Nitrogen-containing heterocyclic compound having MYT1 inhibitory activity

Abstract

The present invention provides a novel compound having inhibitory activity on MYT1, a salt thereof, or a solvate of the compound or the salt. The present invention provides a compound represented by the formula, a salt thereof, or a solvate of the compound or the salt [In the formula, R4 is selected from the group consisting of an optionally substituted C6 to C10 aryl group (R4A), an optionally substituted quaternary to ten-membered heterocyclyl group, and an optionally substituted five to ten-membered heteroaryl group (R4HA); r5 and R6 together with the atoms to which they are bonded form an optionally substituted ring D; ring D is selected from the group consisting of a three to ten membered monocyclic alicyclic ring, a benzene ring, a three to twelve membered monocyclic heterocyclic ring, and a five to six membered monocyclic aromatic heterocyclic ring (DHA); and any two adjacent substituents on ring D, together with the atom to which they are bonded, may form an optionally substituted ring E. ]

Description

Technical Field

[0001] The present invention relates to a nitrogen-containing heterocyclic compound having MYT1 inhibitory activity, or a salt or solvate thereof, and also to a drug for treating and preventing cancer, which contains any one of the compounds as an active ingredient. Background Art

[0002] Cell is exposed to exogenous or endogenous stress factors every day, and its DNA is damaged. Usually, cells with damaged DNA repair DNA damage by activating DDR (DNA damage response) pathway. Known many types of cancer have abnormalities in genes and proteins involved in DDR pathways, and have studied therapeutic methods (non-patent literature 1 to 2). One of the therapeutic methods for cancers with abnormal genes and proteins involved in DDR pathways is to use PARP inhibitors, which are used to treat cancers with BRCA1 mutations or BRCA2 mutations (non-patent literature 3). In addition, genes and proteins ATM, ATR, CHK1, DNA-PK, WEE1 involved in DDR pathways have been referred to as target candidates so far, and have been widely studied (non-patent literature 4).

[0003] MYT1 is a kind of enzyme of WEE1 family, and is referred to as the negative regulator of CDK1.MYT1 inactivates CDK1 by phosphorylation, and plays an important role in cell cycle regulation.In recent years, a kind of novel MYT1 inhibitor is reported to cause synthetic lethality (non-patent literature 5) in specific cancers.However, there is no approved medicine, and therefore expect a kind of novel therapeutic agent.

[0004] [Citation List]

[0005] [Non-patent literature]

[0006] [Non-patent document 1] Cancers (Basel), April 23, 2020;12(4):1050.

[0007] [Non-patent document 2] Front Pharmacol., February 8, 2021;11:629266.

[0008] [Non-patent document 3] N. Engl. J. Med., December 27, 2018; 379(26): 2495-2505.

[0009] [Non-patent document 4] Nat. Rev. Cancer, 2023 23, 78-94.

[0010] [Non-patent document 5] Nature, April 2022; 604(7907): 749-756.

[0011] [Non-Patent Document 6] TW Greene, PGM Wuts, Protective Groups in Organic Synthesis (5th edition, John Wiley & Sons 2014)

[0012] [Non-Patent Document 7] Tetrahedron Lett., 2019, Vol. 60, 151147

[0013] [Non-patent document 8] Chem. Rev., 1995, Vol. 95, No. 7, pp. 2457-2483.

[0014] [Non-patent document 9] Acc. Chem. Res., 2008, Vol. 41, No. 11, pp. 1461-1473.

[0015] [Non-patent document 10] Synthesis, 1992, Vol. 9, pp. 803-815.

[0016] [Non-patent document 11] Org. Process Res. December 2018, Vol. 22, No. 4, pp. 430-445.

[0017] [Non-patent document 12] Tetrahedron, 1992, Vol. 48, No. 44, pp. 9577-9648.

[0018] [Non-patent document 13] Aldrichimica Acta, 2005, Vol. 38, No. 4, pp. 71-88.

[0019] [Non-patent document 14] Chem. Soc. Rev., 2011, Vol. 40, pp. 5084-5121.

[0020] [Non-patent document 15] Chem. Rev., 2016, Vol. 116, pp. 12564-12649.

[0021] [Non-patent document 16]Org.Process Res.December 2022,Vol.26,No.6,Pages1690-1750.

[0022] [Non-patent document 17] J. Am. Chem. Soc., 2016, Vol. 138, No. 26, pp. 8084-8087.

[0023] [Non-patent document 18] ACS Med. Chem. Lett., 2020, Vol. 11, No. 4, pp. 597-604.

[0024] [Non-patent document 19] Nature, 2021, 598, pp. 451-456.

[0025] [Non-patent document 20] ACS Cent. Sci. 2017, Vol. 3, No. 6, pp. 647-653.

[0026] [Non-patent document 21] Tetrahedron 2008, Issue 64, Pages 5139-5146.

[0027] [Non-patent document 22] Nature. 2019 May; 569(7757): 503-508.

[0028] [Non-patent document 23] PLoS Comput Biol. 2019 May 20;15(5):e1006752. Summary of the Invention

[0029] [Problems to be Solved by the Invention]

[0030] The present invention aims to provide a novel compound having MYT1 inhibitory activity or a salt or solvate thereof. Another object is to provide a drug useful for treating and preventing cancer, which contains any one of them as an active ingredient.

[0031] [Methods of solving the problem]

[0032] That is, in one aspect of the present invention, the following invention is provided.

[0033] [A1]

[0034] A compound represented by formula (1):

[0035] [Formula 1]

[0036]

[0037] in

[0038] R4 is selected from the group consisting of: 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 );

[0039] R5 and R6, together with the atoms to which they are attached, form an optionally substituted ring D;

[0040] Ring D is selected from the group consisting of 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

[0041] Any two adjacent substituents on Ring D, taken together with the atoms to which they are attached, can form an optionally substituted Ring E;

[0042] or a salt thereof, or a solvate thereof.

[0043] [A2]

[0044] The compound according to [A1], or a salt thereof, or a solvate thereof, wherein ring D is a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle (D HA ).

[0045] [A3]

[0046] The compound according to [A1], or a salt thereof, or a solvate thereof, wherein ring D is a benzene ring.

[0047] [A4]

[0048] The compound according to [A1], wherein ring D is a 5- to 6-membered monocyclic aromatic heterocycle (D HA ), or a salt or a solvate thereof.

[0049] [A5]

[0050] The compound according to [A4], or a salt thereof, or a solvate thereof, wherein the 5- to 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.

[0051] [A6]

[0052] The compound according to [A4], or a salt thereof, or a solvate thereof, wherein the 5- to 6-membered monocyclic aromatic heterocycle (D HA ) is selected from the group consisting of a pyridine ring, a pyrimidine ring, a pyridazine ring and a pyrazine ring.

[0053] [A7]

[0054] The compound according to [A4], or a salt thereof, or a solvate thereof, wherein the 5- to 6-membered monocyclic aromatic heterocycle (D HA ) is a pyridine ring.

[0055] [A8]

[0056] The compound according to any one of [A1] to [A7], or a salt thereof, or a solvate thereof, wherein

[0057] Ring D is unsubstituted or substituted with one or more R D replace;

[0058] One or more R D Each of the following is independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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; and

[0059] The hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

[0060] [A9]

[0061] The compound according to any one of [A1] to [A7], or a salt thereof, or a solvate thereof, wherein

[0062] Ring D is unsubstituted or substituted with one or more R D replace;

[0063] One or more R D Each of the following is independently selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkylthio, C1-C6 acylamino, mono C1-C6 alkylamino, C1-C6 alkylsulfonylamino, C3-C8 cycloalkylsulfonylamino, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C3-C8 cycloalkyl C1-C6 alkoxy, 4-membered to 10-membered heterocyclyl C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4- to 10-membered heterocyclic radicals, C1-C6 acyl radicals, mono-C3-C8 cycloalkylaminocarbonyl radicals, 4- to 8-membered cycloaminocarbonyl radicals, di-C1-C6 alkylphosphoryl radicals, C1-C6 alkyl radicals, halogenated C1-C6 alkyl radicals, hydroxy C1-C6 alkyl radicals, di-C1-C6 alkylaminocarbonyl C1-C6 alkyl radicals, C3-C8 cycloalkyl C1-C6 alkyl radicals, C2-C6 alkenyl radicals, hydroxy C2-C6 alkenyl radicals, C2-C6 alkynyl radicals, hydroxy C2-C6 alkynyl radicals, C3-C8 cycloalkyl radicals, 4- to 10-membered heterocyclic radicals, C6-C 10aryl and 5- to 10-membered heteroaryl; and

[0064] The C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C3-C8 cycloalkyl C1-C6 alkoxy, 4-membered to 10-membered heterocyclic C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4-membered to 10-membered heterocyclic, C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkyl, 4-membered to 10-membered heterocyclic, C6-C 10 The aryl and 5- to 10-membered heteroaryl groups are independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, oxo, halo-C1-C6 alkyl, and C3-C8 cycloalkyl.

[0065] [A10]

[0066] The compound according to any one of [A1] to [A7], or a salt thereof, or a solvate thereof, wherein

[0067] Ring D is unsubstituted or substituted with one or more R D replace; and

[0068] One or more R D Each of the following is independently selected from the group consisting of halogen, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, C3-C8 cycloalkyloxy, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl and C3-C8 cycloalkyl.

[0069] [A11]

[0070] The compound according to any one of [A1] to [A7], or a salt thereof, or a solvate thereof, wherein

[0071] Ring D is unsubstituted or substituted with one or more R D replace; and

[0072] One or more R D Each of the groups is independently selected from the group consisting of C1-C6 alkoxy, C1-C6 alkyl, and C3-C8 cycloalkyl.

[0073] [A12]

[0074] The compound according to any one of [A1] to [A7], or a salt thereof, or a solvate thereof, wherein

[0075] Ring D is unsubstituted or substituted with one or more R D replace; and

[0076] One or more R D Each of which is independently selected from the group consisting of methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-but-2-yl]oxy, [(2R)-but-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, but-2-yl, 3-methylbutyl, pent-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl, and spiro[2.3]hex-5-yl.

[0077] [A13]

[0078] The compound according to any one of [A1] to [A12], or a salt thereof, or a solvate thereof, wherein any two adjacent substituents on ring D form an optionally substituted ring E together with the atoms to which they are attached.

[0079] [A14]

[0080] The compound according to any one of [A1] to [A13], or a salt thereof, or a solvate thereof, wherein ring E is selected from the group consisting of a 3-membered to 10-membered monocyclic alicyclic ring, a benzene ring, a 3-membered to 12-membered monocyclic heterocyclic ring, and a 5-membered to 6-membered monocyclic aromatic heterocyclic ring (E HA ).

[0081] [A15]

[0082] The compound according to any one of [A1] to [A13], or a salt thereof, or a solvate thereof, wherein ring E is a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle (E HA ).

[0083] [A16]

[0084] The compound according to any one of [A1] to [A13], or a salt thereof, or a solvate thereof, wherein ring E is a benzene ring.

[0085] [A17]

[0086] The compound according to any one of [A1] to [A13], or a salt thereof, or a solvate thereof, wherein ring E is a 5- to 6-membered monocyclic aromatic heterocycle (E HA ).

[0087] [A18]

[0088] The compound according to [A17], or a salt thereof, or a solvate thereof, wherein the 5- to 6-membered monocyclic aromatic heterocycle (E 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.

[0089] [A19]

[0090] The compound according to [A17], or a salt thereof, or a solvate thereof, wherein the 5- to 6-membered monocyclic aromatic heterocycle (E HA ) 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.

[0091] [A20]

[0092] The compound according to [A17], or a salt thereof, or a solvate thereof, wherein the 5- to 6-membered monocyclic aromatic heterocycle (E HA ) is selected from the group consisting of a pyridine ring, a pyrimidine ring, a pyridazine ring and a pyrazine ring.

[0093] [A20.5]

[0094] The compound according to [A17], or a salt thereof, or a solvate thereof, wherein the 5- to 6-membered monocyclic aromatic heterocycle (E HA ) is a pyridine ring or a pyrazine ring.

[0095] [A21]

[0096] The compound according to [A17], or a salt thereof, or a solvate thereof, wherein the 5- to 6-membered monocyclic aromatic heterocycle (E HA ) is a pyridine ring.

[0097] [A22]

[0098] The compound according to [A17], or a salt thereof, or a solvate thereof, wherein

[0099] Ring D and ring E form a bicyclic ring represented by the following formula:

[0100] [Formula 2]

[0101]

[0102] wherein * represents the carbon to which R5 is attached in the formula (1), and ** represents the carbon to which R6 is attached in the formula (1); in the formula, the ring D is referred to as the "D ring" and the ring E is referred to as the "E ring".

[0103] [A23]

[0104] The compound according to [A17], or a salt thereof, or a solvate thereof, wherein

[0105] Ring D and ring E form a bicyclic ring represented by the following formula:

[0106] [Formula 3]

[0107]

[0108] wherein * represents the carbon to which R5 is attached in the formula (1), and ** represents the carbon to which R6 is attached in the formula (1); in the formula, the ring D is referred to as the "D ring" and the ring E is referred to as the "E ring".

[0109] [A24]

[0110] The compound or salt or solvate thereof according to any one of [A14] to [A23], wherein

[0111] Ring E is unsubstituted or substituted with one or more R E replace;

[0112] One or more R E Each of the following is independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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; and

[0113] The hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

[0114] [A25]

[0115] The compound or salt or solvate thereof according to any one of [A14] to [A23], wherein

[0116] Ring E is unsubstituted or substituted with one or more R E replace; and

[0117] One or more R E Each of the is independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, and boron.

[0118] [A25.5]

[0119] The compound or salt or solvate thereof according to any one of [A14] to [A23], wherein

[0120] Ring E is unsubstituted or substituted with one or more R E replace; and

[0121] One or more R E Each of the is independently selected from the group consisting of fluoro, chloro, methoxy, dihydroxyboryl, methyl, and tert-butyl.

[0122] [A26]

[0123] The compound according to any one of [A1] to [A25.5], or a salt thereof, or a solvate thereof, wherein R4 is an optionally substituted C6-C 10 Aryl (R 4A ) or an optionally substituted 5- to 10-membered heteroaryl (R 4HA ).

[0124] [A27]

[0125] The compound according to any one of [A1] to [A26], or a salt thereof, or a solvate thereof, wherein R4 is an optionally substituted C6-C 10 Aryl (R 4A ).

[0126] [A28]

[0127] The compound according to [A26] or [A27], or a salt thereof, or a solvate thereof, wherein the C6-C 10 Aryl (R 4A ) is phenyl.

[0128] [A29]

[0129] The compound or salt or solvate thereof according to any one of [A26] to [A28], wherein

[0130] The C6-C 10 Aryl (R 4A ) is unsubstituted or substituted with one or more R a replace;

[0131] One or more R a Each of the following is independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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; and

[0132] The hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

[0133] [A30]

[0134] The compound or salt or solvate thereof according to any one of [A26] to [A28], wherein

[0135] The C6-C 10 Aryl (R 4A ) is unsubstituted or substituted with one or more R a replace; and

[0136] One or more R a Each of the groups is independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and C1-C6 alkylsulfonylamino.

[0137] [A31]

[0138] The compound or salt or solvate thereof according to any one of [A26] to [A28], wherein

[0139] The C6-C 10 Aryl (R 4A ) is unsubstituted or substituted with one or more R a replace; and

[0140] One or more R a Each of the groups is independently selected from the group consisting of halogen, hydroxy, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and C1-C6 alkylsulfonylamino.

[0141] [A32]

[0142] The compound according to any one of [A1] to [A26], or a salt thereof, or a solvate thereof, wherein R4 is an optionally substituted 5- to 10-membered heteroaryl group (R 4HA ).

[0143] [A33]

[0144] The compound according to [A26] or [A32], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R4HA ) is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzodiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, pyrrolopyrazinyl, and fluoropyridinyl.

[0145] [A34]

[0146] The compound according to [A26] or [A32], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzodiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, pyrrolopyrazinyl, and fluoropyridinyl.

[0147] [A35]

[0148] The compound according to [A26] or [A32], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is selected from the group consisting of pyridyl, pyrimidinyl, benzimidazolyl, indolyl, indazolyl and pyrazolopyridinyl.

[0149] [A36]

[0150] The compound according to [A26] or [A32], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is selected from the group consisting of pyrimidinyl, benzimidazolyl, indolyl, indazolyl and pyrazolopyridinyl.

[0151] [A37]

[0152] The compound according to [A26] or [A32], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-6-yl or 1H-indazol-4-yl.

[0153] [A38]

[0154] The compound according to [A26] or [A32], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl.

[0155] [A39]

[0156] The compound or salt or solvate thereof according to any one of [A32] to [A38], wherein

[0157] The 5- to 10-membered heteroaryl group (R 4HA ) is unsubstituted or substituted with one or more R a replace;

[0158] One or more R a Each of the following is independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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; and

[0159] The hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

[0160] [A40]

[0161] The compound or salt or solvate thereof according to any one of [A32] to [A38], wherein

[0162] The 5- to 10-membered heteroaryl group (R 4HA ) is unsubstituted or substituted with one or more R a replace; and

[0163] One or more R a Each of the groups is independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and C1-C6 alkylsulfonylamino.

[0164] [A41]

[0165] The compound or salt or solvate thereof according to any one of [A32] to [A38], wherein

[0166] The 5- to 10-membered heteroaryl group (R 4HA ) is unsubstituted or substituted with one or more R a replace; and

[0167] One or more R a Each of the is independently selected from the group consisting of halogen, cyano, amino, C1-C6 alkyl and halogenated C1-C6 alkyl.

[0168] [A42]

[0169] The compound according to any one of [A32] to [A38], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl or 1H-indazol-4-yl substituted with one or more halogens.

[0170] [A43]

[0171] The compound according to any one of [A32] to [A38], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl substituted by one or more halogens.

[0172] [A44]

[0173] The compound according to any one of [A32] to [A38], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl, wherein at least one of position 5, position 6 and position 7 is substituted with halogen.

[0174] [A44.5]

[0175] The compound according to any one of [A32] to [A38], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is represented by the following formula:

[0176] [Formula 4]

[0177]

[0178] Where * represents the carbon to which R4 is bonded in formula (1), R a5 、R a6 and R a7 are each independently hydrogen or halogen, and R a5 、R a6 and Ra7 At least one of them is not hydrogen.

[0179] [A45]

[0180] The compound or salt or solvate thereof according to any one of [A32] to [A38], wherein

[0181] The 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl, wherein at least one of position 5, position 6, and position 7 is substituted with halogen; and

[0182] The halogen is fluorine or chlorine.

[0183] [A46]

[0184] The compound or salt or solvate thereof according to any one of [A32] to [A38], wherein

[0185] The 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl, wherein any one or both of position 5, position 6 and position 7 are substituted with halogen; and

[0186] The halogen is selected from the group consisting of fluorine, chlorine, a combination of fluorine and fluorine, and a combination of fluorine and chlorine.

[0187] [A46.5]

[0188] The compound or salt or solvate thereof according to any one of [A32] to [A38], wherein

[0189] The 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl substituted with halogen at any one or both of positions 5, 6 and 7, and

[0190] The halogen is independently fluorine or chlorine.

[0191] [B1]

[0192] A compound or a salt or a solvate thereof represented by formula (2):

[0193] [Formula 5]

[0194]

[0195] in

[0196] R4 is selected from the group consisting of: optionally substituted C6-C 10 Aryl (R 4A ), optionally substituted 4- to 10-membered heterocyclyl and optionally substituted 5- to 10-membered heteroaryl (R4HA );

[0197] X5 for CR x5 or N;

[0198] X6 for CR x6 or N;

[0199] X 10a CR x10a or N;

[0200] R x5 、R x6 、R 6a and R x10a Each of the following is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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;

[0201] The hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl are optionally substituted; and

[0202] R x5 and R x6 、R x6 and R 6a , or R 6a and R x10a Together with the atoms to which they are attached, they can form an optionally substituted ring E.

[0203] [B2]

[0204] The compound according to [B1], or a salt thereof, or a solvate thereof, wherein

[0205] X5 for CR x5 or N;

[0206] X6 for CR x6 ;and

[0207] X 10a CR x10a or N.

[0208] [B3]

[0209] The compound according to [B1] or [B2], or a salt thereof, or a solvate thereof, wherein

[0210] X5 is CH;

[0211] X6 for CR x6 ;and

[0212] X 10a CR x10a .

[0213] [B4]

[0214] The compound or salt or solvate thereof according to any one of [B1] to [B3], wherein

[0215] R x6 Selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkylthio, C1-C6 acylamino, mono C1-C6 alkylamino, C1-C6 alkylsulfonylamino, C3-C8 cycloalkylsulfonylamino, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C3-C8 cycloalkyl C1-C6 alkoxy, 4- to 10-membered heterocyclyl C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4- to 10-membered heterocyclyl C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkyl, C2 ... 10 aryl and 5- to 10-membered heteroaryl; and

[0216] The C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C3-C8 cycloalkyl C1-C6 alkoxy, 4-membered to 10-membered heterocyclic C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4-membered to 10-membered heterocyclic oxy, C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkyl, 4-membered to 10-membered heterocyclic, C6-C 10 The aryl and 5- to 10-membered heteroaryl groups are independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, oxo, halo-C1-C6 alkyl, and C3-C8 cycloalkyl.

[0217] [B5]

[0218] The compound according to any one of [B1] to [B3], or a salt thereof, or a solvate thereof, wherein R x6 Selected from the group consisting of halogen, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, C3-C8 cycloalkyloxy, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl and C3-C8 cycloalkyl.

[0219] [B6]

[0220] The compound according to any one of [B1] to [B3], or a salt thereof, or a solvate thereof, wherein R x6 Selected from the group consisting of hydrogen, C1-C6 alkoxy, C1-C6 alkyl and C3-C8 cycloalkyl.

[0221] [B7]

[0222] The compound according to any one of [B1] to [B3], or a salt thereof, or a solvate thereof, wherein R x6 Selected from the group consisting of hydrogen, methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-but-2-yl]oxy, [(2R)-but-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, but-2-yl, 3-methylbutyl, pent-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl and spiro[2.3]hex-5-yl.

[0223] [B8]

[0224] The compound according to any one of [B1] to [B7], or a salt thereof, or a solvate thereof, wherein R x10a Selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C3-C8 cycloalkyl.

[0225] [B9]

[0226] The compound according to any one of [B1] to [B7], or a salt thereof, or a solvate thereof, wherein R x10a Selected from the group consisting of hydrogen, chlorine, bromine, cyano, methyl, ethyl, propyl, propan-2-yl, vinyl, ethynyl and cyclopropyl.

[0227] [B10]

[0228] The compound according to any one of [B1] to [B9], or a salt thereof, or a solvate thereof, wherein R 6a Selected from the group consisting of hydrogen, halogen, cyano, halogenated C1-C6 alkoxy and C1-C6 alkyl.

[0229] [B11]

[0230] The compound according to any one of [B1] to [B9], or a salt thereof, or a solvate thereof, wherein R 6a Selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, difluoromethoxy, methyl and ethyl.

[0231] [B12]

[0232] The compound according to any one of [B1] to [B7], or a salt thereof, or a solvate thereof, wherein R 6a and R x10a Together with the atoms to which they are attached they form an optionally substituted Ring E.

[0233] [B13]

[0234] The compound according to [B12], or a salt thereof, or a solvate thereof, wherein ring E is selected from the group consisting of a 3-membered to 10-membered monocyclic alicyclic ring, a benzene ring, a 3-membered to 12-membered monocyclic heterocyclic ring, and a 5-membered to 6-membered monocyclic aromatic heterocyclic ring (E HA ).

[0235] [B14]

[0236] The compound according to [B12], or a salt thereof, or a solvate thereof, wherein ring E is a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle (E HA ).

[0237] [B15]

[0238] The compound according to [B13] or [B14], or a salt thereof, or a solvate thereof, wherein the 5- to 6-membered monocyclic aromatic heterocycle (E HA ) 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.

[0239] [B16]

[0240] The compound according to [B13] or [B14], or a salt thereof, or a solvate thereof, wherein the 5- to 6-membered monocyclic aromatic heterocycle (E HA ) is selected from the group consisting of a pyridine ring, a pyrimidine ring, a pyridazine ring and a pyrazine ring.

[0241] [B17]

[0242] The compound according to [B13] or [B14], or a salt thereof, or a solvate thereof, wherein the 5- to 6-membered monocyclic aromatic heterocycle (E HA ) is a pyridine ring or a pyrazine ring.

[0243] [B18]

[0244] The compound according to [B13] or [B14], or a salt thereof, or a solvate thereof, wherein the 5- to 6-membered monocyclic aromatic heterocycle (E HA ) is a pyridine ring.

[0245] [B19]

[0246] The compound according to [B12], or a salt thereof, or a solvate thereof, wherein

[0247] Ring E is represented by the following formula:

[0248] [Formula 6]

[0249]

[0250] Where * represents R 6a In the formula (2), the carbon to which the carbon is attached, and ** represents R x10a The carbon to which it is attached in the formula (2); the ring E in the formula is referred to as the "E ring".

[0251] [B20]

[0252] The compound according to [B12], or a salt thereof, or a solvate thereof, wherein

[0253] Ring E is represented by the following formula:

[0254] [Formula 7]

[0255]

[0256] Where * represents R 6a In the formula (2), the carbon to which the carbon is attached, and ** represents R x10a The carbon to which it is attached in the formula (2); the ring E in the formula is referred to as the "E ring".

[0257] [B21]

[0258] The compound or salt or solvate thereof according to any one of [B12] to [B20], wherein

[0259] Ring E is unsubstituted or substituted with one or more R E replace;

[0260] One or more R EEach of the following is independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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; and

[0261] The hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

[0262] [B22]

[0263] The compound or salt or solvate thereof according to any one of [B12] to [B20], wherein

[0264] Ring E is unsubstituted or substituted with one or more R E replace; and

[0265] One or more R E Each of the is independently selected from the group consisting of halogen, C1-C6 alkoxy, boronyl, and C1-C6 alkyl.

[0266] [B23]

[0267] The compound or salt or solvate thereof according to any one of [B12] to [B20], wherein

[0268] Ring E is unsubstituted or substituted with one or more R E replace; and

[0269] One or more R E Each of the is independently selected from the group consisting of fluoro, chloro, methoxy, dihydroxyboryl, methyl, and tert-butyl.

[0270] [B24]

[0271] The compound according to any one of [B1] to [B23], or a salt thereof, or a solvate thereof, wherein R4 is an optionally substituted C6-C 10 Aryl (R 4A ) or an optionally substituted 5- to 10-membered heteroaryl (R 4HA ).

[0272] [B25]

[0273] The compound according to any one of [B1] to [B23], or a salt thereof, or a solvate thereof, wherein R4 is an optionally substituted C6-C 10 Aryl (R 4A ).

[0274] [B26]

[0275] The compound according to [B24] or [B25], or a salt thereof, or a solvate thereof, wherein the C6-C 10 Aryl (R 4A ) is phenyl.

[0276] [B27]

[0277] The compound or salt or solvate thereof according to any one of [B24] to [B26], wherein

[0278] The C6-C 10 Aryl (R 4A ) is unsubstituted or substituted with one or more R a replace;

[0279] One or more R a Each of the following is independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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; and

[0280] The hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

[0281] [B28]

[0282] The compound or salt or solvate thereof according to any one of [B24] to [B26], wherein

[0283] The C6-C 10 Aryl (R 4A ) is unsubstituted or substituted with one or more R a replace; and

[0284] One or more R aEach of the groups is independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and C1-C6 alkylsulfonylamino.

[0285] [B29]

[0286] The compound or salt or solvate thereof according to any one of [B24] to [B26], wherein

[0287] The C6-C 10 Aryl (R 4A ) is unsubstituted or substituted with one or more R a replace;

[0288] One or more R a Each of the groups is independently selected from the group consisting of halogen, hydroxy, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and C1-C6 alkylsulfonylamino.

[0289] [B30]

[0290] The compound according to any one of [B1] to [B23], or a salt thereof, or a solvate thereof, wherein R4 is an optionally substituted 5- to 10-membered heteroaryl group (R 4HA ).

[0291] [B31]

[0292] The compound according to [B24] or [B30], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzodiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, pyrrolopyrazinyl, and fluoropyridinyl.

[0293] [B32]

[0294] The compound according to [B24] or [B30], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA) is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzodiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, pyrrolopyrazinyl, and fluoropyridinyl.

[0295] [B33]

[0296] The compound according to [B24] or [B30], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is selected from the group consisting of pyridyl, pyrimidinyl, benzimidazolyl, indolyl, indazolyl and pyrazolopyridinyl.

[0297] [B34]

[0298] The compound according to [B24] or [B30], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is selected from the group consisting of pyrimidinyl, benzimidazolyl, indolyl, indazolyl and pyrazolopyridinyl.

[0299] [B35]

[0300] The compound according to [B24] or [B30], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-6-yl or 1H-indazol-4-yl.

[0301] [B36]

[0302] The compound according to [B24] or [B30], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl.

[0303] [B37]

[0304] The compound or salt or solvate thereof according to any one of [B31] to [B36], wherein

[0305] The 5- to 10-membered heteroaryl group (R 4HA ) is unsubstituted or substituted with one or more R a replace;

[0306] One or more R aEach of the following is independently selected from the group consisting of halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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; and

[0307] The hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

[0308] [B38]

[0309] The compound or salt or solvate thereof according to any one of [B31] to [B36], wherein

[0310] The 5- to 10-membered heteroaryl group (R 4HA ) is unsubstituted or substituted with one or more R a replace; and

[0311] One or more R a Each of the groups is independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and C1-C6 alkylsulfonylamino.

[0312] [B39]

[0313] The compound or salt or solvate thereof according to any one of [B31] to [B36], wherein

[0314] The 5- to 10-membered heteroaryl group (R 4HA ) is unsubstituted or substituted with one or more R a replace; and

[0315] One or more R a Each of the is independently selected from the group consisting of halogen, cyano, amino, C1-C6 alkyl and halogenated C1-C6 alkyl.

