WO2016017699A1

WO2016017699A1 - Azole carboxylic acid derivative

Info

Publication number: WO2016017699A1
Application number: PCT/JP2015/071516
Authority: WO
Inventors: 旭河名; 親志金澤; 正行寺; 良昌高橋
Original assignee: 帝人ファーマ株式会社
Priority date: 2014-07-30
Filing date: 2015-07-29
Publication date: 2016-02-04
Also published as: AR101364A1; TW201619141A; JP2017165653A

Abstract

Provided are a compound indicated by formula (I), a pharmaceutically acceptable salt thereof, or a drug or pharmaceutical composition containing these as an effective component thereof, said compound having excellent xanthine oxidase inhibitory activity and effective as a treatment agent or prophylactic agent for diseases related to xanthine oxidase, such as gout, hyperuricemia, tumor lysis syndrome, urinary tract stones, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arterial sclerosis and heart failure, renal diseases such as diabetic nephropathy etc., respiratory diseases such as chronic obstructive pulmonary disease etc., and autoimmune diseases such as inflammatory bowel disease, etc.

Description

Azolecarboxylic acid derivatives

The present invention relates to a novel compound having xanthine oxidase inhibitory activity, a method for producing the same, and a xanthine oxidase inhibitor containing the compound as an active ingredient.
In particular, the present invention includes gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, renal diseases such as diabetic nephropathy, The present invention relates to an azolecarboxylic acid derivative useful as a therapeutic or prophylactic agent for diseases involving xanthine oxidase, such as respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease or autoimmune disease.

Xanthine oxidase is an enzyme that catalyzes the conversion of hypoxanthine to xanthine and further to uric acid in nucleic acid metabolism.
In contrast to the action of xanthine oxidase, xanthine oxidase inhibitors reduce uric acid synthesis by inhibiting uric acid synthesis. That is, it is effective for treating hyperuricemia and various diseases resulting therefrom. On the other hand, pathological conditions that occur as a result of persistent hyperuricemia and deposition of urate crystals include gout arthritis called gout and gout nodules. Hyperuricemia is regarded as an important factor in lifestyle-related diseases and metabolic syndrome related to obesity, hypertension, dyslipidemia, and diabetes. Recently, epidemiological studies have shown that nephropathy, urolithiasis, cardiovascular disease It is being clarified that it is a risk factor for cancer (Japan Gout / Nucleic Acid Metabolism Society Guidelines Revision Committee, edited by “Guideline for Treatment of Hyperuricemia / Gout, Second Edition”, Medical Review, 2010). In addition, xanthine oxidase inhibitors are expected to be useful for the treatment of diseases involving reactive oxygen species, for example, for the treatment of cardiovascular diseases through the effect of improving vascular function, due to the activity of inhibiting the generation of reactive oxygen species. (Circulation. 2006; 114: 2508-2516).

Clinically, allopurinol and febuxostat are used as therapeutic agents for hyperuricemia, but allopurinol has reported side effects such as Stevens-Johnson syndrome, toxic epidermal necrosis, liver damage, and renal dysfunction (Nippon Rinsho, 2003; 61, Suppul. 1: 197-201).

Examples of compounds having xanthine oxidase inhibitory activity include 2-phenylthiazole derivatives (Patent Documents 1 to 3), phenylpyrazole derivatives (Patent Documents 4 to 6), and triarylcarboxylic acid derivatives (Patent Documents 7 to 10). Has been. Further, carboxylic acid derivatives which are central bicyclic heterocycles such as 6-indolethiazole derivatives (Patent Documents 11 and 12) and 6-indolepyrazole derivatives (Patent Document 12) have been reported.

On the other hand, Patent Document 13 and Patent Document 14 report a dithiazolecarboxylic acid derivative having a benzene ring at the center. Patent Document 15 and Patent Document 16 report biphenylthiazolecarboxylic acid derivatives.

International Publication No. 92/09279 JP 2002-105067 A International Publication No. 96/31211 JP 59-95272 A International Publication No. 98/18765 JP-A-10-310578 International Publication No. 2007/043457 International Publication No. 2007/099743 International Publication No. 2008/126770 International Publication No. 2008/1267772 International Publication No. 2010/044404 International Publication No. 2010/093191 International Publication No. 2011/139886 International Publication No. 2011/101867 International Publication No. 2010/018458 International Publication No. 2010/128163

The problem to be solved by the present invention is to provide a novel compound having xanthine oxidase inhibitory activity. Furthermore, the subject of this invention is providing the compound which has the outstanding uric acid reduction effect | action. Another subject of the present invention is gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, diabetic nephropathy, etc. It is intended to provide a compound useful as a therapeutic or prophylactic agent for diseases involving xanthine oxidase, such as renal diseases, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases or autoimmune diseases.

As a result of intensive studies on compounds having xanthine oxidase inhibitory activity, the inventors have found that the following formula (I)

A compound having a xanthine oxidase inhibitory activity, a xanthine oxidase inhibitory activity with an excellent uric acid lowering action, and a particularly excellent sustained uric acid lowering action over a long period of time. The present invention was completed by finding that it has a typical xanthine oxidase inhibitory activity. Furthermore, this azole carboxylic acid derivative is used for gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, diabetic nephropathy, etc. The present invention has been completed by finding that it can be a good therapeutic or preventive drug for respiratory diseases such as kidney disease, chronic obstructive pulmonary disease, inflammatory bowel disease or autoimmune disease.
That is, the present invention provides [1] a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:

[Where:
R ⁰ represents the following R ⁰¹ or R ⁰² .

R ¹ represents one or a plurality of alkyl groups having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group optionally substituted with a halogen atom, OR, or NRR ′ which may form a ring. Or SR, wherein R and R ′ are each independently a hydrogen atom, one or more alkoxy groups having 1 to 8 carbon atoms, a halogen atom or a hydroxyl group optionally substituted with a hydroxyl group. 1 or a plurality of alkyl groups having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group optionally substituted with a halogen atom or a cyano group, or one or more carbon atoms having 1 to 6 carbon atoms 6 represents an alkyl group having 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a heteroaryl group optionally substituted with a halogen atom.
R ² represents a hydrogen atom, an amino group, or an alkyl group having 1 to 8 carbon atoms which may be substituted with one or more halogen atoms.
X ¹ represents CR ³ or a nitrogen atom, wherein R ³ represents a hydrogen atom or a halogen atom.
Ring A is an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more alkoxy groups having 1 to 3 carbon atoms or a halogen atom, and the number of carbons which may be substituted with one or more halogen atoms. It represents a 5- or 6-membered monocyclic heteroarene which may be substituted with 1 to 6 alkoxy groups and 1 to 4 groups selected from the group consisting of halogen atoms. ];
[2] The heteroarene in ring A is

Or a pharmaceutically acceptable salt thereof according to [1];
[3] The compound or a pharmaceutically acceptable salt thereof according to [1] or [2], wherein X ¹ is CR ³ and R ³ is a hydrogen atom or a fluorine atom;
[4] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein X ¹ is a nitrogen atom;
[5] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein R ⁰ is R ⁰¹ ;
[6] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [5], wherein R ² is a methyl group;
[7] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [5], wherein R ² is a hydrogen atom;
[8] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein R ⁰ is R ⁰² ;
[9] The compound according to [8] or a pharmaceutically acceptable salt thereof, wherein R ² is a hydrogen atom or an amino group;
[10] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [9], wherein R ¹ is OR;
[11] The compound according to [10] or a pharmaceutically acceptable salt thereof, wherein R is one or more alkoxy groups having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms which may be substituted with a halogen atom. Acceptable salts;
[12] The compound according to [10], wherein R is an aryl group optionally substituted by one or more alkyl groups having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom or a cyano group. Or a pharmaceutically acceptable salt thereof;
[13] R ¹ is 1 or more carbon atoms 1-3 alkyl group, an aryl group which may be substituted with an alkoxy group or halogen atom having 1-3 carbon atoms, of [1] to [9] Any of the compounds or pharmaceutically acceptable salts thereof;
[14] Any compound selected from compound numbers (1) to (175) or a pharmaceutically acceptable salt thereof. . [15] A pharmaceutical composition comprising the compound according to any one of [1] to [14] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier;
[16] A xanthine oxidase inhibitor comprising the compound according to any one of [1] to [14] or a pharmaceutically acceptable salt thereof as an active ingredient;
[17] Gout, hyperuricemia, tumor lysis syndrome, urinary calculus, hypertension comprising the compound according to any one of [1] to [14] or a pharmaceutically acceptable salt thereof as an active ingredient Dyslipidemia, diabetes, cardiovascular disease, kidney disease, respiratory disease, inflammatory bowel disease or autoimmune disease therapeutic or prophylactic agent; and [18] A compound represented by formula (II).

[Where:
R ⁴ represents the following R ⁴¹ or R ⁴² .

R ⁵ represents a protecting group for a carboxyl group.
The definitions of R ¹ , R ² , X ¹ and ring A are the same as in formula (I). ]
It is.

The present invention provides a novel compound having high xanthine oxidase inhibitory activity and a method for producing the same. Furthermore, the compounds of the present invention are particularly useful for gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, kidneys such as diabetic nephropathy, etc. It is useful as a therapeutic or prophylactic agent for diseases involving xanthine oxidase such as diseases, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel diseases or autoimmune diseases.

The terms used alone or in combination in this specification are explained below. Unless otherwise specified, the description of each substituent is common to each site. When any variable is present in any constituent element, its definition is independent in each constituent element. Also, combinations of substituents and variables are permissible as long as such combinations result in chemically stable compounds. The wavy line across the bond in the substituent represents the point of attachment.

“Xanthine oxidase” is generally used in the broad sense of an enzyme that catalyzes an oxidation reaction from hypoxanthine to xanthine and further to uric acid, and in the narrow sense of an oxidase-type xanthine oxidoreductase that is one of the enzymes that catalyze the reaction. In the present invention, “xanthine oxidase” is a general term for enzymes that catalyze an oxidation reaction from hypoxanthine to xanthine and further to uric acid, unless otherwise specified. There are two types of xanthine oxidoreductase responsible for this reaction, an oxidase type and a dehydrogenase type, both of which are included in the xanthine oxidase of the present invention. In “xanthine oxidase inhibitory activity”, “xanthine oxidase inhibitor” and the like, “xanthine oxidase” has the same meaning as defined above unless otherwise specified.

In the present invention, “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the present invention, the “alkyl group” means a monovalent saturated linear, cyclic or branched aliphatic hydrocarbon group. Examples of the “alkyl group having 1 to 8 carbon atoms” include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, isopropyl group, isobutyl group, and s-butyl. Group, t-butyl group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3, 3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group 2-ethylbutyl group, t-pentyl group, isohexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, B propyl methyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, and cycloheptylmethyl group and the like. Examples of the “alkyl group having 1 to 6 carbon atoms” include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, isopropyl group, isobutyl group, s-butyl group, t-butyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3- Dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group, 2 -Ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentyl Chill group, and the like. Examples of the “C 1-3 alkyl group” include methyl group, ethyl group, n-propyl group, isopropyl group and the like.

In the present invention, the “alkylene group” means a divalent group derived by further removing one hydrogen atom at an arbitrary position from the “alkyl group”. Examples of the “C 1-6 alkylene group” include methylene group, ethylene group, n-propylene group, isopropylene group, n-butylene group, isobutylene group, n-pentylene group, n-hexylene group, cyclopropylene group , Cyclobutylene group, cyclohexylene group and the like.

In the present invention, the “alkoxy group” means a monovalent saturated linear, cyclic or branched aliphatic hydrocarbon oxy group. Examples of the “alkoxy group having 1 to 8 carbon atoms” include methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-pentyloxy group, n-hexaoxy group, isopropoxy group, isobutoxy group, s- Butoxy group, t-butoxy group, isopentyloxy group, 2-methylbutoxy group, neopentyloxy group, cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, cyclopropylmethoxy group, A cyclobutyl methoxy group, a cyclopentyl methoxy group, a cyclohexyl methoxy group, etc. are mentioned. Examples of the “C 1-3 alkoxy group” include methoxy group, ethoxy group, n-propoxy group, isopropoxy group and the like.

In the present invention, the “aryl group” means a monocyclic or bicyclic monovalent aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples of the aryl group include a phenyl group, a naphthyl group, an indenyl group, a tetrahydronaphthyl group, an indanyl group, and an azulenyl group.

In the present invention, “heteroarene” means a monocyclic or bicyclic aromatic heterocycle having 1 to 5 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom. Pyridine, pyrazine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyran, imidazole, oxazole, thiazole, oxadiazole, thiadiazole, pyrazole, triazine, triazole, tetrazole, benzofuran, benzothiophene, benzothiazole, benzimidazole , Benzoxazole, benzisoxazole, and the like. The “5- or 6-membered monocyclic heteroarene” means a 5- or 6-membered monocyclic one of the above “heteroarenes”.

In the present invention, the “heteroaryl group” refers to a monocyclic or monovalent bicyclic aromatic heterocyclic group having 1 to 5 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom. means. Heteroaryl groups include pyridyl, pyrazyl, pyrimidyl, furyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoimidazolyl, benzoxazolyl, pyranyl Group, imidazolyl group, oxazolyl group, thiazolyl group, triazinyl group, triazolyl group, benzoxazolyl group, benzoisoxazolyl group and the like.

In the present invention, the “optionally substituted alkyl group having 1 to 8 carbon atoms” represents an alkyl group having 1 to 8 carbon atoms which may have one or more substituents at substitutable positions. . When a plurality of substituents are present, each substituent may be the same or different. The “optionally substituted alkyl group having 1 to 6 carbon atoms”, the “optionally substituted alkyl group having 1 to 3 carbon atoms” and the like have the same meaning.

In the present invention, “optionally substituted alkoxy group having 1 to 8 carbon atoms” represents an alkoxy group having 1 to 8 carbon atoms which may have one or more substituents at substitutable positions. . When a plurality of substituents are present, each substituent may be the same or different. The “optionally substituted alkoxy group having 1 to 6 carbon atoms”, the “optionally substituted alkoxy group having 1 to 3 carbon atoms” and the like have the same meaning.

In the present invention, when the alkyl group is substituted with an alkoxy group, the alkyl group and alkoxy may be combined to form an oxygen-containing saturated ring. Such rings include oxirane, oxetane, tetrahydrofuran, tetrahydropyran and the like.

In the present invention, the “optionally substituted aryl group” means an aryl group which may have one or more substituents at substitutable positions. When a plurality of substituents are present, each substituent may be the same or different.

In the present invention, the “optionally substituted heteroarene” and the “optionally substituted heteroaryl group” refer to a heteroarene, heteroaryl optionally having one or more substituents at substitutable positions. Each represents an aryl group. When a plurality of substituents are present, each substituent may be the same or different.

In the present invention, “carboxyl-protecting group” means, for example, PROTECTIVE GROUPS in ORGANIC SYNTHESIS, THIRD EDITION, John Wiley & Sons, Inc. General carboxyl group protecting groups described in, for example, methyl group, ethyl group, isopropyl group, heptyl group, t-butyl group, methoxymethyl group, methylthiomethyl group, methoxyethoxymethyl group, methoxyethyl group, Examples thereof include a benzyl group and a t-butyldimethylsilyl group.

In the present invention, “protective group for phenolic hydroxyl group” means, for example, PROTECTED GROUPS in ORGANIC SYNTHESIS, THIRD EDITION, John Wiley & Sons, Inc. A protecting group for a general phenolic hydroxyl group described in, for example, methyl group, isopropyl group, allyl group, t-butyl group, methoxymethyl group, methylthiomethyl group, methoxyethoxymethyl group, 1-ethoxyethyl group, Examples include benzyl group, 4-methoxybenzyl group, acetyl group, trimethylsilyl group, t-butyldimethylsilyl group and the like.

R ⁰ represents the following R ⁰¹ or R ⁰² .

In the formula (I), R ¹ forms one or more alkyl groups having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an aryl group optionally substituted with a halogen atom, OR, and a ring. NRR ′ that may be present, or SR. Here, R and R ′ are independently a hydrogen atom, one or a plurality of alkoxy groups having 1 to 8 carbon atoms, a halogen atom or an alkyl group having 1 to 8 carbon atoms which may be substituted with a hydroxyl group, 1 or A plurality of alkyl groups having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group optionally substituted with a halogen atom or a cyano group, or one or more alkyl groups having 1 to 6 carbon atoms, carbon It represents a heteroaryl group which may be substituted with an alkoxy group of 1 to 6 or a halogen atom. In “NRR ′ which may form a ring”, “NRR ′ forms a ring” means that R and R ′ together with the nitrogen atom to which they are bonded form a nitrogen-containing saturated ring. That means. R ¹ is preferably OR. When R ¹ is OR or SR, R preferably represents one or more alkoxy groups having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms which may be substituted with a halogen atom or a hydroxyl group, or 1 Alternatively, the aryl group may be substituted with a plurality of alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, halogen atoms, or cyano groups. More preferably, it is an alkyl group having 1 to 8 carbon atoms which may be substituted with one or more alkoxy groups having 1 to 8 carbon atoms or a halogen atom. Particularly preferred are isopropyl group, isobutyl group and neopentyl group.

When R ¹ is one or a plurality of alkyl groups having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group optionally substituted with a halogen atom or a cyano group, preferably one or more carbon atoms An alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, or an aryl group optionally substituted with a halogen atom, more preferably a phenyl group optionally substituted with a fluorine atom.

In the formula (I), R ² represents a hydrogen atom, an amino group, or an alkyl group having 1 to 8 carbon atoms which may be substituted with one or more halogen atoms. Preferably, they are a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and specific examples include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. More preferably, they are a hydrogen atom and a methyl group. Particularly preferred is a methyl group.

In the case where R ⁰ is R ⁰¹ or R ⁰² , preferred R ¹ and R ² are as described above. Further, when R ⁰ is R ⁰² , preferred R ^{2 can also} include an amino group and an alkyl group having 1 to 3 carbon atoms which may be substituted with one or more halogen atoms. When R ⁰ is R ⁰² , more preferable R ² is a hydrogen atom and an amino group.

In the formula (I), X ¹ represents CR ³ or a nitrogen atom, R ³ represents a hydrogen atom or a halogen atom, and can be represented by the following structural formula, for example.

In formula (I), ring A is bonded to a benzene or pyridine ring containing X ¹ by a carbon atom on ring A. Ring A is an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more alkoxy groups having 1 to 3 carbon atoms or a halogen atom, and the number of carbons which may be substituted with one or more halogen atoms. It represents a 5- or 6-membered monocyclic heteroarene which may be substituted with 1 to 6 alkoxy groups and 1 to 4 groups selected from the group consisting of halogen atoms. Examples of the 5- or 6-membered monocyclic heteroarene in ring A include the following structures.

Ring A is preferably 5 or 6 optionally substituted with 1 or 2 alkyl groups having 1 to 3 carbon atoms which may be substituted with 1 or 2 alkoxy groups having 1 to 3 carbon atoms. Represents a membered monocyclic heteroarene. More preferably, it represents a 5- or 6-membered monocyclic heteroarene which may be substituted with 1 or 2 methyl groups. Specific examples of preferable ring A are as follows, for example.

The compound of the present invention is a compound that exhibits excellent xanthine oxidase inhibitory activity. Further, the compound of the present invention has an excellent uric acid lowering action.
Specific examples of preferred compounds include the following compounds.

Among these, more preferable compounds are compounds 2, 3, 6, 9, 10, 12, 14, 15, 16, 18, 19, 20, 22, 23, 24, 25, 26, 27, 32, 33, 34. , 35, 36, 37, 38, 39, 41, 42, 43, 45, 46, 47, 48, 49, 51, 52, 53, 54, 55, 56, 58, 59, 62, 63, 65, 66 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 89, 90, 91, 92 93, 94, 95, 96, 97, 99, 103, 105, 106, 108, 109, 110, 111, 112, 113, 114, 122, 123, 124, 125, 126, 127, 128, 129, 130 139, 140, 14 147, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 165, 167, 168, 169, 170, 172, 173, 174 and 175 It is.

In the compound represented by the above formula (II) that can be used as an intermediate for producing the compound represented by the above formula (I) of the present invention, R ¹ , R ² , ring A, and X ¹ are the above Is the same as defined in formula (I). R ⁵ represents a protecting group for a carboxyl group. The definition of the protective group of a carboxyl group is as above-mentioned, Preferably they are a methyl group, an ethyl group, and a benzyl group.

<General synthesis method>
Formula (I) of the present invention can be synthesized, for example, according to any of the synthetic methods described below. In each formula, R ¹ , R ² , X ¹ and ring A are as defined in formula (I). In each formula, R ⁵ is as defined in formula (II). Moreover, the reagent or solvent as a condition described in the chemical formula is merely an example as described in the text. Each substituent may be protected with an appropriate protecting group as necessary, and may be deprotected at an appropriate stage. In addition, as a suitable protecting group and its removal method, the protecting group of each substituent generally used in this field and a publicly known method can be adopted. . It is described in.

