Heterocyclic compounds

Abstract

Provided is a compound which has an effect of inhibiting neuron degeneration, in particular, an effect of inhibiting motor neuron degeneration and which is useful as a prophylactic or therapeutic agent for motor neuron diseases (for example, amyotrophic lateral sclerosis, progressive bulbar paralysis, progressive muscular atrophy, primary lateral sclerosis, progressive pseudobulbar paralysis, spinal muscular atrophy, Parkinson's disease, Lewy body dementia, multiple system atrophy and Friedreich's ataxia), etc.　The present invention pertains to a compound represented by formula (I) [wherein each symbol is as defined in the description] or a salt thereof.

Description

[Technical field]

[0001] The present invention relates to a heterocyclic compound having an inhibitory effect on cell degeneration, in particular an inhibitory effect on motor neuron degeneration, and is useful for the treatment of motor neuron diseases (e.g., amyotrophic lateral sclerosis, progressive bulbar palsy, progressive muscular atrophy, primary lateral sclerosis, progressive pseudobulbar palsy, spinal muscular atrophy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Friedreich's ataxia) and the like, and a medicine containing the same.

[0002] BACKGROUND OF THEINVENTION Abnormal cell degeneration caused by a disease is a pathological change that is widely observed as the disease progresses. If the abnormal cell degeneration can be suppressed by therapeutic intervention to maintain and restore the normal function of cell tissue, this can directly lead to the suppression of disease progression, improvement of symptoms, and treatment of the disease (Non-Patent Documents 1, 2, and 3). In many neurodegenerative diseases, analysis of pathological samples obtained after the death of a patient has observed degeneration and loss of neural tissue, which is presumed to be due to cell degeneration caused by the disease (Non-Patent Documents 4 and 5). Based on this fact, a research strategy has been proposed to search for compounds that suppress neuronal degeneration as candidate therapeutic drugs, and compound screening has been carried out using cell-based assays that mimic neuronal degeneration in vitro (Non-Patent Documents 6 and 7). In particular, drug discovery research has been intensified in which disease model cells are differentiated from induced pluripotent stem cells (hereinafter, iPS cells) obtained by initializing somatic cells collected from a patient and then subjected to compound screening (Non-Patent Document 8). In motor neuron diseases such as amyotrophic lateral sclerosis (hereinafter sometimes referred to as "ALS"), selective degeneration and loss of motor neurons has been observed in many cases (Non-Patent Document 9). Therefore, if a compound that suppresses the spontaneous cell degeneration observed in motor neurons induced to differentiate from patient-derived iPS cells can be found, it is expected that new drugs that suppress the progression of the disease and improve symptoms can be created (Non-Patent Documents 10, 11, and 12, and Patent Documents 1 and 2). From the above, it is suggested that motor neuron degeneration inhibitors may be used as preventive or therapeutic agents for motor neuron diseases (e.g., amyotrophic lateral sclerosis, progressive bulbar palsy, progressive muscular atrophy, primary lateral sclerosis, progressive pseudobulbar palsy, spinal muscular atrophy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Friedreich's ataxia) and the like. Friedreich's ataxia (hereinafter referred to as FA) is an autosomal recessive genetic disease caused by mutations in the Frataxin (FXN) gene. Because FXN is a protein that regulates iron in mitochondria, it has been suggested that iron-dependent cell death is involved in the disease, and it has been reported that skin fibroblasts derived from FA patients are highly sensitive to erastin and RSL3, which are known to be iron-dependent cell death inducers (Non-Patent Document 13).

[0003] The following compounds are known as heterocyclic compounds. Patent Document 3 describes the following formula:

[0004] [ka]

[0005] (In the formula, each symbol is as defined in Patent Document 3.) It is disclosed that a compound represented by the formula: is useful for treating asthma and chronic obstructive pulmonary disease (COPD). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] WO 2016 / 114322 [Patent Document 2] WO 2012 / 029994 [Patent Document 3] EP 2489663 [Non-patent literature]

[0007] [Non-licensed document 1] S. Zhang et al, Cell Death and Disease 2017, 8, e2905 [Non-licensed document 2] TV Berghe et al, Nature Reviews Molecular Cell Biology 2014, 15, 135-147. [Non-licensed document 3] Z. Lia et al, European Journal of Pharmacology 2019, 844, 156-164.

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

[0008] An object of the present invention is to provide a compound which has an inhibitory effect on cell degeneration, in particular an inhibitory effect on motor neuron degeneration, and is useful as an agent for the prevention or treatment of motor neuron diseases (e.g., amyotrophic lateral sclerosis, progressive bulbar palsy, progressive muscular atrophy, primary lateral sclerosis, progressive pseudobulbar palsy, spinal muscular atrophy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Friedreich's ataxia) and the like. [Means for solving the problem]

[0009] As a result of intensive studies aimed at solving the above-mentioned problems, the present inventors have found that a compound represented by the following formula (I) has an inhibitory effect on cell degeneration, in particular an inhibitory effect on motor neuron degeneration, and is therefore useful as an agent for the prevention or treatment of motor neuron diseases (e.g., amyotrophic lateral sclerosis, progressive bulbar palsy, progressive muscular atrophy, primary lateral sclerosis, progressive pseudobulbar palsy, spinal muscular atrophy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Friedreich's ataxia) and the like, and have completed the present invention.

[0010] That is, the present invention is as follows. (1) Formula (I):

[0011] [ka]

[0012] [During the ceremony, R 1 is a hydrogen atom, optionally substituted C 1-6 Alkyl group or optionally substituted C 3-6 Cycloalkyl groups; R 2 is optionally substituted C 1-6 an alkyl group or an optionally substituted cyclic group; R 3 is optionally substituted C 1-6 Alkyl groups; R 4 is optionally substituted C 1-6 Alkyl groups; Ring A is an optionally further substituted benzene ring; Showing or a salt thereof (hereinafter, may be abbreviated as "compound (I)");

[0013] (2) R 1 but, (1) a hydrogen atom, (2) 1 to 3 optionally halogenated C 3-6 C optionally substituted with a cycloalkyl group 1-6 an alkyl group, or (3) C 3-6 is a cycloalkyl group; R 2 but, (1) C 3-6 Cycloalkyl groups, (2)(a) a halogen atom, (b) Optionally halogenated C 1-6 Alkyl groups, (c) C 1-6 alkoxy groups, and (d) 1 to 3 C 1-6 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted with an alkyl group C which is optionally substituted by 1 to 3 substituents selected from 6-10 Aryl groups, (3)(a) a halogen atom, (b)(i) a halogen atom, and (ii) C 1-6 Alkoxy group C which is optionally substituted by 1 to 3 substituents selected from 1-6 Alkyl groups, (c) C 3-6 cycloalkyl groups, and (d) C 1-6 Alkoxy group or a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from (4)(a) halogen atoms, and (b) C 1-6 Alkyl group is a 9- to 14-membered fused polycyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from R 3 But unsubstituted C 1-6 is an alkyl group; R 4 But unsubstituted C 1-6 is an alkyl group; and Ring A is a benzene ring optionally further substituted with a halogen atom. The compound according to (1) above or a salt thereof;

[0014] (3) R 1 but, (1) a hydrogen atom, (2) 1 to 3 C’s 3-6 C optionally substituted with a cycloalkyl group 1-6 an alkyl group, or (3) C 3-6 Cycloalkyl group and; R 2 but, (1)(a) C 1-6 alkoxy groups, and (b) 1 to 3 C1-6 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted with an alkyl group C which is optionally substituted by 1 to 3 substituents selected from 6-10 an aryl group, or (2)(a) 1 to 3 C 1-6 C optionally substituted with an alkoxy group 1-6 Alkyl groups, and (b) C 1-6 Alkoxy group A 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from and; R 3 But unsubstituted C 1-6 is an alkyl group; R 4 But unsubstituted C 1-6 an alkyl group; and Ring A is a group represented by the formula: -C(OH)R 3 R 4 (In the formula, R 3 and R 4 is a benzene ring having no substituent other than the above-defined substituents, The compound according to (1) above or a salt thereof;

[0015] (4) 2-{3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-5-yl}propan-2-ol or a salt thereof; (5) 2-{1-(cyclopropylmethyl)-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol or a salt thereof; (6) 2-{3-[2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}propan-2-ol or a salt thereof;

[0016] (7) A medicine comprising the compound according to (1) above or a salt thereof; (8) The pharmaceutical agent according to the above (7), which is a motor neuron degeneration inhibitor; (9) The pharmaceutical agent according to (7) above, which is a preventive or therapeutic agent for a motor neuron disease; (10) The pharmaceutical composition according to (9) above, wherein the motor neuron disease is amyotrophic lateral sclerosis or Friedreich's ataxia;

[0017] (11) The compound or salt thereof according to (1) above for use in the prevention or treatment of a motor neuron disease; (12) The compound or salt thereof according to (11) above, wherein the motor neuron disease is amyotrophic lateral sclerosis or Friedreich's ataxia;

[0018] (13) A method for inhibiting motor neuron degeneration in a mammal, which comprises administering to the mammal an effective amount of the compound according to (1) above or a salt thereof; (14) A method for preventing or treating a motor neuron disease in a mammal, which comprises administering to the mammal an effective amount of the compound according to (1) above or a salt thereof; (15) The method according to (14) above, wherein the motor neuron disease is amyotrophic lateral sclerosis or Friedreich's ataxia;

[0019] (16) Use of the compound according to (1) or a salt thereof for the manufacture of an agent for the prevention or treatment of a motor neuron disease; and (17) The use according to (16) above, wherein the motor neuron disease is amyotrophic lateral sclerosis or Friedreich's ataxia. Effect of the Invention

[0020] According to the present invention, it is possible to provide a compound which has an excellent inhibitory effect on cell degeneration, in particular an inhibitory effect on motor neuron degeneration, and is useful as an agent for preventing or treating motor neuron diseases (e.g., amyotrophic lateral sclerosis, progressive bulbar palsy, progressive muscular atrophy, primary lateral sclerosis, progressive pseudobulbar palsy, spinal muscular atrophy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Friedreich's ataxia) and the like.

[0021] Detailed Description of the Invention The present invention will be described in detail below.

[0022] The definition of each substituent used in the present specification is described in detail below. Unless otherwise specified, each substituent has the following definition. In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine. In this specification, "C 1-6 Examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. In the present specification, "optionally halogenated C 1-6 The alkyl group may, for example, be a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples of the alkyl group include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, and 6,6,6-trifluorohexyl. In this specification, "C2-6 Examples of the "alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, and 5-hexenyl. In this specification, "C 2-6 Examples of the "alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl. In this specification, "C 3-10 Examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl. In the present specification, "optionally halogenated C 3-10 The "cycloalkyl group" is, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 3-10 Specific examples of the cycloalkyl group include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In this specification, "C 3-10 Examples of the "cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. In this specification, "C 6-14 The "aryl group" includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl. In this specification, "C 7-16The aralkyl group includes, for example, benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0023] In this specification, "C 1-6 Examples of the "alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy. In the present specification, "optionally halogenated C 1-6 The "alkoxy group" is, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples of the alkoxy group include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy. In this specification, "C 3-10 Examples of the "cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy. In this specification, "C 1-6 Examples of the "alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio. In the present specification, "optionally halogenated C 1-6 The "alkylthio group" includes, for example, C alkylthio groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples of the alkylthio group include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio. In this specification, "C 1-6Examples of the "alkyl-carbonyl group" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl. In the present specification, "optionally halogenated C 1-6 The "alkyl-carbonyl group" includes, for example, C alkyl groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Examples of the alkyl-carbonyl group include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl. In this specification, "C 1-6 Examples of the "alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl. In this specification, "C 6-14 The "aryl-carbonyl group" includes, for example, benzoyl, 1-naphthoyl, and 2-naphthoyl. In this specification, "C 7-16 The "aralkyl-carbonyl group" includes, for example, phenylacetyl and phenylpropionyl.

[0033] In the present specification, examples of the "5- to 14-membered aromatic heterocyclyl carbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[0043] In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

[0024] As used herein, "mono- or di-C 1-6 The "alkyl-carbamoyl group" includes, for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl. As used herein, "mono- or di-C 7-16 The "aralkyl-carbamoyl group" includes, for example, benzylcarbamoyl and phenethylcarbamoyl. In this specification, "C 1-6 Examples of the "alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl. In the present specification, "optionally halogenated C 1-6 The "alkylsulfonyl group" includes, for example, C alkylsulfonyl groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl. In this specification, "C 6-14 The "arylsulfonyl group" includes, for example, phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0025] In the present specification, examples of the "substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group, and an optionally substituted silyl group. In the present specification, examples of the "hydrocarbon group" (including the "hydrocarbon group" in the "optionally substituted hydrocarbon group") include, for example, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10Cycloalkenyl group, C 6-14 Aryl group, C 7-16 Examples of such groups include aralkyl groups.

[0026] In the present specification, examples of the "optionally substituted hydrocarbon group" include a hydrocarbon group which may have a substituent selected from the following Substituent Group A. [Substituent group A] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) Optionally halogenated C 1-6 Alkoxy groups, (7) C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy), (8) C 7-16 aralkyloxy groups (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclic oxy groups (e.g., morpholinyloxy, piperidinyloxy), (11) C 1-6 Alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy), (12) C 6-14 Aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (13) C 1-6 Alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) Mono- or di-C 1-6 Alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy); (15) C 6-14 Aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy); (16) 5- to 14-membered aromatic heterocyclylcarbonyloxy groups (e.g., nicotinoyloxy), (17) 3- to 14-membered non-aromatic heterocyclylcarbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) Optionally halogenated C 1-6 Alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), (19)C 1-6 C optionally substituted with an alkyl group 6-14 Arylsulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) Optionally halogenated C 1-6 Alkylthio groups, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxy group, (25) Optionally halogenated C 1-6 Alkyl-carbonyl groups, (26)C 6-14 Aryl-carbonyl groups, (27) a 5- to 14-membered aromatic heterocyclic carbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group, (29)C 1-6 Alkoxy-carbonyl groups, (30)C 6-14 Aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl); (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) Mono- or di-C 1-6 Alkyl-carbamoyl groups, (35)C6-14 Aryl-carbamoyl groups (e.g., phenylcarbamoyl), (36) 5- to 14-membered aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl groups (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) Optionally halogenated C 1-6 Alkylsulfonyl groups, (39)C 6-14 Arylsulfonyl groups, (40) 5- to 14-membered aromatic heterocyclylsulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl), (41) Optionally halogenated C 1-6 an alkylsulfinyl group, (42)C 6-14 Arylsulfinyl groups (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) 5- to 14-membered aromatic heterocyclylsulfinyl groups (e.g., pyridylsulfinyl, thienylsulfinyl), (44) an amino group, (45) Mono- or di-C 1-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino); (46) Mono- or di-C 6-14 Arylamino groups (e.g., phenylamino), (47) 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), (48)C 7-16 aralkylamino groups (e.g., benzylamino), (49) a formylamino group, (50)C 1-6 Alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino), (51)(C 1-6 Alkyl)(C 1-6alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino); (52)C 6-14 Aryl-carbonylamino groups (e.g., phenylcarbonylamino, naphthylcarbonylamino); (53)C 1-6 alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino); (54)C 7-16 aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55)C 1-6 Alkylsulfonylamino groups (e.g., methylsulfonylamino, ethylsulfonylamino), (56)C 1-6 C optionally substituted with an alkyl group 6-14 Arylsulfonylamino groups (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) Optionally halogenated C 1-6 Alkyl groups, (58)C 2-6 Alkenyl groups, (59)C 2-6 Alkynyl groups, (60)C 3-10 Cycloalkyl groups, (61)C 3-10 Cycloalkenyl groups, and (62)C 6-14 Aryl groups.

[0027] The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different. In the present specification, examples of the "heterocyclic group" (including the "heterocyclic group" in "optionally substituted heterocyclic group") include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7- to 10-membered bridged heterocyclic group, each of which contains, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0028] In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0029] In the present specification, examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrrolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrrolinyl, oxazolidinyl, pyrazolinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl ... 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as isoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexyl Examples of such 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups include tetrahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0030] In the present specification, preferable examples of the "7- to 10-membered heterobridged ring group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl. In the present specification, the term "nitrogen-containing heterocyclic group" includes "heterocyclic groups" which contain at least one nitrogen atom as a ring-constituting atom. In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group which may have a substituent selected from the above-mentioned Substituent group A. The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0031] As used herein, the term "acyl group" refers to, for example, a halogen atom, an optionally halogenated C 1-6 C may have 1 to 3 substituents selected from an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group; 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 Examples of the heterocyclic group include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group, and a phosphono group, each of which optionally has "1 or 2 substituents selected from an aralkyl group, a 5- to 14-membered aromatic heterocyclic group, and a 3- to 14-membered non-aromatic heterocyclic group." Further, the "acyl group" also includes a hydrocarbon-sulfonyl group, a heterocycle-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocycle-sulfinyl group. Here, the term "hydrocarbon-sulfonyl group" refers to a sulfonyl group having a hydrocarbon group bonded thereto, the term "heterocycle-sulfonyl group" refers to a sulfonyl group having a heterocyclic group bonded thereto, the term "hydrocarbon-sulfinyl group" refers to a sulfinyl group having a hydrocarbon group bonded thereto, and the term "heterocycle-sulfinyl group" refers to a sulfinyl group having a heterocyclic group bonded thereto. Suitable examples of the "acyl group" include a formyl group, a carboxy group, and C 1-6 Alkyl-carbonyl group, C 2-6 Alkenyl-carbonyl group (e.g., crotonoyl), C 3-10Cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 Cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7-16 Aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (e.g., pyridylthiocarbamoyl), sulfino group, C 1-6 Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C 1-6 Alkylsulfonyl group, C 6-14 Arylsulfonyl group, phosphono group, mono- or di-C 1-6 Examples of the alkylphosphono group include dimethylphosphono, diethylphosphono, diisopropylphosphono, and dibutylphosphono groups.

[0032] As used herein, the term "optionally substituted amino group" refers to, for example, "amino group optionally having 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and an arylsulfonyl group, optionally having 1 or 2 substituents selected from the group consisting of arylsulfonyl groups. Preferable examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C 1-6 alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6Alkenylamino groups (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino groups (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino groups (e.g., phenylamino), mono- or di-C 7-16 Aralkylamino groups (e.g., benzylamino, dibenzylamino), mono- or di-(optionally halogenated C 1-6 Alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), mono- or di-C 6-14 Aryl-carbonylamino group (e.g., benzoylamino), mono- or di-C 7-16 Aralkyl-carbonylamino group (e.g., benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), mono- or di-C 1-6 Alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), carbamoylamino group, (mono- or di-C 1-6 Alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), (mono- or di-C 7-16 aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), C 1-6 Alkyl sulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), C 6-14 Arylsulfonylamino group (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 Alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino), (C 1-6 Alkyl)(C 6-14 aryl-carbonyl)amino groups (e.g., N-benzoyl-N-methylamino).

[0033] As used herein, examples of the "optionally substituted carbamoyl group" include "carbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and aralkyl-carbamoyl groups, which may have 1 or 2 substituents selected from the group consisting of aryl, arylalkyl, and arylcarbamoyl. Suitable examples of the optionally substituted carbamoyl group include carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 Examples of the aryl-carbonyl-carbamoyl group include aryl-carbonyl-carbamoyl groups (eg, benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl).

[0034] As used herein, examples of the "optionally substituted thiocarbamoyl group" include "thiocarbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and thiocarbamoyl groups which may have 1 or 2 substituents selected from aralkyl-carbamoyl groups. Suitable examples of the optionally substituted thiocarbamoyl group include thiocarbamoyl groups, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14Examples of such groups include aryl-carbonyl-thiocarbamoyl groups (eg, benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (eg, pyridylthiocarbamoyl).

[0035] As used herein, examples of the "optionally substituted sulfamoyl group" include "a sulfamoyl group which may optionally have 1 to 3 substituents selected from substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and an aralkyl-carbamoyl group, which may have 1 or 2 substituents selected from the group consisting of aryl, arylalkyl, and arylcarbamoyl. Suitable examples of the optionally substituted sulfamoyl group include sulfamoyl groups, mono- or di-C 1-6 Alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 Alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), mono- or di-C 3-10 Cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 Aryl-sulfamoyl group (e.g., phenylsulfamoyl), mono- or di-C 7-16 Aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C 1-6Alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C 6-14 Examples thereof include aryl-carbonyl-sulfamoyl groups (eg, benzoylsulfamoyl) and 5- to 14-membered aromatic heterocyclic sulfamoyl groups (eg, pyridylsulfamoyl).

[0036] In the present specification, examples of the "optionally substituted hydroxy group" include "a hydroxy group which may have 1 to 3 substituents selected from the substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and arylsulfonyl groups, each of which may have a substituent selected from the group consisting of arylsulfonyl groups and arylsulfonyl groups. Preferable examples of the optionally substituted hydroxy group include a hydroxy group, 1-6 Alkoxy group, C 2-6 Alkenyloxy groups (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C 3-10 Cycloalkyloxy group (e.g., cyclohexyloxy), C 6-14 Aryloxy groups (e.g., phenoxy, naphthyloxy), C 7-16 Aralkyloxy group (e.g., benzyloxy, phenethyloxy), C 1-6Alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C 6-14 Aryl-carbonyloxy group (e.g., benzoyloxy), C 7-16 Aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), C 1-6 Alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), carbamoyloxy group, C 1-6 Alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), C 7-16 Aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), C 1-6 Alkyl sulfonyloxy group (e.g., methyl sulfonyloxy, ethyl sulfonyloxy), C 6-14 Arylsulfonyloxy groups (eg, phenylsulfonyloxy) are included.

[0037] As used herein, examples of the "optionally substituted sulfanyl group" include "a sulfanyl group which may have 1 to 3 substituents selected from the substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 and a halogenated sulfanyl group, which may have a substituent selected from an aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group. Preferable examples of the optionally substituted sulfanyl group include a sulfanyl (-SH) group, 1-6 Alkylthio group, C 2-6 Alkenylthio groups (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10Cycloalkylthio groups (e.g., cyclohexylthio), C 6-14 Arylthio groups (e.g., phenylthio, naphthylthio), C 7-16 Aralkylthio groups (e.g., benzylthio, phenethylthio), C 1-6 Alkyl-carbonylthio groups (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 Examples of such groups include aryl-carbonylthio groups (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio groups (eg, pyridylthio), and halogenated thio groups (eg, pentafluorothio).

[0038] In the present specification, examples of the "optionally substituted silyl group" include "a silyl group which optionally has 1 to 3 substituents selected from the substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl groups and C 7-16 and aralkyl groups. Suitable examples of the optionally substituted silyl group include tri-C 1-6 Examples of the silyl groups include alkylsilyl groups (eg, trimethylsilyl, tert-butyl(dimethyl)silyl).

[0039] In the present specification, examples of the "hydrocarbon ring" include C 6-14 Aromatic hydrocarbon ring, C 3-10 Cycloalkane, C 3-10 Cycloalkenes are mentioned. In this specification, "C 6-14 The aromatic hydrocarbon ring includes, for example, benzene and naphthalene. In this specification, "C 3-10 Examples of the "cycloalkane" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. In this specification, "C 3-10Examples of the "cycloalkene" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene. In the present specification, examples of the "heterocycle" include aromatic heterocycles and non-aromatic heterocycles each containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms and oxygen atoms.

[0040] In the present specification, examples of the "aromatic heterocycle" include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms. Preferable examples of the "aromatic heterocycle" include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine and 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocycles such as benzene, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0041] In the present specification, examples of the "non-aromatic heterocycle" include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocycle" include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepine, azocane, diazocane, and oxepane; Examples of the heterocyclic ring include 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, and octahydroisoquinoline. In the present specification, the "nitrogen-containing heterocycle" includes a "heterocycle" containing at least one nitrogen atom as a ring-constituting atom.

[0042] In the present specification, the term "cyclic group" refers to a group including "C 3-10 Cycloalkyl group, C 3-10 Cycloalkenyl group, C 6-14 "aryl groups" and "heterocyclic groups."

[0043] The definition of each symbol in formula (I) is explained in detail below.

[0044] R 1 is a hydrogen atom, optionally substituted C 1-6 Alkyl group or optionally substituted C 3-6 This represents a cycloalkyl group. R 1 "Optionally substituted C 1-6 "Alkyl group" and "Optionally substituted C 3-6 The substituent in the "cycloalkyl group" may be the same as that in the substituent group A, and the group may have 1 to 3 substituents at substitutable positions.

[0045] Among them, R 1 As for the following: (1) a hydrogen atom, (2) 1 to 3 optionally halogenated C 3-6 C optionally substituted with a cycloalkyl group (e.g., cyclopropyl, 2,2-difluorocyclopropyl) 1-6 an alkyl group (e.g., methyl, ethyl, isopropyl), or (3) C 3-6 Cycloalkyl groups (eg cyclobutyl) are preferred. In particular, R 1 As for the following: (1) a hydrogen atom, (2) 1 to 3 C’s 3-6 C optionally substituted with a cycloalkyl group (e.g., cyclopropyl) 1-6 an alkyl group (e.g., methyl, isopropyl), or (3) C 3-6 Cycloalkyl groups (eg cyclobutyl) are preferred.

[0046] R2 is optionally substituted C 1-6 It represents an alkyl group or an optionally substituted cyclic group. R 2 "Optionally substituted C 1-6 The substituents in the "alkyl group" and the "optionally substituted cyclic group" include the same as those in the substituent group A, and the group may have 1 to 3 substituents at substitutable positions.

[0047] Among them, R 2 As R, an optionally substituted cyclic group is preferable. 2 As for the following: (1) C 3-6 cycloalkyl groups (e.g., cyclohexyl); (2)(a) A halogen atom (e.g., a fluorine atom), (b) Optionally halogenated C 1-6 Alkyl groups (e.g., trifluoromethyl), (c) C 1-6 Alkoxy groups (e.g., methoxy), and (d) 1 to 3 C 1-6 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl (4-pyrazolyl)) optionally substituted with an alkyl group (e.g., methyl) C which is optionally substituted by 1 to 3 substituents selected from 6-10 Aryl groups (e.g., phenyl), (3)(a) A halogen atom (e.g., a chlorine atom), (b)(i) a halogen atom (e.g., a fluorine atom), and (ii) C 1-6 Alkoxy groups (e.g., methoxy) C which is optionally substituted by 1 to 3 substituents selected from 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl, isobutyl), (c) C 3-6 Cycloalkyl groups (e.g., cyclobutyl), and (d) C 1-6 Alkoxy groups (e.g., methoxy, ethoxy, isopropyloxy) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl (3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl)) optionally substituted by 1 to 3 substituents selected from (4)(a) Halogen atoms (e.g., fluorine atoms), and (b) C 1-6 Alkyl group (e.g., methyl) and a 9- to 14-membered fused polycyclic non-aromatic heterocyclic group (e.g., dihydrobenzofuryl (2,3-dihydro-7-benzofuryl), tetrahydropyrazolopyridyl (4,5,6,7-tetrahydropyrazolo[1,5-a]-3-pyridyl), dihydropyrazolooxazinyl (6,7-dihydropyrazolo[5,1-b][1,3]-3-oxazinyl)) optionally substituted by 1 to 3 substituents selected from the above.

