HK1101080A

HK1101080A - Novel aminoindazole derivatives as medicines and pharmaceutical compositions containing same

Info

Publication number: HK1101080A
Application number: HK07108742.7A
Authority: HK
Inventors: Dominique Lesuisse; Gilles Dutruc-Rosset; Franck Halley; Diddier BABIN; Thomas Rooney
Original assignee: Aventis Pharma S. A.
Priority date: 2002-09-05
Filing date: 2007-08-13
Publication date: 2007-10-05

Description

Novel aminoindazole derivatives as medicaments and pharmaceutical compositions containing them

This application is a divisional application of PCT application PCT/FR03/002633 entitled "novel aminoindazole derivatives as a drug and pharmaceutical compositions containing them", filed on 3/9/2003, on a date of 2005-3/1, with application number 03820729.X, entering the national phase of china.

Technical Field

The present invention relates to the use of derivatives of formula (I) or pharmaceutically acceptable salts thereof, as kinase inhibitors:

disclosure of Invention

The invention relates to the use of aminoindazole derivatives of formula (I) and the pharmaceutically acceptable salts thereof for preparing pharmaceutical compositions, these pharmaceutical compositions are useful for the prevention and treatment of diseases caused by abnormal kinase activity, such as, for example, those involved in neurodegenerative diseases, alzheimer's disease, parkinson's disease, frontotemporal dementia, corticobasal degeneration, Pick's disease, cerebrovascular accident, cranial and spinal cord injury, as well as peripheral neuropathy, obesity, metabolic diseases, type II diabetes, essential hypertension, atherosclerotic cardiovascular diseases, polycystic ovary syndrome, syndrome X, immunodeficiency and cancer, and also pharmaceutical compositions containing these and their pharmaceutically acceptable salts.

The invention relates to derivatives of formula (I) wherein:

r3 is (1-6C) alkyl, aryl (1-6C) alkyl, heteroaryl (1-6C) alkyl, aryl or heteroaryl fused with (1-10C) cycloalkyl, heterocyclyl, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, CSNR1R2, COOR1, SO₂R1, C (═ NH) R1 or C (═ NH) NR 1; these groups are optionally substituted with one or more substituents selected from: halogen, CN, NO₂、NH₂、OH、OR1、COOH、C(O)OR1、-O-C(O)R1、NR1R2、NHC(O)R1、C(O)NR1R2、SR1、S(O)R1、SO₂R1、NHSO₂R1、SO₂NR1R2、C(S)NR1R2、NHC(S)R1、-O-SO₂R1、-SO₂-O-R1, aryl, heteroaryl, heterocyclyl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, and (1-6C) alkyl;

r5 and R6 are independently selected from the following groups: halogen, CN, NO₂、NH₂、OH、COOH、C(O)OR8、-O-C(O)R8、NR8R9、NHC(O)R8、C(O)NR8R9、NHC(S)R8、C(S)NR8R9、SR8、S(O)R8、SO₂R8、NHSO₂R8、SO₂NR8R9、-O-SO₂R8、-SO₂-O-R8, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl, (1-6C) alkoxy, aryl (1-6C) alkyl, heteroaryl (1-6C) alkyl, heterocyclyl, cycloalkyl, alkenyl, alkynyl, adamantyl, and polycycloalkyl; these groups are optionally substituted with one or more substituents selected from: halogen, CN, NO₂、NH₂、OH、OR10、COOH、C(O)OR10、-O-C(O)R10、NR10R11、NHC(O)R10、C(O)NR10R11、NHC(S)R10、C(S)NR10R11、SR10、S(O)R10、SO₂R10、NHSO₂R10、SO₂NR10R11、-O-SO₂R10、-SO₂-O-R10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy and (1-6C) alkyl;

r1, R2, R8, R9, R10, R11 are independently from each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl or heteroaryl, which are themselves optionally substituted by one or more substituents selected from: halogen, (1-6C) alkyl,(1-6C) alkoxy, CN, NO₂、NH₂OH, COOH, COOalkyl, CONH₂Formyl, trifluoromethyl and trifluoromethoxy;

r1 and R2 or R8 and R9 or R10 and R11 may form a 5-or 6-membered ring with or without heteroatoms, such as O, S, N;

when R3 is a 6-membered nitrogen-containing heteroaryl or thiazolyl or imidazolyl or oxazolyl, then at least one of R5, R6 is aryl, which is optionally substituted with one or more substituents selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、OR10、COOH、C(O)OR10、-O-C(O)R10、NR10R11、NHC(O)R10、C(O)NR10R11、NHC(S)R10、C(S)NR10R11、SR10、S(O)R10、SO₂R10、NHSO₂R10、SO₂NR10R11、-O-SO₂R10、-SO₂-O-R10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy and (1-6C) alkyl;

their racemates, enantiomers, diastereomers and mixtures thereof, their tautomers and their pharmaceutically acceptable salts.

More particularly, the invention relates to derivatives of formula (I) wherein:

r3 is (1-6C) alkyl, aryl (1-6C) alkyl, heteroaryl (1-6C) alkyl, aryl or heteroaryl fused with (1-10C) cycloalkyl, heterocyclyl, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO₂R1 or C (═ NH) NR 1; these groups are optionally substituted with one or more substituents selected from: halogen, CN, NO₂、NH₂、OH、OR1、COOH、C(O)OR1、-O-C(O)R1、NR1R2、NHC(O)R1、C(O)NR1R2、SR1、S(O)R1、SO₂R1、NHSO₂R1、SO₂NR1R2、C(S)NR1R2、NHC(S)R1、-O-SO₂R1、-SO₂-O-R1, aryl, heteroaryl, formyl, oxo, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, and (1-6C) alkyl;

r5 is aryl optionally substituted with one or more substituents selected from: halogen, CN, NO₂、NH₂、OH、OR10、COOH、C(O)OR10、-O-C(O)R10、NR10R11、NHC(O)R10、C(O)NR10R11、NHC(S)R10、C(S)NR10R11、SR10、S(O)R10、SO₂R10、NHSO₂R10、SO₂NR10R11、-O-SO₂R10、-SO₂-O-R10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy and (1-6C) alkyl;

r6 is halogen, methyl, cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethenyl, ethynyl, trifluoromethoxy, NO₂、NH₂Or NMe₂；

R1, R2 are independently from each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl or heteroaryl, which are themselves optionally substituted by one or more substituents selected from: halogen, (1-6C) alkyl, (1-6C) alkoxy, CN, NO₂、NH₂OH, COOH, COOalkyl, CONH₂Formyl, oxo, trifluoromethyl, trifluoromethoxy;

r1 and R2 may form a 5-or 6-membered ring with or without heteroatoms such as O, S, N;

Preferably, the present invention relates to derivatives of formula (I) wherein:

r5 is a phenyl group optionally substituted with one or more substituents selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、OR10、COOH、C(O)OR10、-O-C(O)R10、NR10R11、NHC(O)R10、C(O)NR10R11、NHC(S)R10、C(S)NR10R11、SR10、S(O)R10、SO₂R10、NHSO₂R10、SO₂NR10R11、-O-SO₂R10、-SO₂-O-R10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy and (1-6C) alkyl;

R1, R2 are independently from each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl or heteroaryl, which are themselves optionally substituted by one or more substituents selected from: halogen, (1-6C) alkyl, (1-6C) alkoxy, CN, NO₂、NH₂OH, COOH, COOalkyl, CONH₂Formyl, oxo, trifluoromethyl and trifluoromethoxy;

r1 and R2 may form a5 or 6 membered ring with or without heteroatoms, for example O, S, N;

r3 is (1-6C) alkyl, aryl (1-6C) alkyl, heteroaryl (1-6C) alkyl, or (1-10C)Cycloalkyl-fused aryl or heteroaryl, heterocyclyl, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, COOR1, SO₂R1, C (═ NH) R1 or C (═ NH) NR 1; these groups are optionally substituted with one or more substituents selected from: halogen, CN, NO₂、NH₂、OH、OR1、COOH、C(O)OR1、-O-C(O)R1、NR1R2、NHC(O)R1、C(O)NR1R2、SR1、S(O)R1、SO₂R1、NHSO₂R1、SO₂NR1R2、C(S)NR1R2、NHC(S)R1、-O-SO₂R1、-SO₂-O-R1, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy and (1-6C) alkyl;

r5 is phenyl;

r6 is chloro;

r1, R2 are independently from each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl or heteroaryl, which are themselves optionally substituted by one or more substituents selected from: halogen, (1-6C) alkyl, (1-6C) alkoxy, CN, NO₂、NH₂OH, COOH, COOalkyl, CONH₂Formyl, trifluoromethyl and trifluoromethoxy;

their isomers, mixtures, racemates, enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts.

In the foregoing and following definitions, (1-6C) alkyl contains 1-6 carbon atoms and is straight or branched; said alkenyl group containing 2 to 6 carbon atoms and 1 to 3 conjugated or unconjugated double bonds in a straight or branched chain; alkynyl contains 2-6 carbon atoms and 1-3 conjugated or unconjugated triple bonds in a straight or branched chain; aryl is selected from phenyl, naphthyl and indenyl; heteroaryl has 3 to 10 atoms in the ring, optionally containing one or more heteroatoms selected from oxygen, sulphur and nitrogen, in particular thiazolyl, thienyl, pyrrolyl, pyridyl, furyl, imidazolyl, oxazolyl, pyrazinyl, tetrazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl, isoxazolyl, triazolyl, pyrazolyl indolyl; halogen is chlorine, iodine, fluorine or bromine; the polycycloalkyl is selected from adamantyl, quinuclidinyl, camphanyl, norbornanyl, camphene and norbornenyl; heteroaryl fused with (1-10C) cycloalkyl is selected from indanyl, isochromanyl, chromanyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, 1, 2, 3, 4-tetrahydroquinolinyl; the heterocyclic group contains 1 to 2 hetero atoms selected from oxygen, sulfur and nitrogen, and specific examples thereof are a piperidyl group, a morpholinyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group (pyrazolidinyl group), an isothiazolidinyl group, a thiazolidinyl group, an isoxazolidinyl group, an oxazolidinyl group, a piperazinyl group, an azetidinyl group, a 2-piperidonyl group, a 3-piperidonyl group, a 4-piperidonyl group, a 2-pyrrolidone group and a 3-pyrrolidone group.