Synthesis method (A)
Synthesis of compound (A-2)

(In the formula, Z ¹ represents a leaving group.)
Examples of the leaving group represented by Z ¹ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (A-2) by reacting a phenolic hydroxyl group in compound (A-1) with an alkylating reagent having a leaving group in the presence of a base. Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc. Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used. This reaction is carried out by reacting compound (A-1) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., and then an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited. For example, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N— Examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.

Synthesis of compound (A-3)

In this reaction, the bromo group in the compound (A-2) is lithiated with a strong base, then reacted with a boric acid ester, and then the boronic acid ester is hydrolyzed with an acid to a boronic acid, whereby the compound (A -3). In this reaction, compound (A-2) and boric acid ester are used in an equal amount or one in excess, and an equal amount or a small excess of strong base is added at −78 to 0 ° C. in a solvent inert to the reaction, Usually, the reaction is carried out by adding an acid such as hydrochloric acid after reacting for 0.5 to 12 hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. As the strong base to be used, n-butyllithium, t-butyllithium, s-butyllithium or the like is used. Examples of boric acid esters include trimethoxyboric acid, triethoxyboric acid, and triisopropoxyboric acid. Here, the solvent is not particularly limited, but ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, or a mixture thereof A solvent etc. are mentioned.

Synthesis of compound (A-4)

(In the formula, Z ² represents a leaving group.)
Examples of the leaving group represented by Z ² include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (A-4) by coupling reaction of boronic acid compound (A-3) and a heterocyclic compound having a leaving group. In this reaction, the compound (A-3) and the heterocyclic compound are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, from room temperature to heating under reflux, usually 0. It is carried out by reacting for 5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases And a solution obtained by diluting with water or the like. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.

Synthesis of compound (A-5)

This reaction is a conversion reaction from a cyano group to a thioamide group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (A-4) with a sulfur source under acidic conditions. In this reaction, compound (A-4) and sulfur source are used in the same amount or in excess, and in an inert solvent for reaction, in the presence of an acid, at room temperature to heating under reflux, usually 0.5 hours to 2 This is done by reacting for a day. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Hydrogen sulfide, thioacetamide or thioacetic acid is used as the sulfur source. As the acidic substance, organic acids such as hydrochloric acid, sulfuric acid and acetic acid, or aqueous solutions of these acids are used. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof. An acid such as acetic acid can also be used as a solvent.

Synthesis of compound (A-7)

(In the formula, Z ³ represents a leaving group.)
Examples of the leaving group represented by Z ³ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, compounds (A-5) and (A-6) are used in an equal amount or in excess, and in an inert solvent for the reaction, usually at room temperature to heating under reflux, usually 0.5 hours to 2 days. This is done by reacting. Further, an equal amount or an excess amount of a base can be added. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof. Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).

Synthesis of compound (A-8)

This reaction is a method for synthesizing the compound (A-8) of the present invention by deprotecting the protecting group R ⁵ of the compound (A-7) with an acid or a base. In this reaction, compound (A-7) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

Hereinafter, the synthesis method in the case where R ¹ of the compound of the formula (I) is OR, NRR ′ which may form a ring, or SR will be shown.

Synthesis of compound (A-10)

In this reaction, the bromo group in compound (A-9) is lithiated with a strong base and then reacted with boric acid ester, followed by hydrolysis of boronic acid ester to boronic acid with acid. -10). In this reaction, an equal amount of compound (A-9) and boric acid ester or an excess of one are used, and an equal amount or a small excess of strong base is added at −78 ° C. to 0 ° C. in a solvent inert to the reaction. The reaction is usually carried out by adding an acid such as hydrochloric acid after reacting for 0.5 to 12 hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. As the strong base to be used, n-butyllithium, t-butyllithium, s-butyllithium or the like is used. Examples of boric acid esters include trimethoxyboric acid, triethoxyboric acid, and triisopropoxyboric acid. Here, the solvent is not particularly limited, but ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, or a mixture thereof A solvent etc. are mentioned.

Synthesis of Compound (A-11)

(In the formula, Z ² represents a leaving group.)
Examples of the leaving group represented by Z ² include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method for synthesizing compound (A-11) by coupling reaction of boronic acid compound (A-10) with a heterocyclic compound having a leaving group. In this reaction, the compound (A-10) and the heterocyclic compound are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, from room temperature to heating under reflux, usually 0. It is carried out by reacting for 5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Bases include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, metal alkoxides such as sodium BR> G toxide, sodium methoxide, or Examples include solutions obtained by diluting these bases with water or the like. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.

Synthesis of compound (A-12)

This reaction is a method for synthesizing compound (A-12) by lithiating, sodiumating or potassiumating alcohols, amines or thiols with a base and then reacting with compound (A-11). . Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc. Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used. This reaction is carried out at −20 ° C. to 120 ° C. in an solvent inert to the reaction, after reacting compound (A-11) with an equal amount or a small excess of base, and then an equal amount or an excess amount of alcohols. , Amines or thiols are added, and the reaction is usually carried out for 0.5 to 12 hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.

Synthesis of compound (A-13)

This reaction is a conversion reaction from a cyano group to a thioamide group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (A-12) with a sulfur source under acidic conditions. In this reaction, the compound (A-12) and sulfur source are used in an equal amount or one of them in excess, and in an inert solvent for the reaction, in the presence of an acid, from room temperature to heating under reflux, usually from 0.5 hour to 2 This is done by reacting for a day. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Hydrogen sulfide, thioacetamide or thioacetic acid is used as the sulfur source. As the acidic substance, organic acids such as hydrochloric acid, sulfuric acid and acetic acid, or aqueous solutions of these acids are used. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof. An acid such as acetic acid can also be used as a solvent.

Synthesis of compound (A-14)

(In the formula, Z ³ represents a leaving group.)
Examples of the leaving group represented by Z ³ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, compounds (A-13) and (A-6) are used in an equal amount or in excess, and in an inert solvent for the reaction, at room temperature to heating under reflux, usually 0.5 hours to 2 days This is done by reacting. Further, an equal amount or an excess amount of a base can be added. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof. Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).

Synthesis of compound (A-15)

This reaction is a method for synthesizing the compound (A-15) of the present invention by deprotecting the protecting group R ⁵ of the compound (A-14) with an acid or a base. In this reaction, compound (A-14) is usually reacted for 0.5 hours to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

The compound of formula (A-8) can also be synthesized according to a synthesis method as described below.

(Synthesis method B)
Synthesis of compound (B-1)

This reaction is a conversion reaction from a cyano group to a thioamide group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (A-2) with a sulfur source under acidic conditions. In this reaction, compound (A-2) and sulfur source are used in an equal amount or in excess, and in an inert solvent for reaction, in the presence of an acid, at room temperature to heating under reflux, usually 0.5 hours to 2 This is done by reacting for a day. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Hydrogen sulfide, thioacetamide or thioacetic acid is used as the sulfur source. As the acidic substance, organic acids such as hydrochloric acid, sulfuric acid and acetic acid, or aqueous solutions of these acids are used. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof. An acid such as acetic acid can also be used as a solvent.

Synthesis of compound (B-2)

(In the formula, Z ³ represents a leaving group.)
Examples of the leaving group represented by Z ³ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, compounds (B-1) and (A-6) are used in equal amounts or in excess, and the reaction is inert to the reaction at room temperature to heating under reflux, usually for 0.5 hour to 2 days. This is done by reacting. Further, an equal amount or an excess amount of a base can be added. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof. Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).

Synthesis of compound (B-3)

In this reaction, the bromo group in the compound (B-2) is lithiated with a strong base, then reacted with a boric acid ester, and then the boronic acid ester is hydrolyzed with an acid to a boronic acid, whereby the compound (B -3). In this reaction, the compound (B-2) and boric acid ester are used in an equal amount or in an excess amount, and an equal amount or a small excess of a strong base is added at −78 to 0 ° C. in a solvent inert to the reaction, Usually, the reaction is carried out by adding an acid such as hydrochloric acid after reacting for 0.5 to 12 hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. As the strong base to be used, n-butyllithium, t-butyllithium, s-butyllithium or the like is used. Examples of boric acid esters include trimethoxyboric acid, triethoxyboric acid, and triisopropoxyboric acid. Here, the solvent is not particularly limited, but ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, or a mixture thereof A solvent etc. are mentioned.

Synthesis of compound (A-8)

(In the formula, Z ² represents a leaving group.)
Examples of the leaving group represented by Z ² include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (A-10) by coupling reaction of boronic acid compound (B-3) and a heterocyclic compound having a leaving group. In this reaction, the compound (B-3) and the heterocyclic compound are used in an equal amount or one of them in excess, and in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, from room temperature to heating under reflux, usually 0. It is carried out by reacting for 5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases And a solution obtained by diluting with water or the like. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.

(Synthesis Method C)
Synthesis of compound (C-2)

This reaction is a conversion reaction from a cyano group to a thioamide group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (C-1) with a sulfur source under acidic conditions. In this reaction, an equal amount of compound (C-1) and a sulfur source, or one of them in excess, is used in an inert solvent for the reaction, in the presence of an acid, at room temperature to heating under reflux, usually for 0.5 hour to 2 hours. This is done by reacting for a day. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Hydrogen sulfide, thioacetamide or thioacetic acid is used as the sulfur source. As the acidic substance, organic acids such as hydrochloric acid, sulfuric acid and acetic acid, or aqueous solutions of these acids are used. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof. An acid such as acetic acid can also be used as a solvent.

Synthesis of compound (C-3)

(In the formula, Z ³ represents a leaving group.)
Examples of the leaving group represented by Z ³ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, compounds (C-2) and (A-6) are used in an equal amount or in excess, and the reaction is inert to the reaction at room temperature to heating under reflux, usually for 0.5 hour to 2 days. This is done by reacting. Further, an equal amount or an excess amount of a base can be added. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof. Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).

Synthesis of compound (C-4)

This reaction is a method in which the compound (C-3) is reacted with hexamethylenetetramine (HMT) in the presence of an acid catalyst to formylate. In this reaction, the compound (C-3) and hexamethylenetetramine (HMT) are used in an equal amount or in excess, and usually in an inert solvent in the reaction in the presence of an acid catalyst at room temperature to heating under reflux, usually 0 By reacting for 5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Examples of the acid catalyst include formic acid, acetic acid, trifluoroacetic acid, polyphosphoric acid, and the like. An acid catalyst can also be used as a solvent.

Synthesis of compound (C-5)

(In the formula, Z ¹ represents a leaving group.)
Examples of the leaving group represented by Z ¹ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (C-5) by reacting a phenolic hydroxyl group in compound (C-4) with an alkylating reagent having a leaving group in the presence of a base. Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc. Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used. This reaction is carried out by reacting compound (C-4) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., followed by an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited. For example, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N— Examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.

Synthesis of compound (C-7)

This reaction is a method in which a compound (C-5) is reacted with p-toluenesulfonylacetonitrile (C-6) to synthesize a 1,3-oxazole ring. In this reaction, compound (C-5) and p-toluenesulfonylacetonitrile (C-6) are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base, at room temperature to under reflux. The reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Examples of the base used include carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5. 4.0] -7-undecene (DBU) and other organic amines are used. Solvents used in these reactions include toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2 -Dimethoxyethane, 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.

The compound of formula (C-7) can also be synthesized according to the synthesis method as described below.

Synthesis of compound (C-9)

(In the formula, R ⁶ represents a protecting group for a phenolic hydroxyl group.)

This reaction is a method of synthesizing compound (C-9) by deprotecting protecting group R ⁶ of compound (C-8) with an acid or a base. In this reaction, compound (C-8) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

Synthesis of compound (C-7)

This reaction is a method of synthesizing compound (C-7) by reacting compound (C-9) with alcohols by Mitsunobu reaction or the like. This reaction is a method of synthesizing compound (C-7) by reacting alcohols with triphenylphosphine and carbodiimide and then reacting with compound (C-9). Examples of the carbodiimide used include diethyl carbodiimide and diisopropyl carbodiimide. In this reaction, an equivalent amount or an excess amount of alcohol, triphenylphosphine and carbodiimide is usually added to 0.5 to 12 in a solvent inert to the reaction at −20 ° C. to 120 ° C. This is done by reacting for hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.

Synthesis of compound (C-10)

This reaction is a method for synthesizing the compound (C-10) of the present invention by deprotecting the protecting group R ⁵ of the compound (C-7) with an acid or a base. In this reaction, compound (C-7) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal or excess amount of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

(Synthesis Method D)
Synthesis of compound (D-1)

This reaction is a conversion reaction from a formyl group to a cyano group, and is performed by reacting an aromatic aldehyde derivative represented by the above formula (C-5) with hydroxylamine. As hydroxylamine, other salts such as hydrochloride thereof may be used. In that case, it is preferable to add an appropriate basic substance. In addition, the reaction can be accelerated by adding 1.0 to 3.0 equivalents of acetic anhydride, acetyl chloride, trichloroacetyl chloride and the like. The amount of hydroxylamine or a salt thereof used in these reactions is usually 1 equivalent or more, preferably 1.0 to 2.0 equivalents. When a basic substance is used, 1.0 to 3.0 equivalents are used with respect to the hydroxylamine salt. As basic substances to be used, carboxylates such as sodium formate, potassium formate and sodium acetate, carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, organic amine salts such as triethylamine, pyridine and 4-aminopyridine are used. It is done. The reaction is carried out in an inert solvent in the presence of a base at room temperature to heating under reflux, usually for 0.5 hour to 3 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Solvents used in these reactions include acetic acid, formic acid, toluene, benzene, pyridine, ethyl acetate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane. 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), methanol, ethanol, 2-propanol and the like.

Synthesis of compound (D-2)

This reaction is a reaction in which a tetrazole ring is cyclized from a cyano group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (D-1) with an azide compound in the presence of an acid. In this reaction, compound (D-1) and an azide compound are used in an equal amount or in excess, and in an inert solvent for the reaction, in the presence of an acid, from room temperature to heating under reflux, usually from 0.5 hour to This is done by reacting for 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Examples of the azide compound include sodium azide and trimethylsilyl azide. Examples of the acid to be used include organic acids such as formic acid and acetic acid, inorganic acids such as hydrochloric acid and sulfuric acid, and inorganic salts such as ammonium chloride and ammonium acetate. Solvents used in these reactions include toluene, benzene, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1 , 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.

Synthesis of compound (D-3)

This reaction is a method for synthesizing the compound (D-3) of the present invention by deprotecting the protecting group R ⁵ of the compound (D-2) with an acid or a base. In this reaction, compound (D-2) is usually reacted for 0.5 hours to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

Synthesis of compounds (D-4) and (D-5)

(In the formula, Z ⁴ represents a leaving group, and R ⁷ follows the definition of the substituent on ring A.)

Examples of the leaving group represented by Z ⁴ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is performed by reacting nitrogen at the 1-position and 2-position on the tetrazole ring in compound (D-2) with an alkylating reagent having a leaving group in the presence of a base. This is a method for synthesizing D-5). This reaction is carried out at 0 ° C. to 140 ° C. in the presence of a base in the presence of a base using an equal amount of compound (D-2) and an alkylating reagent in a solvent inert to the reaction, or in a small excess. This is done by reacting for 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc. Organic amine salts such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Is used. Here, the solvent is not particularly limited. For example, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N— Examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.

Synthesis of compounds (D-6) and (D-7)

(Wherein R ⁷ follows the definition of substituents on ring A.)

In this reaction, the protecting groups R ⁵ of the compounds (D-4) and (D-5) are deprotected with an acid or a base to synthesize the compounds (D-6) and (D-7) of the present invention. Is the method. In this reaction, compounds (D-4) and (D-5) are used in an equivalent amount or in excess of an acid or a base in a solvent inert to the reaction, and the reaction is usually carried out at room temperature to heating under reflux for 0.5 hours. Performed by reacting for ~ 5 days. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

(Synthesis method E)
Synthesis of compound (E-1)

This reaction is a method of synthesizing compound (E-1) by reacting compound (D-1) with hydroxylamine. In this reaction, compound (D-1) and hydroxylamine are used in an equal amount or in excess, and in the presence of a base, in a solvent inert to the reaction, at room temperature to heating under reflux, usually 0.5 hours to 2 days This is done by reacting. Here, organic bases such as triethylamine, pyridine, 4-aminopyridine are used as the base. Moreover, the base used can also be used as a solvent.

Synthesis of compound (E-3)

(Wherein R ⁷ follows the definition of substituents on ring A.)

This reaction is a method of synthesizing compound (E-3) by reacting compound (E-1) with acid chloride (E-2). In this reaction, the compound (E-1) and acid chloride (E-2) are used in an equal amount or in excess, and in the presence of a base, in a solvent inert to the reaction, usually at room temperature to heating under reflux, usually 0. The reaction is performed for 5 hours to 2 days. Here, organic bases such as triethylamine, pyridine, 4-aminopyridine are used as the base. Moreover, the base used can also be used as a solvent.

Synthesis of compound (E-4)

(Wherein R ⁷ follows the definition of substituents on ring A.)

This reaction is a method for synthesizing the compound (E-4) of the present invention by deprotecting the protecting group R ⁵ of the compound (E-3) with an acid or a base. In this reaction, compound (E-3) is usually reacted for 0.5 hours to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

Synthesis of compound (E-6)

(Wherein R ⁸ represents an alkyl group having 1 to 3 carbon atoms)

This reaction is a method of synthesizing the oxadiazole ring compound (E-6) by reacting the compound (E-1) with the orthoformate ester (E-5). In this reaction, an equal amount of compound (E-1) and orthoformate ester (E-5), or an excess of either, are used in an inert solvent for the reaction in the presence of an acid at room temperature to heating under reflux. Usually, the reaction is performed for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Examples of the orthoformate ester (E-5) include trimethyl orthoformate and triethyl orthoformate. Examples of the acid used include organic acids such as formic acid, acetic acid, hydrochloric acid, sulfuric acid and trifluoroacetic acid. Solvents used in these reactions include toluene, benzene, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1 , 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof. An acid such as trifluoroacetic acid may be used as a solvent. .

Synthesis of compound (E-7)

This reaction is a method for synthesizing the compound (E-7) of the present invention by deprotecting the protecting group R ⁵ of the compound (E-6) with an acid or a base. In this reaction, compound (E-6) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

(Synthesis Method F)
Synthesis of compound (F-1)

This reaction is a method of synthesizing compound (F-1) by reacting compound (C-5) with hydroxylamine. In this reaction, compound (C-5) and hydroxylamine are used in an equal amount or in excess, and in the presence of a base, in a solvent inert to the reaction, at room temperature to heating under reflux, usually 0.5 hours to 2 days. This is done by reacting. Here, organic bases such as triethylamine, pyridine, 4-aminopyridine are used as the base. Moreover, the base used can also be used as a solvent.

Synthesis of compound (F-2)

This reaction is a method of synthesizing compound (F-2) by reacting compound (F-1) with a chlorinating reagent. In this reaction, compound (F-1) and a chlorinating reagent are used in an equal amount or in excess, and in the presence of a base, in a solvent inert to the reaction, at room temperature to heating under reflux, usually 0.5 hours to 2 This is done by reacting for days. Here, N-chlorosuccinimide or the like can be used as the chlorinating reagent. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethylsulfoxide (DMSO), or these A mixed solvent etc. are mentioned.

Synthesis of compound (F-4)

(Wherein R ⁷ follows the definition of substituents on ring A.)

This reaction is a method of synthesizing compound (F-4) by reacting compound (F-2) with acetylene compound (F-3). In this reaction, the compound (F-2) and the acetylene compound (F-3) are used in an equal amount or in excess, and in the presence of a base, in a solvent inert to the reaction, usually at room temperature to under reflux with heating. The reaction is performed for 5 hours to 2 days. Examples of the base used include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the like. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.

Synthesis of compound (F-5)

This reaction is a method for synthesizing the compound (F-5) of the present invention by deprotecting the protecting group R ⁵ of the compound (F-4) with an acid or a base. In this reaction, compound (F-4) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

(Synthesis method G)
Synthesis of compound (G-2)

(In the formula, Z ¹ and Z ⁵ each represent a leaving group, and R ⁹ represents a protecting group for a carboxyl group.)
Examples of the leaving group represented by Z ¹ and Z ⁵ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (G-2) by reacting a phenolic hydroxyl group in compound (G-1) with an alkylating reagent having a leaving group in the presence of a base. Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc. Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used. This reaction is carried out by reacting compound (G-1) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., and then an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited. For example, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N— Examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.

Synthesis of compound (G-3)

(In the formula, Z ⁵ represents a leaving group, and R ⁹ represents a protecting group for a carboxyl group.)

This reaction is a method of synthesizing compound (G-3) by deprotecting protecting group R ⁹ of compound (G-2) with an acid or a base. In this reaction, compound (G-2) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

Synthesis of compound (G-4)

(In the formula, Z ⁵ represents a leaving group.)

