4-pyridinol derivative

Abstract

[Problem] To provide a new compound having 17β-hydroxysteroid dehydrogenase-13 (HSD17B13) inhibitory activity. [Solution] A compound represented by general formula (1) 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 will be collectively called "steatotic liver disease" (SLD), and the former NAFLD and NASH will be called "metabolic dysfunction associated steatotic liver disease" (MASLD / metabolic dysfunction-related fatty liver disease) and "metabolic dysfunction associated steatohepatitis" (MASH / metabolic dysfunction-related steatohepatitis), 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, novel compounds and the like having 17β-hydroxysteroid dehydrogenase 13 (HSD17B13) inhibitory activity are in demand.

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

[0010] [1] The following general formula (1): [In the above general formula (1), 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, X １ to X ５Each of them is independent of the other, CR 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 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. １～６ Alkyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. 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. １～６ 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 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. 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 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. 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 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. ２～６ Heterocycloalkyl; 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 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. 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 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 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 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. １～６ 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 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. 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 C may be substituted with alkoxy or halogen compounds. ３～８ C may be substituted with cycloalkyl or halogen. ２～６Heterocycloalkyl, 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, C optionally substituted with halogen 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 A compound represented by ] or a pharmaceutically acceptable salt thereof.

[0011] [2] The following general formulas (2-1) to (2-4): [In the above general formulas (2-1) to (2-4), R １ to R ５ are the same as in general formula (1)] A compound or a pharmaceutically acceptable salt thereof as described in the above [1].

[0012] [3] The compound or a pharmaceutically acceptable salt thereof as described in the above [1] or [2], wherein W is formula (A-2) or formula (A-3). [4] The compound or a pharmaceutically acceptable salt thereof as described in the above [1] or [2], wherein W is formula (A-5) or formula (A-6). [5] The compound or a pharmaceutically acceptable salt thereof as described in the above [1] or [2], wherein W is formula (A-7) or formula (A-10).

[0013] [6] The compound or a pharmaceutically acceptable salt thereof as described in any one of the above [1] to [5], wherein R １ and R ２ are the same halogen. [7] R １ and R ２However, the compound described in any of [1] to [5] above, which is fluorine, or a pharmaceutically acceptable salt thereof. [8]R ３ However, hydrogen or CF ３ The compound described in [2] above or a pharmaceutically acceptable salt thereof.

[0014] [9] A compound according to any of [2] to [8] above, represented by general formula (2-1), or a pharmaceutically acceptable salt thereof.

[10] A compound according to any of [2] to [8] above, represented by general formula (2-2), or a pharmaceutically acceptable salt thereof.

[11] A compound according to any of [2] to [8] above, represented by general formula (2-3), or a pharmaceutically acceptable salt thereof.

[12] A compound according to any of [2] to [8] above, represented by general formula (2-4), or a pharmaceutically acceptable salt thereof.

[0015]

[13] R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. 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. １～６ Alkyl; or C which may be substituted with halogen, cyano, or halogen. 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. １～６ Alkylcarbonyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５C 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. 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 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. 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 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. ２～６ Heterocycloalkyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. 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. １～９C 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 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 A heteroaryl compound, as described in any of [2] to

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

[0016]

[14] 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 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. 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 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. ６～１２C may be substituted with aryl, or halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. 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 A heteroaryl compound, as described in any of [2] to

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

[0017]

[15] R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. １～５ C may be substituted with alkoxy or halogen compounds. ３～８ Cyclohexyl 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 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 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 [2] to

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

[0018]

[16] The following general formulas (3-1-1) to (3-4-2): [In the above general formulas (3-1-1) to (3-4-2), R ８ C may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. 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. 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 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. 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 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. ２～６ Heterocycloalkyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. 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. １～９C 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 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 a heteroaryl, R ９ These are, independently, hydrogen; halogen; NR １１ R １２ OR １１ ; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. 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. １～６ Alkyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. 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. １～６ Alkylcarbonyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６C may be substituted with alkyl or halogen. 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. 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 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. 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 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. ２～６ It is a heterocycloalkyl, and R １１ and R １２ 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 ２～６Heterocycloalkylcarbonyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. 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 at least one substituent selected from the group consisting of heterocycloalkyls. 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 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 at least one substituent selected from the group consisting of heterocycloalkyls. ３～８ It is a cycloalkyl, R １０ NR １３ R １４ And R １３ 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 halogen 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; 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 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. 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 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. 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 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 a heteroaryl, R １４ C may be substituted with hydrogen or halogen. 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 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. １～６ 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 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. 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 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. 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 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. １～９A compound according to any of [2] to

[16] above, or a pharmaceutically acceptable salt thereof, which is represented by any of the following: [heteroaryl].

[0019]

[17] The following formulas (1) to (90): A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

[0020]

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

[17] above or a pharmaceutically acceptable salt thereof.

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

[17] above or a pharmaceutically acceptable salt thereof.

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

[17] above or a pharmaceutically acceptable salt thereof.

[21] The preventive or therapeutic agent according to

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

[0021] 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.

[0022] 1. Definitions The terms used herein are defined below.

[0023] 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.).

[0024] 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).

[0025] 2. Compounds represented by general formula (1) or pharmaceutically acceptable salts thereof The compounds relating to this disclosure are represented by the following general formula (1). 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 6-membered aromatic ring linked to each other by linking groups of formulas (A-1) to (A-12), which is considered to provide greater freedom in the design of the compounds. Note that in this specification, "compounds represented by general formula (1) or pharmaceutically acceptable salts thereof" or "compounds represented by general formula (1)" may be referred to as "compounds relating to this disclosure".

[0026]

[0027] In the above general formula (1), R １ and R ２ Each is independently hydrogen; halogen; or cyano, and R １ and R ２ 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] 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.

[0031] C１～６ 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. １～６ Alkyl compounds include fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoropropyl, 3-fluoropropyl, 3,3,3-trifluoropropyl, 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, etc. C substituted with halogen １～６ The alkyl group is preferably trifluoromethyl or 2,2,2-trifluoroethyl, and more preferably trifluoromethyl.

[0032] 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.

[0033] 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.

[0034] W is selected from the group consisting of the following formulas (A-1) to (A-12).

[0035] In the above formulas (A-1) to (A-12), A is C which may be substituted with a halogen. １～６ It is alkylene.

[0036] 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.

[0037] In one embodiment, A is preferably methylene, ethylene, isopropylene, or isobutylene, more preferably methylene, ethylene, or isopropylene, and even more preferably methylene.

[0038] 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.

[0039] 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].

[0040] 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.

[0041] In one embodiment, W is selected from the group consisting of the following formulas (A-1) to (A-12-2).

[0042] 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).

[0043] X １ ~X ５ Each of them is independent of the other, CR ５ Or it is N.

[0044] In one embodiment, X １ It is preferable that X is N. １ is N, and X ３ CR ５ It is more preferable that X １ is N, and X ２ ~X ５ CR ５ It is even more preferable that X ５ It is preferable that X is N. ５ is N, and X ３ CR ５ It is more preferable that X ５ is N, and X １ ~X ４ CR ５ It is even more preferable that X １ and X ５ It is preferable that X is N. １ and X ５ is N, and X ３ CR ５ It is more preferable that X １ and X ５ is N, and X ２ ~X ４ CR ５ It is even more preferable that X ３ CR ５ It is preferable that X ３CR ５ And, X １ and X ５ Preferably, at least one of them is N, and X ２ ~X ４ CR ５ And, X １ and X ５ It is even more preferable that at least one of them is N.

[0045] In one embodiment, X １ ~X ５ The six-membered ring containing is preferably one of the following formulas (B-1) to (B-5).

[0046] In the above formulas (B-1) to (B-5), "*" represents the connection with W. Of the above, it is preferable that it is any of the formulas (B-1) to (B-3), more preferably formula (B-1) or formula (B-2), and even more preferably formula (B-1).

[0047] 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 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. １～６ Alkyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. 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. １～６ 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 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. 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 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. 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 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. ２～６ Heterocycloalkyl; 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 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. 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 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 a heteroaryl compound.

[0048] Below, R ５ I will explain this.

[0049] [Halogen] The halogen includes fluorine, chlorine, bromine, iodine, etc., and preferably contains fluorine, chlorine, and bromine, and more preferably fluorine.

[0050] [Substituents] C (described later) １～６ Alkyl, C １～６ Alkylcarbonyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkenyl, C ２～６ Heterocycloalkyl, C ６～１２ Aryl, and C １～９ The heteroaryl may be substituted with a substituent. The substituent may be hydroxyl, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５C 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 Heteroaryls are one example.

[0051] The halogen substituents include fluorine, chlorine, bromine, iodine, etc. The halogen substituent is preferably fluorine, chlorine, or bromine, and more preferably fluorine.

[0052] 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. １～６ Alkyl; 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. １～６The 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.

[0053] 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.

[0054] C may be substituted with a halogen as a substituent. ３～８ Cycloalkyls include unsubstituted C molecules such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, and bicyclo[2.2.2]octanyl. ３～８Cycloalkyl; 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 ３～８ 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-difluorocyclohexyl, or 4,4-difluorocyclohexyl, and more preferably 4,4-difluorocyclohexyl.

[0055] C may be substituted with a halogen as a substituent. ２～６ Heterocycloalkyls 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 ２～６Includes 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.

[0056] 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. ６～１２ The aryl is preferably phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, or 2,4,6-trifluorophenyl, and more preferably phenyl.

[0057] 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. １～９Heteroaryls; 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.

[0058] [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.

[0059] Here, C １～６ The alkyl group may be substituted with hydroxy, halogen, cyano, nitro, or halogen C. 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 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.

[0060] C having substituents １～６Alkyl 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-difluorocyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 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. C compounds having substituents １～６ Alkyl is a halogen-substituted C １～６ It is preferably an alkyl group, more preferably trifluoromethyl, more preferably 2,2,2-trifluoroethyl, and even more preferably trifluoromethyl.

[0061] 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-difluorocyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 4-tetrahydropyranylmethyl, or benzyl, and more preferably methyl or trifluoromethyl.

[0062] [C １～６ [Alkylcarbonyl] C １～６Alkyl 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.

[0063] Here, C １～６ The alkylcarbonyl may be substituted with hydroxy, halogen, cyano, nitro, or halogen C 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 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.

[0064] 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, 1-morpholylmethyl carbonyl, benzyl carbonyl, 2-pyridylmethyl carbonyl, etc. C with substituents １～６ The alkylcarbonyl is preferably a trifluoromethylcarbonyl.

[0065] Of these, C １～６ C having an alkylcarbonyl or substituent １～６The alkylcarbonyl is preferably a methylcarbonyl.

[0066] [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.

[0067] 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 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 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.

[0068] 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-dibromo This includes cyclopropyl, 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, 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.

[0069] 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.

[0070] [C ３～８ Cycloalkenyl C ３～８ Cycloalkenyls include 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 1-cyclohexen-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, etc. ３～８The cycloalkenyl is preferably 1-cyclohexen-1-yl.

[0071] 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 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 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.

[0072] 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-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.

[0073] Of these, C ３～８ Cycloalkenyl or substituted C ３～８ The cycloalkenyl is preferably 1-cyclohexen-1-yl, 4,4-difluoro-1-cyclohexen-1-yl, or 4-methoxy-1-cyclohexen-1-yl.

[0074] [C ２～６ [Heterocycloalkyl] C ２～６Heterocycloalkyls include aziridyl, azetidyl, pyrrolidyl, piperidyl, oxyranil (epoxy), oxetanil, tetrahydrofuranil, tetrahydropyranil, tetrahydrothienyl, morpholyl, etc. ２～６ The heterocycloalkyl group is preferably tetrahydrofuranyl or morpholyl.

[0075] 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 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 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.

[0076] 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, and 2,6-ditrifluoromethyl-4-tetrahydropyranyl. This includes ropyranil, 4-trifluoromethyl-2-tetrahydropyranil, 3-trifluoromethyl-4-morpholyl, 2,6-ditrifluoromethyl-4-morpholyl, 2-cyclopropyl-4-tetrahydropyranil, 4-cyclopropyl-2-tetrahydropyranil, 3-cyclopropyl-4-morpholyl, 2-phenyl-4-tetrahydropyranil, 4-phenyl-2-tetrahydropyranil, 3-phenyl-4-morpholyl, 2-(2-pyridyl)-4-tetrahydropyranil, 4-(2-pyridyl)-2-tetrahydropyranil, 3-(2-pyridyl)-4-morpholyl, etc. A substituent C ２～６ The heterocycloalkyl group is preferably 2,6-dimethyl-4-morpholyl.

[0077] 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.

[0078] [C ６～１２ [Aryl] C ６～１２ Aryls include phenyl, naphthyl, anthracenyl, phenalenyl, etc. ６～１２ The aryl group is preferably phenyl.

[0079] Here, C ６～１２ The aryl group may be substituted with hydroxy, halogen, cyano, nitro, or halogen C. １～６ C may be substituted with alkyl or halogen.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 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.

[0080] C having substituents ６～１２ Aryls 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, Includes 4,5-tribromophenyl, 2,4,6-tribromophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-cyano-4-fluorophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-nitro-4-fluorophenyl, 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, biphenyl, 4-(2-pyridyl)phenyl, etc. A substituent C ６～１２The 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, 2-methylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, or 4-methoxyphenyl.

[0081] Of these, C ６～１２ C 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, 2-methylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, or 4-methoxyphenyl.

[0082] [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.

[0083] Here, C １～９The heteroaryl may be substituted with hydroxy, halogen, cyano, nitro, or halogen C １～６ C may be substituted with alkyl or halogen. 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 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.

[0084] 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-pyradyl, 6-Methoxy-2-pyradyl, 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-S Clopropyl-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, 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 Includes dil, 5-cyclopropyl-3-pyridazyl, 6-cyclopropyl-3-pyridazyl, 3-phenyl-2-pyrrol, 4-phenyl-2-pyridyl, 5-phenyl-2-pyrazyl, 4-phenyl-2-pyrimidyl, 5-phenyl-3-pyridazyl, 3-(2-pyridyl)-2-pyrrol, 4-(2-pyridyl)-2-pyridyl, 5-(2-pyridyl)-2-pyrazyl, 4-(2-pyridyl)-2-pyrimidyl, 5-(2-pyridyl)-3-pyridazyl, etc.

[0085] 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.

[0086] [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 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. １～６ 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 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. 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 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. 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 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 a heteroaryl compound.

[0087] R ６ and R ７ Of these, C １～６ C having alkyl or substituent １～６ Alkyl (may be substituted with hydroxy, halogen, cyano, nitro, or halogen C) 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. １～６ Alkyl), C ３～８ Cycloalkyl or substituent C ３～８ Cycloalkyl (C) which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. 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. ６～１２C 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 (C may be substituted with hydroxy, halogen, cyano, nitro, or halogen) １～６ C may be substituted with alkyl or halogen. 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. 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 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 Heteroaryls are R ５ It is similar to that.

[0088] (C may be substituted with halogen) １～６ (Alkylcarbonyl) C １～６Alkyl 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.

[0089] (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.

[0090] (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 Heterocycloalkylcarbonyls include 3-fluoropyrrolidine-2-carbonyl, 3-fluoropyrrolidine-3-carbonyl, 2-fluoropiperidine-1-carbonyl, 3-fluoropiperidine-1-carbonyl, 2-fluoro-4-morpholylcarbonyl, 3-fluoro-4-morpholylcarbonyl, etc. C may be substituted with a halogen. ２～６ The heterocycloalkyl carbonyl is preferably tetrahydropyran-4-carbonyl or 4-morpholylcarbonyl.

[0091] In one embodiment, NR ６ R ７ R ７ It is preferable that is hydrogen or methyl. In one embodiment, NR ６ R ７ It is preferable that it is one of the following formulas (C-1) to (C-32).

[0092]

[0093] In the above formulas (C-1) to (C-32), "*" represents a bond with C (carbon atom). Of the above, NR ６ R ７ Preferably, the formulas are (C-1), (C-7), (C-17), (C-18), (C-20), (C-24) to (C-26), (C-28), and (C-30).

[0094] [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.

[0095] In one embodiment, R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. 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. １～６ Alkyl; or C which may be substituted with halogen, cyano, or halogen. 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. １～６ Alkylcarbonyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ 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. 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 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. 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 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. ２～６Heterocycloalkyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. 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. 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 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.

[0096] 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 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. 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 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. 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 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.

[0097] In one embodiment, R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. １～５ C may be substituted with alkoxy or halogen compounds. ３～８ Cyclohexyl 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 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.

[0098] In one embodiment, R ５At least one of the following formulas (D-1) to (D-68) is preferable.

[0099] 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 it is one of the formulas (D-65) to (D-68).

[0100] In a preferred embodiment, the compound represented by general formula (1) or a pharmaceutically acceptable salt thereof is preferably a compound represented by any of the following general formulas (2-1) to (2-4) or a pharmaceutically acceptable salt thereof.

[0101] In the above general formulas (2-1) to (2-4), R １ ~R ５ This is the same as in general formula (1).

[0102] In a preferred embodiment, the compound represented by general formula (1) or a pharmaceutically acceptable salt thereof is preferably a compound represented by any of the following general formulas (3-1-1) to (3-4-2) or a pharmaceutically acceptable salt thereof, more preferably a compound represented by any of general formulas (3-1-1), (3-2-1), (3-3-1), or (3-4-1) or a pharmaceutically acceptable salt thereof, and even more preferably a compound represented by general formula (3-1-1) or general formula (3-2-1) or a pharmaceutically acceptable salt thereof.

[0103] R ８ C may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. 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. 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 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. 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 C may be substituted with alkoxy or halogen compounds. 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 C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. 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. 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 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 a heteroaryl compound.