These compounds of formula (I) have one or more asymmetric carbon atoms and may thus be in the form of isomers, racemates, enantiomers and diastereomers; they and their mixtures also form part of the invention.

Among the compounds of formula (I) which can be used according to the invention, the following compounds may be mentioned:

n- (bicyclo [2, 2, 1] hept-5-en-2-ylmethyl) -6-chloro-5-phenyl-1H-indazol-3-amine;

6-chloro-N- (3, 3-dimethylbutyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N- (3-phenylpropyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N- (cyclopropylmethyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N- (cyclopentylmethyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N- [3- (methylthio) propyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-N- (phenylethyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N- (cyclohexylmethyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N-propyl-5-phenyl-1H-indazol-3-amine;

6-chloro-N- (2, 2, 3, 3, 4, 4, 4-heptafluorobutyl) -5-phenyl-1H-indazol-3-amine hydrate;

6-chloro-N- (4, 4, 4-trifluorobutyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N- [ (4-methoxyphenyl) methyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-N- (phenylmethyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N- [ (4-cyanophenyl) methyl ] -5-phenyl-1H-indazol-3-amine;

n- [ (4-chlorophenyl) methyl ] -6-chloro-5-phenyl-1H-indazol-3-amine;

6-chloro-N- [ (3-methoxyphenyl) methyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-N- [ [4- (trifluoromethoxy) phenyl ] methyl ] -5-phenyl-1H-indazol-3-amine;

n- [4- [ [ [ 6-chloro-5-phenyl-1H-indazol-3-yl ] amino ] methyl ] phenyl ] -acetamide;

6-chloro-N- [ (3, 5-dichlorophenyl) methyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N- [ [4- (trifluoromethyl) phenyl ] methyl ] -1H-indazol-3-amine;

6-chloro-N- [ (4-fluorophenyl) methyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-N- [3- (4-methylphenoxy) phenylmethyl ] -5-phenyl-1H-indazol-3-amine;

n- (2, 2, 3, 3, 4, 4, 4-heptafluorobutyl ] -6-chloro-5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N- [ [3, 5-bis (trifluoromethyl) phenyl ] methyl ] -1H-indazol-3-amine;

6-chloro-5-phenyl-N- [ [3- (trifluoromethyl) phenyl ] methyl ] -1H-indazol-3-amine;

6-chloro-N- [ (6-methoxy-2-naphthyl) methyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-N- [ (pentafluorophenyl) methyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-N- [ [4- (methylthio) phenyl ] methyl ] -5-phenyl-1H-indazol-3-amine;

n- [ (4-chloro-3-fluorophenyl) methyl ] -6-chloro-5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N- (3, 3, 3-trifluoropropyl) -1H-indazol-3-amine;

6-chloro-5-phenyl-N- (3-thienylmethyl) -1H-indazol-3-amine;

n- ([1, 1' -biphenyl ] -4-ylmethyl) -6-chloro-5-phenyl-1H-indazol-3-amine;

6-chloro-N- [ [4- (dimethylamino) phenyl ] -5-phenyl-1H-indazol-3-amine;

n- ([2, 2' -bithiophene) ] -5-ylmethyl) -6-chloro-5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N- [ [1- (phenylmethyl) -1H-imidazol-2-yl ] methyl ] -1H-indazol-3-amine;

6-chloro-N- [ [ 1-methyl-1H-imidazol-2-yl ] methyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-N- [ (1-methyl-1H-indol-3-yl) methyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-N- [ (5-methyl-2-furanyl) methyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N- (1H-pyrrol-2-ylmethyl) -1H-indazol-3-amine;

6-chloro-5-phenyl-N- (1H-imidazol-2-ylmethyl) -1H-indazol-3-amine;

6-chloro-5-phenyl-N- (1H-imidazol-4-ylmethyl) -1H-indazol-3-amine;

6-chloro-5-phenyl-N- (1H-pyrazol-3-ylmethyl) -1H-indazol-3-amine;

6-chloro-N- [ [ 2-methyl-1H-imidazol-4-yl ] methyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-N- [ [3, 5-dimethyl-1-phenyl-1H-pyrazol-4-yl ] methyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N- [ [ 2-phenyl-1H-imidazol-4-yl ] methyl ] -1H-indazol-3-amine;

6-chloro-N- [ [5- (4-chlorophenyl) -2-furyl ] methyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N- [ (1-methyl-1H-pyrrol-2-yl) methyl ] -1H-indazol-3-amine;

4- [5- [ [ [ 6-chloro-5-phenyl-1H-indazol-3-yl ] amino ] methyl ] -2-furanyl ] -benzenesulfonamide;

6-chloro-5-phenyl-N- (3-thienylmethyl) -1H-indazol-3-amine;

2- [ [ [ 6-chloro-5-phenyl-1H-indazol-3-yl ] amino ] methyl ] -5- (methylthio) -1H-imidazole-4-carboxylic acid ethyl ester;

6-chloro-5-phenyl-N- [ [5- [4- (trifluoromethyl) phenyl ] -2-furanyl ] methyl ] -1H-indazol-3-amine;

6-chloro-5-phenyl-N- [2- (1-piperidinyl) ethyl ] -1H-indazol-3-amine;

6-chloro-N- [2- (4-morpholinyl) ethyl ] -5-phenyl-1H-indazol-3-amine;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' - (3, 5-dichlorophenyl) -urea;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' -4- (2-propenyl) -urea;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' - (phenylmethyl) -urea;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' -4- (phenoxyphenyl) -urea;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' - [ (4-methoxyphenyl) methyl ] -urea;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' - [4- (trifluoromethyl) phenyl ] -urea;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' - (4-methoxyphenyl) -urea;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' -cyclohexyl-urea;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' -propyl-urea;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' - (4-chlorophenyl) -urea;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' - (4-fluorophenyl) -urea;

n- [ 6-chloro-5-phenyl-1H-indazol-3-yl ] -N' -tricyclo [3.3.1.13, 7] decan-1-yl-urea;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' - (4-methylphenyl) -urea;

n- [ 6-chloro-5-phenyl-1H-indazol-3-yl ] -4-methyl-benzenesulfonamide;

n- [ 6-chloro-5-phenyl-1H-indazol-3-yl ] -methanesulfonamide;

2-propanesulfonamide, N- [ 6-chloro-5-phenyl-1H-indazol-3-yl ] -amide;

2, 2, 2-trifluoro-ethanesulfonamide, [ 6-chloro-5-phenyl-1H-indazol-3-yl ] -N- [2- (trifluoromethyl) -l-propyl ] -sulfonamide;

2-thiophenesulfonamide, N- [ 6-chloro-5-phenyl-1H-indazol-3-yl ] -amide;

n- [ 6-chloro-5-phenyl-1H-indazol-3-yl ] -benzenesulfonamide;

4- (trifluoromethyl) -N- [ 6-chloro-5-phenyl-1H-indazol-3-yl ] -benzenesulfonamide;

n- [ 6-chloro-5-phenyl-1H-indazol-3-yl ] -5- (3-isoxazolyl) -2-thiophenesulfonamide;

n- [ 6-chloro-5-phenyl-1H-indazol-3-yl ] -4-fluoro-benzenesulfonamide;

4-methoxy-N- [ 6-chloro-5-phenyl-1H-indazol-3-yl ] -benzenesulfonamide;

n- [ 6-chloro-5-phenyl-1H-indazol-3-yl ] -phenylmethanesulfonamide;

1-methyl-1H-indazol-3-yl-6-chloro-5-phenyl-1H-imidazole-4-sulfonamide;

n [ 6-chloro-5-phenyl-1H-indazol-3-yl ] -4- (1, 1-dimethylethyl) -benzenesulfonamide;

n- [4- [ [ (6-chloro-5-phenyl-1H-indazol-3-yl) amino ] sulfonyl ] phenyl ] -acetamide;

4-methyl-N- [ 6-chloro-5-phenyl-1H-indazol-3-yl ] -benzenesulfonamide;

6-chloro-N- (pentafluorophenyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N- (3, 4-difluorophenyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-5-phenyl-N- (2, 3, 5, 6-tetrafluorophenyl) -1H-indazol-3-amine;

6-chloro-5-phenyl-N- (2, 4, 6-trifluorophenyl) -1H-indazol-3-amine;

6-chloro-N- (4-fluorophenyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N- [3- (trifluoromethyl) phenyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-N- [4- (trifluoromethyl) phenyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-N- [ 3-fluoro-5- (trifluoromethyl) phenyl ] -5-phenyl-1H-indazol-3-amine;

6-chloro-N- (4-nitrophenyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N- (3-nitrophenyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N- (3-methoxyphenyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N- (4-methoxyphenyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N, 5-diphenyl-1H-indazol-3-amine;

6-chloro-N- (1-pyridyl) -5-phenyl-1H-indazol-3-amine;

6-chloro-N- (2-pyridyl) -5-phenyl-1H-indazol-3-amine;

their isomers, mixtures, racemates, enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts thereof,

more particularly the following compounds:

N-butyl-6-chloro-5-phenyl-1H-indazol-3-amine;

3- (6-chloro-5-phenyl-1H-indazol-3-yl) -thiophene-2-carbonitrile;

(6-chloro-5-phenyl-1H-indazol-3-yl) -pyridin-2-yl-amine;

(6-chloro-5-phenyl-1H-indazol-3-yl) - (5-nitro-pyridin-2-yl) -amine;

(6-chloro-5-phenyl-1H-indazol-3-yl) - (6-methoxy-pyridin-2-yl) -amine;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' -phenyl-urea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (4-ethoxy-phenyl) -urea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (3, 4-dichloro-phenyl) -urea;

3- [3- (6-chloro-5-phenyl-1H-indazol-3-yl) -ureido ] -propionic acid methyl ester;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (4-dimethylamino-phenyl) -urea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3-isopropyl-urea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3-cyclohexyl-urea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (3-fluoromethyl-phenyl) -urea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (2-thiophen-2-yl-ethyl) -urea;

1-benzo [1, 3] dioxol-5-yl-3- (6-chloro-5-phenyl-1H-indazol-3-yl) -urea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (3, 5-dimethyl-isoxazol-4-yl) -urea;

