (tert-butoxycarbonyl)
-2- [2- (chlorosulfonyl) ethyl] piperazine (1.05 g) and diisopropylethylamine (50
0l) were mixed. Under ice-cooling, the previously adjusted saturated ammonia-dichloromethane was added to the mixture, and the mixture was added at room temperature for 14 hours.
Stirred for hours. After completion of the stirring, insolubles were removed by filtration, the filtrate was distilled off under reduced pressure, and the residue was subjected to flash column chromatography using silica gel as a carrier (hexane: ethyl acetate =
1: 1) to give the title compound (796 mg) as a colorless amorphous powder. ¹ H NMR (CDCl ₃ ) 1.47, 1.47 (18
H, each s), 2.00-2.20 (2H,
m), 2.70-3.35 (5H, m), 3.75-
4.35 (4H, m), 4.80-5.05 (2H, b
r). MS (FAB) m / z 394 (M + H) ^<+> .

<2- [2- (benzyloxycarbonylaminosulfonyl) ethyl] -1,4-bis (tert)
-Butoxycarbonyl) piperazine> 2- [2- (aminosulfonyl) ethyl] -1,4 under argon atmosphere
-Bis (tert-butoxycarbonyl) piperazine (105.8 mg), 4-dimethylaminopyridine (1
0.7 mg) was dissolved in dichloromethane (10 ml). Under ice-cooling, triethylamine (0.10 ml) and benzyl chloroformate (0.10 ml) were sequentially added, and the mixture was stirred at room temperature for 21.5 hours. Water was added to the reaction solvent, and after a liquid separation operation, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to flash column chromatography (hexane: ethyl acetate = 1: 1) using silica gel as a carrier to obtain the title compound (76.5 mg) as a pale yellow oil. _{^{1 H NMR (CDCl 3) 1.44}} (9H, s), 1.
45 (9H, s), 1.90-2.00 (1H, m),
2.05-2.20 (1H, m), 2.65-3.0
0, 3.10-3.50, 3.60-4.35 (9H,
m), 5.15 (2H, s), 7.35 (5H, s). MS (FAB) m / z 528 (M + H) ^<+> .

<3- [2- (benzyloxycarbonylaminosulfonyl) ethyl] -1-[(5-chloro-1
-Phenylsulfonylindol-2-yl) sulfonyl] piperazine> 2- [2- (benzyloxycarbonylaminosulfonyl) ethyl] -1,4-bis (ter
(t-Butoxycarbonyl) piperazine (78 mg) was dissolved in dichloromethane (2.0 ml) and methanol saturated with hydrochloric acid (7 ml) and stirred at room temperature for 5.5 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in diisopropylethylamine (130 l) and dichloromethane (5 ml), (5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl chloride (55.3 mg) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. did. The solvent is distilled off under reduced pressure,
The residue was subjected to flash column chromatography (4% methanol-dichloromethane) using silica gel as a carrier to obtain the title compound (72.7 mg) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) 1.80-1.90 (1H,
m), 2.10-2.20 (1H, m), 2.90-
3.85 (10H, m), 5.04 (2H, s), 7.
15-7.35 (5H, m), 7.40-7.50 (4
H, m), 7.50-7.60 (2H, m), 7.99
(2H, d, J = 7.8 Hz), 8.17 (1H, d,
J = 9.1 Hz). MS (FAB) m / z 681 [(M + H) ⁺ , C
l ³⁵ ], 683 [(M + H) ⁺ , Cl ³⁷ ].

Example 346 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] Pyridazin-2-yl) carbonyl] -2-ethoxycarbonylpiperazine hydrochloride It was synthesized in the same manner as in Example 236. IR (KBr) cm ^-1 3106,2973,2869,
1735, 1629, 1504, 1467, 1450,
1415, 1359, 1307, 1270, 1241,
1218, 1197, 1159, 1103, 1060,
1033,977,952,939,916,844,
809. ¹ H NMR (DMSO-d ₆ ) 1.10-1.25 (3
H, m), 2.60-2.90 (7H, m), 3.10
-3.80 (2H, m), 4.00-4.55, 5.3
0-5.50, 6.25-6.35 (10H, each
m), 7.05 (1H, s), 7.32 (1H, d
d, J = 8.8, 1.9 Hz), 7.49 (1H, d,
J = 8.8 Hz), 7.77 (1H, d, J = 1.9H)
z), 12.50 (1H, s). MS (FAB) m / z 567 [(M + H) ⁺ , C
l ³⁵ ], 569 [(M + H) ⁺ , Cl ³⁷ ].

Example 347 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (N, N-dimethylcarbamoyl) -1-
[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine hydrochloride 4-[(5-chloroindol-2-yl) Sulfonyl] -1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -2-ethoxycarbonylpiperazine (300 mg, 0.1 mg). 53 mmol) was dissolved in tetrahydrofuran (5.0 ml) and ethanol (5 ml).
To this reaction solution was added sodium hydroxide (28 mg,
(0.70 mmol) / water (5.0 ml) was added dropwise, and the mixture was heated and refluxed at room temperature for 4 hours. Under ice cooling, 1N hydrochloric acid (710
l) was added to make it weakly acidic. Next, the reaction solution was distilled off under reduced pressure to obtain a crudely purified carboxylic acid (308 mg). To the obtained carboxylic acid, dimethylamine hydrochloride (96 mg),
1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (208 mg) and 1-hydroxybenzotriazole (149 mg) were added and dissolved in N, N-dimethylformamide (15 ml). Further, diisopropylamine (760 l, 564 mg) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 12.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to liquid separation operation by adding dichloromethane and a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to flash column chromatography (5% methanol-dichloromethane) using silica gel as a carrier to give a crude product of the title compound (154 mg).
I got This crude product was dissolved in dichloromethane, 1N hydrochloric acid-ethanol (272 l) was added, and the mixture was dried once,
It was again dissolved in dichloromethane, solidified by adding ethyl acetate, collected by filtration, washed with ethyl acetate, and dried to obtain the title compound (162 mg) as a colorless amorphous powder. IR (KBr) cm ^-1 3430, 3116, 3014
2967, 2937, 2869, 2350, 1731,
1650, 1627, 1502, 1465, 1402
1355, 1307, 1286, 1267, 1241,
1160, 1099, 1058, 952, 809. _{^{1 H NMR (DMSO-d 6}} ) 2.55-2.90 (9
H, m), 3.00-3.10 (4H, m), 3.45
(1H, br), 3.60-3.90 (3H, m),
4.10-4.50, 5.15-5.40, 6.10-
6.20 (6H, reach m), 7.04 (1H,
d, J = 1.5 Hz), 7.20-7.20 (1H,
m), 7.40-7.50 (1H, m), 7.74 (1
H, s), 12.47 (1H, s). MS (FAB) m / z 566 [(M + H) ⁺ , C
l ³⁵ ], 5668 [(M + H) ⁺ , Cl ³⁷ ].

