JPH10195063A - Ethynylthiazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide the subject composition having antagonistic action on leukotriene and action to suppress isolation of histamine from mast cell and useful as an active component of an agent for the treatment and prevention of allergic diseases. SOLUTION: This compound is expressed by the formula I [R<1> and R<2> are each H, a halogen, a (substituted)alkyl, etc.; A is a (substituted)phenyl, etc.; G<1> is O, carbonyl, etc.; G<2> is a (substituted)phenyl, etc.; (m) and (n) are each 0 or 1; Q is carboxyl, etc.; excluding the case that both (m) and (n) are 0 and Q is carboxyl or an alkoxycarbonyl], e.g. 5-(3-(2-(4-cyclobutyl-2-thiazolyl)ethyl) phenyl)-1H-tetrazole. The compound of the formula I can be produced by the coupling reaction of an ethynylthiazole compound of the formula II with a compound of the formula III (L is a polyfluorosulfonylakoxy, etc.) in an inert solvent in the presence of triphenyl phosphine, etc., at a temperature between 0 deg.C and the boiling point of the solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an ethynylthiazole derivative which has a physiological activity such as an anti-allergic effect and is useful as an active ingredient of a medicine.

[0002]

BACKGROUND ART Bronchial asthma is classified as allergic disease is a disease characterized by chronic inflammation of the airways, leukotrienes (LTs) as the causative agent, thromboxane A ₂ (TXA _2), platelet-activating factor ( Various chemical substances (inflammatory mediators) such as PAF), histamine, and prostaglandin (PG) are known to be involved. Leukotrienes, one of these inflammatory mediators, are thought to be one of the main factors involved in the development of allergic tracheal and bronchial diseases, allergic lung diseases, allergic shock, or allergic inflammation. (Proc. Natl. Acad. Sci. U
SA. 80: 1712-1716, 1983). Also,
Peptide leukotrienes (LTs) are inflammatory mediators produced by arachidonic acid metabolism, and include leukotriene C ₄ (LTC ₄ ), leukotriene D ₄ (LT
D _4), and leukotriene E ₄ (LTE ₄₎ are known (Science, 220: 568-575,1
983).

[0003] Many physiologically active substances (receptor antagonists) which bind to these leukotriene receptors (receptors) and antagonize leukotrienes have been reported (Chi).
Mia 46: 304-311, 1992; M
ed. Chem. 1996, 39 (14) 2629-2
654). Also, a leukotriene receptor antagonist 4-oxo-8- (4- (4-phenylbutoxy) benzoylamino) -2- (tetrazol-5-yl) -4H-1
-Benzopyran hemihydrate (Pranlukast:
Drugs of the Future 1988,
13,317-320) is being reported [History of Medicine, 164 (4): 225-24].
7, 1993; Immunopharmacology, 12 (2): 116 (22
2) -118 (224), 1994; and clinical medicine,
9 (S-1): 71-107, 1993], the usefulness of these leukotriene receptor antagonists is being recognized.

[0004] On the other hand, mast cells, eosinophils, basophils, etc. are cells producing the above-mentioned inflammatory mediators, and include allergic tracheal and bronchial diseases, allergic lung diseases, allergic shock, or allergic diseases. It plays an important role in the pathology of various inflammations. Mast cells, one of the representative inflammatory cells, are activated when exposed to an antigen again in a sensitized state (a state in which an IgE antibody against the antigen is bound to an Fc receptor on the cell surface),
As a result, histamine, chemical mediators of LTC ₄ or the like is released, vascular hyperpermeability, telangiectasia, cause smooth muscle spasm and the like.

As an agent for suppressing this series of reactions, disodium chromoglycate (DSCG) [The
Merck Index, 9th edition 2585 (197
6)] and 9-methyl-3- (1H-tetrazole-5
-Yl) -4H-pyrido [1,2-a] pyrimidine-4
-One potassium salt (pemirolast potassium) (JP-A-54-36294) is known. Antiallergic drugs are classified into basic antiallergic drugs having an antihistamine action and acidic antiallergic drugs having no such action. Pemirolast potassium is a typical example of an acidic antiallergic drug. Acidic antiallergic drugs have no antihistamine action and thus have no side effects such as dry mouth feeling and drowsiness. [Modern medicine, 26 (7) 137 (2143) -139 (21
45), 1994; Modern Medicine, 26 (7) 251 (2)
257) -255 (2261), 1994; and Pr
Ogres in Medicine, Volume 13 (1
0), 137 (2247) -147 (2257), 19
93]. However, although these drugs can be applied to bronchial asthma, they have the problem that their clinical satisfaction is not so high.

[0006]

The reason why the above-mentioned antiallergic drugs are not clinically satisfactory is that the causative substances (inflammatory mediators) that cause allergic diseases differ from individual to individual, and a plurality of causative substances are involved simultaneously. And that the diagnostic technique for identifying the causative substance is generally complicated. Therefore, when preventing or treating an allergic disease using an anti-allergic agent, a drug which simultaneously exerts a plurality of anti-allergic actions is more effective than a drug having a single action as a conventional anti-allergic drug. It is expected to be useful for prevention and treatment of a wider range of allergic diseases. In addition, by administering a single drug having a plurality of actions in this way, attenuated actions due to drug interactions when multiple drugs are simultaneously administered, manifesting various side effects, or reducing medical economics, etc. Problem may be avoided.

In particular, if a compound having both an antagonistic action against leukotriene, which has been proven to have a clinical therapeutic and / or preventive effect, and an action to inhibit the release of mediators such as histamine, can be provided, a more widespread allergic disease It is expected that the treatment and / or prevention of will become possible. Therefore, an object of the present invention is to provide a therapeutic and / or prophylactic agent for allergic diseases represented by bronchial asthma, and more specifically, a leukotriene antagonism and a histamine release inhibitory effect from mast cells. And to provide a compound useful as an active ingredient of a drug for treating and / or preventing an allergic disease.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies in order to achieve the above object, and as a result, have found that an ethynylthiazole derivative represented by the following formula has a leukotriene antagonism and histamine release from mast cells. It has been found that the compound has both an inhibitory effect and that the above two effects can be simultaneously and continuously expressed by orally administering the compound. The present invention has been completed based on the above findings.

That is, the present invention provides a compound represented by the general formula (1):

Embedded image [Wherein, R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or R ¹ and R ² are A represents a ring formed together; A represents a phenyl group which may have a substituent, a pyridyl group which may have a substituent, a furyl group which may have a substituent, and a group which may have a substituent Thienyl group, benzofuranyl group which may have a substituent, benzo [b] thienyl group which may have a substituent, benzooxazolyl group which may have a substituent, benzothiazolyl group which may have a substituent, A pyrido [1,2-a] pyrimidinyl group which may have a substituent, a quinazolinyl group which may have a substituent, a benzotriazinyl group which may have a substituent, or 2 which may have a substituent
G ¹ represents an oxygen atom, a carbonyl group, an ethynyl group, a group —NR ³ CO—, a group —NR ⁴ —,
Group -NR ⁵ SO ₂ -, group -SO ₂ NR ⁶ -, group -CON
R ⁷ —, group —C (＝ CHR ⁸ ) —, or group —CR ⁹
= CR ^10- (where R ³ , R ⁴ , R ⁵ , R ⁶ ,
And R ⁷ represent a hydrogen atom, a hydroxyl group, or an alkyl group which may have a substituent, R ⁸ represents a cyano group, a carboxyl group, or an alkoxycarbonyl group which may have a substituent, R ⁹ and R ¹⁰ is each independently a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or R ⁹ and R ¹⁰ means a ring formed together. )
G ² represents a phenyl group which may have a substituent, a pyridyl group which may have a substituent, a thiazolyl group which may have a substituent, an isoxazolyl group which may have a substituent, also thienyl group may have, also pyrimidinyl group which may be substituted, group -CHR ¹¹ -CHR ¹² -, or a group -CR ¹³ = CR ¹⁴ -
(CR ¹⁵ = CR ¹⁶ ) y- (wherein, R ¹¹ and R ¹² mean a ring formed together; R ¹³ , R ¹⁴ , R ¹⁵ ,
And R ¹⁶ are each independently a hydrogen atom, a halogen atom,
An alkyl group which may have a substituent, an aryl group which may have a substituent, a ring formed by R ¹³ and R ¹⁴ or R ¹⁵ and R ¹⁶ together, and y is an integer of 0 to 3. Means M and n each independently represent an integer of 0 or 1; Q represents a carboxyl group, an optionally substituted alkoxycarbonyl group, -CO
NH- (5-tetrazolyl) group, 5-tetrazolyl group which may have a substituent, 1,2,3-triazolyl group which may have a substituent, 2,4-dioxo which may have a substituent A thiazolidine-5-yridenyl group,
4-oxo-2-thioxothiazolidine-5-yridenyl group which may have a substituent, 5-oxo-4-tetrazolyl group which may have a substituent, 3- (5- Oxo)-[1,2,4] oxadiazolidinyl group, which may have a substituent 2-
(3,5-dioxo)-[1,2,4] oxadiazolinyl group, 5- (3-oxo) which may have a substituent
—A [1,2,4] oxadiazolidinyl group or a group represented by a 3- (5-oxo) -isoxazolidyl group which may have a substituent. (Wherein m and n are 0, and Q is a carboxyl group or an alkoxycarbonyl group) and salts thereof.

According to a preferred embodiment of the present invention, the above-mentioned compounds wherein R ¹ in the formula (1) is a hydrogen atom and salts thereof; an alkyl group wherein R ² in the formula (1) may have a substituent Or the above compound which is a cycloalkyl group which may have a substituent, and salts thereof; A in the formula (1)
Is a phenyl group which may have a substituent, or a salt thereof; the group represented by A in the formula (1) is a phenyl group, and a 2-ethynylthiazolyl group and-(G ¹ ) _m
- (G ²⁾ the compound group represented by _n -Q is meta arrangement and salts thereof; the compounds and their salts is of formula (1) Q in the 5-tetrazolyl group; Formula (1 Wherein m and n are 0, and salts thereof; m and n in the formula (1) are 1, and G ¹ is —NR ³ CO—.
Wherein G ² is a phenyl group which may have one or more substituents, and salts thereof;
In addition, there is provided the above compound wherein G ² in the formula (1) is a phenyl group which may have one or more substituents, and G ¹ and Q are in a para configuration, and salts thereof. .

According to another aspect of the present invention, a medicament comprising the above-mentioned compound or a salt thereof; and in a preferred embodiment thereof, treatment and / or treatment of an allergic disease containing the above-mentioned compound or a salt thereof as an active ingredient. Prophylactic drugs are provided. In addition, a therapeutic and / or prophylactic agent for a disease associated with leukotriene, preferably an allergic disease associated with leukotriene, containing the compound or a salt thereof as an active ingredient; and an allergy caused by overexpression of leukotriene The therapeutic and / or prophylactic agent for sexual diseases is provided. Further, a therapeutic and / or preventive drug for a histamine-related disease, preferably a histamine-related allergic disease, containing the compound or a salt thereof as an active ingredient; and an allergy caused by the histamine overexpression. The therapeutic and / or prophylactic agent for sexual diseases is provided.

Further, according to a particularly preferred embodiment of the present invention, treatment of a disease involving leukotriene and histamine containing the above-mentioned compound or a salt thereof as an active ingredient, preferably allergic disease involving leukotriene and histamine and / or A prophylactic agent; and the above therapeutic and / or prophylactic agent, wherein the disease is an allergic disease caused by excessive expression of leukotriene and histamine. Furthermore, according to another aspect of the present invention, there is provided a method for treating and / or preventing a disease involving leukotriene and / or histamine, preferably an allergic disease involving leukotriene and / or histamine, wherein Administering to a mammal, including a human, an effective amount of a substance selected from the group consisting of:
There is provided use of the above compound or a salt thereof for the manufacture of a therapeutic and / or prophylactic agent for the above allergic disease.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, "alkyl group"
"Means, for example, a linear or branched saturated hydrocarbon having 1 to 12 carbon atoms, and" cycloalkyl group "means, for example, a 3- to 8-membered cyclic alkyl group. ing. Further, the term “halogen atom” is used as a concept including any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom unless otherwise specified.
Examples of the “alkoxyl group” include, for example, those having 1 to 1 carbon atoms.
Two straight or branched alkoxyl groups can be used.

R ¹ and R ² are each independently a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or R ¹ and R ² are taken together. Means a ring formed by As the alkyl group, a linear or branched alkyl group having 1 to 8 carbon atoms is preferably used, and a linear or branched alkyl group having 1 to 5 carbon atoms is more preferably used. it can. Specifically, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a normal butyl group, an isobutyl group, a tertiary butyl group, a pentyl group, and the like can be used. Examples of the substituent bonded to the alkyl group include a halogen atom, a phenyl group, a methoxyphenyl group, a halogenophenyl group, a benzyl group,
One or more, preferably one, substituents selected from a methoxybenzyl group, a dimethoxybenzyl group, a halogenobenzyl group and the like can be mentioned. A chlorophenyl group can be used as the halogenophenyl group, and a chlorobenzyl group can be used as the halogenobenzyl group.

The cycloalkyl group represented by R ¹ and R ² is preferably a cycloalkyl group having 3 to 5 carbon atoms,
For example, a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group can be used. Examples of the substituent bonded to the cycloalkyl group include a halogen atom and the like. The ring formed by R ¹ and R ² together can be a 5- to 8-membered ring, preferably a 6- or 7-membered ring. For example, a cyclohexane ring, a benzene ring or a cycloheptane ring is used be able to. As a combination of R ¹ and R ² , R ¹ is preferably a hydrogen atom, and R ² is preferably an alkyl group which may have a substituent or a cycloalkyl group which may have a substituent.

A is a phenyl group which may have a substituent, a pyridyl group which may have a substituent, a furyl group which may have a substituent, a thienyl group which may have a substituent, and a group which has a substituent. A benzofuranyl group, a benzo [b] thienyl group which may have a substituent, a benzooxazolyl group which may have a substituent,
Benzothiazolyl group which may have a substituent, pyrido [1,2-a] pyrimidinyl group which may have a substituent, quinazolinyl group which may have a substituent, benzotriazinyl group which may have a substituent Or 2H-chromenyl group which may have a substituent.
As the substituent, one or more, preferably one halogen atom can be used. A is preferably a phenyl group which may have a substituent.

G ¹ is an oxygen atom, a carbonyl group, an ethynyl group, a group —NR ³ CO—, a group —NR ⁴ —, a group —NR ⁵ SO
₂ -, group -SO ₂ NR ⁶ -, group -CONR ⁷ -, group -
(C = CHR ⁸ — or the group —CR ⁹ ＣＲCR ¹⁰ —, of which the group —NR ³ CO— is preferred. In the above groups, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is
Each means a hydrogen atom, a hydroxyl group, or an alkyl group which may have a substituent. As the alkyl group, a linear or branched alkyl group having 1 to 8 carbon atoms is preferably used, and a linear or branched alkyl group having 1 to 5 carbon atoms is more preferably used. it can. For example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a normal butyl group, an isobutyl group, a pentyl group, or the like can be used. The above alkyl group is
For example, it may have one or two or more substituents selected from a halogen atom, a phenyl group which may have a substituent, a carboxyl group, or an alkoxycarbonyl group, and preferably one substituent. . R ³ , R ⁴ ,
R ⁵ , R ⁶ and R ⁷ are preferably each a hydrogen atom.

R ⁸ represents a cyano group, a carboxyl group, or an alkoxycarbonyl group which may have a substituent. Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, and a 4-methoxybenzylcarbonyl group. R ⁹
And R ¹⁰ are each independently a hydrogen atom, a halogen atom,
An alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a ring formed by R ⁹ and R ¹⁰ together. As the cycloalkyl group, a cycloalkyl group having preferably 3 to 5 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group can be used. Examples of the substituent bonded to the cycloalkyl group include a halogen atom and the like. Examples of the ring formed by R ⁹ and R ¹⁰ together include a 5- to 8-membered ring, preferably a 6- or 7-membered ring. Can be. As the aryl group, a phenyl group or the like can be used, and as the substituent on the aryl group, for example, a halogen atom or the like can be used. Preferably, R ⁹ and R ¹⁰ are hydrogen atoms.

G ² has a phenyl group which may have a substituent, a pyridyl group which may have a substituent, a thiazolyl group which may have a substituent, an isoxazolyl group which may have a substituent, and a group which has a substituent. A thienyl group, a pyrimidinyl group which may have a substituent, a group —CHR ¹¹ —CHR ¹² —, or a group —CR ¹³ ＣＲCR ¹⁴ —
(CR ¹⁵ = CR ¹⁶ ) means y−. The number of the substituents present in the phenyl group and the like is not particularly limited, and one or more substituents may be present. In particular, in some cases, the phenyl group preferably has two or more substituents. Such substituents include, for example, a halogen atom, a nitro group, an amino group which may have a substituent, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, and a substituent. Alkynyl group, hydroxyl group, alkoxyl group which may have a substituent, alkyl or arylthio group which may have a substituent, alkyl or arylsulfonyl group which may have a substituent, alkyl which may have a substituent Or an arylsulfinyl group, a carboxyl group, or an alkoxycarbonyl group which may have a substituent. Examples of the ring formed by R ¹¹ and R ¹² together include a cyclic alkyl group having 3 to 6 carbon atoms.
A cyclopropane ring, a cyclopentane ring, a cyclohexane ring, a cyclohexene ring, or the like can be suitably used.

In the above groups, R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, a halogen atom, an alkyl group which may have a substituent or an aryl which may have a substituent. The radical R ¹³ and R ¹⁴ together or R ¹⁵ and R ¹⁶ together form a ring. R ¹³ and R ¹⁴ are preferably a hydrogen atom, a halogen atom, or an alkyl group which may have a substituent, and R ¹⁵ and R ¹⁶ are preferably a hydrogen atom. Examples of the ring formed by R ¹³ and R ¹⁴ or R ¹⁵ and R ¹⁶ together include a cyclopropane ring, a cyclopentane ring, a cyclopentene ring, a cyclohexane ring, and a cyclohexene ring. be able to. y represents an integer of 0 to 3, and is preferably 0 or 1.

In the formula (1), m and n are 0 or 1.
Means an integer. If m and / or n are 0, G
¹ and / or G ² represents a single bond. Q is a carboxyl group, an alkoxycarbonyl group which may have a substituent, a -CONH- (5-tetrazolyl) group, a 5-tetrazolyl group which may have a substituent, 1,2,3 which may have a substituent A triazolyl group, a 2,4-dioxothiazolidine-5-ylidenyl group which may have a substituent, a 4-oxo-2-thioxothiazolidine-5-ylidenyl group which may have a substituent, and a substituent 5-oxo-4-tetrazolyl group, which may be substituted, and 3- (5-oxo)-[1,2,
4] oxadiazolidinyl group, 2- (3,5-dioxo)-[1,2,4] oxadiazolinyl group which may have a substituent, 5- (3- Oxo)-[1,2,4] oxadiazolidinyl group or 3- (5-oxo) -isoxazolidyl group which may have a substituent, among which 5-tetrazolyl group Is preferred.

In the compound of the formula (1), R ¹ and R ³ are preferably a hydrogen atom. A is preferably a phenyl group, and it is preferable that the 2-ethynylthiazolyl group and the group-(G ¹ ) m- (G ² ) nQ are bonded via A in a meta configuration. Q is preferably a 5-tetrazolyl group. When m is 1, G ¹ is a group —NR ³ CO
Is preferable, and when n is 1, G ² is preferably a phenyl group. When G ² represents a phenyl group, one or more substituents may be present on the phenyl group, but when two or more substituents are present, they are the same. But they may be different. Examples of the substituent on the phenyl group include a halogen atom such as a fluorine atom and a chlorine atom; a methyl group, an ethyl group, a propyl group, an n-butyl group, an isobutyl group, a hydroxymethyl group, an acetoxymethyl group, and a 1-propenyl group. Alkyl, alkenyl, or alkynyl groups such as, 2-propenyl, ethynyl, or 1-propynyl; ethoxyl, n-propoxyl, n-butoxyl, isobutoxyl, 2-fluoroethoxyl, 2 Alkoxyl groups such as 2,2,2-trifluoroethoxyl group, phenoxyl group and benzyloxy group; alkylthio groups such as ethylthio group, n-propylthio group, butylthio group, benzylthio group and 2-hydroxyethylthio group; Alkylsulfonyl group obtained by oxidizing sulfur atom of alkylthio group Methylamino group, and alkyl amino groups such as n- butylamino group can be used.

R ² is preferably a cyclobutyl, isopropyl, tert-butyl or cyclopropyl group. When A is a phenyl group having a substituent, the substituent is preferably a fluorine atom. When A and G ² each represent a phenyl group having a substituent, it goes without saying that any compound obtained by variously combining the substituents on each phenyl group is included in the scope of the compound of the present invention. .

As a preferred compound of the present invention, 5- (3
-(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1H-tetrazole; 5- (3- (2
-(4-isopropyl-2-thiazolyl) ethynyl) phenyl) -1H-tetrazole; 5- (3- (2- (4
-Cyclopropyl-2-thiazolyl) ethynyl) phenyl) -1H-tetrazole; 5- (3- (2- (4-n
-Propyl-2-thiazolyl) ethynyl) phenyl)-
1-H-tetrazole; 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -1H-tetrazole; 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -1H-tetrazole; 5- (3- (2
-(4-isopropyl-2-thiazolyl) ethynyl)-
2-fluorophenyl) -1H-tetrazole; 5-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methylphenyl) -1H-tetrazole; 5- (3- (2-chloro-2- (4-cyclobutyl-2-thiazolyl) ethynyl) ) Phenyl) -1H-tetrazole; 5- (4- (2- (4-cyclobutyl-2-)
Thiazolyl) ethynyl) -2-thienyl) -1H-tetrazole; 5- (5- (2- (4-cyclobutyl-2-
Thiazolyl) ethynyl) -3-pyridyl) -1H-tetrazole; 5- (5- (2- (4-cyclobutyl-2-
Thiazolyl) ethynyl) -2-benzoxazolyl)-
1H-tetrazole; 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-benzo [b]
Thienyl) -1H-tetrazole; 5- (6- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) -2
-Oxo-2H-benzopyran-3-yl) -1H-tetrazole; and 3- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4H-
Compounds such as [1,2,4] -oxadiazol-5-one can be mentioned.

Further, as a more preferred compound, a compound wherein m and n in the formula (1) are 1 and A and G ² are phenyl groups, for example, N- (4- (1H-tetrazol-5-yl) ) -Phenyl-3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide;
(3- (1H-tetrazol-5-yl) phenyl-3
-(2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide; N- (2-methoxy-4- (1H-
Tetrazol-5-yl) phenyl) -3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) benzamide; N- (2-methyl-4- (1H-tetrazole-
5-yl) phenyl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide; N- (2
-Fluoro-4- (1H-tetrazol-5-yl) phenyl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide; N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -4-
(1H-tetrazol-5-yl) benzamide; N-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -2-fluoro-4
-(1H-tetrazol-5-yl) benzamide; N
-(3- (2- (4-cyclobutyl-2-thiazolyl)
Ethynyl) phenyl) -3-methyl-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-methoxy-4- (1H-tetrazole-5
-Yl) benzamide; N- (3- (2- (4-ter
t-butyl-2-thiazolyl) ethynyl) phenyl)-
2-fluoro-4- (1H-tetrazol-5-yl)
Benzamide; N- (3- (2- (4-cyclobutyl-
2-thiazolyl) ethynyl) phenyl) -2-chloro-
4- (1H-tetrazol-5-yl) benzamide;
N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methyl-4- (1H-
N- (3-tetrazol-5-yl) benzamide
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methoxy-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methylthio-4- (1H-tetrazole-5
-Yl) benzamide; N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-
Amino-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (1H-tetrazol-5-yl) -2 -Vinylbenzamide; N-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (1H-tetrazole-5
Yl) -2-trifluoromethoxybenzamide; N-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-hydroxy-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2
-(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2,6-difluoro-4- (1H-tetrazol-5-yl) benzamide; and N- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2,6-methyl-4- (1H-tetrazole-
5-yl) benzamide and the like. Compounds obtained by substituting the cyclobutyl group, which is the R ² moiety of the above compound, with a cyclopropyl group, an isopropyl group, a tert-butyl group, or the like are also preferred compounds of the present invention.

Further, as compounds which can be similarly produced,
For example, N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -2-
Chloro-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -2-
Hydroxy-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) -6-fluorophenyl)-
2-methyl-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) -6-fluorophenyl)-
2-methylthio-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -2-methylsulfinyl-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -2-methylamino-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2
-(4-cyclobutyl-2-thiazolyl) ethynyl)-
6-fluorophenyl) -2-amino-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2
-(4-cyclobutyl-2-thiazolyl) ethynyl)-
6-fluorophenyl) -2-butylamino-4- (1
H-tetrazol-5-yl) benzamide; N- (3
-(2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -2,6-dichloro-4
-(1H-tetrazol-5-yl) benzamide; N
-(3- (2- (4-cyclobutyl-2-thiazolyl)
Ethynyl) phenyl) -2-fluoro-6-hydroxy-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- Fluoro-6-methylamino-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4-cyclobutyl-2-
Thiazolyl) ethynyl) phenyl) -2-amino-6-
Fluoro-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4-cyclobutyl-2-
Thiazolyl) ethynyl) phenyl) -2-butylamino-6-fluoro-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) 2-fluoro-6-methylsulfinyl-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-6-hydroxymethyl-4- (1
H-tetrazol-5-yl) benzamide; N- (3
-(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (2-fluoroethoxy) -4-
(1H-tetrazol-5-yl) benzamide; N-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (2,2,2-trifluoro) ethoxy) -4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methylsulfinyl-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4-cyclobutyl) -2-thiazolyl) ethynyl) phenyl) -2-n-
Butylamino-4- (1H-tetrazol-5-yl)
Benzamide; N- (3- (2- (4-cyclobutyl-
2-thiazolyl) ethynyl) phenyl) -2- (2-hydroxyethyl) thio-4- (1H-tetrazole-5
-Yl) benzamide; N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-
Ethynyl-4- (1H-tetrazol-5-yl) benzamide; N- (3- (2- (4-cyclobutyl-2-
Thiazolyl) ethynyl) phenyl) -2- (1-propenyl) -4- (1H-tetrazol-5-yl) benzamide; and N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -2- (2-propenyl) -4- (1H-tetrazol-5-yl) benzamide and the like. Compounds obtained by substituting the cyclobutyl group, which is the R ² moiety of the above compounds, with a cyclopropyl group, an isopropyl group, a tert-butyl group, or the like are also compounds that can be synthesized.

The compound of the present invention represented by the formula (1) may have one or more asymmetric carbon atoms depending on the type of the substituent, but may have one or more asymmetric carbon atoms. Any optically pure isomers, mixtures of any optical isomers, or racemates based on the above are all included in the scope of the present invention. Also, any mixture of diastereoisomers based on two or more asymmetric carbons is within the scope of the invention. Further, for example, the compound of the present invention having a tetrazole group or the like may have a tautomer, and it is understood that each tautomer or an arbitrary mixture thereof is also included in the scope of the present invention. You should understand. The compound of the present invention may form an acid addition salt or a base addition salt depending on the kind of the substituent, and the compound in a free form or a salt thereof exists as a hydrate or a solvate. In some cases, these are all included in the scope of the present invention.

The compound of the present invention can be synthesized, for example, according to the following [Scheme 1] to [Scheme 8]. The compound represented by the formula (1) can be produced by a coupling reaction between an ethynylthiazole (2) and a compound of the formula (3) as shown in [Scheme 1] (in the scheme, R ¹ , R ² , A, G ¹ , G ² , Q,
m and n are as defined above, and L represents a polyfluorosulfonylalkoxyl group or a leaving group such as bromine or iodine).

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The 2-ethynylthiazole (2) shown in [Scheme 1] can be produced by a known method. The 2-ethynylthiazole (2) and the compound (3) are converted into an appropriate inert solvent, for example, an inert ether solvent such as tetrahydrofuran or 1,2-dimethoxyethane, triethylamine or diisopropyl according to a method known per se in the literature. The compound of the formula (1) is produced by coupling in an organic amine solvent such as an amine or an inert polar solvent such as N, N-dimethylformamide at a temperature ranging from 0 ° C. to the boiling point of the solvent. can do. The reaction may be performed in the presence or absence of triphenylphosphine and cuprous iodide, and may include palladium [2] acetate, tetrakis (triphenylphosphine) palladium [0] or bis (triphenylphosphine) palladium [ 2] Dichloride may be added in a catalytic amount, preferably about 0.1 to 10% mol. The reaction can be carried out under a stream of an inert gas such as nitrogen or argon.

In the compound represented by the formula (1), when Q is an alkoxycarbonyl group which may have a substituent, the compound is subjected to acidic or alkaline hydrolysis to give the corresponding free carboxylic acid type. Can be converted to a compound. Q is a cyclic heterocyclic group,
When a protecting group such as a substituted benzyl group or 2- (trimethylsilyl) ethoxymethyl group is present as a substituent in the ring, these compounds are subjected to a known deprotection reaction so that Q becomes acidic. A compound that is a cyclic acidic group in a free form having a hydrogen atom can be produced. For example, when a substituted benzyl group or a 4-methoxybenzyl group is present as a substituent, the temperature ranges from 0 ° C. to the boiling point of the solvent in trifluoroacetic acid in the presence of anisole, which is a scavenger of the generated cation. The substituted benzyl group and 4-methoxybenzyl group can be removed by carrying out the reaction, preferably in the range of room temperature to the boiling point of the solvent. The compound having a 2- (trimethylsilyl) ethoxymethyl group or the like as a protective group on the heterocycle is treated with tetra-n-butylammonium fluoride or cesium fluoride in an inert ether solvent such as tetrahydrofuran. Thereby, the protecting group can be removed. During this reaction, an equal amount of acetic acid may be added.

The following [Scheme 2] shows a method for synthesizing 2-ethynylthiazole (2) used as a raw material compound in the above reaction (in the scheme, R ¹ and R ² are as defined above, and X Represents a chlorine atom or a bromine atom).

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The 2-thiazole esters (7) are
Halogenoketones (5) [which are known per se or can be easily produced from compound (4) by a known method and are sometimes commercially available] and thioamide compounds [ethyl which are commercially available] Thiooxamate (6)] in an inert alcoholic solvent such as ethyl alcohol or in acetic acid at a temperature in the range of 0 ° C to the boiling point of the solvent. The ester (7) can be converted to the alcohol (8) by a known reduction method. The reduction reaction can be performed in a range of -20 to 50 ° C, preferably 0 ° C to room temperature, using a reducing agent such as sodium borohydride in an inert alcohol solvent such as ethyl alcohol. The alcohol (8) can be converted to the aldehyde (9) according to a known method of oxidizing a primary hydroxyl group to an aldehyde. This oxidation reaction is carried out, for example, by oxidation using a chromic acid in an inert halogenated hydrocarbon solvent such as methylene chloride in the range of −78 ° C. to the boiling point of the solvent, preferably −78 ° C. to room temperature, or Swern ( Swern) Oxidation or the like, or in an inert hydrocarbon solvent such as toluene or in an inert ketone solvent such as acetone, at a temperature in the range of 0 ° C to the boiling point of the solvent, preferably room temperature to the boiling point of the solvent. This can be done by treating with active manganese dioxide below.

The 2-ethynylthiazole (2) can also be synthesized from the aldehyde (9) by the following method. By using lithium diisopropylamide or lithium hexamethyldisilazide as a base and treating trimethylsilyldiazomethane or diazomethane in an inert ether solvent such as tetrahydrofuran at -100 ° C to -20 ° C, preferably at -50 ° C or lower, diazomethane is obtained. Form carbanions. To the solution containing the carbanion, 2-thiazole carbaldehyde (9) is added preferably at a temperature of -50 ° C or lower, and then the temperature is raised from 0 ° C to room temperature to give 2-ethynylthiazole (2) as a rearranged product. Obtainable.

Alternatively, 2-ethynylthiazole (2) may be synthesized as follows. According to the method described in the literature, 2-thiazole carbaldehyde (9) is reacted with an inert halogenated hydrocarbon solvent such as methylene chloride with a phosphorus reagent such as carbon tetrabromide and triphenylphosphine at -20 ° C to By reacting in the range of the boiling point of the solvent, preferably from 0 ° C. to room temperature, 1,1-dibromo-
A 2- (2-thiazolyl) ethylene compound (10) can be obtained. Then, the compound (10) was placed in an inert ether solvent such as tetrahydrofuran at -78 ° C to room temperature,
Preferably at a temperature in the range of -78 to 0 ° C, 1.8 to 3
After treating with an equivalent amount of an organic alkyllithium such as n-butyllithium, neutralize with a dilute mineral acid such as dilute hydrochloric acid or a saturated aqueous solution of ammonium chloride at a low temperature of -78 to 30 ° C, preferably 0 ° C or lower. By doing so, 2-ethynylthiazole (2) can be obtained.

Compound (3) used in [Scheme 1]
Is a compound (11) as shown in the following [Scheme 3].
In the R ¹⁷ can be synthesized by the method of converting the Q ^{(Scheme, A, G 1, G 2} , Q, m, n, and L
Has the same meaning as described above, and R ¹⁷ represents a cyano group, a formyl group, an acetyl group, a carboxyl group, a carbamoyl group, a hydroxylamino group, or an amino group. )

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In the following [Scheme 3A], as a specific example of the reaction according to "Scheme 3", A is a phenyl group,
From the compound (11a) in which m and n are 0, L is a bromine atom, and R ¹⁷ is a cyano group, the compound in which Q is a tetrazolyl group having a 4-methoxybenzyl group or a 2- (trimethylsilyl) ethoxymethyl group as a protecting group (3b) and a method for synthesizing a compound (3c) in which L is an iodine atom (in the scheme, R ¹⁸ represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group having a substituent, an alkoxy group having a substituent, Or an alkoxycarbonyl group;
¹⁹ means a 4-methoxybenzyl group or a 2- (trimethylsilyl) ethoxymethyl group. ).

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The benzonitrile compound (11a) is known per se or can be produced by a known method. According to a known reaction for converting a cyano group into a tetrazolyl group, the benzonitrile compound (11a) is converted to the tetrazole compound (3a). Can be manufactured. For example, by treating the benzonitrile compound (11a) with aluminum azide or ammonium azide in an inert polar solvent such as N, N-dimethylformamide at a temperature in the range of, for example, room temperature to the boiling point of the solvent, the tetrazole compound (3a) is obtained. ) Can be obtained. Aluminum azide or ammonium azide used in the above reaction can be easily prepared by treating sodium azide with aluminum chloride or a quaternary ammonium salt such as ammonium chloride or pyridine hydrochloride according to a known method.

The tetrazole compound (3a) preferably has a protective group suitable for carrying out the next coupling reaction. As the protecting group, the above-mentioned substituted benzyl group or 2- (trimethylsilyl) ethoxymethyl group is preferable. The reaction conditions for introducing the protecting group are as follows. For example, the tetrazole compound (3a) is treated with 4-methoxybenzyl chloride or 2- (trimethylsilyl) ethoxymethyl chloride in an inert polar solvent such as N, N-dimethylformamide, for example, in the presence of an inorganic base such as potassium carbonate. The protecting group can be introduced by treating at a temperature in the range of from 0 ° C to the boiling point of the solvent, preferably in the range of room temperature to 80 ° C. Generally, alkylation of a tetrazolyl group gives a mixture of 1- and 2-substituted compounds, which can be separated by column chromatography on silica gel. The leaving group of the compound (3) is preferably an iodine atom, and the compound (3c) can be obtained by converting a bromine atom of the compound (3b) into an iodine atom according to a known method. For example, the compound (3b) is heated with cuprous iodide and potassium iodide in an inert polar solvent such as N, N-dimethylformamide at a temperature preferably in the range of 80 ° C. to the boiling point of the solvent. (3c) can be manufactured.

In the following [Scheme 4], compound (1)
Compounds by completing G ¹ from 2) (3d)
Is shown. [Scheme 4A] includes:
A method for synthesizing a compound (3d) in which Q is a 5-tetrazole group having a 4-methoxybenzyl group or a 2- (trimethylsilyl) ethoxymethyl group as a protecting group from a compound (12a) in which A is a phenyl group was shown. [In the scheme, L, A, G ¹ , G ² , n, Q and R ¹⁸ are as defined above, m is 1, R ²⁰ is a formyl group, acetyl group, carboxyl group, N-methoxy-N -Represents a methylcarbamoyl group, an amino group which may have a substituent, a thiol group or a chlorosulfonyl group, and R ²¹ represents a 4-methoxybenzyl group or a 2- (trimethylsilyl) ethoxymethyl group. ].

[0040]

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[0041]

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A benzaldehyde derivative or acetophenone derivative (1) wherein R ²⁰ is a formyl group or an acetyl group
From 2a), to synthesize a compound (3e) in which G ¹ is a group —CR ⁹ ＣＲCR ¹⁰ — (R ⁹ and R ¹⁰ are as defined above), a Wittig reaction or Horner-Wad
After G ¹ is formed from the carbonyl group of the benzaldehyde derivative or acetophenone derivative (12a) by the swirth-Emmons reaction, the terminal cyano group is similarly converted to a tetrazolyl group, and a 4-methoxybenzyl group or 2- (trimethylsilyl) is used as a protecting group. An ethoxymethyl group or the like may be introduced. The compound of the formula (3e) in which G ¹ is a group — (C ＝ O) — or — (CＣCHR ⁸ ) — is obtained from the compound (12a) in which R ²⁰ is an N-methoxy-N-methylcarbamoyl group. It can be synthesized (R ⁸ is as defined above).

The compound (12a) wherein R ²⁰ is N-methoxy-N-methylcarbamoyl group can be easily prepared from the corresponding benzoyl chloride and a commercially available N, O-dimethylhydroxylamine hydrochloride by a known method. Can be prepared. This compound and 1- (4-methoxybenzyl) -1H-tetrazole produced by the method described in the literature are combined with an organic alkyllithium such as n-butyllithium in an inert ether solvent such as tetrahydrofuran.
The compound (3e) can be prepared by treating at a temperature in the range of 100 ° C. to room temperature and then neutralizing at a low temperature with a dilute mineral acid such as dilute hydrochloric acid or a saturated aqueous ammonium chloride solution. Further, the carbonyl group of the compound (3) is converted into various Wittig reaction reagents or Horner-Wa.
by treatment with dsworth-Emmons reagent, group - (C = CHR ⁸⁾ - can be prepared a compound (3e) having a.

Compound (3e) wherein G ¹ is a group —NR ⁴ —
(R ⁴ has the same meaning as above.) Is an aniline derivative (12a) wherein R ²⁰ is an amino group which may have a substituent.
A group -NR ⁴ -C a reagent cyanation such as cyanogen bromide
After N, the compound can be produced by performing tetrazole of a cyano group and introducing a protecting group in the same manner as described above. Further, a compound (3) in which G ¹ is a group —NR ³ CO—
e) (R ³ is as defined above) is an aniline derivative (12) wherein R ²⁰ is an amino group which may have a substituent.
a) is condensed with a cyanobenzoyl chloride derivative which may have a substituent to form a group G ¹ —NR ³ CO—, and then similarly, tetrazolation of a cyano group and introduction of a protecting group. can do. Furthermore, G
Compound (3e) in which ¹ is a group —NR ⁵ SO ₂ — (R ⁵ is as defined above) is obtained by substituting an aniline derivative (12a) in which R ²⁰ is an amino group that may have a substituent with a substituent. cyanobenzenesulfenyl also have a sulfonyl chloride group -NR derivatives condensed with G ^{1 5} sO ₂ - after forming, be prepared by carrying out the introduction of the tetrazole of the protecting group of similarly cyano group it can.

The aniline derivative (12) used in the above reaction
a) is commercially available or can be easily prepared by reduction of a nitrobenzene derivative. It can also be produced by subjecting a benzoic acid derivative to a Curtius rearrangement reaction. For example, the third
In a butyl alcohol or a mixed solvent in which an inert aromatic hydrocarbon solvent such as toluene is further combined, a benzoic acid derivative is converted to an acid azide such as diphenylphosphoryl azide in the presence of an organic amine base such as triethylamine. By reacting the compound with a chemical reagent at a temperature within the range of 0 ° C. to the boiling point of the solvent, preferably at a temperature within the range of room temperature to the boiling point of the solvent, an acylamino compound which is a Curtius reaction product can be obtained. The aniline derivative (12a) can be obtained by treating this acylamino compound with an acid such as hydrochloric acid or trifluoroacetic acid.

An alkylaniline derivative having an alkyl group which may have a substituent (mono-substituted aniline, 12
a) is directly produced by reacting an aniline derivative as a primary amine with an active halide such as bromoacetates in an inert polar solvent such as N, N-dimethylformamide in the presence of a base such as potassium carbonate. It is possible to In addition, after trifluoroacetylation of the aniline derivative which is a primary amine using trifluoroacetic anhydride, it is reacted with an alkyl halide which may have a substituent in the presence of a base such as potassium carbonate, preferably an iodide, Further, the monosubstituted aniline derivative (12a) can also be produced by detrifluoroacetylation. Further, R ²⁰ is an alkyl group which may have a substituent, and the substituent is a hydroxyl group.
-Hydroxyaniline derivative (12a) can be prepared by subjecting a nitrobenzene derivative to reduction in zinc dust in aqueous ethanol in the presence of ammonium chloride.

The compound (3a) wherein G ¹ is an oxygen atom or a sulfur atom is a benzenethiol derivative or a phenol derivative (12a) wherein R ²⁰ is --SH or --OH.
Can be synthesized from For example, in an inert ether solvent such as tetrahydrofuran, the above 1- (4-methoxybenzyl) -1H-tetrazole is mixed with lithium diisopropylamide or lithium hexamethyldisilazide at −100 ° C. in the presence of bromine or iodine. By treating at a temperature in the range of to room temperature, a 1- (4-methoxybenzyl) -1H-tetrazole derivative having a bromine or iodine atom at the 5-position can be produced. This 5-bromo- or 5-iodo-1- (4-methoxybenzyl) -1H-tetrazole is reacted with a benzenethiol derivative or a phenol derivative (12a) and carbonic acid in an inert polar solvent such as N, N-dimethylformamide. The compound (3d) can be synthesized by treating in the presence of an inorganic base such as potassium or an organic amine such as triethylamine.

Scheme 5 shows a scheme for synthesizing compound (3f) by completing G ² from compound (13) (in the scheme, L, A, G ¹ ,
G ² , m, Q and R ¹⁸ are as defined above, n is 1 and R ²² is an ethynyl group, an amino group, a thiocarbamoyl group, a bromoacetyl group or a chloroacetyl group which may have a substituent. Represents ).

[0049]

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R ²² is an ethynyl group which may have a substituent, and m is 0;
Compound (3) in which G ² is an isoxazolyl group can be synthesized from 3). The ethynylbenzene derivative (13) as a raw material compound can be produced from ethyl propiolic acid and an aryl halide, preferably an iodobenzene derivative, by a coupling reaction using the above-mentioned organic palladium (0-valent or divalent) catalyst. it can. An alkylnitro compound is treated with a dehydrating agent such as phenyl isocyanate in an inert hydrocarbon-based solvent such as toluene or an inert ether-based solvent such as tetrahydrofuran to generate a nitrile oxide. By reacting with the ethynylbenzene derivative (13), an isoxazole derivative (3f) which is a [2 + 3] cycloadduct can be produced. From the aniline derivative (13) in which R ²² is an amino group and m is 0, the compound (3f) in which G ² is a pyrimidinyl group is converted into an N- (carbomethoxy) -methoxymethylene acetamide derivative and an aniline derivative ( 13) is heated in a high-boiling hydrocarbon solvent such as toluene or xylene, preferably at a temperature in the range of 100 ° C. to the boiling point of the solvent, to form a pyrimidine ring, and a cyano group is further formed according to the method described above. It can be produced by converting to a tetrazolyl group.

[Scheme 6] shows an example of a method for producing a compound of the formula (1) including a step of forming a triple bond portion.
A scheme for synthesizing an ethynylthiazole derivative (1a) in which m and n are 0 by forming a triple bond portion from the 2-bromothiazole derivative (14) was shown (in the scheme, R ¹ , R ² , A, And Q are as defined above, and R ²³ represents an active amide such as an alkoxycarbonyl group or an N-methoxy-N-methylcarbamoyl group.

[0052]

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A commercially available product or a 2-bromothiazole derivative (14) known per se or can be produced by a known method (for example, easily obtained by dehydration condensation of a known haloketone with thiourea) From 2-aminothiazoles obtained by bromination by Sandmeyer reaction via a diazonium salt according to the method described in the literature) in an inert ether solvent such as tetrahydrofuran at -78 ° C to room temperature, preferably Is subjected to a metal exchange reaction with 1.8 to 3 equivalents of an alkyllithium such as n-butyllithium or a Grignard reagent such as methylmagnesium bromide at a temperature in the range of −78 to 0 ° C., and then the compound ( 15) and, for example,-
The reaction is carried out at a low temperature in the range of 78 to 30 ° C., preferably in the range of 0 ° C. to room temperature, and then neutralized at a temperature of 0 ° C. or lower with a dilute mineral acid such as dilute hydrochloric acid or a saturated aqueous solution of ammonium chloride. 2- (1-oxoethyl) thiazole (16) can be produced. Then, 2-
(1-oxoethyl) thiazole (16) is dissolved in an inert halogenated hydrocarbon solvent such as 1,2-dichloroethylene, and triphenylphosphine oxide and trifluoromethane are dissolved at a temperature in the range of -10 ° C to room temperature. The desired ethynylthiazole (1b) can be produced by adding sulfonic anhydride and reacting the mixture at a temperature ranging from -10 ° C to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent. .

[Scheme 7] shows a method of synthesizing a compound of formula (1) by completing Q from compound (17) (in the scheme, R ¹ , R ² , A, G ¹ ,
G ² , m, n, and Q are as defined above, and R ²⁴ represents a formyl group, a carboxyl group, or a cyano group. ).

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According to [Scheme 7], to produce a compound (1) in which Q is a tetrazolyl group from a compound (17) in which R ²⁴ is a cyano group, ethynylthiazole (2 ) Is coupled with an aryl halide to produce a compound (17) in which R ²⁴ is a cyano group.
Dissolved in an inert polar solvent such as dimethylformamide,
Treatment with sodium azide in the presence of a Lewis acid such as aluminum chloride at a temperature in the range of 0 ° C. to the boiling point of the solvent, or quaternary such as trifluoroacetate of pyridine or 2,6-lutidine, or ammonium chloride What is necessary is just to process with ammonium salt and sodium azide in room temperature to the boiling point of a solvent.

The compound of the formula (1) can also be prepared by completing G ¹ as shown in [Scheme 8] (in the scheme, R ¹ , R ² , n and Q are as defined above) Has the same meaning, m is 1, R ²⁵ is a carboxyl group,
Or an also amino group which may be substituted, R ²⁶
Is an amino group, a carboxyl group,
Or, represents a chlorosulfonyl group, and R ²⁷ represents a hydroxyl group or an alkoxy group. ).

[0057]

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From the benzoic acid derivative (18) in which R ²⁵ is a carboxyl group and A is a phenyl group, G ¹ is -CO
In order to produce a compound (1b) in which NR ⁴ — (R ⁴ is as defined above) and Q is a tetrazolyl group,
In accordance with the coupling reaction shown in [Scheme 1], iodobenzoic acid ester and ethynylthiazole are coupled to produce a benzoic acid derivative (18), and further the ester portion is alkali-hydrolyzed and then a mineral acid such as hydrochloric acid. May be added for neutralization. This benzoic acid derivative (1
8) is replaced with an inert halogenated hydrocarbon solvent such as methylene chloride, an inert hydrocarbon solvent such as toluene, an inert ether solvent such as tetrahydrofuran, or N,
In an inert polar solvent such as N-dimethylformamide,
Using a condensing agent which is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N'-dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole, or the like, at -20 ° C. The compound (1b) can be prepared by reacting with the amino compound (19) wherein R ²⁶ is an amino group at a temperature within the range of the boiling point of the solvent, preferably within the range of 0 ° C. to room temperature.

Alternatively, compound (18) is converted into a chlorinating agent such as thionyl chloride and the like in an inert hydrocarbon solvent such as toluene or an inert halogenated hydrocarbon solvent such as methylene chloride. And the reaction is carried out in the range of room temperature to the boiling point of the solvent to prepare an acid chloride of the compound (18). In an inert halogenated hydrocarbon-based solvent such as methylene chloride, an inert hydrocarbon-based solvent such as toluene, or an inert ether-based solvent such as tetrahydrofuran, the acid chloride is optionally added with triethylamine or pyridine. In the presence of an organic base or an inorganic base such as sodium acetate, a commercially available product or an amino derivative (19) that can be produced by a known method is used in a range from -10 ° C to the boiling point of the solvent, preferably 0 ° C. By reacting at a temperature in the range of ° C. to room temperature, it can be converted to the corresponding compound (1d).

An aniline derivative (18) wherein R ²⁴ is an amino group which may have a substituent, and A is a phenyl group
From that G ¹ is a group —NR ³ CO— or a group —NR ⁵ SO ₂
(R ³ and R ⁵ are as defined above),
When n is 0 or when n is 1, compound (1b) wherein G ² is a phenyl group which may have one or more substituents and Q is a tetrazolyl group can be produced. it can. The aniline derivative (18) used as a starting material compound undergoes the coupling reaction shown in [Scheme 1] from iodo-nitrobenzoic acid and ethynylthiazole, and then further reduces the nitro group using a known reducing agent. It can be manufactured by the following. When, for example, stannous chloride and the like are used as the reducing agent, the reaction can be carried out using an inert alcohol-based solvent such as ethyl alcohol in the range of 0 ° C to the boiling point of the solvent. When a metal such as tin or copper is used as a reducing agent, a diluted mineral acid such as dilute hydrochloric acid, or a mixed solvent of a mineral acid such as dilute hydrochloric acid and an ether-based inert solvent such as dioxane may be used at 0 ° C. The reaction is carried out at a temperature within the range of the boiling point of the solvent, and after the reaction is completed, the acidic solution is made slightly alkaline, whereby the aniline derivative (18) can be produced. The condensation reaction between the aniline derivative (18) and the 5-tetrazolecarboxylic acid derivative (19) (when n is 0) or the benzoic acid derivative (19) (when n is 1) is carried out by an inert ether solvent such as tetrahydrofuran. Or 1-ethyl-3- (3-dimethylaminopropyl) in an inert polar solvent such as N, N-dimethylformamide.
Carbodiimide hydrochloride, N, N′-dicyclohexylcarbodiimide, N, N′-carbonyldiimidazole,
Or using a condensing agent that is the same as them,
The reaction can be carried out in the range of the boiling point of the solvent, preferably from 0 ° C. to room temperature, and if necessary, for example, triethylamine or 4
-The reaction can be carried out in the presence of an organic base such as dimethylaminopyridine or an inorganic base such as sodium acetate to obtain the corresponding compound (1b).

Alternatively, the aniline derivative (18) is
By treating with an acid chloride derived from a 5-tetrazolecarboxylic acid derivative (19) (when n is 0) or a benzoic acid derivative (19) (when n is 1),
The group -NR ³ CO- of G ¹ can be completed and converted to the compound (1b). Also, G ¹ is -NR ⁵ SO ₂ -
The compound (1b) is an aniline derivative (1) in an inert halogenated hydrocarbon solvent such as methylene chloride, an inert ether solvent such as tetrahydrofuran, or an inert polar solvent such as N, N-dimethylformamide.
8) in the presence of organic amines such as triethylamine or pyridine, arylsulfonyl chloride (19) known per se or commercially available
And can be obtained by condensation.

The compound (18) in which R ²⁵ is an amino group which may have a substituent may be obtained from a commercially available product,
Alternatively, the compound (1c) can also be produced by acylation with a cyclic acid anhydride (20) that can be produced by a known method. This method comprises the steps of preparing G ^{1 of} compound (1c),
G ^2, and a method for synthesizing at once Q [G ¹ is a group -
NR ³ CO— and G ² is a group —CHR ¹¹ —CHR ¹² —
Or a group ^{-CHR 13 = CHR 14 - (CR} 15 = CR 16) y
And Q is a carboxyl group (R ³ , R ¹¹ , R
^{12, R 13, R 14,} R 15, R 16 and y are as defined above)]. An aniline derivative (18) and a cyclic acid anhydride (20) are mixed with an inert halogenated hydrocarbon solvent such as methylene chloride, an inert hydrocarbon solvent such as toluene,
Or in an inert ether solvent such as tetrahydrofuran, at a temperature in the range of −10 ° C. to the boiling point of the solvent, if necessary, in the presence of an inert organic amine such as triethylamine or an inert inorganic base such as sodium acetate. The corresponding compound (1c) can be obtained by reacting and then neutralizing with a mineral acid such as dilute hydrochloric acid. Alternatively, an aniline derivative (18) and a monocarboxylic acid monoester (21) may be converted into an inert halogenated hydrocarbon solvent such as methylene chloride, an inert ether solvent such as tetrahydrofuran, or N, N-dimethyl. Using an N, N′-dicyclohexylcarbodiimide, N, N′-carbonyldiimidazole, or a condensing agent thereof, in an inert polar solvent such as formamide,
The compound (1c) can be produced by condensing at -20 ° C to the boiling point of the solvent, preferably at 0 ° C to room temperature, and then hydrolyzing the ester.

The compound of the present invention represented by the formula (1) is characterized by having both a strong peptide leukotriene antagonistic action and an action of inhibiting the release of mediators such as histamine, and is useful as an active ingredient of a medicine. Pharmaceuticals comprising the compound of the present invention include, for example, various diseases involving histamine released from leukotriene and / or mast cells, preferably various diseases caused by excessive expression of leukotriene and / or excessive release of histamine, for example, bronchi Asthma, pulmonary anaphylaxis, cystic fibrosis,
It is useful for treating and / or preventing chronic bronchitis, bronchiectasis, respiratory distress syndrome, pulmonary edema, dryness, nephritis, allergic rhinitis or atopic dermatitis. It is also useful for treating and / or preventing cerebral edema and cerebral vasospasm due to cerebral ischemia, angina pectoris due to decreased coronary blood flow, or hepatitis.

When the compound of the present invention is used as a medicine,
In addition to the compound in the free form, a compound in the form of a physiologically acceptable salt may be used. When the compound of the formula (1) has an acidic group such as a 5-tetrazolyl group or a carboxyl group, it is generally possible to form a base addition salt.
Physiologically acceptable salts may be any of organic salts and inorganic salts, and preferred examples thereof include, for example, alkali metal salts such as lithium salts, sodium salts, and potassium salts, such as magnesium salts and calcium salts. Examples thereof include alkaline earth metal salts, ammonium salts, triethylamine salts, N-methylglucamine salts, and tris (hydroxymethyl) aminomethane salts. In addition, as the medicament of the present invention, in addition to a compound in a free form or a compound in a salt form, a hydrate or a solvate thereof may be used.

When the compound of the formula (1) or a salt thereof, or a hydrate or solvate thereof is administered as a medicament to mammals including humans, the substance itself may be administered. It is preferable to prepare and administer a pharmaceutical composition containing the substance as an active ingredient according to a method well known to those skilled in the art. Such a pharmaceutical composition can be administered orally or parenterally, and in addition to the substance of the active ingredient,
It is also possible to mix other pharmaceutical active ingredients, for example, antihistamines, xanthine derivatives, beta (β) stimulants, or antiasthmatic steroids (eg, prednisolone and prednisoline). Examples of the pharmaceutical composition suitable for oral administration include, for example, tablets, powders, granules, fine granules, capsules, suspensions, solutions, syrups, elixirs and the like. Examples of pharmaceutical compositions suitable for parenteral administration include, for example, intravenous injections, drops, suppositories for rectal administration, nasal drops, ear drops, topical external preparations such as ointments and creams, transdermal Absorbent, transmucosal absorbent,
Aerosols, inhalants in the form of finely ground powders or nebulized solutions and the like can be mentioned.

For the preparation of a pharmaceutical composition suitable for oral administration,
For example, talc, starch, lactose, or other physiologically acceptable pharmaceutical carriers can be used, as well as sugar or other sweeteners, flavors, colorants, adhesives, or other pharmaceutical additives. An object may be used. In the case of parenteral administration, solutions or suspensions can be prepared using conventional liquid media, for example, distilled water for injection, buffers, peanut oil and the like. When administered as aerosols, they can be dissolved in a suitable physiologically acceptable solvent such as ethyl alcohol or a combination of miscible solvents and mixed with a physiologically acceptable propellant. The pharmaceutical composition for aerosol is preferably packaged in a pressurized container fitted with an aerosol valve suitable for release of the pressurized composition for use, in which the container is provided. Preferably, a metering valve is provided so that a single effective action can release a predetermined effective dosage of the pharmaceutical composition. The administration schedule such as the dose and administration frequency of the medicament of the present invention is not particularly limited,
It can be appropriately selected according to the potency and duration of the activity of the substance of the active ingredient to be administered, the administration route, and the severity and age of the animal to be treated and / or prevented.
For example, the oral dose of a pharmaceutical composition containing the compound of the formula (1) or a salt thereof may be about 0.1 mg to about 0.1 mg per day as a single dose or divided doses.
2000 mg, preferably about 0.1 mg to about 500 mg
Range.

The use of the compound of the present invention is not limited to a drug having a pharmacological activity per se, but is also useful as a synthetic intermediate or a prodrug. For example, an alkyl group, a benzyl group,
Compounds having an alkoxyalkyl group, a phenylalkyl group or the like are useful as synthetic intermediates. Further, a compound having an acidic group moiety as a substituent, for example, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a dimethylaminoethyl group, or a 5-indanyl group can also be used as a prodrug. It is.

[0068]

The present invention will be described in more detail with reference to the following examples, which are provided only for illustrative purposes and do not limit the scope of the present invention. The symbols [IR], [NMR] and [MS] in the examples are [infrared absorption spectrum] and [nuclear magnetic resonance spectrum], respectively.
And [mass spectrometry]. The ratio of the elution solvent described in the column of separation by chromatography indicates a volume ratio. [IR] is measured by the KBr tableting method. [NMR] means [< ¹ > H] -NMR, the solvent in parentheses indicates the measurement solvent, and tetramethylsilane (TMS) was used as an internal standard in all cases. In addition, as is well known, for example, a 5-tetrazolyl group, 4- [1,2,3]-
The triazolyl group and the 5- [1,2,3] -triazolyl group have a tautomeric hydrogen atom. For convenience, the notations in the examples for these groups are 1H-tetrazol-5-yl, 1H- [1,2,3] -triazol-4-yl, and 1H- [1,2,2, 3] -triazol-5-yl group).

REFERENCE EXAMPLE 1 4-Cyclobutyl-2-ethynylthiazole: (Step 1) Synthesis of ethyl 4-cyclobutyl-2-thiazolecarboxylate 9 g of ethyl thiooxamate and 11.96 g of bromomethylcyclobutyl ketone were placed in 70 ml of ethanol. 2
Heated to reflux for an hour. After cooling, the reaction solution was concentrated. 200 ml of methylene chloride was added to the residue, and the mixture was washed with saturated sodium hydrogen carbonate and then with saturated saline. The methylene chloride layer was dried over anhydrous sodium sulfate and evaporated. The residual oil was purified by column chromatography on silica gel (eluent: n-hexane: ethyl acetate = 8: 1) to give 13.7 g of ethyl 4-cyclobutyl-2-thiazolecarboxylate as a pale yellow oil As obtained. NMR (400 MHz, CDCl ₃ ) δ ppm 1.4
3 (3H, t), 1.88 to 2.44 (6H,
m), 3.78 (1H, quint), 4.48
(2H, q), 7.23 (1H, s).

(Step 2) Synthesis of 4-cyclobutyl-2-thiazolemethanol 13.7 g of ethyl 4-cyclobutyl-2-thiazolecarboxylate was dissolved in 60 ml of ethanol, and 2.45 g of sodium borohydride was gradually added under ice-cooling. Added. The reaction was further stirred at room temperature for 8 hours. Under ice cooling, water was added to the reaction solution to decompose excess sodium borohydride, and then extracted with methylene chloride. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 8.39 g of 4-cyclobutyl-2-thiazolemethanol as a pale brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
5-2.43 (6H, m), 3.63 (1H,
m), 3.77 (1H, br), 4.91 (2
H, d), 6.86 (1H, s).

(Step 3) Synthesis of 4-cyclobutyl-2-thiazolecarbaldehyde a) Method 43.2 g of oxalyl dichloride was added to methylene chloride 35.
Then, 53.1 g of dimethyl sulfoxide (hereinafter abbreviated as DMSO) was added dropwise at −70 ° C. with stirring.
After completion of the dropwise addition, the mixture was further stirred at the same temperature for 0.5 hour. To this solution was added dropwise a solution of 28.8 g of 4-cyclobutyl-2-thiazolemethanol in 100 ml of methylene chloride at the same temperature. One hour after the completion of the dropwise addition, 103 g of triethylamine was added. After the temperature of the reaction solution was raised to room temperature, 100 ml of water was added, and the mixture was extracted twice with 500 ml of ether. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 8: 1).
4-cyclobutyl-2-thiazolecarbaldehyde 1
9.9 g were obtained as a pale yellow oil.

Method b) 1.18 g of 4-cyclobutyl-2-thiazolemethanol and 1.2 of active manganese dioxide
1 g was heated and refluxed in 50 ml of toluene for 4 hours. After cooling, the insolubles were filtered off under reduced pressure using celite. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 8: 1) to give 4-cyclobutyl-2-thiazolecarbaldehyde 800 mg. Was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
2-2.48 (6H, m), 3.76 (1H, m),
7.35 (1H, s), 9.99 (1H, s).

(Step 4) 1,1-Dibromo-2- (4
Synthesis of -cyclobutyl-2-thiazolyl) ethylene 3.97 g of carbon tetrabromide was dissolved in 50 ml of methylene chloride, and 6.27 g of triphenylphosphine was added at -10 ° C. A solution of 1 g of 4-cyclobutyl-2-thiazolecarbaldehyde in 5 ml of methylene chloride was added dropwise to the solution at the same temperature. After the completion of the dropwise addition, the reaction solution was returned to room temperature. The reaction solution was neutralized by adding an aqueous solution of saturated sodium hydrogen carbonate, and then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 4: 1) to give 1, 1-dibromo-2- (4-cyclobutyl-2
1.9 g of (thiazolyl) ethylene were obtained as a pale brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
9 to 2.41 (6H, m), 3.68 (1H,
m), 7.02 (1H, s), 7.95 (1H,
s).

(Step 5) Synthesis of 4-cyclobutyl-2-ethynylthiazole Method a) 1,1-Dibromo-2- (4-cyclobutyl-2)
1.48 g of (thiazolyl) ethylene was dissolved in 20 ml of tetrahydrofuran (hereinafter abbreviated as THF), and n-butyllithium (1.5 M
6.1 ml of n-hexane solution) was added dropwise. After completion of the dropwise addition, the reaction solution was further stirred at the same temperature for 1 hour. After adding 50 ml of a saturated aqueous solution of ammonium chloride to the reaction solution, the temperature was returned to room temperature. The reaction solution was extracted twice with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The oil obtained by evaporating the solvent under reduced pressure was subjected to column chromatography using silica gel (eluent: n-
The residue was purified by hexane: ethyl acetate = 8: 1) to obtain 546 mg of 4-cyclobutyl-2-ethynylthiazole as a pale brown oil.

