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] Specifically, the following compounds are shown as examples. TIFF2026113758000126.tif72127

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 A cyclic ether of a 4- to 6-membered ring, which may be substituted with a cycloalkyl, fluorine atom, cyano, or hydroxyl atom, R2 ~R 10 is each independently 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, 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 A is the following formula (A-1) or (A-2): A is the following formula (A-1) or (A-2):

Chemical formula

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

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

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

[13] 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.

[14] 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.

[15] 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.

[16] 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.

[17] R 1 However, C 1~3 A compound described in any of the above [1] to

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

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

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

[19] R 13 ~R 16 and R 19 ~R 20 At least one of them is a fluorine atom, methyl, trifluoromethyl, or R 13 and R 14 , R 15 and R 16 , and R 19 and R 20 At least one combination selected from the group consisting of hydroxy, halogen, cyano, nitro, and C forms a single unit. 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 3~10 A compound described in any of [1] to

[18] above, which forms a cycloalkyl group, or a pharmaceutically acceptable salt thereof.

[20] R 15 and R 16 A compound or a pharmaceutically acceptable salt thereof described in any of the above [1] to

[19] , wherein the compound is a fluorine atom.

[21] R 13 ~R 14 and R 19 ~R 20 At least one of them is a fluorine atom, methyl, trifluoromethyl, or R 13 and R 14 R 19 and R 20 At least one combination selected from the group consisting of hydroxy, halogen, cyano, nitro, and C forms a single unit. 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 3~10 A compound described in

[20] above, or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl group.

[22] R 1 However, C 1~3 Alkyl or cyclopropyl, R 2 However, it is a hydrogen atom or a fluorine atom, R 4 However, it is a fluorine atom or a chlorine atom, R 15 and R 16 A compound or a pharmaceutically acceptable salt thereof described in any of the above [1] to

[16] , wherein the compound is a fluorine atom.

[23] R 13 ~R 14 and R 19 ~R 20 At least one of them is a fluorine atom, methyl, trifluoromethyl, or R 13 and R 14 R 19 and R 20 At least one combination selected from the group consisting of hydroxy, halogen, cyano, nitro, and C forms a single unit. 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 3~10The compound described in the above

[22] that forms a cycloalkyl or a pharmaceutically acceptable salt thereof.

[24] W is a sulfur atom, A is of formula (A-1), Y is CH, Z is N, R 1 is C 1~3 alkyl or cyclopropyl, R 2 is a hydrogen atom or a fluorine atom, R 4 is a fluorine atom or a chlorine atom, R 15 and R 16 are fluorine atoms, the compound described in the above [1] or a pharmaceutically acceptable salt thereof.

[25] R 13 ~ R 14 and R 19 ~ R 20 At least one of them is a fluorine atom, methyl, trifluoromethyl, or R 13 and R 14 as well as R 19 and R 20 At least one combination selected from the group consisting of is integrally substituted with at least one substituent selected from the group consisting of hydroxy, a halogen atom, cyano, nitro, and C 1~5 alkoxy and may be a cycloalkyl formed by C 3~10 The compound described in the above

[24] that forms a cycloalkyl or a pharmaceutically acceptable salt thereof.

[26] R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 17 and R 18 are hydrogen atoms, the compound described in the above [1] or a pharmaceutically acceptable salt thereof.

[27] The following formula:

Chemical formula

[28] The following formula: [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. [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" means α-amino-β-carboxymuconate 6-semialdehyde decarboxylase (ACMS decarboxylase). ACMSD converts α-amino-β-carboxymuconate 6-semialdehyde (ACMS), which has been 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., into the glutarate pathway, and decomposed 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). 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 1C 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 cyclic ether of a 4- to 6-membered ring, which may be substituted with a cycloalkyl, fluorine, cyano, or hydroxyl atom.

[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 isobutyl. C substituted with a fluorine atom, cyano, or hydroxyl atom 1~6 Alkyl 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 atom3~6 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. Cyclic ethers of 4- to 6-membered rings substituted with a fluorine atom, cyano, or hydroxyl include 2-fluorooxetan-2-yl, 3-fluorooxetan-2-yl, 2,3-difluorooxetan-2-yl, 2-fluorotetrahydrofuran-2-yl, 3-fluorotetrahydrofuran-2-yl, 2,3-difluorotetrahydrofuran-2-yl, 2-cyanooxetan-2-yl, 3-cyanooxetan-2-yl, and 2,3-dicyanooxetan-2-yl. This includes tan-2-yl, 2-cyanotetrahydrofuran-2-yl, 3-cyanotetrahydrofuran-2-yl, 2,3-dicyanotetrahydrofuran-2-yl, 2-hydroxyoxetan-2-yl, 3-hydroxyoxetan-2-yl, 2,3-dihydroxyoxetan-2-yl, 2-hydroxytetrahydrofuran-2-yl, 3-hydroxytetrahydrofuran-2-yl, 2,3-dihydroxytetrahydrofuran-2-yl, etc.

[0022] In one embodiment, R1 Even if substituted with a fluorine atom, C 1~3 It is preferably alkyl or cyclopropyl, C 1~3 It is more preferably alkyl or cyclopropyl, and even more preferably methyl, ethyl, propyl, isopropyl, 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 cyclic ether of a 4- to 5-membered ring which may be substituted with a cycloalkyl, fluorine atom, cyano, or hydroxyl atom, 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, even more preferably methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, or cyclobutyl, and particularly preferably methyl, ethyl, propyl, isopropyl, difluoromethyl, cyclopropyl, or cyclobutyl. In another embodiment, R 1 C may be substituted with a fluorine atom, cyano, or hydroxyl atom. 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 10These 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.

[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. 1~6 The 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.

[0027] R 2 ~R 4 Each of these atoms is preferably a hydrogen atom and a halogen atom, more preferably a hydrogen atom, a fluorine atom, and a chlorine atom, and even more preferably a hydrogen atom and a fluorine atom.

[0028] In one embodiment, R 4However, it 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] In another 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.

[0030] Furthermore, in another embodiment, R 2 However, it is a hydrogen atom or a fluorine atom, R 4 However, it is preferable that it be a fluorine atom or a chlorine atom, R 2 However, it is a hydrogen atom, R 4 However, it is more preferably a fluorine atom or a chlorine atom, R 2 However, it is a hydrogen atom, R 4 However, it is particularly preferable that it be a fluorine atom.

[0031] R 5 ~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. 1~4It 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.

[0032] 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.

[0033] A is given by either (A-1) or (A-2) below. [ka]

[0034] Q 1 This refers to a single bond, an oxygen atom, or a CR. 19 R 20 That is the case. Also, Q 1 If the bond is a single bond, the ring structure of equation (A-1) will be a five-membered ring.

[0035] In one embodiment, Q 1 It is preferable that the bond is a single bond. In another embodiment, Q 1 It is preferable that it is an oxygen atom. In another embodiment, Q 1 CR 19 R 20 It is preferable that this be the case.

[0036] Q 2 This refers to a single bond, an oxygen atom, or a CR. 19 R 20 That is the case. Also, Q 2 If it is a single bond, the ring structure of equation (A-2) will be a 5-membered ring. Also, Q 3 is an oxygen atom, or CR 13 R 14 That is the case. Furthermore, Q 4 is an oxygen atom, or CR 11 R 12 That is the case.

[0037] In one embodiment, Q 2 It is preferable that the bond is a single bond. In another embodiment, Q 2 It is preferable that it is an oxygen atom. In another embodiment, Q 2 CR 19 R 20 It is preferable that this be the case.

[0038] In one embodiment, Q 3 It is preferable that it is an oxygen atom. In another embodiment, Q 3 CR 13 R 14 It is preferable that this be the case.

[0039] In one embodiment, Q 4 It is preferable that it is an oxygen atom. In another embodiment, Q 4 CR 11 R 12 It is preferable that this be the case.

[0040] In one embodiment, Q 2 It is a single bond, Q 3 CR 13 R 14 Q 4 CR 11 R 12 It is preferable that this be the case. In another embodiment, Q 2 It is a single bond, Q 3 Q is an oxygen atom. 4 CR 11 R 12 It is preferable that this be the case. In another embodiment, Q 2 It is a single bond, Q 3 CR 13 R 14 Q 4 It is preferable that it is an oxygen atom. In another embodiment, Q 2 Q is an oxygen atom. 3 CR 13 R 14 Q 4 CR 11 R 12 It is preferable that this be the case. In another embodiment, Q 2 CR 19 R 20 Q 3 CR 13 R 14 Q 4 CR 11 R 12 It is preferable that this be the case. In another embodiment, Q 2 CR 19 R 20 Q 3 Q is an oxygen atom. 4 CR 11 R 12 It is preferable that this be the case. In another embodiment, Q 2 CR 19 R 20 Q 3 CR 13 R 14Q 4 It is preferable that it is an oxygen atom.

[0041] In one embodiment, it is preferable that A is formula (A-1). In another embodiment, it is preferable that A is given by formula (A-2).

[0042] R 11 ~R 20 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.

[0043] In this case, R 11 ~R 20 Two of these groups combine to form hydroxyl, halogen, cyano, nitro, and C 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 3~10 A cycloalkyl group may be formed. In one embodiment, R 11 ~R 20 Two adjacent C groups may be substituted together with the above substituent. 3~10 A cycloalkyl condensed ring may be formed. In another embodiment, R 11 ~R 20 In some cases, two groups bonded to the same carbon atom may be substituted together with the above substituents. 3~10 A cycloalkyl spiro ring may be formed. For example, in formula (A-1), adjacent R 13 and R 19 When these combine to form fluorocyclobutane, they form a fused ring represented by the following formula (cy-1) or formula (cy-2). Also, in formula (A-1), R bonded to the same carbon atom 13 and R14 When these combine to form cyclopropane, they form a spiro ring represented by the following formula (cy-3). Of these, R 11 ~R 20 In some cases, two groups bonded to the same carbon atom may be substituted together with the above substituents. 3~10 It is preferable to form a cycloalkyl spiro ring. [ka]

[0044] Halogen atoms, as well as hydroxy, 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].

[0045] Note that "*" indicates the bonding site with the B ring.

[0046] In one embodiment, equation (A-1) can be any of the following equations (R-1) to (R-3). [ka]

[0047] In one embodiment, equation (A-2) can be any of the following equations (R-4) to (R-10). [ka]

[0048] In the above formula, R 13 ~R 16 , R 19 ~R 20Each of these may independently be substituted with a hydrogen atom, a halogen atom, or a halogen atom. 1~6 C may be substituted with alkyl or halogen atoms. 1~6 It is an alkoxy, preferably a hydrogen atom, a fluorine atom, or a C atom which may be substituted with a fluorine atom. 1~3 C may be substituted with alkyl or halogen atoms. 1~3 It is an alkoxy, more preferably a hydrogen atom, a halogen atom, methyl, trifluoromethyl, or methoxy, and even more preferably a hydrogen atom or a halogen atom.

[0049] In this case, R 13 ~R 16 and R 19 ~R 20 Two of the groups may be substituted together with a halogen atom. 3~10 A cycloalkyl group may be formed. The C may be substituted with the halogen atom. 3~10 Examples of cycloalkyl groups include cyclopropyl, fluorocyclopropyl, difluorocyclopropyl, cyclobutyl, fluorocyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In this case, the halogen atom of the substituent is the formed C 3~10 Substitute a hydrogen atom with a cycloalkyl group.

