RS52767B - NEW AMINOINDASOL DERIVATIVES AS THE MEDICINAL PRODUCTS AND PHARMACEUTICAL FORMS CONTAINING THEM - Google Patents

Abstract

Compounds of formula (I): wherein R 3 is (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, aryl or heteroaryl radical fused to (1-10C) cycloalkyl, heterocycle , heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO2R1 or C (= NH) NR1; these are optionally substituted by one or more substituents selected from halogen, CN, NO2, NH2, OH, OR1, COOH, C (O) OR1, -OC (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, -OC (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, ethylene, acetylenyl, trifluoromethoxy, NO2, NH2 or NMe2 radical, R1 R2 , R 10 and R 11 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 halogen on, (1-6C) alkyl, (1-6C) alkoxy, CN, NO2, NH2, OH, COOH, COOalkyl, CONH2, formyl, oxo, trifluoromethyl and trifluoromethoxy, their racemates, enantiomers and diastereoisomers and mixtures thereof, their tautomers and pharmaceutically acceptable salts. The application comprises a further 12 claims.

Description

The present invention relates to the application of derivatives of formula (I):

or pharmaceutically acceptable salts thereof as kinase inhibitors.

Patent applications WO 02/22603, WO 02/50065, WO 02/50066 and WO 02/22601 disclose pyrazole derivatives and their use as inhibitory agents of protein kinases such as GSK-3 and Aurora-2.

Additionally, application WO 03/078403 (Document as defined in Article 54 (3) EPC) discloses aminoindazole derivatives and their use in the treatment of diseases in which Tau protein phosphorylation is observed.

The subject invention relates to the use of aminoindazole derivatives of formula (I) and their pharmaceutically acceptable salts for obtaining pharmaceutical forms intended for the prevention and treatment of diseases that can result in abnormal activity of kinases such as those that appear in neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, frontoparietal dementia, corticobasal degeneration, Pick's disease, cerebrovascular damage, cranial and spinal trauma, peripheral neuropathy, obesity, metabolic disorders, type II diabetes, essential hypertension, atherosclerotic cardiovascular diseases, polycystic ovary syndrome, syndrome X, immunodeficiency and cancer, where the pharmaceutical forms contain new aminoindazole derivatives and their pharmaceutically acceptable salts.

The present invention relates to aminoindazole derivatives of formula (I) in which:

R3 is (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, aryl or heteroaryl radical fused to (1-1OC)cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO2R1, C(=NH)NR1; where these radicals may optionally be substituted with one or more substituents selected from halogen, CN, N02, NH2, OH, ORI, COOH, C(0)ORl, -0-C(0)Rl, NR1R2, NHC(0)R1, C(0)NR1R2, SR1, S(0)R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, (1-6C)alkyl;

R5 is aryl optionally substituted with 1 or more substituents selected from halogen CN, NO2, NH2, OH, ORIO, 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, (1-6C)alkyl;

R6 is halogen, methyl, cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethyleneyl, acetylenyl, trifluoromethoxy, NO2, NH2, NMe2 radical;

R1, R2, R10 and R11 are independently hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl, heteroaryl which may themselves be substituted with 1 or more substituents selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO2, NH2, OH, COOH, COOalkyl, CONH2, formyl, oxo, trifluoromethyl, trifluoromethoxy ;

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

Most preferably, the present invention relates to derivatives of formula (I) where: R3 is (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, aryl or heteroaryl radical fused with cycloalkyl (1-1OC), heterocycle, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO2R1, C(=NH)NR1; wherein these radicals may be optionally substituted with 1 or more substituents selected from halogen, CN,N02, NH2, OH, ORI, COOH, C(0)ORl, -0-C(0)Rl, NR1R2, NHC(0)R1, C(0)NR1R2, SR1, S(0)R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, oxo, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, (1-6C)alkyl;

R5 is phenyl optionally substituted with 1 or more substituents selected from halogen, CN, NO2, NH2, OH, ORIO, COOH, C(O)OR10, -O-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10Rl 1, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10R11, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy, (1-6C)alkyl;

R6 is halogen, methyl, cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethyleneyl, acetylenyl, trifluoromethoxy, NO2, NH2, NMe2 radical;

R1, R2, R10 and R11 are independently of each other hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl, heteroaryl which may themselves be substituted with 1 or more substituents selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO2, NH2, OH, COOH, COOalkyl, CONH2, formyl, oxo, trifluoromethyl, trifluoromethoxy;

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

Most conveniently, the present invention relates to derivatives of formula (I) where: R 3 is (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, aryl or heteroaryl radical fused with (1-1OC)cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CONR1R2, COOR1, SO2R1, C(=NH)NR1; wherein these radicals may be optionally substituted with 1 or more substituents selected from halogen, CN, N02, NH2, OH, ORI, COOH, C(0)ORl, -0-C(0)Rl, NR1R2, NHC(0)R1, C(0)NR1R2, SR1, S(0)R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, oxo, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, (1-6C)alkyl;

R5 is phenyl;

R6 is chlorine;

R1, R2 are independently of each other hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl, heteroaryl, which themselves can optionally be substituted with 1 or more substituents selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO2, NH2, OH, COOH, COOalkyl, CONH2, formyl, trifluoromethyl, trifluoromethoxy;

their isomers, their mixtures, their racemates, enantiomers, diastereoisomers, tautomers as well as their pharmaceutically acceptable salts.

In the preceding definitions and in those that follow, alkyl(1-6C) radicals contain 1 to 6 carbon atoms in a straight or branched chain; alkenyl radicals of 2 to 6 carbon atoms and one to three double bonds conjugated or not in a straight or branched chain;

Aryl radicals are selected from phenyl, naphthol or indenyl; heteroaryl radicals contain 3 to 10 members, and optionally contain one or more heteroatoms selected from oxygen, sulfur and nitrogen, especially thiazolyl, thienyl, pyrrolyl, pyridinyl, furyl, imidazolyl, oxazolyl, pyrazinyl, tetrazolyl, oxadiazolyl, thiadiazolyl, isoxadiazolyl, isothiadiazolyl, isothiazolyl, isoxazolyl, triazolyl, pyrazolyl indolyl; halogen radical can be chlorine, iodine, fluorine, bromine; polycycloalkyl derivatives are selected from adamantyl, quinucyclidinyl, bornanyl, norbornanyl, bornenyl, norbornenyl; heteroaryl radicals fused to one cycloalkyl (1-1OC) are selected from indanyl, isochromanyl, chromanyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl; heterocyclic radicals consist of 1 to 2 heteroatoms selected from oxygen, sulfur, nitrogen and are primarily represented by piperidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolidinyl, thiazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, acetidinyl, 2-piperidone, 3-piperidone, 4-piperidone, 2-pyrrolidone, 3-pyrrolidone.

Compounds of the general formula (I) contain one or more asymmetric carbons and can be presented in the form of isomers, racemates, enantiomers and diastereomers; and these form an integral part of this invention as well as their mixtures.