[0048] In particular, R 2 As for the following: (1)(a) C 1-6 Alkoxy groups (e.g., methoxy), and (b) 1 to 3 C 1-6 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl (4-pyrazolyl)) optionally substituted with an alkyl group (e.g., methyl) C which is optionally substituted by 1 to 3 substituents selected from 6-10 an aryl group (e.g., phenyl), or (2)(a) 1 to 3 C 1-6 C optionally substituted with an alkoxy group (e.g., methoxy) 1-6 Alkyl groups (e.g., methyl), and (b) C 1-6 Alkoxy groups (e.g., methoxy) and preferably a 5- or 6-membered monocyclic aromatic heterocyclic group (eg, pyrazolyl (4-pyrazolyl)) optionally substituted by 1 to 3 substituents selected from the above.

[0049] R 3 is optionally substituted C 1-6 Indicates an alkyl group. R 3 "Optionally substituted C1-6 The substituent in the alkyl group may be the same as that in the substituent group A, and the alkyl group may have 1 to 3 substituents at substitutable positions. Among them, R 3 As for the unsubstituted C 1-6 Alkyl groups are preferred. In particular, R 3 As the alkyl group, methyl is preferable.

[0050] R 4 is optionally substituted C 1-6 Indicates an alkyl group. R 4 "Optionally substituted C 1-6 The substituent in the alkyl group may be the same as that in the substituent group A, and the alkyl group may have 1 to 3 substituents at substitutable positions. Among them, R 4 As for the unsubstituted C 1-6 Alkyl groups are preferred. In particular, R 4 As the alkyl group, methyl is preferable.

[0051] Formula:-C(OH)R 3 R 4 (In the formula, R 3 and R 4 has the same meaning as above) may be located at any one of the 4- to 7-positions on the benzene ring (on ring A) of the 1H-indazole ring, and preferably at the 5- or 6-position of the 1H-indazole ring.

[0052] Ring A is an optionally further substituted benzene ring. The "benzene ring" of the "optionally further substituted benzene ring" represented by ring A is -C(OH)R 3 R 4 (In the formula, R 3 and R 4 is as defined above), may be further substituted, and examples of the substituent include those similar to those in the substituent group A, and may have 1 to 3 substituents at substitutable positions. Formula in ring A: -C(OH)R 3 R 4 (In the formula, R 3 and R 4 is as defined above), a halogen atom (eg, a fluorine atom) is preferred. Formula in ring A: -C(OH)R 3 R 4 (In the formula, R 3 and R 4 The position of the substituent other than (having the same meaning as above) is preferably the 4-position, 5-position or 7-position of the 1H-indazole ring. As the ring A, the formula: -C(OH)R 3 R 4 (In the formula, R 3 and R 4 It is preferable that the aryl group does not have any substituent other than (having the same meaning as above).

[0053] Compound (I) may be R 1 is a hydrogen atom, optionally substituted C 1-6 Alkyl group or optionally substituted C 3-6 Cycloalkyl groups; R 2 an optionally substituted cyclic group; R 3 may be substituted C 1-6 Alkyl groups; R 4 may be substituted C 1-6 an alkyl group; and Ring A is an optionally further substituted benzene ring; Preferred are compounds in which:

[0054] Compound (I) is, among others, R 1 but, (1) a hydrogen atom, (2) 1 to 3 optionally halogenated C 3-6 C optionally substituted with a cycloalkyl group (e.g., cyclopropyl, 2,2-difluorocyclopropyl) 1-6an alkyl group (e.g., methyl, ethyl, isopropyl), or (3) C 3-6 a cycloalkyl group (e.g., cyclobutyl); R 2 but, (1) C 3-6 cycloalkyl groups (e.g., cyclohexyl); (2)(a) A halogen atom (e.g., a fluorine atom), (b) Optionally halogenated C 1-6 Alkyl groups (e.g., trifluoromethyl), (c) C 1-6 Alkoxy groups (e.g., methoxy), and (d) 1 to 3 C 1-6 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl (4-pyrazolyl)) optionally substituted with an alkyl group (e.g., methyl) C which is optionally substituted by 1 to 3 substituents selected from 6-10 Aryl groups (e.g., phenyl), (3)(a) A halogen atom (e.g., a chlorine atom), (b)(i) a halogen atom (e.g., a fluorine atom), and (ii) C 1-6 Alkoxy groups (e.g., methoxy) C which is optionally substituted by 1 to 3 substituents selected from 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl, isobutyl), (c) C 3-6 Cycloalkyl groups (e.g., cyclobutyl), and (d) C 1-6 Alkoxy groups (e.g., methoxy, ethoxy, isopropyloxy) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl (3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl)) optionally substituted by 1 to 3 substituents selected from (4)(a) Halogen atoms (e.g., fluorine atoms), and (b) C 1-6 Alkyl group (e.g., methyl) a 9- to 14-membered fused polycyclic non-aromatic heterocyclic group (e.g., dihydrobenzofuryl (2,3-dihydro-7-benzofuryl), tetrahydropyrazolopyridyl (4,5,6,7-tetrahydropyrazolo[1,5-a]-3-pyridyl), dihydropyrazolooxazinyl (6,7-dihydropyrazolo[5,1-b][1,3]-3-oxazinyl)) optionally substituted by 1 to 3 substituents selected from R 3 But unsubstituted C 1-6 is an alkyl group (e.g., methyl); R 4 But unsubstituted C 1-6 is an alkyl group (e.g., methyl); and Ring A is a benzene ring optionally further substituted with a halogen atom (e.g., a fluorine atom); Compounds are preferred.

[0055] Compound (I) is, inter alia, R 1 but, (1) a hydrogen atom, (2) 1 to 3 C’s 3-6 C optionally substituted with a cycloalkyl group (e.g., cyclopropyl) 1-6 an alkyl group (e.g., methyl, isopropyl), or (3) C 3-6 a cycloalkyl group (e.g., cyclobutyl); R 2 but, (1)(a) C 1-6 Alkoxy groups (e.g., methoxy), and (b) 1 to 3 C 1-6 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl (4-pyrazolyl)) optionally substituted with an alkyl group (e.g., methyl) C which is optionally substituted by 1 to 3 substituents selected from 6-10 an aryl group (e.g., phenyl), or (2)(a) 1 to 3 C 1-6 C optionally substituted with an alkoxy group (e.g., methoxy) 1-6 Alkyl groups (e.g., methyl), and (b) C 1-6 Alkoxy groups (e.g., methoxy) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl (4-pyrazolyl)) optionally substituted by 1 to 3 substituents selected from R 3 But unsubstituted C 1-6 is an alkyl group (e.g., methyl); R 4 But unsubstituted C 1-6 Alkyl groups (e.g., methyl); and Ring A is a group represented by the formula: -C(OH)R 3 R 4 (In the formula, R 3 and R 4 is a benzene ring having no substituent other than the above-defined substituents; Compounds are preferred.

[0056] Another preferred embodiment of compound (I) is represented by the formula

[0057] [ka]

[0058] [During the ceremony, R 1a teeth, (1) 1 to 3 optionally halogenated C 3-6 C optionally substituted with a cycloalkyl group (e.g., cyclopropyl, 2,2-difluorocyclopropyl) 1-6 an alkyl group (e.g., methyl, isopropyl), or (2) C 3-6 cycloalkyl groups (e.g., cyclobutyl); R 2a teeth, (1) C 3-6 cycloalkyl groups (e.g., cyclohexyl); (2)(a) A halogen atom (e.g., a chlorine atom), (b) 1 to 3 C 1-6 C optionally substituted with an alkoxy group (e.g., methoxy) 1-6Alkyl groups (e.g., methyl, isopropyl, isobutyl), (c) C 3-6 Cycloalkyl groups (e.g., cyclobutyl), and (d) C 1-6 Alkoxy groups (e.g., methoxy) or a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl (4-pyrazolyl)) optionally substituted by 1 to 3 substituents selected from (3) 9- to 14-membered fused polycyclic non-aromatic heterocyclic groups optionally substituted by 1 to 3 halogen atoms (e.g., fluorine atoms) (e.g., dihydropyrazolooxazinyl (6,7-dihydropyrazolo[5,1-b][1,3]-3-oxazinyl)); R 3a is unsubstituted C 1-6 Alkyl groups (e.g., methyl); R 4a is unsubstituted C 1-6 Alkyl groups (e.g., methyl); and Ring A a represents a benzene ring having no further substituents. or a compound (Ia) represented by the formula

[0059] [ka]

[0060] [During the ceremony R 1b teeth, (1) a hydrogen atom, (2) 1 to 3 optionally halogenated C 3-6 C optionally substituted with a cycloalkyl group (e.g., cyclopropyl, 2,2-difluorocyclopropyl) 1-6 an alkyl group (e.g., methyl, ethyl, isopropyl), or (3) C 3-6 cycloalkyl groups (e.g., cyclobutyl); R 2b teeth, (1)(a) A halogen atom (e.g., a fluorine atom), (b) Optionally halogenated C 1-6 Alkyl groups (e.g., trifluoromethyl), (c) C 1-6 Alkoxy groups (e.g., methoxy), and (d) 1 to 3 C 1-6 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl (4-pyrazolyl)) optionally substituted with an alkyl group (e.g., methyl) C which is optionally substituted by 1 to 3 substituents selected from 6-10 Aryl groups (e.g., phenyl), (2)(a) A halogen atom (e.g., a chlorine atom), (b)(i) a halogen atom (e.g., a fluorine atom), and (ii) C 1-6 Alkoxy groups (e.g., methoxy) C which is optionally substituted by 1 to 3 substituents selected from 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl, isobutyl), and (c) C 1-6 Alkoxy groups (e.g., methoxy, ethoxy, isopropyloxy) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl (3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl)) optionally substituted by 1 to 3 substituents selected from (3) 1 to 3 C’s 1-6 9- to 14-membered fused polycyclic non-aromatic heterocyclic groups optionally substituted by an alkyl group (e.g., methyl) (e.g., dihydrobenzofuryl (2,3-dihydro-7-benzofuryl), tetrahydropyrazolopyridyl (4,5,6,7-tetrahydropyrazolo[1,5-a]-3-pyridyl), dihydropyrazolooxazinyl (6,7-dihydropyrazolo[5,1-b][1,3]-3-oxazinyl)); R 3b is unsubstituted C 1-6 Alkyl groups (e.g., methyl); R 4b is unsubstituted C 1-6 Alkyl groups (e.g., methyl); and Ring A brepresents a benzene ring which may be further substituted with a halogen atom (e.g., a fluorine atom) at the 4-, 5- or 7-position of the 1H-indazole ring. Also included is compound (Ib) represented by the following formula:

[0061] Another more preferred embodiment of compound (I) is

[0062] [ka]

[0063] [During the ceremony, R 1a is C 1-6 Alkyl groups (e.g., methyl); R 2a is C 1-6 Alkyl groups (e.g., methyl) and C 1-6 a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl (4-pyrazolyl)) optionally substituted by 1 to 3 substituents selected from an alkoxy group (e.g., methoxy); R 3a is unsubstituted C 1-6 Alkyl groups (e.g., methyl); R 4a is unsubstituted C 1-6 Alkyl groups (e.g., methyl); and Ring A a represents a benzene ring having no further substituents. or a compound (Ia) represented by the formula

[0064] [ka]

[0065] [During the ceremony R 1b teeth, (1) a hydrogen atom, (2) 1 to 3 C’s 3-6 C optionally substituted with a cycloalkyl group (e.g., cyclopropyl) 1-6 an alkyl group (e.g., methyl, isopropyl), or (3) C 3-6 cycloalkyl groups (e.g., cyclobutyl); R 2b teeth, (1)(a) C 1-6 Alkoxy groups (e.g., methoxy), and (b) 1 to 3 C 1-6 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl (4-pyrazolyl)) optionally substituted with an alkyl group (e.g., methyl) C which is optionally substituted by 1 to 3 substituents selected from 6-10 an aryl group (e.g., phenyl), or (2)(a) 1 to 3 C 1-6 C optionally substituted with an alkoxy group (e.g., methoxy) 1-6 Alkyl groups (e.g., methyl), and (b) C 1-6 Alkoxy groups (e.g., methoxy) a 5- or 6-membered monocyclic aromatic heterocyclic group (e.g., pyrazolyl (4-pyrazolyl)) optionally substituted by 1 to 3 substituents selected from the above; R 3b is unsubstituted C 1-6 Alkyl groups (e.g., methyl); R 4b is unsubstituted C 1-6 Alkyl groups (e.g., methyl); and Ring A b represents a benzene ring having no further substituents. Also included is compound (Ib) represented by the following formula:

[0066] Specific examples of compound (I) include the compounds of Examples 1 to 89. Among them, 2-{3-[2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}propan-2-ol (Example 12) or a salt thereof, 2-{3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-5-yl}propan-2-ol (Example 41) or a salt thereof, 2-{1-(cyclopropylmethyl)-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol (Example 49) or a salt thereof, 2-(1-cyclobutyl-3-{[3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl)propan-2-ol (Example 82) or a salt thereof, 2-[1-(cyclopropylmethyl)-3-{[3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl]propan-2-ol (Example 84) or a salt thereof, 2-[3-{[3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1-(propan-2-yl)-1H-indazol-6-yl]propan-2-ol (Example 85) or a salt thereof is preferred. In particular, 2-{3-[2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}propan-2-ol (Example 12) or a salt thereof, 2-{3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-5-yl}propan-2-ol (Example 41) or a salt thereof, 2-{1-(cyclopropylmethyl)-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol (Example 49) or a salt thereof is preferred.

[0067] When compound (I) is a salt, such salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Suitable examples of metal salts include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts, magnesium salts and barium salts; and aluminum salts. Suitable examples of salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc. Suitable examples of salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Suitable examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. Among these, pharma- ceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, examples of the salt include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt, etc.), and ammonium salts. When the compound has a basic functional group, examples of the salt include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. When compound (I) has isomers such as tautomers, optical isomers, stereoisomers, positional isomers, and rotational isomers, either one of the isomers and a mixture thereof are included in the compound of the present invention. Furthermore, when compound (I) has optical isomers, optical isomers resolved from the racemate are also included in compound (I). Compound (I) may be in the form of a crystal, and both a single crystal form and a mixture of crystal forms are included in Compound (I). Compound (I) may be a pharma- ceutically acceptable cocrystal or cocrystal salt. Here, a cocrystal or cocrystal salt refers to a crystalline substance that is composed of two or more unique solids at room temperature, each of which has different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). A cocrystal or cocrystal salt can be prepared according to a cocrystallization method known per se. Compound (I) may be a solvate (for example, a hydrate) or a non-solvate, and both are encompassed in compound (I). Isotopes (e.g. 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 Compounds labeled or substituted with isotopes such as isotopes I are also encompassed in compound (I). Compounds labeled or substituted with isotopes can be used, for example, as tracers (PET tracers) used in positron emission tomography (PET), and are expected to be useful in fields such as medical diagnosis.

[0068] The process for producing the compound of the present invention is explained below.

[0069] The raw materials and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt. Examples of such salts include the same salts as those of the compounds of the present invention described above.

[0070] When the compound obtained in each step is a free compound, it can be converted into the desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted into a free form or another type of desired salt by a method known per se.

[0071] The compound obtained in each step can be used in the next reaction either as a reaction solution or as a crude product, or the compound obtained in each step can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc. in accordance with a conventional method.

[0072] When the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as they are.

[0073] In the reaction of each step, the reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

[0074] In the reactions of each step, the reaction temperature may vary depending on the reagents and solvents used, but is usually from -78°C to 300°C, preferably from -78°C to 150°C, unless otherwise specified.

[0075] In the reaction of each step, the pressure may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

[0076] In the reactions of each step, a microwave synthesis device such as Biotage Initiator may be used. The reaction temperature may vary depending on the reagents and solvents used, but is usually room temperature to 300° C., preferably 50° C. to 250° C., unless otherwise specified. The reaction time may vary depending on the reagents and solvents used, but is usually 1 minute to 48 hours, preferably 1 minute to 8 hours, unless otherwise specified.

[0077] In the reaction of each step, unless otherwise specified, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, relative to the substrate. When the reagent also serves as a reaction solvent, the reagent is used in an amount equivalent to the solvent.

[0078] Unless otherwise specified, the reactions in each step are carried out without a solvent or by dissolving or suspending the components in a suitable solvent. Specific examples of the solvent include those described in the Examples and the following. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc.; Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc.; Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, hexane, etc.; Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc.; Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water. The above solvents may be used as a mixture of two or more kinds in an appropriate ratio.

[0079] When a base is used in the reaction of each step, for example, the base shown below or the base described in the Examples can be used. Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc.; Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc.; Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; Organolithium compounds: n-butyllithium, etc.

[0080] When an acid or an acid catalyst is used in the reaction of each step, for example, the acids and acid catalysts shown below or the acids and acid catalysts described in the Examples can be used. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride, etc.

[0081] Unless otherwise specified, the reactions in each step are carried out by a method known per se, for example, in Experimental Chemistry Lectures, 5th Edition, Vol. 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry Lectures, Vol. 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (LF Tietze, Th. Eicher, Nankodo); Revised Organic Named Reactions: Their Mechanisms and Key Points (by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volumes I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (by Jie Jack Li, published by OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol. 1-14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (translated and supervised by Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers The method may be carried out in accordance with the method described in, for example, the 1989 issue of "The Method for Producing a Fluorescent Protein," published by the Japanese Patent Laid-Open Publication No. 2002-2003444, or the method described in the Examples.

[0082] In each step, the protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, a method described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter GM Wuts), published by Wiley-Interscience in 2007; "Protecting Groups, 3rd Ed." (PJ Kocienski), published by Thieme in 2004, or a method described in the Examples. Examples of the protecting group for the hydroxyl group of an alcohol or the like or a phenolic hydroxyl group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylate-type protecting groups such as acetate; sulfonate-type protecting groups such as methanesulfonate; and carbonate-type protecting groups such as tert-butyl carbonate. Examples of the protecting group for the carbonyl group of an aldehyde include acetal-type protecting groups such as dimethylacetal; and cyclic acetal-type protecting groups such as 1,3-dioxane. Examples of protecting groups for the carbonyl group of a ketone include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone. Examples of the carboxy-protecting group include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N,N-dimethylamide. Examples of the thiol-protecting group include ether-type protecting groups such as benzylthioether; and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate. Examples of the protecting group for an amino group or an aromatic heterocycle such as imidazole, pyrrole, or indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-triphenylmethylamine; and sulfonamide-type protecting groups such as methanesulfonamide. The protecting group can be removed by a method known per se, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or a reduction method.

[0083] In each step, when a reduction reaction is carried out, examples of the reducing agent used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; etc. When a carbon-carbon double bond or triple bond is reduced, a catalyst such as palladium-carbon or Lindlar catalyst may be used.

[0084] In each step, when an oxidation reaction is carried out, examples of the oxidizing agent used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and tert-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0085] In each step, when a radical cyclization reaction is carried out, examples of the radical initiator used include azo compounds such as azobisisobutyronitrile (AIBN), water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA), triethylboron in the presence of air or oxygen, benzoyl peroxide, etc. Examples of the radical reaction reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0086] When a Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidene phosphoranes, etc. The alkylidene phosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0087] When the Horner-Emmons reaction is carried out in each step, examples of the reagent used include phosphonoacetates such as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate and the like; and bases such as alkali metal hydrides, organolithium compounds and the like.

[0088] In each step, when the Friedel-Crafts reaction is carried out, examples of the reagent used include a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.). Alternatively, an organic acid or an inorganic acid can be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of the acid chloride.

[0089] In each step, when an aromatic nucleophilic substitution reaction is carried out, a nucleophile (eg, amines, imidazole, etc.) and a base (eg, organic bases, etc.) are used as reagents.

[0090] In each step, when a nucleophilic addition reaction by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion, or a nucleophilic substitution reaction by a carbanion is performed, examples of the base used to generate the carbanion include organolithiums, metal alkoxides, inorganic bases, and organic bases.

[0091] When a Grignard reaction is carried out in each step, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide, and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with metallic magnesium in ether or tetrahydrofuran as a solvent.

[0092] In each step, when a Knoevenagel condensation reaction is carried out, an active methylene compound sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and a base (e.g., organic bases, metal alkoxides, inorganic bases) are used as reagents.

[0093] In each step, when the Vilsmeier-Haack reaction is carried out, phosphoryl chloride and an amide derivative (eg, N,N-dimethylformamide, etc.) are used as reagents.

[0094] In each step, when an azidation reaction of alcohols, alkyl halides, or sulfonate esters is carried out, examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, when azidating alcohols, there are a method using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and a method using trimethylsilyl azide and a Lewis acid.

[0095] In each step, when a reductive amination reaction is carried out, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of the amines used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0096] In each step, when Mitsunobu reaction is carried out, an azodicarboxylate (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0097] In each step, when an esterification reaction, an amidation reaction, or a urea reaction is performed, examples of the reagents used include acyl halides such as acid chlorides and acid bromides; activated carboxylic acids such as acid anhydrides, active esters, and sulfates. Examples of activators for carboxylic acids include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); Examples of suitable condensing agents include 2-chloro-1-methyl-pyridinium iodide (Mukaiyama's reagent), thionyl chloride, lower alkyl haloformates such as ethyl chloroformate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), sulfuric acid, or combinations thereof. When using a carbodiimide-based condensing agent, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) may be added to the reaction.

[0098] In each step, when a coupling reaction is carried out, examples of the metal catalyst used include palladium compounds such as palladium acetate (II), tetrakis(triphenylphosphine)palladium (0), dichlorobis(triphenylphosphine)palladium (II), dichlorobis(triethylphosphine)palladium (II), tris(dibenzylideneacetone)dipalladium (0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel (0); rhodium compounds such as tris(triphenylphosphine)rhodium (III) chloride; cobalt compounds; copper compounds such as copper oxide and copper iodide (I); and platinum compounds. A base may be added to the reaction, and examples of such bases include inorganic bases.

[0099] When a thiocarbonylation reaction is carried out in each step, diphosphorus pentasulfide is typically used as the thiocarbonylating agent. In addition to diphosphorus pentasulfide, a reagent having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure, such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson's reagent), may also be used.

[0100] In each step, when a halogenation reaction is carried out, examples of the halogenating agent used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.

[0101] In each step, when a halogenation reaction of a hydroxy group is carried out, examples of the halogenating agent used include hydrohalic acid and an acid halide of an inorganic acid, specifically, for chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc., and for bromination, 48% hydrobromic acid, etc. may be mentioned. In addition, a method of obtaining an alkyl halide from an alcohol by the reaction of triphenylphosphine with carbon tetrachloride or carbon tetrabromide, etc. may be used. Alternatively, a method of synthesizing an alkyl halide through a two-step reaction in which an alcohol is converted into a sulfonic acid ester and then reacted with lithium bromide, lithium chloride, or sodium iodide may be used.

[0102] When Arbuzov reaction is carried out in each step, examples of the reagent used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite and the like.

[0103] When a sulfonyl esterification reaction is carried out in each step, examples of the sulfonylating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0104] In each step, when a hydrolysis reaction is carried out, an acid or a base is used as a reagent. When an acid hydrolysis reaction of a tert-butyl ester is carried out, formic acid or triethylsilane may be added to reductively trap the by-product tert-butyl cation.

[0105] When a dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

[0106] In each step, when an alkylation reaction is carried out, an electrophile (eg, alkyl halide, etc.) and a base (eg, organic bases, inorganic bases, metal alkoxides, metal amides, etc.) are used as reagents.

[0107] Compound (I) can be produced according to the following production methods A to L or methods similar thereto. The abbreviations in each general formula in the reaction scheme are the same as those defined above unless otherwise specified. HAL represents a halogen atom (e.g., a chlorine atom, a bromine atom, an iodine atom). R 9 is optionally substituted C 1-6 R indicates an alkyl group (e.g., methyl, ethyl). 10 represents a hydrogen atom or a substituent. Furthermore, if desired, compound (I) can be produced by carrying out a deprotection reaction, an amidation reaction, a urea reaction, an alkylation reaction, a Mitsunobu reaction, an oxidation reaction, a reduction reaction, a halogenation reaction, a coupling reaction, a nucleophilic addition reaction with a carbanion, a Grignard reaction, a dehydration reaction, or the like, either alone or in combination of two or more thereof.

[0108] Compound (I) can be produced from compound (1) and each starting material derived from compound (1) by the methods shown in the following reaction schemes 1 to 4. In the formulas, HAL represents a halogen atom (e.g., a chlorine atom, a bromine atom, an iodine atom). 9 is optionally substituted C 1-6 Indicates an alkyl group (e.g., methyl, ethyl). 1 represents a protecting group, and the other symbols are as defined above.

[0109] [ka]

[0110] Compound (1) may be a commercially available product as is, or may be produced by a known method or a method analogous thereto.

[0111] Compound (2) can be produced by subjecting compound (1) to a carbon monoxide insertion reaction in the presence of a metal catalyst. Examples of the metal catalyst used include palladium compounds such as palladium acetate (II), tetrakis(triphenylphosphine)palladium (0), dichlorobis(triphenylphosphine)palladium (II), dichlorobis(triethylphosphine)palladium (II), tris(dibenzylideneacetone)dipalladium (0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) chloride. A base may also be added to the reaction, and examples of such bases include organic bases such as triethylamine and diisopropylethylamine. Examples of the reaction solvent include alcohols (R 9 -OH) to obtain the alcohol substituent R 9 is introduced as a substituent on the ester group of compound (2).

[0112] Compound (3) can be produced by subjecting compound (2) to a Grignard reaction. Examples of Grignard reagents include alkylmagnesium halides such as methylmagnesium bromide. Grignard reagents can be prepared by a method known per se, for example, by reacting R 3 and / or R 4 Alternatively, a commercially available Grignard reagent solution can be used as it is.

[0113] Compound (4) can be produced by halogenation of compound (3). Examples of halogenating agents that can be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, and iodine. Furthermore, the reaction can be accelerated by adding an inorganic base such as sodium hydroxide or potassium hydroxide to the reaction.