This reaction is a method of synthesizing compound (G-4) which is acid chloride from compound (G-3). In this reaction, compound (G-3) is usually reacted for 0.5 hour to 2 days at room temperature to heating under reflux using an equal or excessive amount of a chlorinating reagent in a solvent inert to the reaction. Is done. Examples of the chlorinating reagent used include thionyl chloride, oxalyl chloride, and phosphoryl chloride. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform, N, N-dimethylformamide ( DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.

Synthesis of compound (G-6)

(In the formula, Z ⁵ represents a leaving group, and R ⁷ follows the definition of the substituent on ring A.)

This reaction is a method of synthesizing the compound (G-6) which is an oxadiazole ring from the compound (G-4) which is an acid chloride and the compound (G-5). In this reaction, compound (G-4) is used in an equivalent amount or in excess of compound (G-5) in the presence of a base in a solvent inert to the reaction, and the reaction is usually carried out at room temperature to heating under reflux. The reaction is performed for a time to 2 days. Examples of the base used include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N-ethyl-N, Examples include organic amines such as N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU). An organic amine can also be used as a solvent.

Synthesis of compound (G-8)

This reaction is a method of synthesizing compound (G-8) by coupling compounds (G-6) and (G-7). Examples of the leaving group represented by Z ⁵ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. In this reaction, compounds (G-6) and (G-7) are used in equal amounts or in excess, and in a solvent inert to the reaction, in the presence of a base and a transition metal catalyst, optionally a ligand, a carboxyl It is carried out by adding an acid and a copper (I or II) salt and reacting at room temperature to heating under reflux, usually for 0.5 hour to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Bases include lithium hydride, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, tripotassium phosphate, sodium acetate, acetic acid Metal salts of alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salts, potassium salts, magnesium salts), metal salts of alkyl anions having 1 to 6 carbon atoms (lithium salts, sodium salts, potassium salts, magnesium salts) ), Tetra (alkyl having 1 to 4 carbon atoms) ammonium (fluoride, chloride, bromide), diisopropylethylamine, tributylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclooctane, or Examples include imidazole. Examples of the transition metal catalyst include copper, palladium, cobalt, iron, rhodium, ruthenium, and iridium. Examples of the ligand include tri (t-butyl) phosphine, tri (cyclohexyl) phosphine, t-butyldicyclohexylphosphine, di (t-butyl) cyclohexylphosphine, and di (t-butyl) methylphosphine. Copper (I or II) salts include copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) acetate, copper (II) fluoride, copper (II) chloride , Copper bromide (II), copper (II) iodide, copper (II) acetate and hydrates thereof, and mixtures thereof. Examples of the carboxylic acid include formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid, and trifluoroacetic acid.

Synthesis of compound (G-9)

(R ⁷ follows the definition of substituents on ring A.)

This reaction is a method for synthesizing the compound (G-9) of the present invention by deprotecting the protecting group R ⁵ of the compound (G-8) with an acid or a base. In this reaction, compound (G-8) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

(Synthesis method H)
Synthesis of compound (H-2)

(In the formula, Z ¹ and Z ⁶ represent a leaving group.)
Examples of the leaving group represented by Z ¹ and Z ⁶ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (H-2) by reacting a phenolic hydroxyl group in compound (H-1) with an alkylating reagent having a leaving group in the presence of a base. Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc. Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used. This reaction is carried out by reacting compound (H-1) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., followed by an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited. For example, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N— Examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.

Synthesis of compound (H-4)

(In the formula, Z ⁶ represents a leaving group.)

This reaction is a method of synthesizing compound (H-4) by coupling compounds (H-2) and (H-3). Examples of the leaving group represented by Z ⁶ include an iodine atom, a bromine atom, and a chlorine atom. In this reaction, compounds (H-2) and (H-3) are used in an equal amount or in excess, and the reaction is carried out in a solvent inert to the reaction in the presence of a base, a copper catalyst and a ligand at room temperature to heating. The reaction is usually carried out under reflux for usually 0.5 hours to 3 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), Or these mixed solvents etc. are mentioned. Bases include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, metal alkoxides such as sodium ethoxide, sodium methoxide, triethylamine, N-ethyl -N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the like. Examples of the copper catalyst include copper chloride, copper bromide, copper iodide, and copper oxide. Examples of the ligand include proline, trans-N, N′-dimethylcyclohexane-1,2-diamine, N, N-dimethylaminoacetic acid, 1,10-phenanthroline and the like.

Synthesis of compound (H-5)

This reaction is a method of synthesizing compound (H-5) by brominating the ortho position of the alkoxy group of compound (H-4). In this reaction, compound (H-4) and a bromine source are used in an equal amount or in excess, and in an inert solvent for the reaction, in the presence of an acid, from room temperature to heating under reflux, usually from 0.5 hours to This is done by reacting for 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Examples of the bromine source include bromine. Examples of the acid used include organic acids such as formic acid, acetic acid, hydrochloric acid, sulfuric acid and trifluoroacetic acid. Examples of the solvent used in these reactions include dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, or a mixed solvent thereof, and an acid such as acetic acid may be used as the solvent.

Synthesis of compound (H-7)

This reaction is a method of synthesizing compound (H-7) which is a borate ester by coupling compound (H-5) and pinacol diborane (H-6). In this reaction, compounds (H-5) and (H-6) are used in equal amounts or in excess, and usually in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature to heating under reflux. The reaction is performed for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, and tripotassium phosphate, or solutions obtained by diluting these bases with water. Can be mentioned. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1'-bis (diphenylphosphino) ferrocene and the like are preferable.

Synthesis of compound (H-8)

(In the formula, Z ² represents a leaving group.)
Examples of the leaving group represented by Z ² include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (H-8) by coupling reaction of borate ester compound (H-7) and a heterocyclic compound having a leaving group. In this reaction, the compound (H-7) and the heterocyclic compound are used in an equal amount or in excess, and in an inert solvent for reaction, in the presence of a base and a palladium catalyst, the reaction temperature is usually from 0 to 0 at reflux. It is carried out by reacting for 5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases And a solution obtained by diluting with water or the like. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.

Synthesis of compound (H-9)

This reaction is a method for synthesizing the compound (H-9) of the present invention by deprotecting the protecting group R ⁵ of the compound (H-8) with an acid or a base. In this reaction, compound (H-8) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

(Synthesis Method I)
Synthesis of compound (I-2)

(In the formula, Z ¹ and Z ⁷ represent a leaving group.)
Examples of the leaving group represented by Z ¹ and Z ⁷ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (I-2) by reacting a phenolic hydroxyl group in compound (I-1) with an alkylating reagent having a leaving group in the presence of a base. Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc. Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used. This reaction is carried out by reacting compound (I-1) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., and then an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited. For example, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N— Examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.

Synthesis of compound (I-3)

(In the formula, Z ⁷ represents a leaving group.)

This reaction is a method of synthesizing compound (I-3) which is a 1,3-oxazole ring by reacting compound (I-2) with p-toluenesulfonylacetonitrile (C-6). In this reaction, compound (I-2) and p-toluenesulfonylacetonitrile (C-6) are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base, at room temperature to under reflux. The reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Examples of the base used include carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5. 4.0] -7-undecene (DBU) and other organic amines are used. Solvents used in these reactions include toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2 -Dimethoxyethane, 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.

Synthesis of compound (I-4)

(In the formula, Z ⁷ represents a leaving group.)

This reaction is a method of synthesizing compound (I-4) by coupling compounds (I-3) and (H-3). Examples of the leaving group represented by Z ⁷ include an iodine atom, a bromine atom, and a chlorine atom. In this reaction, compounds (I-3) and (H-3) are used in an equal amount or in excess, and the reaction is carried out in a solvent inert to the reaction in the presence of a base, a copper catalyst and a ligand at room temperature to heating. The reaction is usually carried out under reflux for usually 0.5 hours to 3 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), Or these mixed solvents etc. are mentioned. Bases include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, metal alkoxides such as sodium ethoxide, sodium methoxide, triethylamine, N-ethyl -N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the like. Examples of the copper catalyst include copper chloride, copper bromide, copper iodide, and copper oxide. Examples of the ligand include proline, trans-N, N′-dimethylcyclohexane-1,2-diamine, N, N-dimethylaminoacetic acid, 1,10-phenanthroline and the like.

Synthesis of Compound (I-5)

This reaction is a method for synthesizing the compound (I-5) of the present invention by deprotecting the protecting group R ⁵ of the compound (I-4) with an acid or a base. In this reaction, compound (I-4) is usually reacted for 0.5 hours to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

Synthesis method (J)
Synthesis of compound (J-2)

(In the formula, Z ⁸ and Z ⁹ represent a leaving group.)
Examples of the leaving group represented by Z ⁸ and Z ⁹ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (J-2) by lithiating or sodiumating the 4-position of pyridine in compound (J-1) with a base and then formylating with a formylating agent. Examples of the base include lithium diisopropylamine (LDA) prepared from diisopropylamine and n-butyllithium. Examples of the formylating agent include N, N-dimethylformamide (DMF) and N-formylmorpholine. This reaction is carried out at −78 ° C. to 0 ° C. in a solvent inert to the reaction by subjecting compound (J-1) to an equal amount or a small excess of the base, followed by an equal amount or an excess amount of formylation. The reaction is usually performed by adding an agent and reacting for 0.5 to 5 hours. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, or a mixture thereof A solvent etc. are mentioned.

Synthesis of compound (J-4)

(Wherein Z ⁸ and Z ⁹ represent a leaving group, Z ¹⁰ represents —B (OH) ₂ or —B (OR ¹⁰ ) OR ¹¹ , where R ¹⁰ and R ¹¹ independently represent 1 carbon atom. An alkyl group of ˜6, or R ¹⁰ and R ¹¹ together represent an alkylene group of 1 to 6 carbon atoms.) In this method, compound (J-4) is synthesized by coupling J-3). Examples of the leaving group represented by Z ⁸ and Z ⁹ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, compounds (J-2) and (J-3) are used in equal amounts or in excess, and usually in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature to heating under reflux. The reaction is performed for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases And a solution obtained by diluting with water or the like. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.

Synthesis of compound (J-5)

(In the formula, Z ⁸ represents a leaving group.)
Examples of the leaving group represented by Z ⁸ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a conversion reaction from a formyl group to a cyano group, and is performed by reacting an aromatic aldehyde derivative represented by the above formula (J-4) with hydroxylamine. As hydroxylamine, other salts such as hydrochloride thereof may be used. In that case, it is preferable to add an appropriate basic substance. In addition, the reaction can be accelerated by adding 1.0 to 3.0 equivalents of acetic anhydride, acetyl chloride, trichloroacetyl chloride and the like. The amount of hydroxylamine or a salt thereof used in these reactions is usually 1 equivalent or more, preferably 1.0 to 2.0 equivalents. When a basic substance is used, 1.0 to 3.0 equivalents are used with respect to the hydroxylamine salt. As basic substances to be used, carboxylates such as sodium formate, potassium formate and sodium acetate, carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, organic amines such as triethylamine, pyridine and 4-aminopyridine are used. . The reaction is carried out in an inert solvent in the presence of a base at room temperature to heating under reflux, usually for 0.5 hour to 3 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Solvents used in these reactions include acetic acid, formic acid, toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1, Examples include 2-dimethoxyethane, 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), methanol, ethanol, 2-propanol and the like.

Synthesis of compound (J-6)

(In the formula, Z ⁸ represents a leaving group.)

This reaction is a method of synthesizing compound (J-6) by coupling compound (J-5) and (G-7). Examples of the leaving group represented by Z ⁸ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, compounds (J-5) and (G-7) are used in equal amounts or in excess, and in a solvent inert to the reaction, in the presence of a base and a transition metal catalyst, optionally a ligand, a carboxyl It is carried out by adding an acid and a copper (I or II) salt and reacting at room temperature to heating under reflux, usually for 0.5 hour to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Bases include lithium hydride, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, tripotassium phosphate, sodium acetate, acetic acid Metal salts of alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salts, potassium salts, magnesium salts), metal salts of alkyl anions having 1 to 6 carbon atoms (lithium salts, sodium salts, potassium salts, magnesium salts) ), Tetra (alkyl having 1 to 4 carbon atoms) ammonium (fluoride, chloride, bromide), diisopropylethylamine, tributylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclooctane, or Examples include imidazole. Examples of the transition metal catalyst include copper, palladium, cobalt, iron, rhodium, ruthenium, and iridium. Examples of the ligand include tri (t-butyl) phosphine, tri (cyclohexyl) phosphine, t-butyldicyclohexylphosphine, di (t-butyl) cyclohexylphosphine, and di (t-butyl) methylphosphine. Copper (I or II) salts include copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) acetate, copper (II) fluoride, copper (II) chloride , Copper bromide (II), copper (II) iodide, copper (II) acetate and hydrates thereof, and mixtures thereof. Examples of the carboxylic acid include formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid, and trifluoroacetic acid.

Synthesis of compound (J-7)

This reaction is a reaction in which a tetrazole ring is cyclized from a cyano group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (J-6) with an azide compound in the presence of an acid. In this reaction, compound (J-6) and an azide compound are used in an equal amount or in excess, and in an inert solvent for the reaction, in the presence of an acid, from room temperature to heating under reflux, usually from 0.5 hour to This is done by reacting for 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Examples of the azide compound include sodium azide and trimethylsilyl azide. Examples of the acid to be used include organic acids such as formic acid and acetic acid, inorganic acids such as hydrochloric acid and sulfuric acid, and inorganic salts such as ammonium chloride and ammonium acetate. Solvents used in these reactions include toluene, benzene, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1 , 2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.

Synthesis of compound (J-8)

This reaction is a method for synthesizing the compound (J-8) of the present invention by deprotecting the protecting group R ⁵ of the compound (J-7) with an acid or a base. In this reaction, compound (J-7) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned. Note that the synthesis method (J) described above is performed on a compound in which R ¹ is an alkyl group having 1 or 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an aryl group optionally substituted with a halogen atom. It is common.

(Synthesis Method K)
Synthesis of compound (K-1)

(In the formula, Z ⁸ represents a leaving group.)

This reaction is a method of synthesizing compound (K-1) by coupling compound (J-4) and (G-7). Examples of the leaving group represented by Z ⁸ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, compounds (J-4) and (G-7) are used in equal amounts or in excess, and in a solvent inert to the reaction, in the presence of a base and a transition metal catalyst, optionally a ligand, a carboxyl It is carried out by adding an acid and a copper (I or II) salt and reacting at room temperature to heating under reflux, usually for 0.5 hour to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Bases include lithium hydride, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, tripotassium phosphate, sodium acetate, acetic acid Metal salts of alkoxides having 1 to 6 carbon atoms such as potassium (lithium salts, sodium salts, potassium salts, magnesium salts), metal salts of alkyl anions having 1 to 6 carbon atoms (lithium salts, sodium salts, potassium salts, magnesium salts) ), Tetra (alkyl having 1 to 4 carbon atoms) ammonium (fluoride, chloride, bromide), diisopropylethylamine, tributylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclooctane, or Examples include imidazole. Examples of the transition metal catalyst include copper, palladium, cobalt, iron, rhodium, ruthenium, and iridium. Examples of the ligand include tri (t-butyl) phosphine, tri (cyclohexyl) phosphine, t-butyldicyclohexylphosphine, di (t-butyl) cyclohexylphosphine, and di (t-butyl) methylphosphine. Copper (I or II) salts include copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) acetate, copper (II) fluoride, copper (II) chloride , Copper bromide (II), copper (II) iodide, copper (II) acetate and hydrates thereof, and mixtures thereof. Examples of the carboxylic acid include formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid, and trifluoroacetic acid.

Synthesis of compound (K-2)

This reaction is a method of synthesizing a 1,3-oxazole ring by reacting compound (K-1) with p-toluenesulfonylacetonitrile (C-6). In this reaction, compound (K-1) and p-toluenesulfonylacetonitrile (C-6) are used in an equal amount or in excess, and in a solvent inert to the reaction in the presence of a base, from room temperature to heating under reflux. The reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Examples of the base used include carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5. 4.0] -7-undecene (DBU) and other organic amines are used. Solvents used in these reactions include toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2 -Dimethoxyethane, 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.

Synthesis of compound (K-3)

This reaction is a method for synthesizing the compound (K-3) of the present invention by deprotecting the protecting group R ⁵ of the compound (K-2) with an acid or a base. In this reaction, compound (K-2) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned. Note that the synthesis method (K) described above is performed on a compound in which R ¹ is an alkyl group having 1 or 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or an aryl group optionally substituted with a halogen atom. It is common.

Synthesis method (L)
Synthesis of compound (L-2)

(Wherein R ⁶ represents a protecting group for a phenolic hydroxyl group, and Z ¹¹ represents a leaving group.)
Examples of the leaving group represented by Z ¹¹ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (L-2) by reacting a phenolic hydroxyl group in compound (L-1) with an alkylating reagent having a leaving group in the presence of a base. Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc. Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used. This reaction is carried out by reacting the compound (L-1) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., followed by an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited. For example, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N— Examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.

Synthesis of compound (L-3)

This reaction is a method of synthesizing compound (L-3) by lithiating the 4-position of pyridine in compound (L-2) with a strong base and then brominating. In this reaction, an equal amount or a small excess of strong base was added to compound (L-2) in a solvent inert to the reaction at −78 ° C. to 0 ° C., and the reaction was usually performed for 0.5 to 12 hours. Later, by adding a bromine source. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. As the strong base to be used, n-butyllithium, t-butyllithium, s-butyllithium or the like is used. Examples of the bromination reagent include carbon tetrabromide. The solvent is not particularly limited, and examples thereof include ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane.

Synthesis of compound (L-4)

This reaction is a method for synthesizing compound (L-4) by deprotecting protecting group R ⁶ of compound (L-3) with an acid or a base. In this reaction, compound (L-3) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

Synthesis of compound (L-5)

(In the formula, Z ¹ represents a leaving group.)
Examples of the leaving group represented by Z ¹ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (L-5) by reacting a phenolic hydroxyl group in compound (L-4) with an alkylating reagent having a leaving group in the presence of a base. Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc. Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used. This reaction is carried out by reacting the compound (L-4) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., and then an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited. For example, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N— Examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.

Synthesis of compound (L-6)

This reaction is a method of synthesizing compound (L-6) by oxidizing the methyl group at the 2-position of pyridine in compound (L-5) with an oxidizing agent. As the oxidizing agent to be used, a manganese salt such as potassium permanganate is used. In this reaction, an equal amount or a small excess of an oxidizing agent is added to compound (L-5) in a solvent inert to the reaction at 0 ° C. to 120 ° C., and the reaction is usually performed for 0.5 hour to 2 days. Is done by. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited. For example, ethers such as 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N-dimethylformamide (DMF), water or These mixed solvents are exemplified.

Synthesis of compound (L-7)

This reaction is a method of synthesizing the amide compound (L-7) by reacting the carboxyl group of the compound (L-6) with ammonia. This reaction is performed according to literature methods (for example, peptide synthesis basics and experiment, Nobuo Izumiya et al., Maruzen, 1983, Comprehensive Organic Synthesis, Vol. 6, Pergamon Press, 1991, etc.) The conventional amide formation reaction may be carried out by a method according to the above or a combination thereof with a conventional method, that is, by using a condensing agent well known to those skilled in the art, or an ester available to those skilled in the art. It can be performed by an activation method, a mixed acid anhydride method, an acid chloride method, a carbodiimide method, or the like. Examples of such amide-forming reagents include thionyl chloride, oxalyl chloride, N, N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, N, N′-carbonyldiimidazole, diphenylphosphoryl chloride, diphenyl. Phosphoryl azide, N, N′-disuccinimidyl carbonate, N, N′-disuccinimidyl oxalate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, benzotriazole- 1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate, 2- (5-norbornene -2,3-dicarboxyl D) -1,1,3,3-tetramethyluronium tetrafluoroborate, O- (N-succinimidyl) -1,1,3,3-tetramethyluronium tetrafluoroborate, bromotris (pyrrolidino) phosphonium hexafluoro Phosphate, ethyl chloroformate, isobutyl chloroformate or 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate, etc. Among them, for example, thionyl chloride, oxalyl chloride, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3 -Tetramethyluronium, hexafluorophosphate, etc. are preferred. In the amide forming reaction, a base and a condensation aid may be used together with the amide forming reagent. Examples of the condensation aid used include N-hydroxybenzotriazole hydrate and N-hydroxysuccinimide.