[0104] 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. ３～８Cycloalkyl (C may be substituted with halogen, cyano, or halogen) １～６ C may be substituted with alkyl or halogen. 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 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-dibromo This includes chloropropyl, 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, 4-cyanocyclohexyl, 4-methylcyclohexyl, 4-trifluoromethylcyclohexyl, 4-methoxycyclohexyl, 4-cyclopropylcyclohexyl, 4-morpholylcyclohexyl, 4-phenylcyclohexyl, 4-(2-pyridyl)cyclohexyl, etc. Substituting C ３～８ The cycloalkyl group is preferably 4,4-difluorocyclohexyl or 4-methoxycyclohexyl. Of these, C ３～８ Cycloalkyl or substituent C ３～８The cycloalkyl group is preferably cyclopropyl, cyclopentyl, cyclohexyl, 4,4-difluorocyclohexyl, or 4-methoxycyclohexyl.

[0105] C ３～８ Cycloalkenyls 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. ３～８ Cycloalkenyl (may be substituted with halogen, cyano, or halogen) C １～６ C may be substituted with alkyl or halogen. 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 substituted with at least one substituent selected from the group consisting of heteroaryls ３～８ Cycloalkenyls include 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-methoxy-1-cyclohexen-1-yl, 4-phenyl-1-cyclohexen-1-yl, 4-(2-pyridyl)-1-cyclohexen-1-yl, etc. C with substituents ３～８ The cycloalkenyl is preferably 4,4-difluoro-1-cyclohexen-1-yl or 4-methoxy-1-cyclohexen-1-yl. Of these, C ３～８ Cycloalkenyl or substituted C ３～８ The cycloalkenyl is preferably 1-cyclohexen-1-yl, 4,4-difluoro-1-cyclohexen-1-yl, or 4-methoxy-1-cyclohexen-1-yl.

[0106] C ２～６Heterocycloalkyls include aziridyl, azetidyl, pyrrolidyl, piperidyl, oxyranil (epoxy), oxetanil, tetrahydrofuranil, tetrahydropyranil, tetrahydrothienyl, morpholyl, etc. ２～６ The heterocycloalkyl is preferably tetrahydrofuranyl or morpholyl. A substituted C ２～６ Heterocycloalkyl (C) which may be substituted with halogen, cyano, or halogen １～６ C may be substituted with alkyl or halogen. 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 substituted with at least one substituent selected from the group consisting of heteroaryls ２～６ Heterocycloalkyls include 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-2-tetrahydropyranyl. This includes C, 3-trifluoromethyl-4-morpholyl, 2,6-ditrifluoromethyl-4-morpholyl, 2-cyclopropyl-4-tetrahydropyranyl, 4-cyclopropyl-2-tetrahydropyranyl, 3-cyclopropyl-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 is preferably 2,6-dimethyl-4-morpholyl. Of these, C２～６ Heterocycloalkyl or substituent-containing C ２～６ The heterocycloalkyl group is preferably 2-tetrahydrofuranyl, 4-tetrahydrofuranyl, 4-morpholyl, or 2,6-dimethyl-4-morpholyl.

[0107] C ６～１２ Aryls include phenyl, naphthyl, anthracenyl, phenalenyl, etc. ６～１２ The aryl is preferably phenyl. A substituted C ６～１２ Aryl (C which may be substituted with halogen, cyano, or halogen) １～６ C may be substituted with alkyl or halogen. 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 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, and 2,4-dibromophenyl. This includes methylphenyl, 3,4-dibromophenyl, 3,4,5-tribromophenyl, 2,4,6-tribromophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-cyano-4-fluorophenyl, 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, biphenyl, 4-(2-pyridyl)phenyl, etc. This includes substituted 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, 2-methylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, or 4-methoxyphenyl. 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, 2-cyanophenyl, 2-cyano-4-fluorophenyl, 2-methylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, or 4-methoxyphenyl.

[0108] 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, triazyl, and more preferably pyrrolyl, pyridyl, pyrizyl, pyrimidyl, pyrazolyl, thiazolyl, pyridyl, pyrizyl, pyrimidyl, pyridazyl. １～９ Heteroaryl (C which may be substituted with halogen, cyano, or halogen) １～６ C may be substituted with alkyl or halogen. 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 substituted with at least one substituent selected from the group consisting of heteroaryls １～９Heteroaryls include 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-fluoro-2-pyradyl, 6-fluoroaryls. Luoro-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-methyl-2-pyrrolyl, 4-methyl-2-oxazolyl, 5-methyl-2-oxazolyl, 3-methyl-5-iso Xasazolyl, 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-pyradyl, 6-methyl-2-pyradyl, 2-methyl-4-pyrimidyl, 2-methyl-5-pyrimidyl, 3-methyl-2-pyrimidyl, 4-methyl-2-pyrimidyl, 5-methyl-2-pyrimidyl,5-methyl-3-pyridadyl, 6-methyl-3-pyridadyl, 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-trifluoromethyl-3-isothiazolyl, 3-trifluoromethyl-2-pyridyl, 4-trifluoromethyl-2-pyridyl, 5-trifluoromethyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl L, 2-trifluoromethyl-3-pyridyl, 4-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl, 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-pyridyl, 6-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, 5-Cyclopropyl-2-pyradyl, 6-Cyclopropyl-2-pyradyl, 2-Cyclopropyl-4-pyrimidyl, 2-Cyclopropyl-5-pyrimidyl, 3-Cyclopropyl-2 Includes -pyrimidyl, 4-cyclopropyl-2-pyrimidyl, 5-cyclopropyl-2-pyrimidyl, 5-cyclopropyl-3-pyridazyl, 6-cyclopropyl-3-pyridazyl, 3-phenyl-2-pyrrolyl, 4-phenyl-2-pyridyl, 5-phenyl-2-pyrazyl, 4-phenyl-2-pyrimidyl, 5-phenyl-3-pyridazyl, 3-(2-pyrimidyl)-2-pyrrolyl, 4-(2-pyrimidyl)-2-pyridyl, 5-(2-pyrimidyl)-2-pyrazyl, 4-(2-pyrimidyl)-2-pyrimidyl, 5-(2-pyrimidyl)-3-pyridazyl, etc.

[0109] 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.

[0110] In one embodiment, R ８ is preferably any one of the above formulas (D-1) to (D-68).

[0111] In one embodiment, R ８ is preferably any one of formulas (D-1) to (D-5). In one embodiment, R ８ is preferably any one of formulas (D-6) to (D-10). In one embodiment, R ８ is preferably any one of formulas (D-11) to (D-14). In one embodiment, R ８ is preferably any one of formulas (D-15) to (D-45). In one embodiment, R ８ is preferably any one of formulas (D-46) to (D-56). In one embodiment, R ８ is preferably any one of formulas (D-57) to (D-64). In one embodiment, R ８ is preferably any one of formulas (D-65) to (D-68).

[0112] R ９ is each independently hydrogen; halogen; NR １１ R １２ ; OR １１ ; or C optionally substituted with hydroxy, halogen, cyano, nitro, halogen １～５ alkoxy, C optionally substituted with halogen 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 heteroaryl, C optionally substituted with at least one substituent selected from the group consisting of １～６ alkyl; or C optionally substituted with hydroxy, halogen, cyano, nitro, halogen １～５ alkoxy, C optionally substituted with halogen ３～８ cycloalkyl, C optionally substituted with 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. １～６ 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 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. 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 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. 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 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.２～６ It is heterocycloalkyl.

[0113] The aforementioned R ９ Of these, halogen, C １～６ C having alkyl or substituent １～６ Alkyl (may be substituted with hydroxy, halogen, cyano, nitro, or halogen C) 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. １～６ Alkyl), C １～６ C having an alkylcarbonyl or substituent １～６ Alkylcarbonyl (C may be substituted with hydroxy, halogen, cyano, nitro, or halogen) 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. １～６ Alkylcarbonyl), C ３～８ Cycloalkyl or substituent C ３～８ Cycloalkyl (C) which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. 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. １～９C optionally substituted with at least one substituent selected from the group consisting of heteroaryl ３～８ cycloalkyl), C ３～８ cycloalkenyl or C having a substituent ３～８ cycloalkenyl (hydroxy, halogen, cyano, nitro, C optionally substituted with halogen １～６ alkyl, C optionally substituted with halogen １～５ alkoxy, C optionally substituted with halogen 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 cycloalkenyl), C ２～６ heterocycloalkyl or C having a substituent ２～６ heterocycloalkyl (hydroxy, halogen, cyano, nitro, C optionally substituted with halogen １～６ alkyl, C optionally substituted with halogen １～５ alkoxy, C optionally substituted with halogen 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 ２～６ heterocycloalkyl) is the same as R ５ as above.

[0114] Among the above R ９ in NR １１ R １２ where R １１ and R １２ are each independently hydrogen; C optionally substituted with halogen １～６ alkylcarbonyl; C optionally substituted with halogen ３～８Cycloalkylcarbonyl; 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 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 at least one substituent selected from the group consisting of heterocycloalkyls. 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 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 at least one substituent selected from the group consisting of heterocycloalkyls. ３～８ It is a cycloalkyl group.

[0115] R １１ and R １２ C may be substituted with halogen in this case. １～６ C may be substituted with alkylcarbonyl or halogen. ３～８ C may be substituted with a cycloalkylcarbonyl or halogen. ２～６ Heterocycloalkylcarbonyl, C １～６ C having alkyl or substituent １～６ Alkyl (may be substituted with hydroxy, halogen, cyano, nitro, or halogen C) 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 at least one substituent selected from the group consisting of heterocycloalkyls. １～６ Alkyl), C ３～８ Cycloalkyl or substituent C ３～８ Cycloalkyl (C) which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６C may be substituted with alkyl or halogen. 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 at least one substituent selected from the group consisting of heterocycloalkyls. ３～８ Cycloalkyl) is R ６ and R ７ It is similar to that.

[0116] In one embodiment, NR １１ R １２ R １１ It is preferable that is hydrogen or methyl. In one embodiment, NR １１ R １２ It is preferable that it is one of the above formulas (C-1) to (C-5), formulas (C-7) to (C-11), formulas (C-17) to (C-21), or formulas (C-23) to (C-27), and more preferably one of formulas (C-1), formula (C-7), formulas (C-18) to (C-20), or formulas (C-24) to (C-26).

[0117] The aforementioned R ９ Among them, OR １１ This includes methylcarbonyloxy, trifluoromethylcarbonyloxy, cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclopentylcarbonyloxy, cyclohexylcarbonyloxy, 4-tetrahydropyranylcarbonyloxy, 1-pyrrolidylcarbonyloxy, 1-piperidylcarbonyloxy, 4-morpholylcarbonyloxy, methoxy, ethoxy, propyloxy, isopropyloxy, trifluoromethyloxy, cyclopropylmethyloxy, cyclohexylmethyloxy, 4,4-difluorocyclohexylmethyloxy, 4-tetrahydropyranylmethyl, 4-morpholylmethyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. Among these, OR １１ It is preferable that the compound is methoxy or cyclopropylmethyloxy.

[0118] R １０ NR１３ R １４ That is. R １３ 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 halogen 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; 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 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. 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 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. ６～１２ C may be substituted with aryl, hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. １～５C 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 a heteroaryl compound.

[0119] R １３ Of these, C may be substituted with halogen. ３～８ C may be substituted with a cycloalkylcarbonyl or halogen. ２～６ Heterocycloalkylcarbonyl, C ３～８ Cycloalkyl or substituent C ３～８ Cycloalkyl (C) which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. １～６ C may be substituted with alkyl or halogen. 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. ３～８ Cycloalkyl), C ６～１２ C having an aryl or substituent ６～１２ Aryl (C may be substituted with hydroxy, halogen, cyano, nitro, or halogen) １～６ C may be substituted with alkyl or halogen. 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. １～９C 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 (C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen) １～６ C may be substituted with alkyl or halogen. 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 Heteroaryls are R ６ and R ７ It is similar to that.

[0120] R １３ Among them, C having a substituent １～６ Alkyl (C which may be substituted with halogen) 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 １～６Alkyl compounds include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, bicyclo[2.2.2]octanemethyl, 1-fluorocyclopropylmethyl, 3,3-difluorocyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 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. １～６ The alkyl group is preferably cyclohexylmethyl, bicyclo[2.2.2]octanemethyl, 4,4-difluorocyclohexylmethyl, or benzyl.

[0121] R １４ C may be substituted with hydrogen or halogen. 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 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. １～６ 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 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. 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 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. 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 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 a heteroaryl compound. １４ R ６ and R ７ It is similar to that.

[0122] In one embodiment, NR １３ R １４ R １４ It is preferable that is hydrogen or methyl. In one embodiment, NR １３ R １４It is preferable that it is one of the above formulas (C-2) to (C-6), formulas (C-8) to (C-16), formulas (C-18) to (C-22), or formulas (C-24) to (C-32), and more preferably one of the formulas (C-18) to (C-20), formulas (C-24) to (C-26), formula (C-28), or formula (C-30).

[0123] The compound represented by general formula (1) or its pharmaceutically acceptable salt is preferably a compound selected from the group consisting of the following formulas (1) to (90) or its pharmaceutically acceptable salt.

[0124] Of the above, the compound represented by general formula (1) or a pharmaceutically acceptable salt thereof is preferably a compound selected from the group consisting of formulas (2) to (4), formulas (11) to (14), formula (16), formula (20), formulas (23) to (24), formulas (27) to (28), formula (34), formula (36), formulas (47) to (49), formulas (52) to (53), formula (55), formula (61), formula (64), formulas (68) to (70), formula (72), formula (78), formulas (80) to (81), formulas (83) to (84), formula (86), and formula (90), or a pharmaceutically acceptable salt thereof.

[0125] In a preferred embodiment, the compound represented by general formula (1) or a pharmaceutically acceptable salt thereof is preferably a compound selected from the group consisting of formulas (13), (16), (47), (52), (68) to (69), (72), (80) to (81), and (83), or a pharmaceutically acceptable salt thereof.

[0126] Compounds represented by general formula (1) (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 final product according to conventional methods. Furthermore, compounds represented by general formula (1) (4-pyridinol derivatives) may also include stable isotopes and radioactive isotopes.

[0127] The compound represented by general formula (1) can be a pharmaceutically acceptable salt as needed. Examples of pharmaceutically acceptable salts of the compound represented by general formula (1) 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. Furthermore, examples of pharmaceutically acceptable salts of compounds represented by general formula (1) 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 (1) 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.

[0128] Methods for forming a pharmaceutically acceptable salt of the compound represented by general formula (1) can be appropriately employed using known methods. For example, methods include mixing the compound according to this 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 this disclosure.

[0129] Compounds represented by general formula (1) or their pharmaceutically acceptable salts may also include solvates thereof, such as hydrates and alcohol adducts.

[0130] 3. Method for producing the compound represented by general formula (1) The method for producing the compound represented by general formula (1) is not particularly limited and can be produced by known methods.

[0131] A method for synthesizing a compound represented by general formula (1) 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.

[0132]

[0133] 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 (1) can be synthesized by carrying out an aromatic nucleophilic substitution reaction 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.

[0134] Note that compound X １ and compound Y １ As shown in the reaction equation, the 6-membered ring compound 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, the 6-membered ring compound A ２ It has a (nucleophilic group), and the 4-pyridinol compound is A １ It may have a (leaving group).

[0135] In this case, the W that is formed is given by the following equations (A-1) to (A-6).

[0136] 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 (1) 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.

[0137] Note that compound X １ and compound Y １ As shown in the reaction equation, the 6-membered ring compound 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, the 6-membered ring compound A ２ (Having a carboxyl-containing group), the 4-pyridinol compound is A １ It may have an amino acid-containing group.

[0138] In this case, the W that is formed is given by the following equations (A-7) to (A-12).

[0139] 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.

[0140] Note that compound X １ , compound X２ , compound Y １ , and compound Y ２ It is publicly known or can be manufactured by publicly known methods.

[0141] 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 (1) 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 (1) 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 (1) 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).

[0142] 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-associated fatty liver disease (MASLD), non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-associated steatohepatitis (MASH), alcoholic fatty liver, alcoholic hepatitis, viral hepatitis (hepatitis B, hepatitis C), hepatic fibrosis, cirrhosis, and liver cancer (HCC) (e.g., N Engl J Med. 2018 Mar 22; 378(12) 1096-1106, Hepatology. 2019 Apr;69(4)1504-1519).

[0143] In one preferred embodiment, the compound represented by general formula (1) 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 (1) 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 (1) 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 (1) 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.

[0144] 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 the compound represented by general formula (1) 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 the compound represented by general formula (1) or a pharmaceutically acceptable salt thereof. In a preferred embodiment, an agent for the prevention or treatment of cirrhosis is provided, comprising HSD17B13 containing the compound represented by general formula (1) 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 the compound represented by general formula (1) or a pharmaceutically acceptable salt thereof.

[0145] The pharmaceutical composition, HSD17B13 inhibitor, and agent for the prevention or treatment of diseases involving HSD17B13 contain a compound represented by general formula (1) 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.

[0146] [Compounds represented by general formula (1) or pharmaceutically acceptable salts thereof] The compounds represented by general formula (1) or pharmaceutically acceptable salts thereof that are described above shall be used.

[0147] A compound represented by general formula (1) 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 (1) or a pharmaceutically acceptable salt thereof, it may be bound to amino acids or sugars.

[0148] The content of a compound represented by general formula (1) 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.

[0149] [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.

[0150] 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.

[0151] Lubricants include, for example, magnesium stearate, sodium lauryl sulfate, and talc.

[0152] Disintegrants include, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextran, pectin, etc.

[0153] Colorants include, for example, those permitted for use in pharmaceuticals.

[0154] Flavoring and odor-modifying agents include, for example, cocoa powder, peppermint sap, aromatic acid, peppermint oil, borneol, cinnamon powder, etc.

