Nitrogen-containing heterocyclic derivatives

Abstract

This invention provides a novel compound that exhibits inhibitory activity against α-amino-β-carboxymuconate 6-semialdehyde decarboxylase (ACMSD). [Solution] A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. TIFF2026083449000168.tif73131

Description

[Technical Field]

[0001] The present invention relates to nitrogen-containing heterocyclic derivatives having α-amino-β-carboxymuconate 6-semialdehyde decarboxylase (ACMSD) inhibitory activity. [Background technology]

[0002] Tryptophan is an aromatic amino acid and is one of the essential amino acids in humans. In the body, tryptophan is used in protein synthesis and is converted into serotonin, a neurotransmitter, and nicotinamide adenine dinucleotide (NAD), which contributes to intracellular redox reactions.

[0003] For example, tryptophan is converted to NAD through the following metabolic pathway. Specifically, tryptophan is first converted to N'-formylkynurenine (a tryptophan metabolic intermediate) by the tryptophan-degrading enzymes L-tryptophan-2,3-dioxygenase (TDO) or indoleamine-2,3-dioxygenase (IDO), and then, via kynurenine and 3-hydroxykynurenine, α-amino-β-carboxymuconate 6-semialdehyde (ACMS) is produced. ACMS is then cyclized by a non-enzymatic reaction to form quinolinic acid, and this quinolinic acid is metabolized by quinolinic acid phosphoribosyltransferase (QPRT) to biosynthesize NAD (NAD synthesis pathway).

[0004] As mentioned above, ACMS can be used for conversion to NAD via the NAD synthesis pathway, but the majority of it is used in other pathways. For example, ACMS can be decarboxylated by α-amino-β-carboxymuconate 6-semialdehyde decarboxylase (ACMS decarboxylase: ACMSD), then enter the glutarate pathway, where it can be broken down into water and carbon dioxide via the TCA cycle to produce energy.

[0005] ACMSD activity is known to have a negative correlation with the conversion rate of tryptophan to NAD. Specifically, high ACMSD activity increases the proportion of tryptophan metabolized in the TCA cycle, while low ACMSD activity increases the proportion metabolized into the NAD synthesis pathway. Therefore, ACMSD is considered an important enzyme that controls the metabolic fate of tryptophan and is thought to be a key enzyme in the NAD synthesis pathway. ACMSD is primarily highly expressed in the liver and kidneys of mammals.

[0006] As mentioned above, NAD plays a central role in intracellular redox reactions and functions as a cofactor in energy production reactions in mitochondria. Furthermore, NAD plays an important role in various conditions such as metabolism, inflammation, and aging through NAD-consuming enzymes, represented by sirtuins (histone deacetylases) synthesized from sirtuin genes, which are known as longevity genes or anti-aging genes. Intracellular NAD levels are known to decrease with age, and this decrease in intracellular NAD levels is thought to be involved in the development of age-related diseases such as metabolic diseases, neurodegenerative diseases, kidney diseases, cancer, and Alzheimer's disease. Therefore, increasing intracellular NAD levels is expected to slow aging, restore muscle function, promote nerve regeneration in the brain, and provide protection against metabolic diseases.

[0007] Against this backdrop, studies are being conducted to treat and prevent diseases associated with decreased NAD biosynthesis and NAD metabolic enzyme activity by inhibiting ACMSD, thereby increasing intracellular NAD concentration. For example, ACMSD inhibitors are reported in Patent Documents 1-4 and Non-Patent Documents 1-2. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2016 / 030534 [Patent Document 2] International Publication No. 2018 / 069532 [Patent Document 3] International Publication No. 2018 / 125983 [Patent Document 4] International Publication No. 2020 / 104456 [Non-patent literature]

[0009] [Non-Patent Document 1] Roberto Pelliciari et al., Journal of Medicinal Chemistry, 2018, 61, 745-759. [Non-Patent Document 2] Yu Yang et al., Journal of Medicinal Chemistry, 2021, 64, 797-811. [Overview of the project] [Problems that the invention aims to solve]

[0010] In this situation, there is a need for novel compounds that possess α-amino-β-carboxymuconate 6-semialdehyde decarboxylase (ACMSD) inhibitory activity. [Means for solving the problem]

[0011] According to the present invention, for example, the following compounds are provided.

[0012] [1] General formula (I): [ka] [In the above general formula (I), R 1 C may be substituted with a fluorine atom, cyano, or hydroxyl atom. 1~6 C may be substituted with an alkyl, fluorine, cyano, or hydroxyl atom. 3~6 It is a cycloalkyl, 4-6 membered ring cyclic ether, R 2 ~R 10is, independently of each other, a hydrogen atom, a halogen atom, or a C optionally substituted with at least one substituent selected from the group consisting of hydroxy, halogen atom, cyano, nitro, and C 1~5 alkyl optionally substituted with at least one substituent selected from the group consisting of alkoxy, or a C optionally substituted with at least one substituent selected from the group consisting of hydroxy, halogen atom, cyano, and nitro 1~6 alkoxy, and 1~6 W is a sulfur atom or an oxygen atom, A is one of the following formulas (A-1) to (A-5):

Chemical formula

[10] A is a compound according to any of the above [1] to [7] or a pharmaceutically acceptable salt thereof, wherein A is formula (A-2).

[11] A is a compound according to any of the above [1] to [7] or a pharmaceutically acceptable salt thereof, wherein A is formula (A-3).

[12] A is a compound according to any of the above [1] to [7] or a pharmaceutically acceptable salt thereof, wherein A is formula (A-4).

[13] A is a compound according to any of [1] to [7] above, wherein A is formula (A-5), or a pharmaceutically acceptable salt thereof.

[14] W is a sulfur atom, A compound or a pharmaceutically acceptable salt thereof as described in [1] above, wherein Z is N.

[15] W is a sulfur atom, A compound described in [1] above, wherein Y is CH, or a pharmaceutically acceptable salt thereof.

[16] W is a sulfur atom, A compound described in [1] above, wherein A is formula (A-1), or a pharmaceutically acceptable salt thereof.

[17] W is a sulfur atom, Y is CH, A compound or a pharmaceutically acceptable salt thereof as described in [1] above, wherein Z is N.

[18] W is a sulfur atom, A is equation (A-1), A compound or a pharmaceutically acceptable salt thereof as described in [1] above, wherein Z is N.

[19] W is a sulfur atom, A is equation (A-1), A compound described in [1] above, wherein Y is CH, or a pharmaceutically acceptable salt thereof.

[20] W is a sulfur atom, A is equation (A-1), Y is CH, A compound or a pharmaceutically acceptable salt thereof as described in [1] above, wherein Z is N.

[21] R 4 A compound or a pharmaceutically acceptable salt thereof described in any of the above [1] to

[20] , wherein the compound is a fluorine atom or a chlorine atom.

[22] R 1 However, C may be substituted with a fluorine atom. 1~3 A compound described in any of the above [1] to

[21] , which is alkyl or cyclopropyl, or a pharmaceutically acceptable salt thereof.

[23] R 2 and R 3 However, it is a hydrogen atom or a halogen atom, R 4 A compound or a pharmaceutically acceptable salt thereof described in any of the above [1] to

[20] , wherein the compound is a hydrogen atom, a fluorine atom, or a chlorine atom.

[24] R 1 However, C may be substituted with a fluorine atom. 1~3 Alkyl or cyclopropyl, R 2 and R 3 However, it is a hydrogen atom or a halogen atom, R 4 A compound or a pharmaceutically acceptable salt thereof described in any of the above [1] to

[20] , wherein the compound is a hydrogen atom, a fluorine atom, or a chlorine atom.

[25] R 1 However, C may be substituted with a fluorine atom. 1~3 Alkyl or cyclopropyl, R 2 and R 3 However, it is a hydrogen atom, R 4 However, it is a hydrogen atom, a fluorine atom, or a chlorine atom, A is given by equation (A-1), and R11 ~R 13 A compound or a pharmaceutically acceptable salt thereof described in any of the above [1] to [7], wherein is a hydrogen atom.

[26] R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 A compound or a pharmaceutically acceptable salt thereof described in any of the above [1] to

[25] , wherein is a hydrogen atom.

[27] The following formula: [ka] [ka] [ka] [ka] [ka] [ka] A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

[28] The following formula: [ka] [ka] [ka] A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

[29] A pharmaceutical composition containing any of the compounds described in [1] to

[28] above or a pharmaceutically acceptable salt thereof.

[30] An ACMSD inhibitor comprising any of the compounds described in [1] to

[28] above or a pharmaceutically acceptable salt thereof.

[31] A prophylactic or therapeutic agent for diseases involving ACMSD, comprising any of the compounds described in [1] to

[28] above or a pharmaceutically acceptable salt thereof.

[32] The preventive or therapeutic agent according to

[31] above, wherein the disease in which the ACMSD is involved is a genetic mitochondrial disorder, a metabolic disorder, a neurodegenerative disorder, a renal disorder, a chronic inflammatory disorder, or an age-related disorder.

[33] A method for preventing or treating a disease in which ACMSD is involved, comprising administering any of the compounds described in [1] to

[28] above or a pharmaceutically acceptable salt thereof.

[34] Use of any of the compounds described in [1] to

[28] above or pharmaceutically acceptable salts thereof for the prevention or treatment of diseases in which ACMSD is involved.

[35] Use of any of the compounds described in [1] to

[28] above or a pharmaceutically acceptable salt thereof for the manufacture of a medicine for the prevention or treatment of a disease in which ACMSD is involved. [Effects of the Invention]

[0013] The present invention provides novel compounds having α-amino-β-carboxymuconate 6-semialdehyde decarboxylase (ACMSD) inhibitory activity. [Modes for carrying out the invention]

[0014] 1.Definition The terms used in this specification are defined below.

[0015] In this specification, "ACMSD" refers to α-amino-β-carboxymuconate 6-sequester This refers to aldehyde decarboxylase (ACMS decarboxylase). ACMSD converts α-amino-β-carboxymuconate 6-semialdehyde (ACMS), which is converted from tryptophan, into α-aminomuconate 6-semialdehyde (AMS) through decarboxylation. AMS can then be converted to picolinic acid through a ring-closing reaction, or it can be further metabolized via 2-aminomuconate, 2-oxoadipic acid, etc., to enter the glutarate pathway and be broken down into water and carbon dioxide via the TCA cycle.

[0016] In this specification, "inhibition of ACMSD" means reducing or eliminating the enzymatic activity of ACMSD. By inhibiting ACMSD, the metabolism (decarboxylation) of ACMS by ACMSD is suppressed, and the conversion to NAD via the NAD synthesis pathway is promoted, which can lead to an increase in intracellular NAD concentration (e.g., Katsyuba, E. et al. De novo NAD+ synthesis enhances mitochondrial function and improves health. Nature 2018, 563, 354-359).

[0017] 2. Compounds represented by general formula (I) or pharmaceutically acceptable salts thereof. The compounds according to the present invention are represented by the following general formula (I). When A is a trifluoromethylpyridine ring (when A is formula (A-1), formula (A-3), or formula (A-4)), the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof can be called a trifluoromethylpyridine derivative. When A is a trifluoromethylpyrimidine ring (when A is formula (A-2)), the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof can be called a trifluoromethylpyrimidine derivative. Furthermore, when A is a trifluoromethylpyridazine ring (when A is formula (A-5)), the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof can be called a trifluoromethylpyridazine derivative. In this specification, "the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof" or "the compound represented by general formula (I)" may be referred to as "the compound according to the present invention."

[0018] [ka] In the above general formula (I), R 1 C may be substituted with a fluorine atom, cyano, or hydroxyl atom. 1~6 C may be substituted with an alkyl, fluorine, cyano, or hydroxyl atom. 3~6 It is a cycloalkyl or cyclic ether with a 4- to 6-membered ring.

[0019] C 1~6 Alkyl refers to a linear or branched alkyl group. 1~6 Alkyl compounds include, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, tert-pentyl, neopentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, etc. 1~6 The alkyl group is preferably methyl, ethyl, isopropyl, or isopropyl. It's chill. C substituted with a fluorine atom, cyano, or hydroxyl atom 1~6Alkyl compounds include fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropyl, 4-hydroxybutyl, fluorohydroxymethyl, 1-fluoro-2-hydroxyethyl, 1-hydroxy-2,2,2-trifluoroethyl, etc.

[0020] C 3~6 Cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, etc. 3~6 The cycloalkyl group is preferably cyclopropyl. C substituted with a fluorine atom, cyano, or hydroxyl atom 3~6 Cycloalkyls include 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 3-fluorocyclobutanyl, 3,3-difluorocyclobutanyl, 2-cyanocyclopropyl, 2,2-dicyanocyclopropyl, 2,3-dicyanocyclopropyl, 2-cyanocyclobutanyl, 2-hydroxycyclopropyl, 2,2-dihydroxycyclopropyl, 2,3-dihydroxycyclopropyl, 3,3-dihydroxycyclobutanyl, 2-cyano-3-fluorocyclopropyl, 2-cyano-2-fluorocyclobutanyl, 2-fluoro-3-hydroxycyclopropyl, 3-fluoro-3-hydroxycyclobutanyl, 3-fluorobicyclo[1.1.1]pentan-1-yl, 3-cyanobicyclo[1.1.1]pentan-1-yl, etc.

[0021] A cyclic ether with 4 to 6 members refers to a cyclic alkyl group containing an oxygen atom. Examples of cyclic ethers with 4 to 6 members include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, and dioxanyl. The cyclic ether with 4 to 6 members is preferably oxetanyl.

[0022] In one embodiment, R 1 Even if substituted with a fluorine atom, C 1~3 It is preferable that it be alkyl or cyclopropyl. In another embodiment, R 1 C may be substituted with a fluorine atom, cyano, or hydroxyl atom. 1~4 C may be substituted with alkyl, fluorine, cyano, or hydroxyl atoms. 3~4 It is preferably a cycloalkyl or a cyclic ether with a 4- to 5 membered ring, and more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxy-2-methylpropyl, cyclopropyl, 2-cyanocyclopropyl, 2-hydroxycyclopropyl, cyclobutyl, 2-cyanocyclobutyl, 2-hydroxycyclobutyl, oxetanyl, or tetrahydrofuranyl. It is more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxy-2-methylpropyl, cyclopropyl, and cyclobutyl; particularly preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl; and most preferably methyl, ethyl, isopropyl, and cyclopropyl. In another embodiment, R 1It is formed by fluorine atoms, cyano, or hydroxyl atoms. Exchange is OK C 3~6 It is preferably a cycloalkyl compound, and more preferably bicyclo[1.1.1]pentanyl, 3-fluorobicyclo[1.1.1]pentan-1-yl, or 3-cyanobicyclo[1.1.1]pentan-1-yl.

[0023] R 2 ~R 10 These are, independently, a hydrogen atom, a halogen atom, or hydroxyl, halogen atom, cyano, nitro, and C. 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 1~6 C may be substituted with at least one substituent selected from the group consisting of alkyl, hydroxyl, halogen, cyano, and nitro atoms. 1~6 It is an alkoxy. In this case, C 1~5 Examples of alkoxys include methoxy, ethoxy, propyloxy, isopropyloxy, butoxy, and tert-butoxy.

[0024] Halogen atoms refer to, for example, fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc. Halogen atoms are preferably fluorine atoms and chlorine atoms, and more preferably fluorine atoms.

