WO2002051849A1

WO2002051849A1 - Cdk4 inhibitors

Info

Publication number: WO2002051849A1
Application number: PCT/JP2001/011354
Authority: WO
Inventors: Kouichi Uoto; Takao Horiuchi; Kouichi Akabane; Yasuyuki Takeda
Original assignee: Daiichi Pharmaceutical Co., Ltd.
Priority date: 2000-12-26
Filing date: 2001-12-25
Publication date: 2002-07-04
Also published as: JPWO2002051849A1

Abstract

Compounds of the general formula (IA) or (IB) having cyclin-dependent kinase 4 inhibiting activity, or salts thereof: (IA) (IB) wherein X is S, O, or N-R5 (wherein R5 is hydrogen or alkyl); Y is N or CH; Z is N or C-R6 (wherein R6 is hydrogen, halogeno, or alkyl); R?1 and R2¿ are each hydrogen, alkyl, alkoxy, or the like; R3 is hydrogen, alkyl, or aryl; R4 is hydrogen or alkyl; and A is a group represented by the general formula (II) or the like: (II) (wherein R7 is hydrogen or alkyl; and R8 is alkyl, aryl, or a heterocyclic group).

Description

' Specification -

C dk 4 activity inhibitor Technical field

The present invention relates to a novel conjugate or a salt thereof, or a hydrate or solvate thereof, having an antitumor effect by a cell cycle regulating action. The present invention also relates to an antitumor agent containing the above substance as an active ingredient, and a method for preventing, treating or treating a tumor using the antitumor agent. Background art

Currently, many chemotherapeutic agents are used as antitumor agents. However, conventional chemotherapeutic agents act on gene replication and cell division mechanisms in the S phase and M phase, which are the proliferative phases of the cell cycle, and thus kill cells in the proliferative phase non-specifically. This also affects the growth of normal cells typified by bone marrow hematopoietic cells. These are mainly responsible for the side effects of chemotherapeutic agents. Among them, serious side effects include reduced immunity due to a decrease in blood cells, infection associated therewith, and diarrhea due to a decrease in gastrointestinal mucosal cells. In addition, side effects such as liver dysfunction, nausea, and hair loss and numbness of limbs are known.

Conventional chemotherapeutic agents having these side effects place a heavy burden on patients, and it has been difficult to prevent cancer recurrence by long-term administration after chemotherapy treatment or surgery. At present, reduction of side effects by antitumor agents having a different mechanism of action has been desired. If side effects can be reduced, the burden on patients will be reduced and QOL (QualityofLife, quality of life) can be expected to improve. In addition, the reduction of side effects enables long-term administration for the purpose of preventing recurrence after anticancer drug treatment or surgery.

For example, the development of a new antitumor ^ j focused on the regulatory action of the compound that inhibits cyclin-dependent kinase (hereinafter referred to as Cdk) activity in the cell cycle Have been.

The onset of cancer, a malignant tumor, involves the function of oncogenes and tumor suppressor genes, and it is said that the impairment of the function of these genes would lead to the breakdown of the cell growth control mechanism. In particular, tumor suppressor genes are closely related to the growth control mechanism, but their deficits are frequently observed in cancer, and the failure of the growth control mechanism causes cancer illness (Tr endsin). Ge netics, 15, M53-M56, 1999.). When cancer suppressor genes (Rb, pi6, PTEN, BRC, A1, etc.) are overexpressed in cancer cells, most of the population of cells accumulates during the GO / G1 phase of the cell cycle. In many cases (Ex p. Gerontol., 35, 317-329, 2000.), tumor suppressor genes regulate the cell cycle mainly in the G1 phase, which is a stage before the initiation of cell division. The present inventor believes that this is the case. Therefore, compounds that accumulate cell populations in the G1 phase of the cell cycle can inhibit the growth of cancer cells whose growth control mechanisms are disrupted by impaired function of tumor suppressor genes. The present inventors believe that this may result in a highly specific antitumor effect.

The transition from the G1 phase to the S phase of the cell cycle is regulated mainly by the action of the transcription factor E 2 F-1 and the complex of citalin and C dk (Ce 11, 79, 573-582). , 1 994). The transcription factor E2F-1 is inactivated in the G1 phase by Rb protein, a product of the tumor suppressor gene Rb. When the cell cycle shifts from the G1 phase to the S phase, which is the DNA replication phase, the intracellular concentration of cyclin D, a subtype of cyclin, is increased by the action of growth factors, followed by the concentration of cyclin E. Rises. Next, a complex of cyclin D and C dk subtype Cdk 4 or C dk 6 and a complex of cyclin E and Cdk 2 are formed, and the complex of these cyclins and C dk is formed. Phosphorylates the Rb protein that is activated and bound to E 2 F-1. The phosphorylated Rb protein is released from E2F-1, and E2F-1 induces the transcription of various genes, and the cell cycle shifts from G1 to S phase (Cancer D etect P Rev., 24, 107-118, 2000.). Breast of cancer cells Certain cancer cells, such as cancer, colorectal cancer, and skin cancer, have increased expression of cyclin D and E (Breast Cancer Res. Treat., 52, 1-15, 1998 ·) .

Endogenous proteins that suppress the phosphorylation ability of the complex between cyclin and C dk include the pi6, p27 and p21 proteins (Cancer and Chemotherapy., 24, 1407-1413, 1997) ). The pi6 protein is the product of the tumor suppressor gene p16, which binds specifically to Cdk4 and is complexed with cyclin D and Cdk4: inhibits phosphorylation of Rb protein (proteins, nucleic acids, enzymes, 42 , Sup pl., 1 554-1561, 1997.). In addition, the binding of pi6 protein to Cdk4 causes the p27 protein to dissociate from Cdk4 and bind to the complex of Cdk2 and cyclin E, and the Rb protein by the complex of Cdk2 and cyclin E. Inhibits the phosphoric acid illness (Cancer Res., 60, 3689 -3695, 2000 ·). The expression of p21 protein is induced by the product of the tumor suppressor gene p53.It binds to the complex of Cdk2 and cyclin E and inhibits the phosphorylation of Rb protein by the complex of Cdk2 and cyclin E. It suppresses the transition of the cell cycle to the S phase and is also involved in gene repair (Pathoi. Biol., 48, 190-202, 2000.).

As described above, due to the deletion of gene p16, gene p27 and gene p21, the endogenous proteins p16 and p27 which suppress the phosphorylation ability of Cdk When the intracellular concentration of the p21 protein decreases, the transition of the cell from the G1 phase to the S phase cannot be suppressed, and the growth control mechanism is disrupted. In fact, mutations and Z or deletions in the p16 gene are widely observed in lung cancer and skin cancer (Protein 'Nucleic Acid / Enzyme, 42, Suppl., 1554-1561, 1997.). In addition, postoperative prognosis tends to be poor in cancers where the intracellular concentration of p27 protein is low (Annu. Rev. Med., 50, 401-423, 1999.).

A compound inhibiting C dk 4 activity suppresses the phosphorylation of the Rb protein by the complex of cytaline D and C dk 4, thereby suppressing the transition of the cell from G 1 phase to S phase, and inhibiting cell population. Is likely to accumulate in the G1 phase. The present inventors have proposed that the activity of the transcription factor E 2 F-1 is determined when a compound inhibiting C dk 4 activity binds to C dk 4 and phosphorylation of the R b protein by the complex of cyclin D and C dk 4 is inhibited. Therefore, it is considered that the transition from G1 phase to S phase is suppressed, and as a result, the compound inhibiting Cdk4 activity suppresses the growth of cancer cells whose growth control mechanism has been disrupted. Therefore, it is considered that the C dk4 activity-inhibiting compound has a potential as an antitumor agent with reduced side effects.

Also, as described above, C d k has subtypes. One of them, C dk 4, is specifically activated as a complex with cytalin D in the G 1 phase in preparation for transition to the S phase of the cell cycle. On the other hand, C dk 2 is activated in the final stage of the transition of the cell cycle to the S phase as a complex with cytaline E in the G1 phase, and as a complex with cytaline A in the S phase. Activated during the transition from S phase to G2 phase. Furthermore, subtypes that form a complex with cyclin B and are involved in the transition from G2 phase to M phase, such as Cdkl, are also known.

The present inventors have found that inhibition of the activity of each of the above subtypes of C dk without quantitatively discriminating it does not increase the G1 phase mainly in the population of cells. To accumulate in the G1 phase, it is necessary to specifically inhibit the activity of Cdk4, which is involved in cell cycle regulation, only in the G1 phase.

In other words, the present inventors induced cancer cells in which the proliferation mechanism was disrupted because the tumor suppressor gene became nonfunctional due to a defect or the like in the G1 phase to the G1 phase (G1-phase inducing action). It is thought that suppressing growth is effective in suppressing cancer itself (growth suppressing effect) and can reduce side effects. Therefore, as a compound that can be an antitumor agent by this new mechanism of action, a compound that specifically increases the G1 phase in a cell population is desirable, and a compound that specifically inhibits C dk4 activity is that compound. We believe it will be a powerful catcher.

At present, flavopiridol, oromoisin, roscovitine, etc. are being developed as inhibitors of Cdk activity of low molecular weight compounds, but these compounds have no inhibitory specificity for Cdk4 (Curr. Pharmac). , 6, 37 9—39 2, 2 0 0 0 ·). Also, some of these compounds cannot increase only the G1 phase in cell populations. Disclosure of the invention

'The problem of the present invention is that it has a novel chemical structure that has not been known before and acts on the cell growth phase (S phase or M phase) like a conventional chemotherapeutic agent with serious side effects. Rather, it is a compound that specifically inhibits the activity of Cdk4, which is involved in the cell cycle, in the G1 phase, which is the early stage of cell division, and inhibits the growth of cancer cells by inducing the G1 phase. An object of the present invention is to provide an antitumor compound having an effect and, consequently, reduced side effects.

As a result of diligent research, the present inventor has expressed the following general formula (I) (in this specification, "general formula (I)" means either of the following general formulas (IA) or (IB)). Completed the present invention by discovering that a compound with a novel structure that is specifically inhibited Cdk4, a subtype of cytaline-dependent kinase, and has an antitumor effect by inducing the G1 phase of the cell cycle did.

That is, the present invention provides a compound represented by the following general formula (I) or a salt thereof, or a hydrate or solvate thereof.

In the formula, X represents a sulfur atom, an oxygen atom, or N—R ⁵ (R ⁵ represents a hydrogen atom or an alkyl group which may have a substituent);

Y represents a nitrogen atom or CH;

Z is a nitrogen atom or C-R ⁶ ( ⁶ is a hydrogen atom, a halogen atom, an alkyl group, a hydroxyalkyl group, an aminoalkyl group, a cyano group, a carbamoyl group, a carboxy group, or a C〇 ₂ R ⁶¹ (R ⁶¹ is Which represents an alkyl group); R ¹ and R ² each independently represent a hydrogen atom, an alkyl group, an 'alkoxy group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an acyl group, a mercapto group, an alkylthio group, an alkylsulfiel group, an alkylsulfo- An amino group, an amino group, a monoalkylamino group, a dianolequinolamino group, a diluvamoyl group, a monoalkylaminocarboxyl group, or a dialkylaminocarboxyl group, and these groups have a substituent. Or R ¹ and R ² may be bonded to each other to form a 3- to 7-membered hydrocarbon ring or a 3- to 7-membered heterocyclic ring; The heterocyclic ring may have a substituent;

R ³ represents a hydrogen atom, an alkyl group, or an aryl group, and the alkyl group or the aryl group may have a substituent;

R ⁴ represents a hydrogen atom or an alkyl group which may have a substituent;

A is the formula (II):

(Wherein, R ⁷ represents a hydrogen atom or an alkyl group which may have a substituent; R ⁸ represents an alkyl group, an aryl group, or a heterocyclic group, and these groups may have a substituent. A group represented by:

Formula (III):

(Wherein R ⁹ represents a hydrogen atom or an alkyl group which may have a substituent); or

Formula (IV): ·

(Wherein B represents an aryl or heteroaryl ring fused to the above-mentioned cyclic hexane ring) (in the above formulas (11), (111), and (IV) In the group represented by, the bond represented by a wavy line indicates that the compound represented by the formula (I) is either syn or anti isomer, or a mixture of both isomers). From another viewpoint, according to the present invention, a compound selected from the group consisting of the compound represented by the above general formula (I), a salt thereof, and a hydrate and a solvate thereof is contained as an active ingredient A medicament is provided. The above medicament is useful for the prevention and / or treatment of tumors, especially for the prevention and Z or treatment of malignant tumors.

Further, according to the present effort, a cyclin containing, as an active ingredient, a compound represented by the above general formula (I) and a salt thereof, and a substance selected from the group consisting of a hydrate and a solvate thereof. A cell containing a substance selected from the group consisting of the compound represented by the general formula (I) and salts thereof, and hydrates and solvates thereof as an active ingredient; Periodic regulator; cell cycle G1 phase containing as an active ingredient a compound represented by the above general formula (I), a salt thereof, a hydrate thereof, or a solvate thereof. An accumulating agent is provided. From a further aspect, the present invention provides a compound represented by the above general formula (I) and a salt thereof, and a hydrate and a solvate thereof for the production of the above-mentioned medicament. Use of the selected substance; a method for preventing and / or treating a tumor, preferably a method for preventing and / or treating a malignant tumor, wherein the compound represented by the above general formula (I) and a salt thereof, and a salt thereof A method comprising administering a prophylactically and / or therapeutically effective amount of a substance selected from the group consisting of hydrates and solvates thereof to mammals, including humans; A method comprising the step of contacting a cell with an effective amount of a substance selected from the group consisting of the compound represented by the general formula (I) and a salt thereof, and a hydrate and a solvate thereof. Provided. BEST MODE FOR CARRYING OUT THE INVENTION

The definitions of the terms used in the present specification are as follows.

Unless otherwise specified, an alkyl group or an alkyl moiety in a substituent containing an alkyl moiety (such as an alkoxy group) may be linear, branched, cyclic, or a combination thereof. . In the case of other than a ring, the number of carbon atoms is 1 to 15, preferably 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. Further, in the case of a ring, the number of carbon atoms is 3 to 18, preferably 3 to 15 carbon atoms, and more preferably 3 to 10 carbon atoms. Specifically, as the alkyl group, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl group, cyclopropylmethyl group, n-propyl group —Pentyl / le, isopentyl, neopentyl, cyclopentyl, 1,1-dimethylpropyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl, n-octyl, etc. Can be mentioned.

The “alkenyl group” may be linear, branched, cyclic, or a combination thereof, unless otherwise specified, and has one or more carbon-carbon double bonds. When it has two or more double bonds, they may be either conjugated or non-conjugated. In the case other than cyclic, the number of carbon atoms is 2 to 15, preferably 2 to 10 carbon atoms, and more preferably 2 to 6 carbon atoms. In the case of a ring, the number of carbon atoms is from 4 to 18, preferably from 4 to 15, and more preferably from 4 to 10. Specifically, a vinyl group, a propenyl group, a butene-11-yl group, an isoptenyl group, a pentene-11-yl group, a 2-cyclopentene-1-ynole group, a 2,4-cyclopentene-1-yl Groups, 2-methylbutene-11-yl group, 3-methynolebutene-11-yl group, hexene-11-yl group, heptene-11-yl group, octene-11-yl group, and the like.

An “alkynyl group” may be linear, branched, cyclic, or a combination thereof, unless otherwise specified, and has one or two carbon-carbon triple bonds. Have more. In the case of other than a ring, the number of carbon atoms is 2 to 15, preferably 2 to 10 carbon atoms, and more preferably 2 to 6 carbon atoms. Further, in the case of a ring, the number of carbon atoms is from 6 to 18, preferably from 6 to 15, and more preferably from 6 to 10. Specific examples include an ethyl group and a propynyl group.

“Halogen atom” means any of a fluorine, chlorine, bromine or iodine atom.

“Aryl group” means a monovalent group obtained by removing one hydrogen atom from an aromatic ring of an aromatic hydrocarbon. The aromatic ring constituting the aryl group may be either a single ring or a condensed ring. The number of carbon atoms is from 6 to 25, and among them, the number of carbon atoms is preferably from 6 to 20, and the number of carbon atoms is more preferably from 6 to 15. For example, a phenyl group, a tolyl group, a biphenyl group, a naphthyl group and the like can be mentioned. “Aryl ring” means a ring structure of an aromatic hydrocarbon, and is preferably a benzene ring.

“Aralkyl group” means a group in which one or more hydrogen atoms of an alkyl group are substituted with the above-mentioned aryl group. The number of carbon atoms is 7 to 26, preferably 7 to 21 carbon atoms, and more preferably 7 to 16 carbon atoms. For example, a benzyl group, a benzhydryl group, a trityl group and the like can be mentioned.

The term "acyl group" means a carbonyl group to which a hydrogen atom, an alkyl group, an 'or an aryl group is bonded, and examples thereof include a formyl group, an acetyl group, a propanol group and a benzoyl group.

The term "heterocyclic group" means a group derived from a monocyclic or bicyclic saturated or unsaturated heterocyclic compound, and includes, as a ring structure atom, an oxygen atom, a nitrogen atom or a sulfur atom. Contains one or more heteroatoms selected. Examples of the heterocyclic ring constituting a monocyclic heterocyclic group having a carbon atom number of, for example, pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, isoxazonole, Thiazole, isotiazole, oxaziazole, thiadiazo Pyridine, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, triazine, pyrazine, piperazine, dioxane, pyran, or morpholine. Examples of the heterocyclic ring constituting the bicyclic heterocyclic group include benzofuran, indolizine, benzothienephen, indone, naphthyridine, quinoxaline, quinazoline, and chroman.

“Heteroaryl ring” means a ring structure of an aromatic heterocyclic compound, and the aromatic heterocyclic compound may be monocyclic or polycyclic. The heteroaryl ring contains one or more hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. For example, a pyridine ring is suitable.

In this specification, in the case where a functional group may be "substituted", the type, number, or substitution position of the substituent is not particularly limited.

In the general formula (I), X is preferably a sulfur atom, and Y and Z are each preferably a nitrogen atom. Preferably, R ³ is a hydrogen atom. Among the compounds represented by the general formula (I), a compound represented by the formula (IA) is preferable.

In the compound represented by the general formula (I), R ² is preferably an alkyl group. As the alkyl group, in addition to an unsubstituted alkyl group, a halogen atom, a hydroxyl group, an alkoxy group, an amino group, a monoalkylamino group Also, an alkyl group having one or more substituents selected from the group consisting of a dialkylamino group, a dialkylglycyloxy group, an alkylsulfonyloxy group, and a sulfamoyloxy group is preferable. Preferred among the above substituents are hydroxyl groups. As the alkyl group represented by R ^{2, a} branched alkyl group having about 3 to 6 carbon atoms is preferable.

R ² is more preferably a t-butyl group which may be substituted with one or more hydroxyl groups. .

In the compound represented by the general formula (I), A is preferably a group represented by the following formula (II).

In the formula (II), a phenyl group can be suitably used as R ⁸ . Examples of the phenyl group include an unsubstituted phenyl group and the following groups:

Fluoro, chloro, bromo, eodo, alkyl, hydroxyalkyl, substituted silyloxyalkyl, propyloxyl, alkoxycarbonyl, tetrazolyl, amino, monoalkylamino, dialkylamino, Cyano group, carbamoyl group, nitro group, hydroxyl group, alkoxy group, mercapto group, sulfonamide group, benzyloxy group, N-alkylsulfamoyl group, N, N- '

Expression (V)

0

II 10

-S— N— R (V)

II \

0, no

(Wherein, ^{1 G} represents a hydrogen atom or an alkyl group)

Equation (VI):

(Wherein, represents an integer of 0 to 6; R ¹¹ represents a hydrogen atom, an alkyl group or a hydroxyalkynole group), and

Formula (VII):

R 12

H ₂ C ten N. (VII)

m ₂ R 13

(Wherein, m ₂ represents an integer of 0 to 6; R ¹² and R ¹³ each independently represent a hydrogen atom, an alkyl group, an alkoxycarbonylalkyl group, or a hydroxyalkyl group) Base

And a phenyl group having one or more substituents selected from

Further, in the compound represented by the general formula (I),

Is a group group represented by A is represented by formula (II), R ⁷ is a hydrogen atom or an alkyl group, a group R ⁸ is represented by formula (VII), from m ₂ is 0 An integer of 6, ^{When 12} and R ¹³ are each independently a hydrogen atom, an alkynole group, an α / recoxycarboninoalkyl group or a hydroxyalkyl group; and

The group represented by A is represented by the formula (VIII):

(Wherein, R ⁷ has the same meaning as described above, the nitrogen-containing ring fused to the benzene ring is a 5- to 7-membered ring, and R ¹⁴ is a hydrogen atom, an alkoxycarbonyl group, an alkyl group, an alkoxycarbonylalkyl Or a methoxylalkyl group).

Further, in the compound represented by the general formula (I),

A group represented by A is a group represented by the formula (II), R ⁷ is as defined above, and R ⁸ is a 5- or 6-membered heterocyclic group (the heterocyclic group has a substituent; And when the ring-constituting atom is 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, it is preferably a 5-membered heterocyclic group (the The heterocyclic group may have a substituent, and contains 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom);

A group represented by A is a group represented by the formula (II), R ⁷ is as defined above, and R ⁸ is a thiazolyl group, an oxazolyl group, a chenyl group, an imidazolyl group, a pyridinyl group, an isoxoxazolyl group , Isothiazolyl, or furyl (the above group is one selected from the group consisting of a fluoro group, a chloro group, a bromo group, an odo group, an alkyl group, an aminoalkyl group, a monoanolealkyl aminoalkyl group, and a dialkylaminoalkyl group Or may have two or more substituents); and

When the group represented by A is a group represented by the formula (II), R ⁷ has the same meaning as described above, and R ⁸ is a pyridyl group. Fluoro, chloro, bromo, eodo, hydroxyl, alkoxy, benzyloxy, nitro, amino, alkyl, hydroxyalkyl, formula (IX):

(Wherein m ₃ represents an integer of 0 to 6; R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom, an alkyl group, a dialkylaminoalkyl group or a cycloalkyl group) Group,

Formula (X):

I ~ \

-H ₂ leaves NG (X)

m

(Wherein, m ₄ is an integer of 0 to 6; G is an oxygen atom, a sulfur atom, SO, S 0 _2, means a CH ₂ or N- R ^{^{1 7,}} R ^{1 7} is hydrogen atom or an alkyl group £), and

Equation (Π):

(XI)

(Wherein, m ₅ represents an integer of 0 to 6), and may have one or more substituents selected from the groups represented by

Is also preferred.

Further, in the compound represented by the general formula (I),

The group represented by A is represented by the formula (XII):

(Wherein, R ⁷ has the same meaning as described above; the nitrogen-containing ring fused to the thiazolyl ring is a 5- to 7-membered ring; R ¹⁸ is a hydrogen atom, an alkyl group, an alkoxyl alkyl group, a carboxyl group An alkynole group or an alkoxyl group), or

The group represented by A has the formula (XIII):

(Wherein, R ⁷ has the same meaning as described above, and R ¹⁹ and R ² each independently represent a hydrogen atom, an alkyl group, an alkoxy group, an amino group, a monoalkylamino group, a dialkylamino group, or a nitrogen-containing heterocyclic group. A cyclic group, and the above-mentioned alkyl group may be substituted with an amino group, a monoalkylamino group or a dialkylamino group).

Further, when the group represented by A in the compound represented by the general formula (I) is a group represented by the formula (IV), an aryl ring or a B represented by B condensed to a cyclohexane ring As the heteroaryl ring, a benzene ring or a pyridine ring is preferable. More specifically, it is preferable that the group represented by A is a group represented by the following formula (XIV) or (XV).

In the compound represented by the general formula (I), R ⁴ is preferably a hydrogen atom, and the group represented by A is preferably the above formula (XIII). In this compound group, R ¹⁹ or R ² It is more preferable that one of the degrees is a hydrogen atom and the other is an alkyl group substituted with an amino group, a monoalkylamino group, or a dialkylamino group. In this case, the number of carbon atoms of the alkyl group substituted by the amino group, the monoalkylamino group, or the dialkylamino group (including the number of carbon atoms of the alkyl group on the amino group) is 1 to 4, more preferably 2 to 3 The number is particularly preferably 2.

In the compound represented by the general formula (IA), X is preferably a sulfur atom, R ¹ is a hydrogen atom, and R ² is preferably an alkyl group. In this case, the alkyl group represented by R ² Has preferably about 3 to 6 carbon atoms, more preferably 4 carbon atoms, and the alkyl group is preferably an alkyl group having a branched chain. In the compound represented by the general formula (IB), X is a sulfur atom, R ² is an alkyl group, and R ¹ is preferably a hydrogen atom. In this case, the carbon atom of the alkyl group represented by R ² The number is preferably about 3 to 6, more preferably 4, and the alkyl group is preferably an alkyl group having a branched chain.

Among the compounds represented by the general formula (I), a preferred compound group is

(1) a compound in which Z and Y in the formula (I) are nitrogen atoms;

(2) In the above (2), wherein R ³ is a hydrogen atom; and

③ The compound in which X is a sulfur atom in ① or ② above

It is.

In addition, in the above compound groups ① to ③,

化合物 A compound wherein R ⁴ is a hydrogen atom;

{The above}, wherein A is a compound represented by the above formula (II); and

In the above ⑤, the compound wherein R ⁷ is a hydrogen atom Is more preferred.

Further, in the compound group of the above ①,

化合物 A compound wherein R ⁸ is an aryl group or a heterocyclic group (the aryl group or the heterocyclic group may have a substituent);

{The compound in which the aryl group is a phenyl group which may have a substituent in the above};

{The compound according to the above}, wherein the phenyl group is a phenyl group having a substituent containing at least one nitrogen atom;

In the above (1), the heterocyclic group may be substituted with a 5-membered heteroaryl group, a heterocyclic group comprising a phenyl group condensed with a saturated heterocyclic ring, or a condensed heterocyclic group 5 Compounds which are membered heteroaryl groups;

{The compound according to the above}, wherein the heteroaryl group is a thiazolyl group;

(4) The compound in (3) above, wherein the heteroaryl group is a 2-thiazolyl group

Is preferred.

More specifically,

表 In the general formula (IA), R ¹ is a hydrogen atom, R ² is a branched alkyl group having about 3 to 6 carbon atoms, R ³ is a hydrogen atom, and R ⁴ is A hydrogen atom, the group represented by A is the above formula (XIII), R ⁷ is a hydrogen atom, and R ¹⁹ or R ² . A compound in which one of is a hydrogen atom and the other is an alkyl group having 2 to 3 carbon atoms substituted with an amino group, a monoalkylamino group, or a dialkylamino group; and

表 In the general formula (IB), R ¹ is a branched alkyl group having about 3 to 6 carbon atoms, R ² is a hydrogen atom, R ³ is a hydrogen atom, and R ⁴ is A hydrogen atom, a group represented by A is the above formula (XIII), R ⁷ is a hydrogen atom, R ¹⁹ or one of ² ° is a hydrogen atom, and the other is an amino group; A compound having 2 to 3 carbon atoms, which is substituted with a monoalkylamino group or a dialkylamino group.

Is a particularly preferred compound. However, the scope of the present invention is not limited to any of the preferred compound groups described above.

The compound of the present invention represented by the general formula (I) may have one or more asymmetric carbons depending on the type of the substituent, but may have an optical activity based on one or more asymmetric carbons. Stereoisomers in pure form, such as isomers or diastereoisomers, any mixture of stereoisomers, or racemates are all within the scope of the invention. When the compound of the present invention has an olefinic double bond, the arrangement of the double bond may be either Z or E, and a mixture of Z form or E form is also within the scope of the present invention. It is included in. Further, in the formula (11), the formula (、), and the formula (IV), the bond represented by a wavy line indicates that the compound represented by the formula (I) is either syn or anti isomer, or both isomers. In addition to the above-mentioned isomer in a pure form, the mixture containing the above-mentioned isomer in any ratio is also included in the scope of the present invention.

The compound of the present invention can be produced by various methods. One example of the production method is shown below.

The reaction can be carried out, if necessary, by protecting the substituent with a protecting group, but the order of conversion of each substituent is not particularly limited.

(5) The compound (5) of the present invention is obtained by reacting a hydrazine compound represented by the formula (3) with a small excess amount of an aldehyde compound or a ketone compound represented by the formula (4), and then, if necessary, removing a protecting group. Or by converting the functional group. Usually, the reaction is carried out in a solvent at room temperature or under heating, but depending on the type of aldehyde and ketone, the reaction proceeds smoothly by heating under reflux, and the reaction can be further performed using a dehydrator. More advantageous.

The solvent is not particularly limited as long as it does not adversely affect the reaction. For example, ethanol, methanol, athenole, tetrahydrofuran, benzene, tonolene, dichloroethane, dichloromethane, chlorophonolem, carbon tetrachloride, dioxane, dimethoxymethane, dimethoxetane, ethyl acetate, acetonitrile,, -dimethylformam Dimethyl sulfoxide and the like, and a mixed solvent thereof can be used. Preferably, ethanol, methanol, Oh benzene or toluene O ₀

The removal of the protecting group may be performed according to a conventional method. As an example of the functional group conversion, an esterified compound is obtained by subjecting an alcohol compound of the compound obtained by the above-mentioned production method to acylation using a carboxylic acid or an acid chloride by a usual organic chemical method. be able to. Further, an ether compound can be obtained by, for example, a method of reacting an alcohol compound with an alkyl halide. Further, olebamate can be obtained by a method of reacting an isocyanate with an alcohol compound. Further, a halogen compound can be obtained by reacting a commonly used hagogenizing agent with the alcohol compound.

The compound (5) of the present invention produced by the above production method can be isolated and purified as a free form or a salt thereof. Isolation and purification can be performed by applying ordinary chemical operations such as extraction, distillation, crystallization, filtration, recrystallization, and various types of mouth chromatography.

The thus obtained free conjugate or its salt can be further converted to another salt by subjecting it to a usual salt formation reaction.

The intermediate (3) of the compound of the present invention can be produced from the chloro compound represented by the formula (2). The starting compound (2) is dissolved in an alcohol, for example, methanol, ethanol, isopropyl alcohol, butanol or an organic solvent that does not participate in the reaction, and hydrazine is cooled, at room temperature, heated or refluxed by a usual method. Compound By acting, compound (3) can be produced.

When the substituent R ³ is a hydrogen atom, X is a sulfur atom, and Z and Y are both nitrogen atoms, the intermediate (2) of the compound of the present invention can be obtained from the aldehyde compound or ketone compound represented by the formula (1): It can be produced using the method described in literature Synth. Commun. 1996, 26, 3733). When R ³ is other than a hydrogen atom, X is a sulfur atom, and Z and Y are both nitrogen atoms, they can be produced by the method reported in literature, Chein. Ber. 1966, 99, 94).

In the case of R ^{2 or} an acyl group, the compound (2) can also be produced according to the method described in Patent (SU-725433).

Further, when X is a sulfur or oxygen atom and either Z or Y is a nitrogen atom, it is described in (J. Heterocyclic Chem. 1998, 35, 1237, J. Med. Chem. 1989, 32, 1147). Compound (2) can be produced according to the method.

On the other hand, the compound (9) having a different position of the sulfur atom can be obtained from the starting compound (7) obtained from the compound represented by the formula (6) according to the method described in the literature (J. Heterocyclic Chem. 1989, 26, 1575). ) Can be manufactured from mosquitoes.

The compound of the present invention can be converted into a salt, preferably a physiologically acceptable salt, using an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, or an organic acid such as formic acid, acetic acid or methanesulfonic acid, if desired. it can. The scope of the present invention includes any salt form of the substance.

The free form or salt of the compound of the present invention may exist as a solvate such as a hydrate. It goes without saying that these substances are also included in the scope of the present invention.

The medicament of the present invention is useful as an antitumor agent. The active ingredient of the medicament of the present invention includes the compound represented by the above general formula (I), a physiologically acceptable salt thereof, and a compound thereof. A substance selected from the group consisting of these hydrates and their solvates can be used. As the medicament of the present invention, the above-mentioned substance which is an active ingredient may be administered as it is, but usually, a pharmaceutical composition is prepared by using one or more pharmaceutically acceptable additives for preparation. It is desirable to administer. The administration route of the medicament of the present invention is not particularly limited. For example, parenteral administration by various injections such as intravenous injection, intramuscular injection, and subcutaneous injection, or oral administration can be selected. Among these administration methods, intravenous administration and oral administration by an aqueous preparation are preferred.

The form of the drug or composition can be appropriately selected depending on the administration route.For example, aqueous preparations for parenteral administration are generally prepared using physiologically acceptable salts having excellent water solubility. In the case of a pharmaceutical composition for oral administration, it can be prepared using a free substance or a physiologically acceptable salt.

Pharmaceutical compositions suitable for oral administration include, for example, tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like. Examples of suitable pharmaceutical compositions include injections, drops, inhalants, and suppositories. These pharmaceutical compositions can be supplemented by commonly used preparation methods.

Injectables may generally contain a stabilizer, a preservative, a solubilizing agent, or a painless pill. A solution containing the above-mentioned substance as an active ingredient and, if necessary, these pharmaceutical additives is prepared and stored in a container, and then a pharmaceutical composition for time preparation is prepared as a solid preparation by freeze-drying or the like. You may. Also, one dose may be stored in a container, or a plurality of doses may be stored in the same container.

Liquid preparations for oral administration include, for example, liquid preparations, suspensions, emulsions and the like.In preparing these preparations, suspensions, emulsifiers and the like can be used as additives. . '

When the medicament of the present invention is used as an antitumor agent, it is preferable to administer once a day for an adult and repeat the administration at appropriate intervals. The dose is in the range of 1 Omg to 3 g, preferably 5 Omg to 2 g per day for an adult, in terms of the weight of the active substance. Example

Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. The nuclear magnetic resonance spectrum shows the result of 400MHz-'H-MR (TMS internal standard).

[Reference Example 1] Step 2

Process 1

3-[-dimethylamino) methyl] methyl benzoate

2.30 g of methyl 3- (bromomethyl) benzoate was dissolved in 13 ml of tetrahydrofuran, 10 ml of 2M dimethylamine (tetrahydrofuran solution) was added, and the mixture was stirred at room temperature for 18 hours. Ethyl acetate and water were added to the reaction mixture, and the mixture was separated.The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 1.89 g of the title compound. Obtained as a yellow oil.

MS (EI) m / z 193 (M *).

¾ parts (CDC1 ₃ ) δ: 2.24 (s, 3H), 3.46 (s, 2H), 3.91 (s, 6H), 7.38-7.54 (m, 2H), 7.93—7.97 (m, 2H).

3--Dimethylamino) methyl] benzaldehyde

360 mg of lithium aluminum hydride was suspended in 20 ml of anhydrous ether, and ice-cooled under a nitrogen atmosphere. Next, 20 ml of a solution of 1.85 g of the compound obtained in the above step 1 in anhydrous tetrahydrofuran was added dropwise, and the mixture was stirred at the same temperature for 1 hour. 0.8 ml of methanol, 0.36 ml of water, 0.36 ml of 15% aqueous sodium hydroxide solution, and 1.08 ml of water were added in this order while paying attention to foaming, and the mixture was returned to room temperature and stirred for 30 minutes. After filtering off the insoluble matter, the filtrate was distilled off under reduced pressure. Was. The obtained residue was dissolved in 40 ml of chloroform, and 6.85 g of activated manganese dioxide was added at room temperature, and the mixture was stirred for 1 hour, and the same amount of a manganese reagent was further added for 1 hour. The reaction solution was filtered through celite, the mother liquor was concentrated, and the obtained residue was subjected to silica gel chromatography [form: methanol = 9: 1 (v / v)] to give 1.05 g of the title compound as a pale yellow oil. Was.

MS (FAB) m / z 164 (M + H ⁺ ).

¾ thigh _{(CDC1 3) δ: 2.26 (} s, 6H), 3.49 (s, 2H), 7. 7-7.83 (m, 4H), 10.01 (s, 1H).

[Reference Example 2]

'Step 1 rf ^ r ^ Br Step 2

, ∞ ₂ Me ^ C0 ₂ Me ^ CHO process 1

Methyl 2- (bromomethyl) benzoate

2.0 g of 0-methyl toluate, 2.6 g of -bromosuccinic acid imide and 22 mg of azobisisobutyronitrile were dissolved in 20 ml of carbon tetrachloride and stirred at 50 ° C for 5 hours. The reaction solution was allowed to cool, filtered through celite, and then the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography -hexane: ethyl acetate = 10: 1-5: 1 (v / v)] to give 3.3 g of the title compound as a colorless oil.

MS (FAB) m / z 230 (M + H ⁺ ).

_{¾ NMR (CDC1 3) 8 3.95} (s, 3H), 4.96 (s, 2H), 7.37 (dt, 2H, = 7.1, 1.7 Hz), 7.45- 7.50 (m, 2H), 7.97 (d, 2H, / = 7.8 Hz) .Step 2

2-[(-dimethylamino) methyl] benzaldehyde

Using the compound obtained in Step 1 as a raw material, the same operation as in Step 1 of Reference Example 1 was performed, and then the same operation as in Step 2 of Reference Example 1 was performed to obtain the title compound as a colorless oily substance. MS (FAB) m / z 164 (M + H +).

¾舰_{(CDC1 3) δ: 2.24 (} s, 6H), 3.74 (s, 2H), 7.38 (d, 1H, / = 7.6 Hz), 7.42 (t, 1H, / = 7.3 Hz), 7.51 (dt, 1H, J = 7.3, 1.5 Hz), 7.87 (dd, 1H, zo = 7.8, 1.5 Hz), 10.0 (s, 1H).

[Reference Example 3]

4-Methyl [(M-dimethylamino) methyl] benzoate

The same operation as in Step 1 of Reference Example 1 was carried out using methyl 4- (bromomethyl) benzoate as the starting material to obtain the title compound as a yellow oily substance.

MS (FAB) m / z 194 (M + H ⁺ ).

_{¾ NMR (CDC1 3) δ:} 2.25 (s, 6H), 3.47 (s, 2H), 3.91 (s, 3H), 7.38 (d, 2H, / = 8.3 Hz), 7.99 (d, 2H, / = 8.3 Hz). Step 2

4-[(M-dimethylamino) methyl] benzaldehyde

The same operation as in Step 2 of Reference Example 1 was performed using the compound obtained in Step 1 as a starting material to obtain the title compound as a yellow oily substance.

MS (FAB) m / z 164 (M + H +).

¾ thigh _{(CDC1 3) δ: 2.26 (} s, 6H), 3.50 (s, 2H), 7.49 (d, 2H, = 8.1 Hz), 7.84 (d, 2H, zo = 8.1 Hz), 10.00 (s , 1H ).

[Reference Example 4]

CI

Process 1

3- [½-dimethylamino) sulfonyl] benzoic acid

3-Chlorosulfonylbenzoic acid (ei 1997, 4, 315, J. Med. Chem. 1999, 42, 515) 1. Dissolve Og in 20 ml of tetrahydrofuran, and add 2M dimethylamine (tetrahydrofuran solution) under ice-cooling. 4.76 ml was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with a 1N aqueous sodium hydroxide solution, washed with ethyl acetate, the aqueous layer was acidified with a 1N aqueous hydrochloric acid solution, and the precipitated solid was collected by filtration to obtain 747 mg of the title compound as a colorless solid. MS (FAB) m / z 230 (M + H ⁺ ).

_{¾ NMR (CDC1 3) δ:} 2.63 (s, 6H), 7.80 (t, 1H, J: 7.8 Hz), 7.99 (d, 1H, J = 8.0 Hz), 8.19 (s, 1H), 8.25 (d, 1H, J = 7.8Hz)-. Process 2

Nl, N \ -Dimethyl-3-formyl-1-benzenesnoreon amide

Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 1 was performed to obtain the title compound as a pale brown solid.

MS (FAB) m / z 214 (M + H +).

¾ NMR (CDCI3) δ: 2.76 (s, 6H), 7.75 (t, 1H, / = 7.3 Hz), 8.04 (dt, 1H, J = 7.8, 1.0 Hz), 8.13 (dt, 1H, J = 7.8, 1.0 Hz), 8.27 (t, 1H, = 1.5 Hz), 10.10 (s, 1H).

[Reference Example 5] ci

Process 1

3-[(-Butylamyl] benzoic acid The title compound was obtained as a colorless solid by performing the same operation as in Step 1 ′ of Reference Example 4 using 3-ku mouth mouth sulfonylbenzoic acid and -butylamine as raw materials.

MS (FAB) m / z 258 (M + H ⁺ ).

¾satsu (SO- ₆ ) δ: 1.09 (s, 9H), 7.70 (t, 1H, / = 7.8 Hz), 7.72 (s, 1H), 8.05 (d, 1H, / = 8.8 Hz), 8.12 ( d, 1H, / = 7.8 Hz), 8.37 (s, 1H).

1- (ί-butyl) -3-formyl-: [-benzenesulfonamide

Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 4 was carried out to obtain the title compound as a pale yellow oily substance.

MS (FAB) m / z 242 (M + H +).

¾ thigh _{(CDC1 3) δ: 1.26 (} s, 9Η), 4.53 (s, 1Η), 7.69 (t, 1H, / = 7.8 Hz), 8.07 (dd, 1H, / = 7.8, 1.5 Hz), 8.15 ( dd, 1H, J = 7.8, 1.2 Hz), 8.39 (d, 1H, J = 1.7 Hz), 10.08 (s, 1H).

[Reference Example 6]

Process 1

4-[-dimethylamino) sulfonyl] benzoic acid

Using 4-chlorosulfonylbenzoic acid and dimethylamine as raw materials, the same operation as in Step 1 of Reference Example 4 was performed to obtain the title compound as a colorless solid.

MS (FAB) m / z 230 (M + H +).

¾ thigh _{(DMS0- 6) δ: 2.63 (} s, 6H), 7.86 (d, 2H, zo = 6.9 Hz), 8.16 (d , 2H, / = 7.3 Hz) -. Process 2

Nl, 1_Dimethinole-4-formyl-1-benzenesulfonamide

Using the compound obtained in the above step 1 as a raw material, the same operation as in step 2 of Example 4 was performed to obtain the title compound as a yellow solid.

MS (FAB) m / z 214 (Μ + Η +)

_{¾ NMR (CDC1 3) δ 2.76} (s, 6H), 7.95 (d, 2H, / = 8.0 Hz), 8.06 (d, 2H, J = 8.0 Hz), 10.12 (s, 1H).