[0155] Coating agents include, for example, sugar coatings, gelatin coatings, and enteric coatings (hydroxypropyl methylcellulose (HPMC), cellulose acetate phthalate, etc.).

[0156] [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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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).

[0161] 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.

[0162] 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).

[0163] 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).

[0164] 5. Methods of prevention or treatment, use of the compound represented by general formula (1) 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 (1) or a pharmaceutically acceptable salt thereof. Also according to one embodiment of the present disclosure, the use of the compound represented by general formula (1) or a pharmaceutically acceptable salt thereof is provided for the prevention or treatment of a disease involving HSD17B13. Also according to one embodiment of the present disclosure, the use of the compound represented by general formula (1) or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for the prevention or treatment of a disease involving HSD17B13.

[0165] The compound represented by general formula (1) or its pharmaceutically acceptable salts used in the aforementioned prevention or treatment method and use, as well as the method of administration and dosage thereof, are as described above.

[0166] 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.

[0167] [Synthesis Example 1] Synthesis of (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A)

[0168] 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).

[0169] Step (2) Synthesis of 3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-carboaldehyde: To a solution of 3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (7.5 g), the compound obtained in Step 1, in tetrahydrofuran (150 mL), 2.5 M n-butyllithium hexane solution (18 mL) was added dropwise 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 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 to obtain the crude product 3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-carboaldehyde (9.1 g).

[0170] Step (3) Synthesis of (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol: To 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 was then stopped with water, and the reaction 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).

[0171] [Synthesis Example 2] Synthesis of (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B)

[0172] Step (1) Synthesis of 3,5-difluoro-4-iodopyridine: 10 g of 3,5-difluoropyridine, a known substance, was added dropwise to 100 mL of tetrahydrofuran solution with 52 mL of 2.5 M n-butyllithium hexane solution under a nitrogen atmosphere at -78°C, and the mixture was stirred for 30 minutes. Then, 44 g of iodine was added dropwise to the reaction mixture with 50 mL of tetrahydrofuran solution, and the mixture was stirred at -78°C for 2 hours. The reaction mixture 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 resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 20 g of 3,5-difluoro-4-iodopyridine.

[0173] Step (2) Synthesis of 4-(benzyloxy)-3,5-difluoropyridine A mixture 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 under a nitrogen atmosphere for 16 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-(benzyloxy)-3,5-difluoropyridine (5.0 g).

[0174] Step (3) Synthesis of 4-(benzyloxy)-3,5-difluoropyridine-2-carboaldehyde: To a solution of 4-(benzyloxy)-3,5-difluoropyridine (15 g), the compound obtained in step (2), in tetrahydrofuran (150 mL), 2.5 M n-butyllithium hexane solution (41 mL) was added dropwise under a nitrogen atmosphere at -78°C and the mixture was stirred for 1 hour. Then, a solution of dimethylformamide (9.9 g) in tetrahydrofuran (20 mL) was added dropwise to the reaction mixture and the mixture was stirred at -78°C for 1 hour. Subsequently, 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, 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).

[0175] Step (4) Synthesis of (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol: To a methanol (150 mL) solution of 4-(benzyloxy)-3,5-difluoropyridine-2-carboaldehyde (8.5 g), the compound obtained in step (3), sodium borohydride (2.6 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 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).

[0176] [Synthesis Example 3] Synthesis of (4-(benzyloxy)-3,5-difluoro-6-(trifluoromethyl)pyridine-2-yl)methanol (intermediate C)

[0177] Step (1) Synthesis of 4-(benzyloxy)-3,5-difluoro-2-iodopyridine: To a solution of 4-(benzyloxy)-3,5-difluoropyridine (3.2 g), the compound obtained in Step (2) of Synthesis Example 2, in tetrahydrofuran (60 mL), a 2.5 M n-butyllithium hexane solution (9 mL) was added dropwise under a nitrogen atmosphere at -78°C and the mixture was stirred for 30 minutes. Then, a solution of iodine (5.5 g) in tetrahydrofuran (6 mL) was added dropwise to the reaction mixture and the mixture was 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).

[0178] 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) were mixed in N,N-dimethylformamide (100 mL) and stirred at 80°C under a nitrogen atmosphere for 16 hours. 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).

[0179] Step (3) Synthesis of (4-(benzyloxy)-3,5-difluoro-6-(trifluoromethyl)pyridine-2-yl)methanol: To a solution of 4-(benzyloxy)-3,5-difluoro-2-(trifluoromethyl)pyridine (2.9 g), the compound obtained in step (2), in tetrahydrofuran (100 mL), 8 mL of 2 M lithium diisopropylamide (LDA) tetrahydrofuran solution was added dropwise at -78°C under a nitrogen atmosphere 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. Subsequently, 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. 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).

[0180]

[0181] [Synthesis Example 4] Synthesis of 5-bromo-2-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-4,6-dimethylpyrimidine (intermediate D)

[0182] To a solution of 5-bromo-2-chloro-4,6-dimethylpyridine (1.6 g), a known substance, in 1,4-dioxane (20 mL), t-butoxy potassium (1.2 g) and (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (1.0 g) were added and the mixture was stirred at 60°C for 24 hours. Then, 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. 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 5-bromo-2-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-4,6-dimethylpyrimidine (760 mg).

[0183] [Synthesis Example 5] Synthesis of 2-(((5-bromo-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (intermediate E)

[0184] Step (1) Synthesis of 5-bromo-2-fluoro-4-(trifluoromethyl)pyridine A solution of nitrosonium tetrafluoroborate (3.2 g) in dichloromethane (50 mL) was added dropwise at 0°C to a solution of 5-bromo-4-(trifluoromethyl)pyridine-2-amine (5.0 g), a known substance, in dichloromethane (30 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then stopped with water and 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 column chromatography (hexane-ethyl acetate) to obtain 5-bromo-2-fluoro-4-(trifluoromethyl)pyridine (3.8 g).

[0185] Step (2) Synthesis of 2-(((5-bromo-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (6.9 g) and 5-bromo-2-fluoro-4-(trifluoromethyl)pyridine (6.0 g), the compound obtained in Step (1), were dissolved in tetrahydrofuran (150 mL), to which t-butoxy potassium (3.3 g) was added at 0°C and the mixture was stirred at room temperature for 1 hour. 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 2-(((5-bromo-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (5.1 g).

[0186] [Synthesis Example 6] Synthesis of 2-(((5-bromo-4,6-dimethylpyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (intermediate F)

[0187] Step (1) Synthesis of 3-bromo-6-fluoro-2,4-dimethylpyridine A solution of nitrosonium tetrafluoroborate (7.6 g) in dichloromethane (100 mL) was added dropwise at 0°C to a solution of 5-bromo-4,6-dimethylpyridine-2-amine (10 g), a known substance, in dichloromethane (100 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then stopped with water and 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 column chromatography (hexane-ethyl acetate) to obtain 3-bromo-6-fluoro-2,4-dimethylpyridine (10 g).

[0188] Step (2) Synthesis of 2-(((5-bromo-4,6-dimethylpyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine: 3-bromo-6-fluoro-2,4-dimethylpyridine (5.0 g), the compound obtained in Step (1), and (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (6.9 g) were dissolved in tetrahydrofuran (120 mL), to which t-butoxy potassium (3.3 g) was added at 0°C and the mixture was stirred for 2 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 2-(((5-bromo-4,6-dimethylpyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (3.1 g).

[0189] [Synthesis Example 7] Synthesis of 6-((4-benzyloxy)-3,5-difluoropyridine-2-yl)methoxy-3-bromo-2,4-dimethylpyridine (intermediate G)

[0190] t-butoxypotassium (1.6 g) was added at 0°C to a solution of 3-bromo-6-fluoro-2,4-dimethylpyridine (2.4 g), the compound obtained in step (1) of Synthesis Example 6, and 4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (3.0 g) in tetrahydrofuran (80 mL), and the mixture was stirred at room temperature for 1 hour. 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 resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 6-((4-benzyloxy)-3,5-difluoropyridine-2-yl)methoxy-3-bromo-2,4-dimethylpyridine (1.4 g).

[0191] The intermediates produced in Synthesis Examples 1 to 7 are shown in Tables 1-1 to 1-2 below.

[0192]

[0193] [Example 1] Synthesis of 3,5-difluoro-2-(((4-(methyl(phenyl)amino)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0194] Step (1) Synthesis of 2-chloro-N-methyl-N-phenylpyridine-4-amine: A toluene (10 mL) solution containing 4-bromo-2-chloropyridine (400 mg), N-methylaniline (223 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (38 mg), 50% tri-t-butylphosphinetoluene solution (34 mg), and t-butoxysodium (300 mg) was stirred at 100°C for 16 hours under a nitrogen atmosphere. The filtrate was then filtered, and ethyl acetate was added to the resulting 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 2-chloro-N-methyl-N-phenylpyridine-4-amine (300 mg).

[0195] Step (2) Synthesis of 3,5-difluoro-2-(((4-(methyl(phenyl)amino)pyridine-2-yl)oxy)methyl)pyridine-4-ol A mixture of 2-chloro-N-methyl-N-phenylpyridine-4-amine (150 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (193 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (36 mg), (2R)-1-((1R)-1-(bis(1,1-dimethylethyl)phosphino)ethyl)-2-(dicyclohexylphosphino)ferrocene (38 mg), and cesium carbonate (447 mg) in 1,4-dioxane (10 mL) was stirred under a nitrogen atmosphere at 140°C for 16 hours. Subsequently, ethyl acetate was added to the filtrate obtained by filtration, 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 crude product (300 mg), trifluoroacetic acid (TFA) (1 mL), and dichloromethane (4 mL) solution were stirred at room temperature for 1 hour. The reaction mixture was then 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-(((4-(methyl(phenyl)amino)pyridine-2-yl)oxy)methyl)pyridine-4-ol (12 mg).

[0196] [Example 2] Synthesis of 3,5-difluoro-2-(((5-phenylpyridine-2-yl)oxy)methyl)-6-(trifluoromethyl)pyridine-4-ol

[0197] Step (1) Synthesis of 4-(benzyloxy)-3,5-difluoro-2-(((5-phenylpyridine-2-yl)oxy)methyl)-6-(trifluoromethyl)pyridine: A solution of 2-chloro-5-phenylpyridine (30 mg), (4-(benzyloxy)-3,5-difluoro-6-(trifluoromethyl)pyridine-2-yl)methanol (intermediate C) (50 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (16 mg), (2-biphenyl)di-t-butylphosphine (5 mg), and cesium carbonate (102 mg) in 1,4-dioxane (3 mL) was stirred at 80°C under a nitrogen atmosphere for 5 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 column chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 4-(benzyloxy)-3,5-difluoro-2-(((5-phenylpyridine-2-yl)oxy)methyl)-6-(trifluoromethyl)pyridine (25 mg).

[0198] Step (2) Synthesis of 3,5-difluoro-2-(((5-phenylpyridine-2-yl)oxy)methyl)-6-(trifluoromethyl)pyridine-4-ol Step (1), a solution of the obtained compound 4-(benzyloxy)-3,5-difluoro-2-(((5-phenylpyridine-2-yl)oxy)methyl)-6-(trifluoromethyl)pyridine (20 mg) in trifluoroacetic acid (4 mL) was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure using a rotary evaporator. The obtained residue was purified by reverse-phase column chromatography (water (containing 0.05% formic acid)-acetonitrile) to obtain 3,5-difluoro-2-(((5-phenylpyridine-2-yl)oxy)methyl)-6-(trifluoromethyl)pyridine-4-ol (12 mg).

[0199]

[0200] [Example 3] Synthesis of 3,5-difluoro-2-(((4-methyl-5-phenylpyridine-2-yl)oxy)methyl)pyridine-4-ol

[0201] Step (1) Synthesis of 2-chloro-4-methyl-5-phenylpyridine: A mixture of 5-bromo-2-chloro-4-methylpyridine (1.0 g), phenylboronic acid (1.2 g), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (350 mg), and potassium carbonate (2.0 g) in 1,4-dioxane (8 mL) and water (2 mL) was stirred at 80°C under a nitrogen atmosphere for 8 hours. Then, water was added to the reaction mixture 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 2-chloro-4-methyl-5-phenylpyridine (760 mg).

[0202] Step (2) Synthesis of 2-((3,5-difluoro-4-((4-methoxyphenyl)methoxy)pyridine-2-yl)methoxy)-4-methyl-5-phenylpyridine Compound obtained in Step (1) is 2-chloro-4-methyl-5-phenylpyridine (300 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (414 mg), methanesulfonate (dicyclohexyl (3-(1-methylethoxy) A mixture of 1,4-dioxane (10 mL) containing -2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (135 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (79 mg), and cesium carbonate (960 mg) was stirred at 100°C for 2 hours under a nitrogen atmosphere. Water was then added to the reaction mixture, 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 obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2-((3,5-difluoro-4-((4-methoxyphenyl)methoxy)pyridine-2-yl)methoxy)-4-methyl-5-phenylpyridine (220 mg).

[0203] Step (3) Synthesis of 3,5-difluoro-2-(((4-methyl-5-phenylpyridine-2-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step (2), 2-((3,5-difluoro-4-((4-methoxyphenyl)methoxy)pyridine-2-yl)methoxy)-4-methyl-5-phenylpyridine (220 mg), was mixed with trifluoroacetic acid (2 mL) and dichloromethane (8 mL) and 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 high-performance liquid chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 3,5-difluoro-2-(((4-methyl-5-phenylpyridine-2-yl)oxy)methyl)pyridine-4-ol (83 mg).

[0204]

[0205] [Example 4] Synthesis of 3,5-difluoro-2-(((6-methyl-5-phenylpyridine-2-yl)oxy)methyl)pyridine-4-ol

[0206] Step (1) Synthesis of 6-chloro-2-methyl-3-phenylpyridine: A mixture of 3-bromo-6-chloro-2-methylpyridine (300 mg), phenylboronic acid (354 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (119 mg), and potassium carbonate (602 mg) in 1,4-dioxane (6 mL) and water (1.5 mL) was stirred at 80°C under a nitrogen atmosphere for 2 hours. The mixture was then filtered, and ethyl acetate was added to the resulting 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 6-chloro-2-methyl-3-phenylpyridine (140 mg).

[0207] Step (2) Synthesis of 3,5-difluoro-2-(((6-methyl-5-phenylpyridine-2-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step (1) is 6-chloro-2-methyl-3-phenylpyridine (120 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (331 mg), methanesulfonate (dicyclohexyl (3-(1-methylethoxy)-2',4 A mixture of ',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (54 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (32 mg), and cesium carbonate (384 mg) in 1,4-dioxane (5 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The mixture was then filtered, and ethyl acetate was added to the resulting 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 trifluoroacetic acid (2 mL) and dichloromethane (8 mL) and stirred at room temperature for 1 hour. Subsequently, 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-(((6-methyl-5-phenylpyridine-2-yl)oxy)methyl)pyridine-4-ol (20 mg).

[0208]

[0209] [Example 5] Synthesis of 3,5-difluoro-2-(((4-(methylamino)-5-phenylpyridine-2-yl)oxy)methyl)pyridine-4-ol

[0210] Step (1) Synthesis of 2-chloro-5-phenylpyridine-4-amine: A mixture of 2-chloro-5-iodopyridine-4-amine (2.0 g), phenylboronic acid (1.2 g), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (320 mg), 12 mL of 2 M aqueous sodium carbonate solution, and 1,4-dioxane (30 mL) was stirred at 100°C under a nitrogen atmosphere for 2 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 resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2-chloro-5-phenylpyridine-4-amine (1.3 g).

[0211] Step (2) Synthesis of 2-chloro-N-methyl-5-phenylpyridine-4-amine A solution of 2-chloro-5-phenylpyridine-4-amine (400 mg), the compound obtained in Step (1), in acetic acid (15 mL) was slowly added with paraformaldehyde (86 mg) at room temperature and stirred at 30°C for 1 hour. Then, sodium cyanoborohydride (246 mg) was added to the reaction mixture at 0°C and stirred at 30°C for 16 hours. The reaction mixture was concentrated under reduced pressure using a rotary evaporator, and then water and saturated sodium bicarbonate aqueous solution were added to adjust the pH to 8. The reaction mixture was then extracted three times with ethyl acetate, and 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% ammonium bicarbonate) - acetonitrile) to obtain 2-chloro-N-methyl-5-phenylpyridine-4-amine (220 mg).

[0212] Step (3) Synthesis of 3,5-difluoro-2-(((4-(methylamino)-5-phenylpyridine-2-yl)oxy)methyl)pyridine-4-ol Compound obtained in Step (2) is 2-chloro-N-methyl-5-phenylpyridine-4-amine (180 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (186 mg), methanesulfonate (dicyclohexyl (3-(1-methylethoxy)-2', A mixture of 4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (76 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (44 mg), and cesium carbonate (536 mg) in 1,4-dioxane (10 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. Ethyl acetate 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 crude product (200 mg) was mixed with trifluoroacetic acid (1 mL) and dichloromethane (4 mL) and stirred at room temperature for 6 hours. Subsequently, 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-(((4-(methylamino)-5-phenylpyridine-2-yl)oxy)methyl)pyridine-4-ol (57 mg).

[0213]

[0214] [Example 6] Synthesis of N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-phenylpyridine-4-yl)acetamide

[0215] Step (1) Synthesis of N-(2-chloro-5-phenylpyridine-4-yl)acetamide In a solution of 2-chloro-5-phenylpyridine-4-amine (500 mg) and triethylamine (494 mg), which were obtained in Step (1) of Example 5, in tetrahydrofuran (6 mL), acetyl chloride (230 mg) was added dropwise at 0°C and the mixture was stirred at room temperature for 2 hours. The 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 silica gel column chromatography (hexane-ethyl acetate) to obtain N-(2-chloro-5-phenylpyridine-4-yl)acetamide (140 mg).