[0114] Compound (5) can be produced by alkylation of compound (4). 1 A combination of an electrophile (e.g., alkyl halide, cycloalkyl halide, etc.) and a base (e.g., organic bases, inorganic bases, metal alkoxides, metal amides, etc.) corresponding to the above is used. The electrophile may be a commercially available product as it is, or may be produced by a method known per se or a method equivalent thereto.

[0115] Compound (I) can be produced by a coupling reaction between compound (5) and compound (6). Metal catalysts used in the coupling reaction include palladium compounds such as palladium acetate (II), tetrakis(triphenylphosphine)palladium (0), dichlorobis(triphenylphosphine)palladium (II), dichlorobis(triethylphosphine)palladium (II), tris(dibenzylideneacetone)dipalladium (0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel (0); rhodium compounds such as tris(triphenylphosphine)rhodium (III) chloride; cobalt compounds; copper compounds such as copper oxide and copper iodide (I); and platinum compounds. A base may also be added to the reaction, and examples of such bases include inorganic bases. Compound (6) can be produced by using a commercially available product as is, or by a method known per se or a method equivalent thereto.

[0116] [ka]

[0117] Compound (7) can be produced by halogenation of compound (2). Examples of halogenating agents that can be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, and iodine. Furthermore, the reaction can be accelerated by adding an inorganic base such as sodium hydroxide or potassium hydroxide to the reaction.

[0118] Compound (8) can be produced by alkylation of compound (7). 1 A combination of an electrophile (e.g., alkyl halide, cycloalkyl halide, etc.) and a base (e.g., organic bases, inorganic bases, metal alkoxides, metal amides, etc.) corresponding to the above is used. The electrophile may be a commercially available product as it is, or may be produced by a method known per se or a method equivalent thereto.

[0119] Compound (9) can be produced by a coupling reaction between compound (8) and compound (6). Metal catalysts used in the coupling reaction include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel(0); rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper iodide(I); and platinum compounds. A base may also be added to the reaction, and examples of such bases include inorganic bases. Compound (6) can be produced by using a commercially available product as is, or by a method known per se or a method equivalent thereto.

[0120] Compound (I) can be produced by the Grignard reaction of compound (9). Grignard reagents include alkylmagnesium halides such as methylmagnesium bromide. Grignard reagents can be produced by a method known per se, for example, by reacting R 3 and / or R 4 Alternatively, a commercially available Grignard reagent solution can be used as it is.

[0121] [ka]

[0122] Compound (10) can be produced by a protection reaction of the NH group of compound (7). Examples of the protecting group include a methoxymethyl group, a benzyl group, a tert-butyldimethylsilyl group, and a tetrahydropyranyl group. These protecting groups can be introduced into the NH group of compound (7) by a method known per se or a method equivalent thereto.

[0123] Compound (11) can be produced by a coupling reaction between compound (10) and compound (6). Metal catalysts used in the coupling reaction include palladium compounds such as palladium acetate (II), tetrakis(triphenylphosphine)palladium (0), dichlorobis(triphenylphosphine)palladium (II), dichlorobis(triethylphosphine)palladium (II), tris(dibenzylideneacetone)dipalladium (0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel (0); rhodium compounds such as tris(triphenylphosphine)rhodium (III) chloride; cobalt compounds; copper compounds such as copper oxide and copper iodide (I); and platinum compounds. A base may also be added to the reaction, and examples of such bases include inorganic bases. Compound (6) can be produced by using a commercially available product as is, or by a method known per se or a method equivalent thereto.

[0124] Compound (12) can be produced by subjecting compound (11) to a Grignard reaction. Examples of Grignard reagents include alkyl magnesium halides such as methyl magnesium bromide. Grignard reagents can be prepared by a method known per se, for example, by reacting R 3 and / or R 4 Alternatively, a commercially available Grignard reagent solution can be used as it is.

[0125] R 1 Compound (I) in which is hydrogen can be prepared by a deprotection reaction of compound (12).

[0126] [ka]

[0127] Compound (13) can be produced by a deprotection reaction of compound (11).

[0128] R 1 Compound (I) in which R is hydrogen can be produced by the Grignard reaction of compound (13). Grignard reagents include alkyl magnesium halides such as methyl magnesium bromide. Grignard reagents can be prepared by a method known per se, for example, by reacting R 3 and / or R 4 Alternatively, a commercially available Grignard reagent solution can be used as it is.

[0129] As for the configurational isomer (E,Z isomer) of compound (I), when isomerization occurs, it can be isolated and purified by ordinary separation means such as extraction, recrystallization, distillation, chromatography, etc., to produce a pure compound. In addition, according to the method described in New Experimental Chemistry Lectures 14 (edited by the Chemical Society of Japan), pages 251-253, and 4th Edition Experimental Chemistry Lectures 19 (edited by the Chemical Society of Japan), pages 273-274, or methods equivalent thereto, the isomerization of the double bond can be advanced by heating, an acid catalyst, a transition metal complex, a metal catalyst, a radical species catalyst, light irradiation, or a strong base catalyst, to obtain the corresponding pure isomer.

[0130] Compound (I) may have stereoisomers depending on the type of substituents, and both the isomers alone and mixtures thereof are included in the present invention. When the target compound is obtained in a free state by the above reaction, it may be converted into a salt according to a conventional method, and when it is obtained as a salt, it may be converted into a free form or another salt according to a conventional method. Compound (I) thus obtained can be isolated and purified from the reaction solution by known means, such as transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, etc. When compound (I) exists as configurational isomers, diastereomers, conformers, etc., they can be isolated by the above-mentioned separation and purification means, if desired. When compound (I) is a racemate, it can be separated into d- and l-forms, or S- and R-forms, by a conventional optical resolution means.

[0131] Compound (I) thus obtained, other reaction intermediates and starting compounds thereof can be isolated and purified from the reaction mixture by a method known per se, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin layer chromatography, preparative high performance liquid chromatography (preparative HPLC), medium pressure preparative liquid chromatography (medium pressure preparative LC), or the like.

[0132] The salt of compound (I) can be produced by a method known per se, for example, by adding an inorganic acid or an organic acid when compound (I) is a basic compound, or by adding an organic base or an inorganic base when compound (I) is an acidic compound. When compound (I) may have optical isomers, all of these individual optical isomers and mixtures thereof are naturally included in the scope of the present invention, and if desired, these isomers can be optically resolved or individually produced according to known means.

[0133] The compound of the present invention can be used to inhibit, for example, the following in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.): (1) Mental disorders (e.g., depression, major depression, bipolar depression, dysthymic disorder, affective disorder (such as seasonal affective disorder), recurrent depression, postpartum depression, stress disorder, depressive symptoms, mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, post-traumatic stress disorder, Tourette syndrome, autism, fragile X syndrome, Rett syndrome, adaptation disorders, bipolar disorder, neurosis, schizophrenia (e.g., positive symptoms, negative symptoms, cognitive impairment), chronic fatigue syndrome, anxiety neurosis, obsessive-compulsive disorder, panic disorder, epilepsy, anxiety disorder, anxiety symptoms, dysphoric mental state, dysthymia, cyclothymia, irritability, syncope, addiction, decreased libido, attention-deficit hyperactivity disorder (ADHD), major psychotic depression, treatment-resistant major depression, treatment-resistant depression, depressive disorder, catalepsy, schizophrenia of the hemorrhagic type, schizophrenia of the paranoid type], (2) Neurodegenerative diseases [e.g., progressive bulbar palsy, progressive muscular atrophy, primary lateral sclerosis, progressive pseudobulbar palsy, spinal muscular atrophy, Alzheimer's disease, senile dementia of the Alzheimer type, Parkinson's disease, Huntington's disease, multi-infarct dementia, frontotemporal dementia, Parkinson's dementia, progressive supranuclear palsy, Pick's syndrome, corticobasal degeneration, Down's syndrome, vascular dementia, postencephalitic Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Friedreich's ataxia, HIV-related dementia, amyotrophic lateral sclerosis (ALS), motor neurogenic disease (MND), Creutzfeldt-Jakob disease or prion disease, cerebral palsy, progressive supranuclear palsy, traumatic brain injury, glaucoma, multiple sclerosis, neuromyelitis optica (NMO), postoperative cognitive dysfunction (POCD), postoperative delirium (POD), delirium], (3) Age-related cognitive and memory disorders (e.g., age-related memory disorder, senile dementia), (4) Sleep disorders [e.g., endogenous sleep disorders (e.g., psychophysiological insomnia, etc.), exogenous sleep disorders, circadian rhythm disorders (e.g., time zone shift syndrome (jet lag), shift work sleep disorder, irregular sleep-wake patterns, delayed sleep phase syndrome, advanced sleep phase syndrome, non-24-hour sleep-wake, etc.), parasomnia, sleep disorders associated with medical or psychiatric disorders (e.g., chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, vascular dementia, schizophrenia, depression, anxiety neurosis), stress insomnia, insomnia, insomnia neurosis, sleep apnea syndrome], (5) Respiratory depression caused by anesthetics, trauma, or neurodegenerative diseases, etc. (6) traumatic brain injury, stroke, cerebral edema, cerebral ischemia, ischemia, anorexia nervosa, eating disorders, anorexia nervosa, bulimia, other eating disorders, alcoholism, alcohol abuse, alcoholic amnesia, alcohol delusion, alcohol preference, alcohol withdrawal, alcoholic psychosis, alcohol poisoning, alcoholic jealousy, alcoholic mania, alcohol-dependent mental disorder, alcoholic psychosis, drug preference, drug phobia, drug mania, drug withdrawal, migraine, stress headache, tension headache, diabetic neuropathy , obesity, diabetes, muscle spasms, Meniere's disease, autonomic nervous system dysfunction, alopecia, glaucoma, high blood pressure, heart disease, tachycardia, congestive heart failure, hyperventilation, bronchial asthma, apnea, sudden infant death syndrome, inflammatory diseases, allergic diseases, impotence, menopausal disorders, infertility, tumors (e.g., cancer, liver cancer, colon cancer, breast cancer, prostate cancer, neuroblastoma, bone cancer, oral cancer, mast cell tumor, bile duct cancer, Lewis lung carcinoma), immunodeficiency syndrome due to HIV infection, immunodeficiency syndrome due to stress, cerebrospinal meningitis, acromegaly, incontinence, metabolic syndrome ulcer, osteoporosis, peptic ulcer, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, stress-related gastrointestinal disorder, nervous vomiting, diarrhea, constipation, postoperative ileus, rheumatoid arthritis, osteoarthritis, functional dyspepsia, hyperalgesia, insulin resistance, dementia pugilistica, nausea, vomiting, tumor metastasis, brain injury, seizures, weight change, weight gain, weight loss, colitis, alcoholism, hypothermia, fatty liver, non-alcoholic steatohepatitis (NASH), cirrhosis, atherosclerosis, infection, muscle spasms, high blood pressure, stroke Malignant transitional partial seizures of childhood, diabetes mellitus, type 2 diabetes mellitus, dyslipidemia, visceral obesity, hypotony, anorexia, fibrosis, myocardial infarction, cachexia, induced psychotic disorder, ataxia, AIDS wasting syndrome, cardiomyopathy of cirrhosis, uremic pruritus, neurobehavioral symptoms, tubulointerstitial nephritis and uveitis syndrome, interstitial cystitis, retinitis pigmentosa, complex regional pain syndrome, autoimmune diseases, coronary artery disease, aspirin asthma, platelet storage pool deficiency, diabetic embryo, Arthus type urticaria, asthma, toxic oil syndrome, otitis, etc. (7) Pain (e.g., inflammatory pain, cancer pain, neuropathic pain, acute pain, pain due to peripheral neuropathy, central pain, fibromyalgia, vasoocclusive painful crises in sickle cell disease, spasticity or pain mediated by multiple sclerosis, functional chest pain, complex regional pain syndrome, etc.) (8) Lysosomal storage diseases (e.g., Gaucher disease, Krabbe disease, Niemann-Pick syndrome), It is expected that this compound will be useful as a preventive or therapeutic agent for the following diseases:

[0134] The compound of the present invention has excellent inhibitory activity against cell degeneration, and is therefore expected to have excellent preventive and therapeutic effects against the above-mentioned diseases.

[0135] The compound of the present invention also has an excellent inhibitory effect on motor neuron degeneration, and is therefore expected to have excellent preventive and therapeutic effects, particularly against motor neuron diseases (motor neuron neurodegenerative diseases) (e.g., amyotrophic lateral sclerosis, progressive bulbar palsy, progressive muscular atrophy, primary lateral sclerosis, progressive pseudobulbar palsy, spinal muscular atrophy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Friedreich's ataxia) and the like.

[0136] Compound (I) may be used as a prodrug.

[0137] A prodrug of compound (I) refers to a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, or the like, or a compound that is converted to compound (I) by hydrolysis due to gastric acid, etc.

[0138] Examples of the prodrug of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, or tert-butylated); compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, or pivaloylated). , succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); compounds in which the carboxy group of compound (I) is esterified or amidated (for example, compounds in which the carboxy group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, methylamidated compounds, etc.). These compounds can be produced from compound (I) by known methods. In addition, the prodrug of compound (I) may be one that changes to compound (I) under physiological conditions as described in "Drug Development" Vol. 7, Molecular Design, pp. 163 to 198, published by Hirokawa Shoten in 1990.

[0139] The compound of the present invention has excellent pharmacokinetics (e.g., blood drug half-life, brain transferability, metabolic stability) and low toxicity (e.g., superior as a medicine in terms of acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interactions, carcinogenicity, etc.), and can be safely administered orally or parenterally to mammals (e.g., humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, etc.) as a medicine as it is or as a pharmaceutical composition mixed with a pharmaceutically acceptable carrier, etc. "Parenteral" includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, rectal, vaginal, intraperitoneal, intratumor, proximal to a tumor, etc., and administration directly to a lesion.

[0140] The dosage of the compound of the present invention varies depending on the administration route, symptoms, etc., but for example, when orally administered to a patient with amyotrophic lateral sclerosis (adult, body weight 40 to 80 kg, for example 60 kg), the dosage is, for example, 0.001 to 1000 mg / kg body weight per day, preferably 0.01 to 100 mg / kg body weight per day, more preferably 0.1 to 10 mg / kg body weight per day. This amount can be administered in one to three divided doses per day.

[0141] The pharmaceutical agent containing the compound of the present invention can be used alone or as a pharmaceutical composition in which the compound of the present invention is mixed with a pharma- ceutical carrier, according to a method known per se (e.g., a method described in the Japanese Pharmacopoeia, etc.) as a method for producing pharmaceutical preparations. Pharmaceutical agents containing the compound of the present invention can be used in the form of tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules), troches, syrups, liquids, emulsions, suspensions, controlled-release preparations (e.g., immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (e.g., orally disintegrating films ...

[0043] The composition can be safely administered orally or parenterally (e.g., intravenous, intramuscular, subcutaneous, intravisceral, intranasal, intradermal, eye drops, intracerebral, rectal, vaginal, intraperitoneal, etc.) in the form of an injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), infusion, transdermal preparation, ointment, lotion, patch, suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalation preparation), eye drops, etc.

[0142] As the "pharmaceutical acceptable carrier", various organic or inorganic carriers commonly used as starting materials for preparations are used. For example, excipients, lubricants, binders, disintegrants, etc. are used in solid preparations, while solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. are used in liquid preparations. Furthermore, preparation additives such as preservatives, antioxidants, colorants, sweeteners, etc. can also be used as necessary. Examples of excipients include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid. Examples of lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, and the like. Examples of binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, and sodium carboxymethyl cellulose. Examples of disintegrants include starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylstarch, and L-hydroxypropylcellulose. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like. Examples of solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate. Examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of isotonicity agents include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, and the like. Examples of the buffering agent include buffer solutions such as phosphate, acetate, carbonate, and citrate. An example of the soothing agent is benzyl alcohol. Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, and sorbic acid. Antioxidants include, for example, sulfites, ascorbic acid, α-tocopherol, and the like.

[0143] Pharmaceutical compositions vary depending on the dosage form, administration method, carrier, etc., but can be produced according to conventional methods by adding the compound of the present invention in a proportion of usually 0.01 to 100% (w / w), preferably 0.1 to 95% (w / w), based on the total amount of the formulation.

[0144] The compound of the present invention may be used in combination with other active ingredients (hereinafter, abbreviated as concomitant drugs).

[0145] Concomitant medications include, for example: Benzodiazepines (chlordiazepoxide, diazepam, potassium clorazepate, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel blockers (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.), selective serotonin reuptake inhibitors (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrochloride, sertraline hydrochloride, etc.) , paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitors (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), noradrenaline reuptake inhibitors (reboxetine mesylate, etc.), noradrenaline-dopamine reuptake inhibitors (bupropion hydrochloride, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT 1AAgonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT3 antagonists (cyamemazine, etc.), non-cardiac selective beta blockers (propranolol hydrochloride, oxyprenolol hydrochloride, etc.), histamine H1 antagonists (hydroxyzine hydrochloride, etc.), schizophrenia medications (chlorpromazine, haloperidol, sulpride, clozapine, trifluoperazine hydrochloride, fluphenazine hydrochloride, olanzapine, quetiapine fumarate, risperidone, aripiprazole, etc.), CRF antagonists, other anxiolytics (meprobamate, etc.), tachykinin antagonists (MK-869, saredutant, etc.), drugs acting on metabotropic glutamate receptors agents, CCK antagonists, β3 adrenergic antagonists (amibegron hydrochloride, etc.), GAT-1 inhibitors (tiagabine hydrochloride, etc.), N-type calcium channel inhibitors, type 2 carbonic anhydrase inhibitors, NMDA glycine site agonists, NMDA antagonists (memantine, etc.), peripheral benzodiazepine receptor agonists, vasopressin antagonists, vasopressin V1b antagonists, vasopressin V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid receptor agonists, thyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), 5-HT 2A Antagonist, 5-HT 2AInverse agonists, COMT inhibitors (entacapone, etc.), bipolar disorder medications (lithium carbonate, sodium valproate, lamotrigine, riluzole, felbamate, etc.), cannabinoid CB1 antagonists (rimonabant, etc.), FAAH inhibitors, sodium channel blockers, anti-ADHD drugs (methylphenidate hydrochloride, methamphetamine hydrochloride, etc.), alcoholism medications, autism medications, chronic fatigue syndrome medications, convulsant medications, fibromyalgia medications, headache medications, insomnia medications (etizolam, zopiclone, triazolam, zolpidem, ramelteon, indiplon etc.), smoking cessation medication, myasthenia gravis medication, cerebral infarction medication, mania medication, hypersomnia medication, pain medication, mood disorders medication, autonomic nervous system disorders medication, male and female sexual dysfunction medication, migraine medication, pathological gambling medication, restless legs syndrome medication, substance addiction medication, alcohol-related disorders medication, irritable bowel syndrome medication, Alzheimer's disease medication (donepezil, galantamine, memantine, rivastigmine etc.), Parkinson's disease medication (levodopa, carbidopa, benserazide, selegiline, zonisamide, endacavone, amantadine, talipes Drugs for treating Huntington's disease (chlorpromazine hydrochloride, haloperidol, reserpine, etc.), drugs for treating Gaucher disease (imiglucerase, taliglucerase alfa, velaglucerase alfa, eliglustat, miglustat, etc.), drugs for treating ALS (riluzole, neurotrophic factors, etc.), drugs for treating multiple sclerosis (molecular markers such as fingolimod, interferon beta 1b, natalizumab, etc.) antiepileptic drugs (phenytoin, carbamazepine, phenobarbital, primidone, zonizamide, sodium valproate, ethosuximide, diazepam, nitrazepam, clonazepam, clobazam, gabapentin, topiramate, lamotrigine, levetiracetam, stiripentol, rufinamide, etc.), dyslipidemia drugs such as cholesterol-lowering drugs (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthesis inhibitors),Drugs for treating abnormal behavior or suppressing wandering habits due to dementia (sedatives, anti-anxiety drugs, etc.), apoptosis inhibitors, anti-obesity drugs, drugs for treating diabetes, drugs for treating high blood pressure, drugs for treating low blood pressure, drugs for treating rheumatism (DMARDs), anti-cancer drugs, drugs for treating parathyroid gland (PTH), calcium receptor antagonists, sex hormones or derivatives thereof (progesterone, estradiol, estradiol benzoate, etc.), drugs for promoting neuronal differentiation, drugs for promoting neuronal regeneration, non-steroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroids (dexamethasone, cortisone acetate, etc.), anti-cytokine drugs (TNF inhibitors, MAP kinase inhibitors, etc.), antibody drugs, nucleic acids or nucleic acid derivatives, aptamer drugs, etc.

[0146] By combining the compound of the present invention with a concomitant drug, (1) The dose of the compound of the present invention or a concomitant drug can be reduced compared to when the compound is administered alone. (2) Drugs to be used in combination with the compounds of the present invention can be selected depending on the symptoms of the patient (mild, severe, etc.). (3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be extended. (4) By selecting a concomitant drug having a different mechanism of action from that of the compound of the present invention, the therapeutic effect can be sustained. (5) By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.

[0147] Hereinafter, the combined use of the compound of the present invention and a concomitant drug will be referred to as "the combined drug of the present invention." When using the combination drug of the present invention, the administration time of the compound of the present invention and the combination drug is not limited, and the compound of the present invention or its pharmaceutical composition and the combination drug or its pharmaceutical composition may be administered to the subject at the same time or at a time lag. The dosage of the combination drug may be in accordance with the dosage used in clinical practice, and may be appropriately selected depending on the subject, administration route, disease, combination, etc. The administration form of the combination drug of the present invention is not particularly limited, and it is sufficient that the compound of the present invention and the combination drug are combined at the time of administration.Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the combination drug, (2) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug by the same administration route, (3) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug by the same administration route with a time difference, (4) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug by the different administration routes, (5) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug by the different administration routes with a time difference (for example, administration in the order of the compound of the present invention; administration in the reverse order).

[0148] The combination drug of the present invention has low toxicity, and for example, the compound of the present invention or (and) the combination drug described above can be mixed with a pharma- ceutically acceptable carrier according to a known method and safely administered orally or parenterally (e.g., topically, rectally, intravenously, etc.) as a pharmaceutical composition, for example, a tablet (including sugar-coated tablet, film-coated tablet), powder, granule, capsule (including soft capsule), liquid, injection, suppository, sustained-release agent, etc. Injection can be administered intravenously, intramuscularly, subcutaneously or intraorgan, or directly to the lesion. Examples of pharma- ceutically acceptable carriers that may be used in the production of the combination agent of the present invention include the same as those mentioned above.

[0149] The mixing ratio of the compound of the present invention to the concomitant drug in the combination agent of the present invention can be appropriately selected depending on the subject of administration, the administration route, the disease, etc. For example, the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of the formulation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight based on the total formulation. The content of the concomitant drug in the concomitant agent of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight based on the total preparation. EXAMPLES

[0150] The present invention will be further explained in detail by the following examples, test examples and formulation examples, but these are not intended to limit the present invention and may be modified without departing from the scope of the present invention. In the following examples, "room temperature" generally refers to about 10° C. to about 35° C. Ratios shown in mixed solvents are by volume unless otherwise specified. % refers to weight % unless otherwise specified.

[0151] In the examples, elution in column chromatography was performed under observation by TLC (Thin Layer Chromatography) unless otherwise specified. In the TLC observation, a 60 F TLC plate manufactured by Merck was used. 254 The solvent used as the elution solvent in column chromatography was used as the developing solvent. A UV detector was used for detection. In the case of silica gel column chromatography, aminopropylsilane-bonded silica gel was used when NH was used. In the preparative HPLC (High Performance Liquid Chromatography) in the examples, the eluent solvent system used for purifying the compounds was any one of the following, unless otherwise specified. Acetonitrile / water mixed solvent system containing 0.1% trifluoroacetic acid Acetonitrile / water mixed solvent system containing 10 mM ammonium bicarbonate Acetonitrile / water mixed solvent system containing 0.05% ammonia

[0152] 1H NMR analysis was performed using ACD / SpecManager (trade name) software, etc. Peaks with very gentle proton peaks such as hydroxyl and amino groups may not be recorded. MS was measured by LC / MS. ESI or APCI was used as the ionization method. Data shown are actual measurements (found). Molecular ion peaks are usually observed, but may be observed as fragment ions. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.

[0153] The following abbreviations are used in the following examples: MS: Mass spectrum M: Molar concentration N: Normality CDCl3: deuterated chloroform DMSO-d6: deuterated dimethyl sulfoxide 1 H NMR: Proton nuclear magnetic resonance LC / MS: Liquid chromatograph mass spectrometer ESI: electrospray ionization APCI: atomic pressure chemical ionization Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(OAc)2: Palladium(II) acetate PdCl2(dppf): [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride BrettPhos Pd G3: [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate BrettPhos: 2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl NaOt Bu: sodium tert-butoxide XPhos Pd G3: (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate CuI: Copper(I) iodide XANTPHOS: (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) TFA: Trifluoroacetic acid IPE: Diisopropyl Ether DMF: N,N-dimethylformamide THF: Tetrahydrofuran DME: 1,2-dimethoxyethane MeOH: Methanol EtOH: Ethanol DMSO: Dimethyl sulfoxide Et2O: Diethyl ether SFC: Supercritical Fluid Chromatography

[0154] Example 1 2-{3-[2-methoxy-5-(trifluoromethyl)anilino]-1H-indazol-6-yl}propan-2-ol

[0155] A) Methyl 3-[2-methoxy-5-(trifluoromethyl)anilino]-1-(oxan-2-yl)-1H-indazole-6-carboxylate A mixture of methyl 3-iodo-1-(oxan-2-yl)-1H-indazole-6-carboxylate (300 mg), 2-methoxy-5-(trifluoromethyl)aniline (180 mg), Pd2(dba)3 (36.7 mg), XANTPHOS (45.0 mg), cesium carbonate (770 mg) and DME (6.0 ml) was heated at 90°C overnight. Insoluble matter was removed by filtration through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (273 mg). MS: [M+H] + 450.1.

[0156] B) 2-{3-[2-methoxy-5-(trifluoromethyl)anilino]-1-(oxan-2-yl)-1H-indazol-6-yl}propan-2-ol To a mixture of methylmagnesium bromide (1 mol / l, THF solution) (2.0 ml) and THF (2.0 ml), methyl 3-[2-methoxy-5-(trifluoromethyl)anilino]-1-(oxan-2-yl)-1H-indazole-6-carboxylate (100 mg) was added at 0°C, and the mixture was stirred at 40°C under a nitrogen atmosphere for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound (98 mg). MS: [M+H] + 450.1.