[0050] Also, "*" indicates the bonding site with the B ring.

[0051] In one embodiment, R 13 ~R 16 and R 19 ~R 20 At least one of them is a fluorine atom, methyl, trifluoromethyl, or R 13 and R 14 , R 15 and R 16 , and R 19 and R 20 At least one combination selected from the group consisting of hydroxy, halogen, cyano, nitro, and C forms a single unit. 1~5C may be substituted with at least one substituent selected from the group consisting of alkoxys. 3~10 It is preferable to form a cycloalkyl group. In another embodiment, R 15 and R 16 However, it is preferable that it be a fluorine atom. In this case, R 13 ~R 14 and R 19 ~R 20 At least one of them is a fluorine atom, methyl, trifluoromethyl, or R 13 and R 14 R 19 and R 20 At least one combination selected from the group consisting of hydroxy, halogen, cyano, nitro, and C forms a single unit. 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 3~10 It is more preferable to form a cycloalkyl group.

[0052] In one preferred embodiment, R 13 and R 14 And / or R 15 and R 16 It is preferable that R is a fluorine atom or a methyl atom, 13 and R 14 And / or R 15 and R 16 It is more preferable that R is a fluorine atom. 13 ~R 16 It is even more preferable that it be a fluorine atom.

[0053] In one embodiment, formula (A-1) or formula (A-2) is preferably one of the following formulas (R-1-1) to (R-10-19). Note that "*" indicates a binding site with the B ring.

[0054] [ka] [ka]

Chem.

Chem.

[0055] Among the above, A is preferably any one of formula (R-1-1), formula (R-1-3), formula (R-1-4), formula (R-1-7), formula (R-1-10), formula (R-1-17), formula (R-2-4), formula (R-3-3), formula (R-3-4), formula (R-3-5), formula (R-4-4), formula (R-6-3), formula (R-8-3), formula (R-9-4), formula (R-10-4), more preferably any one of formula (R-1-4), formula (R-1-7), formula (R-2-4), formula (R-3-4), formula (R-4-4), formula (R-6-3), and even more preferably any one of formula (R-1-4), formula (R-2-4), formula (R-3-4), formula (R-4-4), formula (R-6-3).

[0056] Y is CH or N.

[0057] In one embodiment, Y is preferably CH. In another embodiment, Y is preferably N.

[0058] Z is C(C≡N) or N.

[0059] In one embodiment, Z is preferably N. In another embodiment, Z is preferably C(C≡N).

[0060] In a preferred embodiment, it is preferable that W is a sulfur atom and Z is N. In another preferred embodiment, it is preferable that W is a sulfur atom and Y is CH. In another preferred embodiment, it is preferable that W is 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.

[0061] In one preferred embodiment, R 1 However, C 1~3 Alkyl or cyclopropyl, R 2 However, it is a hydrogen atom or a fluorine atom, R 4 However, it is a fluorine atom or a chlorine atom, R 15 and R 16 However, it is preferable that it be a fluorine atom. In this case, R 13 ~R 14 and R 19 ~R 20 At least one of them is a fluorine atom, methyl, trifluoromethyl, or R 13 and R 14 R 19 and R 20 At least one combination selected from the group consisting of hydroxy, halogen, cyano, nitro, and C forms a single unit. 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 3~10 It is more preferable to form a cycloalkyl group.

[0062] In another preferred embodiment, W is a sulfur atom, A is formula (A-1), Y is CH, Z is N, and R 1 However, C 1~3 Alkyl or cyclopropyl, R 2 However, it is a hydrogen atom or a fluorine atom, R 4 However, it is a fluorine atom or a chlorine atom, R 15 and R16 However, it is preferable that it be a fluorine atom. In this case, R 13 ~R 14 and R 19 ~R 20 At least one of them is a fluorine atom, methyl, trifluoromethyl, or R 13 and R 14 R 19 and R 20 At least one combination selected from the group consisting of hydroxy, halogen, cyano, nitro, and C forms a single unit. 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 3~10 It is more preferable to form a cycloalkyl group.

[0063] In another preferred embodiment, R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 17 and R 18 It is preferable that it is a hydrogen atom.

[0064] 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]

[0065] 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. 3~6A cyclic ether of a 4- to 6-membered ring which may be substituted with a cycloalkyl, fluorine atom, cyano, or hydroxyl atom, preferably C which 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 The cyclic ethers are cycloalkyl, 4- to 5-membered ring cyclic ethers, 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, even more preferably methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, and particularly preferably methyl, ethyl, propyl, isopropyl, difluoromethyl, cyclopropyl, cyclobutyl.

[0066] R 2 and 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. 1~6 C may be substituted with alkyl, hydroxy, or halogen atoms. 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 and a halogen atom; even more preferably a hydrogen atom, a fluorine atom, or a chlorine atom; and particularly preferably a hydrogen atom and a fluorine atom.

[0067] In one embodiment, R 2 is a hydrogen atom or a halogen atom, and it is preferable that R 4 is a fluorine atom, a chlorine atom, or a bromine atom. R 2 is a hydrogen atom or a halogen atom, and it is more preferable that R 4 is a hydrogen atom, a fluorine atom, or a chlorine atom. R 2 is a hydrogen atom or a halogen atom, and it is even more preferable that R 4 is a fluorine atom or a chlorine atom. It is particularly preferable that R 2 is a hydrogen atom and R 4 is a fluorine atom.

[0068] A is represented by the following formula (A-3) or (A-4).

Chemical formula

[0069] In the above formulas (A-3) to (A-4), Q 1 is a single bond, an oxygen atom, or CR 19 R 20 is. Q 2 [[ID=z43]]is a single bond, an oxygen atom, or CR 19 R 20 is. Q 3 is an oxygen atom, or CR 13 R 14 is. Q 4 is an oxygen atom, or CH2.

[0070] In one embodiment, Q 2 is a single bond, Q 3 is CR 13 R 14 is, and it is preferable that Q 4 is CH2. In another embodiment, Q 2 is a single bond, Q 3 is an oxygen atom, and Q 4It is preferable that it be CH2. In another embodiment, Q 2 It is a single bond, Q 3 CR 13 R 14 Q 4 It is preferable that it is an oxygen atom. In another embodiment, Q 2 Q is an oxygen atom. 3 CR 13 R 14 Q 4 It is preferable that it be CH2. In another embodiment, Q 2 CR 19 R 20 Q 3 CR 13 R 14 Q 4 It is preferable that it be CH2. In another embodiment, Q 2 CR 19 R 20 Q 3 Q is an oxygen atom. 4 It is preferable that it be CH2. In another embodiment, Q 2 CR 19 R 20 Q 3 CR 13 R 14 Q 4 It is preferable that it is an oxygen atom.

[0071] R 13 ~R 16 and R 19 ~R 20 Each of these C atoms may be independently substituted with at least one substituent selected from the group consisting of a hydrogen atom, a halogen atom, or hydroxyl and halogen atoms. 1~6 C may be substituted with at least one substituent selected from the group consisting of alkyl, hydroxyl, and halogen atoms. 1~6 It is an alkoxy, and in this case, R 13 ~R 16 and R19 ~R 20 Two of these groups combine to form hydroxyl and halogen atoms, cyano, nitro, and C 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 3~10 They may form a cycloalkyl group.

[0072] In one embodiment, R 13 ~R 16 and R 19 ~R 20 At least one of them is a fluorine atom, methyl, trifluoromethyl, or R 13 and R 14 , R 15 and R 16 , and R 19 and R 20 At least one combination selected from the group consisting of hydroxy, halogen, cyano, nitro, and C forms a single unit. 1~5 C may be substituted with at least one substituent selected from the group consisting of alkoxys. 3~10 It is preferable to form a cycloalkyl group.

[0073] R 13 ~R 16 Preferably, each of these is independently a hydrogen atom, a fluorine atom, a methyl atom, and a trifluoromethyl atom. In one embodiment, R 13 and R 14 And / or R 15 and R 16 It is preferable that R is a fluorine atom or a methyl atom, 13 and R 14 And / or R 15 and R 16 It is more preferable that R is a fluorine atom. 13 ~R 16 It is even more preferable that it be a fluorine atom.

[0074] R 19 ~R 20 These are, independently, a hydrogen atom, a fluorine atom, a methyl atom, a trifluoromethyl atom, or R19 and R 20 It is preferable that these elements combine to form a cyclopropyl group.

[0075] Note that "*" indicates the bonding site with the B ring.

[0076] W is a sulfur atom or an oxygen atom, preferably a sulfur atom.

[0077] Y is either CH or N, preferably CH.

[0078] Z is either N or C (C≡N), and is preferably N.

[0079] In a more preferred embodiment, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof is preferably a compound represented by general formulas (III-1) to (III-10) below or a pharmaceutically acceptable salt thereof. [ka] [ka]

[0080] In the above general formulas (III-1) to (III-10), R 1These 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, and tetrahydrofuranyl, preferably methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentanyl, 3-fluorobicyclo[1.1.1]pentan-1-yl, and more preferably methyl, ethyl, propyl, isopropyl, difluoromethyl, cyclopropyl, and cyclobutyl.

[0081] 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.

[0082] R 4 The atoms are hydrogen atoms, halogen atoms, preferably hydrogen atoms, fluorine atoms, chlorine atoms, and bromine atoms, more preferably fluorine atoms and chlorine atoms, and even more preferably fluorine atoms.

[0083] R 13 ~R 16 and R 19 ~R 20 Each of these may independently be substituted with a hydrogen atom, a halogen atom, or a halogen atom. 1~3 C may be substituted with alkyl or halogen atoms. 1~3 It is an alkoxy, and in this case, R 19 and R 20 C may be substituted with halogen atoms as a whole. 3~6 They may form a cycloalkyl group. In one embodiment, R13 and R 14 is a fluorine atom, R 15 and R 16 R is preferably a hydrogen atom, a fluorine atom, a methyl atom, or a trifluoromethyl atom. 13 and R 14 is a fluorine atom, R 15 and R 16 R is more preferably a fluorine atom or a methyl atom. 13 ~R 16 It is even more preferable that it be a fluorine atom. In one embodiment, R 19 and R 20 R is preferably a hydrogen atom, methyl, trifluoromethyl, methoxy, or a combination that forms a cyclopropyl group. 19 and R 20 It is more preferable that it is a hydrogen atom, or that it forms a cyclopropyl group together with it.

[0084] Z is C (C≡N) or N, preferably N.

[0085] 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]

[0086] Of the above, the compound represented by general formula (I) or its pharmaceutically acceptable salt is more preferably a compound selected from the group consisting of the following formulas or its pharmaceutically acceptable salt. [ka] [ka]

[0087] 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 the racemic intermediate or final product according to conventional methods. In this specification, "dl" or "(±)" means a racemic mixture (i.e., a chiral compound that does not exhibit optical activity). Also, "(+)" or "d" means a chiral compound that exhibits dextrorotatory activity (rotates plane-polarized light to the right), and "(-)" or "l" means a chiral compound that exhibits levorotatory activity (rotates plane-polarized light to the left). In this specification, if a given compound is a chiral compound, it means a racemic mixture unless otherwise specified. Furthermore, compounds represented by general formula (I) (nitrogen-containing heterocyclic derivatives) may also include stable isotopes and radioactive isotopes.

[0088] 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.

[0089] 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.

[0090] Compounds represented by general formula (I) or their pharmaceutically acceptable salts may also include their solvates, such as hydrates and alcohol adducts.

[0091] 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.