Method b) 10.1 g of diisopropylamine was dissolved in 20 ml of THF, and 59 ml of n-butyllithium (1.7 M n-hexane solution) was added dropwise with stirring at -78 ° C. under a nitrogen stream. The reaction was further added at 0 ° C. for 0.5
After stirring for an hour, the mixture was cooled again to -78 ° C, and 50 ml of trimethylsilyldiazomethane (2M n-hexane solution) was added dropwise while maintaining the internal temperature at -50 ° C or lower. After completion of the dropwise addition, the reaction solution was stirred at -78 ° C for 0.5 hours. A solution of 15.8 g of 4-cyclobutyl-2-thiazolecarbaldehyde in 100 ml of THF was added dropwise to the solution while maintaining the internal temperature at -50 ° C or lower. The reaction solution was stirred at -78 ° C for 1 hour, then at 0 ° C for 1 hour, and further at room temperature for 1 hour. The reaction solution was poured into 300 ml of ice and a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over sodium sulfate. The oil obtained by distilling off the solvent was purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 8: 1), and 11.1 g of 4-cyclobutyl-2-ethynylthiazole was purified. Was obtained as a light brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
8 to 2.38 (6H, m), 3.44 (1H,
s), 3.67 (1H, m), 6.93 (1H,
s).

Reference Example 2 2-Ethynylbenzothiazole: (Step 1) Synthesis of 2- (2,2-dibromoethenyl) benzothiazole 2.00 g of benzothiazole-2-carbaldehyde was used in Step 4 of Reference Example 1. And crystallized from n-hexane to obtain 1.79 g of 2- (2,2-dibromoethenyl) benzothiazole as a crystalline powder. Melting point: 102 to 103 ° C .; NMR (400 MHz, CD
Cl ₃₎ δppm 7.44~7.48 (1H,
m), 7.50-7.54 (1H, m), 7.9
0 to 7.92 (1H, m), 8.06 (1H,
s), 8.06-8.08 (1H, m).

(Step 2) Synthesis of 2-ethynylbenzothiazole 1.75 g of 2- (2,2-dibromoethenyl) benzothiazole was treated in the same manner as in Method a of Step 5 of Reference Example 1.
The product was purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 10: 1) to obtain 0.63 g of 2-ethynylbenzothiazole as a pale brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 7.4
5 to 7.49 (1H, m), 7.51 to 7.55 (1
H, m), 7.86-7.88 (1H, m),
8.07-8.09 (1H, m).

Reference Example 3 4-n-propyl-2-ethynylthiazole: 1.36 g of 4-n-propyl-2-carbaldehyde was treated in the same manner as in Method b of Step 5 of Reference Example 1 to give a product. Is subjected to column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 10: 1)
To give 0.73 g of 4-n-propyl-2-ethynylthiazole as a pale brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 0.9
6 (3H, t), 1.74 (2H, m), 3.
44 (2H, t), 6.92 (1H, s).

Reference Example 4 4-Cyclopropyl-2-
Ethinylthiazole: 4-cyclopropyl-2-carbaldehyde was treated in the same manner as in Method b of Reference Example 1 to give 4
-Cyclopropyl-2-ethynylthiazole 0.73 g
Was obtained as a light brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 0.9
2 to 0.99 (4H, m), 2.01 to 2.08 (1
H, m), 3.42 (1H, s), 6.88
(1H, s).

Reference Example 5 4-Isopropyl-2-ethynylthiazole: 4-isopropyl-2-carbaldehyde The same treatment was carried out as in Method b of Reference Example 1 to give 4-isopropyl-2-ethynylthiazole. Obtained as a brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.3
2 (6H, d), 3.31 (1H, m),
44 (1H, s), 6.92 (1H, s).

Reference Example 6 4-tert-butyl-2
-Ethynylthiazole: 4-tert-butyl-2-carbaldehyde was treated in the same manner as in Method b of Reference Example 1 to give 4-tert-butyl-2-ethynylthiazole as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.3
6. (9H, s), 3.43 (1H, s),
94 (1H, s).

Reference Example 7 4-isopropyl-5-methyl-2-ethynylthiazole: 4-isopropyl-5
-Methyl-2-carbaldehyde was used in Step 5b of Reference Example 1.
And then treated with 4-isopropyl-5-methyl-2
-Ethynylthiazole was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.2
7 (6H, d), 2.38 (3H, s), 3.
06 (1H, m), 3.39 (1H, s).

Reference Example 8 4-Cyclopentyl-2-
Ethinylthiazole: 4-cyclopentyl-2-carbaldehyde was treated in the same manner as in Method b of Step 5 of Reference Example 1,
4-Isopropyl-2-ethynylthiazole was obtained as a pale brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.6
0 to 2.70 (8H, m), 3.21 (1H,
m), 3.43 (1H, s), 6.92 (1H,
s).

Reference Example 9 4-Cyclohexyl-2-
Ethinylthiazole: 4-cyclohexyl-2-carbaldehyde was treated in the same manner as in Method b of Reference Example 1 to give 4
-Cyclopentyl-2-ethynylthiazole was obtained as prism crystals. Melting point 77-78 ° C; NMR (400 MHz, CDC
l ₃ ) δ ppm 1.20 to 2.10 (10H,
m), 2.77 (1H, m), 3.42 (1H,
s), 6.89 (1H, s); MS (EI) m
/ Z 191 (M ⁺ ); Elemental analysis value Calculated value for C ₁₁ H ₁₃ NS (%); C, 69.06; H, 6.85;
N, 7.32; measured value (%); C, 68.91;
H, 6.83; N, 7.14.

Reference Example 10 4- (Methylthio) methyl-2-ethynylthiazole: 4- (methylthio) methyl-2-carbaldehyde was treated in the same manner as in the method b in Step 5 of Reference Example 1 to give 4- (methylthio) methyl-2-carbaldehyde. Methylthio) methyl-2-ethynylthiazole was obtained as a light brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 2.1
1. (3H, s), 3.47 (1H, s),
83 (2H, s), 7.18 (1H, s).

Reference Example 11 4-methoxymethyl-2
-Ethynylthiazole: treating 4-methoxymethyl-2-carbaldehyde in the same manner as in Method b of Step 5 of Reference Example 1,
4-Methoxymethyl-2-ethynylthiazole was obtained as a pale reddish brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 3.4
7. (4H, s), 4.60 (2H, s),
27 (1H, s).

Reference Example 12 4-Methyl-2-ethynylthiazole: 4-methyl-2-carbaldehyde was treated in the same manner as in the method b in Step 5 of Reference Example 1 to give 4-methyl-2-carboxy.
Ethinylthiazole was obtained as a light brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 2.4
7. (3H, s), 3.44 (1H, s),
92 (1H, s).

[Reference Example 13] 4-Isobutyl-2-ethynylthiazole: 4-Isobutyl-2-carbaldehyde was treated in the same manner as in the method b in Step 5 of Reference Example 1 to give 4-isobutyl-2-ethynylthiazole. Obtained as a light brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 0.9
2 (6H, d), 2.08 (1H, m),
64 (2H, d), 3.44 (1H, s),
6.90 (1H, s).

REFERENCE EXAMPLE 14 4-ethyl-2-ethynylthiazole: 4-ethyl-2-carbaldehyde was treated in the same manner as in the method b in step 5 of reference example 1 to give 4-ethyl-2-ethyl-2-carbaldehyde.
Ethinylthiazole was obtained as a light brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.3
1. (3H, t), 2.82 (2H, q),
44 (1H, s), 6.92 (1H, s).

Reference Example 15 4-n-octyl-2-
Ethinylthiazole: 4-n-octyl-2-carbaldehyde was treated in the same manner as in Method b of Step 5 of Reference Example 1 to give 4-
n-Octyl-2-ethynylthiazole was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 0.8
7 (3H, t), 1.26 to 1.74 (12H,
m), 2.77 (2H, t), 3.43 (1H,
s), 6.90 (1H, s).

Reference Example 16 4-Cyclobutyl-2-
(2- (3-nitrophenyl) ethynyl) thiazole:
519 mg of 3-iodonitrobenzene, cuprous iodide 4
0 mg, 120 mg of tetrakis (triphenylphosphine) palladium [0] and 10 m of diisopropylamine
l, and 340 mg of 4-cyclobutyl-2-ethynylthiazole was added with stirring at room temperature under a nitrogen stream. The reaction was stirred at room temperature for another hour. The oil obtained by evaporating the reaction solution under reduced pressure was subjected to column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 8:
Purified in 1), 4-cyclobutyl-2- (2- (3-
502 mg of nitrophenyl) ethynyl) thiazole were obtained as pale yellow fine needles. Melting point 107-109 ° C; IRνmax cm ^-1 152
8; NMR (400 MHz, CDCl ₃ ) δ ppm
1.90 to 2.44 (6H, m), 3.71 (1
H, quint), 7.02 (1H, s),
7.57 (1H, t), 7.89 (1H, t),
8.24 (1H, ddd), 8.44 (1H, ddd)
t); MS (FAB) m / z 285 (M ⁺⁺ 1).

Reference Example 17 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline: 500 mg of 4-cyclobutyl-2- (2- (3-nitrophenyl) ethynyl) thiazole and tin chloride (2 Hydrate) 1.
43 g was heated and refluxed in 10 ml of ethanol with stirring for 2 hours. After cooling, the solvent was distilled off. The resulting oil was made alkaline by adding a 4N aqueous sodium hydroxide solution under ice-cooling, and then extracted twice with methylene chloride. The combined methylene chloride layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The oil obtained by distilling off the solvent under reduced pressure was purified by column chromatography using silica gel (eluent: chloroform: ethyl alcohol = 20: 1) to give 3- (2- (4-cyclobutyl-2-thiazolyl). ) Ethynyl) aniline 410 mg as a pale brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
8 to 2.40 (6H, m), 3.69 (1H, qu)
int), 6.71 (1H, ddd), 6.89.
(1H, t), 6.93 (1H, s), 7.1
4 (1H, t).

Reference Example 18 Ethyl 3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) benzoic acid: 8.45 g of ethyl 3-iodobenzoic acid, tetrakis (triphenylphosphine) palladium [0]
77 g of 4-cyclobutyl-2-ethynylthiazole and 5 g of 4-cyclobutyl-2-ethynylthiazole were stirred in 100 ml of diisopropylamine under a nitrogen stream at room temperature for 1 hour. The oil obtained by evaporating the reaction solution under reduced pressure was purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 8: 1), and ethyl 3- (2- (4-cyclobutyl) was obtained. -2
9.27 g of -thiazolyl) ethynyl) benzoic acid were obtained as a pale brown oil. IRνmax cm ^-1 2220; NMR (400 MH
z, CDCl ₃ ) δ ppm 1.41 (3H, t),
1.91 to 2.42 (6H, m), 3.70 (1
H, quint), 4.40 (2H, q),
6.97 (1H, s), 7.46 (1H, t),
7.75 (1H, dt), 8.06 (1H, d
t), 8.28 (1H, t); MS (FAB) m
/ Z 312 (M ⁺⁺ 1).

REFERENCE EXAMPLE 19 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzoic acid: ethyl 9.28 g of 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzoic acid was obtained. It was dissolved in 100 ml of THF, 200 ml of a 0.25N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was cooled with ice and stirred with 1N
It was poured into 100 ml of hydrochloric acid. The precipitated crystals were collected, washed with water, and air-dried. The obtained crude crystals were recrystallized from chloroform-n-hexane to give 3- (2- (4-cyclobutyl-
6.85 g of 2-thiazolyl) ethynyl) benzoic acid were obtained as pale yellow fine needles. 139-140 ° C; IR νmax cm ^-1 222
0; NMR (400 MHz, CDCl ₃ ) δ ppm
1.90 to 2.45 (6H, m), 3.76 (1
H, quint), 6.97 (1H, s),
7.50 (1H, t), 7.80 (1H, d)
t), 8.14 (1H, dt), 8.38 (1
H, t); MS (FAB ) m / z 284 (M + +
1); Elemental analysis value Calculated value of C ₁₆ H ₁₃ NO ₂ S (%)
H, 4.62; N, 4.94, measured value (%) C, 67.38; H, 4.63; N,
4.94.

Reference Example 20 Ethyl 1- (4-methoxybenzyl) -tetrazole-5-carboxylate and ethyl 2- (4-methoxybenzyl) -tetrazole-5-carboxylate: To 22 ml of 2,6-lutidine Under ice cooling and stirring, 4 ml of trifluoroacetic acid was added. 3.25 g of sodium azide and 4.82 g of ethyl cyanoformate were added to the reaction solution,
Stirred at C for 5 hours. After cooling, the reaction solution was treated with acetic acid and ethyl 1
The mixture was diluted with 00 ml, and the precipitated crystals were collected by filtration. The crystals were suspended in 20 ml of N, N-dimethylformamide, 2.64 g of potassium carbonate and 6.19 g of 4-methoxybenzyl chloride were added, and the mixture was stirred at 70 to 80 ° C. for 2 hours. After cooling, 100 ml of water was added to the reaction solution, which was extracted with toluene. The extract was washed with water and dried over sodium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 2: 1), and the mixture of 1st: 2nd ≒ 1: 1 ethyl 1 and 2- (4-methoxybenzyl) -tetrazole-5-carboxylate 11.7
g were obtained as an oil. (Both isomers can be separated by column chromatography using silica gel.) NMR (400 MHz, CDCl ₃ ) δ ppm 1.4
4 and 1.45 (3H, each t),
3.79 and 3.80 (3H, eachs),
4.51 and 4.52 (2H, each
q), 5.78 and 5.86 (2H, each
s), 6.86 and 6.89 (2H, ea)
ch d), 7.35 and 7.38 (2H,
each d).

Reference Example 21 1- (4-methoxybenzyl) -tetrazole-5-carboxylic acid and 2- (4
-Methoxybenzyl) -tetrazole-5-carboxylic acid: 0.77 g of a mixture of ethyl 1- (4-methoxybenzyl) -tetrazole-5-carboxylate and ethyl 2- (4-methoxybenzyl) -tetrazole-5-carboxylate To the mixture were added 3.5 ml of a 1N aqueous sodium hydroxide solution and 15 ml of methanol, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, 5 ml of 1N hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over sodium sulfate. Ether-n-hexane was added to the residue obtained by distilling off the solvent, and the precipitated crystals were collected and the title compound of the mixture of 1st: 2nd ≒ 1: 1 0.4
5 was obtained as prism crystals. NMR (400 MHz, CDCl ₃ ) δ ppm 3.8
0 and 3.82 (3H, each s),
5.53 and 5.79 (2H, eachs),
6.89 and 6.92 (2H, each
d), 7.27 and 7.38 (2H, each
d), 8.12 and 8.58 (1H, ea)
ch s).

Example 1 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl)-
1H-tetrazole: (Step 1) Synthesis of 3-iodobenzonitrile 10.38 g of 3-iodobenzamide in 50 ml of DM
F. Then, 4.7 ml of phosphorus oxychloride was added dropwise at 0 ° C. while stirring. After stirring at the same temperature for 1 hour, the reaction solution was
Poured into 0 ml ice water. The precipitated crystals were collected by filtration, washed with water, and dried to obtain 9.23 g of 3-iodobenzonitrile as prism crystals. Melting point 35-37 ° C; NMR (400 MHz, CDC
l ₃ ) δ ppm 7.22 (1H, t), 7.64
(1H, dt), 7.95 (1H, dt), 7.9
9 (1H, t).

(Step 2) 3- (iodophenyl) -1
Synthesis of H-tetrazole 33.35 g of sodium azide was suspended in 150 ml of DMF, 15.20 g of aluminum chloride was gradually added at 0 ° C with stirring, and the mixture was stirred at room temperature for 1 hour. 8.70 in the reaction solution
g of 3-iodobenzonitrile was added and stirred at 90 ° C. for 3 hours. After cooling, the reaction mixture was stirred under ice-cooling with 1N hydrochloric acid 3
Poured into 00 ml. The precipitated crystals were collected by filtration, washed with water, and dried. The crude crystals were recrystallized from chloroform-ethanol-n-hexane to obtain 9.34 g of 3- (iodophenyl) -1H-tetrazole as needles. Melting point 170-172 ° C; NMR (400 MHz, D
MSO-d ₆ ) δ ppm 7.42 (1H, dd),
7.96 (1H, d), 8.06 (1H, d),
8.39 (1H, s); MS (FAB) m / z
273 (M ⁺ +1); Calculated elemental analysis _{C 7 H 5 IN 4 (%} ) C, 30.90; H, 1.85; N, 2
1.59, measured value (%) C, 30.56; H,
1.89; N, 20.69.

(Step 3) 5- (3-iodophenyl)
Synthesis of -2- (4-methoxybenzyl) -2H-tetrazole 3- (iodophenyl) -1H-tetrazole 8.98
g and potassium carbonate 6.91 g were suspended in 50 ml of DMF, and 4-methoxybenzyl chloride was added dropwise with stirring under ice-cooling. After the addition was completed, the reaction solution was stirred at room temperature for 15 hours. The reaction solution was poured into 300 ml of water, and the precipitated crystals were collected by filtration, washed with water, and dried. The obtained crude crystals were recrystallized from chloroform-n-hexane to obtain 11.43 g of 5- (3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole. NMR (400 MHz, CDCl ₃ ) δ ppm 3.8
5. 0 (3H, s), 5.73 (2H, s),
90 to 6.92 (2H, m), 7.20 (1H,
t), 7.37-7.39 (2H, m), 7.7
8 (1H, dt), 8.10 (1H, dt),
8.48 (1H, t); MS (FAB) m / z 3
93 (M ⁺ +1); Elemental analysis C ₁₅ H ₁₃ IN ₄ O Calculated (%) C, 45.94; H , 3.34;
N, 14.29; measured value (%) C, 45.81;
H, 3.35; N, 14.27.

(Step 4) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of-(4-methoxybenzyl) -2H-tetrazole 23.53 g of 5- (3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole, tetrakis (triphenylphosphine) [0] palladium 4
To 7 g and 1.14 g of cuprous iodide, 100 ml of diisopropylamine and 50 ml of DMF were added, and under a nitrogen stream,
Stirred at room temperature for 0.5 hour. 11.43 g to this reaction solution
Of 4-cyclobutyl-2-ethynylthiazole in DMF
50 ml of the solution was added dropwise, and the mixture was further stirred at room temperature for 2 hours.
The reaction solution was diluted with 1000 ml of ethyl acetate,
After washing with N hydrochloric acid and saturated saline, it was dried over sodium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography using silica gel (eluent: ethyl acetate: n-hexane = 1: 8), and crystallized from n-hexane to give 5- (3 -(2- (4-cyclobutyl-
18.86 g of 2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained as a crystalline powder. 87-89 ° C; NMR (400 MHz, CDC
l ₃ ) δ ppm 1.90 to 2.42 (6H, m),
3.66 to 3.75 (1H, m), 3.80 (3
H, s), 5.74 (2H, s), 6.90-
6.92 (2H, m), 6.97 (1H, s),
7.39 to 7.41 (2H, m), 7.48 (1H,
t), 7.65 (1H, d), 8.16 (1
H, d), 8.37 (1H, s); MS (E
I) m / z 427 (M ⁺ ); Elemental analysis C ₂₄ H ₂₁ N
₅ Calculated value of OS (%) C, 67.43; H, 4.9
5; N, 16.38, measured value (%) C, 67.2
1; H, 5.02; N, 16.27.

(Step 5) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1
Synthesis of H-tetrazole 17.96 g of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was added to anisole 8
and trifluoroacetic acid at room temperature.
Stir for 4 hours at 60 ° C. for 2 hours. 500 ml of reaction solution
The precipitate was collected by filtration, washed with water and dried. The obtained crude crystals were subjected to chloroform-ethanol-n-
Recrystallization from hexane gave 11.01 g of the title compound as a crystalline powder. Melting point 190-193 ° C; IR νmax cm ^-1 222
0; NMR (400 MHz, DMSO-d ₆ ) δpp
m 1.84 to 2.35 (6H, m), 3.64 to
3.73 (1H, m), 7.57 (1H, s),
7.73 (1H, t), 7.88 (1H, t)
d), 8.16 (1H, d), 8.29 (1H,
s); MS (EI) m / z 307 (M +); Elemental analysis C ₁₆ H ₁₃ N ₅ calcd S (%) C, 62.5
H, 4.26; N, 22.78, measured value (%) C, 62.33; H, 4.35; N, 2
2.62.

Example 2 5- (3- (2- (2-thiazolyl) ethynyl) phenyl) -1H-tetrazole: (Step 1) Methyl 3- (1H-tetrazole-5
Synthesis of yl) phenyl acetate 3.10 g of methyl 3-cyanophenyl acetate was treated in the same manner as in step 2 of Example 1, and the obtained crude crystals were recrystallized from ethanol-n-hexane to give methyl 3- (1H
-Tetrazol-5-yl) phenyl acetate 1.7
2 g were obtained as needles. 141-142 ° C; IRν max cm ^-1 173
2; NMR (400 MHz, DMSO-d ₆ ) δpp
m 3.68 (3H, s), 3.77 (2H,
s), 7.44 to 7.55 (2H, m), 7.9
5~8.00 (2H, m); Elemental analysis C ₁₀ H ₁₀ N
Calculated value of ₄ O ₂ (%) C, 55.04; H, 4.6
2; N, 25.68, measured value (%) C, 55.0
8; H, 4.64; N, 25.78.

(Step 2) Synthesis of methyl 3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenylacetate 1.67 g of methyl 3- (1H-tetrazol-5-yl) phenylacetate The same treatment as in Step 3 of Example 1 was carried out, and methyl 3- (2- (4-methoxybenzyl)-
2.06 g of (2H-tetrazol-5-yl) phenyl acetate was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 3.7
0 (3H, s), 3.75 (2H, s), 3.
79 (3H, s), 5.73 (2H, s),
6.89 (2H, d), 7.38 (2H, d),
7.40 to 7.45 (3H, m), 8.05 (1
H, d).

(Step 3) Synthesis of 2- (4-methoxybenzyl) -5- (3- (2-oxo-2- (2-thiazolyl) ethyl) -2H-tetrazole 2.25 g of 2-bromothiazole was added to 30 ml of THF. Then, 15 ml of magnesium bromide (0.95 M THF solution) was added under ice-cooling and stirring, and the mixture was stirred at room temperature for 1 hour, cooled to 0 ° C. again, and 3- (2- (4
A solution of 2.00 g of -methoxybenzyl) -2H-tetrazol-5-yl) phenylacetate in 10 ml of THF was added dropwise. After stirring at room temperature for 1 hour, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over sodium sulfate. The residue obtained by distilling off the solvent was subjected to column chromatography using silica gel (eluent: ethyl acetate: n-hexane = 1: 1).
The resulting crystals were recrystallized from ether-n-hexane to give 2- (4-methoxybenzyl) -5.
1.81 g of-(3- (2-oxo-2- (2-thiazolyl) ethyl) -2H-tetrazole were obtained as needles, mp 80-81 ° C; IR νmax cm ^-1 1678;
2. NMR (400 MHz, CDCl ₃ ) δ ppm
80 (3H, s), 4.54 (2H, s), 6.8
9. (2H, d), 7.38 (2H, d),
39 to 7.46 (2H, m), 7.70 (1H,
d), 8.04 (1H, d); Elemental analysis C ₂₀ H ₁₇
N ₅ O ₂ Calculated S (%) C, 61.37; H,
4.38; N, 17.89, measured value (%) C, 6
1.11; H, 4.51; N, 17.82.

(Step 4) Synthesis of 2- (4-methoxybenzyl) 5- (3- (2- (2-thiazolyl) ethynyl) phenyl) -2H-tetrazole To 1.56 g of triphenylphosphine oxide, 1
15 ml of 2-dichloroethane was added, and 0.80 g of trifluoromethanesulfonic anhydride was added under ice-cooling and stirring, followed by stirring at the same temperature for 15 minutes. To the reaction solution, 1.2 ml of triethylamine and 2- (4-methoxybenzyl) -5 were added.
0.73 g of-(3- (2-oxo-2- (2-thiazolyl) ethyl) -2H-tetrazole was added, and the mixture was heated under reflux for 20 hours.
And washed successively with 1N hydrochloric acid and water, and dried over sodium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography using silica gel (eluent: ethyl acetate: n-hexane = 1: 3), and the obtained crystals were recrystallized from chloroform-ether. , 2- (4
-Methoxybenzyl) -5- (3- (2- (2-thiazolyl) ethynyl) phenyl) -2H-tetrazole
21 g were obtained as needles. Melting point 95-96 ° C; IRν max cm ^-1 2216;
2. NMR (400 MHz, CDCl ₃ ) δ ppm
80 (3H, s), 5.73 (2H, s),
6.91 (2H, d), 7.36 to 7.43 (3
H, m), 7.49 (1H, t), 7.67
(1H, ddd), 7.88 (1H, d),
8.18 (1H, ddd), 8.37 (1H, d
d); Elemental analysis value Calculated value of C ₂₀ H ₁₅ N ₅ OS (%)
C, 64.33; H, 4.05; N, 4.05,
Measured value (%) C, 64.23; H, 4.19;
N, 18.79.

(Step 5) Synthesis of 5- (3- (2- (2-thiazolyl) ethynyl) phenyl) -1H-tetrazole 2- (4-methoxybenzyl) -5- (3- (2- (2
150 mg of -thiazolyl) ethynyl) phenyl) -2H-tetrazole were treated in the same manner as in Step 5 of Example 1, and the obtained crude crystals were recrystallized from ethanol-ether to give 30 mg of the title compound as a crystalline powder. Melting point 174-175 ° C; IRνmax cm ^-1 221
6; NMR (400 MHz, DMSO-d ₆ ) δpp
m 7.75 (1H, s), 7.88 (1H, s)
d), 7.99 (1H, d), 8.02 (1H,
d), 8.17 (1H, d), 8.39 (1
H, s); Elemental analysis value Calculated value of C ₁₂ H ₇ N ₅ S (%)
C, 56.90; H, 2.79; N, 27.6.
5, measured value (%) C, 57.14; H, 2.8
7; N, 26.84.

Example 3 5- (3- (2- (2-benzothiazolyl) ethynyl) phenyl) -1H-tetrazole: (Step 1) 2- (2- (3- (2- (4-methoxybenzyl) ) -2H-Tetrazol-5-yl) phenyl)
Synthesis of ethynyl) benzothial 318 mg of 2-ethynylbenzothiazole and 5- (3
-Iodophenyl) -2- (4-methoxybenzyl)-
784 mg of 2H-tetrazole was subjected to the same coupling reaction as in Step 4 of Example 1, and crystallized from n-hexane to give 2- (2- (3- (2- (4-methoxybenzyl)).
468 mg of -2H-tetrazol-5-yl) phenyl) ethynyl) benzothial were obtained as a pale brown crystalline powder. 133-135 ° C; NMR (400 MHz, C
4. DCL ₃ ) δ ppm 3.80 (3H, s),
75 (2H, s), 6.90-6.93 (2H,
m), 7.39-7.43 (2H, m), 7.4
7 (1H, t), 7.50 to 7.56 (2H,
m), 7.71 (1H, d), 7.89 (1H,
d), 8.09 (1H, d), 8.20 (1
H, d), 8.42 (1H, s).

(Step 2) Synthesis of 5- (3- (2- (2-benzothiazolyl) ethynyl) phenyl) -1H-tetrazole 2- (2- (3- (2- (4-methoxybenzyl) -2)
423 mg of H-tetrazol-5-yl) phenyl) ethynyl) benzothiazole was subjected to a 4-methoxybenzylation reaction in the same manner as in Step 5 of Example 1, and the crude crystals were recrystallized from chloroform-ethanol to give the title compound. Was. 208-210 ° C; NMR (400 MHz, D
_{MSO-d 6) δppm7.56~7.65 (2H} ,
m), 7.75 (1H, t), 7.94 (1H,
d), 8.11 (1H, d), 8.19-8.
21 (2H, m), 8.36 (1H, s); MS
(FAB) m / z 304 ( M + +1); Elemental analysis _{C 16 H 9 N 5 S ·} 1 / 4H 2 O Calculated (%) C,
H, 3.11; N, 22.75, measured value (%) C, 62.60; H, 3.00; N, 2
2.56.

Example 4 5- (3- (2- (4-n)
-Propyl-2-thiazolyl) ethynyl) phenyl)-
1H-tetrazole: (Step 1) 5- (3- (2- (4-n-propyl-2)
Synthesis of -thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole 4-n-propyl-2-ethynylthiazole and 5-
Using (3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole, treatment was conducted in the same manner as in Step 5 of Example 1, and 5- (3- (2- (4-n-propyl-
2-Thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained as pale yellow needles. Melting point 57-58 ° C; NMR (400 MHz, CDC
l ₃ ) δ ppm 0.98 (3H, t), 1.77
(2H, m), 2.79 (2H, t), 3.84
(3H, s), 5.74 (2H, s), 6.9
6. 1 (2H, d), 6.96 (1H, s), 7.
6. 41 (2H, d), 7.48 (1H, t), 7.
65 (1H, dt), 8.16 (1H, dt),
8.36 (1H, t); Elemental analysis: C ₂₃ H ₂₁ N ₅
OS · 1 / 4H ₂ O Calculated (%) C, 65.77;
H, 5.16; N, 16.67, measured value (%)
C, C, 66.21; H, 5.15; N, 16.3.
0.

(Step 2) 5- (3- (2- (4-n-
Propyl-2-thiazolyl) ethynyl) phenyl) -1
Synthesis of H-tetrazole 5- (3- (2- (4-n-propyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was prepared in the same manner as in Step 5 of Example 1. The resulting crude crystals were recrystallized from water-ethanol,
The title was obtained as a crystalline powder. Melting point: 154 to 156 ° C .; NMR (400 MHz, D
MSO-d ₆ ) δ ppm 0.93 (3H, t),
1.70 (2H, m), 2.74 (2H, t),
7.52 (1H, s), 7.71 (1H, t),
7.84 (1H, d), 8.16 (1H, d)
d), 8.28 (1H, s); Elemental analysis C ₁₅ H
3. Calculated value for ₁₃ N ₅ S (%) C, 61.00;
44; N, 23.71; measured value (%) C, 61.
01; H, 4.48; N, 23.55.

Example 5 5- (3- (2- (4-cyclopropyl-2-thiazolyl) ethynyl) phenyl)
-1H-tetrazole: (Step 1) 5- (3- (2- (4-cyclopropyl-
Synthesis of 2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole 1.04 g of 4-cyclopropyl-2-ethynylthiazole and 5
2.73 g of-(3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole were treated in the same manner as in Step 5 of Example 1 to give 2.13 g of 5- (3- (2-
(4-Cyclopropyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained as needles. Melting point 106-107 ° C; NMR (400 MHz, C
DCl ₃ ) δ ppm 0.94 to 0.99 (4H,
m), 2.04 to 2.11 (1H, m), 3.8
5. 0 (3H, s), 5.74 (2H, s),
91 (1H, s), 6.89-6.93 (2H,
m), 7.40 (2H, d), 7.47 (1H,
t), 7.65 (1H, dd), 8.15 (1
H, dd), 3.35 (1H, t); MS (F
AB) m / z 414 (M ⁺ ).

(Step 2) 5- (3- (2- (4-cyclopropyl-2-thiazolyl) ethynyl) phenyl)-
Synthesis of 1H-tetrazole 2.07 g of 5- (3- (2- (4-cyclopropyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was prepared in the same manner as in Example 1. The resulting crude crystals were treated in the same manner as in Step 5 above.
Recrystallization from n-hexane gave 1.16 g of the title compound as needles. 184-185 ° C (decomp.); IRν
max cm ^-1 2216; NMR (400 MHz, DMS
_{O-d 6) δppm 0.84~0.90 (} 2H,
m), 0.92-0.98 (1H, m), 2.0
9 to 2.19 (1H, m), 7.54 (1H,
s), 7.72 (1H, t), 7.86 (1H,
d), 8.16 (1H, d), 8.28 (1
H, s); MS (FAB) m / z 294 (M ⁺⁺ ).
1); Elemental analysis value Calculated value of C ₁₅ H ₁₁ N ₅ S.1 / 2H ₂ O (%) C, 59.59; H, 4.00; N,
23.16, measured value (%) C, 59.75; H,
3.80; N, 23.02.

Example 6 5- (3- (2- (4-isopropyl-2-thiazolyl) ethynyl) phenyl)-
1H-tetrazole: (Step 1) 5- (3- (2- (4-isopropyl-2)
Synthesis of -thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole 850 mg of 4-isopropyl-2-ethynylthiazole
And 2.5 (5 g) of 5- (3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole were treated in the same manner as in Step 5 of Example 1 and column chromatography using silica gel (eluent: acetic acid) Purification with ethyl: n-hexane = 1: 8) gave 5- (3- (2- (4-isopropyl-2-thiazolyl) ethynyl) phenyl) -2.
-(4-methoxybenzyl) -2H-tetrazole
08 g was obtained as a pale brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.3
5 (6H, d), 3.16 (1H, m), 3.
81 (3H, s), 5.74 (2H, s),
6.91 (2H, dt), 6.96 (1H,
d), 7.41 (2H, dt), 7.48 (1
H, t), 7.66 (1H, dt), 8.16
(1H, dt), 8.37 (1H, t).

(Step 2) 5- (3- (2- (4-isopropyl-2-thiazolyl) ethynyl) phenyl) -1
Synthesis of H-tetrazole 1.85 g of 5- (3- (2- (4-isopropyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was added to Step 5 of Example 1. The crude crystals obtained were treated with chloroform-
Recrystallized from isopropyl ether to give the title compound (383 mg)
Was obtained as a pale brown crystalline powder. 177-179 ° C; NMR (400 MHz, D
MSO-d ₆ ) δ ppm 1.44 (6H, d),
3.25 (1H, m), 7.70 (1H, s),
7.88 (1H, t), 8.03 (1H, d),
8.32 (1H, d), 8.45 (1H, d)
s): Elemental analysis value Calculated value of C ₁₅ H ₁₃ N ₅ S (%)
C, 61.00; H, 4.44; N, 23.71,
Measured value (%) C, 61.05; H, 4.54;
N, 23.88.

Example 7 5- (3- (2- (4-t)
tert-butyl-2-thiazolyl) ethynyl) phenyl) -1H-tetrazole: (Step 1) 5- (3- (2- (4-tert-butyl-2-thiazolyl) ethynyl) phenyl) -2- (4-
Synthesis of (methoxybenzyl) -2H-tetrazole 4-tert-butyl-2-ethynylthiazole 402
mg and 2.73 g of 5- (3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole were treated in the same manner as in Step 5 of Example 1, and column chromatography using silica gel (eluent: Purification with ethyl acetate: n-hexane = 1: 10, crystallization from n-hexane, and 5- (3- (2- (4-tert-butyl-2)
1.91 g of -thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole were obtained. 113-115 ° C; NMR (400 MHz, C
2. DCL ₃ ) δ ppm 1.39 (9H, s),
80 (3H, s), 5.74 (2H, s),
6.91 (2H, d), 6.98 (1H, s),
7.40 (2H, d), 7.48 (1H, t),
7.66 (1H, dt), 8.16 (1H, d
t), 8.37 (1H, t); MS (FAB) m
/ Z 430 (M ⁺⁺ 1).

(Step 2) 5- (3- (2- (4-te)
rt-butyl-2-thiazolyl) ethynyl) phenyl)
Synthesis of -1H-tetrazole 1.73 g of 5- (3- (2- (4-tert-butyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was prepared in Example 1. The resulting crude crystals were recrystallized from chloroform-IPE to give 1.06 g of the title compound as needles. Melting point 176-178 ° C; NMR (400 MHz, D
MSO-d ₆ ) δ ppm 1.33 (9H, s),
7.54 (1H, s), 7.73 (1H, t),
7.88 (1H, d), 8.17 (1H, d),
8.30 (1H, s); MS (FAB) m / z
310 (M ⁺ +1); Elemental analysis _{C 16 H 15 N 5 S ·} 1
/ 5H ₂ O calculated value (%) C, 61.22; H,
4.98; N, 22.31, measured value (%) C, 6
1.27; H, 4.87; N, 22.14.

Example 8 5- (3- (2- (4-isopropyl-5-methyl-2-thiazolyl) ethynyl)
(Phenyl) -1H-tetrazole: (Step 1) 5- (3- (2- (4-isopropyl-5)
-Methyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of-(4-methoxybenzyl) -2H-tetrazole 240 mg of 4-isopropyl-5-methyl-2-ethynylthiazole and 5- (3-iodophenyl) -2-
(4-methoxybenzyl) -2H-tetrazole 471
mg was treated in the same manner as in Step 5 of Example 1, purified by column chromatography using silica gel (eluent: ethyl acetate: n-hexane = 1: 8), and crystallized from n-hexane. 5- (3- (2- (4-isopropyl-5-methyl-2-thiazolyl) ethynyl) phenyl)
1.91 g of -2- (4-methoxybenzyl) -2H-tetrazole was obtained as needles. Melting point 101-103 ° C; NMR (400 MHz, C
_{DCl 3) δppm 1.31 (6H,} d), 2.
41 (3H, s), 3.09 (1H, m),
3.80 (3H, s), 5.74 (2H, s),
6.91 (2H, d), 7.40 (2H, d),
7.46 (1H, brt), 7.64 (1H, brt)
d), 8.14 (1H, d), 8.35 (1
H, s).

(Step 2) Synthesis of 5- (3- (2- (4-isopropyl-5-methyl-2-thiazolyl) ethynyl) phenyl) -1H-tetrazole 5- (3- (2- (4-isopropyl) -5-methyl2-
387 mg of thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1, and the obtained crude crystals were recrystallized from chloroform-n-hexane. 206 mg of the title
Was obtained as a crystalline powder. 153-155 ° C .; NMR (400 MHz, D
MSO-d ₆ ) δ ppm 1.22 (6H, d),
2.43 (3H, s), 3.14 (1H, m),
7.71 (1H, brt), 7.86 (1H,
d), 8.15 (1H, d), 8.27 (1H,
s); MS (FAB) m / z 310 (M ⁺⁺ ).
1); Elemental analysis value Calculated value of C ₁₆ H ₁₅ N ₅ S (%) C,
H, 4.89; N, 22.64, measured value (%) C, 61.99; H, 4.92; N, 2
2.86.

Example 9 5- (3- (2- (4-cyclopentyl-2-thiazolyl) ethynyl) phenyl)
-1H-tetrazole: (Step 1) 5- (3- (2- (4-cyclopentyl-
Synthesis of 2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole 249 mg of 4-cyclopentyl-2-ethynylthiazole and 5
500 mg of-(3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1, and column chromatography using silica gel (eluent: ethyl acetate: n- Hexane =
1: 8), and purified by 5- (3- (2- (4-cyclopentyl-2-thiazolyl) ethynyl) phenyl) -2-.
(4-methoxybenzyl) -2H-tetrazole 420
mg were obtained as a pale brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.6
5 to 2.85 (8H, m), 3.24 (1H,
m), 3.80 (3H, s), 5.74 (2H,
s), 6.91 (2H, d), 6.96 (1
H, s), 7.40 (2H, d), 7.48
(1H, t), 7.64 (1H, dt), 8.1
5 (1H, dt), 8.37 (1H, t).

(Step 2) 5- (3- (2- (4-cyclopentyl-2-thiazolyl) ethynyl) phenyl)-
Synthesis of 1H-tetrazole 400 mg of 5- (3- (2- (4-cyclopentyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was used in the same manner as in Step 5 of Example 1. And the obtained crude crystals were subjected to chloroform-
Recrystallized from ethanol-n-hexane to give the title compound (280 m)
g were obtained as fine needles. 145 ° C. (decomp.); NMR (400
MHz, CDCl ₃ -DMSO-d ₆ ) δ ppm
60 to 2.75 (8H, m), 3.25 (1H,
m), 7.00 (1H, s), 7.54 (1H,
t), 7.71 (1H, d), 8.17 (1
H, d), 8.37 (1H, s); MS (EI).
m / z 321 (M ⁺ ).

Example 10 5- (3- (2- (4-
Cyclohexyl-2-thiazolyl) ethynyl) phenyl) -1H-tetrazole: (Step 1) 5- (3- (2- (4-cyclohexyl-
Synthesis of 2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole 268 mg of 4-cyclohexyl-2-ethynylthiazole and 5
500 mg of-(3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1, and column chromatography using silica gel (eluent: ethyl acetate: n- Hexane =
1: 8) to give 5- (3- (2- (4-cyclohexyl-2-thiazolyl) ethynyl) phenyl) -2-.
(4-methoxybenzyl) -2H-tetrazole 400
mg were obtained as a pale brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.2
5 to 2.15 (10H, m), 2.81 (1H,
m), 3.81 (1H, s), 5.74 (2H,
s), 6.92 (2H, d), 6.93 (1
H, s), 7.41 (2H, d), 7.65.
(1H, dt), 8.15 (1H, dt),
8.36 (1H, t).

(Step 2) 5- (3- (2- (4-cyclohexyl-2-thiazolyl) ethynyl) phenyl)-
Synthesis of 1H-tetrazole 473 mg of 5- (3- (2- (4-cyclohexyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained in the same manner as in Step 5 of Example 1. And the obtained crude crystals were subjected to chloroform-
Recrystallized from ethanol-n-hexane to give the title compound 240
mg were obtained as fine needles. Melting point 166-169 ° C; IRνmax cm ^-1 221
6; NMR (400 MHz, CDCl ₃ ) δ ppm
1.25 to 2.20 (10H, m), 2.96 (1
H, m), 7.05 (1H, s), 7.55
(1H, dd), 8.15 (1H, s), 8.1
6 (1H, dd); MS (EI) m / z 335
(M ⁺ ); calculated value of elemental analysis value C ₁₈ H ₁₇ N ₅ S (%)
C, 64.45; H, 5.11; N, 20.8
8, measured value (%) C, 64.46; H, 5.10;
N, 20.62.

Example 11 5- (3- (2- (4-
Methylthiomethyl-2-thiazolyl) ethynyl) phenyl) -1H-tetrazole: (Step 1) 2- (4-methoxybenzyl) -5- (3
Synthesis of-(2- (4-methylthiomethyl-2-thiazolyl) ethynyl) phenyl) -2H-tetrazole 508 mg of 2-ethynyl-4-methylthiothiazole and 5- (3-iodophenyl) -2- (4-methoxybenzyl) 981 mg of -2H-tetrazole was subjected to the same coupling reaction as in Step 4 of Example 1, purified by column chromatography using silica gel (eluent: ethyl acetate: n-hexane = 1: 4), and purified by chloroform. Recrystallized from -n-hexane to give 2- (4-methoxybenzyl) -5- (3- (2- (4-methylthiomethyl-2-
867 mg of thiazolyl) ethynyl) phenyl) -2H-tetrazole were obtained as pale yellow crystalline powder. 104-106 ° C; NMR (400 MHz, C
_{DCl 3) δppm 2.14 (3H,} s), 3.
81 (3H, s), 3.86 (2H, s),
5.74 (2H, s), 6.90-6.93 (2
H, m), 7.21 (1H, s), 7.39-
7.41 (2H, m), 7.49 (1H, t),
7.65 (1H, d), 8.17 (1H, d),
8.36 (1H, s); MS (EI) m / z 4
33 (M ⁺ ); Elemental analysis value Calculated value of C ₂₂ H ₁₉ N ₅ S ₂ (%) C, 60.95; H, 4.42; N, 1
6.15, measured value (%) C, 60.66; H,
4.45; N, 16.10.

(Step 2) 5- (3- (2- (4-methylthiomethyl-2-thiazolyl) ethynyl) phenyl)
Synthesis of -1H-tetrazole 2- (4-methoxybenzyl) -5- (3- (2- (4
433 mg of -methylthiomethyl-2-thiazolyl) ethynyl) phenyl) -2H-tetrazole were treated as in step 5 of Example 1, and the crude crystals were recrystallized from chloroform-n-hexane to give 285 mg of the title compound. Melting point 159-162 ° C; NMR (400 MHz, D
MSO-d ₆ ) δ ppm 2.07 (3H, s),
3.85 (2H, s), 7.71 (1H, s),
7.73 (1H, t), 7.88 (1H, d)
t), 8.17 (1H, dt), 8.29 (1
H, t); MS (EI) m / z 313 (M ^<+> );
Elemental analysis _{C 14 H 11 N 5 S 2} · 1 / 4H 2 O Calculated (%) C, 52.89; H , 3.65; N, 2
2. 03, measured value (%) C, 52.87; H,
3.54; N, 21.70.

Example 12 5- (3- (2- (4-
Methoxymethyl-5-methyl-2-thiazolyl) ethynyl) phenyl) -1H-tetrazole: (Step 1) 2- (4-methoxybenzyl) -5- (3
Synthesis of-(2- (4-methoxymethyl-2-thiazolyl) ethynyl) phenyl) -2H-tetrazole 659m of 2-ethynyl-4-methoxymethylthiazole
g, and 1.41 g of 5- (3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole were treated in the same manner as in Step 4 of Example 1, and the product was subjected to column chromatography using silica gel ( Eluent: ethyl acetate:
Purified with n-hexane-chloroform = 2: 1), recrystallized from chloroform-n-hexane, and 2- (4-methoxybenzyl) -5- (3- (2- (4-methoxymethyl-2-) Thiazolyl) ethynyl) phenyl) -2H-
1.487 g of tetrazole were obtained as a crystalline powder. Melting point 105-107 ° C; NMR (400 MHz, C
_{DCl 3) δppm 3.49 (3H,} s), 3.
80 (3H, s), 4.63 (2H, s),
5.74 (2H, s), 6.90-6.92 (2
H, m), 7.30 (1H, s), 7.39-
7.41 (2H, m), 7.49 (1H, t),
7.65 (1H, d), 8.17 (1H, d),
8.36 (1H, s); MS (EI) m / z 4
17 (M ⁺ ); Elemental analysis: calculated for C ₂₂ H ₁₉ N ₅ O ₂ S (%) C, 63.29; H, 4.59; N, 1
6.77, measured value (%) C, 63.12; H,
4.62; N, 16.66.

(Step 2) 5- (3- (2- (4-methoxymethyl-2-thiazolyl) ethynyl) phenyl)-
Synthesis of 1H-tetrazole 2- (4-methoxybenzyl) -5- (3- (2- (4
1.169 g of -methoxymethyl-2-thiazolyl) ethynyl) phenyl) -2H-tetrazole were treated in the same manner as in Step 5 of Example 1, and the crude crystals were recrystallized from ethanol-n-hexane to obtain 794 mg of the title compound. Was. Melting point 211-214 ° C; IRνmax cm ^-1 221
6; NMR (400 MHz, DMSO-d ₆ ) δpp
m 3.35 (3H, s), 4.54 (2H,
s), 7.73 (1H, s), 7.80 (1H,
t), 7.87 (1H, dt), 8.17 (1
H, dt), 8.29 (1H, t); MS (E
I) m / z 297 (M ⁺ ); Elemental analysis C ₁₄ H ₁₁
Calculated N ₅ OS (%) C, 56.55; H, 3.
73; N, 23.55; measured value (%) C, 56.
52; H, 3.84; N, 23.66.

Example 13 5- (3- (2- (4-
Methyl-2-thiazolyl) ethynyl) phenyl) -1H
-Tetrazole: (Step 1) 5- (3- (2- (4-methyl-2-thiazolyl) -2-oxoethyl) phenyl) -2- (4-
Synthesis of methoxybenzyl) -2H-tetrazole 1.04 g of diisopropylamine was dissolved in 20 ml of THF, and n-butyllithium (1.7) was stirred at -78 ° C.
5.6 ml of 1M n-hexane solution was added,
Stirred for 0 minutes. The mixture was cooled again to -78 ° C, a solution of 1.00 g of 4-methylthiazole in 5 ml of THF was added, and the mixture was stirred at the same temperature for 0.5 hour. Methyl 3- (2- (4
A solution of 1.45 g of -methoxybenzyl) -5-tetrazolyl) phenylacetic acid in THF was added, and the mixture was further stirred at the same temperature for 1 hour. Water was added to the reaction solution, the temperature was returned to room temperature, 1N hydrochloric acid was added to make the reaction solution acidic, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, and then dried over sodium sulfate. The solvent was distilled off, and the residue was purified by column chromatography using silica gel (eluent: ethyl acetate: n-hexane = 1: 3), and recrystallized from ether-n-hexane to give 5- (3- ( 0.60 g of 2- (4-methyl-2-thiazolyl) -2-oxoethyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained as needles. Melting point 90-91 ° C; NMR (400 MHz, CDC
l ₃ ) δ ppm 2.52 (3H, s), 3.79
(3H, s), 4.51 (2H, s), 5.72
(2H, s), 6.89 (2H, d), 7.3
7 (2H, d), 7.40 to 7.45 (3H,
m), 8.04 (1H, t), 8.12 (1H,
s); Elemental analysis value Calculated value of C ₂₁ H ₁₉ N ₅ O ₂ S (%) C, 62.11; H, 4.92; N, 1
7.27, measured value (%) C, 61.78; H,
4.78; N, 16.99.

(Step 2) 5- (3- (2- (4-methyl-2-thiazolyl) ethynyl) phenyl) -2- (4
Synthesis of -methoxybenzyl) -2H-tetrazole 5- (3- (2- (4-methyl-2-thiazolyl) -2)
-Oxoethyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 3 of Example 2, and the product was subjected to column chromatography using silica gel (eluent: ethyl acetate: n- Hexane = 1:
The obtained crystals were recrystallized from ether-n-hexane to give 5- (3- (2- (4-methyl-2).
29 mg of -thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole were obtained as needles. 95-96 ° C; NMR (400 MHz, CDC
l ₃ ) δ ppm 2.50 (3H, s), 3.80
(3H, s), 5.74 (2H, s), 6.91
(2H, d), 6.95 (1H, s), 7.4
0 (2H, d), 7.48 (1H, t), 7.
64 (1H, d), 8.16 (1H, d),
36 (1H, s).

(Step 3) Synthesis of 5- (3- (2- (4-methyl-2-thiazolyl) ethynyl) phenyl) -1H-tetrazole 5- (3- (2- (4-methyl-2-thiazolyl) ) Ethynyl) phenyl) -2- (4-methoxybenzyl) -2
H-tetrazole (12.1 mg) was treated in the same manner as in Step 5 of Example 1, and the crude crystals were recrystallized from ethanol-ether to give the title compound (6 mg). Melting point: 224 to 227 ° C. (decomp.); NMR
(400 MHz, DMSO-d ₆ ) δ ppm 2.43
(3H, s), 7.53 (1H, s), 7.7
7. 2 (1H, t), 7.85 (1H, d),
17 (1H, d), 8.27 (1H, s); M
S (EI) m / z 267 (M ⁺ ); Elemental analysis value C ₁₃ H
_{9 N 5 S · 1 / 10H} 2 O Calculated (%) C, 58.
H, 3.45; N, 26.02, measured value (%) C, 58.06; H, 3.69; N, 2
5.49.

Example 14 5- (3- (2- (4-
Isobutyl-2-thiazolyl) ethynyl) phenyl)-
1H-tetrazole: (Step 1) 5- (3- (2- (4-isobutyl-2-
Synthesis of thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole 480 mg of 2-ethynyl-4-isobutylthiazole and 5- (3-iodophenyl) -2- (4-methoxybenzyl) -2H- 880 mg of tetrazole was treated in the same manner as in step 4 of Example 1, and the product was purified by column chromatography using silica gel (eluent: ethyl acetate: n-hexane = 1: 4) to give chloroform-n-hexane. And recrystallized from 5- (3- (2- (4-isobutyl-
867 mg of 2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained as a pale brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 0.9
5 (6H, d), 2.12 (1H, m), 2.
67 (2H, d), 3.80 (3H, s),
5.74 (2H, s), 6.91 (2H, d),
6.94 (1H, s), 7.40 (2H, d),
7.48 (1H, t), 7.64 (1H, t)
d), 8.15 (1H, d), 8.36 (1H,
s).

(Step 2) 5- (3- (2- (4-isobutyl-2-thiazolyl) ethynyl) phenyl) -1H
Synthesis of -tetrazole 5- (3- (2- (4-isobutyl-2-thiazolyl))
Ethynyl) phenyl) -2- (4-methoxybenzyl)
970 mg of -2H-tetrazole was treated in the same manner as in Step 5 of Example 1, and the crude crystals were recrystallized from chloroform-n-hexane to obtain 360 mg of the title compound. 177-178 ° C; NMR (400 MHz, D
MSO-d ₆ ) δ ppm 0.90 (6H, d),
2.03 (1H, m), 2.63 (2H, d),
7.54 (1H, s), 7.73 (1H, t),
7.86 (1H, d), 8.16 (1H, d)
d), 8.32 (1H, s); MS (EI) m /
z 309 (M ⁺ ); Elemental analysis value C ₁₆ H ₁₅ N ₅ S · 1
Calculated value of / 4H ₂ O (%) C, 61.22; H,
4.98; N, 22.31, measured value (%) C, 6
0.90; H, 4.86; N, 21.97.

Example 15 5- (3- (2- (4-
Ethyl-2-thiazolyl) ethynyl) phenyl) -1H
-Tetrazole: (Step 1) Synthesis of 5- (3- (2- (4-ethyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole 4-ethyl-2-ethynyl 460 mg of -thiazole and 1.0 g of 5- (3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole are treated in the same manner as in Step 4 of Example 1, and the product is subjected to column chromatography using silica gel. (Eluent: ethyl acetate: n-hexane = 1: 3), and recrystallized from ethanol-n-hexane to give 5- (3- (2- (4-ethyl-2-thiazolyl) ethynyl) phenyl) 730 mg of 2- (4-methoxybenzyl) -2H-tetrazole was obtained as pale yellow needles. Melting point 116-117 ° C; NMR (400 MHz, C
_{DCl 3) δppm 1.34 (3H,} t), 2.
85 (2H, q), 3.80 (3H, s),
6.90 (2H, d), 6.96 (1H, s),
7.39 (2H, d), 7.48 (1H, t),
7.66 (1H, d), 8.15 (1H, d)
d), 8.36 (1H, s); Elemental analysis C ₂₂ H _{19
N 5 OS · 1 / 2H 2} O Calculated (%) C, 64.3
H, 4.91; N, 17.06, measured value (%) C, 64.62; H, 4.78; N, 1
6.73.

(Step 2) Synthesis of 5- (3- (2- (4-ethyl-2-thiazolyl) ethynyl) phenyl) -1H-tetrazole 5- (3- (2- (4-ethyl-2-thiazolyl) ) Ethynyl) phenyl) -2- (4-methoxybenzyl) -2
736 mg of H-tetrazole was treated in the same manner as in Step 5 of Example 1, and the crude crystals were recrystallized from ethanol-ether to give 268 mg of the title compound as pale yellow crystalline powder. 198-200 ° C; NMR (400 MHz, D
MSO-d ₆ ) δ ppm 1.26 (3H, t),
2.78 (2H, q), 7.54 (1H, s),
7.73 (1H, t), 7.86 (1H, d),
8.16 (1H, d), 8.29 (1H, d)
s); Elemental analysis value Calculated value of C ₁₄ H ₁₁ N ₅ S (%)
C, 59.77; H, 3.94; N, 24.89,
Measured value (%) C, 59.30; H, 4.07;
N, 24.71.

Example 16 5- (3- (2- (4-
n-octyl-2-thiazolyl) ethynyl) phenyl)
-1H-tetrazole: (Step 1) 2- (4-methoxybenzyl) -5- (3
Synthesis of-(2- (4-n-octyl-2-thiazolyl) ethynyl) phenyl) -2H-tetrazole 410 mg of 2-ethynyl-4-n-octylthiazole
And 726 mg of 5- (3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole in Example 1
And the product was subjected to column chromatography using silica gel (eluent: ethyl acetate: n-
Hexane = 1: 7) and crystallized from n-hexane to give 2- (4-methoxybenzyl) -5- (3-
593 mg of (2- (4-n-octyl-2-thiazolyl) ethynyl) phenyl) -2H-tetrazole were obtained as a pale yellow crystalline powder. Melting point 47-48 ° C; NMR (400 MHz, CDC
l ₃ ) δ ppm 0.88 (3H, t), 1.27
~ 1.75 (12H, m), 2.80 (2H,
t), 3.79 (3H, s), 5.55 (2H,
5.s), 6.89-6.92 (2H, m),
94 (1H, s), 7.38-7.41 (2H,
m), 7.47 (1H, t), 7.64 (1H,
d), 8.15 (1H, d), 8.36 (1
H, s); MS (EI) m / z 485 (M ^<+> );
Elemental analysis value Calculated value of C ₂₈ H ₃₁ N ₅ OS (%) C, 6
9.24; H, 6.43; N, 14.42, measured value (%) C, 68.98; H, 6.32; N, 1
4.35.

(Step 2) 5- (3- (2- (4-n-
Octyl-2-thiazolyl) ethynyl) phenyl) -1
Synthesis of H-tetrazole 2- (4-methoxybenzyl) -5- (3- (2- (4
486 mg of -n-octyl-2-thiazolyl) ethynyl) phenyl) -2H-tetrazole were treated in the same manner as in Step 5 of Example 1, and the crude crystals were recrystallized from chloroform-n-hexane to give 186 mg of the title compound as crystalline. Obtained as a powder. 104-105 ° C; NMR (400 MHz, D
MSO-d ₆ ) δ ppm 0.86 (3H, t),
1.25 to 1.68 (12H, m), 2.74 (2
H, t), 7.53 (1H, s), 7.72
(1H, t), 7.86 (1H, d), 8.16
(1H, d), 8.28 (1H, s); MS
(EI) m / z 365 ( M +); Elemental analysis C ₂₀ H ₂₃
N ₅ Calculated S (%) C, 65.72; H, 6.3
4; N, 19.17, measured value (%) C, 65.6
9; H, 6.27; N, 19.24.

Example 17 5- (4- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-thienyl) -1H-tetrazole: (Step 1) 5- (4-bromo-2-thienyl) -2-
Synthesis of (4-methoxybenzyl) -2H-tetrazole 5- (4-bromo-2-thienyl) -1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to give 5- (4-bromo-2-thienyl). ) -2- (4-Methoxybenzyl)-
2H-tetrazole was obtained. 70-72 ° C (recrystallization solvent: chloroform-n-
Hexane); IR max cm ^-1 ; 3108,300
4,2964,2836,1682,1614,158
8, 1574, 1516; NMR (400 MHz, C
4. DCL ₃ ) δ ppm 3.80 (3H, s),
70 (2H, s), 6.88-6.91 (2H,
m), 7.31 (1H, d), 7.35-7.3.
8 (2H, m), 7.67 (1H, d); MS
(EI) m / z 352 [(M ⁺⁺ 2) +1], 350
[(M ⁺ ) +1]; Elemental analysis value C ₁₃ H ₁₁ BrN ₄ OS
Calculated value (%) for C, 44.46; H, 3.16;
N, 15.95; measured value (%) C, 44.54;
H, 3.11; N, 15.99.

(Step 2) Synthesis of 5- (4- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-thienyl) -1H-tetrazole 5- (4-bromo-2-thienyl) -2 -(4-Methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1, followed by demethoxylation of 4-methoxy as in Step 5 of Example 1. Was performed to obtain the title compound. 224-230 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 ; 3088,2
216, 1580, 1518; NMR (400 MH
_{z, DMSO-d 6) δppm} 1.84~2.31
(6H, m), 3.63-3.71 (1H,
m), 7.54 (1H, s), 7.93 (1H,
s), 8.40 (1H, s); MS (FAB)
^{m / z 314 (M + +1} ); Elemental analysis C ₁₄ H ₁₁
N ₅ Calculated _{S 2 (%) C, 52.15} ; H, 3.7
5; N, 21.72; measured value (%) C, 52.1
5; H, 3.67; N, 21.91.

Example 18 5- (5- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-thienyl) -1H-tetrazole: (Step 1) 5- (5-bromo-2-thienyl) -2-
Synthesis of (4-methoxybenzyl) -2H-tetrazole 5- (5-bromo-2-thienyl) -1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to give 5- (5-bromo-2-thienyl). ) -2- (4-Methoxybenzyl)-
2H-tetrazole was obtained. 87-89 ° C (recrystallization solvent: chloroform-n-
Hexane); IRνmax cm ^-1 ; 3000,284
0, 1614, 1580, 1520; NMR (400
MHz, CDCl ₃ ) δ ppm 3.79 (3H,
s), 5.69 (2H, s), 6.88-6.9.
6. 1 (2H, m), 7.07 (1H, d), 7.
37-7.35 (2H, m), 7.51 (1H,
d); MS (EI) m / z 352 [(M ⁺⁺ 2) +
1], 350 [(M ⁺ ) +1]; Elemental analysis C ₁₃ H ₁₁
Calculated value of BrN ₄ OS (%) C, 44.46; H,
3.16; N, 15.95, measured value (%) C, 4
4.65; H, 3.11; N, 15.94.

(Step 2) Synthesis of 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-thienyl) -1H-tetrazole 5- (5-bromo-2-thienyl) -2 -(4-Methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole are treated in the same manner as in Step 4 of Example 1, followed by a demethoxylation reaction in the same manner as in Step 5 of Example 1. Was performed to obtain the title compound. 252-257 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 ; 2976,22
00, 1566, 1510; NMR (400 MHz,
_{DMSO-d 6) δppm 1.84~2.34 (} 6
H, m), 3.62 to 3.71 (1H, m),
7.44 (1H, d), 7.52 (1H, s),
7.55 (1H, d); MS (FAB) m / z
314 (M ⁺ +1); Elemental analysis _{C 14 H 11 N 5 S 2} ·
Calculated value of 1/2 H ₂ O (%) C, 52.15; H,
3.75; N, 21.72, measured value (%) C, 5
2.15; H, 3.67; N, 21.91.

Example 19 5- (5- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-furyl) -1H-tetrazole: (Step 1) 5- (5-bromo-2-furyl) -1-
(4-methoxybenzyl) -1H-tetrazole and 5
Synthesis of-(5-bromo-2-furyl) -2- (4-methoxybenzyl) -2H-tetrazole Treatment, separation of the two isomers by column chromatography on silica gel,
Instrumental data for 5- (5-bromo-2-thienyl) -1- (4-methoxybenzyl) -1H-tetrazole are as follows. Melting point 70-71 ° C (crystallized in n-hexane); N
MR (400 MHz, CDCl ₃ ) δ ppm 3.79
(3H, s), 5.72 (2H, s), 6.46
(1H, d), 6.87-6.91 (2H,
m), 7.05 (1H, d), 7.36-7.3.
8 (2H, m); MS (EI) m / z 337
[(M ⁺⁺ 2) +1], 335 [(M ⁺ ) + 1);
Elemental analysis C ₁₃ H ₁₁ BrN ₄ O ₂ Calculated (%) C, 4
6.58; H, 3.31; N, 16.72, measured value (%) C, 46.66; H, 3.33; N, 1
6.89. And 5- (5-bromo-2-thienyl)-
Instrumental data for 2- (4-methoxybenzyl) -2H-tetrazole are as follows. 113-114 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.78 (3H, s), 5.76
(2H, s), 6.55 (1H, d), 6.8
4 to 6.88 (2H, m), 7.18 (1H,
d), 7.27-7.31 (2H, m); MS (E
I) m / z 337 [(M ⁺⁺ 2) +1), 335
[(M ⁺ ) +1]; calculated value of elemental analysis C ₁₃ H ₁₁ BrN ₄ O ₂ (%) C, 46.58; H, 3.31;
N, 16.72; measured value (%) C, 46.69;
H, 3.33; N, 16.93.

(Step 2) Synthesis of 5- (5-iodo-2-furyl) -1- (4-methoxybenzyl) -2H-tetrazole 5- (5-bromo-2-thienyl) -1- (4- 833 mg of (methoxybenzyl) -2H-tetrazole, 3.98 g of potassium iodide and 2.29 g of cuprous iodide were added to DM
In 20 ml of F, the mixture was heated to reflux under a nitrogen stream. After cooling, the reaction solution was poured into 200 ml of water, and the precipitated crystals were collected by filtration. The precipitated crystals were suspended in chloroform, dehydrated with magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography using silica gel (eluent: chloroform: n-hexane = 1: 1) to give 5- (5-iodo-2-furyl) -1- (4-methoxybenzyl) -2H. -88 mg of tetrazole were obtained as pale yellow crystalline powder. 103-105 ° C (crystallized in n-hexane);
NMR (400 MHz, CDCl ₃ ) δ ppm 3.7
9 (3H, s), 5.72 (2H, s), 6.6
9 (1H, d), 6.87-6.91 (2H,
m), 7.00 (1H, d), 7.36-7.3.
8 (2H, m).

