TW201625545A - Substituted azole compound and antidiabetes agent - Google Patents

Abstract

To provide a novel substituted azole compound having a GPR119-activating activity and useful particularly for the prevention and/or treatment of diabetes and obesity. Provided are: a novel substituted azole compound represented by formula (I) (wherein each substituent is as defined in detail in the description; the ring A represents an aromatic ring which may be substituted by a substituent as defined in the description; the ring B represents a ring selected from rings represented by formula (II); R1 represents a hydrogen atom, an alkyl group or the like; R2 represents an alkyl group or the like; the ring C represents a benzene ring, a 5- to 6-membered aromatic heterocyclic ring or the like; and R3 and R4 independently represent an alkyl group which may be substituted or the like), a tautomer or pharmaceutically acceptable salt of the compound, or a solvate of the compound or the tautomer or pharmaceutically acceptable salt.

Description

Substituted azole compound and diabetes therapeutic drug

This invention relates to novel substituted azole compounds having GPR119 activation.

Regarding diabetes, especially for the treatment of type 2 diabetes, most drugs such as insulin, metformin, sulfhydryl urea, thiazolidine, acarbose, GLP-1 rim, DPP4 inhibitor, SGLT2 inhibitor are used. However, problems such as hypoglycemia or weight gain, abdominal discomfort, and urinary tract infections have been reported. Among them, sulfolamide-based urea drugs often cause hypoglycemia, so novel diabetes medicines that are difficult to cause hypoglycemia are expected.

GPR119 (G protein-coupled receptor 119) is a GPCR (G protein-based conjugated receptor) mainly expressed in the pancreas and the digestive tract. GPR119 is a Gs-conjugated GPCR, and intracellular cAMP can be enhanced by activation (Non-Patent Document 1). Since one of the endogenous ligands, the oily ethanolamine (OEA) can activate the pancreatic GPR119, it can increase intracellular cAMP and promote glucose concentration-dependent insulin secretion (Non-Patent Document 2). Further, the gastrointestinal tube can also secrete an insulin secretion-promoting hormone called GLP-1 or GIP by activation of GPR119 by OEA (Non-Patent Document 3). Increased cAMP in pancreatic beta cells stimulated by GLP-1 or GIP can promote insulin secretion dependent on glucose concentration, and also promote inhibition of pancreatic beta cell death and proliferation of pancreatic beta cells. Patent Document 4 and Non-Patent Document 5). Since the physiological action of activation of these GPRs 119 is related to insulin secretion dependent on glucose concentration, the activator of GPR119 is set as a therapeutic drug for diabetes having a low risk of hypoglycemia. In fact, several GPR119 activators have been reported, and diabetes has been improved by administration to db/db mice, and pancreatic β- cell protective effects have also been reported (Non-Patent Document 6). In addition, in the test of the GPR119 activator of the high-fat-fed rat, it has been reported that the body weight-suppressing action by the ingestion inhibition is expected to have an anti-obesity effect (Non-Patent Document 7).

In recent years, several piperidine-based compounds having a GPR119 activation activity have been reported (for example, refer to Patent Documents 1 to 3), and further drug development is expected. Further, as a compound having a blood sugar lowering action and/or a pancreatic β cell protective action, a mercaptobenzene derivative and an N-heterocyclic substituted guanamine derivative are also reported (see Patent Documents 4 and 5).

[Advanced technical literature] [Patent Literature]

[Patent Document 1] International Publication No. 2008/070692

[Patent Document 2] International Publication No. 2008/081205

[Patent Document 3] International Publication No. 2009/012275

[Patent Document 4] International Publication No. 2012/050151

[Patent Document 5] International Publication No. 2013/108800

[Non-patent literature]

[Non-Patent Document 1] Biochemistry Biochem Biophys Res Commun. 2005:326, p.744-751

[Non-Patent Document 2] Mol Endocrinol. 2010: 24, p161-170

[Non-Patent Document 3] Diabetes. 2009: 58, p1058-1066

[Non-Patent Document 4] Physiol Rev. 2007: 87, p1409-1439

[Non-Patent Document 5] Diabetologia. 2004: 47, p806-815

[Non-Patent Document 6] Diabetes Obes Metab. 2011: 13, p34-41

[Non-Patent Document 7] Cell Metabolism. 2006: 3, p167-175

[Summary of the Invention]

The present invention is directed to providing novel pharmaceutical compounds having excellent GPR119 activation, particularly for the prevention and/or therapeutic use of diabetes, obesity.

The inventors of the present invention have found that the compound of the present invention has a high GPR119 activation effect after a detailed review of the GPR119 activator. The present invention has been completed.

That is, the present invention has the following features.

(1) A compound, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture of the formula (I)

Wherein ring A is a C _6-10 aromatic hydrocarbon ring or a 5-10 membered aromatic heterocyclic ring (the C _6-10 aromatic hydrocarbon ring and the 5-10 membered aromatic heterocyclic ring are unsubstituted or selected The substituent of the free substituent group R _a is substituted by a single or different substituent of 1 to 3), and the ring B is of the formula (II-1), the formula (II-2) or the formula (II-3)

(wherein * represents a bonding position with ring C, and R ⁵ is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _3-6 cycloalkyl group, a halogen atom or a cyano group) Either ring C is a benzene ring or a 5-6 membered aromatic heterocyclic ring (the benzene ring and the 5-6 membered aromatic heterocyclic ring are unsubstituted or selected from a halogen atom, a hydroxyl group, an amine group, a cyano group, Individual or heterogeneous groups of C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy and C _1-3 alkylsulfonyl Substituted by a substituent of 1 to 4), R ¹ is a hydrogen atom, a C _1-6 alkyl group or a C _1-6 haloalkyl group, and R ² is a C _1-6 alkyl group, a C _3-6 cycloalkyl group or C _1-6 haloalkyl, or R ¹ and R ² together form a C _3-6 cycloalkyl ring, and R ³ and R ^{4 are} each independently a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group (the C _1-6 alkyl group, the C _2-6 alkenyl group, and the C _2-6 alkynyl group are unsubstituted or one or more selected from the group consisting of the substituent groups R _b alone or different Substituted by a substituent), a C _3-6 cycloalkyl group or a 4-11 membered heterocyclic group (the C _3-6 cycloalkyl group and the 4-11 membered heterocyclic group are unsubstituted or selected from the group consisting of substituents R _c alone or differently substituted by more than one substituent), or R ³ together with R ⁴ A 4-11 member nitrogen-containing heterocyclic ring may be formed (the 4-11 member nitrogen-containing heterocyclic ring is unsubstituted or is selected from a single or different substituent selected from the substituent group R _c Substituted), the substituent group R _a is a halogen atom, a cyano group, a nitro group, a phosphonium group, a phosphinomethoxy group, a sulfonic acid group, a fluorenylene group, an aminosulfonyl group, a C _1-6 alkyl group, a C ₂ group _{a -6} alkenyl group, a C _2-6 alkynyl group (the C _1-6 alkyl group, a C _2-6 alkenyl group and a C _2-6 alkynyl group are unsubstituted or selected from the group consisting of the substituent group R _b alone or in phase Substituted by one or more substituents), C _3-6 cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered aromatic heterocyclic group (the C _3-6 cycloalkyl group, 4-7 The heterocyclic group and the 5-6 membered aromatic heterocyclic group are unsubstituted or substituted by one or more substituents selected from the substituent group R _c alone or differently) and the formula (III) Structure

(wherein T is an oxygen atom, a sulfur atom or NR ¹³ , and R ¹¹ , R ¹² and R ^{13 are} each independently a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group ( The C _1-6 alkyl group, the C _2-6 alkenyl group and the C _2-6 alkynyl group are unsubstituted or substituted by one or more substituents selected from the group of substituents R _b alone or different), C _3-6 cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered aromatic heterocyclic group (the C _3-6 cycloalkyl group, 4-7 membered heterocyclic group and 5-6 membered aromatic hetero The cyclic group is unsubstituted or substituted by one or more substituents selected from the group of substituents R _c alone or in combination, a C _1-6 alkylcarbonyl group, a C _1-6 haloalkylcarbonyl group, C _{3 -6} cycloalkylcarbonyl, C _3-6 halocycloalkylcarbonyl, C _1-6 alkylsulfonyl, C _1-6 haloalkylsulfonyl, C _3-6 cycloalkylsulfonyl, C _1-6 alkoxycarbonyl group, mono-C _1-6 alkylamino carbonyl or di- C _1-6 alkylamino-carbonyl group) consisting of a substituent group, the substituent group R _b train consisting of a halogen atom, a hydroxyl group, an amine Base, nitro, oxo, cyano, carboxyl, aminomethyl sulfonyl, phosphonium, phosphinomethoxy, sulfonate, fluorenylene, aminosulfonyl, tetrazolyl, C _{3- 6} cycloalkyl, C _1-3 alkoxy, C _3-6 cycloalkoxy, C _1-3 alkylsulfonyl group, C _1-3 alkoxycarbonyl, mono C _1-3 alkyl amino, di C _1-3 alkyl amino, mono-C _1-3 alkylaminocarbonyl, di C _1-3 alkylaminocarbonyl, C _1-3 alkylcarbonylamino, C _1-3 alkoxycarbonylamino, C _1-3 alkylcarbonyloxy , a mono C _1-3 alkylaminocarbonyloxy group, a di C _1-3 alkylaminocarbonyloxy group, and a 4-7 membered heterocyclic group (the C _3-6 cycloalkyl group, C _1-3 alkoxy group) a group, a C _3-6 cycloalkoxy group, a C _1-3 alkylsulfonyl group, a C _1-3 alkoxycarbonyl group, a mono C _1-3 alkylamino group, a di C _1-3 alkylamino group, Mono C _1-3 alkylaminocarbonyl, di C _1-3 alkylaminocarbonyl, C _1-3 alkylcarbonylamino, C _1-3 alkoxycarbonylamino, C _1-3 alkylcarbonyl An oxy group, a mono C _1-3 alkylaminocarbonyloxy group, a di C _1-3 alkylaminocarbonyloxy group, and a 4-7 membered heterocyclic group are unsubstituted or selected from a halogen atom, a hydroxyl group, an amine a group of substituents consisting of a group consisting of a group of cyano and aminomethyl fluorenyl groups substituted by 1 or 3 substituents, and a group of substituents R _c is a C _1-6 alkyl group, C _2-6 alkenyl, C _2-6 alkynyl (which C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl group is not taken , Or substituted by a radical selected from the group consisting of R _b alone or in one or more different substituents.) And constituting Substituents of R _b substituents consisting of Substituents] FIG.

(2) Ring B is of formula (II-1)

(wherein * represents a bonding position with ring C, and R ⁵ is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _3-6 cycloalkyl group, a halogen atom or a cyano group) (1) A compound described, a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture.

(3) A compound described in (2), wherein R ¹ and R ⁵ are a hydrogen atom, and R ² is a C _1-3 alkyl group, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof .

(4) Ring C is a benzene ring or a 5-6 membered aromatic heterocyclic ring (the benzene ring and the 5-6 membered aromatic heterocyclic ring are unsubstituted or selected from a halogen atom, a cyano group, a C _1-3 alkyl group) a compound described in (2) or (3), a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent thereof, which is substituted by a single or different 1 to 4 substituents. mixture.

(5) Ring C is of formula (IV-1)

(wherein * represents a bonding position with ring B, and V and W are each independently a nitrogen atom or CR ⁶ , and R ⁶ is a hydrogen atom, a halogen atom or a C _1-3 alkyl group, and when V and W are CR ⁶ , R ⁶ may be the same or different, m is 0 to 2, when m is 1 or 2, R ⁷ is a halogen atom or a C _1-3 alkyl group, and when m is 2, R ⁷ may be the same or different) (4) A compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture thereof.

(6) a compound described in (5) wherein V and W are CH, m is 1, and R ⁷ is a fluorine atom, a chlorine atom or a methyl group, a tautomer of the compound or a pharmaceutically acceptable salt thereof or These solvent mixtures.

(7) Ring C is of formula (IV-2)

(wherein, * represents a bonding position with ring B, V is a nitrogen atom, W is a nitrogen atom or CR ⁶ , R ⁶ is a fluorine atom, and m is 0). The compound described in (4), the mutual compound of the compound Isomers or their pharmaceutically acceptable salts or mixtures of these solvents.

(8) Ring A is of formula (V)

(wherein X is a nitrogen atom or CH, and R ⁸ is a formula (VI-1) or a formula (VI-2)

(wherein T is an oxygen atom or a sulfur atom, and R ⁹ is a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a 4-7 membered heterocyclic group (the C _1-6 alkyl group, C _3-6) The compound described in any one of (2) to (7), wherein the cycloalkyl group and the 4-7 membered heterocyclic group are unsubstituted or substituted by one or more halogen atoms. Tautomers or their pharmaceutically acceptable salts or mixtures of these solvents.

(9) R ⁸ is a C _3-6 cycloalkylcarbonyl group or a C _3-6 halocycloalkylcarbonyl group, the compound described in (8), a tautomer of the compound or a pharmaceutically acceptable salt thereof or These solvent mixtures.

(10) Ring A is each structure described in formula (VII)

(wherein R ²¹ is a C _1-6 alkyl group or a C _3-6 cycloalkyl group (the C _1-6 alkyl group and the C _3-6 cycloalkyl group are unsubstituted or may be substituted by one or more halogen atoms) The compound according to any one of (2) to (7), the tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture thereof.

(11) Ring A is each structure described in formula (VIII)

(wherein R ²² is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or is a single or different one selected from the group consisting of a halogen atom and a C _3-6 cycloalkyl group) (2) to (7) of any of the above substituents or C _3-6 cycloalkyl (the C _3-6 cycloalkyl group is unsubstituted or may be substituted by one or more halogen atoms)) A compound according to any one of the above, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture.

(12) The compound of (11) wherein R ²² is a C _1-3 haloalkyl group or a cyclopropylmethyl group, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof.

(13) R ³ is a hydrogen atom, and R ⁴ is a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a 4-7 membered heterocyclic group (the C _1-6 alkyl group, C _3-6 cycloalkyl group) And a 4-7 membered heterocyclic group is unsubstituted or has 1 or 3 substituents selected from a group consisting of a halogen atom, a hydroxyl group, an aminocarbamyl group, a carboxyl group, a cyano group and an oxo group. Substituted), or R ³ and R ⁴ together are a 4-7 membered nitrogen-containing heterocyclic ring (the 4-7 membered nitrogen-containing heterocyclic ring is unsubstituted or selected from a halogen atom, a hydroxyl group, an amine group A) a compound according to any one of (2) to (12), wherein the compound is a thiol group, a carboxyl group, a cyano group, or a oxo group, or a group of 1 to 3 substituents, Isomers or their pharmaceutically acceptable salts or mixtures of these solvents.

(14) R ³ is a hydrogen atom, and R ⁴ is a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a 4-7 membered heterocyclic group (the C _1-6 alkyl group, C _3-6 cycloalkyl group) And the 4-7 membered heterocyclic group is unsubstituted or substituted by a single or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, an aminomethylmethyl group and an oxo group, or R ³ and R ⁴ is a 4-7 membered nitrogen-containing heterocyclic ring (the 4-7 membered nitrogen-containing heterocyclic ring is unsubstituted or is selected from a group consisting of a hydroxyl group, an aminomethyl group and an oxo group). Or a compound of (13), a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture thereof, which is substituted by a different one to three substituents.

(15) R ³ is a hydrogen atom, and R ⁴ is a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a 4-7 membered heterocyclic group (the C _1-6 alkyl group, C _3-6 cycloalkyl group) And a compound of (14), wherein the 4-7 membered heterocyclic group is substituted by a single or different one to three substituents selected from the group consisting of a hydroxyl group, an aminomethylmethyl group and an oxo group, Tautomers of the compounds or their pharmaceutically acceptable salts or mixtures of these solvents.

(16) R ³ is a hydrogen atom, and R ⁴ is a C _1-3 alkyl group or a cyclopropyl group (the C _1-3 alkyl group and the cyclopropyl group are unsubstituted or selected from an aminomethyl fluorenyl group, a cyano group A compound described in (13), a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture thereof, which is substituted by one substituent of a group of carboxyl groups.

(17) R ³ and R ⁴ together are a 4-7 member nitrogen-containing heterocyclic ring (the 4-7 member nitrogen-containing heterocyclic ring is unsubstituted or selected from a hydroxyl group, an aminomethyl fluorenyl group, a carboxyl group, a compound of (13), a tautomer of the compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the cyano group and the oxo group are substituted by a single or different 1 to 3 substituents. These solvent mixtures.

(18) R ³ and R ⁴ together are pyrrolidine (the pyrrolidine is substituted by a single substituent selected from a group consisting of a hydroxyl group, an aminomethyl fluorenyl group, a carboxyl group, and a cyano group). (17) A compound described, a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture.

(19) Ring B is of formula (II-2) or formula (II-3)

(wherein * represents the bonding position with ring C), and ring C is formula (IX)

(wherein, * represents a bonding position with ring B, R ¹⁰ is a fluorine atom, a chlorine atom or a methyl group), R ¹ is a hydrogen atom, and R ² is a C _1-3 alkyl group (1) a tautomer of the compound or a pharmaceutically acceptable salt thereof or a mixture of these solvents.

(20) Ring A is of formula (V)

(wherein, X is a nitrogen atom or CH, R ⁸ is a C _3-6 cycloalkylcarbonyl group or a C _3-6 halocycloalkylcarbonyl group), the compound of (19), a tautomer of the compound or A pharmaceutically acceptable salt or a mixture of these solvents.

(21) Ring A is of formula (VIII-1)

(wherein R ²² is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or is a single or different one selected from the group consisting of a halogen atom and a C _3-6 cycloalkyl group) (Substituted by the above substituent), or a C _3-6 cycloalkyl group (the C _3-6 cycloalkyl group is unsubstituted or may be substituted by one or more halogen atoms) (19) A compound, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a mixture of these solvents.

(22) R ³ is a hydrogen atom, and R ⁴ is a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a 4-7 membered heterocyclic group (the C _1-6 alkyl group, C _3-6 cycloalkyl group) And the 4-7 membered heterocyclic group is unsubstituted or substituted by a single or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, an aminomethylmethyl group and an oxo group, or R ³ and R ⁴ is a 4-7 member nitrogen-containing heterocyclic ring (the 4-7 member nitrogen-containing heterocyclic ring is unsubstituted or is selected from a group consisting of a hydroxyl group, an aminomethyl group and an oxo group). Or a compound described in any one of (19) to (21), or a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof, which is substituted by a different one or three substituents. .

(23) R ³ is a hydrogen atom, and R ⁴ is a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a 4-7 membered heterocyclic group (the C _1-6 alkyl group, C _3-6 cycloalkyl group) And a 4-7 membered heterocyclic group is a compound described in (22), which is substituted by 1 or 3 substituents selected from a group consisting of a hydroxyl group, an aminocarbamyl group and an oxo group, or a group thereof, Tautomers of the compounds or their pharmaceutically acceptable salts or mixtures of these solvents.

(24) A GPR119 activator containing the compound according to any one of (1) to (23), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvent mixture as an active ingredient.

(25) The GPR119 activation effect of the compound according to any one of (1) to (23), a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture as an active ingredient is effective Disease prevention, treatment and/or improvement medicine.

(26) A therapeutic agent for diabetes containing the compound according to any one of (1) to (23), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvent mixture thereof as an active ingredient.

(27) A pharmaceutical containing the compound according to any one of (1) to (23), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvent mixture thereof as an active ingredient.

According to the present invention, a novel substituted azole compound which is excellent in the activation of GPR119, particularly for the prevention and/or treatment of diabetes and obesity, can be improved.

[Formation of the Invention]

The invention is further described in detail below.

In the present invention, "n-" means positive, "i-" means different, "s-" and "sec-" means second, "t-" and "tert-" mean third, "c-" means ring "o-" means o, "m-" means "p-" means pair, "cis-" means colloid, "trans-" means reflex, "rac-" and "racemate" means racemate "diastereomixture" means a diastereomeric mixture, "Ph" means a phenyl group, "Py" means a pyridyl group, "Me" means a methyl group, "Et" means an ethyl group, "Pr" means a propyl group, and "Bu" means a butyl group. The group "Bn" represents a benzyl group, [Boc" represents a third butoxycarbonyl group, "Ms" represents a methanesulfonyl group, "Tf" represents a trifluoromethanesulfonyl group, and "Ts" represents p-toluenesulfonate. The base "TBS" means a third butyl dimethyl fluorenyl group.

First, the description of the chemical structure in this specification is used. The terminology.

The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

"C _1-3 alkyl" means methyl, ethyl, n-propyl or isopropyl.

"C _1-3 haloalkyl" means that the hydrogen atom at any position of the above definition "C _1-3 alkyl group" is independently or in a phase selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. A substituent substituted by one or more halogen atoms.

The "C _1-6 alkyl group" means a straight or branched chain alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n- group. Butyl, isobutyl, t-butyl, n-pentyl, n-hexyl and the like.

"C _1-6 haloalkyl" means that the hydrogen atom at any position defined by the above "C _1-6 alkyl group" is independently or differently selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. A substituent substituted by one or more halogen atoms.

"C _3-6 cycloalkyl" means a single ring system, a condensed ring system, a crosslinked ring system or a spiro ring aliphatic hydrocarbon ring having 3 to 6 carbon atoms constituting the ring, and one hydrogen at any position is removed. Specific examples of the monovalent substituent of the atom include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

"C _3-6 halocycloalkyl" means that the hydrogen atom at any position defined by the above-mentioned "C _3-6 cycloalkyl group" is selected from a group consisting of a group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Or a substituent substituted by one or more different halogen atoms.

"C _2-6 alkenyl" means a straight-chain or branched-chain alkenyl group having at least one double bond and having 2 to 6 carbon atoms, and specific examples thereof include a vinyl (vinyl) group and 1- Propenyl, 2-propenyl (allyl), isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl (homoallyl), 4-pentenyl, 5 - Hexyl group and the like.

The "C _2-6 alkynyl group" means a straight-chain or branched-chain alkynyl group having at least one reference bond and having 2 to 6 carbon atoms, and specific examples thereof include an ethynyl group, a 1-propynyl group, and 2 a propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a 4-pentynyl group, a 5-hexynyl group or the like.

The "C _6-10 aromatic hydrocarbon ring" means a monocyclic or bicyclic aromatic hydrocarbon ring in which all of the atoms constituting the ring are carbon atoms and have 6 to 10 carbon atoms, and specific examples thereof include benzene and a ring. Pentadiene, naphthalene, etc.

The "5-10 member aromatic heterocyclic ring" has 5 to 10 atoms in the ring, and the atom constituting the ring contains 1 to 5 hetero atoms (the hetero atom represents a nitrogen atom, an oxygen atom or a sulfur atom, 2 The monocyclic or condensed cyclic aromatic heterocyclic group which may be the same or different) may, for example, be furan, thiophene, pyrrole, imidazole, triazole, tetrazole, thiazole or pyrazole. Oxazole, isoxazole, isothiazole, thiadiazole, oxadiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, anthracene, pteridine, quinoline, isoquinoline, azaphthalene, quinoxaline , porphyrin, quinazoline, pyridazine, imidazopyridine, imidazothiazole, imidazoxazole, benzothiazole, benzoxazole, benzimidazole, pyrrolopyridine, thienopyridine, furopidine, benzene Thiadiazole, benzoxoxadiazole, pyridopyrimidine, benzofuran, benzo Thiophene, thienofuran, and the like.

Further, when the "5-10 member aromatic heterocyclic ring" has a C=N double bond, the N-oxide body is also contained.

The "5-6 member aromatic heterocyclic ring" is a monocyclic ring in which the number of atoms constituting the ring is 5 to 6 in the above-mentioned definition "5-10 member aromatic heterocyclic ring", and specific examples thereof include pyrrole, Pyrazole, imidazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, furan, thiophene, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, thiadiazole and the like.

The "5-6 member aromatic heterocyclic group" means a monovalent substituent in which one hydrogen atom at an arbitrary position is removed from the above-mentioned definition "5-6 member aromatic heterocyclic ring".

The "C _3-6 cycloalkyl ring" means a monocyclic system, a condensed ring system, a crosslinked ring system or a spiro ring aliphatic hydrocarbon ring having 3 to 6 carbon atoms constituting the ring, and specific examples thereof may be mentioned. Out of cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like.

The "4-11 membered heterocyclic ring" means 1) the number of atoms constituting the ring is 4 to 11, and 2) the atom constituting the ring contains 1 to 5 hetero atoms (the hetero atom represents a nitrogen atom, an oxygen atom or sulfur) An atom may be the same or different when two or more, 3) may contain a carbonyl group, a double bond or a ginseng bond in the ring, and 4) when the atom constituting the ring contains a sulfur atom, the sulfur atom may be sulfinium sulfonate. Base or sulfo group, 5) monocyclic system, condensed ring system (condensed ring system can be non-aromatic ring The condensation may be carried out in a non-aromatic ring-condensed aromatic ring), a cross-linked ring system or a spiro ring-based non-aromatic heterocyclic ring, and specific examples thereof include azetidine and pyrrolidine. , piperidine, azepane, Azocane, tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine, piperazine, thiazolidine, 1,4-dioxane, imidazoline, thiazoline, 1,2 -benzopyran, isochroman, chroman, porphyrin, isoporphyrin, azaindane, azatetralin, azachroman, 4,5,6,7-tetrahydrobenzofuran , 4,5,6,7-tetrahydrobenzo[b]thiophene, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, 6,7-dihydro-5H-pyrrolo[ 3,2-d]pyrimidine, 2,3-dihydro-1H-pyrrolo[2,3-d]pyridazine, 5,6,7,8-tetrahydro-[1,2,4]triazole [1,5-a]pyrazine, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine, 4,5,6,7-tetrahydro-3H-imidazo[4, 5-c]pyridine, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine, 5,6,7,8-tetrahydropyrido[4,3-d] Pyrimidine, 1,2,3,4-tetrahydro-2,7-azaphthalene, 2,7-diazaspiro[4.4]nonane, 6-oxa-2,9-diazaspiro[4.5癸 癸, 1,8-diaza snail [5 .5] undecane, 3-azabicyclo[3.3.1]nonane, and the like.

The "4-11 membered heterocyclic group" means a monovalent substituent in which a hydrogen atom at an arbitrary position is taken out from the above-mentioned definition "4-11 membered heterocyclic ring". Further, these bonding positions are not particularly limited, and may be bonded at a desired position. However, in the case of a condensed ring system in which a non-aromatic ring condenses an aromatic ring, substitution is performed on the non-aromatic ring side.

The "4-11 member nitrogen-containing heterocyclic ring" is a group of the "4-11 member heterocyclic ring", and the atom constituting the ring contains one or more nitrogen atoms. Specific examples include nitrogen. Heterocyclobutane, pyrrolidine, Pyrrolidone, piperidine, piperidone, azepane, Azocane, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperazine, piperazinone, morpholine, thiomorpholine, high? Porphyrin, 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine, 2,3-dihydro-1H-pyrrolo[2,3-d]pyridazine, 5,6,7,8 -tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, 2,7-diazaspiro[4.4]nonane, 6-oxa-2,9-diaza Snail [4.5] decane, 1,8-diazaspiro[5.5]undecane, 3-azabicyclo[3.3.1]nonane, and the like.

The "4-7 membered heterocyclic ring" means that 1) the number of atoms constituting the ring is 4 to 7, and 2) the atom constituting the ring contains 1 to 3 hetero atoms (the hetero atom represents a nitrogen atom, an oxygen atom) Or a sulfur atom may be the same or different when two or more, 3) may contain a carbonyl group, a double bond or a ginseng bond in the ring, and 4) when the atom constituting the ring contains a sulfur atom, the sulfur atom may be a sulfinyl group or a sulfo group, and 5) a monocyclic non-aromatic heterocyclic ring, specific examples thereof include azetidine, pyrrolidine, pyrrolidone, piperidine, piperidone, oxazolidine, and the like. Oxazolidine, thiazolidine, isothiazolidine, piperazine, piperazinone, morpholine, thiomorpholine, azepinin, dioxin, oxetane, tetrahydrofuran, 1,3-difuran, Tetrahydropyran, 1,4-dioxane, oxetane, homomorpholine, 4,5-dihydropyridazin-3(2H)-one, 1,2,5-thiadiazepine Heptane and the like.

The "4-7 membered heterocyclic group" means a monovalent substituent in which one hydrogen atom at an arbitrary position is taken out from the above-mentioned definition "4-7 membered heterocyclic ring".

The "4-7 member nitrogen-containing heterocyclic ring" is a group of the "4-7 member heterocyclic ring", and the atom constituting the ring contains one or more nitrogen atoms. Specific examples include aza. Cyclobutane, pyrrolidine, pyrrolidone, piperidine, piperidone, azepanidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperazine, piperazinone, morpholine, thio Morpholine, high morpholine, 1,2,5-thiadiazepine, and the like.

The "C _1-6 alkoxy group" means a linear or branched alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, and an isopropyl group. Oxyl, n-butoxy, isobutoxy, t-butoxy, n-pentyloxy, n-hexyloxy and the like.

"C _1-3 alkoxy" means methoxy, ethoxy, n-propoxy or isopropoxy.

The "C _3-6 cycloalkoxy group" means a group in which the above-mentioned definition "C _3-6 cycloalkyl group" is bonded to an oxy group, and specific examples thereof include a cyclopropoxy group, a cyclobutoxy group, and a cyclopenta group. Alkoxy group, cyclohexyloxy group, and the like.

"C _1-6 haloalkoxy" means that the hydrogen atom at any position defined by the above "C _1-6 alkoxy group" is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. A substituent substituted by one or more halogen atoms, alone or differently.

"C _1-3 haloalkoxy" means that the hydrogen atom at any position defined by the above "C _1-3 alkoxy group" is selected from a group selected from a group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Or a substituent substituted with one or more different halogen atoms.

The "C _1-3 alkylcarbonyl group" means a group in which the above-mentioned definition "C _1-3 alkyl group" is bonded to a carbonyl group, which is a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group or an isopropylcarbonyl group.

The "C _1-6 alkylcarbonyl group" means a group in which the above-mentioned definition "C _1-6 alkyl group" is bonded to a carbonyl group, and specific examples thereof include an ethyl group, a propyl group, a butyl group, an isobutyl group, and a pentylene group. Base, 3-methylbutanyl, neopentyl, hexyl, decyl, and the like.

The "C _1-6 haloalkylcarbonyl group" means a hydrogen atom at any position defined by the above-mentioned "C _1-6 alkylcarbonyl group" which is selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. A substituent substituted by one or more halogen atoms, alone or in combination.

The "C _3-6 cycloalkylcarbonyl group" means a group in which the above-mentioned definition "C _3-6 cycloalkyl group" is bonded to a carbonyl group, and specific examples thereof include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, and a cyclopentyl group. A carbonyl group, a cyclohexylcarbonyl group or the like.

The "C _3-6 halocycloalkylcarbonyl group" means that the hydrogen atom at any position of the above definition "C _3-6 cycloalkylcarbonyl group" may be selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. A substituent substituted by one or more halogen atoms, alone or differently.

The "C _1-6 alkylsulfonyl group" means a group in which the above-mentioned definition "C _1-6 alkyl group" is bonded to a sulfonyl group, and specific examples thereof include a methylsulfonyl group and an ethylsulfonyl group. , n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, t-butylsulfonyl, n-pentylsulfonyl, n-hexyl Sulfonyl and the like.

"C _1-3 alkylsulfonyl" means a radical of the above-mentioned definition "C _1-3 alkyl" bonded to a sulfonyl group, which is methylsulfonyl, ethylsulfonyl, n-propyl. Alkylsulfonyl or isopropylsulfonyl.