[0092] Examples of methods for synthesizing compounds represented by general formula (I) include reacting intermediate X represented by the following formula with compound A, and reacting intermediate Y represented by the following formula with compound B.

[0093] [ka]

[0094] 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.

[0095] 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.

[0096] Examples of reaction solvents for the reaction between intermediate X and compound A include N,N-dimethylformamide (DMF) and tetrahydrofuran (THF).

[0097] 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.

[0098] 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.

[0099] Examples of reaction solvents for the reaction between intermediate Y and compound B include N,N-dimethylformamide (DMF) and tetrahydrofuran (THF).

[0100] (Synthesis of intermediate X) Intermediate X is either known or can be synthesized from known compounds.

[0101] 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. In this case, the order of (1) to (3) is not particularly restricted and can be changed as appropriate.

[0102] [ka]

[0103] 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.

[0104] (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). The reaction temperature for N-alkylation is preferably -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.

[0105] (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.

[0106] 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).

[0107] (3) The introduction of ring A can be carried out by the following method.

[0108] If A is of formula (A-1), then, 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 Goldberg amination reaction or a Buchwald-Hartwig cross-coupling reaction.

[0109] In this case, the Goldberg amination reaction is not particularly limited, but it is preferably carried out in the presence of a copper catalyst and a base. A ligand may be further added. Examples of the copper catalyst include copper(II) acetate, copper(I) iodide, or copper(II) oxide. Examples of the aforementioned bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, potassium tert-butoxide, and sodium tert-butoxide. Examples of the ligands include N,N'-dimethylethylenediamine and L-proline. Examples of reaction solvents include dimethyl sulfoxide, 1,4-dioxane, toluene, and N-methylpyrrolidinone.

[0110] Furthermore, the Buchwald-Hartwig cross-coupling is not particularly limited, but is preferably carried out in the presence of a palladium catalyst and a base. A ligand may also be added. Examples of the palladium catalyst include bis(tri-tert-butylphosphine), (±)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl, or tris(dibenzylideneacetone)dipalladium(0)palladium(0). Examples of the aforementioned bases include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, potassium tert-butoxide, and sodium tert-butoxide. Examples of the ligand include 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (Xantphos). Examples of reaction solvents include 1,4-dioxane, toluene, and xylene.

[0111] If A is of formula (A-2), then, 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, decarboxylation cross-coupling or Negishi coupling.

[0112] In this case, the decarboxylation cross-coupling is not particularly limited, but it is preferable to react the alkylcarboxylic acid with a metal catalyst (e.g., nickel catalyst, iridium catalyst, etc.) and a hydrogen transfer source (e.g., Hantchu ester, etc.) under ultraviolet light irradiation. A ligand may be added further. Alternatively, the alkylcarboxylic acid may be pre-activated by methods such as esterifying it with phthalimide.

[0113] Furthermore, the Negishi coupling reaction is not particularly limited, but it is preferable to react alkylzinc in the presence of a palladium catalyst. Ligands may also be added.

[0114] When carrying out any of the above reactions (1) to (3), it is preferable to protect the thiol group or hydroxyl group with a protecting group in order to suppress side reactions. For example, examples of thiol group protecting 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 hydroxyl group protecting 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. Furthermore, the 2-(2-ethylhexyloxycarbonyl)ethyl group is deprotected under strong base conditions (e.g., potassium tert-butoxide).

[0115] (Synthesis of compound A) Compound A is either publicly known or can be synthesized from known compounds.

[0116] In one embodiment, for example, it can be synthesized by the following three steps.

[0117] [ka]

[0118] 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.

[0119] The first step described above is to convert the phenylacetic acid derivative into a nitrile derivative by reacting it with a cyanating agent (e.g., sodium cyanide, potassium cyanide, etc.). In this step, a solvent such as dimethyl sulfoxide (DMSO) is used.

[0120] 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.

[0121] 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.

[0122] (Synthesis of intermediate Y) Intermediate Y is either known or can be synthesized from known compounds.

[0123] For example, intermediate Y can be synthesized by performing (1') N-alkylation and (2') introduction of an A ring on a starting material represented by the following formula. In this case, the order of (1') and (2') is not particularly restricted and can be changed as appropriate.

[0124] [ka]

[0125] 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.

[0126] (1')N-alkylation can be carried out in the same manner as in (1) in the synthesis of intermediate X described above.

[0127] 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.

[0128] (Synthesis of compound B) Compound B is either known or can be synthesized from known compounds.

[0129] 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.

[0130] 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 is provided that contains a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. Furthermore, according to one embodiment of the present invention, an ACMSD inhibitor containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is provided. Furthermore, according to one embodiment of the present invention, a preventive or therapeutic agent for ACMSD-related diseases (e.g., hereditary mitochondrial diseases, metabolic diseases, neurodegenerative diseases, renal diseases, chronic inflammatory diseases, age-related diseases, cisplatin-induced ototoxicity, and diisocyanate-induced asthma) is provided, containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

[0131] Compounds represented by general formula (I) or pharmaceutically acceptable salts thereof may inhibit the metabolism (decarboxylation) of ACMS (α-amino-β-carboxymuconate 6-semialdehyde) by ACMSD (α-amino-β-carboxymuconate 6-semialdehyde decarboxylase: ACMS decarboxylase) by ACMSD. This increases the rate at which ACMS is metabolized into the NAD synthesis pathway (promotes conversion to NAD via the NAD synthesis pathway), thereby increasing intracellular NAD concentration. As a result, diseases associated with intracellular NAD concentration, such as hereditary mitochondrial disorders, metabolic disorders, neurodegenerative diseases, renal diseases, chronic inflammatory diseases, age-related diseases, cisplatin-induced ototoxicity, and diisocyanate-induced asthma, can be treated or prevented (e.g., International Publication 2020 / 104456). In this specification, diseases associated with the intracellular NAD concentration may be treated or prevented by inhibiting ACMSD, and therefore such diseases may be referred to as "diseases involving ACMSD."

[0132] The pharmaceutical composition, ACMSD inhibitor, and preventive or therapeutic agent for ACMSD-related diseases contain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition, ACMSD inhibitor, and preventive or therapeutic agent for ACMSD-related diseases may further contain a pharmaceutically acceptable carrier.

[0133] [Compounds represented by general formula (I) or their pharmaceutically acceptable salts] The compound represented by general formula (I) or its pharmaceutically acceptable salts are those listed above.

[0134] 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.

[0135] 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.

[0136] 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.

[0137] [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.

[0138] 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.

[0139] Lubricants include, for example, magnesium stearate, sodium lauryl sulfate, and talc.

[0140] Disintegrants include, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextran, pectin, etc.

[0141] Lubricants include, for example, magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil.

[0142] Colorants include, for example, those permitted for use in pharmaceuticals.

[0143] Flavoring and odor-modifying agents include, for example, cocoa powder, peppermint sap, aromatic acid, peppermint oil, borneol, cinnamon powder, etc.

[0144] Coating agents include, for example, sugar coatings, gelatin coatings, and enteric coatings (hydroxypropyl methylcellulose (HPMC), cellulose acetate phthalate, etc.).

[0145] [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.

[0146] 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.

[0147] 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.

[0148] The method of administering the pharmaceutical composition, ACMSD inhibitor, or agent for the prevention or treatment of ACMSD-related diseases may be oral or parenteral (e.g., intravenous, subcutaneous, intramuscular, suppository, enema, ointment, patch, sublingual, eye drops, inhalation, etc.), but oral administration is preferred.

[0149] The dosage of pharmaceutical compositions, ACMSD inhibitors, and agents for the prevention or treatment of diseases involving ACMSD is determined by the desired therapeutic effect, method of administration, duration of treatment, age, body weight, etc. However, the usual daily dose for adults is preferably 1 μg to 10 g when administered orally, and preferably 0.01 μg to 1 g when administered parenterally. The method of administration is not particularly limited, but it is 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).

[0150] Furthermore, as described above, the compounds according to the present invention have ACMSD inhibitory activity against mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, pigs, cattle, sheep, horses, monkeys, humans, etc., preferably humans). For this reason, they are useful as ACMSD inhibitors. Furthermore, the compounds or pharmaceutical compositions according to the present invention may be used for the prevention and / or treatment of diseases involving ACMSD. For this reason, the compounds or pharmaceutical compositions according to the present invention may be provided as preventive or therapeutic agents for diseases involving ACMSD.

[0151] Diseases associated with ACMSD include hereditary mitochondrial disorders, metabolic disorders, neurodegenerative diseases, renal diseases, chronic inflammatory diseases and age-related diseases, cisplatin-induced ototoxicity and diisocyanate-induced asthma, etc.

[0152] Examples of the aforementioned hereditary mitochondrial disorders include mitochondrial diseases, among others.

[0153] Examples of metabolic diseases include obesity, diabetes mellitus, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), and metabolic disorder-related fatty liver disease (MAFLD).

[0154] 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.

[0155] Examples of the aforementioned kidney diseases include acute kidney injury (AKI), chronic kidney disease (CKD), and diabetic nephropathy (DKD).

[0156] Examples of age-related diseases include cancer, dementia, atherosclerosis, hypertension, diabetes, arthritis, cataracts, Alzheimer's disease, macular degeneration, or osteoporosis.

[0157] 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, the use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for the prevention or treatment of a disease involving ACMSD.

[0158] 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]

[0159] 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.

[0160] [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.

[0161] 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

[0162] [Synthesis Example 1] Synthesis of 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 1) [ka]

[0163] 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 1 (1.05 g).

[0164] [Synthesis Example 2] Synthesis of 7-bromo-2-chloro-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 2) [ka]

[0165] To a solution of 7-bromo-2-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.5 g) in N,N-dimethylformamide (12 mL), cesium carbonate (4.2 g) and 2-iodopropane (0.97 mL) were added at 0°C and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride and sodium chloride were added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with hexane / ethyl acetate (2 / 1) to obtain intermediate 2 (1.3 g).

[0166] [Synthesis Example 3] Synthesis of 2-chloro-5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (intermediate 3) [ka]

[0167] (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 sulfoxide 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).

[0168] (Step 2) Synthesis of 2-chloro-5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (intermediate 3) 1.00 g of 2-chloro-5-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine was dissolved in acetonitrile (15 mL), to which 1.28 g of N-iodosuccinimide was added and stirred overnight at room temperature, followed by overnight at 60 °C. The reaction mixture was then dissolved in aqueous sodium bisulfite solution and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered off the drying agent, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with diisopropyl ether to obtain intermediate 3 (1.6 g).

[0169] [Synthesis Example 4] Synthesis of 7-bromo-2-chloro-5-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 4) [ka]

[0170] N-bromosuccinimide (1.52 g) was added to a solution of 2-chloro-5-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine (1.50 g) in N,N-dimethylformamide (15 mL) and the mixture was stirred at room temperature for 1 hour. A 10% aqueous sodium thiosulfate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered off the drying agent, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with diisopropyl ether to obtain intermediate 4 (1.65 g).

[0171] [Synthesis Example 5] Synthesis of 7-bromo-2-chloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 5) [ka]

[0172] To a solution of 7-bromo-2-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.00 g) in N,N-dimethylformamide (5 mL), cesium carbonate (2.80 g) and iodoethane (0.521 mL) were added at 0°C and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride and sodium chloride were added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with diisopropyl ether to obtain intermediate 5 (0.975 g).

[0173] Table 1 below shows the intermediates prepared in Synthesis Examples 1-5 and their mass spectrometry (MS) results.