[0025] C 1~6 Alkyl is R 1 It is the same as described in [the document]. Hydroxyl, halogen atoms, cyano, nitro, and C 1~5 C substituted with at least one substituent selected from the group consisting of alkoxys 1~6Alkyls include, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropyl, 4-hydroxybutyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, bromomethyl, dibromomethyl, tribromomethyl, 1-bromoethyl, 2-bromoethyl, 1,2-dibromoethyl, 2,2-dibromoethyl, 2,2,2-tribromoethyl, 3-bromopropyl, 3,3,3-tribromopropyl, This includes chloromethyl, dichloromethyl, trichloromethyl, 1-chloroethyl, 2-chloroethyl, 1,2-dichloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 3-chloropropyl, 3,3,3-trichloropropyl, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, nitromethyl, 1-nitroethyl, 2-nitroethyl, 3-nitropropyl, methoxymethyl, ethoxymethyl, propyloxymethyl, butoxymethyl, tert-butoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1,2-dimethoxyethyl, 2-tert-butoxyethyl, 3-methoxypropyl, 3-tert-butoxypropyl, fluorohydroxymethyl, 1-fluoro-2-hydroxyethyl, 1-hydroxy-2,2,2-trifluoroethyl, etc. Hydroxy, halogen atom, cyano, nitro, and C 1~5 C substituted with at least one substituent selected from the group consisting of alkoxys 1~6 The alkyl is preferably substituted with at least one substituent selected from the group consisting of hydroxyl and halogen atoms. 1~6 C is alkyl and more preferably substituted with at least one substituent selected from the group consisting of hydroxyl and fluorine atoms. 1~6Alkyl, more preferably hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropyl, 4-hydroxybutyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, fluorohydroxymethyl, 1-fluoro-2-hydroxyethyl, 1-hydroxy-2,2,2-trifluoroethyl, and particularly preferably 1-hydroxyethyl, 2-hydroxyethyl, fluoromethyl These are difluoromethyl and trifluoromethyl. In another embodiment, hydroxy, halogen atoms, cyano, nitro, and C 1~5 C substituted with at least one substituent selected from the group consisting of alkoxys 1~6 Alkyl is a C atom substituted with a halogen atom. 1~6 Preferably alkyl, and C substituted with a fluorine atom. 1~6 It is more preferably alkyl, even more preferably fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, and particularly preferably fluoromethyl, difluoromethyl, trifluoromethyl, and 2,2,2-trifluoroethyl.

[0026] C 1~6 An alkoxy refers to a linear or branched alkoxy molecule. 1~6 Alkoxys include, for example, methoxy, ethoxy, n-propyloxy, n-butoxy, n-pentyloxy, n-hexyloxy, isopropyloxy, isobutoxy, sec-butoxy, tert-butoxy, etc. 1~6The alkoxy is preferably methoxy or ethoxy. C substituted with at least one substituent selected from the group consisting of hydroxyl, halogen, cyano, and nitro atoms. 1~6 Alkoxys include, for example, hydroxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1,2-dihydroxyethoxy, 2,2-dihydroxyethoxy, 3-hydroxypropyloxy, 2-hydroxy-2-methoxypropyloxy, 4-hydroxybutoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 1,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoropropyloxy, 3-fluoropropyloxy, 3,3,3-trifluoropropyloxy, bromomethoxy, dibromomethoxy, tribromomethoxy, 1-bromoethoxy, 2-bromoethoxy, 1,2- This includes dibromoethoxy, 2,2-dibromoethoxy, 2,2,2-tribromoethoxy, 3-bromopropyloxy, 3,3,3-tribromopropyloxy, chloromethoxy, dichloromethoxy, trichloromethoxy, 1-chloroethoxy, 2-chloroethoxy, 1,2-dichloroethoxy, 2,2-dichloroethoxy, 2,2,2-trichloroethoxy, 3-chloropropyloxy, 3,3,3-trichloropropyloxy, cyanomethoxy, 1-cyanoethoxy, 2-cyanoethoxy, 3-cyanopropyloxy, nitromethoxy, 1-nitroethoxy, 2-nitroethoxy, 3-nitropropyloxy, fluorohydroxymethoxy, 1-fluoro-2-hydroxyethoxy, 1-hydroxy-2,2,2-trifluoroethoxy, etc. C substituted with at least one substituent selected from the group consisting of hydroxy, halogen atoms, cyano, and nitro. 1~6 The alkoxy is preferably a C substituted with a halogen atom. 1~6 An alkoxy, more preferably a C substituted with a fluorine atom 1~6is an alkoxy group, more preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, 1,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1-fluoropropyloxy, 3-fluoropropyloxy, 3,3,3-trifluoropropyloxy, and particularly preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy.

[0027] R 2 ~R 4 is each independently preferably a hydrogen atom or a halogen atom, and more preferably a hydrogen atom or a fluorine atom.

[0028] In one embodiment, R 4 is preferably a fluorine atom, a chlorine atom, or a bromine atom, more preferably a fluorine atom or a chlorine atom, and even more preferably a fluorine atom.

[0029] Also, in another embodiment, R 2 and R 3 are a hydrogen atom or a halogen atom, and R 4 is preferably a hydrogen atom, a fluorine atom, a chlorine atom, or a bromine atom, R 2 and R 3 are a hydrogen atom or a halogen atom, R 4 is more preferably a hydrogen atom, a fluorine atom, or a chlorine atom, R 2 and R 3 are a hydrogen atom or a halogen atom, R 4 is even more preferably a fluorine atom or a chlorine atom, R 2 and R 3 are hydrogen atoms, and R 4 is a fluorine atom, which is particularly preferred.

[0030] R 5This includes hydrogen atoms, halogen atoms, or hydroxyl, halogen atoms, cyano, nitro, and C 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 1~4 It is preferably an alkyl group, more preferably a hydrogen atom, a halogen atom, methyl, ethyl, propyl, or isopropyl group, even more preferably a hydrogen atom or a fluorine atom, and particularly preferably a hydrogen atom.

[0031] R 6 and R 7 This includes hydrogen atoms, halogen atoms, or hydroxyl, halogen atoms, cyano, nitro, and C 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 1~4 It is preferably alkyl, more preferably hydrogen, halogen, methyl, or ethyl, even more preferably hydrogen or fluorine, and particularly preferably hydrogen.

[0032] R 8 These include hydrogen atoms, halogen atoms, hydroxyl or halogen atoms, cyano, nitro, and C 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 1~4 It is preferably alkyl, more preferably hydrogen, halogen, methyl, or ethyl, even more preferably hydrogen or fluorine, and particularly preferably hydrogen.

[0033] R 9 and R 10 This includes hydrogen atoms, halogen atoms, or hydroxyl, halogen atoms, cyano, nitro, and C 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 1~4 It is preferably alkyl, more preferably hydrogen, halogen, methyl, or ethyl, even more preferably hydrogen or fluorine, and particularly preferably hydrogen.

[0034] In one embodiment, R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 It is preferable that R is a hydrogen atom. 2 However, it is a hydrogen atom or a halogen atom, R 4 is a halogen atom, R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 It is more preferable that R is a hydrogen atom. 4 is a fluorine atom or a chlorine atom, R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 It is even more preferable that it is a hydrogen atom.

[0035] W is either a sulfur atom or an oxygen atom.

[0036] In one embodiment, W is preferably a sulfur atom. In another embodiment, W is preferably an oxygen atom.

[0037] A is given by the following equations (A-1) to (A-5). [ka]

[0038] R 11 ~R 23 These are, independently, a hydrogen atom, a halogen atom, or hydroxyl, halogen atom, cyano, nitro, and C. 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 1~6C may be substituted with at least one substituent selected from the group consisting of alkyl, hydroxyl, halogen, cyano, and nitro atoms. 1~6 It is an alkoxy, and * represents the binding site to the B ring.

[0039] Hydroxyl, halogen atoms, cyano, nitro, and C 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 1~6 C may be substituted with alkyl, and at least one substituent selected from the group consisting of hydroxy, halogen, cyano, and nitro. 1~6 Alkoxy is R 2 ~R 10 It is the same as described in [the document].

[0040] In one embodiment, A is preferably one of formulas (A-1) to (A-4), and more preferably one of formulas (A-1) or (A-2).

[0041] In another embodiment, A is preferably formula (A-1). Furthermore, in yet another embodiment, A is preferably formula (A-2). Furthermore, in yet another embodiment, A is preferably formula (A-3). Furthermore, in yet another embodiment, A is preferably formula (A-4). Furthermore, in yet another embodiment, A is preferably formula (A-5).

[0042] R 11 , R 12 , R 14 , R 15 , R 16 , R 17 , R 19 , R 20 , R 22 , R 23 These are, independently, a hydrogen atom, a halogen atom, or hydroxyl, halogen atom, cyano, nitro, and C. 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 1~6It is preferably alkyl, and may contain a hydrogen atom, a fluorine atom, or a hydroxyl, halogen atom, cyano, nitro, and C 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 1~3 It is more preferably alkyl, even more preferably a hydrogen atom, a fluorine atom, methyl, ethyl, propyl, or isopropyl, and particularly preferably a hydrogen atom. R 13 , R 18 , R 21 These are, independently, a hydrogen atom, a halogen atom, or hydroxyl, halogen atom, cyano, nitro, and C. 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 1~6 C may be substituted with at least one substituent selected from the group consisting of alkyl, hydroxyl, halogen, cyano, and nitro atoms. 1~6 Preferably an alkoxy, and containing a hydrogen atom, a fluorine atom, or a hydroxyl, halogen atom, cyano, nitro, and C 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 1~3 C may be substituted with at least one substituent selected from the group consisting of alkyl, hydroxyl, halogen, cyano, and nitro atoms. 1~3 It is more preferably an alkoxy, even more preferably a hydrogen atom, a fluorine atom, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyloxy, isopropyloxy, and particularly preferably a hydrogen atom, a fluorine atom, methyl, or methoxy.

[0043] Y is either CH or N.

[0044] In one embodiment, Y is preferably CH. In another embodiment, Y is preferably N.

[0045] Z is either N or C (C≡N).

[0046] In one embodiment, Z is preferably N. In another embodiment, Z is preferably C (C≡N).

[0047] In one preferred embodiment, W is preferably a sulfur atom and Z is preferably nitrogen. In another preferred embodiment, W is preferably a sulfur atom and Y is preferably CH. In another preferred embodiment, W is preferably a sulfur atom and A is of formula (A-1). In another preferred embodiment, W is preferably a sulfur atom, Y is preferably CH, and Z is preferably N. In another preferred embodiment, it is preferable that W is a sulfur atom, A is formula (A-1), and Z is N. In another preferred embodiment, W is preferably a sulfur atom, A is of formula (A-1), and Y is preferably CH. In another preferred embodiment, it is preferable that W is a sulfur atom, A is of formula (A-1), Y is CH, and Z is N.

[0048] In one preferred embodiment, R of the above general formula (I) 1 It is substituted with a fluorine atom and is not limited to C 1~3 Alkyl or cyclopropyl, R 2 and R 3 R consists of hydrogen atoms and halogen atoms. 4 R is preferably a hydrogen atom, a fluorine atom, or a chlorine atom. 1 These are methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, and cyclopropyl, and R 2 and R 3 These are hydrogen atoms and fluorine atoms, and R 4 R is a fluorine atom or a chlorine atom, 13 R is more preferably a hydrogen atom, a fluorine atom, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyloxy, or isopropyloxy, 1These are methyl, ethyl, and isopropyl, and R 2 and R 3 R is a hydrogen atom, 4 is a fluorine atom, R 13 It is even more preferable that it be a hydrogen atom.

[0049] In another preferred embodiment, R of the general formula (I) 1 It is substituted with a fluorine atom and is not limited to C 1~3 Alkyl or cyclopropyl, R 2 and R 3 R consists of hydrogen atoms and halogen atoms. 4 A is a hydrogen atom, a fluorine atom, or a chlorine atom, and A is given by formula (A -1) and R 11 ~R 13 It is preferably a hydrogen atom, R 1 These are methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, and cyclopropyl, and R 2 and R 3 R is a hydrogen atom or a halogen atom, 4 is a fluorine atom or a chlorine atom, A is formula (A-1), and R 11 ~R 13 It is more preferable that R is a hydrogen atom. 1 These are methyl, ethyl, and isopropyl, and R 2 and R 3 R is a hydrogen atom, 4 is a fluorine atom, A is formula (A-1), and R 11 ~R 13 It is even more preferable that it is a hydrogen atom.

[0050] In one preferred embodiment, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is preferably the compound represented by the following general formula (II) or a pharmaceutically acceptable salt thereof. [ka]

[0051] In the above general formula (II), R 1 C may be substituted with a fluorine atom, cyano, or hydroxyl atom. 1~6 C may be substituted with an alkyl, fluorine, cyano, or hydroxyl atom. 3~6 C is a cycloalkyl, 4-6 membered ring cyclic ether, which may preferably be substituted with a fluorine atom, cyano, or hydroxyl atom. 1~4 C may be substituted with alkyl, fluorine, cyano, or hydroxyl atoms. 3~4 Cycloalkyl, cyclic ethers of 4-5 membered rings, more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxy-2-methylpropyl, cyclopropyl, 2-cyanocyclopropyl, 2-hydroxycyclopropyl, cyclobutyl, 2-cyanocyclobutyl, 2-hydroxycyclobutyl, oxetanyl, tetrahydrofuranyl, bicyclo[1.1.1]pentanyl, 3-fluorobicyclo[1.1 .1]pentan-1-yl, 3-cyanobicyclo[1.1.1]pentan-1-yl, more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxy-2-methylpropyl, cyclopropyl, cyclobutyl, particularly preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and most preferably methyl, ethyl, isopropyl.

[0052] R 2 ~R 4 Each of these C atoms may be independently substituted with a hydrogen atom, a halogen atom, a hydroxyl atom, or a halogen atom. 1~6Substituted with alkyl, hydroxy, or halogen atoms Even if it is C 1~6 The alkoxy is preferably a hydrogen atom, a halogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, or trifluoromethyl; more preferably a hydrogen atom, a halogen atom, methyl, or trifluoromethyl; even more preferably a hydrogen atom, a halogen atom, or a hydrogen atom; and particularly preferably a hydrogen atom and a fluorine atom.

[0053] In one embodiment, R 2 and R 3 However, it is a hydrogen atom or a halogen atom, R 4 However, it is preferable that it be a hydrogen atom, a fluorine atom, a chlorine atom, or a bromine atom, R 2 and R 3 is a hydrogen atom or a halogen atom, and R 4 However, it is more preferable that it be a hydrogen atom, a fluorine atom, or a chlorine atom, R 2 and R 3 is a hydrogen atom or a halogen atom, and R 4 However, it is more preferably a fluorine atom or a chlorine atom, R 2 and R 3 is a hydrogen atom, and R 4 It is particularly preferable that the atom is a fluorine atom.

[0054] W is a sulfur atom or an oxygen atom, preferably a sulfur atom.

[0055] A is one of the following equations (A-1) to (A-5). [ka]

[0056] In this case, R 11 , R 12 , R 14 , R 15 , R 16 , R 17 , R19 , R 20 , R 22 , R 23 Each of these C atoms may be independently substituted with a hydrogen atom, a halogen atom, a hydroxyl atom, or a halogen atom. 1~6 C is alkyl and may be substituted with hydrogen, fluorine, hydroxyl, or halogen atoms. 1~3 It is an alkyl group, more preferably a hydrogen atom, a fluorine atom, a methyl group, an ethyl group, a propyl group, or an isopropyl group, and particularly preferably a hydrogen atom or a methyl group. Also, R 13 , R 18 , R 21 Each of these C atoms may be independently substituted with a hydrogen atom, a halogen atom, a hydroxyl atom, or a halogen atom. 1~6 C may be substituted with alkyl, hydroxy, or halogen atoms. 1~6 C is an alkoxy, and may preferably be substituted with a hydrogen atom, a fluorine atom, a hydroxyl atom, or a halogen atom. 1~3 C may be substituted with alkyl, hydroxy, or halogen atoms. 1~3 It is an alkoxy, more preferably a hydrogen atom, a fluorine atom, methyl, ethyl, propyl, isopropyl, or methoxy. These are ethoxy, propyloxy, and isopropyloxy, more preferably a hydrogen atom, a fluorine atom, methyl, and methoxy, and particularly preferably a hydrogen atom and methyl. Also, * indicates the binding site to the B ring.

[0057] Y is either CH or N, preferably CH.

[0058] Z is either N or C (C≡N), and is preferably N.

[0059] In a more preferred embodiment, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof is preferably the compound represented by the following general formula (III) or a pharmaceutically acceptable salt thereof. [ka]

[0060] In the above general formula (III), R 1 The surfactants are methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclopropyl, 2-cyanocyclopropyl, 2-hydroxycyclopropyl, cyclobutyl, 2-cyanocyclobutyl, 2-hydroxycyclobutyl, oxetanyl, tetrahydrofuranyl, bicyclo[1.1.1]pentanyl, 3-fluorobicyclo[1.1.1]pentan-1-yl, and 3-cyanobicyclo[1.1.1]pentan-1-yl, preferably methyl, ethyl, isopropyl, difluoromethyl, cyanomethyl, 2-cyanoethyl, 2-hydroxy-2-methylpropyl, cyclopropyl, and oxetanyl, and more preferably methyl, ethyl, and isopropyl.