"C _1-6 haloalkylsulfonyl" means that the hydrogen atom at any position of the above definition "C _1-6 alkylsulfonyl" is substituted by a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. A substituent in which one or more halogen atoms of the group are substituted by one or more halogen atoms.

The "C _3-6 cycloalkylsulfonyl group" means a group in which the above-mentioned definition "C _3-6 cycloalkyl group" is bonded to a sulfonyl group, and specific examples thereof include a cyclopropylsulfonyl group and a cyclobutyl group. Alkylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl and the like.

The "C _1-6 alkoxycarbonyl group" means a group in which the above-mentioned definition "C _1-6 alkoxy group" is bonded to a carbonyl group, and specific examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and an n-propyl group. An oxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a t-butoxycarbonyl group, an n-pentyloxycarbonyl group, an n-hexyloxycarbonyl group or the like.

"C _1-3 alkoxycarbonyl" means a group in which the above-mentioned definition "C _1-3 alkoxy group" is bonded to a carbonyl group, which is a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group or Isopropoxycarbonyl.

The "mono C _1-6 alkylamino group" means a group in which the above-mentioned definition "C _1-6 alkyl group" is bonded to an amine group, and specific examples thereof include a methylamino group, an ethylamino group, and an n- group. A propylamino group, an isopropylamino group, an n-butylamino group, an isobutylamino group, a t-butylamino group, an n-pentylamino group, an n-hexylamino group, or the like.

"Single C _1-3 alkylamino group" means a group in which the above-mentioned definition "C _1-3 alkyl group" is bonded to an amine group, which is a methylamino group, an ethylamino group, and an n-propylamino group. Or isopropylamine.

The "di-C _1-6 alkylamino group" means a group in which two or more of the above-mentioned definitions "C _1-6 alkyl group" are bonded to an amine group, and specific examples thereof include a dimethylamino group and two. Ethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, di-t-butylamino, di-n-pentylamino, two n-Hexylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-N-methylamino, Nn-butyl-N- Amino group, N-isobutyl-N-methylamino group, Nt-butyl-N-methylamino group, N-methyl-Nn-pentylamino group, Nn-hexyl-N-methylamine Base, N-ethyl-Nn-propylamino, N-ethyl-N-isopropylamino, Nn-butyl-N-ethylamine, N-ethyl-N-isobutylamine A group, Nt-butyl-N-ethylamino group, N-ethyl-Nn-pentylamino group, N-ethyl-Nn-hexylamino group and the like.

The " _{diC 1-3} alkylamino group" means a group in which two or more of the above-mentioned definitions "C _1-3 alkyl group" are bonded to an amine group, and specific examples thereof include a dimethylamino group and two. Ethylamino, di-n-propylamino, diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-N a methylamino group, an N-ethyl-Nn-propylamino group, an N-ethyl-N-isopropylamino group or the like.

The "mono C _1-6 alkylaminocarbonyl group" means a group in which the above-mentioned definition "mono C _1-6 alkylamino group" is bonded to a carbonyl group, and specific examples thereof include a methylaminocarbonyl group and an ethylamine. Carbocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, t-butylaminocarbonyl, n-pentylaminocarbonyl, n a hexylaminocarbonyl group or the like.

"Single C _1-3 alkylaminocarbonyl" means a carbonyl-bonded group of one of the aforementioned definitions "mono C _1-3 alkylamino group" which is methylaminocarbonyl, ethylaminocarbonyl, n - propylaminocarbonyl or isopropylaminocarbonyl.

"Di-C _1-6 alkylaminocarbonyl" means a group in which the above-mentioned definition " _{diC 1-6} alkylamino group" is bonded to a carbonyl group, and specific examples thereof include dimethylaminocarbonyl group and diethyl group. Aminocarbonyl, di-n-propylaminocarbonyl, diisopropylaminocarbonyl, di-n-butylaminocarbonyl, diisobutylaminocarbonyl, di-t-butylaminocarbonyl, di-n-pentyl Aminocarbonyl, di-n-hexylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-N-methylamine Carbonyl, Nn-butyl-N-methylaminocarbonyl, N-isobutyl-N-methylaminocarbonyl, Nt-butyl-N-methylaminocarbonyl, N-methyl-Nn-pentyl Aminocarbonyl, Nn-hexyl-N-methylaminocarbonyl, N-ethyl-Nn-propylaminocarbonyl, N-ethyl-N-isopropylaminocarbonyl, Nn-butyl-N -ethylaminocarbonyl, N-ethyl-N-isobutylaminocarbonyl, Nt-butyl-N-ethylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl, N-B A group-Nn-hexylaminocarbonyl group or the like.

"Di-C _1-3 alkylaminocarbonyl" means a group in which the above-mentioned definition "di-C _1-3 alkylamino group" is bonded to a carbonyl group, and specific examples thereof include dimethylaminocarbonyl group and diethyl group. Aminocarbonyl, di-n-propylaminocarbonyl, diisopropylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-iso Propyl-N-methylaminocarbonyl, N-ethyl-Nn-propylaminocarbonyl, N-ethyl-N-isopropylaminocarbonyl, and the like.

The "C _1-3 alkylcarbonylamino group" means a group in which the above-mentioned definition "C _1-3 alkylcarbonyl group" is bonded to an amine group, which is a methylcarbonylamino group, an ethylcarbonylamino group, and an n-propyl group. A carbonylamino group or an isopropylcarbonylamino group.

The "C _1-3 alkoxycarbonylamino group" means a group in which the above-mentioned definition "C _1-3 alkoxycarbonyl group" is bonded to an amine group, which is a methoxycarbonylamino group or an ethoxycarbonylamino group. , n-propoxycarbonylamino or isopropoxycarbonylamino.

"C _1-3 alkylcarbonyloxy" means a radical of the above-mentioned definition "C _1-3 alkylcarbonyl" and an oxy group which is a methylcarbonyloxy group, an ethylcarbonyloxy group, or an n-propyl group. Alkylcarbonyloxy or isopropylcarbonyloxy.

"mono C _1-3 alkylaminocarbonyloxy" means a group in which the above-mentioned definition "mono C _1-3 alkylamino group" is bonded to a carbonyloxy group, which is a methylaminocarbonyloxy group, B. Aminocarbonyloxy, n-propylaminocarbonyloxy or isopropylaminocarbonyloxy.

The "di-C _1-3 alkylaminocarbonyloxy group" means a group in which the above-mentioned definition "di-C _1-3 alkylamino group" is bonded to a carbonyloxy group, and specific examples thereof include a dimethylamino group. Carbonyloxy, diethylaminocarbonyloxy, di-n-propylaminocarbonyloxy, diisopropylaminocarbonyloxy, N-ethyl-N-methylaminocarbonyloxy, N- Methyl-Nn-propylaminocarbonyloxy, N-isopropyl-N-methylaminocarbonyloxy, N-ethyl-Nn-propylaminocarbonyloxy, N-ethyl-N - isopropylaminocarbonyloxy group and the like.

The "oxo group" means a substituent (=O) in which an oxygen atom is substituted via a double bond. Therefore, when an oxo group is substituted by a carbon atom, a carbonyl group is formed together with the carbon atom, and when an oxo group is substituted by a sulfur atom, a sulfinyl group is formed together with the sulfur atom, and two oxo groups are derived from a sulfur atom. When substituted, a sulfonyl group is formed together with the sulfur atom. In the present invention, specific examples of the case where the oxo group is substituted by a C _3-6 cycloalkyl group include 3-oxocyclobutyl group, 2-oxocyclopentyl group and the like. Specific examples of the case where the oxo group is substituted by a 4-7 membered heterocyclic group include 3-oxotetrahydrofuranyl group, 2-oxotetrahydrofuranyl group, 2-oxopyrrolidinyl group, and 1,1-dioxide. Tetrahydrothiophene and the like.

In the present invention, the bonding form of the ring B will be described.

Ring B is any one of the formulae (II-1) to (II-3) in the formula (II), and the ring B is bonded to the ring C at each position of the formula (II). The right side of the paper of the formula (II-1) to the formula (II-3) in the formula (II) is bonded to a carbon atom bonded to R ¹ , R ² and an oxygen atom in the formula (I).

Therefore, when the ring B is of the formula (II-1), the entire molecule becomes the formula (I)-1,

When the ring B is of the formula (II-2), the entire molecule becomes the formula (I)-2,

When the ring B is of the formula (II-3), the entire molecule becomes the formula (I)-3.

Next, preferred structures of the respective substituents in the present invention are given.

Ring A is preferably a benzene ring or a 5-6 membered aromatic heterocyclic ring (the benzene ring or the 5-6 membered aromatic heterocyclic ring is selected from 1 or 2 substituents selected from the group of substituents R _d alone or dissimilar) Replace).

Ring A is preferably of formula (V)

(wherein X is a nitrogen atom and R ⁸ is a formula (VI-1) or a formula (VI-2)

(wherein T is an oxygen atom or a sulfur atom, and R ⁹ is a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a 4-7 membered heterocyclic group (the C _1-6 alkyl group, C _3-6) The cycloalkyl group and the 4-7 membered heterocyclic group are unsubstituted or may be substituted by one or more halogen atoms)).

Ring A is more preferably each structure described in formula (X)

(wherein, X is a nitrogen atom).

Ring A is more excellent (XI)

(wherein X is a nitrogen atom).

As another aspect, the ring A is preferably a formula (V) (wherein, X is CH, and R ⁸ is any one of the above formulas (VI-1) and (VI-2)).

The ring A is more preferably any of the structures (wherein X is CH) described in the formula (X).

Ring A is more particularly preferably of formula (XI) (wherein X is CH).

As another aspect, the ring A is preferably each structure described in the formula (VIII).

(wherein R ²² is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or is a single or different one selected from the group consisting of a halogen atom and a C _3-6 cycloalkyl group) Any of the above substituents may be substituted or a C _3-6 cycloalkyl group (the C _3-6 cycloalkyl group may be unsubstituted or may be substituted by one or more halogen atoms)).

Ring A is more preferably (VIII-1)

(wherein R ²² is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or is a single or different one selected from the group consisting of a halogen atom and a C _3-6 cycloalkyl group) The above substituent is substituted) or a C _3-6 cycloalkyl group (the C _3-6 cycloalkyl group is unsubstituted or may be substituted by one or more halogen atoms)).

More preferably, Ring A is of the formula (VIII-1) (wherein R ²² is a C _1-3 haloalkyl group or a cyclopropylmethyl group).

Ring B is preferably of formula (II-1)

(wherein * represents a bonding position with ring C, and R ⁵ is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _3-6 cycloalkyl group, a halogen atom or a cyano group).

Ring B is preferably of formula (II-4)

(wherein * represents the bonding position with ring C).

As another aspect, the ring B is preferably of the formula (II-2)

(wherein * represents the bonding position with ring C).

As another aspect, the ring B is preferably of the formula (II-3)

(wherein * represents the bonding position with ring C.).

Ring C is preferably a benzene ring or a 5-6 membered aromatic heterocyclic ring (the benzene ring and the 5-6 membered aromatic heterocyclic ring are unsubstituted or selected from the group consisting of a halogen atom, a cyano group, and a C _1-3 alkyl group). Groups of 1 or 4 substituents, either individually or differently, are substituted).

Ring C is better as formula (IV-1)

(wherein * represents a bonding position with ring B, and V and W are each independently a nitrogen atom or CR ⁶ , and R ⁶ is a hydrogen atom, a halogen atom or a C _1-3 alkyl group, and when V and W are CR ⁶ , R ⁶ may be the same or different, m is 0 to 2, when m is 1 or 2, R ⁷ is a halogen atom or a C _1-3 alkyl group, and when m is 2, R ⁷ may be the same or different).

Ring C is better for formula (IX)

(wherein * represents a bonding position with ring B, and R ¹⁰ is a fluorine atom, a chlorine atom or a methyl group).

Ring C is more excellent (XII)

(wherein * represents the bonding position with the ring B).

As another aspect, the ring C is more preferably the formula (IV-2)

(wherein * represents a bonding position with ring B, V is a nitrogen atom, W is a nitrogen atom or CR ⁶ , R ⁶ is a fluorine atom, and m is 0).

The ring C is more preferably the formula (IV-2) (wherein * represents a bonding position with the ring B, V is a nitrogen atom, W is CR ⁶ , R ⁶ is a fluorine atom, and m is 0).

R ^{1 is} preferably a hydrogen atom or a C _1-6 alkyl group.

R ^{1 is more} preferably a hydrogen atom.

R ^{2 is} preferably a C _1-6 alkyl group.

R ^{2 is more} preferably a methyl group or an ethyl group.

R ³ and R ⁴ are each independently a hydrogen atom (however, both of R ³ and R ⁴ are a hydrogen atom), a C _1-6 alkyl group, a C _2-6 alkenyl group, and a C _2-6 alkynyl group. (The C _1-6 alkyl group, C _2-6 alkenyl group, and C _2-6 alkynyl group are unsubstituted or substituted by one or more substituents selected from the substituent group R _e alone or different) a C _3-6 cycloalkyl group or a 4-11 membered heterocyclic group (the C _3-6 cycloalkyl group and the 4-11 membered heterocyclic group are unsubstituted or selected from the group consisting of the substituent group R _f alone or in phase Substituted by one or more substituents).

R ³ and R ^{4 are more} preferably each independently a hydrogen atom (however, both of R ³ and R ⁴ are a hydrogen atom), a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a 4-7 member. a cyclic group (the C _1-6 alkyl group, the C _3-6 cycloalkyl group, and the 4-7 membered heterocyclic group are unsubstituted or isolated from a group selected from the group consisting of a hydroxyl group, an aminomethyl fluorenyl group, and an oxo group. Or substituted with 1 to 3 substituents).

R ^{3 is more} preferably a hydrogen atom.

R ^{4 is more} preferably a C _1-3 alkyl group (the C _1-3 alkyl group is substituted by two or three substituents selected from a group consisting of a hydroxyl group and an aminocarbamyl group, alone or differently).

As another aspect, R ³ and R ^{4 are more} preferably R ³ is a hydrogen atom, and R ⁴ is a C _1-3 alkyl group or a cyclopropyl group (the C _1-3 alkyl group and the cyclopropyl group are unsubstituted or It is selected to be substituted by one substituent grouped by an aminomethylmercapto group, a cyano group or a carboxyl group).

As a further aspect, R ³ and R ⁴ preferably together form a 4-11 membered nitrogen-containing heterocyclic ring (the 4-11 membered nitrogen-containing heterocyclic ring is unsubstituted or selected from the group consisting of R Alternate or different one or more substituents of _f are substituted).

R ³ and R ^{4 are} preferably a 4-7 membered nitrogen-containing heterocyclic ring (the 4-7 membered nitrogen-containing heterocyclic ring is unsubstituted or selected from the group consisting of a hydroxyl group, an aminomethyl group, a carboxyl group, The cyano and oxo groups are substituted by a single or different 1 to 3 substituents).

R ³ and R ^{4 are more} preferably a 4-7 membered nitrogen-containing heterocyclic ring (the 4-7 membered nitrogen-containing heterocyclic ring is unsubstituted or selected from the group consisting of a hydroxyl group, an aminomethyl group and an oxo group). The group is replaced by a single or different 1 to 3 substituents).

The substituent group R _d is a halogen atom, a cyano group, a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted, or one or more selected from the group consisting of the substituent group R _e alone or different) Substituted by a substituent), a C _3-6 cycloalkyl group, a 4-7 membered heterocyclic group, a 5-6 membered aromatic heterocyclic group (the C _3-6 cycloalkyl group, a 4-7 membered heterocyclic group, and 5 The 6-membered aromatic heterocyclic group is unsubstituted or substituted by one or more substituents selected from the substituent group R _f alone or differently) and each structure described in the formula (III)

(wherein T is an oxygen atom, a sulfur atom or NR ¹³ , and R ¹¹ , R ¹² and R ^{13 are} each independently a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or selected a single or different one or more substituents of the free substituent group R _e are substituted), a C _3-6 cycloalkyl group or a 4-7 membered heterocyclic group (the C _3-6 cycloalkyl group and 4-7) The heterocyclic group is a group of substituents which are unsubstituted or substituted by a single or different substituent selected from the substituent group R _f or the like.

The substituent group R _e is composed of a halogen atom, a hydroxyl group, an amine group, an oxo group, a cyano group, a carboxyl group, an aminomethyl decyl group, a C _1-3 alkoxy group, a mono C _1-3 alkylamino group, and C _{1 . a} group of substituents consisting of a _3- alkylsulfonyl group, a C _3-6 cycloalkyl group, and a 4-7 membered heterocyclic group.

The substituent group R _f is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more substituents selected from the substituent group R _e alone or different) and A group of substituents constituting each substituent of the substituent group R _e .

Preferred compounds for use as a prophylactic, therapeutic or/and ameliorating agent for a disease in which GPR119 activator or GPR119 activation is effective in the present invention are as follows.

1) Formula (I)

Wherein ring A is a benzene ring or a 5-6 membered aromatic heterocyclic ring (the benzene ring or the 5-6 membered aromatic heterocyclic ring is substituted by 1 or 2 selected from the group consisting of the substituent group R _d alone or differently Substituted by a base), ring B is of formula (II-1), formula (II-2) or formula (II-3)

(wherein * represents a bonding position with ring C, and R ⁵ is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _3-6 cycloalkyl group, a halogen atom or a cyano group) Either ring C is a benzene ring or a 5-6 membered aromatic heterocyclic ring (the benzene ring and the 5-6 membered aromatic heterocyclic ring are unsubstituted or selected from a halogen atom, a cyano group, a C _1-3 alkane) Substituted by a group of 1 or 4 substituents, alone or differently substituted, R ¹ is a hydrogen atom or a C _1-6 alkyl group, R ² is a C _1-6 alkyl group, and R ³ and R ^{4 are} each independently Is a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group (the C _1-6 alkyl group, the C _2-6 alkenyl group, and the C _2-6 alkynyl group are unsubstituted, Or by a single or different substituent selected from the substituent group R _e , a C _3-6 cycloalkyl group or a 4-11 membered heterocyclic group (the C _3-6 cycloalkyl group and The 4-11 membered heterocyclic group is unsubstituted or substituted by one or more substituents selected from the substituent group R _f alone or in combination, or R ³ and R ⁴ together form a 4-11 member. a nitrogen heterocyclyl ring (the 4-11 member nitrogen-containing heterocyclic ring is unsubstituted or substituted by one or more substituents selected from the substituent group R _f alone or different), and the substituent group R _d, a substituted The group R _e and R _f group of substituents as previously defined based Substituents on the compound, the tautomer thereof, or a pharmaceutical compound that can be licensed salt or mixture of these solvents] FIG.

2) Ring B is of formula (II-4)

(wherein, * represents a bonding position with ring C), a compound described in the above 1), a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture.

3) Ring B is of formula (II-2)

(wherein, * represents a bonding position with ring C), a compound described in the above 1), a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture.

4) Ring B is of formula (II-3)

(wherein, * represents a bonding position with ring C), a compound described in the above 1), a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture.

5) The compound according to any one of the above 1) to 4), wherein the R ¹ is a hydrogen atom, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture.

6) R ² methyl or ethyl the above 1) to 5) A compound according to any one of, tautomers of the compound, or a pharmaceutically salt thereof can be licensed or mixture of these solvents.

7) Ring C is of formula (IV-1)

(wherein * represents a bonding position with ring B, and V and W are each independently a nitrogen atom or CR ⁶ , and R ⁶ is a hydrogen atom, a halogen atom or a C _1-3 alkyl group, and when V and W are CR ⁶ , R ⁶ may be the same or different, m is 0 to 2, when m is 1 or 2, R ⁷ is a halogen atom or a C _1-3 alkyl group, and when m is 2, R ⁷ may be the same or different) The compound according to any one of the above 1) to 6), a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture.

8) a compound described in the above 7) wherein V and W are CH, m is 1, and R ⁷ is a fluorine atom, a chlorine atom or a methyl group; a tautomer of the compound or a pharmaceutically acceptable salt thereof or these Solvent mixture.

9) Ring C is of formula (IX)

(wherein, * represents a bonding position with ring B, and R ¹⁰ is a fluorine atom, a chlorine atom or a methyl group), the compound of the above 8), a tautomer of the compound or a pharmaceutically acceptable substance thereof Salt or these solvent mixture.

10) Ring C is of formula (XII)

(wherein, * represents a bonding position with ring B), a compound described in the above 9), a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture.

11) Ring C is of formula (IV-2)

(wherein * represents a bonding position with ring B, V is a nitrogen atom, W is a nitrogen atom or CR ⁶ , R ⁶ is a fluorine atom, and m is 0), as described in any one of the above 1) to 6) a compound, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a mixture of these solvents.

12) V is a nitrogen atom, W is CR ^6, R ⁶ is a fluorine atom, m is 0 the above 11) salt of the compound described in, tautomers of the compound, or a pharmaceutically licensed or these vehicles agents .

13) Ring A is of formula (V)

(wherein X is a nitrogen atom or CH, and R ⁸ is a formula (VI-1) or a formula (VI-2)

(wherein T is an oxygen atom or a sulfur atom, and R ⁹ is a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a 4-7 membered heterocyclic group (the C _1-6 alkyl group, C _3-6) The compound according to any one of the above 1) to 12), wherein the cycloalkyl group and the 4-7 membered heterocyclic group are unsubstituted or substituted by one or more halogen atoms)) Tautomers or their pharmaceutically acceptable salts or mixtures of these solvents.

14) Ring A is each structure described in formula (X)

The compound described in the above 13) (wherein X is a nitrogen atom or CH), a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture thereof.

15) Ring A is of formula (XI)

(In the formula, X is a nitrogen atom or CH), the compound described in the above 14), a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture.

And a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof.

And a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof.

18) Ring A is each structure described in formula (VIII)

(wherein R ²² is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or is a single or different one selected from the group consisting of a halogen atom and a C _3-6 cycloalkyl group) The above 1) to 12) of any of the above substituents or C _3-6 cycloalkyl (the C _3-6 cycloalkyl group is unsubstituted or may be substituted by one or more halogen atoms)) A compound according to any one of the compounds, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture.

19) Ring A is of formula (VIII-1)

(wherein R ²² is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or is a single or different one selected from the group consisting of a halogen atom and a C _3-6 cycloalkyl group) The compound described in the above 18), which is substituted by the above substituent or a C _3-6 cycloalkyl group (the C _3-6 cycloalkyl group is unsubstituted or substituted by one or more halogen atoms)) Tautomers or their pharmaceutically acceptable salts or mixtures of these solvents.

20) The compound according to the above 18) or 19) wherein R ²² is a C _1-3 haloalkyl group or a cyclopropylmethyl group, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof .

21) R ³ and R ^{4 are} each independently a hydrogen atom (but in the case where both of R ³ and R ⁴ are a hydrogen atom), a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a 4-7 membered heterocyclic group. (The C _1-6 alkyl group, the C _3-6 cycloalkyl group, and the 4-7 membered heterocyclic group are unsubstituted or are selected from a group consisting of a hydroxyl group, an aminomethyl fluorenyl group, and an oxo group. The compound according to any one of the above 1) to 20), the tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture thereof, which is substituted by 1 to 3 substituents.

22) R ³ is a hydrogen atom, and R ⁴ is a C _1-3 alkyl group (the C _1-3 alkyl group is a single or different 2 or 3 substituents selected from the group consisting of a hydroxyl group and an aminomethyl fluorenyl group. The compound described in the above 21), the tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture thereof.

23) R ³ is a hydrogen atom, and R ⁴ is a C _1-3 alkyl group or a cyclopropyl group (the C _1-3 alkyl group and the cyclopropyl group are unsubstituted or selected from an aminomethyl fluorenyl group, a cyano group or a carboxyl group) The compound according to any one of the above 1) to 20), the tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture thereof.

24) R ³ and R ⁴ together are a 4-7 member nitrogen-containing heterocyclic ring (the 4-7 member nitrogen-containing heterocyclic ring is unsubstituted or selected from the group consisting of a hydroxyl group, an aminomethyl group, a carboxyl group, and a cyanogen group). A compound according to any one of the above 1) to 20), which is substituted by a group of 1 or 3 substituents, which are substituted by a group of oxo groups, or a thiol group, or a pharmaceutically acceptable substance thereof Permissible salts or mixtures of these solvents.

25) R ³ and R ⁴ together are a 4-7 membered nitrogen-containing heterocyclic ring (the 4-7 membered nitrogen-containing heterocyclic ring is unsubstituted or selected from a hydroxyl group, an aminomethyl group and an oxo group) The compound of the above 24), the tautomer of the compound, or a pharmaceutically acceptable salt thereof, or a mixture of these solvents, which are substituted by a single or different 1 to 3 substituents.

26) by the formula (XIII)

R ² is a methyl group, R ⁷ is a fluorine atom, and a combination of the compounds described in the following Tables (Table 1) and the tautomers of the compounds or their pharmaceutically acceptable substances are permitted. Salt or these solvent mixtures.

And the symbols of (Table 1) are as shown in the following substituents.

27) R ² represented by the formula (XIII) is a methyl group, R ⁷ is a fluorine atom, and the rings A and E are a combination of the compounds described below (Table 2), tautomers of the compounds or A pharmaceutically acceptable salt or a mixture of these solvents.

And the symbols in (Table 2) are as shown in the following substituents.

28) As shown by the formula (XIII), R ² is a methyl group, R ⁷ is a fluorine atom, and rings A and E are a combination of the compounds described below (Table 3), and tautomers of the compound. Or a pharmaceutically acceptable salt or a mixture of these solvents.

And the symbols of (Table 3) are as shown in the following substituents.

29) by the formula (XIV)

R ² is a methyl group, R ⁷ is a fluorine atom, and rings A and E are a compound represented by the combination described in the above (Table 1), a tautomer of the compound, or a pharmaceutically acceptable substance thereof. Salt or these solvent mixtures.

30) a compound obtained by the combination of the formula (XIV) wherein R ² is a methyl group, R ⁷ is a fluorine atom, and the rings A and E are as described above (Table 2), and the tautomerism of the compound Or a pharmaceutically acceptable salt or a mixture of these solvents.

31) A compound represented by the formula (XIV) wherein R ² is a methyl group, R ⁷ is a fluorine atom, and the rings A and E are as described above (Table 3), and the tautomer of the compound Or a pharmaceutically acceptable salt or a mixture of these solvents.

32) by the formula (XV)

R ² is a methyl group, R ⁷ is a fluorine atom, and a compound of the combination of the ring A and the E as described above (Table 1), a tautomer of the compound or a pharmaceutically acceptable substance thereof Salt or these solvent mixtures.

33) A compound obtained by the combination of the formula (XV), wherein R ² is a methyl group, R ⁷ is a fluorine atom, and the rings A and E are as described above (Table 2), and the tautomerism of the compound Or a pharmaceutically acceptable salt or a mixture of these solvents.

34) A compound obtained by the combination of the formula (XV), wherein R ² is a methyl group, R ⁷ is a fluorine atom, and the rings A and E are as described above (Table 3), and the tautomerism of the compound Or a pharmaceutically acceptable salt or a mixture of these solvents.

35) by the formula (XVI)

R ² is a methyl group, R ⁷ is a fluorine atom, and a compound of the combination of the ring A and the E as described above (Table 1), a tautomer of the compound or a pharmaceutically acceptable substance thereof Salt or these solvent mixtures.

36) A compound obtained by the combination of the formula (XVI), wherein R ² is a methyl group, R ⁷ is a fluorine atom, and the rings A and E are as described above (Table 2), and the tautomerism of the compound Or a pharmaceutically acceptable salt or a mixture of these solvents.

37) A compound obtained by the combination of the formula (XVI), wherein R ² is a methyl group, R ⁷ is a fluorine atom, and the rings A and E are as described above (Table 3), and the tautomerism of the compound Or a pharmaceutically acceptable salt or a mixture of these solvents.

A combination of compounds as described in the 38) R ² is an ethyl above 26) to 37) to any of the tautomeric compound or a pharmaceutically salt thereof can be permitted or mixture of these solvents.

39) R ⁷ is a methyl group of the above 26) to 38) salt composition according to any one of the compounds as, tautomers of the compound, or a pharmaceutically or licensed agents such vehicles.

40) A GPR119 activator containing the compound according to any one of 1) to 39), a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture as an active ingredient.

41) The compound of any one of 1) to 39), a tautomer of the compound, or a pharmaceutically acceptable salt thereof or a solvent mixture thereof as an active ingredient, is effective for preventing disease, Treat or/and improve the medicine.

42) A therapeutic agent for diabetes containing the compound according to any one of 1) to 39), a tautomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvent mixture thereof as an active ingredient.

43) A pharmaceutical containing the compound according to any one of 1) to 39), a tautomer of the compound, a pharmaceutically acceptable salt thereof, or a solvent mixture thereof as an active ingredient.

In the present invention, the compound of the formula (I) of the present invention exists, for example, in the ring or the ring, via these mutual variability and geometric anisotropy. In addition to this, it also exists as a mixture of the mixture or the respective isomers. Further, when there is an asymmetric center or as a result of isomerization, when an asymmetric center is generated, it also contains a mixture of optical isomers and an arbitrary ratio. Further, in the case of a compound having two or more asymmetric centers, diastereomers by optical anisotropy may further exist. The compounds of the invention also include all of these types in any proportion. For example, the enantiomer can be isolated by a method well known to those skilled in the art, for example, by a separate crystallization method or the like, and the optically active substance can be obtained by a method of organic chemistry well known for the purpose.

The compound of the formula (I) of the present invention or these pharmaceutically acceptable salts may exist in any crystal form by the production conditions, and may exist as any hydrated form, but these crystal forms or hydrates and these mixtures are also It is included in the scope of the invention. Further, it is also contained as a solvent mixture containing an organic solvent such as acetone, ethanol, 1-propanol or 2-propanol, but these forms are all included in the scope of the present invention.

The pharmaceutically acceptable salt of the formula (I) of the present invention is also contained in the present invention.

The compound of the formula (I) of the present invention can be converted into a pharmaceutically acceptable salt, if necessary, or can be freed from the resulting salt. Examples of the pharmaceutically acceptable salt of the present invention include alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, and organic bases. Amino acid, inorganic acid (hydrochloric acid, hydrogen bromide, phosphoric acid, sulfuric acid, etc.) or organic acid (acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, p-toluene) Salt of acid, etc.).

The prodrug of the compound of the formula (I) of the present invention may also be contained in the present invention.

A prodrug is a derivative of a pharmaceutical compound having a chemically or metabolically decomposable group, which is decomposed into a pharmacologically active substance by decomposition in a solvent or in vivo after being decomposed in physiological conditions. a compound of a pharmaceutical compound. Methods and methods of making appropriate prodrug derivatives, such as those described in Design of Prodrugs (Elsevier, Amsterdam 1985). In the case of a hydroxyl group in the case of the present invention, a prodrug such as a decyloxy derivative which is produced by reacting the compound with an appropriate mercapto halide, a suitable acid anhydride or a suitable haloalkoxycarbonyl compound can be exemplified. As a prodrug, among them, a particularly preferable structure includes -O-COC ₂ H ₅ , -O-CO(t-Bu), -O-COC ₁₅ H ₃₁ , and -O-CO (m-CO ₂ Na-). Ph), -O-COCH ₂ CH ₂ CO ₂ Na, -OCOCH(NH ₂ )CH ₃ , -O-COCH ₂ N(CH ₃ ) ₂ or -O-CH ₂ OC(=O)CH ₃ or the like. When the compound of the present invention has a -NH- group, a prodrug can be produced by reacting a compound having a -NH- group with a suitable acid halide, a suitable mixed acid anhydride or a suitable haloalkoxycarbonyl compound. As a particularly preferable structure of the prodrug, -N-CO(CH ₂ ) ₂₀ OCH ₃ , -N-COCH(NH ₂ )CH ₃ , -N-CH ₂ O(C=O)CH ₃ or the like can be given.

