Nitrogen-containing heterocyclic compound having MYT1 inhibitory activity

Abstract

To provide a new compound having inhibitory activity against MYT1, its salts or their solvates.SOLUTION: Wherein, R4 is selected from optionally substituted C6 - C10 aryl and the like; R5 and R6 are taken together with the atoms to which they are attached to form an optionally substituted D ring; D ring is selected from 3 - to 10-membered mono-alicyclic ring and the like; any two adjacent substituents on D ring may be taken together with the atoms to which they are attached to form an optionally substituted E ring. Or a salt thereof, or a solvate thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a nitrogen-containing heterocyclic compound or a salt thereof, or a solvate thereof, which has MYT1 inhibitory activity, and also to a pharmaceutical composition containing the compound or salt as an active ingredient, which is useful for treating and preventing cancer. [Background technology]

[0002] Cells are exposed to exogenous or endogenous stressors daily, resulting in DNA damage. Normally, cells with DNA damage repair the DNA damage by activating the DNA Damage Response (DDR) pathway. It is known that many cancers have abnormalities in genes and proteins involved in the DDR pathway, and therapeutic approaches are being investigated (Non-Patent Documents 1-2). One method for treating cancers with abnormalities in genes and proteins involved in the DDR pathway is the use of PARP inhibitors, which are used to treat cancers with BRCA1 or BRCA2 mutations (Non-Patent Document 3). Currently, genes and proteins involved in the DDR pathway, such as ATM, ATR, CHK1, DNA-PK, and WEE1, are being identified as potential targets, and active research is being conducted on these targets (Non-Patent Document 4).

[0003] MYT1 is an enzyme of the WEE1 family and is known to be a negative regulator of CDK1. MYT1 phosphorylates CDK1, inactivating it and playing an important role in regulating the cell cycle. In recent years, new MYT1 inhibitors have been reported to induce synthetic lethality in certain cancers (Non-Patent Document 5), but no approved drugs have yet been developed, and new therapeutic agents are desired. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Cancers (Basel), 2020 Apr 23;12(4):1050. [Non-licensed document 2] Front Pharmacol.,2021 Feb 8;11:629266. [Non-licensed document 3] N.Engl.J.Med.,2018 Dec 27;379(26):2495-2505.

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[0005] The object of the present invention is to provide a novel compound or a salt thereof, or a solvate thereof, which has inhibitory activity against MYT1, and to provide a pharmaceutical agent containing the compound or salt as an active ingredient, which is useful for the treatment and prevention of cancer. [Means for solving the problem]

[0006] That is, in one aspect of the present invention, the following invention is provided. [A1] Formula (1): [ka] [In the formula, R4 is an optionally substituted C6-C 10 Aryl (R 4A ), optionally substituted 4- to 10-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl (R 4HA ) selected from the group consisting of; R5 and R6 together with the atoms to which they are attached form an optionally substituted D ring; The D ring is a 3- to 10-membered monocyclic alicyclic ring, a benzene ring, a 3- to 12-membered monocyclic heterocyclic ring, and a 5- to 6-membered monocyclic aromatic heterocyclic ring (D HA ) selected from the group consisting of; Any two adjacent substituents on ring D may be joined together with the atoms to which they are attached to form an optionally substituted ring E. A compound represented by the formula (I), a salt thereof, or a solvate thereof. [A2] Ring D is a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle (D HA The compound according to [A1], or a salt thereof, or a solvate of the compound or the salt, wherein [A3] The compound according to [A1], a salt thereof, or a solvate of the compound or the salt, wherein ring D is a benzene ring. [A4] Ring D is a 5- to 6-membered monocyclic aromatic heterocycle (D HA The compound according to [A1], or a salt thereof, or a solvate of the compound or the salt, wherein [A5] 5-6 membered monocyclic aromatic heterocycle (D HA) is selected from the group consisting of a furan ring, a thiophene ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, an oxadiazole ring, a thiadiazole ring, a triazole ring, a tetrazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, and a triazine ring, or a salt thereof, according to [A4], or a solvate thereof. [A6] 5-6 membered monocyclic aromatic heterocycle (D HA The compound or salt thereof, or a solvate thereof according to [A4], wherein R 1 is selected from the group consisting of a pyridine ring, a pyrimidine ring, a pyridazine ring, and a pyrazine ring. [A7] 5-6 membered monocyclic aromatic heterocycle (D HA The compound according to [A4], or a salt thereof, or a solvate of the compound or the salt, wherein [A8] The D ring is unsubstituted or contains one or more R D is replaced by One or more R D are each independently deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted. A compound according to any one of [A1] to [A7], a salt thereof, or a solvate thereof. [A9] The D ring is unsubstituted or contains one or more R D is replaced by One or more R D are each independently halogen, cyano, hydroxy, C1-C6 alkylthio, C1-C6 acylamino, mono C1-C6 alkylamino, C1-C6 alkylsulfonylamino, C3-C8 cycloalkylsulfonylamino, C1-C6 alkoxy, haloC1-C6 alkoxy, hydroxyC1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, 4-10 membered heterocyclylC1-C6 alkoxy, C3-C8 cycloalkoxy, 4-10 membered heterocyclyl oxy, C1-C6 acyl, mono C3-C8 cycloalkylaminocarbonyl, 4-8 membered cyclic aminocarbonyl, di C1-C6 alkylphosphoryl, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, di C1-C6 alkylaminocarbonyl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, C2-C6 alkenyl, hydroxy C2-C6 alkenyl, C2-C6 alkynyl, hydroxy C2-C6 alkynyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, 4-10 membered heterocyclylC1-C6 alkoxy, C3-C8 cycloalkoxy, 4-10 membered heterocyclyloxy, C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted independently with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, oxo, haloC1-C6 alkyl, and C3-C8 cycloalkyl; A compound according to any one of [A1] to [A7], a salt thereof, or a solvate thereof. [A10] The D ring is unsubstituted or contains one or more R D is replaced by One or more R D are each independently selected from the group consisting of halogen, C-C alkoxy, haloC-C alkoxy, C-C cycloalkylC-C alkoxy, C-C cycloalkoxy, C-C alkyl, haloC-C alkyl, C-C cycloalkylC-C alkyl, and C-C cycloalkyl; A compound according to any one of [A1] to [A7], a salt thereof, or a solvate thereof. [A11] The D ring is unsubstituted or contains one or more R D is replaced by One or more R D are each independently selected from the group consisting of C1-C6 alkoxy, C1-C6 alkyl, and C3-C8 cycloalkyl; A compound according to any one of [A1] to [A7], a salt thereof, or a solvate thereof. [A12] The D ring is unsubstituted or contains one or more R D is replaced by One or more R D are each independently selected from the group consisting of methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-butan-2-yl]oxy, [(2R)-butan-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, butan-2-yl, 3-methylbutyl, pentan-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl, and spiro[2.3]hexan-5-yl; A compound according to any one of [A1] to [A7], a salt thereof, or a solvate thereof. [A13] A compound according to any one of [A1] to [A12], a salt thereof, or a solvate thereof, wherein any two adjacent substituents on ring D, together with the atoms to which they are attached, form ring E which may be substituted. [A14] The ring E is a 3- to 10-membered monocyclic alicyclic ring, a benzene ring, a 3- to 12-membered monocyclic heterocyclic ring, and a 5- to 6-membered monocyclic aromatic heterocyclic ring (E HA The compound or salt thereof, or a solvate thereof according to any one of [A1] to [A13], selected from the group consisting of: [A15] Ring E is a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle (E HA The compound or salt thereof, or a solvate of the compound or salt according to any one of [A1] to [A13], wherein [A16] The compound according to any one of [A1] to [A13], or a salt thereof, or a solvate of the compound or the salt, wherein ring E is a benzene ring. [A17] Ring E is a 5- to 6-membered monocyclic aromatic heterocycle (E HA The compound or salt thereof, or a solvate of the compound or salt according to any one of [A1] to [A13], wherein [A18] 5-6 membered monocyclic aromatic heterocycle (E HA The compound or salt thereof according to [A17], or a solvate thereof, wherein R is selected from the group consisting of a furan ring, a thiophene ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, an oxadiazole ring, a thiadiazole ring, a triazole ring, a tetrazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, and a triazine ring. [A19] 5-6 membered monocyclic aromatic heterocycle (E HA The compound or salt thereof according to [A17], or a solvate thereof, wherein R 1 is selected from the group consisting of a thiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, and a pyrazine ring. [A20] 5-6 membered monocyclic aromatic heterocycle (E HA The compound or salt thereof, or a solvate thereof according to [A17], wherein R 1 is selected from the group consisting of a pyridine ring, a pyrimidine ring, a pyridazine ring, and a pyrazine ring. [A20.5] 5-6 membered monocyclic aromatic heterocycle (E HA The compound according to [A17], a salt thereof, or a solvate of the compound or the salt, wherein R is a pyridine ring or a pyrazine ring. [A21] 5-6 membered monocyclic aromatic heterocycle (E HA The compound according to [A17], or a salt thereof, or a solvate of the compound or the salt, wherein [A22] The D and E rings have the following formula: [ka] (wherein * represents the carbon atom to which R5 is bonded in formula (1), and ** represents the carbon atom to which R6 is bonded in formula (1). In the formula, the D ring is represented as "D ring", and the E ring is represented as "E ring"), or a salt thereof, or a solvate thereof, according to [A17], which forms a bicyclic ring represented by the following formula: [A23] The D and E rings have the following formula: [ka] (wherein * represents the carbon atom to which R5 is bonded in formula (1), and ** represents the carbon atom to which R6 is bonded in formula (1). In the formula, the D ring is represented as "D ring", and the E ring is represented as "E ring"), or a salt thereof, or a solvate thereof, according to [A17], which forms a bicyclic ring represented by the following formula: [A24] The E ring is unsubstituted or contains one or more R E is replaced by One or more R Eare each independently deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted. A compound according to any one of [A14] to [A23], a salt thereof, or a solvate thereof. [A25] The E ring is unsubstituted or contains one or more R E is replaced by One or more R E are each independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, and boryl; A compound according to any one of [A14] to [A23], a salt thereof, or a solvate thereof. [A25.5] The E ring is unsubstituted or contains one or more R E is replaced by One or more R E are each independently selected from the group consisting of fluorine, chlorine, methoxy, dihydroxyboryl, methyl, and t-butyl; A compound according to any one of [A14] to [A23], a salt thereof, or a solvate thereof. [A26] R4 is an optionally substituted C6-C 10 Aryl (R 4A ) or optionally substituted 5- to 10-membered heteroaryl (R 4HAThe compound or salt thereof, or a solvate thereof according to any one of [A1] to [A25.5], wherein [A27] R4 is an optionally substituted C6-C 10 Aryl (R 4A The compound or salt thereof, or a solvate of the compound or salt according to any one of [A1] to [A26], wherein [A28] C6-C 10 Aryl (R 4A The compound according to [A26] or [A27], or a salt thereof, or a solvate of the compound or the salt, wherein R is 1 or 2; [A29] C6-C 10 Aryl (R 4A ) is unsubstituted or contains one or more R a is replaced by One or more R a are each independently deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted. A compound according to any one of [A26] to [A28], a salt thereof, or a solvate thereof. [A30] C6-C 10 Aryl (R 4A ) is unsubstituted or contains one or more R a is replaced by One or more R a are each independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, haloC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, and C1-C6 alkylsulfonylamino; A compound according to any one of [A26] to [A28], a salt thereof, or a solvate thereof. [A31] C6-C 10 Aryl (R 4A ) is unsubstituted or contains one or more R a is replaced by One or more R a are each independently selected from the group consisting of halogen, hydroxy, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, and C1-C6 alkylsulfonylamino; A compound according to any one of [A26] to [A28], a salt thereof, or a solvate thereof. [A32] R4 is an optionally substituted 5- to 10-membered heteroaryl (R 4HA The compound or salt thereof, or a solvate of the compound or salt according to any one of [A1] to [A26], wherein [A33] 5-10 membered heteroaryl (R 4HAThe compound according to [A26] or [A32], or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, pyrrolopyrazinyl, and furopyridyl. [A34] 5-10 membered heteroaryl (R 4HA The compound according to [A26] or [A32], or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, pyrrolopyrazinyl, and furopyridyl. [A35] 5-10 membered heteroaryl (R 4HA The compound according to [A26] or [A32], or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of pyridyl, pyrimidyl, benzimidazolyl, indolyl, indazolyl, and pyrazolopyridyl. [A36] 5-10 membered heteroaryl (R 4HAThe compound according to [A26] or [A32], or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of pyrimidyl, benzimidazolyl, indolyl, indazolyl, and pyrazolopyridyl. [A37] 5-10 membered heteroaryl (R 4HA The compound according to [A26] or [A32], or a salt thereof, or a solvate of the compound or the salt, wherein R is 1H-indazol-6-yl or 1H-indazol-4-yl. [A38] 5-10 membered heteroaryl (R 4HA The compound according to [A26] or [A32], or a salt thereof, or a solvate of the compound or the salt, wherein [A39] 5-10 membered heteroaryl (R 4HA ) is unsubstituted or contains one or more R a is replaced by One or more R a are each independently deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted. A compound according to any one of [A32] to [A38], a salt thereof, or a solvate thereof. [A40] 5-10 membered heteroaryl (R 4HA ) is unsubstituted or contains one or more Ra is replaced by One or more R a are each independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, haloC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, and C1-C6 alkylsulfonylamino; A compound according to any one of [A32] to [A38], a salt thereof, or a solvate thereof. [A41] 5-10 membered heteroaryl (R 4HA ) is unsubstituted or contains one or more R a is replaced by One or more R a are each independently selected from the group consisting of halogen, cyano, amino, C1-C6 alkyl, and haloC1-C6 alkyl; A compound according to any one of [A32] to [A38], a salt thereof, or a solvate thereof. [A42] 5-10 membered heteroaryl (R 4HA The compound or salt thereof, or a solvate of the compound or salt according to any one of [A32] to [A38], wherein R is 1H-indazol-4-yl or 1H-indazol-4-yl substituted with one or more halogens. [A43] 5-10 membered heteroaryl (R 4HA The compound according to any one of [A32] to [A38], or a salt thereof, or a solvate of the compound or the salt, wherein R is 1H-indazol-4-yl substituted with one or more halogens. [A44] 5-10 membered heteroaryl (R 4HA The compound or salt thereof, or a solvate of the compound or the salt according to any one of [A32] to [A38], wherein (A) is 1H-indazol-4-yl substituted with halogen at least at any one of the 5-, 6-, and 7-positions. [A44.5] 5-10 membered heteroaryl (R 4HA ) is expressed as: [ka] [wherein * represents the carbon atom to which R4 is bonded in formula (1), and R a5 , R a6 and R a7 are independently hydrogen or halogen, and R a5 , R a6 and R a7 At least one of the is not hydrogen.] The compound according to any one of [A32] to [A38], or a salt thereof, or a solvate thereof, represented by the following formula: [A45] 5-10 membered heteroaryl (R 4HA ) is 1H-indazol-4-yl substituted with halogen at least one of the 5-, 6-, and 7-positions, The halogen is fluorine or chlorine. A compound according to any one of [A32] to [A38], a salt thereof, or a solvate thereof. [A46] 5-10 membered heteroaryl (R 4HA ) is 1H-indazol-4-yl substituted with halogen at any one or two of the 5-, 6-, and 7-positions, The halogen is selected from the group consisting of fluorine, chlorine, a combination of fluorine and fluorine, and a combination of fluorine and chlorine; A compound according to any one of [A32] to [A38], a salt thereof, or a solvate thereof. [A46.5] 5-10 membered heteroaryl (R 4HA ) is 1H-indazol-4-yl substituted with halogen at any one or two of the 5-, 6-, and 7-positions, the halogens are independently fluorine or chlorine; A compound according to any one of [A32] to [A38], a salt thereof, or a solvate thereof. [B1] Formula (2): [ka] [In the formula, R4 is an optionally substituted C6-C 10 Aryl (R 4A ), optionally substituted 4- to 10-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl (R 4HA ) selected from the group consisting of; X5 is CR x5 or N, X6 is CR x6 or N, X 10a is CR x10a or N, R x5、 R x6 , R 6a and R x10a are each independently hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted or R x5 and R x6 , R x6 and R 6a , or R 6a and R x10a may be taken together with the atom to which they are attached to form an optionally substituted E ring. A compound represented by the formula (I), a salt thereof, or a solvate thereof. [B2] X5 is CR x5 or N, X6 is CR x6 and X 10a is CR x10a or N, The compound according to [B1], a salt thereof, or a solvate thereof. [B3] X5 is CH, X6 is CR x6 and X 10a is CR x10a That is, A compound according to [B1] or [B2], a salt thereof, or a solvate thereof. [B4] R x6 is hydrogen, halogen, hydroxy, C1-C6 alkylthio, C1-C6 acylamino, mono C1-C6 alkylamino, C1-C6 alkylsulfonylamino, C3-C8 cycloalkylsulfonylamino, C1-C6 alkoxy, haloC1-C6 alkoxy, hydroxyC1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, 4-10 membered heterocyclylC1-C6 alkoxy, C3-C8 cycloalkoxy, 4-10 membered heterocyclyloxy, C 1-C6 acyl, mono C3-C8 cycloalkylaminocarbonyl, 4-8 membered cyclic aminocarbonyl, di C1-C6 alkylphosphoryl, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, di C1-C6 alkylaminocarbonyl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, C2-C6 alkenyl, hydroxy C2-C6 alkenyl, C2-C6 alkynyl, hydroxy C2-C6 alkynyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, 4-10 membered heterocyclylC1-C6 alkoxy, C3-C8 cycloalkoxy, 4-10 membered heterocyclyloxy, C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted independently with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, oxo, haloC1-C6 alkyl, and C3-C8 cycloalkyl; The compound according to any one of [B1] to [B3], a salt thereof, or a solvate thereof. [B5] R x6 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, haloC1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C6 alkyl, haloC1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl, and C3-C8 cycloalkyl, or a salt thereof, or a solvate thereof, according to any one of [B1] to [B3]. [B6] R x6 is selected from the group consisting of hydrogen, C1-C6 alkoxy, C1-C6 alkyl, and C3-C8 cycloalkyl, or a salt thereof, or a solvate thereof according to any one of [B1] to [B3]. [B7] R x6is selected from the group consisting of hydrogen, methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-butan-2-yl]oxy, [(2R)-butan-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, butan-2-yl, 3-methylbutyl, pentan-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl, and spiro[2.3]hexan-5-yl, or a salt thereof, or a solvate thereof, according to any one of [B1] to [B3]. [B8] R x10a is selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C8 cycloalkyl, or a salt thereof, or a solvate thereof, according to any one of [B1] to [B7]. [B9] R x10a is selected from the group consisting of hydrogen, chlorine, bromine, cyano, methyl, ethyl, propyl, propan-2-yl, vinyl, ethynyl, and cyclopropyl, or a salt thereof, or a solvate thereof, according to any one of [B1] to [B7]. [B10] R 6a is selected from the group consisting of hydrogen, halogen, cyano, haloC1-C6 alkoxy, and C1-C6 alkyl, or a salt thereof, or a solvate thereof according to any one of [B1] to [B9]. [B11] R 6a is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, difluoromethoxy, methyl, and ethyl, or a salt thereof, or a solvate thereof according to any one of [B1] to [B9]. [B12] R 6a and R x10a are taken together with the atom to which they are attached to form an optionally substituted E ring, or a salt thereof, or a solvate thereof, according to any one of [B1] to [B7]. [B13] The ring E is a 3- to 10-membered monocyclic alicyclic ring, a benzene ring, a 3- to 12-membered monocyclic heterocyclic ring, and a 5- to 6-membered monocyclic aromatic heterocyclic ring (E HA The compound according to [B12], or a salt thereof, or a solvate thereof, selected from the group consisting of: [B14] Ring E is a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle (E HA The compound according to [B12], or a salt thereof, or a solvate thereof, wherein [B15] 5-6 membered monocyclic aromatic heterocycle (E HA The compound according to [B13] or [B14], or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of a thiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, and a pyrazine ring. [B16] 5-6 membered monocyclic aromatic heterocycle (E HA The compound according to [B13] or [B14], or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of a pyridine ring, a pyrimidine ring, a pyridazine ring, and a pyrazine ring. [B17] 5-6 membered monocyclic aromatic heterocycle (E HA The compound according to [B13] or [B14], or a salt thereof, or a solvate of the compound or the salt, wherein R is a pyridine ring or a pyrazine ring. [B18] 5-6 membered monocyclic aromatic heterocycle (E HA The compound according to [B13] or [B14], or a salt thereof, or a solvate of the compound or the salt, wherein [B19] The E ring has the formula: [ka] (where * represents R in formula (2) 6a indicates the carbon atom to which R is bonded, and ** indicates the R x10aand each represent a carbon atom to which the rings are bonded. In the formula, the ring E is represented as "E ring". The compound according to [B12], or a salt thereof, or a solvate thereof, is represented by the following formula: [B20] The E ring has the formula: [ka] (where * represents R in formula (2) 6a indicates the carbon atom to which R is bonded, and ** indicates the R x10a and each represent a carbon atom to which the rings are bonded. In the formula, the ring E is represented as "E ring". The compound according to [B12], or a salt thereof, or a solvate thereof, is represented by the following formula: [B21] The E ring is unsubstituted or contains one or more R E is replaced by One or more R E are each independently deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted. A compound according to any one of [B12] to [B20], a salt thereof, or a solvate thereof. [B22] The E ring is unsubstituted or contains one or more R E is replaced by One or more R Eare each independently selected from the group consisting of halogen, C1-C6 alkoxy, boryl, and C1-C6 alkyl; A compound according to any one of [B12] to [B20], a salt thereof, or a solvate thereof. [B23] The E ring is unsubstituted or contains one or more R E is replaced by One or more R E are each independently selected from the group consisting of fluorine, chlorine, methoxy, dihydroxyboryl, methyl, and t-butyl; A compound according to any one of [B12] to [B20], a salt thereof, or a solvate thereof. [B24] R4 is an optionally substituted C6-C 10 Aryl (R 4A ) or optionally substituted 5- to 10-membered heteroaryl (R 4HA The compound or salt thereof, or a solvate of the compound or salt according to any one of [B1] to [B23], wherein [B25] R4 is an optionally substituted C6-C 10 Aryl (R 4A The compound or salt thereof, or a solvate of the compound or salt according to any one of [B1] to [B23], wherein [B26] C6-C 10 Aryl (R 4A The compound according to [B24] or [B25], or a salt thereof, or a solvate of the compound or the salt, wherein R is 1 or 2; [B27] C6-C 10 Aryl (R 4A ) is unsubstituted or contains one or more R a is replaced by One or more R aare each independently deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted. The compound according to any one of [B24] to [B26], a salt thereof, or a solvate thereof. [B28] C6-C 10 Aryl (R 4A ) is unsubstituted or contains one or more R a is replaced by One or more R a are each independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, haloC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, and C1-C6 alkylsulfonylamino; The compound according to any one of [B24] to [B26], a salt thereof, or a solvate thereof. [B29] C6-C 10 Aryl (R 4A ) is unsubstituted or contains one or more R a is replaced by One or more R a are each independently selected from the group consisting of halogen, hydroxy, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy and C1-C6 alkylsulfonylamino; The compound according to any one of [B24] to [B26], a salt thereof, or a solvate thereof. [B30] R4 is an optionally substituted 5- to 10-membered heteroaryl (R 4HA The compound or salt thereof, or a solvate of the compound or salt according to any one of [B1] to [B23], wherein [B31] 5-10 membered heteroaryl (R 4HA The compound according to [B24] or [B30], or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, pyrrolopyrazinyl, and furopyridyl. [B32] 5-10 membered heteroaryl (R 4HA The compound according to [B24] or [B30], or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, pyrrolopyrazinyl, and furopyridyl. [B33] 5-10 membered heteroaryl (R 4HA The compound according to [B24] or [B30], or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of pyridyl, pyrimidyl, benzimidazolyl, indolyl, indazolyl, and pyrazolopyridyl. [B34] 5-10 membered heteroaryl (R 4HA The compound according to [B24] or [B30], or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of pyrimidyl, benzimidazolyl, indolyl, indazolyl, and pyrazolopyridyl. [B35] 5-10 membered heteroaryl (R 4HA The compound according to [B24] or [B30], or a salt thereof, or a solvate of the compound or the salt, wherein R is 1H-indazol-6-yl or 1H-indazol-4-yl. [B36] 5-10 membered heteroaryl (R 4HA The compound according to [B24] or [B30], or a salt thereof, or a solvate of the compound or the salt, wherein [B37] 5-10 membered heteroaryl (R 4HA ) is unsubstituted or contains one or more R a is replaced by One or more R a are each independently selected from halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted. A compound according to any one of [B31] to [B36], a salt thereof, or a solvate thereof. [B38] 5-10 membered heteroaryl (R 4HA ) is unsubstituted or contains one or more R a is replaced by One or more R a are each independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, haloC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy and C1-C6 alkylsulfonylamino; A compound according to any one of [B31] to [B36], a salt thereof, or a solvate thereof. [B39] 5-10 membered heteroaryl (R 4HA ) is unsubstituted or contains one or more R a is replaced by One or more R a are each independently selected from the group consisting of halogen, cyano, amino, C1-C6 alkyl, and haloC1-C6 alkyl; A compound according to any one of [B31] to [B36], a salt thereof, or a solvate thereof. [B40] 5-10 membered heteroaryl (R 4HA The compound or salt thereof, or a solvate of the compound or salt according to any one of [B31] to [B36], wherein R is 1H-indazol-4-yl or 1H-indazol-4-yl substituted with one or more halogens. [B41] 5-10 membered heteroaryl (R 4HAThe compound according to any one of [B31] to [B36], or a salt thereof, or a solvate of the compound or the salt, wherein R is 1H-indazol-4-yl substituted with one or more halogen atoms. [B42] 5-10 membered heteroaryl (R 4HA The compound or salt thereof, or a solvate of the compound or the salt according to any one of [B31] to [B36], wherein (B31) is 1H-indazol-4-yl substituted with halogen at least at any one of the 5-, 6-, and 7-positions. [B43] 5-10 membered heteroaryl (R 4HA ) is 1H-indazol-4-yl substituted with halogen at least one of the 5-, 6-, and 7-positions, The halogen is fluorine or chlorine. A compound according to any one of [B31] to [B36], a salt thereof, or a solvate thereof. [B44] 5-10 membered heteroaryl (R 4HA ) is 1H-indazol-4-yl substituted with halogen at any one or two of the 5-, 6-, and 7-positions, The halogen is selected from the group consisting of fluorine, chlorine, a combination of fluorine and fluorine, and a combination of fluorine and chlorine; A compound according to any one of [B31] to [B36], a salt thereof, or a solvate thereof. [B44.5] 5-10 membered heteroaryl (R 4HA ) is 1H-indazol-4-yl substituted with halogen at any one or two of the 5-, 6-, and 7-positions, the halogens are independently fluorine or chlorine; A compound according to any one of [B31] to [B36], a salt thereof, or a solvate thereof. [C1] Formula (3): [ka] [In the formula, R4 is an optionally substituted C6-C 10 Aryl (R 4A ), optionally substituted 4- to 10-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl (R 4HA ) selected from the group consisting of; X5 is CR x5 or N, X6 is CR x6 or N, X7 is CR x7 or N, X8 is CR x8 or N, X9 is CR x9 or N, X 10 is CR x10 or N, R x5、 R x6 , R x7 , R x8 , R x9 and R x10 are each independently hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted.] A compound represented by the formula (I), a salt thereof, or a solvate thereof. [C2] X5 is CR x5 or N, X6 is CRx6 and X7 is CR x7 or N, X8 is CR x8 or N, X9 is CR x9 or N, X 10 is CR x10 or N, The compound according to [C1], a salt thereof, or a solvate thereof. [C3] X5 is CH, X6 is CR x6 and X7 is CR x7 or N, X8 is CR x8 or N, X9 is CR x9 or N, X 10 is CR x10 or N, A compound according to [C1] or [C2], a salt thereof, or a solvate thereof. [C4] X7 is N and X8 is CR x8 and X9 is CR x9 and X 10 is CR x10 Or X7 is CR x7 , X8 is N, and X9 is CR x9 and X 10 is CR x10 Or X7 is CR x7 and X8 is CR x8 and X9 is N and X 10 is CR x10 Or X7 is CR x7 and X8 is CR x8 and X9 is CR x9 and X 10 is N or X7 is N and X8 is CR x8 and X9 is CR x9 and X10 is N or X7 is CR x7 , X8 is N, and X9 is CR x9 and X 10 is N or X7 is N, X8 is N, and X9 is CR x9 and X 10 is CR x10 Or The compound according to any one of [C1] to [C3], a salt thereof, or a solvate thereof. [C4.5] X7 is N and X8 is CR x8 and X9 is CR x9 and X 10 is CR x10 Or X7 is CR x7 , X8 is N, and X9 is CR x9 and X 10 is CR x10 Or X7 is CR x7 and X8 is CR x8 and X9 is N and X 10 is CR x10 Or X7 is CR x7 and X8 is CR x8 and X9 is CR x9 and X 10 is N, The compound according to any one of [C1] to [C3], a salt thereof, or a solvate thereof. [C5] R x6is hydrogen, halogen, hydroxy, C1-C6 alkylthio, C1-C6 acylamino, mono C1-C6 alkylamino, C1-C6 alkylsulfonylamino, C3-C8 cycloalkylsulfonylamino, C1-C6 alkoxy, haloC1-C6 alkoxy, hydroxyC1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, 4-10 membered heterocyclylC1-C6 alkoxy, C3-C8 cycloalkoxy, 4-10 membered heterocyclyloxy, C 1-C6 acyl, mono C3-C8 cycloalkylaminocarbonyl, 4-8 membered cyclic aminocarbonyl, di C1-C6 alkylphosphoryl, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, di C1-C6 alkylaminocarbonyl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, C2-C6 alkenyl, hydroxy C2-C6 alkenyl, C2-C6 alkynyl, hydroxy C2-C6 alkynyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, 4-10 membered heterocyclylC1-C6 alkoxy, C3-C8 cycloalkoxy, 4-10 membered heterocyclyloxy, C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted independently with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, oxo, haloC1-C6 alkyl, and C3-C8 cycloalkyl; The compound according to any one of [C1] to [C4], a salt thereof, or a solvate thereof. [C5.1] R x6is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, haloC1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C6 alkyl, haloC1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl, and C3-C8 cycloalkyl, or a salt thereof, or a solvate thereof, according to any one of [C1] to [C3]. [C5.2] R x6 is selected from the group consisting of hydrogen, C1-C6 alkoxy, C1-C6 alkyl, and C3-C8 cycloalkyl, or a salt thereof, or a solvate thereof, according to any one of [C1] to [C4]. [C6] R x6 is selected from the group consisting of hydrogen, methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-butan-2-yl]oxy, [(2R)-butan-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, butan-2-yl, 3-methylbutyl, pentan-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl, and spiro[2.3]hexan-5-yl, or a salt thereof, or a solvate thereof, according to any one of [C1] to [C4]. [C6.5] Formula (3): [ka] [In the formula, R4 is an optionally substituted 5- to 10-membered heteroaryl (R 4HA ) and 5-10 membered heteroaryl (R 4HA ) is 1H-indazol-4-yl or 1H-indazol-4-yl substituted with one or more halogens; X5 is CR x5 or N, X6 is CR x6 and Rx6 is selected from the group consisting of hydrogen, methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-butan-2-yl]oxy, [(2R)-butan-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, butan-2-yl, 3-methylbutyl, pentan-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl, and spiro[2.3]hexan-5-yl; X7 is CR x7 or N, X8 is CR x8 or N, X9 is CR x9 or N, X 10 is CR x10 or N, R x5、 R x7 , R x8 , R x9 and R x10 are each independently hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted.] A compound represented by the formula (I), a salt thereof, or a solvate thereof. [C6.6] Formula (3): [ka] [In the formula, R4 is 1H-indazol-4-yl or 1H-indazol-4-yl substituted with one or more halogens; X5 is CR x5 or N, X6 is CR x6 and R x6 is selected from the group consisting of hydrogen, methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-butan-2-yl]oxy, [(2R)-butan-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, butan-2-yl, 3-methylbutyl, pentan-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl, and spiro[2.3]hexan-5-yl; X7 is CR x7 or N, X8 is CR x8 or N, X9 is CR x9 or N, X 10 is CR x10 or N, R x5、 R x7 , R x8 , R x9 and R x10 are each independently hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted.] A compound represented by the formula (I), a salt thereof, or a solvate thereof. [C7] X7 is CR x7 The compound according to any one of [C1] to [C6.5], or a salt thereof, or a solvate thereof, [C8] R x7 The compound according to [C7], a salt thereof, or a solvate thereof, wherein is hydrogen, halogen, C1-C6 alkoxy, or C1-C6 alkyl. [C9] The compound or salt thereof, or a solvate of the compound or salt according to any one of [C1] to [C6.5], wherein X7 is N. [C10] X8 is CR x8 The compound according to any one of [C1] to [C9], or a salt thereof, or a solvate thereof, [C11] R x8 The compound according to [C10], a salt thereof, or a solvate thereof, wherein is hydrogen, halogen, C1-C6 alkoxy, or C1-C6 alkyl. [C12] The compound or salt thereof, or a solvate of the compound or salt according to any one of [C1] to [C9], wherein X8 is N. [C13] X9 is CR x9 The compound according to any one of [C1] to [C12], or a salt thereof, or a solvate thereof, [C14] R x9 is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, and boryl, or a salt thereof, or a solvate thereof according to [C13]. [C15] The compound or salt thereof, or a solvate of the compound or salt according to any one of [C1] to [C12], wherein X9 is N. [C16] X 10 is CR x10 The compound according to any one of [C1] to [C15], or a salt thereof, or a solvate thereof. [C17] R x10 The compound according to [C16], a salt thereof, or a solvate thereof, wherein is hydrogen, halogen, C1-C6 alkoxy, or C1-C6 alkyl. [C18] X 10 The compound according to any one of [C1] to [C12], or a salt thereof, or a solvate of the compound or the salt, wherein is N. [C20] R4 is an optionally substituted C6-C 10 Aryl (R 4A ) or optionally substituted 5- to 10-membered heteroaryl (R 4HA A compound or a salt thereof, or a solvate thereof, according to any one of [C1] to [C18] (excluding [C6.5] and [C6.6]), wherein [C21] R4 is an optionally substituted C6-C 10 Aryl (R 4A A compound or a salt thereof, or a solvate thereof, according to any one of [C1] to [C18] (excluding [C6.5] and [C6.6]), wherein [C22] C6-C 10 Aryl (R 4A The compound according to [C20] or [C21], or a salt thereof, or a solvate thereof, wherein R is 1 or 2; [C23] C6-C 10 Aryl (R 4A ) is unsubstituted or contains one or more R a is replaced by One or more R aare each independently deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted. A compound according to any one of [C20] to [C22], a salt thereof, or a solvate thereof. [C24] C6-C 10 Aryl (R 4A ) is unsubstituted or contains one or more R a is replaced by One or more R a are each independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, haloC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, and C1-C6 alkylsulfonylamino; A compound according to any one of [C20] to [C22], a salt thereof, or a solvate thereof. [C25] C6-C 10 Aryl (R 4A ) is unsubstituted or contains one or more R a is replaced by One or more R a are each independently selected from the group consisting of halogen, hydroxy, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, and alkylsulfonylamino; A compound according to any one of [C20] to [C22], a salt thereof, or a solvate thereof. [C26] R4 is an optionally substituted 5- to 10-membered heteroaryl (R 4HA A compound or a salt thereof, or a solvate thereof, according to any one of [C1] to [C18] (excluding [C6.5] and [C6.6]), wherein [C27] 5-10 membered heteroaryl (R 4HA The compound according to [C20] or [C26], or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, pyrrolopyrazinyl, and furopyridyl. [C28] 5-10 membered heteroaryl (R 4HAThe compound according to [C20] or [C26], or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, pyrrolopyrazinyl, and furopyridyl. [C29] 5-10 membered heteroaryl (R 4HA The compound according to [C20] or [C26], or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of pyridyl, pyrimidyl, benzimidazolyl, indolyl, indazolyl, and pyrazolopyridyl. [C30] 5-10 membered heteroaryl (R 4HA The compound according to [C20] or [C26], or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of pyrimidyl, benzimidazolyl, indolyl, indazolyl, and pyrazolopyridyl. [C31] 5-10 membered heteroaryl (R 4HA The compound according to [C20] or [C26], or a salt thereof, or a solvate thereof, wherein R is 1H-indazol-6-yl or 1H-indazol-4-yl. [C32] 5-10 membered heteroaryl (R 4HA The compound according to [C20] or [C26], or a salt thereof, or a solvate thereof, wherein: [C33] 5-10 membered heteroaryl (R 4HA ) is unsubstituted or contains one or more Ra is replaced by One or more R a are each independently deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted. A compound according to any one of [C27] to [C32], a salt thereof, or a solvate thereof. [C34] 5-10 membered heteroaryl (R 4HA ) is unsubstituted or contains one or more R a is replaced by One or more R a are each independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, haloC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, and alkylsulfonylamino; A compound according to any one of [C27] to [C32], a salt thereof, or a solvate thereof. [C35] 5-10 membered heteroaryl (R 4HA ) is unsubstituted or contains one or more R a is replaced by One or more R a are each independently selected from the group consisting of halogen, cyano, amino, C1-C6 alkyl, and haloC1-C6 alkyl; A compound according to any one of [C27] to [C32], a salt thereof, or a solvate thereof. [C36] 5-10 membered heteroaryl (R 4HA The compound according to any one of [C27] to [C32], or a salt thereof, or a solvate thereof, wherein (C27) is 1H-indazol-4-yl or 1H-indazol-4-yl substituted with one or more halogens. [C37] 5-10 membered heteroaryl (R 4HA The compound according to any one of [C27] to [C32], or a salt thereof, or a solvate of the compound or the salt, wherein R is 1H-indazol-4-yl substituted with one or more halogen atoms. [C38] 5-10 membered heteroaryl (R 4HA ) is 1H-indazol-4-yl substituted with halogen at least one of the 5-, 6-, and 7-positions; A compound according to any one of [C27] to [C32], a salt thereof, or a solvate thereof. [C39] 5-10 membered heteroaryl (R 4HA ) is 1H-indazol-4-yl substituted with halogen at least one of the 5-, 6-, and 7-positions, The halogen is fluorine or chlorine. A compound according to any one of [C27] to [C32], a salt thereof, or a solvate thereof. [C40] 5-10 membered heteroaryl (R 4HA ) is 1H-indazol-4-yl substituted with halogen at any one or two of the 5-, 6-, and 7-positions, The halogen is selected from the group consisting of fluorine, chlorine, a combination of fluorine and fluorine, and a combination of fluorine and chlorine; A compound according to any one of [C27] to [C32], a salt thereof, or a solvate thereof. [C40.5] 5-10 membered heteroaryl (R4HA ) is 1H-indazol-4-yl substituted with halogen at any one or two of the 5-, 6-, and 7-positions, the halogens are independently fluorine or chlorine; A compound according to any one of [C27] to [C32], a salt thereof, or a solvate thereof. [D1] A compound selected from the following compounds, or a salt thereof, or a solvate thereof: 3-amino-7-chloro-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-benzo[h]quinolin-2-one, 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-benzo[h]quinolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-benzo[h]quinolin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclopropyl-1H-benzo[h]quinolin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methyl-1H-benzo[h]quinolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propan-2-yl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclopropyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclobutyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-ethyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(5-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-6-cyclopropyl-4-(5-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one, (S)-3-amino-6-cyclopropyl-4-(5-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-ethyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-ethoxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-cyclopropyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propoxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-ethoxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one, 3-amino-6-ethoxy-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one, 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one, 3-amino-6-cyclobutyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,10-phenanthrolin-2-one, 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,10-phenanthrolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,10-phenanthrolin-2-one, 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,10-phenanthrolin-2-one, 3-amino-9-fluoro-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one, 3-amino-9-fluoro-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-9-fluoro-6-methoxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-9-fluoro-6-methyl-1H-1,7-phenanthrolin-2-one, 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-methoxy-10H-pyrido[2,3-f]quinoxalin-9-one, 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-propan-2-yloxy-10H-pyrido[2,3-f]quinoxalin-9-one, 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-methyl-10H-pyrido[2,3-f]quinoxalin-9-one, 8-amino-5-cyclopropyl-7-(7-fluoro-1H-indazol-4-yl)-10H-pyrido[2,3-f]quinoxalin-9-one, 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-methyl-10H-pyrido[3,2-h]quinazolin-9-one, 8-amino-5-cyclopropyl-7-(7-fluoro-1H-indazol-4-yl)-10H-pyrido[3,2-h]quinazolin-9-one, 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,8-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5,6-dimethyl-1H-1,7-phenanthrolin-2-one, 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-5-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-1H-1,7-phenanthrolin-2-one, 3-amino-4-(5,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-6-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yl)-1H-1,7-phenanthrolin-2-one, 3-amino-4-(1H-benzotriazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, and 3-Amino-6-(tert-butyl)-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one. [D2] 3-amino-7-chloro-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-benzo[h]quinolin-2-one or a salt thereof, or a solvate thereof. [D3] 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-benzo[h]quinolin-2-one or a salt thereof, or a solvate thereof. [D4] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-benzo[h]quinolin-2-one or a salt thereof, or a solvate thereof. [D5] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclopropyl-1H-benzo[h]quinolin-2-one or a salt thereof, or a solvate thereof. [D6] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methyl-1H-benzo[h]quinolin-2-one or a salt thereof, or a solvate thereof. [D7] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propan-2-yl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D8] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D9] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclopropyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D10] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclobutyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D11] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-ethyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D12] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D13] 3-amino-4-(5-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D14] 3-Amino-6-cyclopropyl-4-(5-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D15] (S)-3-Amino-6-cyclopropyl-4-(5-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D16] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D16.5] 3-Amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one hydrochloride monohydrate. [D17] 3-Amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D18] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-ethyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D19] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-ethoxy-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D20] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D21] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-cyclopropyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D22] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D23] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D23.5] Hydrochloride salt of 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one. [D24] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propoxy-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D25] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D26] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-ethoxy-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D27] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D28] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D29] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D30] 3-amino-6-ethoxy-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D31] 3-Amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D31.5] Solvate of 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one. [D32] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D32.5] 3-Amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one hydrochloride monohydrate. [D33] 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D34] 3-Amino-6-cyclobutyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D35] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,10-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D36] 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,10-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D37] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,10-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D38] 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,10-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D39] 3-amino-9-fluoro-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D40] 3-amino-9-fluoro-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D41] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-9-fluoro-6-methoxy-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D42] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-9-fluoro-6-methyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D43] 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-methoxy-10H-pyrido[2,3-f]quinoxalin-9-one or a salt thereof, or a solvate thereof. [D44] 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-propan-2-yloxy-10H-pyrido[2,3-f]quinoxalin-9-one or a salt thereof, or a solvate thereof. [D45] 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-methyl-10H-pyrido[2,3-f]quinoxalin-9-one or a salt thereof, or a solvate thereof. [D46] 8-Amino-5-cyclopropyl-7-(7-fluoro-1H-indazol-4-yl)-10H-pyrido[2,3-f]quinoxalin-9-one or a salt thereof, or a solvate thereof. [D47] 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-methyl-10H-pyrido[3,2-h]quinazolin-9-one or a salt thereof, or a solvate thereof. [D48] 8-Amino-5-cyclopropyl-7-(7-fluoro-1H-indazol-4-yl)-10H-pyrido[3,2-h]quinazolin-9-one or a salt thereof, or a solvate thereof. [D49] 3-Amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,8-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D49.1] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5,6-dimethyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D49.2] 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-5-methyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D49.3] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-methyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D49.4] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-6-methyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D49.5] 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D49.6] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D49.7] 3-amino-4-(5,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D49.8] 3-amino-6-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yl)-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D49.9] 3-amino-4-(1H-benzotriazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D49.10] 3-amino-6-(tert-butyl)-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one or a salt thereof, or a solvate thereof. [D50] The compound or salt thereof, or solvate thereof according to any one of [A1] to [A46], [B1] to [B44], and [C1] to [C40], wherein the compound represented by formula (1), formula (2), or formula (3), or salt thereof, or solvate thereof is a compound represented by formula (1), formula (2), or formula (3), or salt thereof. [D51] The compound or salt thereof, or solvate thereof according to any one of [A1] to [A46], [B1] to [B44], and [C1] to [C40], wherein the compound represented by formula (1), formula (2), or formula (3), or salt thereof, or solvate thereof is a compound represented by formula (1), formula (2), or formula (3). [D52] The compound or salt thereof, or solvate thereof according to any one of [A1] to [A46], [B1] to [B44], and [C1] to [C40], wherein the compound represented by formula (1), formula (2), or formula (3), or salt thereof, or solvate thereof is a salt of the compound represented by formula (1), formula (2), or formula (3). [D53] The compound or salt thereof, or solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], and [C1] to [C40], wherein the compound represented by formula (1), formula (2), or formula (3), or salt thereof, or solvate thereof, is a solvate of the compound represented by formula (1), formula (2), or formula (3), or salt thereof. [D54] The compound or salt thereof, or solvate thereof according to any one of [A1] to [A46], [B1] to [B44], and [C1] to [C40], wherein the compound represented by formula (1), formula (2), or formula (3), or salt thereof, or solvate thereof is a compound represented by formula (1), formula (2), or formula (3), or salt thereof, or hydrate thereof. [D55] The compound or salt thereof, or solvate thereof according to any one of [A1] to [A46], [B1] to [B44], and [C1] to [C40], wherein the compound represented by formula (1), formula (2), or formula (3), or salt thereof, or solvate thereof is a hydrate of the compound represented by formula (1), formula (2), or formula (3), or salt thereof. [D56] A compound or a salt thereof, or a solvate thereof, according to any one of [D1] to [D49], wherein the compound or a salt thereof, or a solvate thereof, according to any one of [D1] to [D49], is a compound or a salt thereof, according to any one of [D1] to [D49]. [D57] A compound or a salt thereof, or a solvate thereof, according to any one of [D1] to [D49], wherein the compound or a salt thereof, or a solvate thereof, according to any one of [D1] to [D49], is a compound according to any one of [D1] to [D49]. [D58] A compound or a salt thereof, or a solvate thereof, according to any one of [D1] to [D49], wherein the compound or a salt thereof, or a solvate thereof, according to any one of [D1] to [D49], is a salt of a compound according to any one of [D1] to [D49]. [D59] A compound or a salt thereof, or a solvate thereof, according to any one of [D1] to [D49], wherein the compound or a salt thereof, or a solvate thereof, according to any one of [D1] to [D49], is a solvate of a compound or a salt thereof, according to any one of [D1] to [D49]. [D60] A compound or a salt thereof, or a solvate thereof, according to any one of [D1] to [D49], wherein the compound or a salt thereof, or a solvate thereof, according to any one of [D1] to [D49], is a compound or a salt thereof, or a hydrate thereof, according to any one of [D1] to [D49]. [D61] A compound or a salt thereof, or a solvate thereof, according to any one of [D1] to [D49], wherein the compound or a salt thereof, or a solvate thereof, according to any one of [D1] to [D49], is a hydrate of the compound or a salt thereof, according to any one of [D1] to [D49]. [E1] A pharmaceutical composition comprising, as an active ingredient, a compound or a salt thereof, or a solvate thereof according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61]. [E2] A cancer preventive and / or therapeutic agent comprising, as an active ingredient, a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61]. [E3] An MYT1 inhibitor comprising a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61]. [E4] A method for preventing and / or treating cancer, comprising administering to a subject an effective amount of a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61], or a salt thereof, or a solvate thereof. [E5] A compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61] for use in the prevention and / or treatment of cancer. [E6] Use of a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61] for the manufacture of a pharmaceutical composition for the prevention and / or treatment of cancer. [E6.2] A pharmaceutical composition, a cancer preventive and / or therapeutic agent, a MYT1 inhibitor, a method, a compound or a salt thereof, or a solvate thereof, described in any one of [E1] to [E6], used in combination with a chemotherapeutic agent, described in any one of [E1] to [E6], ... [E7] The present invention relates to a method for treating or preventing cancer in a patient with a cancer in which a positive RB1 gene mutation or a decreased expression of the RB1 gene or protein has been detected, the method comprising: A pharmaceutical composition, wherein the MYT1 inhibitor is a compound or a salt thereof according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61], or a solvate thereof. [E7.2] The present invention relates to a method for treating or preventing cancer in a patient with a cancer that is positive for an RB1 gene mutation or has reduced expression of the RB1 gene or protein, the method comprising: A pharmaceutical composition, wherein the MYT1 inhibitor is a compound or a salt thereof according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61], or a solvate thereof. [E7.5] The present invention relates to a method for treating or preventing cancer in a patient with a cancer in which a positive RB1 gene mutation or a decreased expression of the RB1 gene or protein has been detected, the method comprising: A pharmaceutical composition, wherein the MYT1 inhibitor is a compound or a salt thereof according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61], or a solvate thereof. [E7.7] The present invention relates to a method for treating or preventing cancer in a patient with a cancer that is positive for RB1 gene mutation or has reduced expression of the RB1 gene or protein, the method comprising: A pharmaceutical composition, wherein the MYT1 inhibitor is a compound or a salt thereof according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61], or a solvate thereof. [E8] A method for treating or preventing cancer in a cancer patient in which a positive RB1 gene mutation or a decrease in expression of the RB1 gene or protein has been detected, comprising: administering a combination of a chemotherapy agent and an MYT1 inhibitor to the cancer patient; The method, wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61]. [E8.1] 1. A method for treating or preventing cancer, comprising: Detecting or having a third party detect the positive RB1 gene mutation or the decreased expression of the RB1 gene or protein in a biological sample from a cancer patient; administering a combination of a chemotherapy agent and an MYT1 inhibitor to the cancer patient; The method, wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61]. [E8.2] A method for treating or preventing cancer in a cancer patient who is positive for RB1 gene mutation or has reduced expression of the RB1 gene or protein, comprising: administering a combination of a chemotherapy agent and an MYT1 inhibitor to the cancer patient; The method, wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61]. [E9] A method for suppressing the proliferation of cancer cells in a cancer patient in which a positive RB1 gene mutation or decreased expression of the RB1 gene or protein has been detected, the method comprising contacting the cancer cells with an MYT1 inhibitor and a chemotherapeutic agent, The method, wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61]. [E9.1] A method for inhibiting cancer cell proliferation, comprising: Detecting or having a third party detect the positive RB1 gene mutation or the decreased expression of the RB1 gene or protein in a biological sample from a cancer patient; contacting the cancer cells with an MYT1 inhibitor and a chemotherapeutic agent; The method, wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61]. [E9.2] A method for suppressing the proliferation of cancer cells in a cancer patient who is positive for RB1 gene mutation or has reduced expression of the RB1 gene or protein, the method comprising contacting the cancer cells with an MYT1 inhibitor and a chemotherapeutic agent, The method, wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61]. [E10] 1. A method for improving responsiveness to cancer treatment with a chemotherapeutic agent, comprising: The cancer is a cancer of a patient in which RB1 gene mutation or decreased expression of RB1 gene or protein has been detected, administering an MYT1 inhibitor to the cancer patient together with a chemotherapeutic agent; The method, wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61]. [E10.1] 1. A method for improving responsiveness to cancer treatment with a chemotherapeutic agent, comprising: Detecting or having a third party detect the positive RB1 gene mutation or the decreased expression of the RB1 gene or protein in a biological sample from a cancer patient; administering an MYT1 inhibitor to the cancer patient together with a chemotherapeutic agent; The method, wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61]. [E10.2] 1. A method for improving responsiveness to cancer treatment with a chemotherapeutic agent, comprising: The cancer of the patient is RB1 gene mutation-positive or has decreased expression of the RB1 gene or protein, administering an MYT1 inhibitor to the cancer patient together with a chemotherapeutic agent; The method, wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61]. [E11] A method for predicting responsiveness to cancer treatment with a combination of an MYT1 inhibitor and a chemotherapeutic agent, comprising: Detecting or having a third party detect the presence or absence of RB1 gene mutation or the presence or absence of reduced expression of RB1 gene or protein in a biological sample derived from a cancer patient; determining that the patient is responsive to cancer treatment with a combination of an MYT1 inhibitor and a chemotherapeutic agent if the RB1 gene mutation is positive or if expression of the RB1 gene or protein is reduced; The method, wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61]. [E12] 1. A method for selecting a cancer patient for whom administration of a combination of a MYT1 inhibitor and a chemotherapeutic agent is more effective than administration of a MYT1 inhibitor or / and a chemotherapeutic agent alone, comprising: Detecting or having a third party detect the presence or absence of RB1 gene mutation or the presence or absence of reduced expression of RB1 gene or protein in a biological sample derived from a cancer patient; and determining, based on the presence of the mutation or the decreased expression, that the cancer patient is one for whom administration of a combination of an MYT1 inhibitor and a chemotherapeutic agent is more effective than administration of an MYT1 inhibitor or / and a chemotherapeutic agent alone; The method, wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61]. [E13] A method for screening for a compound effective in treating or preventing cancer in a cancer patient in which a positive RB1 gene mutation or a decrease in expression of the RB1 gene or protein has been detected, comprising: A method comprising measuring the MYT1 inhibitory activity of a candidate compound and selecting a candidate compound having MYT1 inhibitory activity as a compound effective in treating cancer. [E13.2] A method for screening for a compound effective in treating or preventing cancer in a cancer patient who is positive for RB1 gene mutation or has reduced expression of the RB1 gene or protein, comprising: A method comprising measuring the MYT1 inhibitory activity of a candidate compound and selecting a candidate compound having MYT1 inhibitory activity as a compound effective in treating cancer. [E14] 1. A MYT1 inhibitor for use in combination with a chemotherapeutic agent in the treatment or prevention of cancer in a cancer patient in which RB1 gene mutation or reduced expression of the RB1 gene or protein has been detected, The MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61]. [E14.2] 1. An MYT1 inhibitor for use in combination with a chemotherapeutic agent in the treatment or prevention of cancer in a cancer patient who is positive for an RB1 gene mutation or has reduced expression of the RB1 gene or protein, The MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61]. [E15] A chemotherapeutic agent for use in combination with an MYT1 inhibitor in the treatment or prevention of cancer in a cancer patient in which RB1 gene mutation or reduced expression of the RB1 gene or protein has been detected, comprising: A chemotherapeutic agent, wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61]. [E15.2] A chemotherapeutic agent for use in combination with an MYT1 inhibitor in the treatment or prevention of cancer in a cancer patient who is positive for an RB1 gene mutation or has reduced expression of the RB1 gene or protein, A chemotherapeutic agent, wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61]. [E16] Use of an MYT1 inhibitor for the manufacture of a pharmaceutical composition for treating or preventing cancer in a cancer patient in which RB1 gene mutation or reduced expression of the RB1 gene or protein has been detected, the composition being administered in combination with a chemotherapeutic agent, comprising: Use wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, selected from the group consisting of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61]. [E16.2] Use of an MYT1 inhibitor for the manufacture of a pharmaceutical composition for treating or preventing cancer in a cancer patient who is positive for RB1 gene mutation or has reduced expression of the RB1 gene or protein, the composition being administered in combination with a chemotherapeutic agent, comprising: Use wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, selected from the group consisting of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61]. [E17] 1. Use of a chemotherapeutic agent for the manufacture of a pharmaceutical composition for treating or preventing cancer in a cancer patient in which RB1 gene mutation or reduced expression of RB1 gene or protein has been detected, the pharmaceutical composition being administered in combination with an MYT1 inhibitor, Use wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, selected from the group consisting of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61]. [E17.2] 1. Use of a chemotherapeutic agent for the manufacture of a pharmaceutical composition for treating or preventing cancer in a cancer patient who is positive for RB1 gene mutation or has reduced expression of the RB1 gene or protein, the composition being administered in combination with an MYT1 inhibitor, Use wherein the MYT1 inhibitor is a compound or a salt thereof, or a solvate thereof, selected from the group consisting of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61]. [E18] The pharmaceutical composition, method, MYT1 inhibitor for use, chemotherapeutic agent for use, or use according to any one of [E7] to [E17], wherein the chemotherapeutic agent is an antimetabolite. [E19] The pharmaceutical composition, method, MYT1 inhibitor for use, chemotherapeutic agent for use, or use according to [E18], wherein the metabolic antagonist is a folate antagonist. [E20] The pharmaceutical composition, method, MYT1 inhibitor for use, chemotherapeutic agent for use, or use according to [E19], wherein the folate metabolic antagonist is pemetrexed. [E21] The pharmaceutical composition, method, MYT1 inhibitor for use, chemotherapeutic agent for use, or use according to any one of [E7] to [E20], wherein the cancer is lung cancer.