[Reference Example 7] N, S ',

0

, CHO process 1

4-[(4-methylpiperazino) sulfonyl] benzoic acid

Using 4-chlorosulfonylbenzoic acid and methylbiperazine as raw materials, the same operation as in Reference Example 4, step 1 was performed to obtain the title compound as a colorless solid.

MS (FAB) m / z 285 (M + H ⁺ ).

¾ NMR (DMSO- ₆ ) δ: 2.73 (s, 9H), 3.16 (br s, 2H), 3.34 (br s, 4H), 3.79 (br s, 2H), 7.90 (d, 2H, / = 8.3 Hz ), 8.20 (d, 2H, / = 8.3 Hz).

4-([4-methylpiperazino) sulfonyl] benzaldehyde

Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Example 4 was performed to obtain the title compound as a pale yellow oily substance.

MS (FAB) m / z 269 (M + H +).

¾ NMR (CDCI3) δ: 1.56 (br s, 2H), 1.56 (s, 3H), 2.17 (br s, 2H), 2.53 (br s, 2H), 3.12 (br s, 2H), 7.92 (d, 2H, ZO = 8.3 Hz), 8.04 (d, 2H, / = 8.3 Hz), 10.11 (s, 1H). [Reference Example 8]

Me〇 ₂ C

Process 1

4-IN, N-di (2-hydroxyethyl) amino] methyl benzoate

The same operation as in Step 1 of Reference Example 1 was carried out using methyl 4- (bromomethyl) benzoate and diethanolamine as raw materials to obtain the title compound as a pale yellow oily substance.

MS (FAB) m / z 254 (M + H ⁺ ).

¾ Fiber (CDC1 ₃ ) δ: 2.71-2.74 (m, 4H), 3.62— 3.65 (m, 4H), 3.77 (s, 2H), 3.91 (s, 3H), 7.40 (d, 2H, / = 8.5 Hz ), 7.99 (d, 2H, 8.2 Hz). Process 2

4-½N-di (2-hydroxyethyl) amino] methylbenzaldehyde

Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 1 was performed to obtain the title compound as a yellow oily substance.

MS (FAB) m / z 224 (M + H ⁺ ).

¾ MR (CDC1 ₃ ) δ: 2.74 (t, 4H, / = 5.4 Hz), 3.65 (t, 4H, / = 5.4 Hz), 3.80 (s, 2H), 7.51 (d, 2H, / = 8.1 Hz) , 7.85 (d, 2H, = 8.1 Hz), 9.99 (s, 1H).

[Reference Example 9] H

Process 1

4-_N- (2-hydroxyxethyl) -methylamino] methyl benzoate The same operation as in Step 1 of Reference Example 1 was carried out using methyl 4- (bromomethyl) benzoate-methylethanolamine as a raw material to obtain the title compound as a pale yellow oily substance. MS (FAB) m / z 224 (M + H ⁺ )-

_{¾ MR (CDC1 3) δ 2.24} (s, 3H), 2.62 (t, 2H, / = 5.4 Hz), 3.63 (s, 2H), 3.64 (t, 2H, = 5.4 Hz), 3.92 (s, 3H) , 7.38 (d, 2H, = 8.1 Hz), 8.00 (d, 2H, 8.1 Hz). Step 2

4-[-(2-hydroxyethyl)--methylamino] methylbenzaldehyde

The same operation as in Step 2 of Reference Example 1 was performed using the compound obtained in Step 1 as a raw material to obtain the title compound as a yellow oily substance.

MS (FAB) m / z 194 (M + H ⁺ ).

¾ MR (CDCI3) δ: 2.26 (s, 3H), 2.63 (t, 2H, / = 5.4 Hz), 3.65 (s, 4H), 7.49 (d, 2H, = 8.1 Hz), 7.85 (dd, 2H, = 8.1, 1.7 Hz), 10.00 (s, 1H).

[Reference Example 10]

Me0 ₂ C ^ process] Me0 ₂ C process 2 ^ OHC ^ process 1

Methyl 4-[(4-methylpiperazino) methyl] benzoate

The same procedure as in Step 1 of Reference Example 1 was carried out using methyl 4- (bromomethyl) benzoate-methylpiperazine as a raw material to obtain the title compound as a pale yellow oily substance.

MS (FAB) m / z 249 (M + H ⁺ ).

¾賺_{(CDC1 3) δ: 2.29 (} s, 3H), 2.47 (br s, 8H), 3.55 (s, 2H), 3.91 (s, 3H), 7.40 (d, 2H, d 8.6 Hz), 7.98 ( dd, 2H, J "= 8.6, 1.7 Hz). Process 2 4-[(4-methylpiperazino) methyl] benzaldehyde

MS (FAB) m / z 219 (M + If).

_{¾NMR (CDC1 3) δ: 2.29} (s, 3H), 2.49 (br s, 8H), 3.58 (s, 2H), 7.51 (d, 2H, / = 8.1 Hz), 7.83 (d, 2H, / = 8.1 Hz), 9.99 (s, 1H).

[Reference Example 1 1]

Step 1.

4- [4- (2-hydroxyethyl) pidrazino] methyl benzoate

The same operation as in Step 1 of Reference Example 1 was carried out using methyl 4- (bromomethyl) benzoate and-(2-hydroxyethyl) pirazine as starting materials to obtain the title compound as a brown solid.

MS (FAB) m / z 279 (M + H ⁺ ).

¾ MR (CDCI3) δ: 2.50 (br s, 8H), 2.56 (t, 2H, / = 5.4 Hz), 3.56 (s, 2H), 3.61 (t, 2H, zo = 5.4 Hz), 3.91 (s, 3H), 7.39 (d, 2H, J = 8.1 Hz), 7.98 (d, 2H, / = 8.1 Hz).

4- [4- (2-Hydroxitytyl) piperazino] methylbenzaldehyde

The same operation as in Step 2 of Reference Example 1 was performed using the compound obtained in Step 1 as a raw material to obtain the title compound as a colorless solid.

MS (FAB): m / z 249 (M + H ⁺ ).

_{¾ NMR (CDC1 3) δ:} 2.58 (m, 10H), 3.59 (s, 2H), 3.63 (t, 2H, zo = 5.1 Hz), 7.50 (d , 2H, J = 8.3 Hz), 7; 84 ( d, 2H, = 8.3 Hz), 10.00 (s, 1H). [Reference Example 1 2]

Me0 ₂ C ^^ OHC

OTBDPS

1.0 g of methyl 4- (bromomethyl) benzoate and 860 mg of imidazole were dissolved in 20 ml of tetrahydrofuran, and 1.64 ml of -butyldiphenylsilyl chloride was added, followed by stirring at room temperature for 7 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline. The extract was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the obtained residue was subjected to silica gel chromatography [/?-Hexane: ethyl acetate = 5: 1 (v / v)] to obtain a silyl compound. Using the obtained silyl compound as a raw material, the same operation as in Step 2 of Reference Example 1 was performed to obtain 1.86 g of the title compound as a yellow oily substance.

MS (FAB) m / z 375 (M + if).

_{¾ NMR (CDC1 3) δ 1.12} (s, 9H), 4.84 (s, 2H), 7.39-7.44 (m 5H), 7.51 (d, 2H, 8.3 Hz), 7.68 (dd, 4H, J = 7.8, 1.7 Hz), 7.85 (d, 2H, / = 8.3 Hz), 10.00 (s 1H).

[Reference Example 13]

5- [3-(-butyldiphenylsilinole) oxy] phenyl-] ^-tetrazole

500 mg of 3-cyanobenzyl alcohol and 614 mg of imidazole were dissolved in 5 ml of tetrahydrofuran, and 1.17 ml of プ -butyldiphen.ersilyl chloride was added, followed by stirring at room temperature for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline. It is dried over anhydrous sodium sulfate, the solvent is concentrated under reduced pressure, and the obtained residue is subjected to silica gel chromatography. Hexane: ethyl acetate = 5: 1 (v / v)] Thus, 1.32 g of a silyl compound was obtained. The obtained silyl compound was dissolved in 6 ml of -dimethylformamide, and 208 mg of sodium azide and 172 mg of sodium chloride were added. The mixture was stirred at 100 ° C for 18 hours. The reaction solution was returned to room temperature, a 1N aqueous hydrochloric acid solution was added thereto, extracted with ethyl acetate, and the organic layer was washed with saturated saline. The extract was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure to obtain 519 mg of the title compound as a pale yellow oily substance. MS (FAB) m / z 415 (M + H ⁺ ).

¾ thigh _{(CDC1 3) δ:. 1.07} (s, 9H), 4.83 (s, 2H), 7.35- 7.43 (m, 10H), 7.69 -7.73 (m, 4H) Step 2

3- (1-trityl-! ^-Tetrazol-5-yl) benzaldehyde

549 mg of the compound obtained in the above step 1 was dissolved in 5.5 ml of -dimethylformamide, 738 mg of trityl chloride and 0.37 ml of triethylamine were added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, extracted with getyl ether, and the organic layer was washed with saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a trityl compound. The obtained trityl body was dissolved in 30 ml of tetrahydrofuran, 2.7 ml of 1M tetra-2-butynoleammonium fluoride (tetrahydrofuran solution) was added, and the mixture was stirred at 60 ° C. for 21 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water and saturated saline in this order. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel chromatography [ethyl acetate: -hexane = 1: 1 (v / v)] to give 253 mg of the alcohol. Obtained as a yellow oil. The obtained alcohol was dissolved in 6 ml of chloroform, added with 0.5 g of activated manganese dioxide, and heated under reflux for 3 hours. After allowing to cool, the mixture was filtered through celite and the solvent was concentrated to obtain 247 mg of the title compound as a yellow oily substance.

MS (FAB) m / z 417 (M + H ⁺ ).

_{¾ NMR (CDC1 3) δ:} 7.17 (dd, 4H, / = 8.3, 2.0 Hz), 7.33-7.40 (m, 11H), 7.63 (t, 1H, / = 7.6 Hz), 7.97 (dd, "4H, 7.8, 1.2 Hz), 8.42 (dd, 4H, J = 7.8, 1.2 Hz), 8.62 (s, 1H), 10.08 (s, 1H). [Reference Example 14]

5-forminole-1,3-dihydro-isoidindole-2-carboxylate ί-butyl

Dissolve 500 mg of 5- (hydroxymethyl) -1,3-dihydroxy-isoindole-2-carboxylic acid t-butyl (Japanese Patent Application 2000-16984) in 15 ml of tetrachloromethane carbon, and activate manganese dioxide.

2.0 g was added, and the mixture was heated under reflux for 30 minutes. After insolubles were filtered through celite, the mother liquor was concentrated, and the obtained residue was subjected to silica gel chromatography [ethyl acetate: -hexane = 1: (v / v)] to give 325 mg of the title compound as a colorless solid.

MS (EI) m / z 247 (¾f).

_{¾ NMR (CDC1 3) δ ··} 1. 53 (s, 9H), 4. 72 (br s, 2H), 4. 76 (br s, 2H), 7. 38- 7. 5 (m, 1H) , 7.75—7.81 (m, 2H), 10.00 (s, 1H).

[Reference Example 15]

N-Boc process ¹

Process 1

5- (Hydroxymethyl) -1,3-dihydro-2H-isoindoleacetate-butyl

1.50 g of the compound obtained in Reference Example 14 was dissolved in 2 ml of dioxane, 15 ml of 4N dioxane hydrochloride was added, and the mixture was stirred at room temperature for 45 minutes. After concentration, azeotroped with ethanol three times to obtain a powder. Next, the obtained hydrochloride was dissolved in 45 ml of TV ",-dimethylformamide, and 3.30 g of carbonated lime and 1.05 ml of t-butyl bromoacetate were added, followed by stirring at room temperature for 18 hours. To the solution was added a saturated aqueous solution of sodium hydroxide, washed successively with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 2-hexane = 2: Kv / v)] to give 720 mg of the title compound as a yellow solid. ¾ NMR (CDCI3) δ: 1.48 (s, 9H), 3.50 (s, 2H), 4.11 (s, 4H), 4.65 (s, 2H), 7.14-7.17 (m, 3H).

5-Honoremil-1,3-dihydro-W-isoindolenoacetic acid ί-ptinole 'Using the compound obtained in the above step 1 as a raw material, the same operation as in Reference Example 14 was performed to obtain the title compound as a yellow oily substance.

_{¾ NMR (CDC1 3) δ:} 1.49 (s, 9H), 3.55 (s, 2H), 4.15 (s, 4H), 7.14-7.17 (m, 3H), 10.05 (s, 1H).

[Reference example 1 6] ·

2-methyl-5-isoindolinecarboxaldehyde

Dissolve 200 mg of t-butyl 5- (hydroxymethyl) -1,3, -dihydrodiisoindoleate / re-2-enolevonic acid in 0.4 ml of dichloromethane, add 1 ml of trifluoroacetic acid, stir at room temperature for 2 minutes, and react. The liquid was concentrated under reduced pressure. The obtained trifluoroacetate was dissolved in 2.4 ml of dichloromethane, 0.223 ml of triethylamine was added, and the mixture was stirred at room temperature for 15 minutes. Further, 0.115 ml of acetic acid and 0.138 ml of a 35% aqueous formaldehyde solution were added, and the mixture was stirred for 5 minutes. Finally, 272 mg of sodium triacetoxypolyhydride was added, and the mixture was stirred for 1.5 hours. A 1N aqueous solution of sodium hydroxide was added to the reaction solution, extracted with ethyl acetate, and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain 110 mg of an alcohol. Using the obtained alcohol compound as a raw material, the same operation as in Reference Example 14 was performed to obtain 100 mg of the title compound as a pale yellow oily substance.

MS (FAB) m / z 162 (M + H +).

¾ NMR (CDCI3) δ: 2.60 (s, 3H), 3.91 (d, 4H, / = 2.9 Hz), 7.16 (d, 2H, J: 1.7 Hz), 7.71 (s, 1H), 9.97 (s, 1H) ). [Reference Example 17]

2-Isopropyl-5-isoindolinecarboxyaldehyde

5- (Hydroxymethyl) -1,3-dihydroxy-isoindole-2-carboxylic acid ί-butyl was used as a raw material, and the same operation as in Reference Example 16 was carried out using acetone instead of formaldehyde. The same operation as in Reference Example 14 was performed to give the title compound as a yellow oily substance.

MS (FAB) / z 190 (M + H ⁺ ).

_{¾ MR (CDC1 3) δ ··} 1.21 (d, 6H, / = 6.3 Hz), 2.75-2.80 (m, 1H), 3.95 (d, 2H, / = 8.1 Hz), 4.02 (s, 2H), 7.16 (s, 1H), 7.36 (d, 1H, = 8.1 Hz), 7.72 (d, 1H, J = 3.4 Hz), 9.98 (s, 1H).

[Reference Example 18] ヽ N

M, N,

-CN, CHO

4- (4-methylbiperazino) benzaldehyde

750 mg of 4- (4-methylbiperazino) benzonitrile, Bioorg. Med. Chem. Lett. 1995, 5, 1909) is dissolved in 14 ml of dichloromethane, and 1 M diisopropylethyl hydride (toluene at 176 ° C) (Solution) 3.72 ml was added dropwise and stirred at the same temperature for 1.5 hours. After completion of the reaction, a saturated aqueous solution of sodium chloride was added, and extraction with getyl ether was performed. The organic layer was washed with saturated saline. The extract was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel chromatography [form: methanol = 10: 1 (v / v)] to give 546 mg of the title compound. Obtained as a yellow solid.

MS (FAB) m / z 205 (M + H ⁺ ). _{¾ NM (CDC1 3) δ:} 2.35 (d, 3H, / = 2.4 Hz), 2.54 (d, 2H, / = 4. Hz), 2.56

(d, 2H, / = 4.4 Hz), 3.34 (t, 2H, zo = 5.1 Hz), 3.42 (t, 2H, 5.1 Hz), 6.86

(dd, 1H, / = 9.0, 2.0 Hz), 6.92 (d, 1H, / = 9.0 Hz), 7.49 (d, 1H, / = 8.8 Hz), 7.75 (d, 1H, / = 8.8 Hz), 9.78 (s, 1H).

[Reference Example 19]

Process 1

4- [C¾-dimethylamino) methyl] -3-fluoromethyl benzoate

Using methyl 3-fluoro-4-methylbenzoate as a raw material, the same operation as in Step 1 of Reference Example 2 was performed, and then the same operation as in Step 1 of Reference Example 1 was performed to obtain the title compound as a pale red oily substance.

MS (FAB) m / z 212 (M + H +).

¾ MR (CDCI3) δ: 2.28 (s, 6H), 3.54 (s, 2H), 3.92 (s, 3H), 7.46 (t, 1H, / = 7.6 Hz), 7.69 (dd, 1H, zo = 10.3, 1.5 Hz), 7.80 (dd, 1H, = 8.1, 1.5 Hz). Process 2

4-[(-dimethylamino) methyl] -3-fluorobenzaldehyde

MS (FAB) m / z 182 (M + H ⁺ ).

¾ NMR (CDCI3) δ: 2.29 (s, 6H), 3.56 (s, 2H), 7.54-7.67 (m, 3H), 9.96 (s, 1H).

[Reference Example 20]

r

Process 1

3-Methoxy-4-methyl benzoate

Dissolve 5.0 g of 4-methyl-3-dibenzobenzoic acid in 50 ml of methanol and 150 ml of benzene, and add 17.9 ml of 2M trimethylsilyldiazomethane (/ 2-hexane solution) under ice-cooling. The mixture was stirred at room temperature for 19 hours. The reaction solvent was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added, extracted with ethyl acetate, and washed with brine. The organic layer was concentrated under reduced pressure to obtain an ester. The obtained ester was dissolved in 100 ml of ethanol, 10.8 g of 10% palladium on carbon was added, and the mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give the amino compound (3.8 g). 2.0 g of the obtained amino compound was suspended in 4 ml of water, and 12 ml of concentrated hydrochloric acid was added. Under ice cooling, 0.85 g of sodium nitrite dissolved in 2 ml of water was added dropwise to prepare a diazodium salt. A solution of diazonium salt was added dropwise to a solution of 1.39 g of cuprous chloride in 3 ml of concentrated hydrochloric acid under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated saline. After drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography-hexane: ethyl acetate = 10: 1 (v / v)] to give 1.33 g of the title compound as a colorless oil.

MS (EI) / z 184 (M ⁺ ).

_{¾ NMR (CDC1 3) δ:} 2.43 (s, 3H), 3.91 (s, 3H), 7.29 (d, 1H, / = 7.8 Hz), 7.82 (dd, 1H, J = 7.8, 1.7 Hz), 8.00 ( d, 1H, = 1.7 Hz). Process 2

3-Kuguchi-4-[-dimethylamino) methyl] benzaldehyde

Using the compound obtained in the above step 1 as a raw material, the same operation as in step 1 of reference example 2 was performed, and then the same operation as in step 1 of reference example 1 and further step 2 of reference example 1 was performed, whereby the title compound was converted into a yellow oil As obtained.

MS (FAB) m / z 198 (M + H ⁺ ) .-

¾ MR (CDCI3) δ: 2.32 (s, 6H), 3.60 (s, 2H), 7.66 (d, 1H, / = 8.1 Hz), 7.76 (dd, 1H, zo = 8.5 Hz), 7.87 (d, 1H, = 1.5 Hz), 9.96 (s, 1H).

[Reference Example 21] Step 2

Process 1

Methyl 2- (ί-butyldimethylsilyl) oxy-4-methylbenzoate

Dissolve 2.0 g of 2-hydroxy-4-methylbenzoic acid in a mixed solvent of 25 ml of methanol and 90 ml of benzene, add 8.5 ml of 2M trimethylsilyldiazomethane 0-hexane solution), and add at room temperature for 15 hours. Stirred. The reaction solution was concentrated under reduced pressure, and 500 mg of the obtained ester form and 287 mg of imidazole were dissolved in 10 ml of ^ -dimethylformamide, and 544 mg of ί-butyldimethylsilyl chloride was added. Stirred for hours. Water was added to the reaction solution, extracted with getyl ether, and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain 770 mg of the title compound as a pale yellow oil.

MS (FAB) m / z 281 (M + H ⁺ ).

_{¾ NMR (CDC1 3) δ:} 0.20 (d, 6H, zo = 0.7 Hz), 1.01 (d , 9H, = 0.7 Hz), 2.32 (s, 3H), 3.84 (d, 3H, J = 0.1 Hz), 6.67 (s, 1H), 6.79 (dt, 1H, ZO = 8.1, 0.7 Hz), 7.67 (d, 1H, / = 8.1 Hz). Step 2

2 - (ί-: Okishi - ₄ - _[½ - Jimechiruamino) methyl] benzoate

Using the compound obtained in the above step 1 as a raw material, the same operation as in step 1 of Reference Example 2 was performed, and the same operation as in step 1 of Reference Example 1 was performed using the compound to obtain the title compound as a pale yellow oily substance. MS (FAB) m / z 324 (M + H ⁺ ).

¾ NMR (CDCI3) δ: 0.21 (s, 6H), 1.01 (s, 9H), 2.22 (s, 6H), 3.39 (s, 2H), 6.83 (s, 1H), 6.94 (dd, 1H, = 8.1 , 1.0 Hz), 7.72 (d, 1H, zo = 8.1 Hz). Step 3.

4-[(-dimethylamino) methyl] -2-hydroxybenzaldehyde

The title compound was obtained as a pale yellow oily substance by performing the same operation as in Step 2 of Reference Example 1 using the compound obtained in the above Step 2 as the original product. .

MS (FAB) m / z 180 (M + H +).

¾ NMR (CDCI3) δ: 2.25 (s, 6H), 3.43 (s, 2Η), 6.95 (s, 1Η), 7.00 (d, 1H, = 7.8 Hz), 7.50 (d, 1H, J: 7.8 Hz) , 9.86 (s, 1H), 11.03 (br s, 1H).

[Reference Example 2 2]

(4-formylbenzyl) methylcarbamic acid ί-butynole

2.0 g of methyl 4-formylbenzoate was dissolved in 200 ml of toluene, 6.1 ml of 2M methylamine (tetrahydrofuran solution) was added, and the solvent was concentrated under reduced pressure. After azeotropic distillation with toluene, 200 ml of methanol was added, 510 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 2 hours. The pH was adjusted to 2 or less with a 1N aqueous hydrochloric acid solution; The reaction solution was made alkaline with a 10% aqueous sodium hydroxide solution, and extracted with a porcine form. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was dissolved in 50 ml of dichloromethane, 2.8 ml of di-butyl dicarbonate and a catalytic amount of 4- (dimethylamino) pyridine were added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, the obtained residue was subjected to silica gel chromatography, hexane: ethyl acetate = 10: 1 (v / v)], and the same operation as in Reference Example 1, step 2 was performed. 290 mg of the title compound as a colorless oil, MS (FAB) m / z 250 (M + H +).

¾ MR (CDCI3) δ: 1.45-1.50 (br, 9H), 2.83-2.89 (br, 3H), 4.50 (br s, 2H):

7.38 (d, 2H, J = 8.1 Hz), 7.86 (d, 2H, / = 8.1 Hz), 10.01 (s, 1H).

[Reference Example 23]

4-[(l, 3-dioxo-1,3-dihydro-2 ^ -isindole-2-yl) methyl] benzaldehyde

-Xylene glycol (5.0 g) was dissolved in toluene (50 ml), 48% hydrogen bromide aqueous solution (5.6 ml) was added, and the mixture was stirred at 90 ° C for 1 hour. Neutralized with 1N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The mixture was azeotropically distilled with benzene to obtain a monobromide as a colorless oily substance. The obtained monobromide was dissolved in -dimethylformamide (35 ml), phthalimide potassium salt (6.33 g) was added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was diluted with ethyl acetate and getyl ether, washed with water and saturated saline in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was reprecipitated with -hexane and ethyl acetate to give 3.64 g of a monoalcohol as a colorless solid. Then, the same procedure as in Reference Example 14 was performed using the obtained alcohol compound as a raw material, to give 2.87 g of the title compound as a colorless solid.

MS (FAB) m / z 266 (M + H ⁺ ).

¾ NMR (CDCI3) δ: 4.91 (s, 2H), 7.57 (d, 2H, / = 8.1 Hz), 7.73 (dd, 2H, J = 5.4, 2.9 Hz), 7.82-7.87 (m, 4H), 9.97 (s, 1H).

[Reference Example 24]

Process 1

[4- (azomethyl) phenyl] methanol

5.0 g of xylene glycol was dissolved in 50 ml of toluene, 5.6 ml of a 48% aqueous hydrogen bromide solution was added, and the mixture was stirred at 90 ° C. for 1 hour. Neutralized with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The mixture was azeotropically distilled with benzene to obtain a monobromide as a colorless substance. The obtained monobromide was dissolved in 70 ml of -dimethylformamide, 7.06 g of sodium azide was added, and the mixture was stirred at 120 ° C for 20 hours. The reaction solution was returned to room temperature, filtered through celite, and concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate and getyl ether, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography [-hexane: ethyl acetate = 5: 1 (v / v)] to give the title compound (3.64 g) as a colorless oil.

¾ thigh _{(CDC1 3) δ: 1.75 (} br s, 1H), 4.34 (s, 2H), 4.71 (s, 2H), 7.33 (d, 2H, / = 8.3 Hz), 7.39 (d, 2H, / = (8.3 Hz) .Step 2

(4-forminolebenzyl) potamic acid バ -butynole

Dissolve 3.64 g of the compound obtained in the above step 1 in 36 ml of ethyl acetate, 6.1 ml of di-ί-butyl dicarbonate and 10 ° /. 0.36 g of palladium carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. The insolubles were filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was reprecipitated with ethyl acetate and hexane to give 2.89 g of an alcohol as a colorless solid. Using the obtained alcohol compound as a raw material, the same operation as in Reference Example 14 was performed to obtain 2.32 g of the title compound as a colorless solid.

MS (FAB) m / z 236 (M + H ⁺ ).

_{¾ NM (CDC1 3) 8:} 1.47 (s, 9H), 4.39 (d, 2H, / = 5.6 Hz), 4.98 (br s, 1H), 7. 5 (d, 2H, J two 8.1 Hz), 7 , 85 (d, 2H, = 8.1 Hz), 10.00 (s, 1H). [Reference Example 25]

Process 1

4-Butyl 4- [4- (ethoxycarbonyl) phenyl] -1-azidinecarboxylate Active zinc powder 1.19 g of, -Dimethylformamide 25 ml 0.10 ml of promoetane was added and stirred at 70 ° C for 3 minutes and at room temperature for 30 minutes. Then, 0.19 ml of chlorotrimethylsilane was added, and for 15 minutes, 4.88 g of -3-butyl-1-azetidinecarboxylate (5¾Jel998, 379), 25 ml of a, -dimethylformamide solution was slowly added, followed by stirring for 60 minutes. did. Furthermore, a solution of 162 mg of tris (dibenzylideneaceton) diparadipum and 164 mg of tris-2-furylphosphine in 4 ml of, -dimethylformamide was added, followed by stirring for 10 minutes, followed by 4.75 g of diethyl 4-ethyl benzoate. A 25 ml solution of methylformamide was added, and the mixture was stirred at 65 ° C for 4 hours and at room temperature for 40 minutes. The reaction solution was diluted with ether, washed successively with a saturated aqueous solution of sodium hydroxide and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography [ethyl acetate: -hexane = 1: 9-1: (v / v)] to give 3.80 g of the title compound as a yellow oily substance.

MS (ESI) m / z 347 (M + MeC *).

_{¾ NMR (CDC1 3) δ:} 1.40 (t, 3H, / = 7.0 Hz), 1.47 (s, 9H), 3.74-3.82 (m, 1H), 3.98 (dd, 2H, / = 8.5, 6.0 Hz), 4.33-4.41 (m, 4H), 7.38 (d, 2H, J: 8.5 Hz), 8.03 (d, 2H, / = 8.5 Hz). Step 2

3- (4-Honolemyl.phenyl) -1-azetidinecarboxylic acid ί-Putinole

Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 1 was performed to obtain the title compound as a colorless oily substance.

MS (FAB) m / z 262 (M + H ⁺ ). ¾ NMR (CDCI3) 8: 1.47 (s, 9H), 3.77—3.85 (m, 1H), 3.99 (dd, 2H, Zoni 8.5,

5.9 Hz), 4.38 (dd, 2H, / = 8.8, 8.5 Hz), 7.49 (d, 2H, / = 8.1Hz), 7.88 (d, 2H, / = 8.1Hz), 10.01 (s, 1H).

[Reference Example 26]

4- (1-Methyl-3-azetidyl) benzaldehyde

Reference Example 25 Using the compound obtained in Step 1 as a raw material, the same operation as in Reference Example 16 was performed, and then the same operation as in Step 2 of Reference Example 1 was performed to obtain the title compound as a pale brown oily substance. .

MS (FAB) m / z 176 (M + H ⁺ ).

¾NMR (CDCI3) δ: 2.38 (s, 3H), 3.21 (s, 2H), 3.76 (br s, 3H), 7.46 (d, 2H, two 7.1 Hz), 7.84 (d, 2H, / = 7.1 Hz) , 9.99 (s, 1H).

[Reference Example 27]

Process 1

6-[() -3-Ethoxy-3-oxo-1-propenyl) -3,4-dihydroisoquinoline-2 (1) -canoleponic acid-butynole

6-{[(trifluoromethane) sulfonyl] oxy} -3,4-dihydro-2 (1 ^)-butylisoquinolinecarboxylate (W09916747) 2.0 g, ethyl acrylate 0.72 ml, triethylamine 1.45 ml acetonitrile Dissolved in 20 ml. Further, 118 mg of palladium acetate and 319 mg of tris (0-tolyl) phosphine were added, and the mixture was stirred at 90 ° C for 45 hours under a nitrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was extracted with ethyl acetate, and washed sequentially with a saturated aqueous solution of ammonium chloride and a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue is subjected to silica gel chromatography [73-hexane: ethyl acetate = 4: 1].

(v / v)] to give 310 mg of the title compound as a yellow oily substance.

MS (FAB) m / z 332 (M + H ⁺ ).

¾NM (CDC1 ₃ ) δ1.34 (t, 3H, / = 7.3 Hz), 1.49 (s, 9H), 2.85 (m, 2H), 3.65 (m, 2H), 4.26 (q, 2H, J = 7.3 Hz), 4.58 (s, 2H), 6.1 (d, 1H, / = 16.1 Hz), 7.12 (d, 1H, = 8.1 Hz), 7.29 (s, 1H), 7.35 (d, 1H, = 8.1) Hz), 7.64 (d, 1H, / = 16.1 Hz). Process 2

6-formyl-3,4-dihydro-2 (1 ^ -isoquinolinecarboxylic acid ί-butyl

309 mg of the compound obtained in the above step 1 was dissolved in 4.0 ml of tetrahydrofuran, and 2.0 ml of water was added. 2.4 mg of osmium tetroxide was added, and the mixture was stirred at 50 ° C. To the reaction solution, 398 mg of sodium periodate was added little by little, and the mixture was stirred at the same temperature for 3.5 hours. After completion of the reaction, a saturated aqueous solution of sodium sulfite was added, extracted with ethyl acetate, and washed with water and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography (sword-hexane: ethyl acetate = 4: 1 (v / v)) to obtain 112 mg of the title compound as a colorless solid.

MS (FAB) m / z 262 (M + H ⁺ )-

_{¾ NMR (CDC1 3) δ:} 1.50 (s, 9H), 2.92 (t, 2H, / = 5.8 Hz), 3.68 (t, 2H, J = 5.8 Hz), 4.65 (s, 2H), 7.28 (d, 1H, ZO = 7.3 Hz), 7.66 (s, 1H), 7.69 (d, 1H, ZO = 7.3 Hz), 9.96 (s, 1H).

Process 1

Ί-Butyl 4- (1-hydroxyshethylbenzyl) methylcarbamate 0.83 ml of 0.93M methylmagnesium bromide (tetrahydrofuran solution) was added to 2 ml of tetrahydrofuran, and 2 ml of tetrahydrofuran of 200 mg of the compound obtained in Reference Example 22 was added dropwise at 178 ° C, followed by heating to room temperature. And stirred overnight. The reaction solution was added to a saturated aqueous ammonium chloride solution, and extracted three times with getyl ether. The obtained organic layer was washed with a saturated saline solution, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography [form of mouth: methanol: 20: 1 (v / v)] to obtain 113 mg of the title compound as a yellow oily substance.

MS (FAB) m / z 266 (M + H +).

_{¾ NMR (CDC1 3) δ:} 1.48 (s, 9H), 1.56 (s, 3H), 1.78 (s, 1H), 2.81 (s, 3H), 4.41 (s, 2H), 4.90 (m, 1H), 7.20 (d, 2H, J "= 8.1 Hz), 7.33 (d, 2H, / = 8.1 Hz). Step 2

4--Butyl (4-acetylbenzyl) methylcarbamate

Using the compound obtained in the above step 1 as a raw material, the same operation as in Reference Example 14 was performed to obtain the title compound as a colorless oily substance.

¾丽_{(CDC1 3) δ: 1.48 (} s, 9Η), 2.59 (s, 3H), 2.85 (br s, 3H), 4.47 (s, 2H), 7.30 (d, 2H, / = 8.3 Hz), 7.92 (d, 2H, / = 8.3 Hz).

[Reference Example 29]

4- [Hdimethylamino] methyl] thiazole-2-carboxyaldehyde

Dissolve 0.93 ml of 1.59Μ-butyllithium-hexane solution in 2 ml of getyl ether, and add 2 ml of a 200 mg solution of, -dimethyl-ga- (thiazol-4-ylmethyl) amine (W09916747) in 200 ml of getyl ether. Was added dropwise at 178 ° C. After stirring at the same temperature for 1 hour, 0.15 ml of formylmorpholine was added, and the mixture was stirred at −20 ° C. for 18 hours. Reaction liquid Was added to water, extracted with ethyl acetate, and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography [chloroform form: methanol = 20: 1 (v / v)] to obtain 106 mg of the title compound as a brown oily substance.

MS (FAB) m / z 171 (M + H ⁺ ).

¾ MR (CDC1) δ 2.32 (s 6H), 3.69 (s, 2H), 7.58 (s, 1H), 10.00 (s 1H).

[Reference Example 30] Step 1

Process 1

N, -Dimethyl--(thiazole_5-ylmethyl) amine

Using 5-methyl-thiazole as a raw material, the same operation as in Step 1 of Reference Example 2 was performed, and then the same operation as in Step 1 of Reference Example 1 was performed to obtain the title compound as a brown oil. MS (FAB) m / z 143 (M + H ⁺ ).

_{¾ NMR (CDC1 3) δ:} . 2.27 (s, 6H), 3.69 (s, 2H), 7.70 (s, 1H), 8.76 (s, 1H) Step 2

5- [0-dimethylamino) methyl] thiazole-2-carboxaldehyde

Using the compound obtained in the above step 1 as a raw material, the same operation as in Reference Example 29 was carried out to obtain the title compound as a brown oily substance.

MS (EI) m / z 170 (t).

¾ NMR (CDCI3) δ: 2.29 (s, 6H), 3.73 (s 2H), 7.90 (s, 1H), 9.94 (s, 1H).

[Reference Example 3 1]

Br-T ¾ ^ ^0HC

"Boc S" Boc T-butyl 2-formyl-6,7-dihydro [1,3] thiazolo [5,4-c] pyridine-5 (4 ^)-carboxylate

Starting from 2-promo-6,7-dihydro [1,3] thiazolo [5,4-c] pyridine_5 carboxylate t-butyl (W09916747) as a raw material, the same procedure as in Reference Example 29 was carried out to give the title compound. Obtained as a yellow oil.

MS (FAB) m / z 269 (M + H ⁺ ).

¾賺_{(CDC1 3) δ: 1.50 (} s, 1H), 3.00 (br s, 2H), 3.80 (br s, 2H), 4.76 (br s, 2H), 9.93 (s, 1H).

[Reference Example 32] X ^——-oH

2-Honolemyl-5-methyl-4,5,6,7-tetrahydro [1,3] thiazo [5,4-c] pyridine 2-butamo-5-methyl-4,5,6,7- The title compound was obtained as a yellow solid by performing the same operation as in Reference Example 29 using tetrahydro [1,3] thiazolo [5,4_c] pyridine (W09916747) as a raw material.

_{¾NMR (CDC1 3) δ: 2.53} (s, 3Η), 2.85-2.88 (m, 2H), 3.02-3.05 (m, 2H), 3.77 (s, 2H), 9.92 (s, 1H).

[Reference Example 33]

Process 1

2-methylthiazole-4-ethyl carboxylate

1.0 g of thioacetamide and 2.7 g of ethyl bromopyruvate were dissolved in 30 ml of acetonitrile, and the solution was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue To the mixture was added ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the two layers were separated. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated saline, and 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 = 2: 1 (v / v)], and the desired fraction was concentrated to give the title compound as an orange solid 1.65 g were obtained. .

_{¾ NM (CDC1 3) δ ··} 1.41 (t, 3H, / = 7.1 Hz), 2.77 (s, 3H), 4.42 (q, 2H, J = 7.1 Hz), 8.03 (s, 1H). Step 2

2-[(-dimethylamino) methyl] thiazole-4-ethyl ether

Using the compound obtained in the above step 1 as a raw material, the same operation as in step 1 of Reference Example 2 was performed, and then the same operation as in step 1 of Reference Example 1 was performed to obtain the title compound as a brown oily substance. Awakening (CDC1 ₃ ) δ: 1.41 (t, 3H, / = 7.1 Hz), 2.37 (s, 6H), 3.82 (s, 2H), 4.42 (q, 2H, J2 7.1 Hz), 8.15 (s, 1H). Step 3

2-[(M-dimethylamino) methyl] thiazole-4-propoxyaldehyde

Using the compound obtained in the above step 2 as a raw material, the same operation as in Reference Example 18 was performed to obtain the title compound as a yellow oily substance.

_{¾ NMR (CDC1 3) δ:} . 2.39 (s, 6H), 3.82 (s, 2H), 8.16 (s, 1H), 9.99 (s, 1H) [ Reference Example 34]

Process 1

Thiazole-4-ethyl carboxylate

Under ice-cooling, add 20.2 g of diphosphorus pentasulfide to 50.0 ml of formamide, and add Stirred for hours. Water was added to the reaction solution, extracted with 100 ml of getyl ether, and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Using 7.44 g of the obtained thioformamide as a raw material, the same operation as in Step 1 of Reference Example 3 was carried out to obtain 11.2 g of the title compound as a brown oily substance.

MS (EI) m / z 157 (if).

_{¾ MR (CDC1 3) δ ··} 1.43 (t, 3H, zo = 7.1 Hz), 4.44 (q , 2H, / = 7.1 Hz), 8.25 (d, 1H, J = 2.2 Hz), 8.86 (d, 1H , J: 2.2 Hz). Process 2

Thiazole-4-carpoxyaldehyde

MS (FAB) m / z 114 (M + H ⁺ ).

¾ NMR (CDCI3) S: 8.26 (d, 1H, / = 2.0 Hz), 8.92 (d, 1H, / = 2.0 Hz), 10.1 (s, 1H).

[Reference Example 3 5] Step 2 N

J OHC

S 'process 1

4-methylthiazole

Reference Example 33 3 The same operation as in Step 1 was performed using aminoethyl oxoacetate and chloroacetone as starting materials to obtain the title compound as a yellow oily substance.

_{¾ NMR (CDC1 3) δ 1.44} (t, 3H, / = 7.0 Hz), 2.55 (s, 3H), 4.48 (q, 2H, J = 7.0 Hz), 7.19 (s, 1H). Step 2 4-Methylthiazole-2-potoxy aldehyde

Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 1 was performed to obtain the compound as a colorless oily substance.

_{¾ NMR (CDC1 3) δ 2.58} (s, 3H), 7.33 (s, 1H), 9.95 (s, 1H).

[Reference Example 36]

H N

Process 1

4-cyclopropynolethiazole 2-ethyl carboxylate

Reference Example 33 3 The same operation as in step 1 was performed using aminoethyl oxoacetate and 2_bromo-1-cyclopropylethanone as the starting materials to obtain the title compound as a yellow oily substance.

MS (ESI) m / z 198 (M + H ⁺ ).

_{¾ MR (CDC1 3) δ:} 0.92-1.00 (m, 4H), 1.42 (ΐ, 3H, / = 7.0 Hz), 2.12-2.20 (m, 1H), 4.46 (q, 2H, = 7.0 Hz), 7.09 (s, 1H). Process 2

4-cyclopropyl thiazole-2-carboxyaldehyde

Using the compound obtained in the above step 1 as a raw material, the same operation as in step 2 of the reference example 1 was performed to obtain the title compound as a colorless oily substance.

¾ thigh _{(CDC1 3) δ: 0.81-0.99 (} m, 4H), 2.10-2.17 (m, 1H), 7.28 (s, 1H), 10.13 (s, 1H).

[Reference Example 3 7]

Process 1

4-Methylthiazole-5-ethyl ester

The same operation as in Step 1 of Reference Example 34 was carried out using formamide and ethyl 2-chloroacetoacetate as raw materials to obtain the title compound as a yellow oily substance.

_{¾ NMR (CDC1 3) δ:} . 1.38 (t, 3H, = 7.1 Hz), 2.78 (s, 3H), 4.35 (q, 2H, J = 7.1 Hz), 8.77 (s, 1H) Step 2

4-Methylthiazole-5-Rubonic acid

2.90 g of the compound obtained in the above step 1 was suspended in 30 ml of ethanol, a 1N aqueous solution of sodium hydroxide was added dropwise at room temperature, and the mixture was stirred for 3 hours. The reaction solution was ice-cooled, 20 ml of a 1N aqueous hydrochloric acid solution was added, and the precipitate was collected by filtration and dried to obtain 1.90 g of the title compound as a colorless solid.

¾ NMR (DMS0-) δ 2.64 (s, 3H), 9.14 (s, 1H), 13.33 (br, 1H). Step 3

4-Methylthiazole -5-Methyl rubonic acid amide

To a solution of 1.50 g of the compound obtained in Step 2 above in 30 ml of dichloromethane at room temperature was added 12.5 ml of a 2M methylamine solution (tetrahydrofuran solution), 0.28 g of trihydroxybenzotriazole, and 1-ethyl-3- [3 2.60 g of-(-dimethylamino) propyl] carposimido 'hydrochloride were sequentially added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was washed with brine, 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 [chlorophonolem:

50: 1 (v / v)] to give 1.45 g of the title compound as a colorless solid.