Among the compounds of general formula (I) that are used according to this invention, we can mention the following: N-(bicyclo[2,2,1]hept-5-en-2ylmethyl)-6-chloro-5-phenyl-1H-indazol-3-amine 6-chloro-N-(3,3-dimethylbutyl)-5-phenyl-1 H-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-1 H-indazol-3-amine 6-chloro-N-[3-(methylthio)propyl]-5-phenyl-1 H-indazol-3-amine 6-chloro-N-(phenylethyl)-5-phenyl-1 H-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 6-chloro-N-(4,4,4-trifluorobutyl)-5-phenyl-1H-indazol-3-amine, hydrate H-indazol-3-amine 6-chloro-N-[(4-methoxyphenyl)methyl]-5-phenyl-1 H-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-naphthalenyl)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-(3,33-trifluoropropyl)-1H-indazol-3-amine 6-chloro-5-phenyl-N-(3 -thienylmethyl)-1 H-indazol-3-amine N-(bicyclo[2,2J]hept-5-en-2ylmethyl)-6-chloro-5-phenyl-1H-indazol-3-amine N-([1,1 '-biphenyl]-4-ylmethyl)-6-chloro-5-phenyl-1H-indazol-3-amine 6-chloro-N-[[4-(dimethylamino)phenyl]methyl]-5-phenyl-1H-indazol-3-amine N-([2,2'-bithiophen]-5-ylmethyl)-6-chloro-5-phenyl-1H-indazol-3-amine 6-chloro-5-phenyl-N-[[l-(phenylmethyl)-lH-imidazol-241]methyl]-lH-indazol-3-amine 6-chloro-N-[[l-methyl-lH-imidazol-2-yl]methyl]-5-phenyl-lH-indazol-3-amine 6-chloro-N- [(1 -methyl-1H-indazol-3-yl)methyl]-5-phenyl-1H-indazol-3-yl] -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-yl)methyl]-1H-indazol-3-amine 6-chloro-5-phenyl-N-(1H-imidazol-4-yl)methyl-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-furanyl]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-mranyl]-benzenesulfonam 6-chloro-5-phenyl-N-(3-thienylmethyl)-1H-indazol-3-amine

6-chloro-5-phenyl-N-[[2-phenyl-1H-imidazol-4-yl]methyl]-1H-indazol-3-amine ethyl 2-[[[6-chloro-5-phenyl-1H-indazol-3-yl]amino]methyl]-5-(methylthio)-1H-imidazol-4-carboxylate

6-chloro-5-phenyl-N-[[5-[4-(trifluoromethyl)phenyl]-2-furanyl]methyl]-1H-indazo 6-chloro-5-phenyl-N-[2-(1-piperidinyl)ethyl]-1H-indazol-3-arnine 6-chloro-N-[2-(4-morpholinyl)ethyl]-5-phenyl-1H-indazol-3-arnine N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-(3,5-dichlorophenyl)-urea N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-(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-1 H-indazol-3-yl)-N'-[(4-methoxyphenyl)methyl]-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]dec-1 -yl-urea N-[6-chloro-5-phenyl-1H-indazol-3-yl]-4-methyl-benzenesulfonamide N-[6-chloro-5-phenyl-1H-indazol-3-yl]-methanesulfonamide

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

N-[6-chloro-5-phenyl-1H-indazol-3-yl]-2-thiophenesulfonamide N-[6-chloro-5-phenyl-1 H-indazol-3-yl]-benzenesulfonamide N-[6-chloro-5-phenyl-1H-indazol-3-yl]-4-(trifluoromethyl)-benzenesulfonamide N-[6-chloro-5-phenyl-1H-indazol-3-yl]-5-(3-isoxazolyl)-24iophenesulfonamide N-[6-chloro-5-phenyl-1H-indazol-3-yl]-4-fluoro-benzenesulfonamide N-[6-chloro-5-phenyl-1H-indazol-3-yl]-4-methoxy-benzenesulfonamide H-indazol-3-yl]-benzenemethanesulfonamide N-[6-chloro-5-phenyl-1 H-indazol-3-yl]-1 -methyl-1 H-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 N-[6-chloro-5-phenyl-1H-indazol-3-yl]-4-methyl-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-1 H-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-pyridinyl)-5-phenyl-1H-indazol-3-amine

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

their isomers, their mixtures, their enantiomeric racemates, diastereoisomers, tautomers as well as their pharmaceutically acceptable salts,

and especially the following compounds:

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

3-(6-chloro-5-phenyl-1H-indazol-3-ylamino)-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 H-indazol-3-yl)-N'-phenyl-urea 1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(4-ethoxy-phenyl)-urea

l-(6-Chloro-5-phenyl-lH-indazol-3-yl)-3-(3,4-dichloro-phenyl)-urea methyl ester 3-[3-(6-chloro-5-phenyl-lH-indazol-3-yl)-ureido]-propionic acid l-(6-chloro-5-phenyl-lH-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-trifluoromethyl-phenyl)-urca l-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(2-thiophen-2-yl-ethyl)-urea l-benzo[l,3]dioxol-5-yl-3-(6-chloro-5-phenyl-1H-indazol-3-yl)-urea l-(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 l-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-phenethyl-thiourea l-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-[3-(4-methyl-piperazin-1-yl)-propyl]-urea 1 -(6-chloro-5 -phenyl-1 H -indazol-3 -yl)-3 -(3 -imidazol-1 -yl)-urea

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

(6-Chloro-5-phenyl-1H-indazol-3-yl)-3-[3-(4-methyl-piperazin-1-yl)-propyl]-urea methyl ester (6-Chloro-5-phenyl-1H-indazol-3-yl)-carbamic acid (6-Chloro-5-phenyl-1H-indazol-3-yl)-urea

Benzyl ester (6-Chloro-5-phenyl-1H-indazol-3-yl)-carbamic acid allyl ester (6-Chloro-5-phenyl-1H-indazol-3-yl)-carbamic acid isobutyl ester (6-Chloro-5-phenyl-1H-imdazol-3-yl)-carbamic acid 1 -(3 -azetidin-1 -yl-propyl)-3-(6-chloro-5-phenyl-1H-indazol-3-yl)-carbamic acid H-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-indazol-1-yl)-butyl]-urea 1 -(6-chloro-5-phenyl-1H-indazol-3-yl)-3- {2-pyrrolidin-3-yl-ethyl)-urea

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

their isomers, mixtures, racemic enantiomeric isomers, diastereoisomers, tautomers

as well as their pharmaceutically acceptable salts,

The present invention also relates to pharmaceutical forms which as an active principle contain derivatives of formula (I) where: R3 is (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, aryl or heteroaryl radical condenses with (1-1OC)cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO2R1, C(=NH)NR1; where these radicals may optionally be substituted with one or more substituents selected from halogen, CN, N02, NH2, OH, ORI, COOH, C(0)ORl, -0-C(0)Rl, NR1R2, NHC(0)R1, C(0)NR1R2, SR1, S(0)R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, (1-6C)alkyl;

R5 is aryl optionally substituted with 1 or more substituents selected from halogen CN, NO2, NH2, OH, ORIO, COOH, C(O)OR10, -O-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10Rl 1, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2RIO, SO2NRIORI1, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy, (1-6C)alkyl;

R6 is halogen, methyl, cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethyleneyl, acetylenyl, trifluoromethoxy, NO2, NH2, NMe2 radical;