Example 348 2-Carboxy-4-[(5-chloroindole-2-
Yl) sulfonyl] -1-[(5,6-dimethyl-4,
5,6,7-Tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine It was synthesized in the same manner as in Example 336. IR (KBr) cm ^-1 3401, 3239, 3021
2954, 2854, 1731, 1623, 1538,
1504, 1459, 1357, 1309, 1278,
1224, 1159, 1106, 1060, 981, 9
54, 809. _{^{1 H NMR (DMSO-d 6}} ) 2.20-2.45 (6
H, m), 2.60-2.80 (1H, m), 3.10
-3.55 (1H, m), 3.65-3.80 (4H,
m), 3.90-4.00 (2H, m), 4.15-
4.25, 4.35-4.45, 5.15-5.25,
5.45-5.55, 6.50-6.60 (3H, ea
ch m), 7.05 (1H, s), 7.31 (1H,
dd, J = 8.8, 1.9 Hz), 7.49 (1H,
d, J = 8.8 Hz), 7.77 (1H, d, J = 1.
9Hz), 12.47 (1H, s). MS (FAB) m / z 539 [(M + H) ⁺ , C
l ³⁵ ], 541 [(M + H) ⁺ , Cl ³⁷ ].

Example 349 4-[(5-Chloroindol-2-yl) sulfonyl] -1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] Pyridazin-2-yl) carbonyl] -2- (N-methylcarbamoyl) piperazine hydrochloride It was synthesized by the same method as in Example 266. IR (KBr) cm ^-1 3237, 3116, 2969,
2875, 2370, 1670, 1627, 1544,
1502, 1467, 1413, 1355, 1307,
1276,1159,1106,952,939,80
9. _{^{1 H NMR (DMSO-d 6}} ) 2.62 (3H, s),
2.65-2.75 (3H, m), 2.83 (3H,
s), 3.15-3.75 (4H, m), 4.20-
4.60, 4.95-5.05, 5.40-5.50,
6.00-6.10 (7H, each m), 7.01.
(1H, d, J = 3.7 Hz), 7.30 (1H, d
d, J = 8.8, 2.0 Hz), 7.48 (1H, d,
J = 8.8 Hz), 7.76 (1H, d, J = 1.6H)
z), 8.05-8.20 (1H, m), 12.41
(1H, s). MS (FAB) m / z 552 [(M + H) ⁺ , C
l ³⁵ ], 554 [(M + H) ⁺ , Cl ³⁷ ].

Example 350 4-[(5-Chloroindol-2-yl) sulfonyl] -2- (N-cyanomethyl-N-methylcarbamoyl) -1-[(5,6-dimethyl-4,5,6 , 7-Tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] piperazine hydrochloride It was synthesized in the same manner as in Example 347. IR (KBr) cm ^-1 3423, 3114, 2975,
2867, 2362, 1729, 1666, 1627,
1504, 1465, 1411, 1355, 1282
1159, 1126, 1099, 952, 809. _{^{1 H NMR (DMSO-d 6}} ) 2.65-2.85 (6
H, m), 2.90-3.20 (5H, m), 3.25
-4.50, 5.15-5.25, 5.40-5.5
0, 6.00-6.10 (11H, reach m),
7.04 (1H, s), 7.30 (1H, d, J = 8.
8 Hz), 7.46 (1H, d, J = 8.8 Hz),
7.75 (1H, s), 12.48 (1H, s). MS (FAB) m / z 591 [(M + H) ⁺ , C
l ³⁵ ], 593 [(M + H) ⁺ , Cl ³⁷ ].

Example 351 2- [2- (tert-butyldiphenylsilyloxy) ethyl] -1-[(5,6-dimethyl-4,5,
6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine 3- [2- (tert-butyldiphenyl) Silyloxy) ethyl] -1-[(1-phenylsulfonyl-5-
Trimethylsilylethynylindol-2-yl) sulfonyl] piperazine and 5,6-dimethyl-4,5,
Example 232 using lithium 6,7-tetrahydrothiazolo [4,5-d] pyridazine-2-carboxylate
The title compound (542 mg) was obtained as a pale yellow amorphous in the same manner as in. ¹ H NMR (CDCl ₃ ) 0.26 (9H, s), 0.
95-1.05 (9H, m), 2.05-2.15 (2
H, m), 2.25-2.70 (5H, m), 2.88
(3H, s), 2.96 (3H, m), 3.10-3.
20, 3.40-4.05, 4.50-4.60, 5.
05-5.10, 5.55-5.65, 5.95-6.
05 (8H, reach m), 7.30-7.45 (8
H, m), 7.55-7.70 (4H, m), 7.82.
(1H, s), 8.02 (1H, s), 8.85-8.
95 (1H, m). MS (FAB) m / z 839 (M + H) ^<+> .

Example 352 1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(5-ethynyl) Indole-2-yl) sulfonyl] -2- (2-hydroxyethyl) piperazine 2- [2- (tert-butyldiphenylsilyloxy) ethyl] -1-[(5,6-dimethyl-4,
5,6,7-Tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine was treated as in Example 320. The title compound was obtained as a colorless amorphous powder. IR (KBr) cm ^-1 3278, 3120, 2950,
2925, 2856, 2103, 1616, 1511,
1459, 1357, 1309, 1276, 1162
1118, 1054, 954, 927, 815. _{^{1 H NMR (CDCl 3) 1.85-2.00}} (1H,
m), 2.20-2.80 (9H, m), 3.04 (1
H, s), 3.10-3.90 (7H, m), 3.95
-4.05, 4.60-4.70, 4.85-4.9
5, 5.35-5.45, 5.75-5.85 (4H,
each m), 6.99 (1H, d, J = 15.4H)
z), 7.35-7.50 (2H, m), 7.85 (1
H, s), 9.40 (1H, d, J = 19.8 Hz). MS (ESI) m / z 529 (M + H) ^<+> .

Example 353 1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -2- (2-methoxyethyl ) -4-[(5
-Trimethylsilylethynylindol-2-yl) sulfonyl] piperazine 3- (2-methoxyethyl) -1-[(1-phenylsulfonyl-5-trimethylsilylethynylindole-
2-yl) sulfonyl] piperazine and 5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5
-D] Pyridazine-2-carboxylic acid Lithium salt was obtained in the same manner as in Example 232, using the title compound (14
2 mg) was obtained as a pale yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 0.26 (9H, s), 1.
55-1.65 (2H, m), 1.95-2.15 (1
H, m), 2.41 (3H, s), 2.53 (3H,
s), 2.55-2.75 (2H, m), 3.15-
3.55 (5H, m), 3.70-4.10 (5H,
m), 4.50-4.60, 4.90-5.00, 5.
55-5.65, 5.90-6.00 (2H, each
m), 6.95-7.45 (4H, m), 7.83
(1H, s).