(Step 3) Synthesis of 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-thienyl) -1H-tetrazole 5- (5- (2- (4-cyclobutyl- 2-thiazolyl) ethynyl) -2-furyl) -1- (4-methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2
-Ethynylthiazole was treated in the same manner as in Step 4 of Example 1 to give 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-furyl) -1- (4-methoxybenzyl)- 2H-tetrazole was obtained as a pale yellow crystalline powder. Melting point 107-108 ° C; NMR (400 MHz, CD
Cl ₃₎ δppm 1.88~2.10 (2H,
m), 2.26 to 2.41 (4H, m), 3.6
4-3.73 (1H, m), 3.80 (3H,
s), 5.74 (2H, s), 6.89 (1H,
d), 6.89-6.92 (2H, m), 6.9
9. (1H, s), 7.14 (1H, d),
37-7.41 (2H, m).

(Step 4) 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-furyl)
Synthesis of -1H-tetrazole 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-furyl) -1- (4-methoxybenzyl) -2H-tetrazole was used in Step 5 of Example 1. The title compound was obtained. 164-166 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, DMSO-
d ₆ ) δ ppm 1.86 to 2.34 (6H, m);
3.64 to 3.73 (1H, m), 7.41 (1
H, d), 7.43 (1H, d), 7.64
(1H, s); MS (FAB) m / z 298 (M ⁺
+1); calcd Elemental analysis _{C 14 H 11 N 5 OS (} %) C, 56.55; H, 3.73; N, 23.
56, measured value (%) C, 56.22; H, 3.8
1; N, 23.86.

Example 20 5- (5- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -3-pyridyl) -1H-tetrazole: (Step 1) Synthesis of 3-bromo-5- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) pyridine 3 -Bromo-5- (1H-5-tetrazolyl) pyridine was treated in the same manner as in Step 3 of Example 1 to give 3-bromo-5-
(2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) pyridine was obtained. 113-115 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.80 (3H, s), 5.76
(2H, s), 6.90-6.93 (2H,
m), 7.38-7.40 (2H, m), 8.5
5 (1H, t), 8.75 (1H, d), 9.2
6 (1H, d); Elemental analysis C ₁₄ H ₁₂ BrN ₅ O Calculated (%) C, 48.57; H , 3.49; N,
20.23, measured value (%) C, 48.48; H,
3.40; N, 20.30.

(Step 2) 3-Iodo-5- (2- (4
Synthesis of -methoxybenzyl) -2H-tetrazol-5-yl) pyridine 5- (5-bromo-2-thienyl) -1- (4-methoxybenzyl) -2H-tetrazole was treated as in Example 19; 3-Iodo-5- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) pyridine was obtained. 123-125 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.81 (3H, s), 5.76
(2H, s), 6.90-6.93 (2H,
m), 7.39-7.41 (2H, m), 8.7
4 (1H, t), 8.80 (1H, d), 9.2
8 (1H, d).

(Step 3) Synthesis of 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -3-pyridyl) -1H-tetrazole 3-Iodo-5- (2- (4-methoxy) Benzyl) -2
(H-tetrazol-5-yl) pyridine and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 and then treated in the same manner as in Step 5 of Example 1 to obtain the title compound. . 113-115 ° C (recrystallization solvent: chloroform); NMR (400 MHz, CDCl ₃ ) δppm
1.87 to 2.33 (6H, m), 3.65 to
3.73 (1H, m), 7.57 ((1H, m)
s), 8.43 (1H, t), 8.73 (1H,
d), 9.20 (1H, d); MS (FAB) m
^{/ Z 309 (M + +1)} ; Elemental analysis C ₁₅ H ₁₂ N ₆
Calculated S (%) C, 58.43; H, 3.92;
N, 27.25; measured value (%) C, 58.44;
H, 3.68; N, 27.25.

Example 21 5- (6- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-pyridyl) -1H-tetrazole: (Step 1) 6-bromo-2- (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) pyridine,
And synthesis of 6-bromo-2- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) pyridine 6-bromo-2- (1H-5-tetrazolyl) pyridine was prepared according to Treated in the same manner, 6-bromo-2-
(1- (4-methoxybenzyl) -1H-tetrazol-5-yl) pyridine, and 6-bromo-2- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Il) pyridine was obtained as a mixture of about 2: 3. NMR (400 MHz, CDCl ₃ ) δ ppm 3.7
6 and 3.79 (3H, each s),
5.79 and 6.10 (2H, eachs),
6.83 and 6.89 (2H, d);
40 and 7.44 (2H, each d),
7.57-7.75 (2H, m), 8.17 an
d 8.30 (1, d).

(Step 2) 6-Iodo-2- (1- (4
Synthesis of -methoxybenzyl) -1H-tetrazol-5-yl) pyridine and 6-iodo-2- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) pyridine Worked up as in step 2 of example 19 and give 6-iodo-2- (1- (4-methoxybenzyl)
1H-tetrazol-5-yl) pyridine, and 6
-Iodo-2- (2- (4-methoxybenzyl) -2H
-Tetrazol-5-yl) pyridine was obtained as a mixture of about 3: 2. NMR (400 MHz, CDCl ₃ ) δ ppm 3.7
6 and 3.79 (3H, each s),
5.79 and 6.09 (2H, eachs),
6.83 and 6.89 (2H, each
d), 7.39 and 7.44 (2H, eac
hd), 7.38 to 7.52 (1H, m),
7.78-7.86 (1H, m), 8.17 an
d 8.30 (1H, d).

(Step 3) 5- (6- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-pyridyl) -1- (4-methoxybenzyl) -1H-tetrazole and 5- (6 -(2- (4-cyclobutyl-2
-Thiazolyl) ethynyl) -2-pyridyl) -2- (4
Synthesis of -methoxybenzyl) -2H-tetrazole The above iodine compound was treated in the same manner as in Step 4 of Example 1,
5- (6- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-pyridyl) -1- (4-methoxybenzyl) -1H-tetrazole, and 5- (6-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-pyridyl) -2- (4-methoxybenzyl)
-2H-tetrazole was obtained as a mixture of 1st: 2nd ≒ 3: 2. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
8 to 2.10 (2H, m), 2.27 to 2.45 (4
H, m), 3.70 (1H, m), 3.75
and 3.79 (3H, each s), 5.8
1 and 6.15 (2H, each s),
6.82 and 6.89 (2H, each
d), 7.02 and 7.08 (1H, eac
hs), 7.41 and 7.49 (2H, e
ach d), 7.68 to 7.72 (1H, m),
7.84-7.92 (1H, m), 8.22a
nd 8.32 (1H, each d) ; Elemental analysis C ₂₃ H ₂₀ N ₆ Calculated OS (%) C, 64.47;
H, 4.70; N, 19.61, measured value (%)
C, 64.36; H, 4.76; N, 19.78.

(Step 4) Synthesis of 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-pyridyl) -1H-tetrazole Work-up as in 5 to give the title product. 162-168 ° C (recrystallization solvent: ether-n-
Hexane); NMR (400 MHz, DMSO-d)
₆ ) δ ppm 1.88-2.13 (2H, m),
2.34 to 2.42 (4H, m), 3.72 (1
H, m), 7.60 (1H, s), 7.68
(1H, d), 7.94 (1H, t), 8.10
(1H, d).

[Example 22] 5- (6- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-benzothiazolyl) -1H-tetrazole: (Step 1) Synthesis of 6-acetoxy-2- (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) benzothiazole 6-acetoxy-2- (1H-tetrazol-5-yl) benzothiazole was treated as in step 3 of Example 1 to give 6-acetoxy-2- (2- (4-methoxybenzyl) -2H-tetrazole- 5-yl) benzothiazole was obtained. 144-148 ° C (crystalline powder);
cm ^-1 1754; NMR (400 MHz, CDCl
₃ ) δ ppm 2.36 (3H, s), 3.80
(3H, s), 5.80 (2H, s), 6.9
1 (2H, d), 7.28 (2H, d), 7.4
4 (1H, d), 7.74 (1H, d), 8.1
9 (1H, d); MS (FAB) m / z 382
(M ⁺ +1); Elemental analysis value Calculated value for C ₁₈ H ₁₅ N ₅ O ₃ S (%) C, 56.68; H, 3.96; N, 1
8.36, measured value (%) C, 56.73; H,
4.04; N, 18.55.

(Step 2) 6-hydroxy-2- (1-
(4-methoxybenzyl) -1H-tetrazole-5
Synthesis of yl) benzothiazole 6-acetoxy-2- (1- (4-methoxybenzyl)
-1H-tetrazol-5-yl) benzothiazole 6
68 mg was dissolved in THF 20 ml, 0.25 N aqueous sodium hydroxide solution 10 ml was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 300 ml of 0.2N hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and dried, to give 6-hydroxy-2-.
594 mg of (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) benzothiazole were obtained as a yellow powder. 177-180 ° C (crystalline powder); NMR (4
00 MHz, DMSO-d ₆ ) δ ppm 3.75 (3
H, s), 5.98 (2H, s), 6.98
(2H, d), 7.07 (2H, dd), 7.
44 (2H, d), 7.50 (1H, d),
7.96 (1H, d), 10.13 (1H, d)
s); MS (FAB) m / z 340 (M ⁺⁺ 1);
Elemental analysis value Calculated value of C ₁₆ H ₁₃ N ₅ O ₂ S (%) C,
N, 20.64; measured value (%) C, 56.26; H, 3.98; N, 56.63;
20.31.

(Step 3) Synthesis of 2- (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) benzothiazol-5-yl) trifluoromethanesulfonate 6-hydroxy-2- (1- (4-methoxybenzyl)
-1H-tetrazol-5-yl) benzothiazole 5
94 mg and 1 ml of ethyldiisopropylamine were dissolved in 10 ml of methylene chloride, and 0.44 ml of trifluoromethanesulfonic anhydride was added with stirring at -78 ° C.
The reaction solution was further stirred at room temperature for 15 hours,
Poured into 50 ml and extracted with ethyl acetate. Extract 1N
After washing with hydrochloric acid and saturated saline, the extract was dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography using silica gel (eluent: n-hexane-ethyl acetate = 5: 1) to give 2- (1- (4-methoxybenzyl)- 546 mg of 1H-tetrazol-5-yl) benzothiazol-5-yl) trifluoromethanesulfonate was obtained as a powder. 115-116 ° C; NMR (400 MHz, C
DCL ₃ ) δ ppm 3.80 (3H, s), 5.8
5 (2H, s), 6.91 (2H, d), 7.4
5 (2H, d), 7.47 (1H, dd),
7.93 (1H, d), 8.27 (1H, d);
MS (FAB) m / z 472 (M + +1); Elemental analysis C ₁₇ H ₁₂ F ₃ N ₅ calcd _{O 4 S 2 (%) C} , 4
3.31, H, 2.57; N, 14.86, measured value (%) C, 43.58; H, 2.68; N, 1
5.11.

(Step 4) 5- (6- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzothiazol-5-yl) -1- (4-methoxybenzyl) -1H
Synthesis of -tetrazole 471 mg of 2- (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) benzothiazol-5-yl) trifluoromethanesulfonate, 19 mg of cuprous iodide, and bis (triphenyl) To 35 mg of phosphine) palladium [2] dichloride, 0.2 ml of triethylamine and 5 ml of DMF were added, and the mixture was stirred at room temperature for 1 hour under a nitrogen stream. 245 mg of 4-cyclobutyl-2-ethynylthiazole was added to the reaction solution, and the mixture was stirred at 90 ° C for 4 hours. After cooling, the reaction solution was poured into 250 ml of 1N hydrochloric acid,
Extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography using silica gel (eluent: n-hexane-ethyl acetate = 4: 1) to give 5- (6- (2- (4-cyclobutyl) -2-thiazolyl) ethynyl) benzothiazol-5-yl)-
1- (4-methoxybenzyl) -1H-tetrazole 3
08 mg was obtained as needles. Melting point 161 ° C .; NMR (400 MHz, CDCl
₃ ) δ ppm 1.91 to 2.12 (2H, m),
2.28 to 2.43 (4H, m), 3.71 (1
H, m), 3.80 (3H, s), 5.83
(2H, s), 6.91 (2H, d), 6.9
9 (1H, s), 7.45 (2H, d), 7.7
4 (1H, dd), 8.19 (1H, d),
8.21 (1H, d).

(Step 5) Synthesis of 5- (6- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-benzothiazolyl) -1H-tetrazole 5- (6- (2- (4-cyclobutyl- 2-thiazolyl) ethynyl) benzothiazol-5-yl) -1-
(4-Methoxybenzyl) -1H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound as a yellow powder. 225-227 ° C (recrystallization solvent: chloroform); NMR (400 MHz, DMSO-d ₆ ) δp
pm 1.90 to 2.04 (2H, m), 2.22
~ 2.32 (4H, m), 3.69 (1H,
m), 7.57 (1H, s), 7.89 (1H,
d), 8.25 (1H, d), 8.65 (1H,
s); MS (FAB) m / z 365 (M ⁺⁺ 1);
Elemental analysis value Calculated value of C ₁₇ H ₁₂ N ₆ S ₂ (%) C, 5
H, 3.32; N, 23.06, measured value (%) C, 55.79; H, 3.35; N, 2
3.06.

[Example 23] 5- (5- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-benzoxazolyl) -1H-tetrazole: (Step 1) 5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2- (2- (4- Synthesis of methoxybenzyl) -2H-tetrazol-5-yl) benzoxazole 5-iodo-2- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzoxazole was prepared according to Step 4 of Example 1. The same processing is performed, and 5- (2
-(4-cyclobutyl-2-thiazolyl) ethynyl)-
2- (2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) benzoxazole was obtained. Melting point 178-180; NMR (400 MHz, CDC
l ₃ ) δ ppm 1.92 to 2.11 (2H, m),
2.28 to 2.40 (4H, m), 3.71 (1
H, m), 3.80 (3H, s), 5.85
(2H, s), 6.92 (2H, d), 6.98
(1H, s), 7.45 (2H, s), 7.7
6-7.71 (2H, d), 8.10 (1H,
s).

(Step 2) Synthesis of 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-benzoxazolyl) -1H-tetrazole 5- (2- (4-cyclobutyl- 2-thiazolyl) ethynyl) -2- (2- (4-methoxybenzyl) -2H-
The tetrazol-5-yl) benzoxazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound as fine needles. Melting point 226-229 ° C (decomp.); NMR
(400 MHz, DMSO-d ₆ ) δ ppm 1.84
~ 2.06 (2H, m), 2.20 ~ 2.34 (4
H, m), 3.68 (1H, m), 7.54
(1H, s), 7.84 (1H, dd), 8.0
4 (1H, d), 8.29 (1H, d); MS
(FAB) m / z 349 ( M + +1); Elemental analysis C ₁₇ H ₁₂ N ₆ Calculated OS (%) C, 57.13;
H, 3.67; N, 23.52, measured value (%)
C, 57.55; H, 3.54; N, 23.33.

Example 24 7- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) -3- (1H-tetrazol-5-yl) -4H-pyrido [1,2-a]
Pyrimidin-3-one: (Step 1) 7-bromo-3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidin-3-one 3.57 g of 2-amino-5-bromopyridine and 7.94 g of ethyl 3-dimethylamino-2- (2- (4- (methoxybenzyl) -2H-tetrazol-5-yl) acrylic acid were added to 30 ml of propionic acid. The reaction solution was poured into 300 ml of water, and the precipitated crystals were collected by filtration, washed with water, and dried, and then subjected to column chromatography using silica gel (eluent: chloroform: methanol = 200: 1). And purified by 7-bromo-3- (2
-(4-methoxybenzyl) -2H-tetrazole-5
-Yl) -4H-pyrido [1,2-a] pyrimidine-3
4.03 g of -one was obtained as a crystalline powder. Melting point 172-175 ° C; IR νmax cm ^-1 170
6; NMR (400 MHz, CDCl ₃ ) δ ppm
3.79 (3H, s), 5.82 (2H, s),
6.88-6.91 (2H, m), 7.41-7.
43 (2H, m), 7.67 (1H, d), 7.
90 (1H, dd), 9.22 (1H, s),
9.38 (1H, d); MS (EI) m / z 41
4 [(M ⁺⁺ 2) +1)], 412 [(M ⁺⁺ ) +
1)]; Calculated value of elemental analysis C ₁₇ H ₁₃ BrN ₆ O ₂ (%) C, 49.41; H, 3.17; N, 2
0.34, measured value (%) C, 49.24; H,
3.24; N, 20.39.

(Step 2) 7- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) -3- (1H-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidine-3- Synthesis of 7-bromo-3- (2- (4-methoxybenzyl) -2
H-tetrazol-5-yl) -4H-pyrido [1,2
-A] Pyrimidin-3-one 413 mg, 4-cyclobutyl-2-ethynylthiazole 163 mg, palladium acetate [2] 22 mg, and triphenylphosphine 5
2 mg was heated and refluxed for 4 hours in 20 ml of triethylamine. The reaction solution was concentrated, 50 ml of chloroform was added, and 1N hydrochloric acid, water, a saturated aqueous solution of sodium hydrogencarbonate, and
After washing with saturated saline, it was dried over sodium sulfate.
The solvent was distilled off, and the residue was subjected to column chromatography using silica gel (eluent: chloroform: methanol = 2).
After purification in 00: 1), the obtained coupling product was treated in the same manner as in Step 5 of Example 1 without further purification to obtain 105 mg of the title compound as a pale yellow crystalline powder. . Melting point> 300 ° C. (recrystallization solvent: chloroform-n-hexane); IRνmaxcm ⁻¹ 1706; NMR
(400 Mz, DMSO-d ₆ ) δ ppm 1.84-
2.32 (6H, m), 3.65 to 3.73 (1
H, m), 7.61 (1H, s), 7.80
(1H, d), 8.09 (1H, d), 8.94
(1H, br s), 9.34 (1H, s);
MS (FAB) m / z 376 (M + +1); Elemental analysis C ₁₈ H ₁₃ N ₇ Calculated OS (%) C, 57.5
N, 26.12, measured value (%) C, 57.95; H, 3.40; N, 2
5.93.

[Example 25] 5- (5- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-benzo [b] thienyl) -1H-tetrazole: (Step 1) 5- (5-bromo-2-benzo [b] thienyl) -2- (4-methoxybenzyl) Synthesis of -2H-tetrazole 5- (5-bromo-2-benzo [b] thienyl) -1H
-Treating tetrazole as in step 3 of example 1
-(5-bromo-2-benzo [b] thienyl) -2-
(4-Methoxybenzyl) -2H-tetrazole was obtained. 140-142 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 3080,28
40, 1614, 1584, 1538, 1516; N
MR (400 Mz, CDCl ₃ ) δ ppm 3.81
(3H, s), 5.75 (2H, s), 6.90
-6.93 (2H, m), 7.39-7.41 (2
H, m), 7.48 (1H, dd), 7.73
(1H, d), 7.96 (1H, s), 7.98
(1H, d); MS (EI) m / z 402 [(M
⁺ +2) +1], 402 [(M ⁺ ) +1]; calculated value of elemental analysis value C ₁₇ H ₁₃ BrN ₄ OS (%) C, 50.8
H, 3.27; N, 13.96, measured value (%) C, 50.57; H, 3.27; N, 1
3.91.

(Step 2) 5- (5-Iodo-2-benzo [b] thienyl) -2- (4-methoxybenzyl)-
Synthesis of 2H-tetrazole 5- (5-bromo-2-benzo [b] thienyl) -1H
Treating the tetrazole as in step 2 of example 19,
5- (5-iodo-2-benzo [b] thienyl) -2-
(4-Methoxybenzyl) -2H-tetrazole was obtained. 131-134 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 Mz, CDCl ₃ )
δ ppm 3.80 (3H, s), 5.75 (2
H, s), 6.90-6.92 (2H, m),
7.39-7.41 (2H, m), 7.66-7.
7. 60 (2H, m), 7.94 (1H, s),
19 (1H, s).

(Step 3) Synthesis of 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-benzo [b] thienyl) -1H-tetrazole 5- (5-iodo-2-) Benzo [b] thienyl) -2-
(4-methoxybenzyl) -2H-tetrazole and 4-
The cyclobutyl-2-ethynylthiazole was treated in the same manner as in Step 4 of Example 1, and the obtained coupling product was subjected to demethoxymethoxylation with Step 5 of Example 1 without further purification. The title was obtained. Melting point: 241 to 244 ° C (recrystallization solvent: chloroform-
Ethanol); IRνmax cm ^-1 2208,158
4,1532,1504; NMR (400 Mz, DM
_{SO-d 6) δppm 1.85~2.34 (} 6H,
m), 3.64 to 3.73 (1H, m), 7.5
7. 4 (1H, s), 7.71 (1H, dd),
20 (1H, s), 8.24 (1H, d),
8.41 (1H, s); MS (FAB) m / z 3
64 (M ⁺ +1); Elemental analysis C ₁₈ H ₁₃ N ₅ S ₂ Calculated (%) C, 59.48; H , 3.60; N,
19.27, measured value (%) C, 59.21; H,
3.70; N, 19.31.

[Example 26] 5- (6- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-oxo-2H-benzopyran-3-yl) -1H-tetrazole: (Step 1) 5- (5-bromo-2-oxo-2H-benzopyran-3-yl)- 1- (4-methoxybenzyl) -1H-tetrazole, and 5- (5-bromo-
2-oxo-2H-benzopyran-3-yl) -2-
Synthesis of (4-methoxybenzyl) -2H-tetrazole 5- (5-bromo-2-oxo-2H-benzopyran-
3-yl) -1H-tetrazole was treated as in step 3 of Example 1 to give 5- (5-bromo-2-oxo-2H-
Benzopyran-3-yl) -1- (4-methoxybenzyl) -1H-tetrazole, and 5- (5-bromo-
2-oxo-2H-benzopyran-3-yl) -2-
(4-methoxybenzyl) -2H-tetrazole
Position: 2 position obtained as a 1: 1 mixture. IRνmax cm ⁻¹ 2840, 1750, 1722, ¹
614, 1606, 1568, 1516; NMR (4
00Mz, CDCl ₃ ) δppm 3.68 and
3.80 (3H, each s), 5.76 (1
H, s), 5.81 (1H, s), 6.71-
6.74 (1H, m), 6.89-6.92 (1
H, m), 7.06 to 7.08 (1H, m),
7.29 and 7.31 (1H, each d),
7.40-7.42 (1H, m), 7.65, 7.
70, 7.75 and 7.76 (2H, each
m), 7.99 (1 / 2H, s), 8.58 (1
/ 2H, s); MS (FAB) m / z 414
[(M ⁺ +2) +1], 412 [(M ⁺ ) +1]; Elemental analysis value Calculated value (%) of C ₁₈ H ₁₃ N ₄ BrO ₃ C, 5
2.32; H, 3.17; N, 13.56, measured value (%) C, 51.93; H, 3.24; N, 1
3.38.

(Step 2) 5- (6- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-oxo-
Synthesis of 2H-benzopyran-3-yl) -1H-tetrazole The bromo compound and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1, and the obtained coupling product was further processed. The title compound was obtained in the same manner as in Step 5 of Example 1 without purification. Melting point> 300 ° C. (recrystallization solvent: chloroform-n-hexane); IRνmaxcm ⁻¹ 2980, 2944,
2216,1742,1708,1622,1606
1578, 1504; NMR (400 Mz, CDCl
₃ ) δ ppm 1.87 to 2.33 (6H, m),
3.63 to 3.72 (1H, m), 7.51 (1
H, d), 7.54 (1H, s), 7.85
(1H, dd), 8.20 (1H, d), 8.
53 (1H, s); MS (FAB) m / z 376.
(M ⁺ +1); Elemental analysis value Calculated value of C ₁₉ H ₁₃ N ₅ O ₂ (%) C, 60.79; H, 3.49; N, 1
8.66, measured value (%) C, 60.47; H,
3.52; N, 18.61.

[Example 27] 5- (5- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-benzo [b] furyl) -1H-tetrazole: (Step 1) 5- (5-bromo-2-benzo [b] furyl) -2- (4-methoxybenzyl) Synthesis of -2H-tetrazole 5- (5-bromo-2-benzo [b] furyl) -1H-
The tetrazole was treated as in Step 3 of Example 1 to give 5-
(5-bromo-2-benzo [b] furyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole was obtained. 143-145 ° C (recrystallization solvent: chloroform-
Ether); NMR (400 Mz, CDCl ₃ ) δp
pm 3.79 (3H, s), 5.78 (2H,
s), 6.90 (2H, d), 7.41 (2H,
d), 7.43 (1H s), 7.47 (1H,
s), 7.79 (1H, s).

(Step 2) 5- (5-Iodo-2-benzo [b] furyl) -2- (4-methoxybenzyl) -2
Synthesis of H-tetrazole 5- (5-bromo-2-benzo [b] furyl) -2-
(4-Methoxybenzyl) -2H-tetrazole Treated as in Step 2 of Example 19 to give 5- (5-iodo-2-
Benzo [b] furyl) -2- (4-methoxybenzyl)
2H-tetrazole was obtained. 136-138 ° C. (recrystallization solvent: ether-hexane); NMR (400 Mz, CDCl ₃ ) δ ppm
3.80 (3H, s), 5.78 (2H, s),
6.90 (2H, d), 7.37 (1H,
d), 7.41 (1H s), 7.41 (1H,
d), 7.63 (1H, dd), 8.00 (1
H, d).

(Step 3) 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-benzo [b] furyl) -2- (4-methoxybenzyl) -2H
Synthesis of tetrazole 5- (5-iodo-2-benzo [b] furyl) -2-
(4-methoxybenzyl) -2H-tetrazole and 4-
Cyclobutyl-2-ethynylthiazole was treated as in step 4 of Example 1 to give 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-benzo [b] furyl) -2 -(4-methoxybenzyl) -2H
-Tetrazole was obtained. Melting point: 154 to 155 ° C (recrystallization solvent: chloroform-
Ether); NMR (400 Mz, CDCl ₃ ) δp
pm 1.89 to 2.11 (2H, m), 2.28
~ 2.43 (4H, m), 3.70 (1H,
m). 3.80 (3H, s), 5.79 (2H, s)
s), 6.91 (2H, d), 6.95 (1
H, s), 7.42 (2H, d), 7.49
(1H, s), 7.60 (2H, s), 7.92
(1H, s).

(Step 4) Synthesis of 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-benzo [b] furyl) -1H-tetrazole 5- (5- (2- ( 4-cyclobutyl-2-thiazolyl) ethynyl) -2-benzo [b] furyl) -2- (4
-Methoxybenzyl) -2H-tetrazole in Example 1
And the title compound was obtained. Mp 207 to 212 ° C. (recrystallization solvent: ethanol - chloroform -n- hexane); IRνmax cm ^-1 2
216; NMR (400 Mz, DMSO-d ₆ ) δp
pm 1.85 to 2.06 (2H, m), 2.19
~ 2.52 (4H, m), 3.68 (1H,
m). 7.53 (1H, s), 7.74 (1H, s)
d), 7.77 (1H, s), 7.88 (1
H, d), 8.16 (1H , s); Elemental analysis C ₁₈ H ₁₃ N ₅ calcd OS (%) C, 62.23;
H, 3.77; N, 20.16, measured value (%)
C, 61.95; H, 3.96; N, 20.10.

Example 28 5- (7- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -4-oxo-4H-benzopyran-2-yl) carboxylic acid: (Step 1) Ethyl 5- (4-oxo-7-trifluoromethanesulfonyloxy-4H-benzopyran-
Synthesis of 2-yl) carboxylate Ethyl 5- (7-hydroxy-4-oxo-4H-benzopyran-2-yl) carboxylate was prepared in Example 22.
And then treated with ethyl 5- (4-oxo-
7-trifluoromethanesulfonyloxy-4H-benzopyran-2-yl) carboxylate was obtained. 125-127 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2216; NM
R (400 Mz, CDCl ₃ ) δ ppm 1.45 (3
H, t), 4.48 (2H, q), 7.15
(1H, s), 7.37 (1H, dd), 7.5
9 (1H, d), 8.31 (1H, d).

(Step 2) Ethyl 5- (7- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) -4
Synthesis of -oxo-4H-benzopyran-2-yl) carboxylate Ethyl 5- (4-oxo-7-trifluoromethanesulfonyloxy-4H-benzopyran-2-yl) carboxylate and 4-cyclobutyl-2-ethynylthiazole Treated in the same manner as in Step 4 of Example 1,
-(7- (2- (4-cyclobutyl-2-thiazolyl))
(Ethynyl) -4-oxo-4H-benzopyran-2-yl) carboxylate was obtained. 138-141 ° C (recrystallization solvent: ether-n-
Hexane); NMR (400 Mz, CDCl ₃ ) δp
pm 1.44 (3H, t), 1.91 to 2.43
(6H, m), 3.68 to 3.76 (1H,
m), 4.47 (2H, q), 7.04 (1H,
s), 7.13 (1H, s), 7.61 (1
H, dd), 7.82 (1H, d), 8.18
(1H, d).

(Step 3) 5- (7- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-oxo-
Synthesis of 4H-benzopyran-2-yl) carboxylic acid 5- (7- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-oxo-4H-benzopyran-2
-Yl) carboxylate (228 mg) and sodium hydrogencarbonate (230 mg) were added with ethanol (10 ml) and water (1 ml), and the mixture was heated under reflux for 2 hours. After cooling, add 100
Then, the mixture was adjusted to pH 3 with 1N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried. The obtained crude crystals were recrystallized from chloroform-n-hexane to give the title compound 17
5 mg were obtained as a crystalline powder. 240-243 ° C (decomp.); IRν
max cm ^-1 2216, 1734, 1654; NMR
(400 Mz, DMSO-d ₆ ) δ ppm 1.87-
2.32 (6H, m), 3.65 to 3.73 (1
H, m), 6.96 (1H, s), 7.62
(1H, s), 7.76 (1H, d), 8.08
(1H, s), 8.09 (1H, d); MS
(FAB) m / z 352 ( M + +1); Elemental analysis _{C 19 H 13 NO 4 S ·} 1 / 4H 2 O Calculated (%) C,
N, 3.94; H, 3.82; N, 3.94; Found (%) C, 64.29; H, 3.83;
81.

[Example 29] 5- (5- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -3-benzo [b] thienyl) -1H-tetrazole: (Step 1) 5- (5-iodo-3-benzo [b] thienyl) -2- (4-methoxybenzyl) Synthesis of -2H-tetrazole 5- (5-iodo-3-benzo [b] thienyl) -1H
-Treating tetrazole as in step 3 of example 1
-(5-Iodo-3-benzo [b] thienyl) -2-
(4-Methoxybenzyl) -2H-tetrazole was obtained. 134-136 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 Mz, CDCl ₃ )
δ ppm 3.80 (3H, s), 5.80 (2
H, s), 6.91 to 6.94 (2H, m),
7.42 to 7.45 (2H, m), 7.64 (1
H, d), 7.70 (1H, dd), 8.27
(1H, s), 9.09 (1H, d).

(Step 2) 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -3-benzo [b] thienyl) -2- (4-methoxybenzyl) -2
Synthesis of H-tetrazole 5- (5-iodo-3-benzo [b] thienyl) -2-
(4-methoxybenzyl) -2H-tetrazole and 4-
Cyclobutyl-2-ethynylthiazole was treated as in step 4 of Example 1 to give 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -3-benzo [b].
Thienyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained as a brown oil. NMR (400 Mz, CDCl ₃ ) δ ppm 1.95
To 2.12 (2H, m), 2.30 to 2.41 (4
H, m), 3.67-3.75 (1H, m),
3.79 (3H, s), 5.83 (2H, s),
6.91-6.93 (2H, m), 7.44-
7.46 (2H, m), 7.62 (1H, d
d), 7.89 (1H, d), 8.37 (1H,
s), 8.99 (1H, d).

(Step 3) Synthesis of 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -3-benzo [b] thienyl) -1H-tetrazole 5- (5- (2- ( 4-cyclobutyl-2-thiazolyl) ethynyl) -3-benzo [b] thienyl) -2-
(4-Methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 125-127 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2212; N
MR (400 Mz, DMSO-d ₆ ) δ ppm 1.90
~ 2.08 (2H, m), 2.28 ~ 2.32 (4
H, m), 3.64 to 3.72 (1H, m),
7.54 (1H, s), 7.75 (1H, d
d), 8.28 (1H, d), 8.67 (1H,
s), 8.93 (1H, d); MS (FAB)
^{m / z 364 (M + +1} ); Elemental analysis C ₁₈ H ₁₃ N
₅ Calculated _{S 2 (%) C, 59.48} ; H, 3.6
1: N, 19.27, measured value (%) C, 59.4
4; H, 3.40; N, 17.13.

Example 30 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -5-benzo [b] thienyl) -1H-tetrazole: (Step 1) 5- (3-iodo-5-benzo [b] thienyl) -2- (4-methoxybenzyl) Synthesis of 2H-tetrazole 5- (3-iodo-5-benzo [b] thienyl) -1H
-Treating tetrazole as in step 3 of example 1
-(3-Iodo-5-benzo [b] thienyl) -2-
(4-Methoxybenzyl) -2H-tetrazole was obtained. 155-157 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 Mz, CDCl ₃ )
δ ppm 3.80 (3H, s), 5.77 (2
H, s), 6.90-6.93 (2H, m),
7.41 to 7.43 (2H, m), 7.67 (1
H, s), 7.94 (1H, d), 8.16
(1H, d), 8.52 (1H, s).

(Step 2) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -5-benzo [b] thienyl) -1H-tetrazole 5- (3-iodo-5) Benzo [b] thienyl) -2-
(4-methoxybenzyl) -2H-tetrazole and 4-
The cyclobutyl-2-ethynylthiazole was treated in the same manner as in Step 4 of Example 1, followed by debenzylation as in Step 5 of Example 1 to obtain the title compound. 195-197 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2212; N
MR (400 Mz, DMSO-d ₆ ) δ ppm 1.88
~ 2.05 (2H, m), 2.21-2.36 (4
H, m), 3.67-3.75 (1H, m),
7.60 (1H, s), 8.16 (1H, d),
8.38 (1H, d), 8.58 (1H, d)
s), 8.62 (1H, s); MS (FAB) m
^{/ Z 364 (M + +1)} ; Elemental analysis C ₁₈ H ₁₃ N ₅
Calculated S ₂ · H ₂ O (%) C, 58.04; H,
3.79; N, 18.80, measured value (%) C, 5
8.28; H, 3.56; N, 18.67.

Example 31 5- (6- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2,4-
Dioxo-1,2,3,4-tetrahydroquinazoline-
3-yl) -1H-tetrazole: (Step 1) N- (1- (4-methoxybenzyl) -1
H-tetrazol-5-yl) -2-amino-5-iodo-benzamide and N- (2- (4-methoxybenzyl) -2-H-tetrazol-5-yl) -2-amino-5-iodo -Synthesis of benzamide N- (1H-tetrazol-5-yl) -2-amino-
5-Iodo-benzamide was treated as in step 3 of Example 1 to give N- (1- (4-methoxybenzyl) -1H-
Tetrazol-5-yl) -2-amino-5-iodo-
Benzamide and N- (2- (4-methoxybenzyl) -2-H-tetrazol-5-yl) -2-amino-5-iodo-benzamide were obtained as oils. NMR (400 MHz, CDCl ₃ ) δ ppm 3.7
5 (3Hs), 5.80 (2H, s), 6.6
1 (1H, d), 6.70 to 6.80 (2H, b
r), 6.93 (2H, d), 7.39 (2H,
d), 7.50 (1H d), 7.97 (1H,
brs), 8.02 (1H, d).

(Step 2) 5- (6-Iodo-2,4-
Dioxo-1,2,3,4-tetrahydroquinazoline-
Synthesis of 3-yl) -2- (4-methoxybenzyl) -2H-tetrazole 1.4 g of the above iodine compound was dissolved in 10 ml of DMF,
0.61 g of 1,1′-carbonyldiimidazole was added, and the mixture was stirred at 80 ° C. for 2 hours. After cooling, the reaction solution was diluted with 1N hydrochloric acid
Poured into 00 ml and extracted with ethyl acetate. The extract was washed with saturated saline and dried over sodium sulfate. The residue obtained by distilling off the solvent is subjected to column chromatography using silica gel (eluent: n-hexa: -ethyl acetate =
2: 1) to give 5- (6-iodo-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) -2- (4-methoxybenzyl) -2H-tetrazole. Obtained as a yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 3.8
2 (3H s), 5.79 (2H, s), 6.6
3 (2H, dd), 6.70-6.80 (1H,
m), 7.10 (2H, d), 7.38 (1H,
d), 7.89 (1H dd), 8.31 (1
H, d).

(Step 3) 5- (6- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-
Synthesis of yl) -2- (4-methoxybenzyl) -2H-tetrazole 5- (6-Iodo-2,4-dioxo-1,2,3,4
-Tetrahydroquinazolin-3-yl) -2- (4-methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in step 4 of Example 1 to give 5- (6- (2 -(4-cyclobutyl-2-thiazolyl) ethynyl) -2,4-dioxo-
1,2,3,4-tetrahydroquinazolin-3-yl)
-2- (4-Methoxybenzyl) -2H-tetrazole obtained as a brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.00 (1H, m), 2.00 to 2.10 (1
H, m), 2.20 to 2.40 (4H, m),
3.61 (3H, s), 3.60-3.70 (1
H, m), 5.79 (2H, s), 6.65
(2H, d), 7.00 (1H, s), 7.0
0 to 7.10 (1H, m), 7.12 (2H,
d), 7.37 (1H, d), 7.77 (1H,
dd), 8.21 (1H, d).

(Step 4) 5- (6- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-
Synthesis of yl) -1H-tetrazole 5- (6- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2,4-dioxo-1,2,3,4-
The title compound was obtained by treating tetrahydroquinazolin-3-yl) -2- (4-methoxybenzyl) -2H-tetrazole in the same manner as in Step 5 of Example 1. Melting point> 300 ° C .; NMR (400 MHz, DMSO-
d ₆ ) δ ppm 1.80-1.90 (1H, m),
1.90 to 2.10 (1H, m), 2.20 to
2.40 (4H, m), 3.60 to 3.70 (1
H, m), 7.32 (1H, d), 7.52
(1H, s), 7.50 to 7.60 (1H, b
r), 7.99 (1H, dd), 8.13 (1
H, d), 12.10 (1H, br); MS
(FAB) m / z 392 ( M + +1); Elemental analysis _{C 18 H 13 N 7 O 2} S · 3 / 2H 2 O Calculated (%)
C, 55.38; H, 4.13; N, 17.94,
Measured value (%) C, 55.59; H, 3.86;
N, 17.78.

Example 32 5- (6- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -4-oxo-3,4-dihydroquinazolin-3-yl) -1H-
Tetrazole: (Step 1) 5- (6-Iodo-4-oxo-3,4-
Synthesis of dihydroquinazolin-3-yl) -2- (4-methoxybenzyl) -2H-tetrazole N- (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) -2-amino-5-iodo -Benzamide, and N- (2- (4-methoxybenzyl) -2
1.8 ml of ethyl orthoformate was added to 200 mg of a mixture of (H-tetrazol-5-yl) -2-amino-5-iodo-benzamide, and the mixture was heated and stirred for 8 hours. The residue obtained by concentrating the reaction solution is subjected to column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 2:
Purify in 1) and give 5- (6-iodo-4-oxo-3,4
-Dihydroquinazolin-3-yl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 3.8
5. 1 (3H, s), 5.80 (2H, s),
93 (2H, dd), 7.43 (2H, d),
7.50 (1H, d), 8.10 (1H, d)
d), 8.27 (1H, s), 8.69 (1H,
d).

(Step 2) 5- (6- (2- (4-cyclobutyl-2-thiazolyl) ethynyl-4-oxo-
3,4-dihydroquinazolin-3-yl) -2- (4-
Synthesis of (methoxybenzyl) -2H-tetrazole 5- (6-Iodo-4-oxo-3,4-dihydroquinazolin-3-yl) -2- (4-methoxybenzyl)-
2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1,
-(6- (2- (4-cyclobutyl-2-thiazolyl))
Ethynyl-4-oxo-3,4-dihydroquinazoline-
3-yl) -2- (4-Methoxybenzyl) -2H-tetrazole was obtained as a brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.00 (1H, m), 2.00 to 2.10 (1
H, m), 2.20 to 2.40 (4H, m),
3.61 (3H, s), 3.60-3.70 (1
H, m), 5.79 (2H, s), 6.65
(2H, d), 7.00 (1H, s), 7.4
7. 3 (2H, d), 7.50 (1H, d),
10 (1H, dd), 8.27 (1H, s),
8.69 (1H, d).

(Step 3) 5- (6- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-oxo-
Synthesis of 3,4-dihydroquinazolin-3-yl) -1H-tetrazole 5- (6- (2- (4-cyclobutyl-2-thiazolyl) ethynyl-4-oxo-3,4-dihydroquinazolin-3-yl ) -2- (4-Methoxybenzyl) -2H
-The tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 189-190 ° C (recrystallization solvent: chloroform-
Ethanol); IRνmax cm ⁻¹ 1956,188
6,1550, 1290, 1048; NMR (400
_{MHz, DMSO-d 6) δppm} 1.80~1.9
0 (1H, m), 1.90 to 2.00 (1H,
m), 2.20 to 2.40 (4H, m), 3.5
0 to 3.60 (1H, m), 7.52 (1H,
s), 7.84 (1H, d), 8.10 (1H,
s), 8.25 (1H, dd), 8.39 (1
H, d), 12.60 (1H, brs); M
S (FAB) m / z 394 (M ⁺⁺ 1).

[Example 33] 5- (6- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -4-oxo-3H-triazin-3-yl) -1H-tetrazole: (Step 1) 5- (6-iodo-4-oxo-3H-triazin-3-yl)- 2- (4-methoxybenzyl)
Synthesis of 2H-tetrazole N- (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) -2-amino-5-iodobenzamide and N- (2- (4-methoxybenzyl)- 2H-
To 300 mg of a mixture of tetrazol-5-yl) -2-amino-5-iodobenzamide was added 1.2 m of 5.3% sulfuric acid.
and 0.2 ml of ethanol were added, and 56 mg of sodium nitrite was added at 0 to 5 ° C., followed by stirring for 4 hours. The reaction solution was poured into ice water (100 ml), and the precipitated crystals were collected by filtration, washed with water, and dried, and then dried.
The tetrazole was obtained as a yellow caramel oil. NMR (400 MHz, CDCl ₃ ) δ ppm 3.7
6. (3H, s), 6.04 (2H, s),
99 (2H, dd), 7.45 (2H, d),
8.07 (1H, d), 8.52 (1H, d)
d), 8.59 (1H, d).

(Step 2) 5- (6- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-oxo-
Synthesis of 3H-triazin-3-yl) -2- (4-methoxybenzyl) -2H-tetrazole 5- (6-Iodo-4-oxo-3H-triazine-3
-Yl) -2- (4-methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as step 4 of Example 1 to give 5- (6-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-oxo-3H-triazin-3-yl) -2
-(4-Methoxybenzyl) -2H-tetrazole was obtained as a brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.00 (1H, m), 2.00 to 2.10 (1
H, m), 2.20 to 2.40 (4H, m),
3.61 (3H, s), 3.60-3.70 (1
H, m), 6.04 (2H, s), 7.00.
(1H, s), 7.12 (2H, dd), 7.
20 (2H, d), 8.07 (1H, d),
8.60 (1H, dd), 8.63 (1H, dd)
d).

(Step 3) 5- (6- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-oxo-
Synthesis of 3H-triazin-3-yl) -1H-tetrazole 5- (6- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-oxo-3H-triazine-3-
Yl) -2- (4-Methoxybenzyl) -2H-tetrazole Treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 189-190 ° C (recrystallization solvent: water-ethanol); IRν max cm ⁻¹ 1618, 1550, 139
4,1290,996; NMR (400 MHz, DM
_{SO-d 6) δppm 1.80~1.90 (} 1H,
m), 1.90-2.00 (1H, m), 2.2
0 to 2.40 (4H, m), 3.50 to 3.60
(1H, m), 7.50 (1H, s), 7.9
9. (1H, d), 8.55 (1H, dd),
58 (1H, d), 12.56 (1H, br
s); MS (FAB) m / z 377 (M ⁺⁺ 1);
Elemental analysis value Calculated value of C ₁₇ H ₁₂ N ₈ OS · H ₂ O (%)
C, 51.77; H, 3.58; N, 28.4.
1, measured value (%) C, 52.01; H, 3.6
0; N, 28.79.

Example 34 5- (7- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -3-methoxy-benzo [b] thiophen-2-yl) -1H-tetrazole: (Step 1) 5- (7-iodo-3-methoxy-benzo [b] thiophen-2- Synthesis of yl) -2- (4-methoxybenzyl) -2H-tetrazole 5- (7-iodo-3-methoxy-benzo [b] thiophen-2-yl) -1H-tetrazole was used as in Step 3 of Example 1. To give 5- (7-iodo-3-methoxy-benzo [b] thiophen-2-yl) -2- (4-methoxybenzyl) -2H-tetrazole. 156-158 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.80 (3H, s), 4.07
(3H, s), 5.77 (2H, s), 6.9
0 to 6.92 (2H, m), 7.16 (1H,
t), 7.41-7.43 (2H, m), 7.78
(1H, d), 7.87 (1H, d); MS
(EI) m / z 478 (M ⁺ ); Elemental analysis value C ₁₈ H ₁₅
Calculated value of IN ₄ O ₂ (%) C, 45.20; H,
3.16; N, 11.72, measured value (%) C,
45.40; H, 3.28; N, 11.48.

(Step 2) 5- (7- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -3-methoxy-benzo [b] thiophen-2-yl) -2- (4-methoxybenzyl)- Synthesis of 2H-tetrazole 5- (7-iodo-3-methoxy-benzo [b] thiophen-2-yl) -2- (4-methoxybenzyl) -2
H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as step 4 of Example 1 to give 5-
(7- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -3-methoxy-benzo [b] thiophen-2
-Yl) -2- (4-Methoxybenzyl) -2H-tetrazole was obtained as a brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
5 to 2.07 (2H, m), 2.31 to 2.42 (4
H, m), 3.68 to 3.77 (1H, m),
3.80 (3H, s), 4.09 (3H, s),
5.78 (2H, s), 6.89-6.93 (2
H, m), 7.01 (1H, s), 7.41-
7.45 (2H, m), 7.67 (1H, d
d), 7.88 (1H, dd).

(Step 3) Synthesis of 5- (7- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -3-methoxy-benzo [b] thiophen-2-yl) -1H-tetrazole 5- (7 -(2- (4-cyclobutyl-2-thiazolyl) ethynyl) -3-methoxy-benzo [b] thiophen-2-yl) -2- (4-methoxybenzyl) -2H
-The tetrazole was treated as in step 1 of example 1 to give the title compound as an orange-brown crystalline powder. 156-158 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, DMSO-
d ₆ ) δ ppm 1.88 to 2.02 (2H, m),
2.24 to 2.34 (4H, m), 3.67 to 3.
76 (1H, m), 4.16 (3H, s), 7.
61 to 7.65 (2H, m), 7.89 (1H,
d), 8.16 (1H, d); MS (FAB) m
/ Z394 (M ⁺ +1); Elemental analysis C ₁₉ H ₁₅ N ₅
Calculated value of OS ₂ · 1 / 4H ₂ O (%) C, 57.3
H, 3.93; N, 17.60, measured value (%) C, 57.33; H, 3.93; N, 1
7.49.

Example 35 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -1H-tetrazole: (Step 1) Synthesis of 5- (3-iodo-6-fluorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole 5- (3-Iodo-6-fluorophenyl) -1H-tetrazole was treated as in step 3 of Example 1 to give 5-
(3-Iodo-6-fluorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained. Melting point 99-101 ° C (recrystallization solvent: chloroform-n
-Hexane); NMR (400 MHz, CDCl ₃ )
δ ppm 3.80 (3H, s), 5.77 (2
H, s), 6.89-6.92 (2H, m),
7.39 to 7.42 (2H, m), 7.71 to 7.
75 (1H, m), 8.41 to 8.43 (1H,
m).

(Step 2) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole 3-iodo-6-fluorophenyl) -2- (4
-Methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were used in Step 4 of Example 1.
To give 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole. 126-128 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 1.89 to 2.42 (6H, m),
3.66 to 3.74 (1H, m), 3.80 (3
H, s), 5.78 (2H, s), 6.90-
6.93 (2H, m), 6.97 (1H, s),
7.21 to 7.26 (1H, m), 7.41 to 7.
43 (2H, m), 7.63-7.67 (1H,
m), 8.35 to 8.38 (1H, m).

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -1H-tetrazole 5- (3- (2- (4-cyclobutyl) -2-thiazolyl) ethynyl) -6-fluorophenyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 223 to 225 ° C. (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 3080, 2220, 1620, 1556, 150
8; NMR (400 MHz, DMSO-d ₆ ) δpp
m 1.84 to 2.35 (6H, m), 3.64 to
3.72 (1H, m), 7.56 (1H, s),
7.62 to 7.66 (1H, m), 7.94 to
7.98 (1H, m), 8.30 to 8.32 (1
H, m); MS (FAB ) m / z326 (M + +
1); Elemental analysis value Calculated value of C ₁₆ H ₁₂ FN ₅ S (%)
C, 59.06; H, 3.72; N, 21.52.
Measured value (%) C, 59.01; H, 3.84;
N, 21.76.

[Example 36] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -4-methylphenyl) -1H-tetrazole: (Step 1) 5- (3-iodo-4-methylphenyl)
Synthesis of 2- (4-methoxybenzyl) -2H-tetrazole 5- (3-Iodo-4-methylphenyl) -1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to give 5- (3
-Iodo-4-methylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained. 136-138 ° C (recrystallization solvent: ether-n-
Hexane); NMR (400 MHz, CDCl ₃ ) δ
ppm 2.74 (3H, s), 3.80 (3H, s)
s), 5.72 (2H, s), 6.90 (2
H, d), 7.31 (1H, d), 7.37
(2H, d), 7.99 (1H, dd), 8.
77 (1H, d).

(Step 2) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-methylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-methylphenyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as Step 4 of Example 1 to give 5- (3- (2
-(4-cyclobutyl-2-thiazolyl) ethynyl)-
4-methylphenyl) -2- (4-methoxybenzyl)
-2H-tetrazole was obtained as a brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.11 (2H, m), 2.27 to 2.43 (4
H, m), 2.57 (3H, s), 3.71.
(1H, m), 3.80 (3H, s), 5.7
5. 3 (2H, s), 6.91 (2H, d), 6.
97 (1H, s), 7.34 (1H, d),
40 (2H, d), 8.04 (1H, dd),
8.32 (1H, d).

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-methylphenyl) -1H-tetrazole 5- (3- (2- (4-cyclobutyl) -2-Thiazolyl) ethynyl) -4-methylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 180-182 ° C. (recrystallization solvent: water-ethanol); NMR (400 MHz, DMSO-d ₆ ) δp
pm 1.91 to 2.08 (2H, m), 2.22
~ 2.34 (4H, m), 2.57 (3H,
s), 3.69 (1H, m), 7.47 (1H,
s), 7.57 (1H, d), 8.04 (1
H, d), 8.25 (1H, s); Calculated value (%) of elemental analysis value C ₁₇ H ₁₅ N ₅ S C, 63.53;
H, 4.70; N, 21.79, measured value (%)
C, 63.30; H, 4.83; N, 20.99.

[Example 37] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -4-methoxyphenyl) -1H-tetrazole: (Step 1) of 5- (3-iodo-4-methoxyphenyl) -2- (4- (methoxybenzyl) -2H-tetrazole Synthesis 5- (3-Iodo-4-methoxyphenyl) -1H-tetrazole was treated in the same manner as Step 3 of Example 1 to give 5
-(3-Iodo-4-methoxyphenyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole was obtained. 125-126 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.80 (3H, s), 3.93
(3H, s), 5.71 (2H, s), 6.8
8 (1H, d), 6.91 (2H, d), 7.3
7 (2H, d), 8.09 (1H, dd),
8.54 (1H, d).

(Step 2) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-methoxyphenyl) -2- (4-methoxybenzyl) -2H-tetrazole 3-iodo-4-methoxyphenyl) -2- (4
-Methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were used in Step 4 of Example 1.
To give 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-methoxyphenyl) -2- (4-methoxybenzyl) -2H-tetrazole. Melting point 99-100 ° C (recrystallization solvent: ether-n-hexane); NMR (400 MHz, CDCl ₃ ) δp
pm 1.89 to 2.10 (2H, m), 2.27
~ 2.41 (4H, m), 3.73 (1H,
m), 3.80 (3H, s), 3.96 (3H,
s), 5.72 (2H, s), 6.91 (2
H, d), 6.95 (1H, s), 6.99
(1H, d), 7.39 (2H, d), 8.13
(1H, dd), 8.31 (1H, d).

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-methoxyphenyl) -1H-tetrazole 5- (3- (2- (4-cyclobutyl) -2-thiazolyl) ethynyl) -4-methoxyphenyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Mp 215-217 ° C (recrystallization solvent: ethanol-ether); NMR (400 MHz, DMSO-d ₆ )
δ ppm 1.85 to 2.06 (2H, m), 2.1
9 to 2.34 (4H, m), 3.68 (1H,
m), 3.99 (3H, s), 7.40 (1H,
d), 7.55 (1H, s), 8.15 (1
H, dd), 8.23 (1H, d); Calculated value (%) of elemental analysis value C ₁₇ H ₁₅ N ₅ OS · １ ／ H ₂ O (%) C,
H, 4.66; N, 20.22, measured value (%) C, 59.36; H, 4.63; N,
19.90.

[Example 38] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -6-hydroxyphenyl) -1H-tetrazole: (Step 1) 5- (3-Iodo-6- (4-methoxybenzyl) oxyphenyl) -2- (4-methoxybenzyl) Synthesis of 2H-tetrazole 5- (3-iodo-6-hydroxyphenyl) -1H-
The tetrazole was treated with 2 equivalents of 4-methoxybenzyl chloride and potassium carbonate in the same manner as in Step 3 of Example 1 to give 5- (3-iodo-6- (4-methoxybenzyl) oxyphenyl) -2- (4-methoxybenzyl)
2H-tetrazole was obtained. 159-160 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.79 (3H, s), 3.81
(3H, s), 5.10 (2H, s), 5.7
5 (2H, s), 6.84 (1H, d), 6.8
5. (2H, d), 6.87 (2H, d),
34 (2H, d), 7.35 (2H, d),
7.64 (1H, dd), 8.27 (1H, dd)
d).

(Step 2) 5- (3- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) -6- (4-methoxybenzyl) oxyphenyl) -2- (4-methoxybenzyl) -2H- Synthesis of tetrazole 5- (3-iodo-6- (4-methoxybenzyl) oxyphenyl) -2- (4-methoxybenzyl) -2H-
Tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to give 5- (3
-(2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6- (4-methoxybenzyl) oxyphenyl)
-2- (4-Methoxybenzyl) -2H-tetrazole was obtained. 159-160 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 1.88-2.10 (2H, m),
2.26 to 2.41 (4H, m), 3.68 (1
H, m), 3.79 (3H, s), 3.81
(3H, s), 5.17 (2H, s), 5.74
(2H, s), 6.87 (2H, d), 6.8
8. (2H, d), 6.92 (1H, d),
07 (1H, d), 7.35 (2H, d),
7.39 (2H, d), 7.62 (1H, d)
d), 8.23 (1H, d).

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-hydroxyphenyl) -1H-tetrazole 5- (3- (2- (4-cyclobutyl) -2-Thiazolyl) ethynyl) -6- (4-methoxybenzyl) oxyphenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. . Melting point 205-209 ° C (decomp.) (Recrystallization solvent: ethanol-ether); NMR (400 MH
_{z, DMSO-d 6) δppm} 1.84~2.03
(2H, m), 2.18 to 2.33 (4H,
m), 3.66 (1H, m), 7.15 (1H,
d), 7.49 (1H, s), 7.70 (1H,
dd), 8.44 (1H, d); Elemental analysis value C
₁₆ H ₁₃ N ₅ calcd OS (%) C, 57.82;
H, 4.25; N, 21.07, measured value (%)
C, 57.43; H, 4.32; N, 20.79.

Example 39 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -1H-tetrazole: (Step 1) Synthesis of 5- (3-iodo-2-fluorophenyl) -1H-tetrazole To 1.65 g of 2,6-lutidine Under ice cooling and stirring, 0.32 ml of trifluoroacetic acid was added. After stirring at the same temperature for 0.5 hour, 270 mg of sodium azide was added, and the mixture was stirred at room temperature for 1 hour.
Stirred for hours. To this was added 1 g of 3-iodo-2-fluorobenzonitrile, and the mixture was stirred at 80 ° C for 16 hours. The reaction solution was added to 50 ml of 2N hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water and dried. The crude crystals were recrystallized from chloroform-ethanol to give 5- (3-iodo-2-fluorophenyl)
1.05 g of -1H-tetrazole was obtained as prism crystals. Melting point: 182 to 184 ° C .; NMR (400 MHz, DM
_{SO-d 6) δppm7.25 (1H} , m), 8.
16 (1H, m), 8.21 (1H, m); M
S (EI) m / z 290 (M ⁺ ); Elemental analysis value C ₇
H ₄ FIN ₄ Calculated (%) C, 28.99; H,
1.39; N, 19.32, measured value (%) C, 2
9.26; H, 1.59; N, 19.05.

(Step 2) 5- (3-Iodo-2-fluorophenyl) -2- (4-methoxybenzyl) -2H
Synthesis of -tetrazole 5- (3-iodo-2-fluorophenyl) -1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to give 5-
(3-Iodo-2-fluorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained. 124-126 ° C; NMR (400 MHz, DM
_{SO-d 6) δppm3.75 (3H} , s), 5.
95 (2H, s), 6.97 (2H, d),
7.18 (1H, t), 7.40 (2H, d),
8.03 (2H, m); MS (EI) m / z 4
10 (M ⁺ ); Elemental analysis value Calculated value of C ₁₅ H ₁₂ FIN ₄ O (%) C, 43.92; H, 2.95; N, 1
3.66, measured (%) C, 43.89; H, 3.
02; N, 13.83.

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole 3-iodo-2-fluorophenyl) -2- (4
-Methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were used in Step 4 of Example 1.
To give 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole. 114-116 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 1.92 to 2.40 (6H, m),
3.66 to 3.75 (1H, m), 3.80 (3
H, s), 5.78 (2H, s), 6.89-
6.93 (2H, m), 6.99 (1H, s),
7.27 (1H, t), 7.40 to 7.43 (2
H, m), 7.65 to 7.69 (1H, m),
8.13-8.17 (1H, m); MS (FAB) m
^{/ Z 445 (M + +1)} ; Elemental analysis C ₂₄ H ₂₀ F
Calculated N ₅ OS (%) C, 64.70; H, 4.
52; N, 15.72; measured value (%) C, 64.
73; H, 4.56; N, 15.81.

(Step 4) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -1H-tetrazole 5- (3- (2- (4-cyclobutyl) -2-thiazolyl) ethynyl) -2-fluorophenyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 192 to 195 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2224; N
MR (400 MHz, CDCl ₃ ) δ ppm 1.85
~ 2.35 (6H, m), 3.65 to 3.74 (1
H, m), 7.55 (1H, t), 7.61
(1H, s), 7.97 to 8.01 (1H,
m), 8.17-8.21 (1H, m); MS
(FAB) m / z326 (M + +1); Elemental analysis C ₁₆ H ₁₂ FN ₅ Calculated S (%) C, 59.06;
H, 3.72; N, 21.52, measured value (%)
C, 58.89; H, 3.79; N, 21.45.

Example 40 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -6-methylthiophenyl) -1H-tetrazole: (Step 1) Synthesis of 5- (3-iodo-6-methylthiophenyl) -2- (4-methoxybenzyl) -2H-tetrazole 5- (3-iodo-2-fluorophenyl) -2- (4
-Methoxybenzyl) -2H-tetrazole 204mg
Was dissolved in 10 ml of DMSO, 0.5 ml of methanethiol sodium salt (aqueous solution containing about 15%) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into 100 ml of 1N hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water and dried. The crude crystals were recrystallized from chloroform-n-hexane to give 183 mg of 5- (3-iodo-6-methylthiophenyl) -2- (4-methoxybenzyl) -2H-tetrazole as needles. 138-140 ° C; NMR (400 MHz, CD
Cl ₃ ) δ ppm 2.46 (3H, s), 3.8
0 (3H, s), 5.77 (2H, s), 6.8
9-6.91 (2H, m), 7.05 (1H,
d), 7.69 (1H, dd), 8.29 (1
H, d); MS (EI) m / z 438 (M ^<+> );
Elemental analysis value Calculated value of C ₁₆ H ₁₅ IN ₄ OS (%) C,
43.85; H, 3.45; N, 12.78, found (%) C, 44.17; H, 3.55; N, 1
2.91.

(Step 2) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methylthiophenyl) -1H-tetrazole 5- (3-iodo-6-methylthiophenyl) -2-
(4-methoxybenzyl) -2H-tetrazole and 4-
Cyclobutyl-2-ethynylthiazole was treated in the same manner as step 4 of example 1, followed by step 5 of example 1.
The title compound was obtained. 114-116 ° C (recrystallization solvent: chloroform-
Ethanol); IRνmax cm ^-1 2216; NM
R (400 MHz, DMSO-d ₆ ) δ ppm 1.86
~ 2.32 (6H, m), 2.67 (3H,
s), 3.63-3.71 (1H, m), 7.5.
6. 3 (1H, s), 7.57 (1H, t), 7.
82 (1H, dd), 7.99 (1H, d);
MS (FAB) m / z 354 (M + +1); Elemental analysis C ₁₇ H ₁₅ N ₅ S ₂ Calculated (%) C, 57.7
H, 4.28; N, 19.81, measured value (%) C, 57.31; H, 4.34; N, 1
9.65.

Example 41 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -6-chlorophenyl) -1H-tetrazole: (Step 1) 5- (6-chloro-3-iodophenyl)
Synthesis of -2- (4-methoxybenzyl) -2H-tetrazole 5- (6-Chloro-3-iodophenyl) -1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to give 5- (6
-Chloro-3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained. Melting point 90-91 ° C; NMR (400 MHz, CDCl
₃ ) δ ppm 3.80 (3H, s), 5.77
(2H, s), 6.89 (2H, d), 7.2
6. 3 (1H, d), 7.39 (2H, d), 7.
68 (1H, d), 8.25 (1H, d).

(Step 2) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-chlorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole 5- (6 -Chloro-3-iodophenyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to give 5- (3- (2- (4-cyclobutyl-
2-thiazolyl) ethynyl) -6-chlorophenyl)-
2- (4-Methoxybenzyl) -2H-tetrazole was obtained. 66-67 ° C. (recrystallization solvent: ether-n-hexane); NMR (400 MHz, CDCl ₃ ) δpp
m 1.88 to 2.11 (2H, m), 2.26 to
2.42 (4H, m), 3.69 (1H, m),
3.81 (3H, s), 5.79 (2H, s)
s), 6.91 (2H, d), 6.97 (1H,
s), 7.41 (2H, d), 7.51 (1
H, d), 7.58 (1H, dd), 8.17
(1H, d).

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-chlorophenyl) -1H-tetrazole 5- (3- (2- (4-cyclobutyl- 2-Thiazolyl) ethynyl) -6-chlorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Mp 183-185 ° C. (recrystallization solvent: ethanol - ether); NMR (400MHz, DMSO- d 6)
δ ppm 1.86 to 2.02 (2H, m), 2.1
8-2.31 (4H, m), 3.68 (1H,
m), 7.57 (1H, s), 7.83 (1H,
d), 7.90 (1H, d), 8.13 (1
H, s); MS (EI) m / z 341 (M ^<+> );
Elemental analysis value Calculated value of C ₁₆ H ₁₂ N ₅ ClS (%) C,
H, 3.54; N, 20.49, measured value (%) C, 56.02; H, 3.63; N,
20.21.