[0316] [B40]

[0317] The compound according to any one of [B31] to [B36], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA) is 1H-indazol-4-yl or 1H-indazol-4-yl substituted by one or more halogens.

[0318] [B41]

[0319] The compound according to any one of [B31] to [B36], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl substituted by one or more halogens.

[0320] [B42]

[0321] The compound according to any one of [B31] to [B36], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl, wherein at least one of position 5, position 6 and position 7 is substituted with halogen.

[0322] [B43]

[0323] The compound or salt or solvate thereof according to any one of [B31] to [B36], wherein

[0324] The 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl, wherein at least one of position 5, position 6, and position 7 is substituted with halogen; and

[0325] The halogen is fluorine or chlorine.

[0326] [B44]

[0327] The compound or salt or solvate thereof according to any one of [B31] to [B36], wherein

[0328] The 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl, wherein any one or both of position 5, position 6 and position 7 are substituted with halogen; and

[0329] The halogen is selected from the group consisting of fluorine, chlorine, a combination of fluorine and fluorine, and a combination of fluorine and chlorine.

[0330] [B44.5]

[0331] The compound or salt or solvate thereof according to any one of [B31] to [B36], wherein

[0332] The 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl substituted with halogen at any one or both of positions 5, 6 and 7, and

[0333] The halogen is independently fluorine or chlorine.

[0334] [C1]

[0335] A compound represented by formula (3):

[0336] [Formula 8]

[0337]

[0338] in

[0339] R4 is selected from the group consisting of: 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 );

[0340] X5 for CR x5 or N;

[0341] X6 for CR x6 or N;

[0342] X7 for CR x7 or N;

[0343] X8 for CR x8 or N;

[0344] X9 for CR x9 or N;

[0345] X 10 CR x10 or N;

[0346] R x5 、R x6 、R x7 、R x8 、R x9 and R x10 Each of the following is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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; and

[0347] The hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10Aryl and 5- to 10-membered heteroaryl are optionally substituted,

[0348] or a salt thereof, or a solvate thereof.

[0349] [C2]

[0350] The compound according to [C1], or a salt thereof, or a solvate thereof, wherein

[0351] X5 for CR x5 or N;

[0352] X6 for CR x6 ;

[0353] X7 for CR x7 or N;

[0354] X8 for CR x8 or N;

[0355] X9 for CR x9 or N; and

[0356] X 10 CR x10 or N.

[0357] [C3]

[0358] The compound according to [C1] or [C2], or a salt thereof, or a solvate thereof, wherein

[0359] X5 is CH;

[0360] X6 for CR x6 ;

[0361] X7 for CR x7 or N;

[0362] X8 for CR x8 or N;

[0363] X9 for CR x9 or N; and

[0364] X 10 CR x10 or N.

[0365] [C4]

[0366] The compound according to any one of [C1] to [C3], or a salt thereof, or a solvate thereof, wherein

[0367] X7 is N, X8 is CR x8 , X9 is CR x9 , and X 10 CR x10 ;

[0368] X7 for CR x7 , X8 is N, X9 is CR x9 , and X 10 CR x10 ;

[0369] X7 for CR x7 , X8 is CR x8 , X9 is N, and X 10 CR x10 ;

[0370] X7 for CR x7 , X8 is CR x8 , X9 is CR x9 , and X 10 is N;

[0371] X7 is N, X8 is CR x8 , X9 is CR x9 , and X 10 is N;

[0372] X7 for CR x7 , X8 is N, X9 is CR x9 , and X 10 is N; or

[0373] X7 is N, X8 is N, X9 is CR x9 , and X 10 CR x10 .

[0374] [C4.5]

[0375] The compound according to any one of [C1] to [C3], or a salt thereof, or a solvate thereof, wherein

[0376] X7 is N, X8 is CR x8 , X9 is CR x9 , and X 10 CR x10 ,or

[0377] X7 for CR x7 , X8 is N, X9 is CR x9 , and X 10 CR x10 ,or

[0378] X7 for CR x7 , X8 is CR x8 , X9 is N, and X 10 CR x10 ,or

[0379] X7 for CR x7, X8 is CR x8 , X9 is CR x9 , and X 10 is N.

[0380] [C5]

[0381] The compound according to any one of [C1] to [C4], or a salt thereof, or a solvate thereof, wherein

[0382] R x6 Selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkylthio, C1-C6 acylamino, mono C1-C6 alkylamino, C1-C6 alkylsulfonylamino, C3-C8 cycloalkylsulfonylamino, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C3-C8 cycloalkyl C1-C6 alkoxy, 4- to 10-membered heterocyclyl C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4- to 10-membered heterocyclyl C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkyl, C2 ... 10 aryl and 5- to 10-membered heteroaryl; and

[0383] The C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C3-C8 cycloalkyl C1-C6 alkoxy, 4-membered to 10-membered heterocyclic C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4-membered to 10-membered heterocyclic oxy, C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkyl, 4-membered to 10-membered heterocyclic, C6-C 10 The aryl and 5- to 10-membered heteroaryl groups are independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, oxo, halo-C1-C6 alkyl, and C3-C8 cycloalkyl.

[0384] [C5.1]

[0385] The compound according to any one of [C1] to [C3], or a salt thereof, or a solvate thereof, wherein R x6Selected from the group consisting of halogen, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, C3-C8 cycloalkyloxy, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl and C3-C8 cycloalkyl.

[0386] [C5.2]

[0387] The compound according to any one of [C1] to [C4], or a salt thereof, or a solvate thereof, wherein R x6 Selected from the group consisting of hydrogen, C1-C6 alkoxy, C1-C6 alkyl and C3-C8 cycloalkyl.

[0388] [C6]

[0389] The compound according to any one of [C1] to [C4], or a salt thereof, or a solvate thereof, wherein R x6 Selected from the group consisting of hydrogen, methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-but-2-yl]oxy, [(2R)-but-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, but-2-yl, 3-methylbutyl, pent-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl and spiro[2.3]hex-5-yl.

[0390] [C6.5]

[0391] A compound represented by formula (3):

[0392] [Formula 9]

[0393]

[0394] in

[0395] R4 is an optionally substituted 5- to 10-membered heteroaryl group (R 4HA );

[0396] The 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl or 1H-indazol-4-yl substituted with one or more halogens;

[0397] X5 for CR x5 or N;

[0398] X6 for CR x6 ;

[0399] R x6selected from the group consisting of methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-but-2-yl]oxy, [(2R)-but-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, but-2-yl, 3-methylbutyl, pent-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl, and spiro[2.3]hex-5-yl;

[0400] X7 for CR x7 or N;

[0401] X8 for CR x8 or N;

[0402] X9 for CR x9 or N;

[0403] X 10 CR x10 or N;

[0404] R x5 、R x7 、R x8 、R x9 and R x10 Each of the following is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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; and

[0405] The hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 The aryl group and the 5- to 10-membered heteroaryl group are optionally substituted; or a salt thereof, or a solvate thereof.

[0406] [C6.6]

[0407] A compound represented by formula (3):

[0408] [Equation 10]

[0409]

[0410] in

[0411] R4 is 1H-indazol-4-yl or 1H-indazol-4-yl substituted by one or more halogen atoms,

[0412] X5 for CR x5 or N,

[0413] X6 for CR x6 ,

[0414] R x6 is selected from the group consisting of methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-but-2-yl]oxy, [(2R)-but-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, but-2-yl, 3-methylbutyl, pent-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl and spiro[2.3]hex-5-yl,

[0415] X7 for CR x7 or N,

[0416] X8 for CR x8 or N,

[0417] X9 for CR x9 or N,

[0418] X 10 CR x10 or N,

[0419] R x5 、R x7 、R x8 、R x9 and R x10 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxyl, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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, and

[0420] The hydroxyl group, the thiol group, the amino group, the C1-C6 alkoxy group, the C1-C6 alkylthio group, the carbonyl group, the carboxyl group, the sulfonyl group, the phosphoryl group, the boron group, the C1-C6 alkyl group, the C2-C6 alkenyl group, the C2-C6 alkynyl group, the C3-C8 cycloalkyl group, the 4-membered to 10-membered heterocyclic group, the C6-C 10 Aryl and the 5- to 10-membered heteroaryl are each optionally further substituted,

[0421] or a salt thereof, or a solvate thereof.

[0422] [C7]

[0423] The compound according to any one of [C1] to [C6.5], or a salt thereof, or a solvate thereof, wherein X7 is CR x7 .

[0424] [C8]

[0425] The compound according to any one of [C7], or a salt thereof, or a solvate thereof, wherein R x7 is hydrogen, halogen, C1-C6 alkoxy or C1-C6 alkyl.

[0426] [C9]

[0427] The compound according to any one of [C1] to [C6.5], or a salt thereof, or a solvate thereof, wherein X7 is N.

[0428] [C10]

[0429] The compound according to any one of [C1] to [C9], or a salt thereof, or a solvate thereof, wherein X8 is CR x8 .

[0430] [C11]

[0431] The compound according to any one of [C10], or a salt thereof, or a solvate thereof, wherein R x8 is hydrogen, halogen, C1-C6 alkoxy or C1-C6 alkyl.

[0432] [C12]

[0433] The compound according to any one of [C1] to [C9], or a salt thereof, or a solvate thereof, wherein X8 is N.

[0434] [C13]

[0435] The compound according to any one of [C1] to [C12], or a salt thereof, or a solvate thereof, wherein X9 is CR x9 .

[0436] [C14]

[0437] The compound according to [C13], or a salt thereof, or a solvate thereof, wherein R x9 Selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl and boronyl.

[0438] [C15]

[0439] The compound according to any one of [C1] to [C12], or a salt thereof, or a solvate thereof, wherein X9 is N.

[0440] [C16]

[0441] The compound according to any one of [C1] to [C15], or a salt thereof, or a solvate thereof, wherein X 10 CR x10 .

[0442] [C17]

[0443] The compound according to any one of [C16], or a salt thereof, or a solvate thereof, wherein R x10 is hydrogen, halogen, C1-C6 alkoxy or C1-C6 alkyl.

[0444] [C18]

[0445] The compound according to any one of [C1] to [C12], or a salt thereof, or a solvate thereof, wherein X 10 is N.

[0446] [C20]

[0447] The compound according to any one of [C1] to [C18] (except [C6.5] and [C6.6]), or a salt or a solvate thereof, wherein R4 is an optionally substituted C6-C 10 Aryl (R 4A ) or an optionally substituted 5- to 10-membered heteroaryl (R 4HA ).

[0448] [C21]

[0449] The compound according to any one of [C1] to [C18] (except [C6.5] and [C6.6]), or a salt or a solvate thereof, wherein R4 is an optionally substituted C6-C 10 Aryl (R 4A ).

[0450] [C22]

[0451] The compound according to [C20] or [C21], or a salt thereof, or a solvate thereof, wherein the C6-C 10 Aryl (R 4A ) is phenyl.

[0452] [C23]

[0453] The compound or salt or solvate thereof according to any one of [C20] to [C22], wherein

[0454] The C6-C 10 Aryl (R 4A ) is unsubstituted or substituted with one or more R a replace;

[0455] One or more Ra Each of the following is independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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; and

[0456] The hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

[0457] [C24]

[0458] The compound or salt or solvate thereof according to any one of [C20] to [C22], wherein

[0459] The C6-C 10 Aryl (R 4A ) is unsubstituted or substituted with one or more R a replace; and

[0460] One or more R a Each of the groups is independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and C1-C6 alkylsulfonylamino.

[0461] [C25]

[0462] The compound or salt or solvate thereof according to any one of [C20] to [C22], wherein

[0463] The C6-C 10 Aryl (R 4A ) is unsubstituted or substituted with one or more R a replace; and

[0464] One or more R a Each of the groups is independently selected from the group consisting of halogen, hydroxy, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and alkylsulfonylamino.

[0465] [C26]

[0466] The compound according to any one of [C1] to [C18] (except [C6.5] and [C6.6]), or a salt thereof, or a solvate thereof, wherein R4 is an optionally substituted 5- to 10-membered heteroaryl group (R 4HA ).

[0467] [C27]

[0468] The compound according to [C20] or [C26], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzodiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, pyrrolopyrazinyl, and fluoropyridinyl.

[0469] [C28]

[0470] The compound according to [C20] or [C26], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzodiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, pyrrolopyrazinyl, and fluoropyridinyl.

[0471] [C29]

[0472] The compound according to [C20] or [C26], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is selected from the group consisting of pyridyl, pyrimidinyl, benzimidazolyl, indolyl, indazolyl and pyrazolopyridinyl.

[0473] [C30]

[0474] The compound according to [C20] or [C26], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R4HA ) is selected from the group consisting of pyrimidinyl, benzimidazolyl, indolyl, indazolyl and pyrazolopyridinyl.

[0475] [C31]

[0476] The compound according to [C20] or [C26], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-6-yl or 1H-indazol-4-yl.

[0477] [C32]

[0478] The compound according to [C20] or [C26], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl.

[0479] [C33]

[0480] The compound or salt or solvate thereof according to any one of [C27] to [C32], wherein

[0481] The 5- to 10-membered heteroaryl group (R 4HA ) is unsubstituted or substituted with one or more R a replace;

[0482] One or more R a Each of the following is independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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; and

[0483] The hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

[0484] [C34]

[0485] The compound or salt or solvate thereof according to any one of [C27] to [C32], wherein

[0486] The 5- to 10-membered heteroaryl group (R 4HA ) is unsubstituted or substituted with one or more R areplace; and

[0487] One or more R a Each of the groups is independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and alkylsulfonylamino.

[0488] [C35]

[0489] The compound or salt or solvate thereof according to any one of [C27] to [C32], wherein

[0490] The 5- to 10-membered heteroaryl group (R 4HA ) is unsubstituted or substituted with one or more R a replace; and

[0491] One or more R a Each of the is independently selected from the group consisting of halogen, cyano, amino, C1-C6 alkyl and halogenated C1-C6 alkyl.

[0492] [C36]

[0493] The compound according to any one of [C27] to [C32], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl or 1H-indazol-4-yl substituted with one or more halogens.

[0494] [C37]

[0495] The compound according to any one of [C27] to [C32], or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl substituted by one or more halogens.

[0496] [C38]

[0497] The compound or salt or solvate thereof according to any one of [C27] to [C32], wherein

[0498] The 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl, wherein at least one of position 5, position 6 and position 7 is substituted with halogen.

[0499] [C39]

[0500] The compound or salt or solvate thereof according to any one of [C27] to [C32], wherein

[0501] The 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl, wherein at least one of position 5, position 6, and position 7 is substituted with halogen;

[0502] as well as

[0503] The halogen is fluorine or chlorine.

[0504] [C40]

[0505] The compound or salt or solvate thereof according to any one of [C27] to [C32], wherein

[0506] The 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl, wherein any one or both of position 5, position 6 and position 7 are substituted with halogen; and

[0507] The halogen is selected from the group consisting of fluorine, chlorine, a combination of fluorine and fluorine, and a combination of fluorine and chlorine.

[0508] [C40.5]

[0509] The compound or salt or solvate thereof according to any one of [C27] to [C32], wherein

[0510] The 5- to 10-membered heteroaryl group (R 4HA ) is 1H-indazol-4-yl substituted with halogen at any one or both of positions 5, 6 and 7, and

[0511] The halogen is independently fluorine or chlorine.

[0512] [D1]

[0513] A compound selected from the group consisting of:

[0514] 3-amino-7-chloro-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-benzo[h]quinolin-2-one,

[0515] 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-benzo[h]quinolin-2-one,

[0516] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-benzo[h]quinolin-2-one,

[0517] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclopropyl-1H-benzo[h]quinolin-2-one,

[0518] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methyl-1H-benzo[h]quinolin-2-one,

[0519] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propan-2-yl-1H-1,7-phenanthroline-2-one,

[0520] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthroline-2-one,

[0521] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclopropyl-1H-1,7-phenanthroline-2-one,

[0522] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclobutyl-1H-1,7-phenanthroline-2-one,

[0523] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-ethyl-1H-1,7-phenanthroline-2-one,

[0524] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one,

[0525] 3-amino-4-(5-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one,

[0526] 3-amino-6-cyclopropyl-4-(5-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one,

[0527] (S)-3-amino-6-cyclopropyl-4-(5-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one,

[0528] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one,

[0529] 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one,

[0530] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-ethyl-1H-1,7-phenanthroline-2-one,

[0531] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-ethoxy-1H-1,7-phenanthroline-2-one,

[0532] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthroline-2-one,

[0533] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-cyclopropyl-1H-1,7-phenanthroline-2-one,

[0534] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one,

[0535] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one,

[0536] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propoxy-1H-1,7-phenanthroline-2-one,

[0537] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one,

[0538] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-ethoxy-1H-1,7-phenanthroline-2-one,

[0539] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthroline-2-one,

[0540] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one,

[0541] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one,

[0542] 3-amino-6-ethoxy-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one,

[0543] 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one,

[0544] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one,

[0545] 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one,

[0546] 3-amino-6-cyclobutyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one,

[0547] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,10-phenanthroline-2-one,

[0548] 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,10-phenanthroline-2-one,

[0549] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,10-phenanthroline-2-one,

[0550] 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,10-phenanthroline-2-one,

[0551] 3-amino-9-fluoro-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one,

[0552] 3-amino-9-fluoro-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one,

[0553] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-9-fluoro-6-methoxy-1H-1,7-phenanthroline-2-one,

[0554] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-9-fluoro-6-methyl-1H-1,7-phenanthroline-2-one,

[0555] 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-methoxy-10H-pyrido[2,3-f]quinoxalin-9-one,

[0556] 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-propan-2-yloxy-10H-pyrido[2,3-f]quinoxalin-9-one,

[0557] 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-methyl-10H-pyrido[2,3-f]quinoxalin-9-one,

[0558] 8-amino-5-cyclopropyl-7-(7-fluoro-1H-indazol-4-yl)-10H-pyrido[2,3-f]quinoxalin-9-one,

[0559] 8-amino-7-(7-fluoro-1H-indazol-4-yl)-5-methyl-10H-pyrido[3,2-h]quinazolin-9-one,

[0560] 8-amino-5-cyclopropyl-7-(7-fluoro-1H-indazol-4-yl)-10H-pyrido[3,2-h]quinazolin-9-one,

[0561] 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,8-phenanthroline-2-one,

[0562] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5,6-dimethyl-1H-1,7-phenanthroline-2-one,

[0563] 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-5-methyl-1H-1,7-phenanthroline-2-one,

[0564] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-methyl-1H-1,7-phenanthroline-2-one,

[0565] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-6-methyl-1H-1,7-phenanthroline-2-one,

[0566] 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-1H-1,7-phenanthroline-2-one,

[0567] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-1H-1,7-phenanthroline-2-one,

[0568] 3-amino-4-(5,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one,

[0569] 3-amino-6-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yl)-1H-1,7-phenanthroline-2-one,

[0570] 3-amino-4-(1H-benzotriazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, or

[0571] 3-amino-6-(tert-butyl)-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one,

[0572] or a salt thereof, or a solvate thereof.

[0573] [D2]

[0574] 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.

[0575] [D3]

[0576] 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.

[0577] [D4]

[0578] 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.

[0579] [D5]

[0580] 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.

[0581] [D6]

[0582] 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.

[0583] [D7]

[0584] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propan-2-yl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0585] [D8]

[0586] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0587] [D9]

[0588] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclopropyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0589] [D10]

[0590] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclobutyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0591] [D11]

[0592] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-ethyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0593] [D12]

[0594] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0595] [D13]

[0596] 3-amino-4-(5-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0597] [D14]

[0598] 3-amino-6-cyclopropyl-4-(5-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0599] [D15]

[0600] (S)-3-amino-6-cyclopropyl-4-(5-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0601] [D16]

[0602] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0603] [D16.5]

[0604] 3-Amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one hydrochloride monohydrate.

[0605] [D17]

[0606] 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0607] [D18]

[0608] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-ethyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0609] [D19]

[0610] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-ethoxy-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0611] [D20]

[0612] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0613] [D21]

[0614] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-cyclopropyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0615] [D22]

[0616] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0617] [D23]

[0618] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0619] [D23.5]

[0620] 3-Amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one hydrochloride.

[0621] [D24]

[0622] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propoxy-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0623] [D25]

[0624] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0625] [D26]

[0626] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-ethoxy-1H-1,7-phenanthroline-2-one, or a salt or a solvate thereof.

[0627] [D27]

[0628] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0629] [D28]

[0630] 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0631] [D29]

[0632] 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0633] [D30]

[0634] 3-amino-6-ethoxy-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0635] [D31]

[0636] 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0637] [D31.5]

[0638] A solvate of 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthrolin-2-one.

[0639] [D32]

[0640] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0641] [D32.5]

[0642] 3-Amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one hydrochloride monohydrate.

[0643] [D33]

[0644] 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0645] [D34]

[0646] 3-amino-6-cyclobutyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0647] [D35]

[0648] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,10-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0649] [D36]

[0650] 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,10-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0651] [D37]

[0652] 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,10-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0653] [D38]

[0654] 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,10-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0655] [D39]

[0656] 3-amino-9-fluoro-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0657] [D40]

[0658] 3-amino-9-fluoro-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0659] [D41]

[0660] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-9-fluoro-6-methoxy-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0661] [D42]

[0662] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-9-fluoro-6-methyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0663] [D43]

[0664] 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.

[0665] [D44]

[0666] 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.

[0667] [D45]

[0668] 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.

[0669] [D46]

[0670] 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.

[0671] [D47]

[0672] 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.

[0673] [D48]

[0674] 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.

[0675] [D49]

[0676] 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,8-phenanthroline-2-one 2,2,2-trifluoroacetate, or a salt thereof or a solvate thereof.

[0677] [D49.1]

[0678] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5,6-dimethyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0679] [D49.2]

[0680] 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-5-methyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0681] [D49.3]

[0682] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-methyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0683] [D49.4]

[0684] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-6-methyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0685] [D49.5]

[0686] 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0687] [D49.6]

[0688] 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0689] [D49.7]

[0690] 3-amino-4-(5,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0691] [D49.8]

[0692] 3-amino-6-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yl)-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0693] [D49.9]

[0694] 3-amino-4-(1H-benzotriazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0695] [D49.10]

[0696] 3-amino-6-(tert-butyl)-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, or a salt thereof or a solvate thereof.

[0697] [D50]

[0698] The compound or its salt or its solvate according to any one of [A1] to [A46], [B1] to [B44] and [C1] to [C40], wherein the compound or its salt or its solvate represented by the formula (1), the formula (2) and the formula (3) is a compound or its salt represented by the formula (1), the formula (2) and the formula (3).

[0699] [D51]

[0700] A compound or a salt or a solvate thereof according to any one of [A1] to [A46], [B1] to [B44] and [C1] to [C40], wherein the compound or a salt or a solvate thereof represented by the formula (1), the formula (2) and the formula (3) is a compound represented by the formula (1), the formula (2) and the formula (3).

[0701] [D52]

[0702] The compound or its salt or solvate according to any one of [A1] to [A46], [B1] to [B44] and [C1] to [C40], wherein the compound or its salt or solvate represented by the formula (1), the formula (2) and the formula (3) is a salt of the compound represented by the formula (1), the formula (2) and the formula (3).

[0703] [D53]

[0704] The compound or its salt or solvate according to any one of [A1] to [A46], [B1] to [B44] and [C1] to [C40], wherein the compound or its salt or solvate represented by the formula (1), the formula (2) and the formula (3) is a solvate of the compound represented by the formula (1), the formula (2) and the formula (3).

[0705] [D54]

[0706] The compound or its salt or solvate according to any one of [A1] to [A46], [B1] to [B44] and [C1] to [C40], wherein the compound or its salt or solvate represented by the formula (1), the formula (2) and the formula (3) is a compound or its salt or hydrate represented by the formula (1), the formula (2) and the formula (3).

[0707] [D55]

[0708] The compound or its salt or solvate according to any one of [A1] to [A46], [B1] to [B44] and [C1] to [C40], wherein the compound or its salt or solvate represented by the formula (1), the formula (2) and the formula (3) is a hydrate of the compound represented by the formula (1), the formula (2) and the formula (3).

[0709] [D56]

[0710] The compound or salt thereof or solvate thereof according to any one of [D1] to [D49], wherein the compound or salt thereof or solvate thereof according to any one of [D1] to [D49] is the compound or salt thereof according to any one of [D1] to [D49].

[0711] [D57]

[0712] The compound according to any one of [D1] to [D49], or a salt thereof, or a solvate thereof, wherein the compound according to any one of [D1] to [D49], or a salt thereof, or a solvate thereof is a compound according to any one of [D1] to [D49].

[0713] [D58]

[0714] The compound according to any one of [D1] to [D49], or a salt thereof, or a solvate thereof, wherein the compound according to any one of [D1] to [D49], or a salt thereof, or a solvate thereof is a salt of the compound according to any one of [D1] to [D49].

[0715] [D59]

[0716] The compound according to any one of [D1] to [D49], or a salt thereof, or a solvate thereof, wherein the compound according to any one of [D1] to [D49], or a salt thereof, or a solvate thereof is a solvate of the compound according to any one of [D1] to [D49].

[0717] [D60]

[0718] The compound according to any one of [D1] to [D49], or a salt thereof, or a solvate thereof, wherein the compound according to any one of [D1] to [D49], or a salt thereof, or a solvate thereof is the compound according to any one of [D1] to [D49], or a salt thereof, or a hydrate thereof.

[0719] [D61]

[0720] The compound according to any one of [D1] to [D49], or a salt thereof, or a solvate thereof, wherein the compound according to any one of [D1] to [D49], or a salt thereof, or a solvate thereof is a hydrate of the compound or salt according to any one of [D1] to [D49].

[0721] [E1]

[0722] A pharmaceutical composition comprising the compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0723] [E2]

[0724] A preventive and / or therapeutic agent for cancer, comprising the compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0725] [E3]

[0726] A MYT1 inhibitor comprising the compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0727] [E4]

[0728] 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 or solvate thereof.

[0729] [E5]

[0730] The 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, for use in preventing and / or treating cancer.

[0731] [E6]

[0732] Use of the compound or salt or solvate thereof according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61] for producing a pharmaceutical composition for preventing and / or treating cancer.

[0733] [E6.2]

[0734] The pharmaceutical composition, preventive and / or therapeutic agent for cancer, MYT1 inhibitor, method, compound or salt or solvate thereof according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40] and [D1] to [D61], or the use according to any one of [E1] to [E6], which is used in combination with a chemotherapeutic agent.

[0735] [E7]

[0736] A pharmaceutical composition for treating or preventing cancer in combination with a chemotherapeutic agent in a cancer patient in whom RB1 gene mutation positivity or decreased expression of the RB1 gene or protein has been detected, the pharmaceutical composition comprising a MYT1 inhibitor as an active ingredient,

[0737] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0738] [E7.2]

[0739] A pharmaceutical composition for treating or preventing cancer in combination with a chemotherapeutic agent in a cancer patient in which RB1 gene mutation-positive or RB1 gene or protein expression is reduced, the pharmaceutical composition comprising a MYT1 inhibitor as an active ingredient,

[0740] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0741] [E7.5]

[0742] A pharmaceutical composition for treating or preventing cancer in combination with a MYT1 inhibitor in a cancer patient in whom RB1 gene mutation positivity or decreased expression of the RB1 gene or protein has been detected, the pharmaceutical composition comprising a chemotherapeutic agent as an active ingredient,

[0743] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0744] [E7.7]

[0745] A pharmaceutical composition for treating or preventing cancer in a cancer patient in combination with a MYT1 inhibitor, wherein the cancer patient has RB1 gene mutation positive or reduced expression of RB1 gene or protein, the pharmaceutical composition comprising a chemotherapeutic agent as an active ingredient,

[0746] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0747] [E8]

[0748] A method for treating or preventing cancer in a cancer patient in whom RB1 gene mutation-positive or reduced expression of RB1 gene or protein has been detected, comprising:

[0749] administering a chemotherapeutic agent in combination with a MYT1 inhibitor to the cancer patient,

[0750] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0751] [E8.1]

[0752] A method for treating or preventing cancer, comprising:

[0753] Testing a biological sample from a cancer patient for a positive RB1 gene mutation or decreased expression of the RB1 gene or protein, or allowing a third party to perform the test; and

[0754] administering a chemotherapeutic agent in combination with a MYT1 inhibitor to the cancer patient,

[0755] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0756] [E8.2]

[0757] A method for treating or preventing cancer in a cancer patient, wherein the cancer patient has RB1 gene mutation-positive or reduced expression of RB1 gene or protein, the method comprising:

[0758] The cancer patient is administered a chemotherapeutic agent in combination with a MYT1 inhibitor, wherein

[0759] The MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0760] [E9]

[0761] A method for inhibiting the growth of cancer cells in a cancer patient, wherein the cancer patient has been detected to be positive for RB1 gene mutation or reduced expression of RB1 gene or protein, the method comprising:

[0762] contacting the cancer cells with a MYT1 inhibitor and a chemotherapeutic agent,

[0763] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0764] [E9.1]

[0765] A method for inhibiting the growth of cancer cells, comprising:

[0766] Testing a biological sample from a cancer patient for a positive RB1 gene mutation or decreased expression of the RB1 gene or protein, or allowing a third party to perform the test; and

[0767] contacting the cancer cells with a MYT1 inhibitor and a chemotherapeutic agent,

[0768] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0769] [E9.2]

[0770] A method for inhibiting the growth of cancer cells in a cancer patient, wherein the cancer patient has RB1 gene mutation positive or reduced expression of RB1 gene or protein, the method comprising:

[0771] contacting the cancer cells with a MYT1 inhibitor and a chemotherapeutic agent,

[0772] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0773] [E10]

[0774] A method for improving responsiveness to cancer treatment with a chemotherapeutic agent,

[0775] The cancer is a cancer of a cancer patient, in which RB1 gene mutation-positive, RB1 gene or protein expression-reduced, or hyperphosphorylated RB1 protein-positive expression has been detected,

[0776] The method comprises administering a MYT1 inhibitor and the chemotherapeutic agent to the cancer patient.