[0061] R 2 This is a hydrogen atom, a halogen atom, preferably a hydrogen atom, a fluorine atom, a chlorine atom, or a bromine atom, more preferably a hydrogen atom, a fluorine atom, and even more preferably a hydrogen atom.

[0062] R 4 The atoms are hydrogen atoms, halogen atoms, preferably hydrogen atoms, fluorine atoms, chlorine atoms, and bromine atoms, more preferably hydrogen atoms and fluorine atoms, and even more preferably fluorine atoms.

[0063] A is one of the following equations (A-1-1) to (A-5-1). [ka]

[0064] Note that * indicates the binding site to the B ring. A is preferably formula (A-1-1)~(A-1-4), formula (A-2-1), formula (A-3-1)~(A-3-3), formula (A-4-1)~(A-4-3), and more preferably formula (A-1-1)~(A-1-3), formula (A-2-1), formula (A-3-2)~(A-3-3), and formula (A-4-2)~(A-4-3).

[0065] Y is either CH or N, preferably CH.

[0066] The compound represented by general formula (I) or its pharmaceutically acceptable salt is preferably a compound selected from the group consisting of the following formulas or its pharmaceutically acceptable salt. [ka] [ka] [ka] [ka] [ka] [ka]

[0067] Of the above, the compound represented by general formula (I) or its pharmaceutically acceptable salt is: More preferably, the compound is selected from the group consisting of the following formulas or a pharmaceutically acceptable salt thereof. [ka] [ka] [ka]

[0068] Compounds represented by general formula (I) (nitrogen-containing heterocyclic derivatives) may include optical isomers, stereoisomers, tautomers, rotational isomers, or mixtures thereof. These isomers can be obtained individually by known synthesis and separation methods. For example, optical isomers can be obtained individually by methods using optically active synthetic intermediates, or by optical resolution of a racemic mixture of the synthetic intermediate or the final product according to conventional methods. Furthermore, compounds represented by general formula (I) (nitrogen-containing heterocyclic derivatives) may also include stable isotopes and radioactive isotopes.

[0069] The compound represented by general formula (I) can be a pharmaceutically acceptable salt as needed. Examples of pharmaceutically acceptable salts of compounds represented by general formula (I) include ammonium salts, alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, aluminum salts, zinc salts, organic amine salts such as triethylamine, ethanolamine, morpholine, piperidine, and dicyclohexylamine, and basic amino acid salts such as arginine and lysine, which are formed with acidic groups such as carboxyl groups of compounds represented by general formula (I). Furthermore, examples of pharmaceutically acceptable salts of compounds represented by general formula (I) include inorganic salts such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, and hydrobromic acid, which are formed with the basic group of the compound represented by general formula (I); organic carboxylate salts such as acetic acid, trifluoroacetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, tannic acid, butyric acid, hibenzic acid, pamoic acid, enanthic acid, decanoic acid, theoclic acid, salicylic acid, lactic acid, oxalic acid, mandelic acid, and malic acid; and organic sulfonates such as methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0070] Methods for forming pharmaceutically acceptable salts of compounds represented by general formula (I) can be appropriately employed using known methods. For example, methods include mixing the compound according to the present invention with a necessary acid or base in an appropriate ratio in a solvent and / or a dispersant, and performing cation exchange or anion exchange using a pharmaceutically acceptable salt of the compound according to the present invention.

[0071] Compounds represented by general formula (I) or their pharmaceutically acceptable salts may also include their solvates, such as hydrates and alcohol adducts.

[0072] 3. Method for producing compounds represented by general formula (I) The method for producing the compound represented by general formula (I) is not particularly limited and can be produced by known methods.

[0073] Examples of methods for synthesizing the compound represented by general formula (I) include reacting intermediate X represented by the following formula with compound A, reacting intermediate Y represented by the following formula with compound B, and reacting intermediate Z represented by the following formula with compound C.

[0074] [ka]

[0075] The "-WH" in intermediate X is either "-SH" or "-OH". Also, the "A" in compound A 1 The group is preferably a leaving group, more preferably a halogen atom, an alkyl sulfone group, and even more preferably a chlorine atom, a bromine atom, an iodine atom, or a methyl sulfone group. Thus, intermediate X and compound A can be used to produce a compound represented by general formula (I) by, for example, a nucleophilic substitution reaction.

[0076] The reaction conditions for intermediate X and compound A can be appropriately selected depending on their structure, but it is preferable to carry out the reaction under basic conditions. Examples of bases that can be used include sodium hydroxide, potassium hydroxide, and potassium tert-butoxide.

[0077] Examples of reaction solvents for the reaction between intermediate X and compound A include N,N-dimethylformamide (DMF) and tetrahydrofuran (THF).

[0078] The "-WH" in compound B is either "-SH" or "-OH". Also, the "A" in intermediate Y 2 The group is preferably a leaving group, more preferably a halogen atom, an alkyl sulfone group, and even more preferably a chlorine atom, a methyl sulfone group. Thus, intermediate Y and compound B can be used to produce a compound represented by general formula (I) by, for example, an aromatic nucleophilic substitution reaction.

[0079] The reaction conditions for intermediate Y and compound B can be appropriately selected depending on their structure, but it is preferable to carry out the reaction under basic conditions. Examples of bases that can be used in this case include sodium hydride, lithium diisopropylamide, potassium carbonate, cesium carbonate, and potassium tert-butoxide.

[0080] Examples of reaction solvents for the reaction between intermediate Y and compound B include N,N-dimethylformamide (DMF) and tetrahydrofuran (THF).

[0081] Also, the intermediate Z's "A 3 " is preferably a halogen atom, a trifluoromethylsulfonyloxy group, and more preferably a bromine atom, an iodine atom. Also, "A" of compound C 4 " is preferably a boronic acid or a boronic acid ester, and more preferably "B(OH)2" or "B(OR)2" (where R is independently alkyl, alkenyl, aryl, aralkyl, etc., and in this case, the two Rs may bond to each other to form a ring structure). Thus, intermediate Z and compound C can be used, for example, to produce a compound represented by general formula (I) by a Suzuki-Miyaura coupling reaction.

[0082] The reaction between intermediate Z and compound C is not particularly limited, but is preferably carried out in the presence of a palladium catalyst and a base. A ligand may be further added.

[0083] Examples of the palladium catalyst include palladium acetate, PdCl2(PPh3)2, Pd(DIPHOS)2, Pd2(dba)3, Pd(dba)2, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), and the like.

[0084] Examples of the aforementioned bases include sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and tripotassium phosphate.

[0085] Examples of the ligands include tri(tert-butyl)phosphine, di(tert-butyl)(methyl)phosphine, tricyclohexylphosphine, and triphenylphosphine. Examples include phosphate, tri-(4-methoxyphenyl)phosphine, tri-(2-methylphenyl)phosphine, [P(t-Bu)3H]BF4, etc.

[0086] Suitable reaction solvents for intermediate Z and compound C include solvents that do not adversely affect the reaction, such as 1,4-dioxane, toluene, and butanol.

[0087] (Synthesis of intermediate X) Intermediate X is either known or can be synthesized from known compounds.

[0088] For example, intermediate X can be synthesized from a starting material represented by the following formula by (1) N-alkylation, (2) introduction of "W", and (3) introduction of an A ring (trifluoromethylpyridine ring, trifluoromethylpyrimidine ring, or trifluoromethylpyridazine ring). In this case, the order of (1) to (3) is not particularly limited and can be changed as appropriate.

[0089] [ka]

[0090] Starting material "A 5 The group is preferably a leaving group, more preferably a halogen atom, an alkyl sulfone group, and even more preferably a chlorine atom, a bromine atom, an iodine atom, or a methyl sulfone group.

[0091] (1) N-alkylation includes N-alkylation using alkyl halides (e.g., methyl iodide, isopropyl iodide, etc.) and coupling reactions (e.g., Chan-Lam-Evans coupling) in which boronic acids or their derivatives (e.g., β-alkylpinacol boronate, catecholborane, N-methyliminodiacetate boronic acid) are reacted in the presence of a copper catalyst (e.g., copper acetate) and a base (e.g., pyridine, 2,6-lutidine, triethylamine). The N-alkylation is carried out in a solvent such as N,N-dimethylformamide (DMF), acetonitrile, or tetrahydrofuran (THF). In this case, the reaction temperature for N-alkylation is preferably The temperature range is -20 to 80°C, more preferably 0 to 60°C. Furthermore, the coupling reaction is carried out in a solvent such as dimethyl sulfoxide (DMSO). In this case, the reaction temperature of the coupling reaction is preferably 40 to 160°C, more preferably 60 to 100°C.

[0092] (2) The introduction of "W" can be carried out by the following method. For example, W can be introduced by a coupling reaction using a catalyst (e.g., tris(dibenzylideneacetone)dipalladium(0)(Pd2(dba)3)), a ligand (e.g., 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene(Xantphos)), and a base (e.g., N-ethyldiisopropylamine, triethylamine). The coupling reaction described above is carried out in a solvent such as 1,4-dioxane or toluene.

[0093] Furthermore, W can be introduced by aromatic nucleophilic substitution. In this case, it is preferable to carry out the aromatic nucleophilic substitution reaction under basic conditions. Examples of bases that can be used include sodium hydride, lithium diisopropylamide, potassium carbonate, cesium carbonate, and potassium tert-butoxide. Examples of reaction solvents include N,N-dimethylformamide (DMF) and tetrahydrofuran (THF).

[0094] (3) The A ring can be introduced by the following methods. For example, a halogen atom can be introduced using a halogenating agent (e.g., N-iodosuccinimide, iodine, N-bromosuccinimide, etc.), and then the A ring can be introduced by, for example, a Suzuki-Miyaura coupling reaction. In this case, the Suzuki-Miyaura coupling reaction can be carried out under the same reaction conditions as the reactions of intermediate Z and compound C.

[0095] When carrying out any of the above reactions (1) to (3), it is preferable to protect the thiol group and hydroxyl group with a protecting group in order to suppress side reactions. For example, examples of protecting groups for thiol groups include acetyl group, pivaloyl group, trichloroacetyl group, benzoyl group, ferrosenoyl group, 2,4,6-triisopropyl group, dimethylphenylacetyl group, 2-methoxyisobutyryl group, tert-butoxycarbonyl group, and 2-(2-ethylhexyloxycarbonyl)ethyl group. Examples of protecting groups for hydroxyl groups include benzyl group, p-methoxybenzyl group (PMB), 2-tetrahydropyranyl group (THP), acetyl group (Ac), pivaloyl group (Piv), benzoyl group (Bz), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), and tert-butyldiphenylsilyl (TBDPS). These protecting groups can be appropriately selected depending on the reaction. For example, from the viewpoint of functioning suitably as a protecting group even under the conditions under which the Suzuki-Miyaura coupling reaction takes place, the protecting group of the thiol group is preferably a 2-(2-ethylhexyloxycarbonyl)ethyl group. The 2-(2-ethylhexyloxycarbonyl)ethyl group is deprotected under strong base conditions (e.g., potassium tert-butoxide).

[0096] (Synthesis of compound A) Compound A is either publicly known or can be synthesized from known compounds.

[0097] In one embodiment, for example, it can be synthesized by the following three steps.

[0098] [ka]

[0099] Note that "A 6 The group is preferably a leaving group, more preferably a halogen atom, and even more preferably a chlorine atom, a bromine atom, or an iodine atom.

[0100] The first step described above is to convert the product into a nitrile derivative by reacting it with a cyanating agent (e.g., sodium cyanide, potassium cyanide, etc.) to obtain a phenylacetic acid derivative. In this step, a solvent such as dimethyl sulfoxide (DMSO) is used.

[0101] The second step is to hydrolyze the cyano group with an acid or a base. The acid includes, for example, acetic acid, hydrochloric acid, sulfuric acid, and bromate. The base includes, for example, sodium hydroxide and potassium hydroxide. In this step, a solvent such as water or alcohol (for example, methanol, ethanol, tert-butyl alcohol, etc.) is used.

[0102] The third step is A 1 This is the process of introducing A. 1 If the halogen is present, it is reacted with the halogenating agent in the presence or absence of a radical initiator. In this process, the radical initiator includes, for example, N,N'-azobisisobutyronitrile (AIBN) and benzoyl peroxide. The halogenating agent includes, for example, N-bromosuccinimide, bromine, and N-chlorosuccinimide. Solvents such as dichloromethane, acetonitrile, and carbon tetrachloride are used in this process.

[0103] (Synthesis of intermediate Y) Intermediate Y is either known or can be synthesized from known compounds.

[0104] For example, intermediate Y can be synthesized by (1') N-alkylation and (2') introduction of an A ring (trifluoromethylpyridine ring, trifluoromethylpyrimidine ring, or trifluoromethylpyridazine ring) to a starting material represented by the following formula. In this case, the order of (1') and (2') is not particularly limited and can be changed as appropriate.

[0105] [ka]

[0106] Starting material "A 2 The group is preferably a leaving group, more preferably a halogen atom, an alkyl sulfone group, and even more preferably a chlorine atom, a bromine atom, an iodine atom, or a methyl sulfone group.

[0107] (1')N-alkylation can be carried out in the same manner as in (1) in the synthesis of intermediate X described above.

[0108] The introduction of the (2')A ring can be carried out in the same manner as in (3) in the synthesis of intermediate X described above.

[0109] (Synthesis of compound B) Compound B is either known or can be synthesized from known compounds.

[0110] For example, the above compound A can be synthesized by nucleophilic substitution of a nucleophile with a nucleophile. When W is an oxygen atom, the nucleophilic substitution reaction can be carried out by reacting compound A with a base (e.g., sodium carbonate, sodium hydroxide, etc.) in a solvent containing water, alcohol, etc.

[0111] (Synthesis of intermediate Z) Intermediate Z is either known or can be synthesized from known compounds.

[0112] For example, with respect to the starting material represented by the following formula, (1'') N-alkylation, (2'') introduction of "W" and introduction of phenylmethyl acetate group, (3'') "A 3 By introducing '', intermediate Z can be synthesized. In this case, the order of (1'') to (3'') is not particularly restricted and can be changed as appropriate.

[0113] [ka]

[0114] Starting material "A 5"] is preferably a leaving group, more preferably a halogen atom or an alkylsulfone group, and still more preferably a chlorine atom, a bromine atom, an iodine atom or a methylsulfone group.

[0115] (1'') N-alkylation can be carried out in the same manner as (1) in the synthesis of the above intermediate X.

[0116] (2'') The introduction of "W" and the phenylmethyl acetate group can be carried out by a method of introducing the phenylmethyl acetate group after introducing "W", or by a method of introducing compound B by an aromatic nucleophilic substitution reaction.

[0117] In the method of introducing the phenylmethyl acetate group after introducing "W", the introduction of "W" can be carried out in the same manner as (2) in the synthesis of the above intermediate X. Further, the subsequent introduction of the phenylmethyl acetate group can be carried out by reacting a thiol group when W is a sulfur atom or a hydroxy group when W is an oxygen atom with compound A. The specific reaction conditions can be carried out in the same manner as the reaction conditions of the above intermediate X and compound A.

[0118] Also, the method of introducing compound B by an aromatic nucleophilic substitution reaction can be carried out in the same manner as the reaction conditions of the above intermediate Y and compound B.

[0119] (3'') The introduction of "A 3 " can be carried out by a known method, for example, by introducing a halogen atom using a halogenating agent (for example, N-iodosuccinimide, iodine, N-bromosuccinimide, etc.).

[0120] 4. Pharmaceutical compositions, ACMSD inhibitors, and agents for the prevention or treatment of diseases involving ACMSD. According to one embodiment of the present invention, a pharmaceutical composition containing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is provided. Also, according to one embodiment of the present invention, an ACMSD inhibitor containing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is provided. According to one embodiment of the present invention, there is provided a preventive or therapeutic agent for diseases involving ACMSD (e.g., hereditary mitochondrial diseases, metabolic diseases, neurodegenerative diseases, kidney diseases, chronic inflammatory diseases, age-related diseases, cisplatin-induced ototoxicity, and diisocyanate-induced asthma, etc.) containing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof.