[0174] [Table 1]

[0175] [Example 1] Synthesis of 2-(2-chloro-5-(((5-isopropyl-7-(piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0176] (Step 1) Synthesis of 2-chloro-5-isopropyl-7-(piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 1) (300 mg), copper(I) iodide (53 mg), L-proline (64 mg), and potassium carbonate (387 mg) were added to a solution of dimethyl sulfoxide (3 mL) and piperidine (0.277 mL), and the mixture was heated and stirred overnight at 90°C. Ethyl acetate was added to the reaction mixture, and the resulting solution was sequentially washed with water and saturated brine. The organic layer was 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-chloro-5-isopropyl-7-(piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine (167 mg).

[0177] (Step 2) Synthesis of 2-ethylhexyl 3-((5-isopropyl-7-(piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of 2-chloro-5-isopropyl-7-(piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine (167 mg) in 1,4-dioxane (5 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (30 mg), tris(dibenzylideneacetone)dipalladium (0) (31 mg), 2-ethylhexyl 3-mercaptopropionate (0.163 mL), and N-ethyldiisopropylamine (0.315 mL) 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-isopropyl-7-(piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (244 mg).

[0178] (Step 3) Synthesis of 2-(2-chloro-5-(((5-isopropyl-7-(piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid 2-(5-(bromomethyl)-2-chlorophenyl)acetic acid (41 mg) was added to a solution of 2-ethylhexyl 3-((5-isopropyl-7-(piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (60 mg) and potassium tert-butoxide (37 mg) in N,N-dimethylformamide (3 mL). After stirring at room temperature for 3 hours, 1 M hydrochloric acid was added to the reaction mixture and 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 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-chloro-5-(((5-isopropyl-7-(piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (22 mg). [ka]

[0179] [Example 2] Synthesis of dl-2-(3-(((7-(((cis)-3,4-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0180] (Step 1) Synthesis of 2-chloro-7-((cis)-3,4-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine A solution of 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 1) (100 mg), cis-3,4-difluoropiperidine hydrochloride (98 mg), copper(I) iodide (30 mg), L-proline (36 mg), and potassium carbonate (215 mg) in dimethyl sulfoxide (2 mL) was heated and stirred at 90°C for 4 days, followed by 110°C for 1 day. Insoluble matter in the reaction mixture was removed by filtration, and the resulting filtrate was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-chloro-7-((cis)-3,4-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (55 mg).

[0181] (Step 2) Synthesis of 2-ethylhexyl 3-((7-((cis)-3,4-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of 2-chloro-7-((cis)-3,4-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (55 mg) in 1,4-dioxane (2 mL), tris(dibenzylideneacetone)dipalladium (0) (16 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg), 2-ethylhexyl 3-mercaptopropionate (0.051 mL), and N-ethyldiisopropylamine (0.091 mL) 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-((7-((cis)-3,4-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (56 mg).

[0182] (Step 3) Synthesis of dl-2-(3-(((7-((cis)-3,4-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid To a solution of 25 mg of 2-ethylhexyl 3-((7-((cis)-3,4-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate in N,N-dimethylformamide (1.5 mL), potassium tert-butoxide (17 mg) and 2-(3-(bromomethyl)phenyl)acetic acid (18 mg) were added. After stirring at room temperature for 10 minutes, trifluoroacetic acid was added to the reaction mixture, and the mixture was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain dl-2-(3-(((7-((cis)-3,4-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (6.1 mg). [ka]

[0183] [Example 3] Synthesis of 2-(2-chloro-5-(((7-(3,3-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0184] (Step 1) Synthesis of 2-chloro-7-(3,3-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine A solution of 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 1) (306 mg), 3,3-difluoropiperidine hydrochloride (301 mg), copper(II) acetate (87 mg), L-proline (55 mg), and potassium carbonate (395 mg) in dimethyl sulfoxide (3 mL) was heated and stirred at 120°C for 3 days. The reaction mixture was diluted with ethyl acetate, and the resulting solution was sequentially washed with water and saturated saline solution, and then 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-chloro-7-(3,3-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (61 mg).

[0185] (Step 2) Synthesis of 2-ethylhexyl 3-((7-(3,3-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of 2-chloro-7-(3,3-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (71 mg) in 1,4-dioxane (2 mL), tris(dibenzylideneacetone)dipalladium (0) (21 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13 mg), 2-ethylhexyl 3-mercaptopropionate (0.076 mL), and N-ethyldiisopropylamine (0.118 mL) 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 26 mg of ethylhexyl 3-((7-(3,3-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate.

[0186] (Step 3) Synthesis of 2-(2-chloro-5-(((7-(3,3-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid To a solution of 26 mg of 2-ethylhexyl 3-((7-(3,3-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate in N,N-dimethylformamide (1.5 mL), potassium tert-butoxide (18 mg) and 2-(5-(bromomethyl)-2-chlorophenyl)acetic acid (22 mg) were added. After stirring at room temperature for 2 hours, the reaction mixture was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(2-chloro-5-(((7-(3,3-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (3.7 mg). [ka]

[0187] [Example 4] Synthesis of 2-(2-chloro-5-(((5-isopropyl-7-(4-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0188] (Step 1) Synthesis of 2-chloro-5-isopropyl-7-(4-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 1) (210 mg), copper(I) iodide (62 mg), L-proline (75 mg), and potassium carbonate (270 mg) were dissolved in dimethyl sulfoxide (1.5 mL). 4-(trifluoromethyl)piperidine (0.169 mL) was added to this solution and heated and stirred overnight at 90°C. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-chloro-5-isopropyl-7-(4-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine (23 mg).

[0189] (Step 2) Synthesis of 2-ethylhexyl 3-((5-isopropyl-7-(4-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of 2-chloro-5-isopropyl-7-(4-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine (23 mg) in 1,4-dioxane (2 mL), tris(dibenzylideneacetone)dipalladium (0) (3.5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.3 mg), 2-ethylhexyl 3-mercaptopropionate (0.019 mL), and N-ethyldiisopropylamine (0.034 mL) 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 20 mg of ethylhexyl 3-((5-isopropyl-7-(4-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate.

[0190] (Step 3) Synthesis of 2-(2-chloro-5-(((5-isopropyl-7-(4-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid To a solution of 20 mg of 2-ethylhexyl 3-((5-isopropyl-7-(4-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate in N,N-dimethylformamide (1.5 mL), potassium tert-butoxide (13 mg) and 2-(5-(bromomethyl)-2-chlorophenyl)acetic acid (17 mg) were added. After stirring at room temperature for 2 hours, the reaction mixture was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 4.5 mg of 2-(2-chloro-5-(((5-isopropyl-7-(4-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid. [ka]

[0191] [Example 5] Synthesis of 2-(5-(((7-(3,3-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0192] To a solution of 2-ethylhexyl 3-((7-(3,3-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (80 mg) in N,N-dimethylformamide (1.5 mL), potassium tert-butoxide (90 mg) and 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (119 mg) were added. After stirring at room temperature for 2 hours, the reaction mixture was purified by high-performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((7-(3,3-difluoropiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (8.1 mg). [ka]

[0193] [Example 6] Synthesis of 2-(5-(((7-(3,3-difluoropyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0194] (Step 1) Synthesis of 2-chloro-7-(3,3-difluoropyrrolinidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 1) (200 mg) and 3,3-difluoropyrrolidine hydrochloride (179 mg) were dissolved in dimethyl sulfoxide (2 mL). Potassium carbonate (344 mg), L-proline (36 mg), and copper(II) acetate (57 mg) were added, and the mixture was heated and stirred overnight at 120°C. Ethyl acetate was added to the reaction mixture, and after filtering off the insoluble matter, 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-chloro-7-(3,3-difluoropyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (33 mg).

[0195] (Step 2) Synthesis of 2-ethylhexyl 3-((7-(3,3-difluoropyrrolinidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of 2-chloro-7-(3,3-difluoropyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (33 mg) in 1,4-dioxane (1.5 mL), 2-ethylhexyl 3-mercaptopropionate (0.032 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13 mg), N-ethyldiisopropylamine (0.057 mL), and tris(dibenzylideneacetone)dipalladium (0) (10 mg) were added, and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. After filtering off the insoluble matter from the reaction mixture, 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-(3,3-difluoropyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (47 mg).

[0196] (Step 3) Synthesis of 2-(5-(((7-(3,3-difluoropyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid To a solution of 2-ethylhexyl 3-((7-(3,3-difluoropyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (45 mg) in tetrahydrofuran (1 mL), potassium tert-butoxide (37 mg) was added and the mixture was stirred at room temperature for 10 minutes, after which 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (46 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.036 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-(((7-(3,3-difluoropyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (10 mg). [ka]

[0197] [Example 7] Synthesis of dl-2-(5-(((7-(3,3-difluoro-4-methoxypiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0198] (Step 1) Synthesis of 2-chloro-7-(3,3-difluoro-4-methoxypiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine To a solution of 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 1) (300 mg) and 3,3-difluoropyrroridine-4-ol (192 mg) in dimethyl sulfoxide (3 mL), potassium carbonate (387 mg), L-proline (54 mg), and copper(II) acetate (85 mg) were added, and the mixture was heated and stirred at 120°C for 1 day. To the reaction mixture, 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 1) (150 mg), potassium carbonate (129 mg), L-proline (27 mg), and copper(II) acetate (42 mg) were further added, and the mixture was heated and stirred at 120°C for 1 day. Ethyl acetate was added to the reaction mixture, and after filtering off insoluble matter, 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 mixture (64 mg) containing 2-chloro-7-(3,3-difluoro-4-hydroxypiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine. To a solution of the mixture obtained in tetrahydrofuran (2 mL), 60% sodium hydride (12 mg) was added at 0°C and the mixture was stirred at 0°C for 10 minutes. Iodomethane (0.024 mL) was added to the reaction mixture at 0°C and the mixture was stirred at room temperature for 4 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was sequentially washed with saturated sodium bicarbonate solution 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-chloro-7-(3,3-difluoro-4-methoxypiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (26 mg).

[0199] (Step 2) Synthesis of 2-ethylhexyl 3-((7-(3,3-difluoro-4-methoxypiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of 2-chloro-7-(3,3-difluoro-4-methoxypiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (25 mg) in 1,4-dioxane (1.8 mL), 2-ethylhexyl 3-mercaptopropionate (0.033 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8 mg), N-ethyldiisopropylamine (0.051 mL), and tris(dibenzylideneacetone)dipalladium (0) (7 mg) were added, and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. After filtering off the insoluble matter from the reaction mixture, 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-(3,3-difluoro-4-methoxypiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (31 mg).

[0200] (Step 3) Synthesis of dl-2-(5-(((7-(3,3-difluoro-4-methoxypiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid To a solution of 31 mg of 2-ethylhexyl 3-((7-(3,3-difluoro-4-methoxypiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate in tetrahydrofuran (0.5 mL), potassium tert-butoxide (23 mg) was added and the mixture was stirred at room temperature for 10 minutes, after which 29 mg of 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (29 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.023 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 dl-2-(5-(((7-(3,3-difluoro-4-methoxypiperidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (7 mg). [ka]

[0201] [Example 8] Synthesis of dl-2-(2-fluoro-5-(((5-isopropyl-7-(3-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0202] (Step 1) Synthesis of 2-ethylhexyl 3-((5-isopropyl-7-(3-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 1) (570 mg) and 3-(trifluoromethyl)piperidine hydrochloride (672 mg) were dissolved in dimethyl sulfoxide (2 mL), to which potassium carbonate (980 mg), L-proline (102 mg), and copper(II) acetate (161 mg) were added, and the mixture was heated and stirred at 80°C for 1 day. Ethyl acetate was added to the reaction mixture, and after filtering off the insoluble matter, 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 mixture containing 2-chloro-5-isopropyl-7-(3-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine (174 mg).