[0007] In the above numbering scheme, unless otherwise specified, the numbers referred to in dependent claims include numbers with different decimal points. For example, [C6] referred to in a dependent claim indicates that it includes [C6] as well as [C6.5]. The same applies to other numbering schemes. [Effects of the Invention]

[0008] The present invention provides a novel compound or a salt thereof, or a solvate thereof, which has inhibitory activity against MYT1, and a pharmaceutical agent containing the compound or salt as an active ingredient, which is useful for treating and preventing cancer. [Brief explanation of the drawings]

[0009] [Figure 1] 1 is a graph showing the cell viability calculated in a pemetrexed-induced cytotoxicity test when example compounds (A12, A59, B3, B22, B23, B24, B32, B35, and B37) were added. [Figure 2]1 is a graph showing the cell viability calculated in a pemetrexed-induced cytotoxicity test when example compounds (B46, B47, B48, B49, C1, C4, C8, C13, and C64) were added. [Figure 3] 1 is a graph showing the cell viability calculated in a pemetrexed-induced cell damage test when example compounds (C65, C67, C69, C76, C78, ​​C83, C84, C85, and C86) were added. [Figure 4] 1 is a graph showing the cell viability calculated in a pemetrexed-induced cell damage test when example compounds (C88, C90, C91, C92, C98, C100, C101, C102, and C134) were added. [Figure 5] 1 is a graph showing the cell viability calculated in a pemetrexed-induced cell damage test when example compounds (C135, C136, C137, C138, C139, C140, C141, C143, and C144) were added. [Figure 6] 1 is a graph showing the cell viability calculated in a pemetrexed-induced cell damage test when example compounds (C146, C155, C156, C185, C190, C195, C200, D2, and F2) were added. [Figure 7] 1 is a graph showing the cell viability calculated in a pemetrexed-induced cell damage test when example compounds (G16, H3, K4, L3, M4, N2, O1, P1, and P4) were added. [Figure 8] 1 is a graph showing the cell viability calculated in a cell damage test using pemetrexed when an example compound (Q1) was added. [Figure 9] The results of simultaneous measurements of thermogravimetry, differential scanning calorimetry, and mass spectrometry for sample A are shown. The horizontal axis is temperature (°C). The left vertical axis is the weight change (%) of the sample in thermogravimetry. The right vertical axis is the heat flow (mW / mg) observed in differential thermal analysis (left) and the peak intensity observed in mass spectrometry (right). [Figure 10]The results of simultaneous measurements of thermogravimetry, differential scanning calorimetry, and mass spectrometry for sample A-1 are shown below. The horizontal axis is temperature (°C). The left vertical axis is the weight change (%) of the sample in thermogravimetry (this is a reference value, as the results are direct measurements of a sample that was filtered through a mesh and dried). The right vertical axis is the heat flow (mW / mg) observed in differential thermal analysis (left) and the peak intensity observed in mass spectrometry (right). [Figure 11] The results of simultaneous thermogravimetric and differential thermal analysis of sample A-2 are shown below. The horizontal axis is temperature (°C). The right vertical axis is the weight change (%) of the sample in the thermogravimetric analysis. The left vertical axis is the heat flow (μV) observed in the differential thermal analysis. [Figure 12] The results of simultaneous measurements of thermogravimetry, differential scanning calorimetry, and mass spectrometry for sample B are shown. The horizontal axis is temperature (°C). The left vertical axis is the weight change (%) of the sample in thermogravimetry. The right vertical axis is the heat flow (mW / mg) observed in differential thermal analysis (left) and the peak intensity observed in mass spectrometry (right). [Figure 13] The results of simultaneous thermogravimetric and differential thermal analysis of sample B-2 are shown below. The horizontal axis is temperature (°C). The right vertical axis is the weight change (%) of the sample in the thermogravimetric analysis. The left vertical axis is the heat flow observed in the differential thermal analysis. [Figure 14] The results of simultaneous measurements of thermogravimetry, differential scanning calorimetry, and mass spectrometry for sample B-3 are shown below. The horizontal axis is temperature (°C). The left vertical axis is the weight change (%) of the sample in thermogravimetry (this is a reference value, as the results are direct measurements of a sample that was filtered and dried through a mesh). The right vertical axis is the heat flow (mW / mg) observed in differential thermal analysis (left) and the peak intensity observed in mass spectrometry (right). [Figure 15] The results of simultaneous measurements of thermogravimetry, differential scanning calorimetry, and mass spectrometry for sample C are shown. The horizontal axis is temperature (°C). The left vertical axis is the weight change (%) of the sample in thermogravimetry. The right vertical axis is the heat flow (mW / mg) observed in differential thermal analysis (left) and the peak intensity observed in mass spectrometry (right). [Figure 16]The results of simultaneous measurements of thermogravimetry, differential scanning calorimetry, and mass spectrometry for sample C-1 are shown below. The horizontal axis is temperature (°C). The left vertical axis is the weight change (%) of the sample in thermogravimetry (this is a reference value, as the results are direct measurements of a sample that was filtered and dried through a mesh). The right vertical axis is the heat flow (mW / mg) observed in differential thermal analysis (left) and the peak intensity observed in mass spectrometry (right). [Figure 17] The results of simultaneous measurements of thermogravimetry, differential scanning calorimetry, and mass spectrometry for sample C-2 are shown below. The horizontal axis is temperature (°C). The left vertical axis is the weight change (%) of the sample in thermogravimetry (this is a reference value, as the results are direct measurements of a sample that was filtered and dried through a mesh). The right vertical axis is the heat flow (mW / mg) observed in differential thermal analysis (left) and the peak intensity observed in mass spectrometry (right). [Figure 18] The results of simultaneous thermogravimetric and differential thermal analysis of sample D are shown below. The horizontal axis is temperature (°C). The right vertical axis is the weight change (%) of the sample in the thermogravimetric analysis. The left vertical axis is the heat flow (μV) observed in the differential thermal analysis. [Figure 19] This shows the asymmetric unit of the crystal structure of sample E. It is drawn using an ellipsoid model (probability level: 50%). DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention will be described in detail below by showing definitions of symbols, terms, etc. used in this specification, and embodiments of the present invention.