[0157] C) 2-{3-[2-methoxy-5-(trifluoromethyl)anilino]-1H-indazol-6-yl}propan-2-ol To a mixture of 2-{3-[2-methoxy-5-(trifluoromethyl)anilino]-1-(oxan-2-yl)-1H-indazol-6-yl}propan-2-ol and EtOH (2.0 ml), 6 mol / l hydrochloric acid (0.30 ml) was added at room temperature, and the mixture was stirred at 50°C for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate / hexane to obtain the title compound (30.1 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.48 (6H, s), 4.00 (3H, s), 5.10 (1H, s), 7.11-7.20 (3H, m), 7.48 (1H, s), 7.86 (1H, d, J = 8.7 Hz), 8.01 (1H, s), 8.54 (1H, s), 12.17 (1H, s).

[0158] Example 2 2-{3-[(2,3-dihydro-1-benzofuran-7-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol

[0159] A) Methyl 3-iodo-1-methyl-1H-indazole-6-carboxylate Cesium carbonate (17.37 g) was added to a mixture of methyl 3-iodo-1H-indazole-6-carboxylate (11.5 g) and DMF (69 ml), and the mixture was stirred at room temperature for 30 minutes. A mixture of iodomethane (7.14 ml) and DMF (23 ml) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (8.63 g). MS: [M+H] + 316.8.

[0160] B) Methyl 3-[(2,3-dihydro-1-benzofuran-7-yl)amino]-1-methyl-1H-indazole-6-carboxylate A mixture of methyl 3-iodo-1-methyl-1H-indazole-6-carboxylate (3 g), 2,3-dihydro-1-benzofuran-7-amine (1.54 g), cesium carbonate (6.18 g), XANTPHOS (1.10 g), Pd(OAc)2 (0.21 g) and toluene (40 ml) was stirred overnight at 80°C under a nitrogen atmosphere. Insoluble matter was removed by filtration through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (2.02 g). MS: [M+H] + 324.0.

[0161] C) 2-{3-[(2,3-dihydro-1-benzofuran-7-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol To a mixture of methylmagnesium bromide (1 mol / l THF solution) (2.0 ml) and THF (2.0 ml), methyl 3-[(2,3-dihydro-1-benzofuran-7-yl)amino]-1-methyl-1H-indazole-6-carboxylate (100 mg) was added at 0°C, and the mixture was stirred at 40°C under a nitrogen atmosphere for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (67 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.49 (6H, s), 3.23 (2H, t, J = 8.8 Hz), 3.87 (3H, s), 4.60 (2H, t, J = 8.7 Hz), 5.07 (1H, s), 6.72-6.79 (2H, m), 7.10 (1H, d, J = 8.6 Hz), 7.48 (1H, s), 7.78-7.87 (3H, m).

[0162] Example 3 2-(3-{[1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol

[0163] A) 1-(difluoromethyl)-5-methyl-4-nitro-1H-pyrazole A mixture of 3-methyl-4-nitro-1H-pyrazole (5 g), cesium carbonate (12.82 g) and DMF (50 ml) was stirred at 120°C for 20 minutes. Sodium 2-chloro-2,2-difluoroacetate (12 g) was added at 120°C and stirred for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.55 g). 1 H NMR (400 MHz, DMSO-d6) δ 2.77 (3H, s), 8.00 (1H, t, J = 56.7 Hz), 8.50 (1H, s).

[0164] B) 1-(difluoromethyl)-5-methyl-1H-pyrazol-4-amine To a mixture of 1-(difluoromethyl)-5-methyl-4-nitro-1H-pyrazole (50 mg) and THF (1 ml), zinc powder (185 mg) and saturated aqueous ammonium chloride solution (1 ml) were added at 0°C, and the mixture was stirred at room temperature for 30 minutes, and then stirred at 75°C for 30 minutes. Insoluble matter was removed by filtration, and water and ethyl acetate were added to the filtrate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (21.25 mg). MS: [M+H] + 147.9.

[0165] C) 2-(3-{[1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (45 mg), 1-(difluoromethyl)-5-methyl-1H-pyrazol-4-amine (25.1 mg), NaO t A mixture of Bu (41 mg), BrettPhos Pd G3 (10.3 mg), BrettPhos (6.1 mg) and THF (1 ml) was stirred under microwave irradiation for 2 hours at 100° C. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and then by HPLC to obtain the title compound (10 mg). 1 H NMR (300 MHz, CD3OD) δ 0.08 (6H, s), 0.90 (3H, s), 2.29 (3H, s), 5.62 (1H, dd, J = 8.6, 1.3 Hz), 5.73-6.05 (2H, m), 6.10 (1H, d, J = 8.6 Hz), 6.33 (1H, s)

[0166] Example 4 2-{3-[(1,4-dimethyl-1H-pyrazol-3-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.5 mg), 1,4-dimethyl-1H-pyrazol-3-amine (32 mg), NaO t A mixture of Bu (53 mg), BrettPhos Pd G3 (6.9 mg), BrettPhos (4.8 mg) and THF (2 ml) was stirred at 120°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate and ethyl acetate / MeOH) and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate / hexane to give the title compound (17.6 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.47 (6H, s), 1.84 (3H, s), 3.66 (3H, s), 3.75 (3H, s), 5.04 (1H, s), 7.02 (1H, dd, J = 8.7, 1.5 Hz), 7.32 (1H, s), 7.41 (1H, s), 7.48 (1H, d, J = 8.0 Hz), 7.94 (1H, s).

[0167] Example 5 2-(1-methyl-3-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl)propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (81.5 mg), 1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (48 mg), NaO t A mixture of Bu (54.3 mg), BrettPhos Pd G3 (7.8 mg), BrettPhos (4.5 mg) and THF (2 ml) was stirred at 120°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate / hexane to give the title compound (42.5 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.48 (6H, s), 3.83 (3H, s), 3.91 (3H, s), 5.08 (1H, s), 7.07-7.14 (1H, m), 7.45 (1H, s), 7.79 (1H, d, J = 8.0 Hz), 8.01 (1H, s), 8.24 (1H, s).

[0168] Example 6 2-{3-[(5-chloro-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.3 mg), 5-chloro-1-methyl-1H-pyrazol-4-amine dihydrochloride (60.7 mg), NaO t A mixture of Bu (80.3 mg), BrettPhos Pd G3 (21 mg), BrettPhos (10.8 mg) and THF (1 ml) was stirred under microwave irradiation at 100° C. for 1 hour. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (13.3 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.48 (6H, s), 3.72-3.83 (6H, m), 5.07 (1H, s), 7.08 (1H, dd, J = 8.5, 1.3 Hz), 7.42 (1H, s), 7.73 (1H, d, J = 9.1 Hz), 7.86 (1H, s), 7.98 (1H, s).

[0169] Example 7 2-{3-[(3-chloro-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.3 mg), 3-chloro-1-methyl-1H-pyrazol-4-amine (38.7 mg), NaOt A mixture of Bu (50.2 mg), BrettPhos Pd G3 (10.3 mg), BrettPhos (6.8 mg) and THF (2 ml) was stirred at 120°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and then concentrated under reduced pressure. The resulting residue was crystallized from EtOH-ethyl acetate / hexane to give the title compound (43.4 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.48 (6H, s), 3.79-3.83 (6H, m), 5.07 (1H, s), 7.04-7.14 (1H, m), 7.44 (1H, s), 7.84 (1H, d, J = 8.0 Hz), 8.04-8.11 (2H, m).

[0170] Example 8 2-{3-[(1,5-dimethyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (81 mg), 1,5-dimethyl-1H-pyrazol-4-amine (33.7 mg), NaO t A mixture of Bu (52.3 mg), BrettPhos Pd G3 (10.4 mg), BrettPhos (6.6 mg) and THF (2 ml) was stirred at 120°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and then concentrated under reduced pressure. Ethyl acetate and water were added to the resulting residue, and the organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was crystallized from EtOH-ethyl acetate / hexane to give the title compound (48.6 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.47 (6H, s), 2.20 (3H, s), 3.71 (3H, s), 3.74 (3H, s), 5.04 (1H, s), 7.04 (1H, dd, J = 8.5, 1.3 Hz), 7.39 (1H, s), 7.54-7.60 (2H, m), 7.64 (1H, d, J = 8.3 Hz).

[0171] Example 9 2-(1-methyl-3-{[1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl)propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.3 mg), 1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride (55.6 mg), NaO t A mixture of Bu (75.2 mg), BrettPhos Pd G3 (10.3 mg), BrettPhos (6.8 mg) and THF (2 ml) was stirred under microwave irradiation for 2 hours at 100° C. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and then by HPLC to obtain the title compound (13 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.48 (6H, s), 3.81 (3H, s), 3.90-3.96 (3H, m), 5.08 (1H, s), 7.08-7.15 (1H, m), 7.46 (1H, s), 7.70 (1H, d, J = 8.0 Hz), 7.93 (1H, s), 8.01 (1H, s).

[0172] Example 10 2-{3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.3 mg), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (47.6 mg), NaO t A mixture of Bu (75.2 mg), BrettPhos Pd G3 (10.3 mg), BrettPhos (6.8 mg) and THF (2 ml) was stirred under microwave irradiation at 100° C. for 1 hour. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (45.8 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.47 (6H, s), 3.67 (3H, s), 3.78 (3H, s), 3.84 (3H, s), 5.04 (1H, s), 6.99-7.07 (1H, m), 7.39 (1H, s), 7.78-7.90 (3H, m).

[0173] Example 11 2-{3-[(1,3-dimethyl-1H-pyrazol-5-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.3 mg), 1,3-dimethyl-1H-pyrazol-5-amine (32.6 mg), NaO t A mixture of Bu (53.2 mg), BrettPhos Pd G3 (11.3 mg), BrettPhos (7.2 mg) and THF (2 ml) was stirred under microwave irradiation for 1 hour at 100° C. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and then by HPLC to obtain the title compound (29.8 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.48 (6H, s), 2.08 (3H, s), 3.64 (3H, s), 3.83 (3H, s), 5.09 (1H, s), 5.99 (1H, s), 7.13 (1H, dd, J = 8.5, 1.3 Hz), 7.48 (1H, s), 7.65 (1H, d, J = 9.1 Hz), 8.47 (1H, s).

[0174] Example 12 2-{3-[2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}propan-2-ol

[0175] A) Methyl 3-iodo-1-(oxan-2-yl)-1H-indazole-6-carboxylate To a mixture of methyl 3-iodo-1H-indazole-6-carboxylate (30 g), 3,4-dihydro-2H-pyran (13.6 ml) and THF (150 ml), p-toluenesulfonic acid monohydrate (1.89 g) was added at room temperature and stirred overnight at 50°C under a nitrogen atmosphere. Silica gel (135 g) was added to the reaction mixture and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate / hexane to give the title compound (27.7 g). MS: [M+H] + 387.2.

[0176] B) 2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline XPhos Pd G3 (0.251 g) was added to a mixture of 4-bromo-2-methoxyaniline (2 g), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.47 g), cesium carbonate (5.48 g), DME (40 ml) and water (12 ml), and the mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with a mixture of ethyl acetate and hexane to obtain the title compound (1.91 g). MS: [M+H] + 204.0.

[0177] C) Methyl 3-[2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1-(oxan-2-yl)-1H-indazole-6-carboxylate A mixture of methyl 3-iodo-1-(oxan-2-yl)-1H-indazole-6-carboxylate (150 mg), 2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (87 mg), cesium carbonate (253 mg), Pd(OAc)2 (8.7 mg), XANTPHOS (44.9 mg) and toluene (2 ml) was stirred overnight at 80°C under a nitrogen atmosphere. Insoluble matter was removed by filtration through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / MeOH) to obtain the title compound (120 mg). MS: [M+H] + 462.1.

[0178] D) Methyl 3-[2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazole-6-carboxylate To a mixture of methyl 3-[2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1-(oxan-2-yl)-1H-indazole-6-carboxylate (133 mg), EtOH (0.45 ml) and THF (1.35 ml), 6 mol / l hydrochloric acid (0.24 ml) was added at room temperature and stirred at 50°C for 30 minutes. A saturated aqueous solution of sodium bicarbonate, a mixture of ethyl acetate and THF was added to the reaction mixture, and the organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound (107 mg). MS: [M+H] + 378.0.

[0179] E) 2-{3-[2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}propan-2-ol To a mixture of methylmagnesium bromide (1 mol / l THF solution) (1.7 ml) and THF (2.0 ml), methyl 3-[2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazole-6-carboxylate (107 mg) was added at 0°C, and the mixture was stirred at 40°C under a nitrogen atmosphere for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate / MeOH) to obtain the title compound (67 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.48 (6H, s), 3.85 (3H, s), 3.96 (3H, s), 5.07 (1H, s), 7.05-7.14 (2H, m), 7.17 (1H, d, J = 1.7 Hz), 7.46 (1H, s), 7.51 (1H, s), 7.76 (1H, d, J = 8.6 Hz), 7.79 (1H, s), 8.01 (1H, d, J = 8.3 Hz), 8.04 (1H, s), 11.95 (1H, s).

[0180] Example 13 2-(3-{[5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol

[0181] A) 1-(difluoromethyl)-4-nitro-1H-pyrazole A mixture of 4-nitro-1H-pyrazole (5 g), cesium carbonate (14.5 g) and DMF (40 ml) was stirred at 120°C for 5 minutes. Sodium 2-chloro-2,2-difluoroacetate (13.5 g) was added at 120°C and stirred for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with Et2O. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (6.48 g). 1 H NMR (300 MHz, DMSO-d6) δ 7.64-8.11 (1H, m), 8.59 (1H, s), 9.43 (1H, s).

[0182] B) 5-chloro-1-(difluoromethyl)-4-nitro-1H-pyrazole A mixture of 1-(difluoromethyl)-4-nitro-1H-pyrazole (5.96 g) and THF (150 ml) was added with a THF solution of lithium (bistrimethylsilyl)amide (1.3 mol / l, 57 ml) while maintaining the internal temperature at -75°C to -70°C, and stirred for 30 minutes. A mixture of ethane hexachloride (10.3 g) and THF (50 ml) was added to the reaction mixture while maintaining the internal temperature at -75°C to -70°C, and the mixture was stirred at -78°C for 30 minutes under a nitrogen atmosphere, and then stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with a mixture of ethyl acetate and Et2O. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.23 g). 1 H NMR (300 MHz, DMSO-d6) δ 7.84-8.32 (1H, m), 8.74 (1H, s).

[0183] C) 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine To a mixture of 5-chloro-1-(difluoromethyl)-4-nitro-1H-pyrazole (1.23 g), ammonium chloride (1.7 g), MeOH (15 ml) and THF (15 ml), zinc powder (2.0 g) was added at 50° C. and stirred at 50° C. for 30 minutes. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.52 g). MS: [M+H] + 167.9.

[0184] D) 2-(3-{[5-chloro-1-(difluoromethyl)-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.3 mg), 5-chloro-1-(difluoromethyl)-1H-pyrazol-4-amine (53.2 mg), NaO t A mixture of Bu (40.2 mg), BrettPhos Pd G3 (19.8 mg), BrettPhos (12.8 mg) and THF (2 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate / hexane to give the title compound (9.8 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.49 (6H, s), 3.83 (3H, s), 5.09 (1H, s), 7.13 (1H, dd, J = 8.7, 1.5 Hz), 7.47 (1H, s), 7.64-8.06 (2H, m), 8.34 (1H, s), 8.43 (1H, s).

[0185] Example 14 2-{3-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.1 mg), 1,5-dimethyl-1H-pyrazol-3-amine (33 mg), NaO t A mixture of Bu (37 mg), BrettPhos Pd G3 (20.3 mg), BrettPhos (12.4 mg) and THF (1 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and then concentrated under reduced pressure. The resulting residue was crystallized from EtOH-ethyl acetate / heptane to give the title compound (46.8 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.47 (6H, s), 2.23 (3H, s), 3.60 (3H, s), 3.81 (3H, s), 5.04 (1H, s), 6.34 (1H, s), 7.05 (1H, dd, J = 8.5, 1.3 Hz), 7.42 (1H, s), 7.85 (1H, d, J = 8.6 Hz), 8.98 (1H, s).

[0186] Example 15 2-{3-[(5-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (81.1 mg), 5-methoxy-1-methyl-1H-pyrazol-4-amine (37 mg), NaO t A mixture of Bu (38.1 mg), BrettPhos Pd G3 (19.8 mg), BrettPhos (12.4 mg) and THF (1 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate and ethyl acetate / MeOH) and then concentrated under reduced pressure. The resulting residue was crystallized from MeOH / water to give the title compound (22.4 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.47 (6H, s), 3.59 (3H, s), 3.73 (3H, s), 3.91 (3H, s), 5.03 (1H, br s), 7.02 (1H, dd, J = 8.5, 1.3 Hz), 7.36 (1H, s), 7.39 (1H, s), 7.48 (1H, s), 7.56 (1H, d, J = 8.6 Hz).

[0187] Example 16 2-{3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.1 mg), 1,3-dimethyl-1H-pyrazol-4-amine (33 mg), NaO t A mixture of Bu (37 mg), BrettPhos Pd G3 (20.3 mg), BrettPhos (12.4 mg) and THF (1 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and then concentrated under reduced pressure. The resulting residue was crystallized from EtOH-ethyl acetate / heptane to give the title compound (49.7 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.48 (6H, s), 2.18 (3H, s), 3.73 (3H, s), 3.79 (3H, s), 5.05 (1H, s), 7.04-7.11 (1H, m), 7.41 (1H, s), 7.75-7.83 (2H, m), 7.89 (1H, s).

[0188] Example 17 2-{3-[(4-chloro-1-methyl-1H-pyrazol-3-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (82.3 mg), 4-chloro-1-methyl-1H-pyrazol-3-amine (37.8 mg), NaO t A mixture of Bu (38.1 mg), BrettPhos Pd G3 (18.8 mg), BrettPhos (12 mg) and THF (1 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate and ethyl acetate / MeOH) and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate / heptane to give the title compound (39.6 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.47 (6H, s), 3.71 (3H, s), 3.78 (3H, s), 5.06 (1H, s), 7.05 (1H, dd, J = 8.5, 1.3 Hz), 7.41-7.48 (2H, m), 7.81 (1H, s), 8.11 (1H, s).

[0189] Example 18 2-{3-[(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (82.3 mg), 4-chloro-1,5-dimethyl-1H-pyrazol-3-amine (42.4 mg), NaO t A mixture of Bu (38.1 mg), BrettPhos Pd G3 (18.8 mg), BrettPhos (12 mg) and THF (1 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate and ethyl acetate / MeOH) and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate / heptane to give the title compound (45 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.47 (6H, s), 2.22 (3H, s), 3.64 (3H, s), 3.78 (3H, s), 5.06 (1H, s), 7.05 (1H, dd, J = 8.5, 1.3 Hz), 7.42-7.50 (2H, m), 8.05 (1H, s).

[0190] Example 19 2-{1-methyl-3-[(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)amino]-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (60.9 mg), 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-amine hydrochloride (36 mg), NaO t A mixture of Bu (46.1 mg), BrettPhos Pd G3 (19.8 mg), BrettPhos (10.1 mg) and THF (1 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate and ethyl acetate / MeOH) and then concentrated under reduced pressure. The resulting residue was crystallized from EtOH / ethyl acetate / heptane to give the title compound (35.3 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.47 (6H, s), 1.72-1.84 (2H, m), 1.89-2.00 (2H, m), 2.69 (2H, t, J = 6.2 Hz), 3.75 (3H, s), 4.02 (2H, t, J = 6.1 Hz), 5.05 (1H, s), 7.05 (1H, dd, J = 8.5, 1.3 Hz), 7.39 (1H, s), 7.60-7.69 (3H, m).

[0191] Example 20 2-{3-[(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (60.9 mg), 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-amine hydrochloride (37 mg), NaO t A mixture of Bu (46.1 mg), BrettPhos Pd G3 (17.8 mg), BrettPhos (10.1 mg) and THF (1 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate / heptane to give the title compound (18.1 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.46 (6H, s), 2.10-2.24 (2H, m), 3.72 (3H, s), 4.09 (2H, t, J = 6.1 Hz), 4.22-4.30 (2H, m), 5.03 (1H, s), 7.00 (1H, dd, J = 8.5, 1.3 Hz), 7.34-7.40 (2H, m), 7.46 (1H, s), 7.57 (1H, d, J = 8.7 Hz).

[0192] Example 21 2-{3-[(1-ethyl-5-methyl-1H-pyrazol-3-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (100 mg), 1-ethyl-5-methyl-1H-pyrazol-3-amine (47.5 mg), NaO t A mixture of Bu (91 mg), BrettPhos Pd G3 (22.9 mg), BrettPhos (13.6 mg) and THF (2 ml) was stirred under microwave irradiation at 100° C. for 1 hour. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (73 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.29 (3H, t, J = 7.2 Hz), 1.48 (6H, s), 2.24 (3H, s), 3.81 (3H, s), 3.92 (2H, q, J = 7.2 Hz), 5.04 (1H, s), 6.34 (1H, s), 7.05 (1H, dd, J = 8.6, 1.3 Hz), 7.42 (1H, s), 7.86 (1H, d, J = 8.4 Hz), 9.02 (1H, s).

[0193] Example 22 2-(1-Methyl-3-{[5-methyl-1-(2-methylpropyl)-1H-pyrazol-3-yl]amino}-1H-indazol-6-yl)propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (60.9 mg), 5-methyl-1-(2-methylpropyl)-1H-pyrazol-3-amine (33 mg), NaO tA mixture of Bu (28.1 mg), BrettPhos Pd G3 (17.8 mg), BrettPhos (10.1 mg) and THF (1 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate / heptane to give the title compound (31.4 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.87 (6H, d, J = 6.8 Hz), 1.47 (6H, s), 2.04-2.19 (1H, m), 2.23 (3H, s), 3.68 (2H, d, J = 7.2 Hz), 3.81 (3H, s), 5.05 (1H, s), 6.36 (1H, d, J = 0.8 Hz), 7.04 (1H, dd, J = 8.5, 1.3 Hz), 7.42 (1H, s), 7.87 (1H, d, J = 8.7 Hz), 9.06 (1H, s).

[0194] Example 23 2-{3-[(5-ethyl-1-methyl-1H-pyrazol-3-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (60.9 mg), 5-ethyl-1-methyl-1H-pyrazol-3-amine (27 mg), NaO t A mixture of Bu (26.1 mg), BrettPhos Pd G3 (17.8 mg), BrettPhos (10.1 mg) and THF (1 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and then concentrated under reduced pressure. The resulting residue was crystallized from EtOH / ethyl acetate / heptane to give the title compound (29.6 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.20 (3H, t, J = 7.6 Hz), 1.47 (6H, s), 2.53-2.66 (2H, m), 3.61 (3H, s), 3.81 (3H, s), 5.05 (1H, s), 6.35 (1H, s), 6.99-7.11 (1H, m), 7.42 (1H, s), 7.86 (1H, d, J = 8.3 Hz), 9.00 (1H, s).

[0195] Example 24 2-(1-Methyl-3-{[5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]amino}-1H-indazol-6-yl)propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (60.9 mg), 5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-amine (37 mg), NaO t A mixture of Bu (28.1 mg), BrettPhos Pd G3 (17.8 mg), BrettPhos (10.1 mg) and THF (1 ml) was stirred at 100°C for 3 hours under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and then concentrated under reduced pressure. The resulting residue was crystallized from EtOH / ethyl acetate / heptane, and the resulting solid was purified by HPLC to give the title compound (8.3 mg). 1 H NMR (300 MHz, CD3OD) δ 1.60 (6H, s), 2.32 (3H, s), 3.89 (3H, s), 4.72 (2H, q, J = 9.0 Hz), 6.28 (1H, s), 7.15 (1H, dd, J = 8.5, 1.3 Hz), 7.44-7.49 (1H, m), 7.69 (1H, dd, J = 8.7, 0.8 Hz), (NH and OH peaks were not observed).

[0196] Example 25 2-{3-[(6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (60.9 mg), 6,6-dimethyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-amine hydrochloride (42 mg), NaO t A mixture of Bu (46.1 mg), BrettPhos Pd G3 (17.8 mg), BrettPhos (10.1 mg) and THF (1 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate / heptane, and the resulting solid was purified by HPLC to give the title compound (19.1 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.06 (6H, s), 1.46 (6H, s), 3.72 (3H, s), 3.83 (2H, s), 3.94 (2H, s), 5.03 (1H, s), 6.99 (1H, dd, J = 8.5, 1.3 Hz), 7.37 (1H, s), 7.44 (1H, s), 7.50 (1H, s), 7.55 (1H, d, J = 8.3 Hz).

[0197] Example 26 2-{3-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}propan-2-ol

[0198] A) 2-Fluoro-4-(1-methyl-1H-pyrazol-4-yl)aniline XPhos Pd G3 (0.37 g) was added to a mixture of 4-bromo-2-fluoroaniline (8.02 g), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (9.55 g), cesium carbonate (20.7 g), DME (120 ml) and water (40 ml), and the mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered through Celite, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate / hexane to obtain the title compound (6.47 g). MS: [M+H] + 191.9.

[0199] B) Methyl 3-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1-(oxan-2-yl)-1H-indazole-6-carboxylate A mixture of methyl 3-iodo-1-(oxan-2-yl)-1H-indazole-6-carboxylate (250 mg), 2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)aniline (124 mg), cesium carbonate (422 mg), Pd(OAc)2 (14.5 mg), XANTPHOS (74.9 mg) and toluene (5 ml) was stirred overnight at 80° C. under a nitrogen atmosphere. Insoluble matter was removed by filtration through Celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (165 mg). MS: [M+H] + 450.1.

[0200] C) 2-{3-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1-(oxan-2-yl)-1H-indazol-6-yl}propan-2-ol A mixture of methyl 3-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1-(oxan-2-yl)-1H-indazole-6-carboxylate (165 mg) and THF (3.5 ml) was added to methylmagnesium bromide (1 mol / l THF solution) (2.2 ml) at 0°C, and then stirred at 40°C under a nitrogen atmosphere for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (81 mg). MS: [M+H] + 450.1.