1- (2-methoxyethyl) -1-[(1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] used as a starting material
Piperazine was synthesized by the following method.

<1,4-bis (tert-butoxycarbonyl) -2-methoxyethylpiperazine> Sodium hydride (60% in oi) under ice-cooling and argon atmosphere
l) (71.1 mg) of tetrahydrofuran (3 ml)
To the suspension was added 1,4-bis (tert-butoxycarbonyl) -2-hydroxyethylpiperazine (300 mg).
Of tetrahydrofuran (4 ml) was added dropwise. After stirring at room temperature for 10 minutes, a solution of methyl iodide (112 l) in tetrahydrofuran (2 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 6 hours. Under ice-cooling, water and ethyl acetate were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (248 mg) as a pale-yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 1.46 (9H, s), 1.
47 (9H, s), 1.70-1.80 (1H, m),
1.80-1.90 (1H, m), 2.77 (1H, b
r), 2.90-3.00 (2H, m), 3.80-
4.30 (4H, m). MS (FAB) m / z 345 (M + H) ^<+> .

<3- (2-methoxyethyl) -1-
[(1-Phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl] piperazine> 1,4-bis (tert-butoxycarbonyl) -2
-(2-Methoxyethyl) piperazine (239 mg) was dissolved in ethanol saturated with hydrochloric acid (10 ml), and the solution was dissolved in ethanol at room temperature.
Stir for 5 hours. The solvent was distilled off under reduced pressure, and the residue was diisopropylethylamine (480 l) and dichloromethane (1 liter).
0 ml), (1-phenylsulfonyl-5-trimethylsilylethynylindol-2-yl) sulfonyl chloride (250 mg) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 14 hours. Sulfonyl-5-trimethylsilylethynylindole-2
-Yl) sulfonyl chloride (25.8 mg) was added and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added thereto to carry out a liquid separation operation. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to flash column chromatography (3% methanol-dichloromethane) using silica gel as a carrier to obtain the title compound (245 mg) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) 0.25 (9H, s), 1.
55-1.65 (2H, m), 2.50-2.70 (1
H, m), 2.85-3.05 (4H, m), 3.30.
(3H, s), 3.45-3.50 (2H, m), 3.
76 (2H, d, J = 2.0 Hz), 7.35-7.4
5 (3H, m), 7.50-7.60 (2H, m),
7.65-7.70 (1H, m), 7.95-8.05
(2H, m), 8.21 (1H, d, J = 9.0H
z). MS (FAB) m / z 560 (M + H) ⁺ .

Example 354 1-[(5,6-Dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazin-2-yl) carbonyl] -4-[(5-ethynyl) Indole-2-yl) sulfonyl] -2- (2-methoxyethyl) piperazine 1-[(5,6-dimethyl-4,5,6,7-tetrahydrothiazolo [4,5-d] pyridazine-2- Yl) carbonyl] -2- (2-methoxyethyl) -4-[(5
-Trimethylsilylethynylindol-2-yl) sulfonyl] piperazine was treated in the same manner as in Example 320 to give the title compound as a colorless amorphous powder. IR (KBr) cm ^-1 3276, 2950, 2923,
2856, 1617, 1457, 1347, 1309,
1276, 1162, 1166, 954, 921, 81
5. ¹ H NMR (CDCl ₃ ) 2.00-2.20 (3H,
m), 2.41 (3H, s), 2.52 (3H, s),
2.55-2.65 (1H, m), 2.70-2.80
(1H, m), 3.04 (1H, s), 3.10-4.
10 (14H, m), 4.50-4.60, 4.90-
5.00, 5.55-5.65, 5.90-6.00
(2H, each m), 7.00 (1H, d, J =
1.5 Hz), 7.37 (1H, d, J = 8.6H)
z), 7.40-7.50 (1H, m), 7.86 (1
H, s), 9.13 (1H, br d, J = 24.5H)
z). MS (ESI) m / z 543 (M + H) ^<+> .

Example 355 4-[(5-Chloroindol-2-yl) sulfonyl] -2- [2- (dimethylaminosulfonyl) ethyl] -1-[(5-methyl-4,5,6,7 -Tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [2- (dimethyl Aminosulfonyl) ethyl] piperazine and 5-methyl-4,5,6,7-tetrahydrothiazolo [5,4-
c] Using lithium salt of pyridine-2-carboxylic acid,
The title compound was obtained as a colorless amorphous powder in the same manner as in Example 236. IR (KBr) cm ^-1 3396,3116,3014
2965, 2925, 2869, 2669, 2543,
2375, 1619, 1504, 1465, 1423
1355, 1326, 1272, 1159, 1097,
1060,956,916,809. _{^{1 H NMR (DMSO-d 6}} ) 2.102.35 (2
H, m), 2.55-2.75 (1H, m), 2.78
(6H, s), 2.91 (3H, s), 3.00-3.
30 (6H, m), 3.40-3.80 (4H, m),
4.30-4.90, 5.30-5.50 (4H, ea
ch m), 7.03 (1H, s), 7.31 (1H,
dd, J = 8.8, 2.0 Hz), 7.48 (1H,
d, J = 8.8 Hz), 7.76 (1H, d, J = 1.
7 Hz), 11.30 (1H, br), 12.46 (1
H, s). MS (ESI) m / z 615 [(M + H) ^<+> , C
l ³⁵ ], 617 [(M + H) ⁺ , Cl ³⁷ ].

The starting material 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl]-
3- [2- (dimethylaminosulfonyl) ethyl] piperazine was synthesized by the following method.

<1,4-bis (tert-butoxycarbonyl) -2- [2- (dimethylaminosulfonyl) ethyl] piperazine> 1,4-bis (tert-butoxycarbonyl) -2- [2- (chlorosulfonyl) ) Ethyl] piperazine (3.01 g) and dimethylamine hydrochloride (718 mg) were dissolved in dichloromethane (50 ml), and diisopropylethylamine (5.60 m
l) was added and the mixture was stirred at room temperature for 37 hours. Dilute hydrochloric acid was added thereto to carry out a liquid separation operation, and the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane → 1 to
Flash column chromatography (hexane: ethyl acetate = 1: 1) using 2% methanol-dichloromethane) and silica gel as carriers gave the title compound (2.04 g) as a yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 1.47 (18H, s),
1.55-1.70 (1H, m), 1.90-2.00
(1H, m), 2.10-2.20 (1H, m), 2.
70-2.90 (2H, m), 2.86 (6H, s),
2.90-3.10 (2H, m), 3.80-4.30
(3H, m). MS (ESI) m / z 422 (M + H) ^<+> .