[0203] To a solution of the obtained mixture in 1,4-dioxane (2 mL), 2-ethylhexyl 3-mercaptopropionate (0.246 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (50 mg), N-ethyldiisopropylamine (0.302 mL), and tris(dibenzylideneacetone)dipalladium (0) (40 mg) were added, and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. After filtering off the insoluble matter from the reaction mixture, 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-isopropyl-7-(3-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (65 mg).

[0204] (Step 2) Synthesis of dl-2-(2-fluoro-5-(((5-isopropyl-7-(3(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid To a solution of 3-((5-isopropyl-7-(3-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (65 mg) in tetrahydrofuran (1 mL), potassium tert-butoxide (48 mg) was added and stirred at room temperature for 10 minutes, then 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (46 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.047 mL) was added to the reaction mixture and 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 dl-2-(2-fluoro-5-(((5-isopropyl-7-(3-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (31 mg). [ka]

[0205] [Example 9] Synthesis of 2-(5-(((7-(3,3-difluoro-4,4-dimethylpyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0206] (Step 1) Synthesis of 2-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine A solution of 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 1) (500 mg), 3,3-difluoro-4,4-dimethylpyrrolidine hydrochloride (550 mg), copper(I) iodide (460 mg), L-proline (370 mg), and potassium carbonate (440 mg) in dimethyl sulfoxide (10 mL) was heated and stirred at 90°C for 2 days. The reaction mixture was allowed to return to room temperature, and water was added to the reaction mixture and extracted twice with ethyl acetate. The organic layers were washed together 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, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain 2-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (50 mg).

[0207] (Step 2) Synthesis of 2-ethylhexyl 3-((7-(3,3-difluoro-4,4-dimethylpyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of 2-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (23 mg), 2-ethylhexyl 3-mercaptopropionate (31 mg), and N-ethyldiisopropylamine (0.04 mL) in 1,4-dioxane (5 mL), tris(dibenzylideneacetone)dipalladium (0) (13 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg) were added, and the mixture was heated and stirred overnight at 140 °C under a nitrogen atmosphere. The reaction mixture was allowed to return to room temperature, and the reaction mixture was extracted three times with ethyl acetate after adding water. 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 2-ethylhexyl 3-((7-(3,3-difluoro-4,4-dimethylpyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (14 mg).

[0208] (Step 3) Synthesis of 2-(5-(((7-(3,3-difluoro-4,4-dimethylpyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid To a solution of 3-((7-(3,3-difluoro-4,4-dimethylpyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (14 mg) in tetrahydrofuran (0.15 mL), potassium tert-butoxide (11 mg) was added and the mixture was stirred at room temperature for 10 minutes, after which 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (8 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.011 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-(((7-(3,3-difluoro-4,4-dimethylpyrrolidine-1-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (7 mg). [ka]

[0209] [Example 10] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrro[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0210] (Step 1) Synthesis of 2-ethylhexyl 3-((5-isopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 1) (500 mg) and 3,3,4,4-tetrafluoropyrrolidine hydrochloride (698 mg) in dimethyl sulfoxide (3 mL), potassium carbonate (860 mg), L-proline (90 mg), and copper(II) acetate (141 mg) were added, and the mixture was heated and stirred at 100°C for 2 days. After filtering off the insoluble matter from the reaction mixture, the filtrate was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a mixture (72 mg) containing 2-chloro-5-isopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine.

[0211] To a solution of the obtained mixture in 1,4-dioxane (3 mL), 2-ethylhexyl 3-mercaptopropionate (0.140 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25 mg), N-ethyldiisopropylamine (0.149 mL), and tris(dibenzylideneacetone)dipalladium (0) (20 mg) were added, and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. After filtering off the insoluble matter of the reaction mixture, 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-isopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (45 mg).

[0212] (Step 2) Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid To a solution of 2-ethylhexyl 3-((5-isopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (45 mg) in tetrahydrofuran (1.5 mL), potassium tert-butoxide (34 mg) was added and the mixture was stirred at room temperature for 20 minutes. Then, 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (32 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-(2-fluoro-5-(((5-isopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (18 mg). [ka]

[0213] [Example 11] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrro[3,2-d]pyrimidine-2-yl)oxy)methyl)phenyl)acetic acid [ka]

[0214] Argon gas was passed through a toluene (3 mL) solution of 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 1) (200 mg) and 3,3,4,4-tetrafluoropyrrolidine hydrochloride (262 mg) for 5 minutes. Then, bis(tri-tert-butylphosphine)palladium (0) (149 mg) and sodium tert-butoxide (245 mg) were added under an argon atmosphere, and the mixture was heated and stirred at 90°C for 3 hours. The reaction mixture was allowed to return to room temperature, and trifluoroacetic acid (0.224 mL) was added. The insoluble matter was filtered off, and the mixture was washed with ethyl acetate. The filtrate, combined with the washing solution, 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 mixture (80 mg) containing 2-chloro-5-isopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine.

[0215] To a solution of 2-(2-fluoro-5-(hydroxymethyl)phenyl)acetic acid (66 mg) in N,N-dimethylformamide (1.6 mL), 60% sodium hydride (14 mg) was added at room temperature and the mixture was stirred for 2 minutes. Another 60% sodium hydride (16 mg) was added to the reaction mixture and the mixture was stirred for 5 minutes. The mixture containing the above-mentioned 2-chloro-5-isopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine (80 mg) was added to the reaction mixture and the mixture was heated and stirred at 80°C for 3 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted twice with a mixed solvent of ethyl acetate / tetrahydrofuran = 6 / 1. The organic layers were washed together with 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, 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-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)oxy)methyl)phenyl)acetic acid (6 mg). [ka]

[0216] [Example 12] Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0217] (Step 1) Synthesis of 2-ethylhexyl 3-((5-isopropyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate A solution of 7-bromo-2-chloro-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 2) (100 mg) and 2,2,6,6-tetrafluoromorpholine (58 mg) in toluene (2 mL) was passed through with argon gas for 5 minutes. Then, bis(tri-tert-butylphosphine)palladium (0) (37 mg) and sodium tert-butoxide (105 mg) were added under an argon atmosphere, and the mixture was heated and stirred at 90°C for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and it was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was 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 purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a mixture (43 mg) containing 2-chloro-5-isopropyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine.

[0218] To a solution of the resulting mixture in 1,4-dioxane (1.5 mL), 2-ethylhexyl 3-mercaptopropionate (0.044 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg), N-ethyldiisopropylamine (0.059 mL), and tris(dibenzylideneacetone)dipalladium (0) (9 mg) were added, 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-isopropyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (39 mg).

[0219] (Step 2) Synthesis of 2-(2-fluoro-5-(((5-isopropyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid To a solution of 39 mg of 2-ethylhexyl 3-((5-isopropyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate in tetrahydrofuran (0.5 mL), potassium tert-butoxide (29 mg) was added and the mixture was stirred at room temperature for 10 minutes. Then, 22 mg of 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (22 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.028 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-fluoro-5-(((5-isopropyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (26 mg). [ka]

[0220] [Example 13] Synthesis of 2-(5-(((7-(4,4-difluoro-6-azapiro[2.5]octan-6-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0221] (Step 1) Synthesis of 2-chloro-7-(4,4-difluoro-6-azapiro[2.5]octan-6-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine A solution of 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 1) (500 mg), 4,4-difluoro-6-azaspiro[2.5]octane hydrochloride (570 mg), copper(II) acetate (470 mg), L-proline (360 mg), and potassium carbonate (440 mg) in dimethyl sulfoxide (10 mL) was heated and stirred at 90°C for 2 days. The reaction mixture was allowed to return to room temperature, and the reaction mixture was extracted twice with ethyl acetate after adding water. The organic layers were washed together 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, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain 2-chloro-7-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (90 mg).

[0222] (Step 2) Synthesis of 2-ethylhexyl 3-((7-(4,4-difluoro-6-azapiro[2.5]octan-6-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of 2-chloro-7-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (37 mg), 2-ethylhexyl 3-mercaptopropionate (48 mg), and N-ethyldiisopropylamine (0.05 mL) in 1,4-dioxane (5 mL), tris(dibenzylideneacetone)dipalladium (0) (20 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13 mg) were added, and the mixture was heated and stirred overnight at 140 °C under a nitrogen atmosphere. The reaction mixture was allowed to return to room temperature, and the reaction mixture was extracted three times with ethyl acetate after adding water. 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 2-ethylhexyl 3-((7-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (45 mg).

[0223] (Step 3) Synthesis of 2-(5-(((7-(4,4-difluoro-6-azapiro[2.5]octan-6-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid To a solution of 2-ethylhexyl 3-((7-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (40 mg) in tetrahydrofuran (0.5 mL), potassium tert-butoxide (30 mg) was added and the mixture was stirred at room temperature for 20 minutes, after which 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (28 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.024 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-(((7-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (10 mg). [ka]

[0224] [Example 14] Synthesis of 2-(5-(((6-cyano-3-(3,3-difluoropiperidine-1-yl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0225] (Step 1) Synthesis of 5-chloro-6-cyano-1-isopropyl-1H-pyrrolo[3,2-b]pyridine To a solution of 5-chloro-6-cyano-1H-pyrrolo[3,2-b]pyridine (1.1 g) in N,N-dimethylformamide (10 mL), 2-iodopropane (1.7 g) and cesium carbonate (4.2 g) were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was purified by silica gel column chromatography to obtain 5-chloro-6-cyano-1-isopropyl-1H-pyrrolo[3,2-b]pyridine (1.1 g).

[0226] (Step 2) Synthesis of 5-chloro-6-cyano-3-iodo-1-isopropyl-1H-pyrrolo[3,2-b]pyridine To a solution of 5-chloro-6-cyano-1-isopropyl-1H-pyrrolo[3,2-b]pyridine (1.0 g) in N,N-dimethylformamide (5 mL), N-iodosuccinimide (1.6 g) was added and stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was purified by silica gel column chromatography to obtain 5-chloro-6-cyano-3-iodo-1-isopropyl-1H-pyrrolo[3,2-b]pyridine (1.2 g).

[0227] (Step 3) Synthesis of 5-chloro-6-cyano-3-(3,3-difluoropiperidine-1-yl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine To a solution of 5-chloro-6-cyano-3-iodo-1-isopropyl-1H-pyrrolo[3,2-b]pyridine (300 mg) and 3,3-difluoropiperidine hydrochloride (273 mg) in dimethyl sulfoxide (10 mL), potassium carbonate (600 mg), copper(II) acetate (236 mg), and L-proline (150 mg) were added, and the mixture was heated and stirred at 90°C for 18 hours. The reaction mixture was allowed to return to room temperature, water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was sequentially washed with saturated ammonium chloride aqueous solution and saturated brine, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain 5-chloro-6-cyano-3-(3,3-difluoropiperidine-1-yl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine (22 mg).