R1, R2, R10 and R11 are independently hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl, heteroaryl which may themselves be substituted with 1 or more substituents selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO2, NH2, OH, COOH, COOalkyl, CONH2, formyl, oxo, trifluoromethyl, trifluoromethoxy;

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

In the most acceptable manner, the present invention relates to pharmaceutical forms which as an active component contain derivatives of formula (I) where: R3 is (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, aryl or heteroaryl radical condensed with cycloalkyl (1-10C), heterocycle, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, COOR1, SO2R1, C(=NH)NR1; wherein these radicals may be optionally substituted with 1 or more substituents selected from halogen, CN,N02, NH2, OH, ORI, COOH, C(0)0R1, -0-C(0)Rl, NR1R2, NHC(0)R1, C(0)NR1R2, SR1, S(0)R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethyl-sulfanyl, trifluoromethoxy, (1-6C)alkyl;

R5 is phenyl;

R6 is chlorine;

R1, R2 are independently of each other hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl, heteroaryl which themselves can be substituted with 1 or more substituents selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO2, NH2, OH, COOH, COOalkyl, CONH2, formyl, trifluoromethyl, trifluoromethoxy; their isomers, smile,

racemates, enantiomers, diastereoisomers, tautomers as well as their pharmaceutically acceptable salts.

The present invention also relates to the use as a drug of an aminoindazole derivative of formula (I) where: R3 is (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, aryl or heteroaryl radical condensed radical condensed with (1-1 OC) cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO2R1, C(=NH)NR1; wherein these radicals may be optionally substituted with one or more substituents selected from halogen, CN, N02, NH2, OH, ORI, COOH, C(0)0R1, -0-C(0)Rl, NR1R2, NHC(0)R1, C(0)NR1R2, SR1, S(0)R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, oxo, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, (1-6C)alkyl;

R5 is aryl optionally substituted with 1 or more substituents selected from halogen CN, NO2, NH2, OH, ORIO, 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, (1-6C)alkyl;

R6 is halogen, methyl, cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethyleneyl, acetylenyl, trifluoromethoxy, NO2, NH2, NMe2 radical;

R1, R2, R10 and R11 are independently hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl, heteroaryl which may themselves be substituted with 1 or more substituents selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO2, NH2, OH, COOH, COOalkyl, CONH2, formyl, oxo, trifluoromethyl, trifluoromethoxy; their racemates, enantiomers, diastereoisomers and mixtures thereof, their tautomers and their pharmaceutically acceptable salts.

Most preferably, the present invention relates to the use of an aminoindazole derivative of formula (I) as a drug, where: R3 is (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, aryl or heteroaryl radical fused to (1-1OC)cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, COOR1, SO2R1, C(=NH)NR1; wherein these radicals may be optionally substituted with 1 or more substituents selected from halogen, CN, N02, NH2, OH, ORI, COOH, C(0)ORl, -0-C(0)Rl, NR1R2, NHC(0)R1, C(0)NR1R2, SR1, S(0)R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2R1, -SO2-O-R1, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, (1-6C)alkyl;

R5 is phenyl;

R6 is chlorine;

R1, R2 are independently of each other hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl, heteroaryl which themselves can be substituted with 1 or more substituents selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO2, NH2, OH, COOH, COOalkyl, CONH2, formyl, trifluoromethyl, trifluoromethoxy; their isomers, their mixtures,

their racemates, enantiomers, diastereoisomers, tautomers as well as their pharmaceutically acceptable salts.

Derivatives of formula (I) can be obtained starting from the corresponding 3-amino derivative (V), in which the nitrogen at position 1 is optionally protected with the Pr group. Pr is a radical trimethylsilyletoxymethyl, tosyl, mesyl, benzyl or groups known to protect NH-heterocyclic aromatic amines as indicated in T. W. GREENE, Protective

groups in organic Synthesis, J. Wiley- Interscience Publication (1999)

3-amino 1H-indazoles of formula (II) can be obtained in the reaction of one 2-fluorobenzonitrile with hydrazine, hydrate or chlorohydrate under reflux for 2 to 18 hours in ethanol or n-butanol type alcohol according to (R.F. KALTENBACH, Bioorg. Med. Chem. Lett, 9J15), 2259-62, (1999)).

Compounds in which R5, R6 are independently selected from halogen, CN, NO2, NH2, OH, trifluoromethyl, trifluoromethoxy, aryl, cyclopropyl, ethylenyl, acetylenyl, methyl, methoxy, NMe2where these radicals may be optionally substituted with 1 or more substituents selected from halogen, CN, NO2, NH2, OH, ORIO, COOH, C(O)OR10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy, (1-6C)alkyl; can be obtained in reactions in which palladium is used: Suzuki, (A. SUZUKI, Pure Appl. Chem.63, 419-22, (1991), Stille (J.

Stille, Angew. Chem. Int. Ed. 25, 508-24, (1986), Heck, (R.F. HECK, Org. React., 27^

345-90, (1982), Sonogashira, (K. SONOGASHIRA, Synthesis 777, (1977), Buckwald ( FIG.

BUCKWALD, Acc. Chem. Re., 32, 805, (1998) starting from the corresponding halogen derivatives.

For this it is necessary to protect reactive functional groups. Also, OH, SH, COOR, NH2 functional groups need to be protected before coupling. Protective groups are introduced by methods known to those skilled in the art, primarily those described by T.W. GREENE, Protective groups in Organic Synthesis, J. Wiley-Interscience Publication

(1999). It is preferred to protect the nitrogen in position 1 with groups such as tert-butoxycarbonyl or derivatives which are silicified. It is preferable to choose one silyl group such as tert-butyldimethylsilyl, triisopropylsilyl which can be eliminated with fluorinated anions or with acetic acid and even more specifically it can be one trimethylsilylethoxymethyl group which can be removed with tetrabutylammonium fluoride under reflux in a solvent such as tetrahydrofuran, dioxane ( J. P. WHITTEN, J. Org. Chem., 51, 1891, (1986) ; B. H. L1PSHUTZ, Tetrahedron Lett., 4095, (1986)) or with 2N hydrochloric acid in methanol or ethanol under reflux.

Derivatives protected in position 1 with trimethylsilylethoxymethyl were obtained by reacting the starting compound starting from trimethylsilylethoxymethyl in the presence of sodium hydroxide in a solvent such as dimethylformamide at room temperature J.P. WHITTEN, J. Org. Chem., 51, 1891,

(1986); M. P. EDW ARDS, Tetrahedron, 42, 3723, (1986)).