[0777] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0778] [E10.1]

[0779] A method for improving responsiveness to cancer treatment with a chemotherapeutic agent, the method comprising:

[0780] Testing a biological sample from a cancer patient for a positive RB1 gene mutation or decreased expression of the RB1 gene or protein, or allowing a third party to perform the test; and

[0781] A MYT1 inhibitor is administered to the cancer patient together with the chemotherapeutic agent.

[0782] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0783] [E10.2]

[0784] A method for improving responsiveness to cancer treatment with a chemotherapeutic agent,

[0785] The cancer is a cancer in a cancer patient characterized by positive RB1 gene mutation or decreased expression of RB1 gene or protein,

[0786] The method comprises administering a MYT1 inhibitor and the chemotherapeutic agent to the cancer patient.

[0787] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0788] [E11]

[0789] A method for predicting responsiveness to cancer treatment with a combination of a MYT1 inhibitor and a chemotherapeutic agent, the method comprising:

[0790] Detecting the presence or absence of an RB1 gene mutation or decreased expression of the RB1 gene or protein in a biological sample derived from a cancer patient, or allowing a third party to perform the detection; and

[0791] When the RB1 gene mutation is positive, or when the expression of the RB1 gene or protein is reduced, or when the expression of the hyperphosphorylated RB1 protein is positive, the patient is determined to be responsive to cancer treatment with a combination of a MYT1 inhibitor and a chemotherapeutic agent.

[0792] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0793] [E12]

[0794] A method for selecting a cancer patient for whom a combination of a MYT1 inhibitor and a chemotherapeutic agent is more effective than monotherapy of the MYT1 inhibitor or / and the chemotherapeutic agent, the method comprising:

[0795] Detecting the presence or absence of an RB1 gene mutation or decreased expression of the RB1 gene or protein in a biological sample derived from a cancer patient, or allowing a third party to perform the detection; and

[0796] Based on the presence of the mutation or the decreased expression, the cancer patient is identified as a cancer patient for whom administration of a MYT1 inhibitor and a chemotherapeutic agent in combination is more effective than monotherapy of the MYT1 inhibitor and / or the chemotherapeutic agent,

[0797] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0798] [E13]

[0799] A method for screening a compound effective for treating or preventing cancer in a cancer patient in whom RB1 gene mutation-positive or reduced expression of RB1 gene or protein has been detected, comprising:

[0800] measuring the MYT1 inhibitory activity of the candidate compound; and selecting the candidate compound having the MYT1 inhibitory activity as a compound effective for treating the cancer.

[0801] [E13.2]

[0802] A method for screening a compound effective for treating or preventing cancer in a cancer patient, wherein the cancer patient has RB1 gene mutation-positive or reduced expression of RB1 gene or protein, the method comprising:

[0803] measuring the MYT1 inhibitory activity of the candidate compound; and selecting the candidate compound having the MYT1 inhibitory activity as a compound effective for treating the cancer.

[0804] [E14]

[0805] A MYT1 inhibitor for use in combination with a chemotherapeutic agent in treating or preventing cancer in a cancer patient in whom RB1 gene mutation, decreased expression of RB1 gene or protein, or hyperphosphorylated RB1 protein expression has been detected.

[0806] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0807] [E14.2]

[0808] A MYT1 inhibitor for use in combination with a chemotherapeutic agent in treating or preventing cancer in a cancer patient in whom RB1 gene mutation-positive or RB1 gene or protein expression is reduced,

[0809] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0810] [E15]

[0811] A chemotherapeutic agent for use in combination with a MYT1 inhibitor in treating or preventing cancer in a cancer patient in whom RB1 gene mutation-positive or reduced expression of RB1 gene or protein has been detected,

[0812] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0813] [E15.2]

[0814] A chemotherapeutic agent for use in combination with a MYT1 inhibitor in treating or preventing cancer in a cancer patient in whom RB1 gene mutation-positive or reduced expression of RB1 gene or protein has occurred,

[0815] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0816] [E16]

[0817] Use of a MYT1 inhibitor for producing a pharmaceutical composition for treating or preventing cancer in a cancer patient in whom RB1 gene mutation positivity or reduced expression of RB1 gene or protein has been detected, wherein the MYT1 inhibitor is administered in combination with a chemotherapeutic agent,

[0818] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0819] [E16.2]

[0820] Use of a MYT1 inhibitor for producing a pharmaceutical composition for treating or preventing cancer in a cancer patient in which the cancer patient has developed RB1 gene mutation-positive or reduced expression of the RB1 gene or protein, wherein the pharmaceutical composition is administered in combination with a chemotherapeutic agent,

[0821] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0822] [E17]

[0823] Use of a chemotherapeutic agent for producing a pharmaceutical composition for treating or preventing cancer in a cancer patient in whom RB1 gene mutation positivity or reduced expression of RB1 gene or protein has been detected, wherein the pharmaceutical composition is administered in combination with a MYT1 inhibitor,

[0824] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0825] [E17.2]

[0826] Use of a chemotherapeutic agent for producing a pharmaceutical composition for treating or preventing cancer in a cancer patient in whom RB1 gene mutation-positive or reduced expression of RB1 gene or protein has occurred, wherein the pharmaceutical composition is administered in combination with a MYT1 inhibitor,

[0827] wherein the MYT1 inhibitor is a compound according to any one of [A1] to [A46], [B1] to [B44], [C1] to [C40], and [D1] to [D61], or a salt or solvate thereof.

[0828] [E18]

[0829] 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.

[0830] [E19]

[0831] The pharmaceutical composition, method, MYT1 inhibitor for use, chemotherapeutic agent for use or use according to [E18], wherein the antimetabolite is an antifolate.

[0832] [E20]

[0833] The pharmaceutical composition, method, MYT1 inhibitor for use, chemotherapeutic agent for use or use according to [E19], wherein the antifolate is pemetrexed.

[0834] [E21]

[0835] 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.

[0836] In the above numbering, unless otherwise specified, a number cited in a dependent item also includes the same number but with a different number after the decimal point. For example, a reference to [C6] in a dependent item includes not only [C6] but also [C6.5]. The same applies to other numbers.

[0837] [Beneficial Effects of the Invention]

[0838] The present invention can provide a compound having novel MYT1 inhibitory activity, or a salt or solvate thereof. The present invention can also provide a drug useful for treating and preventing cancer, which contains any one of them as an active ingredient. BRIEF DESCRIPTION OF THE DRAWINGS

[0839] [ Figure 1 ] Figure 1 is a graph showing cell viability calculated in a cytotoxicity test using pemetrexed when exemplary compounds (A12, A59, B3, B22, B23, B24, B32, B35, and B37) were added.

[0840] [ Figure 2 ] Figure 2 is a graph showing cell viability calculated in a cytotoxicity test using pemetrexed when exemplary compounds (B46, B47, B48, B49, C1, C4, C8, C13, and C64) were added.

[0841] [ Figure 3 ] Figure 3 is a graph showing cell viability calculated in a cytotoxicity test using pemetrexed when exemplary compounds (C65, C67, C69, C76, C78, ​​C83, C84, C85, and C86) were added.

[0842] [ Figure 4 ] Figure 4 is a graph showing cell viability calculated in a cytotoxicity test using pemetrexed when exemplary compounds (C88, C90, C91, C92, C98, C100, C101, C102, and C134) were added.

[0843] [ Figure 5 ] Figure 5 is a graph showing cell viability calculated in a cytotoxicity test using pemetrexed when exemplary compounds (C135, C136, C137, C138, C139, C140, C141, C143, and C144) were added.

[0844] [ Figure 6 ] Figure 6 is a graph showing cell viability calculated in a cytotoxicity test using pemetrexed when exemplary compounds (C146, C155, C156, C185, C190, C195, C200, D2, and F2) were added.

[0845] [ Figure 7 ] Figure 7is a graph showing cell viability calculated in a cytotoxicity test using pemetrexed when exemplary compounds (G16, H3, K4, L3, M4, N2, O1, P1, and P4) were added.

[0846] [ Figure 8 ] Figure 8 is a graph showing the cell viability calculated in a cytotoxicity test using pemetrexed when an exemplary compound (Q1) was added.

[0847] [ Figure 9 ] Figure 9 The results of simultaneous measurements of thermogravimetry, differential scanning calorimetry, and mass spectrometry for sample A are shown. The horizontal axis depicts temperature (°C). The left vertical axis depicts the change in weight (%) of the sample in the thermogravimetric analysis. The right vertical axis depicts the heat flow (mW / mg) observed in the differential thermal analysis (left) and the peak intensity observed in the mass spectrometry (right).

[0848] [ Figure 10 ] Figure 10 The results of simultaneous measurements of thermogravimetry, differential scanning calorimetry, and mass spectrometry of sample A-1 are shown. The horizontal axis depicts temperature (°C). The left vertical axis depicts the change in weight (%) of the sample in the thermogravimetric analysis (this result is a reference value because the sample filtered and dried through a mesh is directly measured). The right vertical axis depicts the heat flow (mW / mg) observed in the differential scanning calorimetry (left) and the peak intensity observed in the mass spectrometry (right).

[0849] [ Figure 11 ] Figure 11 The results of simultaneous thermogravimetric and differential thermal analysis measurements of sample A-2 are shown. The horizontal axis depicts temperature (°C). The right vertical axis depicts the change in weight (%) of the sample during thermogravimetric analysis. The left vertical axis depicts the heat flow (μV) observed during differential thermal analysis.

[0850] [ Figure 12 ] Figure 12 The results of simultaneous measurements of thermogravimetry, differential scanning calorimetry, and mass spectrometry for sample B are shown. The horizontal axis depicts temperature (°C). The left vertical axis depicts the change in weight (%) of the sample in the thermogravimetric analysis. The right vertical axis depicts the heat flow (mW / mg) observed in the differential scanning calorimetry (left) and the peak intensity observed in the mass spectrometry (right).

[0851] [ Figure 13 ] Figure 13 The results of simultaneous thermogravimetric and differential thermal analysis measurements of sample B-2 are shown. The horizontal axis depicts temperature (°C). The right vertical axis depicts the change in weight (%) of the sample during thermogravimetric analysis. The left vertical axis depicts the heat flow observed during differential thermal analysis.

[0852] [ Figure 14 ] Figure 14 The results of simultaneous measurements of thermogravimetry, differential scanning calorimetry, and mass spectrometry for sample B-3 are shown. The horizontal axis depicts temperature (°C). The left vertical axis depicts the change in weight (%) of the sample in the thermogravimetric analysis (this result is a reference value because the sample filtered and dried through a mesh is measured directly). The right vertical axis depicts the heat flow (mW / mg) observed in the differential scanning calorimetry (left) and the peak intensity observed in the mass spectrometry (right).

[0853] [ Figure 15 ] Figure 15 The results of simultaneous measurements of thermogravimetry, differential scanning calorimetry, and mass spectrometry for sample C are shown. The horizontal axis depicts temperature (°C). The left vertical axis depicts the change in weight (%) of the sample in the thermogravimetric analysis. The right vertical axis depicts the heat flow (mW / mg) observed in the differential scanning calorimetry (left) and the peak intensity observed in the mass spectrometry (right).

[0854] [ Figure 16 ] Figure 16 The results of simultaneous measurements of thermogravimetry, differential scanning calorimetry, and mass spectrometry of sample C-1 are shown. The horizontal axis depicts temperature (°C). The left vertical axis depicts the change in weight (%) of the sample in the thermogravimetric analysis (this result is a reference value because the sample filtered and dried through a mesh is measured directly). The right vertical axis depicts the heat flow (mW / mg) observed in the differential scanning calorimetry (left) and the peak intensity observed in the mass spectrometry (right).

[0855] [ Figure 17 ] Figure 17 The results of simultaneous measurements of thermogravimetry, differential scanning calorimetry, and mass spectrometry of sample C-2 are shown. The horizontal axis depicts temperature (°C). The left vertical axis depicts the change in weight (%) of the sample in the thermogravimetric analysis (this result is a reference value because the sample filtered and dried through a mesh is measured directly). The right vertical axis depicts the heat flow (mW / mg) observed in the differential scanning calorimetry (left) and the peak intensity observed in the mass spectrometry (right).

[0856] [ Figure 18 ] Figure 18 The results of simultaneous thermogravimetric and differential thermal analysis measurements of sample D are shown. The horizontal axis depicts temperature (°C). The right vertical axis depicts the change in weight (%) of the sample in the thermogravimetric analysis. The left vertical axis depicts the heat flow (μV) observed in the differential thermal analysis.

[0857] [ Figure 19 ] Figure 19 Shown is the asymmetric unit of the crystal structure of Sample E. The figure is based on an ellipsoid model (probability level: 50%). DETAILED DESCRIPTION

[0858] Hereinafter, definitions of symbols, terms, etc., as used herein, embodiments of the present invention, etc. will be described, and the present invention will be described in detail.

[0859] As used herein, the term "halogen" means fluorine, chlorine, bromine, or iodine.

[0860] As used herein, the term "thio(thiol)" refers to -SH.

[0861] As used herein, the term "amino" means -NRR'. In this context, each of R and R' is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or R and R' together with the nitrogen atom to which they are attached form a group that forms a ring. The amino group is preferably -NH2, mono C1-C6 alkylamino (hereinafter, "C p -C q " means a C1-C6 alkylamino group having p to q carbon atoms, or a 4- to 8-membered cyclic amino group.

[0862] As used herein, the term "alkoxy" refers to an oxy group attached to an "alkyl" as defined herein. The alkoxy group is preferably a C1-C6 alkoxy group, and more preferably a C1-C4 alkoxy group. Specific examples of the alkoxy group include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and 3-methylbutoxy.

[0863] As used herein, the term "alkylthio" refers to a "thio" group attached to an "alkyl" group as defined herein. The alkylthio group is preferably a C1-C6 alkylthio group, and more preferably a C1-C4 alkylthio group. Specific examples of alkylthio groups include methylthio, ethylthio, 1-propylthio, 2-propylthio, n-butylthio, isobutylthio, sec-butylthio, and tert-butylthio.

[0864] As used herein, the term "sulfonyl" refers to -S(=O)2-R. In this context, R is selected from the group consisting of hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. The sulfonyl group is preferably a C1-C6 alkylsulfonyl group.

[0865] As used herein, the term "phosphoryl" refers to -P(=O)RR'. In this context, each of R and R' is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. The phosphoryl group is preferably a mono-C1-C6 alkylphosphoryl group or a di-C1-C6 alkylphosphoryl group.

[0866] As used herein, the term "boryl" means -BRR'. In this context, each of R and R' is independently selected from the group consisting of hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or R and R' together with the boron atom to which they are attached form a ring. Boryl is preferably dihydroxyboryl, mono-C1-C6 alkylboryl, di-C1-C6 alkylboryl or 4- to 8-membered ring boryl. Specific examples of boryl include dihydroxyboryl groups, pinacol boryl groups, neopentanediol boryl groups, catechol boryl groups and 9-boron bicyclo [3.3.1] nonyl -9- base groups.

[0867] As used herein, the term "alkyl" is a monovalent group derived from an aliphatic hydrocarbon by removing any one hydrogen atom and having a hydrocarbon group or a subset of hydrocarbon group structures that do not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds and contain hydrogen and carbon atoms in the main chain. Alkyl groups include not only straight-chain forms but also branched forms. The alkyl group is preferably a C1-C6 alkyl group, and more preferably a C1-C4 alkyl group. Specific examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-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.

[0868] As used herein, the term "alkenyl" is an alkenyl group having at least one double bond (two adjacent sp 2 Alkenyl refers to a monovalent group having 1 to 2 carbon atoms. Depending on the configuration of the double bond and the substituent (if present), the geometry of the double bond can be entgegen (E) or zusammen (Z) as well as cis or trans conformation. Alkenyl includes not only straight-chain forms but also branched forms. Alkenyl is preferably C2-C6 alkenyl, and more preferably C2-C4 alkenyl. Specific examples of alkenyl include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl and hexenyl.

[0869] As used herein, the term "alkynyl" is a monovalent group having at least one triple bond (two adjacent sp carbon atoms). Alkynyl includes not only straight chain forms but also branched forms. Alkynyl is preferably a C2-C6 alkynyl, and more preferably a 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.

[0870] As used herein, the term "cycloalkyl" means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group and includes monocyclic, bicyclic and spirocyclic rings. The cycloalkyl group is preferably a C3-C8 cycloalkyl group, and more preferably a C3-C6 cycloalkyl group. Specific examples of cycloalkyl groups 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.

[0871] As used herein, the term "aryl" means a monovalent aromatic hydrocarbon ring, i.e., an aromatic hydrocarbon ring group. 10 Aryl. Specific examples of the aryl group include phenyl and naphthyl (eg, 1-naphthyl and 2-naphthyl).

[0872] As used herein, the term "heterocyclic group" means a non-aromatic cyclic monovalent group containing carbon atoms and 1 to 5 heteroatoms. The heterocyclic group may have a double bond and / or a triple bond in the ring. The carbon atoms in the ring may be oxidized to form a carbonyl group, and the ring may be a monocycle, a condensed ring or a spirocycle. In the case of a condensed ring, an aromatic ring such as a benzene ring, a pyridine ring or a pyrimidine ring may form a condensed 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 ring of the heterocyclic group is preferably 4 to 10 (4- to 10-membered heterocyclic group), and more preferably 4 to 7 (4- to 7-membered heterocyclic group). Specific examples of heterocyclic groups include azetidinyl, oxazetidinyl, oxiranyl, oxetanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl (oxolan-2-yl, oxolan-3-yl), dihydropyranyl, tetrahydropyranyl (oxolan-4-yl), tetrahydropyridinyl, tetrahydropyrimidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, oxopyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isoxazolidinyl, Thiazolidinyl, 1,2-thiazinane, thiadiazolidinyl, oxazolidinone, benzodioxirane, benzoxazolyl, dioxolanyl, dioxirane, tetrahydropyrrolo[1,2-c]imidazole, thiocyclobutane, 3,6-diazabicyclo[3.1.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 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, azolanyl, dicyclohexanyl, 5,9-dioxaspiro[3.5]nonyl, 1,1-dioxo-1,4-thiazolin-4-yl, carbonylazetidinyl, acetylpiperidinyl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 2-oxa-7-azaspiro[3.4]octan-7-yl, 3-oxa-6-azabicyclo[3.1. 1]hept-6-yl, 6-oxa-3-azabicyclo[3.1.1]hept-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-(oxiran-4-yl)piperidin-4-yl, 4-pyrrolidin-1-ylpiperidin-1-yl, and 4-morpholin-4-ylpiperidin-1-yl.

[0873] As used herein, the term "heteroaryl" refers to an aromatic cyclic monovalent group containing carbon atoms and 1 to 5 heteroatoms, i.e., an aromatic heterocyclic group. The ring may be a single ring or a fused 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 groups include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, and imidazopyridyl, pyrazolopyridyl, triazolopyridyl, pyrrolopyrazinyl, and fluoropyridyl.

[0874] As used herein, the term "alkylsulfonyl" refers to a "sulfonyl" group attached to an "alkyl" or "cycloalkyl" group as defined herein. The alkylsulfonyl group is preferably a C1-C6 alkylsulfonyl group or a C3-C8 cycloalkylsulfonyl group, and more preferably a C1-C4 alkylsulfonyl group or a C3-C6 cycloalkylsulfonyl group. Specific examples of the alkylsulfonyl group include methylsulfonyl, ethylsulfonyl, 1-propylsulfonyl, 2-propylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl.

[0875] As used herein, the term "acylamino" means a group wherein R is hydrogen and R' is "acyl" as defined herein in the context of "amino" as defined herein. The acylamino group is preferably a C1-C6 acylamino group, and more preferably a C1-C4 acylamino group. Specific examples of the acylamino group include acetylamino.

[0876] As used herein, the term "monoalkylamino" means a group wherein R is hydrogen and R' is an "alkyl" group as defined herein, in the context of "amino" as defined herein. The monoalkylamino group is preferably a mono-C1-C6 alkylamino group, and more preferably a mono-C1-C4 alkylamino group. Specific examples of the monoalkylamino group include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, and tert-butylamino.

[0877] As used herein, the term "alkylsulfonylamino" means a group wherein R is hydrogen and R' is an "alkylsulfonyl" group as defined herein in the context of "amino" as defined herein. The alkylsulfonylamino group is preferably a C1-C6 alkylsulfonylamino group or a C3-C8 cycloalkylsulfonylamino group, and more preferably a C1-C4 alkylsulfonylamino group or a C3-C6 cycloalkylsulfonylamino group. Specific examples of the alkylsulfonylamino group include methylsulfonylamino, ethylsulfonylamino, and cyclopropylsulfonylamino groups.

[0878] As used herein, the term "haloalkoxy" means a group in which one or more hydrogens in an "alkoxy" as defined herein are replaced by a "halogen". The haloalkoxy group is preferably a halo C1-C6 alkoxy group, and more preferably a halo C1-C4 alkoxy group. Specific examples of haloalkoxy groups 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-trifluoropropane-2-yl]oxy, [(2R)-1,1,1-trifluoropropane-2-yl]oxy and 3,3,3-trifluoro-2,2-dimethylpropoxy.

[0879] As used herein, the term "hydroxyalkoxy" refers to a group in which one or more hydrogen atoms in an "alkoxy" group, as defined herein, are replaced by a hydroxyl group. The hydroxyalkoxy group is preferably a hydroxyC1-C6 alkoxy group, and more preferably a hydroxyC1-C4 alkoxy group. Specific examples of the hydroxyalkoxy group include 2-hydroxy-2-methylpropoxy, 3-hydroxy-3-methylbutoxy, and 4-hydroxybutoxy.

[0880] As used herein, the term "alkoxyalkoxy" refers to a group in which an "alkoxy" group is attached to an "alkoxy" group as defined herein. The alkoxyalkoxy group is preferably a C1-C6 alkoxy C1-C6 alkoxy group, and more preferably a C1-C4 alkoxy C1-C4 alkoxy group. Specific examples of the alkoxyalkoxy group include 2-methoxyethoxy, (2S)-2-methoxypropoxy, and (2R)-2-methoxypropoxy.

[0881] As used herein, the term "cycloalkylalkoxy" refers to an oxy group attached to a "cycloalkylalkyl" as defined herein. The cycloalkylalkoxy group is preferably a C3-C8 cycloalkylC1-C6 alkoxy group, and more preferably a C3-C6 cycloalkylC1-C4 alkoxy group. Specific examples of the cycloalkylalkoxy group include cyclopropylmethoxy, cyclobutanemethoxy, cyclopentanemethoxy, cyclohexanemethoxy, and 1-bicyclo[1.1.1]pentanemethoxy.

[0882] As used herein, the term "heterocyclylalkoxy" means an oxy group attached to a "heterocyclyl" as defined herein via an "alkyl" group. The heterocyclylalkoxy group is preferably a 4- to 10-membered heterocyclyl C1-C6 alkoxy group, and more preferably a 4- to 7-membered heterocyclyl C1-C4 alkoxy group. Specific examples of heterocyclylalkoxy groups include (1,1-dioxathiolane-4-yl)oxy, oxolane-2-ylmethoxy, oxolane-3-ylmethoxy, oxirane-4-ylmethoxy, 1,4-dioxirane-2-ylmethoxy, (1-methylpiperidin-4-yl)methoxy, 3-morpholin-4-ylpropoxy, and (oxetane-3-yl)methoxy.

[0883] As used herein, the term "cycloalkoxy" means an oxy group attached to a "cycloalkyl" as defined herein. The cycloalkoxy group is preferably a C3-C8 cycloalkoxy group, and more preferably a C3-C6 cycloalkoxy group. Specific examples of the cycloalkoxy group include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0884] As used herein, the term "heterocyclyloxy" refers to an oxy group attached to a "heterocyclyl" as defined herein. The number of atoms constituting the heterocyclyl ring is preferably 4 to 10 (4-membered to 10-membered heterocyclyloxy), and more preferably 4 to 7 (4-membered to 7-membered heterocyclyloxy). Specific examples of the heterocyclic oxy group include azetidinyloxy, oxiranyloxy, oxetanyloxy, azetidinyloxy, dihydrofuranyloxy, tetrahydrofuranyloxy ([(3R)-oxolan-3-yl]oxy, [(3S)-oxolan-3-yl]oxy), dihydropyranyloxy, tetrahydropyranyloxy (oxiran-4-yloxy), [(3S)-oxiran-3-yl]oxy, [(3R)-oxiran-3-yl]oxy), tetrahydropyridinyloxy, tetrahydropyrimidinyloxy, morpholinyloxy, thiomorpholinyloxy, pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, pyrazolidinyloxy, imidazolinyloxy , imidazolidinyloxy, oxazolidinyloxy, isoxazolidinyloxy, thiazolidinyloxy, isothiazolidinyloxy, 1,2-thiazolidinyloxy, thiadiazolidinyloxy, oxazolidinonyloxy, benzodieoxiranyloxy, benzoxazolyloxy, dioxolanyloxy, dioxiranyloxy, tetrahydropyrrolo[1,2-c]imidazolyloxy, thiocycloetanyloxy, 3,6-diazabicyclo[3.1.1]heptanyloxy, 2,5-diazabicyclo[2.2.1]heptanyloxy, 3-oxa-8-azabicyclo[3.2.1]octanyloxy, sultamyloxy, 2-oxaspiro[3.3]heptyloxy, and tetrahydrothiopyranyloxy.

[0885] As used herein, the term "acyl (alkanoyl)" means a group in which a carbonyl group is attached to a hydrogen or "alkyl" group as defined herein. The acyl group is preferably a C1-C6 acyl group, and more preferably a C2-C4 acyl group. Specific examples of acyl groups include formyl, acetyl, propionyl, and butyryl.

[0886] As used herein, the term "aminocarbonyl" means a carbonyl group attached to an "amino" as defined herein. Preferred examples of aminocarbonyl include -CONH2, mono-C1-C6 alkylaminocarbonyl, mono-C3-C8 cycloalkylaminocarbonyl, di-C1-C6 alkylaminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl. Specific examples of aminocarbonyl include -CONH2, dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxythiomorpholinyl-4-ylcarbonyl, 3-oxa-8-azabicyclo[3.2.1]octane-8-ylcarbonyl, and N-cyclopropylaminocarbonyl.

[0887] As used herein, the term "alkylphosphoryl" means a "phosphoryl group" attached to an "alkyl group" as defined herein. The alkylphosphoryl group is preferably a mono-C1-C6 alkylphosphoryl group, a di-C1-C6 alkylphosphoryl group, and more preferably a mono-C1-C4 alkylphosphoryl group or a di-C1-C4 alkylphosphoryl group. Specific examples of the alkylphosphoryl group include a methylphosphoryl group, an ethylphosphoryl group, a dimethylphosphoryl group, and a diethylphosphoryl group.

[0888] As used herein, the term "haloalkyl" means a group in which one or more hydrogens in an "alkyl" as defined herein are replaced by a "halogen". The haloalkyl is preferably a halo-C1-C6 alkyl, and more preferably a 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, and 5,5-difluoropentyl.

[0889] As used herein, the term "hydroxyalkyl" means a group in which one or more hydrogen atoms in an "alkyl" group as defined herein are replaced by a hydroxyl group. The hydroxyalkyl group is preferably a hydroxyC1-C6 alkyl group, and more preferably a hydroxyC1-C4 alkyl group. Specific examples of the hydroxyalkyl group include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, and 5-hydroxypentyl.

[0890] As used herein, the term "aminocarbonylalkyl" means a group in which one or more hydrogen atoms in an "alkyl" group as defined herein are replaced by an "aminocarbonyl" group as defined herein. The aminocarbonylalkyl group is preferably an aminocarbonyl C1-C6alkyl group, a mono-C1-C6alkylaminocarbonyl C1-C6alkyl group, or a di-C1-C6alkylaminocarbonyl C1-C6alkyl group, and more preferably an aminocarbonyl C1-C4alkyl group, a mono-C1-C4alkylaminocarbonyl C1-C4alkyl group, or a di-C1-C4alkylaminocarbonyl C1-C4alkyl group. Specific examples of aminocarbonylalkyl groups include methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, tert-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.

[0891] As used herein, the term "cycloalkylalkyl" means a group in which one or more hydrogen atoms in the above-defined "alkyl" group are replaced by a "cycloalkyl" group as defined above. The cycloalkylalkyl group is preferably a C3-C8 cycloalkylC1-C6 alkyl group, and more preferably a C3-C6 cycloalkylC1-C4 alkyl group. Specific examples of the cycloalkylalkyl group include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0892] As used herein, the term "hydroxyalkenyl" means a group in which one or more hydrogen atoms in an "alkenyl" group as defined herein are replaced by a hydroxyl group. The hydroxyalkenyl group is preferably a hydroxy C2-C6 alkenyl group, and more preferably a hydroxy C2-C4 alkenyl group. Specific examples of hydroxyalkenyl groups include (E)-4-hydroxybut-1-enyl.

[0893] As used herein, the term "hydroxyalkynyl" means a group in which one or more hydrogen atoms in an "alkynyl" group as defined herein are replaced by a hydroxyl group. The hydroxyalkynyl group is preferably a hydroxyC2-C6 alkynyl group, and more preferably a hydroxyC2-C4 alkynyl group. Specific examples of the hydroxyalkynyl group include 3-hydroxy-3-methylbut-1-ynyl.