[0011] As used herein, "halogen" means fluorine, chlorine, bromine, or iodine.

[0012] As used herein, "thio(thiol)" refers to -SH.

[0013] As used herein, "amino" refers to -NRR', where R and R' are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or R and R' are taken together with the nitrogen atom to which they are attached to form a ring. Preferred examples of amino include -NH2, mono C1-C6 alkylamino (hereinafter referred to as "C p -C q " means that the number of carbon atoms is p to q), diC1-C6 alkylamino, and 4- to 8-membered cyclic amino.

[0014] As used herein, "alkoxy" refers to an oxy group bonded to an "alkyl" as defined herein. Preferred examples of alkoxy include C1-C6 alkoxy, and more preferably C1-C4 alkoxy. Specific examples of alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentyloxy, and 3-methylbutoxy.

[0015] As used herein, "alkylthio" refers to a "thio" group bonded to an "alkyl" as defined herein. Preferred alkylthio groups include C1-C6 alkylthio, and more preferably C1-C4 alkylthio. Specific examples of alkylthio groups include methylthio, ethylthio, 1-propylthio, 2-propylthio, n-butylthio, i-butylthio, s-butylthio, and t-butylthio.

[0016] As used herein, "sulfonyl" refers to -S(=O)2-R, where R is selected from the group consisting of hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Preferred examples of sulfonyl include C1-C6 alkylsulfonyl.

[0017] As used herein, "phosphoryl" refers to -P(=O)RR', where R and R' are each independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. Preferred examples of phosphoryl include mono-C1-C6 alkylphosphoryl and di-C1-C6 alkylphosphoryl.

[0018] As used herein, "boryl" refers to -BRR', where R and R' are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or R and R' form a ring together with the boron atom to which they are attached. Preferred examples of boryl include dihydroxyboryl, mono-C1-C6 alkylboryl, di-C1-C6 alkylboryl, and 4- to 8-membered cyclic boryl. Specific examples of boryl include dihydroxyboryl, pinacolatoboryl, neopentanediolateboryl, catecholatoboryl, and 9-borabicyclo[3.3.1]nonan-9-yl.

[0019] As used herein, "alkyl" refers to a monovalent group derived from an aliphatic hydrocarbon by removing any one hydrogen atom, and does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in the skeleton, but has a subset of hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. Alkyl includes not only linear but also branched chains. Preferred examples of alkyl include C1-C6 alkyl, and more preferably C1-C4 alkyl. Specific examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (2-methylpropyl), n-pentyl, s-pentyl (1-methylbutyl), t-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl.

[0020] As used herein, "alkenyl" refers to an alkyl group having at least one double bond (two adjacent sp 2 It is a monovalent group having 1 carbon atom. Depending on the configuration of the double bond and substituents (if any), the geometry of the double bond can be Entgegen (E) or Zusammen (Z), cis or trans. Alkenyl includes not only straight chain but also branched chain. Preferred alkenyls include C2-C6 alkenyls, more preferably C2-C4 alkenyls. Specific examples of alkenyls include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, hexenyl, etc.

[0021] As used herein, "alkynyl" refers to a monovalent group having at least one triple bond (two adjacent SP carbon atoms). Alkynyl includes not only straight-chain but also branched-chain alkynyl. Preferred examples of alkynyl include C2-C6 alkynyl, and more preferably C2-C4 alkynyl. Specific examples of alkynyl include ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl, 3-(3-fluorophenyl)-2-propynyl, and 3-methyl-(5-phenyl)-4-pentynyl.

[0022] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclic, and spirocyclic rings. Preferred examples of cycloalkyl include C3-C8 cycloalkyl, and more preferably C3-C6 cycloalkyl. Specific examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptyl, spiro[2.3]hexyl, and spiro[4.5]decyl.

[0023] As used herein, the term "aryl" refers to a monovalent aromatic hydrocarbon ring, i.e., an aromatic hydrocarbon ring group. The aryl is preferably a C6-C 10 Specific examples of the aryl include phenyl and naphthyl (e.g., 1-naphthyl, 2-naphthyl).

[0024] As used herein, the term "heterocyclyl" refers to a non-aromatic cyclic monovalent group containing 1 to 5 heteroatoms in addition to carbon atoms. Heterocyclyl may have a double and / or triple bond within the ring, and a carbon atom within the ring may be oxidized to form a carbonyl. It includes monocyclic, fused, and spirocyclic rings. In the case of fused rings, an aromatic ring such as a benzene ring, pyridine ring, or pyrimidine ring may be fused with a saturated alicyclic ring such as a cyclopentane ring or a cyclohexane ring, or with a saturated heterocyclic ring such as a tetrahydropyran ring, dioxane ring, or pyrrolidine ring. The number of atoms constituting the heterocyclyl ring is preferably 4 to 10 (4- to 10-membered heterocyclyl), and more preferably 4 to 7 (4- to 7-membered heterocyclyl).Specific examples of heterocyclyl include azetidinyl, oxoazetidinyl, oxiranyl, oxetanyl, azetidinyl, dihydrofuryl, tetrahydrofuryl (oxolan-2-yl, oxolan-3-yl), dihydropyranyl, tetrahydropyranyl (oxan-4-yl), tetrahydropyridyl, tetrahydropyrimidyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxopyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxa Zolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-thiazinane, thiadiazolidinyl, oxazolidonyl, benzodioxanyl, benzoxazolyl, dioxolanyl, dioxanyl, tetrahydropyrrolo[1,2-c]imidazole, thietanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 2,4,5-trimethylpiperazin-1-yl, sultam , 2-oxaspiro[3.3]heptyl, 6,7-dihydro-pyrrolo[1,2-a]imidazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, azepanyl, dioxepanyl, 5,9-dioxaspiro[3.5]nonanyl, 1,1-dioxo-1,4-thiazinan-4-yl, carbonylazetidinyl, acetylpiperidinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2-oxa-7-azaspiro[3.4]octan-7-yl, 3-oxa-6-azabicyclo[ 3.1.1]heptan-6-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, (9aR)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl, 3-(azetidin-1-yl)azetidin-1-yl, 1-(oxetan-3-yl)piperidin-4-yl, 1-(oxan-4-yl)piperidin-4-yl, 4-pyrrolidin-1-ylpiperidin-1-yl, 4-morpholin-4-ylpiperidin-1-yl, and the like.

[0025] As used herein, the term "heteroaryl" refers to an aromatic monovalent cyclic group containing 1 to 5 heteroatoms in addition to carbon atoms, i.e., an aromatic heterocyclic group. The ring may be a single ring or a condensed ring with another ring. The number of atoms constituting the heteroaryl ring is preferably 5 to 10 (5- to 10-membered heteroaryl), and more preferably 5 to 7 (5- to 7-membered heteroaryl). Specific examples of heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, pyrrolopyrazinyl, and furopyridyl.

[0026] As used herein, "alkylsulfonyl" refers to a "sulfonyl" group bonded to an "alkyl" or "cycloalkyl" as defined herein. Preferred alkylsulfonyl groups include C1-C6 alkylsulfonyl and C3-C8 cycloalkylsulfonyl, more preferably C1-C4 alkylsulfonyl and C3-C6 cycloalkylsulfonyl. Specific examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, 1-propylsulfonyl, 2-propylsulfonyl, n-butylsulfonyl, i-butylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, and the like.

[0027] As used herein, "acylamino" refers to a group in which R is hydrogen and R' is "acyl" as defined herein, within the meaning of "amino" as defined herein. Preferred examples of acylamino include C1-C6 acylamino, and more preferably C1-C4 acylamino. Specific examples of acylamino include acetylamino.

[0028] As used herein, "monoalkylamino" refers to an "amino" as defined herein, in which R is hydrogen and R' is an "alkyl" as defined herein. Preferred examples of monoalkylamino include mono-C1-C6 alkylamino, and more preferred examples of mono-C1-C4 alkylamino. Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, and t-butylamino.

[0029] As used herein, "alkylsulfonylamino" refers to an "amino" as defined herein, in which R is hydrogen and R' is "alkylsulfonyl" as defined herein. Preferred alkylsulfonylamino groups include C1-C6 alkylsulfonylamino and C3-C8 cycloalkylsulfonylamino, more preferably C1-C4 alkylsulfonylamino and C3-C6 cycloalkylsulfonylamino. Specific examples of alkylsulfonylamino groups include methylsulfonylamino, ethylsulfonylamino, cyclopropylsulfonylamino, etc.

[0030] As used herein, "haloalkoxy" refers to a group in which one or more hydrogen atoms of an "alkoxy" as defined herein are substituted with a "halogen". Preferred examples of haloalkoxy include halo C1-C6 alkoxy, and more preferably halo C1-C4 alkoxy. Specific examples of haloalkoxy include difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 3,3-difluoropropoxy, (2R)-2-fluoropropoxy, [(2S)-1,1,1-trifluoropropan-2-yl]oxy, [(2R)-1,1,1-trifluoropropan-2-yl]oxy, 3,3,3-trifluoro-2,2-dimethylpropoxy, and the like.

[0031] As used herein, "hydroxyalkoxy" refers to a group in which one or more hydrogen atoms of an "alkoxy" as defined herein have been replaced with a hydroxyl group (hydroxy group). Preferred examples of hydroxyalkoxy include hydroxy C1-C6 alkoxy, and more preferably hydroxy C1-C4 alkoxy. Specific examples of hydroxyalkoxy include 2-hydroxy-2-methylpropoxy, 3-hydroxy-3-methylbutoxy, 4-hydroxybutoxy, etc.

[0032] As used herein, "alkoxyalkoxy" refers to a group in which an "alkoxy" is bonded to an "alkoxy" as defined herein. Preferred examples of alkoxyalkoxy include C1-C6 alkoxyC1-C6 alkoxy, and more preferably C1-C4 alkoxyC1-C4 alkoxy. Specific examples of alkoxyalkoxy include 2-methoxyethoxy, (2S)-2-methoxypropoxy, (2R)-2-methoxypropoxy, etc.

[0033] As used herein, "cycloalkylalkoxy" refers to an oxy group bonded to a "cycloalkylalkyl" as defined herein. Preferred examples of cycloalkylalkoxy include C3-C8 cycloalkylC1-C6 alkoxy, and more preferably C3-C6 cycloalkylC1-C4 alkoxy. Specific examples of cycloalkylalkoxy include cyclopropylmethoxy, cyclobutanylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, 1-bicyclo[1.1.1]pentanylmethoxy, and the like.

[0034] As used herein, "heterocyclylalkoxy" refers to an oxy group in which a "heterocyclyl" as defined herein is bonded via an "alkyl". Preferred examples of heterocyclylalkoxy include 4- to 10-membered heterocyclyl C1-C6 alkoxy, and more preferably 4- to 7-membered heterocyclyl C1-C4 alkoxy. Specific examples of heterocyclylalkoxy include (1,1-dioxothian-4-yl)oxy, oxolan-2-ylmethoxy, oxolan-3-ylmethoxy, oxan-4-ylmethoxy, 1,4-dioxan-2-ylmethoxy, (1-methylpiperidin-4-yl)methoxy, 3-morpholin-4-ylpropoxy, (oxetan-3-yl)methoxy, and the like.

[0035] As used herein, "cycloalkoxy" refers to an oxy group bonded to a "cycloalkyl" as defined herein. Preferred examples of cycloalkoxy include C3-C8 cycloalkoxy, and more preferably C3-C6 cycloalkoxy. Specific examples of cycloalkoxy include cyclopropoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.

[0036] As used herein, "heterocyclyloxy" refers to an oxy group bonded to a "heterocyclyl" as defined herein. The number of atoms constituting the heterocyclyl ring is preferably 4 to 10 (4- to 10-membered heterocyclyloxy), more preferably 4 to 7 (4- to 7-membered heterocyclyloxy). Specific examples of heterocyclyloxy include azetidinyloxy, oxiranyloxy, oxetanyloxy, azetidinyloxy, dihydrofuryloxy, tetrahydrofuryloxy ([(3R)-oxolan-3-yl]oxy, [(3S)-oxolan-3-yl]oxy), dihydropyranyloxy, tetrahydropyranyloxy (oxan-4-yloxy), [(3S)-oxan-3-yl]oxy, [(3R)-oxan-3-yl]oxy), tetrahydropyridyloxy, tetrahydropyrimidyloxy, morpholinyloxy, thiomorpholinyloxy, pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, pyrazolidinyloxy, imidazolinyloxy, and methyl. Midazolidinyloxy, oxazolidinyloxy, isoxazolidinyloxy, thiazolidinyloxy, isothiazolidinyloxy, 1,2-thiazinaneoxy, thiadiazolidinyloxy, oxazolidonyloxy, benzodioxanyloxy, benzoxazolyloxy, dioxolanyloxy, dioxanyloxy, tetrahydropyrrolo[1,2-c]imidazoloxy, thietanyloxy, 3,6-diazabicyclo[3.1.1]heptanyloxy, 2,5-diazabicyclo[2.2.1]heptanyloxy, 3-oxa-8-azabicyclo[3.2.1]octanyloxy, sultamoxy, 2-oxaspiro[3.3]heptyloxy, tetrahydrothiopyranyloxy, and the like.

[0037] As used herein, "acyl (alkanoyl)" refers to a group in which a carbonyl group is bonded to hydrogen or "alkyl" as defined herein. Preferred examples of acyl include C1-C6 acyl, and more preferably C2-C4 acyl. Specific examples of acyl include formyl, acetyl, propionyl, butanoyl, etc.

[0038] As used herein, "aminocarbonyl" refers to a carbonyl group bonded to "amino," as defined herein. Preferred examples of aminocarbonyl include -CONH, mono-C1-C6 alkylaminocarbonyl, mono-C3-C8 cycloalkylaminocarbonyl, di-C1-C6 alkylaminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl. Specific examples of aminocarbonyl include -CONH, dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxidethiomorpholinyl-4-ylcarbonyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl, and N-cyclopropylaminocarbonyl.

[0039] As used herein, "alkylphosphoryl" refers to a "phosphoryl" bonded to an "alkyl" as defined herein. Examples of alkylphosphoryl include mono-C1-C6 alkylphosphoryl and di-C1-C6 alkylphosphoryl, more preferably mono-C1-C4 alkylphosphoryl and di-C1-C4 alkylphosphoryl. Specific examples of alkylphosphoryl include methylphosphoryl, ethylphosphoryl, dimethylphosphoryl, diethylphosphoryl, etc.

[0040] As used herein, the term "haloalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with a "halogen." Preferred examples of haloalkyl include halo C1-C6 alkyl, and more preferably halo C1-C4 alkyl. Specific examples of haloalkyl include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 1,1,1-trifluoro-2-propyl, 4,4-difluorobutyl, 5,5-difluoropentyl, and the like.

[0041] As used herein, "hydroxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein have been replaced with a hydroxyl group (hydroxy group). Preferred examples of hydroxyalkyl include hydroxy C1-C6 alkyl, and more preferably hydroxy C1-C4 alkyl. Specific examples of hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 5-hydroxypentyl, etc.

[0042] As used herein, "aminocarbonylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with an "aminocarbonyl" as defined herein. Preferred examples of aminocarbonylalkyl include aminocarbonyl C1-C6 alkyl, mono-C1-C6 alkylaminocarbonyl C1-C6 alkyl, and di-C1-C6 alkylaminocarbonyl C1-C6 alkyl, and more preferably aminocarbonyl C1-C4 alkyl, mono-C1-C4 alkylaminocarbonyl C1-C4 alkyl, and di-C1-C4 alkylaminocarbonyl C1-C4 alkyl. Specific examples of aminocarbonylalkyl include methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, t-butylaminocarbonylmethyl, 1-azetidinylcarbonylmethyl, 1-pyrrolidinylcarbonylmethyl, 1-piperidinylcarbonylmethyl, 4-morpholinylcarbonylmethyl, 2-(methylaminocarbonyl)ethyl, 2-(dimethylaminocarbonyl)ethyl, 2-(1-azetidinylcarbonyl)ethyl, 2-(1-pyrrolidinylcarbonyl)ethyl, 2-(4-morpholinylcarbonyl)ethyl, 3-(dimethylaminocarbonyl)propyl, and 4-(dimethylaminocarbonyl)butyl.

[0043] As used herein, "cycloalkylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined above are substituted with a "cycloalkyl" as defined above. Preferred examples of cycloalkylalkyl include C3-C8 cycloalkylC1-C6 alkyl, and more preferably C3-C6 cycloalkylC1-C4 alkyl. Specific examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc.

[0044] As used herein, "hydroxyalkenyl" refers to a group in which one or more hydrogen atoms of an "alkenyl" as defined herein have been replaced with a hydroxyl group (hydroxy group). Preferred examples of hydroxyalkenyl include hydroxy C2-C6 alkenyl, and more preferably hydroxy C2-C4 alkenyl. Specific examples of hydroxyalkenyl include (E)-4-hydroxybut-1-enyl.

[0045] As used herein, "hydroxyalkynyl" refers to a group in which one or more hydrogen atoms of an "alkynyl" as defined herein have been replaced with a hydroxyl group (hydroxy group). Preferred examples of hydroxyalkynyl include hydroxy C2-C6 alkynyl, and more preferred examples of hydroxy C2-C4 alkynyl. Specific examples of hydroxyalkynyl include 3-hydroxy-3-methylbut-1-ynyl, etc.

[0046] As used herein, the term "alicyclic ring" refers to a non-aromatic hydrocarbon ring. The alicyclic ring may have an unsaturated bond within the ring. The carbon atoms constituting the ring may be oxidized to form a carbonyl. The alicyclic ring may be a monocyclic ring (referred to as a monocyclic alicyclic ring in this specification) or may form a condensed ring with a saturated alicyclic ring such as a cyclopentane ring or a cyclohexane ring, or an aromatic hydrocarbon ring such as a benzene ring or a naphthalene ring. Preferred examples of the alicyclic ring include 3- to 10-membered alicyclic rings. Specific examples of the alicyclic ring include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, and a bicyclo[2.2.1]heptane ring.

[0047] As used herein, the term "aromatic hydrocarbon ring" refers to a hydrocarbon ring consisting of a single ring or fused rings that exhibits aromaticity. Preferred examples of the aromatic hydrocarbon ring include 6- to 10-membered aromatic hydrocarbon rings. Specific examples of the aromatic hydrocarbon ring include a benzene ring and a naphthalene ring.

[0048] As used herein, the term "heterocycle" refers to a non-aromatic heterocycle containing preferably 1 to 5, and more preferably 1 to 3, heteroatoms among the atoms constituting the ring. The heterocycle may have a double and / or triple bond in the ring, and a carbon atom in the ring may be oxidized to form a carbonyl. The heterocycle may be a monocycle (referred to as a monocyclic heterocycle in this specification) or may form a fused ring or a spiro ring with a saturated alicyclic ring such as a cyclopentane ring or a cyclohexane ring, or a saturated heterocycle such as a tetrahydropyran ring, a dioxane ring, or a pyrrolidine ring. The number of atoms constituting the heterocycle ring is preferably 3 to 12 (3- to 12-membered heterocycle), more preferably 4 to 10 (4- to 10-membered heterocycle). Specific examples of heterocyclic rings include an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 4-oxopyrrolidine ring, a piperidine ring, a 4-oxopiperidine ring, a piperazine ring, a pyrazolidine ring, an imidazolidine ring, an oxazolidine ring, an isoxazolidine ring, a thiazolidine ring, an isothiazolidine ring, a thiadiazolidine ring, and an oxazolidone ring. , dioxolane ring, dioxane ring, thietane ring, octahydroindole ring, 6,7-dihydro-pyrrolo[1,2-a]imidazole ring, azocane ring, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine ring, azepane ring, dioxepane ring, 5,9-dioxaspiro[3.5]nonane ring, or rings in which one or more single bonds in these saturated heterocycles are replaced with double bonds or triple bonds.

[0049] As used herein, the term "aromatic heterocycle" refers to a cyclic compound consisting of a single ring or fused rings containing one or more heteroatoms and exhibiting aromaticity. In this specification, a cyclic compound consisting of a single ring exhibiting aromaticity is referred to as a monocyclic aromatic heterocycle. Preferred examples of aromatic heterocycles include 5- to 10-membered aromatic heterocycles. Specific examples of the aromatic heterocycle include a furan ring, a thiophene ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, an oxadiazole ring, a thiadiazole ring, a triazole ring, a tetrazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, a triazine ring, a benzofuran ring, a benzothiophene ring, a benzothiadiazoline ring, a benzothiazoline ring, a benzoxazoline ring, a benzoxadiazoline ring, a benzimidazole ring, a benzotriazole ring, an indole ring, an isoindole ring, an indazole ring, an azaindole ring, a quinoline ring, an isoquinoline ring, a cinnoline ring, a quinazoline ring, a quinoxaline ring, a benzodioxole ring, an indolizine ring, an imidazopyridine ring, a pyrazolopyridine ring, an imidazopyridine ring, a triazolopyridine ring, a pyrrolopyrazine ring, and a furopyridine ring.

[0050] As used herein, the term "optionally substituted" means that a group is unsubstituted or substituted with one or more substituents. When a group is substituted with multiple substituents, the substituents may be the same or different from one another. Furthermore, each of these groups may be substituted with a substituent, and the substituents are not limited. For example, one or more substituents may be independently selected from any substituents containing a halogen atom, an oxygen atom, a sulfur atom, a nitrogen atom, a boron atom, a silicon atom, or a phosphorus atom. Examples of the substituents include deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10Examples include aryl and 5- to 10-membered heteroaryl.

[0051] As used herein, "one or more" means one or more than one. When "one or more" is used in the context of substituents on a group, the term means from one to the maximum number of substituents permitted by the group.

[0052] In this specification, the use of "to" indicating a numerical range includes both ends of the range. For example, "A to B" means a numerical range that is equal to or greater than A and equal to or less than B.

[0053] As used herein, the term "about" when used in conjunction with a numerical value means a range of values ​​of plus and minus 10% of that numerical value.

[0054] As used herein, the term "and / or" includes any combination of "and" and "or." Specifically, for example, "A, B, and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, and (vii) A, B, and C.

[0055] One embodiment of the present invention is a compound represented by general formula (1) (hereinafter also referred to as "compound (1)"), a salt thereof, or a solvate thereof.

[0056] In compound (1), R4 is an optionally substituted C6-C 10 Aryl (R 4A ), optionally substituted 4- to 10-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl (R 4HA ) is selected from the group consisting of

[0057] R4 is preferably an optionally substituted C6-C 10 Aryl (R 4A ) or optionally substituted 5- to 10-membered heteroaryl (R4HA )

[0058] R4 is optionally substituted C6-C 10 Aryl (R 4A ), then R 4A is preferably phenyl.

[0059] C6-C 10 Aryl (R 4A As a preferred embodiment (i) of R 4A is unsubstituted or contains one or more R a and one or more R a are each independently deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, and the hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted.

[0060] C6-C 10 Aryl (R 4A As a preferred embodiment (ii) of R 4A is unsubstituted or contains one or more R a and one or more R a are each independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, haloC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, and C1-C6 alkylsulfonylamino.

[0061] C6-C 10 Aryl (R 4A As a preferred embodiment (iii) of R 4A is unsubstituted or contains one or more R a and one or more R a are each independently selected from the group consisting of halogen, hydroxy, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, and C1-C6 alkylsulfonylamino.

[0062] R4 is an optionally substituted 5- to 10-membered heteroaryl (R 4HA ), then R 4HAPreferred examples of the alkyl group include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, and iodo. isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, pyrrolopyrazinyl, and furopyridyl, and more preferably furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl ... imidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, triazolopyridyl, pyrrolopyrazinyl and It is preferably selected from the group consisting of pyridyl, pyrimidyl, benzimidazolyl, indolyl, indazolyl, and pyrazolopyridyl, more preferably selected from the group consisting of pyrimidyl, benzimidazolyl, indolyl, indazolyl, and pyrazolopyridyl, and is particularly preferably 1H-indazol-6-yl or 1H-indazol-4-yl, and most preferably 1H-indazol-4-yl.

[0063] 5-10 membered heteroaryl (R 4HA As a preferred embodiment (i) of R 4HA is unsubstituted or contains one or more R a and one or more R aare each independently deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, and the hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted.

[0064] 5-10 membered heteroaryl (R 4HA As a preferred embodiment (ii) of R 4HA is unsubstituted or contains one or more R a and one or more R a are each independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, haloC1-C6 alkyl, hydroxyC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, and C1-C6 alkylsulfonylamino.

[0065] 5-10 membered heteroaryl (R 4HA As a preferred embodiment (iii) of R 4HA is unsubstituted or contains one or more R a and one or more R a are each independently selected from the group consisting of halogen, cyano, amino, C1-C6 alkyl, and haloC1-C6 alkyl.

[0066] 5-10 membered heteroaryl (R 4HA As a preferred embodiment (iv) of R 4HAis 1H-indazol-4-yl or 1H-indazol-4-yl substituted with one or more halogens.

[0067] 5-10 membered heteroaryl (R 4HA As a preferred embodiment (v) of R 4HA is 1H-indazol-4-yl substituted with one or more halogens.

[0068] 5-10 membered heteroaryl (R 4HA As a preferred embodiment (vi) of R 4HA is 1H-indazol-4-yl substituted with halogen at least one of the 5-, 6-, and 7-positions.

[0069] 5-10 membered heteroaryl (R 4HA As a preferred embodiment (vii) of R 4HA is 1H-indazol-4-yl substituted with a halogen at least one of the 5-, 6-, and 7-positions, and the halogen is fluorine or chlorine.

[0070] 5-10 membered heteroaryl (R 4HA As a preferred embodiment (viii) of the formula (I), R 4HA is 1H-indazol-4-yl substituted with halogen at any one or two of the 5-, 6-, and 7-positions, and the halogen is selected from the group consisting of fluorine, chlorine, a combination of fluorine and fluorine, and a combination of fluorine and chlorine.

[0071] In compound (1), R5 and R6 together with the atom to which they are attached form an optionally substituted D ring, and the D ring is a 3- to 10-membered monocyclic alicyclic ring, a benzene ring, a 3- to 12-membered monocyclic heterocyclic ring, and a 5- to 6-membered monocyclic aromatic heterocyclic ring (D HA ), and any two adjacent substituents on ring D may be taken together with the atoms to which they are attached to form an optionally substituted ring E.

[0072] The D ring is preferably a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle (D HA )

[0073] Ring D is a 5- to 6-membered monocyclic aromatic heterocycle (D HA ), then D HA is preferably selected from the group consisting of a furan ring, a thiophene ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, an oxadiazole ring, a thiadiazole ring, a triazole ring, a tetrazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, and a triazine ring, more preferably selected from the group consisting of a pyridine ring, a pyrimidine ring, a pyridazine ring, and a pyrazine ring, and even more preferably a pyridine ring.

[0074] In one preferred embodiment of the D ring (i), the D ring is unsubstituted or contains one or more R D and one or more R D are each independently deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, and the hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted.

[0075] In a preferred embodiment (ii) of the D ring, the D ring is unsubstituted or contains one or more R D and one or more R Dare each independently halogen, cyano, hydroxy, C1-C6 alkylthio, C1-C6 acylamino, mono C1-C6 alkylamino, C1-C6 alkylsulfonylamino, C3-C8 cycloalkylsulfonylamino, C1-C6 alkoxy, haloC1-C6 alkoxy, hydroxyC1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, 4-10 membered heterocyclylC1-C6 alkoxy, C3-C8 cycloalkoxy, 4-10 membered heterocyclyl oxy, C1-C6 acyl, mono C3-C8 cycloalkylaminocarbonyl, 4-8 membered cyclic aminocarbonyl, di C1-C6 alkylphosphoryl, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, di C1-C6 alkylaminocarbonyl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, C2-C6 alkenyl, hydroxy C2-C6 alkenyl, C2-C6 alkynyl, hydroxy C2-C6 alkynyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; The C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, 4-10 membered heterocyclylC1-C6 alkoxy, C3-C8 cycloalkoxy, 4-10 membered heterocyclyloxy, C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted independently with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, oxo, haloC1-C6 alkyl, and C3-C8 cycloalkyl.

[0076] In a preferred embodiment (iii) of the D ring, the D ring is unsubstituted or contains one or more R D and one or more R Dare each independently selected from the group consisting of halogen, C1-C6 alkoxy, haloC1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, C3-C8 cycloalkoxy, C1-C6 alkyl, haloC1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl, and C3-C8 cycloalkyl.

[0077] In a preferred embodiment (iv) of the D ring, the D ring is unsubstituted or contains one or more R D and one or more R D are each independently selected from the group consisting of C1-C6 alkoxy, C1-C6 alkyl, and C3-C8 cycloalkyl.

[0078] In a preferred embodiment (v) of the D ring, the D ring is unsubstituted or contains one or more R D and one or more R D are each independently selected from the group consisting of methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-butan-2-yl]oxy, [(2R)-butan-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, butan-2-yl, 3-methylbutyl, pentan-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl, and spiro[2.3]hexan-5-yl.

[0079] In one embodiment of compound (1), any two adjacent substituents on ring D, together with the atoms to which they are attached, form ring E, which may be substituted. In this case, ring E is preferably a 3- to 10-membered monocyclic alicyclic ring, a benzene ring, a 3- to 12-membered monocyclic heterocyclic ring, or a 5- to 6-membered monocyclic aromatic heterocyclic ring (E HA ), more preferably a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle (E HA )

[0080] In compound (1), ring E is a 5- to 6-membered monocyclic aromatic heterocycle (E HA), then E HA is preferably selected from the group consisting of a furan ring, a thiophene ring, a pyrrole ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, an oxadiazole ring, a thiadiazole ring, a triazole ring, a tetrazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring, and a triazine ring, more preferably selected from the group consisting of a thiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, and a pyrazine ring, even more preferably selected from the group consisting of a pyridine ring, a pyrimidine ring, a pyridazine ring, and a pyrazine ring, particularly preferably a pyridine ring or a pyrazine ring, and most preferably a pyridine ring.

[0081] In one embodiment of the present invention, the D ring and the E ring in compound (1) are represented by the following formula: [ka] (In the formula, * represents the carbon atom to which R5 is bonded in formula (1), and ** represents the carbon atom to which R6 is bonded in formula (1). In the formula, the D ring is represented as "D ring" and the E ring is represented as "E ring.")

[0082] In a preferred embodiment of the present invention, the D ring and the E ring in compound (1) are represented by the following formula: [ka] (In the formula, * represents the carbon atom to which R5 is bonded in formula (1), and ** represents the carbon atom to which R6 is bonded in formula (1). In the formula, the D ring is represented as "D ring" and the E ring is represented as "E ring.")

[0083] In a preferred embodiment (i) of the E ring in compound (1), the E ring is unsubstituted or contains one or more R E and one or more R Eare each independently deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, and the hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted.

[0084] In a preferred embodiment (ii) of the E ring in compound (1), the E ring is unsubstituted or contains one or more R E and one or more R E are each independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, and boryl.

[0085] In a preferred embodiment (iii) of the ring E in compound (1), the ring E is unsubstituted or contains one or more R E and one or more R E are each independently selected from the group consisting of fluorine, chlorine, methoxy, dihydroxyboryl, methyl, and t-butyl.

[0086] Another embodiment of the present invention is a compound represented by general formula (2) (hereinafter also referred to as "compound (2)"), a salt thereof, or a solvate thereof.