Example 42 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-chlorophenyl) -1H-tetrazole: (Step 1) 5- (2-chloro-3-iodophenyl)
Synthesis of -2- (4-methoxybenzyl) -2H-tetrazole 5- (2-chloro-3-iodophenyl) -1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to give 5- (2
-Chloro-3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained. Melting point 91-92 ° C; NMR (400 MHz, CDC
l ₃ ) δ ppm 3.76 (3H, s), 5.78
(2H, s), 6.90 (2H, d), 7.06
(1H, t), 7.40 (2H, d), 7.8
2 (1H, d), 7.99 (1H, d).

(Step 2) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-chlorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole -Chloro-3-iodophenyl) -2- (4-
Methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in step 4 of Example 1 to give 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2. -Chlorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained. Melting point 69-70 ° C (recrystallization solvent: ether-n-hexane); NMR (400 MHz, CDCl ₃ ) δpp
m 1.89 to 2.11 (2H, m), 2.26 to
2.40 (4H, m), 3.72 (1H, m),
3.80 (3H, s), 5.79 (2H, s)
s), 6.91 (2H, d), 7.00 (1H,
s), 7.34 (1H, t), 7.41 (2
H, d), 7.72 (1H, d), 7.97
(1H, d).

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-chlorophenyl) -1H-tetrazole 5- (3- (2- (4-cyclobutyl- 2-Thiazolyl) ethynyl) -2-chlorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point 167 to 170 ° C (recrystallization solvent: water-ethanol); IRν max cm ^-1 2220; NMR (400
_{MHz, DMSO-d 6) δppm} 1.83~2.1
0 (2H, m), 2.19 to 2.35 (4H,
m), 3.70 (1H, m), 7.61 (1H,
s), 7.65 (1H, t), 7.92 (1
H, dd), 8.02 (1H, dd); MS
(EI) m / z 341 (M ⁺ ); Elemental analysis value C ₁₆ H ₁₂
Calculated N ₅ ClS (%) C, 56.22; H,
3.54; N, 20.49, measured value (%) C, 5
6.35; H, 3.76; N, 19.94.

Example 43 5- (3- (2- (4-
(Isopropyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -1H-tetrazole (Step 1) 5- (3- (2- (4-isopropyl-2)
-Thiazolyl) ethynyl) -2-fluorophenyl)-
Synthesis of 2- (4-methoxybenzyl) -2H-tetrazole Synthesized in Example 39, 5- (3-iodo-2-fluorophenyl) -2- (4-methoxybenzyl) -2H-
The tetrazole and 4-isopropyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to give 5- (3-
(2- (4-Isopropyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained. Melting point 116-119 ° C; NMR (400 MHz, CD
Cl ₃ ) δ ppm 1.35 (6H, d), 3.1
2-3.19 (1H, m), 3.80 (3H,
s), 5.78 (2H, s), 6.89-6.9.
2 (2H, d), 6.98 (1H, s), 7.2
7 (1H, t), 7.39 to 7.41 (2H,
d), 7.64 to 7.68 (1H, m), 8.1
2-8.17 (1H, m); MS (EI) m / z
433 (M ⁺ ); Elemental analysis value Calculated value for C ₂₃ H ₂₀ FN ₅ OS (%) C, 63.73; H, 4.65; N,
16.16, measured value (%) C, 63.69; H,
4.69; N, 16.22.

(Step 2) Synthesis of 5- (3- (2- (4-isopropyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -1H-tetrazole 5- (3-iodo-2-fluorophenyl) -2- (4
-Methoxybenzyl) -2H-tetrazole and 4-isopropyl-2-ethynylthiazole were prepared in Step 5 of Example 1.
The title compound was obtained. 155-158 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ^-1 2220; NM
R (400 MHz, DMSO-d ₆ ) δ ppm 1.28
(6H, d), 3.07-3.16 (1H,
m), 7.55 (1H, t), 7.58 (1H,
7.s), 7.97-8.00 (1H, m),
17-8.20 (1H, m); MS (EI) m / z
313 (M ⁺ ); Elemental analysis value Calculated value for C ₁₅ H ₁₂ FN ₅ S (%) C, 57.49; H, 3.86; N,
22.35, measured value (%) C, 57.50; H,
3.95; N, 22.29.

[Example 44] 5- (3- (2- (4-
n-propyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -1H-tetrazole: (Step 1) 5- (3- (2- (4-n-propyl-2)
-Thiazolyl) ethynyl) -2-fluorophenyl)-
Synthesis of 2- (4-methoxybenzyl) -2H-tetrazole 5- (3-iodo-2-fluorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole and 4-n used in Example 39 -Propyl-2-ethynylthiazole was treated as in step 4 of example 1 to give 5- (3- (2
-(4-n-propyl-2-thiazolyl) ethynyl)-
2-Fluorophenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained. Melting point 97-99 ° C; NMR (400 MHz, CDCl
₃ ) δ ppm 0.98 (3H, t), 1.78
(2H, m), 2.80 (2H, t), 3.8
5. 0 (3H, s), 5.78 (2H, s),
89-6.91 (2H, d), 6.98 (1H,
s), 7.27 (1H, t), 7.40-7.4.
2 (2H, d), 7.64 to 7.68 (1H,
m), 8.12-8.16 (1H, m); MS
(EI) m / z 433 (M ⁺ ); Elemental analysis value C ₂₃ H
₂₀ FN ₅ OS calculated (%) C, 63.73; H,
4.65; N, 16.16, measured value (%) C, 6
3.58; H, 4.71; N, 16.02.

(Step 2) 5- (3- (2- (4-n-
Synthesis of propyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -1H-tetrazole 5- (3- (2- (4-n-propyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 149-152 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2224; N
MR (400 MHz, DMSO-d ₆ ) δ ppm 0.9
2 (3H, t), 1.70 (2H, m), 2.
75 (2H, t), 7.55 (1H, t), 7.
59 (1H, s), 7.94 to 8.01 (1H,
m), 8.14-8.22 (1H, m); MS
(EI) m / z 313 (M ⁺ ); Elemental analysis value C ₁₅ H
Calculated value for ₁₂ FN ₅ S (%) C, 57.49; H,
3.86; N, 22.35, measured value (%) C, 5
7.47; H, 3.98; N, 22.11.

Example 45 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-methylphenyl) -1H-tetrazole: (Step 1) 5- (3-iodo-2-methylphenyl)
Synthesis of 2- (4-methoxybenzyl) -2H-tetrazole 5- (3-Iodo-2-methylphenyl) -1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to give 5- (3
-Iodo-2-methylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 2.7
6 (3H, s), 3.80 (3H, s), 5.
75 (2H, s), 6.90 (2H, d),
7.39 (2H, d), 7.81 (1H, d)
d), 7.94 (1H, dd).

(Step 2) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole 3-iodo-2-methylphenyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to give 5- (3- (2- (4-cyclobutyl-
2-thiazolyl) ethynyl) -2-methylphenyl)-
2- (4-Methoxybenzyl) -2H-tetrazole was obtained. 140-142 ° C (recrystallization solvent: ether-n-
Hexane); NMR (400 MHz, CDCl ₃ ) δ
ppm 1.88-2.11 (2H, m), 2.27
~ 2.42 (4H, m), 2.77 (3H,
s), 3.69 (1H, m), 3.81 (3H,
s), 5.77 (2H, s), 6.91 (2
H, d), 6.97 (1H, s), 7.30
(1H, t), 7.41 (2H, d), 7.67
(1H, dd), 7.96 (1H, dd); elemental analysis value calculated value of C ₂₅ H ₂₃ N ₅ OS (%) C, 68.0
H, 5.25; N, 15.86, measured value (%) C, 67.83; H, 5.26; N, 1
5.94.

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methylphenyl) -1H-tetrazole 5- (3- (2- (4-cyclobutyl) -2-Thiazolyl) ethynyl) -2-methylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Mp 209 to 211 ° C. (recrystallization solvent: ethanol - ether); NMR (400MHz, DMSO- d 6)
δ ppm 1.84 to 2.06 (2H, m), 2.1
9 to 2.34 (4H, m), 2.64 (3H,
s), 3.69 (1H, m), 7.52 (1H,
t), 7.56 (1H, s), 7.79 (1
H, d), 7.85 (1H, d); MS (E
I) m / z 321 (M ⁺ ); Elemental analysis: C ₁₇ H ₁₅ N
₅ Calculated S (%) C, 63.53; H, 4.70;
N, 21.79; measured value (%) C, 63.44;
H, 4.80; N, 21.73.

Example 46 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-trifluoromethylphenyl) -1H-tetrazole: (Step 1) 5- (3-Iodo-2-trifluoromethylphenyl) -2- (4-methoxybenzyl) -2H −
Synthesis of tetrazole 5- (3-iodo-2-trifluoromethylphenyl)
1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to obtain 5- (3-iodo-2-trifluoromethylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole as an oil. . NMR (400 MHz, CDCl ₃ ) δ ppm 3.8
5. 1 (3H, s), 5.76 (2H, s),
91 (2H, d), 7.22 (1H, t),
7.36 (2H, d), 7.48 (1H, d),
8.22 (1H, d).

(Step 2) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-trifluoromethylphenyl) -2- (4-methoxybenzyl)
Synthesis of -2H-tetrazole 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-trifluoromethylphenyl)-
Example 1 2- (4-methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole
And treated in the same manner as in Step 4 of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-trifluoromethylphenyl) -2- (4-methoxybenzyl)
-2H-tetrazole was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.11 (2H, m), 2.26 to 2.43 (4
H, m), 3.63 to 3.77 (1H, m),
3.81 (3H, s), 5.78 (2H, s),
6.91 (2H, d), 7.02 (1H,
s), 7.38 (2H, d), 7.57-7.6.
3 (1H, m), 7.88 to 7.90 (1H,
m).

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-trifluoromethylphenyl) -1H-tetrazole 5- (3- (2- (4 -Cyclobutyl-2-thiazolyl) ethynyl) -2-trifluoromethylphenyl)-
2- (4-Methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point 209-211 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2224; N
MR (400 MHz, DMSO-d ₆ ) δ ppm 1.8
9 to 2.04 (2H, m), 2.21 to 2.35
(1H, m), 3.70 (1H, m), 7.63
(1H, s), 7.80 (1H, d), 7.94
(1H, t), 8.19 (1H, d); MS
(FAB) m / z 376 ( M + +1); Elemental analysis _{C 17 H 12 F 3 N 5} S · 1 / 2H 2 O Calculated (%)
C, 53.12; H, 3. 41; N, 18.2
2, measured value (%) C, 53.39; H, 3.27;
N, 18.44.

Example 47 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -6-trifluoromethylphenyl) -1H-tetrazole: (Step 1) 5- (3-Iodo-6-trifluoromethylphenyl) -2- (4-methoxybenzyl) -2H −
Synthesis of tetrazole 5- (3-iodo-6-trifluoromethylphenyl)
The -1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to obtain 5- (3-iodo-6-trifluoromethylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole. Melting point 59-61 ° C; NMR (400 MHz, CDCl
₃ ) δ ppm 3.81 (3H, s), 5.77
(2H, s), 6.91 (2H, d), 7.3
8. (2H, d), 7.52 (1H, d),
94 (1H, dd), 8.22 (1H, d).

(Step 2) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-trifluoromethylphenyl) -2- (4-methoxybenzyl)
Synthesis of -2H-tetrazole 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-trifluoromethylphenyl)-
1H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated as in step 4 of Example 1 to give 5-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-trifluoromethylphenyl) -2-
(4-Methoxybenzyl) -2H-tetrazole was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
9 to 2.17 (2H, m), 2.27 to 2.41 (4
H, m), 3.70 (1H, m), 3.81
(3H, s), 5.78 (2H, s), 6.9
2 (2H, d), 7.00 (1H, s),
39 (2H, d), 7.78 (1H, d), 7.
83 (1H, d), 8.08 (1H, s).

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-trifluoromethylphenyl) -1H-tetrazole 5- (3- (2- (4 -Cyclobutyl-2-thiazolyl) ethynyl) -6-trifluoromethylphenyl)-
2- (4-Methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point 209-211 ° C (recrystallization solvent: chloroform-
Ethanol -n- hexane); IRνmax cm ^-1 2
224; NMR (400 MHz, DMSO-d ₆ ) δ
ppm 1.84 to 2.06 (2H, m), 2.1
9 to 2.34 (1H, m), 3.69 (1H,
m), 7.61 (1H, s), 8.03-8.1.
3 (1H, m), 8.16 (1H, s); MS
(FAB) m / z 376 ( M + +1); Elemental analysis C ₁₇ H ₁₂ F ₃ N ₅ Calculated S (%) C, 54.40;
H, 3.22; N, 18.66, measured value (%)
C, 54.29; H, 3.38; N, 18.41.

Example 48 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -5-methoxycarbonylphenyl) -1H-tetrazole: (Step 1) 5- (3-Iodo-5-methoxycarbonylphenyl) -2- (4-methoxybenzyl) -2H-
Synthesis of tetrazole 5- (3-iodo-5-methoxycarbonylphenyl)
The -1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to obtain 5- (3-iodo-5-methoxycarbonylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole. Melting point 97 ° C; IRνmax cm ^-1 1728; NM
R (400 MHz, CDCl ₃ ) δ ppm 3.80
(3H, s), 3.95 (3H, s), 5.7
5. (2H, s), 6.91 (2H, d),
39 (2H, d), 8.44 (1H, s),
8.66 (1H, d), 8.74 (1H, s);
MS (EI) m / z 450 (M ⁺ ); Elemental analysis value C
₁₇ H ₁₅ Calculated _{IN 4 O 3 (%) C} , 46.35;
H, 3.36; N, 12.44, measured value (%) C,
46.08; H, 3.65; N, 12.50.

(Step 2) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -5-methoxycarbonylphenyl) -2- (4-methoxybenzyl)
Synthesis of -2H-tetrazole 5- (3-iodo-5-methoxycarbonylphenyl)
2- (4-Methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to give 5- (3- (2- (4-cyclobutyl-2-yl). Thiazolyl) ethynyl) -5-methoxycarbonylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained as a brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
3 to 2.40 (6H, m), 3.71 (1H,
m), 3.81 (3H, s), 3.97 (3H,
s), 5.75 (2H, s), 6.92 (2
H, d), 6.99 (1H, s), 7.41
(2H, d), 8.32 (1H, d), 8.54
(1H, t), 8.79 (1H, d).

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -5-methoxycarbonylphenyl) -1H-tetrazole 5- (3- (2- (4- Cyclobutyl-2-thiazolyl) ethynyl) -5-methoxycarbonylphenyl)-
2- (4-Methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 189-191 ° C (recrystallization solvent: methylene chloride); IRν max cm ⁻¹ 2224, 1720; NM
R (400 MHz, DMSO-d ₆ ) δ ppm 1.8
0 to 2.32 (6H, m), 3.69 (1H,
m), 3.98 (3H, s), 7.60 (1H,
s), 8.32 (1H, s), 8.53 (1
H, s), 8.68 (1H, s); MS (FA
B) m / z 366 (M ⁺⁺ 1); Elemental analysis _C18.
Calculated _{H 15 N 5 O 2 S (} %) C, 59.16;
H, 4.14; N, 19.17, measured value (%)
C, 58.79; H, 4.14; N, 18.76.

Example 49 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -6-methoxyphenyl) -1H-tetrazole: (Step 1) Synthesis of 5- (3-iodo-6-methoxyphenyl) -2- (4-methoxybenzyl) -2H-tetrazole 5- (3-Iodo-6-methoxyphenyl) -1H-tetrazole was treated as in step 3 of Example 1 to give 5-
(3-Iodo-6-methoxyphenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained. 133-135 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.80 (3H, s), 5.76
(2H, s), 6.80 (1H, d), 6.8
9 to 6.91 (2H, m), 7.37 to 7.39 (1
H, m), 7.70 (1H, dd), 8.20
(1H, d); MS (EI) m / z 422
(M ⁺ ); Elemental analysis value Calculated value for C ₁₆ H ₁₅ IN ₄ O ₂ (%) C, 45.52; H, 3.58; N, 13.
27, measured value (%) C, 45.49; H, 3.6
8; N, 13.29.

(Step 2) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methoxyphenyl) -2- (4-methoxybenzyl) -2H-tetrazole 3-iodo-6-methoxyphenyl) -2- (4
-Methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were used in Step 4 of Example 1.
To give 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methoxyphenyl) -2- (4-methoxybenzyl) -2H-tetrazole. Melting point: 98 to 101 ° C .; NMR (400 MHz, CDC
l ₃ ) δ ppm 1.93 to 2.40 (6H, m),
3.71 (1H, m), 3.64 to 3.73 (1
H, m), 3.80 (3H, s), 3.96
(3H, s), 5.77 (2H, s), 6.89
６6.92 (2H, m), 6.93 (1H,
s), 7.03 (1H, d), 7.38-7.4.
2 (2H, m), 7.66 (1H, dd),
8.17 (1H, d); MS (EI) m / z 45
7 (M ⁺ ); Elemental analysis value Calculated value for C ₂₅ H ₂₃ N ₅ O ₂ S (%) C, 65.63; H, 5.07; N, 1
5.31, measured value (%) C, 65.40; H,
5.03; N, 15.45.

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methoxyphenyl) -1H-tetrazole 5- (3- (2- (4-cyclobutyl) -2-thiazolyl) ethynyl) -6-methoxyphenyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 219-221 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2216; NM
R (400 MHz, DMSO-d ₆ ) δ ppm 1.86
~ 2.34 (6H, m), 3.63-3.71 (1
H, m), 4.04 (3H, s), 7.39 (1
H, d), 7.51 (1H, s), 7.88
(1H, dd), 8.29 (1H, d); MS
(EI) m / z 337 ( M +); Elemental analysis C ₁₇ H
₁₅ N ₅ OS calculated (%) C, 60.52; H,
4.48; N, 20.76, measured value (%) C, 6
0.50; H, 4.60; N, 20.93.

Example 50 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-methylthiophenyl) -1H-tetrazole: (Step 1) Synthesis of 5- (3-iodo-2-methylthiophenyl) -2- (4-methoxybenzyl) -2H-tetrazole 5- (3-iodo-2-methylthiophenyl) -1H-
The tetrazole was treated as in Step 3 of Example 1 to give 5-
(3-Iodo-2-methylthiophenyl) -2- (4-
Methoxybenzyl) -2H-tetrazole was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 2.3
0 (3H, s), 3.80 (3H, s), 5.
77 (2H, s), 6.88-6.92 (2H,
m), 7.07 (1H, t), 7.38-7.4
1 (2H, m), 7.61 (1H, dd),
8.06 (1H, dd).

(Step 2) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methylthiophenyl) -2- (4-methoxybenzyl) -2H-
Synthesis of tetrazole 5- (3-iodo-2-methylthiophenyl) -2-
(4-methoxybenzyl) -2H-tetrazole and 4-
Cyclobutyl-2-ethynylthiazole was treated as in step 4 of Example 1 to give 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methylthiophenyl) -2- (4- Methoxybenzyl) -2H-tetrazole was obtained as a brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
9 to 2.40 (6H, m), 2.44 (3H,
s), 3.67-3.75 (1H, m), 3.8
5. 0 (3H, s), 5.79 (2H, s),
89-6.91 (2H, m), 6.99 (1H,
s), 7.36 (1H, d), 7.40-7.4
2 (2H, m), 7.69 (1H, dd),
7.73 (1H, dd).

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methylthiophenyl) -1H-tetrazole 5- (3- (2- (4-cyclobutyl) -2-thiazolyl) ethynyl) -2-methylthiophenyl) -2- (4
-Methoxybenzyl) -2H-tetrazole in Example 1
And the title compound was obtained. 151-154 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2212; NM
R (400 MHz, DMSO-d ₆ ) δ ppm 1.86
~ 2.32 (6H, m), 2.39 (3H,
s), 3.65-3.73 (1H, m), 7.5
9. (1H, s), 7.62 (1H, t),
72 (1H, d), 7.95 (1H, d); M
S (EI) m / z 353 (M ⁺ ); Elemental analysis value C ₁₇
Calculated value for H ₁₅ N ₅ S ₂ (%) C, 57.77; H,
4.28; N, 19.81, measured value (%) C, 5
7.64; H, 4.38; N, 19.60.

[Example 51] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -5-bromophenyl) -1H-tetrazole: (Step 1) 5- (3-iodo-5-bromophenyl)
Synthesis of -2- (4-methoxybenzyl) -2H-tetrazole 5- (3-Iodo-5-bromophenyl) -1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to give 5- (3
-Iodo-5-bromophenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained. Melting point: 154 to 155 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.80 (3H, s), 5.72
(2H, s), 6.90 (2H, d), 7.3
7 (2H, d), 7.92 (1H, t), 8.2
4 (1H, t), 8.40 (1H, t); MS
(FAB) m / z 473 ( M + +1); Elemental analysis C ₁₅ H ₁₂ BrIN ₄ O Calculated (%) C, 38.2
H, 2.57; N, 11.90, measured value (%) C, 38.25; H, 2.54; N, 1
2.10.

(Step 2) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -5-bromophenyl) -2- (4-methoxybenzyl) -2H-tetrazole 3-iodo-5-bromophenyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to give 5- (3- (2- (4-cyclobutyl-
2-thiazolyl) ethynyl) -5-bromophenyl)-
2- (4-Methoxybenzyl) -2H-tetrazole was obtained. 127-129 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 1.95 to 2.09 (2H, m),
2.29-2.40 (4H, m), 3.68-3.
72 (1H, m), 3.80 (3H, s),
5.73 (2H, s), 6.91 (2H, d),
6.99 (1H, s), 7.40 (1H, d),
7.78 (1H, t), 8.29 to 8.39 (1
H, m); MS (FAB ) m / z508 [(M + +
2) +1)], 506 [(M ⁺ ) +1)]; Elemental analysis value Calculated value of C ₂₄ H ₂₀ BrN ₅ OS · １ ／ H ₂ O (%
N) 13. C) 56.42; H, 4.04;
71, measured value (%) C, 56.49; H, 4.0
7; N, 13.69.

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -5-bromophenyl) -1H-tetrazole 5- (3- (2- (4-cyclobutyl) 2-Thiazolyl) ethynyl) -5-bromophenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 104-105 ° C (decomp.) (Recrystallization solvent: chloroform-ethanol-n-hexane);
Rνmax cm ⁻¹ 2210; NMR (400 MHz,
_{DMSO-d 6) δppm 2.06 (} 2H, m),
2.19 to 2.32 (4H, m), 3.73 (1
H, m), 7.59 (1H, s), 8.14 (1
H, s), 8.28 (1H, s), 8.30
(1H, s); MS (FAB) m / z 388 [(M
⁺ +2) +1)], 386 [(M ⁺ ) +1)]; Elemental analysis value Calculated value (%) of C ₁₆ H ₁₂ BrN ₅ S 5H ₂ O (%) C, 49.18; H, 3.22 N, 17.
92, measured value (%) C, 49.20; H, 3.1
2; N, 17.88.

Example 52 5- (3,5-bis (2
-(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1H-tetrazole: (Step 1) 5- (3,5-diodophenyl) -2-
Synthesis of (4-methoxybenzyl) -2H-tetrazole 5- (3-bromo-5-iodophenyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole in Example 16
To give 5- (3,5-diodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole. 177-178 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.80 (3H, s), 5.72
(2H, s), 6.91 (2H, d), 7.3
7 (2H, d), 8.11 to 8.12 (1H,
m), 8.43 (2H, d).

(Step 2) 5- (3,5-bis (2-
Synthesis of (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole 5- (3,5-diodophenyl) -2- (4-methoxybenzyl) -2H -Tetazole and 4-cyclobutyl-2-ethynylthiazole were treated as in step 4 of Example 1 to give 5- (3,5-bis (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2 − (4-
Methoxybenzyl) -2H-tetrazole was obtained as a brown amorphous. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.11 (4H, m), 2.28 to 2.42 (8
H, m), 3.66 to 3.75 (1H, m),
3.80 (3H, s), 5.74 (2H, s),
6.92 (2H, d), 6.98 (2H, d)
s), 7.41 (2H, d), 7.82 (1H,
s), 8.37 (2H, d).

(Step 3) 5- (3,5-bis (2-
Synthesis of (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1H-tetrazole 5- (3,5-bis (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxy) (Benzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 212-214 ° C (decomp.) (Recrystallization solvent: chloroform-ethanol-n-hexane);
Rνmax cm ⁻¹ 2216; NMR (400 MHz,
_{DMSO-d 6) δppm 1.85~2.06 (} 4
H, m), 2.19 to 2.34 (8H, m),
3.65 to 3.73 (2H, m), 7.59 (1
H, s), 8.16 (1H, s), 8.36
(2H, d); MS (FAB) m / z 469 (M ⁺
+1); Elemental analysis _{C 25 H 20 N 6 S 2} · 3 / 4H 2 O Calculated (%) C, 62.28; H , 4.49;
N, 17.43, measured value (%) C, 62.46;
H, 4.38; N, 17.49.

[Example 53] 5- (5- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -3- (1
H-tetrazol-5-yl) phenyl) -1H-tetrazole: (Step 1) 5- (5-iodo-3-(-2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl)- Synthesis of 2- (4-methoxybenzyl) -2H-tetrazole 5- (5-iodo-3-(-2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl) -1
H-tetrazole is treated as in step 3 of example 1,
5- (5-iodo-3-(-2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl) -2
-(4-Methoxybenzyl) -2H-tetrazole was obtained. 183-186 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.80 (6H, s), 5.74
(4H, s), 6.91 (4H, d), 7.3
9 (4H, d), 8.56 (2H, d), 8.8
2-8.83 (1H, m).

(Step 2) 5- (5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -3- (1H-
Synthesis of tetrazol-5-yl) phenyl) -1H-tetrazole 5- (5-iodo-3-(-2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl) -2
-(4-methoxybenzyl) -2H-tetrazole and 4
-Cyclobutyl-2-ethynylthiazole was treated as in step 4 of example 1 and subsequently treated as in step 5 of example 1 to give the title compound. Melting point> 300 ° C. (recrystallization solvent: chloroform-ethanol-n-hexane); IRνmax cm ⁻¹ 2220;
NMR (400 MHz, DMSO-d ₆ ) δ ppm
1.88 to 2.04 (2H, m), 2.23 to 2.
35 (4H, m), 3.66 to 3.74 (1H,
m), 7.61 (1H, s), 8.46 (2H,
d), 8.86~8.87 (1H, m ); Elemental analysis _{C 17 H 13 N 9 S ·} 1 / 2H 2 O Calculated (%)
C, 53.12; H, 3.67; N, 32.79,
Measured value (%) C, 53.25; H, 4.05;
N, 33.06.

Example 54 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-methoxyphenyl) -1H-tetrazole: (Step 1) Synthesis of 5- (3-iodo-2-methoxyphenyl) -2- (4-methoxybenzyl) -2H-tetrazole 5- (3-Iodo-2-methoxyphenyl) -1H-tetrazole was treated as in step 3 of Example 1 to give 5-
(3-Iodo-2-methoxyphenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained. Melting point 65-69 ° C (recrystallization solvent: chloroform-n-
Hexane); NMR (400 MHz, CDCl ₃ ) δ
ppm 3.78 (3H, s), 3.80 (3H, s)
s), 5.77 (2H, s), 6.88-6.
91 (2H, m), 6.97 (1H, t),
7.39 to 7.41 (2H, m), 7.90 (1
H, dd), 8.02 (1H, dd); MS
(EI) m / z 422 (M ⁺ ); Elemental analysis value C ₁₆ H ₁₅
Calculated value of IN ₄ O ₂ (%) C, 45.52; H,
3.58; N, 13.27, measured value (%) C, 4
5.69; H, 3.75; N, 13.48.

(Step 2) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methoxyphenyl) -1H-tetrazole 5- (3-iodo-2-methoxyphenyl) -2- (4
-Methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were used in Step 4 of Example 1.
Then, this was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 153-155 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2216; N
MR (400 MHz, DMSO-d ₆ ) δ ppm 1.8
5 to 2.34 (6H, m), 3.65 to 3.73
(1H, m), 4.01 (3H, s), 7.42
(1H, t), 7.59 (1H, s), 7.88
(1H, dd), 8.12 (1H, dd); M
S (EI) m / z 337 (M ^<+> ); Elemental analysis _C17.
H ₁₅ N ₅ OS Calculated (%) C, 60.52; H,
4.48; N, 20.76, measured value (%) C, 6
0.34; H, 4.53; N, 20.60.

Example 55 Ethyl 4- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl-2- (1
H-tetrazol-5-yl) phenoxyacetate: (Step 1) Ethyl 4- (2-iodo-2- (1-
(4-methoxybenzyl) -1H-tetrazole-5
Il) phenoxyacetate and ethyl 4- (2
-Iodo-2- (2- (4-methoxy-5-yl) -2
Synthesis of H-tetrazol-5-yl) phenoxyacetate 4- (2-Iodo-2- (1H-tetrazol-5-yl) phenoxyacetate was treated in the same manner as in Step 3 of Example 1 to give 4- (2- Iodo-2- (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) phenoxyacetate and ethyl 4- (2-iodo-2-
(2- (4-Methoxy-5-yl) -2H-tetrazol-5-yl) phenoxyacetate was obtained as an approximately 1: 1 mixture. NMR (400 MHz, CDCl ₃ ) δ ppm 1.2
6 and 1.29 (3H, each t),
3.76 and 3.79 (3H, eachs),
4.23 and 4.25 (2H, each
q), 4.59 and 4.70 (2H, s),
5.58 and 5.75 (2H, each
s), 6.63 and 6.72 (1H, eac
hd), 6.74-6.76 and 6.88-
6.90 (2H, each m), 6.98-7.0.
0 and 7.38 to 7.41'2H, each
m), 7.52 (1 / 2H, d), 7.67 an
d 7.76 (1H, each dd), 8.27
(1 / 2H, d).

(Step 2) Ethyl 4- (2- (4-cyclobutyl-2-thiazolyl) ethynyl-2- (1H-
Synthesis of tetrazol-5-yl) phenoxyacetate Ethyl 4- (2-iodo-2- (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) phenoxyacetate and ethyl 4- (2-iodo-2) − (2-
(4-methoxybenzyl) -2H-tetrazole-5
Il) a mixture of phenoxyacetate (1: 1) and 4-
Cyclobutyl-2-ethynylthiazole was treated as in step 4 of example 1 and subsequently treated as in step 5 of example 1 to give the title compound. 176-178 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2216,17
30; NMR (400 MHz, DMSO-d ₆ ) δp
pm 1.26 (3H, t), 1.84 to 2.33
(6H, m), 3.63 to 3.71 (1H, m),
4.17 (2H, q), 5.13 (2H, q)
s), 7.34 (1H, d), 7.52 (1H,
s), 7.83 (1H, d), 8.31 (1
H, s); MS (EI) m / z 409 (M +);
Elemental analysis value Calculated value of C ₂₀ H ₁₉ N ₅ O ₃ S (%) C, 5
H, 4.68; N, 17.10, measured value (%) C, 58.67; H, 4.68; N, 1
7.16.

Example 56 4- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl-2- (1H-tetrazol-5-yl) phenoxyacetic acid: ethyl 4-
To 350 mg of (2- (4-cyclobutyl-2-thiazolyl) ethynyl-2- (1H-tetrazol-5-yl) phenoxyacetate, 5 ml of THF and 10 ml of a 0.25N aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 1 hour. The solution is poured into 100 ml of water, and 10 ml of 1N hydrochloric acid is added.
Was added. The precipitated crystals were collected by filtration, washed with water and dried. The crude crystals were recrystallized from chloroform-ethanol to give 290 mg of the title compound as crystalline powder. Melting point 251 to 255 ° C; IRνmax cm ^-1 221
6,1720; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.86 to 2.34 (6H, m),
3.63 to 3.71 (1H, m), 5.06 (2
H, s), 7.34 (1H, d), 7.52
(1H, s), 7.85 (1H, dd), 8.
34 (1H, d); MS (EI) m / z 381
(M ⁺ ); Elemental analysis value Calculated value for C ₁₈ H ₁₅ N ₅ O ₃ S (%) C, 56.68; H, 3.96; N, 18.
36, measured value (%) C, 56.54; H, 4.1
0; N, 18.14.

[Example 57] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-hydroxyphenyl) -1H-tetrazole: (Step 1) Synthesis of 5- (2-hydroxy-3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole 5 -(2-hydroxy-3-iodophenyl) -1H-
The tetrazole was treated as in step 3 of Example 1 with 2 equivalents of 4-methoxybenzyl chloride and potassium carbonate to give 5- (2-hydroxy-3-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 3.7
3. 8 (3H, s), 3.82 (3H, s),
89 (2H, s), 5.73 (2H, s),
6.84 to 6.88 (4H, m), 6.99 (1
H, t), 7.32 to 7.34 (2H, m),
7.37 to 7.40 (2H, m), 7.94 (1
H, dd), 8.04 (1H, dd).

(Step 2) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-hydroxyphenyl) -1H-tetrazole 5- (2-hydroxy-3-iodophenyl)- 2-
(4-methoxybenzyl) -2H-tetrazole and 4-
Cyclobutyl-2-ethynylthiazole was treated as in step 4 of example 1 and subsequently treated as in step 5 of example 1 to give the title compound. 195-199 ° C (decomp.) (Recrystallization solvent: chloroform); IRν max cm ⁻¹ 3116,2
980, 2948, 2216, 1616, 1588, 1
554, 1512; NMR (400 MHz, DMSO
−d ₆ ) δ ppm 1.84 to 2.34 (6H, m);
3.63 to 3.72 (1H, m), 7.16 (1
H, t), 7.52 (1H, s), 7.75
(1H, dd), 8.04 (1H, dd); MS
(EI) m / z 323 (M ⁺ ); Elemental analysis value C ₁₆ H
Calculated for ₁₃ N ₅ OS (%) C, 58.61; H,
4.15; N, 21.36, measured value (%) C, 5
8.69; H, 4.13; N, 21.04.

[Example 58] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-isopropoxyphenyl) -1H-tetrazole: (Step 1) 5- (3-Iodo-2-isopropoxyphenyl) -1- (4-methoxybenzyl) -1H-tetrazole Synthesis of 5- (3-iodo-2-isopropoxyphenyl) -1
H-tetrazole is treated as in step 3 of example 1,
5- (3-iodo-2-isopropoxyphenyl) -1
-(4-Methoxybenzyl) -1H-tetrazole was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.0
3. 5 (6H, d), 3.71 (3H, s),
05-4.06 (1H, m), 5.51 (2H,
s), 6.68-6.71 (2H, m), 6.8
9-6.92 (2H, m), 6.91 (1H,
t), 7.29 (1H, dd), 7.99 (1
H, dd).

(Step 2) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-isopropoxyphenyl) -1H-tetrazole 5- (3-iodo-2-isopropoxy) Phenyl) -1
-(4-methoxybenzyl) -1H-tetrazole and 4
-Cyclobutyl-2-ethynylthiazole was treated as in step 4 of example 1 and subsequently treated as in step 5 of example 1 to give the title compound. Melting point 193 to 196 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 3096, 2976, 2216, 1600; NMR
(400 MHz, CDCl ₃ ) δ ppm 1.33 (6
H, d), 1.92-2.45 (6H, m),
3.72 to 3.80 (1H, m), 5.10 to 5.1
8 (1H, m), 7.04 (1H, s), 7.
28 (1H, t), 7.66 (1H, d),
8.37 (1H, d), 13.30 (1H, br)
MS (EI) m / z 365 (M ⁺ ); Elemental analysis: calculated for C ₁₉ H ₁₉ N ₅ OS (%) C, 62.
H, 5.24; N, 19.16, measured value (%) C, 62.45; H, 5.27; N, 1
9.29.

[Example 59] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -6-methylphenyl) -1H-tetrazole (Step 1) 5- (3-iodo-6-methylphenyl)
Synthesis of 2- (4-methoxybenzyl) -2H-tetrazole 5- (3-Iodo-6-methylphenyl) -1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to give 5- (3
-Iodo-6-methylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained. Melting point 67-69 ° C (recrystallization solvent: ethanol-water);
NMR (400 MHz, CDCl ₃ ) δ ppm
33 (6H, d), 2.56 (3H, s),
3.81 (3H, s), 5.75 (2H, s),
6.21 (2H, d), 7.04 (1H, d),
7.39 (2H, d), 7.65 (1H, d)
d), 8.33 (1H, d).

(Step 2) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole 3-iodo-6-methylphenyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to give 5- (3- (2- (4-cyclobutyl-
2-thiazolyl) ethynyl) -6-methylphenyl)-
2- (4-Methoxybenzyl) -2H-tetrazole was obtained as a yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.00 (1H, m), 2.00 to 2.10 (1
H, m), 2.30 to 2.50 (4H, m),
2.65 (3H, s), 3.60 to 3.80 (1
H, m), 3.81 (3H, s), 5.76
(2H, s), 6.92 (1H, s), 6.9
3. (2H, d), 7.31 (1H, d),
42 (2H, dd), 7.55 (1H, dd),
8.25 (1H, d).

(Step 3) Synthesis of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methylphenyl) -1H-tetrazole 5- (3- (2- (4-cyclobutyl) -2-Thiazolyl) ethynyl) -6-methylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 131-132 ° C (decomp.) (Recrystallization solvent: chloroform); IRνmax cm ⁻¹ 1662.1
586, 1390, 1286, 994; NMR (40
_{0MHz, DMSO-d 6) δppm} 1.80~2.
00 (1H, m), 2.00 to 2.10 (1H,
m), 2.20 to 2.40 (4H, m), 2.5
6 (3H, s), 3.60 to 3.70 (1H,
m), 7.54 (1H, s), 7.56 (1H,
d), 7.76 (1H, dd), 8.02 (1
H, br), 8.12 (1H, s); MS (F
AB) m / z 322 (M ⁺⁺ 1); Elemental analysis
_{C 17 H 15 N 5 S ·} H 2 O Calculated (%) C, 52.3
8; H, 3.97; N, 15.42, measured value (%) C, 52.42; H, 4.04; N, 1
5.51.

[Example 60] 5- (2- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-1H-tetrazole: (Step 1) 5- (2-iodophenyl) -2- (4-
Synthesis of methoxybenzyl) -2H-tetrazole 5- (2-Iodophenyl) -1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to give 5- (2-Iodophenyl) -2- (4-methoxybenzyl)- 2H-tetrazole was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 3.8
5. 0 (3H, s), 5.77 (2H, s),
88-6.92 (2H, d), 7.11-7.15
(1H, m), 7.40 to 7.45 (3H,
m), 7.71 to 7.73 (1H, m), 8.0
0-8.02 (1H, m).

(Step 2) 5- (2- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of-(4-methoxybenzyl) -2H-tetrazole 5- (2-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-
The ethynylthiazole was treated in the same manner as in Step 4 of Example 1 to give 5- (2- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole. Obtained as a brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
1-2.08 (2H, m), 2.30-2.39 (4
H, m), 3.68 to 3.73 (1H, m),
3.77 (3H, s), 5.79 (2H, s),
6.81 to 6.84 (2H, m), 6.96 (1
H, s), 7.41 to 7.43 (2H, m),
7.43 to 7.52 (2H, m), 7.72 to 7.
75 (1H, m), 8.13-8.15 (1H,
m).

(Step 3) 5- (2- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1
Synthesis of H-tetrazole 5- (2- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1. To give the title. 146-147 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 2216; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.82 to 2.04 (2H, m),
2.18 to 2.46 (4H, m), 3.61 to 3.46.
6. 70 (1H, m), 7.53 (1H, s),
67-7.73 (2H, m), 7.88-7.91
(2H, m); MS (FAB) m / z 308 (M ⁺
+1); calculated value of elemental analysis value C ₁₆ H ₁₃ N ₅ S (%)
C, 62.51; H, 4.26; N, 22.79,
Measured value (%) C, 62.09; H, 4.28;
N, 22.56.

[Example 61] 5- (4- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-1H-tetrazole: (Step 1) 5- (4-Iodophenyl) -2- (4-
Synthesis of (methoxybenzyl) -2H-tetrazole 5- (4-Iodophenyl) -1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to give 5- (4-Iodophenyl) -2- (4-methoxybenzyl)- 2H-tetrazole was obtained as an oil. 122-123 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.79 (3H, s), 5.72
(2H, s), 6.88-6.91 (2H,
d), 7.36-7.39 (3H, m), 7.7
9-7.86 (4H, m); MS (FAB) m / z
393 (M ⁺ +1); Elemental analysis C ₁₅ H ₁₃ IN ₄
Calculated value of S (%) C, 45.93; H, 3.34;
N, 14.29; measured value (%) C, 46.13;
H, 3.35; N, 14.47.

(Step 2) 5- (4- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of-(4-methoxybenzyl) -2H-tetrazole 5- (4-iodophenyl) -2- (4-methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-
The ethynylthiazole was treated in the same manner as in Step 4 of Example 1 to give 5- (4- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole. Obtained as a brown oil. 140-141 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 1.91 to 2.08 (2H, m),
2.29-2.39 (4H, m), 3.65-3.
74 (1H, m), 3.97 (3H, s),
5.73 (2H, s), 6.90 (2H, d),
6.96 (1H, s), 7.38 (2H, d),
7.67 (2H, d), 8.14 (2H, d)
m); MS (FAB) m / z 428 (M + +
1); Elemental analysis value Calculated value of C ₂₄ H ₂₁ N ₅ OS (%)
C, 67.43; H, 4.95; N, 16.38,
Measured value (%) C, 67.15; H, 4.99;
N, 16.12.

(Step 3) 5- (4- (4- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1
Synthesis of H-tetrazole 5- (4- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1. To give the title. Melting point: 166 to 167 ° C. (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 2208; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.86 to 2.03 (2H, m),
2.21-2.33 (4H, m), 3.63-3.3.
72 (1H, m), 7.56 (1H, s), 7.
89 (2H, d), 8.12 (2H, d); M
S (FAB) m / z 308 (M + +1); Calculated elemental analysis _{C 16 H 13 N 5 S (} %) C, 62.51;
H, 4.26; N, 22.79, measured value (%)
C, 62.31; H, 4.28; N, 22.60.

[Example 62] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -6- (N
-Methyl-N-trifluoroacetyl) aminophenyl) -1H-tetrazole: (Step 1) 5- (3-Iodo-6- (N-methyl-N
Synthesis of-(trifluoroacetyl) amino) benzonitrile 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6- (N-methyl-N-trifluoroacetyl) amino) benzonitrile and 4 -Cyclobutyl-2-ethynylthiazole was treated in the same manner as in Step 4 of Example 1 to obtain 5- (3-iodo-6- (N-methyl-N-trifluoroacetyl) amino) benzonitrile. 94-96 ° C (recrystallization solvent: chloroform-n-
Hexane); NMR (400 MHz, CDCl ₃ ) δ
ppm 1.85 to 2.45 (6H, m), 3.44
(3H, s), 3.72 (1H, m), 7.0
6. 5 (1H, s), 7.42 (1H, d),
87 (1H, d), 7.97 (1H, s); M
S (FAB) m / z 390 (M + +1); Elemental analysis _{C 19 H 14 F 3 N 3} OS Calculated (%) C, 58.6
H, 3.62; N, 10.79, measured value (%) C, 58.18; H, 3.87; N, 1
0.57.

(Step 2) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6- (N-methyl-N-trifluoroacetyl) aminophenyl)-
Synthesis of 1H-tetrazole To 396 mg of 2,6-urtidine and 3 ml of DMF, 0.095 ml of trifluoroacetic acid was added under ice-cooling and stirring. After stirring this at room temperature for 30 minutes, sodium azide 80m
g was further added and the mixture was further stirred at room temperature for 1 hour. 5-
320 mg of (3-iodo-6- (N-methyl-N-trifluoroacetyl) amino) benzonitrile was added, and 7
Stirred at 0-75 ° C for 6 hours. After cooling, the reaction solution was poured into 50 ml of 2N hydrochloric acid. The precipitated crystals are collected by filtration, washed with water,
Dried. The crude crystals were recrystallized from ether-n-hexane to give 270 mg of the title compound as needles. Melting point 155-156 ° C; IRνmax cm ^-1 224
4,1728,1714; NMR (400 MHz, C
DCl ₃₎ δppm 1.93~2.45 (6H,
m), 3.47 (3H, s), 3.70 (1H,
m), 7.00 (1H, s), 7.47 (1
H, d), 8.58 (1H, dd), 9.08
(1H, d); MS (FAB) m / z 433 (M
⁺ +1); Elemental analysis value Calculated value for C ₁₉ H ₁₅ N ₆ OS (%) C, 52.77; H, 3.50; N, 1
9.44, measured value (%) C, 53.10; H,
3.83; N, 19.61.

[Example 63] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -6-methylaminophenyl) -1H-tetrazole: 5- (3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6- (N-methyl-N-trifluoroacetyl)
(Aminophenyl) -1H-tetrazole (160 mg), 0.5N sodium carbonate aqueous solution (3 ml) and methanol (3)
Then, the mixture was stirred at room temperature for 5 hours. 0.5N reaction solution
The mixture was poured into hydrochloric acid (10 ml), and the precipitated crystals were collected by filtration. The crude crystals were recrystallized from chloroform-ethanol to give the title compound as needles. Melting point 157-161 ° C; IRνmax cm ^-1 221
6; NMR (400 MHz, CDCl ₃ ) δ ppm
1.92 to 2.45 (6H, m), 2.99 (3
H, s), 3.70 (1H, m), 4.84
(1H, br), 6.72 (1H, d), 6.9
4 (1H, s), 8.16 (1H, brd),
8.62 (1H, brs); MS (FAB) m
/ Z 337 (M ⁺⁺ 1).

Example 64 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -6-trifluoroacetoaminophenyl) -1H-tetrazole: 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-trifluoroacetoamino) benzo The nitrile was treated as in step 2 of example 62 to give the title. Melting point 210-212 ° C (recrystallization solvent: chloroform-
Ethanol); NMR (400 MHz, DMSO-d)
₆ ) δ ppm 1.85 to 2.40 (6H, m),
3.70 (1H, m), 7.14 (1H, s),
7.76 (1H, s), 7.78 (1H, d)
d), 8.47 (1H, d), 8.70 (1H,
d), 12.59 (1H, s); MS (FA
B) m / z 418 (M ⁺⁺ 1); Elemental analysis _C18
Calculated _{H 13 F 3 N 6 OS (} %) C, 51.67;
H, 3.13; N, 20.09, measured value (%)
C, 51.51; H, 3.33; N, 19.97.

[Example 65] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -6-aminophenyl) -1H-tetrazole: 5- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) -6
-Trifluoroacetaminophenyl) -1H-tetrazole was treated in the same manner as in Example 63 to obtain the title compound. 128-136 ° C (recrystallization solvent: chloroform-
Ethanol -n- hexane); IRνmax cm ^-1 2
196; NMR (400 MHz, CDCl ₃ ) δpp
m 1.83 to 2.45 (6H, m), 3.83
(1H, m), 6.72 (1H, d), 7.04
(1H, s), 7.27 (1H, m), 8.0
3 (1H, d); MS (FAB) m / z 323
(M ⁺ +1); calculated value of elemental analysis value C ₁₆ H ₁₄ N ₆ S (%) C, 59.61; H, 4.38; N, 2
6.07, measured value (%) C, 59.78; H,
4.79; N, 25.24.

[Example 66] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-acetoxymethylphenyl) -1H-tetrazole: (Step 1) 5- (3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) -2-acetoxymethylbenzonitrile 5- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) -2-acetoxymethylbenzonitrile was obtained. Melting point 84-87 ° C (recrystallization solvent: chloroform-n-
Hexane); NMR (400 MHz, CDCl ₃ ) δ
ppm 1.87-2.45 (6H, m), 3.71
(1H, m), 5.49 (2H, s), 7.0
6. 3 (1H, s), 7.49 (1H, t), 7.
72 (1H, d), 7.85 (1H, d); M
S (FAB) m / z 337 (M + +1); Elemental analysis _{C 19 H 16 N 2 O 2} S · 1 / 4H 2 O Calculated (%)
C, 66.94; H, 4.88; N, 8.22,
Measured value (%) C, 66.80; H, 4.83;
N, 7.78.

(Step 2) 5- (3- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) -2-acetoxymethylbenzonitrile was treated in the same manner as in Step 2 of Example 62 to obtain the title compound. 128-136 ° C (recrystallization solvent: chloroform-
Ethanol -n- hexane); IRνmax cm ^-1 2
232, 1716; NMR (400 MHz, CDCl
₃ ) δ ppm 1.76 to 2.32 (6H, m),
1.95 (3H, s), 3.55 (1H,
m), 5.25 (1H, d), 6.88 (1H,
s), 7.55 (1H, t), 7.81 (1
H, m), 7.85 (1H, m); MS (FA
B) m / z 380 (M ⁺⁺ 1); Elemental analysis C ₁₉ H
₁₇ N ₅ O ₂ Calculated S (%) C, 60.19; H,
4.52; N, 18.46, measured value (%) C, 6
0.61, H, 4.81; N, 18.48.

Example 67 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-hydroxymethylphenyl) -1H-tetrazole: 5-
(3- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) -2-acetoxymethylphenyl) -1H-tetrazole was treated in the same manner as in Example 63 to obtain the title compound. 255-259 ° C (recrystallization solvent: chloroform-
Ethanol); NMR (400 MHz, DMSO-d)
₆ ) δ ppm 1.95 to 2.48 (6H, m),
3.50 (1H, m), 5.83 (2H, s),
7.53 (1H, brs), 7.67 (1H, brs)
t), 8.04 (1H, t), 8.17 (1
H, brs), 8.72 (1H, d); MS
(FAB) m / z 338 ( M + +1); Elemental analysis _{C 17 H 15 N 5 OS ·} 1 / 2H 2 O Calculated (%) C,
H, 4.66; N, 20.21; measured value (%) C, 58.72; H, 4.46; N,
20.24.

[Example 68] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-2-acetyl-2H-tetrazole: 5- (3- (2
-(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1H-tetrazole (615 mg) was treated with acetic anhydride (5).
ml and pyridine (1 ml) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into 100 ml of 1N hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water and dried. The crude crystals were recrystallized from ether-n-hexane to give 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-acetyl-2H-tetrazole. Melting point 110-112 ° C; IRν max cm ^-1 221
6,1778; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.90 to 2.42 (6H, m),
3.03 (3H, s), 3.69 to 3.76 (1
H, m), 6.99 (1H, s), 7.56
(1H, t), 7.67 (1H, dt), 8.
30 (1H, dt), 8.52 (1H, t);
MS (EI) m / z 349 (M ^<+> ); Elemental analysis C
₁₈ H ₁₅ Calculated _{N 5 OS (%) C,} 61.87; H,
4.33; N, 20.04, measured value (%) C, 6
1.87; H, 4.49; N, 20.06.

[Example 69] 3- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-4H- [1,2,4] oxadiazol-5-one: (Step 1) 3- (3-iodophenyl) -4- (4-
Synthesis of (methoxybenzyl)-[1,2,4] oxadiazol-5-one 3, and treated with 3- (3-iodophenyl) -4- (4-methoxybenzyl)-[1,2,4] oxadiazole-5
The -one was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 3.8
5. 0 (3H, s), 4.74 (2H, s),
84 to 6.86 (2H, m), 7.03 to 7.05
(2H, m), 7.23 (1H, t), 7.4
6. 1 (1H, d), 7.73 (1H, s),
91 (1H, d).

(Step 2) 3- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4
Synthesis of-(4-methoxybenzyl)-[1,2,4] oxadiazol-5-one 3- (3-iodophenyl) -4- (4-methoxybenzyl)-[1,2,4] oxadi Example 1 was conducted using azole-5-one and 4-cyclobutyl-2-ethynylthiazole.
And then treated in the same manner as in Step 4 of 3- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4.
-(4-Methoxybenzyl)-[1,2,4] oxadiazol-5-one was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.40 (6H, m), 3.68 to 3.79 (1
H, m), 3.76 (3H, s), 4.77.
(2H, s), 6.81 to 6.83 (2H, s)
m), 7.01 (1H, s), 7.01-7.0.
6. 3 (2H, m), 7.45 (1H, d), 7.
50 (1H, t), 7.65 (1H, s),
7.77 (1H, d).

(Step 3) 3- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4
Synthesis of H- [1,2,4] oxadiazol-5-one 3- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (4-methoxybenzyl)-[ [1,2,4] oxadiazol-5-one was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 246-249 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2224,17
82; NMR (400 MHz, DMSO-d ₆ ) δp
pm 1.84 to 2.34 (6H, m), 3.64
~ 3.72 (1H, m), 7.57 (1H,
s), 7.69 (1H, t), 7.91 (1H,
d), 7.92 (1H, d), 8.07 (1
H, s), 13.01 (1H, s); MS (E
I) m / z 323 (M ⁺ ); Elemental analysis: C ₁₇ H ₁₃ N
₃ O ₂ Calculated S (%) C, 63.14; H, 4.0
5; N, 12.99, measured value (%) C, 62.7
4; H, 4.07; N, 12.61.

Example 70 (Z) -5- (3- (2
-(4-Cyclobutyl-2-thiazolyl) ethynyl) benzylidene) -2-thioxothiazolidine-4-one: (Step 1) Synthesis of 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzaldehyde 3- Iodobenzaldehyde and 4-cyclobutyl-2
-Ethynylthiazole was treated as in step 4 of example 1 to give 3- (2- (4-cyclobutyl-2-thiazolyl)
(Ethynyl) benzaldehyde was obtained. Melting point 77-79 ° C; NMR (400 MHz, CDCl
₃ ) δ ppm 1.89 to 2.43 (6H, m),
3.67 to 3.75 (1H, m), 6.99 (1
H, s), 7.56 (1H, t), 7.83
7. (1H, dt), 7.91 (1H, dt),
09 (1H, t), 10.02 (1H, s).

(Step 2) (Z) -5- (3- (2-
Synthesis of (4-cyclobutyl-2-thiazolyl) ethynyl) benzylidene) -2-thioxothiazolidine-4-one 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzaldehyde 535 mg, rhodanin 266 m
g and 656 mg of sodium acetate were added with 20 ml of acetic acid, and the mixture was refluxed for 4 hours. After cooling, the reaction solution was
and the precipitated crystals were collected. This was purified by column chromatography using silica gel (eluent: chloroform: ethyl acetate = 20: 1), and recrystallized from chloroform-n-hexane to obtain the title compound as a pale yellow crystalline powder. 198-201 ° C; IRνmax cm ^-1 220
8,1732; NMR (400 MHz, CDCl ₃ )
δ ppm 1.91 to 2.41 (6H, m), 3.6
9 to 3.77 (1H, m), 7.00 (1H,
s), 7.49-7.51 (2H, m), 7.6
3 (1H, s), 7.64 to 7.67 (1H,
m), 7.69 (1H, s), 9.77 (1H,
MS (EI) m / z 382 (M ⁺ ); Elemental analysis value Calculated value for C ₁₉ H ₁₄ N ₂ OS ₃ (%) C, 5
H, 3.69; N, 7.32, found (%) C, 59.52; H, 3.66; N, 7.2.
2.

[Example 71] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-[1,2,4] oxadiazolin-3-one: (Step 1) 5- (3-Iodophenyl) -2- (4-
Synthesis of methoxybenzyl)-[1,2,4] oxadiazoline-3-one 5- (3-iodophenyl)-[1,2,4] oxadiazoline-3-one was prepared by treating Treatment in the same manner gave 5- (3-iodophenyl) -2- (4-methoxybenzyl)-[1,2,4] oxadiazolin-3-one as a red-brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 3.8
5. 0 (3H, s), 5.32 (2H, s),
92 (2H, d), 7.42 (1H, d),
7.85 (1H, d), 7.94 (1H, t),
8.06 (1H, d), 8.43 (1H, s).

(Step 2) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of-(4-methoxybenzyl)-[1,2,4] oxadiazolin-3-one 5- (3-iodophenyl) -2- (4-methoxybenzyl)-[1,2,4] oxadiazo Example 1 was performed using phosphorus-3-one and 4-cyclobutyl-2-ethynylthiazole.
And then treated in the same manner as in Step 4 of 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2.
-(4-Methoxybenzyl)-[1,2,4] oxadiazolin-3-one was obtained as a reddish brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.00 (1H, m), 2.00 to 2.10 (1
H, m), 2.20 to 2.40 (4H, m),
3.60 to 3.80 (1H, m), 3.82 (3
H, s), 5.34 (2H, s), 6.92
(2H, d), 6.99 (1H, s), 7.4
6. 4 (2H, d), 7.53 (1H, t), 7.
7. 78 (1H, d), 8.09 (1H, d),
30 (1H, s).

(Step 3) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl)-
Synthesis of [1,2,4] oxadiazolin-3-one 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl)-[1, [2,4] oxadiazolin-3-one was treated in the same manner as in step 5 of example 1 to obtain the title compound. 208-212 ° C (recrystallization solvent: chloroform-
Methanol -n- hexane); IRνmax cm ^-1 1
600, 1470, 1380, 1248, 1136;
NMR (400 MHz, DMSO-d ₆ ) δ ppm
1.80 to 1.90 (1H, m), 1.90 to 2.
10 (1H, m), 2.20 to 2.40 (4H,
m), 3.60-3.80 (1H, m), 7.5
5 (1H, s), 7.61 (1H, t), 7.8
8. (1H, d), 8.03 (1H, d),
25 (1H, s), 10.66 (1H, br
s); MS (FAB) m / z 324 (M ⁺⁺ 1);
Elemental analysis value Calculated value for C ₁₇ H ₁₃ N ₃ O ₂ S.0.475 H ₂ O (%) C, 61.51; H, 4. 24;
N, 12.66; measured value (%) C, 61.92;
H, 4.64; N, 12.50.

[Example 72] 3- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-5-Hydroxyisoxazole: 3- (3-iodophenyl) -5-hydroxyisoxazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to obtain the title compound. 143-148 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 1.90 to 2.00 (1H, m),
2.00 to 2.10 (1H, m), 2.20 to 2.
40 (4H, m), 3.60-3.80 (1H,
m), 4.20 (2H, ds), 6.99 (1
H, s), 7.54 (1H, t), 7.56
(1H, d), 7.63 (1H, s), 7.66
(1H, d); MS (FAB) m / z 323 (M
⁺ +1).

[Example 73] 2- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-[1,3,4] oxadiazolin-5-one: 2-
(3-Iodophenyl)-[1,3,4] oxadiazolin-5-one and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to obtain the title compound. 186-190 ° C; NMR (400 MHz, DM
_{SO-d 6) δppm1.90~2.00 (1H} ,
m), 2.00 to 2.10 (1H, m), 2.20
~ 2.50 (4H, m), 3.60 ~ 3.80 (1
H, m), 7.00 (1H, s), 7.50 (1
H, t), 7.71 (1H, d), 7.85
(1H, d), 8.08 (1H, s); MS
(FAB) m / z 324 ( M + +1); Elemental analysis _{C 17 H 13 N 3 O 2} S · 0.3H 2 O Calculated (%)
C, 63.44; H, 4. 02; N, 12.3
3, measured value (%) C, 63.15; H, 4.24;
N, 12.34.

[Example 74] 2- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-[1,2,4] oxadiazolidine-3,5-dione: 2- (3-iodophenyl)-[1,2,4] oxadiazolidine-3,5-dione and 4-cyclobutyl-
The 2-ethynylthiazole was treated in the same manner as in Step 4 of Example 1 to obtain the title compound. 141-145 ° C (decomp.); IRν
max cm ^-1 1738, 1574, 1358, 118
2; NMR (400 MHz, DMSO-d ₆ ) δpp
m 1.90 to 2.00 (1H, m), 2.00
2.10 (1H, m). 2.20 to 2.40 (4H,
m), 3.60-3.80 (1H, m), 6.9
6. (1H, s), 7.48 (1H, t),
61 (1H, d), 8.14 (1H, d),
8.47 (1H, s); MS (FAB) m / z 3
40 (M ⁺⁺ 1).

[Example 75] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) benzylidene) thiazolidine-2,4-dione: 3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) benzaldehyde and 2,4-thiazolinedione were treated as in Example 70 to give the title product. 198-201 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2212,17
48; NMR (400 MHz, CDCl ₃ ) δ ppm
1.89 to 2.44 (6H, m), 3.69 to
3.77 (1H, m), 7.00 (1H, s),
7.47 to 7.53 (2H, m), 7.63 to 7.
65 (1H, m), 7.73 (1H, s),
7.83 (1H, s), 9.09 (1H, s);
MS (EI) m / z 366 (M ^<+> ); Elemental analysis C
_{19 H 19 N 2 O 2 S} 2 2 · 1 / 4H 2 O Calculated (%)
C, 61.52; H, 3.94; N, 7.55,
Measured value (%) C, 61.51; H, 3.89; N,
7.31.

[Example 76] 1- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-4H-tetrazolin-5-one: (Step 1) 1- (3-Iodophenyl) -4- (2-
Synthesis of (trimethylsilyl) ethoxy) methyl-4H-tetrazolin-5-one 1- (3-iodophenyl) -4H-tetrazoline-5
-DMF 5 in 202 mg of potassium carbonate and 152 mg of potassium carbonate
Then, 133 mg of (2-chloromethoxyethyl) trimethylsilane was added thereto while stirring at 0 ° C. The mixture was stirred at the same temperature for 30 minutes and further at room temperature for 2 hours. The reaction solution was
It was poured into 0 ml and extracted with ethyl acetate. The extract was washed with saturated saline and dried over sodium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography using silica gel (eluent: chloroform: n-hexane = 1: 1) to give 1- (3-iodophenyl) -4.
-(2- (trimethylsilyl) ethoxy) methyl-4H
-Tetrazolin-5-one was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 0.0
2. 3 (9H, s), 0.99 (2H, t),
75 (2H, t), 5.39 (2H, s),
7.24 (1H, t), 7.70 to 7.73 (1
H, m), 7.97 to 7.99 (1H, m),
8.35 (1H, s).

(Step 2) 1- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4
Synthesis of H-tetrazolin-5-one 1- (3-iodophenyl) -4- (2- (trimethylsilyl) ethoxy) methyl-4H-tetrazoline-5
On and 4-cyclobutyl-2-ethynylthiazole were treated as in step 4 of Example 1, followed by DMF
3 ml of tetrabutylammonium fluoride (1.
(0M THF solution) (1 ml) was added and the mixture was stirred at 60 ° C for 2 hours. The reaction solution was poured into 1N hydrochloric acid (100 ml), and the precipitated crystals were collected by filtration. The crude crystals were recrystallized from chloroform-n-hexane to give the title compound as pale brown crystalline powder. 196-199 ° C; IRνmax cm ^-1 221
2,1742; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.91 to 2.46 (6H, m),
3.71 to 3.80 (1H, m), 7.01 (1
H, s), 7.52 (1H, t), 7.59
(1H, d), 7.99 (1H, d), 8.33
(1H, s); MS (FAB) m / z 323 (M
⁺ +1); Elemental analysis value Calculated value for C ₁₆ H ₁₃ N ₅ OS (%) C, 59.43; H, 4.05; N, 2
1.66, measured value (%) C, 59.06; H,
4.09; N, 21.33.

[Example 77] 4- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-1 or 2 or 3H- [1,2,3] -triazole: (step 1) ethyl 4- (3-bromophenyl) -1
Synthesis of H- [1,2,3] -triazole-5-carboxylate 1.11 g of sodium azide was suspended in 10 ml of DMF, and 1.45 of aluminum chloride was gradually added under ice-cooling and stirring. After stirring the reaction solution at room temperature for 1 hour, a solution of 1.3 g of ethyl propiolate in 5 ml of DMF was added dropwise over 5 minutes. After stirring the reaction at room temperature for 1 hour,
The mixture was further stirred at 60 ° C. for 30 minutes. After cooling, the reaction was poured into 100 ml of ice and 50 ml of 2M hydrochloric acid. The precipitated crystals were collected by filtration and air-dried. The crude crystals were dissolved in chloroform and purified by column chromatography using silica gel (eluent: chloroform: ethanol = 8: 2).
4- (3-bromophenyl) -1H- [1,2,3]-
1.52 g of triazole were obtained. NMR (400 MHz, CDCl ₃ ) δ ppm 1.3
9. (3H, t), 4.44 (2H, q),
34 (1H, t), 7.58 (1H, m),
7.84 (1H, d), 8.05 (1H, br)
s).