<1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [2
-(Dimethylaminosulfonyl) ethyl] piperazine>
1,4-bis (tert-butoxycarbonyl) -2-
[2- (Dimethylaminosulfonyl) ethyl] piperazine (0.97 g) was dissolved in dichloromethane (20 ml), and ethanol saturated with hydrochloric acid (50 ml) was added, followed by stirring at room temperature for 4.5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in diisopropylethylamine (1.44 ml) and dichloromethane (50 ml).
Chloro-1-phenylsulfonylindol-2-yl) sulfonyl chloride (805 mg) was added, and the mixture was stirred at room temperature for 13.5 hours. Further, (5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl chloride (82.0 mg) was added, and the mixture was stirred at room temperature for 5.5 hours. Water and dichloromethane were added thereto to carry out a liquid separation operation, and the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to flash column chromatography (3% methanol-dichloromethane) using silica gel as a carrier to give the title compound (72.
7 mg) as a green amorphous solid. ¹ H NMR (CDCl ₃ ) 1.75-1.90 (1H,
m), 1.90-2.00 (1H, m), 2.60-
2.70 (1H, m), 2.80-3.10 (6H,
m), 2.87 (6H, s), 5.65-5.85 (2
H, m), 7.40-7.50 (4H, m), 7.50
−7.60 (2H, m), 8.00 to 8.05 (2H,
m), 8.22 (1H, d, J = 9.0 Hz). MS (ESI) m / z 575 [(M + H) ^<+> , C
l ³⁵ ], 577 [(M + H) ⁺ , Cl ³⁷ ].

Example 356 4-[(5-Chloroindol-2-yl) sulfonyl] -2- [2- (methylaminosulfonyl) ethyl]
-1-[(5-Methyl-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] piperazine hydrochloride 1-[(5-chloro-1-phenylsulfonyl) Indole-2-yl) sulfonyl] -3- [2- (methylaminosulfonyl) ethyl] piperazine and 5-methyl-
4,5,6,7-tetrahydrothiazolo [5,4-c]
The title compound (44.5m) was obtained in the same manner as in Example 236 using lithium pyridine-2-carboxylate.
g, 37%) as a colorless amorphous powder. _{^{1 H NMR (DMSO-d 6}} ) 2.00-2.70 (3
H, m), 2.57 (3H, d, J = 4.7 Hz),
2.80-3.20 (6H, m), 2.91 (3H,
s), 3.20-3.80 (4H, m), 4.30-
4.90, 5.30-5.60 (4H, each
m), 6.95-7.15 (1H, m), 7.31 (1
H, dd, J = 8.9, 1.6 Hz), 7.48 (1
H, d, J = 8.5 Hz), 7.76 (1H, s), 1
1.15 (1H, br), 12.44 (1H, s). MS (ESI) m / z 679 [(M + H + DMSO)
⁺ , Cl ³⁵ ], 681 [(M + H + DMSO) ⁺ , C
l ³⁷ ].

The starting material 1-[(5-chloro-1-phenylsulfonylindol-2-yl) sulfonyl]-
3- [2- (Methylaminosulfonyl) ethyl] piperazine was synthesized by the following method.

<1,4-bis (tert-butoxycarbonyl) -2- [2- (methylaminosulfonyl) ethyl] piperazine> 1,4-bis (tert-butoxycarbonyl) -2- [2- (chlorosulfonyl) )ethyl]
Piperazine (3.07 g) and methylamine hydrochloride (6
25 mg) was dissolved in dichloromethane (50 ml), diisopropylethylamine (5.80 ml) was added under ice cooling, and the mixture was stirred at room temperature for 65 hours. Dilute hydrochloric acid was added to carry out a liquid separation operation, and the organic layer was washed again with diluted hydrochloric acid, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Flash column chromatography using silica gel as a carrier for the residue (hexane: ethyl acetate = 1: 1)
The title compound (117 mg) was obtained as a yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 1.47 (18H, s),
1.90-2.20 (3H, m), 2.10-2.20
(1H, m), 2.78 (3H, d, J = 5.1H
z), 2.80-3.20 (4H, m), 3.80-
4.30 (4H, m), 4.82 (1H, br). MS (ESI) m / z 408 (M + H) ^<+> .

<1-[(5-Chloro-1-phenylsulfonylindol-2-yl) sulfonyl] -3- [2
-(Methylaminosulfonyl) ethyl] piperazine>
1,4-bis (tert-butoxycarbonyl) -2-
To [2- (methylaminosulfonyl) ethyl] piperazine (116 mg), methanol saturated with hydrochloric acid (10 ml) was added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in diisopropylethylamine (180 l), dichloromethane (10 ml) and methanol (1 ml). ) Sulfonyl chloride (90.2 mg) was added, and the mixture was stirred at room temperature for 25 hours.
The solvent is distilled off under reduced pressure, and the residue is subjected to flash column chromatography using silica gel as a carrier (3% methanol-dichloromethane → 5% methanol-dichloromethane).
To give the title compound (101 mg, 64%) as a yellow amorphous solid. ¹ H NMR (CDCl ₃ ) 1.80-2.00 (2H,
m), 2.65-2.70 (1H, m), 2.80 (3
H, s), 2.80-3.20 (6H, m), 3.67.
(1H, d, J = 12.5 Hz), 3.81 (1H,
d, J = 11.0 Hz), 4.75 (1H, br),
7.40-7.50 (4H, m), 7.55-7.60
(2H, m), 8.02 (2H, d, J = 7.6H
z), 8.22 (1H, d, J = 9.1 Hz). MS (ESI) m / z 561 [(M + H) ^<+> , C
l ³⁵ ], 563 [(M + H) ⁺ , Cl ³⁷ ].

Example 357 1-[(5-Chloroindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] pyridine- 2-yl) thiocarbonyl] piperazine 1-[(5-chloroindol-2-yl) sulfonyl] -4-[(5-methyl-4,5,6,7-tetrahydrooxazolo [5,4-c] Pyridin-2-yl) carbonyl] piperazine (336 mg) was suspended in dimethoxyethane (20 ml) and 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4- Disulfide (Lawesson's reagent) (8
66 mg) and heated under reflux for 5 hours. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (0 to 10% methanol-dichloromethane) and thin-layer chromatography (Merck 2.0 mm, 10% methanol-dichloromethane) to give a crude product of the title compound ( 368 mg). The crude product was dissolved in dichloromethane, 1N hydrochloric acid in ethanol (770 l) was added, the mixture was dried once, solidified from ethyl acetate, collected by filtration and washed with ethyl acetate to give the title compound (340 mg) as a yellow amorphous substance. Obtained as a solid. IR (KBr) cm ^-1 3376, 3118, 3014
2925, 2865, 2661, 2528, 1646,
1502, 1482, 1436, 1351, 1307,
1280, 1238, 1159, 1116, 1097,
1056, 952, 925, 809. _{^{1 H NMR (DMSO-d 6}} ) 2.80-3.00 (5
H, m), 3.16 (2H, br), 3.27 (2H,
br), 3.50-3.70 (2H, m), 4.00-
4.10 (2H, m), 4.30-4.70 (4H,
m), 7.06 (1H, s), 7.31 (1H, dd,
J = 8.8, 1.7 Hz), 7.50 (1H, d, J =
9.0Hz), 7.78 (1H, d, J = 1.5H)
z), 11.45-11.65 (1H, m), 12.5
0 (1H, s). . MS (FAB) m / z 480 [(M + H) ⁺ , Cl
³⁵ ], 482 [(M + H) ⁺ , Cl ³⁷ ].