[0087] R4 in the compound (2) has the same meaning as R4 in the compound (1) described above.

[0088] In compound (2), X5 is CR x5or N. X5 is preferably CR x5 and more preferably CH.

[0089] In compound (2), X6 is CR x6 or N. X6 is preferably CR x6 is.

[0090] In compound (2), X 10a is CR x10a Or N. X 10a Preferably CR x10a is.

[0091] In compound (2), R x5、 R x6 , R 6a and R x10a are each independently hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, and the hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted or R x5 and R x6 , R x6 and R 6a , or R 6a and R x10a may be taken together with the atom to which they are attached to form an optionally substituted E ring.

[0092] R x6 As a preferred embodiment (i) of R x6is hydrogen, halogen, hydroxy, C1-C6 alkylthio, C1-C6 acylamino, mono C1-C6 alkylamino, C1-C6 alkylsulfonylamino, C3-C8 cycloalkylsulfonylamino, C1-C6 alkoxy, haloC1-C6 alkoxy, hydroxyC1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, 4-10 membered heterocyclylC1-C6 alkoxy, C3-C8 cycloalkoxy, 4-10 membered heterocyclyloxy, C1 -C6 acyl, mono C3-C8 cycloalkylaminocarbonyl, 4-8 membered cyclic aminocarbonyl, di C1-C6 alkylphosphoryl, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, di C1-C6 alkylaminocarbonyl C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, C2-C6 alkenyl, hydroxy C2-C6 alkenyl, C2-C6 alkynyl, hydroxy C2-C6 alkynyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, and the C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, 4-10 membered heterocyclylC1-C6 alkoxy, C3-C8 cycloalkoxy, 4-10 membered heterocyclyloxy, C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted independently with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, oxo, haloC1-C6 alkyl, and C3-C8 cycloalkyl.

[0093] R x6 As a preferred embodiment (ii) of R x6is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, haloC1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxyC3-C8 cycloalkyl, C3-C8 cycloalkoxy, C1-C6 alkyl, haloC1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl, and C3-C8 cycloalkyl.

[0094] R x6 As a preferred embodiment (iii) of R x6 is selected from the group consisting of hydrogen, C1-C6 alkoxy, C1-C6 alkyl, and C3-C8 cycloalkyl.

[0095] R x6 As a preferred embodiment (iv) of the formula (I), R x6 is selected from the group consisting of hydrogen, methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-butan-2-yl]oxy, [(2R)-butan-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, butan-2-yl, 3-methylbutyl, pentan-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl, and spiro[2.3]hexan-5-yl.

[0096] R x10a As a preferred embodiment (i) of R x10a is selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C8 cycloalkyl.

[0097] R x10a As a preferred embodiment (ii) of R x10a is selected from the group consisting of hydrogen, chlorine, bromine, cyano, methyl, ethyl, propyl, propan-2-yl, vinyl, ethynyl, and cyclopropyl.

[0098] R 6a As a preferred embodiment (i) of R 6ais selected from the group consisting of hydrogen, halogen, cyano, haloC1-C6 alkoxy, and C1-C6 alkyl.

[0099] R 6a As a preferred embodiment (ii) of R 6a is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, difluoromethoxy, methyl, and ethyl.

[0100] In one embodiment of compound (2), R 6a and R x10a are taken together with the atoms to which they are attached to form an optionally substituted ring E. In this case, ring E is preferably a 3- to 10-membered monocyclic alicyclic ring, a benzene ring, a 3- to 12-membered monocyclic heterocyclic ring, or a 5- to 6-membered monocyclic aromatic heterocyclic ring (E HA ), more preferably a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle (E HA )

[0101] E ring is a 5-6 membered monocyclic aromatic heterocycle (E HA ), then E HA is preferably selected from the group consisting of a thiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, an isothiazole ring, a pyridine ring, a pyrimidine ring, a pyridazine ring, and a pyrazine ring, more preferably selected from the group consisting of a pyridine ring, a pyrimidine ring, a pyridazine ring, and a pyrazine ring, even more preferably a pyridine ring or a pyrazine ring, and most preferably a pyridine ring.

[0102] In a preferred embodiment of the present invention, in compound (2), the E ring is represented by the following formula: [ka] (where * represents R in formula (2) 6a indicates the carbon atom to which R is bonded, and ** indicates the R x10a In the formula, the E ring is represented as "E ring".

[0103] In a preferred embodiment of the present invention, in compound (2), the E ring is represented by the following formula: [ka] (where * represents R in formula (2) 6a indicates the carbon atom to which R is bonded, and ** indicates the R x10a In the formula, the E ring is represented as "E ring".

[0104] In a preferred embodiment (i) of the E ring in compound (2), the E ring is unsubstituted or contains one or more R E and one or more R E are each independently deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, and the hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted.

[0105] In a preferred embodiment (ii) of the ring E in compound (2), the ring E is unsubstituted or contains one or more R E and one or more R E are each independently selected from the group consisting of halogen, C1-C6 alkoxy, boryl, and C1-C6 alkyl.

[0106] In a preferred embodiment (iii) of the ring E in compound (2), the ring E is unsubstituted or contains one or more R Eand one or more R E are each independently selected from the group consisting of fluorine, chlorine, methoxy, dihydroxyboryl, methyl, and t-butyl.

[0107] Another embodiment of the present invention is a compound represented by general formula (3) (hereinafter also referred to as "compound (3)"), a salt thereof, or a solvate thereof.

[0108] R4 in compound (3) has the same meaning as R4 in compound (1) described above, and X5 and X6 in compound (3) have the same meaning as X5 and X6 in compound (2) described above.

[0109] In compound (3), X7 is CR x7 Or N.

[0110] In compound (3), X8 is CR x8 Or N.

[0111] In compound (3), X9 is CR x9 Or N.

[0112] In compound (3), X 10 is CR x10 Or N.

[0113] In compound (3), X7, X8, X9 and X 10 The combination of X7 is N and X8 is CR. x8 and X9 is CR x9 and X 10 is CR x10 Or X7 is CR x7 , X8 is N, and X9 is CR x9 and X 10 is CR x10 Or X7 is CR x7 and X8 is CR x8 and X9 is N and X 10 is CR x10 Or X7 is CR x7 and X8 is CRx8 and X9 is CR x9 and X 10 is N or X7 is N and X8 is CR x8 and X9 is CR x9 and X 10 is N or X7 is CR x7 , X8 is N, and X9 is CR x9 and X 10 is N, or X7 is N, X8 is N, and X9 is CR x9 and X 10 is CR x10 It is preferable that:

[0114] In compound (3), X7, X8, X9 and X 10 The combination of X7 is N and X8 is CR. x8 and X9 is CR x9 and X 10 is CR x10 Or X7 is CR x7 , X8 is N, and X9 is CR x9 and X 10 is CR x10 Or X7 is CR x7 and X8 is CR x8 and X9 is N and X 10 is CR x10 Or X7 is CR x7 and X8 is CR x8 and X9 is CR x9 and X 10 More preferably, is N.

[0115] In compound (3), R x7 , R x8 , R x9 and R x10 are each independently hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10aryl, and 5- to 10-membered heteroaryl, and the hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl may be further substituted.

[0116] R x7 is preferably selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy and C1-C6 alkyl.

[0117] R x8 is preferably selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy and C1-C6 alkyl.

[0118] R x9 is preferably selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl, and boryl.

[0119] R x10 is preferably selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy and C1-C6 alkyl.

[0120] Another embodiment of the present invention is a compound or salt or solvate thereof set forth in Table 11 below. [Table 11] JPEG2026000973000016.jpg222149 JPEG2026000973000017.jpg222149 JPEG2026000973000018.jpg222149 JPEG2026000973000019.jpg222149 JPEG2026000973000020.jpg200149

[0121] As used herein, the term "a compound or a salt thereof, or a solvate thereof" includes a compound, a salt of a compound, a solvate of a compound, and a solvate of a salt of a compound. The compounds described herein can be in the form of salts, preferably pharmaceutically acceptable salts. The compounds described herein or their salts can be in the form of solvates, preferably pharmaceutically acceptable solvates. Salts of the compounds include, for example, hydrochlorides; hydrobromides; hydroiodides; phosphates; phosphonates; sulfates; sulfonates such as methanesulfonates and p-toluenesulfonates; carboxylates such as acetates, citrates, malates, tartrates, succinates, and salicylates; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts. These salts can be prepared, for example, by contacting the compound with an acid or a base. As used herein, the term "solvate" refers to a compound that forms a molecular group together with a solvent, and is not particularly limited as long as it is a solvate formed with a solvent that is acceptable for ingestion accompanying the administration of a drug. Examples of solvates include not only hydrates, alcoholates (ethanol solvates, methanol solvates, 1-propanol solvates, 2-propanol solvates, etc.), and solvates with a single solvent such as dimethyl sulfoxide, but also solvates formed with multiple solvents per molecule of the compound, or solvates formed with multiple types of solvents per molecule of the compound. When the solvent is water, it is called a hydrate. As the solvate of the compound of the present invention, hydrates are preferred, and specific examples of such hydrates include mono- to decahydrates, preferably mono- to pentahydrates, and more preferably mono- to trihydrates.

[0122] When the compound according to the present invention is obtained in a free form, the compound can be converted into a salt thereof, or a hydrate or solvate thereof, according to a conventional method. Examples include hydrates and ethanolates of the compound represented by formula (1) or its salts. Specific examples include, but are not limited to, the hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nodahydrate, decahydrate, or monoethanolate of the compound represented by formula (1), or the hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nodahydrate, decahydrate, or monoethanolate of the sodium salt of the compound represented by formula (1), or the hydrate or ethanolate of the hydrochloride of the compound represented by formula (1). The hydrate or solvate may be produced in a crystalline or amorphous form, and in the case of a crystalline form, it may take the form of a crystalline polymorph. As a method for producing the hydrate or solvate, for example, the hydrate or solvate can be obtained by a conventional method, such as adding a solvent such as ethanol and / or water to the compound represented by formula (1), and stirring, cooling, concentrating, and / or drying.

[0123] Furthermore, when the compound according to the present invention is obtained as a salt, hydrate, or solvate of the compound, the compound can be converted into its free form by a conventional method.

[0124] The compounds described herein may contain unnatural proportions of isotope atoms in one or more atoms constituting such compounds. The present invention also includes compounds in which any atom in a compound is substituted with another isotope atom having the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons), thereby substituting isotopes with an abundance ratio different from the abundance ratio of isotopes in nature, i.e., compounds labeled with isotope atoms. Examples of isotope elements contained in the compounds of the present specification include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, etc., and each of these isotopes is 2 H, 3 H, 13 C. 14 C. 15N, 17 O. 18 O. 32 P, 35 S, 18 F, 36 Isotopic atom-labeled compounds include Cl and the like. Compounds labeled with isotope atoms are useful as therapeutic or preventive agents, research reagents (e.g., assay reagents), and diagnostic agents (e.g., in vivo imaging diagnostic agents). Compounds herein containing radioactive or non-radioactive isotopes in all proportions are encompassed within the scope of the present invention. Compounds labeled with isotope atoms can be produced using reagents and solvents containing the corresponding isotope atoms in the same manner as in the production of unlabeled compounds.

[0125] The compounds described herein, their salts, or solvates thereof include all stereoisomers thereof (e.g., enantiomers, diastereomers (including cis and trans geometric isomers)), racemates of said isomers, and other mixtures thereof. For example, the compounds of the present invention may have one or more asymmetric centers, and the present invention includes racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds. Also, for example, the compounds of the present invention may have axial chirality, and the present invention includes each stereoisomer of such compounds and mixtures thereof.

[0126] <General manufacturing method> Examples of methods for producing compounds represented by Formulas (1) to (3), salts thereof, or solvates thereof are described below using the following schemes. The compounds of the present invention can be synthesized by various methods. The following production methods are illustrative, and the present invention is not limited to the explicitly described chemical reactions and conditions. In the following production schemes, some substituents are omitted for clarity, but this is not intended to limit the disclosure of the schemes. Representative compounds of the present invention can be synthesized using appropriate intermediates, known compounds, and reagents. Variables represented by R1, R2, etc. and variables represented by n, etc. in the formulae of the following general synthesis methods have the same meanings as the variable groups represented by R1, R2, etc. and variables represented by n, etc. in compounds represented by the general formulae defined herein, unless otherwise specified. If the starting material or target product of a certain process undergoes an undesired chemical transformation under the reaction conditions of that process, the target product of that process can be obtained by, for example, protecting and deprotecting functional groups. For the selection of protecting groups and the selection of protection and deprotection methods, reference can be made to, for example, T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis (5th ed., John Wiley & Sons 2014) (Non-Patent Document 6). Some of the protection and deprotection of functional groups are also described in the following schemes. The compounds obtained at each step may be isolated by conventional techniques and, if necessary, purified by crystallization or chromatography.

[0127] Examples of abbreviations used in this specification are listed below along with their meanings. Boc: tert-butoxycarbonyl DCM: dichloromethane DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide EtOH: Ethanol MeOH: Methanol NMP: N-methyl-2-pyrrolidone TFA: trifluoroacetic acid THF: tetrahydrofuran TBME: tert-butyl methyl ether TFE: 2,2,2-trifluoroethanol HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate DIPEA: N,N-diisopropylethylamine XPhos Pd G3: (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2-(2'-amino-1,1'-biphenyl))palladium(II) methanesulfonate (CAS number: 1445085-55-1) XPhos Pd G4: (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2-(2'-(N-methyl)amino-1,1'-biphenyl))palladium(II) methanesulfonate (CAS number: 1599466-81-5) DPPF Pd G4: (1,1'-bis(diphenylphosphino)ferrocene)(2-(2'-(N-methyl)amino-1,1'-biphenyl))palladium(II) methanesulfonate (CAS number: 1621274-17-6) CPhos Pd G3: (2-Dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl)(2-(2'-amino-1,1-biphenyl))palladium(II) methanesulfonate (CAS number: 1447963-73-6) CPhos Pd G2: Chloro[(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (CAS number: 2230788-62-0) tBuBrettPhos Pd G3: [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS number: 1536473-72-9) BINAP Pd G4: [(±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene] (2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonic acid (CAS number: 1599466-90-6) Xantphos Pd G3: [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (CAS number: 1445085-97-1) Xantphos Pd G4: [9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene](2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (CAS number: 1621274-19-8) tBuXPhos Pd G3: [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (CAS number: 1447963-75-8) DCC: N,N'-dicyclohexylcarbodiimide EDC: N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide COMU: (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate LiHMDS: Lithium hexamethyldisilazide NaHMDS: sodium hexamethyldisilazide KHMDS: potassium hexamethyldisilazide LDA: lithium diisopropylamide DIAD: Diisopropyl azodicarboxylate CMMP: (cyanomethylene)trimethylphosphorane CMBP: (cyanomethylene)tributylphosphorane DCE: 1,2-dichloroethane FA: Formic acid

[0128] The compounds of the present invention can be synthesized, for example, by the following production methods.

[0129] (General manufacturing method 1-1) General Production Method 1-1 is a method for producing a compound represented by general formulas (1) to (3) in which R4 is an optionally substituted C6-C 10 This is a preferred method for producing a compound which is an aryl or an optionally substituted 5- to 10-membered heteroaryl. [ka]

[0130] Process 1-1 This step is a formylation step of aromatic bromide 1a. Compound 1b can be produced by reacting aromatic bromide 1a with a metal species, followed by a reaction with a formylating reagent. Examples of metal species include magnesium, lithium, and other metals, and organometallic reagents. Examples of organometallic reagents include isopropylmagnesium bromide, isopropylmagnesium chloride-lithium chloride complex, n-butyllithium, and sec-butyllithium, with isopropylmagnesium chloride-lithium chloride complex being preferred. The formylating reagent is selected from N-formamides and orthoformates, with DMF being preferred as the N-formamide and trimethyl orthoformate being preferred as the orthoformates. Examples of the solvent used in this step include aprotic solvents such as n-hexane, cyclohexane, ethers (examples include dialkyl ethers such as diethyl ether, and cyclic ethers such as 1,2-dimethoxyethane, THF, and 2-methyltetrahydrofuran), toluene, and mixed solvents thereof, and THF, 1,2-dimethoxyethane, toluene, and mixed solvents thereof are preferred.

[0131] Process 1-2 This step is a step of producing an aromatic ester from aromatic bromide 1a. Aromatic ester 1c (wherein R represents C1-C6 alkyl, 2,4,6-trichlorophenyl, or 2,5-dioxopyrrolidin-1-yl) can be produced by reacting aromatic bromide 1a with a carbonylation reagent in the presence of a Pd catalyst and a base. This step can be performed, for example, with reference to the method described in Tetrahedron Lett., 2019 vol. 60, 151147 (Non-Patent Document 7). Examples of the carbonylation reagent include formate esters, oxalate esters, and salts thereof, with 2,4,6-trichlorophenyl formate being preferred. Examples of the base include tertiary amines, with triethylamine and DIPEA being preferred. Solvents used in this step include aprotic solvents such as toluene, acetonitrile, THF, and DMF, as well as mixed solvents thereof, with toluene being preferred. Preferred Pd catalysts include a combination of palladium acetate and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, Xantphos Pd G4, and Xantphos Pd G3. This step can be carried out at a reaction temperature of from -20°C to about the boiling point of the solvent, preferably from 60°C to about the boiling point of the solvent.

[0132] Process 1-3 This step is a hydrolysis step of aromatic ester 1c. Aromatic carboxylic acid 1d can be produced by reacting aromatic ester 1c with a hydroxide. The hydroxide can be selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, and barium hydroxide. Solvents used in this step include polar solvents such as water, ethers, alcohols, and DMSO, as well as mixed solvents thereof. Mixed solvents of THF and water and mixed solvents of methanol and water are preferred.

[0133] Process 1-4 This step is the amidation step of aromatic carboxylic acid 1d. Aromatic amide 1e (wherein X represents methyl(methoxy)amino or morpholinyl) can be produced by reacting aromatic carboxylic acid 1d with an amine or an amine salt in the presence of a condensing agent. The condensing agent can be selected from the group consisting of DCC, EDC, EDC hydrochloride, HATU, COMU, and propylphosphonic anhydride (cyclic trimer), with HATU being preferred. A base may also be used as an additive in this step. Examples of the base include DIPEA, triethylamine, and diazabicycloundecene, with DIPEA being preferred. Examples of solvents used in this step include DMF, DMA, NMP, DCM, THF, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, acetonitrile, and mixtures thereof. Examples of amines or amine salts include N,O-dimethylhydroxylamine hydrochloride and morpholine, with N,O-dimethylhydroxylamine hydrochloride being preferred.

[0134] Process 1-5 This step is an alternative method for synthesizing aromatic amide 1e, and involves an ester-amide exchange reaction of aromatic ester 1c. This step can be performed when R in aromatic ester 1c is 2,4,6-trichlorophenyl, 2,5-dioxopyrrolidin-1-yl, or the like. Aromatic amide 1e (wherein X represents methyl(methoxy)amino or morpholinyl) can be produced by reacting aromatic ester 1c with an amine. Morpholine is preferred as the amine. Examples of solvents used in this step include toluene, DMF, DMA, THF, 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile, and mixed solvents thereof, with toluene being preferred. This step can be performed at a reaction temperature of -20°C to near the boiling point of the solvent, preferably at a temperature of 60°C or higher to near the boiling point of the solvent.

[0135] (General manufacturing method 1-2) General Production Method 1-2 is a method for producing a compound represented by general formulas (1) to (3) in which R4 is an optionally substituted C6-C 10This is a preferred method for producing a compound which is an aryl or an optionally substituted 5- to 10-membered heteroaryl. [ka] [ka]

[0136] Process 1-6 This step involves iodinating aromatic amine 1f. Aromatic amine 1g can be produced by reacting aromatic amine 1f with an iodinating reagent. Examples of iodinating reagents include iodine, N-iodosuccinimide, 1,3-diiodo-5,5-dimethylhydantoin, N-iodosaccharin, and iodine chloride, with N-iodosuccinimide being preferred. Solvents used in this step include DCM, acetonitrile, ethyl acetate, DMSO, and acetic acid, with DCM and DMSO being preferred. Acids such as TFA, acetic acid, sulfuric acid, methanesulfonic acid, and trifluoromethanesulfonic acid may be used as additives in this step.

[0137] Process 1-7 This step involves converting the amino group of aromatic amine 1g using an N,N-dimethylformamidination reagent. Aromatic iodine compound 1h can be produced by converting the amino group of aromatic amine 1g to an N,N-dimethylformamidino group. Examples of N,N-dimethylformamidination reagents include N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide di-tert-butyl acetal, and a combination of DMF and phosphorus(V) oxychloride, with N,N-dimethylformamide dimethyl acetal being preferred. Examples of solvents used in this step include alcohols, DMSO, THF, DMF, DMA, NMP, toluene, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, acetonitrile, and mixtures thereof, with ethanol and DMSO being preferred. This step can be performed at a reaction temperature of −20°C to near the boiling point of the solvent, preferably 40°C to near the boiling point of the solvent.

[0138] Process 1-8 In this step, aromatic iodine compound 1h is reacted with a metal species followed by reaction with aromatic amide 1e (where X represents methyl(methoxy)amino or morpholinyl) to synthesize ketone 1i. Examples of metal species include magnesium and lithium, as well as organometallic reagents. Examples of organometallic reagents include isopropylmagnesium bromide, isopropylmagnesium chloride-lithium chloride complex, n-butyllithium, and sec-butyllithium, with isopropylmagnesium chloride-lithium chloride complex being preferred. Examples of solvents used in this step include aprotic solvents such as n-hexane, cyclohexane, ethers, and toluene, as well as mixed solvents thereof. Preferred are THF, 1,2-dimethoxyethane, toluene, and mixed solvents thereof. Optionally, additives such as hexamethylphosphoric triamide, N,N'-dimethylpropylene urea, or crown ether may be added, with N,N'-dimethylpropylene urea being preferred.

[0139] Process 1-9 This step converts dimethylformamidine 1i into aniline 1j by hydrolysis. Aniline 1j can be produced by reacting dimethylformamidine compound 1i with a hydroxide. Examples of hydroxides include sodium hydroxide, lithium hydroxide, potassium hydroxide, and barium hydroxide, with sodium hydroxide being preferred. Solvents used in this step include polar solvents such as THF, alcohol, and DMSO, with DMSO being preferred.

[0140] Process 1-10 This process involves reacting aromatic iodine compound 1h with a metal species followed by reaction with aromatic aldehyde 1b to produce an alcohol. Examples of metal species include magnesium and lithium, as well as organometallic reagents. Examples of organometallic reagents include isopropylmagnesium bromide, isopropylmagnesium chloride-lithium chloride complex, n-butyllithium, and sec-butyllithium, with isopropylmagnesium chloride-lithium chloride complex being preferred. Solvents used in this process include aprotic solvents such as n-hexane, cyclohexane, ethers, and toluene, as well as mixtures thereof. THF, 1,2-dimethoxyethane, toluene, and mixtures thereof are preferred. Additives such as hexamethylphosphoric triamide, N,N'-dimethylpropylene urea, or crown ether may also be added, with N,N'-dimethylpropylene urea being preferred. The N,N-dimethylformamidino group can be converted to an amino group by sequentially adding an acid and a base to the reaction mixture. Formic acid is preferred as the acid. The base is preferably ethylenediamine.

[0141] Process 1-11 This step converts benzyl alcohol 1o into a ketone by oxidation. Aromatic amine 1j can be produced by reacting benzyl alcohol 1o with an oxidizing agent. Examples of oxidizing agents include manganese dioxide, Dess-Martin periodinane, chromium (IV) oxide, and pyridinium dichromate, with manganese dioxide being preferred. Solvents used in this step include aprotic solvents such as DCM, chloroform, acetonitrile, and ethyl acetate, as well as mixtures thereof, with DCM being preferred.

[0142] Process 1-12 This step is a step of haloacetylating aromatic amine 1j, and can be carried out according to the following Method-1 or Method-2. Method 1: Haloacetamide 1k (wherein Y represents a halogen) can be produced by reacting aromatic amine 1j with a haloacetylating agent. Examples of haloacetylating agents that can be used include chloroacetyl chloride and bromoacetyl chloride. In this step, a base may be used as appropriate, and examples of the base that can be used include organic bases such as DIPEA, triethylamine, and pyridine. Examples of solvents that can be used in this step include DCM, acetonitrile, THF, DMF, DMA, and NMP, with DCM and DMA being preferred. Method 2: Haloacetamide 1k (wherein Y represents a halogen) can be produced by reacting aromatic amine 1j with haloacetic acid in the presence of a condensing agent. Chloroacetic acid and bromoacetic acid can be used as the haloacetic acid. Condensing agents include, for example, DCC, EDC, EDC hydrochloride, HATU, COMU, and propylphosphonic anhydride (cyclic trimer), with HATU and propylphosphonic anhydride (cyclic trimer) being preferred. Bases include, for example, DIPEA and triethylamine, with DIPEA being preferred. Solvents used in this step include, for example, DMF, DMA, NMP, DCM, acetone, THF, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, acetonitrile, and mixtures thereof, with DMF being preferred.

[0143] Process 1-13 This step is a step of constructing a pyridone skeleton from haloacetamide 1k (wherein Y represents a halogen) by a cyclization reaction. Pyridinium ylide 1l (wherein Y represents a halogen) can be produced by reacting haloacetamide 1k with pyridine. Pyridine may be used as a solvent in this step. Alternatively, the reaction mixture from step 1-12 may be reacted with pyridine. This step can be performed at a reaction temperature of -20°C to near the boiling point of the solvent, preferably at a temperature of 40°C to near the boiling point of the solvent.

[0144] Process 1-14 This step is a deprotection step of pyridinium ylide 1l. 3-Aminopyridone compound 1n1 can be produced by reacting pyridinium ylide 1l with a nucleophile. Examples of nucleophiles include hydrazine, hydrazine hydrochloride, hydrazine monohydrate, and hydroxylamine, with hydrazine monohydrate and hydrazine hydrochloride being preferred. Alternatively, the reaction mixture from step 1-13 may be used as is. This step can be performed at a reaction temperature of -20°C to about the boiling point of the solvent, preferably 40°C to about the boiling point of the solvent.

[0145] Process 1-15 In this step, when R4 of 3-aminopyridone compound 1n1 has an acid-removable protecting group, such as 2-tetrahydropyranyl, an acid is added to 3-aminopyridone compound 1n1 to remove the acid-removable protecting group, such as 2-tetrahydropyranyl. Examples of acids include sulfuric acid, hydrochloric acid, sulfonic acids, and carboxylic acids, with TFA being preferred. Examples of solvents used in this step include alcohols (such as alkyl alcohols and fluoroalkyl alcohols), water, and DCM. Alternatively, an acid may be generated using, for example, chlorotrimethylsilane (TMSCl) in the alcohol solvent to remove the acid-removable protecting group, such as 2-tetrahydropyranyl. Examples of preferred combinations of acids and solvents include TMSCl and TFE, TFA and DCM, and TFA and water.

[0146] (General manufacturing method 2) General Production Method 2 is another preferred method for synthesizing 3-aminopyridone compounds 1n2. General Production Method 2 is a method for synthesizing 3-aminopyridone compounds 1n2 in which R4 is an optionally substituted C6-C 10 This is a preferred method for producing a compound which is an aryl or an optionally substituted 5- to 10-membered heteroaryl. [ka] [ka]

[0147] Process 2-1 Step 2-1 is a step of condensing an acid chloride 2a-1 (wherein X represents chlorine) or a carboxylic acid 2a-2 (wherein X represents hydroxy) with a glycine alkyl ester or a salt of a glycine alkyl ester. This step can be carried out according to the following Method-1 or Method-2. Method-1: Amide 2b can be prepared by reacting acid chloride 2a-1 with a glycine alkyl ester or a salt of a glycine alkyl ester (wherein R is C1-C6 alkyl) in the presence of a base. The salt of a glycine alkyl ester is preferably glycine alkyl ester hydrochloride. Examples of the base include organic bases such as DIPEA, triethylamine, and pyridine, and inorganic bases such as carbonates and sodium hydroxide. Triethylamine or DIPEA is preferred. Examples of solvents used in this step include DCM, acetonitrile, THF, DMF, DMA, NMP, and water. DCM and THF are preferred. Method 2: Amide 2b can be prepared by reacting carboxylic acid 2a-2 with a glycine alkyl ester or a salt of a glycine alkyl ester in the presence of a condensing agent. The salt of a glycine alkyl ester is preferably a glycine alkyl ester hydrochloride. Examples of condensing agents include DCC, EDC, EDC hydrochloride, HATU, COMU, and propylphosphonic anhydride (cyclic trimer), with HATU and propylphosphonic anhydride (cyclic trimer) being preferred. A base may also be used as an additive in this step. Examples of bases include DIPEA and triethylamine, with DIPEA being preferred. Examples of solvents used in this step include solvents selected from the group consisting of DMF, DMA, NMP, DCM, acetone, THF, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, and acetonitrile, or a mixture thereof, with DMF being preferred.

[0148] Process 2-2 In this step, amide 2b is protected with Boc. Boc-protected compound 2c can be produced by reacting amide 2b with a Boc-modifying reagent. In this step, a base and a catalyst can be used as appropriate. Examples of bases include DIPEA, triethylamine, and diazabicycloundecene. Examples of catalysts include DMAP. Examples of solvents used in this step include solvents selected from the group consisting of DMF, DMA, DCM, acetone, THF, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, and acetonitrile, or mixed solvents thereof, with DMF being preferred.

[0149] Process 2-3 This step involves rearranging the acyl group of Boc-protected compound 2c in the presence of a base. Examples of the base include sodium tert-butoxide, potassium tert-butoxide, LiHMDS, NaHMDS, KHMDS, and LDA, used alone or in combination. Potassium tert-butoxide, LiHMDS, and mixtures thereof are preferred. Examples of the solvent used in this step include toluene, xylene, n-hexane, cyclohexane, THF, 1,2-dimethoxyethane, N,N'-dimethylpropylene urea, and hexamethylphosphoric acid triamide, or a mixture thereof. THF is preferred.

[0150] Process 2-4 This step involves tosylation of ketone compound 2d using a base. Examples of the base include sodium tert-butoxide, potassium tert-butoxide, LiHMDS, NaHMDS, KHMDS, LDA, DIPEA, triethylamine, and diazabicycloundecene, or a combination of these bases. LDA, LiHMDS, DIPEA, and triethylamine are preferred. Examples of the solvent used in this step include toluene, xylene, n-hexane, cyclohexane, THF, 1,2-dimethoxyethane, acetonitrile, and DCM, or a mixture thereof. THF is preferred. Alternatively, the reaction mixture from step 2-3 may be used directly to carry out the reaction.