[0121] By inhibiting ACMSD (α-amino-β-carboxymuconic acid 6-semialdehyde decarboxylase: ACMS decarboxylase), the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof can suppress the metabolism (decarboxylation) of ACMS (α-amino-β-carboxymuconic acid 6-semialdehyde) by ACMSD. As a result, the proportion of ACMS metabolized into the NAD synthesis pathway increases (the conversion of ACMS to NAD via the NAD synthesis pathway is promoted), so that the intracellular NAD concentration can be increased. Consequently, diseases related to the intracellular NAD concentration, such as hereditary mitochondrial diseases, metabolic diseases, neurodegenerative diseases, kidney diseases, chronic inflammatory diseases, age-related diseases, cisplatin-induced ototoxicity, and diisocyanate-induced asthma, etc. can be treated or prevented (e.g., International Publication No. 2020 / 104456). In the present specification, since the diseases related to the intracellular NAD concentration can be treated or prevented by inhibiting ACMSD, such diseases may be referred to as "diseases involving ACMSD".

[0122] The pharmaceutical composition, ACMSD inhibitor, and preventive or therapeutic agent for diseases involving ACMSD contain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof. Further, the pharmaceutical composition, ACMSD inhibitor, and preventive or therapeutic agent for diseases involving ACMSD may further contain a pharmaceutically acceptable carrier.

[0123] [Compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof] The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as described above is used.

[0124] A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof may be included as a prodrug. In this specification, "prodrug" means a compound that is converted in the body to produce the compound of the present invention. For example, if the active substance contains a carboxyl group or a phosphate group, examples include their esters, amides, etc. If the active substance contains an amino group, examples include its amide, carbamate, etc. If the active substance contains a hydroxyl group, examples include its ester, carbonate, carbamate, etc. When prodrugizing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, it may be bound to amino acids or sugars.

[0125] Compounds represented by general formula (I) or pharmaceutically acceptable salts thereof may be included as metabolites. In this specification, "metabolites" refer to compounds obtained by metabolic enzymes in living organisms from compounds represented by general formula (I) or pharmaceutically acceptable salts thereof. Examples include compounds in which a hydroxyl group has been introduced by metabolism on the benzene ring of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, and compounds in which glucuronic acid, glucose, or amino acids are bonded to the carboxylic acid portion and / or the hydroxyl group introduced by metabolism of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

[0126] The content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition, ACMSD inhibitor, or preventive or therapeutic agent for ACMSD-related diseases is preferably 0.0001 to 100% by mass, and more preferably 0.01 to 100% by mass, based on the total mass of the pharmaceutical composition, ACMSD inhibitor, or preventive or therapeutic agent for ACMSD-related diseases.

[0127] [Medically acceptable carriers] Medicinally acceptable carriers include conventional organic or inorganic carrier materials used as formulation materials. Examples include excipients, lubricants, binders, disintegrants, water-soluble polymers, and basic inorganic salts in solid formulations; and solvents, solubilizers, suspending agents, isotonic agents, buffers, and analgesics in liquid formulations. In addition, preservatives, antioxidants, flavoring agents, colorants, sweeteners, acidulants, foaming agents, fragrances, and coating agents may be used as needed.

[0128] Excipients include, for example, lactose, corn starch, sucrose, glucose, sorbitol, and crystalline cellulose, while binders include, for example, polyvinyl alcohol, ethylcellulose, methylcellulose, acacia gum, tragacanth, gelapolyvinylethine, shellac, hydroxypropylcellulose, hydroxypropyl starch, and polyvinylpyrrolidone.

[0129] Lubricants include, for example, magnesium stearate, sodium lauryl sulfate, and talc.

[0130] Disintegrants include, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextran, pectin, etc.

[0131] Lubricants include, for example, magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil.

[0132] Colorants include, for example, those permitted for use in pharmaceuticals.

[0133] Flavoring and odor-modifying agents include, for example, cocoa powder, peppermint sap, aromatic acid, peppermint oil, borneol, cinnamon powder, etc.

[0134] Coating agents include, for example, sugar coatings, gelatin coatings, and enteric coatings (hydroxypropyl methylcellulose (HPMC), cellulose acetate phthalate, etc.).

[0135] [Dosage form, etc.] Examples of dosage forms for pharmaceutical compositions, ACMSD inhibitors, and agents for the prevention or treatment of diseases involving ACMSD include tablets, powders, pills, granules, capsules, suppositories, liquids, sugar-coated preparations, depot preparations, syrups, suspensions, emulsions, lozenges, sublingual preparations, patches, orally disintegrating agents (tablets), inhalants, enemas, ointments, patches, tapes, eye drops, etc. Such preparations can be manufactured by methods commonly used in the pharmaceutical technology field, for example, by methods described in the Japanese Pharmacopoeia.

[0136] For example, when preparing a pharmaceutical composition, an ACMSD inhibitor, or a preventive or therapeutic agent for a disease involving ACMSD as an oral formulation, the compound according to the present invention, an excipient, and optionally a binder, disintegrant, lubricant, colorant, flavoring agent, etc. are added, and then the formulation is prepared by conventional methods, for example, as a tablet, powder, pill, granule, capsule, solution, sugar-coated preparation, depot preparation, or syrup.

[0137] Furthermore, when preparing pharmaceutical compositions, ACMSD inhibitors, or preventive or therapeutic agents for diseases involving ACMSD as injectable preparations, the compounds according to the present invention, along with pH adjusters, buffers, stabilizers, preservatives, etc. as necessary, are added, and the preparations are administered by conventional methods for subcutaneous, intramuscular, or intravenous injection.

[0138] Pharmaceutical compositions, ACMSD inhibitors, and agents for the prevention or treatment of diseases involving ACMSD. The method of administration may be oral or parenteral (e.g., intravenous, subcutaneous, intramuscular, suppositories, enemas, ointments, patches, sublingual, eye drops, inhalation, etc.), but oral administration is preferred.

[0139] The dosage of the pharmaceutical composition, the ACMSD inhibitor, and the preventive or therapeutic agent for diseases involving ACMSD is determined by the intended therapeutic effect, administration method, treatment period, age, body weight, etc. Usually, as the daily dosage for an adult, in the case of oral administration, it is preferably 1 μg to 10 g, and in the case of parenteral administration, it is preferably 0.01 μg to 1 g. The usage is not particularly limited, but it can be administered once to several times a day (for example, once a day, twice a day, three times a day, four times a day), or once every few days (for example, once every two days, once every three days, once every four days, once every five days, once every six days, once every seven days, once every ten days, once every fourteen days).

[0140] Also, as described above, the compound according to the present invention has ACMSD inhibitory activity against mammals (for example, mice, rats, hamsters, rabbits, cats, dogs, pigs, cows, sheep, horses, monkeys, humans, etc., preferably humans). Therefore, it is useful as an ACMSD inhibitor. In addition, the compound or pharmaceutical composition according to the present invention has the potential to be used for the prevention and / or treatment of diseases involving ACMSD. Therefore, the compound or pharmaceutical composition according to the present invention can be provided as a preventive or therapeutic agent for diseases involving ACMSD.

[0141] Diseases involving ACMSD include hereditary mitochondrial diseases, metabolic diseases, neurodegenerative diseases, kidney diseases, chronic inflammatory diseases, age-related diseases, cisplatin-induced ototoxicity, and diisocyanate-induced asthma, etc.

[0142] Specific examples of the hereditary mitochondrial disease include mitochondrial diseases, etc.

[0143] Specific examples of the metabolic diseases include obesity, diabetes, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction-associated fatty liver disease (MAFLD), etc.

[0144] The aforementioned neurodegenerative diseases include, specifically, Alzheimer's disease, epilepsy, Lewy body dementia, Parkinson's disease, ataxia, myasthenia gravis, neuropathy, spinal and bulbar muscular atrophy, and spinocerebellar degeneration.

[0145] Examples of the aforementioned kidney diseases include acute kidney injury (AKI), chronic kidney disease (CKD), and diabetic nephropathy (DKD).

[0146] Examples of age-related diseases include cancer, dementia, atherosclerosis, hypertension, diabetes, arthritis, cataracts, Alzheimer's disease, macular degeneration, or osteoporosis.

[0147] 5. Methods of prevention or treatment, use of compounds represented by general formula (I) or pharmaceutically acceptable salts thereof. According to one embodiment of the present invention, a method for preventing or treating a disease involving ACMSD is provided, comprising administering a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. Furthermore, according to one embodiment of the present invention, the use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is provided for the prevention or treatment of diseases involving ACMSD. Furthermore, according to one embodiment of the present invention, a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical for the prevention or treatment of a disease involving ACMSD. Use of is provided.

[0148] The compound represented by general formula (I) or its pharmaceutically acceptable salt used in the aforementioned prevention or treatment method and method of use, as well as the method of administration and dosage thereof, are as described above. [Examples]

[0149] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. Furthermore, unless otherwise specified, the apparatus, reagents, etc. used in these examples are either readily available or commercially available according to methods commonly used in the art.

[0150] [Mass spectrometry (MS)] The peak intensities of the mass spectra of the compounds prepared in the synthesis examples and embodiments were measured using UPLC / MS (liquid chromatography-mass spectrometry). ESI (electrospray ionization) was used as the ionization method. The data listed are the measured values ​​(found). In mass spectra, molecular ion peaks are typically observed. In the case of salts, either the molecular ion peak of the free form or the fragment ion peak is typically observed. The UPLC (ultrahigh-performance liquid chromatography) analysis conditions were as follows.

[0151] Column: ACQUITY_UPLC(registered trademark) BEH C18, 50×2.1mm, 1.7μm Mobile phase A: Water + 0.1% formic acid Mobile phase B: Acetonitrile + 0.1% formic acid Column temperature: 30℃ Flow rate: 0.5mL / min %B: 5% in 0 minutes, 95% in 2 minutes, 95% in 2.5 minutes, 100% in 2.51 minutes, 5% in 3 minutes

[0152] [Synthesis Example 1] Synthesis of 3-((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (intermediate 1) [ka]

[0153] (Step 1) Synthesis of 2-ethylhexyl 3-((5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate A mixture of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.70 g), tris(dibenzylideneacetone)dipalladium (0) (0.253 g), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (0.320 g) contains 1,4- Dioxane (10 mL), 2-ethylhexyl 3-mercaptopropionate (3.26 mL), and N-ethyldiisopropylamine (5.80 mL) were added, and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. The reaction mixture was left at room temperature overnight, and the resulting insoluble matter was filtered off. The filtrate was then concentrated under reduced pressure using a rotary evaporator. This procedure was repeated three times, and the three resulting residues were combined and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a yellow liquid (10.7 g) of 2-ethylhexyl 3-((5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate.

[0154] (Step 2) Synthesis of 2-ethylhexyl 3-((7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of the compound obtained in step 1 (10.6 g) in N,N-dimethylformamide (30 mL), N-iodosuccinimide (11.5 g) was added and the mixture was stirred at room temperature for 4 hours. After adding aqueous sodium bisulfite solution to the reaction mixture and stirring for 20 minutes, the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed sequentially with water and saturated brine, and the organic layers were dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a light brown solid residue. Hexane was added to the residue and the mixture was stirred overnight at room temperature, from which the insoluble material was filtered off. The filtered solid was washed with hexane and dried under reduced pressure to obtain a light brown solid (13.2 g) of 2-ethylhexyl 3-((7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate.

[0155] (Step 3) Synthesis of 2-ethylhexyl 3-((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (intermediate 1) To a solution of the compound obtained in step 2 (4.98 g) in N,N-dimethylformamide (20 mL), cesium carbonate (10.65 g) and 2-iodopropane (1.30 mL) were added and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extracted twice with ethyl acetate. After combining the organic layers, they were sequentially washed with water and saturated brine, and the organic layers were dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the yellow liquid intermediate 1 (5.19 g).

[0156] [Synthesis Example 2] Synthesis of 3-((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (intermediate 2) [ka]

[0157] To a solution of 3-((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (intermediate 1) (1.71 g) in 1,4-dioxane (14 mL), (6-(trifluoromethyl)pyridine-3-yl)borone (0.847 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.255 g), and 2 mol / L aqueous sodium carbonate solution (7 mL) were added and the mixture was heated and stirred at 80°C for 2 hours. Water was added to the reaction mixture and extracted twice with ethyl acetate. After combining the organic layers, they were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a light brown solid (1.57 g) of intermediate 2.

[0158] [Synthesis Example 3] Synthesis of 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 3) [ka]

[0159] 3-((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (intermediate 1) (5.19 g) is added to tetrahydrofuran (50 mL) solution, potassium tert-butoxide (4.07 g) is added, and after stirring at room temperature for 10 minutes, 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid ( 3.03 g) was added. After stirring at room temperature for 20 minutes, water was added to the reaction mixture and it was washed twice with ethyl acetate. The aqueous layer was acidified with 1 mol / L hydrochloric acid and extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure using a rotary evaporator. Ethyl acetate / hexane (1 / 2) was added to the residue, and the solid was filtered off from the resulting suspension to obtain intermediate 3 (3.11 g).

[0160] [Synthesis Example 4] Synthesis of 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 4) [ka]

[0161] 2-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (1.00 g) was dissolved in N,N-dimethylformamide (10 mL), to which cesium carbonate (3.50 g) and 2-iodopropane (0.429 mL) were added and the mixture was stirred at room temperature for 3 days. Water (100 mL) was added to the reaction mixture and the mixture was stirred at room temperature for 3 hours, and the resulting insoluble material was filtered off. The filtered material was dissolved in ethyl acetate, the solution was dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure to obtain intermediate 4 (1.05 g).

[0162] [Synthesis Example 5] Synthesis of 2-(2-fluoro-5-(((7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 5) [ka]

[0163] (Step 1) Synthesis of 2-ethylhexyl 3-((7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 400 mg of 2-ethylhexyl 3-((7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate was dissolved in 3 mL of N,N-dimethylformamide, to which 847 mg of cesium carbonate and 0.070 mL of iodomethane were added under ice cooling and stirred overnight at room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 407 mg of 2-ethylhexyl 3-((7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate.

[0164] (Step 2) Synthesis of 2-(2-fluoro-5-(((7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 5) Potassium tert-butoxide (285 mg) was added to a solution of the compound obtained in step 1 (345 mg) in tetrahydrofuran (4 mL), and the mixture was stirred at room temperature for 10 minutes. Then, 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (215 mg) was added. After stirring at room temperature for 20 minutes, water was added to the reaction mixture and it was washed twice with ethyl acetate. The aqueous layer was acidified with 1 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Ethyl acetate (4 mL) and hexane (8 mL) were added to the resulting residue, insoluble matter was filtered off, the mixture was washed with hexane, and then dried under reduced pressure to obtain intermediate 5 (226 mg).

[0165] [Synthesis Example 6] Synthesis of 2-(5-(((5-ethyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 6) [ka]

[0166] (Step 1) Synthesis of 2-ethylhexyl 3-((5-ethyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of 3-((7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (1.00 g) in N,N-dimethylformamide (7 mL), cesium carbonate (2.12 g) and iodoethane (0.228 mL) were added under ice cooling. The mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-ethylhexyl 3-((5-ethyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (1.00 g).

[0167] (Step 2) Synthesis of 2-(5-(((5-ethyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 6) Potassium tert-butoxide (546 mg) was added to a solution of the compound obtained in step 1 (680 mg) in tetrahydrofuran (8 mL), and the mixture was stirred at room temperature for 10 minutes. Then, 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (412 mg) was added. After stirring at room temperature for 20 minutes, water was added to the reaction mixture and it was washed twice with ethyl acetate. The aqueous layer was acidified with 1 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Ethyl acetate (4 mL) and hexane (8 mL) were added to the resulting residue, insoluble matter was filtered off, the mixture was washed with hexane, and then dried under reduced pressure to obtain intermediate 6 (433 mg).

[0168] [Synthesis Example 7] Synthesis of 2-(2-fluoro-5-(((7-iodo-5-(oxetan-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 7) [ka]

[0169] (Step 1) Synthesis of 2-chloro-5-(oxetan-3-yl)-5H-pyrrolo[3,2-d]pyrimidine To a solution of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.00 g) in N-methyl-2-pyrrolidinone (50 mL), cesium carbonate (6.36 g) and 3-bromooxetane (1.07 g) were added and the mixture was heated and stirred at 100°C for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-chloro-5-(oxetan-3-yl)-5H-pyrrolo[3,2-d]pyrimidine (194.0 mg).