1-benzyl-3- (6-chloro-5-phenyl-1H-indazol-3-yl) -urea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3-phenethyl-thiourea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- [3- (4-methyl-piperazin-1-yl) -propyl ] -urea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (3-imidazol-1-yl-propyl) -urea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (2-hydroxy-ethyl) -urea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- [3- (4-methylpiperazin-1-yl) -propyl ] -urea;

pyrrolidine-1-carboxylic acid (6-chloro-5-phenyl-1H-indazol-3-yl) -amide;

(6-chloro-5-phenyl-1H-indazol-3-yl) -carbamic acid methyl ester;

(6-chloro-5-phenyl-1H-indazol-3-yl) -urea;

(6-chloro-5-phenyl-1H-indazol-3-yl) -carbamic acid benzyl ester;

(6-chloro-5-phenyl-1H-indazol-3-yl) -allyl carbamate;

(6-chloro-5-phenyl-1H-indazol-3-yl) -carbamic acid isobutyl ester;

piperidine-1-carboxylic acid (6-chloro-5-phenyl-1H-indazol-3-yl) -amide;

1- (3-azetidin-1-yl-propyl) -3- (6-chloro-5-phenyl-1H-indazol-3-yl) -urea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (3-chloro-propyl) -urea;

1- (6, 7-difluoro-5-phenyl-1H-indazol-3-yl) -3- (3-imidazol-1-yl-propyl) -urea;

1- (3-amino-propyl) -3- (6-chloro-5-phenyl-1H-indazol-3-yl) -urea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- [4- (4-pyridin-3-yl-imidazol-1-yl) -butyl ] -urea;

1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (2-pyrrolidin-1-yl-ethyl) -urea;

2, 5-dimethyl-pyrrolidine-1-carboxylic acid (6-chloro-5-phenyl-1H-indazol-3-yl) -amide;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -acetamidine;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -6-methoxy-pyrazine-2-carboxamidine;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -benzamidine;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -pyridine-2-carboxamidine;

n- (6-chloro-5-phenyl-1H-indazol-3-yl) -3-methoxy-benzenesulfonamide;

their isomers, mixtures, racemates, enantiomers, diastereomers, tautomers and pharmaceutically acceptable salts thereof.

The invention also relates to pharmaceutical compositions containing as active ingredient a derivative of formula (I) wherein:

r1, R2, R8, R9, R10, R11 are independently from each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl or heteroaryl, which are themselves optionally substituted by one or more substituents selected from: halogen, (1-6C) alkyl, (1-6C) alkoxy, CN, NO₂、NH₂OH, COOH, COOalkyl, CONH₂Formyl, trifluoromethyl and trifluoromethoxy;

More particularly, the present invention relates to pharmaceutical compositions containing as active ingredient a derivative of formula (I) wherein:

r1 and R2 may form a5 or 6 membered ring with or without heteroatoms such as O, S, N;

Preferably, the present invention relates to pharmaceutical compositions containing as active ingredient a derivative of formula (I) wherein:

r3 is (1-6C) alkyl, aryl (1-6C) alkyl, heteroaryl (1-6C) alkyl, aryl or heteroaryl fused with (1-10C) cycloalkyl, heterocyclyl, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, COOR1, SO₂R1, C (═ NH) R1 or C (═ NH) NR 1; these groups are optionally substituted with one or more substituents selected from: halogen, CN, NO₂、NH₂、OH、OR1、COOH、C(O)OR1、-O-C(O)R1、NR1R2、NHC(O)R1、C(O)NR1R2、SR1、S(O)R1、SO₂R1、NHSO₂R1、SO₂NR1R2、C(S)NR1R2、NHC(S)R1、-O-SO₂R1、-SO₂-O-R1, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy and (1-6C) alkyl;

r5 is phenyl;

r6 is chloro;

The invention also relates to the use of aminoindazole derivatives of formula (I) as medicaments, in which:

r5 and R6 are independently selected from the following groups: halogen, CN, NO₂、NH₂、OH、COOH、C(O)OR8、-O-C(O)R8、NR8R9、NHC(O)R8、C(O)NR8R9、NHC(S)R8、C(S)NR8R9、SR8、S(O)R8、SO₂R8、NHSO₂R8、SO₂NR8R9、-O-SO₂R8、-SO₂-O-R8, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl, (1-6C) alkoxy, aryl (1-6C) alkyl, heteroaryl (1-6C) alkyl, heterocyclyl, cycloalkyl, alkenyl, alkynyl, adamantyl, and polycycloalkyl; these groups are optionally substituted with one or more substituents selected from: halogen, CN, NO₂、NH₂、OH、OR10、COOH、C(O)OR10、-O-C(O)R10、NR10R11、NHC(O)R10、C(O)NR10R11、NHC(S)R10、C(S)NR10RI1、SR10、S(O)R10、SO₂R10、NHSO₂R10、SO₂NR10R11、-O-SO₂R10、-SO₂-O-R10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy and (1-6C) alkyl;

More particularly, the invention relates to the use of aminoindazole derivatives of formula (I) as medicaments, in which:

R1, R2 are each independently of the other hydrogen(1-6C) alkyl, aryl, alkenyl, alkynyl or heteroaryl, which are themselves optionally substituted with one or more substituents selected from: halogen, (1-6C) alkyl, (1-6C) alkoxy, CN, NO₂、NH₂OH, COOH, COOalkyl, CONH₂Formyl, oxo, trifluoromethyl and trifluoromethoxy;

Preferably, the present invention relates to the use of aminoindazole derivatives of formula (I) as medicaments, wherein:

r5 is phenyl;

r6 is chloro;

r1, R2 are independently from each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl or heteroaryl, which are themselves optionally substituted by one or more substituents selected from: halogen, (1-6C) alkyl, (1-6C) alkoxy, CN, NO₂、NH₂OH, COOH, COO alkyl、CONH₂Formyl, trifluoromethyl and trifluoromethoxy;

The derivatives of formula (I) can be obtained using the corresponding 3-amino derivatives (V), the nitrogen in position 1 of which is optionally protected with a Pr group. Pr is trimethylsilylethoxymethyl, tosyl, mesyl, benzyl or a known group protecting the aromatic heterocycle NH-, as indicated in t.w.green, "Protective groups in organic Synthesis", j.wiley-inter Publication (1999):

according to (R.F.KALTENBACH, bioorg.Med.chem.Lett., 9, (15), 2259-62, (1999)), 2-fluorobenzonitrile is reacted with hydrazine hydrate or hydrochloride under reflux in ethanol or alcohols of n-butanol for 2-18 hours to give 3-amino 1H-indazole of formula (II):

for these compounds, wherein R5 and R6 are independent of each other, are selected from the following groups: hydrogen, halogen, CN, NO₂、NH₂、OH、COOH、C(O)OR8、-O-C(O)R8、NR8R9、NHC(O)R8、C(O)NR8R9、NHC(S)R8、C(S)NR8R9、SR8、S(O)R8、SO₂R8、NHSO₂R8、SO₂NR8R9、-O-SO₂R8、-SO₂-O-R8, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl, (1-6C) alkoxy, aryl (1-6C) alkyl, heteroaryl (1-6C) alkyl, cycloalkyl, alkenyl, alkynyl and adamantyl; these groups are optionally substituted with one or more substituents selected from: halogen, halogen,CN、NO₂、NH₂、OH、OR10、COOH、C(O)OR10、-O-C(O)R10、NR10R11、NHC(O)R10、C(O)NR10R11、NHC(S)R10、C(S)NR10R11、SR10、S(O)R10、SO₂R10、NHSO₂R10、SO₂NR10R11、-O-SO₂R10、-SO₂-O-R10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy and (1-6C) alkyl; can be obtained by reaction using palladium chemistry using the corresponding halogen-containing derivatives: suzuki, (a. Suzuki, "Pure appl. chem.," an angle of attack63，419-22，(1991)，Stille(J..STILLE，Angew.Chem.Int.Ed. 25508-24, (1986), Heck, (r.f. Heck, "organic reactions (org. fact.),27345-90, (1982), Sonogashira, (k. Sonogashira, Synthesis 777, (1977), Buckwald (s.l. Buckwald, acc. chem. re.),31，805，(1998)。

for this reason, these reactive functional groups need to be protected. Therefore, OH, SH, COOH, NH should be protected before the coupling reaction is carried out₂A functional group. These protecting groups are introduced according to any method known to the person skilled in the art, in particular the method described by T.W.GREENE in "protecting groups in organic Synthesis", J.Wiley-Interscience Publication (1999). It is preferred to protect the nitrogen at the 1-position with a group such as tert-butoxycarbonyl or a silicon-containing derivative. Silyl groups such as tert-butyldimethylsilyl, triisopropylsilyl are preferably chosen, which can be removed with fluoride anions or with acetic acid, more particularly trimethylsilylethoxymethyl, which can be cleaved off with tetrabutylammonium fluoride under reflux in solvents such as tetrahydrofuran, dioxane (J.P.WHITTEN, J.Org.chem., 51, 1891, (1986); B.H.LIPSHUTZ, Tetrahedron letters, 4095, (1986)), or with 2N hydrochloric acid under reflux in methanol or ethanol.

The starting compound is reacted with trimethylsilylethoxymethyl chloride in a solvent such as dimethylformamide at room temperature in the presence of sodium hydride to give a derivative protected in the 1-position with trimethylsilylethoxymethyl (J.P. WHITTEN, J.Org. chem., 51, 1891, (1986); M.P. EDWARDS, Tetrahedron (Tetrahedron), 42, 3723, (1986)).

Similarly, the 1-NH nitrogen functionality of the indazole can be protected with groups such as tosyl, carbamate, benzyl, or silyl derivatives. For example, when a coupling reaction between a halogen-containing derivative at the 6-position and palladium is desired, nitrogen at the 1-position should be protected as shown below (X ═ Cl, Br, I):

deprotection is carried out according to methods known to the person skilled in the art and the method described in T.W.GREENE in Protective groups in Organic Synthesis, J.Wiley-Interscience Publication (1999). For example, if the protecting group at the 1-position is trimethylsilylethoxymethyl, deprotection can be carried out by reaction with tetrabutylammonium fluoride, as shown below:

where one of the R5 groups attached using a coupling reaction of palladium chemistry, R6 groups itself contains a reactive function such as a hydroxyl, amine, thiol, acid group, or more generally a heteroatom, these latter functional groups need to be protected prior to coupling with palladium. Thus, for example, a phenolic function in protected form (e.g., O-benzyl) is introduced using a chlorine-containing derivative in which the nitrogen in the 1-position has been protected, as explained in more detail below:

the benzyl groups are then removed, for example, using a trimethylsilyl iodide reflux treatment in acetonitrile. Protection with trimethylsilyl ethoxymethyl groups cleavable with tetrabutylammonium fluoride can also be carried out under reflux in solvents such as tetrahydrofuran, dioxane, etc. (J.P.WHITTEN, J.org.chem., 51, 1891, (1986); B.H.LIPSHUTZ, Tetrahedron letters, 4095, (1986)), or under reflux in methanol or ethanol with 2N hydrochloric acid.