[Test Example 1] FXa inhibitory activity (IC ₅₀ value)
Measurement 10 μl of the sample solution in a 96-well microplate, 100 m
M Tris, 200 mM sodium chloride, 0.2% BSA
(PH 7.4) buffer 40 μl, 0.05 U / ml human FXa (Cosmo Bio-ERL HFXa-1011,
Dissolve and dilute with measurement buffer) 10 μl
50 μM S2222 (Chromogenix) 4
0 ml was added, and the increase in absorbance at 405 nm (mOD / min) was measured at room temperature. The inhibition% of each sample is calculated by the following formula, and the horizontal axis of the log probability paper indicates the final concentration of the sample,
The percentage of inhibition is plotted on the vertical axis, and the 50% inhibitory concentration (IC ₅₀ )
I asked.

Inhibition rate (%) = (1−OD of sample ÷ OD of control) × 100

(Results) The compounds of Example 32, Example 54, Example 61, Example 63, Example 99, Example 289, Example 310, Example 329, and Example 349 each had a 50% inhibitory concentration of FXa. As 20 nM, 5.0 n
M, 30 nM, 12.5 nM, 1.7 nM, 2.5 n
M, 2.5 nM, 6.3 nM, and 10 nM were shown.

[Test Example 2] Thrombin inhibitory action (IC ₅₀
Measurement) 10 μl of the sample solution in a 96-well microplate, 100 m
M Tris, 200 mM sodium chloride, 0.2% BSA
(PH 7.4) 40 μl of a buffer solution and 10 μl of 4 U / ml human thrombin (dissolved and diluted in a measurement buffer solution, Sigma Chemical Co.) were dispensed, and 500 μM S
2266 (Chromogenix) was added and the increase in absorbance at 405 nm at room temperature (mOD /
min). Calculate the inhibition% of each sample by the following formula.
Was plotted to determine the 50% inhibitory concentration.

Inhibition rate (%) = (1−OD of sample ÷ OD of control) × 100

(Results) The thrombin 50% inhibitory concentration of the compound of Example 54 was 1.05 μM.

Test Example 3 Measurement of Coagulation Time Prolonging Effect (Measurement of Prothrombin Time) 20 μl of plasma and 20 μl of a sample solution are mixed, and coagulation time is measured by adding 40 ml of symplastin (OrganonTeknika). The concentration (CT2) of the sample that prolonged the clotting time of plasma by a factor of 2 was determined and used as an index of the anticoagulant effect.

(Results) The compound of Example 33 had a concentration of 0.35 μm.
M showed CT2.

[Test Example 4] Anti-FXa activity in blood and prolongation of prothrombin time 1) Method A sample was dissolved or suspended in a 0.5% (w / v) methylcellulose solution and fasted overnight for 8 to 11 weeks old. Rat (W
It was orally administered (10 ml / kg) to istar male rats (Japan SLC, Inc.). After administration of the sample, 1/10 volume 3.13 from the jugular vein under halothane anesthesia as appropriate
% (W / v) sodium citrate-supplemented blood was collected and the rats were awake except during blood collection. Feeding was resumed after blood collection 6 hours later. Plasma was separated from each blood sample by centrifugation, and blood anti-FXa activity and prothrombin time elongation were measured.

2) Measurement method 2-1) Measurement of anti-FXa activity in plasma 5 μl of plasma was dispensed into a 96-well plate, and 100 mM Tris, 200 mM sodium chloride, 0.2% BSA (pH
7.4) 8 of buffer, water and 0.1 U / ml human factor Xa solution (dissolved and diluted in measurement buffer):
55 μl of the 1: 2 mixture, 750 μM S-2222
40 μl was added. After stirring with a plate mixer for 10 seconds, the increase in absorbance at 405 nm (mOD / mi)
n) was measured at room temperature. The inhibition rate was calculated as follows.

Inhibition rate (%) = (1−OD of sample / average value of OD of control corresponding to blood sampling time of sample) × 100

2-2) Measurement of Coagulation Time Prolonging Effect in Oral Administration (Measurement of Prothrombin Time) Simplastin (Organon Te) was added to 20 μl of plasma.
(Knika, USA) 40 μl was added and the coagulation time was measured. The ratio of the prothrombin time after administration of the sample to the prothrombin time before administration of the sample was used as an index of the clotting time extension effect.

3) Results The compound of Example 36 was orally administered to a sample at 30 mg / kg.
After an hour, plasma anti-FXa activity was 68%, and prothrombin time was prolonged.

Test Example 5 Antithrombotic Effect Test in Tissue Thromboplastin-Induced Rat DIC Model Rats were anaesthetized with halothane and 1/10 volume 3.1 from jugular vein.
After blood collection (for platelet count, anti-FXa activity, and TAT measurement) using 3% (w / v) sodium citrate, the sample was orally administered. Nembutal (50 mg / ml sodium pentobarbital, A
Intraperitoneal anesthesia (1 ml / kg) with Bbott Laboratories,) and 0.2 U / ml tissue thromboplastin (Thromboplastin C)
plus, Dade Diagnostics of
P. R. Inc. ,) From 2.5 to 3.0 ml / kg / m
in for 1 minute intravenously from the femoral vein, and 10 minutes later, blood was collected from the jugular vein (for measurement of platelet count and anti-FXa activity), followed by 2 more minutes.
0 minutes later, blood was collected from the jugular vein (for TAT measurement).
The platelet count, plasma anti-FXa activity and TAT concentration of each blood sample were measured. The platelet count is measured by an automatic hemocytometer, and the method for measuring the anti-FXa activity in plasma is the same as that in Test Example 4.

[1602] Also, TAT (Thrombin-ant)
i Thrombin = complex) is measured by Enzyg
This was performed using nostR TAT micro kit (manufactured by Bering Belke).

By orally administering 30 mg / kg of the compound of Example 36, a clear anti-Xa action in plasma was observed, and a decrease in platelet count and an increase in TAT concentration were suppressed. After hours).