[0201] D) 2-{3-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}propan-2-ol 2-{3-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1-(oxan-2-yl)-1H-indazol-6-yl}propan-2-ol (81 mg), EtOH (0.27 ml) and THF (0.8 ml) were added with 6 mol / l hydrochloric acid (0.15 ml) at room temperature and stirred for 1 hour. A saturated aqueous solution of sodium bicarbonate, a mixture of ethyl acetate and THF were added to the reaction mixture, and the organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by HPLC and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate / hexane to obtain the title compound (23 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.48 (6H, s), 3.85 (3H, s), 5.06 (1H, s), 7.11 (1H, dd, J = 8.6, 1.3 Hz), 7.28 (1H, dd, J = 8.5, 1.7 Hz), 7.41 (1H, dd, J = 13.1, 1.9 Hz), 7.45-7.48 (1H, m), 7.80 (1H, s), 7.85 (1H, d, J = 8.6 Hz), 7.99-8.07 (2H, m), 8.30 (1H, d, J = 1.5 Hz), 12.01 (1H, s).

[0202] Example 27 2-{4-fluoro-3-[(5-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol

[0203] A) 5-chloro-1-methyl-4-nitro-1H-pyrazole A mixture of 1-methyl-4-nitro-1H-pyrazole (6.02 g) and THF (60 ml) was added with a THF solution of lithium (bistrimethylsilyl)amide (1.3 mol / l, 40 ml) while maintaining the internal temperature at -75°C to -70°C, and stirred for 30 minutes. Hexachloroethane (13.5 g) was added to the reaction mixture at -78°C, and the mixture was stirred at -78°C under a nitrogen atmosphere for 1 hour, and then stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with a mixture of ethyl acetate and hexane. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (6.23 g). 1 H NMR (300 MHz, DMSO-d6) δ 3.89 (3H, s), 8.43 (1H, s).

[0204] B) 5-Methoxy-1-methyl-4-nitro-1H-pyrazole To a mixture of 60% sodium hydride (361 mg) and DMF (25 ml), MeOH (0.31 ml) was added at 0°C and stirred for 5 minutes. 5-Chloro-1-methyl-4-nitro-1H-pyrazole (1010 mg) was added to the reaction mixture at 0°C and stirred under nitrogen atmosphere for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture at 0°C and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (890 mg). MS: [M+H] + 157.9.

[0205] C) 5-Methoxy-1-methyl-1H-pyrazol-4-amine A mixture of 5-methoxy-1-methyl-4-nitro-1H-pyrazole (330 mg), 10% palladium on carbon (36 mg) and MeOH (7 ml) was stirred under hydrogen atmosphere at room temperature for 3 hours. Insoluble matter was removed by filtration, and an aqueous solution of potassium carbonate was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (99 mg). MS: [M+H] + 127.9.

[0206] D) 2-{4-fluoro-3-[(5-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(4-Fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (100 mg), 5-methoxy-1-methyl-1H-pyrazol-4-amine (49.4 mg), NaO tA mixture of Bu (43.2 mg), BrettPhos Pd G3 (20.5 mg), BrettPhos (12.3 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and then concentrated under reduced pressure. The resulting residue was crystallized from EtOH / ethyl acetate / heptane to give the title compound (24.8 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.46 (6H, s), 3.57 (3H, s), 3.73 (3H, s), 3.92 (3H, s), 5.16 (1H, s), 6.78 (1H, dd, J = 12.7, 0.9 Hz), 7.00 (1H, s), 7.20 (1H, s), 7.24 (1H, s).

[0207] Example 28 2-{7-fluoro-3-[(5-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol

[0208] A) 6-bromo-7-fluoro-1H-indazole A mixture of 4-bromo-2,3-difluorobenzaldehyde (4 g), O-methylhydroxylamine hydrochloride (1.97 g), potassium carbonate (3.00 g) and DME (48 ml) was stirred at 40°C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. DME (40 ml) and hydrazine monohydrate (12 ml) were added to the resulting residue, and the mixture was stirred at 90°C for 22 hours. The reaction mixture was cooled to room temperature, and water (30 ml) was added. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (3.18 g). MS: [M+H] + 216.8.

[0209] B) Methyl 7-fluoro-1H-indazole-6-carboxylate A mixture of 6-bromo-7-fluoro-1H-indazole (3.18 g), PdCl2(dppf) (0.54 g), triethylamine (6.17 ml) and MeOH (50 ml) was stirred under carbon monoxide pressure (50 psi) at 90° C. for 4 hours. Water (450 ml) was added to the reaction mixture, and the resulting solid was collected by filtration, washed with water and dried under reduced pressure to obtain the title compound (2.62 g). MS: [M+H] + 194.9.

[0210] C) 2-(7-fluoro-1H-indazol-6-yl)propan-2-ol A mixture of methyl 7-fluoro-1H-indazole-6-carboxylate (1.45 g) and THF (60 ml) was added to methylmagnesium bromide (1 mol / l THF solution) (44.8 ml) at 0°C, and the mixture was stirred at 40°C under a nitrogen atmosphere for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (1.61 g). MS: [M+H] + 194.9.

[0211] D) 2-(7-fluoro-3-iodo-1H-indazol-6-yl)propan-2-ol To a mixture of 2-(7-fluoro-1H-indazol-6-yl)propan-2-ol (1.45 g), potassium carbonate (2.06 g) and DMF (23 ml), iodine (3.79 g) was added at 0°C, and the mixture was stirred at room temperature until the starting materials disappeared. A mixture of sodium hydrogen sulfite (2.33 g) and water (8 ml) was added to the reaction mixture. Water was further added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound (3.54 g). MS: [M+H] + 320.8.

[0212] E) 2-(7-fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol Cesium carbonate (3.41 g) was added to a mixture of 2-(7-fluoro-3-iodo-1H-indazol-6-yl)propan-2-ol (2.39 g) and DMF (14 ml), and the mixture was stirred at room temperature for 30 minutes. A mixture of methyl iodide (1.4 ml) and DMF (4.8 ml) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.26 g). MS: [M+H] + 334.9.

[0213] F) 2-{7-fluoro-3-[(5-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(7-Fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (100 mg), 5-methoxy-1-methyl-1H-pyrazol-4-amine (45.7 mg), NaO t A mixture of Bu (101 mg), BrettPhos Pd G3 (27.1 mg), BrettPhos (16.1 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and then concentrated under reduced pressure. The resulting residue was purified by HPLC and concentrated under reduced pressure. The resulting residue was crystallized from EtOH-ethyl acetate / hexane to give the title compound (17 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.54 (6H, s), 3.59 (3H, s), 3.85 (3H, s), 3.90 (3H, s), 5.27 (1H, s), 7.19 (1H, dd, J = 8.6, 6.6 Hz), 7.36 (1H, s), 7.42 (1H, d, J = 8.6 Hz), 7.61 (1H, s).

[0214] Example 29 2-(3-{[5-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol

[0215] A) 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol Methyl iodide (1.55 ml) was added to a mixture of 2-(3-iodo-1H-indazol-6-yl)propan-2-ol (4.95 g), cesium carbonate (8.01 g) and DMF (40 ml), and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (3.87 g). MS: [M+H] + 316.9.

[0216] B) (1-Methyl-1H-pyrazol-5-yl)methanol Isobutyl chloroformate (2.5 ml) was added to a mixture of 1-methyl-1H-pyrazole-5-carboxylic acid (2.04 g), 4-methylmorpholine (2.1 ml) and THF (40 ml) at 0°C, and the mixture was stirred for 30 minutes. Insoluble matter was removed by filtration, and the filtrate was added to a mixture of sodium borohydride (1.34 g) and water (8 ml) at 0°C, and the mixture was stirred at room temperature for 1 hour. 6 mol / l hydrochloric acid (6 ml) was added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for 10 minutes. Anhydrous sodium sulfate was added to the reaction mixture, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.78 g). MS: [M+H] + 112.9.

[0217] C) 5-(methoxymethyl)-1-methyl-1H-pyrazole To a mixture of (1-methyl-1H-pyrazol-5-yl)methanol (926 mg) and DMF (25 ml), 60% sodium hydride (370 mg) was added at 0°C and stirred at room temperature for 3 minutes. Methyl iodide (0.58 ml) was added to the reaction mixture at 0°C and stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (786 mg). MS: [M+H] + 126.9.

[0218] D) 5-(methoxymethyl)-1-methyl-4-nitro-1H-pyrazole To a mixture of 5-(methoxymethyl)-1-methyl-1H-pyrazole (124 mg) and concentrated sulfuric acid (1 ml), potassium nitrate (120 mg) was added at 0°C, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere and at 50°C overnight. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the title compound. MS: [M+H] + 171.9.

[0219] E) 5-(methoxymethyl)-1-methyl-1H-pyrazol-4-amine Sodium dithionite (358 mg) was added to a mixture of 5-(methoxymethyl)-1-methyl-4-nitro-1H-pyrazole (70.3 mg), THF (1 ml) and water (1 ml) at room temperature, and the mixture was stirred at 60° C. for 1 hour. Heptane was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / MeOH) to obtain the title compound (20.2 mg). MS: [M+H] + 141.9.

[0220] F) 2-(3-{[5-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (40.9 mg), 5-(methoxymethyl)-1-methyl-1H-pyrazol-4-amine (20.2 mg), NaO t A mixture of Bu (18.1 mg), BrettPhos Pd G3 (10.8 mg), BrettPhos (6.5 mg) and THF (0.6 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and then concentrated under reduced pressure. The resulting residue was crystallized from EtOH / ethyl acetate / hexane, further purified by HPLC and concentrated under reduced pressure. The resulting residue was crystallized from EtOH / ethyl acetate / hexane to give the title compound (13.2 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.48 (6H, s), 3.26 (3H, s), 3.75-3.80 (6H, m), 4.55 (2H, s), 5.06 (1H, s), 7.07 (1H, dd, J = 8.5, 1.3 Hz), 7.42 (1H, s), 7.69-7.76 (2H, m), 7.84 (1H, s).

[0221] Example 30 2-{3-[(5-ethoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol

[0222] A) 5-ethoxy-1-methyl-4-nitro-1H-pyrazole EtOH (0.47 ml) was added to a mixture of 60% sodium hydride (360 mg) and DMF (25 ml) at 0°C and stirred for 5 minutes. 5-Chloro-1-methyl-4-nitro-1H-pyrazole (1000 mg) was added to the reaction mixture at 0°C and stirred under nitrogen atmosphere for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture at 0°C and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1050 mg). MS: [M+H] + 171.9.

[0223] B) 5-ethoxy-1-methyl-1H-pyrazol-4-amine A mixture of 5-ethoxy-1-methyl-4-nitro-1H-pyrazole (1040 mg), 10% palladium on carbon (100 mg) and MeOH (20 ml) was stirred at room temperature under a hydrogen atmosphere for 3 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (790 mg). MS: [M+H] + 142.0.

[0224] C) 2-{3-[(5-ethoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.9 mg), 5-ethoxy-1-methyl-1H-pyrazol-4-amine (42 mg), NaO t A mixture of Bu (36.1 mg), BrettPhos Pd G3 (17.8 mg), BrettPhos (10.1 mg) and THF (1 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and silica gel column chromatography (ethyl acetate / MeOH), and then concentrated under reduced pressure. The resulting residue was purified by HPLC and concentrated under reduced pressure to give the title compound (31.5 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.23 (3H, t, J = 7.2 Hz), 1.46 (6H, s), 3.59 (3H, s), 3.72 (3H, s), 4.21 (2H, q, J = 7.2 Hz), 5.04 (1H, s), 7.02 (1H, dd, J = 8.5, 1.3 Hz), 7.35-7.40 (2H, m), 7.45 (1H, s), 7.55 (1H, d, J = 8.3 Hz).

[0225] Example 31 2-{5-fluoro-3-[(5-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol

[0226] A) Methyl 5-fluoro-1H-indazole-6-carboxylate A mixture of 6-bromo-5-fluoro-1H-indazole (700 mg), PdCl2(dppf) (119 mg), triethylamine (1.36 ml) and MeOH (5.6 ml) was stirred at 90°C for 4 hours under carbon monoxide pressure (50 psi). Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (504 mg). MS: [M+H] + 194.9.

[0227] B) 2-(5-fluoro-1H-indazol-6-yl)propan-2-ol A mixture of methyl 5-fluoro-1H-indazole-6-carboxylate (504 mg) and THF (21 ml) was added to methylmagnesium bromide (1 mol / l THF solution) (15.6 ml) at 0°C, and the mixture was stirred at 40°C under a nitrogen atmosphere for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (503 mg). MS: [M+H] + 194.9.

[0228] C) 2-(5-fluoro-3-iodo-1H-indazol-6-yl)propan-2-ol To a mixture of 2-(5-fluoro-1H-indazol-6-yl)propan-2-ol (502 mg), potassium carbonate (714 mg) and DMF (8 ml), iodine (1312 mg) was added at 0°C, and the mixture was stirred at room temperature until the starting materials disappeared. A mixture of sodium hydrogen sulfite (807 mg) and water (3 ml) was added to the reaction mixture. Water was further added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (896 mg). MS: [M+H] + 320.8.

[0229] D) 2-(5-fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol Cesium carbonate (1178 mg) was added to a mixture of 2-(5-fluoro-3-iodo-1H-indazol-6-yl)propan-2-ol (827 mg) and DMF (5 ml), and the mixture was stirred at room temperature for 30 minutes. A mixture of methyl iodide (0.49 ml) and DMF (1.7 ml) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (343 mg). MS: [M+H] + 334.8.

[0230] E) 2-{5-fluoro-3-[(5-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(5-Fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (100 mg), 5-methoxy-1-methyl-1H-pyrazol-4-amine (45.7 mg), NaO t A mixture of Bu (101 mg), BrettPhos Pd G3 (27.1 mg), BrettPhos (16.1 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and then concentrated under reduced pressure. The resulting residue was purified by HPLC and concentrated under reduced pressure to give the title compound (39 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.51 (6H, s), 3.57-3.62 (3H, m), 3.71-3.77 (3H, m), 3.87-3.93 (3H, m), 7.34-7.40 (2H, m), 7.52 (2H, d, J = 6.5 Hz).

[0231] Example 32 2-{3-[(1-ethyl-5-methoxy-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol

[0232] A) 1-Ethyl-4-nitro-1H-pyrazole Ethyl iodide (7.8 ml) was added to a mixture of 4-nitro-1H-pyrazole (10 g), potassium carbonate (13.6 g) and DMSO (90 ml) and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and it was extracted with a mixture of ethyl acetate and hexane. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (12.4 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.40 (3H, t, J = 7.2 Hz), 4.20 (2H, q, J = 7.4 Hz), 8.25 (1H, s), 8.90 (1H, s).

[0233] B) 5-chloro-1-ethyl-4-nitro-1H-pyrazole A mixture of 1-ethyl-4-nitro-1H-pyrazole (10 g) and THF (100 ml) was added with a THF solution of lithium (bistrimethylsilyl)amide (1.3 mol / l, 60 ml) while maintaining the internal temperature at -75°C to -70°C, and stirred for 30 minutes. Hexachloroethane (20 g) was added to the reaction mixture at -78°C, and the mixture was stirred at -78°C under a nitrogen atmosphere for 1 hour, and then stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with a mixture of ethyl acetate and hexane. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (5.67 g). 1H NMR (300 MHz, DMSO-d6) δ 1.37 (3H, t, J = 7.2 Hz), 4.24 (2H, q, J = 7.2 Hz), 8.46 (1H, s).

[0234] C) 1-Ethyl-5-methoxy-4-nitro-1H-pyrazole To a mixture of 60% sodium hydride (322 mg) and DMF (18 ml), MeOH (0.3 ml) was added at 0°C and stirred for 5 minutes. 5-Chloro-1-ethyl-4-nitro-1H-pyrazole (1000 mg) was added to the reaction mixture at 0°C and stirred under nitrogen atmosphere for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture at 0°C and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (860 mg). MS: [M+H] + 171.9.

[0235] D) 1-Ethyl-5-methoxy-1H-pyrazol-4-amine A mixture of 1-ethyl-5-methoxy-4-nitro-1H-pyrazole (860 mg), 10% palladium on carbon (85.3 mg) and MeOH (20 ml) was stirred at room temperature under a hydrogen atmosphere for 3 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (620 mg). MS: [M+H] + 142.0.

[0236] E) 2-{3-[(1-ethyl-5-methoxy-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.9 mg), 1-ethyl-5-methoxy-1H-pyrazol-4-amine (40 mg), NaO tA mixture of Bu (36.1 mg), BrettPhos Pd G3 (17.8 mg), BrettPhos (10.1 mg) and THF (1 ml) was stirred under microwave irradiation for 1 hour at 100° C. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / MeOH) and basic silica gel column chromatography (hexane / ethyl acetate) to give the title compound (47.4 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.29 (3H, t, J = 7.2 Hz), 1.46 (6H, s), 3.73 (3H, s), 3.86-3.98 (5H, m), 5.04 (1H, s), 7.02 (1H, dd, J = 8.5, 1.3 Hz), 7.34-7.41 (2H, m), 7.45-7.56 (2H, m).

[0237] Example 33 2-[1-methyl-3-({1-methyl-5-[(propan-2-yl)oxy]-1H-pyrazol-4-yl}amino)-1H-indazol-6-yl]propan-2-ol

[0238] A) 1-Methyl-4-nitro-5-[(propan-2-yl)oxy]-1H-pyrazole 2-Propanol (0.66 ml) was added to a mixture of 60% sodium hydride (360 mg) and DMF (25 ml) at 0°C and stirred for 5 minutes. 5-Chloro-1-methyl-4-nitro-1H-pyrazole (1000 mg) was added to the reaction mixture at 0°C and stirred at room temperature under nitrogen atmosphere for 4 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture at 0°C and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (784 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.36 (6H, d, J = 6.1 Hz), 3.67 (3H, s), 4.80-4.95 (1H, m), 8.16 (1H, s).

[0239] B) 1-Methyl-5-[(propan-2-yl)oxy]-1H-pyrazol-4-amine A mixture of 1-methyl-4-nitro-5-[(propan-2-yl)oxy]-1H-pyrazole (784 mg), 10% palladium on carbon (78.3 mg) and MeOH (20 ml) was stirred at room temperature under a hydrogen atmosphere for 2 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / ethyl acetate) to give the title compound (531 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.24 (6H, d, J = 6.1 Hz), 3.28-3.40 (2H, m), 3.47 (3H, s), 4.40-4.55 (1H, m), 6.86 (1H, s).

[0240] C) 2-[1-methyl-3-({1-methyl-5-[(propan-2-yl)oxy]-1H-pyrazol-4-yl}amino)-1H-indazol-6-yl]propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.9 mg), 1-methyl-5-[(propan-2-yl)oxy]-1H-pyrazol-4-amine (44 mg), NaO t A mixture of Bu (36.1 mg), BrettPhos Pd G3 (17.8 mg), BrettPhos (10.1 mg) and THF (1 ml) was stirred under microwave irradiation for 1 hour at 100° C. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / MeOH) and basic silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (50.2 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.21 (6H, d, J = 6.1 Hz), 1.46 (6H, s), 3.58 (3H, s), 3.72 (3H, s), 4.56-4.70 (1H, m), 5.04 (1H, s), 7.01 (1H, dd, J = 8.5, 1.3 Hz), 7.36-7.45 (3H, m), 7.55 (1H, d, J = 8.3 Hz).

[0241] Example 34 2-{1-ethyl-3-[(5-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol

[0242] A) 2-(1-ethyl-3-iodo-1H-indazol-6-yl)propan-2-ol Potassium carbonate (0.68 g) was added to a mixture of 2-(3-iodo-1H-indazol-6-yl)propan-2-ol (1.15 g) and DMF (7 ml), and the mixture was stirred at room temperature for 30 minutes. A mixture of ethyl iodide (0.92 ml) and DMF (2.3 ml) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.88 g). MS: [M+H] + 330.9.

[0243] B) 2-{1-ethyl-3-[(5-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol 2-(1-ethyl-3-iodo-1H-indazol-6-yl)propan-2-ol (100 mg), 5-methoxy-1-methyl-1H-pyrazol-4-amine (46.2 mg), NaO tA mixture of Bu (102 mg), BrettPhos Pd G3 (27.5 mg), BrettPhos (16.3 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and silica gel column chromatography (ethyl acetate / MeOH), and then concentrated under reduced pressure. The resulting residue was crystallized from EtOH / hexane to give the title compound (28 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.26 (3H, t, J = 7.1 Hz), 1.46 (6H, s), 3.59 (3H, s), 3.90 (3H, s), 4.13 (2H, q, J = 7.1 Hz), 5.02 (1H, s), 7.01 (1H, dd, J = 8.5, 1.2 Hz), 7.38 (1H, s), 7.41 (1H, s), 7.49 (1H, s), 7.54 (1H, d, J = 8.4 Hz).

[0244] Example 35 2-(3-{[5-methoxy-1-(propan-2-yl)-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol

[0245] A) 4-nitro-1-(propan-2-yl)-1H-pyrazole 2-Iodopropane (9.8 ml) was added to a mixture of 4-nitro-1H-pyrazole (10 g), potassium carbonate (13.6 g) and DMSO (90 ml), and the mixture was stirred at 40°C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with a mixture of ethyl acetate and hexane. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (12.5 g). 1H NMR (300 MHz, DMSO-d6) δ 1.45 (6H, d, J = 6.4 Hz), 4.50-4.67 (1H, m), 8.25 (1H, s), 8.92 (1H, s).

[0246] B) 5-chloro-4-nitro-1-(propan-2-yl)-1H-pyrazole A mixture of 4-nitro-1-(propan-2-yl)-1H-pyrazole (10 g) and THF (100 ml) was added with a THF solution of lithium (bistrimethylsilyl)amide (1.3 mol / l, 55 ml) while maintaining the internal temperature at -75°C to -70°C, and stirred for 30 minutes. Hexachloroethane (18.5 g) was added to the reaction mixture at -78°C, and the mixture was stirred at -78°C for 1 hour under a nitrogen atmosphere, and then stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (8.96 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.42 (6H, d, J = 6.8 Hz), 4.70-4.86 (1H, m), 8.48 (1H, s).

[0247] C) 5-Methoxy-4-nitro-1-(propan-2-yl)-1H-pyrazole To a mixture of 60% sodium hydride (292 mg) and DMF (20 ml), MeOH (0.28 ml) was added at 0°C and stirred for 5 minutes. 5-Chloro-4-nitro-1-(propan-2-yl)-1H-pyrazole (1000 mg) was added to the reaction mixture at 0°C and stirred under nitrogen atmosphere for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture at 0°C and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (926 mg). MS: [M+H]+ 185.9.

[0248] D) 5-Methoxy-1-(propan-2-yl)-1H-pyrazol-4-amine A mixture of 5-methoxy-4-nitro-1-(propan-2-yl)-1H-pyrazole (926 mg), 10% palladium on carbon (93.3 mg) and MeOH (20 ml) was stirred overnight at room temperature under a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / ethyl acetate) to give the title compound (622 mg). MS: [M+H] + 155.9.

[0249] E) 2-(3-{[5-methoxy-1-(propan-2-yl)-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.8 mg), 5-methoxy-1-(propan-2-yl)-1H-pyrazol-4-amine (43 mg), NaO t A mixture of Bu (38.1 mg), BrettPhos Pd G3 (18.3 mg), BrettPhos (11.1 mg) and THF (1.0 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and silica gel column chromatography (ethyl acetate / MeOH), and then concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound (42.1 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.35 (6H, d, J = 6.8 Hz), 1.46 (6H, s), 3.73 (3H, s), 3.90 (3H, s), 4.38-4.50 (1H, m), 5.04 (1H, s), 7.01 (1H, dd, J = 8.5, 1.3 Hz), 7.37-7.41 (2H, m), 7.44-7.53 (2H, m).

[0250] Example 36 2-{1-ethyl-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol 2-(1-ethyl-3-iodo-1H-indazol-6-yl)propan-2-ol (100 mg), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (49.6 mg), NaO t A mixture of Bu (102 mg), BrettPhos Pd G3 (27.5 mg), BrettPhos (16.3 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and silica gel column chromatography (ethyl acetate / MeOH), and then concentrated under reduced pressure. The resulting residue was crystallized from EtOH / hexane to give the title compound (20 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.32 (3H, t, J = 7.1 Hz), 1.47 (6H, s), 3.68 (3H, s), 3.85 (3H, s), 4.17 (2H, q, J = 7.1 Hz), 5.02 (1H, s), 7.02 (1H, dd, J = 8.6, 1.2 Hz), 7.41 (1H, s), 7.79-7.88 (3H, m).

[0251] Example 37 2-{3-[(5-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-(propan-2-yl)-1H-indazol-6-yl}propan-2-ol 2-[3-iodo-1-(propan-2-yl)-1H-indazol-6-yl]propan-2-ol (100 mg), 5-methoxy-1-methyl-1H-pyrazol-4-amine (44.3 mg), NaO t A mixture of Bu (98 mg), BrettPhos Pd G3 (26.3 mg), BrettPhos (15.6 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and silica gel column chromatography (ethyl acetate / MeOH), and then concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound (19.4 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.36 (6H, d, J = 6.8 Hz), 1.46 (6H, s), 3.60 (3H, s), 3.91 (3H, s), 4.63-4.76 (1H, m), 5.02 (1H, s), 6.99 (1H, dd, J = 8.5, 1.3 Hz), 7.44 (2H, s), 7.50 (1H, d, J = 8.7 Hz), 7.55 (1H, s).

[0252] Example 38 2-{1-(cyclopropylmethyl)-3-[(5-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol 2-[1-(cyclopropylmethyl)-3-iodo-1H-indazol-6-yl]propan-2-ol (100 mg), 5-methoxy-1-methyl-1H-pyrazol-4-amine (42.8 mg), NaO tA mixture of Bu (94 mg), BrettPhos Pd G3 (25.4 mg), BrettPhos (15.1 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and silica gel column chromatography (ethyl acetate / MeOH), and then concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound (22.9 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.27-0.48 (4H, m), 1.09-1.22 (1H, m), 1.46 (6H, s), 3.60 (3H, s), 3.91 (3H, s), 4.00 (2H, d, J = 6.8 Hz), 5.02 (1H, s), 7.01 (1H, dd, J = 8.5, 1.3 Hz), 7.40 (1H, s), 7.43 (1H, s), 7.49-7.57 (2H, m).

[0253] Example 39 2-{3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-(propan-2-yl)-1H-indazol-6-yl}propan-2-ol 2-[3-iodo-1-(propan-2-yl)-1H-indazol-6-yl]propan-2-ol (80.3 mg), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (40.6 mg), NaO t A mixture of Bu (65.2 mg), BrettPhos Pd G3 (11.5 mg), BrettPhos (6.9 mg) and THF (1.3 ml) was stirred under microwave irradiation for 1 hour at 100° C. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (49.4 mg). 1H NMR (300 MHz, DMSO-d6) δ 1.41 (6H, d, J = 6.8 Hz), 1.47 (6H, s), 3.68 (3H, s), 3.85 (3H, s), 4.65-4.80 (1H, m), 5.03 (1H, s), 7.00 (1H, dd, J = 8.5, 1.3 Hz), 7.44 (1H, s), 7.77-7.93 (3H, m).