When R5 and R6 are independently aryl and halogen, the aryl function is introduced by coupling with palladium at the bromine-containing position, with the nitrogen at the 1 and 3 positions being appropriately protected. Preferably, Pr represents a trimethylsilylethoxymethyl group and Pr' represents a n-butylcarboxyl group, which forms a n-butylamide with the nitrogen. The amide deprotection step can be carried out in DMF under reflux in the presence of ethanolamine for one week. This cleavage can also be carried out with stannous chloride in ethanol (R J Griffin, J. chem. Soc. Perkin I1992, 1811-1819), or with sodium methylate in methanol (Y. Furukawa, chem. pharm. Bull. 1968, 16, 1076), or with any other alcoholate in the corresponding alcohol.

A wide variety of products can be obtained starting from compounds of formula II by reacting the primary amine function of a 3-aminoindazole in various classical reactions such as: alkylation, acylation, reaction with carbonylated derivatives followed by reduction, sulfonation, conversion to urea or carbamate, arylation (Castro or Buchwald reactions), and the like.

In R1C in dichloromethane under the conditions described in Organic Reactions 591-vol 714(E.Baxter, A.Reitz)Amino reduction of a derivative of formula (I) wherein R3 is H when Pr is trimethylsilylethoxymethyl, using a boron derivative (e.g. sodium triacetoxyborohydride), or other reducing agent commonly used in the reduction of imines, in the presence of an aldehyde of the HO type, to give products wherein R3 is (1-6C) alkyl, aryl (1-6C) alkyl, heteroaryl (1-6C) alkyl, heterocycloalkyl, cycloalkyl or polycycloalkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, CN, NO₂、NH₂、OH、OR1、COOH、C(O)OR1、-O-C(O)R1、NR1R2、NHC(O)R1、C(O)NR1R2、SR1、S(O)R1、SO₂R1、NHSO₂R1、SO₂NR1R2、C(S)NR1R2、NHC(S)R1、-O-SO₂R1、-SO₂-O-R1, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy and (1-6C) alkyl.

According to the examples described in Comprehensive Organic functional group Transformations, Vol 6(Katritzky, Meth-Cohn, Rees 1995), in tetrahydrofuran, it is possible in particular to condense isocyanates of the OCNR1 type with derivatives of the general formula (I) in which R3 is H, in which R3 is CONR1R2, R1, R2 are, independently of one another, hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl or heteroaryl, which are themselves optionally substituted by one or more substituents selected from the group consisting of: halogen, (1-6C) alkyl, (1-6C) alkoxy, CN, NO₂、NH₂OH, COOH, COOalkyl, CONH₂Formyl, trifluoromethyl and trifluoromethoxy.

Using R1SO in the presence of a base (especially tertiary amines like triethylamine or aromatic amines like pyridine) in a common solvent like for example dichloromethane₂Sulfonyl chlorides of the Cl type may sulfonate derivatives of formula (I) wherein R3 is H to give products wherein R3 is SO₂R1, R1 are hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl or heteroaryl, which are themselves optionally substituted with one or more substituents selected from: halogen, (1-6C) alkyl, (1-6C) alkoxy, CN, NO₂、NH₂OH, COOH, COOalkyl, CONH₂Formyl, trifluoromethyl and trifluoromethoxy.

Compound IV, where Pr is trimethylsilylethoxymethyl, is 3-amino-5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl ] -indazole, prepared in the following manner:

3-amino-5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl ] -indazole

To 2.4g N- [ [ 5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl group]-indazol-3-yl]]Butanamide (described below) at 75cm³Adding 1.63cm of solution in dimethylformamide³Ethanolamine, then 2.24g of potassium carbonate was added, and heated under reflux for one week. The reaction medium is concentrated to dryness under reduced pressure and then 250cm³Ethyl acetate and 100cm³And (4) dissolving in water. After the organic phase had been decanted, it was successively poured over 100cm³Water and 75cm³Brine wash 2 times. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2kPa-50 ℃). The crude oil obtained was purified by chromatography using a silica gel column (particle size 40-60 μm; diameter 4cm) under argon pressure of 50kP, eluted with a cyclohexane-ethyl acetate mixture (80/20 by volume) and the fractions were recovered in a number of fractions of 35cm each³. These fractions containing the desired product were combined and evaporated under reduced pressure (2 kPa; 50 ℃). After drying (90Pa-45 ℃ C.) 0.43g of 3-amino-5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl are obtained]Indazoles, as yellow oil.

¹H NMR Spectrum (300MHz, (CD)₃)₂SOd₆δ, in ppm): -0.05 (s: 9H); 0.83(t, J ═ 8 Hz: 2H); 3.52(t, J ═ 8 Hz: 2H); 5.49 (s: 2H); 5.75 (width s: 2H); 7.30-7.55 (mt: 5H); 7.77 (s: 1H); 7.81 (s: 1H).

N- [ [ 5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl ] -indazol-3-yl ] ] -butanamide can be obtained in the following manner:

to 2g N- [ [ 5-bromo-6-chloro-1- (2-trimethylmethyl)Silane ethoxy) methyl]-indazol-3-yl]]Butanamide (described below) at 180cm³Solution in dioxane, 821mg of phenylboronic acid, 1.14g of sodium carbonate in 30cm³A solution in distilled water, and finally 347mg of tetrakis (triphenylphosphine) palladium were added. Heating and refluxing for 90 min, then cooling back to 20 deg.C, and adding 100cm³Ethyl acetate and 100cm³And (4) distilled water. The organic phase is 100cm³The extract was washed with saturated aqueous sodium chloride solution, and then, decanted and dried over magnesium sulfate. After filtration through a sintered glass filter, the filtrate was concentrated to dryness under reduced pressure (2kPa-50 ℃). The residue was purified by chromatography on a silica gel column (particle size 40-60 μm, diameter 4.5cm) under 50kP argon pressure, eluting with a cyclohexane-ethyl acetate mixture (80/20 by volume) to recover fractions of 35cm each³. These fractions containing the desired product were combined and evaporated under reduced pressure (2 kPa; 50 ℃). After drying (90Pa-45 ℃ C.), 2g N- [ [ 5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl ] is obtained]-indazol-3-yl]]-butyramide, in yellow oil.

¹H NMR Spectrum (300MHz, (CD)₃)₂SOd₆δ, in ppm): -0.05(s, 9H), 0.85(t, J ═ 8Hz, 2H), 0.92(t, J ═ 7.5Hz, 3H), 1.63(mt, 2H), 2.38(t, J ═ 7.5Hz, 2H), 3.56(t, J ═ 8Hz, 2H), 5.70(s, 2H), 7.30-7.55(mt, 5H), 7.91(s, 1H), 7.99(s, 1H), 10.59 (width s, 1H).

N- [ [ 5-bromo-6-chloro-1- (2-trimethylsilylethoxy) methyl ] -indazol-3-yl ] ] -butanamide is obtained in the following manner:

to 1g N- [ [ 6-chloro-1- (2-trimethylsilylethoxy) methyl group]-indazol-3-yl]]Butanamide (described below) at 15cm³Adding 0.22cm of chloroform solution³Pyridine, then 0.14cm³Bromine. Stirring at 20 deg.C for 24 hr, and adding 50cm³Dichloromethane and 50cm³Saturated aqueous sodium sulfate solution. After stirring for 10 minutes, the insoluble matter was removed by filtration using a sintered glass filter, and the organic phase was 50cm in volume³Saturated aqueous sodium chloride solutionAnd (6) washing. The organic phase is decanted, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2 kPa; 45 ℃). The residue was purified by chromatography using a silica gel column (particle size 40-60 μm; diameter 3.5cm) under 50kP argon pressure, eluted with an ethyl acetate-cyclohexane mixture (20/80 by volume) and fractions of 35cm each were recovered³. The fractions containing the desired product were combined and evaporated under reduced pressure (2 kPa; 50 ℃). Drying (90Pa-45 ℃) gave 0.94g N- [ [ 5-bromo-6-chloro-1- (2-trimethylsilylethoxy) methyl group]-indazol-3-yl]]-butanamide, in the form of a white solid, melting at 130 ℃.

¹H NMR(300MHz，(CD₃)₂SO, d6, δ, in ppm): -0.08(s, 9H), 0.82(t, J ═ 8Hz, 2H), 0.95(t, J ═ 7.5Hz, 3H), 1.66(mt, 2H), 2.40(t, J ═ 7.5Hz, 2H), 3.52(t, J ═ 8Hz, 2H), 5.66(s, 2H), 8.13(s, 1H), 8.34(s, 1H), 10.67 (width s, 1H).

N- [ [ 6-chloro-1- (2-trimethylsilylethoxy) methyl ] -indazol-3-yl ] ] -butanamide is obtained in the following manner:

to 606mg of 60% sodium hydride at 20cm³To a solution of 3g N- (6-chloro-1H-indazol-3-yl) -butanamide at 40cm³Solution in dimethylformamide. After cooling to 5 ℃ 2.68cm were added³2- (trimethylsilyl) -ethoxymethyl chloride at 10cm³Solution in dimethylformamide. The temperature was allowed to rise back to 21 ℃ and stirred for 2 hours. The reaction medium is again evaporated under reduced pressure (2 kPa; 45 ℃). The residue used was 200cm³Ethyl acetate and 100cm³Dissolving with distilled water. Then 100cm³Distilled water and 100cm³The washing was performed 2 times with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered through a sintered glass filter and then evaporated under reduced pressure (2 kPa; 50 ℃). The residue was purified by chromatography on a silica gel column (particle size 40-60 μm; diameter 4.5cm) under argon pressure of 50kP, eluted with a cyclohexane-ethyl acetate mixture (80/20 by volume) and the fractions recovered,each fraction was 100cm³. The fractions containing the desired product were combined and evaporated under reduced pressure (2 kPa; 50 ℃). Drying (90 Pa; 50 ℃) gives 3g N- [ [ 6-chloro-1- (2-trimethylsilylethoxy) methyl ] -2]-indazol-3-yl]]-butyramide, in yellow oil.

