4-pyridinol derivative

Abstract

[Problem] To provide a novel compound having 17β-hydroxysteroid dehydrogenase 13 (HSD17B13) inhibitory activity. [Solution] A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.　

Description

4-Pyridinol derivatives

[0001] This disclosure relates to 4-pyridinol derivatives and the like that have 17β-hydroxysteroid dehydrogenase 13 (HSD17B13) inhibitory activity.

[0002] In recent years, due to changes in lifestyle and lack of exercise, the number of people with metabolic disorders such as obesity, diabetes, hypertension, and hyperlipidemia has been increasing worldwide, and consequently, the incidence of liver disease has been rising. Examples of liver diseases caused by such obesity and metabolic disorders include non-alcoholic fatty liver disease (NAFLD), in which fat accumulates in the liver; non-alcoholic steatohepatitis (NASH), in which inflammation of the liver occurs as NAFLD progresses; cirrhosis, which occurs as liver fibrosis progresses; and liver cancer, which occurs as NASH or cirrhosis progresses.

[0003] Recently, a change in the name of fatty liver disease has been announced. Specifically, fatty liver disease is now collectively referred to as "steatotic liver disease" (SLD), while the former NAFLD and NASH are now called "metabolic dysfunction associated steatotic liver disease" (MASLD) and "metabolic dysfunction associated steatohepatitis" (MASH), respectively.

[0004] In recent years, cohort studies have investigated the association between the presence and severity of chronic liver disease and genetic factors, and have reported that loss-of-function mutations in 17β-hydroxysteroid dehydrogenase 13 (HSD17B13) are associated with a reduced risk of chronic liver disease and progression from fatty liver to steatohepatitis (NASH or MASH) and fibrosis (Non-Patent Literature 1). Therefore, HSD17B13 is being targeted as a therapeutic agent for liver diseases caused by obesity and metabolic disorders.

[0005] For example, Patent Document 1 describes an invention related to a substrate-specific HSD17B13 inhibitor and its use. Patent Document 1 exemplifies the following compounds as HSD17B13 inhibitors.

[0006] International Publication No. 2021 / 211981

[0007] Abul-Husn NS et al, A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease, N Engl J Med. 2018, 22, 1096-1106.

[0008] In such a situation, there is a need for novel compounds and the like having 17β-hydroxysteroid dehydrogenase 13 (HSD17B13) inhibitory activity.

[0009] According to the present disclosure, for example, the following compounds and the like are provided.

[0010] [1] The following general formula (I): [In the above general formula (I), R １ and R ２ are each independently hydrogen; halogen; or cyano, and at least one of R １ and R ２ is halogen or cyano, R ３ is hydrogen; halogen; cyano; C １～６ [[ID= 30]]alkyl optionally substituted with halogen; or C ３～８ cycloalkyl optionally substituted with halogen, W is the following formula (A-1) to (A-12): (In the above formula (A-1) to (A-12), A is C １～６ alkylene optionally substituted with halogen, R ４ is hydrogen; cyano; C １～６ alkyl optionally substituted with halogen; or C ３～８ cycloalkyl optionally substituted with halogen), and Z is a bicyclic heterocycle] a compound represented by or a pharmaceutically acceptable salt thereof.

[0011] [2] The following general formulas (1) to (8): [In the above general formulas (1) to (8), R １ ~R ３ And W is the same as in general formula (I), and X １ ~X ３ Each of them operates independently, CR ５ or N and Y １ ~Y ６ Each of them is independent of C(R) ５ ) ２ , C=O, NR ５ , or O, or CR when the dashed line indicates a connection ５ or N, R ５ These are, independently, hydrogen; halogen; NR ６ R ７ OR ６ ; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６ Alkyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６Alkylcarbonyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkenyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ２～６Heterocycloalkyl; or hydroxy, halogen, cyano, nitro, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ C may be substituted with aryl, hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ It is a heteroaryl, R ６ and R ７ These are C, which may be substituted with hydrogen or halogen, independently of each other. １～６ Alkylcarbonyl; C may be substituted with halogen. ３～８ Cycloalkylcarbonyl; C which may be substituted with halogen ２～６ Heterocycloalkylcarbonyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８Cycloalkyl, C optionally substituted with halogen ２～６ Heterocycloalkyl, C optionally substituted with halogen ６～１２ Aryl, C optionally substituted with halogen １～９ C optionally substituted with at least one substituent selected from the group consisting of heteroaryl １～６ Alkyl; or hydroxy, halogen, cyano, nitro, C optionally substituted with halogen １～６ Alkyl, C optionally substituted with halogen １～５ Alkoxy, halogen and / or C １～６ C optionally substituted with alkylaminocarbonyl ３～８ Cycloalkyl, C optionally substituted with halogen ２～６ Heterocycloalkyl, C optionally substituted with halogen ６～１２ Aryl, C optionally substituted with halogen １～９ C optionally substituted with at least one substituent selected from the group consisting of heteroaryl ３～８ Cycloalkyl; or hydroxy, halogen, cyano, nitro, C １～６ C optionally substituted with alkylcarbonylamino, C optionally substituted with halogen １～６ Alkyl, C optionally substituted with halogen １～５ Alkoxy, halogen and / or C １～６ C optionally substituted with alkylaminocarbonyl ３～８ Cycloalkyl, C optionally substituted with halogen ２～６ Heterocycloalkyl, C optionally substituted with halogen ６～１２ Aryl, C optionally substituted with halogen １～９ C optionally substituted with at least one substituent selected from the group consisting of heteroaryl ６～１２ Aryl; or hydroxy, halogen, cyano, nitro, C optionally substituted with halogen １～６ Alkyl, C optionally substituted with halogen １～５ Alkoxy, halogen and / or C １～６ C optionally substituted with alkylaminocarbonyl ３～８C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ A compound described in [1] above, represented as a heteroaryl compound, or a pharmaceutically acceptable salt thereof.

[0012] [3] The following general formulas (1-1) to (1-6), general formulas (2-1) to (2-6), general formula (3-1), general formula (4-1), and general formula (5-1): [In the above general formulas (1-1) to (1-6), general formulas (2-1) to (2-6), general formula (3-1), general formula (4-1), and general formula (5-1), R １ ~R ５ , W, X １ and X ３ The compound described in [2] above or a pharmaceutically acceptable salt thereof, which is represented by any of the following formulas: (1) to (8) above.

[0013] [4] A compound according to any of [1] to [3] above, wherein W is formula (A-2) or formula (A-3), or a pharmaceutically acceptable salt thereof. [5] A compound according to any of [1] to [3] above, wherein W is formula (A-5) or formula (A-6), or a pharmaceutically acceptable salt thereof. [6] A compound according to any of [1] to [3] above, wherein W is formula (A-7) or formula (A-10), or a pharmaceutically acceptable salt thereof.

[0014] [7] R １ and R ２ However, the compound described in any of [1] to [6] above, which is the same halogen, or a pharmaceutically acceptable salt thereof. [8]R １ and R ２ However, the compound described in any of [1] to [6] above, which is fluorine, or a pharmaceutically acceptable salt thereof. [9]R １ and R ２A compound according to any of [1] to [6] above, wherein one of the compounds is a halogen and the other is hydrogen, or a pharmaceutically acceptable salt thereof.

[10] R ３ However, hydrogen or CF ３ The compound described in any of [1] to [9] above, or a pharmaceutically acceptable salt thereof.

[0015]

[11] X １ CR ５ The compound described in any of [2] to

[10] above or a pharmaceutically acceptable salt thereof.

[12] X １ A compound or a pharmaceutically acceptable salt thereof according to any of [2] to

[10] above, wherein is N.

[13] X ２ CR ５ The compound described in any of [2] to

[12] above or a pharmaceutically acceptable salt thereof.

[14] X ２ A compound or a pharmaceutically acceptable salt thereof described in any of [2] to

[12] above, wherein N is

[15] X ３ CR ５ The compound described in any of [2] to

[14] above or a pharmaceutically acceptable salt thereof.

[16] X ３ A compound according to any of [2] to

[14] above, wherein N is present, or a pharmaceutically acceptable salt thereof.

[0016]

[17] Y １ is C(R ５ ) ２ Either or when the dashed line indicates a connection, it is CR. ５ The compound described in any of [2] to

[16] above or a pharmaceutically acceptable salt thereof.

[18] Y １ NR ５ A compound or a pharmaceutically acceptable salt thereof according to any of [2] to

[16] above, which is either or, when the dashed line indicates a bond, is N.

[19] Y ２ is C(R ５ ) ２ Either or when the dashed line indicates a connection, it is CR. ５ The compound described in any of [2] to

[18] above or a pharmaceutically acceptable salt thereof.

[20] Y ２ NR５ A compound or a pharmaceutically acceptable salt thereof according to any of [2] to

[18] above, which is either or, when the dashed line indicates a bond, is N.

[21] Y ３ is C(R ５ ) ２ Either or when the dashed line indicates a connection, it is CR. ５ The compound described in any of [2] to

[20] above or a pharmaceutically acceptable salt thereof.

[22] Y ３ NR ５ A compound or a pharmaceutically acceptable salt thereof, as described in any of [2] to

[20] above, or N when the dashed line indicates a bond.

[23] Y ６ A compound according to any of [2] to

[22] above, wherein the compound is O, or a pharmaceutically acceptable salt thereof.

[0017]

[24] R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６ Alkyl; or C which may be substituted with halogen, cyano, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６Alkylcarbonyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkenyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ２～６ Heterocycloalkyl; or halogen, cyano, C １～６C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ C may be substituted with aryl, or halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ A heteroaryl compound, one of the compounds described in any of [3] to

[23] above, or a pharmaceutically acceptable salt thereof.

[25] R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls.３～８ Cycloalkyl; or halogen, cyano, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ C may be substituted with aryl, or halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ A heteroaryl compound, one of the compounds described in any of [3] to

[23] above, or a pharmaceutically acceptable salt thereof.

[26] R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ Cyclohexyl which may be substituted with at least one substituent selected from the group consisting of cycloalkyls; or halogen, cyano, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～５ Alkoxy, halogen and / or C １～６C may be substituted with alkylaminocarbonyl. ３～８ Phenyl which may be substituted with at least one substituent selected from the group consisting of cycloalkyls; or C which may be substituted with halogen, cyano, or halogen １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ A pyridyl which may be substituted with at least one substituent selected from the group consisting of cycloalkyl groups, the compound according to any one of [3] to

[23] above, or a pharmaceutically acceptable salt thereof.

[0018]

[27] The following formulas (1) to (77): A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

[0019]

[28] A pharmaceutical composition containing the compound described in any of [1] to

[27] above or a pharmaceutically acceptable salt thereof.

[29] An HSD17B13 inhibitor containing the compound described in any of [1] to

[27] above or a pharmaceutically acceptable salt thereof.

[30] A preventive or therapeutic agent for a disease involving HSD17B13, containing the compound described in any of [1] to

[27] above or a pharmaceutically acceptable salt thereof.

[31] The preventive or therapeutic agent according to

[30] above, wherein the disease involving HSD17B13 is a liver disease.

[0020] This disclosure provides novel compounds, etc., that have 17β-hydroxysteroid dehydrogenase 13 (HSD17B13) inhibitory activity. According to preferred embodiments of this disclosure, compounds, etc., that have excellent HSD17B13 inhibitory activity are provided. Furthermore, according to preferred embodiments of this disclosure, compounds, etc., that are less susceptible to metabolism by glucuronidation and have a long duration of HSD17B13 inhibitory activity are provided. Moreover, according to preferred embodiments of this disclosure, compounds, etc., that offer a high degree of design flexibility are provided.

[0021] 1. Definitions The terms used herein are defined below.

[0022] In this specification, "HSD17B13" means 17β-hydroxysteroid dehydrogenase 13. 17β-hydroxysteroid dehydrogenase (HSD17B) is a group of enzymes that primarily catalyze redox reactions involving steroid hormones, lipids, and retinoids, and plays a physiologically important role. Numerous subtypes of HSD17B are known, each possessing different substrate specificities and tissue distributions. Of these, HSD17B13 is mainly distributed in the liver and is involved in lipid metabolism and steroid metabolism. Studies such as those described in Non-Patent Document 1 have reported that HSD17B13 is associated with liver diseases (e.g., non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-related fatty liver disease (MASLD), non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-related steatohepatitis (MASH), cirrhosis, liver cancer, etc.).

[0023] In this specification, "inhibition of HSD17B13" means reducing or eliminating the enzymatic activity of HSD17B13. Inhibiting HSD17B13 may be effective in treating or preventing liver diseases by reducing hepatic fat accumulation, suppressing hepatitis, suppressing hepatic fibrosis, and suppressing hepatic cancer (e.g., N Engl J Med. 2018 Mar 22; 378(12) 1096-1106, Hepatology. 2019 Apr;69(4)1504-1519).

[0024] In this specification, "bicyclic heterocycle" means a structure consisting of one heterocycle (heteroaryl) and one ring structure fused to the heterocycle. In this case, the ring structure fused to the heterocycle (heteroaryl) is a 3- to 10-membered cycloalkyl, a 3- to 10-membered cycloalkenyl, a 3- to 10-membered heterocycloalkyl, a 3- to 10-membered heterocycloalkenyl, a 5- to 6-membered aryl, or a 5- to 6-membered heteroaryl. For example, isoquinoline, which is formed by the fusion of the heterocycle (heteroaryl) pyridine and the aryl phenyl, is a bicyclic heterocycle. On the other hand, 2,2'-dipyridine, in which the heterocycle (heteroaryl) pyridine and the heteroaryl pyridine are linked by a single bond, is not a bicyclic heterocycle.

[0025] 2. Compounds represented by general formula (I) or pharmaceutically acceptable salts thereof The compounds relating to this disclosure are represented by the following general formula (I). Note that the conventional compounds described in Patent Document 1 are phenols or their derivatives, and are therefore susceptible to metabolism by glucuronidation, which may necessitate frequent administration. In contrast, the compounds relating to this disclosure have a 4-pyridinol ring, making them less susceptible to metabolism by glucuronidation, and thus expected to have a longer duration of HSD17B13 inhibitory activity. Furthermore, the conventional compounds described in Patent Document 1 have a rigid structure in which two or more aromatic rings are linked to each other by single bonds or carbonyl groups, which may limit the design of the compounds. In contrast, the compounds relating to this disclosure have a 4-pyridinol ring and a bicyclic heterocycle linked to each other by linking groups of formulas (A-1) to (A-12), which is expected to provide greater freedom in the design of the compounds. Note that in this specification, "compounds represented by general formula (I) or pharmaceutically acceptable salts thereof" or "compounds represented by general formula (I)" may be referred to as "compounds relating to this disclosure".

[0026]

[0027] In the above general formula (I), R １ and R ２ Each is independently hydrogen; halogen; or cyano, and R １ and R２ At least one of them is a halogen or a cyanoacrylate.

[0028] Halogens include fluorine, chlorine, bromine, iodine, and others.

[0029] In one embodiment, R １ and R ２ It is preferable that the halogen is the same, and more preferably that it is fluorine.

[0030] In one embodiment, R １ and R ２ Preferably, one of them is a halogen and the other is hydrogen, and more preferably, one is fluorine and the other is hydrogen. In a preferred embodiment, R １ is fluorine, R ２ is hydrogen. In a preferred embodiment, R １ is hydrogen, R ２ That is fluorine.

[0031] R ３ C may be substituted with hydrogen; halogen; cyano; halogen. １～６ C may be substituted with alkyl or halogen compounds. ３～８ It is a cycloalkyl group.

[0032] 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, and more preferably methyl. C is substituted with a halogen. １～６Alkyl compounds include fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, bromomethyl, dibromomethyl, tribromomethyl, 1-bromoethyl, 2-bromoethyl, 1,1-dibromoethyl, 2,2-dibromoethyl, 1,2-dibromoethyl, 2,2,2-tribromoethyl, 1-bromopropyl, 3-bromopropyl, 3,3,3-tribromopropyl, chloromethyl, dichloromethyl, trichloromethyl, 1-chloroethyl, 2-chloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,2-dichloroethyl, 2,2,2-trichloroethyl, 1-chloropropyl, 3-chloropropyl, 3,3,3-trichloropropyl, and the like. C substituted with halogen １～６ The alkyl group is preferably trifluoromethyl or 2,2,2-trifluoroethyl, and more preferably trifluoromethyl.

[0033] C ３～８ Cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, and the like. ３～８ The cycloalkyl group is preferably cyclopropyl or bicyclo[2.2.2]octanyl, and more preferably cyclopropyl. C is substituted with a halogen. ３～８Cycloalkyls include 1-fluorocyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 1-fluorocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 3-fluorocyclopentyl, 3,3-difluorocyclopentyl, 3-fluorocyclohexyl, 3,3-difluorocyclohexyl, 4-fluorocyclohexyl, 4,4-difluorocyclohexyl, and 3-fluorochloropropyl. This includes olobicyclo[1.1.1]pentan-1-yl, 2-bromocyclopropyl, 2,2-dibromocyclopropyl, 2,3-dibromocyclopropyl, 3-bromocyclobutyl, 3,3-dibromocyclobutyl, 3-bromovicyclo[1.1.1]pentan-1-yl, 2-chlorocyclopropyl, 2,2-dichlorocyclopropyl, 2,3-dichlorocyclopropyl, 3-chlorocyclobutyl, 3,3-dichlorocyclobutyl, 3-chlorobicyclo[1.1.1]pentan-1-yl, etc., and halogen-substituted C ３～８ The cycloalkyl group is preferably 3,3-difluorocyclohexyl or 4,4-difluorocyclohexyl, and more preferably 4,4-difluorocyclohexyl.

[0034] In one embodiment, R ３ It is preferably hydrogen, halogen, cyano, optionally halogen-substituted methyl, optionally halogen-substituted ethyl, optionally halogen-substituted propyl, or optionally halogen-substituted isopropyl, more preferably hydrogen, fluorine, cyano, or optionally halogen-substituted methyl, and hydrogen or CF ３ It is even more preferable that it be (trifluoromethyl). In one embodiment, R ３ It is preferably hydrogen. In one embodiment, R ３ It is preferably a halogen, and more preferably a fluorine. In one embodiment, R ３ It is preferably cyanoacrylate. In one embodiment, R ３ C may be substituted with halogen. １～６Preferably alkyl, methyl, CF ３ More preferably ethyl, propyl, or isopropyl, and more preferably methyl or CF ３ It is even more preferable that CF ３ It is particularly preferable that R ３ C may be substituted with halogen. ３～８ It is preferably a cycloalkyl compound, more preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, even more preferably cyclopropyl or cyclobutyl, and particularly preferably cyclopropyl.

[0035] W is selected from the group consisting of the following formulas (A-1) to (A-12).

[0036] In the above formulas (A-1) to (A-12), A is C which may be substituted with a halogen. １～６ It is alkylene.

[0037] C １～６ Alkylene refers to linear or branched alkylenes. １～６ Alkylenes include, for example, methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, isopropylene, isobutylene, sec-butylene, tert-butylene, isopentylene, tert-pentylene, neopentylene, 2-pentylene, 3-pentylene, 2-hexylene, and the like.

[0038] In one embodiment, A is preferably methylene, ethylene, isopropylene, or isobutylene, more preferably methylene, ethylene, or isopropylene, and even more preferably methylene.

[0039] R ４ C may be substituted with hydrogen; cyano; or halogen. １～６ C may be substituted with alkyl or halogen compounds. ３～８ It is a cycloalkyl group.

[0040] C １～６ C substituted with alkyl and halogen １～６Alkyl, C ３～８ Cycloalkyl, halogen-substituted C ３～８ Cycloalkyl is R ３ It is the same as described in [the document].

[0041] In one embodiment, R ４ It is preferably hydrogen, halogen, cyano, optionally halogen-substituted methyl, optionally halogen-substituted ethyl, optionally halogen-substituted propyl, or optionally halogen-substituted isopropyl, more preferably hydrogen, fluorine, cyano, or optionally halogen-substituted methyl, and hydrogen or CF ３ It is even more preferable that it be (trifluoromethyl). In one embodiment, R ４ It is preferably hydrogen. In one embodiment, R ４ It is preferably a halogen, and more preferably a fluorine. In one embodiment, R ４ It is preferably cyanoacrylate. In one embodiment, R ４ C may be substituted with halogen. １～６ Preferably alkyl, methyl, CF ３ More preferably ethyl, propyl, or isopropyl, and more preferably methyl or CF ３ It is even more preferable that CF ３ It is particularly preferable that R ４ C may be substituted with halogen. ３～８ It is preferably a cycloalkyl compound, more preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, even more preferably cyclopropyl or cyclobutyl, and particularly preferably cyclopropyl.

[0042] In one embodiment, W is selected from the group consisting of the following formulas (A-1) to (A-12-2).

[0043] In one embodiment, W is formula (A-1), formula (A-2-1), formula (A-3-1), formula (A-4-1), formula (A-4-2), formula (A-5-1), formula (A-5-2), formula (A-6-1), formula (A-6-2), formula (A-7-1), formula (A-7-2), formula (A-8-1), formula (A-8-2), formula (A-9-1), formula (A-9-2), formula (A-10-1), formula (A-10-2), formula (A-11-1), formula (A-11-2), formula (A- It is preferable that W is formula (A-12-1), formula (A-12-2), more preferably formula (A-1), formula (A-2-1), formula (A-3-1), formula (A-7-1), formula (A-7-2), formula (A-10-1), formula (A-10-2), even more preferably formula (A-1), formula (A-2-1), formula (A-3-1), particularly preferably formula (A-2-1), formula (A-3-1), and most preferably formula (A-2-1). In one embodiment, W is preferably formula (A-1). In one embodiment, W is preferably formula (A-2) or formula (A-3), more preferably formula (A-2-1), formula (A-2-2), formula (A-3-1), formula (A-3-2), even more preferably formula (A-2-1), formula (A-3-1), and particularly preferably formula (A-2-1). In one embodiment, W is preferably formula (A-4), more preferably formula (A-4-1), formula (A-4-2), formula (A-4-4), even more preferably formula (A-4-2), formula (A-4-4), and particularly preferably formula (A-4-2). In one embodiment, W is preferably formula (A-5) or formula (A-6), more preferably formula (A-5-1), formula (A-5-2), formula (A-6-1), formula (A-6-2), even more preferably formula (A-5-2), formula (A-6-2), and particularly preferably formula (A-5-2). In one embodiment, W is preferably formula (A-7) or formula (A-10), more preferably formula (A-7-1), formula (A-7-2), formula (A-10-1), or formula (A-10-2), and even more preferably formula (A-7-2) or formula (A-10-2).In one embodiment, W is preferably formula (A-8), formula (A-9), formula (A-11), or formula (A-12), more preferably formula (A-8-1), formula (A-8-2), formula (A-9-1), formula (A-9-2), formula (A-11-1), formula (A-11-2), formula (A-12-1), or formula (A-12-2), and even more preferably formula (A-8-2), formula (A-9-2), formula (A-11-2), or formula (A-12-2).

[0044] Z is a bicyclic heterocycle. The bicyclic heterocycle consists of one heterocycle (heteroaryl) and one ring structure fused to the heterocycle. In this case, the ring structure is a 3- to 10-membered cycloalkyl ring, a 3- to 10-membered cycloalkenyl ring, a 3- to 10-membered heterocycloalkyl ring, a 3- to 10-membered heterocycloalkenyl ring, a 5- to 6-membered aryl ring, or a 5- to 6-membered heteroaryl ring.

[0045] A biring complex algebra includes the following equations (X-1) to (X-32).

[0046] In the above equations (X-1) to (X-32), "*" represents the connection with W. Each X is independently of CR. ５ Or N. Also, Y is independently C(R). ５ ) ２ , C=O, NR ５ , or O, or CR when the dashed line indicates a connection ５ or N. However, in equations (X-1) to (X-16), at least one X is N and / or at least one Y is NR ５ Alternatively, it is O, or N when the dashed line indicates connection. ５ This will be discussed later.

[0047] In one embodiment, the biring heterocycle is preferably any of formulas (X-1), (X-5), (X-9), (X-13), (X-17), (X-21), (X-25), or (X-29), more preferably any of formulas (X-1), (X-5), (X-17), or (X-21), and even more preferably formula (X-1) or (X-5).

[0048] In one preferred embodiment, the biring heterocycle is preferably one of the following formulas (X-1-1) to (X-21-3).

[0049] In the above equations (X-1-1) to (X-21-3), "*", R ５ This is the same as equations (X-1) to (X-32).

[0050] In a preferred embodiment, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is preferably a compound represented by any of the following general formulas (1) to (8) or a pharmaceutically acceptable salt thereof.

[0051] In the above general formulas (1) to (8), R １ ~R ３ And W is the same as in general formula (I).

[0052] X １ ~X ３ Each of them operates independently, CR ５ Or it is N.

[0053] In one embodiment, X １ CR ５ It is preferable that X １ It is preferable that is N. In one embodiment, X ２ CR ５ It is preferable that X ２ It is preferable that is N. In one embodiment, X ３ CR ５ It is preferable that X ３ It is preferable that is N. In one embodiment, X１ is N, and X ２ ~X ３ CR ５ It is preferable that X ３ is N, and X １ ~X ２ CR ５ It is preferable that X １ and X ３ It is preferable that X is N. １ and X ３ is N, and X ２ CR ５ It is preferable that it be so.

[0054] Y １ ~Y ６ Each of them is independent of C(R) ５ ) ２ , C=O, NR ５ , or O, or CR when the dashed line indicates a connection ５ Or it is N.

[0055] In one embodiment, Y １ C(R) ５ ) ２ Either or when the dashed line indicates a connection, it is CR. ５ It is preferable that Y １ NR ５ It is preferable that it is either or, when the dashed line indicates a connection, it is N. In one embodiment, Y １ It is preferable that C = O. In one embodiment, Y １ It is preferable that it is O.

[0056] In one embodiment, Y ２ C(R) ５ ) ２ Either or when the dashed line indicates a connection, it is CR. ５ It is preferable that Y ２ NR ５ It is preferable that it is either or, when the dashed line indicates a connection, it is N. In one embodiment, Y ２It is preferable that C = O. In one embodiment, Y ２ It is preferable that it is O.

[0057] In one embodiment, Y ３ C(R) ５ ) ２ Either or when the dashed line indicates a connection, it is CR. ５ It is preferable that Y ３ NR ５ It is preferable that it is either or, when the dashed line indicates a connection, it is N. In one embodiment, Y ３ It is preferable that C = O. In one embodiment, Y ３ It is preferable that it is O.

[0058] In one embodiment, Y ４ C(R) ５ ) ２ Either or when the dashed line indicates a connection, it is CR. ５ It is preferable that Y ４ NR ５ It is preferable that it is either or, when the dashed line indicates a connection, it is N. In one embodiment, Y ４ It is preferable that C = O. In one embodiment, Y ４ It is preferable that it is O.

[0059] In one embodiment, Y ５ C(R) ５ ) ２ Either or when the dashed line indicates a connection, it is CR. ５ It is preferable that Y ５ NR ５ It is preferable that it is either or, when the dashed line indicates a connection, it is N. In one embodiment, Y ５ It is preferable that C = O. In one embodiment, Y ５ It is preferable that it is O.

[0060] In one embodiment, Y ６ C(R) ５ ) ２Either or when the dashed line indicates a connection, it is CR. ５ It is preferable that Y ６ NR ５ It is preferable that it is either or, when the dashed line indicates a connection, it is N. In one embodiment, Y ６ It is preferable that C = O. In one embodiment, Y ６ It is preferable that it is O.

[0061] In one embodiment, X of general formula (1) １ is N, X ２ CR ５ or N, X ３ CR ５ Or N, Y １ NR ５ Y ２ CR ５ Or N, Y ３ CR ５ It is preferable that this is the case. In one embodiment, X of general formula (1) １ is N, X ２ CR ５ X ３ CR ５ Y １ NR ５ Y ２ CR ５ Or N, Y ３ CR ５ It is preferable that this is the case. In one embodiment, X of general formula (1) １ is N, X ２ CR ５ X ３ is N, Y １ NR ５ Y ２ CR ５ Or N, Y ３ CR ５ It is preferable that this be the case.

[0062] In one embodiment, X of general formula (2) １ is N, X ２ CR ５ or N, X ３ CR５ Or N, Y １ is C(R ５ ) ２ , NR ５ , C=O and Y ２ is C(R ５ ) ２ , NR ５ , or C=O, Y ３ is C(R ５ ) ２ Y ４ is C(R ５ ) ２ Alternatively, it is preferable that it is O. In one embodiment, X of general formula (2) １ is N, X ２ CR ５ X ３ CR ５ Y １ NR ５ Or C = O, Y ２ NR ５ Or C = O, Y ３ and Y ４ is C(R ５ ) ２ It is preferable that this be the case.