[0894] As used herein, the term "alicyclic ring" means a non-aromatic hydrocarbon ring. The alicyclic ring may have an unsaturated bond in the ring. The carbon atoms constituting the ring may form a carbonyl group by oxidation. The alicyclic ring may be a monocyclic ring (referred to herein as a monocyclic alicyclic ring), or may form a condensed ring with a saturated alicyclic ring (such as a cyclopentane ring and a cyclohexane ring) or an aromatic hydrocarbon ring (such as a benzene ring and a naphthalene ring). The alicyclic ring is preferably a 3- to 10-membered alicyclic ring. 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.

[0895] As used herein, the term "aromatic hydrocarbon ring" means a hydrocarbon ring consisting of a single ring or a condensed ring exhibiting aromaticity. The aromatic hydrocarbon ring is preferably a 6- to 10-membered aromatic hydrocarbon ring. Specific examples of the aromatic hydrocarbon ring include a benzene ring and a naphthalene ring.

[0896] As used herein, the term "heterocycle" means a non-aromatic heterocycle preferably containing 1 to 5, more preferably 1 to 3 heteroatoms in the atoms constituting the ring. The heterocycle may have a double bond and / or a triple bond in the ring, and the carbon atoms in the ring may form a carbonyl group by oxidation. The heterocycle may be a monocycle (referred to herein as a monocyclic heterocycle), or may be formed into a condensed ring or spirocycle 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 is preferably 3 to 12 (3- to 12-membered heterocycle), and more preferably 4 to 10 (4- to 10-membered heterocycle). Specific examples of the heterocyclic ring 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 thiadiazole lysine ring, an oxazolidinone ring, a dioxolane ring, a dioxane ring a hexane ring, a thietane ring, an octahydroindole ring, a 6,7-dihydro-pyrrolo[1,2-a]imidazole ring, an azacyclooctane ring, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine ring, an azepane ring, a dioxepane ring, a 5,9-dioxaspiro[3,5]nonane ring, or a ring in which one or more single bonds in any of these saturated heterocycles are replaced by a double bond or a triple bond.

[0897] As used herein, the term "aromatic heterocycle" refers to a cyclic compound consisting of a single ring or condensed ring containing one or more heteroatoms and exhibiting aromaticity. As used herein, a cyclic compound consisting of a single ring exhibiting aromaticity is referred to as a monocyclic aromatic heterocycle. The aromatic heterocycle is preferably a 5- to 10-membered aromatic heterocycle. Specific examples of the aromatic heterocycle include a furan ring, a thiophene ring, a pyrrole ring, a 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 indoline ring, an imidazopyridine ring, a pyrazolopyridine ring, an imidazopyridine ring, a triazolopyridine ring, a pyrrolopyridine ring and a furopyridine ring.

[0898] The term "optionally substituted" means that the group is unsubstituted or substituted with one or more substituents, and when the group is substituted with multiple substituents, these substituents may be the same or different from each other. In addition, a substituent may be added to each substituent. Such substituents are not limited and may be one or two or more substituents each independently and freely selected from any substituent comprising a halogen atom, an oxygen atom, a sulfur atom, a nitrogen atom, a boron atom, a silicon atom or a phosphorus atom. Examples of substituents include deuterium, halogen, cyano, nitro, hydroxyl, sulfenyl, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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.

[0899] As used herein, the term "one / kind or more / species" means a number of 1 or 2 or more. When the term "one or more" is used in the context of substituents of a particular group, the term means a number from 1 to the maximum number of substituents that the group can accept.

[0900] As used herein, the term "to" indicates that a numerical range includes values ​​at both ends thereof. For example, "A to B" refers to a numerical range of A or above and B or below.

[0901] As used herein, the term "about" when used in combination with a numerical value means a range of values ​​between +10% and -10% of the numerical value.

[0902] As used herein, the meaning of the term "and / or" includes any combination in which "and" and "or" are appropriately combined. Specifically, for example, the term "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.

[0903] One embodiment of the present invention is a compound represented by formula (1) (hereinafter also referred to as "compound (1)") or a salt or solvate thereof.

[0904] In compound (1), R4 is selected from the group consisting of 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 ).

[0905] R4 is preferably an optionally substituted C6-C 10 Aryl (R 4A ) or an optionally substituted 5- to 10-membered heteroaryl (R 4HA ).

[0906] When R4 is an optionally substituted C6-C 10 Aryl (R 4A ), R 4A Preferred is phenyl.

[0907] As C6-C 10 Aryl (R 4A ) in a preferred aspect (i), R 4A unsubstituted or substituted with one or more R a Substitution; one or more R a Each is independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 and the hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

[0908] As C6-C 10 Aryl (R 4A) in a preferred aspect (ii), R 4A unsubstituted or substituted with one or more R a substituted, and one or more R a Each of the groups is independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and C1-C6 alkylsulfonylamino.

[0909] As C6-C 10 Aryl (R 4A ) in a preferred aspect (iii), R 4A unsubstituted or substituted with one or more R a substituted, and one or more R a Each of the groups is independently selected from the group consisting of halogen, hydroxy, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and C1-C6 alkylsulfonylamino.

[0910] When R4 is an optionally substituted 5- to 10-membered heteroaryl (R 4HA ), R 4HAPreferably selected from the group consisting of furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indol ... indolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, pyrrolopyrazinyl and fluoropyridinyl; more preferably selected from the group consisting of furyl, thienyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl benzothiophene, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, pyrrolopyridinyl, oxazolyl and fluoropyridyl; further preferably selected from the group consisting of pyridyl, pyrimidinyl, benzimidazolyl, indolyl, indazolyl and pyrazolopyridinyl; further more preferably selected from the group consisting of pyrimidinyl, benzimidazolyl, indolyl, indazolyl and pyrazolopyridinyl; particularly preferably 1H-indazol-6-yl or 1H-indazol-4-yl; and most preferably 1H-indazol-4-yl.

[0911] As a 5- to 10-membered heteroaryl group (R 4HA ) in a preferred aspect (i), R 4HA unsubstituted or substituted with one or more R a Substitution; one or more R a Each is independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 and the hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

[0912] As a 5- to 10-membered heteroaryl group (R4HA ) in a preferred aspect (ii), R 4HA unsubstituted or substituted with one or more R a substituted, and one or more R a Each of the groups is independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and C1-C6 alkylsulfonylamino.

[0913] As a 5- to 10-membered heteroaryl group (R 4HA ) in a preferred aspect (iii), R 4HA unsubstituted or substituted with one or more R a substituted, and one or more R a Each of the is independently selected from the group consisting of halogen, cyano, amino, C1-C6 alkyl and halogenated C1-C6 alkyl.

[0914] As a 5- to 10-membered heteroaryl group (R 4HA ) a preferred aspect (iv), R 4HA It is 1H-indazol-4-yl or 1H-indazol-4-yl substituted by one or more halogens.

[0915] As a 5- to 10-membered heteroaryl group (R 4HA ) a preferred aspect (v), R 4HA is 1H-indazol-4-yl substituted by one or more halogens.

[0916] As a 5- to 10-membered heteroaryl group (R 4HA ) a preferred aspect (vi), R 4HA is 1H-indazol-4-yl, wherein at least one of position 5, position 6, and position 7 is substituted with halogen.

[0917] As a 5- to 10-membered heteroaryl group (R 4HA ) a preferred aspect (vii), R 4HA is 1H-indazol-4-yl, wherein at least one of position 5, position 6, and position 7 is substituted with halogen, and the halogen is fluorine or chlorine.

[0918] As a 5- to 10-membered heteroaryl group (R 4HA ) a preferred aspect (viii), R 4HA is 1H-indazol-4-yl, wherein at least one or both of position 5, position 6 and position 7 are substituted with halogen, 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.

[0919] In compound (1), R5 and R6 together with the atoms to which they are attached form an optionally substituted ring D; ring D is selected from the group consisting of a 3- to 10-membered monocyclic alicyclic ring, a benzene ring, a 3- to 12-membered monocyclic heterocycle, and a 5- to 6-membered monocyclic aromatic heterocycle (D HA ); and any two adjacent substituents on Ring D together with the atoms to which they are attached can form an optionally substituted Ring E.

[0920] Ring D is preferably a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle (D HA ).

[0921] When ring D is a 5- to 6-membered monocyclic aromatic heterocycle (D HA ) when D HA It 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 pyrazine ring and a triazine ring, more preferably selected from the group consisting of a pyridine ring, a pyrimidine ring, a pyridine ring and a pyrazine ring, and further preferably a pyridine ring.

[0922] As a preferred aspect (i) of ring D, ring D is unsubstituted or substituted with one or more R D Substitution; one or more R a Each is independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 and the hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

[0923] As a preferred aspect (ii) of ring D, ring D is unsubstituted or substituted with one or more R D Substitution; one or more R DEach of the following is independently selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkylthio, C1-C6 acylamino, mono C1-C6 alkylamino, C1-C6 alkylsulfonylamino, C3-C8 cycloalkylsulfonylamino, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C3-C8 cycloalkyl C1-C6 alkoxy, 4-membered to 10-membered heterocyclyl C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4- to 10-membered heterocyclic radicals, C1-C6 acyl radicals, mono-C3-C8 cycloalkylaminocarbonyl radicals, 4- to 8-membered cycloaminocarbonyl radicals, di-C1-C6 alkylphosphoryl radicals, C1-C6 alkyl radicals, halogenated C1-C6 alkyl radicals, hydroxy C1-C6 alkyl radicals, di-C1-C6 alkylaminocarbonyl C1-C6 alkyl radicals, C3-C8 cycloalkyl C1-C6 alkyl radicals, C2-C6 alkenyl radicals, hydroxy C2-C6 alkenyl radicals, C2-C6 alkynyl radicals, hydroxy C2-C6 alkynyl radicals, C3-C8 cycloalkyl radicals, 4- to 10-membered heterocyclic radicals, C6-C 10 aryl and 5- to 10-membered heteroaryl, and

[0924] The C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C3-C8 cycloalkyl C1-C6 alkoxy, 4-membered to 10-membered heterocyclic C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4-membered to 10-membered heterocyclic, C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkyl, 4-membered to 10-membered heterocyclic, C6-C 10 The aryl and 5- to 10-membered heteroaryl groups are independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkoxy, oxo, haloC1-C6 alkyl, and C3-C8 cycloalkyl.

[0925] As a preferred aspect of ring D (iii), ring D is unsubstituted or substituted with one or more R D substituted, and one or more R D Each of the following is independently selected from the group consisting of halogen, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, C3-C8 cycloalkyloxy, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl and C3-C8 cycloalkyl.

[0926] As a preferred aspect of ring D (iv), ring D is unsubstituted or substituted with one or more R D substituted, and one or more R D Each of the groups is independently selected from the group consisting of C1-C6 alkoxy, C1-C6 alkyl, and C3-C8 cycloalkyl.

[0927] As a preferred aspect of ring D (v), ring D is unsubstituted or substituted with one or more R D Substituted, one or more R D Each of which is independently selected from the group consisting of methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-but-2-yl]oxy, [(2R)-but-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, but-2-yl, 3-methylbutyl, pent-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl, and spiro[2.3]hex-5-yl.

[0928] As one aspect of compound (1), any two adjacent substituents on ring D together with the atoms to which they are attached form an optionally substituted ring E. In this case, ring E is preferably selected from the group consisting of a 3- to 10-membered monocyclic alicyclic ring, a benzene ring, a 3- to 12-membered monocyclic heterocycle, and a 5- to 6-membered monocyclic aromatic heterocycle (E HA ), and more preferably a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle (E HA ).

[0929] When ring E is a 5- to 6-membered monocyclic aromatic heterocycle (E HA ) when E HA It 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, further 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 pyridazine ring, and most preferably a pyridine ring.

[0930] As one aspect of the present invention, in compound (1), ring D and ring E form a bicyclic ring represented by the following formula:

[0931]

[0932] wherein * represents the carbon to which R5 is attached in the formula (1), and ** represents the carbon to which R6 is attached in the formula (1); in the formula, the ring D is referred to as the "D ring" and the ring E is referred to as the "E ring".

[0933] As a preferred aspect of the present invention, in compound (1), ring D and ring E form a bicyclic ring represented by the following formula:

[0934] [Equation 12]

[0935]

[0936] wherein * represents the carbon to which R5 is attached in the formula (1), and ** represents the carbon to which R6 is attached in the formula (1); in the formula, the ring D is referred to as the "D ring" and the ring E is referred to as the "E ring".

[0937] As a preferred aspect (i) of ring E in compound (1), ring E is unsubstituted or substituted with one or more R E Substitution; one or more R E Each is independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 and the hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

[0938] As a preferred aspect (ii) of ring E in compound (1), ring E is unsubstituted or substituted with one or more R E substituted, and one or more R E Each of the is independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, and boron.

[0939] As a preferred aspect (iii) of ring E in compound (1), ring E is unsubstituted or substituted with one or more R E substituted, and one or more R E Each of the is independently selected from the group consisting of fluoro, chloro, methoxy, dihydroxyboryl, methyl, and tert-butyl.

[0940] Another embodiment of the present invention is a compound represented by the general formula (2) (hereinafter also referred to as "compound (2)") or a salt or solvate thereof.

[0941] R4 in compound (2) has the same meaning as R4 in the above-mentioned compound (1).

[0942] In compound (2), X5 is CR x5 Or N. X5 is preferably CRx5 , and more preferably C H .

[0943] In compound (2), X6 is CR x6 Or N. X6 is preferably CR x6 .

[0944] In compound (2), X 10a CR x10a or N. X 10a Preferably CR x10a .

[0945] In compound (2), R x5 、R x6 、R 6a and R x10a Each of the following is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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 hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic, C6-C 10 Aryl and 5- to 10-membered heteroaryl are optionally substituted; and R x5 and R x6 、R x6 and R 6a , or R 6a and R x10a Together with the atoms to which they are attached, they can form an optionally substituted ring E.

[0946] As R x6 In a preferred aspect (i), R x6Selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkylthio, C1-C6 acylamino, mono C1-C6 alkylamino, C1-C6 alkylsulfonylamino, C3-C8 cycloalkylsulfonylamino, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C3-C8 cycloalkyloxy C1-C6 alkoxy, 4- to 10-membered heterocyclyl C1-C6 alkoxy, C3-C8 cycloalkyl, 4- to 10-membered Heterocyclyl, C1-C6 acyl, mono-C3-C8 cycloalkylaminocarbonyl, 4- to 8-membered cycloaminocarbonyl, di-C1-C6 alkylphosphoryl, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, di-C1-C6 alkylaminocarbonyl C1-C6 alkyl, C3-C8 cycloalkoxy C1-C6 alkyl, C2-C6 alkenyl, hydroxy C2-C6 alkenyl, C2-C6 alkynyl, hydroxy C2-C6 alkynyl, C3-C8 cycloalkoxy, 4- to 10-membered heterocyclyl, C6-C 10 Aryl and 5- to 10-membered heteroaryl; the C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C3-C8 cycloalkyl C1-C6 alkoxy, 4- to 10-membered heterocyclyl C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4- to 10-membered heterocyclyl, C1-C6 alkyl, C3-C8 cycloalkyloxy C1-C6 alkyl, C3-C8 cycloalkyloxy, 4- to 10-membered heterocyclyl, C6-C 10 The aryl and 5- to 10-membered heteroaryl groups are further independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkoxy, oxo, haloC1-C6 alkyl, and C3-C8 cycloalkyl.

[0947] As R x6 In a preferred aspect (ii), R x6 Selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxyC3-C8 cycloalkoxy, C3-C8 cycloalkyl, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl and C3-C8 cycloalkyl.

[0948] As R x6 In a preferred aspect (iii), R x6 Selected from the group consisting of hydrogen, C1-C6 alkoxy, C1-C6 alkyl and C3-C8 cycloalkyl.

[0949] As R x6 In a preferred aspect (iv), R x6Selected from the group consisting of methoxy, ethoxy, propoxy, propan-2-yloxy, 3-methylbutoxy, [(2S)-but-2-yl]oxy, [(2R)-but-2-yl]oxy, methyl, ethyl, propyl, propan-2-yl, 2-methylpropyl, but-2-yl, 3-methylbutyl, pent-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, 1-methylcyclopropyl, 3,3-dimethylcyclobutyl and spiro[2.3]hex-5-yl.

[0950] As R x10a In a preferred aspect (i), R x10a Selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C3-C8 cycloalkyl.

[0951] As R x10a In a preferred aspect (ii), R x10a Selected from the group consisting of hydrogen, chlorine, bromine, cyano, methyl, ethyl, propyl, propan-2-yl, vinyl, ethynyl and cyclopropyl.

[0952] As R 6a In a preferred aspect (i), R 6a Selected from the group consisting of hydrogen, halogen, cyano, halogenated C1-C6 alkoxy and C1-C6 alkyl.

[0953] As R 6a In a preferred aspect (ii), R 6a Selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, difluoromethoxy, methyl and ethyl.

[0954] As one aspect of compound (2), R 6a and R x10a Together with the atoms to which they are attached, they form an optionally substituted ring E. In this case, ring E is preferably selected from the group consisting of a 3- to 10-membered monocyclic alicyclic ring, a benzene ring, a 3- to 12-membered monocyclic heterocycle, and a 5- to 6-membered monocyclic aromatic heterocycle (E HA ), and more preferably a benzene ring or a 5- to 6-membered monocyclic aromatic heterocycle (E HA ).

[0955] When ring E is a 5- to 6-membered monocyclic aromatic heterocycle (E HA ) when E HA It 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, further preferably a pyridine ring or a pyrazine ring, and most preferably a pyridine ring.

[0956] As a preferred aspect of the present invention, in compound (2), ring E is represented by the following formula:

[0957] [Equation 13]

[0958]

[0959] Where * represents R 6a In the formula (2), the carbon to which the carbon is attached, and ** represents R x10a The carbon to which it is attached in the formula (2); the ring E in the formula is referred to as the "E ring".

[0960] As a preferred aspect of the present invention, in compound (2), ring E is represented by the following formula:

[0961] [Equation 14]

[0962]

[0963] Where * represents R 6a In the formula (2), the carbon to which the carbon is attached, and ** represents R x10a The carbon to which it is attached in the formula (2); the ring E in the formula is referred to as the "E ring".

[0964] As a preferred aspect (i) of the E ring in compound (2), the E ring is unsubstituted or substituted with one or more R E Substitution; one or more R E Each is independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 and the hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

[0965] As a preferred aspect (ii) of ring E in compound (2), ring E is unsubstituted or substituted with one or more R E substituted, and one or more R E Each of the is independently selected from the group consisting of halogen, C1-C6 alkoxy, boronyl, and C1-C6 alkyl.

[0966] As a preferred aspect (iii) of ring E in compound (2), ring E is unsubstituted or substituted with one or more R E substituted, and one or more R E Each of the is independently selected from the group consisting of fluoro, chloro, methoxy, dihydroxyboryl, methyl, and tert-butyl.

[0967] Another embodiment of the present invention is a compound represented by the general formula (3) (hereinafter also referred to as "compound (3)") or a salt or solvate thereof.

[0968] R4 in the compound (3) has the same meaning as R4 in the above-mentioned compound (1), and X5 and X6 in the compound (3) have the same meaning as X5 and X6 in the above-mentioned compound (2).

[0969] In compound (3), X7 is CR x7 or N.

[0970] In compound (3), X8 is CR x8 or N.

[0971] In compound (3), X9 is CR x9 or N.

[0972] In compound (3), X 10 CR x10 or N.

[0973] In compound (3), X7, X8, X9 and X 10 The combination is preferably X7 is N, X8 is CR x8 、X9 is CR x9 And X 10 CR x10 Combination of X7 and CR x7 , X8 is N, X9 is CR x9 And X 10 CR x10 Combination of X7 and CR x7 、X8 is CR x8 、X9 is N and X 10 CR x10 Combination of X7 and CR x7 、X8 is CR x8 、X9 is CR x9 And X 10 Combination of N, X7 is N, X8 is CR x8 、X9 is CR x9 And X 10 is the combination of N, X7 is CR x7 , X8 is N, X9 is CRx9 And X 10 N combination; or X7 is N, X8 is N, X9 is CR x9 And X 10 CR x10 combination.

[0974] In compound (3), X7, X8, X9 and X 10 The combination is more preferably X7 is N, X8 is CR x8 、X9 is CR x9 And X 10 CR x10 Combination of X7 and CR x7 , X8 is N, X9 is CR x9 And X 10 CR x10 Combination of X7 and CR x7 、X8 is CR x8 、X9 is N and X 10 CR x10 Combination of, or X7 for CR x7 、X8 is CR x8 、X9 is CR x9 And X 10 A combination of N.

[0975] In compound (3), R x7 、R x8 、R x9 and R x10 Each of the following is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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, and the hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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 groups are optionally substituted.

[0976] R x7 Preferably it is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy and C1-C6 alkyl.

[0977] R x8 Preferably it is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy and C1-C6 alkyl.

[0978] R x9 Preferably it is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl and boron.

[0979] R x10 Preferably it is selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy and C1-C6 alkyl.

[0980] Another embodiment of the present invention is a compound as described in Table 1-1 below, or a salt or solvate thereof.

[0981] [Table 1-1]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991] 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.

[0992] The compounds described herein may be salts thereof, preferably pharmaceutically acceptable salts thereof. The compounds described herein or their salts may be solvates thereof, preferably pharmaceutically acceptable solvates thereof. Examples of salts of compounds include: 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 and potassium salts; alkaline earth metal salts, such as magnesium and calcium salts; and ammonium salts, such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts and tetraalkylammonium salts. These salts are produced, for example, by contacting the compound with an acid or a base. A solvate as used herein is a solvate in which the compound and a solvent together form a molecular aggregate, and is not particularly limited as long as it is a solvate formed by a solvent acceptable for ingestion when administered with a drug. The example of solvate includes hydrate, alcohol solvate (such as ethanol solvate, methanol solvate, 1-propanol solvate and 2-propanol solvate), not only includes the solvate formed with a single solvent such as dimethyl sulfoxide, but also includes the solvate formed with multiple solvents for each compound molecule, or the solvate formed with multiple types of solvents for each compound molecule. When the solvent is water, the solvate is referred to as a hydrate. The solvate of the compounds of the present invention is preferably a hydrate. The specific example of this hydrate includes monohydrate to decahydrate, preferably monohydrate to pentahydrate, further preferably monohydrate to trihydrate.

[0993] When obtaining the compound according to the present invention in free form, the compound can be conventionally converted into the state of the salt, its hydrate or its solvate that can be formed by the compound. Its examples include hydrates and ethanolates of the compound represented by formula (1) or its salt. Its specific examples include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate or monoethanolate of the compound represented by formula (1); hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate or monoethanolate of the sodium salt of the compound represented by formula (1); or hydrate or ethanolate of the hydrochloride of the compound represented by formula (1). Hydrates or solvates can be produced in crystalline form or non-crystalline form. In the case of crystalline form, hydrates or solvates can have crystalline polymorphs. Regarding the method for producing a hydrate or solvate, the hydrate or solvate can be obtained by a conventional method, for example, by adding a solvent (such as ethanol and / or water) to the compound represented by formula (1), followed by stirring, cooling, concentrating and / or drying.

[0994] When the compound according to the present invention is obtained as a salt, hydrate or solvate of the compound, the compound can be conventionally converted into its free form.

[0995] The compounds described herein may contain isotopic atoms in an unnatural ratio in one or more atoms constituting the compound. The present invention also includes compounds in which any atom in the compound is replaced by another isotopic atom having the same atomic number (number of protons) and a different mass number (the sum of the number of protons and neutrons), whereby the abundance ratio of the isotopes is different from that in nature, i.e., compounds labeled with isotopic atoms. Examples of isotopic elements contained in the compounds herein include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine atoms, and they include 2 H. 3 H; 13 C. 14 C; 15 N; 17 O. 18 O; 32 P; 35 S; 18 F; 36 Cl; etc. Compounds labeled with isotope atoms can be used as therapeutic agents or preventive agents, research reagents (e.g., assay reagents) and diagnostic agents (e.g., in vivo imaging diagnostic agents). For compounds as used herein, all compounds containing radioactive or non-radioactive isotope elements in any proportion are encompassed within the scope of the present invention. Compounds labeled with isotope atoms can be produced in a manner similar to the method of producing unlabeled compounds by using reagents or solvents containing corresponding isotope atoms.

[0996] The compounds described herein, their salts, or solvates thereof include all stereoisomers (e.g., enantiomers and diastereomers (including cis and trans geometric isomers)), racemates, and other mixtures of isomers. For example, the compounds of the present invention may have one or more points of asymmetry, and the present invention includes racemic mixtures, diastereomeric mixtures, and enantiomers of such compounds. In addition, for example, the compounds of the present invention may have axial asymmetry, and the present invention includes each stereoisomer of such compounds and mixtures thereof.

[0997] <General Generation Method>

[0998] Examples of methods for producing compounds represented by formula (1) to formula (3) or their salts or solvates thereof are described by the following scheme groups. The compounds of the present invention can be synthesized by various methods. The following production methods are illustrative only, and the present invention is not limited to the chemical reactions and conditions shown. In the schemes of the production methods below, some substituents have been deleted for the sake of clarity, but this is not intended to limit the disclosure of the schemes. Typical compounds of the present invention can be synthesized by using appropriate intermediates, known compounds and reagents. Unless otherwise indicated, the variable groups represented by R1, R2, etc. in the formulas below in the general synthesis methods have the same meaning as the variable groups represented by R1, R2, etc. and the variables represented by n, etc. in the compounds represented by the general formula defined herein. When the starting material or expected product in a step is not expected to be chemically transformed under the reaction conditions of the step, the expected product of the step can be obtained, for example, by protecting and deprotecting functional groups. Here, for the selection of protecting groups and the selection of protection and deprotection methods, for example, reference can be made to TW Greene, PGM Wuts, Protective Groups in Organic Synthesis (5th edition, John Wiley & Sons 2014) (Non-patent Document 6). Some protection and deprotection of functional groups are also described in the schemes below.

[0999] The compound obtained in each step can be isolated by general techniques and, if necessary, purified by crystallization or chromatography.

[1000] Listed below are examples and meanings of abbreviations used herein.

[1001] Boc: tert-Butoxycarbonyl

[1002] DCM: dichloromethane

[1003] DMA: N,N-dimethylacetamide

[1004] DMF: N,N-dimethylformamide

[1005] DMSO: dimethyl sulfoxide

[1006] EtOH: ethanol

[1007] MeOH: methanol

[1008] NMP: N-methyl-2-pyrrolidone

[1009] TFA: trifluoroacetoacetic acid

[1010] THF: Tetrahydrofuran

[1011] TBME: tert-butyl methyl ether

[1012] TFE: 2,2,2-trifluoroethanol

[1013] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[1014] DIPEA: N,N-diisopropylethylamine

[1015] XPhos Pd G3: (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2-(2'-amino-1,1'-biphenyl))methanesulfonate palladium(II) (CAS No. 1445085-55-1)

[1016] XPhos Pd G4: (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2-(2'-(N-methyl)amino-1,1'-biphenyl))methanesulfonate palladium(II) (CAS No. 1599466-81-5)

[1017] DPPF Pd G4: (1,1'-bis(diphenylphosphino)ferrocene)(2-(2'-(N-methyl)amino-1,1'-biphenyl))methanesulfonate palladium(II) (CAS No. 1621274-17-6)

[1018] CPhos Pd G3: (2-Dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl)(2-(2'-amino-1,1'-biphenyl))methanesulfonate palladium(II) (CAS No. 1447963-73-6)

[1019] CPhos Pd G2: Chloro[(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (CAS No. 2230788-62-0)

[1020] tBuBrettPhos Pd G3: [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (CAS No. 1536473-72-9)

[1021] BINAP Pd G4: [(±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl](2'-methylamino-1,1'-biphenyl-2-yl)methanesulfonate palladium(II) (CAS No. 1599466-90-6)

[1022] Xantphos Pd G3: [9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene](2'-amino-1,1'-biphenyl-2-yl)methanesulfonate palladium(II) (CAS No. 1445085-97-1)

[1023] Xantphos Pd G4: [9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene](2'-methylamino-1,1'-biphenyl-2-yl)methanesulfonate palladium(II) (CAS No. 1621274-19-8)

[1024] tBuXPhos Pd G3: [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]methanesulfonate palladium(II) (CAS No. 1447963-75-8)

[1025] DCC:N,N'-dicyclohexylcarbodiimide

[1026] EDC: N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide

[1027] COMU: (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbonium hexafluorophosphate

[1028] LiHMDS: lithium hexamethyldisilazide

[1029] NaHMDS: sodium hexamethyldisilazide

[1030] KHMDS: potassium hexamethyldisilazide

[1031] LDA: lithium diisopropylamide

[1032] DIAD: diisopropyl azodicarboxylate

[1033] CMMP: (cyanomethylene)trimethylphosphane

[1034] CMBP: (cyanomethylene)tributylphosphane

[1035] DCE: 1,2-dichloroethane

[1036] FA: Formic acid

[1037] The compound of the present invention can be synthesized, for example, by the production method described below.

[1038] (General production method 1-1)

[1039] General production method 1-1 is a compound represented by general formula (1) to (3) wherein R4 is an optionally substituted C6-C10 Preferred methods for producing compounds containing aryl or optionally substituted 5- to 10-membered heteroaryl groups.

[1040] [Equation 15]

[1041]

[1042] Step 1-1

[1043] This step is the formylation step of aromatic bromide 1a. Compound 1b can be produced by reacting aromatic bromide 1a with a metal species and then reacting with a formylation agent. Examples of metal species include metals (such as magnesium and lithium) and organometallic reagents. Examples of organometallic reagents include isopropylmagnesium bromide, isopropylmagnesium chloride-lithium chloride complex, n-butyllithium and sec-butyllithium. Isopropylmagnesium chloride-lithium chloride complex is preferred. The formylation agent is selected from N-formamide and orthoformate. N-formamide is preferably DMF, and orthoformate is preferably trimethyl orthoformate. Examples of solvents used in this step include aprotic solvents, such as n-hexane, cyclohexane, ether (exemplifying dialkyl ethers, such as diethyl ether, and cyclic ethers, such as 1,2-dimethoxyethane, THF and 2-methyltetrahydrofuran) and toluene, and mixed solvents thereof. THF, 1,2-dimethoxyethane, toluene and mixed solvents thereof are preferred.