[0216] Step (2) Synthesis of N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-phenylpyridine-4-yl)acetamide: N-(2-chloro-5-phenylpyridine-4-yl)acetamide (100 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (102 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) (37 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (22 mg), and cesium carbonate (264 mg) in 1,4-dioxane (2 mL) was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was then filtered, and ethyl acetate was added to the resulting 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 (240 mg) was mixed with trifluoroacetic acid (5 mL) and stirred at room temperature for 1 hour. Subsequently, 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 N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-phenylpyridine-4-yl)acetamide (25 mg).

[0217]

[0218] [Example 7] Synthesis of 3,5-difluoro-2-(((4-((4-fluorophenyl)(methyl)amino)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0219] Step (1) Synthesis of 2-chloro-N-(4-fluorophenyl)-N-methylpyridine-4-amine: A solution of 60 mL of toluene containing 4-bromo-2-chloropyridine (600 mg), 4-fluoro-N-methylaniline (312 mg), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (57 mg), 50% tri-t-butylphosphinetoluene solution (51 mg), and t-butoxysodium (449 mg) was stirred at 80°C for 1 hour under a nitrogen atmosphere. The filtrate was then filtered and 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 2-chloro-N-(4-fluorophenyl)-N-methylpyridine-4-amine (210 mg).

[0220] Step (2) Synthesis of 3,5-difluoro-2-(((4-((4-fluorophenyl)(methyl)amino)pyridine-2-yl)oxy)methyl)pyridine-4-ol Compound obtained in Step (1) is 2-chloro-N-(4-fluorophenyl)-N-methylpyridine-4-amine (150 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (239 mg), methanesulfonate (dicyclohexyl (3-(1-methyl eth A mixture of (xy)-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (116 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (68 mg), and cesium carbonate (413 mg) in 1,4-dioxane (15 mL) was stirred under a nitrogen atmosphere at 140°C for 2 hours. The mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting crude product (450 mg) was mixed with trifluoroacetic acid (5 mL) and stirred at room temperature for 1 hour. Subsequently, 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-(((4-((4-fluorophenyl)(methyl)amino)pyridine-2-yl)oxy)methyl)pyridine-4-ol (27 mg).

[0221]

[0222] [Example 8] Synthesis of 3,5-difluoro-2-(((6-(methylamino)-5-phenylpyridine-2-yl)oxy)methyl)pyridine-4-ol

[0223] Step (1) Synthesis of 6-chloro-3-phenylpyridine-2-amine: A mixture of 6-chloro-3-iodopyridine-2-amine (2.0 g), phenylboronic acid (1.2 g), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (640 mg), and sodium carbonate (2.5 g) in 1,4-dioxane (20 mL) and water (2 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The mixture was then filtered, and ethyl acetate was added to the resulting 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 6-chloro-3-phenylpyridine-2-amine (1.6 g).

[0224] Step (2) Synthesis of 6-chloro-N-methyl-3-phenylpyridine-2-amine A solution of 6-chloro-3-phenylpyridine-2-amine (400 mg), the compound obtained in Step (1), and paraformaldehyde (88 mg) in acetic acid (15 mL) was stirred at 30°C for 1 hour. Then, sodium cyanoborohydride (246 mg) was added to the reaction mixture at 0°C and stirred at 30°C for 2 hours. Water and saturated sodium bicarbonate aqueous solution were added to the reaction mixture to adjust the pH to 8. The reaction mixture was then extracted three times with ethyl acetate, and 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 reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 6-chloro-N-methyl-3-phenylpyridine-2-amine (160 mg).

[0225] Step (3) Synthesis of 3,5-difluoro-2-(((6-(methylamino)-5-phenylpyridine-2-yl)oxy)methyl)pyridine-4-ol: 6-chloro-N-methyl-3-phenylpyridine-2-amine (140 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (129 mg), methanesulfonate (dicyclohexyl (3-(1-methylethoxy)-2' A mixture of 1,4-dioxane (5 mL) containing ,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 (417 mg) was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. Ethyl acetate 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 crude product (200 mg) was mixed with trifluoroacetic acid (2.5 mL) and dichloromethane (10 mL) and stirred at room temperature for 1 hour. Subsequently, 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-(((6-(methylamino)-5-phenylpyridine-2-yl)oxy)methyl)pyridine-4-ol (48 mg).

[0226]

[0227] [Example 9] Synthesis of N-(6-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-3-phenylpyridine-2-yl)acetamide

[0228] Step (1) Synthesis of N-(6-chloro-3-phenylpyridine-2-yl)acetamide A solution of 6-chloro-3-phenylpyridine-2-amine (400 mg), the compound obtained in Step (1) of Example 8, and acetic anhydride (10 mL) was stirred at 60°C for 16 hours. 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 N-(6-chloro-3-phenylpyridine-2-yl)acetamide (250 mg).

[0229] Step (2) Synthesis of N-(6-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-3-phenylpyridine-2-yl)acetamide: N-(6-chloro-3-phenylpyridine-2-yl)acetamide (170 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (173 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) (63 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (37 mg), and cesium carbonate (449 mg) in 1,4-dioxane (5 mL) was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was then filtered, and ethyl acetate was added to the resulting 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 obtained residue was purified by reverse-phase column chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain N-(6-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-3-phenylpyridine-2-yl)acetamide (32 mg).

[0230]

[0231] [Example 10] Synthesis of 2-(((4-(((cyclohexylmethyl)(methyl)amino)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0232] Step (1) Synthesis of 2-chloro-N-(cyclohexylmethyl)pyridine-4-amine: A mixture of 1 g of the known substance 4-bromo-2-chloropyridine, 588 mg of (aminomethyl)cyclohexane, 238 mg of tris(dibenzylideneacetone)dipalladium, 210 mg of 50% tri-t-butylphosphine-toluene solution, and 749 mg of t-butoxysodium in toluene (15 mL) was stirred at 80°C under a nitrogen atmosphere for 2 hours. The mixture was then filtered, and ethyl acetate was added to the resulting 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 2-chloro-N-(cyclohexylmethyl)pyridine-4-amine (305 mg).

[0233] Step (2) Synthesis of 2-chloro-N-(cyclohexylmethyl)-N-methylpyridine-4-amine: To a solution of 2-chloro-N-(cyclohexylmethyl)pyridine-4-amine (300 mg), the compound obtained in Step (1), in N,N-dimethylformamide (8 mL), sodium hydride (60%, 160 mg) was added at 0°C and stirred for 10 minutes. Then, iodomethane (284 mg) was added dropwise to the reaction mixture and stirred at room temperature for 3 hours. The reaction 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 column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 2-chloro-N-(cyclohexylmethyl)-N-methylpyridine-4-amine (260 mg).

[0234] Step (3) Synthesis of 2-(((4-((cyclohexylmethyl)(methyl)amino)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol Compound obtained in Step (2) is 2-chloro-N-(cyclohexylmethyl)-N-methylpyridine-4-amine (50 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (53 mg), methanesulfonate (dicyclohexyl(3-(1-methyl eth A mixture of 1,4-dioxane (2 mL) containing (xy)-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (10 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (11 mg), and cesium carbonate (136 mg) was stirred at 100°C for 3 hours under a nitrogen atmosphere. 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 resulting crude product (500 mg) was mixed with trifluoroacetic acid (5 mL) and dichloromethane (5 mL) and stirred at room temperature for 1 hour. Subsequently, 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 2-(((4-((cyclohexylmethyl)(methyl)amino)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (12 mg).

[0235]

[0236] [Example 11] Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0237] Step (1) Synthesis of 2-chloro-5-(4-fluorophenyl)-4-(trifluoromethyl)pyridine: A mixture of 5-bromo-2-chloro-4-(trifluoro)pyridine (1 g), 4-fluorophenylboronic acid (484 mg), tetrakis(triphenylphosphine)palladium (0) (133 mg), and sodium carbonate (814 mg) in toluene (9 mL), water (6 mL), and ethanol (3 mL) was stirred at 80°C under a nitrogen atmosphere for 1.5 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 column chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 2-chloro-5-(4-fluorophenyl)-4-(trifluoromethyl)pyridine (200 mg).

[0238] Step (2) Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step (1) is 2-chloro-5-(4-fluorophenyl)-4-(trifluoromethyl)pyridine (180 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (164 mg), methanesulfonate (dicyclohexyl (3-(1-methyl A mixture of 1,4-dioxane (8 mL) containing thylethoxy)-2',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 (426 mg) was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. Trifluoroacetic acid (15 mL) was added to the resulting crude product (640 mg), and the mixture was stirred at room temperature for 1 hour. Subsequently, 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-(((5-(4-fluorophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol (26 mg).

[0239]

[0240] [Example 12] Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0241] Step (1) Synthesis of 6-chloro-3-(4-fluorophenyl)-2-(trifluoromethyl)pyridine: A mixture of 3-bromo-6-chloro-2-(trifluoromethyl)pyridine (500 mg), 4-fluorophenylboronic acid (269 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (16 mg), and potassium carbonate (1.3 g) in 1,2-dimethoxyethane (30 mL) was stirred at 90°C under a nitrogen atmosphere for 2 hours. The mixture was then filtered, and ethyl acetate was added to the resulting 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 6-chloro-3-(4-fluorophenyl)-2-(trifluoromethyl)pyridine (480 mg).

[0242] Step (2) Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step (1) is 6-chloro-3-(4-fluorophenyl)-2-(trifluoromethyl)pyridine (120 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (77 mg), methanesulfonate (dicyclohexyl (3-(1-methyl A mixture of 1,4-dioxane (7.5 mL) containing 40 mg of lutethoxy)-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II), 23 mg of dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine, and 284 mg of cesium carbonate was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was then filtered, and ethyl acetate was added to the resulting 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 obtained residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 3,5-difluoro-2-(((5-(4-fluorophenyl)-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol (54 mg).

[0243]

[0244] [Example 13] Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4,6-dimethylpyridine-2-yl)oxy)methyl)pyridine-4-ol

[0245] Step (1) Synthesis of 6-chloro-3-(4-fluorophenyl)-2,4-dimethylpyridine: A mixture of 3-bromo-6-chloro-2,4-dimethylpyridine (500 mg), 4-fluorophenylboronic acid (317 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (19 mg), and potassium carbonate (1.6 g) in 1,2-dimethoxyethane (10 mL) was stirred at 90°C under a nitrogen atmosphere for 16 hours. The mixture was then filtered, and ethyl acetate was added to the resulting 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 6-chloro-3-(4-fluorophenyl)-2,4-dimethylpyridine (230 mg).

[0246] Step (2) Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4,6-dimethylpyridine-2-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step (1) is 6-chloro-3-(4-fluorophenyl)-2,4-dimethylpyridine (120 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (102 mg), methanesulfonate (dicyclohexyl (3-(1-methylethoxy A mixture of 1,4-dioxane (5 mL) containing (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (47 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (27 mg), and cesium carbonate (332 mg) was stirred at 100°C for 16 hours under a nitrogen atmosphere. The resulting filtrate was then filtered, ethyl acetate was added, 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 column chromatography (water (containing 0.05% ammonium bicarbonate)-acetonitrile) and high-performance liquid chromatography to obtain 3,5-difluoro-2-(((5-(4-fluorophenyl)-4,6-dimethylpyridine-2-yl)oxy)methyl)pyridine-4-ol (23 mg).

[0247]

[0248] [Example 14] Synthesis of 3,5-difluoro-2-(((5-(3-fluorophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0249] To a solution of 2-(((5-bromo-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (intermediate E) (100 mg) in 1,4-dioxane (1 mL) and water (0.2 mL), 3-fluorophenylboronic acid (42 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (14 mg), and potassium carbonate (82 mg) were added, and the mixture was stirred at 80°C under an argon atmosphere for 2 hours. After that, water was added to the reaction mixture and washed with ethyl acetate. 2 M hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Hexane and ethyl acetate were added to the resulting residue, and the resulting solid was filtered off. The solid was then dried to obtain 3,5-difluoro-2-(((5-(3-fluorophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol (59 mg).

[0250]

[0251] [Example 15] Synthesis of N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-(4-fluorophenyl)pyridine-4-yl)-N-((4,4-difluorocyclohexyl)methyl)acetamide

[0252] Step (1) Synthesis of 2-chloro-5-(4-fluorophenyl)pyridine-4-amine: A mixture of 5-bromo-2-chloropyridine-4-amine (1.0 g), 4-fluorophenylboronic acid (674 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (197 mg), and sodium carbonate (1.53 g) in 1,4-dioxane (12 mL) and water (6 mL) was stirred at 100°C under a nitrogen atmosphere for 2 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 resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 2-chloro-5-(4-fluorophenyl)pyridine-4-amine (830 mg).

[0253] Step (2) Synthesis of 2-chloro-N-((4,4-difluorocyclohexyl)methyl)-5-(4-fluorophenyl)pyridine-4-amine: To a solution of 2-chloro-5-(4-fluorophenyl)pyridine-4-amine (770 mg), the compound obtained in Step (1), in acetic acid (10 mL), 4,4-difluorocyclohexane-1-carboaldehyde (1.54 g) was added at room temperature and the mixture was stirred at 30°C for 24 hours. Then, sodium cyanoborohydride (435 mg) was added to the reaction mixture at 0°C and the mixture was stirred at room temperature for 5 hours. The 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 obtained residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 2-chloro-N-((4,4-difluorocyclohexyl)methyl)-5-(4-fluorophenyl)pyridine-4-amine (660 mg).

[0254] Step (3) Synthesis of N-(2-chloro-5-(4-fluorophenyl)pyridine-4-yl)-N-((4,4-difluorocyclohexyl)methyl)acetamide A solution of 2-chloro-N-((4,4-difluorocyclohexyl)methyl)-5-(4-fluorophenyl)pyridine-4-amine (540 mg), the compound obtained in Step (2), in acetic anhydride (12 mL) was stirred at 140°C for 18 hours. The reaction mixture was stopped with an aqueous sodium bicarbonate 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 reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain N-(2-chloro-5-(4-fluorophenyl)pyridine-4-yl)-N-((4,4-difluorocyclohexyl)methyl)acetamide (400 mg).

[0255] Step (4) Synthesis of N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-(4-fluorophenyl)pyridine-4-yl)-N-((4,4-difluorocyclohexyl)methyl)acetamide: The compound obtained in step (3) is N-(2-chloro-5-(4-fluorophenyl)pyridine-4-yl)-N-((4,4-difluorocyclohexyl)methyl)acetamide (200 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (127 mg). A mixture of 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) (46 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (27 mg), and cesium carbonate (328 mg) in 1,4-dioxane (8 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The filtrate was then filtered and concentrated under reduced pressure using a rotary evaporator. The resulting crude product (700 mg) was mixed with trifluoroacetic acid (15 mL) and stirred at room temperature for 30 minutes. Subsequently, 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 N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-(4-fluorophenyl)pyridine-4-yl)-N-((4,4-difluorocyclohexyl)methyl)acetamide (67 mg).

[0256]

[0257] [Example 16] Synthesis of 2-(((5-(2,4-difluorophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0258] A mixture of 2-(((5-bromo-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (intermediate E) (100 mg), 2,4-difluorophenylboronic acid (31 mg), bis(di-t-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (14 mg), and tripotassium phosphate (84 mg) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. Trifluoroacetic acid (2 mL) was added to a solution of the obtained crude product (200 mg) in dichloromethane (8 mL), and the mixture was stirred at room temperature for 1 hour. Subsequently, 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 2-(((5-(2,4-difluorophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (32 mg).

[0259]

[0260] [Example 17] Synthesis of 3,5-difluoro-2-(((4-(trifluoromethyl)-5-(4-(trifluoromethyl)phenyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0261] A mixture of 2-(((5-bromo-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (intermediate E) (100 mg), (4-(trifluoromethyl)phenyl)boronic acid (56 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (32 mg), and sodium carbonate (63 mg) in 1,4-dioxane (2 mL) and water (0.5 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The filtrate was then filtered and concentrated under reduced pressure using a rotary evaporator. Trifluoroacetic acid (2 mL) was added to a solution of the obtained crude product (200 mg) in dichloromethane (8 mL) and stirred at room temperature for 1 hour. The filtrate was then filtered and ethyl acetate was added, 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 (150 mg), trifluoroacetic acid (1 mL), and dichloromethane (3 mL) solution were stirred at room temperature for 1 hour. Subsequently, 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-(((4-(trifluoromethyl)-5-(4-(trifluoromethyl)phenyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol (36 mg).

[0262]

[0263] [Example 18] Synthesis of 3,5-difluoro-2-(((5-(2-methoxyphenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0264] Step (1) Synthesis of 2-chloro-5-(2-methoxyphenyl)-4-(trifluoromethyl)pyridine: A mixture of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (500 mg), 2-methoxyphenylboronic acid (291 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (16 mg), and potassium carbonate (1.3 g) in 1,2-dimethoxyethane (15 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The 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 2-chloro-5-(2-methoxyphenyl)-4-(trifluoromethyl)pyridine (190 mg).

[0265] Step (2) Synthesis of 3,5-difluoro-2-(((5-(2-methoxyphenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step (1) is 2-chloro-5-(2-methoxyphenyl)-4-(trifluoromethyl)pyridine (60 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (52 mg), methanesulfonate (dicyclohexyl (3-(1-methyl A mixture of 1,4-dioxane (3 mL) containing lutethoxy)-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (19 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (11 mg), and cesium carbonate (136 mg) was stirred under a nitrogen atmosphere at 100°C for 2 hours. The filtrate was then filtered and concentrated under reduced pressure using a rotary evaporator. The resulting crude product (480 mg) was mixed with trifluoroacetic acid (1 mL) and stirred at room temperature for 30 minutes. Subsequently, 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-(((5-(2-methoxyphenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol (48 mg).