MS (ESI) m / z 157 (M + H ⁺ ).

_{¾ MR (CDC1 3) δ:} . 2.73 (s, 3H), 2.99-3; 01 (m, 3H), 5.87 (br, 1H), 8.69 (s, 1H) Step 4

Methyl (4-methylthiazole-5-ylmethyl) t-butyl rubamate

1.0 g of lithium aluminum hydride was suspended in 20 ml of tetrahydrofuran and cooled with ice. Then, a solution obtained by dissolving 1.42 g of the compound obtained in the above Step 3 in 5 ml of tetrahydrofuran was added dropwise, and the mixture was returned to room temperature and refluxed for 1.5 hours and 0.5 hours. After allowing to cool, the reaction mixture was ice-cooled, added with water (1 ml), 15% aqueous sodium hydroxide solution (1 ml) and water (3 ml) in this order, paying attention to bubbling. The mixture was returned to room temperature and stirred for 30 minutes. After filtering off the insoluble matter, the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in 30 ml of tetrahydrofuran, 2.3 ml of di-ί-butyl dicarbonate was added, and the mixture was stirred at room temperature for 1 hour. After concentration, the obtained residue was subjected to silica gel chromatography [ethyl acetate: -hexane = 1: 4 (v / v)] to give the title compound (1.08 g) as a pale-yellow oil.

MS (ESI) m / z 243 (M + H +).

¾ NMR (CDCI3) δ: 1.49 (s, 9H), 2.46 (s, 3H), 2.83 (s, 3H), 4.53 (s, 2H), 8.63 (s, 1H). Step 5

Methyl (2-formyl-4-methylthiazole-5-ylmethyl) -rubbamate-butyl The compound obtained in the above step 4 was used as a raw material, and the same procedure as in Reference Example 29 was carried out to give the title compound as a yellow oil. Obtained as material.

MS (ESI) m / z 271 (M + H ⁺ ).

¾ NMR (CDCI3) δ: 1.49 (s, 9H), 2.52 (s, 3H), 2.88 (s, 3H), 4.58 (s, 2H), 9.88 (s, 1H). [Reference Example 38]

Process 1

Methinole (thiazole-4-ylmethinole) 力 -butyl rubamate

Dissolve 3.0 g of 4-methylthiazole in 60 ml of carbon tetrachloride, add 5.6 g of bromosuccinic acid imid and 250 mg of 2,2'-azobisisobutyronitrile, and heat at 90 ° C for 30 minutes Refluxed. The reaction was allowed to cool to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure until the amount of the solvent was reduced to about 1/3, and the obtained bromo compound was dissolved in 15 ml of tetrahydrofuran. Stirred for hours. After completion of the reaction, the precipitated solid was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 60 ml of tetrahydrofuran, 6.9 ml of di-butyl dicarbonate and 4.6 ml of triethylamine were added, and the mixture was stirred at room temperature for 5 hours. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography hexane: ethyl acetate = 3: 1 (v / v)] to give 2.41 g of the title compound as a yellow oil.

Ms (FAB) m / z 229 (Μ).

_{¾ NMR (CDC1 3) δ:} . 1.46 (s, 9H), 2.96 (s, 3H), 4.59 (s, 2H), 7.09-7.17 (br, 1H), 8.77 (d, 1H, = 1.7 Hz) Step Two

[(2-Formyl-thiazol-4-yl) methyl] methylcarbamic acid t-petit / le The compound obtained in the above step 1 was used as a raw material and the same operation as in Reference Example 29 was carried out to convert the title compound into a yellow oily substance. As obtained.

MS (EI) m / z 256 (Ma).-

¾ Anonymous _{(CDC1 3) δ: 1.47 (} s, 9H), 2.98 (s, 3H), 4.62 (s, 2H), 7.48-7.58 (br, 1H), 9.97 (s, 1H) .i ■ s

[Reference Example 39] Step 1 Boc

N 1 Process 2 N Boc

OHC- '/, N,

, S 's

Step 1 '.

Methyl (thiazol-5-ylmethyl) potassium rubamic acid

Reference Example 38 8 The same procedure as in Step 1 was carried out using 5-methylthiazole as a raw material to obtain the title compound as a yellow oily substance.

MS (FAB) m / z 229 (M + H +).

_{¾ NMR (CDC1 3) δ:} . 1.50 (s, 9H), 2.85 (s, 3H), 4.58 (s, 2H), 7.73 (s, 1H), 8.73 (s, 1H) Step 2

(-Butyl [(2-formi 7-rethiazol-5-yl) methyl] methylcarbamate Using the compound obtained in the above step 1 as a raw material, the same operation as in Reference Example 29 was carried out to give the title compound as a yellow oily substance. As obtained.

MS (EI) m / z 256 (It).

NMR · NMR (CDCI3) δ: 1.50 (s, 9H), 2.90 (s, 3H), 4.63 (s, 2H), 7.93 (s, 1H), 9.94 (s, 1H).

[Reference Example 40]

Ts-N Step 1 Ts-N ■ ~ ^S Step ² > Ts ~ ^S

Ό OBn N OBn

OH process ^ ^B. ^c ¾h _oH process

Process 1 2-benzyloxymethyl-5- (p-toluenesulfonyl) -4,5,6,6a-tetrahydropyrro [4,3-d] thiazol-3a-ol

1- (p-Toluenesulfonyl) pyrrolidin-3-one (ktsrocylces 41, 1995, 1389) To a solution of 1.4 g of acetic acid in 15 ml, add 0.33 ml of bromine in 15 ml of acetic acid, and add 50 minutes at 50 ° C for 10 minutes Stirred. Water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in 15 ml of, -dimethylformamide. To this solution, 1.2 g of 2-benzyloxythioacetamide was added, and the mixture was stirred at 50 ° C for 7 hours. 0.5 g of sodium hydrogen carbonate was added to the reaction solution, and the mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue. After separating the two layers, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oily substance as a crude product, which was used in the next step without purification.

MS (ESI) m / z 419 (M + H +) Step 2

2-Benzyloxymethyl-5-p-tonolenesnorefoninole) -4,6-dihydro and others H-pyro [3,4-] thiazole

To a solution of the compound obtained in the above step 1 in 50 ml of methane at the mouth of the mouth were added, under ice cooling, 4.1 ml of triethylamine and 0.91 ml of methanesulfonolenin chloride, followed by stirring at room temperature for 22 hours. Water was added to the reaction solution, the two layers were separated, and the aqueous layer was extracted with black hole form. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [form: methanol: = 100: 1 (v / v)] to obtain 1.0 g of the title compound as a brown solid. . ¾ parts (CDC1 ₃ ) δ: 2.41 (s, 3H), 4.52-4.54 (m, 2H), 4.63 (s, 2H), 4, 63-4.65 (m, 2H) ), 4.72 (s, 2H), 7.31—7.36 (m, 7H), 7.76 (d, 2H, / = 8.3 Hz) .Step 3

2-Hydroxymethinole-4,6-dihydro-5-pyro-mouth [3,4-d] thiazole-5-capillonic acid ί -Puchinore

47 ° / to 1.0 g of the compound obtained in the above step 2 and 2.0 g of phenol. 3 ml of an aqueous solution of hydrogen bromide was added, and the mixture was heated under reflux for 1 hour. After cooling the reaction solution to room temperature, water and getyl ether were added, and the mixture was stirred for 1 hour. The two layers were separated, and the organic layer was extracted with a 1N aqueous hydrochloric acid solution. The extract was made alkaline with a 10N aqueous sodium hydroxide solution under ice-cooling, a solution of 0.55 g of di-dibutylbutyl dicarbonate in 20 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 23 hours. The reaction solution was extracted with ethyl acetate, and the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [chloroform: methanol = 50: 1 (v / v)] to obtain 0.13 g of the title compound as a brown solid. '

MS (ESI) m / z 257 (M + H ⁺ )

_{¾ NMR (CDC1 3) δ:} 1.52 (s, 9H), 2.48 (br s, 1H), 4, 52-4.53 (m, 1H), 4.58 (br s, 1H), 4.66-4.67 (m, 2H) , 4.94 (s, 2H). Step 4

2-Formyl-4,6-dihydro-5-pyrro [3,4-dthiazole-5-pyruonic acid-butyl The compound obtained in the above step 3 was used as a starting material, and the same operation as in Reference Example 14 was performed. This gave the title compound as a brown solid.

_{¾ NMR (CDC1 3) δ:} 1.53 (s, 9H), 4.64-4.66 (m, 1H), 4.69 (br s, 1H), 4.77 -4.88 (m, 2H), 9.93 (s, 1H).

[Reference Example 4 1]

Process 1

[2- (4-Methylthiazole-5-yl) ethyl] dibutyl butylamine

5- (2-hydroxyxetil) -5.0 g of 4-methylthiazole, 5.14 g of phthalimid, g 9.15 g of rifenylphosphine was added to 100 ml of tetrahydrofuran, and 5.5 ml of acetyl-dicarboxylate was added dropwise at room temperature, followed by stirring for 3 days. After concentration, the residue was subjected to silica gel chromatography [ethyl acetate: hexane = 1: 2 (v / v)], and the obtained target fraction was reconcentrated and dissolved in 150 ml of ethanol. 4.0 ml of monohydrate was added and stirred. To the reaction mixture were added 150 ml of a saturated aqueous solution of sodium hydrogen carbonate and 150 ml of dichloromethane, and 27 ml of di- ml-butyl dicarbonate was added dropwise, followed by stirring at room temperature for 2 hours. 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 silica gel chromatography [ethyl acetate: ./?-hexane=1:4 (v / v)] to obtain 6.37 g of the title compound as a pale yellow solid. MS (ESI) m / z 243 (M + H ⁺ ).

¾ MR (CDC1 ₃ ) δ ··· 1.44 (s, 9H), 2.40 (s, 3H), 2.97 (t, 2H, / = 6.6 Hz), 3.31 — 3.36 (m, 2H), 4.69 (br, 1H) , 8.58 (s, 1H). Step 2

[2- (2-Formyl-4-methylthiazol-5-yl) ethyl] rubbamate-butynole Using the compound obtained in the above step 1 as a raw material, the same operation as in Reference Example 29 was carried out to give the title compound Was obtained as a pale yellow solid.

MS (ESI) m / z 271 (Μ + Ι-Γ)-

¾NMR (CDCI3) δ: 1.44 (s, 9H), 2.48 (s, 3H), 3.06 (t, 2H, / = 6.6 Hz), 3.35 -3.40 (m, 2H), 4.70 (br, 1H), 9.86 ( s, 1H).

[Reference Example 42] fi

Process 1

Dimethyl- [2- (4-methylthiazol-5-yl) ethyl] amine

Reference Example 41 The compound obtained in Step 1 was used as a raw material, and the same operation as in Reference Example 16 was performed. The title compound was obtained as a colorless oil.

¾ thigh _{(CDC1 3) δ: 2.30 (} s, 6Η), 2.40 (s, 3H), 2.51 (t, 2H, / = 7.1 Hz), 2.90 (t, 2H, J = 7.1 Hz), 8.55 (s, 1H). Step 2

Dimethyl [2- (2-formyl-4-methylthiazonole-5-inole) ethyl] amine

Using the compound obtained in the above step 1 as a raw material, the same operation as in Reference Example 29 was performed to obtain the title compound as a yellow oily substance.

MS (ESI) m / z 199 (M + H ⁺ )-

_{¾NMR (CDC1 3) δ: 2.29} (s, 6H), 2.47 (s, 3H), 2.56 (t, 2H, 7.1 Hz), 2.95 (t, 2H, / = 7.1 Hz), 9.87 (s, 1H).

[Reference Example 43]

Process 1

4-trifluoromethylthiazole-5-carboxylate

2.40 g of 2-ethylamino-4-trifluoromethyl-thiazole-5-carboxylate (J. Heterocyclic. Chem. 1991, 28, 907) and 2.02 g of second salted copper were added to 50 ml of acetonitrile and nitrogen was added. Under an atmosphere, 1.80 ml of nitrite-butyl was added dropwise at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was mixed with water and black-mouthed form, cooled with ice, acidified with concentrated hydrochloric acid, and the aqueous layer was extracted twice with black-mouthed form. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography [ethyl acetate: sword-hexane = 1: 9 (v / v)] to obtain 2.27 g of the title compound as a pale yellow solid. -MS (EI) m / z 259 (M ⁺ ). ¾ thigh _{(CDC1 3) δ: 1. 39} . (T, 3H, J: 7. 3 Hz), 4. 40 (q, 2H, / = 7. 3 Hz) Step 2

4-trifluoromethylthiazole-5-carboxyaldehyde

MS (ESI) m / z 181 (Μ + ίΓ).

_{¾ NMR (CDC1 3) δ:} . 9. 08 (s, 1H), 10. 28 (s, 1H) Step 3

Methyl (4-trifluoromethylthiazole-5-ylmethyl) rubbamate バ -butyl

1.00 g of the compound obtained in Step 2 above, 0.95 ml of acetic acid and 8.3 ml of a 2M methylamine solution (tetrahydrofuran solution) were added to 10 ml of ethanol, and at room temperature, 350 mg of sodium cyanoborohydride Was added little by little, and the mixture was stirred for 20 hours. After concentration, the resultant was diluted with chloroform, washed with a saturated aqueous solution of sodium bicarbonate and brine in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 10 ml of tetrahydrofuran, 1.30 ml of di-butyl dicarbonate was added, and the mixture was stirred at room temperature for 2 hours. After concentration, the obtained residue was subjected to silica gel chromatography [ethyl acetate: -hexane = 1: 4 (v / v)] to give 1.01 g of the title compound as a colorless oil.

MS (ESI) m / z 338 (M + MeCN ¹ ")

¾ NMR (CDCI3) δ: 1.49 (s, 9H), 2.90 (s, 3H), 4.75 (s, 2H), 8.74 (s, 1H). Step 4.

Methyl (2-formyl-4 -trifluoromethyl-thiazole-5-ylmethyl) -butylamine

Using the compound obtained in the above Step 3 as a raw material, the same operation as in Reference Example 29 was performed to obtain the title compound as a colorless oily substance. ¾ NMR (CDCI3) δ: 1.49 (s, 9H), 2.94 (s, 3H), 4.78 (s, 2H), 9.91 (s, 1H). [Reference Example 44]

Step 1.

4-Hydroxymethinole 2- (trans-β-styryl) oxazonole

4-Ethoxycarbonyl-2- (trans-β-styryl) oxazole (J. Org. Chem. 1996, 61, 6496) 8. A solution of 57 g of 80 ml of dichloromethane in 1 ml of 1 M 66.0 ml of soptylanolinium (n-hexane solution) was added dropwise. After stirring for 15 minutes, 11 ml of methanol was added dropwise, and the temperature was raised to room temperature in 1 hour. The reaction solution was filtered through celite, 200 ml of ethyl acetate and an aqueous solution of saturated sodium chloride were added to the filtrate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in that order, dried over anhydrous sodium sulfate, and dried under reduced pressure. The solvent was distilled off. The resulting residue was subjected to silica gel column chromatography [dichloromethane: ethyl acetate = 5: 1 (v / v) -dichloromethane: methanol = 10: 1 (v / v)] to obtain 650 mg of the title compound. Obtained as a colorless solid.

MS (FAB) m / z 202 (M + H ⁺ ).

¾ NMR (CDCI3) δ2.65 (s, 1H), 4.65 (s, 2H), 6.92 (d, 1H, J: 16.1 Hz), 7.20-7.70 ( m, 6H). Step 2.

N-{[2- (trans-β-styryl) oxazonole-1-4-inole] methyl} phthalanolide

To a solution of 5.70 g of the compound obtained in Step 1 above in 300 ml of tetrahydrofuran was added 4.17 g of phthalimide, 7.43 g of triphenyl / phosphine, and dimethyldiazolate Was added at room temperature, followed by stirring for 12 hours. After the reaction solution was concentrated under reduced pressure, 200 ml of dichloromethane was added, and the resulting colorless solid was filtered off. After the filtrate was concentrated, the obtained residue was subjected to silica gel column chromatography [dichloromethane: methanol = 20: 1 (v / v)] to obtain 7.0 g of the title compound as a colorless solid.

MS (EI) m / z 330 (M ⁺ ).

_{¾ NMR (CDC1 3) δ:} 4.84 (s, 2H), 6.90 (d, 1H, / = 16.6 Hz), 7.29-7.40 (m, 3H), 7. 3-7.53 (m, 3H), 7.62 (s , 1H), 7.70—7.80 (m, 2H), 7.85—7.91 (m, 2H). Step 3

{2- [)-2_phenylethenyl] oxazole-4-yl} t-butyl methylcarbamate

Dissolve 6.62 g of the compound obtained in the above step 2 in 150 ml of ethanol, add 1.6 ml of hydrazine 'monohydrate, and stir at room temperature for 6 hours, then 1.6 ml of hydrazine · monohydrate Was added at room temperature and stirred for 12 hours. The resulting precipitate was removed by filtration, and the filtrate was concentrated. Then, dichloromethane and a saturated aqueous solution of sodium bicarbonate (13.0 g of di-di-butyl dicarbonate) were added at room temperature. After stirring for 1 hour, the aqueous layer was extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography [-hexane: ethyl acetate = 3: 1—1: 1 (v / v)] to give 5.2 g of the title compound as a colorless oil.

MS (ESI) m / z 301 (M + H +).

¾ NMR (CDCI3) δ: 1.46 (s, 9H),% .25 (d, 2Η, / = 5.9 Hz), 5.06 (br s, 1H), 6.90 (d, 1H, / = 16.4 Hz), 7.29- 7.42 (m, 3H), 7.42-7.57 (m, 4H). Process 4

(2-Formyloxazole-4-yl) methylcarbamic acid ί-butynole

Using the compound obtained in the above Step 3 as a raw material, the same operation as in Reference Example 27, Step 2, was carried out to obtain the title compound as a colorless oily substance. _{¾ MR (CDC1 3) δ:} 1.45 (s, 9H), 4.32 (d, 2H, zo = 6.1 Hz), 5.08 (br , 1H): 7.81 (s, 1H), 9.74 (s, 1H).

[Reference Example 4 5] NBI

g H Step 1 N-rf ^ ^ Step 2

Ph ^ ^. 》 Boc OHC process 1

Reference Example 44 460 mg of the compound obtained in Step 3 was dissolved in 9.2 ml of tetrahydrofuran, and 67.4 mg of sodium hydride (ice-cooled) was added to the reaction mixture. (-Butyl [(2-formyloxazole-4-inole) methyl] methylcarbamate Reference Example 44 60% oil) was added. The mixture was stirred at room temperature for 30 minutes, cooled to 0 ° C, added with 0.10 ml of methyl iodide, and stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, and washed with water and saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography [hexane: ethyl acetate = 2: 1 (v / v)] to give 490 mg of the title compound as a colorless oil. 10 MS (FAB) m / z 315 (Μ + ίΤ) .NBI

Thigh (CDC1 ₃ ) δ '· 1.48 (s, 9H), 2.97 (s, 3H), 4.35 (s, 2H), 6.92 (d, 1H, J: 16.4 Hz), 7.34-7.7 (m, 3H), 7.52 (s, 1H), 7.53 (s, 2H), 7.54 (s, 1H). Process 2

(-Butyl [(2-honolemiloxazole-4-yl) methyl] methinorecanolebamate Using the compound obtained in the above step 1 as a raw material, Reference Example 2 7 The title compound was obtained as a colorless oil. MS (EI) m / z 240 (It).

¾ NMR (CDCI3) δ: 1.47 (s, 9H), 2.97 (s, 3H), 4.41 (s, 2H), 7.73-7.80 (m, 1H), 9.74 (s, 1H).- [Reference Example 46] OH

Process

2-({[ί-butyl (diphenyl) silyl] methyl} methyl) thiazole-4-ethyl carboxylate

Reference Example 34 The same procedure as in Step 1 of Reference Example 34 was performed using 2-{[{-butyl (diphenyl) silyl] oxy} acetamide as a raw material to obtain the title compound as a pale yellow oil.

MS (FAB) m / z 426 (M + H +).

_{¾ NM (CDC1 3) δ:} 1.13 (s, 9H), 1.39 (t, 3H, J two 7.1 Hz), 4.40 (q, 2H, J = 7.1 Hz), 5.01 (s, 2H), 7.37-7.47 ( m, 6H), 7.67—7.71 (m, 4H), 8.12 (s, 1H). Process 2

[2-({[ί-butyl (diphenyl) silyl] oxy} methyl) thiazole-4-yl] methano —;

Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 1 of Reference Example 44 was carried out to obtain the title compound as a brown oily substance.

MS (FAB) m / z 384 (M + H +).

¾ NMR (CDCI3) S: 1.12 (s, 9H), 4.70 (s, 2H), 4.95 (s, 2H), 7.14 (s, 1H), 7.36-7.44 (m, 6H), 7.67-7.70 (m, 4H). Step 3

[2-({[i-butyl (dipheninole) silyl] methyl} methyl) thiazol-4-yl] methyl ル -butynole Using the compound obtained in the above Step 2 as a raw material, the same operation as in Step 1 of Reference Example 41 was carried out to obtain the title compound as a colorless oily substance.

MS (FAB) m / z 483 (M + H +).

_{¾NM (CDC1 3) δ: 1.12} (s, 9H), 1.44 (s, 9H), 4.35 (d, 2H, 5.6 Hz), 4.94 (s, 2H), 5.04 (br, 1H), 7.08 (br, 1H ), 7.36-7. 6 (m, 6H), 7.67-7.69 (m, 4H).

-Butyl (2-formylthiazol-4-yl) methylcarbamate

181 mg of the compound obtained in the above Step 3 was dissolved in 1.8 ml of tetrahydrofuran, and 0.41 ml of 1M tetra-butylammonium fluoride (tetrahydrofuran solution) was added under ice-cooling, followed by stirring at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel gel column chromatography [black form: methanol = 20: 1 (v / v)] to obtain an alcohol compound. Using the obtained alcohol compound as a raw material, the same operation as in Reference Example 14 was performed to obtain 41 mg of the title compound as a yellow oily substance.

MS (EI) m / z 242 Q).

_{¾ MMR (CDC1 3) δ:} 1.46 (s, 9H), 4.52 (d, 2H, / = 6.1 Hz), 5.19 (br s, 1H), 7.59 (s, 1H), 9.96 (s, 1H) '.

[Reference Example 47] \

-Boc

Process 1

3- [2- (ί-Butoxycarboninole-methylamino) ethoxy] isoxazole-5-methionolecarbonate

1.43 g of methyl 3-hydroxy-5-isoxazolecarboxylate, 1.76 g of 2- (ί-butoxycarbonyl-methylamino) ethanol, 2.63 g of triphenylphosphine To 30 ml of tetrahydrofuran was added 1.6 ml of acetyl-dicarboxylate dropwise at room temperature, followed by stirring for 3 days. After concentration, the residue was subjected to silica gel chromatography [ethyl acetate: hexane = 1: 2 (v / v)] to give the title compound (0.44 g) as a colorless oil.

_{¾ MR (CDC1 3) δ:} 1.45 (s, 9H), 2.93 (s, 3H), 3.62 (br, 2H), 3.95 (s, 3H), 4.40 (br, 2H), 6.53 (s, 1H). Process 2

3- [2-(-Butoxycarpenyl-methylamino) ethoxy] isoxazole-5-carboxya ^ / dehyde

Using the compound obtained in the above step 1 as a raw material, the same operation as in Reference Example 18 was performed to obtain the title compound as a colorless oily substance.

¾墮_{(CDC1 3) δ: 1.45 (} s, 9H), 2.95 (s, 3H), 3.64 (br, 2H), 4.44 (br, 2H), 6.57 (s, 1H), 9.84 (s, 1H).

[Reference Example 48]

OH 0,

Process 1 Process 2

Me0 ₂ C _σ ^Ν Me0 ₂ C

'Boc

Process 1

4- (5-Methoxycarbonylisoxazole-3-yloxo) piperidine ί-butyl-1-carboxylate

The same operation as in Step 1 of Reference Example 47 was carried out using 4-butyl 4-hydroxypiperidine-1-butyrate as a raw material to obtain the title compound as a colorless solid.

¾ Spirit _{(CDC1 3) δ: 1.47 (} s, 9H), 1.73- 182 (m, 2H), 2.01-2.06 (m, 2H), 3.23 one 3.30 (m, 2H), 3.73-3.76 (m, 2H) , 3.95 (s, 3H), 4.85-4.90 (m, 1H), 6.53 (s, 1H).

Process 2 4- (5-formylisoxazole-3-yloxo) piperidine-1- t-butyl sorbate

The title compound was obtained as a colorless solid by performing the same operation as in Reference Example 18 using the compound obtained in the above Step 1 as a starting material.

¾ NMR (CDC1 ₃ ) δ: 1.47 (s, 9H), 1.77-182 (m, 2H), 2.02-2.08 (m, 2H), 3.25 — 3.31 (m, 2H), 3.73-3.77 (ra, 2H) , 4.88-4.93 (m, 1H), 6.56 (s, 1H), 9.84 (s, 1H).

[Reference Example 49]

CO Tsu Et O

> HO

,

2- (Hydroxymethyl)--methylthiazole -4-propanolamide

Reference Example 4 6 The compound 450 nig obtained in Step 1 was dissolved in 9.0 ml of a 40% aqueous solution of methylamine, and heated at 50 ° C for 15 hours in a sealed tube. The reaction solution was returned to room temperature and concentrated under reduced pressure. An aqueous saturated sodium bicarbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline. After drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography [form: methanol = 20: 1 (v / v)] to obtain 18.5 mg of the title compound as a yellow oily substance.

MS (FAB) m / z 173 (M + H +).

_{¾ NMR (CDC1 3) δ:} 2.98 (d, 3H, / = 4.9 Hz), 4.92 (s, 2H), 7.32 (br s, 1H), 8.02 (s, 2H).

[Reference Example 50]

OHC- ■ Br OHC _S ^ -N ' 5- (4-Methylpyrazine-1-yl) thiophene-2--2-propyloxyaldehyde

1.0 g of 5-bromothiophene-2-carpoxyaldehyde, 0.64 ml of N-tinorebiperazine and 1.46 ml of triethylamine were added to 30 ml of water, and the mixture was heated under reflux for 24 hours. After cooling, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography [form: methanol = 20: 1 (v / v)] to give 0.22 g of the title compound as a yellow oil.

¾ parts (CDC1 ₃ ) δ: 2.35 (s, 3H), 2.53-2.56 (m, 4H), 3.36-3.39 (m, 4H), 6.09 (d, 1H, / = 4.4 Hz), 7.49 (d, 1H , / = 4.4 Hz), 9.54 (s, 1H).

[Reference Example 51]

Process 1

(5- [1,3] dioxolan-2-ylthiophene-2-5- [1,3] dioxolan-2-ylthiophene-2-carboxyaldehyde JCS Perkin I. 1974, 37) 0.55 g, acetic acid 0.52 ml and 2M 4.5 ml of a dimethylamine solution (tetrahydrofuran solution) was added to 10 ml of ethanol, and 190 mg of sodium cyanoborohydride was added little by little at room temperature, followed by stirring for 20 hours. After concentration, the resultant was diluted with chloroform, washed with a saturated aqueous solution of sodium bicarbonate and brine in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography [chloroform: methanol = 20: 1 (v / v)] to give 0.25 g of the title compound as a colorless oil.

¾ thigh _{(CDC1 3) δ: 2.27 (} s, 6H), 3.60 (s, 2H), 3.99-4.05 (m, 2H), 4.11- 4.15 (m, 2H), 6.06 (s, 1H), 6.78 (d , 1H, /-3.4 Hz), 7.00 (d, 1H, zo = 3.4 Hz).- Process 2

Five - [

Tylamino) methyl] thiophene-2-carboxylic acid

0.15 g of the compound obtained in the above step 1 was dissolved in 4 ml of methanol, 1 ml of a 1N aqueous hydrochloric acid solution was added, and the mixture was stirred at room temperature for 18 hours. After concentration, dilute with chloroform and neutralize with saturated aqueous sodium bicarbonate solution, dry the organic layer over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain 0.12 g of the title compound as a brown oil. As obtained.

Hidden (CDC1 ₃ ) δ: 2.30 (s, 6H), 3.67 (s, 2H), 7.02 (dd, 1H, / = 3.4, 0.8 Hz), 7.64 ( d, 1H, J = 3.4 Hz), 9.86 (d, 1H, / = 0.8 Hz).

[Reference Example 5 2]

Process 3

H. j., NHBoc process 1

1-Diazo-3-phthalimidobutan-2-one

To 2.19 g of DL-phthaloylalanine, catalytic amounts of N, N-dimethylformamide and 1.09 ml of thionyl chloride were added, and the mixture was heated under reflux for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 10 ml of tetrahydrofuran. This solution was added to 12.5 ml of a solution of 2M trimethylsilyldiazomethane (sword-hexane solution) in 25 ml of tetrahydrofuran under ice cooling, and the mixture was stirred at 0 ° C for 18 hours. The reaction solution was concentrated under reduced pressure, and getyl ether and saturated aqueous sodium hydrogen carbonate were added to the residue. The two layers were separated and the aqueous layer was extracted with getyl ether. The organic layers were combined, washed with a saturated saline solution, and 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 = 2: 1 (v / v)] to give 2.35 g of the title compound as an orange oily substance Obtained.

¾ NM (CDCI3) δ: 1.68 (d, 3H, / = 7.3 Hz), 4.91 (q, 1H, / = 7.3 Hz), 5.40 (s, 1H), 7.75-7.79 (m, 2H), 7.87—7.89 (m, 2H). Process 2

1-bromo-3-phthalimidovbutan-2-one

To a solution of 0.49 g of the compound obtained in the above step 1 in 10 ml of getyl ether was added 0.28 ml of a 47% aqueous hydrogen bromide solution under ice-cooling, followed by stirring at room temperature for 50 minutes. After the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate, two layers were separated. The aqueous layer was extracted with getyl ether, and the organic layers were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.6 g of the title compound as a pale yellow oily substance.

_{¾ NMR (CDC1 3) δ:} 1.67 (d, 3H, zo = 7.1 Hz), 3.99 (ABq , 2H, J = 12.7 Hz), 5.23 (q, 1H, zo = 7.1 Hz), 7.77-7.79 (m , 2H), 7.88—7.91 (m, 2H). Process 3

2-Hydroxymethyl-4_ (tophthalimidethyl) thiazolone

Using the compound obtained in the above Step 2 and 2- (ブチル -butyldiphenylsilyloxy) thioacetamide as raw materials, the same operation as in Step 1 of Reference Example 33 was carried out to obtain the title compound as an orange oily substance. Was.

_{¾ NMR (CDC1 3) δ:} 1.92 (d, 3H, / = 7.3 Hz), 2.60 (br s, 1H), 4.85 (s, 2H), 5.66 (q, 1H, / = 7.3 Hz), 7.24 (s , 1H), 7.69—7.72 (m, 2H), 7.81-7.84 (m, 2H). Process 4

1- (2-Hydroxymethylthiazole-4-ylmethyl) ethylcarbamic acid ί-butynole The compound obtained in the above Step 3 is used as a starting material. Obtained as an oil.

¾ thigh _{(CDC1 3) δ: 1.44 (} s, 9H), 1.48 (d, 3H, zo = 6.9 Hz), 2.90 (br s, 1H), 4.92 (m, 3H), 5.09 (br s, 1H), 7.05 (s, 1H). Process 5

1- (2-formylthiazole-4-ylmethyl) ethylcarbamic acid ί-butyl ester

Using the compound obtained in the above step 4 as a raw material, the same operation as in Reference Example 14 was performed to obtain the title compound as a yellow oily substance.

_{¾ NMR (CDC1 3) δ:} 1.44 (s ,. 9H), 1.56 (d, 3H, / = 6.8 Hz), 5.01 (br s, 1H), 5.09 (br s, 1H), 7.53 (s, 1H) , 9.95 (d, 1H, / = 1.3 Hz).

[Reference Example 53]

Process 1

(3-Methoxy-2-pyridyl) methanol

Dissolve 2.16 g (60% oil) of sodium hydride in 75 ml of tetrahydrofuran, add 5.00 g of 2- (hydroxymethyl) -3-pyridinol dissolved in 25 ml of dimethylformamide under ice-cooling, and add 0 ° C. For 30 minutes. Further, 1.80 ml of methyl iodide was added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography [chloroform: methanol = 10: 1 (v / v)] to give 1.79 g of the title compound as a colorless oil.

MS (FAB) m / z 140 (M + H ⁺ )-

_{¾ NMR (CDC1 3) δ:} 2.88 (s, 3H), 2.96 (s, 3H), 3.86 (s, 3H), 4.74 (s, 2H), 7.12-7.22 (m, 2H), 8.01 (s, 1H ), 8.15 (d, 1H, / = 4.9 Hz) .Step 2 3-Methoxy-2-pyridinecarboxyaldehyde

The same operation as in Reference Example 14 was carried out using the compound obtained in the above Step 1 as a starting material, to give the title compound as a pale-yellow oily substance.

_{¾ NMR (CDC1 3) 5 3.98} (s 3H 7. 2 (d, 1H, / = 8.5 Hz), 7.49 (dd 1H, J = 8.5 4.1 Hz) 8.41 (dd, 1H / = 4.1, 1.2 Hz) 10.35 ( s, 1H).

'[Reference Example 54]

Process 1

2-[(β) -2-phenyl-1-ether] -3-pyridinol

The title compound was obtained as a colorless solid substance by performing the same operations as in Step 1 of Reference Example 27 using 2-chloro_3-hydroxypyridine and styrene as raw materials.

MS (FAB) m / z 198 (M + H ¹ ").

¾ NMR (DMSO- ₆ ) δ 7.10 (dd, 1H, / = 8.1, 4.4 Hz), 7.21 (dd, 1H, / = 8.1, 1.5 Hz), 7.29 (d, 1H, = 7.3 Hz), 7.37 (d 1H, = 7.8 Hz) 7.50 (d 1H, J = 15.9 Hz), 7.59 (s 1H), 7.61 (s, 1H) 7.64 (d, 1H, J = 15.9 Hz), 8.05 (dd, 1H, / = 4.4 , 1.2 Hz) .Step 2

3-hydroxy-2-pyridinecarboxaldehyde

Using the compound obtained in the above step 1 as a raw material, the same operation as in step 2 of Reference Example 27 was performed to obtain 17 mg of the title compound as a yellow solid.

¾ NMR (CDC1 ₃ ) δ 7.37 (dt, 1H, / = 8.8, 0.7 Hz) 7.45 (dd, 1H, zo = 8.8, 4.4 Hz), 8.36 (dd, 1H / = 4.4, 1.2 Hz), 10.08 (s , 1H), 10.73 (s, 1H).

[Reference Example 55]

4 _ {[2_-dimethylamino) ethyl] methylamino} -pyridine-2-carboxyaldehyde

4-Hydroxy- 2-hydroxymethylpyridine [^ Chemical H 43, 1175) 500 mg was added to 80, Ν, Ν'-trimethylethylenediamine 1.80 ml, and the tube was sealed at 150 ° C. Time Heated and stirred. The reaction solution was diluted with chloroform and washed with a 2N aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Using the obtained residue as a raw material and performing the same operation as in Reference Example 14, 320 mg of the title compound was obtained as a yellow solid.

†

_{¾ NMR (CDC1 3) δ:} 2.29 (s, 6H), 2.46-2.50 (m, 2H), 3.06 (s, 3H), 3.50- 3.54 (m, 2H), 6.67 (dd, 1H, / = 5.5, 1.5 Hz), 7.26 (d, 1H, J = 1.5 Hz), 8.36 (d, 1H, / = 5.5 Hz), 9.98 (s, 1H).

[Reference Example 56]

4- (4-Methyl-pyrazinediyl) pyridine_2-dipropyloxyaldehyde

Using -methylbiperazine as a raw material, the same operation as in Reference Example 55 was performed to obtain the title compound as a yellow solid.

_{¾ NMR (CDC1 3) δ:} 2.35 (s, 3H), 2.54 (t, 4H, / = 5.0 Hz), 3. 3 (t, H, J = 5.0 Hz), 6.81 (dd, 1H, / = 6.0 , 2.0 Hz), 7.35 (d, 1H, = 2.0 Hz), 8.42 (d, 1H, / = 6.0 Hz), 9.99 (s, 1H).

[Reference Example 57]

Process 1

2-(-butynoledimethylsilyloxy) methyl-4-hydroxymethylpyridine

1.39 g of 2,6-pyridinemethanol and 1.58 g of dimethylsilane at the mouth of ク -butyloctane were dissolved in 14 ml of dimethylformamide, 715 mg of imidazole was added, and the mixture was stirred for 3 hours. The reaction solution was diluted with water, extracted with ethyl acetate, 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 chromatography [ethyl acetate: 3-hexane = 1: -1: 1 (v / v)] to give 1.15 g of the title compound as a liquid-free liquid.

_{¾ NMR (CDC1 3) δ:} . 0.14 (s, 6H), 0.99 (s, 9H), 4.93 (s, 2H), 5.05 (s, 2H), 7.77-7.93 (m, 3H) Step 2

2-0-Butyldimethylsilyloxy) methinole 4-honoleminoleviridine

Using the compound obtained in the above step 1 as a raw material, the same operation as in Reference Example 14 was performed to obtain the title compound as a colorless solid.

_{¾ NMR (CDC1 3) δ 0.15} (s, 6H), 0.97 (s, 9H), 4.93 (s, 2H), 7.75-7.91 (m, 3H), 10.05 (s, 1H).

[Reference Example 58]

Process 1

2_ [(/ V-ί-butoxycarbonyl- -methyl) amino] methyl-butyldimethylsilyloxy) methylpyridine Reference Example 5 7 Using the compound obtained in Step 2 as a raw material, Reference Example 4 3 The same operation as in Step 3 was performed to obtain the title compound as a colorless oily substance.

_{¾ MR (CDC1 3) δ:} 0.12 (s, 6H), 0.96 (s, 9H), 1.50 (br s, 9H), 2.95 (br s, 3H), 4.80 (br s, 2H), 4.85 (s, 2H), 7.06 (br, 1H), 7.40 (d, 1H, / = 7.5 Hz), 7.68 (t, 1H, / = 7.5 Hz). Step 2

2-[(pishi-butoxycarbonyl-methyl) amino] methyl-4-formylpyridine Using the compound obtained in the above step 1 as a starting material, perform the same operation as in step 4 of Reference Example 46 to give the title compound. Was obtained as a colorless solid.

MS (ESI) m / z 251 (M + H +).

¾ thigh _{(CDC1 3) δ:. 1} 1 (br s, 9H), 2.99 (br s, 3H), 4.98 (br s, 2H), 7.45 (br, 1H), 7.85-7.87 (m, 2H), 10.04 (s, 1H).

[Reference example 59]

Process 1

2-W-p-toxoxycarpoel- -cyclopropyl) amino] methyl-4-(-butyldimethylsilyloxy) methylpyridine

Reference Example 5 7 The same operation as in Step 3 of Reference Example 43 was carried out using the compound obtained in Step 2 as a raw material and cyclopropylamine in place of methylamine to obtain the title compound as a colorless oily substance.

MS (ESI) m / z 393 (M + H +).

¾ thigh _{(CDC1 3) δ: 0.12 (} s, 6H), 0.64 (br, 4H), 0.96 (s, 9H), 1.47 (br s, 9H), 1.66 (br, 1H), 4.52 (br s, 2H ), 4.80 (s, 2H), 6.99 (d, 1H, = 8.0 Hz), 7.36 (d, 1H, 7 = 8.0 Hz), 7.66 (t, 1H, / = 8.0 Hz). Step 2 '

2-W-deoxytoxoxycarbonyl-cyclopropyl) amino] methyl-4-formylpyr Using the compound obtained in the above step 1 as a raw material, the same operation as in step 4 of Reference Example 46 was carried out to give the title compound as a colorless solid. Obtained.

_{¾ NMR (CDC1 3) δ:} 0.71- 0.76 (m, 4H), 1.43 (br s, 9H), 2.70 (br, 1H), 4.64 (s, 2H), 7.39 (t, 1H, zo = 5.0 Hz) , 7.80-7.85 (m, 2H), 10.03 (s, 1H).

[Reference Example 60]

Process 1

2-[OV-butoxycanolebonyl--cyclobutyl] amino] methyl-4- (ί-butyldimethylsilyloxy) methylpyridine

Reference Example 5 7 The same operation as in Step 3 of Reference Example 43 was carried out using the compound obtained in Step 2 as a raw material and using cyclobutylamine instead of methylamine to obtain the title compound as a colorless oily substance.

MS (ESI) m / z 407 (M + H +).

¾ testimony _{(CDC1 3) δ: 0.12 (} s, 6H), 0.96 (s, 9H), 1.36 (br s, 9H), 1.38- 1.44 (m, 4H), 1.95-2.03 (m, 3H), 4.64 ( br s, 2H), 4.81 (s, 2H), 6.99 (d, 1H, J = 8.0 Hz), 7.37 (d, 1H, / = 8.0 Hz), 7.67 (t, 1H, / = 8.0 Hz). Two

2-[ί-Butoxycarbonyl- -cyclohexyl) amino] methyl-4-formylpyridin Using the compound obtained in the above step 1 as a raw material, the same operation as in step 4 of reference example 46 was performed to obtain the title compound as a colorless solid.

MS (FAB) m / z 323 (M + Na ⁺ ).

_{¾ NMR (CDC1 3) δ:} . 1.38 (br s, 9H), 1.56-1.63 (m, 4H), 1.99- 2.10 (m, 3'H), 4.67 (s, 2H), 7.40 (br, 1H) , 7.82-7.85 (m, 2H), 10.07 (s, 1H).

[Reference Example 6 1] 1 process l process 2 Y ^0Bn

OH

^N

Process 1

3-benzyloxy-2-hydroxomethylpyridine

Reference Example 5 3 The same operation as in Step 1 was carried out using 3-hydroxy-2-hydroxymethylpyridine hydrochloride as a raw material and benzyl bromide instead of methyl iodide to obtain the title compound as a yellow solid. .