[0151] Process 2-5 This step is a Pd-catalyzed cross-coupling step and a cyclocondensation step. In the presence of a Pd catalyst, compound 2e is reacted with the corresponding organoboron compound (wherein R' is exemplified by hydrogen, alkyl, or alkylene) or organotin compound (wherein R' is exemplified by hydrogen, alkyl, or alkylene). The organoboron compound or organotin compound used has an amino group at the ortho position of the boron or tin, and the cross-coupling step is followed by a cyclocondensation step. This step can be carried out according to the following Method-1 or Method-2. Method 1 (Suzuki-Miyaura Cross-Coupling): Method 1 can be carried out, for example, by the method described in Chem. Rev. 1995, vol. 95, no. 7, pp. 2457-2483 (Non-Patent Document 8) and Acc. Chem. Res. 2008, vol. 41, no. 11, pp. 1461-1473 (Non-Patent Document 9). Examples of bases used in this method include inorganic salts such as carbonates, phosphates, and hydroxides, as well as amines such as triethylamine and DIPEA. Cesium carbonate, potassium carbonate, and triethylamine are preferred. Examples of solvents used in this method include polar solvents such as toluene, xylene, THF, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DMF, DMA, NMP, and water, as well as mixtures thereof. Mixtures of 2-methyltetrahydrofuran, 4-methyltetrahydropyran, and water are preferred. Examples of Pd catalysts include PdCl2(PPh3)2, Pd(PPh3)4, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, 1,4-bis(diphenylphosphino)butane]palladium(II) dichloride, XPhos Pd G3, and XPhos Pd G4, with [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, 1,4-bis(diphenylphosphino)butane]palladium(II) dichloride, XPhos Pd G3, and XPhos Pd G4 being preferred. This step can be carried out at a reaction temperature of from -20°C to near the boiling point of the solvent, and preferably at a temperature of 80°C or higher to near the boiling point of the solvent. Method 2 (Stille Cross-Coupling): Method 2 can be carried out, for example, by the method described in Synthesis 1992, vol. 9, pp. 803-815 (Non-Patent Document 10). Examples of Pd catalysts include PdCl(PPh), Pd(PPh), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, and 1,4-bis(diphenylphosphino)butane]palladium(II) dichloride, with Pd(PPh) being preferred. Examples of solvents used in this method include toluene, xylene, THF, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DMF, DMA, and NMP, with toluene being preferred. This step can be carried out at a reaction temperature of -20°C to near the boiling point of the solvent, preferably 80°C to near the boiling point of the solvent.

[0152] Process 2-6 This step is a step of deprotecting the Boc of the Boc-protected compound 2f, and can be carried out under the same conditions as in step 1-15.

[0153] Process 2-7 This step involves the Wittig reaction of formyl compound 2g. α,β-Unsaturated ester compound 2h can be produced by reacting formyl compound 2g with a phosphorus reagent in the presence of a base. Examples of phosphorus reagents include 2-(BOC-amino)-2-(dimethoxyphosphoryl)acetic acid ester and its equivalents (wherein R is C1-C6 alkyl), with 2-(BOC-amino)-2-(dimethoxyphosphoryl)methyl acetate being preferred. Examples of bases include sodium tert-butoxide, potassium tert-butoxide, LiHMDS, NaHMDS, KHMDS, LDA, and 1,4-diazabicyclo[2.2.2]octane, or a mixture thereof. Examples of solvents used in this process include toluene, THF, 1,2-dimethoxyethane, acetonitrile, and DCM.

[0154] Process 2-8 This step is the bromination of α,β-unsaturated ester compound 2h. Aromatic nitro compound 2i can be produced by reacting α,β-unsaturated ester 2h with a bromination reagent followed by isomerization in the presence of a base. Bromination reagents include NBS, 1,3-dibromo-5,5'-dimethylhydantoin, and N-bromosaccharin, with NBS being preferred. Bases include 1,4-diazabicyclo[2.2.2]octane, diazabicycloundecene, sodium tert-butoxide, potassium tert-butoxide, LiHMDS, NaHMDS, and KHMDS, with 1,4-diazabicyclo[2.2.2]octane and diazabicycloundecene being preferred. Solvents used in this process include acetonitrile and DCM.

[0155] Process 2-9 This step involves the reduction of aromatic nitro compound 2i and a subsequent cyclization step. The reduction step can be carried out, for example, by the method described in Org. Process Res. Dev. 2018, vol. 22, no. 4, pp. 430-445 (Non-Patent Document 11). It is particularly preferable to carry out the reaction using a combination of Pd(OH)2 / H2 in a solvent such as methanol or ethyl acetate, or a combination of Fe / NH4Cl in ethanol. The cyclization step can be carried out continuously by carrying out the reaction at a temperature between room temperature and near the boiling point of the solvent.

[0156] Process 2-10 This step is a Pd-catalyzed cross-coupling step. Compound 2i or 2j is reacted with the corresponding organoboron compound (R-B(OR) or R-BFK) or organotin compound (R-SnR) (wherein R is hydrogen or alkyl). This step can be carried out under the same conditions as in step 2-5.

[0157] (General manufacturing method 3) General Production Method 3 is a method for producing 3-aminopyridone compound 1n1 or 1n2, wherein X6 is CR x6 and R x6 is a halogen. [ka]

[0158] Process 3-1 In this step, 3-aminopyridone compound 1n1 or 1n2 is reacted with a substituent R x6 This step can be carried out according to any one of the following methods 1 to 6. Method 1 (Suzuki-Miyaura cross-coupling): 3-aminopyridone compound 1n1 or 1n2 is reacted with the corresponding organoboron compound (R x6 -B(OR)2,R x6 -BF3K) or organotin compounds (R x6 —SnR3) (wherein R is exemplified by hydrogen and alkyl) can be reacted under the same conditions as in Method-1 of Step 2-5. Method 2 (Alkylation or alkenylation by Negishi cross-coupling): 3-aminopyridone compound 3a can be prepared by reacting 3-aminopyridone compound 1n1 or 1n2 with the corresponding organozinc reagent (R x6-ZnX) (wherein X is a halogen). Method-2 can be carried out, for example, by the method described in Tetrahedron. 1992, vol. 48, no. 44, pp. 9577-9648 (Non-Patent Document 12) or Aldrichimica Acta. 2005, vol. 38, pp. 71-88 (Non-Patent Document 13). Solvents used in this step include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, etc., or mixed solvents thereof, with THF being preferred. Examples of Pd or Ni include those described in Tetrahedron. 1992, vol. 48, no. 44, pp. 9577-9648 (Non-Patent Document 12) or Aldrichimica Acta. 2005, vol. 38, pp. 71-88 (Non-Patent Document 13), as well as PdCl2(PPh3)2, Pd(PPh3)4, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, with PdCl2(PPh3)2, Pd(PPh3)4, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride being preferred. Method-3 (Sonogashira cross-coupling): 3-aminopyridone compound 3a can be prepared by reacting 3-aminopyridone compound 1n1 or 1n2 with the corresponding alkyne (RC≡CH, where RC≡C- is R x6-) can be produced. Method-3 can be carried out, for example, by the method described in Chem. Soc. Rev. 2011, vol. 40, pp. 5084-5121. (Non-Patent Document 14). The corresponding alkyne may have a silyl group, for example, trimethylsilylacetylene. Examples of bases include amines such as triethylamine, DIPEA, and diazabicycloundecene, and inorganic bases such as sodium acetate, with triethylamine and DIPEA being preferred. Examples of Pd include PdCl2(PPh3)2, Pd(PPh3)4, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, Pd(OAc)2, and Pd2(dba)3, with PdCl2(PPh3)2, Pd(PPh3)4, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride being preferred. Examples of Cu include copper iodide, copper bromide, and copper chloride, with copper iodide being preferred. Examples of solvents used in this step include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, DMSO, methanol, ethanol, 2-propanol, and mixtures thereof, with DMSO, DMF, DMA, and NMP being preferred. Method 4 (Thioetherification): 3-Aminopyridone Compound 3a can be prepared by reacting 3-aminopyridone Compound 1n1 or 1n2 with the corresponding mercaptan or mercaptan salt in the presence of Pd and a base. Examples of mercaptans include 2-ethylhexyl and 3-mercaptopropionic acid. Examples of bases include amines such as triethylamine, DIPEA, diazabicycloundecene, and piperidine, with triethylamine and DIPEA being preferred. Examples of Pd include zero-valent Pd complexes such as Pd(PPh3)4, with Xantphos Pd G3 being preferred. Examples of solvents used in this step include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, DMSO, methanol, ethanol, and 2-propanol, as well as mixtures thereof, with 1,4-dioxane being preferred. Method-5 (Etherification or Hydroxylation): 3-aminopyridone compound 3a can be prepared by reacting 3-aminopyridone compound 1n1 or 1n2 with the corresponding alcohol or water in the presence of Pd. For etherification, the sodium salt or potassium salt of the corresponding alcohol can be used as a base. For hydroxylation, sodium hydroxide or potassium hydroxide can be used. Examples of Pd include zero-valent Pd complexes such as Pd(PPh3)4, with tBuBrettPhos Pd G3 being preferred. Examples of solvents used in this step include polar solvents such as THF, 1,4-dioxane, DMF, DMA, and NMP, with 1,4-dioxane being preferred. Method 6 (amination): 3-aminopyridone compound 3a can be prepared by reacting 3-aminopyridone compound 1n1 or 1n2 with the corresponding amine in the presence of Pd or Cu and a base. When Pd is used, the method described in Chem. Rev. 2016, vol. 116, pp. 12564-12649 (Non-Patent Document 15) can be used. Examples of Pd include zero-valent Pd complexes such as Pd(PPh3)4, with Xantphos Pd G3, Xantphos Pd G4, and tBuXPhos Pd G3 being preferred. Examples of bases include carbonates, phosphates, sodium tert-butoxide, potassium tert-butoxide, and the like, with sodium tert-butoxide being preferred. Solvents used in this step include, for example, polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, DMSO, and mixed solvents thereof, with 1,4-dioxane being preferred. When Cu is used, the method described in Org. Process Res. Dev. 2022, vol. 26, no. 6, pp. 1690-1750 (Non-Patent Document 16) can be used. Examples of Cu include copper iodide, copper bromide, and copper chloride, with copper iodide being preferred. Ligands for Cu include 1,10-phenanthroline, L-proline, and 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (DMPAO), with 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (DMPAO) being preferred. Examples of the base include carbonates, phosphates, sodium tert-butoxide, and potassium tert-butoxide, with cesium carbonate, potassium carbonate, and tripotassium phosphate being preferred. Examples of the solvent used in this step include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, and DMSO, as well as mixed solvents thereof, with DMSO being preferred.

[0159] Process 3-2 In the case where 3-aminopyridone compound 3a has a Boc group, a 2-tetrahydropyranyl group, or both, this step is a step of deprotecting the Boc group, the 2-tetrahydropyranyl group, or both, and can be performed under the same conditions as in Step 1-15.

[0160] Step 3-3-1, Step 3-3-2, and Step 3-3-3 are all steps for protecting the 3-aminopyridone compound 1n1 or 1n2 with a protecting group.

[0161] Step 3-3-1: Protection by Boc-conjugation This step is a step of protecting 3-aminopyridone compound 1n1 or 1n2 with a Boc group. Protected 3-aminopyridone compound 3c can be produced by reacting 3-aminopyridone compound 1n1 or 1n2 with a Boc-containing reagent. In this step, a base and a catalyst can be used as appropriate. In this step, in the formula, P1 is a Boc group, and P3 is a Boc group or H. This step can be performed under the same conditions as in step 2-2.

[0162] Step 3-3-2: Protection by para-methoxybenzylation In this step, 3-aminopyridone compound 1n1 or 1n2 is reacted with a p-methoxybenzylation reagent in the presence of a base to perform para-methoxybenzylation. In this step, in the formula, P1 is a p-methoxybenzyl group, and P3 is H. Examples of the p-methoxybenzylation reagent include p-methoxybenzyl chloride and p-methoxybenzyl bromide. Examples of the base include inorganic bases such as potassium carbonate, silver carbonate, cesium carbonate, and sodium hydride, with potassium carbonate and silver carbonate being preferred. Examples of the solvent used in this step include aprotic solvents such as DMF, DMA, NMP, THF, DCM, and DCE, with DMF, DMA, or DCE being preferred.

[0163] Step 3-3-3: Protection by 2-(trimethylsilyl)ethoxymethylation In this step, 3-aminopyridone compound 1n1 or 1n2 is reacted with a 2-(trimethylsilyl)ethoxymethylating reagent in the presence of a base to perform 2-(trimethylsilyl)ethoxymethylation. In this step, in the formula, P1 is a 2-(trimethylsilyl)ethoxymethyl group, and P3 is H. Examples of the 2-(trimethylsilyl)ethoxymethylating reagent include 2-(trimethylsilyl)ethoxymethyl chloride. Examples of the base include inorganic bases such as potassium carbonate, silver carbonate, cesium carbonate, and sodium hydride, with potassium carbonate or cesium carbonate being preferred. Examples of the solvent used in this step include aprotic solvents such as DMF, DMA, NMP, THF, DCM, and 1,2-dichloroethane, with DMF and DMA being preferred.

[0164] Process 3-4 This step is an alkylation step of the protected 3-aminopyridone 3c. In the presence of a photoredox catalyst, the protected 3-aminopyridone 3c is alkylated with an alcohol (R x6 -OH) or haloalkyl (R x6 -X, where X is a halogen) and alkylation can be performed. This can be performed with reference to the methods described in JACS. 2016, vol. 138, no. 26, pp. 8084-8087 (Non-Patent Document 17), ACS Med. Chem. Lett. 2020, 11, 597-604 (Non-Patent Document 18), and Nature 2021, vol. 598, pp. 451-456 (Non-Patent Document 19).

[0165] Process 3-5 When the 3-aminopyridone 3d has a Boc group or a 2-tetrahydropyranyl group, this step is for deprotecting the Boc group or the 2-tetrahydropyranyl group, and can be carried out under the same conditions as in Step 1-15.

[0166] Process 3-6 This step is a hydroxylation step of the protected 3-aminopyridone 3c, which can be carried out under the same conditions as in the hydroxylation of Method 5 in Step 3-1.

[0167] Process 3-7 This step is an alkylation step of the hydroxyl compound 3e, which can be carried out according to the following Method-1 or Method-2. Method-1 (nucleophilic substitution reaction): alkylation compound 3f (wherein R x6a O is R x6 (representing the formula:) can be prepared by reacting hydroxyl compound 3e with the corresponding haloalkyl, alkyl triflate, or alkyl nonaflate in the presence of a base. Examples of the base include inorganic bases such as carbonates and phosphates, with cesium carbonate and potassium carbonate being preferred. Examples of solvents used in this step include THF, 1,4-dioxane, DMF, DMA, and NMP. Method 2 (Mitsunobu reaction): alkylated product 3f (wherein R x6a O is R x6 (representing the formula:) can be prepared by reacting hydroxyl compound 3e with the corresponding alcohol in the presence of a Mitsunobu reagent. Examples of Mitsunobu reagents include a combination of triphenylphosphine and DIAD, CMMP, and CMBP. Solvents used in this step include aprotic solvents such as toluene, DCM, THF, n-hexane, cyclohexane, ethyl acetate, DMA, DMF, NMP, and 1,4-dioxane, with DCM and THF being preferred.

[0168] Process 3-8 In the case where alkylated compound 3f has a 2-(trimethylsilyl)ethoxymethyl group, a p-methoxybenzyl group, or a 2-tetrahydropyranyl group, this step is a step for deprotecting the 2-(trimethylsilyl)ethoxymethyl group, a p-methoxybenzyl group, or a 2-tetrahydropyranyl group, and can be performed under the same conditions as in step 1-15.

[0169] Process 3-9 This step is a p-methoxybenzylation step of 3-aminopyridone compound 1n1 or 1n2. Step 3-9 can be performed under the same conditions as in Step 3-3-2. In the formula, P2 represents a p-methoxybenzyl group.

[0170] Process 3-10 This step is a hydroxylation step of the p-methoxybenzyl-protected compound 3g, which can be carried out under the same conditions as in the hydroxylation of Method 5 in Step 3-1.

[0171] Process 3-11 This step is an alkylation step of hydroxyl compound 3h. It can be carried out under the same conditions as in step 3-7. (In the formula of compound 3i, R x6a O is R x6 (represents

[0172] Process 3-12 When Compound 3i has a p-methoxybenzyl group or a 2-tetrahydropyranyl group, this step is a step of deprotecting the p-methoxybenzyl group or the 2-tetrahydropyranyl group, and can be performed under the same conditions as in Step 1-15.

[0173] (General manufacturing method 4) General production method 4 is a preferred method for producing compounds represented by general formulas (1) to (3) in which R4 is an optionally substituted 4- to 10-membered heterocyclyl. [ka]

[0174] Process 4-1 This step is a nitration step of 4-hydroxylpyridone compound 4a. 3-Nitropyridone compound 4b can be produced by reacting 4-hydroxylpyridone compound 4a with a nitrating reagent under acidic conditions. Examples of the nitrating reagent include nitric acid and nitrates. Examples of the solvent used in this step include acetic acid, sulfuric acid, and nitric acid.

[0175] Process 4-2 This step is a chlorination step of 3-nitropyridone compound 4b. 4-Chloropyridone compound 4c can be produced by reacting 3-nitropyridone compound 4b with a chlorinating reagent. Examples of the chlorinating reagent include phosphorus oxychloride, thionyl chloride, and oxalyl chloride, and these chlorinating reagents may be used in a solvent amount. DMF may be used as a catalyst in this step.

[0176] Process 4-3 This step involves the aromatic nucleophilic substitution of 4-chloropyridone compound 4c. 3-Nitropyridone compound 4d can be produced by reacting 4-chloropyridone compound 4c with the corresponding amine (e.g., piperidine). Examples of solvents used in this step include aprotic solvents such as toluene, THF, n-hexane, cyclohexane, ethyl acetate, DMA, DMF, NMP, 1,4-dioxane, and DMSO, with DMF being preferred.

[0177] Process 4-4 This step is a reduction step of 3-nitropyridone compound 4d. 3-Aminopyridone compound 4e can be produced by reacting 3-nitropyridone compound 4d with a reducing reagent. This step can be carried out, for example, by the method described in Org. Process Res. Dev. 2018, vol. 22, no. 4, pp. 430-445 (Non-Patent Document 11). A combination of Pd(OH)2 / H2 in a solvent such as methanol or ethyl acetate, or a combination of Fe / NH4Cl in ethanol is preferred.

[0178] <Pharmaceutical Composition> The present invention provides a pharmaceutical composition containing a compound represented by formula (1) of the present invention or a salt thereof, or a solvate of the compound or salt (first ingredient) (hereinafter also referred to as "the pharmaceutical composition of the present invention"). The pharmaceutical composition of the present invention can be formulated by a known method by incorporating a pharmaceutically acceptable carrier in addition to the compound represented by formula (1) of the present invention, or a salt thereof, or a solvate thereof. For formulation, commonly used excipients, binders, lubricants, colorants, flavoring agents, and, if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, etc. can be used, and the composition is formulated by a conventional method by blending ingredients generally used as raw materials for pharmaceutical preparations. In the formulation, active ingredients used in pharmaceuticals can be processed by known methods into the optimal shape or properties, i.e., dosage form, suited to the method and purpose of use. Examples of commonly used dosage forms include liquid pharmaceutical preparations (liquids) such as injections, suspensions, emulsions, and eye drops, and solid pharmaceutical preparations (solid preparations) such as tablets, powders, fine granules, granules, coated tablets, capsules, dry syrups, lozenges, and suppositories, but are not limited to these.

[0179] For example, to prepare a liquid formulation, a pharmacologically acceptable carrier or vehicle, specifically, pharmaceutically acceptable additives commonly used in the field of pharmaceutical formulations, such as sterile water, physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, binder, etc., are added in appropriate combination to the compound represented by formula (1) of the present invention or its salt, or a solvate thereof, and then the mixture is mixed to form a unit dose required for generally accepted pharmaceutical practice. Alternatively, a solid formulation prepared for liquid formulation can be dissolved as needed by adding an appropriate solvent, such as sterile water or physiological saline, before administration, and then used for administration.

[0180] Such liquid preparations can also be used parenterally, for example, in the form of a sterile solution or suspension injection in water or other pharmaceutically acceptable liquid. For example, they can be formulated by appropriately combining them with pharmacologically acceptable carriers or vehicles, specifically, sterile water, physiological saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavoring agents, excipients, vehicles, preservatives, binders, etc., and blending them in a unit dosage form required for generally accepted pharmaceutical practice. Specific examples of carriers include light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium-chain fatty acid triglycerides, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, cornstarch, inorganic salts, etc. The amount of active ingredient in these preparations is such that an appropriate dose within the indicated range can be obtained. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice using a vehicle such as distilled water for injection.

[0181] Examples of aqueous solutions for injection include isotonic solutions containing physiological saline or other adjuvants, such as D-sorbitol, D-mannose, D-mannitol, and sodium chloride, and may be used in combination with an appropriate solubilizing agent, such as alcohol, specifically ethanol, polyalcohols such as propylene glycol and polyethylene glycol, or nonionic surfactants such as Polysorbate 80 (registered trademark) and HCO-50.

[0182] Examples of oily liquids include sesame oil and soybean oil, and they may be used in combination with solubilizing agents such as benzyl benzoate and benzyl alcohol. They may also contain buffers such as phosphate buffer and sodium acetate buffer, soothing agents such as procaine hydrochloride, stabilizers such as benzyl alcohol, phenol, and antioxidants. The prepared injection solution is usually filled into suitable ampoules.

[0183] For example, to produce a solid preparation, an excipient and, if necessary, pharmaceutically acceptable additives commonly used in the field of pharmaceutical preparations such as a binder, a disintegrant, a lubricant, a colorant, a flavoring agent, etc. are added appropriately in combination to the compound represented by formula (1) of the present invention, or a salt thereof, or a solvate thereof, and then the mixture is made into tablets, powders, fine granules, granules, coated tablets, capsules, dry syrups, troches, suppositories, etc. by a conventional method.

[0184] Examples of pharmaceutically acceptable additives used in such solid preparations include animal and vegetable oils such as soybean oil, beef tallow, and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane, and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, and polyoxyethylene polyoxypropylene block copolymers; water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymers, polyethylene glycol, polyvinylpyrrolidone, and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and sorbitol; sugars such as lactose, lactose hydrate, fructose, and sucrose; inorganic powders such as silicic anhydride, aluminum magnesium silicate, and aluminum silicate; and purified water.

[0185] Examples of excipients include sugars (e.g., lactose, lactose hydrate, fructose, sucrose, etc.), sugar alcohols (e.g., mannitol, etc.), starch (corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, etc.), cellulose (e.g., crystalline cellulose), inorganic salts (e.g., calcium silicate, anhydrous calcium hydrogen phosphate, precipitated calcium carbonate, etc.), etc.

[0186] Examples of the binder include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polypropylene glycol-polyoxyethylene block polymer, and the like.

[0187] Examples of the disintegrant include croscarmellose sodium, carmellose sodium, hydroxypropyl cellulose, carmellose, carmellose calcium, methyl cellulose, crystalline cellulose, sodium lauryl sulfate, povidone, or polysorbate, and the like.

[0188] Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, hydrogenated oil, and the like.

[0189] Those permitted to be added to pharmaceuticals can be used as the coloring agent, and cacao powder, peppermint oil, aromatic powder, peppermint oil, borneol, cinnamon powder, and the like can be used as the flavoring and deodorizing agent.

[0190] These tablets and granules can be appropriately coated with a sugar coating or other coatings as necessary. When producing liquid preparations such as syrup preparations and injection preparations, a pH adjuster, a solubilizer, an isotonic agent, and the like, and optionally a solubilizing aid, a stabilizer, and the like are added to the compound according to the present invention or its pharmacologically acceptable salt, and formulated by a conventional method.

[0191] <Treatment or prevention of cancer in cancer patients in whom a positive RB1 gene mutation or a decrease in the expression of the RB1 gene or protein has been detected, and cancer patients in whom a positive RB1 gene mutation or a decrease in the expression of the RB1 gene or protein has occurred> MYT1 inhibitors can be used alone or in combination with chemotherapeutic agents for the treatment or prevention of cancer in cancer patients who have been detected as having a positive RB1 gene mutation or reduced expression of the RB1 gene or protein, or in cancer patients who have been detected as having a positive RB1 gene mutation or reduced expression of the RB1 gene or protein.

[0192] The term "combination" refers to the use of two or more components in combination. For example, a combination of a MYT1 inhibitor (hereinafter sometimes referred to as the "first component") and a chemotherapeutic agent (hereinafter sometimes referred to as the "second component") includes "administration as a single formulation containing the first component and the second component" (i.e., administration of the first component and the second component as a combined drug) and "administration of the first component and the second component as separate formulations, either simultaneously or separately." In the latter embodiment, the formulation containing the first component may be administered first, or the formulation containing the second component may be administered first. The latter embodiment may be any of "administration of the first component and the second component separately as formulations and administered simultaneously via the same administration route," "administration of the first component and the second component separately as formulations and administered separately at different times via the same administration route," "administration of the first component and the second component separately as formulations and administered simultaneously via different administration routes (administration to different sites in the same patient)," and "administration of the first component and the second component separately as formulations and administered separately at different times via different administration routes." In the case of "an embodiment in which the first component and the second component are formulated separately and administered simultaneously via the same administration route," the two formulations may be mixed immediately before administration. "Separately" means that one formulation is administered before or after the other formulation.

[0193] In other words, "combined use" can also be said to be a method of use in which one component is present in the patient's body while the other component is present in the patient's body. That is, a preferred embodiment is one in which the first component and the second component are administered so that they are simultaneously present in the patient's body, for example, in the blood, and a preferred embodiment is one in which one formulation is administered to the patient simultaneously, or one formulation is administered to the patient within 48 hours of the other formulation being administered.

[0194] "Cancer treatment" in the present invention means a reduction in the number of cancer cells in an individual, inhibition of cancer cell proliferation, reduction in tumor volume, reduction in tumor weight, inhibition of cancer cell metastasis, or amelioration of various symptoms caused by cancer, or a combination thereof. Furthermore, "cancer prevention" in the present invention means preventing the development of new cancer cells, preventing an increase in the number of cancer cells due to the re-proliferation of reduced cancer cells, preventing the regrowth of cancer cells whose proliferation has been inhibited, preventing a re-increase in the volume or weight of reduced tumors, or a combination thereof.

[0195] [First embodiment related to cancer treatment or prevention] One embodiment of the present invention is a pharmaceutical composition comprising an MYT1 inhibitor as an active ingredient, in combination with a chemotherapeutic agent, for treating or preventing cancer in patients who have been detected to have a positive RB1 gene mutation or reduced expression of the RB1 gene or protein. One embodiment of the present invention is a pharmaceutical composition comprising an MYT1 inhibitor as an active ingredient, in combination with a chemotherapeutic agent, for treating or preventing cancer in cancer patients who are positive for RB1 gene mutation or have reduced expression of the RB1 gene or protein.

[0196] RB1 (retinoblastoma gene, also known as Rb or RB) is a gene encoding the RB1 protein, a representative cell cycle regulator, and is involved in the G1 / S checkpoint. RB1 protein (also known as RB1 or pRb) forms a complex with E2F, a transcription factor responsible for inducing the expression of genes involved in the transition from the G1 to S phase of the cell cycle, thereby suppressing the activity of E2F. When E2F activity is suppressed, the transition from the G1 to S phase is inhibited.

[0197] During the cell cycle, cyclin D is generally synthesized in response to cell proliferation stimuli and binds to CDK4 to form a complex. This complex is phosphorylated (activated) by CAK, which phosphorylates the RB protein. When the RB protein is phosphorylated, the transcription factor E2F bound to the RB protein is released, inducing the expression of a group of genes required for S phase progression or DNA replication. Among the induced genes is cyclin E, which forms a complex with CDK2 and further phosphorylates RB1, further inactivating the RB1 protein. If there is a mutation in the RB1 gene (particularly a mutation that reduces the function of the RB1 protein) or if the expression level of the RB1 gene or protein is reduced, the cell cycle will progress.

[0198] As used herein, "positive for RB1 gene mutation" means that, when the nucleotide sequence corresponding to the RB1 gene of interest is analyzed, some mutation (e.g., a mutation resulting in the insertion, substitution, deletion, and / or addition of at least one amino acid residue relative to the wild-type RB1 protein) is found in the nucleotide sequence compared to the nucleotide sequence of the wild-type RB1 gene; or, if a mutation in the nucleotide sequence of the RB1 gene is reflected in a base change in a transcription product or an amino acid change in a translation product, the change is detected in the transcription product or translation product. In certain embodiments, a positive RB1 gene mutation is detected in a biological sample (e.g., cancer cells) derived from a cancer patient. As used herein, "detecting a mutation" generally refers to detecting a mutation in genomic DNA. However, if the mutation in the genomic DNA is reflected in a base change in a transcription product or an amino acid change in a translation product, it also includes detecting the change in the transcription product or translation product (i.e., indirect detection). A preferred embodiment of the method herein is a method for detecting a mutation by directly determining the nucleotide sequence of the RB1 gene region in cancer cells. There are no particular limitations on the method for detecting a positive RB1 gene mutation, but for example, confirmation and determination can be performed using NGS (next generation sequencer).

[0199] In the present invention, the term "RB1 gene region" refers to a specific region on genomic DNA that contains the RB1 gene. This region independently includes not only the translated region but also the untranslated region, such as the expression control region of each gene (e.g., promoter region, enhancer region) and the 3'-terminal untranslated region of each gene. In this method, a DNA sample is first prepared from a biological sample. Examples of DNA samples include genomic DNA samples and cDNA samples prepared by reverse transcription from RNA.

[0200] There are no particular limitations on the method for extracting genomic DNA or RNA from a biological sample, and any known method can be appropriately selected and used. For example, methods for extracting genomic DNA include the SDS-phenol method (a method in which tissue stored in a solution containing urea or ethanol is denatured with a protease (proteinase K), a surfactant (SDS), and phenol to denature the proteins in the tissue, and then DNA is precipitated and extracted from the tissue with ethanol), and DNA extraction methods using Clean Columns (registered trademark, manufactured by NexTec), AquaPure (registered trademark, manufactured by Bio-Rad), ZR Plant / Seed DNA Kit (manufactured by Zymo Research), AquaGenomicSolution (registered trademark, manufactured by MoBiTec), prepGEM (registered trademark, manufactured by ZyGEM), and BuccalQuick (registered trademark, manufactured by TrimGen).

[0201] Furthermore, there are no particular limitations on the method for extracting RNA from a biological sample and the method for preparing cDNA from the extracted RNA, and known methods can be appropriately selected and used. Examples include extraction methods using phenol and chaotropic salts (more specifically, extraction methods using commercially available kits such as Trizol (Invitrogen) and Isogen (Wako Pure Chemical Industries, Ltd.)), and methods using other commercially available kits (RNAPrep Total RNA Extraction Kit (Beckman Coulter), RNeasy Mini (QIAGEN), RNA Extraction Kit (Pharmacia Biotech), etc.). Furthermore, the reverse transcriptase used to prepare cDNA from the extracted RNA is not particularly limited, and examples include reverse transcriptases derived from retroviruses such as Rous associated virus (RAV) and Avian myeloblastosis virus (AMV), and reverse transcriptases derived from mouse retroviruses such as Moloney murine leukemia virus (MMLV).

[0202] In this embodiment, DNA containing the RB1 gene region is then isolated, and the nucleotide sequence of the isolated DNA is determined. The DNA can be isolated, for example, by PCR using genomic DNA or RNA as a template, using a pair of oligonucleotide primers designed to flank all or part of the RB1 gene region. The nucleotide sequence of the isolated DNA can be determined by methods known to those skilled in the art, such as the Maxam-Gilbert method or the Sanger method. Next-generation sequencers, which are capable of rapid and comprehensive analysis of gene nucleotide sequences, can also be used.