[0063] In one embodiment, X of general formula (3) １ is N, X ２ CR ５ or N, X ３ CR ５ Or N, Y １ is C(R ５ ) ２ , NR ５ , or O, Y ２ ~Y ４ is C(R ５ ) ２ Y ５ is C(R ５ ) ２ , NR ５ It is preferable that it is either or O. In one embodiment, X of general formula (3) １ is N, X ２ CR ５ X ３ CR ５ Y １NR ５ Y ２ ~Y ４ is C(R ５ ) ２ Y ５ is C(R ５ ) ２ Alternatively, it is preferable that it be O.

[0064] In one embodiment, X of general formula (4) １ is N, X ２ CR ５ or N, X ３ CR ５ Or N, Y １ is C(R ５ ) ２ , NR ５ , or O, Y ２ ~Y ５ is C(R ５ ) ２ Y ６ is C(R ５ ) ２ , NR ５ It is preferable that it is either or O. In one embodiment, X of general formula (4) １ is N, X ２ CR ５ X ３ CR ５ Y １ NR ５ Y ２ ~Y ５ is C(R ５ ) ２ Y ６ is C(R ５ ) ２ Alternatively, it is preferable that it be O.

[0065] In one embodiment, X of general formula (5) １ CR ５ or N, X ２ CR ５ X ３ CR ５ Or N, Y １ CR ５ Y ２ is CR, Y ３ is C(R ５) ２ Or NR ５ It is preferable that this is the case. In one embodiment, X of general formula (5) １ CR ５ or N, X ２ CR ５ X ３ CR ５ Or N, Y １ CR ５ Y ２ is CR, Y ３ NR ５ It is preferable that this be the case.

[0066] In one embodiment, X of general formula (6) １ CR ５ or N, X ２ CR ５ X ３ CR ５ Or N, Y １ is C(R ５ ) ２ , NR ５ , or C=O, Y ２ is C(R ５ ) ２ , NR ５ , or C=O, Y ３ is C(R ５ ) ２ Y ４ is C(R ５ ) ２ Alternatively, it is preferable that it be O. In one embodiment, X of general formula (6) １ CR ５ or N, X ２ CR ５ X ３ CR ５ Or N, Y １ NR ５ Y ２ is C(R ５ ) ２ Or C = O, Y ３ is C(R ５ ) ２ Y ４ is C(R ５ ) ２Alternatively, it is preferable that it be O.

[0067] In one embodiment, X of general formula (7) １ CR ５ or N, X ２ CR ５ or N, X ３ CR ５ Or N, Y １ is C(R ５ ) ２ , NR ５ , or O, Y ２ ~Y ４ is C(R ５ ) ２ Y ５ is C(R ５ ) ２ , NR ５ It is preferable that it is either or O. In one embodiment, X of general formula (7) １ CR ５ or N, X ２ CR ５ X ３ CR ５ Or N, Y １ NR ５ Y ２ ~Y ４ is C(R ５ ) ２ Y ５ is C(R ５ ) ２ Alternatively, it is preferable that it be O.

[0068] In one embodiment, X of general formula (8) １ CR ５ or N, X ２ CR ５ or N, X ３ CR ５ Or N, Y １ is C(R ５ ) ２ , NR ５ , or O, Y ２ ~Y ５ is C(R ５ ) ２ Y ６ is C(R ５ )２ , NR ５ It is preferable that it is either , or O. In one embodiment, X of general formula (8) １ CR ５ or N, X ２ CR ５ X ３ CR ５ Or N, Y １ NR ５ Y ２ ~Y ５ is C(R ５ ) ２ Y ６ is C(R ５ ) ２ Alternatively, it is preferable that it be O.

[0069] R ５ These are, independently, hydrogen; halogen; NR ６ R ７ OR ６ ; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６ Alkyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls.１～６ Alkylcarbonyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkenyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ２～６Heterocycloalkyl; or hydroxy, halogen, cyano, nitro, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ C may be substituted with aryl, hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ It is a heteroaryl compound.

[0070] Below, R ５ I will explain this.

[0071] [Halogen] The halogen includes fluorine, chlorine, bromine, iodine, etc., and preferably contains fluorine, chlorine, and bromine, and more preferably fluorine.

[0072] [Substituents] C (described later) １～６ Alkyl, C １～６ Alkylcarbonyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkenyl, C ２～６ Heterocycloalkyl, C６～１２ Aryl, and C １～９ The heteroaryl may be substituted with substituents. These substituents may be hydroxyl, halogen, cyano, nitro, or C. １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ Heteroaryls are one example.

[0073] The halogen substituents include fluorine, chlorine, bromine, iodine, etc. Preferably, the halogen substituent is fluorine, chlorine, or bromine, and more preferably fluorine.

[0074] C as a substituent １～６ Alkylcarbonylaminos include methylcarbonylamino, N-(methylcarbonylamino)-N-methylamino, ethylcarbonylamino, N-(ethylcarbonylamino)-N-methylamino, etc. C as a substituent. １～６ The alkylcarbonylamino is preferably a methylcarbonylamino.

[0075] C may be substituted with a halogen as a substituent. １～６ Alkyls include unsubstituted C such as 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, and 2-hexyl. １～６Alkyl; halogen-substituted C such as 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, 1,1-dibromoethyl, 2,2-dibromoethyl, 1,2-dibromoethyl, 2,2,2-tribromoethyl, 1-bromopropyl, 3-bromopropyl, 3,3,3-tribromopropyl, chloromethyl, dichloromethyl, trichloromethyl, 1-chloroethyl, 2-chloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,2-dichloroethyl, 2,2,2-trichloroethyl, 1-chloropropyl, 3-chloropropyl, 3,3,3-trichloropropyl １～６ Contains alkyl. C may be substituted with halogen as a substituent. １～６ The alkyl group is preferably methyl, ethyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, trifluoromethyl, or 2,2,2-trifluoroethyl, and more preferably methyl or trifluoromethyl.

[0076] C may be substituted with a halogen as a substituent. １～５ Alkoxys include unsubstituted C such as methoxy, ethoxy, propyloxy, n-butyloxy, n-pentyloxy, isopropyloxy, isobutyloxy, sec-butyloxy, and tert-butyloxy. １～５ Alkoxy; halogen-substituted C such as fluoromethyloxy, difluoromethyloxy, trifluoromethyloxy, and 2,2,2-trifluoroethyloxy. １～５ Contains alkoxy. C may be substituted with halogens as substituents. １～５ The alkoxy is preferably methoxy, ethoxy, isopropyloxy, trifluoromethyloxy, or 2,2,2-trifluoroethyloxy, and more preferably methoxy.

[0077] Halogens and / or C as substituents １～６ C may be substituted with alkylaminocarbonyl. ３～８ Cycloalkyls include unsubstituted C molecules such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, and bicyclo[2.2.2]octanyl. ３～８ Cycloalkyl; 1-fluorocyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 1-fluorocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 3-fluorocyclopentyl, 3,3-difluorocyclopentyl, 3-fluorocyclohexyl, 3,3-difluorocyclohexyl, 4-fluorocyclohexyl, 4,4-difluorocyclohexyl, 3-fluoro Halogen-substituted C such as bicyclo[1.1.1]pentan-1-yl, 2-bromocyclopropyl, 2,2-dibromocyclopropyl, 2,3-dibromocyclopropyl, 3-bromocyclobutyl, 3,3-dibromocyclobutyl, 3-bromovicyclo[1.1.1]pentan-1-yl, 2-chlorocyclopropyl, 2,2-dichlorocyclopropyl, 2,3-dichlorocyclopropyl, 3-chlorocyclobutyl, 3,3-dichlorocyclobutyl, 3-chlorobicyclo[1.1.1]pentan-1-yl ３～８Cycloalkyl; 2-methylaminocarbonylcyclobutyl, 2-methylaminocarbonylcyclopentyl, 3-methylaminocarbonylcyclopentyl, 2-methylaminocarbonylcyclohexyl, 3-methylaminocarbonylcyclohexyl, 4-methylaminocarbonylcyclohexyl, 2-ethylaminocarbonylcyclobutyl, 2-ethylaminocarbonylcyclopentyl, 3-ethylaminocarbonylcyclopentyl, 2-ethylaminocarbonylcyclohexyl, 3-ethylaminocarbonylcyclohexyl, 4-ethylaminocarbonylcyclohexyl, 2-isopropylaminocarbonylcyclobutyl, 2-isopropylaminocarbonylcyclopentyl, 3-isopropylaminocarbonylcyclopentyl, 2-isopropylaminocarbonylcyclohexyl, 3-isopropylaminocarbonylcyclohexyl, 4-isopropylaminocarbonylcyclohexyl, etc. １～６ Alkylaminocarbonyl-substituted C ３～８ Cycloalkyl; halogens and C such as 2-fluoro-3-methylaminocarbonylcyclopentyl, 3-fluoro-2-methylaminocarbonylcyclopentyl, 2,2-difluoro-3-methylaminocarbonylcyclopentyl, 3,3-difluoro-2-methylaminocarbonylcyclopentyl, 3-fluoro-4-methylaminocarbonylcyclohexyl, 4-fluoro-3-methylaminocarbonylcyclohexyl, 3,3-difluoro-4-methylaminocarbonylcyclohexyl, 4,4-difluoro-3-methylaminocarbonylcyclohexyl １～６ Alkylaminocarbonyl-substituted C ３～８ Contains cycloalkyl groups. C may be substituted with halogens as substituents. ３～８ The cycloalkyl is preferably cyclopropyl, cyclohexyl, bicyclo[2.2.2]octanyl, 3,3-difluorocyclobutyl, 3,3-difluorocyclohexyl, 4,4-difluorocyclohexyl, or 4-methylaminocarbonylcyclohexyl, and more preferably 4,4-difluorocyclohexyl.

[0078] C may be substituted with a halogen as a substituent. ２～６Heterocycloalkyls include unsubstituted C2 molecules such as aziridyl, azetidyl, pyrrolidyl, piperidyl, oxyranil (epoxy), oxetanyl, tetrahydrofuranil, tetrahydropyranil, tetrahydrothienyl, and morpholyl. ２～６ Heterocycloalkyl; halogen-substituted C such as 3-fluoro-2-pyrrolidyl, 3-fluoro-1-pyrrolidyl, 3-fluoro-4-piperidyl, 4-fluoro-1-piperidyl, 4,4-difluoro-1-piperidyl, 2-fluorooxylan-2-yl, 3-fluoro-2-tetrahydrofuranil, 3-fluoro-4-tetrahydrofuranil ２～６ Includes heterocycloalkyl groups. C may be substituted with halogens as substituents. ２～６ The heterocycloalkyl is preferably 1-pyrrolidyl, 2-pyrrolidyl, 1-piperidyl, 4-piperidyl, 2-tetrahydrofuranil, 3-tetrahydrofuranil, 2-tetrahydropyranil, or 4-tetrahydropyranil, and more preferably 4-tetrahydropyranil.

[0079] C may be substituted with a halogen as a substituent. ６～１２ Aryls are unsubstituted C such as phenyl, naphthyl, anthracenyl, and phenalenyl. ６～１２ Aryl; halogen-substituted C such as 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3,5-dibromophenyl, 2,4,6-tribromophenyl, 1-fluoro-2-naphthyl, 4-fluoro-2-naphthyl, 6-fluoro-2-naphthyl, 2-fluoro-1-naphthyl, 3-fluoro-1-naphthyl, 4-fluoro-1-naphthyl, 6-fluoro-1-naphthyl, etc. ６～１２ Contains aryl compounds. C may be substituted with halogens as substituents. ６～１２The aryl is preferably phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, or 2,4,6-trifluorophenyl, and more preferably phenyl.

[0080] C may be substituted with a halogen as a substituent. １～９ Heteroaryls include unsubstituted C compounds such as furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazol, pyrimidyl, pyridazyl, triazyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, phthalazyl, phenanthridyl, and acridyl. １～９ Heteroaryls; halogen-substituted C such as 2-fluoro-1-pyrrolyl, 1-fluoro-2-pyrrolyl, 4-fluoro-2-pyridyl, and 2-fluoro-4-pyridyl. １～９ Contains heteroaryl compounds. C may be substituted with halogens as substituents. １～９ The heteroaryl is preferably pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyridyl, pyrimidyl, pyridazyl, triadyl, 2-fluoro-1-pyrrolyl, 1-fluoro-2-pyrrolyl, 4-fluoro-2-pyridyl, or 2-fluoro-4-pyridyl, more preferably pyrrolyl or pyridyl, and even more preferably pyridyl.

[0081] [C １～６ Alkyl C １～６ Alkyl compounds include 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, and more preferably methyl.

[0082] Here, C １～６ The alkyl group may be substituted with hydroxy, halogen, cyano, nitro, or halogen C.１～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ It may be substituted with at least one substituent selected from the group consisting of heteroaryl compounds. In this case, each substituent is as described above.

[0083] C having substituents １～６ Alkyl compounds include hydroxymethyl, 2-hydroxyethyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyanomethyl, 2-cyanoethyl, nitromethyl, 2-nitromethyl, methoxymethyl, ethoxymethyl, methoxyethyl, trifluoromethoxymethyl, 2-trifluoromethoxyethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, bicyclo[2.2.2]octanemethyl, 1-fluorocyclopropylmethyl, 3,3-difluorocyclobutylmethyl, 3,3- This includes difluorocyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 4-methylaminocarbonylcyclohexylmethyl, 4-tetrahydropyranylmethyl, 1-pyrrolidinylmethyl, 1-piperidinylmethyl, 4-morpholylmethyl, benzyl, phenethyl, naphthylmethyl, 4-fluorophenylmethyl, 1,3,5-trifluorophenylmethyl, 2-furanylmethyl, 3-furanylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-pyrimidylmethyl, 3-pyridadylmethyl, etc. In one embodiment, a substituent C １～６ Alkyl is a halogen-substituted C １～６ It is preferably alkyl, more preferably trifluoromethyl, 2,2,2-trifluoroethyl, and even more preferably trifluoromethyl. In one embodiment, a substituted C １～６ Alkyls are halogens and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８Cycloalkyl-substituted C １～６ It is preferably alkyl, and more preferably cyclohexylmethyl, bicyclo[2.2.2]octanemethyl, 3,3-difluorocyclobutylmethyl, 3,3-difluorocyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 4-methylaminocarbonylcyclohexylmethyl, and more preferably 4,4-difluorocyclohexylmethyl. In one embodiment, a substituent C １～６ Alkyl is C ２～６ C substituted with heterocycloalkyl １～６ It is preferably an alkyl group, and more preferably 4-tetrahydropyranylmethyl.

[0084] Of these, C １～６ C having alkyl or substituent １～６ The alkyl group is preferably methyl, isopropyl, isobutyl, isopentyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, cyclohexylmethyl, bicyclo[2.2.2]octanemethyl, 3,3-difluorocyclobutylmethyl, 3,3-difluorocyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 4-methylaminocarbonylcyclohexylmethyl, 4-tetrahydropyranylmethyl, or benzyl, and more preferably methyl or trifluoromethyl.

[0085] [C １～６ [Alkylcarbonyl] C １～６ Alkyl carbonyls include methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, n-butyl carbonyl, n-pentyl carbonyl, n-hexyl carbonyl, isopropyl carbonyl, isobutyl carbonyl, sec-butyl carbonyl, tert-butyl carbonyl, isopentyl carbonyl, tert-pentyl carbonyl, neopentyl carbonyl, 2-pentyl carbonyl, 3-pentyl carbonyl, n-hexyl carbonyl, 2-hexyl carbonyl, etc. １～６ The alkylcarbonyl is preferably a methylcarbonyl.

[0086] Here, C１～６ The alkylcarbonyl may be substituted with hydroxy, halogen, cyano, nitro, or halogen C １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ It may be substituted with at least one substituent selected from the group consisting of heteroaryl compounds. In this case, each substituent is as described above.

[0087] C having substituents １～６ Alkyl carbonyls include hydroxymethyl carbonyl, trifluoromethyl carbonyl, 2,2,2-trifluoroethyl carbonyl, cyanomethyl carbonyl, nitromethyl carbonyl, methoxymethyl carbonyl, cyclopropylmethyl carbonyl, cyclobutylmethyl carbonyl, cyclohexylmethyl carbonyl, 4,4-difluorocyclohexylmethyl carbonyl, 4-methylaminocarbonylcyclohexylmethyl carbonyl, 1-morpholylmethyl carbonyl, benzyl carbonyl, 2-pyridylmethyl carbonyl, etc. C with substituents １～６ The alkylcarbonyl is preferably a trifluoromethylcarbonyl.

[0088] Of these, C １～６ C having an alkylcarbonyl or substituent １～６ The alkylcarbonyl is preferably a methylcarbonyl.

[0089] [C ３～８ Cycloalkyl C ３～８ Cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, etc. ３～８ The cycloalkyl group is preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and more preferably cyclopropyl.

[0090] Here, C ３～８ The cycloalkyl group may be substituted with hydroxy, halogen, cyano, nitro, or halogen C. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ It may be substituted with at least one substituent selected from the group consisting of heteroaryl compounds. In this case, each substituent is as described above.

[0091] C having substituents ３～８Cycloalkyls include 4-hydroxycyclohexyl, 1-fluorocyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 1-fluorocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 3-fluorocyclopentyl, 3,3-difluorocyclopentyl, 3-fluorocyclohexyl, 3,3-difluorocyclohexyl, 4-fluorocyclohexyl, 4,4-difluorocyclohexyl, 3-fluorobicyclo[1.1.1]pentan-1-yl, 2-bromocyclopropyl, 2,2-dibromocyclopropyl, 2,3-dibromocyclopropyl, and 3-bromocyclo This includes butyl, 3,3-dibromocyclobutyl, 3-bromovicyclo[1.1.1]pentan-1-yl, 2-chlorocyclopropyl, 2,2-dichlorocyclopropyl, 2,3-dichlorocyclopropyl, 3-chlorocyclobutyl, 3,3-dichlorocyclobutyl, 3-chlorobicyclo[1.1.1]pentan-1-yl, 4-(4-methylaminocarbonylcyclohexyl)cyclohexyl, 4-cyanocyclohexyl, 4-nitrocyclohexyl, 4-methylcyclohexyl, 4-trifluoromethylcyclohexyl, 4-methoxycyclohexyl, 4-cyclopropylcyclohexyl, 4-morpholylcyclohexyl, 4-phenylcyclohexyl, 4-(2-pyridyl)cyclohexyl, etc. A substituent C ３～８ The cycloalkyl group is preferably 4,4-difluorocyclohexyl or 4-methoxycyclohexyl.

[0092] Of these, C ３～８ Cycloalkyl or substituent C ３～８ The cycloalkyl group is preferably cyclopropyl, cyclopentyl, cyclohexyl, 4,4-difluorocyclohexyl, or 4-methoxycyclohexyl.

[0093] [C ３～８ Cycloalkenyl C ３～８Cycloalkenyls include 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 1-cyclohexen-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, etc. ３～８ The cycloalkenyl is preferably 1-cyclohexen-1-yl.

[0094] Here, C ３～８ Cycloalkenyl may be substituted with hydroxy, halogen, cyano, nitro, or halogen C １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ It may be substituted with at least one substituent selected from the group consisting of heteroaryl compounds. In this case, each substituent is as described above.

[0095] C having substituents ３～８ Cycloalkenyls include 4-hydroxy-1-cyclohexen-1-yl, 4-fluoro-1-cyclohexen-1-yl, 4,4-difluoro-1-cyclohexen-1-yl, 4-methyl-1-cyclohexen-1-yl, 4-trifluoromethyl-1-cyclohexen-1-yl, 4-(4-methylaminocarbonylcyclohexyl)-1-cyclohexen-1-yl, 4-methoxy-1-cyclohexen-1-yl, 4-phenyl-1-cyclohexen-1-yl, 4-(2-pyridyl)-1-cyclohexen-1-yl, etc. Substituent C ３～８ The cycloalkenyl is preferably 4,4-difluoro-1-cyclohexen-1-yl or 4-methoxy-1-cyclohexen-1-yl.

[0096] Of these, C ３～８ Cycloalkenyl or substituted C ３～８The cycloalkenyl is preferably 1-cyclohexen-1-yl, 4,4-difluoro-1-cyclohexen-1-yl, or 4-methoxy-1-cyclohexen-1-yl.

[0097] [C ２～６ [Heterocycloalkyl] C ２～６ Heterocycloalkyls include aziridyl, azetidyl, pyrrolidyl, piperidyl, oxyranil (epoxy), oxetanil, tetrahydrofuranil, tetrahydropyranil, tetrahydrothienyl, morpholyl, etc. ２～６ The heterocycloalkyl group is preferably tetrahydrofuranyl or morpholyl.

[0098] Here, C ２～６ The heterocycloalkyl group may be substituted with hydroxy, halogen, cyano, nitro, or halogen C. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ It may be substituted with at least one substituent selected from the group consisting of heteroaryl compounds. In this case, each substituent is as described above.

[0099] C having substituents ２～６Heterocycloalkyls include 2-hydroxy-4-tetrahydropyranyl, 4-hydroxy-2-tetrahydropyranyl, 3-hydroxy-4-morpholyl, 2-fluoro-4-tetrahydropyranyl, 4-fluoro-2-tetrahydropyranyl, 3-fluoro-4-morpholyl, 2-methyl-4-tetrahydropyranyl, 2,6-dimethyl-4-tetrahydropyranyl, 4-methyl-2-tetrahydropyranyl, 3-methyl-4-morpholyl, 2,6-dimethyl-4-morpholyl, 2-trifluoromethyl-4-tetrahydropyranyl, 2,6-ditrifluoromethyl-4-tetrahydropyranyl, and 4-trifluoromethyl This includes C1-2-tetrahydropyranyl, 3-trifluoromethyl-4-morpholyl, 2,6-ditrifluoromethyl-4-morpholyl, 2-cyclopropyl-4-tetrahydropyranyl, 4-cyclopropyl-2-tetrahydropyranyl, 3-cyclopropyl-4-morpholyl, 2-(4-methylaminocarbonylcyclohexyl)-4-morpholyl, 2-phenyl-4-tetrahydropyranyl, 4-phenyl-2-tetrahydropyranyl, 3-phenyl-4-morpholyl, 2-(2-pyridyl)-4-tetrahydropyranyl, 4-(2-pyridyl)-2-tetrahydropyranyl, 3-(2-pyridyl)-4-morpholyl, etc. ２～６ The heterocycloalkyl group is preferably 2,6-dimethyl-4-morpholyl.

[0100] Of these, C ２～６ Heterocycloalkyl or substituent-containing C ２～６ The heterocycloalkyl group is preferably 2-tetrahydrofuranyl, 4-tetrahydrofuranyl, 4-morpholyl, or 2,6-dimethyl-4-morpholyl.

[0101] [C ６～１２ [Aryl] C ６～１２ Aryls include phenyl, naphthyl, anthracenyl, phenalenyl, etc. ６～１２ The aryl group is preferably phenyl.

[0102] Here, C ６～１２ Aryls are hydroxy, halogen, cyano, nitro, and C. １～６C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ It may be substituted with at least one substituent selected from the group consisting of heteroaryl compounds. In this case, each substituent is as described above.

[0103] C having substituents ６～１２Aryls include 4-hydroxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,6-dibromophenyl, 2,4-dibromophenyl, 3,4-dibromophenyl, 3,4,5-tribromophenyl, 2,4,6-tribromophenyl, 2- This includes cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-cyano-4-fluorophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-nitro-4-fluorophenyl, 3-methylcarbonylaminophenyl, 4-methylcarbonylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-cyclohexylphenyl, 4-(4,4-difluorocyclohexyl)phenyl, 4-(4-methylaminocarbonylcyclohexyl)phenyl, biphenyl, 4-(2-pyridyl)phenyl, etc. A substituent C ６～１２ The aryl is preferably 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-cyanophenyl, 2-cyano-4-fluorophenyl, 3-methylcarbonylaminophenyl, 4-methylcarbonylaminophenyl, 2-methylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, or 4-methoxyphenyl.

[0104] Of these, C ６～１２C having an aryl or substituent ６～１２ The aryl is preferably phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-cyanophenyl, 2-cyano-4-fluorophenyl, 3-methylcarbonylaminophenyl, 4-methylcarbonylaminophenyl, 2-methylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, or 4-methoxyphenyl.

[0105] [C １～９ [Heteroaryl] C １～９ Heteroaryls include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazol, pyrimidyl, pyridazyl, triazyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, phthalazyl, phenanthridyl, acridyl, etc. １～９ The heteroaryl is preferably pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrizyl, pyrimidyl, pyridazyl, and triazyl, and more preferably pyrrolyl, pyridyl, pyrizyl, pyrimidyl, pyrazolyl, thiazolyl, pyridyl, pyrizyl, pyrimidyl, and pyridazyl.

[0106] Here, C １～９ The heteroaryl may be substituted with hydroxy, halogen, cyano, nitro, or halogen C １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２C may be substituted with aryl or halogen. １～９ It may be substituted with at least one substituent selected from the group consisting of heteroaryl compounds. In this case, each substituent is as described above.