_{¾ NMR (CDC1 3) δ:} 4.34 (br, 1H), 4.81 (s, 2H), 5.11 (s, 2H), 7.16-7.23 (m, 2H), 7.32-7.42 (m, 5H), 8.16 (t , 1H, J "= 2.5 Hz). Step 2

3-benzyloxy-2-formylpyri'zine

Using the compound obtained in the above step 1 as a raw material, the same operation as in Reference Example 14 was performed to obtain the title compound as a yellow oily substance.

¾ thigh _{(CDC1 3) δ: 5.26 (} s, 2Η), 7.34-7.47 (m, 7H), 8.41 (t, 1H, / = 2.5 Hz), 10.4 (s, 1H).

[Reference Example 6 2] Process 3

Process 1

2- (2-diazoacetyl) pyrrolidine-1-benzyl carboxylate

Using # -carbobenzyloxy-L-proline as a raw material, the same operation as in Step 1 of Reference Example 52 was performed to obtain the title compound as a brown oily substance.

_{¾ NMR (CDC1 3) δ 1.88-2.23} (m, 4H), 3.48-3.56 (m, 2H), 4.29-4.35 (m, 1H), 5.00-5.25 (m, 3H), 7.33-7.36 (m, 5H ). Process 2

2- (2-bromoacetyl) pyrrolidine-1-benzyl carboxylate

Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Reference Example 52 was carried out to obtain the title compound as a pale yellow oily substance.

_{¾ NMR (CDC1 3) δ:} 1.90-2.07 (m, 3H), 2.20-2.27 (m, 1H), 3.54-3.63 (m, 2H), 4.03 (d, 1H, = 13.0 Hz), 4.15 (d, 1H, J = 13.0 Hz), 4.61-4.65 (m, 1H), 5.03-5.18 (m, 2H), 7.28-7.36 (m, 5H).

2- (2-Hydroxymethyl-4-thiazolinole) pyrrolidine-1-benzylcarboxylate

Using the compound obtained in the above step 2 as a raw material, the same operation as in step 3 of Reference Example 52 was carried out to obtain the title compound as an orange oily substance.

¾ thigh _{(CDC1 3) δ: 1.92-2.17 (} m, 4H), 2.63 (br s, 1H), 3.55-3.65 (m, 2H), 4.88 (s, 2H), 4.99-5.15 (m, 3H), 7.13 (s, 1H), 7.37 (br s, 5H). Process 4

2- (2-Hydroxymethyl-4-thiazolyl) pyrrolidine-: L-butyl sorbate-butyl 1M trichloride boron (dichloromethane) was added under ice-cooling to a solution of 0.36 g of the compound obtained in the above step 3 in 20 ml of dichloromethane. 2.26 ml) was added and stirred at the same temperature for 20 minutes and at room temperature for 6 hours. The reaction solution was supplemented with 2.26 ml of 1M boron trichloride (dichloromethane solution) and further stirred at room temperature for 17 hours. After neutralizing the reaction solution with saturated aqueous sodium hydrogen carbonate, the solvent was distilled off under reduced pressure. To the obtained residue, a solution of 0.28 g of di-di-butyl dicarbonate in 10 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate, and the extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [chloroform: methanol = 40: 1 (v / v)] to give 0.16 g of the title compound as a pale yellow oily substance . Thigh (CDC1 ₃ ) δ 1.31 (s, 9Η), 1.86-1.92 (m, 2H), 2.09 (br s, 1H), 2.17 — 2.21 (m, 1H), 2.63-2.69 (m, 1H), 3.58 (br s, 2H), 4.90 (s, 2H), 4.97- 5.08 (m, 1H), 6.96 (s, 1H). Process 5

2-butyl 2- (2-formyl-4-thiazolinole) pyrrolidine-1-carboxylate

Using the compound obtained in the above Step 4 as a raw material, the same operation as in Reference Example 14 was performed to obtain the title compound as a brown oily substance.

_{¾ MR (CDC1 3) δ:} 1.46 (s, 9Η), 1.94-2.17 (m, 4H), 3.49-3.57 (m, 3H), 5.06 -5.14 (m, 1H), 7. 0 (s, 1H) , 9.95 (s, 1H).

[Example 1]

Process

Process 1

Methyl 2-amino-5-ethyl-3-thiophenecarboxylate

To a mixed solution of 4.18 ml of triethylamine and 4.65 ml of dimethylformamide at room temperature under a nitrogen atmosphere, 2.65 ml of methyl cyanoacetate and 2.70 ml of sword-butylaldehyde were added, and the mixture was stirred for 45 minutes, and 962 mg of sulfur was further added. The mixture was stirred for 18 hours. After water was added to the reaction solution, it was diluted and extracted with ether. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After the sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography k-hexane: ethyl acetate = 4: 1 (v / v)] to give 2.41 g of the title compound as a yellow solid.

^{_{X HM (CDC1 3) δ:}} 1.22 (t, 3H, zo = 7.6 Hz), 2.60 (q , 2H, J = 7.6 Hz), 3.79 (s, 3H), 5.78 (br, 2H), 6.62 (d, 1H, J = 1.3 Hz). Process 2

6-ethylthieno [2,3-d] pyrimidine-4 (3-one

10 ml of a solution of 2.0 g of the compound obtained in the above step 1 in formamide was refluxed at 210 ° C. for 14 hours. The reaction solution was diluted with methanol and solidified with hexane to obtain 1.12 g of the title compound as a brown solid.

MS (FAB) m / z 181 (M + H +) .-

'HNMR (DMS0-4) δ: 1.26 (t, 3H, 7.6 Hz), 2.85 (q, 2H, / = 7.6 Hz), 7.11 (s, 1H), 8.05 (s, 1H), 12.1 (br, 1H). Step 3

4-chloro-6-ethylthieno [2,3-d] pyrimidine

60 ml of a solution of 3.0 g of the compound obtained in the above step 2 in oxysalt ichryline was heated at 110 ° C for 40 minutes. The reaction was allowed to return to room temperature, then 0. The mixture was cooled to C, neutralized by adding a small amount of saturated aqueous sodium hydrogen carbonate, and diluted and extracted with ethyl acetate. After the organic layer was washed with saturated saline, anhydrous sodium sulfate was added thereto and dried. After removing the sodium sulfate by filtration, the solvent was distilled off under reduced pressure. 3-Hexane and ether were added to the obtained residue, and the precipitated solid was filtered off. The mother liquor was concentrated under reduced pressure to obtain 1.56 g of the title compound as a brown oil.

MS (FAB) m / z 199 (M + H +).

^{_{X HM (CDC1 3) δ:}} 1.42 (t, 3H, zo = 7.6 Hz), 3.00 (q , 2H, J = 7.6 Hz), 7.11 (t, 1H, J = 1.3 Hz), 8.77 (s, 1H) Step 4

6-ethyl-4-hydrazinothieno [2,3-] pyrimidine

To a solution of 970 mg of the compound obtained in the above step 3 in 30 ml of ethanol was added 30 ml of hydrazine 'monohydrate at room temperature, and the mixture was heated to 80 ° C and stirred for 50 minutes. After returning the reaction solution to room temperature, the solvent was distilled off under reduced pressure, ether was added, and the precipitated solid was collected by filtration. It was dried at room temperature under reduced pressure to obtain 660 mg of the title compound as a yellow solid.

MS (EI) m / z 194 (M ⁺ ).

_{lE NMR (CDC1 3) δ:} 1.27 (t, 3H, zo = 7.6 Hz), 2.86 (q , 2H, / = 7.6 Hz), 4.55 (br, 2H), 7.32 (br, 1H), 8.30 (s, 1H), 9.00 (br, 1H) .Step 5

2-thiophenecarboxaldehyde-(6-ethylthieno [2,3-d] pyrimidine-4-inole) hydrazone-the compound obtained in step 4 above 261 mg and 2-thiophenecarboxaldehyde 125 An appropriate amount of anhydrous sodium sulfate was added as a dehydrating agent to 7 mg of an anhydrous benzene solution of 7 mg, and the mixture was heated to 100 ° C and stirred for 2.5 hours. After returning the reaction solution to room temperature and removing sodium sulfate by filtration, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography. [-Hexane: ethyl acetate = 4: 1 to chromatoform: acetone] = 5: 1 (v / v)], and the target fraction was concentrated and solidified with ethyl acetate and ether to give 201 mg of the title compound as a pale yellow solid. Table 1 shows the structural formula and physicochemical properties of the compound of this example.

[Example 2]

5-Methyl-! ^-Indole-2,3-dione 3-[-(6-Ethylthieno [2,3-d] pyrimidine-4-yl) hydrazone] '

Using the compound obtained in Step 4 of Example 1 and 5-methylisatin as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 1 shows the structural formula and physical properties of the compound of this example.

[Example 3]

4-Methoxybenzaldehyde y- (6-ethylthieno [2,3-d] pyrimidine-4-yl) hydrazone

Example 1 Using the compound obtained in Step 4 and 4-methoxybenzaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 1 shows the structural formula and physicochemical properties of the compound of this example.

[Example 4] '

2,2-dimethylpropanal-(6-ethylthieno [2,3-d] pyrimidine-4-yl) hydrazone

Example 1 Using the compound obtained in Step 4 and trimethylacetaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 1 shows the structural formula and physical properties of the compound of this example. [Example 5]

Cyclopropanecarboxyaldehyde-(6-ethynorecheno [2,3-d] pyrimidine-4-yl) hydrazone

Example 1 Using the compound obtained in Step 4 and cyclopropanecanoleboxaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 1 shows the structural formula and physicochemical properties of the compound of this example.

[Example 6]

Thiazole-2-carboxyaldehyde-(6-ethyl / rethieno [2,3-] pyrimidin-4-yl) hydrazone

Example 1 The same procedure as in Step 5 of Example 1 was carried out using the compound obtained in Step 4 and thiazole-2-phenoloxyaldehyde as raw materials to obtain the title compound as a yellow solid. Table 1 shows the structural formula and physical properties of the compound of this example.

[Example 7]

Thiol-zole-5-hexyl aldehyde (6-ethylthieno [2,3-d] pyrimidin-4-yl) hydrazone

Using the compound obtained in Step 4 of Example 1 and thiazole-5-phenoloxyaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 1 shows the structural formula and physical properties of the compound of this example.

[Example 8]

2-Fluoraldehyde V- (6-Ethylthieno [2,3-d] pyrimidin-4-yl) hydrazone Example 1 Step 1 Using the compound obtained in Step 4 and 2-furaldehyde as raw materials, Example 1 Step By the same operation as in 5, the title compound was obtained as a yellow solid. Table 1 shows the structural formula and physicochemical properties of the compound of this example. [Example 9]

Trimethyl-! ^-Imidazole-2-hexyl aldehyde- (6-ethylthieno [2,3-d] pyrimidin-4-yl) hydrazone

Example 1 Using the compound obtained in Step 4 and 1-methyl-imidazole-2-hexyloxyaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 1 shows the structural formula and physical properties of the compound of this example.

[Example 10]

5-Bromo-2-thiophenecarboxyaldehyde-(6-ethylthieno [2,3-d] pyrimidine-4-inole) hydrazone

Using the compound obtained in Example 1, Step 4 and 5-bromo-2-thiophenecarboxaldehyde as raw materials, the same operation as in Example 1, Step 5 was performed to obtain the title compound as a yellow solid. Table 1 shows the structural formula and physical properties of the compound of this example.

[Example 1 11

Benzaldehyde (6-ethylthieno [2,3-d] pyrimidine-4-yl) hydrazone Example 1 Using the compound obtained in Step 4 and benzaldehyde as raw materials, the same operation as in Step 1 of Example 1 was performed. The title compound was obtained as a yellow solid. Table 1 shows the structural formula and physicochemical properties of the compound of this example. '

[Example 12]

2-pyridinecarboxyaldehyde- (6-ethylthieno [2,3-d] pyrimidine-4-yl) hydrazone

Using the compound obtained in Step 4 of Example 1 and 2-pyridinecarboxaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 1 shows the structural formula and physicochemical properties of the compounds of this example.

[Example 13] 5-Methyl-2-thiophenecarboxyaldehyde z-y- (6-ethynorethieno [2,3-d] pyrimidine-4-yl) hydrazone

Using the compound obtained in Step 4 of Example 1 and 5-methyl-2-thiophenecarboxaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 1 shows the structural formula and physical properties of the compound of this example.

[Example 14]

3-Methyl-2-thiophenecarboxaldehyde- (6-ethylthieno [2,3-d] pyrimidine-4-yl) hydrazone

Using the compound obtained in Example 1, Step 4 and 3-methyl-2-thiophenecarboxaldehyde as raw materials, the same operation as in Example 1, Step 5 was performed to obtain the title compound as a yellow solid. Table 1 shows the structural formula and physical properties of the compound of this example.

[Example 15]

Engineering

Process 1

Methyl 2-amino-5-isopropyl-3-thiophenecarboxylate

The same operation as in step 1 of Example 1 was carried out using 3-methylbutyraldehyde as a raw material to obtain the title compound as a yellow oily substance.

_{'H MR (CDC1 3) δ} : 1.24 (d, 6H, / = 6.8 Hz), 2.89 (m, 1H), 3.79 (s, 3H), 5.78 (br, 2H), 6.62 (s, 1H) -. Process 2

6-Sopropylcheno [2,3-d] pyrimidine-4 (3-one

Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Example 1 was performed to obtain the title compound as a yellow-green solid.

^{_{: H NMR (CDC1 3) δ}} :. 1.39 (d, 6H, / = 6.8 Hz), 3.20 (q, 1H, / = 6.8 Hz), 7.19 (d, 1H, _ / two 1.0 Hz), 8.00 (d , 1H, / = 1.5 Hz), 8.23 (d, 1H, zo = 6.7 Hz). Step 3

4-Black mouth-6-Isopropyl cheno [2,3-d] pyrimidine

The same operation as in step 3 of Example 1 was performed using the compound obtained in the above step 2 as a starting material, to give the title compound as a brown oil.

^{_{X H NMR (CDC1 3) δ}} :. 1.43 (d, 6H, / = 6.8 Hz), 3.29 (q, 1H, / = 6.8 Hz), 7.11 (s, 1H), 8.77 (s, 1H) Step 4

4-hydrazino-6-isopropylcheno [2,3-d] pyrimidine

Using the compound obtained in the above Step 3 as a starting material, the same operation as in Step 4 of Example 1 was performed to obtain the title compound as a pale yellow solid.

'HNMR (DMS0-) δ: 1.31 (d, 6H, J = 6.8 Hz), 3.18 (q, 1H, 6.8 Hz), 4.55 (br, 2H), 7.35 (br, 1H), 8.30 (s, 1H) , 9.00 (br, 1H). Process 5

2-thiophenecarboxyaldehyde-(6-isopropylcheno [2,3-d] pyrimidin-4-yl) hydrazone

The title compound was obtained as a pale yellow solid by performing the same operation as in Step 1 of Example 1 using the compound obtained in the above Step 4 as a starting material. Table 2 shows the structural formula and physicochemical properties of the compound of this example. . [Example 16]

2-Fluoraldehyde- (6-isopropylcheno [2,3-d] pyrimidine-4-yl) hydrazone

Example 15 Using the compound obtained in Step 4 and 2-furaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 17]

Thiazole-5-carboxyaldehyde- (6-isopropylcheno [2,3-d] pyrimidin-4-yl) hydrazone

Example 15 Using the compound obtained in Step 4 and thiazole-5-carboxaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 18]

Thiazole-2-carboxyaldehyde- (6-isopropylcheno [2,3-d] pyri'midin-4-yl) hydrazone

Example 1 5 The same operation as in Step 1 of Example 1 was carried out using the compound obtained in Step 4 and thiazole-2-hexylcarboxyaldehyde as the starting materials to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 19]

1_ (2-Chenyl)-1-Ethanone-(6-Isopropylcheno [2,3-d] pyrimidine-4-Yinole) hydrazone

Example 15 The same operation as in Example 1, Step 5 was performed using the compound obtained in Step 4 and 1- (2-thenyl) -1-ethanone as the starting materials to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example. [Example 20]

Benzaldehyde-(6-Isopropylcheno [2,3-d] pyrimidine-4-yl) hydrazone

Example 15 Using the compound obtained in Step 4 and benzaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 21]

2-Chlorobenzaldehyde V- (6-Isopropylcheno [2,3-d] pyrimidine-4-yl) hydrazone

Example 15 The same operation as in Step 5 of Example 1 was carried out using the compound obtained in Step 4 and 2-cyclopentene benzaldehyde as raw materials to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 22]

3-Chlorobenzonoledehydro- (6-isopropinorethieno [2,3-d} pyrimidine-4-yl) hydrazone

Example 15 Using the compound obtained in Step 4 and 3-chlorobenzaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 23]

4-Chlorobenzaldehyde-(6-Isopropylcheno [2,3 ~ d] pyrimidine-4-inolide) Hydrazone

Example 15 The same operation as in Step 1 of Example 1 was carried out using the compound obtained in Step 4 and 4-neck mouth benzaldehyde as raw materials to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example. [Example 24]

2-pyridinecarboxyaldehyde- (6-isopropylcheno [2,3-d] pyrimidine-4-yl) hydrazone

Example 15 Using the compound obtained in Step 4 and 2-pyridinecarboxaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 25]

2-Fluorobenzaldehyde #-(6-isopropylcheno [2,3-d] pyrimidine-4-inole) hydrazone

Example 15 Using the compound obtained in Step 4 and 2-fluorobenzaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 26]

3-Fluorobenzaldehyde-(6-isopropylcheno [2,3-d] pyrimidine-4-inole) hydrazone

Example 15 The same operation as in Step 1 of Example 1 was carried out using the compound obtained in Step 4 and 3-fluorobenzaldehyde as raw materials to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 27]

3-pyridinecarboxaldehyde- (6-isopropylcheno [2,3-d] pyrimidine-1-inole) hydrazone

Example 15 Using the compound obtained in Step 4 and 3-pyridinecarboxaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example. [Example 28]

4-pyridinecarboxaldehyde- (6-isopropylcheno [2,3-d] pyrimidine-4-yl) hydrazone

Example 15 Using the compound obtained in Step 4 and 4-pyridinepyridine as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 29]

3- [0V, -Dimethylamino] methyl] benzaldehyde #-(6-isopropylcheno [2,3-d] pyrimidine-4-yl) hydrazone

Example 15 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 1 as starting materials to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 30]

Process

2-Amino _5-(-butyl) -3-methyl thiophenecarbonate

The same operation as in step 1 of Example 1 was performed using 3,3-dimethylbutyraldehyde as a raw material to obtain the title compound as a yellow solid.

_{'Η MR (CDC1 3) δ} : 1.29 (s, 9H), 3.79 (s, 3H), 5.76 (br, 2H), 6.62 (s, 1H). Process 2

6-(-butyl) thieno [2,3-d] pyrimidine-4 (3-one

Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Example 1 was performed to obtain the title compound as a pale yellow solid.

_{'HNMR (CDC1 3) δ:} . 1.43 (s, 9H), 7.21 (s, 1H), 8.01 (s, 1H), 12.15 (br, 1H) Step 3

6-(-butyl) -4-chlorocheno [2,3 ~ d] pyrimidine

^{X H NMR (CDCI3) δ 1.49} (s, 9H), 7.11 (s, 1H), 8.77 (s, 1H). Step 4

6- (ί-butyl) -4-hydrazinocheno [2,3-d] pyrimidine

^{_{1 H NMR (CDC1 3) δ}} :. 1. 3 (s, 9H), 6.89 (s, 1H), 8. 9 (s, 1Η) Step 5.

2-thiophenecarboxyaldehyde-[6-(-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

The same operation as in step 5 of Example 1 was performed using the compound obtained in the above step 4 as a raw material to obtain the title compound as a colorless solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 31]

2-pyridinecarboxaldehyde-[6-(-butyl) thieno [2,3-] pyrimidine-4-yl] hydrazone Example 30 Using the compound obtained in Step 4 and 2-pyridinecarboxaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physical properties of the compound of this example.

[Example 32]

3-Pyridinecarboxaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in Step 5 of Example 1 was carried out using the compound obtained in Step 4 and 3-pyridinecarboxyaldehyde as the starting materials to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 33]

4-Pyridinecarboxyaldehyde-[6- (ブチル -butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and 4-pyridinecarboxaldehyde as raw materials, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 3 4]

5-Methyl-2-pyridinecarboxaldehyde-[6-(-butyl) thieno [2,3-d] pyrimidin-4-yl] hydrazone

Example 3 Using the compound obtained in Step 4 and 5-methyl-2-pyridine-functional carboxylic acid (Zr 1994, 43, 1175) as raw materials, the same operation as in Step 1 of Example 1 was performed to convert the title compound to a yellow solid. As obtained. The structural formula and physicochemical properties of the compound of this example are not shown in o.

[Example 35] -3-Fluoro-2-pyridinecarboxaldehyde- [6- (ί-butyl) thieno [2,3-] pi Limidine-4-yl] hydrazone

Example 30 The same operation as in Step 1 of Example 1 was performed using the compound obtained in Step 4 and 3-tetrafluoro-2-pyridine terboxylaldehyde (Tetrahedron 1998, 54, 6311) as raw materials, and the title compound was converted to a yellow solid. As obtained. Table 3 shows the structural formula and physical properties of the compound of this example.

[Example 36]

5-Methoxy-2-pyridinecarboxaldehyde-[6- (ί-butyl) thieno [2,3-] pyrimidine-4-inole] hydrazone

Example 30 Compound obtained in step 4 and 5-methoxy-2-pyridinecarboxaldehyde

1994, 43, 1175) as a raw material, and the same operation as in step 1 of Example 1 was performed to obtain the title compound as a yellow solid. The structural formula and physicochemical properties of the compound of this example are not 3.

[Example 3 7]

3-benzyloxy-2-pyridine power. Ruboxaldehyde- [6--butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 1 of Step 1 as starting materials to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compounds of this example.

[Example 38]

3-Nitro-2-pyridinecarboxyaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidin-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and 3-nitro-2-pyridinecarboxaldehyde (Tetrahedron 1998, 54, 6311) as raw materials, the same operation as in Step 5 of Example 1 was performed, The title compound was obtained as a yellow solid. Table 3 shows the structural formula and physical properties of the compound of this example. [Example 3 9]

2-({2- [6- (ί-butyl) cheno [2,3-d] pyrimidine-4-yl] hydrazono} methyl) -3-pyridinylcarbamic acid-butynole

Example 30 Using the compound obtained in Step 4 and 3-(-butoxycarbonyl) amino-2-pyridinecarboxaldehyde (etrahedron 1998, 54, 6311) as starting materials, the same operation as in Example 1 Step 5 was carried out. The title compound was obtained as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 40]

6,7-dihydro-8 (5 ^ -quinolinone- [6-(-butyl) thieno [2,3-] pyrimidine-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and 6, 7-dihydro-8 (5-quinolinone (J. Org. Chem. 1984, 49, 2208) as raw materials, the same operation as in Step 5 of Example 1 was performed. The title compound was obtained as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 4 1]

3-hydroxy-2-pyridinecarboxyaldehyde- [6- (ί-butyl) thieno [2,3-] pyrimidine-4-yl] hydrazone

Example 30 4 Using the compound obtained in Step 4 and Reference Example 5 4 as the starting material, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compounds of this example.

[Example 4 2]

3-methoxy-2-pyridinecarboxaldehyde- [6-(-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone-Example 30 Compound obtained in Step 4 and Reference Example 53 Using the compound obtained in step 2 as a raw material, The same operation as in step 1 of Example 1 was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compounds of this example.

[Example 4 3]

6 _ [(-dimethylamino) methyl] -2-pyridinecarboxaldehyde-[6-(-butynole) cheno [2,3-d] pyrimidine-4-inole] hydrazone

Example 30 The same operation as in Step 5 of Example 1 using the compound obtained in Step 4 and 6-[(/ V; -dimethylamino) methyl] -2-pyridinecarboxaldehyde (Japanese Patent Application No. 4-1021159) as raw materials Was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physical properties of the compound of this example.

[Example 4 4]

6-Methyl-2-pyridinecarboxyaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidin-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and 6-methyl-2-pyridinecarboxyaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physical properties of the compound of this example.

[Example 45]

5-Fluoro-2-pyridinecarboxyaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidin-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and 5-fluoro-2-pyridinecarboxaldehyde a Med. Chem. 1970, 13, 1124) as the starting materials, the same operation as in Step 1 of Example 1 was performed, and the title compound was yellow. Obtained as a solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 4 6]-4--Mouth mouth-2-pyridinecarboxyaldehyde-[6--butyl) thieno [2,3-] Mizin-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and 4-chloro-2-pyridinecarboxyaldehyde (Analytical Chemistry 1994, 43, 1175) as raw materials, the same operation as in Step 5 of Example 1 was performed. The title compound was obtained as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 4 7]

6-[(1,3-Dioxo-1,3-dihydro 27-isoindole-2-yl) methyl] -1-pyridincarboxaldehyde- [6- (ί-butyl) thieno [2,3- d] pyrimidine-4-yl] hydrazone

Example 30 The compound obtained in Step 4 and 6-[(1,3-dioxo-1,3-dihydro-2 ^ -isoindole-2-inole) methyl] -2-pyridinecarboxaldehyde (Japanese Patent Application No. -1021159) as a starting material, and the same operation as in step 5 of example 1 was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 4 8]

4-{[2- (N, N-dimethylamino) ethyl] (Ν'-methyl) amino} -2-pyridinecarboxaldehyde- [6--butyl) thieno [2,3-d} pyrimidine-4-inole Hydrazone Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 55 as raw materials, the same operation as in Step 5 of Example 1 was carried out to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 4 9]

4- (4-methyl-1-pirazinyl) -2-pyridinecarboxyaldehyde N- [6- (ί-butylinole) thieno [2,3-] pyrimidine-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 56 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physical properties of the compound of this example. [Example 50]

6- (Hydroxymethyl)-2-pyridinecarboxaldehyde-[6- (ί-butyl) cheno [2, 3-d] pyrimidine-4-yl] hydrazone

Example 30 Compound 1 obtained in Step 4 and Reference Example 5 7 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 5 of Example 1 was performed. The title compound was obtained as a yellow solid. Table 3 shows the structural formula and physical properties of the compound of this example.

[Example 5 1]

6-piperidinomethyl-2-pyridinecarboxyaldehyde [6- (ί-butyl) thieno [2,3-dlpyrimidin-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and 6-piperidinomethyl-2-pyridine lipoxyaldehyde (Japanese Patent Application No. 4-1021159) as raw materials, the same operation as in Step 1 of Example 1 was performed. The compound was obtained as a yellow solid. Table 3 shows the structural formula and physical properties of the compound of this example.

[Example 52]

6-Monoleholinomethyl-2-pyridinepyridine canoleboxia / redide-[6-(-butyl) thieno [2,3-] pyrimidine-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and 6-morpholinomethyl-2-pyridinecarboxyaldehyde (Japanese Patent Application No. 4-1021159) as starting materials, the same operation as in Step 5 of Example 1 was performed to give the title compound as yellow. Obtained as a solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 53]

6- (4-Methylpiperazinyl) methyl-2-pyridinecarboxaldehyde-[6- (butyl) thieno [2,3-d pyrimidine-4-yl] hydrazone Example 30 Using the compound obtained in Step 4 and 6- (4-methylpyrazinyl) methyl-2-pyridinecarboxaldehyde (Japanese Patent Application No. 4-1021159) as starting materials, the same operation as in Step 5 of Example 1 was performed. The title compound was obtained as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 54]

5-methyl-4,5,6,7_tetrahydro [1,3] thiazolo [5,4_c] pyridine-2-carboxyaldehyde #-[6-butyl) thieno [2,3-d] pyrimidine-4- [Yr] hydrazone Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 32 as raw materials, the same operation as in Step 1 of Example 1 was carried out to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 55]

ί-Butyl 2-({[6-(-butyl) cheno [2,3-] pyrimidine-4-yl] hydrazono} methyl)-6,7-dihydro [1,3] thiazolo [5,4 -c] pyridine-5 (4¾-carboxylate Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 31 as raw materials, the same operation as in Step 5 of Example 1 was performed, and the title compound was yellow. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 56]

4- [V; -dimethylamino) methyl] -thiazole-2-carboxyaldehyde-[6-(-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 29 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physical properties of the compound of this example.

[Example 5 7] '

5--Dimethylamino) methyl] -thiazole-2-carboxyaldehyde #-[6-(-butyl) thieno [2,3-d] pyrimidin-4-yl] hydrazine Example 30 Compound obtained in Step 4 and Reference Example 30 The compound obtained in Step 2 was used as a starting material. The same operation as in step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compounds of this example.

[Example 5 8]

Benzanoledehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in Step 1 of Example 1 was carried out using the compound obtained in Step 4 and benzaldehyde as raw materials to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physical properties of the compound of this example.

[Example 5 9]

2-Nitrate Benzaldehyde-[6_ (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and 2--2-trobenzaldehyde as raw materials, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 60]

3-[(V; -dimethylamino) methyl] benzaldehyde _ [6-(-butyl) thieno [2,3-d] pyrimidine-4--4-//] hydrazone

Example 30 Using the compound obtained in Step 4 of Reference Example 1 and the compound obtained in Step 2 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 6 1]-2,6-Difluorobenzaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidine-4- Ill] hydrazone

Example 30 Using the compound obtained in Step 4 and 2,6-difluorobenzaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physical properties of the compound of this example.

[Example 6 2]

1 ^ -indole-2,3-dione-3-{-[6-(-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone}

Example 30 Using the compound obtained in Step 4 and isatin as raw materials, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 6 3]

4-dimethylamino) methylbenzaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 3 as starting materials to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physical properties of the compound of this example. '

[Example 6 4]

2- (Λζ-dimethylamino) methylbenzaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in Step 5 of Example 1 was carried out using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 2 as starting materials to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 6 5]-

3-({2- [6-0-butyl) thieno [2,3-] pyrimidine-4-yl] hydrazono} methyl ) -N, N-dimethylbenzenesnorrenamide

Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 4 as starting materials to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 6 6]

4_ ({2- [6- (ί-butyl) thieno [2,3-] pyrimidine-4-yl] hydrazono} methyl) -Ν, -dimethylbenzenesulfonamide

Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 6 as starting materials to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 6 7]

Ν- (ί-butyl) -3--({2- [6- (ί-butyl) cheno [2,3-d] pyrimidine-4-yl] hydrazono} methyl) benzenesulfonamide

Example 30 Using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 5 as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 6 8]

4-[(4-Methyl-1-piperazinyl) sulfonyl] benzaldehyde-[6- -butyl] cheno [2,3-d] pyrimidin-4-yl] hydrazone

Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 7 as starting materials to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

Example 6 9 - 4- ({2- [6- (- butyl) Cheno ^[2, 3 -] pyrimidine - 4 I le ί arsenide Dorazono} methyl) repose Example 30 Using the compound obtained in Step 4 and -phthalaldehyde acid as raw materials, the same operation as in Step 1 of Example 5 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 70]

3-({2- [6--Butyl) cheno [2,3-] pyrimidin-4-yl] hydrazono} methyl) benzo Example 30 Using the compound obtained in Step 4 and phthalaldehyde acid as raw materials The same operation as in step 1 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 7 1]

4-({2- [6-(-butyl) cheno [2,3-d] pyrimidin-4-yl] hydrazono} methyl) methyl benzoate

Example 30 Using the compound obtained in Step 4 and methyl phthalaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 7 2]

-Butyl 5-({2- [6 _ (-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazono} methyl)-1,3-Dihydro-isoindolinone-2-carboxylate

Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 14 as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 7 3] -4-[(4-Methylbiperazino) methyl] benzaldehyde- [6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 10 Step 2 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compounds of this example.

[Example 7 4]

4-({[-Butyl (diphenyl) silyl] oxy} methyl) benzaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 12 as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 75]

2- [5-({2- [6-(-butyl) thieno [2,3-^] pyrimidin-4-yl] hydrazono} methino) 1, 3-dihydro-2 ^ -isoindone -2-Inole] acetic acid ί—butinole

Example 30 The same operation as in step 5 of Example 1 was performed using the compound obtained in step 4 and the compound obtained in reference example 15 and step 2 as raw materials to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compounds of this example.

[Example 76]

3- (1 ^ -1,2,3,4-tetrazol-5-yl) benzaldehyde-[6-(-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 Using 60 mg of the compound obtained in Step 4 and 124 mg of the compound obtained in Step 2 of Reference Example 15 as raw materials, the same operation as in Step 5 of Example 1 was performed, and the condensate obtained was treated with ethanol. Was dissolved in 8 ml of acetic acid, and 0.4 ml of acetic acid was added, and the mixture was heated at 40 ° C for 1.5 hours and at 70 ° C for 3.5 hours. The temperature was returned to room temperature, the solvent was distilled off under reduced pressure, and the residue was solidified with ethyl acetate-hexane to obtain 95 mg of the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example. [Example 7 7]

4-{[(2-Hydroxitytyl) methylamino] methyl} benzaldehyde N- [6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in step 5 of Example 1 was performed using the compound obtained in step 4 and the compound obtained in step 2 of Reference Example 9 as starting materials to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 7 8]

4- [bis (2-hydroxyxethyl) methylamino] benzaldehyde N- [6-(-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 8 as raw materials to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 7 9]

4- (Methylsulfanyl) benzaldehyde- [6-(-butyl) thieno [2,3-] pyrimidine-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and 4-methylthiobenzaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compounds of this example.

[Example 80]

-Butyl 7-({2- [6- (ί-butyl) cheno [2,3-d] pyrimidin-4-yl] hydrazono} methyl) -3,4-Dihydro-2 (1 ^ ) -Isoquinoline carboxylate

Example 30 Same as step 5 in Example 1 except that the compound obtained in Step 4 and 7-formyl-3,4-dihydro-1 ^ -isoquinoline-2-carboxylate-butyl (Japanese Patent Application No. 2000-16984) were used as raw materials. By the same operation, the title compound was obtained as a yellow solid. The structural formula of the compound of the present example and Table 4 shows the physical properties. [Example 8 1]

4-{[4- (2-hydroxyethyl) piperazino] methyl} benzaldehyde- [6-(-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Reference Example 1 1 Step 2 as raw materials to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compounds of this example.

[Example 82]

4- (4-methylbiperazino) benzaldehyde-[6-(-butyl) thieno [2,3-] pyrimidine-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 18 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 8 3]

2-methyl-5-isoindolinecarboxyaldehyde [6- (ί-butyl) thieno [2,3-cJpyrimidine_4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 16 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 84]

3-Hydroxy-4-methoxybenzaldehyde zo \ [6_ (ί-butyl) thieno [2,3-] pyrimidin-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and 3-hydroxy-4-methoxybenzaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Was. Table 4 shows the structural formula and physicochemical properties of the compound of this example. [Example 85]

4-[(Λζ-Dimethylamino) methyl] _3 -Fluorobenzaldehyde _ [6- (-Petinole) Ceno [2, pyrimidine-4-yl] hydrazone

Example 30 The same operation as in Step 5 of Example 1 was carried out using the compound obtained in Step 4 and the compound obtained in Reference Example 19 Step 2 as raw materials to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compounds of this example.

[Example 8 6]

2-Isopropyl-5-isoindolinecarboxaldehyde-[6- (ί-butyl) ceno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 17 as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 8 7]

4_ [(Λζ-dimethylamino) methyl] -2-hydroxybenzanoledehyde-[6-(-butynole) cheno [2,3-] pyrimidine-1 4-inole] hydrazone

Example 30 The same operation as in step 5 of Example 1 was performed using the compound obtained in step 4 and the compound obtained in reference example 2 1 as a raw material to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physical properties of the compounds of this example.

[Example 8 8]

4-({2- [6- (ί-butyl) cheno [2,3-d] pyrimidine-4-yl] hydrazono} methyl) benzylmethylca //-butyl levamine

Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 22 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Example compound Table 4 shows the structural formula and physicochemical properties of 1: Example 8 9]

3-chloro-4-[(Λζ-dimethylamino) methyl] benzaldehyde- [6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Reference Example 20 Step 2 as raw materials to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compounds of this example.

[Example 90]

t-Butyl 3- [4-({2- [6-(-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazono} methyl) phenyl] -1-azetidinecarboxylate

Example 30 Using the compound obtained in Step 4 and Reference Example 2 5 as the starting material, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of the compounds of this example.

[Example 9 1]

4- (1-methyl-3-azetidinyl) benzaldehyde-[6-(-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 26 as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physical properties of the compound of this example.

[Example 9 2]

4-[(1,3-Dioxo-1,3-dihydro-2 ^ -isindole-2-yl) methyl] benzaldehyde- [6- (ί-butyl) thieno [2,3-d] pyrimidine-4 -Ill] Hydrazon

Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 23 as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Example compound Table 4 shows the structural formula and physicochemical properties of

[Example 93]

Process 1

2, 2-dimethyl-1-(-butyldiphenylsilyloxy) -4-pentene

2.28 g of 2,2-dimethyl-4-pentenomono (Tetrahedron 1987, 43, 5637) and 5.7 ml of t-butylchlorodiphenylsilane were dissolved in 50 ml of tetrahydrofuran, 1.50 g of imidazole was added, and the mixture was stirred for 20 hours. The reaction solution was diluted with water, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography [ethyl acetate: 2-hexane = 1: 50 (v / v)] to give 5.05 g of the title compound as a colorless oil.

_{'HNMR (CDC1 3) δ:} 0.85 (s, 6H), 1.05 (s, 9H), 2.05 (d, 2H, 8.0 Hz), 3.32 (s, 2H), 4.95-5.02 (m, 2H), 5.71- 5.82 (m, 1H), 7.35-7.77 (m, 10H). Process 2

2,2-dimethyl-3- (ί-butyldiphenylsilyloxy) butanal

5.00 g of the compound obtained in the above step 1 and 180 mg of osmium tetroxide were dissolved in 225 ml of tetrahydrofuran: water [2: 1 (v / v)] and heated to 50 ° C. Next, 6.10 g of sodium periodate was added little by little over 1 hour, and the mixture was further stirred for 1 hour. A saturated aqueous sodium sulfite solution was added to the reaction solution, and the mixture was stirred for 1 hour, and then extracted with ether. After washing with saturated saline and drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure did. The obtained residue is subjected to silica gel chromatography [ethyl acetate: 72-hexane]

= 1: 20 (v / v)] to give 2.50 g of the title compound as a colorless oil. MS (FAB) m / z 355 (M + if).

_{'H MR (CDC1 3) δ} : 1.04 (s, 6H), 1.07 (s, 9H), 2.37 (d, 2H, / = 3.0 Hz), 3.39 (s, 2H), 7.37-7.64 (m, 10H) , 9.86 (t, 1H, J = 3.0 Hz). Step 3

2-Amino-5- [2- (ί-butyldiphenylsilyloxy) _1,1-dimethylethyl] -3-methylthiophenate

Using the compound obtained in Step 2 as a starting material, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a pale yellow oily substance.

MS (FAB) m / z 468 (M + H ⁺ ).

^{X H NMR (CDCI3) δ:} 1.05 (s, 9H), 1.29 (s, 6H), 3.48 (s, 2H), 3.78 (s, 3H), 5.77 (br, 2H), 6.68 (s, 1H), 7.33-7.61 (m, 10H) .Step 4

6- [2- (ί-butyldiphenylsilyloxy) -1,1-dimethinoleethynole] thieno [2,3-d] pyrimidine-4 (3-one

Using the compound obtained in the above Step 3 as a raw material, the same operation as in Step 2 of Example 1 was performed to obtain the title compound as a colorless solid.

MS (FAB) m / z 463 (M + H ⁺ ).

NMR (CDCI3) δ: 1.04 (s, 9H), 1.42 (s, 6H), 3.61 (s, 2H), 7.26 (s, 1H), 7.32-7.59 (m, 10H), 8.01 (br, 1H). Process 5

6- [2-(-Butyldiphenylsilyloxy 1-dimethylethyl) -4-hydrazinothieno [2,3-] pyrimidine-Using the compound obtained in the above step 4 as a raw material, Do the operation and get The same operation as in step 1 of Example 1 was performed on the obtained chlorinated compound to obtain the title compound as a colorless solid.

MS (FAB) m / z 477 (M + H ⁺ ).

_{MR (CDC1 3) δ ·· 1.02} (s, 9H), 1.42 (s, 6H), 3.63 (s, 2H), 6.35 (br, 1H), 6.90 (s "1H), 7.32-7.55 (m, 10H ), 8.51 (s, 1H). Step 6

2-Pyridine carboxylic acid _ [6- [2- (ί-butyl) diphenylsilyloxy-1,1,1-dimethylethyl] thieno [2,3-d] pyrimidin-4-yl] hydrazone

Using the compound obtained in the above Step 5 as a raw material, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a pale yellow solid. Table 5 shows the structural formula and physical properties of the compound of this example.

[Example 94]

HO one

s one N

2-pyridinecarboxaldehyde-[6- (2-hydroxy-1,1-dimethylethyl) thieno [2,3-d] pyrimidin-4-yl] hydrazone

Construed soluble compound 116 mg obtained in the above Example 9 3 Step 6 in tetrahydrofuran 3.5 ml, and one晚攪拌with 1M tetra Petit Ruan monitor © beam fluoride (tetrahydrofuran solution) 0.8 ² ml was added 60 ° C. After allowing the reaction solution to cool, it was diluted with ethyl acetate, washed with 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 solidified from methanol to give the title compound (38 mg) as a pale-yellow solid. Table 5 shows the structural formula and physical properties of the compound of this example. [Example 95]

2-Pyridinecarboxaldehyde-[6- (2-fluoro-1,1-dimethylethyl) cheno [2,3-d] pyrimidine-4-yl] hydrazone

100 mg of the compound obtained in the above Example 94 was dissolved in 5 ml of dichloromethane and cooled to 178 ° C. Next, 0.081 ml of getylaminosulfur trifluoride was added, and the temperature was raised to room temperature over 4 hours. Saturated aqueous sodium bicarbonate and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic layer was washed with 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 subjected to silica gel thin-layer chromatography [chloroform: methanol = 19: 1 (v / v)], and solidified from methanol and ether to give 62 mg of the title compound as a pale yellow solid. Table 5 shows the structural formula and physicochemical properties of the compound of this example.

[Example 9 6]

4- (JV, -Dimethylamino) methylbenzaldehyde N- [6- (2-Hydroxy-1,1-dimethylethyl) cheno [2,3-d] pyrimidine-4-yl] hydrazone

Using the compound obtained in Step 9 of Step 9 and the compound obtained in Step 2 of Reference Example 3 as starting materials, the same operation as in Step 5 of Example 1 was performed, and then the same operation as in Example 94 was performed. The title compound was obtained as a yellow solid. Table 5 shows the structural formula and physicochemical properties of the compound of this example.