(Step 2) Ethyl 4- (3-bromophenyl) -1- (4-methoxybenzyl) -1H-
[1,2,3] -Triazole-5-carboxylate, ethyl 4- (3-bromophenyl) -2- (4-methoxybenzyl) -2H- [1,2,3] -triazole-5-carboxylate And ethyl 4- (3-bromophenyl) -3- (4-methoxybenzyl) -3H
Synthesis of-[1,2,3] -triazole-5-carboxylate Ethyl 4- (3-bromophenyl) -1H- [1,
2,3] -Triazole-5-carboxylate was treated as in step 3 of Example 1 to give ethyl 4- (3-bromophenyl) -1- (4-methoxybenzyl) -1H-
[1,2,3] -Triazole-5-carboxylate, ethyl 4- (3-bromophenyl) -2- (4-
Methoxybenzyl) -2H- [1,2,3] -triazole-5-carboxylate and ethyl 4- (3-
Bromophenyl) -3- (4-methoxybenzyl) -3
H- [1,2,3] -triazole-5-carboxylate was obtained as a mixture of the 1-, 2- and 3-positions. NMR (400 MHz, CDCl ₃ ) δ ppm 1.2
4 to 1.34 (3H, m), 3.78 (3H,
s), 4.25-4.45 (2H, m), 5.5
9-5.87 (2H, series of s),
6.83-7.97 (8H, m).

(Step 3) 4- (3-iodophenyl)
-1H- (4-methoxybenzyl) -1H- [1,2,
3] -triazole or 4- (3-iodophenyl) -2- (4-methoxybenzyl) -2H- [1,
2,3] -triazole or 4- (3-iodophenyl) -3- (4-methoxybenzyl) -3H- [1,
Synthesis of 2,3] -triazole The bromide of Step 3 was treated in the same manner as in Step 2 of Example 19, and purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 5: 1). ,
4- (3-iodophenyl), a single isomer at the 1-, 2-, or 3-position, deesterified simultaneously with halogen exchange
-1H- (4-methoxybenzyl) -1H- [1,2,
3] -triazole or 4- (3-iodophenyl) -2- (4-methoxybenzyl) -2H- [1,
2,3] -triazole or 4- (3-iodophenyl) -3- (4-methoxybenzyl) -3H-
[1,2,3] -Triazole was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 3.8
5. 2 (3H, s), 5.51 (2H, s),
93 (2H, d), 7.13 (1H, t),
7.27 (2H, d), 7.60 (1H, m),
7.70 (1H, d), 8.12 (1H, m).

(Step 4) 4- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1
or 2 or 3- (4-methoxybenzyl) -1
Synthesis of H- [1,2,3] -triazole The iodo compound obtained in Step 3 and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1, and
-(3- (2- (4-cyclobutyl-2-thiazolyl)
Ethynyl) phenyl) -1- (4-methoxybenzyl)
-1H- [1,2,3] -triazole, or 4-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl)-
2H- [1,2,3] -triazole, or 4-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (4-methoxybenzyl)-
3H- [1,2,3] -Triazole was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
5-2.43 (6H, m), 3.69 (1H,
m), 3.83 (3H, s), 5.52 (2H,
s), 6.94 (2H, d), 6.96 (1
H, s), 7.28 (2H, d), 7.42
(1H, t), 7.53 (1H, m), 7.63
(1H, s), 7.88 (1H, m), 7.9
5 (1H, t).

(Step 5) 4- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1
Synthesis of H- [1,2,3] -triazole The compound obtained in the above Step 3 was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 146-150 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2216; N
MR (400 MHz, CDCl ₃ ) δ ppm 1.85
２2.45 (6H, m), 3.71 (1H,
m), 6.97 (1H, s), 7.47 (1H,
t), 7.59 (1H, d), 7.87 (1
H, d), 7.79 (1H, s), 8.05
(1H, br); MS (EI) m / z 306
(M ⁺ ); Elemental analysis value C ₁₇ H ₁₄ N ₄ S · 1 / 5H ₂ O
C, 65.68; H, 4.70;
N, 18.02, found (%) C, 65.83;
H, 4.67; N, 17.55.

Example 78 Ethyl 4- (3- (2
-(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1H- [1,2,3] -triazole-5
Carboxylate: (Step 1) Ethyl 3- (2- (4-cyclobutyl-
Synthesis of 2-thiazolyl) ethynyl) phenylpropiolic acid Ethyl 3-iodophenylpropiolic acid and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in step 4 of Example 1 to give ethyl 3- (2- (4- Cyclobutyl-2-thiazolyl) ethynyl) phenylpropiolic acid was obtained as a reddish brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.3
7 (3H, t), 1.85 to 2.45 (6H,
m), 3.70 (1H, m), 4.31 (2H,
q), 6.98 (1H, s), 7.38 (1
H, t), 7.59 (1H, d), 7.65
(1H, d), 7.79 (1H, s).

(Step 2) Ethyl 4- (3- (2-
Synthesis of (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1H- [1,2,3] -triazole-5-carboxylate Ethyl 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenylpropy The orthoacid was treated as in Example 77, Step 1, to give the title compound. 142-145 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2216,17
12; NMR (400 MHz, CDCl ₃ ) δ ppm
1.37 (3H, t), 1.85 to 2.45 (6
H, m), 3.73 (1H, m), 4.42
(2H, q), 6.99 (1H, s), 7.4
6. 5 (1H, t), 7.62 (1H, d),
89 (1H, d), 7.99 (1H, s); MS
(EI) m / z 378 ( M +); Elemental analysis C ₂₀ H ₁₈
Calculated value of N ₄ O ₂ S (%) C, 63.47; H,
4.79; N, 14.81, measured value (%) C, 6
3.37; H, 4.90; N, 14.55.

Example 79 4- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-1H- [1,2,3] -triazole-5-carboxylic acid: ethyl 4- (3- (2- (4-cyclobutyl-2
-Thiazolyl) ethynyl) phenyl) -1H- [1,
[2,3] -Triazole-5-carboxylate was treated in the same manner as in Example 56 to obtain the title compound. 142-145 ° C (recrystallization solvent: chloroform-
Ethanol); IRνmax cm ⁻¹ 2216,174
0; NMR (400 MHz, DMSO-d ₆ ) δpp
m 1.85 to 2.40 (6H, m), 3.68
(1H, m), 7.32 (1H, s), 7.54
(1H, t), 7.65 (1H, m), 7.9
5 (1H, br), 8.09 (1H, br);
MS (EI) m / z 350 (M ⁺ ); Elemental analysis value C
₁₈ H ₁₄ Calculated _{N 4 O 2 S (%)} C, 61.70;
H, 4.03; N, 15.99, measured value (%)
C, 61.84; H, 4.27; N, 15.71.

[Example 80] 4- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-1-Methyl-1H- [1,2,3] -triazole-
5-carboxylic acid: (Step 1) Ethyl 4- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1-methyl-1H- [1,2,3] -triazole-5- Carboxylate and ethyl 4- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-2-Methyl-2H- [1,2,3] -triazole-
Synthesis of 5-carboxylate Ethyl 4- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1H- [1,2,2
3] -triazole-5-carboxylate in Example 1
In place of 4-methoxybenzyl chloride in Step 3, the same treatment was carried out using methyl iodide, and the 1st: 2nd
As a 1: 1 mixture, ethyl 4- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-1-Methyl-1H- [1,2,3] -triazole-
5-carboxylate, and ethyl 4- (3- (2-
(4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methyl-2H- [1,2,3] -triazole-5-carboxylate was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.3
2 and 1.39 (3H, each t),
1.85 to 2.45 (6H, m), 3.70 (1
H, m), 4.31 and 4.36 (3H,
each s), 4.37 and 4.43 (2
H, each q), 6.96 (1H, s),
7.46 (1H, t), 7.64 (1H, br)
d), 7.78 and 7.88 (1H, each
br d), 7.97 and 8.07 (1H,
each brs).

(Step 2) 4- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1
-Methyl-1H- [1,2,3] -triazole-5-
Synthesis of Carboxylic Acid The mixture of the above-mentioned 1-methyl form and 2-methyl form was treated in the same manner as in Example 56 and recrystallized from chloroform-n-hexane to give the title compound. Melting point 142-145 [deg.] C .; IR? Max cm- ¹ 221
6; NMR (400 MHz, DMSO-d ₆ ) δpp
m 1.82 to 2.35 (6H, m), 3.68
(1H, m), 4.18 (3H, s), 7.4
9 (1H, t), 7.53 (1H, s), 7.6
2 (1H, d), 8.13 (1H, d), 8.4
4 (1H, s); MS (EI) m / z 364 (M
⁺ ).

[Example 81] 4- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-2-Methyl-2H- [1,2,3] -triazole-
5-carboxylic acid: Example of 4- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methyl-2H- [1,2,3] -triazole-5-carboxylate Treatment as in 56 gave the title. Melting point 142-145 [deg.] C .; IR? Max cm- ¹ 221
6; NMR (400 MHz, DMSO-d ₆ ) δpp
m 1.82 to 2.35 (6H, m), 3.67.
(1H, m), 4.10 (3H, s), 7.4
8 (1H, t), 7.53 (1H, s), 7.5
7 (1H, d), 8.17 (1H, d), 8.3
7 (1H, s); MS (EI) m / z 364 (M
⁺ ).

[Example 82] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-1- (2-methoxyethoxy) methyl-1H- [1,
2,3] -Triazole-4-carboxylic acid: (Step 1) Ethyl 5- (3-iodophenyl) -1
-(2-methoxyethoxy) methyl-1H- [1,2,2
3] -Triazole-4-carboxylate, ethyl
5- (3-iodophenyl) -2- (2-methoxyethoxy) methyl-2H- [1,2,3] -triazole-
4-carboxylate, and ethyl 5- (3-iodophenyl) -3- (2-methoxyethoxy) methyl-3
Synthesis of H- [1,2,3] -triazole-4-carboxylate Ethyl 5- (3-iodophenyl) -1H- [1,
2,3] -Triazole-4-carboxylate was treated in the same manner using 2- (2-methoxyethoxy) methyl chloride instead of 4-methoxybenzyl chloride in Step 3 of Example 1, and And a mixture of the 3-position ethyl 5- (3-iodophenyl) -1- (2-methoxyethoxy) methyl-1H- [1,2,3] -triazole-4-carboxylate, ethyl 5- (3-iodophenyl) -2- (2-methoxyethoxy) methyl-
2H- [1,2,3] -triazole-4-carboxylate, and ethyl 5- (3-iodophenyl)-
3- (2-methoxyethoxy) methyl-3H- [1,
[2,3] -Triazole-4-carboxylate was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.2
5 to 1.42 (3H, m), 3.25 to 3.40 (3
H, series of s), 3.36 (1H,
s), 3.54 (2H, m), 3.49-3.
85 (4H, m), 4.30-4.48 (2H,
m), 5.80-6.12 (3H, series o
fs), 7.15 to 8.23 (4H, m).

(Step 2) Ethyl 5- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1- (2-methoxyethoxy) methyl-1H-
Synthesis of [1,2,3] -triazole-4-carboxylate The iodo compound and 4-cyclobutyl-
The 2-ethynylthiazole was treated in the same manner as in Step 4 of Example 1, and the product was subjected to column chromatography using silica gel (eluent: n-hexane-ethyl acetate = 4: 1).
And ethyl 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1- (2
-Methoxyethoxy) methyl-1H- [1,2,3]-
The triazole-4-carboxylate was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.3
1 (3H, t), 1.88 to 2.43 (6H,
m), 3.36 (3H, s), 3.54 (2H,
m), 3.68 (1H, m), 3.82 (2
H, m), 4.35 (2H, q), 5.70
(2H, s), 6.97 (1H, s), 7.52
(1H, t), 7.57 (1H, m), 7.7
4 (1H, m), 7.76 (1H, m).

(Step 3) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1
-(2-methoxyethoxy) methyl-1H- [1,2,2
Synthesis of 3] -triazole-4-carboxylic acid Ethyl 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1- (2-methoxyethoxy) methyl-1H- [1,2 [3,-]-Triazole-4-carboxylate was treated in the same manner as in Example 56 to obtain the title compound. 143-146 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, DMSO-
d ₆ ) δ ppm 1.82 to 2.38 (6H, m),
3.23 (3H, s), 3.43 (2H, m),
3.64 (3H, m), 5.61 (2H,
s), 7.41 (1H, s), 7.59 (1H,
t), 7.67 (1H, br d), 7.75
(1H, brd), 7.84 (1H, brd)
s); MS (EI) m / z 439 (M ⁺⁺ 1).

Example 83 5- (2- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4-thiazolyl) -1H-tetrazole: (Step 1) 5- (2- (3-iodophenyl) -4-
Thiazolyl) -2- (4-methoxybenzyl) -2H-
Synthesis of tetrazole 5- (2- (3-iodophenyl) -4-thiazolyl)
-1H-Tetrazole was treated in the same manner as in Step 3 of Example 1 to give 5- (2- (3-iodophenyl) -4-thiazolyl) -2- (4-methoxybenzyl) -2H-tetrazole. Melting point 173 to 176 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.76 (3H, s), 6.13
(2H, s), 6.84 to 6.87 (2H, s)
m), 7, 25 (1H, t), 7.31 to 7.34
(2H, m), 7.84 (1H, d), 7.93
(1H, d), 8.32 (1H, s), 8.3
5 (1H, s); MS (EI) m / z 475 (M
⁺ +1); Elemental analysis value Calculated value for C ₁₈ H ₁₄ IN ₄ OS (%) C, 45.49; H, 2.97; N, 1
4.73, measured value (%) C, 45.46; H, 3.
06; N, 14.74.

(Step 2) 5- (2- (3- (2- (4
Synthesis of -cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4-thiazolyl) -1H-tetrazole 5- (2- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4-thiazolyl ) -2
-(4-methoxybenzyl) -2H-tetrazole and 4
-Cyclobutyl-2-ethynylthiazole was treated in the same manner as in Step 4 of Example 1 and subsequently treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Mp 156 to 159 ° C. (recrystallization solvent: chloroform) (decomp.); IRνmax cm -1 2216;
NMR (400 MHz, DMSO-d ₆ ) δ ppm
1.88-2.33 (6H, m), 3.65-3.
73 (1H, m), 7.57 (1H, s),
7, 69 (1H, t), 7.84 (1H, d),
8.17 (1H, d), 8.39 (1H, d)
s), 8.66 (1H, s); MS (FAB) m
/ Z 391 (M ⁺ +1); elemental analysis C ₁₉ H ₁₄ N ₆
Calculated _{S 2 (%) C, 58.44} ; H, 3.6
1; N, 21.52, measured value (%) C, 58.6
0; H, 3.34; N, 21.55.

[Example 84] 3- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
Benzoic acid: (Step 1) 3- (3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) -1-bromobenzene 4-Cyclobutyl-2-ethynylthiazole and 1-bromo-3-iodobenzene were treated as in Step 4 of Example 1 to give 3- (3- (2- ( 4-cyclobutyl-2-thiazolyl) ethynyl) -1-bromobenzene was obtained as an oil NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
5 to 2.45 (6H, m), 3.70 (1H,
m), 6.97 (1H, s), 7.24 (1H, s)
t), 7.52 (1H, m), 7.74 (1
H, s).

(Step 2) Synthesis of 3- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) benzaldehyde 3- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -1-Bromobenzene 600 mg, 3-
Formylphenylboronic acid 232 mg and tetrakis (triphenylphosphine) [0] palladium 109 mg in 2 Mcm −1 sodium carbonate aqueous solution 3.
5 ml and 25 ml of 1,2-dimethoxyethane were added,
The mixture was heated under reflux for 2 hours. After cooling, 100 m of water was added. Extracted with methylene chloride. The extract layer was washed with a saturated saline solution and dried over sodium sulfate. The residue obtained by distilling off the solvent was separated by column chromatography using silica gel (eluent: n-hexane-ethyl acetate = 3: 1) to give 3
-(3- (2- (4-cyclobutyl-2-thiazolyl)
325 mg of ethynyl) phenyl) benzaldehyde was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
5 to 2.45 (6H, m), 3.71 (1H,
m), 6.97 (1H, s), 7.49 (1H,
t), 7.58 to 7.67 (3H, m), 7.
84 to 7.92 (3H, m), 8.12 (1H,
t), 10.11 (1H, s).

(Step 3) Synthesis of 3- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) benzonitrile 3- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) ) Phenyl) benzaldehyde 300 m
g, 65 mg of hydroxylamine hydrochloride and 119 mg of sodium formate were added with 5 ml of formic acid and heated under reflux for 2 hours. After cooling, 50 ml of water was added to the reaction solution, which was extracted with methylene chloride. The extract layer was washed with a saturated saline solution and dried over sodium sulfate. The residue obtained by distilling off the solvent is subjected to column chromatography using silica gel (eluent: n
-Hexane-ethyl acetate = 9: 1) separated and 3- (3-
280 mg of (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) benzonitrile was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
7 to 2.45 (6H, m), 3.71 (1H,
m), 6.98 (1H, s), 7.48 (1H,
t), 7.54-7.94 (7H, m).

(Step 4) Synthesis of 3- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) benzoic acid 3- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) ) Phenyl) benzonitrile (250 mg), 4N aqueous sodium hydroxide solution (5 ml) and ethanol (10)
ml was added and the mixture was heated under reflux for 5 hours. After cooling, 1N
It was poured into 50 ml of hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and dried. The crude crystals were recrystallized from chloroform-ethanol to give the title compound as fine prism crystals. Melting point 119-120 ° C; IRνmax cm ^-1 221
6,1694; NMR (400 MHz, CDCl ₃ )
δ ppm 1.85 to 2.45 (6H, m), 3.7
6. 1 (1H, m), 6.97 (1H, s), 7.
45-8.14 (7H, m), 8.35 (1H, b
MS (EI) m / z 359 (M ⁺ );
Elemental analysis value C ₂₂ H ₁₇ N ₂ S calculated value (%) C, 73.
51; H, 4.77; N, 3.90, measured value (%)
C, 73.80; H, 5.00; N, 3.52.

[Example 85] 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-3-Ethylisoxazole-4-carboxylic acid: (Step 1) Synthesis of 5- (3-iodophenyl) -3-ethylisoxazole-4-carboxylate 750 mg of ethyl 3-iodopropiolic acid, 4 -Chlorophenyl isocyanic acid 1.19 g, 1-nitropropane 334 mg, and triethylamine 0.087 ml
To the mixture was added 30 ml of benzene, and the mixture was stirred for 2 days. The insoluble matter was removed by filtration, and the filtrate was distilled off. The residue was separated by column chromatography using silica gel (eluent: n-hexane-ethyl acetate = 10: 1) to give 856 mg of 5- (3-iodophenyl) -3-ethylisoxazol-4-carboxylate as a pale yellow oil. As obtained. NMR (400 MHz, CDCl ₃ ) δppm 1.3
3 (3H, t), 1.34 (3H, t), 2.
97 (2H, q), 4.31 (2H, q),
7.22 (1H, m), 7.83 (2H, m),
8.22 (1H, d).

(Step 2) Ethyl 5- (3- (2-
Synthesis of (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-ethylisoxazol-4-carboxylate 5- (3-iodophenyl) -3-ethylisoxazol-4-carboxylate And 4-cyclobutyl-2-
The ethynylthiazole was treated as in step 4 of Example 1 and treated with ethyl 5- (3- (2- (4-cyclobutyl-2).
-Thiazolyl) ethynyl) phenyl) -3-ethylisoxazole-4-carboxylate was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.3
3 (3H, t), 1.36 (3H, t), 1.
85 to 2.45 (6H, m), 2.98 (2H,
q), 3.70 (1H, m), 4.33 (2H,
q), 6.97 (1H, s), 7.49 (1
H, t), 7.72 (1H, d), 7.89 (1
H, d), 8.10 (1H, s).

(Step 3) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3
Synthesis of -ethylisoxazole-4-carboxylic acid ethyl 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-ethylisoxazole-4-carboxylate Was treated in the same manner as in Example 56 to obtain the title compound. 149-150 ° C (recrystallization solvent: ether);
IRνmax cm ⁻¹ 2224, 1710; NMR (4
00 MHz, CDCl ₃ ) δ ppm 1.37 (3H,
2. t), 1.85 to 2.43 (6H, m);
01 (2H, q), 3.71 (1H, m),
5.70 (1H, br), 6.98 (1H, br)
s), 7.47 (1H, t), 7.67 (1H,
d), 7.92 (1H, d), 8.08 (1
H, s); MS (EI) m / z 378 (M ^<+> );
Elemental analysis value Calculated value for C ₂₁ H ₁₈ N ₂ O ₃ S.1 / 2H ₂ O (%) C, 65.10; H, 4.94; N, 7.
23, measured value (%) C, 65.16; H, 4.7
8; N, 7.08.

Example 86 N- (1H-tetrazol-5-yl) -5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-ethylisoxazole -4-carboxamide: 5- (3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-ethylisoxazole-4-carboxylic acid 300 mg, 5-amino-1H-tetrazole 85 mg, and 1,1′-carbonyldiimidazole 1
DMF (5 ml) was added to 74 mg and the mixture was stirred at 80 to 85 ° C for 5 hours. After cooling, the reaction solution was poured into 100 ml of water, and the precipitated crystals were collected by filtration. The crude crystals were recrystallized from chloroform-ethanol to give the title compound. 265-268 ° C; IR νmax cm ^-1 222
0,1682; NMR (400 MHz, DMSO-d
₆ ) δppm 1.25 (3H, t), 1.85
2.35 (6H, m), 2.85 (2H, q),
3.67 (1H, m), 7.56 (1H, m
s), 7.64 (1H, t), 7.86 (2H,
d), 8.04 (1H, s), 12.61 (1
H, br); MS (EI) m / z 445 (M ^<+> );
Elemental analysis value C ₂₂ H ₁₉ N ₇ O ₂ S calculated value (%) C,
59.31; H, 4.30; N, 22.01, measured value (%) C, 59.16; H, 4.30; N,
21.83.

Example 87 1- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-3-Methyl-5- (1H-tetrazol-5-yl)
-2,4- (1H, 3H) -pyrimidinedione: 1-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-methyl-5- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl)-
The 2,4- (1H, 3H) -pyrimidinedione was prepared in Example 1.
The title compound was obtained by the same treatment as in Step 5 of. Melting point 256-259 ° C (recrystallization solvent: chloroform-
Ethanol -n- hexane); IRνmax cm ^-1 1
722, 1658; NMR (400 MHz, DMSO
−d ₆ ) δ ppm 1.86 to 2.02 (2H,
m), 2.20 to 2.31 (4H, m), 3.3
5 (3H, s), 3.63-3.71 (1H,
m), 7.54 (1H, s), 7.62-7.6.
9 (2H, m), 7.77 (1H, d), 7.
87 (1H, s), 8.64 (1H, s); MS
(EI) m / z 431 (M ⁺ ); Elemental analysis value C ₂₁ H
₁₇ Calculated _{N 7 O 2 S (%)} C, 58.45; H,
3.97; N, 22.73, found (%) C, 5
8.19; H, 4.03; N, 22.62.

Example 88 Ethyl 1- (3- (2
-(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -5- (1H-tetrazol-5-yl)-
2,4-dioxo-3- (1H, 3H) -pyrimidine acetate: (Step 1) Ethyl 1- (3-iodophenyl) -5
-(2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) -2,4-dioxo-3- (1H, 3
Synthesis of H) -pyrimidine acetate Ethyl 1- (3-iodophenyl) -5- (1H-tetrazol-5-yl) -2,4-dioxo-3- (1
(H, 3H) -pyrimidine acetate was treated as in step 3 of Example 1 to give ethyl 1- (3-iodophenyl)-
5- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2,4-dioxo-3- (1H, 3
H) -pyrimidine acetate was obtained as an amorphous. NMR (400 MHz, CDCl ₃ ) δ ppm 1.2
3. 9 (3H, t), 3.78 (3H, s),
23 (2H, q), 4.81 (2H, s),
5.75 (2H, s), 6.87 to 6.89 (2
H, m), 7.24 (1H, t), 7.36-
7.38 (2H.m), 7.40 (1H, d),
7.77 (1H, s), 7.81 (1H, d),
8.30 (1H, s).

(Step 2) Ethyl 1- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -5- (2- (4-methoxybenzyl) -2H-
Tetrazol-5-yl) -2,4-dioxo-3-
Synthesis of (1H, 3H) -pyrimidine acetate Ethyl 1- (3-iodophenyl) -5- (2- (4
-Methoxybenzyl) -2H-tetrazol-5-yl) -2,4-dioxo-3- (1H, 3H) -pyrimidine acetate and 4-cyclobutyl-2-ethynylthiazole in the same manner as in Step 4 of Example 1. Treat with ethyl 1-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -5- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2,4-dioxo-3- ( (1H, 3H) -pyrimidine acetate was obtained as amorphous. NMR (400 MHz, CDCl ₃ ) δ ppm 1.3
4 (3H, t), 1.91 to 2.08 (2H, t)
m), 2.28 to 2.39 (4H, m), 3.6
5-3.74 (1H, m), 3.78 (3H,
s), 4.30 (2H, q), 4.81 (2H,
s), 5.70 (2H, s), 6.86-6.
88 (2H, m), 6.99 (1H, s),
7.16 to 7.18 (2H, m), 7.29 (1
H, d), 7.45 (1H, s), 7.49 (1
H, t), 7.64 to 7.67 (1H, m),
7.67 (1H, s).

(Step 3) Ethyl 1- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -5- (1H-tetrazol-5-yl) -2,
Synthesis of 4-dioxo-3- (1H, 3H) -pyrimidine acetate Ethyl 1- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -5- (2- (4-methoxybenzyl) ) -2H-Tetrazol-5-yl)-
2,4-Dioxo-3- (1H, 3H) -pyrimidine acetate was treated in the same manner as in Step 1 of Example 1 to obtain the title compound. 247-249 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 2216, 1752, 1720, 1656, 160
2; NMR (400 MHz, DMSO-d6) δpp
m 1.22 (3H, t), 2.18 to 2.32
(4H, m), 3.63-3.71 (H,
m), 4.18 (2H, q), 4.74 (2H,
d), 7.55 (1H, s), 7.65 (1
H, t), 7.71 (1H, d), 7.79 (1
H, d), 7.92 (1H, d), 8.75
(1H, s); MS (EI) m / z 503
(M ⁺ ); Elemental analysis value C ₂₄ H ₂₁ N ₇ O ₄ S ・ H
Calculated value of ₂ O (%) C, 56.74; H, 4.2
7; N, 19.30, measured value (%) C, 56.5
4; H, 4.28; N, 19.12.

[Example 89] 1- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-3-Methyl-5- (1H-tetrazol-5-yl)
-2,4-Dioxo-3- (1H, 3H) -pyrimidineacetic acid: ethyl 1- (3- (2- (4-cyclobutyl-
2-thiazolyl) ethynyl) phenyl) -5- (1H-
Tetrazol-5-yl) -2,4-dioxo-3-
(1H, 3H) -pyrimidine acetate was treated in the same manner as in Example 56 to obtain the title compound. Melting point: 219 to 222 ° C. (decomp.) (Recrystallization solvent: chloroform-ethanol); IRνmax cm ⁻¹
2220, 1726, 1666, 1658, 160
4; NMR (400 MHz, DMSO-d ₆ ) δpp
m 1.95 to 2.02 (2H, m), 2.20 to
2.30 (4H, m), 3.62 to 3.71 (1
H, m), 4.65 (2H, s), 7.54
(1H, s), 7.65 (1H, t), 7.71
(1H, d), 7.79 (1H, d), 7.92
(1H, s), 8.74 (1H, s); MS
(EI) m / z 475 ( M +); Elemental analysis C ₂₂ H
_{17 N 7 O 4 S · 3} / 4H 2 O Calculated (%) C, 5
4.04; H, 3.81; N, 20.05, measured value (%) C, 53.91; H, 3.93; N, 1
9.94.

[Example 90] 1- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-3- (4-Methoxybenzyl) -5- (1H-tetrazol-5-yl) -2,4- (1H, 3H) -pyrimidinedione: (Step 1) 1- (3- (2- (4- Cyclobutyl-2
-Thiazolyl) ethynyl) phenyl) -3- (4-methoxybenzyl) -5- (2- (4-methoxybenzyl)
-2H-tetrazol-5-yl) -2,4- (1H,
Synthesis of 3H) -pyrimidinedione 1- (3-iodophenyl) -3- (4-methoxybenzyl) -5- (2- (4-methoxybenzyl) -2H-
Tetrazol-5-yl) -2,4- (1H, 3H)-
Pyrimidinedione and 4-cyclobutyl-2-ethynylthiazole were treated as in step 4 of Example 1 to give 1- (3
-(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (4-methoxybenzyl) -5-
(2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) -2,4- (1H, 3H) -pyrimidinedione was obtained as an amorphous. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
1-2.08 (2H, m), 2.28-2.41 (4
H, m), 3.65 to 3.74 (1H, m),
3.77 (3H, s), 3.78 (3H, s),
5.19 (2H, s), 5.76 (2H, s)
s), 6.82-6.88 (4H, m), 6.9
7 (1H, s), 7.35 to 7.37 (2H,
m), 7.41 (1H, d), 7.50 (1H,
t), 7.55 to 7.57 (2H, m), 7.6
0 (1H, s), 7.65 (1H, d), 8.
26 (1H, s).

(Step 2) 1- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3
Synthesis of-(4-methoxybenzyl) -5- (1H-tetrazol-5-yl) -2,4- (1H, 3H) -pyrimidinedione 1- (3- (2- (4-cyclobutyl-2-thiazolyl ) Ethynyl) phenyl) -3- (4-methoxybenzyl) -5- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2,4- (1H, 3H) -pyrimidinedione Treat as in Step 5 of Example 1, 3
The title compound having a 4-methoxybenzyl group at the position was obtained. Melting point 205-207 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm ^-1
2216, 1718, 1666, 1604; NMR
(400 MHz, DMSO-d ₆ ) δppm 1.88
-2.02 (2H, m), 2.20-2.30 (4
H, m), 3.65 to 3.69 (1H, m),
3.72 (3H, s), 5.08 (2H, s),
6.82-6.91 (2H, m), 7.36-
7.38 (2H, m), 7.54 (1H, s),
7.64 (1H, t), 7.71 (1H,
d), 7.78 (1H, d), 7.92 (1H,
s), 8.67 (1H, s); MS (EI) m
/ Z 537 (M ⁺ ).

Example 91 N- (1H-tetrazol-5-yl) -3- (2- (4-cyclobutyl-2-
Thiazolyl) ethynyl) benzamide: 3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) benzoic acid and 5-amino-1H-tetrazole were treated in the same manner as in Example 88 to give the title compound. Melting point 244 to 246 ° C. (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 2220, 1674, 1590; NMR (400
_{MHz, DMSO-d 6) δppm} 1.84~2.1
0 (2H, m), 2.19 to 2.35 (4H,
m), 3.68 (1H, m), 7.56 (1H,
s), 7.69 (1H, t), 7.95 (1
H, d), 8.17 (1H, d), 8.41 (1
H, s), 12.57 (1H, s); MS (FA
B) m / z 351 (M ⁺ +1); Elemental analysis value C ₁₇
H ₁₄ N ₆ OS calculated (%) C, 58.27; H,
4.03; N, 23.98, measured value (%) C, 5
8.10; H, 4.00; N, 23.82.

Example 92 N- (1H-tetrazol-5-yl) -3- (2- (4-cyclobutyl-2-
(Thiazolyl) ethynyl) -6-methoxybenzamide: (Step 1) Synthesis of 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methoxybenzoic acid Ethyl 3 obtained in the same manner as in Reference Example 18. − (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) -6
-Methoxyphenylcarboxylate was treated in the same manner as in Reference Example 19 to obtain 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methoxybenzoic acid. 141-144 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 2212, 1700, 1678; NMR (400
MHz, CDCl ₃₎ δppm 1.89~2.41
(6H, m), 3.65 to 3.74 (1H, m),
4.12 (3H, s), 6.96 (1H,
s), 7.08 (1H, d), 7.77 (1H,
dd), 8.41 (1H, d); MS (EI)
m / z 313 (M ⁺ ); Elemental analysis: C ₁₇ H ₁₅ N ₃ O
S · 1 / 4H ₂ O Calculated (%) C, 64.23;
H, 4.91; N, 4.41, measured value (%) C,
H, 4.89; N, 4.16.

(Step 2) N- (1H-tetrazole-
Synthesis of 5-yl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methoxybenzamide 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methoxybenzoic acid And 5-amino-1H-tetrazole were treated as in Example 88 to give the title. Melting point 233-235 ° C. (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 2212,1680,1614,1564,152
8,1502; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.88-2.28 (6H, m),
3.63 to 3.68 (1H, m), 3.94 (3
H, s), 7.30 (1H, d), 7.50
(1H, s), 7.84 to 7.88 (2H,
m), 12.01 (1H, s); MS (EI) m
/ Z 380 (M ⁺ ); Elemental analysis C ₁₈ H ₁₆ N ₆ O ₂
Calculated value of S (%) C, 56.83; H, 4.24;
N, 22.09, measured value (%) C, 56.74;
H, 4.15; N, 22.35.

Example 93 N- (1H-tetrazol-5-yl) -3- (2- (4-cyclobutyl-2-
Thiazolyl) ethynyl) -6-isopropoxybenzamide: (Step 1) Synthesis of 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-isopropoxybenzoic acid Obtained in the same manner as in Reference Example 18. Isopropyl 3-
(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) -6-isopropoxyphenylcarboxylate was treated as in Reference Example 19 to give 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl)- 6-isopropoxybenzoic acid was obtained. 168-170 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2216,17
38,1692,1602,1500; NMR (40
0 MHz, CDCl ₃ ) δ ppm 1.52 (6H,
d), 1.89-2.41 (6H, m), 3.6
5-3.72 (1H, m), 4.86-4.96
(1H, m), 6.96 (1H, s), 7.0
6. (1H, d), 7.74 (1H, dd),
43 (1H, d), 10.98 (1H, s);
MS (EI) m / z 341 (M ⁺ ); Elemental analysis value C
Calculated value of ₁₉ H ₁₉ N ₃ OS · １ ／ H ₂ O (%) C, 6
5.97; H, 5.68; N, 4.05, found (%) C, 66.09; H, 5.59;
83.

(Step 2) N- (1H-tetrazole-
Synthesis of 5-yl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-isopropoxybenzamide 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-isopropoxy Benzoic acid and 5-amino-1
H-Tetrazole was treated as in Example 88 to give the title compound. Melting point 211-214 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 2216, 1664, 1592; NMR (400
MHz, DMSO-d ₆ ) δ ppm 1.34 (6H,
d), 1.88-2.30 (6H, m), 3.
61 to 3.68 (1H, m), 4.83 to 4.86
(1H, m), 7.32 (1H, d), 7.5
0 (1H, s), 7.80 (1H, d), 7.9
1 (1H, s), 11.88 (1H, br
MS (EI) m / z 408 (M ⁺ ); Elemental analysis value C ₂₀ H ₂₀ N ₆ O ₂ S calculated value (%) C, 58.
81; H, 4.93; N, 20.57, measured value (%) C, 58.61; H, 5.05; N, 2
0.58.

Example 94 N- (1H-tetrazol-5-yl) -3- (2- (4-cyclobutyl-2-
(Thiazolyl) ethynyl) -2-methylbenzamide: (Step 1) Synthesis of 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methylbenzoic acid Ethyl 3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) -2-methylphenylcarboxylate was treated in the same manner as in Reference Example 19 to give 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methylbenzoic acid. Obtained. 115 ° C. (recrystallization solvent: chloroform-n-hexane); NMR (400 MHz, DMSO-d ₆ ) δ
ppm 1.85 to 2.40 (6H, m), 2.55
(3H, s), 3.69 (1H, m), 7.4
6. 4 (1H, t), 7.48 (1H, s), 7.
72 (1H, d), 7.80 (1H, d), 1
3.40 (1H, br).

(Step 2) N- (1H-tetrazole-
Synthesis of 5-yl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methylbenzamide 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methylbenzoic acid And 5-amino-1H-tetrazole were treated as in Example 88 to give the title. Melting point 289 ° C. (decomp.) (Recrystallization solvent: chloroform-ethanol); IRν max cm ^-1 164
6; NMR (400 MHz, DMSO-d ₆ ) δpp
m 1.85 to 2.35 (6H, m), 2.57
(3H, s), 3.66 (1H, m), 7.44
(1H, t), 7.56 (1H, s), 7.6
9 (1H, d), 7.80 (1H, d), 1
2.52 (1H, brs); MS (FAB) m /
z 365 (M ⁺ +1); elemental analysis value C ₁₈ H ₁₆ N ₆
Calculated value of OS (%) C, 59.32; H, 4.4
3; N, 23.06, measured value (%) C, 59.1
3; H, 4.48; N, 23.34.

Example 95 N- (1H-tetrazol-5-yl) -3- (2- (4-cyclobutyl-2-
(Thiazolyl) ethynyl) -4-fluorobenzamide: (Step 1) Synthesis of 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-fluorobenzoic acid Ethyl 3 obtained in the same manner as in Reference Example 18. − (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) -4
-Fluorophenylcarboxylate was treated in the same manner as in Reference Example 19 to obtain 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-fluorobenzoic acid. Melting point 156 ° C. (recrystallization solvent: chloroform-n-hexane); NMR (400 MHz, DMSO-d ₆ ) δ
ppm 1.82 to 2.35 (6H, m), 3.68
(1H, m), 7.53 (1H, t), 7.6
7. 0 (1H, s), 8.09 (1H, m),
21 (1H, m), 13.39 (1H, br).

(Step 2) N- (1H-tetrazole-
Synthesis of 5-yl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-fluorobenzamide 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4-fluorobenzoic acid And 5-amino-1H-tetrazole were treated in the same manner as in Example 88 to obtain the title compound. Melting point 247-259 ° C (recrystallization solvent: chloroform-
Ethanol); IRνmax cm ^-1 1668; NM
R (400 MHz, DMSO-d ₆ ) δ ppm 1.85
~ 2.40 (6H, m), 3.69 (1H,
m), 7.63 (2H, m), 8.24 (1H,
m), 8.50 (1H, m), 12.50 (1
H, br); MS (FAB) m / z 369 (M ⁺
+1); Elemental analysis value C ₁₇ H ₁₃ FN ₆ OS calculated value (%) C, 55.42; H, 3.56; N, 2
2.81, measured value (%) C, 55.47; H,
3.76; N, 23.17.

Example 96 N- (1H-tetrazol-5-yl) -3- (2- (4-cyclobutyl-2-)
Thiazolyl) ethynyl) -6-methylbenzamide: (Step 1) Synthesis of 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methylbenzoic acid Ethyl 3 obtained in the same manner as in Reference Example 18 − (2-
(4-Cyclobutyl-2-thiazolyl) ethynyl) -6
-Methylphenylcarboxylate was treated in the same manner as in Reference Example 19 to obtain 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methylbenzoic acid. Melting point: 163 to 165 ° C. (decomp.) (Recrystallization solvent: chloroform-methanol); NMR (400 M
Hz, CDCl ₃ ) δ ppm 1.90 to 2.00 (1
H, m), 2.00 to 2.10 (1H, m),
2.20 to 2.50 (4H, m), 2.68 (3
H, s), 3.70 to 3.80 (1H, m),
6.98 (1H, s), 7.29 (1H, d),
7.63 (1H, d), 8.31 (1H, d)
s).

(Step 2) N- (1H-tetrazole-
Synthesis of 5-yl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methylbenzamide 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methylbenzoic acid And 5-amino-1H-tetrazole were treated in the same manner as in Example 88 to obtain the title compound. 250-253 ° C (decomp.) (Recrystallization solvent: chloroform-methanol); NMR (400M
_{Hz, DMSO-d 6) δppm} 1.80~2.00
(1H, m), 2.00 to 2.10 (1H,
m), 2.20 to 2.40 (4H, m), 2.5
5 (3H, s), 3.60 to 3.80 (1H,
m), 7.49 (1H, d), 7.57 (1H,
s), 7.77 (1H, d), 7.97 (1
H, s), 8.02 (1H, br), 12.52
(1H, s); MS (FAB) m / z 365 (M
⁺ +1); Elemental analysis value C ₁₈ H ₁₆ N ₆ OS · 3 / 4H ₂ O
Calculated value (%) for C, 58.52; H, 4.52;
N, 21.55, measured value (%) C, 58.75;
H, 4.59; N, 21.35.

Example 97 N- (1H-tetrazol-5-yl) -2- (2- (4-cyclobutyl-2-
(Thiazolyl) ethynyl) benzamide: (Step 1) Synthesis of 2- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzoic acid Ethyl 2- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenylcarboxylate was treated in the same manner as in Reference Example 19,
2- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) benzoic acid was obtained. Melting point 142-145 ° C (decomp.) (Recrystallization solvent: chloroform-methanol); NMR (400M
Hz, DMSO-d ₆ ) δppm 1.80 to 1.90
(1H, m), 1.90-2.00 (1H,
m), 2.20 to 2.50 (4H, m), 3.7.
0 to 3.80 (1H, m), 7.08 (1H,
11. s), 7.50-7.70 (4H, m).
50-12.70 (1H, br).

(Step 2) N- (1H-tetrazole-
Synthesis of 5-yl) -2- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide 2- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzoic acid and 5-amino-1H-tetrazole Was treated in the same manner as in Example 88 to obtain the title. Melting point 168-170 ° C (decomp.) (Recrystallization solvent: chloroform-methanol); NMR (400M
Hz, DMSO-d ₆ ) δppm 1.80 to 1.90
(1H, m), 1.90-2.00 (1H,
m), 2.10 to 2.40 (4H, m), 3.6.
0 to 3.80 (1H, m), 7.07 (1H, m
11. s), 7.50-7.70 (4H, m).
20 (1H, br); MS (FAB) m / z 35
1 (M ⁺ +1).

Example 98 (E) -5- (2- (3
-(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) ethenyl) -1H-tetrazole: (Step 1) (E) -5- (2- (3-Iodophenyl) ethenyl) -2- (4- Methoxybenzyl) -2H
Synthesis of -tetrazole (E) -5- (2- (3-iodophenyl) ethenyl)
1H-tetrazole was treated in the same manner as in Step 3 of Example 1 to obtain (E) -5- (2- (3-iodophenyl) ethenyl) -2- (4-methoxybenzyl) -2H-tetrazole. 115-116 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.80 (3H, s), 5.69
(2H, s), 6.88-6.92 (2H,
m), 7.10 (1H, d), 7.11 (1H,
t), 7.34-7.37 (2H, m), 7.48
(1H, d), 7.59 (1H, d), 7.6
4 (1H, d), 7.88 (1H, s); MS
(EI) m / z 418 ( M +); Elemental analysis C ₁₇ H
₁₅ IN ₄ O calculated (%) C, 48.82; H,
3.62; N, 13.40, measured value (%) C, 4
8.99; H, 3.72; N, 13.24.

(Step 2) (E) -5- (2- (3-
Synthesis of (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) ethenyl) -2- (4-methoxybenzyl) -2H-tetrazole (E) -5- (2- (3-iodophenyl) ethenyl)
2- (4-Methoxybenzyl) -2H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to give (E) -5- (2- (3-
(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) ethenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained as a pale oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
1-2.08 (2H, m), 2.30-2.30 (4
H, m), 3.66 to 3.74 (1H, m),
3.80 (3H, s), 5.70 (2H, s),
6.89 to 6.92 (2H, m), 6.96 (1
H, s), 7.14 (1H, d), 7.35-
7.41 (3H, m), 7.53 to 7.56 (2
H, m), 7.68 (1H, d), 7.75
(1H, s).

(Step 3) (E) -5- (2- (3-
Synthesis of (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) ethenyl) -1H-tetrazole (E) -5- (2- (3- (2- (4-cyclobutyl-
2-thiazolyl) ethynyl) phenyl) ethenyl) -2
-(4-Methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 158 to 168 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane);
^-1 2216, 1650, 1598, 1574, 155
4,1504; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.86 to 2.03 (2H, m),
2.18 to 2.33 (4H, m), 3.63 to 3.3.
71 (1H, m), 7.47 (1H, d),
7.53 (1H, s), 7.54 (1H, t),
7.63 to 7.67 (1H, m), 7.65 (1
H, d), 7.83 (1H, d), 8.04
(1H, s); MS (EI) m / z 333
(M ⁺ ): Elemental analysis value Calculated value of C ₁₈ H ₁₅ N ₅ S (%)
C, 64.84; H, 4.53; N, 21.0
1, measured value (%) C, 65.05; H, 4.6
0; N, 20.70.

Example 99 (E) -5- (2- (3
-(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1-propen-1-yl) -1H-tetrazole: (Step 1) (E) -5- (2- (3-Iodophenyl)- Synthesis of 1-propen-1-yl) -2- (4-methoxybenzyl) -2H-tetrazole (E) -5- (2- (3-iodophenyl) -1-propen-1-yl) -1H-tetrazole In the same manner as in Step 3 of Example 1 to give (E) -5- (2- (3-iodophenyl) -1-propen-1-yl) -2- (4-methoxybenzyl) -2H-tetrazole Obtained as amorphous. NMR (400 MHz, CDCl ₃ ) δ ppm 2.6
6 (3H, d), 3.79 (3H, s), 5.
72 (2H, s), 6.75-7.45 (8H,
m), 7.88 (1H, s).

(Step 2) (E) -5- (2- (3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1-propen-1-yl) -2- (4
Synthesis of (Methoxybenzyl) -2H-tetrazole (E) -5- (2- (3-Iodophenyl) -1-propen-1-yl) -2- (4-methoxybenzyl) -2
H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to give (E)-
5- (2- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1-propen-1-yl) -2- (4-methoxybenzyl) -2H-tetrazole as a brown oil As obtained. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
5 to 2.44 (6H, m), 2.62 (3H,
d), 3.70 (3H, s), 3.80 (3H,
s), 5.72 (2H, s), 6.86-7.
80 (10H, m).

(Step 3) (E) -5- (2- (3-
Synthesis of (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1-propen-1-yl) -1H-tetrazole (E) -5- (2- (3- (2- (4-cyclobutyl) −
2-thiazolyl) ethynyl) phenyl) -1-propen-1-yl) -2- (4-methoxybenzyl) -2H-
The tetrazole was treated as in step 5 of example 1 to give the title. 134-135 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2216; N
_{MR (400MHz, DMSO-d 6} -CDCl 3) δ
ppm 1.85 to 2.42 (6H, m);
68 (3H, d), 3.69 (1H, m),
6.80 (1H, s), 7.15 (1H, s),
7.48 (1H, t), 7.58 (1H, t)
d), 7.63 (1H, d), 7.78 (1H,
m); MS (FAB) m / z 348 (M + +
1); Elemental analysis value Calculated value (%) of C ₁₉ H ₁₇ N ₅ S ・ H ₂ O (%) C, 64.84; H, 5.01; N, 1
9.90, measured value (%) C, 65.01; H,
5.06; N, 19.89.

[Example 100] (E) -5- (1-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1-propen-2-yl) -1H
-Tetrazole: (Step 1) Synthesis of (E) -5- (1- (3-iodophenyl) -1-propen-2-yl) -2- (4-methoxybenzyl) -2H-tetrazole (E) -5 -(21 (3-Iodophenyl) -1-propen-2-yl) -1H-tetrazole was treated as in step 3 of Example 1 to give (E) -5- (1- (3-Iodophenyl) -1 -Propen-2-yl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained as an amorphous. NMR (400 MHz, CDCl ₃ ) δ ppm 2.3
4. (3H, d), 3.80 (3H, s), 5.
69 (2H, s), 6.90 (2H, d),
7.13 (1H, t), 7.47 (3H, m),
7.63 (2H, m), 7.76 (1H, s).

(Step 2) (E) -5- (1- (3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1-propen-2-yl) -2- (4
Synthesis of -methoxybenzyl) -2H-tetrazole (E) -5- (1- (3-Iodophenyl) -1-propen-2-yl) -2- (4-methoxybenzyl) -2
H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to give (E)-
5- (1- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1-propen-2-yl) -2- (4-methoxybenzyl) -2H-tetrazole was converted to a brown oil. As obtained. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
5 to 2.40 (6H, m), 2.38 (3H,
d), 3.70 (1H, s), 3.77 (3H,
s), 5.70 (2H, s), 6.90 (2
H, d), 6.95 (1H, s), 7.38
(2H, d), 7.43 (1H, m), 7.51
(1H, m), 7.64 (1H, brs),
7.71 (1H, brs).

(Step 3) (E) -5- (1- (3-
Synthesis of (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1-propen-2-yl) -1H-tetrazole (E) -5- (1- (3- (2- (4-cyclobutyl) −
2-thiazolyl) ethynyl) phenyl) -1-propen-2-yl) -2- (4-methoxybenzyl) -2H-
The tetrazole was treated as in step 5 of example 1 to give the title. 134-136 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2216; N
MR (400 MHz, CDCl ₃ ) δ ppm 1.85
~ 2.40 (6H, m), 2.42 (3H,
d), 3.78 (1H, m), 7.04 (1H,
s), 7.35-7.45 (4H, m), 7.
61 (1H, s); MS (EI) m / z 347.
(M ⁺ ); Elemental analysis value Calculated value of C19 H17 N5 S (%)
C, 65.68; H, 4.93; N, 20.1
6, measured value (%) C, 65.40; H, 5.0
5; N, 19.89.

[Example 101] (E) -5- (2-
(4- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-thienyl) -2-ethenyl) -1H-tetrazole: (Step 1) (E) -5- (2- (4-bromo- Synthesis of 2-thienyl) -2-ethenyl) -2- (4-methoxybenzyl) -2H-tetrazole (E) -5- (2- (4-bromo-2-thienyl) -2
-Ethenyl) -1H-tetrazole in Step 3 of Example 1
And treated in the same manner as in (E) -5- (2- (4-bromo-2
-Thienyl) -2-ethenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained. Melting point 83-84 ° C (recrystallization solvent: chloroform-n-
Hexane); NMR (400 MHz, CDCl ₃ ) δ
ppm 3.79 (3H, s), 5.67 (2H,
s), 6.88-6.95 (2H, m), 7.
07 (1H, s), 7.17 (1H, s),
7.34-7.36 (2H, m), 7.85 (1
H, d).

(Step 2) Synthesis of (E) -5- (2- (4-Iodo-2-thienyl) -2-ethenyl) -2- (4-methoxybenzyl) -2H-tetrazole (E) -5 -(2- (4-bromo-2-thienyl) -2
-Ethenyl) -2- (4-methoxybenzyl) -2H-
Treating the tetrazole as in Step 2 of Example 16,
(E) -5- (2- (4-Iodo-2-thienyl) -2
-Ethenyl) -2- (4-methoxybenzyl) -2H-
The tetrazole was obtained. 103-104 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.80 (3H, s), 5.68
(2H, s), 6.89-6.94 (2H,
m), 7.13 (1H, s), 7.34-7.37.
(3H, m), 7.73 (1H, d).

(Step 3) (E) -5- (2- (4-
Synthesis of (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-thienyl) -2-ethenyl) -2- (4-methoxybenzyl) -2H-tetrazole (E) -5- (2- (4 -Iodo-2-thienyl) -2
-Ethenyl) -2- (4-methoxybenzyl) -2H-
The tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to obtain (E) -5-
(2- (4- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-thienyl) -2-ethenyl) -2
-(4-Methoxybenzyl) -2H-tetrazole was obtained. 133-135 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 1.90 to 2.10 (2H, m),
2.28 to 2.38 (4H, m), 3.64 to 3.
73 (1H, m), 3.80 (3H, s),
5.68 (2H, s), 6.89-6.92 (2
H, m), 6.94 (1H, s), 6.95
(1H, d), 7.34 to 7.37 (2H, m),
7.56 (1H, s), 7.74 (1H, s)
d).

(Step 4) (E) -5- (2- (4-
Synthesis of (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-thienyl) -2-ethenyl) -1H-tetrazole (E) -5- (2- (4- (2- (4-cyclobutyl-
2-Thiazolyl) ethynyl) -2-thienyl) -2-ethenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 156-163 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 2216; NMR (400 MHz, DMSO-d
₆ ) δppm 1.83 to 2.05 (2H, m),
2.18 to 2.32 (4H, m), 3.62 to 3.
70 (1H, m), 7.12 (1H, d), 7.
52 (1H, s), 7.74 (1H, s),
7.80 (1H, d), 8.21 (1H, s);
MS (EI) m / z 339 (M +); Elemental analysis _{C 16 H 13 N 5 S2 ·} 1 / 4H 2 O Calculated (%) C,
55.87; H, 3.96; N, 20.36, measured value (%) C, 56.11; H, 3.92; N,
20.32.

Example 102 (E) -5- (2-
(5- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-benzo [b] thienyl) -2-ethenyl) -1H-tetrazole: (Step 1) (E) -5- (2- ( Synthesis of 5-iodo-2-benzo [b] thienyl) -2-ethenyl) -2- (4-methoxybenzyl) -2H-tetrazole (E) -5- (2- (5-iodo-2-benzo [ b] Thienyl) -2-ethenyl) -1H-tetrazole was treated as in step 3 of example 1 to give (E) -5- (2- (5
-Iodo-2-benzo [b] thienyl) -2-ethenyl) -2- (4-methoxybenzyl) -2H-tetrazole was obtained. 144-146 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 3.80 (3H, s), 5.69
(2H, s), 6.90 (2H, d), 7.0
0 (1H, d), 7.26 (1H, s), 7.3
6. (2H, d), 7.52 (1H, d),
59 (1H, d), 7.87 (1H, d),
8.08 (1H, s).

(Step 2) (E) -5- (2- (5-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-benzo [b] thienyl) -2-ethenyl)-
Synthesis of 2- (4-methoxybenzyl) -2H-tetrazole (E) -5- (2- (5-Iodo-2-benzo [b] thienyl) -2-ethenyl) -2- (4-methoxybenzyl) -H-tetrazole and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1,
(E) -5- (2- (5- (2- (4-cyclobutyl-
2-thiazolyl) ethynyl) -2-benzo [b] thienyl) -2-ethenyl) -2- (4-methoxybenzyl)
2H-tetrazole was obtained. 145-148 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, CDCl
₃ ) δ ppm 1.89 to 2.11 (2H, m),
2.30 to 2.41 (4H, m), 3.68 to 3.
76 (1H, m), 3.80 (3H, s),
5.70 (2H, s), 6.89 to 6.92 (2
H, m), 6.95 (1H, s), 7.02
(1H, d), 7.38 to 7.35 (3H, m),
7.52 (1H, d), 7.77 (1H,
d), 7.89 (1H, d), 7.96 (1H,
s).

(Step 3) (E) -5- (2- (5-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-benzo [b] thienyl) -2-ethenyl)-
Synthesis of 1H-tetrazole (E) -5- (2- (5- (2- (4-cyclobutyl-
2-thiazolyl) ethynyl) -2-benzo [b] thienyl) -2-ethenyl) -2- (4-methoxybenzyl)
-2H-tetrazole was treated as in Step 5 of Example 1 to give the title compound. Melting point 222-224 ° C (decomp.) (Recrystallization solvent: chloroform-ethanol-n-hexane);
Rνmax cm ⁻¹ 2216, 1638; NMR (40
_{0MHz, DMSO-d 6) δppm} 1.86~2.
03 (2H, m), 2.21-2.31 (4H,
m), 3.63 to 3.72 (1H, m), 7.1
1 (1H, d), 7.53 (1H, s), 7.
64 (1H, d), 7.82 (1H, s),
7.98 (1H, d), 8.12 (1H, d),
8.20 (1H, s); MS (FAB) m / z
390 (M ⁺ +1); Elemental analysis C ₂₀ H ₁₅ N ₅ S ₂ Calculated (%) C, 61.67; H , 3.88; N, 1
7.98, measured value (%) C, 61.97; H,
3.99; N, 17.61.

Example 103 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1H-tetrazole-5-carboxamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole-5-carboxamide 3- (2- (4-cyclobutyl-2-thiazolyl) ethynylaniline 509 mg, carboxylic acid of Reference Example 19 1.
10 ml of methylene chloride was added to 14 g, 1.04 g of 1-ethyl-1 ′-(3-dimethylamino) propylcarbodiimide hydrochloride and 598 mg of 4-dimethylaminopyridine, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with 100 ml of chloroform, saturated aqueous sodium hydrogen carbonate solution,
After washing with saturated saline, it was dried over sodium sulfate. The residue obtained by distilling off the solvent was subjected to column chromatography using silica gel (eluent: n-hexane: ethyl acetate =
3: 2) and the obtained crude crystals were recrystallized from chloroform-ether to give N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-.
(4-Methoxybenzyl) -2H-tetrazole-5-
1 g of carboxamide was obtained as pale yellow needle crystals. Melting point 114-115 ° C; NMR (400 MHz, CD
Cl ₃ ) δppm 1.88 to 2.11 (2H,
m), 2.27 to 2.41 (4H, m), 3.7.
2 (1H, m), 3.80 (3H, s), 5.
79 (2H, s), 6.90 (2H, d), 6.
96 (1H, s), 7.37 to 7.42 (4H,
m), 7.77 (1H, ddd), 7.78 (1
H, s), 8.06 (1H, s); Elemental analysis C
Calculated value for ₂₅ H ₂₂ N ₆ O ₂ S (%) C, 63.81;
H, 4.71; N, 17.86, measured value (%)
C, 63.73; H, 4.84; N, 17.78.

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1
Synthesis of H-tetrazole-5-carboxamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole-5-carboxamide is used as an example. This was treated in the same manner as in Step 3 of 1 to give the title compound. Melting point 214-215 ° C (decomp.) (Recrystallization solvent: chloroform-ethanol-n-hexane);
Rνmax cm ⁻¹ 2216, 1660; NMR (40
_{0MHz, DMSO-d 6) δppm} 1.85~2.
06 (2H, m), 2.20 to 2.51 (4H,
m), 3.68 (1H, m), 7.44 to 7.5.
2 (3H, m), 7.95 (1H, d), 8.
16 (1H, s); Elemental analysis value Calculated value for C ₁₇ H ₁₄ N ₆ OS (%) C, 58.27; H, 4.03; N,
23.98, measured value (%) C, 58.15; H,
4.25; N, 23.55.

Example 104 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) -2-methylphenyl) -1H-tetrazole-5-carboxamide: (Step 1) 3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) -2-methylaniline − (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) -2
-Methylaniline was obtained as a pale brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
1-2.40 (9H, m), 3.70 (1H,
m), 6.71 (1H, dd), 6.94 (1
H, s), 6.99-7.05 (2H, m).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole-5-carboxamide Synthesis To 1.26 g of the carboxylic acid of Reference Example 19 and 0.5 ml of thionyl chloride, 5 ml of toluene and a catalytic amount of DMF were added, and the mixture was heated under reflux for 3 hours. After cooling, the reaction solution was distilled off.
The residue was dissolved in 20 ml of methylene chloride, and this was added to 3- (2
-(4-cyclobutyl-2-thiazolyl) ethynyl)-
A solution of 966 mg of 2-methylaniline and 0.8 ml of triethylamine in 20 ml of methylene chloride was added at 0 ° C. with stirring. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. The reaction solution was poured into 50 ml of 1N hydrochloric acid and extracted with chloroform. After washing the extract layer with saturated sodium bicarbonate,
Dried over sodium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography using silica gel (eluent: chloroform: methanol = 100: 1) to give N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl). ) -2-Methylphenyl) -2- (4-
1.95 g of (methoxybenzyl) -2H-tetrazole-5-carboxamide was obtained as a brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
2 to 2.08 (2H, m), 2.28 to 2.40 (4
H, m), 2.56 (3H, s), 3.66-
3.72 (1H, m), 3.80 (3H, s),
5.80 (2H, s), 6.90 (2H, s)
d), 6.97 (1H, s), 7.27 (1H,
t), 7.42 (2H, d), 7.46 (1
H, d), 8.11 (1H, d), 8.82 (1
H, s).

(Step 3) Synthesis of N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methylphenyl) -1H-tetrazole-5-carboxamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methylphenyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole-5-carboxamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point 190-191 ° C. (decomp.) (Recrystallization solvent: chloroform-ethanol-n-hexane); I
Rν max cm ^-1 2208, 1700, 1672, 16
00, 1542, 1504; NMR (400 MHz,
DMSO-d ₆ ) δppm 1.88 to 2.03 (2
H, m), 2.19 to 2.31 (4H, m),
2.42 (3H, s), 3.63 to 3.72 (1
H, m), 7.36 (1H, t), 7.51-
7.54 (1H, m), 7.54 (1H, s),
7.60 (1H, d), 10.96 (1H, d)
s); MS (FAB) m / z 365 (M + +
1); Elemental analysis value Calculated value of C ₁₈ H ₁₆ N ₆ OS (%)
C, 59.32; H, 4.43; N, 23.07,
Measured value (%) C, 59.28; H, 4.34;
N, 23.26.

Example 105 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) -6-methylphenyl) -1H-tetrazole-5-carboxamide: (Step 1) 3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) -6-methylaniline − (2-
(4-Cyclobutyl-2-thiazolyl) ethynyl) -6
-Methylaniline was obtained. 125-126 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 3460, 33
48, 2980, 2940, 2200, 1624, 15
66; NMR (400 MHz, CDCl ₃ ) δ ppm
1.90 to 2.07 (2H, m), 2.17 (3
H, s), 2.28 to 2.38 (4H, m),
3.63 to 3.70 (1H, m), 6.88 (1
H, d), 6.91 (1H, s), 6.94 (1
H, dd), 7.03 (1H, d); MS (FA
B) m / z 269 (M ⁺⁺ 1); Elemental analysis C ₁₆ H
Calculated value of ₁₆ N ₂ S (%) C, 71.60; H, 6.
01; N, 10.44 measured value (%) C, 71.3
2; H, 5.85; N, 10.37.

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole-5-carboxamide Synthesis The carboxylic acid of Reference Example 19 and 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methylaniline were treated in the same manner as in Step 2 of Example 104 to give N- (3-
(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) -6-methylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole-5-carboxamide was obtained. 138-140 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 3408,22
12, 1704, 1614; NMR (400 MHz,
CDCl ₃ ) δ ppm 1.93 to 2.07 (2H,
m), 2.29 to 2.36 (4H, m), 2.3
9 (3H, s), 3.66 to 3.71 (1H,
m), 3.80 (3H, s), 5.80 (2H,
5.s), 6.89-6.91 (2H, m),
94 (1H, s), 7.23 (1H, d),
7.35 (1H, d), 7.40 to 7.42 (2
H, m), 8.32 (1H, s), 8.78
(1H, s); MS (FAB) m / z 485 (M
⁺ +1); calcd Elemental analysis _{C 26 H 24 N 6 O 2} S (%) C, 64.44; H, 4.99; N, 17.
35, measured value (%) C, 64.22; H, 5.1
4; N, 17.64.

(Step 3) Synthesis of N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methylphenyl) -1H-tetrazole-5-carboxamide N- (3- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) -6-methylphenyl) -2- (4-methoxybenzyl) -2H-tetrazol-5-carboxamide was treated in the same manner as in Step 5 of Example 1 to give the title compound. Obtained. Melting point 214-215 ° C (decomp.) (Recrystallization solvent: chloroform-ethanol-n-hexane);
Rνmax cm ⁻¹ 3412, 3092, 2204, 17
10, 1570; NMR (400 MHz, DMSO-
d ₆ ) δ ppm 1.85 to 2.02 (2H, m),
2.20 to 2.31 (4H, m), 2.50 (3H,
s), 3.64-3.70 (1H, m), 7.
41 (1H, d), 7.50 to 7.51 (1H, d)
m), 7.54 (1H, s), 7.68 (1H,
s), 10.84 (1H, s); MS (FA
B) m / z 365 (M ⁺⁺ 1); Elemental analysis _C18.
Calculated value (%) of H ₁₆ N ₆ OS · １ ／ H ₂ O C, 58.
H, 4.51; N, 22.78, measured value (%) C, 58.76; H, 4.53; N, 2
3.16.