[0107] C having substituents １～９Heteroaryls include 2-hydroxy-1-pyrrolyl, 3-fluoro-2-pyrrolyl, 4-fluoro-2-oxazolyl, 5-fluoro-2-oxazolyl, 3-fluoro-5-isoxazolyl, 4-fluoro-2-thiazolyl, 5-fluoro-2-thiazolyl, 5-fluoro-3-isothiazolyl, 3-fluoro-2-pyridyl, 4-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-fluoro-2-pyridyl, 2-fluoro-3-pyridyl, 4-fluoro-3-pyridyl, 5-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, and 5-fluoro- Luoro-2-pyradyl, 6-fluoro-2-pyradyl, 2-fluoro-4-pyrimidyl, 2-fluoro-5-pyrimidyl, 3-fluoro-2-pyrimidyl, 4-fluoro-2-pyrimidyl, 5-fluoro-2-pyrimidyl, 5-fluoro-3-pyridadyl, 6-fluoro-3-pyridadyl, 3-cyano-2-pyrrolyl, 4-cyano-2-oxazolyl, 5-cyano-2-oxazolyl, 3-cyano-5-isoxazolyl, 4-cyano-2-thiazolyl, 5-cyano-2-thiazolyl, 5-cyano-3-isothiazolyl, 3-cyano-2-pyridyl, 4-cyano No-2-pyridyl, 5-cyano-2-pyridyl, 6-cyano-2-pyridyl, 2-cyano-3-pyridyl, 4-cyano-3-pyridyl, 5-cyano-3-pyridyl, 6-cyano-3-pyridyl, 5-cyano-2-pyradyl, 6-cyano-2-pyradyl, 2-cyano-4-pyrimidyl, 2-cyano-5-pyrimidyl, 3-cyano-2-pyrimidyl, 4-cyano-2-pyrimidyl, 5-cyano-2-pyrimidyl, 5-cyano-3-pyridadyl, 6-cyano-3-pyridadyl, 3-nitro-2-pyrrolyl, 4-nitro-2-oxazolyl, 5-nitro-2-oxazolyl Zolyl, 3-nitro-5-isoxazolyl, 4-nitro-2-thiazolyl, 5-nitro-2-thiazolyl, 5-nitro-3-isothiazolyl, 3-nitro-2-pyridyl, 4-nitro-2-pyridyl, 5-nitro-2-pyridyl, 6-nitro-2-pyridyl, 2-nitro-3-pyridyl, 4-nitro-3-pyridyl, 5-nitro-3-pyridyl, 6-nitro-3-pyridyl, 5-nitro-2-pyradyl, 6-nitro-2-pyradyl, 2-nitro-4-pyrimidyl, 2-nitro-5-pyrimidyl, 3-nitro-2-pyrimidyl, 4-nitro-2-pyrimidyl,5-Nitro-2-pyrimidyl, 5-Nitro-3-pyridadyl, 6-Nitro-3-pyridadyl, 3-Methyl-2-pyrrolyl, 4-Methyl-2-oxazolyl, 5-Methyl-2-oxazolyl, 3-Methyl-5-isoxazolyl, 4-Methyl-2-thiazolyl, 5-Methyl-2-thiazolyl, 5-Methyl-3-isothiazolyl, 3-Methyl-2-pyridyl, 4-Methyl-2-pyridyl, 5-Methyl-2-pyridyl, 6-Methyl-2-pyridyl, 2-Methyl-3-pyridyl, 4-Methyl-3-pyridyl, 5-Methyl-3-pyridyl, 6-Methyl-3-pyridyl, 5 -Methyl-2-pyrazyl, 6-methyl-2-pyrazyl, 2-methyl-4-pyrimidyl, 2-methyl-5-pyrimidyl, 3-methyl-2-pyrimidyl, 4-methyl-2-pyrimidyl, 5-methyl-2-pyrimidyl, 5-methyl-3-pyridazyl, 6-methyl-3-pyridazyl, 3-trifluoromethyl-2-pyrrolyl, 4-trifluoromethyl-2-oxazolyl, 5-trifluoromethyl-2-oxazolyl, 3-trifluoromethyl-5-isoxazolyl, 4-trifluoromethyl-2-thiazolyl, 5-trifluoromethyl-2-thiazolyl, 5-tri Fluoromethyl-3-isothiazolyl, 3-trifluoromethyl-2-pyridyl, 4-trifluoromethyl-2-pyridyl, 5-trifluoromethyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl, 2-trifluoromethyl-3-pyridyl, 4-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-2-pyradyl, 6-trifluoromethyl-2-pyradyl, 2-trifluoromethyl-4-pyrimidyl, 2-trifluoromethyl-5-pyrimidyl, 3- Trifluoromethyl-2-pyrimidyl, 4-trifluoromethyl-2-pyrimidyl, 5-trifluoromethyl-2-pyrimidyl, 5-trifluoromethyl-3-pyridadyl, 6-trifluoromethyl-3-pyridadyl, 3-methoxy-2-pyrrolyl, 4-methoxy-2-oxazolyl, 5-methoxy-2-oxazolyl, 3-methoxy-5-isoxazolyl, 4-methoxy-2-thiazolyl, 5-methoxy-2-thiazolyl, 5-methoxy-3-isothiazolyl, 3-methoxy-2-pyridyl, 4-methoxy-2-pyridyl, 5-methoxy-2-pyridyl6-Methoxy-2-pyridyl, 2-Methoxy-3-pyridyl, 4-Methoxy-3-pyridyl, 5-Methoxy-3-pyridyl, 6-Methoxy-3-pyridyl, 5-Methoxy-2-pyrazyl, 6-Methoxy-2-pyrazyl, 2-Methoxy-4-pyrimidyl, 2-Methoxy-5-pyrimidyl, 3-Methoxy-2-pyrimidyl, 4-Methoxy-2-pyrimidyl, 5-Methoxy-2-pyrimidyl, 5-Methoxy-3-pyridazyl, 6-Methoxy-3-pyridazyl, 3-Cyclopropyl-2-pyrrolyl, 4-Cyclopropyl-2-oxazolyl, 5-Cyclopropyl 2-oxazolyl, 3-cyclopropyl-5-isoxazolyl, 4-cyclopropyl-2-thiazolyl, 5-cyclopropyl-2-thiazolyl, 5-cyclopropyl-3-isothiazolyl, 3-cyclopropyl-2-pyridyl, 4-cyclopropyl-2-pyridyl, 5-cyclopropyl-2-pyridyl, 5-cyclopropyl-4-trifluoromethyl-2-pyridyl, 6-cyclopropyl-2-pyridyl, 2-cyclopropyl-3-pyridyl, 4-cyclopropyl-3-pyridyl, 5-cyclopropyl-3-pyridyl, 6-cyclopropyl-3-pyridyl Lysyl, 5-cyclopropyl-2-pyrazyl, 6-cyclopropyl-2-pyrazyl, 2-cyclopropyl-4-pyrimidyl, 2-cyclopropyl-5-pyrimidyl, 3-cyclopropyl-2-pyrimidyl, 4-cyclopropyl-2-pyrimidyl, 5-cyclopropyl-2-pyrimidyl, 5-cyclopropyl-3-pyridazyl, 6-cyclopropyl-3-pyridazyl, 3-(4-methylaminocarbonylcyclohexyl)-2-pyrrolyl, 4-(4-methylaminocarbonylcyclohexyl)-2-oxazolyl, 5-(4-methylaminocarbonylcyclohexyl (4-methylaminocarbonylcyclohexyl)-2-oxazolyl, 3-(4-methylaminocarbonylcyclohexyl)-5-isoxazolyl, 4-(4-methylaminocarbonylcyclohexyl)-2-thiazolyl, 5-(4-methylaminocarbonylcyclohexyl)-2-thiazolyl, 5-(4-methylaminocarbonylcyclohexyl)-3-isothiazolyl, 3-(4-methylaminocarbonylcyclohexyl)-2-pyridyl, 4-(4-methylaminocarbonylcyclohexyl)-2-pyridyl, 5-(4-methylaminocarbonylcyclohexyl)-2-pyridyl,5-(4-methylaminocarbonylcyclohexyl)-4-trifluoromethyl-2-pyridyl, 6-(4-methylaminocarbonylcyclohexyl)-2-pyridyl, 2-(4-methylaminocarbonylcyclohexyl)-3-pyridyl, 4-(4-methylaminocarbonylcyclohexyl)-3-pyridyl, 5-(4-methylaminocarbonylcyclohexyl)-3-pyridyl, 6-(4-methylaminocarbonylcyclohexyl)-3-pyridyl, 5-(4-methylaminocarbonylcyclohexyl)-2-pyradyl, 6-(4-methylaminocarbonylcyclohexyl)-2-pyradyl, 2-(4-methylaminocarbonylcyclohexyl)-4-pyrimidyl, 2-(4-methylaminocarbonylcyclohexyl)-5-pyrimidyl This includes 3-(4-methylaminocarbonylcyclohexyl)-2-pyrimidyl, 4-(4-methylaminocarbonylcyclohexyl)-2-pyrimidyl, 5-(4-methylaminocarbonylcyclohexyl)-2-pyrimidyl, 5-(4-methylaminocarbonylcyclohexyl)-3-pyridadyl, 6-(4-methylaminocarbonylcyclohexyl)-3-pyridadyl, 3-phenyl-2-pyrrolyl, 4-phenyl-2-pyridyl, 5-phenyl-2-pyrazyl, 4-phenyl-2-pyrimidyl, 5-phenyl-3-pyridadyl, 3-(2-pyridyl)-2-pyrrolyl, 4-(2-pyridyl)-2-pyridyl, 5-(2-pyridyl)-2-pyrazyl, 4-(2-pyridyl)-2-pyrimidyl, 5-(2-pyridyl)-3-pyridadyl, etc.

[0108] Of these, C １～９ Heteroaryl or substituent-containing C １～９Heteroaryls include 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridadyl, 4-pyrimidadyl, 3-fluoro-2-pyrrolyl, 4-fluoro-2-pyrrolyl, 2-fluoro-3-pyrrolyl, 4-fluoro-3-pyrrolyl, 3-fluoro-2-imidazolyl, 4-fluoro-2-imidazolyl, 2-fluoro-4-imidazolyl, and 4-fluoro-3-pyrazolyl. Ryl, 4-fluoro-3-pyrazolyl, 3-fluoro-4-pyrazolyl, 4-fluoro-2-thiazolyl, 5-fluoro-2-thiazolyl, 2-fluoro-4-thiazolyl, 3-fluoro-2-pyridyl, 4-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 2-fluoro-3-pyridyl, 4-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, 2-fluoro-4-pyridyl, 3-fluoro-4-pyridyl, 2-fluoro-5-pyridyl, 4-fluoro-2-pyrimidyl, 5-fluoro-2-pyrimidyl, 2-fluoro-4-pyrimidyl, 6-Fluoro-4-pyrimidyl, 2-Fluoro-5-pyrimidyl, 4-Fluoro-5-pyrimidyl, 5-Fluoro-3-pyridadyl, 3-Fluoro-4-pyridadyl, 1-Methyl-2-pyrrolyl, 3-Methyl-2-pyrrolyl, 4-Methyl-2-pyrrolyl, 1-Methyl-3-pyrrolyl, 2-Methyl-3-pyrrolyl, 4-Methyl-3-pyrrolyl, 1-Methyl-2-imidazolyl, 3-Methyl-2-imidazolyl, 4-Methyl-2-imidazolyl, 2-Methyl-4-imidazolyl, 4-Methyl-3-pyrazolyl, 1-Methyl-4-pyrazolyl, 3-Methyl-4- Pyrazolyl, 4-methyl-2-thiazolyl, 5-methyl-2-thiazolyl, 2-methyl-4-thiazolyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 2-methyl-3-pyridyl, 4-methyl-3-pyridyl, 6-methyl-3-pyridyl, 2-methyl-4-pyridyl, 3-methyl-4-pyridyl, 2-methyl-5-pyridyl, 4-methyl-2-pyrimidyl, 5-methyl-2-pyrimidyl, 2-methyl-4-pyrimidyl, 6-methyl-4-pyrimidyl, 2-methyl-5-pyrimidyl, 4-methyl-5-pyrimidyl5-methyl-3-pyridadyl, 3-methyl-4-pyridadyl, 1-trifluoromethyl-2-pyrrolyl, 3-trifluoromethyl-2-pyrrolyl, 4-trifluoromethyl-2-pyrrolyl, 1-trifluoromethyl-3-pyrrolyl, 2-trifluoromethyl-3-pyrrolyl, 4-trifluoromethyl-3-pyrrolyl, 1-trifluoromethyl-2-imidazolyl, 3-trifluoromethyl-2-imidazolyl, 4-trifluoromethyl-2-imidazolyl, 2-trifluoromethyl-4-imidazolyl, 4-trifluoromethyl-3-pyrazolyl, 1- Lifluoromethyl-4-pyrazolyl, 3-trifluoromethyl-4-pyrazolyl, 4-trifluoromethyl-2-thiazolyl, 5-trifluoromethyl-2-thiazolyl, 2-trifluoromethyl-4-thiazolyl, 3-trifluoromethyl-2-pyridyl, 4-trifluoromethyl-2-pyridyl, 5-trifluoromethyl-2-pyridyl, 2-trifluoromethyl-3-pyridyl, 4-trifluoromethyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 2-trifluoromethyl-4-pyridyl, 3-trifluoromethyl-4-pyridyl 2-trifluoromethyl-5-pyridyl, 4-trifluoromethyl-2-pyrimidyl, 5-trifluoromethyl-2-pyrimidyl, 2-trifluoromethyl-4-pyrimidyl, 6-trifluoromethyl-4-pyrimidyl, 2-trifluoromethyl-5-pyrimidyl, 4-trifluoromethyl-5-pyrimidyl, 5-trifluoromethyl-3-pyridadyl, 3-trifluoromethyl-4-pyridadyl, 1-cyclopropyl-2-pyrrolyl, 3-cyclopropyl-2-pyrrolyl, 4-cyclopropyl-2-pyrrolyl, 1-cyclopropyl-3-pyrrolyl, 2- Cyclopropyl-3-pyrrolyl, 4-cyclopropyl-3-pyrrolyl, 1-cyclopropyl-2-imidazolyl, 3-cyclopropyl-2-imidazolyl, 4-cyclopropyl-2-imidazolyl, 2-cyclopropyl-4-imidazolyl, 4-cyclopropyl-3-pyrazolyl, 1-cyclopropyl-4-pyrazolyl, 3-cyclopropyl-4-pyrazolyl, 4-cyclopropyl-2-thiazolyl, 5-cyclopropyl-2-thiazolyl, 2-cyclopropyl-4-thiazolyl, 3-cyclopropyl-2-pyridyl, 4-cyclopropyl-2-pyridyl5-Cyclopropyl-2-pyridyl, 5-Cyclopropyl-4-trifluoromethyl-2-pyridyl, 2-Cyclopropyl-3-pyridyl, 4-Cyclopropyl-3-pyridyl, 6-Cyclopropyl-3-pyridyl, 2-Cyclopropyl-4-pyridyl, 3-Cyclopropyl-4-pyridyl, 2-Cyclopropyl-5-pyridyl, 4-Cyclopropyl-2-pyrimidyl, 5-Cyclopropyl-2-pyrimidyl, 2-Cyclopropyl-4-pyrimidyl, 6-Cyclopropyl-4-pyrimidyl, 2-Cyclopropyl-5-pyrimidyl, 4-Cyclopropyl-5 - Pyrimidyl, 5-cyclopropyl-3-pyridadyl, 3-cyclopropyl-4-pyridadyl, 1-methoxy-2-pyrrolyl, 3-methoxy-2-pyrrolyl, 4-methoxy-2-pyrrolyl, 1-methoxy-3-pyrrolyl, 2-methoxy-3-pyrrolyl, 4-methoxy-3-pyrrolyl, 1-methoxy-2-imidazolyl, 3-methoxy-2-imidazolyl, 4-methoxy-2-imidazolyl, 2-methoxy-4-imidazolyl, 4-methoxy-3-pyrazolyl, 1-methoxy-4-pyrazolyl, 3-methoxy-4-pyrazolyl, 4-methoxy-2-thiazolyl 5-Methoxy-2-thiazolyl, 2-Methoxy-4-thiazolyl, 3-Methoxy-2-pyridyl, 4-Methoxy-2-pyridyl, 5-Methoxy-2-pyridyl, 2-Methoxy-3-pyridyl, 4-Methoxy-3-pyridyl, 6-Methoxy-3-pyridyl, 2-Methoxy-4-pyridyl, 3-Methoxy-4-pyridyl, 2-Methoxy-5-pyridyl, 4-Methoxy-2-pyrimidyl, 5-Methoxy-2-pyrimidyl, 2-Methoxy-4-pyrimidyl, 6-Methoxy-4-pyrimidyl, 2-Methoxy-5-pyrimidyl, 4-Methoxy-5-pyrimidyl, 5- It is preferably methoxy-3-pyridadyl or 3-methoxy-4-pyridadyl, and more preferably 3-fluoro-2-pyrrolyl, 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 1-methyl-4-pyrazolyl, 1-methyl-3-pyrazolyl, 2-trifluoromethyl-5-pyridyl, 5-trifluoromethyl-2-pyridyl, 2-trifluoromethyl-5-pyrimidyl, 5-cyclopropyl-4-trifluoromethyl-2-pyridyl, 2-methoxy-4-pyridyl, 2-methoxy-5-pyridyl, or 2-methoxy-5-pyrimidyl.

[0109] [NR ６ R ７ ] R ６ and R ７ These are C, which may be substituted with hydrogen or halogen, independently of each other. １～６ Alkylcarbonyl; C may be substituted with halogen. ３～８ Cycloalkylcarbonyl; C which may be substituted with halogen ２～６ Heterocycloalkylcarbonyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６ Alkyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkyl; or hydroxy, halogen, cyano, nitro, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６C optionally substituted with alkylaminocarbonyl ３～８ cycloalkyl, C optionally substituted with halogen ２～６ heterocycloalkyl, C optionally substituted with halogen ６～１２ aryl, C optionally substituted with halogen １～９ C optionally substituted with at least one substituent selected from the group consisting of heteroaryl ６～１２ aryl; or hydroxy, halogen, cyano, nitro, C optionally substituted with halogen １～６ alkyl, C optionally substituted with halogen １～５ alkoxy, halogen and / or C １～６ C optionally substituted with alkylaminocarbonyl ３～８ cycloalkyl, C optionally substituted with halogen ２～６ heterocycloalkyl, C optionally substituted with halogen ６～１２ aryl, C optionally substituted with halogen １～９ C optionally substituted with at least one substituent selected from the group consisting of heteroaryl １～９ is heteroaryl.

[0110] R ６ and R ７ Of these, C １～６ alkyl or C having a substituent １～６ alkyl (hydroxy, halogen, cyano, nitro, C optionally substituted with halogen １～５ alkoxy, halogen and / or C １～６ C optionally substituted with alkylaminocarbonyl ３～８ cycloalkyl, C optionally substituted with halogen ２～６ heterocycloalkyl, C optionally substituted with halogen ６～１２ aryl, C optionally substituted with halogen １～９ C optionally substituted with at least one substituent selected from the group consisting of heteroaryl １～６ alkyl), C ３～８ cycloalkyl or C having a substituent ３～８Cycloalkyl (C) which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkyl), C ６～１２ C having an aryl or substituent ６～１２ Aryl (hydroxy, halogen, cyano, nitro, C) １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ Aryl), and C １～９ Heteroaryl or substituent-containing C １～９ Heteroaryl (C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen) １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ Heteroaryls are R ５ It is similar to that.

[0111] (C may be substituted with halogen) １～６ (Alkylcarbonyl) C １～６ Alkyl carbonyls include methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, n-butyl carbonyl, n-pentyl carbonyl, n-hexyl carbonyl, isopropyl carbonyl, isobutyl carbonyl, sec-butyl carbonyl, tert-butyl carbonyl, isopentyl carbonyl, tert-pentyl carbonyl, neopentyl carbonyl, 2-pentyl carbonyl, 3-pentyl carbonyl, n-hexyl carbonyl, 2-hexyl carbonyl, etc. C substituted with halogens. １～６ Alkyl carbonyls include trifluoromethyl carbonyl, 2,2,2-trifluoroethyl carbonyl, etc. C may be substituted with a halogen. １～６ The alkylcarbonyl is preferably a methylcarbonyl.

[0112] (C may be substituted with halogen) ３～８ Cycloalkylcarbonyl) C ３～８ Cycloalkylcarbonyls include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, bicyclo[1.1.1]pentanylcarbonyl, bicyclo[2.2.2]octanylcarbonyl, etc. C substituted with halogens. ３～８Cycloalkylcarbonyls include 1-fluorocyclopropylcarbonyl, 2-fluorocyclopropylcarbonyl, 2,2-difluorocyclopropylcarbonyl, 2,3-difluorocyclopropylcarbonyl, 1-fluorocyclobutylcarbonyl, 2-fluorocyclobutylcarbonyl, 3-fluorocyclobutylcarbonyl, 3,3-difluorocyclobutylcarbonyl, 3-fluorocyclopentylcarbonyl, 3,3-difluorocyclopentylcarbonyl, 3-fluorocyclohexylcarbonyl, 3,3-difluorocyclohexylcarbonyl, 4-fluorocyclohexylcarbonyl, and 4,4-difluorocyclohexylcarbonyl. This includes 3-fluorobicyclo[1.1.1]pentan-1-ylcarbonyl, 2-bromocyclopropylcarbonyl, 2,2-dibromocyclopropylcarbonyl, 2,3-dibromocyclopropylcarbonyl, 3-bromocyclobutylcarbonyl, 3,3-dibromocyclobutylcarbonyl, 3-bromovicyclo[1.1.1]pentan-1-ylcarbonyl, 2-chlorocyclopropylcarbonyl, 2,2-dichlorocyclopropylcarbonyl, 2,3-dichlorocyclopropylcarbonyl, 3-chlorocyclobutylcarbonyl, 3,3-dichlorocyclobutylcarbonyl, 3-chlorobicyclo[1.1.1]pentan-1-ylcarbonyl, etc. C may be substituted with a halogen. ３～８ The cycloalkylcarbonyl is preferably cyclopropylcarbonyl or 4,4-difluorocyclohexylcarbonyl.

[0113] (C may be substituted with halogen) ２～６ (heterocycloalkylcarbonyl) C ２～６ Heterocycloalkylcarbonyls include aziridine-1-carbonyl, azetidine-1-carbonyl, pyrrolidine-1-carbonyl, pyrrolidine-2-carbonyl, piperidine-1-carbonyl, piperidine-2-carbonyl, epoxycarbonyl, oxetane-2-carbonyl, tetrahydrofuran-2-carbonyl, tetrahydropyran-2-carbonyl, tetrahydropyran-3-carbonyl, tetrahydropyran-4-carbonyl, 4-morpholylcarbonyl, etc. C substituted with halogens.２～６ Heterocycloalkylcarbonyl includes 3-fluoropyrrolidine-2-carbonyl, 3-fluoropyrrolidine-3-carbonyl, 2-fluoropiperidine-1-carbonyl, 3-fluoropiperidine-1-carbonyl, 2-fluoro-4-morpholinylcarbonyl, 3-fluoro-4-morpholinylcarbonyl, etc. C which may be substituted with halogen ２～６ Heterocycloalkylcarbonyl is preferably tetrahydropyran-4-carbonyl or 4-morpholinylcarbonyl.

[0114] In one embodiment, NR ６ R ７ is preferably such that R ７ is hydrogen or methyl. In one embodiment, NR ６ R ７ is preferably any one of the following formulas (C-1) to (C-34).

[0115]

[0116] In the above formulas (C-1) to (C-34), "*" is the bonding part with C (carbon atom). Among the above, NR ６ R ７ is preferably formula (C-1), formula (C-7), formula (C-17), formula (C-18), formula (C-20), formulas (C-24) to (C-26), formula (C-28), formula (C-30).

[0117] [OR ６ OR ６These include methylcarbonyloxy, trifluoromethylcarbonyloxy, cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclopentylcarbonyloxy, cyclohexylcarbonyloxy, 4-tetrahydropyranylcarbonyloxy, 1-pyrrolidylcarbonyloxy, 1-piperidylcarbonyloxy, 4-morpholylcarbonyloxy, methoxy, ethoxy, propyloxy, isopropyloxy, trifluoromethyloxy, cyclopropylmethyloxy, cyclohexylmethyloxy, 4,4-difluorocyclohexylmethyloxy, and 4-tetrahydropyranylmethyloxy. This includes 4-morpholylmethyloxy, benzyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, phenyloxy, 2-fluorophenyloxy, 3-fluorophenyloxy, 4-fluorophenyloxy, 2-methylphenyloxy, 3-methylphenyloxy, 4-methylphenyloxy, 2-trifluoromethylphenyloxy, 3-trifluoromethylphenyloxy, 4-trifluoromethylphenyloxy, 2-methoxyphenyloxy, 3-methoxyphenyloxy, 4-methoxyphenyloxy, 2-pyridyloxy, etc. Among these, OR ６ It is preferable that the compound is methoxy or cyclopropylmethyloxy.

[0118] In one embodiment, R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６ Alkyl; or C which may be substituted with halogen, cyano, or halogen. １～５ Alkoxy, halogen and / or C１～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６ Alkylcarbonyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkenyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ２～６ Heterocycloalkyl; or halogen, cyano, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ C may be substituted with aryl, or halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ It is preferable that it be a heteroaryl.

[0119] In one embodiment, R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C１～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ Aryl; or halogen, cyano, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ Alkyl, halogen, and / or C １～６ C may be substituted with alkylaminocarbonyl. １～５ C may be substituted with alkoxy or halogen compounds. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ It is preferable that it be a heteroaryl.

[0120] In one embodiment, R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. １～５Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ Cyclohexyl which may be substituted with at least one substituent selected from the group consisting of cycloalkyls; or halogen, cyano, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ Phenyl which may be substituted with at least one substituent selected from the group consisting of cycloalkyls; or C which may be substituted with halogen, cyano, or halogen １～５ C may be substituted with alkoxy or halogen compounds. ３～８ It is preferable that the pyridyl is substituted with at least one substituent selected from the group consisting of cycloalkyl groups.

[0121] In one embodiment, R ５ At least one of the C atoms may be substituted with a hydroxyl, halogen, cyano, nitro, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６ Preferably alkyl, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with at least one substituent selected from the group consisting of aryl atoms. １～６It is more preferably alkyl, and even more preferably methyl, ethyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2,2,2-trifluoroethyl, cyclohexylmethyl, bicyclo[2.2.2]octanemethyl, 3,3-difluorocyclobutylmethyl, 3,3-difluorocyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 4-methylaminocarbonylcyclohexylmethyl, 4-tetrahydropyranylmethyl, or benzyl.

[0122] In one embodiment, R ５ At least one of these is preferably one of the following formulas (D-1) to (D-81).

[0123] In one embodiment, R ５ It is preferable that is one of the formulas (D-1) to (D-5). In one embodiment, R ５ It is preferable that is one of formulas (D-6) to (D-10). In one embodiment, R ５ It is preferable that is one of the formulas (D-11) to (D-14). In one embodiment, R ５ It is preferable that is one of the formulas (D-15) to (D-45). In one embodiment, R ５ It is preferable that is one of formulas (D-46) to (D-56). In one embodiment, R ５ It is preferable that it is one of formulas (D-57) to (D-64). In one embodiment, R ５ It is preferable that is one of the formulas (D-65) to (D-68). In one embodiment, R ５ It is preferable that is one of formulas (D-69) to (D-79). In one embodiment, R ５ It is preferable that it is one of the formulas (D-80) to (D-81).

[0124] In a preferred embodiment, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is preferably a compound represented by any of the following general formulas (1-1) to (1-6), general formulas (2-1) to (2-6), general formula (3-1), general formula (4-1), and general formula (5-1) or a pharmaceutically acceptable salt thereof.

[0125] In the above general formulas (1-1) to (1-6), general formulas (2-1) to (2-6), general formula (3-1), general formula (4-1), and general formula (5-1), R １ ~R ５ , W, X １ and X ３ This is the same as general formulas (1) to (8).

[0126] In one embodiment, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is preferably a compound represented by any of the following general formulas (1-1-1) to (5-5-2) or a pharmaceutically acceptable salt thereof, and more preferably a compound represented by any of the following general formulas (1-2-1) to (1-2-3), general formula (1-3-1), general formula (1-3-4), general formula (1-5-1) to (1-5-2), general formula (2-1-1), general formula (2-2-1), general formula (2-4-1), general formula (2-5-1), general formula (2-6-1), general formula (4-1-1), or general formula (5-1-1) or a pharmaceutically acceptable salt thereof.

[0127] R ８ C is hydrogen; halogen, or C may be substituted with halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６ alkyl; or halogen, or C which may be substituted with halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６ Alkylcarbonyl; or halogen, or C which may be substituted with a halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkyl; or halogen, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２Aryl; or halogen, or C which may be substituted with a halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ It is a heteroaryl compound.

[0128] In one embodiment, R in general formulas (1-2-1) to (4-1-2) ８ It is preferably hydrogen. In one embodiment, R in general formulas (5-1-1) to (5-1-2) ８ C may be a halogen or a halogen substitute. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６ alkyl; or halogen, or C which may be substituted with halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６Alkylcarbonyl; or halogen, or C which may be substituted with a halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkyl; or halogen, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ Aryl; or halogen, or C which may be substituted with a halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ It is preferable that it be a heteroaryl.

[0129] C １～６ Alkyl compounds include 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, isobutyl, or isopentyl, more preferably methyl, isopropyl, isobutyl, or isopentyl, and even more preferably methyl. １～６ Alkyl (C, which may be substituted with halogens) １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C substituted with at least one substituent selected from the group consisting of heteroaryls １～６ Alkyl compounds include trifluoromethyl, 2,2,2-trifluoroethyl, methoxymethyl, ethoxymethyl, methoxyethyl, trifluoromethoxymethyl, 2-trifluoromethoxyethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, bicyclo[2.2.2]octanemethyl, 1-fluorocyclopropylmethyl, 3,3-difluorocyclobutylmethyl, 3,3-difluorocyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 4-methylaminocarbonylcyclohexylmethyl, 4-tetrahydropyranylmethyl, 1-pyrrolidinylmethyl, 1-piperidinylmethyl, 4-morpholylmethyl, benzyl, phenethyl, naphthylmethyl, 4-fluorophenylmethyl, 1,3,5-trifluorophenylmethyl, 2-furanylmethyl, 3-furanylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 2-pyrimidylmethyl, 3-pyridadylmethyl, etc. １～６The alkyl group is preferably 2,2,2-trifluoroethyl, cyclohexylmethyl, bicyclo[2.2.2]octanemethyl, 3,3-difluorocyclobutylmethyl, 3,3-difluorocyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 4-tetrahydropyranylmethyl, 4-methylaminocarbonylcyclohexylmethyl, or benzyl.

[0130] Of these, C １～６ C having alkyl or substituent １～６ The alkyl group is preferably methyl, isopropyl, isobutyl, isopentyl, 2,2,2-trifluoroethyl, cyclohexylmethyl, bicyclo[2.2.2]octanemethyl, 3,3-difluorocyclobutylmethyl, 3,3-difluorocyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 4-tetrahydropyranylmethyl, 4-methylaminocarbonylcyclohexylmethyl, or benzyl.