[0228] (Step 4) Synthesis of 2-ethylhexyl 3-((6-cyano-3-(3,3-difluoropiperidine-1-yl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl)thio)propionate To a solution of 5-chloro-6-cyano-3-(3,3-difluoropiperidine-1-yl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine (22 mg) in 1,4-dioxane (2 mL), N-ethyldiisopropylamine (25 mg), 2-ethylhexyl 3-mercaptopropionate (43 mg), tris(dibenzylideneacetone)dipalladium (0) (6 mg), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4 mg) were added and heated and stirred overnight at 140°C under a nitrogen atmosphere. The reaction mixture was allowed to return to room temperature, and water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layer was 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 to obtain 25 mg of ethylhexyl 3-((6-cyano-3-(3,3-difluoropiperidine-1-yl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl)thio)propionate.

[0229] (Step 5) Synthesis of 2-(5-(((6-cyano-3-(3,3-difluoropiperidine-1-yl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl)thio)methyl)-2-fluorophenyl)acetic acid To a solution of 23 mg of 2-ethylhexyl 3-((6-cyano-3-(3,3-difluoropiperidine-1-yl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl)thio)propionate in 0.3 mL of tetrahydrofuran, potassium tert-butoxide (17 mg) was added and the mixture was stirred at room temperature for 10 minutes. Then, 13 mg of 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.017 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-(((6-cyano-3-(3,3-difluoropiperidine-1-yl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-5-yl)thio)methyl)-2-fluorophenyl)acetic acid (11 mg). [ka]

[0230] [Example 15] Synthesis of 2-(5-(((5-cyclopropyl-7-(3,3-difluoropiperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0231] 2-chloro-5-cyclopropyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (intermediate 3) (350 mg) and 3,3-difluoropiperidine hydrochloride (432 mg) were dissolved in dimethyl sulfoxide (2.5 mL). Potassium carbonate (606 mg), L-proline (63 mg), and copper(II) acetate (99 mg) were added, and the mixture was heated and stirred at 120°C for 1 day. Ethyl acetate was added to the reaction mixture, and after filtering off the insoluble matter, 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 mixture (35 mg) containing 2-chloro-5-isopropyl-7-(3-(trifluoromethyl)piperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine.

[0232] To a solution of the obtained mixture in 1,4-dioxane (1 mL), 2-ethylhexyl 3-mercaptopropionate (0.051 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13 mg), N-ethyldiisopropylamine (0.078 mL), and tris(dibenzylideneacetone)dipalladium (0) (10 mg) were added, and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. After filtering off the insoluble matter of the reaction mixture, 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 mixture (46 mg) containing 2-ethylhexyl 3-((5-cyclopropyl-7-(3,3-difluoropiperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate.

[0233] Potassium tert-butoxide (36 mg) was added to a tetrahydrofuran (0.5 mL) solution of the obtained mixture, and after stirring at room temperature for 10 minutes, 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (34 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.035 mL) was added to the reaction mixture, and it 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-cyclopropyl-7-(3,3-difluoropiperidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (11 mg). [ka]

[0234] [Example 16] Synthesis of 2-(5-(((5-cyclopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0235] (Step 1) Synthesis of 2-chloro-5-cyclopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine 7-Bromo-2-chloro-5-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 4) (200 mg) and 3,3,4,4-tetrafluoropyrrolidine hydrochloride (264 mg) were dissolved in toluene (3 mL) and palladium was passed through with argon gas for 5 minutes. Then, bis(tri-tert-butylphosphine)palladium (0) (150 mg) and sodium tert-butoxide (353 mg) were added under an argon atmosphere, and the mixture was heated and stirred at 90°C for 5 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was 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-chloro-5-cyclopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine (73 mg).

[0236] (Step 2) Synthesis of 2-ethylhexyl 3-((5-cyclopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of 2-chloro-5-cyclopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine (80 mg) in 1,4-dioxane (2 mL), 2-ethylhexyl 3-mercaptopropionate (0.082 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28 mg), N-ethyldiisopropylamine (0.125 mL), and tris(dibenzylideneacetone)dipalladium (0) (22 mg) were added, and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. After filtering off the insoluble matter from the reaction mixture, 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-cyclopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (99 mg).

[0237] (Step 3) Synthesis of 2-(5-(((5-cyclopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid To a solution of 3-((5-cyclopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (50 mg) in tetrahydrofuran (1 mL), potassium tert-butoxide (38 mg) was added and the mixture was stirred at room temperature for 10 minutes, after which 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (31 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.037 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-cyclopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (24 mg). [ka]

[0238] [Example 17] Synthesis of 2-(5-(((5-cyclopropyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0239] (Step 1) Synthesis of 2-ethylhexyl 3-((5-cyclopropyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate A solution of 7-bromo-2-chloro-5-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 4) (130 mg) and 2,2,6,6-tetrafluoromorpholine (91 mg) in toluene (2.5 mL) was passed through with argon gas for 5 minutes. Then, bis(tri-tert-butylphosphine)palladium (0) (49 mg) and sodium tert-butoxide (160 mg) were added under an argon atmosphere, and the mixture was heated and stirred at 90°C for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and it was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was 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 purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a mixture (49 mg) containing 2-chloro-5-cyclopropyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine.

[0240] To a solution of the obtained mixture in 1,4-dioxane (1.5 mL), 2-ethylhexyl 3-mercaptopropionate (0.048 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (16 mg), N-ethyldiisopropylamine (0.073 mL), and tris(dibenzylideneacetone)dipalladium (0) (13 mg) were added, and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. After filtering off the insoluble matter of the reaction mixture, 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-cyclopropyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (47 mg).

[0241] (Step 2) Synthesis of 2-(5-(((5-cyclopropyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid To a solution of 2-ethylhexyl 3-((5-cyclopropyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (45 mg) in tetrahydrofuran (1 mL), potassium tert-butoxide (33 mg) was added and the mixture was stirred at room temperature for 10 minutes, after which 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (29 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.033 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-cyclopropyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (24 mg). [ka]

[0242] [Example 18] Synthesis of 2-(5-(((5-cyclopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2,4-difluorophenyl)acetic acid [ka]

[0243] To a solution of 2-ethylhexyl 3-((5-cyclopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (53 mg) in tetrahydrofuran (0.5 mL), potassium tert-butoxide (40 mg) was added and the mixture was stirred at room temperature for 20 minutes. Then, 2-(5-(bromomethyl)-2,4-difluorophenyl)acetic acid (41 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.032 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-cyclopropyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2,4-difluorophenyl)acetic acid (25 mg). [ka]

[0244] [Example 19] Synthesis of 2-(5-(((5-cyclopropyl-7-(4,4-difluoro-6-azapiro[2.5]octan-6-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0245] (Step 1) Synthesis of 2-ethylhexyl 3-((5-cyclopropyl-7-(4,4-difluoro-6-azapiro[2.5]octan-6-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate A solution of 2-chloro-7-iodo-5-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 3) (300 mg), 4,4-difluoro-6-azaspiro[2.5]octane hydrochloride (259 mg), copper(II) acetate (85 mg), L-proline (54 mg), and potassium carbonate (519 mg) in dimethyl sulfoxide (2 mL) was heated and stirred at 100°C for 17 hours. The reaction mixture was allowed to return to room temperature, and ethyl acetate was added to the reaction mixture to filter off the insoluble matter. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain a mixture (62 mg) containing 2-chloro-7-(4,4-difluoro-6-azaspiro[2.5]octane-6-yl)-5-cyclopropyl-5H-pyrrolo[3,2-d]pyrimidine.

[0246] To a solution of the resulting mixture in 1,4-dioxane (1 mL), 2-ethylhexyl 3-mercaptopropionate (0.083 mL), N-ethyldiisopropylamine (0.096 mL), tris(dibenzylideneacetone)dipalladium (0) (17 mg), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21 mg) were added, 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-cyclopropyl-7-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (55 mg).

[0247] (Step 3) Synthesis of 2-(5-(((5-cyclopropyl-7-(4,4-difluoro-6-azapiro[2.5]octan-6-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid To a solution of 3-((5-cyclopropyl-7-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (55 mg) in tetrahydrofuran (1 mL), potassium tert-butoxide (42 mg) was added and the mixture was stirred at room temperature for 10 minutes, after which 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (34 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.041 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-cyclopropyl-7-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (18 mg). [ka]

[0248] [Example 20] Synthesis of 2-(2-fluoro-5-(((5-methyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrro[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0249] (Step 1) Synthesis of 2-ethylhexyl 3-((5-methyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate Argon gas was passed through a toluene (9 mL) solution of 7-bromo-2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (600 mg) and 3,3,4,4-tetrafluoropyrrolidine hydrochloride (874 mg) for 5 minutes. Then, bis(tri-tert-butylphosphine)palladium (0) (249 mg) and sodium tert-butoxide (819 mg) were added under an argon atmosphere, and the mixture was heated and stirred at 90°C for 8 hours. The reaction mixture was allowed to return to room temperature, and trifluoroacetic acid (0.75 mL) was added. The insoluble matter was filtered off, and the mixture was washed with ethyl acetate. The filtrate, combined with the washing solution, 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 mixture (688 mg) containing 2-chloro-5-methyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine.

[0250] To a solution of the obtained mixture in 1,4-dioxane (15 mL), 2-ethylhexyl 3-mercaptopropionate (1.00 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (255 mg), N-ethyldiisopropylamine (1.54 mL), and tris(dibenzylideneacetone)dipalladium (0) (202 mg) were added, and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. After filtering off the insoluble matter of the reaction mixture, 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-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (70 mg).

[0251] (Step 2) Synthesis of 2-(2-fluoro-5-(((5-methyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid To a solution of 35 mg of 2-ethylhexyl 3-((5-methyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate in tetrahydrofuran (0.35 mL), potassium tert-butoxide (28 mg) was added and the mixture was stirred at room temperature for 20 minutes, after which 26 mg of 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (26 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.022 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-fluoro-5-(((5-methyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (30 mg). [ka]

[0252] [Example 21] Synthesis of 2-(2-chloro-5-(((5-methyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrro[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0253] To a solution of 35 mg of 2-ethylhexyl 3-((5-methyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate in tetrahydrofuran (0.35 mL), potassium tert-butoxide (28 mg) was added and the mixture was stirred at room temperature for 20 minutes. Then, 28 mg of 2-(5-(bromomethyl)-2-chlorophenyl)acetic acid (28 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.022 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-chloro-5-(((5-methyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (19 mg). [ka]

[0254] [Example 22] Synthesis of 2-(2-fluoro-5-(((5-methyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0255] (Step 1) Synthesis of 2-ethylhexyl 3-((5-methyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 7-Bromo-2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (186 mg) and 2,2,6,6-tetrafluoromorpholine (80 mg) were dissolved in toluene (2 mL) and palladium (2 mL) was passed through with argon gas for 5 minutes. Then, bis(tri-tert-butylphosphine)palladium (0) (51 mg) and sodium tert-butoxide (169 mg) were added under an argon atmosphere, and the mixture was heated and stirred at 90 °C for 4 hours. Saturated ammonium chloride aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was 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 mixture (29 mg) containing 2-chloro-5-methyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine.

[0256] To a solution of the obtained mixture in 1,4-dioxane (1 mL), 2-ethylhexyl 3-mercaptopropionate (0.041 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), N-ethyldiisopropylamine (0.047 mL), and tris(dibenzylideneacetone)dipalladium (0) (8 mg) were added, 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-methyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (22 mg).