[Example 9 7]

3-(V, -Dimethylamino) methyl / levenzaldehyde-[6- (2-hydroxy-1,1-dimethylethyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone Example 9 3 Compound obtained in Step 5 Reference f! L 1 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 1 of Example 1 was performed. The operation was performed to obtain the title compound as a yellow solid. Table 5 shows the structural formula and physicochemical properties of the compound of this example.

[Example 9 8]

4- [bis (2-hydroxyxethyl) methylamino] benzaldehyde- [6- (2-hydroxy-1,1-dimethylethyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone Example 9 3 The compound obtained in Step 5 and Reference Example 8 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 1 of Example 1 was performed, and then the same operation as in Example 94 was performed. The title compound was obtained as a yellow solid. Table 5 shows the structural formula and physicochemical properties of the compound of this example.

[Example 9 9]

4-{[(2-Hydroxyshetyl) methylamino] methyl} benzaldehyde "[6- (2-Hydroxy-1,1; L-dimethylethyl) thieno [2,3-d] pyrimidin-4-yl] h Drazone Example 9 Using the compound obtained in Step 5 and the compound obtained in Step 2 of Reference Example 9 as starting materials, the same operation as in Step 1 of Example 1 was performed, and then the same operation as in Example 94 was performed. The title compound was obtained as a yellow solid The structural formula and physicochemical properties of the compound of this example are shown in Table 5.

[Example 100]

-Butyl 5-({2- [6- (2-hydroxy-1,1-dimethylethyl) thieno [2,3-d] pyrimidine-4-ylcohydrazono} methyl) -2-isoindolinecarboxylate

Example 9 3 Using the compound obtained in Step 5 and the compound obtained in Reference Example 14 as starting materials, performing the same operation as in Step 5 of Example 1 and then performing the same operation as in Example 94 to obtain the title compound. Obtained as a yellow solid. -Table 5 shows the structural formula and physicochemical properties of the compound of this example. [Example 10 1]

4- (hydroxymethyl) benzaldehyde N- [6- (ί-butyl) cheno [2,3-d] pyrimidine-4-yl] hydrazone

Using the compound obtained in Example 74 as a raw material, the same operation as in Example 94 was performed to obtain the title compound as a colorless solid. Table 4 shows the formula and physical properties of the compound of this example.

[Example 10 2]

3-Amino-2-pyridine lipoxyaldehyde-[6-(-butyl) thieno [2,3-d] pyrimidin-4-yl] hydrazone dihydrochloride

To 7 mg of the compound obtained in Example 39 was added 0.2 ml of 4 N hydrochloric acid / dioxane, followed by stirring at room temperature for 1 hour. The reaction solution was distilled off under reduced pressure, and azeotroped with getyl ether three times. The obtained orange solid was dried at 40 ° C. under reduced pressure to obtain 38 mg of the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 10 3] -6-[(^-Methylamino) methyl] -2-pyridinecarboxyaldehyde- [6- (ί-butyi) Le) Thieno [2,3-d] pyrimidine-4-yl] hydrazone2.5 hydrochloride

Example 30 Compound obtained in Step 4 Reference Example 5 8 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 5 of Example 1 was performed. The operation was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of this compound.

[Example 10 4]

6-[(cyclopropylamino) methyl] -2-pyridine lipoxyaldehyde N- [6- (t-butyl) thieno [2,3-d] pyrimidin-4-yl] hydrazone · 2.5 HCl salt

Example 30 Compound obtained in Step 4 and Reference Example 5 9 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 5 of Example 1 was performed. The operation was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physical properties of this compound.

[Example 10 5]

6-[(Cyclobutylamino) methyl] -2-pyridinecarboxaldehyde #-[6-(-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone dihydrochloride

Example 30 The compound obtained in Step 4 and the reference example 60 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 5 of Example 1 was performed. The operation was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of this compound.

[Example 10 6]

4,5,6,7-Tetrahydro [1,3] thiazolo [5,4-c] pyridine-2-carboxyaldehyde- [6-(-butyl) thieno [2,3-d] pyrimidine-4 [-Yl] hydrazone dihydrochloride Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 31 as starting materials, the same operation as in Step 1 of Example 1 was carried out. The same operation as in Example 102 was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formulas and physical properties of the compound. [Example 107]

5-isoindolin carboxyaldehyde-[6- (ί-butyl) thieno [2,3-dlpyrimidine-4-yl] hydrazone dihydrochloride

Using the compound obtained in Example 72 as a raw material, the same operation as in Example 102 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of this compound.

[Example 108]

1, 2, 3, 4 Tetorahi mud - 7 I isoquinolin carboxymethyl aldehyde heat de - [6 - - heptyl) thieno ^[2, 3-d] pyrimidine - 4 - I le] arsenide Dorazon dihydrochloride

Using the compound obtained in Example 80 as a raw material, the same operation as in Example 102 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of this compound.

[Example 109]

5_isoindolinecarboxyaldehyde-[6- (2-hydroxy-1, todimethylethyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone dihydrochloride

Using the compound obtained in Example 100 as a raw material, the same operation as in Example 102 was performed to obtain the title compound as a yellow solid. Table 5 shows the structural formula and physicochemical properties of this compound.

[Example 110]

4-[(/ ^ -Methylamino) methyl] benzaldehyde-[6-(-butyl) thieno [2,3-d] pyridine_4-yl] hydrazone dihydrochloride

Using the compound obtained in Example 88 as a raw material, the same procedure as in Example 102 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physicochemical properties of this compound.

[Example 11 1]

4- (3-azetidinyl) benzaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidin-4-yl] hydrazone Using the compound obtained in Example 90 as a raw material, the same operation as in Example 102 was performed to obtain the title compound as a yellow solid. Table 4 shows the structural formula and physical properties of this compound.

[Example 1 1 2]

6-Aminomethyl-2-pyridinecarboxyaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidine -4-inole] hydrazone · dihydrochloride

305 mg of the compound obtained in Example 47 was suspended in 6 ml of ethanol, 3 ml of hydrazine monohydrate was added, and the mixture was stirred at 60 ° C for 3 hours. After allowing to cool and removing the insolubles by filtration, the residue was concentrated. To the resulting residue was added a porphyrin form, and the insolubles were removed by filtration. The obtained residue was solidified from methanol to give the title compound (155 mg) as a pale-yellow solid. Table 3 shows the structural formula and physicochemical properties of this compound. .

[Example 1 1 3]

2- (5- {2- [6- (ί-butyl) cheno [2,3-d] pyrimidine-4-yl] hydrazonomethine} -1,3-dihydro-2H-isoindole-2- Yl) acetic acid

100 mg of the compound obtained in Example 5 was dissolved in 2 ml of tetrahydrofuran, 6 ml of concentrated hydrochloric acid was added, and the mixture was stirred at 60 ° C. under reduced pressure. After concentration, 15 ml of water was added, the pH was adjusted to 5 with saturated aqueous sodium hydrogen carbonate, and the mixture was concentrated again. The obtained residue was developed and purified by silica gel thin-layer chromatography [closed form: methanol: water = 7: 3: 1 (v / v / v) (lower layer)]. Table 4 shows the structural formula and physicochemical properties of the present compound ( _{c), which} was obtained by subjecting the title compound (35 mg) as a yellow solid by solidification from mouth and hexane.

[Example 1 1 4]

Benzaldehyde-[6-(-butyl) thieno [2,3-d] pyrimidine—4-inole] hydrazone

The same operation as in Step 1 of Example 1 was carried out using 4-hydrazino-5-methylthieno [2,3-] pyrimidine and 2-thiophenecarboxyaldehyde as starting materials to obtain the title compound as a yellow solid.

MS (EI) m / z 274 (M ").

^{_{: H MR (CDC1 3) δ}} : 2.61 (s, 3H), 6.80 (s, 1H), 7.08 (dt, 1H, J = 3.7, 1.7 Hz), 7.29 (d, 1H, / = 3.4 Hz), 7.36 (d, 1H, / = 4.6 Hz), 7.72 (s, 1H), 8.16 (s, 1H), 10.29 (br, 1H).

[Example 1 1 5]

'

Process 3

Process 1

2-amino-3-methyl 3-thiophenecarboxylate

Using 3-Feed as a raw material, the same operation as in Step 1 of Example 1 was performed. The title compound was obtained as a brown oil.

_{^ NMR (CDC1 3) δ:} . 3.83 (s, 3H), 5.80 (br, 2H), 6.66 (s, 1H), 7.19-7.32 (m, 5H) Step 2

6-benzylthieno [2,3-] pyrimidine-4 (3 ^)-one

Using the compound obtained in the above Step 1 as a starting material, the same operation as in Step 2 of Example 1 was performed to obtain the title compound as a pale yellow solid.

_{'Ε MR (CDC1 3) δ} : 4.18 (s, 2H), 7.16 (t, 1H, J: 1.2 Hz), 7,23-7.36 (m, 5H), 7.96 (s, 1H), 8.23 (d, 1H, J 13.4 Hz). Process 3

6-benzyl-4- thieno [2,3-d} pyrimidine

Using the compound obtained in the above Step 2 as a raw material, the same operation as in Step 3 of Example 1 was performed to obtain the title compound as a brown oily substance.

^{X H NMR (CDCI3) δ:} . 4.27 (s, 2H), 7.11 (t, 1H, = 1.2 Hz), 7.28-7.39 (m, 5H), 8.77 (s, 1H) Step 4

6-benzyl-4-hydrazinothieno [2,3-d] pyrimidine

Using the compound obtained in Step 3 as a raw material, the same operation as in Step 4 of Example 1 was performed to obtain the title compound as a pale brown solid.

NMR (DMS0—) δ ··· 4.20 (s, 2H), 4.56 (br, '2Η), 7.24-7.37 (m, 6H), 8.29 (s, 1H), 9.06 (br, 1H). Step 5

2-thiophenecarboxaldehyde-(6-benzylthieno [2,3-] pyrimidine-4-yl) hydrazone Using the compound obtained in the above Step 4 as a raw material, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a pale yellow solid.

MS (EI) m / z 350 Q).

_{'HNMR (CDC1 3) δ ··} 4.26 (s, 2H), 7.06 (d, 1H, / = 4.6, 3.7 Hz), 7.19 (d, 1H, / = 2.1 Hz), 7.27-7.40 (m, 6H) , 7.74 (br, 1H), 8.00 (br, 1H), 8.44 (br, 1H).

[Example 1 1 6]

Process 1

Methyl 2-amino-5- (1,3,3-trimethylbutyl) -3-thiophenecarboxylate

The same operation as in Step 1 of Example 1 was performed using 3,5,5-trimethylhexanal as a raw material to obtain the title compound as a yellow solid.

^X E NMR (CDCI3) δ: 0.88 (s, 9H), 1.22 (d, 3H, = 6.9 Hz), 2.28 (q, 1H, J = 6.9 Hz), 3.78 (s, 3H), 5.76 (br, 2H ), 6.61 (s, 1H). Step 2

6 - (1, 3, 3-trimethyl-butyl) Cheno [2, 3-C ^7] pyrimidin - 4 (M - ON

_{^ NMR (CDC1 3) δ:} 0.89 (s, 9E), 1.36 (d, 3H, = 6.8 Hz), 1.62 (dd, 1H, J = 14.2, 4.4 Hz), 1.77 (dd, 1H, J = 14.2, 7.6 Hz), 3.17 (ddq, 1H, / = 7.6, 6.8, 4.4 Hz), 7.20 (s, 1H), 7.99 (s, 1H), 11.70 (br, 1H).

4-口口 -6- (1,3,3-trimethylbutyl) thieno [2,3-] pyrimidine

^{_{X H NMR (CDC1 3) δ}} : 0.91 (s, 9H), 1.40 (d, 3H, = 7.1 Hz), 1.60 (dd, '1H, J = 13.6, 4.6 Hz), 1.81 (dd, 1H, / = 13.6, 7.3 Hz), 3.27 (m, 1H), 7.11 (s, 1H), 8.77 (s, 1H) .Step 4

4-hydrazino-6- (1,3,3-trimethylbutyl) thieno [2,3-d] pyrimidine

Using the compound obtained in the above Step 3 as a raw material, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a brown solid.

^{X H NMR (CDCI3) δ:} 0.89 (s, 9H), 1.36 (d, 3H, / = 6.8 Hz), 1.56 (dd, 1H, J co 14.1, 4.4 Hz), 1.78 ( dd, 1H, / = 14.1 , 7.6 Hz), 3.19 (dd, 1H, J = 7.6, 4.4 Hz), 6.38 (br, 1H), 6.88 (s, 1H), 8.49 (s, 1H).

2-thienocarboxyaldehyde-[6- (1,3,3-trimethylbutyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Using the compound obtained in the above step 4 as a raw material, the same operation as in step 1 of example 1 was performed to obtain the title compound as a yellow solid.

MS (EI) m / z 358 (It).

'HNMR (CDCI3) δ: 0.94 (s, 9H), 1.42 (d, 3H, 7 = 6.8 Hz), 1.62 (m, 1H), 1.89 (dd, 1H, J: 14.5, 7.6 Hz), 3.26 (m , 1H), 7.08 (dd, 1H, / = 4.9, 3.7 Hz), 7.39 (d, 1H, J: 5.1 Hz), 7.-84 (s, 1H), '8.03 (s, 1H), 8.44 ( s, 1H). [Example 1 1 7]

Step 1.

6-methylcheno [2,3-d] pyrimidine-4 (M-one

Using propionaldehyde as a raw material, the same operation as in step 1 of Example 1 was performed, and then the same operation as in step 2 of Example 1 was performed to obtain the title compound as a brown solid.

_{JH NMR (CDC1 3) δ ··} 2.56 (s, 3H, J "= 1.0 Hz), 7.14 (d, 1H, / = 1.3 Hz), 7.95 (br, 1H). Step 2

4-chloro-6-methylthieno [2,3-d] pyrimidine

Using the compound obtained in the above step 1 as a raw material, the same operation as in step 3 of Example 1 was performed to obtain the title compound as a brown solid.

^: H NMR (CDCI3) δ: 2.66 (d, 3H, J = 1.2 Hz), 7.09 (d, 1H, 1.2 Hz), 8.77 (s, 1H). Step 3

4-hydrazino-6-methylthieno [2,3-d] pyrimidine

The same operation as in Step 1 of Example 1 was performed using the compound obtained in the above Step 2 as a starting material to obtain the title compound as a brown solid.

lE NMR (CDCI3) δ: 2.58 (d, -3Η, / = 1.3 Hz), 6.35 (br, 1H), 6.86 (s, 1H), 8.9 (s, 1H). Process 4

2-thiophenecarboxaldehyde-[6-methylthieno [2,3-d] pyrimidine-4-yl] hydrazone

Using the compound obtained in the above Step 3 as a raw material, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a yellow solid.

MS (EI) m / z 274 (M ⁺ ).

^{_{X H MR (CDC1 3) δ}} : 2.64 (s, 3H), 7.09 (dd, 1H, / = 5.1, 3.7 Hz), 7.26 (br,

1H), 7.40 (d, 1H, / = 5.1 Hz), 7.77 (br, 1H), 8.04 (br, 1H), 8.45 (br, 1H).

[Example 1 1 8]

Process 1

6-pentylthieno [2,3-d] pyrimidine-4 (3τ¾-one

Using heptanal as a raw material, the same operation as in step 1 of Example 1 was punched, and then the same operation as in step 2 of Example 1 was performed to obtain the title compound as a colorless solid.

: H NMR (CDCI3) 5: 0.91 (dt, 3H, J = 7.1, 2.7 Hz), 1.37 (m, 4H), 1.73 (m, 2H), 2.86 (dt, 2H, zo = 8.1, 1.0 Hz), 7.17 (t, 1H, = 1.0 Hz), 7.97 (s, 1H), 11.33 (br, 1H).

4- ク口口 -6-pentylthieno [2, .3-] pyrimidine

Using the compound obtained in the above step 1 as the original substance, the same operation as in step 3 of Example 1 was performed, The compound was obtained as a brown oil.

^{X H NMR (CDCI3) δ 0.92} (dt, 3H, J = 7.1, 1.2 Hz), 1.39 (m, 4H), 1.78 (m, 2H), 2.95 (dt, 2H, 7 "= 8.0, 1.0 Hz), 7.09 (d, 1H, / = 1.2 Hz), 8.77 (s, 1H) .Step 3

4-Hydrazino-6-pentylcheno [2,3rd] pyrimidine ′ Using the compound obtained in the above step 2 as a raw material, the same operation as in step 4 of Example 1 was performed to obtain the title compound as a colorless solid.

^X HNM (CDCI3) δ: 0.91 (d, 3H, zo = 7.1 Hz), 1.37 (m, 4H), 1.73 (m, 2H), 2.87 (t, 2H, = 7.6 Hz), 4.16 (br, 2H) , 6.44 (br, 1H), 6.87 (s, 1H), 8.49 (s, 1H) Step 4 '

2-thiophenecarboxaldehyde-[6-pentylino [2,3-d] pyrimidine-4-yl] hydrazone

Using the compound obtained in the above Step 3 as a raw material, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a pale yellow solid.

MS (EI) m / z 330 (M +).

'HR (CDCI3) δ: 0.93 (t, 3H, zo = 7.1 Hz), 1.3 (m, 4H), 1.82 (m, 2H), 2.95 (t, 2H, / = 7.3 Hz), 7.09 (dd , 1H, ZO = 5.1, 1.5 Hz), 7.25 (br, 1H), 7.40 (d, 1H, / = 4.9 Hz), 7.81 (br, 1H), 8.05 (br, 1H), 8.46 (br, 1H) .

[Example 1 1 9] '

Process 1

Methyl 2-Tamino-5-isobutyl-3-thiophenecarboxylate

4.0 ml of 4-methyl-1-pentanol was added to 60 ml of a dichloromethane solution of 10 g of pyridium chromate chromate at a time, and the mixture was vigorously stirred for 1.5 hours. After adding 80 ml of ether and stirring for about 30 minutes, the mixture was passed through a florisil column (getyl ether) and concentrated to obtain an aldehyde as a colorless oil. Then, to a mixed solution of 2.65 ml of triethylamine and 3.0 ml of -dimethylformamide at room temperature under a nitrogen atmosphere, 1.68 ml of methyl cyano ftate and 2.15 g of the obtained aldehyde were added. The mixture was stirred for 3 minutes, 610 mg of sulfur was added, and the mixture was further stirred for 60 hours. After water was added to the reaction solution, the mixture was diluted and extracted with ethyl acetate. After the organic layer was washed with a saturated saline solution, anhydrous sodium sulfate was added thereto and dried. After removing sodium sulfate by filtration, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography [ethyl acetate: hexane-1: 9 (v / v)] to give the title compound as a pale-yellow oily substance.

MS (ESI) m / z 254 (M + eCl).

_{^ MR (CDC1 3) δ:} 0. 91 (s, 3H), 0. 93 (s, 3H), 1. 73- 1. 81 (m, 1H), 2. 43 (dd, 2H, / = 7 0, 1.5 Hz), 3.79 (s, 3H), 5.77 (br, 2H), 6.60 (s, 1H)

6-isobuchinorecheno [2,3-d] pyrimidine-4 (3H) -one

Using the compound obtained in the above step 1 as a starting material, the same operation as in step 2 of Example 1 was performed to obtain the title compound as a colorless solid. M (DMS0-if ₆ ) δ: 0.91 (s, 3H), 0.93 (s, 3H), 1.82—1.92 (m, 1H), 2.71 (d, 2H, = 7.0 Hz), 7.09 (d, 1H, = 0.5 Hz), 8.05 (s, 1H), 12.42 (br, 1H). Process 3

4-Chloro-6-isobutynorethieno [2,3-d] pyrimidine

Using the compound obtained in the above step 2 as a raw material, the same operation as in step 3 of Example 1 was performed to obtain the title compound as a colorless solid.

MS (FAB) m / z 227 (M + H ⁺ ).

_{'HNMR (CDC1 3) δ ··} 1.00 (s, 3H), 1.03 (s, 3H), 2.00-2.09 (m, 1H), 2.82 (dd, 2H, / = 7.0, 1.0 Hz), 7.09 (d, 1H, / = 1.0 Hz), 8.78 (s, 1H). Process 4

4-Hydrazino-6-isobutylthieno [2,3-d] pyrimi, :)

Using the compound obtained in the above Step 3 as a raw material, the same operation as in Step 4 of Example 1 was performed to obtain the title compound as a colorless solid.

MS (FAB) m / z 223 (M + H +).

lE MR (CDCI3) δ: 0.97 (s, 3H), 0.99 (s, 3H), 1.94-2.00 (m, 1H), 2.74 (d, 2H, J "= 7.0 Hz), 6.48 (br, 1H), 6.86 (s, 1H), 8.51 (s, 1H). Process 5

6-[(Λζ-dimethylamino) methyl] -2-pyridinecarboxaldehyde- [6-isobutylthieno [2,3-] pyrimidine-4-yl] hydrazone

Using the compound obtained in the above step 4 and 6-[(-dimethylamino) methyl] _2-pyridine lipoxyaldehyde as raw materials, the same operation as in step 5 of Example 1 was performed to obtain the title compound as a pale yellow solid. .

MS (FAB) m / z 369 (M + H ⁺ ).

NMR (DMSO- ₆ ) δ: 1.03 (s, 3H), 1.05 (s, 3H), 2.02-2.09 (m, 1H), 2.32 (s, 6H), 2.83 (d, 2H, / = 7.0 Hz), 3.62 (s, 2H), 7.40 (d, 1H, / = 7.5 Hz), 7.75 (s, 1H), 7.78 (d, 1H, = 7.5 Hz), 7.85 (d, 1H, = 7.5 Hz), 8.03 (s, 1H), 8.58 (s, 1H), 9.16 (br, 1H).

[Example 1 20]

Process

2-Amino-5-sec-butyl-3-methyl thiophenecarbonate

Using 3-methyl-: L-pentanol as a raw material, the same operation as in step 1 of Example 119 was performed to obtain the title compound as a pale yellow oily substance.

MS (ESI) m / z 254 (M + MeCN ⁺ ).

NMR (CDC1 ₃ ) δ 0.88 (t, 3H, / = 7.0 Hz), 1.22 (d, 3H, / = 7.0 Hz), 1.50-1.60 (m, 2H), 2.62-2.69 (m, 1H), 3.79 ( s, 3H), 5.79 (br, 2H), 6.62 (s, 1H). Process 2

6- (sec-butyl) cheno [2,3-d] pyrimidine-4 (M-one

Using the compound obtained in the above step 1 as a starting material, the same operation as in step 2 of Example 1 was performed to obtain the title compound as a colorless solid.

^{X H NMR (CDCI3) δ:} 0.93 (t, 3H, / = 7.0 Hz), 1.37 (d, 3H, / = 7.0 Hz), 1.67 -1.74 (m, 2H), 2.93-3.02 (m, 1H), 7.19 (d, 1H, / = 0.5 Hz), 8.04 (s, 1H), 12.53 (br, 1H). 4-black mouth-6-Oec-butyl) Ceno [2,3-d] pyrimidine

Using the compound obtained in the above Step 2 as a raw material, the same operation as in Step 3 of Example 1 was performed to obtain the title compound as a colorless oily substance.

MS (ESI) m / z 267 (M + MeCif).

^{_{X H NMR (CDC1 3) δ}} : 0.95 (t, 3H, = 7.0 Hz), 1.41 (d, 3H, zo = 7.0 Hz), 1.69

— 1.79 (m, 2H), 3.01-3.09 (m, 1H), 7.11 (d, 1H, / = 1.0 Hz), 8.78 (s, 1H).

4-hydrazino-6-Csec-butyl) cheno [2,3-dl pyrimidine

Using the compound obtained in the above Step 3 as a raw material, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a colorless solid.

MS (FAB) m / z 223 (thigh +).

'H-MR (CDCI3) δ: 0.91 (t, 3H, J = 7.0 Hz), 1.36 (d, 3H, J "= 7.0 Hz), 1.64

— 1.72 (m, 2H), 2.91-2.99 (m, 1H), 6.57 (br, 1H), 6.89 (s, 1H), 8.50 (s, 1H).

6-[(^ -Dimethylamino) methyl] -2-pyridi ^ carboxaldehyde-[6-C? Ec-butyl) thieno [2,3-d] pyrimidin-4-yl] hydrazone

6-[(JV, N-dimethylamino) methyl] -2-pyridine power Using the compound obtained in step 4 above, the same operation as in example 43 was carried out using ruboxaldehyde as the starting material. Obtained as a solid.

MS (FAB) m / z 369 (M + H ⁺ ).

^: H NMR (DMSO- ₆ ) δ 0.98 (t, 3H, = 7.0 Hz), 1.43 (d, 3H, = 7.0 Hz), 1.73-1.82 (m, 2H), 2.33 (s, 6H), 3.04-3.09 (m, 1H), 3.62 (s, 2H), 7.40 (d, 1H, / = 7.5 Hz), 7.76 (s, 1H), 7.80 (d, 1H, = 7.5 Hz), 7.85 (d, 1H, = 7.5 Hz), 8.03 (s, 1H), 8.53 (s, .1H), 9.22 (br, 1H). [Example 121]

CHO

Process 3

Process 1

2-Amino-5-0? -Propyl) -methyl 3-thiophenecarboxylate

The same operation as in step 1 of Example 1 was performed using pentanal as a thickener to obtain the title compound as a colorless solid.

MS (EI) m / z 199 (M ").

^{_{1 YL MR (CDC1 3) δ}} 0.94 (t, 3H, zo = 7.0 Hz) 1.55-1.64 (m, 2H), 2.54 (t, 2H, = 7.0 Hz) 3.78 (s 3H), 5.77 (br, 2H 6.61 (s, 1H). Step 2

6-, n-Pup pill) Cheno [2,3-d] pyrimidine-4 (3-on

The same operation as in step 2 of Example 1 was performed using the compound obtained in the above-mentioned step 1 as a raw material to obtain the title compound as a colorless solid.

MS (EI) m / z 194 Q).

lENMR (DMSO- ₆ ) δ 1.81-2.01 (m 2H), 2.10-2.19 (m, 2H), 2.34-2.41 (m 2H), 7.11 (s, 1H), 8.06 (s 1H), 12.43 (br, 1H ). Process 3

4-chloro-6-propyl) thieno [2,3-d] pyrimidine

The same operation as in step 3 of Example 1 was performed using the compound obtained in the above-mentioned step 2 as a starting material to obtain the title compound as a colorless oily substance.

^X H NMR (CDCI3) δ: 1.04 (t 3H, = 7.0 Hz), 1.77-- 1.86 (m 2H), 2.93 (t 2H, 7.0 Hz), 7.10 (s, 1H), 8.77 (s, 1H). Process 4

4-hydrazino-6- (fl-f.mouth pill) cheno [2,3-d] pyrimidine

MS (EI) m / z 208 (M ⁺ ).

_{NMR (CDC1 3) δ: 1.00} (t, 3H, / = 7.0 Hz), 1.71- 1.80 (m, 2H), 2.83-2.88 (m, 2H), 6.51 (br, 1H); 6.87 (s, 1H) , 8.50 (s, 1H). Process 5

6-[(^-dimethylamino) methyl] -2-pyridinecarboxaldehyde- [6-pyryl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

The compound obtained in the above step 4 6-[(Λζ-dimethylamino) methyl] -2-pyridine power Using ropoxyaldehyde as a raw material, the same operation as in step 1 of Example 1 is performed to give the title compound as a pale yellow color Obtained as a solid.

MS (FAB) m / z 355 (M + H ⁺ ).

^X H MR (DMSO- ₆ ) δ: 1.07 (t, 3H, / = 7.0 Hz), 1.81-1.88 (m, 2H), 2.33 (s, 6H), 2.94 (t, 2H, zo = 7.0 Hz), 3.62 (s, 2H), 7.39 (d, 1H, J = 7.5 Hz), 7.75 -7.79 (m, 2H), 7.85 (d, 1H, J = 7.5 Hz), 8.03 (s, 1H), 8.52 (s , 1H), 9.33 (br, 1H).

[Example 122]

Process 1

Starting from methyl citronellal 2-amino-3- (1,5-dimethyl-4-hexenyl) -3-thiophenecarboxylate, the same operation as in step 1 of Example 1 was carried out to give the title compound as a yellow oil. Obtained.

MS (FAB) m / z 268 (M + H ⁺ ).

^{_{X H MR (CDC1 3) δ}} : 1.22 (d, 3H, / = 6.9 Hz), 1.48- 1.60 (m, 1H), 1.57 (s, 3H), 1.68 (d, 3H, / = 1.0 Hz), 1.96 (dd, 2H, / = 14.9, 7.3 Hz), 2.75 (m, 1H), 3.79 (s, 3H), 5.06-5.10 (m, 1H), 6.61 (d, 1H, zo = 0.7 Hz). Process 2

4- ク口口 -6- (1,5-Dimethyl-4-hexenyl) thieno [2,3-d] pyrimidine

Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Example 1 was performed, and then the same operation as in Step 3 of Example 1 was performed to obtain the title compound as a yellow oily substance. MS (FAB) m / z 281 (M + H ⁺ ).

^ NMR (CDCI3) δ: 1.41 (d, 3H, / = 6.9 Hz), 1.56 (s, 3H), 1.69 (s, 3H), 1.70 -1.98 (m, 2H), 2.01 (q, 2H, zo = 7,3Hz), 3.14 (dd, 1H, J 23.7, 6.8 Hz), 5.09 (t, 1H, / = 7.3 Hz), 7.09 (s, 1H), 8.77 (s, 1H).

6- (1,5-dimethyl-4hexenyl) -4-hydrazinothieno [2,3-d] pyrimidine

Using the compound obtained in the above Step 2 as a raw material, the same operation as in Step 4 of Example 1 was performed to obtain a target. The title compound was obtained as a colorless solid.

MS (FAB) m / z 277 (M + H ⁺ ).

NMR (CDCI3) δ: 1.36 (d, 3H, / = 6.9 Hz), 1.55 (s, 3H), 1.68 (s, 3H), 1.58-1.77 (m, 2H), 1.98 (dt, 2H, / = 14.7 , 7.3 Hz), 3.02-3.09 (m, 1H), 5.07-5.11 (m, 1H), 6.50 (br s, 1H), 6.89 (s, 1H), 8.9 (s, 1H).

3-[(Λζ-dimethylamino) methyl] benzaldehyde-[6- (1,5-dimethyl-4-hexenyl) cheno [2,3-d] pyrimidine-4-yl] hydrazone

Using the compound obtained in the above step 3 and the compound obtained in the step 2 of Reference Example 1 as a raw material, the same operation as in the step 5 of Example 1 was performed to obtain the title compound as a yellow solid.

MS (FAB) m / z 422 (M + H ⁺ ).

^{X H NMR (CDCL) δ:} 0.88 (dd, 3H, .7 = 6.6, 2.2 Hz), 34- 39 (m, 3H), 1.44

(dd, 3H, / = 6.8, 1.0 Hz), 1.67 (s, 3H), 1.70—1.85 (m, 2H), 2.05 (m, 1H), 2.29 (s, 6H), 3.10-3.17 (m, 1H ), 3.49 (s, 2H), 5.11-5.15 (m, 1H), 7.36 (d, 1H, = 7.6 Hz), 7.41 (t, 1H, / = 7.6 Hz), 7.66 (s, 1H), 7.84 ( d, 1H, J: 1.0 Hz), 7.88 (s, 1H), 8.49 (s, 1H), 9.02 (br s, 1H).

[Example 123]

Process 1-

2-amino-4,5,6,7-tetrahydro-1--methyl-zonothiophen-3-carboxylate The same operation as in Step 1 of Example 1 was carried out using hexoxanone as a raw material to obtain the title compound as a colorless solid.

_{l NMR (CDC1 3) δ:} . 1.75 (m, 4H), 2.49 (m, 2H), 2.68 (m, 2H), 3.78 (s, 3H), 5.92 (br, 2H) Step 2

5,6,7,8-tetrahydro [1] benzothieno [2,3-d] pyrimidine _4 (3¾-one

^{X H NMR (CDCI3) δ:} . 1.87 (m, 4H), 2.79 (m, 2H), 3.03 (m, 2H), 7.93 (s, 1H), 8.22 (br, 1H) Step 3

4-c-mouth- 5,6,7,8-tetrahydro [1] benzothieno [2,3-d] pyrimidine

The same operation as in step 3 of Example 1 was performed using the compound obtained in the above-mentioned step 2 as a raw material to obtain the title compound as a colorless solid.

^{X H NMR (CDCI3) δ:} . 1.56 (m, 4H), 1.93 (m, 4H), 2.90 (m, 2H), 3.11 (m, 2H), 8.72 (s, 1H) Step 4

4-Hydrazino-5,6,7,8-tetrahydro [1] benzothieno [2,3-] pyrimidine Using the compound obtained in the above step 3 as a raw material, the same operation as in step 4 of Example 1 is performed to give the title compound. Obtained as a pale yellow solid.

^{X H NMR (CDCI3) δ:} 1.90 (m, 4H), 2.81 (m, 2H), 2.89 (m, 2H), 4.15 (br, 2H), 6.50 (br, 1H), 8.46 (s, 1H). Process 5-

2-thiophenecarboxaldehyde-(5,6,7,8-tetrahydro [1] benzothieno [2,3-d] pyrimidine-4-yl) hydrazone

The same operation as in step 5 of Example 1 was performed using the compound obtained in the above-mentioned step 4 as a raw material to obtain the title compound as a yellow solid.

MS (EI) m / z 314 (M ⁺ ).

_{'HM (CDC1 3) δ:} 1.91 (br, 4H), 2.82 (br, 2H), 3.05 (br, H), 3.33 (br, 2H), 7.08 (m, 1H), 7. 0 (d, 1H , / = 3.7 Hz), 7.58 (d, 1H, zo = 47 Hz), 7.71 (s, 1H), 7.95 (s, 1H).

[Example 1 24]

, 0 Process 1

Process

Process 1

5-Ethyl-6-methylcheno [2,3-d] pyrimidine-4 (M-one

Using 3-pentanone as a raw material, the same operation as in step 1 of Example 1 was performed, and then the same operation as in step 2 of Example 1 was performed to obtain the title compound as a brown solid.

^{X H NMR (CDCI3) δ:} 1.19 (t, 3H, / = 7.3 Hz), 2.44 (s, 3H), 2.96 (q, 2H, J = 7.3 Hz), 7.96 (s, 1H), 12.06 (br, 1H). Process 2

4-kuro-5-ethyl-6-methylcheno [2,3-] pyrimidine

Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 3 of Example 1 was performed to obtain the title compound as a brown oily substance.

^{X H NMR (CDCI3) δ:} 1.24 (t, "3H, / = 7.6 Hz), 2.55 (s, 3H), 3.05 (q, 2H, J = 7.6 Hz), 8.73 (s, 1H). Process 3

5-ethyl-4-hydrazino-6-methylthieno [2,3-d] pyrimidine

Using the compound obtained in the above step 2 as a raw material, the same operation as in step 1 of example 1 was performed to obtain the title compound as a pale brown solid.

^{_{: H NMR (CDC1 3) δ}} : 1.25 (t, 3H, = 7.8 Hz), 2.61 (s, 3H), 2.78 (q, 2H, J = 7.8 Hz), 4.22 (br, 2H), 6.55 (br, 1H), 8.48 (s, 1H) .Step 4

2-thiophenecarboxaldehyde N- (5-ethyl-6-methylcheno [2,3-dJpyrimidine-4-yl) hydrazone

Using the compound obtained in the above Step 3 as a starting material, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.

MS (EI) m / z 303 ().

^{J H NMR (CDCI3) δ:} 1.24 (t, 3H, J = 7.3 Hz), 2. 6 (s, 3H), 3.31 (q, 2H, J = 7.3 Hz), 7.10 (dd, 1H, / = 5.1 , 3.9 Hz), 7.42 (dd, 1H, / = 3.7, 0.7 Hz), 7.57 (d ,, 1H / = 5.1 Hz), 7.74 (s, 1H), 7.95 (s, 1H).

[Example 1 2 5]

Process 1

2-Amino. Methyl -4,7-dihydro-5-thieno [2,3-c] pyran-3-carboxylic acid

Using tetrahydro-W-pyran-4-one as a raw material, the same operation as in step 1 of Example 1 was performed. The title compound was obtained as a yellow solid.

_{MR (CDC1 3) δ: 2.82} (m, 2H), 3.80 (s, 3H), 3.91 (dt, 2H, / = 5.6, 0.7 Hz), 4.56 (d, 2H, J = 1.2 Hz), 5.99 (br , 2H). Process 2

3,5,6,8-Tetrahydro-4y-pyrano [4,, 3 ': 4,5] thieno [2,3-d] pyridin-4-one Using the compound obtained in the above step 1 as a raw material, The same operation as in Step 2 of Example 1 was performed to obtain the title compound as a brown solid.

_{NMR (CDC1 3) δ:.} 3.12 (m, 2H), 4.03 (m, 2H), 4.82 (s, 2H), 7.89 (s, 1H) Step 3

4- ク口口 -5, 8-dihydro-6-pyrano [4,3 ': 4,5] thieno [2,3-d] pyrimidine

Using the compound obtained in the above Step 2 as a raw material, the same operation as in Step 3 of Example 1 was performed to obtain the title compound as a pale brown solid.

^ NMR (CDCI3) δ: 3.21 (ηι, 2H), 4.08 (m, 2H), 4.90 (t, 2H, / = 2.0 Hz), 8.76 (s, 1H). Step 4

4-Hydrazino-5,8-dihydro-6-pyrano [4 ', 3,: 4,5] thieno [2,3-] pyrimidine The compound obtained in the above step 3 was used as a starting material, The same operation was performed to obtain the title compound as a pale brown solid.

^{X H NMR (CDCI3) δ:} 3.00 (m, 2H), 4.07 (t, 2H, / = 5.6 Hz), 4.19 (br, 2H),

4.85 (t, 2H, / = 2.0 Hz), 6.42 (br, 1H), 8.49 (s, 1H).

2-thiophenecarpoxyaldehyde-(5,8-dihydro-6-pyrano [4,, 3 :: 4,5] thieno [2,3-] pyrimidin-4-yl) hydrazone

Using the compound obtained in the above step 4 as the original compound, the same operation as in step 5 of Example 1 was performed. The compound was obtained as a yellow solid.

MS (EI) m / z 317 (¾f).

^: H MR (CD \ cC \ I3) δ3.44 (br, 2H), 4.08 (t, 2H, / = 5.6 Hz), 4.86 (s, 2H) _: 7.10 (t, 1H, one f-3.9 Hz ), 7.40 (d, 1H, / = 3.4 Hz), 7.58 (d, 1H, / = 4.6 Hz) _: 7.46 (s, 1H), 7.96 (s, 1H).

[Example 126]

C0 „Me process 1

,thigh.

Process 3

Process 1

Thieno [3,2-d] pyrimidin-4 (3) -one

The same operation as in step 1 of example 1 was performed using methyl 3-amino-2-thiophenecarboxylate as a raw material to obtain the title compound as a brown solid.

^X H NMR (CDCI3) δ 7.42 (d, 1H, / = 5.4 Hz), 7.88 (d, 1H, J = 5Λ Hz), 8.16 (s, 1H).

4-c-mouth thieno [3,2-d] pyrimidine

^: H NMR (CDCI3) δ: 7.61 (d, 1H, J: 5.6 Hz), 8.06 (d, 1H, J: 5.4 Hz), 8.99 (s, 1H). Step 3-

4-Hydrazinothieno [3,2-d] pyrimidine Using the compound obtained in the above Step 2 as a raw material, the same operation as in Step 4 of Example 1 was performed to obtain the title compound as a yellow solid.

^{_{X H NMR (CDC1 3) δ}} : 4.83 (br, 2H), 7.27 (d, 1H, / = 5. Hz), 8.05 (d, 1H, J = 5.4 Hz), 8.25 (s, 1H), 8.91 ( br, 1H). Process 4

2-thiophenecarboxyaldehyde-thieno [3,2-] pyrimidine-4-ylhydrazone

Using the compound obtained in the above Step 3 as a raw material, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a pale yellow solid.

MS (EI) m / z 260 (M +).

lE NMR (CDCI3) δ: 7.10 (dd, 1H, 5.1, 3.7 Hz), 7.30 (dd, 1H, / = 3.7, 0.5 Hz), 7.44 (d, 1H, = 5.1 Hz), 7.47 (d, 1H, Zo = 5.4 Hz), 7.97 (d, 1H, = 5.6 Hz), 8.09 (s, 1H), 8.64 (s, 1H).

[Example 127]

Process 3

Process 1

2- (benzoylamide) -5-ethyl-3-thiophencarboxamide

1.82 g of 2-amino-5-ethyl-3-thiophenecarboxamide (hem. Ber. 1996, 99, 94) was dissolved in 55 ml of benzene, and 5.5 ml of triethylamine and 1.7 ml of benzoyl chloride were added at room temperature. , 100. The mixture was heated under reflux at C for 3 hours. The mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give the title compound (2.78 g) as a pale-brown solid. 'H MR (CDCI3) δ: 1.33 (t, 3H, zo = 7.6 Hz), 2.80 (q, 2H, 7.6 Hz), 6.71 (t, 1H, 1.0 Hz), 7.36 (s, 1H), 7.50—7.57 (m, 3H), 8.02 (dd, 2H, J = 7.1, 1.4 Hz).

6-Ethyl_2-phenylthieno [2,3-d] pyrimidine-4 (3-one

To 2.78 g of the amide obtained in the above step 1, 50 ml of a 2N aqueous sodium hydroxide solution was added, and the mixture was heated under reflux at 100 ° C. for 2 hours. The reaction solution was cooled to room temperature, 1N hydrochloric acid was added, and the precipitated crude product was subjected to silica gel chromatography [ethyl acetate:? -Hexane = 1: 2 (v / v)] to give 700 mg of the title compound in pale yellow color Obtained as a solid.

_{NMR (CDC1 3) δ: 1.39} (t, 3H, / = 7.6 Hz), 2.91 (q, 2H, = 7.6 Hz), 7.25 (s, 1H), 7.55 (111, 3H), 8.11 (m, 2H) , 11.09 (br, 1H). Process 3

6-Ethyl-4-hydrazino-2-phenylthieno [2,3-d] pyrimidine

Using the compound obtained in Step 2 as a raw material, the same operation as in Step 3 of Example 1 was performed, and then the same operation as in Step 4 of Example 1 was performed to obtain the title compound as a colorless solid.