In this reaction, compound (L-6) and ammonia are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a condensing agent and a base, usually at room temperature to heating under reflux, usually 0.5 It is carried out by reacting for a time to 3 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), Examples thereof include pyridine or a mixed solvent thereof. Examples of the base used include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N, N-dimethylaniline, and 1,8-diazabicyclo [5. 4.0] tertiary aliphatic amines such as undec-7-ene, 1,5-azabicyclo [4.3.0] non-5-ene; pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline or Examples include aromatic amines such as isoquinoline, among which tertiary aliphatic amines are preferable, and triethylamine or N, N-diisopropylethylamine is particularly preferable.

Synthesis of compound (L-8)

This reaction is a method of synthesizing compound (L-8) by dehydrating the amide group of compound (L-7) with an acid. This reaction is carried out by reacting compound (L-7) with an acid in an equivalent amount or in excess in a solvent inert to the reaction, usually at room temperature to heating under reflux, usually for 0.5 hour to 5 days. Done. Here, the solvent is not particularly limited, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform. Examples of the acid include thionyl chloride, oxalyl chloride, phosphoryl chloride, and phenylphosphonyl dichloride.

Synthesis of compound (L-9)

(Wherein Z ² represents —B (OH) ₂ or —B (OR ¹⁰ ) OR ¹¹ , wherein R ¹⁰ and R ¹¹ are independently an alkyl group having 1 to 6 carbon atoms, or R ¹⁰ and R ¹¹ together represents an alkylene group having 1 to 6 carbon atoms.)
Examples of the leaving group represented by Z ² include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (L-9) by coupling reaction of compound (L-8) and a heterocyclic compound having boric acid or boric acid ester. In this reaction, the compound (L-8) and the heterocyclic compound are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, from room temperature to heating under reflux, usually 0. It is carried out by reacting for 5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate, metal alkoxides such as sodium ethoxide and sodium methoxide, or these bases And a solution obtained by diluting with water or the like. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene and the like are preferable.

Synthesis of compound (L-10)

This reaction is a conversion reaction from a cyano group to a thioamide group, and is performed by reacting an aromatic cyano group derivative represented by the above formula (L-9) with a sulfur source under acidic conditions. In this reaction, compound (L-9) and a sulfur source are used in an equal amount or in excess, and in an inert solvent for the reaction, in the presence of an acid, at room temperature to heating under reflux, usually 0.5 hours to 2 This is done by reacting for a day. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Hydrogen sulfide, thioacetamide or thioacetic acid is used as the sulfur source. As the acidic substance, organic acids such as hydrochloric acid, sulfuric acid and acetic acid, or aqueous solutions of these acids are used. Here, the solvent is not particularly limited. For example, aromatic hydrocarbons such as benzene, toluene and xylene, alcohols such as methanol and ethanol, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1, Examples thereof include ethers such as 2-dimethoxyethane and 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof. An acid such as acetic acid can also be used as a solvent.

Synthesis of compound (L-11)

(In the formula, Z ³ represents a leaving group.)
Examples of the leaving group represented by Z ³ include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. In this reaction, compounds (L-10) and (A-6) are used in an equal amount or in excess, and the reaction is inert to the reaction at room temperature to heating under reflux, usually for 0.5 hour to 2 days. This is done by reacting. Further, an equal amount or an excess amount of a base can be added. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof. Examples of the base used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, triethylamine, N- Examples include ethyl-N, N-diisopropylamine (DIPEA) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).

Synthesis of compound (L-12)

This reaction is a method for synthesizing the compound (L-12) of the present invention by deprotecting the protecting group R ⁵ of the compound (L-11) with an acid or a base. In this reaction, compound (L-11) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

(Synthesis method M)
Synthesis of compound (M-2)

(In the formula, Z ¹ and Z ¹² each represent a leaving group.)
Examples of the leaving group represented by Z ¹ and Z ¹² include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (M-2) by reacting a phenolic hydroxyl group in compound (M-1) with an alkylating reagent having a leaving group in the presence of a base. Examples of basic substances used include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, t-butoxy potassium, etc. Organic amines such as metal alkoxide, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Used. This reaction is carried out by reacting compound (M-1) with an equal amount or a small excess of a base in a solvent inert to the reaction at 0 ° C. to 140 ° C., followed by an equal amount or an excess amount of an alkylating reagent. And the reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited. For example, ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane, N, N— Examples thereof include dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof.

Synthesis of compound (M-3)

(In the formula, Z ¹² represents a leaving group.)
Examples of the leaving group represented by Z ¹² include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing compound (M-3) by lithiating the 4-position of pyridine in compound (M-2) with a strong base and then formylating. In this reaction, an equal amount or a small excess of strong base was added to compound (M-2) at −78 ° C. to 0 ° C. in a solvent inert to the reaction, and the reaction was usually carried out for 0.5 to 12 hours. Later it is done by adding a formylating agent. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. As the strong base to be used, n-butyllithium, t-butyllithium, s-butyllithium or the like is used. Examples of the formylation reagent include methyl formate, hexamethylenetetramine, N, N-dimethylformamide and the like. The solvent is not particularly limited, and examples thereof include ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxyethane.

Synthesis of compound (M-4)

(In the formula, Z ¹² represents a leaving group.)
Examples of the leaving group represented by Z ¹² include a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and a trifluoromethanesulfonyloxy group. This reaction is a method of synthesizing a 1,3-oxazole ring by reacting compound (M-3) with p-toluenesulfonylacetonitrile (C-6). In this reaction, compound (M-3) and p-toluenesulfonylacetonitrile (C-6) are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base, at room temperature to heating under reflux. The reaction is usually carried out for 0.5 hours to 2 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Examples of the base used include carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, triethylamine, pyridine, 4-aminopyridine, N-ethyl-N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5. 4.0] -7-undecene (DBU) and other organic amines are used. Solvents used in these reactions include toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2 -Dimethoxyethane, 1,2-diethoxyethane, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof.

Synthesis of compound (M-5)

(In the formula, Z ¹² represents a leaving group.)

This reaction is a method of synthesizing compound (M-5) by coupling compound (M-4) and (H-3). Examples of the leaving group represented by Z ¹² include an iodine atom, a bromine atom, and a chlorine atom. In this reaction, compounds (M-4) and (H-3) are used in an equal amount or in excess, and in a solvent inert to the reaction, in the presence of a base, a copper catalyst and a ligand, from room temperature to heating The reaction is usually carried out under reflux for usually 0.5 hours to 3 days. This reaction is preferably carried out in an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate, N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), Or these mixed solvents etc. are mentioned. Bases include inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, metal alkoxides such as sodium ethoxide, sodium methoxide, triethylamine, N-ethyl -N, N-diisopropylamine (DIPEA), 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) and the like. Examples of the copper catalyst include copper chloride, copper bromide, copper iodide, and copper oxide. Examples of the ligand include proline, trans-N, N′-dimethylcyclohexane-1,2-diamine, N, N-dimethylaminoacetic acid, 1,10-phenanthroline and the like.

Synthesis of compound (M-6)

This reaction is a method for synthesizing the compound (M-6) of the present invention by deprotecting the protecting group R ⁵ of the compound (M-5) with an acid or a base. In this reaction, compound (M-5) is usually reacted for 0.5 hour to 5 days at room temperature to heating under reflux using an equal amount or excess of acid or base in a solvent inert to the reaction. Is done. Here, the solvent is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, 1,2 -Ethers such as diethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, alcohols such as methanol, ethanol, 2-propanol, butanol, N, N-dimethylformamide (DMF), Examples thereof include N-methylpyrrolidone, dimethyl sulfoxide (DMSO), water, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, and phosphoric acid, or solutions obtained by diluting these acids with water or an organic solvent. Examples of the base include inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, metal alkoxides such as sodium ethoxide and sodium methoxide, or solutions obtained by diluting these bases with water, etc. Is mentioned.

Hereinafter, the pharmaceutically acceptable salt of the compound represented by the formula (I) is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of such a salt include hydrogen chloride, Salts with inorganic acids such as hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, carbonic acid; maleic acid, fumaric acid, citric acid, malic acid, tartaric acid, lactic acid, succinic acid, benzoic acid, oxalic acid, methanesulfonic acid, benzene Salts with organic acids such as sulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, formic acid; salts with amino acids such as glycine, lysine, arginine, histidine, ornithine, glutamic acid, aspartic acid; sodium, potassium, lithium Salts with alkali metals such as calcium; Salts with alkaline earth metals such as calcium and magnesium; Salts with metals such as aluminum, zinc and iron; Tetramethy Salts with organic oniums such as ammonium and choline; ammonia, propanediamine, pyrrolidine, piperidine, pyridine, ethanolamine, N, N-dimethylethanolamine, 4-hydroxypiperidine, t-octylamine, dibenzylamine, morpholine , Glucosamine, phenylglycylalkyl ester, ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzylphenylamine, piperazine, And salts with organic bases such as tris (hydroxymethyl) aminomethane.

Furthermore, the present invention (I) and salts thereof include various hydrates and solvates.

The various pharmaceutically acceptable salts of the compound represented by the formula (I) can be appropriately produced based on ordinary knowledge in this technical field.

The compounds of the present invention also include stereoisomers, racemates, and all possible optically active forms of the compounds represented by formula (I).

The compound represented by the formula (I) of the present invention and a pharmaceutically acceptable salt thereof have particularly excellent xanthine oxidase inhibitory activity. Due to its excellent xanthine oxidase inhibitory activity, the compounds represented by the formula (I) of the present invention and pharmaceutically acceptable salts thereof are useful as xanthine oxidase inhibitors.

The compound represented by the formula (I) of the present invention and a pharmaceutically acceptable salt thereof are clinically applicable as a xanthine oxidase inhibitor, gout, hyperuricemia, oncolysis syndrome, urolithiasis , Hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, kidney diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease or autoimmune disease It can be used as a therapeutic or prophylactic agent for diseases involving xanthine oxidase. Here, in the present invention, “prevention” means prevention of morbidity or onset in an individual who has not yet been affected or developed, and “treatment” refers to disease or It means healing, suppressing or ameliorating symptoms.

The compound represented by the formula (I) and a pharmaceutically acceptable salt thereof can be made into a pharmaceutical composition together with a pharmaceutically acceptable carrier and / or diluent. This pharmaceutical composition can be formed into various dosage forms and administered orally or parenterally. Parenteral administration includes, for example, intravenous, subcutaneous, intramuscular, transdermal, or rectal administration.

Formulations containing one or more of the compounds represented by the formula (I) of the present invention or salts thereof as active ingredients are prepared using carriers, excipients and other additives that are usually used for formulation. Prepared. The carrier or excipient for the preparation may be either solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, etc. The usual thing is mentioned. Administration may be in any form of oral administration such as tablets, pills, capsules, granules, powders, liquids, or parenteral administration such as injections such as intravenous injection and intramuscular injection, suppositories, and transdermal. Good.

The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the type of disease, administration route, patient symptom, age, sex, body weight, etc. It can be administered in the range of 0.01 to 1000 mg per dose or divided into several doses. However, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or a dose exceeding the above range may be required.

The present invention will be described below based on specific examples. However, the present invention is not limited to these examples.

The structure of the isolated novel compound was confirmed by ¹ H NMR and / or mass spectrometry using a single quadrupole instrument equipped with an electron spray source, and other appropriate analytical methods.
For those measured for ¹ H NMR spectrum (400 MHz, DMSO-d ₆ , CDCl ₃ or CD ₃ OD), the chemical shift (δ: ppm) and the coupling constant (J: Hz) are shown. About the result of mass spectrometry, the measured value observed as a value which added proton (H ^<+> ) to M ^< + ^> + H, ie, a compound molecular mass (M), is shown. The following abbreviations represent the following:
Equipment: JEOL JMTC-400 / 54 / SS
s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet.
For compounds synthesized according to the methods of the following examples, a high-performance liquid chromatography (HPLC) analysis and a time-of-flight mass spectrometer (TOF-MS) equipped with an electrospray ion source were further analyzed. Analysis was also performed by the mass spectrometry used.
The retention time (unit: minute) of a compound in HPLC analysis under the following analysis conditions is shown as HPLC retention time.
HPLC measurement condition measuring apparatus: Hewlett-Packard 1100 HPLC
Column: Imtakt Cadenza CD-Cl8 100 mm × 4.6 mm 3 μm
UV: PDA detection (254 nm)
Column temperature: 40 degree Gradient condition:
Solvent: A: H ₂ O / acetonitrile = 95/5
0.05% TFA (trifluoroacetic acid)
B: H ₂ O / acetonitrile = 5/95
0.05% TFA (trifluoroacetic acid)
Flow rate: 1.0 mL / min Gradient: 0 to 1 minute, Solvent B: 2% Solvent A: 98%
1-14 minutes, solvent B: 2% → 100% solvent A: 98% → 0%
14-17 minutes, solvent B: 100% solvent A: 0%
17-19 minutes, solvent B: 100% → 2% solvent A: 0% → 98%
As for the results of mass spectrometry, the value of “M ⁺ + H” (obs. Mass: that is, actual measurement in which proton (H ⁺ ) was added to the molecular mass (M) of the compound, which was observed by the apparatus and analysis conditions described below. value), the calculated value of ^"M + + H" (pred. Mass), actually measured ^"M + + H" value calculated from the composition formula of (formula) are also shown.
TOF-MS measurement condition mass spectrometer: Shimadzu LCMS-IT-TOF
LC: Prominence
Column: Phenomenex Synergy Hydro-RP 4.0 mm × 20 mm 2.5 μm
UV: PDA detection (254 nm)
Flow rate: 0.6 mL / min Column temperature: 40 degrees Detection voltage: 1.63 kV
Gradient conditions:
Solvent: A: H ₂ O / acetonitrile = 95/5
0.1% HCOOH
B: H ₂ O / acetonitrile = 5/95
0.1% HCOOH
Flow rate: 0.5 mL / min Gradient: 0 to 0.2 minutes, Solvent B: 2% Solvent A: 98%
0.2-2.5 minutes, solvent B: 2% → 100% solvent A: 98% → 0%
2.5-3.8 minutes, solvent B: 100% solvent A: 0%
3.8 to 4.0 minutes, solvent B: 100% → 2% solvent A: 0% → 98%
4.0-5.0 min, Solvent B: 2% Solvent A: 98%

[Reference Example] Synthesis of ethyl 2- [3-formyl-4- (2-methylpropoxy) phenyl] -4-methyl-1,3-thiazole-5-carboxylate (reference example compound) from 4-hydroxybenzonitrile With reference to JP-A-10-45733, ethyl 2- [3-formyl-4- (2-methylpropoxy) phenyl] -4-methyl-1,3-thiazole-5-carboxylate was obtained.

[Example 1] Synthesis of 4-methyl-2- [4-isobutoxy-3- (pyridin-2-yl) phenyl] -1,3-thiazole-5-carboxylic acid (Compound No. 1 ) (Synthesis Method A)
(1) 3.0 g of 3-bromo-4-fluorobenzonitrile, 1.50 g of 2-methylpropanol and 2.76 g of potassium carbonate were suspended in 50 mL of dimethyl sulfoxide and heated at 100 ° C. for 14 hours in a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography to obtain 2.58 g of 3-bromo-4-isobutoxybenzonitrile.
(2) 2.58 g of 3-bromo-4-isobutoxybenzonitrile obtained above was suspended in 20 mL of tetrahydrofuran, added 1.88 g of triisopropoxyboric acid, and cooled to −78 ° C. in a nitrogen atmosphere. . To the reaction mixture, 2.30 mL of 2.6 M n-butyllithium was slowly added dropwise, and the mixture was stirred at −78 ° C. for 1 hour. Thereafter, the temperature was raised to 0 ° C., 10 mL of 2.0 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain 1.21 g of a crude 3- (dihydroxyboranyl) -4-isobutoxybenzonitrile.
(3) 109.5 mg of crude 3- (dihydroxyboranyl) -4-isobutoxybenzonitrile, 118.5 mg of 2-bromopyridine, 138 mg of potassium carbonate, palladium chloride-1,1′-bis (diphenylphosphino) 40.8 mg of ferrocene was added, suspended in 1.6 mL of 1,4-dioxane and 0.4 mL of water, and heated at 100 ° C. for 14 hours under a nitrogen atmosphere. Thereafter, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure. The resulting crude product is purified by a conventional method to obtain 67.0 mg of 4-isobutoxy-3- (pyridin-2-yl) benzonitrile. It was.
ESI / MS m / e: 253.1 (M ⁺ + H, C ₁₆ H ₁₇ N ₂ O)
(4) 67.0 mg of 4-isobutoxy-3- (pyridin-2-yl) benzonitrile was suspended in 0.3 mL of acetic acid and 0.5 mL of thioacetic acid, and heated at 50 ° C. for 14 hours under a nitrogen atmosphere. Thereafter, concentration under reduced pressure was performed to obtain a crude product of 4-isobutoxy-3- (pyridin-2-yl) benzene-1-carbothioamide.
ESI / MS m / e: 287.1 (M ⁺ + H, C ₁₆ H ₁₉ N ₂ OS)
(5) Add 65.6 mg of ethyl-2-chloroacetoacetate to the crude 4-isobutoxy-3- (pyridin-2-yl) benzene-1-carbothioamide obtained above and suspend in 2 mL of ethanol. The mixture was heated at 70 ° C. for 5 hours in a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure, and the resulting crude product is separated and purified by silica gel column chromatography to obtain ethyl 4-methyl-2- [4-isobutoxy-3- (pyridine- There were obtained 37.7 mg of 2-yl) phenyl] -1,3-thiazole-5-carboxylate.
(6) 37.7 mg of ethyl 4-methyl-2- [4-isobutoxy-3- (pyridin-2-yl) phenyl] -1,3-thiazole-5-carboxylate obtained above was added to tetrahydrofuran / methanol = It melt | dissolved in 1 mL of 1/1 mixed solution, 0.2 mL of 2M sodium hydroxide aqueous solution was added, and it stirred at room temperature for 4 hours. To the reaction mixture was added 0.2 mL of 2M hydrochloric acid, and 3 mL of water and 4 mL of ethyl acetate were added and stirred. The organic phase was concentrated and purified by a conventional method, and 4-methyl-2- [4-isobutoxy-3- ( Pyridin-2-yl) phenyl] -1,3-thiazole-5-carboxylic acid 21.8 mg was obtained.
¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 0.95 (6H, d, J = 6.4 Hz), 2.00-2.06 (1H, m), 2.66 (3H, s), 3.93 (2H, d, J = 6.0 Hz), 7.30 (1H, d, J = 8.8 Hz), 7.54 (1H, t, J = 5.2 Hz), 8. 02-8.09 (3H, m), 8.36 (1H, d, J = 2.4Hz), 8.78 (1H, d, J = 4.4Hz)
HPLC retention time: 8.75 minutes Obs Mass (M ⁺ + H): 369.1247
Pred Mass (M ⁺ + H): 369.1267
Formula (M): C ₂₀ H ₂₀ N ₂ O ₃ S

[Example 2-6]
In the same manner as in Example 1, Compound Nos. 2 to 6 were synthesized.