[0257] (Step 2) Synthesis of 2-(2-fluoro-5-(((5-methyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid To a solution of 22 mg of 2-ethylhexyl 3-((5-methyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate in 0.5 mL of tetrahydrofuran, potassium tert-butoxide (17 mg) was added and the mixture was stirred at room temperature for 10 minutes. Then, 13 mg of 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.017 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-fluoro-5-(((5-methyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (17 mg). [ka]

[0258] [Example 23] Synthesis of 2-(5-(((7-(3,3-difluoropiperidine-1-yl)-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0259] (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 (1.9 g) in N,N-dimethylformamide (10 mL), cesium carbonate (4.4 g) and iodoethane (0.82 mL) were added at 0°C and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride and sodium chloride were added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with hexane / ethyl acetate (2 / 1) to obtain 2-chloro-5-ethyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine (1.6 g).

[0260] (Step 2) Synthesis of 2-(5-(((7-(3,3-difluoropiperidine-1-yl)-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid 500 mg of 2-chloro-5-ethyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidine and 641 mg of 3,3-difluoropiperidine hydrochloride were dissolved in dimethyl sulfoxide (3 mL). Potassium carbonate (899 mg), L-proline (94 mg), and copper(II) acetate (148 mg) were added, and the mixture was heated and stirred at 100°C for 1 day. Water was added to the reaction mixture, and it was 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 a mixture (100 mg) containing 2-chloro-7-(3,3-difluoropiperidine-1-yl)-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine.

[0261] To a solution of the obtained mixture in 1,4-dioxane (3 mL), 2-ethylhexyl 3-mercaptopropionate (0.151 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (39 mg), N-ethyldiisopropylamine (0.232 mL), and tris(dibenzylideneacetone)dipalladium (0) (30 mg) were added, and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. After filtering off the insoluble matter of the reaction mixture, 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 mixture (107 mg) containing 2-ethylhexyl 3-((7-(3,3-difluoropiperidine-1-yl)-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate.

[0262] Potassium tert-butoxide (87 mg) was added to a tetrahydrofuran (2.5 mL) solution of the obtained mixture, and after stirring at room temperature for 20 minutes, 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (82 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.068 mL) was added to the reaction mixture, and it 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), and the obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate), followed by high-performance liquid chromatography again (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to obtain 2-(5-(((7-(3,3-difluoropiperidine-1-yl)-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (11 mg). [ka]

[0263] [Example 24] Synthesis of 2-(5-(((5-ethyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrro[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0264] (Step 1) Synthesis of 2-ethylhexyl 3-((5-ethyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 7-Bromo-2-chloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 5) (600 mg) and 3,3,4,4-tetrafluoropyrrolidine hydrochloride (827 mg) were dissolved in toluene (9 mL) and palladium was passed through with argon gas for 5 minutes. Then, bis(tri-tert-butylphosphine)palladium (0) (235 mg) and sodium tert-butoxide (775 mg) were added under an argon atmosphere, and the mixture was heated and stirred at 90°C for 8 hours. The reaction mixture was allowed to return to room temperature, insoluble matter was filtered off, and the mixture was washed with ethyl acetate. The filtrate, combined with the washing solution, 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 mixture (210 mg) containing 2-chloro-5-ethyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine.

[0265] To a solution of the obtained mixture in 1,4-dioxane (3.5 mL), 2-ethylhexyl 3-mercaptopropionate (0.296 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (75 mg), N-ethyldiisopropylamine (0.455 mL), and tris(dibenzylideneacetone)dipalladium (0) (60 mg) were added, and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. After filtering off the insoluble matter of the reaction mixture, 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-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (248 mg).

[0266] (Step 2) Synthesis of 2-(5-(((5-ethyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid To a solution of 3-((5-ethyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (70 mg) in tetrahydrofuran (0.7 mL), potassium tert-butoxide (55 mg) was added and the mixture was stirred at room temperature for 20 minutes, after which 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (51 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.043 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-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (45 mg). [ka]

[0267] [Example 25] Synthesis of 2-(5-(((5-ethyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0268] (Step 1) Synthesis of 2-ethylhexyl 3-((5-ethyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 7-Bromo-2-chloro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 5) (163 mg) and 2,2,6,6-tetrafluoromorpholine (83 mg) were dissolved in toluene (2 mL) and passed through with argon gas for 5 minutes. Then, bis(tri-tert-butylphosphine)palladium (0) (53 mg) and sodium tert-butoxide (175 mg) were added under an argon atmosphere, and the mixture was heated and stirred at 90°C for 4 hours. Trifluoroacetic acid (0.121 mL) was added to the reaction mixture, and the mixture 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 mixture (27 mg) containing 2-chloro-5-ethyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine.

[0269] To a solution of the obtained mixture in 1,4-dioxane (1 mL), 2-ethylhexyl 3-mercaptopropionate (0.036 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9 mg), N-ethyldiisopropylamine (0.042 mL), and tris(dibenzylideneacetone)dipalladium (0) (7 mg) were added, 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-ethyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (24 mg).

[0270] (Step 2) Synthesis of 2-(5-(((5-ethyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid To a solution of 23 mg of 2-ethylhexyl 3-((5-ethyl-7-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate in 0.5 mL of tetrahydrofuran, potassium tert-butoxide (17 mg) was added and the mixture was stirred at room temperature for 10 minutes. Then, 13 mg of 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.017 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-(2,2,6,6-tetrafluoromorpholino)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (16 mg). [ka]

[0271] [Example 26] Synthesis of 2-(2-chloro-5-(((5-ethyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid [ka]

[0272] To a solution of 2-ethylhexyl 3-((5-ethyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (80 mg) in tetrahydrofuran (1 mL), potassium tert-butoxide (62 mg) was added and the mixture was stirred at room temperature for 10 minutes, after which 2-(5-(bromomethyl)-2-chlorophenyl)acetic acid (50 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.061 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-chloro-5-(((5-ethyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)phenyl)acetic acid (55 mg). [ka]

[0273] [Example 27] Synthesis of 2-(5-(((5-(difluoromethyl)-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0274] (Step 1) Synthesis of 7-bromo-2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine 7-Bromo-2-chloro-5H-pyrrolo[3,2-d]pyrimidine (2.00 g) was dissolved in N,N-dimethylformamide (20 mL) and 60% sodium hydride (413 mg) was added at 0°C and the mixture was stirred at 0°C for 2 minutes. 2-(chloromethoxy)ethyltrimethylsilane (1.83 mL) was added dropwise to the reaction mixture at 0°C and the mixture was stirred at 0°C for 1 hour. Saturated ammonium chloride aqueous solution 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 solid was washed with diisopropyl ether to obtain 7-bromo-2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine (2.59 g).

[0275] (Step 2) Synthesis of 2-chloro-7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine 7-Bromo-2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine (2.00 g) and 3,3,4,4-tetrafluoropyrrolidine hydrochloride (1.98 g) were dissolved in toluene (30 mL) and palladium (564 mg) and sodium tert-butoxide (1.86 g) were added under an argon atmosphere, and the mixture was heated and stirred at 90°C for 9 hours. The reaction mixture was allowed to return to room temperature, insoluble matter was filtered off, and the mixture was washed with ethyl acetate. The filtrate, combined with the washing solution, 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-chloro-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine (0.53 g).

[0276] (Step 3) Synthesis of 2-chloro-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine A mixed solution of 2-chloro-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidine (260 mg) in tetrahydrofuran (2.5 mL) and N,N-dimethylformamide (2.5 mL) was mixed with a tetrahydrofuran solution of tetrabutylammonium fluoride (TBAF) (1 M, 1.2 mL), and the mixture was heated and stirred at 90°C for 2 hours. The reaction mixture was allowed to return to room temperature and purified by silica gel column chromatography (hexane / ethyl acetate). The resulting compound was diluted with ethyl acetate and washed sequentially with saturated ammonium chloride aqueous solution (three times), 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 to obtain 2-chloro-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine (58 mg).

[0277] (Step 4) Synthesis of 2-chloro-5-(difluoromethyl)-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine 58 mg of 2-chloro-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine was dissolved in acetonitrile (2 mL), to which 0.026 mL of methyl bromodifluoroacetate and 33 mg of potassium carbonate were added, and the mixture was heated and stirred at 80°C for 1 hour. 0.026 mL of methyl bromodifluoroacetate and 33 mg of potassium carbonate were added to the reaction mixture at room temperature, and the mixture was heated and stirred at 80°C for 1 hour. The reaction mixture was allowed to return to room temperature, insoluble matter was filtered off, and the mixture was washed with ethyl acetate. The filtrate, combined with the washing solution, was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 43 mg of 2-chloro-5-(difluoromethyl)-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine.

[0278] (Step 5) Synthesis of 2-ethylhexyl 3-((5-(difluoromethyl)-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of 2-chloro-5-(difluoromethyl)-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine (43 mg) in 1,4-dioxane (0.6 mL), 2-ethylhexyl 3-mercaptopropionate (0.057 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14 mg), N-ethyldiisopropylamine (0.087 mL), and tris(dibenzylideneacetone)dipalladium (0) (11 mg) were added, and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. After filtering off the insoluble matter from the reaction mixture, 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-(difluoromethyl)-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (55 mg).

[0279] (Step 6) Synthesis of 2-(5-(((5-(difluoromethyl)-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid To a solution of 2-ethylhexyl 3-((5-(difluoromethyl)-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (55 mg) in tetrahydrofuran (0.6 mL), potassium tert-butoxide (41 mg) was added and the mixture was stirred at room temperature for 20 minutes, after which 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (39 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.032 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-(difluoromethyl)-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (5 mg). [ka]

[0280] [Example 28] Synthesis of 2-(5-(((5-cyclobutyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0281] (Step 1) Synthesis of 2-chloro-5-cyclobutyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine 100 mg of 2-chloro-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine was dissolved in 1 mL of N,N-dimethylformamide, to which 0.096 mL of bromocyclobutane and cesium carbonate (332 mg) were added, and the mixture was heated and stirred at 80°C for 4 hours. Water was added to the reaction mixture, and it was 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 64 mg of 2-chloro-5-cyclobutyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine.

[0282] (Step 2) Synthesis of 2-ethylhexyl 3-((5-cyclobutyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate To a solution of 2-chloro-5-(cyclobutyl)-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine (64 mg) in 1,4-dioxane (1 mL), 2-ethylhexyl 3-mercaptopropionate (0.083 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21 mg), N-ethyldiisopropylamine (0.128 mL), and tris(dibenzylideneacetone)dipalladium (0) (17 mg) were added, and the mixture was heated and stirred at 140°C for 2 hours using a microwave reactor. After filtering off the insoluble matter from the reaction mixture, 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-cyclobutyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (69 mg).

[0283] (Step 3) Synthesis of 2-(5-(((5-cyclobutyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid To a solution of 3-((5-cyclobutyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl (69 mg) in tetrahydrofuran (1.5 mL), potassium tert-butoxide (51 mg) was added and the mixture was stirred at room temperature for 15 minutes, after which 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid (48 mg) was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.040 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-cyclobutyl-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (43 mg). [ka]

[0284] [Example 29]

[0285] Synthesis of (+)-2-(5-(((7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0286] (Step 1) Synthesis and optical resolution of (2-chloro-7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine) To a solution of 1,3-difluorocyclohexane-1-carboxylic acid 1,3-dioxoisoindorin-2-yl (2.8 g) in N,N-dimethylacetamide (50 mL), 2-chloro-7-iodo-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (intermediate 1) (1.94 g), 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate diethyl (3.0 g), and NiBr2(dtBpy) (0.29 g) were added and stirred at room temperature for 18 hours under 400 nm LED irradiation. Water was added to the reaction mixture and extracted three times with ethyl acetate. The organic layers were washed together 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 silica gel column chromatography (petroleum ether / ethyl acetate) to obtain 2-chloro-7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (400 mg).