[0266]

[0267] [Example 19] Synthesis of 3,5-difluoro-2-(((5-(3-methoxyphenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0268] A mixture of 2-(((5-bromo-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (intermediate E) (150 mg), 3-methoxyphenylboronic acid (68 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (49 mg), and sodium carbonate (94 mg) was stirred in 1,4-dioxane (8 mL) and water (2 mL) under a nitrogen atmosphere at 100°C for 2 hours. The mixture was then filtered, and ethyl acetate was added to the resulting 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, and the resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 3,5-difluoro-2-(((5-(3-methoxyphenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol (24 mg).

[0269]

[0270] [Example 20] Synthesis of 3,5-difluoro-2-(((5-(4-methoxyphenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0271] Step (1) Synthesis of 2-chloro-5-(4-methoxyphenyl)-4-(trifluoromethyl)pyridine: A mixture of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (500 mg), 4-methoxyphenylboronic acid (292 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (16 mg), and potassium carbonate (1.3 g) in 1,2-dimethoxyethane (50 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The 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-acetonitrile) to obtain 2-chloro-5-(4-methoxyphenyl)-4-(trifluoromethyl)pyridine (140 mg).

[0272] Step (2) Synthesis of 3,5-difluoro-2-(((5-(4-methoxyphenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step (1) is 2-chloro-5-(4-methoxyphenyl)-4-(trifluoromethyl)pyridine (160 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (140 mg), methanesulfonate (dicyclohexyl (3-(1-methyl A mixture of 1,4-dioxane (14 mL) containing thylethoxy)-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (51 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (30 mg), and cesium carbonate (363 mg) was stirred under a nitrogen atmosphere at 100°C for 2 hours. The filtrate was then filtered and concentrated under reduced pressure using a rotary evaporator. The resulting crude product (310 mg) was mixed with trifluoroacetic acid (12 mL) and stirred at room temperature for 1 hour. Subsequently, the reaction mixture was concentrated under reduced pressure using a rotary evaporator, and the resulting residue was purified by reverse-phase column chromatography (water-acetonitrile) to obtain 3,5-difluoro-2-(((5-(4-methoxyphenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol (31 mg).

[0273]

[0274] [Example 21] Synthesis of 3,5-difluoro-2-(((2'-methoxy-4-(trifluoromethyl)-[3,4'-bipyridine]-6-yl)oxy)methyl)pyridine-4-ol

[0275] Step (1) Synthesis of 6-chloro-2'-methoxy-4-(trifluoromethyl)-3,4'-bipyridine: A mixture of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (500 mg), (2-methoxypyridine-4-yl)boronic acid (294 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (16 mg), and potassium carbonate (1.3 g) in 1,2-dimethoxyethane (20 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The 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 column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 6-chloro-2'-methoxy-4-(trifluoromethyl)-3,4'-bipyridine (190 mg).

[0276] Step (2) Synthesis of 3,5-difluoro-2-(((2'-methoxy-4-(trifluoromethyl)-[3,4'-bipyridine]-6-yl)oxy)methyl)pyridine-4-ol The compounds obtained in Step (1) are 6-chloro-2'-methoxy-4-(trifluoromethyl)-3,4'-bipyridine (100 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (87 mg), methanesulfonate (dicyclohexyl (3-(1-methyl A mixture of 1,4-dioxane (10 mL) containing thylethoxy)-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (32 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (19 mg), and cesium carbonate (226 mg) was stirred under a nitrogen atmosphere at 100°C for 2 hours. The filtrate was then filtered and concentrated under reduced pressure using a rotary evaporator. The resulting crude product (320 mg) was mixed with trifluoroacetic acid (5 mL) and stirred at room temperature for 30 minutes. Subsequently, 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-(((2'-methoxy-4-(trifluoromethyl)-[3,4'-bipyridine]-6-yl)oxy)methyl)pyridine-4-ol (27 mg).

[0277]

[0278] [Example 22] Synthesis of 3,5-difluoro-2-(((6'-methoxy-4-(trifluoromethyl)-[3,3'-bipyridine]-6-yl)oxy)methyl)pyridine-4-ol

[0279] Step (1) Synthesis of 6-chloro-6'-methoxy-4-(trifluoromethyl)-3,3'-bipyridine: A mixture of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (500 mg), (6-methoxypyridine-3-yl)boronic acid (294 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (16 mg), and potassium carbonate (1.3 g) in 1,2-dimethoxyethane (50 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The 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 column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 6-chloro-6'-methoxy-4-(trifluoromethyl)-3,3'-bipyridine (210 mg).

[0280] Step (2) Synthesis of 3,5-difluoro-2-(((6'-methoxy-4-(trifluoromethyl)-[3,3'-bipyridine]-6-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step (1) is 6-chloro-6'-methoxy-4-(trifluoromethyl)-3,3'-bipyridine (172 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (150 mg), methanesulfonate (dicyclohexyl (3-(1- A mixture of methylethoxy)-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine)(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 (389 mg) in 1,4-dioxane (14 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting crude product (390 mg) was dissolved in trifluoroacetic acid (15 mL) and stirred at room temperature for 1 hour. Subsequently, 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-(((6'-methoxy-4-(trifluoromethyl)-[3,3'-bipyridine]-6-yl)oxy)methyl)pyridine-4-ol (37 mg).

[0281]

[0282] [Example 23] Synthesis of 3,5-difluoro-2-(((5-(2-fluorophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0283] 3,5-difluoro-2-(((5-(2-fluorophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol (38 mg) was obtained by the same method as in Example 14.

[0284] [Example 24] Synthesis of 2-(((5-(2-chlorophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0285] 2-(((5-(2-chlorophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (22 mg) was obtained using the same method as in Example 14.

[0286] [Example 25] Synthesis of 3,5-difluoro-2-(((4-(trifluoromethyl)-5-(2-(trifluoromethyl)pyrimidine-5-yl)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0287] 3,5-difluoro-2-(((4-(trifluoromethyl)-5-(2-(trifluoromethyl)pyrimidine-5-yl)pyridine-2-yl)oxy)methyl)pyridine-4-ol (52 mg) was obtained by the same method as in Example 14.

[0288] [Example 26] Synthesis of 3,5-difluoro-2-(((5-(2-methoxypyrimidine-5-yl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0289] Step (1) Synthesis of 5-(6-chloro-4-(trifluoromethyl)pyridine-3-yl)-2-methoxypyrimidine: A mixture of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (500 mg), 2-methoxypyrimidine-5-ylboronic acid (296 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (136 mg), and tripotassium phosphate (815 mg), along with 1,4-dioxane (12 mL) and water (3 mL), was stirred at 100°C under a nitrogen atmosphere for 2 hours. The reaction mixture was then filtered, and ethyl acetate was added to the resulting 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 chromatography (hexane-ethyl acetate) to obtain 5-(6-chloro-4-(trifluoromethyl)pyridine-3-yl)-2-methoxypyrimidine (320 mg).

[0290] Step (2) Synthesis of 3,5-difluoro-2-(((5-(2-methoxypyrimidine-5-yl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step (1) is 5-(6-chloro-4-(trifluoromethyl)pyridine-3-yl)-2-methoxypyrimidine (100 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (118 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) (54 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (31 mg), and cesium carbonate (382 mg) in 1,4-dioxane (14 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting crude product (250 mg) and a solution of trifluoroacetic acid (3 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, and the resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 3,5-difluoro-2-(((5-(2-methoxypyrimidine-5-yl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol (48 mg).

[0291]

[0292] [Example 27] Synthesis of 2-(((5-(2-bromophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0293] Step (1) Synthesis of 2-((3,5-difluoro-4-((4-(methoxyphenyl)methoxy)pyridine-2-yl)methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-4-(trifluoromethyl)pyridine 2-(((5-bromo-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (intermediate E) (300 mg), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaboran-2-yl)-1,3,2-dioxaboran (754 mg), potassium acetate (291 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (24 mg) The mixture of ,4-dioxane (10 mL) was stirred under a nitrogen atmosphere at 80°C for 2 hours. The filtrate was then filtered and concentrated under reduced pressure using a rotary evaporator. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 2-((3,5-difluoro-4-((4-(methoxyphenyl)methoxy)pyridine-2-yl)methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (280 mg).

[0294] Step (2) Synthesis of 2-(((5-(2-bromophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol The compound obtained in Step (1) is 2-((3,5-difluoro-4-((4-(methoxyphenyl)methoxy)pyridine-2-yl)methoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridine (280 mg), 1-bromo-2-iodobenzene (72 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (19 mg), sodium carbonate (81 mg), and 1,4-dioxane (6 mL) The mixture with water (2 mL) was stirred at 100°C under a nitrogen atmosphere for 1 hour. The filtrate was then filtered and concentrated under reduced pressure using a rotary evaporator. The crude product (500 mg) was mixed with trifluoroacetic acid (5 mL) and dichloromethane (50 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 residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) and high-performance liquid chromatography to obtain 2-(((5-(2-bromophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (11 mg).

[0295]

[0296] [Example 28] Synthesis of 2-(((5-(3,4-difluorophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0297] Step (1) Synthesis of 2-chloro-5-(3,4-difluorophenyl)-4-(trifluoromethyl)pyridine: A mixture of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine (500 mg), 3,4-difluorophenylboronic acid (303 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (16 mg), and potassium carbonate (1.3 g) in 1,2-dimethoxyethane (10 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. Then, water was added to the reaction mixture 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% ammonium bicarbonate) - acetonitrile) to obtain 2-chloro-5-(3,4-difluorophenyl)-4-(trifluoromethyl)pyridine (230 mg).

[0298] Step (2) Synthesis of 2-(((5-(3,4-difluorophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol The compound obtained in Step (1) is 2-chloro-5-(3,4-difluorophenyl)-4-(trifluoromethyl)pyridine (220 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (188 mg), methanesulfonate (dicyclohexyl (3-(1 A mixture of (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (69 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (40 mg), and cesium carbonate (488 mg) in 1,4-dioxane (10 mL) was stirred at 100°C under a nitrogen atmosphere for 16 hours. Water was then added to the reaction mixture, 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 crude product (260 mg) was mixed with trifluoroacetic acid (5 mL) and dichloromethane (5 mL) and stirred at room temperature for 1 hour. Subsequently, 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 2-(((5-(3,4-difluorophenyl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (11 mg).

[0299]

[0300] [Example 29] Synthesis of 2-(((4,6'-bis(trifluoromethyl)-[3,3'-bipyridine]-6-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0301] 2-(((4,6'-bis(trifluoromethyl)-[3,3'-bipyridine]-6-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (12 mg) was obtained using the same method as in Example 14.

[0302] [Example 30] Synthesis of 2-(((5-cyclopropyl-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0303] To a solution of 2-(((5-bromo-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (intermediate E) (100 mg) in 1,4-dioxane (1 mL) and water (0.2 mL), cyclopropylboronic acid (34 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (14 mg), and potassium carbonate (82 mg) were added, and the mixture was stirred at 80°C under an argon atmosphere for 2 hours. After that, water was added to the reaction mixture and washed with ethyl acetate. 2 M hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Hexane and ethyl acetate were added to the resulting residue, and the resulting solid was filtered off. The solid was then dried to obtain 2-(((5-cyclopropyl-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (3 mg).

[0304]

[0305] [Example 31] Synthesis of 2-(((6-cyclopropyl-5-(4-fluorophenyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0306] Step (1) Synthesis of 2,6-dichloro-3-(4-fluorophenyl)pyridine: A mixture of 3-bromo-2,6-dichloropyridine (500 mg), 4-fluorophenylboronic acid (308 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (180 mg), and sodium carbonate (701 mg) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The mixture was then filtered, and ethyl acetate was added to the resulting 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 chromatography (hexane-ethyl acetate) to obtain 2,6-dichloro-3-(4-fluorophenyl)pyridine (510 mg).

[0307] Step (2) Synthesis of 6-chloro-2-cyclopropyl-3-(4-fluorophenyl)pyridine: A mixture of 2,6-dichloro-3-(4-fluorophenyl)pyridine (2.0 g), cyclopropylboronic acid (781 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (337 mg), and potassium carbonate (2.9 g) in 1,4-dioxane (60 mL) was stirred at 100°C under a nitrogen atmosphere for 16 hours. The 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 6-chloro-2-cyclopropyl-3-(4-fluorophenyl)pyridine (170 mg).

[0308] Step (3) Synthesis of 2-(((6-cyclopropyl-5-(4-fluorophenyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol The compound obtained in step (2) is 6-chloro-2-cyclopropyl-3-(4-fluorophenyl)pyridine (170 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (172 mg), methanesulfonate (dicyclohexyl (3-(1-methyl eth A mixture of 1,4-dioxane (10 mL) containing (xy)-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'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (37 mg), and cesium carbonate (447 mg) was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting crude product (280 mg) was mixed with trifluoroacetic acid (5 mL) and stirred at room temperature for 1 hour. Subsequently, 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 2-(((6-cyclopropyl-5-(4-fluorophenyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (30 mg).

[0309]

[0310] [Example 32] Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-isopropyl-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0311] Step (1) Synthesis of 3-chloro-2-(trifluoromethyl)pyridine: A mixture of 2-bromo-3-chloropyridine (20 g), methyl-2,2-difluoro-2-(fluorosulfonyl) acetate (40 g), and copper iodide (40 g) in N,N-dimethylformamide (80 mL) was stirred at 110°C under a nitrogen atmosphere 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 resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 3-chloro-2-(trifluoromethyl)pyridine (13 g).

[0312] Step (2) Synthesis of 3-chloro-4-iodo-2-(trifluoromethyl)pyridine: To a solution of 3-chloro-2-(trifluoromethyl)pyridine (12 g), the compound obtained in step (1), in tetrahydrofuran (100 mL), 50 mL of 2 M lithium diisopropylamide tetrahydrofuran solution was added dropwise at -78°C under a nitrogen atmosphere and stirred for 30 minutes. Then, a solution of iodine (25 g) in tetrahydrofuran (50 mL) was added dropwise at -78°C and stirred for 2 hours. Subsequently, 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 resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 3-chloro-4-iodo-2-(trifluoromethyl)pyridine (14 g).

[0313] Step (3) Synthesis of 3-chloro-4-(prop-1-en-2-yl)-2-(trifluoromethyl)pyridine The compounds obtained in Step (2), 3-chloro-4-iodo-2-(trifluoromethyl)pyridine (500 mg), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (547 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (133 mg), and sodium carbonate (345 mg), were mixed with 1,4-dioxane (10 mL) and water (2 mL) and stirred at 80°C for 16 hours under a nitrogen atmosphere. 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 resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 3-chloro-4-(prop-1-en-2-yl)-2-(trifluoromethyl)pyridine (280 mg).

[0314] Step (4) Synthesis of 3-(4-fluorophenyl)-4-(prop-1-en-2-yl)-2-(trifluoromethyl)pyridine The compound obtained in step (3), 3-chloro-4-(prop-1-en-2-yl)-2-(trifluoromethyl)pyridine (640 mg), 4-fluorophenylboronic acid (404 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (204 mg), and tripotassium phosphate (1.2 g) were mixed with 1,4-dioxane (10 mL) and water (2 mL) and stirred at 100°C for 2 hours under a nitrogen atmosphere. 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 resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 3-(4-fluorophenyl)-4-(prop-1-en-2-yl)-2-(trifluoromethyl)pyridine (575 mg).

[0315] Step (5) Synthesis of 3-(4-fluorophenyl)-4-isopropyl-2-(trifluoromethyl)pyridine A mixture of 3-(4-fluorophenyl)-4-(prop-1-en-2-yl)-2-(trifluoromethyl)pyridine (2.1 g), the compound obtained in step (4), and platinum(IV) oxide (136 mg) in methanol (40 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere and pressure (5 atm). The 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 chromatography (hexane-ethyl acetate) to obtain 3-(4-fluorophenyl)-4-isopropyl-2-(trifluoromethyl)pyridine (2.1 g).

[0316] Step (6) Synthesizing 6-chloro-3-(4-fluorophenyl)-4-isopropyl-2-(trifluoromethyl)pyridine: To a solution of urea peroxide (996 mg) in dichloromethane (60 mL), the compound obtained in Step (5), 3-(4-fluorophenyl)-4-isopropyl-2-(trifluoromethyl)pyridine (500 mg) and trifluoroacetic anhydride (2.2 g) in dichloromethane (10 mL) were added at 0°C and stirred for 1 hour. The reaction mixture was then stopped with an aqueous sodium bicarbonate solution and 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. To a solution of the obtained crude product (500 mg) in N,N-dimethylformamide (10 mL), oxalyl chloride (0.28 mL) was added dropwise at 0°C and stirred at room temperature for 2 hours. Subsequently, the reaction mixture was stopped with methanol, water was added, 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 chromatography (hexane-ethyl acetate) to obtain 6-chloro-3-(4-fluorophenyl)-4-isopropyl-2-(trifluoromethyl)pyridine (275 mg).

[0317] Step (7) Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-isopropyl-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol The compound obtained in Step (6) is 6-chloro-3-(4-fluorophenyl)-4-isopropyl-2-(trifluoromethyl)pyridine (270 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (320 mg), methanesulfonate (dicyclohex A mixture of sil(3-(1-methylethoxy)-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (78 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (45 mg), and cesium carbonate (554 mg) in 1,4-dioxane (20 mL) was stirred at 100°C for 2 hours under a nitrogen atmosphere. The filtrate was then filtered and concentrated under reduced pressure using a rotary evaporator. The obtained residue was purified by reverse-phase column chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-isopropyl-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol (105 mg).