Medicine containing the compound of the present invention as an active ingredient Specific examples of the administration method include oral administration, rectal administration, transdermal absorption or injection.

Specific examples of the pharmaceutical preparation containing the compound of the present invention as an active ingredient include a tablet, a capsule, a powder, a granule, a pill or a syrup.

The agent can be administered as a therapeutic agent or as a mixture with other therapeutic agents.

These can be administered by a monomer, but can also be administered in the form of a general pharmaceutical composition. These preparations can be added according to conventional methods by adding pharmacologically, pharmaceutically acceptable additives. That is, an additive such as a general excipient, a slip agent, a binder, a breaker, a wetting agent, a plasticizer, or a coating agent can be used for the oral preparation.

The oral liquid preparation can be in the form of an aqueous or oily suspension, a solution, an emulsion, a syrup, a mash or the like, or as a dry syrup prepared by using water or other suitable solvent before use. The aforementioned liquid preparations may contain a suspending agent, a perfume, a diluent or a general additive such as an emulsifier.

It can be administered as a suppository when administered intrarectally. The suppository is cocoa butter, lauric fat, polyethylene glycol, glycerin gelatin, weitaisu suppository base (WITEPSOL), sodium stearate or a mixture thereof, and the appropriate substance is used as a base, and an emulsifier or suspension may be added as necessary. Chemical agents, preservatives, etc.

The injection is a preparation component such as a distilled water for injection, a physiological saline solution, a 5% dextrose solution, a propylene glycol or the like, a dissolution aid, a dissolution aid, a pH adjuster, an isotonic agent, a stabilizer, etc., which are in the form of an aqueous or dissolved form. .

When the agent of the present invention is administered to a human, the administration amount may be determined according to the age and state of the patient, and in general, the oral administration or intrarectal administration is 0.1 to 1000 mg/human/day, and the injection is 0.05mg~500mg/human/day degree. These values are for illustration only and the amount of administration must be determined in conjunction with the patient's symptoms.

In addition to primates such as humans, a variety of other mammals can be treated by the methods of the present invention. Although not limited to these, it may be mentioned that it contains a cow, a sheep, a goat, a horse, a dog, a cat, a guinea pig, or another bovine. Sheep (ovine), equine, canine, feline, mouse, and other mammals are treated. Moreover, the method can also be applied to other species such as birds (eg chickens).

Examples of the use of the present invention include diseases related to activation of GPR119, such as prevention, treatment, or/and improvement of diseases such as diabetes. Diabetes in this case includes other diabetes caused by specific causes such as type 1 diabetes, type 2 diabetes, and hereditary. Examples of other diseases related to the regulation of GPR119 include microvascular comorbidities associated with diabetes, macrovascular complications associated with diabetes, circulatory diseases, metabolic disease syndromes (and partial states thereof), and obesity. , lipid abnormalities, arteriosclerosis, renal disorders, neurological disorders, omental disease, delayed wound healing, stroke, cerebral infarction, hypertension, bone disease, vascular disorders, cognitive disorders, dementia, and mental illness. Others are also beneficial for gastrointestinal diseases such as inflammatory bowel disease, ulcerative colitis, and Crohn's disease. And it can also be given to the pancreatic island by the protection of pancreatic β-cells. Stability after transplantation.

In the case of using the present invention, the prevention, treatment, or/and improvement of the disease as described above may be set, but it is not limited thereto.

The compound of the present invention can be synthesized by the method shown below. However, the following synthesis method is exemplified by a general synthesis method, and is not limited to such a synthesis method.

The compound of the present invention is generally obtained by column chromatography, thin layer chromatography, high speed liquid chromatography (HPLC), high speed liquid chromatography/mass analysis (LC/MS), supercritical fluid chromatography (SFC). Purification is carried out, and if necessary, it can be obtained by recrystallization or solvent washing to obtain a high purity.

The acid in the description of the general synthesis method of the compound of the present invention may, for example, be an organic acid such as acetic acid, trifluoroacetic acid or p-toluenesulfonic acid, or an inorganic acid such as sulfuric acid or hydrochloric acid.

Examples of the base in the description of the general synthesis method of the compound of the present invention include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, lithium hydride, and sodium. Alkali metal salts such as guanamine, sodium ethoxide, t-butoxide, sodium t-butoxide, n-butyl lithium, sec-butyl lithium, t-butyl lithium, lithium diisopropyl decylamine, Amines such as pyridine, triethylamine, diisopropylethylamine, pyrrolidine, N-methylpiperidine, diazabicycloundecene, N,N-dimethyl-4-aminopyridine Hexamethyldiazane is a representative decane-based reagent, sodium acetate or potassium acetate.

The solvent in the description of the general synthesis method of the compound of the present invention is only stable under the reaction conditions, and is inert to the reaction. It is not particularly limited, and examples thereof include an anthraquinone solvent represented by dimethyl hydrazine, N,N-dimethylformamide or N,N-dimethyl B. The guanamine is a representative amide solvent, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether as a representative ether solvent, Methyl chloride, chloroform, 1,2-dichloroethane as a representative halogen solvent, acetonitrile, propionitrile as a representative nitrile solvent, benzene, toluene, xylene as a representative aromatic hydrocarbon solvent, hexane, g The hydrocarbon is a representative hydrocarbon solvent, ethyl acetate is a representative ester solvent, methanol, ethanol, 1-propanol, 2-propanol, ethylene glycol as a representative alcohol solvent, and water. Further, the above solvent may be reacted under the conditions of any mixing or solvent-free.

The reaction temperature in the general synthesis method of the compound of the present invention is an appropriate temperature selected from the range of -78 ° C to the boiling point of the solvent used for the reaction, and the synthesis method can be under reduced pressure, under normal pressure, under pressure, under microwave Under the illumination, etc.

In the general synthesis method of the compound of the present invention shown below, the general formula of the intermediate and the final product in each step is shown, but these intermediates and final products also include their precursors. The term "precursor" as used herein means a compound which can be derivatized as a target by hydrolysis, deprotection, reduction, oxidation, alkylation, etc., and includes, for example, a chemically acceptable protective group for the compound. Protected. Protection and deprotection can be achieved by a generally known protection ‧ deprotection reaction (see, for example, Protective Groups in Organic Synthesis, Fourth edition, T. W. Greene, John Wiley & Sons Inc. (2006) Year), etc.).

The hydrolysis, reduction, and oxidation can be carried out by a generally known functional group conversion method (for example, refer to Comprehensive Organic Transformations, Second Edition, R.C. Larock, Wiley-VCH (1999), etc.).

In the general synthesis method shown below, each of the reagents and each of the raw material compounds is appropriately used in an amount of the molar amount or the excess molar amount based on one of the raw material compounds.

The compound of the formula (I) can be synthesized, for example, by the synthesis method of the following Scheme 1. (In the scheme, E represents CONR ³ R ⁴ or an ester, and examples of the ester include methyl ester, ethyl ester, tert-butyl ester, benzyl ester, etc. X ¹ represents a halogen atom, and L represents a halogen. a leaving group such as an atom, a mesylate or a tosylate. Other marks are the same as defined above)

The compound 1-(4) can be synthesized by using the compound 1-(1), the compound 1-(2), the light-expansion reagent, and the phosphine reagent. As a light delay test Examples thereof include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and di-tert-butyl azodicarboxylate. Examples of the phosphinic reagent include three. Phenylphosphinyl and tributylphosphinium, and the like.

The compound 1-(4) can be synthesized by using the compound 1-(1) and the compound 1-(3) in the presence of a base such as a palladium catalyst or a copper catalyst or a base such as sodium hydride.

Compound 1-(4) can be synthesized in stages by the compound 1-(5). When L is a halogen, the compound 1-(5) can be synthesized using the compound 1-(1) and a halogenating agent, and examples of the halogenating agent include sulfinium chloride and phosphorus tribromide. Further, when L is a mesylate or a tosylate, the compound 1-(1), a base, and a sulfhydryl grouping agent can be used for the synthesis. Examples of the base include pyridine and triethylamine. Examples of the sulfhydryl grouping agent include methanesulfonyl chloride and p-toluenesulfonyl chloride.

Compound 1-(4) was synthesized using Compound 1-(5), a base and Compound 1-(2).

Further, when E is an ester, the compound (I) of the present invention can be derived by hydrolysis and dehydration condensation. Examples of the hydrolysis and dehydration condensation include the following.

The compound 1-(6) can be synthesized from the compound 1-(4) under basic conditions such as sodium hydroxide or potassium hydroxide. Further, when E is tert-butyl ester, it can be synthesized under acidic conditions such as hydrogen chloride or trifluoroacetic acid, and when E is a benzyl ester, it can be synthesized by contact hydrogenation.

The compound (I) of the present invention can be synthesized by using the compound 1-(6), NHR ³ R ⁴ and a dehydrating condensing agent. Examples of the dehydrating condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 1-hydroxybenzotriene. Oxazole and carbonyl diimidazole. As another method, the compound 1-(6) is synthesized by reacting with NHR ³ R ⁴ using hydrazine chloride, sulfinium chloride or the like as the hydrazine chloride. In order to allow the reaction to proceed smoothly, it is effective to carry out the reaction in the presence of an acid or a base.

(Material synthesis 1)

The compounds of the following 2-(6), 2-(10) and 2-(11) in the above compound 1-(1) can be synthesized, for example, by the synthesis method of the following Scheme 2. (In the scheme, R ⁵ -M represents an organometallic reagent for the commonly known coupling reaction such as an organic boron reagent, an organic hydrazine reagent, an organic zinc reagent, an organomagnesium reagent, and an organic copper reagent, and X ² represents Chlorine or bromine atom, other marks are the same as defined above)

The compound 2-(2) can be synthesized by using a base such as the compound 2-(1) and sodium hydroxide or potassium carbonate, if necessary, in the presence of hydrogen peroxide. Compound 2-(3) can be synthesized by using the compound 2-(2) with a chlorocarbonylsulfinyl chloride.

The compound 2-(5) can be synthesized using the compound 2-(3) and the compound 2-(4), if necessary under microwave irradiation or in a high-pressure autoclave.

Compound 2-(6) is synthesized using Compound 2-(5) with a reducing agent or using an organometallic reagent. Examples of the reducing agent include a generally known reducing agent such as sodium borohydride, lithium aluminum hydride, and a CBS reducing agent. Examples of the organometallic reagent include an alkyl magnesium halide and a trialkyl aluminum.

Compound 2-(6) can be synthesized via the compound 2-(8).

Compound 2-(8) can be synthesized using Compound 2-(3) and Compound 2-(7), if necessary under microwave irradiation or in a high pressure autoclave.

Compound 2-(6) can be synthesized by using the compound 2-(8), a base and the compound 2-(9). Examples of the base include n-butyllithium and LDA.

Compound 2-(10) can be synthesized using compound 2-(6) with a halogenating agent. Examples of the halogenating agent include succinimide N-chlorosuccinate and succinimide N-bromosuccinate.

The compound 2-(11) can be synthesized using the compound 2-(10) and an organometallic reagent, if necessary in the presence of a metal catalyst and/or a base. Examples of the type of the organometallic reagent include an organic boron reagent, an organic hydrazine reagent, an organic zinc reagent, an organomagnesium reagent, and an organic copper reagent. Examples thereof include an alkylboronic acid, an alkylmagnesium halide, trifluoromethyltrimethylnonane, zinc (II) cyanide, and copper (I) cyanide. Examples of the type of the metal catalyst include a palladium catalyst, a nickel catalyst, a copper catalyst, and an iron catalyst. Examples thereof include decyltriphenylphosphinium palladium (0) and copper (I) iodide. Iron (III) acetoacetate or the like.

(Material Synthesis 2)

Among the above compounds 1-(1), the compound represented by the following 3-(4) can be synthesized, for example, by the synthesis method of the following Scheme 3. (In the process, the mark is the same as the above definition)

Compound 3-(2) can be synthesized using compound 3-(1) with a hydroxylamine. In order to allow the reaction to proceed smoothly, it is effective to carry out the reaction in the presence of an acid or a base.

Compound 3-(4) can be synthesized using Compound 3-(2) with Compound 3-(3) and a halogenating agent. Examples of the halogenating agent include quinone imine N-chlorosuccinate and sodium hypochlorite.

(Material Synthesis 3)

The compound of the following 4-(8) in the above compound 1-(1) can be synthesized, for example, by the synthesis method of the following Scheme 4. (In the process, P Indicates a protecting group, and other tokens are the same as defined above. )

Compound 4-(2) can be synthesized using the compound 4-(1) and an organometallic reagent. Examples of the organometallic reagent include alkyl magnesium halides, trialkyl aluminums, and the like.

Compound 4-(3) can be synthesized using Compound 4-(2) with an oxidizing agent. The oxidizing agent may, for example, be a generally well-known oxidizing agent such as manganese oxide or a Dess-Martin reagent.

Compound 4-(4) can be synthesized using Compound 4-(3) with a deprotected reagent. The deprotection reagent can be selected in accordance with the type of the protecting group P, but a generally well-known method as described in the above reference can be cited.

The compound 4-(7) can be synthesized by using a copper catalyst such as a compound 4-(4) with a base such as 4-(5) or pyridine or copper (II) acetate.

Compound 4-(7) can be synthesized using compound 4-(6) in the presence of a metal catalyst and/or a base. Examples of the type of the metal catalyst include a palladium catalyst and a copper catalyst.

Compound 4-(8) is a compound 4-(7) and a reducing agent, Or use an organometallic reagent for synthesis. Examples of the reducing agent include a generally known reducing agent such as sodium borohydride, lithium aluminum hydride, and a CBS reducing agent. Examples of the organometallic reagent include an alkyl magnesium halide and a trialkyl aluminum.

As another method, the compound of the following 5-(8) in the above compound 1-(4) can be synthesized, for example, by the synthesis method of the following Scheme 5. (In the scheme, M represents a metal species used in a generally well-known coupling reaction such as boron, tin, antimony, zinc, and magnesium, and other symbols are the same as defined above.)

The compound 5-(1) can be synthesized, for example, by the method described in RSC Advances, 2014, 4, 7735-7748.

Compound 5-(2) can be synthesized using Compound 5-(1) with a reducing agent. Examples of the reducing agent include hydrogenated isobutyl aluminum and the like.

Compound 5-(3) can be synthesized using the compound 5-(2) and an organometallic reagent. Examples of the organometallic reagent include alkyl lithium, alkyl magnesium halide, and trialkyl aluminum.

Compound 5-(6) can be used as compound 5-(3), compound 5- (4), light-diffusing reagents and phosphine reagents for synthesis. Examples of the light-expansion reagent include diethyl azodicarboxylate, diisopropyl azodicarboxylate, and di-tert-butyl azodicarboxylate, as examples of phosphinic acid reagents. Triphenylphosphinium and tributylphosphinium can be mentioned.

The compound 5-(6) can be synthesized using a compound 5-(3) or a compound 5-(5) in the presence of a base such as a palladium catalyst or a copper catalyst and/or a potassium tert-butoxide. .

The compound 5-(8) can be synthesized by using the compound 5-(6) and the compound 5-(7), if necessary in the presence of a metal catalyst and/or a base. Examples of the type of the metal catalyst include a palladium catalyst and a nickel catalyst, and examples thereof include decyltriphenylphosphinium palladium (0).

[Examples]

Hereinafter, the present invention will be described in more detail with reference to Synthesis Examples, Synthesis Examples, Evaluation Examples, and Preparation Examples, but the present invention is not limited by the examples.

Further, in the examples, NMR indicates a nuclear magnetic resonance spectrum, and LC/MS indicates a liquid chromatography/mass analysis. The description of Ex in the table and the figure indicates a synthesis example, and Structure indicates a chemical structural formula.

When the ¹ H-NMR data is described, it is measured at 300 MHz (JNM-ECP300; manufactured by JEOL Co., Ltd., or JNM-ECX300; manufactured by JEOL Co., Ltd.), and tetramethyl decane is used as an internal standard. The chemical shift of the message δ (unit: ppm) (split pattern, integral value). "s" means single weight, "d" means double, "t" means triple, "q" means quadruple, "quint" means five, "sextet" means six, "septet" means seven, "dd" Double in double, "m" means multiple, "br" means wide, "brs" means wide single weight, "J" means coupling constant, "CDCl ₃ " means heavy chloroform, "CD ₃ OD" means heavy methanol, "DMSO-d ₆ " means heavy dimethyl sulfoxide.

When the purification of the ruthenium column chromatography is not particularly described, any of Hi-Flash column, Merck 矽 60, Fujitsu Chemical PSQ60B or Biotage SNAP column can be used.

When the purification of the silica gel thin layer chromatography was not specifically described, a PLC plate made of Merck was used.

The microwave reaction apparatus was an Initiator sixty manufactured by Biotage.

When an absolute configuration is described, the absolute configuration is known as a compound or derived from a known compound, or by a single crystal X-ray crystal structure (device: SMART APEX II ULTRA (Bruker AXS, Inc.), X-ray: CuKa (50 kV, 24 mA), measurement temperature: -50 ° C).

When "*" (asterisk) is described in the structural formula of the embodiment, the absolute arrangement is not determined, but it is an optically active substance. Further, when it is described as Isomer A and Isomer B, each is a stereoisomer.

LC/MS was measured by ESI (electrospray ionization) under the following conditions, "ESI ⁺ " indicates ESI positive ion mode, and "ESI ^- " indicates ESI negative ion mode. Further, "RT" indicates the retention time of the compound, and "cond." indicates the condition.

For each chromatographic method and experimental operation, "numerical/numerical" indicates the volume ratio of each solvent unless otherwise specified.

LC/MS cond.1:

Device: Waters ACQUITY UPLC H CLASS/SQ Detector 2

Column: ACQUITY UPLC BEH C18 (1.7μm, 2.1×50mm)

Column temperature: 40 ° C

Solvent:

Liquid A: 0.1% formic acid aqueous solution

Solution B: 0.1% formic acid-acetonitrile solution

Gradient conditions:

The flow rate was 0.6 mL/min, the mixing ratio of the A liquid and the B liquid was 90/10, and the linear change was 10/90 at 3 minutes after the start of the measurement.

Thereafter, the mixing ratio of the A liquid to the B liquid was fixed at 10/90 in 0.7 minutes.

At the next 0.1 minutes, the mixing ratio of the A liquid and the B liquid was linearly changed to 90/10, and the flow rate linearly changed by 0.8 mL/min.

The mixing ratio of the A liquid and the B liquid was fixed at 90/10 in one minute thereafter.

Detection wavelength: PDA (190-500nm)

LC/MS cond.2:

Device: Waters ACQUITY UPLC/Thermo LTQ XL

Column: Waters AQUITY UPLC BEH C18 (1.7μm, 2.1×50mm)

Column temperature: 40 ° C

Solvent:

Liquid A: 0.1% formic acid aqueous solution

Solution B: 0.1% formic acid-acetonitrile solution

Gradient conditions:

The flow rate was 0.6 mL/min, and the mixing ratio of the A liquid and the B liquid was fixed at 90/10, and the mixing ratio of the A liquid and the B liquid was linearly changed to 10/90 at 2.5 minutes after 0.5 minutes.

Thereafter, the mixing ratio of the A liquid and the B liquid was fixed at 10/90 in 0.7 minutes, and then the mixing ratio of the A liquid and the B liquid was linearly changed to 90/10 at 0.1 minute, and the flow rate linearity was changed to 0.8 mL/min. Then fixed for 1 minute.

Detection wavelength: PDA (190-399nm)

LC/MS cond.3:

Device: Waters ACQUITY UPLC/Thermo LTQ XL

Column: Waters AQUITY UPLC BEH C18 (1.7μm, 2.1×50mm)

Column temperature: 40 ° C

Solvent:

Liquid A: 0.1% formic acid aqueous solution

Solution B: 0.1% formic acid-acetonitrile solution

Gradient conditions:

The flow rate is 0.6 mL/min, and the mixing ratio of the A liquid and the B liquid is fixed at 80/20, and the mixing ratio of the A liquid and the B liquid is straight in 2.5 minutes. The change in sex is 0/100.

Then, the mixing ratio of the A liquid and the B liquid was fixed at 0/100 in 1.2 minutes, and then the mixing ratio of the A liquid and the B liquid was linearly changed to 80/20 in 0.1 minutes, and the linearity of the flow rate was changed to 0.8 mL/min. Then fixed for 1 minute.

Detection wavelength: PDA (190-399nm)

LC/MS cond.4:

Device: Waters UPLC-TUV-ELSD

Column: Waters AQUITY UPLC BEH C18 (1.7μm, 2.1×50mm)

Column temperature: 40 ° C

Solvent:

Liquid A: 0.1% formic acid aqueous solution

Solution B: 0.1% formic acid-acetonitrile solution

Gradient conditions:

The flow rate was 0.6 mL/min, and the mixing ratio of the A liquid and the B liquid was fixed at 90/10, and the mixing ratio of the A liquid and the B liquid was linearly changed to 10/90 at 1.5 minutes after 0.5 minutes.

Thereafter, the mixing ratio of the A liquid and the B liquid was fixed at 10/90 in 0.8 minutes, and then the mixing ratio of the A liquid and the B liquid was linearly changed to 90/10 in 0.1 minutes, and the linearity of the flow rate was changed to 0.8 mL/min. , fixed 1 minute later. Thereafter, the flow rate was changed to 0.6 mL/min at 0.1 minutes.

Detection wavelength: UV (254nm)

Reference Synthesis Example 1 2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester

(1) 4-cyano-2-fluorobenzoic acid tert-butyl ester

In a solution of 4-cyano-2-fluorobenzoic acid (5.00 g, 30.3 mmol) in tetrahydrofuran (25 mL), tert-butanol (50 mL) and N,N-dimethyl-4-amine The pyridine (370 mg, 3.03 mmol) was stirred at 60 ° C, and di-tert-butyl dicarbonate (13.2 g, 60.6 mmol) was further added to the reaction mixture, and stirred at 60 ° C for 3 hours. To the reaction mixture was added 28% aqueous ammonia, and the mixture was extracted with a 1/1 mixture of hexane and ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to afford 4-(c-c- </RTI> &lt;RTI ID=0.0&gt; Colorless solid.

^{1 H-NMR (300MHz, CDCl} 3) δ: 1.59 (s, 9H), 7.38-7.42 (m, 1H), 7.46-7.49 (m, 1H), 7.92-7.97 (m, 1H).

(2) 4-aminomethylmercapto-2-fluorobenzoic acid tert-butyl ester

Add potassium carbonate (1.12 g, 8.14 mmol) and 30% at 0 ° C in a solution of 4-cyano-2-fluorobenzoic acid tert-butyl ester (6.00 g, 27.1 mmol) in dimethyl hydrazine (10 mL). Hydrogen peroxide water (3.8 mL) was stirred at room temperature for 5 minutes. Water was added to the reaction mixture, and the precipitated solid was filtered. The obtained solid was completely dissolved in a 1/1 mixture of 2-propanol and toluene, and concentrated under reduced pressure. After further adding ethyl acetate and completely dissolving, it was dried over anhydrous magnesium sulfate, and filtered under reduced pressure to give 4-aminomethylmercapto-2-fluorobenzoic acid tert-butyl ester (6.24 g, yield 96%) ) a colorless solid.

MS (ESI ⁺ ): 240 [M+H] ⁺ . (LC/MS cond.2, RT=1.90min)

(3) 2-fluoro-4-(2-oxo-1,3,4-oxathiazol-5-yl)benzoic acid tert-butyl ester

To a solution of 4-aminomethylmercapto-2-fluorobenzoic acid tert-butyl ester (6.00 g, 25.1 mmol) in toluene (100 mL), 1,4-dioxane (30 mL) and carbonic acid at room temperature Potassium (10.4 g, 75.3 mmol) was stirred at 100 °C. Further, chlorocarbonylsulfinyl chloride (3.94 g, 30.1 mmol) was added dropwise to the reaction mixture, and the mixture was allowed to stand at 100 ° C for 2 hours. Stir. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→90/10) to give 2-fluoro-4-(2-oxo-1,3,4-ox. Thiazol-5-yl) tert-butyl benzoate (5.29 g, 71% yield) as a colorless solid.

^{1 H-NMR (300MHz, CDCl} 3) δ: 1.61 (s, 9H), 7.69-7.73 (m, 1H), 7.76-7.79 (m, 1H), 7.94-7.99 (m, 1H).

(4) 4-(5-Ethylisothiazol-3-yl)-2-fluorobenzoate tert-butyl ester

2-fluoro-4-(2-oxo-1,3,4-oxathiazol-5-yl)benzoic acid tert-butyl ester (2.49 g, 8.38 mmol), 3-butyne was sealed in a reaction vessel for microwave synthesis. 2-ketone (1.94 mL, 25.1 mmol) and o-xylene (15 mL) were stirred at 170 ° C for 3 hours under microwave irradiation. The reaction mixture was cooled and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→85/15) to give 4-(5-ethyiisothiazol-3-yl)-2-fluorobenzoin Acid tert-butyl ester (723 mg, yield 27%) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62 (s, 9H), 2.67 (s, 3H), 7.60-7.76 (m, 2H), 7.94-7.99 (m, 2H).

To a solution of (5) 4-(5-ethyiisothiazol-3-yl)-2-fluorobenzoate tet-butyl ester (150 mg, 0.467 mmol) in tetrahydrofuran (4.0 mL), sodium borohydride at 0 ° C (22.0 mg, 0.560 mmol) was stirred at room temperature for 2 hours. Saturated brine was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO.

¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.61 (s, 9H), 1.68 (d, J = 6.6 Hz, 3H), 2.25 (d, J = 5.1 Hz, 1H), 5.31 (m, 1H), 7.44 (d, J = 1.2 Hz, 1H), 7.66-7.73 (m, 2H), 7.92 (t, J = 7.2 Hz, 1H).

Reference Synthesis Example 2 (S)-2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester

(1) 2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester

4-(5-Ethylisothiazol-3-yl)-2-fluorobenzoic acid tert-butyl ester (250 mg, 0.779 mmol) and (R) obtained under reference to the synthesis example 1-(4) under argon atmosphere a solution of -5,5-diphenyl-2-methyl-3,4-propanol-1,3,2-oxazol borane (21.5 mg, 0.0776 mmol) in dichloromethane (5.0 mL) A 2 M solution of dimethyl sulfide borane in tetrahydrofuran (584 μL, 1.17 mmol) was added at 0 ° C over 2 hours and stirred at 0 ° C for 15 hours. Methanol was added to the reaction mixture, and the mixture was evaporated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15→70/30) to give 2-fluoro-4-[5-(1-hydroxyethyl)isothiazole- 3-amino]tert-butyl benzoate (239 mg, yield 95%, S-body - optical purity 51% ee) of an orange solid.

(2) 2-Fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester (239 mg, S-body - optical purity 51% ee) as a chiral column Perform optical separation. The classification conditions are shown below.

‧Chiral column: CHIRALFLASH (registered trademark) IA (inner diameter 30mm, length 100mm, Daicel Co., Ltd.)

‧ Temperature: room temperature

‧Flow rate: 10mL/min

‧ Gradient conditions:

0-10min: hexane/ethanol = 100/0

10-20min: hexane/ethanol = 100/0 → 95/5

20-170min: hexane/ethanol = 95/5

By concentrating the fraction having a holding time of 100-170 min, (S)-2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid is obtained. A pale orange solid of tert-butyl ester (155 mg, yield 62%, optical purity 99% ee).

¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.61 (s, 9H), 1.68 (d, J = 6.6 Hz, 3H), 2.25 (d, J = 5.1 Hz, 1H), 5.31 (m, 1H), 7.44 (d, J = 1.2 Hz, 1H), 7.66-7.73 (m, 2H), 7.92 (t, J = 7.2 Hz, 1H).

Reference Synthesis Example 3 (R)-2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester

2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester obtained by the same method as Reference Synthesis Example 2-(1) by chiral tube The column was subjected to optical resolution under the same conditions as in Reference Synthesis Example 2-(2). The fraction having a holding time of 60-100 min was concentrated to obtain a pale orange solid of (R)-2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester. (50.0 mg, optical purity 99% ee).

¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.61 (s, 9H), 1.68 (d, J = 6.6 Hz, 3H), 2.25 (d, J = 5.1 Hz, 1H), 5.31 (m, 1H), 7.44 (d, J = 1.2 Hz, 1H), 7.66-7.73 (m, 2H), 7.92 (t, J = 7.2 Hz, 1H).

Further, the optical purity of Reference Synthesis Example 2 and Reference Synthesis Example 3 was determined by the following analysis conditions.

‧ Chiral column: CHIRALPAK (registered trademark) IA-3 (inner diameter 4.6mm, length 150mm, particle diameter 3μm, Daicel Co., Ltd.)

‧ Temperature: 40 ° C

‧Flow rate: 1.5mL/min

‧Dissolved solution: hexane/ethanol=95/5

‧Detection wavelength: 254nm

‧Retention time: 12.07min (refer to Synthesis Example 2), 9.11min

(Refer to Synthesis Example 3) Reference Synthesis Example 4 2-fluoro-4-[5-(1-hydroxypropyl)isothiazol-3-yl]benzoic acid tert-butyl ester

(1) 3-[4-(tert-Butoxycarbonyl)-3-fluorophenyl]isothiazole-5-carboxylic acid ethyl ester

2-fluoro-4-(2-oxo-1,3,4-oxathiazol-5-yl)benzoic acid tert-butyl ester (2.00 g, 6.73 mmol), propiolate B was enclosed in a reaction vessel for microwave synthesis The ester (1.65 g, 16.8 mmol) and o-xylene (10 mL) were stirred at 170 ° C for 4 hours under microwave irradiation. The reaction mixture was cooled and concentrated under reduced pressure. To the obtained residue, tetrahydrofuran (10 mL), tert-butanol (20 mL) and N,N-dimethyl-4-aminopyridine (41.0 mg, 0.336 mmol) were added at room temperature, and stirred at 60 ° C. Further, di-tert-butyl dicarbonate (2.93 g, 13.4 mmol) was further added to the reaction mixture, and the mixture was stirred at 60 ° C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with a 1/1 mixture of hexane and ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→90/10) to give 3-[4-(tert-butoxycarbonyl)-3-fluorophenyl. Ethyl isothiazole-5-carboxylate (864 mg, yield 37%) as a colorless solid.

¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.43 (t, J = 7.2 Hz, 3H), 1.62 (s, 9H), 4.44 (q, J = 7.2 Hz, 2H), 7.71-7.77 (m, 2H) ), 7.96 (t, J = 8.9 Hz, 1H), 8.12 (s, 1H).

(2) 2-fluoro-4-[5-(hydroxymethyl)isothiazol-3-yl]benzoic acid tert-butyl ester

Ethyl 3-[4-(tert-butoxycarbonyl)-3-fluorophenyl]isothiazole-5-carboxylate (646 mg, 1.84 mmol) in tetrahydrofuran (5.0 mL) Sodium borohydride (209 mg, 5.52 mmol) was added to a solution of methanol (7.0 mL) at 0 ° C, and stirred at 0 ° C for 6 hours. Saturated brine was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. 613 mg) of a colorless solid.

MS (ESI ⁺ ): 310 [M+H] ⁺ . (LC/MS cond.2, RT=2.42min)

(3) 2-fluoro-4-(5-methylmercaptoisothiazol-3-yl)benzoic acid tert-butyl ester

To a solution of the crude product of tert-butyl 2-fluoro-4-[5-(hydroxymethyl)isothiazol-3-yl]benzoate (613 mg) in dichloromethane (15 mL) 5.64 mmol), iodine (543 mg, 2.14 mmol) and 2-azaadamantane-N-oxyl (30.0 mg, 0.197 mmol) were stirred at room temperature for 3 hours. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture, and extracted with dichloromethane. The organic layer was dried with anhydrous magnesium sulfate and filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 5/1) to give 2-fluoro-4-(5-methylmercaptoisothiazol-3-yl)benzoic acid tert- Butyl ester (362 mg, yield 64% (2 steps)) as a colorless solid.

¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.62 (s, 9H), 7.70- 7.80 (m, 2H), 7.90-8.01 (m, 1H), 8.11 (s, 1H), 10.16 (s, 1H) .

MS (ESI ^-): 324 [M + H ₂ OH] ^-. (LC/MS cond.2, RT=2.83min)

(4) In a solution of 2-fluoro-4-(5-methylmercaptoisothiazol-3-yl)benzoic acid tert-butyl ester (360 mg, 1.17 mmol) in dichloromethane (6.0 mL), at 0 ° C A 0.95 M solution of triethylaluminum-toluene (1.85 mL, 1.76 mmol) was stirred at 0 ° C for 1 hour. A saturated aqueous ammonium chloride solution and 1 M hydrochloric acid were added to the mixture, and the mixture was extracted with dichloromethane. The organic layer was dried with anhydrous magnesium sulfate and filtered and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjj

¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.06 (t, J = 7.5 Hz, 3H), 1.61 (s, 9H), 1.91-1.97 (m, 2H), 2.25 (d, J = 4.8 Hz, 1H) ), 5.05-5.10 (m, 1H), 7.44 (s, 1H), 7.66-7.73 (m, 2H), 7.92 (t, J = 7.2 Hz, 1H).

MS (ESI ⁺ ): 338 [M+H] ⁺ . (LC/MS cond.2, RT=2.70min)

Reference Synthesis Example 5 Methyl 2-fluoro-4-[5-(1-hydroxyethyl)isoxazol-3-yl]benzoate

(1) Methyl 2-fluoro-4-methionyl benzoate

To a solution of 2-fluoro-4-carboxylic acid (1.00 g, 5.98 mmol) in N,N-dimethylformamide (10 mL), sodium hydride (55% by weight in mineral oil) at 0 ° C The dispersion, 312 mg, 7.14 mmol) was stirred at room temperature for 20 minutes, then io methane (1.69 g, 11.9 mmol) was added to the reaction mixture and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed three times with saturated aqueous ammonium chloride. The organic layer was dried with anhydrous magnesium sulfate and filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1 → 1/1) to give methyl 2-fluoro-4-carbazyl benzoate (820 mg, yield 75 %) of a pale yellow solid.

¹ H-NMR (300MHz, CDCl ₃ ) δ: 3.97 (s, 3H), 7.64 (dd, J = 10.1, 1.5 Hz, 1H), 7.72 (dd, J = 7.9, 1.5 Hz, 1H), 8.10 (dd , J = 7.7, 7.1 Hz, 1H), 10.0 (s, 1H).

(2) 2-fluoro-4-[(hydroxyimine)methyl]benzoic acid methyl ester

Hydroxyamine hydrochloride (153 mg, 2.20 mmol) and sodium acetate (180 mg, 2.20 mmol) were added to a solution of methyl 2-fluoro-4-carbamoylbenzoate (200 mg, 1.10 mmol) in ethanol (2.0 mL). Stir at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate was evaporated and evaporated. The organic layer was dried over anhydrous magnesium sulfate (MgSO4).

¹ H-NMR (300MHz, CDCl ₃ ) δ: 3.96 (s, 3H), 7.69 (dd, J = 10.3, 9.5 Hz, 2H), 8.11 (t, J = 9.5 Hz, 1H), 10.0 (s, 1H) ).

(3) A solution of a crude product of methyl 2-fluoro-4-[(hydroxyimine)methyl]benzoate (217 mg, 1.10 mmol) in dichloromethane (6.0 mL) After adding succinimide (147 mg, 1.10 mmol) of N-chlorosuccinate, the mixture was stirred at room temperature for 1 hour, and then 3-butyn-2-ol (92.5 mg, 1.32 mmol) was added to the reaction mixture. The mixture was stirred for 3 days at a temperature, and stirred at 45 ° C for 4 hours. Ethyl acetate was added to the reaction mixture, which was washed with saturated aqueous sodium hydrogen sulfate. The organic layer was dried with anhydrous magnesium sulfate and filtered and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjj

MS (ESI ⁺ ): 266 [M+H] ⁺ . (LC/MS cond. 2, RT = 1.87 min)

Reference Synthesis Example 6 Methyl 2-fluoro-4-[5-(1-hydroxypropyl)isoxazol-3-yl]benzoate

The same reaction as in Reference Synthesis Example 5-(3) was carried out, except that 1-butyn-2-ol was used instead of 1-butyn-2-ol, to give the title compound (48 mg, yield 11%). Light yellow solid.

¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.04 (t, J = 7.6 Hz 3H), 1.80-2.10 (m, 2H), 2.94 (brs, 1H), 3.95 (s, 3H), 4.80-4.90 ( m, 1H), 6.54 (s, 1H), 7.50-7.68 (m, 2H), 7.91 - 8.08 (m, 1H).

Reference Synthesis Example 7 {3-Fluoro-4-[(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane-6-yl)amine A Mercapto]phenyl}boronic acid

Under a nitrogen atmosphere, 4-carboxy-3-fluorobenzeneboronic acid (1.18 g, 6.42 In a solution of mmol, N,N-dimethylformamide (35 mL), 2,2,3,3,9,9,10,10-octamethyl-4,8- Dioxa-3,9-disilaundecane-6-amine (3.07 g, 9.62 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.47 g, 7.68 mmol) and 1-hydroxybenzotriazole (865 mg, 6.40 mmol) were stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted once with chloroform. The organic layer was washed twice with a saturated aqueous solution of ammonium chloride. The organic layer was dried with anhydrous magnesium sulfate and filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

¹ H-NMR (300MHz, CDCl ₃ ) δ: 0.00 (d, J = 2.5 Hz, 12H), 0.83 (s, 18H), 3.52-3.63 (m, 2H), 3.75-3.84 (m, 2H), 4.13 (brs, 1H), 7.34 - 7.63 (m, 3H), 7.91 - 8.07 (m, 1H).

Reference Synthesis Example 8 6-(5-isopropyl-1,2,4-oxadiazol-3-yl)pyridin-3-ol

(1) 5-[(4-Methoxybenzyl)oxy]methylpyridinecarbonitrile

Add sodium hydride (11.0 g, 274 mmol) at room temperature to a solution of 4-methoxybenzyl alcohol (22.7 g, 164 mmol) in N,N-dimethylformamide (250 mL) Stir for 15 minutes. 5-Bromo-2-cyanopyridine (25.0 g, 137 mmol) was added to the reaction mixture, and the mixture was stirred at 70 ° C for 2 hours. The reaction mixture was cooled to 0.degree. C., aq. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (chloroform) to give 5-[(4-methoxyphenylmethyl)oxy]methylpyridonitrile (14.4 g, yield 44%) as a yellow solid. .

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 3.83 (s, 3H), 5.04 (s, 2H), 6.79 (dd, J = 6.6,2.1Hz, 2H), 7.26-7.35 (m, 3H), 7.63 ( d, J = 8.7 Hz, 1H), 8.43 (d, J = 2.7 Hz, 1H).

MS (ESI ^+): 241 [M + H] ^{+, MS (ESI -):} . 239 [MH] ^-. (LC/MS cond.2, RT=2.20min)

(2) (Z)-N'-hydroxy-5-[(4-methoxybenzyl)oxy]methylpyridinium imine amide

Add a hydroxylamine (50% aqueous solution, 382 μL, 6.24 mmol) to a solution of 5-[(4-methoxybenzyloxy)methylpyridinonitrile (500 mg, 2.08 mmol) in EtOAc (EtOAc) Stirring was carried out at 80 ° C for 2 hours and 20 minutes. The reaction mixture was cooled, water was added and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give (3)-N--hydroxy-5-[(4-methoxybenzyl)oxy]methylpyridinium imineamine as a crude product (425 mg. Rate 75%) of a yellow solid.

MS (ESI ⁺ ): 274 [M+H] ⁺ . (LC/MS cond.2, RT=1.55min)

(3) 5-Isopropyl-3-{5-[(4-methoxybenzyl)oxy]pyridin-2-yl}-1,2,4-oxadiazole

a solution of (Z)-N'-hydroxy-5-[(4-methoxybenzyl)oxy]methylpyridinium imide amide (425 mg, 1.56 mmol) in pyridine (2.13 mL) Isobutylguanidinyl chloride (180 μL, 1.72 mmol) was added at room temperature, and stirred at 100 ° C for 2 days. The reaction mixture was cooled and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (hexane/ Ethyl acetate = 3/1) was purified to give 5-isopropyl-3-{5-[(4-methoxybenzyl)oxy]pyridin-2-yl}-1,2,4- Oxadiazole (472 mg, yield 95%) of a colorless solid.

MS (ESI ⁺ ): 326 [M+H] ⁺ . (LC/MS cond.2, RT=2.46min)

(4) 5-isopropyl-3-{5-[(4-methoxybenzyl)oxy]pyridin-2-yl}-1,2,4-oxadiazole (472 mg, 1.45 mmol) In a dichloromethane (4.7 mL) solution, trifluoroacetic acid (944 μL) was added at room temperature, and stirred at room temperature for 4 hours. A saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc EtOAcjjjj(

Reference Synthesis Example 9 1-(5-hydroxypyridin-2-yl)-2-methylpropan-1-one

(1) 1-{5-[(4-Methoxybenzyl)oxy]pyridin-2-yl}-2-methylpropan-1-one

To a solution of 5-[(4-methoxybenzyl)oxy]methylpyridinecarbonitrile (500 mg, 2.08 mmol) in tetrahydrofuran (10 mL) Isopropyl magnesium bromide (15% tetrahydrofuran solution, 3.38 mL, 2.50 mmol) was stirred at room temperature for 3.5 hours. After a saturated aqueous solution of ammonium chloride was added and the mixture was evaporated to ethyl ether. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1→2/1) to give 1-{5-[(4-methoxybenzyl)oxy] Pyridin-2-yl}-2-methylpropan-1-one (541 mg, yield 91%) as a pale yellow solid.

MS (ESI ^+): 286 [M + H] ^{+, MS (ESI -):} . 284 [MH] ^-. (LC/MS cond.2, RT=2.62min)

(2) Substituting 1-isopropyl-3-{5-[(4-methoxybenzyl)oxy]pyridin-2-yl}-1,2,4-oxadiazole The same reaction as in Reference Synthesis Example 8-(4) was carried out except for {5-[(4-methoxybenzyl)oxy]pyridin-2-yl}-2-methylpropan-1-one. The title compound (328 mg, yield quantitative) was obtained as a colourless solid.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 1.20 (d, J = 6.9Hz, 6H), 4.00-4.20 (m, 1H), 7.29 (dd, J = 8.7,3.0Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 8.30 (d, J = 3.0 Hz, 1H).

MS (ESI ^+): 166 [M + H] ^{+, MS (ESI -):} . 164 [MH] ^-. (LC/MS cond. 2, RT = 1.46 min)

Reference Synthesis Example 10 1-(5-hydroxypyridin-2-yl)-2,2-dimethylpropan-1-one

(1) 1-{5-[(4-Methoxybenzyl)oxy]pyridin-2-yl}-2,2-dimethylpropan-1-one

To a solution of 5-[(4-methoxybenzyl)oxy]methylpyridinecarbonitrile (500 mg, 2.08 mmol) in tetrahydrofuran (10 mL) Tert-butyl magnesium bromide (2M diethyl ether solution, 1.25 mL, 2.50 mmol) was stirred at room temperature for 2 days. After a saturated aqueous solution of ammonium chloride was added and the mixture was evaporated to ethyl ether. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1→2/1) to give 1-{5-[(4- Phenoxybenzyl)oxy]pyridin-2-yl}-2,2-dimethylpropan-1-one (128 mg) as a yellow solid.

(2) Substituting 1-isopropyl-3-{5-[(4-methoxybenzyl)oxy]pyridin-2-yl}-1,2,4-oxadiazole Except for {5-[(4-methoxybenzyl)oxy]pyridin-2-yl}-2,2-dimethylpropan-1-one, substantially the same as Reference Synthesis Example 8-(4) After the same reaction, the title compound (41 mg, yield: 53%)

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 1.42 (s, 9H), 7.21 (dd, J = 8.7,2.7Hz, 1H), 7.93 (d, J = 8.1Hz, 1H), 8.23 (d, J = 2.7 Hz, 1H).

MS (ESI ^+): 180 [M +] ^{+, MS (ESI -):} . 178 [MH] ^-. (LC/MS cond.2, RT=1.96min)

Reference Synthesis Example 11 2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid

To a solution of 4-(5-ethyiisothiazol-3-yl)-2-fluorobenzoic acid tert-butyl ester (3.21 g, 10.0 mmol) in tetrahydrofuran (30 mL) obtained with reference to the synthesis of 1-(4) Sodium borohydride (454 mg, 12 mmol) was added at room temperature and 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 dried over anhydrous sodium sulfate It was dried and concentrated under reduced pressure by filtration. The residue was purified by silica gel column chromatography (hexane /EtOAc Trifluoroacetic acid (3.0 mL) was added to the obtained yellow oil and stirred at room temperature for 30 min. The reaction mixture was combined with EtOAc (EtOAc m.

MS (ESI ^+): 268 [M + H] ^{+, MS (ESI -):} . 266 [MH] ^-. (LC/MS cond.1, RT=1.59min)

Reference Synthesis Example 12 N-{(S)-1-amino-3-[(tert-butyldimethylmethyl)oxy]-1-oxopropan-2-yl}-2-fluoro-4-[5- (1-hydroxyethyl)isothiazol-3-yl]benzoguanamine

N,N-dimethylformamidine of 2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid (2.02 g, 7.56 mmol) obtained in Reference Synthesis Example 11 To a solution of the amine (10 mL), (S)-2-amino-3-[(tert-butyldimethylmethyl)oxy]propane decylamine (1.98 g, 9.07 mmol, Synthesis, 45 (10) , 1300-1311; synthesized according to the method described in 2013), 1-hydroxybenzotriazole (1.02 g, 7.56 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl The carbodiimide hydrochloride (2.90 g, 15.1 mmol) was stirred at room temperature for 16 hours. reaction After the end, water was added and extraction was carried out with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by EtOAc EtOAcjjjj(

MS (ESI ⁺ ): 468 [M+H] ⁺ . (LC/MS cond.1, RT=2.50min)

¹ H-NMR (300MHz, CDCl ₃ ) δ: 0.13 (d, J = 5.7 Hz, 6H), 0.92 (s, 9H), 1.65 (d, J = 6.6 Hz, 3H), 3.35-3.42 (m, 1H) ), 3.74 (dd, J = 9.9, 7.2 Hz, 1H), 4.20 (dd, J = 9.9, 3.6 Hz, 1H), 4.65 (brs, 1H), 5.23-5.32 (m, 1H), 5.81 (brs, 1H), 6.60 (brs, 1H), 7.39 (s, 1H), 7.65-7.80 (m, 3H), 8.50 (t, J = 8.1 Hz, 1H).

Reference Synthesis Example 13 (S)-2-amino-4-hydroxybutane decylamine

To (S)-3-aminopyrrolidin-2-one hydrochloride (138 mg, 1.00 mmol) was added 28% aqueous ammonia (2.0 mL), and stirred at room temperature for 16 hours. After the end of the reaction, it was concentrated under reduced pressure. Ethyl alcohol (2.0 mL) was added to the residue, and the residue was evaporated to dryness crystals crystals crystals

Reference Synthesis Example 14 (R)-2-amino-4-hydroxybutane decylamine

Instead of using (S)-3-aminopyrrolidin-2-one hydrochloride, (R)-3-aminopyrrolidin-2-one hydrochloride (138 mg, 1.00 mmol) was used, and substantially The title compound (118 mg, quantitative yield) was obtained as a colorless crystals.

Reference Synthesis Example 15 (S)-3-amino-4-hydroxybutane decylamine

(S)-4-Aminodihydrofuran-2(3H)-one hydrochloride (138 mg, 1.00 mmol) was used instead of (S)-3-aminopyrrolidin-2-one hydrochloride. The same reaction as in Reference Synthesis Example 13 was carried out to give the title compound (119 mg, yield quantitative) as a colorless amorphous material.

Reference Synthesis Example 16 (S)-3-Amino-4,4,4-trifluorobutan-1-ol hydrochloride

(S)-3-Amino-4,4,4-trifluorobutanoic acid ethyl (D)-(-)-tartrate (340 mg, 1.00 mmol, Journal of Fluorine Chemistry, 131(4), 477 -486; Synthesis according to the method described in 2010) A saturated aqueous solution of sodium hydrogencarbonate was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. Lithium aluminum hydride (75.9 mg, 2.00 mmol) was added to a solution of the obtained colorless oil in THF (2OmL), and stirred at room temperature for 2 hours. A 1 M aqueous sodium hydroxide solution (2.0 mL) was added to the reaction mixture, and stirred at room temperature for 30 minutes. Further, 4-tert-butyl dicarbonate (218 mg, 1.00 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was extracted with EtOAc. A 4 M hydrogen chloride/dioxane solution (1.0 mL) was added to the obtained colorless oil, and stirred at room temperature for 16 hours. After the reaction was completed, it was concentrated under reduced pressure. Ethyl alcohol was added to the residue, and the residue was evaporated.

MS (ESI ⁺ ): 144 [M+H] ⁺ . (LC/MS cond.1, RT=1.72min)

Reference Synthesis Example 17 (R)-3-Amino-4,4,4-trifluorobutan-1-ol hydrochloride

Instead of using (S)-3-amino-4,4,4-trifluorobutanoic acid ethyl(D)-(-)-tartrate, (R)-3-amino-4,4,4 -Trifluorobutanoic acid ethyl (L)-(+)-tartrate (340 mg, 1.00 mmol, Journal of Fluorine Chemistry, 131(4), 477-486; synthesized according to the method described in 2010) The reaction of the title compound (178 mg, yield quantitative) was obtained as a colorless oil.

MS (ESI ⁺ ): 144 [M+H] ⁺ . (LC/MS cond.1, RT=1.72min)

Reference Synthesis Example 18 (S)-2-amino-3-hydroxy-N-methylpropane decylamine

To a solution of L-silylamine methyl ester hydrochloride (311 mg, 2.00 mmol) was added 12M methylamine-methanol (2.0 mL), and stirred at room temperature for 48 hours. After completion of the reaction, the title compound (236 mg, yield quantitative) was obtained.

Reference Synthesis Example 19 N-cyclopropyl-5-hydroxymethylpyridinium

To a solution of 5-hydroxypyridine-2-carboxylic acid (1.0 g, 7.19 mmol) in N,N-dimethylformamide (10 mL) was added cyclopropylamine (758 μL, 10.8 mmol), 1-hydroxybenzotriene Azole (972 mg, 7.19 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.76 g, 14.4 mmol) and triethylamine (5.02 mL, 36.0) Methyl), stirred at room temperature for 3 days. After the reaction was completed, a saturated aqueous solution of sodium hydrogencarbonate was added, and ethyl acetate was evaporated. The residue was purified by EtOAc EtOAcjjjjj(

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 0.50-0.80 (m, 4H), 2.75-2.90 (m, 1H), 7.27 (dd, J = 8.6,3.0Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 3.0 Hz, 1H), 8.40 (d, J = 5.1 Hz, 1H), 10.5 (s, 1H).

Reference Synthesis Example 20 Cyclopropyl (3-fluoro-4-hydroxyphenyl)methanone

Cyclopropyl magnesium bromide (0.7 M tetrahydrofuran solution, 5.0 mL, 3.5 mmol) was added at 0 ° C in a solution of 3-fluoro-4-hydroxybenzonitrile (200 mg, 1.46 mmol) in THF (2.0 mL) Stir overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to the mixture and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium The residue was purified by EtOAc EtOAcjjjj(

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 0.98-1.09 (m, 2H), 1.19-1.28 (m, 2H), 2.53-2.64 (m, 1H), 6.41 (d, J = 3.7Hz, 1H), 7.07 (t, J = 8.5 Hz, 1H), 7.73 - 7.82 (m, 2H).

MS (ESI ^+): 181 [M + H] ^{+, MS (ESI -):} . 192 [MH] ^-. (LC/MS cond.2, RT=1.69min)

Reference Synthesis Example 21 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine

5-Bromo-2-(2,2,2-trifluoroethoxy)pyridine (2.04 g, 7.97 mmol, synthesized according to the method described in International Publication No. 2010/042642), [1, 1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (325 mg, 0.398 mmol), bis(pinacol) diboron (2.22 g, 8.76 mmol) and acetic acid A solution of potassium (2.35 g, 23.9 mmol) in 1,4-dioxane (28 mL) was stirred at 100 ° C for 30 min. After the reaction, ethyl acetate was added, and the mixture was filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:

MS (ESI ⁺ ): 304 [M+H] ⁺ . (LC/MS cond.2, RT = 2.85min)

Reference Synthesis Example 22 6-(2,2,2-trifluoroethoxy)pyridin-3-ol

5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-tri) obtained by reference to Synthesis Example 21. Fluoroethoxy)pyridine (2.41g, A solution of 7.97 mmol of tetrahydrofuran (15 mL) was added to a 1M aqueous sodium hydroxide solution (8 mL) at room temperature, and 30% hydrogen peroxide water (2.5 mL) was added dropwise at 0 ° C, and stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture at 0 ° C and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and filtered and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjjj

MS (ESI ^+): 194 [M + H] ^{+, MS (ESI -):} . 192 [MH] ^-. (LC/MS cond.1, RT=1.78min)

¹ H-NMR (300MHz, CDCl ₃ ) δ: 4.68 (q, J = 8.7 Hz, 2H), 4.84 (s, 1H), 6.78 (d, J = 9.0 Hz, 1H), 7.22 (dd, J = 9.0 , 3.0 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H).

Reference Synthesis Example 23 2-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Instead of using 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine, 5-bromo-2-(cyclopropylmethoxy)pyridine (18.9 g, 82.9 mmol, internationally disclosed) The method described in 2010/050445 is subject to synthesis) The title compound (22.3 g, yield 98%) was obtained as a pale yellow oil.

MS (ESI ⁺ ): 276 [M+H] ⁺ . (LC/MS cond.2, RT=2.80min)

Reference Synthesis Example 24 6-(cyclopropylmethoxy)pyridin-3-ol

Instead of using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine Further, 2-(cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) obtained in Reference Synthesis Example 23 was used. The title compound (10.2 g, yield 77%) was obtained as a colorless solid.

MS (ESI ⁺ ): 166 [M+H] ⁺ . (LC/MS cond. 2, RT = 1.48 min)

Reference Synthesis Example 25 2-(2,2,2-trifluoroethoxy)pyrimidine-5-ol

Instead of using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine Using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyrimidine (304 mg, 1.00 mmol, which was synthesized according to the method described in International Publication No. 2013/086397), the same reaction as in Reference Synthesis Example 22 was carried out to give the title compound (178 mg, yield 91%) as colorless. solid.

MS (ESI ^+): 195 [M + H] ^{+, MS (ESI -):} . 193 [MH] ^-. (LC/MS cond.1, RT=1.39min)

Reference Synthesis Example 26 (R)-2-fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazole-3- Benzoic acid

(S)-2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester (323 mg, 1.00 mmol) obtained from Reference Synthesis Example 2, triphenyl Phosphine (262 mg, 1.00 mmol) and 6-(2,2,2-trifluoroethoxy)pyridin-3-ol (193 mg, obtained in Reference Synthesis 22). To a solution of 1.00 mmol) in tetrahydrofuran (1.0 mL), diisopropyl azodicarboxylate (202 mg, 1.00 mmol) was added at 0 ° C and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. Trifluoroacetic acid (1.0 mL) was added to the obtained yellow solid, and stirred at room temperature for 5 minutes. Chloroform was added to the reaction mixture, and the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform/methanol = 1/0→5/1). The obtained solid was recrystallized from EtOAc (MeOH):

¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.81 (d, J = 6.3 Hz, 3H), 4.68 (q, J = 8.4 Hz, 2H), 5.65 (q, J = 6.3 Hz, 1H), 6.82 ( d, J = 9.0 Hz, 1H), 7.26-7.35 (m, 1H), 7.53 (s, 1H), 7.77-7.85 (m, 3H), 8.11 (t, J = 7.8 Hz, 1H).

MS (ESI ^+): 443 [M + H] ^{+, MS (ESI -):} . 441 [MH] ^-. (LC/MS cond.1, RT=2.80min)

Reference Synthesis Example 27 (R)-4-[5-(1-{[5-(cyclopropanecarbonyl)pyrazin-2-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoic acid

(1) (R)-4-(5-{1-[(5-Cyanopyrazin-2-yl)oxy]ethyl}isothiazol-3-yl)-2-fluorobenzoate tert-butyl ester

(R)-2-(R)-2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester (700 mg, 2.16 mmol) obtained in tetrahydrofuran (700 mg, 2.16 mmol). In a solution of 10 mL), potassium tributoxide (242 mg, 2.16 mmol) was added under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. 2-Chloro-5-cyanopyridine (301 mg, 2.16 mmol) was added to the reaction mixture, and the mixture was further stirred for 1 hour under ice cooling. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=19/1→2/1) to obtain (R)-4-(5-{ 1-[(5-Cyanopyrazin-2-yl)oxy]ethyl}isothiazol-3-yl)-2-fluorobenzoic acid tert-butyl ester (210 mg, yield 23%) as a colorless solid.

MS (ESI ^+): 427 [M + H] ^{+, MS (ESI -):} . 425 [MH] ^-. (LC/MS cond.2, RT=3.05min)

(2) (R)-4-[5-(1-{[5-(cyclopropanecarbonyl)pyrazin-2-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoic acid Tert-butyl ester

(R)-4-(5-{1-[(5-Cyanopyrazin-2-yl)oxy]ethyl}isothiazol-3-yl)-2-fluorobenzoate tert-butyl ester ( A solution of 210 M of cyclopropylmagnesium bromide in tetrahydrofuran (2.11 mL, 1.48 mmol) was added dropwise at -78 °C, and the mixture was stirred at -78 ° C for one hour. After acetic acid was added to the reaction mixture and the temperature was raised to room temperature, water was added and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→80/20) to afford (R)-4-[5-( 1-{[5-(cyclopropanecarbonyl)pyrazin-2-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl ester (190 mg, yield 82%) Colorless amorphous.

MS (ESI ⁺ ): 470 [M+H] ⁺ . (LC/MS cond.2, RT=3.30min)

(3) Substitution using (R)-4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoin (ter)-tert-butyl ester using (R)-4-[5-(1-{[5-(cyclopropanecarbonyl)pyrazin-2-yl]oxy}ethyl)isothiazol-3-yl]-2 In the same manner as in the synthesis of 15-(2) except for the tert-butyl fluorobenzoate, the title compound (166 mg, yield 99%) was obtained. Color solid.

^{1 H-NMR (300MHz, DMSO} -d 6) δ: 1.05-1.15 (m, 4H), 1.85 (d, J = 6.3Hz, 3H), 3.27-3.32 (m, 1H), 6.69 (q, J = 6.3 Hz, 1H), 7.92-7.97 (m, 3H), 8.21 (s, 1H), 8.54 (d, J = 1.2 Hz, 1H), 8.77 (d, J = 1.2 Hz, 1H).

MS (ESI ^+): 414 [M + H] ^{+, MS (ESI -):} . 412 [MH] ^-. (LC/MS cond.2, RT=2.54min)

Reference Synthesis Example 28 2-fluoro-4-[5-(1-{[5-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy}ethyl)isothiazol-3-yl]benzoin acid

(1) 4-(5-{1-[(5-Bromopyrazin-2-yl)oxy]ethyl}isothiazol-3-yl)-2-fluorobenzoate tert-butyl ester

To the tetrahydrofuran (0.10 mL) of 2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester (97.0 mg, 0.300 mmol) obtained in Reference Synthesis Example 1. In the solution, adding a third oxidation at -78 ° C Potassium (33.7 mg, 0.300 mmol) and 2,5-dibromopyrazine (238 mg, 0.300 mmol) were stirred at room temperature for 1 hour. After the completion of the reaction, saturated aqueous sodium chloride solution was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5 / 1) to give 4-(5-{1-[(5-bromopyrazin-2-yl)oxy] Ethyl}isothiazol-3-yl)-2-fluorobenzoate tert-butyl ester (96.5 mg, yield 67%) as a colorless solid.

MS (ESI ⁺ ): 480, 482 [M+H] ⁺ . (LC/MS cond.1, RT=3.56min)

(2) 2-Fluoro-4-[5-(1-{[5-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy}ethyl)isothiazole-3- Tert-butyl 2-fluorobenzoate

4-(5-{1-[(5-Bromopyrazin-2-yl)oxy]ethyl}isothiazol-3-yl)-2-fluorobenzoate tert-butyl ester (96.5 mg, 0.200 mmol) 2,2,2 of copper (I) iodide (7.62 mg, 0.0400 mmol), cesium carbonate (91.2 mg, 0.280 mmol) and ethyl 2-oxocyclohexanecarboxylate (13.6 mg, 0.0800 mmol) A solution of trifluoroethanol (0.10 mL) was stirred at 80 ° C for 48 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered Concentrate under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (hexane/ethyl acetate=5/1) and silica gel column chromatography (hexane/ethyl acetate = 10/1) to give 2-fluoro- 4-[5-(1-{[5-(2,2,2-Trifluoroethoxy)pyrazin-2-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoin Acid tert-butyl ester (3.60 mg, yield 3.6%) of a colorless solid.

MS (ESI ⁺ ): 500 [M+H] ⁺ . (LC/MS cond.1, RT=3.61min)

(3) 2-Fluoro-4-[5-(1-{[5-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy}ethyl)isothiazole-3 2-Phenyl-2-benzoic acid tert-butyl ester (3.60 mg, 0.00720 mmol) was added to trifluoroacetic acid (1.0 mL), and stirred at room temperature for 5 minutes. After chloroform was added to the reaction mixture, the crystal crystal crystal crystal crystal crystal crystal crystal crystal

MS (ESI ^+): 443 [M + H] ^{+, MS (ESI -):} . 441 [MH] ^-. (LC/MS cond.1, RT=2.84min)

Reference Synthesis Example 29 (R)-4-[5-(1-{[6-(cyclopropylmethoxy)pyridin-3-yl)oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoic acid

(1) (R)-4-[5-(1-{[6-(cyclopropylmethoxy)pyridine) 3--3-yloxy}ethyl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl ester

(S)-2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester (300 mg, 0.928 mmol) obtained from Reference Synthesis Example 3, triphenyl Azodicarboxylate in a solution of 6-(cyclopropylmethoxy)pyridin-3-ol (200 mg, 1.21 mmol) in tetrahydrofuran (6.0 mL) obtained from the title compound Acid diisopropyl (220 μL, 1.11 mmol) was added at 0 ° C, stirred at 0 ° C for 30 minutes, and stirred overnight at room temperature. After the completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1→3/1) to give (R)-4-[5-(1-{[6-(cyclopropyl) A yellow oil of methoxymethyl)pyridin-3-yloxy-3-ethyl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl ester (489 mg, quantitatively quantitative). .

MS (ESI ⁺ ): 471 [M+H] ⁺ . (LC/MS cond.2, RT=3.34min)

(2) (R)-4-[5-(1-{[6-(Cyclopropylmethoxy)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]-2- Fluorobenzoic acid tert- Trifluoroacetic acid (5.0 mL) was added to a solution of butyl ester in dichloromethane (5.0 mL), and stirred at room temperature for 1.5 hours. To the reaction mixture, toluene was added, and the residue was evaporated to dryness crystals crystals crystals crystals solid.