[0287] The obtained 2-chloro-7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine was purified by optical resolution high-performance liquid chromatography (IC 250 mm * 4.6 mm 5 μm, Hex-EtOH-60-40-15 MIN) to obtain 2-chloro-7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (peak 1) (160 mg) (optical resolution high-performance liquid chromatography retention time: 7.628 min) and 2-chloro-7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (peak 2) (170 mg) (optical resolution high-performance liquid chromatography retention time: 9.246 min).

[0288] (Step 2) Synthesis of (+)-2-(5-(((7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid To a solution of 2-chloro-7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (peak 1) (160 mg) in 1,4-dioxane (4 mL), 2-ethylhexyl 3-mercaptopropionate (167 mg), N-ethyldiisopropylamine (197 mg), tris(dibenzylideneacetone)dipalladium (0) (47 mg), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57 mg) were added, and the mixture was heated and stirred overnight at 140 °C under a nitrogen atmosphere. The reaction mixture was allowed to return to room temperature, and the reaction mixture was extracted three times with ethyl acetate after adding water. The organic layers were combined and concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography to obtain 2-ethylhexyl 3-(7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (182 mg) in oil form.

[0289] To a solution of 70 mg of 70 mg of the resulting oily 2-ethylhexyl 3-(7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate in 0.7 mL of tetrahydrofuran, potassium tert-butoxide (56 mg) was added and the mixture was stirred at room temperature for 20 minutes. Then, 52 mg of 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid was added. After stirring at room temperature for 20 minutes, trifluoroacetic acid (0.044 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-(((7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (62 mg).

[0290] When the optical rotation was measured using a polarimeter, [α] 20 D The result was +4.4 (c0.567, methanol). [ka]

[0291] [Example 30] Synthesis of (-)-2-(5-(((7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka]

[0292] The same procedure as in Step 2 of Example 29 was performed using 2-chloro-7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (peak 2) obtained in Step 1 of Example 29.

[0293] Specifically, to a solution of 2-chloro-7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine (peak 2) (170 mg) in 1,4-dioxane (4 mL), 2-ethylhexyl 3-mercaptopropionate (177 mg), N-ethyldiisopropylamine (210 mg), tris(dibenzylideneacetone)dipalladium (0) (50 mg), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (62 mg) were added, and the mixture was heated and stirred overnight at 140°C under a nitrogen atmosphere. The reaction mixture was allowed to return to room temperature, and water was added to the reaction mixture, followed by three extractions with ethyl acetate. The organic layers were combined and concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography to obtain 2-ethylhexyl 3-(7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate (182 mg) in oil form.

[0294] To a solution of 70 mg of 70 mg of the resulting oily 3-(7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)propionate 2-ethylhexyl in 1 mL of tetrahydrofuran, potassium tert-butoxide (56 mg) was added and the mixture was stirred at room temperature for 10 minutes. Then, 42 mg of 2-(5-(bromomethyl)-2-fluorophenyl)acetic acid 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-(5-(((7-(3,3-difluorocyclohexyl)-5-isopropyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid (65 mg).

[0295] When the optical rotation was measured using the same method as in Example 29, [α] 20 D The temperature was -4.3 (c0.231, methanol).

[0296] [Example 31] Synthesis of 2-(5-(((5-(bicyclo[1,1,1]pentan-1-yl)-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka] 2-(5-(((5-(bicyclo[1.1.1]pentan-1-yl)-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid was synthesized in the same manner as in Example 27.

[0297] [Example 32] Synthesis of dl-2-(5-(((5-(2,2-difluorocyclopropyl)-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrro[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka] dl-2-(5-(((5-(2,2-difluorocyclopropyl)-7-(3,3,4,4-tetrafluoropyrrolidine-1-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid was synthesized in the same manner as in Example 27.

[0298] [Example 33] Synthesis of (+)-2-(5-(((5-cyclopropyl-7-(3,3-difluorocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka] (+)-2-(5-(((5-cyclopropyl-7-(3,3-difluorocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid was synthesized in the same manner as in Example 29. When the optical rotation was measured using the same method as in Example 29, [α] 20 D The result was +6.0 (c0.26, methanol).

[0299] [Example 34] Synthesis of (-)-2-(5-(((5-cyclopropyl-7-(3,3-difluorocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka] (-)-2-(5-(((5-cyclopropyl-7-(3,3-difluorocyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid was synthesized in the same manner as in Example 30. When the optical rotation was measured using the same method as in Example 29, [α] 20 D The temperature was -5.4 (C0.28, methanol).

[0300] [Example 35] Synthesis of (+)-2-(5-(((5-cyclopropyl-7-(3,3-difluorocyclopentyl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka] (+)-2-(5-(((5-cyclopropyl-7-(3,3-difluorocyclopentyl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid was synthesized in the same manner as in Example 29. When the optical rotation was measured using the same method as in Example 29, [α] 20 D The result was +7.2 (c0.22, methanol).

[0301] [Example 36] Synthesis of (-)-2-(5-(((5-cyclopropyl-7-(3,3-difluorocyclopentyl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka] (-)-2-(5-(((5-cyclopropyl-7-(3,3-difluorocyclopentyl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid was synthesized in the same manner as in Example 30. When the optical rotation was measured using the same method as in Example 29, [α] 20D The value was -7.7 (c0.56, methanol).

[0302] [Example 37] dl-2-(5-(((5-cyclopropyl-7-(5,5-difluorotetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,2-d]pyrimidine-2-yl)thio)methyl)-2-fluorophenyl)acetic acid [ka] dl-2-(5-(((5-cyclopropyl-7-(5,5-difluorotetrahydro-2H-pyran-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 29.

[0303] [ACMSD inhibitory activity] The ACMSD inhibitory activity of the compounds in Examples 1 to 37 was measured.

[0304] (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 37 (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).

[0305] 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).

[0306] 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).

[0307] 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).

[0308] (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.

[0309] 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. ACMS was generated by mixing equal volumes of HAO solution and 3-HAA solution and incubating 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 EnVision 2105 multimode plate reader (PerkinElmer) at 28°C.

[0310] (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. 50The concentration of the test substance that showed a 50% inhibition rate was calculated using XLfit (IDBS) and evaluated according to the following criteria.

[0311] A:IC 50 <0.010 μM B: 0.010 μM ≤ IC 50 < 0.030 μM C: 0.030 μM ≤ IC 50 < 0.30 μM

[0312] The compounds prepared in Examples 1 to 37, along with their MS, UPLC retention times, and ACMSD inhibitory activity results, are shown in Tables 2-1 to 2-8 below.

[0313] [Table 2-1]

[0314] [Table 2-2]

[0315] [Table 2-3]

[0316] [Table 2-4]

[0317] [Table 2-5]

[0318] [Table 2-6]

[0319] [Table 2-7]

[0320] [Table 2-8]

[0321] The results from Tables 2-1 to 2-8 show that the compounds from Examples 1 to 37 exhibit ACMSD inhibitory activity. [Industrial applicability]

[0322] 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 A cyclic ether of a 4- to 6-membered ring, which may be substituted with a cycloalkyl, fluorine atom, cyano, or hydroxyl group. 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, A is given by the following formula (A-1) or (A-2): 【Chemistry 2】 (In the above formulas (A-1) to (A-2), Q １ is a single bond, an oxygen atom, or CR １９ R ２０ where Q ２ is a single bond, oxygen atom, or CR １９ R ２０ And, Q ３ is an oxygen atom, or CR １３ R １４ And, Q ４ is an oxygen atom, or CR １１ R １２ And, R １１ ~R ２０ 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, and in this case, R １１ ~R ２０ Two of these groups combine to form hydroxyl, halogen, cyano, nitro, and C １～５ C may be substituted with at least one substituent selected from the group consisting of alkoxys. ３～１０ They may also form a cycloalkyl group. (* indicates the site of attachment to ring B.) And, Y is CH or N, Z is either C (C≡N) or N, W is either a sulfur atom or an oxygen atom. 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. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is formula (A-2).

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

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

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

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

14. 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.

15. 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.

16. 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.

17. R １ However, C １～３ The compound according to claim 1, which is alkyl or cyclopropyl, or a pharmaceutically acceptable salt thereof.

18. R ２ However, it is a hydrogen atom or a fluorine atom, 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.

19. R １３ ~R １６ and R １９ ~R ２０ At least one of them is a fluorine atom, methyl, trifluoromethyl, or R １３ and R １４ , R １５ and R １６ , and R １９ and R ２０ At least one combination selected from the group consisting of hydroxy, halogen, cyano, nitro, and C forms a single unit. １～５ C may be substituted with at least one substituent selected from the group consisting of alkoxys. ３～１０ A compound according to claim 1 or a pharmaceutically acceptable salt thereof that forms a cycloalkyl group.

20. R １５ and R １６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a fluorine atom.

21. R １３ ~R １４ and R １９ ~R ２０ At least one of them is a fluorine atom, methyl, trifluoromethyl, or R １３ and R １４ And R １９ and R ２０ At least one combination selected from the group consisting of hydroxy, halogen, cyano, nitro, and C forms a single unit. １～５ C may be substituted with at least one substituent selected from the group consisting of alkoxys. ３～１０ A compound according to claim 20 or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl group.

22. R １ However, C １～３ Alkyl or cyclopropyl, R ２ However, it is a hydrogen atom or a fluorine atom, R ４ However, it is a fluorine atom or a chlorine atom, R １５ and R １６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a fluorine atom.

23. R １３ ~R １４ and R １９ ~R ２０ At least one of them is a fluorine atom, methyl, trifluoromethyl, or R １３ and R １４ And R １９ and R ２０ At least one combination selected from the group consisting of hydroxy, halogen, cyano, nitro, and C forms a single unit. １～５ C may be substituted with at least one substituent selected from the group consisting of alkoxys. ３～１０ A compound according to claim 22 or a pharmaceutically acceptable salt thereof, which forms a cycloalkyl group.

24. W is a sulfur atom, A is equation (A-1), Y is CH, Z is N, R １ However, C １～３ Alkyl or cyclopropyl, R ２ However, it is a hydrogen atom or a fluorine atom, R ４ However, it is a fluorine atom or a chlorine atom, R １５ and R １６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a fluorine atom.

25. R １３ ~R １４ and R １９ ~R ２０ At least one of them is a fluorine atom, methyl, trifluoromethyl, or R １３ and R １４ And R １９ and R ２０ At least one combination selected from the group consisting of hydroxy, halogen, cyano, nitro, and C forms a single unit. １～５ C may be substituted with at least one substituent selected from the group consisting of alkoxys. ３～１０ A compound according to claim 24 or a pharmaceutically acceptable salt thereof that forms a cycloalkyl group.

26. R ３ 、 R ５ 、 R ６ 、 R ７ 、 R ８ 、 R ９ 、 R １０ 、 R １１ 、 R １２ 、 R １７ and R １８ are hydrogen atoms, the compound according to claim 1 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】 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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