[Example 7] Synthesis of 4-methyl-2- [4-isobutoxy-3- (pyrazin-2-yl) phenyl] -1,3-thiazole-5-carboxylic acid (Compound No. 7 ) (1) 3- Bromo-4-fluorobenzonitrile (5.32 g) was suspended in tetrahydrofuran (100 mL), triisopropoxyboric acid (10.0 g) was added, and the mixture was cooled to -78 ° C under a nitrogen atmosphere. To the reaction mixture, 20.0 mL of 1.6 M n-butyllithium was slowly added dropwise and allowed to stir at -78 ° C. for 1 hour. Thereafter, the temperature was raised to 0 ° C., 30 mL of 2.0 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain a crude 3- (dihydroxyboranyl) -4-fluorobenzonitrile. Thereafter, the mixture was stirred in a slurry state in 50 mL of hexane for 1 hour, filtered, and dried under reduced pressure to obtain 3.98 g of 3- (dihydroxyboranyl) -4-fluorobenzonitrile.
(2) 3-3.0 mg of 3- (dihydroxyboranyl) -4-fluorobenzonitrile, 34.4 mg of 2-chloropyrazine, 55.3 mg of potassium carbonate, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene 8 .2 mg was added, suspended in 1.0 mL of 1,4-dioxane and 0.2 mL of water, and heated at 100 ° C. for 14 hours under a nitrogen atmosphere. Thereafter, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain a crude 4-fluoro-3- (pyrazin-2-yl) benzonitrile.
ESI / MS m / e: 200.0 (M ⁺ + H, C ₁₁ H ₇ FN ₃ )
(3) In 2-fluoro-3- (pyrazin-2-yl) benzonitrile obtained above, 22.2 mg of 2-methylpropanol and 33.7 mg of potassium t-butoxy were suspended in 1.0 mL of dimethylformamide. The mixture was heated at 100 ° C. for 6 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain a crude product of 4-isobutoxy-3- (pyrazin-2-yl) benzonitrile.
^{ESI / MS m / e: 254.1} (M + + H, C 15 H 16 N 3 O)
(4) The 4-isobutoxy-3- (pyrazin-2-yl) benzonitrile obtained above was suspended in 0.2 mL of acetic acid and 0.5 mL of thioacetic acid and heated at 60 ° C. for 14 hours under a nitrogen atmosphere. . Thereafter, concentration under reduced pressure was performed to obtain a crude product of 4-isobutoxy-3- (pyrazin-2-yl) benzene-1-carbothioamide.
^{ESI / MS m / e: 288.1} (M + + H, C 15 H 18 N 3 OS)
(5) Add 74.0 mg of ethyl-2-chloroacetoacetate to the crude 4-isobutoxy-3- (pyrazin-2-yl) benzene-1-carbothioamide obtained above and suspend in 2 mL of ethanol. The mixture was heated at 70 ° C. for 5 hours in a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure, and the resulting crude product is separated and purified by silica gel column chromatography to obtain ethyl 4-methyl-2- [4-isobutoxy-3- (pyrazine- There was obtained 20.2 mg of 2-yl) phenyl] -1,3-thiazole-5-carboxylate.
^{ESI / MS m / e: 298.1} (M + + H, C 21 H 24 N 3 O 3 S)
(6) 20.2 mg of ethyl 4-methyl-2- [4-isobutoxy-3- (pyrazin-2-yl) phenyl] -1,3-thiazole-5-carboxylate obtained above was added to tetrahydrofuran / methanol = It melt | dissolved in 1 mL of 1/1 mixed solution, 0.2 mL of 2M sodium hydroxide aqueous solution was added, and it stirred at 50 degreeC for 4 hours. To the reaction mixture was added 0.2 mL of 2M hydrochloric acid, and 3 mL of water and 4 mL of ethyl acetate were added and stirred. The organic phase was concentrated and purified by a conventional method, and 4-methyl-2- [4-isobutoxy-3- ( 6.4 mg of pyrazin-2-yl) phenyl] -1,3-thiazole-5-carboxylic acid was obtained.
¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 0.96 (6H, d, J = 6.8 Hz), 2.03-2.10 (1H, m), 2.66 (3H, s), 3.97 (2H, d, J = 6.4 Hz), 7.32 (1H, d, J = 8.8 Hz), 8.03 (1H, dd, J = 2.4, 8.4 Hz) ), 8.61 (1H, d, J = 2.4 Hz), 8.79 (1H, t, J = 2.4 Hz), 9.18 (1H, d, J = 1.6 Hz)
HPLC retention time: 11.97 minutes ^{Obs Mass (M + + H)} : 370.1218
Pred Mass (M ⁺ + H): 370.1220
Formula (M): C ₁₉ H ₁₉ N ₃ O ₃ S

[Example 8-17]
In the same manner as in Example 7, compound numbers 8 to 17 were synthesized.

[Example 18] Synthesis of 4-methyl-2- [4-isobutoxy-3-isothiazol-4-yl-phenyl] -1,3-thiazole-5-carboxylic acid (Compound No. 18 ) (Synthesis Method B)
(1) 2.8 mL of 2-methylpropanol was suspended in 25 mL of toluene, cooled to 0 ° C., added with 3.63 g of potassium t-butoxy under a nitrogen atmosphere, and stirred at 0 ° C. for 30 minutes. Thereafter, 5.0 g of 3-bromo-4-fluorobenzonitrile was added, and the mixture was stirred at 0 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain a crude product of 3-bromo-4-isobutoxybenzonitrile.
(2) The crude 3-bromo-4-isobutoxybenzonitrile obtained above was suspended in 5.0 mL of acetic acid and 10.0 mL of thioacetic acid, and heated at 80 ° C. for 14 hours in a nitrogen atmosphere. Thereafter, concentration under reduced pressure was performed, and the resulting crude product was separated and purified by silica gel column chromatography to obtain 6.21 g of 3-bromo-4-isobutoxybenzene-1-carbothioamide.
(3) Suspend 6.21 g of 3-bromo-4-isobutoxybenzene-1-carbothioamide obtained above in 42 mL of ethanol, add 4.27 g of t-butyl-2-chloroacetoacetate, and add nitrogen atmosphere. Under heating at 80 ° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure, and the resulting crude product is separated and purified by silica gel column chromatography to give t-butyl 2- [3-bromo-4-isobutoxyphenyl] 4. There was obtained 7.73 g of methyl-1,3-thiazole-5-carboxylate.
(4) 843 mg of t-butyl 2- [3-bromo-4-isobutoxyphenyl] 4-methyl-1,3-thiazole-5-carboxylate is suspended in 10 mL of tetrahydrofuran, and 745 mg of triisopropoxyboric acid is added. And cooled to −78 ° C. under a nitrogen atmosphere. To the reaction mixture, 1.50 mL of 1.59 M n-butyllithium was slowly added dropwise, and the mixture was stirred at −78 ° C. for 1 hour. Thereafter, the temperature was raised to 0 ° C., 1.5 mL of 2.0 M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure, and the resulting crude product is separated and purified by silica gel column chromatography to obtain t-butyl 2- [3- (dihydroxyboranyl) -4-iso Butoxyphenyl] 4-methyl-1,3-thiazole-5-carboxylate was obtained.
(5) t-butyl 2- [3- (dihydroxyboranyl) -4-isobutoxyphenyl] 4-methyl-1,3-thiazole-5-carboxylate 80.0 mg to 4-bromo-isothiazole 37 mg, phosphorus 86 mg of potassium acid and 15 mg of palladium chloride-1,1′-bis (diphenylphosphino) ferrocene were added and suspended in 1.0 mL of 1,4-dioxane and 0.2 mL of water, and at 100 ° C. for 14 hours under nitrogen atmosphere Heated. Thereafter, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give t-butyl 4-methyl-2- [4-isobutoxy-3-isothiazol-4-yl-phenyl] -1,3-thiazole-5 A crude carboxylate was obtained.
(6) The crude product of t-butyl 4-methyl-2- [4-isobutoxy-3-isothiazol-4-yl-phenyl] -1,3-thiazole-5-carboxylate obtained above is converted into methylene chloride. It melt | dissolved in 1 mL, 1.0 mL of trifluoroacetic acid was added, and it stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by a conventional method, and 37.2 mg of 4-methyl-2- [4-isobutoxy-3-isothiazol-4-yl-phenyl] -1,3-thiazole-5-carboxylic acid was obtained. Obtained.
¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 0.93 (6H, d, J = 6.4 Hz), 2.01 to 2.08 (1H, m), 2.62 (3H, s), 3.89 (2H, d, J = 6.4 Hz), 7.23 (1H, d, J = 8.8 Hz), 7.91 (1H, dd, J = 2.4, 8.8 Hz) ), 8.07 (1H, d, J = 2.8 Hz), 8.94 (1H, s), 9.30 (1H, s)
HPLC retention time: 13.07 minutes ^{Obs Mass (M + + H)} : 375.0823
Pred Mass (M ⁺ + H): 375.0832
Formula (M): C ₁₈ H ₁₈ N ₂ O ₃ S ₂

[Examples 19-29]
Compound Nos. 19 to 29 were synthesized in the same manner as Example 18.

[Examples 30-54]
Compound Nos. 30 to 54 were synthesized in the same manner as Example 7.

[Examples 55-66]
In the same manner as in Example 18, compound numbers 55 to 66 were synthesized.

Example 67 Synthesis of 4-methyl-2- (4-isobutoxy-3-oxazol-5-yl-phenyl) -1,3-thiazole-5-carboxylic acid (Compound No. 67 ) (Synthesis Method C)
(1) Ethyl 2- [3-formyl-4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylate 319.6 mg, p-toluenesulfonylmethyl isocyanide 233.5 mg and potassium carbonate 165. 3 mg was suspended in 3.0 mL of ethanol and heated at 80 ° C. for 4 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure, and the resulting crude product is separated and purified by silica gel column chromatography to give ethyl 2- [4-isobutoxy-3-oxazol-5-yl-phenyl]. ] 98.7 mg of 4-methyl-1,3-thiazole-5-carboxylate was obtained.
(2) 98.7 mg of ethyl 2- [4-isobutoxy-3-oxazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylate obtained above was added to tetrahydrofuran / methanol = 1. 1 was dissolved in 3.0 mL of a mixed solution, 0.5 mL of 2M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added 0.5 mL of 2M hydrochloric acid, and the mixture was concentrated under reduced pressure and purified by a conventional method. After washing with 50 mL of water and 50 mL of hexane / ethyl acetate = 1/2 mixed solvent, it was dried under reduced pressure to give 4-methyl-2- (4-isobutoxy-3-oxazol-5-yl-phenyl) -1,3- 35.2 mg of thiazole-5-carboxylic acid was obtained.
¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 1.05 (6H, d, J = 6.8 Hz), 2.20 (1H, septet, J = 8.0 Hz), 2.67 ( 3H, s), 4.02 (2H, d, J = 6.0 Hz), 7.30 (1H, d, J = 8.8 Hz), 7.58 (1H, s), 7.93 (1H, dd, J = 8.8, 2.2 Hz), 8.31 (1H, d, J = 2.2 Hz), 8.52 (1H, s)
HPLC retention time: 12.23 minutes ^{Obs Mass (M + + H)} : 359.1075
Pred Mass (M ⁺ + H): 359.1060
Formula (M): C ₁₈ H ₁₈ N ₂ O ₄ S

[Example 68]
Compound No. 68 was synthesized in the same manner as Example 67.

Example 69 Synthesis of 2- [4- (cyclobutylmethoxy) -3-oxazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid (Compound No. 69 ) (Synthesis) Law C)
(1) 10.5 g of 5-bromosalicylaldehyde and 9.0 g of potassium carbonate were suspended in 100.0 mL of dimethylformamide and stirred at 0 ° C. for 30 minutes in a nitrogen atmosphere. To the reaction mixture, 5.6 g of methoxymethyl chloride was slowly added and stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain a crude product of 5-bromo-2- (methoxymethoxy) benzaldehyde.
(2) To the 5-bromo-2- (methoxymethoxy) benzaldehyde obtained above, 1.05 g of potassium bicarbonate, 561 mg of palladium (II) acetate and 4.1 g of copper (I) bromide were added, and 100 mL of toluene was added. Suspended. Thereafter, 9.4 g of ethyl 4-methyl-1,3-thiazole-5-carboxylate, 881 mg of isobutyric acid and 1.4 g of di-t-butylcyclohexylphosphine were added and heated at 130 ° C. for 15 hours under a nitrogen atmosphere. . The reaction mixture was filtered through Celite to remove insolubles, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method to obtain ethyl 2- [3-formyl-4- (methoxymethoxy) phenyl] -1,3-thiazole-5-carboxylate. 34 g was obtained.
(3) 1.24 g of ethyl 2- [3-formyl-4- (methoxymethoxy) phenyl] -1,3-thiazole-5-carboxylate obtained above, 10.8 g of p-toluenesulfonylmethyl isocyanide, potassium carbonate 7.7 g was added, suspended in 100.0 mL of ethanol, and heated at 80 ° C. for 15 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure, and the resulting crude product is separated and purified by silica gel column chromatography to give ethyl 2- [4- (methoxymethoxy) -3-oxazole-5- Yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylate (6.2 g).
(4) 6.2 g of ethyl 2- [4- (methoxymethoxy) -3-oxazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylate obtained above was added to tetrahydrofuran / It melt | dissolved in the mixed solution 80.0mL of methanol = 1/1, 22 mL of 6M hydrochloric acid was added slowly, and it stirred at 50 degreeC for 15 hours. The solvent was removed by concentration under reduced pressure, 100 mL of a mixed solution of hexane / ethyl acetate = 2/1 was added, and the mixture was stirred at 80 ° C. for 1 hour. After the solution is cooled to room temperature, the solid is collected by filtration, washed with 100 ml of a saturated aqueous sodium hydrogen carbonate solution, 100 mL of water, and 100 mL of a mixed solution of hexane / ethyl acetate = 2/1, and dried to give ethyl 2- (4- There were obtained 4.9 g of hydroxy-3-oxazol-5-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylate.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 1.30 (3H, t, J = 7.3 Hz), 2.68 (3H, s), 4.28 (3H, q, J = 7) .3 Hz), 7.09 (1H, d, J = 8.8 Hz), 7.61 (1H, s), 7.83 (1H, dd, J = 8.8, 2.0 Hz), 8.27 (1H, s), 8.46 (1H, s),
11.31 (1H, brs)
(5) 52.5 mg of triphenylphosphine was dissolved in 500 uL of tetrahydrofuran, 17.2 mg of cyclobutylmethanol and 40.4 mg of diethyl azodicarboxylate were added, and the mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. Ethyl 2- (4-hydroxy-3-oxazol-5-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylate (33.0 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give ethyl 2- [4- (cyclobutylmethoxy) -3-oxazol-5-yl) phenyl] -4-methyl-1,3-thiazole- A crude product of 5-carboxylate was obtained.
(6) The crude product of ethyl 2- [4- (cyclobutylmethoxy) -3-oxazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylate obtained above was added to tetrahydrofuran. Dissolved in 1.0 mL of a mixed solution of / methanol = 1/1, 250 uL of 2M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 6 hours. 2- [4- (cyclobutylmethoxy) -3-oxazol-5-yl-phenyl] -4-methyl-1,3 was added to the reaction mixture by adding 250 uL of 2M hydrochloric acid, concentrating under reduced pressure, and purifying by a conventional method. -21.0 mg of thiazole-5-carboxylic acid was obtained.
¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 1.87-2.02 (4H, m), 2.11-2.16 (2H, m), 2.67 (3H, s) 2.89 (1H, m), 4.21 (2H, d, J = 6.8 Hz), 7.29 (1H, d, J = 8.8 Hz), 7.51 (1H, s), 7 .93 (1H, dd, J = 8.8, 2.4 Hz), 8.30 (1H, d, J = 2.4 Hz), 8.50 (1H, s), 13.32 (1H, s)
HPLC retention time: 12.66 minutes Obs Mass (M ⁺ + H): 371.1052
Pred Mass (M ⁺ + H): 371.1060
Formula (M): C ₁₉ H ₁₈ N ₂ O ₄ S

[Examples 70-83]
Compound Nos. 70 to 83 were synthesized in the same manner as Example 69.

[Example 84] Synthesis of 2- [4-isobutoxy-3- (1H-tetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid (Compound No. 84 ) (Synthesis Method) D)
(1) Ethyl 2- [3-cyano-4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylate (689 mg), sodium azide (780 mg) and ammonium chloride (642 mg) were suspended in 10.0 mL of dimethylformamide. It was made turbid and heated at 120 ° C. for 16 hours under a nitrogen atmosphere. To the reaction mixture was added 6 mL of 2M hydrochloric acid, and the resulting solid was filtered, washed with water, dried under reduced pressure, and ethyl 2- [4-isobutoxy-3- (1H-tetrazol-5-yl) phenyl]- 745 mg of 4-methyl-1,3-thiazole-5-carboxylate was obtained.
(2) Ethyl 2- [4-isobutoxy-3- (1H-tetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylate (155 mg) obtained above was added to tetrahydrofuran / methanol = It melt | dissolved in 3.0 mL of 1/1 mixed solution, 2 M sodium hydroxide aqueous solution 0.8 mL was added, and it stirred at room temperature for 2 hours. To the reaction mixture was added 0.8 mL of 2M hydrochloric acid, and the mixture was concentrated under reduced pressure and purified by a conventional method. 2- [4-isobutoxy-3- (1H-tetrazol-5-yl) phenyl] -4-methyl-1,3 -53.7 mg of thiazole-5-carboxylic acid were obtained.
¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 0.90 (6H, d, J = 6.4 Hz), 2.13-2.20 (1H, m), 2.67 (3H, s), 4.05 (2H, d, J = 6.8 Hz), 7.41 (1H, d, J = 8.8 Hz), 8.13 (1H, dd, J = 2.4, 8.0 Hz) ), 8.49-8.50 (1H, m)
HPLC retention time: 9.97 minutes Obs Mass (M ⁺ + H): 360.1127
Pred Mass (M ⁺ + H): 360.1125
Formula (M): C ₁₆ H ₁₇ N ₅ O ₃ S

[Example 85]
Compound No. 85 was synthesized in the same manner as Example 84.

[Examples 86, 87] 2- [4-Isobutoxy-3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid (Compound No. 86 ) and 2 Synthesis of — [4-isobutoxy-3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid (Compound No. 87 ) (Synthesis Method D)
(1) Ethyl 2- [4-isobutoxy-3- (1H-tetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylate (194 mg) and potassium carbonate (172 mg) and dimethylformamide (2.0 mL) And 177 mg of methyl iodide was added, and the mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. To the reaction mixture, 5.0 mL of water and 5.0 mL of ethyl acetate were added and stirred, and the organic layer was concentrated to give ethyl 2- [4-isobutoxy-3- (1-methyltetrazol-5-yl) phenyl]- 4-methyl-1,3-thiazole-5-carboxylate and ethyl 2- [4-isobutoxy-3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5 A mixture of carboxylates was obtained.
(2) The mixture obtained above was dissolved in 4.0 mL of a tetrahydrofuran / methanol = 1/1 mixed solution, 1.0 mL of 2M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added 1.0 mL of 2M hydrochloric acid, and the mixture was concentrated under reduced pressure and purified by a conventional method to obtain 2- [4-isobutoxy-3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1, 67.7 mg of 3-thiazole-5-carboxylic acid and 2- [4-isobutoxy-3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid 1 mg each was obtained.
(Compound No. 86 ) ¹ H-NMR (400 MHz, DMSO d6) δ (ppm): 0.82 (6H, d, J = 8.0 Hz), 1.93 (1H, septet, J = 8.0 Hz), 2.65 (3H, s), 3.92-3.94 (5H, m), 7.40 (1H, d, J = 8.0 Hz), 8.06 (1H, d, J = 4.0 Hz) ), 8.19 (1H, dd, J = 8.0, 4.0 Hz), 13.38 (1H, s)
HPLC retention time: 10.53 minutes ^{Obs Mass (M + + H)} : 374.1276
Pred Mass (M ⁺ + H): 374.1281
Formula (M): C ₁₇ H ₁₉ N ₅ O ₃ S
(Compound No. 87 ) ¹ H-NMR (400 MHz, DMSO d6) δ (ppm): 1.00 (6H, d, J = 8.0 Hz), 2.02 (1H, septet, J = 8.0 Hz), 2.66 (3H, s), 3.94 (2H, d, J = 8.0 Hz), 4.43 (3H, s), 7.32 (1H, d, J = 8.0 Hz), 8. 06 (1H, d, J = 8.0), 8.43 (1H, d, J = 4.0 Hz), 13.34 (1H, s)
HPLC retention time: 11.70 minutes Obs Mass (M ⁺ + H): 374.1281
Pred Mass (M ⁺ + H): 374.1281
Formula (M): C ₁₇ H ₁₉ N ₅ O ₃ S

[Examples 88-105]
Compound Nos. 88 to 105 were synthesized in the same manner as in Examples 86 and 87.

[Examples 106 and 107] 4-Methyl-2- [3- (1-methyltetrazol-5-yl) -4-phenoxyphenyl] -1,3-thiazole-5-carboxylic acid (Compound No. 106 ) and 4 Synthesis of -methyl-2- [3- (2-methyltetrazol-5-yl) -4-phenoxyphenyl] -1,3-thiazole-5-carboxylic acid (Compound No. 107 ) (Synthesis Method D)
(1) In the same manner as in Example 84, using ethyl 2- (3-cyano-4-phenoxyphenyl) -4-methyl-1,3-thiazole-5-carboxylate, ethyl 2- [3- ( 1H-tetrazol-5-yl) -4-phenoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylate was obtained.
(2) Ethyl 2- [3- (1H-tetrazol-5-yl) -4-phenoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylate is obtained in the same manner as in Examples 86 and 87. 1-mg of 4-methyl-2- [3- (1-methyltetrazol-5-yl) -4-phenoxyphenyl] -1,3-thiazole-5-carboxylic acid and 4-methyl-2- [ 14.7 mg of 3- (2-methyltetrazol-5-yl) -4-phenoxyphenyl] -1,3-thiazole-5-carboxylic acid was obtained.
(Compound No. 106 ) ¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 2.68 (3H, s), 4.09 (3H, m), 7.06 (1H, d, J = 8 .8 Hz), 7.18-7.27 (3H, m), 7.40-7.48 (2H, m), 8.20-8.25 (2H, m), 13.44 (1H, brs) )
HPLC retention time: 10.55 minutes ^{Obs Mass (M + + H)} : 394.0970
Pred Mass (M ⁺ + H): 394.0968
Formula (M): C ₁₉ H ₁₅ N ₅ O ₃ S
(Compound No. 107 ) ¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 2.70 (3H, s), 4.43 (3H, s), 7.09-7.24 (4H, m ), 7.41-7.47 (2H, m), 8.08-8.12 (1H, m), 8.62 (1H, d, J = 2.4 Hz), 13.40 (1H, brs) )
HPLC retention time: 11.35 minutes ^{Obs Mass (M + + H)} : 394.0970
Pred Mass (M ⁺ + H): 394.0968
Formula (M): C ₁₉ H ₁₅ N ₅ O ₃ S

[Examples 108-141]
In the same manner as in Example 107, Compound No. 108 - was synthesized 141.