[0131] C １～６ Alkyl carbonyls include methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, n-butyl carbonyl, n-pentyl carbonyl, n-hexyl carbonyl, isopropyl carbonyl, isobutyl carbonyl, sec-butyl carbonyl, tert-butyl carbonyl, isopentyl carbonyl, tert-pentyl carbonyl, neopentyl carbonyl, 2-pentyl carbonyl, 3-pentyl carbonyl, n-hexyl carbonyl, 2-hexyl carbonyl, etc. １～６ The alkylcarbonyl is preferably a methylcarbonyl. A substituted C １～６ Alkylcarbonyl (C, which may be substituted with halogen) １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２C may be substituted with aryl or halogen. １～９ C substituted with at least one substituent selected from the group consisting of heteroaryls １～６ Alkylcarbonyls include trifluoromethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, methoxymethylcarbonyl, cyclopropylmethylcarbonyl, cyclobutylmethylcarbonyl, cyclohexylmethylcarbonyl, 4,4-difluorocyclohexylmethylcarbonyl, 4-methylaminocarbonylcyclohexylmethylcarbonyl, 1-morpholylmethylcarbonyl, benzylcarbonyl, 2-pyridylmethylcarbonyl, etc. １～６ The alkylcarbonyl is preferably a trifluoromethylcarbonyl.

[0132] Of these, C １～６ C having an alkylcarbonyl or substituent １～６ The alkylcarbonyl is preferably methylcarbonyl, ethylcarbonyl, trifluoromethylcarbonyl, or 2,2,2-trifluoroethylcarbonyl, and more preferably methylcarbonyl.

[0133] C ３～８ Cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, etc. ３～８ The cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or bicyclo[2.2.2]octanyl, and more preferably cyclopropyl or bicyclo[2.2.2]octanyl. ３～８ Cycloalkyl (C, which may be substituted with halogens) １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds.６～１２ C may be substituted with aryl or halogen. １～９ C substituted with at least one substituent selected from the group consisting of heteroaryls ３～８ Cycloalkyls include 1-fluorocyclopropyl, 2-fluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 1-fluorocyclobutyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 3-fluorocyclopentyl, 3,3-difluorocyclopentyl, 3-fluorocyclohexyl, 3,3-difluorocyclohexyl, 4-fluorocyclohexyl, 4,4-difluorocyclohexyl, 3-fluorobicyclo[1.1.1]pentan-1-yl, 2-bromocyclopropyl, 2,2-dibromocyclopropyl, 2,3-dibromocyclopropyl, 3- This includes bromocyclobutyl, 3,3-dibromocyclobutyl, 3-bromovicyclo[1.1.1]pentan-1-yl, 2-chlorocyclopropyl, 2,2-dichlorocyclopropyl, 2,3-dichlorocyclopropyl, 3-chlorocyclobutyl, 3,3-dichlorocyclobutyl, 3-chlorobicyclo[1.1.1]pentan-1-yl, 4-(4-methylaminocarbonylcyclohexyl)cyclohexyl, 4-methylcyclohexyl, 4-trifluoromethylcyclohexyl, 4-methoxycyclohexyl, 4-cyclopropylcyclohexyl, 4-morpholylcyclohexyl, 4-phenylcyclohexyl, 4-(2-pyridyl)cyclohexyl, etc. A substituent C ３～８ The cycloalkyl group is preferably 4,4-difluorocyclohexyl or 4-methoxycyclohexyl.

[0134] Of these, C ３～８ Cycloalkyl or substituent C ３～８ The cycloalkyl group is preferably cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octanyl, 3,3-difluorocyclobutyl, 3,3-difluorocyclohexyl, 4,4-difluorocyclohexyl, or 4-methoxycyclohexyl, and more preferably cyclopropyl or cyclohexyl.

[0135] C ６～１２ Aryls include phenyl, naphthyl, anthracenyl, phenalenyl, etc. ６～１２ The aryl is preferably phenyl. A substituted C ６～１２ Aryl(halogen, C) １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C substituted with at least one substituent selected from the group consisting of heteroaryls ６～１２Aryl compounds include 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,6-dibromophenyl, 2,4-dibromophenyl, 3,4-dibromophenyl This includes romomophenyl, 3,4,5-tribromophenyl, 2,4,6-tribromophenyl, 3-methylcarbonylaminophenyl, 4-methylcarbonylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-cyclohexylphenyl, 4-(4,4-difluorocyclohexyl)phenyl, 4-(4-methylaminocarbonylcyclohexyl)phenyl, biphenyl, 4-(2-pyridyl)phenyl, etc. A substituent C ６～１２ The aryl is preferably 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylcarbonylaminophenyl, 4-methylcarbonylaminophenyl, 2-methylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, or 4-methoxyphenyl.

[0136] Of these, C ６～１２ C having an aryl or substituent ６～１２The aryl is preferably phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylcarbonylaminophenyl, 4-methylcarbonylaminophenyl, 2-methylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, or 4-methoxyphenyl, and more preferably phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, or 4-methoxyphenyl.

[0137] C １～９ Heteroaryls include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrazol, pyrimidyl, pyridazyl, triazyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, phthalazyl, phenanthridyl, acridyl, etc. １～９ The heteroaryl is preferably pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, pyridyl, pyrimidyl, pyridazyl, triazyl, more preferably pyrrolyl, pyridyl, pyridyl, pyrimidyl, pyrazolyl, thiazolyl, pyridyl, pyridyl, pyrimidyl, pyridazyl, and still more preferably pyridyl. １～９ Heteroaryl (C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen) １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２C may be substituted with aryl or halogen. １～９ C substituted with at least one substituent selected from the group consisting of heteroaryls １～９Heteroaryl) 2-hydroxy-1-pyrrolyl, 3-fluoro-2-pyrrolyl, 4-fluoro-2-oxazolyl, 5-fluoro-2-oxazolyl, 3-fluoro-5-isoxazolyl, 4-fluoro-2-thiazolyl, 5-fluoro-2-thiazolyl, 5-fluoro-3-isothiazolyl, 3-fluoro-2-pyridyl, 4-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-fluoro-2-pyridyl, 2-fluoro-3-pyridyl, 4-fluoro-3-pyridyl, 5-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, 5-fluoroaryl Oro-2-pyradyl, 6-fluoro-2-pyradyl, 2-fluoro-4-pyrimidyl, 2-fluoro-5-pyrimidyl, 3-fluoro-2-pyrimidyl, 4-fluoro-2-pyrimidyl, 5-fluoro-2-pyrimidyl, 5-fluoro-3-pyridadyl, 6-fluoro-3-pyridadyl, 3-cyano-2-pyrrolyl, 4-cyano-2-oxazolyl, 5-cyano-2-oxazolyl, 3-cyano-5-isoxazolyl, 4-cyano-2-thiazolyl, 5-cyano-2-thiazolyl, 5-cyano-3-isothiazolyl, 3-cyano-2-pyridyl, 4-cyano -2-pyridyl, 5-cyano-2-pyridyl, 6-cyano-2-pyridyl, 2-cyano-3-pyridyl, 4-cyano-3-pyridyl, 5-cyano-3-pyridyl, 6-cyano-3-pyridyl, 5-cyano-2-pyradyl, 6-cyano-2-pyradyl, 2-cyano-4-pyrimidyl, 2-cyano-5-pyrimidyl, 3-cyano-2-pyrimidyl, 4-cyano-2-pyrimidyl, 5-cyano-2-pyrimidyl, 5-cyano-3-pyridadyl, 6-cyano-3-pyridadyl, 3-nitro-2-pyrrolyl, 4-nitro-2-oxazolyl, 5-nitro-2-oxazolyl Zolyl, 3-nitro-5-isoxazolyl, 4-nitro-2-thiazolyl, 5-nitro-2-thiazolyl, 5-nitro-3-isothiazolyl, 3-nitro-2-pyridyl, 4-nitro-2-pyridyl, 5-nitro-2-pyridyl, 6-nitro-2-pyridyl, 2-nitro-3-pyridyl, 4-nitro-3-pyridyl, 5-nitro-3-pyridyl, 6-nitro-3-pyridyl, 5-nitro-2-pyradyl, 6-nitro-2-pyradyl, 2-nitro-4-pyrimidyl, 2-nitro-5-pyrimidyl, 3-nitro-2-pyrimidyl, 4-nitro-2-pyrimidyl,5-Nitro-2-pyrimidyl, 5-Nitro-3-pyridadyl, 6-Nitro-3-pyridadyl, 3-Methyl-2-pyrrolyl, 4-Methyl-2-oxazolyl, 5-Methyl-2-oxazolyl, 3-Methyl-5-isoxazolyl, 4-Methyl-2-thiazolyl, 5-Methyl-2-thiazolyl, 5-Methyl-3-isothiazolyl, 3-Methyl-2-pyridyl, 4-Methyl-2-pyridyl, 5-Methyl-2-pyridyl, 6-Methyl-2-pyridyl, 2-Methyl-3-pyridyl, 4-Methyl-3-pyridyl, 5-Methyl-3-pyridyl, 6-Methyl-3-pyridyl, 5 -Methyl-2-pyrazyl, 6-methyl-2-pyrazyl, 2-methyl-4-pyrimidyl, 2-methyl-5-pyrimidyl, 3-methyl-2-pyrimidyl, 4-methyl-2-pyrimidyl, 5-methyl-2-pyrimidyl, 5-methyl-3-pyridazyl, 6-methyl-3-pyridazyl, 3-trifluoromethyl-2-pyrrolyl, 4-trifluoromethyl-2-oxazolyl, 5-trifluoromethyl-2-oxazolyl, 3-trifluoromethyl-5-isoxazolyl, 4-trifluoromethyl-2-thiazolyl, 5-trifluoromethyl-2-thiazolyl, 5-tri Fluoromethyl-3-isothiazolyl, 3-trifluoromethyl-2-pyridyl, 4-trifluoromethyl-2-pyridyl, 5-trifluoromethyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl, 2-trifluoromethyl-3-pyridyl, 4-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-2-pyradyl, 6-trifluoromethyl-2-pyradyl, 2-trifluoromethyl-4-pyrimidyl, 2-trifluoromethyl-5-pyrimidyl, 3- Trifluoromethyl-2-pyrimidyl, 4-trifluoromethyl-2-pyrimidyl, 5-trifluoromethyl-2-pyrimidyl, 5-trifluoromethyl-3-pyridadyl, 6-trifluoromethyl-3-pyridadyl, 3-methoxy-2-pyrrolyl, 4-methoxy-2-oxazolyl, 5-methoxy-2-oxazolyl, 3-methoxy-5-isoxazolyl, 4-methoxy-2-thiazolyl, 5-methoxy-2-thiazolyl, 5-methoxy-3-isothiazolyl, 3-methoxy-2-pyridyl, 4-methoxy-2-pyridyl, 5-methoxy-2-pyridyl6-Methoxy-2-pyridyl, 2-Methoxy-3-pyridyl, 4-Methoxy-3-pyridyl, 5-Methoxy-3-pyridyl, 6-Methoxy-3-pyridyl, 5-Methoxy-2-pyrazyl, 6-Methoxy-2-pyrazyl, 2-Methoxy-4-pyrimidyl, 2-Methoxy-5-pyrimidyl, 3-Methoxy-2-pyrimidyl, 4-Methoxy-2-pyrimidyl, 5-Methoxy-2-pyrimidyl, 5-Methoxy-3-pyridazyl, 6-Methoxy-3-pyridazyl, 3-Cyclopropyl-2-pyrrolyl, 4-Cyclopropyl-2-oxazolyl, 5-Cyclopropyl 2-oxazolyl, 3-cyclopropyl-5-isoxazolyl, 4-cyclopropyl-2-thiazolyl, 5-cyclopropyl-2-thiazolyl, 5-cyclopropyl-3-isothiazolyl, 3-cyclopropyl-2-pyridyl, 4-cyclopropyl-2-pyridyl, 5-cyclopropyl-2-pyridyl, 5-cyclopropyl-4-trifluoromethyl-2-pyridyl, 6-cyclopropyl-2-pyridyl, 2-cyclopropyl-3-pyridyl, 4-cyclopropyl-3-pyridyl, 5-cyclopropyl-3-pyridyl, 6-cyclopropyl-3-pyridyl Lysyl, 5-cyclopropyl-2-pyrazyl, 6-cyclopropyl-2-pyrazyl, 2-cyclopropyl-4-pyrimidyl, 2-cyclopropyl-5-pyrimidyl, 3-cyclopropyl-2-pyrimidyl, 4-cyclopropyl-2-pyrimidyl, 5-cyclopropyl-2-pyrimidyl, 5-cyclopropyl-3-pyridazyl, 6-cyclopropyl-3-pyridazyl, 3-(4-methylaminocarbonylcyclohexyl)-2-pyrrolyl, 4-(4-methylaminocarbonylcyclohexyl)-2-oxazolyl, 5-(4-methylaminocarbonylcyclohexyl (4-methylaminocarbonylcyclohexyl)-2-oxazolyl, 3-(4-methylaminocarbonylcyclohexyl)-5-isoxazolyl, 4-(4-methylaminocarbonylcyclohexyl)-2-thiazolyl, 5-(4-methylaminocarbonylcyclohexyl)-2-thiazolyl, 5-(4-methylaminocarbonylcyclohexyl)-3-isothiazolyl, 3-(4-methylaminocarbonylcyclohexyl)-2-pyridyl, 4-(4-methylaminocarbonylcyclohexyl)-2-pyridyl, 5-(4-methylaminocarbonylcyclohexyl)-2-pyridyl,5-(4-methylaminocarbonylcyclohexyl)-4-trifluoromethyl-2-pyridyl, 6-(4-methylaminocarbonylcyclohexyl)-2-pyridyl, 2-(4-methylaminocarbonylcyclohexyl)-3-pyridyl, 4-(4-methylaminocarbonylcyclohexyl)-3-pyridyl, 5-(4-methylaminocarbonylcyclohexyl)-3-pyridyl, 6-(4-methylaminocarbonylcyclohexyl)-3-pyridyl, 5-(4-methylaminocarbonylcyclohexyl)-2-pyradyl, 6-(4-methylaminocarbonylcyclohexyl)-2-pyradyl, 2-(4-methylaminocarbonylcyclohexyl)-4-pyrimidyl, 2-(4-methylaminocarbonylcyclohexyl)-5-pyrimidyl This includes 3-(4-methylaminocarbonylcyclohexyl)-2-pyrimidyl, 4-(4-methylaminocarbonylcyclohexyl)-2-pyrimidyl, 5-(4-methylaminocarbonylcyclohexyl)-2-pyrimidyl, 5-(4-methylaminocarbonylcyclohexyl)-3-pyridadyl, 6-(4-methylaminocarbonylcyclohexyl)-3-pyridadyl, 3-phenyl-2-pyrrolyl, 4-phenyl-2-pyridyl, 5-phenyl-2-pyrazyl, 4-phenyl-2-pyrimidyl, 5-phenyl-3-pyridadyl, 3-(2-pyridyl)-2-pyrrolyl, 4-(2-pyridyl)-2-pyridyl, 5-(2-pyridyl)-2-pyrazyl, 4-(2-pyridyl)-2-pyrimidyl, 5-(2-pyridyl)-3-pyridadyl, etc.

[0138] Of these, C １～９ Heteroaryl or substituent-containing C １～９Heteroaryls include 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridadyl, 4-pyrimidadyl, 3-fluoro-2-pyrrolyl, 4-fluoro-2-pyrrolyl, 2-fluoro-3-pyrrolyl, 4-fluoro-3-pyrrolyl, 3-fluoro-2-imidazolyl, 4-fluoro-2-imidazolyl, 2-fluoro-4-imidazolyl, and 4-fluoro-3-pyrazolyl. Ryl, 4-fluoro-3-pyrazolyl, 3-fluoro-4-pyrazolyl, 4-fluoro-2-thiazolyl, 5-fluoro-2-thiazolyl, 2-fluoro-4-thiazolyl, 3-fluoro-2-pyridyl, 4-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 2-fluoro-3-pyridyl, 4-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, 2-fluoro-4-pyridyl, 3-fluoro-4-pyridyl, 2-fluoro-5-pyridyl, 4-fluoro-2-pyrimidyl, 5-fluoro-2-pyrimidyl, 2-fluoro-4-pyrimidyl, 6-Fluoro-4-pyrimidyl, 2-Fluoro-5-pyrimidyl, 4-Fluoro-5-pyrimidyl, 5-Fluoro-3-pyridadyl, 3-Fluoro-4-pyridadyl, 1-Methyl-2-pyrrolyl, 3-Methyl-2-pyrrolyl, 4-Methyl-2-pyrrolyl, 1-Methyl-3-pyrrolyl, 2-Methyl-3-pyrrolyl, 4-Methyl-3-pyrrolyl, 1-Methyl-2-imidazolyl, 3-Methyl-2-imidazolyl, 4-Methyl-2-imidazolyl, 2-Methyl-4-imidazolyl, 4-Methyl-3-pyrazolyl, 1-Methyl-4-pyrazolyl, 3-Methyl-4- Pyrazolyl, 4-methyl-2-thiazolyl, 5-methyl-2-thiazolyl, 2-methyl-4-thiazolyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 2-methyl-3-pyridyl, 4-methyl-3-pyridyl, 6-methyl-3-pyridyl, 2-methyl-4-pyridyl, 3-methyl-4-pyridyl, 2-methyl-5-pyridyl, 4-methyl-2-pyrimidyl, 5-methyl-2-pyrimidyl, 2-methyl-4-pyrimidyl, 6-methyl-4-pyrimidyl, 2-methyl-5-pyrimidyl, 4-methyl-5-pyrimidyl5-methyl-3-pyridadyl, 3-methyl-4-pyridadyl, 1-trifluoromethyl-2-pyrrolyl, 3-trifluoromethyl-2-pyrrolyl, 4-trifluoromethyl-2-pyrrolyl, 1-trifluoromethyl-3-pyrrolyl, 2-trifluoromethyl-3-pyrrolyl, 4-trifluoromethyl-3-pyrrolyl, 1-trifluoromethyl-2-imidazolyl, 3-trifluoromethyl-2-imidazolyl, 4-trifluoromethyl-2-imidazolyl, 2-trifluoromethyl-4-imidazolyl, 4-trifluoromethyl-3-pyrazolyl, 1- Lifluoromethyl-4-pyrazolyl, 3-trifluoromethyl-4-pyrazolyl, 4-trifluoromethyl-2-thiazolyl, 5-trifluoromethyl-2-thiazolyl, 2-trifluoromethyl-4-thiazolyl, 3-trifluoromethyl-2-pyridyl, 4-trifluoromethyl-2-pyridyl, 5-trifluoromethyl-2-pyridyl, 2-trifluoromethyl-3-pyridyl, 4-trifluoromethyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 2-trifluoromethyl-4-pyridyl, 3-trifluoromethyl-4-pyridyl 2-trifluoromethyl-5-pyridyl, 4-trifluoromethyl-2-pyrimidyl, 5-trifluoromethyl-2-pyrimidyl, 2-trifluoromethyl-4-pyrimidyl, 6-trifluoromethyl-4-pyrimidyl, 2-trifluoromethyl-5-pyrimidyl, 4-trifluoromethyl-5-pyrimidyl, 5-trifluoromethyl-3-pyridadyl, 3-trifluoromethyl-4-pyridadyl, 1-cyclopropyl-2-pyrrolyl, 3-cyclopropyl-2-pyrrolyl, 4-cyclopropyl-2-pyrrolyl, 1-cyclopropyl-3-pyrrolyl, 2- Cyclopropyl-3-pyrrolyl, 4-cyclopropyl-3-pyrrolyl, 1-cyclopropyl-2-imidazolyl, 3-cyclopropyl-2-imidazolyl, 4-cyclopropyl-2-imidazolyl, 2-cyclopropyl-4-imidazolyl, 4-cyclopropyl-3-pyrazolyl, 1-cyclopropyl-4-pyrazolyl, 3-cyclopropyl-4-pyrazolyl, 4-cyclopropyl-2-thiazolyl, 5-cyclopropyl-2-thiazolyl, 2-cyclopropyl-4-thiazolyl, 3-cyclopropyl-2-pyridyl, 4-cyclopropyl-2-pyridyl5-Cyclopropyl-2-pyridyl, 5-Cyclopropyl-4-trifluoromethyl-2-pyridyl, 2-Cyclopropyl-3-pyridyl, 4-Cyclopropyl-3-pyridyl, 6-Cyclopropyl-3-pyridyl, 2-Cyclopropyl-4-pyridyl, 3-Cyclopropyl-4-pyridyl, 2-Cyclopropyl-5-pyridyl, 4-Cyclopropyl-2-pyrimidyl, 5-Cyclopropyl-2-pyrimidyl, 2-Cyclopropyl-4-pyrimidyl, 6-Cyclopropyl-4-pyrimidyl, 2-Cyclopropyl-5-pyrimidyl, 4-Cyclopropyl-5 - Pyrimidyl, 5-cyclopropyl-3-pyridadyl, 3-cyclopropyl-4-pyridadyl, 1-methoxy-2-pyrrolyl, 3-methoxy-2-pyrrolyl, 4-methoxy-2-pyrrolyl, 1-methoxy-3-pyrrolyl, 2-methoxy-3-pyrrolyl, 4-methoxy-3-pyrrolyl, 1-methoxy-2-imidazolyl, 3-methoxy-2-imidazolyl, 4-methoxy-2-imidazolyl, 2-methoxy-4-imidazolyl, 4-methoxy-3-pyrazolyl, 1-methoxy-4-pyrazolyl, 3-methoxy-4-pyrazolyl, 4-methoxy-2-thiazolyl 5-Methoxy-2-thiazolyl, 2-Methoxy-4-thiazolyl, 3-Methoxy-2-pyridyl, 4-Methoxy-2-pyridyl, 5-Methoxy-2-pyridyl, 2-Methoxy-3-pyridyl, 4-Methoxy-3-pyridyl, 6-Methoxy-3-pyridyl, 2-Methoxy-4-pyridyl, 3-Methoxy-4-pyridyl, 2-Methoxy-5-pyridyl, 4-Methoxy-2-pyrimidyl, 5-Methoxy-2-pyrimidyl, 2-Methoxy-4-pyrimidyl, 6-Methoxy-4-pyrimidyl, 2-Methoxy-5-pyrimidyl, 4-Methoxy-5-pyrimidyl, 5- It is preferably methoxy-3-pyridadyl, 3-methoxy-4-pyridadyl, and more preferably 3-fluoro-2-pyrrolyl, 3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 1-methyl-4-pyrazolyl, 1-methyl-3-pyrazolyl, 2-trifluoromethyl-5-pyridyl, 5-trifluoromethyl-2-pyridyl, 2-trifluoromethyl-5-pyrimidyl, 5-cyclopropyl-4-trifluoromethyl-2-pyridyl, 2-methoxy-4-pyridyl, 2-methoxy-5-pyridyl, 2-methoxy-5-pyrimidyl,It is even more preferable that it be 5-fluoro-2-pyridyl or 5-trifluoromethyl-2-pyridyl.

[0139] R ９ is hydrogen; halogen, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ Aryl; or halogen, or C which may be substituted with a halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ It is a heteroaryl compound.

[0140] In one embodiment, R in general formulas (1-1-2) to (1-1-4), general formulas (1-2-2) to (1-2-4), general formulas (1-3-2) to (1-3-4), general formulas (1-4-2) to (1-4-4), general formula (2-1-2), general formula (2-2-2), general formula (2-3-2), general formula (2-4-2), general formula (2-5-2), general formula (2-6-2), general formula (4-1-2), general formula (5-1-1) to (5-1-2) ９R is hydrogen. In one embodiment, R in general formulas (1-1-1), (1-2-1), (1-3-1), (1-4-1), (2-1-1), (2-2-1), (2-3-1), (2-4-1), (2-5-1), (2-6-1), and (4-1-1) is hydrogen. ９ R is hydrogen. In one embodiment, R in general formulas (1-1-1), (1-2-1), (1-3-1), (1-4-1), (2-1-1), (2-2-1), (2-3-1), (2-4-1), (2-5-1), (2-6-1), and (4-1-1) is hydrogen. ９ is halogen, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ Aryl; or halogen, or C which may be substituted with a halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ It is preferably a heteroaryl, and includes halogens and C １～６C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ It is more preferable to be aryl.

[0141] The aforementioned R ９ Of these, C ６～１２ C having an aryl or substituent ６～１２ Aryl(halogen, C) １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ Ariel), C １～９ Heteroaryl or substituent-containing C １～９ Heteroaryl (halogen, C which may be substituted with halogen) １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ Heteroaryls are R ８ It is similar to that.

[0142] In one embodiment, R ９ It is preferably hydrogen. In one embodiment, R ９ is halogen, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２It is preferably aryl, and more preferably phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,4,5-trifluorophenyl, 2,4,6-trifluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylcarbonylaminophenyl, 4-methylcarbonylaminophenyl, 2-methylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, more preferably phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 3-methylcarbonylaminophenyl, 4-methylcarbonylaminophenyl, 3-methoxyphenyl, 4-methoxyphenyl, even more preferably phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, and particularly preferably phenyl, 3-methylcarbonylaminophenyl, 4-methylcarbonylaminophenyl, 4-fluorophenyl.

[0143] R １０ is hydrogen; halogen; NR ６ R ７ OR ６ ; C may be substituted with hydroxyl, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ It is a cycloalkyl group.

[0144] In one embodiment, R in general formulas (1-1-2) to (1-1-4), general formulas (1-2-2) to (1-2-4), general formulas (1-3-2) to (1-3-4), general formulas (1-4-2) to (1-4-4), general formula (2-1-2), general formula (2-2-2), general formula (2-3-2), general formula (2-4-2), general formula (2-5-2), general formula (2-6-2), general formula (4-1-2), general formula (5-1-1) to (5-1-2) １０ R is hydrogen. In one embodiment, R in general formulas (1-1-1), (1-2-1), (1-3-1), (1-4-1), (2-1-1), (2-2-1), (2-3-1), (2-4-1), (2-5-1), (2-6-1), and (4-1-1) is hydrogen. １０ R is hydrogen. In one embodiment, R in general formulas (1-1-1), (1-2-1), (1-3-1), (1-4-1), (2-1-1), (2-2-1), (2-3-1), (2-4-1), (2-5-1), (2-6-1), and (4-1-1) is hydrogen. １０ Halogen; NR ６ R ７ OR ６ ; C may be substituted with hydroxyl, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ It is preferably cycloalkyl, NR ６ R ７ OR ６ ; C may be substituted with hydroxyl, halogen, cyano, nitro, or halogen. １～６C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ It is more preferably cycloalkyl, NR ６ R ７ It is even more preferable that this be the case.

[0145] R １０ Of these, halogen, NR ６ R ７ , OR ６ C may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkyl is R ５ It is similar to that.

[0146] In one embodiment, R １０ It is preferably hydrogen. In one embodiment, R １０ NR ６ R ７ , OR ６ C may be substituted with halogen. ３～８It is preferably a cycloalkyl group, and more preferably methylamino, dimethylamino, methylcarbonylamino, methoxy, or cyclopropyl group.

[0147] R １１ is hydrogen or halogen. In this case, R １１ Of these, halogens are R ５ It is similar to that.

[0148] In one embodiment, R １１ It is preferably hydrogen. In one embodiment, R １１ It is preferably a halogen, and more preferably a fluorine.

[0149] 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 (1) to (77) or its pharmaceutically acceptable salt.

[0150] Of the above, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is preferably a compound selected from the group consisting of formulas (8), (27), (34), (36) to (37), (44), (49) to (50), (54) to (55), (63) to (64), (66), and (75) to (77), or a pharmaceutically acceptable salt thereof.

[0151] In one preferred embodiment, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is preferably the compound of formula (34) or a pharmaceutically acceptable salt thereof.

[0152] Compounds represented by general formula (I) (4-pyridinol derivatives) may include optical isomers, stereoisomers, tautomers, rotational isomers, or mixtures thereof. These isomers can be obtained individually by known synthesis and separation methods. For example, optical isomers can be obtained individually by methods using optically active synthetic intermediates, or by optical resolution of a racemic mixture of the synthetic intermediate or the final product according to conventional methods. Furthermore, compounds represented by general formula (I) (4-pyridinol derivatives) may also include stable isotopes and radioactive isotopes.

[0153] Compounds represented by general formula (I) can be pharmaceutically acceptable salts 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 that the compound represented by general formula (I) may have. 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 salts formed with basic groups that the compound represented by general formula (I) may have; 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.

[0154] Methods for forming a pharmaceutically acceptable salt of the compound represented by general formula (I) can be appropriately employed using known methods. For example, methods include mixing the compound according to the disclosure with the 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 disclosure.

[0155] Compounds represented by general formula (I) or their pharmaceutically acceptable salts may also include solvates thereof, such as hydrates and alcohol adducts.

[0156] 3. Method for producing compounds represented by general formula (I) The method for producing compounds represented by general formula (I) is not particularly limited and can be produced by known methods.