Likewise, the nitrogen functional group of 1 -NH indazole will be protected with groups such as tosyl, carbamate, benzyl or silyl derivatives. For example, in cases where we want to perform palladium coupling on a halogen derivative in the 6-position, the nitrogen in the 1-position should be protected as shown below (X = CI, Br, J):

The removal of protective groups takes place according to the methods known to people from pike and which are described in T. W. GREENE, Protective groups in Organic Synthesis, J. Wiley - Interscience Publication (1999). For example, if the protecting group in position 1 is a trimethylsilylethoxymethyl, it can be deprotected by reaction with tetrabutylammonium fluoride as shown below:

If the groups R5, R6 that participate in the coupling and are under the influence of palladium contain some reactive functional group such as hydroxy, amino, thiol, acid or, in general, contain a heteroatom, it is necessary to protect them before performing the coupling with palladium. Also, for example, one phenolic functional group should be introduced in a protected form (O-benzyl for example) starting from a chlorine or nitrogen derivative at position 1 that is thus protected, which can be shown as:

The benzyl group can then be eliminated for example by treatment with refluxing trimethylsilyl iodide in acetonitrile. Protection can also be achieved with the trimethylsilylethoxymethyl group which can be removed with tetrabutylammonium fluoride under reflux in solvents such as tetrahydrofuran, dioxane, (J.P. WHITTEN, J. Org.chem., 51, 1986; B.H. LIPSHUTZ, Tetrahedron Lett., 4095, (1986)), or by hydrochloric acid 2N in methanol or ethanol. in reflux.

If R5 and R6 are independently of each other aryl and some halogen, the aryl functional group is introduced by coupling with palladium at the brominated position, where the nitrogens at positions 1 and 3 are appropriately protected. Preferably, Pr represents one trimethylsilylethoxymethyl and Pr' represents an n-butylcarboxy group which forms N-butylamide with nitrogen. The amide deprotection step is carried out in the presence of ethanolamine under reflux for one week in DMF. This removal can also be performed with stano chloride in ethanol (RJ Griffin, J. Chem. Soc. Perkin 11992, 1811-1819) or with sodium methylate in methanol (Y. Furukawa, Chem. Pharm. Buli. 1968, 16, 1076) or any other alcoholate in a suitable alcohol.

Compounds of the general formula II are the starting point for obtaining a large variety of products that are obtained in the reaction of the primary amino functional group of 3-amino indazole in all classic reactions of this functional group such as: alkylation, acylation, reactions with carbonyl derivatives followed by reduction, sulfonation, transformation into urea or carbamates, arylation (Castro reaction or Buchwald reaction), etc.

Amino reductions of derivatives from derivatives of general formula (I) or R3 and H when Pr is trimethylsilylethoxymethyl can be realized with the help of boron derivatives such as sodium triacetoxyborohydride in dichloromethane in the presence of an aldehyde of the type R1CHO under the conditions described in Organic Reactions vol. 59, 1-714 (E. Baxter, A. Reitz) or by other reductions normally used to reduce imines to give products where R3 is (1-6C)alkyl, aryl (1-6C)alkyl, heteroaryl (1-6C)alkyl, heterocycloalkyl, cycloalkyl, polycycloalkyl, where these radicals may be optionally substituted with 1 or more substituents selected from halogen, CN, NO2, NH2, OH, ORIO, COOH, C(O)OR10, -O-C(O)R10, NR10Rll,NHC(O)R10, C(O)NR10Rl 1, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10R11, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy, (1-6C)alkyl;

Condensation with derivatives of the general formula (I) where R3 is H on isocyanates of the OCNR1 type can primarily be obtained in tetrahydrofuran and according to the examples given in Comprehensive Organic functional Group Transformations vol 6 (Katritzkv, Meth-Cohn, Rees 1995) in order to obtain a product where R3 and CONR1R2, R1, R2 are independently of each other hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl, heteroaryl which may themselves be substituted with 1 or more substituents selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO2, NH2, OH, COOH, COOalkyl, CONH2, formyl, trifluoromethyl, trifluoromethoxy.

Sulfonation of derivatives of general formula (I) where R 3 is H can be carried out starting from a sulfonyl chloride of the type R 1 SO 2 C 1 , in the presence of a base (especially a tertiary amine such as triethylamine or an aromatic such as pyridine) in a common solvent such as triethylamine to give a product in which R 3 and SO 2 R 1 and R 1 are hydrogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO2, NH2, OH, COOH, COOalkyl, CONH2, formyl, trifluoromethyl, trifluoromethoxy.

Compound IV with Pr is trimethylsilylethoxymethyl is 3-amino-5-phenyl-6-chloro-1-(2-trimethylsilylethoxy)methyl]indazole I was obtained as follows:

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

To 2.4 g of N-[[5-phenyl-6-chloro-1-(2-trimethylsilyl ethoxy)methyl]-indazol-3-yl]]-butanamide described above, in 75 cm of dimethylformamide was added 1.63 cm of ethanolamine and then 2.24 g of potassium carbonate and heated at reflux for a week. The reaction mixture was concentrated to dryness under reduced pressure and extracted with 250 cm<3>ethyl acetate and 100 cm<3>water. The organic phase is decanted and washed consecutively 2 times with 100 cm<3> of water and 75 cm<3> of saturated sodium chloride solution. The organic phase is dried with magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa-50°C). The crude oil obtained is purified by chromatography under an argon pressure of 50 kPa, on a silica gel column (granules 40 - 60 µm; diameter 4 cm), eluting with a mixture of cyclohexane - ethyl acetate (80/20 in volumes) and collecting fractions of 35 cm<3>, the fractions containing the desired product are combined and evaporated under reduced pressure (2 kPa; 50°C).

1H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 8 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 (with capital: 2H); from 7.30 to 7.55 (mt: 5H); 7.77 (s : IH); 7.81 (s : IH).

N-[[5-phenyl-6-chloro-1-(2-trimethylsilylethoxy)methyl]-indazol-3-yl]]butanamide is obtained as follows: To 2 g of N-[[5-bromo-6-chloro-1-(2-trimethylsilyl ethoxy)methyl]-indazol-3-yl]]-butanamide described above in 180 cm<3>dioxane, add 821 mg of phenylboric acid, 1.14 g of sodium carbonate in 30 cm<3> of distilled water and finally 347 mg of tetrakis(triphenylphosphine) palladium. Heat at reflux for 90 minutes and then allow the temperature to reach 20°C to add 100 cm<3>ethyl acetate and 100 cm<3>distilled water. The organic phase is washed with 100 cm<3> of saturated aqueous sodium chloride and then decanted and dried with magnesium sulfate. After filtering on a glass plug, the filtrate is concentrated to dryness under reduced pressure (2 kPa — 50°C). The residue was purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (granules 40 - 60 pm; diameter 4.5 cm), eluting with a mixture of cyclohexane - ethyl acetate (80/20 by volume) and collecting fractions of 35 cm<3>. Fractions containing the desired product were combined and evaporated under reduced pressure (2 kPa; 50°C). After drying (2 kPa; 50°C), 2 g of N-[[5-phenyl-6-chloro-1-(2-trimethylsilylethoxy)methyl]-indazol-3-yl]]-butanamide are obtained in the form of a yellow oil.