[Examples 142 and 143] 4-Methyl-2- [3- (1-methyltetrazol-5-yl) -4-phenylphenyl] -1,3-thiazole-5-carboxylic acid (Compound No. 142 ) and 4 Synthesis of —methyl-2- [3- (2-methyltetrazol-5-yl) -4-phenylphenyl] -1,3-thiazole-5-carboxylic acid (Compound No. 143 ) (1) Same as Example 84 To ethyl 2- [3- (1H-tetrazol-5-yl) using ethyl 2- (3-cyano-4-phenylphenyl) -4-methyl-1,3-thiazol-5-carboxylate -4-Phenylphenyl] -4-methyl-1,3-thiazole-5-carboxylate was obtained.
(2) In the same manner as in Examples 86 and 87, ethyl 2- [3- (1H-1,2,3,4-tetrazol-5-yl) -4-phenylphenyl] -4-methyl-1,3 Using 5-thiazole-5-carboxylate, 51.9 mg of 4-methyl-2- [3- (1-methyltetrazol-5-yl) -4-phenylphenyl] -1,3-thiazole-5-carboxylic acid And 32.8 mg of 4-methyl-2- [3- (2-methyltetrazol-5-yl) -4-phenylphenyl] -1,3-thiazole-5-carboxylic acid were obtained.
(Compound No. 142 ) ¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 2.69 (3H, s), 3.44 (3H, m), 7.11-7.13 (2H, m ), 7.35-7.37 (3H, m), 7.79 (1H, d, J = 8.4 Hz), 8.23 (1H, d, J = 2.0 Hz), 8.31 (1H , Dd, J = 2.0, 8.8 Hz)
HPLC retention time: 10.49 minutes ^{Obs Mass (M + + H)} : 378.1017
Pred Mass (M ⁺ + H): 378.1017
Formula (M): C ₁₉ H ₁₅ N ₅ O ₂ S
(Compound No. 143 ) ¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 2.70 (3H, s), 4.31 (3H, m), 7.17-7.20 (2H, m ), 7.32-7.34 (3H, m), 7.64 (1H, d, J = 7.6 Hz), 8.18 (1H, dd, J = 2.0, 8.8 Hz), 8 .34 (1H, d, J = 2.0Hz)
HPLC retention time: 11.34 minutes ^{Obs Mass (M + + H)} : 378.1023
Pred Mass (M ⁺ + H): 378.1017
Formula (M): C ₁₉ H ₁₅ N ₅ O ₂ S

[Example 144] 2- [4-Isobutoxy-3- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid Synthesis of (Compound No. 144 ) (Synthesis Method E)
(1) 8.2 mg of hydroxylamine monohydrochloride is added to 34.4 mg of ethyl 2- [3-cyano-4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylate, and 1 mL of pyridine is added. And heated at 110 ° C. for 14 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography to obtain ethyl 2- [4-isobutoxy-3- (N′-hydroxycarbamimidoyl) phenyl] -4- A crude product of methyl-1,3-thiazole-5-carboxylate was obtained.
^{ESI / MS m / e: 378.1} (M + + H, C 18 H 24 N 3 O 4 S).
(2) A crude product of ethyl 2- [4-isobutoxy-3- (N′-hydroxycarbamimidoyl) phenyl] -4-methyl-1,3-thiazole-5-carboxylate was suspended in 1 mL of pyridine, To the reaction solution, 9.4 mg of acetyl chloride was added and heated at 100 ° C. for 6 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and extracted with water and ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give ethyl 4-methyl-2- [4-isobutoxy-3- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl. ] A crude product of 1,3-thiazole-5-carboxylate was obtained.
^{ESI / MS m / e: 402.1} (M + + H, C 20 H 24 N 3 O 4 S)
(3) Ethyl 4-methyl-2- [4-isobutoxy-3- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] -1,3-thiazole-obtained above The crude product of 5-carboxylate was dissolved in 1 mL of a mixed solution of tetrahydrofuran / methanol = 1/1, 0.2 mL of 2M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added 0.2 mL of 2M hydrochloric acid, and 3 mL of water and 4 mL of ethyl acetate were added and stirred. The organic phase was concentrated and then purified by a conventional method, and 2- [4-isobutoxy-3- (5-methyl- There were obtained 20.6 mg of 1,2,4-oxadiazol-3-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid.
¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 1.02 (6H, d, J = 6.4 Hz), 2.02-2.10 (1H, m), 2.66 (3H, s), 3.95 (2H, d, J = 6.0 Hz), 7.30 (1H, d, J = 8.8 Hz), 8.05 (1H, dd, J = 2.4, 8.8 Hz) ), 8.51 (1H, d, J = 2.4 Hz), 13.34 (1H, brs)
HPLC retention time: 12.40 minutes Obs Mass (M ⁺ + H): 347.1156
Pred Mass (M ⁺ + H): 347.1169
Formula (M): C ₁₈ H ₁₉ N ₃ O ₄ S

Example 145 Synthesis of 2- (4-isobutoxy-3-isoxazol-3-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylic acid (Compound No. 145 ) (Synthesis Method F)
(1) Ethyl 2- (3-formyl-4-isobutoxyphenyl) -4-methyl-1,3-thiazole-5-carboxylate is added to 33.7 mg of hydroxylamine monohydrate to 173.7 mg of pyridine It was suspended in 2 mL and heated at 100 ° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a crude product of ethyl 2- [3- (hydroxyimino) methyl-4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylate.
^{ESI / MS m / e: 363.1} (M + + H, C 18 H 23 N 2 O 4 S)
(2) A crude product of ethyl 2- [3- (hydroxyimino) methyl-4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylate is suspended in 2 mL of dimethylformamide, and the reaction solution Was added with 100.1 mg of N-chlorosuccinimide and heated at 100 ° C. for 14 hours in a nitrogen atmosphere. Water and ethyl acetate were added to the reaction mixture for extraction. The organic layer is washed with brine, dried and concentrated under reduced pressure to give ethyl 2- [3-chloro (hydroxyimino) methyl-4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylate. A crude product was obtained.
ESI / MS m / e: 397.0, 399.0 (M ⁺ + H, C ₁₈ H ₂₂ ClN ₂ O ₄ S).
(3) For the crude half of ethyl 2- [3-chloro (hydroxyimino) methyl-4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylate obtained above, 69.1 mg of potassium carbonate was added, suspended in 2 mL of toluene, and 24.6 mg of ethynyltrimethylsilane was added to the reaction solution, followed by heating at 110 ° C. for 14 hours under a nitrogen atmosphere. Water and ethyl acetate were added to the reaction mixture for extraction. The organic layer is washed with brine, dried and concentrated under reduced pressure to give ethyl 4-methyl-2- (4-isobutoxy-3-isoxazol-3-yl) phenyl) -1,3-thiazole-5-carboxylate A crude product was obtained.
^{ESI / MS m / e: 387.1} (M + + H, C 20 H 23 N 2 O 4 S)
(4) A crude product of ethyl 4-methyl-2- (4-isobutoxy-3-isoxazol-3-yl) phenyl) -1,3-thiazole-5-carboxylate obtained above was added to tetrahydrofuran / methanol = It melt | dissolved in 1 mL of 1/1 mixed solution, 0.2 mL of 2M sodium hydroxide aqueous solution was added, and it stirred at room temperature for 4 hours. To the reaction mixture, 0.2 mL of 2M hydrochloric acid was added, and 3 mL of water and 4 mL of ethyl acetate were added and stirred. The organic phase was concentrated and then purified by a conventional method, and 2- (4-isobutoxy-3-isoxazole-3- 25.7 mg of (yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylic acid were obtained.
¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 0.99 (6H, d, J = 6.4 Hz), 2.07-2.13 (1H, m), 2.66 (3H, s), 3.95 (2H, d, J = 6.4 Hz), 6.96-6.97 (1H, m), 7.31 (1H, d, J = 8.8 Hz), 8.05 ( 1H, dd, J = 2.4, 8.8 Hz), 8.34 (1H, d, J = 2.4 Hz), 13.34 (1H, brs)
HPLC retention time: 12.60 minutes ^{Obs Mass (M + + H)} : 359.1062
Pred Mass (M ⁺ + H): 359.1060
Formula (M): C ₁₈ H ₁₈ N ₂ O ₄ S

[Example 146]
Compound No. 146 was synthesized in the same manner as Example 145.

[Example 147] 2- [4-Isobutoxy-3- (1,2,4-oxadiazol-3-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid (Compound No. 147) ) (Synthesis method E)
(1) Add 12.8 mg of hydroxylamine monohydrate to 68.9 mg of ethyl 2- [3-cyano-4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylate, and add pyridine It was suspended in 1 mL and heated at 100 ° C. for 8 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a crude product of ethyl 2- [3- (N′-hydroxycarbamimidoyl) -4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylate. Obtained.
^{ESI / MS m / e: 378.1} (M + + H, C 18 H 24 N 3 O 4 S)
(2) A crude product of ethyl 2- [3- (N′-hydroxycarbamimidoyl) -4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylate was dissolved in 1 mL of trifluoroacetic acid. Then, 42.4 mg of trimethyl orthoformate was added to the reaction solution, and the mixture was heated at 80 ° C. for 4 hours under a nitrogen atmosphere. After cooling to room temperature, the resulting solid is collected by filtration, dried and concentrated under reduced pressure to give 2- [4-isobutoxy-3- (1,2,4-oxadiazol-3-yl) phenyl]- 47.5 mg of 4-methyl-1,3-thiazole-5-carboxylic acid was obtained.
¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 1.02 (6H, d, J = 6.4 Hz), 2.04-2.10 (1H, m), 2.67 (3H, s), 3.98 (2H, d, J = 6.4 Hz), 7.34 (1H, d, J = 8.8 Hz), 8.10 (1H, dd, J = 2.0, 8.8 Hz) ), 8.53 (1H, d, J = 2.4 Hz), 9.71 (1H, s), 13.34 (1H, s)
HPLC retention time: 12.02 minutes ^{Obs Mass (M + + H)} : 360.0999
Pred Mass (M ⁺ + H): 360.0103
_{_{Formula (M): C 17 H}} 17 N 3 O 4 S

[Example 148] 2- [4-Isobutoxy-3- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid Synthesis of (Compound No. 148 ) (Synthesis Method G)
(1) Suspend 1.16 g of methyl 5-bromo-2-hydroxybenzoate and 1.04 g of potassium carbonate in 20 mL of dimethylformamide, add 1.03 g of isobutyl bromide in a nitrogen atmosphere, and heat at 100 ° C. for 14 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain 2.65 g of a crude product of methyl 5-bromo-2-isobutoxybenzoate.
(2) 2.65 g of a crude product of methyl 5-bromo-2-isobutoxybenzoate was dissolved in 20 mL of a mixed solution of tetrahydrofuran / methanol = 1/1. Stir for hours. To the reaction mixture, 2 M hydrochloric acid (5.0 mL) was added, water (20 mL) and ethyl acetate (40 mL) were added and stirred, and the organic phase was concentrated to obtain a crude product of 5-bromo-2-isobutoxybenzoic acid (1.50 g).
(3) 1.50 g of the crude 5-bromo-2-isobutoxybenzoic acid obtained above is suspended in 20 mL of methylene chloride, 87.7 μM of thionyl chloride is added to the reaction mixture, and the mixture is stirred at room temperature under a nitrogen atmosphere. For 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product of 5-bromo-2-isobutoxybenzoyl chloride.
(4) N'-hydroxyethaneimidoamide prepared from acetonitrile and hydroxylamine monohydrate by suspending 291.6 mg of 5-bromo-2-isobutoxybenzoyl chloride obtained above in 2.0 mL of pyridine After adding 148.1 mg, the mixture was stirred at 100 ° C. for 3 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure, and the resulting crude product is separated and purified by silica gel column chromatography to give 5- (5-bromo-2-isobutoxyphenyl) -3-methyl. As a result, 79.3 mg of -1,2,4-oxadiazole was obtained.
^{ESI / MS m / e: 311.0,313.0} (M + + H, C 13 H 16 BrN 2 O 2).
(5) 31.1 mg of 5- (5-bromo-2-isobutoxyphenyl) -3-methyl-1,2,4-oxadiazole obtained above, 21 mg of potassium hydrogencarbonate, palladium (II) chloride 0.9 mg and 4.1 mg of copper (I) bromide were added and suspended in 1 mL of toluene. Thereafter, 37.5 mg of ethyl 4-methyl-1-1,3-thiazole-5-carboxylate, 1.9 μL of isobutyric acid and 4.6 mg of di-t-butylcyclohexylphosphine were added, and the reaction was performed at 120 ° C. under a nitrogen atmosphere. Heated for 8 hours. The reaction mixture was filtered through Celite to remove insolubles, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method. Ethyl 4-methyl-2- [4-isobutoxy-3- (3-methyl-1,2,4-oxadiazole- There were obtained 29.1 mg of 5-yl) phenyl] -1,3-thiazole-5-carboxylate.
^{ESI / MS m / e: 402.1} (M + + H, C 20 H 24 N 3 O 4 S)
(6) Ethyl 4-methyl-2- [4-isobutoxy-3- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] -1,3-thiazole-5-carboxylate 29 0.1 mg was dissolved in 1.0 mL of a mixed solution of tetrahydrofuran / methanol = 1/1, 0.2 mL of 2M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 0.2 mL of 2M hydrochloric acid, and 2 mL of water and 4 mL of ethyl acetate were added and stirred. The organic phase was concentrated and purified by a conventional method, and 2- [4-isobutoxy-3- (3-methyl- 17.7 mg of 1,2,4-oxadiazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid was obtained.
¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 1.03 (6H, d, J = 6.4 Hz), 2.06-2.12 (1H, m), 2.42 (3H, s), 2.66 (3H, s), 4.00 (2H, d, J = 6.4 Hz), 7.38 (1H, d, J = 8.8 Hz), 8.15 (1H, dd, J = 2.4, 8.8 Hz), 8.55 (1H, d, J = 2.0 Hz), 13.37 (1H, brs)
HPLC retention time: 12.76 minutes ^{Obs Mass (M + + H)} : 374.1156
Pred Mass (M ⁺ + H): 374.1169
Formula (M): C ₁₈ H ₁₉ N ₃ O ₄ S

[Example 149] Synthesis of 1- (4-isobutoxy-3-thiazol-5-yl-phenyl) -1H-pyrazole-4-carboxylic acid (Compound No. 149 ) (Synthesis Method H)
(1) 50 g of 4-hydroxy-bromobenzene and 17.3 g of sodium hydroxide were suspended in 200 mL of dimethylformamide, 66.2 g of isobutyl iodide was added under a nitrogen atmosphere, and the mixture was heated at 60 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method to obtain 34 g of 1-bromo-4-isobutoxybenzene.
(2) 20 g of 1-bromo-4-isobutoxybenzene is dissolved in 200 mL of toluene, and 12.0 g of potassium carbonate, 16.6 g of copper iodide, (1R, 2R) -1-N, 2-N-dimethylcyclohexane- 17.2-diamine 37.2g was added and it stirred at 120 degreeC for 10 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method to obtain 9.4 g of ethyl 1- (4-isobutoxyphenyl) -1H-pyrazole-4-carboxylate.
(3) 9.0 g of 1- (4-isobutoxyphenyl) -1H-pyrazole-4-carboxylate obtained above is suspended in 50 mL of acetic acid, 4.9 g of bromine is added to the reaction mixture, and nitrogen is added. The mixture was stirred at 60 ° C. for 5 hours under an atmosphere. The reaction mixture was concentrated under reduced pressure and extracted by adding a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method to obtain 9.7 g of ethyl 1- (3-bromo-4-isobutoxyphenyl) -1H-pyrazole-4-carboxylate. Got.
(4) 2.4 g of ethyl 1- (3-bromo-4-isobutoxyphenyl) -1H-pyrazole-4-carboxylate obtained above, 2.48 g of pinacol diborane, 1.26 g of potassium acetate, palladium chloride- 265 mg of 1,1′-bis (diphenylphosphino) ferrocene was added, suspended in 30 mL of 1,4-dioxane, and heated at 100 ° C. for 14 hours under a nitrogen atmosphere. Thereafter, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method to give ethyl 1- [4-isobutoxy-3- (4,4,5,5-tetramethyl-1,3, 1.4 g of 2-dioxaboran-2-yl) phenyl] -1H-pyrazole-4-carboxylate was obtained.
(5) Ethyl 1- [4-isobutoxy-3- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) phenyl] -1H-pyrazole-4 obtained above -To 200 mg of carboxylate, add 119 mg of 5-bromo-1,3-thiazole, 134 mg of potassium carbonate, 20 mg of palladium chloride-1,1'-bis (diphenylphosphino) ferrocene, and suspend in 3 mL of 1,4-dioxane and 1 mL of water. It was made turbid and heated at 100 ° C. for 14 hours under a nitrogen atmosphere. Thereafter, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to give crude ethyl 1- [4-isobutoxy-3- (1,3-thiazol-5-yl) phenyl] -1H-pyrazole-4-carboxylate. Got the body.
(6) The crude product of ethyl 1- [4-isobutoxy-3- (1,3-thiazol-5-yl) phenyl] -1H-pyrazole-4-carboxylate obtained above was tetrahydrofuran / methanol = 1 / It melt | dissolved in 4.0 mL of 1 mixed solutions, 0.5 mL of 2M sodium hydroxide aqueous solution was added, and it stirred at room temperature for 3 hours. To the reaction mixture, 0.5 mL of 2M hydrochloric acid was added, and 10 mL of water and 15 mL of ethyl acetate were added and stirred. The organic phase was concentrated and purified by a conventional method, and 1- [4-isobutoxy-3- (1,3- 15.8 mg of thiazol-5-yl) phenyl] -1H-pyrazole-4-carboxylic acid was obtained.
¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm): 1.07 (6H, d, J = 6.9 Hz), 2.13-2.27 (1H, m), 3.99 (2H, d, J = 6.6 Hz), 7.31 (1H, d, J = 9.0 Hz), 7.88 (1H, dd, J = 3.0, 9.0 Hz), 8.08 (1H, s) ), 8.33 (1H, d, J = 2.7 Hz), 8.64 (1H, s), 9.15 (2H, d, J = 3.9 Hz), 12.65 (1H, brs)
HPLC retention time: 10.61 minutes ^{Obs Mass (M + + H)} : 344.1051
Pred Mass (M ⁺ + H): 344.0106
Formula (M): C ₁₇ H ₁₇ N ₃ O ₃ S

[Examples 150-162]
In the same manner as in Example 149, Compound No. 150 - was synthesized 162.

[Example 163] Synthesis of 1- (4-isobutoxy-3-oxazol-5-yl-phenyl) -1H-pyrazole-4-carboxylic acid (Compound No. 163 ) (Synthesis Method I)
(1) 1.00 g of 5-bromosalicylaldehyde, 1.04 mg of potassium carbonate, and 1.03 mg of 2-methylpropyl bromide are suspended in 10.0 mL of N, N-dimethylformamide, and are suspended at 90 ° C. under a nitrogen atmosphere. Stir for hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain a crude product of 5-bromo-2-isobutoxybenzaldehyde.
(2) To the 5-bromo-2-isobutoxybenzaldehyde obtained above, 1.46 g of p-toluenesulfonylmethyl isocyanide and 1.04 g of potassium carbonate are added and suspended in 12.0 mL of ethanol. Heat at 13 ° C. for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure. The resulting crude product is separated and purified by silica gel column chromatography to give 5- (5-bromo-2-isobutoxyphenyl) -1,3. -574.0 mg of oxazole was obtained.
(3) 29.6 mg of 5- (5-bromo-2-isobutoxyphenyl) -1,3-oxazole obtained above, 16.8 mg of ethyl 4-pyrazolecarboxylate, 1.9 mg of copper (I) iodide , (1S, 2S)-(+)-N, N′dimethylcyclohexane-1,2-diamine (2.84 mg) and potassium carbonate (27.6 mg) were added, suspended in 0.5 mL of toluene, and 110 ° C. under a nitrogen atmosphere. For 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain a crude product of ethyl 1- [4-isobutoxy-3- (1,3-oxazol-5-yl) phenyl] -1H-pyrazole-4-carboxylate.
(4) Mixing ethyl 1- [4-isobutoxy-3- (1,3-oxazol-5-yl) phenyl] -1H-pyrazole-4-carboxylate obtained above in tetrahydrofuran / methanol = 1: 1 It melt | dissolved in 1.0 mL of solution, 2 M sodium hydroxide aqueous solution 250uL was added, and it stirred at room temperature for 2 hours. To the reaction mixture was added 2M hydrochloric acid (250 uL), water (2 mL) and ethyl acetate (2 mL) were added and stirred, and the organic phase was concentrated and purified by a conventional method to obtain 1- (4-isobutoxy-3-oxazol-5-yl- 19.7 mg of (phenyl) -1H-pyrazole-4-carboxylic acid was obtained.
¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 1.05 (6H, d, J = 6.4 Hz), 2.15 to 2.22 (1 H, m), 3.99 (2H, d, J = 6.4 Hz), 7.29 (1H, d, J = 8.8 Hz), 7.60 (1H, s), 7.88 (1H, d, J = 8.8 Hz), 8. 05 (1H, d, J = 1.2 Hz), 8.21 (1 H, d, J = 1.2 Hz), 8.50 (1 H, s), 9.01 (1 H, s), 12.61 ( 1H, brs)
HPLC retention time: 10.58 minutes ^{Obs Mass (M + + H)} : 328.1295
Pred Mass (M ⁺ + H): 328.1292
Formula (M): C ₁₇ H ₁₇ N ₃ O ₄

[Examples 164 to 166]
In the same manner as in Example 163, compound numbers 164 to 166 were synthesized.