¹H NMR Spectrum (300MHz, (CD)₃)₂SOd6, δ, in ppm): -0.08(s, 9H), 0.83 (width t, J ═ 8Hz, 2H), 0.96(t, J ═ 7.5Hz, 3H), 1.67(mt, 2H), 2.40(t, J ═ 7.5Hz, 2H), 3.53(t, J ═ 8Hz, 2H), 5.66(s, 2H), 7.16(dd, J ═ 9 and 2Hz, 1H), 7.86(d, J ═ 2Hz, 1H), 7.88(d, J ═ 9Hz, 1H), 10.53(mf, 1H).

N- (6-chloro-1H-indazol-3-yl) -butyramide;

to 750mg of 3-amino-6-chloro-1H-indazole at 10cm³Adding 0.47cm of solution in pyridine³Butyryl chloride, the reaction medium is cooled to 3 ℃. The medium was then allowed to rise back to 19 ℃ for 14 hours. The reaction medium is evaporated to dryness under reduced pressure (2 kPa; 40 ℃). The residue used was 50cm³Ethyl acetate, 50cm³Tetrahydrofuran and 50cm³And (5) treating distilled water. 50cm for organic phase³Distilled water and 50cm³The extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered through a sintered glass filter, and evaporated under reduced pressure. The residue obtained was purified by chromatography using a silica gel column (particle size 40-60 μm; diameter 2.5cm) under argon pressure of 50kPa, eluted with cyclohexane-ethyl acetate (70/30, by volume) to recover fractions of 25cm each³These fractions containing the desired product were combined and then dried under reduced pressure (2 kPa; 40 ℃). After drying (90P; 45 ℃ C.) 200mg of N- (6-chloro-1H-indazol-3-yl) -butyramide are obtained as a white solid which melts at 230 ℃.

¹H NMR Spectrum (300MHz, (CD)₃)₂SOd6, δ, in ppm): 0.98(t, J ═ 7Hz, 3H), 1.67(mt, 2H), 2.40(t, J ═ 7Hz, 2H), 7.08(dd, J ═ 9 and 2Hz, 1H), 7.52(d, J ═ 2Hz, 1H), 7.84 (c), (d, J ═ 2Hz, 1H), and (d, J ═ 3H), respectivelyd, J ═ 9Hz, 1H), 10.39(mf, 1H), 12.50-13.00 (broad mf, 1H).

3-amino-6-chloro-5-phenyl-1H-indazole was obtained using 3-amino-5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl ] -indazole.

To a solution of 108.3mg of 3-amino-5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl ] -indazole compound in 4.7ml of methanol was added 300 μ l of 2N HCl. The reaction was carried out under microwave at 140 ℃ for 150 seconds.

Pouring into saturated KH₂PO₄Solution, extracted with AcOEt. With anhydrous MgSO₄The organic phase was dried, filtered and concentrated. The crude material obtained was purified on silica gel, thus obtaining 63.5mg of 3-amino-6-chloro-5-phenyl-1H-indazole compound.

After isolation, the compound of formula (I) may be purified by generally known methods, such as crystallization, chromatography or extraction.

The compounds of formula (I) may optionally be converted into addition salts with such acids by the action of mineral or organic acids in organic solvents, such as alcohols, ketones, ethers or chlorinated solvents. These salts also form part of the invention.

As examples of pharmaceutically acceptable salts, the following salts can be cited: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, maleate, ethanolate, methanesulfonate, methylene-bis-b-hydroxynaphthoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophylline acetate, and p-toluenesulfonate.

These compounds of formula (I) are kinase inhibitors and are therefore useful for the prevention and treatment of the following diseases: neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, frontal dementia, cortical basal degeneration, Pick's disease, cerebrovascular accidents, cranial and spinal cord injuries and peripheral neuropathies, obesity, essential hypertension, atherosclerotic cardiovascular disease, polycystic ovary syndrome, syndrome X, immunodeficiency and cancer.

Their activity can be determined by measuring the inhibition of tau protein phosphorylation in adult rat cortical sections.

Skinned sections of 300 μm thickness were prepared using decapitated, age 8-10 week OFA (Iffa-Credo) male mice. These sections were incubated in 5ml of DMEM medium containing 4.5g/l pyruvate and glucose for 40 minutes at 37 ℃. The sections were then washed twice with this medium, redistributed to microtubes (50. mu.l in 500. mu.l medium with or without the compound to be tested) and incubated at 37 ℃ with stirring. After 2 hours, the test was terminated by centrifugation. These sections were lysed, sonicated and centrifuged at 18300g for 15 min at 4 ℃. The concentration of Protein in the supernatant was determined using a commercial quantification method (BCA Protein Assay, Pierce) based on the Lowry method.

These samples denatured at 70 ℃ for 10 minutes in advance were separated by 4-12% Bis-Tris longitudinal gel method in the presence of MOPS-SDS buffer, and then were electrotransferred to nitrocellulose membranes. The AD2 monoclonal antibodies were used for immunolabeling and these antibodies specifically recognized the Ser 396/404 phosphorylated epitope of the tau protein. These immunologically active proteins can be visualized by adding a second anti-mouse IgG and an antibody coupled to peroxidase and a chemiluminescent substrate. The resulting autoradiograms were finally quantified using the 'GeneTools' de Syngene software (GeneGnome, Ozyme) to determine CI 50.

The compounds of formula (I) have very interesting activity, especially those with CI50 below 100. mu.M.

Conditions for LC/MS analysis of the product were obtained using a Waters Alliance 2695 instrument for LC and a Waters-MicromalsPlatform II instrument for mass spectrometry.

Detailed Description

The invention is illustrated, without limitation, by the following examples.

Example a 1: N-butyl-6-chloro-5-phenyl-1H-indazol-3-amine;

step 1: 24mg of n-butyraldehyde and 113mg of sodium triacetoxyborohydride are added to 100mg of 3-amino-5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl group]Indazoles at 5cm³In dichloromethane. After 3 hours at room temperature, the reaction medium is hydrolyzed and then extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on a silica gel column (elution: EtOAc/hexane (80/20, v/v)) to give 21mg of butyl- [ 6-chloro-5-phenyl-1- (2-trimethylsilylethoxymethyl) -1H-indazol-3-yl]Amine (yellow solid).

Mass spectrum: 432[ M + H ] +; retention time: 5.26 minutes.

¹H NMR[d₆-DMSO]：7.83(1H，s)，7.73(1H，s)，7.35-7.50(5H，m)，6.25(1H，t，J＝6Hz)，5.49(2H，s)，3.52(2H，t，J＝8Hz)，3.24(2H，m)，1.60(2H，m)，1.39(2H，m)，0.91(3H，t，J＝7Hz)，0.81(2H，t，J＝8Hz)，-0.07(9H，s)。

Step 2: 0.7ml of 2N HCl was added to 21mg of butyl- [ 6-chloro-5-phenyl-1- (2-trimethylsilyl-ethoxymethyl) -1H-indazol-3-yl]Amine at 0.3cm³Solution in methanol. The reaction medium is stirred at room temperature for 48 hours, refluxed for 1 hour and then evaporated. The resulting solid was dried in vacuo to give 16mg of N-butyl-6-chloro-5-phenyl-1H-indazol-3-amine (yellow solid).

Mass spectrum: 300[ M + H ] +; retention time: 4.25 minutes.

¹H NMR[d₆-DMSO]：7.52(1H，s)，7.95(1H，s)，7.35-7.50(5H，m)，3.30(2H，t，J＝7Hz)，1.61(2H，m)，1.40(2H，m)，0.92(3H，t，J＝7Hz)。

Example a 2: 3- (6-chloro-5-phenyl-1H-indazol-3-ylamino) -thiophene-2-carbonitrile

To 52mg of 3-amino-5-phenyl-6-chloro-1- [ (2-trimethylsilylethoxy) methyl group]A solution of the (E) -indazole compound in 0.5ml of NMP (1-methyl-2-pyrrolidone) was added with 38mg of 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl and 20mg of Pd₂dba₃(tris (dibenzylideneacetone) dipalladium (0)), 52mg of 2-cyano 3-bromothiophene, 23mg of sodium tert-butylate.

The reaction was placed under microwave at 140 ℃ for 3 minutes. After usual work up, the crude product was treated with 2N HCl in methanol to give after purification 8.4mg of 3- (6-chloro-5-phenyl-1H-indazol-3-ylamino) -thiophene-2-carbonitrile.

Mass spectrum: 351[ M + H ] +; retention time: 4.19 minutes.

¹H NMR[d₆-DMSO]：7.40(1H，m)，7.48(2H，m)，7.53(3H，m)，7.81(1H，s)，8.09(1H，s)，8.27(1H，d，J＝5.5 Hz)，8.91(2H，s)。

Examples A3-A5

The following examples were carried out in the same manner as a 2.