Example 106 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) -2-methoxyphenyl) -1H-tetrazole-5-carboxamide: (Step 1) 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methoxyaniline Synthesis 3-Iodo-2-methoxynitrobenzene and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Reference Example 16, and then treated in the same manner as in Reference Example 17, to give 3- (2
-(4-cyclobutyl-2-thiazolyl) ethynyl)-
2-methoxyaniline was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.07 (2H, m), 2.28 to 2.39 (4
H, m), 3.65 to 3.74 (1H, m),
4.00 (3H, s), 6.77 (1H, d),
6.88 (1H, t), 6.92 to 6.94 (2
H, m).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methoxyphenyl) -2- (4-methoxybenzyl) -2H-tetrazole-5-carboxamide Synthesis The carboxylic acid of Reference Example 19 and 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methoxyaniline were treated in the same manner as in Step 2 of Example 104 to give N- (3-
(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) -2-methoxyphenyl) -2- (4-methoxybenzyl) -2H-tetrazole-5-carboxamide was obtained. 137-138 ° C; IRνmax cm ^-1 338
4,3100,2212,1704,1606; NM
R (400 MHz, CDCl ₃ ) δ ppm 1.91-
2.09 (2H, m), 2.29 to 2.40 (4
H, m), 3.68 to 3.73 (1H, m),
3.80 (3H, s), 4.17 (3H, s),
5.80 (2H, s), 6.90 (2H, s)
d), 6.99 (1H, s), 7.13 (1H,
t), 7.34 (1H, d), 7.42 (2
H, d), 8.58 (1H, d), 9.56
(1H, s); MS (FAB) m / z 501 (M
⁺ +1); Elemental analysis value C ₂₆ H ₂₄ N ₆ O ₃ S ・
Of H ₂ O Calculated (%) C, 61.83; H , 4.
89; N, 16.64, measured value (%) C, 61.9
6; H, 4.87; N, 16.19.

(Step 3) Synthesis of N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methoxymethylphenyl) -1H-tetrazole-5-carboxamide N- (3- (2 -(4-cyclobutyl-2-thiazolyl) ethynyl) -2-methoxyphenyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole-5-carboxamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point 220-221 ° C (decomp.) (Recrystallization solvent: chloroform-ethanol-n-hexane);
Rνmax cm ⁻¹ 3384, 3090, 2212, 16
06; NMR (400 MHz, DMSO-d ₆ ) δp
pm 1.86 to 2.03 (2H, m), 2.21
2.33 (4H, m), 3.64 to 3.72 (1
H, m), 4.03 (3H, s), 7.27
(1H, t), 7.53 (1H, d), 7.5
6 (1H, d), 8.02 (1H, d), 1
0.32 (1H, s); MS (EI) m / z 38
0 (M ⁺ ); Elemental analysis value Calculated value for C ₁₈ H ₁₆ N ₆ O ₂ S (%) C, 56.82; H, 4.24; N, 2
2.10, measured value (%) C, 56.63; H,
4.38; N, 21.73.

Example 107 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) -6-methoxyphenyl) -1H-tetrazole-5-carboxamide: (Step 1) of 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methoxyaniline Synthesis 3-Iodo-6-methoxynitrobenzene and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Reference Example 16 and subsequently treated in the same manner as in Reference Example 17, to give 3- (2
-(4-cyclobutyl-2-thiazolyl) ethynyl)-
6-Methoxyaniline was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
9 to 2.07 (2H, m), 2.28 to 2.38 (4
H, m), 3.63 to 3.72 (1H, m),
3.87 (3H, s), 6.75 (1H, d),
6.89 (1H, s), 6.92 (1H, s)
d), 7.01 (1H, dd).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methoxyphenyl) -2- (4-methoxybenzyl) -2H-tetrazole-5-carboxamide Synthesis The carboxylic acid of Reference Example 19 and 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methoxyaniline were treated in the same manner as in Step 2 of Example 104 to give N- (3-
(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) -6-methoxyphenyl) -2- (4-methoxybenzyl) -2H-tetrazole-5-carboxamide was obtained. 158-160 ° C; IR νmax cm ^-1 338
4,2212,1698,1612,1550,151
0; NMR (400 MHz, CDCl ₃ ) δ ppm
1.91 to 2.07 (2H, m), 2.29 to 2.
38 (4H, m), 3.64 to 3.73 (1H,
m), 3.80 (3H, s), 3.98 (3H,
s), 5.80 (2H, s), 6.89-6.
92 (4H, m), 7.38 (1H, dd),
7.41 (1H, d), 8.75 (1H, d),
9.46 (1H, s); MS (EI) m / z 5
00 (M ⁺ ); Elemental analysis value Calculated value for C ₂₆ H ₂₄ N ₆ O ₃ S (%) C, 62.38; H, 4.83; N, 1
6.79, measured value (%) C, 62.15; H,
4.93; N, 16.75.

(Step 3) Synthesis of N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methoxymethylphenyl) -1H-tetrazole-5-carboxamide N- (3- (2 -(4-cyclobutyl-2-thiazolyl) ethynyl) -6-methoxyphenyl) -2- (4-
(Methoxybenzyl) -2H-tetrazole-5-carboxamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point> 300 ° C. (recrystallization solvent: chloroform-n-hexane); NMR (400 MHz, DMSO-d ₆ )
δ ppm 1.89 to 2.02 (2H, m), 2.2
2 to 2.29 (4H, m), 3.64 to 3.68
(1H, m), 4.00 (3H, s), 7.20
(1H, d), 7.40 (1H, d), 7.48
(1H, d), 8.63 (1H, s), 9.6
3 (1H, s); Elemental analysis value Calculated value for C ₁₈ H ₁₆ N ₆ O ₂ S (%) C, 56.82; H, 4.24;
N, 22.10, measured value (%) C, 56.63;
H, 4.38; N, 21.73.

Example 108 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N- (ethoxycarbonylmethyl) -1H-tetrazole-5-carboxamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) phenyl) glycine ethyl ester
5 ml was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with 300 ml of ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 2: 1).
-(3- (2- (4-cyclobutyl-2-thiazolyl)
Ethynyl) phenyl) glycine ethyl ester 21
4 mg were obtained. Melting point 110-112 ° C; NMR (400 MHz, CD
Cl ₃ ) δ ppm 1.31 (3H, t), 1.8
8 to 2.10 (2H, m), 2.27 to 2.42
(4H, m), 3.69 (1H, m), 3.9
0 (2H, d), 4.26 (2H, q), 4.3
7 (1H, t), 6.64 to 6.67 (1H,
m), 6.80 (1H, t), 6.93 (1H,
s), 6.99 (1H, d), 7.17 (1
H, t).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N
Synthesis of-(ethoxycarbonylmethyl) -2- (4-methoxybenzyl) -2H-tetrazole-5-carboxamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) glycine ethyl ester The carboxylic acid of Reference Example 19 was treated in the same manner as in Step 2 of Example 104 to give N- (3- (2- (4-cyclobutyl-2).
-Thiazolyl) ethynyl) phenyl) -N- (ethoxycarbonylmethyl) -2- (4-methoxybenzyl)-
2H-Tetrazole-5-carboxamide was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.2
9 (3H, t), 1.91 to 2.08 (2H, t)
m), 2.28 to 2.39 (4H, m), 3.6
5-3.73 (1H, m), 3.75 (3H,
s), 4.24 (2H, q), 4.58 (2H,
s), 5.54 (2H, s), 6.82 (1
H, d), 6.97 (1H, s), 7.10
(1H, d), 7.19 to 7.23 (2H, m),
7.43 to 7.45 (1H, m), 7.48 (1
H, s).

(Step 3) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N
Synthesis of-(ethoxycarbonylmethyl) -1H-tetrazole-5-carboxamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N- (ethoxycarbonylmethyl) -2- (4 -Methoxybenzyl) -2H-tetrazole-5-carboxamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 184 to 186 ° C (decomp.);
max cm ^-1 3408,2216,1744,162
4: NMR (400 MHz, DMSO-d ₆ ) δpp
m 1.18 (3H, t), 1.85 to 2.04
(2H, m), 2.18-2.30 (4H,
m), 3.62 to 3.70 (1H, m), 4.1
3 (2H, q), 4.71 (2H, br s),
7.27 to 7.45 (4H, m), 7.51 (1
H, s); MS (FAB ) m / z437 (M + +
1); Elemental analysis value Calculated value of C ₂₁ H ₂₀ N ₆ O ₃ S (%)
C, 57.78; H, 4.62; N, 19.2.
6, measured value (%) C, 57.46; H, 4.62;
N, 19.74.

Example 109 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N-methyl-1H-tetrazole-5-carboxamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) phenyl) trifluoroacetamide 209 mg of 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline and 1 ml of triethylamine
To the mixture was added 10 ml of methylene chloride, and 0.126 ml of trifluoroacetic anhydride was added under ice-cooling and stirring. After the reaction solution was stirred at room temperature for 15 hours, 100 ml of 1N hydrochloric acid was added. Extracted with methylene chloride. After washing the extract with saturated saline,
Dried over sodium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 5: 1),
N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) trifluoroacetamide 19
8 mg was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
9 to 2.09 (2H, m), 2.27 to 2.42 (4
H, m), 3.70 (1H, m), 6.98
(1H, s), 7.41 (1H, t), 7.4
7 (1H, dt), 7.61 (1H, d),
7.81 (1H, t), 7.93 (1H, br)
s).

(Step 2) Synthesis of N-3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -N-methylaniline (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl ) Trifluoroacetamide 198m
g, potassium carbonate 117 mg and methyl iodide 0.04
5 ml of DMF was added to the resulting mixture, followed by stirring at room temperature for 8 hours. 10 ml of 1N hydrochloric acid and 100 ml of water were added to the reaction solution, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off, and the residue obtained was 120 mg of sodium carbonate, 5 ml of water and 1 ml of methanol.
5 ml was added, and the mixture was stirred at room temperature for 8 hours. The reaction solution was diluted with 100 ml of ethyl acetate, washed with saturated saline, and dried over sodium sulfate. The solvent was distilled off to give N-3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) -N
130 mg of -methylaniline were obtained as yellow needles. 73-75 ° C; NMR (400 MHz, CDCl
₃ ) δ ppm 1.87-2.10 (2H, m),
2.26 to 2.40 (4H, m), 2.83 (3
H, s), 3.69 (1H, m), 6.63
(1H, d), 6.80 (1H, t), 6.9
6. 2 (1H, s), 6.93 (1H, d),
16 (1H, t).

(Step 3) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N
Synthesis of -methyl-2- (4-methoxybenzyl) -2H-tetrazole-5-carboxamide N-3- (2- (4-cyclobutyl-2-thiazolyl)
Ethynyl) -N-methylaniline and the carboxylic acid of Reference Example 21 were treated in the same manner as in Step 2 of Example 104 to give N- (3
-(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N-methyl-2- (4-methoxybenzyl) -2H-tetrazole-5-carboxamide was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
1-2.09 (2H, m), 2.28-2.39 (4
H, m), 3.50 (3H, s), 3.65-
3.73 (1H, m), 3.75 (3H, s),
5.54 (2H, s), 6.82 (2H,
d), 6.97 (1H, s), 7.08-7.1.
0 (3H, m), 7.20 to 7.21 (1H,
m), 7.34 (1H, s), 7.42 (1H,
d).

(Step 4) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N
Synthesis of -methyl-1H-tetrazole-5-carboxamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N-methyl-2- (4-methoxybenzyl) -2H-tetrazole -5-Carboxamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 229-230 ° C (decomp.); IRν
max cm ^-1 3404,2216,1618; NMR
(400 MHz, DMSO-d ₆ ) δ ppm 1.86
~ 2.01 (2H, m), 2.17 ~ 2.30 (4
H, m), 3.42 (3H, s), 3.61-
3.70 (1H, m), 7.23 (1H, d),
7.34 (1H, t), 7.43 (1H, t)
d), 7.46 (1H, s), 7.51 (1H,
s); MS (FAB) m / z 365 (M + +
1); Elemental analysis value Calculated value of C ₁₈ H ₁₆ N ₆ OS (%)
C, 59.32; H, 4.43; N, 23.07,
Measured value (%) C, 58.89; H, 4.27;
N, 22.78.

Example 110 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1H- [1,2,3] triazole: (Step 1) N- (3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) phenyl) propiolamido 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline and propiolic acid, Step 1 of Example 103
To give N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) propiolamido. 158-160 ° C (recrystallization solvent: chloroform-
Ether); NMR (400 MHz, CDCl ₃ ) δ
ppm 1.88-2.10 (2H, m), 2.27
~ 2.42 (4H, m), 2.99 (1H,
s), 3.70 (1H, m), 6.97 (1H,
s), 7.34 (1H, t), 7.36 (1
H, dd), 7.59 (1H, dd), 7.7
5 (1H, s), 7.77 (1H, br s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1
Synthesis of H- [1,2,3] triazole N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) propiolamide was prepared in Example 7
This was treated in the same manner as in Step 1 of 7 to obtain the title compound. Mp two hundred and fifty-nine to two hundred sixty-two ° C. (recrystallization solvent: ethanol - ether); NMR (400MHz, DMSO- d 6)
δ ppm 1.87 to 2.05 (2H, m), 2.1
9 to 2.31 (4H, m), 3.67 (1H,
m), 7.38 (1H, d), 7.46 (1H,
t), 7.53 (1H, s), 7.92 (1
H, d), 8.16 (1H, s), 8.59
(1H, brs), 10.62 (1H, s);
MS (EI) m / z 341 (M ⁺ ); Elemental analysis value C
_{18 H 15 N 5 OS · 1} / 2H 2 O Calculated (%) C, 6
H, 4.50; N, 19.54, measured value (%) C, 60.58; H, 4.31; N, 1
9.16.

Example 111 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) maleamic acid: 274 mg of 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline and 106 mg of maleic anhydride in 5 ml of toluene and THF.
2 ml was added, and the mixture was heated under reflux for 2 hours. The crystals obtained by cooling were collected and recrystallized from chloroform-ethanol-n-hexane to give the title compound as yellow fine needles. Melting point 170-172 ° C (decomp.);
max cm ^-1 3412, 2216, 1708, 162
8; NMR (400 MHz, DMSO-d ⁶ ) δpp
m 1.84 to 2.09 (2H, m), 2.19 to
2.33 (4H, m), 3.67 (1H, m),
6.32 (1H, d), 6.50 (1H, d),
7.37 (1H, d), 7.44 (1H,
t), 7.53 (1H, s), 7.63 (1H,
d), 7.98 (1H, s), 10.53 (1
H, s), 12.96 (1H, s); MS (E
I) m / z 353 (M ⁺ ).

Example 112 2-N- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) aminocarbonyl-1-cyclohexene-1-carboxylic acid: 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline and 3,4,5,6 -Tetrahydrophthalic anhydride was treated in the same manner as in Example 111 to obtain the title compound. 139-141 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 3300, 29
44,2216,1718,1662,1640,16
06; NMR (400 MHz, DMSO-d ₆ ) δp
pm 1.63 (4H, s), 1.83 to 2.08
(2H, m), 2.20 to 2.33 (8H,
m), 3.62 to 3.70 (1H, m), 7.3
6. 1 (1H, d), 7.39 (1H, d),
52 (1H, s), 7.59 (1H, d),
7.96 (1H, s), 10.17 (1H,
s), 12.46 (1H, br s); MS (F
AB) m / z 407 (M + +1); Elemental analysis C ₂₃ H
₂₂ Calculated value of N ₂ O ₃ S ・ H ₂ O (%) C, 6
H, 5.52; N, 6.82, measured value (%) C, 67.15; H, 5.40; N, 6.7.2;
89.

Example 113 2-N- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) aminocarbonyl-1-cyclopropanecarboxylic acid: (Step 1) Methyl 2- (N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) Synthesis of phenyl) aminocarbonyl) -1-cyclopropanecarboxylate 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline and 2-methoxycarbonyl-1-cyclopropanecarboxylic acid were used in Step 1 of Example 103. To give methyl 2- (N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) aminocarbonyl) -1-cyclopropanecarboxylate as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.4
2 to 1.45 (1H, m), 1.70 to 1.80 (1
H, m), 1.91 to 2.09 (4H, m),
2.11 to 2.38 (4H, m), 3.69 (1
H, m), 3.75 (3H, s), 6.95
(1H, s), 7.27 to 7.30 (2H,
m), 7.60 (1H, d), 7.72 (1H,
s), 8.56 (1H, s).

(Step 2) 2- (N- (3- (2- (4
Synthesis of -cyclobutyl-2-thiazolyl) ethynyl) phenyl) aminocarbonyl) -1-cyclopropanecarboxylic acid methyl 2-N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) aminocarbonyl-1-cyclopropanecarboxylate was treated in the same manner as in Example 56 to obtain the title compound. Mp 177-178 ° C. (recrystallization solvent: ethanol - ether); NMR (400MHz, DMSO- d 6)
δ ppm 1.18 to 1.23 (1H, m), 1.5
8 to 1.62 (1H, m), 1.87 to 2.09
(3H, m), 2.19 to 2.38 (5H, m),
3.65 (1H, m), 7.20 (1H,
s), 7.25 (1H, t), 7.32 (1H,
d), 7.58 (1H, d), 7.98 (1
H, s), 10.20 (1H, s), 12.0
6 (1H, s); Elemental analysis _{C 20 H 18 N 2 O 3} S ·
1 / 4H ₂ O Calculated (%) C, 64.76; H ,
5.03; N, 7.55, measured value (%) C, 6
4.92; H, 5.01; N, 7.53.

Example 114 2-N-((3- (2
-(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) amino) carbonyl-1-cyclopentene-1
-Carboxylic acid: 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline and 1-cyclopentene-
The 1,2-dicarboxylic anhydride was treated in the same manner as in Example 111 to obtain the title compound. 170-172 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 3320,29
48, 2216, 1698, 1590; NMR (40
0 MHz, DMSO-d ₆ ) δ ppm 1.63 (4
H, s), 1.85 to 2.02 (4H, m),
2.20 to 2.30 (4H, m), 2.63 to 2.
65 (2H, m), 2.76 to 2.77 (2H,
m), 3.62 to 3.70 (1H, m), 7.3
6. (1H, d), 7.42 (1H, t),
53 (1H, s), 7.64 (1H, d),
7.97 (1H, s), 10.41 (1H,
s), 12.69 (1H, brs); Elemental analysis value C
Calculated value (%) of ₂₂ H ₂₀ N ₂ O ₃ S ・ H ₂ O C,
H, 5.20; N, 7.06, found (%) C, 66.47; H, 4.98; N, 7.66.
41.

[Example 115] (cis) -2-N-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) aminocarbonyl-4-cyclohexene-1-carboxylic acid: 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline and ( cis)-
The 4-cyclohexene-1,2-dicarboxylic anhydride was treated in the same manner as in Example 111 to obtain the title compound. 176-179 ° C (recrystallization solvent: chloroform-
Ethanol -n- hexane); IRνmax cm ^-1 3
320, 2940, 2216, 1710, 1688;
NMR (400 MHz, DMSO-d ₆ ) δ ppm
1.86-2.02 (2H, m), 2.18-2.
23 (4H, m), 2.25 to 2.62 (6H,
m), 2.90-2.91 (1H, m), 3.0
4-3.05 (1H, m), 3.61-3.70
(1H, m), 7.29 (1H, d), 7.38
(1H, t), 7.51 (1H, s), 7.5
7. (1H, d), 7.95 (1H, s),
92 (1H, s), 12.13 (1H, s);
MS (FAB) m / z 407 (M + +1); Elemental analysis _{C 23 H 22 N 2 O 3} S · 1 / 4H 2 O Calculated (%) C, 67.21; H , 5.52; N, 6.8
2, measured value (%) C, 67.26; H, 5.4
1; N, 6.81.

Example 116 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methylmaleamic acid: 3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) aniline and methylmaleic anhydride were treated in the same manner as in Example 111 to obtain the title compound. 132-136 ° C (decomp.); IRν
max cm ^-1 2216, 1706, 1632; NMR
(400 MHz, DMSO-d ₆ ) δ ppm 1.83
~ 2.09 (2H, m), 2.00 (3H,
d), 2.16 to 2.34 (4H, m), 3.6
7. (1H, m), 6.11 (1H, d),
33 (1H, d), 7.42 (1H, t),
7.53 (1H, s), 7.62 (1H, d),
7.97 (1H, s), 10.33 (1H,
s), 12.85 (1H, s); MS (FAB)
^{m / z 367 (M + +1} ); Elemental analysis C ₂₀ H ₁₈ N
Calculated value for ₂ O ₃ S.H ₂ O (%) C, 62.48;
H, 5.24; N, 7.29, measured value (%) C,
62.77; H, 4.88; N, 7.28.

Example 117 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-phenylmaleamic acid: 3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) aniline and phenylmaleic anhydride were treated in the same manner as in Example 111 to obtain the title compound. Melting point 172-175 ° C (decomp.); IRν
max cm ^-1 2212, 1712, 1686; NMR
(400 MHz, DMSO-d ₆ ) δ ppm 1.84
~ 2.05 (2H, m), 2.19 ~ 2.33 (4
H, m), 3.67 (1H, m), 6.61
(1H, d), 7.37 (1H, d), 7.4
4 to 7.55 (7H, m), 7.65 (1H,
s), 8.04 (1H, s), 10.54 (1
H, s), 13.20 to 13.23 (1H, b
r); MS (FAB) m / z 429 (M ⁺⁺ 1);
Elemental analysis value Calculated value of C ₂₅ H ₂₀ N ₂ O ₃ S (%) C,
H, 4.70; N, 6.54, measured value (%) C, 69.70; H, 4.86; N,
6.43.

Example 118 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2,3-dichloromaleamic acid: 3- (2-
Example 11 was prepared using (4-cyclobutyl-2-thiazolyl) ethynyl) aniline and 2,3-dichloromaleic anhydride.
Work-up as in 1 to give the title product. 153-156 ° C (decomp.); IRν
max cm ^-1 2212, 1724, 1678, 160
8,1586; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.84 to 2.05 (2H, m),
2.18 to 2.33 (4H, m), 3.67 (1
H, m), 7.42 (1H, d), 7.47
(1H, t), 7.54 (1H, s), 7.5
9 (1H, d), 7.90 (1H, s), 1
0.96 (1H, s); MS (FAB) m / z 42
1 (M ⁺ ); Elemental analysis value Calculated value for C ₁₉ H ₁₄ Cl ₂ N ₂ O ₃ S (%) C, 54.17; H, 3.35; N,
6.65, measured value (%) C, 54.01; H,
3.52; N, 6.43.

Example 119 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2,3-dibromomaleamic acid: 3- (2-
Example 11 was prepared using (4-cyclobutyl-2-thiazolyl) ethynyl) aniline and 2,3-dibromomaleic anhydride.
Work-up as in 1 to give the title product. Melting point 119-120 ° C (decomp.); IRν
max cm ^-1 2212, 1674, 1608, 158
4: NMR (400 MHz, DMSO-d ₆ ) δpp
m 1.84 to 2.05 (2H, m), 2.18 to
2.33 (4H, m), 3.67 (1H, m),
7.41 (1H, d), 7.46 (1H, t),
7.54 (1H, s), 7.59 (1H, s)
d), 7.89 (1H, s), 10.86 (1
H, s); MS (FAB) m / z 513 [(M ⁺
+4) +1), 511 [(M ⁺⁺ 2) +1)], [50
9 (M ⁺ ) +1]; Elemental analysis: C ₁₉ H ₁₄ Br ₂ N ₂ O
Calculated value of ₃ S (%) C, 44.73; H, 2.7
7; N, 5.49; measured value (%) C, 44.9
2; H, 3.13; N, 5.39.

Example 120 4-N- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) aminocarbonyl-3-carboxy-3-butenoic acid: 3- (2- (4-cyclobutyl-2-thiazolyl)
(Ethynyl) aniline and (cis) -aconitic anhydride were treated in the same manner as in Example 111 to give the title compound. 131-132 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 2212,1718,1634,1582,155
0; NMR (400 MHz, DMSO-d ₆ ) δpp
m 1.84 to 2.05 (2H, m), 2.19 to
2.33 (4H, m), 3.32 (2H, s),
3.67 (1H, m), 6.46 (1H,
s), 7.36 to 7.33 (1H, m), 7.4
3 (1H, t), 7.53 (1H, s), 7.6
3 (1H, d), 7.97 (1H, s), 1
0.47 (1H, s), 12.59 (1H, b
r), 12.96 (1H, br); MS (FA
B) m / z 411 (M ⁺⁺ 1); Elemental analysis C ₂₁ H
Calculated value for ₁₈ N ₂ O ₅ S.1 / 2H ₂ O (%) C, 6
H, 4.57; N, 6.68, measured value (%) C, 60.44; H, 4.55; N, 6.
62.

Example 121 (cis) -N- (3
-(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1,2-cyclohexaneamidic acid: 3
-(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) aniline and (cis) -1,2-cyclohexanedicarboxylic anhydride were treated in the same manner as in Example 111 to obtain the title compound. 179-180 ° C (recrystallization solvent: chloroform-
Ethanol -n- hexane); IRνmax cm ^-1 2
216, 1706, 1606, 1584, 1544;
NMR (400 MHz, DMSO-d ₆ ) δ ppm
1.31 to 2.31 (14H, m), 2.60 to
2.61 (1H, m), 2.94 to 2.95 (1
H, m), 3.62 to 3.70 (1H, m),
7.29 (1H, d), 7.38 (1H, t),
7.51 (1H, s), 7.56 (1H, d),
7.97 (1H, s), 9.91 (1H,
s), 11.95 (1H, br s); MS (F
AB) m / z 409 (M + +1); Elemental analysis C ₂₃ H
₂₄ Calculated value of N ₂ O ₃ S ・ H ₂ O (%) C, 6
N, 6.78; H, 5.98; N, 6.78; found (%) C, 66.95; H, 5.95;
75.

[Example 122] (trans) -N-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1,2-cyclohexaneamidic acid: 3- (2- (4-cyclobutyl-2-thiazolyl)
(Ethynyl) aniline and (trans) -1,2-cyclohexanedicarboxylic anhydride were treated in the same manner as in Example 111 to obtain the title compound. Melting point 200-201 ° C (recrystallization solvent: chloroform); IRν max cm ⁻¹ 2216,1726,166
6,1644,1608,1582,1500; NMR
(400 MHz, DMSO-d ₆ ) δ ppm 1.85
~ 2.55 (16H, m), 3.62-3.70
(1H, m), 7.29 (1H, d), 7.3
8. (1H, t), 7.51 (1H, s),
58 (1H, d), 7.96 (1H, s), 1
0.13 (1H, s), 12.08 (1H,
s); MS (FAB) m / z 409 (M ⁺⁺ 1);
Elemental analysis value Calculated value of C ₂₃ H ₂₄ N ₂ O ₃ S (%) C,
H, 5.92; N, 6.86, measured value (%) C, 67.51; H, 5.86; N,
6.83.

Example 123 N- (3- (2- (2
-Benzothiazole) ethynyl) phenyl) maleamic acid: 3- (2- (2-benzothiazole) ethynyl) aniline and maleic anhydride were treated in the same manner as in Example 111 to obtain the title compound. Melting point 169-171 ° C (recrystallization solvent: chloroform-
Ethanol); IRνmax cm ⁻¹ 2212,170
2,1628,1554; NMR (400 MHz, C
_{DCl 3) δppm 6.33 (1H,} d), 6.
50 (1H, d), 7.44 to 7.50 (2H,
m), 7.68 (1H, d), 8.05-8.1.
0 (2H, m), 8.18 (1H, s), 1
0.57 (1H, s), 12.95 (1H,
s); MS (FAB) m / z 349 (M ++ 1).

[Example 124] (Z) -N- (3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (1H-tetrazol-5-yl) cinnamamide: (Step 1) 2- (4-methoxybenzyl) -2H-tetrazole-5-carba Synthesis of aldehyde 16 g of carboxylic acid of Reference Example 19 was added to 100 ml of ethanol.
And sodium borohydride at 0 ° C. with stirring.
57 g were added slowly. After the reaction solution was stirred at room temperature for 12 hours, 100 ml of ice water was added, and oxalic acid was added for neutralization. This was extracted with methylene chloride, and the extract was washed with brine and dried over magnesium sulfate. The oily substance obtained by distilling off the solvent was purified without purification using toluene 100
ml and 15.3 g of activated manganese dioxide were added, and the mixture was heated under reflux for 3 hours. After cooling, the solvent was distilled off, and the residue was purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 4: 1) to give 2- (4-methoxybenzyl) -2H-tetrazole-5. 4.5 g of carbaldehyde were obtained as a pale yellow oil. IRνmax cm ⁻¹ 1726; NMR (400 MH
z, CDCl ₃ ) δ ppm 3.80 (3H, s),
5.79 (2H, s), 6.91 (2H, dt),
7.39 (2H, dt), 10.19 (1H, dt)
s).

(Step 2) Synthesis of 2- (2- (4-methoxybenzyl) -2H-tetrazolyl) phenylmethanol 2- (4-methoxybenzyl) -2H-tetrazole-
910 mg of 5-carbaldehyde was dissolved in 20 ml of THF, and 5 ml of phenylmagnesium bromide (1M THF solution) was added at 0 ° C. with stirring. After the reaction solution was stirred at the same temperature for 1 hour, a saturated aqueous ammonium chloride solution 30
ml was added. The mixture was extracted with ethyl acetate, and the extracted layer was washed with brine and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 4: 1) to give 2- (2- (4-methoxybenzyl) -2H- 916 mg of tetrazol-5-yl) phenylmethanol were obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 3.0
1 (1H, br s), 3.79 (3H, s),
5.65 and 5.67 (2H, each
d), 6.11 (1H, d), 6.88 (2H,
dt), 7.25-7.48 (7H, m).

(Step 3) 5-benzoyl-2- (4-
Synthesis of methoxybenzyl) -2H-tetrazole 2- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenylmethanol was oxidized with activated manganese dioxide in the same manner as in Step 1 to give 5-benzoyl-2-
(4-Methoxybenzyl) -2H-tetrazole was obtained. 61-62 ° C .; NMR (400 MHz, CDCl
₃ ) δ ppm 3.80 (3H, s), 5.82
(2H, s), 6.91 (2H, d), 7.4
2 (2H, dt), 7.53 (2H, t),
7.67 (1H, t), 8.34 (2H, d).

(Step 4) (Z) -ethyl 3- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Il) Synthesis of cinnamic acid 148 mg of sodium hydride (60% oil) was added to THF1
The suspension was suspended in 5 ml, and 832 mg of triethyl phosphonoacetic acid was added at 0 ° C., followed by stirring for 1 hour. The reaction mixture was added with 5-benzoyl-2- (4-methoxybenzyl) -2H at 0 ° C.
A solution of 909 mg of tetrazole in 5 ml of THF was added, and the mixture was further stirred at the same temperature for 1 hour. 30 ml of water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 4: 1) to give (Z) -ethyl 3- (2- (4-methoxybenzyl) ) -2H-Tetrazol-5-yl) cinnamic acid 900
mg was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.0
3. 5 (3H, t), 3.76 (3H, s),
01 (2H, q), 5.77 (2H, s),
6.62 (1H, s), 6.89 (2H, d),
7.29-7.49 (7H, m).

(Step 5) Synthesis of (Z) -3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) cinnamic acid (Z) -ethyl 3- (2- (4-methoxybenzyl) )
-2H-tetrazol-5-yl) cinnamic acid was prepared according to Example 56.
To give (Z) -3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) cinnamic acid. Melting point 126 ° C; IRν max cm ^-1 2596,17
12; NMR (400 MHz, CDCl ₃ ) δ ppm
3.79 (3H, s), 5.76 (2H, s),
6.62 (1H, s), 6.89 (2H,
d), 7.27-7.54 (7H, m); MS
(FAB) m / z 336 ( M + +1); Elemental analysis C ₁₈ Calculated _{H 16 N 4 O 3 (%} ) C, 64.28;
H, 4.79; N, 16.66, measured value (%) C,
H, 4.93; N, 16.61.

(Z) -N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-
Synthesis of (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) cinnamamide 3- (2- (2-benzothiazole) ethynyl) aniline and (Z) -3- (2- (4-methoxybenzyl) ) -2
(H-tetrazol-5-yl) cinnamic acid was treated in the same manner as in Step 1 of Example 103 to give (Z) -N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) cinnamamide was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
9 to 2.41 (6H, m), 3.70 (1H,
m), 3.76 (3H, s), 5.74 (2H,
s), 6.74 (1H, s), 6.82 (2
H, d), 6.96 (1H, s), 7.27-
7.40 (9H, m), 7.55 (1H, d),
7.76 (1H, s), 7.96 (1H, s).

(Step 7) (Z) -N- (3- (2-
Synthesis of (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (1H-tetrazol-5-yl) cinnamamide (Z) -N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) )) Phenyl) -3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) cinnamamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 127-129 ° C (recrystallization solvent: chloroform-
n-hexane); NMR (400 MHz, DMSO-
d ₆ ) δ ppm 1.85 to 2.33 (6H, m);
3.66 (1H, m), 7.14 (1H, s),
7.30 to 7.59 (8H, m), 7.93 (1
H, s), 10.69 (1H, s); MS (F
AB) m / z 453 (M ⁺⁺ 1).

Example 125 (E) -N- (3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-3- (1H-tetrazol-5-yl) propenamide: (Step 1) (E) -ethyl 2-fluoro-3- (2
-(4-methoxybenzyl) -2H-tetrazole-5
Synthesis of -yl) acrylic acid 2- (4-methoxybenzyl) -2H-tetrazole-
5-Carbalaldehyde and triethyl 2-fluorophonoacetic acid were treated in the same manner as in Step 4 of Example 124 to give (E)-
Ethyl 2-fluoro-3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) propenamide was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.1
6. (3H, t), 3.80 (3H, s),
22 (2H, q), 5.70 (2H, s),
6.73 (1H, d), 6.89 (2H, d),
7.34 (2H, d).

(Step 2) (E) -2-Fluoro-3-
Synthesis of (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) acrylic acid Ethyl (E) -2-fluoro-3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl ) Acrylic acid was treated in the same manner as in Example 56 to obtain (E) -2-fluoro-3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) acrylic acid. Melting point 65 ° C; IRν max cm ⁻¹ 2952,284
4,2728,2616,2532,1750; NM
R (400 MHz, CDCl ₃ ) δ ppm 3.82
(3H, s), 5.77 (2H, s), 6.9
3 (2H, d), 7.00 (1H, d), 7.3
8 (2H, d); Elemental analysis value Calculated value of C ₁₂ H ₁₁ FN ₄ O ₃ (%) C, 51.80; H, 3.98; N,
20.14, measured value (%) C, 51.92; H,
4.09; N, 20.22.

(Step 3) (E) -N- (3- (2-
Synthesis of (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) propenamide 3- (2- (2- (Benzothiazole) ethynyl) aniline and (E) -2-fluoro-3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) acrylic acid were treated in the same manner as in Step 1 of Example 103. (E) -N
-(3- (2- (4-cyclobutyl-2-thiazolyl)
(Ethynyl) phenyl) -2-fluoro-3- (2- (4
-Methoxybenzyl) -2H-tetrazol-5-yl) propenamide was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.42 (6H, m), 3.70 (1H,
m), 3.80 (3H, s), 5.78 (2H,
s), 6.90-7.00 (4H, m), 7.
35-7.41 (4H, m), 7.84 (1H,
dt), 7.95 (1H, s), 11.74 (1
H, s).

(Step 4) (E) -N- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-3- (1H-tetrazole-5
Synthesis of (E) -N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-3-
(2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) propenamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point 211-212 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2212,16
72; NMR (400 MHz, DMSO-d ₆ ) δp
pm 1.84 to 2.33 (6H, m), 3.67
(1H, m), 7.23 (1H, d), 7.45
~ 7.54 (3H, m), 7.74 (1H,
d), 8.07 (1H, s), 11.14 (1
H, s); MS (FAB ) m / z 395 (M + +
1); Elemental analysis value C ₁₉ H ₁₅ FN ₆ OS · 1 / 2H ₂ O
C, 56.57; H, 4.00;
N, 20.83, measured value (%) C, 56.37;
H, 3.87; N, 20.67.

[Example 126] (Z) -N- (3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-3- (1H-tetrazol-5-yl) propenamide: (Step 1) (Z) -N- (3- (2 -(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-3- (2- (4-methoxybenzyl) -2H-
Synthesis of tetrazol-5-yl) propenamide In step 3 of Example 125, the Z-isomer was separated and (Z)-
N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-3- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Il) Propenamide was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
2-2.44 (6H, m), 3.70 (1H,
m), 3.81 (3H, s), 5.75 (2H,
s), 6.91 (2H, d), 6.97 (1
H, s), 7.35-7.43 (4H, m),
7.68 (1H, m), 7.87 (1H, d),
8.10 (1H, m).

(Step 2) (Z) -N- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-3- (1H-tetrazole-5
Synthesis of -yl) propenamide (Z) -N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-3-
(2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) propenamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 125-128 ° C; elemental analysis C ₁₉ H ₁₅ FN ₆ O
S · 1 / 2H ₂ O Calculated (%) C, 56.57;
H, 4.00; N, 20.83, measured value (%)
C, 56.86; H, 4.29; N, 20.00.

Example 127 (E) -N- (3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-3- (1H-tetrazol-5-yl) -2-butenamide: (Step 1) 1- (2- (4-methoxy) Benzyl) -2
Synthesis of H-tetrazol-5-yl) ethanol 2- (4-methoxybenzyl) -2H-tetrazole-
5-carbaldehyde and methylmagnesium bromide (3
M ether solution) was treated in the same manner as in Step 2 of Example 124 to obtain 1- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) ethanol. 61-62 ° C .; NMR (400 MHz, CDCl
₃ ) δ ppm 1.65 (3H, d), 2.56
(1H, d), 3.80 (3H, s), 5.1
6. (1H, m), 5.67 (2H, s),
89 (2H, dt), 7.34 (2H, dt).

(Step 2) Synthesis of 2-acetyl-2- (4-methoxybenzyl) -2H-tetrazole To give 2-acetyl-2- (4-methoxybenzyl) -2H-tetrazole. Melting point 66-67 ° C; IRν max cm ^-1 1718;
1. NMR (400 MHz, CDCl ₃ ) δ ppm
74 (3H, s), 3.80 (3H, s),
5.77 (2H, s), 6.90 (2H, d),
7.39 (2H, d).

(Step 3) Synthesis of ethyl (E) -2-fluoro-3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-butenoic acid 2-acetyl-2- ( 4-methoxybenzyl) -2H-
Treating the tetrazole as in Step 1 of Example 125,
Ethyl (E) -2-fluoro-3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2
-Butenoic acid was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.0
2. 0 (3H, t), 2.17 (3H, d),
80 (3H, s), 4.04 (2H, q),
5.70 (2H, s), 6.90 (2H, d),
7.36 (2H, d).

(Step 4) (E) -2-Fluoro-3-
Synthesis of (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-butenoic acid Ethyl (E) -2-fluoro-3- (2- (4-methoxybenzyl) -2H-tetrazole- 5-yl) -2
-Butenoic acid was treated in the same manner as in Example 56, and (E) -2-
Fluoro-3- (2- (4-methoxybenzyl) -2H
-Tetrazol-5-yl) -2-butenoic acid was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 2.3
6 (3H, d), 3.81 (3H, s), 5.
76 (2H, s), 6.93 (2H, d),
7.38 (2H, d).

(Step 5) (E) -N- (3- (2-
Synthesis of (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-butenamide 3- (2- ( 2-benzothiazole) ethynyl) aniline and (E) -2-fluoro-3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) butenoic acid were treated in the same manner as in Step 1 of Example 103. And (E) -N-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-3- (2- (4-
Methoxybenzyl) -2H-tetrazol-5-yl)
Butenamide was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
9 to 2.39 (6H, m), 3.69 (1H,
m), 3.78 (3H, s), 5.74 (2H,
s), 6.89 (2H, dt), 7.29-
7.40 (4H, m), 7.59 (1H, d),
7.81 (1H, s), 9.24 (1H,
s).

(Step 6) (E) -N- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-3- (1H-tetrazole-5
Synthesis of (E) -N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-3-
(2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) butenamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point 199-200 ° C; IRνmax cm ^-1 221
6,1672; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.88-2.27 (6H, m),
3.66 (1H, m), 7.42 to 7.47 (2
H, m), 7.52 (1H, s), 7.68
(1H, d), 7.93 (1H, s), 10.7
4 (1H, s); MS (FAB) m / z 409
(M ⁺ +1); elemental analysis value C ₂₀ H ₁₇ FN ₆ OS · 3/4
Of H ₂ O Calculated (%) C, 56.93; H , 4.4
2; N, 19.92; measured value (%) C, 57.1
3; H, 4.18; N, 19.80.

Example 128 (E) -N- (3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (1H-tetrazol-5-yl) -2-propenamide: (Step 1) Ethyl (E) -3- (2- (4 Synthesis of -methoxybenzyl) -2H-tetrazol-5-yl) acrylic acid 2- (4-methoxybenzyl) -2H-tetrazole-
5-Carbaldehyde and triethyl phonoacetic acid were treated in the same manner as in Step 4 of Example 124 to give ethyl (E) -3-
(2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) acrylic acid was obtained. Melting point 36 ° C .; NMR (400 MHz, CDCl ₃ ) δ
ppm 1.33 (3H, t), 3.80 (3H, t)
s), 4.27 (2H, q), 5.70 (2
H, s), 6.90 (2H, dt), 7.35
(2H, dt), 7.66 (1H, d).

(Step 2) Synthesis of (E) -3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) acrylic acid Ethyl (E) -3- (2- (4-methoxybenzyl) )
-2H-tetrazol-5-yl) acrylic acid was treated in the same manner as in Example 56 to obtain (E) -3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) acrylic acid. . Melting point 167-169 ° C; IR νmax cm ^-1 268
8,2268,2556,1694; NMR (400
MHz, CDCl ₃ ) δ ppm 3.80 (3H,
s), 5.71 (2H, s), 6.90 (2H,
d), 7.36 (2H, dt), 7.76 (1
H, d); MS (FAB) m / z 261 (M ⁺
+1); Elemental analysis value Calculated value of C ₁₂ H ₁₂ N ₄ O ₃ (%)
C, 55.38; H, 4.65; N, 21.5
3, measured value (%) C, 55.34; H, 4.70;
N, 21.63.

(Step 3) (E) -N- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (2- (4-methoxybenzyl) -2H-
Synthesis of tetrazol-5-yl) -2-propenamide (E) -3- (2- (4-methoxybenzyl) -2H-
Tetrazol-5-yl) acrylic acid and 3- (2- (4
-Cyclobutyl-2-thiazolyl) aniline in Example 1
03, and treated in the same manner as in Step 1 of (E) -N- (3- (2
-(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (2- (4-methoxybenzyl) -2H
-Tetrazol-5-yl) -2-propenamide was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
4 to 2.36 (6H, m), 3.70 (1H,
m), 3.81 (3H, s), 5.71 (2H,
s), 6.96 (1H, s), 7.14 (2
H, d), 7.34 (4H, m), 7.40
(1H, m), 7.77 (1H, d), 7.83
(1H, s).

(Step 4) (E) -N- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (1H-tetrazol-5-yl) -2-
Synthesis of propenamide (E) -N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) −
The 2-propenamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point> 300 ° C .; IRνmax cm ⁻¹ 2212,1
674; NMR (400 MHz, CDCl ₃ ) δpp
m 1.84 to 2.31 (6H, m), 3.67
(1H, m), 7.30 to 7.59 (5H,
m), 7.71 (1H, d), 8.09 (1H,
s), 10.75 (1H, s); MS (FA
B) m / z 377 (M + +1); Elemental analysis C ₁₉
Calculated value of H ₁₆ N ₆ OS · 1 / 2H ₂ O (%) C, 5
H, 4.45; N, 21.80, measured value (%) C, 59.03; H, 4.29; N, 2
1.66.

Example 129 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (1H-tetrazol-5-yl) -1-cyclopentene-1-carboxamide: (Step 1) ethyl 2- (2- (4-methoxybenzyl) -2H Synthesis of -tetrazol-5-yl) -1-cyclopentene-1-carboxylate Ethyl 2-cyano-1-cyclopentene-1-carboxylate was treated in the same manner as in Reference Example 20 to give ethyl 2-
(2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) -1-cyclopentene-1-carboxylate was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.1
3 (3H, t), 2.05 (2H, q), 2.
85 (2H, t), 2.96 (2H, t),
3.79 (3H, s), 4.15 (2H, q),
5.68 (2H, s), 6.86 (2H, d),
7, 32 (2H, d).

(Step 2) Synthesis of 2- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -1-cyclopentene-1-carboxylic acid Ethyl 2- (2- (4-methoxybenzyl) -2H-
Tetrazol-5-yl) -1-cyclopentene-1-
The carboxylate was treated as in Example 56,
(2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) -1-cyclopentene-1-carboxylic acid was obtained. 106-108 ° C; NMR (400 MHz, CD
Cl ₃ ) δ ppm 1.99 (2H, q), 2.9
3-3.03 (2H, m), 3.10-3.33
(2H, m), 3.80 (3H, s), 5.7
1 (2H, s), 6.91 (2H, d), 7, 3
7 (2H, d); calculated value of elemental analysis value C ₁₅ H ₁₆ N ₄ O ₃ (%) C, 59.99; H, 5.37; N, 1
8.66, found (%) C, 59.69; H, 5.
37; N, 18.19.

(Step 3) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -1-cyclopentene-1-carboxamide 2- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl)- 1-cyclohepentene-1-carboxylic acid and 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline were treated in the same manner as in Step 1 of Example 103 to give N- (3- (2- ( 4-cyclobutyl-2-
Thiazolyl) ethynyl) phenyl) -2- (2- (4-
Methoxybenzyl) -2H-tetrazol-5-yl)
-1-cyclopentene-1-carboxamide was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
To 2.11 (2H, m), 2.28 to 2.41 (4
H, m), 3.08 (2H, t), 3.16
(2H, t), 3.68 (1H, m), 3.7
9 (3H, s), 5.76 (2H, s), 6.9
0 (2H, d), 6.95 (1H, s), 7,
29-7.33 (2H, m), 7.37 (2H,
d), 7.78-7.81 (1H, m), 7.9
6 (1H, s), 11.58 (1H, s).

(Step 4) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of-(1H-tetrazol-5-yl) -1-cyclopentene-1-carboxamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (2- (4- Methoxybenzyl) -2H-tetrazol-5-yl) -1-cyclopentene-1-carboxamide was prepared according to Step 5 of Example 1.
The title compound was obtained. 186-189 ° C (decomp.); NMR
(400 MHz, DMSO-d ₆ ) δ ppm 1.81
~ 2.09 (2H, m), 2.21-2.28 (4
H, m), 2.94 to 2.99 (4H, m),
3.67 (1H, m), 7.38 (1H, d),
7.44 (1H, t), 7.53 (1H, s),
7.67 (1H, d), 8.02 (1H, d)
s), 10.46 (1H, s), 7.30-7.
59 (5H, m), 7.71 (1H, d),
8.09 (1H, s), 10.75 (1H, s);
Elemental analysis value Calculated value of C ₂₂ H ₂₀ N ₆ OS · １ ／ H ₂ O (%) C, 62.76; H, 4.91; N, 1
9.96, measured value (%) C, 62.56; H,
5.04; N, 19.53.

Example 130 (E, E) -N- (3
-(2- (4-isopropyl-2-thiazolyl) ethynyl) phenyl) -5- (1H-tetrazol-5-yl) -2,4-pentadienamide: (Step 1) (E, E) -N- (3 -(2- (4-isopropyl-2-thiazolyl) ethynyl) phenyl) -5
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2,4-pentadienamide 3- (2- (4-
Isopropyl-2-thiazolyl) ethynyl) aniline and (E, E) -5- (2- (4-methoxybenzyl) -2
(H-tetrazol-5-yl) -2,4-pentadienamide was treated in the same manner as in Step 1 of Example 103 to give (E,
E) -N- (3- (2- (4-isopropyl-2-thiazolyl) ethynyl) phenyl) -5- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl)-
2,4-Pentadienamide was obtained. 150-151 ° C; IRνmax cm ^-1 221
2,1678; NMR (400 MHz, CDCl ₃ )
δ ppm 1.35 (6H, d), 3.15 (1
H, m), 3.80 (3H, s), 5.69
(2H, s), 6.90 (2H, d), 6.9
4. (1H, s), 6.95 (1H, d), 7.
18 to 7.68 (8H, m), 7.79 (1H,
br s); MS (FAB) m / z 511 (M + +
1); Elemental analysis value Calculated value of C ₂₈ H ₂₆ N ₆ O ₂ S (%)
C, 65.86; H, 5.13; N, 16.4.
6, measured value (%) C, 65.60; H, 5.1
0; N, 16.72.

(Step 2) (E, E) -N- (3- (2
-(4-isopropyl-2-thiazolyl) ethynyl) phenyl) -5- (1H-tetrazol-5-yl)-
Synthesis of 2,4-pentadienamide (E, E) -N- (3- (2- (4-isopropyl-2
-Thiazolyl) ethynyl) phenyl) -5- (2- (4
-Methoxybenzyl) -2H-tetrazol-5-yl) -2,4-pentadienamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 212-214 ° C (recrystallization solvent: chloroform-
Methanol); NMR (400 MHz, DMSO-d)
₆ ) δ ppm 1.27 (6H, d), 3.08
(1H, m), 6.54 (1H, d), 7.2
2 (1H, d), 7.36 to 7.54 (5H,
m), 7.69 (1H, d), 8.07 (1H,
s), 10.46 (1H, s); Elemental analysis C
₂₀ Calculated _{H 18 N 6 OS (%)} C, 61.52;
H, 4.65; N, 21.52, measured value (%)
C, 61.50; H, 4.73; N, 21.52.

Example 131 3- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) benzoyl-1
H-tetrazole: (Step 1) 5- (3-Iodobenzoyl) -1- (4
-Methoxybenzyl) -1H-tetrazole 3-Iodo-N-methoxy-N-methylbenzamide 5
82 mg and 380 mg of 1- (4-methoxybenzyl) -1H-tetrazole were added to 10 ml of THF and N, N′-.
Add 1 ml of tetramethylethylenediamine and stir-
At 78 ° C., lithium hexamethyldisilazide (1M T
2 ml of HF solution was added dropwise over 5 minutes. After the reaction solution was further stirred at the same temperature for 30 minutes, 10 ml of saturated ammonium chloride was added, and the temperature was returned to room temperature. The reaction solution was extracted with ethyl acetate, and the extract was washed with saturated saline and dried over sodium sulfate. The residue obtained by distilling off the solvent is subjected to column chromatography using silica gel (eluent: n
-Hexane: ethyl acetate = 5: 1) to give 5- (3
-Iodobenzoyl) -1- (4-methoxybenzyl)
1H-tetrazole was obtained. 86-89 ° C; NMR (400 MHz, CDCl
₃ ) δ ppm 3.76 (3H, s), 5.88
(2H, s), 6.83-6.85 (2H, m),
7.27 (1H, t), 7.34 to 7.37 (2
H, m), 8.00 (1H, d), 8.41
(1H, d), 8.67 (1H, s).

(Step 2) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzoyl)-
Synthesis of 1- (4-methoxybenzyl) -1H-tetrazole 5- (3-iodobenzoyl) -1- (4-methoxybenzyl) -1H-tetrazole and 3- (2- (4-cyclobutyl-2-thiazolyl) ) Ethynyl) aniline was treated as in step 4 of example 1 to give 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) benzoyl) -1- (4-methoxybenzyl) -1H-tetrazole was obtained. 83-86 ° C; NMR (400 MHz, CDCl
₃ ) δ ppm 1.92 to 2.40 (6H, m),
3.66 to 3.76 (1H, m), 3.76 (3
H, s), 5.90 (2H, s), 6.83-
6.86 (2H, m), 6.99 (1H, s),
7.35 to 7.37 (2H, m), 7.55 (1
H, t), 7.87 (1H, d), 8.42
(1H, d), 8.59 (1H, s).

(Step 3) Synthesis of 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzoyl-1H-tetrazole 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzoyl ) -1- (4-Methoxybenzyl) -1H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 191 to 196 ° C. (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 3112,3088,2944,2220,166
8, 1596, 1504; NMR (400 MHz, D
_{MSO-d 6) δppm 1.85~2.32 (} 6H,
m), 3.64 to 3.72 (1H, m), 7.5
6. (1H, s), 7.75 (1H, t),
04 (1H, d), 8.44 (1H, d),
8.64 (1H, s); MS (EI) m / z 33
5 (M ⁺ ); Elemental analysis C ₁₇ H ₁₃ N ₅ OS Calculated (%) C, 60.88; H, 3.91; N, 20.
88, measured value (%) C, 60.61; H, 3.9
5; N, 20.82.

Example 132 Ethyl (E) -3-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (1H-tetrazole-5
Yl) propenoic acid: (step 1) ethyl (E) -3- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
Synthesis of -3- (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) propenoic acid 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzoyl) -1- ( 4-Methoxybenzyl) -1H-tetrazole and triethyl phosphonoacetic acid were treated in the same manner as in Step 4 of Example 124 to give ethyl (E) -3- (3- (2- (4-cyclobutyl-2-
Thiazolyl) ethynyl) phenyl) -3- (1- (4-
Methoxybenzyl) -1H-tetrazol-5-yl)
Propenoic acid was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.1
5 (3H, t), 1.84-2.39 (6H,
m), 3.65 to 3.73 (1H, m), 3.7
5 (3H, s), 4.12 (2H, q),
07 (2H, s), 6.67 (1H, s),
6.77 to 6.82 (2H, m), 6.99 (1
H, s), 7.19 (1H, d), 7.32.
(1H, s), 7.38 (1H, t), 7.64
(1H, d).

(Step 2) Ethyl (E) -3- (3-
Synthesis of (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (1H-tetrazol-5-yl) propenoic acid Ethyl (E) -3- (3- (2- (4-cyclobutyl- 2-thiazolyl) ethynyl) phenyl) -3- (1-
(4-methoxybenzyl) -1H-tetrazole-5
Yl) propenoic acid is treated in the same manner as in step 5 of Example 1,
The title was obtained. 122-124 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2216,17
24; NMR (400 MHz, CDCl ₃ ) δ ppm
1.10 (3H, t), 1.86 to 2.37 (6
H, m), 3.58-3.67 (1H, m),
4.07 (2H, q), 6.98 (1H, s),
7.23 (1H, s), 7.30 to 7.44 (4
H, m); MS (EI) m / z 405 (M ^<+> );
Elemental analysis value Calculated value of C ₂₁ H ₁₉ N ₅ O ₂ S (%) C,
H, 4.72; N, 17.27, measured value (%) C, 62.06; H, 4.66; N,
17.02.

Example 133 3- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (1H-tetrazol-5-yl) propenoic acid: ethyl (E) -3- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) Phenyl) -3-
(1H-Tetrazol-5-yl) propenoic acid was treated in the same manner as in Example 56 to obtain the title compound. Melting point> 300 ° C. (recrystallization solvent: chloroform-ethanol); IRνmax cm ⁻¹ 2218, 1707, ¹
629; NMR (400 MHz, DMSO-d ₆ ) δ
ppm 1.88 to 2.33 (6H, m), 3.6
4-3.68 (1H, m), 6.99 (1H,
s), 7.43 (1H, d), 7.52 (1H,
t), 7.52 (1H, s), 7.61 (1
H, s), 7.70 (1H, d); MS (FA
B) m / z 378 (M + +1); Elemental analysis C ₁₉ H
₁₅ Calculated _{N 5 O 2 S (%)} C, 60.46; H,
4.01; N, 18.56, measured value (%) C, 6
0.52; H, 4.15; N, 18.65.

Example 134 (E) -3- (3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (1H-tetrazol-5-yl) acrylonitrile: (Step 1) (E) -3- (3- (2- (4-cyclobutyl) -2-thiazolyl) ethynyl) phenyl) -3-
Synthesis of (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) acrylonitrile 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzoyl) -1- (4-methoxybenzyl ) -1H-Tetrazole and diethyl cyanomethylphosphonic acid were treated in the same manner as in Step 4 of Example 124 to give (E) -3- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -3- (1- (4
-Methoxybenzyl) -1H-tetrazol-5-yl) acrylonitrile was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
2-2.40 (6H, m), 3.70-3.76 (1
H, m), 3.76 (3H, s), 5.08
(2H, s), 6.14 (1H, s), 6.6
2-6.79 (4H, m), 7.00 (1H,
s), 7.40-7.42 (2H, m), 7.5
1 (1H, t), 7.75 (1H, d).

(Step 2) (E) -3- (3- (2-
Synthesis of (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (1H-tetrazol-5-yl) acrylonitrile (E) -3- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) )) Phenyl) -3- (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) acrylonitrile was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Mp 179-182 ° C (decomp.) (Recrystallization solvent: chloroform-ethanol-n-hexane);
Rνmax cm ^-1 2220; NMR (400 MHz,
_{DMSO-d 6) δppm 1.83~2.32 (} 6
H, m), 3.62 to 3.71 (1H, m),
6.93 (1H, s), 7.54 (1H, s),
7.43 (1H, d), 7.52 (1H,
t), 7.52 (1H, s), 7.66 (1H,
t), 7.71 (1H, d), 7.85 (1
H, d), 7.88 (1H, s); MS (FA
B) m / z 359 (M ⁺⁺ 1); Elemental analysis C ₁₉ H
Calculated for ₁₄ N ₆ S (%) C, 62.88; H, 4.
03; N, 23.16, measured value (%) C, 62.
88; H, 4.02; N, 23.13.

Example 135 3- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) amino-1H-tetrazole: (Step 1) 5- (3-iodophenyl) amino-1-
Synthesis of (4-methoxybenzyl) -1H-tetrazole and 5- (3-iodophenyl) amino-2- (4-methoxybenzyl) -2H-tetrazole Performed 5- (3-iodophenyl) amino-1H-tetrazole Worked up as in step 3 of example 1 to give 5- (3-iodophenyl) amino-1- (4-methoxybenzyl)-
1H-tetrazole and 5- (3-iodophenyl) amino-2- (4-methoxybenzyl) -2H-tetrazole were obtained. 138-139 ° C; NMR (400 MHz, CD
Cl ₃ ) δ ppm 3.81 (3H, s), 5.6
1 (2H, s), 6.86 (1H, s), 6.9
6. 2 (2H, d), 7.03 (1H, t), 7.
31 (1H, dd), 7.37 (1H, dd),
7.38 (2H, d), 7.83 (1H, t).

(Step 2) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) amino-1- (4-methoxybenzyl) -1H-tetrazole and 5- (3- ( 2- (4-cyclobutyl-2-
Thiazolyl) ethynyl) phenyl) amino-2- (4-
Synthesis of methoxybenzyl) -2H-tetrazole The iodine compound and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to give 5- (3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) amino-1- (4-methoxybenzyl)
-1H-tetrazole, and 5- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
Amino-2- (4-methoxybenzyl) -2H-tetrazole was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.50 (6H, m), 3.60 to 3.70 (1
H, m), 3.80 (3H, s), 5.64
(2H, s), 6.91 (2H, d), 6.9
6. (1H, s), 7.16 (1H, s),
21 (1H, dd), 7.32 (1H, t),
7.39 (2H, d), 7.43 (1H, d
d), 7.71 (1H, t).

(Step 3) 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) amino-1
Synthesis of H-tetrazole The compound obtained in the above Step 2 was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 133-135 ° C (recrystallization solvent: chloroform-
Ethanol); NMR (400 MHz, DMSO-d)
₆ ) δ ppm 1.80-2.40 (6H, m),
3.20-3.40 (1H, brs), 3.60
~ 3.80 (1H, m), 7.22 (1H,
d), 7.42 (1H, t), 7.53 (1H,
s), 7.86 (1H, s), 10.09 (1
H, s); MS (FAB ) m / z 323 (M + +
1).

Example 136 5- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenoxy) -1H-tetrazole: (Step 1) 5- (3-iodophenoxy) -1- (4
Synthesis of -methoxybenzyl) -1H-tetrazole 948 g of 5-iodo-1- (4-methoxybenzyl) -1H-tetrazole, 741 mg of 3-iodophenol
And 20 ml of DMF to 1.24 g of potassium carbonate,
Stirred at 70 ° C. for 3 days. The reaction solution was poured into 200 ml of water and extracted with ethyl acetate. The extract was washed with water and dried over sodium sulfate. The residue obtained by evaporating the solvent is purified by column chromatography using silica gel (eluent: chloroform) to give 5- (3-iodophenoxy).
-1- (4-Methoxybenzyl) -1H-tetrazole was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 3.8
5. 0 (3H, s), 5.37 (2H, s),
91 to 6.87 (2H, m), 7.13 (1H,
t), 7.30-7.34 (3H, m), 7.6
0 (1H, d), 7.64 (1H, s).

(Step 2) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenoxy)-
Synthesis of 1- (4-methoxybenzyl) 1-H-tetrazole 5- (3-iodophenoxy) -1- (4-methoxybenzyl) -1H-tetrazo and 4-cyclobutyl-2-
The ethynylthiazole was treated as in step 4 of Example 1 to give 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenoxy) -1- (4-methoxybenzyl) 1-H-tetrazole Was obtained as a red-brown oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
9 to 2.40 (6H, m), 3.65 to 3.74 (1
H, m), 3.81 (3H, s), 5.39
(2H, s), 6.90-6.92 (2H,
m), 6.98 (1H, m), 7.32-7.3.
4 (2H, m), 7.40 to 7, 44 (2H,
m), 7.48 to 7.50 (1H, m), 7.5
3 (1H, s).

(Step 3) 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenoxy)-
Synthesis of 1H-tetrazole 5- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenoxy) -1- (4-methoxybenzyl) 1-H-tetrazole was prepared in the same manner as in Step 5 of Example 1. Work-up provided the title. Melting point 161-163 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2212; N
MR (400 MHz, DMSO-d ₆ ) δ ppm 1.8
3 to 2.30 (6H, m), 3.63 to 3.71
(1H, m), 7.48 to 7.58 (4H, m),
7.68 (1H, s); MS (EI) m / z 3
23 (M ⁺ ); Elemental analysis value C ₁₆ H ₁₃ N ₅ OS · 1/4
Of H ₂ O Calculated (%) C, 58.61; H , 4.1
5; N, 21.36, measured value (%) C, 58.8
5; H, 4.10; N, 21.32.

[Example 137] 5- (3- (2- (3
-(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) ethynyl) phenyl) -1H-tetrazole: (Step 1) 5- (3- (2- (3- (2- (4-cyclobutyl-2) -Thiazolyl) ethynyl) phenyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2
Synthesis of H-tetrazole 5- (3-ethynylphenyl) -2- (4-methoxybenzyl) -2H-tetrazole and 1-bromo-3- (2
-(4-Cyclobutyl-2-thiazolyl) ethynyl) benzene was treated in the same manner as in Step 4 of Example 1 to give 5- (3-
(2- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) ethynyl) phenyl) -2-
(4-Methoxybenzyl) -2H-tetrazole was obtained as a yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.50 (6H, m), 3.60 to 3.80 (1
H, m), 3.81 (3H, s), 5.75
(2H, s), 6.92 (2H, d), 6.9
8 (1H, m), 7.30 to 7.40 (3H,
m), 7.49 (1H, t), 7.50-7.6.
0 (2H, m), 7.60 (1H, d), 7.
7. 77 (1H, s), 8.12 (1H, d),
32 (1H, s).