[0203] By comparing the determined DNA or cDNA base sequence with a control (for example, if the biological sample is derived from a cancer patient, with the DNA or cDNA base sequence derived from non-cancerous tissue of the same patient or with a publicly known database), the presence or absence of a mutation in the RB1 gene region in the cancer cells of the biological sample can be determined.

[0204] Mutations in the RB1 gene region can be detected by various methods that allow detection of mutations, in addition to direct determination of the base sequence of DNA or cDNA.

[0205] For example, mutation detection in the present invention can also be performed by the following method. First, a DNA or cDNA sample is prepared from a biological sample. Next, an oligonucleotide probe is prepared, which has a base sequence complementary to the base sequence containing the mutation site in the RB1 gene region and is labeled with a reporter fluorescent dye and a quencher fluorescent dye. The oligonucleotide probe is then hybridized to the DNA or cDNA sample. The base sequence containing the mutation site in the RB1 gene region is then amplified using the DNA or cDNA sample hybridized with the oligonucleotide probe as a template. Fluorescence emitted by the reporter fluorescent dye due to degradation of the oligonucleotide probe during amplification is then detected, and the detected fluorescence is then compared with that of a control. Examples of such methods include the double-dye probe method, also known as the TaqMan® probe method.

[0206] In yet another method, a DNA or cDNA sample is prepared from a biological sample. The DNA or cDNA sample is then used as a template in a reaction system containing an intercalator that emits fluorescence when inserted into the DNA double strand, and a base sequence containing the mutation site in the RB1 gene region is amplified. The temperature of the reaction system is then changed, and changes in the intensity of the fluorescence emitted by the intercalator are detected. The detected changes in the intensity of the fluorescence associated with the temperature change are compared with a control. Examples of such methods include high-resolution melting (HRM) analysis.

[0207] In yet another method, a DNA or cDNA sample is first prepared from a biological sample. DNA containing all or part of the RB1 gene region is then amplified. The amplified DNA is then cleaved with a restriction enzyme. The DNA fragments are then separated according to size. The sizes of the detected DNA fragments are then compared with a control. Examples of such methods include methods using restriction fragment length polymorphism (RFLP) and PCR-RFLP.

[0208] In yet another method, a DNA or cDNA sample is first prepared from a biological sample. DNA containing all or part of the RB1 gene region is then amplified. The amplified DNA is then dissociated into single-stranded DNA. The dissociated single-stranded DNA is then separated on a non-denaturing gel. The mobility of the separated single-stranded DNA on the gel is compared with that of a control. Such a method includes, for example, PCR-SSCP (single-strand conformation polymorphism) method.

[0209] In yet another method, a DNA or cDNA sample is first prepared from a biological sample. DNA containing all or part of the RB1 gene region is then amplified. The amplified DNA is then separated on a gel containing increasing concentrations of DNA denaturing agent. The mobility of the separated DNA on the gel is then compared with that of a control. Such a method includes, for example, denaturant gradient gel electrophoresis (DGGE).

[0210] Another method is to use DNA containing the mutation site in the RB1 gene region prepared from a biological sample and a substrate on which an oligonucleotide probe that hybridizes to the DNA is immobilized, such as a DNA array method.

[0211] In yet another method, a DNA or cDNA sample is first prepared from a biological sample. An oligonucleotide primer is also prepared, which has a base sequence complementary to the base 3' of all or part of the RB1 gene region and the base sequence 3' of that base. A ddNTP primer extension reaction is then carried out using the DNA as a template and the primer. The primer extension reaction product is then subjected to a mass spectrometer to measure the mass. The genotype is then determined based on the mass measurement results. The determined genotype is then compared with a control. Examples of such methods include MALDI-TOF / MS.

[0212] In yet another method, a DNA or cDNA sample is first prepared from a biological sample. An oligonucleotide probe is then prepared, consisting of 5'-"all or a portion of the RB1 gene region and a base sequence complementary to the 5'-side base sequence"-"all or a portion of the RB1 gene region, one base 3'-side base, and a base sequence that does not hybridize to the 3'-side base sequence"-3' (flap). An oligonucleotide probe having a base sequence complementary to all or a portion of the RB1 gene region and a base sequence complementary to the 3'-side base sequence" is also prepared. The two oligonucleotide probes are then hybridized to the prepared DNA or cDNA sample. The hybridized DNA is then cleaved with a single-stranded DNA cleaving enzyme to release the flap. The single-stranded DNA cleaving enzyme is not particularly limited, and examples include cleavase. In this method, an oligonucleotide probe having a sequence complementary to the flap and labeled with a reporter fluorescent compound and a quencher fluorescent compound is then hybridized to the flap. The intensity of the emitted fluorescence is then measured. The measured fluorescence intensity is then compared with that of a control. Examples of such methods include the Invader method.

[0213] In yet another method, a DNA or cDNA sample is first prepared from a biological sample. DNA containing all or part of the RB1 gene region is then amplified. The amplified DNA is then dissociated into single strands, and one strand of the dissociated single-stranded DNA is isolated. An extension reaction is then carried out one base at a time, starting from the vicinity of all or part of the base in the RB1 gene region. The pyrophosphate produced during this process is enzymatically induced to emit light, and the intensity of the luminescence is measured. The measured fluorescence intensity is then compared with that of a control. Examples of such methods include pyrosequencing.

[0214] In yet another method, a DNA or cDNA sample is first prepared from a biological sample. DNA containing all or part of the RB1 gene region is then amplified. An oligonucleotide primer is then prepared, which has a base sequence complementary to the base one base 3' of all or part of the RB1 gene region and the base sequence 3' of that base. A single-base extension reaction is then carried out using the prepared primer and the amplified DNA as a template in the presence of fluorescently labeled nucleotides. The degree of fluorescence polarization is then measured. The measured degree of fluorescence polarization is then compared with a control. Examples of such methods include the AcycloPrime method.

[0215] In yet another method, a DNA or cDNA sample is first prepared from a biological sample. Then, DNA containing all or part of the RB1 gene region is amplified. Next, an "oligonucleotide primer having a base one base 3' of all or part of the RB1 gene region and a base sequence complementary to the base sequence 3' of that base" is prepared. Next, a single-base extension reaction is performed using the prepared primer and the amplified DNA as a template in the presence of fluorescently labeled nucleotides. The base type used in the single-base extension reaction is then determined. The determined base type is then compared with a control. An example of such a method is the SNuPE method.

[0216] If the mutation involves an amino acid change in the RB1 protein, the sample prepared from the biological sample may be a protein. In such cases, the mutation can be detected using a method using a molecule (e.g., an antibody) that specifically binds to the site where the amino acid change occurs due to the mutation, peptide mass fingerprinting (PMF), protein sequencer (Edman degradation), etc.

[0217] As used herein, "decreased expression of the RB1 gene or protein" means that, when the RB1 gene or protein of a subject is analyzed, the expression level of the RB1 gene or protein is lower than that of a control (e.g., expression level in a healthy subject or non-cancerous tissue of the same patient). In certain embodiments, the decreased expression level of the RB1 gene or protein is detected in a biological sample (e.g., cancer cells) derived from a cancer patient.

[0218] Methods for detecting decreased RB1 gene expression include, but are not limited to, methods in which the expression level of RB1 is detected at the transcription or translation level and compared with the control. In methods for detecting the expression level of RB1 gene at the transcription level, RNA or cDNA is first prepared from a biological sample. Methods for extracting RNA from a biological sample and preparing cDNA from the extracted RNA are also not particularly limited, and known methods can be appropriately selected and used. Examples include extraction methods using phenol and chaotropic salts (more specifically, extraction methods using commercially available kits such as Trizol (Invitrogen) and Isogen (Wako Pure Chemical Industries)), and methods using other commercially available kits (RNAPrep Total RNA Extraction Kit (Beckman Coulter), RNeasy Mini (QIAGEN), RNA Extraction Kit (Pharmacia Biotech), etc.). Furthermore, the reverse transcriptase used to prepare cDNA from the extracted RNA is not particularly limited, and examples thereof include reverse transcriptases derived from retroviruses such as RAV (Rous associated virus) and AMV (Avian myeloblastosis virus), and reverse transcriptases derived from mouse retroviruses such as MMLV (Moloney murine leukemia virus).

[0219] The oligonucleotide primers or oligonucleotide probes are then used in an amplification reaction or hybridization reaction, respectively, to detect the amplified or hybridized products. Examples of such methods include RT-PCR, Northern blotting, dot blotting, DNA array analysis, in situ hybridization, RNase protection assay, and mRNA-seq. Those skilled in the art can routinely design oligonucleotide primers or oligonucleotide probes suitable for each method based on the nucleotide sequence of the RB1 cDNA.

[0220] It is known in the art that promoter hypermethylation is one of the factors that contribute to decreased gene expression. Therefore, in detecting whether or not RB1 function is inhibited, it is possible to detect methylation of the RB1 gene promoter as an indicator. Promoter methylation can be detected by known methods, such as a direct method of detecting changes in the base sequence after bisulfite treatment, which has the activity of converting methylated cytosine to uracil, by base sequencing, or an indirect method using a restriction endonuclease that can recognize (cleave) the base sequence before bisulfite treatment but cannot recognize (cleave) the base sequence after bisulfite treatment.

[0221] There are no particular limitations on the method for detecting decreased RB1 protein expression. For example, it can be confirmed and assessed by IHC (immunohistochemical staining) using an antibody specific to RB1 protein. In antibody-based protein detection methods, a protein sample is first prepared from a biological sample. Then, RB1 protein is detected by an antigen-antibody reaction using an antibody specific to RB1 protein. If the antibody specific to RB1 protein is labeled, RB1 protein can be detected directly. However, if the antibody is unlabeled, RB1 protein can be detected indirectly by further reacting it with a labeled molecule that recognizes the antibody (e.g., a secondary antibody or protein A) and utilizing the label of the molecule. Examples of such methods include immunohistochemistry (immunostaining), Western blotting, ELISA, flow cytometry, imaging cytometry, radioimmunoassay, immunoprecipitation, and analysis using antibody arrays. This method also has the advantage of simultaneously obtaining additional information, such as the morphology and distribution of cancer cells in tissue, through immunohistochemistry.

[0222] There are no particular limitations on the type or origin of the antibody used, but a monoclonal antibody is preferred. Oligoclonal antibodies (a mixture of several to several dozen types of antibodies) or polyclonal antibodies can also be used, as long as they can detect RB1 protein with sufficient specificity. Functional fragments of antibodies, such as Fab, Fab', F(ab')2, Fv, scFv, sc(Fv)2, dsFv, and diabodies, or multimers thereof (e.g., dimers, trimers, tetramers, polymers) can also be used. Commercially available anti-RB1 protein antibodies may also be used.

[0223] RB1 protein can also be detected using mass spectrometry (MS). Analysis using a mass spectrometer coupled to liquid chromatography (LC / MS) is particularly advantageous due to its sensitivity. Detection by mass spectrometry can be performed, for example, by labeling the protein in the protein sample, fractionating the labeled protein, subjecting the fractionated protein to mass spectrometry, and identifying the RB1 protein from the mass spectrometry values. Isotopic labeling reagents known in the art can be used for labeling, and suitable labeling reagents are commercially available. Fractionation can also be performed by methods known in the art, for example, using commercially available ion exchange columns.

[0224] As used herein, amplification of the copy number of the CCNE1 gene can be determined in a diagnostic or prognostic assay by assessing the copy number of the CCNE1 gene using a biological sample derived from a cancer patient (e.g., by next-generation sequencing, digital PCR, array CGH, or FISH).

[0225] As used herein, a "patient" may be a mouse, rat, guinea pig, monkey, dog, sheep, horse, or human. In the present invention, a "cancer patient" may refer not only to a person currently suffering from cancer, but also to a person suspected of suffering from cancer. In certain embodiments, the subject to be treated or prevented is a cancer patient in whom an increase in the CCNE1 gene expression has not been detected compared to a control. Furthermore, in certain embodiments, the subject to be treated or prevented is not a mouse transplanted with OVCAR3. The pharmaceutical composition can be suitably used in humans.

[0226] As used herein, the term "biological sample derived from a cancer patient" is not particularly limited as long as it is a biological sample capable of detecting the presence or absence of an RB1 gene mutation or reduced expression of the RB1 gene or protein, but is preferably a sample such as a cancer biopsy specimen, blood, urine, body cavity fluid, or tumor cell-derived circulating tumor DNA (ctDNA). Protein extracts or nucleic acid extracts (e.g., mRNA extracts, cDNA preparations or cRNA preparations prepared from mRNA extracts) obtained from the specimens may also be used. As used herein, "biological sample" includes samples derived from cancer patients and samples derived from cancer cell cultures.

[0227] The RB1 gene mutation may include a mutation that results in the insertion, deletion, or addition of at least one amino acid residue, or the substitution of an existing amino acid residue, relative to the wild-type RB1 protein. The RB1 gene mutation may also be a nonsense mutation, a frameshift mutation, a splice site mutation, a heterozygous deletion, or a homozygous deletion. The RB1 gene mutation is preferably a mutation that reduces the function of RB1. The term "mutation that reduces the function of RB1" can be used, for example, as described on the Internet.<URL:https: / / www.oncokb.org / gene / RB1> This can be confirmed by [Searched February 20, 2023].

[0228] A typical DNA (cDNA) nucleotide sequence of a human wild-type RB1 gene is shown in SEQ ID NO: 1 (NCBI Reference No.: NM_000321.3), and a typical amino acid sequence of a human wild-type RB1 protein is shown in SEQ ID NO: 2 (NCBI Reference No.: NP_000312.2). In the case of a human RB1 gene, an RB1 gene mutation refers to a nucleotide sequence that differs from the human RB1 genomic sequence listed at positions 48,303,751 to 48,481,890 in NCBI Reference No. NC_13.11, a nucleotide sequence that differs from the human RB1 genomic sequence listed at positions 4921 to 5161 in NCBI Reference No. NG_9009.1, or a mutation that results in an amino acid sequence that differs from the amino acid sequence of the human RB1 protein listed in SEQ ID NO: 2, and may result in at least one of the following mutations (1) to (5): Even in unmutated RB1, individual differences in sequence may occur due to polymorphisms, etc. (1) The codon corresponding to the serine residue (S) at position 82 of the amino acid sequence of SEQ ID NO: 2 is replaced with a stop codon; (2) the codon corresponding to the arginine residue (R) at position 467 in the amino acid sequence of SEQ ID NO: 2 is replaced with a stop codon; (3) At least one base is inserted or deleted in the codon corresponding to the 182nd amino acid residue in the amino acid sequence of SEQ ID NO: 2, forming a new reading frame starting from an isoleucine residue (I), and the third reading frame therefrom is a stop codon. (4) The glutamic acid residue (E) at position 837 of the amino acid sequence of SEQ ID NO: 2 is replaced with a lysine residue (K), and a portion of the RB1 gene is homozygously deleted. (5) The glycine residue (G) at position 449 of the amino acid sequence of SEQ ID NO: 2 is replaced with a glutamic acid residue (E), and a portion of the RB1 gene is homozygously deleted.

[0229] As used herein, decreased expression of the RB1 gene or protein includes decreased gene expression due to methylation of the RB1 gene or via microRNA.

[0230] The pharmaceutical composition of the present invention can be used to treat or prevent cancer, and is particularly suitable for treating or preventing cancer in cancer patients who have been detected as having a positive RB1 gene mutation or reduced expression of the RB1 gene or protein, or in cancer patients who have been detected as having a positive RB1 gene mutation or reduced expression of the RB1 gene or protein. The pharmaceutical composition of the present invention can be used alone or in combination with a chemotherapeutic agent.

[0231] In a particular embodiment, the cancer is lung cancer. The pharmaceutical composition of the present invention is more suitable for the treatment or prevention of cancer, particularly for the treatment or prevention of lung cancer.

[0232] In one embodiment, the compounds represented by formulae (1) to (3) of the present invention, or salts thereof, or solvates thereof can be used as MYT1 inhibitors.

[0233] A pharmaceutical composition comprising, as an active ingredient, a compound represented by any one of formulas (1) to (3) of the present invention, a salt thereof, or a solvate thereof (first ingredient) (hereinafter also referred to as "pharmaceutical composition of the present invention") may be administered in combination with a chemotherapeutic agent (second ingredient). In one embodiment, the pharmaceutical composition of the present invention is administered simultaneously with or separately from the chemotherapeutic agent. In another embodiment, the pharmaceutical composition of the present invention is administered as a combination drug with the chemotherapeutic agent.

[0234] A chemotherapeutic agent is a substance that has anti-cancer activity (also called anti-tumor activity). A chemotherapeutic agent can be, for example, an antimetabolite.

[0235] An antimetabolite is a substance that has a chemical structure similar to that of a metabolic substance (e.g., folic acid) and antagonizes or inhibits the metabolic mechanism of an organism. Examples of an antimetabolite include antifolates.

[0236] Antifolates are substances that inhibit DNA biosynthesis by suppressing or inhibiting the activity of enzymes that reduce folic acid to active folic acid, which is essential for nucleic acid synthesis. Examples of antifolates include methotrexate and pemetrexed. Pemetrexed is a more preferred antifolate.

[0237] In this embodiment, a preferred combination of an MYT1 inhibitor and a chemotherapeutic agent is one in which the MYT1 inhibitor is a compound represented by any of formulas (1) to (3) of the present invention, or a salt thereof, or a solvate thereof, and the chemotherapeutic agent is pemetrexed.

[0238] The dosage of the compounds represented by formulas (1) to (3) of the present invention, or salts thereof, or solvates thereof, is preferably 0.001 to 50 mg per kg of body weight of the subject per day (0.001 to 50 mg / kg / day), more preferably 0.001 to 20 mg / kg / day, and even more preferably 0.002 to 10 mg / kg / day. When the dosage of the compounds represented by formulas (1) to (3) of the present invention, or salts thereof, or solvates thereof, falls within these ranges, the therapeutic or preventive effect on cancer is enhanced. The frequency of administration of the compounds represented by formulas (1) to (3) of the present invention, or salts thereof, or solvates thereof can be, for example, once or more per week, twice per week, once per day, or twice per day.

[0239] The dosage of the chemotherapeutic agent is preferably 0.005 to 300 mg per kg of body weight of the subject per day (0.005 to 300 mg / kg / day), more preferably 0.01 to 250 mg / kg / day, and even more preferably 0.02 to 200 mg / kg / day. When the dosage of the chemotherapeutic agent is within these ranges, the cancer treatment or prevention effect is further enhanced. The frequency of administration of the chemotherapeutic agent can be, for example, once or more per week, twice per week, once per day, or twice per day.

[0240] The dosage of the compound represented by formulas (1) to (3) of the present invention, or a salt thereof, or a solvate thereof (first component) and the chemotherapeutic agent (second component) is, per kg of the subject's body weight, preferably 0.0001 to 50 mg / kg / day for the first component and 0.005 to 300 mg / kg / day for the second component, more preferably 0.001 to 20 mg / kg / day for the first component and 0.01 to 250 mg / kg / day for the second component, and even more preferably 0.002 to 10 mg / kg / day for the first component and 0.02 to 200 mg / kg / day for the second component. When the dosages of the first component and the second component are within these ranges, the therapeutic or preventive effect on cancer is further enhanced.

[0241] In the present invention, administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous, transdermal), intracisternal, intravaginal, intraperitoneal, intravesical, or topical (injection, infusion, powder, ointment, gel, or cream) administration, and inhalation (buccal or nasal spray). Dosage forms include, for example, tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for individual dosages. Dosage forms can also be adapted for various administration methods, including controlled-release formulations such as subcutaneous implants.

[0242] The first component can be administered by, for example, any of the above-mentioned administration methods, and the second component can be administered by, for example, the same or different administration method as the first component. The interval between administrations of the first and second components can be, for example, 0 to 14 days, 0 to 10 days, or 0 to 7 days. The administration interval can be determined using, for example, AUC, Cmax, Tmax, elimination half-life, or the subject's health status as an index. For example, the first component can be administered orally (tablets, capsules, etc.), and the second component can be administered by infusion. For example, both the first component and the second component can be administered orally (tablets, capsules, etc.). For example, the first component can be administered by infusion, and the second component can be administered orally (tablets, capsules, etc.). For example, both the first component and the second component can be administered by infusion. In such cases, the first component and the second component can be administered at any interval, such as three times a day, twice a day, once a day, once a week, or once every two weeks. More specifically, both the first and second components may be administered once daily, and in this case, they may be administered before, between, or after meals. "Before, between, or after meals" may refer to before, between, or after breakfast, lunch, dinner, a midnight snack, or a snack. If the administration interval between the first and second components is within 24 hours, both components can be administered once daily. If necessary, the first and second components may be administered twice a day and once a day, once a day and once a day, once a day and twice a day, once a day and once every two days, once a day and once every three days, once a day and once every seven days, three times a day and once every seven days, or twice a day and once every seven days. If necessary, the administration interval of the second component alone and / or the administration interval of the first component alone can be increased or decreased. The administration of the second component may be initiated on the same day as the administration of the first component, or the administration of the first component and the administration of the second component may be initiated on different days. The administration period is 7 days per course, and the total number of courses can be one or more courses, or two or more courses. Furthermore, each course may be administered consecutively or with a drug-free period. A drug-free period may be interspersed between courses.If necessary, during the course of treatment, only the first component can be continuously administered and the second component can be discontinued, or only the first component can be discontinued and the second component can be continuously administered. The first and second components can also be contained in the same tablet, capsule, etc.

[0243] The pharmaceutical composition of this embodiment can be administered in combination with, for example, a pharmaceutical composition containing a MYT1 inhibitor described below as "Second embodiment for the treatment or prevention of cancer" (combined administration).

[0244] One aspect of this embodiment is a MYT1 inhibitor for use in combination with a chemotherapeutic agent in the treatment or prevention of cancer in patients who have been detected as having a positive RB1 gene mutation or reduced expression of the RB1 gene or protein. One aspect of this embodiment is a MYT1 inhibitor for use in combination with a chemotherapeutic agent in the treatment or prevention of cancer in cancer patients who are positive for RB1 gene mutation or have reduced expression of the RB1 gene or protein.

[0245] Another aspect of this embodiment is the use of a MYT1 inhibitor for the manufacture of a medicament for the treatment or prevention of cancer in patients detected to be positive for an RB1 gene mutation or to have reduced expression of the RB1 gene or protein, administered in combination with a chemotherapeutic agent. Another aspect of this embodiment is the use of a MYT1 inhibitor for the manufacture of a medicament for the treatment or prevention of cancer in cancer patients who are positive for an RB1 gene mutation or have reduced expression of the RB1 gene or protein, administered in combination with a chemotherapeutic agent.

[0246] [Second embodiment related to cancer treatment or prevention] A second embodiment of the present invention relating to the treatment or prevention of cancer is a pharmaceutical composition comprising a chemotherapeutic agent as an active ingredient, in combination with an MYT1 inhibitor, for treating or preventing cancer in patients who have been detected to have a positive RB1 gene mutation or reduced expression of the RB1 gene or protein.

[0247] For each term used herein (e.g., MYT1 inhibitor, chemotherapeutic agent, RB1 gene mutation, administration method, type of cancer, etc.), reference can be made to the definitions in "First embodiment of cancer treatment or prevention." Herein, cancer in a patient who has been detected as positive for an RB1 gene mutation or reduced expression of the RB1 gene or protein may be cancer in a patient who has been detected as positive for an RB1 gene mutation or reduced expression of the RB1 gene or protein. The pharmaceutical composition according to this embodiment can be administered in combination with a pharmaceutical composition containing an MYT1 inhibitor described in "First embodiment of cancer treatment or prevention" (combined administration), for example.

[0248] In certain embodiments, the pharmaceutical composition comprises a chemotherapeutic agent (second component) as an active ingredient. The pharmaceutical composition comprising a chemotherapeutic agent as an active ingredient is used in combination with a MYT1 inhibitor (first component). In some embodiments, the pharmaceutical composition comprising a chemotherapeutic agent is administered simultaneously or separately with the MYT1 inhibitor. In other embodiments, the pharmaceutical composition comprising a chemotherapeutic agent is administered as a combination drug with the MYT1 inhibitor.

[0249] In this embodiment, a preferred combination of an MYT1 inhibitor and a chemotherapeutic agent is one in which the MYT1 inhibitor is a compound represented by any of formulas (1) to (3) of the present invention, or a salt thereof, or a solvate thereof, and the chemotherapeutic agent is pemetrexed.

[0250] The dosage of the MYT1 inhibitor (first component) and the chemotherapeutic agent (second component) is preferably 0.0001 to 50 mg / kg / day of the first component and 0.005 to 300 mg / kg / day of the second component per kg of body weight of the subject, more preferably 0.001 to 20 mg / kg / day of the first component and 0.01 to 250 mg / kg / day of the second component, and even more preferably 0.002 to 10 mg / kg / day of the first component and 0.02 to 200 mg / kg / day of the second component. When the dosages of the first component and the second component are within these ranges, the therapeutic or preventive effect on cancer is further enhanced.

[0251] One aspect of this embodiment is also a chemotherapeutic agent for use in combination with a MYT1 inhibitor in the treatment or prevention of cancer in patients who have been detected as positive for RB1 gene mutation or in whom reduced expression of the RB1 gene or protein has been detected.

[0252] Another aspect of this embodiment is the use of a chemotherapeutic agent for the manufacture of a medicament for the treatment or prevention of cancer in patients who have been detected to have a positive RB1 gene mutation or reduced expression of the RB1 gene or protein, administered in combination with a MYT1 inhibitor.

[0253] [Third embodiment related to cancer treatment or prevention] A third embodiment of the present invention relating to the treatment or prevention of cancer is a method for treating or preventing cancer in a patient in whom a positive RB1 gene mutation or reduced expression of the RB1 gene or protein has been detected, the method comprising administering a combination of a chemotherapeutic agent and an MYT1 inhibitor to the cancer patient. One aspect of this embodiment is a method for treating or preventing cancer, the method comprising detecting or having a third party detect a positive RB1 gene mutation or reduced expression of the RB1 gene or protein in a biological sample from the cancer patient, and administering a combination of a chemotherapeutic agent and an MYT1 inhibitor to the cancer patient.

[0254] The dosage of the MYT1 inhibitor (first component) and the chemotherapeutic agent (second component) is preferably 0.0001 to 50 mg / kg / day of the first component and 0.005 to 300 mg / kg / day of the second component per kg of body weight of the subject, more preferably 0.001 to 20 mg / kg / day of the first component and 0.01 to 250 mg / kg / day of the second component, and even more preferably 0.002 to 10 mg / kg / day of the first component and 0.02 to 200 mg / kg / day of the second component. When the dosages of the first component and the second component are within these ranges, the therapeutic or preventive effect on cancer is further enhanced.

[0255] When administering a combination of a chemotherapeutic agent and an MYT1 inhibitor, the MYT1 inhibitor and the chemotherapeutic agent may be administered simultaneously or separately at a fixed interval. The administration routes of the MYT1 inhibitor and the chemotherapeutic agent may be the same or different. They may also be administered in the form of a combination drug containing the MYT1 inhibitor and the chemotherapeutic agent. That is, the pharmaceutical composition may contain both the MYT1 inhibitor and the chemotherapeutic agent.

[0256] [Fourth embodiment related to cancer treatment or prevention] A fourth embodiment of the present invention relating to the treatment or prevention of cancer is a method for suppressing cancer cell proliferation in a subject in whom a positive RB1 gene mutation or reduced expression of the RB1 gene or protein has been detected, the method comprising contacting the cancer cells with an MYT1 inhibitor and a chemotherapeutic agent. One aspect of this embodiment is a method for suppressing cancer cell proliferation, the method comprising detecting, or having a third party detect, a positive RB1 gene mutation or reduced expression of the RB1 gene or protein in a biological sample from the cancer patient, and contacting the cancer cells with an MYT1 inhibitor and a chemotherapeutic agent.

[0257] The method according to this embodiment encompasses in vivo, in vitro, and ex vivo methods. For example, a subject in which a positive RB1 gene mutation or a detected decrease in RB1 gene or protein expression has been detected may be any animal in which a positive RB1 gene mutation or a detected decrease in RB1 gene or protein expression has been detected, and the animal species may be a mouse, rat, guinea pig, monkey, dog, sheep, horse, or human. In the in vivo method, cancer cell proliferation can be suppressed by administering an MYT1 inhibitor and a chemotherapeutic agent to the subject. In the in vitro method, cancer cell proliferation can be suppressed by adding an MYT1 inhibitor and a chemotherapeutic agent to a system containing cancer cells collected from the subject. In the ex vivo method, cancer cell proliferation can be suppressed by collecting an organ containing cancer cells from the subject (e.g., lungs in the case of lung cancer) and administering an MYT1 inhibitor and a chemotherapeutic agent to the organ. The dosages of the first component (MYT1 inhibitor) and the second component (chemotherapeutic agent) can be appropriately determined depending on the amount of cancer cells and the type of MYT1 inhibitor and chemotherapeutic agent used.

[0258] Fifth embodiment related to cancer treatment or prevention A fifth embodiment of the present invention relating to cancer treatment or prevention is a method for improving responsiveness to cancer treatment with a chemotherapeutic agent, the method comprising administering an MYT1 inhibitor to a cancer patient in whom a positive RB1 gene mutation or reduced expression of the RB1 gene or protein has been detected, together with the chemotherapeutic agent. One aspect of this embodiment is a method for improving responsiveness to cancer treatment with a chemotherapeutic agent, the method comprising detecting, or having a third party detect, a positive RB1 gene mutation or reduced expression of the RB1 gene or protein in a biological sample from the cancer patient, and administering an MYT1 inhibitor to the cancer patient together with the chemotherapeutic agent.

[0259] The method of this embodiment involves administering a chemotherapeutic agent to a patient in whom a positive RB1 gene mutation or decreased expression of the RB1 gene or protein has been detected in combination with an MYT1 inhibitor, thereby improving the efficacy of cancer treatment with the chemotherapeutic agent.

[0260] When administering a MYT1 inhibitor to a cancer patient together with a chemotherapeutic agent, both the MYT1 inhibitor and the chemotherapeutic agent may be administered simultaneously, or may be administered separately at a fixed interval. The administration routes of the MYT1 inhibitor and the chemotherapeutic agent may be the same or different. The MYT1 inhibitor and the chemotherapeutic agent may also be administered in the form of a combination drug containing the MYT1 inhibitor and the chemotherapeutic agent. Even for patients for whom existing chemotherapeutic agents are insufficiently effective, sufficient therapeutic efficacy can be achieved by combining the MYT1 inhibitor with the MYT1 inhibitor.

[0261] The dosage of the MYT1 inhibitor (first component) and the chemotherapeutic agent (second component) is preferably 0.0001 to 50 mg / kg / day of the first component and 0.005 to 300 mg / kg / day of the second component per kg of body weight of the subject, more preferably 0.001 to 20 mg / kg / day of the first component and 0.01 to 250 mg / kg / day of the second component, and even more preferably 0.002 to 10 mg / kg / day of the first component and 0.02 to 200 mg / kg / day of the second component. When the dosages of the first component and the second component are within these ranges, the therapeutic or preventive effect on cancer is further enhanced.

[0262] Sixth embodiment related to cancer treatment or prevention A sixth embodiment of the present invention relating to the treatment or prevention of cancer is a method for predicting responsiveness to cancer treatment with a combination of an MYT1 inhibitor and a chemotherapy agent, the method comprising detecting, or having a third party detect, the presence or absence of an RB1 gene mutation or the presence or absence of reduced expression of the RB1 gene or protein in cancer cells derived from a cancer patient, and determining that the cancer patient will be responsive to cancer treatment with a combination of the MYT1 inhibitor and a chemotherapy agent if the RB1 gene mutation is positive or the expression of the RB1 gene or protein is reduced.