[1044] Steps 1-2

[1045] This step is a step of producing an aromatic ester from an aromatic bromide 1a. Aromatic ester 1c (wherein R represents a C1-C6 alkyl, 2,4,6-trichlorophenyl or 2,5-dioxopyrrolidin-1-yl) can be produced by reacting aromatic bromide 1a with a carbonylation agent in the presence of a Pd catalyst and a base. This step can be carried out, for example, with reference to the method described in Tetrahedron Lett., 2019 Vol. 60, 151147 (Non-Patent Document 7) and the like. Examples of carbonylation agents include formates, oxalates and their salts. 2,4,6-trichlorophenyl formate is preferred. Examples of bases include tertiary amines. Triethylamine and DIPEA are preferred. Examples of solvents used in this step include aprotic solvents such as toluene, acetonitrile, THF and DMF, and mixed solvents thereof. Toluene is preferred. The Pd catalyst is preferably a combination of palladium acetate and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, Xantphos Pd G4, and Xantphos Pd G3. This step can be performed at a reaction temperature of -20°C to near the boiling point of the solvent, and is preferably performed at a temperature of 60°C to near the boiling point of the solvent.

[1046] Steps 1-3

[1047] This step is a hydrolysis step for 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 hydrate, and barium hydroxide. Examples of solvents used in this step include polar solvents such as water, ether, alcohol, and DMSO, as well as mixed solvents thereof. Mixed solvents of THF and water and mixed solvents of methanol and water are preferred.

[1048] Steps 1-4

[1049] 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 amine or amine salt in the presence of a condensing agent. The condensing agent can be, for example, selected from the group consisting of: DCC, EDC, EDC hydrochloride, HATU, COMU and propylphosphonic anhydride (cyclic trimer), and is preferably HATU. In this step, a base can be used as an additive. Examples of bases include DIPEA, triethylamine and diazabicycloundecene, and DIPEA is preferred. Examples of solvents used in this step include DMF, DMA, NMP, DCM, THF, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, acetonitrile and mixed solvents thereof. Examples of amines or amine salts include N, O-dimethylhydroxylamine hydrochloride and morpholine, and N, O-dimethylhydroxylamine hydrochloride is preferred.

[1050] Steps 1-5

[1051] This step is an alternative method for synthesizing aromatic amide 1e, and is a step for performing 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, etc. Aromatic amide 1e (wherein X represents a methyl(methoxy)amino group or a morpholinyl group) can be produced by reacting aromatic ester 1c with an amine. The amine is preferably morpholine. Examples of solvents used in this step include toluene, DMF, DMA, THF, 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile, and mixed solvents thereof, and toluene is preferred. This step can be performed at a reaction temperature of -20°C to near the boiling point of the solvent, and is preferably performed at a temperature of 60°C or higher to near the boiling point of the solvent.

[1052] (General generation method 1-2)

[1053] The general production method 1-2 is a compound represented by the general formula (1) to (3) wherein R4 is an optionally substituted C6-C 10 Preferred methods for producing compounds containing aryl or optionally substituted 5- to 10-membered heteroaryl groups.

[1054] [Equation 16]

[1055]

[1056] [Equation 17]

[1057]

[1058] Steps 1-6

[1059] This step is the step of iodination of aromatic amine 1f. Aromatic amine 1g can be produced by reacting aromatic amine 1f with an iodination reagent. Examples of iodination reagents include iodine, N-iodosuccinimide, 1,3-diiodo-5,5-dimethylhydantoin, N-iodosaccharin and iodine chloride, and N-iodosuccinimide is preferred. Examples of solvents used in this step include DCM, acetonitrile, ethyl acetate, DMSO and acetic acid, and DCM and DMSO are preferred. As the additive in this step, the acid exemplified by TFA, acetic acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, etc. can be appropriately used.

[1060] Steps 1-7

[1061] This step is a step of converting the amino group in the aromatic amine 1g by using an N,N-dimethylformamidating agent. Aromatic iodine compound 1h can be produced by converting the amino group in the aromatic amine 1g into an N,N-dimethylformamidating group. Examples of N,N-dimethylformamidating agents include N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide di-tert-butyl acetal, and a combination of DMF and phosphorus oxychloride (V). N,N-dimethylformamide dimethyl acetal is 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 mixed solvents thereof. Ethanol and DMSO are preferred. This step can be carried out at a reaction temperature of -20°C to near the boiling point of the solvent, and is preferably carried out at a temperature of 40°C to near the boiling point of the solvent.

[1062] Steps 1-8

[1063] This step is a step of synthesizing ketone 1i by reacting aromatic iodine compound 1h with metal species and then reacting aromatic amide 1e (wherein X represents methyl (methoxy) amino or morpholinyl). Examples of metal species include metals (such as magnesium and lithium) and organometallic reagents. Examples of organometallic reagents include isopropylmagnesium bromide, isopropylmagnesium chloride-lithium chloride complex, n-butyllithium and sec-butyllithium. Isopropylmagnesium chloride-lithium chloride complex is preferred. Examples of solvents used in this step include aprotic solvents such as n-hexane, cyclohexane, ether and toluene, and mixed solvents thereof. THF, 1,2-dimethoxyethane, toluene and mixed solvents thereof are preferred. Additives such as hexamethylphosphoric acid triamide, N,N'-dimethylpropylene urea or crown ethers can be optionally added. The additive is preferably N,N'-dimethylpropylene urea.

[1064] Steps 1-9

[1065] This step converts dimethylformamidine 1i into aniline 1j through a hydrolysis reaction. Aniline 1j can be produced by reacting dimethylformamidine compound 1i with a hydroxide. Examples of hydroxides include sodium hydroxide, lithium hydroxide, potassium hydrate, and barium hydroxide. Sodium hydroxide is preferred. Examples of solvents used in this step include polar solvents such as THF, alcohols, and DMSO. DMSO is preferred.

[1066] Steps 1-10

[1067] This step is a step of producing an alcohol by reacting an aromatic iodine compound 1h with a metal species and then reacting with an aromatic aldehyde 1b. Examples of metal species include metals (such as magnesium and lithium) and organometallic reagents. Examples of organometallic reagents include isopropylmagnesium bromide, isopropylmagnesium chloride-lithium chloride complex, n-butyllithium and sec-butyllithium. Isopropylmagnesium chloride-lithium chloride complex is preferred. Examples of solvents used in this step include aprotic solvents such as n-hexane, cyclohexane, ether and toluene, and mixed solvents thereof. THF, 1,2-dimethoxyethane, toluene and mixed solvents thereof are preferred. As additives, hexamethylphosphoric acid triamide, N,N'-dimethylpropylene urea, crown ethers, etc. can be added. The additive is preferably N,N'-dimethylpropylene urea. By sequentially adding acid and base to the reaction mixture, the N,N-dimethylformamidinyl group can be converted into an amino group. The acid is preferably formic acid. The base is preferably ethylenediamine.

[1068] Steps 1-11

[1069] This step is a step of converting benzyl alcohol 1o into a ketone by an oxidation reaction. 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. Manganese dioxide is preferred. Examples of solvents used in this step include aprotic solvents such as DCM, chloroform, acetonitrile, and ethyl acetate, as well as mixed solvents thereof. DCM is preferred.

[1070] Steps 1-12

[1071] This step is a step for halogenating and acetylation of aromatic amine 1j. This step can be performed according to the following method 1 or method 2.

[1072] Method-1: Haloacetamide 1k (wherein Y represents a halogen) can be produced by reacting an aromatic amine 1j with a haloacetylating agent. As the haloacetylating agent, for example, chloroacetyl chloride, bromoacetyl chloride, etc. can be used. In this step, a base can be used as appropriate. For example, as the base, an organic base such as DIPEA, triethylamine, or pyridine can be used. Examples of solvents used in this step include DCM, acetonitrile, THF, DMF, DMA, and NMP. DCM and DMA are preferred.

[1073] Method-2: Haloacetamide 1k (wherein Y represents a halogen) can be produced by reacting an aromatic amine 1j with a haloacetic acid in the presence of a condensing agent. As the haloacetic acid, chloroacetic acid and bromoacetic acid can be used. Examples of condensing agents include DCC, EDC, EDC hydrochloride, HATU, COMU and propylphosphonic anhydride (cyclic trimer). HATU and propylphosphonic anhydride (cyclic trimer) are preferred. Examples of bases include DIPEA and triethylamine. DIPEA is preferred. Examples of solvents used in this step include DMF, DMA, NMP, DCM, acetone, THF, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, acetonitrile and mixed solvents thereof. DMF is preferred.

[1074] Steps 1-13

[1075] This step is a step of constructing a pyridone skeleton from a haloacetamide 1k (wherein Y represents a halogen) through a cyclization reaction. Pyridinium ylide 1l (wherein Y represents a halogen) can be produced by reacting haloacetamide 1k with pyridine. Pyridine can be used as a solvent for this step. In addition, the reaction mixture of steps 1-12 can be reacted with pyridine. This step can be carried out at a reaction temperature of -20°C to near the boiling point of the solvent, and is preferably carried out at a temperature of 40°C to near the boiling point of the solvent.

[1076] Steps 1-14

[1077] This step is a deprotection step for 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. Hydrazine monohydrate and hydrazine hydrochloride are preferred. The reaction mixture from Steps 1-13 can be used as is. This step can be carried out at a reaction temperature from -20°C to near the boiling point of the solvent, and is preferably carried out at a temperature from 40°C to near the boiling point of the solvent.

[1078] Steps 1-15

[1079] This step is to add acid to 3-aminopyridone compound 1n1 and when R4 in 3-aminopyridone compound 1n1 has the protecting group that can be removed by the acid exemplified by 2-tetrahydropyranyl, the step of removing the protecting group by the acid exemplified by 2-tetrahydropyranyl. The example of acid includes sulfuric acid, hydrochloric acid, sulfonic acid and carboxylic acid. TFA is preferred. The example of the solvent used in this step includes alcohol (for example, alkyl alcohol and fluoroalkyl alcohol), water and DCM. In addition, for example, trimethylsilyl chloride (TMSCl) in the alcohol used as solvent can be used to produce acid to eliminate the protecting group that can be removed by the acid exemplified by 2-tetrahydropyranyl. As the combination of acid and solvent, for example, the combination of TMSCl and TFE, the combination of TFA and DCM and the combination of TFA and water are preferred.

[1080] (General generation method 2)

[1081] General Production Method 2 is another preferred method for synthesizing 3-aminopyridone compound 1n2. General Production Method 2 is a compound represented by formula (1) to (3) wherein R4 is an optionally substituted C6-C 10 Preferred methods for producing compounds containing aryl or optionally substituted 5- to 10-membered heteroaryl groups.

[1082] [Equation 18]

[1083]

[1084] [Equation 19]

[1085]

[1086] Step 2-1

[1087] Step 2-1 is a step of condensing an acidic chloride 2a-1 (wherein X represents chlorine) or a carboxylic acid 2a-2 (wherein X represents a hydroxyl group) 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.

[1088] Method-1: Amide 2b can be produced by reacting acid chloride 2a-1 with glycine alkyl ester or a salt of glycine alkyl ester (wherein R is a C1-C6 alkyl group) in the presence of a base. As the salt of glycine alkyl ester, glycine alkyl ester hydrochloride is preferred. 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 the solvent used in this step include DCM, acetonitrile, THF, DMF, DMA, NMP and water. DCM and THF are preferred.

[1089] Method-2: Amide 2b can be produced by reacting carboxylic acid 2a-2 with glycine alkyl ester or a salt of glycine alkyl ester in the presence of a condensing agent. As the salt of glycine alkyl ester, glycine alkyl ester hydrochloride is preferred. Examples of condensing agents include DCC, EDC, EDC hydrochloride, HATU, COMU and propylphosphonic anhydride (cyclic trimer). HATU and propylphosphonic anhydride (cyclic trimer) are preferred. In this step, a base can be used as an additive. Examples of the base include DIPEA and triethylamine, and DIPEA is preferred. The solvent used in this step is a solvent selected from the group consisting of: DMF, DMA, NMP, DCM, acetone, THF, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate and acetonitrile, or a mixed solvent thereof. DMF is preferred.

[1090] Step 2-2

[1091] This step is a step of protecting amide 2b with Boc. Boc-protected compound 2c can be produced by reacting amide 2b with a tert-butoxycarbonylating agent. 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. The solvent used in this step is a solvent selected from the group consisting of: DMF, DMA, DCM, acetone, THF, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate, and acetonitrile, or a mixed solvent thereof. DMF is preferred.

[1092] Steps 2-3

[1093] This step is a step of rearranging the acyl group of the Boc-protected compound 2c in the presence of a base. As the base, for example, a base selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, LiHMDS, NaHMDS, KHMDS, and LDA can be used alone or in combination. Potassium tert-butoxide, LiHMDS, and mixtures thereof are preferred. The solvent used in this step is a solvent selected from the group consisting of toluene, xylene, n-hexane, cyclohexane, THF, 1,2-dimethoxyethane, N,N'-dimethylpropyleneurea, and hexamethylphosphoric acid triamide, or a mixed solvent thereof. THF is preferred.

[1094] Steps 2-4

[1095] This step is a step of tosylation of ketone compound 2d using a base. For example, as a base, a base selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, LiHMDS, NaHMDS, KHMDS, LDA, DIPEA, triethylamine and diazabicycloundecene, or a combination of these bases can be used. LDA, LiHMDS, DIPEA and triethylamine are preferred. The solvent used in this step is a solvent selected from the group consisting of toluene, xylene, n-hexane, cyclohexane, THF, 1,2-dimethoxyethane, acetonitrile and DCM, or a mixed solvent thereof. THF is preferred. The reaction can be carried out by using the reaction mixture of steps 2-3 as is.

[1096] Steps 2-5

[1097] This step is a cross-coupling step and a ring condensation step with a Pd catalyst. Compound 2e reacts with a corresponding organoboron compound (wherein R' is exemplified by hydrogen, alkyl or alkylene) or an organotin compound (wherein R' is exemplified by hydrogen, alkyl or alkylene) in the presence of a Pd catalyst. Due to the organoboron compound or organotin compound to be used having an amino group at the orthogonal position of boron or tin, a cross-coupling step occurs, and a ring condensation step occurs subsequently. This step can be carried out according to the following method-1 or method-2.

[1098] Method-1 (Suzuki-Miyaura cross coupling): Method-1 can be carried out by the method described in the following: for example, Chem.Rev.1995, Vol.95, No.7, pp.2457-2483. (Non-patent document 8) or 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, and 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, and mixed solvents thereof. A mixed solvent of 2-methyltetrahydrofuran and 4-methyltetrahydropyran and water is preferred. Examples of Pd catalysts include PdCl2(PPh3)2, Pd(PPh3)4, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, 1,4-bis(diphenylphosphino)butane]palladium(II) dichloride, XPhosPdG3, and XPhosPdG4. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, 1,4-bis(diphenylphosphino)butane]palladium(II) dichloride, XPhosPdG3, and XPhosPdG4 are preferred. This step can be carried out at a reaction temperature of -20°C to near the boiling point of the solvent, and is preferably carried out at a temperature of 80°C or higher to near the boiling point of the solvent.

[1099] Method-2 (Stille cross coupling): Method-2 can be carried out by the method described in: for example, Synthesis 1992, Vol. 9, pp. 803-815. (Non-patent document 10). Examples of Pd catalysts include PdCl2(PPh3)2, Pd(PPh3)4 and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and 1,4-bis(diphenylphosphino)butane]dichloropalladium(II). Pd(PPh3)4 is preferred. Examples of solvents used in this method include toluene, xylene, THF, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, 1,4-dioxane, DMF, DMA and NMP. Toluene is preferred. This step can be carried out at a reaction temperature of -20°C to near the boiling point of the solvent, and is preferably carried out at a temperature of 80°C to near the boiling point of the solvent.

[1100] Steps 2-6

[1101] This step is to deprotect the Boc group of the Boc-protected compound 2f. This step can be performed under the same conditions as Step 1-15.

[1102] Steps 2-7

[1103] This step is a step of Wittig reaction of formyl compound 2g. αβ,-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)acetate and its equivalent (wherein R is a C1-C6 alkyl). 2-(BOC-amino)-2-(dimethoxyphosphoryl)methyl acetate is preferred. The base is a base selected from the group consisting of 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 method include toluene, THF, 1,2-dimethoxyethane, acetonitrile and DCM.

[1104] Steps 2-8

[1105] This step is a bromination step of the α,β-unsaturated ester compound 2h. The aromatic nitro product 2i can be produced by reacting the α,β-unsaturated ester 2h with a brominating agent and further isomerizing the reaction product in the presence of a base. Examples of brominating agents include NBS, 1,3-dibromo-5,5'-dimethylhydantoin, and N-bromosaccharin. NBS is preferred. Examples of bases include 1,4-diazabicyclo[2.2.2]octane, diazabicycloundecene, sodium tert-butoxide, potassium tert-butoxide, LiHMDS, NaHMDS, and KHMDS. 1,4-diazabicyclo[2.2.2]octane and diazabicycloundecene are preferred. Examples of solvents used in this method include acetonitrile and DCM.

[1106] Steps 2-9

[1107] This step is a reduction step and a continuous cyclization step of the aromatic nitro compound 2i. The reduction step can be carried out by the method described in: for example, Org.Process Res.Dev.2018, Vol. 22, No. 4, pp. 430-445. (Non-patent Document 11), and in particular, the reaction is preferably carried out with a combination of Pd(OH)2 / H2 in a solvent such as methanol and ethyl acetate, or with a combination of Fe / NH4Cl in ethanol. By reacting at room temperature to a temperature close to the boiling point of the solvent, the cyclization step can be carried out continuously.

[1108] Steps 2-10

[1109] This step is a cross-coupling step with a Pd catalyst. Compound 2i or 2j reacts with the corresponding organoboron compound (R4-B(OR)2, R4-BF3K) or organotin compound (R4-SnR3) (where R is exemplified by hydrogen or an alkyl group). This step can be carried out under the same conditions as Steps 2-5.

[1110] (General generation method 3)

[1111] The general generation method 3 is when X6 is CR x6 And R x6 The method can be carried out when the halogen in the 3-aminopyridone compound 1n1 or 1n2 is present.

[1112] [Equation 20]

[1113]

[1114] Step 3-1

[1115] This step is to remove the substituent R in the presence of a metal catalyst. x6 Step of introducing into 3-aminopyridone compound 1n1 or 1n2: This step can be carried out according to any one of the following methods 1 to 6.

[1116] 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 or an alkyl group). This step can be performed under the same conditions as in Step 2-5 of Method-1.

[1117] Method-2 (alkylation or alkenylation via Negishi cross-linking): 3-aminopyridone compound 3a can be prepared by reacting 3-aminopyridone compound 1n1 or 1n2 with an organozinc reagent (R x6-ZnX) (wherein X is a halogen) reaction to produce. Method-2 can be carried out by the method described in: for example, 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). Examples of the solvent used in this step include polar solvents such as THF, 1,4-dioxane, DMF, DMA and NMP, or mixed solvents thereof. THF is 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); PdCl2(PPh3)2, Pd(PPh3)4, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). PdCl2(PPh3)2, Pd(PPh3)4, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) are preferred.

[1118] 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, wherein RC≡C- represents R x6 -) reaction to produce. Method-3 can be carried out by the method described in the following: for example, Chem.Soc.Rev.2011, Vol. 40, pp. 5084-5121. (Non-patent document 14). The corresponding alkyne may have a silyl group, and examples thereof include trimethylsilyl acetylene. Examples of bases include amines such as triethylamine, DIPEA and diazabicycloundecene, and inorganic bases such as sodium acetate. Triethylamine and DIPEA are preferred. Examples of Pd include PdCl2(PPh3)2, Pd(PPh3)4, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), Pd(OAc)2 and Pd2(dba)3. PdCl2(PPh3)2, Pd(PPh3)4 and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) are preferred. Examples of copper include copper iodide, copper bromide, and copper chloride. Copper iodide is preferred. Examples of the solvent used in this step include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP, DMSO, methanol, ethanol, and 2-propanol, and mixed solvents thereof. DMSO, DMF, DMA, and NMP are preferred.

[1119] Method-4 (thioetherification): 3-aminopyridone compound 3a can be produced by reacting 3-aminopyridone compound 1n1 or 1n2 with the corresponding thiol or thiolate in the presence of Pd and a base. Examples of thiols include 2-ethylhexyl and 3-mercaptopropionic acid. Examples of bases include amines such as triethylamine, DIPEA, diazabicycloundecene and piperidine. Triethylamine and DIPEA are preferred. Examples of Pd include zerovalent Pd complexes such as Pd(PPh3)4. Xantphos Pd G3 is 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, and mixed solvents thereof. 1,4-dioxane is preferred.

[1120] Method-5 (etherification or hydroxylation): 3-aminopyridone compound 3a can be produced by reacting 3-aminopyridone compound 1n1 or 1n2 with the corresponding alcohol or water in the presence of Pd. In the case of etherification, for example, sodium salts and potassium salts of the corresponding alcohol can be used as a base. In the case of hydroxylation, for example, sodium hydroxide and potassium hydrate can be used. Examples of Pd include zero-valent Pd complexes such as Pd(PPh3)4. tBuBrettPhosPdG3 is preferred. Examples of solvents used in this step include polar solvents such as THF, 1,4-dioxane, DMF, DMA and NMP. 1,4-dioxane is preferred.

[1121] Method-6 (amination): 3-aminopyridone compound 3a can be produced by reacting 3-aminopyridone compound 1n1 or 1n2 with the corresponding amine in the presence of Pd or Cu and a base. In the case of using Pd, method-6 can be carried out by the method described in the following: for example, Chem.Rev.2016, Vol. 116, pp. 12564-12649. (Non-patent literature 15). Examples of Pd include zerovalent Pd complexes such as Pd(PPh3)4. Xantphos Pd G3, Xantphos Pd G4 and tBuXPhos Pd G3 are preferred. Examples of bases include carbonates, phosphates, sodium tert-butoxide, potassium and tert-butanol. Sodium tert-butoxide is preferred. Examples of solvents used in this step include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP and DMSO, or mixed solvents thereof. 1,4-dioxane is preferred. In the case of using Cu, method-6 can be carried out by the method described in the following: Org.Process Res.Dev.2022, Vol. 26, No. 6, pp. 1690-1750. (Non-patent literature 16). Examples of copper include copper iodide, copper bromide and copper chloride. Copper iodide is preferred. Examples of Cu ligands include 1,10-phenanthroline, L-proline and 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (DMPAO). 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (DMPAO) is preferred. Examples of bases include carbonates, phosphates, sodium tert-butoxide and potassium tert-butoxide. Cesium carbonate, potassium carbonate and tripotassium phosphate are preferred. Examples of solvents used in this step include polar solvents such as THF, 1,4-dioxane, DMF, DMA, NMP and DMSO, or mixed solvents thereof. DMSO is preferred.

[1122] Step 3-2

[1123] When the 3-aminopyridone compound 3a has a Boc group, a 2-tetrahydropyranyl group, or both, this step is to deprotect the Boc group, the 2-tetrahydropyranyl group, or both. This step can be carried out under the same conditions as Step 1-15.

[1124] Each of Step 3-3-1, Step 3-3-2, and Step 3-3-3 is a step of protecting the 3-aminopyridone compound 1n1 or 1n2 with a protecting group.

[1125] Step 3-3-1: Protection by tert-butoxycarbonylation

[1126] This step is to protect the 3-aminopyridone compound 1n1 or 1n2 with a Boc group. 3-Aminopyridone compound 3c can be produced by reacting 3-aminopyridone compound 1n1 or 1n2 with a tert-butoxycarbonylating agent. A base and a catalyst can be used as appropriate in this step. In this step, in the formula, P1 is a Boc group, and P3 is a Boc group or H. This step can be carried out under the same conditions as Step 2-2.

[1127] Step 3-3-2: Protection by p-methoxybenzylation

[1128] This step is a step of reacting 3-aminopyridone compound 1n1 or 1n2 with a p-methoxybenzylating agent in the presence of a base to perform p-methoxybenzylation. In this step, in the formula, P1 is a p-methoxybenzyl group, and P3 is H. Examples of p-methoxybenzylating agents include p-methoxybenzyl chloride or p-methoxybenzyl bromide. Examples of bases include inorganic bases such as potassium carbonate, silver carbonate, cesium carbonate, and sodium hydride. Potassium carbonate and silver carbonate are preferred. Examples of solvents used in this step include aprotic solvents such as DMF, DMA, NMP, THF, DCM, and DCE. DMF, DMA, or DCE are preferred.

[1129] Step 3-3-3: Protection by 2-(trimethylsilyl)ethoxymethylation

[1130] This step is to react 3-aminopyridone compound 1n1 or 1n2 with 2-(trimethylsilyl) ethoxymethylating agent in the presence of a base to carry out the step of 2-(trimethylsilyl) ethoxymethylation. In this step, in the formula, P1 is a 2-(trimethylsilyl) ethoxymethyl group, and P3 is H. Examples of 2-(trimethylsilyl) ethoxymethylating agents include 2-(trimethylsilyl) ethoxymethyl chloride. Examples of bases include inorganic bases such as potassium carbonate, silver carbonate, cesium carbonate and sodium hydride. Potassium carbonate or cesium carbonate are preferred. Examples of solvents used in this step include aprotic solvents such as DMF, DMA, NMP, THF, DCM and 1,2-dichloroethane. DMF and DMA are preferred.

[1131] Steps 3-4

[1132] This step is the alkylation step of the protected 3-aminopyridone 3c. The protected 3-aminopyridone 3c can be alkylated with an alcohol (R x6 -OH) or haloalkyl (R x6-X, where X is a halogen) to alkylate. This step 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), Nature 2021, Vol. 598, pp. 451-456 (Non-Patent Document 19), etc.

[1133] Steps 3-5

[1134] When the 3-aminopyridone product 3d has a Boc group or a 2-tetrahydropyranyl group, this step is a step of deprotecting the Boc group or the 2-tetrahydropyranyl group. This step can be carried out under the same conditions as steps 1-15.

[1135] Steps 3-6

[1136] This step is the hydroxylation step of the protected 3-aminopyridone 3c and can be carried out under the same conditions as those for the hydroxylation of step 3-1, method 5.

[1137] Steps 3-7

[1138] This step is the alkylation step of the hydroxy compound 3e and can be carried out according to the following method 1 or method 2.

[1139] Method-1 (nucleophilic substitution reaction): Alkylation of compound 3f (wherein R x6a O stands for R x6 ) can be produced by reacting the hydroxy compound 3e with the corresponding haloalkyl, alkyl trifluoromethanesulfonate or alkyl perfluorobutanesulfonate in the presence of a base. Examples of bases include inorganic bases such as carbonates and phosphates. Cesium carbonate and potassium carbonate are preferred. Examples of solvents used in this step include THF, 1,4-dioxane, DMF, DMA and NMP.

[1140] Method-2 (Mitsunobu reaction): Alkylation product 3f (where R x6a O stands for R x6 ) can be produced by reacting the hydroxy 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. Examples of 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. DCM and THF are preferred.

[1141] Steps 3-8

[1142] When the 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, the p-methoxybenzyl group, or the 2-tetrahydropyranyl group. This step can be carried out under the same conditions as Step 1-15.

[1143] Steps 3-9

[1144] This step is a p-methoxybenzylation step for 3-aminopyridone compound 1n1 or 1n2. Step 3-9 can be carried out under the same conditions as Step 3-3-2. In the formula, P2 represents a p-methoxybenzyl group.

[1145] Steps 3-10

[1146] This step is a hydroxylation step of the p-methoxybenzyl protected compound 3g. This step can be carried out under the same conditions as the hydroxylation of method 5 in step 3-1.

[1147] Steps 3-11

[1148] This step is the alkylation step of the hydroxy compound 3h. This step can be carried out under the same conditions as step 3-7 (in the formula of compound 3i, R x6a O stands for R x6 ).

[1149] Steps 3-12

[1150] When compound 3i has a p-methoxybenzyl group or a 2-tetrahydropyranyl group, this step is a step for deprotecting the p-methoxybenzyl group or the 2-tetrahydropyranyl group. This step can be carried out under the same conditions as step 1-15.

[1151] (General generation method 4)

[1152] General Production Method 4 is a preferred production method for compounds represented by the general formulae (1) to (3) wherein R4 is an optionally substituted 4- to 10-membered heterocyclic group.

[1153] [Equation 21]

[1154]

[1155] Step 4-1

[1156] This step is a nitration step for 4-hydroxypyridone compound 4a. 3-Nitropyridone compound 4b can be produced by reacting 4-hydroxypyridone compound 4a with a nitrating agent under acidic conditions. Examples of nitrating agents include nitric acid and nitrates. Examples of solvents used in this step include acetic acid, sulfuric acid, and nitric acid.

[1157] Step 4-2

[1158] This step is a chlorination step for 3-nitropyridone compound 4b. 4-Chloropyridone compound 4c can be produced by reacting 3-nitropyridone compound 4b with a chlorinating agent. Examples of chlorinating agents include phosphorus oxychloride, thionyl chloride, and oxalyl chloride, and these chlorinating agents can be used in a solvent amount. In this step, DMF can be used as a catalyst.

[1159] Step 4-3

[1160] This step is a step of carrying out an aromatic nucleophilic substitution reaction of 4-chloropyridone compound 4c. 3-nitropyridone compound 4d can be produced by reacting 4-chloropyridone compound 4c with a corresponding amine (e.g., piperidine). Examples of the solvent used in this step include aprotic solvents such as toluene, THF, n-hexane, cyclohexane, ethyl acetate, DMA, DMF, NMP, 1,4-dioxane, and DMSO. DMF is preferred.