[0318]

[0319] [Example 33] Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-methoxy-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0320] Step (1) Synthesis of 3-chloro-4-methoxy-2-(trifluoromethyl)pyridine A mixture of 3-chloro-4-iodo-2-(trifluoromethyl)pyridine (700 mg), the compound obtained in Step (2) of Example 32, and sodium methoxide (271 mg) in methanol (12 mL) was stirred at 70°C for 2 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 resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 3-chloro-4-methoxy-2-(trifluoromethyl)pyridine (450 mg).

[0321] Step (2) Synthesis of 3-(4-fluorophenyl)-4-methoxy-2-(trifluoromethyl)pyridine: The compound obtained in Step (1), 3-chloro-4-methoxy-2-(trifluoromethyl)pyridine (550 mg), 4-fluorophenylboronic acid (364 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (184 mg), and tripotassium phosphate (1.1 g), were mixed with 1,4-dioxane (8 mL) and water (2 mL) and stirred at 100°C under a nitrogen atmosphere for 2 hours. The mixture was then filtered, and ethyl acetate was added to the resulting 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 chromatography (hexane-ethyl acetate) to obtain 3-(4-fluorophenyl)-4-methoxy-2-(trifluoromethyl)pyridine (540 mg).

[0322] Step (3) Synthesis of 6-chloro-3-(4-fluorophenyl)-4-methoxy-2-(trifluoromethyl)pyridine: In a solution of 3-(4-fluorophenyl)-4-methoxy-2-(trifluoromethyl)pyridine (400 mg), the compound obtained in step (2), and trifluoroacetic anhydride (1.2 g), in dichloromethane (10 mL), urea peroxide (694 mg) was added at 0°C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then stopped with an aqueous sodium bicarbonate solution and 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. In a solution of the obtained crude product (400 mg) in N,N-dimethylformamide (5 mL), oxalyl chloride (0.29 mL) was added dropwise at 0°C and the mixture was stirred for 30 minutes. The reaction mixture was then stopped with methanol 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-(4-fluorophenyl)-4-methoxy-2-(trifluoromethyl)pyridine (100 mg).

[0323] Step (4) Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-methoxy-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol The compound obtained in step (3) is 6-chloro-3-(4-fluorophenyl)-4-methoxy-2-(trifluoromethyl)pyridine (100 mg), (4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (intermediate B) (66 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) (30 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (18 mg), and cesium carbonate (213 mg) in 1,4-dioxane (5 mL) was stirred at 100°C for 2 hours under a nitrogen atmosphere. The filtrate was then filtered and concentrated under reduced pressure using a rotary evaporator. The obtained residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-methoxy-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol (27 mg).

[0324]

[0325] [Example 34] Synthesis of 2-(((4-cyclopropyl-5-(4-fluorophenyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0326] Step (1) Synthesis of 5-chloro-4-cyclopropyl-2-methoxypyridine: A mixture of 5-chloro-4-iodo-2-methoxypyridine (2.0 g), cyclopropylboronic acid (1.9 g), palladium(II) acetate (80 mg), tricyclohexylphosphine (210 mg), and tripotassium phosphate (4.7 g) in toluene (18 mL) and water (2 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The 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 chromatography (hexane-ethyl acetate) to obtain 5-chloro-4-cyclopropyl-2-methoxypyridine (1.0 g).

[0327] Step (2) Synthesis of 4-Cyclopropyl-5-(4-Fluorophenyl)-2-methoxypyridine: The compound obtained in Step (1), 5-chloro-4-cyclopropyl-2-methoxypyridine (880 mg), 4-fluorophenylboronic acid (670 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (339 mg), and tripotassium phosphate (2.0 g), were mixed with 1,4-dioxane (32 mL) and water (8 mL) and stirred at 100°C under a nitrogen atmosphere for 2 hours. The 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 chromatography (hexane-ethyl acetate) to obtain 4-cyclopropyl-5-(4-fluorophenyl)-2-methoxypyridine (1.0 g).

[0328] Step (3) Synthesis of 2-chloro-4-cyclopropyl-5-(4-fluorophenyl)pyridine: A mixture of 4-cyclopropyl-5-(4-fluorophenyl)-2-methoxypyridine (880 mg), p-toluenesulfonic acid (3.7 g), and lithium chloride (920 mg) in N,N-dimethylformamide (10 mL) was stirred at 100°C for 1 hour. 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. A solution of the obtained crude product (300 mg) in phosphorus oxychloride (5 mL) was stirred at 100°C for 16 hours. Ethyl acetate was added to the reaction mixture, the organic layer was washed with aqueous sodium bicarbonate solution and 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 chromatography (hexane-ethyl acetate) to obtain 2-chloro-4-cyclopropyl-5-(4-fluorophenyl)pyridine (250 mg).

[0329] Step (4) Synthesis of 2-(((4-cyclopropyl-5-(4-fluorophenyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol: 2-chloro-4-cyclopropyl-5-(4-fluorophenyl)pyridine (100 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (114 mg), methanesulfonate (dicyclohexyl (3-(1-methyl A mixture of 1,4-dioxane (10 mL) containing thylethoxy)-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (37 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (22 mg), and cesium carbonate (263 mg) was stirred under a nitrogen atmosphere at 140°C for 2 hours. The filtrate was then filtered and concentrated under reduced pressure using a rotary evaporator. The resulting crude product (320 mg) was mixed with a 4 M hydrogen chloride aqueous solution and a solution of 1,4-dioxane (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 column chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 2-(((4-cyclopropyl-5-(4-fluorophenyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (11 mg).

[0330]

[0331] [Example 35] Synthesis of 2-(((4-cyclopropyl-5-(4-fluorophenyl)-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0332] Step (1) Synthesis of 3-chloro-4-cyclopropyl-2-(trifluoromethyl)pyridine The compound obtained in Step (2) of Example 32, 3-chloro-4-iodo-2-(trifluoromethyl)pyridine (4.0 g), cyclopropylboronic acid (3.4 g), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (1.1 g), and sodium carbonate (2.8 g), were mixed with 1,4-dioxane (160 mL) and water (40 mL) and stirred at 80°C under a nitrogen atmosphere 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 resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 3-chloro-4-cyclopropyl-2-(trifluoromethyl)pyridine (440 mg).

[0333] Step (2) Synthesis of 4-Cyclopropyl-3-(4-Fluorophenyl)-2-(Trifluoromethyl)pyridine: The compound obtained in Step (1), 3-chloro-4-cyclopropyl-2-(trifluoromethyl)pyridine (1.9 g), 4-fluorophenylboronic acid (1.2 g), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (610 mg), and tripotassium phosphate (3.6 g), were mixed with 1,4-dioxane (40 mL) and water (10 mL) and stirred at 100°C under a nitrogen atmosphere for 2 hours. The 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 chromatography (hexane-ethyl acetate) to obtain 4-cyclopropyl-3-(4-fluorophenyl)-2-(trifluoromethyl)pyridine (2.2 g).

[0334] Step (3) Synthesis of 6-chloro-4-cyclopropyl-3-(4-fluorophenyl)-2-(trifluoromethyl)pyridine: To a solution of urea peroxide (1.2 g) in dichloromethane (100 mL), the compound obtained in Step (2), 4-cyclopropyl-3-(4-fluorophenyl)-2-(trifluoromethyl)pyridine (700 mg) and trifluoroacetic anhydride (3.1 g) in dichloromethane (20 mL) were added dropwise at 0°C and stirred for 30 minutes. The reaction mixture was then stopped with an aqueous sodium bicarbonate solution and 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 (800 mg) was stirred in a solution of phosphorus oxychloride (8 mL) at 80°C for 2 hours. The reaction mixture was then concentrated under reduced pressure using a rotary evaporator. The obtained residue was purified by reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) and high-performance liquid chromatography to obtain 6-chloro-4-cyclopropyl-3-(4-fluorophenyl)-2-(trifluoromethyl)pyridine (340 mg).

[0335] Step (4) Synthesis of 2-(((4-cyclopropyl-5-(4-fluorophenyl)-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol The compound obtained in step (3) is 6-chloro-4-cyclopropyl-3-(4-fluorophenyl)-2-(trifluoromethyl)pyridine (150 mg), 4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (119 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) (44 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (25 mg), and cesium carbonate (310 mg) in 1,4-dioxane (15 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. The mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting crude product (360 mg) was dissolved in dichloromethane (8 mL), to which trifluoroacetic acid (8 mL) was added, and 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 2-(((4-cyclopropyl-5-(4-fluorophenyl)-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (23 mg).

[0336]

[0337] [Example 36] Synthesis of 2-(((4',5-bis(trifluoromethyl)-[2,3'-bipyridine]-6'-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0338] 2-(((4',5-bis(trifluoromethyl)-[2,3'-bipyridine]-6'-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (11 mg) was obtained using the same method as in Example 14.

[0339] [Example 37] Synthesis of 2-(((4-(cyclopropylmethoxy)-5-(4-fluorophenyl)-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0340] Step (1) Synthesis of 3-chloro-4-(cyclopropylmethoxy)-2-(trifluoromethyl)pyridine Sodium hydride (60%, 1.3 g) was slowly added at 0°C to a solution of cyclopropylmethanol (2.4 g) in tetrahydrofuran (50 mL) and stirred for 30 minutes. 3-chloro-4-iodo-2-(trifluoromethyl)pyridine (5.0 g), the compound obtained in Step (2) of Example 32, was added to this reaction mixture at 0°C and stirred at room temperature for 16 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. The resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 3-chloro-4-(cyclopropylmethoxy)-2-(trifluoromethyl)pyridine (2.0 g).

[0341] Step (2) Synthesis of 4-(cyclopropylmethoxy)-3-(4-fluorophenyl)-2-(trifluoromethyl)pyridine The compound obtained in Step (1), 3-chloro-4-(cyclopropylmethoxy)-2-(trifluoromethyl)pyridine (2.0 g), 4-fluorophenylboronic acid (1.1 g), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (550 mg), and tripotassium phosphate (3.3 g), were mixed with 1,4-dioxane (20 mL) and water (5 mL) and stirred at 100°C under a nitrogen atmosphere for 2 hours. Water was added to the reaction mixture 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 chromatography (hexane-ethyl acetate) to obtain 4-(cyclopropylmethoxy)-3-(4-fluorophenyl)-2-(trifluoromethyl)pyridine (2.2 g).

[0342] Step (3) Synthesis of 6-chloro-4-(cyclopropylmethoxy)-3-(4-fluorophenyl)-2-(trifluoromethyl)pyridine: To a solution of urea peroxide (1.2 g) in dichloromethane (20 mL), the compound obtained in Step (2), 4-(cyclopropylmethoxy)-3-(4-fluorophenyl)-2-(trifluoromethyl)pyridine (800 mg) and trifluoroacetic anhydride (2.2 g) in dichloromethane (20 mL) was added dropwise at 0°C and stirred at room temperature for 30 minutes. The reaction mixture was then stopped with an aqueous sodium bicarbonate 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 (1.3 g) and a solution of oxalyl chloride (1.0 g) in N,N-dimethylformamide (20 mL) were stirred at room temperature for 1 hour. Subsequently, the reaction mixture was stopped with cold 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 chromatography (hexane-ethyl acetate) to obtain 6-chloro-4-(cyclopropylmethoxy)-3-(4-fluorophenyl)-2-(trifluoromethyl)pyridine (410 mg).

[0343] Step (4) Synthesis of 2-(((4-(cyclopropylmethoxy)-5-(4-fluorophenyl)-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol The compound obtained in step (3) is 6-chloro-4-(cyclopropylmethoxy)-3-(4-fluorophenyl)-2-(trifluoromethyl)pyridine (220 mg), 4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (160 mg), methanesulfonate (disic A mixture of lohexyl(3-(1-methylethoxy)-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (58 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (34 mg), and cesium carbonate (415 mg) in 1,4-dioxane (10 mL) was stirred at 100°C under a nitrogen atmosphere for 2 hours. Water was then added to the reaction mixture, 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 crude product (450 mg) obtained was mixed with dichloromethane (5 mL) and 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 column chromatography (water (containing 0.05% formic acid)-acetonitrile) and high-performance liquid chromatography to obtain 2-(((4-(cyclopropylmethoxy)-5-(4-fluorophenyl)-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (40 mg).

[0344]

[0345] [Example 38] Synthesis of 2-(((4,6-dimethyl-5-(thiazole-4-yl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0346]

[0347] A mixture of 6-((4-benzyloxy)-3,5-difluoropyridine-2-yl)methoxy-3-bromo-2,4-dimethylpyridine (intermediate G) (150 mg), 4-(tributylstanyl)-1,3-thiazole (193 mg), and tetrakis(triphenylphosphine)palladium (0) (20 mg) in toluene (5 mL) was stirred under a nitrogen atmosphere at 100°C for 2 hours. The 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) and a solution of trifluoroacetic acid (4 mL) in dichloromethane (8 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 reverse-phase column chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 2-(((4,6-dimethyl-5-(thiazole-4-yl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (41 mg).

[0348]

[0349] [Example 39] Synthesis of 2-(((4,6-dimethyl-5-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0350] A mixture of 6-((4-benzyloxy)-3,5-difluoropyridine-2-yl)methoxy-3-bromo-2,4-dimethylpyridine (intermediate G) (170 mg), 1-methylpyrazole-4-ylboronic acid (49 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (28 mg), and tripotassium phosphate (166 mg) in 1,4-dioxane (8 mL) and water (2 mL) was stirred at 80°C under a nitrogen atmosphere for 2 hours. Water was added to the reaction mixture 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 (320 mg) was mixed with trifluoroacetic acid (5 mL) and dichloromethane (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 column chromatography (water (containing 0.05% formic acid)-acetonitrile) and high-performance liquid chromatography to obtain 2-(((4,6-dimethyl-5-(1-methyl-1H-pyrazole-4-yl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (69 mg).

[0351]

[0352] [Example 40] Synthesis of 2-(((4,6-dimethyl-5-(1-methyl-1H-pyrazole-3-yl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0353] A mixture of 6-((4-benzyloxy)-3,5-difluoropyridine-2-yl)methoxy-3-bromo-2,4-dimethylpyridine (intermediate G) (200 mg), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (96 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (33 mg), and tripotassium phosphate (195 mg) in 1,4-dioxane (10 mL) and water (2.5 mL) was stirred under a nitrogen atmosphere at 80°C for 30 minutes. The mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The resulting crude product (370 mg) 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 column chromatography (water (containing 0.05% formic acid)-acetonitrile) and high-performance liquid chromatography to obtain 2-(((4,6-dimethyl-5-(1-methyl-1H-pyrazole-3-yl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (60 mg).

[0354]

[0355] [Example 41] Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)pyridine-4-ol

[0356] 5-bromo-2-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-4,6-dimethylpyrimidine (intermediate D) (90 mg) was mixed with 1,4-dioxane (1 mL) and water (0.5 mL). 4-fluorophenylboronic acid (81 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (27 mg), and potassium carbonate (133 mg) were added, and the mixture was stirred at 100°C under an argon atmosphere for 2 hours. Water was then added to the reaction mixture, and it was washed with ethyl acetate. 2 M hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Hexane and ethyl acetate were added to the obtained residue, and the resulting solid was filtered off. The solid was then dried to obtain 3,5-difluoro-2-(((5-(4-fluorophenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)pyridine-4-ol (11 mg).

[0357]

[0358] [Example 42] Synthesis of 3,5-difluoro-2-(((5-(3-fluorophenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)pyridine-4-ol

[0359] 5-bromo-2-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-4,6-dimethylpyrimidine (intermediate D) (100 mg) was mixed with 1,4-dioxane (1.5 mL) and water (0.5 mL). To this mixture, 3-fluorophenylboronic acid (150 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (30 mg), and potassium carbonate (228 mg) were added, and the mixture was stirred at 80°C under an argon atmosphere for 2 hours. After that, water was added to the reaction mixture, and it was washed with ethyl acetate. 2 M hydrochloric acid was added to the aqueous layer, and it was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Hexane and ethyl acetate were added to the obtained residue, and the resulting solid was filtered off. The solid was then dried to obtain 3,5-difluoro-2-(((5-(3-fluorophenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)pyridine-4-ol (27 mg).

[0360]

[0361] [Example 43] Synthesis of 3,5-difluoro-2-(((5-(2-fluorophenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)pyridine-4-ol

[0362] To a mixture of 1,4-dioxane (1.5 mL) and water (0.5 mL) containing 100 mg of 5-bromo-2-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-4,6-dimethylpyrimidine (intermediate D), 2-fluorophenylboronic acid (150 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (30 mg), and potassium carbonate (228 mg) were added, and the mixture was stirred at 80°C under an argon atmosphere for 2 hours. After that, water was added to the reaction mixture and washed with ethyl acetate. 2 M hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Hexane and ethyl acetate were added to the resulting residue, and the resulting solid was filtered off. The solid was then dried to obtain 3,5-difluoro-2-(((5-(2-fluorophenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)pyridine-4-ol (25 mg).

[0363]

[0364] [Example 44] Synthesis of 3,5-difluoro-2-(((5-(2-methoxyphenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)pyridine-4-ol

[0365] To a mixture of 5-bromo-2-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-4,6-dimethylpyrimidine (intermediate D) (100 mg) with 1,4-dioxane (1.5 mL) and water (0.5 mL), 2-methoxyphenylboronic acid (163 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (30 mg), and potassium carbonate (228 mg) were added, and the mixture was stirred at 80°C under an argon atmosphere for 2 hours. After that, water was added to the reaction mixture and washed with ethyl acetate. 2 M hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Hexane and ethyl acetate were added to the obtained residue, and the resulting solid was filtered off. The solid was then dried to obtain 3,5-difluoro-2-(((5-(2-methoxyphenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)pyridine-4-ol (46 mg).