[0263] In the method of this embodiment, the presence or absence of RB1 gene mutation or the presence or absence of reduced expression of the RB1 gene or protein is detected in cancer cells collected from a cancer patient to be treated, or a third party is asked to detect this, and if the RB1 gene mutation is positive or the expression of the RB1 gene or protein is reduced, the cancer patient is determined to be responsive (effective) to treatment involving administration of a combination of a MYT1 inhibitor and a chemotherapeutic agent.

[0264] According to the method of this embodiment, even in patients for whom existing chemotherapeutic agents are insufficiently effective, if the cancer patient is RB1 gene mutation-positive or has reduced expression of the RB1 gene or protein, administering the chemotherapeutic agent in combination with an MYT1 inhibitor can be determined to be therapeutically effective. This makes it possible to suggest effective chemotherapy in advance to cancer patients for whom existing chemotherapeutic agents alone have not produced sufficient therapeutic effects.

[0265] Detection of RB1 gene mutations or reduced expression of the RB1 gene or protein in cancer cells can be carried out by methods well known to those skilled in the art, such as direct sequencing, PCR, TaqMan Genotyping, and next-generation sequencing.

[0266] One aspect of this embodiment is a method for selecting a cancer patient for whom administration of a combination of an MYT1 inhibitor and a chemotherapeutic agent is more effective. This method includes detecting or having a third party detect the presence or absence of an RB1 gene mutation or reduced expression of the RB1 gene or protein in cancer cells derived from the cancer patient, and identifying the cancer patient as a cancer patient for whom administration of a combination of an MYT1 inhibitor and a chemotherapeutic agent is more effective based on the presence of the mutation.

[0267] Another aspect of this embodiment is a method for diagnosing whether administration of a combination of an MYT1 inhibitor and a chemotherapeutic agent is more effective for cancer treatment in a specific cancer patient than administration of the chemotherapeutic agent alone. This method includes detecting or having a third party detect the presence or absence of an RB1 gene mutation or reduced expression of the RB1 gene or protein in cancer cells derived from the cancer patient, and identifying the cancer patient as a cancer patient for whom administration of a combination of an MYT1 inhibitor and a chemotherapeutic agent would be more effective based on the presence of the mutation.

[0268] [Seventh embodiment related to cancer treatment or prevention] A seventh embodiment of the present invention relating to the treatment or prevention of cancer is a method for screening for compounds effective in the treatment or prevention of cancer in patients who have been detected as having a positive RB1 gene mutation or reduced expression of the RB1 gene or protein, the method comprising measuring the MYT1 inhibitory activity of candidate compounds and selecting candidate compounds having MYT1 inhibitory activity as compounds effective in the treatment of cancer.

[0269] The method according to this embodiment includes measuring the MYT1 inhibitory activity of a candidate compound, and selecting the candidate compound as a compound effective in treating cancer if the candidate compound has MYT1 inhibitory activity.

[0270] In the present invention, an MYT1 inhibitor refers to a substance that can directly or indirectly neutralize, block, inhibit, reduce, or interfere with the activity of MYT1, such as threonine kinase activity or tyrosine kinase activity. The inhibition of MYT1 threonine kinase activity or tyrosine kinase activity by a compound can be confirmed, for example, by treating a purified MYT1 protein preparation with a test compound, adding ATP, and measuring the degree of ATP hydrolysis. The degree of ATP hydrolysis can be assessed using Kinase-Glo (Promega) or ADP-Glo ​​(Promega) (Non-Patent Document 8). When the test compound inhibits MYT1 threonine kinase activity or tyrosine kinase activity in comparison with a control (e.g., the degree of ATP hydrolysis by MYT1 not treated with the test compound), attenuation of the ATP hydrolysis is confirmed.

[0271] Inhibition of the threonine kinase activity of MYT1 protein by a compound can be confirmed, for example, by treating a purified MYT1 protein preparation with a test compound, adding CDK1, a substrate of MYT1, and measuring the level of phosphorylation of CDK1 at Thr14. The level of phosphorylation at this site can be assessed by Western blotting using an antibody (Abcam) that specifically recognizes phosphorylation at Thr14 of CDK1, ELISA using an antibody that specifically recognizes CDK1 and an antibody that specifically recognizes phosphorylation at Thr14 of CDK1, or AlphaLISA (PerkinElmer) using an antibody that specifically recognizes CDK1 and an antibody that specifically recognizes phosphorylation at Thr14 of CDK1. When the test compound inhibits the threonine kinase activity of MYT1 compared with a control (e.g., the level of phosphorylation at Thr14 of CDK1 by MYT1 not treated with the test compound), attenuation of the phosphorylation is confirmed.

[0272] Furthermore, whether a compound inhibits the threonine kinase activity of MYT1 can be confirmed, for example, by measuring the level of phosphorylation at Thr14 of CDK1, a substrate protein for the threonine kinase activity of MYT1, in a lysate of cells treated with the test compound. The level of phosphorylation at this site can be assessed by Western blotting using an antibody (Abcam) that specifically recognizes phosphorylation at Thr14 of CDK1, ELISA using an antibody that specifically recognizes CDK1 and an antibody that specifically recognizes phosphorylation at Thr14 of CDK1, or AlphaLISA (PerkinElmer) (Non-Patent Document 8) using an antibody that specifically recognizes CDK1 and an antibody that specifically recognizes phosphorylation at Thr14 of CDK1. If the test compound inhibits the threonine kinase activity of MYT1, as compared with a control (e.g., the level of phosphorylation at Thr14 of CDK1 in a lysate of cells not treated with the test compound), then attenuation of the phosphorylation is confirmed.

[0273] Furthermore, whether a compound inhibits MYT1 expression can be confirmed, for example, by detecting decreased MYT1 expression in cells treated with the test compound. Decreased MYT1 expression can usually be detected by detecting the expression level of MYT1 at the transcriptional or translational level and confirming that the expression level is lower than that of a control (e.g., the expression level in cells not treated with the test compound).

[0274] In a method for detecting the expression level of MYT1 at the transcription level, RNA or cDNA is first prepared from cells treated with a test compound. The method for extracting RNA from the cells is not particularly limited, and any known method can be appropriately selected and used. Examples include extraction methods using phenol and chaotropic salts (more specifically, extraction methods using commercially available kits such as Trizol (Invitrogen) and Isogen (Wako Pure Chemical Industries, Ltd.)) and methods using other commercially available kits (RNAPrep Total RNA Extraction Kit (Beckman Coulter), RNeasy Mini (QIAGEN), RNA Extraction Kit (Pharmacia Biotech), etc.). Furthermore, the reverse transcriptase used to prepare cDNA from the extracted RNA is not particularly limited, and examples include reverse transcriptases derived from retroviruses such as Rous associated virus (RAV) and Avian myeloblastosis virus (AMV), and reverse transcriptases derived from murine retroviruses such as Moloney murine leukemia virus (MMLV).

[0275] The oligonucleotide primers or oligonucleotide probes are then used in an amplification reaction or hybridization reaction, respectively, to detect the amplified or hybridized products. Examples of such methods include RT-PCR, Northern blotting, dot blotting, DNA array analysis, in situ hybridization, RNase protection assay, and mRNA-seq. Those skilled in the art can routinely design oligonucleotide primers or oligonucleotide probes suitable for each method based on the nucleotide sequence of the MYT1 cDNA.

[0276] In a method for detecting MYT1 expression levels at the translational level, a protein sample is first prepared from cells treated with a test compound. MYT1 protein is then detected by an antigen-antibody reaction using an antibody specific to the MYT1 protein. In such an antibody-based protein detection method, for example, an antibody specific to the MYT1 protein is added to the protein sample, an antigen-antibody reaction is carried out, and binding of the antibody to the MYT1 protein is detected. If the antibody specific to the MYT1 protein is labeled, MYT1 protein can be detected directly. However, if the antibody is unlabeled, MYT1 protein can be detected indirectly by further reacting it with a labeled molecule that recognizes the antibody (e.g., a secondary antibody or protein A), utilizing the label of the molecule. Examples of such methods include immunohistochemistry (immunostaining), Western blotting, ELISA, flow cytometry, imaging cytometry, radioimmunoassay, immunoprecipitation, and analysis using an antibody array.

[0277] There are no particular limitations on the type or origin of the antibody used, but a monoclonal antibody is preferred. Oligoclonal antibodies (a mixture of several to several dozen types of antibodies) or polyclonal antibodies can also be used, as long as they are capable of detecting MYT1 protein with sufficient specificity. Functional fragments of antibodies, such as Fab, Fab', F(ab')2, Fv, scFv, sc(Fv)2, dsFv, and diabodies, or multimers thereof (e.g., dimers, trimers, tetramers, polymers), can also be used. Such anti-MYT1 protein antibodies may be commercially available.

[0278] MYT1 protein can also be detected using mass spectrometry (MS). Analysis using a mass spectrometer coupled to liquid chromatography (LC / MS) is particularly advantageous due to its sensitivity. Detection by mass spectrometry can be performed, for example, by labeling the protein in the protein sample, fractionating the labeled protein, subjecting the fractionated protein to mass spectrometry, and identifying the MYT1 protein from the mass spectrometry values. Isotopic labeling reagents known in the art can be used for labeling, and suitable labeling reagents are commercially available. Fractionation can also be performed by methods known in the art, for example, using commercially available ion exchange columns.

[0279] As used herein, "having MYT1 inhibitory activity" means reducing MYT1 activity in vitro, in a cell culture system, or in animals, and is, for example, measured as MYT1 inhibitory activity IC 50 is preferably 10 μM or less, 5 μM or less, or 1 μM or less. More preferably, the MYT1 inhibitory activity (IC 50 ) is 100 nM or less, 10 nM or less, 3 nM or less, 100 pM or less, or 10 pM or less. 50 ) is 1 nM to 1 μM, 1 nM to 750 nM, 1 nM to 500 nM, or 1 nM to 250 nM. Particularly preferred are compounds having an MYT1 inhibitory activity (IC 50 ) is less than 20 nM, or 1 nM to 20 nM. 50 The smaller the RB1 gene mutation, the more effective the compound can be in treating or preventing cancer in patients in whom a positive RB1 gene mutation or decreased expression of the RB1 gene or protein has been detected.

[0280] The compounds selected by the method of this embodiment have increased therapeutic effectiveness when used in combination with chemotherapeutic agents in the treatment of cancer in patients who have been detected to be positive for RB1 gene mutation or have had reduced expression of the RB1 gene or protein. [Example]

[0281] The present disclosure will be described in more detail below based on examples, but the present disclosure is not limited to the following examples.

[0282] NMR analysis was performed using a BRUKER AVANCE III HD400 (400 MHz) NMR data are given in parts per million (ppm) (δ) and referenced to the deuterium lock signal from the sample solvent.

[0283] Mass spectral data were obtained using a Shimadzu single quadrupole mass spectrometer (LCMS-2020) equipped with an ultra-high performance liquid chromatograph (Nexera UC) or a Waters single quadrupole mass spectrometer (SQD or SQD2) equipped with an Acquity ultra-high performance liquid chromatograph (UPLC or UPLC I-Class).

[0284] The analysis by high performance liquid chromatography was carried out under any of the analytical conditions A to W shown in Tables 1 and 2 below. In Tables 1 and 2 below, "TFA" means trifluoroacetic acid, "FA" means formic acid, "AA" means ammonium acetate, and "AC" means ammonium hydrogen carbonate.

[0285] [Table 1]

[0286] [Table 2] JPEG2026000973000030.jpg220149

[0287] The microwave reaction was carried out using a Biotage Initiator. Snap-cap reaction vials were used for the microwave reaction. The operation of the instrument was carried out according to the manual that came with the instrument.

[0288] The photoredox catalytic reaction was carried out using a Penn PhD M2 Integrated Photoreactor (ACS Cent. Sci. 2017, vol. 3, issue 6, pp. 647-653 (Non-Patent Document 20)). The instrument was operated according to the manual provided with the instrument.

[0289] Commercially available reagents were used without further purification. All non-aqueous reactions were carried out using commercially available anhydrous solvents. Concentration under reduced pressure and solvent removal were carried out using a rotary evaporator.

[0290] In this specification, "room temperature" means a temperature of about 20°C to about 25°C.

[0291] compound a-1 4-Bromo-7-chloro-2-(oxan-2-yl)indazole [ka] 3,4-Dihydro-2H-pyran (32.68 g, 388 mmol) and pyridinium p-toluenesulfonate (9.77 g, 38.9 mmol) were added to a DCM solution (900 mL) of 4-bromo-7-chloro-1H-indazole (44.97 g, 194 mmol) in a reaction vessel, and the mixture was stirred at room temperature for 6 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted twice with DCM. The organic layer was dried over anhydrous sodium sulfate, and the drying agent was removed by filtration. The mixture was then concentrated under reduced pressure. The resulting residue was suspended in a mixture of hexane / ethyl acetate (3 / 1), and the solid was collected by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. The residue was combined with the previously obtained solid to give the title compound (55.17 g, 90% yield) as a yellow solid. LCMS: m / z 315[M+H] + HPLC retention time: 4.97 minutes (Analysis conditions J)

[0292] compound a-2 (2,4,6-trichlorophenyl) 7-chloro-2-(oxan-2-yl)indazole-4-carboxylate [ka] Triethylamine (15.5 g, 153.18 mmol) was added to a toluene solution (340 mL) of 4-bromo-7-chloro-2-(oxan-2-yl)indazole (compound a-1, 24.16 g, 76.55 mmol) in a reaction vessel, and the reaction vessel was degassed under reduced pressure and purged with nitrogen. Xantphos Pd G4 (3.69 g, 3.83 mmol) was added to the mixture, and the reaction vessel was degassed under reduced pressure and purged with nitrogen. The reaction mixture was heated to 65°C, and a toluene solution (54 mL) of 2,4,6-trichlorophenyl formate (19.85 g, 88 mmol) that had been degassed under reduced pressure and purged with nitrogen was added dropwise over 3 hours. The reaction mixture was stirred at 65°C under a nitrogen atmosphere for an additional 20 minutes, then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give the title compound (46.69 g) as a crude product. LCMS: m / z 459[M+H] + HPLC retention time: 4.86 minutes (analysis condition K)

[0293] compound a-3 7-chloro-2-(oxan-2-yl)indazole-4-carboxylic acid [ka] A 2M aqueous sodium hydroxide solution (230 mL, 460 mmol) was added to a THF suspension (470 mL) of crude (2,4,6-trichlorophenyl) 7-chloro-2-(oxan-2-yl)indazole-4-carboxylate (compound a-2) (46.69 g) in a reaction vessel, and the mixture was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, and ethyl acetate, water, and aqueous phosphoric acid solution were added to adjust the pH to 4. The mixture was then extracted twice with ethyl acetate. The organic layer was washed with water (500 mL) and then extracted four times with saturated aqueous sodium bicarbonate solution (400 mL) and 5% aqueous sodium bicarbonate solution (400 mL). The resulting aqueous layers were combined, cooled to 5°C, and aqueous phosphoric acid solution was added to adjust the pH to 4. The mixture was extracted four times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and then the organic layer was combined with that of another lot synthesized in the same manner and concentrated under reduced pressure to give the title compound (38.76 g) as a pale yellow solid. LCMS: m / z 281[M+H] + HPLC retention time: 2.79 minutes (analysis condition K)

[0294] compound a-4 7-chloro-N-methoxy-N-methyl-2-(oxan-2-yl)indazole-4-carboxamide [ka] Triethylamine (55.89 g, 552 mmol), N,O-dimethylhydroxylamine hydrochloride (26.94 g, 276 mmol), and HATU (68.25 g, 180 mmol) were added to a THF solution (388 mL) of 7-chloro-2-(oxan-2-yl)indazole-4-carboxylic acid (compound a-3, 38.76 g, 138 mmol) in a reaction vessel, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The mixture was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (31.74 g, 71% yield) as a colorless solid. LCMS: m / z 324[M+H] + HPLC retention time: 0.66 minutes (Analysis conditions A)

[0295] compound a-5 4-Bromo-5-fluoro-2-iodoaniline [ka] N-iodosuccinimide (19.18 g, 85.248 mmol) was added to a solution of 4-bromo-3-fluoroaniline (15.43 g, 81.2 mmol) in acetic acid (200 mL) in a reaction vessel, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction mixture was cooled to 0°C, and the solid was collected by filtration and washed with water. The resulting solid was dissolved in DCM and washed with saturated aqueous sodium carbonate. The organic layer was dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (22.01 g, 86% yield) as a brown solid. LCMS: m / z 316[M+H] + HPLC retention time: 4.55 minutes (Analysis conditions J)

[0296] compound a-6 (E)-N'-(4-bromo-5-fluoro-2-iodophenyl)-N,N-dimethylmethanimidamide [ka] 4-Bromo-5-fluoro-2-iodoaniline (compound a-5, 28.58 g, 190.47 mmol) in a reaction vessel was dissolved in EtOH (180 mL), and N,N-dimethylformamide dimethyl acetal (43.12 g, 361.9 mmol) was added and stirred at 80 °C for 1.5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / DCM) to give the title compound (31.7 g, 95% yield) as a pale red solid. LCMS: m / z 371[M+H] + HPLC retention time: 2.59 minutes (Analysis conditions J)

[0297] compound a-7 (E)-N'-[4-bromo-2-[7-chloro-2-(oxan-2-yl)indazole-4-carbonyl]-5-fluorophenyl]-N,N-dimethylmethanimidamide [ka] A toluene solution (164 mL) of (E)-N'-(4-bromo-5-fluoro-2-iodophenyl)-N,N-dimethylmethanimidamide (Compound a-6, 16.39 g, 44.18 mmol) in a reaction vessel was cooled to -40 °C, and a 1.3 M solution of isopropyl magnesium chloride and lithium chloride complex in THF (34 mL, 44.2 mmol) was added dropwise, followed by stirring for 1 hour. A toluene solution (110 mL) of 7-chloro-N-methoxy-N-methyl-2-(oxan-2-yl)indazole-4-carboxamide (Compound a-4, 11.14 g, 34 mmol) was added dropwise to the reaction mixture over 30 minutes, followed by stirring at 0 °C for 1 hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and then the filtrate was concentrated under reduced pressure to give the crude product of the title compound (22.38 g). LCMS: m / z 507[M+H] + HPLC retention time: 3.65 minutes (Analysis conditions J)

[0298] compound a-8 (2-amino-5-bromo-4-fluorophenyl)-[7-chloro-2-(oxan-2-yl)indazol-4-yl]methanone [ka] The crude product of (E)-N'-[4-bromo-2-[7-chloro-2-(oxan-2-yl)indazole-4-carbonyl]-5-fluorophenyl]-N,N-dimethylmethanimidamide (Compound a-7, 22.38 g) in a reaction vessel was dissolved in DMSO (220 mL), and 5 M aqueous sodium hydroxide (20.4 mL) was added and stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride (300 mL) and water (1 L) were added to the reaction mixture. The solid was collected by filtration and washed with water. The resulting solid was purified three times by silica gel column chromatography to give the title compound (7.41 g, 48% yield) as a yellow solid. LCMS: m / z 452[M+H] + HPLC retention time: 5.42 minutes (Analysis conditions J)

[0299] compound a-9 N-[4-bromo-2-[7-chloro-2-(oxan-2-yl)indazole-4-carbonyl]-5-fluorophenyl]-2-chloroacetamide [ka] A DMA solution (120 mL) of (2-amino-5-bromo-4-fluorophenyl)-[7-chloro-2-(oxan-2-yl)indazol-4-yl]methanone (compound a-8, 7.41 g, 16.37 mmol) in a reaction vessel was cooled to 0°C, and chloroacetyl chloride (1.96 mL, 24.64 mmol) was added and stirred at room temperature for 1 hour to obtain a DMA solution of the title compound. LCMS: m / z 528[M+H] + HPLC retention time: 5.57 minutes (Analysis conditions J)

[0300] compound a-10 6-Bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-3-pyridin-1-ium-1-yl-1H-quinolin-2-one; Chloride [ka] Pyridine (74 mL) was added to a DMA solution of N-[4-bromo-2-[7-chloro-2-(oxan-2-yl)indazole-4-carbonyl]-5-fluorophenyl]-2-chloroacetamide (Compound a-9) in a reaction vessel, and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was cooled to room temperature to obtain a DMA / pyridine solution of the title compound. LCMS: m / z 553[M] + HPLC retention time: 3.44 minutes (Analysis conditions J)

[0301] compound a-11 3-amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1H-quinolin-2-one [ka] To a DMA / pyridine solution of 6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-3-pyridin-1-ium-1-yl-1H-quinolin-2-one; chloride (compound a-10), hydrazine monohydrate (8.2 g, 163.8 mmol) was added and stirred at 60 ° C. for 4 hours, then at room temperature for 13 hours. After adding water to the reaction mixture, the resulting solid was filtered and washed with water. The resulting solid was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (7.3 g, 91% yield) as a colorless solid. LCMS: m / z 491[M+H] + HPLC retention time: 4.65 minutes (Analysis conditions J)

[0302] compound a-12 3-amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1-[(4-methoxyphenyl)methyl]quinolin-2-one [ka] 3-Amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1H-quinolin-2-one (compound a-11, 7.3 g, 14.84 mmol) and potassium carbonate (5.13 g, 37.12 mmol) were suspended in NMP (73 mL) in a reaction vessel, and p-methoxybenzyl chloride (2.83 mL, 20.78 mmol) was added and stirred at 70 °C for 2 hours. The reaction mixture was cooled to room temperature, and water was added. The solid was collected by filtration and washed with water and hexane. The resulting solid was purified by silica gel column chromatography to give the title compound (4.79 g, 53% yield) as a pale yellow solid. LCMS: m / z 611[M+H] + HPLC retention time: 5.76 minutes (Analysis conditions J)

[0303] compound a-13 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-6-hydroxy-1-[(4-methoxyphenyl)methyl]quinolin-2-one [ka] 3-Amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1-[(4-methoxyphenyl)methyl]quinolin-2-one (Compound a-12, 500 mg, 0.817 mmol) and tBuBrettPhos Pd G3 (69.8 mg, 0.0817 mmol) were added to a reaction vessel, and the reaction vessel was degassed under reduced pressure and replaced with argon. DMA (8 mL) and 8 M potassium hydroxide (245.1 μL, 1.961 mmol) were added, and the reaction vessel was degassed under reduced pressure and replaced with argon. The mixture was stirred at room temperature for 21 hours. Potassium dihydrogen phosphate (445 mg) and water were added, and the resulting solid was collected by filtration. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the mixture was concentrated under reduced pressure. The residue was combined with the solid obtained earlier and purified by silica gel column chromatography to give the title compound (308 mg, yield 68.7%) as a pale brown solid. LCMS: m / z 549[M+H] + HPLC retention time: 4.49 minutes (Analysis conditions J)

[0304] compound a-14 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1-[(4-methoxyphenyl)methyl]-6-propan-2-yloxyquinolin-2-one [ka] 3-Amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-6-hydroxy-1-[(4-methoxyphenyl)methyl]quinolin-2-one (compound a-13, 210 mg, 0.383 mmol) and potassium carbonate (265 mg, 1.917 mmol) were suspended in DMF (4.4 mL) in a reaction vessel, and 2-iodopropane (190.2 μL, 1.913 mmol) was added and stirred at room temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (201 mg, 89% yield) as a yellow solid. LCMS: m / z 591[M+H] + HPLC retention time: 5.60 minutes (Analysis conditions J)

[0305] Compound A1 3-amino-4-(7-chloro-1H-indazol-4-yl)-7-fluoro-6-propan-2-yloxy-1H-quinolin-2-one [ka] TFA / water (3 / 1, 3 mL) was added to 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1-[(4-methoxyphenyl)methyl]-6-propan-2-yloxyquinolin-2-one (compound a-14, 201 mg, 0.34 mmol) in a reaction vessel, and the mixture was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. MeOH was added to the residue, and the mixture was further concentrated. MeOH (4 mL) and 12 M hydrochloric acid (100 μL) were added to the residue, and the mixture was stirred at room temperature for 20 hours. After concentrating the reaction mixture, the resulting residue was dissolved in MeOH, and triethylamine was added. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (48.3 mg, 37% yield) as a pale yellow solid. LCMS: m / z 387[M+H] + HPLC retention time: 0.67 min (Analysis conditions A)

[0306] compound a-15 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-6-(3,3-difluoropropoxy)-7-fluoro-1-[(4-methoxyphenyl)methyl]quinolin-2-one [ka] 0.5M cyanomethylenetrimethylphosphorane THF solution (2.53 mL, 1.265 mmol) was added to 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-6-hydroxy-1-[(4-methoxyphenyl)methyl]quinolin-2-one (compound a-13, 231 mg, 0.421 mmol) and 3,3-difluoropropan-1-ol (123 mg, 1.28 mmol) in a reaction vessel. The reaction vessel was degassed under reduced pressure and purged with argon, and then stirred at 80 ° C. for 2.5 hours. The reaction mixture was cooled to room temperature, water (231 μL) was added, and the mixture was stirred at 80 ° C. for 15 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. THF was added to the resulting residue, and the mixture was further concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the title compound (233 mg, yield 88%) as a pale yellow solid. LCMS: m / z 627[M+H] + HPLC retention time: 5.40 minutes (Analysis conditions J)

[0307] Compound A2 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-(3,3-difluoropropoxy)-7-fluoro-1H-quinolin-2-one [ka] The title compound was synthesized from 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-6-(3,3-difluoropropoxy)-7-fluoro-1-[(4-methoxyphenyl)methyl]quinolin-2-one (compound a-15) under the same conditions as in the production example of compound A1. LCMS: m / z 423[M+H] + HPLC retention time: 0.65 min (Analysis conditions A)

[0308] compound a-22 3-amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1-(2-trimethylsilylethoxymethyl)quinolin-2-one [ka] A THF solution (25 mL) of 3-amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1H-quinolin-2-one (Compound a-11, 1.732 g, 3.522 mmol) was cooled to 0 °C in a reaction vessel, and 60% sodium hydride in mineral oil (564 mg, 14.08 mmol) was added and stirred for 30 minutes. 2-(Chloromethoxy)ethyltrimethylsilane (1.86 mL, 10.6 mmol) was added to the reaction mixture, and the mixture was stirred for an additional 30 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.87 g, 85% yield) as a pale yellow solid. LCMS: m / z 621[M+H] + HPLC retention time: 6.33 minutes (Analysis conditions J)

[0309] compound a-23 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-6-hydroxy-1-(2-trimethylsilylethoxymethyl)quinolin-2-one [ka] The title compound was synthesized from 3-amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1-(2-trimethylsilylethoxymethyl)quinolin-2-one (compound a-22) under the same conditions as in the production example for compound a-13. LCMS: m / z 559[M+H] + HPLC retention time: 5.35 minutes (Analysis conditions J)

[0310] compound a-24 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-6-cyclobutyloxy-7-fluoro-1-(2-trimethylsilylethoxymethyl)quinolin-2-one [ka] The title compound was synthesized from 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-6-hydroxy-1-(2-trimethylsilylethoxymethyl)quinolin-2-one (compound a-23) under the same conditions as in the preparation example of compound a-14. However, bromocyclobutane was used instead of 2-iodopropane used in the preparation example of compound a-14. The reaction mixture was heated to 70 °C. LCMS: m / z 613[M+H] + HPLC retention time: 5.00 minutes (analysis condition K)

[0311] Compound A7 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclobutyloxy-7-fluoro-1H-quinolin-2-one [ka] Anisole (125 mg, 1.15 mmol) and TFA (0.8 mL) were added to a DCM solution (0.8 mL) of 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-6-cyclobutyloxy-7-fluoro-1-(2-trimethylsilylethoxymethyl)quinolin-2-one (Compound a-24, 70.8 mg, 0.115 mmol) in a reaction vessel, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure, MeOH was added, and the mixture was further concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (0.1% TFA aqueous solution / 0.1% TFA acetonitrile solution). Fractions containing the title compound were combined and neutralized with saturated sodium bicarbonate. The mixture was concentrated under reduced pressure, and the resulting solid was collected by filtration and washed with water to give the title compound (10.7 mg, 23% yield) as a yellow solid. LCMS: m / z 399[M+H] + HPLC retention time: 0.69 minutes (Analysis conditions A)

[0312] Compound A72 3-amino-4-(7-chloro-1H-indazol-4-yl)-7-fluoro-6-[(1-fluorocyclopropyl)methoxy]-1H-quinolin-2-one [ka] The title compound was synthesized from 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-6-hydroxy-1-(2-trimethylsilylethoxymethyl)quinolin-2-one (Compound a-23) under the same conditions as in the preparation example for Compound a-15 and Compound A7, except that (1-fluorocyclopropyl)methanol was used instead of 3,3-difluoropropan-1-ol used in the preparation example for Compound a-15. LCMS: m / z 417[M+H] + HPLC retention time: 0.65 min (Analysis conditions A)

[0313] compound a-16 6-Bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-2-[(4-methoxyphenyl)methoxy]quinolin-3-amine [ka] 3-Amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1H-quinolin-2-one (compound a-11, 1.496 g, 3.042 mmol) and silver carbonate (1.26 g, 4.57 mmol) were suspended in 1,2-dichloroethane (37 mL), followed by addition of p-methoxybenzyl chloride (705 μL, 5.18 mmol) and stirring at 95 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (765 mg, 41% yield).

[0314] compound a-17 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-2-[(4-methoxyphenyl)methoxy]quinolin-6-ol [ka] The title compound was synthesized from 6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-2-[(4-methoxyphenyl)methoxy]quinolin-3-amine (Compound a-16) under the same conditions as in the production example for Compound a-13. LCMS: m / z 549[M+H] + HPLC retention time: 4.39 minutes (Analysis conditions L)

[0315] Compound A3 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-(cyclopropylmethoxy)-7-fluoro-1H-quinolin-2-one [ka] The title compound was synthesized from 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-2-[(4-methoxyphenyl)methoxy]quinolin-6-ol (Compound a-17) under the same conditions as in the preparation example for Compound a-14 and A7, except that (iodomethyl)cyclopropane was used instead of 2-iodopropane used in the preparation example for Compound a-14. LCMS: m / z 399[M+H] + HPLC retention time: 0.67 min (Analysis conditions A)

[0316] compound a-102 (1s,3s)-3-Fluorocyclobutyl trifluoromethanesulfonate [ka] A DCM solution (2 mL) of (1s,3s)-3-fluorocyclobutan-1-ol (200 mg, 2.22 mmol) in a reaction vessel was cooled to 0 °C, and pyridine (197 μL, 2.44 mmol) and trifluoromethanesulfonic anhydride (413 μL, 2.44 mmol) were added and stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (DCM) to give the title compound (540 mg). 1 H-NMR (d6-DMSO) δ: 5.41-5.16 (1H, m), 5.28-5.16 (1H, m), 2.69-2.57 (4H, m)

[0317] compound a-103 (1s,3s)-3-Cyanocyclobutyl trifluoromethanesulfonate [ka] The title compound was synthesized using the corresponding alcohol under the same conditions as in the preparation example for compound a-102. 1 H-NMR (d6-DMSO) δ: 5.22-5.12 (1H, m), 3.61-3.39 (1H, m), 2.79-2.55 (4H, m).