[0170] (Step 2) Synthesis of 2-ethylhexyl 3-((5-(oxetan-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate A mixture of the compound obtained in step 1 (137 mg), tris(dibenzylideneacetone)dipalladium (0) (119 mg), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (37.7 mg) was mixed with 1,4-dioxane (4 mL), 2-ethylhexyl 3-mercaptopropionate (0.30 mL), and N-ethyldiisopropylamine (0.23 mL). The mixture was heated and stirred at 120°C for 1 hour under an argon atmosphere using a microwave reactor. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-ethylhexyl 3-((5-(oxetan-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (187 mg).

[0171] (Step 3) Synthesis of 2-ethylhexyl 3-((5-(oxetan-3-yl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of the compound obtained in step 2 (187 mg) in acetonitrile (3 mL), N-iodosuccinimide (118 mg) was added at 0°C and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-ethylhexyl 3-((5-(oxetan-3-yl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (280 mg).

[0172] (Step 4) Synthesis of 2-(2-fluoro-5-(((7-iodo-5-(oxetan-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 7) To a solution of the compound obtained in step 3 (278 mg) in N,N-dimethylformamide (5.0 mL), potassium tert-butoxide (182 mg) and 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (200 mg) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain intermediate 7 (97.6 mg).

[0173] [Synthesis Example 8] Synthesis of 2-(2-fluoro-5-(((5-(2-hydroxy-2-methylpropyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 8) [ka]

[0174] (Step 1) Synthesis of 2-chloro-5-(2-hydroxy-2-methylpropyl)-5H-pyrrolo[3,2-d]pyrimidine 1.00 g of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine was dissolved in 12 mL of N,N-dimethylformamide, to which 365 mg of 60% sodium hydride was added dropwise at 0°C and the mixture was stirred at room temperature for 15 minutes. Then, 1.17 mL of isobutylene oxide was added to the reaction mixture and the mixture was stirred overnight at 55°C. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 850 mg of 2-chloro-5-(2-hydroxy-2-methylpropyl)-5H-pyrrolo[3,2-d]pyrimidine.

[0175] (Step 2) Synthesis of 2-ethylhexyl 3-((5-(2-hydroxy-2-methylpropyl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate A mixture of the compound obtained in step 1 (850 mg), tris(dibenzylideneacetone)dipalladium (0) (103 mg), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (131 mg) was mixed with 1,4-dioxane (15 mL), 2-ethylhexyl 3-mercaptopropionate (1.11 mL), and N-ethyldiisopropylamine (1.97 mL), and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-ethylhexyl 3-((5-(2-hydroxy-2-methylpropyl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (730 mg).

[0176] (Step 3) Synthesis of 2-ethylhexyl 3-((5-(2-hydroxy-2-methylpropyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of the compound obtained in step 2 (530 mg) in acetonitrile (10 mL), N-iodosuccinimide (322 mg) was added at 0°C and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-ethylhexyl 3-((5-(2-hydroxy-2-methylpropyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (750 mg).

[0177] (Step 4) Synthesis of 2-(2-fluoro-5-(((5-(2-hydroxy-2-methylpropyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 8) Potassium tert-butoxide (526 mg) was added to a solution of the compound obtained in step 3 (500 mg) in tetrahydrofuran (8 mL), and the mixture was stirred at room temperature for 10 minutes. Then, 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (278 mg) was added. After stirring at room temperature for 30 minutes, saturated ammonium chloride aqueous solution and sodium chloride were added to the reaction mixture, and it was extracted three times with ethyl acetate / tetrahydrofuran (1 / 1). After combining the organic layers, the organic layers were dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain intermediate 8 (206 mg).

[0178] [Synthesis Example 9] Synthesis of 2-(5-(((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9) [ka]

[0179] (Step 1) Synthesis of 2-chloro-5-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (5.27 mL) was added to a dimethyl sulfide solution (25 mL) of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (2.00 g), cyclopropylboronic acid (2.24 g), and copper(II) acetate (2.37 g). The mixture was heated and stirred at 90°C for 18 hours under an oxygen atmosphere. After adding water, aqueous ammonia and ethyl acetate were added. The resulting insoluble matter was filtered off and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-chloro-5-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine (1.79 g).

[0180] (Step 2) Synthesis of 2-ethylhexyl 3-((5-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a mixture of 2-chloro-5-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine (1.80 g), tris(dibenzylideneacetone)dipalladium (0) (1.70 g), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.538 g), 1,4-dioxane (15 mL), 2-ethylhexyl 3-mercaptopropionate (4.23 mL), and N-ethyldiisopropylamine (3.25 mL) were added, and the mixture was heated and stirred at 120°C for 3 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-ethylhexyl 3-((5-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (2.08 g).

[0181] (Step 3) Synthesis of 2-ethylhexyl 3-((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 1.33 g of 2-ethylhexyl 3-((5-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate was added to 30 mL of acetonitrile with 0.878 g of N-iodosuccinimide at 0°C and stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 1.69 g of 2-ethylhexyl 3-((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate.

[0182] (Step 4) 2-(5-(((5-Cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9 ) synthesis To a solution of 2-ethylhexyl 3-((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (0.60 g) in tetrahydrofuran (15 mL), potassium tert-butoxide (0.403 g) and 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (0.414 g) were added and the mixture was stirred at room temperature for 1 hour. 1 mol / L hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and a hexane / ethyl acetate (1 / 1) mixture was added to the resulting residue. Insoluble matter was filtered from the mixture to obtain intermediate 9 (0.429 g).

[0183] Table 1 below shows the intermediates prepared in Synthesis Examples 1-9 and their mass spectrometry (MS) results.

[0184] [Table 1]

[0185] [Example 1] Synthesis of 2-(2-fluoro-5-(((5-methyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0186] To a solution of 2-(2-fluoro-5-(((7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 5) (35 mg) in 1,4-dioxane (2 mL), (6-(trifluoromethyl)pyridine-3-yl)boronic acid (29 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.6 mg) and 2 mol / L aqueous sodium carbonate solution (0.2 mL) were added and heated and stirred at 80°C for 1 hour. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.062 mL) was added, insoluble matter was filtered off, and the filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-methyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (21 mg).

[0187] [ka]

[0188] [Example 2] 2-(5-(((5-ethyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)2-fluoro Synthesis of phenylacetic acid [ka]

[0189] (Step 1) Synthesis of 2-chloro-5-ethyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine To a solution of 2-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (0.51 g) in dichloromethane (8 mL), tetrabutylammonium bromide (59 mg), 4 mol / L aqueous sodium hydroxide solution (1.5 mL), and iodoethane (0.192 mL) were added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the solid from the resulting suspension was filtered and washed with water. The solid was then dissolved in an ethyl acetate-tetrahydrofuran mixed solvent, and the resulting solution was dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain 2-chloro-5-ethyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (458 mg).

[0190] (Step 2) Synthesis of 2-chloro-5-ethyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine To a solution of 2-chloro-5-ethyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in 1,4-dioxane (2 mL), (6-(trifluoromethyl)pyridine-3-yl)boronic acid (75 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24 mg) and 2 mol / L aqueous sodium carbonate solution (1 mL) were added and the mixture was heated and stirred at 60°C for 12 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a slightly brown solid (71 mg) of 2-chloro-5-ethyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine.

[0191] (Step 3) Synthesis of 2-ethylhexyl 3-((5-ethyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-Chloro-5-ethyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine (66 mg) in a 1,4-dioxane (3 mL) solution, with 2-ethylhexyl 3-mercaptopropionate (0.060 mL) and 4,5-bis (Diphenylphosphino)-9,9-dimethylxanthene (23 mg), N-ethyldiisopropylamine (0.106 mL), and tris(dibenzylideneacetone)dipalladium (0) (19 mg) were added, and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-ethylhexyl 3-((5-ethyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (89 mg).

[0192] (Step 4) Synthesis of 2-(5-(((5-ethyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)2-fluorophenyl)acetic acid To a solution of 2-ethylhexyl 3-((5-ethyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (44 mg) in tetrahydrofuran (2 mL), potassium tert-butoxide (34 mg) was added and the mixture was stirred at room temperature for 10 minutes. Then, 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (26 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.027 mL) was added to the reaction mixture and the mixture was concentrated under reduced pressure using a rotary evaporator. The obtained residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-ethyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)2-fluorophenyl)acetic acid (25 mg). [ka]

[0193] [Example 3] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0194] To a solution of 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 3) (50.0 mg) in 1,4-dioxane (2.0 mL), (6-(trifluoromethyl)pyridine-3-yl)boronic acid (23.6 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.1 mg), and 2 mol / L aqueous sodium carbonate solution (2.0 mL) were added, and the mixture was heated and stirred at 60°C for 2 hours under an argon atmosphere. After filtering off the insoluble material with Celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (4.13 mg). [ka]

[0195] [Example 4] Synthesis of 2-(5-(((5-cyclopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)2-fluorophenyl)acetic acid [ka]

[0196] To a solution of 2-(5-(((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9) (50.0 mg) in 1,4-dioxane (1.0 mL), 6-(trifluoromethyl)pyridine-3-yl)boronic acid (29.6 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.1 mg), and 2 mol / L aqueous sodium carbonate solution (1.0 mL) were added, and the mixture was heated and stirred at 60°C for 2 hours under an argon atmosphere. 1 mol / L hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-cyclopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (36.2 mg). [ka]

[0197] [Example 5] Synthesis of 2-(5-(((5-(difluoromethyl)-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)2-fluorophenyl)acetic acid [ka]

[0198] (Step 1) Synthesis of 2-ethylhexyl 3-((5-(trifluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate A 1,4-dioxane solution (16 mL) of 2-chloro-5-(difluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine (0.65 g), 2-ethylhexyl 3-mercaptopropionate (0.94 mL), and N-ethyldiisopropylamine (2.79 mL) were added to a mixture of tris(dibenzylideneacetone)dipalladium (0) (0.29 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.37 g). The mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. After the reaction mixture cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a yellow liquid (1.22 g) of 2-ethylhexyl 3-((5-(trifluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate.

[0199] (Step 2) Synthesis of 2-ethylhexyl 3-((5-(difluoromethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 3-((5-(trifluoromethyl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (1.15 g) was added to acetonitrile (10 mL) under ice cooling, and N-iodosuccinimide (0.81 g) was heated and stirred at 80°C for 12 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain 3-((5-(difluoromethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (1.7 g) as the crude product.

[0200] (Step 3) Synthesis of 2-(5-(((5-(difluoromethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid Potassium tert-butoxide (549 mg) was added to a solution of 2-ethylhexyl 3-((5-(difluoromethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (500 mg) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 10 minutes. Then, 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (483 mg) was added. After stirring at room temperature for 1 hour, water and 1 mol / L hydrochloric acid were added to the reaction mixture. In addition, it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-(difluoromethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (84 mg).

[0201] (Step 4) Synthesis of 2-(5-(((5-(difluoromethyl)-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)2-fluorophenyl)acetic acid To a solution of 2-(5-(((5-(difluoromethyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (40.0 mg) in 1,4-dioxane (1.0 mL), 6-(trifluoromethyl)pyridine-3-yl)boronic acid (23.2 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11.9 mg), and 2 mol / L aqueous sodium carbonate solution (1.0 mL) were added, and the mixture was heated and stirred at 60°C for 2 hours under an argon atmosphere. 1 mol / L hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-(difluoromethyl)-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)2-fluorophenyl)acetic acid (13.4 mg). [ka]

[0202] [Example 6] Synthesis of 2-(3-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0203] (Step 1) Synthesis of 2-chloro-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine 10 g of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine was dissolved in 200 mL of N,N-dimethylformamide, to which 42 g of cesium carbonate and 22 g of 2-iodopropane were added and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. After filtering off the insoluble matter, water was added to the filtrate and it was extracted three times with ethyl acetate. The organic layers were combined and concentrated under reduced pressure, and ethyl acetate / petroleum ether (100 mL / 400 mL) was added to the resulting residue to remove the insoluble matter by filtration, and the mixture was dried under reduced pressure to obtain 10 g of 2-chloro-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine.

[0204] (Step 2) Synthesis of 2-ethylhexyl 3-((5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 4.0 g of 2-chloro-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine, 1.8 g of tris(dibenzylideneacetone)dipalladium, and 2.3 g of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene were mixed with 50 mL of 1,4-dioxane, 8.9 g of 2-ethylhexyl 3-mercaptopropionate, and 7.9 g of N-ethyldiisopropylamine. The mixture was heated and stirred in a sealed tube at 140°C for 18 hours. Water was added to the reaction mixture, and it was extracted three times with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain 2-ethylhexyl 3-((5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (5.0 g).

[0205] (Step 3) Synthesis of 2-(3-(((5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)methyl acetate A solution of 2-ethylhexyl 3-((5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (10 g) in tetrahydrofuran (50 mL) was cooled to -60°C, and potassium tert-butoxide (1 mol / L tetrahydrofuran solution, 5.3 mL) was added dropwise under a nitrogen atmosphere. The completion of the reaction was confirmed by LC-MS, and 1 mol / L hydrochloric acid (5.3 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Acetonitrile (20 mL), methyl 3-(bromomethyl)phenylacetate (2.5 g), and cesium carbonate (6.7 g) were added to the resulting residue, and the mixture was heated and stirred at 50°C for 2 hours under a nitrogen atmosphere. Insoluble matter was filtered off from the reaction mixture, and the filtrate was washed with water after adding ethyl acetate. After extracting the aqueous layer three times with ethyl acetate, all the organic layers were combined and concentrated under reduced pressure. The resulting residue was collected in a silica gel column. The solution was purified by chromatography (petroleum ether / ethyl acetate) to obtain methyl 2-(3-(((5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetate (3.3g).

[0206] (Step 4) Synthesis of 2-(3-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)methyl acetate 5.0 g of methyl 2-(3-(((5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetate was dissolved in acetonitrile (50 mL), to which 4.7 g of N-iodosuccinimide was added and stirred overnight at room temperature under a nitrogen atmosphere. Insoluble matter was filtered off from the reaction mixture, and the filtrate was washed with water after adding ethyl acetate. The aqueous layer was extracted three times with ethyl acetate, and all the organic layers were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain methyl 2-(3-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetate (5.0 g).