[0366]

[0367] [Example 45] Synthesis of 3,5-difluoro-2-(((5-(3-methoxyphenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)pyridine-4-ol

[0368] 5-bromo-2-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-4,6-dimethylpyrimidine (intermediate D) (100 mg) was mixed with 1,4-dioxane (1.5 mL) and water (0.5 mL). To this mixture, 3-methoxyphenylboronic acid (163 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (30 mg), and potassium carbonate (228 mg) were added, and the mixture was stirred at 80°C under an argon atmosphere for 2 hours. After that, water was added to the reaction mixture, and it was washed with ethyl acetate. 2 M hydrochloric acid was added to the aqueous layer, and it was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Hexane and ethyl acetate were added to the resulting residue, and the obtained solid was filtered off. The solid was then dried to obtain 3,5-difluoro-2-(((5-(3-methoxyphenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)pyridine-4-ol (59 mg).

[0369]

[0370] [Example 46] Synthesis of 3,5-difluoro-2-(((5-(4-methoxyphenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)pyridine-4-ol

[0371] 5-bromo-2-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-4,6-dimethylpyrimidine (intermediate D) (100 mg) was mixed with 1,4-dioxane (1.5 mL) and water (0.5 mL). To this mixture, 4-methoxyphenylboronic acid (163 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (30 mg), and potassium carbonate (228 mg) were added, and the mixture was stirred at 80°C under an argon atmosphere for 2 hours. After that, water was added to the reaction mixture, and it was washed with ethyl acetate. 2 M hydrochloric acid was added to the aqueous layer, and it was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Hexane and ethyl acetate were added to the resulting residue, and the obtained solid was filtered off. The solid was then dried to obtain 3,5-difluoro-2-(((5-(4-methoxyphenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)pyridine-4-ol (39 mg).

[0372]

[0373] [Example 47] Synthesis of 2-(((5-cyclohexyl-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0374] Step (1) Synthesis of 5-(cyclohexa-1-en-1-yl)-2-((3,5-difluoro-4-((4-methoxyphenyl)methoxy)pyridine-2-ylmethoxy)-4-(trifluoromethyl)pyridine 2-(((5-bromo-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxyphenyl)methoxy)pyridine (intermediate E) (300 mg), cyclohexa-1-en-1-ylboronic acid (112 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (49 mg), sodium carbonate (189 mg) mixed with 1,4-dioxane (10 mL) and water (1 mL) is prepared at 100°C under a nitrogen atmosphere. The mixture was stirred for 1 hour. 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 resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 5-(cyclohexa-1-en-1-yl)-2-((3,5-difluoro-4-((4-methoxyphenyl)methoxy)pyridine-2-ylmethoxy)-4-(trifluoromethyl)pyridine (160 mg).

[0375] Step (2) Synthesis of 2-(((5-cyclohexyl-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol The compound obtained in Step (1) is 5-(cyclohexa-1-en-1-yl)-2-((3,5-difluoro-4-((4-methoxyphenyl)methoxy)pyridine-2-ylmethoxy)-4-(trifluoromethyl)pyridine (14 mg), palladium carbon (14 mg), methanol ( The 15 mL mixture was stirred under a hydrogen atmosphere and pressure (20 atm) at room temperature for 72 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% formic acid) - acetonitrile) to obtain 2-(((5-cyclohexyl-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (24 mg).

[0376]

[0377] [Example 48] Synthesis of 2-(((4-((cyclohexylmethyl)(methyl)amino)-5-(4-fluorophenyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0378] Step (1) Synthesis of 2-chloro-5-iodopyridine-4-amine: To a solution of 2-chloro-5-iodopyridine-4-amine (10 g), a known substance, in N,N-dimethylformamide (200 mL), sodium hydride (60%, 1.6 g) was slowly added at 0°C and stirred for 30 minutes. Iodomethane (5.6 g) was added dropwise to this reaction mixture at 0°C and stirred at room temperature for 30 minutes. 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 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 2-chloro-5-iodo-N-methylpyridine-4-amine (4.6 g).

[0379] Step (2) Synthesis of 2-chloro-5-(4-fluorophenyl)-N-methylpyridine-4-amine The compound obtained in Step (1), 2-chloro-5-iodo-N-methylpyridine-4-amine (4.5 g), 4-fluorophenylboronic acid (2.3 g), 1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (1.4 g), and cesium carbonate (11.0 g) were mixed with 1,4-dioxane (90 mL) and water (9 mL) and stirred at 100°C under a nitrogen atmosphere for 1 hour. 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 chromatography (hexane-ethyl acetate) to obtain 2-chloro-5-(4-fluorophenyl)-N-methylpyridine-4-amine (3.4 g).

[0380] Step (3) Synthesis of 2-chloro-N-(cyclohexylmethyl)-5-(4-fluorophenyl)-N-methylpyridine-4-amine: To a solution of 2-chloro-5-(4-fluorophenyl)-N-methylpyridine-4-amine (300 mg), the compound obtained in Step (2), in N,N-dimethylformamide (5 mL), sodium hydride (60%, 101 mg) was slowly added at 0°C and the mixture was stirred for 30 minutes. (Bromomethyl)cyclohexane (516 mg) was added dropwise to this reaction mixture at 0°C and the mixture was stirred at room temperature for 1 hour. 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 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 2-chloro-N-(cyclohexylmethyl)-5-(4-fluorophenyl)-N-methylpyridine-4-amine (400 mg).

[0381] Step (4) Synthesis of 2-(((4-((cyclohexylmethyl)(methyl)amino)-5-(4-fluorophenyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol: 2-chloro-N-(cyclohexylmethyl)-5-(4-fluorophenyl)-N-methylpyridine-4-amine (150 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (254 mg), methanesulfonate A mixture of (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) (124 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (48 mg), and cesium carbonate (294 mg) in toluene (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. Trifluoroacetic acid (4 mL) was added to a solution of the resulting crude product (769 mg) in dichloromethane (4 mL), and 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 reverse-phase column chromatography (water (containing 0.05% formic acid)-acetonitrile) and high-performance liquid chromatography to obtain 2-(((4-((cyclohexylmethyl)(methyl)amino)-5-(4-fluorophenyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (21 mg).

[0382]

[0383] [Example 49] Synthesis of 2-(((4-(((4,4-difluorocyclohexyl)methyl)(methyl)amino)-5-(4-fluorophenyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0384] Step (1) Synthesis of 2-chloro-N-((4,4-difluorocyclohexyl)methyl)-5-(4-fluorophenyl)-N-methylpyridine-4-amine The compound obtained in Step (2) of Example 48, 2-chloro-5-(4-fluorophenyl)-N-methylpyridine-4-amine (300 mg), was dissolved in N,N-dimethylformamide (15 mL) and sodium hydride (60%, 76 mg) was slowly added at 0°C and stirred for 30 minutes. 4-(bromomethyl)-1,1-difluorocyclohexane (810 mg) was added to this reaction mixture and stirred at room temperature for 2 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 silica gel chromatography (hexane-ethyl acetate) to obtain 2-chloro-N-((4,4-difluorocyclohexyl)methyl)-5-(4-fluorophenyl)-N-methylpyridine-4-amine (250 mg).

[0385] Step (2) Synthesis of 2-(((4-(((4,4-difluorocyclohexyl)methyl)(methyl)amino)-5-(4-fluorophenyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol Compound obtained in Step (1) is 2-chloro-N-((4,4-difluorocyclohexyl)methyl)-5-(4-fluorophenyl)-N-methylpyridine-4-amine (200 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (305 A mixture of palladium(II) (2'-methylamino-1,1'-biphenyl-2-yl) (50 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (29 mg), and cesium carbonate (353 mg) in toluene (20 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 (400 mg) was mixed in 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% formic acid)-acetonitrile) and high-performance liquid chromatography to obtain 2-(((4-(((4,4-difluorocyclohexyl)methyl)(methyl)amino)-5-(4-fluorophenyl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (53 mg).

[0386]

[0387] [Example 50] Synthesis of N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-(4-fluorophenyl)pyridine-4-yl)-N-methyltetrahydro-2H-pyran-4-carboxamide

[0388] Step (1) Synthesis of N-(2-chloro-5-(4-fluorophenyl)pyridine-4-yl)-N-methyltetrahydro-2H-pyran-4-carboxamide A pyridine solution (7 mL) of 2-chloro-5-(4-fluorophenyl)-N-methylpyridine-4-amine (300 mg), tetrahydro-2H-pyran-4-carbonyl chloride (565 mg), and 4-dimethylaminopyridine (232 mg), which was obtained in Step 2 of Example 48, was stirred at 120°C for 6 hours. Ethyl acetate was added to this reaction mixture, and 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 reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain N-(2-chloro-5-(4-fluorophenyl)pyridine-4-yl)-N-methyltetrahydro-2H-pyran-4-carboxamide (320 mg).

[0389] Step (2) Synthesis of N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-(4-fluorophenyl)pyridine-4-yl)-N-methyltetrahydro-2H-pyran-4-carboxamide, which is the compound obtained in Step (1): N-(2-chloro-5-(4-fluorophenyl)pyridine-4-yl)-N-methyltetrahydro-2H-pyran-4-carboxamide (50 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (40 mg), (tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (15 mg), (2R)-1-((1R)-1-(bis(1,1-dimethylethyl)phosphino)ethyl)-2-(dicyclohexylphosphino)ferrocene (8 mg) A mixture of cesium carbonate (93 mg) and 1,4-dioxane (2 mL) was stirred under a nitrogen atmosphere at 140°C for 1 hour. The reaction mixture was then filtered, and the resulting filtrate was concentrated under reduced pressure using a rotary evaporator. The crude product (480 mg) was mixed with trifluoroacetic acid (3 mL) and dichloromethane (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 N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-(4-fluorophenyl)pyridine-4-yl)-N-methyltetrahydro-2H-pyran-4-carboxamide (42 mg).

[0390]

[0391] [Example 51] Synthesis of 2-(((4,6-dimethyl-5-(thiazole-2-yl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0392] A mixture of 6-((4-benzyloxy)-3,5-difluoropyridine-2-yl)methoxy-3-bromo-2,4-dimethylpyridine (intermediate G) (100 mg), 2-(tributylstanyl)-1,3-thiazole (516 mg), and tetrakis(triphenylphosphine)palladium (0) (13 mg) in toluene (10 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 (460 mg) was mixed in trifluoroacetic acid (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 column chromatography (water (containing 0.05% formic acid)-acetonitrile) and high-performance liquid chromatography to obtain 2-(((4,6-dimethyl-5-(thiazole-2-yl)pyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (23 mg).

[0393]

[0394] [Example 52] Synthesis of 2-(((5-(2,6-difluorophenyl)-4,6-dimethylpyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0395] A mixture of 2-(((5-bromo-4,6-dimethylpyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine (intermediate F) (260 mg), 2,6-difluorophenylboronic acid (132 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (40 mg), and tripotassium phosphate (237 mg) in N,N-dimethylformamide (1 mL) was stirred at 100°C under a nitrogen atmosphere 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 (300 mg) and a solution of trifluoroacetic acid (4 mL) in dichloromethane (8 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 reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) high-performance liquid chromatography to obtain 2-(((5-(2,6-difluorophenyl)-4,6-dimethylpyridine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (20 mg).

[0396]

[0397] [Example 53] Synthesis of 3-(6-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-2,4-dimethylpyridine-3-yl)benzonitrile

[0398] 3-(6-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-2,4-dimethylpyridine-3-yl)benzonitrile (56 mg) was obtained using the same method as in Example 52.

[0399] [Example 54] Synthesis of 2-(((5-(2,4-difluorophenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0400] 5-bromo-2-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-4,6-dimethylpyrimidine (intermediate D) (100 mg) was mixed with 1,4-dioxane (2 mL) and water (0.5 mL). 2,4-difluorophenylboronic acid (169 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (30 mg), and potassium carbonate (228 mg) were added, and the mixture was stirred at 80°C for 2 hours. Water was then added to the reaction mixture, and it was washed with ethyl acetate. 2 M hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Hexane and ethyl acetate were added to the obtained residue, and the resulting solid was filtered off. The solid was then dried to obtain 2-(((5-(2,4-difluorophenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (39 mg).

[0401]

[0402] [Example 55] Synthesis of 2-(((4,6-dimethyl-5-(o-tolyl)pyrimidine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0403] To a mixture of 5-bromo-2-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-4,6-dimethylpyrimidine (intermediate D) (100 mg) with 1,4-dioxane (2 mL) and water (0.5 mL), o-trilboronic acid (146 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (30 mg), and potassium carbonate (228 mg) were added, and the mixture was stirred at 80°C under an argon atmosphere for 2 hours. After that, water was added to the reaction mixture and washed with ethyl acetate. 2 M hydrochloric acid was added to the aqueous layer, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Hexane and ethyl acetate were added to the resulting residue, and the resulting solid was filtered off. The solid was then dried to obtain 2-(((4,6-dimethyl-5-(o-tolyl)pyrimidine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (39 mg).

[0404]

[0405] [Example 56] Synthesis of 3,5-difluoro-2-(((5-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0406] Step (1) Synthesis of 2-(3,5-difluoro-4-((4-methoxyphenyl)methoxy)pyridine-2-yl-methoxy)-5-(3,6-dihydro-2H-pyran-4-yl)-4-(trifluoromethyl)pyridine A mixture of 1,4-dioxane (10 mL) and water (1 mL) containing 2-(((5-bromo-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)-3,5-difluoro-4-((4-methoxyphenyl)methoxy)pyridine (intermediate E) (300 mg), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (125 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (49 mg), and sodium carbonate (189 mg) was stirred at 100°C for 2 hours under a nitrogen atmosphere. 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 chromatography (hexane-ethyl acetate) to obtain 2-(3,5-difluoro-4-((4-methoxyphenyl)methoxy)pyridine-2-yl-methoxy)-5-(3,6-dihydro-2H-pyran-4-yl)-4-(trifluoromethyl)pyridine (220 mg).

[0407] Step (2) Synthesis of 3,5-difluoro-2-(((5-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol: A mixture of 2-(3,5-difluoro-4-((4-methoxyphenyl)methoxy)pyridine-2-yl-methoxy)-5-(3,6-dihydro-2H-pyran-4-yl)-4-(trifluoromethyl)pyridine (220 mg), palladium carbon (22 mg), and methanol (20 mL) was stirred under a hydrogen atmosphere (5 atm) at room temperature for 16 hours. 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 achiral SFC and high-performance liquid chromatography to obtain 3,5-difluoro-2-(((5-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol (24 mg).

[0408]

[0409] [Example 57] Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-methoxy-6-(trifluoromethyl)pyrimidine-2-yl)oxy)methyl)pyridine-4-ol

[0410] Step (1) Synthesis of 2-chloro-4-methoxy-6-(trifluoromethyl)pyrimidine: Sodium methoxide (1.0 g) was added to a methanol (100 mL) solution of 2,4-dichloro-6-(trifluoromethyl)pyrimidine (5.0 g), a known substance, at 0°C and stirred for 30 minutes. 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 resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 2-chloro-4-methoxy-6-(trifluoromethyl)pyrimidine (3.3 g).

[0411] Step (2) Synthesis of 2-chloro-5-iodo-4-methoxy-6-(trifluoromethyl)pyrimidine A solution of 2-chloro-4-methoxy-6-(trifluoromethyl)pyrimidine (500 mg), the compound obtained in Step (1), in tetrahydrofuran (10 mL) was added dropwise with 2 M lithium diisopropylamide tetrahydrofuran solution (2.4 mL) at -78°C and stirred for 30 minutes. Then, a solution of iodine (716 mg) in tetrahydrofuran (10 mL) was added dropwise to the reaction mixture at -78°C and stirred 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 reverse-phase column chromatography (water-acetonitrile) to obtain 2-chloro-5-iodo-4-methoxy-6-(trifluoromethyl)pyrimidine (430 mg).

[0412] Step (3) Synthesis of 2-chloro-5-(4-fluorophenyl)-4-methoxy-6-(trifluoromethyl)pyrimidine The compound obtained in Step (2), 2-chloro-5-iodo-4-methoxy-6-(trifluoromethyl)pyrimidine (380 mg), 4-fluorophenylboronic acid (141 mg), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct (183 mg), and sodium carbonate (357 mg) were mixed with 1,4-dioxane (8 mL) and water (2 mL) and stirred at 60°C for 1 hour under a nitrogen atmosphere. 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 obtained residue was purified by reverse-phase column chromatography (water-acetonitrile) to obtain 2-chloro-5-(4-fluorophenyl)-4-methoxy-6-(trifluoromethyl)pyrimidine (90 mg).

[0413] Step (4) Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-methoxy-6-(trifluoromethyl)pyrimidine-2-yl)oxy)methyl)pyridine-4-ol A mixture of 2-chloro-5-(4-fluorophenyl)-4-methoxy-6-(trifluoromethyl)pyrimidine (80 mg), 4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (52 mg), and t-butoxypotassium (35 mg) in 1,4-dioxane (6 mL), obtained in Step (3), was stirred at room temperature for 1 hour. 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 resulting crude product (150 mg) was mixed with dichloromethane (3 mL) and trifluoroacetic acid (3 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 high-performance liquid chromatography to obtain 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-methoxy-6-(trifluoromethyl)pyrimidine-2-yl)oxy)methyl)pyridine-4-ol (41 mg).

[0414]

[0415] [Example 58] Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0416] Step (1) Synthesis of 2-chloro-5-(4-fluorophenyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridine-4-amine Step (2) of Example 48: 2-chloro-5-(4-fluorophenyl)-N-methylpyridine-4-amine (300 mg), the compound obtained in Step (2) of Example 48, was dissolved in N,N-dimethylformamide (5 mL) and sodium hydride (60%, 76 mg) was slowly added at 0°C and stirred for 30 minutes. 4-(bromomethyl)tetrahydro-2H-pyran (681 mg) was added to this reaction mixture and stirred at room temperature 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 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 chromatography (hexane-ethyl acetate) to obtain 2-chloro-5-(4-fluorophenyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridine-4-amine (420 mg).