Numbering	Name (R)	Starting materials	Retention time/[ M + H]⁺	NMRDMSO-d6, unless otherwise indicated
Numbering	Name (R)	Starting materials	Retention time/[ M + H]⁺	NMRDMSO-d6, unless otherwise indicated	A3	(6-chloro-5-phenyl-1H-indazol-3-yl) -pyridin-2-yl-amine	2-bromopyridine	2.89/321	7.07ppm (b, 1H), 7.36 ppm-7.50ppm (m, 5H), 7.55ppm (b, 1H), 7.67ppm (s, 1H), 7.87ppm (s, 1H), 7.95ppm (1, 1H), 8.21ppm (b, 1H) in MeOD
A4	(6-chloro-5-phenyl-1H-indazol-3-yl) - (5-nitro-pyridin-2-yl) -amine	2-bromo-5-nitropyridines	4.58/366	7.42-7.52ppm (m, 5H), 7.63ppm (s, 1H), 7.65ppm (s, 1H), 7.94ppm (d, J ═ 9Hz, 1H), 8.43ppm (dd, J ═ 2.5 and 9Hz, 1H), 9.13ppm (d, J ═ 2.5Hz, 1H), 7.77ppm (bs, 1H), 9.55ppm (bs, 1H)	A3	(6-chloro-5-phenyl-1H-indazol-3-yl) -pyridin-2-yl-amine	2-bromopyridine	2.89/321
A4		2-bromo-5-nitropyridines	4.58/366		A5	(6-chloro-5-phenyl-1H-indazol-3-yl) - (6-methoxy-pyridin-2-yl) -amine	2-bromo-6-methoxypyridine		3.87ppm (s, 3H), 6.31ppm (d, J ═ 7.5Hz, 1H), 7.36ppm (bd, J ═ 7.5Hz, 1H), 7.35-7.50ppm (m, 5H), 7.36ppm (t, J ═ 7.5Hz, 1H), 7.54ppm (s, 1H), 7.69ppm (bs, 1H), in CDCl₃In

Example B1: n- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' -phenyl-urea

Step 1: 39 μm phenyl isocyanate was added to 102.2mg 3-amino-5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl]Indazole at 2.5cm³In tetrahydrofuran solution. The reaction medium is stirred at room temperature for 24 hours and then evaporated. The crude product was purified by chromatography on a silica gel column (eluent: dichloromethane/acetone (98/2, v/v)) to give 122.5mg of 1- [ 6-chloro-5-phenyl-1- (2-trimethylsilyl-ethoxymethyl) -1H-indazol-3-yl]-3-phenyl-urea (colorless solid).

Mass spectrum: 493[ M + H ] +; retention time: 6.02 minutes.

¹H NMR[d₆-DMSO]: 9.89(1H, width s), 9.86(1H, width s), 8.20(1H, s), 8.07(1H, s), 7.35-7.50(5H, m), 5.81(2H, s), 3.66(2H, t, J ═ 8Hz), 0.92(2H, t, J ═ 8Hz), -0.12(9H, s).

Step 2: 1ml of 2N HCl was added to 106mg of 1- [ 6-chloro-5-phenyl-1- (2-trimethylsilyl-ethoxymethyl) -1H-indazol-3-yl]-3-phenyl-urea at 12cm³In solution in methanol. The reaction medium is stirred at room temperature for 48 hours, refluxed for 5 hours and then evaporated. The resulting solid was dried in vacuo to give 82mg of N- (6-chloro-5-phenyl-1H-indazol-3-yl) -N' -phenyl-urea (colorless solid).

Mass spectrum: 363[ M + H ] +; retention time: 5.15 minutes.

¹H NMR [d₆-DMSO]: 12.64(1H, width s), 9.70(1H, width s), 9.59(1H, width s), 8.07(1H, s), 7.64(1H, s), 7.50(7H, m), 7.30(2H, m), 7.0(1H, m).

Example B2: 1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (4-ethoxy-phenyl) -urea

To a solution of 80mg of 3-amino-5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl group]-indazole in 1ml THF, 36.4mg 4-ethoxyphenyl isocyanate was added. Heating at 50 deg.C for 1h, and then at saturated KH₂PO₄The solution was hydrolyzed and extracted with dichloromethane. After drying and evaporation, the crude product was purified by chromatography using a silica gel column using an AcOEt/hexane mixture. The product obtained is deprotected in 2ml 1/1 MeOH/2N HCl mixture at reflux for 3 h. This gave 62.5mg of 1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (4-ethoxy-phenyl) -urea.

Mass spectrum: 407[ M + H ] +; retention time: 4.36 minutes

¹H NMR [d₆-DMSO]：1.3(3H，t，J＝7Hz)，3.98(2H，q，J＝7Hz)，6.87and7.36(AA’-BB’，4H)，7.36-7.50(5H，m)，7.63(1H，s)，8.08(1H，s)，9.53(2H，s)，12.53(1H，s)。

Example B3-Bl 2:

the product B3-B12 was obtained in the same manner as the product B2

Numbering	Name (R)	Starting materials	Retention time/[ M + H]⁺	NMRd₆-DMSO
Numbering	Name (R)	Starting materials	Retention time/[ M + H]⁺	NMRd₆-DMSO	B3	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (3, 4-dichloro-phenyl) -urea	3, 4-dichlorophenyl isocyanate	4.75/407[M-H]	7.38-7.48ppm(m，6H)，7.53ppm(d，J＝8.5Hz，1H)，7.66ppm(s，1H)，7.90ppm(d，J＝2.5Hz，1H)，8.01ppm(s，1H)，9.70ppm(s，1H)，9.84ppm(s，1H)，12.72ppm(bs，1H)
B4	3- [3- (6-chloro-5-phenyl-1H-indazol-3-yl) -ureido]-propionic acid methyl ester	Isophenyl ethyl isocyanate	3.71/373	2.56ppm(t，J＝6.5Hz，2H)，3.44ppm(m，2H)，3.61(s，3H)，7.36-7.50ppm(m，5H)，7.58ppm(s，1H)，7.81(b，1H)，8.08ppm(s，1H)，9.48ppm(s，1H)，12.52ppm(bs，1H)	B3		3, 4-dichlorophenyl isocyanate	4.75/407[M-H]
B4		Isophenyl ethyl isocyanate	3.71/373		B5	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (4-dimethylamino-phenyl) -urea	4-Dimethylaminophenyl isocyanate	3.26/406	3.10ppm(s，6H)，7.38-7.50ppm(m，5H)，7.64(b，4H)，7.66ppm(s，1H)，8.03ppm(s，1H)，9.70ppm(s，1H)，9.95ppm(s，1H)，12.72ppm(bs，1H)
B6	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3-isopropyl-urea	Isopropyl isocyanate	3.95329	1.16ppm(d，J＝6.5Hz，6H)，3.85ppm(m，1H)，7.38-7.50ppm(m，5H)，7.58ppm(b，1H)，7.60ppm(s，1H)，8.10ppm(s，1H)，9.36ppm(s，1H)，12.48ppm(bs，1H)	B5		4-Dimethylaminophenyl isocyanate	3.26/406
B6	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3-isopropyl-urea	Isopropyl isocyanate	3.95329		B7	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3-cyclohexyl-urea	Cyclohexyl isocyanate	4.37/369	1.3-1.9ppm(m，10H)，3.58ppm(m，1H)，from 7.38 to 7.49ppm(m，5H)，7.57ppm(s，1H)，7.68ppm(bd，J＝5.5Hz，1H)，8.10ppm(s，1H)，9.38ppm(s，1H)，12.48ppm(bs，1H)
B8	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (3-trifluoromethylphenyl) -urea	3-trifluoromethylphenyl isocyanate	4.61/431	7.34ppm(bd，J＝8Hz，1H)，7.38ppm-7.49ppm(m，5H)，7.53ppm(t，J＝8Hz，1H)，7.66ppm(s，1H)，7.69ppm(bd，J＝8Hz，1H)，7.98ppm(bs，1H)，8.03ppm(s，1H)，9.71ppm(s，1H)，9.96ppm(s，1H)，12.76ppm(bs，1H)	B7	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3-cyclohexyl-urea	Cyclohexyl isocyanate	4.37/369
B8		3-trifluoromethylphenyl isocyanate	4.61/431		B9	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (2-thiophen-2-ylethyl) -urea	2-thien-2-ylethyl isocyanate	4.2/397	3.02ppm (t, J ═ 7Hz, 2H), 3.46ppm (m, 2H), 6.92ppm (dd, J ═ 1.5 and 3.5Hz, 1H), 6.95ppm (dd, J ═ 3.5 and 5Hz, 1H), 7.32ppm (dd, J ═ 1.5 and 5Hz, 1H), 7.37-7.49ppm (m, 5H), 7.58ppm (s, 1H), 7.80ppm (m, 5H)

				ppm(bt，J＝6Hz，1H)，8.08ppm(s，1H)，9.50ppm(s，1H)，12.48ppm(bs，1H)
					B10	1-benzo [1, 3]]Metadioxacyclopenta-5-yl-3- (6-chloro-5-phenyl-1H-indazol-3-yl) -urea	1-benzo [1, 3]]Metadioxacyclopenta-5-yl isocyanate		5.97ppm (s, 2H), 6.81ppm (dd, J ═ 2.5 and 8.5Hz, 1H), 6.84ppm (d, J ═ 8.5Hz, 1H), 7.22ppm (d, J ═ 2.5Hz, 1H), 7.35-7.50ppm (m, 5H), 7.65ppm (s, 1H), 8.05ppm (s, 1H), 9.56ppm (s, 1H), 9.6ppm (s, 1H), 12.65(bs, 1H)
B11	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (3, 5-dimethylisoxazol-4-yl) -urea	3, 5-dimethylisoxazol-4-yl isocyanate	3.76/382	2.13ppm(s，3H)，2.29ppm(s，3H)，7.36-7.50ppm(m，5H)，7.64ppm(s，1H)，8.03ppm(s，1H)，8.75ppm(s，1H)，9.74ppm(s，1H)，12.68ppm(bs，1H)	B10		1-benzo [1, 3]]Metadioxacyclopenta-5-yl isocyanate
B11		3, 5-dimethylisoxazol-4-yl isocyanate	3.76/382		B12	1-benzyl-3- (6-chloro-5-phenyl-1H-indazol-3-yl) -urea	Benzyl isocyanate	4.2/377	4.43ppm(d，J＝6Hz，2H)，7.20-7.50ppm(m，10H)，7.58ppm(s，1H)，8.10ppm(bs，2H)，9.57ppm(s，1H)，12.50ppm(s，1H)
B13	(6-chloro-5-phenyl-1H-indazol-3-yl) -3-phenethylthiourea	Phenethylthioisocyanic acidEsters		2.96ppm (t, J ═ 7.0Hz, 2H), 3.86ppm (dt, J ═ 5.5 and 7.0Hz, 2H), 7.15-7.35ppm (m, 5H), 7.35-7.50ppm (m, 5H), 7.64ppm (s, 1H), 8.37ppm (s, 1H), 10.14ppm (t, J ═ 5.5Hz, 1H), 10.97ppm (s, 1H), 12.73ppm (s, 1H)	B12	1-benzyl-3- (6-chloro-5-phenyl-1H-indazol-3-yl) -urea	Benzyl isocyanate	4.2/377

Example C1: 1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- [3- (4-methyl-piperazin-1-yl) -propyl ] -urea;

step 1

To a solution of 387.8mg of 3-amino-5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl ] -indazole in 2ml of dichloromethane were added 62 μ l of pyridine and 125 μ l of ethyl chloroformate in that order. After 75 minutes, the reaction was stopped. Hydrolysis, extraction and evaporation gave 571mg of crude carbamate: (6-chloro-5-phenyl-1H-indazol-3-yl) -carbamic acid ethyl ester.