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61K 31/496 A61K 31/496 4C063 31/5025 31/5025 4C065 31/519 31/519 4C071 31/5377 31/5377 4C072 31/5383 31/5383 4C086 31/695 31/695 4C204 A61P 7/02 A61P 7/02 4H049 9/00 9/00 9/10 9/10 43/00 43/00 111 111 C07D 215/48 C07D 215 / 48 217/26 217/26 235/06 235/06 277/68 277/68 295/22 295/22 A 307/84 307/84 333/68 333/68 417/12 417/12 471/04 104 471 / 04 104Z 113 113 113 117 117N 487/04 140 487/04 140 491/048 491/048 495/04 105 495/04 105A 498/04 105 498/04 105 513/04 301 513/04 301 343 343 351 351 // C07F 7/18 C07F 7/18 A (72) Inventor Masanori Suzuki 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd. Tokyo R & D Center Within (72) Inventor Toshiharu Yoshino 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Inside Daiichi Pharmaceutical Co., Ltd.Tokyo R & D Center (72) Inventor Takayasu Nagahara 1-16-113 Kita-Kasai, Edogawa-ku, Tokyo No. 1 Daiichi Pharmaceutical Co., Ltd. Tokyo R & D Center (72) Inventor Kenji Yoshikawa 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd. Tokyo R & D Center (72) Inventor Ryo Muto 1-16-13 Kita-Kasai-ku, Tokyo Daiichi Pharmaceutical Co., Ltd., Tokyo R & D Center (72) Inventor Ken Takeuchi 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd., Tokyo R & D Center ( 72) Inventor Yumi Nakamoto 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Inside the Daiichi Pharmaceutical Co., Ltd.Tokyo R & D Center (72) Inventor Meiyoshi Mochizuki 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Ichi Pharmaceutical Co., Ltd.Tokyo R & D Center (72) Inventor Tsutomu Nagata 1-16-13 Kita-Kasai, Kawa-ku F-term in Tokyo Research & Development Center, Daiichi Pharmaceutical Co., Ltd. 4C031 MA01 4C033 AE16 AE17 AE20 4C034 AN10 4C037 QA13 4C050 AA01 BB04 CC08 EE03 FF03 HH04 4C063 AA01 AA03 BB09 CC07 CC07 CC07 DD15 DD25 DD34 EE01 4C065 AA05 BB04 BB09 BB11 CC01 DD02 HH01 HH09 JJ01 KK08 KK09 LL01 PP15 4C071 AA01 BB01 CC01 CC11 CC21 EE05 EE13 FF06 GG01 HH28 JJ05 JJ07 JJ08 FF01 FF01 FF01 FF01 FF01 FF01 FF01 FF01 MM08 4C086 AA01 AA02 AA03 BA06 BB03 BC13 BC30 BC39 BC50 BC84 CB05 CB09 CB22 CB26 CB31 DA44 GA07 GA10 MA10 4C204 BB01 CB03 DB26 EB02 FB03 GB01 GB03 4H049 VN01 VP01 VQ04 VU06 VW01

Claims (17)