[0207] (Step 5) Synthesis of 2-(3-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid A mixture of 2-(3-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)methyl acetate (41.0 mg), (6-(trifluoromethyl)pyridine-3-yl)borone (21.2 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.4 mg) was mixed with 1,4-dioxane (1.5 mL) and 2 mol / L aqueous sodium carbonate solution (0.5 mL), and heated and stirred in a microwave reactor at 120°C for 40 minutes. After cooling to room temperature, 4 mol / L aqueous sodium hydroxide solution (0.5 mL) and methanol (0.5 mL) were added to the reaction mixture and stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted twice with ethyl acetate. The organic layers were dried together over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(3-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl) (20.5 mg). [ka]

[0208] [Example 7] Synthesis of 2-(2-chloro-5-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0209] 3-((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (intermediate 2) (53.8 mg) was dissolved in tetrahydrofuran (2 mL) and potassium tert-butoxide (34.7 mg) and 2-(5-(bromomethyl)-2-chlorophenyl)acetic acid (54.3 mg) were added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-chlorophenyl)acetic acid. Roro-5-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (14.6 mg) was obtained. [ka]

[0210] [Example 8] Synthesis of 2-(2-bromo-5-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0211] To a solution of 3-((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (intermediate 2) (50 mg) in tetrahydrofuran (1 mL), potassium tert-butoxide (53.7 mg) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 10 minutes. Then, a solution of 2-(2-bromo-5-(bromomethyl)phenyl)acetic acid (58.9 mg) in tetrahydrofuran (0.5 mL) was added. After stirring at room temperature for 1 hour, trifluoroacetic acid (0.044 mL) was added to the reaction mixture, and after concentration under reduced pressure, the resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-bromo-5-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (17 mg). [ka]

[0212] [Example 9] Synthesis of 2-(2,4-difluoro-5-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0213] To a solution of 3-((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (intermediate 2) (50 mg) in tetrahydrofuran (1 mL), potassium tert-butoxide (53.7 mg) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 10 minutes. Then, a solution of 2-(5-(bromomethyl)-2,4-difluorophenyl)acetic acid (50.7 mg) in tetrahydrofuran (0.5 mL) was added. After stirring at room temperature for 1 hour, trifluoroacetic acid (0.044 mL) was added to the reaction mixture, and after concentration under reduced pressure, the resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2,4-difluoro-5-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (19 mg). [ka]

[0214] [Example 10] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(5-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0215] To a solution of 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 3) (50.0 mg) in 1,4-dioxane (1.0 mL), (5-methyl-6-(trifluoromethyl)pyridine-3-yl)boronic acid (25.3 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.1 mg), and a 2 mol / L aqueous sodium carbonate solution (1.0 mL) were added, and the mixture was heated and stirred at 60°C for 2 hours. After filtering off the insoluble material with Celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-isopropyl-7-(5-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (3.2 mg). [ka]

[0216] [Example 11] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(5-methoxy-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0217] To a solution of 5-bromo-3-methoxy-2-(trifluoromethyl)pyridine (150 mg) in 1,4-dioxane (3 mL), bis(pinacolate)diborone (298 mg), potassium acetate (104 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (34 mg) were added and the mixture was heated and stirred at 90°C for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and one-third of the resulting residue was dissolved in 1,4-dioxane (2 mL). To the resulting solution, 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 3) (40 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg), and 2 mol / L aqueous sodium carbonate solution (0.2 mL) were added, and the mixture was heated and stirred at 80°C for 5 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.062 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-isopropyl-7-(5-methoxy-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl Acetic acid (15 mg) was obtained. [ka]

[0218] [Example 12] Synthesis of 2-(2-fluoro-5-(((7-(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0219] To a solution of 5-bromo-3-fluoro-2-(trifluoromethyl)pyridine (150 mg) in 1,4-dioxane (3 mL), bis(pinacolate)diborone (312 mg), potassium acetate (109 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg) were added and the mixture was heated and stirred at 90°C for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and one-third of the resulting residue was dissolved in 1,4-dioxane (2 mL). To the obtained solution, 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 3) (40 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg) and 2 mol / L aqueous sodium carbonate solution (0.2 mL) were added and the mixture was heated and stirred at 80°C for 5 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.062 mL) was added, and insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-( ((7-(5-fluoro-6-(trifluoromethyl)pyridine-3-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (13 mg) was obtained. [ka]

[0220] [Example 13] Synthesis of 2-(2-fluoro-5-(((5-methyl-7-(5-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0221] To a solution of 5-bromo-3-methyl-2-(trifluoromethyl)pyridine (150 mg) in 1,4-dioxane (3 mL), bis(pinacolate)diborone (317 mg), potassium acetate (111 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg) were added and the mixture was heated and stirred at 90°C for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was dissolved in 1,4-dioxane (4 mL). To the obtained solution, 2-(2-fluoro-5-(((7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 5) (48 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8 mg), and 2 mol / L aqueous sodium carbonate solution (0.4 mL) were added, and the mixture was heated and stirred at 80°C for 5 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.123 mL) was added, and insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid), and the resulting compound was again purified by high-performance liquid chromatography. The compound was purified with water and acetonitrile, each containing 0.1% trifluoroacetic acid. The resulting compound was precipitated from the water-acetonitrile mixed solvent, and the solid was collected by filtration to obtain 2-(2-fluoro-5-(((5-methyl-7-(5-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (12 mg). [ka]

[0222] [Example 14] Synthesis of 2-(2-fluoro-5-(((7-(5-methoxy-6-(trifluoromethyl)pyridine-3-yl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0223] To a solution of 5-bromo-3-methoxy-2-(trifluoromethyl)pyridine (150 mg) in 1,4-dioxane (3 mL), bis(pinacolate)diborone (298 mg), potassium acetate (104 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (34 mg) were added and the mixture was heated and stirred at 90°C for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and one-third of the resulting residue was dissolved in 1,4-dioxane (2 mL). To the obtained solution, 2-(2-fluoro-5-(((7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 5) (35 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg), and 2 mol / L aqueous sodium carbonate solution (0.2 mL) were added, and the mixture was heated and stirred at 80°C for 5 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.062 mL) was added, and insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator, and the resulting residue was subjected to high-performance liquid chromatography (water-acetonitrile, etc.). The two compounds were purified (each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((7-(5-methoxy-6-(trifluoromethyl)pyridine-3-yl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (11 mg). [ka]

[0224] [Example 15] Synthesis of 2-(5-(((5-ethyl-7-(5-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0225] To a solution of 5-bromo-3-methyl-2-(trifluoromethyl)pyridine (300 mg) in 1,4-dioxane (5 mL), bis(pinacolate)diborone (635 mg), potassium acetate (368 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg) were added and the mixture was heated and stirred at 90°C for 3 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a crude product. One-third of the obtained crude product was dissolved in 1,4-dioxane (2 mL). To the obtained solution, 2-(5-(((5-ethyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 6) (60 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg), and 2 mol / L aqueous sodium carbonate solution (0.4 mL) were added, and the mixture was heated and stirred at 80°C for 5 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.123 mL) was added, and insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure in a rotary evaporator, and the resulting residue was rapidly evaporated. The solution was purified by liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-ethyl-7-(5-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (23 mg). [ka]

[0226] [Example 16] Synthesis of 2-(5-(((5-ethyl-7-(5-methoxy-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0227] To a solution of 5-bromo-3-methoxy-2-(trifluoromethyl)pyridine (100 mg) in 1,4-dioxane (3 mL), bis(pinacolate)diborone (149 mg), potassium acetate (115 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23 mg) were added and the mixture was heated and stirred at 90°C for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was dissolved in 1,4-dioxane (4 mL). To the resulting solution, 2-(5-(((5-ethyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 6) (70 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg), and 2 mol / L aqueous sodium carbonate solution (0.4 mL) were added, and the mixture was heated and stirred at 80°C for 5 hours. After the reaction mixture returned to room temperature, trifluoroacetic acid (0.123 mL) was added, and the insoluble matter was filtered off. The filtered solid was then subjected to a 0.1% trifluoroacetic acid acetonite trinitrate. The mixture was washed with water. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-ethyl-7-(5-methoxy-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (41 mg). [ka]

[0228] [Example 17] Synthesis of 2-(2,4-difluoro-5-(((5-methyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0229] (Step 1) Synthesis of 2-ethylhexyl 3-((7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 3.56 g of 2-ethylhexyl 3-((7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate and cesium carbonate (4.21 g) were suspended in N,N-dimethylformamide (10 mL), to which iodomethane (0.579 mL) was added and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water, and the resulting aqueous layer was extracted with ethyl acetate. After combining all the organic layers, they were washed with saturated brine, and the organic layers were dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-ethylhexyl 3-((7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (3.10 g).

[0230] (Step 2) Synthesis of 2-ethylhexyl 3-((5-methyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of 3-((7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (3.10 g) in 1,4-dioxane (26 mL), 13 mL of 2 mol / L aqueous sodium carbonate solution, 1.62 g of (6-(trifluoromethyl)pyridine-3-yl)borone, and 0.482 g of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) were added and the mixture was heated and stirred at 80°C for 2 hours. Water was added to the reaction mixture and extracted twice with ethyl acetate. After combining the organic layers, they were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-ethylhexyl 3-((5-methyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (2.05 g).

[0231] (Step 3) Synthesis of 2-(2,4-difluoro-5-(((5-methyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid To a solution of 2-ethylhexyl 3-((5-methyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (69 mg) in tetrahydrofuran (2 mL), potassium tert-butoxide (55 mg) was added and the mixture was stirred at room temperature for 10 minutes. Then, 2-(5-(bromomethyl)-2,4-difluorophenyl)acetic acid (56 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.054 mL) was added to the reaction mixture and the mixture was concentrated under reduced pressure using a rotary evaporator. The obtained residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2,4-difluoro-5-(((5-methyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (27 mg). [ka]

[0232] [Example 18] Synthesis of 2-(2-fluoro-5-(((5-methyl-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0233] To a solution of 2-(2-fluoro-5-(((7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 5) (30 mg) in 1,4-dioxane (2 mL), 2-trifluoromethylpyrimidine-5-ylboronic acid (19 mg), 2 mol / L aqueous sodium carbonate solution (0.2 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 mg) were added and the mixture was heated and stirred at 80°C for 5 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.062 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-methyl-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (19 mg). [ka]

[0234] [Example 19] Synthesis of 2-(5-(((5-ethyl-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)2-fluorophenyl)acetic acid [ka]

[0235] To a solution of 2-(5-(((5-ethyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 6) (40 mg) in 1,4-dioxane (2 mL), 2-trifluoromethylpyrimidine-5-ylboronic acid (24 mg), 2 mol / L aqueous sodium carbonate solution (0.2 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6 mg) were added and the mixture was heated and stirred at 80°C for 5 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.062 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-ethyl-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)2-fluorophenyl)acetic acid (25 mg). [ka]

[0236] [Example 20] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0237] (Step 1) Synthesis of 2-chloro-5-isopropyl-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine To a solution of 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 4) (100 mg) in 1,4-dioxane (1.0 mL), (2-(trifluoromethyl)pyrimidine-5-yl)boronic acid (59.7 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.8 mg) and 2 mol / L aqueous sodium carbonate solution (1 mL) were added, and the mixture was heated and stirred at 60°C for 2 hours under an argon atmosphere. Saturated saline solution was added to the reaction mixture, and it was extracted twice with ethyl acetate. After combining the organic layers, the organic layers were concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-chloro-5-isopropyl-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine (89.3 mg).

[0238] (Step 2) Synthesis of 2-ethylhexyl 3-((5-isopropyl-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate The compound obtained in step 1 (89.3 mg), tris(dibenzylideneacetone)dipalladium (0) (47.9 mg), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (15.1 mg) were mixed with 1,4-dioxane (2 mL), 3-mercaptopropionate 2-ethylhexyl (0.12 mL), and N-ethyldiisopropylamine (0.09 mL). The mixture was heated and stirred at 120°C for 1.5 hours under an argon atmosphere using a microwave reactor. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 3-((5-isopropyl-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (123.0 mg).

[0239] (Step 3) Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid To a solution of the compound obtained in step 2 (123.0 mg) in N,N-dimethylformamide (2.0 mL), potassium tert-butoxide (79.0 mg) and 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (87.0 mg) were added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-isopropyl-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (67.8 mg). [ka]

[0240] [Example 21] Synthesis of 2-(5-(((5-cyclopropyl-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)2-fluorophenyl)acetic acid [ka]

[0241] To a solution of 2-(5-(((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9) (50.0 mg) in 1,4-dioxane (1.0 mL), 2-(trifluoromethyl)pyrimidine-5-ylboronic acid (29.8 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.1 mg), and 2 mol / L aqueous sodium carbonate solution (1.0 mL) were added, and the mixture was heated and stirred at 60°C for 2 hours under an argon atmosphere. 1 mol / L hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was analyzed by high-performance liquid chromatography (water-acetonitrile, 0.1% truffles). Purified with ruoroacetic acid, 2-(5-(((5-cyclopropyl-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)2-fluorophenyl)acetic acid (27.6 mg). [ka]

[0242] [Example 22] Synthesis of 2-(2-fluoro-5-(((1-isopropyl-3-(6-(trifluoromethyl)pyridine-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-5-yl)thio)methyl)phenyl)acetic acid [ka]

[0243] (Step 1) Synthesis of 2-ethylhexyl 3-((1H-pyrazolo[4,3-d]pyrimidine-5-yl)thio)propionate To a solution of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine (200 mg) in 1,4-dioxane (4 mL), 2-ethylhexyl 3-mercaptopropionate (0.383 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (150 mg), N-ethyldiisopropylamine (0.678 mL), and tris(dibenzylideneacetone)dipalladium (0) (118 mg) were added, and the mixture was heated and stirred at 140 °C for 2 hours using a microwave reactor. After filtering off insoluble matter from the reaction mixture, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-ethylhexyl 3-((1H-pyrazolo[4,3-d]pyrimidine-5-yl)thio)propionate (362 mg).

[0244] (Step 2) 3-((3-iodo-1-isopropyl-1H-pyrazolo[4,3-d]py Synthesis of 2-ethylhexyl limidine-5-yl)thio)propionate 3-((1H-pyrazolo[4,3-d]pyrimidine-5-yl)thio)propionate 2-ethylhexyl (300 mg) was added to a solution of N,N-dimethylformamide (4 mL) and N-iodosuccinimide (241 mg) and stirred overnight at room temperature, then stirred at 35 °C for 5 hours. Subsequently, cesium carbonate (872 mg) and 2-iodopropane (0.134 mL) were added to the reaction mixture and stirred overnight at room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 3-((3-iodo-1-isopropyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl)thio)propionate 2-ethylhexyl (250 mg).

[0245] (Step 3) Synthesis of 2-(2-fluoro-5-(((3-iodo-1-isopropyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl)thio)methyl)phenyl)acetic acid To a solution of 240 mg of 2-ethylhexyl 3-((3-iodo-1-isopropyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl)thio)propionate in 5 mL of tetrahydrofuran, potassium tert-butoxide (187 mg) was added and the mixture was stirred at room temperature for 10 minutes. Then, 141 mg of 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid was added. After stirring at room temperature for 20 minutes, 1 mol / L hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The obtained residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((3-iodo-1-isopropyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl)thio)methyl)phenyl)acetic acid (116 mg).

[0246] (Step 4) Synthesis of 2-(2-fluoro-5-(((1-isopropyl-3-(6-(trifluoromethyl)pyridine-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-5-yl)thio)methyl)phenyl)acetic acid To a solution of 2-(2-fluoro-5-(((3-iodo-1-isopropyl-1H-pyrazolo[4,3-d]pyrimidine-5-yl)thio)methyl)phenyl)acetic acid (52 mg) in 1,4-dioxane (2 mL), (6-(trifluoromethyl)pyridine-3-yl)borone (41 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8 mg) and 2 mol / L aqueous sodium carbonate solution (0.4 mL) were added and heated and stirred at 80°C for 5 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.123 mL) was added, insoluble matter was filtered off, and the filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((1-isopropyl-3-(6-(trifluoromethyl)pyridine-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-5-yl)thio)methyl)phenyl)acetic acid (43 mg). [ka]

[0247] [Example 23] Synthesis of 2-(2-fluoro-5-(((5-(2-hydroxy-2-methylpropyl)-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid [ka]

[0248] 2-(2-fluoro-5-(((5-(2-hydroxy-2-methylpropyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 8) (28 mg) in a 1,4-dioxane (1 mL) solution, with (6-(trifluoromethyl)pyridine-3-yl)borone (21 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4 mg) and 2 mol / L 0.2 mL of aqueous sodium carbonate solution was added and the mixture was heated and stirred at 80°C for 2 hours. After the reaction mixture was allowed to return to room temperature, 0.031 mL of trifluoroacetic acid was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-(2-hydroxy-2-methylpropyl)-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid (18 mg). [ka]

[0249] [Example 24] Synthesis of 2-(2-fluoro-5-(((5-(2-hydroxy-2-methylpropyl)-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid [ka]

[0250] To a solution of 2-(2-fluoro-5-(((5-(2-hydroxy-2-methylpropyl)-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 8) (28 mg) in 1,4-dioxane (1 mL), 2-trifluoromethylpyrimidine-5-ylboronic acid (21 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4 mg) and 2 mol / L aqueous sodium carbonate solution (0.2 mL) were added and heated and stirred at 80°C for 2 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.031 mL) was added, and the insoluble matter was filtered off. The body was washed with acetonitrile containing 0.1% trifluoroacetic acid. The resulting filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-(2-hydroxy-2-methylpropyl)-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid (22 mg). [ka]

[0251] [Example 25] Synthesis of 2-(2-fluoro-5-(((5-(oxetan-3-yl)-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid [ka]

[0252] To a solution of 2-(2-fluoro-5-(((7-iodo-5-(oxetan-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 7) (30.0 mg) in 1,4-dioxane (1.0 mL), 2-(trifluoromethyl)pyrimidine-5-ylboronic acid (13.8 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.79 mg), and 2 mol / L aqueous sodium carbonate solution (1.0 mL) were added, and the mixture was heated and stirred at 60°C for 2 hours under an argon atmosphere. 1 mol / L hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-(oxetan-3-yl)-7-(2-(trifluoromethyl)pyrimidine-5-yl)-5H- Pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid (10.1 mg) was obtained. [ka]

[0253] [Example 26] Synthesis of 2-(2-fluoro-5-(((5-(oxetan-3-yl)-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid [ka]

[0254] To a solution of 2-(2-fluoro-5-(((7-iodo-5-(oxetan-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 7) (100.0 mg) in 1,4-dioxane (3.0 mL), 6-(trifluoromethyl)pyridine-3-ylboronic acid (45.9 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (29.3 mg), and 2 mol / L aqueous sodium carbonate solution (2.0 mL) were added, and the mixture was heated and stirred at 60°C for 2 hours under an argon atmosphere. 1 mol / L hydrochloric acid was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-(oxetan-3-yl)-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid (21.0 mg). [ka]

[0255] [Example 27] Synthesis of 2-(4-fluoro-3-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid [ka]

[0256] To a solution of 2 mL of tetrahydrofuran containing 2-ethylhexyl 3-((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (intermediate 2) (64 mg), potassium tert-butoxide (48 mg) was added and the mixture was stirred at room temperature for 10 minutes. Then, 2-(3-(bromomethyl)-4-fluorophenyl)acetic acid (45 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.047 mL) was added to the reaction mixture and the mixture was concentrated under reduced pressure using a rotary evaporator. The obtained residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(4-fluoro-3-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid (45 mg). [ka]

[0257] [Example 28] Synthesis of 2-(5-(((5-cyclopropyl-7-(5-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0258] (Step 1) Synthesis of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine To a solution of 5-bromo-3-methyl-2-(trifluoromethyl)pyridine (460 mg) in 1,4-dioxane (15 mL), bis(pinacolate)diborone (973 mg), potassium acetate (564 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (140 mg) were added, and the mixture was heated and stirred at 90°C for 3 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (442 mg).