[1161] Step 4-4

[1162] 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 agent. This step can be carried out by the method described in: For example, Org. Process Res. Dev. 2018, Vol. 22, No. 4, pp. 430-445. (Non-Patent Document 11), and a combination of Pd(OH)2 / H2 in a solvent such as methanol and ethyl acetate or a combination of Fe / NH4Cl in ethanol is preferred.

[1163] <Pharmaceutical Composition>

[1164] The present invention provides a pharmaceutical composition containing the compound represented by formula (1) of the present invention, or a salt thereof, or a solvate thereof (first component) (hereinafter also referred to as "the pharmaceutical composition of the present invention").

[1165] The pharmaceutical composition of the present invention can be formulated by a known method by introducing a pharmaceutically acceptable carrier other than the compound represented by formula (1) of the present invention, or a salt thereof, or a solvate thereof. The pharmaceutical composition of the present invention can be formulated together with conventional excipients, binders, lubricants, colorants or flavorings, and, if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, pH regulators, preservatives, antioxidants, etc., and can be formulated by conventional methods by mixing ingredients commonly used as raw materials for pharmaceutical formulations.

[1166] In the formulation, the active ingredient used in the drug can be processed into an optimal form or shape by known methods, that is, a dosage form according to the method of use or the purpose of use. Examples of conventional dosage forms include, but are not limited to, liquid drug formulations (liquids) such as injections, suspensions, emulsions, and ophthalmic solutions; and solid drug formulations (solid formulations) such as tablets, powders, fine particles, granules, coated tablets, capsules, dry syrups, lozenges, and suppositories.

[1167] For the production of liquids, pharmaceutical compositions can be prepared, for example, by appropriately combining pharmaceutically acceptable carriers or media (specifically, pharmaceutically acceptable additives commonly used in the field of pharmaceutical formulations, such as sterile water or physiological saline, vegetable oils, emulsifiers, suspending agents, surfactants, stabilizers, flavorings, excipients, vehicles, preservatives, and adhesives), adding them to the compound represented by formula (1) or its salt or solvate, and then mixing the mixture into a unit dosage form required by generally accepted pharmaceutical practice. In addition, solid formulations prepared by dissolving into a liquid by adding an appropriate solvent (such as sterile water or physiological saline) before administration can also be used, and then the liquid can be used for administration.

[1168] For example, such liquid can be used parenterally in the form of an injection of a suspension of a sterile solution or with water or other pharmaceutically acceptable liquids. Such liquid can be, for example, by being mixed into the unit dosage form required for generally acceptable pharmaceutical practice with a suitable combination of a pharmacologically acceptable carrier or medium (particularly, sterile water or physiological saline, vegetable oil, emulsifier, suspending agent, surfactant, stabilizer, flavoring, excipient, vehicle, preservative, adhesive, etc.) to prepare. The specific example of carrier includes light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carboxymethylcellulose calcium, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylamino acetate, polyvinyl pyrrolidone, gelatin, medium-chain fatty acid triglycerides, polyoxyethylene hardened castor oil 60, sucrose, carboxymethyl cellulose, corn starch and inorganic salts. Determine the amount of the active component in these formulations, so that appropriate volume is provided within the specified range.

[1169] Sterile compositions for injection can be formulated according to customary pharmaceutical practices using vehicles such as distilled water for injection.

[1170] Examples of aqueous solutions for injection include isotonic solutions containing saline or other adjuvants (e.g., D-sorbitol, D-mannose, D-mannitol, and sodium chloride), which may be used in combination with appropriate solubilizers (e.g., alcohols, specifically ethanol, polyols (e.g., propylene glycol or polyethylene glycol)) and nonionic surfactants (e.g., polysorbate 80 (registered trademark) or HCO-50).

[1171] Examples of oily liquids include sesame oil and soybean oil, which can be used in combination with benzyl benzoate and benzyl alcohol as solubilizers. In addition, it can also be mixed with buffers (e.g., phosphate buffer solution and sodium acetate buffer solution), soothing agents (e.g., procaine hydrochloride), stabilizers (e.g., benzyl alcohol and phenol) and antioxidants. The prepared injection solution is usually filled into an appropriate ampoule.

[1172] In order to produce a solid formulation, for example, excipients and, if necessary, pharmaceutically acceptable additives commonly used in the field of pharmaceutical formulations (e.g., binders, disintegrants, lubricants, colorants and flavorings) are added in appropriate combinations to the compound represented by formula (1) or a salt thereof or a solvate thereof, and thereafter, the mixture is formed into tablets, powders, fine granules, granules, coated tablets, capsules, dry syrups, lozenges, suppositories, etc. by conventional methods.

[1173] Examples of pharmaceutically acceptable additives used in such solid formulations include animal and vegetable oils, such as soybean oil, beef tallow, and synthetic glycerides; hydrocarbons, such as liquid paraffin, squalane, and paraffin wax; ester oils, such as octyldodecyl myristate and isopropyl myristate; higher alcohols, such as cetearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants, such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerol 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, polyvinyl pyrrolidone, and methylcellulose; lower alcohols, such as ethanol and isopropyl alcohol; polyols, such as glycerol, propylene glycol, dipropylene glycol, and sorbitol; sugars, such as lactose, lactose monohydrate, fructose, and sucrose; inorganic powders, such as silicic anhydride, magnesium aluminum silicate, and aluminum silicate; and purified water.

[1174] Examples of excipients include sugars (e.g., lactose, lactose monohydrate, fructose, and sucrose), sugar alcohols (e.g., mannitol), starches (corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, and pregelatinized starch), celluloses (e.g., crystalline cellulose), and inorganic salts (e.g., calcium silicate, anhydrous dibasic calcium phosphate, and precipitated calcium carbonate).

[1175] Examples of the binder include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, gum tragacanth, gelatin, shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, and polypropylene glycol-polyoxyethylene block polymers.

[1176] Examples of the disintegrant include croscarmellose sodium, carboxymethylcellulose sodium, hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, methylcellulose, crystalline cellulose, sodium lauryl sulfate, povidone, and polysorbate.

[1177] Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate and hardened oil.

[1178] Examples of coloring agents include coloring agents permitted to be added to medicines. Examples of flavoring agents include cocoa powder, menthol, aromatic powder, mint oil, borneol, and cinnamon powder.

[1179] These tablets and granules can of course be sugar-coated and, if necessary, can also be coated with other appropriate coatings. In addition, liquid formulations (such as syrups or injectable formulations) can be produced by adding pH regulators, solubilizers, isotonic agents, etc. to the compound according to the present invention or its pharmacologically acceptable salt, and further adding solubilizers, stabilizers, etc. if necessary, and preparing the mixture by conventional methods.

[1180] <Treatment or prevention of cancer in cancer patients who have been detected to be RB1 gene mutation-positive or whose expression of RB1 gene or protein has been reduced, or in cancer patients who have developed RB1 gene mutation-positive or whose expression of RB1 gene or protein has been reduced>

[1181] MYT1 inhibitors can be used alone or in combination with chemotherapeutic agents to treat or prevent cancer in cancer patients who have been tested positive for RB1 gene mutations or have decreased expression of RB1 gene or protein.

[1182] The term "combination" means the combined use of two or more components. For example, the combined use of a MYT1 inhibitor (hereinafter also referred to as the "first component") and a chemotherapeutic agent (hereinafter also referred to as the "second component") includes "an aspect in which a single formulation containing the first component and the second component is administered" (i.e., an aspect in which the first component and the second component are combined and used as a compound) and "an aspect in which each of the first component and the second component is administered simultaneously or separately as a separate formulation." In the latter aspect, the formulation containing the first component may be administered first, or the formulation containing the second component may be administered first. The latter aspect may be any of "an aspect in which the first component and the second component are separately formulated and administered simultaneously via the same administration route," "an aspect in which the first component and the second component are separately formulated and administered separately via the same administration route with a time difference," "an aspect in which the first component and the second component are separately formulated and administered simultaneously via different administration routes (administered to different sites on the same patient)," and "an aspect in which the first component and the second component are separately formulated and administered separately via different administration routes with a time difference." In the case of "an aspect in which the first component and the second component are formulated separately and administered simultaneously via the same administration route", the two preparations may be mixed immediately before administration. The term "separately" means that a certain preparation is administered before or after the other preparation.

[1183] In other words, the term "combination" refers to 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. Specifically, it is preferred to administer the first and second components so that they are present simultaneously in the patient's body, for example, in the blood. Furthermore, it is preferred to administer certain preparations to the patient simultaneously or to administer another preparation within 48 hours of administering a certain preparation.

[1184] "Treatment of cancer" in the present invention refers to a reduction in the number of cancer cells in an individual, suppression of cancer cell growth, reduction in tumor volume, reduction in tumor weight, suppression of cancer cell metastasis, or improvement of various symptoms caused by cancer, and combinations thereof. "Prevention of cancer" in the present invention refers to preventing the generation of new cancer cells, preventing an increase in the number of cancer cells due to the regrowth of reduced cancer cells, preventing the regrowth of cancer cells whose growth has been suppressed, preventing the re-increase in the volume or weight of a reduced tumor, and combinations thereof.

[1185] [First embodiment related to treatment or prevention of cancer]

[1186] One embodiment of the present invention is a pharmaceutical composition for treating or preventing cancer in combination with a chemotherapeutic agent in a cancer patient in whom RB1 gene mutation positivity or decreased expression of the RB1 gene or protein has been detected, the pharmaceutical composition comprising a MYT1 inhibitor as an active ingredient.

[1187] One embodiment of the present invention is a pharmaceutical composition for treating or preventing cancer in combination with a chemotherapeutic agent in a cancer patient in whom RB1 gene mutation-positive or RB1 gene or protein expression is reduced, the pharmaceutical composition comprising a MYT1 inhibitor as an active ingredient.

[1188] RB1 (retinoblastoma gene, also known as Rb or RB) is the gene that encodes the RB1 protein, a classic cell cycle regulator involved in the G1 / S checkpoint. The RB1 protein (also known as RB1 or pRb) forms a complex with the transcription factor E2F, suppressing the action of E2F. This transcription factor induces the expression of genes involved in the transition from the G1 to the S phase of the cell cycle. When E2F is suppressed, the transition from the G1 to the S phase is inhibited.

[1189] In the cell cycle, usually, cyclin D is synthesized by cell growth stimulation and binds to CDK4 to form a complex. This complex is phosphorylated (activated) by CAK, thereby phosphorylating the RB protein. When the RB protein is phosphorylated, the transcription factor E2F bound to the RB protein is released, and the transcription factor induces the expression of the genome required for the S phase or DNA replication progression. The gene among the induced genes is cyclin E, which is complexed with CDK2 and further phosphorylated RB1, thereby further inactivating the RB1 protein. When the RB1 gene has a mutation (particularly a mutation that reduces the function of the RB1 protein) or the expression level of the RB1 gene or protein is reduced, the cell cycle advances.

[1190] As used herein, "RB1 gene mutation positive" means that when the nucleotide sequence of the RB1 gene corresponding to the subject is analyzed, any mutation (for example, a mutation that causes the insertion, substitution, deletion and / or addition of at least one amino acid residue of the wild-type RB1 protein) is found in the nucleotide sequence of the nucleotide sequence of the wild-type RB1 gene; or when the mutation of the nucleotide sequence of the RB1 gene is reflected in a change of bases in the transcript or a change of amino acids in the translation product, the change is detected in the transcript or translation product. In a specific embodiment, RB1 gene mutation positive is detected in a biological sample (for example, a cancer cell) derived from a cancer patient. As used herein, the term "detecting mutations" in principle means detecting mutations on genomic DNA. When a mutation on genomic DNA is reflected in a change of bases in the transcript or a change of amino acids in the translation product, its meaning also includes detecting changes in the transcript or translation product (i.e., indirect detection). A preferred aspect of the method of the present specification is a method for detecting mutations by directly determining the base sequence of the gene region of RB1 in cancer cells. The method for detecting RB1 gene mutation positivity is not particularly limited, but for example, RB1 gene mutation positivity can be confirmed and determined by a next generation sequencer (NGS).

[1191] In the present invention, the term "RB1 gene region" means a specific region on the genomic DNA of the gene comprising RB1. In addition to the translated region, these regions also independently include untranslated regions, such as expression control regions (e.g., promoter regions or enhancer regions) of related genes, 3' untranslated regions of related genes, etc. In this method, first, a DNA sample is prepared from a biological sample. Examples of DNA samples include genomic DNA samples and cDNA samples prepared by reverse transcription from RNA.

[1192] The method for extracting genomic DNA or RNA from organism sample is not particularly limited, can suitably select and use known method.The example for extracting the method for genomic DNA comprises SDS phenol method (wherein with protease (proteinase K), surfactant (SDS) and phenol, makes the protein denaturation of the tissue being stored in urea solution or ethanol, and uses ethanol to precipitate and extract the method for DNA from this tissue), and use Clean Columns (registered trademark, by NexTecCo., Ltd. manufacture), AquaPure (registered trademark, by Bio-Rad Laboratories manufacture), ZR Plant / Seed DNA test kit (by Zymo Research manufacture), AquaGenomicSolution (registered trademark, by Mo Bi Tec GmbH manufacture), prepGEM (registered trademark, by ZyGEM LLC manufacture) and BuccalQuick (registered trademark, by TrimGenCorporation manufacture) DNA extraction method.

[1193] The method for extracting RNA from a biological sample and the method for preparing cDNA from the extracted RNA are not particularly limited, and known methods can be appropriately selected and used. Examples thereof include extraction methods using phenol and chaotropic salts (more specifically, extraction methods using commercially available kits such as TRIzol (manufactured by Invitrogen Corporation) or ISOGEN (manufactured by Wako Pure Chemical Industries, Ltd.)) and methods using another commercially available kit (e.g., RNAPrep total RNA extraction kit (manufactured by Beckman Coulter Inc.), RNeasy Mini (manufactured by QIAGEN NV), or RNA extraction kit (manufactured by Pharmacia Biotech, Inc.)). In addition, the reverse transcriptase for preparing cDNA from the extracted RNA is not particularly limited, and examples thereof include reverse transcriptases derived from retroviruses such as RAV (Rous-associated virus), AMV (avian myeloblastosis virus), and reverse transcriptases derived from mouse retroviruses such as MMLV (Moloney murine leukemia virus).

[1194] In this regard, DNA containing the RB1 gene region is subsequently isolated, and the nucleotide sequence of the isolated DNA is determined. DNA isolation can be performed using PCR, for example, with genomic DNA or RNA as a template, using a pair of oligonucleotide primers designed to encompass all or part of the RB1 gene region. The nucleotide sequence of the isolated DNA can be determined using methods known to those skilled in the art, such as the Maxam-Gilbert method or the Sanger method. Alternatively, a next-generation sequencer capable of rapid and comprehensive analysis of gene nucleotide sequences can be used.

[1195] By comparing the determined nucleotide sequence of the DNA or cDNA (for example, when the biological sample is a sample derived from a cancer patient, the nucleotide sequence of the DNA or cDNA derived from non-cancerous tissue of the same patient; or a known database), the presence or absence of a mutation in the gene region of RB1 in the cancer cells of the biological sample can be determined.

[1196] As a method for detecting a mutation in the gene region of RB1, various methods capable of detecting a mutation can be used in addition to a method for directly determining the nucleotide sequence of DNA or cDNA.

[1197] For example, mutation detection in the present invention can also be carried out by the following method. First, a DNA or cDNA sample is prepared from a biological sample. Subsequently, an oligonucleotide probe is prepared, which has a nucleotide sequence complementary to the nucleotide sequence of the mutation site in the gene region containing RB1 and is labeled with a reporter fluorescent dye and a quencher fluorescent dye. The oligonucleotide probe is hybridized with the DNA or cDNA sample, and the DNA or cDNA sample hybridized with the oligonucleotide probe is used as a template to amplify the nucleotide sequence of the mutation site in the gene region containing RB1. The fluorescence produced by the reporter fluorescent dye due to the degradation of the oligonucleotide probe caused by the amplification is detected, and the detected fluorescence is then compared with the control. Examples of such methods include a dual dye probe method, the so-called TaqMan (registered trademark) probe method.

[1198] In another method, a DNA or cDNA sample is prepared from a biological sample. Subsequently, the DNA or cDNA sample is used as a template to amplify the nucleotide sequence of the mutation site in the gene region containing RB1 in a reaction system containing an intercalator that produces fluorescence when inserted between double-stranded DNA. The temperature of the reaction system is changed, and the change in fluorescence intensity caused by the intercalator is detected. The change in fluorescence intensity with the detected temperature change is compared with a control. Examples of such methods include HRM (high resolution melting) analysis.

[1199] In another method, first, a DNA or cDNA sample is prepared from a biological sample. Subsequently, DNA from all or part of the region containing the RB1 gene is amplified. In addition, the amplified DNA is cut by a restriction enzyme. Subsequently, the DNA fragments are separated according to their size. Subsequently, the size of the detected DNA fragments is compared with a control. Examples of such methods include methods utilizing restriction fragment length polymorphism (RFLP) and PCR-RFLP methods.

[1200] In another method, first, a DNA or cDNA sample is prepared from a biological sample. Subsequently, DNA from all or part of the region containing the RB1 gene is amplified. In addition, the amplified DNA is dissociated into single-stranded DNA. Subsequently, the dissociated single-stranded DNA is separated on a non-denaturing gel. The mobility of the separated single-stranded DNA on the gel is compared with a control. Examples of such methods include PCR-SSCP (single-strand conformation polymorphism) methods.

[1201] In another method, first, a DNA or cDNA sample is prepared from a biological sample. Subsequently, DNA containing all or part of the region of the RB1 gene is amplified. Furthermore, the amplified DNA is separated on a gel, wherein the concentration of a DNA denaturant is gradually increased. Subsequently, the mobility of the separated DNA on the gel is compared with a control. Examples of such methods include denaturant gradient gel electrophoresis (DGGE).

[1202] Another method includes a method using DNA prepared from a biological sample and containing a mutation site in the RB1 gene region, and a substrate on which an oligonucleotide probe hybridizing with the DNA is immobilized. Examples of such methods include DNA array methods.

[1203] In another method, first, a DNA or cDNA sample is prepared from a biological sample. An "oligonucleotide primer having a nucleotide sequence complementary to the base on the 3' side of the base in all or part of the gene of RB1 and a nucleotide sequence on its 3' side" is prepared. Subsequently, a ddNTP primer extension reaction is performed using the primer using the DNA as a template. Subsequently, the primer extension reaction product is applied to a mass analyzer for mass measurement. Subsequently, the gene type is determined from the result of the mass measurement. Subsequently, the determined gene type is compared with a control. Examples of such methods include MALDI-TOF / MS methods.

[1204] In another method, first, a DNA or cDNA sample is prepared from a biological sample. Subsequently, an oligonucleotide probe consisting of 5'-"a nucleotide sequence complementary to the bases of the entire or partial region of the gene of RB1 and a nucleotide sequence on its 5' side"-"a nucleotide sequence that does not hybridize with the bases on the 3' side of the entire or partial region of the gene of RB1 through one base and a nucleotide sequence on its 3' side"-3' (flap) is prepared. "An oligonucleotide probe having a nucleotide sequence complementary to the bases of the entire or partial region of the gene of RB1 and a nucleotide sequence on its 3' side" is prepared. Subsequently, the two oligonucleotide probes are hybridized with the prepared DNA or cDNA sample. Subsequently, the hybridized DNA is cut by a single-stranded DNA cleavage enzyme to release the flap. The single-stranded DNA cleavage enzyme is not particularly limited, and examples thereof include cleavage enzymes. In this method, subsequently, an oligonucleotide probe having a sequence complementary to the flap and labeled with reporter fluorescence and quencher fluorescence is hybridized with the flap. Subsequently, the intensity of the generated fluorescence is measured. Subsequently, the measured fluorescence intensity is compared with a control. Examples of such methods include the Invader method.

[1205] In another method, first, a DNA or cDNA sample is prepared from a biological sample. Subsequently, DNA from all or part of the region containing the RB1 gene is amplified. The amplified DNA is dissociated into single-stranded DNA, and only one strand is isolated from the dissociated single-stranded DNA. Subsequently, a base-by-base extension reaction is performed near the bases of all or part of the region of the RB1 gene, and the pyrophosphate generated at this time is subjected to enzymatic luminescence, and the luminescence intensity is measured. The measured fluorescence intensity is compared with a control. Examples of such methods include pyrophosphate sequencing.

[1206] In another method, first, a DNA or cDNA sample is prepared from a biological sample. Then, DNA containing the entire or partial region of the RB1 gene is amplified. Then, "an oligonucleotide primer having a nucleotide sequence complementary to the base on the 3' side of the base in the entire or partial region of the RB1 gene and a nucleotide sequence on its 3' side" is prepared. Then, a single base extension reaction is carried out using the prepared primer in the presence of a fluorescently labeled nucleotide using the amplified DNA as a template. The degree of polarization of the fluorescence is measured. Then, the measured degree of fluorescence polarization is compared with a control. Examples of such methods include the AcycloPrime method.

[1207] In another method, first, a DNA or cDNA sample is prepared from a biological sample. Subsequently, DNA containing all or part of the gene of RB1 is amplified. Subsequently, "an oligonucleotide primer having a nucleotide sequence complementary to the base on the 3' side of the base in all or part of the gene of RB1 by one base and a nucleotide sequence on its 3' side" is prepared. Subsequently, a single base extension reaction is carried out using the prepared primer in the presence of fluorescently labeled nucleotides using the amplified DNA as a template. Subsequently, the base type used for the single base extension reaction is determined. Subsequently, the determined base type is compared with a control. Examples of such methods include the SNuPE method.

[1208] When the mutation is associated with an amino acid change in the RB1 protein, the sample prepared from the biological sample can be a protein. Methods using molecules that specifically bind to the site where the amino acid change occurs due to the mutation, peptide mass fingerprinting (PMF), protein sequencers (Edman degradation), and the like can be used to detect the mutation.

[1209] As used herein, "reduction in expression of the RB1 gene or protein" means that, when analyzing the RB1 gene or protein in a subject, the expression level of the RB1 gene or protein is lower compared to a control (e.g., the expression level in a healthy individual or in non-cancerous tissue of the same patient). In one embodiment, the reduction in the expression level of the RB1 gene or protein is detected in a biological sample (e.g., cancer cells) derived from a cancer patient.

[1210] Examples of methods for detecting a decrease in the expression of the RB1 gene include, but are not particularly limited to, methods in which the expression level of RB1 is detected at the transcriptional level or translational level and compared with a control. In the method for detecting the expression level of the RB1 gene at the transcriptional level, first, RNA or cDNA is prepared from a biological sample. The method for extracting RNA from a biological sample and the method for preparing cDNA from the extracted RNA are not particularly limited, and known methods can be appropriately selected and used. Examples include extraction methods using phenol and a chaotropic salt (more specifically, extraction methods using commercially available kits such as TRIzol (manufactured by Invitrogen Corporation) or ISOGEN (manufactured by Wako Pure Chemical Industries, Ltd.)) and methods using another commercially available kit (e.g., RNAPrep Total RNA Extraction Kit (manufactured by Beckman Coulter Inc.), RNeasy Mini (manufactured by QIAGEN NV), or RNA Extraction Kit (manufactured by Pharmacia Biotech, Inc.)). In addition, 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), AMV (avian myeloblastosis virus), and reverse transcriptases derived from mouse retroviruses such as MMLV (Moloney murine leukemia virus).

[1211] Subsequently, an amplification reaction or hybridization reaction is performed using oligonucleotide primers or oligonucleotide probes, and the amplified product or hybridization product is detected. Such methods include, for example, RT-PCR, Northern blotting, dot blotting, DNA arrays, in situ hybridization, RNase protection assays, mRNA-seq, etc. Those skilled in the art can design oligonucleotide primers or oligonucleotide probes suitable for each method in a conventional manner based on the nucleotide sequence of the RB1 cDNA.

[1212] One of the reasons for reduced gene expression known in the art is excessive methylation of the promoter. Therefore, the methylation of the RB1 gene promoter can be used as an indicator to detect whether the function of RB1 is suppressed. In order to detect the methylation of the promoter, for example, a known method can be used, such as a method in which the nucleotide sequence is directly detected by determining the nucleotide sequence or a restriction endonuclease (which can recognize (cut) the nucleotide sequence before bisulfite treatment and cannot recognize (cut) the nucleotide sequence after bisulfite treatment) is used to indirectly detect the change of the nucleotide sequence after bisulfite treatment with the activity of converting methylated cytosine to uracil.

[1213] The method for detecting the reduction in the expression of RB1 protein is not particularly limited, but for example, the reduction can be confirmed and determined by IHC (immunohistochemistry) using an antibody specific for RB1 protein. In the method for detecting proteins using antibodies, first, a protein sample is prepared from a biological sample. Subsequently, an antibody specific for RB1 protein is used, an antigen-antibody reaction is used, and RB1 protein is detected. When the sample is labeled with an antibody specific for RB1 protein, RB1 protein can be directly detected; and when the sample is not labeled, a labeled molecule that recognizes the antibody (such as a secondary antibody or protein A) can be further applied to indirectly detect RB1 protein using the label of the molecule. As such methods, for example, immunohistochemistry (immunostaining), Western blotting, ELISA, flow cytometry, imaging cytometry, radioimmunoassay, immunoprecipitation, or an analysis method using an antibody array can be used. This method also has the following advantages: additional information, such as the form or distribution status of cancer cells in the tissue, can also be obtained by immunohistochemistry.

[1214] The type and source of the antibody used are not particularly limited, and monoclonal antibodies are preferred. Oligoclonal antibodies (a mixture of several antibodies or dozens of antibodies) or polyclonal antibodies can also be used, as long as they can detect the RB1 protein with sufficient specificity. Functional portions of antibodies such as Fab, Fab', F(ab')2, Fv, scFv, sc(Fv)2, dsFv and diabodies, and multimers thereof (e.g., dimers, trimers, tetramers and polymers) can also be used. Such anti-RB1 protein antibodies can be commercially available products.

[1215] The RB1 protein can also be detected by mass spectrometry (MS). In particular, analysis by mass spectrometry coupled with liquid chromatography (LC / MS) is sensitive and therefore advantageous. Detection by mass spectrometry can be performed, for example, by labeling a protein sample with a protein, fractionating the labeled protein, performing mass analysis on the fractionated protein, and identifying the RB1 protein based on the mass analysis values. As labels, isotope-labeled reagents known in the art can be used, and suitable labeling reagents are available as commercially available products. Fractionation can be performed by methods known in the art, and, for example, commercially available ion exchange columns can be used.

[1216] As used herein, amplification of CCNE1 gene copy number can be determined by evaluating the copy number of the CCNE1 gene using a biological sample derived from a cancer patient in a diagnostic or prognostic assay (eg, next generation sequencer, digital PCR, array CGH method, or FISH method).

[1217] As used herein, a "patient" can be a mouse, rat, guinea pig, monkey, dog, sheep, horse, or human. In the present invention, a "cancer patient" can include not only humans suffering from cancer but also humans at risk of developing cancer. In one embodiment, the subject to be treated or prevented is a cancer patient in whom no increase in CCNE1 gene expression compared to a control is detected. Furthermore, in one embodiment, the subject to be treated or prevented is not an OVCAR3-implanted mouse. This pharmaceutical composition is suitable for use in humans.

[1218] As used herein, a "biological sample derived from a cancer patient" is not particularly limited, as long as it is a biological sample that allows detection of the presence or absence of an RB1 gene mutation, or the presence or absence of a decrease in the expression of the RB1 gene or protein, and specimen materials such as cancer biopsy specimen materials, blood, urine, body cavity fluid, or circulating DNA derived from tumor cells (circulating tumor DNA: ctDNA). A biological sample derived from a cancer patient may be a protein extract or a nucleic acid extract (e.g., an mRNA extract, or a cDNA preparation or cRNA preparation prepared from an mRNA extract) obtained from the specimen material. As used herein, a "biological sample" includes samples derived from cancer patients and samples derived from cancer cell cultures.

[1219] RB1 gene mutations may include mutations that cause insertion, deletion or addition of at least one amino acid residue in the wild-type RB1 protein or substitution of an existing amino acid residue. RB1 gene mutations may be nonsense mutations, frameshift mutations, splice site mutations, heterozygous deletions or homozygous deletions. RB1 gene mutations are preferably mutations that reduce the function of RB1. "Mutations that reduce the function of RB1" can be found, for example, on the internet.<URL:https: / / www.oncokb.org / gene / RB1> [Retrieved February 20, 2023] to confirm.

[1220] The nucleotide sequence of a representative DNA (cDNA) of the wild-type human RB1 gene is shown in SEQ ID NO: 1 (NCBI Reference Number: NM_000321.3), and the representative amino acid sequence of the wild-type human RB1 gene is shown in SEQ ID NO: 2 (NCBI Reference Number: NP_000312.2). In the case of the human RB1 gene, an RB1 gene mutation means a nucleotide sequence that is different from the human RB1 genomic sequence described at positions 48,303,751 to 48,481,890 in NCBI Document Number NC_13.11, which means a nucleotide sequence that is different from the human RB1 nucleotide sequence described at positions 4921 to 5161 in NCBI Reference Number NG_9009.1, or includes a mutation that produces an amino acid sequence that is different from the amino acid sequence of the human RB1 protein shown in SEQ ID NO: 2. This mutation can produce at least one of the following (1) to (5). Note that even in RB1 without a mutation, the sequence may vary from individual to individual due to polymorphisms, etc.

[1221] (1) the codon for the serine residue (S) at position 82 of the amino acid sequence corresponding to SEQ ID No: 2 is replaced with a stop codon,

[1222] (2) the codon for the arginine residue (R) at position 467 of the amino acid sequence corresponding to SEQ ID No: 2 is replaced with a stop codon,

[1223] (3) at least one base is inserted or deleted in the codon corresponding to the amino acid residue at position 182 of SEQ ID No: 2, forming a new reading frame starting with an isoleucine residue (I), and the third reading frame therefrom is a stop codon,

[1224] (4) the glutamic acid residue (E) at position 837 of the amino acid sequence of SEQ ID No: 2 is replaced by a lysine residue (K), and a portion of the RB1 gene is homozygously deleted, and

[1225] (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.