MS (ESI ⁺ ): 415 [M+H] ⁺ . (LC/MS cond.2, RT=2.63min)

Reference Synthesis Example 30 (S)-1-(3-chloroisothiazol-5-yl)ethanol

(1) 3-chloroisothiazole-5-formaldehyde

In a solution of 3-chloroisothiazole-5-carbonitrile (1.75 g, 12.1 mmol, RSC Advances, synthesized according to the method described in 2014, 4, 7735-7748) in dichloromethane (30 mL), at - A hexane solution of diisobutylaluminum hydride (1.02 M, 14.2 mL, 14.5 mmol) was added dropwise at 78 ° C, and stirred at -78 ° C for 2 hours. A 1 M aqueous hydrogen chloride solution (30 mL) was added to the reaction mixture, and stirred at room temperature for 1 hour. Dichloromethane was added to the reaction mixture and extracted, and the organic layer was concentrated under reduced pressure. Will The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→70/30) to give 3-chloroisothiazol-5-carbaldehyde (1.16 g, yield 65%). Yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ: 7.56 (s, 1H), 10.05 (s, 1H).

(2) 1-(3-chloroisothiazol-5-yl)ethanol

To a solution of 3-chloroisothiazol-5-carboxaldehyde (1.17 g, 7.93 mmol) in THF (25 mL) The mixture was stirred at -78 ° C for 3 hours, and stirred at room temperature for 15 minutes. A saturated aqueous solution of ammonium chloride was added and the mixture was evaporated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→70/30) to give 1-(3-chloroisothiazol-5-yl)ethanol (970 mg, yield 75%) light yellow oil.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 1.62 (d, J = 6.8Hz, 3H), 2.37 (d, J = 5.7Hz, 1H), 5.22 (quin, J = 6.0Hz, 1H), 6.89 (s , 1H).

MS (ESI ⁺ ): 163 [M+H] ⁺ . (LC/MS cond.2, RT=1.41min)

(3) in 1-(3-chloroisothiazol-5-yl)ethanol (970) Mg, 5.93 mmol), dimethylaminopyridine (36 mg, 0.297 mmol), triethylamine (991 μL, 7.11 mmol) in tetrahydrofuran (10 mL), EtOAc (EtOAc, EtOAc. Stir for 1 hour. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, saturated aqueous ammonium chloride and saturated aqueous sodium hydrogen carbonate. The organic layer was dried with anhydrous magnesium sulfate and filtered and evaporated.

To a solution of the obtained residue (1.06 g) in isopropyl ether (10 mL), a neutral phosphate (10 mL) and a lipase PL (manufactured by Meite Sugar Co., Ltd., 1.00 g) were added, and the mixture was carried out at 40 ° C for 3 hours. Stir. Ethanol (5.0 mL) was added to the reaction mixture, and the mixture was filtered over Celite, and the filtrate was washed with water. The organic layer was dried with anhydrous magnesium sulfate and filtered and evaporated. To a solution of the obtained residue in tetrahydrofuran (10 mL), triphenylphosphine (1.36 g, 5.17 mmol), acetic acid (887 μL, 15.5 mmol) and diisopropyl azodicarboxylate (1.02 mL, 5. Stir at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→80/20) to give acetic acid (S)-1-(3- Chloroisothiazol-5-yl)ethyl ester (1.06 g, yield 3 steps 87%, 97% ee) as pale yellow oil.

MS (ESI ⁺ ): 206 [M+H] ⁺ . (LC/MS cond.2, RT=2.08min)

Moreover, the optical purity was determined under the following analysis conditions.

‧ Chiral column: CHIRALPAK (registered trademark) IA-3 (inner diameter 4.6mm, length 150mm, particle diameter 3μm, Daicel Co., Ltd. Division)

‧ Temperature: 40 ° C

‧Flow rate: 1.5mL/min

‧Dissolved solution: hexane/methyl tert-butyl ether=90/10

‧Detection wavelength: 254nm

‧Retention time: 3.87 min ((R)-1-(3-chloroisothiazol-5-yl)ethyl acetate), 4.22 min ((S)-1-(3-chloroisothiazol-5-yl) acetate Ethyl ester)

(4) (S)-1-(3-chloroisothiazol-5-yl)ethanol

Add potassium carbonate (1.43 g, 10.3 mmol) at room temperature to a solution of (S)-1-(3-chloroisothiazol-5-yl)ethyl acetate (1.06 g, 5.17 mmol) in methanol (10 mL) Water (1.0 mL) was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, which was washed with water and a saturated aqueous solution of ammonium chloride. The organic layer was dried with EtOAcjjjjjjjjj

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 1.62 (d, J = 6.8Hz, 3H), 2.37 (d, J = 5.7Hz, 1H), 5.22 (quin, J = 6.0Hz, 1H), 6.89 (s , 1H).

MS (ESI ⁺ ): 163 [M+H] ⁺ . (LC/MS cond.2, RT=1.41min)

Reference Synthesis Example 31 Tert-butyl 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-picolinate

(1) tert-butyl 5-bromo-3-fluoromethylpyridine

4-Dimethylaminopyridine (55.5 mg, 0.454 mmol), di-tert-dicarbonate in a solution of 5-bromo-3-fluoromethylpyridine acid (1.0 g, 4.54 mmol) in tetrahydrofuran (10 mL) The butyl ester was added at 0 ° C and stirred at 60 ° C for 2.5 hours. After the end of the reaction, the reaction mixture was cooled at 0 ° C, and water was added and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine, and evaporated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1) to give tert-butyl 5-bromo-3-fluoromethyl pyridine acid (1.32 g, yield quantitative ) a pale yellow oil.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 1.63 (s, 9H), 7.69-7.73 (m, 1H), 8.58-8.59 (m, 1H).

(2) Instead of using 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine, using 5-bromo-3-fluoromethylpyridine acid tert-butyl ester (300 mg, 1.09 mmol), The same reaction as in Reference Synthesis Example 21 was carried out to give the title compound (358 mg, yield quantitative) as a pale yellow solid.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 1.35 (s, 12H), 1.63 (s, 9H), 7.81-7.84 (m, 1H), 8.77 (s, 1H).

Reference Synthesis Example 32 1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-5-ol

(1) 5-Bromo-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine

To a solution of 5-bromo-7-azaindole (300 mg, 1.52 mmol) in tetrahydrofuran (1.0 mL), sodium hydride (99.7 mg, 2.28 mmol), trifluoromethanesulfonic acid 2,2,2- Trifluoroethyl (329 μL, 2.28 mmol) was stirred at room temperature for 3 hours. After the reaction was completed, water was added and extracted with ethyl acetate, and the organic layer was washed with saturated brine. net. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1→5/1) to give 5-bromo-1-(2,2,2-trifluoroethyl)- 1H-pyrrolo[2,3-b]pyridine (438 mg, quantitative yield) of a pale yellow solid.

MS (ESI ⁺ ): 279, 281 [M+H] ⁺ . (LC/MS cond.1, RT=2.56min)

(2) Substituting 5-bromo-1-(2,2,2-trifluoroethoxy)pyridine for 5-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrrole The title compound (54.0 mg, yield 2 step 70%) was obtained as a colorless solid, which was obtained from the title compound (2, 3-).

MS (ESI ⁺ ): 217 [M+H] ⁺ . (LC/MS cond.2, RT=1.64min)

Reference Synthesis Example 33 6-[(2,2,2-trifluoroethyl)amino]pyridin-3-ol

(1) 5-Bromo-N-(2,2,2-trifluoroethyl)pyridin-2-amine

To a solution of 2-amino-5-bromopyridine (300 mg, 1.73 mmol) in N,N-dimethylformamide (1.0 mL), EtOAc (EtOAc (EtOAc) The sulfonic acid 2,2,2-trifluoroethyl (374 μL, 2.59 mmol) was allowed to stand at room temperature for 30 minutes, at 60 ° C for 1 hour, and at 100 ° C for 2 hours. After the completion of the reaction, water was added and extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→1/1) to give 5-bromo-N-(2,2,2-trifluoroethyl)pyridine. 2-Amine (188 mg, 43% yield) of yellow solid.

MS (ESI ⁺ ): 255, 257 [M+H] ⁺ . (LC/MS cond.1, RT=2.23min)

(2) Substitution of 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine using 5-bromo-N-(2,2,2-trifluoroethyl)pyridin-2-amine (95.0 mg, 0.372 mmol), the title compound (31.0 mg, yield 2 step 43%) was obtained as a yellow solid.

MS (ESI ⁺ ): 193 [M+H] ⁺ . (LC/MS cond.2, RT=0.51min)

Reference Synthesis Example 34 2-(2,2,2-trifluoroethoxy)pyridin-4-ol

To a solution of 4-(benzyloxy)-2-chloropyridine (264 mg, 1.20 mmol) in N,N-dimethylformamide (1.0 mL), sodium hydride (524 mg, 12.0) Methyl) 2,2,2-trifluoroethanol (862 μL, 12.0 mmol) was stirred at room temperature for 2 hours and at 80 ° C for 5 hours. The reaction mixture was cooled, water was added and extracted with ethyl acetate, and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. Palladium/carbon (80 mg) was added to a methanol solution (10 mL) of the obtained residue (807 mg), and the mixture was stirred at room temperature for 3.5 hours under a hydrogen atmosphere. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. The residue was purified by silica gel chromatography eluting elut elut elut elut elut elut

_{^{1 H NMR (300MHz, CH 3}} OD) δ: 4.71-4.80 (m, 2H), 6.20 (d, J = 2.1Hz, 1H), 6.48 (dd, J = 5.7,2.1Hz, 1H), 7.83 (d , J = 5.7 Hz, 1H).

Reference Synthesis Example 35 3-chloro-4-cyclopropoxyphenol

Instead of using 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine And 2-(3-chloro-4-cyclopropoxyphenyl)-5,5-dimethyl-1,3,2-dioxaborane (described in International Publication No. 2011/068211) The title compound (118 mg, yield 89%) was obtained as a colorless oil.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 0.62-0.90 (m, 4H), 3.65-3.85 (m, 1 H), 4.90-5.30 (br, 1H), 6.71 (dd, J = 8.8,3.0Hz, 1H), 6.88 (d, J = 3.0 Hz, 1H), 7.14 (d, J = 8.9 Hz, 1H).

Reference Synthesis Example 36 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carboxylic acid tert-butyl

(1) 5-bromopyrimidine-2-carboxylic acid tert-butyl

To a solution of 5-bromopyrimidine-2-carboxylic acid (1.50 g, 7.39 mmol) in tetrahydrofuran (20 mL), di-tert-butyl dicarbonate (4.19 g, 19.2 mmol), and N,N- Dimethyl-4-aminopyridine (181 mg, 1.48 mmol) was stirred at 60 ° C for 6.5 hours. After the reaction was completed, the reaction mixture was cooled, aq. The organic layer was dried with anhydrous magnesium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4 / 1 → 3 / 2) to give 5-bromopyrimidine-2-carboxylic acid tert-butyl (1.15 g, yield 60%) yellow solid.

MS (ESI ⁺ ): 259 [M+H] ⁺ . (LC/MS cond.2, RT=1.80min)

(2) Substituting 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine and using 5-bromopyrimidine-2-carboxylic acid tert-butyl (200 mg, 0.772 mmol), substantially The title compound (154 mg, yield: 65%) was obtained as a yellow solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ: 1.37 (s, 12H), 1.68 (s, 9H), 9.14 (s, 2H).

Reference Synthesis Example 37 4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}B Isothiazol-3-yl]-3-fluorobenzoic acid

(1) 3-fluoro-4-(2-oxo-1,3,4-oxathiazol-5-yl)benzoic acid tert-butyl

Instead of using 4-cyano-2-fluorobenzoic acid instead of 4-cyano-3-fluorobenzoic acid (2.50 g, 15.1 mmol), substantially the same as Reference Synthesis Examples 1-(1) to (3) The same reaction gave 3-fluoro-4-(2-oxo-1,3,4-oxathiazol-5-yl)benzoic acid tert-butyl ester (2.78 g, 3 step, 64%) as a colourless solid.

¹ H-NMR (CDCl ₃ ) δ: 1.61 (s, 9H), 7.78-7.82 (m, 1H), 7.85-7.88 (m, 1H), 7.93-7.98 (m, 1H).

(2) 4-(5-Ethylisothiazol-3-yl)-3-fluorobenzoate tert-butyl ester

Instead of using 2-fluoro-4-(2-oxo-1,3,4-oxathiazol-5-yl)benzoic acid tert-butyl, 3-fluoro-4-(2-oxo-1,3) 4-(5-acetamidine) was obtained by substantially reacting with the same reaction example with reference to Synthesis Example 1-(4) except that 4-oxothiazole-5-yl)benzoic acid tert-butyl ester (2.87 g, 9.65 mmol) was used. Isothiazol-3-yl)-3-fluorobenzoate tert-butyl ester (1.49 g, yield 48%) as a pale yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 1.60 (s, 9H), 2.68 (s, 3H), 7.76-7.81 (m, 1H), 7.85-7.88 (m, 1H), 8.14 (d, J = 2.7 Hz) , 1H), 8.21 (t, J = 7.7 Hz, 1H).

MS (ESI ⁺ ): 322 [M+H] ⁺ . (LC/MS cond.2, RT=2.93min)

(3) Substituting 4-(5-ethyiisothiazol-3-yl)-3-fluorobenzoin for 4-(5-ethyiisothiazol-3-yl)-2-fluorobenzoate tet-butyl ester Acid tert-butyl ester (200 mg, 0.622 mmol), substituted with 6-(2,2,2-trifluoroethoxy)pyridin-3-ol, using cyclopropyl(5-hydroxypyridin-2-yl)- In the same manner as in Reference Synthesis Example 1-(5) and Reference Synthesis Example 26, the title compound (172 mg, yield) was obtained. 3 steps 65%) of a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05-1.09 (m, 2H), 1.20-1.23 (m, 2H), 1.88 (d, J = 6.3 Hz, 3H), 3.36-3.44 (m, 1H) , 5.92 (q, J = 6.6 Hz, 1H), 7.32 - 7.36 (m, 1H), 7.73 (d, J = 3.0 Hz, 1H), 7.87 - 8.03 (m, 3H), 8.25 (t, J = 7.7) Hz, 1H), 8.44 (d, J = 2.7 Hz, 1H).

MS (ESI ^+): 413 [M + H] ^{+, MS (ESI -):} . 411 [MH] ^-. (LC/MS cond.2, RT=2.50min)

Reference Synthesis Example 38 Methyl 2-fluoro-4-[5-(1-hydroxypropyl)isoxazol-3-yl]benzoate (optically active)

The methyl 2-fluoro-4-[5-(1-hydroxypropyl)isoxazol-3-yl]benzoate (1.0 g, 3.58 mmol) obtained in Reference Synthesis Example 6 was subjected to supercritical fluid chromatography. The method (SFC) performs optical separation. The classification conditions are shown below.

‧Device: Waters 4280 Thar 80

‧Tube: CHIRALPAK (registered trademark) AD (length 250mm, inner diameter 30mm, particle diameter 5μm, Daicel Co., Ltd.)

‧Mobile phase: carbon dioxide / methanol = 70/30

‧Flow rate: 70mL/min

‧column temperature: 40 ° C

After separately concentrating the fractions with earlier retention time and the fractions with a later retention time, methyl 2-fluoro-4-[5-(1-hydroxypropyl)isoxazol-3-yl]benzoate was separately obtained ( Isomer B, RT = 3.66 min, 359 mg, yield 35%, optical purity 99.8% ee) of colorless solid and methyl 2-fluoro-4-[5-(1-hydroxypropyl)isoxazol-3-yl]benzoate (Isomer A, RT = 3.86 min, 302 mg, yield 30%, optical purity 96% ee) as a colorless solid.

Moreover, the optical purity can be determined by the following analysis conditions.

‧Device: Agilent 1260 (Agilent Technologies, Inc.)

‧Tube: CHIRALPAK (registered trademark) AD-3 (length 100mm, inner diameter 4.6mm, particle diameter 3μm, Daicel Co., Ltd.)

‧Mobile phase: A; carbon dioxide, B; methanol (0.05% diethylamine)

‧ Gradient conditions:

0-4.5min: A/B=95/5→60/40

4.5-7.0min: A/B=60/40

7.0-8.0min: A/B=95/5

‧Flow rate: 2.8mL/min

‧column temperature: 40 ° C

Reference Synthesis Example 39 Methyl 2-fluoro-4-[4-(1-hydroxypropyl)-1H-pyrazol-1-yl]benzoate (optically active)

Methyl 2-fluoro-4-[4-(1-hydroxypropyl)-1H-pyrazol-1-ylbenzoate (900 mg, 3.23 mmol) obtained in Synthesis Example 8-(2) by supercritical Fluid chromatography (SFC) performs optical resolution. The classification conditions are shown below.

‧Device: SFC-MGII (METTLER TOLEDO GmbH)

‧Tube: CHIRALPAK (registered trademark) AS (length 250mm, inner diameter 30mm, particle diameter 5μm, Dasaiyu Co., Ltd.)

‧Mobile phase: carbon dioxide/2-propanol = 60/40

‧Flow rate: 50mL/min

‧column temperature: 40 ° C

After separately concentrating the fractions with earlier retention time and the fractions with later retention time, each obtained methyl 2-fluoro-4-[4-(1-hydroxypropyl)-1H-pyrazol-1-yl]benzoate Colorless solid (Isomer B, RT = 5.01 min, 387 mg, yield 43%, optical purity 100% ee) and 2-fluoro-4-[4-(1-hydroxypropyl)-1H-pyrazole-1- A colorless solid of methyl benzoate (Isomer A, RT = 6.48 min, 402 mg, yield 45%, optical purity 100% ee).

And the optical purity is determined by the following analysis conditions.

‧Device: Thar SFC (Waters)

‧Tube: CHIRALPAK (registered trademark) AS-H (length 100 Mm, inner diameter 4.6mm, particle diameter 3μm, Dasaiyu Co., Ltd.)

‧Mobile phase: A; carbon dioxide, B; 2-propanol (0.05% diethylamine)

‧ Gradient conditions:

0-4.5min: A/B=95/5→60/40

4.5-7.0min: A/B=60/40

7.0-8.0min: A/B=95/5

‧Flow rate: 2.5mL/min

‧column temperature: 40 ° C

Synthesis Example 1 4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-N-(1,3-dihydroxypropan-2-yl)-2-fluoro Benzoguanamine

(1) 4-(5-Ethylisothiazol-3-yl)-2-fluorobenzoic acid

4-(5-Ethylisothiazol-3-yl)-2-fluorobenzoic acid tert-butyl ester (66.0 mg, 0.205 mmol) obtained in methylene chloride (3.0 mL) In the solution, trifluoroacetic acid (1.0 mL) was added at room temperature, and the mixture was stirred at room temperature for 3 hours. Toluene was added to the reaction mixture, and concentrated under reduced pressure to give a white crystals of crude product of 4-(5-ethylisothiazol-3-yl)-2-fluorobenzoic acid.

(2) 4-(5-Ethylisothiazol-3-yl)-2-fluoro-N-(2,2,3,3,9,9,10,10-octamethyl-4,8-di Oxa-3,9-disilaundecane-6-yl)benzoguanamine

In a solution of the crude product of 4-(5-ethyiisothiazol-3-yl)-2-fluorobenzoic acid in N,N-dimethylformamide (1.0 mL), sequentially added at room temperature 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (79.0 mg, 0.412 mmol), 1-hydroxybenzotriazole (28.0 mg, 0.206 mmol), triethyl Base amine (57.0 μL, 0.410 mmol) and 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane-6-amine (98.0 mg , 0.307 mmol), stirred at room temperature for 1 day. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate = 5 / 1) to give 4-(5-ethylisothiazol-3-yl)-2-fluoro-N- (2, 2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane-6-yl)benzoguanamine (122 mg) as a pale yellow solid.

MS (ESI ⁺ ): 567 [M+H] ⁺ . (LC/MS cond.3, RT=3.09min)

(3) 2-Fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]-N-(2,2,3,3,9,9,10,10-octamethyl- 4,8-dioxa-3,9-disilaundecane-6-yl)benzoguanamine

4-(5-Ethylisothiazol-3-yl)-2-fluoro-N-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa -3,9-disilaundecane-6-yl) benzoguanamine (122 mg) in tetrahydrofuran (2.0 mL), sodium borohydride (10.0 mg, 0.264 mmol) was added at room temperature and stirred at room temperature for 5 hours. . Saturated brine was added to the mixture and the mixture was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=78/22) to give 2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl] -N-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane-6-yl)benzoguanamine (93.0 mg, Yield 80% (3 steps) of a pale yellow oil.

MS (ESI ⁺ ): 569 [M+H] ⁺ . (LC/MS cond.3, RT=2.97min)

(4) 4-(5-{1-[4-(Cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluoro-N-(2,2,3,3,9 , 9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane-6-yl)benzoguanamine

Under argon, 2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]-N-(2,2,3,3,9,9,10,10-eight Methyl-4,8-dioxa-3,9-disilaundecane-6-yl)benzoguanamine (93.0 mg, 0.163 Methyl), triphenylphosphinium (51.0 mg, 0.194 mmol) and cyclopropyl (4-hydroxyphenyl)methanone (26.0 mg, 0.160 mmol, based on the method described in International Publication No. 2012/050151) A solution of di-tert-butyl azodicarboxylate (45.0 mg, 0.196 mmol) in tetrahydrofuran (0.5 mL) was added to a solution of THF. The reaction mixture was purified by silica gel column chromatography (hexane/ethyl acetate = 4/1) to give 4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl} Thiazol-3-yl)-2-fluoro-N-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane-6- Benzo) benzoguanamine (124 mg) as a colorless solid.

¹ H-NMR (300MHz, CDCl ₃ ) δ: 0.08 (s, 12H), 0.91 (s, 18H), 0.98-1.02 (m, 2H), 1.20-1.22 (m, 2H), 1.82 (d, J = 6.6 Hz, 3H), 2.60 (brs, 1H), 3.63-3.68 (m, 2H), 3.86-3.90 (m, 2H), 4.22 (s, 1H), 5.84 (q, J = 6.6 Hz, 1H), 6.19 (brs, 1H), 7.00 (d, J = 9.0 Hz, 2H), 7.52 (s, 1H), 7.72 - 7.76 (m, 2H), 7.99 (d, J = 9.0 Hz, 2H), 8.19 (t , J = 8.9 Hz, 1H).

(5) 4-(5-{1-[4-(Cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluoro-N-(2,2,3,3, a solution of 9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane-6-yl)benzoguanamine (124 mg) in tetrahydrofuran (1.0 mL) at room temperature A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (417 μL, 0.417 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Saturated brine was added to the mixture and the mixture was evaporated. Will The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

Synthesis Example 2 (R)-4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-N-(1,3-dihydroxypropan-2-yl) 2-fluorobenzoguanamine Synthesis Example 3 (S)-4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-N-(1,3-dihydroxypropan-2-yl) 2-fluorobenzoguanamine

4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-N-(1,3-dihydroxypropane-2-) obtained in Synthesis Example 1. 2-fluorobenzoguanamine (16 mg) was optically isolated on a chiral column. The classification conditions are shown below.

‧ Chiral column: CHIRALPAK (registered trademark) IE (inner diameter 20mm, length 250mm, Daicel Co., Ltd.)

‧Detection wavelength: 254nm

‧ Temperature: 40 ° C

‧Flow rate: 12mL/min

‧ Gradient conditions:

The mixing ratio of hexane to ethanol was changed to 30/70 in 60 minutes after the start of 70/30.

After concentrating the fraction which is held earlier, (R)-4-(5-{1- [4-(Cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-N-(1,3-dihydroxypropan-2-yl)-2-fluorobenzoguanamine (1.33 mg, A colorless solid having an optical purity of 99% ee) (Synthesis Example 2).

Further, after concentrating the fraction having a relatively late hold time, (S)-4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-N-( A colorless solid of 1,3-dihydroxypropan-2-yl)-2-fluorobenzoguanamine (0.71 mg, optical purity: 99% ee) (Synthesis Example 3).

And the optical purity is determined by the following analysis conditions.

‧ Chiral column: CHIRALPAK (registered trademark) IE (inner diameter 4.6mm, length 150mm, particle diameter 3μm, Daicel Co., Ltd.)

‧ Temperature: 40 ° C

‧Flow rate: 1.5mL/min

‧ Gradient conditions:

The mixing ratio of hexane to ethanol was changed to 30/70 in 13 minutes after the start of the measurement at 70/30.

The mixing ratio of hexane to ethanol was fixed at 30/70 7 minutes later.

‧Detection wavelength: 254nm

‧ Hold time: 10.51 min (synthesis example 2), 10.95 min (synthesis example 3)

Synthesis Example 4 4-(4-{1-[4-(Cyclopropanecarbonyl)phenoxy]ethyl}-1H-pyrazol-1-yl)-N-(1,3-dihydroxypropan-2-yl)- 2-fluorobenzoguanamine

(1) 4-(4-Ethyl-1H-pyrazol-1-yl)-2-fluoro-N-(2,2,3,3,9,9,10,10-octamethyl-4, 8-dioxa-3,9-disilaundecane-6-yl)benzoguanamine

Under a argon atmosphere, a solution of 1-(1H-pyrazol-4-yl)ethanone (25.3 mg, 0.230 mmol) in dichloromethane (1.0 mL) 4-[(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane-6-yl)aminomethane]benzene Boron acid (223 mg, 0.459 mmol), copper (II) acetate (62.7 mg, 0.345 mmol) and pyridine (37.1 μL, 0.461 mmol) were stirred at room temperature for 3 days. After the reaction mixture was filtered over Celite, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to give 4-(4-ethyl-1H-pyrazol-1-yl)-2-fluoro-N. -(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane-6-yl)benzoguanamine (60.3 mg, yield 48%) colorless amorphous material.

MS (ESI ⁺ ): 550 [M+H] ⁺ . (LC/MS cond.2, RT = 3.82min)

(2) Substituting 4-(5-acetylisothiazol-3-yl)-2-fluoro-N-(2,2,3,3,9,9,10,10-octamethyl-4,8 -Dioxa-3,9-disilaundecane-6-yl)benzoguanamine using 4-(4-acetam-1H-pyridyl) Zin-1-yl)-2-fluoro-N-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecane-6- The title compound (9.66 mg, yield 32% (3 steps) was obtained after the reaction of the same procedure as the compound of 1-(3)-(5). a colorless amorphous material.

Synthesis Example 5 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl} Isoxazol-3-yl)-2-fluorobenzoguanamine

(1) Methyl 4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isoxazol-3-yl)-2-fluorobenzoate

Instead of using 2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]-N-(2,2,3,3,9,9,10,10-octamethyl-4 , 8-dioxa-3,9-disilaundecane-6-yl)benzoguanamine oxime was used to give 2-fluoro-4-[5-(1-hydroxyethyl)isoxazole obtained in Synthesis Example 5. 3-(5-{1-[4-(cyclopropanecarbonyl)benzene) was obtained by the same reaction as the synthesis of 1-(4) except for methyl 3-benzo]benzoate (27.8 mg, 0.105 mmol). Methyl oxy]ethyl}isoxazol-3-yl)-2-fluorobenzoate (57.6 mg) as a pale yellow solid.

(2) 4-(5-{1-[4-(Cyclopropanecarbonyl)phenoxy]ethyl}isoxazol-3-yl)-2-fluorobenzoic acid

1,4-Bisyl 4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isoxazol-3-yl)-2-fluorobenzoate (53.8 mg) A 1 M aqueous sodium hydroxide solution (525 μL) was added to a solution of methylene chloride (1.5 mL), and stirred at room temperature for 6 hours. Water was added to the reaction mixture, which was washed with ethyl acetate. After adding 1 M hydrochloric acid to the aqueous layer to adjust the pH to 4, extraction was carried out twice with ethyl acetate. The organic layer was concentrated under reduced pressure to give 4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isooxazol-3-yl)-2-fluorobenzoic acid (31.0 mg Yield 57% (2 steps) of a pale yellow solid.

MS (ESI ⁺ ): 396 [M+H] ⁺ . (LC/MS cond.2, RT = 2.39min)

(3) N in 4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isoxazol-3-yl)-2-fluorobenzoic acid (15.0 mg, 0.0379 mmol) To a solution of N-dimethylformamide (1.0 mL), L-serinate decylamine hydrochloride (8.00 mg, 0.0569 mmol), 1-hydroxybenzotriazole (5.10 mg, 0.0379 mmol), Triethylamine (16.0 μL, 0.114 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15.0 mg, 0.0759 mmol). day Stir. After the completion of the reaction, the reaction mixture was poured into water, extracted three times with chloroform, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→ethyl acetate/methanol=80/20) to give the title compound (13.7 mg, yield 75%) as colorless. solid.

Synthesis Example 6 4-(5-{1-[4-(Cyclopropanecarbonyl)phenoxy]ethyl}isoxazol-3-yl)-N-(1,3-dihydroxypropan-2-yl)-2- Fluorobenzoguanamine

The same reaction as in the synthesis example 5-(3) was carried out, except that the 2-amino-1,3-propanediol was used instead of the L-hamidosylamine hydrochloride, and the title compound was obtained in pale yellow. Solid (6.00 mg, yield 34%).

Synthesis Example 7 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]propyl} Isoxazol-3-yl)-2-fluorobenzoguanamine

The 2-fluoro-4-[5-(1-) obtained in Reference Example 6 was used instead of using methyl 2-fluoro-4-[5-(1-hydroxyethyl)isoxazol-3-yl]benzoate. The same reaction as in the synthesis of 5-(1) to (3) was carried out, and the title compound (47.6) was obtained after the reaction of the hydroxy propyl) isoxazole-3-yl] benzoic acid methyl ester (48.0 mg, 0.172 mmol). Mg, yield 57% (3 steps) of a colorless solid.

Synthesis Example 8 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-4-(4-{1-[4-(cyclopropanecarbonyl)phenoxy]propyl} -1H-pyrazol-1-yl)-2-fluorobenzoguanamine

(1) 1-(1H-pyrazol-4-yl)propan-1-one

To a solution of 1H-pyrazole-4-carbaldehyde (961 mg, 10.0 mmol) in tetrahydrofuran (20 mL), sodium hydride (55% by weight dispersion in mineral oil, 655 mg, 15.0 mmol) was added at 0 ° C. Stir in minutes. 2-(Chloromethoxy)ethyltrimethylnonane (1.95 mL, 11.0 mmol) was added, and stirred at room temperature for 2 hours. After the completion of the reaction, saturated brine and water were added, and the mixture was extracted three times with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and filtered and evaporated. Ethyl magnesium bromide (0.95 M tetrahydrofuran solution, 11.4 mmol, 12.0 mL) was added dropwise to the obtained residue in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution and water were added to the mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and filtered and evaporated. Manganese dioxide (4.34 g, 50.0 mmol) was added to a solution of the obtained residue in chloroform (10 mL), and the mixture was stirred under reflux for 6 hours, and stirred at room temperature for 12 hours. After the completion of the reaction, the mixture was cooled and filtered over Celite, and the filtrate was concentrated under reduced pressure. Yusho Trifluoroacetic acid (5.0 mL) was added to a solution of methylene chloride (5.0 mL). After the completion of the reaction, the residue was concentrated under reduced pressure. EtOAc m. 938 mg, yield 76%).