[Claims] 1. A compound of the general formula (I) Q ¹ -Q ² -T ¹ -Q ³ -SO ₂ -Q ^A (I) wherein Q ¹ is a saturated or unsaturated 2 which may have a substituent. A cyclic fused ring group or a saturated or unsaturated tricyclic fused ring group which may have a substituent is meant. Q ² is a single bond, an oxygen atom, a sulfur atom, a linear or branched alkylene group having 1 to 6 carbon atoms, a linear or branched alkenylene group having 2 to 6 carbon atoms, A branched alkynylene group having 2 to 6 carbon atoms, a group -N (R ¹ ) -CO- (wherein R ¹ represents a hydrogen atom or an alkyl group), a group -N (R ² )-( during CH ₂₎ m- (group, R ² is a hydrogen atom or an alkyl group, m
Represents an integer of 0 to 6. ) Or a group (This group is a divalent saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent, or a divalent saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group which may have a substituent. A heterocyclic group or a divalent saturated or unsaturated bicyclic fused ring group which may have a substituent, wherein ← C indicates that a carbon atom of this group is bonded to Q ¹ . ). Q ³ means any of the following groups. Embedded image (In these groups, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰
And when the carbon atom to which R ¹¹ is bonded is not adjacent to the nitrogen atom are each independently a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxyl group, an alkoxyalkyl group, an alkoxyalkyl group, hydroxyalkyl group, hydroxyalkyloxy Group, hydroxyalkylcarbonyl group, hydroxyalkylsulfonyl group, formyl group,
Formylalkyl group, formylalkylcarbonyl group,
Formylalkylsulfonyl group, alkylcarbonyl group, alkylsulfonyl group, alkylcarbonylalkyl group, alkylsulfonylalkyl group, carboxyl group, carboxyalkyl group, carboxyalkyloxy group carboxyalkylcarbonyl group, carboxyalkylsulfonyl group, carboxyalkylcarbonylalkyl group, Carboxyalkylsulfonylalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkyloxy group, alkoxycarbonylalkylcarbonyl group, alkoxycarbonylalkylsulfonyl group, amino group which may have one or two substituents, amino group 1 substituent on the moiety
An aminoalkyl group which may have 1 or 2 amino groups, an aminoalkyloxy group which may have 1 or 2 substituents on the amino group, and 1 substituent on the amino group.
An aminoalkylcarbonyl group, which may have one or two substituents, an aminoalkylcarbonyloxy group, which may have one or two substituents on the amino group, and one or two substituents on the amino group. An aminocarbonyl group, an aminocarbonylalkyl group which may have one or two substituents on the amino group part, an aminocarbonylalkyloxy group or an amino group which may have one or two substituent groups on the amino group part An alkylsulfonylaminocarbonylalkyl group, which may have one substituent in the moiety, an arylsulfonylaminocarbonylalkyl group, which may have one substituent in the amino group, one or two substituents in the amino group An aminosulfonylalkyl group which may have
A cyanoalkyl group, an alkoxyalkylaminocarbonylalkyl group, which may have one substituent in the amino group, an alkylcarbonyloxyalkyl group, or a group A ¹ -B ^1- (wherein A ¹ has a substituent A saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or a saturated or unsaturated 5- or 6-membered heterocyclic group which may have a substituent, wherein B ¹ is a single bond, a carbonyl group , An alkylene group, a carbonylalkyl group, a group -OC
₁ -C ₆ alkylene group, a group -COO-C _{1 ~C 6} alkylene group means a group -NHCO- or a group -NHCO-C _{1 ~C 6} alkylene group. ). Also, R ³ , R ⁴ ,
When the carbon atom to which R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ and R ¹¹ are bonded is adjacent to a nitrogen atom, each independently represents a hydrogen atom, an alkyl group, a hydroxyalkyl group, a hydroxyalkylcarbonyl group, Hydroxyalkylsulfonyl group, formyl group, formylalkyl group, formylalkylcarbonyl group, formylalkylsulfonyl group, alkylcarbonyl group, alkylsulfonyl group, alkylcarbonylalkyl group, alkylsulfonylalkyl group,
Carboxyl group, carboxyalkyl group, carboxyalkylcarbonyl group, carboxyalkylsulfonyl group, carboxyalkylcarbonylalkyl group, carboxyalkylsulfonylalkyl group, alkoxyalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylcarbonyl group, alkoxycarbonyl An alkylsulfonyl group, an aminoalkyl group optionally having one or two substituents on the amino group, an aminoalkylcarbonyl group optionally having one or two substituents on the amino group,
An aminocarbonyl group which may have one or two substituents on the amino group, an aminocarbonylalkyl group which may have one or two substituents on the amino group, one substituent on the amino group An alkylsulfonylaminocarbonylalkyl group, which may have one substituent, an arylsulfonylaminocarbonylalkyl group, which may have one substituent in the amino group, and an aminosulfonylalkyl, which may have one or two substituents in the amino group A group, a cyanoalkyl group, an alkoxyalkylaminocarbonylalkyl group, which may have one substituent in the amino group, an alkylcarbonyloxyalkyl group, or a group A ² -B ^2- (wherein A ² represents a substituent A saturated or unsaturated 5- or 6-membered cyclic hydrocarbon group or .B ² is a single bond which means also 5-6 membered heterocyclic group, saturated or unsaturated having a group, a carbonyl group, an alkylene group, a carbonyl group, group -O-C ₁ ~C ₆ alkylene Group, group -COO-C ₁
-C ₆ alkylene group, a group -NHCO- or a group -NHC
Means O-C ₁ ~C ₆ alkylene group. ).
R ³ and R ⁴ , R ⁵ and R ⁶ , R ⁷ and R ⁸ , R
¹⁰ and R ¹¹ together with the carbon atoms constituting the ring may be a saturated or unsaturated 5 which may have a substituent.
May represent a 7 to 7 membered cyclic hydrocarbon group or a saturated or unsaturated 5 to 7 membered heterocyclic group which may have a substituent, wherein R ⁹ and R ¹² are each independently a hydrogen atom , Alkyl group, hydroxyalkyl group, hydroxyalkylcarbonyl group, hydroxyalkylsulfonyl group, alkoxyl group, alkoxyalkyl group, alkoxyalkylcarbonyl group, alkoxyalkylsulfonyl group, formyl group, formylalkyl group, formylalkylcarbonyl group, formylalkylsulfonyl Group, alkylcarbonyl group, alkylcarbonylalkyl group,
Alkylsulfonyl group, alkylsulfonylalkyl group, carboxyalkyl group, carboxyalkylcarbonyl group, carboxyalkylsulfonyl group, carboxyalkylcarbonylalkyl group, carboxyalkylsulfonylalkyl group, alkoxycarbonyl group, alkoxycarbonylalkyl group, alkoxycarbonylalkylcarbonyl group, An alkoxycarbonylalkylsulfonyl group, an amino group which may have one or two substituents, an aminoalkyl group which may have one or two substituents on the amino group, one substituent on the amino group Or an aminoalkyloxy group which may have two, an aminoalkylcarbonyl group which may have one or two substituents on the amino group, and one substituent on the amino group Or two or more aminoalkyloxycarbonyl groups, one or two substituents on the amino group, and one or two substituents on the amino group An aminocarbonylalkyl group, an aminocarbonyloxyalkyl group which may have one or two substituents on the amino group, an alkylsulfonylaminocarbonylalkyl group which may have one substituent on the amino group, an amino group An arylsulfonylaminocarbonylalkyl group which may have one substituent,
An aminosulfonylalkyl group, a cyanoalkyl group, which may have one or two substituents on the amino group part;
It means an alkoxyalkylaminocarbonylalkyl group or an alkylcarbonyloxyalkyl group which may have one substituent in the amino group part. Also, R ⁹
Represents a saturated or unsaturated 5- to 7-membered heterocyclic group which may have a substituent, together with a carbon atom constituting a ring together with R ⁷ or R ⁸ and a nitrogen atom to which R ⁹ is bonded. May be. R ¹² is a saturated or unsaturated 5- to 7-membered heterocyclic ring which may have a substituent, together with a carbon atom constituting a ring together with R ¹⁰ or R ¹¹ and a nitrogen atom to which R ¹² is bonded. It may mean a formula group. a, b,
d, e and g each independently represent an integer of 0 or 1. c represents an integer of 0 to 3. f, h and i each independently represent an integer of 1 to 3. However, the sum of a, b and c means an integer of 2 or 3, the sum of d and e means an integer of 0 or 1, and the sum of f, g and h means an integer of 3 to 5. . Q ^A represents an arylalkenyl group which may have a substituent, a heteroarylalkenyl group which may have a substituent, a saturated or unsaturated bicyclic fused ring group which may have a substituent, or a substituent. A saturated or unsaturated tricyclic fused ring group which may have a group Ar-C (H) = N