[0417] Step (2) Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridine-2-yl)oxy)methyl)pyridine-4-ol: The compound obtained in Step (1) is 2-chloro-5-(4-fluorophenyl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridine-4-amine (180 mg), (3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methanol (intermediate A) (270 mg) A mixture of 1,4-dioxane (5 mL) containing 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) (99 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (58 mg), and cesium carbonate (350 mg) 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 crude product (250 mg) and a solution of trifluoroacetic acid (4 mL) in dichloromethane (8 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 reverse-phase column chromatography (water (containing 0.05% ammonium bicarbonate)-acetonitrile) and high-performance liquid chromatography to obtain 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-(methyl((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridine-2-yl)oxy)methyl)pyridine-4-ol (28 mg).

[0418]

[0419] [Example 59] Synthesis of N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-(4-fluorophenyl)pyridine-4-yl)-N-methylcyclohexanecarboxamide

[0420] Step (1) Synthesis of N-(2-chloro-5-(4-fluorophenyl)pyridine-4-yl)-N-cyclohexanecarboxamide: To a solution of 2-chloro-5-(4-fluorophenyl)-N-methylpyridine-4-amine (300 mg), the compound obtained in Step (2) of Example 48, in N,N-dimethylformamide (2 mL), sodium hydride (60%, 152 mg) was slowly added at 0°C and the mixture was stirred for 30 minutes. Cyclohexanecarboxychloride (558 mg) was added to this reaction mixture and the mixture was stirred at room temperature 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 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 N-(2-chloro-5-(4-fluorophenyl)pyridine-4-yl)-N-cyclohexanecarboxamide (270 mg).

[0421] Step (2) Synthesis of N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-(4-fluorophenyl)pyridine-4-yl)-N-methylcyclohexanecarboxamide: The compound obtained in Step (1) is N-(2-chloro-5-(4-fluorophenyl)pyridine-4-yl)-N-cyclohexanecarboxamide (150 mg), 4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (109 mg), methanesulfonate (dicyclo A mixture of hexyl(3-(1-methylethoxy)-2',4',6'-tris(1-methylethyl)-1,1'-biphenyl-2-yl)phosphine)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (40 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (23 mg), and cesium carbonate (282 mg) in toluene (15 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 (370 mg) was mixed with trifluoroacetic acid (4 mL) and dichloromethane (4 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 N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-(4-fluorophenyl)pyridine-4-yl)-N-methylcyclohexanecarboxamide (54 mg).

[0422]

[0423] [Example 60] Synthesis of 2-(((5-(2,6-difluorophenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0424] Step (1) Synthesis of 2-((4-(benzyloxy)-3,5-difluoropyridine-2-yl)methoxy)-5-bromo-4,6-dimethylpyrimidine: A mixture of 5-bromo-2-chloro-4,6-dimethylpyrimidine (200 mg), a known substance, and 4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (227 mg) in tetrahydrofuran (5 mL) was mixed with t-butoxy potassium (122 mg) at 0°C and 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 (hexane-ethyl acetate) to obtain 2-((4-(benzyloxy)-3,5-difluoropyridine-2-yl)methoxy)-5-bromo-4,6-dimethylpyrimidine (390 mg).

[0425] Step (2) Synthesis of 2-(((5-(2,6-difluorophenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol The compound obtained in Step (1), 2-((4-(benzyloxy)-3,5-difluoropyridine-2-yl)methoxy)5-bromo-4,6-dimethylpyrimidine (310 mg), 2,6-difluorophenylboronic acid (1.1 g), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (50 mg), and tripotassium phosphate (302 mg), was mixed with 1,4-dioxane (10 mL) and water (2.5 mL) and stirred at 100°C for 1 hour under a nitrogen atmosphere. 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 crude product (500 mg) obtained was mixed with trifluoroacetic acid (3 mL) and dichloromethane (9 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 2-(((5-(2,6-difluorophenyl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (10 mg).

[0426]

[0427] [Example 61] Synthesis of 2-(6-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-2,4-dimethylpyridine-3-yl)benzonitrile

[0428] 2-(6-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-2,4-dimethylpyridine-3-yl)benzonitrile (19 mg) was obtained using the same method as in Example 52.

[0429] [Example 62] Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-isopropoxy-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol

[0430] Step (1) Synthesis of 3-chloro-4-isopropoxy-2-(trifluoromethyl)pyridine: Slowly add sodium hydride (60%, 940 mg) to a solution of isopropyl alcohol (940 mg) in tetrahydrofuran (40 mL) under a nitrogen atmosphere at 0°C and stir for 30 minutes. Slowly add 3-chloro-4-iodo-2-(trifluoromethyl)pyridine (4.0 g), the compound obtained in Step 2 of Example 32, to this reaction mixture at 0°C and stir at room temperature for 16 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 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 3-chloro-4-isopropoxy-2-(trifluoromethyl)pyridine (1.1 g).

[0431] Step (2) Synthesis of 3-(4-fluorophenyl)-4-isopropoxy-2-(trifluoromethyl)pyridine: The compound obtained in Step (1), 3-chloro-4-isopropoxy-2-(trifluoromethyl)pyridine (1.1 g), 4-fluorophenylboronic acid (640 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (325 mg), and tripotassium phosphate (2.0 g), were mixed with 1,4-dioxane (20 mL) and water (5 mL) and stirred at 100°C under a nitrogen atmosphere for 2 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 resulting residue was purified by silica gel chromatography (hexane-ethyl acetate) to obtain 3-(4-fluorophenyl)-4-isopropoxy-2-(trifluoromethyl)pyridine (1.5 g).

[0432] Step (3) Synthesis of 3-(4-fluorophenyl)-4-isopropoxy-2-(trifluoromethyl)pyridine-1-oxide: To a solution of 3-(4-fluorophenyl)-4-isopropoxy-2-(trifluoromethyl)pyridine (1.1 g), the compound obtained in step (2), in dichloromethane (20 mL), urea peroxide (1.4 g) and trifluoroacetic anhydride (3.9 g) were added at 0°C and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then stopped with an aqueous sodium bicarbonate 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 3-(4-fluorophenyl)-4-isopropoxy-2-(trifluoromethyl)pyridine-1-oxide (160 mg).

[0433] Step (4) Synthesis of 6-chloro-3-(4-fluorophenyl)-4-isopropoxy-2-(trifluoromethyl)pyridine: 140 mg of 3-(4-fluorophenyl)-4-isopropoxy-2-(trifluoromethyl)pyridine-1-oxide, the compound obtained in step (3), was added dropwise to a solution of 5 mL of N,N-dimethylformamide with 282 mg of oxalyl chloride at 0°C and stirred at room temperature for 2 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. The resulting residue was purified by reverse-phase column chromatography (water (containing 0.05% formic acid) - acetonitrile) to obtain 100 mg of 6-chloro-3-(4-fluorophenyl)-4-isopropoxy-2-(trifluoromethyl)pyridine.

[0434] Step (5) Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-isopropoxy-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol The compound obtained in step (4) is 6-chloro-3-(4-fluorophenyl)-4-isopropoxy-2-(trifluoromethyl)pyridine (100 mg), 4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (75 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) (27 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (16 mg), and cesium carbonate (195 mg) in 1,4-dioxane (5 mL) was stirred at 100°C for 2 hours under a nitrogen atmosphere. 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 column chromatography (water (containing 0.05% formic acid)-acetonitrile) and high-performance liquid chromatography to obtain 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-isopropoxy-6-(trifluoromethyl)pyridine-2-yl)oxy)methyl)pyridine-4-ol (21 mg).

[0435]

[0436] [Example 63] Synthesis of N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-(4-fluorophenyl)pyridine-4-yl)-4,4-difluoro-N-methylcyclohexane-1-carboxamide

[0437] Step (1) Synthesis of 4,4-difluorocyclohexane-1-carbonyl chloride: 2.0 g of 4,4-difluorocyclohexane-1-carboxylic acid, a known substance, was stirred in thionyl chloride (20 mL) at 80°C under a nitrogen atmosphere for 2 hours. The reaction mixture was then concentrated under reduced pressure using a rotary evaporator to obtain the crude product of 4,4-difluorocyclohexane-1-carbonyl chloride (2.1 g).

[0438] Step (2) Synthesis of N-(2-chloro-5-(4-fluorophenyl)pyridine-4-yl)-N-methylcyclohexane-1-carboxamide In a solution of 2-chloro-5-(4-fluorophenyl)-N-methylpyridine-4-amine (300 mg), the compound obtained in Step (2) of Example 48, in N,N-dimethylformamide (10 mL), sodium hydride (60%, 197 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 the crude product 4,4-difluorocyclohexane-1-carbonyl chloride (2.1 g) obtained in Step 1, in N,N-dimethylformamide (10 mL) was added dropwise at 0°C and the mixture was stirred at room temperature 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 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 column chromatography (water (containing 0.05% ammonium bicarbonate) - acetonitrile) to obtain N-(2-chloro-5-(4-fluorophenyl)pyridine-4-yl)-N-methylcyclohexane-1-carboxamide (140 mg).

[0439] Step (3) Synthesis of N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-(4-fluorophenyl)pyridine-4-yl)-4,4-difluoro-N-methylcyclohexane-1-carboxamide, the compound obtained in Step (2), N-(2-chloro-5-(4-fluorophenyl)pyridine-4-yl)-N-methylcyclohexane-1-carboxamide (140 mg), 4-(benzyloxy)-3,5-difluoropyridine-2-yl)methanol (92 mg), methanesulfate A mixture of fonate (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) (34 mg), dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (20 mg), and cesium carbonate (238 mg) in toluene (8 mL) was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction mixture was then filtered, and water was added to the filtrate, which 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 crude product (300 mg) obtained 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 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 N-(2-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-5-(4-fluorophenyl)pyridine-4-yl)-4,4-difluoro-N-methylcyclohexane-1-carboxamide (25 mg).

[0440]

[0441] [Example 64] Synthesis of 4-(6-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-2,4-dimethylpyridine-3-yl)benzonitrile

[0442] 4-(6-((3,5-difluoro-4-hydroxypyridine-2-yl)methoxy)-2,4-dimethylpyridine-3-yl)benzonitrile (20 mg) was obtained using the same method as in Example 52.

[0443] [Example 65] Synthesis of 2-(((5-(cyclohexa-1-en-1-yl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol

[0444] To a mixture of 5-bromo-2-((3,5-difluoro-4-((4-methoxybenzyl)oxy)pyridine-2-yl)methoxy)-4,6-dimethylpyrimidine (intermediate D) (120 mg) with 1,4-dioxane (2 mL) and water (0.5 mL), cyclohexa-1-en-1-ylboronic acid (97 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (18 mg), and potassium carbonate (164 mg) were added, and the mixture was stirred at 80°C under an argon atmosphere for 5 hours. After that, water was added to the reaction mixture and washed with ethyl acetate. 2 M hydrochloric acid was added to the aqueous layer and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure using a rotary evaporator. Hexane and ethyl acetate were added to the resulting residue, and the resulting solid was filtered off. The solid was then dried to obtain 2-(((5-(cyclohexa-1-en-1-yl)-4,6-dimethylpyrimidine-2-yl)oxy)methyl)-3,5-difluoropyridine-4-ol (12 mg).

[0445]

[0446] [Example 66] Synthesis of 3,5-difluoro-2-(((5-(4-fluorophenyl)-4-methyl-6-(trifluoromethyl)pyrimidine-2-yl)oxy)methyl)pyridine-4-ol

[0447] Step (1) Synthesis of 5-bromo-4-chloro-6-(trifluoromethyl)pyrimidine-2-amine: A solution of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine (5.0 g), a known substance, and N-bromosucciimide (7.9 g) in acetonitrile (75 mL) was stirred at room temperature for 16 hours. Then, ethyl acetate was added to the reaction mixture, and the organic layer was washed with an aqueous sodium thiosulfate solution 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 chromatography (hexane-ethyl acetate) to obtain 5-bromo-4-chloro-6-(trifluoromethyl)pyrimidine-2-amine (6.9 g).

[0448] Step (2) Synthesis of 5-bromo-4-methyl-6-(trifluoromethyl)pyrimidine-2-amine The compound obtained in Step (1), 5-bromo-4-chloro-6-(trifluoromethyl)pyrimidine-2-amine (3.0 g), trimethylboroxine (5.5 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (900 mg), and cesium carbonate (10.6 g) were mixed with 1,4-dioxane (60 mL) and water (30 mL) and stirred at 80°C under a nitrogen atmosphere for 1 hour. The 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 chromatography (hexane-ethyl acetate) to obtain 5-bromo-4-methyl-6-(trifluoromethyl)pyrimidine-2-amine (650 mg).

[0449] Step (3) Synthesis of 5-(4-fluorophenyl)-4-methyl-6-(trifluoromethyl)pyrimidine-2-amine: The compound obtained in step (2), 5-bromo-4-methyl-6-(trifluoromethyl)pyrimidine-2-amine (650 mg), 4-fluorophenylboronic acid (533 mg), dichlorobis[di-t-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (180 mg), and tripotassium phosphate (1.1 g) were mixed with 1,4-dioxane (12 mL) and water (3 mL) and stirred at 100°C under a nitrogen atmosphere for 1 hour. The 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 chromatography (hexane-ethyl acetate) to obtain 5-(4-fluorophenyl)-4...

Claims

1. The following general formula (1): [In the above general formula (1), R ３～８ , １～６ , ６～１２ , １～５ , １～９ , ２～６ and R ２ are each independently hydrogen; halogen; or cyano, and at least one of R １ and R ２ is halogen or cyano, and R ３ is hydrogen; halogen; cyano; C １～６ alkyl optionally substituted with halogen; or C ３～８ cycloalkyl optionally substituted with halogen, and W is one of the following formulas (A-1) to (A-12): (In the above formulas (A-1) to (A-12), A is C １～６ alkylene optionally substituted with halogen, and 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, X １ to X ５ are each independently C—R ５ or N, and R ５ are each independently hydrogen; halogen; NR ６ R ７ ; OR ６ ; or at least one substituent selected from the group consisting of hydroxy, halogen, cyano, nitro, C １～５ alkoxy optionally substituted with halogen, C ３～８ cycloalkyl optionally substituted with halogen, C ２～６ heterocycloalkyl optionally substituted with halogen, C ６～１２ aryl optionally substituted with halogen, C １～９ heteroaryl, and is optionally substituted with C １～６ alkyl; or hydroxy, halogen, cyano, nitro, C １～５ alkoxy optionally substituted with halogen, C ３～８ cycloalkyl optionally substituted with 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 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. 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 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. 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 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. ２～６ Heterocycloalkyl; 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 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. 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 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 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 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 optionally substituted with aryl, 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, C optionally substituted with halogen 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 optionally substituted with halogen １～６ alkyl, C optionally substituted with halogen １～５ alkoxy, C optionally substituted with halogen 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, C optionally substituted with halogen 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 a compound represented by [heteroaryl] or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

8. R ３ However, hydrogen or CF ３ The compound according to claim 2 or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 2, represented by general formula (2-1), or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 2, represented by general formula (2-2), or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 2, represented by general formula (2-3), or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 2, represented by general formula (2-4), or a pharmaceutically acceptable salt thereof.

13. R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. 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. １～６ Alkyl; or C which may be substituted with halogen, cyano, or halogen. 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. １～６ Alkylcarbonyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. １～５ 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. 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 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. 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 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. ２～６ Heterocycloalkyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. 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. 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 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 A compound according to claim 2, which is a heteroaryl compound, or a pharmaceutically acceptable salt thereof.

14. 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 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. 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 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. 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 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 A compound according to claim 2, which is a heteroaryl compound, or a pharmaceutically acceptable salt thereof.

15. R ５ At least one of the C atoms may be substituted with a halogen, cyano, or halogen. １～５ C may be substituted with alkoxy or halogen compounds. ３～８ Cyclohexyl 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 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 The compound according to claim 2 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.

16. The following general formulas (3-1-1) to (3-4-2): [In the above general formulas (3-1-1) to (3-4-2), R ８ C may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. 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. 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 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. 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 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. ２～６ Heterocycloalkyl; or C which may be substituted with halogen, cyano, or halogen. １～６ C may be substituted with alkyl or halogen. 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. 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 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 a heteroaryl, R ９ These are, independently, hydrogen; halogen; NR １１ R １２ OR １１ ; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. 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. １～６ Alkyl; or C which may be substituted with hydroxy, halogen, cyano, nitro, or halogen. 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. １～６ 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 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. 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 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. 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 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. ２～６ It is a heterocycloalkyl, and R １１ and R １２ 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 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 at least one substituent selected from the group consisting of heterocycloalkyls. 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 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 at least one substituent selected from the group consisting of heterocycloalkyls. ３～８ It is a cycloalkyl, R １０ NR １３ R １４ And R １３ 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 halogen 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; 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 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. 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 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. 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 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 a heteroaryl, R １４ C may be substituted with hydrogen or halogen. 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 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. １～６ 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 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. 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 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. 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 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 The compound according to claim 2 or a pharmaceutically acceptable salt thereof, which is represented by any of the following: [heteroaryl].

17. The following formulas (1) to (90): A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

18. A pharmaceutical composition containing a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

19. An HSD17B13 inhibitor comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

20. A preventive or therapeutic agent for diseases involving HSD17B13, comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

21. The preventive or therapeutic agent according to claim 20, wherein the disease in which HSD17B13 is involved is a liver disease.

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