TWI345561B - Novel aminoindazole derivatives as medicaments and pharmaceutical compositions including them - Google Patents

Description

1345561 Ministry of Economic Affairs Intellectual Property Bureau Beigong Consumer Cooperative Printed A7 V. Invention Description (!) The present invention relates to a derivative of formula (1):

Use of R7 or a pharmaceutically acceptable salt thereof as a kinase inhibitor. The subject of the present invention is the use of an aminocarbazole derivative of the formula (1) and a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the prevention and treatment of diseases 10 caused by abnormal kinase activity, for example, they involve neurodegeneration. Disease, Alzheimer's disease, Parkinson's disease, frontal and parietal dementia, cortical basal degeneration, Pick's disease, milk-(4) 'Stroke, Gu and spine trauma, and _ _ change, obesity, Dai Mihe, Type II Diabetes, Essential Hypertension, Arteriosclerotic Cardiovascular Disease, Polycystic Infection Syndrome, χI5 Syndrome, Immunodeficiency and Cancer, and Containing the New Amino-Based Decoction A pharmaceutical composition with a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof. Patent Application W0 02/074388 describes the amidocarbazole derivative of the & type, which is a potassium channel activator. 20 Paper-scale (CNS) A4 specification (210x297 public) ---_——

G, ΝΗ

1345561 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description where G is Z for NXO, E is N or (5 Y is halogen, X2 or 0X2, X0, XI and X2 are acicular, alkyl or Substituted alkyl, A, B and D are hydrogen, ac' substituted or unsubstituted alkyl, C(0)pR13, C(0)NR13R14, S02NR13, R14, S(0)pR15, OR15 or NR13R14 10 p is an integer 0 to 2, R 13 and R 14 are hydrogen, substituted or unsubstituted alkyl, green substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Heterocyclic, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl-heteroalkyl, or substituted or unsubstituted aryl-heteroalkyl, 15 R15 is substituted or unsubstituted Alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heteroalkyl, substituted or unsubstituted hetero Aryl-heteroalkyl or substituted or unsubstituted aryl-heteroalkyl. The present invention relates to a derivative of formula (1), which is a racemate, enantiomer or 20 non-pair Isomers and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof, wherein: R3 is (1-6C)alkyl, aryl, aryl (1-6C)alkyl, heteroaryl, heteroaryl a (1-6C)alkyl group, an aryl or heteroaryl group fused to a (1-10C)cycloalkyl group, a heterocyclic ring, a heterocyclic sulfo group, a cycloalkyl group, a diamond group, a polycyclic group, a compound Base

S or 0: X1 > -4-

1345561 A7 A7 B7 V. INSTRUCTIONS (3) Group, C0NR1R2, CSNR1R2, COOR1, S02Ri 'C(=NH)Ri or C(=NH)NR1 groups; such groups may optionally be selected from one or more Substituted by the following substituents: halogen 'CN, N〇2, NH2, 0H, 0R1, COOH ' C(0)0R1 ' -0-C(0)Rl, NR1R2, 5 NHC(0)R1, C(0) NR1R2, SRI, S(0)R1 'S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R1, -O-SO2RI, -SO2-O-RI, aryl, heteroaryl, heterocyclic, Methyl, trifluoromethyl, trifluoromethylsulfanyl 'trifluoromethoxy or (1-6C)alkyl; R5, R6 and R7 are each independently selected from the group consisting of halogen, CN, 10 N〇2, NH2, OH, COOH, C(0)0R8, -0-C(0)R8, NR8R9, NHC(0)R8, C(Q)NR8R9, NHC(S)R8. Property Bureau Bayer Consumer Cooperatives printed C(S)NR8R9, SR8, S(0)R8, S02R8, NH§b2R8, S02NR8R9, -0-S02R8, -S02-0-R8, trifluoromethyl, main fluorocarbon Oxyl, (1-6C)alkyl '(1-6C)alkoxy, aryl, aryl(1-6C)alkyl, 15 heteroaryl, heteroaryl(1-6C)alkyl, hetero Ring, cycloalkyl, alkenyl, alkynyl, adamantyl or polycycloalkyl These groups may be substituted with one or more substituents selected from the group consisting of halogen, CN, N〇2, NH2'OH, ORIO, COOH, C(O)OR10, -OC(O)R10, NR10R11, NHC(O)R10 'C(O)NR10Rll, NHC(S)R10, 20 C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10Rll, -〇-SO2R10, -SO2-O-R10 , aryl, heteroaryl, indolyl, trifluoromethyl 'trifluoromethoxy or (1-6C)alkyl; RJ, R2, R8, R9, R10 and R11 are each independently hydrogen, (1- 6C) Alkyl, aryl, alkenyl, alkynyl, heteroaryl, which can be applied to a Chinese standard (CNS) A4 specification (210 x 297 public «) 1345561 A7 B7 (4) or a plurality of substituents selected from the group consisting of halogen, (1_6C)alkyl, (1_6C) alkoxy, CN, N〇2, NH2, OH, COOH, COO alkyl, CONH2 Mercapto, trifluoromethyl, trifluoromethoxy; R1 and R2 or R8 and R9 or R1 and RU can form a 5- or 6-membered ring, which may or may not contain a hetero atom, such as: , S or N; and when R3 is a 6-membered nitrogen-containing heteroaryl or thiazolyl or imidazolyl or carbazolyl group