(Step 2) 5- (3- (2- (3- (2
Synthesis of-(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) ethynyl) phenyl) -1H-tetrazole 5- (3- (2- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) ethynyl) phenyl) -2- (4-methoxybenzyl) -2H-tetrazole was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 106-108 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane); NMR (400
_{MHz, DMSO-d 6) δppm} 1.80~2.4
0 (6H, m), 3.60 to 3.80 (1H,
m), 7.70 (1H, s), 7.74 (1H,
t), 7.60-7.80 (3H, m), 7.
80 (1H, d), 7.90 (1H, s),
8.11 (1H, d), 8.25 (1H, s);
MS (FAB) m / z 408 (M + +1); Calculated elemental analysis _{C 24 H 17 N 5 S (} %) C, 58.2
5; H, 3.77; N, 12.82, measured value (%) C, 58.51; H, 3.52; N, 1
2.82.

Example 138 N- (1H-tetrazol-5-yl) -4-((3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) aminosulfonyl) benzamide: (Step 1) ) 4-((3- (2- (4-cyclobutyl-
Synthesis of 2-thiazolyl) ethynyl) phenyl) aminosulfonyl) benzoic acid (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline 293m and pyridine were dissolved in 10 ml of methylene chloride to give 4-chlorosulfonylbenzoic acid. 2
54 mg was added and the mixture was stirred at room temperature for 1 hour. 10 ml of 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with methylene chloride. The extract was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off, and the resulting crude crystals were recrystallized from chloroform-n-hexane to give 4-((3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) aminosulfonyl) benzoic acid. Was. Melting point: 213 to 216 ° C. (decomp.);
max cm ^-1 2216, 1704, 1602, 158
0, 1504, 1338; NMR (400 MHz, D
_{MSO-d 6) δppm 1.89~2.33 (} 6H,
m), 3.64 (1H, m), 7.21-7.
24 (1H, m), 7.31 to 7.40 (3H,
m), 7.54 (1H, s), 7.90 (1H,
d), 8.10 (1H, d), 10.76 (1
H, s); MS (FAB ) m / z439 (M + +
1); Elemental analysis _{C 22 H 18 N 2 O 4} S 2 · H 2 O Calculated (%) C, 57.88; H , 4.42; N,
6.14, measured value (%) C, 58.02; H,
4.13; N, 5.86.

(Step 2) N- (1H-tetrazole-
5-yl) -4-((3- (2- (4-cyclobutyl-
Synthesis of 2-thiazolyl) ethynyl) phenyl) aminosulfonyl) benzamide 4-((3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) aminosulfonyl) benzoic acid and 5-amino-1H-tetrazo- Was treated as in Example 86 to give the title product. 203-206 ° C (decomp.) (Recrystallization solvent: chloroform-ethanol-n-hexane);
Rνmax cm ⁻¹ 2216,1692,1588,15
48, 1504, 1406, 1338; NMR (40
_{0MHz, DMSO-d 6) δppm} 1.83~2.
33 (6H, m), 3.66 (1H, m), 7.
26 (1H, dt), 7.30-7.39 (3H,
m), 7.53 (1H, s), 7.96 (1H,
d), 8.20 (1H, d), 10.78 (1
H, s), 12.63 (1H, br); MS
(FAB) m / z 506 ( M + +1); Elemental analysis _{C 23 H 29 N 7 O 3} S 2 Calculated (%) C, 54.6
N, 19.39, measured value (%) C, 54.24; H, 3.83; N, 1
8.98.

Example 139 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) -4-
(1H-tetrazol-5-yl) benzenesulfonamide: (Step 1) N- (3-iodophenyl) -4- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Synthesis of yl) benzenesulfonamide N- (3-Iodophenyl) -4- (1H-tetrazol-5-yl) benzenesulfonamide was treated in the same manner as in Step 3 of Example 1 to give N- (3-Iodophenyl)-
4- (2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) benzenesulfonamide was obtained. 139-140 ° C (recrystallization solvent: methylene chloride); NMR (400 MHz, CDCl ₃ ) δppm
3.80 (3H, s), 5.74 (2H,
s), 6.73 (1H, s), 6.90 (2H,
d), 6.95 (1H, t), 7.05-7.
07 (1H, m), 7.38 (2H, d), 7.
44-7.46 (2H, m), 7.86 (2H,
d), 8.23 (2H, d); MS (FAB) m
/ Z 538 (M ⁺ +1); Elemental analysis C ₂₁ H ₁₈ IN
₅ O ₃ S Calculated (%) C, 46.08; H, 3.3
1; N, 12.79; measured value (%) C, 46.8
7; H, 3.67; N, 12.15.

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzenesulfonamide N- (3-iodophenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazole-5- Yl) Benzenesulfonamide and 4-cyclobutyl-2-ethynylthiazole were treated in the same manner as in Step 4 of Example 1 to give N-
(3- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzenesulfonamide was obtained. 130-132 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2216; NM
R (400 MHz, CDCl ₃ ) δ ppm 1.88-
2.40 (6H, m), 3.69 (1H, m),
3.79 (3H, s), 5.73 (2H,
s), 6.80 (1H, brs), 6.89
(2H, d), 7.00 (1H, s), 7.1
4 (1H, d), 7.21 (1H, t), 7.2
9 (1H, t), 7.32 (1H, d), 7.3
8. (2H, d), 7.84 (2H, d),
19 (2H, d); MS (FAB) m / z 583
(M ⁺ +1); Elemental analysis value C ₃₀ H ₂₆ N ₆ O ₃ S ₂ .H
₂ O calculated value (%) C, 59.99; H, 4.70;
N, 13.99, measured value (%) C, 59.91;
H, 4.37; N, 13.88.

(Step 3) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -4- (1H-
Synthesis of tetrazol-5-yl) benzenesulfonamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazole-5 -Yl) benzenesulfonamide is treated as in step 5 of example 1;
The title was obtained. Mp 172-175 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 2216,1656,1602,1576,153
8,1352; NMR (400 MHz, CDCl ₃ )
2. δ ppm 1.88 to 2.40 (6H, m);
69 (1H, m), 3.79 (3H, s), 5.
73 (2H, s), 6.80 (1H, br)
s), 6.89 (2H, d), 7.00 (1H,
s), 7.14 (1H, d), 7.21 (1H,
t), 7.29 (1H, t), 7.32 (1
H, d), 7.38 (2H, d), 7.84 (2
H, d), 8.19 (2H, d); MS (FA
B) m / z 463 (M + +1); Elemental analysis C ₂₂
H ₁₈ N ₆ O ₂ S ₂ .1 / 2H ₂ O Calculated value (%) C, 5
N, 17.82; H, 4.06; N, 17.82, found (%) C, 56.12; H, 3.93;
94.

Example 140 N- (4- (1H-tetrazol-5-yl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzenesulfonamide: (Step 1) N- ( Synthesis of 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -3-bromobenzenesulfonamide N- (4- (1H-tetrazol-5-yl) -3-bromobenzenesulfur The vonamide was treated in the same manner as in Step 3 of Example 1 to obtain N- (4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -3-bromobenzenesulfonamide. 190 to 192 ° C (recrystallization solvent: methylene chloride-
n-hexane); IRvmax cm ^-1 1614,15
16, 1348; NMR (400 MHz, CDCl
₃ ) δ ppm 3.79 (3H, s), 5.71
(2H, s), 6.71 (1H, s), 6.8
9. (2H, d), 7.18 (2H, d),
30 (1H, t), 7.37 (2H, d),
7.67 (2H, d), 7.97 (1H, t),
8.03 (2H, d); MS (FAB) m / z 5
01 [(M ⁺⁺ 2) +1], 499 [(M ⁺⁺ ) + 1];
Elemental analysis _{C 21 H 18 BrN 5 O 3} S Calculated (%)
C, 50.41; H, 3.63; N, 14.00,
Measured value (%) C, 50.73; H, 3.87;
N, 13.99.

(Step 2) N- (4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -3
-Synthesis of iodobenzenesulfonamide N- (4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -3-bromobenzenesulfonamide was treated in the same manner as in Step 2 of Example 19. , N-
(4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -3-iodobenzenesulfonamide was obtained. Melting point 197-201 ° C. (recrystallization solvent: methylene chloride-
n-hexane); IRvmax cm ^-1 1614,15
16, 1348; NMR (400 MHz, CDCl
₃ ) δ ppm 3.79 (3H, s), 5.71
(2H, s), 6.89 (2H, d), 7.1
5. (1H, t), 7.17 (2H, d),
37 (2H, d), 7.69 (2H, d),
7.86 (1H, d), 8.03 (2H, d),
8.16 (2H, d); MS (EI) m / z 54
7 (M ⁺ ); Elemental analysis C ₂₁ H ₁₈ IN ₅ O ₃ S Calculated (%) C, 46.08; H, 3.31; N, 12.7
9, measured value (%) C, 46.36; H, 3.4
8; N, 12.66.

(Step 3) N- (4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -3
Synthesis of-(2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzenesulfonamide N- (4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -3-iodobenzenesulfone The amide and 4-cyclobutyl-2-ethynylthiazole were treated as in Step 4 of Example 1 to give N- (4- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Yl) -3- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) benzenesulfonamide was obtained. 167-169 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2216,16
14, 1514, 1480, 1388, 1846; N
MR (400 MHz, CDCl ₃ ) δ ppm 1.89
２2.40 (6H, m), 3.72 (1H,
m), 3.79 (3H, s), 5.70 (2H,
s), 6.88 (2H, d), 7.00 (1
H, s), 7.07 (1H, s), 7.21
(2H, d), 7.36 (2H, d), 7.3
9 (1H, t), 7.57 (1H, dt),
7.72 (1H, dt), 8.03 (1H, dt)
t), 8.03 (2H, d); MS (FAB) m
^{/ Z 583 (M + +1)} ; Elemental analysis C ₃₀ H ₂₆ N
₆ O ₃ S ₂ · １ ／ H ₂ O calculated value (%) C, 61.3
H, 4.55; N, 14.31, measured value (%) C, 61.21; H, 4.49; N, 1
4.31.

(Step 4) N- (4- (1H-tetrazol-5-yl) -3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) benzenesulfonamide N- (4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) The benzenesulfonamide was treated in the same manner as in step 5 of Example 1 to obtain the title compound: melting point: 139 to 142 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane);
^-1 2220; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.83 to 2.34 (6H, m),
3.67 (1H, m), 7.34 (2H, d),
7.57 (1H, s), 7.68 (1H, t),
7.90 to 7.94 (4H, m), 8.06 (1
H, t), 10.87 (1H, s); MS (F
AB) m / z 463 (M + +1); Elemental analysis C ₂₂
H ₁₈ N ₆ O ₂ S ₂ · H ₂ O calculated value (%) C, 54.9
9; H, 4.19; N, 17.14, measured value (%)
C, 54.69; H, 3.97; N, 17.1
8.

Example 141 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (1H-tetrazol-5-yl) benzamide: (Step 1) 4- (2- (4-methoxybenzyl) -2
Synthesis of H-tetrazol-5-yl) benzoic acid Ethyl 4- (2- (4-methoxybenzyl) -2H-
Tetrazol-5-yl) benzoic acid was treated as in Example 56 to give 4- (2- (4-methoxybenzyl) -2H
-Tetrazol-5-yl) benzoic acid was obtained. NMR (400 MHz, DMSO-d ₆ ) δ ppm
3.75 (3H, s), 5.94 (2H, s),
6.96 (2H, d), 7.41 (2H, d),
8.11 (2H, d), 8.16 (2H, d);
Elemental analysis value C ₁₆ H ₁₄ N ₄ O ₃ Calculated value (%) C, 6
H, 4.55; N, 18.06, measured value (%) C, 61.59; H, 4.56; N, 1
7.80.

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzoic acid and 3- (2- Example 1 using (4-cyclobutyl-2-thiazolyl) ethynyl) aniline
04, and treated in the same manner as in Step 2 of N- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-4- (2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) benzamide was obtained as a yellow foam. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
9 to 2.41 (6H, m), 3.70 (1H,
m), 3.80 (3H, s), 5.76 (2H,
s), 6.91 (2H, d), 6.96 (1
H, s), 7.38-7.41 (4H, m),
7.71 to 7.75 (1H, br), 7.89 (1
H, d), 7.97 (2H, d), 8.27
(2H, d); MS (FAB) m / z 547 (M ⁺
+1).

(Step 3) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4
Synthesis of-(1H-tetrazol-5-yl) benzamide Example of N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (1H-tetrazol-5-yl) benzamide The same procedure as in step 5 of 1 was performed to obtain the title compound. 225-227 ° C (recrystallization solvent: chloroform-
Methanol); NMR (400 MHz, DMSO-d)
₆ ) δ ppm 1.83 to 2.35 (6H, m),
3.68 (1H, m), 7.42 (1H, d),
7.50 (1H, t), 7.53 (1H,
s), 7.89 (1H, dd), 8.16 (1
H, d), 8.19 (2H, d), 8.23
(2H, d), 10.58 (1H, br); MS
(FAB) m / z 427 ( M + +1); Elemental analysis C ₂₃ H ₁₈ N ₆ OS Calculated (%) C, 64.77;
H, 4.25; N, 19.70, measured value (%) C,
H, 4.33; N, 19.47.

Example 142 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (1H-tetrazol-5-yl) benzamide: (Step 1) 3- (2- (4-methoxybenzyl) -2
Synthesis of H-tetrazol-5-yl) benzoic acid Ethyl 3- (2- (4-methoxybenzyl) -2H-
Tetrazol-5-yl) benzoic acid was treated as in Example 56 to give 3- (2- (4-methoxybenzyl) -2H
-Tetrazol-5-yl) benzoic acid was obtained. NMR (400 MHz, DMSO-d ₆ ) δ ppm
3.75 (3H, s), 5.92 (2H, s),
6.97 (2H, d), 7.41 (2H, d),
7.69 (1H, t), 8.08 (1H, d),
8.27 (1H, d), 8.58 (1H, d)
s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzoic acid and 3- (2- Example 1 using (4-cyclobutyl-2-thiazolyl) ethynyl) aniline
04, and treated in the same manner as in Step 2 of N- (3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) phenyl)
-3- (2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) benzamide was obtained. Melting point 140-142 ° C; NMR (400 MHz, CD
Cl ₃₎ δppm 1.92~2.39 (6H,
m), 3.69 (1H, m), 3.80 (3H,
s), 5.75 (2H, s), 6.91 (2
H, d), 6.95 (1H, s), 7.35-
7.41 (4H, m), 7.61 (1H, t),
7.73 (1H, m), 7.92 (1H, s),
8.02 (1H, d), 8.07 (1H,
s), 8.31 (1H, d), 8.57 (1H,
s).

(Step 3) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3
Synthesis of-(1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (2- (4-methoxybenzyl) -2H-tetrazole -5-yl) benzamide was treated as in step 5 of example 1 to give the title compound. Melting point 168-170 ° C; NMR (400 MHz, DM
_{SO-d 6) δppm1.87~2.31 (6H} ,
m), 3.68 (1H, m), 7.42 (1H,
d), 7.50 (1H, t), 7.54 (1
H, s), 7.81 (1, d), 8.27 (1
H, d), 8.65 (1H, s), 10.66
(1H, s); Elemental analysis value C ₂₃ H ₁₈ N ₆ OS · 1 /
Calculated 4H ₂ O (%) C, 64.10; H, 4.3
3; N, 19.5, measured value (%) C, 63.83;
H, 4.17; N, 19.59.

Example 143 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N- (4- (2- (4-methoxybenzyl) tetrazol-5-yl) benzoyl) glycine: (Step 1) N- (3- (2- (4 -Cyclobutyl-2
-Thiazolyl) ethynyl) phenyl) -N- (4- (2
-(4-methoxybenzyl) tetrazol-5-yl)
Synthesis of benzoyl) glycine ethyl ester 3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzoic acid and N- (4- (2- (4-methoxybenzyl) tetrazol-5-yl) The benzoyl) glycine ethyl ester was treated as in step 2 of Example 104 to give N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N- (4
-(2- (4-methoxybenzyl) tetrazole-5
The yl) benzoyl) glycine ethyl ester was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.3
1 (3H, t), 1.88 to 2.41 (6H,
m), 3.68 (1H, m), 3.78 (3H,
s), 4.26 (2H, q), 4.60 (2
H, s), 5.70 (2H, s), 6.86-
6.90 (2H, m), 6.96 (1H, s),
7.11 (1H, d), 7.18 (1H, t),
7.34 to 7.38 (3H, m), 7.44 to
7.46 (3H, m), 7.97 (1H, d).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N
Synthesis of-(4- (2- (4-methoxybenzyl) tetrazol-5-yl) benzoyl) glycine N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N- (4 -(2- (4-Methoxybenzyl) tetrazol-5-yl) benzoyl) glycine ethyl ester was treated in the same manner as in Example 56 to obtain the title compound. 94-96 ° C .; NMR (400 MHz, DMS
_{O-d 6) δppm 1.83~2.32 (} 6H,
m), 3.65 (1H, m), 3.73 (3H,
s), 4.57 (2H, s), 5.88 (2
H, s), 6.94 (2H, d), 7.22.
(1H, d), 7.31 (1H, t), 7.36
(2H, d), 7.43 to 7.47 (3H,
m), 7.53 (1H, s), 7.57 (1H,
s), 7.92 (2H, d), 12.96 (1
H, s).

Example 144 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N- (4- (1H-tetrazol-5-yl) benzoyl) glycine ethyl ester: N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) )) Phenyl) -N- (4- (2- (4-methoxybenzyl) tetrazol-5-yl) benzoyl) glycine ethyl ester was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point 89-91 ° C; IRν max cm ⁻¹ 2216,
1746, 1660; NMR (400 MHz, DMSO
−d ₆ ) δ ppm 1.30 (3H, s), 1.83
~ 2.32 (6H, m), 3.66 (1H,
m), 4.17 (2H, q), 4.67 (2H,
s), 7.26 (1H, d), 7.34 (1
H, t), 7.47 (1H, d), 7.52-
7.53 (3H, m), 7.61 (1H, s),
7.93 (2H, d); MS (FAB) m / z
513 (M ⁺⁺ 1).

Example 145 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N- (4- (1H-tetrazol-5-yl) benzoyl) glycine: N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl ) -N- (4- (1H-Tetrazol-5-yl) benzoyl) glycine ethyl ester was treated in the same manner as in Example 56 to obtain the title compound. 135-138 ° C; IRνmax cm ^-1 221
6, 1738, 1656; NMR (400 MHz, DM
_{SO-d 6) δppm 1.86~2.33 (} 6H,
m), 3.65 (1H, m), 4.58 (2H,
s), 7.26 (1H, d), 7.33 (1
H, t), 7.46 (1H, d), 7.52
(1H, s), 7.52 (2H, d), 7.5
9 (1H, s), 7.93 (2H, d), 1
2.95 (1H, s); MS (FAB) m / z 4
85 (M ⁺⁺ 1).

Example 146 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N-methyl-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -N-methyl-4
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -N-methyl-aniline and 4- (2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) benzoic acid was treated as in step 2 of Example 104 to give N- (3
-(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N-methyl-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
8 to 2.41 (6H, m), 3.51 (3H,
s), 3.68 (1H, m), 3.78 (3H,
s), 5.69 (2H, s), 6.88 (2
H, d), 6.96 (1H, s), 6.99
(1H, d), 7.18 (1H, t), 7.34
~ 7.38 (4H, m), 7.41 (2H,
d), 7.97 (2H, d).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N
Synthesis of -methyl-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N-methyl-4- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Ile) Benzamide was treated as in step 1 of example 1 to give the title. 126-128 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane);
^-1 2216, 1650; NMR (400 MHz, D
_{MSO-d 6) δppm 1.83~2.32 (} 6H,
m), 3.42 (3H, s), 3.66 (1
H, m), 7.28 (1H, d), 7.34 (1
H, t), 7.45 (1H, d), 7.53
(1H, s), 7.53 (2H, d), 7.6
6 (1H, s), 7.91 (2H, d); MS
(FAB) m / z 441 ( M + +1); Elemental analysis _{C 24 H 20 N 6 OS ·} 1 / 4H 2 O Calculated (%) C, 6
4.77; H, 4.64; N, 18.88, found (%) C, 64.98; H, 4.75; N, 1
9.04.

Example 147 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2-methyl-tetrazol-5-yl) benzamide: (Step 1) 4- (2-methyl-2H-tetrazole-
Synthesis of 5-yl) benzoic acid Methyl 4- (2-methyl-2H-tetrazole-5
Il) Benzoic acid was treated as in Example 56 and 4- (2
-Methyl-2H-tetrazol-5-yl) benzoic acid was obtained. NMR (400 MHz, DMSO-d ₆ ) δ ppm
4.45 (3H, s), 8.11 (2H, d),
8.18 (2H, d), 13.2 (1H, br
s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4
Synthesis of-(2-methyl-tetrazol-5-yl) benzamide 4- (2-methyl-2H-tetrazol-5-yl) benzoic acid and 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl)- Example 10 with N-methyl-aniline
The same procedure as in step 2 of 4 was performed to obtain the title compound. 200-202 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2216,16
56, 1606; NMR (400 MHz, DMSO-
d ₆ ) δ ppm 1.84 to 2.41 (6H, m);
3.71 (1H, m), 4.46 (3H,
s), 7.41 (1H, d), 7.48 (1H,
t), 7.53 (1H, s), 7.88 (1
H, d), 8.15-8.16 (3H, m),
8.21 to 8.24 (2H, m), 10.56 (1
H, s); MS (FAB ) m / z 441 (M + +
1); Elemental analysis value C ₂₄ H ₂₀ N ₆ OS · 1 / 2H ₂ O calculated value (%) C, 64.13; H, 4.71; N, 1
8.70, measured value (%) C, 63.89; H,
4.56; N, 18.66.

Example 148 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) -2-methylphenyl) -4- (1H-tetrazol-5-yl) benzamide: 4- (2- (methoxybenzyl)-
2H-tetrazol-5-yl) benzoic acid and 3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) -2
-Methylaniline was treated in the same manner as in Step 2 of Example 104, and then treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 223-225 ° C (recrystallization solvent: chloroform-
Ethanol n-hexane); IRνmax cm ^-1 22
08, 1640; NMR (400 MHz, DMSO-
d ₆ ) δ ppm 1.89 to 2.29 (6H, m),
2.43 (3H, s), 3.66 to 3.70 (1
H, m), 7.31 (1H, t), 7.51 (1
H, d), 7.53 (1H, s), 7.57
(1H, d), 8.21 (4H, s), 10.2
6 (1H, s); MS (FAB) m / z 441
(M ⁺ +1); Elemental analysis value C ₂₄ H ₂₀ N ₆ OS · 1 /
Calculated 4H ₂ O (%) C, 64.77; H, 4.6
4; N, 18.88, measured value (%) C, 64.6
0; H, 4.58; N, 19.08.

Example 149 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-methoxy-4- (1H-tetrazole-5-
Yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -3-methoxy-
4- (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) benzamide, and N- (3- (2
Synthesis of-(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-methoxy-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 3-methoxy-4- (1 -(Methoxybenzyl) -1H
-Tetrazol-5-yl) benzoic acid and a mixture of 3-methoxy-4- (2- (methoxybenzyl) -2H-tetrazol-5-yl) benzoic acid (1st: 2nd}
1: 1) and 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline were treated in the same manner as in Step 1 of Example 103 to obtain N- (3- (2- (4-cyclobutyl-aniline).
2-thiazolyl) ethynyl) phenyl) -3-methoxy-4- (1- (4-methoxybenzyl) -1H-tetrazol-5-yl) benzamide and N- (3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-methoxy-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide (about 1: 1 mixture) Was obtained as a pale yellow foam. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
8 to 2.39 (6H, m), 3.70 (1H,
m), 3.75, 3.77, 3.80 and 3.9.
6 (6H, each s), 5.39 and
5.79 (2H, each s), 6.74 and
6.90 (2H, each d), 6.95-6.
97 (2H, m), 7.31 (1 / 2H, d),
7.38-7.42 (4H, m), 7.57-
7.59 (1H, m), 7.77 (1H, m),
7.92 (1 / 2H, d), 7.95 (1/2
H, d), 7.99 (1 / 2H, d), 8.27
(1 / 2H, s), 8.44 (1 / 2H, s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3
Synthesis of -methoxy-4- (1H-tetrazol-5-yl) benzamide The compound obtained in the above Step 1 was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 197-199 ° C; IR νmax cm ^-1 220
8,1654; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.85 to 2.35 (6H, m),
3.68 (1H, m), 4.10 (3H, s),
7.43 (1H, d), 7.51 (1H,
t), 7.54 (1H, s), 7.77 (1H,
d), 7.78 (1H, s), 8.13 (1
H, s), 8.29 (1H, m), 10.58
(1H, s); MS (FAB) m / z 457 (M ⁺
+1); Elemental analysis _{C 24 H 20 N 6 O 2} S · H 2 O Calculated (%) C, 60.75; H , 4.67; N, 1
7.71, measured value (%) C, 60.74; H,
4.32; N, 17.16.

Example 150 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-methyl-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -3-methyl-4
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 3-methyl-4- (2- (methoxybenzyl) -2H-
Tetrazol-5-yl) benzoic acid and 3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated in the same manner as in Step 1 of Example 103 to give N- (3-
(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-methyl-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide was obtained as a pale yellow foam. Was. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
1-2.39 (6H, m), 2.71 (3H,
s), 3.69 (1H, m), 3.81 (3H,
s), 5.78 (2H, s), 6.92 (2
H, d), 6.96 (1H, s), 7.38-
7.43 (4H, m), 7.73 to 7.77 (2
H, m), 7.82 (1H, s), 7.91
(2H, m), 8.16 (1H, d).

N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -3-methyl-4
Synthesis of-(1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-methyl-4- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Ile) Benzamide was treated as in step 1 of example 1 to give the title. 128-130 ° C (recrystallization solvent: chloroform-
Methanol); IRνmax cm ⁻¹ 2212,167
6,1654; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.87-2.35 (6H, m),
2.61 (3H, s), 3.68 (1H, m),
7.41 (1H, d), 7.49 (1H, t),
7.54 (1H, s), 7.87 to 7.98 (3
H, m), 8.02 (1H, s), 8.14
(1H, s), 8.29 (1H, m), 10.
54 (1H, s); MS (FAB) m / z 441.
(M ⁺ +1); Elemental analysis value C ₂₄ H ₂₀ N ₆ OS · 1/2
H ₂ O calculated value (%) C, 64.13; H, 4.7
1; N, 18.70, measured value (%) C, 64.4
4; H, 4.71; N, 18.70.

Example 151 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -6- (1H-tetrazol-5-yl) -2-thiophenecarboxamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -6- (2- (4
Synthesis of -methoxybenzyl) -2H-tetrazol-5-yl) -2-thiophencarboxamide 5- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-thiophenecarboxylic acid and 3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 1 of example 103;
N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -6- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-thiophenecarboxamide is pale yellow Obtained as a foam. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
1-2.39 (6H, m), 3.70 (1H,
m), 3.81 (3H, s), 5.73 (2H,
s), 6.91 (2H, dt), 6.96 (1
H, s), 7.37-7.41 (4H, m),
7.64 (1H, d), 7.68 (1H, m),
7.78 (1H, d), 7.84 (1H, d)
s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -6
Synthesis of-(1H-tetrazol-5-yl) -2-thiophenecarboxamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -6- (2- (4-methoxybenzyl) -H-tetrazol-5-yl) -2-thiophencarboxamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 224-228 ° C (recrystallization solvent: chloroform-
Methanol); NMR (400 MHz, DMSO-d)
₆ ) δ ppm 1.84 to 2.34 (6H, m),
3.68 (1H, m), 7.41 (1H, d
t), 7.49 (1H, t), 7.52 (1H,
s), 7.82 ((1H, m), 7.87 (1
H, d), 8.08 (1H, t), 8.13
(1H, d), 10.61 (1H, s); MS
(FAB) m / z 433 (M ⁺⁺ 1); elemental analysis value C
₂₁ H ₁₆ N ₆ OS ₂ Calculated (%) C, 58.32;
3.73; N, 19.43, measured value (%) C, 5
8.26; H, 3.90; N, 19.48.

Example 152 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methyl-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -2-methyl-4
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 2-methyl-4- (2- (methoxybenzyl) -2H-
Tetrazol-5-yl) benzoic acid and 3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated in the same manner as in Step 1 of Example 103 to give N- (3-
(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methyl-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide was obtained. 128-130 ° C .; NMR (400 MHz, C
DCl ₃ ) δ ppm 1.91 to 2.40 (6H,
m), 2.56 (3H, s), 3.68 (1H,
m), 3.80 (3H, s), 5.74 (2
H, s), 6.91 (2H, d), 6.95.
(1H, s), 7.37 to 7.41 (3H, m),
7.56 (1H, d), 7.70 (2H, br)
s), 7.89 (1H, br s), 7.98
(1H, d), 8.03 (1H, s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of -methyl-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methyl-4- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Ile) Benzamide was treated as in step 1 of example 1 to give the title. 135-137 ° C; NMR (400 MHz, DM
_{SO-d 6) δppm1.84~2.33 (6H} ,
m), 2.50 (3H, s), 3.67 (1H,
m), 7.41 (1H, d), 7.48 (1
H, t), 7.54 (1H, s), 7.73
(1H, d), 7.79 (1H, d), 7.9
8. (1H, d), 8.02 (1H, s),
11 (1H, s), 10.65 (1H, s); M
S (FAB) m / z 431 (M + +1); Elemental analysis _{C 24 H 20 N 6 OS ·} 1 / 4H 2 O Calculated (%) C,
H, 4.64; N, 18.88, measured value (%) C, 64.87; H, 4.87; N,
18.48.

Example 153 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methoxy-4- (1H-tetrazole-5
Yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -2-methoxy-
Synthesis of 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 3-methoxy-4- (2- (methoxybenzyl) -2H
-Tetrazol-5-yl) benzoic acid and 3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) aniline in the same manner as in Step 1 of Example 103 to give N- (3-
(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methoxy-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide was obtained as a pale yellow oil. . NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.40 (6H, m), 3.70 (1H,
m), 3.81 (3H, s), 4.19 (3H,
s), 5.76 (2H, s), 6.92 (2
H, d), 6.96 (1H, s), 7.31
(1H, d), 7.35 to 7.42 (4H, m),
7.83 to 7.90 (4H, m), 8.03 (1
H, m), 9.88 (1H, s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of -methoxy-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methoxy-4- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Ile) Benzamide was treated as in step 1 of example 1 to give the title. 153-155 ° C (recrystallization solvent: chloroform-
Methanol -n- hexane); IRνmax cm ^-1 2
212, 1672; NMR (400 MHz, DMSO
−d ₆ ) δ ppm 1.83 to 2.33 (6H,
m), 3.67 (1H, m), 4.01 (3H,
s), 7.40 (1H, dd), 7.47 (1
H, t), 7.54 (1H, s), 7.75
(1H, dd), 7.82-7.84 (3H,
m), 8.08 (1H, s), 10.44 (1
H, s); MS (FAB ) m / z 457 (M + +
1); Elemental analysis _{C 24 H 20 N 6 O 2} S Calculated (%)
C, 63.14; H, 4.42; N, 18.41,
Measured value (%) C, 63.54; H, 4.58;
N, 18.57.

Example 154 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) -2-methoxyphenyl) -4- (1H-tetrazol-yl)
Benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) -2-methoxyphenyl)-
Synthesis of 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 4- (2- (methoxybenzyl) -2H-tetrazol-5-yl) benzoic acid and 3- (2- ( 4-cyclobutyl-2-thiazolyl) ethynyl) -2-methoxyaniline was treated in the same manner as in Step 2 of Example 104 to give N- (3-
(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) -2-methoxyphenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide was obtained as a pale yellow oil. . NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
4 to 2.40 (6H, m), 3.67 to 3.74 (1
H, m), 3.80 (3H, s), 4.17
(3H, s), 5.76 (2H, s), 6.9
0 to 6.93 (2H, m), 6.99 (1H,
s), 7.15 (1H, t), 7.32 (1H,
dd), 7.40 to 7.42 (2H, m),
7.98-8.00 (2H, m), 8.27-8.
29 (2H, m), 8.59 (1H, dd),
8.65 (1H, s).

(Step 2) Synthesis of N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methoxyphenyl) -4- (1H-tetrazol-5-yl) benzamide Perform 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methoxyphenyl) -2-methoxy-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide Step 5 of Example 1
The title compound was obtained. 186-187 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm ^-1
2216, 1658; NMR (400 MHz, DM
_{SO-d 6) δppm 1.86~2.31 (} 6H,
m), 3.63 to 3.72 (1H, m), 3.9
7 (3H, s), 7.24 (1H, t), 7.5
1 (1H, dd), 7.55 (1H, s),
7.86 (1H, dd), 8.19 (2H, dd)
d), 8.22 (2H, d), 10.04 (1
H, s); MS (FAB ) m / z 457 (M + +
1); Elemental analysis value C ₂₄ H ₂₀ N ₆ O ₂ S · 1 / 2H ₂ O
Calculated value (%) C, 61.92; H, 4.55; N, 1
8.05, measured value (%) C, 62.18; H,
4.53; N, 18.27.

Example 155 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (1H-tetrazol-5-yl) -2-trifluoromethoxybenzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -4- (2- (4
Synthesis of -methoxybenzyl) -2H-tetrazol-5-yl) -2-trifluoromethoxybenzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-trifluoromethoxybenzoic acid And 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline were treated in the same manner as in Step 2 of Example 104 to give N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl). ) Phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2
-Trifluoromethoxybenzamide was obtained. Melting point 97-100 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm ^-1
3288, 2940, 2216, 1656, 160
8, 1586, 1548, 1514; NMR (400
MHz, CDCl ₃₎ δppm 1.89~2.42
(6H, m), 3.66 to 3.74 (1H, m),
3.81 (3H, s), 5.77 (2H,
s), 6.91 to 6.93 (2H, m), 6.9
6 (1H, s), 7.37 to 7.43 (4H,
m), 7.69-7.72 (1H, m), 7.8
9. (1H, s), 8.14 (1H, s),
22 (2H, s), 8.39 (1H, s); M
S (EI) m / z 630 (M ⁺ ); Elemental analysis value C ₃₂
Calculated _{H 25 F 3 N 6 O 3} S (%) C, 60.95;
H, 4.00; N, 13. 33, measured value (%)
C, 60.69; H, 4.16; N, 13.5.
4.

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4
Synthesis of-(1H-tetrazol-5-yl) -2-trifluoromethoxybenzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methoxy-4- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Il) -2-trifluoromethoxybenzamide was treated as in step 5 of example 1 to give the title compound. Melting point: 199 to 202 ° C (decomp.) (Recrystallization solvent: chloroform); IRνmax cm ⁻¹ 3316,3
104, 2976, 2948, 2868, 2212, 1
658, 1624, 1608, 1584, 1548;
NMR (400 MHz, DMSO-d ₆ ) δ ppm
1.83-2.31 (6H, m), 3.63-3.3.
72 (1H, m), 7.44 (1H, d),
7.50 (1H, t), 7.54 (1H, s),
7.75 (1H, d), 8.01 (1H,
d), 8.06 (1H, s), 8.14 (1H,
s), 8.22 (1H, d), 10.87 (1
H, s); MS (FAB ) m / z511 (M + +
1); Elemental analysis value C ₂₄ H ₁₇ F ₃ N ₆ O ₂ S · 0.25
Of H ₂ O Calculated (%) C, 55.97; H , 3.4
2; N, 16.32, measured value (%) C, 55.8
8; H, 3.42; N, 16.44.

Example 156 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (1H-tetrazol-5-yl) -2-trifluoromethylbenzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -4- (2- (4
Synthesis of -methoxybenzyl) -2H-tetrazol-5-yl) -2-trifluoromethylbenzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-trifluoromethylbenzoic acid And 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline were treated in the same manner as in Step 1 of Example 103 to give N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl). ) Phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-
Trifluoromethylbenzamide was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
8 to 2.41 (6H, m), 3.63 to 3.72 (1
H, m), 3.81 (3H, s), 5.76
(2H, s), 6.91 to 6.94 (2H,
m), 6.95 (1H, s), 7.36-7.4
2 (4H, m), 7.66 to 7.69 (1H,
m), 7.73 (1H, s), 7.74 (1H,
d), 7.84 (1H, s), 8.36 (1H,
d), 8.49 (1H, s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4
Synthesis of-(1H-tetrazol-5-yl) -2-trifluoromethylbenzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxy Benzyl) -2H-tetrazol-5-yl) -2-trifluoromethylbenzamide was treated in the same manner as in Step 1 of Example 1 to obtain the title compound. Melting point: 201 to 205 ° C. (decomp.) (Recrystallization solvent: ethanol-n-hexane); IRνmax cm ⁻¹
3280, 2948, 2216, 1662, 160
8, 1580, 1538; NMR (400 MHz, D
_{MSO-d 6) δppm 1.86~2.31 (} 6H,
m), 3.63 to 3.71 (1H, m), 7.
44 (1H, d), 7.50 (1H, t),
7.54 (1H, s), 7.72 (1H, d),
8.03 (1H, d), 8.05 (1H, d)
s), 8.46 (1H, d), 8.48 (1H,
s), 10.93 (1H, s); MS (EI)
m / z 494 (M ⁺ ); Elemental analysis: C ₂₄ H ₁₇ F ₃ N
₆ Calculated value of OS (%) C, 58.29; H, 3.4
6; N, 17.00, measured value (%) C, 58.1
1; H, 3.61; N, 16.73.

Example 157 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-4- (1H-tetrazole-5-
Yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -4- (2- (4
Synthesis of -methoxybenzyl) -2H-tetrazol-5-yl) -2-fluorobenzamide 2-fluoro-4- (2- (4-methoxybenzyl)-
2H-tetrazol-5-yl) benzoic acid and 3- (2-
(4-Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 2 of Example 104 to give N-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-4- (2- (4-
Methoxybenzyl) -2H-tetrazol-5-yl)
Benzamide was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
1-2.08 (2H, m), 2.29-2.41 (4
H, m), 3.65 to 3.77 (1H, m),
3.80 (3H, s), 5.75 (2H, s),
6.90 to 6.92 (2H, m), 6.95 (1
H, s), 7.36-7.41 (4H, m),
7.72 to 7.74 (1H, m), 7.92 (1
H, s), 7.97 (1H, d), 8.08
(1H, dd), 8.28 (1H, t), 8.
50 (1H, d).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of -Fluoro-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-4- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Ile) Benzamide was treated as in step 1 of example 1 to give the title. 179-181 ° C (deco
mp. ) (Recrystallization solvent: chloroform-ethanol);
IRνmax cm ^-1 3268, 2980, 2936,
2216, 1650, 1606, 1582, 1556;
NMR (400 MHz, DMSO-d ₆ ) δ ppm
1.86 to 2.03 (2H, m), 2.19 to 2.
33 (4H, m), 3.63 to 3.71 (1H,
m), 7.43 (1H, d), 7.49 (1H,
t), 7.53 (1H, s), 7.78 (1
H, d), 7.94 (1H, t), 7.98-
8.03 (2H, m), 8.08 (1H, s),
10.78 (1H, s); MS (FAB) m / z 4
45 (M ⁺ +1); Elemental analysis C ₂₃ H ₁₇ FN ₆ OS
· 0.75H ₂ O Calculated (%) C, 60.32;
H, 4.07; N, 18.35, measured value (%)
C, 60.41; H, 3.84; N, 18.10.

Example 158 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-fluoro-4- (1H-tetrazol-5-
Yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -3-fluoro-
Synthesis of 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 3-Fluoro-4- (2- (4-methoxybenzyl)-
2H-tetrazol-5-yl) benzoic acid and 3- (2-
(4-Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 2 of Example 104 to give N-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-fluoro-4- (2- (4-
Methoxybenzyl) -2H-tetrazol-5-yl)
Benzamide was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.07 (2H, m), 2.27 to 2.37 (4
H, m), 3.63 to 3.72 (1H, m),
3.79 (3H, s), 5.78 (2H, s),
6.89 to 6.91 (2H, m), 6.95 (1
H, s), 7.37-7.41 (4H, m),
7.71 to 7.76 (3H, m), 7.86 (1
H, s), 8.18 to 8.22 (2H, m).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3
Synthesis of -fluoro-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3-fluoro-4- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Ile) Benzamide was treated as in step 1 of example 1 to give the title. Melting point: 224 to 226 ° C. (decomp.) (Recrystallization solvent: chloroform-ethanol); IRνmax cm ⁻¹
2976, 2940, 2864, 2212, 168
6,1628,1604,1582,1548; NM
R (400 MHz, DMSO-d ₆ ) δ ppm 1.8
6 to 2.03 (2H, m), 2.21 to 2.33
(4H, m), 3.63 to 3.71 (1H, m),
7.43 (1H, d), 7.50 (1H, d)
t), 7.54 (1H, s), 7.87 (1H,
d), 8.03 (1H, d), 8.07 (1
H, d), 8.14 (1H, s), 8.25 (1
H, t), 10.63 (1H, s); MS (FA
B) m / z 445 (M + +1); Elemental analysis C _{23
H 17 FN 6 OSF · 0.25H 2} O Calculated (%)
C, 61.53; H, 3.93; N, 18.72,
Measured value (%) C, 61.25; H, 3.94;
N, 18.39.

Example 159 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (4-fluorophenoxy) methyl-4-
(1H-tetrazol-5-yl) benzamide: (Step 1) 2- (4-fluorophenoxy) methyl-
Synthesis of 4- (2- (2- (trimethylsilyl) ethoxymethyl) -2H-tetrazol-5-yl) benzoic acid Methyl 2- (4-fluorophenoxy) methyl-4-
(2- (2- (trimethylsilyl) ethoxymethyl)-
2H-tetrazol-5-yl) benzoic acid was prepared according to Example 56.
To give 2- (4-fluorophenoxy) methyl-4- (2- (2- (trimethylsilyl) ethoxymethyl) -2H-tetrazol-5-yl) benzoic acid. Melting point 102-104 ° C; NMR (400 MHz, CD
Cl ₃ ) δ ppm -0.01 (9H, s), 0.
97 (2H, t), 3.76 (2H, t),
5.54 (2H, s), 5.96 (2H, s),
7.02 (4H, m), 8.25 (1H, d),
8.29 (1H, d), 8.65 (1H,
s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
-(4-fluorophenoxy) methyl-4- (1 or
Synthesis of 2H-tetrazol-5-yl) benzamide 3-Fluoro-4- (2- (2- (trimethylsilyl))
An oil obtained by treating ethoxymethyl-2H-tetrazol-5-yl) benzoic acid and 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline in the same manner as in Step 2 of Example 104. To Example 76
Deprotection was performed in the same manner as in Step 2 of the above to give the title compound. Melting point 98-99 ° C (recrystallization solvent: chloroform-methanol); IRνmaxcm ⁻¹ 2216, 1674;
NMR (400 MHz, DMSO-d ₆ ) δ ppm
1.86 to 2.32 (6H, m), 3.67 (1
H, quint), 5.38 (2H, s),
6.99-7.02 (2H, m), 7.08-7.
12 (2H, m), 7.40 (1H, d),
7.46 (1H, t), 7.53 (1H, s),
7.75 (1H, d), 7.89 (1H, d),
8.06 (1H, s), 8.15 (1H, s)
d), 8.33 (1H, s), 10.76 (1
H, s); MS (FAB ) m / z551 (M + +
1); Elemental analysis value C ₃₀ H ₂₃ FN ₆ O ₂ S · 0.25H
Calculated value of ₂ O (%) C, 64.91; H, 4.2
7; N, 15.14, measured value (%) C, 64.8
7; H, 4.30; N, 15.19.

Example 160 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3,5-dimethoxy-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) phenyl) -3,5-dimethoxy-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 3,5-dimethoxy-4- (2- (4 -Methoxybenzyl) -2H-tetrazol-5-yl) benzoic acid and 3-
(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) aniline is treated as in step 1 of Example 103 to give N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3,5-dimethoxy-4
-(2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) benzamide was obtained as a pale yellow oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
8 to 2.40 (6H, m), 3.46 (6H,
s), 3.65 to 3.73 (1H, m), 3.7
5. 3 (3H, s), 5.22 (2H, s),
71 to 6.73 (2H, m), 6.90 to 6.92
(2H, m), 6.96 (1H, s), 7.0
3 (2H, s), 7.33-7.37 (2H,
m), 7.66-7.69 (1H, m), 8.1.
7 (1H, s), 10.11 (1H, s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl)-
3,5-dimethoxy-4- (1H-tetrazole-5
Synthesis of yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3,5-dimethoxy-3-fluoro-4- (2- (4-methoxybenzyl) -2H-
The tetrazol-5-yl) benzamide was treated in the same manner as in Step 1 of Example 1 to obtain the title compound. Melting point: 223 to 226 ° C. (decomp.) (Recrystallization solvent: chloroform-ethanol); IRνmax cm ⁻¹
2940, 2212, 1650, 1606, 157
8, 1530; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.85 to 2.33 (6H, m),
3.63 to 3.71 (1H, m), 3.85 (6
H, s), 7.37 (2H, s), 7.43
(1H, d), 7.51 (1H, t), 7.53
(1H, s), 7.89 (1H, d), 8.09
(1H, s), 10.50 (1H, s); MS
(FAB) m / z 487 ( M + +1); Elemental analysis _{C 25 H 22 N 6 O 3} S · 0.25H 2 O Calculated (%)
C, 61.15; H, 4.62; N, 17.1
1, measured value (%) C, 61.05; H, 4.6
5; N, 16.77.

Example 161 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2,6-dimethoxy-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2-)
Synthesis of thiazolyl) ethynyl) phenyl) -2,6-dimethoxy-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 2,6-dimethoxy-4- (2- (4- Methoxybenzyl) -2H-tetrazol-5-yl) benzoic acid and 3-
(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 2 of Example 104 to give N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2,6-dimethoxy-4
-(2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) benzamide was obtained. Melting point: 174 to 178 ° C. (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 3348, 2940, 2212, 1684, 161
2, 1584, 1534, 1514; NMR (400M
Hz, CDCl3) [delta] ppm 1.89 to 2.39 (6
H, m), 3.65 to 3.73 (1H, m),
3.74 (3H, s), 3.94 (6H, s),
5.76 (2H, s), 6.91 to 6.93 (2
H, m), 6.95 (1H, s), 7.35-
7.41 (4H, m), 7.40 (2H, s),
7.52 (1H, s), 7.76 to 7.79 (1
H, m), 7.84 (1H, s); MS (E
I) m / z 606 (M ⁺ ); Elemental analysis: C ₃₃ H ₃₀ N
Calculated value for ₆ O ₄ S.0.5H ₂ O (%) C, 64.3
H, 5.07; N, 13.65, measured value (%) C, 64.63; H, 4.91; N, 1
3.29.

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl)-
2,6-dimethoxy-4- (1H-tetrazole-5
Synthesis of yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2,6-dimethoxy-4-
(2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) benzamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 169 to 173 ° C. (decomp.) (Recrystallization solvent: ethanol-n-hexane); IRνmax cm ⁻¹
2976, 2940, 2212, 1606, 158
4,1554; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.84 to 2.31 (6H, m),
3.65 to 3.74 (1H, m), 3.90 (6
H, s), 7.37 (1H, d), 7.43
(2H, s), 7.44 (1H, t), 7.53
(1H, s), 7.73 (1H, d), 8.06
(1H, s), 10.57 (1H, s); MS
(FAB) m / z 487 ( M + +1); Calculated elemental analysis _{C 25 H 22 N 6 O 3} S (%) C, 61.7
H, 4.56; N, 17.27; N, 17.27; found (%) C, 61.43; H, 4.55;
02.

Example 162 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-chloro-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -2-chloro-4
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 2-chloro-4- (2- (4-methoxybenzyl) -2
H-tetrazol-5-yl) benzoic acid and 3- (2-
(4-Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 2 of Example 104 to give N-
(3- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-chloro-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide as yellow amorphous Obtained. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
9 to 2.41 (6H, m), 3.65 to 3.73
(1H, m), 3.81 (3H, s), 5.76
(2H, s), 6.91 to 6.93 (2H, s)
m), 6.96 (1H, s), 7.39-7.4
2 (4H, m), 7.72 to 7.74 (1H,
m), 7.88 (1H, s), 7.89 (1
H, d), 8.04 (1H, s), 8.13
(1H, d), 8.24 (1H, s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of -chloro-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-chloro-4- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Ile) Benzamide was treated as in step 1 of example 1 to give the title. Melting point: 213 to 216 ° C. (decomp.) (Recrystallization solvent: ethanol-n-hexane); IRνmax cm ⁻¹
2944, 2212, 1644, 1612, 158
0, 1548, 1502; NMR (400 MHz, D
_{MSO-d 6) δppm 1.84~2.33 (} 6H,
m), 3.63 to 3.72 (1H, m), 7.
43 (1H, d), 7.50 (1H, t),
7.54 (1H, s), 7.76 (1H, d),
7.89 (1H, d), 8.07 (1H, d)
s), 8.13 (1H, dd), 8.22 (1
H, d), 10.87 (1H, s); MS (FA
B) m / z 461 (M + +1); Elemental analysis C ₂₃ H ₁₇
Calculated value of ClN ₆ OS (%) C, 59.93; H,
3.72; N, 18.23, measured value (%) C, 5
9.78; H, 3.79; N, 17.88.

Example 163 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) -2-fluorophenyl)-
Synthesis of 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzoic acid and 3- (2 -(4-Cyclobutyl-2-thiazolyl) ethynyl) -2-fluoroaniline was treated as in step 2 of Example 104 to give N-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -4- (2- (4-
Methoxybenzyl) -2H-tetrazol-5-yl)
Benzamide was obtained as a pale yellow oil. IRνmax cm ⁻¹ 2216; NMR (400 MH
_{z, CDCl 3) δppm1.87~2.45 (6H} ,
m), 3.71 (1H, m), 3.81 (3
H, s), 5.77 (2H, s), 6.92
(2H, d), 7.00 (1H, s), 7.2
6. 2 (1H, t), 7.34 (1H, m), 7.
42 (2H, d), 7.99 (2H, d),
8.13 (1H, brd), 8.25-8.33
(2H, m), 8.55 (1H, m); MS
(EI) m / z 564 ( M +); Elemental analysis C ₃₁ H
Calculated value of ₂₅ FN ₆ O ₂ S.0.25H ₂ O (%) C,
H, 4.52; N, 14.77,
Measured value (%) C, 64.96; H, 4.42;
N, 15.01.

(Step 2) Synthesis of N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -4- (1H-tetrazol-5-yl) benzamide 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-fluorophenyl) -4- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Ile) Benzamide was treated as in step 1 of example 1 to give the title. 249-252 ° C; IR νmax cm ^-1 330
0, 2220, 1650; NMR (400 MHz, DM
_{SO-d 6) δppm 1.77~2.35 (} 6H,
m), 3.68 (1H, m), 7.35 (1H,
t), 7.58 (1H, s), 7.63 (1
H, m), 7.76 (1H, m), 8.22
(4H, m), 10.50 (1H, s); MS
(FAB) m / z445 (M + +1); Elemental analysis _{C 23 H 17 FN 6 OS ·} H 2 O Calculated (%) C, 5
9.73; H, 4.14; N, 18.17, found (%) C, 59.75; H, 3.93; N, 1
8.08.

Example 164 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -5-chloro-2-methyl-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl- 2
-Thiazolyl) ethynyl) phenyl) -5-chloro-2
-Methyl-4- (2- (4-methoxybenzyl) -2H
Synthesis of -tetrazol-5-yl) benzamide 5-chloro-4- (2- (4-methoxybenzyl) -2
H-tetrazol-5-yl) -2-methylbenzoic acid and 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-fluoroaniline are treated as in step 2 of Example 104; N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -5-chloro-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-methyl Benzamide was obtained. Melting point 67-69 ° C (decomp.) (Recrystallization solvent:
Methanol-water); NMR (400 MHz, CDCl
₃ ) δ ppm 1.90 to 2.00 (1H, m),
2.00 to 2.10 (1H, m), 2.20 to 2.
40 (4H, m), 3.60 to 3.70 (1H,
m), 3.81 (3H, s), 4.15 (3H,
s), 5.81 (2H, s), 6.91 (2
H, d), 7.30-7.40 (2H, m),
7.43 (1H, d), 7.71 (1H, s),
7.80 (1H, s), 7.85 (1H, s)
d), 8.43 (1H, s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -5
-Chloro-2-methyl-4- (1H-tetrazole-5
Synthesis of -yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -5-chloro-4- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Il) -2-methylbenzamide was treated as in step 5 of example 1 to give the title compound. 130-133 ° C (decomp.) (Recrystallization solvent: chloroform-methanol-n-hexane);
Rνmax cm ⁻¹ 1604, 1488, 1426, 13
80, 1286; NMR (400 MHz, DMSO-
d ₆ ) δ ppm 1.80-1.90 (1H, m),
1.90 to 2.10 (1H, m), 2.20 to 2.4
0 (4H, m), 3.60 to 3.80 (1H,
m), 3.95 (3H, s), 7.42 (1H,
d), 7.48 (1H, t), 7.53 (1H,
s), 7.62 (1H, s), 7.78 (1
H, d), 7.88 (1H, s), 8.06
(1H, s), 10.52 (1H, br s);
MS (FAB) m / z 475 (M + +1); Elemental analysis _{C 24 H 19 ClN 6 OS ·} H 2 O Calculated (%)
C, 54.60; H, 3.94; N, 15.28,
Measured value (%) C, 54.87; H, 3.92;
N, 15.18.

Example 165 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methylthio-4- (1H-tetrazole-5
-Yl) benzamide: (Step 1): N- (3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) phenyl) -2-methylthio-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H-tetrazole -5-yl) -2-methylthiobenzoic acid and 3- (2
-(4-Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 2 of Example 104 to give N-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-methylthiobenzamide as yellow oil As obtained. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
1-2.08 (2H, m), 2.29-2.38 (4
H, m), 2,58 (3H, s), 3.65-
3.73 (1H, m), 3.80 (3H, s),
5.57 (2H, s), 6.91 (2H,
d), 6.95 (1H, s), 7.37-7.4
1 (4H, m), 7.77 to 7.84 (2H,
m), 7.98-8.00 (2H, m), 8.1
4 (1H, d), 8.56 (1H, s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
-Methylthio-4- (1H-tetrazol-5-yl)
Synthesis of benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-methylthiobenzamide Was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 154 to 156 ° C. (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 2212,1650,1606,1582,154
2; NMR (400 MHz, DMSO-d ₆ ) δpp
m 1.86 to 2.02 (2H, m), 2.18 to
2.31 (4H, m), 2.56 (3H, s),
3.62 to 3.71 (1H, m), 7.41 (1
H, d), 7.48 (1H, t), 7.53
(1H, s), 7.77 (1H, d), 7.78
(1H, d), 7.98 (1H, d), 8.0
2 (1H, s), 8.07 (1H, s), 1
0.69 (1H, s); MS (EI) m / z 47
3 (M ⁺ +1); Elemental analysis _{C 24 H 20 N 6 OS 2} · 1
Calculated value of / 4H ₂ O (%) C, 60.42; H,
4.33; N, 17.62, measured value (%) C, 6
H, 4.39; N, 17.58.

Example 166 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) -6-fluorophenyl)-
Synthesis of 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzoic acid and 3- (2 -(4-Cyclobutyl-2-thiazolyl) ethynyl) -6-fluoroaniline was treated as in step 2 of Example 104 to give N-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -4- (2- (4-
Methoxybenzyl) -2H-tetrazol-5-yl)
Benzamide was obtained. 156-158 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2216,16
56; NMR (400 MHz, CDCl ₃ ) δ ppm
1.91 to 2.39 (6H, m), 3.65 to
3.74 (1H, m), 3.80 (3H, s),
5.76 (2H, s), 6.90-6.92 (2
H, m), 6.95 (1H, s), 7.33-
7.36 (1H, m), 7.39 to 7.42 (2
H, m), 7.98-8.00 (2H, m),
8.09 (1H, d), 8.27 to 8.29 (2
H, m), 8.77 (1H, dd); MS (F
AB) m / z 565 (M + +1); Elemental analysis C ₃₁
H ₂₅ Calculated _{FN 6 O 2 S (%)} C, 65.94;
H, 4.46; N, 14.89, measured value (%)
C, 65.90; H, 4.46; N, 14.77.

(Step 2) Synthesis of N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -4- (1H-tetrazol-5-yl) benzamide 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-fluorophenyl) -4- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Ile) Benzamide was treated as in step 1 of example 1 to give the title. 218-220 ° C (decomp.) (Recrystallization solvent: chloroform-ethanol-n-hexane);
Rνmax cm ⁻¹ 2216, 1650; NMR (40
^{0MHz, DMSO-d 6) δppm} 1.85~2.
31 (6H, m), 3.62 to 3.71 (1H,
m), 7.44 to 7.48 (1H, m), 7.5
3 (1H, s), 7.58 to 7.62 (1H,
m), 7.98 (1H, dd), 8.18-8.
23 (4H, m), 10.46 (1H, s);
MS (FAB) m / z 445 (M + +1); Calculated elemental analysis _{C 23 H 17 FN 6 OS (} %) C, 62.1
H, 3.86; N, 18.91, measured value (%) C, 61.85; H, 3.93; N, 1
8.78.

Example 167 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (1H-tetrazol-5-yl) -5-pyridinecarboxamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -1- (2- (4
-Methoxybenzyl) -1H-tetrazol-5-yl) -5-pyridinecarboxamide, and N- (3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (2- (4-methoxybenzyl)
Synthesis of 2H-tetrazol-5-yl) -5-pyridinecarboxamide 6- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) nicotinic acid and 3- (2- (4-cyclobutyl-2) -Thiazolyl) ethynyl) aniline was treated as in Step 1 of Example 103 to give N- (3- (2-
(4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -1- (2- (4-methoxybenzyl) -1H-
Tetrazol-5-yl) -5-pyridinecarboxamide and N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2- (2- (4-methoxybenzyl) -2H-tetrazole -5-yl)-
5-pyridinecarboxamide (about a 1: 1 mixture) was obtained. 208-230 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ^-1 1690; N
MR (400 MHz, DMSO-d ₆ ) δ ppm 3.7
0 and 3.75 (3H, each s),
5.97 and 6.13 (2H, each s),
6.88-6.98 (2H, m), 7.31-7.
43 (2H, m), 8.26 and 8.38
(1H, each d), 8.45 and 8.5
2 (1H, each dd), 9.19 and
9.31 (1H, each d), 13.69 (1
H, br s); MS (EI) m / z 311 (M
⁺ ); Elemental analysis value Calculated value of C ₁₅ H ₁₃ N ₅ O ₃ (%)
C, 57.88; H, 4.216; N, 22.5
0, measured value (%) C, 58.24; H, 4.2
5; N, 22.55.

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of-(1H-tetrazol-5-yl) -5-pyridinecarboxamide The compound of Step 1 described above was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 149 to 153 ° C. (decomp.) (Recrystallization solvent: chloroform-ethanol); IRνmax cm ⁻¹
2212, 1642; NMR (400 MHz, DM
_{SO-d 6) δppm 1.84~2.35 (} 6H,
m), 3.65-3.72 (1H, m), 7.4
4 (1H, d), 7.52 (1H, t), 7.5
7. 4 (1H, s), 7.87 (1H, d),
14 (1H, s), 8.41 (1H, d),
8.59 (1H, dd), 9.30 (1H, dd)
d), 10.79 (1H, s); MS (FAB)
^{m / z428 (M + +1)} ; Elemental analysis C ₂₂ H ₁₇ N ₇
OS · 1 / 4H ₂ O Calculated (%) C, 61.17;
H, 4.08; N, 22.70, measured value (%)
C, 61.04; H, 4.14; N, 22.52.

Example 168 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2,6-dimethyl-4- (1H-tetrazole-
5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) phenyl) -2,6-dimethyl-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H -Tetrazol-5-yl) -2,6-dimethylbenzoic acid and 3-
(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 2 of Example 104 to give N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2,
6-Dimethylbenzamide was obtained as a pale yellow amorphous. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
9 to 2.41 (6H, m), 2.44 (6H,
s), 3.65 to 3.73 (1H, m), 3.8
5. 1 (3H, s), 5.74 (2H, s),
90-6.93 (2H, m), 6.96 (1H,
s), 7.36-7.41 (4H, m), 7.5
2 (1H, brs), 7.67 to 7.70 (1
H, m), 7.83 (2H, s), 7.91 (1
H, s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl)-
Synthesis of 2,6-dimethyl-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4- (Methoxybenzyl) -2H-tetrazol-5-yl) -2,6
-Dimethylbenzamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 218 to 222 ° C. (decomp.) (Recrystallization solvent: ethanol-n-hexane); IRνmax cm ⁻¹
2212, 1656; NMR (400 MHz, DM
_{SO-d 6) δppm 1.84~2.35 (} 6H,
m), 2.40 (6H, s), 3.63-3.7.
1 (1H, m), 7.42 (1H, d), 7.4
8. (1H, t), 7.53 (1H, s),
76 (1H, d), 7.83 (2H, s),
8.10 (1H, s), 10.74 (1H,
s); MS (FAB) m / z 455 (M + +
1); Elemental analysis value calculated value of C ₂₅ H ₂₂ N ₆ OS · 1 / 2H ₂ O (%) C, 64.78; H, 5.00;
N, 18.13, measured value (%) C, 65.02;
H, 5.03; N, 17.83.

Example 169 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-bromo-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -2-bromo-4
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-bromobenzoic acid and 3 − (2-
(4-Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 2 of Example 104 to give N-
(3- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-bromobenzamide was obtained as an amorphous. Was. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
9 to 2.41 (6H, m), 3.69 (1H,
m), 3.74 (3H, s), 5.65 (2H,
s), 6.74-7.81 (13H, m).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of -bromo-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -H-tetrazol-5-yl) -2-bromobenzamide was treated in the same manner as in Step 5 of Example 1.
The title was obtained. 173-175 ° C (recrystallization solvent: chloroform-
Methanol) IRνmax cm ⁻¹ 2212,166
2; NMR (400 MHz, DMSO-d ₆ ) δpp
m 1.88-2.28 (6H, m), 3.66
(1H, m), 7.38 (1H, d), 7.44
(1H, t), 7.52 (1H, s), 7.6
3. (1H, d), 7.74 (1H, d),
96 (2H, s), 8.11 (1H, s), 1
0.68 (1H, s); MS (FAB) m / z 5
07 [(M ⁺ +2) +1], 505 [(M ⁺ ) +
1]; Elemental analysis C ₂₃ H ₁₇ BrN ₆ Calculated OS (%)
C, 54.66; H, 3.39; N, 16.6.
3, measured value (%) C, 54.30; H, 3.8
6; N, 16.42.

Example 170 Methyl N- (3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) aminocarbonyl-3- (1H-tetrazol-5-yl) benzoic acid: (Step 1) Methyl N- (3- (2- (4-cyclobutyl) -2-thiazolyl) ethynyl) phenyl) aminocarbonyl-3- (2- (4-methoxybenzyl) -2H
Synthesis of -tetrazol-5-yl) benzoic acid Methyl 3- (2- (4-methoxybenzyl) -2H-
Tetrazol-5-yl) -5-bromobenzoic acid 1 g,
695 mg of 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline, 52 mg of 1,3-bis (diphenylphosphino) propane, and 28 mg of palladium [2] acetate in 5 mg of triethylamine and DMSO
15 ml was added. Replace the reaction system with carbon monoxide gas,
Stirred at 120 ° C. for 10 hours. After cooling, the reaction solution was concentrated. 100 ml of toluene was added, and this was washed with 1N hydrochloric acid and then with a saturated saline solution, and then dried over sodium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography using silica gel (eluent: n-hexane: ethyl acetate = 3: 1), crystallized from ether, and methyl N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) aminocarbonyl-3- (2
-(4-methoxybenzyl) -2H-tetrazole-5
-Yl) benzoic acid was obtained. 112-120 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2212,17
28; NMR (400 MHz, CDCl ₃ ) δ ppm
1.87 to 2.44 (6H, m), 3.70 (1
H, m), 3.81 (3H, s), 4.00.
(3H, s), 5.78 (2H, s), 6.9
6. 3 (2H, d), 6.97 (1H, s), 7.
38-7.45 (4H, m), 7.73 (1H,
m), 7.95 (1H, brs), 8.01
(1H, brs), 8.61 (1H, t),
8.82 (1H, t), 8.97 (1H, t);
MS (FAB) m / z 605 (M + +1); Calculated elemental analysis _{C 33 H 28 N 6 O 4} S (%) C, 64.
H, 4.76; N, 13.70, measured value (%) C, 64.55; H, 4.66; N, 13.
36.