1H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 8 in ppm) : -0.05 (s : 9H); 0.85 (t, J = 8 Hz : 2H); 0.92 (t, J = 7.5 Hz : 3H); 1.63 (mt: 2H); 2.38 (t, J = 7.5 Hz : 2H); 3.56 (t, J = 8 Hz : 2H); 5.70 (s : 2H); from 7.30 to 7.55 (mt: 5H); 7.91 (s: IH); 7.99 (s: IH); 10.59 (with capital: IH). N-[[5-bromo-6-chloro-1-(2-trimethylsilylethoxy)methyl]-indazol-3-yl]]-butanamide was prepared as follows: To 1 g of N-[[6-chloro-1-(2-trimethylsilylethoxy)methyl]-indazol-3-yl]]-butanamide described above in 15 cm<3>chloroform, 0.22 cm<3>pyridine was added and then 0.14 cm<3>bromine. It is stirred for 24 hours at 20°C and then 50 cm<3> of dichloromethane and 50 cm<3> of a saturated aqueous solution of sodium sulfate are added. After stirring for 10 minutes, the insoluble part is removed by filtration on a glass plug, the organic phase is decanted, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2 kPa; 45°C). The residue is purified by chromatography under an argon pressure of 50 kPa, on a silica gel column (granules 40 - 60 nm; diameter 3.5 cm), eluting with a mixture of ethyl acetate - cyclohexane (20/80 by volume) and collecting fractions of 35 cm<3>. Fractions containing the desired product are combined and evaporated under reduced pressure (2 kPa; 50°C). After drying (90 Pa - 45°C), 0.94 g of N-[[5-bromo-6-chloro-1-(2-trimethylsilylethoxy)methyl]-indazol-3-yl]]-butanamide is obtained in the form of a white substance that melts at 130°C.

H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 5 in ppm) : -0.08 (s : 9H); 0.82 (t, J = 8 Hz: 2H); 0.95 (t, J = 7.5 Hz : 3H); 1.66 (mt: 2H); 2.40 (t, J = 7.5 Hz: 2H); 3.52 (t, J = 8 Hz : 2H); 5.66 (s : 2H); 8.13 (with: IH); 8.34 (s: IH); 10.67 (with capital: IH).

N-[[6-chloro-1-(2-trimethylsilylethoxy)methyl]-indazol-3-yl]]-butanamide is obtained as follows: 3g of N-(6-chloro-1H-indazol-3-yl)-butanamide is added to 606 mg of 60% sodium hydride in 20 cm<3>dimethylformamide in a solution of 40 cm<3>dimethylformamide. After cooling to 5°C, 2.68 cm<3> of 2-(trimethylsilyl)ethoxymethyl chloride was added in 10 cm<3>. Let the temperature rise to 21°C and stir for another two hours. The reaction mixture was evaporated under reduced pressure (2 kPa; 45°C). The residue is combined with 200 cm<3>ethyl acetate and with 100 cm<3>distilled water. It is washed again with 100 cm<3> of a saturated aqueous solution of sodium chloride. The organic phase is dried with magnesium sulfate, filtered with magnesium sulfate and evaporated under reduced pressure (2 kPa; 50°C). The residue is purified by chromatography under an argon pressure of 50 kPa, on a silica gel column (granules 40 - 60 um; diameter 4.5 cm), eluting with a mixture of cyclohexane - ethyl acetate (80/20 by volume) and collecting fractions of 100 cm each <3.> Fractions containing the desired product are combined and evaporated under reduced pressure (2 kPa; 50°C). After drying (90 Pa; 50°C), 3g of N-[[6-chloro-1-(2-trimethylsilylethoxy)methyl]-indazol-3-yl]]-butanamide is obtained in the form of a yellow oil.

1H NMR spectrum (300 MHz, (CD 3 ) 2 SO d 6 , 5 in ppm) : -0.08 (s : 9H); .0.83 (t large, J=8 Hz : 2H); 0.96 (t, J = 7.5 Hz : 3H); 1.67 (mt: 2H); 2.40 (t, J = 7.5 Hz : 2H); 3.53 (t, J = 8 Hz; 2H); 5.66 (s : 2H); 7.16 (dd, J = 9 and 2 Hz; IH); 7.86 (d, J - 2 Hz: IH); 7.88 (d, J = 9 Hz : IH); 10.53 (mf:1H).

N-(6-chloro-1H-indazol-3-yl)-butanamide

To 750 mg of 3-amino-6-chloro-1H-indazole in 10 cm<3>pyridine, 0.47 cm<3>butyryl chloride was added, after the reaction mixture had previously been cooled to 3°C. Then the reaction mixture is kept at 19°C for 14 hours. The reaction mixture was evaporated to dryness under reduced pressure (2 kPa; 40°C). The residue is extracted with 50 cm<3> of distilled water. The organic phase is washed again with 50 cm of tetrahydrofuran and with 50 cm of saturated aqueous sodium chloride and then dried with magnesium sulfate, filtered on a glass plug and evaporated under reduced pressure. The resulting residue is purified by chromatography under an argon pressure of 50 kPa, on a silica gel column (granules 40 - 60 pm; diameter 2.5 cm), eluting with cyclohexane - ethyl acetate (70/30 in volume) and collecting fractions of 25 cm<3>. Fractions containing the desired product are combined and then evaporated under reduced pressure (2 kPa; 40°C). After drying (90 Pa, 45°C), 200 mg of N-(6-chloro-1H-indazol-3-yl)-butanamide is obtained, in the form of a white solid that melts at 230°C.

NMR spectrum<*>H (300 MHz, (CD 3 ) 2 SO d 6 , 5 in ppm) : 0.98 (t, J = 7 Hz : 3H); 1.67 (mt: 2H); 2.40 (t, J = 7 Hz; 2H); 7.08 (dd, J = 9 and 2 Hz: IH); 7.52 (d, J = 2 Hz: IH); 7.84 (d, J - 9 Hz: IH); 10.39 (mf: IH); from 12.50 to 13.00 (mf highlighted: IH).

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

To 108.3 mg of the compound 3-amino-5-phenyl-6-chloro-1-(2-trimethylsilylethoxy)methyl]-indazole in 4.7 ml of methanol was added 300 ul of HC1 2N. The reaction vessel is placed in a microwave oven for 150 seconds at 140°C.

The reaction mixture was poured onto saturated KH 2 PO 4 solution and extracted with AcOEt. The organic phases were dried with anhydrous MgSO 4 , filtered and concentrated. The obtained raw material was purified on silica gel and 63.5 mg of the compound 3-amino-6-chloro-5-phenyl-1H-indazole was obtained.

The compounds of formula (I) are isolated and can be purified by conventional methods, for example by crystallization, chromatography or extraction.

Compounds of formula (I) can optionally be transformed into salts by addition with mineral or organic acids, by the action of one such acid in the medium of an organic solvent such as an alcohol, ketone, ether or chlorinated solvent. These salts are an integral part of the present invention.

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

Compounds of formula (I) are kinase inhibitors and are used for the prevention and treatment of neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, frontoparietal dementia, corticobasal degeneration, Pick's disease, cerebrovascular damage, cranial and spinal trauma, peripheral neuropathy, obesity, essential hypertension, atherosclerotic cardiovascular diseases, polycystic ovary syndrome, X syndrome, immunodeficiency and cancer.

Their activity was determined by measuring the inhibition of tau protein phosphorylation in cortical lobes of adult rats.

Cortical sections 300 µm thick were obtained from diseased OFA (Iffa-Credo) rats aged 8 to 10 weeks, sacrificed by decapitation. They were then incubated in 5 ml DMEM medium containing pyruvates and glucose 4.5 g/l at 37°C for 40 min. The lobes were then washed 2 times with the solution, distributed in microtubes (50 µl in 500 µl of solution with or without the test compound) and incubated at 37°C with agitation. Two hours later, the experiment was stopped by centrifugation. Lobes were lysed, passed through ultrasound and centrifuged at 18300 g, 15 min. at 4°C. The concentration in the supernatant proteins was determined by commercial dosers (BCA Protein Assay, Pierce) based on the Lowry method.