[0157] A method for synthesizing a compound represented by general formula (I) is, for example, compound X represented by the following formula. １ and compound Y １ A method for reacting compound X, represented by the following formula. ２ and compound Y ２ One method involves reacting the compound Y. １ and compound Y ２ The "P" in this formula is a protecting group, and examples 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), tert-butyldiphenylsilyl (TBDPS), and the like.

[0158]

[0159] A １ However, these are leaving groups such as fluorine, chlorine, bromine, iodine, methanesulfonyl, and 4-toluenesulfonyl, and A ２ However, in the case of nucleophilic groups such as hydroxyl groups and amino groups, the compounds represented by general formula (I) can be synthesized by carrying out aromatic nucleophilic substitution reactions in a solvent that does not adversely affect the reaction (e.g., N,N-dimethylformamide, etc.) in the presence of a basic compound (e.g., cesium carbonate, potassium carbonate, etc.), and then deprotecting the protecting group.

[0160] Note that compound X １ and compound Y １ As shown in the reaction equation, a bicyclic heterocyclic compound is A １ (Having a leaving group), the 4-pyridinol compound is A ２ Compound X may have a nucleophilic group.２ and compound Y ２ As shown in the reaction equation, a bicyclic heterocyclic compound is A ２ It has a (nucleophilic group), and the 4-pyridinol compound is A １ It may have a (leaving group).

[0161] In this case, the W that is formed is given by the following equations (A-1) to (A-6).

[0162] A １ However, it is an amino acid-containing group, A ２ However, in the case of a carboxyl-containing group, the compound represented by general formula (I) can be synthesized by carrying out an amidation reaction using a condensing agent (e.g., WSC) in a solvent (e.g., dichloromethane) that does not adversely affect the reaction, and then deprotecting the protecting group.

[0163] Note that compound X １ and compound Y １ As shown in the reaction equation, a bicyclic heterocyclic compound is A １ It has an amino acid-containing group, and the 4-pyridinol compound is A ２ Compound X may have a (carboxyl-containing group), ２ and compound Y ２ As shown in the reaction equation, a bicyclic heterocyclic compound is A ２ (Having a carboxyl-containing group), the 4-pyridinol compound is A １ It may have an amino acid-containing group.

[0164] In this case, the W that is formed is given by the following equations (A-7) to (A-12).

[0165] As described above, the compounds relating to this disclosure can be formed by an aromatic nucleophilic substitution reaction or an amidation reaction. Therefore, the starting compound X １ and compound Y １ , and compound X ２ and compound Y ２ Each of these can be designed with a high degree of freedom. Therefore, the compounds related to this disclosure can be said to have a high degree of design freedom.

[0166] Note that compound X１ , compound X ２ , compound Y １ , and compound Y ２ It is publicly known or can be manufactured by publicly known methods.

[0167] 4. Pharmaceutical composition, HSD17B13 inhibitor, preventive or therapeutic agent for diseases involving HSD17B13 According to one embodiment of the present disclosure, a pharmaceutical composition is provided that contains a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. Also according to one embodiment of the present disclosure, an HSD17B13 inhibitor is provided that contains a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. Also according to one embodiment of the present disclosure, a preventive or therapeutic agent for diseases involving HSD17B13 is provided that contains a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. In this case, the disease is preferably a liver disease, and more preferably non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-related fatty liver disease (MASLD), non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-related steatohepatitis (MASH), alcoholic fatty liver, alcoholic hepatitis, viral hepatitis (hepatitis B, hepatitis C), hepatic fibrosis, cirrhosis, or liver cancer (HCC).

[0168] Inhibition of HSD17B13 (17β-hydroxysteroid dehydrogenase 13) can reduce fat accumulation in the liver and suppress inflammation, fibrosis, or malignancy in the liver (particularly inflammation, fibrosis, or malignancy caused by hepatic fat). Therefore, HSD17B13 inhibitors can treat or prevent liver diseases such as non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-related fatty liver disease (MASLD), non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-related steatohepatitis (MASH), alcoholic fatty liver, alcoholic hepatitis, viral hepatitis (hepatitis B, hepatitis C), hepatic fibrosis, cirrhosis, and liver cancer (HCC) (N Engl J Med. 2018 Mar 22; 378(12) 1096-1106, Hepatology. 2019 Apr;69(4)1504-1519).

[0169] In one preferred embodiment, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, is used for the treatment or prevention of non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-related fatty liver disease (MASLD) associated with HSD17B13. In one preferred embodiment, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, is used for the treatment or prevention of non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-related steatohepatitis (MASH) associated with HSD17B13. In one preferred embodiment, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, is used for the treatment or prevention of cirrhosis associated with HSD17B13. In one preferred embodiment, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, is used for the treatment or prevention of liver cancer (HCC) associated with HSD17B13.

[0170] In a preferred embodiment, an agent for the prevention or treatment of non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-related fatty liver disease (MASLD) is provided, comprising HSD17B13 containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. In a preferred embodiment, an agent for the prevention or treatment of non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-related steatohepatitis (MASH) is provided, comprising HSD17B13 containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. In a preferred embodiment, an agent for the prevention or treatment of cirrhosis is provided, comprising HSD17B13 containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. In a preferred embodiment, an agent for the prevention or treatment of liver cancer (HCC) is provided, comprising HSD17B13 containing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

[0171] The pharmaceutical composition, HSD17B13 inhibitor, and agent for the prevention or treatment of diseases involving HSD17B13 contain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition, HSD17B13 inhibitor, and agent for the prevention or treatment of diseases involving HSD17B13 may further contain a pharmaceutically acceptable carrier.

[0172] [Compounds represented by general formula (I) or pharmaceutically acceptable salts thereof] The compounds represented by general formula (I) or pharmaceutically acceptable salts thereof that are described above shall be used.

[0173] 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 compounds of this disclosure. 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.

[0174] The content of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof contained in a pharmaceutical composition, an HSD17B13 inhibitor, or a preventive or therapeutic agent for a disease involving HSD17B13 is preferably 0.0001 to 100% by mass, more preferably 0.01 to 100% by mass, and even more preferably 0.1 to 100% by mass or 1.0 to 100% by mass, based on the total mass of the pharmaceutical composition, the HSD17B13 inhibitor, or the preventive or therapeutic agent for a disease involving HSD17B13.

[0175] [Medically Acceptable Carriers] Medically 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 and odor-correcting agents, colorants, sweeteners, acidulants, foaming agents, fragrances, and coating agents may be used as needed.

[0176] Excipients include, for example, lactose, corn starch, sucrose, glucose, sorbitol, and crystalline cellulose, while binders include, for example, polyvinyl alcohol, ethylcellulose, methylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropyl starch, and polyvinylpyrrolidone.

[0177] Lubricants include, for example, magnesium stearate, sodium lauryl sulfate, and talc.

[0178] Disintegrants include, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextran, pectin, etc.

[0179] Colorants include, for example, those permitted for use in pharmaceuticals.

[0180] Flavoring and odor-modifying agents include, for example, cocoa powder, peppermint sap, aromatic acid, peppermint oil, borneol, cinnamon powder, etc.

[0181] Coating agents include, for example, sugar coatings, gelatin coatings, and enteric coatings (hydroxypropyl methylcellulose (HPMC), cellulose acetate phthalate, etc.).

[0182] [Dosage Forms, etc.] Examples of dosage forms for pharmaceutical compositions, HSD17B13 inhibitors, and agents for the prevention or treatment of diseases involving HSD17B13 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.

[0183] For example, when preparing a pharmaceutical composition, an HSD17B13 inhibitor, or a preventive or therapeutic agent for a disease involving HSD17B13 as an oral formulation, the compound relating to this disclosure, excipients, and optionally binders, disintegrants, lubricants, colorants, flavoring agents, 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.

[0184] Furthermore, when preparing pharmaceutical compositions, HSD17B13 inhibitors, or agents for the prevention or treatment of diseases involving HSD17B13 as injectable preparations, the compounds relating to this disclosure, 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.

[0185] The method of administering the pharmaceutical composition, the HSD17B13 inhibitor, or the agent for the prevention or treatment of diseases involving HSD17B13 may be oral or parenteral (e.g., intravenous, subcutaneous, intramuscular, suppository, enema, ointment, patch, sublingual, eye drops, inhalation, etc.), but oral administration is preferred.

[0186] The dosage of pharmaceutical compositions, HSD17B13 inhibitors, and agents for the prevention or treatment of diseases involving HSD17B13 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, more preferably 0.01 μg to 1.0 g when administered parenterally, and even more preferably 0.1 μg to 1.0 g or 1.0 μg to 1.0 g. 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).

[0187] Furthermore, as described above, the compounds relating to this disclosure have HSD17B13 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 HSD17B13 inhibitors. In addition, the compounds or pharmaceutical compositions relating to this disclosure may be used for the prevention and / or treatment of diseases involving HSD17B13. For this reason, the compounds or pharmaceutical compositions relating to this disclosure may be provided as preventive or therapeutic agents for diseases involving HSD17B13.

[0188] Diseases involving HSD17B13 include liver diseases. In this case, the liver disease includes at least one selected from the group consisting of non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-related fatty liver disease (MASLD), non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-related steatohepatitis (MASH), alcoholic fatty liver, alcoholic hepatitis, viral hepatitis (hepatitis B, hepatitis C), hepatic fibrosis, cirrhosis, and liver cancer (HCC), preferably at least one selected from the group consisting of NAFLD or MASLD, NASH or MASH, cirrhosis, and liver cancer (HCC).

[0189] In one preferred embodiment, the diseases in which HSD17B13 is involved include non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-related fatty liver disease (MASLD). In one preferred embodiment, the diseases in which HSD17B13 is involved include non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-related steatohepatitis (MASH). In one preferred embodiment, the diseases in which HSD17B13 is involved include cirrhosis. In one preferred embodiment, the diseases in which HSD17B13 is involved include liver cancer (HCC).

[0190] 5. Methods of prevention or treatment, use of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof According to one embodiment of the present disclosure, a method of prevention or treatment for a disease involving HSD17B13 is provided, comprising administering the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. According to another embodiment of the present disclosure, the use of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is provided for the prevention or treatment of a disease involving HSD17B13. According to another embodiment of the present disclosure, the use of the 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 HSD17B13.

[0191] The compound represented by general formula (I) or its pharmaceutically acceptable salt used in the aforementioned prevention or treatment method and use, as well as the method of administration and dosage thereof, are as described above.

[0192] The present disclosure will be described in detail below with reference to examples, but the disclosure is not limited to these examples. Furthermore, unless otherwise specified, the apparatus, reagents, etc., used in these examples are readily available or commercially available according to methods commonly used in the art.

[0193] [Synthesis Example 1] Synthesis of (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A)

[0194] <Step 1> Synthesis of 3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine: 4.5 g of 3,4,5-trifluoropyridine (4.5 g), a known substance, and 4-methoxyphenyl)methanol (4.7 g) were dissolved in tetrahydrofuran (90 mL). 4.6 g of t-butoxy potassium was added at 0°C and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was then added to the reaction mixture, 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 resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (7.5 g).

[0195] <Step 2> Synthesis of 3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-carboaldehyde The compound obtained in Step 1, 3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (7.5 g), was added dropwise to a solution of tetrahydrofuran (150 mL) with a 2.5 M n-butyllithium hexane solution (18 mL) under a nitrogen atmosphere at -78°C and stirred for 1 hour. Then, N,N-dimethylformamide (4.4 g) was added dropwise and stirred at -78°C for 1 hour. Subsequently, the reaction was stopped with an aqueous solution of ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain the crude product 3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-carboaldehyde (9.1 g).

[0196] <Step 3> Synthesis of (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol. In a methanol (90 mL) solution of 3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-carboaldehyde (4.3 g), the compound obtained in Step 2, sodium borohydride (1.7 g) was slowly added at 0°C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then stopped with water, and the reaction mixture was concentrated under reduced pressure using a rotary evaporator to remove methanol. Water was added to the resulting residue, and it was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (2.0 g).

[0197]

[0198] [Synthesis Example 2] Synthesis of (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B)

[0199] <Step 1> Synthesis of 3,5-difluoro-4-iodopyridine A 2.5 M n-butyllithium hexane solution (52 mL) was added dropwise to a tetrahydrofuran solution (10 g) of 3,5-difluoropyridine (a known substance) under a nitrogen atmosphere at -78°C and stirred for 30 minutes. Then, a tetrahydrofuran solution (50 mL) of iodine (44 g) was added dropwise to the reaction mixture and stirred at -78°C for 2 hours. The reaction reaction was stopped with aqueous ammonium chloride solution and aqueous sodium thiosulfate solution, and extracted three times with ethyl acetate. The combined 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 silica gel column chromatography (hexane-ethyl acetate) to obtain 3,5-difluoro-4-iodopyridine (20 g).

[0200] <Step 2> Synthesis of 4-(benzyloxy)-3,5-difluoropyridine A solution of 3,5-difluoro-4-iodopyridine (12 g), benzyl alcohol (22 g), copper iodide (950 mg), 1,10-phenanthroline (900 mg), and cesium carbonate (32 g) in toluene (200 mL) was stirred at 110°C for 16 hours under a nitrogen atmosphere. The reaction mixture was then filtered, and the resulting 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 4-(benzyloxy)-3,5-difluoropyridine (5.0 g).

[0201] <Step 3> Synthesis of 4-(benzyloxy)-3,5-difluoropyridine-2-carboaldehyde: 15 g of 4-(benzyloxy)-3,5-difluoropyridine (150 mL), the compound obtained in Step 2, was added dropwise to a solution of tetrahydrofuran (150 mL) with a 2.5 M n-butyllithium hexane solution (41 mL) under a nitrogen atmosphere at -78°C and stirred for 1 hour. Then, a solution of N,N-dimethylformamide (9.9 g) in tetrahydrofuran (20 mL) was added dropwise to the reaction mixture and stirred at -78°C for 1 hour. The reaction mixture was then stopped with an aqueous solution of ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-(benzyloxy)-3,5-difluoropyridine-2-carboaldehyde (8.0 g).

[0202] <Step 4> Synthesis of (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol: Sodium borohydride (2.6 g) was slowly added at 0°C to a methanol (150 mL) solution of 4-(benzyloxy)-3,5-difluoropyridine-2-carboaldehyde (8.5 g), the compound obtained in Step 3, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then stopped with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (5.0 g).

[0203]

[0204] [Synthesis Example 3] Synthesis of (4-(benzyloxy)-3,5-difluoro-6-(trifluoromethyl)pyridine-2-yl)methanol (intermediate C)

[0205] <Step 1> Synthesis of (4-(benzyloxy)-3,5-difluoro-2-iodopyridine) A solution of 4-(benzyloxy)-3,5-difluoropyridine (3.2 g), the compound obtained in Step 2 of Synthesis Example 2, was added dropwise to a solution of tetrahydrofuran (60 mL) with a 2.5 M n-butyllithium hexane solution (9 mL) under a nitrogen atmosphere at -78°C and stirred for 30 minutes. Then, a solution of iodine (5.5 g) in tetrahydrofuran (6 mL) was added dropwise to the reaction mixture and stirred at -78°C for 2 hours. The reaction reaction was stopped with aqueous ammonium chloride solution and aqueous sodium thiosulfate solution, and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain (4-(benzyloxy)-3,5-difluoro-2-iodopyridine) (4.0 g).

[0206] <Step 2> Synthesis of 4-(benzyloxy)-3,5-difluoro-2-(trifluoromethyl)pyridine The compound obtained in Step 1, (4-(benzyloxy)-3,5-difluoro-2-iodopyridine (4.0 g), methyl-2,2-difluoro-2-(fluorosulfonyl) acetate (4.4 g), and copper iodide (4.4 g), was mixed in N,N-dimethylformamide (100 mL) and stirred at 80°C for 16 hours under a nitrogen atmosphere. The reaction mixture was then filtered, ethyl acetate was added to the filtrate, 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 resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-(benzyloxy)-3,5-difluoro-2-(trifluoromethyl)pyridine (2.9 g).

[0207] <Step 3> To a solution of 4-(benzyloxy)-3,5-difluoro-6-(trifluoromethyl)pyridine-2-yl)methanol, obtained in Step 2, 4-(benzyloxy)-3,5-difluoro-2-(trifluoromethyl)pyridine (2.9 g) in tetrahydrofuran (100 mL), 8 mL of 2 M lithium diisopropylamide (LDA) tetrahydrofuran solution was added dropwise under a nitrogen atmosphere at -78°C and the mixture was stirred for 30 minutes. Then, a solution of dimethylformamide (1.5 g) in tetrahydrofuran (20 mL) was added dropwise to the reaction mixture and the mixture was stirred at -78°C for 2 hours. The reaction mixture was then stopped with an aqueous solution of ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Sodium borohydride (480 mg) was slowly added to a methanol (40 mL) solution of the resulting crude product (2.0 g) at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then stopped with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain (4-(benzyloxy)-3,5-difluoro-6-(trifluoromethyl)pyridine-2-yl)methanol (1.1 g).

[0208]

[0209] The intermediates produced in Synthesis Examples 1 to 3 are shown in Table 1 below.

[0210]

[0211] [Example 1] Synthesis of 3,5-difluoro-2-(((7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol

[0212] A mixture of (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (150 mg), the known substance 4-chloro-7-phenylpyrrolo[2,3-d]pyrimidine (147 mg), ((2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)palladium(II)methanesulfonate methanesulfonate (48 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (29 mg), and cesium carbonate (348 mg) in toluene (15 mL) was heated under a nitrogen atmosphere at 90°C. The mixture was stirred for 16 hours. The reaction mixture was filtered, and ethyl acetate was added to the filtrate. 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. A solution of the obtained crude product (300 mg) in trifluoroacetic acid (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) and high-performance liquid chromatography to obtain 3,5-difluoro-2-(((7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol (19 mg).

[0213]

[0214] [Example 2] Synthesis of 3,5-difluoro-2-(((7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol

[0215] To a solution of (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (150 mg) in N,N-dimethylformamide (15 mL), sodium hydride (60%, 32 mg) was slowly added at 0°C and the mixture was stirred for 20 minutes. To this reaction mixture, a solution of the known substance 4-chloro-7-methylpyrrolo[2,3-d]pyrimidine (134 mg) in N,N-dimethylformamide (2 mL) was added dropwise at 0°C and the mixture was stirred for 2 hours. The reaction reaction was stopped with aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting crude product (350 mg) was a solution of trifluoroacetic acid (10 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) and high-performance liquid chromatography to obtain 3,5-difluoro-2-(((7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol (32 mg).

[0216]

[0217] [Example 3] Synthesis of 3,5-difluoro-2-(((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol

[0218] <Step 1> Synthesis of 4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (700 mg), 2-iodopropane (770 mg), and cesium carbonate (3.0 g) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was filtered, and ethyl acetate was added to the filtrate. 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 resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (650 mg).

[0219] <Step 2> Synthesis of 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (90 mg) in tetrahydrofuran (5 mL), sodium hydride (60%, 19 mg) was slowly added at 0°C under a nitrogen atmosphere and the mixture was stirred for 30 minutes. To this reaction mixture, a solution of 4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (50 mg), the compound obtained in Step 1, in tetrahydrofuran (2 mL) was added dropwise at 0°C and the mixture was stirred at room temperature for 2 hours. The reaction was stopped with aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (80 mg).

[0220] <Step 3> Synthesis of 3,5-difluoro-2-(((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol. 130 mg of 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (130 mg) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (6 mL) was added at room temperature and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 3,5-difluoro-2-(((7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol (30 mg).

[0221]

[0222] [Example 4] Synthesis of 2-(((7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0223] <Step 1> Synthesis of 4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine A mixture of 1,2-dichloroethane (16 mL) containing 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g), cyclopropylboronic acid (1.7 g), copper(II) acetate (1.2 g), sodium carbonate (1.4 g), and 2-(pyridine-2-yl)pyridine (1.0 g), which are known substances, was stirred at 70°C for 5 hours. The reaction mixture was then filtered, and the resulting 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 4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (533 mg). Steps 2 and 3 were carried out in the same manner as in Example 3 to obtain 2-(((7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (38 mg).

[0224] [Example 5] Synthesis of 3,5-difluoro-2-(((1-methyl-1H-pyrazolo[4,3-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol

[0225] <Step 1> Synthesis of 3,5-difluoro-4-((4-methoxybenzyl)oxy)-2-(((1-methylpyrazolo[4,3-c]pyridine-4-yloxy)methyl)pyridine: 4-chloro-1-methylpyrazolo[4,3-c]pyridine (180 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (302 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (56 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl A mixture of di-t-butylphosphine (60 mg), cesium carbonate (700 mg), and 1,4-dioxane (15 mL) was stirred under a nitrogen atmosphere at 140°C for 2 hours. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 3,5-difluoro-4-((4-methoxybenzyl)oxy)-2-(((1-methylpyrazolo[4,3-c]pyridine-4-yloxy)methyl)pyridine (85 mg).

[0226] <Step 2> Synthesis of 3,5-difluoro-2-(((1-methyl-1H-pyrazolo[4,3-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step 1, 3,5-difluoro-4-((4-methoxybenzyl)oxy)-2-(((1-methylpyrazolo[4,3-c]pyridine-4-yloxy)methyl)pyridine (70 mg), was mixed with dichloromethane (4 mL) and trifluoroacetic acid (1 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate)-acetonitrile) and high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-methyl-1H-pyrazolo[4,3-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol (31 mg).

[0227]

[0228] [Example 6] Synthesis of 3,5-difluoro-2-(((1-methyl-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol

[0229] A mixture of 4-chloro-1-methylpyrrolo[3,2-c]pyridine (90 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (152 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (25 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (30 mg), and cesium carbonate (352 mg) in 1,4-dioxane (13.5 mL) was stirred under a nitrogen atmosphere at 140°C for 2 hours. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting crude product (220 mg) was mixed with dichloroethane (8 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate)-acetonitrile) and high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-methyl-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol (24 mg).

[0230]

[0231] [Example 7] Synthesis of 5-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-1-methyl-3,4-dihydro-1,6-naphthyridine-2(1H)-one

[0232] <Step 1> Synthesis of 5-chloro-3,4-dihydro-1H-1,6-naphthyridine-2-one: 5.0 g of 2-chloro-3-iodopyridine-4-amine, tributyltin hydride (8.6 g), and 2,2'-azodiisobutyronitrile (1.6 g) were prepared by adding methyl acrylate (14 g) to a dimethyl sulfoxide (100 mL) solution under a nitrogen atmosphere at 0°C and stirring at 120°C for 16 hours. Ethyl acetate was then added to the reaction mixture, 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 resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 5-chloro-3,4-dihydro-1H-1,6-naphthyridine-2-one (700 mg).

[0233] <Step 2> Synthesis of 5-chloro-1-methyl-3,4-dihydro-1,6-naphthyridine-2-one The compound obtained in Step 1, 5-chloro-3,4-dihydro-1H-1,6-naphthyridine-2-one (300 mg), was dissolved in N,N-dimethylformamide (7 mL). Sodium hydride (60%, 99 mg) was slowly added at 0°C and the mixture was stirred at room temperature for 30 minutes. Iodomethane (233 mg) was added to this reaction mixture at 0°C and the mixture was stirred at room temperature for 1 hour. The reaction reaction was stopped with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 5-chloro-1-methyl-3,4-dihydro-1,6-naphthyrizin-2-one (100 mg).

[0234] <Step 3> Synthesis of 5-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-1-methyl-3,4-dihydro-1,6-naphthyridine-2(1H)-one The compound obtained in Step 1, 5-chloro-1-methyl-3,4-dihydro-1,6-naphthyridine-2-one (100 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (143 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (23 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (28 mg), and cesium carbonate (331 mg) were mixed in 1,4-dioxane (10 mL) and stirred at 140°C for 2 hours under a nitrogen atmosphere. Subsequently, the reaction mixture was filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The crude product (200 mg) was mixed with dichloroethane (8 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% formic acid)-acetonitrile) and high-performance liquid chromatography to obtain 5-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-1-methyl-3,4-dihydro-1,6-naphthyridine-2(1H)-one (42 mg).

[0235]

[0236] [Example 8] Synthesis of 3,5-difluoro-2-(((1-phenyl-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol

[0237] <Step 1> Synthesis of 4-chloro-1-phenylpyrrolo[3,2-c]pyridine A mixture of 4-chloro-1H-pyrrolo[3,2-c]pyridine (250 mg), phenylboronic acid (400 mg), copper(II) acetate (298 mg), sodium carbonate (347 mg), and 2-(pyridine-2-yl)pyridine (256 mg) in 1,2-dichloroethane (10 mL) was stirred at 70°C for 16 hours. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. Dichloroethane was added to the resulting residue, 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 resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-chloro-1-phenylpyrrolo[3,2-c]pyridine (110 mg).

[0238] <Step 2> Synthesis of 3,5-difluoro-4-((4-methoxybenzyl)oxy)-2-(((1-phenylpyrrolo[3,2-c]pyridine-4-yloxy)methyl)pyridine Compound obtained in Step 1: 4-chloro-1-phenylpyrrolo[3,2-c]pyridine (140 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (172 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (32 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (34 mg), cesium carbonate A mixture of 399 mg of 1,4-dioxane (8 mL) was stirred at 140°C under a nitrogen atmosphere for 2 hours. The reaction mixture was then filtered, and ethyl acetate was added to the filtrate. 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 resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 3,5-difluoro-4-((4-methoxybenzyl)oxy)-2-(((1-phenylpyrrolo[3,2-c]pyridine-4-yloxy)methyl)pyridine (100 mg).

[0239] <Step 3> Synthesis of 3,5-difluoro-2-(((1-phenyl-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step 2, 3,5-difluoro-4-((4-methoxybenzyl)oxy)-2-(((1-phenylpyrrolo[3,2-c]pyridine-4-yloxy)methyl)pyridine (90 mg), was mixed with dichloromethane (4 mL) and trifluoroacetic acid (1 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate)-acetonitrile) and high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-phenyl-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol (30 mg).

[0240]

[0241] [Example 9] Synthesis of 3-fluoro-2-(((7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)-6-(trifluoromethyl)pyridine-4-ol

[0242] <Step 1> Synthesis of 2-chloro-3-fluoro-4-(methoxymethoxy)-6-(trifluoromethyl)pyridine: A mixture of 2-chloro-3-fluoro-6-(trifluoromethyl)pyridine (2.0 g), bis(pinacolate)diborone (3.1 g), bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) (170 mg), and 4,4'-di-t-butyl-2,2'-dipyridyl (70 mg) in t-butyl methyl ether (40 mL) was stirred under a nitrogen atmosphere at room temperature for 16 hours. After cooling the reaction mixture to 0°C, 72 mL of 70% t-butyl hydroperoxide aqueous solution was added dropwise, and the mixture was stirred at room temperature for 2 hours. Subsequently, the reaction mixture was stopped with sodium thiosulfate aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. To a solution of the obtained crude product (520 mg) in tetrahydrofuran (10 mL), triethylamine (0.67 mL) and bromomethoxymethane (452 ​​mg) were added dropwise at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction was then stopped with water, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2-chloro-3-fluoro-4-(methoxymethoxy)-6-(trifluoromethyl)pyridine (440 mg).

[0243] <Step 2> Synthesis of 3-fluoro-4-(methoxymethoxy)-6-(trifluoromethyl)pyridine-2-yl)methanol A mixture of 2-chloro-3-fluoro-4-(methoxymethoxy)-6-(trifluoromethyl)pyridine (440 mg), (tributylstanyl)methanol (2.2 g), and tetrakis(triphenylphosphine)palladium (0) (392 mg) in 1,4-dioxane (14 mL) was stirred under a nitrogen atmosphere at 100°C for 16 hours. Then, ethyl acetate was added to the reaction mixture, 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 silica gel column chromatography (hexane-ethyl acetate) to obtain 3-fluoro-4-(methoxymethoxy)-6-(trifluoromethyl)pyridine-2-yl)methanol (120 mg).

[0244] <Step 3> Synthesis of 3-fluoro-4-(methoxymethoxy)-2-(((7-phenylpyrrolo[2,3-d]pyrimidine-4-yloxy)methyl)-6-(trifluoromethyl)pyridine A mixture of 3-fluoro-4-(methoxymethoxy)-6-(trifluoromethyl)pyridine-2-yl)methanol (120 mg), a compound obtained in Step 2, 4-chloro-7-phenylpyrrolo[2,3-d]pyrimidine (108 mg), a known substance, tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (24 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (26 mg), and cesium carbonate (306 mg) in 1,4-dioxane (2 mL) was stirred under a nitrogen atmosphere at 140°C for 16 hours. Subsequently, the reaction mixture was filtered, and the resulting 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 3-fluoro-4-(methoxymethoxy)-2-(((7-phenylpyrrolo[2,3-d]pyrimidine-4-yloxy)methyl)-6-(trifluoromethyl)pyridine (60 mg).