Step 2

To a solution of 106mg of the urethane obtained above in 2.5ml of trifluorotoluene was added 377mg of 3-aminopropyl-1-methylpiperazine, and the reaction was carried out at 200 ℃ for 20 minutes under a microwave. After purification by preparative LC/MS (acetonitrile/buffer pH ═ 9) 60mg of 1- [ 6-chloro-5-phenyl-1- (2-trimethylsilyl-ethoxymethyl) -1H-indazol-3-yl ] -3- [3- (4-methyl-piperazin-1-yl) -propyl ] -urea was obtained.

Step 3

The previous compound was dissolved in 2ml of 1/1 MeOH/2N HCl mixture and refluxed at elevated temperature for 3 h.

¹HNMR[DMSO-d₆]：1.63(2H，m)；2.18(3H，s)；2.33(10H，m)；3.21(2H，m)；7.36-7.48(5H，m)；7.58(1H，s)；7.66(1H，t，J＝5.5Hz)；8.08(1H，s)；9.37(1H，s)；12.70(1H，s)。

Example (b): C2-C19

Obtaining C2-C19 products in the same way as the C1 products

Numbering	Name (R)	Starting materials	Retention time/[ M + H]⁺	NMRd₆-DMSO
Numbering	Name (R)	Starting materials	Retention time/[ M + H]⁺	NMRd₆-DMSO	C2	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (3-imidazol-1-ylpropyl) -urea	3-imidazole-propyl-1-amines	3/395	2.05ppm(m，2H)，3.24ppm(m，2H)，4.25ppm(t，J＝6Hz，2H)，7.38-7.49ppm(m，5H)，7.61ppm(s，1H)，7.69ppm(bs，1H)，7.76ppm(d，J＝5.5Hz，1H)，7.83ppm(bs，1H)，8.08ppm(s，1H)，9.19ppm(s，1H)，9.53ppm(s，1H)，12.53ppm(bs，1H)
C4	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (2-hydroxy-ethyl) -urea	Ethanolamine	3.36/331	3.27ppm(m，2H)，3.49ppm(t，J＝6.5Hz，2H)，7.38-7.50ppm(m，5H)，7.59ppm(s，1H)，7.83ppm(b，1H)，8.10ppm(s，1H)，9.49ppm(s，1H)，12.50ppm(bs，1H)	C2		3-imidazole-propyl-1-amines	3/395
C4		Ethanolamine	3.36/331		C5	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- [3- (4-methyl-piperazin-1-yl) -propyl]-urea	(4-methyl-piperazin-1-yl) -propylamine	2.52/427
C6	Pyrrolidine-1-carboxylic acid (6-chloro-5-phenyl-1H-indazol-3-yl) amine	Pyrrolidine as a therapeutic agent	4/340	1.84ppm(m，4H)，3.37ppm(m，4H)，7.37-7.49ppm(m，5H)，7.61ppm(s，1H)，7.72ppm(s，1H)，8.80ppm(s，1H)，12.62ppm(s，1H)	C5		(4-methyl-piperazin-1-yl) -propylamine	2.52/427
C6		Pyrrolidine as a therapeutic agent	4/340		C7	(6-chloro-5-phenyl-1H-indazol-3-yl) -carbamic acid methyl ester	Chlorocarboxylic acid methyl ester	4.1/302	3.66ppm(s，3H)，7.33ppm-7.49ppm(m，5H)，7.65ppm(s，1H)，7.78ppm(s，1H)，10.1ppm(s，1H)，12.80ppm(s，1H)
C8	(6-chloro-5-phenyl-1H-indazol-3-yl) -urea	Ammonia	3.39/287	6.89ppm(bs，2H)，7.37ppm-7.49ppm(m，5H)，7.59ppm(s，1H)，8.09ppm(s，1H)，9.37ppm(s，1H)，12.51	C7		Chlorocarboxylic acid methyl ester	4.1/302

				ppm(bs，1H)
				ppm(bs，1H)	C9	(6-chloro-5-phenyl-1H-indazol-3-yl) -carbamic acid benzyl ester	Benzoic acid methyl chloroformate	4.5/378	5.14ppm(s，2H)，7.29-7.49ppm(m，10H)，7.65ppm(s，1H)，7.76ppm(s，1H)，10.08ppm(bs，1H)，10.77ppm(bs，1H)
C10	(6-chloro-5-phenyl-1H-indazol-3-yl) -allyl carbamate	Allyl chloroformate	4.4/328	4.61ppm(dl，J＝5Hz，2H)，5.21ppm(dl，H＝11Hz，1H)，5.34ppm(dl，J＝17.5Hz，1H)，5.96ppm(m，1H)，7.39-7.49ppm(m，5H)，7.65ppm(s，1H)，7.78ppm(s，1H)，10.06ppm(bs，1H)，12.76ppm(bs，1H)	C9		Benzoic acid methyl chloroformate	4.5/378
C10	(6-chloro-5-phenyl-1H-indazol-3-yl) -allyl carbamate	Allyl chloroformate	4.4/328		C11	(6-chloro-5-phenyl-1H-indazol-3-yl) -carbamic acid isobutyl ester	Chlorocarboxylic acid isobutyl ester	4.55/344	0.90ppm(d，J＝6.5Hz，6H)，1.90ppm(m，1H)，3.86ppm(d，J＝6.5Hz，2H)，7.38ppm-7.49ppm(m，5H)，7.66ppm(s，1H)，7.79ppm(s，1H)，9.93ppm(bs，1H)，12.93ppm(bs，1H)
C12	Piperidine-1-carboxylic acid (6-chloro-5-phenyl-1H-indazol-3-yl) amide	Piperidine derivatives	3.92/355	1.40ppm(m，4H)，1.60ppm(m，2H)，3.43ppm(m，4H)，7.37ppm-7.50ppm(m，5H)，7.61ppm(s，1H)，7.62ppm(s，1H)，9.07ppm(s，1H)，12.62ppm(s，1H)	C11		Chlorocarboxylic acid isobutyl ester	4.55/344
C12		Piperidine derivatives	3.92/355		C13	1- (3-azetidin-1-yl-propyl) -3- (6-chloro-5-phenyl-1H-indazole-3-yl) urea	Azetidine (bis adduct)		1.50ppm (m, 2H), 2.02ppm (m, 1H), 3.20ppm (m, 2H), 2.54ppm (masked, 2H), 3.27ppm (masked, 4H), 7.35ppm-7.50ppm (m, 5H), 7.59ppm (s, 1H), 7.72ppm (bt, J ═ 6Hz, 1H), 8.09ppm (s, 1H), 9.44ppm (s, 1H), 12.50ppm (s, 1H)
C14	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (3-chloropropyl) -urea	Azetidine (open HCl)	4.26/363	1.94ppm (m, 2H), 3.30ppm (masked, 2H), 3.60ppm (t, J ═ 6.5Hz, 2H), 7.38ppm-7.50ppm (m, 5H), 7.58ppm (s, 1H), 7.60ppm (bt, J ═ 6Hz, 1H), 8.07ppm (s, 1H), 9.40ppm (s, 1H), 12.41ppm (s, 1H)	C13		Azetidine (bis adduct)
C14		Azetidine (open HCl)	4.26/363		C15	1- (6, 7-difluoro-5-phenyl-1H-indazol-3-yl) -3- (3-imidazol-1-ylpropyl) -urea	3-imidazol-1-ylpropylamines		1.94ppm(m，2H)，3.18ppm(q，J＝6.5Hz，2H)，4.02ppm(t，J＝6.5Hz，2H)，6.89ppm(s，1H)，7.21ppm(s，1H)，7.42ppm(bt，J＝7.5Hz，1H)，7.50ppm(bt，J＝7.5Hz，2H)，7.55ppm(bd，J＝7.5Hz，2H)，7.65ppm(s，1H)，7.73ppm(bt，J＝6.5Hz，1H)，8.05ppm(d，J＝6.0Hz，1H)，9.58ppm(s，1H)
C16	1- (3-Aminopropanol)	3-Aminopropanol	2.74/344	1.77ppm(m，2H)，2.81ppm(m，	C15		3-imidazol-1-ylpropylamines

	3- (6-chloro-5-phenyl-1H-indazol-3-yl) -urea	Amines as pesticides		2H)，3.28ppm(m，2H)，7.38ppm-7.50ppm(m，5H)，7.60ppm(s，1H)，7.81ppm(m，3H)，8.08ppm(s，1H)，9.54ppm(s，1H)，12.54ppm(s，1H)
	3- (6-chloro-5-phenyl-1H-indazol-3-yl) -urea	Amines as pesticides			C17	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- [4- (4-pyridin-3-yl-imidazol-1-yl) -butyl]-urea	4- (4-pyridin-3-yl-imidazol-1-yl) -butylamine	2.95/486	1.51ppm(m，2H)，1.90ppm(m，2H)，3.26ppm(m，2H)，4.23ppm(t，J＝7Hz，2H)，7.37ppm-749ppm(m，5H)，7.58ppm(s，1H)，7.75ppm(m，2H)，8.08ppm(s，1H)，8.37ppm(d，J＝2Hz，1H)，8.47ppm(m，1H)，8.69ppm(dd，J＝1.5 and 5Hz，1H)，9.00ppm(bs，1H)，9.12ppm(d，J＝2Hz，1H)，9.48ppm(s，1H)，12.40ppm(bs，1H)
C18	1- (6-chloro-5-phenyl-1H-indazol-3-yl) -3- (2-pyrrolidin-1-yl-ethyl) -urea	2-pyrrolidin-1-yl-ethyl-amine	2.8/384	1.83ppm (m, 2H), 1.99ppm (m, 2H), 3.03ppm (m, 2H), 3.28ppm (m, 2H), 3.56ppm (masked, 4H), 7.36ppm-7.49ppm (m, 5H), 7.61ppm (s, 1H), 7.80ppm (bt, J ═ 5.5Hz, 1H), 8.08ppm (s, 1H), 9.65ppm (s, 1H), 10.02 ppm (m, 2H), 3.03ppm (m, 2H), 3.28ppm (m, 2H), 3.56ppm (masked, 4H), 7.36ppm-7.49ppm (m, 5H), 7ppm(bs，1H)，12.62ppm(bs，1H)	C17		4- (4-pyridin-3-yl-imidazol-1-yl) -butylamine	2.95/486
C18		2-pyrrolidin-1-yl-ethyl-amine	2.8/384		C19	2, 5-dimethyl-pyrrolidine-1-carboxylic acid (6-chloro-5-phenyl-1H-indazol-3-yl) -amide	2, 5-dimethyl-pyrrolidine	4.08/369	1.10 and 1.21ppm (d, J. 7Hz, 6H), 1.50 and 1.61ppm (m, 2H), 1.99 and 2.12ppm (m, 2H), 4.03 and 4.15ppm (m, 2H), 7.36-7.49ppm (m, 5H), 7.60ppm (s, 1H), 7.67 and 7.69ppm (s, 1H), 8.52 and 8.66ppm (s, 1H), 12.60ppm (bs, 1H)