Portions, previously denatured for 10 min at 70°C, were separated on a vertical gel 4-12% Bis-Tris in the presence of MOPS-SDS buffer and electrotransported on a nitrocellulose membrane. Immunolabeling was performed using AD2 monoclonal antibodies that recognize specific epitopes that are phosphorylated at Ser 396/404 of the tau protein. Immunoreactive protein were visualized by the addition of another antibody directed against mouse IgG and coupled to peroxidase and in a chemiluminescent substrate. The resulting autoradiograms were finally quantified using the 'Gene Tools' software from Syngene (GeneGnome, Ozyme) to determine the CI50.

The compounds of formula (I) show interesting values for activity and in particular certain compounds having a CI50 of less than 100 pM.

Product analysis conditions for TH/MS were achieved on a Waters Alliance instrument for LC and a Waters-Micromass Platform II for the mass part.

The following examples illustrate the invention in a non-limiting manner.

Example A1: N-butyl-6-chloro-5-phenyl-1H-indazol-3-amine

Step 1: 24 mg of n-butyraldehyde and 113 mg of sodium triacetoxyborohydride were added to a solution of 100 mg of 3-amino-5-phenyl-6-chloro-1-(2-trimethylsilylethoxy)methyl]-indazole in 5 cm of methylene chloride. After 3 hours at room temperature, the reaction mixture is hydrolyzed and then extracted into methylene chloride. The organic phase is dried with magnesium sulfate, filtered and evaporated. Purification of the raw material by chromatography on silica gel (eluent: ethyl acetate/hexane (80/20 v/v)) allows obtaining 21 mg of butyl-[6-chloro-5-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-yl]-amine (yellow solid)

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

NMR1H [DMSO-d6] : 7.52 (1H, s); 7.95 (IH, s); 7.35-7.50 (5H, m); 6.25 (IH, 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: 0.7 ml of HC12N was added to a solution of 21 mg of butyl-[6-chloro-5-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-yl]amine in 0.3 cm<3>methanol. The reaction mixture was stirred at room temperature for 48 hours, refluxed for 1 hour and then evaporated. The resulting solid was dried under vacuum to give 16 mg of N-butyl-6-chloro-5-phenyl-1H-indazol-3-amine (yellow solid).

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

NMR1H [DMSO-d6] : 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 A2: 3-(6-chloro-5-phenyl-1H-indazol-3-ylamino)-thiophene-2-carbonitrile

38 mg of 2-dicyclohexylphosphino-2-(N,N-dimethylamino) biphenyl, 20 mg of Pd2dba3(tris(dibenzylideneacetone)dipalalium(0)), 52 mg of 3-amino-5-phenyl-6-chloro-1-[(2-trimethylsilylethoxy)methyl]-indazole in 0.5 ml of NMP (1-methyl-2-pyrrolidone) were added. 2-cyano 3-bromo thiophene, 23 mg sodium tetrabutylate.

The reaction takes place in a microwave oven for 3 minutes at 140°C. After the usual workup, the crude is treated with HCl 2N in methanol to give 8.4 mg of 3-(6-chloro-5-phenyl-1H-indazol-3-ylamino)-thiophene-2-carbonitrile after purification.

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

NMR 1 H [DMSO-d 6 ]: 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 to A5

The examples below were obtained in a manner equivalent to A2

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

Step 1: 39 µl of phenyl diisocyanate was added to a solution of 102.2 mg of 3-amino-5-phenyl-6-chloro-1-(2-trimethylsilylethoxy)methyl]-indazole in 2.5 cm<3>tetrahydrofuran. The reaction mixture was stirred for 24 hours at room temperature and then evaporated. Purification of the crude compound by chromatography on silica gel (eluent: methylene chloride/acetone (98/2, v/v)) allows obtaining 122.5 mg of l-[6-chloro-5-phenyl-l-(2-trimethylsilanyl-eoxymethyl)-lH-indazol-3-yl]-3-phenyl-urea (colorless substance).

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

NMR'H [DMSO-d6] : 9.89 (1H, s large); 9.86(1H, s large); 8.20 (IH, s); 8.07 (IH, 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: 1 ml of HCl 2N is added to a solution of 106 mg of 1-[6-chloro-5-phenyl-1-(2-trimethylsilaml-ethoxymethyl)-1H-indazol-3-yl]-3-phenyl-urea in 12 cm<3>methanol. The reaction mixture was stirred at room temperature for 48 hours, refluxed for 5 hours and then evaporated. The resulting solid was dried under vacuum to give 82 mg of N-(6-chloro-5-phenyl-1H-indazole-

3-yl)-N'-phenylurea (colorless substance)

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

NMR 1 H [DMS0-d6] : 12.64 (11H, s large); 9.70 (1 H, s large); 9.59 (IH, s large); 8.07 (IH, s); 7.64 (IH, s); 7.50 (7H, m); 7.30 (2H, m); 7.0 (IH, m).

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

36.4 mg of 4-ethoxyphenyl isocyanate was added to 80 mg of 3-amino-5-phenyl-6-chloro-1-(2-trimethylsilylethoxy)methyl]-indazole in 1 ml of THF. It is heated to 50°C for 1 h and then hydrolyzed in a saturated solution of KH2PO4I and extracted in methylene chloride. After drying and evaporation, the raw material is purified by chromatography on silica gel with an AcOEt/hexane mixture. The obtained product is deprotected in 2 ml of a mixture of 1/1 MeOH/HCl 2N3h at reflux. 62.5 mg of 1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(4-ethoxy-phenyl)-urea is obtained.

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

1H NMR [DMSO-d 6 ]: 1.3 (3H, t, J=7 Hz); 3.98 (2H,q,J=7Rz); 6.87 and 7.36 (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)

Examples B3 to B12:

Products B3 to BI2 were obtained in a manner equivalent to product B2

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

To 387.8 mg of 3-amino-5-phenyl-6-chloro-1-(2-trimethylsilylethoxy)methyl]-indazole in 2 ml of methylene chloride, 62 µl of pyridine and 125 µl of ethyl chloroformate are added sequentially. After 75 min the reaction is complete. After hydrolysis, extraction and evaporation, 571 mg of crude carbamate: (6-chloro-5-phenyl-1H-indazol-3-yl)-carbamic acid ethyl ester is obtained.

Stage 2

In 106 mg of the previously described carbamate in 2.5 ml of trifluorotoluene, 377 mg of 3-aminopropyl-1-methyl piperazine was added and the reaction was carried out in a microwave oven for 20 min at 200°C. After purification with TH/MS preparative (acetonitrile/buffer pH=9), 60 mg of 1-[6-chloro-5-phenyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-3-yl]-3-[3-(4-methyl-piperazin-1-yl)-propyl]-urea is obtained.