[0245] <Step 4> Synthesis of 3-Fluoro-2-(((7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)-6-(trifluoromethyl)pyridine-4-ol The compound obtained in Step 3, 3-Fluoro-4-(methoxymethoxy)-2-(((7-phenylpyrrolo[2,3-d]pyrimidine-4-yloxy)methyl)-6-(trifluoromethyl)pyridine (60 mg), was stirred at room temperature for 1 hour in a 4 M aqueous solution of hydrogen chloride and a solution of 1,4-dioxane (2 mL). The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 3-Fluoro-2-(((7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)-6-(trifluoromethyl)pyridine-4-ol (12 mg).

[0246]

[0247] [Example 10] Synthesis of 3-fluoro-6-(((7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)-2-(trifluoromethyl)pyridine-4-ol

[0248] <Step 1> Synthesis of 6-chloro-3-fluoro-2-(trifluoromethyl)pyridine-4-ol: A mixture of 6-chloro-3-fluoro-2-(trifluoromethyl)pyridine (1.5 g), bis(pinacolate)diborone (2.3 g), bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) (125 mg), and 4,4'-di-t-butyl-2,2'-dipyridyl (50 mg) in t-butyl methyl ether (30 mL) was stirred at room temperature under a nitrogen atmosphere for 16 hours. After cooling the reaction mixture to 0°C, 70% t-butyl hydroperoxide aqueous solution (5 mL) was added dropwise, and the mixture was stirred at room temperature for 6 hours. Subsequently, the reaction mixture was stopped with sodium thiosulfate aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 6-chloro-3-fluoro-2-(trifluoromethyl)pyridine-4-ol (1.1 g).

[0249] <Step 2> Synthesis of 6-chloro-3-fluoro-4-(methoxymethoxy)-2-(trifluoromethyl)pyridine: Triethylamine (1.0 g) and bromomethoxymethane (3.8 g) were added dropwise to a solution of 6-chloro-3-fluoro-2-(trifluoromethyl)pyridine-4-ol (1.1 g), the compound obtained in Step 1, in tetrahydrofuran (30 mL) at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then stopped with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 6-chloro-3-fluoro-4-(methoxymethoxy)-2-(trifluoromethyl)pyridine (1.3 g).

[0250] <Step 3> Synthesis of 5-fluoro-4-(methoxymethoxy)-6-(trifluoromethyl)pyridine-2-yl)methanol A solution of 6-chloro-3-fluoro-4-(methoxymethoxy)-2-(trifluoromethyl)pyridine (1.3 g), (tributylstanyl)methanol (6.4 g), and tetrakis(triphenylphosphine)palladium (0) (1.2 g) in 1,4-dioxane (45 mL) was stirred at 100°C for 16 hours under a nitrogen atmosphere. The reaction mixture was then filtered, and the resulting 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 5-fluoro-4-(methoxymethoxy)-6-(trifluoromethyl)pyridine-2-yl)methanol (700 mg).

[0251] <Step 4> Synthesis of 3-fluoro-6-(((7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)-2-(trifluoromethyl)pyridine-4-ol. The mixture of 5-fluoro-4-(methoxymethoxy)-6-(trifluoromethyl)pyridine-2-yl)methanol (110 mg), a compound obtained in Step 3, 4-chloro-7-phenylpyrrolo[2,3-d]pyrimidine (99 mg), a known substance, tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (22 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (24 mg), and cesium carbonate (281 mg) in 1,4-dioxane (11 mL) was stirred under a nitrogen atmosphere at 140°C for 2 hours. Subsequently, the reaction mixture was filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The crude product (500 mg) was mixed with 4 M hydrogen chloride and 1,4-dioxane (20 mL) and stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) and high-performance liquid chromatography to obtain 3-fluoro-6-(((7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)-2-(trifluoromethyl)pyridine-4-ol (49 mg).

[0252]

[0253] [Example 11] Synthesis of 3,5-difluoro-2-(((7-phenyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol

[0254] <Step 1> Sodium triacetoxyborohydride (757 mg) was added at -15°C to a solution of 222 mg of synthetic aniline of 4-chloro-7-phenyl-5H,6H-pyrrolo[2,3-d]pyrimidine in trifluoroacetic acid (10 mL) and stirred for 10 minutes. A solution of 500 mg of the known substance 2-(4,6-dichloropyrimidine-5-yl)acetaldehyde in dichloromethane (10 mL) was added dropwise to this reaction mixture at -15°C and stirred for 30 minutes, then stirred at room temperature for 16 hours. The reaction mixture was then adjusted to pH 8 with an aqueous sodium carbonate solution and extracted three times with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 4-chloro-7-phenyl-5H,6H-pyrrolo[2,3-d]pyrimidine (140 mg).

[0255] <Step 2> Synthesis of 3,5-difluoro-2-(((7-phenyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol. The compound obtained in Step 1, 4-chloro-7-phenyl-5H,6H-pyrrolo[2,3-d]pyrimidine (140 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (170 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (31 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (37 mg), and cesium carbonate (395 mg) were mixed in 1,4-dioxane (10 mL) and stirred at 140°C for 2 hours under a nitrogen atmosphere. Subsequently, the reaction mixture was filtered, and ethyl acetate was added to the filtrate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting crude product (340 mg) and a solution of trifluoroacetic acid (2.5 mL) in dichloromethane (10 mL) were stirred at room temperature for 1 hour. Subsequently, the reaction mixture was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 3,5-difluoro-2-(((7-phenyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol (50 mg).

[0256]

[0257] [Example 12] Synthesis of 5-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-1-phenyl-3,4-dihydro-1,6-naphthyridine-2(1H)-one

[0258] <Step 1> Synthesis of 5-chloro-3,4-dihydro-1H-1,6-naphthyridine-2-one: A solution of 2-chloro-3-iodopyridine-4-amine (5.0 g), tributyltin hydride (8.6 g), and 2,2'-azodiisobutyronitrile (1.6 g) in dimethyl sulfoxide (100 mL) was prepared by adding methyl acrylate (20 g) under a nitrogen atmosphere at 0°C and stirring at 120°C for 16 hours. The reaction mixture was stopped with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 5-chloro-3,4-dihydro-1H-1,6-naphthyridine-2-one (1.0 g).

[0259] <Step 2> Synthesis of 5-chloro-1-phenyl-3,4-dihydro-1,6-naphthyrizin-2-one A mixture of 5-chloro-3,4-dihydro-1H-1,6-naphthyrizin-2-one (1.0 g), the compound obtained in Step 1, phenylboronic acid (670 mg), copper(II) acetate (200 mg), and triethylamine (1.1 g) in dichloromethane (20 mL) was stirred at room temperature under an oxygen atmosphere for 16 hours. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. Dichloroethane was added to the resulting residue, 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 resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 5-chloro-1-phenyl-3,4-dihydro-1,6-naphthyrizin-2-one (800 mg).

[0260] <Step 3> Synthesis of 5-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-1-phenyl-3,4-dihydro-1,6-naphthyridine-2(1H)-one The compound obtained in Step 2, 5-chloro-1-phenyl-3,4-dihydro-1,6-naphthyridine-2-one (150 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (163 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (30 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (32 mg), and cesium carbonate (378 mg) were mixed in 1,4-dioxane (15 mL) and stirred at 140°C for 2 hours under a nitrogen atmosphere. Subsequently, the reaction mixture was filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The crude product (390 mg) was mixed with trifluoroacetic acid (7.5 mL) and dichloromethane (30 mL) and stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by reverse-phase column chromatography (water (containing 0.05 g formic acid) - acetonitrile) and high-performance liquid chromatography to obtain 5-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-1-phenyl-3,4-dihydro-1,6-naphthyridine-2(1H)-one (21 mg).

[0261]

[0262] [Example 13] Synthesis of 3,5-difluoro-2-(((1-methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl)oxy)methyl)pyridine-4-ol

[0263] <Step 1> Synthesis of ethyl 2-methyl-1-(triisopropylsilyl)pyrrole-3-carboxylate: To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (600 mg), a known substance, in tetrahydrofuran (4 mL), sodium hydride (60%, 235 mg) was slowly added at 0°C and stirred for 20 minutes. Chlorotriisopropylsilane (982 mg) was added to this reaction mixture and stirred for 3 hours. The reaction reaction was stopped with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. A solution of the obtained crude product (350 mg) in trifluoroacetic acid (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 2-methyl-1-(triisopropylsilyl)pyrrole-3-carboxylate (900 mg).

[0264] <Step 2> Synthesis of ethyl 2-formyl-1H-pyrrole-3-carboxylate Ethyl 2-methyl-1-(triisopropylsilyl)pyrrole-3-carboxylate (1.8 g), the compound obtained in Step 1, was mixed with acetic acid (18 mL), tetrahydrofuran (22 mL), and water (18 mL). Ammonium hexanitratocerium(IV) (CAN) (13 g) was added at room temperature and the mixture was stirred for 45 minutes. Ethyl acetate was added to this reaction mixture, 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 resulting residue was purified by reverse-phase chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain ethyl 2-formyl-1H-pyrrole-3-carboxylate (570 mg).

[0265] <Step 3> Synthesis of 1-methylpyrrolo[2,3-d]pyridazin-4-ol A mixture of ethyl 2-formyl-1H-pyrrole-3-carboxylate (480 mg), potassium carbonate (198 mg), and iodomethane (611 mg) obtained in Step 2, in N,N-dimethylformamide (10 mL) was stirred at 60°C for 2 hours. Ethyl acetate was added to this reaction mixture, 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 resulting crude product (550 mg) and a solution of hydrazine monohydrate in acetic acid (12 mL) were stirred at 100°C for 1 hour. This reaction mixture was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain 1-methylpyrrolo[2,3-d]pyridazin-4-ol (450 mg).

[0266] <Step 4> Synthesis of 4-chloro-1-methylpyrrolo[2,3-d]pyridazine: A solution of 1-methylpyrrolo[2,3-d]pyridazine-4-ol (300 mg), the compound obtained in Step 3, in phosphorus oxychloride (10 mL) was stirred at 100°C for 2 hours. The reaction mixture was then stopped with cold water and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by reverse-phase chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 4-chloro-1-methylpyrrolo[2,3-d]pyridazine (160 mg).

[0267] <Step 5> Synthesis of 3,5-difluoro-4-((4-methoxybenzyl)oxy)-2-((1-methylpyrrolo[2,3-d]pyridazin-4-yloxy)methyl)pyridine: 4-chloro-1-methylpyrrolo[2,3-d]pyridazin (100 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (118 mg), methanesulfonate (dicyclohexyl (3-(1-methylethoxy A mixture of 1,4-dioxane (8 mL) containing (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (55 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (32 mg), and cesium carbonate (292 mg) was stirred at 100°C for 2 hours under a nitrogen atmosphere. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The obtained residue was purified by reverse-phase chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 3,5-difluoro-4-((4-methoxybenzyl)oxy)-2-((1-methylpyrrolo[2,3-d]pyridazine-4-yloxy)methyl)pyridine (110 mg).

[0268] <Step 6> Synthesis of 3,5-difluoro-2-(((1-methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step 5, 3,5-difluoro-4-((4-methoxybenzyl)oxy)-2-((1-methylpyrrolo[2,3-d]pyridazin-4-yloxy)methyl)pyridine (150 mg), trifluoroacetic acid (5 mL), and a solution of dichloromethane (5 mL) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl)oxy)methyl)pyridine-4-ol (39 mg).

[0269]

[0270] [Example 14] Synthesis of 5-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-2-methyl-3,4-dihydro-2,6-naphthyridine-1(2H)-one

[0271] <Step 1> Synthesis of t-butyl N-(2-(2-fluoro-4-iodopyridine-3-yl)ethyl)carbamate A tetrahydrofuran solution (67 mL) of 2 M lithium diisopropylamide (LDA) tetrahydrofuran solution was added dropwise at -78°C under a nitrogen atmosphere and stirred for 1 hour. A tetrahydrofuran solution (20 mL) of t-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide solution was added dropwise to this reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was then stopped with an aqueous solution of ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 t-butyl N-(2-(2-fluoro-4-iodopyridine-3-yl)ethyl)carbamate (11 g).

[0272] <Step 2> Synthesis of 3-(2-((t-butoxycarbonyl)amino)ethyl-2-fluoropyridine-4-carboxylic acid The compound obtained in Step 1, t-butyl N-(2-(2-fluoro-4-iodopyridine-3-yl)ethyl)carbamate (2.0 g), acetic anhydride (840 mg), palladium(II) acetate (120 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (320 mg), and diisopropylethylamine (1.1 g) were mixed in N,N-dimethylformamide (20 mL) and stirred at 100°C for 16 hours under a nitrogen atmosphere. Then, water and 1 M hydrochloric acid were added to the reaction mixture. The H3 to H4 solution was adjusted and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 3-(2-((t-butoxycarbonyl)amino)ethyl-2-fluoropyridine-4-carboxylic acid (750 mg).

[0273] <Step 3> Synthesis of 5-fluoro-2-methyl-3,4-dihydro-2,6-naphthyridine-1-one: The compound obtained in Step 2, 3-(2-((t-butoxycarbonyl)amino)ethyl-2-fluoropyridine-4-carboxylic acid (700 mg), was mixed with 4 M aqueous hydrogen chloride, 1,4-dioxane (6 mL), and dichloroethane (6 mL) and stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure using a rotary evaporator, and the resulting crude product (420 mg), along with a solution of chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) (768 mg) and 1-methylimidazole (NMI) (655 mg) in acetonitrile (6 mL), was stirred at 80°C for 16 hours. The reaction mixture was then stopped with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and extracted with anhydrous sodium sulfate. The product was dried with thorium. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Sodium hydride (60%, 246 mg) was slowly added to a solution of the crude product (680 mg) in tetrahydrofuran (6 mL) at 0°C and the mixture was stirred for 30 minutes. Iodomethane (871 mg) was added dropwise to this reaction mixture at 0°C and the mixture was stirred at room temperature for 2 hours. The reaction was then stopped with aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by reverse-phase chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 5-fluoro-2-methyl-3,4-dihydro-2,6-naphthyridine-1-one (200 mg).

[0274] <Step 4> Synthesis of 5-(3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-ylmethoxy)-2-methyl-3,4-dihydro-2,6-naphthyridine-1-one The compound obtained in Step 3, 5-fluoro-2-methyl-3,4-dihydro-2,6-naphthyridine-1-one (180 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (281 mg), and t-butoxypotassium (135 mg) were mixed in tetrahydrofuran (6 mL) and stirred at room temperature for 16 hours. The reaction mixture was then stopped with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 5-(3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-ylmethoxy)-2-methyl-3,4-dihydro-2,6-naphthyrizin-1-one (150 mg).

[0275] <Step 5> The compound 5-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-2-methyl-3,4-dihydro-2,6-naphthyridine-1(2H)-one, obtained in Step 4 of the synthesis, was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 5-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-2-methyl-3,4-dihydro-2,6-naphthyridine-1(2H)-one (55 mg).

[0276]

[0277] [Example 15] Synthesis of 3,5-difluoro-2-(((1-phenyl-1H-pyrazolo[4,3-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol

[0278] <Step 1> Synthesis of 4-chloro-1-phenylpyrazolo[4,3-c]pyridine A mixture of 4-chloro-1H-pyrazolo[4,3-c]pyridine (500 mg), phenylboronic acid (596 mg), copper(II) acetate (591 mg), sodium carbonate (690 mg), and 2-(pyridine-2-yl)pyridine (509 mg) in 1,2-dichloroethane (20 mL) was stirred at 70°C for 16 hours. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. Dichloromethane was added to the resulting residue, and 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 resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-chloro-1-phenylpyrazolo[4,3-c]pyridine (250 mg).

[0279] <Step 2> Synthesis of 3,5-difluoro-2-(((1-phenyl-1H-pyrazolo[4,3-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol A mixture of 4-chloro-1-phenylpyrazolo[4,3-c]pyridine (150 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (184 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (34 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (36 mg), and cesium carbonate (426 mg) in 1,4-dioxane (15 mL) was stirred under a nitrogen atmosphere at 100°C for 16 hours. Subsequently, the reaction mixture was filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The crude product (390 mg) was mixed with dichloromethane (16 mL) and trifluoroacetic acid (4 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 3,5-difluoro-2-(((1-phenyl-1H-pyrazolo[4,3-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol (25 mg).

[0280]

[0281] [Example 16] Synthesis of 3,5-difluoro-2-(((1-phenyl-1H-pyrrolo[2,3-d]pyridazin-4-yl)oxy)methyl)pyridine-4-ol

[0282] <Step 1> Synthesis of ethyl 2-formyl-1-phenylpyrrole-3-carboxylate A mixture of ethyl 2-formyl-1H-pyrrole-3-carboxylate (500 mg), the compound obtained in Step 2 of Example 13, phenylboronic acid (547 mg), copper(II) acetate (109 mg), and triethylamine (605 mg) in dichloromethane (15 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered, and the resulting 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 ethyl 2-formyl-1-phenylpyrrole-3-carboxylate (521 mg).

[0283] <Step 2> Synthesis of 1-phenylpyrrolo[2,3-d]pyridazin-4-ol: A solution of ethyl 2-formyl-1-phenylpyrrole-3-carboxylate (500 mg), a compound obtained in Step 1, and hydrazine monohydrate (151 mg) in acetic acid (10 mL) was stirred at 90°C for 1 hour. This reaction mixture was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain 1-phenylpyrrolo[2,3-d]pyridazin-4-ol (410 mg).

[0284] <Step 3> Synthesis of 4-chloro-1-phenylpyrrolo[2,3-d]pyridazine: A solution of 1-phenylpyrrolo[2,3-d]pyridazine-4-ol (300 mg), the compound obtained in Step 2, in phosphorus oxychloride (6 mL) was stirred at 100°C for 2 hours. The reaction mixture was then concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by reverse-phase chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 4-chloro-1-phenylpyrrolo[2,3-d]pyridazine (274 mg).

[0285] <Step 4> Synthesis of 3,5-difluoro-4-((4-methoxybenzyl)oxy)-2-((1-phenylpyrrolo[2,3-d]pyridazin-4-yloxy)methyl)pyridine The compound obtained in Step 3 is 4-chloro-1-phenylpyrrolo[2,3-d]pyridazin (110 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (135 mg), methanesulfonate (dicyclohexyl (3-(1-methylethoxy A mixture of (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (26 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (26 mg), and cesium carbonate (312 mg) in 1,4-dioxane (15 mL) was stirred at 100°C for 2 hours under a nitrogen atmosphere. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate and dichloromethane-methanol) to obtain 3,5-difluoro-4-((4-methoxybenzyl)oxy)-2-((1-phenylpyrrolo[2,3-d]pyridazine-4-yloxy)methyl)pyridine (100 mg).

[0286] <Step 5> Synthesis of 3,5-difluoro-2-(((1-phenyl-1H-pyrrolo[2,3-d]pyridazin-4-yl)oxy)methyl)pyridine-4-ol. 3,5-difluoro-4-((4-methoxybenzyl)oxy)-2-((1-phenylpyrrolo[2,3-d]pyridazin-4-yloxy)methyl)pyridine (100 mg), the compound obtained in Step 4, was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL) was added at room temperature and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-phenyl-1H-pyrrolo[2,3-d]pyridazin-4-yl)oxy)methyl)pyridine-4-ol (19 mg).

[0287]

[0288] [Example 17] Synthesis of 3,5-difluoro-2-(((7-(3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol

[0289] <Step 1> Synthesis of 4-chloro-7-(3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine: 200 mg of the known substance 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, 364 mg of 3-fluorophenylboronic acid, and 473 mg of copper(II) acetate were mixed with pyridine (5 mL) and stirred at 60°C for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 4-chloro-7-(3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (354 mg).

[0290] <Step 2> Synthesis of 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-7-(3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (194 mg) in tetrahydrofuran (5 mL), sodium hydride (60%, 106 mg) and 4-chloro-7-(3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (132 mg), the compound obtained in Step 1, were added at 0°C and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-7-(3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (370 mg).

[0291] <Step 3> Synthesis of 3,5-difluoro-2-(((7-(3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol. To a solution of 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-7-(3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine (370 mg), a compound obtained in Step 2, in acetonitrile (1 mL), trifluoroacetic acid (0.58 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain 3,5-difluoro-2-(((7-(3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol (25 mg).

[0292]

[0293] [Example 18] Synthesis of 3,5-difluoro-2-(((7-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol

[0294] 3,5-difluoro-2-(((7-(4-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol (9 mg) was obtained by the same procedure (steps 1-3) as in Example 17.

[0295] [Example 19] Synthesis of 3,5-difluoro-2-(((7-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol

[0296] 3,5-difluoro-2-(((7-(2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol (9 mg) was obtained by the same procedure (steps 1-3) as in Example 17.

[0297] [Example 20] Synthesis of 2-(((7-benzyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0298] <Step 1> Synthesis of 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine: To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (200 mg), a known substance, in N,N-dimethylformamide (5 mL), sodium hydride (60%, 104 mg) and benzyl bromide (0.31 mL) were added at 0°C, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (304 mg).

[0299] <Step 2> Synthesis of 7-benzyl-4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7H-pyrrolo[2,3-d]pyrimidine To a solution of (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (456 mg) in tetrahydrofuran (5 mL), sodium hydride (60%, 249 mg) and 7-benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (304 mg), the compound obtained in step 1, were added at 0°C and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 7-benzyl-4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7H-pyrrolo[2,3-d]pyrimidine (150 mg).

[0300] <Step 3> Synthesis of 2-(((7-benzyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol. 7-benzyl-4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7H-pyrrolo[2,3-d]pyrimidine (150 mg), the compound obtained in Step 2, was dissolved in acetonitrile (1 mL) and trifluoroacetic acid (0.24 mL) was added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain 2-(((7-benzyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (22 mg).

[0301]

[0302] [Example 21] Synthesis of 3,5-difluoro-2-(((7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol

[0303] <Step 1> Synthesis of 4-chloro-7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine: To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (200 mg), a known substance, in N,N-dimethylformamide (5 mL), sodium hydride (60%, 104 mg) and 1-iodo-2-methylpropane (0.3 mL) were added at 0°C, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 4-chloro-7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine (282 mg).

[0304] <Step 2> Synthesis of 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (491 mg) in tetrahydrofuran (5 mL), sodium hydride (60%, 269 mg) and 4-chloro-7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine (282 mg), the compound obtained in step 1, were added at 0°C and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine (38 mg).

[0305] <Step 3> Synthesis of 3,5-difluoro-2-(((7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol. To a solution of 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine (38 mg), a compound obtained in Step 2, in acetonitrile (0.5 mL), trifluoroacetic acid (0.065 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain 3,5-difluoro-2-(((7-isobutyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol (12 mg).

[0306]

[0307] [Example 22] Synthesis of 3,5-difluoro-2-(((7-isopentyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol

[0308] <Step 1> Synthesis of 4-chloro-7-isopentyl-7H-pyrrolo[2,3-d]pyrimidine A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg), a known substance, in N,N-dimethylformamide (5 mL) was mixed with sodium hydride (60%, 52 mg) and 1-iodo-3-methylbutane (0.17 mL) at 0°C, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 4-chloro-7-isopentyl-7H-pyrrolo[2,3-d]pyrimidine (120 mg).

[0309] <Step 2> Synthesis of 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7-isopentyl-7H-pyrrolo[2,3-d]pyrimidine To a solution of (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (226 mg) in tetrahydrofuran (2 mL), sodium hydride (60%, 107 mg) and 4-chloro-7-isopentyl-7H-pyrrolo[2,3-d]pyrimidine (120 mg), the compound obtained in step 1, were added at 0°C and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7-isopentyl-7H-pyrrolo[2,3-d]pyrimidine (66 mg).

[0310] <Step 3> Synthesis of 3,5-difluoro-2-(((7-isopentyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol. To a solution of 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7-isopentyl-7H-pyrrolo[2,3-d]pyrimidine (66 mg), a compound obtained in Step 2, in acetonitrile (1 mL), trifluoroacetic acid (0.11 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain 3,5-difluoro-2-(((7-isopentyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol (19 mg).

[0311]

[0312] [Example 23] Synthesis of 3,5-difluoro-2-(((7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol

[0313] <Step 1> Synthesis of 4-chloro-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg), a known substance, in N,N-dimethylformamide (2 mL) was mixed with potassium carbonate (180 mg) and 1,1,1-trifluoroethyl-2-iodoethane (0.13 mL) at 0°C and stirred at 40°C for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 4-chloro-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine (65 mg).

[0314] <Step 2> Synthesis of 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine To a solution of (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (116 mg) in tetrahydrofuran (1 mL), sodium hydride (60%, 55 mg) and 4-chloro-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine (65 mg), the compound obtained in Step 1, were added at 0°C and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine (58 mg).

[0315] <Step 3> Synthesis of 3,5-difluoro-2-(((7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step 2 is 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine (58 mg) To a solution of acetonitrile (1 mL), trifluoroacetic acid (0.092 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain 3,5-difluoro-2-(((7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)pyridine-4-ol (26 mg).

[0316]

[0317] [Example 24] Synthesis of 5-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-2-phenyl-3,4-dihydro-2,6-naphthyridine-1(2H)-one

[0318] <Step 1> Synthesis of 3-(2-hydroxyethyl)-N-phenylpyridine-4-carboxamide: To a solution of N-phenylpyridine-4-carboxamide (1.0 g), a known substance, in tetrahydrofuran (20 mL), 2.5 M n-butyllithium hexane solution (5 mL) was added dropwise at -78°C and the mixture was stirred for 1 hour. To this reaction mixture, 2.5 M ethylene oxide tetrahydrofuran solution (2 mL) was added dropwise at -78°C and the mixture was stirred for 4 hours. Subsequently, the reaction reaction was stopped with aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain 3-(2-hydroxyethyl)-N-phenylpyridine-4-carboxamide (730 mg).

[0319] <Step 2> Synthesis of 2-phenyl-3,4-dihydro-2,6-naphthyrizin-1(2H)-one: In a solution of 3-(2-hydroxyethyl)-N-phenylpyridine-4-carboxamide (700 mg) and triphenylphosphine (1.1 g) in tetrahydrofuran (14 mL), diethyl azodicarboxylate (DEAD) (1.3 g) was added dropwise at 0°C and the mixture was stirred at 60°C for 2 hours. Ethyl acetate was added to the reaction mixture, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 2-phenyl-3,4-dihydro-2,6-naphthyrizin-1(2H)-one (620 mg).

[0320] <Step 3> Synthesis of 5-chloro-2-phenyl-3,4-dihydro-2,6-naphthyrizin-1(2H)-one: In a solution of 2-phenyl-3,4-dihydro-2,6-naphthyrizin-1-one (670 mg), the compound obtained in Step 2, in dichloromethane (15 mL), methachloroperbenzoic acid (mCPBA) (564 mg) was added at 0°C and the mixture was stirred for 1 hour. Dichloromethane was added to the reaction mixture, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting crude product (800 mg), pyridine (1.3 g), and phosphorus oxychloride (2.6 g) in a solution of toluene (15 mL) was stirred at 100°C for 2 hours. Subsequently, the reaction mixture was stopped with cold water, concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 5-chloro-2-phenyl-3,4-dihydro-2,6-naphthyrizine-1(2H)-one (180 mg).

[0321] <Step 4> A mixture of 5-chloro-2-phenyl-3,4-dihydro-2,6-naphthyridine-1(2H)-one (120 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (131 mg), tris(dibenzylideneacetone)dipalladium(0)dichloromethane adduct (48 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (26 mg), and cesium carbonate (302 mg) in 1,4-dioxane (10 mL) was stirred under a nitrogen atmosphere at 140°C for 4 hours. The reaction mixture was filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by reverse-phase chromatography (water (containing 0.05% ammonium bicarbonate)-acetonitrile) and high-performance liquid chromatography to obtain 5-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-2-phenyl-3,4-dihydro-2,6-naphthyridine-1(2H)-one (25 mg).

[0322]

[0323] [Example 25] Synthesis of 2-(((7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0324] <Step 1> Synthesis of 4-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine A solution of cyclohexanol (0.15 mL) and triphenylphosphine (384 mg) in tetrahydrofuran (3 mL) was mixed with a 40% toluene solution of diethyl azodicarboxylate (DEAD) (0.67 mL) and the known substance 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg) at 0°C, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 4-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine (42 mg).