XH NMR (CDCI3) δ: 1.38 (t, 3H, = 7.6 Ηζ) '2.92 (q, 2H, J = 7.6 Hz), 4.28 (br, 2H), 6.36 (br, 1H), 6.85 (s, 1H) , 7.45 (m, 3H), 8.47 (m, 2H). Process 4

2-thiophenecarboxya / redehyde- (6-ethyl-2-phenenothieno [2,3-d] pyrimidine-4-yl) hydrazone

MS (EI) m / z 364 (it).

^: H NMR (CDCI3) δ: 1.47 (t, 3H, / = 7.6 Hz), 3.00 (q, 2H, -7.6 Hz), 7.07 (dd, 1H, / = 5.1, .1 Hz), 7.24 (br, 1H), 7.37 (d, 1H, / = 4.9 Hz), 7.46 (m, 3H), 7.82 (s, 1H), 7.93 (br, 1H), 8.1 (d, 2H, / = 6.8 Hz), 9.10 (br, 1H).

[Example 1 28]

Process 1

-Acetyl-2- (acetylamino) -5-ethyl-3-thiophenecarboxamide

1.57 g of 2-amino-5-ethyl-3-thiophencarpoxamide [phem. Ber. 1996, 99, 94) was dissolved in 32 ml of acetic anhydride, and the mixture was refluxed under heating at 140 ° C for 3.5 hours. After returning the reaction solution to room temperature, it was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium carbonate, a saturated saline solution, a saturated sodium bicarbonate solution and a saturated saline solution in this order, and the organic layer was dried over anhydrous sodium sulfate. After the sodium sulfate was removed by filtration, the solvent was partially distilled off under reduced pressure, and the precipitated solid was collected by filtration to obtain 550 rag of the title compound as a pale brown solid.

_{H MR (CDC1 3) δ:} 1.30 (t, 3H, J: 7.6 Hz), 2.29 (s, 3H), 2.57 (s, 3H), 2.75 (q, 2H, / - 7.6 Hz), 6.64 (s, 1H), 8.22 (br, 1H), 11.37 (br, 1H).

6-Ethyl-2-methylthieno [2,3-d] pyrimidine-4 (3-one

To 70 ml of a ethanol solution of 3.35 g of the compound obtained in the above step 1, 2.69 g of sodium methoxide was added at room temperature, and the mixture was heated and refluxed at 100 ° C for 3.5 hours. The reaction solution was returned to room temperature, the solvent was distilled off under reduced pressure, diluted with ethyl acetate and water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtering off sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.45 g of the title compound as a brown solid.

XH NMR (CDCI3) δ: 1.35 (t, '3H, J = 7.6 Hz), 2.55 (s, 3H), 2.87 (q, 2H, J = 7.6 Hz), 7.13 (d, 1H, = 1.1 Hz). Process 3

4-chloro-6-ethyl-2-methylthieno [2,3-^] pyrimidine

The same operation as in step 3 of Example 1 was carried out using the compound obtained in the above step 2 as a starting material, to obtain the title compound as a brown oily substance.

^{_{X H NMR (CDC1 3) δ}} '· 1.40 (t, 3H, / = 7.3 Hz), 2.78, (s, 3H), 2.96 (q, 2H, J = 7.3 Hz), 7.04 (s, 1H). Step Four

6-Ethyl-4-hydrazino-2-methylthieno [2,3-d] pyrimidine

The same operation as in step 4 of Example 1 was carried out using the compound obtained in the above step 3 as a starting material to obtain the title compound as a yellow oily substance.

NMR (CDCI3) δ: 1.35 (t, 3H, / = 7.6 Hz), 1.74 (br, 2H), 2.63 (s, 3H), 2.89 (q, 2H, zo = 7.6 Hz), 6.44 (br, 1H) , 6.84 (s, 1H). Process 5

2-thiophenecarboxaldehyde-(6-ethyl-2-methylthieno [2,3-] pyrimidine-4-yl) hydrazone

Using the compound obtained in the above Step 4 as a raw material, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a pale brown solid.

MS (EI) m / z 302 (M ").

^X NMR (CDCI3) δ: 1.43 (t, 3H, / = 7.6 Hz), 2.59 (d, 3H, J = 1.7 Hz), 2.95 (q, 2H, / = 7.6 Hz), 7.08 (dd, 1H, = 4.9, 3.4 Hz), 7.24 (d, 1H, / = 3. Hz), 7.37 (dd, 1H, J = 4.9, 0.7 Hz), 7.75 (br, 1H), 8.01 (br, 1H). [Example 1 2 9]

.τ'Ν

S eight w

Process

6- (ί-butyl) -4- (1-methylhydrazino) cheno [2,3-d] pyrimidine

Example 30 The same operation as in Step 4 of Example 1 was carried out using the compound obtained in Step 3 and methylhydrazine as the starting material, to give the title compound as a colorless solid.

_{MR (CDC1 3) δ:.} 1.42 (s, 9H), 3.51 (s, 3H), 4.17 (br, 2H), 7.77 (s, 1H), 8.38 (s, 1H) Step 2

Benzaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl]--Methylhydrazone

The same operation as in Step 1 of Example 1 was performed using the compound obtained in Step 1 and benzaldehyde as raw materials to obtain the title compound as a pale yellow solid.

MS (FAB) m / z 325 (M + H ⁺ ).

'Ε NMR (DMSO- ₆ ) δ: 1.49 (s, 9H), 3.82 (s, 3H), 7.39-7.47 (m, 3H), 7.77 (d, 2H, / = 7.0 Hz), 7.88 (s, 1H) ), 8.08 (s, 1H), 8.56 (s, 1H).

[Example 13] Skin

Process

⁶ -[(JV, ジメチル -dimethylamino) methyl]-2-pyri, de-[6- (ί-butyl) cheno [2, 3-d] pyrimidine-4-yl]--methylhydrazone

Example 12 9 The compound obtained in Step 1 and 6 _ [(Λζ-dimethylamino) methyl] -2-pi The same operation as in Step 1 of Example 1 was performed using lysine carboxaldehyde as a raw material to obtain the title compound as a pale yellow solid.

MS (FAB) m / z 383 (M + H ⁺ ).

'HNMR (DMSO- ₆ ) δ: 1.49 (s, 9H), 2.33 (s, 6H), 3.63 (s, 2H), 3.83 (s, 3H), 7.37 (d, 1H, / = 7.5 Hz), 7.73 (t, 1H, / = 7.5 Hz), 7.91 (d, 1H, / = 7.5 Hz), 8.03 (s, 1H), 8.59 (s, -1H).

[Example 1 3 1]

Process 1

Methyl 2-amino-5-cyclopropyl-3-thiophenecarboxylate

The same operation as in step 1 of Example 1 19 was carried out using 2-cyclopropyl-1-ethanol as a raw material to obtain the title compound as a pale yellow solid.

MS (EI) m / z 197

'Ε MR (CDC1 ₃ ) δ0.60--0.67 (m, 2Η), 0.80--0.86 (m, 2Η), 1.77—1.83 (m, 1H), 3.78 (s, 3H), 5.78 (br, 2H) , 6.59 (s, 1H). Process 2

6-cyclopropylcheno [2,3-d] pyrimidin-4 (3) -one

MS (EI) m / z 192 (¾f) .-

^X H NMR (DMSO-) δ: 0.76-0.80 (m, 2H), 1.03-1.07 (m, 2H), 2.16-2.22 (m, 1H), 7.06 (s, 1H), 8.04 (s, 1H), 12.41 (br, 1H). Process 3

4-Black mouth-6-Six mouth propylcheno [2,3-d] pyrimidine

^{_{X H MR (CDC1 3) δ}} : 0.92-1.00 (m, 2H), 1.14-1.22 (m, 2H), 2.19-2.25 (m, 1H), 7.04 (d, 1H, / = 1.0 Hz), 8.75 ( s, 1H). Step 4

6-cyclopropyl-4-hydrazinothieno [2,3-d] pyrimidine

MS (EI) m / z 206 (¾f).

^X H NMR (CDCI3) δ: 0.81-0.86 (m, 2H), 1.08-1.12 (m, 2H), 2.11-2.18 (m, 1H), 6.39 (br, 1H), 6.85 (d, 1H, zo = 1.0 Hz), 8.48 (s, 1H). Process 5

6- (, -Dimethylamino) methyl-2-pyridinecarboxaldehyde-(6-cyclopropylpropyleno [2,3-d] pyrimidin-4-yl) hydrazone

Using the compound obtained in the above Step 4 and 6- (Λζ-dimethylamino) methyl-2-pyridine lipoxyaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a pale yellow solid. .

MS (FAB) m / z 352 (M + H ⁺ ).

^ NMR (DMS0-) δ: 0.90-0.96 (m, 2H), 1.12—1.23 (m, 2H), 2.22-2.26 (m, 1H), 2.33 (s, 6H), 3.62 (s, 2H), 7.40 (d, 1H, 7.5 Hz), 7.76 (s, 1H), 7.79 (d, 1H, / = 7.5 Hz), 7.86 (d; 1H, / = 7.5 Hz), 8.02 (s, 1H), 8.51 (s , 1H), 9.17 (br, 1H). [Example 132]

Process 1

2-Amino-5-cyclohexyl butyl-3-thiophenecarboxylate

The same operation as in Step 1 of Example 19 was carried out using 2-cyclohexyl butyl-1-ethanol as a raw material to obtain the title compound as a pale yellow oily substance.

_{'H MR (CDC1 3) δ} :. 1.79-2.34 (m, 6H), 3.40-3.49 (m, 1H), 3.79 (s, 3H), 5.79 (br, 2H), 6.62 (s, 1H) Step 2

6-cyclobutylthieno [2,3-d] pyrimidine-4 (3-one

MS (EI) m / z 206 (If).

'Η NM (DMS0-i ₆ ) δ: 1.81-2.01 (m, 2H), 2.10-2.19 (m, 2H), 2.34-2.41 (m, 2H), 7.11 (s, 1H), 8.06 (s, 1H ), 12.43 (br, 1H) .- Step 3

4-chloro-6-cyclobutyltyleno [2,3-d] pyrimidine

lE MR (CDCI3) δ: 1.94-2.17 (m, 2H), 2.25-2.34 (m, 2H), 2.7-2.55 (m, 2H) 2H), 3.78-3.87 (m, 1H), 7.08 (d, 1H, = 1.0 Hz), 8.77 (s, 1H).

6-small mouth petit / le-4-hydrazinothieno [2,3-d] pyrimidine

MS (EI) m / z 220

_{lE NMR (CDC1 3) δ:} 1.90-2.12 (m, 2H), 2.19- 2.29 (m, 2H), 2.42-2.50 (m, 2H), 3.71-3.80 (m, 1H), 6.43 (br, 1H) , 6.86 (d, 1H, = 1.0 Hz), 8.50 (s, 1H).

6- (N, -dimethylamino) methyl-2-pyridinecarboxaldehyde H-cyclobutythieno [2,3-d] pyrimidine-4-yl) hydrazone

Using the compound obtained in the above step 4 and 6-dimethylamino) methyl-2-pyridine lipoxyaldehyde as raw materials, the same operation as in step 1 of Example 1 was performed to obtain the title compound as a pale yellow solid.

MS (FAB) m / z 367 (M + H ⁺ ).

^! HNMR (DMSO-) δ: 1.98-2.16 (m, 2H), 2.30-2.37 (m, 2H), 2. 8-2.55 (m, 2H), 2.33 (s, 6H), 3.63 (s, 2H) , 3.82-3.89 (m, 1H), 7.40 (d, 1H, / = 7.5 Hz), 7.76 (d, 1H, / = 7.5 Hz), 7.79 (s, 1H), 7.86 (d, 1H, J = 7.5 Hz), 8.03 (s, 1H), 8.52 (s, 1H), 9.19 (br, 1H).

[Example 133]

Process 1

4-Hydrazino-2-methylph [2,3-b] pyridine

Using 4-methyl-2-methylfuro [2,3-] pyridine J. Heterocyclic. Chem. 1998, 35, 1237) as the starting material, the same operation as in Step 4 of Example 1 was performed to obtain the title compound as a colorless solid. Was.

MS (EI) m / z 163 (¾f).

_{'HNMR (CDC1 3) δ:} 2.35 (s, 3H), 4.36 (br, 2H), 6.62-6.63 (m, 2H), 7.75 (d,

1H, = 5.5 Hz), 7.94 (br, 1H). Process 2

2-thiophenecarboxyaldehyde-(2-methylfuran [2,3-d] pyrimidine-4-yl) hydrazone

The same operation as in step 5 of Example 1 was performed using the compound obtained in the above-mentioned step 1 as a raw material to obtain the title compound as a pale yellow solid.

MS (FAB) m / z 258 (M + H ⁺ ).

^{_{X H NMR (DMSO- 6) δ}} : 2.45 (s, 3H), 6.76 (d, 1H, zo = 5.0 Hz), 6.83 (d , 1H, / = 1.0 Hz), 7.37 (dd, 1H, / = 3.5 , 1.0 Hz), 7.58 (dd, 1H, = 5.0, 1.0 Hz), 7.89 (d, 1H, 5.0 Hz), 8.26 (s, 1H), 11.07 (br, 1H).

[Example 134]

Process 1

4-hydrazino-2-methylph [3; 2-c] pyridine

4-methyl-2-methylfuro [3,2-c] pyridine {J. Heterocyclic. Chem. 1998, 35, 1237) was used as a starting material, and the same operation as in step 4 of example 1 was performed to obtain the title compound as a colorless solid.

MS (EI) m / z 163).

_{H NM (CDC1 3) δ:} . 2.44 (s, 3H), 5.90 (br, 1H), 6.85 (dd, 1H, / = 5.5, 0.5 Hz), 7.95 (d, 1H, J = 5.5 Hz) - Step Two

2-thiophenecarboxyaldehyde- (2-methylfuro [3,2-c] pyrimidine-4-yl) hydrazone

MS (EI) m / z 257 (M ⁺ ).

^{X H NMR (CDCI3) δ:} 2.50 (s, 3H), 6.91 (d, 1H, / = 5.5 Hz), 7.04-7.06 (m, 2H), 7.15-7.16 (m, 1H), 7.30 (d, 1H , / = 5.0 Hz), 7.90 (br d, 1H, /-5.0 Hz), 7.97 (s, 1H).

[Example 1 3 5]

Process 1

4-hydrazino-2-methylcheno [3,2-c] pyridine

4 - black port - 2 -.. Methylthieno [3, ² -c] pyridine J. Med Chem 1989, 32, 1147 ) was used as a starting material, the same procedure as in Example 1, Step 4, the title compound as a colorless solid Especially o ―

MS (EI) m / z 179 QT). ^{_{2 H NMR (CDC1 3) δ}} : 2.59 (s, 3H), 6.04 (br, 1H), 6.89 (d, 1H, = 0.5 Hz), 7.12 (d, 1H, = 5.5 Hz), 7.96 (d, 1H , /--5.5 Hz). Step 2

2-thiophene lipoxydehyde- (2-methylthieno [3,2-c] pyrimidine-4-yl) hydrazone

The same operation as in Step 1 of Example 1 was performed using the compound obtained in the above Step 1 as a starting material, to give the title compound as a yellow solid.

MS (FAB) m / z 273 (M ⁺ ).

NMR (CDCI3) δ: 2.63 (s, 3H), 7.04-7.06 (m, 2H), 7.24 (d, 1H, / = 2.5 Hz), 7.26 (br, 1H), 7.30 (d, 1H, / = 5.0 Hz), 7.96 (m, 2H).

[Example 1 3 6]

S, N process 1

2- {4- [2-({4-[(jV, N-dimethylamino) methyl] phenyl} methylidene) hydrazino] thieno [2,3-d] pyrimidine-6-yl} -2-methyl Propyl power rubamic acid

50 mg of the compound obtained in Example 96 was dissolved in 1.0 ml of ethyl acetate, and 0.016 ml of tric-mouth acetyl isocyanate was added under ice cooling, followed by stirring at the same temperature for 1 hour. n-Hexane was added, and the precipitated solid was collected by filtration and dried. The obtained crude rubamic acid form was dissolved in 1.5 ml of methanol, 10.6 mg of sodium formate and 0.2 ml of water were added, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the obtained residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. Dry with anhydrous sodium sulfate After drying and distilling off the solvent, the residue was developed and purified by silica gel thin-layer chromatography [black-mouthed form: methanol _: 5 _: 1 (v / v)] to obtain 2.9 mg of the title compound as a yellow solid.

MS (FAB) m / z 427 (M + H +).

'H MR (DMSO- ₆ ) δ: 1.44 (s, 6H), 2.16 (s, 6H), 3.30 (s, 2H), 3.42 (s, 2H), 4.09 (s, 2H), 7.39 (d, 2H , 8.0 Hz), 7.67 (d, 2H, zo = 8.0 Hz), 7.90 (b »: rs, 2H), 8.23 (s, 1H), 8.43 (s, 1H).

[Example 1 3 7]

Process 1 +

(3i?) -4-{[-butyl (diphenyl) silyl] oxy}}-3-methylbutyl aldehyde

(25)-5.00 g of methyl 3-hydroxy-2-methylpropionate, 11.5 ml of ί-butyldiphenylsilyl chloride, and 3.46 g of imidazole were dissolved in 100 ml of dichloromethane and stirred at room temperature for 3 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 100 ml of ethanol, and gradually added to 200 ml of an ethanol solution containing 24.9 g of Shiridani calcium 'dihydrate and 6.4 g of sodium borohydride at _25 ° C. The mixture was stirred at room temperature for 19 hours, added with 169 ml of 1N aqueous hydrochloric acid under ice cooling, neutralized with sodium hydrogen carbonate, and filtered through celite. The filtrate was evaporated under reduced pressure, water was added to the obtained residue, extracted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained hydroxide is dissolved in 90 ml of dichloromethane, and 260 mg of 4-dimethylaminopyridine, 7.0 ml of triethylamine are added under ice-cooling. 12.4 g of ruensulfonyl chloride was added and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 15.5 g of the obtained colorless oil was dissolved in 30 ml of dimethyl sulfoxide, 3.08 g of sodium cyanide was added, and the mixture was stirred at 50 ° C for 6 hours. Water was added to the reaction solution, extracted with getyl ether, and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography [-hexane: ethyl acetate = 20: 1 (v / v)] to obtain 12.2 g of a cyano compound as a colorless oily substance. The obtained cyano compound was dissolved in 200 ml of dichloromethane, cooled to 178 ° C, and 35 ml of 1M diisobutylaluminum hydride (toluene solution) was added dropwise. The mixture was stirred at the same temperature for 2.5 hours. To the reaction solution were added a 1N aqueous hydrochloric acid solution and a saturated aqueous solution of Uschel salt, extracted with chloroform, and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography hexane: ethyl acetate = 10: 1 (v / v)] to give 5.67 g of the title compound as a pale yellow oil.

_{¾ MR (CDC1 3) δ:} 0.94 (d, 3H, = 15.7 Hz), 1.05 (s, 9H), 2.25-2.33 (m, 2H), 2.57-2.60 (m, 1H), 3.44 (dd, 1H, J = 10.0, 7.1 Hz), 3.58 (dd, 1H, J = 10.0, 4.9 Hz), 7.36-7.5 (m, 6H), 7.62-7.73 (m, 4H), 9.78 (t, 1H, / = 2.2 Hz) .Step 2

2-Amino-5 _ ((15) -2-{[ί-butyl (diphenyl) silyl] oxy}-1-methylethyl) -3-methyl thiophenecarboxylate

Using the compound obtained in the above step 1 as a raw material, the same operation as in step 1 of Example 1 was performed to obtain the title compound as a brown oily substance.

MS (FAB) m / z 454 (M + H ⁺ ).

_{¾ MR (CDC1 3) δ:} 1.05 (s, 9H), 1.27 (3H, d, zo = 7.1 Hz), 2.95 (1H , m), 3.60 (dd, 1H, zo = 9.8, 6.1 Hz), 3.66 (dd, 1H, zo = 9.8, 6.1 Hz), 3.78 (s, 3H), 5.78 (br s, 2H), 6.65 (s, 1H), 7.34 -7.44 (m, 6H), 7.61— 7.64 (m, 4H). Process 3

6-((15) -2 {[ί-butyl (diphenyl) silyl] oxy} -1-methinoleethyl) thieno [2,3-d] pyrimidine-4 (3-one

Using the compound obtained in the above Step 2 as a raw material, the same operation as in Step 2 of Example 1 was performed to obtain the title compound as a colorless oily substance.

MS (FAB) / z 449 (M + H ⁺ ).

_{¾ NMR (CDC1 3) δ:} 1.05 (s, 9H), 1.39 (d, 3H, = 7.1 Hz), 3.23-3.26 (m, 1H), 3.75 (d, 2H, zo = 6.1 Hz), 7.21 (s , 1H), 7.34-7.4 (m, 6H), 7.59—7.63 (m, 4H), 7.97 (s, 1H).

4-[(Λζ-dimethylamino) methyl] benzaldehyde- {6-[(15) -2-hydroxy-tomethylethyl] thieno [2,3-] pyrimidine-4-yl} hydrazone

Using the compound obtained in the above Step 3 and the compound obtained in the Step 2 of Reference Example 3 as a raw material, the same operation as in the Step 3 of Example 1 was performed, and then the same operation as in Step 4 of Example 1 was performed. Using the obtained hydrazone and the aldehyde form obtained in Reference Example 3, Step 2, as raw materials, the same operation as in Step 1 of Example 1 was performed, and then the same operation as in Example 94 was performed to obtain the title compound as a yellow solid. . '

MS (FAB) m / z 370 (M + H ⁺ ).

¾ NMR (CDCI3) δ: 1.47 (d, 3H, = 6.8 Hz), 2.28 (s, 6H), 3.37-3.39 (m, 1H), 3.48 (s, 2H), 3.81-3.90 (m, 2H), 7.40 (d, 2H, = 8.0 Hz), 7.64 (d, 2H, = 8.0 Hz), 7.85 (s, 1H), 7.94 (s, 1H), 8.5 (s, 1H). [Example 1 38]

^H0 , SCO. M process 3

Process 1

(35) I 4 -— {[t-butyl (diphenyl) silyl] methyl} -3-methylbutanal

The same operation as in step 1 of Example 1337 was carried out using methyl (2 ^)-3-hydroxy-2-methylpropionate as a starting material, to obtain the title compound as a colorless oily substance.

MS (FAB) m / z 341 (M + H +)

_{¾ MR (CDC1 3) δ:} 0.96 (d, 3H, J: 15.7 Hz), 1.05 (s, 9H), 2.25-2.33 (m, 2H), 2.56-2.65 (m, 1H), 3.44 (dd, 1H , / = 9.8, 6.8 Hz), 3.58 (dd, 1H, J 9.8, 5.1 Hz), 7.34-7.5 (m, 6H), 7.65 (dd, 1H, / = 7.8, 1.7 Hz), 9.78 ( s, 1H). Process 2

2-Amino-5-((li?)-2-({[-butyl (diphenyl) silyl] oxy} _1} -methylethyl) -3-methyl thiophenecarboxylate

The same operation as in step 1 of Example 1 was carried out using the compound obtained in step 1 of the above 3 as a raw material to obtain the title compound as a yellow oily substance.

MS (FAB) m / z 454 (M + H +).

Thigh (CDC1 ₃ ) δ1.05 (s, 9Η), 1.27 (d, 3H, / = 6.8 Hz), 2.95 (m, 1H), 3.59 (dd, 1H, /=9.8, 6.4 Hz), 3.63 (dd, 1H, 9.8, 6.4 Hz), 3.78 (s, 3H), 5.77 (br s, 2H), 6.65 (s, 1H), 7.34-7.43 (m, 6H), 7.61-7.64 (m, 4H) Step 3 6-((L?)-2-{_ t-butyl (diphenyl) silyl] oxy} -1-methylethyl) thieno [2,3-d] pyrimidine-4 (M-one

Using the compound obtained in Step 2 as a raw material, the same operation as in Step 3 of Example 1 was performed to obtain the title compound as a colorless oily substance.

MS (FAB) m / z 449 (M + H +).

_{¾ NMR (CDC1 3) δ:} 1.05 (s, 9H), 1.43 (d, 3H, / = 6.9 Hz), 3.29- 3.35 (m, 1H), 3.79-3.82 (m, 2H), 7.19 (s, 1H ), 7.31— 7.43 (m, 6H), 7.57-7.62 (m, 4H), 8.32 (s, 1H). Process 4

4-[(^-dimethylamino) methyl] benzaldehyde #-{6-[(L?)-2-Hydroxy-1-methylethyl] thieno [2,3-d] pyrimidine-4-yl} hydrazone

Using the compound obtained in the above Step 3 as a raw material, the same operation as in Step 1 of Example 1 was performed, and in Step V, the same operation as in Step 4 of Example 1 was performed. Reference Example 3 Using the aldehyde obtained in Step 2 as a raw material, the same operation as in Example 1 was performed, and the same operation as in Example 94 was performed. Obtained as a yellow solid. MS (FAB) m / z 370 (M + H ⁺ ).

¾ NMR (DMSO-) δ: 1.36 (d, 3H, = 6.8 Hz), 2.29 (s, 6H), 3.14-3.32 (m, 3H), 3.61 (m, 2H), 7.44 (d, 2H, / = 7.3 Hz), 7.71 (d, 2H, J = 7.3 Hz), 7.87 (s, 1H), 8.24 (s, 1H), 8.2 (s, 1H).

[Example 139]

4-Hydroxybenzaldehyde-[6-(-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in Step 1 of Example 1 was performed using the compound obtained in Step 4 as a raw material and 4-hydroxybenzaldehyde as a raw material, thereby obtaining the title compound as a colorless solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example. [Example 140]

2-Hydroxybenzaldehyde-[6-(-butyl) thieno [2,3-d] pyrimidine-4-inole] hydrazone

Example 30 The same operation as in Step 5 of Example 1 was carried out using the compound obtained in Step 4 and 2-hydroxybenzaldehyde as a starting material to obtain the title compound as a colorless solid. The structural formula and physical properties of the compound of this example are shown in Table 4.

[Example 14 1]

4- (1-Methyl-3-azetidinyl) benzaldehyde-[6--(2-Hydroxy-1,1-dimethylethyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 9 3 The compound obtained in Step 5 and the compound obtained in Reference Example 26 were used as raw materials, and the same operation as in Example 1, Step 5 was performed.Then, the same operation as in Example 94 was performed. The title compound was obtained as a pale yellow solid. Table 5 shows the structural formula and physicochemical properties of the compound of this example.

[Example 1 4 2]

ί-Butyl 4-({2- [6- (ί-butyl) cheno [2,3-d] pyrimidine-4-yl] hydrazono} methinole) benzyl carbamate

Example 30 Compound obtained in Step 4 Reference Example 2 4 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a pale yellow solid. Obtained. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 1 4 3]

4- (aminomethyl) benzaldehyde-[6-(-butyl) thieno [2,3 ~ d] pyrimidine-4-yl] hydrazone · dihydrochloride

Using the compound obtained in Example 14 as a raw material, the same operation as in Example 102 was performed, P leak 1 / the title compound was obtained as an orange solid. The structural formula and physicochemical properties of the compound of this example are shown.

See Figure 4. '[Example 1 4 4]

4- (Aminomethyl) benzaldehyde-[6- (2-hydroxy-1,1-dimethylethyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone dihydrochloride

Example 9 3 The compound obtained in Step 5 and Reference Example 2 4 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 5 of Example 1 was performed to obtain a hydrazone. Then, the same operation as in Example 94 was performed, and further the same operation as in Example: L02 was performed to obtain the title compound as a pale green solid. Table 5 shows the structural formula and physical properties of the compound of this example.

[Example 1 4 5]

1,2,3,4-tetrahydro-6-isoquinolinecarboxyaldehyde-[6- (--butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone · dihydrochloride

Example 30 The compound obtained in Step 4 and Reference Example 2 7 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 1 of Example 1 was performed, and then the same operation as in Example 102 was performed. The title compound was obtained as an orange solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 1 4 6] '4-[^ Methylamino) methyl] benzaldehyde-[6- (2-hydroxy-1,1-dimethylethyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone Dihydrochloride

Example 9 3 Using the compound obtained in Step 5 and the compound obtained in Reference Example 22 as raw materials, the same operation as in Step 1 of Example 1 was performed to obtain a hydrazone. Then, the same operation as in Example 94 was performed, and further the same operation as in Example 102 was performed, to obtain the title compound as a pale yellow solid. Table 5 shows the structural formula and physicochemical properties of the compound of this example. [Example 14 7]

2- {4- [2-({4-[(Λζ-dimethylamino) methyl] phenyl} methylidene) hydrazino] thieno [2, Z-d] pyrimidine-6-yl} -2-methylpropylacetate

50 mg of the compound obtained in Example 96 was dissolved in 1.0 ml of pyridine, 0.014 ml of acetic anhydride was added under ice cooling, and the mixture was stirred for 15 hours. Further, 0.027 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was distilled off under reduced pressure, and chloroform was added, followed by extraction with a 1N aqueous hydrochloric acid solution. The aqueous layer was adjusted to pH 12 with a 1N aqueous sodium hydroxide solution and extracted with dichloromethane. The 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 thin-layer chromatography [form: methanol: water = 7 _: 3: 1 (v / v / v) (lower layer)] to give 19 mg of the title compound as a colorless solid As obtained.

MS (FAB) m / z 426 (M + H +).

_{¾ NMR (CDC1 3) δ '} · 1.47 (s, 6H), 1.99 (s, 3H)., 2.18 (s, 6H), 3.45 (s, 2H), 4.17 (s, 2H), 7.40 (d, 2H , = 8.1 Hz), 7.68 (d, 2H, d 8.1 Hz), 7.93 (br s, 1H), 8.24 (s, 1H), 8.44 (s, 1H).

[Example 1 4 8]

1,2,3,4-tetrahydro-7-isoquinolinecarboxaldehyde-[6- (2-hydroxy-1,1-dimethylethyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone. Dihydrochloride Example 9 3 The compound obtained in Step 5 and Reference Example 2 7 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 1 of Example 1 was performed to obtain a hydrazone. Subsequently, the same operation as in Example 94 was performed, and further the same operation as in Example 102 was performed to obtain the title compound as a pale yellow solid. Table 5 shows the structural formula and physical properties of the compound of this example. [Example 149]

Tofuenil-1-ethanone-[6- (ί-butyl) thieno [2,3-d] pyrimidine-4-inole] hydrazone

Example 30 The same operation as in Example 1, Step 5 was carried out using the compound obtained in Step 4 and acetophenone as raw materials to obtain the title compound as a pale yellow solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 150]

4--Methylamino) methyl] benzaldehyde- (6-isopropylcheno

[2,3-] pyrimidine-4-yl) hydrazone dihydrochloride

Example 15 Using the compound obtained in Step 4 and the compound obtained in Reference Example 22 as starting materials, the same operation as in Step 1 of Example 1 was performed, and then the same operation as in Example 102 was performed. The compound was obtained as a colorless solid. The structural formula and physicochemical properties of the compound of this example are shown.

See Figure 2.

[Example 151]

Benzaldehyde- [6- (2-hydroxy-1,1-dimethylethyl) thieno [2,3-] pyrimidine-4-yl] hydrazone

Example 93 Using the compound obtained in Step 5 and benzaldehyde as raw materials, the same operation as in Step 1 of Example 1 was performed, and then the same operation as in Example 94 was performed to obtain the title compound as a pale yellow solid. Table 5 shows the structural formula and physical properties of the compound of this example.

[Example 152]

1- {4-[(^-Methylamino) methyl] phenyl}-1-ethanone-[6-(-butyl) thieno [2,3-d] pyrimidine-4-yl] hydradrazone · 2HCl salt Example 30 The compound obtained in Step 4 and Reference Example 2 8 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 1 of Example 1 was performed.Then, the same operation as in Example 102 was performed. The title compound was obtained as a colorless solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 1 5 3]

3,4-dihydro-1 (2 ^ -naphthalenone [6-(-butyl) thieno [2,3-] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in Step 5 of Example 1 was carried out using the compound obtained in Step 4 as a raw material and tetrapotane as a raw material to obtain the title compound as an orange solid. Table 4 shows the structural formula and physicochemical properties of the compound of this example.

[Example 1 54]

4- (Λζ-dimethylamino) methylbenzaldehyde Ν- (2-methylph [2,3-opyrimidine_4-yl) hydrazone

Example 13 3 Step 1 and Reference Example 3 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 2 as a starting material to obtain the title compound as a yellow solid.

MS (FAB) m / z 309 (M + H ⁺ ).

^ NMR (DMSO-d ₆ ) δ: 2.19 (s, 6H), 2.45 (s, 3H), 3.47 (s, 2H), 6.86 (s, 1H), 6.88 (m, 1H), 7.37 (d, 2H , = 8.0 Hz), 7.69 (d, 2H, = 8.0 Hz), 7.89 (d, 1H, zo = 5.6 Hz), 8.08 (s, 1H), 11.07 (s, 1H). [Example 1 5 5]

4- (N, -dimethylamino) methylbenzaldehyde N- (2-methylph [3,2-c] pyrimidine-4-yl) hydrazone

Example 1 Step 1 and Reference Example 3 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 2 as a starting material to obtain the title compound as a yellow solid.

MS (FAB) m / z 309 (M + H +).

^{_{X H NMR (DMSO- 6) δ}} 2.17 (s, 6H), 2.49 (s, 3H), 3.42 (s, 2H), 6.98 (d, 1H, / = 5.2 Hz), 7.04 (s, 1H), 7.35 (d, 2H, / = 8.1 Hz), 7.63 (d, 2H, / = 8.1 Hz), 7.89 (d, 1H, J = 5.6 Hz), 8.06 (s, 1H), 11.12 (s, 1H).

[Example 1 5 6]

4- (N, -dimethylamino) methylbenzaldehyde N- (2-methylcheno [3,2-c] pyrimidin-4-yl) hydrazone

Example 1 35 The same operation as in Step 5 of Example 1 was performed using the compounds obtained in Step 1 and Step 2 of Reference Example 3 as starting materials to obtain the title compound as a yellow solid.

MI (EI) m / z 324 ().

_{lE NMR (CDC1 3) δ ·} '2.26 (s, 6H), 2.64 (s, 3H), 3.45 (s, 2H), 7.23 (br, 1H), 7.36 (d, 2H, zo = 8.0 Hz), 7.64 (d, 2H, / = 8.0 Hz), 7.80 (br, 1H), 7.92 (br, 1H), 7.96 (br, 1H), 8.79 (br, 1H). [Example 1 5 7]

4 Methylamino) methylbenzaldehyde-(2-methylph [3,2-c] pyrimidin-4-yl) hydrazone

Example 13 Using the compounds obtained in Step 1 and Reference Example 22 as raw materials, the same operation as in Step 1 of Example 1 was performed, and then the same operation as in Example 102 was performed to convert the title compound to a yellow solid. As obtained.

MS (EI) m / z 294 (If).

NMR (DMS0-) δ: 2.27 (s, 3H), 2.49 (s, 3H), 3.67 (s, 2H), 6.98 (d, 1H, / = 5.8 Hz), 7.05 (s, 1H), 7.39 (d , 1H, = 8.0 Hz), 7.62 (d, 1H, / = 8.0 Hz), 7.90 (d, 1H, = 5.6 Hz), 8.07 (s, 1H), 11.11 (s, 1H).

[Example 1 5 8]

Thiazole-2-carboxaldehyde-[6- (ί-butyl) cheno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in Step 5 of Example 1 was carried out using the compound obtained in Step 4 and thiazole-2-propoxyaldehyde as raw materials to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 15 9]

Thiazo-I / le-5-carboxaldehyde- [6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and thiazole-5-carboxaldehyde as raw materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as an orange solid. Was. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 16]

Thiazole -4--propyloxyaldehyde-[6- (ί-butyl) thieno [2,3--/] pyrimidine-4-yl] hydrazone

Example 30 Compound obtained in Step 4 * 4 Reference Example 3 4 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a pale yellow solid. . Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 16 1]

Pyrazole-3-hydroxypropyloxy- [6-butyl] thieno [2,3-d] pyrimidin-4-yl] hydrazone

Example 30 Using the compound obtained in Step 4 and pyrazole-3-carboxyaldehyde as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a colorless solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 16 2]

4-Methylthiazole-2-carboxyaldehyde-[6- (ί-butyl) thieno [2,3 ~ d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in step 5 of Example 1 was performed using the compound obtained in step 4 and the compound obtained in reference example 3 5 as the starting material to obtain the title compound as a pale yellow solid. Table 3 shows the structural formula and physical properties of the compound of this example.

[Example 16 3]

4-cyclopropyl thiazonole-2-carboxyaldehyde-[6-(-butynole) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 Compounds obtained in Step 4 and Reference Example 36 Compounds obtained in Step 2 were used as starting materials, The same operation as in step 1 of Example 1 was performed to obtain the title compound as a pale yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 16 4]

2--Dimethylamino) methyl] -4 -thiazolecarboxyaldehyde N- [6-(-butyl) cheno [2,3-d] pyrimidine-4-inole] hydrazone

Example 30 The same operation as in Step 1 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 3 of Reference Example 3 as starting materials to obtain the title compound as a colorless solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 16 5]

4-[(^ -Methylamino) methyl] thiazole -2 -Holepoxyaldehyde-[6- (-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone · dihydrochloride

Example 30 Compound obtained in step 4 Reference Example 3 8 The compound obtained in step 2 was used as a starting material, and the same operation as in step 1 of example 1 was performed, and then the same operation as in example 102 Was performed to obtain the title compound as a pale yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 1 6 6]

4, 6-dihydro-5-pyrro [3, thiazole-2-pyroxylaldehyde-[6- (ί-butyl) thieno [2,3-d pyrimidine-4-yl] hydrazone 'dihydrochloride

Example 30 Compounds obtained in Step 4 and Reference Example 40 Compounds obtained in Step 4 were used as raw materials, and the same operation as in Step 5 of Example 1 was performed.Then, the same operation as in Example 102 was performed. The title compound was obtained as a pale yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example. [Example 1 6 7]

4- [CV-Methylamino) methyl] thiazole _2_Holpoxyaldehyde N- (6-isop-pirceno [2,3-dpyrimidine-4-yl) hydrazone.2 hydrochloride

Example 1 5 Compound obtained in step 4 Reference Example 3 8 The compound obtained in step 2 was used as a starting material, and the same operation as in step 1 of example 1 was performed, and then the same operation as in example 102 Was performed to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 1 6 8]

5-[(^-methylamino) methyl] thiazole 2-carboxyaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone dihydrochloride

Example 30 The compound obtained in Step 4 and the reference example 3 9 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 1 of Example 1 was performed, followed by the same operation as in Example 102. Was carried out to give the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 16 9]

5-[(^ "Methylamino) methyl] thiazole -2 -Holepoxyaldehyde-(6-isop-pirceno [2,3-pyrimidine-4-inole) hydrazone · dihydrochloride

Example 1 5 The compound obtained in Step 4 and Reference Example 3 9 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 5 of Example 1 was performed, and then the same operation as in Example 102 was performed. The title compound was obtained as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 170]

4-Methyl-5-[(^-methylamino) methyl] thiazole-2-carboxyaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone · 2 Hydrochloride Example 30 The compound obtained in Step 4 and the reference example 3 7 The compound obtained in Step 5 was used as a starting material, and the same operation as in Step 5 of Example 1 was performed, and then the same operation as in Example 102 was performed. The title compound was obtained as a yellow solid. Table 3 shows the structural formula and physical properties of the compound of this example.

[Example 17 1]

4-[(V-methylamino) methyl] thiazole-2-carboxaldehyde- (6-ethylthieno [2,3-d] pyrimidine-4-inole) hydrazone dihydrochloride

Example 1 Compound obtained in Step 4 Reference Example 3 8 Using the compound obtained in Step 2 as a raw material, the same operation as in Step 1 of Example 1 was performed, and then the same operation as in Example 102 was performed. The title compound was obtained as a light brown solid. Table 1 shows the structural formula and physicochemical properties of the compound of this example.

[Example 17 2]

5- (2-Amino) ethyl-4-methylthiazole-2-carboxaldehyde- [6- (ブ -butyl) cheno [2,3-d] pyrimidine-4-yl] hydrazone.3 hydrochloride

Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 4 1 in Step 2 as raw materials, performing the same operation as in Step 5 of Example 1 and then performing the same operation as in Example 102. The title compound was obtained as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 17 3]

4-[(-Methylamino) methyl] thiazole-2-carboxoxyaldehyde N- [6- (2-Hydroxy-1,1-dimethynoleethyl) thieno [2,3-d] pyrimidine-4-yl] Hydrazone ♦ 1.5 Example 9 3 Compound obtained in Step 5 Reference Example 3 8 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 1 of Example 1 was performed to obtain a hydrazone. Then, Example 94 and The same operation was performed and further the same operation as in Example 102 was performed to obtain the title compound as a yellow solid. Table 5 shows the structural formula and physicochemical properties of the compound of this example.

[Example 17 4]

5- [2- (Λζ-dimethylamino) ethyl] -4--methylthiazole-2-carboxyaldehyde Ν- [6-(-butyl) cheno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in step 5 of Example 1 was performed using the compound obtained in step 4 and the compound obtained in reference example 4 2 as the starting material to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 1 75]

5-[(^ -Methylamino) methyl]-4-trifluoromethylthiazole -2-hexylboxaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone Example 2 Using the compound obtained in Step 4 and the compound obtained in Step 4 as a starting material, the same operation as in Step 5 of Example 1 was performed, followed by the same operation as in Example 102. Was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physical properties of the compound of this example.