Stage S

The aforementioned compound is extracted with 2 ml of a mixture of 1/1 MeOH/HCl 2N and transferred to reflux for 3 hours

NMR 1 H [DMSO-d 6 ] : 1.63 (2H,m); 2.18(3H,s); 2.33(10H,m);3.21(2H,m);7.36 7.48(5H,m);

7.58(lH,s); 7.66(lH,t,J=5.5Hz); 8.08(lH,s);9.37(lH,s) 12.70(lH,s).

Examples: C2 to C5, C7 to C11, C13 to C18

Products C2 to C5, C7 to Cl 1, C13 to C18 were obtained by the method

equivalent as for product Cl

Example El: N-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-methoxy benzenesulfuramide

Step 1: 0.236 cm of pyridine and 26.5 mg of 3-methoxyphenyl sulfonyl chloride are added to a solution of 54.1 mg of 3-amino-5-phenyl-6-chloro-1-(2trimethylsilylethoxy)methyl]-indazole in 2 ml of methylene chloride. The reaction mixture was stirred for 24 hours at room temperature and then evaporated. Purification of the raw material is carried out by chromatography on silica gel (eluent: methylene chloride/acetone (98/2, v/v) allows obtaining 70 mg of 1N-[6-chloro-5-phenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-yl]-3-methoxy-benzenesulfonamide (colorless cream).

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

NMR1H [DMSO-d6] : 10.96 (1H, s); 7.37 (IH, s); 7.58 (IH, s); 7.30-7.55 (8H, m); 7.17 (IH, 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).

The pharmaceutical forms according to the present invention consist of a compound of formula (I) or a salt of such a compound, in pure form or in the form in which they are combined with products which are pharmaceutically compatible and which can be inert or physiologically active. The drugs of this invention can be used orally, parenterally, rectally or topically.

As solid forms for oral use, compresses, pills, powders (gelatin capsules, cachets) or granules can be used. In these forms, the active component according to the present invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica under argon flow. These forms may also contain substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, or colors, tablet coating agents (drags) or glazes.

In liquid form for oral use, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oils can be used. These compounds may also contain other substances, for example wetting agents, dyes, thickeners, flavorings or stabilizers.

Sterile forms for parenteral use can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As a solvent or carrier, water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents can be used. These forms may also contain additives such as humectants, isotonic agents, emulsifiers, dispersions and stabilizers.

Sterilization can be done in a number of ways, for example by aseptic filtration, addition to the form of sterilizing agents, irradiation or heating. They may also be prepared in a solid sterile form which can be dissolved, at the time of use, in sterile water or in any sterile medium suitable for injection.

Forms for rectal use are suppositories or rectal capsules containing, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Forms for use on the skin can be creams, lotions, ointments, gels, nasal drops or aerosols.

This invention has for its subject the compounds and their use of aminoindazoles of formula (I) and their pharmaceutically acceptable salts for obtaining pharmaceutical forms intended for the prevention and treatment of diseases that can result in an abnormal activity of the kinase, such as in the case of neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, frontoparietal dementia, corticobasal degeneration, Pick's disease, cerebrovascular injuries, traumatism of the skull and spine and peripheral neuropathy, obesity, metabolic diseases, diabetes type II, basic hypertension, atherosclerotic cardiovascular diseases, polycystic ovary syndrome, X syndrome, immunodeficiency and cancer.

As abnormal kinase activity, we can cite the example of PI3K, AkT, GSK3beta, CDK

In the treatment of humans, the compounds of this invention are particularly useful for the treatment and/or prevention of neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, frontoparietal dementia, corticobasal degeneration, Pick's disease, cerebrovascular injury, cranial and spinal trauma and peripheral neuropathy, obesity, metabolic disease, type II diabetes, essential hypertension, atherosclerotic cardiovascular disease, polycystic ovary syndrome, syndrome X, immunodeficiency and cancer.

The dosage depends on the expected effect, on the nature of the treatment and the method of application; they generally range between 5 mg and 1000 mg per day orally for adults with single doses of 1 mg to 250 mg of active substance.

In general, the physician should determine the appropriate dosage depending on the age, weight and all other factors appropriate for the given subject.

The following examples illustrate forms according to the invention:

EXAMPLE A

According to the usual techniques, tablets of 50 mg of the active product are prepared, which have the following composition:

EXAMPLE B

According to the usual techniques, coprimates of 50 mg of the active product are prepared, which have the following composition:

-Mixture of dihydroxymethylcellulose, glycerin, titanium oxide (72-3.5) q.s.p., 1 compress ends at 245 mg

EXAMPLE C

An injectable solution containing 10 mg of the active product with the following composition is prepared:

The subject invention equally relates to methods of prevention and treatment of diseases in which Tau protein phosphorylation is involved, by administering the compound of formula (I) and its pharmaceutically acceptable salts.

Claims (13)