[0325] <Step 2> Synthesis of 7-cyclohexyl-4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7H-pyrrolo[2,3-d]pyrimidine To a solution of (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (101 mg) in tetrahydrofuran (2 mL), sodium hydride (60%, 72 mg) and 4-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine (42 mg), the compound obtained in step 1, were added at 0°C and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 7-cyclohexyl-4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7H-pyrrolo[2,3-d]pyrimidine (68 mg).

[0326] <Step 3> Synthesis of 2-(((7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol. 7-cyclohexyl-4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-7H-pyrrolo[2,3-d]pyrimidine (68 mg), the compound obtained in Step 2, was dissolved in acetonitrile (1 mL), to which trifluoroacetic acid (0.11 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by high-performance liquid chromatography to obtain 2-(((7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (10 mg).

[0327]

[0328] [Example 26] Synthesis of 3,5-difluoro-2-(((1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridine-5-yl)oxy)methyl)pyridine-4-ol

[0329] <Step 1> Synthesis of 1-methyl-5-oxo-6H-1,6-naphthyridine-1-ium iodide: A solution of 1,6-naphthyridine-5(6H)-one (1.6 g), a known substance, and iodomethane (4 mL) in N,N-dimethylformamide (80 mL) was stirred at room temperature for 16 hours. The reaction mixture was slowly added to acetone (25 mL) while stirring. The resulting solid was filtered off and washed with acetone to obtain 1-methyl-5-oxo-6H-1,6-naphthyridine-1-ium iodide (1.2 g). The filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was added to ethyl acetate (50 mL) while stirring. The resulting solid was filtered off and washed with acetone to obtain 1-methyl-5-oxo-6H-1,6-naphthyridine-1-ium iodide (1.8 g) as a separate batch.

[0330] <Step 2> Synthesis of 1-methyl-2,3,4,6-tetrahydro-1,6-naphthyridine-5-one The compound obtained in Step 1, 1-methyl-5-oxo-6H-1,6-naphthyridine-1-ium iodide (1.8 g), was dissolved in a solution of formic acid (10 mL) to which a borane-pyridine complex (2 mL) was added dropwise at 0°C and the mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 1-methyl-2,3,4,6-tetrahydro-1,6-naphthyridine-5-one (930 mg).

[0331] <Step 3> Synthesis of 5-chloro-1-methyl-3,4-dihydro-2H-1,6-naphthirizine A solution of 1-methyl-2,3,4,6-tetrahydro-1,6-naphthirizine-5-one (930 mg), the compound obtained in Step 2, in phosphorus oxychloride (12 mL) was stirred at 100°C for 40 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 5-chloro-1-methyl-3,4-dihydro-2H-1,6-naphthirizine (320 mg).

[0332] <Step 4> The compounds obtained in step 3 of the synthesis of 5-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-1-methyl-3,4-dihydro-2H-1,6-naphthyridine are 5-chloro-1-methyl-3,4-dihydro-2H-1,6-naphthyridine (250 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (385 mg), methanesulfonate (dicyclohexyl(3-(1-methylethoxy)-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine), (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (63 mg), dicyclohexyl(3-isopropoxy-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl) A mixture of sopropyl-[1,1'-biphenyl]-2-yl)phosphine (73 mg), cesium carbonate (892 mg), and 1,4-dioxane (10 mL) was stirred at 100°C under a nitrogen atmosphere for 3 hours. The reaction mixture was then concentrated under reduced pressure using a rotary evaporator, and ethyl acetate was added to the resulting residue. 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, and the resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 5-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-1-methyl-3,4-dihydro-2H-1,6-naphthiridine (70 mg).

[0333] <Step 5> Synthesis of 3,5-difluoro-2-(((1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridine-5-yl)oxy)methyl)pyridine-4-ol. 5-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-1-methyl-3,4-dihydro-2H-1,6-naphthyridine (70 mg), the compound obtained in Step 4, was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (0.8 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridine-5-yl)oxy)methyl)pyridine-4-ol (19 mg).

[0334]

[0335] [Example 27] Synthesis of 3,5-difluoro-2-(((1-phenyl-1,2,3,4-tetrahydro-1,6-naphthyridine-5-yl)oxy)methyl)pyridine-4-ol

[0336] <Step 1> Synthesis of 5-chloro-3,4-dihydro-1H-1,6-naphthyridine-2-one: 5.0 g of 2-chloro-3-iodopyridine-4-amine, tributyltin hydride (8.6 g), and 2,2'-azodiisobutyronitrile (1.6 g) were prepared in a dimethyl sulfoxide solution (100 mL). Methyl acrylate (20 mL) was added under a nitrogen atmosphere at 0°C and the mixture was stirred at 120°C for 16 hours. The reaction was stopped with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 5-chloro-3,4-dihydro-1H-1,6-naphthyridine-2-one (1.0 g).

[0337] <Step 2> Synthesis of 5-chloro-1-phenyl-3,4-dihydro-1,6-naphthyrizin-2-one A mixture of 5-chloro-3,4-dihydro-1H-1,6-naphthyrizin-2-one (1.0 g), the compound obtained in Step 1, phenylboronic acid (670 mg), copper(II) acetate (200 mg), and triethylamine (1.1 g) in dichloromethane (20 mL) was stirred at room temperature under an oxygen atmosphere for 16 hours. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. Dichloromethane was added to the resulting residue, 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 resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 5-chloro-1-phenyl-3,4-dihydro-1,6-naphthyrizin-2-one (800 mg).

[0338] <Step 3> Synthesis of 5-chloro-1-phenyl-3,4-dihydro-1,6-naphthyridine: The compound obtained in Step 2, 5-chloro-1-phenyl-3,4-dihydro-1,6-naphthyridine-2-one (450 mg), was mixed with a 10 mL solution of tetrahydrofuran in 1 M borane and tetrahydrofuran (10 mL). The solution was stirred at room temperature for 6 hours. The reaction mixture was then stopped by adding methanol at 0°C and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate). 4 M hydrochloric acid (2 mL) and tetrahydrofuran (2 mL) were added to the crude product and stirred at 60°C for 1 hour. The pH was then adjusted to 8 with an aqueous sodium bicarbonate solution, and the precipitate was filtered to obtain 5-chloro-1-phenyl-3,4-dihydro-1,6-naphthyridine (100 mg).

[0339] <Step 4> Synthesis of 3,5-difluoro-2-(((1-phenyl-1,2,3,4-tetrahydro-1,6-naphthyridine-5-yl)oxy)methyl)pyridine-4-ol. The compound obtained in Step 3, 5-chloro-1-phenyl-3,4-dihydro-1,6-naphthyridine (200 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (161 mg), tris(dibenzylideneacetone)dipalladium(0)dichloromethane adduct (85 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (45 mg), and cesium carbonate (399 mg) were mixed in 1,4-dioxane (20 mL) and stirred under a nitrogen atmosphere at 140°C for 2 hours. The reaction mixture was filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. A solution of the obtained crude product (300 mg) in dichloromethane (5 mL) was mixed with trifluoroacetic acid (5 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid)-acetonitrile) and high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-phenyl-1,2,3,4-tetrahydro-1,6-naphthyrizin-5-yl)oxy)methyl)pyridine-4-ol (13 mg).

[0340] [Example 28] Synthesis of 3,5-difluoro-2-(((1-phenyl-1H-pyrrolo[2,3-b]pyridine-4-yl)oxy)methyl)pyridine-4-ol

[0341] <Step 1> Synthesis of 4-chloro-1-phenylpyrrolo[2,3-b]pyridine A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (500 mg), iodobenzene (669 mg), copper(I) iodide (125 mg), tripotassium phosphate (1.4 g), and trans-1,2-diaminocyclohexane (75 mg) in 1,4-dioxane (15 mL) was stirred under a nitrogen atmosphere at 110°C for 16 hours. The reaction mixture was then filtered, and ethyl acetate was added to the filtrate. 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 resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-chloro-1-phenylpyrrolo[2,3-b]pyridine (690 mg).

[0342] <Step 2> Synthesis of 3,5-difluoro-2-(((1-phenyl-1H-pyrrolo[2,3-b]pyridine-4-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step 1 is 4-chloro-1-phenylpyrrolo[2,3-b]pyridine (150 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (184 mg), methanesulfonate (dicyclohexyl(3-(1-methylethoxy)-2' A mixture of 1,4-dioxane (15 mL) containing ,4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (60 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (35 mg), and cesium carbonate (427 mg) was stirred under a nitrogen atmosphere at 100°C for 2 hours. The reaction mixture was then filtered, and ethyl acetate was added to the filtrate. 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 resulting crude product (220 mg) was mixed with dichloromethane (3 mL), 4 M hydrogen chloride aqueous solution, and 1,4-dioxane (3 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 3,5-difluoro-2-(((1-phenyl-1H-pyrrolo[2,3-b]pyridine-4-yl)oxy)methyl)pyridine-4-ol (53 mg).

[0343]

[0344] [Example 29] Synthesis of 2-(((1-cyclohexyl-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0345] <Step 1> Synthesis of 1-(cyclohexa-1-en-1-yl)-4-methoxypyrrolo[3,2-c]pyridine A mixture of 4-methoxy-1H-pyrrolo[3,2-c]pyridine (1.0 g), cyclohexa-1-en-1-ylboronic acid (2.1 g), copper(II) acetate (200 mg), and triethylamine (1.3 g) in dichloromethane (25 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered, and ethyl acetate was added to the filtrate. 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 resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 1-(cyclohexa-1-en-1-yl)-4-methoxypyrrolo[3,2-c]pyridine (1.1 g).

[0346] <Step 2> Synthesis of 4-chloro-1-cyclohexylpyrrolo[3,2-c]pyridine A mixture of 1-(cyclohexa-1-en-1-yl)-4-methoxypyrrolo[3,2-c]pyridine (1.0 g), the compound obtained in Step 1, and palladium carbon (200 mg) in methanol (20 mL) was stirred at room temperature under a hydrogen atmosphere (5 atm) for 16 hours. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. A solution of the obtained crude product (500 mg) in phosphorus oxychloride (25 mL) was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 4-chloro-1-cyclohexylpyrrolo[3,2-c]pyridine (242 mg).

[0347] <Step 3> Synthesis of 2-(((1-cyclohexyl-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol Compound obtained in Step 2 is 4-chloro-1-cyclohexylpyrrolo[3,2-c]pyridine (150 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (126 mg), methanesulfonate (dicyclohexyl(3-(1-methylethoxy)- A mixture of 2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (59 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (34 mg), and cesium carbonate (312 mg) in 1,4-dioxane (15 mL) was stirred under a nitrogen atmosphere at 100°C for 16 hours. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting crude product (300 mg) was mixed with dichloromethane (5 mL), 4 M hydrogen chloride aqueous solution, and 1,4-dioxane (5 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 2-(((1-cyclohexyl-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (21 mg).

[0348]

[0349] [Example 30] Synthesis of 2-(((1-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0350] <Step 1> Synthesis of 4-chloro-1-(cyclohexa-1-en-1-yl)pyrrolo[2,3-b]pyridine A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (1.0 g), cyclohexa-1-en-1-ylboronic acid (2.1 g), copper(II) acetate (600 mg), and triethylamine (1.3 g) in dichloromethane (20 mL) was stirred at room temperature under air for 16 hours. The reaction mixture was filtered, and dichloromethane was added to the filtrate. 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 resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-chloro-1-(cyclohexa-1-en-1-yl)pyrrolo[2,3-b]pyridine (660 mg).

[0351] <Step 2> Synthesis of 1-(cyclohexa-1-en-1-yl)pyrrolo[2,3-b]pyridine-4-ol: A mixture of 4-chloro-1-(cyclohexa-1-en-1-yl)pyrrolo[2,3-b]pyridine (840 mg), potassium hydroxide (405 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (132 mg), and di-t-butyl(2',4',6'-triisopropyl-(1,1'-biphenyl)-2-yl)phosphine (123 mg) with 1,4-dioxane (12 mL) and water (6 mL) was stirred at 100°C for 1 hour under a nitrogen atmosphere. The reaction mixture was then filtered and the resulting 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 1-(cyclohexa-1-en-1-yl)pyrrolo[2,3-b]pyridine-4-ol (650 mg).

[0352] <Step 3> Synthesis of 2-((1-cyclohexylpyrrolo[2,3-b]pyridine-4-yloxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine A methanol (15 mL) solution of 1-(cyclohexa-1-en-1-yl)pyrrolo[2,3-b]pyridine-4-ol (630 mg), the compound obtained in Step 2, and palladium carbon (63 mg) was stirred at room temperature under a hydrogen atmosphere (5 atm) for 2 hours. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The crude product obtained (150 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (195 mg), and triphenylphosphine (273 mg) were dissolved in toluene (5 mL). Diethyl azodicarboxylate (DEAD) (302 mg) was added at 0°C and the mixture was stirred at 60°C for 2 hours. Ethyl acetate was then added to the reaction mixture, 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 resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 2-((1-cyclohexylpyrrolo[2,3-b]pyridine-4-yloxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (110 mg).

[0353] <Step 4> The compound 2-(((1-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol, obtained in Step 3, was mixed with a solution of 2-((1-cyclohexylpyrrolo[2,3-b]pyridine-4-yloxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (110 mg) in dichloromethane (2 mL), a 4 M aqueous solution of hydrogen chloride, and a solution of 1,4-dioxane (2 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 2-(((1-cyclohexyl-1H-pyrrolo[2,3-b]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (37 mg).

[0354]

[0355] [Example 31] Synthesis of 3,5-difluoro-2-(((1-phenyl-1H-indazole-4-yl)oxy)methyl)pyridine-4-ol

[0356] <Step 1> Synthesis of 4-bromo-1-phenylindazole A mixture of 2-bromo-6-fluorobenzaldehyde (2.0 g), phenylhydrazine (1.1 g), and potassium carbonate (2.7 g) in dimethyl sulfoxide (20 mL), which are known substances, was stirred at 140°C for 16 hours. The reaction mixture was then stopped with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 4-bromo-1-phenylindazole (1.5 g).

[0357] <Step 2> Synthesis of 3,5-difluoro-2-(((1-phenyl-1H-indazole-4-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step 1 is 4-bromo-1-phenylindazole (100 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (103 mg), methanesulfonate (dicyclohexyl (3-(1-methylethoxy)-2',4',6'-tri A mixture of (1-methylethyl)-1,1'-biphenyl-2-yl)phosphine (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (34 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (20 mg), and cesium carbonate (239 mg) in 1,4-dioxane (10 mL) was stirred under a nitrogen atmosphere at 100°C for 16 hours. The reaction mixture was then filtered, and ethyl acetate was added to the filtrate. 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 resulting crude product (200 mg) was mixed with dichloromethane (2 mL), 4 M hydrogen chloride, and 1,4-dioxane (2 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) and high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-phenyl-1H-indazole-4-yl)oxy)methyl)pyridine-4-ol (20 mg).

[0358]

[0359] [Example 32] Synthesis of 2-(((1-cyclohexyl-1H-indazole-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0360] <Step 1> Synthesis of 4-bromo-1-cyclohexyl-1H-indazole A mixture of 2-bromo-6-fluorobenzaldehyde (2.0 g), cyclohexylhydrazine (1.1 g), and potassium carbonate (4.1 g) in dimethyl sulfoxide (20 mL), which are known substances, was stirred at 140°C for 16 hours. Then, ethyl acetate was added to the reaction mixture, 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 reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 4-bromo-1-cyclohexyl-1H-indazole (1.4 g).

[0361] <Step 2> Synthesis of 1-cyclohexyl-1H-indazole-4-ol: A mixture of 4-bromo-1-cyclohexyl-1H-indazole (800 mg), potassium hydroxide (402 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (105 mg), and di-t-butyl(2',4',6'-triisopropyl-(1,1'-biphenyl)-2-yl)phosphine (97 mg) in 1,4-dioxane (12 mL) and water (6 mL) was stirred under a nitrogen atmosphere at 60°C for 1 hour. The reaction mixture was then filtered, and ethyl acetate was added to the filtrate. 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 resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 1-cyclohexyl-1H-indazole-4-ol (400 mg).

[0362] <Step 3> Synthesis of 1-cyclohexyl-4-(3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1H-indazole. The compound obtained in Step 2, 1-cyclohexyl-1H-indazole-4-ol (220 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (243 mg), triphenylphosphine (267 mg), and diethyl azodicarboxylate (221 mg) were mixed in toluene (20 mL) and stirred at 60°C for 2 hours under a nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 1-cyclohexyl-4-(3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1H-indazole (220 mg).

[0363] <Step 4> Synthesis of 2-(((1-cyclohexyl-1H-indazole-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol The compound obtained in Step 3, 1-cyclohexyl-4-(3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1H-indazole (200 mg), was mixed with dichloromethane (4 mL), 4 M aqueous hydrogen chloride solution, and 1,4-dioxane (4 mL) solution and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 2-(((1-cyclohexyl-1H-indazole-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (92 mg).

[0364]

[0365] [Example 33] Synthesis of 3,5-difluoro-2-(((1-(4-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol

[0366] <Step 1> Synthesis of 4-chloro-1-(4-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine: 200 mg of the known substance 4-chloro-1H-pyrrolo[3,2-c]pyrimidine, 550 mg of 4-fluorophenylboronic acid, and 714 mg of copper(II) acetate were mixed with pyridine (5 mL) and stirred at 60°C for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 4-chloro-1-(4-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine (160 mg).

[0367] <Step 2> To a solution of 4-chloro-1-(4-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine (100 mg), a compound obtained in step 1 of the synthesis of 4-(3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1-(4-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine, in 1,4-dioxane (6 mL), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (171 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (37 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (45 mg), and cesium carbonate (396 mg) were added, and the mixture was stirred at 100°C for 6 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1-(4-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine (100 mg).

[0368] <Step 3> Synthesis of 3,5-difluoro-2-(((1-(4-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol. To a solution of 4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1-(4-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine (100 mg), the compound obtained in Step 2, in acetonitrile (1 mL), trifluoroacetic acid (0.16 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-(4-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol (10 mg).

[0369]

[0370] [Example 34] Synthesis of 2-(((1-(cyclohexylmethyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0371] <Step 1> Synthesis of 4-chloro-1-(cyclohexylmethyl)-1H-pyrrolo[3,2-c]pyridine A solution of 4-chloro-1H-pyrrolo[3,2-c]pyrimidine (200 mg), a known substance, in N,N-dimethylformamide (15 mL) was mixed with sodium hydride (60%, 105 mg) and (bromomethyl)cyclohexane (0.36 mL) at 0°C, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 4-chloro-1-(cyclohexylmethyl)-1H-pyrrolo[3,2-c]pyridine (296 mg).

[0372] <Step 2> Synthesis of 1-(cyclohexylmethyl)4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine A solution of 4-chloro-1-(cyclohexylmethyl)-1H-pyrrolo[3,2-c]pyridine (296 mg), which is the compound obtained in Step 1, in 1,4-dioxane (10 mL) is dissolved in (3,5-difluoro-4-((4- Methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (503 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (109 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (132 mg), and cesium carbonate (1164 mg) were added, and the mixture was stirred at 100°C for 6 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 1-(cyclohexylmethyl)4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine (280 mg).

[0373] <Step 3> Synthesis of 2-(((1-(cyclohexylmethyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol. 1-(cyclohexylmethyl)4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine (280 mg), the compound obtained in Step 2, was dissolved in acetonitrile (1 mL), to which trifluoroacetic acid (0.16 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain 2-(((1-(cyclohexylmethyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (17 mg).

[0374]

[0375] [Example 35] Synthesis of 3,5-difluoro-2-(((1-phenyl-1H-pyrrolo[2,3-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol

[0376] <Step 1> Synthesis of 4-bromo-1-phenylpyrrolo[2,3-c]pyridine A mixture of 4-bromo-1H-pyrrolo[2,3-c]pyridine (1.0 g), phenylboronic acid (1.2 g), copper(II) acetate (920 mg), sodium carbonate (1.1 g), and 2-(pyridine-2-yl)pyridine (790 mg) in N,N-dimethylformamide (25 mL) was stirred at 70°C for 2 hours. The reaction mixture was then filtered, and the resulting 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 4-bromo-1-phenylpyrrolo[2,3-c]pyridine (970 mg).

[0377] <Step 2> Synthesis of 1-phenylpyrrolo[2,3-c]pyridine-4-ol A mixture of 4-bromo-1-phenylpyrrolo[2,3-c]pyridine (920 mg), the compound obtained in Step 1, potassium hydroxide (567 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (309 mg), and di-t-butyl(2',4',6'-triisopropyl-(1,1'-biphenyl)-2-yl)phosphine (286 mg) with 1,4-dioxane (14 mL) and water (7 mL) was stirred at 100°C for 2 hours. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by reverse-phase chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 1-phenylpyrrolo[2,3-c]pyridine-4-ol (150 mg).

[0378] <Step 3> Synthesis of 3,5-difluoro-2-(((1-phenyl-1H-pyrrolo[2,3-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol A mixture of 1-phenylpyrrolo[2,3-c]pyridine-4-ol (100 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methyl4-methylbenzenesulfonate (207 mg), and potassium carbonate (132 mg) in N,N-dimethylformamide (10 mL) was stirred at 70°C for 16 hours. Ethyl acetate was added to the reaction mixture, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting crude product was mixed with trifluoroacetic acid (2 mL) and dichloromethane (4 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% ammonium bicarbonate)-acetonitrile) and high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-phenyl-1H-pyrrolo[2,3-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol (11 mg).

[0379]

[0380] [Example 36] Synthesis of 3,5-difluoro-2-(((1-(4-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol

[0381] <Step 1> Synthesis of 4-chloro-1-(4-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine: A mixture of 4-chloro-1H-pyrrolo[3,2-c]pyrimidine (200 mg), 4-methoxyphenylboronic acid (299 mg), and copper(II) acetate (357 mg) in N,N-dimethylformamide (4 mL) was mixed with triethylamine (0.27 mL) and pyridine (0.16 mL), and the mixture was stirred at 60°C for 24 hours. The reaction mixture was filtered through Celite and the solid was washed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 4-chloro-1-(4-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine (135 mg).

[0382] <Step 2> Synthesis of 3,5-difluoro-2-(((1-(4-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol. To a solution of 4-chloro-1-(4-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine (135 mg), a compound obtained in Step 1, in 1,4-dioxane (5 mL), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (220 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (48 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (58 mg), and cesium carbonate (1.6 g) were added, and the mixture was stirred at 100°C for 6 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting crude product was dissolved in acetonitrile (2 mL). Trifluoroacetic acid (0.4 mL) was added to the solution, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-(4-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol (29 mg).

[0383]

[0384] [Example 37] Synthesis of 3,5-difluoro-2-(((1-(3-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol

[0385] <Step 1> Synthesis of 4-chloro-1-(3-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine: A mixture of 4-chloro-1H-pyrrolo[3,2-c]pyrimidine (200 mg), 3-methoxyphenylboronic acid (299 mg), and copper(II) acetate (357 mg) in N,N-dimethylformamide (4 mL) was mixed with triethylamine (0.27 mL) and pyridine (0.16 mL), and the mixture was stirred at 60°C for 24 hours. The reaction mixture was filtered through Celite and the solid was washed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 4-chloro-1-(3-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine (200 mg).

[0386] <Step 2> Synthesis of 3,5-difluoro-2-(((1-(3-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol. To a solution of 4-chloro-1-(3-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine (200 mg), a compound obtained in Step 1, in 1,4-dioxane (5 mL), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (326 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (71 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (86 mg), and cesium carbonate (756 mg) were added, and the mixture was stirred at 100°C for 6 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting crude product was dissolved in acetonitrile (2 mL). Trifluoroacetic acid (0.6 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-(3-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol (40 mg).

[0387] [Example 38] Synthesis of 3,5-difluoro-2-(((1-(6-(trifluoromethyl)pyridine-3-yl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol

[0388] <Step 1> Synthesis of 4-chloro-1-(6-(trifluoromethyl)pyridine-3-yl)-1H-pyrrolo[3,2-c]pyridine: A mixture of 4-chloro-1H-pyrolo[3,2-c]pyrimidine (200 mg), (6-(trifluoromethyl)pyridine-3-yl)boronic acid (500 mg), and copper(II) acetate (476 mg) in N,N-dimethylformamide (4 mL) was mixed with triethylamine (0.27 mL) and pyridine (0.16 mL) and stirred at 60°C for 72 hours. The reaction mixture was filtered through Celite and the solid was washed with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 4-chloro-1-(6-(trifluoromethyl)pyridine-3-yl)-1H-pyrrolo[3,2-c]pyridine (30 mg).

[0389] <Step 2> Synthesis of 3,5-difluoro-2-(((1-(6-(trifluoromethyl)pyridine-3-yl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol. 30 mg of 4-chloro-1-(6-(trifluoromethyl)pyridine-3-yl)-1H-pyrrolo[3,2-c]pyridine (30 mg) is dissolved in 1 mL of 1,4-dioxane. Oro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (43 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (9 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (11 mg), and cesium carbonate (100 mg) were added, and the mixture was stirred at 100°C for 6 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting crude product was dissolved in acetonitrile (2 mL). Trifluoroacetic acid (0.6 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-(6-(trifluoromethyl)pyridine-3-yl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol (3 mg).

[0390]

[0391] [Example 39] Synthesis of 3,5-difluoro-2-((pyrazolo[1,5-c]pyrimidine-7-yloxy)methyl)pyridine-4-ol

[0392] <Step 1> Synthesis of 7-(methylthio)pyrazolo[1,5-c]pyrimidine A mixture of 4H-pyran-4-one (3.0 g), S-methylisothiosemicarbozidohydroiodide (11 g), and trifluoroacetic acid (5.3 g) in isopropanol (60 mL) was stirred at 80°C under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 7-(methylthio)pyrazolo[1,5-c]pyrimidine (210 mg).

[0393] <Step 2> Synthesis of 3,5-difluoro-2-((pyrazolo[1,5-c]pyrimidine-7-yloxy)methyl)pyridine-4-ol A solution of 7-(methylthio)pyrazolo[1,5-c]pyrimidine (180 mg), the compound obtained in Step 1, and metachloroperbenzoic acid (mCPBA) (564 mg) in dichloromethane (10 mL) was stirred at room temperature for 2 hours. The reaction was stopped with an aqueous sodium carbonate solution and extracted three times with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain the crude product 7-methanesulfonylpyrazolo[1,5-c]pyrimidine (143 mg). Next, sodium hydride (60%, 41 mg) was slowly added at 0°C to a solution of (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (143 mg) in tetrahydrofuran (4 mL), and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture, a solution of the crude product obtained in the above step (100 mg) in tetrahydrofuran (1 mL) was added dropwise at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was then stopped with cold water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting crude product (450 mg), trifluoroacetic acid (5 mL), and dichloromethane (20 mL) solution were stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain 3,5-difluoro-2-((pyrazolo[1,5-c]pyrimidine-7-yloxy)methyl)pyridine-4-ol (15 mg).

[0394]

[0395] [Example 40] Synthesis of 2-(((1-cyclohexyl-1H-pyrrolo[2,3-c]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0396] <Step 1> Synthesis of 4-bromo-1-(cyclohexa-1-en-1-yl)pyrrolo[2,3-c]pyridine A mixture of 4-bromo-1H-pyrrolo[2,3-c]pyridine (2.0 g), cyclohexa-1-en-1-ylboronic acid (2.6 g), copper(II) acetate (1.8 g), sodium carbonate (2.2 g), and 2-(pyridine-2-yl)pyridine (1.6 g) in N,N-dimethylformamide (60 mL) was stirred at 70°C for 16 hours. The reaction mixture was filtered and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. Ethyl acetate was added to the resulting residue, 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 resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 4-bromo-1-(cyclohexa-1-en-1-yl)pyrrolo[2,3-c]pyridine (770 mg).

[0397] <Step 2> Synthesis of 1-(cyclohexa-1-en-1-yl)pyrrolo[2,3-c]pyridine-4-ol: A mixture of 4-bromo-1-(cyclohexa-1-en-1-yl)pyrrolo[2,3-c]pyridine (770 mg), potassium hydroxide (468 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (127 mg), and di-t-butyl(2',4',6'-triisopropyl-(1,1'-biphenyl)-2-yl)phosphine (118 mg) with 1,4-dioxane (8 mL) and water (4 mL) was stirred at 100°C for 2 hours. The reaction mixture was then filtered and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain 1-(cyclohexa-1-en-1-yl)pyrrolo[2,3-c]pyridine-4-ol (570 mg).