[0318] Compound A4 3-amino-4-(7-chloro-1H-indazol-4-yl)-7-fluoro-6-((1r,3r)-3-fluorocyclobutyl)oxy-1H-quinolin-2-one [ka] The title compound was synthesized from 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-2-[(4-methoxyphenyl)methoxy]quinolin-6-ol (Compound a-17) under the same conditions as in the preparation example of Compound a-14 and A7, except that (1s,3s)-3-fluorocyclobutyl trifluoromethanesulfonate Compound (a-102) was used instead of 2-iodopropane used in the preparation example of Compound a-14. LCMS: m / z 417[M+H] + HPLC retention time: 0.65 min (Analysis conditions A)

[0319] Compound A5 (1r,3r)-3-[[3-amino-4-(7-chloro-1H-indazol-4-yl)-7-fluoro-2-oxo-1H-quinolin-6-yl]oxy]cyclobutane-1-carbonitrile [ka] The title compound was synthesized from 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-2-[(4-methoxyphenyl)methoxy]quinolin-6-ol (Compound a-17) under the same conditions as in the preparation example for Compound a-14 and A7, except that (1s,3s)-3-cyanocyclobutyl trifluoromethanesulfonate (Compound a-103) was used instead of 2-iodopropane used in the preparation example for Compound a-14. LCMS: m / z 424[M+H] + HPLC retention time: 0.60 min (Analysis conditions A)

[0320] Compound A6 3-amino-4-(7-chloro-1H-indazol-4-yl)-7-fluoro-6-(3-fluoropropoxy)-1H-quinolin-2-one [ka] The title compound was synthesized from 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-2-[(4-methoxyphenyl)methoxy]quinolin-6-ol (Compound a-17) under the same conditions as in the preparation example of Compound a-14 and A7, except that 1-fluoro-3-iodopropane was used instead of 2-iodopropane used in the preparation example of Compound a-14. LCMS: m / z 405[M+H] + HPLC retention time: 0.64 min (Analysis conditions A)

[0321] compound a-25 4-Bromo-5-chloro-2-iodoaniline [ka] The title compound was synthesized from 4-bromo-3-chloroaniline under the same conditions as in the production example for compound a-5. LCMS: m / z 332[M+H] + HPLC retention time: 4.42 minutes (Analysis conditions N)

[0322] compound a-26 (E)-N'-(4-bromo-5-chloro-2-iodophenyl)-N,N-dimethylmethanimidamide [ka] The title compound was synthesized from 4-bromo-5-chloro-2-iodoaniline (compound a-25) under the same conditions as in the production example for compound a-6. LCMS: m / z 387[M+H] + HPLC retention time: 2.60 minutes (Analysis conditions N)

[0323] compound a-27 (E)-N'-[4-bromo-5-chloro-2-[7-chloro-2-(oxan-2-yl)indazole-4-carbonyl]phenyl]-N,N-dimethylmethanimidamide [ka] The title compound was synthesized from (E)-N'-(4-bromo-5-chloro-2-iodophenyl)-N,N-dimethylmethanimidamide (Compound a-26) under the same conditions as in the production example for Compound a-7. LCMS: m / z 523[M+H] + HPLC retention time: 3.88 minutes (Analysis conditions J)

[0324] compound a-28 (2-Amino-5-bromo-4-chlorophenyl)-[7-chloro-2-(oxan-2-yl)indazol-4-yl]methanone [ka] The title compound was synthesized from (E)-N'-[4-bromo-5-chloro-2-[7-chloro-2-(oxan-2-yl)indazole-4-carbonyl]phenyl]-N,N-dimethylmethanimidamide (Compound a-27) under the same conditions as in the production example for Compound a-8. LCMS: m / z 468[M+H] + HPLC retention time: 5.66 minutes (Analysis conditions J)

[0325] compound a-31 3-amino-6-bromo-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-1H-quinolin-2-one [ka] The title compound was synthesized from (2-amino-5-bromo-4-chlorophenyl)-[7-chloro-2-(oxan-2-yl)indazol-4-yl]methanone (compound a-28) under the same conditions as in the production examples for compounds a-9, a-10, and a-11. LCMS: m / z 507[M+H] + HPLC retention time: 4.96 minutes (Analysis conditions J)

[0326] compound a-32 3-Amino-6-bromo-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-1-[(4-methoxyphenyl)methyl]quinolin-2-one [ka] The title compound was synthesized from 3-amino-6-bromo-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-1H-quinolin-2-one (compound a-31) under the same conditions as in the production example for compound a-12. LCMS: m / z 627[M+H] + HPLC retention time: 4.14 minutes (analysis condition O)

[0327] compound a-33 3-amino-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-6-hydroxy-1-[(4-methoxyphenyl)methyl]quinolin-2-one [ka] The title compound was synthesized from 3-amino-6-bromo-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-1-[(4-methoxyphenyl)methyl]quinolin-2-one (compound a-32) under the same conditions as in the production example for compound a-13. LCMS: m / z 565[M+H] + HPLC retention time: 3.09 minutes (analysis condition O)

[0328] compound a-34 3-amino-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-1-[(4-methoxyphenyl)methyl]-6-propan-2-yloxyquinolin-2-one [ka] The title compound was synthesized from 3-amino-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-6-hydroxy-1-[(4-methoxyphenyl)methyl]quinolin-2-one (compound a-33) under the same conditions as in the production example for compound a-14. LCMS: m / z 607[M+H] + HPLC retention time: 3.98 minutes (analysis condition O)

[0329] Compound A8 3-amino-7-chloro-4-(7-chloro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-quinolin-2-one [ka] The title compound was synthesized from 3-amino-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-1-[(4-methoxyphenyl)methyl]-6-propan-2-yloxyquinolin-2-one (compound a-34) under the same conditions as in the production example for compound A1. LCMS: m / z 403[M+H] + HPLC retention time: 0.72 minutes (Analysis conditions A)

[0330] compound a-35 3-amino-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-6-(3,3-difluoropropoxy)-1-[(4-methoxyphenyl)methyl]quinolin-2-one [ka] The title compound was synthesized from 3-amino-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-6-hydroxy-1-[(4-methoxyphenyl)methyl]quinolin-2-one (Compound a-33) under the same conditions as in the preparation example for Compound a-15, except that cyanomethylenetributylphosphorane and THF were used instead of the 0.5 M cyanomethylenetrimethylphosphorane THF solution used in the preparation example for Compound a-15. LCMS: m / z 643[M+H] + HPLC retention time: 3.68 minutes (analysis condition O)

[0331] Compound A9 3-amino-7-chloro-4-(7-chloro-1H-indazol-4-yl)-6-(3,3-difluoropropoxy)-1H-quinolin-2-one [ka] The title compound was synthesized from 3-amino-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-6-(3,3-difluoropropoxy)-1-[(4-methoxyphenyl)methyl]quinolin-2-one (Compound a-35) under the same conditions as in the production example for Compound A1. LCMS: m / z 439[M+H] + HPLC retention time: 0.69 minutes (Analysis conditions A)

[0332] compound a-36 6-Bromo-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-2-[(4-methoxyphenyl)methoxy]quinolin-3-amine [ka] The title compound was synthesized from 3-amino-6-bromo-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-1H-quinolin-2-one (compound a-31) under the same conditions as in the production example for compound a-16. LCMS: m / z 627[M+H] + HPLC retention time: 5.04 minutes (analysis condition O)

[0333] compound a-37 3-Amino-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-2-[(4-methoxyphenyl)methoxy]quinolin-6-ol [ka] The title compound was synthesized from 6-bromo-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-2-[(4-methoxyphenyl)methoxy]quinolin-3-amine (Compound a-36) under the same conditions as in the production example for Compound a-13. LCMS: m / z 565[M+H] + HPLC retention time: 2.98 minutes (analysis condition O)

[0334] Compound A10 3-amino-7-chloro-4-(7-chloro-1H-indazol-4-yl)-6-cyclobutyloxy-1H-quinolin-2-one [ka] The title compound was synthesized from 3-amino-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-2-[(4-methoxyphenyl)methoxy]quinolin-6-ol (Compound a-37) under the same conditions as in the preparation example for Compound a-15 and A7, except that cyanomethylenetributylphosphorane, THF, and cyclobutanol were used instead of 0.5 M cyanomethylenetrimethylphosphorane THF solution and 3,3-difluoropropan-1-ol used in the preparation example for Compound a-15. LCMS: m / z 415[M+H] + HPLC retention time: 0.74 min (Analysis conditions A)

[0335] Compound A11 3-amino-7-chloro-4-(7-chloro-1H-indazol-4-yl)-6-((1r,3r)-3-fluorocyclobutyl)oxy-1H-quinolin-2-one [ka] The title compound was synthesized from 3-amino-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-2-[(4-methoxyphenyl)methoxy]quinolin-6-ol (Compound a-37) under the same conditions as in the preparation example for Compound a-14 and A7, except that (1s,3s)-3-fluorocyclobutyl trifluoromethanesulfonate Compound (a-102) was used instead of 2-iodopropane used in the preparation example for Compound a-14. LCMS: m / z 433[M+H] + HPLC retention time: 0.70 minutes (Analysis conditions A)

[0336] Compound A12 (1r,3r)-3-[[3-amino-7-chloro-4-(7-chloro-1H-indazol-4-yl)-2-oxo-1H-quinolin-6-yl]oxy]cyclobutane-1-carbonitrile [ka] The title compound was synthesized from 3-amino-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-2-[(4-methoxyphenyl)methoxy]quinolin-6-ol (Compound a-37) under the same conditions as in the preparation example for Compound a-14 and A7, except that (1s,3s)-3-cyanocyclobutyl trifluoromethanesulfonate (Compound a-103) was used instead of 2-iodopropane used in the preparation example for Compound a-14. LCMS: m / z 440[M+H] + HPLC retention time: 0.64 min (Analysis conditions A)

[0337] Compound A13 3-amino-7-chloro-4-(7-chloro-1H-indazol-4-yl)-6-(cyclopropylmethoxy)-1H-quinolin-2-one [ka] The title compound was synthesized from 3-amino-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-2-[(4-methoxyphenyl)methoxy]quinolin-6-ol (Compound a-37) under the same conditions as in the preparation example for Compound a-14 and A7, except that (iodomethyl)cyclopropane was used instead of 2-iodopropane used in the preparation example for Compound a-14. LCMS: m / z 415[M+H] + HPLC retention time: 0.72 minutes (Analysis conditions A)

[0338] Compound A14 3-amino-7-chloro-4-(7-chloro-1H-indazol-4-yl)-6-(3-fluoropropoxy)-1H-quinolin-2-one [ka] The title compound was synthesized from 3-amino-7-chloro-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-2-[(4-methoxyphenyl)methoxy]quinolin-6-ol (Compound a-37) under the same conditions as in the preparation example for Compound a-14 and A7, except that 1-fluoro-3-iodopropane was used instead of 2-iodopropane used in the preparation example for Compound a-14. LCMS: m / z 421[M+H] + HPLC retention time: 0.68 min (Analysis conditions A)

[0339] compound a-43 5-Bromo-3-iodo-6-methylpyridin-2-amine [ka] The title compound was synthesized from 6-amino-3-bromo-2-methylpyridine under the same conditions as in the production example for compound a-5. LCMS: m / z 313[M+H] + HPLC retention time: 2.55 minutes (Analysis conditions N)

[0340] compound a-44 (E)-N'-(5-bromo-3-iodo-6-methylpyridin-2-yl)-N,N-dimethylmethanimidamide [ka] The title compound was synthesized from 5-bromo-3-iodo-6-methylpyridin-2-amine (Compound a-43) under the same conditions as in the production example for Compound a-6. LCMS: m / z 368[M+H] + HPLC retention time: 2.37 minutes (Analysis conditions N)

[0341] compound a-45 (E)-N'-[5-bromo-3-[7-chloro-2-(oxan-2-yl)indazole-4-carbonyl]-6-methylpyridin-2-yl]-N,N-dimethylmethanimidamide [ka] The title compound was synthesized from (E)-N'-(5-bromo-3-iodo-6-methylpyridin-2-yl)-N,N-dimethylmethanimidamide (Compound a-44) under the same conditions as in the production example for Compound a-7. LCMS: m / z 504[M+H] + HPLC retention time: 3.69 minutes (Analysis conditions J)

[0342] compound a-46 (2-Amino-5-bromo-6-methylpyridin-3-yl)-[7-chloro-2-(oxan-2-yl)indazol-4-yl]methanone [ka] The title compound was synthesized from (E)-N'-[5-bromo-3-[7-chloro-2-(oxan-2-yl)indazole-4-carbonyl]-6-methylpyridin-2-yl]-N,N-dimethylmethanimidamide (Compound a-45) under the same conditions as in the production example for Compound a-8. LCMS: m / z 449[M+H] + HPLC retention time: 4.53 minutes (Analysis conditions J)

[0343] compound a-49 3-amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-methyl-1H-1,8-naphthyridin-2-one [ka] The title compound was synthesized from (2-amino-5-bromo-6-methylpyridin-3-yl)-[7-chloro-2-(oxan-2-yl)indazol-4-yl]methanone (compound a-46) under the same conditions as in the preparation examples of compounds a-9, a-10, and a-11. LCMS: m / z 488[M+H] + HPLC retention time: 4.61 minutes (Analysis conditions J)

[0344] compound a-50 3-Amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-methyl-1-(2-trimethylsilylethoxymethyl)-1,8-naphthyridin-2-one [ka] The title compound was synthesized from 3-amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-methyl-1H-1,8-naphthyridin-2-one (Compound a-49) under the same conditions as in the preparation example for Compound a-22. However, potassium carbonate and DMA were used instead of 60% sodium hydride / mineral oil and THF used in the preparation example for Compound a-22. The reaction mixture was heated to 70 °C. LCMS: m / z 618[M+H] + HPLC retention time: 6.51 minutes (Analysis conditions J)

[0345] compound a-51 3-Amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-6-hydroxy-7-methyl-1-(2-trimethylsilylethoxymethyl)-1,8-naphthyridin-2-one [ka] The title compound was synthesized from 3-amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-methyl-1-(2-trimethylsilylethoxymethyl)-1,8-naphthyridin-2-one (compound a-50) under the same conditions as in the production example for compound a-13. LCMS: m / z 556[M+H] + HPLC retention time: 5.44 minutes (Analysis conditions J)

[0346] Compound A15 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-((1r,3r)-3-fluorocyclobutyl)oxy-7-methyl-1H-1,8-naphthyridin-2-one [ka] The title compound was synthesized from 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-6-hydroxy-7-methyl-1-(2-trimethylsilylethoxymethyl)-1,8-naphthyridin-2-one (Compound a-51) under the same conditions as in the preparation example of Compound a-14 and A7, except that (1s,3s)-3-fluorocyclobutyl trifluoromethanesulfonate (Compound a-102) was used instead of 2-iodopropane used in the preparation example of Compound a-14. LCMS: m / z 414[M+H] + HPLC retention time: 0.65 min (Analysis conditions A)

[0347] Compound A16 (1r,3r)-3-[[6-amino-5-(7-chloro-1H-indazol-4-yl)-2-methyl-7-oxo-8H-1,8-naphthyridin-3-yl]oxy]cyclobutane-1-carbonitrile [ka] The title compound was synthesized from 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-6-hydroxy-7-methyl-1-(2-trimethylsilylethoxymethyl)-1,8-naphthyridin-2-one (Compound a-51) under the same conditions as in the preparation example of Compound a-14 and A7, except that (1s,3s)-3-cyanocyclobutyl trifluoromethanesulfonate (Compound a-103) was used instead of 2-iodopropane used in the preparation example of Compound a-14. LCMS: m / z 421[M+H] + HPLC retention time: 0.59 minutes (Analysis condition...

Claims

1. Formula (1): 【Chemistry 1】 [In the formula, R ４ is an optionally substituted C ６ -C １０ Aryl (R ４Ａ ), optionally substituted 4- to 10-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl (R ４ＨＡ ) selected from the group consisting of; R ５ and R ６ together with the atoms to which they are attached form an optionally substituted D ring; Ring D is a 3- to 10-membered monocyclic alicyclic ring, a benzene ring, a 3- to 12-membered monocyclic heterocyclic ring, and a 5- to 6-membered monocyclic aromatic heterocyclic ring (D ＨＡ ) selected from the group consisting of; Any two adjacent substituents on ring D may be taken together with the atoms to which they are attached to form an optionally substituted ring E. A compound represented by the formula (I), a salt thereof, or a solvate thereof.

2. Ring D is a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle (D ＨＡ 2. The compound according to claim 1, or a salt thereof, or a solvate thereof, wherein

3. The D ring is unsubstituted or contains one or more R Ｄ is replaced by One or more R Ｄ are each independently a halogen, a cyano, a hydroxy, １ -C ６ Alkylthio, C １ -C ６ Acylamino, Mono C １ -C ６ Alkylamino, C １ -C ６ Alkylsulfonylamino, C ３ -C ８ Cycloalkylsulfonylamino, C １ -C ６ Alkoxy, HaloC １ -C ６ Alkoxy, hydroxy C １ -C ６ Alkoxy, C １ -C ６ Alkoxy C １ -C ６ Alkoxy, C ３ -C ８ Cycloalkyl C １ -C ６ Alkoxy, 4- to 10-membered heterocyclyl C １ -C ６ Alkoxy, C ３ -C ８ cycloalkoxy, 4- to 10-membered heterocyclyloxy, C １ -C ６ Acyl, Mono C ３ -C ８ Cycloalkylaminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, diC １ -C ６ Alkylphosphoryl, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, hydroxy C １ -C ６ Alkyl, diC １ -C ６ Alkylaminocarbonyl C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, Hydroxy C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, hydroxy C ２ -C ６ Alkynyl, C ３ -C ８ cycloalkyl, 4- to 10-membered heterocyclyl, C ６ -C １０ aryl, and 5- to 10-membered heteroaryl; The C １ -C ６ Alkylthio, C １ -C ６ Alkoxy, C １ -C ６ Alkoxy C １ -C ６ Alkoxy, C ３ -C ８ Cycloalkyl C １ -C ６ Alkoxy, 4- to 10-membered heterocyclyl C １ -C ６ Alkoxy, C ３ -C ８ cycloalkoxy, 4- to 10-membered heterocyclyloxy, C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl C １ -C ６ Alkyl C ３ -C ８ cycloalkyl, 4- to 10-membered heterocyclyl, C ６ -C １０ The aryl and 5- to 10-membered heteroaryl may further independently be selected from halogen, cyano, hydroxy, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, oxo, haloC １ -C ６ Alkyl, and C ３ -C ８ optionally substituted with one or more substituents selected from the group consisting of cycloalkyl; 3. The compound according to claim 1 or 2, or a salt thereof, or a solvate thereof.

4. The D ring is unsubstituted or contains one or more R Ｄ is replaced by One or more R Ｄ are each independently a halogen, C １ -C ６ Alkoxy, HaloC １ -C ６ Alkoxy, C ３ -C ８ Cycloalkyl C １ -C ６ Alkoxy, C ３ -C ８ Cycloalkoxy, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl C １ -C ６ Alkyl, and C ３ -C ８ selected from the group consisting of cycloalkyl, The compound according to any one of claims 1 to 3, or a salt thereof, or a solvate thereof.

5. The compound according to any one of claims 1 to 4, or a salt thereof, or a solvate thereof, wherein any two adjacent substituents on ring D, together with the atoms to which they are attached, form ring E which may be substituted.

6. The D and E rings are of the following formula: 【Chemistry 2】 (where * represents R in formula (1) ５ is the carbon to which R is bonded, and ** is the carbon to which R is bonded in formula (1). ６ and represent carbon atoms to which they are bonded. In the formula, the D ring is represented as "D ring" and the E ring is represented as "E ring". The compound according to any one of claims 1 to 5, or a salt thereof, or a solvate thereof, wherein the compound forms a bicyclic ring represented by the formula:

7. Formula (2): 【Transformation 3】 [In the formula, R ４ is an optionally substituted C ６ -C １０ Aryl (R ４Ａ ), optionally substituted 4- to 10-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl (R ４ＨＡ ) selected from the group consisting of; X ５ is CR ｘ５ or N, X ６ is CR ｘ６ or N, X １０ａ is CR ｘ１０ａ or N, R ｘ５、 R ｘ６ , R ６ａ and R ｘ１０ａ are each independently hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ８ cycloalkyl, 4- to 10-membered heterocyclyl, C ６ -C １０ aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ８ cycloalkyl, 4- to 10-membered heterocyclyl, C ６ -C １０ Aryl and 5- to 10-membered heteroaryl may be further substituted or R ｘ５ and R ｘ６ , R ｘ６ and R ６ａ , or R ６ａ and R ｘ１０ａ may be taken together with the atom to which they are attached to form an optionally substituted E ring. The compound according to claim 1, or a salt thereof, or a solvate thereof, represented by:

8. X ５ is CH, X ６ is CR ｘ６ and X １０ａ is CR ｘ１０ａ The compound according to claim 7, or a salt thereof, or a solvate thereof,

9. R ６ａ But hydrogen, halogen, cyano, halo C １ -C ６ Alkoxy, and C １ -C ６ The compound according to claim 7 or 8, or a salt thereof, or a solvate thereof, wherein the compound is selected from the group consisting of alkyl.

10. R ｘ１０ａ But hydrogen, halogen, cyano, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, and C ３ -C ８ The compound according to any one of claims 7 to 9, or a salt thereof, or a solvate thereof, wherein the compound is selected from the group consisting of cycloalkyl.

11. The E ring has the following formula: 【Chemistry 4】 (where * represents R in formula (2) ６ａ is the carbon atom to which R is bonded, and ** is the carbon atom to which R is bonded in formula (2). ｘ１０ａ and each represent a carbon atom to which the ring is bonded. In the formula, the E ring is represented as "E ring". The compound according to any one of claims 7 to 10, or a salt thereof, or a solvate thereof,

12. The E ring is unsubstituted or contains one or more R Ｅ is replaced by One or more R Ｅ are each independently a halogen, C １ -C ６ Alkoxy, boryl, and C １ -C ６ The compound according to any one of claims 1 to 11, or a salt thereof, or a solvate thereof, wherein the compound is selected from the group consisting of alkyl.

13. Formula (3): 【Transformation 5】 [In the formula, R ４ is an optionally substituted C ６ -C １０ Aryl (R ４Ａ ), optionally substituted 4- to 10-membered heterocyclyl, and optionally substituted 5- to 10-membered heteroaryl (R ４ＨＡ ) selected from the group consisting of; X ５ is CR ｘ５ or N, X ６ is CR ｘ６ or N, X ７ is CR ｘ７ or N, X ８ is CR ｘ８ or N, X ９ is CR ｘ９ or N, X １０ is CR ｘ１０ or N, R ｘ５、 R ｘ６ , R ｘ７ , R ｘ８ , R ｘ９ and R ｘ１０ are each independently hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ８ cycloalkyl, 4- to 10-membered heterocyclyl, C ６ -C １０ aryl, and 5- to 10-membered heteroaryl; The hydroxy, thio, amino, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, carbonyl, carboxy, sulfonyl, phosphoryl, boryl, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ８ cycloalkyl, 4- to 10-membered heterocyclyl, C ６ -C １０ The aryl and 5- to 10-membered heteroaryl may be further substituted. The compound according to claim 1 or 7, or a salt thereof, or a solvate thereof, represented by:

14. X ５ is CH, X ６ is CR ｘ６ and X ７ is CR ｘ７ or N, X ８ is CR ｘ８ or N, X ９ is CR ｘ９ or N, X １０ is CR ｘ１０ or N, or a salt thereof, or a solvate thereof according to claim 13.

15. X ７ is N and X ８ is CR ｘ８ and X ９ is CR ｘ９ and X １０ is CR ｘ１０ Or X ７ is CR ｘ７ and X ８ is N and X ９ is CR ｘ９ and X １０ is CR ｘ１０ Or X ７ is CR ｘ７ and X ８ is CR ｘ８ and X ９ is N and X １０ is CR ｘ１０ Or X ７ is CR ｘ７ and X ８ is CR ｘ８ and X ９ is CR ｘ９ and X １０ is N or X ７ is N and X ８ is CR ｘ８ and X ９ is CR ｘ９ and X １０ is N or X ７ is CR ｘ７ and X ８ is N and X ９ is CR ｘ９ and X １０ is N or X ７ is N and X ８ is N and X ９ is CR ｘ９ and X １０ is CR ｘ１０ That is, 15. The compound according to claim 13 or 14, or a salt thereof, or a solvate thereof.

16. R ｘ６ is hydrogen, halogen, hydroxy, C １ -C ６ Alkylthio, C １ -C ６ Acylamino, Mono C １ -C ６ Alkylamino, C １ -C ６ Alkylsulfonylamino, C ３ -C ８ Cycloalkylsulfonylamino, C １ -C ６ Alkoxy, HaloC １ -C ６ Alkoxy, hydroxy C １ -C ６ Alkoxy, C １ -C ６ Alkoxy C １ -C ６ Alkoxy, C ３ -C ８ Cycloalkyl C １ -C ６ Alkoxy, 4- to 10-membered heterocyclyl C １ -C ６ Alkoxy, C ３ -C ８ cycloalkoxy, 4- to 10-membered heterocyclyloxy, C １ -C ６ Acyl, Mono C ３ -C ８ Cycloalkylaminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, diC １ -C ６ Alkylphosphoryl, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, hydroxy C １ -C ６ Alkyl, diC １ -C ６ Alkylaminocarbonyl C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, Hydroxy C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, hydroxy C ２ -C ６ Alkynyl, C ３ -C ８ cycloalkyl, 4- to 10-membered heterocyclyl, C ６ -C １０ aryl, and 5- to 10-membered heteroaryl; The C １ -C ６ Alkylthio, C １ -C ６ Alkoxy, C １ -C ６ Alkoxy C １ -C ６ Alkoxy, C ３ -C ８ Cycloalkyl C １ -C ６ Alkoxy, 4- to 10-membered heterocyclyl C １ -C ６ Alkoxy, C ３ -C ８ cycloalkoxy, 4- to 10-membered heterocyclyloxy, C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl C １ -C ６ Alkyl, C ３ -C ８ cycloalkyl, 4- to 10-membered heterocyclyl, C ６ -C １０ The aryl and 5- to 10-membered heteroaryl may further independently be selected from halogen, cyano, hydroxy, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, oxo, haloC １ -C ６ Alkyl, and C ３ -C ８ The compound according to any one of claims 7 to 15, or a salt thereof, or a solvate thereof, optionally substituted with one or more substituents selected from the group consisting of cycloalkyl.

17. R ｘ６ is selected from the group consisting of hydrogen, methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-butan-2-yl]oxy, [(2R)-butan-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, butan-2-yl, 3-methylbutyl, pentan-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl, and spiro[2.3]hexan-5-yl, or a salt thereof, or a solvate thereof according to any one of claims 7 to 16.

18. R ｘ７ is hydrogen, halogen, C １ -C ６ Alkoxy or C １ -C ６ The compound according to any one of claims 13 to 17, or a salt thereof, or a solvate thereof, wherein R is alkyl.

19. R ｘ８ is hydrogen, halogen, C １ -C ６ Alkoxy or C １ -C ６ The compound according to any one of claims 13 to 18, or a salt thereof, or a solvate thereof, wherein R is alkyl.

20. R ｘ９ is hydrogen, halogen, C １ -C ６ Alkoxy, C １ -C ６ The compound according to any one of claims 13 to 19, or a salt thereof, or a solvate thereof, which is selected from the group consisting of alkyl and boryl.

21. R ｘ１０ is hydrogen, halogen, C １ -C ６ Alkoxy or C １ -C ６ The compound according to any one of claims 13 to 20, or a salt thereof, or a solvate thereof, wherein R is alkyl.

22. R ４ is an optionally substituted 5- to 10-membered heteroaryl (R ４ＨＡ 22. The compound according to claim 1, or a salt thereof, or a solvate thereof, wherein

23. 5- to 10-membered heteroaryl (R ４ＨＡ 23. The compound according to claim 22, or a salt thereof, or a solvate thereof, wherein R is selected from the group consisting of pyrimidyl, benzimidazolyl, indolyl, indazolyl, and pyrazolopyridyl.

24. 5- to 10-membered heteroaryl (R ４ＨＡ ) is unsubstituted or contains one or more R ａ is replaced by One or more R ａ are each independently a halogen, a cyano, a hydroxy, an amino, １ -C ６ Alkyl, haloC １ -C ６ Alkyl, hydroxy C １ -C ６ Alkyl, C １ -C ６ Alkoxy, HaloC １ -C ６ 24. The compound according to claim 22 or 23, or a salt thereof, or a solvate thereof, which is selected from the group consisting of alkoxy and alkylsulfonylamino.

25. 5- to 10-membered heteroaryl (R ４ＨＡ 25. The compound according to any one of claims 22 to 24, or a salt thereof, or a solvate thereof, wherein R is 1H-indazol-4-yl or 1H-indazol-4-yl substituted with one or more halogens.

26. A compound selected from the following compounds, a salt thereof, or a solvate thereof: 3-amino-7-chloro-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-benzo[h]quinolin-2-one, 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-benzo[h]quinolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-benzo[h]quinolin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclopropyl-1H-benzo[h]quinolin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methyl-1H-benzo[h]quinolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propan-2-yl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclopropyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclobutyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-ethyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(5-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-6-cyclopropyl-4-(5-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one, (S)-3-amino-6-cyclopropyl-4-(5-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-ethyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-ethoxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-cyclopropyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propoxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-ethoxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one, 3-amino-6-ethoxy-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one, 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one, 3-amino-6-cyclobutyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,10-phenanthrolin-2-one, 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,10-phenanthrolin-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,10-phenanthrolin-2-one, 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,10-phenanthrolin-2-one, 3-amino-9-fluoro-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthrolin-2-one, 3-amino-9-fluoro-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-9-fluoro-6-methoxy-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-9-fluoro-6-methyl-1H-1,7-phenanthrolin-2-one, 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-methoxy-10H-pyrido[2,3-f]quinoxalin-9-one, 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-propan-2-yloxy-10H-pyrido[2,3-f]quinoxalin-9-one, 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-methyl-10H-pyrido[2,3-f]quinoxalin-9-one, 8-amino-5-cyclopropyl-7-(7-fluoro-1H-indazol-4-yl)-10H-pyrido[2,3-f]quinoxalin-9-one, 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-methyl-10H-pyrido[3,2-h]quinazolin-9-one, 8-amino-5-cyclopropyl-7-(7-fluoro-1H-indazol-4-yl)-10H-pyrido[3,2-h]quinazolin-9-one, 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,8-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5,6-dimethyl-1H-1,7-phenanthrolin-2-one, 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-5-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-1H-1,7-phenanthrolin-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-1H-1,7-phenanthrolin-2-one, 3-amino-4-(5,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, 3-amino-6-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yl)-1H-1,7-phenanthrolin-2-one, 3-amino-4-(1H-benzotriazol-4-yl)-6-methyl-1H-1,7-phenanthrolin-2-one, and 3-amino-6-(tert-butyl)-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one.

27. A pharmaceutical composition comprising the compound according to any one of claims 1 to 26, or a salt thereof, or a solvate thereof as an active ingredient.

28. The present invention relates to a method for treating or preventing cancer in a patient with a cancer in which a positive RB1 gene mutation or a decreased expression of the RB1 gene or protein has been detected, the method comprising: A pharmaceutical composition, wherein the MYT1 inhibitor is the compound according to any one of claims 1 to 26, or a salt thereof, or a solvate thereof.

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