[0259] (Step 2) Synthesis of 2-(5-(((5-cyclopropyl-7-(5-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid 2-(5-(((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9) (130 mg), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxabolo) To a solution of lan-2-yl)-2-(trifluoromethyl)pyridine (154 mg) in 1,4-dioxane (5 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg) and 2 mol / L aqueous sodium carbonate solution (0.4 mL) were added, and the mixture was heated and stirred at 80°C for 5 hours under an argon atmosphere using a microwave reactor. After the reaction mixture was allowed to return to room temperature, 2 mol / L hydrochloric acid (3 mL) was added, and insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid). The resulting compound was precipitated from a hexane-ethyl acetate mixed solvent, and the solid was collected by filtration to obtain 2-(5-(((5-cyclopropyl-7-(5-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (44 mg). [ka]

[0260] [Example 29] Synthesis of 2-(5-(((5-cyclopropyl-7-(5-methoxy-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0261] To a solution of 5-bromo-3-methoxy-2-(trifluoromethyl)pyridine (85 mg) in 1,4-dioxane (2 mL), bis(pinacolate)diborone (169 mg), potassium acetate (98 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg) were added and the mixture was heated and stirred at 90°C for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was dissolved in 1,4-dioxane (3 mL). To the resulting solution, 2-(5-(((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9) (100 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg), and 2 mol / L aqueous sodium carbonate solution (0.3 mL) were added, and the mixture was heated and stirred at 80°C for 5 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.092 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-cyclopropyl-7-(5-methoxy-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (19 mg). [ka]

[0262] [Example 30] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(5-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0263] To a solution of 3-bromo-5-(trifluoromethyl)pyridine (500 mg) in 1,4-dioxane (8 mL), bis(pinacolate)diborone (1.12 g), potassium acetate (651 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (130 mg) were added and the mixture was heated and stirred at 90°C for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. It shrunk. One-third of the obtained crude material was dissolved in 1,4-dioxane (3 mL). 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 3) (100 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg), and 2 mol / L sodium carbonate aqueous solution (0.6 mL) were added to the resulting solution and heated and stirred at 80°C for 1 hour. After the reaction mixture returned to room temperature, trifluoroacetic acid (0.185 mL) was added, insoluble matter was filtered off, and the filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-isopropyl-7-(5-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (58 mg). [ka]

[0264] [Example 31] Synthesis of 2-(5-(((5-cyclopropyl-7-(5-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0265] To a solution of 3-bromo-5-(trifluoromethyl)pyridine (500 mg) in 1,4-dioxane (8 mL), bis(pinacolate)diborone (1.12 g), potassium acetate (651 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (130 mg) were added and the mixture was heated and stirred at 90°C for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. One-third of the resulting crude material was dissolved in 1,4-dioxane (3 mL). To the resulting solution, 2-(5-(((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9) (100 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg), and 2 mol / L aqueous sodium carbonate solution (0.6 mL) were added, and the mixture was heated and stirred at 80°C for 5 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.185 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-cyclopropyl-7-(5-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (33 mg). [ka]

[0266] [Example 32] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(6-methoxy-5-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0267] 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 3) (80 mg) in a 1,4-dioxane (3 mL) solution with (6-methoxy-5-(trifluoromethyl)pyridine-3-yl)boronic acid (73 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12 mg), and 2 mol / L sodium carbonate. A 0.6 mL aqueous solution was added, and the mixture was heated and stirred at 80°C for 2 hours under an argon atmosphere. After the reaction mixture was allowed to return to room temperature, 0.185 mL of trifluoroacetic acid was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting solid was washed with an acetonitrile / water = 2 / 1 solution to obtain 2-(2-fluoro-5-(((5-isopropyl-7-(6-methoxy-5-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (71 mg). [ka]

[0268] [Example 33] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(2-(trifluoromethyl)pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0269] To a solution of 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 3) (80 mg) and (2-(trifluoromethyl)pyridine-4-yl)boronic acid (63 mg) in 1,4-dioxane (3 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12 mg) and 2 mol / L aqueous sodium carbonate solution (0.6 mL) were added, and the mixture was heated and stirred at 80°C for 5 hours under an argon atmosphere. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.185 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-isopropyl-7-(2-(trifluoromethyl)pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl Phenylacetic acid (43 mg) was obtained. [ka]

[0270] [Example 34] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)oxy)methyl)phenyl)acetic acid [ka]

[0271] (Step 1) Synthesis of 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)oxy)methyl)phenyl)acetic acid To a solution of 2-(2-fluoro-5-(hydroxymethyl)phenyl)acetic acid (258 mg) in N,N-dimethylformamide (3 mL), 60% sodium hydride (56 mg) was added under an argon atmosphere, followed immediately by the addition of another 60% sodium hydride (63 mg), and the mixture was stirred at room temperature for 5 minutes. 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 4) (300 mg) was added to the reaction mixture, and the mixture was heated and stirred at 80°C for 3 hours under an argon atmosphere. After the reaction mixture was allowed to return to room temperature, saturated ammonium chloride aqueous solution was added, and the mixture was extracted three times with ethyl acetate. The organic layers were washed sequentially with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was dissolved in a water / acetonitrile 1 / 2 solution, and unwanted materials were removed. The filtrate was then purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)oxy)methyl)phenyl)acetic acid (50 mg).

[0272] (Step 2) 2-(2-fluoro-5-(((5-isopropyl-7-(6-(triflu Synthesis of oromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)oxy)methyl)phenyl)acetic acid To a solution of (6-(trifluoromethyl)pyridine-3-yl)boronic acid (45 mg) in 1,4-dioxane (2 mL), 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)oxy)methyl)phenyl)acetic acid (55 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg), and a 2 mol / L aqueous sodium carbonate solution (0.4 mL) were added, and the mixture was heated and stirred at 80°C for 2 hours under an argon atmosphere. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.123 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-isopropyl-7-(6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)oxy)methyl)phenyl)acetic acid (48 mg). [ka]

[0273] [Example 35] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(6-methyl-5-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0274] To a solution of 5-bromo-2-methyl-3-(trifluoromethyl)pyridine (350 mg) in 1,4-dioxane (5 mL), bis(pinacolate)diborone (741 mg), potassium acetate (429 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (85 mg) were added and the mixture was heated and stirred at 90°C for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. One-third of the resulting crude material was dissolved in 1,4-dioxane (3 mL). To the resulting solution, 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 3) (100 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg), and 2 mol / L aqueous sodium carbonate solution (0.6 mL) were added, and the mixture was heated and stirred at 80°C for 1 hour. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.185 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid), and then recrystallized (water-acetonitrile = 1:1) to obtain 2-(2-fluoro-5-(((5-isopropyl-7-(6-methyl-5-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (14 mg). [ka]

[0275] [Example 36] Synthesis of 2-(5-(((5-cyclopropyl-7-(6-methyl-5-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0276] To a solution of 5-bromo-2-methyl-3-(trifluoromethyl)pyridine (350 mg) in 1,4-dioxane (5 mL), bis(pinacolate)diborone (741 mg), potassium acetate (429 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (85 mg) were added and the mixture was heated and stirred at 90°C for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was evaporated in a rotary evaporator. The mixture was concentrated under reduced pressure. One-third of the resulting crude material was dissolved in 1,4-dioxane (3 mL). To the resulting solution, 2-(5-(((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9) (100 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg), and 2 mol / L aqueous sodium carbonate solution (0.6 mL) were added, and the mixture was heated and stirred at 80°C for 1 hour. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.185 mL) was added, and the insoluble material was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-cyclopropyl-7-(6-methyl-5-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (25 mg). [ka]

[0277] [Example 37] Synthesis of 2-(5-(((5-cyclopropyl-7-(2-methoxy-6-(trifluoromethyl)pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0278] To a solution of 2-(5-(((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9) (80.0 mg) in 1,4-dioxane (3.0 mL), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (75 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12 mg), and 2 mol / L aqueous sodium carbonate solution (0.3 mL) were added, and the mixture was heated and stirred at 80°C for 1 hour under an argon atmosphere. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.092 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. Water-acetonitrile (1 / 2) was added to the resulting residue, and the resulting solid was filtered off. The obtained solid was washed with water-acetonitrile (1 / 2) to obtain 2-(5-(((5-cyclopropyl-7-(2-methoxy-6-(trifluoromethyl)pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (19 mg). [ka]

[0279] [Example 38] 2-(5-(((5-cyclopropyl-7-(6-methoxy-5-(trifluoromethyl Synthesis of pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thiomethyl)-2-fluorophenyl)acetic acid [ka]

[0280] To a solution of (6-methoxy-5-(trifluoromethyl)pyridine-3-yl)boronic acid (91 mg) in 1,4-dioxane (3 mL), 2-(5-(((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9) (100 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg), and a 2 mol / L aqueous sodium carbonate solution (0.55 mL) were added, and the mixture was heated and stirred at 80°C for 2 hours under an argon atmosphere. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.2 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure in a rotary evaporator. Water-acetonitrile (1 / 2) was added to the resulting residue, and the resulting solid was filtered off. The obtained solid was washed with water-acetonitrile (1 / 2), followed by water. The obtained solid was dissolved in methanol, water was added, and the solid precipitated. The obtained solid was filtered off, washed with water, and dried under reduced pressure to obtain 2-(5-(((5-cyclopropyl-7-(6-methoxy-5-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (34 mg). [ka]

[0281] [Example 39] 2-(5-(((5-cyclopropyl-7-(2-(trifluoromethyl)pyridine-4 Synthesis of -yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0282] To a solution of (2-(trifluoromethyl)pyridine-4-yl)boronic acid (79 mg) in 1,4-dioxane (3 mL), 2-(5-(((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9) (100 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg), and 2 mol / L aqueous sodium carbonate solution (0.55 mL) were added, and the mixture was heated and stirred at 80°C for 2 hours under an argon atmosphere. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.2 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-cyclopropyl-7-(2-(trifluoromethyl)pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (71 mg). [ka]

[0283] [Example 40] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(6-methoxy-5-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)oxy)methyl)phenyl)acetic acid [ka]

[0284] To a solution of 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)oxy)methyl)phenyl)acetic acid (50 mg) in 1,4-dioxane (2 mL), (6-methoxy-5-(trifluoromethyl)pyridine-3-yl)boronic acid (47 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8 mg), and 2 mol / L aqueous sodium carbonate solution (0.3 mL) were added, and the mixture was heated and stirred at 80°C for 3 hours under an argon atmosphere. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.103 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-isopropyl-7-(6-methoxy-5-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)oxy)methyl)phenyl)acetic acid (34 mg). [ka]

[0285] [Example 41] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(2-methyl-6-(trifluoromethyl)pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0286] (Step 1) Synthesis of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine Under an argon atmosphere, di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (4 mg), 4,4'-di-tert-butyl-2,2'-dipyridyl (3 mg), and bis(pinacolate)diborone (410 mg) were added to hexane (30 mL) and heated and stirred at 50°C for 10 minutes. Then, 2-methyl-6-(trifluoromethyl)pyridine (400 mg) was added dropwise to the reaction mixture and stirred for a further 3 hours. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (434 mg).

[0287] (Step 2) Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(2-methyl-6-(trifluoromethyl)pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid To a solution of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (118 mg) in 1,4-dioxane (3 mL), 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 3) (100 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg), and a 2 mol / L aqueous sodium carbonate solution (0.55 mL) were added, and the mixture was heated and stirred at 80°C for 2 hours under an argon atmosphere. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.2 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-isopropyl-7-(2-methyl-6-(trifluoromethyl)pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (99 mg). [ka]

[0288] [Example 42] Synthesis of 2-(5-(((5-cyclopropyl-7-(2-methyl-6-(trifluoromethyl)pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0289] To a solution of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (119 mg) in 1,4-dioxane (3 mL), 2-(5-(((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9) (100 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg), and a 2 mol / L aqueous sodium carbonate solution (0.55 mL) were added, and the mixture was heated and stirred at 80°C for 2 hours under an argon atmosphere. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.2 mL) was added, and the insoluble matter was filtered off. The filtered solid was then analyzed for 0.1% The solution was washed with acetonitrile containing trifluoroacetic acid. The resulting filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-cyclopropyl-7-(2-methyl-6-(trifluoromethyl)pyridine-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (62 mg).

[0290] [ka]

[0291] [Example 43] Synthesis of 2-(5-(((6-cyano-1-isopropyl-3-(6-(trifluoromethyl)pyridine-3-yl)-1H-pyrrolo[3,2-b]pyridine-5-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0292] (Step 1) Synthesis of 3-bromo-5-chloro-6-cyano-1H-pyrrolo[3,2-b]pyridine 5-Chloro-6-cyano-1H-pyrrolo[3,2-b]pyridine (11 g) was dissolved in N,N-dimethylformamide (50 mL), to which N-bromosuccinimide (NBS) (11 g) was added and the mixture was stirred overnight at room temperature. After adding water, the resulting solid was filtered and dried to obtain 3-bromo-5-chloro-6-cyano-1H-pyrrolo[3,2-b]pyridine. (14g) was obtained.

[0293] (Step 2) Synthesis of 3-bromo-5-chloro-6-cyano-1-isopropyl-1H-pyrrolo[3,2-b]pyridine 3-Bromo-5-chloro-6-cyano-1H-pyrrolo[3,2-b]pyridine (320 mg) and cesium carbonate (812 mg) were dissolved in N,N-dimethylformamide (5 mL), to which 2-iodopropane (423 mg) was added and the mixture was heated and stirred overnight at 80°C. Water was added to the reaction mixture and extracted three times with ethyl acetate. The organic layers were combined and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain 3-bromo-5-chloro-6-cyano-1-isopropyl-1H-pyrrolo[3,2-b]pyridine (300 mg).

[0294] (Step 3) Synthesis of 3-bromo-6-cyano-1-isopropyl-5-mercapto-1H-pyrrolo[3,2-b]pyridine 250 mg of 3-bromo-5-chloro-6-cyano-1-isopropyl-1H-pyrrolo[3,2-b]pyridine was dissolved in 5 mL of N,N-dimethylformamide, and sodium sulfide (292 mg) was added. The mixture was heated and stirred overnight at 110°C. After adding water to the reaction mixture, the pH was adjusted to 6-7 with 1 mol / L hydrochloric acid. The resulting solid was filtered and dried to obtain 200 mg of 3-bromo-6-cyano-1-isopropyl-5-mercapto-1H-pyrrolo[3,2-b]pyridine.