MS (ESI ⁺ ): 125 [M+H] ⁺ . (LC/MS cond.2, RT=0.70min)

(2) Methyl 2-fluoro-4-[4-(1-hydroxypropyl)-1H-pyrazol-1-yl]benzoate

[4-(ethoxycarbonyl)-3-fluorophenyl was added to a solution of 1-(1H-pyrazol-4-yl)propan-1-one (938 mg, 7.55 mmol) in dichloromethane (25 mL) Boric acid (2.52 g, 15.1 mmol), copper (II) acetate (2.06 g, 11.3 mmol) and pyridine (1.22 mL, 15.1 mmol) were stirred at room temperature for 60 hours. After the reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 3 / 1). Sodium borohydride (285.6 mg, 7.55 mmol) was added to a solution of the obtained solid in methanol (30 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extraction was carried out with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) to give 2-fluoro-4- [4-(1-Hydroxypropyl)-1H-pyrazol-1-yl]benzoic acid methyl ester (17.8 mg, yield 0.8%) as a colorless solid.

MS (ESI ⁺ ): 279 [M+H] ⁺ . (LC/MS cond.2, RT=1.93min)

(3) 4-(4-{1-[4-(Cyclopropanecarbonyl)phenoxy]propyl}-1H-pyrazol-1-yl)-2-fluorobenzoic acid

Methyl 2-fluoro-4-[4-(1-hydroxypropyl)-1H-pyrazol-1-yl]benzoate (17.8 mg, 0.064 mmol), triphenylphosphinium (16.8 mg, 0.0640 mmol) And a solution of cyclopropyl (4-hydroxyphenyl)methanone (10.4 mg, 0.0640 mmol, synthesized according to the method described in International Publication No. 2012/050151) in tetrahydrofuran (1.0 mL) at room temperature Diisopropyl azodicarboxylate (12.9 mg, 0.064 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by EtOAc EtOAc (EtOAc:EtOAc A 1 M aqueous sodium hydroxide solution (0.5 mL) was added to a solution of the obtained solid in ethanol (0.5 mL), and the mixture was stirred under reflux for 1 hour. After the reaction was completed, 1M hydrochloric acid (0.5 mL) was added and ethyl acetate was evaporated. The organic layer was dried over anhydrous sodium sulfate and filtered and concentrated under reduced pressure to give 4-(4-{1-[4-(cyclopropanecarbonyl)phenoxy]propyl}-1H-pyrazole-1- Colorless of the crude product of 2-fluorobenzoic acid (26.1 mg) solid.

MS (ESI ^+): 409 [M + H] ^{+, MS (ESI -):} . 407 [MH] ^-. (LC/MS cond.1, RT=2.57min)

(4) N-[(S)-1-Amino-3-hydroxy-1-oxopropan-2-yl]-4-(4-{1-[4-(cyclopropanecarbonyl)phenoxy] Propyl}-1H-pyrazol-1-yl)-2-fluorobenzoguanamine

N,N-di in 4-(4-{1-[4-(cyclopropanecarbonyl)phenoxy]propyl}-1H-pyrazol-1-yl)-2-fluorobenzoic acid (26.1 mg) To a solution of methylformamide (1.0 mL), L-serinate guanamine hydrochloride (10.8 mg, 0.0768 mmol), 1-hydroxybenzotriazole (8.65 mg, 0.064 mmol), triethylamine (10.7 μL, 0.0768 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24.5 mg, 0.128 mmol) were stirred at room temperature for 18 hours. After the end of the reaction, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate / 2-propanol = 10/1) to give N-[(S)-1-amino-3-hydroxy-1-oxopropane. 2-yl]-4-(4-{1-[4-(cyclopropanecarbonyl)phenoxy]propyl}-1H-pyrazol-1-yl)-2-fluorobenzoguanamine (12.7 mg , colorless amorphous material with a yield of 40% (3 steps).

(5) The obtained N-[(S)-1-amino-3-carbyl-1-oxopropan-2-yl]-4-(4-{1-[4-(cyclopropanecarbonyl) Phenoxy]propyl}-1H-pyrazol-1-yl)-2-fluorobenzoguanamine (12.7 mg) was optically isolated on a chiral column. The classification conditions are shown below.

‧Chiral column: CHIRALPAK (registered trademark) IA (inner diameter 30mm, length 100mm, particle diameter 20μm, Daicel Co., Ltd.)

‧ Temperature: room temperature

‧Flow rate: 15mL/min

‧Detection wavelength 280nm

‧gradient conditions

0-40 min: hexane/2-propanol = 35/65

40-80min: Hexane/2-propanol = 10/90

After concentration of the fraction which was maintained for 28 min, a diastereomer A (3.9 mg, optical purity: 99% ee) of the title compound was obtained as a colorless solid. Further, the fraction having a retention time of 58 min was concentrated, and then the other diastereomer B (Synthesis Example 8) (4.5 mg, optical purity: 99% ee) of the title compound was obtained as a colorless solid.

And the optical purity is determined by the following analysis conditions.

‧ Chiral column: CHIRALPAK (registered trademark) IA-3 (inner diameter 4.6mm, length 150mm, particle diameter 3μm, Daicel Co., Ltd.)

‧ Temperature: 40 ° C

‧Flow rate: 1.5mL/min

‧Dissolved solution:hexane/2-propanol=30/70

‧Detection wavelength: 280nm

‧ Hold time: 4.60 min (diastereomer A), 7.82 min (diastereomer B (synthesis example 8))

Synthesis Example 9 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl} Isothiazol-3-yl)-2-fluorobenzoguanamine

(1) 4-(5-{1-[4-(Cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluorobenzoate tert-butyl ester

2-Terto-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester (55.0 mg, 0.170 mmol) obtained from Reference Synthesis Example 1, triphenylphosphinium ( 53.5 mg, 0.204 mmol) and a solution of cyclopropyl (4-hydroxyphenyl)methanone (27.6 mg, 0.173 mmol, synthesized according to the method described in International Publication No. 2012/050151) in tetrahydrofuran (1.0 mL) A solution of di-tert-butyl azodicarboxylate (47.0 mg, 0.204 mmol) in tetrahydrofuran (0.5 mL) was added and stirred at room temperature for 16 hours. The reaction mixture was purified by column chromatography (hexane/ethyl acetate = 100/0→95/5) to give 4-(5-{1-[4- A crude oil of (cyclopropanylcarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluorobenzoate tert-butyl ester (100 mg) as a yellow oil. .

MS (ESI ^+): 468 [M + H] ^{+, MS (ESI -):} . 466 [MH] ^-. (LC/MS cond.2, RT = 3.29min)

(2) 4-(5-{1-[4-(Cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluorobenzoic acid

1, 4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluorobenzoate tet-butyl ester (105 mg, 0.225 mmol) In a solution of 4-dioxane (1.0 mL), a 1 M aqueous sodium hydroxide solution (900 μL) was added at room temperature, and the mixture was stirred at room temperature for 6 hours. 1,4-Dioxane (1.5 mL) was added to the reaction mixture, and the mixture was further allowed to stand at room temperature for 15 hours, at 50 ° C for 2 hours, at 65 ° C for 5 hours, and at 75 ° C for 2 hours at 80 ° C. Stir for 1 hour. The reaction mixture was cooled and concentrated under reduced pressure. Water and 1 M hydrochloric acid were added to the reaction mixture to adjust the pH to 3 to 4, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous MgSO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. - a colorless solid of benzobenzoic acid (83.2 mg, yield 90%).

MS (ESI ^+): 412 [M + H] ^{+, MS (ESI -):} . 410 [M- H] -. (LC/MS cond.2, RT=2.52min)

(3) Substituting 4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isoxazol-3-yl)-2-fluorobenzoic acid using 4-(5-{ 1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluorobenzoic acid (41.1 mg, 0.0999 mmol) was substantially carried out in the same manner as in Synthesis Example 5-(3) After the same reaction, the title compound (33.0 mg, yield: 66%)

Synthesis Example 10 4-(5-{1-[4-(Cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-N-[(S)-2,3-dihydroxypropyl]-2- Fluorobenzoguanamine

Instead of using 4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isoxazol-3-yl)-2-fluorobenzoic acid, the compound obtained in Synthesis Example 9-(2) was used. 4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluorobenzoic acid (40.7 mg, 0.0989 mmol), substituting L-silylamine In the same manner as in the synthesis of the 5-(3), the title compound (28.8 mg) was obtained. A colorless amorphous material with a rate of 60%).

Synthesis Example 11 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-4-(5-{(R)-1-[4-(cyclopropanecarbonyl)phenoxy) Ethyl}isothiazol-3-yl)-2-fluorobenzoguanamine

(1) (R)-4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy] Ethyl}isothiazol-3-yl)-2-fluorobenzoate tert-butyl ester

(S)-2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester (60.0 mg, 0.186 mmol) obtained in Reference Synthesis Example 2, Tetrahydrofuran (phenylidene phosphine (48.8 mg, 0.186 mmol) and cyclopropyl (4-hydroxyphenyl) ketone (30.2 mg, 0.186 mmol, synthesized according to the method described in International Publication No. 2012/050151) In a 1.0 mL) solution, diisopropyl azodicarboxylate (36.8 μL, 0.186 mmol) was added at 0 ° C, and stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→80/20) to give (R)-4-(5-{1-[4-(cyclopropanecarbonyl) a colorless amorphous material of tert-butyl ester of phenoxy]ethyl}isothiazol-3-yl)-2-fluorobenzoate (79.0 mg, yield 91%).

MS (ESI ^+): 468 [M + H] ^{+, MS (ESI -):} . 466 [MH] ^-. (LC/MS cond.1, RT=3.51min)

(2) (R)-4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluorobenzoic acid

(R)-4-(5-{1-[4-(Cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluorobenzoate tert-butyl ester (79.0 mg, 0.169 To a solution of dichloromethane (2.0 mL) was added trifluoroacetic acid (1.0 mL) at room temperature and stirred at room temperature for 3 hours. Chloroform was added to the reaction mixture, and concentrated under reduced pressure to give (R)-4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2 - a crude product of fluorobenzoic acid (85.5 mg).

MS (ESI ⁺ ): 412 [M+H] ⁺ . (LC/MS cond.2, RT=2.54min)

(3) Substituting (R)-4- using 4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isoxazol-3-yl)-2-fluorobenzoic acid (5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluorobenzoic acid crude product (85.5 mg) was substantially carried out and synthesis example 5 After the same reaction of (3), the title compound (58.0 mg, yield 66% (2 step), optical purity 96% ee) was obtained as a colorless solid.

And the optical purity is determined by the following analysis conditions.

‧ Chiral column: CHIRALPAK (registered trademark) IA-3 (inner diameter 4.6mm, length 150mm, particle diameter 3μm, Daicel Co., Ltd.)

‧ Temperature: 40 ° C

‧Flow rate: 1.5mL/min

‧Solution: hexane/2-propanol = 50/50

‧Detection wavelength: 280nm

‧Retention time: 6.07min

Synthesis Example 12 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-4-(5-{(S)-1-[4-(cyclopropanecarbonyl)phenoxy Ethyl}isothiazol-3-yl)-2-fluorobenzoguanamine

(1) (S)-4-(5-{1-[4-(Cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluorobenzoate tert-butyl ester

The (R)-2-fluoro group obtained in Reference Synthesis Example 3 was used instead of (S)-2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester. -4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester (50.0 mg, 0.155 mmol) was substantially reacted in the same manner as in Synthesis Example 11-(1) Obtained (S)-4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluorobenzoate tert-butyl ester (75.6 mg, produced Rate quantitative) of a colorless oil.

MS (ESI ^+): 468 [M + H] ^{+, MS (ESI -):} . 466 [M- H] ^-. (LC/MS cond.2, RT = 3.29min)

(2) Substituting (R)-4-(5-{1-[4-(cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluorobenzoate tert-butyl ester (S)-4-(5-{1-[4-(Cyclopropanecarbonyl)phenoxy]ethyl}isothiazol-3-yl)-2-fluorobenzoate tert-butyl ester (75.6 mg, 0.162) The title compound (53.0 mg, yield 70% (2 steps), optical purity 99% ee) was obtained as a colorless solid, which was obtained in the same manner as the compound of the compound of the formula (1) and (3).

And the optical purity is determined by the following analysis conditions.

‧ Chiral column: CHIRALPAK (registered trademark) IA-3 (inner diameter 4.6mm, length 150mm, particle diameter 3μm, Daicel Co., Ltd.)

‧ Temperature: 40 ° C

‧Flow rate: 1.5mL/min

‧Solution: hexane/2-propanol = 50/50

‧Detection wavelength: 280nm

‧Retention time: 9.19min

Synthesis Example 13 4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]-N-(1,3-dihydroxypropane-2- 2-fluorobenzoguanamine

(1) 4-[5-(1-{[6-(Cyclopropanecarbonyl)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl ester

2-Terto-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester (117 mg, 0.362 mmol) obtained from Reference Synthesis Example 2, triphenylphosphinium ( Tetrahydrofuran (1.0 mL) of 104 mg, 0.398 mmol) and cyclopropyl(5-hydroxypyridin-2-yl)methanone (64.9 mg, 0.398 mmol, synthesized according to the method described in International Publication No. 2013/108800) To the solution, diisopropyl azodicarboxylate (78.8 μL, 0.398 mmol) was added at 0 ° C, and stirred at room temperature for 1 hour. The reaction mixture was purified by column chromatography (hexane/ethyl acetate = 4/1) to give 4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy A pale yellow solid of tert-butyl ester (131 mg, yield 77%).

MS (ESI ⁺ ): 469 [M+H] ⁺ . (LC/MS cond.1, RT=3.47min)

(2) 4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoic acid

4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy A solution of tert-butyl ester (131 mg, 0.280 mmol) in ethanol (1.0 mL) was added with a 1M aqueous solution of sodium hydroxide (1.0 mL). Stirring was carried out for 2 hours under reflux. After the reaction was completed, 1M hydrochloric acid (1.0 mL) was added, and ethyl acetate was evaporated. The organic layer was dried over anhydrous sodium sulfate and filtered and concentrated under reduced pressure to give 4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}ethyl)isothiazole A colorless amorphous material of -3-yl]-2-fluorobenzoic acid (115 mg, yield 99%).

MS (ESI ^+): 413 [M + H] ^{+, MS (ESI -):} . 411 [MH] ^-. (LC/MS cond.1, RT=2.56min)

(3) 4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoic acid (57.6 mg, 2-Amino-1,3-propaneamine (15.3 mg, 0.168 mmol), 1-hydroxybenzotriazole (0.14 mmol) in N,N-dimethylformamide (1.0 mL) 18.9 mg, 0.140 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53.7 mg, 0.280 mmol) were stirred at room temperature for 18 hours. After the completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

Synthesis Example 14 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-4-[5-(1- {[6-(Cyclopropanecarbonyl)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoguanamine

4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}ethyl)isothiazol-3-yl]-2- obtained in Synthesis Example 13-(2) To a solution of fluorobenzoic acid (57.6 mg, 0.140 mmol) in N,N-dimethylformamide (1.0 mL) was added L-silylamine amide hydrochloride (23.5 mg, 0.168 mmol), 1-hydroxyl Benzotriazole (18.9 mg, 0.140 mmol), triethylamine (23.4 μL, 0.168 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( 53.7 mg, 0.280 mmol), stirred at room temperature for 18 hours. After the completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

Synthesis Example 15 N-[(S)-1-Amino-3-hydroxy-1-oxopropan-2-yl]-4-[5-((R)-1-{[6-(cyclopropanecarbonyl)pyridine- 3-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoguanamine

(1) (R)-4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoic acid tert -butyl ester

Instead of using 2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester, (S)-2-fluoro-4- obtained by referring to Synthesis Example 2 was used. (5-(1-Hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester (65.0 mg, 0.201 mmol) was obtained by substantially the same reaction as in Synthesis Example 13-(1). - 4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl ester (80.0 Mg, yield 85%) of a pale yellow solid.

MS (ESI ⁺ ): 469 [M+H] ⁺ . (LC/MS cond.1, RT=3.47min)

(2) (R)-4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoic acid

(R)-4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl Add a solution of the ester (80.0 mg, 0.171 mmol) in dichloromethane (1.0 mL). mix. Ethyl acetate and toluene were added to the reaction mixture, and concentrated under reduced pressure to give (R)-4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}ethyl Crude product of isothiazol-3-yl]-2-fluorobenzoic acid (74.0 mg).

MS (ESI ⁺ ): 413 [M+H] ⁺ . (LC/MS cond.2, RT=2.47min)

(3) Substituting 4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoic acid for use ( R)-4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoic acid (74.0 mg) The same reaction as in Synthesis Example 14 was carried out to give the title compound (74.6 mg, yield 52% (2 steps), optical purity 99% ee) as a colorless solid.

And the optical purity is determined by the following analysis conditions.

‧ Chiral column: CHIRALPAK (registered trademark) IA-3 (inner diameter 4.6mm, length 150mm, particle diameter 3μm, Daicel Co., Ltd.)

‧ Temperature: 40 ° C

‧Flow rate: 1.5mL/min

‧ Gradient conditions:

The mixing ratio of hexane to ethanol was changed to a linear change of 10/90 at 13 minutes after the start of the measurement at 60/40.

‧Detection wavelength: 254nm

‧Retention time: 6.43min

Synthesis Example 16 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl] Oxy}propyl)isothiazol-3-yl]-2-fluorobenzoguanamine

(1) 4-[5-(1-{[6-(Cyclopropanecarbonyl)pyridin-3-yl]oxy}propyl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl ester

2-fluoro-4-[5-(1-) obtained by substituting Synthesis Example 4 was used instead of 2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester. The same reaction as in the synthesis example 13-(1) was carried out, except that the hydroxypropyl)isothiazol-3-yl]benzoic acid tert-butyl ester (95.8 mg, 0.284 mmol) was obtained, and 4-[5-(1- {[6-(Cyclopropanecarbonyl)pyridin-3-yl]oxy}propyl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl ester (125 mg, yield 91%) as a colorless oil Things.

¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.02-1.28 (m, 7H), 1.61 (s, 9H), 2.07-2.26 (m, 2H), 3.37-3.45 (m, 1H), 5.63 (t, J=6.6 Hz, 1H), 7.30 (dd, J=9.0, 2.7 Hz, 1H), 7.51 (s, 1H), 7.65-7.70 (m, 2H), 7.93 (t, J = 8.1 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 8.40 (d, J = 2.7 Hz, 1H).

MS (ESI ⁺ ): 483 [M+H] ⁺ . (LC/MS cond.1, RT=3.58min)

(2) 4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}propyl)isothiazol-3-yl]-2-fluorobenzoic acid

Substituting 4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl ester, using 4 -[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}propyl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl ester (53.0 mg, 0.110 In the same manner as in the above-mentioned Synthesis Example 13-(2), 4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}propyl) A crude oil of thiazol-3-yl]-2-fluorobenzoic acid (61.0 mg) as a yellow oil.

MS (ESI ⁺ ): 427 [M+H] ⁺ . (LC/MS cond.2, RT=2.64min)

(3) Substituting 4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoic acid and using 4- [5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}propyl)isothiazol-3-yl]-2-fluorobenzoic acid was substantially carried out in the same manner as in Synthesis Example 14. The reaction was carried out to give the title compound (21.0 mg, yield 37% (2 step)

Synthesis Example 17 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-2-fluoro-4-[5-({R}-1-{[6-(5- Isopropyl-1,2,4-oxadiazol-3-yl)pyridin-3-yloxy}ethyl)isothiazol-3-yl]benzoguanamine

(1) (R)-2-Fluoro-4-[5-(1-{[6-(5-isopropyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl] Oxyethyl}ethyl)isothiazol-3-yl]benzoic acid-tert-butyl ester

(S)-2-fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester (50.0 mg, 0.155 mmol) in tetrahydrofuran obtained by reference to Synthesis Example 2. (2.0 mL), 6-(5-isopropyl-1,2,4-oxadiazol-3-yl)pyridin-3-ol (38.2 mg, 0.186 mmol) obtained in Reference Synthesis Example 8 was added. Triphenylphosphinium (61.0 mg, 0.233 mmol) and diisopropyl azodicarboxylate (46.1 μL, 0.233 mmol) were stirred at room temperature for 12 hours. After the reaction mixture was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5→70/30) to give (R)-2-fluoro-4. -[5-(1-{[6-(5-isopropyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl Benzoic acid-tert-butyl ester (45.0 mg, yield 57%) of a colorless oil.

MS (ESI ^+): 511 [M + H] ^{+, MS (ESI -):} . 509 [MH] ^-. (LC/MS cond.1, RT=3.39min)

(2) (R)-2-Fluoro-4-[5-(1-{[6-(5-isopropyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl) a solution of oxy]ethyl)isothiazol-3-yl]benzoic acid-tert-butyl ester (45.0 mg, 0.0881 mmol) in dichloromethane (3.0 mL), trifluoroacetic acid (1.0 mL) ), stirring at room temperature for 3 hours. Toluene was added to the reaction mixture, which was concentrated under reduced pressure. To a solution of the obtained residue in N,N-dimethylformamide (2.0 mL), EtOAc (18.6 mg, 0.132 mmol), 1-hydroxybenzotriazole (11.9) Mg, 0.0881 mmol), triethylamine (61.5 μL, 0.441 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (33.7 mg, 0.176 mmol) Stir at room temperature for 3 days. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc Colorless solid.

Synthesis Example 18 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-2-fluoro-4-(5-{(R)-1-[(6-isobutylguanidinopyridine) -3-yl)oxy]ethyl}isothiazol-3-yl)benzoguanamine

Substituting 6-(5-isopropyl-1,2,4-oxadiazol-3-yl)pyridin-3-ol, The same reaction as in Synthesis Example 17 was carried out, except that 1-(5-hydroxypyridin-2-yl)-2-methylpropan-1-one obtained in Reference Example 9 was used to give the title compound (50.8 mg, Yield 3 steps 63%) of a colorless solid.

Synthesis Example 19 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-2-fluoro-4-(5-{(R)-1-[(6-pentamethylene fluorene) Pyridin-3-yl)oxy]ethyl}isothiazol-3-yl)benzoguanamine

Substituting 6-(5-isopropyl-1,2,4-oxadiazol-3-yl)pyridin-3-ol, 1-(5-hydroxypyridin-2-yl) obtained by referring to Synthesis Example 10 was used. The title compound (59.4 mg, yield 3 step 43%) was obtained as a colorless solid.

Synthesis Example 20 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-2-fluoro-4-(5-{1-[(1-methyl-1H-pyrrole) [2,3-b]pyridin-5-yl)oxy]ethyl}isothiazol-3-yl)benzoguanamine

N-{(S)-1-amino-3-[(tert-butyldimethylmethyl)oxy]-1-oxopropan-2-yl}-2 obtained in Reference Synthesis Example 12 To a solution of fluoro-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoguanamine (20.0 mg, 0.0428 mmol) in tetrahydrofuran (0.5 mL), triphenylphosphine (13.5) Mg, 0.0513 mmol), 1-methyl-1H-pyrrolo[ 2,3-b]pyridine-5-ol (7.60 mg, 0.0513 mmol) and diisopropyl azodicarboxylate (10.2 μL, 0.0513 mmol) were stirred overnight at room temperature. Triphenylphosphinium (13.5 mg, 0.0513 mmol), 1-methyl-1H-pyrrolo[2,3-b]pyridin-5-ol (7,60 mg, 0.0513 mmol) and azo were added to the reaction mixture. Diisopropyl dicarboxylate (10.2 μL, 0.0513 mmol), further stirred for 2 hours, then added 1M tetrabutylammonium fluoride in tetrahydrofuran (85.6 μL, 0.0856 mmol) at room temperature, at room temperature Stir for 30 minutes. The reaction mixture was purified by EtOAc EtOAc EtOAc. Yield 34%) of a grey solid.

Synthesis Example 21~40

Substituting 1-methyl-1H-pyrrolo[2,3-b]pyridine-5-ol, the 1-(2,2,2-trifluoroethyl)-1H-pyrrole obtained by referring to Synthesis Example 32 was used. [2,3-b]pyridine-5-ol, using 6-(cyclopropylmethoxy)pyridin-3-ol obtained in Reference Synthesis 24, 6-[(2, 2,2-Trifluoroethyl)amino]pyridin-3-ol, 2-(2,2,2-trifluoroethoxy)pyridin-4-ol, 2-chloro- obtained in Reference Synthesis Example 34 5-hydroxypyridine, 4-hydroxybenzotrifluoride, 4-propylphenol, N-cyclopropyl-5-hydroxymethylpyridiniumamine obtained in Reference Synthesis Example 19, 6-(trifluoromethyl) Pyridin-3-ol, 2-fluoro-5-hydroxypyridine, 4-hydroxybenzonitrile, 4-(trifluoromethoxy)phenol, 6-(2,2,2-three obtained in Reference Synthesis Example 22 Fluoroethoxy)pyridin-3-ol, 3-chloro-4-cyclopropoxy group obtained by referring to Synthesis Example 35 Phenol, 3-chloro-4-methoxyphenol, 4-(difluoromethoxy)-3-methylphenol, 4-(cyclopentyloxy)phenol, the cyclopropyl group obtained in Reference Synthesis Example 20 ( 3-fluoro-4-hydroxyphenyl)methanone, 2-(2,2,2-trifluoroethoxy)pyrimidine-5-ol, 2-fluoro-4-hydroxybenzoic acid obtained in Reference Synthesis Example 25. The compounds of Synthesis Examples 21 to 40 were synthesized by substantially the same reaction as in Synthesis Example 20 except for the methyl ester. The compound names, shapes and yields of the synthesized compounds are shown in Table 4. Further, Ex described in the table indicates a synthesis example.

Synthesis Example 41 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-2-fluoro-4-[5-(1-{3-fluoro-4-[(2, 2,2-Trifluoroethyl)aminomethylindolyl]phenoxy}ethyl)isothiazol-3-yl]benzoindole

4-{1-[3-(4-{[(S)-1-Amino-3-hydroxy-1-oxopropan-2-yl]aminocarbazinyl}-3 obtained in Synthesis Example 40 To a solution of methyl fluorophenyl)isothiazol-5-yl]ethoxy}-2-fluorobenzoate (30.0 mg, 0.0614 mmol) in MeOH (0.5 mL) 0.123 mmol) was stirred overnight at room temperature. Ethanol was added to the reaction mixture, and the mixture was concentrated twice under reduced pressure and dried under reduced pressure for 4 hours. To a solution of the obtained residue in N,N-dimethylformamide (0.6 mL), 1-hydroxybenzotriazole (8.30 mg, 0.0614 mmol), 1-(3-dimethylaminopropyl) 3-Ethylcarbodiimide hydrochloride (23.5 mg, 0.123 mmol) and 2,2,2-trifluoroethylamine (14.5 μL) were stirred at room temperature for 2 days. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by EtOAc EtOAcjjjjj(

Synthesis Example 42 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-4-{5-[1- ({6-[(E)-(ethoxyimino)methyl]pyridin-3-yl}oxy)ethyl]isothiazol-3-yl}-2-fluorobenzoguanamine

On N-{(S)-1-amino-3-[(tert-butyldimethylmethyl)oxy]-1-oxopropan-2-yl}-2-fluoro-4-{5 -[(S)-1-hydroxyethyl]isothiazol-3-yl}benzoguanamine (46.8 mg, 0.100 mmol), triphenylphosphinium (39.3 mg, 0.150 mmol) and 5-hydroxypyridine-2 - a solution of formaldehyde (18.5 mg, 0.150 mmol) in tetrahydrofuran (0.20 mL), diisopropyl azodicarboxylate (1.9 M in toluene, 0.200 mmol, 0.105 mL) was added at 0 ° C at room temperature Stir for 16 hours. A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.200 mL, 0.200 mmol) was added to the mixture and the mixture was stirred at room temperature for 2 hours. O-ethylhydroxylamine hydrochloride (19.1 mg, 0.200 mmol) was added to the reaction mixture, and stirred at room temperature for 16 hours. The title compound (19.4 mg, yield 39%) eluted

Synthesis Example 43 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-2-fluoro-4-(5-{1-[(6-{(E)-[( 2,2,2-trifluoroethoxy)imine]methyl}pyridin-3-yl)oxy]ethyl}isothiazol-3-yl)benzoguanamine

The same procedure as in Synthesis Example 42 was carried out except that O-(2,2,2-trifluoroethyl)hydroxylamine hydrochloride (30.3 mg, 0.200 mmol) was used instead of O-ethylhydroxylamine hydrochloride. Reaction gave the title compound (10.5 mg, yield 19%)

Synthesis Example 44 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-4-[5-(1-{[5-(cyclopropanecarbonyl)pyrazin-2-yl Oxy]ethyl)isothiazol-3-yl]-2-fluorobenzoguanamine

(R)-4-[5-(1-{[5-(cyclopropanecarbonyl)pyrazin-2-yl]oxy}ethyl)isothiazol-3-yl]- obtained by reference to Synthesis Example 27 To a solution of 2-fluorobenzoic acid (0.0640 mmol) in N,N-dimethylformamide (1.0 mL), L-serinate guanamine hydrochloride (10.0 mg, 0.0700 mmol), 1-hydroxybenzene Triazole (9.40 mg, 0.0700 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.0 mg, 0.0700 mmol) and triethylamine (10 μL) , 0.0700 mmol), stirred at room temperature for 20 hours. After the completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

Synthesis Example 45 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-4-[5-(1-{[5-(cyclopropanecarbonyl)pyridin-2-yl] Oxyethyl}ethyl)isothiazol-3-yl]-2-fluorobenzoguanamine

(1) 4-[5-(1-{[5-(cyclopropanecarbonyl)pyridin-2-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl

2-Terto-4-[5-(1-hydroxyethyl)isothiazol-3-yl]benzoic acid tert-butyl ester (150.1 mg, 0.464 mmol) in tetrahydrofuran (3.0 mL) In the solution, potassium tributoxide (57.4 mg, 0.512 mmol) was added at 0 ° C, and stirred at 0 ° C for 30 minutes. (6-Chloropyridin-3-yl)(cyclopropyl)methanone (92.9 mg, 0.512 mmol) was added to the reaction mixture at 0 ° C, and stirred at room temperature for 3 hours. After the completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80 / 20) to give 4-[5-(1-{[5-(cyclopropanecarbonyl)pyridin-2-yl] Ethyl}ethyl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl ester (105 mg, yield 48%) as a colorless solid.

MS (ESI ⁺ ): 469 [M+H] ⁺ . (LC/MS cond.2, RT = 3.27min)

(2) 4-[5-(1-{[5-(cyclopropanecarbonyl)pyridin-2-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoic acid

4-[5-(1-{[5-(cyclopropanecarbonyl)pyridin-2-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl ester (50.0 mg A solution of 0.107 mmol of dichloromethane (0.5 mL) was added trifluoroacetic acid (0.5 mL) at room temperature and stirred at room temperature for 2 hours. Toluene was added to the reaction mixture, and concentrated under reduced pressure to give 4-[5-(1-{[5-(cyclopropanecarbonyl)pyridin-2-yl]oxy}ethyl)isothiazol-3-yl] A yellow oil of the crude product of 2-fluorobenzoic acid.

MS (ESI ⁺ ): 413 [M+H] ⁺ . (LC/MS cond.2, RT=2.53min)

(3) Crude product of 4-[5-(1-{[5-(cyclopropanecarbonyl)pyridin-2-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoic acid (44.1 mg, 0.107 mmol) of N,N-dimethylformamide (1.0 mL) was added with L-serinate guanamine hydrochloride (22.6 mg, 0.161 mmol), 1-hydroxybenzotriene Azole (14.5 mg, 0.107 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (41.0 mg, 0.214 mmol) and triethylamine (44.7 μL, 0.321 mmol), stirred at room temperature for 4 days. After the completion of the reaction, a saturated aqueous solution of ammonium chloride and water were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered and evaporated. The residue was purified by EtOAc EtOAc (EtOAc)

Synthesis Example 46 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-2-fluoro-4-[5-((R)-1-{[6-(2, 2,2-Trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]benzoguanamine

Instead of using (R)-4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoic acid, (R)-2-fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy} obtained by reference to Synthesis Example 26 was used. The title compound (33.3 mg, yield: 92%) was obtained as a colorless solid (yield: m.p.