[Example 1 7 6]

4- (Aminomethyl) oxazole-2-carboxaldehyde- [6- (ί-butyl) ceno [2,3-d] pyrimidine-4-yl] hydrazone '1.75 hydrochloride

Example 30 Compound obtained in step 4 Reference Example 4 4 The compound obtained in step 4 was used as the starting material, and the same operation as in step 1 of example 1 was performed, followed by the same procedure as in example 102. The operation was performed to obtain the title compound as a colorless solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example. [Example 1 7 7]

4- (Aminomethyl) oxazole-2-carboxyaldehyde- (6-isopropylthieno [2,3-d] pyrimidine-4-yl) hydrazone dihydrochloride

Example 1 5 The compound obtained in Step 4 and Reference Example 4 4 The compound obtained in Step 4 was used as a starting material, and the same operation as in Step 1 of Example 1 was performed, and then the same operation as in Example 1 and 2 was performed. The title compound was obtained as a colorless solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 1 7 8]

4- (Aminomethyl) thiazole_2-carboxaldehyde- [6-(-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone.2 hydrochloride

Example 30 The compound obtained in Step 4 and Reference Example 4 6 The compound obtained in Step 4 was used as a starting material, and the same operation as in Step 1 of Example 1 was performed, and then the same operation as in Example 102 was performed. Was performed to obtain the title compound as a pale yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 17 9]

4,5,6,7-tetrahydro [1,3] thiazo [5,4-c] pyridine-2-carboxyaldehyde- (6-isopropylcheno [2,3-d] pyrimidine-4 -Yl) hydrazone dihydrochloride Example 1 5 Using the compound obtained in Step 4 and the compound obtained in Reference Example 31 as starting materials, the same operation as in Step 1 of Example 1 was performed, and then Example 10 The same operation as in 2 was performed to obtain the title compound as a pale yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 180]

4-[(/ V-Methylamino) methyl] oxazole-2-hexanoloxy (6-isopropylcheno [2,3-] pyrimidine-4-yl) hydrazone dihydrochloride Example 15 5 The compound obtained in Step 4 and Reference Example 4 5 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 1 of Example 1 was performed.Then, the same operation as in Example 102 was performed. The title compound was obtained as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 18 1]

2-{[2- (6-Isopropylcheno [2,3-dlpyrimidine-4-yl) hydrazono] methyl} -N-tyl-thiazole-4-carboxamide

Using the compound obtained in Reference Example 49 as a raw material, the same operation as in Reference Example 14 was performed to obtain an aldehyde form. Next, using the obtained aldehyde compound and the compound obtained in Step 4 of Example 15 as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 2 shows the structural formula and physicochemical properties of the compound of this example.

[Example 18 2]

3- [2-(-Methylamino) ethoxy] -5-isoxazolecarboxyaldehyde-[6-(-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone. 1.75 Hydrochloride Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 4 7 in Step 2 as starting materials, the same operation as in Step 1 of Example 1 was performed, and then the same operation as in Example 102 was performed. This gave the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 18 3]

3- (4-piperidinyloxy) -5-isoxazolecarboxyaldehyde- [6-(-butyl) thieno [2,3-dlpyrimidine-4-yl] hydrazone. 1.75 hydrochloride Example 30 Using the compound obtained in Step 4 and the compound obtained in Reference Example 4 8 in Step 2 as raw materials, the same operation as in Step 5 of Example 1 was performed, and then the same operation as in Example 102 was performed. The compound was obtained as a colorless solid. The structural formula and physicochemical properties of the compound of this example See Table 3.

[Example 18 4].

5- (4-Methyl-1-piperazinyl) -2-thiophenecarpoxyaldehyde- [6--butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Reference Example 50 Step 1 as raw materials to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 18 5]

5-[Ov; -dimethylamino) methyl] -2-thiophenecarboxyaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 30 The same operation as in Step 1 of Example 1 was performed using the compound obtained in Step 4 and the compound obtained in Step 2 of Reference Example 5 as starting materials to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 1 86]

4- (1-Aminoethyl) thiazole-2-propyloxyaldehyde-[6- (ί-butyl) chen [2,3-d] pyrimidine-4-yl] hydrazone.2 hydrochloride

Example 30 The compound obtained in Step 4 and Reference Example 5 2 The compound obtained in Step 5 was used as a starting material, and the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 18 7]

Process 1

Monomethyl 3,3-dimethylglutarate

Under ice-cooling, 27.3 ml of Shii-Dai-Thionyl was added to 100 ml of methanol, the mixture was stirred at the same temperature for 30 minutes, 10 g of 3,3-dimethyldartaric acid was further added, and the mixture was stirred at room temperature for 13 hours. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate and saturated aqueous sodium hydrogen carbonate. The two layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with a saturated saline solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in 55 ml of methanol. Under ice-cooling, 3.4 ml of potassium hydroxide in 55 ml of water was added to the solution, and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and washed with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 8.5 g of the title compound as a colorless oily substance.

_{¾ NMR (CDC1 3) δ:} . 1. 14 (s, 6H), 2. 5 (s, 2H), 2. 48 (s, 2H), 3. 68 (s, 3H) Step 2

Methyl 3,3-dimethyl-5-morpholino-5-oxopentanoate

In a solution of 2.0 g of the compound obtained in the above step 1 and 1.0 g of morpholine in 40 ml of dichloromethane, i-ethyl- _3- ( ₃ -dimethylaminopropyl) -force levodizimide hydrochloride 2.6 g, triethylamine 1.9 ml was added and the mixture was stirred at room temperature for 18.5 hours. The reaction solution was washed sequentially with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate. Under reduced pressure The solvent was distilled off to obtain 2.5 g of the title compound as a colorless oily substance.

¾ Anonymous _{(CDC1 3) δ: 1.14 (} s, 6H), 2.46 (s, 2H), 2.52 (s, 2H), 3.52 (br s, 2H),

3.61 (br s, 2H), 3.65 (s, 3H), 3.66 (br s, 4H). Process 3

3,3-Dimethinole-5-morpholino-1-pentanol

A solution of 2.5 g of the compound obtained in Step 2 in 10 ml of tetrahydrofuran was added to a suspension of 0.78 g of lithium aluminum hydride in 20 ml of tetrahydrofuran under ice cooling, and the mixture was refluxed for 2 hours. 0.78 ml of water, 0.78 ml of 15% aqueous sodium hydroxide solution and 2.3 ml of water were sequentially added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After the precipitate was removed by filtration, the filtrate was diluted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.9 g of the title compound as a colorless oily substance.

_{¾ NM (CDC1 3) δ:} 0.93 (s, 6H), 1.46 (t, 2H, / = 7.3 Hz), 1.54 (t, 2H, J = 6.8 Hz), 2.34 (t, 2H, / = 7.3 Hz) , 2. 6 (br s, 4H), 3.69-3.72 (m, 6H). Step 4

2-Amino-5- (1, tridimethyl-3-morpholinopropyl) thiophen-3-methyl carboxylate

To a solution of 1.0 g of the compound obtained in the above step 3 in 20 ml of dichloromethane was added -methylmorpholine-oxide 0.87 g, molecular sieves 4 A2.5 g and tetra-propylammonium pearltenate 87 under ice-cooling. mg was added and the mixture was stirred at room temperature for 20 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. Using the obtained aldehyde compound as a raw material, the same operation as in step 1 of Example 1 was performed to obtain 0.8 g of the title compound as a brown oily substance.

MS (ESI) m / z 313 (M + H +)

¾ testimony _{(CDC1 3) δ: 1.28 (} s, 6H), 1.72-1.74 (m, 2H), 2.22-2.26 (m, 2H), 2.42 (br s, 4H), 3.70-3.71 (m, H), 3.80 (s, 3H), 5.79 (br s, 2H), 6.60 (s, 1H). Process 5

6- (1,1-Dimethyl-3-morpholinopropyl) thieno [2,3-d] pyrimidin-4- (3-one) Using the compound obtained in Step 4 as a starting material, the same operation as in Step 1 of Example 1 Was carried out to obtain the title compound as an off-white solid.

MS (ESI) m / z 308 (M + If)

_{¾ MR (CDC1 3) δ:} 1.44 (s, 6H), 1.86-1.90 (m, 2H), 2.22-2.26 (m, 2H), 2.38 (br s, 4H), 3.66-3.69 (m, 4H), 7.20 (s, 1H), 7.98 (s, 1H) .Step 6

4-kuguchiguchi-6- (1,1-dimethyl-3-morpholinopropyl) thieno [2,3-d] pyrimidine The compound obtained in the above step 5 was used as a starting material, and the same procedure as in step 3 of Example 1 was carried out. To give the title compound as a yellow oil.

MS (ESI) m / z 326 (M + H +)

¾ MR (CDCI3) δ 1.49 (s, 6H), 1.91-1.95 (m, 2H), 2.24-2.27 (m, 2H), 2.39 (br s, 4H), 3.66-3.68 (m, 4H), 7.09 ( s, 1H), 8.78 (s, 1H). Process 7

6- (1,1-dimethyl-3-morpholinopropyl) -4-hydrazinothieno [2,3-d] pyrimidine

Using the compound obtained in the above Step 6 as a raw material, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as an orange oily substance.

¾ testimony _{(CDC1 3) δ 1.45 (s} , 6Η), 1.88- 1.93 (m, 2H), 2.25-2.29 (m, 2H), 2.40 (br s, 4H), 3.68 (t, 4H, 4.4 Hz), 7.69 (s, 1H), 8.18 (brs, 1H), 8.43 (s, 1H). Step 8 Thiazole-2-carboxyaldehyde- [6- (1, todimethyl-3-morpholinopropyl) thieno [2,3-d] pyrimidine-4-inole] hydrazone

The same operation as in step 5 of Example 1 was carried out using the compound obtained in the above step 7 and thiazole-2-propoxyaldehyde as raw materials to obtain the title compound as a yellow solid. MS (FAB) m / z 417 (M + H ⁺ )

¾ thigh _{(CDC1 3) δ: 1.53 (} s, 6H), 1.95 (t, 2H, / = 7.5 Hz), 2.30 (t, 2H, J = 7.5 Hz), 2.40 (m, 4H), 3.67 (ΐ, 4H, = 4.4 Hz), 7.42 (d, 1H, / = 3.4 Hz), 7.82 (s, 1H), 7.90 (d, 1H, = 3.4 Hz), 8.15 (s, 1H), 8.54 (s, 1H) .

[Example 1 8 8]

CO _z Et

Step 1 Step 2 0 = -OMe Step 3

CO _z Et

-OMe

Process:

5-methoxy-4-methoxymethoxy-pent-L-ene

5.7 g of lithium aluminum hydride was suspended in 160 ml of ether, and ice-cooled under a nitrogen atmosphere. Then, a solution prepared by dissolving 12 g of acetylmethyl malonate in 40 ml of ether was dropped, and the mixture was returned to room temperature and stirred for 20 hours. After the reaction solution was cooled with ice, methanol was added in 5.7 ml of water, 5.7 ml of 15% aqueous sodium hydroxide solution and 17.1 ml of water in this order while paying attention to foaming, and the mixture was returned to room temperature and stirred for 2 hours. After removing the insoluble matter by filtration, the filtrate was distilled off under reduced pressure. The obtained residue was dissolved in 70 ml of tetrahydrofuran, and dropped into a solution of 5.04 g (60% oil) of sodium hydride suspended in 80 ml of tetrahydrofuran under ice-cooling, followed by stirring at the same temperature for 30 minutes. Then add 7.8 ml of methyl iodide, A solution dissolved in 50 ml of muamide was added dropwise, and the mixture was returned to room temperature and stirred overnight. After concentration, saturated aqueous ammonium chloride was added, extracted with ethyl acetate, washed with water and saturated saline in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography (ethyl acetate: hexane 1: 9 (v / v)) to give 6.67 g of the title compound as a colorless oil.

¾丽_{(CDC1 3) δ: 1.91-1.96 (} m, 1H), 2.13 (t, 2H, / = 7.1 Hz), 3.32 (s, 6H), 3.30-3.36 (m, 4H), 4.99-5.06 (m , 2H). Step 2

4-methoxy-3-methoxymethyl-butyraldehyde

Using the compound obtained in the above Step 1 as a raw material, the same operation as in Step 2 of Example 93 was performed to obtain the title compound as a pale yellow oily substance.

¾ Hokusatsu _{(CDC1 3) δ 2.47-2.55 (m} , 3H), 3.31 (s, 6H), 3.29-3.33 (m, 2H), 3.40 -3.49 (m, 2H), 9.75 (t, 1H, / = 2.0 Hz). Step 3

2 "Amino-5- (2-methoxy-1-methoxymethyl-ethyl) thiophene-3-methyl methyl sulfonate

The same operation as in step 1 of Example 1 was performed using the compound obtained in the above-mentioned step 2 as a raw material to obtain the title compound as a yellow oily substance.

MS (ESI) m / z 260 (M + H ⁺ ).

_{¾ MR (CDC1 3) δ 3.14-3.19} (m, 1H), 3.35 (s, 6H), 3.54-3.56 (m, 4H), 3.78 (s, 3H), 5.82 (br, 2H), 6.74 (s, 1H). Process 4

6- (2-Methoxy-1-methoxymethyl) ethylchino [2,3-d] pyrimidin-4 (3-one) Using the compound obtained in the above Step 3 as a raw material, the same operation as in Step 2 of Example 1 was performed. , Mark The title compound was obtained as a colorless solid.

MS (EI) m / z 254 (M ⁺ ).

¾ original (CDC1 ₃ ) δ: 3.38 (s, 6H), 3.41-3.47 (m, 1H), 3.67-3.71 (s, 1H), 7.31 (s, 1H), 8.08 (s, 1H), 12.18 (br , 1H). Step 5

6- (2-Methoxy-1 -methoxymethyl) ethyl-4-c-mouth cheno [2,3-d] pyrimidine Using the compound obtained in the above step 4 as a raw material, the same operation as in step 3 of Example 1 was performed. The title compound was obtained as a colorless oily substance.

MS (ESI) m / z 273 (M + H ⁺ ).

Read (CDC1 ₃ ) δ 3.39 (s, 6H), 3.51—3.54 (m, 1H), 3.71 (d, 4H, / = 5.8 Hz), 7.24 (s, 1H), 8.79 (s, 1H). 6

6- (2-Methoxy-1-methylmethyl) ethyl-4-hydrazinoceno [2,3-d] pyrimidine.

Using the compound obtained in the above Step 5 as a raw material, the same operation as in Step 4 of Example 1 was performed to obtain the title compound as a colorless solid.

MS (EI) m / z 268

_{¾NMR (CDC1 3) δ: 3.37} (s, 6H), 3.43-3.48 (m, 1H), 3.64-3.69 (m, 4H), 6.51 (br, 1H), 7.05 (s, 1H), 8.49 (s, 1H). 'Step 7

Thiazole-2-carboxyaldehyde-{6- [2-Methoxy-1- (methoxymethyl) ethyl] cheno [2,3-d] pyrimidine-4-inole} hydrazone

The same operation as in step 1 of Example 1 was performed using the compound obtained in the above-mentioned step 6 and thiazole-2-phenoloxyaldehyde as raw materials to obtain the title compound as a yellow solid. MS (EI) m / z 363 (M ⁺ ).

MR (MSO- ₆ ) δ 3.30 (s, 6H), 3.51-3.56 (m, 1H), 3.66-3.68 (m, 4H),

7.84 (s, 1H), 7.86 (s, 1H), 7.95 (s, 1H), 8.43 (s, 1H), 8.50 (s, 1H), 12.17 (br, 1H).

[Example 189]

Process 1

Jetyl arylmethylmarate

Under ice-cooling, a solution of 4.4 g (60% oil) of sodium hydride suspended in 120 ml of tetrahydrofuran was added dropwise with a solution of 17 ml of methyl methate getyl in 50 ml of tetrahydrofuran, followed by stirring at the same temperature for 30 minutes. Then, 9.3 ml of bromide bromide was dropped, and the mixture was returned to room temperature and stirred for 2 hours. After concentration, saturated aqueous ammonium chloride was added, extracted with ethyl acetate, washed with water and saturated saline in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by distillation under reduced pressure to obtain 18 g of the title compound as a colorless oily substance.

_{¾ NMR (CDC1 3) δ:} 1.25 (t, 6H, = 7.0 Hz), 1.39 (s, 3H), 2.61 (d, 2H, J: 7.3 Hz), 4.17 (q, 4H, = 7.0 Hz), 5.08 — 5.13 (m, 2H), 5.64-5.75 (m, 1H). Boiling point 76—77 ° C (4mmHg) Process 2

4-methyl-5-methoxy-4-ment-1-ene Using the compound obtained in the above step 1 as a raw material, the same operation as in step 1 of Example 188 was performed to obtain the title compound as a colorless oily substance.

_{¾ NMR (CDC1 3) δ:} 0.86 (s, 3H), 2.05 (d, 2H, zo = 7.3 Hz), 3.15 (AB type d, each 2H, J = 9.0 Hz), 3.32 (s, 6H), 5.01 —5.02 (m, 1H), 5.05 (s, 1H), 5.01 to 5.05 (m, 1H). Process 3

3-Methynole-4-methoxy-3- methymethyl-butyraldehyde

Using the compound obtained in the above Step 2 as a raw material, the same operation as in Step 2 of Example 9 3 was carried out to obtain the title compound as a colorless oily substance.

_{¾ NMR (CDC1 3) δ 1.05} (s, 3H), 2.35 (s, 2H), 3.22-3.25 (m, 4H), 3.31 (s, 6H), 9.76-9.79 (m, 1H). Step 4

2-Amino-5- (1-methyl-2-methoxy-1-methoxymethyl-ethyl) -thiophene-3- 3-methyl

Using the compound obtained in the above Step 3 as a raw material, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a yellow oily substance.

MS (ESI) m / z 274 (M + H +).

_{¾ NMR (CDC1 3) δ:} 1.28 (s, 3H), 3.34 (s, 6H), 3. 0 (s, 4H), 3.78 (s, 3H), 5.81 (br, 2H), 6.74 (s, 1H Step 5

6- (Trimethyl-2-methoxy-1-methoxymethyl) ethylchino [2,3-d] pyrimidine-4 (3τ¾-one

Using the compound obtained in the above step 4 as a raw material, the same operation as in step 1 of example 1 was performed to obtain the title compound as a colorless solid. MS (EI) m / z 269 (M ⁺ ).

¾賺_{(CDC1 3) δ: 1.42 (} s, 3H), 3.25 (AB type d, each 2H, / = 9.0 Hz), 3.37 (s, 6H), 7.33 (s, 1H), 8.02 (s, 1H) , 12.15 (br, 1H). Step 6

Example 1 Step 3 using 6- (1-methyl-2-methoxy-1-methoxymethyl) ethyl 4-cyclooctenothieno [2,3-d] pyri, the compound obtained in Step 5 above as a starting material The title compound was obtained as a colorless oily substance.

MS (ESI) m / z 287 (M + H +).

¾ 'MR (CDC1 ₃ ) δ 1.47 (s, 3H), 3.38 (s, 6H), 3.57 (AB type d, each 2H, J = 9.0 Hz), 7.22 (s, 1H), 8.78 (s, 1H). Step 7 '

6- (Tomethyl-2-methoxy-methoxymethyl) ethyl-41-hydrazinoceno [2,3-d] pyrimidine

Using the compound obtained in the above Step 6 as a raw material, the same operation as in Step 4 of Example 1 was performed to obtain the title compound as a colorless solid.

MS (EI) m / z 282

¾ NMR (CDCI3) δ: 1.42 (s, 3H), 3.37 (s, 6H), 3.54 (m, 4H), 6.50 (br, 1H), 7.03 (s, 1H), 8.50 (s, 1H). 8

Thiazole-2-carboxyaldehyde- {6- [1-methyl-2-methoxy-1- (methoxymethyl) ethynole] cheno [2,3-d] pyrimidine-4-yl} hydrazone

Using the compound obtained in the above step 7 and thiazole-2-carboxylic acid as starting materials, the same operation as in step 1 of Example 1 was performed to obtain the title compound as a yellow solid. MS (EI) m / z 377 (it).

^: H MR (DMSC / ₆ ) δ: 1.45 (s, 3H), 3.29 (s, 6H), 3.54 (AB type d, each 2H, 9.0 Hz), 7.88 (s, 1H), 7.89 (s, 1H) , 7.96 (s, 1H), 8.43 (s, 1H), 8.50 (s, 1H), 12.19 (br, 1H).

[Example 190]

Process 1

2,2-dimethyl-1,4-butanediol

To a solution of 6.1 g of 2,2-dimethosuccinic acid in 30 ml of tetrahydrofuran was added 100 ml of a borane-tetrahydrofuran solution (1.0 molar solution) under ice-cooling, followed by stirring for 14 hours. The reaction solution was poured into ice water, saturated with potassium carbonate, and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [form: methanol = 30: 1 (v / v)] to give 4.6 g of the title compound as a colorless oil.

_{¾ NMR (CDC1 3) δ:} 0.92 (s, 6H), 1.56 (t, 2H, / = 5.8 Hz), 2.90 (br s, IE),

3.36 (s, 2H), 3.73 (t, 2H, / = 5.8 Hz). Process 2

4- (ί-butyldiphenylsilyl / reoxy) -2,2-dimethyl-1-butanol

Using the compound obtained in the above step 1 as a raw material, the same operation as in step 1 of Example 93 was performed, The title compound was obtained as a colorless oil.

¾ Ran _{(CDC1 3) δ: 0.89 (} s, 6H), 1.05 (s, 9H), 1.54 (t, 2H, / = 5.9 Hz), 3.18 (br s, 1H), 3.37 (d, 2H, / = 6.9 Hz), 3.71 (t, 2H, zo = 5.9 Hz), 7.38-7.44 (m, 6H), 7.67 (d, H, J = 7.8 Hz).

4- (ί-butyldiphenylsilyloxy) -2,2-dimethyl-1-methoxybutane

To a solution of 8.0 g of the compound obtained in the above step 2 in 40 ml of acetonitrile were added 24 g of silver oxide and 80 ml of methyl iodide, and the mixture was refluxed for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography-hexane: ethyl acetate = 5: 1 (v / v)] to give 7.4 g of the title compound as a colorless oil.

Hidden (CDC1 ₃ ) δ: 0.86 (s, 6H), 1.04 (s, 9H), 1.60 (t, 2H, / = 7.3 Hz), 3.01 (s, 2H), 3.26 (s, 3H), 3.72 ( t, 2H, / = 7.3 Hz), 7.36-7.2 (m, 6H), 7.67 (d, 4H, = 7.6 Hz). Process 4

3,3-dimethyl-4-methoxy-1-butanol

Using the compound obtained in the above Step 3 as a raw material, the same operation as in Example 94 was carried out to obtain 0.32 g of the title compound as a colorless oily substance.

¾ thigh _{(CDC1 3) δ: 0.93 (} s, 6Η), 1.56 (t, 2H, / = 5.8 Hz), 3.12 (s, 2H), 3.36 (s, 3H), 3.64 (t, 2H, zo = 5.8 Hz) Process 5

Methyl 2-amino-5- (l, 1-dimethyl-2-methoxethyl) thiophene-3-carboxylate Using the compound obtained in the above step 4 as a raw material, the same operation as in step 4 of Example 18 The title compound was obtained as a yellow oil. MS (ESI) m / z 244 (M + H +)

¾ NMR (CDCI3) δ: 1.28 (s, 6H), 3.28 (s, 2H), 3.34 (s, 3H), 3.79 (s, 3H), 5.78 (br s, 2H), 6.68 (s, 1H). Process 6

6- (1,1-Dimethyl-2-methoxethyl) thieno [2,3-d] pyrimidin-4 (3-one) Using the compound obtained in the above Step 5 as a raw material, the same operation as in Step 2 of Example 1 was performed. This gave the title compound as an off-white solid.

MS (ESI) / z 239 (M + H ⁺ )

¾ NMR (CDCI3) δ: 1.42 (s, 6H), 3.36 (s, 3H), 3.1 (s, 2H), 7.28 (s, 1H), 8.01 (s, 1H), 11.91 (br s, 1H ). Step 7

4- ク口口 -6- (1,1-dimethyl-2-methoxethyl) thieno [2,3-d] pyrimidine

Using the compound obtained in the above Step 6 as a raw material, the same operation as in Step 3 of Example 1 was performed to obtain the title compound as a yellow oily substance.

MS (ESI) m / z 257 (Μ + Η

¾ NMR (CDCI3) δ: 1.47 (s, 6H), 3.37 (s, 3H), 3.45 (s, 2H), 7.16 (s, 1H), 8.77 (s, 1H). Step 8

6- (1,1-Dimethyl-2-methoxethyl) -4-hydrazinocheno [2,3-dl pyrimidine Using the compound obtained in the above step 7 as a raw material, the same operation as in step 4 of Example 1 was performed to obtain a target. The title compound was obtained as a colorless solid.

MS (ESI) m / z 253 (M + H ⁺ )

¾ MR (CDCI3) δ: 1.42 (s, 6H), 3.35 (s, 3H), 3.42 (s, _2H), 6.38 (br s, 1H), 6.95 (s, 1H), 8.50 (s, 1H). ' Process 9

Thiazole-2-hydroxypropyloxy- [6- (1,1-dimethyl-2-methoxethyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

The same operation as in step 1 of Example 1 was carried out using the compound obtained in the above step 8 and thiazole 2--2-propyloxyaldehyde as raw materials to obtain the title compound as a yellow solid. MS (FAB) m / z 348 (M + H +)

_{¾ MR (CDC1 3) δ:} 1.52 (s, 6H), 3.39 (s, 3H), 3.50 (s, 2H), 7.28 (d, 1H, = 3.2 Hz), 7.41 (d, 1H, / = 3.2 Hz ), 7.90 (s, 1H), 8.14 (s, 1H), 8.53 (s, 1H), 9.22 (br s, 1H).

[Example 1991]-Thiazole-2-carboxyaldehyde-[6- (2-hydroxy-1,1-dimethylethyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone

Example 9 3 Using the compound thiazole-2-carboxyaldehyde obtained in Step 5 as a raw material, the same operation as in Step 1 of Example 1 was performed, and then the same operation as in Example 94 was performed to obtain the title compound. Obtained as a pale yellow solid. Table 5 shows the structural formula and physicochemical properties of the compound of this example.

[Example 1 92]

5-isoindolinecarboxyaldehyde-[6- (2-methoxy-1,1-ethyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone dihydrochloride Example 1 Using the compound obtained in Step 8 and the compound obtained in Reference Example 14 as starting materials, the same operation as in Example 1, Step 5 was performed, and then the same operation as in Example 102 was performed to obtain the title compound. Obtained as a light brown solid.

MS (FAB) m / z 382 (M + H +).

¾ NMR (DMSO- ₆ ) δ: 1.42 (s, 6H), 3.30 (d, 3H, zo = 0.7 Hz), 3.44 (s, 2H), 4.56 (s, 4H), 7.55 (d, 1H, = 8.1) Hz), 7.93 (br s, 1H), 8.06 (br s, 1H), 8.55 (s, 1H), 10.01 (s, 1H), 10.50 (br s, 1H).

[Example 193]

Process 1

4-Methoxy-3-ethylbutyrate

Under ice-cooling, a suspension of 2.4 g of sodium hydride in 48 ml of tetrahydrofuran was added at night to a solution of 11.2 g of ethyl phosphonoacetate in 20 ml of tetrahydrofuran, and the mixture was stirred at the same temperature for 30 minutes. A solution of 4.4 g of methoxyacetone in 20 ml of tetrahydrofuran was added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in methanol (100 ml), and thereto was added 5% palladium-carbon (1.6 g), and the mixture was stirred under a hydrogen atmosphere for 14 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography using hexane: ethyl acetate = 6: 1 (v / v)] to give 5.6 g of the title compound as a colorless oil. _{¾ NMR (CDC1 3) δ:} 0.96 (d, 3H, zo = 6.8 Hz), 1.26 (t , 3H, = 7.3 Hz), 2.09 -2.26 (m, 2H), 2.43 (dd, 1H, J = 14.9, 5.9 Hz), 3.19-3.28 (m, 2H), 3.32 (s, 3H), 4.13 (q, 2H, / = 7.3 Hz). Process 2

6- (2-Methoxy-1-methylethyl) thieno [2,3-d] pyrimidine-4 (3-one

21 ml of 0.95M diisobutylaluminum hydride-hexane solution at 178 ° C under a nitrogen atmosphere was added to a solution of 2.9 g of the compound obtained in the above step 1 in a 100 ml solution of sword-hexane in a nitrogen atmosphere. Minutes. The reaction solution was added with 3 ml of methanol, returned to room temperature, and filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained aldehyde compound was used as a raw material, and the same operation as in step 1 of Example 1 was performed, and then the same operation as in step 2 of Example 1 was performed to obtain 0.5 g of the title compound as a colorless solid. As obtained.

MS (ESI) m / z 225 (M + H ⁺ )

_{¾ NMR (CDC1 3) δ ··} 1.40 (d, 3H, / = 7.1 Hz), 3.30- 3.36 (m, 1H), 3.39 (s, 3H), 3.53 (d, 2H, / = 6.4 Hz), 7.26 (s, 1H), 8.00 (s, 1H), 11.65 (br s, 1H). Process 3

4-6-Mouth mouth _6- (2-Methoxy-1-methylethyl) thieno [2,3-d] pyrimidine

Using the compound obtained in the above Step 2 as a raw material, the same operation as in Step 3 of Example 1 was performed to obtain the title compound as a pale yellow oily substance. ,

MS (ESI) m / z 243 (M + H +)

¾ NMR (CDCI3) δ: 1.45 (d, 3H, = 6.9 Hz), 3.39 (s, 3H), 3.0-3.44 (m, 1H), 3.54-3.60 (m, 2H), 7.18 (s, 1H ), 8.79 (s, 1H). Step 4

4-hydrazino-6_ (2-methoxy-1-methylethyl) thieno [2,3-d] pyrimidine

Using the compound obtained in the above Step 3 as a raw material, the same operation as in Step 4 of Example 1 was performed to obtain the title compound as a brown oily substance.

¾ 歷 (CDC1 ₃ ) δ 1.41 (d, 3H, / = 6.8 Hz), 3.36-3.38 (m, 1H), 3.38 (s, 3H), 3.51-3.60 (m, 2H), 7.75 (s, 1H) , 8.21 (br s, 1H), 8.43 (s, 1H). Process 5

Thiazole-2-carboxyaldehyde- [6- (2-methoxy-1-methylethyl) cheno [2,3-d] pyrimidine-4-yl] hydrazone

The same operation as in step 5 of Example 1 was carried out using the compound obtained in the above step 4 and thiazole-2-carboxylic acid aldehyde as raw materials to obtain the title compound as a brown solid. MS (FAB) m / z 334 (M + H ⁺ )

_{¾ NMR (CDC1 3) δ:} 1.50 (d, 3H, = 6.8 Hz), 3.39-3.42 (m, 1H), 3.41 (s, 3H), 3.58-3.66 (m, 2H), 7.41 (d, 1H, / = 2.6 Hz), 7.87 (s, 1H), 7.90 (d, 1H, / = 2.6 Hz), 8.15 (s, 1H), 8.54 (s, 1H).

[Example 1 94]

4-[(^-methylamino) methyl] -thiazole-2-carboxyaldehyde N— [6- (2-methoxy-; L-methylethyl) thieno [2,3-d] pyrimidine-4-yl ] Hydrazone dihydrochloride Example 1 9 3 The compound obtained in Step 4 and Reference Example 3 8 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 5 of Example 1 was performed. The same operation as in Example 02 was performed to obtain the title compound as a yellow solid.

MS (FAB) m / z 377 (M + H ⁺ )

¾ NMR (DMSO- ₆ ) δ: 1.39 (d, 3H, / = 6.9 Hz), 2.60-2.62 (m, 4H), 3.30 (s, 3H), 3.39-3.41 (m, 2H), 4.29-4.30 ( m, 2H), 7.82 (s, 1H), 7.92 (s, 1H), 8.53 (s, 2H), 9.17 (br s, 2H). [Example 1 95]

Process 1

4- (ί-butyldiphenylsilyloxy) -3-methylbutanoic acid

Using 3-butyldiphenylsilyloxyacetone as a raw material, the same operation as in Example 1, step 3 was carried out to give the title compound as a colorless oily substance.

¾ thigh _{(CDC1 3) δ '· 0.96} (d, 3H, zo = 6.6 Hz), 1.05 (s , 9H), 1.24 (t, 3H, J = 7.1 Hz), 2.12-2.17 (m, 1H), 2.56 (dd, 1H, / = 14.7, 5.1 Hz), 3.46 (dd, 1H, = 10.0, 6.3 Hz), 3.55 (dd, 1H, ZO = 10.0, 5.4 Hz), 4.10 (q, 2H, = 7, 1 Hz), 7.35—7.42 (m, 6H), 7.63-7.66 (m, 4H).

4- (ί-butyldiphenylsilyloxy) -3-methylbutanal

To a solution of 7.68 g of the compound obtained in the above step 1 in 100 ml of Λ-hexane, add 23.2 ml of 0.95M diisobutylaluminum hydride (-hexane solution) at 78 ° C under a nitrogen atmosphere at the same temperature. Stir for 30 minutes. 3 ml of methanol was added to the reaction solution, the temperature was returned to room temperature, and 20 ml of dichloromethane and 20 ml of a saturated aqueous sodium chloride solution were added. The two layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed successively with a 10% aqueous solution of citric acid and a saturated saline solution, and 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 = 6: 1 (v / v) 3] to give 5-6 g of the title compound as a colorless oily substance As obtained.

_{¾ NMR (CDC1 3) δ:} 0.95 (d, 3H, / = 6.6 Hz), 1.04 (s, 9H), 2.22-2.32 (m, 2H), 2.59-2.62 (m, 1H), 3.43 (dd, 1H, / = 10.0, 7.1 Hz), 3.57 (dd, 1H, J = 10.0, 5.1 Hz), 7.36-7.43 (m, 6H), 7.62 —7.70 (m, 4H), 9.78 (t, 1H, / = 2.0 Hz). Step 3

2-Amino-5- [2- (ί-butyldiphenylsilyloxy) -1-methylethyl] thiophene-3-carboxylate

Using the compound obtained in the above step 2 as a raw material, the same operation as in step 1 of Example 1 was performed to obtain the title compound as an orange oily substance.

Stomach (CDC1 ₃ ) δ: 1.05 (s, 9H), 1.27 (d, 3H, = 7.1 Hz), 2.96 (m, 1H), 3.58 — 3.68 (m, 2H), 3.78 (s, 3H), 5.78 (br s, 2H), 6.66 (s, 1H), 7.34-7.4 (m, 6H), 7.61-7.64 (m, 4H) .Step 4

6- [2- (ί-butyldiphenylsilyloxy) _1-methylethyl) thieno [2,3-d] pyrimidine-4 (3-one

Using the compound obtained in the above Step 3 as a raw material, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a brown oily substance.

MS (ESI) m / z 449 (M + H +)

_{¾ MR (CDC1 3) δ 1.05} (s, 9H), 1.46 (d, 3H, / = 7.1 Hz), 3.23-3.25 (m, 1H), 3.76 (d, 2H, / = 5.8 Hz), 7.21 (s , 1H), 7.34—7.42 (m, 6H), 7.59—7.63 (m, 4H), 8.00 (s, 1H). Process 5

[2-({6- [2- (ί-butyldiphenylsilyloxy) -1-methylethyl] cheno [2,3-d] pyrimidine-4-yl} hydrazonomethyl) thiazole-4-ylmethyl] -methylcarbamine Acid-butyl '' Using the compound obtained in the above step 4 as a raw material, the same operation as in step 3 of example 1 was performed, and the same operation as in step 4 of example 1 was performed. Using the obtained hydrazone and Reference Example 38, the aldehyde compound obtained in Step 2 was used as a raw material, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a pale yellow oily substance.

¾ original (CDC1 ₃ ) δ 1.03 (s, 9H), 1.48 (s, 9H), 1.49 (d, 3H, / = 6.9 Hz), 2.97 (br s, 3H), 3.35 (m, 1H), 3.84-3.87 (m, 2H), 4.55 (br s, 2H), 7.29-7.39 (m, 6H), 7.59-7.62 (m, 4H), 7.80 (s, 1H), 8.07 (s, 1H), 8.53 (s, 1H). Step 6

(2-{{6- (2-Hydroxy-1-methylethyl)) 'cheno [2,3-d] pyrimidine-4-yl] hydrazonomethyl} thiazole-4-ylmethyl) -t-butyl methylcarbamate Using the compound obtained in the above step 5 as a raw material, the same operation as in Example 94 was carried out to obtain the title compound as a brown oily substance.

_{¾ MR (CDC1 3) δ:} 1.34-1.37 (m, 3H), 1.48 (s, 9H), 2.97 (br s, 3H), 3.34 (m, 1H), 3.85-3, 92 (m, 2H), 4.54 (br s, 2H), 7.10 (br s, 1H), 7.82 (s, 1H), 8.01 (s, 1H), 8.44 (s, 1H). Step 7

4-(/ V-Methylaminomethyl) -thiazole-2-caproxyaldehyde N- [6- (2-Hydroxy-1-methylethyl) cheno [2,3-d] pyrimidine-4-y [Hydrazone dihydrochloride] The title compound was obtained as a yellow solid using the compound obtained in the above Step 6 as a raw material and performing the same operation as in Example 102.

MS (FAB) m / z 363 (M + H +)

¾ NMR (DMSO- ₆ ) δ: 1.26 (d, 3H, J = 6.9 Hz), 2.63-2.64 (m, 4H), 3.06- 3.09 (m, 2H), 4.12-4.18 (m, 2H), 7.68 ( s, 1H), 7.79 (s, 1H), 8.38 (s, 1H), 8.39 (s, 1H), 9.01 (br s, 2H). [Example 1 96]

4-[[// Methylamino) methyl] -thiazole-2 -caproloxyaldehyde N- (6-isobutylthieno [2,2> -d] pyrimidine-4-yl) hydrazone dihydrochloride

Example 1 19 Using the compound obtained in Step 4 and Reference Example 3 8 The compound obtained in Step 2 as starting materials, the same operation as in Step 5 of Example 1 was performed, and then the same operation as in Example 102 was performed. The title compound was obtained as a colorless solid.

MS (FAB) / z 361 (M + H +).

¾ MR (DMSO- ₆ ) δ: 0.99 (d, 6H, = 6.8 Hz), 1.93—2.01 (m, 1H), 2.58—2.61 (m, 3H), 2.83 (d, 2H, J = 6.8 Hz), 4.29 (m, 2H), 7.78 (s, 1H), 7.95 (s, 1H), 8.54 (s, 1H), 8.60 (br, 1H), 9.31 (br, 2H).

[Example 1 9 7]

4--Methylamino) methyl] -thiazole-2-carboxaldehyde _ (6-cyclobutythieno [2,3-d] pyrimidine-4-yl) hydrazone .2 hydrochloride

Example 1 3 2 Compound obtained in Step 4 Reference Example 3 8 Using the compound obtained in Step 2 as a raw material, the same operation as in Step 1 of Example 1 was performed, and then the same operation as in Example 102 The title compound was obtained as a yellow solid.

MS (FAB) m / z 359 (fcT + H)-

¾ NMR (DMSO- ₆ ) 5: 1.89-1 / 97 (m, 1H), 2.01-2.12 (m, 1H), 2.19-2.29 (m, 2H), 2.45-2.49 (m, 2H), 2.58-2.61 (t, 3H, / = 5.8 Hz), 3.86 (td, 3H, / = 8.5, 16.8 Hz), 4.29 (m, 2H), 7.83 (s , 1H), 7.96 (s, 1H), 8.54 (s, 1H), 8.61 (br, 1H), 9.33 (br, 2H).

[Example 1 98]

4_ [G ¥ ~ methylamino) methyl] -thiazole-2-carboxaldehyde N-[<-{sec-butyl) thieno [2,3-dlpyrimidine-4-yl] hydrazone · dihydrochloride

Example 12 The compound obtained in Step 4 and Reference Example 3 8 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 5 of Example 1 was performed.Then, the same operation as in Example 102 'was performed. This gave the title compound as a yellow solid.

MS (FAB) m / z 361 (M + H ⁺ ).

¾ NMR (DMSO—) δ: 0.92 (t, 3H, 7.3 Hz), 1.38 (d, 3H, / = 6.8 Hz), 1.68 — 1.76 (m, 2H), 2.58—2.61 (m, 3H), 3.06- 3.13 (m, 1H), 4.29 (m, 2H), 7.83 (s, 1H), 7.95 (s, 1H), 8.53 (s, 1H), 8.59 (br, 1H), 9.29 (br, 2H).

[Example 1 9 9]

4- [0V-Methylamino) methyl] -thiazole-2-carboxyaldehyde N-, la-cyc-propylpropyleno-3-d] pyrimidine-4-yl) hydrazone dihydrochloride

Example 1 3 1 The compound obtained in Step 4 and Reference Example 3 8 The compound obtained in Step 2 was used as a starting material. The same operation as in step 5 of Example 1 was performed, and then the same operation as in Example 102 was performed to obtain the title compound as a yellow solid.

MS (FAB) m / z 345 (M + H ⁺ ).

¾ MR (DMSO—) δ: 0.84-0.88 (m, 2H), 1.15-1.23 (m, 2H), 4.29 (t, 2H, / = 5.4 Hz), 7.77 (br, 1H), 7.98 (s, 1H) ), 8.53 (s, 1H), 8.66 (br, 1H), 9.83 (br, 2H).

[Example 200]

4,5,6,7-Tetrahydro [1,3] thiazolo [5,4-c] pyridine-2- 2-propoxyaldehyde N- [6-C? Ec-butyl) cheno [2,3-d] pyrimidine 4-Hyl] hydrazone .2 hydrochloride Example 12 Compound obtained in Step 4 Reference Example 31 The compound obtained in Step 1 was used as a starting material, and the same operation as in Step 5 of Example 1 was performed. Subsequently, the same operation as in Example 102 was performed to obtain the title compound as a red solid.

MS (FAB) m / z 373 (M + H ⁺ ).

¾ NMR (DMSO-4) δ: 0.91 (t, 3H, = 7.3 Hz), 1.38 (d, 3H, = 6.8 Hz), 1.71 (m, 2H), 3.04-3.11 (m, 3H), 3.49 (s , 2H), 4.48 (s, 2H), 7.78 (s, 1H), 8.9 (br, 1H), 8.53 (s, 1H), 9.76 (s, 1H), 9.80 (br, 1H).

[Example 201]

5--Methylamino) methyl] -thiazolyl-2-carboxylic acid- [6-Oec-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone dihydrochloride

Example 1 Compound obtained in Step 4 Reference Example 3 9 Using the compound obtained in Step 2 as a raw material, the same operation as in Step 5 of Example 1 was performed, and then the same operation as in Example 102 The title compound was obtained as an orange solid.