Example 167 Synthesis of 2- [5-phenyl-4- (2H-tetrazol-5-yl) -2-pyridyl] -1,3-thiazole-5-carboxylic acid (Compound No. 167 ) (Synthesis Method J )
(1) Suspend 8.80 g of 5-bromo-2-chloropyridine-4-carbaldehyde, 5.36 g of phenylboronic acid and 11.06 g of potassium carbonate in 100 mL of a mixed solution of 1,4-dioxane / water = 4/1. The mixture was made turbid, tetrakis (triphenylphosphine) palladium (924 mg) was added, and the mixture was heated at 80 ° C. for 5 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain 10.80 g of 2-chloro-5-phenylpyridine-4-carbaldehyde.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.3-7.42 (2H, m), 7.50-7.60 (3H, m), 7.81 (1H, d, J = 0.6 Hz), 8.61 (1H, d, J = 0.6 Hz), 9.99 (1H, s)
ESI / MS m / e: 218.0, 220.0 (M ⁺ + H, C ₁₂ H ₉ ClNO)
(2) Suspend 10.80 g of 2-chloro-5-phenylpyridine-4-carbaldehyde, 5.56 g of hydroxylamine monohydrochloride and 5.44 g of sodium formate in 100 mL of formic acid, and add 12.2 g of acetic anhydride. The mixture was heated at 100 ° C. for 2 hours in a nitrogen atmosphere. 100 mL of water was added and the mixture was purified by a conventional method to obtain 6.34 g of 2-chloro-5-phenylpyridine-4-carbonitrile.
¹ H-NMR (400 MHz, CDCl ₃ ) δ (ppm): 7.27 (1H, s), 7.5-7.6 (4H, m), 7.67 (1H, s), 8.63 ( 1H, s)
ESI / MS m / e: 215.0, 217.0 (M ⁺ + H, C ₁₂ H ₈ ClN ₂ )
(3) To 3.02 g of 2-chloro-5-phenylpyridine-4-carbonitrile, 3.06 g of potassium hydrogen carbonate, 129 mg of palladium (II) chloride and 598 mg of copper (I) bromide were added, and suspended in 40 mL of toluene. I let you. Thereafter, 3.43 g of ethyl 1,3-thiazole-5-carboxylate, 269 μL of isobutyric acid and 664 mg of di-t-butylcyclohexylphosphine were added, followed by heating at 120 ° C. for 6 hours in a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove insolubles, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method to obtain ethyl 2- (4-cyano-5-phenylpyridin-2-yl) -1,3-thiazole-5-carboxylate 2 .92 g was obtained.
^{ESI / MS m / e: 336.0} (M + + H, C 18 H 14 N 3 O 2 S)
¹ H-NMR (400 MHz, DMSO d6) δ (ppm): 1.33 (3H, t, J = 6.8 Hz), 4.35 (2H, q, J = 6.8 Hz), 7.58-7 .63 (3H, m), 7.73-7.76 (2H, m), 8.60 (1H, s), 8.65 (1H, s), 9.03 (1H, s)
(4) The obtained ethyl 2- (4-cyano-5-phenylpyridin-2-yl) -1,3-thiazole-5-carboxylate was treated in the same manner as in Example 84 to give 2- [5-phenyl- 4- (2H-tetrazol-5-yl) -2-pyridyl] -1,3-thiazole-5-carboxylic acid was obtained.
HPLC retention time: 8.92 minutes Obs Mass (M ⁺ + H): 351.0669
Pred Mass (M ⁺ + H): 351.0659
Formula (M): C ₁₆ H ₁₀ N ₆ O ₂ S

[Example 168]
Compound No. 168 was synthesized in the same manner as Example 167.

Example 169 Synthesis of 2- (4-oxazol-5-yl-5-phenyl-2-pyridyl) -1,3-thiazole-5-carboxylic acid (Compound No. 169 ) (Synthesis Method K)
(1) To 312 mg of 2-chloro-5-phenylpyridine-4-carbaldehyde obtained in Example 167, 306 mg of potassium bicarbonate, 12.9 mg of palladium (II) chloride, and 59.8 mg of copper (I) bromide were added. In addition, it was suspended in 4.0 mL of toluene. Thereafter, 343 mg of ethyl 1,3-thiazole-5-carboxylate, 26.9 μL of isobutyric acid and 66.4 mg of di-t-butylcyclohexylphosphine were added, and the mixture was heated at 120 ° C. for 6 hours in a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove insolubles, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method to obtain ethyl 2- (4-formyl-5-phenylpyridin-2-yl) -1,3-thiazole-5-carboxylate. A crude product was obtained.
(2) The crude product of ethyl 2- (4-formyl-5-phenylpyridin-2-yl) -1,3-thiazole-5-carboxylate obtained above was suspended in 1.5 mL of methanol, and p. -Toluenesulfonylmethyl isocyanide (117.1 mg) and potassium carbonate (110.6 mg) were added, and the mixture was heated at 80 ° C for 4 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure, and the resulting crude product is separated and purified by silica gel column chromatography to obtain ethyl 2- [4- (1,3, -oxazol-5-yl). ) -5-Phenylpyridin-2-yl] -1,3-thiazole-5-carboxylate was obtained.
(3) Crude product of ethyl 2- [4- (1,3, -oxazol-5-yl) -5-phenylpyridin-2-yl] -1,3-thiazole-5-carboxylate obtained above Was dissolved in 2.0 mL of a mixed solution of tetrahydrofuran / methanol = 1/1, 0.6 mL of 2M aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with 0.6 mL of 2M hydrochloric acid, concentrated under reduced pressure, and purified by a conventional method. After washing with 50 mL of water and 20 mL of hexane / ethyl acetate = 1/1 mixed solvent, it was dried under reduced pressure to give 2- (4-oxazol-5-yl-5-phenyl-2-pyridyl) -1,3-thiazole- 6.7 mg of 5-carboxylic acid was obtained.
¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 6.57 (1H, s), 7.40-7.44 (2H, s), 7.52 to 7.55 (3H, m) , 8.48 (1H, s), 8.52 (2H, d, J = 1.2 Hz), 8.64 (1H, s), 13.74 (1H, s)
HPLC retention time: 10.67 minutes ^{Obs Mass (M + + H)} : 350.0586
Pred Mass (M ⁺ + H): 350.0594
Formula (M): C ₁₈ H ₁₁ N ₃ O ₃ S

[Example 170]
Compound No. 170 was synthesized in the same manner as Example 169.

[Example 171] Synthesis of 2- (5-isobutoxy-4-oxazol-5-yl-2-pyridyl) -4-methyl-1,3-thiazole-5-carboxylic acid (Compound No. 171 ) (Synthesis Method K) )
(1) 1.30 g of 2-chloro-5-hydroxypyridine and 4.89 g of cesium carbonate are suspended in 20 mL of N, N-dimethylformamide, 2.06 g of isobutyl bromide is added, and 4% at 40 ° C. under a nitrogen atmosphere. Heated for hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain 1.73 g of 2-chloro-5-isobutoxypyridine.
(2) Dissolve 1.73 g of 2-chloro-5-isobutoxypyridine obtained above in 50 mL of tetrahydrofuran, add 2.01 mL of tetramethylethylenediamine (TMEDA) under nitrogen atmosphere, and cool to −78 ° C. did. To the solution, 7.0 mL of 1.6 M n-butyllithium hexane solution was slowly added dropwise and stirred for 3 hours, and then 691 μL of methyl formate was added dropwise and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure. The resulting crude product is separated and purified by silica gel column chromatography to obtain 366 mg of 2-chloro-5-isobutoxypyridine-4-carbaldehyde. Obtained.
(3) In the same manner as in Example 169, 2- (5-isobutoxy-4-oxazol-5-yl-2-pyridyl) was obtained in the same manner as in Example 169. ) -4-Methyl-1,3-thiazole-5-carboxylic acid was obtained.
¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 1.05 (6H, d, J = 7.2 Hz), 2.18-2.24 (1H, m), 2.67 (3H, s), 4.07 (2H, d, J = 6.4 Hz), 7.76-7.79 (2H, m), 8.10 (1H, dd, J = 4.0, 8.0 Hz), 8.06 (1H, s)
HPLC retention time: 11.35 minutes Obs Mass (M ⁺ + H): 360.1010
Pred Mass (M ⁺ + H): 360.0103
_{_{Formula (M): C 17 H}} 17 N 3 O 4 S

Example 172 Synthesis of 2- (5-isobutoxy-4-pyrimidin-5-yl-2-pyridyl) -4-methyl-1,3-thiazole-5-carboxylic acid (Compound No. 172 ) (Synthesis Method L )
(1) 5.0 g of 5-hydroxy-2-methylpyridine was suspended in 50 mL of tetrahydrofuran, and 2.4 g of sodium hydride was added little by little at 0 ° C. in a nitrogen atmosphere. After stirring at 0 ° C. for 1 hour, 4.43 g of methoxymethyl chloride was added dropwise, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography to obtain 5.6 g of 5- (methoxymethoxy) -2-methylpyridine. .
(2) 5.6 g of 5- (methoxymethoxy) -2-methylpyridine is suspended in 50 mL of tetrahydrofuran, and 27.42 mL of 1.6 M t-butyllithium hexane solution is slowly added dropwise at −78 ° C. in a nitrogen atmosphere. Then, after stirring for 1 hour, 18.20 g of carbon tetrabromide was added dropwise and allowed to stir at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure, and the resulting crude product is separated and purified by silica gel column chromatography to give 4-bromo-5- (methoxymethoxy) -2-methylpyridine. 1 g was obtained.
(3) Suspend 5.1 g of 4-bromo-5- (methoxymethoxy) -2-methylpyridine in 50 mL of methylene chloride, add 3.76 g of trifluoromethylacetic acid at room temperature under a nitrogen atmosphere, and stir overnight. It was. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure. The resulting crude product is separated and purified by silica gel column chromatography to obtain 2.8 g of 4-bromo-5-hydroxy-2-methylpyridine. It was.
(4) 2.8 g of 4-bromo-5-hydroxy-2-methylpyridine and 3.07 g of potassium carbonate are suspended in 40 mL of N, N-dimethylformamide, and 3.06 g of isobutyl bromide is added. Heated at 110 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure. The resulting crude product is separated and purified by silica gel column chromatography to obtain 2.7 g of 4-bromo-5-isobutoxy-2-methylpyridine. It was.
(5) 2.7 g of 4-bromo-5-isobutoxy-2-methylpyridine was suspended in 20 mL of water, 3.48 g of potassium permanganate was added, and the mixture was stirred at 80 ° C. overnight under a nitrogen atmosphere. The reaction mixture was acidified with 2M hydrochloric acid, 2M aqueous sodium hydroxide solution and methylene chloride were added and separated, and the aqueous layer was acidified again with 2M hydrochloric acid to give 4-bromo-5-isobutoxypyridine- 1.3 g of 2-carboxylic acid was obtained.
(6) Suspend 1.3 g of 4-bromo-5-isobutoxypyridine-2-carboxylic acid in 10 mL of N, N-dimethylformamide, add 722 mg of oxalyl chloride, and stir at room temperature for 2 hours in a nitrogen atmosphere. After that, 20 mL of methylene chloride was added, and aqueous ammonia was added dropwise at 0 ° C. The reaction mixture was allowed to stir at room temperature for 1 hour, saturated layered water was added, and the mixture was extracted with methylene chloride. The organic layer is washed with brine, dried and concentrated under reduced pressure. The resulting crude product is separated and purified by silica gel column chromatography to give 1.1 g of 4-bromo-5-isobutoxypyridine-2-carboxamide. Got.
(7) Suspend 1.5 g of 4-bromo-5-isobutoxypyridine-2-carboxamide in 20 mL of tetrahydrofuran, add 2.89 g of triphenylphosphine and 1.35 g of diisopropylethylamine, and add 50 ° C. under a nitrogen atmosphere. And allowed to stir overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure. The resulting crude product is separated and purified by silica gel column chromatography to obtain 1.2 g of 4-bromo-5-isobutoxypyridine-2-carbonitrile. Got.
(8) 200 mg of 4-bromo-5-isobutoxypyridine-2-carbonitrile, 146 mg of pyrimidine-5-boronic acid and 217 mg of potassium carbonate are suspended in 2.0 mL of a mixed solution of 1,4-dioxane / water = 4/1. The mixture was made turbid, 45 mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was heated at 100 ° C. for 12 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method to obtain 85 mg of 5-isobutoxy-4- (pyrimidin-5-yl) pyridine-2-carbonitrile.
(9) 85 mg of 5-isobutoxy-4- (pyrimidin-5-yl) pyridine-2-carbonitrile was suspended in 2.0 mL of ethanol, hydrogen sulfide gas was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method to obtain 70 mg of 5-isobutoxy-4- (pyrimidin-5-yl) pyridine-2-carbothioamide.
(10) 70 mg of 5-isobutoxy-4- (pyrimidin-5-yl) pyridine-2-carbothioamide is suspended in 2.0 mL of ethanol, 60.0 mg of ethyl-2-chloroacetoacetate is added, and under a nitrogen atmosphere, Heated at 80 ° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method to give ethyl 4-methyl-2- [5-isobutoxy-4- (pyrimidin-5-yl) pyridin-2-yl. ] 65 mg of 1,3-thiazole-5-carboxylate was obtained.
(11) 65 mg of ethyl 4-methyl-2- [5-isobutoxy-4- (pyrimidin-5-yl) pyridin-2-yl] -1,3-thiazole-5-carboxylate was added to tetrahydrofuran / methanol = 1/1. Was dissolved in 2.0 mL of a mixed solution, and 0.6 mL of 2M aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture was added 0.6 mL of 2M hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method to give 2- (5-isobutoxy-4-pyrimidin-5-yl-2-pyridyl) -4-methyl-1, 30.6 mg of 3-thiazole-5-carboxylic acid was obtained.
¹ H-NMR (300 MHz, DMSO d ₆ ) δ (ppm): 0.98 (6H, d, J = 6.6 Hz), 2.01-2.12 (1H, m), 2.74 (3H, s), 4.12 (2H, d, J = 6.3 Hz), 8.25 (1H, s), 8.68 (1H, s), 9.17 (2H, s), 9.32 (1H) , S), 13.41 (1H, brs)
HPLC retention time: 10.66 minutes ^{Obs Mass (M + + H)} : 371.1160
Pred Mass (M ⁺ + H): 371.1172
Formula (M): C ₁₈ H ₁₈ N ₄ O ₃ S

[Examples 173 and 174]
In the same manner as in Example 172, compound numbers 173 and 174 were synthesized.

Example 175 Synthesis of 1- (5-isobutoxy-4-oxazol-5-yl-2-pyridyl) -1H-pyrazole-4-carboxylic acid (Compound No. 175 ) (Synthesis Method M)
(1) 2-Bromo-5-isobutoxypyridine-4-carbaldehyde was obtained from 2-bromo-5-hydroxypyridine in the same manner as in Example 171.
(2) 103 g of 2-bromo-5-isobutoxypyridine-4-carbaldehyde was suspended in 2.0 mL of ethanol, 117.1 mg of p-toluenesulfonylmethyl isocyanide and 82.9 mg of potassium carbonate were added, and under a nitrogen atmosphere, Heated at 80 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to give a crude product of 2-bromo-5-isobutoxy-4- (1,3-oxazol-5-yl) pyridine.
(3) 119 mg of the crude 2-bromo-5-isobutoxy-4- (1,3-oxazol-5-yl) pyridine obtained above was added to 84.1 mg of ethyl 4-pyrazolecarboxylate and copper iodide (I ) 11.4 mg, (1S, 2S)-(+)-N, N′-dimethylcyclohexane-1,2-diamine (17.1 mg) and potassium carbonate (110.6 mg) are added, suspended in 1.6 mL of toluene, and nitrogen is added. The mixture was stirred at 110 ° C. for 13 hours under an atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with brine, dried, concentrated under reduced pressure, and purified by a conventional method to give ethyl 1- [5-isobutoxy-4- (1,3-oxazol-5-yl) pyridin-2-yl ] -1 H-pyrazole-4-carboxylate 31 mg was obtained.
(4) 31 mg of ethyl 1- [5-isobutoxy-4- (1,3-oxazol-5-yl) pyridin-2-yl] -1H-pyrazole-4-carboxylate obtained above was added to tetrahydrofuran / methanol = It melt | dissolved in 1.0 mL of 1: 1 mixed solution, 2 M sodium hydroxide aqueous solution 250uL was added, and it stirred at room temperature for 3 hours. To the reaction mixture was added 2M hydrochloric acid (250 uL), water (2 mL) and ethyl acetate (2 mL) were added and stirred, and the organic phase was concentrated and purified by a conventional method to obtain 1- (5-isobutoxy-4-oxazol-5-yl- 11.9 mg of 2-pyridyl) -1H-pyrazole-4-carboxylic acid was obtained.
¹ H-NMR (400 MHz, DMSO d ₆ ) δ (ppm): 1.06 (6H, d, J = 6.8 Hz), 2.19-2.25 (1H, m), 4.14 (2H, d, J = 6.4 Hz), 7.79 (1H, s), 8.13 (1H, s), 8, 17 (1H, s), 8.43 (1H, s), 8.67 (1H) , S), 8.84 (1H, s), 12.74 (1H, brs)
HPLC retention time: 10.61 minutes ^{Obs Mass (M + + H)} : 329.1235
Pred Mass (M ⁺ + H): 329.1244
Formula (M): C ₁₆ H ₁₆ N ₄ O ₄

[Example 176]
About the compound synthesize | combined according to the method of the above Example, the xanthine oxidase inhibitory activity was measured.
(1) Preparation of test compound A test compound was dissolved in DMSO (manufactured by Sigma) so as to have a concentration of 20 mM, and then adjusted to a target concentration at the time of use.
(2) Measurement method The xanthine oxidase inhibitory activity of the compounds of the present invention was evaluated by partially modifying the method described in the literature (Method Enzymatic Analysis, 1,521-522, 1974). This evaluation is based on the evaluation of oxidase type xanthine oxidase inhibitory activity. That is, a xanthine (manufactured by Sigma) solution prepared to 10 mM in a 20 mM sodium hydroxide solution in advance was prepared to 30 μM using a 100 mM phosphate buffer, and 75 μL / well was added to a 96-well plate. Each test compound diluted with DMSO to a final concentration of 100 times was added at 1.5 μL / well, and after mixing, the absorbance at 290 nm was measured with a microplate reader SPECTRA max Plus 384 (manufactured by Molecular Devices). Subsequently, oxidase-type xanthine oxidase (derived from buttermilk, Calbiochem) was prepared to 30.6 mU / mL using 100 mM phosphate buffer, and 73.5 μL / well was added. Immediately after mixing, the change in absorbance at 290 nm was measured for 5 minutes. The inhibition rate of the test compound was calculated by setting the enzyme activity when DMSO was added instead of the test compound solution as 100%, and a 50% inhibitory concentration against the oxidase type xanthine oxidase was calculated by fitting to a dose response curve.
The results are shown in the following table. However, the symbols (+, ++, ++) in the table represent the inhibitory activity values as follows.
10.0 nM ≦ IC ₅₀ : +
5.0 nM ≦ IC ₅₀ <10.0 nM: ++
1.0 nM ≦ IC ₅₀ <5.0 nM: +++

[Example 177]
Blood uric acid lowering effect (normal rat)
The compounds Nos. 6 , 67 and 86 were confirmed to have a blood uric acid lowering effect. Test compounds suspended in 0.5% methylcellulose solution were forcibly administered to male Sprague-Dawley rats (Charles River Japan Co., Ltd.) 8-9 weeks old using an oral sonde. Two hours after administration, blood was collected from the tail vein, and plasma was separated. The blood uric acid level was measured using a uric acid measurement kit (L type Wako UA • F: Wako Pure Chemical Industries) with an absorptiometer by the uricase method, and the uric acid reduction rate was determined by the following equation.
Uric acid reduction rate (%) = (Uric acid level of control animals−Uric acid level of animals receiving test compound) × 100 / Uric acid level of control animals Compound Nos. 6 , 67 and 86 were administered at a dose of 10 mg / kg at 2 hours after administration. The uric acid reduction rate was 50% or more. As described above, the strong uric acid lowering action of the compound of the present invention was shown.