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
-Methylthio-4- (1H-tetrazol-5-yl)
Synthesis of Benzamide Methyl N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) aminocarbonyl-3
-(2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) benzoic acid was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 190 ° C. (decomp.) (Recrystallization solvent: chloroform-ethanol); IRνmax cm ⁻¹ 221
2,1730; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.82 to 2.36 (6H, m),
3.68 (1H, m), 3.99 (3H, s),
7.45 (1H, d), 7.52 (1H, t),
7.54 (1H, s), 7.91 (1H, s)
d), 8.15 (1H, s), 8.73 (1H,
s), 8.83 (1H, s), 8.93 (1H,
s), 10.85 (1H, s); MS (FA
B) m / z 485 (M + +1); Elemental analysis C _{25
H 20 N 6 O 3 S ·} 1 / 2H 2 O Calculated (%) C, 6
H, 4.29; N, 17.03, measured value (%) C, 60.59; H, 4.17; N, 1
6.85.

Example 171 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-ethyl-4- (1H-tetrazol-5-yl) benzamide (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -2-ethyl-4
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-ethylbenzoic acid and 3 − (2-
(4-Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 2 of Example 104 to give N-
(3- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-ethylbenzamide was obtained as amorphous. Was. NMR (400 MHz, CDCl ₃ ) δ ppm 1.2
6 (3H, t), 1.91 to 2.39 (6H,
m), 2.93 (2H, q), 3.69 (1H,
m), 3.81 (3H, s), 5.76 (2
H, s), 6.92 (2H, d), 6.95
(1H, s), 7.30 to 8.10 (10H,
m).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of -ethyl-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) 2H-Tetrazol-5-yl) -2-ethylmethylthiobenzamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 160-162 ° C (recrystallization solvent: ethyl acetate-n
-Hexane); IRνmax cm ⁻¹ 2216,165
2; NMR (400 MHz, DMSO-d ₆ ) δpp
m 1.26 (3H, t), 1.87-2.33
(6H, m), 2.85 (2H, q), 3.67
(1H, m), 7.41 (1H, d), 7.4
8. (1H, t), 7.53 (1H, s),
63 (1H, d), 7.99 (1H, d),
8.05 (1H, s), 10.69 (1H,
s); MS (FAB) m / z 455 (M ⁺⁺ 1);
Elemental analysis value Calculated value of C ₂₅ H ₂₂ N ₆ OS · 3 / 4H ₂ O (%) C, 64.15; H, 5.06; N, 1
7.96, measured value (%) C, 64.43; H,
5.13; N, 17.65.

Example 172 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-vinyl-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -2-vinyl-4
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-vinylbenzoic acid and 3 − (2-
(4-Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated in the same manner as in Step 1 of Example 103 to give N-
(3- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-vinylbenzamide was obtained as an amorphous substance. Was. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
1-2.39 (6H, m), 3.68 (1H,
m), 3.81 (3H, s), 5.51 (1H,
d), 5.76 (2H, s), 5.91 (1
H, d), 6.69-8.35 (14H, m).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of -vinyl-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -H-tetrazol-5-yl) -2-vinylbenzamide was treated in the same manner as in Step 5 of Example 1.
The title was obtained. Melting point: 168 to 172 ° C. (decomp.) (Recrystallization solvent: ethyl acetate-n-hexane); IRνmax cm ⁻¹
2212, 1646; NMR (400 MHz, DM
_{SO-d 6) δppm 1.83~2.34 (} 6H,
m), 3.67 (1H, m), 5.51 (1H,
d), 6.00 (1H, d), 7.04 (1
H, dd), 7.42 (1H, d), 7.48
(1H, t), 7.53 (1H, s), 7.7
7 to 7.80 (2H, m), 8.07 to 8.10.
(2H, m), 8.43 (1H, s), 10.
76 (1H, s); MS (FAB) m / z 453.
(M ⁺ +1); Elemental analysis C ₂₅ H ₂₀ N ₆ Calculated OS (%) C, 66.35; H, 4.45; N, 1
8.15, measured value (%) C, 66.19; H,
4.44; N, 17.79.

Example 173 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2,6-difluoro-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) phenyl) -2,6-difluoro-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H -Tetrazol-5-yl) -2-2,6-difluorobenzoic acid and 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) aniline were treated in the same manner as in Step 1 of Example 103 to give N -(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2,
6-Difluorobenzamide was obtained. Melting point 150-153 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2216,16
58; NMR (400 MHz, CDCl ₃ ) δ ppm
1.89 to 2.41 (6H, m), 3.64 to
3.73 (1H, m), 5.75 (2H, s),
6.91 to 6.93 (2H, m), 6.95 (1
H, s), 7.36-7.41 (4H, m),
7.71 to 7.73 (1H, m), 7.76 (2
H, d), 7.87 (2H, s); MS (E
I) m / z 512 (M ⁺ ); Elemental analysis value C ₃₁ H ₂₄ F
Calculated value for ₂ N ₆ O ₂ S (%) C, 63.91; H,
4.15; N, 14.42; measured value (%) C, 6
4.14; H, 4.21; N, 14.40.

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl)-
2,6-difluoro-4- (1H-tetrazole-5
Synthesis of yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2, 6
-Difluorobenzamide was treated as in step 5 of example 1 to give the title compound. 227-233 ° C (decomp.) (Recrystallization solvent: ethanol-n-hexane); IRνmax cm ^-1
2212, 1664; NMR (400 MHz, DM
_{SO-d 6) δppm 1.84~2.31 (} 6H,
m), 3.63-3.71 (1H, m), 7.4
6 (1H, d), 7.51 (1H, t), 7.5
4. (1H, s), 7.72 (1H, d),
90-7.92 (2H, m), 8.05 (1H,
s), 11.15 (1H, s); MS (FAB)
^{m / z 463 (M + +1} ); Elemental analysis C ₂₃ H ₁₆
Calculated value of F ₂ N ₆ OS (%) C, 59.73; H,
3.49; N, 18.17, measured value (%) C, 5
9.83; H, 3.60; N, 18.19.

Example 174 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-6-methylthio-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl- 2
-Thiazolyl) ethynyl) phenyl) -2-fluoro-
6-methylthio-4- (2- (4-methoxybenzyl)
Synthesis of -2H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-fluoro-6-methylthiobenzoic acid and 3- (2- (4 -Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 2 of Example 104 to give N- (3- (2- (4-cyclobutyl-2).
-Thiazolyl) ethynyl) phenyl) -4- (2- (4
-Methoxybenzyl) -2H-tetrazol-5-yl) -2-fluoro-6-methylthiobenzamide was obtained as a yellow amorphous. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
1-2.40 (6H, m), 2.58 (3H,
s), 3.65 to 3.73 (1H, m), 5.7
6 (2H, s), 6.91 to 6.93 (2H,
m), 6.96 (1H, s), 7.38-7.4
2 (4H, m), 7.67 to 7.70 (1H,
m), 7.71 to 7.74 (1H, m), 7.7
6. (1H, s), 7.87 (1H, s),
90 (1H, s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of -fluoro-6-methylthio-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4 -Methoxybenzyl) -2H-tetrazol-5-yl) -2-fluoro-6-methylthiobenzamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 182 to 187 ° C. (decomp.) (Recrystallization solvent: ethanol-chloroform); IRνmax cm ⁻¹
2212, 1656; NMR (400 MHz, DM
_{SO-d 6) δppm 1.84~2.33 (} 6H,
m), 2.62 (3H, s), 3.63-3.72
(1H, m), 7.44 (1H, d), 7.5
6. 0 (1H, t), 7.54 (1H, s),
71 (1H, d), 7.75 to 7.78 (1H,
m), 7.86 (1H, s), 8.05 (1H,
s), 11.00 (1H, s); MS (FAB)
^{m / z 491 (M + +1} ); Elemental analysis C ₂₄ H ₁₉
Calculated value of FN ₆ OS ₂ (%) C, 58.76; H,
3.90; N, 17.13, measured value (%) C, 5
8.61; H, 4.12; N, 17.36.

Example 175 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-6-methoxy-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl- 2
-Thiazolyl) ethynyl) phenyl) -2-fluoro-
6-methoxy-4- (2- (4-methoxybenzyl)-
Synthesis of 2H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-fluoro-6-methoxybenzoic acid and 3- (2- (4- Cyclobutyl-2-thiazolyl)
The ethynyl) aniline was treated as in step 2 of Example 104 to give N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl)-
2-Fluoro-6-methoxybenzamide was obtained as a pale yellow amorphous. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
9 to 2.41 (6H, m), 3.65 to 3.74 (1
H, m), 3.81 (3H, s), 4.01.
(3H, s), 5.76 (2H, s), 6.9
1 to 6.94 (2H, m), 6.95 (1H,
s), 7.37-7.39 (2H, m), 7.3.
9-7.42 (2H, m), 7.55-7.58
(1H, m), 7.58 (1H, s), 7.7
6-7.78 (1H, m), 7.84 (1H,
s), 7.88 (1H, s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of -Fluoro-6-methoxy-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4 -Methoxybenzyl) -2H-tetrazol-5-yl) -2-fluoro-6-methoxybenzamide was prepared in Step 5 of Example 1.
The title compound was obtained. Melting point 210-213 ° C (decomp.) (Recrystallization solvent: ethanol-chloroform); IRνmax cm ^-1
2216, 1680; NMR (400 MHz, DM
_{SO-d 6) δppm 1.86~2.33 (} 6H,
m), 3.63-3.71 (1H, m), 3.9
7 (3H, s), 7.42 (1H, d), 7.4
8. (1H, t), 7.53 (1H, s),
58 (1H, d), 7.65 (1H, s),
7.72 (1H, d), 8.05 (1H, s),
10.87 (1H, s); MS (FAB) m / z
475 (M ⁺ +1); Elemental analysis C ₂₄ H ₁₉ FN ₆ O
Calculated value of ₂ S (%) C, 60.75; H, 4.0
4; N, 17.71; measured value (%) C, 60.8
1; H, 4.25; N, 17.62.

Example 176 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-isopropoxy-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) phenyl) -2-isopropoxy-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H- Tetrazol-5-yl) -2-isopropoxybenzoic acid and 3-
(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 2 of Example 104 to give N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-
Isopropoxybenzamide was obtained. 124-125 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2212,16
70; NMR (400 MHz, CDCl ₃ ) δ ppm
1.58 (6H, d), 1.91 to 2.40 (6
H, m), 3.66 to 3.74 (1H, m),
3.80 (3H, s), 4.97 to 5.03 (1
H, m), 5.75 (2H, s), 6.89-
6.93 (2H, m), 6.96 (1H, s),
7.34 to 7.41 (4H, m), 7.76 to
7.79 (1H, m), 7.84 (1H, s),
7.86 to 7.88 (2H, m), 8.39 (1
H, d), 10.26 (1H, s); MS (E
I) m / z 604 (M ⁺ ); Elemental analysis C ₃₄ H ₃₂ N
Calculated ₆ O ₃ S (%) C, 67.52; H, 5.3
3; N, 13.90, measured value (%) C, 67.4
7; H, 5.44; N, 14.02.

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of -isopropoxy-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) ) -2H-Tetrazol-5-yl) -2-isopropoxybenzamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point 207-210 ° C (decomp.) (Recrystallization solvent: chloroform); IRνmax cm ⁻¹ 2216,1
672; NMR (400 MHz, DMSO-d ₆ ) δ
ppm 1.41 (6H, d), 1.86-2.3
3 (6H, m), 3.63 to 3.71 (1H,
m), 4.80-4.86 (1H, m), 7.4
0 (1H, d), 7.48 (1H, t), 7.
53 (1H, s), 7.72 to 7.76 (2H,
m), 7.79 (1H, s), 7.85 (1H,
d), 8.09 (1H, s), 10.38 (1
H, s); MS (EI) m / z 484 (M ^<+> );
Elemental analysis value Calculated value of C ₂₆ H ₂₄ N ₆ O ₂ S (%) C, 6
3.27; H, 5.10; N, 17.03, found (%) C, 63.39; H, 4.87; N, 1
7.25.

Example 177 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-hydroxy-4- (1H-tetrazole-5
-Yl) benzamide: 97 mg of 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-isopropoxybenzoic acid and 53 m of aluminum chloride
20 g of 1,2-dichloroethane was added to g, and the mixture was heated under reflux for 20 hours. After cooling, the reaction solution was added to 1N hydrochloric acid (30 ml), and the precipitated crystals were collected by filtration to obtain the title compound. 160-163 ° C (decomp.) (Recrystallization solvent: chloroform-ethanol-n-hexane);
Rνmax cm ⁻¹ 2212, 1644; NMR (40
_{0MHz, DMSO-d 6) δppm} 1.84~2.
33 (6H, m), 3.63 to 3.71 (1H,
m), 7.43 (1H, d), 7.49 (1H,
t), 7.53 (1H, s), 7.63 (1
H, dd), 7.71 (1H, d), 7.81
(1H, d), 8.08 (1H, d), 8.10
(1H, s), 10.58 (1H, s), 1
1.83 (1H, brs); MS (FAB) m /
z 443 (M ⁺⁺ 1).

Example 178 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-nitro-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -2-nitro-4
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-nitrobenzoic acid and 3 − (2-
(4-Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 2 of Example 104 to give N-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-nitrobenzamide as pale yellow amorphous As obtained. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
8 to 2.40 (6H, m), 3.68 (1H,
m), 3.81 (3H, s), 5.78 (2H,
s), 6.93 (2H, d), 6.96 (1
H, s), 7.39-7.83 (8H, m),
8.47 (1H, d), 8.83 (1H, s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of -nitro-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -H-tetrazol-5-yl) -2-nitrobenzamide was treated in the same manner as in Step 5 of Example 1.
The title was obtained. Melting point> 300 ° C. (recrystallization solvent: chloroform-methanol); IRνmax cm ⁻¹ 2204,1658,1
584, 1536, 1362, 1320; NMR (4
00 MHz, DMSO-d ₆ ) δppm 1.84 ~
2.33 (6H, m), 3.67 (1H, m),
7.44 (1H, d), 7.50 (1H, t),
7.54 (1H, s), 7.69 (1H,
d), 7.99 (1H, d), 8.03 (1H,
s), 8.52 (1H, d), 8.78 (1H,
s), 11.00 (1H, s); Elemental analysis value C ₂₃
Calculated _{H 17 N 7 O 3 S (} %) C, 58.59;
H, 3.63; N, 20.79, measured value (%)
C, 58.20; H, 3.86; N, 20.61.

Example 179 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-amino-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -2-amino-4
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-nitro-4- (2-
(4-methoxybenzyl) -2H-tetrazole-5
Il) Benzamide was treated in the same manner as in Reference Example 17 to give N-
(3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-aminobenzamide was converted to pale yellow amorphous As obtained. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.41 (6H, m), 3.68 (1H,
m), 3.80 (3H, s), 5.67 (2H,
br), 5.75 (2H, s), 6.91 (2
H, d), 6.96 (1H, s), 7.38-
7.56 (8H, m).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of -amino-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -H-tetrazol-5-yl) -2-aminobenzamide was treated in the same manner as in Step 5 of Example 1.
The title was obtained. 164-168 ° C (recrystallization solvent: chloroform-
Methanol); NMR (400 MHz, DMSO-d)
₆ ) δ ppm 1.84 to 2.33 (6H, m),
3.67 (1H, m), 7.22 (1H, d),
7.39 (1H, t), 7.51 (1H,
s), 7.53 (1H, s), 7.80 (1H,
d), 7.85 (1H, d), 8.11 (1
H, s), 10.32 (1H, s); MS (F
AB) m / z 442 (M + +1); Elemental analysis C _{23
H 19 N 7 OS · 3 /} 4H 2 O Calculated (%) C, 6
H, 4.54; N, 21.55, measured value (%) C, 60.88; H, 4.23; N, 2
1.33.

Example 180 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-iodo-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -2-iodo-4
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-iodobenzoic acid and 3 − (2-
(4-Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 2 of Example 104 to give N-
(3- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-iodobenzamide was obtained as amorphous. Was. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
4 to 2.39 (6H, m), 3.67 (1H,
m), 3.81 (3H, s), 5.75 (2H,
s), 6.92 (2H, d), 6.94 (1
H, s), 7.39-7.41 (4H, m),
7.61 (1H, d), 7.67 (1H, m),
7.72 to 7.74 (1H, m), 7.89 (1
H, s), 8.18 (1H, d), 8.67 (1
H, s).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
Synthesis of -Iodo-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -H-tetrazol-5-yl) -2-iodobenzamide was treated as in step 5 of example 1;
The title was obtained. 152-154 ° C (decomp.) (Recrystallization solvent: chloroform-methanol); NMR (400M
_{Hz, DMSO-d 6) δppm} 1.84~2.34
(6H, m), 3.67 (1H, m), 7.4
6. 3 (1H, d), 7.50 (1H, t),
7. 54 (1H, s), 7.76 (2H, d),
07 (1H, s), 8.18 (1H, d),
8.58 (1H, s), 10.77 (1H, s);
Elemental analysis value Calculated value of C ₂₃ H ₁₇ IN ₆ OS · １ ／ H ₂ O (%) C, 49.61; H, 3.17; N, 1
5.09, measured value (%) C, 49.45; H,
3.42; N, 15.02.

Example 181 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-methoxy-6-methyl-4- (1H-tetrazol-5-yl) benzamide (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -2-methoxy-
6-methyl-4- (2- (4-methoxybenzyl) -2
Synthesis of H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-methoxy-6-methylbenzoic acid and 3- (2- (4- Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 2 of Example 104 to give N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2
-Methoxy-6-methylbenzamide was obtained. Melting point 75-77 ° C (recrystallization solvent: water-ethanol);
NMR (400 MHz, CDCl ₃ ) δ ppm
90 to 2.30 (6H, m), 2.34 (3H,
s), 3.60-3.70 (1H, m), 3.7
6 (3H, s), 3.88 (3H, s), 5.
93 (2H, s), 6.97 (2H, d),
98 (1H, s), 7.39-8.08 (8H,
m).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
-Methoxy-6-methyl-4- (1H-tetrazole-
Synthesis of 5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl)- 2-methoxy-6-methylbenzamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. 181-184 ° C (recrystallization solvent: chloroform-
Methanol); NMR (400 MHz, DMSO-d)
₆ ) δ ppm 1.90-2.30 (6H, m),
2.34 (3H, s), 3.60 to 3.70 (1
H, m), 3.76 (3H, s), 3.88
(3H, s), 7.39 (1H, t), 7.45
(1H, d), 7.53-8.08 (5H,
m), 10.52 (1H, br s); MS (F
AB) m / z 471 (M + +1); Elemental analysis C ₂₅
Calculated value (%) of H ₂₂ N ₆ O ₂ S · 1/10 H ₂ O C,
H, 4.56; N, 16.97, measured value (%) C, 61.87; H, 4.80; N,
16.62.

Example 182 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-chloro-6-fluoro-4- (1 or 2
H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -2-chloro-6
-Fluoro-4- (2- (4-methoxybenzyl) -2
Synthesis of H-tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-chloro-6-fluorobenzoic acid and 3- (2- (4- Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated as in step 2 of Example 104 to give N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2
-Chloro-6-fluorobenzamide was obtained as amorphous. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.30 (6H, m), 3.60 to 3.70 (1
H, m), 3.76 (3H, s), 5.93
(2H, s), 6.97 (2H, d), 6.9
8 (1H, s), 7.39 to 8.08 (9H,
m).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2
-Chloro-6-fluoro-4- (1H-tetrazole-
Synthesis of 5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl)- 2-Chloro-6-fluorobenzamide was treated in the same manner as in Step 1 of Example 1 to obtain the title compound. 216-236 ° C (recrystallization solvent: chloroform-
Methanol); NMR (400 MHz, DMSO-d)
₆ ) δ ppm 1.90-2.30 (6H, m),
2.34 (3H, s), 3.60 to 3.70 (1
H, m), 3.76 (3H, s), 7.39
(1H, t), 7.45 (1H, d), 7.54
８8.08 (5H, m), 10.52 (1H, b
rs); MS (FAB) m / z 479 (M ⁺⁺ ).
1).

Example 183 N- (3- (2- (4
-Tert-butyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-4- (1H-tetrazole-5
-Yl) benzamide: (Step 1) N- (3- (2- (4-tert-butyl-2-thiazolyl) ethynyl) phenyl) -2-fluoro-4- (2- (4-methoxybenzyl) -2H Synthesis of -tetrazol-5-yl) benzamide 4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-fluorobenzoic acid and 3- (2-
(4-tert-butyl-2-thiazolyl) ethynyl)
The aniline was treated as in Step 2 of Example 104,
-(3- (2- (4-tert-butyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-fluorobenzamide Obtained. 212-213 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2212,16
58; NMR (400 MHz, CDCl ₃ ) δ ppm
1.38 (9H, s), 3.80 (3H,
s), 5.76 (2H, s), 6.90-6.9.
6. 3 (2H, m), 6.97 (1H, s), 7.
36-7.42 (4H, m), 7.71-7.74
(1H, m), 7.93 (1H, s), 7.9
7 (1H, dd), 8.08 (1H, dd),
8.28 (1H, t), 8.50 (1H, d);
MS (FAB) m / z 567 (M + +1); Elemental analysis _{C 31 H 27 FN 6 O 2} S · 1 / 4H 2 O Calculated (%) C, 65.19; H , 4.85; N, 1
4.71, measured value (%) C, 64.96; H,
4.80; N, 14.57.

(Step 2) N- (3- (2- (4-te)
rt-butyl-2-thiazolyl) ethynyl) phenyl)
Synthesis of -2-fluoro-4- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-tert-butyl-2-thiazolyl) ethynyl) phenyl) -4- (2- (4 -Methoxybenzyl) -2H-tetrazol-5-yl) -2-
The fluorobenzamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point 214-216 ° C (decomp.) (Recrystallization solvent: chloroform); NMR (400 MHz, DMSO
−d ₆ ) δ ppm 1.32 (9H, s), 7.47
~ 7.50 (1H, m), 7.50 (1H, m)
s), 7.77 (1H, d), 7.94 (1H,
t), 7.98-8.03 (2H, m), 8.0
8 (1H, s), 10.77 (1H, s); M
S (EI) m / z 446 (M ⁺ ); Elemental analysis value C ₂₃ H
₁₉ Calculated value of FN ₆ OS · 1 / 4H ₂ O (%) C, 6
1.25; H, 4.36; N, 18.63, measured value (%) C, 61.36; H, 4.42; N, 1
8.52.

Example 184 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-bromo-4- (1H-tetrazol-5-yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
-Thiazolyl) ethynyl) phenyl) -5-bromo-3
Synthesis of-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide 3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -5-bromobenzoic acid and 3 − (2-
(4-Cyclobutyl-2-thiazolyl) ethynyl) aniline was treated in the same manner as in Step 1 of Example 103 to give N-
(3- (2- (4-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -5-bromobenzamide was obtained. 167-174 ° C (recrystallization solvent: chloroform-
n-hexane); IRvmax cm ^-1 2212; N
MR (400 MHz, CDCl ₃ ) δ ppm 1.87
~ 2.44 (6H, m), 3.70 (1H,
m), 3.80 (3H, s), 5.75 (2H,
s), 6.92 (2H, d), 6.96 (1
H, s), 7.36 to 7.42 (4H, m),
7.73 (1H, m), 7.90 (1H, br)
s), 8.07 (1H, br s), 8.15 (1
H, t), 8.45 (1H, t), 8.49
(1H, br s); MS (FAB) m / z 625
(M ⁺ +1); Elemental analysis value C ₃₁ H ₂₅ BrN ₆ O ₂ S
· H ₂ O Calculated (%) C, 57.85; H , 3.
70; N, 13.06, measured value (%) C, 58.
11; H, 4.26; N, 13.31.

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -5
Synthesis of -bromo-3- (1H-tetrazol-5-yl) benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -3- (2- (4-methoxybenzyl) -H-tetrazol-5-yl) -5-bromobenzamide was treated as in step 5 of example 1;
The title was obtained. 217-222 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane); NMR (400
MHz, DMSO-d ₆ ) δ ppm 1.85 to 2.3
8 (6H, m), 3.68 (1H, m), 7.
32 (1H, s), 7.37 (1H, d),
7.44 (1H, t), 7.88 (1H, br)
d), 8.15 (1H, brt), 8.36
(1H, brt), 8.44 (1H, br)
t), 8.72 (1H, br t), 10.63
(1H, s); MS (FAB) m / z 505
[(M ⁺ +2) +1], 503 [(M ⁺ ) +1];
Elemental analysis _{C 23 H 17 BrN 6 OS ·} 3 / 4H 2 O Calculated (%) C, 53.23; H , 3.59; N, 1
6.20, found (%) C, 53.54; H, 3.
65; N, 15.72.

Example 185 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -2-hydroxy-6-methyl-4- (1H-tetrazol-5-benzamide: N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) Phenyl) -2-methoxy-6-methyl-4- (1H-tetrazol-5-benzamide was treated in the same manner as in Example 177 to give the title compound, mp 214-218 ° C (decomp.) (Recrystallization solvent) : Chloroform-methanol); NMR (400M
_{Hz, DMSO-d 6) δppm} 1.90~2.30
(6H, m), 2.34 (3H, s), 3.6
0 to 3.70 (1H, m), 7.35 (1H,
t), 7.49 (1H, d), 7.53 (1H,
s), 7.55 (1H, s), 7.62 (1
H, s), 7.82 (1H, d), 8.08 (1
H, s), 10.43 (1H, s), 10.52
(1H, s); MS (FAB) m / z 471 (M
⁺ +1).

Example 186 N- (3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N-hydroxy-4- (1H-tetrazole-5
-Yl) benzamide: (Step 1) N- (3- (2- (4-cyclobutyl-2)
Synthesis of -thiazolyl) ethynyl) phenyl) -N-hydroxy-4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide N- (3-iodophenyl) -N-hydroxy-4-
(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) benzamide and 4-cyclobutyl-2-ynylthiazole were treated in the same manner as in Step 4 of Example 1,
N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N-hydroxy-4- (2
-(4-methoxybenzyl) -2H-tetrazole-5
-Yl) benzamide was obtained as an oil. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.40 (6H, m), 3.60 to 3.70 (1
H, m), 3.80 (3H, s), 5.75
(2H, s), 6.90 (2H, d), 7.3
5-8.30 (12H, m).

(Step 2) N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N
-Hydroxy-4- (1H-tetrazol-5-yl)
Synthesis of benzamide N- (3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) phenyl) -N-hydroxy-4- (2
-(4-methoxybenzyl) -2H-tetrazole-5
-Yl) benzamide was treated as in step 1 of example 1 to give the title compound. Melting point 167 to 170 ° C (decomp.) (Recrystallization solvent: ethyl acetate-methanol); NMR (400 MH)
_{z, DMSO-d 6) δppm} 1.90~2.40
(6H, m), 3.60-3.70 (1H,
m), 7.53 (1H, s), 7.64 (1H,
t), 7.87 (1H, d), 7.92 (1
H, s), 8.07 (1H, d), 8.30-
8.40 (5H, m); MS (FAB) m / z 44
3 (M ⁺⁺ 1).

Example 187 N- (4- (1H-tetrazol-5-yl) phenyl) -3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) benzamide: (Step 1) N- (4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl) -3
Synthesis of-(2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzoic acid and 4- (2- (4-methoxybenzyl) benzoic acid
2H-tetrazol-5-yl) aniline in Example 1
03, and treated in the same manner as in step 1 of N- (4- (2- (4-
Methoxybenzyl) -2H-tetrazol-5-yl)
Phenyl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide was obtained. 179-180 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2216,16
62; NMR (400 MHz, CDCl ₃ ) δ ppm
1.94 to 2.40 (6H, m), 3.66 to
3.73 (1H, m), 3.80 (3H, s),
5.73 (2H, s), 6.89-6.92 (2
H, m), 6.99 (1H, s), 7.38-
7.40 (2H, m), 7.52 (1H, t),
7.75 (1H, d), 7.80 (2H, d)
d), 7.93 (1H, d), 8.03 (1H,
s), 8.06 (1H, s), 8.15 (2H,
d); MS (FAB) m / z 547 (M ⁺⁺ 1);
Elemental analysis value Calculated value of C ₃₁ H ₂₆ N ₆ O ₂ S (%) C,
H, 4.79; N, 15.38, measured value (%) C, 67.79; H, 4.81; N,
15.24.

(Step 2) Synthesis of N- (4- (1H-tetrazol-5-yl) phenyl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide N- (4- (2 -(4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl) -3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) benzamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 245 to 246 ° C. (decomp.) (Recrystallization solvent: chloroform-ethanol); IRνmax cm ⁻¹
2216, 1654; NMR (400 MHz, DM
_{SO-d 6) δppm 1.96~2.32 (} 6H,
m), 3.64-3.72 (1H, m), 7.5
5 (1H, s), 7.67 (1H, t), 7.8
9 (1H, d), 8.01 to 8.04 (3H,
m), 8.07 (2H, d), 8.29 (1H,
s), 10.65 (1H, s); MS (FA
B) m / z 427 (M + +1); Elemental analysis C ₂₃
Calculated value of H ₁₈ N ₆ OS · 1 / 4H ₂ O (%) C, 6
4.10; H, 4.33; N, 19.50, measured value (%) C, 63.89; H, 4.25; N, 1
9.37.

Example 188 N- (3- (1H-tetrazol-5-yl) phenyl) -3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) benzamide: (Step 1) N- (3- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl) -3
Synthesis of-(2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzoic acid and 3- (2- (4-methoxybenzyl)
2H-tetrazol-5-yl) aniline in Example 1
04, and treated in the same manner as in Step 2 of N- (3- (2- (4-
Methoxybenzyl) -2H-tetrazol-5-yl)
Phenyl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide was obtained. 185-186 ° C (recrystallization solvent: chloroform-
n-hexane); IRνmax cm ⁻¹ 2216,16
58; NMR (400 MHz, CDCl ₃ ) δ ppm
1.92 to 2.40 (6H, m), 3.69 to
3.73 (1H, m), 3.79 (3H, s),
5.72 (2H, s), 6.88-6.90 (2
H, m), 6.99 (1H, s), 7.37-
7.39 (2H, m), 7.46 to 7.51 (2
H, m), 7.72 to 7.74 (1H, m),
7.92 to 7.96 (3H, m), 8.07 (1
H, s), 8.17 (1H, br s), 8.
29 (1H, s); MS (FAB) m / z 547.
(M ⁺ +1); Elemental analysis value Calculated value of C ₃₁ H ₂₆ N ₆ O ₂ S (%) C, 68.11; H, 4.79; N,
15.38, measured value (%) C, 67.73; H,
4.86; N, 15.22.

(Step 2) Synthesis of N- (3- (1H-tetrazol-5-yl) phenyl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide N- (3- (2 -(4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl) -3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) benzamide was treated in the same manner as in Step 5 of Example 1 to obtain the title compound. Melting point: 162 to 164 ° C. (decomp.) (Recrystallization solvent: chloroform-ethanol); IRνmax cm ⁻¹
2216, 1662; NMR (400 MHz, DM
_{SO-d 6) δppm 1.87~2.34 (} 6H,
m), 3.64-3.72 (1H, m), 7.5
5 (1H, s), 7.61 (1H, t), 7.6
7. (1H, t), 7.77 (1H, d),
89 (1H, d), 7.98 (1H, d),
8.10 (1H, d), 8.32 (1H, s),
8.62 (1H, s), 10.63 (1H,
s); MS (FAB) m / z 427 (M ⁺⁺ 1);
Elemental analysis value Calculated value of C ₂₃ H ₁₈ N ₆ OS · １ ／ H ₂ O (%) C, 64.10; H, 4.33; N, 1
9.50, measured value (%) C, 64.38; H,
4.33; N, 19.45.

Example 189 N- (4- (1H-tetrazol-5-yl) -2-methoxyphenyl) -3
-(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) benzamide: (Step 1) N- (4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-methoxyphenyl) Synthesis of -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzoic acid and 2-methoxy-4- (2- (4 -Methoxybenzyl) -2H-tetrazol-5-yl) aniline was treated as in step 1 of Example 103 to give N- (4
-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-methoxyphenyl) -3- (2-
(4-Cyclobutyl-2-thiazolyl) ethynyl) benzamide was obtained as amorphous. NMR (400 MHz, CDCl ₃ ) δ ppm 1.9
0 to 2.42 (6H, m), 3.67 to 3.75 (1
H, m), 3.80 (3H, s), 4.06
(3H, s), 5.74 (2H, s), 6.9
6. 1 (2H, d), 6.99 (1H, s), 7.
6. 40 (2H, d), 7.53 (1H, t),
72 (1H, d), 7.77 (1H, d),
7.81 (1H, dd), 7.96 (1H, dd)
d), 8.08 (1H, s), 8.63 (1H,
s), 8.65 (1H, d).

(Step 2) N- (4- (1H-tetrazol-5-yl) -2-methoxyphenyl) -3- (2
Synthesis of-(4-cyclobutyl-2-thiazolyl) ethynyl) benzamide N- (4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-methoxyphenyl) -3
Treating-(2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide as in step 5 of example 1;
The title was obtained. 220-221 ° C (decomp.) (Recrystallization solvent: chloroform-n-hexane); IRνmax cm
^-1 2216, 1682, 1656; NMR (400
_{MHz, DMSO-d 6) δppm} 1.89~2.2
9 (6H, m), 3.66 to 3.72 (1H,
m), 3.97 (3H, s), 7.55 (1H,
s), 7.64 (1H, d), 7.67 (1
H, t), 7.74 (1H, s), 7.88 (1
H, d), 8.04 (1H, d), 8.05-
8.08 (1H, m), 8.27 (1H, s),
9.86 (1H, s); MS (FAB) m / z
427 (M ⁺ +1); Elemental analysis _{C 24 H 20 N 6 O 2} S
· 1 / 2H ₂ O Calculated (%) C, 61.92;
H, 4.55; N, 18.05, measured value (%)
C, 62.21; H, 4.42; N, 17.94.

Example 190 N- (4- (1H-tetrazol-5-yl) phenyl) -N-methyl-3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide: (Step 1) N- (4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl) -N
Synthesis of -methyl-3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide 3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzoic acid and N-methyl-4- (2- (4-Methoxybenzyl) -2H-tetrazol-5-yl) aniline was treated as in Step 2 of Example 104 to give N- (4-
(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl) -N-methyl-3- (2- (4
-Cyclobutyl-2-thiazolyl) ethynyl) benzamide was obtained. NMR (400 MHz, CDCl ₃ ) δ ppm 1.8
7 to 2.41 (6H, m), 3.53 (3H,
s), 3.68 (1H, m), 3.79 (3H,
s), 5.70 (2H, s), 6.88 (2
H, d), 6.94 (1H, s), 7.13
(1H, d), 7.15 (1H, t), 7.24
(1H, d), 7.36 (2H, d), 7.4
7. 5 (1H, d), 7.62 (1H, s),
01 (1H, d).

(Step 2) N- (4- (1H-tetrazol-5-yl) phenyl) -N-methyl-3- (2-
Synthesis of (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide N- (4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl) -N-methyl-3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide was treated as in step 5 of example 1;
The title was obtained. Melting point 114-117 ° C (decomp.); IRν
max cm ^-1 2216, 1650; NMR (400M
_{Hz, DMSO-d 6) δppm} 1.83~2.32
(6H, m), 3.44 (3H, s), 3.6
5. (1H, m), 7.33 (1H, t),
36 (1H, d), 7.46 (2H, d), 7.
52 (1H, s), 7.58 (1H, d),
7.63 (1H, s), 7.93 (2H, d);
MS (FAB) m / z 441 (M + +1); Elemental analysis _{C 24 H 20 N 6 OS ·} 1 / 2H 2 O Calculated (%) C, 64.12; H , 4.71; N, 18.
70, measured value (%) C, 64.13; H, 4.9
2; N, 19.17.

Example 191 N- (4- (1H-tetrazol-5-yl) phenyl) -3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -6-methylbenzamide: N- (4
-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-methylbenzamide is similarly deprotected, The title was obtained. Mp 225-228 ° C (decomp.) (Recrystallization solvent: chloroform-ethanol); NMR (400M
_{Hz, DMSO-d 6) δppm} 1.80~2.40
(6H, m), 2.46 (3H, s), 3.6
0 to 3.80 (1H, m), 7.45 (1H,
d), 7.52 (1H, s), 7.69 (1H,
d), 7.82 (1H, s), 7.97 (2
H, d), 8.04 (2H, d), 10.72
(1H, brs); MS (FAB) m / z 441
(M ⁺ +1); Elemental analysis value C ₂₄ H ₂₀ N ₆ OS · 1 /
Calculated 2H ₂ O (%) C, 64.12; H, 4.7
1; N, 18.69, measured value (%) C, 63.9
2; H, 4.65; N, 18.58.

Example 192 N- (4- (1H-tetrazol-5-yl) phenyl) -3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-methylbenzamide: N- (4
-(2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-methylbenzamide is similarly deprotected, The title was obtained. 184-186 ° C (decomp.) (Recrystallization solvent: chloroform-methanol); IRνmax cm ^-1
1664; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.80-2.40 (6H, m),
2.56 (3H, s), 3.60 to 3.80 (1H,
m), 7.44 (1H, t), 7.55 (1
H, s), 7.61 (1H, d), 7.77.
(1H, d), 7.97 (2H, d), 8.0
4 (2H, d), 10.78 (1H, br
s); MS (FAB) m / z 441 (M ⁺⁺ 1);
Elemental analysis _{C 24 H 20 N 6 OS ·} 1 / 2H 2 O Calculated (%) C, 64.12; H , 4.71; N, 1
8.69, measured value (%) C, 64.12; H,
4.62; N, 18.52.

Example 193 N- (4- (1H-tetrazol-5-yl) -2-methylphenyl) -3-
(2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide: N- obtained in the same manner as described above.
(4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-methylphenyl) -3- (2
-(4-Cyclobutyl-2-thiazolyl) ethynyl) benzamide was similarly deprotected to give the title compound. 135-138 ° C (decomp.) (Recrystallization solvent: chloroform-methanol-n-hexane); N
MR (400 MHz, DMSO-d ₆ ) δ ppm 1.8
0 to 2.40 (6H, m), 2.38 (3H,
s), 3.60-3.80 (1H, m), 7.5
5 (1H, s), 7.60 to 7.70 (2H,
m), 7.80-7.90 (2H, m), 8.0
0 (1H, s), 8.09 (1H, d), 8.3
0 (1H, s), 10.20 (1H, s); M
S (FAB) m / z 441 (M ⁺⁺ 1).

Example 194 N- (4- (1H-tetrazol-5-yl) phenyl) -3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -2-fluorobenzamide: N-
(4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -2-fluorobenzamide is similarly deprotected To give the title. Melting point 222-226 ° C (decomp.) (Recrystallization solvent: chloroform-methanol); IRνmax cm ^-1
1682; NMR (400 MHz, DMSO-d
₆ ) δ ppm 1.90-2.40 (6H, m),
3.60 to 3.80 (1H, m), 7.51 (1
H, t), 7.54 (1H, s), 7.90
(1H, d), 7.91 (1H, d), 7.9
5 (2H, d), 8.05 (2H, d), 1
0.86 (1H, s); MS (FAB) m / z 4
45 (M ⁺⁺ 1).

Example 195 N- (4- (1H-tetrazol-5-yl) phenyl) -3- (2- (4-
Cyclobutyl-2-thiazolyl) ethynyl) -6-fluorobenzamide: N-
(4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) phenyl) -3- (2- (4-cyclobutyl-2-thiazolyl) ethynyl) -6-fluorobenzamide is similarly deprotected To give the title. 226-229 ° C (decomp.) (Recrystallization solvent: chloroform-methanol); NMR (400M
Hz, DMSO-d6) [delta] ppm 1.90-2.40
(6H, m), 3.60-3.80 (1H,
m), 7.45 (1H, d), 7.48 (1H,
s), 7.60 (1H, s), 7.83 (1
H, dd), 7.95 (2H, d), 8.05
(2H, d), 10.88 (1H, s); MS
(FAB) m / z 445 (M ⁺⁺ 1); elemental analysis value C
₂₃ H ₁₇ FN ₆ OS · 1 / 2H ₂ O calculated value (%) C,
H, 4.00; N, 18.53, measured value (%) C, 60.73; H, 4.12; N,
18.29.

Example 196 N- (4- (1H-tetrazol-5-yl) -2-fluorophenyl) -3
-(2- (4-cyclobutyl-2-thiazolyl) ethynyl) benzamide: N- obtained in the same manner as described above.
(4- (2- (4-methoxybenzyl) -2H-tetrazol-5-yl) -2-fluorophenyl) -3-
(2- (4-Cyclobutyl-2-thiazolyl) ethynyl) benzamide was similarly deprotected to give the title compound. 236-239 ° C (decomp.) (Recrystallization solvent: chloroform-methanol); NMR (400M
_{Hz, DMSO-d 6) δppm} 1.90~2.40
(6H, m), 3.60-3.80 (1H,
m), 7.55 (1H, s), 7.68 (1H,
7.t), 7.90-8.00 (5H, m),
09 (1H, d), 8.31 (1H, s), 1
0.54 (1H, s); MS (FAB) m / z 4
45 (M ⁺⁺ 1).

Example 197 Formulation Example: Preparation of Tablet 1000 mg of the compound of Example 1 pulverized well. Lactose 59
00 mg, microcrystalline cellulose (MCC) 2000 mg, low-substituted hydroxypropylcellulose (LHPC) 10
00 mg and 100 mg of magnesium stearate are mixed well, and the above-mentioned compound 1
An uncoated tablet containing 0 mg was produced. The uncoated tablets were sugar-coated or film-coated to produce sugar-coated tablets and film-coated tablets.

[Example 198] Formulation example: Production of tablet 1000 mg of the compound of Example 157, lactose 5900 mg, microcrystalline cellulose (MCC) 2000 m which was pulverized well.
g, low-substituted hydroxypropylcellulose (LHP
C) 1000 mg, magnesium stearate 100 m
g were mixed well, and an uncoated tablet containing 10 mg of the compound per 100 mg of a tablet was produced by a direct tableting method. The uncoated tablets were sugar-coated or film-coated to produce sugar-coated tablets and film-coated tablets.

Example 199 Formulation Example: Production of Capsules 1000 mg of the compound of Example 1 which was pulverized well, 3000 mg of corn starch (corn starch), lactose 6
900 mg, microcrystalline cellulose (MCC) 1000 mg,
Mix well with 100mg of magnesium stearate and add 1
Capsule tablets containing 10 mg of the compound in 120 mg capsules were prepared.

[Example 200] Formulation example: Production of capsules [0542] 1000 mg of the compound of Example 157, corn starch (corn starch) 3000 mg, lactose 6900 mg, microcrystalline cellulose (MCC) 1000 m
g and 100 mg of magnesium stearate were mixed well to prepare a capsule tablet containing 10 mg of the above compound in 120 mg of one capsule.

Example 201 Formulation Example: Production of Inhalant 50 mg of sorbitan monooleate was taken into a 5 ml aluminum container for aerosol, and suspended by adding 111 ml of Freon. 50 mg of the compound of Example 1 which was well pulverized and dried was added and dispersed by irradiating ultrasonic waves. Attach a 100 μl metering valve, and pressurize it via Freon-124
Fill ml. Compound 1 per 100 μl of injection
A metered dose inhaler (MDI) containing mg was prepared.

Example 202 Formulation Example: Production of Inhalant 50 mg of sorbitan monooleate was ingested into a 5 ml aluminum container for aerosol, and 1 ml of Freon-11 was added and suspended. 50 m of the compound of Example 157 that was well ground and dried.
g was added and the mixture was dispersed by irradiation with ultrasonic waves. Attach a 100 μl metering valve, and pressurize the Freon-1
Fill with 4 ml. A metered dose inhaler (MDI) containing 1 mg of the compound per 100 μl injection was prepared.

The compounds of the present invention represented by the formula (1) and salts thereof have, for example, an inhibitory activity on bronchial stenosis, and are useful as broncho-pulmonary drugs capable of reducing or preventing asthma and allergic reactions. Useful. Examples of useful pharmacological activity of the compounds of the formula (1) of the present invention are specifically shown by the following test examples, but the action of the compounds of the present invention is limited to those demonstrated in these test examples. However, the scope of the present invention is not limited by the following test examples.

[Test Example 1] LTD ₄ antagonistic test using guinea pig isolated ileum [0546] The ileum of a male Hartley guinea pig was measured by the Magnus method. That is, after the guinea pig was killed by exsanguination, the ileum was removed. The ileum was cut to a length of 1 to 1.5 cm, and further cut in the direction of the longitudinal muscle to prepare an ileum specimen.
This sample was suspended in a Magnus tube filled with 10 ml of Tyrode's solution (35 ° C., 95% oxygen-5% carbon dioxide gas aeration), and then 1 g was loaded. 3 ~ with histamine (10 ^-4 M)
After 4 times shrinkage, contraction reaction of LTD ₄ was studied the effect of the test substance on the stability to the LTD ₄ from the contracted. The contraction of the ileum can be monitored by a recorder (Rika Electric:
R-64VS). The test substance was dissolved in dimethylsulfoxide (DMSO), and LTD ₄ (final concentration 1
0 ^-8 M) Five minutes before the addition, it was added into a Magnus tube. The grade is
Using the same sample as the control, ileal contraction caused by LTD ₄ treated with solvent was used as a control, and ileal contraction caused by LTD ₄ treated with the test substance was compared to determine the inhibition rate. (IC ₅₀ ) was calculated.

Test Example 2 Histamine Release Inhibition Test Male Sprague-Dawley rats (250-
After decapitation and death, a modified-Tyrode solution containing 5 U / ml of heparin [Na
Cl 124 mM, KCl 4 mM, CaCl ₂ 1.0
mM, MgCl ₂ 0.5 mM, NaH ₂ PO ₄ .H ₂
O 0.64 mM, NaHCO ₃ 10 mM, Guluc
ose 5.6 mM, Gelatin 0.05% (w /
v)] 20 ml was injected intraperitoneally into rats. 60 abdomen
After gentle massage for 2 seconds, the incision was made and the intraperitoneal fluid was collected. The cells obtained by centrifuging the peritoneal fluid (250 × g, 4 ° C., 5 minutes) were used to obtain heparin-free modified-
Washed twice with Tyrode solution. 80 μl of this peritoneal exudate cell solution (approximately 10 ⁷ cells / ml as mast cells)
The mast cells were sensitized by adding 1 l of anti-DNP-IgE antibody and incubating at 37 ° C for 30 minutes. Thereafter, the number of mast cells contained in the peritoneal exudate cell fluid was 8 × 10 ⁵
mopar without heparin so as to be cells / ml
It was adjusted by adding a modified-Tyrode solution. The antigen (final concentration 30 ng / m2) was added to 250 μl of this cell suspension.
l) was added to the test solution, and the mixture was incubated at 37 ° C for 5 minutes, followed by a reaction stop solution [NaCl 1
20 mM, KCl 5 mM, EDTA 1 mM, Tri
s-HCl (pH = 7.4) 25 mM, BSA 200
[μg / ml] was added to stop the reaction. Thereafter, the histamine concentration in 250 μl of the supernatant obtained by centrifugation (250 × g, 4 ° C., 5 minutes) was measured using the method of Shore et al. The test substance was added at the same time as the addition of the antigen, and the inhibitory effect was shown by a 50% inhibitory dose (IC ₅₀ ) calculated by the least squares method from a linear regression line of the inhibitory rate of each concentration.

The IC ₅₀ values of the compounds of the Examples in the LTD ₄ antagonistic test and the histamine release inhibition test using guinea pig isolated ileum were as follows.

[0549]

Table 1 ───────────────────────────── Test substance Inhibition rate of ileal contraction Histamine release (Example number) (IC ₅₀ ) Inhibitory action (IC ₅₀ ) ───────────────────────────── 1 3.6 × 10 ^-8 6.5 × 10 ^-8 4 1.9 × 10 ^-8 1.2 × 10 ^-7 5 2.8 × 10 ^-8 1.5 × 10 ^-7 6 3.0 × 10 ^-8 1.2 × 10 ^-7 7 1.2 × 10 ^-8 9.9 × 10 ^-8 17 1.2 × 10 ^-8 7.5 × 10 ^-7 20 1.3 × 10 ^-7 2.2 × 10 ^-7 23 2.0 × 10 ^-7 5 × 10 ⁻⁷ 25 1.7 × 10 ⁻⁷ 1.2 × 10 ⁻⁷ 26 2.8 × 10 ⁻⁷ 1.1 × 10 ⁻⁸ 35 1.1 × 10 ⁻⁷ 1.0 × 10 ^{−7 39 1.3 × 10 -8 1.7 × 10} -7 40 6.6 × 10 -8 2.8 × 10 -7 41 7.9 × 10 -8 3.1 × 10 -7 42 2. ^{× 10 -8 2.0 × 10 -6 45} 4.1 × 10 -8 1.8 × 10 -6 68 7.3 × 10 -9 3.5 × 10 -8 69 7.8 × 10 -9 1 0.1 × 10 ^-7 70 1.5 × 10 ^-8 7.1 × 10 ^-7 76 1.1 × 10 ^-8 2.4 × 10 ^-7 78 2.6 × 10 ^-9 5.5 × 10 ^{− 7} 101 2.2 × 10 ^-8 5.4 × 10 ^-7 103 1.5 × 10 ^-8 1.2 × 10 ^-9 104 4.9 × 10 ^-8 1.5 × 10 ^-8 110 3.2 ^{× 10 -8 1.3 × 10 -7 125} 2.0 × 10 -9 2.7 × 10 -8 126 1.9 × 10 -9 2.6 × 10 ^over 7 127 1.8 × 10 ^-9 3 0.8 × 10 ⁻⁷ 129 7.0 × 10 ⁻⁹ 7.0 × 10 ⁻⁷ 131 8.5 × 10 ⁻⁸ 1.7 × 10 ⁻⁷ 141 141 9.4 × 10 ⁻¹⁰ 5.9 × 10 ^{− 9 142 1.9 × 10 -9 5.4 ×} 10 -7 152 2.5 × 10 -10 1.5 × 10 -8 153 5.4 × 10 -10 7.4 × 0 ^{over 9 155 1.0 × 10 -8 7.4 ×} 10 -9 157 5.7 × 10 -10 9.3 × 10 -9 161 2.3 × 10 -10 7.0 × 10 -9 162 7 .9 × 10 ^-10 1.8 × 10 ^{over 9 163 1.1 × 10 -9 8.2 ×} 10 -8 164 2.6 × 10 -9 1.0 × 10 -7 165 1.0 × 10 - ⁹ 9.4 × 10 ^-9 167 4.5 × 10 ^-9 1.0 × 10 ^-7 168 8.2 × 10 ^-10 3.1 × 10 ^-8 172 1.6 × 10 ^-9 4.7 × ^{10 -10 173 6.4 × 10 -10 4.1} × 10 -8 174 6.6 × 10 -10 4.0 × 10 -8 175 2.0 × 10 ^{over 10} 1.8 × ^{10 -8} 179 2 6.6 × 10 ^-9 8.1 × 10 ^-8 180 2.3 × 10 ^-10 2.5 × 10 ^-8 181 1.1 × 10 ^-10 5.9 × 10 ^-8 182 2.3 × 10 ^{− 9 2.6 × 10 -8 183 1.8 ×} 10 -9 5.5 × 10 -9 189 1.2 × 10 -8 1.7 × ^{0 -8 196 4.2 × 10 -8 7.8} × 10 -8 ─────────────────────────────

[0550] [Test Example 3] LTD using _4-induced bronchoconstriction inhibition test Hartley male guinea pigs were inserted tracheal cannula over and venous cannula over to urethane anesthesia (1.5g / 5ml / kg, i.p .). The artificial respirator was connected to the tracheal cannula, and the artificial respiration was performed at a ventilation volume of about 10 ml / kg and a ventilation frequency of 60 times / min. LTD ₄ administration 5
Minutes before propranolol (1 mg / kg), 3 minutes before succinylcholine (1 mg / kg, to stop spontaneous breathing) and 2 minutes before indomethacin (2 mg / kg)
Was administered intravenously. Ventilation volume is 10 cm H ₂ O
/ L / sec. After adjusting to be LTD ₄ (4
μg / kg) was administered intravenously to induce airway constriction.
The test substance was 0.5% carboxymethylcellulose (C
MC) and orally administered at the optimal administration time before induction. The airway contraction was expressed as a percentage of the maximum response obtained by completely obstructing the trachea, and the inhibition rate was determined from the maximum contraction rate of the test substance-administered group using the maximum contraction rate of LTD ₄ of the vehicle-administered group as a control. The results were shown as a 50% inhibitory dose (ID ₅₀ ) obtained by a least squares method from a temporary regression line of the inhibition rate. The ID ₅₀ values of the example compounds in the LTD ₄ -induced airway contraction inhibition test were as follows. The duration of airway contraction inhibition was determined by oral administration of the test substance (10 mg / k
g) Then, the inhibition rate after 8 hours or 12 hours was measured.

[0551]

[Table 2] ─────────────────────────────────── Test substance ID ₅₀ (mg / kg) Continuous activity [10mg / kg (po)] (Example number) 8h 12h ─────────────────────────────────── 1 1.1 75% 4 1.3 60% 5 2.6 6 2.4 76% 17 4.1 20 3.1 39 1.3 67% 42 2.7 45 1.9 78 5.1 125 125 0.875% 127 1.9 150 3.0 152 0.7 155 2.0 157 0.4 81% ──────────────────────── ───────────

[Test Example 4] PCA (Passive)
cutaneous anaphylaxis) reaction inhibition test Sprague-Dawley male rat (170-
After shaving 220 g) of the back, anti-egg albumin rat serum (rat 48-hour PCA titer: 514-fold) diluted 15-fold with physiological saline was added to back 2.
The mice were sensitized by intradermal injection (50 μl / site) in several places.
Forty-eight hours after the sensitization, 1 ml of 0.5% Evans blue physiological saline containing 5 / mg of egg albumin was intravenously administered to elicit a PCA reaction. Thirty minutes later, the animals were killed by decapitation, and the blue stain on the back was cut off, and the pigment in the blue stain on the skin was extracted and measured by the method of Katayama et al. 2). The test substance was suspended in 0.5% carboxymethylcellulose and orally administered at the optimal administration time immediately before the initiation. The results were obtained by calculating the inhibition rate from the amount of dye leakage in the solvent-administered group, and using the regression line of the inhibition rate to determine the 50% inhibition concentration (I
D ₅₀ ). ID ₅₀ value of the PCA tests were as follows.

[0553]

[Table 3] 率 Test substance suppression rate (Example number) (ID ₅₀ ) ────────── ───────────── 1 1.5 4 2.3 5 3.6 6 2.4 7 0.5 19 0.6 39 2.3 125 125 151 153 4.1 157 3.8 ───────────────────────

Test Example 5 Light Stability Test A test substance was dissolved in methanol so as to have a concentration of 10 μg / ml, and filtered with a membrane filter. This solution was dispensed in 3 ml portions into a 5 ml transparent glass sample tube to obtain a sample. One is shaded as a control,
The other is placed horizontally and irradiated with light (fluorescent lamp: 1000 lx
Time). Under light-shielded conditions, the peak area of the compound was obtained by a reversed-phase liquid chromatography method, and the residual ratio was determined according to the following equation. Residual rate (%) = peak area of light-irradiated sample / peak area of light-shielded sample × 100 Analytical conditions by liquid chromatography are as follows. The analytical column was Shiseido UG-120 (4.6 mmφ ×
250 mm), and a 0.01% aqueous solution of trifluoroacetic acid: methanol = 2: 1 (v / v) was used for the moving layer. For detection, use a UV detector.
As shown in FIG.

As a result of the photostability test, the double bond compound [(E) -4-((3- (2- (4-cyclobutyl-2
-Thiazolyl) ethenyl) phenyl) amino) -2,2
-Diethyl-4-oxobutyric acid (Ro24-591
3) (JP-A-2-69468) and (E) -2-
((3- (2- (4-cyclobutyl-2-thiazolyl)
Ethenyl) phenylamino) -2-oxoethyl) benzoic acid (Japanese Unexamined Patent Publication No. 6-80654)] had residual rates of 55.5% and 56.4%, respectively, whereas the triple bond compound [Example 1] , 141, 142 and 187] were all 100%, and no generation of decomposition products was observed. Solution stability test results (fluorescent lamp:
100 lx. 3 hours) is shown in Table 4.

[0556]

[Table 4] ───────────────────────────────── Residual rate of test substance (%) Detection wavelength ────化合物 Compound of Example 1 101.4 315 nm Compound of Example 141 100.4 253 nm Example 142 Compound 99.9 312 nm Compound 99.9 300 nm of Example 187 Compound ^A 55.5 240 nm described in JP-A-2-69468 Compound ^B 56.4 235 nm described in JP-A-6-80654 ────────────────────────────── A: (E) -4-((3- (2- (4-cyclobutyl- 2-Thiazolyl) ethenyl) phenyl) amino) -2,2-diethyl-4-oxobutyric acid (Ro24- 5913) B: (E) -2-((3- (2- (4-cyclobutyl-2-thiazolyl) ethenyl) phenylamino) -2-oxoethyl) benzoic acid

[Test Example 6] Safety test Example 1 was performed on Sprague-Dawley rats.
4, 6, 7, 39, and 157 compounds once daily
When 50 mg / kg was orally administered for 14 days, no death was observed in any of the compound administrations.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/53 ACD A61K 31/53 ACD C07D 277/24 C07D 277/24 277/26 277/26 277/28 277/28 277 / 34 277/34 277/36 277/36 277/38 277/38 277/56 277/56 417/10 213 417/10 213 255 255 255 257 257 261 261 261 263 263 263 271 271 311 311 417/14 213 417/14 213 239 239 257 257 471/04 117 471/04 117A (72) Inventor, Kojimi 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Inside Daiichi Pharmaceutical Co., Ltd. Tokyo Research and Development Center (72) Inventor, Hiroyuki Naito Tokyo 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd. Tokyo Research and Development Center (72) Inventor Masashi Hasegawa Edogawa-ku, Tokyo 1-16-13 Kita-Kasai Daiichi Pharmaceutical Co., Ltd. Tokyo Research and Development Center (72) Inventor Makoto Haruta 1-16-13 Kita-Kasai Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd. Tokyo Research and Development Center

Claims (14)

[Claims] 1. A compound of the general formula (1) [Wherein, R ¹ and R ² each independently represent a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or R ¹
And R ² represent a ring formed together; A represents a phenyl group which may have a substituent, a pyridyl group which may have a substituent, a furyl group which may have a substituent,
A thienyl group which may have a substituent, a benzofuranyl group which may have a substituent, a benzo [b] thienyl group which may have a substituent, a benzooxazolyl group which may have a substituent, A benzothiazolyl group which may have a pyrido [1,2-a] pyrimidinyl group which may have a substituent, a quinazolinyl group which may have a substituent, a benzotriazinyl group which may have a substituent, or a substituent 2H which may have a group
G ¹ represents an oxygen atom, a carbonyl group, an ethynyl group, a group —NR ³ CO—, a group —NR ⁴ —, a group —NR ⁵ SO ₂ —, a group —SO ₂ NR ⁶ —, a group —. CONR
⁷ -, group -C (= CHR ⁸⁾ -, or a group -CR ⁹ =
CR ^10- (wherein, R ³ , R ⁴ , R ⁵ , R ⁶ , and R
⁷ represents a hydrogen atom, a hydroxyl group, or an alkyl group which may have a substituent, R ⁸ represents a cyano group, a carboxyl group, or an alkoxycarbonyl group which may have a substituent, and R ⁹ and R ^{9 10} are each independently a hydrogen atom, a halogen atom, also alkyl group which may be substituted, also cycloalkyl group which may be substituted, also aryl group which may be substituted or R,
⁹ and R ¹⁰ mean a ring formed together. G ² represents a phenyl group which may have a substituent,
Pyridyl group which may have a substituent, thiazolyl group which may have a substituent, isoxazolyl group which may have a substituent, thienyl group which may have a substituent, pyrimidinyl group which may have a substituent, Group-C
HR ¹¹ —CHR ¹² — or the group —CR ¹³ ＣＲCR ¹⁴ — (C
R ¹⁵ = CR ¹⁶ ) y- (wherein, R ¹¹ and R ¹² mean a ring formed together, and R ¹³ , R ¹⁴ , R ¹⁵ , and R ¹⁶ each independently represent hydrogen. An atom, a halogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, a ring formed by R ¹³ and R ¹⁴ or R ¹⁵ and R ¹⁶ together, and y is M and n are each independently 0
Or an integer of 1; Q is a carboxyl group, an alkoxycarbonyl group which may have a substituent, -CON
An H- (5-tetrazolyl) group; a 5-tetrazolyl group which may have a substituent;
2,3-triazolyl group, 2,4-dioxothiazolidine-5-yridenyl group which may have a substituent, 4-oxo-2-thioxothiazolidine-5-yridenyl group which may have a substituent, substitution A 5-oxo-4-tetrazolyl group which may have a group, a 3- (5-oxo)-[1,2,4] oxadiazolidinyl group which may have a substituent, and a substituent 2- (3,
5- (3-oxo)-[1,2,4] oxadiazolinyl group, 5- (3-oxo)-which may have a substituent
[1,2,4] means a group represented by an oxadiazolidinyl group or a 3- (5-oxo) -isoxazolidyl group which may have a substituent. (Wherein m and n are 0 and Q is a carboxyl group or an alkoxycarbonyl group) and salts thereof. 2. The compound according to claim ¹ , wherein R ¹ in the formula (1) is a hydrogen atom, and salts thereof. 3. The compound according to claim 1, wherein R ² in the formula (1) is an alkyl group which may have a substituent or a cycloalkyl group which may have a substituent. And their salts. 4. The compound according to claim 1, wherein A in the formula (1) is a phenyl group which may have a substituent, and salts thereof. 5. A group represented by A in the formula (1) is a phenyl group, a 2-ethynylthiazolyl group and-(G ¹ ) _m-
The compound according to any one of claims 1 to 4, wherein the group represented by (G ² ) _n -Q is in a meta configuration, and a salt thereof. 6. The compound according to claim 1, wherein Q in the formula (1) is a 5-tetrazolyl group, and a salt thereof. 7. The compound according to claim 1, wherein m and n in the formula (1) are 0, and a salt thereof. 8. m and n in the formula (1) are 1, and G ¹
There -NR ³ a CO-, compounds and salts thereof according to any one of from G ² is claims 1 is a phenyl group which may have one or more substituents 6. 9. The compound according to claim 1, wherein G ² in the formula (1) is a phenyl group which may have one or more substituents, and G ¹ and Q are in a para configuration. And the salts thereof. 10. A pharmaceutical comprising the compound according to any one of claims 1 to 9 or a salt thereof. 11. A therapeutic and / or prophylactic agent for an allergic disease, comprising the compound according to any one of claims 1 to 9 or a salt thereof as an active ingredient. 12. A therapeutic and / or prophylactic agent for a disease associated with leukotriene, comprising the compound according to any one of claims 1 to 9 or a salt thereof as an active ingredient. 13. A therapeutic and / or prophylactic agent for a disease involving histamine, comprising the compound according to any one of claims 1 to 9 or a salt thereof as an active ingredient. 14. A therapeutic and / or prophylactic agent for a disease in which leukotriene and histamine are simultaneously involved, comprising the compound according to any one of claims 1 to 9 or a salt thereof as an active ingredient.