And at least one of R5 and R6 is an aryl group which may optionally be substituted with one or more substituents selected from the group consisting of halogen, CN, N02, NH2, OH, ORIO, COOH, C(O)OR10, -〇 -C(O)R10, 10 NR10R11, NHC(0)R1〇, C(O)NR10Rll, NHC(S)R10, C(S)NR1GR11, S§;10, S(O)R10, SO2R10, NHSO2R10, SO2NR10RU, -〇4〇2R1〇, -S〇2-〇-R1〇, aryl, heteroaryl, fluorenyl, trifluoromethane, trifluoromethoxy or (1.6% alkyl). More particularly, the invention relates to derivatives of formula (1), racemates, 15 enantiomers or diastereomers thereof and mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof, wherein: The R3 of the Intellectual Property Office of the Ministry of Economic Affairs printed R3 as (1-6C) alkyl, aryl, aryl (1-6C), heteroaryl, heteroaryl (1-6C) alkyl, and 1-10C) cycloalkyl fused aryl or heteroaryl, heterocyclic, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkyne 20, CONR1R2, CSNR1R2, COOR1 'S02R1, c(=NH)Rl or C(=NH)NR1 groups; such groups may be substituted by one or more substituents selected from the group consisting of halogen, CN, N02, NH2, OH, OR1 COOH, C(0)0R1, -0-C(0)Rl, NR1R2, NHC(0)R1, C(0)NR1R2 ' SRI, S(0)R1, S〇2R1, -6- Use China S standard (CNS) A4 specification (210x297 public '' 1345561 A7 A7 B7 5. Invention description (5) NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R1,-0-S02R1, -S02 -0-Rl, aryl, heteroaryl, heterocyclic, indolyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoro Methoxy or (1-6C)alkyl; R5 and R6 are each independently selected from the group consisting of halogen, CN, N〇2, 5 NH2, OH, C00H, C(0)0R8 ' -0-C (0) R8, NR8R9, NHC(0)R8, C(0)NR8R9, NHC(S)R8, C(S)NR8R9, SR8, S(0)R8, S02R8, NHS02R8, S02NR8R9, -0-SO2R8, -SO2-O-R8, trifluoromethyl, trifluoromethoxy, (1-6C)alkyl, (1-6C) alkoxy, aryl, aryl (1-6C) alkyl, heteroaryl , heteroaryl 10 (1-6C)alkyl, heterocyclic, cycloalkyl, alkenyl, alkynyl, adamantyl, polycycloalkyl; such groups may optionally be selected from one or more selected from the group consisting of Substituent substitution: halogen 'CN, N〇2, NH2, OH, ORIO, fc〇OH, C(O)OR10, -〇-C(O)R10, NR10R11, NHC(0)R10 'C(O) NR10Rll, NHC(S)R10, C(S)NR10R11, SR10, 15 s(o)rio, so2rio 'nhso2rio, SO2NR10Rll, -0-S〇2R10, -S02-0-R10, aryl, heteroaryl, Mercapto, trifluoromethyl, trifluoromethoxy or (1-6C)alkyl; Ministry of Economic Affairs Intellectual Property Bureau Bayer Consumer Cooperative printed R7 as halogen, fluorenyl, cyclopropyl, CN, OH, A Oxyl, trifluoromethyl, vinyl, acetylene , trifluoromethoxy, N〇2, NH2 or NMe2, 20, R2, R8, R9, R10 and R11 are each independently hydrogen, (i_6C)alkyl, aryl, dilute, alkynyl or heteroaryl , which may itself be substituted by one or more substituents selected from the group consisting of halogen, (1_6C)alkyl, (1_6C) alkoxy, CN, NO2, NH2, OH 'COOH, COO alkyl, CONH2, 曱Brewed base, trifluoroantimony or tri-methoxy methoxy; this paper ruler from China National Standard (CNS) A4 specifications (_2丨0 x 297 mm) 1345561 A7 5, invention description (ο 10 15 Ministry of Economic Affairs The Intellectual Property Office employee consumption cooperative prints 20 R1 and R2 or R8 and R9 or Ri〇 and RU to form a 5_ or 6• member ring, which may or may not contain helium atoms, such as: 〇, S or N; When R3 is a 6-membered nitrogen-containing heteroaryl or thiazolyl, imidazolyl or oxazolyl group, then at least one of R5 and R6 is aryl, which may optionally be substituted with one or more substituents selected from the group consisting of: , cn, n〇2, NH2, OH, OR10, COOH, c(O)OR10, -〇-C(〇)R1〇, NR10R11, NHC(0)R1〇, c(O)NR10Rll, NHC(S ) R10, C(S)NR10R11, SRl〇, s(〇)Ri〇, s〇 2R10, NHS02R1〇, SO2NR10Rl, -O-SO2Rl0, ·3〇2_〇·ια〇, aryl, heteroaryl, decyl, trifluoromethyl, trifluoromethoxy, and (1_6C)alkyl a preferred derivative of the invention, a derivative of the formula (1), a racemate, an enantiomer or a diastereomer thereof, a mixture thereof, a tautomer thereof and a pharmaceutically acceptable salt thereof, wherein: R3 Is (1-6C) aryl, aryl, aryl (i_6C) alkyl, heteroaryl 'heteroaryl (1-6C) alkyl, aryl fused to (1-10C) cycloalkyl or Heteroaryl, heterocyclic, heterocycloalkyl, cycloalkyl 'adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, S02R1 or C(=NH)NR1 base maps; The group may be optionally substituted with one or more substituents selected from the group consisting of halogen, CN, N02, NH2 'OH, OR1, COOH, C(0)0R1, -0-C(0)Rl, NR1R2, NHC ( 0) R1, C(0)NJUR2, SRI, S(0)R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)IU, -0-S02Rl, -S〇2-〇-R1 Aryl 'heteroaryl'methanyl, oxo, trifluoromethyl, trifluoromethylsulfanyl 'trifluoromethoxy or (1-6C)alkyl; -8- The paper scale is applicable to the Chinese national standard ((8) 8 4 specifications (2ΐ〇χ297 mm). 1345561 A7 B7 5. Inventive Note (7) R5 is an aryl group; R6 and R7 are independently halogen 'fluorenyl, cyclopropyl Base, cn, 0H, methoxy, dimethyl, ethylene, ethyl, trimethoxy, N〇2, NH2 or NMe2, .5 R1 and R2. are independently hydrogen, (1 -6C) alkyl, aryl, dilute, alkynyl or heteroaryl' may itself be substituted by one or more substituents selected from the group consisting of halogen, (1-6C)alkyl, (1_6C) Oxy, CN, N〇2, NH2, oh, COOH, COO alkyl, CONH2, fluorenyl, oxo, trifluoromethyl or trifluoromethoxy; 10 R1 and R2 can form 5- or 6 - Member rings, with or without heteroatoms such as: 〇, S or N. The present invention is preferably a derivative of the formula (1), a racemate, a enantiomer or a diastereomer such as a mixture thereof, a tautomer thereof and a pharmaceutically acceptable salt thereof, wherein: The property bureau employee consumption cooperative printed 15 R3 as (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, and (1- 10C) cycloalkyl fused aryl or heteroaryl, heterocyclic, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, C0NR1R2, CSNR1R2, C00R1, S02R1 or a C(=NH)NR1 group; such groups may be substituted by one or more substituents selected from the group consisting of: halogen 'CN, N〇2, NH2, OH, OR1, COOH, C(0)0R1 ,-0-C(0)Rl, NR1R2, NHC(0)R1, C(0)NR1R2, SRI, S(0)R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)IU, -0-S02Rl, -S02-0-R1, aryl, heteroaryl, methyl, oxo, trifluoromethyl, trifluoromethyl-9- This paper scale applies to China B standard (CNS> A4 Specification (210 X 297 mm) 1345561 A7 B7 V. Description of the invention (mercaptosulfanyl, trifluoromethoxyl) (1-6C)alkyl; R5 is aryl; R6 is halogen, methyl, cyclopropyl, CN, OH, methoxy, trifluoromethyl, vinyl, ethynyl, trifluoromethoxy, N02 , NH2 or NMe2; 5 R7 is a producer; R1 and R2 are each independently hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl or heteroaryl, which may itself be selected by one or more Substituted from the following substituents: halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, N02, NH2, OH, COOH, COO alkyl, CONH2, fluorenyl, oxo 10 , trifluoromethyl or trifluoromethoxy; Khan 'R1 and R2 can form a ruthenium or a 6-membered ring, which may optionally contain a hetero atom, such as: Ο, S or Ν. .; i 'Ministry of Finance The property bureau employee consumption cooperative printed the above and below, the (1-6C) alkyl group contains 1 to 6 carbon atoms in the linear or branched chain; the alkenyl group contains 2 to 6 15 carbons in the linear or branched chain. An atom and 1 to 3 conjugated or non-conjugated double bonds; the alkyne contains 2 to 6 carbon atoms and 1 to 3 conjugated or non-conjugated bonds in a straight or branched chain; the aryl group is selected from the group consisting of: Phenyl, naphthyl or anthracenyl; heteroaryl contains 3 10 ring members, which can be ordered as needed - one or more selected from: oxygen, sulfur and heteroatoms in the atmosphere 'specifically, 隹 隹 、, 叹 基, 吼 基, 比 咬 base, 20 ϋ夫基基, miso base, 基基, "比基' tetradecyl, hydrazine. succinyl, thiadiazolyl, isoxadiazolyl, isothiadiazolyl, isothiazolyl, isoxazolyl , triazolyl, "bisazolyl or fluorenyl; dentate group is gas, iodine, fluorine or bromine; polycycloalkyl is selected from the group consisting of: adamantyl, quinuclidinyl, borneol, raw ice -10- This paper scale applies to China's sleepy standard &CNS) A4 regulations ¥ (210 X 297 il il) 1345561 A7 B7 V. Description of invention (9) Alkyl, borneyl, norbornene; L_l〇C) cycloalkyl fused heteroaryl is selected from the group consisting of: indanyl 'isochroman, chromanyl, 1,2,3,4-tetrahydroisoquinolinyl or 1,2,3, 4-tetrahydroquinolinyl; heterocyclyl contains 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and in particular represents hexahydro. Bipyridyl, .5 morpholinyl, pyrrolidinyl, imidazolidinyl, pyrimidinyl, isothiazolidinyl, sulphate, iso-bite, sputum, hexahydro Well base, oxime, danyl, 2-hexahydropyridone, 3-hexahydropyridone, 4-hexahydropyridone, 2-pyrazine or 3-indole. The compound of formula (1) has one or more a symmetrical carbon, and thus may be in the form of isomeric steroids, racemates, enantiomers and diastereomers; the latter also as part of the invention, a part of the invention β according to the invention In the compound of the formula (I), the description and the Kelvin compound are included. · · · · N-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)-6-chloro-7-fluoro _5 *Phenyl_ 1 H_吲15 Oleo-3-amine Ministry of Economic Affairs Intellectual Property Bureau Bayer Consumer Cooperative Printed ό-Gas-7-Fluoro-N-(3,3-dimercaptobutyl)_5_ phenyl_1H, oxazol-3-amine 6-gas-7-fluoro-N-(3-phenylpropyl)_5-phenyl-1 H-« oxazolamide 6-gas-7- Fluorine (cyclopropylmethyl)-5-phenyl-1H-indazole-3-amine 6-gas-7-fluoro-N-(cyclopentylmethyl)-5-phenyl-1H-carbazole+ Amine 20 6-gas-7ϋ[3-(indolyl)propyl]-5-styl-1H-0 丨3_amine 6- -7-fluoro-indole·(phenethyl)-5-phenyl-1H-indazole-3-amine 6·gas-7-fluoro-N-(cyclohexylmethyl)-5-phenyl-1H- Oxazol-3-amine 6-gas-7-fluoro-N-propyl-5-phenyl-1H-indazol-3-amine 6·gas-7·fluoro-N-(2,2,3,3 ,4,4,4-heptafluorobutyl)-5-benzamine-11- This paper size is applicable to the Chinese national standard (〇^>Α4 specification (21〇χ297 mm) 1345561 A7 B7 V. Invention description ( 10) Hydrate 6-gas-7-fluoro·Ν·(4,4,4-trifluorobutyl)-5-phenyl-1H-indazole-3-amine 6-gas-7-fluoro-N- [(4-decyloxy)indolyl]-5-phenyl-1H-indazol-3-amine 6-gas-7-fluoro-N-(phenylmethyl)-5-phenyl-1H -carbazole-3-amine 5 6-gas-7-fluoro-N-[(4-cyanophenyl)methyl]-5-phenyl-1H-indazol-3-amine N-[(4- Sulfuryl] fluorenyl]-6-chloro-7-fluoro-5-phenyl-1H-indazole-3-amine 6-gas-7-fluoro-N-[(3-decyloxyphenyl)fluorene 5-yl-l-yl-1H-indazol-3-amine 6-gas-7-fluoro-N-[[4-(trifluorodecyloxy)phenyl]mercapto]-5-phenyl-1H -carbazol-3-amine 10 N-[4-[[[6-gas-7-fluoro-5-phenyl-1H-indazol-3-yl]amino]]]yl]phenyl]acetamide 6-Gas-7-fluoro-N-[(3,5-dioxa)indolyl]-5-styl-1H-indazol-3-amine 6-gas-7-fluoro-5-phenyl -N-[[4-(trifluoromethyl)benzene Methyl]-1H-indazole-3-amine 15 6-chloro-7-fluoro-N-[(4-fluorophenyl)methyl]-5-phenyl-1H-indazol-3-amine 6-Chloro-7-fluoro-N-[3-(4-mercaptophenoxy)phenylindolyl]-5-phenyl-1H-carbazole-•3-Amine Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Printed bismuth (2,2,3,3,4,4,4-heptafluorobutyl)-6-gas-7-fluoro-5-phenyl-111-oxazol-3-amine 6-gas-7 -fluoro-5-phenyl-N-[[3,5-bis(trifluoromethyl)phenyl]methyl]-1H-indole 20 oxazol-3-amine 6-chloro-7-fluoro-5-benzene --N-[[3-(trifluoromethyl)phenyl]indolyl]-1 H-indazol-3-amine 6-gas-7-fluoro-N-[(6-decyloxy-2- Naphthyl)fluorenyl]-5-phenyl-1H-indazole-3·amine 6-gas-7-fluoro-N-[(pentafluorophenyl)methyl]-5-phenyl-1H-carbazole -3-Amine-12- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1345561 Α7 Β7 V. Invention description (11) 6-Chloro-7-gas-N-[[4-(A Thio)phenyl]methyl]-5-phenyl-lH-n 丨啥3_amine N-[(4- gas-3-fluorophenyl)methyl]-6-gas-7-fluoro -5-Streprise-1H-% salino 6-chloro-7-fluoro-5-phenyl-N-(3,3,3-trimethylpropyl)-1 Η·π. -3--3-amine 6-gas-7-gas-5-phenyl-indole-(3-p-phenanthryl)-1Η-η丨丨_3-amineΝ-(bicyclo[2.2.1]g -5·en-2-ylmethyl)-6-gas-7-fluoro-5-phenyl_1indole, carbazole-3-amine oxime-(1, fluorene-biphenyl-4-ylmethyl)- 6-Chloro-7-fluoro-5-phenyl-1 oxime-oxazole·3-amine 6-gas-7-fluoro-indole·[[4-(dimethylamino)phenyl]methyl]-5 -Phenyl-ΐΗ-ΐ „坐_ 3-amine 10 Ν-(2,2 Ί 吩-5-ylmethyl)-6-gas-7-fluoro-5-phenyl-lH-β bow sitting _ 3_amine 6-chloro-7-fluoro-5-phenylphenylmethyl)-1Η-imidyl-2·yl]▼-based]_ιη_ carbazole-3-amine 6-chloro-7-fluoro-N- [[l-fluorenyl-1Η-imidazol-2-yl]methyl]-5-phenyl-1HH 3-amine 15 6-gas-7-fluoro-N-[(l-methyl-1Η-»引-3--3-yl) fluorenyl]-5-phenyl-1HH 3-amine Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 6-gas-7-fluoro-Ν-[(5-methyl-2-"味] 曱 ]]]-5-phenyl-1HH3-amine 6-chloro-7-gas-5-phenyl-l-l-ylmethyl)-1Η-β5-sodium-3-amine 6-chloro- 7-Fluoro-5-phenyl-indole-[(1Ή-Miso-2-yl)methyl]-1Η-Qiao丨唆-3-amine 20 6-Chlorofluoro-5-phenyl-indole-[ (ΙΗ-Mi®® -4-yl)methyl]-1Η-β5丨s-s--3-amine 6-gas-7-fluoro-5-phenyl-indole-(1Η-0 ratio 0--3-yl Methyl)-1Η -0弓卜垒-3-amine 6-gas-7-fluoro-Ν-[[2·曱基-1Η-咪. 坐基]曱基]_5_phenyl_出_吲. Sit -3- 3-amine 6-Gas-7-fluoro-Ν·[(3,5-Dimethyl-1-indolyl-1Η-0-wow-4-yl)methyl]-5-benzene-13- This paper size applies to China 0 standard (CNS) A4 specifications (210X297 public) A7 1345561 B7 V. Description of invention (12) yl-1H-carbazole-3-amine 6-gas-7-fluoro-5-stupyl-N-[ [2-phenyl-1H-imidazol-4-yl]methyl]-1H-indazol-3-amine 6-gas-7-fluoro-N-[[5-(4-phenylphenyl)-2- Furyl]mercapto]-5-phenyl-1H-indole-5oxazol-3-amine 6-chloro-7-fluoro-5-phenyl-N-[(l-fluorenyl-1H-pyrrol-2-yl)曱]]Η-carbazole-3-amine 4-[5-[[[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]amino]indolyl]- 2-furyl]-benzenesulfonamide 10 6-gas-7-fluoro-5-phenyl-N-(3-thienylmethyl)-1Η-indazole-3-amine 6-gas-7-fluoro -5-phenyl: ϊί-[[2-phenyl-1H-imidazol-4-yl]methyl]-1H-indazol-3-amine 2-[[[6-chloro-7-fluoroindolyl- 1Η-oxazol-3-yl]amino]methyl]-5-(methylthio)-1Η-weijun-4-rebel acid B 6-15 6-gas-7-fluoro-5-phenyl- N-[[5-[4-(Trifluoromethyl)phenyl]-2-furanyl]indolyl]-1H-indazole-3-amine Ministry of Economic Affairs Intellectual Property Bureau 6-Gas-7-fluoro-5-phenyl-N-[2-(l-hexahydropyridyl)ethyl]-1H-indazol-3-amine 6-gas-7-fluoro- N-[2-(4-morpholinyl)ethyl]-5-phenyl-1H-indazole-3-amine N-(6-gas-7-fluoro-5-phenyl-1H-carbazole- 3-yl)-N'-(3,5-dichlorophenyl)urea 20 N-(6-gas-7-fluoro-5-phenyl-1H-indazol-3-yl)-NM:2- Propylene-urea N-(6-gas-7-fluoro-5-phenyl-1H-indazol-3-yl)-indole-(phenylmercapto)urea-(6-gas-7-fluoro -5-stupyl-1Η-carbazol-3-yl)-rush-(4-phenoxyphenyl)urea-(6-gas-7-fluoro-5-phenyl-1Η-carbazole-3 -Base)-Ν·-(4-methoxyphenyl)methyl]urea-14- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1345561 Δ7 Α7 Β7 V. Description of invention ( 13) N-(6-Gas-7-fluoro-5-phenyl-1H-indazol-3-yl)-indole-[4-(trifluoromethyl)phenyl]urea-(6-gas -7-fluoro-5-phenyl-1Η-oxazol-3-yl)-Ν'-(4-methoxyphenyl)urea-(6-gas-7-fluoro-5-phenyl-1Η -oxazol-3-yl)-oxime-cyclohexylurea 5 Ν-(6-gas-7"fluoro-5-phenyl-1 fluorene-3-carbazol-3-yl)-oxime-propylurea N- (6-Gas-7-fluoro-5-phenyl-1H-indazol-3-yl)-indole-(4-phenylphenyl)urea-(6-chloro-7-fluoro-5-phenyl -1Η-oxazol-3-yl)-Ν·- (4-fluorophenyl)urea-[6-chloro-7-fluoro-5-phenyl-1indole-indazol-3-yl;|-Ν,-(tricyclic [3.3.1.13,7]癸) -1-based urea 10 Ν-(6-gas-7-fluoro-5-phenyl-1 fluorene-3-oxazol-3-yl)-indole-(4-methylphenyl)urea-(6-gas _7_Fluorine_5_Bistly-lH-carbazolyl)urea··. j* Ν-(6-Gas-7-indolyl-5-phenyl-1Η-oxazol-3-yl)urea -(6-chloro-7-cyano-5-phenyl-1indole-3-yl)urea-(6-gas-7-cyclopropyl-5-phenyl-1?-carbazole-3 -Based Urea 15 Ν-(6-Gas-7-hydroxy-5-phenyl-1Η-oxazol-3-yl)urea Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Ν-(6-Chloro-7-曱oxy-5-phenyl-1Η-oxazol-3-yl)urea-(6-gas-7-trifluoromethyl-5-phenyl-1Η-oxazol-3-yl)urea- (6-chloro-7-trifluorodecyloxy-5-phenyl-1 fluoren-3-yl)urea-(6-gas-7-nitro-5-phenyl-1 oxime-carbazole -3-yl)urea 20 Ν-(6-gas-7-amino-5-phenyl-1Η-Ή丨β--3-yl) adenine-(6-chloro-7-dimethylamino group -5-phenyl-1Η-oxazol-3-yl)urea-(6-gas-7-ethynyl-5-phenyl-1-oxazol-3-yl)urea-[6-gas- 7-fluoro-5-phenyl-1Η-oxazol-3-yl]-4-mercapto-benzenesulfonamide-[6-gas-7-fluoro-5-phenyl-1Η-carbazole-3 -基] sulfonamide-15- This paper size is suitable Use Chinese national standard "(0^) 八4 specification (210 X 297 mm) 1345561 Λ7 Α7 Β7 V. Invention description (14) N-[6-gas-7-fluoro-5-stupyl-1H- Oxazol-3-yl]-2-propanesulfonamide N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]-2,2,2-trifluoroethanesulfonate Indoleamine N-[6-gas-7-fluoro-5-phenyl-1H-indazol-3-yl]-2-thiophenesulfonamide N-[6-gas-7-fluoro-5-stupyl- 1H-carbazol-3-yl]benzenesulfonamide 5 N-[6-gas-7-fluoro-5-phenyl-1H-indazol-3-yl]-4-(trifluoromethyl)benzene- Sulfonamide N-[6-gas-7-fluoro-5-phenyl-1H-indazol-3-yl]-5-(3-isoxazolyl)-2-thiophene-branched amine N-[ 6-Gas-7-fluoro-5-phenyl-1H-indazol-3-yl]-4-fluorobenzenesulfonamide N-[6-chloro-7-fluoro-5-phenyl-1H-carbazole -3-yl]-4-decyloxybenzenesulfonamide 10 N-[6-gas-7-fluoro-5-phenyl-1H-indazol-3-yl]benzimidamide N-[6 ·Gas_7_Fluor tomb-1H-carbazole_3_棊]-1-mercapto-1H-imidazole_4_sulfonate: ^ · * - Amine N-[6-gas-7-fluoro-5 -phenyl-1H-indazol-3-yl]-4-(1,1-dimethylethyl)benzenesulfonamide 15 N-[4-[[(6-chloro-7-fluoro-5-) Phenyl-1H-indazol-3-yl)amino]sulfonyl]phenyl]-acetamide, Ministry of Economic Affairs, Intellectual Property Office, Staff Consumption Cooperative, Printing N-[6-Gas-7-Fluoro-5-Benzene base- 1H-carbazol-3-yl]-4-mercaptophenylsulfonamide 6-chloro-7-fluoro-N-(pentafluorophenyl)-5-phenyl-1H-indazol-3-amine 6 - gas-7-fluoro-N-(3,4-difluorophenyl)-5-phenyl-1H-indazol-3-amine 20 6-chloro-7-fluoro-5-phenyl-N-( 2,3,5,6-tetrafluorophenyl)-1Η-indazol-3-amine 6-gas-7-fluoro-5-phenyl-N-(2,4,6-trifluorophenyl)- 1Η-carbazol-3-amine 6-gas-7-fluoro-N-(4-fluorophenyl)-5-phenyl-1H-indazole-3-amine 6-gas-7-fluoro-N-[ 3-(Trifluoromethyl)phenyl]-5-phenyl-1H-indazol-3-amine 6-gas-7-fluoro-N-[4-(trifluoromethyl)phenyl]-5- Phenyl-1H-indazole-3-amine-16- This paper scale applies to Chinese national standards (CNS> A4 specification (210 X 297 mm) 1345561 A7 B7 V. Description of invention (15 6-gas-7-fluoro- N-[3-Fluoro-5-(trifluoromethyl)phenyl]-5-phenyl-1HH3 amine 6-gas-7-fluoro-N-(4-rephenyl)-5-phenyl-1Η -β51 坐-3-amine 6-gas-7-fluoro-Ν-(3-wall phenyl)-5-phenyl-1Η-° 坐____6-α-7-fluoro-Ν-( 3-methoxyphenyl)-5-phenyl-1-oxazol-3-amine.5 6-gas-7-fluoroza (4-methoxyphenyl)-5-phenyl-1H-&quot ; azole _3·amine 6-gas-7-fluoro-N,5-diphenyl-1H-carbazol-3-amine 6-gas-7-gas-N-(l-〇 ratio) 5-stupyl-1H-D bow 丨 丨-3-amine 6 _ gas - 7-fluoro-indole-(2-β ratio thiol)-5-phenyl-1H-B5丨嗤-3-amine N-butyl-6-gas-7-fluoro-5-phenyl-1Η-β5丨Salt-3-amine 10 Ν·(6-gas-7-fluoro-5-phenyl-1Η-0丨丨° sitting-3-yl)-Ν'-phenyl adenine-(6-gas_7 _Fluoro-5_acyl-1 Η-carbazolyl)·3_methoxy oxasulfonamide, an isomer thereof, a mixture thereof, a racemate, an enantiomer, a diastereomeric or mutual The isomers, and their pharmaceutically acceptable salts, and, in particular, the following compounds: 15 hexahydropine bite · 1 · acid (6,7-difluoro-5-phenyl·1Η-called 丨Zyridin-3-yl)-acrylpyridin-1-one (6,7-di-5-phenyl-111,oxazol-3-yl)-amine 