The compound represented by the above formula (I) of the present invention and a pharmaceutically acceptable salt thereof have xanthine oxidase inhibitory activity and are clinically applicable as xanthine oxidase inhibitors. Respiratory organs such as uricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and heart failure, renal diseases such as diabetic nephropathy, chronic obstructive pulmonary disease It can be used as a therapeutic or prophylactic agent for diseases involving xanthine oxidase such as diseases, inflammatory bowel diseases or autoimmune diseases.

Claims

A compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[Where:
R 0 represents the following R 01 or R 02 .

R 1 represents one or a plurality of alkyl groups having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group optionally substituted with a halogen atom, OR, or NRR ′ which may form a ring. Or SR, wherein R and R ′ are each independently a hydrogen atom, one or more alkoxy groups having 1 to 8 carbon atoms, a halogen atom or a hydroxyl group optionally substituted with a hydroxyl group. 1 or a plurality of alkyl groups having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group optionally substituted with a halogen atom or a cyano group, or one or more carbon atoms having 1 to 6 carbon atoms 6 represents an alkyl group having 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a heteroaryl group optionally substituted with a halogen atom.
R 2 represents a hydrogen atom, an amino group, or an alkyl group having 1 to 8 carbon atoms which may be substituted with one or more halogen atoms.
X 1 represents CR 3 or a nitrogen atom, wherein R 3 represents a hydrogen atom or a halogen atom.
Ring A is an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more alkoxy groups having 1 to 3 carbon atoms or a halogen atom, and the number of carbons which may be substituted with one or more halogen atoms. It represents a 5- or 6-membered monocyclic heteroarene which may be substituted with 1 to 6 alkoxy groups and 1 to 4 groups selected from the group consisting of halogen atoms. ]
The heteroarene in ring A is

The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X 1 is CR 3 and R 3 is a hydrogen atom or a fluorine atom.
X 1 is a nitrogen atom, a compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2 wherein.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 0 is R 01 .
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 2 is a methyl group.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 2 is a hydrogen atom.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 0 is R 02 .
The compound or a pharmaceutically acceptable salt thereof according to claim 8, wherein R 2 is a hydrogen atom or an amino group.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 1 is OR.
11. The compound according to claim 10 or a pharmaceutically acceptable compound thereof, wherein R is one or more alkoxy groups having 1 to 8 carbon atoms or an alkyl group having 1 to 8 carbon atoms which may be substituted with a halogen atom. salt.
The compound according to claim 10, wherein R is an aryl group optionally substituted by one or more alkyl groups having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom or a cyano group, or a pharmaceutical thereof A chemically acceptable salt.
The R 1 is one or more alkyl groups having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, or an aryl group optionally substituted with a halogen atom. A compound or a pharmaceutically acceptable salt thereof.
Any compound selected from the following (1) to (175) or a pharmaceutically acceptable salt thereof:
(1) 2- [4-Isobutoxy-3- (2-pyridyl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(2) 2- [4-Isobutoxy-3- (3-pyridyl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(3) 2- [4-Isobutoxy-3- (4-pyridyl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(4) 2- (4-Isobutoxy-3-thiazol-2-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylic acid
(5) 2- (4-Isobutoxy-3-thiazol-4-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylic acid
(6) 2- (4-Isobutoxy-3-thiazol-5-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylic acid
(7) 2- (4-Isobutoxy-3-pyrazin-2-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylic acid
(8) 2- [4-Isobutoxy-3- (3-thienyl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(9) 2- [3- (3-Furyl) -4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(10) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(11) 2- [4- (2,2-dimethylpropoxy) -3-thiazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(12) 2- [4- (Cyclobutylmethoxy) -3-thiazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(13) 2- [4- (Cyclopentylmethoxy) -3-thiazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(14) 2- [4- (Cyclopentoxy) -3-thiazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(15) 2- [4- (Cyclohexaoxy) -3-thiazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(16) 2- [3- (3-Furyl) -4-phenoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(17) 2- [4- (2-Fluorophenoxy) -3- (3-furyl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(18) 2- (4-Isobutoxy-3-isothiazol-4-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylic acid
(19) 2- [4-Isobutoxy-3- (1,3,4-thiadiazol-2-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(20) 2- (4-Isobutoxy-3-isoxazol-4-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylic acid
(21) 2- [4-Isobutoxy-3- (1H-pyrazol-4-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(22) 2- [4-Isobutoxy-3- (3-methyl-1H-pyrazol-4-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(23) 2- [3- (1H-imidazol-4-yl) -4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(24) 2- [4-Isobutoxy-3- (3-methylimidazol-4-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(25) 2- [4-Isobutoxy-3- (1-methylpyrazol-4-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(26) 2- (4-Isobutoxy-3-pyrimidin-5-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylic acid
(27) 2- [4-Isobutoxy-3- (2-methylthiazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(28) 2- [3- (1,2-Dimethylimidazol-4-yl) -4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(29) 2- [3- (2,3-Dimethylimidazol-4-yl) -4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(30) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4- (2,2-dimethylpropoxy) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(31) 2- [4- (Cyclopentylmethoxy) -3- (3,5-dimethylisoxazol-4-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(32) 2- [4- (Cyclopentoxy) -3- (3,5-dimethylisoxazol-4-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(33) 2- [4- (Cyclohexaoxy) -3- (3,5-dimethylisoxazol-4-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(34) 2- [4- (2,2-difluoroethoxy) -3- (3,5-dimethylisoxazol-4-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(35) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4-isopropoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(36) 2- (4-Isopropoxy-3-pyrimidin-5-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylic acid
(37) 2- [4- (2,2-Dimethylpropoxy) -3-pyrimidin-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(38) 2- [4- (2,2-Difluoroethoxy) -3-pyrimidin-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(39) 4-Methyl-2- (4-phenoxy-3-pyrimidin-5-yl-phenyl) -1,3-thiazole-5-carboxylic acid
(40) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4-phenoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(41) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4- (2-fluorophenoxy) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(42) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4- (2-methoxyphenoxy) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(43) 2- [4- (2,6-Difluorophenoxy) -3- (3,5-dimethylisoxazol-4-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(44) 4-Methyl-2- [4- (2-methylphenoxy) -3-pyrimidin-5-yl-phenyl] -1,3-thiazole-5-carboxylic acid
(45) 2- [4- (2-Fluorophenoxy) -3-pyrimidin-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(46) 2- [4- (2-Fluoro-5-methylphenoxy) -3-pyrimidin-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(47) 2- [4- (2,5-Difluorophenoxy) -3-pyrimidin-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(48) 2- [4- (2,6-Difluorophenoxy) -3-pyrimidin-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(49) 4-Methyl-2- [4-phenoxy-3- (3-pyridyl) phenyl] -1,3-thiazole-5-carboxylic acid
(50) 4-Methyl-2- [4-phenoxy-3- (4-pyridyl) phenyl] -1,3-thiazole-5-carboxylic acid
(51) 4-Methyl-2- (4-phenoxy-3-thiazol-5-yl-phenyl) -1,3-thiazole-5-carboxylic acid
(52) 2- [4- (2,2-difluoroethoxy) -3-thiazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(53) 4-Methyl-2- [3-thiazol-5-yl-4- (2,2,2-trifluoroethoxy) phenyl] -1,3-thiazole-5-carboxylic acid
(54) 4-Methyl-2- [4-[(3R) -tetrahydrofuran-3-yl] oxy-3-thiazol-5-yl-phenyl] -1,3-thiazole-5-carboxylic acid
(55) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4- (3-fluorophenoxy) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(56) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4- (2-methylphenoxy) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(57) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4- (3-methylphenoxy) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(58) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4- (4-methylphenoxy) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(59) 2- [4- (2-Chlorophenoxy) -3- (3,5-dimethylisoxazol-4-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(60) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4- (4-fluoro-3-methylphenoxy) phenyl] -4-methyl-1,3-thiazole-5-carvone acid
(61) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4- (4-fluoro-2-methylphenoxy) phenyl] -4-methyl-1,3-thiazole-5-carvone acid
(62) 2- [4- (2,4-Difluorophenoxy) -3- (3,5-dimethylisoxazol-4-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(63) 2- [4- (2,5-difluorophenoxy) -3- (3,5-dimethylisoxazol-4-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(64) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4- (2-fluoro-5-methylphenoxy) phenyl] -4-methyl-1,3-thiazole-5-carvone acid
(65) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4- (3-fluoro-5-methylphenoxy) phenyl] -4-methyl-1,3-thiazole-5-carvone acid
(66) 2- [3- (3,5-Dimethylisoxazol-4-yl) -4- (2-fluoro-6-methoxyphenoxy) phenyl] -4-methyl-1,3-thiazole-5-carbon acid
(67) 2- (4-Isobutoxy-3-oxazol-5-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylic acid
(68) 2- (2-Fluoro-4-isobutoxy-5-oxazol-5-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylic acid
(69) 2- [4- (Cyclobutylmethoxy) -3-oxazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(70) 2- [4- (Cyclopentylmethoxy) -3-oxazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(71) 2- [4- (Cyclobutoxy) -3-oxazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(72) 2- [4- (Cyclopentoxy) -3-oxazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(73) 2- [4- (Cyclopropylmethoxy) -3-oxazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(74) 4-Methyl-2- [4-[(1R) -1-methylpropoxy] -3-oxazol-5-yl-phenyl] -1,3-thiazole-5-carboxylic acid
(75) 2- [4- (2,2-difluoroethoxy) -3-oxazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(76) 4-Methyl-2- [3-oxazol-5-yl-4-[(3R) -tetrahydrofuran-3-yl] oxyphenyl] -1,3-thiazole-5-carboxylic acid
(77) 2- [4-[(1R, 2R) -2-Fluorocyclohexaoxy] -3-oxazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(78) 2- [4- (1-Cyclopropylethoxy) -3-oxazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(79) 2- [4- (1,2-Dimethylpropoxy) -3-oxazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(80) 4-Methyl-2- [4-[(2-methylcyclopropyl) methoxy] -3-oxazol-5-yl-phenyl] -1,3-thiazole-5-carboxylic acid
(81) 2- [4- (2,2-Dimethylpropoxy) -3-oxazol-5-yl-phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(82) 4-Methyl-2- [4-[(3-methyloxetan-3-yl) methoxy] -3-oxazol-5-yl-phenyl] -1,3-thiazole-5-carboxylic acid
(83) 2- [4-Isobutoxy-3- (4-methyloxazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(84) 2- [4-Isobutoxy-3- (1H-tetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(85) 2- [4-Isobutoxy-3- (2H-tetrazol-5-yl) phenyl] -1,3-thiazole-5-carboxylic acid
(86) 2- [4-Isobutoxy-3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(87) 2- [4-Isobutoxy-3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(88) 2- [3- (2-Ethyltetrazol-5-yl) -4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(89) 2- [3- (1-Ethyltetrazol-5-yl) -4-isobutoxyphenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(90) 2- [4- (2,2-Dimethylpropoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(91) 4-Methyl-2- [4-[(1R) -1-methylpropoxy] -3- (1-methyltetrazol-5-yl) phenyl] -1,3-thiazole-5-carboxylic acid
(92) 4-Methyl-2- [4-[(1S) -1-methylpropoxy] -3- (1-methyltetrazol-5-yl) phenyl] -1,3-thiazole-5-carboxylic acid
(93) 2- [4- (Cyclobutylmethoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(94) 2- [4- (Cyclopentylmethoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(95) 2- [4- (Cyclopentoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(96) 2- [4- (Cyclohexaoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(97) 2- [4- (2,2-Dimethylpropoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(98) 4-Methyl-2- [4-[(1R) -1-methylpropoxy] -3- (2-methyltetrazol-5-yl) phenyl] -1,3-thiazole-5-carboxylic acid
(99) 4-Methyl-2- [4-[(1S) -1-methylpropoxy] -3- (2-methyltetrazol-5-yl) phenyl] -1,3-thiazole-5-carboxylic acid
(100) 2- [4- (Cyclobutylmethoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(101) 2- [4- (Cyclopentylmethoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(102) 2- [4- (Cyclopentoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(103) 2- [4- (Cyclohexaoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(104) 2- [2-Fluoro-4-isobutoxy-5- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(105) 2- [2-Fluoro-4-isobutoxy-5- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(106) 4-Methyl-2- [3- (1-methyltetrazol-5-yl) -4-phenoxyphenyl] -1,3-thiazole-5-carboxylic acid
(107) 4-Methyl-2- [3- (2-methyltetrazol-5-yl) -4-phenoxyphenyl] -1,3-thiazole-5-carboxylic acid
(108) 2- [4- (2-methoxyphenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(109) 2- [4- (2-Fluorophenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(110) 4-Methyl-2- [4- (4-methylphenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -1,3-thiazole-5-carboxylic acid
(111) 2- [4- (2,5-Difluorophenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(112) 2- [4- (2-Fluoro-5-methylphenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(113) 2- [4- (3-Fluoro-5-methylphenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(114) 2- [4- (2-Fluoro-6-methoxyphenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(115) 2- [4- (2-Fluorophenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(116) 4-Methyl-2- [4- (3-methylphenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -1,3-thiazole-5-carboxylic acid
(117) 4-Methyl-2- [4- (4-methylphenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -1,3-thiazole-5-carboxylic acid
(118) 2- [4- (2,5-difluorophenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(119) 2- [4- (2-Fluoro-5-methylphenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(120) 2- [4- (3-Fluoro-5-methylphenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(121) 2- [4- (2-Fluoro-6-methoxyphenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(122) 2- [4- (3-Fluorophenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(123) 4-Methyl-2- [4- (2-methylphenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -1,3-thiazole-5-carboxylic acid
(124) 4-Methyl-2- [4- (3-methylphenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -1,3-thiazole-5-carboxylic acid
(125) 2- [4- (2-Chlorophenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(126) 2- [4- (4-Fluoro-3-methylphenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(127) 2- [4- (4-Fluoro-2-methoxyphenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(128) 2- [4- (4-Fluoro-2-methylphenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(129) 2- [4- (2,4-Difluorophenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(130) 2- [4- (2,6-Difluorophenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(131) 2- [4- (2-Methoxyphenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(132) 2- [4- (3-Fluorophenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(133) 4-Methyl-2- [4- (2-methylphenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -1,3-thiazole-5-carboxylic acid
(134) 2- [4- (2-Chlorophenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(135) 2- [4- (4-Fluoro-3-methylphenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(136) 2- [4- (4-Fluoro-2-methoxyphenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(137) 2- [4- (4-Fluoro-2-methylphenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(138) 2- [4- (2,4-Difluorophenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(139) 2- [4- (2,6-Difluorophenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(140) 2- [4- (2-Cyanophenoxy) -3- (1-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(141) 2- [4- (2-Cyanophenoxy) -3- (2-methyltetrazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(142) 4-Methyl-2- [3- (1-methyltetrazol-5-yl) -4-phenylphenyl] -1,3-thiazole-5-carboxylic acid
(143) 4-Methyl-2- [3- (2-methyltetrazol-5-yl) -4-phenylphenyl] -1,3-thiazole-5-carboxylic acid
(144) 2- [4-Isobutoxy-3- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(145) 2- (4-Isobutoxy-3-isoxazol-3-yl-phenyl) -4-methyl-1,3-thiazole-5-carboxylic acid
(146) 2- [4-Isobutoxy-3- [5- (methoxymethyl) isoxazol-3-yl] phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(147) 2- [4-Isobutoxy-3- (1,2,4-oxadiazol-3-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(148) 2- [4-Isobutoxy-3- (3-methyl-1,2,4-oxadiazol-5-yl) phenyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(149) 1- (4-Isobutoxy-3-thiazol-5-yl-phenyl) -1H-pyrazole-4-carboxylic acid
(150) 3-Amino-1- (4-isobutoxy-3-thiazol-5-yl-phenyl) -1H-pyrazole-4-carboxylic acid
(151) 1- [4-Isobutoxy-3- (2-methylthiazol-5-yl) phenyl] -1H-pyrazole-4-carboxylic acid
(152) 1- (4-Isobutoxy-3-isothiazol-4-yl-phenyl) -1H-pyrazole-4-carboxylic acid
(153) 3-Amino-1- (4-isobutoxy-3-isothiazol-4-yl-phenyl) -1H-pyrazole-4-carboxylic acid
(154) 1- [4-Isobutoxy-3- (1,3,4-thiadiazol-2-yl) phenyl] -1H-pyrazole-4-carboxylic acid
(155) 1- [3- (3,5-Dimethylisoxazol-4-yl) -4-isobutoxy-phenyl] -1H-pyrazole-4-carboxylic acid
(156) 1- (4-Isobutoxy-3-pyrimidin-5-yl-phenyl) -1H-pyrazole-4-carboxylic acid
(157) 3-Amino-1- (4-isobutoxy-3-pyrimidin-5-yl-phenyl) -1H-pyrazole-4-carboxylic acid
(158) 3-Amino-1- [4-isobutoxy-3- (2-methylthiazol-5-yl) phenyl] -1H-pyrazole-4-carboxylic acid
(159) 3-Amino-1- [4-isobutoxy-3- (1,3,4-thiadiazol-2-yl) phenyl] -1H-pyrazole-4-carboxylic acid
(160) 3-Amino-1- [3- (3,5-dimethylisoxazol-4-yl) -4-isobutoxyphenyl] -1H-pyrazole-4-carboxylic acid
(161) 1- (4-Isobutoxy-3-isoxazol-4-yl-phenyl) -1H-pyrazole-4-carboxylic acid
(162) 3-Amino-1- (4-isobutoxy-3-isoxazol-4-yl-phenyl) -1H-pyrazole-4-carboxylic acid
(163) 1- (4-Isobutoxy-3-oxazol-5-yl-phenyl) -1H-pyrazole-4-carboxylic acid
(164) 1- (4-Isobutoxy-3-oxazol-5-yl-phenyl) -3-methyl-1H-pyrazole-4-carboxylic acid
(165) 3-Amino-1- (4-isobutoxy-3-oxazol-5-yl-phenyl) -1H-pyrazole-4-carboxylic acid
(166) 1- (4-Isobutoxy-3-oxazol-5-yl-phenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid
(167) 2- [5-Phenyl-4- (2H-tetrazol-5-yl) -2-pyridyl] -1,3-thiazole-5-carboxylic acid
(168) 4-Methyl-2- [5-phenyl-4- (2H-tetrazol-5-yl) -2-pyridyl] -1,3-thiazole-5-carboxylic acid
(169) 2- (4-Oxazol-5-yl-5-phenyl-2-pyridyl) -1,3-thiazole-5-carboxylic acid
(170) 4-Methyl-2- (4-oxazol-5-yl-5-phenyl-2-pyridyl) -1,3-thiazole-5-carboxylic acid
(171) 2- (5-Isobutoxy-4-oxazol-5-yl-2-pyridyl) -4-methyl-1,3-thiazole-5-carboxylic acid
(172) 2- (5-Isobutoxy-4-pyrimidin-5-yl-2-pyridyl) -4-methyl-1,3-thiazole-5-carboxylic acid
(173) 2- [4- (3,5-Dimethylisoxazol-4-yl) -5-isobutoxy-2-pyridyl] -4-methyl-1,3-thiazole-5-carboxylic acid
(174) 2- (5-Isobutoxy-4-isothiazol-4-yl-2-pyridyl) -4-methyl-1,3-thiazole-5-carboxylic acid
(175) 1- (5-isobutoxy-4-oxazol-5-yl-2-pyridyl) -1H-pyrazole-4-carboxylic acid
A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
A xanthine oxidase inhibitor comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient.
Gout, hyperuricemia, tumor lysis syndrome, urolithiasis, hypertension, dyslipidemia comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof as an active ingredient Drugs for treating or preventing diabetes, cardiovascular disease, kidney disease, respiratory disease, inflammatory bowel disease or autoimmune disease.
A compound represented by the formula (II).

[Where:
R 4 represents the following R 41 or R 42 .

R 5 represents a protecting group for a carboxyl group.
The definitions of R 1 , R 2 , X 1 and ring A are the same as in formula (I). ]