[0254] Example 40 2-(3-{[5-methoxy-1-(2-methylpropyl)-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.5 mg), 5-methoxy-1-(2-methylpropyl)-1H-pyrazol-4-amine (48.5 mg), NaO t A mixture of Bu (38.7 mg), BrettPhos Pd G3 (15.3 mg), BrettPhos (9.1 mg) and THF (1 ml) was stirred under microwave irradiation for 1 hour at 100° C. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (56.7 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.86 (6H, d, J = 6.8 Hz), 1.46 (6H, s), 2.01-2.15 (1H, m), 3.66-3.76 (5H, m), 3.90 (3H, s), 5.04 (1H, s), 7.00 (1H, dd, J = 8.7, 1.5 Hz), 7.39 (2H, s), 7.46-7.53 (2H, m).

[0255] Example 41 2-{3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-5-yl}propan-2-ol

[0256] A) 2-(1H-indazol-5-yl)propan-2-ol To a mixture of methyl 1H-indazole-5-carboxylate (3 g) and THF (60 ml), methylmagnesium bromide (3 mol / l, Et2O solution) (34.1 ml) was added at 0°C, and the mixture was stirred at 40°C under a nitrogen atmosphere for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (2.91 g). MS: [M+H] + 176.9.

[0257] B) 2-(3-iodo-1H-indazol-5-yl)propan-2-ol To a mixture of 2-(1H-indazol-5-yl)propan-2-ol (2.91 g), potassium carbonate (4.56 g) and DMF (46 ml), iodine (8.38 g) was added at 0°C, and the mixture was stirred at room temperature until the starting materials disappeared. To the reaction mixture, a mixture of sodium hydrogen sulfite (5.16 g) and water (15 ml) was added. Water was further added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (4.37 g). MS: [M+H] + 302.8.

[0258] C) 2-(3-iodo-1-methyl-1H-indazol-5-yl)propan-2-ol Cesium carbonate (6.6 g) was added to a mixture of 2-(3-iodo-1H-indazol-5-yl)propan-2-ol (4.37 g) and DMF (26.2 ml), and the mixture was stirred at room temperature for 30 minutes. A mixture of methyl iodide (2.7 ml) and DMF (8.7 ml) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (3.77 g). MS: [M+H] + 316.9.

[0259] D) 2-{3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-5-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-5-yl)propan-2-ol (100 mg), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (51.8 mg), NaO t A mixture of Bu (106 mg), BrettPhos Pd G3 (28.7 mg), BrettPhos (17 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and silica gel column chromatography (ethyl acetate / MeOH) and concentrated under reduced pressure. The resulting residue was crystallized from EtOH / hexane to give the title compound (24.6 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.47 (6H, s), 3.67 (3H, s), 3.73-3.79 (3H, m), 3.85 (3H, s), 4.89 (1H, s), 7.26 (1H, d, J = 8.8 Hz), 7.50 (1H, dd, J = 8.8, 1.6 Hz), 7.83 (1H, s), 7.92 (1H, s), 8.05 (1H, d, J = 0.9 Hz).

[0260] Example 42 2-{3-[(5-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-5-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-5-yl)propan-2-ol (120 mg), 5-methoxy-1-methyl-1H-pyrazol-4-amine (48.3 mg), NaO t A mixture of Bu (128 mg), BrettPhos Pd G3 (34.4 mg), BrettPhos (20.4 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and silica gel column chromatography (ethyl acetate / MeOH) and concentrated under reduced pressure. The resulting residue was purified by HPLC and concentrated under reduced pressure. The resulting residue was crystallized from EtOH / hexane to give the title compound (12 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.46 (6H, s), 3.59 (3H, s), 3.72 (3H, s), 3.91 (3H, s), 4.92 (1H, s), 7.25 (1H, d, J = 8.8 Hz), 7.38 (1H, s), 7.45 (1H, dd, J = 8.8, 1.7 Hz), 7.55 (1H, s), 7.85 (1H, d, J = 1.0 Hz).

[0261] Example 43 2-{3-[(1-ethyl-3-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.5 mg), 1-ethyl-3-methyl-1H-pyrazol-4-amine dihydrochloride (62.4 mg), NaO tA mixture of Bu (86.7 mg), BrettPhos Pd G3 (15.3 mg), BrettPhos (8.7 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and silica gel column chromatography (hexane / ethyl acetate) and concentrated under reduced pressure. The resulting residue was crystallized from EtOH / water to give the title compound (33.1 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.34 (3H, t, J = 7.2 Hz), 1.48 (6H, s), 2.18 (3H, s), 3.79 (3H, s), 4.01 (2H, q, J = 7.2 Hz), 5.05 (1H, s), 7.04-7.11 (1H, m), 7.41 (1H, s), 7.73-7.81 (2H, m), 7.91 (1H, s).

[0262] Example 44 2-(4-Fluoro-3-{[5-methoxy-1-(2-methylpropyl)-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol

[0263] A) Methyl 4-fluoro-1H-indazole-6-carboxylate A mixture of 6-bromo-4-fluoro-1H-indazole (4 g), PdCl2(dppf) (0.68 g), triethylamine (7.77 ml) and MeOH (32 ml) was stirred under carbon monoxide pressure (50 psi) at 90° C. for 4 hours. Water was added to the reaction mixture, and the resulting solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (3.46 g). MS: [M+H] + 194.9.

[0264] B) 2-(4-fluoro-1H-indazol-6-yl)propan-2-ol To a mixture of methyl 4-fluoro-1H-indazole-6-carboxylate (1.7 g) and THF (30 ml), methylmagnesium bromide (3 mol / l Et2O solution) (15 ml) was added at 0°C, and the mixture was stirred at 30°C under a nitrogen atmosphere for 1 hour. A saturated aqueous citric acid solution was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then filtered through Celite. The filtrate was concentrated under reduced pressure to obtain the title compound (1.7 g). MS: [M+H] + 194.9.

[0265] C) 2-(4-fluoro-3-iodo-1H-indazol-6-yl)propan-2-ol To a mixture of 2-(4-fluoro-1H-indazol-6-yl)propan-2-ol (1.7 g), potassium carbonate (2.43 g) and DMF (30 ml), iodine (4.45 g) was added at 0° C., and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, a mixture of sodium hydrogen sulfite (2 g) and water (60 ml) was added at 0° C., and further water was added, followed by extraction with a mixture of ethyl acetate and hexane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound (2.8 g). MS: [M+H] + 320.8.

[0266] D) 2-(4-fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol Methyl iodide (0.83 ml) was added to a mixture of 2-(4-fluoro-3-iodo-1H-indazol-6-yl)propan-2-ol (2.8 g), cesium carbonate (4.35 g) and DMF (20 ml), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with a mixture of ethyl acetate and hexane. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.95 g). MS: [M+H] + 334.8.

[0267] E) 1-(2-methylpropyl)-4-nitro-1H-pyrazole 1-Bromo-2-methylpropane (10.8 ml) was added to a mixture of 4-nitro-1H-pyrazole (10 g), potassium carbonate (13.6 g) and DMSO (90 ml) at room temperature, and the mixture was stirred at 60°C under a nitrogen atmosphere for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with a mixture of ethyl acetate and hexane. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (14.6 g). 1 H NMR (300 MHz, DMSO-d6) δ 0.85 (6H, d, J = 6.8 Hz), 2.15 (1H, m), 4.00 (2H, d, J = 7.2 Hz), 8.26 (1H, d, J = 0.8 Hz), 8.90 (1H, s).

[0268] F) 5-chloro-1-(2-methylpropyl)-4-nitro-1H-pyrazole A mixture of 1-(2-methylpropyl)-4-nitro-1H-pyrazole (10 g) and THF (90 ml) was added with a THF solution of lithium (bistrimethylsilyl)amide (1.3 mol / l, 50 ml) while maintaining the internal temperature at -75°C to -70°C, and stirred for 30 minutes. Hexachloroethane (16.8 g) was added to the reaction mixture at -78°C, and the mixture was stirred for 20 minutes at -78°C under a nitrogen atmosphere, and then stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with a mixture of ethyl acetate and hexane. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (11 g). MS: [M+H] + 203.9.

[0269] G) 5-Methoxy-1-(2-methylpropyl)-4-nitro-1H-pyrazole To a mixture of 60% sodium hydride (280 mg) and DMF (15 ml), MeOH (0.26 ml) was added at 0°C and stirred for 3 minutes. To the reaction mixture, a mixture of 5-chloro-1-(2-methylpropyl)-4-nitro-1H-pyrazole (1000 mg) and DMF (5 ml) was added and stirred at 0°C for 3 hours under a nitrogen atmosphere. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added at 0°C and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (739 mg). MS: [M+H] + 199.9.

[0270] H) 5-Methoxy-1-(2-methylpropyl)-1H-pyrazol-4-amine A mixture of 5-methoxy-1-(2-methylpropyl)-4-nitro-1H-pyrazole (739 mg), 10% palladium on carbon (70.3 mg) and MeOH (20 ml) was stirred at room temperature under a hydrogen atmosphere for 4 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / ethyl acetate) to give the title compound (500 mg). MS: [M+H] + 169.9.

[0271] I) 2-(4-fluoro-3-{[5-methoxy-1-(2-methylpropyl)-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol 2-(4-Fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (100 mg), 5-methoxy-1-(2-methylpropyl)-1H-pyrazol-4-amine (58 mg), NaO tA mixture of Bu (43.2 mg), BrettPhos Pd G3 (20.5 mg), BrettPhos (12.3 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and silica gel column chromatography (hexane / ethyl acetate) and concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound (65.8 mg). 1 H NMR (300 MHz, DMSO-d6) δ 0.86 (6H, d, J = 6.8 Hz), 1.46 (6H, s), 1.96-2.15 (1H, m), 3.68 (2H, d, J = 7.6 Hz), 3.73 (3H, s), 3.92 (3H, s), 5.16 (1H, s), 6.77 (1H, dd, J = 12.5, 1.1 Hz), 7.02 (1H, s), 7.21 (1H, s), 7.28 (1H, s).

[0272] Example 45 2-{3-[(1-ethyl-3-methyl-1H-pyrazol-4-yl)amino]-4-fluoro-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(4-Fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (100 mg), 1-ethyl-3-methyl-1H-pyrazol-4-amine dihydrochloride (65.2 mg), NaO t A mixture of Bu (101 mg), BrettPhos Pd G3 (27.1 mg), BrettPhos (16.1 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and silica gel column chromatography (ethyl acetate / MeOH) and concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate / hexane to give the title compound (53 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.34 (3H, t, J = 7.3 Hz), 1.47 (6H, s), 2.11 (3H, s), 3.79 (3H, s), 4.01 (2H, q, J = 7.2 Hz), 5.16 (1H, s), 6.81 (1H, d, J = 12.5 Hz), 7.09 (1H, s), 7.23 (1H, s), 7.79 (1H, s).

[0273] Example 46 2-{4-fluoro-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(4-Fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (102 mg), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (58 mg), NaO t A mixture of Bu (64 mg), BrettPhos Pd G3 (20.5 mg), BrettPhos (12.3 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and silica gel column chromatography (hexane / ethyl acetate) and concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate / heptane to give the title compound (69.9 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.46 (6H, s), 3.67 (3H, s), 3.79 (3H, s), 3.82 (3H, s), 5.18 (1H, s), 6.72 (1H, s), 6.81 (1H, dd, J = 12.5, 0.8 Hz), 7.24 (1H, s), 7.73 (1H, s).

[0274] Example 47 2-(3-{[5-(1-methoxyethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (102 mg), 5-(1-methoxyethyl)-1-methyl-1H-pyrazol-4-amine (55.2 mg), NaO t A mixture of Bu (47.1 mg), BrettPhos Pd G3 (20.8 mg), BrettPhos (12 mg) and THF (1.5 ml) was stirred under microwave irradiation for 1 hour at 100° C. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (57.7 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.42-1.50 (9H, m), 3.14 (3H, s), 3.75 (3H, s), 3.84 (3H, s), 4.71 (1H, q, J = 6.8 Hz), 5.06 (1H, s), 7.06 (1H, dd, J = 8.5, 1.3 Hz), 7.41 (1H, s), 7.52 (1H, s), 7.57-7.64 (2H, m).

[0275] Example 48 2-(4-Fluoro-3-{[5-(1-methoxyethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol

[0276] A) 1-(1-methyl-1H-pyrazol-5-yl)ethan-1-ol A mixture of 1-methyl-1H-pyrazole-5-carbaldehyde (3 g) and THF (10 ml) was added to a mixture of methylmagnesium bromide (3 mol / l Et2O solution) (15 ml) and THF (50 ml) at 0°C, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (1.97 g). MS: [M+H] + 126.9.

[0277] B) 5-(1-methoxyethyl)-1-methyl-1H-pyrazole To a mixture of 1-(1-methyl-1H-pyrazol-5-yl)ethan-1-ol (1.97 g) and DMF (40 ml), 60% sodium hydride (750 mg) was added at 0°C and stirred for 5 minutes. Methyl iodide (1.3 ml) was added to the reaction mixture at 0°C and stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.44 g). MS: [M+H] + 140.9.

[0278] C) 5-(1-methoxyethyl)-1-methyl-4-nitro-1H-pyrazole To a mixture of 5-(1-methoxyethyl)-1-methyl-1H-pyrazole (1.44 g) and concentrated sulfuric acid (10 ml), potassium nitrate (1.3 g) was added at 0°C, and the mixture was stirred at room temperature for 10 minutes under a nitrogen atmosphere and then at 50°C overnight. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.16 g). MS: [M+H] +185.9.

[0279] D) 5-(1-Methoxyethyl)-1-methyl-1H-pyrazol-4-amine A mixture of 5-(1-methoxyethyl)-1-methyl-4-nitro-1H-pyrazole (1.16 g), 10% palladium on carbon (114 mg) and MeOH (30 ml) was stirred at room temperature under a hydrogen atmosphere for 5 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.96 g). MS: [M+H] + 155.9.

[0280] E) 2-(4-fluoro-3-{[5-(1-methoxyethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol 2-(4-Fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (102 mg), 5-(1-methoxyethyl)-1-methyl-1H-pyrazol-4-amine (55.2 mg), NaO t A mixture of Bu (47.1 mg), BrettPhos Pd G3 (20.8 mg), BrettPhos (12 mg) and THF (1.5 ml) was stirred under microwave irradiation for 1 hour at 100° C. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate) and silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (79 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.41-1.48 (9H, m), 3.22 (3H, s), 3.79 (6H, s), 4.68 (1H, q, J = 6.8 Hz), 5.18 (1H, s), 6.82 (1H, dd, J = 12.5, 0.8 Hz), 7.18 (1H, s), 7.24 (1H, s), 7.65 (1H, s).

[0281] Example 49 2-{1-(cyclopropylmethyl)-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol

[0282] A) 2-(1H-indazol-6-yl)propan-2-ol To a mixture of methyl 1H-indazole-6-carboxylate (6 g) and THF (120 ml), methylmagnesium bromide (3 mol / l Et2O solution) (68 ml) was added at 0°C, and the mixture was stirred at 40°C under a nitrogen atmosphere for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (5.86 g). MS: [M+H] + 176.9.

[0283] B) 2-(3-iodo-1H-indazol-6-yl)propan-2-ol To a mixture of 2-(1H-indazol-6-yl)propan-2-ol (5.86 g), potassium carbonate (9.19 g) and DMF (94 ml), iodine (16.88 g) was added at 0°C, and the mixture was stirred at room temperature until the starting materials disappeared. A mixture of sodium hydrogen sulfite (10.38 g) and water (15 ml) was added to the reaction mixture. Water was further added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (9.15 g). MS: [M+H] + 302.8.

[0284] C) 2-[1-(cyclopropylmethyl)-3-iodo-1H-indazol-6-yl]propan-2-ol Potassium carbonate (0.81 g) was added to a mixture of 2-(3-iodo-1H-indazol-6-yl)propan-2-ol (1.18 g) and DMF (7 ml), and the mixture was stirred at room temperature for 30 minutes. A mixture of (bromomethyl)cyclopropane (1.71 ml) and DMF (2.2 ml) was added dropwise to the reaction mixture, and the mixture was stirred at 50°C overnight and at 80°C for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.93 g). MS: [M+H] + 356.9.

[0285] D) 2-{1-(cyclopropylmethyl)-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol 2-[1-(cyclopropylmethyl)-3-iodo-1H-indazol-6-yl]propan-2-ol (200 mg), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (101 mg), NaO t A mixture of Bu (135 mg), BrettPhos Pd G3 (50.9 mg), BrettPhos (30.1 mg) and THF (3.6 ml) was stirred at 100°C for 1 h under microwave irradiation. The reaction mixture was filtered through a pad of basic silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated under reduced pressure. The resulting residue was crystallized from Et2O / hexane to give the title compound (94 mg). 1H NMR (400 MHz, DMSO-d6) δ 0.33-0.49 (4H, m), 1.15-1.29 (1H, m), 1.47 (6H, s), 3.67 (3H, s), 3.85 (3H, s), 4.04 (2H, d, J = 6.7 Hz), 5.02 (1H, s), 7.02 (1H, d, J = 8.6 Hz), 7.43 (1H, s), 7.82 (1H, d, J = 8.6 Hz), 7.85-7.88 (2H, m).

[0286] Example 50 2-{3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-4-fluoro-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(4-Fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (100 mg), 1,3-dimethyl-1H-pyrazol-4-amine (36.6 mg), NaO t A mixture of Bu (101 mg), BrettPhos Pd G3 (27.1 mg), BrettPhos (16.1 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and silica gel column chromatography (ethyl acetate / MeOH) and concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound (24 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.47 (6H, s), 2.10 (3H, s), 3.73 (3H, s), 3.79 (3H, s), 5.16 (1H, s), 6.81 (1H, d, J = 12.5 Hz), 7.11 (1H, s), 7.23 (1H, s), 7.76 (1H, s).

[0287] Example 51 2-{3-[(3-ethoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (80.3 mg), 3-ethoxy-1-methyl-1H-pyrazol-4-amine (47.6 mg), NaO t A mixture of Bu (75.2 mg), BrettPhos Pd G3 (10.3 mg), BrettPhos (6.8 mg) and THF (2 ml) was stirred under microwave irradiation for 90 minutes at 100° C. The reaction mixture was purified by basic silica gel column chromatography (hexane / ethyl acetate and ethyl acetate / MeOH) and silica gel column chromatography (hexane / ethyl acetate) to give the title compound (20.5 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.33 (3H, t, J = 7.0 Hz), 1.47 (6H, s), 3.66 (3H, s), 3.78 (3H, s), 4.20 (2H, q, J = 6.9 Hz), 5.04 (1H, s), 7.03 (1H, dd, J = 8.7, 1.5 Hz), 7.39 (1H, s), 7.75 (1H, s), 7.80-7.86 (2H, m).

[0288] Examples 52 and 53 2-{4-Fluoro-1-methyl-3-[(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)amino]-1H-indazol-6-yl}propan-2-ol and 2-{4-Fluoro-1-methyl-3-[(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)amino]-1H-indazol-6-yl}propan-2-ol hydrochloride 2-(4-Fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (60 mg), 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-amine hydrochloride (34.3 mg), NaO tA mixture of Bu (43.1 mg), BrettPhos Pd G3 (16.3 mg), BrettPhos (9.6 mg) and THF (1 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and concentrated under reduced pressure. The resulting residue was crystallized from EtOH / heptane to give 2-{4-fluoro-1-methyl-3-[(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)amino]-1H-indazol-6-yl}propan-2-ol (28.5 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.46 (6H, s), 1.70-1.82 (2H, m), 1.89-2.01 (2H, m), 2.64 (2H, t, J = 6.3 Hz), 3.75 (3H, s), 4.02 (2H, t, J = 6.0 Hz), 5.15 (1H, s), 6.79 (1H, d, J = 12.5 Hz), 7.09 (1H, s), 7.21 (1H, s), 7.48 (1H, s).

[0289] A few drops of 4 mol / l hydrogen chloride in ethyl acetate were added to the mother liquor of the crystallization, and the resulting solid was collected by filtration and dried under reduced pressure to give 2-{4-fluoro-1-methyl-3-[(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)amino]-1H-indazol-6-yl}propan-2-ol hydrochloride (6.2 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.46 (6H, s), 1.71-1.82 (2H, m), 1.90-2.01 (2H, m), 2.66 (2H, t, J = 6.2 Hz), 3.75 (3H, s), 4.00-4.07 (2H, m), 6.80 (1H, d, J = 12.5 Hz), 6.99-7.44 (2H, m), 7.55 (1H, s).

[0290] Example 54 2-{3-[(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)amino]-4-fluoro-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(4-Fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (60 mg), 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-amine hydrochloride (34.7 mg), NaO t A mixture of Bu (43.1 mg), BrettPhos Pd G3 (16.3 mg), BrettPhos (9.6 mg) and THF (1 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate / IPE / hexane to give the title compound (14.3 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.46 (6H, s), 2.16 (2H, m), 3.72 (3H, s), 4.07 (2H, t, J = 6.2 Hz), 4.21-4.28 (2H, m), 5.15 (1H, s), 6.69 (1H, s), 6.76 (1H, d, J = 12.5 Hz), 7.19 (1H, s), 7.35 (1H, s).

[0291] Example 55 2-(5-fluoro-3-{[5-methoxy-1-(2-methylpropyl)-1H-pyrazol-4-yl]amino}-1-methyl-1H-indazol-6-yl)propan-2-ol 2-(5-Fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (60 mg), 5-methoxy-1-(2-methylpropyl)-1H-pyrazol-4-amine (33.4 mg), NaO tA mixture of Bu (43.1 mg), BrettPhos Pd G3 (16.3 mg), BrettPhos (9.6 mg) and THF (1.2 ml) was stirred under microwave irradiation at 100° C. for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate) and basic silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (26.3 mg). 1 H NMR (400 MHz, DMSO-d6) δ 0.86 (6H, d, J = 6.6 Hz), 1.51 (6H, s), 2.08 (1H, m), 3.70 (2H, d, J = 7.2 Hz), 3.75 (3H, s), 3.90 (3H, s), 5.34 (1H, s), 7.27 (1H, d, J = 12.5 Hz), 7.41 (1H, s), 7.48-7.55 (2H, m).

[0292] Example 56 2-{3-[(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)amino]-5-fluoro-1-methyl-1H-indazol-6-yl}propan-2-ol 2-(5-Fluoro-3-iodo-1-methyl-1H-indazol-6-yl)propan-2-ol (60 mg), 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-amine hydrochloride (37.8 mg), NaO t A mixture of Bu (60.4 mg), BrettPhos Pd G3 (16.3 mg), BrettPhos (9.6 mg) and THF (1.2 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by silica gel column chromatography (ethyl acetate / MeOH) and concentrated under reduced pressure. The resulting residue was crystallized from THF / hexane to give the title compound (13.4 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.51 (6H, s), 2.11-2.23 (2H, m), 3.73 (3H, s), 4.09 (2H, t, J = 6.1 Hz), 4.27 (2H, t, J = 5.0 Hz), 5.33 (1H, s), 7.36-7.45 (2H, m), 7.46-7.52 (2H, m).

[0293] Example 57 2-{3-[2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}propan-2-ol

[0294] A) 2-Methoxy-3-(1-methyl-1H-pyrazol-4-yl)aniline XPhos Pd G3 (0.114 g) was added to a mixture of 3-bromo-2-methoxyaniline (3.03 g), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.7 g), cesium carbonate (8.13 g), DME (60 ml) and water (20 ml), and the mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / ethyl acetate) and concentrated under reduced pressure to obtain the title compound (2.47 g). MS: [M+H] + 203.9.

[0295] B) Methyl 3-[2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)anilino]-1-(oxan-2-yl)-1H-indazole-6-carboxylate A mixture of methyl 3-iodo-1-(oxan-2-yl)-1H-indazole-6-carboxylate (300 mg), 2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)aniline (174 mg), cesium carbonate (506 mg), Pd(OAc)2 (17.4 mg), XANTPHOS (90 mg) and toluene (5 ml) was stirred overnight at 80° C. under a nitrogen atmosphere. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (358 mg). MS: [M+H] + 462.1.

[0296] C) 2-{3-[2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)anilino]-1-(oxan-2-yl)-1H-indazol-6-yl}propan-2-ol To a mixture of methyl 3-[2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)anilino]-1-(oxan-2-yl)-1H-indazole-6-carboxylate (356 mg) and THF (7 ml), methylmagnesium bromide (1 mol / l THF solution) (4.6 ml) was added at 0°C, and the mixture was stirred at 40°C for 6 hours under a nitrogen atmosphere, and then stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then filtered through a pad of silica gel. The filtrate was concentrated under reduced pressure to give the title compound (298 mg). MS: [M+H] + 462.2.

[0297] D) 2-{3-[2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}propan-2-ol 6 mol / l hydrochloric acid (0.53 ml) was added to a mixture of 2-{3-[2-methoxy-3-(1-methyl-1H-pyrazol-4-yl)anilino]-1-(oxan-2-yl)-1H-indazol-6-yl}propan-2-ol (296 mg), EtOH (2 ml) and THF (3 ml) at 0°C, and the mixture was stirred at room temperature for 3 hours, and then stirred at 50°C for 25 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated under reduced pressure. The residue was crystallized from ethyl acetate / IPE to give the title compound (105 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.48 (6H, s), 3.67 (3H, s), 3.91 (3H, s), 5.08 (1H, s), 6.95-7.05 (2H, m), 7.12 (1H, d, J = 8.7 Hz), 7.48 (1H, s), 7.71-7.79 (2H, m), 7.83 (1H, s), 7.89 (1H, s), 8.13 (1H, s), 12.07 (1H, s).

[0298] Example 58 2-{3-[(3-chloro-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-5-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-5-yl)propan-2-ol (100 mg), 3-chloro-1-methyl-1H-pyrazol-4-amine (45.8 mg), NaO t A mixture of Bu (76 mg), BrettPhos Pd G3 (28.7 mg), BrettPhos (17 mg) and THF (1.8 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate / toluene / hexane to give the title compound (22.4 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.48 (6H, s), 3.74-3.84 (6H, m), 4.96 (1H, s), 7.30 (1H, d, J = 8.8 Hz), 7.50 (1H, d, J = 9.3 Hz), 8.04-8.11 (2H, m), 8.15 (1H, s).