Example D1: n- (6-chloro-5-phenyl-1H-indazol-3-yl) -acetamidine

To a solution of 50mg of 3-amino-6-chloro-5-phenyl-1H-indazole in 3ml of acetonitrile and 12mg of acetic acid, 33mg of acetylimino acid methyl ester (acteyl) was added. The reaction was carried out under microwave at 180 ℃ for 5 minutes. After usual workup and purification on silica gel, 35mg of n- (6-chloro-5-phenyl-1H-indazol-3-yl) -acetamidine were obtained.

Examples D2 to D4

The following product was obtained in the same manner as D1.

Numbering	Name (R)	Starting materials	Retention time/[ M + H]⁺	NMR
Numbering	Name (R)	Starting materials	Retention time/[ M + H]⁺	NMR	D2	(6-chloro-5-phenyl-1H-indazole-3-)	6-methoxy-pyrazine-2-ethoxy	3.61/379	4.08ppm(s，3H)，7.40-7.50ppm(m，5H)，7.68ppm(s，1H)，7.93ppm

	6-methoxy-pyrazine-2-carboxamidine	Imino acid esters (imidate)	(s，1H)，8.24ppm(bs，1H)，8.43ppm(s，1H)，8.69ppm(bs，1H)，9.27ppm(s，1H)，12.80ppm(bs，1H)
	6-methoxy-pyrazine-2-carboxamidine	Imino acid esters (imidate)		D3	N- (6-chloro-5-phenyl-1H-indazol-3-yl) -benzamidine	Phenylethoxyimino acid esters	3.42/347	7.36ppm-7.50ppm(m，8H)，7.64ppm(s，1H)，7.80ppm(s，1H)，8.12ppm(m，2H)，8.24ppm(bs，1H)，8.76ppm(bs，1H)，12.60ppm(bs，1H)
D4	N- (6-chloro-5-phenyl-1H-indazol-3-yl) -pyridine-2-carboxamidine	Pyridine-2-ethoxy imino acid ester	7.35-7.50ppm (m, 5H), 7.54ppm (dd, J ═ 5.0 and 7.5Hz, 1H), 7.67ppm (s, 1H), 7.87ppm (s, 1H), 7.94ppm (dt, J ═ 1.5 and 7.5Hz, 1H), 8.30ppm (bs, 1H), 8.58ppm (d, J ═ 7.5Hz, 1H), 8.64ppm (bs, 1H), 8.58ppm (dd, J ═ 1.5 and 5.0Hz, 1H), 12.70ppm (bs, 1H)	D3	N- (6-chloro-5-phenyl-1H-indazol-3-yl) -benzamidine	Phenylethoxyimino acid esters	3.42/347

Example E1: n- (6-chloro-5-phenyl-1H-indazol-3-yl) -3-methoxy-benzenesulfonamide

Step 1: 0.236cm³Pyridine and 26.5mg 3-methoxyphenylsulfonyl chloride to 54.1mg 3-amino-5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl]-indazole in solution in 2ml dichloromethane. This reaction medium is stirred at room temperature for 24 hours and then evaporated. The crude product was purified by chromatography on a silica gel column (eluent: dichloromethane/acetone (98/2, v/v)) to give 70mg of 1N- [ 6-chloro-5-phenyl-1- (2-trimethylsilyl-ethoxymethyl) -1H-indazol-3-yl]-3-methoxy-benzenesulfonamide (colorless foam).

Mass spectrum: 546[ M + H ] +; retention time: 4.24 minutes.

¹H NMR[d₆-DMSO]：10.96(1H，s)，7.37(1H，s)，7.58(1H，s)，7.30-7.55(8H，m)，7.17(1H，dd)，5.63(2H，s)，3.74(3H，s)，3.38(2H，t，J＝8Hz)，0.74(2H，t，J＝8Hz)，-0.12(9H，s)。

Step 2:

mixing 1cm³2N HCl to 10.8mg of 1N- [ 6-chloro-5-phenyl-1- (2-trimethylsilyl-ethoxymethyl) -1H-indazol-3-yl]-3-methoxy-benzenesulfonamide at 1cm³In solution in methanol. The reaction medium is stirred at room temperature for 48 hours, refluxed for 1 hour and then evaporated. The resulting solid was dried in vacuo to give 8mg of N- (6-chloro-5-phenyl-1H-indazol-3-yl) -3-methoxy-benzenesulfonamide as a colorless solid.

Mass spectrum: 414[ M + H ] +; retention time: 4.04 min.

¹H NMR[d₆-DMSO]: 12.90(1H, width s), 10.74(1H, width s), 7.67(1H, s), 7.31-7.56(10H, s), 7.20(1H, dd), 3.77(3H, s).

The pharmaceutical compositions of the present invention comprise a compound of formula (I) or a salt of such a compound, either as pure compounds or in the form of a composition in which it can be combined with any other pharmaceutically compatible product, which may be inert or physiologically active. The medicament of the invention can be administered orally, parenterally, rectally or topically.

As oral solid compositions, tablets, pills, powders (gelatin capsules, powders) or granules may be used. In these compositions, the active ingredient of the invention may be mixed under an argon atmosphere with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica. These compositions may also contain substances other than diluents, for example one or more lubricants, like magnesium stearate or talc, colorants, coatings (dragees) or lacquers.

As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable or paraffin oils may be used. These compositions may contain substances other than diluents, for example wetting agents, sweeteners, thickeners, flavoring agents or stabilizers.

The sterile composition for parenteral use may preferably be an aqueous or non-aqueous solution, suspension or emulsion. As solvents or carriers, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents can be used. These compositions may also contain additives, in particular wetting agents, isotonizing agents, emulsifying agents, dispersing agents and stabilizing agents. Sterilization can be accomplished in a variety of ways, such as sterile filtration, addition of a sterilizing agent to the composition, sterilization by radiation, or sterilization by heat. They may also be formulated as sterile solid compositions which can be dissolved in sterile water or any other sterile injectable medium at the time of use.

Rectal compositions are suppositories or rectal capsules which contain, in addition to the active ingredient, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Topical compositions may be, for example, creams, lotions, eye washes, mouthwashes, nasal drops or aerosols.

Objects of the present invention are these aminoindazole compounds of formula (I) and pharmaceutically acceptable salts thereof, the use of aminoindazoles of formula (I) and pharmaceutically acceptable salts thereof for the preparation of pharmaceutical compositions for the prevention and treatment of diseases caused by abnormal kinase activity, such as, for example, those related to neurodegenerative diseases, alzheimer's disease, parkinson's disease, frontier dementia, corticobasal degeneration, Pick's disease, cerebrovascular accidents, cranial and spinal injuries, as well as peripheral neuropathies, obesity, metabolic disorders, type II diabetes, essential hypertension, atherosclerotic cardiovascular disease, polycystic ovary syndrome, syndrome X, immunodeficiency and cancer.

As the abnormal kinase activity, for example, kinase activities of PI3K, AkT, GSK3 β, CDK's and the like can be mentioned.

For human therapy, the compounds of the invention are particularly useful for the prevention and/or treatment of the following diseases: neurodegenerative diseases, alzheimer's disease, parkinson's disease, frontal dementia, corticobasal degeneration, Pick's disease, cerebrovascular accidents, cranial and spinal injuries and peripheral neuropathies, obesity, metabolic diseases, type II diabetes, essential hypertension, atherosclerotic cardiovascular disease, polycystic ovary syndrome, syndrome X, immunodeficiency and cancer.

Their dosage depends on the desired effect, treatment time and method of administration, and is generally 5-1000mg per day for an adult, with a unit dose of 1-250mg of active substance.

Generally, the physician will determine the appropriate dosage depending on the age, weight and other factors of the patient to be treated.

The following examples illustrate the compositions of the invention:

example A

Capsules are prepared according to the usual techniques at a dose of 50mg of active ingredient, the composition of which is as follows:

a

.

Example B

Tablets with a dose of 50mg of active ingredient are prepared according to the usual techniques for producing tablets, the composition of which is as follows:

a

.

-hydroxymethylcellulose, glycerol, titanium dioxide mixture (72-3.5-24.5) in suitable amounts up to a final tablet of 245mg in 1 tablet.

Example C

An injectable solution containing 10mg of active ingredient was prepared, consisting of:

a

.

The.

The invention also relates to methods of preventing and treating diseases involving tau protein phosphorylation by administering compounds of formula (I) and pharmaceutically acceptable salts thereof.

Claims

1. A compound selected from the group consisting of:

3-amino-5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl ] -indazole;

n- [ [ 5-phenyl-6-chloro-1- (2-trimethylsilylethoxy) methyl ] -indazol-3-yl ] ] -butanamide;

n- [ [ 5-bromo-6-chloro-1- (2-trimethylsilylethoxy) methyl ] -indazol-3-yl ] ] -butanamide;

n- [ [ 6-chloro-1- (2-trimethylsilylethoxy) methyl ] -indazol-3-yl ] ] -butanamide.