[0398] <Step 3> Synthesis of 2-((1-cyclohexylpyrrolo[2,3-c]pyridine-4-yloxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine A mixture of 1-(cyclohexa-1-en-1-yl)pyrrolo[2,3-c]pyridine-4-ol (520 mg), the compound obtained in Step 2, and palladium carbon (129 mg) in methanol (15 mL) was stirred at 50°C under a hydrogen atmosphere (5 atm) for 16 hours. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting crude product (260 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methyl 4-methylbenzenesulfonate (524 mg), and potassium carbonate (332 mg) in N,N-dimethylformamide (20 mL) was stirred at 70°C for 2 hours. Ethyl acetate was added to the reaction mixture, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 2-((1-cyclohexylpyrrolo[2,3-c]pyridine-4-yloxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (160 mg).

[0399] <Step 4> The compound 2-(((1-cyclohexyl-1H-pyrrolo[2,3-c]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol, obtained in Step 3, was mixed with a solution of 2-((1-cyclohexylpyrrolo[2,3-c]pyridine-4-yloxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (140 mg) in dichloromethane (5 mL), a 4 M aqueous solution of hydrogen chloride, and a solution of 1,4-dioxane (4 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 2-(((1-cyclohexyl-1H-pyrrolo[2,3-c]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (25 mg).

[0400]

[0401] [Example 41] Synthesis of N-(3-(4-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide

[0402] <Step 1> Synthesis of N-(3-(4-chloro-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide: To a solution of 4-chloro-1H-pyrrolo[3,2-c]pyrimidine (200 mg), a known substance, in N,N-dimethylformamide (10 mL), 3-acetamidophenylboronic acid (469 mg), copper(II) acetate (238 mg), and pyridine (0.21 mL) were added and the mixture was stirred at 60°C for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 N-(3-(4-chloro-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide (309 mg).

[0403] <Step 2> Synthesis of N-(3-(4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide A solution of N-(3-(4-chloro-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide (309 mg), a compound obtained in Step 1, in 1,4-dioxane (10 mL) Luoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (456 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (43 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (52 mg), and cesium carbonate (454 mg) were added, and the mixture was stirred at 100°C for 6 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 N-(3-(4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide (40 mg).

[0404] <Step 3> Synthesis of N-(3-(4-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide The compound obtained in Step 2, N-(3-(4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide (40 mg) was dissolved in acetonitrile (1 mL), and trifluoroacetic acid (0.058 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain N-(3-(4-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide (9 mg).

[0405]

[0406] [Example 42] Synthesis of N-(4-(4-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide

[0407] <Step 1> Synthesis of N-(4-(4-chloro-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide: To a solution of 4-chloro-1H-pyrrolo[3,2-c]pyrimidine (200 mg), a known substance, in N,N-dimethylformamide (10 mL), 4-acetamidophenylboronic acid (469 mg), copper(II) acetate (238 mg), and pyridine (0.21 mL) were added and the mixture was stirred at 60°C for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 N-(4-(4-chloro-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide (198 mg).

[0408] <Step 2> Synthesis of N-(4-(4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide A solution of N-(4-(4-chloro-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide (198 mg), a compound obtained in Step 1, in 1,4-dioxane (10 mL) Luoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (293 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (43 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (52 mg), and cesium carbonate (454 mg) were added, and the mixture was stirred at 100°C for 6 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 N-(4-(4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide (40 mg).

[0409] <Step 3> Synthesis of N-(4-(4-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide The compound obtained in Step 2, N-(4-(4-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide (40 mg) was dissolved in acetonitrile (1 mL), and trifluoroacetic acid (0.058 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain N-(4-(4-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-1H-pyrrolo[3,2-c]pyridine-1-yl)phenyl)acetamide (5 mg).

[0410]

[0411] [Example 43] Synthesis of 3,5-difluoro-2-(((1-(5-fluoropyridine-2-yl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol

[0412] <Step 1> Synthesis of 4-chloro-1-(5-(fluoropyridine-2-yl)-1H-pyrrolo[3,2-c]pyridine: To a solution of 4-chloro-1H-pyrrolo[3,2-c]pyrimidine (200 mg), a known compound, in toluene (10 mL), 2-bromo-5-fluoropyridine (346 mg), copper(II) acetate (25 mg), tripotassium phosphate (556 mg), and N,N'-dimethylethylenediamine (0.028 mL) were added and the mixture was stirred at 60°C for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 4-chloro-1-(5-(fluoropyridine-2-yl)-1H-pyrrolo[3,2-c]pyridine (52 mg).

[0413] <Step 2> Synthesis of 4-(3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-1-(5-(fluoropyridine-2-yl)-1H-pyrrolo[3,2-c]pyridine A solution of 4-chloro-1-(5-(fluoropyridine-2-yl)-1H-pyrrolo[3,2-c]pyridine (40 mg), a compound obtained in Step 1, in 1,4-dioxane (1 mL) contains (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl) methanol (intermediate A) (68 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (42 mg), (R)-1-[(S)-2-(dicyclohexyl chloroform) 52 mg of sphino)ferrocenyl]ethyl di-t-butylphosphine and 454 mg of cesium carbonate were added, and the mixture was stirred at 100°C for 6 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 4-(3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy-1-(5-(fluoropyridine-2-yl)-1H-pyrrolo[3,2-c]pyridine (60 mg).

[0414] <Step 3> To a solution of 4-(3,5-difluoro-2-(((1-(5-fluoropyridine-2-yl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol (60 mg), a compound obtained in step 2 of the synthesis of 3,5-difluoro-2-(((1-(5-fluoropyridine-2-yl)-1H-pyrrolo[3,2-c]pyridine)oxy)methyl)pyridine-4-ol, in acetonitrile (1 mL), trifluoroacetic acid (0.094 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-(5-fluoropyridine-2-yl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol (12 mg).

[0415] [Example 44] Synthesis of 3,5-difluoro-2-(((1-(5-(trifluoromethyl)pyridine-2-yl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol

[0416] <Step 1> Synthesize 4-chloro-1-(5-(trifluoromethyl)pyridine-2-yl)-1H-pyrrolo[3,2-c]pyrimidine. To a solution of 4-chloro-1H-pyrrolo[3,2-c]pyrimidine (200 mg), a known synthetic substance, in toluene (10 mL), add 2-bromo-(5-(trifluoromethyl)pyridine (444 mg), copper(II) acetate (25 mg), tripotassium phosphate (556 mg), and N,N'-dimethylethylenediamine (0.03 mL), and heat at 60°C. The mixture was stirred for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The 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 4-chloro-1-(5-(trifluoromethyl)pyridine-2-yl)-1H-pyrrolo[3,2-c]pyridine (230 mg).

[0417] <Step 2> Synthesis of 3,5-difluoro-2-(((1-(5-(trifluoromethyl)pyridine-2-yl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol. 4-chloro-1-(5-(trifluoromethyl)pyridine-2-yl)-1H-pyrrolo[3,2-c]pyridine (230 mg), a compound obtained in Step 1, is dissolved in a 1,4-dioxane (5 mL) solution containing (3,5-difluoro Oro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (326 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (71 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (86 mg), and cesium carbonate (755 mg) were added, and the mixture was stirred at 100°C for 6 hours. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting crude product was dissolved in acetonitrile (1 mL). Trifluoroacetic acid (0.6 mL) was added to the solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-(5-(trifluoromethyl)pyridine-2-yl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol (33 mg).

[0418]

[0419] [Example 45] Synthesis of 3,5-difluoro-2-(((1-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol

[0420] 3,5-difluoro-2-(((1-(4-fluorophenyl)-1H-pyrazolo[4,3-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol (26 mg) was obtained by the same procedure as in Example 15.

[0421] [Example 46] Synthesis of 2-(((1-(cyclohexylmethyl)-1H-pyrazolo[4,3-c]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0422] <Step 1> Synthesis of 4-chloro-1-(cyclohexylmethyl)pyrazolo[4,3-c]pyridine A mixture of 4-chloro-1H-pyrazolo[4,3-c]pyridine (1 g), (bromomethyl)cyclohexane (1.73 g), and cesium carbonate (4.2 g) in acetonitrile (20 mL) was stirred at 70°C for 3 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 4-chloro-1-(cyclohexylmethyl)pyrazolo[4,3-c]pyridine (900 mg). Steps 2 and 3 were carried out in the same manner as in Example 15 to obtain 2-(((1-(cyclohexylmethyl)-1H-pyrazolo[4,3-c]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (40 mg).

[0423]

[0424] [Example 47] Synthesis of 3,5-difluoro-2-(((1-phenyl-1H-pyrazolo[4,3-c]pyridine-4-yl)oxy)methyl)-6-(trifluoromethyl)pyridine-4-ol

[0425] 3,5-difluoro-2-(((1-phenyl-1H-pyrazolo[4,3-c]pyridine-4-yl)oxy)methyl)-6-(trifluoromethyl)pyridine-4-ol (13 mg) was obtained by the same procedure as in Example 15.

[0426] [Example 48] Synthesis of 3,5-difluoro-2-(((1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol

[0427] <Step 1> Synthesis of 4-chloro-1H-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolo[3,2-c]pyridine A mixture of 4-chloro-1H-pyrrolo[3,2-c]pyridine (320 mg), 4-(bromomethyl)oxane (563 mg), and cesium carbonate (1.4 g) in acetonitrile (10 mL) was stirred at 80°C for 2 hours. The reaction mixture was filtered, and the resulting 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 4-chloro-1H-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolo[3,2-c]pyridine (500 mg). Steps 2 and 3 were carried out in the same manner as in Example 8 to obtain 3,5-difluoro-2-(((1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)pyridine-4-ol (24 mg).

[0428]

[0429] [Example 49] Synthesis of 2-(((1-((4,4-difluorocyclohexyl)methyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0430] <Step 1> Synthesis of 4-chloro-1-((4,4-difluorocyclohexyl)methyl)pyrrolo[3,2-c]pyridine A mixture of 4-chloro-1H-pyrrolo[3,2-c]pyridine (300 mg), 4-(bromomethyl)-1,1-difluorocyclohexane (922 mg), and cesium carbonate (1.3 g) in acetonitrile (20 mL) was stirred at 80°C for 1 hour. The reaction mixture was filtered, and the resulting 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 4-chloro-1-((4,4-difluorocyclohexyl)methyl)pyrrolo[3,2-c]pyridine (540 mg). Steps 2 and 3 were carried out in the same manner as in Example 8 to obtain 2-(((1-((4,4-difluorocyclohexyl)methyl)-1H-pyrrolo[3,2-c]pyridine-4-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (17 mg).

[0431]

[0432] [Example 50] Synthesis of 3,5-difluoro-2-(((1-methyl-8-phenyl-1,2,3,4-tetrahydro-1,6-naphthyridine-5-yl)oxy)methyl)pyridine-4-ol

[0433] <Step 1> Synthesis of 5-chloro-8-iodo-1,6-naphthyridine 1,6-naphthyridine-5-ol (3.0 g) and iodine (5.2 g) in a 0.4 M sodium hydroxide aqueous solution (60 mL) were stirred at 80°C for 3 hours. Water was added to the reaction mixture, the precipitate was filtered, washed with methanol, and the resulting crude product (900 mg) was mixed with phosphorus oxychloride (10 mL) and stirred at 100°C for 1.5 hours. The reaction mixture was then concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 5-chloro-8-iodo-1,6-naphthyridine (900 mg).

[0434] <Step 2> Synthesis of 5-methoxy-8-phenyl-1,6-naphthyridine The compound obtained in Step 1, 5-chloro-8-iodo-1,6-naphthyridine (900 mg), and sodium methoxide (335 mg) were mixed in methanol (15 mL) and stirred at 80°C for 1 hour. The reaction mixture was filtered, and water was added to the filtrate, which was then extracted three times with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting crude product (440 mg), phenylboronic acid (188 mg), 1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (113 mg), and cesium carbonate (1.5 g) were mixed in 1,4-dioxane (16 mL) and ethanol (1.6 mL) and stirred at 80°C for 2 hours under a nitrogen atmosphere. Subsequently, ethyl acetate was added to the reaction mixture, 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, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 5-methoxy-8-phenyl-1,6-naphthiridine (340 mg).

[0435] <Step 3> Synthesis of 5-methoxy-1-methyl-8-phenyl-3,4-dihydro-2H-1,6-naphthyridine The compound obtained in Step 2, 5-methoxy-8-phenyl-1,6-naphthyridine (320 mg), and platinum(IV) oxide (25 mg) were mixed in methanol (8 mL) and stirred at room temperature under a hydrogen atmosphere (5 atm) for 1 hour. The reaction mixture was filtered and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. Sodium hydride (60%, 52 mg) was slowly added to the resulting crude product (260 mg) in an N,N-dimethylformamide (8 mL) solution at 0°C and stirred for 20 minutes. Then, iodomethane (307 mg) was added dropwise to the reaction mixture and stirred at room temperature for 16 hours. The reaction mixture was stopped with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 5-methoxy-1-methyl-8-phenyl-3,4-dihydro-2H-1,6-naphthyridine (200 mg).

[0436] <Step 4> Synthesis of 1-methyl-8-phenyl-3,4-dihydro-2H-1,6-naphthiridine-5-ol: 130 mg of 5-methoxy-1-methyl-8-phenyl-3,4-dihydro-2H-1,6-naphthiridine (130 mg), the compound obtained in Step 3, was dissolved in 6 mL of dichloromethane. 5 mL of 1 M boron bromide dichloromethane solution was added dropwise at 0°C and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to obtain 1-methyl-8-phenyl-3,4-dihydro-2H-1,6-naphthiridine-5-ol (100 mg).

[0437] <Step 5> Synthesis of 5-((4-(benzyloxy)-3,5-difluoropyridine-2-yl)methoxy-1-methyl-8-phenyl-3,4-dihydro-2H-1,6-naphthyridine. Add trifluoromethanesulfonic acid anhydride (141 mg) to a pyridine (6 mL) solution of 1-methyl-8-phenyl-3,4-dihydro-2H-1,6-naphthyridine-5-ol (100 mg), the compound obtained in Step 4, at 0°C, and leave at room temperature. The mixture was stirred for 2 hours. Water was added to the reaction mixture at 0°C and stirred for 1 hour. The precipitate was filtered off and the resulting crude product (70 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (57 mg), methanesulfonate (dicyclohexyl(3-(1-methylethoxy)-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine) A mixture of (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (17 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (10 mg), and cesium carbonate (123 mg) in 1,4-dioxane (6 mL) was stirred at 100°C for 2 hours under a nitrogen atmosphere. Ethyl acetate was then added to the reaction mixture, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. 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 5-((4-(benzyloxy)-3,5-difluoropyridine-2-yl)methoxy-1-methyl-8-phenyl-3,4-dihydro-2H-1,6-naphthiridine (80 mg).

[0438] <Step 6> Synthesis of 3,5-difluoro-2-(((1-methyl-8-phenyl-1,2,3,4-tetrahydro-1,6-naphthyridine-5-yl)oxy)methyl)pyridine-4-ol. A solution of 5-((4-(benzyloxy)-3,5-difluoropyridine-2-yl)methoxy-1-methyl-8-phenyl-3,4-dihydro-2H-1,6-naphthyridine (70 mg), the compound obtained in Step 5, in trifluoroacetic acid (4 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by high-performance liquid chromatography (water (containing 0.05% ammonium bicarbonate)-acetonitrile) to obtain 3,5-difluoro-2-(((1-methyl-8-phenyl-1,2,3,4-tetrahydro-1,6-naphthyridine-5-yl)oxy)methyl)pyridine-4-ol (22 mg).

[0439]

[0440] [Example 51] Synthesis of 3,5-difluoro-2-(((1-(4-fluorophenyl)-1,2,3,4-tetrahydro-1,6-naphthyridine-5-yl)oxy)methyl)pyridine-4-ol

[0441] <Step 1> Synthesis of 5-chloro-3,4-dihydro-1H-1,6-naphthyridine-2-one: A solution of 4-amino-2-chloro-3-iodopyridine (5.0 g), tributyltin hydride (8.6 g), and 2,2'-azodiisobutyronitrile (1.6 g), known synthetic compounds, in dimethyl sulfoxide (50 mL) was added to a nitrogen atmosphere at 0°C, and the mixture was stirred at 120°C for 16 hours. The reaction mixture was stopped with water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 5-chloro-3,4-dihydro-1H-1,6-naphthyridine-2-one (1.8 g).

[0442] <Step 2> Synthesis of 5-chloro-1-(4-fluorophenyl)-3,4-dihydro-2H-1,6-naphthyridine-2-one The compound obtained in Step 1, 5-chloro-3,4-dihydro-1H-1,6-naphthyridine-2-one (2.3 g), 4-fluorophenylboronic acid (3.5 g), copper(II) acetate (4.6 g), and triethylamine (3.8 g), mixed in dichloromethane (30 mL) was stirred at room temperature under an oxygen atmosphere for 16 hours. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. Water was added to the resulting residue, and it was extracted three times with dichloromethane. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 5-chloro-1-(4-fluorophenyl)-3,4-dihydro-2H-1,6-naphthyridine-2-one (1.0 g).

[0443] <Step 3> Synthesis of 5-chloro-1-(4-fluorophenyl)-3,4-dihydro-2H-1,6-naphthyridine The compound obtained in Step 2, 5-chloro-1-(4-fluorophenyl)-3,4-dihydro-2H-1,6-naphthyridine-2-one (400 mg), was mixed with a tetrahydrofuran solution (8 mL) of 1 M borane and tetrahydrofuran (8 mL). The solution was stirred at 60°C for 3 hours. Then, methanol was added to the reaction mixture at 0°C to stop the reaction, 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 5-chloro-1-(4-fluorophenyl)-3,4-dihydro-2H-1,6-naphthyridine (110 mg).

[0444] <Step 4> Synthesis of 3,5-difluoro-2-(((1-(4-fluorophenyl)-1,2,3,4-tetrahydro-1,6-naphthyridine-5-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step 3 is 5-chloro-1-(4-fluorophenyl)-3,4-dihydro-2H-1,6-naphthyridine (100 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (96 mg), methanesulfonate (dicyclohexyl A mixture of (3-(1-methylethoxy)-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (35 mg), (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (20 mg), and cesium carbonate (248 mg) in 1,4-dioxane (5 mL) was stirred at 100°C for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. After adding water to the resulting residue, it was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. To a solution of the obtained crude product (300 mg) in dichloromethane (4 mL), trifluoroacetic acid (8 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid)-acetonitrile) and high-performance liquid chromatography to obtain 3,5-difluoro-2-(((1-(4-fluorophenyl)-1,2,3,4-tetrahydro-1,6-naphthyridine-5-yl)oxy)methyl)pyridine-4-ol (28 mg).

[0445]

[0446] [Example 52] Synthesis of 3,5-difluoro-2-(((3-phenylpyrazolo[1,5-c]pyrimidine-7-yl)oxy)methyl)pyridine-4-ol

[0447] <Step 1> Synthesis of 7-(methylthio)-3-phenylpyrazolo[1,5-c]pyrimidine A solution of 7-(methylthio)pyrazolo[1,5-c]pyrimidine (240 mg) and N-bromosuccinimide (NBS) (310 mg), obtained by the same procedure as in Step 1 of Example 39, in dichloromethane (10 mL) was stirred at room temperature for 1 hour. The reaction was stopped with an aqueous sodium nitrite solution and extracted three times with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and the resulting crude product (140 mg), phenylboronic acid (175 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (47 mg), and sodium carbonate (122 mg) were mixed with 1,4-dioxane (10 mL) and water (2.5 mL). This mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. Ethyl acetate was then added to the reaction mixture, 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, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 7-(methylthio)-3-phenylpyrazolo[1,5-c]pyrimidine (60 mg).

[0448] <Step 2> Synthesis of 3,5-difluoro-2-(((3-phenylpyrazolo[1,5-c]pyrimidine-7-yl)oxy)methyl)pyridine-4-ol A solution of 7-(methylthio)-3-phenylpyrazolo[1,5-c]pyrimidine (110 mg), a compound obtained in Step 1, and metachloroperbenzoic acid (mCPBA) (236 mg) in dichloromethane (6 mL) was stirred at room temperature for 2 hours. The reaction was stopped with an aqueous sodium carbonate solution and extracted three times with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator to obtain the crude product 7-methanesulfonyl-3-phenylpyrazolo[1,5-c]pyrimidine (100 mg). Next, sodium hydride (60%, 23 mg) was slowly added at 0°C to a solution of (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (74 mg) in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture, a solution of the crude product obtained in the above step (80 mg) in tetrahydrofuran (2 mL) was added dropwise at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was then stopped with cold water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure using a rotary evaporator, and a solution of the obtained crude product (170 mg) in trifluoroacetic acid (4 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase chromatography (water (containing 0.05% formic acid) - acetonitrile) and high-performance liquid chromatography to obtain 3,5-difluoro-2-(((3-phenylpyrazolo[1,5-c]pyrimidine-7-yl)oxy)methyl)pyridine-4-ol (3 mg).

[0449]

[0450] [Example 53] Synthesis of 1-(5-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-8-phenyl-3,4-dihydro-1,6-naphthyridine-1(2H)-yl)ethane-1-one

[0451] <Step 1> Synthesis of 1-(5-methoxy-8-phenyl-3,4-dihydro-1,6-naphthirizine-1(2H)-yl)ethanone. The crude product obtained in Step 3 of Example 50, 5-methoxy-8-phenyl-1,2,3,4-tetrahydro-2H-1,6-naphthirizine (500 mg), was dissolved in acetic anhydride (15 mL) and stirred at 100°C for 16 hours. Ethyl acetate was added to the reaction mixture, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the drying agent was filtered off. The ...

Claims

1. The following general formula (I): [In the above general formula (I), R １ and R ２ are each independently hydrogen; halogen; or cyano, and at least one of R １ and R ２ is halogen or cyano, R ３ is hydrogen; halogen; cyano; C １～６ alkyl optionally substituted with halogen; or C ３～８ cycloalkyl optionally substituted with halogen, W is the following formula (A-1) to (A-12): (In the above formula (A-1) to (A-12), A is C １～６ alkylene optionally substituted with halogen, R ４ is hydrogen; cyano; C １～６ alkyl optionally substituted with halogen; or C ３～８ cycloalkyl optionally substituted with halogen), and is selected from the group consisting of, Z is a bicyclic heterocyclic ring] a compound represented by or a pharmaceutically acceptable salt thereof.

2. The following general formulas (1) to (8): [In the above general formulas (1) to (8), R １ ~R ３ And W is the same as in general formula (I), and X １ ~X ３ Each of them operates independently, CR ５ or N and Y １ ~Y ６ Each of them is independent of C(R) ５ ) ２ , C=O, NR ５ , or O, or CR when the dashed line indicates a connection ５ or N, R ５ These are, independently, hydrogen; halogen; NR ６ R ７ OR ６ ; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６ Alkyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６ Alkylcarbonyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkenyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ２～６ Heterocycloalkyl; or hydroxy, halogen, cyano, nitro, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ C may be substituted with aryl, hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ It is a heteroaryl, R ６ and R ７ These are C, which may be substituted with hydrogen or halogen, independently of each other. １～６ Alkylcarbonyl; C may be substituted with halogen. ３～８ Cycloalkylcarbonyl; C which may be substituted with halogen ２～６ Heterocycloalkylcarbonyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ Cycloalkyl, C optionally substituted with halogen ２～６ Heterocycloalkyl, C optionally substituted with halogen ６～１２ Aryl, C optionally substituted with halogen １～９ C optionally substituted with at least one substituent selected from the group consisting of heteroaryl １～６ Alkyl; or hydroxy, halogen, cyano, nitro, C optionally substituted with halogen １～６ Alkyl, C optionally substituted with halogen １～５ Alkoxy, halogen and / or C optionally substituted with alkylaminocarbonyl １～６ C optionally substituted with alkylaminocarbonyl ３～８ Cycloalkyl, C optionally substituted with halogen ２～６ Heterocycloalkyl, C optionally substituted with halogen ６～１２ Aryl, C optionally substituted with halogen １～９ C optionally substituted with at least one substituent selected from the group consisting of heteroaryl ３～８ Cycloalkyl; or hydroxy, halogen, cyano, nitro, C １～６ Alkylcarbonylamino, C optionally substituted with halogen １～６ Alkyl, C optionally substituted with halogen １～５ Alkoxy, halogen and / or C optionally substituted with alkylaminocarbonyl １～６ C optionally substituted with alkylaminocarbonyl ３～８ Cycloalkyl, C optionally substituted with halogen ２～６ Heterocycloalkyl, C optionally substituted with halogen ６～１２ Aryl, C optionally substituted with halogen １～９ C optionally substituted with at least one substituent selected from the group consisting of heteroaryl ６～１２ Aryl; or hydroxy, halogen, cyano, nitro, C optionally substituted with halogen １～６ Alkyl, C optionally substituted with halogen １～５ Alkoxy, halogen and / or C optionally substituted with alkylaminocarbonyl １～６ C optionally substituted with alkylaminocarbonyl ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ The compound according to claim 1, represented as [heteroaryl], or a pharmaceutically acceptable salt thereof.

3. The following general formulas (1-1) to (1-6), general formulas (2-1) to (2-6), general formula (3-1), general formula (4-1), and general formula (5-1): [In the above general formulas (1-1) to (1-6), general formulas (2-1) to (2-6), general formula (3-1), general formula (4-1), and general formula (5-1), R １ ~R ５ , W, X １ and X ３ The compound according to claim 2 or a pharmaceutically acceptable salt thereof, which is represented by any one of the following formulas: (1) to (8) (the same as the general formulas).

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is formula (A-2) or formula (A-3).

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is formula (A-5) or formula (A-6).

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein W is formula (A-7) or formula (A-10).

7. R １ and R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is the same halogen.

8. R １ and R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is fluorine.

9. R １ and R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein one of the elements is a halogen and the other is hydrogen.

10. R ３ However, hydrogen or CF ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. X １ CR ５ The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

12. X １ A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is N.

13. X ２ CR ５ The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

14. X ２ A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is N.

15. X ３ CR ５ The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

16. X ３ A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is N.

17. Y １ is C(R ５ ) ２ Either or when the dashed line indicates a connection, it is CR. ５ The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

18. Y １ NR ５ The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein it is N when the dashed line indicates a bond.

19. Y ２ is C(R ５ ) ２ Either or when the dashed line indicates a connection, it is CR. ５ The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

20. Y ２ NR ５ The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein it is N when the dashed line indicates a bond.

21. Y ３ is C(R ５ ) ２ Either or when the dashed line indicates a connection, it is CR. ５ The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

22. Y ３ NR ５ The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein it is N when the dashed line indicates a bond.

23. Y ６ A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound is O.

24. R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６ Alkyl; or C which may be substituted with halogen, cyano, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～６ Alkylcarbonyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkenyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ２～６ Heterocycloalkyl; or halogen, cyano, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ C may be substituted with aryl, or halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ A compound according to claim 3, which is a heteroaryl compound, or a pharmaceutically acceptable salt thereof.

25. R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ３～８ Cycloalkyl; or halogen, cyano, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. ６～１２ C may be substituted with aryl, or halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ C may be substituted with cycloalkyl or halogen. ２～６ C may be substituted with heterocycloalkyl or halogen compounds. ６～１２ C may be substituted with aryl or halogen. １～９ C may be substituted with at least one substituent selected from the group consisting of heteroaryls. １～９ A compound according to claim 3, which is a heteroaryl compound, or a pharmaceutically acceptable salt thereof.

26. R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ Cyclohexyl which may be substituted with at least one substituent selected from the group consisting of cycloalkyls; or halogen, cyano, C １～６ C may be substituted with alkylcarbonylamino or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ Phenyl which may be substituted with at least one substituent selected from the group consisting of cycloalkyls; or C which may be substituted with halogen, cyano, or halogen. １～５ Alkoxy, halogen and / or C １～６ C may be substituted with alkylaminocarbonyl. ３～８ The compound according to claim 3 or a pharmaceutically acceptable salt thereof, which is a pyridyl that may be substituted with at least one substituent selected from the group consisting of cycloalkyl groups.

27. The following equations (1) to (77): A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

28. A pharmaceutical composition containing a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

29. An HSD17B13 inhibitor comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

30. A preventive or therapeutic agent for diseases involving HSD17B13, comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

31. The preventive or therapeutic agent according to claim 30, wherein the disease in which HSD17B13 is involved is a liver disease.

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