-(Wherein, Ar represents an aryl group which may have a substituent) or group Het-C (H) = N- (where Het represents a heteroaryl group which may have a substituent. Yes.) T ¹ represents a carbonyl group, a group —CH (R ¹³ ) — (wherein, R ¹³ represents a hydrogen atom, an alkyl group, a hydroxyalkyl group in which a hydroxyl group may be protected, an alkoxyalkyl group, a carboxyalkyl group, an alkoxycarbonylalkyl . mean group, an aryl group, an aralkyl group, a heteroaryl group, an also aminoalkyl group having a heteroarylalkyl group or an amino group moiety in a substituent (protecting group)) group -C (= NOR ¹⁴⁾ - or Group -C (= N-NH
R ^{14 ′} ) — wherein R ¹⁴ and R ^{14 ′} each independently represent a hydrogen atom, an alkyl group, a carboxyalkyl group, an alkoxycarbonyl group, an aryl group, an aralkyl group, a heteroaryl group, a heteroarylalkyl group or Means an aminoalkyl group which may have a substituent in the amino group part). And salts thereof and solvates thereof. 2. In the formula (I), Q^AIs one of the following groups
The compound according to claim 1, which means: or a salt thereof.
And their solvates. Embedded image[In the group, R^FifteenIs hydrogen atom, hydroxyl group, nitro group, cyano
Group, halogen atom, alkyl group, hydroxyalkyl
Group, alkoxyl group, alkoxyalkyl group, carboxy
Sil group, carboxyalkyl group, alkylcarbonyl
Group, alkoxycarbonyl group, alkoxycarbonyl group
Alkyl group, alkylcarbonyloxy group, or group A^Three-B^Three-(In the group, A^ThreeMay have one or two substituents
A certain amino group, may have a saturated or
Having unsaturated 5- to 6-membered cyclic hydrocarbon group or substituent
Saturated or unsaturated 5- or 6-membered heterocyclic
Means a group. B ^ThreeIs a single bond, carbonyl group, alkylene
Group, carbonylalkyl group, carbonylalkyloxy
Represents a silyl group or an alkylenecarbonyloxy group
You. ). R¹⁶And R¹⁷Are independent
Hydrogen, halogen, alkyl and hydroxyl groups
Hydroxyalkyl or alcohol which may be protected
It means a xyalkyl group. Also, R¹⁶Or R¹⁷Is
R^FifteenTogether with an alkylene group having 1 to 3 carbon atoms or
It may mean an alkenylene group. R¹⁸And R¹⁹Haso
Each independently represents a hydrogen atom, a hydroxyl group, a halogen atom,
Logenoalkyl, alkyl, alkoxyl, al
Alkylsilyl groups may be substituted as kenyl groups or protecting groups.
Alkynyl group, trifluoromethyl group, cyano
Group, amino group, aminoalkyl group, alkylaminoal
Kill group, amidino group, hydroxyamidino group or alkyl group
A oxycarbonylamidino group (provided that R¹⁸
And R¹⁹Are not simultaneously hydrogen atoms. ). X
¹And X^TwoAre each independently a methine group or a nitrogen atom
Means ][In the group, X^ThreeIs a nitrogen atom or a group = C (R¹⁰⁰)-(In the group, R¹⁰⁰Is hydrogen atom, halogen atom, alkyl
Group, alkoxycarbonyl group, aralkyloxycarbo
Nilalkyl group, alkoxycarbonylalkyl group,
Toro group, amino group or amino group which may have a protecting group
Aminoalkyl group which may have a protecting group
Means ). X^FourIs oxygen atom, sulfur atom
Or a group -N (R¹⁰¹)-(In the group, R¹⁰¹Represents a hydrogen atom, an alkyl group, an alkoxy group
Rubonyl group, aralkyloxycarbonyl group, alkoxy
A cyclocarbonylalkyl group, an alkylsulfonyl group or
It means an arylsulfonyl group. ). X^Five
And X⁸Are each independently a nitrogen atom or a group -C (R¹⁰²)-(In the group, R¹⁰²Represents a hydrogen atom or a halogen atom
I do. ). X⁶And X⁷Are independent of each other
A nitrogen atom or a group -C (R¹⁰³)-(In the group, R¹⁰³Represents a hydrogen atom, a hydroxyl group, a halogen atom,
Halogenoalkyl group, alkyl group, alkoxyl group,
Alkylsilyl group as alkenyl group and protective group
Alkynyl, cyano, amino, amino
Alkyl group, alkylaminoalkyl group, amidino group,
Hydroxyamidino group or alkoxycarbonylamido
It means a dino group. )][In the group, X⁹And X¹²Are each independently a nitrogen atom
Or a group -C (R¹⁰⁴)-(In the group, R¹⁰⁴Represents a hydrogen atom or a halogen atom
I do. ). X^{1 0}And X¹¹Are independent
And a nitrogen atom or a group -C (R¹⁰⁵)-(In the group, R¹⁰⁵Represents a hydrogen atom, a hydroxyl group, a halogen atom,
Halogenoalkyl group, alkyl group, alkoxyl group,
Alkylsilyl group as alkenyl group and protective group
Alkynyl, cyano, amino, amino
Alkyl group, alkylaminoalkyl group, amidino group,
Hydroxyamidino group or alkoxycarbonylamido
It means a dino group. ) W and z are each independently 1
Or an integer of 2. ] 3. A group represented by the general formula (I): Is Or [In the above groups, R ¹⁶ , R ¹⁸ , R ¹⁹ , X ¹ and X ² are the same as described above. The compound according to claim 2, which means
Its salts and their solvates. 4. The compound according to claim 2 or 3, wherein R ¹⁸ represents a halogen atom or an ethynyl group, a salt thereof, and a solvate thereof. 5. A group represented by the general formula (I): Is a compound of the following group, a salt thereof and a solvate thereof. Embedded image Embedded image Embedded image [In the above groups, R ¹⁰¹ and R ¹⁰³ are the same as described above. R ^{103 '}
Means a is the same as R ^103. ] 6. The compound according to claim 5, wherein one of R ^{103 and} R ^{103 ′ represents} a halogen atom or an ethynyl group, a salt thereof, and a solvate thereof. 7. A group represented by the general formula (I): Is Wherein R ¹⁰⁵ is the same as above. R ^{105 ′} means the same as R ¹⁰⁵ . The compound according to claim 2, a salt thereof and a solvate thereof. 8. The compound according to claim 7, wherein one of R ^{105 and} R ^{105 ′ represents} a halogen atom or an ethynyl group, a salt thereof, and a solvate thereof. 9. also thienopyridyl group that Q ¹ is has a substituent, it may have a substituent tetrahydrothieno pyridyl group, which may be substituted group thiazolopyridyl group, which may be substituted group tetrahydro Thiazolopyridyl group, thiazolopyridazinyl group which may have a substituent, tetrahydrothiazolopyridazinyl group which may have a substituent, pyranothiazolyl group which may have a substituent, having a substituent Sometimes dihydropyranothiazolyl group, fluoridyl group which may have a substituent, tetrahydrofuropyridyl group which may have a substituent, oxazolopyridyl group which may have a substituent, may also have a substituent A certain tetrahydrooxazolopyridyl group, an oxazolopyridazinyl group which may have a substituent, or Sulfonyl derivative, salt thereof and solvate thereof according to claims 1 to 8 is intended to mean may have a substituent tetrahydropyran oxazolone pyridazinyl group. 10. The sulfonyl derivative according to any one of claims 1 to 9, wherein Q ² represents a single bond, a phenylene group, a cyclohexylene group or a cyclohexenylene group, a salt thereof, and a salt thereof. Solvate of 11. Q ³ is a group represented by the following formula: Wherein R ³ , R ⁴ , a, b and c are the same as above. 11. The method according to any one of claims 1 to 10, wherein
The compounds according to the above, salts thereof and solvates thereof. 12. T ¹ is a carbonyl group or a group —CH
(R ¹³⁾ - (group in, R ¹³ is as defined above.) Compound, a salt thereof and solvate thereof according to any one of claims 1 to 11 is intended to mean. 13. A medicament comprising the compound according to any one of claims 1 to 12, a salt thereof, or a solvate thereof as an active ingredient. 14. An activated blood coagulation factor X inhibitor comprising the compound according to any one of claims 1 to 12, a salt thereof, or a solvate thereof as an active ingredient. 15. A blood coagulation inhibitor comprising the compound according to any one of claims 1 to 12, a salt thereof, or a solvate thereof as an active ingredient. 16. A prophylactic and / or therapeutic agent for thrombus or emboli comprising the compound according to any one of claims 1 to 12, a salt thereof or a solvate thereof as an active ingredient. 17. A cerebral infarction, a cerebral embolism, a myocardial infarction, a pulmonary infarction, a pulmonary embolism, comprising the compound according to any one of claims 1 to 12, a salt thereof or a solvate thereof as an active ingredient. Prevention and / or treatment of Berger disease, deep vein thrombosis, generalized intravascular coagulation, thrombus formation after artificial valve replacement, reocclusion after revascularization, thrombus formation during extracorporeal circulation or blood coagulation during blood collection .