[1226] As used herein, reduction in expression of the RB1 gene or protein includes reduction in gene expression through methylation of the RB1 gene or microRNA.

[1227] 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 patients who have been tested positive for RB1 gene mutations or reduced expression of the RB1 gene or protein, or in patients who have been tested positive for RB1 gene mutations 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.

[1228] In a specific embodiment, the cancer is lung cancer. The pharmaceutical composition of the present invention is suitable for treating or preventing cancer, and is particularly suitable for treating or preventing lung cancer.

[1229] On the one hand, the compounds represented by formulae (1) to (3) of the present invention, or salts thereof, or solvates thereof can be used as MYT1 inhibitors.

[1230] A pharmaceutical composition containing a compound represented by formula (1) to (3) of the present invention, or a salt thereof, or a solvate thereof (first component) as an active ingredient (hereinafter also referred to as the "pharmaceutical composition of the present invention") can be used in combination with a chemotherapeutic agent (second component). In one embodiment, the pharmaceutical composition of the present invention and the chemotherapeutic agent are administered simultaneously or separately. In another embodiment, the pharmaceutical composition of the present invention and the chemotherapeutic agent are administered as a combined agent.

[1231] A chemotherapeutic agent is a substance that has anticancer activity (also called antitumor activity). A chemotherapeutic agent can be, for example, an antimetabolite.

[1232] Antimetabolites are substances with a similar chemical structure to a metabolite (eg, folic acid) that compete with or inhibit the metabolic machinery of an organism. Examples of antimetabolites include antifolates.

[1233] Antifolates are substances that inhibit DNA synthesis by suppressing or inhibiting the action of an enzyme that reduces folic acid to active folic acid, which is necessary for nucleic acid biosynthesis. Examples of antifolates include methotrexate and pemetrexed. The antifolate is more preferably pemetrexed.

[1234] In this embodiment, a preferred combination of the MYT1 inhibitor and the chemotherapeutic agent is such that the MYT1 inhibitor is a compound represented by formula (1) to (3) of the present invention or a salt thereof or a solvate thereof, and the chemotherapeutic agent is pemetrexed.

[1235] The dosage of the compound represented by formula (1) to (3) of the present invention or its salt or its solvate is preferably 0.001 to 50 mg (0.001 to 50 mg / kg / day) per kg of subject's body weight to be administered per day, more preferably 0.001 to 20 mg / kg / day, and further preferably 0.002 to 10 mg / kg / day. When the dosage of the compound represented by formula (1) to (3) of the present invention or its salt or its solvate falls within the range, the effect of treating or preventing cancer is further enhanced. The frequency of administration of the compound represented by formula (1) to (3) of the present invention or its salt or its solvate can be, for example, once a week or more, twice a week, once a day or twice a day.

[1236] The dosage of chemotherapeutic agent is preferably 0.005 to 300mg (0.005 to 300mg / kg / day) of subject's body weight to be administered per kg per day, more preferably 0.01 to 250mg / kg / day, further preferably 0.02 to 200mg / kg / day. When the dosage of chemotherapeutic agent falls within this range, the effect of treating or preventing cancer is further enhanced. The frequency of administration of chemotherapeutic agent can be, for example, once a week or more, twice a week, once a day or twice a day.

[1237] The compound represented by formula (1) to (3) of the present invention, or a salt thereof, or a solvate thereof (first component) and the chemotherapeutic agent (second component) are preferably administered at a dose of 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 at a dose of 0.001 to 20 mg / kg / day for the first component and 0.01 to 250 mg / kg / day for the second component, and further preferably at a dose of 0.002 to 10 mg / kg / day for the first component and 0.02 to 200 mg / kg / day for the second component per kg of body weight of the subject to be administered. When the doses of the first component and the second component fall within this range, the effect of treating or preventing cancer is further enhanced.

[1238] In the present invention, examples of administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous, percutaneous absorption), intracisternal, intravaginal, intraperitoneal, intravesical or local (injection, instillation, powder, ointment, gel or cream) administration, and by inhalation (oral or nasal spray). Examples of dosage forms include tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions filled in containers suitable for subdivision into individual doses. The dosage form can also be adjusted to be suitable for a variety of administration methods, including controlled-release preparations such as subcutaneous implants.

[1239] The first component can be applied by any one of the above-mentioned methods of application, and the second component can be applied by the method of application identical to the first component or the method of application different from the first component. The dosing interval between the first component and the second component can be, for example, an interval of 0 to 14 days, an interval of 0 to 10 days, or an interval of 0 to 7 days. The dosing interval can be determined using, for example, AUC, Cmax, Tmax, elimination half-life, and the health status of the subject as a criterion. For example, the first component can be orally administered (tablets, capsules, etc.), and the second component can be applied by instillation. For example, the first component and the second component can both be orally administered (tablets, capsules, etc.). For example, the first component can be applied by instillation, and the second component can be orally administered (tablets, capsules, etc.). For example, the first component and the second component can both be applied by instillation. In such cases, the first component and the second component can be applied at any interval, such as three times a day, twice a day, once a day, once a week, and once every two weeks. More specifically, the first component and the second component can both be applied once a day, and in this case, they can be applied before meals, between meals, or after meals. Before meals, between meals or after meals can be before, between or after breakfast, lunch, dinner, supper or snack.When the dosing interval between the first component and the second component is within 24 hours, it means that the two components are applied once a day.If necessary, in some cases, the first component and the second component are applied 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, only the application interval of the second component can be increased or decreased, and only the application interval of the first component can be increased or decreased.The application of the second component can start on the application start day of the first component, and the application start day of the first component and the application start day of the second component can be different from each other.For the duration of application, the total number of courses of treatment can be one course of treatment or more, or two courses of treatment or more, with 7 days as one course of treatment.Each course of treatment can be carried out continuously, or a rest period can be set.A rest period can be set during the course of treatment. If necessary, it is also possible to continuously administer only the first component and stop administering the second component in one course of treatment, or to stop administering only the first component and continue administering the second component.The first component and the second component may be included in the same tablet, capsule, or the like.

[1240] The pharmaceutical composition according to this embodiment can be administered in combination with, for example, a pharmaceutical composition containing a MYT1 inhibitor as described in the "Second embodiment related to the treatment or prevention of cancer" below (combined administration).

[1241] One aspect of this embodiment is a MYT1 inhibitor for use in combination with a chemotherapeutic agent in treating or preventing cancer in a cancer patient in whom RB1 gene mutation, decreased expression of RB1 gene or protein, or hyperphosphorylated RB1 protein expression has been detected.

[1242] One aspect of this embodiment is a MYT1 inhibitor for use in combination with a chemotherapeutic agent in treating or preventing cancer in a cancer patient who has RB1 gene mutation or reduced expression of RB1 gene or protein.

[1243] Another aspect of this embodiment is the use of a MYT1 inhibitor for producing a pharmaceutical composition for treating or preventing cancer in a cancer patient in whom RB1 gene mutation positivity or reduced expression of the RB1 gene or protein has been detected, wherein the MYT1 inhibitor is administered in combination with a chemotherapeutic agent.

[1244] Another aspect of this embodiment is the use of a MYT1 inhibitor to produce a pharmaceutical composition for treating or preventing cancer in a cancer patient who has a positive RB1 gene mutation or reduced expression of the RB1 gene or protein, wherein the pharmaceutical composition is administered in combination with a chemotherapeutic agent. [Second embodiment involving the treatment or prevention of cancer]

[1245] A second embodiment related to the treatment or prevention of cancer is a pharmaceutical composition for treating or preventing cancer in a cancer patient in combination with a MYT1 inhibitor, wherein the cancer patient has been detected to be positive for RB1 gene mutation or reduced expression of RB1 gene or protein, the pharmaceutical composition comprising a chemotherapeutic agent as an active ingredient.

[1246] Each term in this specification (e.g., MYT1 inhibitor, chemotherapeutic agent, RB1 gene mutation, administration method, cancer type) can refer to the definition in the "First Example Involving the Treatment or Prevention of Cancer". In this specification, a cancer in which RB1 gene mutation has been detected to be positive or the expression of RB1 gene or protein has been reduced in a cancer patient can be a cancer in which RB1 gene mutation has been detected to be positive or the expression of RB1 gene or protein has been reduced in the patient. The pharmaceutical composition according to this embodiment can be administered in combination with a pharmaceutical composition containing a MYT1 inhibitor as described in the "First Example Involving the Treatment or Prevention of Cancer" (combined administration).

[1247] In one embodiment, the pharmaceutical composition contains a chemotherapeutic agent (second ingredient) as an active ingredient. The pharmaceutical composition containing the chemotherapeutic agent as an active ingredient is used in combination with a MYT1 inhibitor (first ingredient). In one embodiment, the pharmaceutical composition containing the chemotherapeutic agent and the MYT1 inhibitor are administered simultaneously or separately. In another embodiment, the pharmaceutical composition containing the chemotherapeutic agent and the MYT1 inhibitor are administered as a combination.

[1248] In this embodiment, a preferred combination of the MYT1 inhibitor and the chemotherapeutic agent is such that the MYT1 inhibitor is a compound represented by formula (1) to (3) of the present invention or a salt thereof or a solvate thereof, and the chemotherapeutic agent is pemetrexed.

[1249] The dosage of the MYT1 inhibitor (first component) and the chemotherapeutic agent (second component) is preferably such that the first component is 0.0001 to 50 mg / kg / day and the second component is 0.005 to 300 mg / kg / day, more preferably such that the first component is 0.001 to 20 mg / kg / day and the second component is 0.01 to 250 mg / kg / day, and further preferably such that the first component is 0.002 to 10 mg / kg / day and the second component is 0.02 to 200 mg / kg / day per kg of the subject's body weight to be administered. When the dosage of the first component and the second component falls within this range, the effect of treating or preventing cancer is further enhanced.

[1250] Another aspect of this embodiment is a chemotherapeutic agent used in combination with a MYT1 inhibitor to treat or prevent cancer in a cancer patient in whom RB1 gene mutation-positive or reduced expression of RB1 gene or protein has been detected.

[1251] Another aspect of this embodiment is the use of a chemotherapeutic agent for producing a pharmaceutical composition for treating or preventing cancer in a cancer patient in whom RB1 gene mutation positivity or reduced expression of RB1 gene or protein has been detected, wherein the pharmaceutical composition is administered in combination with a MYT1 inhibitor.

[1252] [Third embodiment related to treatment or prevention of cancer]

[1253] A third embodiment of the present invention, directed to the treatment or prevention of cancer, is a method for treating or preventing cancer in a cancer patient, wherein a positive RB1 gene mutation or decreased expression of the RB1 gene or protein has been detected, the method comprising administering a chemotherapeutic agent and a MYT1 inhibitor in combination to the cancer patient. One aspect of this embodiment is a method for treating or preventing cancer, comprising detecting a positive RB1 gene mutation or decreased expression of the RB1 gene or protein in a biological sample derived from the cancer patient, or permitting a third party to perform the detection, and administering a chemotherapeutic agent and a MYT1 inhibitor in combination to the cancer patient.

[1254] The dosage of the MYT1 inhibitor (first component) and the chemotherapeutic agent (second component) is preferably such that the first component is 0.0001 to 50 mg / kg / day and the second component is 0.005 to 300 mg / kg / day, more preferably such that the first component is 0.001 to 20 mg / kg / day and the second component is 0.01 to 250 mg / kg / day, and further preferably such that the first component is 0.002 to 10 mg / kg / day and the second component is 0.02 to 200 mg / kg / day per kg of the subject's body weight to be administered. When the dosage of the first component and the second component falls within this range, the effect of treating or preventing cancer is further enhanced.

[1255] When administering a chemotherapeutic agent in combination with a MYT1 inhibitor, the MYT1 inhibitor and the chemotherapeutic agent may be administered simultaneously, or may be administered separately at regular dosing intervals. The routes of administration of the MYT1 inhibitor and the chemotherapeutic agent may be the same or different. The MYT1 inhibitor and the chemotherapeutic agent may be administered as a combination containing the MYT1 inhibitor and the chemotherapeutic agent. That is, a pharmaceutical composition may contain both the MYT1 inhibitor and the chemotherapeutic agent.

[1256] [Fourth embodiment related to treatment or prevention of cancer]

[1257] A fourth embodiment related to the treatment or prevention of cancer is a method for inhibiting the growth of cancer cells in a cancer patient, wherein the patient has been tested positive for an RB1 gene mutation or reduced expression of the RB1 gene or protein, the method comprising contacting the cancer cells with a MYT1 inhibitor and a chemotherapeutic agent. One aspect of this embodiment is a method for inhibiting the growth of cancer cells, the method comprising detecting a positive RB1 gene mutation or reduced expression of the RB1 gene or protein in a biological sample derived from a cancer patient, or allowing a third party to perform the detection, and contacting the cancer cells with a MYT1 inhibitor and a chemotherapeutic agent.

[1258] The method described in this embodiment includes any form of in vivo, in vitro and ex vivo. For example, the animal in which the RB1 gene mutation is detected or the expression of the RB1 gene or protein is reduced can be an animal in which the RB1 gene mutation is detected or the expression of the RB1 gene or protein is reduced. Examples of animal species include mice, rats, guinea pigs, monkeys, dogs, sheep, horses or humans. In the case of the body, the growth of cancer cells can be suppressed by administering MYT1 inhibitors and chemotherapeutics to the above-mentioned subjects. In the case of the body, the growth of cancer cells can be suppressed by adding MYT1 inhibitors and chemotherapeutics to a system containing cancer cells collected from the above-mentioned subjects. In the case of ex vivo, the growth of cancer cells can be suppressed by collecting an organ containing cancer cells from the subject (for example, the lung in the case of lung cancer) and administering MYT1 inhibitors and chemotherapeutics to the organ. The dosage of the first component (MYT1 inhibitor) and the second component (chemotherapeutics) can be appropriately set according to the amount of cancer cells and the type of MYT1 inhibitor and chemotherapeutics used.

[1259] [Fifth embodiment related to treatment or prevention of cancer]

[1260] A fifth embodiment of the present invention, directed to the treatment or prevention of cancer, is a method for improving responsiveness to cancer treatment with a chemotherapeutic agent, wherein the cancer is a cancer in a cancer patient in which a positive RB1 gene mutation, decreased expression of the RB1 gene or protein, or positive expression of hyperphosphorylated RB1 protein has been detected, the method comprising administering a MYT1 inhibitor to the cancer patient 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 a positive RB1 gene mutation or decreased expression of the RB1 gene or protein in a biological sample derived from the cancer patient, or allowing a third party to perform the detection, and administering a MYT1 inhibitor to the cancer patient together with the chemotherapeutic agent.

[1261] In treating cancer in patients in whom RB1 gene mutations are detected or expression of the RB1 gene or protein is decreased, the method described in this embodiment includes administering a chemotherapeutic agent in combination with a MYT1 inhibitor to the patient. By administering a chemotherapeutic agent in combination with a MYT1 inhibitor, the efficacy of cancer treatment with the chemotherapeutic agent can be improved.

[1262] When a MYT1 inhibitor is administered to a cancer patient together with a chemotherapeutic agent, both the MYT1 inhibitor and the chemotherapeutic agent may be administered simultaneously or separately at a predetermined dosing interval. The routes of administration of the MYT1 inhibitor and the chemotherapeutic agent may be the same or different. The MYT1 inhibitor and the chemotherapeutic agent may be administered as a combination containing the MYT1 inhibitor and the chemotherapeutic agent. Even in patients for whom existing chemotherapeutic agents have an insufficient therapeutic effect, the chemotherapeutic agent may exhibit a sufficient therapeutic effect by combining with the MYT1 inhibitor.

[1263] The dosage of the MYT1 inhibitor (first component) and the chemotherapeutic agent (second component) is preferably such that the first component is 0.0001 to 50 mg / kg / day and the second component is 0.005 to 300 mg / kg / day, more preferably such that the first component is 0.001 to 20 mg / kg / day and the second component is 0.01 to 250 mg / kg / day, and further preferably such that the first component is 0.002 to 10 mg / kg / day and the second component is 0.02 to 200 mg / kg / day per kg of the subject's body weight to be administered. When the dosage of the first component and the second component falls within this range, the effect of treating or preventing cancer is further enhanced.

[1264] [Sixth embodiment related to treatment or prevention of cancer]

[1265] A sixth embodiment relating to the treatment or prevention of cancer is a method for predicting responsiveness to cancer treatment with a combination of a MYT1 inhibitor and a chemotherapeutic agent, the method comprising detecting the presence or absence of an RB1 gene mutation or the presence or absence of reduced expression of the RB1 gene or protein in a biological sample derived from a cancer patient, or allowing a third party to perform the detection; and determining that the patient is responsive to cancer treatment with a combination of a MYT1 inhibitor and a chemotherapeutic agent when the test is positive for an RB1 gene mutation, or when the expression of the RB1 gene or protein is reduced, or when the expression of hyperphosphorylated RB1 protein is positive.

[1266] In the method according to this embodiment, when the presence or absence of an RB1 gene mutation, the presence or absence of a decrease in the expression of the RB1 gene or protein is detected or detected by a third person, and when the RB1 gene mutation is positive or the expression of the RB1 gene or protein is decreased in cancer cells collected from a cancer patient as a subject to be treated, the cancer patient is determined to be responsive (efficacy) to treatment in which a combination of a MYT1 inhibitor and a chemotherapeutic agent is administered.

[1267] According to the method described in this embodiment, even in patients for whom existing chemotherapeutic agents have insufficient therapeutic effects, as long as the cancer patient is positive for an RB1 gene mutation or has decreased expression of the RB1 gene or protein, the chemotherapeutic agent can be determined to have a therapeutic effect by administering it in combination with a MYT1 inhibitor. Therefore, effective chemotherapy can be provided in advance to cancer patients for whom existing chemotherapeutic agents alone are insufficiently effective.

[1268] Detection of RB1 gene mutations or reduction of RB1 gene or protein expression in cancer cells can be performed by methods well known to those skilled in the art, examples of which include direct sequencing, PCR, TaqMan genotyping, and next-generation sequencing.

[1269] One aspect of this embodiment is also a method for selecting a cancer patient for whom a combination of a MYT1 inhibitor and a chemotherapeutic agent is more effective. The method includes detecting or allowing a third person to detect the presence or absence of an RB1 gene mutation or the presence or absence of decreased 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 a combination of a MYT1 inhibitor and a chemotherapeutic agent is more effective based on the presence of the mutation.

[1270] Another aspect of this embodiment is a method for diagnosing a specific cancer patient as one for whom a combination of a MYT1 inhibitor and a chemotherapeutic agent is more effective for cancer treatment than administration of the chemotherapeutic agent alone. The method includes detecting, or allowing a third person to detect, the presence or absence of an RB1 gene mutation or decreased expression of the RB1 gene or protein in cancer cells derived from the cancer patient, and, based on the presence of the mutation, identifying the cancer patient as one for whom a combination of a MYT1 inhibitor and a chemotherapeutic agent is more effective.

[1271] [Seventh embodiment related to treatment or prevention of cancer]

[1272] The seventh embodiment relating to the treatment or prevention of cancer is a method for screening a compound effective for treating or preventing cancer in a patient in whom RB1 gene mutation positivity or reduced expression of RB1 gene or protein has been detected, the method comprising measuring the MYT1 inhibitory activity of a candidate compound; and selecting a candidate compound having MYT1 inhibitory activity as a compound effective for treating cancer.

[1273] The method according to this embodiment includes measuring the MYT1 inhibitory activity of a candidate compound, and when the candidate compound has the MYT1 inhibitory activity, selecting the candidate compound as a compound effective for treating cancer.

[1274] In the present invention, the MYT1 inhibitor means a substance that can directly or indirectly neutralize, block, inhibit, reduce or prevent MYT1 activity. Examples of the activity of the MYT1 protein include threonine kinase activity or tyrosine kinase activity.

[1275] For example, the inhibition of the threonine kinase activity or tyrosine kinase activity of MYT1 by the compound can be confirmed by treating a purified MYT1 protein standard sample with the test compound, adding ATP, and using the degree of ATP hydrolysis as a criterion. The degree of ATP hydrolysis can be assessed using Kinase-Glo (manufactured by Promega) or ADP-Glo ​​(manufactured by Promega) (Non-Patent Document 8). When the threonine kinase activity or tyrosine kinase activity of MYT1 is inhibited by the test compound, a decrease in ATP hydrolysis can be confirmed compared to a control (e.g., the degree of ATP hydrolysis of MYT1 not treated with the test compound).

[1276] The inhibition of the threonine kinase activity of the MYT1 protein by the compound can be confirmed by, for example, treating a purified MYT1 protein standard sample with the test compound, adding CDK1 as a substrate of MYT1, and using the phosphorylation degree of Thr at position 14 of CDK1 as a criterion. The degree of phosphorylation at this position can be determined by Western blotting using an antibody that specifically recognizes phosphorylation of Thr at position 14 of CDK1 (manufactured by Abcam plc), an ELISA method using an antibody that specifically recognizes CDK1 and an antibody that specifically recognizes phosphorylation of Thr at position 14 of CDK1, or an AlphaLISA method using an antibody that specifically recognizes CDK1 and an antibody that specifically recognizes phosphorylation of Thr at position 14 of CDK1 (manufactured by PerkinElmer, Inc.). When the threonine kinase activity of MYT1 is inhibited by the test compound, the degree of phosphorylation can be confirmed compared to a control (for example, the degree of phosphorylation of Thr at position 14 of CDK1 caused by MYT1 not treated with the test compound).

[1277] For example, the phosphorylation degree of Thr at position 14 of CDK1 (which is a substrate protein of the threonine kinase activity of MYT1) can be used as a criterion to confirm the inhibition of the threonine kinase activity of MYT1 by the compound in the cell lysate treated with the test compound. The phosphorylation degree at this position can be determined by Western blotting using an antibody (manufactured by Abcam plc) that specifically recognizes the phosphorylation of Thr at position 14 of CDK1, an ELISA method using an antibody that specifically recognizes CDK1 and an antibody that specifically recognizes the phosphorylation of Thr at position 14 of CDK1, or an AlphaLISA method (manufactured by PerkinElmer, Inc.) using an antibody that specifically recognizes CDK1 and an antibody that specifically recognizes the phosphorylation of Thr at position 14 of CDK1 (manufactured by PerkinElmer, Inc.) (non-patent literature 8). When the threonine kinase activity of MYT1 is inhibited by the test compound, the degree of phosphorylation can be confirmed compared to the control (e.g., by the phosphorylation degree of Thr at position 14 of CDK1 in the lysate of cells not treated with the test compound).

[1278] For example, inhibition of MYT1 expression by a compound can be confirmed by detecting a decrease in MYT1 expression in cells treated with the test compound. Examples of methods for detecting a decrease in MYT1 expression include methods in which the expression level of MYT1 is detected at the transcriptional level or translational level under normal circumstances and compared with a control (e.g., the expression level in cells not treated with the test compound) to confirm that the expression level is lower than the control.

[1279] In the method for detecting the expression level of MYT1 at the transcriptional level, first, RNA or cDNA is prepared from cells treated with a test compound. The method for extracting RNA from cells is not particularly limited, and a known method can be appropriately selected and used. Examples include extraction methods using phenol and a chaotropic salt (more specifically, extraction methods using commercially available kits such as TRIzol (manufactured by Invitrogen Corporation) or ISOGEN (manufactured by Wako Pure Chemical Industries, Ltd.)) and methods using another commercially available kit (e.g., RNAPrep Total RNA Extraction Kit (manufactured by Beckman Coulter Inc.), RNeasy Mini (manufactured by QIAGEN NV), or RNA Extraction Kit (manufactured by Pharmacia Biotech, Inc.)). In addition, 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 RAV (Rous-associated virus), AMV (avian myeloblastosis virus), and reverse transcriptases derived from mouse retroviruses such as MMLV (Moloney murine leukemia virus).

[1280] Subsequently, an amplification reaction or hybridization reaction is performed using oligonucleotide primers or oligonucleotide probes, and the amplified product or hybridization product is detected. Such methods include, for example, RT-PCR, Northern blotting, dot blotting, DNA arrays, in situ hybridization, RNase protection assays, and mRNA-seq. Those skilled in the art can conventionally design oligonucleotide primers or oligonucleotide probes suitable for each method based on the nucleotide sequence of the MYT1 cDNA.

[1281] In a method for detecting the expression level of MYT1 at the translational level, first, a protein sample is prepared from cells treated with a test compound. Subsequently, an antibody specific for the MYT1 protein is used to perform an antigen-antibody reaction and detect the MYT1 protein. In such methods for detecting proteins using antibodies, for example, an antibody specific for the MYT1 protein is added to the protein sample to perform an antigen-antibody reaction and detect the binding of the antibody to the MYT1 protein. When the sample is labeled with an antibody specific for the MYT1 protein, the MYT1 protein can be directly detected; whereas, when the sample is not labeled, a labeled molecule that recognizes the antibody (e.g., a secondary antibody or protein A) can be further applied to indirectly detect the MYT1 protein using the label of the molecule. Such methods, for example, can be used: immunohistochemistry (immunostaining), Western blotting, ELISA, flow cytometry, imaging cytometry, radioimmunoassay, immunoprecipitation, or an analysis method using an antibody array.

[1282] The type and source of the antibody used are not particularly limited, and monoclonal antibodies are preferred. Oligoclonal antibodies (a mixture of several antibodies or dozens of antibodies) or polyclonal antibodies can also be used, as long as they can detect MYT1 protein with sufficient specificity. Functional portions of antibodies such as Fab, Fab', F(ab')2, Fv, scFv, sc(Fv)2, dsFv and diabodies, and multimers thereof (e.g., dimers, trimers, tetramers and polymers) can also be used. Such anti-MYT1 protein antibodies can be commercially available products.

[1283] MYT1 protein can also be detected by mass spectrometry (MS). In particular, analysis by mass spectrometry coupled with liquid chromatography (LC / MS) is sensitive and therefore advantageous. Detection by mass spectrometry can be performed, for example, by labeling a protein sample with a protein, fractionating the labeled protein, performing mass analysis on the fractionated protein, and identifying the MYT1 protein based on the mass analysis value. As a label, isotope-labeled reagents known in the art can be used, and suitable labeling reagents are available as commercially available products. Fractionation can be performed by methods known in the art, and, for example, commercially available ion exchange columns can be used.

[1284] As used herein, the term "having MYT1 inhibitory activity" means that MYT1 activity is reduced in vitro, in a cell culture system, or in an animal, and for example, the measured MYT1 inhibitory activity IC 50 Preferably, it is 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. Further preferred are compounds having MYT1 inhibitory activity (IC 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 MYT1 inhibitory activity (IC 50 ) is less than 20 nM or 1 nM to 20 nM. Compounds with higher MYT1 inhibitory activity (with lower IC 50 ) as a compound more effective for treating or preventing cancer in patients in whom RB1 gene mutation-positive or decreased expression of RB1 gene or protein is detected.

[1285] In treating cancer in patients in whom RB1 gene mutation-positive or RB1 gene or protein expression is detected to be decreased, the therapeutic efficacy of the compound selected according to the method described in this example is further enhanced by combining the compound with a chemotherapeutic agent.

[1286] [Example]

[1287] Hereinafter, the present disclosure will be described in more detail based on examples, but the present disclosure is not limited to the following examples.

[1288] NMR analysis was performed using AVANCE III HD400 (400 MHz) manufactured by BRUKER. NMR data are expressed in ppm (parts per million) (δ) and are referenced to a deuterium lock signal from the sample solvent.

[1289] Mass spectral data were obtained using a single quadrupole mass detector (LCMS-2020) equipped with an ultra high performance liquid chromatograph (Nexera UC) manufactured by SHIMADZU CORPORATION and a single quadrupole mass detector (SQD or SQD2) equipped with an Acquity ultra high performance liquid chromatograph (UPLC or UPLC I-Class) manufactured by Waters Corporation.

[1290] Analysis was performed by high performance liquid chromatography using any of the analytical conditions A to W described in the following Tables 1 and 2. In the following Tables 1 and 2, "TFA" means trifluoroacetic acid, "FA" means acetic acid, "AA" means ammonium acetate, and "AC" means ammonium bicarbonate.

[1291] [Table 1]

[1292]

[1293]

[1294] [Table 2]

[1295]

[1296]

[1297]

[1298] Microwave reactions were performed using initiators produced by Biotage and snap-capped reaction vials. The equipment was operated according to the manual provided with the equipment.

[1299] Photoredox catalysis was performed using a Penn PhD M2 integrated photoreactor (ACS Cent. Sci. 2017, Vol. 3, No. 6, pp. 647-653 (Non-Patent Document 20)). The device was operated according to the manual included with the device.

[1300] Commercially available reagents were used without further purification. All non-aqueous reactions were performed using commercially available dehydrated solvents. Concentration and solvent distillation were performed using a rotary evaporator under reduced pressure.

[1301] As used herein, the term "room temperature" means a temperature of about 20°C to about 25°C.

[1302] Compound a-1

[1303] 4-Bromo-7-chloro-2-(oxan-2-yl)indazole

[1304] [Equation 22]

[1305]

[1306] To a solution of 4- bromo-7- chloro-1H- indazole (44.97 g, 194 mmol) in DCM (900 mL) in a reaction vessel, 3,4- dihydro-2H- pyran (32.68 g, 388 mmol) and p-toluenesulfonic acid pyridinium salt (9.77 g, 38.9 mmol) were added, and the mixture was stirred at room temperature for 6 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and the mixture was extracted twice with DCM. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was then concentrated under reduced pressure. The obtained residue was suspended in a mixed solution of hexane / ethyl acetate (3 / 1), and the solid was collected by filtration. The filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography, and the purified product was merged with the previously obtained solid to obtain the title compound (55.17 g, yield 90%) as a yellow solid.