[0295] (Step 4) Synthesis of 2-(5-(((3-bromo-6-cyano-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl)thio)methyl)-2-fluorophenyl)acetic acid 3-Bromo-6-cyano-1-isopropyl-5-mercapto-1H-pyrrolo[3,2-b]pyridine (150 mg), 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (129 mg), and sodium carbonate (128 mg) were added to N,N-dimethylformamide (3 mL) and stirred overnight at room temperature. After filtering off unwanted substances from the reaction mixture, the resulting filtrate was purified by high-performance liquid chromatography to obtain 2-(5-(((3-bromo-6-cyano-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl)thio)methyl)-2-fluorophenyl)acetic acid (112 mg).

[0296] (Step 5) Synthesis of 2-(5-(((6-cyano-1-isopropyl-3-(6-(trifluoromethyl)pyridine-3-yl)-1H-pyrrolo[3,2-b]pyridine-5-yl)thio)methyl)-2-fluorophenyl)acetic acid To a solution of 2-(5-(((3-bromo-6-cyano-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl)thio)methyl)-2-fluorophenyl)acetic acid (50 mg) and (6-(trifluoromethyl)pyridine-3-yl)borone (31 mg) in 1,4-dioxane (4 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (79 mg) and 2 mol / L aqueous sodium carbonate solution (0.4 mL) were added, and the mixture was heated and stirred at 80°C for 5 hours using a microwave reactor. After the reaction mixture was allowed to return to room temperature, 2 mol / L hydrochloric acid (3 mL) was added, and insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid). The resulting compound was precipitated from a hexane-ethyl acetate mixed solvent, and the solid was collected by filtration to obtain 2-(5-(((6-cyano-1-isopropyl-3-(6-(trifluoromethyl)pyridine-3-yl)-1H-pyrrolo[3,2-b]pyridine-5-yl)thio)methyl)-2-fluorophenyl)acetic acid (14 mg). [ka]

[0297] [Example 44] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(2-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid [ka]

[0298] To a solution of 3-bromo-2-methyl-6-(trifluoromethyl)pyridine (200 mg) in 1,4-dioxane (4 mL), bis(pinacolate)diborone (423 mg), potassium acetate (245 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (49 mg) were added and the mixture was heated and stirred at 90°C for 3 hours. Water was added to the reaction mixture, and the insoluble matter was filtered off and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was rotary filtered. - The mixture was concentrated under reduced pressure using an evaporator. Half of the resulting crude material was dissolved in 1,4-dioxane (3 mL). 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 3) (100 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg), and 2 mol / L aqueous sodium carbonate solution (0.6 mL) were added to the solution, and the mixture was heated and stirred at 80°C for 4 hours. After the reaction mixture returned to room temperature, trifluoroacetic acid (0.2 mL) was added, and insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-isopropyl-7-(2-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid (68 mg). [ka]

[0299] [Example 45] Synthesis of 2-(5-(((5-cyclopropyl-7-(2-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0300] To a solution of 3-bromo-2-methyl-6-(trifluoromethyl)pyridine (200 mg) in 1,4-dioxane (4 mL), bis(pinacolate)diborone (423 mg), potassium acetate (245 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (49 mg) were added and the mixture was heated and stirred at 90°C for 3 hours. Water was added to the reaction mixture, and the insoluble matter was filtered off and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Half of the resulting crude material was dissolved in 1,4-dioxane (3 mL). To the resulting solution, 2-(5-(((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9) (100 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg), and 2 mol / L aqueous sodium carbonate solution (0.6 mL) were added, and the mixture was heated and stirred at 80°C for 4 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.2 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-cyclopropyl-7-(2-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (47 mg). [ka]

[0301] [Example 46] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(4-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid [ka]

[0302] 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (50 mg) was dissolved in 1,4-dioxane (2 mL). To the resulting solution, 2-(2-fluoro-5-(((7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 3) (70 mg), [1,1'-bis(diphenylphosphin)f [Erocene]dichloropalladium(II) (11 mg) and 2 mol / L aqueous sodium carbonate solution (0.45 mL) were added and the mixture was heated and stirred at 80°C for 4 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.14 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-isopropyl-7-(4-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid (69 mg). [ka]

[0303] [Example 47] Synthesis of 2-(5-(((5-cyclopropyl-7-(4-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0304] 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (50 mg) was dissolved in 1,4-dioxane (2 mL). To the resulting solution, 2-(5-(((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9) (70 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg), and 2 mol / L aqueous sodium carbonate solution (0.45 mL) were added, and the mixture was heated and stirred at 80°C for 4 hours. The reaction mixture was allowed to return to room temperature. Afterward, trifluoroacetic acid (0.14 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-cyclopropyl-7-(4-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (40 mg). [ka]

[0305] [Example 48] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(2-methoxy-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid [ka]

[0306] To a solution of 3-bromo-2-methoxy-6-(trifluoromethyl)pyridine (220 mg) in 1,4-dioxane (4.5 mL), bis(pinacolate)diborone (436 mg), potassium acetate (253 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg) were added and the mixture was heated and stirred at 90°C for 3 hours. Water was added to the reaction mixture, and the insoluble matter was filtered off and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Half of the resulting crude material was dissolved in 1,4-dioxane (2 mL). 2-(2-fluoro-5-(((7-io Do-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (intermediate 3) (70 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg), and 2 mol / L aqueous sodium carbonate solution (0.5 mL) were added, and the mixture was heated and stirred at 80°C for 4 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.14 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-fluoro-5-(((5-isopropyl-7-(2-methoxy-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenylacetic acid (43 mg). [ka]

[0307] [Example 49] Synthesis of 2-(5-(((5-cyclopropyl-7-(2-methoxy-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0308] To a solution of 3-bromo-2-methoxy-6-(trifluoromethyl)pyridine (220 mg) in 1,4-dioxane (4.5 mL), bis(pinacolate)diborone (436 mg), potassium acetate (253 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg) were added and the mixture was heated and stirred at 90°C for 3 hours. Water was added to the reaction mixture, and the insoluble matter was filtered off and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Half of the resulting crude material was dissolved in 1,4-dioxane (2 mL). To the resulting solution, 2-(5-(((5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (intermediate 9) (70 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg), and 2 mol / L aqueous sodium carbonate solution (0.5 mL) were added, and the mixture was heated and stirred at 80°C for 2 hours. After the reaction mixture was allowed to return to room temperature, trifluoroacetic acid (0.14 mL) was added, and the insoluble matter was filtered off. The filtered solid was washed with acetonitrile containing 0.1% trifluoroacetic acid. The obtained filtrate and washing solution were combined and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((5-cyclopropyl-7-(2-methoxy-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (24 mg). [ka]

[0309] [Example 50] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(4-methyl-2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka] 2-(2-fluoro-5-(((5-isopropyl-7-(4-methyl-2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid was synthesized in the same manner as in Example 3.

[0310] [Example 51] Synthesis of 2-(5-(((5-cyclopropyl-7-(4-methyl-2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka] 2-(5-(((5-cyclopropyl-7-(4-methyl-2-(trifluoromethyl)pyrimidine-5-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid was synthesized in the same manner as in Example 4.

[0311] [Example 52] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(6-(trifluoromethyl)pyridazin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka] 2-(2-fluoro-5-(((5-isopropyl-7-(6-(trifluoromethyl)pyridazin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid was synthesized in the same manner as in Example 3.

[0312] [Example 53] Synthesis of 2-(5-(((5-cyclopropyl-7-(6-(trifluoromethyl)pyridazin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka] 2-(5-(((5-cyclopropyl-7-(6-(trifluoromethyl)pyridazin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid was synthesized in the same manner as in Example 4.

[0313] [Example 54] Synthesis of 2-(5-(((5-ethyl-7-(4-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka] 2-(5-(((5-ethyl-7-(4-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid was synthesized in the same manner as in Example 2.

[0314] [Example 55] Synthesis of 2-(2-fluoro-5-(((5-methyl-7-(4-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka] 2-(2-fluoro-5-(((5-methyl-7-(4-methyl-6-(trifluoromethyl)pyridine-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid was synthesized in the same manner as in Example 1.

[0315] [ACMSD inhibitory activity] The ACMSD inhibitory activity of the compounds in Examples 1 to 55 was measured.

[0316] (1) Preparation of the test substance solution, ACMSD solution, HAO solution, and 3-HAA solution The test substance solutions were prepared to contain compounds from Examples 1 to 55 (also called test substances) at various concentrations, 0.8% dimethyl sulfoxide (DMSO), 0.0125% bovine serum albumin (Nacalai Tesque, 01863-77), and 50 mM 2-morpholinoethanesulfonic acid monohydrate (MES, Dojin Chemical Laboratories, GB12) (pH 6.0).

[0317] The ACMSD solution was prepared to contain 12 μg / mL human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) (Pharmaron Beijing), 0.0125% bovine serum albumin, and 50 mM MES (pH 6.0).

[0318] The HAO solution was prepared to contain 120 nM human 3-hydroxyanthranilic acid 3,4-dioxygenase (HAO) (Pharmaron Beijing), 0.0125% bovine serum albumin, and 50 mM MES (pH 6.0).

[0319] The 3-HAA solution was prepared to contain 200 μM 3-hydroxyanthranilic acid (3-HAA) (Sigma-Aldrich, 148776), 2.67 mM ammonium iron(II) sulfate (Nacalai Tesque, 19431-35), 0.0125% bovine serum albumin, and 50 mM MES (pH 6.0).

[0320] (2) Measurement of ACMSD enzyme activity The enzyme activity of ACMSD was measured by the decrease in absorbance at 355 nm of α-amino-β-carboxymuconate-ε-semialdehyde (ACMS), the substrate of ACMSD.

[0321] In a 384-well clear polystyrene plate (Corning, 3702), 12.5 μL / well of ACMSD solution and 12.5 μL / well of the test substance solution were added, and pre-incubation was performed at room temperature for 30 minutes. After mixing equal volumes of HAO solution and 3-HAA solution, ACMS was generated by incubation at room temperature for 10 minutes, and this was used as the substrate solution. After pre-incubation, 25 μL / well of the substrate solution was added, and the absorbance at 355 nm in each well was measured every 2 minutes for 10 minutes using an EnVision2105 multimode plate reader (PerkinElmer) at 28°C.

[0322] (3) Calculation of ACMSD inhibitory activity The inhibitory activity of the test substance against ACMSD was calculated using the absorbance at 355 nm 10 minutes after the start of measurement. The absorbance of the well containing DMSO but no ACMSD or test substance was set as 100% inhibition, and the absorbance of the well containing both ACMSD and DMSO but no test substance was set as 0% inhibition. The inhibition rate (%) of the wells containing the test substance at various concentrations was then calculated. 50 The concentration of the test substance that showed a 50% inhibition rate was calculated using XLfit (IDBS) and evaluated according to the following criteria.

[0323] A:IC 50 <0.010 μM B: 0.010 μM ≤ IC 50 < 0.030 μM C: 0.030 μM ≤ IC 50 < 0.10 μM

[0324] The compounds prepared in Examples 1 to 55, along with their MS, UPLC retention times, and ACMSD inhibitory activity results, are shown in Tables 2-1 to 2-11 below.

[0325] [Table 2-1]

[0326] [Table 2-2]

[0327] Table 2-3

[0328] Table 2-4

[0329] Table 2-5

[0330] Table 2-6

[0331] Table 2-7

[0332] Table 2-8

[0333] Table 2-9

[0334] Table 2-10 Table 2-11

[0335] The results in Tables 2-1 to 2-11 show that the compounds in Examples 1 to 55 exhibit ACMSD inhibitory activity. [Industrial applicability]

[0336] The compounds according to the present invention have ACMSD inhibitory activity and are therefore usable for the prevention and / or treatment of diseases involving ACMSD (e.g., hereditary mitochondrial disorders, metabolic disorders, neurodegenerative disorders, renal disorders, chronic inflammatory diseases, age-related disorders, and cisplatin-induced ototoxicity and diisocyanate-induced asthma).

Claims

1. The following general formula (I): 【Chemistry 1】 [In the above general formula (I), R １ C may be substituted with a fluorine atom, cyano, or hydroxyl atom. １～６ C may be substituted with an alkyl, fluorine, cyano, or hydroxyl atom. ３～６ It is a cycloalkyl or cyclic ether with a 4-6 membered ring. R ２ ~R １０ These are, independently, a hydrogen atom, a halogen atom, or hydroxyl, halogen atom, cyano, nitro, and C. １～５ C may be substituted with at least one substituent selected from the group consisting of alkoxys. １～６ C may be substituted with at least one substituent selected from the group consisting of alkyl, hydroxyl, halogen, cyano, and nitro atoms. １～６ It is an alkoxy, W is a sulfur atom or an oxygen atom. A is represented by the following formulas (A-1) to (A-5): 【Chemistry 2】 (In the above formulas (A-1) to (A-5), R １１ to R ２３ each independently represents a hydrogen atom, a halogen atom, or a C optionally substituted with at least one substituent selected from the group consisting of hydroxy, halogen atom, cyano, nitro, and C １～５ alkyl optionally substituted with at least one substituent selected from the group consisting of alkoxy, or a C optionally substituted with at least one substituent selected from the group consisting of hydroxy, halogen atom, cyano, and nitro １～６ is alkoxy, １～６ ​ (* indicates the site of attachment to ring B.) It is one of the following: Y is CH or N, Z is either N or C (C ≡ N). A compound represented by or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is a sulfur atom.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is an oxygen atom.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is CH.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is N.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is N.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is C (C≡N).

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is formula (A-1).

9. R １３ The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein H is present.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is formula (A-2).

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is formula (A-3).

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is formula (A-4).

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is formula (A-5).

14. W is a sulfur atom, The compound according to claim 1, wherein Z is N, or a pharmaceutically acceptable salt thereof.

15. W is a sulfur atom, The compound according to claim 1, wherein Y is CH, or a pharmaceutically acceptable salt thereof.

16. W is a sulfur atom, A compound according to claim 1, wherein A is formula (A-1), or a pharmaceutically acceptable salt thereof.

17. W is a sulfur atom, Y is CH, The compound according to claim 1, wherein Z is N, or a pharmaceutically acceptable salt thereof.

18. W is a sulfur atom, A is equation (A-1), The compound according to claim 1, wherein Z is N, or a pharmaceutically acceptable salt thereof.

19. W is a sulfur atom, A is equation (A-1), The compound according to claim 1, wherein Y is CH, or a pharmaceutically acceptable salt thereof.

20. W is a sulfur atom, A is equation (A-1), Y is CH, The compound according to claim 1, wherein Z is N, or a pharmaceutically acceptable salt thereof.

21. R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a fluorine atom or a chlorine atom.

22. R １ However, C may be substituted with a fluorine atom. １～３ The compound according to claim 1, which is alkyl or cyclopropyl, or a pharmaceutically acceptable salt thereof.

23. R ２ and R ３ However, it is a hydrogen atom or a halogen atom, R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the atom is a hydrogen atom, a fluorine atom, or a chlorine atom.

24. R １ However, C may be substituted with a fluorine atom. １～３ Alkyl or cyclopropyl, R ２ and R ３ However, it is a hydrogen atom or a halogen atom, R ４ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the atom is a hydrogen atom, a fluorine atom, or a chlorine atom.

25. R １ However, C may be substituted with a fluorine atom. １～３ Alkyl or cyclopropyl, R ２ and R ３ However, it is a hydrogen atom, R ４ However, it is a hydrogen atom, a fluorine atom, or a chlorine atom, A is given by equation (A-1), and R １１ ~R １３ The compound according to claim 1, wherein the atom is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

26. R ３ , R ５ , R ６ , R ７ , R ８ , R ９ , and R １０ The compound according to claim 1, wherein the atom is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

27. The following formula: 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

28. The following formula: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

29. A pharmaceutical composition containing a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.

30. An ACMSD inhibitor comprising a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.

31. An agent for the prevention or treatment of diseases involving ACMSD, comprising a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.

32. The preventive or therapeutic agent according to claim 31, wherein the disease in which the ACMSD is involved is a hereditary mitochondrial disease, a metabolic disease, a neurodegenerative disease, a renal disease, a chronic inflammatory disease, or an age-related disease.

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