MS (FAB) m / z 361 (M + H +).

Hidden (DMS0-) δ 0.92 (t, 3H, / = 7.6 Hz), 1.38 (d, 3H, / = 7.1 Hz), 1.71 (dt, 2H, J = 14.4, 7.3 Hz), 2.57 (m, 3H ), 3.13 (dt, 1H, J = 13.9, 7.1 Hz), 4.48 (m, 2H), 7.77 (s, 1H), 8.05 (s, 1H), 8.47 (br s, 1H), 8.54 (s, 1H ), 9.39 (m, 2H).

[Example 20 2]

Process 4

Process 1

4-[(2-Methoxy-2-oxoethyl) sulfanyl] thieno [2,3-d] pyrimidine-6-force methyl rubonate

4,35-Dichloro-5-pyrimidinecarboxaldehyde (IMo tsh. Chem. 1965, 96, 1567) 2.35 g was dissolved in 50 ml of tetrahydrofuran, and 9.09 g of cesium carbonate and 2.43 ml of methyl thioglycolate were added. The mixture was stirred at ° C for 1 hour. Water was added to the reaction solution, which was extracted with methylene chloride. After the organic layer was washed with saturated saline, anhydrous sodium sulfate was added thereto and dried. The sodium sulfate was removed by filtration, and the solvent was concentrated under reduced pressure. The obtained residue was reprecipitated from ethyl acetate and 72-hexane to give 2.6 g of the title compound as an orange solid. -MS (FAB) m / z 299 (M + H ⁺ ). ¾ MR (CDCI3) δ: 3.78 (s, 3H), 3.98 (s, 3H), 4.18 (s, 2H), 8.07 (s, 1H), 8.55 (s, 1H) Step 2

4-oxo-3,4-dihydrocheno [2,3-d] pyrimidine-6-potassic acid

750 mg of the compound obtained in the above step 1 was dissolved in 15 ml of methanol, 10 ml of a 1 N aqueous sodium hydroxide solution was added, and the mixture was heated under reflux with 1 BJ6. The reaction solution was concentrated under reduced pressure, adjusted to pH 4 with acetic acid, and stirred at room temperature. The precipitated solid was collected by filtration and dried to give 477 mg of the title compound as a colorless solid.

MS (FAB) m / z 197 (M + H ⁺ ).

¾ NMR (CD3OD) δ: 7.88 (s, 1H), 8.25 (s, 1H). Step 3

4-cue mouth thieno [2,3-d] pyrimidine-6-carbonyl chloride

475 mg of the compound obtained in the above step 2 was suspended in 1.19 ml of oxysalt ichryline and stirred at 105 ° C. Goshidani Nirin was added, and the mixture was stirred at 110 ° C for 30 minutes and at 140 ° C for 4 hours. After cooling to room temperature, the mixture was poured into ice water, and the precipitated solid was collected by filtration to obtain 74 mg of the title compound as a pale yellow solid.

_{¾ NMR (CDC1 3) δ:} . 8. 34 (s, 1H), 9. 02 (s, 1H) Step 4

4-Cupro-,-dimethylthieno [2,3-d] pyrimidine-6-carpoxamide

200 mg of the compound obtained in the above step 3 was dissolved in 4 ml of tetrahydrofuran, 0.125 ml of triethylamine and 0.450 ml of 2M dimethylamine (tetrahydrofuran solution) were added under ice cooling, and the mixture was stirred for 30 minutes. The reaction solution was diluted with water, extracted with getyl ether, and washed with saturated saline. The 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 chromatography [chloropho [Lum: methanol = 20: 1 (v / v)], and the target fraction was concentrated to give 131 mg of the title compound as a yellow oily substance.

MS (ESI) m / z 242 (M + H ⁺ ).

_{¾ MR (CDC1 3) δ:} . 3.22 (s, 3H), 3.29 (s, 3H), 7.59 (s, 1H), 8.91 (s, 1H) Step 5

4-Hydrazino-dimethylthieno [2,3-] pyrimidine-6-hexylpoxamide

MS (ESI) m / z 238 (Μ + ίΓ).

¾ original (CD ₃ 0D) δ ·· 1.89 (s, 6H), 7.87 (br, 1H), 8.41 (s, 1H).

Ν, Ν-Dityl-4-[2 _ ({5-[(methylamino) methyl] -thiazol 2-yl} methylidene) hydrazino] thieno [2,3-] pyrimidine-6-carboxamide.2HCl salt

Compound obtained in Step 5 above Reference Example 3 9 Using the compound obtained in Step 2 as a starting material, the same operation as in Step 5 of Example 1 was performed, and then the same operation as in Example 102 was performed. The title compound was obtained as a brown solid.

MS (FAB) m / z 376 (M + H ⁺ ).

¾ NMR (DMSO- ₆ ) δ: 2.57 (m, 3H), 3.11 (br, 3H), 3.43 (br, 3H), 4.48 (m, 2H), 8.08 (s, 1H), 8.64 (s, 1H) , 9.65 (br s, 2H).

[Example 203]

Process 1

4-hydrazino-methylthieno [2,3-] pyrimidine-6-hexylpoxamide

Example 20 2 Using the compound obtained in Step 3 as a raw material and using 2 M methylamine (tetrahydrofuran solution), perform the same operation as in Step 4 of Example 20 2 and then perform the same operation as in Step 1 of Example 1. This gave the title compound as a colorless solid.

MS (ESI) m / z 224 (M + H +).

¾ NMR (DMSO- ₆ ) δ 2.78 (d, 3H, J = 4.4 Hz), 4.73 (br s, 1H), 8.37 (br s, 1H), 8.57 (br s, 1H), 9.0 (br s , 1H). Process 2

No V-Methyl-4 [2- ({5-[(Λmethylamino) methyl] -thiazonole 2-yl} methylidene) hydrazino] thieno [2,3-d] pyrimidine-6-potoxypamide dihydrochloride

Using the compound obtained in the above step 1 and the compound obtained in the reference example 39, step 2 as raw materials, the same operation as in step 5 of example 1 was performed, and then the same operation as in example 102 was performed, and the title compound was colored orange. Obtained as a solid.

MS (FAB) m / z 362 (M + H +).

¾ NMR (DMSO- ₆ ) δ2.58 (m, 3H), 2.83 (d, 3H, zo = 4.2 Hz), 4.48 (t, 2H, 4.2 Hz), 8.07 (s, 1H), '8.1 (s, 1H), 8.52 (s, 1H), 8.59 (s, 1H), 8.66 (br, 1H), 9.44 (br, 1H). [Example 2 04] 3

Process 1

3-Amino-5-(-butyl) -2-ethyl thiophenecarboxylate

2.05 g of sodium ethoxide was added to 15 ml of ethanol, and 1.5 ml of tidalicolic acid was added at room temperature. Then, a solution prepared by dissolving 2.15 g of 3-kuguchi-4,4,4-dimethyl-pent-2-ennitrile (J. Heterocyclic Chem. 1989, 26, 1575) in 2 ml of ethanol was added dropwise and stirred for 3 days. The reaction solution was concentrated, added with water, extracted with ether, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel chromatography [ethyl acetate: 3-hexane-2-1: 9 (v / v)] to give 2.38 g of the title compound as a yellow solid.

MS (EI) m / z 227 (M ⁺ ).

¾ NMR (CDCI3) S: 1.34 (s, 9H), 1.36 (t, 3H, / = 7.0 Hz), 4.27 (q, 2H, J = 7.0 Hz), 5.36 (br, 1H), 6.32 (s, 1H ). Process 2

6-(-Butyl) thieno [3,2-d] pyrimidine-4 (3-one

MS (ESI) m / z 209 (M + H ⁺ ).

^{X H NMR (DMSO -) δ} : 1.40 (s, 9H), 7.20 (s, 1H), 8.11 (s, 1H), 12.38 (br, 1H). Process 3

6- (ί-butyl) -4-chlorocheno [3,2-d] pyrimidine

MS (ESI) m / z 227 (M + H ⁺ )-

^{_{J H NMR (CDC1 3) δ}} :. 1.50 (s, 9H), 7.31 (s, 1H), 8.91 (s, 1H) Step 4

6- (ί-butyl) -1-4-hydrazinothieno [3,2-d] pyrimidine

MS (ESI) m / z 223 (M + H ⁺ ).

^ NMR (Xia SO-〉 6: 1.40 (s, 9H), 4.76 (br, 2H), 7.04 (s, 1H), 8.21 (s, 1H), 8.77 (s, 1H). Process 5

Thiazole-2-carboxaldehyde-[6- (ί-butyl) thieno [3,2-] pyrimidine-4-yl] hydrazone

Using the compound obtained in the above step 4 and thiazole-2 carboxaldehyde as raw materials, the same operation as in step 1 of example 1 was performed to obtain the title compound as a yellow solid. MS (ESI) m / z 317 (M + H ⁺ ).

¹ H NMR (DMS0-c / ₆ ) δ: 1.48 (s, 9H), 7.28 (s, 1H), 7.87 (d, 1H, / = 3.2 Hz), 7.96 (dd, 1H, = 3.2, 1.0 Hz) , 8.39 (s, 1H), 8.58 (s, 1H), 12.40 (s, 1H). [Example 20 5]

Process 1

ί-Butyl [2-({(E) -2- [6- (ί-butyl) cheno [3,2-d] pyrimidin-4-yl] hydrazono} methyl) -thiazol-4-yl] Methyl (methyl) carbamate

Example 204 Compound obtained in Step 1 Reference Example 3 8 Using the compound obtained in Step 2 as a starting material, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. ^{_{X H NMR (CDC1 3) δ}} : 1.48 (s, 9H), 1.53 (s, 9H), 2.98 (s, 3H), 4.57 (s, 2H), 7.23 (br, 1H), 7.25 (s, 1H) , 8.21 (s, 1H), 8.68 (s, 1H), 11.20 (br, 1H).

4-[(/ V-methylamino) methyl] -thiazole-2-carboxaldehyde- [6--butyl) thieno [3,2-dpyrimidine-4-yl] hydrazone · dihydrochloride

Using the compound obtained in the above step 1 as a raw material, the same operation as in Example 102 was carried out to obtain the title compound as a yellow solid. HN. MS (EI) m / z 360 (It).

'Η NMR (DMSO-^) δ: 1.51 (s, 9H), 2.60 (t, 3H, 3.2 Hz), 4.31 (t, 2H, / = 4.9 Hz), 7.39 (s, 1H), 8.05 (s, 1H), 8.65 (s, 1H), 8.85 (s, 1H), 9.36 (br, 1H).

[Example 206]

Process 1

ί-Butyl 2 _ ({2- [6-(-butyl) cheno [3,2-d] pyrimidine-4-yl] hydrazono} methyl) -6,7-dihydro [1,3] thiazolo [ 5, 4-c] pyridine-5 (4¾-hexyl propyloxylate Example 2 Using the compound obtained in Step 4 and the compound obtained in Reference Example 31 as a starting material, the same operation as in Step 5 of Example 1 was performed. . the compound was obtained as a yellow oil _{¾ MR (CDC1 3) δ:} 1.51 (s, 9H), 1.54 (s, 9H), 2.92 (s, 2H), 3.79 (br s, 2H), 4.74 (s, 2H), 7.24 (s, 1H), 8.08 (s, 1H), 8.64 (s, 1H).

4,5,6,7-tetrahydro [1,3] thiazo-mouth [5,4-c] pyridine-2-hydroxypropyl N- [6-(-butyl) cheno [3,2-d] pyrimidine -4-yl] hydrazone dihydrochloride

Using the compound obtained in the above step 1, the same operation as in Example 102 was performed to obtain the title compound as a yellow solid.

MS (FAB) m / z 373 (M + H +).

Concealment (DMS0—) δ: 1.49 (s, 9H), 3.06 (s, 2H), 3.55 (br s, 2H), 4.51 (br s, 2H), 7.36 (s, 1H), 8.50 (s, 1H) ), 9.70 (br s, 2H).

[Example 2 07]

Process 1

ί-butyl [2-({2- [6- (ί-butyl) thieno [3,2-d] pyrimidin-4-yl] hydrazono} methyl) -thiazole 5-yl] methyl (methyl) Carbamate

Example 2 04 The compound obtained in Step 4 and Reference Example 3 9 The same operation as in Step 5 of Example 1 was performed using the compound obtained in Step 2 as a starting material to obtain the title compound as a yellow oily substance. MS (FAB) m / z 461 (M + H ⁺ ).

_{¾NMR (CDC1 3) δ: 1.51} (s, 9H), 2.91 (br s, 3H), 4.63 (s, 2H), 7.24 (s, 1H), 7.70 (s, 1H), 8.13 (s, 1H), 8.66 (s, 1H). Process 2

5-[(^-methylamino) methyl] -thiazole-2-carboxaldehyde [6-(-butyl) cheno [3,2-d] pyrimidine-4-yl] hydrazone dihydrochloride

MS (FAB) m / z 361 (M + H +).

¾ NMR (DMSO-) δ1.52 (s, 9Η), 2.59 (m, 3H), 4.51 (m, 2H), 7.38 (s, 1H), 8.11 (s, 1H), 8.53 (s, 1H) , 8.83 (s, 1H), 9.47 (br, 1H), 9.55 (br, 1H).

[Example 20 8]

4- (2-Pyrrolidino) thiazole-2-carboxyaldehyde-[6- (ί-butyl) thieno [2,3-d] pyrimidine-4-yl] hydrazone dihydrochloride

Example 30 The compound obtained in Step 4 and the reference example 6 2 The compound obtained in Step 5 was used as a starting material, and the same operation as in Step 1 of Example 1 was performed.Then, the same operation as in Example 102 was performed. The title compound was obtained as a pale yellow solid. Table 3 shows the structural formula and physicochemical properties of the compound of this example.

[Example 209]

Process 1 -Butyl-1- [2-({) -2-[6- (ί-butyl) thieno [3,2-d] pyrimidine-4-yl] hydrazono} methyl) thiazole-4-yl] ethylcanolepam G

Example 204 Using the compound obtained in Step 4 of Reference Example 52 and the compound obtained in Step 5 as starting materials, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. _{¾ NM (CDC1 3) δ:} 1.46 (s, 9H), 1.52 (s, 9H), 1.55 (d, 3H, = 7.1 Hz), 4.96 (br s, 1H), 5.18 (br s, 1H), 7.18 (s, 1H), 7.24 (s, 1H), 8.16 (s, 1H), 8.67 (s, 1H). Step 2

4- (1-Aminoethyl) -thiazole-2-carpoxyaldehyde-[6-(-butyl) ceno [3,2-d] pyrimidine-4-inole] hydrazone 'dihydrochloride

Using the compound obtained in the above step 1 as a raw material, the same operation as in Example 102 was carried out to obtain the title compound as a yellow solid.

MS (FAB) m / z 361 (M + H ⁺ )

¾ original (DMSO- ₆ ) δ: 1.49 (s, 9H), 1.58 (d, 3H, / = 6.8 Hz), 4.60-4.63 (m, 1H), 7.37 (s, 1H), 7.94 (s, 1H) , 8.54 (br s, 2H), 8.61 (s, 1H), 8.81 (s, 1H).

[Example 210]

Process 1-3, 3-Dimethinole-4-methoxybutanone Dissolve 7.60 g of 3,3-dimethyl-4-hydroxybutanone (J. Am. Chem. Soc. 1998, 120, 4534) in 500 ml of getyl ether, and add 41.4 ml of methyl iodide and 151 g of silver salt. In addition, the mixture was heated under reflux for 3 days. After filtering the reaction solution, the filtrate was concentrated under normal pressure to obtain 6.83 g of the title compound as a colorless oily substance.

_{¾ MR (CDC1 3) δ:} . 1.13 (s, 6H), 2.16 (s, 3H), 3.32 (s, 3H), 3.37 (s, 2H) Step 2

3,4-Dimethyl-5-methoxypentenenitrile

Using the compound obtained in the above step 1 as a raw material, the title compound was obtained as a pale yellow oily substance according to the method described in the literature (;; Heterocyclic Chem. 1989, 26, 1575).

Thigh (CDC1 ₃ ) δ: 1.21 (s, 6H), 3.33 (s, 3H), 3.34 (s, 2H), 5.61 (s, 1H). Process 3

2-Amino-5-[(1,1-dimethyl-2-methoxy) ethyl methoxycarbonylthiophene

Using the compound obtained in the above Step 2 as a raw material, the same operation as in Step 1 of Example 204 was carried out to obtain the title compound as a pale yellow oily substance.

MS (EI) m / z 257 Of).

_{¾ NMR (CDC1 3) 5:} 1.30-1.35 (m, 9H), 3.33 (s, 2H), 3.34 (s, 3H), 4.27 (q, 2H, / = 7.1 Hz), 6.38 (s, 1H). Process 4

6-[(1,1-Dimethyl-2-methoxy) ethyl] -3-thieno [3,2-d] pyrimidin-4-one Using the compound obtained in the above step 3 as a raw material, The same operation was performed to obtain the title compound as a pale brown solid.

MS (FAB) m / z 239 (M + H +).

¾ MR (CDCI3) δ: 1.5 (s, 6H), 3.37 (s, 3H), 3.44 (s, 2H), 7.20 (s, 1H), 8.13 (s, 1H), 12.46 (br s, 1H) .Step 5

4- ク口口 -6-[(1,1-dimethyl-2-methoxy) ethyl] thieno [3,2-d] pyrimidine Same as step 3 in Example 1 using the compound obtained in step 4 as a starting material The title compound was obtained as a pale yellow oil.

MS (FAB) m / z 257 (M + If).

¾ thigh _{(CDC1 3) δ:. 1.48} (s, 6H), 3.38 (s, 3H), 3.47 (s, 2H), 7.37 (s, 1H), 8.91 (s, 1H) Step 6

{6-[(1,1-Dimethyl-2-methoxy) ethyl] thieno [3,2-d] pyrimidine-4-yl} hydrazine

Using the compound obtained in the above Step 5 as a raw material, the same operation as in Step 1 of Example 1 was performed to obtain the title compound as a pale yellow solid.

MS (FAB) m / z 253 (M + H +).

¾ NMR (DMSO—) δ: 1.36 (s, 6H), 3.26 (s, 3H), 3.1 (s, 2H), 4.77 (br s, 2H), 7.06 (s, 1H), 8.21 (s, 1H), 8.78 (s, 1H) .Step 7

4-[(jV-ty toxiccarbol- -methylamino) methyl] thiazole-2 -hexyloxy aldehyde-[6-[(1, tridimethyl-2-methoxy) ethynole] cheno [3,2-d] pyrimidine -4-yl] Hydrazon

Compound obtained in Step 6 above Reference Example 3 8 Using the compound obtained in Step 2 as a raw material, the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid.

MS (FAB) m / z 491 (M + if).

¾ NMR (CDCI3) δ: 1.8 (s, 9H), 1.51 (s, 6H), 2.97 (s, 3H), 3.40 (s, 3H), 3.52 (s, 2H), 4.56 (s, 2H), 8.13 (s, 1H), 8.66 (s, 1H).-Step 8

4-[(^-methylamino) methyl] thiazole-2-carboxyaldehyde-[6-[(1,1-dimethyl-2-methoxy) ethyl] thieno [3,2-d] pyrimidine-4-yl ] Hydrazone2 The title compound was obtained as a pale yellow solid by performing the same operation as in Example 102 using the compound obtained in the above step 7 as a raw material.

MS (FAB) m / z 391 (M + H ⁺ ).

Thigh (plate SO-) δ: 1.6 (s, 6H), 2.59 (s, 3H), 3.33 (s, 3H), 3.51 (s, 2H),

4.31 (s, 2H), 7.43 (s, 1H), 8.10 (s, 1H), 8.73 (s, 1H), 8.90 (s, 1H), 8.47 (s, 1H), 9.47 (br s, 2H).

[Example 2 1 1]

NH

'

Process 1

5-[(Λ ^ ί-Butoxycarboninole-methylamino) methyl] thiazole-2-carboxyaldehyde-[6-[(1,1-dimethyl-2-methoxy) ethyl] thieno [3,2-d ] Pyrimidine-4-yl] hydrazone

Example 2 10 Compound obtained in Step 6 Reference Example 3 8 The compound obtained in Step 2 was used as a starting material, and the same operation as in Step 5 of Example 1 was performed to obtain the title compound as a yellow solid. MS (FAB) m / z 491 (Μ + ΐΓ).

_{¾NMR (CDC1 3) δ: 1.51} (s, 15H), 2.90 (br s, 3H), 3.39 (s, 3H), 3.51 (s, 2H), 4.64 (s, 2H), 7.30 (s, 1H), 7.70 (s, 1H), 8.16 (s, 1H), 8.66 (s, 1H). Process 2

5-[(V-Methylamino) methyl] thiazole -2 -caproloxyaldehyde-[6-[(1,1-dimethyl-2-methoxy) ethyl] thieno [3,2-d] pyrimidine-4-- [Yield] hydrazone * 2 Using the compound obtained in the above step 1 as a raw material, the same operation as in Example 102 was performed to obtain the title compound as a yellow solid.

MS (FAB) m / z 391 (M + fT)-

¾ NMR (DMSO −) δ: 1.48 (s, 6H), 2.58 (s, 3H), 3.32 (s, 3H), 3.54 (s, 2H), 4.50 (s, 2H), 7.3 (s, 1H) ), 8.16 (s, IE), 8.63 (s, 1H), 8,91 (s, 1H), 9.73 (brs, 2H). Tables 1 to 5 show the physicochemical data of the compounds in the examples. . In the table, Ex indicates the example number, NMR indicates data of a 40 OMHz nuclear magnetic resonance spectrum, and Mass indicates a mass spectrometry value.

902

ll / l0df / X3d 6 so / zo OAV 90S

ll / l0df / X3d 6 so / zo OAV

Ex.- A ¹ H NMR (solv.contains TMS) δ Mass

(CDCI ₃ ) δ: 1.51 (s, 9H), 7.08 (dd, 1H, J = 5.1,

3.0 Hz), 7.24 (d, 1 H, J = 3.2 Hz), 7.39 (d, 1 H, J (EI) m / z 316

30 = 4,6 Hz), 7.89 (br, 1H), 8.05 (br, 1H), 8.46 (br,

(M ⁺ ).

* 1H).

(CDCI ₃ ) 6: 1.51 (s, 9H), 7.28 (m, 1H), 7.79 (dt,

1H, J = 7.8, 1.5 Hz), 7.85 (s, 1H), 7.98 (d, 1H, (EI) m / z 311

31 J = 8.1 Hz), 8.01 (s, 1 H), 8.52 (br, 1 H), 8.64 (d,

( ⁺ ).

* 1H, J = 4.9 Hz).

(CDCI ₃ ) δ: 1.50 (s, 9H), 7.39 (dd, 1H, J = 7.8,

4.9 Hz), 7.80 (br, 1H), 7.91 (br, 1H), 8.02 (dt,

1H, J = 8.1, 1.7 Hz), 8.50 (br, 1H), 8.62 (dd, (EI) m / z 311

32

^ H, J- 4.9, 1 Hz), 8.92 (d, 1 H, J = 2.0 Hz), ( ⁺ ). 9.18 (br, 1 H).

(CDCI ₃ ) 6: 1.52 (s, 9H), 7.55 (d, 1H, J = 5.9

Hz), 7.81 (s, 1H), 7.83 (s, 1H), 8.53 (s, 1H), 8.70 (EI) m / z 311

33

(d, 2H, J = 6.1 Hz). (M ⁺ ).

* ' ^N

(CDCI3) δ: 1.50 (s, 9H), 2.40 (s, 3H), 7.60 (d,

1H, J = 8.1 Hz), 7.84 (s, 1 H), 7.89 (d _t 1 H, J = (FAB) m / z 326

34

(7.8 Hz), 7.99 (s, 1H), 8.47 (s, 1H), 8.51 (s, 1H). (M + H ⁺ ).

(CDCI ₃ ) (5: .49 (s, 9H), 7.32 (dt, 1H, J = 8.3,

4.2 Hz), 7.53 (t, 1H, J = 9.0 Hz), 8.06 (d, 2H, J (FAB) m / z 330

35 = 5.4 Hz), 8.49 (d, 1H, J = 4.4 Hz), 8.53 (s,

(M + H ⁺ ).

* 1H).

(CDCI3) 6: 1.50 (s, 9H), 3.93 (s, 3H), 7.28-7.31

(m, 2H), 7.83 (br s, 1H), 7.91-7.99 (m

36, 2H), 8.32 (FAB) m / z 342

(d, 1H, J = 2.1 Hz), 8.50 (br s, H). 602

/ l0df / X3d 6 so / zo OAV OTC

^ sciT / TOdf / xad 61-81 S0 / Z0 OAV

tiillllddilLJd 6 so / 0 ΟΛΛ

/ lO <If X3d 6 so / zo OAV

^ seii / iodf / i3d *, (DMSO— / ₆ ) δ: 1.47 (s, 9H), 2.64 (d, 3H, J

(ESI) m / z 429

175 3.9 Hz), 4.56 (s, 2H), 7.80 (s, 1H), 8.56 (s, 1H),

(M + H +). 8.58 (br, 1 H), 9.93 (br, 1 H).厂NH ₂

(D SO-d ₆ ) (5: 1.44 (s, 9H), 4.04 (br, 2H), 7.97

(FAB) m / z 331

176 ji (s, 1 H), 8.34 (s, 1 H), 8.52 (br s, 2H), 8.54 (s,

(M + H. 1H).

* ^N ' ^N Factory NH ₂

7 (s, 9H), 4.18 (br, 2H), 7.87

178 XS (DMSO— d ₆ ) δ 1.4

(FAB) m / z 347 (br, 1 H), 7.88 (s, 1 H), 8.49 (br, 3H), 8.53 (s,

(M + H +). 1H).

Ί (DMSO—) 5: 1.44 (s, 9H), 2.60-2.63 (m, 2H),

(EI) m / z 374

182 ^N / ^NH 4.53-4.56 (m, 2H), 6.73 (s, IH), 7.95 (s, 1H),

( ⁺ ). 8.32 (br, 1H), 8.54 (s, 1H), 9.17 (br, 2H).

(DMSO-) (5: 1.43 (s, 9H), 1.91-1.99 (m, 2H),

2.21 (br, 2H), 3.09-3.12 (m, 2H), 3.20-3.24 (m, (EI) m / z 400

183

2H), 4.89-4.93 (m, 1H), 6.70 (s, 1H), 7.89 (s, (M ⁺ ). 1H), 8.24 (br, 1H), 8.52 (s, 1H), 9.00 (br, 2H ).

(DMSO-d ₆ ) (5: 1.44 (s, 9H), 2.23 (s, 3H), 2.45- 2.49 (m, 4H), 3.18-3.21 (m, 4H), 6.12 (d, 1H, J (EI ) m / z 414

184

= 4.2 Hz), 7.10 (d, 1H, J = 4.2 Hz), 7.88 (br, (M ⁺ ). RN 1H), 8.17 (s, 1H), 8.32 (s, 1H), 11.59 (br, 1H) .

(DMSO-d ₆ ) (5: 1.45 (s, 9H), 2.22 (s, 6H), 3.62

(s, 2H), 6.95 (d, 1 H, J = 3.7 Hz), 7.25 (d, 1 H, J (EI) m / z 373

185

= 3.7 Hz), 7.87 (br, 1H), 8.31 (br, 1H), 8.39 (s, (M

*-N 1H), 11.79 (br, 1H).

(DMSO-d ₆ ) δ 1.46 (s, 9H), 1.57 (d, 3H, J =

(FAB) m / z 361

186 6.8 Hz), 4.57-4.61 (m, 1H), 7.87 (brs, 2H), 8.52

(+ H ^. (Br s, 4H).

*-N ST2

SCll / T0df / X3d 6 8lS0 / Z0 OAV 9TZ

Hara / l0df / X3d 6 so / zo OAV LIZ

l / l0df / X3d 6 so / zo OAV 8T2

l / l0df / X3d 6 so / zo OAV 6

SCTT / T0df / X3d 61 ^ 81 SO / ZO OAV ozz

/ l0df / X3d 6 so / zo OAV (CDCIg) (5: 1.51 (s, 9H), 2.57 (s, 3H), 3.48 (br

Wide

s, 2H), 3.92 (m, 1H), 3.99 (br s, 2H), 7.38 (d

0 (FAB) m / z 380 2H J = 7.8 Hz), 7.68 (d 2H, J = 7.8 Hz), 7.86

(M + H. (S, 1 H), 7.87 (s, 1 H 8.48 (s, 1 H 8.92 (br s

0 (CDCI ₃ ) d: 1.50 (s, 9H), 4.89 (s, 2H), 7.52 (d

2H, J = 8.1 Hz), 7.65 (d, 2H, J = 8.1 Hz), 7.73

(FAB) m / z 470 (dd, 2H, J = 5.4, 2.9 Hz), 7.83 (s 1 H), 7.83 (s,

'(Μ + Η · 1 H 7,87 (dd _; 2H, J = 7.4, 2.9 Hz), 8.47 (br s,

1 ri)

(DMSO-c / ₆ ) δ: 1.43 (s 9H), 6.84 (d 2H J =

(FAB) m / z 327 8.5 Hz), 7.54 (d, 2H, J = 8.5 Hz), 7.82 (br s,

(M + H ⁺ ) .2H), 8.13 (s, 1 H), 8.36 (s, 1 H).

* One N

(DMSO— d ₆ ) δ: 1.42 (s, 9H), 6.90 (t, IH, J =

7.3 Hz), 6.92 (d, 1 H, J 7.3 Hz), 7.25 (dt, 1 H (FAB) m / z 327 J = 8.5, 1.5 Hz), 7.66 (t 1 H, J = 6.4 Hz) , 7.67 (M + H ⁺ ).

OH

氺 (br, 1 H), 8.41 (s, 1 H), 8.52 (s, 1 H).

(CDCI3) 6: 1.48 (s, 9H), 1.50 (s 9H), 4.37 (d,

X Boc 2H, J = 5.6 Hz), 4.90 (br s, 1 H), 7.36 (s, 1 H), (FAB) m / z 440

7.37 (d, 2H J = 8.1 Hz), 7.68 (d, 2H J = 8.1 (M + H ⁺ ) .Hz), 7.86 (s, IH), 7.87 (s, 1 H), 8.48 (s, 1 H ).

(DMSO-d ₆ ) (5: 1.46 (s, 9H), 3.68 (br s, 2H

4.08 (s 2H), 7.60 (d, 2H, J = 8.3 Hz), 7.83 (d, (FAB) m / z 340 2H, J = 8.3 Hz), 7.95 (s, 1 H), 8.46 (s 1 H ), 8.48 (M + H

氺 (s, 1 H).

(DMSO-d ₆ ) (5: 1.46 (s, 9H), 3.09 (t 2H J-

^ CG ^NH 6.6 Hz), 3.40 (br s, 2H), 4.30 (s, 2H), 7.34 (d, (FAB) m / z 366

1 H, J = 8.5 Hz), 7.65 (s, 1 H), 7.66 (d, 1 H J (M + H +). 8.5 Hz), 7.93 (s, 1 H).

(CDCIg) d: 1.47 (s, 9H), 2.38 (s, 3H), 7.42 (m

(FAB) m / z 325 3H), 7.82 (d, 2H, J = 7.8 Hz), 7.95 (s 1 H 8.47

(Μ + Η (s, 1 H 8.87 (br, 1 H). zzz

6 so / zo OAV

/ l0df / X3d 6 so / zo OAV fZZ

S £ ll / l0df / X3d 6 so / zo OAV [Experimental example 1 Cd k4 activity inhibition test]

Method

1-1) Cd k activity measurement method

The compound of the present invention is dissolved in dimethyl sulfoxide (hereinafter abbreviated as DMSO), and a complex of cyclin D1 and Cdk4 or a complex of cyclin E and Cdk2, a GST-fused Rb protein and ³³ : P-ATP And reacted at 30 ° C. for 30 minutes, and the radioactivity incorporated into Rb was measured.

o

1-2) Calculation method of inhibitory capacity

The concentration of the drug that inhibits the Cdk4 or Cdk2 activity by 50% when DMSO was added was shown as an IC50 value (μg / m 1). Table 6 shows the results. The compound of the present invention inhibited the phosphorylation of Rb by Cdk4, and showed 6.4 to 43.7 times stronger activity than Cdk2. Table 6 Compounds

C d k 4 C d k 2

Example 62 0.077 0.65

Example 82 0.096 1.0

Example 93 0.062 0.84

Example 104 0.083 0.53

Example 168 0.042 0.35

Example 186 0.019 0.98

Example 198 0.029 0.44

Example 205 "0.050 0.85 [Experimental example 2: Measurement of antitumor activity]

Method

Human colon cancer cell line HCT116 cells were seeded in a 96-well microtiter plate at 1 × 10 ³ to 5 × 10 ³ cells Z 90 μ1 / well, and the following day, the sample was inoculated to 1 μμΖ ゥ well. I cooked it. 3. After culturing for 3 days, dissolve 5 mg / ml of Τ 3 [3-(4, 5-Dimeth-ylthiazol-2-yl) -2, 5-diphenyl-2H-tetrazolium bromide] solution in 10 μl Z The cells were further cultured for 4 hours. After removing the culture solution, DMSO was added to kneaded rice with 150 1 Zell to dissolve the formazan, and the absorbance was measured at 540 nm. The anti-S swelling effect was expressed as the GI 50 value (ngZml), which was the drug concentration at which the cell proliferation in the drug-added group was 50% of the control group.

Result

The results are shown in Table 7. The compound of the present invention suppressed cell proliferation at a low concentration in the HCT116 cell line. Table 7

[Experimental example 3; Cell cycle distribution measurement test] Method

Human colon cancer HCT116 cells were seeded at 2.5 × 10 ⁵ cells in a Z diameter of 6 Omm dish, and the next day, the compound of the present invention was dissolved in DMSO, and a solution prepared to a predetermined concentration was added. . After 16 hours of culture, the cells were collected, and the cell cycle distribution was measured by a flow cytometry method using a cycle test kit (manufactured by Becton Dickinson). Table 8 shows the results. The compound of the present invention increased the rate of G1 phase as compared with the control, and increased the amount of carp. Table 8

Industrial applicability

The compounds of the present invention show a strong C dk 4 inhibitory activity, and And a divergence of 6.4 to 43.7 times is obtained. Furthermore, the compound of the present invention induces the cell cycle distribution in G1, and has a cell regulatory action. Therefore, the compound of the present invention is useful as an active ingredient of a medicament for preventing and / or treating tumors including malignant tumors.

Claims

The scope of the claims

1. The compound represented by the following general formula (IA) or the general formula (IB) or a salt thereof, or a hydrate or a solvate thereof:

Wherein X represents a sulfur atom, an oxygen atom, or N—R ⁵ (R ⁵ represents a hydrogen atom or an alkyl group which may have a substituent);

Y represents a nitrogen atom or CH;

Z is a nitrogen atom or C one R ⁶ (R ⁶ is a hydrogen atom, a halogen atom, an alkyl group, hydrin Rokishiarukiru group, an aminoalkyl group, Shiano group, forces Rubamoiru group, carboxy group or C_〇 ₂ R ^⁶¹ (R ^61, Represents an alkyl group), represents) or represents;

R ¹ and R ² each independently represent a hydrogen atom, an alkyl group, an alkoxy group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an acyl group, a mercapto group, an alkylthio group, an alkylsulfiel group, an alkylsulfonyl group, amino groups, mono- Arukiruamino group, a dialkyl § amino group, a force Rubamoiru group, monoalkyl § amino Karuponiru group or indicates dialkylamino local port two group, these groups may have a substituent, or R ¹ And R ² may combine with each other to form a 3- to 7-membered hydrocarbon ring or a 3- to 7-membered heterocyclic ring, and the formed hydrocarbon ring or the heterocyclic ring has a substituent. May be;

4 represents a hydrogen atom or an alkyl group which may have a substituent;

A is the formula (II):

Equation (ΠΙ):

Formula (IV):

(Wherein B represents an aryl or heteroaryl ring fused to the above-mentioned cyclic hexane ring) (in the above formulas (11), (111) and (IV) In the group represented by the formula, the bond represented by the wavy line indicates that the compound represented by the formula (I) is either a syn or anti isomer, or a mixture of both isomers).

2. The compound according to claim 1, wherein X is a sulfur atom, and Y and Z are each a nitrogen atom, a salt thereof, or a hydrate or solvate thereof.

3. R ² is an alkyl group (the alkyl group is a fluoro group, a chloro group, a bromo group, an aldehyde group, a hydroxyl group, an alkoxy group, an amino group, a monoalkylamino group, a dialkyl ecylamino group, a dialkylglycyloxy group , Alkylsulfonyloxy group and And at least one substituent selected from the group consisting of a carbamoyloxy group and a compound thereof, or a salt thereof. Or hydrates or solvates thereof.

4. The compound or a salt thereof according to claim 3, wherein R ² is a t-butyl group (the t-butyl group may be substituted with one or more hydroxyl groups). Or hydrates or solvates thereof.

5. A is a group represented by the above formula (II), R ⁷ is as defined above, and R ⁸ is a phenyl group [the phenyl group is a group represented by the following:

Fluoro group, chloro group, bromo group, odo group, alkyl group, hydroxyalkyl group, substituted silyloxyalkyl group, carboxyl group, alkoxycarbonyl group, tetrazolyl group, amino group, monoalkylamino group, dialkylamino group , Cyano group, carbamoyl group, nitro group, hydroxyl group, alkoxy group, mercapto group, sulfonamide group, benzyloxy group, N-alkylsulfamoyl group, N, N- '

Equation (V):

(Wherein, R ^{1 Q} represents a hydrogen atom or an alkyl group)

Equation (VI):

(Wherein represents an integer of 0 to 6; R ¹¹ represents a hydrogen atom, an alkyl group or a hydroxyalkyl group), and

Formula (VII):

(Wherein m ₂ represents an integer of 0 to 6; R ¹² and R ¹³ each independently represent a hydrogen atom, an alkyl group, an alkoxycarbonylalkyl group, or a hydroxyalkyl group) Base

The compound according to Claims 1 to 4, or a salt thereof, or a hydrate thereof, which may have one or more substituents selected from the group consisting of Or their solvates.

6. The compound according to claim 5, wherein R ⁸ is a phenyl group having one or more groups represented by the above formula (VII), a salt thereof, or a hydrate thereof. Or their solvates.

7. A is the following formula (VIII):

(Wherein, R ⁷ has the same meaning as described above, the nitrogen-containing ring fused to the benzene ring is a 5- to 7-membered ring, and R ¹⁴ is a hydrogen atom, an alkoxy group, an alkyl group, an alkoxycarbonyl, 5. The compound according to claim 1, which is an alkyl group or a carboxylalkyl group, or a salt thereof, or a hydrate or solvate thereof.

8. Α is a group represented by the above formula (II), R ⁷ is as defined above, and R ⁸ is a 5- or 6-membered heterocyclic group (the heterocyclic group has a substituent. And at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom as a ring-constituting atom). Or a salt thereof, or a hydrate or solvate thereof.

9. A is a group represented by the above formula (Π), R ⁷ is as defined above, and R ⁸ is a 5-membered heterocyclic group (the heterocyclic group may have a substituent Well, nitrogen atoms as ring constituent atoms 9. The compound according to claim 8, wherein the compound has 1 to 3 heteroatoms selected from the group consisting of oxygen, oxygen and sulfur, or a salt thereof, or a hydrate or solvate thereof. object.

10. A is a group represented by the above formula (II), R ⁷ is as defined above, and R ⁸ is a thiazolyl group, an oxazolyl group, a phenyl group, an imidazolyl group, a pyridinyl group, an isoxoxazolyl group. , Isothiazolyl, or furyl (the above groups are selected from the group consisting of fluoro, chloro, bromo, eodo, alkyl, aminoalkyl, monoalkylaminoalkyl, and dialkylaminoalkyl) Or a salt thereof, or a hydrate or a solvate thereof, according to any one of claims 1 to 4, which may have one or more substituents. object. '

11. A is a group represented by the above formula (Π), R ⁷ is as defined above, and R ⁸ is a pyridyl group [the pyridyl group is a group represented by the following:

Fluoro, chloro, bromo, eodo, hydroxyl, alkoxyl, benzyloxy, nitro, amino, alkyl, hydroxyalkyl, formula (IX): (IX)

Formula (X):

(Wherein, m ₄ represents an integer of 0 to 6; G represents an oxygen atom, a sulfur atom, S〇, S〇 ₂ , CH ₂ or N—R ¹⁷ , and R ¹⁷ is a hydrogen atom or alkyl Represents a group), and Formula (XI):

(XI)

(Wherein, m _s is 0 to 6 represents an integer of) the range of the substituents selected from the groups represented by have one or two or more may also be] according paragraph 1 to 4 Or a salt thereof, or a hydrate or solvate thereof. 12. A is the following formula (XII):

(Wherein, R ⁷ is as defined above, the nitrogen-containing ring fused to the thiazolyl ring is a 5- to 7-membered ring, and R ¹⁸ is a hydrogen atom, an alkyl group, an alkoxycarbonylalkyl group, 5. The compound according to claims 1 to 4, or a salt thereof, or a hydrate or a solvate thereof, which is a group represented by the following formula: object.

13. A is the following formula (XIII):

(Wherein, R ⁷ has the same meaning as described above; R ¹⁹ and R each independently represent a hydrogen atom, an alkyl group, an alkoxy group, an amino group, a monoalkylamino group, a dialkylamino group, Or a nitrogen-containing heterocyclic group, wherein the alkyl group may be substituted with an amino group, a monoalkylamino group, or a dialkylamino group). Item 4. The compound according to item 4, a salt thereof, or a hydrate or solvate thereof.

14. The group consisting of the compound according to any one of claims 1 to 13 and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof. A medicament comprising as an active ingredient a substance selected from the group consisting of:

15. The medicament according to claim 14, which is an antitumor agent.

16. The group consisting of the compound according to any one of claims 1 to 13 and physiologically acceptable salts thereof, and hydrates and solvates thereof. Cyclin-dependent kinase 4 containing a substance selected from the group consisting of

17. Consisting of the compound according to any one of claims 1 to 13 and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof. A cell cycle regulator comprising a substance selected from the group as an active ingredient.

18. The group consisting of the compound according to any one of claims 1 to 13 and physiologically acceptable salts thereof, and hydrates and solvates thereof. A cell cycle G1-phase accumulating agent comprising a substance selected from the group consisting of: