JP4764168B2 - Aminoindazole derivatives and their use as kinase inhibitors - Google Patents

Description

の誘導体又はそれらの薬学的許容塩のキナーゼ阻害剤としての使用に関する。 The present invention relates to formula (I):

Or their pharmaceutically acceptable salts as kinase inhibitors.

  The subject of the present invention is a disease of the aminoindazole derivatives of formula (I) and their pharmaceutically acceptable salts which can arise from the abnormal activity of kinases, such as diseases associated with neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, frontal parietal Dementia, cortical basal ganglia degeneration, Pick disease, stroke, head and spine trauma and peripheral neuropathy, obesity, metabolic disease, type II diabetes, essential hypertension, atherosclerotic cardiovascular disease, polycystic ovary syndrome, Use in the manufacture of pharmaceutical compositions intended to prevent and treat syndrome X, immunodeficiency and cancer, pharmaceutical compositions comprising novel aminoindazole derivatives and their pharmaceutically acceptable salts, and novel amino acids Indazole derivatives and their pharmaceutically acceptable salts.

［式中、
Ｇは

ＺはＮＸ０、Ｓ又はＯ、
ＥはＮ又はＣＸ１、
Ｙはハロゲン、Ｘ２又はＯＸ２、
Ｘ０、Ｘ１及びＸ２はハロゲン、アルキル又は置換アルキル、
Ａ、Ｂ及びＤは水素、ハロゲン、置換又は非置換のアルキル、Ｃ（Ｏ）_pＲ１３、Ｃ（Ｏ）ＮＲ１３Ｒ１４、ＳＯ₂ＮＲ１３、Ｒ１４、Ｓ（Ｏ）_pＲ１５、ＯＲ１５又はＮＲ１３Ｒ１４、
ｐは０〜２の整数、
Ｒ１３及びＲ１４は水素、置換若しくは非置換のアルキル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のヘテロアリール、置換若しくは非置換の複素環、置換若しくは非置換のヘテロアルキル、置換若しくは非置換のヘテロアリール−ヘテロアルキル、又は置換若しくは非置換のアリール−ヘテロアルキル、
Ｒ１５は置換若しくは非置換のアルキル、置換若しくは非置換のシクロアルキル、置換若しくは非置換のヘテロアリール、置換若しくは非置換の複素環、置換若しくは非置換のヘテロアルキル、置換若しくは非置換のヘテロアリール−ヘテロアルキル、又は置換若しくは非置換のアリール−ヘテロアルキルである］
を記載する。 WO 02/074388 describes an aminoindazole derivative of type (a) that is a potassium channel activator:

[Where:
G is

Z is NX0, S or O,
E is N or CX1,
Y is halogen, X2 or OX2,
X0, X1 and X2 are halogen, alkyl or substituted alkyl,
A, B and D are hydrogen, halogen, substituted or unsubstituted alkyl, C (O) _p R13, C (O) NR13R14, SO ₂ NR13, R14, S (O) _p R15, OR15 or NR13R14,
p is an integer from 0 to 2,
R13 and R14 are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroalkyl, substituted or unsubstituted Heteroaryl-heteroalkyl or substituted or unsubstituted aryl-heteroalkyl,
R15 represents substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl-hetero Alkyl or substituted or unsubstituted aryl-heteroalkyl]
Is described.

The present invention relates to a compound of formula (I):
[Where:
R3 is (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, aryl or heteroaryl fused to (1-10C) cycloalkyl, heterocycle, heterocycle cycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO 2 R1, C (= NH) R1, or C (= NH) is NR1 radical; optionally these groups is _{halogen, CN, NO 2, NH 2} , OH, OR1, COOH, C (O) OR1, -O-C (O) R1, NR1R2, NHC (O) R1, C (O) NR1R2, SR1, S _{(O) R1, SO 2 R1} , NHSO 2 R1, SO 2 NR1R2, C (S) NR1R2, NHC ( _{) R1, -O-SO 2 R1} , -SO 2 -O-R1, aryl, selected from heteroaryl, heterocycle, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy or (l6C) alkyl Substituted with one or more substituents;

R5, R6 and R7 independently of one another are the following groups: _{halogen, CN, NO 2, NH 2} , 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, SO 2 R8, NHSO 2 R8, SO 2 NR8R9, -O-SO 2 R8, -SO 2 - O-R8, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl, (1-6C) alkoxy, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, heterocycle , heterocycloalkyl, cycloalkyl, alkenyl, alkynyl, selected from adamantyl or polycycloalkyl: halogen optionally these groups, CN, NO _{2 NH 2, 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, SO 2 R10, NHSO 2 R10, SO 2 NR10R11, -O-SO 2 R10, -SO 2 -O-R10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy or Substituted with one or more substituents selected from (1-6C) alkyl;

R 1, R 2, R 8, R 9, R 10 and R 11 are independently of each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl, heteroaryl, optionally halogen, (1-6C) alkyl, (1-6C) substituted with one or more substituents selected from alkoxy, CN, NO ₂ , NH ₂ , OH, COOH, COO alkyl, CONH ₂ , formyl, trifluoromethyl, trifluoromethoxy;
R1 and R2 or R8 and R9 or R10 and R11 can form a 5- or 6-membered ring which may or may not have a heteroatom such as O, S or N;
And if R3 is 6-membered nitrogen heteroaryl or a thiazolyl or imidazolyl or oxazolyl, the at least one halogen as the case of R5 and R6 _{group, CN, NO 2, NH 2} , 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, SO _{2 R10, NHSO 2 R10, SO 2} NR10R11 1 _{which, -O-SO 2 R10, -SO} 2 -O-R10, aryl, heteroaryl, formyl, trifluoromethyl, selected from trifluoromethoxy or (l6C) alkyl Or aryl substituted with more substituents]
Derivatives thereof, their racemates, enantiomers or diastereomers and mixtures thereof, their tautomers (tautomers), and pharmaceutically acceptable salts thereof.

More particularly, the present invention provides compounds of formula (I):
[Where:
R3 is (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, aryl or heteroaryl fused to (1-10C) cycloalkyl, heterocycle, heterocycle cycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO 2 R1, C (= NH) R1, or C (= NH) is NR1 radical; optionally these groups is _{halogen, CN, NO 2, NH 2} , OH, OR1, COOH, C (O) OR1, -O-C (O) R1, NR1R2, NHC (O) R1, C (O) NR1R2, SR1, S _{(O) R1, SO 2 R1} , NHSO 2 R1, SO 2 NR1R2, C (S) NR1R2, NHC ( _{) R1, -O-SO 2 R1} , -SO 2 -O-R1, aryl, selected from heteroaryl, heterocycle, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy or (l6C) alkyl Substituted with one or more substituents;

R5 and R6 independently of one another are the following groups: _{halogen, CN, NO 2, NH 2} , 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, SO ₂ R8, NHSO ₂ R8, SO ₂ NR8R9, —O—SO ₂ R8, —SO ₂ —O— R8, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl, (1-6C) alkoxy, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, heterocycle, cyclo alkyl, alkenyl, alkynyl, selected from adamantyl or polycycloalkyl: halogen optionally these _{groups, CN, NO 2, NH 2} , OH, OR10, C OH, C (O) OR10, -O-C (O) R10, NR10R11, NHC (O) R10, C (O) NR10R11, NHC (S) R10, C (S) NR10R11, SR10, S (O) R10 , SO ₂ R 10, NHSO ₂ R 10, SO ₂ NR 10 R 11, —O—SO ₂ R 10, —SO ₂ —O—R 10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy or (1-6C) alkyl Substituted with one or more selected substituents;

R7 is halogen, methyl, cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethylenyl, acetylenyl, trifluoromethoxy, be NO _2, NH ₂ or NMe _2;
R 1, R 2, R 8, R 9, R 10 and R 11 are independently of each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl, heteroaryl, optionally halogen, (1-6C) alkyl, (l6C) _{alkoxy, CN, NO 2, NH 2} , OH, COOH, COO -alkyl, CONH _2, formyl, substituted with one or more substituents selected from trifluoromethyl or trifluoromethoxy;
R1 and R2 or R8 and R9 or R10 and R11 can form a 5- or 6-membered ring which may or may not have a heteroatom such as O, S or N;
And if R3 is 6-membered nitrogen heteroaryl or a thiazolyl or imidazolyl or oxazolyl, the at least one halogen as the case of R5 and R6 _{group, CN, NO 2, NH 2} , 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, SO _{2 R10, NHSO 2 R10, SO 2} NR10R11 1 _{which, -O-SO 2 R10, -SO} 2 -O-R10, aryl, heteroaryl, formyl, trifluoromethyl, selected from trifluoromethoxy and (l6C) alkyl Or aryl substituted with more substituents]
Derivatives thereof, their racemates, enantiomers or diastereomers and mixtures thereof, their tautomers (tautomers), and pharmaceutically acceptable salts thereof.

The present invention preferably has formula (I):
[Where:
R3 is (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, aryl or heteroaryl fused to (1-10C) cycloalkyl, heterocycle, heterocycle cycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO 2 R1, or C (= NH) is NR1 radical; optionally these groups, halogen, CN, NO ₂ , NH ₂ , OH, OR 1, COOH, C (O) OR 1, —O—C (O) R 1, NR 1 R 2, NHC (O) R 1, C (O) NR 1 R ₂ , SR 1, S (O) R 1, SO _{2 R1, NHSO 2 R1, SO 2} NR1R2, C (S) NR1R2, NHC (S) R1, -O-S _{2 R1, -SO 2 -O-R1} , aryl, heteroaryl, formyl, oxo, trifluoromethyl, trifluoromethylsulfanyl, 1 or more substituents selected from trifluoromethoxy or (l6C) alkyl Is replaced by;
R5 is aryl;
R6 and R7 are independently of each other halogen, methyl, cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethylenyl, acetylenyl, trifluoromethoxy, NO ₂ , NH ₂ or NMe ₂ ;
R1 and R2 are independently of each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl, or heteroaryl, which are optionally halogen, (1-6C) alkyl, (1-6C) alkoxy, _{CN, NO 2, NH 2,} OH, COOH, COO -alkyl, CONH _2, formyl, oxo, substituted with one or more substituents selected from trifluoromethyl or trifluoromethoxy;
R1 and R2 can form a 5- or 6-membered ring which may or may not have heteroatoms such as O, S or N]
Derivatives thereof, their racemates, enantiomers, diastereomers and mixtures thereof, their tautomers (tautomers), and pharmaceutically acceptable salts thereof.

The present invention preferably has formula (I):
[Where:
R3 is (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, aryl or heteroaryl fused to (1-10C) cycloalkyl, heterocycle, heterocycle cycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO 2 R1, or C (= NH) is NR1 radical; optionally these groups, halogen, CN, NO ₂ , NH ₂ , OH, OR 1, COOH, C (O) OR 1, —O—C (O) R 1, NR 1 R 2, NHC (O) R 1, C (O) NR 1 R ₂ , SR 1, S (O) R 1, SO _{2 R1, NHSO 2 R1, SO 2} NR1R2, C (S) NR1R2, NHC (S) R1, -O-S _{2 R1, -SO 2 -O-R1} , aryl, heteroaryl, formyl, oxo, trifluoromethyl, trifluoromethylsulfanyl, 1 or more substituents selected from trifluoromethoxy or (l6C) alkyl Is replaced by;
R5 is aryl;
R6 is halogen, methyl, cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethylenyl, acetylenyl, trifluoromethoxy, be NO _2, NH ₂ or NMe _2;
R7 is halogen;
R1 and R2 are independently of each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl, or heteroaryl, which are optionally halogen, (1-6C) alkyl, (1-6C) alkoxy, _{CN, NO 2, NH 2,} OH, COOH, COO -alkyl, CONH _2, formyl, oxo, substituted with one or more substituents selected from trifluoromethyl or trifluoromethoxy;
R1 and R2 may optionally form a 5- or 6-membered ring which may contain heteroatoms such as O, S or N]
Derivatives thereof, their racemates, enantiomers or diastereomers and mixtures thereof, their tautomers (tautomers), and pharmaceutically acceptable salts thereof.

  In the previous and following definitions, (1-6C) alkyl groups contain 1-6 carbon atoms in straight and branched chains; alkenyl groups have 2-6 carbons in straight and branched chains. Alkynyl groups contain 2 to 6 carbon atoms and 1-3 conjugated or nonconjugated triple bonds in straight and branched chains; aryl; The group is selected from phenyl, naphthyl or indenyl; the heteroaryl group contains from 3 to 10 ring members and optionally contains 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 or indolyl; the halogen atom is chlorine, iodine, fluorine or bromine; the polycycloalkyl group is selected from adamantyl, quinuclidinyl, bornanyl, norbornanyl, bornenyl or norbornenyl; (1-10C) cycloalkyl The heteroaryl group fused to is selected from indanyl, isochromanyl, chromanyl, 1,2,3,4-tetrahydroisoquinolinyl or 1,2,3,4-tetrahydroquinolinyl; the heterocyclic group is oxygen, sulfur Or containing 1-2 heteroatoms selected from nitrogen and in particular piperidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolidinyl, thiazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, a Chijiniru represents 2- piperidone, 3-piperidone, 4-piperidone, 2-pyrrolidone or 3-pyrrolidone.

  The compounds of formula (I) exhibit one or more asymmetric carbons and can therefore exist in the form of isomers, racemates, enantiomers and diastereoisomers; the latter also forms part of the present invention. Their mixtures also form part of the present invention.

Among the compounds of formula (I) useful according to the invention, the following compounds can be mentioned:
N- (bicyclo [2.2.1] hept-5-en-2-ylmethyl) -6-chloro-7-fluoro-5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-N -(3,3-Dimethylbutyl) -5-phenyl-1H-indazole-3-amine 6-chloro-7-fluoro-N- (3-phenylpropyl) -5-phenyl-1H-indazol-3-amine 6 -Chloro-7-fluoro-N- (cyclopropylmethyl) -5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-N- (cyclopentylmethyl) -5-phenyl-1H-indazole-3 -Amine 6-chloro-7-fluoro-N- [3- (methylthio) propyl] -5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro N- (phenylethyl) -5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-N- (cyclohexylmethyl) -5-phenyl-1H-indazole-3-amine 6-chloro-7- Fluoro-N-propyl-5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-N- (2,2,3,3,4,4,4-heptafluorobutyl) -5-phenyl -1H-indazole-3-amine hydrate 6-chloro-7-fluoro-N- (4,4,4-trifluorobutyl) -5-phenyl-1H-indazol-3-amine 6-chloro-7- Fluoro-N-[(4-methoxyphenyl) methyl] -5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-N- (phenylmethyl) -5-phenyl-1 H-indazole-3-amine

6-chloro-7-fluoro-N-[(4-cyanophenyl) methyl] -5-phenyl-1H-indazol-3-amine N-[(4-chlorophenyl) methyl] -6-chloro-7-fluoro- 5-phenyl-
1H-indazol-3-amine 6-chloro-7-fluoro-N-[(3-methoxyphenyl) methyl] -5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-N-[[ 4- (Trifluoromethoxy) phenyl] methyl] -5-phenyl-1H-indazol-3-amine N- [4-[[[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl] ] Amino] methyl] phenyl] acetamide 6-chloro-7-fluoro-N-[(3,5-dichlorophenyl) methyl] -5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-5- Phenyl-N-[[4- (trifluoromethyl) phenyl] methyl] -1H-indazol-3-amine 6-chloro-7-fluoro-N-[(4 -Fluorophenyl) methyl] -5-phenyl-1H-indazole-3-amine 6-chloro-7-fluoro-N- [3- (4-methylphenoxy) phenylmethyl] -5-phenyl-1H-indazole-3 -Amine N- (2,2,3,3,4,4,4-heptafluorobutyl) -6-chloro-7-fluoro-5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro -5-phenyl-N-[[3,5-bis (trifluoromethyl) phenyl] methyl] -1H-indazol-3-amine 6-chloro-7-fluoro-5-phenyl-N-[[3- ( Trifluoromethyl) phenyl] methyl] -1H-indazol-3-amine 6-chloro-7-fluoro-N-[(6-methoxy-2-naphthyl) methyl] -5-phenyl-1H- Ndazoru 3-amine 6-chloro-7-fluoro--N - [(pentafluorophenyl) methyl] -5-phenyl -1H- indazol-3-amine

6-chloro-7-fluoro-N-[[4-methylthio] phenyl] methyl] -5-phenyl-1H-indazol-3-amine N-[(4-chloro-3-fluorophenyl) methyl] -6 Chloro-7-fluoro-5-phenyl-1H-indazole-3-amine 6-Chloro-7-fluoro-5-phenyl-N- (3,3,3-trifluoropropyl) -1H-indazole-3-amine 6-Chloro-7-fluoro-5-phenyl-N- (3-thienylmethyl) -1H-indazol-3-amine N- (bicyclo [2.2.1] hept-5-en-2-ylmethyl)- 6-Chloro-7-fluoro-5-phenyl-1H-indazol-3-amine N- (1,1′-biphenyl-4-ylmethyl) -6-chloro-7-fluoro-5-phenyl-1H Indazol-3-amine 6-chloro-7-fluoro-N-[[4- (dimethylamino) phenyl] methyl] -5-phenyl-1H-indazol-3-amine N- (2,2′-bithiophene-5 -Ylmethyl) -6-chloro-7-fluoro-5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-5-phenyl-N-[[1- (phenylmethyl) -1H-imidazole- 2-yl] methyl] -1H-indazol-3-amine 6-chloro-7-fluoro-N-[[1-methyl-1H-imidazol-2-yl] methyl] -5-phenyl-1H-indazole-3 -Amine 6-chloro-7-fluoro-N-[(1-methyl-1H-indol-3-yl) methyl] -5-phenyl-1H-indazol-3-amine 6 Chloro-7-fluoro-N-[(5-methyl-2-furanyl) methyl] -5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-5-phenyl-N- (1H-pyrrole -2-ylmethyl) -1H-indazol-3-amine 6-chloro-7-fluoro-5-phenyl-N- (1H-imidazol-2-yl) methyl] -1H-indazol-3-amine

6-chloro-7-fluoro-5-phenyl-N- (1H-imidazol-4-yl) methyl) -1H-indazole-3-amine 6-chloro-7-fluoro-5-phenyl-N- (1H- Pyrazol-3-ylmethyl) -1H-indazol-3-amine 6-chloro-7-fluoro-N-[[2-methyl-1H-imidazol-4-yl] methyl] -5-phenyl-1H-indazole-3 -Amine 6-chloro-7-fluoro-N-[(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl) methyl] -5-phenyl-1H-indazol-3-amine 6-chloro- 7-Fluoro-5-phenyl-N-[[2-phenyl-1H-imidazol-4-yl] methyl] -1H-indazol-3-amine 6-chloro-7-fluoro- -[[5- (4-Chlorophenyl) -2-furanyl] methyl] -5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-5-phenyl-N-[(1-methyl-1H -Pyrrol-2-yl] methyl) -1H-indazol-3-amine 4- [5-[[[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl] amino] methyl]- 2-furanyl] -benzenesulfonamide 6-chloro-7-fluoro-5-phenyl-N- (3-thienylmethyl) -1H-indazol-3-amine 6-chloro-7-fluoro-5-phenyl-N- [[2-Phenyl-1H-imidazol-4-yl] methyl] -1H-indazol-3-amine 2-[[[6-Chloro-7-fluoro-5-phenyl-1H-inda Zol-3-yl] amino] methyl] -5- (methylthio) -1H-imidazole-4-carboxylate 6-chloro-7-fluoro-5-phenyl-N-[[5- [4- (trifluoro Methyl) phenyl] -2-furanyl] methyl] -1H-indazol-3-amine 6-chloro-7-fluoro-5-phenyl-N- [2- (1-piperidinyl) ethyl] -1H-indazole-3- Amine 6-Chloro-7-fluoro-N- [2- (4-morpholinyl) ethyl] -5-phenyl-1H-indazol-3-amine

N- (6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl) -N ′-(3,5-dichlorophenyl) urea N- (6-chloro-7-fluoro-5-phenyl- 1H-indazol-3-yl) -N ′-(2-propenyl) urea N- (6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl) -N ′-(phenylmethyl) urea N- (6-Chloro-7-fluoro-5-phenyl-1H-indazol-3-yl) -N′-4- (phenoxyphenyl) urea N- (6-Chloro-7-fluoro-5-phenyl-1H -Indazol-3-yl) -N '-[(4-methoxyphenyl) methyl] urea N- (6-Chloro-7-fluoro-5-phenyl-1H-indazol-3-yl) -N'-[4 -(Trifluoromethyl ) Phenyl] urea N- (6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl) -N ′-(4-methoxyphenyl) urea N- (6-chloro-7-fluoro-5 -Phenyl-1H-indazol-3-yl) -N'-cyclohexylurea N- (6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl) -N'-propylurea N- (6 -Chloro-7-fluoro-5-phenyl-1H-indazol-3-yl) -N '-(4-chlorophenyl) urea N- (6-chloro-7-fluoro-5-phenyl-1H-indazole-3- yl) -N '- (4-fluorophenyl) urea N-[-1H-6- chloro-7-fluoro-5-phenyl-indazol-3-yl]-N'-tricyclo [3.3.1.1 ^{3 , 7} ] Deca-1- Ilurea N- (6-Chloro-7-fluoro-5-phenyl-1H-indazol-3-yl) -N '-(4-methylphenyl) urea N- (6-Chloro-7-fluoro-5-phenyl) -1H-indazol-3-yl) urea

N- (6-Chloro-7-methyl-5-phenyl-1H-indazol-3-yl) urea N- (6-Chloro-7-cyano-5-phenyl-1H-indazol-3-yl) urea N- (6-Chloro-7-cyclopropyl-5-phenyl-1H-indazol-3-yl) urea N- (6-Chloro-7-hydroxy-5-phenyl-1H-indazol-3-yl) urea N- ( 6-chloro-7-methoxy-5-phenyl-1H-indazol-3-yl) urea N- (6-chloro-7-trifluoromethyl-5-phenyl-1H-indazol-3-yl) urea N- ( 6-chloro-7-trifluoromethoxy-5-phenyl-1H-indazol-3-yl) urea N- (6-chloro-7-nitro-5-phenyl-1H-indazol-3-yl) urine Elemental N- (6-Chloro-7-amino-5-phenyl-1H-indazol-3-yl) urea N- (6-Chloro-7-dimethylamino-5-phenyl-1H-indazol-3-yl) urea N- (6-Chloro-7-ethynyl-5-phenyl-1H-indazol-3-yl) -urea N- [6-Chloro-7-fluoro-5-phenyl-1H-indazol-3-yl] -4 -Methyl-benzenesulfonamide N- [6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl] methanesulfonamide N- [6-chloro-7-fluoro-5-phenyl-1H-indazole -3-yl] -2-propanesulfonamide N- [6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl] -2,2,2-trifluoroe Down sulfonamide

N- [6-Chloro-7-fluoro-5-phenyl-1H-indazol-3-yl] -2-thiophenesulfonamide N- [6-Chloro-7-fluoro-5-phenyl-1H-indazole-3- Yl] benzenesulfonamide N- [6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl] -4- (trifluoromethyl) benzenesulfonamide N- [6-chloro-7-fluoro- 5-phenyl-1H-indazol-3-yl] -5- (3-isoxazolyl) -2-thiophenesulfonamide N- [6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]- 4-Fluorobenzenesulfonamide N- [6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl] -4-me Xibenzenesulfonamide N- [6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl] benzenemethanesulfonamide N- [6-chloro-7-fluoro-5-phenyl-1H-indazole- 3-yl] -1-methyl-1H-imidazole-4-sulfonamide N- [6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl] -4- (1,1-dimethylethyl) ) Benzenesulfonamide N- [4-[[(6-Chloro-7-fluoro-5-phenyl-1H-indazol-3-yl) amino] sulfonyl] phenyl] -acetamide N- [6-chloro-7-fluoro -5-phenyl-1H-indazol-3-yl] -4-methylbenzenemethanesulfonamide 6-chloro-7-fluoro-N (Pentafluorophenyl) -5-phenyl -1H- indazol-3-amine 6-chloro-7-fluoro-N-(3,4-difluorophenyl) -5-phenyl -1H- indazol-3-amine

6-chloro-7-fluoro-5-phenyl-N- (2,3,5,6-tetrafluorophenyl) -1H-indazol-3-amine 6-chloro-7-fluoro-5-phenyl-N- ( 2,4,6-trifluorophenyl) -1H-indazol-3-amine 6-chloro-7-fluoro-N- (4-fluorophenyl) -5-phenyl-1H-indazol-3-amine 6-chloro- 7-Fluoro-N- [3- (trifluoromethyl) phenyl] -5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-N- [4- (trifluoromethyl) phenyl] -5 -Phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-N- [3-fluoro-5- (trifluoromethyl) phenyl] -5-phenyl-1H-indazo 3-Amine 6-chloro-7-fluoro-N- (4-nitrophenyl) -5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-N- (3-nitrophenyl) -5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-N- (3-methoxyphenyl) -5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-N- (4-Methoxyphenyl) -5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-N, 5-diphenyl-1H-indazol-3-amine 6-chloro-7-fluoro-N- ( 1-pyridinyl) -5-phenyl-1H-indazol-3-amine 6-chloro-7-fluoro-N- (2-pyridinyl) -5-phenyl-1H-indazo 3-amine

N-butyl-6-chloro-7-fluoro-5-phenyl-1H-indazol-3-amine N- (6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl) -N′- Phenylurea N- (6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl) -3-methoxy-benzenesulfonamide isomers thereof, mixtures thereof, racemates, enantiomers, dia Stereoisomers or tautomers (tautomers) and pharmaceutically acceptable salts thereof.

More specifically, the following compounds can be mentioned:
Piperidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1H-indazol-3-yl) amide Pyrrolidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1H-indazol-3-yl) ) Amido 1- (6,7-difluoro-5-phenyl-1H-indazol-3-yl) -3- [3- (4-methylpiperazin-1-yl) -propyl] -urea N- (6,7 -Difluoro-5-phenyl-1H-indazol-3-yl) -N'-phenylurea,
Its tautomers (tautomers) and pharmaceutically acceptable salts thereof.

The present invention also provides the formula (I) as active ingredient:
[Where:
R3 is (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, aryl or heteroaryl fused to (1-10C) cycloalkyl, heterocycle, heterocycle Cycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO2R1, C (= NH) R1 or C (= NH) NR1 groups; these groups are optionally CN _{, NO 2, NH 2, OH} , OR1, COOH, C (O) OR1, -O-C (O) R1, NR1R2, NHC (O) R1, C (O) NR1R2, SR1, S (O) R1, _{SO 2 R1, NHSO 2 R1,} SO 2 NR1R2, C (S) NR1R2, NHC (S) R1, - _{-SO 2 R1, -SO 2 -O-} R1, aryl, heteroaryl, heterocycle, formyl, trifluoromethyl, trifluoromethylsulfanyl, one or more selected from trifluoromethoxy or (l6C) alkyl Substituted with a substituent of

R5, R6 and R7 independently of one another are the following groups: _{halogen, CN, NO 2, NH 2} , 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, SO 2 R8, NHSO 2 R8, SO 2 NR8R9, -O-SO 2 R8, -SO 2 - O-R8, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl, (1-6C) alkoxy, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, heterocycle It is selected from cycloalkyl, alkenyl, alkynyl, adamantyl or polycycloalkyl: halogen optionally these _{groups, CN, NO 2, NH 2} , OH, OR1 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, SO 2 R10, NHSO 2} R10, SO 2 NR10R11, -O-SO 2 R10, -SO 2 -O-R10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy or (l6C) alkyl Substituted with one or more substituents selected from;

R 1, R 2, R 8, R 9, R 10 and R 11 are independently of each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl, heteroaryl, optionally halogen, (1-6C) alkyl, (1-6C) substituted with one or more substituents selected from alkoxy, CN, NO ₂ , NH ₂ , OH, COOH, COO alkyl, CONH ₂ , formyl, trifluoromethyl, trifluoromethoxy;
R1 and R2 or R8 and R9 or R10 and R11 can form a 5- or 6-membered ring which may or may not have a heteroatom such as O, S or N;
And if R3 is 6-membered nitrogen heteroaryl or a thiazolyl or imidazolyl or oxazolyl, the at least one halogen as the case of R5 and R6 _{group, CN, NO 2, NH 2} , 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, SO _{2 R10, NHSO 2 R10, SO 2} NR10R11 1 _{which, -O-SO 2 R10, -SO} 2 -O-R10, aryl, heteroaryl, formyl, trifluoromethyl, selected from trifluoromethoxy or (l6C) alkyl Or aryl substituted with more substituents]
Derivatives thereof, their racemates, enantiomers or diastereomers and mixtures thereof, their tautomers (tautomers), and pharmaceutically acceptable salts thereof.

The present invention more particularly comprises the formula (I) as active ingredient:
[Where:
R3 is (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, aryl or heteroaryl fused to (1-10C) cycloalkyl, heterocycle, heterocycle cycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO 2 R1, C (= NH) R1, or C (= NH) is NR1 radical; optionally these groups is _{halogen, CN, NO 2, NH 2} , OH, OR1, COOH, C (O) OR1, -O-C (O) R1, NR1R2, NHC (O) R1, C (O) NR1R2, SR1, S _{(O) R1, SO 2 R1} , NHSO 2 R1, SO 2 NR1R2, C (S) NR1R2, NHC ( _{) R1, -O-SO 2 R1} , -SO 2 -O-R1, aryl, selected from heteroaryl, heterocycle, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy or (l6C) alkyl Substituted with one or more substituents;

R5 and R6 independently of one another are the following groups: _{halogen, CN, NO 2, NH 2} , 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, SO ₂ R8, NHSO ₂ R8, SO ₂ NR8R9, —O—SO ₂ R8, —SO ₂ —O— R8, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl, (1-6C) alkoxy, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, heterocycle, cyclo alkyl, alkenyl, alkynyl, selected from adamantyl or polycycloalkyl; halogen optionally these _{groups, CN, NO 2, NH 2} , OH, OR10, C OH, C (O) OR10, -O-C (O) R10, NR10R11, NHC (O) R10, C (O) NR10R11, NHC (S) R10, C (S) NR10R11, SR10, S (O) R10 , SO ₂ R 10, NHSO ₂ R 10, SO ₂ NR 10 R 11, —O—SO ₂ R 10, —SO ₂ —O—R 10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy or (1-6C) alkyl Substituted with one or more selected substituents;

R7 is halogen, methyl, cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethylenyl, acetylenyl, trifluoromethoxy, be NO _2, NH ₂ or NMe _2;
R1, R2, R8, R9, R10 and R11 are independently of each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl or heteroaryl, which are optionally halogen, (1-6C) alkyl, (l6C) _{alkoxy, CN, NO 2, NH 2} , OH, COOH, COO -alkyl, CONH _2, formyl, substituted with one or more substituents selected from trifluoromethyl or trifluoromethoxy;
R1 and R2 or R8 and R9 or R10 and R11 can form a 5- or 6-membered ring which may or may not have a heteroatom such as O, S or N;
And if R3 is 6-membered nitrogen heteroaryl or a thiazolyl or imidazolyl or oxazolyl, the at least one halogen as the case of R5 and R6 _{group, CN, NO 2, NH 2} , 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, SO _{2 R10, NHSO 2 R10, SO 2} NR10R11 1 _{which, -O-SO 2 R10, -SO} 2 -O-R10, aryl, heteroaryl, formyl, trifluoromethyl, selected from trifluoromethoxy and (l6C) alkyl Or aryl substituted with more substituents]
Derivatives thereof, their racemates, enantiomers or diastereomers and mixtures thereof, their tautomers (tautomers), and pharmaceutically acceptable salts thereof.

The present invention preferably has the formula (I):
[Where:
R3 is (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, aryl or heteroaryl fused to (1-10C) cycloalkyl, heterocycle, heterocycle cycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO 2 R1, or C (= NH) is NR1 radical; optionally these groups, halogen, CN, NO ₂ , NH ₂ , OH, OR 1, COOH, C (O) OR 1, —O—C (O) R 1, NR 1 R 2, NHC (O) R 1, C (O) NR 1 R ₂ , SR 1, S (O) R 1, SO _{2 R1, NHSO 2 R1, SO 2} NR1R2, C (S) NR1R2, NHC (S) R1, -O-S _{2 R1, -SO 2 -O-R1} , aryl, heteroaryl, formyl, oxo, trifluoromethyl, trifluoromethylsulfanyl, 1 or more substituents selected from trifluoromethoxy or (l6C) alkyl Is replaced by;
R5 is aryl;
R6 and R7 are independently of each other halogen, methyl, cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethylenyl, acetylenyl, trifluoromethoxy, NO ₂ , NH ₂ or NMe ₂ ;
R1 and R2 are independently of each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl, or heteroaryl, which are optionally halogen, (1-6C) alkyl, (1-6C) alkoxy, _{CN, NO 2, NH 2,} OH, COOH, COO -alkyl, CONH _2, formyl, oxo, substituted with one or more substituents selected from trifluoromethyl or trifluoromethoxy;
R1 and R2 can optionally form a 5- or 6-membered ring that may contain heteroatoms such as O, S or N]
Derivatives thereof, their racemates, enantiomers or diastereomers and mixtures thereof, their tautomers (tautomers), and pharmaceutically acceptable salts thereof.

The present invention also provides a pharmaceutical formula (I):
[Where:
R3 is (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, aryl or heteroaryl fused to (1-10C) cycloalkyl, heterocycle, heterocycle cycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO 2 R1, C (= NH) R1 or C (= NH) is NR1 radical; optionally these groups are , _{halogen, CN, NO 2, NH 2} , OH, OR1, COOH, C (O) OR1, -O-C (O) R1, NR1R2, NHC (O) R1, C (O) NR1R2, SR1, S ( _{O) R1, SO 2 R1,} NHSO 2 R1, SO 2 NR1R2, C (S) NR1R2, NHC (S _{R1, -O-SO 2 R1,} -SO 2 -O-R1, selected aryl, heteroaryl, heterocycle, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy or (l6C) alkyl Substituted with one or more substituents;

R5, R6 and R7 independently of one another are the following groups: _{halogen, CN, NO 2, NH 2} , 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, SO 2 R8, NHSO 2 R8, SO 2 NR8R9, -O-SO 2 R8, -SO 2 - O-R8, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl, (1-6C) alkoxy, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, heterocycle It is selected from cycloalkyl, alkenyl, alkynyl, adamantyl or polycycloalkyl: halogen optionally these _{groups, CN, NO 2, NH 2} , OH, OR1 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, SO 2 R10, NHSO 2} R10, SO 2 NR10R11, -O-SO 2 R10, -SO 2 -O-R10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy or (l6C) alkyl Substituted with one or more substituents selected from;

R 1, R 2, R 8, R 9, R 10 and R 11 are independently of each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl, heteroaryl, optionally halogen, (1-6C) alkyl, (1-6C) substituted with one or more substituents selected from alkoxy, CN, NO ₂ , NH ₂ , OH, COOH, COO alkyl, CONH ₂ , formyl, trifluoromethyl, trifluoromethoxy;
R1 and R2 or R8 and R9 or R10 and R11 can form a 5- or 6-membered ring which may or may not have a heteroatom such as O, S or N;
And if R3 is 6-membered nitrogen heteroaryl or a thiazolyl or imidazolyl or oxazolyl, the at least one halogen as the case of R5 and R6 _{group, CN, NO 2, NH 2} , 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, SO _{2 R10, NHSO 2 R10, SO 2} NR10R11 1 _{which, -O-SO 2 R10, -SO} 2 -O-R10, aryl, heteroaryl, formyl, trifluoromethyl, selected from trifluoromethoxy or (l6C) alkyl Or aryl substituted with more substituents]
Of aminoindazole derivatives thereof, their racemates, enantiomers or diastereomers and mixtures thereof, their tautomers (tautomers), and their pharmaceutically acceptable salts.

The present invention more particularly relates to formula (I) as a medicament:
[Where:
R3 is (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, aryl or heteroaryl fused to (1-10C) cycloalkyl, heterocycle, heterocycle cycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO 2 R1, C (= NH) R1, or C (= NH) is NR1 radical; optionally these groups is _{halogen, CN, NO 2, NH 2} , OH, OR1, COOH, C (O) OR1, -O-C (O) R1, NR1R2, NHC (O) R1, C (O) NR1R2, SR1, S _{(O) R1, SO 2 R1} , NHSO 2 R1, SO 2 NR1R2, C (S) NR1R2, NHC ( _{) R1, -O-SO 2 R1} , -SO 2 -O-R1, aryl, selected from heteroaryl, heterocycle, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy or (l6C) alkyl Substituted with one or more substituents;

R5 and R6 independently of one another are the following groups: _{halogen, CN, NO 2, NH 2} , 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, SO ₂ R8, NHSO ₂ R8, SO ₂ NR8R9, —O—SO ₂ R8, —SO ₂ —O— R8, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl, (1-6C) alkoxy, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, heterocycle, cyclo alkyl, alkenyl, alkynyl, adamantyl, selected from polycycloalkyl; halogen optionally these _{groups, CN, NO 2, NH 2} , OH, OR10, CO H, C (O) OR10, -O-C (O) R10, NR10R11, NHC (O) R10, C (O) NR10R11, NHC (S) R10, C (S) NR10R11, SR10, S (O) R10 , SO ₂ R 10, NHSO ₂ R 10, SO ₂ NR 10 R 11, —O—SO ₂ R 10, —SO ₂ —O—R 10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy or (1-6C) alkyl Substituted with one or more selected substituents;
R7 is halogen, methyl, cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethylenyl, acetylenyl, trifluoromethoxy, be NO _2, NH ₂ or NMe _2;

R1, R2, R8, R9, R10 and R11 are independently of each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl or heteroaryl, which are optionally halogen, (1-6C) alkyl, (l6C) _{alkoxy, CN, NO 2, NH 2} , OH, COOH, COO -alkyl, CONH _2, formyl, substituted with one or more substituents selected from trifluoromethyl or trifluoromethoxy;
R1 and R2 or R8 and R9 or R10 and R11 can form a 5- or 6-membered ring which may or may not have a heteroatom such as O, S or N;
And if R3 is 6-membered nitrogen heteroaryl or a thiazolyl or imidazolyl or oxazolyl, the at least one halogen as the case of R5 and R6 _{group, CN, NO 2, NH 2} , 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, SO _{2 R10, NHSO 2 R10, SO 2} NR10R11 1 _{which, -O-SO 2 R10, -SO} 2 -O-R10, aryl, heteroaryl, formyl, trifluoromethyl, selected from trifluoromethoxy or (l6C) alkyl Or aryl substituted with more substituents]
Of aminoindazole derivatives thereof, their racemates, enantiomers or diastereomers and mixtures thereof, their tautomers (tautomers), and their pharmaceutically acceptable salts.

The present invention preferably has the formula (I) as a medicament:
[Where:
R3 is (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, aryl or heteroaryl fused to (1-10C) cycloalkyl, heterocycle, heterocycle cycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO 2 R1, or C (= NH) is NR1 radical; optionally these groups, halogen, CN, NO ₂ , NH ₂ , OH, OR 1, COOH, C (O) OR 1, —O—C (O) R 1, NR 1 R 2, NHC (O) R 1, C (O) NR 1 R ₂ , SR 1, S (O) R 1, SO _{2 R1, NHSO 2 R1, SO 2} NR1R2, C (S) NR1R2, NHC (S) R1, -O-S _{2 R1, -SO 2 -O-R1} , aryl, heteroaryl, formyl, oxo, trifluoromethyl, trifluoromethylsulfanyl, 1 or more substituents selected from trifluoromethoxy or (l6C) alkyl Is replaced by;
R5 is aryl;
R6 and R7 are independently of each other halogen, methyl, cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethylenyl, acetylenyl, trifluoromethoxy, NO ₂ , NH ₂ or NMe ₂ ;
R1 and R2 are independently of each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl, or heteroaryl, which are optionally halogen, (1-6C) alkyl, (1-6C) alkoxy, _{CN, NO 2, NH 2,} OH, COOH, COO -alkyl, CONH _2, formyl, oxo, substituted with one or more substituents selected from trifluoromethyl or trifluoromethoxy;
R1 and R2 can optionally form a 5- or 6-membered ring that may contain heteroatoms such as O, S or N]
Of aminoindazole derivatives thereof, their racemates, enantiomers or diastereomers and mixtures thereof, their tautomers (tautomers), and their pharmaceutically acceptable salts.

Derivatives of formula (I) can be obtained from the corresponding 3-amino derivatives (V) in which the nitrogen at the 1-position is optionally protected with the group Pr. Pr is a trimethylsilylethoxymethyl, tosyl, mesyl or benzyl group, or an aromatic heterocycle as shown in T.W. GREENE, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1999). It is a group known for protecting the NH group.

3-Amino 1H-indazole of the formula (II) is prepared by the reaction of 2-fluorobenzonitrile with hydrazine hydrate or hydrochloride under reflux in ethanol or n-butanol type alcohol. F. Kaltenbach, Bioorg. Med. Chem. Lett., 9 (15), pages 2259-62 (1999).

R5 and R6 are independently of each other the following groups: _{halogen, CN, NO 2, NH 2} , 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, SO ₂ R8, NHSO ₂ R8, SO ₂ NR8R9, —O—SO ₂ R8, —SO ₂ —O— R8, trifluoromethyl, trifluoromethoxy, (1-6C) alkyl, (1-6C) alkoxy, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, cycloalkyl, alkenyl It is selected from alkynyl or adamantyl; _{halogen, CN, NO 2, NH 2} , OH, OR10, COOH, C (O) OR10, in some cases these groups - -C (O) R10, NR10R11, NHC (O) R10, C (O) NR10R11, NHC (S) R10, C (S) NR10R11, SR10, S (O) R10, SO 2 R10, NHSO 2 R10, SO _{2 NR10R11, -O-SO 2 R10} , -SO 2 -O-R10, aryl, heteroaryl, formyl, oxo, trifluoromethyl, trifluoromethoxy or (l6C) 1 or more substituents selected from alkyl Compounds selected from optionally substituted with groups are derived from the corresponding halogenated derivatives from palladium chemistry: Suzuki, (A. SUZUKI, Pure Appl. Chem. 63 , 419-22, (1991), Stille. (J.Stille, Angew.Chem., Int.Ed. , 25, 508- Page 4, (1986), Heck (R.F.Heck, Org.React. , 27, pp. 345-90, (1982), Sonogashira (K.Snongashira, Synthesis, 777 (1977), Buckwald ( S. L. Buckwald, Acc. Chem. Re., 31 , 805 (1998).

For this purpose, it is necessary to protect the reactive functional group. Therefore, the OH, SH, COOH and NH ₂ functional groups must be protected before performing the coupling. Protecting groups are obtained by methods known to those skilled in the art, in particular by T.W. W. Greene, Protective groups in Organic Synthesis, J. MoI. Introduced according to the method described in Wiley-Interscience Publication (1999). It is preferred to protect the 1-position nitrogen with a group such as tert-butoxycarbonyl or a silicon derivative. It is preferred to select tert-butylmethylsilyl or triisopropylsilylsilyl groups, which can be removed with a fluorine anion or acetic acid, more preferably a trimethylsilylethoxymethyl group, which is more preferably selected from tetrabutylammonium fluoride with tetrahydrofuran. Or tear under reflux in a solvent such as dioxane (JP Whitten, J. Org. Chem., 51, 1891 (1986); B. H. Lipshutz, Tetrahedron Lett., 4095 (1986) Year)), or 2N hydrochloric acid in methanol or ethanol under reflux. Derivatives protected at the 1-position with trimethylsilylethoxymethyl are obtained by reacting the starting material in the presence of trimethylsilylethoxymethyl chloride and sodium hydride in a solvent such as dimethylformamide at room temperature (JP) Whitten, J. Org. Chem., 51, 1891 (1986); MP Edwards, Tetrahedron, 42, 3723 (1986)).

Similarly, the 1-NH nitrogen functional group of indazole will be protected with groups such as silyl derivatives, benzyl, carbamate or tosyl. For example, if it is desirable to carry out the coupling with palladium on a 6-position halogenated derivative, protect the 1-position nitrogen as shown below (X = Cl, Br or I). Would be necessary.

Deprotection is known to those skilled in the art and is described in T.W. W. Green, Protective Groups in Organic Synthesis, J. MoI. It is performed according to the method described in Wiley-Interscience Publication (1999). For example, if the 1-position protecting group is trimethylsilylethoxymethyl, it can be deprotected by reaction with tetrabutylammonium fluoride as shown below.

When one of R5 or R6 itself associated with coupling using palladium chemistry contains a reactive functional group such as hydroxy, amine, thiol or acid or generally contains a heteroatom, coupling with palladium It is also necessary to protect the reactive functional groups before carrying out. Thus, for example, the phenol functionality will be in a protected form (eg, O-benzyl) and the nitrogen at the 1-position will be introduced into the protected chlorinated derivative as previously described:

The benzyl group will then be removed by treatment with trimethylsilyl iodide, for example in acetonitrile under reflux. Protection can also be carried out with a trimethylsilylethoxymethyl group, which can be torn off under reflux in a solvent such as tetrahydrofuran or dioxane with tetrabutylammonium fluoride (JP Whitten, J. Org. Chem. 51, 1891 (1986); BH Lipshutz, Tetrahedron Lett., 4095 (1986)), or 2N hydrochloric acid in methanol or ethanol under reflux.

When R5 and R6 are independently of each other aryl and halogen, the aryl functionality is introduced into the brominated position by coupling with palladium and the 1- and 3-position nitrogens are suitably protected. Preferably Pr represents trimethylsilylethoxymethyl and Pr ′ represents an n-butylcarbonyl group, and the n-butylcarbonyl group forms n-butylamide with nitrogen. The step of deprotecting the amide is carried out at reflux in DMF for 1 week in the presence of ethanolamine. This tearing can also be done with stannous chloride in ethanol (R J Griffin, J. Chem. Soc. Perkin I, 1992, 1811-1819) or in methanol with sodium methoxide (Y. Furukawa, Chem. Pharm. Bull., 1968, 16, 1076), or other alkoxides in the corresponding alcohols.

When R5 and R6 are independently of each other aryl and halogen, the aryl functionality is introduced into the brominated position by coupling with palladium and the 1- and 3-position nitrogens are suitably protected. Preferably, Pr represents trimethylsilylethoxymethyl and Pr ′ represents an n-butylcarboxy group, and the n-butylcarboxy group forms n-butylamide with nitrogen. The electrophilic substitution is performed using, for example, tetrafluoroboric acid nitrile (NO ₂ BF ₄ ). The 5-position coupling is performed using palladium chemistry (Suzuki, Heck or Sonogashira coupling). The 7-position is coupled as a functional group of the desired substituent by reduction, halogenation to introduce bromine, or palladium chemistry to introduce aryl, heteroaryl, alkyl, alkenyl, alkynyl or acetylene functional groups. Functionalized by (coupling of Suzuki, Heck or Sonogashira). The step of deprotecting the amide is carried out at reflux in DMF for 1 week in the presence of ethanolamine. This tearing can also be done with stannous chloride in ethanol (R J Griffin, J. Chem. Soc. Perkin I, 1992, 1811-1819) or in methanol with sodium methoxide (Y. Furukawa, Chem. Pharm. Bull., 1968, 16, 1076), or other alkoxides in the corresponding alcohols. Deprotection at the 3-position produces an NH ₂ functional group that can react with the required group as described on the next page to introduce the desired substituent at the 3-position.

  Compounds of formula (II) can be converted to primary amine functions such as alkylation, acylation, reaction with carbonyl derivatives, followed by reduction, sulfonation, conversion to urea or carbamate, arylation (Castro reaction or Backward reaction), etc. It is the starting point for the production of various products obtained by reaction of the primary amine function of 3-aminoindazole among all conventional reactions of the group.

Reductive amination of derivatives of general formula (I) where R3 is H when Pr is trimethylsilylethoxymethyl is carried out using boron derivatives such as sodium triacetoxyborohydride for aldehydes of type R1CHO in dichloromethane. In the presence, under the conditions described in Organic Reactions Vol. 59, pages 1-714 (E. Baxter, A. Reitz) or with other reducing agents commonly used for the reduction of imines,
R3 is (1-6C) alkyl, aryl (1-6C) alkyl, heteroaryl (1-6C) alkyl, heterocycloalkyl, cycloalkyl or polycycloalkyl; these groups may optionally be halogen, CN _{, NO 2, NH 2, OH} , OR1, COOH, C (O) OR1, -O-C (O) R1, NR1R2, NHC (O) R1, C (O) NR1R2, SR1, S (O) R1, _{SO 2 R1, NHSO 2 R1,} SO 2 NR1R2, C (S) NR1R2, NHC (S) R1, -O-SO 2 R1, -SO 2 -O-Rl, aryl, heteroaryl, formyl, oxo, trifluoromethyl Substituted with one or more substituents selected from methyl, trifluoromethylsulfanyl, trifluoromethoxy or (1-6C) alkyl They are possible to form a product which is have group.

Condensation of derivatives of general formula (I) in which R3 is H with isocyanates of the OCNR1 type is described in Comprehensive Organic Function Transformations, Vol. 6 (Katritzky, Meth-Cohn, Rees 1995), especially in tetrahydrofuran. R3 is CONR1R2 or CSNR1R2, R1 and R2 are independently of each other hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl, or heteroaryl, which may optionally be halogen, ( 1-6C) alkyl, (1-6C) _{alkoxy, CN, NO 2, NH 2} , OH, COOH, COO -alkyl, CONH _2, formyl, oxo, trifluoromethyl or triflic Optionally substituted with one or more substituents selected from Rometokishi can form a good base product also.

Sulfonation of the derivatives of the general formula (I) in which R3 is H is based on the presence of a base (especially a tertiary amine such as triethylamine or an aromatic amine such as pyridine) from a sulfonyl chloride of the R1SO ₂ Cl type. Below, carried out in a conventional solvent such as dichloromethane, R3 is SO ₂ R1 and R1 is hydrogen, (1-6C) alkyl, aryl, alkenyl, alkynyl or heteroaryl, which are optionally 1 halogen, selected from (l6C) alkyl, (l6C) _{alkoxy, CN, NO 2, NH 2} , OH, COOH, COO -alkyl, CONH _2, formyl, oxo, trifluoromethyl or trifluoromethoxy Alternatively, a product can be formed which is a group that may be substituted with more substituents.

  The compound of formula (I) can be isolated and purified by the usual known methods such as crystallization, chromatography or extraction.

  Compounds of formula (I) can optionally be converted to addition salts of inorganic or organic acids in organic solvents such as alcohols, ketones, ethers or chlorinated solvents by the action of inorganic or organic acids. These salts also form part of the present invention.

  As examples of pharmaceutically acceptable salts, the following salts can be mentioned: benzene sulfonate, hydrobromide, hydrochloride, citrate, ethane sulfonate, fumarate, gluconate, iodic acid Salt, maleate, isethionate, methanesulfonate, methylenebis-β-oxynaphthoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartaric acid Salts, theophylline acetate and p-toluenesulfonate.

  The compounds of formula (I) are kinase inhibitors and are therefore neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, frontal parietal dementia, cortical basal ganglia degeneration, Pick's disease, stroke, head and spine trauma and peripheral neuropathy, It is useful for the prevention and treatment of obesity, essential hypertension, atherosclerotic cardiovascular disease, polycystic ovary syndrome, syndrome X, immunodeficiency and cancer.

The activity was determined by measuring the inhibition of tau protein phosphorylation in the cortical part of mature rats.
Prepared from 8-10 week old male OFA rats (Iffa-Credo) in which cortical areas with a thickness of 300 μm are sacrificed by decapitation. They are incubated for 40 minutes at 37 ° C. in 5 ml of DMEM medium containing pyruvate and 4.5 g / l glucose. The part is then washed twice with the medium, dispensed into microtubes (50 μl in 500 μl medium with or without test compound) and incubated at 37 ° C. with agitation. After 2 hours, the experiment is interrupted by centrifugation. The portion is lysed, sonicated and centrifuged at 18300 g for 15 minutes at 4 ° C. The concentration of the protein in the supernatant is determined by a commercially available assay (BCA protein assay, Pierce) based on the Lowry method.

Samples previously denatured at 70 ° C. for 10 minutes are separated on a 4-12% Bis-Tris vertical gel in the presence of MOPS-SDS buffer and electrotransferred to a nitrocellulose membrane. Immunolabeling is performed with monoclonal antibody AD2, which specifically recognizes the Ser396 / 404 phosphorylated epitope of tau protein. The immunoreactive protein is directed against mouse IgG and made visible by the addition of a second antibody conjugated to peroxidase and a chemiluminescent substrate. The resulting autoradiogram is finally quantified using 'GeneTools' software from Syngene (GeneGnome, Ozyme) to determine IC ₅₀ values.

The compounds of formula (I) show very advantageous activity, and in particular some compounds have IC ₅₀ values of less than 100 μM.

  The following examples illustrate the invention without limiting it. The conditions for analysis of the product by LC / MS were generated on a Waters Alliance 2695 device for the LC portion and on a Waters-Micromass Platform II for the main portion.

Production of intermediate product:
6,7-Difluoro-1H-indazol-3-amine :
Add hydrazine monohydrate 0.32 cm ³ in 2,3,4-fluorobenzonitrile 0.46 cm ³ of absolute ethanol 10 cm ^3. Was heated for 17 hours medium at about 75 ° C., then ethyl acetate 10 cm ^3, tetrahydrofuran 5 cm ^3, and distilled water 5 cm ³ is added. The organic phase was separated The phases after settling, distilled water 10 cm ^3, then washed with saturated aqueous sodium chloride solution 10 cm ^3. After the phase has settled, the organic phase is separated, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50 ° C.). The residue obtained is purified by chromatography on column silica gel (particle size 40-60 μm; diameter 1.5 cm), eluting with a cyclohexane / ethyl acetate mixture (50/50 by volume) under an argon pressure of 50 kPa. Fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40 ° C.). After drying (90 Pa; 40 ° C.), 100 mg of 6,7-difluoro-1H-indazol-3-amine are obtained in the form of a white solid that melts at 183 ° C.
¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ (ppm)): 5.57 (unseparated complex: 2H); 6.93 (mt: 1H); 7.52 (ddd, J = 8.5-4.5 and 1 Hz: 1H); 12.01 (unseparated complex: 1H).

N- (6,7-difluoro-1H-indazol-3-yl) -butanamide :
Described above butyryl chloride 0.61 cm ^3, in pyridine 15cm ³ after cooling to about 3 ° C. 6, 7
-1 g of difluoro-1H-indazole-3-amine is added and the mixture is then left at ambient temperature for 76 hours. The reaction medium under reduced pressure; and concentrated under (2kPa 40 ℃), take the residue up in ethyl acetate 25 cm ³ and water 25 cm ^3. The organic phase is washed with 25 cm ³ of distilled water and then with 25 cm ³ of saturated aqueous sodium chloride solution. After drying over magnesium sulfate, filtering and concentrating under reduced pressure (2 kPa; 40 ° C.), the residue obtained is placed on a column of silica gel (particle size 40-60 μm; diameter 3 cm) under an argon pressure of 50 kPa. Purify by chromatography eluting with a dichloromethane / methanol mixture (98/2 by volume). Fractions containing the expected product are combined and then evaporated under reduced pressure (2 kPa; 40 ° C.). After drying (90 Pa; 40 ° C.), 596 mg of N- (6,7-difluoro-1H-indazol-3-yl) -butanamide are obtained in the form of a white solid which melts at 191 ° C.
¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ (ppm)): 0.97 (t, J = 7.5 Hz: 3H); 1.67 (mt: 2H); 2.40 (t , J = 7 Hz: 2H); 7.10 (mt: 1H); 7.63 (broad dd, J = 9 and 4.5 Hz: 1H); 10.47 (broad unseparated complex: 1H); 13 .35 (broad unseparated complex: 1H).

N- [6,7-Difluoro-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazol-3-yl] -butanamide dimethylformamide in 180 cm ³ of the previously prepared N- (6,7- A solution of 1.1 g of difluoro-1H-indazol-3-yl) -butanamide is added dropwise over a period of 3 hours to 1.65 g of 60% sodium hydride in oil in 50 cm ^{3 of} dimethylformamide. The reaction medium is concentrated to dryness under reduced pressure, ethyl acetate 250 cm ³ and taken up in water 200 cm ^3; After settling of the layers, the organic layer was separated, washed with water 150 cm ^3, dried over magnesium sulfate, filtered and vacuum Concentrate to dryness under (2 kPa; 50 ° C.). The crude product is purified by chromatography on a column of silica gel (particle size 40-60 μm; diameter 6 cm), eluting with a cyclohexane / ethyl acetate mixture (80/20 by volume) under an argon pressure of 50 kPa. Fractions containing the expected product were combined and evaporated under reduced pressure (2 kPa; 50 ° C.) to give N- [6,7-difluoro-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazole. 7.3 g of -3-yl] -butanamide are obtained in the form of a yellow oil.
¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ (ppm)): −0.09 (s: 9H); 0.82 (t, J = 8 Hz: 2H); 0.96 (t, J = 7.5 Hz: 3H); 1.67 (mt: 2H); 2.41 (t, J = 7 Hz: 2H); 3.56 (t, J = 8 Hz: 2H); 5.66 (s: 7.22 (ddd, J = 11-9 and 7 Hz: 1H); 7.69 (broad dd, J = 9 and 4.5 Hz: 1H); 10.60 (unseparated complex: 1H) .
Mass spectrum: M = 369

N- [5-Bromo-6,7-difluoro-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazol-3-yl] -butanamide in 30 cm ³ of the above N- [6,7 -0.87 cm ³ of pyridine is added to 1 g of difluoro-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazol-3-yl] -butanamide, then 0.56 cm ³ of bromine is added and the mixture is left overnight. Reflux. Dichloromethane is added 50 cm ³ and 10% aqueous sodium thiosulfate solution 50 cm ³ in the reaction medium. After stirring for 10 minutes, removed by filtration the insoluble matter on a sintered funnel, washing the organic phase with distilled water 50 cm ³ and saturated aqueous sodium chloride solution 50 cm ^3. The organic layer is separated by phase settling, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45 ° C.). 1.1 g of the crude product is purified by chromatography, eluting with a cyclohexane / ethyl acetate mixture (90/10 by volume) on a column of silica gel (particle size 40-60 μm; diameter 3 cm) under an argon pressure of 50 kPa. Fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50 ° C.). After drying (90 Pa; 45 ° C.), 230 mg of N- [5-bromo-6,7-difluoro-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazol-3-yl] -butanamide was colorless oil It is obtained in the form of a thing.
¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ (ppm)): −0.08 (s: 9H); 0.82 (t, J = 8 Hz: 2H); 0.96 (t, J = 7.5 Hz: 3H); 1.67 (mt: 2H); 2.42 (t, J = 7 Hz: 2H); 3.55 (t, J = 8 Hz: 2H); 5.66 (s: 2H); 8.08 (dd, J = 6 and 2 Hz: 1H); 10.72 (unseparated complex: 1H).
Mass spectrum: M = 447

N- [6,7-difluoro-5-phenyl-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazol-3-yl] -butanamidophenylboronic acid 469 mg, sodium carbonate 760 mg in 30 cm ^{3 of} water And N- [5-Bromo-6,7-difluoro-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazole- prepared previously in 379 mg of tetrakis (triphenylphosphine) palladium in 150 cm ³ of dioxane 3-yl] -butanamide is added to 1.15 g and the mixture is refluxed for 4 hours. The reaction medium is diluted with ethyl acetate 100 cm ³ and water 75 cm ^3, and filtered through a sinter funnel packed with Celite. After settling of the layers, the organic layer is separated, washed with 75 cm ^{3 of} water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50 ° C.) to give 2 g of crude product. In the form of a black oil. The crude product is purified by chromatography on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane / ethyl acetate mixture (85/15 by volume) under an argon pressure of 50 kPa. Fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50 ° C.), dried (90 Pa; 45 ° C.), and N- [6,7-difluoro-5-phenyl-1-[[[ 1.1 g of 2- (trimethylsilyl) ethoxy] methyl] -1H-indazol-3-yl] -butanamide are obtained in the form of a yellow oil.
¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ (ppm)): −0.05 (s: 9H); 0.84 (t, J = 8 Hz: 2H); 0.95 (t, 1.66 (mt: 2H); 2.43 (t, J = 7 Hz: 2H); 3.59 (t, J = 8 Hz: 2H); 5.69 (s: J = 7.5 Hz: 3H); 2H); 7.40-7.65 (mt: 5H); 7.82 (broad d, J = 7 Hz: 1H); 10.64 (unseparated complex: 1H).
Mass spectrum: M = 445

N- [6,7-difluoro-5-phenyl-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazol-3-aminedimethylformamide as described above in 50 cm ³ To 1.6 g of -5-phenyl-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazol-3-yl] -butanamide was added 1.1 cm ³ of ethanolamine and then 1.50 g of potassium carbonate. Reflux the mixture for 1 week. The reaction medium is concentrated to dryness under reduced pressure, taken into ethyl acetate 150 cm ³ and water 75 cm ^3. After settling of the layer, the organic layer was separated, subsequently washed with water 75 cm ³ and brine 50 cm ^3. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50 ° C.). The resulting crude oil is purified by chromatography, eluting with a cyclohexane / ethyl acetate mixture (80/20 by volume) on a column of silica gel (particle size 40-60 μm; diameter 4 cm) under an argon pressure of 50 kPa. Fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50 ° C.). After drying (90 Pa; 45 ° C.), 6.32 g of 6,7-difluoro-5-phenyl-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazole-3-amine is obtained.

6,7-Difluoro-5-phenyl-1H-indazol-3-amine:
To 661 mg of 6,7-difluoro-5-phenyl-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazol-3-amine in 15 ml of methanol is added 1.1 ml of 2N HCl. The reaction is subjected to microwave at 140 ° C. for 3 minutes. After hydrolysis with saturated KH ₂ PO ₄ solution and extraction with methylene chloride, the solvent is evaporated and the residue is chromatographed on silica (methylene chloride / ethyl acetate) to give 6,7-difluoro- 314 mg of 5-phenyl-1H-indazole-3-amine are obtained.

Example 1 Piperidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1H-indazol-3-yl) -amide Step 1
To 387.8 mg of (6,7-difluoro-5-phenyl-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazol-3-amine compound in 8 ml of methylene chloride, 131 μl of pyridine and 154 μl of ethyl chloroformate were added. The reaction is complete after 75 minutes and after hydrolysis, extraction and evaporation, 840 mg of crude (6,7-difluoro-5-phenyl-1H-indazol-3-yl) -carbamic acid ethyl ester is obtained.
Step 2
To 161 mg of crude (6,7-difluoro-5-phenyl-1H-indazol-3-yl) -carbamate in 2.5 ml of trifluorotoluene was added 184 mg of piperidine and the reaction was carried out at 200 ° C. under microwave for 20 minutes. Do. After purification by preparative LC / MS (acetonitrile / pH 9 buffer), piperidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazole- 80 mg of 3-yl) -amide are obtained.
Step 3
2 mg of 80 mg of piperidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazol-3-yl) -amide in 2.5 ml of methanol Treat with 0.82 ml of HCl under reflux for 1 hour. After evaporation and purification by preparative LC / MS (acetonitrile / pH 9 buffer), 11 mg of piperidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1H-indazol-3-yl) -amide are obtained.
Mass spectrum: retention time 3.99; 357 = [M + H] ^+
1 H NMR spectrum (300 MHz, DMSO-d6, δ (ppm)): 1.50 (m, 4H); 1.58 (m, 2H); 3.45 (m, 4H); 7.42 (m, 1H); 7.51 (m, 5H); 9.16 (s, 1H); 13.20 (bs, 1H)

Example 2 : Pyrrolidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1H-indazol-3-yl) -amide Step 1
To 161 mg of (6,7-difluoro-5-phenyl-1H-indazol-3-yl) -carbamic acid ethyl ester in 2.5 ml of trifluorotoluene was added 154 mg of pyrrolidine and the reaction was carried out at 200 ° C. under microwave for 20 minutes. Do. The product was purified on a column of silica to give pyrrolidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazol-3-yl ) -Amide 75 mg is obtained.
Step 2
75 ml of pyrrolidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazol-3-yl) -amide in 3 ml of methanol was diluted with 2N HCl. Treat with .82 ml under reflux for 1 hour. After evaporation and purification by preparative LC / MS (acetonitrile / pH 9 buffer), 36 mg of pyrrolidin-1-carboxylic acid (6,7-difluoro-5-phenyl-1H-indazol-3-yl) -amide is obtained.
Mass spectrum: retention time 3.72 min; 343 = [M + H] ^+
1 H NMR spectrum (300 MHz, DMSO-d6, δ (ppm)): 1.86 (m, 4H); 3.40 (m, 4H); 7.42 (m, 1H); 7.45-7. 54 (m, 4H); 7.63 (bd, J = 7 Hz, 1H); 8.84 (s, 1H); 13.20 (bs, 1H)

Example 3 1- (6,7-Difluoro-5-phenyl-1H-indazol-3-yl) according to Example 2, starting from 3- (4-methylpiperazin-1-yl) -propylamine -3- [3- (4-Methyl-piperazin-1-yl) -propyl] urea is obtained.
¹ H NMR spectrum (300 MHz, DMSO-d6, δ (ppm)): 1.92 (m, 2H); 2.82 (s, 3H); 3.01 to 3.75 (m, partially masked) 7.43 (m, 1H); 7.47-7.56 (m, 4H); 7.71 (t, J = 7 Hz, 1H); 8.05 (dd, J = 1) .5-7Hz, 1H); 9.61 (s, 1H)
Mass spectrum: retention time 2.57 min; 429 = [M + H] ⁺

  The pharmaceutical compositions of the present invention are of the formula (I) in the form of a composition in pure form or in combination with other pharmaceutically compatible products that can be inert or physiologically active. Or a salt of such a compound. The medicament of the present invention can be used orally, parenterally, rectally or locally.

  As solid compositions for oral administration, tablets, pills, (hard gelatin capsules, cashews) powders or granules may be used. In these compositions, the active principle of the present invention is mixed with an inert diluent such as one or more starch, cellulose, sucrose, lactose or silica under a stream of argon. These compositions can also contain substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, colorants, coatings (drugs) or polishes. .

  As liquid compositions for oral administration, use pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerin, vegetable oils or liquid paraffin. obtain. These compositions can include substances other than diluents, such as wetting, sweetening, thickening, flavoring or stabilizing products.

  The bactericidal composition for parenteral administration can preferably be a solution, suspension or emulsion in aqueous or non-aqueous form. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters such as ethyl oleate, or other suitable organic solvents may be used. These compositions can also contain adjuvants, especially wetting agents, isotonic agents, emulsifying agents, dispersing agents and stabilizing agents. Sterilization can be carried out in several ways, for example by aseptic filtration, addition of a fungicide to the composition, irradiation or heating. They can also be manufactured in the form of a sterilized solid composition and dissolved in sterilized water or other injectable sterilizing media at the time of use.

Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
Compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

The subject of the present invention is the aminoindazole compounds of formula (I) and their pharmaceutically acceptable salts, and diseases that can arise from abnormal activity of kinases, such as diseases associated with neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, frontal parietal Dementia, cortical basal ganglia degeneration, pick disease, stroke, head and spine trauma and peripheral neuropathy, obesity, metabolic disease, type II diabetes, essential hypertension, atherosclerotic cardiovascular disease, polycystic ovary syndrome, Their use in the manufacture of pharmaceutical compositions intended to prevent and treat Syndrome X, immunodeficiency and cancer.
Examples of abnormal kinase activity include PI3K, AkT or GSK3beta activity, CDK activity, and the like.

  In the treatment of humans, the compounds of the present invention may be used in neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, fronto-parietal dementia, basal ganglia degeneration, Pick's disease, stroke, head and spine trauma and peripheral neuropathy, obesity, metabolism It is particularly useful for the treatment and / or prevention of sexually transmitted diseases, type II diabetes, essential hypertension, atherosclerotic cardiovascular disease, polycystic ovary syndrome, syndrome X, immunodeficiency and cancer.

  The dosage will depend on the desired effect, the duration of treatment and the route of administration used. The dosage is generally between 5 mg and 1000 mg per day for an adult orally and the unit dose is 1 mg to 250 mg of the active substance.

  In general, the physician will determine the appropriate dose according to age, weight and other factors specific to the subject being treated.

The following examples illustrate the compositions of the present invention.
Example A
Hard gelatin capsules having a dose of 50 mg of active product and having the following composition are produced according to conventional techniques:
50 mg of the compound of formula (I)
Cellulose 18mg
Lactose 55mg
Colloidal silica 1mg
Sodium carboxymethyl starch 10mg
Talc 10mg
Magnesium stearate 1mg

Example B
A tablet having a dose of 50 mg of active product and having the following composition is prepared according to conventional techniques:
50 mg of the compound of formula (I)
Lactose 104mg
Cellulose 40mg
Polyvidone 10mg
Sodium carboxylmethyl starch 22mg
Talc 10mg
Magnesium stearate 2mg
Colloidal silica 2mg
Amount of 245 mg of one tablet coated with a mixture of hydroxymethylcellulose, glycerin and titanium oxide (72 / 3.5 / 24.5)

Example C
An injectable preparation containing 10 mg of active product and having the following composition is prepared:
10 mg of the compound of formula (I)
Benzoic acid 80mg
Benzyl alcohol 0.06ml
Sodium benzoate 80mg
0.4% of 95% ethanol
Sodium hydroxide 24mg
Propylene glycol 1.6ml
Amount of water 4ml

  The present invention also relates to a method for preventing and treating diseases associated with tau protein phosphorylation by administration of a compound of formula (I) and pharmaceutically acceptable salts thereof.

Claims (5)

Formula (I):

[Where:
R3 is CONR1R2 ;
R5 is phenyl;
R6 and R7 are halogen;
R1 and R2 are independently of each other hydrogen or (1-6C) alkyl; the group is unsubstituted or substituted with one heterocycle;
R1 and R2 can form a 5- or 6-membered ring]
, Racemates, enantiomers, diastereomers and mixtures thereof, tautomers thereof, and pharmaceutically acceptable salts thereof. The following compounds:
Piperidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1H-indazol-3-yl) amide Pyrrolidine-1-carboxylic acid (6,7-difluoro-5-phenyl-1H-indazol-3-yl) 2. The compound according to claim 1, which is selected from amides, tautomers thereof, and pharmaceutically acceptable salts thereof.   A process for the preparation of a compound of formula (I) according to claim 1, wherein said compound is prepared in tetrahydrofuran from a derivative of formula (I) wherein OCNR1 and R3 are H, and the resulting product is optionally Is a process for converting to a pharmaceutically acceptable salt. The following compounds as intermediate products for the preparation of compounds of formula (I) according to claims 1-3:
N- [6,7-difluoro-5-phenyl-1-[[2- (trimethylsilyl) ethoxy] methyl] -1H-indazol-3-yl] butanamide 6,7-difluoro-5-phenyl-1-[[ 2- (Trimethylsilyl) ethoxy] methyl] -1H-indazol-3-amine 6,7-difluoro-5-phenyl-1H-indazol-3-amine. 1- (6,7-difluoro-5-phenyl-1H-indazol-3-yl) -3- [
3- (4-Methylpiperazin-1-yl) -propyl] urea, its tautomers and pharmaceutically acceptable salts thereof.