[0299] Example 59 2-[3-(cyclohexylamino)-1-methyl-1H-indazol-5-yl]propan-2-ol A mixture of 2-(3-iodo-1-methyl-1H-indazol-5-yl)propan-2-ol (100 mg), cyclohexylamine (0.054 ml), CuI (6 mg), [(2,6-dimethylphenyl)amino](oxo)acetic acid (12.2 mg), tripotassium phosphate (134 mg) and DMSO (1.4 ml) was stirred at 90°C overnight. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (79 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.16-1.36 (6H, m), 1.46 (6H, s), 1.68-1.79 (2H, m), 2.00-2.10 (2H, m), 3.17 (1H, d, J = 5.3 Hz), 3.68 (3H, s), 4.89 (1H, s), 5.73 (1H, d, J = 7.7 Hz), 7.18 (1H, d, J = 8.8 Hz), 7.39-7.45 (1H, m), 7.80 (1H, s).

[0300] Example 60 2-{3-[(6,6-difluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)amino]-1-methyl-1H-indazol-5-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-5-yl)propan-2-ol (60 mg), 6,6-difluoro-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-amine hydrochloride (40.2 mg), NaO t A mixture of Bu (63.8 mg), BrettPhos Pd G3 (17.2 mg), BrettPhos (10.2 mg) and THF (1.5 ml) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was purified by silica gel column chromatography (hexane / ethyl acetate and ethyl acetate / MeOH) and concentrated under reduced pressure. The residue obtained was crystallized by adding hexane to obtain the title compound (27.2 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.46 (6H, s), 3.72 (3H, s), 4.55-4.73 (4H, m), 4.92 (1H, s), 7.25 (1H, d, J = 8.8 Hz), 7.47 (1H, d, J = 8.8 Hz), 7.70 (2H, d, J = 13.4 Hz), 7.87 (1H, s).

[0301] Example 61 2-{1-(cyclopropylmethyl)-3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-5-yl}propan-2-ol

[0302] A) 2-[1-(cyclopropylmethyl)-3-iodo-1H-indazol-5-yl]propan-2-ol Cesium carbonate (8.09 g) was added to a mixture of 2-(3-iodo-1H-indazol-5-yl)propan-2-ol (5 g) and DMF (60 ml), and the mixture was stirred at 25°C for 30 minutes. (Bromomethyl)cyclopropane (6.7 g) was added dropwise to the reaction mixture, and the mixture was stirred at 25°C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the title compound (2.14 g). MS: [M+H] + 357.1.

[0303] B) 2-{1-(cyclopropylmethyl)-3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-5-yl}propan-2-ol 2-[1-(cyclopropylmethyl)-3-iodo-1H-indazol-5-yl]propan-2-ol (100 mg), 1,3-dimethyl-1H-pyrazol-4-amine (37 mg), NaO t A mixture of Bu (5 mg), BrettPhos Pd G3 (18 mg), BrettPhos (11 mg) and 1,4-dioxane (1.5 ml) was stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound (25 mg). 1 H NMR (400 MHz, DMSO-d6) δ 0.30-0.40 (2H, m), 0.41-0.50 (2H, m), 1.10-1.25 (1H, m), 1.48 (6H, s), 2.21 (3H, s), 3.73 (3H, s), 4.04 (2H, d, J = 6.8 Hz), 4.98 (1H, brs), 7.33 (1H, d, J = 8.8 Hz), 7.44 (1H, d, J = 8.8 Hz), 7.88 (1H, s), 7.93 (1H, s), 8.04 (1H, s).

[0304] Example 62 2-(1-methyl-3-{[3-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]amino}-1H-indazol-5-yl)propan-2-ol

[0305] A) 3-methyl-4-nitro-1-(propan-2-yl)-1H-pyrazole and 5-methyl-4-nitro-1-(propan-2-yl)-1H-pyrazole A mixture of 3-methyl-4-nitro-1H-pyrazole (200 mg), potassium carbonate (326 mg) and DMF (8 ml) was stirred at 25°C for 30 minutes, and then 2-iodopropane (802 mg) was added dropwise and stirred at 25°C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a mixture of the title compounds (264 mg). MS: [M+H] + 170.0.

[0306] B) 3-methyl-1-(propan-2-yl)-1H-pyrazol-4-amine and 5-methyl-1-(propan-2-yl)-1H-pyrazol-4-amine A mixture of 3-methyl-4-nitro-1-(propan-2-yl)-1H-pyrazole and 5-methyl-4-nitro-1-(propan-2-yl)-1H-pyrazole (264 mg), 10% palladium carbon (27 mg) and MeOH (5 ml) was stirred under a hydrogen atmosphere at 25°C for 8 hours. Insoluble matter was removed by filtration, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain a mixture of the title compounds (150 mg). MS: [M+H] + 139.9.

[0307] C) 2-(1-methyl-3-{[3-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]amino}-1H-indazol-5-yl)propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-5-yl)propan-2-ol (189 mg), a mixture of 3-methyl-1-(propan-2-yl)-1H-pyrazol-4-amine and 5-methyl-1-(propan-2-yl)-1H-pyrazol-4-amine (100 mg), NaO t A mixture of Bu (115 mg), BrettPhos Pd G3 (38 mg), BrettPhos (22 mg) and 1,4-dioxane (1.5 ml) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (28 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.37 (6H, d, J = 6.8 Hz), 1.47 (6H, s), 2.19 (3H, s), 3.77 (3H, s), 4.25-4.42 (1H, m), 4.98 (1H, brs), 7.27 (1H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 8.8, 1.6 Hz), 7.83 (1H, s), 7.94 (1H, s), 8.00 (1H, brs).

[0308] Example 63 2-(1-methyl-3-{[5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]amino}-1H-indazol-5-yl)propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-5-yl)propan-2-ol (189 mg), a mixture of 3-methyl-1-(propan-2-yl)-1H-pyrazol-4-amine and 5-methyl-1-(propan-2-yl)-1H-pyrazol-4-amine (100 mg), NaO tA mixture of Bu (115 mg), BrettPhos Pd G3 (38 mg), BrettPhos (22 mg) and 1,4-dioxane (1.5 ml) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound (15 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.36 (6H, d, J = 6.8 Hz), 1.46 (6H, s), 2.23 (3H, s), 3.73 (3H, s), 4.35-4.57 (1H, m), 4.97 (1H, brs), 7.26 (1H, d, J = 8.8 Hz), 7.45 (1H, d, J = 8.8 Hz), 7.56-7.65 (2H, m), 7.86 (1H, brs).

[0309] Example 64 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-5-yl}propan-2-ol

[0310] A) 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-iodo-1H-indazol-5-yl}propan-2-ol 2-(3-iodo-1H-indazol-5-yl)propan-2-ol (3 g), cesium carbonate (4.85 g) and DMF (50 ml) were mixed with 2-(bromomethyl)-1,1-difluorocyclopropane (2.55 g) and stirred at 20°C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the title compound (1.4 g). MS: [M+H] + 393.1.

[0311] B) 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-5-yl}propan-2-ol 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-iodo-1H-indazol-5-yl}propan-2-ol (95 mg), 1,3-dimethyl-1H-pyrazol-4-amine (32.3 mg), NaO t A mixture of Bu (46.6 mg), BrettPhos Pd G3 (15 mg), BrettPhos (9.1 mg) and 1,4-dioxane (2 ml) was stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound (43 mg). 1 H NMR (400 MHz, CDCl3) δ 1.25-1.33 (1H, m), 1.46-1.55 (1H, m), 1.65 (6H, s), 1.80 (1H, s), 2.03-2.21 (1H, m), 2.31 (3H, s), 3.86 (3H, s), 4.23-4.40 (2H, m), 5.59 (1H, s), 7.24 (1H, d, J = 8.8 Hz), 7.52 (1H, dd, J = 8.8, 1.6 Hz), 7.66 (1H, s), 7.84 (1H, s).

[0312] Example 65 2-{1-cyclobutyl-3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-5-yl}propan-2-ol

[0313] A) 2-(1-cyclobutyl-3-iodo-1H-indazol-5-yl)propan-2-ol Bromocyclobutane (3.35 g) was added to a mixture of 2-(3-iodo-1H-indazol-5-yl)propan-2-ol (5 g), cesium carbonate (8.09 g) and DMF (80 ml), and the mixture was stirred at 55° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate), and then washed with petroleum ether / ethyl acetate to obtain the title compound (2.25 g). MS: [M+H] + 357.0.

[0314] B) 2-{1-cyclobutyl-3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-5-yl}propan-2-ol 2-(1-Cyclobutyl-3-iodo-1H-indazol-5-yl)propan-2-ol (63 mg), 1,3-dimethyl-1H-pyrazol-4-amine (24 mg), NaO t A mixture of Bu (34 mg), BrettPhos Pd G3 (11 mg), BrettPhos (6.7 mg) and 1,4-dioxane (2 ml) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound (21 mg). 1 H NMR (400 MHz, CDCl3) δ 1.63 (6H, s), 1.72 (1H, br s), 1.81-2.03 (2H, m), 2.31 (3H, s), 2.39-2.57 (2H, m), 2.70-2.85 (2H, m), 3.87 (3H, s), 4.82-5.00 (1H, m), 5.62 (1H, br s), 7.27-7.33 (1H, m), 7.42-7.51 (1H, m), 7.59 (1H, s), 7.79-7.91 (1H, m)

[0315] Example 66 2-{3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1-(propan-2-yl)-1H-indazol-5-yl}propan-2-ol

[0316] A) 2-[3-iodo-1-(propan-2-yl)-1H-indazol-5-yl]propan-2-ol Potassium carbonate (6.96 g) was added to a mixture of 2-(3-iodo-1H-indazol-5-yl)propan-2-ol (10.1 g) and DMF (100 ml), and the mixture was stirred at 25°C for 30 minutes. 2-iodopropane (17.1 g) was added dropwise to the reaction mixture, and the mixture was stirred at 25°C for 14 hours. 2-iodopropane (4.83 g) and potassium carbonate (5.88 g) were further added to the reaction mixture, and the mixture was stirred at 25°C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) and concentrated under reduced pressure. The obtained residue was purified by HPLC to obtain the title compound (4.33 g). MS: [M+H] + 345.1.

[0317] B) 2-{3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1-(propan-2-yl)-1H-indazol-5-yl}propan-2-ol 2-[3-iodo-1-(propan-2-yl)-1H-indazol-5-yl]propan-2-ol (100 mg), 1,3-dimethyl-1H-pyrazol-4-amine (39 mg), NaO t A mixture of Bu (56 mg), BrettPhos Pd G3 (18 mg), BrettPhos (11 mg) and 1,4-dioxane (4 ml) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound (30 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.41 (6H, d, J = 6.8 Hz), 1.49 (6H, s), 2.22 (3H, s), 3.75 (3H, s), 4.65-4.75 (1H, m), 4.97 (1H, s), 7.33 (1H, d, J = 8.8 Hz), 7.45 (1H, dd, J = 8.8 Hz, 1.6 Hz), 7.89 (1H, s), 7.92 (1H, s), 8.03 (1H, d, J = 0.8 Hz).

[0318] Example 67 2-{1-(cyclopropylmethyl)-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-5-yl}propan-2-ol 2-[1-(cyclopropylmethyl)-3-iodo-1H-indazol-5-yl]propan-2-ol (80 mg), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (44 mg), NaO t A mixture of Bu (43 mg), BrettPhos Pd G3 (14 mg), BrettPhos (8.4 mg) and 1,4-dioxane (4 ml) was stirred at 110° C. for 2 hours under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound (21 mg). 1 H NMR (400 MHz, DMSO-d6) δ 0.28-0.46 (4H, m), 1.10-1.25 (1H, m), 1.47 (6H, s), 3.67 (3H, s), 3.85 (3H, s), 4.03 (2H, d, J = 6.8 Hz), 4.91 (1H, s), 7.31 (1H, d, J = 8.8 Hz), 7.40-7.50 (1H, m), 7.86 (1H, s), 7.97 (1H, s), 8.05 (1H, s).

[0319] Example 68 2-{1-cyclobutyl-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol

[0320] A) 2-(1-cyclobutyl-3-iodo-1H-indazol-6-yl)propan-2-ol To a mixture of bromocyclobutane (6.7 g) and DMF (50 ml), cesium carbonate (16.2 g) and 2-(3-iodo-1H-indazol-6-yl)propan-2-ol (6 g) were added at 85°C, and the mixture was stirred at the same temperature for 16 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the title compound (3.3 g). MS: [M+H] + 357.0.

[0321] B) 2-{1-cyclobutyl-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol 2-(1-cyclobutyl-3-iodo-1H-indazol-6-yl)propan-2-ol (100 mg), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (55 mg), NaO t A mixture of Bu (54 mg), BrettPhos Pd G3 (18 mg), BrettPhos (11 mg) and 1,4-dioxane (4 ml) was stirred at 110°C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, distilled with a mixture of petroleum ether / ethyl acetate) to obtain the title compound (15 mg). 1H NMR (400 MHz, CDCl3) δ 1.65 (6H, s), 1.75-2.00 (3H, m), 2.38-2.50 (2H, m), 2.70-2.85 (2H, m), 3.78 (3H, s), 4.00 (3H, s), 4.85-5.00 (1H, m), 5.71 (1H, brs), 7.06 (1H, d, J = 8.4 Hz), 7.39-7.50 (2H, m), 7.80 (1H, s).

[0322] Example 69 2-{3-[2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}propan-2-ol

[0323] A) 2-Methoxy-5-(1-methyl-1H-pyrazol-4-yl)aniline XPhos Pd G3 (0.2 g) was added to a mixture of 5-chloro-2-methoxyaniline (2 g), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.9 g), cesium carbonate (8.26 g), DME (40 ml) and water (15 ml), and the mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The aqueous layer of the reaction mixture was removed, basic silica gel was added, and the mixture was concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (ethyl acetate / MeOH) and concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate / hexane to give the title compound (2.41 g). MS: [M+H] + 203.9.

[0324] B) Methyl 3-[2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)anilino]-1-(oxan-2-yl)-1H-indazole-6-carboxylate A mixture of methyl 3-iodo-1-(oxan-2-yl)-1H-indazole-6-carboxylate (300 mg), 2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)aniline (174 mg), cesium carbonate (506 mg), Pd(OAc)2 (17.4 mg), XANTPHOS (90 mg) and toluene (5 ml) was stirred overnight at 80° C. under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and filtered through a pad of basic silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was washed with a mixture of toluene and IPE and dried under reduced pressure to give the title compound (106 mg). MS: [M+H] + 462.2.

[0325] C) 2-{3-[2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}propan-2-ol To a mixture of methyl 3-[2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)anilino]-1-(oxan-2-yl)-1H-indazole-6-carboxylate (106 mg) and THF (2 ml), methylmagnesium bromide (1 mol / l THF solution) (1.38 ml) was added at 0°C, and the mixture was stirred at 40°C for 6 hours under a nitrogen atmosphere, and then stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure. THF (2 ml) and EtOH (2 ml) were added to the obtained residue, and then 6 mol / l hydrochloric acid (0.53 ml) was added at 0°C, and the mixture was stirred at 50°C for 50 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate / IPE to give the title compound (8.8 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.48 (6H, s), 3.85 (3H, s), 3.91 (3H, s), 5.08 (1H, s), 6.98 (2H, s), 7.12 (1H, d, J = 8.4 Hz), 7.47 (1H, s), 7.55 (1H, s), 7.62 (1H, s), 7.77 (1H, d, J = 8.6 Hz), 7.88 (1H, s), 8.24 (1H, s), 12.02 (1H, s).

[0326] Example 70 2-{1-cyclobutyl-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-5-yl}propan-2-ol 2-(1-cyclobutyl-3-iodo-1H-indazol-5-yl)propan-2-ol (100 mg), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (55 mg), NaO t A mixture of Bu (54 mg), BrettPhos Pd G3 (18 mg), BrettPhos (11 mg) and 1,4-dioxane (2 ml) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (29 mg). 1 H NMR (400 MHz, CDCl3) δ 1.64 (6H, s), 1.77 (1H, br s), 1.83-1.99 (2H, m), 2.39-2.49 (2H, m), 2.73-2.86 (2H, m), 3.79 (3H, s), 4.02 (3H, s), 4.84-5.01 (1H, m), 5.80 (1H, s), 7.23-7.26 (1H, m), 7.49 (1H, d, J = 8.8 Hz), 7.66 (1H, s), 7.85 (1H, s).

[0327] Example 71 2-{3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-(propan-2-yl)-1H-indazol-5-yl}propan-2-ol 2-[3-iodo-1-(propan-2-yl)-1H-indazol-5-yl]propan-2-ol (80 mg), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (46 mg), NaO t A mixture of Bu (45 mg), BrettPhos Pd G3 (15 mg), BrettPhos (8.7 mg) and 1,4-dioxane (2 ml) was stirred at 110°C for 2 hours under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (18 mg). 1H NMR (400 MHz, DMSO-d6) δ 1.40 (6H, d, J = 6.8 Hz), 1.48 (6H, s), 3.69 (3H, s), 3.87 (3H, s), 4.63-4.75 (1H, m), 4.90 (1H, s), 7.32 (1H, d, J = 8.8 Hz), 7.47-7.49 (1H, dd, J = 8.8 Hz, 1.6 Hz), 7.87 (1H, s), 8.00 (1H, s), 8.05 (1H, s).

[0328] Example 72 Optically active 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-5-yl}propan-2-ol (tR1)

[0329] A) Racemic mixture of 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-5-yl}propan-2-ol 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-iodo-1H-indazol-5-yl}propan-2-ol (100 mg), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (50 mg), NaO t A mixture of Bu (49 mg), BrettPhos Pd G3 (16 mg), BrettPhos (9.6 mg) and 1,4-dioxane (2 ml) was stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, distilled with ethyl acetate) to obtain the title compound (60 mg). MS: [M+H] + 392.1.

[0330] B) Optically active 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-5-yl}propan-2-ol (tR1) The racemic mixture of 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-5-yl}propan-2-ol (81 mg) was purified by chiral SFC (Chiralpak AD-3, mobile phase: 2-propanol / carbon dioxide system containing diethylamine), and the fraction with a shorter retention time was concentrated under reduced pressure to obtain the title compound (10 mg). 1H NMR (400 MHz, CDCl3) δ 1.25-1.30 (1H, m), 1.46-1.53 ​​(1H, m), 1.66 (6H, s), 1.77 (1H, s), 2.07-2.22 (1H, m), 3.77 (3H, s), 4.02 (3H, s), 4.25-4.35 (2H, m), 5.79 (1H, s), 7.23 (1H, d, J = 8.8 Hz), 7.53 (1H, dd, J = 8.8, 1.6 Hz), 7.70 (1H, s), 7.82 (1H, s).

[0331] Example 73 2-(1-Methyl-3-{[5-methyl-1-(2-methylpropyl)-1H-pyrazol-4-yl]amino}-1H-indazol-5-yl)propan-2-ol

[0332] A) 3-methyl-1-(2-methylpropyl)-4-nitro-1H-pyrazole and 5-methyl-1-(2-methylpropyl)-4-nitro-1H-pyrazole Cesium carbonate (767 mg) was added to a mixture of 3-methyl-4-nitro-1H-pyrazole (200 mg) and DMF (5 ml), and the mixture was stirred at 25°C for 30 minutes. 1-iodo-2-methylpropane (867 mg) was added dropwise to the reaction mixture, and the mixture was stirred at 25°C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a mixture of the title compounds (333 mg). MS: [M+H] + 183.9.

[0333] B) 3-methyl-1-(2-methylpropyl)-1H-pyrazol-4-amine and 5-methyl-1-(2-methylpropyl)-1H-pyrazol-4-amine A mixture of 3-methyl-1-(2-methylpropyl)-4-nitro-1H-pyrazole and 5-methyl-1-(2-methylpropyl)-4-nitro-1H-pyrazole (253 mg), 10% palladium on carbon (26 mg) and MeOH (5 ml) was stirred under hydrogen atmosphere at 25°C for 8 hours. 10% palladium on carbon (30 mg) and MeOH (3 ml) were further added to the reaction mixture, and the mixture was stirred under hydrogen atmosphere at 25°C for 4 hours. Insoluble matter was removed by filtration, and the filtrate was added to water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain a mixture of the title compounds (163 mg). MS: [M+H] + 153.9.

[0334] C) 2-(1-methyl-3-{[5-methyl-1-(2-methylpropyl)-1H-pyrazol-4-yl]amino}-1H-indazol-5-yl)propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-5-yl)propan-2-ol (280 mg), a mixture of 3-methyl-1-(2-methylpropyl)-1H-pyrazol-4-amine and 5-methyl-1-(2-methylpropyl)-1H-pyrazol-4-amine (163 mg), NaO t A mixture of Bu (170 mg), BrettPhos Pd G3 (56 mg), BrettPhos (33 mg) and 1,4-dioxane (1.5 ml) was stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (8.3 mg). 1H NMR (400 MHz, DMSO-d6) δ 0.86 (6H, d, J = 6.4 Hz), 1.46 (6H, s), 1.96-2.16 (1H, m), 2.23 (3H, s), 3.73 (3H, s), 3.81 (2H, d, J = 7.2 Hz), 4.95 (1H, brs), 7.26 (1H, d, J = 9.2 Hz), 7.38-7.51 (1H, m), 7.60-7.68 (2H, m), 7.89 (1H, brs).

[0335] Example 74 2-{3-[(1-cyclobutyl-3-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-5-yl}propan-2-ol

[0336] A) 1-cyclobutyl-3-methyl-4-nitro-1H-pyrazole and 1-cyclobutyl-5-methyl-4-nitro-1H-pyrazole Cesium carbonate (3.85 g) was added to a mixture of 3-methyl-4-nitro-1H-pyrazole (1 g) and DMF (5 ml), and the mixture was stirred at 25°C for 30 minutes. Bromocyclobutane (3.19 g) was added dropwise to the reaction mixture, and the mixture was stirred at 25°C for 12 hours and at 50°C for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain a mixture of the title compounds (1.11 g). MS: [M+H] + 182.0.

[0337] B) 1-cyclobutyl-3-methyl-1H-pyrazol-4-amine and 1-cyclobutyl-5-methyl-1H-pyrazol-4-amine A mixture of 1-cyclobutyl-3-methyl-4-nitro-1H-pyrazole and 1-cyclobutyl-5-methyl-4-nitro-1H-pyrazole (1.11 g), 10% palladium on carbon (120 mg), concentrated hydrochloric acid (0.5 ml) and MeOH (15 ml) was stirred under a hydrogen atmosphere for 13 hours at 25° C. Insoluble matter was removed by filtration, and the mixture was concentrated under reduced pressure to obtain the title compound mixture (1.03 g) as hydrochloride salts. MS: [M+H] + 151.8.

[0338] C) 2-{3-[(1-cyclobutyl-3-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-5-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-5-yl)propan-2-ol (702 mg), a mixture of 1-cyclobutyl-3-methyl-1H-pyrazol-4-amine and 1-cyclobutyl-5-methyl-1H-pyrazol-4-amine hydrochloride (500 mg), NaO t A mixture of Bu (427 mg), BrettPhos Pd G3 (141 mg), BrettPhos (83.4 mg) and 1,4-dioxane (5 ml) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound (164 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.48 (6H, s), 1.67-1.80 (2H, m), 2.22 (3H, s), 2.14-2.34 (2H, m), 2.36-2.46 (2H, m), 3.78 (3H, s,), 4.61-4.76 (1H, m), 5.00 (1H, s), 7.28 (1H, d, J = 8.8 Hz) 7.46 (1H, dd, J = 8.8, 1.6 Hz), 7.89 (1H, s), 7.98 (1H, s), 8.03 (1H, s).

[0339] Example 75 2-{3-[(1-cyclobutyl-5-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-5-yl}propan-2-ol 2-(3-iodo-1-methyl-1H-indazol-5-yl)propan-2-ol (702 mg), a mixture of 1-cyclobutyl-3-methyl-1H-pyrazol-4-amine and 1-cyclobutyl-5-methyl-1H-pyrazol-4-amine hydrochloride (500 mg), NaO t A mixture of Bu (427 mg), BrettPhos Pd G3 (141 mg), BrettPhos (83.4 mg) and 1,4-dioxane (5 ml) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by HPLC to give the title compound (98 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.46 (6H, s), 1.71-1.86 (2H, m), 2.20 (3H, s), 2.33 (2H, s), 2.54-2.63 (2H, m), 3.72 (3H, s), 4.69-4.86 (1H, m), 4.98 (1H, s), 7.26 (1H, d, J = 8.8 Hz), 7.45 (1H, d, J = 8.8 Hz), 7.60-7.71 (2H, m), 7.89 (1H, s).

[0340] Example 76 Optically active 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol (tR1)

[0341] A) 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-iodo-1H-indazol-6-yl}propan-2-ol Cesium carbonate (6.47 g) and 2-(bromomethyl)-1,1-difluorocyclopropane (3.4 g) were added to a mixture of 2-(3-iodo-1H-indazol-6-yl)propan-2-ol (4 g) and DMF (40 ml), and the mixture was stirred at 10°C for 16 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the title compound (3.6 g). MS: [M+H] + 393.0.

[0342] B) Racemic mixture of 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-iodo-1H-indazol-6-yl}propan-2-ol (200 mg), 1,3-dimethyl-1H-pyrazol-4-amine (68 mg), NaO t A mixture of Bu (98 mg), BrettPhos Pd G3 (32 mg), BrettPhos (19 mg) and 1,4-dioxane (5 ml) was stirred at 110°C for 1 hour under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to give the title compound (51 mg). MS: [M+H] + 376.1.

[0343] C) Optically active 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol (tR1) The racemic mixture of 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol (66 mg) was purified by chiral SFC (Chiralpak AD-3, mobile phase: 2-propanol / carbon dioxide system containing diethylamine), and the fraction with a shorter retention time was concentrated under reduced pressure to obtain the title compound (31.5 mg). 1 H NMR (400 MHz, CDCl3) δ 1.22-1.35 (1H, m), 1.45-1.55 (1H, m), 1.67 (6H, s), 1.87 (1H, brs), 2.12-2.25 (1H, m), 2.29 (3H, s), 3.87 (3H, s), 4.25-4.40 (2H, m), 5.56 (1H, brs), 7.12 (1H, dd, J = 8.8, 1.6 Hz), 7.40 (1H, d, J = 8.8 Hz), 7.46 (1H, s), 7.76 (1H, s).

[0344] Example 77 Optically active 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol (tR1)

[0345] A) Racemic mixture of 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-iodo-1H-indazol-6-yl}propan-2-ol (300 mg), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (150 mg), NaO tA mixture of Bu (147 mg), BrettPhos Pd G3 (48 mg), BrettPhos (29 mg) and 1,4-dioxane (4 ml) was stirred at 110° C. for 1 h under microwave irradiation. The reaction mixture was diluted with NaO t Bu (147 mg), BrettPhos Pd G3 (48 mg), and BrettPhos (29 mg) were further added, and the mixture was stirred at 110°C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the title compound (139 mg). MS: [M+H] + 392.1.

[0346] B) Optically active 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol (tR1) The racemic mixture of 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol (139 mg) was purified by chiral SFC (Chiralpak IC-3, mobile phase: 2-propanol / carbon dioxide system containing diethylamine), and the fraction with a shorter retention time was concentrated under reduced pressure to obtain the title compound (33 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.43-1.50 (7H, m), 1.60-1.71 (1H, m), 2.11-2.23 (1H, m), 3.67 (3H, s), 3.85 (3H, s), 4.18-4.25 (1H, m), 4.27-4.35 (1H, m), 5.06 (1H, s), 7.07 (1H, d, J = 8.8 Hz), 7.45 (1H, s), 7.87 (1H, d, J = 8.8 Hz), 7.91 (1H, s), 8.03 (1H, s).

[0347] Example 78 2-{1-cyclobutyl-3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol 2-(1-Cyclobutyl-3-iodo-1H-indazol-6-yl)propan-2-ol (100 mg), 1,3-dimethyl-1H-pyrazol-4-amine (37 mg), NaO t A mixture of Bu (54 mg), BrettPhos Pd G3 (18 mg), BrettPhos (11 mg) and 1,4-dioxane (2 ml) was stirred at 110°C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, distilled with ethyl acetate) to obtain the title compound (19 mg). 1 H NMR (400 MHz, CDCl3) δ 1.64 (6H, s), 1.78-2.00 (3H, m), 2.27 (3H, s), 2.37-2.50 (2H, m), 2.67-2.88 (2H, m), 3.85 (3H, s), 4.87-5.02 (1H, m), 5.58 (1H, brs), 7.02 (1H, d, J = 8.4 Hz), 7.30 (1H, d, J = 8.8 Hz), 7.46 (1H, s), 7.71 (1H, s).

[0348] Example 79 Optically active 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-5-yl}propan-2-ol (tR2) The racemic mixture of 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-5-yl}propan-2-ol (81 mg) was purified by chiral SFC (Chiralpak AD-3, mobile phase: 2-propanol / carbon dioxide system containing diethylamine), and the fraction with a longer retention time was concentrated under reduced pressure to obtain the title compound (13 mg). 1 H NMR (400 MHz, CDCl3) δ 1.26-1.30 (1H, m), 1.47-1.53 ​​(1H, m), 1.66 (6H, s), 1.77 (1H, s), 2.04-2.22 (1H, m), 3.77 (3H, s), 4.02 (3H, s), 4.25-4.37 (2H, m), 5.78 (1H, s), 7.23 (1H, d, J = 8.8 Hz), 7.53 (1H, dd, J = 8.8, 1.2 Hz), 7.70 (1H, s), 7.82 (1H, s).

[0349] Example 80 Optically active 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol (tR2) The racemic mixture of 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(1,3-dimethyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol (66 mg) was purified by chiral SFC (Chiralpak AD-3, mobile phase: 2-propanol / carbon dioxide system containing diethylamine), and the fraction with a longer retention time was concentrated under reduced pressure to obtain the title compound (31.4 mg). 1H NMR (400 MHz, CDCl3) δ 1.22-1.35 (1H, m), 1.45-1.55 (1H, m), 1.67 (6H, s), 1.80-1.95 (1H, m), 2.12-2.23 (1H, m), 2.29 (3H, s), 3.87 (3H, s), 4.25-4.40 (2H, m), 5.56 (1H, brs), 7.12 (1H, dd, J = 8.4, 1.2 Hz), 7.40 (1H, d, J = 8.4 Hz), 7.46 (1H, s), 7.76 (1H, s).

[0350] Example 81 Optically active 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol (tR2) The racemic mixture of 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol (139 mg) was purified by chiral SFC (Chiralpak IC-3, mobile phase: 2-propanol / carbon dioxide system containing diethylamine), and the fraction with a longer retention time was concentrated under reduced pressure to obtain the title compound (36 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.43-1.50 (7H, m), 1.60-1.71 (1H, m), 2.11-2.23 (1H, m), 3.67 (3H, s), 3.85 (3H, s), 4.16-4.25 (1H, m), 4.26-4.35 (1H, m), 5.06 (1H, s), 7.07 (1H, d, J = 8.4 Hz), 7.45 (1H, s), 7.87 (1H, d, J = 8.4 Hz), 7.91 (1H, s), 8.03 (1H, s).

[0351] Example 82 2-(1-Cyclobutyl-3-{[3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl)propan-2-ol

[0352] A) Methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate To a mixture of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid (5 g) and MeOH (150 ml), concentrated sulfuric acid (1.5 ml) was added and stirred at 85° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the title compound (5.11 g). 1 H NMR (400 MHz, CDCl3) δ 3.98 (3H, s), 4.01 (3H, s), 8.16 (1H, s).

[0353] B) (1-Methyl-4-nitro-1H-pyrazol-3-yl)methanol A solution of diisobutylaluminum hydride in toluene (55.2 ml, 1 mol / l) was added to a mixture of methyl 1-methyl-4-nitro-1H-pyrazole-3-carboxylate (5.11 g) and THF (50 ml) at -20°C, and the mixture was stirred under nitrogen atmosphere for 30 minutes. The reaction mixture was added to a saturated aqueous solution of citric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and insoluble matter was filtered off. The filtrate was washed with a saturated aqueous solution of sodium potassium tartrate, and the organic layer was concentrated under reduced pressure to obtain the title compound (1.66 g). 1 H NMR (400 MHz, DMSO-d6) δ 3.87 (3H, s), 4.75 (2H, d, J = 5.6 Hz), 5.21 (1H, t, J = 5.6 Hz), 8.79 (1H, s).

[0354] C) 3-(Methoxymethyl)-1-methyl-4-nitro-1H-pyrazole To a mixture of (1-methyl-4-nitro-1H-pyrazol-3-yl)methanol (1.16 g) and THF (10 ml), 60% sodium hydride (348 mg) was added at 0°C and stirred for 30 minutes. Dimethyl sulfate (1.12 g) was added to the reaction mixture and stirred at 50°C for 5 hours. The reaction mixture was diluted with water (30 ml), then added to a 5% aqueous ammonium solution (50 ml) and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the title compound. MS: [M+H] + 171.7.

[0355] D) 3-(Methoxymethyl)-1-methyl-1H-pyrazol-4-amine A mixture of 3-(methoxymethyl)-1-methyl-4-nitro-1H-pyrazole (1.39 g), 10% palladium on carbon (139 mg) and MeOH (14 ml) was stirred under a hydrogen atmosphere for 14 hours at 25° C. Insoluble matter was removed by filtration, and the mixture was concentrated under reduced pressure to give the title compounds (1.11 g). 1 H NMR (400 MHz, DMSO-d6) δ 3.04 (2H, brs), 3.34 (3H, s), 3.72 (3H, s), 4.45 (2H, s), 6.90 (1H, s).

[0356] E) 2-(1-cyclobutyl-3-{[3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl)propan-2-ol 2-(1-cyclobutyl-3-iodo-1H-indazol-6-yl)propan-2-ol (100 mg), 3-(methoxymethyl)-1-methyl-1H-pyrazol-4-amine (48 mg), NaO tA mixture of Bu (54 mg), BrettPhos Pd G3 (18 mg), BrettPhos (11 mg) and 1,4-dioxane (3 ml) was stirred at 110°C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, distilled with a mixture of petroleum ether / ethyl acetate) to obtain the title compound (41 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.47 (6H, s), 1.77-1.88 (2H, m), 2.29-2.38 (2H, m), 2.60-2.69 (2H, m), 3.24 (3H, s), 3.82 (3H, s), 4.50 (2H, s), 5.01-5.10 (2H, m), 7.09 (1H, d, J = 9.6 Hz), 7.49 (1H, s), 7.81 (1H, d, J = 8.4 Hz), 7.98 (1H, s), 8.06 (1H, s).

[0357] Example 83 2-(1-[(2,2-difluorocyclopropyl)methyl]-3-{[3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl)propan-2-ol 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-iodo-1H-indazol-6-yl}propan-2-ol (100 mg), 3-(methoxymethyl)-1-methyl-1H-pyrazol-4-amine (43 mg), NaO tA mixture of Bu (49 mg), BrettPhos Pd G3 (16 mg), BrettPhos (10 mg) and 1,4-dioxane (2 ml) was stirred at 110°C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) and preparative TLC (silica gel, distilled with a mixture of petroleum ether / ethyl acetate) to obtain the title compound (33 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.41-1.51 (7H, m), 1.59-1.72 (1H, m), 2.14-2.26 (1H, m), 3.25 (3H, s), 3.79 (3H, s), 4.19-4.29 (1H, m), 4.30-4.39 (1H, m), 4.50 (2H, s), 5.08 (1H, s), 7.14 (1H, d, J = 8.8 Hz), 7.49 (1H, s), 7.87 (1H, d, J = 8.8 Hz), 8.00-8.12 (2H, m).

[0358] Example 84 2-[1-(cyclopropylmethyl)-3-{[3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1H-indazol-6-yl]propan-2-ol 2-[1-(cyclopropylmethyl)-3-iodo-1H-indazol-6-yl]propan-2-ol (100 mg), 3-(methoxymethyl)-1-methyl-1H-pyrazol-4-amine (48 mg), NaO tA mixture of Bu (54 mg), BrettPhos Pd G3 (18 mg), BrettPhos (11 mg) and 1,4-dioxane (2 ml) was stirred at 110°C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, distilled with a mixture of petroleum ether / ethyl acetate) to give the title compound (40 mg). 1 H NMR (400 MHz, DMSO-d6) δ 0.34-0.50 (4H, m), 1.19-1.28 (1H, m), 1.48 (6H, s), 3.24 (3H, s), 3.80 (3H, s), 4.07 (2H, d, J = 6.8 Hz), 4.50 (2H, s), 5.07 (1H, s), 7.09 (1H, dd, J = 8.8, 1.2 Hz), 7.46 (1H, s), 7.83 (1H, d, J = 8.4 Hz), 7.92 (1H, s), 8.03 (1H, s).

[0359] Example 85 2-[3-{[3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1-(propan-2-yl)-1H-indazol-6-yl]propan-2-ol

[0360] A) 2-[3-iodo-1-(propan-2-yl)-1H-indazol-6-yl]propan-2-ol Cesium carbonate (809 mg) was added to a mixture of 2-(3-iodo-1H-indazol-6-yl)propan-2-ol (500 mg), 2-iodopropane (422 mg) and DMF (5 ml), and the mixture was stirred at 10-15°C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate) to obtain the title compound (287 mg). MS: [M+H]+ 344.9.

[0361] B) 2-[3-{[3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1-(propan-2-yl)-1H-indazol-6-yl]propan-2-ol 2-[3-iodo-1-(propan-2-yl)-1H-indazol-6-yl]propan-2-ol (100 mg), 3-(methoxymethyl)-1-methyl-1H-pyrazol-4-amine (49 mg), NaO t A mixture of Bu (56 mg), BrettPhos Pd G3 (18 mg), BrettPhos (11 mg) and 1,4-dioxane (2 ml) was stirred at 110°C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, distilled with a mixture of petroleum ether / ethyl acetate) to give the title compound (65 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.43 (6H, d, J = 6.4 Hz), 1.48 (6H, s), 3.24 (3H, s), 3.81 (3H, s), 4.50 (2H, s), 4.70-4.81 (1H, m), 5.07 (1H, s), 7.07 (1H, d, J = 8.4 Hz), 7.47 (1H, s), 7.81 (1H, d, J = 8.4 Hz) 7.93 (1H, s), 8.01 (1H, s).

[0362] Example 86 2-[3-{[3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1-(propan-2-yl)-1H-indazol-5-yl]propan-2-ol 2-[3-iodo-1-(propan-2-yl)-1H-indazol-5-yl]propan-2-ol (100 mg), 3-(methoxymethyl)-1-methyl-1H-pyrazol-4-amine (49 mg), NaOt A mixture of Bu (56 mg), BrettPhos Pd G3 (18 mg), BrettPhos (11 mg) and 1,4-dioxane (2 ml) was stirred at 110°C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (42 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.42 (6H, d, J = 6.8 Hz), 1.49 (6H, s), 3.24 (3H, s), 3.81 (3H, s), 4.53 (2H, s), 4.67-4.80 (1H, m), 5.00 (1H, s), 7.34 (1H, d, J = 8.8 Hz), 7.44 (1H, dd, J = 8.8, 1.6 Hz), 7.98-8.09 (3H, m).

[0363] Example 87 2-[1-(cyclopropylmethyl)-3-{[3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1H-indazol-5-yl]propan-2-ol 2-[1-(cyclopropylmethyl)-3-iodo-1H-indazol-5-yl]propan-2-ol (100 mg), 3-(methoxymethyl)-1-methyl-1H-pyrazol-4-amine (48 mg), NaO t A mixture of Bu (54 mg), BrettPhos Pd G3 (18 mg), BrettPhos (11 mg) and 1,4-dioxane (2 ml) was stirred at 110°C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, distilled with ethyl acetate) to obtain the title compound (42 mg). 1H NMR (400 MHz, DMSO-d6) δ 0.33-0.39 (2H, m), 0.41-0.48 (2H, m), 1.19-1.25 (1H, m), 1.49 (6H, s), 3.24 (3H, s), 3.80 (3H, s), 4.06 (2H, d, J = 6.8 Hz), 4.52 (2H, s), 5.01 (1H, s), 7.35 (1H, d, J = 9.2 Hz), 7.42-7.47 (1H, m), 7.98-8.09 (3H, m).

[0364] Example 88 2-(1-Cyclobutyl-3-{[3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1H-indazol-5-yl)propan-2-ol 2-(1-cyclobutyl-3-iodo-1H-indazol-5-yl)propan-2-ol (100 mg), 3-(methoxymethyl)-1-methyl-1H-pyrazol-4-amine (48 mg), NaO t A mixture of Bu (54 mg), BrettPhos Pd G3 (18 mg), BrettPhos (11 mg) and 1,4-dioxane (2 ml) was stirred at 110°C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, distilled with ethyl acetate) to obtain the title compound (49 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.48 (6H, s), 1.71-1.91 (2H, m), 2.27-2.41 (2H, m), 2.55-2.71 (2H, m), 3.24 (3H, s), 3.83 (3H, s), 4.54 (2H, s), 4.93-5.10 (2H, m), 7.35 (1H, d, J = 8.8 Hz), 7.44 (1H, dd, J = 8.8, 1.2 Hz), 8.02-8.14 (3H, m).

[0365] Example 89 2-(1-[(2,2-difluorocyclopropyl)methyl]-3-{[3-(methoxymethyl)-1-methyl-1H-pyrazol-4-yl]amino}-1H-indazol-5-yl)propan-2-ol 2-{1-[(2,2-difluorocyclopropyl)methyl]-3-iodo-1H-indazol-5-yl}propan-2-ol (100 mg), 3-(methoxymethyl)-1-methyl-1H-pyrazol-4-amine (43 mg), NaO t A mixture of Bu (49 mg), BrettPhos Pd G3 (16 mg), BrettPhos (10 mg) and 1,4-dioxane (2 ml) was stirred at 110°C for 1 hour under microwave irradiation. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by HPLC to give the title compound (53 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.46-1.52 (7H, s), 1.59-1.69 (1H, m), 2.10-2.25 (1H, m), 3.24 (3H, s), 3.79 (3H, s), 4.19-4.28 (1H, m), 4.29-4.40 (1H, m), 4.53 (2H, s), 5.02 (1H, s), 7.36 (1H, d, J = 8.8 Hz), 7.48 (1H, dd, J = 8.8, 1.6 Hz), 8.06-8.09 (3H, m).

[0366] The example compounds are shown in the following table. MS in the table indicates the measured value. The compounds of Examples 1 to 89 in the following table were produced according to the methods shown in the above examples or methods similar thereto.

[0367] [Table 1-1]

[0368]

Table 1-2

[0369]

Table 1-3

[0370]

Table 1-4

[0371]

Table 1-5

[0372]

Table 1-6

[0373]

Table 1-7

[0374]

Table 1-8

[0375]

Table 1-9

[0376]

Table 1-10

[0377]

Table 1-11

[0378]

Table 1-12

[0379] [Table 1-13]

[0380] [Table 1-14]

[0381] [Table 1-15]

[0382] [Table 1-16]

[0383] [Table 1-17]

[0384] [Table 1-18]

[0385] Test Example 1 ALS is a typical motor neuron disease caused by motor neuron degeneration, of which 5-10% are hereditary familial. Among the iPS cell clones described in Non-Patent Document 11, the effect of the compound according to the present disclosure was examined using the clone ALS1 established from a familial ALS patient with the SOD1 gene mutation L144FVX. Specifically, the degeneration inhibitory effect on a familial ALS cell model was analyzed using a stable line of ALS1 (hereinafter simply referred to as ALS1 cells) into which tetracycline-inducible Lhx3, Ngn2, and Isl1 genes were introduced. ALS1 cells are an ALS cell model that rapidly differentiates (within about 7 days) into motor neurons by adding tetracycline or its derivatives to the medium, and spontaneously causes degeneration after differentiation (Non-Patent Document 11). Thus, in ALS1 cells, significant neurodegeneration and cell death are observed from about 7 to 14 days after induction of differentiation into motor neurons (i.e., induction of expression of the Lhx3, Ngn2, and Isl1 genes) (Non-Patent Document 11). ALS1 cells were cultured on feeder cells (mitomycin-treated SNL cells) in iPS cell maintenance medium consisting of Primate ES Cell medium (ReproCell, RCHEMD001A), 4 ng / ml hbFGF (Wako, 060-04543), 50 μg / ml G418 (Nacalai, 09380-86), and Penicillin-Streptomycin (Thermo Fisher Scientific, 15140-122). The method for seeding ALS1 cells onto the assay plate is as follows. DMEM / F-12 (1:1) (Thermo Fisher Scientific, 11330-057), N2 supplement (Thermo Fisher Scientific, 17502-048), Penicillin-Streptomycin (Thermo Fisher Scientific, 15140-122), 10 ng / ml recombinant human BDNF (PeproTech, 450-02), 10 ng / ml recombinant human GDNF (PeproTech, 450-10), 10 ng / ml recombinant human NT-3 (PeproTech, 450-03), 1 μM Retinoic acid (Sigma, R2625), 1 μg / ml Doxycycline (Clontech, 631311), 1 μM SAG (Enzo life sciences, ALX-270-426-M001), 10 μM Matrigel was diluted 20-fold using an assay medium containing Y-27632 (Wako, 253-00513), and then coated onto a 384-well plate. Next, ALS1 cells were dispersed and suspended in assay medium at 1x10 cells per well. 4 The cells were seeded onto a Matrigel-coated assay plate.

[0386] The method for counting motor neurons differentiated from ALS1 cells was as follows. ALS1 cells were seeded on an assay plate according to the method described above. After 4 days from seeding, assay medium not containing Y-27632 was added and the cells were cultured until 6 days after seeding. They were then fixed with PFA (Wako, 163-20145) and immunostained with βIII-tubulin. After cell fixation, membrane permeabilization, and blocking, a primary antibody solution containing anti-βIII-tubulin antibody (R&D, MAB1195) diluted 10,000 times was added and the cells were left to stand at room temperature for 3.5 hours. After washing and removing the primary antibody, a secondary antibody solution containing Alexa Fluor 488 goat anti-mouse IgG (H+L) (Molecular Probes, A11029) diluted 1,000 times in the same solution as the primary antibody was added and the cells were left to stand at room temperature for 1 hour. Finally, the secondary antibody solution was washed and removed, and D-PBS(-) was dispensed. Most of the βIII-tubulin-positive cells obtained by this method (i.e., differentiation induction by inducing the expression of Lhx3, Ngn2, and Isl1 genes) are motor neurons. The number of βIII-tubulin positive cells (i.e., the number of surviving motor neuron cells) per well was counted by measuring the above plates using a high content analyzer. The high content analyzer used was PerkinElmer's Opera Phenix.

[0387] The method for detecting the activity of a test compound is as follows. From 6 to 14 days after the start of culture, cells were cultured in assay medium (not containing retinoic acid, doxycycline, SAG, or Y-27632) containing a given concentration of the test compound, and the cells 6 and 14 days after the start of culture were immunostained according to the method described above, and the number of surviving motor neurons (number of βIII-tubulin-positive cells) was counted. In motor neurons differentiated from ALS1 cells, most of the motor neurons that began to degenerate have significantly atrophied or fragmented cell bodies by 14 days, so the number of surviving motor neurons can be evaluated by counting the number of cells (more specifically, the number of cell bodies) that were βIII-tubulin-positive after 14 days. As a negative control, cells cultured in assay medium containing DMSO instead of the test substance were used. The degree to which the test compound inhibited the decrease in the number of motor neurons in the negative control was defined as the motor neuron degeneration inhibiting activity of the test compound, which was calculated according to the following formula. Motor neuron degeneration inhibitory activity of the test compound = ((XC) / (TC))x100 X: Number of motor neurons in the test compound group 14 days after the start of culture, C: Number of motor neurons in the DMSO group 14 days after the start of culture, T: Number of motor neurons 6 days after the start of culture The test compounds were added to the assay at six concentrations: 0.03, 0.1, 0.3, 1, 3, and 10 μmol / l. Table 2 below shows the concentration ranges of the test compounds that showed 40% or more activity.

[0388] [Table 2-1]

[0389] [Table 2-2]

[0390] [Table 2-3]

[0391] Test Example 2 The effects of the compounds disclosed herein were evaluated according to the literature (MG Cotticelli et al., J Pharmacol Exp Ther 2019, 369, 47-54.). Skin fibroblasts derived from FA patients (Coriell Institute for Medical Research, GM4078) were cultured in a culture medium consisting of DMEM (Thermo Fisher Scientific, 11995-065), 10% Fetal Bovine Serum (Thermo Fisher Scientific, 26140-087), 1% GlutaMAX supplement (Thermo Fisher Scientific, 35050-061), and 1% Penicillin-Streptomycin Solution (FUJIFILM Wako Pure Chemical Corporation, 168-23191). For the assay, the cells were seeded in a 384-well plate with the same culture medium at 1,500 cells per well, and the test compound and RSL3 at 3 μmol / l (final concentration) were added the day after seeding. The test compound was added to the assay at four concentrations: 0.01, 0.1, 1, and 10 μmol / l, and DMSO was added as a negative control for the test compound and RSL3. 24 hours after the addition of RSL3 / test compound, the cells were lysed by adding CellTiter-Glo Luminescent Cell Viability Assay solution (Promega, G7573), and ATP, an indicator of cell viability, was measured by detecting chemiluminescence with a plate reader. The degree to which the test compound inhibited the decrease in ATP in the presence of RSL3 but without the addition of test compound was defined as the RSL3-induced cell death inhibitory activity of the test compound, and was calculated according to the following formula. RSL3-induced cell death inhibitory activity of the test compound = ((XC) / (TC))x100 X: ATP in the RSL3-added / test compound-added group, C: ATP in the RSL3-added / test compound-free group, T: ATP in the RSL3-free / test compound-free group Table 3 shows the activity of suppressing RSL3-induced cell death at each concentration.

[0392] [Table 3]

[0393] Formulation examples A medicine containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation. 1. Capsules (1) Compound obtained in Example 1 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule: 180mg The total amount of (1), (2), and (3) above is mixed with 5 mg of (4), granulated, to which the remaining 5 mg of (4) is added, and the whole is then enclosed in a gelatin capsule.

[0394] 2. Tablets (1) Compound obtained in Example 1 10 mg (2) Lactose 35 mg (3) Cornstarch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230mg Mix the total amount of (1), (2), and (3) with 20 mg of (4) and 2.5 mg of (5), granulate, add the remaining 10 mg of (4) and 2.5 mg of (5) to the granules, and press-form into tablets. [Industrial Applicability]

[0395] According to the present invention, it is possible to provide a compound which has an excellent inhibitory effect on cell degeneration, in particular an inhibitory effect on motor neuron degeneration, and is useful as an agent for preventing or treating motor neuron diseases (e.g., amyotrophic lateral sclerosis, progressive bulbar palsy, progressive muscular atrophy, primary lateral sclerosis, progressive pseudobulbar palsy, spinal muscular atrophy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Friedreich's ataxia) and the like.

[0396] This application is based on Japanese Patent Application No. 2019-191533 filed on October 18, 2019, the contents of which are incorporated in their entirety herein.

Claims

1. formula 【Chemistry 1】 [During the ceremony, R 1 (1) a hydrogen atom, (2) a C 1-6 alkyl group optionally substituted by 1 to 3 C 3-6 cycloalkyl groups, or (3) a C 3-6 cycloalkyl group; R 2 (1)(a) a C 1-6 alkoxy group, and (b) a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups a C 6-10 aryl group optionally substituted by 1 to 3 substituents selected from (2)(a) a C 1-6 alkyl group optionally substituted by 1 to 3 C 1-6 alkoxy groups, and (b) C1-6 alkoxy group a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from R 3 is unsubstituted C 1-6 Alkyl groups; R 4 is unsubstituted C 1-6 Alkyl groups; Ring A is a benzene ring having no substituent other than the formula: -C(OH)R 3 R 4 (wherein R 3 and R 4 are as defined above); Showing A compound represented by the formula:

2. 2-{3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1-methyl-1H-indazol-5-yl}propan-2-ol or a salt thereof.

3. 2-{1-(cyclopropylmethyl)-3-[(3-methoxy-1-methyl-1H-pyrazol-4-yl)amino]-1H-indazol-6-yl}propan-2-ol or a salt thereof.

4. 2-{3-[2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)anilino]-1H-indazol-6-yl}propan-2-ol or a salt thereof.

5. A medicine comprising the compound according to claim 1 or a salt thereof.

6. The pharmaceutical according to claim 5, which is a motor neuron degeneration inhibitor.

7. The pharmaceutical agent according to claim 5, which is a preventive or therapeutic agent for a motor neuron disease.

8. The pharmaceutical composition according to claim 7, wherein the motor neuron disease is amyotrophic lateral sclerosis or Friedreich's ataxia.

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