[1307] LCMS: m / z 315 [M+H] +

[1308] HPLC retention time: 4.97 min (analysis condition J)

[1309] Compound a-2

[1310] (2,4,6-Trichlorophenyl)7-chloro-2-(oxan-2-yl)indazole-4-carboxylate

[1311] [Equation 23]

[1312]

[1313] To a solution of 4- bromo-7- chloro-2- (oxacyclohexane-2-yl) indazole (compound a-1, 24.16g, 76.55mmol) in toluene (340mL) in a reaction vessel, triethylamine (15.5g, 153.18mmol) was added, and the reaction vessel was degassed under reduced pressure and replaced with nitrogen. Xantphos Pd G4 (3.69g, 3.83mmol) was added to the mixture, and the reaction vessel was further degassed under reduced pressure and replaced with nitrogen. When the reaction mixture was heated to 65°C, a solution of 2,4,6- trichlorophenyl formate (19.85g, 88mmol) in toluene (54mL) degassed under reduced pressure and replaced with nitrogen was added dropwise within 3 hours. The reaction mixture was stirred for another 20min at 65°C under a nitrogen atmosphere, then cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (46.69g) of the title compound.

[1314] LCMS: m / z 459 [M+H] +

[1315] HPLC retention time: 4.86 min (analysis condition K)

[1316] Compound a-3

[1317] 7-Chloro-2-(oxan-2-yl)indazole-4-carboxylic acid

[1318] [Equation 24]

[1319]

[1320] To a suspension of the crude product (46.69 g) of 7-chloro-2-(oxacyclohexane-2-yl) indazole-4-carboxylic acid (2,4,6-trichlorophenyl ester) (compound a-2) in THF (470 mL) in a reaction vessel, 2M aqueous sodium hydroxide solution (230 mL, 460 mmol) was added, and the mixture was stirred at 60 ° C for 16 hours. The reaction mixture was cooled to room temperature, ethyl acetate, water and aqueous phosphoric acid solution were added thereto, and the mixture was adjusted to pH 4, and then extracted twice with ethyl acetate. The organic layer was washed with water (500 mL), and then extracted four times with saturated sodium bicarbonate aqueous solution (400 mL) and 5% aqueous sodium bicarbonate solution (400 mL). The obtained aqueous layers were combined, and then cooled to 5 ° C, aqueous phosphoric acid solution was added, and the mixture was adjusted to pH 4. The mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was combined with the organic layer of another rotten product synthesized by performing the same operation, and the mixture was concentrated under reduced pressure to obtain the title compound (38.76 g) as a pale yellow solid.

[1321] LCMS: m / z 281 [M+H] +

[1322] HPLC retention time: 2.79 min (analysis condition K)

[1323] Compound a-4

[1324] 7-Chloro-N-methoxy-N-methyl-2-(oxan-2-yl)indazole-4-carboxamide

[1325] [Equation 25]

[1326]

[1327] To a solution of 7-chloro-2-(oxacyclohexane-2-yl)indazole-4-carboxylic acid (compound a-3, 38.76 g, 138 mmol) in THF (388 mL) in a reaction vessel, triethylamine (55.89 g, 552 mmol), N, O-dimethylhydroxylamine hydrochloride (26.94 g, 276 mmol) and HATU (68.25 g, 180 mmol) were added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate aqueous solution and dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (31.74 g, 71% yield) as a colorless solid.

[1328] LCMS: m / z 324 [M+H] +

[1329] HPLC retention time: 0.66 min (analysis condition A)

[1330] Compound a-5

[1331] 4-Bromo-5-fluoro-2-iodoaniline

[1332] [Equation 26]

[1333]

[1334] To a solution of 4- bromo-3-fluoroaniline (15.43 g, 81.2 mmol) in acetic acid (200 mL) in a reaction vessel was added N- iodosuccinimide (19.18 g, 85.248 mmol), 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 obtained solid was dissolved in DCM, and the mixture was washed with a saturated aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (22.01 g, 86% yield) as a brown solid.

[1335] LCMS: m / z 316 [M+H] +

[1336] HPLC retention time: 4.55 min (analysis condition J)

[1337] Compound a-6

[1338] (E)-N'-(4-Bromo-5-fluoro-2-iodophenyl)-N,N-dimethylformamidine

[1339] [Equation 27]

[1340]

[1341] 4-Bromo-5-fluoro-2-iodoaniline (compound a-5, 28.58 g, 190.47 mmol) in the reaction vessel was dissolved in EtOH (180 mL), N, N-dimethylformamide dimethyl acetal (43.12 g, 361.9 mmol) was added thereto, and the mixture was stirred at 80 ° C for 1.5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / DCM) to obtain the title compound (31.7 g, yield 95%) as a light red solid.

[1342] LCMS: m / z 371 [M+H] +

[1343] HPLC retention time: 2.59 min (analysis condition J)

[1344] Compound a-7

[1345] (E)-N'-[4-bromo-2-[7-chloro-2-(oxan-2-yl)indazole-4-carbonyl]-5-fluorophenyl]-N,N-diol Methylformamidine

[1346] [Equation 28]

[1347]

[1348] A solution of (E)-N'-(4-bromo-5-fluoro-2-iodophenyl)-N,N-dimethylformamidine (compound a-6, 16.39 g, 44.18 mmol) in toluene (164 mL) was cooled to -40°C in a reaction vessel, and a 1.3 M solution of isopropylmagnesium chloride-lithium chloride complex in THF (34 mL, 44.2 mmol) was added dropwise thereto, and the mixture was then stirred for 1 hour. A solution of 7-chloro-N-methoxy-N-methyl-2-(oxan-2-yl)indazole-4-carboxamide (compound a-4, 11.14 g, 34 mmol) in toluene (110 mL) was added dropwise to the reaction mixture over 30 minutes, and the mixture was then stirred at 0°C for 1 hour. A saturated aqueous sodium bicarbonate solution 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 desiccant was filtered off, and the filtrate was then concentrated under reduced pressure to obtain a crude product of the title compound (22.38 g).

[1349] LCMS: m / z 507 [M+H] +

[1350] HPLC retention time: 3.65 min (analysis condition J)

[1351] Compound a-8

[1352] (2-Amino-5-bromo-4-fluorophenyl)-[7-chloro-2-(oxan-2-yl)indazol-4-yl]methanone

[1353] [Equation 29]

[1354]

[1355] The crude product of (E)-N'-[4-bromo-2-[7-chloro-2-(oxan-2-yl)indazole-4-carbonyl]-5-fluorophenyl]-N,N-dimethylformamidine (compound a-7, 22.38g) in the reaction vessel was dissolved in DMSO (220mL), 5M sodium hydroxide aqueous solution (20.4mL) was added thereto, and the mixture was stirred at room temperature for 30min. Saturated aqueous ammonium chloride solution (300mL) and water (1L) were added to the reaction mixture. The solid was collected by filtration and washed with water. The obtained residue was purified three times by silica gel column chromatography to obtain the title compound (7.41g, 48% yield) as a yellow solid.

[1356] LCMS: m / z 452 [M+H] +

[1357] HPLC retention time: 5.42 min (analysis condition J)

[1358] Compound a-9

[1359] N-[4-Bromo-2-[7-fluoro-2-(oxan-2-yl)indazole-4-carbonyl]-5-fluorophenyl]-2-chloroacetamide

[1360] [Equation 30]

[1361]

[1362] A solution 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 DMA (120 mL) was cooled to 0° C. in a reaction vessel, chloroacetyl chloride (1.96 mL, 24.64 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour to obtain a solution of the title compound in DMA.

[1363] LCMS: m / z 528 [M+H] +

[1364] HPLC retention time: 5.57 min (analysis condition J)

[1365] Compound a-10

[1366] 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

[1367] [Equation 31]

[1368]

[1369] To a solution of N-[4-bromo-2-[7-chloro-2-(oxan-2-yl)indazole-4-carbonyl]-5-fluorophenyl]-2-chloroacetamide (compound a-9) in DMA in a reaction vessel was added pyridine (74 mL), and the mixture was stirred for 4 hours at 60° C. The reaction mixture was cooled to room temperature to obtain a solution of the title compound in DMA / pyridine.

[1370] LCMS: m / z 553[M] +

[1371] HPLC retention time: 3.44 min (analysis condition J)

[1372] Compound a-11

[1373] 3-Amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1H-quinolin-2-one

[1374] [Equation 32]

[1375]

[1376] To a 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) in DMA / pyridine was added hydrazine monohydrate (8.2 g, 163.8 mmol), and the mixture was stirred at 60 ° C for 4 hours and further stirred at room temperature for 13 hours. Water was added to the reaction mixture, and the resulting solid was then collected by filtration and washed with water. The obtained solid was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (7.3 g, 91% yield) as a yellow solid.

[1377] LCMS: m / z 491 [M+H] +

[1378] HPLC retention time: 4.65 min (analysis condition J)

[1379] Compound a-12

[1380] 3-amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1-[(4-methoxyphenyl) 1-[( ...methyl)-1-oxo-2-yl)methyl]quinolin-2-one]

[1381] [Formula 33]

[1382]

[1383] 3-amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1H-quinoline-2-one (compound a-11, 7.3 g, 14.84 mmol) and potassium carbonate (5.13 g, 37.12 mmol) in the reaction vessel are suspended in NMP (73 mL), p-methoxybenzyl chloride (2.83 mL, 20.78 mmol) is added thereto, and the mixture is stirred at 70 ° C for 2 hours. The reaction mixture is cooled to room temperature, and water is added thereto. The solid is collected by filtration and washed with water and hexane. The obtained solid is purified by silica gel column chromatography to obtain the title compound (4.79 g, 53% yield) as a light yellow solid.

[1384] LCMS: m / z 611 [M+H] +

[1385] HPLC retention time: 5.76 min (analysis condition J)

[1386] Compound a-13

[1387] 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-6-hydroxy-1-[(4-methoxy phenyl)methyl]quinolin-2-one

[1388] [Equation 34]

[1389]

[1390] 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 tBuBrettPhosPd G3 (69.8 mg, 0.0817 mmol) were added to the reaction vessel, and the reaction vessel was degassed under reduced pressure and argon purged. DMA (8 mL) and 8M potassium hydrate (245.1 μL, 1.961 mmol) were added, the reaction vessel was degassed under reduced pressure and argon purged, and the mixture was then stirred at room temperature for 21 hours. Potassium dihydrogen phosphate (445 mg) and water were added thereto, and the resulting solid was collected by filtration. The filtrate was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was then concentrated under reduced pressure. The residue was combined with the previously obtained solid, and the mixture was purified by silica gel column chromatography to give the title compound (308 mg, yield 68.7%) as a light brown solid.

[1391] LCMS: m / z 549 [M+H] +

[1392] HPLC retention time: 4.49 min (analysis condition J)

[1393] Compound a-14

[1394] 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1-[(4-methoxyphenyl)methane 6-Propan-2-yloxyquinolin-2-one

[1395] [Equation 35]

[1396]

[1397] 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) in the reaction vessel are suspended in DMF (4.4 mL), 2-iodopropane (190.2 μL, 1.913 mmol) is added thereto, and the mixture is stirred at room temperature for 18 hours. Water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate, the desiccant is filtered off, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (201 mg, 89% yield) as a yellow solid.

[1398] LCMS: m / z 591 [M+H] +

[1399] HPLC retention time: 5.60 min (analysis condition J)

[1400] Compound A1

[1401] 3-Amino-4-(7-chloro-1H-indazol-4-yl)-7-fluoro-6-propan-2-yloxy-1H-quinolin-2-one

[1402] [Equation 36]

[1403]

[1404] To 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1-[(4-methoxyphenyl)methyl]-6-propane-2-yloxyquinoline-2-one (compound a-14, 201 mg, 0.34 mmol) in a reaction vessel, TFA / water (3 / 1, 3 mL) was added, 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 12M hydrochloric acid (100 μL) were added to the residue, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated, and the obtained residue was dissolved in MeOH, and triethylamine was added thereto. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (48.3 mg, 37% yield) as a light yellow solid.

[1405] LCMS: m / z 387 [M+H] +

[1406] HPLC retention time: 0.67 min (analysis condition A)

[1407] Compound a-15

[1408] 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

[1409] [Equation 37]

[1410]

[1411] 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, a solution of 0.5 M cyanomethylenetrimethylphosphane in THF (2.53 mL, 1.265 mmol) was added, the reaction vessel was degassed under reduced pressure and argon substituted, and the mixture was then stirred at 80 ° C for 2.5 hours. The reaction mixture was cooled to room temperature, water (231 μL) was added thereto, 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 residue obtained, and the mixture was further concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (233 mg, yield 88%) as a pale yellow solid.

[1412] LCMS: m / z 627 [M+H] +

[1413] HPLC retention time: 5.40 min (analysis condition J)

[1414] Compound A2

[1415] 3-Amino-4-(7-chloro-1H-indazol-4-yl)-6-(3,3-difluoropropoxy)-7-fluoro-1H-quinolin-2-one

[1416] [Equation 38]

[1417]

[1418] 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.

[1419] LCMS: m / z 423 [M+H] +

[1420] HPLC retention time: 0.65 min (analysis condition A)

[1421] Compound a-22

[1422] 3-amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1-(2-trimethylmethane Silylethoxymethyl)quinolin-2-one

[1423] [Equation 39]

[1424]

[1425] A solution of 3-amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1H-quinoline-2-one (compound a-11, 1.732 g, 3.522 mmol) in THF (25 mL) was cooled to 0 ° C in a reaction vessel, 60% sodium hydride / mineral oil (564 mg, 14.08 mmol) was added, and the mixture was stirred for 30 min. 2-(chloromethoxy)ethyltrimethylsilane (1.86 mL, 10.6 mmol) was added to the reaction mixture, and the mixture was further stirred for 30 min. Saturated aqueous sodium bicarbonate solution 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 filtered off, and the filtrate was then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.87 g, yield 85%) as a light yellow solid.

[1426] LCMS: m / z 621 [M+H] +

[1427] HPLC retention time: 6.33 min (analysis condition J)

[1428] Compound a-23

[1429] 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-6-hydroxy-1-(2-trimethyl Siloxymethyl)quinolin-2-one

[1430] [Equation 40]

[1431]

[1432] The title compound was synthesized from 3-amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1-(2-trimethylsilyloxymethyl)quinolin-2-one (compound a-22) under the same conditions as in the production example of compound a-13.

[1433] LCMS: m / z 559 [M+H] +

[1434] HPLC retention time: 5.35 min (analysis condition J)

[1435] Compound a-24

[1436] 3-amino-4-[7-chloro-2-(oxolan-2-yl)indazol-4-yl]-6-cyclobutoxy-7-fluoro-1-(2-trimethylol (methylsilylethoxymethyl)quinolin-2-one

[1437] [Equation 41]

[1438]

[1439] Under the same conditions as those in the production example of compound a-14, the title compound was synthesized from 3-amino-4-[7-chloro-2-(oxacyclohexane-2-yl)indazol-4-yl]-7-fluoro-6-hydroxy-1-(2-trimethylsilylethoxymethyl)quinoline-2-one (compound a-23), except that bromocyclobutane was used instead of the 2-iodopropane used in the production example of compound a-14. In addition, the reaction was carried out by heating the reaction mixture to 70°C.

[1440] LCMS: m / z 613 [M+H] +

[1441] HPLC retention time: 5.00 min (analysis condition K)

[1442] Compound A7

[1443] 3-Amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclobutoxy-7-fluoro-1H-quinolin-2-one

[1444] [Equation 42]

[1445]

[1446] To a solution of 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-6-cyclobutoxy-7-fluoro-1-(2-trimethylsilylethoxymethyl)quinoline-2-one (compound a-24, 70.8 mg, 0.115 mmol) in DCM (0.8 mL) in a reaction vessel, anisole (125 mg, 1.15 mmol) and TFA (0.8 mL) were added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure, MeOH was added thereto, and the mixture was further concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography (0.1% TFA aqueous solution / 0.1% TFA acetonitrile solution). The fractions containing the title compound were merged, and saturated sodium bicarbonate was added for neutralization. The mixed solution was concentrated under reduced pressure, and the resulting solid was collected by filtration and washed with water to obtain the title compound (10.7 mg, 23% yield) as a yellow solid.

[1447] LCMS: m / z 399 [M+H] +

[1448] HPLC retention time: 0.69 min (analysis condition A)

[1449] Compound A72

[1450] 3-Amino-4-(7-chloro-1H-indazol-4-yl)-7-fluoro-6-[(1-fluorocyclopropyl)methoxy]-1H-quinolin-2-one

[1451] [Equation 43]

[1452]

[1453] 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 production example of compound a-15 and compound A7, except that (1-fluorocyclopropyl)methanol was used instead of 3,3-difluoropropan-1-ol used in the production example of compound a-15.

[1454] LCMS: m / z 417 [M+H] +

[1455] HPLC retention time: 0.65 min (analysis condition A)

[1456] Compound a-16

[1457] 6-Bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-2-[(4-methoxyphenyl)methoxy quinolin-3-amine

[1458] [Equation 44]

[1459]

[1460] 3-amino-6-bromo-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-1H-quinoline-2-one (compound a-11, 1.496g, 3.042mmol) and silver carbonate (1.26g, 4.57mmol) were suspended in 1,2-dichloroethane (37mL), followed by addition of p-methoxybenzyl chloride (705μL, 5.18mmol), and the mixture was stirred at 95°C for 16 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth and washed with ethyl acetate. The filtrate obtained was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (765mg, 41% yield).

[1461] Compound a-17

[1462] 3-amino-4-[7-chloro-2-(oxan-2-yl)indazol-4-yl]-7-fluoro-2-[(4-methoxyphenyl)methane [oxy]quinolin-6-ol

[1463] [Equation 45]

[1464]

[1465] 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 of compound a-13.

[1466] LCMS: m / z 549 [M+H] +

[1467] HPLC retention time: 4.39 min (analysis condition L)

[1468] Compound A3

[1469] 3-Amino-4-(7-chloro-1H-indazol-4-yl)-6-(cyclopropylmethoxy...

Claims

1. A compound represented by formula (1) or a salt thereof, or a solvate thereof: [Formula 1] in R4 is selected from the group consisting of: optionally substituted C6-C 10 Aryl (R4 A ), optionally substituted 4- to 10-membered heterocyclyl and optionally substituted 5- to 10-membered heteroaryl (R 4HA ); R5 and R6, together with the atoms to which they are bound, form an optionally substituted ring D; Ring D is selected from the group consisting of 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, taken together with the atoms to which they are bonded, can form Ring E, which is optionally substituted.

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

3. The compound according to claim 1 or 2, or a salt thereof, or a solvate thereof, wherein ring D is unsubstituted or substituted with one or more R D replace; One or more R D Each of the following is independently selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkylthio, C1-C6 acylamino, mono C1-C6 alkylamino, C1-C6 alkylsulfonylamino, C3-C8 cycloalkylsulfonylamino, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C3-C8 cycloalkyl C1-C6 alkoxy, 4-membered to 10-membered heterocyclyl C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4 4- to 8-membered cycloaminocarbonyl, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkyl halogenated, C1-C6 alkyl, C1-C6 alkyl hydroxyl, C1-C6 alkylaminocarbonyl, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C1-C6 acyl, C3-C8 cycloalkyl, C1-C6 alkyl, C2-C6 alkyl hydroxyl ...3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C1-C6 acyl, C3-C8 cycloalkyl, 4- to 8-membered heterocyclyl, C1-C6 acyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C1-C6 acyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C1-C6 acyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C1-C6 acyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C1-C6 acyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C1-C6 acyl, C3 10 aryl and 5- to 10-membered heteroaryl; and The C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C3-C8 cycloalkyl C1-C6 alkoxy, 4-membered to 10-membered heterocyclic C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4-membered to 10-membered heterocyclic oxy, C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkyl, 4-membered to 10-membered heterocyclic, C6-C 10 The aryl and 5- to 10-membered heteroaryl groups are independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, oxo, halo-C1-C6 alkyl, and C3-C8 cycloalkyl.

4. The compound according to any one of claims 1 to 3, or a salt thereof, or a solvate thereof, wherein Ring D is unsubstituted or substituted with one or more R D replace; and One or more R D Each of the following is independently selected from the group consisting of halogen, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkylC1-C6 alkoxy, C3-C8 cycloalkyloxy, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C8 cycloalkylC1-C6 alkyl and C3-C8 cycloalkyl. 5 . The compound according to claim 1 , or a salt thereof, or a solvate thereof, wherein any two adjacent substituents on ring D, together with the atoms to which they are bonded, form an optionally substituted ring E.

6. The compound according to any one of claims 1 to 5, or a salt thereof, or a solvate thereof, wherein Ring D and ring E form a bicyclic ring represented by the following formula: [Formula 2] wherein * represents the carbon to which R5 is bonded in the formula (1), and ** represents the carbon to which R6 is bonded in the formula (1); in the formula, the ring D is referred to as "D ring" and the ring E is referred to as "E ring".

7. The compound according to claim 1, or a salt thereof, or a solvate thereof, wherein the compound is represented by formula (2): [Formula 3] in R4 is selected from the group consisting of: 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 ); X5 for CR x5 or N; X6 for CR x6 or N; X 10a CR x10a or N; R x5 、R x6 、R 6a and R x10a Each of the following is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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 hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl are optionally substituted; and R x5 and R x6 、R x6 and R 6a , or R 6a and R x10a Together with the atoms to which they are bonded, they may form an optionally substituted ring E.

8. The compound according to claim 7, or a salt thereof, or a solvate thereof, wherein X5 is CH; X6 for CR x6 ;and X 10a CR x10a .

9. The compound according to claim 7 or 8, or a salt thereof, or a solvate thereof, wherein R 6a Selected from the group consisting of hydrogen, halogen, cyano, halogenated C1-C6 alkoxy and C1-C6 alkyl.

10. The compound according to any one of claims 7 to 9, or a salt thereof, or a solvate thereof, wherein R x10a Selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C3-C8 cycloalkyl.

11. The compound according to any one of claims 7 to 10, or a salt thereof, or a solvate thereof, wherein Ring E is represented by the following formula: [Formula 4] Wherein * represents R in the formula (2) 6a The carbon to which it is bonded, and ** represents R in the formula (2) x10a The carbon to which it is bonded; in the formula, the ring E is referred to as the "E ring".

12. The compound according to any one of claims 1 to 11, or a salt thereof, or a solvate thereof, wherein Ring E is unsubstituted or substituted with one or more R E replace; and One or more R E Each of the is independently selected from the group consisting of halogen, C1-C6 alkoxy, boronyl, and C1-C6 alkyl.

13. The compound according to claim 1 or 7, or a salt thereof, or a solvate thereof, wherein the compound is represented by formula (3): [Formula 5] in R4 is selected from the group consisting of: 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 ); X5 for CR x5 or N; X6 for CR x6 or N; X7 for CR x7 or N; X8 for CR x8 or N; X9 for CR x9 or N; X 10 CR x10 or N; R x5 、R x6 、R x7 、R x8 、R x9 and R x10 Each of the following is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, hydroxy, thio, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, 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; and The hydroxyl, thiol, amino, C1-C6 alkoxy, C1-C6 alkylthio, carbonyl, carboxyl, sulfonyl, phosphoryl, boron, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 Aryl and 5- to 10-membered heteroaryl groups are optionally substituted.

14. The compound according to claim 13, or a salt thereof, or a solvate thereof, wherein X5 is CH; X6 for CR x6 ; X7 for CR x7 or N; X8 for CR x8 or N; X9 for CR x9 or N; and X 10 CR x10 or N.

15. The compound according to claim 13 or 14, or a salt thereof, or a solvate thereof, wherein X7 is N, X8 is CR x8 , X9 is CR x9 , and X 10 CR x10 ,or X7 for CR x7 , X8 is N, X9 is CR x9 , and X 10 CR x10 ,or X7 for CR x7 , X8 is CR x8 , X9 is N, and X 10 CR x10 ,or X7 for CR x7 , X8 is CR x8 , X9 is CR x9 , and X 10 is N, or X7 is N, X8 is CR x8 , X9 is CR x9 , and X 10 is N, or X7 for CR x7 , X8 is N, X9 is CR x9 , and X 10 is N, or X7 is N, X8 is N, X9 is CR x9 , and X 10 CR x10 .

16. The compound according to any one of claims 7 to 15, or a salt thereof, or a solvate thereof, wherein R x6 Selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkylthio, C1-C6 acylamino, mono C1-C6 alkylamino, C1-C6 alkylsulfonylamino, C3-C8 cycloalkylsulfonylamino, C1-C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C3-C8 cycloalkyl C1-C6 alkoxy, 4- to 10-membered heterocyclyl C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4- to 10-membered heterocyclyl C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkyl, C2 ... 10 aryl and 5- to 10-membered heteroaryl; and The C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkoxy, C3-C8 cycloalkyl C1-C6 alkoxy, 4-membered to 10-membered heterocyclic C1-C6 alkoxy, C3-C8 cycloalkyloxy, 4-membered to 10-membered heterocyclic oxy, C1-C6 alkyl, C3-C8 cycloalkyl C1-C6 alkyl, C3-C8 cycloalkyl, 4-membered to 10-membered heterocyclic, C6-C 10 The aryl and 5- to 10-membered heteroaryl groups are independently optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, oxo, halo-C1-C6 alkyl, and C3-C8 cycloalkyl.

17. The compound according to any one of claims 7 to 16, or a salt thereof, or a solvate thereof, wherein R x6 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.

18. The compound according to any one of claims 13 to 17, or a salt thereof, or a solvate thereof, wherein R x7 is hydrogen, halogen, C1-C6 alkoxy or C1-C6 alkyl.

19. The compound according to any one of claims 13 to 18, or a salt thereof, or a solvate thereof, wherein R x8 is hydrogen, halogen, C1-C6 alkoxy or C1-C6 alkyl.

20. The compound according to any one of claims 13 to 19, or a salt thereof, or a solvate thereof, wherein R x9 Selected from the group consisting of hydrogen, halogen, C1-C6 alkoxy, C1-C6 alkyl and boronyl.

21. The compound according to any one of claims 13 to 20, or a salt thereof, or a solvate thereof, wherein R x10 is hydrogen, halogen, C1-C6 alkoxy or C1-C6 alkyl.

22. The compound according to any one of claims 1 to 21, or a salt thereof, or a solvate thereof, wherein R4 is an optionally substituted 5- to 10-membered heteroaryl (R4 HA ).

23. The compound according to claim 22, or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R4 HA ) is selected from the group consisting of pyrimidinyl, benzimidazolyl, indolyl, indazolyl and pyrazolopyridinyl.

24. The compound according to claim 22 or 23, or a salt thereof, or a solvate thereof, wherein the 5- to 10-membered heteroaryl group (R4 HA ) is unsubstituted or substituted with one or more R a replace; and One or more R a Each of the groups is independently selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and alkylsulfonylamino.

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

26. A compound or a salt thereof, or a solvate thereof, wherein The compound is selected from the following compounds: 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-phenanthroline-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthroline-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclopropyl-1H-1,7-phenanthroline-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-cyclobutyl-1H-1,7-phenanthroline-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-ethyl-1H-1,7-phenanthroline-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, 3-amino-4-(5-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, 3-amino-6-cyclopropyl-4-(5-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, (S)-3-amino-6-cyclopropyl-4-(5-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-ethyl-1H-1,7-phenanthroline-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-ethoxy-1H-1,7-phenanthroline-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthroline-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-cyclopropyl-1H-1,7-phenanthroline-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-propoxy-1H-1,7-phenanthroline-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-ethoxy-1H-1,7-phenanthroline-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-6-propan-2-yloxy-1H-1,7-phenanthroline-2-one, 3-amino-4-(7-chloro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one, 3-amino-4-(7-chloro-6-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one, 3-amino-6-ethoxy-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, 3-amino-6-cyclobutyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,7-phenanthroline-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,10-phenanthroline-2-one, 3-amino-6-cyclopropyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,10-phenanthroline-2-one, 3-amino-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,10-phenanthroline-2-one, 3-amino-6-ethyl-4-(7-fluoro-1H-indazol-4-yl)-1H-1,10-phenanthroline-2-one, 3-amino-9-fluoro-4-(7-fluoro-1H-indazol-4-yl)-6-methoxy-1H-1,7-phenanthroline-2-one, 3-amino-9-fluoro-4-(7-fluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-9-fluoro-6-methoxy-1H-1,7-phenanthroline-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-9-fluoro-6-methyl-1H-1,7-phenanthroline-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-phenanthroline-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5,6-dimethyl-1H-1,7-phenanthroline-2-one, 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-5-methyl-1H-1,7-phenanthroline-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-methyl-1H-1,7-phenanthroline-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-6-methyl-1H-1,7-phenanthroline-2-one, 3-amino-6-cyclopropyl-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-1H-1,7-phenanthroline-2-one, 3-amino-4-(6,7-difluoro-1H-indazol-4-yl)-5-fluoro-1H-1,7-phenanthroline-2-one, 3-amino-4-(5,7-difluoro-1H-indazol-4-yl)-6-methyl-1H-1,7-phenanthroline-2-one, 3-amino-6-methyl-4-(1H-pyrazolo[4,3-c]pyridin-4-yl)-1H-1,7-phenanthroline-2-one, 3-amino-4-(1H-benzotriazol-4-yl)-6-methyl-1H-1,7-phenanthroline-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. A pharmaceutical composition for treating or preventing cancer in a cancer patient by combining a MYT1 inhibitor with a chemotherapeutic agent, wherein the cancer patient has been detected to be positive for RB1 gene mutation or reduced expression of RB1 gene or protein, the pharmaceutical composition comprising a MYT1 inhibitor as an active ingredient, The MYT1 inhibitor is a compound according to any one of claims 1 to 26, or a salt thereof, or a solvate thereof.

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