Synthesis Example 47 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-2-fluoro-4-[5-(1-{[5-(2,2,2-) Trifluoroethoxy)pyrazine-2-yloxy}ethyl)isothiazol-3-yl]benzoguanamine

Used instead of (R)-4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoic acid The 2-fluoro-4-[5-(1-{[5-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy}ethyl)isoform obtained in Reference Synthesis Example 28 The title compound (3.14 mg, yield 82%) was obtained as a colorless solid, m.p.

Synthesis Example 48~107

Instead of L-serinate guanamine hydrochloride, use L-alanine guanamine hydrochloride, (2S)-2-aminobutyl decylamine, 2-amino-2-methylpropanoguanamine, (2S --2-aminobutanediamine, (S)-3-amino-2-piperidone, (S)-3-amino-2-pyrrolidone, L-valine amide, 2- Piperidine Carboxamide, (S)-(+)-2-Amino-1-propanol, 3-Hydroxyazetidine hydrochloride, (R)-3-pyrrolidinol, 4-hydroxypiperidin Pyridine, cis (hydroxymethyl) aminomethane, 2-amino-2-methyl-1,3-propanediol, azetidine hydrochloride, 1-aminocyclopropanecarbonitrile hydrochloride , 3-oxetanamine, 4-(2-aminoethyl)morpholine, L-α-amino-ε-caprolactam, (S)-3-aminotetrahydrofuran, morpholine, Cyclopropylamine, 2-aminoethanol, (3S,4R)-4-aminotetrahydrofuran-3-ol, (3R,4S)-4-aminotetrahydrofuran-3-ol, 2-amino-1, 3-propanediol, (S)-3-amino-1,2-propanediol, thiazolidine, (R)-(-)-α-amino-γ-butyrolactone hydrochloride, D- Alanine hydrochloride, morpholine-3-carboxamide, 2-amino-2-methyl-1-propanol, 2-(methylamino)ethanol, diethanolamine, D-valeramine , 4-piperidinemethanol, (S)-(+)-tetrahydrofurfurylamine, ( R)-(-)-tetrahydrofurfurylamine, thiomorpholine, thiomorpholine 1,1-dioxide, 3-aminopropionitrile, N,N-dimethylethylenediamine, 2- Aminoethyl methyl hydrazine hydrochloride, (S)-(-)-α-amino-γ-butyrolactone hydrochloride, glycine guanamine hydrochloride, (S)-3-amino group -γ-butyrolactone hydrochloride, D-serine guanamine hydrochloride, (S)-2-amino-4-hydroxybutaneamine obtained in Reference Synthesis Example 13, with reference to Synthesis Example 14 The obtained (R)-2-amino-4-hydroxybutaneamine, (S)-3-amino-4-hydroxybutaneamine obtained by the reference Synthesis Example 15, DL-serine, 1 , 2,5-thiadiazepine 1,1-dioxide, (S) obtained by referring to Synthesis Example 16. 3-Amino-4,4,4-trifluorobutan-1-ol hydrochloride, (R)-3-amino-4,4,4-trifluorobutane obtained in Reference Synthesis Example 17. -1-alcohol hydrochloride, 1-aminocyclopropanecarboxamide (synthesized according to the method described in International Publication No. 2009/070485), β-alanine guanamine hydrochloride, 2-(A) Ethylamino)acetamide, (S)-2-amino-3-hydroxy-N-methylpropaninamine, (S)-azetidin-2-carboxyindole obtained by reference to Synthesis Example 18. An amine trifluoroacetate salt (synthesized in accordance with the method described in International Publication No. 2007/085895) and an aminoacetonitrile hydrogensulfate are substantially synthesized in the same manner as in Synthesis Example 15-(3). 48 to 107 compounds. The compound names, shapes and yields of the synthesized compounds are shown in Tables 5 to 7.

Synthesis Example 108 (S)-N-(1-Amino-3-hydroxy-1-oxopropan-2-yl)-4-[5-(2-{[6-(cyclopropanecarbonyl)pyridin-3-yl] Oxy}propan-2-yl)isothiazol-3-yl]-2-fluorobenzoguanamine

(1) 2-fluoro-4-[5-(2-hydroxypropan-2-yl)isothiazol-3-yl]benzoic acid tert-butyl ester

Diethyl ether of 4-(5-ethyiisothiazol-3-yl)-2-fluorobenzoate tet-butyl ester (1.00 g, 3.09 mmol) obtained by reference to Synthesis Example 1-(4) Methyl lithium (3M dimethoxyethane solution, 1.03 mL, 3.09 mmol) was added at -78 °C in a mixed solution of 3.0 mL) and toluene (5.0 mL), and stirred at -78 °C for 3 hours. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexaneshexanes ethyl acetate=80/20) to give 2-fluoro-4-[5-(2-hydroxypropan-2-yl) Thiazol-3-yl]benzoic acid tert-butyl ester (765 mg, yield 73%) as a colorless solid.

MS (ESI ⁺ ): 338 [M+H] ⁺ . (LC/MS cond.2, RT=2.63min)

(2) 4-[5-(2-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}propan-2-yl)isothiazol-3-yl]-2-fluorobenzoate tert- Butyl ester

Tert-butyl 2-fluoro-4-[5-(2-hydroxypropan-2-yl)isothiazol-3-yl]benzoate (650 mg, 1.93 mmol), phenoxydiphenylphosphinium (590 mg) , 2.12 mmol) and a solution of cyclopropyl (5-hydroxypyridin-2-yl)methanone (347 mg, 2.12 mmol, synthesized according to the method described in International Publication No. 2013/108800) in tetrahydrofuran (5.0 mL) Diisopropyl azodicarboxylate (0.420 mL, 2.12 mmol) was added at 0 ° C and stirred at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by chromatography (hexane/ethyl acetate=96/4→85/15) to give (4-[5-(2-{[ Colorless oil of 6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}propan-2-yl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl ester (583 mg, yield 63%) Shape.

MS (ESI ⁺ ): 483 [M+H] ⁺ . (LC/MS cond.2, RT=3.28min)

(3) 4-[5-(2-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}propan-2-yl)isothiazol-3-yl]-2-fluorobenzoic acid

(4-[5-(2-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}propan-2-yl)isothiazol-3-yl]-2-fluorobenzoate tert-butyl A solution of the ester (215 mg, 0.446 mmol) in ethanol (2.0 mL) was added 1M aqueous sodium hydroxide (2.0 mL) at room temperature and stirred at 85 ° C for 1 hour. After the reaction was finished, 1 M hydrochloric acid (2.0 mL) was added to The organic layer was dried over anhydrous magnesium sulfate and filtered, and the organic layer was concentrated under reduced pressure to give 4-[5-(2-{[6-(cyclopropanecarbonyl)pyridin-3-yl) Ethoxy}propan-2-yl)isothiazol-3-yl]-2-fluorobenzoic acid (134 mg, yield 70%) as a colorless solid.

MS (ESI ^+): 427 [M + H] ^{+, MS (ESI -):} . 425 [MH] ^-. (LC/MS cond.2, RT=2.55min)

(4) 4-[5-(2-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}propan-2-yl)isothiazol-3-yl]-2-fluorobenzoic acid ( In a solution of 100 mg, 0.234 mmol) of N,N-dimethylformamide (1.0 mL), L-silylamine amide hydrochloride (34.0 mg, 0.234 mmol), 1-hydroxybenzotriazole ( 32.0 mg, 0.234 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45.0 mg, 0.234 mmol) and triethylamine (39.0 μL, 0.281 mmol) ), stirring overnight at room temperature. After the reaction was over, water was added and the mixture was taken with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc)

Synthesis Example 109 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-4-[5-({R}-1-{[6-(cyclopropylmethoxy) Pyridin-3-yloxy}ethyl)isothiazol-3-yl]-2-fluorobenzoguanamine

(R)-4-[5-(1-{[6-(cyclopropylmethoxy)pyridin-3-yl)oxy}ethyl)isothiazol-3-yl obtained by the reference of Synthesis Example 29 To a solution of 2-fluorobenzoic acid (30.0 mg, 0.0724 mmol) in N,N-dimethylformamide (1.0 mL), EtOAc (20.3 mg, 0.145 mmol) , 1-hydroxybenzotriazole (9.78 mg, 0.0724 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27.8 mg, 0.145 mmol) and three Ethylamine (61.0 μL, 0.435 mmol) was stirred at room temperature for 4 days. After the completion of the reaction, a saturated aqueous solution of ammonium chloride and ethyl acetate were added and extracted, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc EtOAc (EtOAc)

Synthesis Example 110 (R)-N-(1-Amino-2-methyl-1-oxopropan-2-yl)-4-[5-(1- {[6-(Cyclopropylmethoxy)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]-2-fluorobenzoguanamine

The title compound (59.9 mg, yield 72%) was obtained by the the the the the the the the the the the the the the the the ) a colorless solid.

Synthesis Example 111 (S)-1-{4-[5-((R)-1-{[6-(cyclopropylmethoxy)pyridin-3-yl)oxy}ethyl)isothiazol-3-yl] 2-fluorobenzhydryl}pyrrolidine-2-carboxamide

The title compound (59.8 mg, yield 69%) was obtained as a colorless solid, m. m.

Synthesis Example 112 (R)-N-(1-Amino-2-methyl-1-oxopropan-2-yl)-2-fluoro-4-[5-(1-{[6-(2,2,2) -trifluoroethoxy)pyridin-3-yloxy}ethyl)isothiazol-3-yl]benzoguanamine

(R)-2-Fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy} obtained by reference to Synthesis Example 26. 2-Amino-2-methylpropanoguanamine was added to a solution of ethyl, isothiazol-3-yl]benzoic acid (70.0 mg, 0.158 mmol) in N,N-dimethylformamide (1.0 mL) (32.3 mg, 0.316 mmol), 1-hydroxybenzotriazole (21.3 mg, 0.158 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbamate The imine hydrochloride (60.6 mg, 0.316 mmol) and triethylamine (66.1 μL, 0.474 mmol) were stirred at room temperature for 3 days. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated The residue was purified by EtOAc EtOAcjjjjj(

Synthesis Example 113 (S)-1-{2-Fluoro-4-[5-((R)-1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy}B Isothiazol-3-yl]benzimidyl}pyrrolidine-2-carboxamide

The title compound (52.2 mg, yield: 61%) was obtained as colorless, except that it was obtained by using the same. solid.

Synthesis Example 114 (R)-N-(1-cyanocyclopropyl)-2-fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl) Oxy]ethyl)isothiazol-3-yl]benzoguanamine

The title compound (24.7 mg, m.p. Yield 68%) colorless solid body.

Synthesis Example 115 (R)-N-(1-Amino-2-methyl-1-oxopropan-2-yl)-3-fluoro-5-[5-(1-{[6-(2,2,2) -trifluoroethoxy)pyridin-3-yloxy}ethyl)isothiazol-3-yl]methylpyridinium

(1) (R)-3-Chloro-5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazole

(S)-1-(3-chloroisothiazol-5-yl)ethanol (400 mg, 2.40 mmol), triphenylphosphinium (756 mg, 2.88 mmol) obtained in Reference Synthesis Example 30 and obtained in Reference Synthesis Example 22 a solution of 6-(2,2,2-trifluoroethoxy)pyridin-3-ol (556 mg, 2.88 mmol) in tetrahydrofuran (8.0 mL), diisopropyl azodicarboxylate (1.9 M toluene) The solution, 1.50 mL, 2.88 mmol) was added at 0 ° C and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium The residue was purified by silica gel chromatography (hexane/ethyl acetate = 4/1) to give (R)-3-chloro-5-(1-{[6-(2,2,2-3) Fluorine ethoxy)pyridin-3-yloxy}ethyl)isothiazole (679 mg, yield 83%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.73 (d, J = 6.3 Hz, 3H), 4.69 (q, J = 8.6 Hz, 2H), 5.49-5.57 (m, 1H), 6.81 (dd, J = 8.8 , 0.7 Hz, 1H), 6.96 (d, J = 0.7 Hz, 1H), 7.29 (dd, J = 8.8, 2.9 Hz, 1H), 7.79 (d, J = 2.6 Hz, 1H).

(2) (R)-3-Fluoro-5-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazole -3-yl]methylpyridic acid tert-butyl ester

(R)-3-Chloro-5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazole (100 mg, 0.296 mmol In a solution of 1,4-dioxane/water = 2/1 (3.0 mL), 3-fluoro-5-(4,4,5,5-four obtained in Reference Synthesis 31 was added at room temperature. Tert-butyl methyl-1,3,2-dioxaborolan-2-yl)-picolinate (143 mg, 0.444 mmol), hydrazine (triphenylphosphinyl) palladium (34.2 mg, 0.0296 mmol) Potassium fluoride (51.6 mg, 0.888 mmol) was stirred overnight at 100 ° C under an argon atmosphere. After the reaction was completed, the reaction mixture was cooled and diluted with water and ethyl acetate. After the reaction mixture was washed with brine, EtOAc evaporated The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1→2/1) to afford (R)-3-fluoro-5-[5-(1-{[6-( 2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazole-3- A pale yellow amorphous material of tert-butyl picolinate (106 mg, yield 72%).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ: 1.65 (s, 9H), 1.90 (d, J = 6.6Hz, 3H), 4.64-4.73 (m, 2H), 5.62-5.69 (m, 1H), 6.80- 6.83 (m, 1H), 7.30-7.34 (m, 1H), 7.53 (s, 1H), 7.82-7.83 (m, 1H), 8.06-8.10 (m, 1H), 8.98-8.99 (m, 1H).

MS (ESI ^-): 498,499 [MH] ^-. (LC/MS cond.1, RT=3.29min)

(3) (R)-3-Fluoro-5-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazole -3-yl]methylpyridinic acid

(R)-3-Fluoro-5-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy}ethyl)isothiazole-3 To a solution of tert-butyl pivalate (106 mg, 0.212 mmol) in dichloromethane (1.0 mL), trifluoroacetic acid (1.0 mL) was added at room temperature and stirred at room temperature for 1 hour. Toluene was added to the reaction mixture, which was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform to chloroform/methanol = 10/1) to give (R)-3-fluoro-5-[5-(1-{[6-(2,2,2) -trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]picolinic acid (60.5 mg, yield 64%) as a pale yellow solid.

MS (ESI ⁺ ): 444 [M+H] ⁺ . (LC/MS cond.1, RT=2.57min)

(4) (R)-3-Fluoro-5-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}ethyl) 2-Amino-2-methylpropanamide (11.9) was added to a solution of thiazol-3-yl]methylpyridinic acid (25.5 mg, 0.0575 mmol) in N,N-dimethylformamide (1.0 mL). Mg, 0.0863 mmol), 1-hydroxybenzotriazole (7.77 mg, 0.0575 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.0 mg, 0.115 mmol) and triethylamine (24.0 μL, 0.173 mmol) were stirred at room temperature for 16 hours. 2-Amino-2-methylpropanoguanamine (11.9 mg, 0.0863 mmol), 1-hydroxybenzotriazole (7.77 mg, 0.0575 mmol), 1-(3-dimethylamino group) were added to the reaction mixture. Propyl)-3-ethylcarbodiimide hydrochloride (22.0 mg, 0.115 mmol) and triethylamine (24.0 μL, 0.173 mmol) were allowed to stand at room temperature for 1 hour and stirred at 80 ° C for 3 hours. After the reaction was completed, the reaction mixture was cooled, water was added and extracted with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride, saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjjj

Synthesis Example 116 (S)-1-{3-Fluoro-5-[5-((R)-1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy}B Isothiazol-3-yl]methylpyridyl}pyrrolidine-2-carboxamide

The title compound (21.3 mg, yield) was obtained after the reaction was carried out in the same manner as in the compound of the compound of the formula (1). 70%) of a pale yellow solid.

Synthesis Example 117 N-[(S)-1-Amino-3-hydroxy-1-oxopropan-2-yl]-3-fluoro-5-[5-((R)-1-{[6-(2, 2,2-Trifluoroethoxy)pyridin-3-yloxy}ethyl)isothiazol-3-yl]methylpyridinium

The title compound (28.9 mg) was obtained after the same reaction as in the synthesis of Example 115-(4), except for using 2-amino-2-methylpropionamide. , yield 30%) of a colorless solid.

Synthesis Example 118 (R)-N-(1-Amino-2-methyl-1-oxopropan-2-yl)-5-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl) Oxy]ethyl)isothiazol-3-yl]-3-fluoromethylpyridinium

(1) (R)-{5-[1-(3-chloroisothiazol-5-yl)ethoxy]pyridin-2-yl}(cyclopropyl)methanone

(S)-1-(3-chloroisothiazol-5-yl)ethanol (600 mg, 3.69 mmol), triphenylphosphinium (1.16 g, 4.43 mmol) and cyclopropyl (obtained in Reference Synthesis Example 30). a solution of 5-hydroxypyridin-2-yl)methanone (722 mg, 4.43 mmol, synthesized by the method disclosed in International Publication No. 2013/108800) in tetrahydrofuran (12 mL), diisopropyl azodicarboxylate The base (1.9 M in toluene, 2.33 mL, 4.43 mmol) was added at 0 ° C and 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 dried over anhydrous magnesium sulfate and filtered and evaporated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 4 / 1 → 3 / 2) to give (R)-{5-[1-(3-chloroisothiazol-5-yl) Ethoxy]pyridin-2-yl}(cyclopropyl)methanone (1.15 g, quantitative yield) of colorless solid.

MS (ESI ^+): 309 [M + H] ^{+, MS (ESI -):} . 307 [MH] ^-. (LC/MS cond.1, RT=2.68min)

(2) (R)-5-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]-3-fluoromethylpyridine Acid tert-butyl

1,4-(R)-{5-[1-(3-chloroisothiazol-5-yl)ethoxy]pyridin-2-yl}(cyclopropyl)methanone (200 mg, 0.648 mmol) In a solution of dioxane/water = 2/1 (3.0 mL), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3 obtained in Reference Synthesis 31 was added at room temperature. Tert-butyl ester of 2-dioxaborolan-2-yl)methylpyridinate (419 mg, 1.30 mmol), hydrazine (triphenylphosphinyl) palladium (37 mg, 0.0324 mmol) and potassium fluoride (113 mg, 1.94 mmol) was stirred at 100 ° C for 17 hours under argon. After the reaction was completed, the reaction mixture was cooled, and brine was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate=90/10→50/50) to give (R)-5-[5-(1-{[6-(cyclopropanecarbonyl) Pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]-3-fluoromethylpyridinic acid tert-butyl ester (169 mg, yield 56%) as a yellow solid.

MS (ESI ⁺ ): 470 [M+H] ⁺ . (LC/MS cond.2, RT=2.91min)

(3) (R)-5-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]-3-fluoromethylpyridine acid

(R)-5-[5-(1-{[6-(cyclopropanecarbonyl)pyridine-3- A solution of tert-butyl ester (169 mg, 0.360 mmol) in dichloromethane (1.7 mL) was added to a solution of trifluoro-ethyl)ethyl)isothiazol-3-yl]-3-fluoromethylpyridinic acid (1. Acetic acid (1.7 mL) was stirred at room temperature for 1.5 hours. Toluene was added to the reaction mixture, and concentrated under reduced pressure to give (R)-5-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}ethyl)isothiazole- A crude product of 3-yl]-3-fluoromethylpyridine acid.

MS (ESI ^+): 414 [M + H] ^{+, MS (ESI -):} . 412 [MH] ^-. (LC/MS cond.2, RT=2.21min)

(4) (R)-5-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]-3-fluoromethyl 2-Amino-2-methylpropanamide (25.0 mg, 0.185 mmol) was added to a solution of crude pyridine acid (51.0 mg, 0.123 mmol) in N,N-dimethylformamide (2.0 mL). , 1-hydroxybenzotriazole (16.0 mg, 0.123 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47.0 mg, 0.246 mmol) and three Ethylamine (51.0 μL, 0.369 mmol) was stirred at room temperature for 3 days. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

Synthesis Example 119 (S)-1-{5-[5-((R)-1-{[6-(cyclopropanecarbonyl)pyridine- 3-yl]oxy}ethyl)isothiazol-3-yl]-3-fluoromethylpyridyl}pyrrolidine-2-carboxamide

In the same manner as in the synthesis of Example 118-(4), the title compound (26.1 mg) was obtained. , yield 42%) of a colorless solid.

Synthesis Example 120 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-5-[5-((R)-1-{[6-(cyclopropanecarbonyl)pyridine- 3-yl]oxy}ethyl)isothiazol-3-yl]-3-fluoromethylpyridinium

The title compound (22.3 mg) was obtained after the same reaction as in the compound of Example 118-(4), except for using 2-amino-2-methylpropionamine. , yield 31%) of a colorless solid.

Synthesis Example 121 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-5-[5-((R)-1-{[6-(2,2,2- Trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]pyrimidine-2-carboxamide

(1) (R)-5-[5-(1-{[6-(2,2,2-Trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl Pyrimidine-2-carboxylic acid tert-butyl

(R)-3-chloro-5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxyl obtained by the synthesis of Example 115-(1) Ethyl)isothiazole (100 mg, 0.296 mmol) in 1,4-dioxane / water = 2 / 1 (3.0 mL) was added at room temperature to give the 5-(4,4) obtained in Reference Synthesis Example 36. , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carboxylic acid tert-butyl (233 mg, 0.761 mmol), hydrazine (triphenylphosphinyl) Palladium (37.4 mg, 0.0324 mmol) and potassium fluoride (56.4 mg, 0.972 mmol) were stirred overnight at 100 ° C under argon. After the end of the reaction, the reaction mixture was cooled, and the mixture was filtered, and then filtered, ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue obtained was purified by silica gel chromatography (hexane/ethyl acetate = 2/1 → 1/1) to give (R)-5-[5-(1-{[6-(2,2, 2-Trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]pyrimidine-2-carboxylic acid tert-butyl (124 mg, quantitative yield).

MS (ESI ^+): 427 [M + H-tert-Bu] ^{+, MS (ESI -):} . 425 [MH-tert-Bu] ^-. (LC/MS cond.1, RT=2.99min)

(2) (R)-5-[5-(1-{[6-(2,2,2-Trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl Pyrimidine-2-carboxylic acid

(R)-5-[5-(1-{[6-(2,2,2-Trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]pyrimidine A solution of 2-carboxylic acid tert-butyl (124 mg, 0.257 mmol) in dichloromethane (1.5 mL) was then evaporated. Toluene was added to the reaction mixture, and concentrated under reduced pressure to give (R)-5-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy A crude product of the ethyl}ethyl)isothiazol-3-ylpyrimidine-2-carboxylic acid.

MS (ESI ^+): 427 [M + H] ^{+, MS (ESI -):} . 425 [MH] ^-. (LC/MS cond.1, RT=2.30min)

(3) (R)-5-[5-(1-{[6-(2,2,2-Trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazole-3- To a solution of N-N-dimethylformamide (1.0 mL) in pyridine pyrimidine-2-carboxylic acid (58.0 mg, 0.136 mmol), EtOAc (28.7 mg, 0.204 mmol) , 1-hydroxybenzotriazole (18.4 mg, 0.136 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52.2 mg, 0.272 mmol) and Triethylamine (117 μL, 0.838 mmol) was stirred overnight at room temperature. After the completion of the reaction, water and a saturated aqueous solution of ammonium chloride were added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The obtained residue was subjected to silica gel column chromatography (chlorine) The title compound (19.1 mg, yield 30%) was obtained.

Synthesis Example 122 (R)-N-(1-Amino-2-methyl-1-oxopropan-2-yl)-5-[5-(1-{[6-(2,2,2-trifluoroethyl) Oxy)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]pyrimidine-2-carboxamide

The title compound (13.4 mg) was obtained after the same reaction as in the compound of Example 121-(3), except that 2-amino-2-methylpropionamide was used instead. , yield 22%) of a colorless solid.

Synthesis Example 123 (R)-N-(1-Amino-2-methyl-1-oxopropan-2-yl)-5-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl) Oxyl}ethyl)isothiazol-3-yl]pyrimidine-2-carboxamide

Instead of using 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylpyridinic acid tert-butyl ester for reference synthesis In addition to the tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carboxylate obtained in Example 36, substantially The title compound (28.6 mg, yield 3 step 11%) was obtained as a colorless solid.

Synthesis Example 124 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl] Oxyethyl}ethyl)isothiazol-3-yl]-3-fluorobenzoguanamine

4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl]oxy}ethyl)isothiazol-3-yl]-3-fluorobenzoic acid obtained by reference to Synthesis Example 37 (20.0 mg, 0.0480 mmol) of N,N-dimethylformamide (1.0 mL) was added with L-silylamine amide hydrochloride (6.70 mg, 0.048 mmol), 1-hydroxybenzotriene Azole (6.50 mg, 0.0480 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.20 mg, 0.0480 mmol) and triethylamine (7.0 μL, 0.0480 mmol), stirred at room temperature for 20 hours. After the completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

Synthesis Example 125 {4-[5-(1-{[6-(cyclopropanecarbonyl)pyridin-3-yl)oxy}ethyl)isothiazol-3-yl]-3-fluorophenyl}[(R)-3 -hydroxypyrrolidin-1-yl]methanone

The title compound (25.2 mg, yield: 72%) was obtained from the compound (m.).

Synthesis Example 126 (R)-2-{2-fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}ethyl)isothiazole -3-yl]benzoguanamine}-2-methylpropanate

(1) (R)-2-{2-Fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}ethyl Isothiazol-3-yl]benzoguanamine}-2-methylpropanate methyl

(R)-2-Fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy} obtained by reference to Synthesis Example 26. 2-Amino-2-methylpropanate A was added to a solution of ethyl, isothiazol-3-yl]benzoic acid (50.0 mg, 0.113 mmol) in N,N-dimethylformamide (1.0 mL) Base hydrochloride (26.0 mg, 0.170 mmol), 1-hydroxybenzotriazole (15.3 mg, 0.113 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt The acid salt (43.3 mg, 0.226 mmol) and triethylamine (47.2 μL, 0.339 mmol) were stirred at room temperature for 65 hours. After the completion of the reaction, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1) to afford (R)-2-{2-fluoro-4-[5-(1-{[6- (2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}ethyl) Thiazol-3-yl]benzoguanamine}-2-methylpropanate methyl (28.0 mg, yield 46%) as a colorless oil.

MS (ESI ^+): 542 [M + H] ^{+, MS (ESI -):} . 540 [MH] ^-. (LC/MS cond.1, RT=3.48min)

(2) (R)-2-{2-Fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}B a solution of isothiazol-3-yl]benzoguanamine}-2-methylpropanate methyl (28.0 mg, 0.0517 mmol) in tetrahydrofuran (1.0 mL), 1M aqueous sodium hydroxide (62.0) μL, 0.0620 mmol), stirred at room temperature for 15 hours. After the completion of the reaction, 1 M aqueous hydrogen chloride solution was added to the reaction mixture, and the mixture was concentrated. The residue was purified by EtOAc EtOAcjjjjjjjjj

Synthesis Example 127 (S)-1-{2-Fluoro-4-[5-((R)-1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy}B Isothiazol-3-yl]benzylidene}pyrrolidine-2-carboxylic acid

The same reaction as in Synthesis Example 126-(1), (2) was carried out, except that 2-amino-2-methylpropanic acid methyl hydrochloride was used instead of L-proline acid methyl hydrochloride. After the title compound (50.3 mg, yield 2 step 82%)

Synthesis Example 128 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-2-fluoro-4-[5-(1-{[6-(2,2,2-) Trifluoroethoxy)pyridin-3-yl]oxy}propyl)isoxazol-3-yl]benzoguanamine (Isomer A)

(1) 2-Fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}propyl)isoxazole-3- Methyl benzoate (Isomer A)

Methyl 2-fluoro-4-[5-(1-hydroxypropyl)isoxazol-3-yl]benzoate (Isomer A, 290 mg, 1.04 mmol) obtained from Reference Synthesis 38, triphenyl A solution of phosphine (328 mg, 1.25 mmol) and 6-(2,2,2-trifluoroethoxy)pyridin-3-ol (241 mg, 1.25 mmol) in dichloromethane (2.9 mL) Diisopropyl azodicarboxylate (1.9 M in toluene, 658 μL, 1.25 mmol) was added at 0 ° C and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform, and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate=90/10→70/30) to give 2-fluoro-4-[5-(1-{[6-(2,2, Methyl 2-trifluoroethoxy)pyridin-3-yloxy}propyl)isoxazol-3-yl]benzoate (Isomer A, 446 mg, yield 94%) as a colorless oil.

MS (ESI ^-): 453 [MH] ^-. (LC/MS cond.2, RT=2.94min)

(2) 2-Fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}propyl)isoxazole-3- Isobenzoic acid (Isomer A)

2-Fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}propyl)isoxazol-3-yl] A solution of methyl benzoate (Isomer A, 50.0 mg, 0.110 mmol) in 1,4-dioxane (5.0 mL) was added 1M aqueous sodium hydroxide (2.5 mL) at room temperature and stirred at room temperature for 2.5 hours. . After the completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with chloroform, and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and concentrated under reduced pressure to give 2-fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridine- A colorless solid of the crude product of 3-yl]oxy}propyl)isoxazol-3-yl]benzoic acid.

MS (ESI ^-): 439 [MH] ^-. (LC/MS cond.2, RT=2.64min)

(3) 2-Fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}propyl)isoxazole-3 N-N- of the crude product of benzoic acid (Isomer A, 22.0 mg, 0.0500 mmol) To a solution of dimethylformamide (1.0 mL), L-serinate guanamine hydrochloride (11.0 mg, 0.0750 mmol), 1-hydroxybenzotriazole (6.80 mg, 0.0500 mmol), 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.0 mg, 0.100 mmol) and triethylamine (21 μL, 0.150 mmol) were stirred at room temperature for 12 hours. After the completion of the reaction, ethyl acetate was added, and the mixture was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous sodium hydrogen carbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

Synthesis Example 129 N-(1-Amino-2-methyl-1-oxopropan-2-yl)-2-fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethyl) Oxy)pyridin-3-yl]oxy}propyl)isoxazol-3-yl]benzoguanamine (Isomer A)

The title compound (20.0 mg) was obtained in the same manner as in the compound of Example 128-(3), except that 2-amino-2-methylpropanolamine was used instead of the amine. , yield 76%) of a colorless solid.

Synthesis Example 130 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-2-fluoro-4-[5-(1-{[6-(2,2,2-) Trifluoroethoxy)pyridin-3-yl]oxy}propyl)isoxazol-3-yl]benzoguanamine (Isomer B)

(1) 2-Fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridine) 3-yl]oxy}propyl)isoxazol-3-yl]benzoic acid (Isomer B)

Instead of using 2-fluoro-4-[5-(1-hydroxypropyl)isoxazol-3-yl]benzoic acid methyl ester (Isomer A), the 2-fluoro-4-[ Except for 5-(1-hydroxypropyl)isoxazol-3-yl]benzoate methyl ester (Isomer B), substantially the same reaction as in Synthesis Example 128-(1) and (2) was carried out to obtain 2- Fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}propyl)isoxazol-3-yl]benzoate ( Isomer B, 48.9 mg, yield 2 parts quantitatively of a colorless solid.

MS (ESI ^-): 439 [MH] ^-. (LC/MS cond.2, RT=2.62min)

(2) Substituting 2-fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}propyl)isoxazole- 2-Hydroxy-4-[5-(1-{[6-(2,2,2-trifluoroethoxy)) obtained from Synthesis Example 130-(1) using 3-mer benzoic acid (Isomer A) In the same manner as in the synthesis of Example 128-(3), the title compound (26.4 mg, m. , yield 92%) of a colorless solid.