1. Compounds of formula (I): R3 is (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, aryl or heteroaryl radical fused to (1-1OC)cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO2R1 or C(=NH)NR1; these are optionally substituted with one or more substituents selected from halogen, CN, NO2, NH2, OH, ORI, COOH, C(0)ORl, -0-C(0)Rl, NR1R2, NHC(0)R1, C(0)NR1R2, SR1, S(0)R1, SO2RI, NHSO2RI, S02NR1R2, 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, ORIO, 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, ethyleneyl, acetylenyl, trifluoromethoxy, NO2, NH2 or NMe2 radical; R 1 R 2 , R 10 and R 1 are, independently of each 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, (1-1C)alkyl, CN, NO 2 , NH 2 , OH, COOH, COOalkyl, CONH 2 , formyl, oxo, trifluoromethyl and trifluoromethoxy; their racemates, enantiomers and diastereoisomers and mixtures thereof, their tautomers and pharmaceutically acceptable salts. 2. Compounds of formula (I) according to claim 1: in which R3 is (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, aryl or heteroaryl radical fused with (1-1OC)cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO2RI or C(=NH)NR1; these are optionally substituted with one or more substituents selected from halogen, CN, N02, NH2, OH, ORI, COOH, C(0)ORl, -0-C(0)Rl, NR1R2, NHC(0)R1, C(0)NR1R2, SR1, S(0)R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R 1 , -O-SO 2 R 1 , -SO 2 -O-R 1 , aryl, heteroaryl, formyl, oxo, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy and (1-6C)alkyl; R5 is phenyl optionally substituted with one or more substituents selected from halogen, CN, NO2, NH2, OH, ORIO, COOH, C(0)OR10, -O-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10OR11, -O-SO2R10, -SO2-O-R10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy and (1-6C)alkyl; R6 is halogen, methyl, cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethyleneyl; acetylenyl, trifluoromethoxy, NO 2 , NH 2 or NMe 2 radical; R1, R2, R10 and R11 are, independently of each 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, NH2, OH, COOH, COOalkyl, CONH2, formyl, oxo, trifluoromethyl, and trifluoromethoxy; their racemates, enantiomers and diastereoisomers and mixtures thereof, their tautomers and their pharmaceutically acceptable salts. 3. A compound according to claim 1, characterized in that it is selected from: N-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)-6-chloro-5-enyl-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-indiazol-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-(trifluoro-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-[ 6-chloro-N-[(6-methoxy-2-naphthyl)methyl]-5-phenyl-1H-indazol-3-amine;6-chloro-N-[(pentafluorophenyl)methyl]-5-phenyl-1 H-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)-1-indazol-3-amine; N-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)-6-chloro-5-phenyl-1H-indazol-3-amine; N-(1,1-biphenyl-4-ylmethyl)-6-chloro-5-phenyl-1H-indazol-3-amine; 6-chloro-N-[[4-(dimethylamino)phenyl]methyl]-5-phenyl-1H-indazol-3-amine; N-(2,2'-bithiophen-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-indazol-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-yl)methyl]-1H-indazol-3-amine; 6-chloro-5-phenyl-N-[(1H-imidazol-4-yl)methyl]-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-furanyl]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; 6-chloro-5-phenyl-N-[[2-phenyl-1H-imidazol-4-yl]methyl]-1H-indazol-3-amine; ethyl 2-[[[6-chloro-5-phenyl-1H-indazol-3-yl]amino]-methyl]-5-(methylthio)-1H-imidazole-4-carboxylate; 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'-(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'-cyclohexylurea; N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-propylurea; 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]dec)-1-ylurea; 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; N-[6-chloro-5-phenyl-1H-indazol-3-yl]-2-propanesulfonamide; N-[6-chloro-5-phenyl-1H-indazol-3-yl]-2,2,2-trifluoroethanesulfonamide; N-[6-chloro-5-phenyl-1H-indazol-3-yl]-2-thiophenesulfonamide; N-[6-chloro-5-phenyl-1H-indazol-3-yl]benzenesulfonamide; N-[6-chloro-5-phenyl-1H-indazol-3-yl]-4-(trifluoromethyl)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-fluorobenzenesulfonamide; N-[6-chloro-5-phenyl-1H-indazol-3-yl]-4-methoxybenzenesulfonamide; N-[6-chloro-5-phenyl-1 H-indazol-3-yl]benzene-methanesulfonamide; N-[6-chloro-5-phenyl-1H-indazol-3-yl]-1-methyl-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; N-[6-chloro-5-phenyl-1H-indazol-3-yl]-4-methylbenzenemethanesulfonamide; 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-indiazol-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-pyridinyl)-5-phenyl-1H-indazol-3-amine; 6-chloro-N-(2-pyridinyl)-5-phenyl-1H-indazol-3-amine; their racemates, enantiomers and diastereoisomers and mixtures thereof, their tautomers and their pharmaceutically acceptable salts. 4. A compound according to one of claims 1 and 2, characterized in that it is selected from: N-butyl-6-chloro-5-phenyl-1H-indazol-3-amine; 3-(6-chloro-5-phenyl-1H-indazol-3-ylamino)thiophene-2-carbonitrile; (6-chloro-5-phenyl-1H-indazol-3-yl)(pyridin-2-yl)amine; (6-chloro-5-phenyl-1H-indazol-3-yl)(5-nitropyridin-2-yl)amine; (6-Chloro-5-phenyl-1H-indazoyl-3-yl)(6-methoxypyridin-2-yl)amine; N-(6-chloro-5-phenyl-1H-indazol-3-yl)-N'-phenylurea; 1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(4-ethoxyphenyl)urea; 1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3,4-dichlorophenyl)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-isopropylurea; 1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-cyclohexylurea; 1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(2-(thiophen-2-yl)ethyl)urea; 1-(1,3-benzodioxol-5-yl)-3-(6-chloro-5-phenyl-1H-indazol-3-yl)urea; 1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3,5-dimethylisoxazol-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-methylpiperazin-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-hydroxyethyl)urea; 1-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-[3-(4-methylpiperazin-1-yl)propyl]urea; (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-1-indazol-3-yl)carbamic acid allyl ester; (6-chloro-5-phenyl-1H-indazol-3-yl)carbamic acid isobutyl ester; l-(3-(azetidin-1-yl)propyl)-3-((6-chloro-5-phenyl-1H-indazol-3-yl)urea; l-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-(3-chloropropyl)urea; l-(6,7-difluoro-5-phenyl-1H-indazol-3-yl)-3-(3-imidazol-1-yl)propyl)urea; 1-(3-(aminopropyl)-3-(6-chloro-5-phenyl-1-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-ylethyl)urea; N-(6-chloro-5-phenyl-1H-indazol-3-yl)-3-methoxybenzenesulfonamide; their racemates, enantiomers, tautomers thereof and pharmaceutically acceptable salts thereof. 5. A compound according to one of claims 1 to 4, for use in the preparation of a medicine. 6. Pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable medium, a compound defined according to one of claims 1 to 4. 7. Medicine, which contains in a pharmaceutically acceptable medium, at least one compound defined according to one of claims 1 to 4 for therapeutic use in the treatment of diseases in which Tau protein phosphorylation is observed. 8. The drug according to claim 7, characterized by the fact that it contains at least one compound defined according to one of claims 1 to 4, for therapeutic use in the treatment of neurodegenerative diseases, scoliosis, cranial and spinal trauma and peripheral neuropathies, obesity, metabolic diseases, type II diabetes, essential hypertension, atherosclerotic cardiovascular diseases, polycystic ovary syndrome, syndrome X, immunodeficiency and cancer. 9. The drug according to claim 8, characterized in that the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, frontoparietal dementia, corticobasal degeneration or Pick's disease. 10. Process for obtaining compounds of formula (I) as defined in claim 1 and where R3 is (1-6C)alkyl, aryl(1-6C)alkyl, heteroaryl(1-6C)alkyl, heterocycloalkyl, cycloalkyl or polycycloalkyl radical, these radicals are optionally substituted with one or more substituents selected from halogen, CN, NO2, NH2, OH, ORI, COOH, C(0)OR1, -0-C(0)Rl, NR1R2, -NHC(0)R1, C(0)NR1R2, SR1, S(0)R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R1, -0-S02Rl, -S02-0-Rl, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy and (1-6C)alkyl, and R1 and R2 are independently 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, NH2, OH, COOH, COOalkyl, CONH2, formyl, trifluoromethyl and trifluoromethoxy; starting from the derivative of formula (I) in which R3 is H, the derivative R1CHO and sodium triacetoxyborohydride in dichloromethane and optionally converting the obtained product into a pharmaceutically acceptable salt. 11. Process for obtaining the compound of formula (I) as defined in claim 1 and where R3 is CONR1R2, R1 and R2 are, independently of 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, NH2, OH, COOH, COOalkyl, CONH2, formyl, trifluoromethyl and trifluoromethoxy, starting from OCNR1 and derivatives of formula (I) where R3 is H, in tetrahydrofuran, optionally converting the obtained product into a pharmaceutically acceptable salt. 12. A process for obtaining compounds of formula (I) as defined in claim 1 and where R3 is SO2R1 and R1 is 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, NH2, OH, COOH, COOalkyl, CONH2, formyl, trifluoromethyl and trifluoromethoxy, starting from sulfonyl chloride R1SO2C1 and derivatives of formula (I) where R3 is H, in dichloromethane in the presence of a base, and optionally converting the resulting compound into a pharmaceutically acceptable salt. 13. Intermediate product: 3-amino-5-phenyl-6-chloro-1-(2-trimethylsilylethoxy)-methyl]indazole.