Synthesis Example 131 N-(1-Amino-2-methyl-1-oxopropan-2-yl)-2-fluoro-4-[5-(1-{[6-(2,2,2-trifluoroethyl) Oxy)pyridin-3-yl]oxy}propyl)isoxazol-3-yl]benzoindoleamine (Isomer B)

The title compound (21.5 mg) was obtained after the same reaction as in the compound of Example 130-(2), except that 2-amino-2-methylpropanamide was used instead. , yield 75%) of a colorless solid.

Synthesis Example 132 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-2-fluoro-4-[4-(1-{[6-(2,2,2-) Trifluoroethoxy)pyridin-3-yloxy}propyl)-1H-pyrazol-1-yl]benzoguanamine (Isomer A)

(1) 2-Fluoro-4-[4-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}propyl)-1H-pyrazole- 1-yl]methyl benzoate (Isomer A)

Methyl 2-fluoro-4-[4-(1-hydroxypropyl)-1H-pyrazol-1-ylbenzoate (Isomer A, 390 mg, 1.40 mmol) obtained from Reference Synthesis 39, triphenyl Phosphine (441 mg, 1.68 mmol) and 6-(2,2,2-trifluoroethoxy)pyridin-3-ol (325 mg, 1.68 mmol) obtained in m. In the solution, diisopropyl azodicarboxylate (1.9 M in toluene, 884 μL, 1.68 mmol) was Add at 0 ° C and stir overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform, and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate=90/10→70/30) to give 2-fluoro-4-[4-(1-{[6-(2,2, Colorless oil of methyl 2-trifluoroethoxy)pyridin-3-yloxy}propyl)-1H-pyrazol-1-yl]benzoate (Isomer A, 439 mg, yield 69%) .

MS (ESI ^-): 452 [MH] ^-. (LC/MS cond.2, RT=2.90min)

(2) 2-Fluoro-4-[4-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}propyl)-1H-pyrazole- 1-yl]benzoin (Isomer A)

2-Fluoro-4-[4-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}propyl obtained by the synthesis of Example 132-(1) a solution of methyl-1)-pyrazol-1-yl]benzoate (Isomer A, 50 mg, 0.110 mmol) in 1,4-dioxane (5.0 mL) 2.5 mL), stirred at room temperature for 2.5 hours. After the completion of the reaction, 1 M aqueous hydrogen chloride solution was added to the reaction mixture, and the mixture was extracted with chloroform, and the organic layer was washed with brine. The organic layer is anhydrous Drying with sodium sulfate and filtering, and concentrating under reduced pressure to give 2-fluoro-4-[4-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl] A crude oil of the crude product of oxy}propyl)-1H-pyrazol-1-yl]benzoic acid (Isomer A).

MS (ESI ^-): 438 [MH] ^-. (LC/MS cond.2, RT = 2.60min)

(3) 2-Fluoro-4-[4-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy group obtained in Synthesis Example 132-(2) a solution of the crude product of propyl)-1H-pyrazol-1-yl]benzoic acid (Isomer A) (21.0 mg, 0.0480 mmol) in N,N-dimethylformamide (1.0 mL) L-serinate guanamine hydrochloride (10.0 mg, 0.0717 mmol), 1-hydroxybenzotriazole (6.40 mg, 0.0478 mmol), 1-(3-dimethylaminopropyl)-3-B The carbodiimide hydrochloride (18.0 mg, 0.0956 mmol) and triethylamine (20.0 μL, 0.143 mmol) were stirred at room temperature for 12 hours. After the completion of the reaction, ethyl acetate was added, and the mixture was washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous sodium hydrogen carbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

Synthesis Example 133 N-(1-Amino-2-methyl-1-oxopropan-2-yl)-2-fluoro-4-[4-(1-{[6-(2,2,2-trifluoroethyl) Oxy)pyridin-3-yloxy}propyl)- 1H-pyrazol-1-yl]benzoguanamine (Isomer A)

The title compound (14.8 mg) was obtained in the same manner as in the compound of Example 132-(3), except that 2-amino-2-methylpropanolamine was used instead of the amine. , yield 59%) of a colorless solid.

Synthesis Example 134 N-[(S)-1-amino-3-hydroxy-1-oxopropan-2-yl]-2-fluoro-4-[4-(1-{[6-(2,2,2-) Trifluoroethoxy)pyridin-3-yl]oxy}propyl)-1H-pyrazol-1-yl]benzoguanamine (Isomer B)

(1) 2-Fluoro-4-[4-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}propyl)-1H-pyrazole- 1-yl]benzoin (Isomer B)

2-fluoro-4-[4-(1-hydroxypropyl)-1H-pyrazol-1-yl]benzoic acid methyl ester (Isomer A) was used instead of 2-fluoro-4- obtained in Reference Synthesis Example 39. Other than [4-(1-hydroxypropyl)-1H-pyrazol-1-yl]benzoic acid methyl ester (Isomer B), substantially the same reaction as in Synthesis Example 132-(1) and (2) was carried out. 2-Fluoro-4-[4-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}propyl)-1H-pyrazole-1- Benzoic acid (Isomer B, 45.5 mg, yield 2 steps) 60%) colorless oil.

MS (ESI ^-): 438 [MH] ^-. (LC/MS cond.2, RT=2.62min)

(2) Substituting 2-fluoro-4-[4-(1-{[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]oxy}propyl)-1H-pyridyl 2-oxa-4-[4-(1-{[6-(2,2,2-trifluoroethyl) obtained in Synthesis Example 134-(1) using oxazol-1-yl]benzoic acid (Isomer A) Other than the oxy)pyridin-3-yl]oxy}propyl)-1H-pyrazol-1-yl]benzoic acid (Isomer B), substantially the same reaction as in Synthesis Example 132-(3) was carried out. The title compound (20.1 mg, yield 80%)

Synthesis Example 135 N-(1-Amino-2-methyl-1-oxopropan-2-yl)-2-fluoro-4-[4-(1-{[6-(2,2,2-trifluoroethyl) Oxy)pyridin-3-yl]oxy}propyl)-1H-pyrazol-1-yl]benzoguanamine (Isomer B)

The title compound (17.6 mg) was obtained in the same manner as in the synthesis of 134-(2), except that 2-amino-2-methylpropanolamine was used instead of the compound. , yield 70%) of a colorless solid.

The chemical structural formula of the compound synthesized in each synthesis example is shown below. Further, physical data of each synthesis example is shown in Tables 8 to 14. Further, as described above, the Ex is shown in the figure to show a synthesis example. Further, when "*" (asterisk) is described in the structural formula, the absolute arrangement has not yet been determined, but it means an optically active substance, and when it is not described, it represents a racemic body or an enantiomeric mixture.

Pharmacological analysis

The pharmacological analysis of the compounds of the present invention is explained below.

Evaluation Example 1. Determination of GPR119 activity cAMP analysis

A pcDNA4/TO vector having a bleomycin resistance marker inserted into human GPR119 was prepared. In the T-Rex ^TM -CHO (Invitrogen Corporation) the introduced gene, bleomycin made resistant cell lines, cells to obtain expression of human GPR119 stably.

The functional effects of the compounds of the present invention based cAMP assay using stably expressing human GPR119 of T-Rex ^TM -CHO be confirmed. The cells were cultured in Ham's F-12 medium (Wako) containing 10% FBS, 1% penicillin-streptomycin-glutamic acid, 250 μg/mL bleomycin, and 1 μg/mL oxytocin to 60 The culture was carried out in a 10 cm culture dish until ~80% association.

Cells were seeded at 1 x 10 ⁴ cells/well on 96-well white plates (Corning 3885) 48 hours prior to analysis. The medium in which the cells were removed on the analysis day was replaced with 30 μL/well of the assay medium containing the compound of the target concentration (containing 0.5 mM 3-isobutyl-1-methylxanthine in Ham's F-12 medium). The humidified 5% CO ₂ was cultured at 37 ° C for 30 minutes at a constant temperature. The intracellular concentration of cAMP was a reference time-decomposed fluorescence (HTRF) protocol (Cisbio). Fluorescence detection reagents were each added to each well in 20 μL, and cultured at 37 ° C for 60 minutes at a constant temperature. Fluorescence of 665 nm and 620 nm excited at 320 nm was measured using ARVO-HTS (Perkin Elmer). The cAMP standard curve (4-parameter logic) was converted from the cAMP concentration in each well. The EC ₅₀ value was treated by 5-[1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ylmethoxy]-2-[4-( The cAMP concentration obtained by the methylsulfonyl)phenyl]pyridine (described in International Publication No. 2009/012275) is the maximum value, and the calculated value from the cAMP (dimethyl hydrazine treatment) is increased to half of the maximum value. Agonist concentration. The results of the GPR119 activation concentration of the synthesis example compound are shown below (Table 15).

To check for false positives, analysis can be performed using cells that do not contain GPR119 by the same method. And the above cAMP analysis can compare the maximum cAMP rise value of each compound.

Evaluation Example 2. Determination of GPR119 activity cAMP analysis

A pcDNA4/TO vector having a bleomycin resistance marker inserted into human GPR119 was prepared. In the T-Rex ^TM -CHO (Invitrogen Corporation) the introduced gene, bleomycin made resistant cell lines, cells to obtain expression of human GPR119 stably.

The functional effects of the compounds of the present invention based cAMP assay using stably expressing human GPR119 of T-Rex ^TM -CHO be confirmed. The cells were cultured in Ham's F-12 medium (Wako) containing 10% FBS, 1% penicillin-streptomycin-glutamic acid, 250 μg/mL bleomycin, 1 μg/mL blasticidin, reaching 60 The culture was carried out in a 10 cm culture dish at -80%.

Cells were seeded to 1 x 10 ⁴ cells/well in 96-well white plates (Corning 3885) 24 hours prior to analysis. On the day of analysis, the medium in which the cells were removed was replaced with 30 μL/well of assay medium containing the target concentration of the compound (containing 0.5 mM 3-isobutyl-1-methylxanthine in Ham's F-12 medium) on the plate. The humidified 5% CO ₂ was incubated at 37 ° C for 30 minutes at a constant temperature. The intracellular concentration of cAMP was a reference time-decomposed fluorescence (HTRF) protocol (Cisbio). Fluorescence detection reagents were each added to each well at 20 μL and thermostatically cultured at 37 ° C for 60 minutes. Fluorescence of 665 nm and 620 nm excited at 340 nm was measured using ARVO-HTS (Perkin Elmer). The cAMP standard curve (4-parameter logic) was converted to the cAMP concentration in each well. EC ₅₀ values by processing 5- [1- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-4-ylmethoxy] -2- [4- ( The cAMP concentration obtained by the methylsulfonyl)phenyl]pyridine (described in International Publication No. 2009/012275) is the maximum value, and the calculated value from the cAMP (dimethyl hydrazine treatment) is raised to one-half of the maximum value. The agonist concentration at the time. The results of the GPR119 activation concentration of the synthesis example compound are shown below (Table 16).

[Table 17]

[Table 19]

To detect false positives, cells that do not contain GPR119 can be analyzed by the same method. And the above cAMP analysis can compare the maximum cAMP rise value of each compound.

Evaluation Example 3. Insulin secretion test

The functional action of the compound of the present invention was confirmed as an insulin secretion-promoting action of MIN6 using a mouse pancreatic β-cell strain.

For example, after seeding cells in a plurality of plates, the compound is added simultaneously with a high concentration of glucose (10-20 mM). The clear liquid was recovered after 1 to 3 hours and the amount of insulin secretion was measured.

Insulin is a commercially available kit, and can be measured, for example, using an Insulin assay (Cisbio).

Evaluation Example 4. Rat single sugar load test

Female SD rats (9-11 weeks old) were fasted for 1 night, and 5 animals per group were divided according to plasma glucose and body weight before the start of the experiment. For each group, The solvent (0.5% methylcellulose) and the synthetic compound are forcibly orally administered in an amount of, for example, 10 mg/kg to 5 μL/kg, and after 2 minutes, 2 g/kg of glucose is orally administered to the load. The sugar load test (OGTT) was started. Blood was collected before glucose load (0 minutes) and after 15, 30, 60, and 120 minutes after glucose load, and plasma glucose was measured using Wako (Wako Corporation) using glucose test.

Plot the amount of plasma glucose over time. The area under the glucose curve of the rising plasma glucose value was calculated as DeltaAUC using the plasma glucose value of the blood collection point for 0 minutes as a reference.

The following (Table 17) shows the DeltaAUC% in the administration example of the compound 10 mg/kg when the solvent control group DeltaAUC was taken as 100%.

Further for the above test, the plasma taken can be used, and the commercially available kit can be evaluated, for example, by the high-sensitivity rat insulin assay kit (Son Wing). Similarly, digestive tract hormones (eg, GLP-1) can be evaluated using commercially available kits.

Evaluation Example 5. Rat single sugar load test

Female SD rats (9-11 weeks old) were fasted for 1 night, and were divided into 5 per group according to plasma glucose and body weight before the start of the experiment. The solvent (0.5% methylcellulose) and the synthetic compound were forcibly orally administered in an amount of 10 mg/kg (that is, 10 mg per 1 kg of the female SD rat) in each group (in this case, for example, 5 mL/kg was used). That is, a solution (5 mL of methylcellulose) per kg of female SD rats), and after 30 minutes, 2 g/kg of glucose was orally administered with a load, and a sugar load test (OGTT) was started. Blood was collected before the glucose load (0 points) and at 15, 30, 60, and 120 minutes after the glucose load, and plasma glucose was measured using a glucose test Wako (Wako Corporation).

Plot the amount of plasma glucose over time. The area under the glucose curve for the rising plasma glucose value was calculated as DeltaAUC using the plasma glucose value of the blood collection point for 0 minutes as a reference.

In the following (Table 17), DeltaAUC% in the administration example of the compound 10 mg/kg when the solvent control group DeltaAUC was taken as 100% was shown.

In the above test, the plasma taken may be used as a commercially available kit, for example, the insulin secretion assay kit (Sonyong) is evaluated for the amount of insulin secretion. Similarly, digestive tract hormones (eg, GLP-1) can also be evaluated using commercially available kits.

Evaluation Example 6. Mouse single sugar load test

Male ICR mice (6-8 weeks old) were fasted for 1 night and were divided into plasma glucose and body weight before the start of the experiment. For each group, the oral administration of a solvent (0.5% methylcellulose), the amount of the synthesis compound is, for example, 10 mg/kg at 10 μL/kg, and after 30 minutes to 1 hour, an oral solution of 3 g/kg glucose is carried out. When the load is applied, the blood glucose level is lowered after the blood is taken over time.

Mouse insulin is a commercially available kit, for example, using a Lewis insulin kit (Shibayagi) to assess the amount of insulin. Similarly, digestive tract hormones (eg, GLP-1) can be evaluated using commercially available kits.

Next, a formulation example of the substituted azole compound of the formula (I) of the present invention is shown.

Formulation Example 1

A granule containing the following ingredients was produced.

The compound of formula (I) and lactose were passed through a 60 mesh sieve. The corn starch was passed through a 120 mesh sieve. These were mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution was added to the mixed powder, and the mixture was incubated and granulated (the granulation pore size was 0.5 to 1 mm) and dried. The resulting dried granules were sieved through a vibrating sieve (12/60 mesh) to obtain granules.

Formulation Example 2

A powder for capsule filling containing the following components was produced.

The compound of formula (I) and lactose were passed through a 60 mesh sieve. The corn starch was passed through a 120 mesh sieve. These were mixed with magnesium stearate in a V-type mixer. 10 times of 100 mg was filled in a No. 5 hard gelatin capsule.

Formulation Example 3

A granule for capsule filling containing the following components was produced.

The compound of formula (I) and lactose were passed through a 60 mesh sieve. The corn starch was passed through a 120 mesh sieve. These were mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, and after being granulated and granulated, it is dried. After the obtained dried granules were sieved through a vibrating sieve (12/60 mesh) and sized, the 150 mg was filled in a No. 4 hard gelatin capsule.

Formulation Example 4

A lozenge containing the following ingredients was produced.

The compound of the formula (I), lactose, microcrystalline cellulose and CMC-Na (carboxymethylcellulose sodium salt) were passed through a 60-mesh sieve and mixed. Magnesium stearate was added to the mixed powder to obtain a mixed powder for preparation. The mixed powder was tableted to obtain 150 mg of a tablet.

Formulation Example 5

The intravenous preparation was manufactured as follows.

The solution of the above ingredients is usually administered intravenously to the patient at a rate of 1 mL per minute.

[Industrial availability]

The compounds of the present invention have excellent GPR119 activation, and particularly provide compounds useful for the prevention and/or treatment of diabetes and obesity.

Claims (27)

a compound represented by the formula (1), a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof, which is a formula (I) [Wherein, ring A is C _6-10 aromatic hydrocarbon ring or an aromatic 5-10 membered heterocyclic ring (the C _6-10 aromatic hydrocarbon ring and an aromatic 5-10 membered heterocyclic ring is unsubstituted, or selected from the group Substituted by a single or different 1 to 3 substituents of the free substituent group R _a ), which is a formula (II-1), a formula (II-2) or a formula (II-3) (wherein * represents a bonding position with ring C, and R ⁵ represents a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _3-6 cycloalkyl group, a halogen atom or a cyano group) Either ring C is a benzene ring or a 5-6 membered aromatic heterocyclic ring (the benzene ring and the 5-6 membered aromatic heterocyclic ring are unsubstituted or selected from a halogen atom, a hydroxyl group, an amine group, a cyano group, Individual or heterogeneous groups of C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy and C _1-3 alkylsulfonyl Substituted by 1 to 4 substituents), R ¹ is a hydrogen atom, a C _1-6 alkyl group or a C _1-6 haloalkyl group, and R ² is a C _1-6 alkyl group, a C _3-6 cycloalkyl group or C _1-6 haloalkyl, or R ¹ and R ² together form a C _3-6 cycloalkyl ring, and R ³ and R ^{4 are} each independently a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group (the C _1-6 alkyl group, the C _2-6 alkenyl group, and the C _2-6 alkynyl group are unsubstituted or one or more selected from the group consisting of the substituent groups R _b alone or different Substituted by a substituent), a C _3-6 cycloalkyl group or a 4-11 membered heterocyclic group (the C _3-6 cycloalkyl group and the 4-11 membered heterocyclic group are unsubstituted or selected from the group consisting of substituents R _c alone or substituted with one or more different substituent groups), or R ³ and R ⁴ May be formed with 4-11 membered nitrogen-containing heterocyclic ring (the nitrogen-containing heterocyclic 4-11 membered ring is unsubstituted, or a substituent group R _c alone or in one or more different substituents selected from the group consisting of group), a substituent group R _a line consisting of a halogen atom, cyano, nitro, acyl phosphine, phosphine acyl group, sulfonic group, sulfoxide group, a sulfo group acyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl (the C _1-6 alkyl group, C _2-6 alkenyl group and C _2-6 alkynyl group are unsubstituted or are selected from the group consisting of the substituent group R _b alone Or a different one or more substituents substituted), a C _3-6 cycloalkyl group, a 4-7 membered heterocyclic group, a 5-6 membered aromatic heterocyclic group (the C _3-6 cycloalkyl group, 4 The -7 membered heterocyclic group and the 5-6 membered aromatic heterocyclic group are unsubstituted or substituted by one or more substituents selected from the substituent group R _c alone or different) and the formula (III) Recorded structures (wherein T is an oxygen atom, a sulfur atom or NR ¹³ , and R ¹¹ , R ¹² and R ^{13 are} each independently a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group ( The C _1-6 alkyl group, the C _2-6 alkenyl group and the C _2-6 alkynyl group are unsubstituted or substituted by one or more substituents selected from the group of substituents R _b alone or different), C _3-6 cycloalkyl, 4-7 membered heterocyclic group, 5-6 membered aromatic heterocyclic group (the C _3-6 cycloalkyl group, 4-7 membered heterocyclic group and 5-6 membered aromatic hetero The cyclic group is unsubstituted or substituted by one or more substituents selected from the group of substituents R _c alone or in combination, a C _1-6 alkylcarbonyl group, a C _1-6 haloalkylcarbonyl group, C _{3 -6} cycloalkylcarbonyl, C _3-6 halocycloalkylcarbonyl, C _1-6 alkylsulfonyl, C _1-6 haloalkylsulfonyl, C _3-6 cycloalkylsulfonyl, C _a group of substituents composed of a _1-6 alkoxycarbonyl group, a mono C _1-6 alkylaminocarbonyl group or a di C _1-6 alkylaminocarbonyl group, and the substituent group R _b is a halogen atom, a hydroxyl group or an amine , nitro, oxo, cyano, carboxyl, acyl urethane, acyl phosphine, phosphine acyl group, sulfonic group, sulfoxide group, a sulfo group acyl, tetrazolyl, C _{3- 6} cycloalkyl, C _1-3 alkoxy, C _3-6 cycloalkoxy, C _1-3 alkylsulfonyl group, C _1-3 alkoxycarbonyl, mono C _1-3 alkyl amino, di C _1-3 alkyl amino, mono-C _1-3 alkylaminocarbonyl, di C _1-3 alkylaminocarbonyl, C _1-3 alkylcarbonylamino, C _1-3 alkoxycarbonylamino, C _1-3 alkylcarbonyloxy , a mono C _1-3 alkylaminocarbonyloxy group, a di C _1-3 alkylaminocarbonyloxy group, and a 4-7 membered heterocyclic group (the C _3-6 cycloalkyl group, C _1-3 alkoxy group) a group, a C _3-6 cycloalkoxy group, a C _1-3 alkylsulfonyl group, a C _1-3 alkoxycarbonyl group, a mono C _1-3 alkylamino group, a di C _1-3 alkylamino group, Mono C _1-3 alkylaminocarbonyl, di C _1-3 alkylaminocarbonyl, C _1-3 alkylcarbonylamino, C _1-3 alkoxycarbonylamino, C _1-3 alkylcarbonyl An oxy group, a mono C _1-3 alkylaminocarbonyloxy group, a di C _1-3 alkylaminocarbonyloxy group, and a 4-7 membered heterocyclic group are unsubstituted or selected from a halogen atom, a hydroxyl group, an amine a group of substituents consisting of a group consisting of a group of cyano and aminomethyl fluorenyl groups substituted by 1 or 3 substituents, and a group of substituents R _c is a C _1-6 alkyl group, C _2-6 alkenyl, C _2-6 alkynyl (the C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are unsubstituted , Or substituted by a radical selected from the group consisting of R _b alone or in one or more different substituents) and constituting Substituents of R _b each substituent group consisting of a substituent]. A compound according to claim 1, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture, wherein ring B is of formula (II-1) (wherein * represents a bonding position with ring C, and R ⁵ is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _3-6 cycloalkyl group, a halogen atom or a cyano group). A compound according to claim 2, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture, wherein R ¹ and R ⁵ are a hydrogen atom, and R ² is a C _1-3 alkyl group. A compound according to claim 2 or 3, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture, wherein ring C is a benzene ring or a 5-6 member aromatic heterocyclic ring (the benzene ring and The 5-6 membered aromatic heterocyclic ring is unsubstituted or substituted by 1 or 4 substituents selected from a group consisting of a halogen atom, a cyano group, and a C _1-3 alkyl group. A compound according to claim 4, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture, wherein ring C is of formula (IV-1) (wherein * represents a bonding position with ring B, and V and W are each independently a nitrogen atom or CR ⁶ , and R ⁶ is a hydrogen atom, a halogen atom or a C _1-3 alkyl group, and when V and W are CR ⁶ , R ⁶ may be the same or different, m is 0 to 2, when m is 1 or 2, R ⁷ is a halogen atom or a C _1-3 alkyl group, and when m is 2, R ⁷ may be the same or different). A compound according to claim 5, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof, wherein V and W are CH, m is 1, and R ⁷ is a fluorine atom, a chlorine atom or a methyl group. . A compound according to claim 4, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture, wherein ring C is of formula (IV-2) (wherein * represents a bonding position with ring B, V is a nitrogen atom, W is a nitrogen atom or CR ⁶ , R ⁶ is a fluorine atom, and m is 0). The compound according to any one of claims 2 to 7, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture, wherein ring A is formula (V) (wherein X is a nitrogen atom or CH, and R ⁸ is a formula (VI-1) or a formula (VI-2) (wherein T is an oxygen atom or a sulfur atom, and R ⁹ is a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a 4-7 membered heterocyclic group (the C _1-6 alkyl group, C _3-6) The cycloalkyl group and the 4-7 membered heterocyclic group are unsubstituted or may be substituted by one or more halogen atoms)). The compound of the requested item 8, a tautomer thereof or a salt of the compound which can be a pharmaceutically or licensed agents such vehicles, wherein R ⁸ is C _3-6 cycloalkyl carbonyl group or a halo C _3-6 cycloalkylcarbonyl . The compound according to any one of claims 2 to 7, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture, wherein ring A is each structure described in formula (VII) (wherein R ²¹ is a C _1-6 alkyl group or a C _3-6 cycloalkyl group (the C _1-6 alkyl group and the C _3-6 cycloalkyl group are unsubstituted or may be substituted by one or more halogen atoms) ))). The compound according to any one of claims 2 to 7, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof, wherein ring A is each structure described in formula (VIII) (wherein R ²² is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or is a single or different one selected from the group consisting of a halogen atom and a C _3-6 cycloalkyl group) Any of the above substituents may be substituted or a C _3-6 cycloalkyl group (the C _3-6 cycloalkyl group may be unsubstituted or may be substituted by one or more halogen atoms)). A compound according to claim 11, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture, wherein R ²² is a C _1-3 haloalkyl group or a cyclopropylmethyl group. The compound according to any one of claims 2 to 12, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof, wherein R ³ is a hydrogen atom and R ⁴ is a C _1-6 alkyl group. a C _3-6 cycloalkyl group or a 4-7 membered heterocyclic group (the C _1-6 alkyl group, the C _3-6 cycloalkyl group and the 4-7 membered heterocyclic group are unsubstituted or selected from a halogen atom) a single or different 1 to 3 substituents of a group consisting of a hydroxyl group, an aminomethyl sulfonyl group, a carboxyl group, a cyano group and an oxo group, or a combination of R ³ and R ⁴ is a nitrogenous group of ⁴ to 7 members. a heterocyclic ring (the 4-7 membered nitrogen-containing heterocyclic ring is unsubstituted or is selected from a group consisting of a halogen atom, a hydroxyl group, an aminocarbamyl group, a carboxyl group, a cyano group, and an oxo group. Substituted by 1 to 3 substituents). A compound according to claim 13, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof, wherein R ³ is a hydrogen atom, and R ⁴ is a C _1-6 alkyl group, a C _3-6 ring An alkyl group or a 4-7 membered heterocyclic group (the C _1-6 alkyl group, the C _3-6 cycloalkyl group and the 4-7 membered heterocyclic group are unsubstituted or selected from the group consisting of a hydroxyl group, an aminomethyl group and The oxo group is substituted by a single or different 1 to 3 substituents), or R ³ and R ⁴ together are a 4-7 member nitrogen-containing heterocyclic ring (the 4-7 member nitrogen-containing heterocyclic ring) The base ring is unsubstituted or substituted by a single or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, an aminomethyl group and an oxo group. A compound according to claim 14, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof, wherein R ³ is a hydrogen atom, and R ⁴ is a C _1-6 alkyl group, a C _3-6 ring An alkyl group or a 4-7 membered heterocyclic group (the C _1-6 alkyl group, the C _3-6 cycloalkyl group and the 4-7 membered heterocyclic group are a group of a hydroxyl group, an aminomethyl group and an oxo group) Substituted by 1 or 3 substituents, alone or differently). A compound according to claim 13, a tautomer of the compound or a pharmaceutically acceptable salt thereof, or a solvent mixture, wherein R ³ is a hydrogen atom, and R ⁴ is a C _1-3 alkyl group or a cyclopropyl group. C _1-3 alkyl and cyclopropyl are unsubstituted or substituted by a group selected from the group consisting of methyl acyl, cyano or carboxyl groups of a substituent group). A compound according to claim 13, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof, wherein R ³ and R ⁴ together are a 4-7 member nitrogen-containing heterocyclic ring (the 4- The 7-membered nitrogen-containing heterocyclic ring is unsubstituted or substituted by a single or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, an aminomethyl indenyl group, a carboxyl group, a cyano group and an oxo group. . The compound of the requested item 17, a tautomer thereof or a salt of the compound which can be permitted pharmaceutically or mixture of these solvents, wherein R ³ and R ⁴ together is a pyrrolidine (which is selected from the group consisting of pyrrolidine by hydroxyl, amine A single or different substituent substituted by a group of a fluorenyl group, a carboxyl group, and a cyano group). A compound according to claim 1, a tautomer of the compound or a pharmaceutically acceptable salt thereof, or a solvent mixture, wherein ring B is of formula (II-2) or formula (II-3) (wherein * represents the bonding position with ring C), and ring C is formula (IX) (wherein, * represents a bonding position with ring B, R ¹⁰ is a fluorine atom, a chlorine atom or a methyl group), R ¹ is a hydrogen atom, and R ² is a C _1-3 alkyl group. A compound according to claim 19, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture, wherein ring A is formula (V) (wherein X is a nitrogen atom or CH, and R ⁸ is a C _3-6 cycloalkylcarbonyl group or a C _3-6 halocycloalkylcarbonyl group). A compound according to claim 19, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture, wherein ring A is formula (VIII-1) (wherein R ²² is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or is a single or different one selected from the group consisting of a halogen atom and a C _3-6 cycloalkyl group) Any of the above substituents may be substituted or a C _3-6 cycloalkyl group (the C _3-6 cycloalkyl group may be unsubstituted or may be substituted by one or more halogen atoms)). The compound according to any one of claims 19 to 21, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof, wherein R ³ is a hydrogen atom and R ⁴ is a C _1-6 alkyl group. a C _3-6 cycloalkyl group or a 4-7 membered heterocyclic group (the C _1-6 alkyl group, the C _3-6 cycloalkyl group and the 4-7 membered heterocyclic group are unsubstituted or selected from a hydroxyl group, Substituting a single or different 1 to 3 substituents of a group of aminomethyl thiol and oxo groups, or R ³ and R ⁴ together are a 4-7 member nitrogen-containing heterocyclic ring (the 4- The 7-membered nitrogen-containing heterocyclic ring is unsubstituted or substituted by a single or different 1 to 3 substituents selected from the group consisting of a hydroxyl group, an aminocarbamyl group and an oxo group. A compound according to claim 22, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture thereof, wherein R ³ is a hydrogen atom, and R ⁴ is a C _1-6 alkyl group, a C _3-6 ring An alkyl group or a 4-7 membered heterocyclic group (the C _1-6 alkyl group, the C _3-6 cycloalkyl group and the 4-7 membered heterocyclic group are selected from the group consisting of a hydroxyl group, an aminomethyl fluorenyl group and an oxo group) Individual or different 1 to 3 substituents of the group are substituted). A GPR119 activator characterized by containing a compound according to any one of claims 1 to 23, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture as an active ingredient. An agent for the prophylaxis, treatment, and/or amelioration of a disease, which is characterized by comprising a compound according to any one of claims 1 to 23, a tautomer of the compound or a pharmaceutically acceptable salt thereof Or these solvent mixture as an active ingredient. A therapeutic agent for diabetes, which comprises a compound according to any one of claims 1 to 23, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture as an active ingredient. A medicine comprising a compound according to any one of claims 1 to 23, a tautomer of the compound or a pharmaceutically acceptable salt thereof or a solvent mixture as an active ingredient.