1-(6,7-difluoro-S- Phenyl·1Η_oxazolidyl) ^ (4曱6 氲呲 氲呲 基 基 基)]]]] Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed N-(6,7-difluoro-5-stupidyl -1H-indole-3-yl)-N,-phenyl gland 20, its tautomer and its pharmaceutically acceptable salt. The invention also relates to a medicament comprising a derivative of the formula (I), a racemate 'enantiomer, or a diastereomer thereof and a mixture thereof, a tautomer thereof and a pharmaceutically acceptable salt thereof as an active ingredient The composition, wherein: R3 is (1-6C) alkyl, aryl, aryl (1-6C) group 'heteroaryl, heteroaryl-17- paper scale χ 297^ 1345561 A7 B7 Description of the invention (16) Alkyl (1-6C)alkyl, aryl or heteroaryl fused to (MOC)cycloalkyl, heterocyclic, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkane a group, an alkenyl group, an alkynyl group, a C0NR1R2, a CSNR1R2, a COOR1, a S02R1, a C(=NH)R1 or a C(=NH)NR1 group; such groups may optionally have one or more substituents selected from the group consisting of 5 or less Substitution: CN, N〇2, NH2, OH, 0R1, COOH, C(0)0R1, -0-C(0)Rl, NR1R2, NHC(0)R1, C(0)NR1R2, SRI, S(0 R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R1, -0-S02Rl, -S02-〇-Rl, aryl, heteroaryl, heterocyclic, formazan, trifluoromethyl , trifluoromethyl 10 sulfanyl, trifluoromethoxy or (1-6C)alkyl; R 5 , R 6 and R 7 are separated from the group selected from the group consisting of halogen, CN ·· : - ; I ·. ., t · ·,, 2 N〇2, NH2, OH, COOH, C(0)0R8 弋-0_C(0)R8, •y ·'; ' Ministry of Economic Affairs Intellectual Property Bureau Employee Sales Cooperative Printed NR8R9 > NHC(0:)R8 ' C(0)NR8R9 ' NHC(S)R8 ' C(S)NR8R9, SR8, S(0)R8, S02R8, NHS02R8, 15 S02NR8R9, -0 -S02R8, -S02-0-R8, trifluoromethyl, trifluoromethoxy, (1-6C)alkyl, (1-6C) alkoxy, aryl, aryl (1-6C) alkyl , heteroaryl 'heteroaryl(1-6C)alkyl' heterocycle, cycloalkyl, alkenyl, alkynyl, adamantyl or polycycloalkyl; such groups may optionally be selected by one or more Substituted from the following substituents: halogen, CN, N〇2, NH2, OH, 20 〇R1〇, COOH, C(O)OR10, -OC(O)R10, NR10R11, NHC(O)R10 'C(O )NR10Rll, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10 'SO2NR10Rll, -〇-SO2R10, -so2-o-rio, aryl, heteroaryl, formamidine Base, trifluorodecyl 'trifluorodecyloxy or (丨_6C) alkyl; -18- This paper scale applies to Chinese national standards (CNS> A4 specification (210x297 cm) 1345561 A7 B7 V. Invention description (17 ) R R 2 , R 8 , R 9 ' R 10 and R 11 are each independently hydrogen, (1_6C)alkyl, aryl, alkenyl, alkynyl, heteroaryl, which may itself be substituted by one or more substituents selected from the group consisting of: Halogen, (1_6C)alkyl, (1_6C) alkoxy, CN, N02, NH2, 〇H, COOH 'C00 alkyl, 5 CONH2, carbaryl, trifluoromethyl, trifluoromethoxy; R1 And R2 or R8 and R9 or R10 and RH may form a 5- or 6-membered ring which may or may not contain a hetero atom such as: 0, S or N; and when R3 is a 6-membered nitrogen-containing heteroaryl or When thiazolyl or imidazolyl or oxazolyl, then at least one of R5 and R6 is aryl, which may optionally be substituted with one or more substituents selected from the group consisting of halogen, CN, N〇2, NH2, OH. , ORIO, COOH, C(O)OR10 '-〇-C(O)R10, NR10RH, NHC(0)R1〇, C(O)NR10Rll, NHC(S)R10, C(S)NR10R11, $R10, S(O)R10, SO2R10, NHSO2R10, SOjNRlORll, -0-S〇2R1〇, -S02-0-R1〇, aryl, heteroaryl '15-mercapto, trifluoromethyl, trifluoromethoxy Or (1-6C)alkyl. The Ministry of Economic Affairs, the Intellectual Property Bureau, the Bayer Consumers Cooperative, printed in more detail, the present invention relates to the inclusion of the derivative of formula (1), its racemates, enantiomers or diastereomers and mixtures thereof, tautomerism And a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof as an active ingredient, wherein: 20 R3 is (1-6C)alkyl, aryl, aryl (1-6C)alkyl, heteroaryl, heteroaryl ( 1-6C) an alkyl group or a heteroaryl group fused to a (1-10C) cycloalkyl group, a heterocyclic ring, a heterocycloalkyl group, a cycloalkyl group, an adamantyl group, a polycycloalkyl group, a dilute group, Block base, CONR1R2, CSNR1R2, COOR1, S02R1, C(=NH)R1 or C(=NH)NR1 groups; these groups can be applied to Chinese national ladders by one or more selected Quasi (CNS) A4 specification (210x297 public) 1345561 A7 B7 V. Description of invention (i) Substituted from the following substituents: halogen, CN, N〇2, NH2, 0H 'OR1, COOH, C(0)0R1 -0-C(0)Rl, NR1R2, NHC(0)R1, C(0)NR1R2, SRI, S(0)R1, S02R1, NHS02Rl, S02NRlR2, C(S)NRlR2, NHC(S)Rl,- 0-5 S02R1, -S02-0-Rl, aryl, heteroaryl, heterocyclic, formazan , trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy or (1-6C)alkyl; R5 and R6 are each independently selected from the group consisting of halogen, CN, N02, NH2, OH , COOH, C(0)0R8, -0-C(0)R8, NR8R9, NHC(0)R8, C(0)NR8R9, NHC(S)R8, C(S)NR8R9, 10 SR8, S(0 ) R8 ' S02R8, NHS02R8, S02NR8R9, -O-S02R8, -S02-0_rS, trifluoromethane, trifluoro-free oxy, (l-6 decyl, (1-6C) alkoxy, aryl, Aryl (1_6 〇 _, heteroaryl, heteroaryl...yl (1_6C)alkyl, heterocyclic, cycloalkyl, alkenyl, sulfonate, adamantyl, polycycloalkyl; such groups may optionally Substituted by one or more 15 generations selected from the group consisting of halogen, CN, NO, NH2, OH, OR10, COOH, Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, C(O)OR10, -〇-C (O) R10, NR10R11, NHC(O)R10, C(O)NR10Rll, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, SO2NR10Rll, -O-SO2R10, -S〇2-〇-R1〇, aryl, heteroaryl, methionyl, trifluoromethyl 20, trifluoromethoxy or (1-6C)alkyl; R7 is halogen, methyl, cyclopropyl Base, cn OH, methoxy, trifluoromethyl, vinyl, ethynyl 'trifluoromethoxy, N〇2, leg 2 or NMe2, IU, R2 'R8, R9, R10 and R11 are each independently hydrogen, alkyl , aryl, alkenyl, alkynyl or heteroaryl, which itself can be applied to the Chinese National Standard (CNS) A4 specification via a -20-i paper scale (2丨〇?(297 公^1--1345561 A7 B7) 5. Description of the invention (19) or a plurality of substituents selected from the group consisting of halogen, (1_6C)alkyl, (1_6C) alkoxy, CN, NOS, nh2, OH, COOH, COO alkyl, CONH2, A Anthracenyl, trifluoromethyl or trifluoromethoxy; R1 and R2 or R8 and R9 or Ri and ru may form a 5- or 6-membered ring, which may or may not contain a hetero atom, such as: And s or N; and when R3 is a 6-membered nitrogen-containing heteroaryl or thiazolyl, imidazolyl or oxazolyl group, then at least one of R5 and R6 is aryl, which may optionally be selected from one or more selected from the group consisting of Substituent substitution: halogen, CN, N〇2, NH2, OH, ORIO, COOH, C(O)OR10, -0-C(0)R10, 10 NR10R11, NHC(0)R1〇, c(O) NR10Rll, NHC(S)R10, C(S)NR10R11, S|:l〇, S(0)R4〇, SO2R10, NHSO2R10 SO2NR10Rll, -〇 S02R1〇-, -SO2 R10-O-, aryl; group, an aryl group #, .. 'methyl acyl, Yue trifluoromethyl group, trifluoromethoxy group Yue, and (Shu _6C) burning group. The present invention is preferably a medicament comprising a derivative of the formula (1), a racemate 'enantiomer 15 isomer or diastereomer thereof and a mixture thereof, a tautomer thereof and a pharmaceutically acceptable salt thereof as an active ingredient. Composition, wherein: Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed R3 as (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1-6C) Alkyl, aryl or heteroaryl fused to (M0C)cycloalkyl, heterocyclic, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkyne 20, CONR1R2 a CSNR1R2, COOR1, S02R1 or C(=NH)NRI group; such groups may be substituted with one or more substituents selected from the group consisting of halogen, CN, N〇2, NH2, OH 'OR1 'COOH, C(0)0R1 ' -〇-C(0)Rl ' NR1R2,NHC(0)R1 ' C(0)NR1R2,SRI,S(0)R1,S02R1,NHS02R1 ' -21- This paper size applies to China Standard (CNS) A4 specification (210 X 297 mm) 1345561 A7 V. Description of invention (2〇) S02NR1R2, C(S)NRiR2, NHC(S)Ri ' -0-S02Ri, ·3〇2-〇-

Ri, aryl, heteroaryl, aryl, oxo, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy or (1-6C)alkyl; R5 is aryl; R6 and R7 are independently halogen, methyl, cyclopropyl, CN, hydrazine H, methoxy, trifluoromethyl, vinyl, ethynyl, trifluoromethoxy, N〇2, NH2 or NMe2, R1 Independent of R2, independently of hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl or heteroaryl, may itself be substituted with one or more substituted 1 fluorenyl groups selected from the group consisting of: halogen' ( 1-6C) alkyl, (1-6C) alkoxy, CN, N02, NH2, OH, COOH, C00 alkyl, CONH2, formamyl, trifluoromethyl or tris-methoxy; R1 and R2 A 5- or 6-membered ring can be formed which can optionally contain heteroatoms such as hydrazine, S or N. The present invention preferably also relates to an aminocarbazole derivative of the formula (1), a racemate, an enantiomer or a diastereomer thereof, a mixture thereof, a tautomer thereof and a pharmaceutically acceptable salt thereof. Uses of medicines, among which: R3 of the Intellectual Property Office of the Ministry of Economic Affairs printed R3 is (1-6C) ray, aryl, aryl (ι·6〇 alkyl, heteroaryl, heteroaryl (1-6C) An alkyl group, an aryl or heteroaryl group fused to a (1-10C) cycloalkyl group, a hetero-20 ring, a heterocycloalkyl group, a cycloalkyl group, an adamantyl group, a polycycloalkyl group, an alkenyl group, an alkynyl group , CONR1R2 'CSNR1R2, COOR1, S02R1, C(=NH)R1 or C(=NH)NR1 groups; such groups may be substituted by one or more substituents selected from the group consisting of CN, N〇2, NH2, OH ' OR1 ' COOH, C(0)0R1, _〇-C(〇)Rl, NR1R2, NHC(0)RI, -22- This paper scale is applicable to the national standard (CNS) A4 specification ( 210x297 公) 1345561 A7 B7 V. INSTRUCTIONS (21) C(0)NR1R2, SRI, S(0)R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R1,-0-S02Rl , -S02-0-, aryl, heteroaryl, heterocyclomethyl, trifluoromethyl, trifluoromethyl Sulfphyl, trifluoromethoxy or (1-6C)alkyl; 5 R5, R6 and R7 are each independently selected from the group consisting of halogen, CN, N〇2, NH2, OH, COOH, C ( 0) 0R8, -0-C(0)R8, NR8R9, NHC(0)R8, C(0)NR8R9, NHC(S)R8, C(S)NR8R9, SR8, S(0)R8, S02R8, NHS02R8 , S02NR8R9, -0-S02R8, -S02-0-R8, trifluoromethyl, trifluoromethane oxide, (1-6C) alkyl, (1-6C) alkoxy, aryl, aryl (1-6C) alkyl, heteroaryl 'heteroaryl(1-6C)alkyl, heterocyclic, cycloalkyl, alkenyl, alkynyl, adamantyl or polycycloalkyl; such groups visible It is required to be substituted by two or more substituents selected from the group consisting of halogen, CN, N02, NH2, OH, ORIO, COOH, C(O)OR10, -〇-C(O)R10, NR10R11, 15 NHC(O ) R10 , C(O)NR10Rll , NHC(S)R10 , C(S)NR10R11, SR10, S(0)R1〇, SO2R10, NHSO2R10, SOaNRIORll ' -〇-S〇2R1〇' -S〇2-〇 -R1 〇, aryl, heteroaryl, methionyl, trifluoromethyl, trifluoromethoxy or (1_6C) alkyl; Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed RJ, R2, R8, R9, R10 and R11 are independently hydrogen, 6C) a 20-, aryl, alkenyl, alkynyl or heteroaryl group which may itself be substituted with one or more substituents selected from the group consisting of halogen, (1_6C)alkyl, (1_6C) alkoxy Base, CN 'N〇2, NH2, OH, COOH, COO alkyl, CONH2, formamidine, trifluoromethyl or trifluoromethoxy; R1 and R2 or R8 and R9 or Ri〇 and RU can form 5 _ or 6_member ring, its • 23- This paper size applies f Η B冢 standard (CNS) A4 gauge-4 ( 210 X 2 „ ^ ^ 1345561 A7 B7 V, invention description (22) may or may not Containing a hetero atom such as: 0, S or N; and when R3 is a 6-membered heteroaryl or sinyl, oxime or oxime, then at least one of R5 and R6 is an aryl group, It may be substituted with one or more substituents selected from the group consisting of halogen, CN 'N〇2, NH2, 5 OH, ORIO, COOH, C(0)OR1〇, -〇-C(〇)R1〇, NR10R1卜NHC(O)R10, C(0)NR10R11, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10, NHSO2R10, S02NR10R11, -〇-SO2R10, -S(V〇- R1 hydrazine, aryl, heteroaryl, carbaryl 'trifluoromethyl, trifluoromethoxy or (1-6C)alkyl. 10 More specifically, the present invention relates to an aminocarbazole derivative of the formula (I), a racemate, an enantiomer or a non-preferential isomer thereof and a mixture thereof, and tautomers thereof The acceptable salt is used as a medicine, wherein: • R3 is (1-6C) alkyl, aryl, aryl (1-6C) alkyl, heteroaryl, heteroaryl (1) -6C) alkyl, aryl or heteroaryl fused to (M0C)cycloalkyl, hetero-15, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl , CONR1R2, CSNR1R2, COOR1, S02R1, C(=NH)R1 Ministry of Economic Affairs Intellectual Property Bureau Bayer Consumer Cooperative Printed- or C(=NH)NR1 group; such groups may optionally be selected from one or more Substituted by the following substituents: halogen, CN, N〇2, NH2, OH, OR1, COOH, C(0)0R1, -0-C(0)Rl, NR1R2, 20 NHC(0)R1, C(0) NR1R2, SRI, S(0)R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R1, _〇-S02R1, -S02-0-Rl, aryl, heteroaryl 'heterocycle' Mercapto, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy or (1-6C)alkyl; R5 and R6 are each independently selected from Columns: Halogen, CN, N02, -24- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public « ) 1345561 A7 B7 V. Description of invention (23 ) NH2, OH, COOH, C(0)0R8, -0-C(0)R8, NR8R9, NHC(0)R8, C(0)NR8R9, NHC(S)R8, C(S)NR8R9, SR8, S(0)R8, S02R8 , NHS02R8, S02NR8R9, -0-S02R8, -SCV0-R8, trifluoromethyl, trifluoromethoxy, (1-6C), 5-yl, (1-6G) alkanoyl 'aryl, aryl ( 1-6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, heterocyclic, cycloalkyl, alkenyl, alkynyl adamantyl, polycycloalkyl; such groups may optionally Substituted by one or more substituents selected from the group consisting of halogen, CN 'N02, NH2, OH, OR10, C00H, C(O)OR10, -0-C(0)R10, NR10R11, NHC(O)R10, 10 C(O)NR10Rll, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10 ' S02R10 ' NHSO2R10 > SOzNRIORll ' -〇- ········ « SOzRlO, -SCVO -RIO, aryl, heteroaryl, indolyl, 'trifluoromethyl, trifluoromethoxy or (1-6C) alkyl; Ministry of Economic Affairs, Intellectual Property Bureau, Bayer Consumer Cooperative, printed R7 as halogen, cesium base Cyclopropyl, CN, OH, methoxy, trifluoromethyl-15, vinyl, ethynyl, trifluoromethoxy, n〇2 'NH2 or NMe2, IU, R2, R8, R9, R10 and R11, respectively Independently hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl or heteroaryl, which may itself be substituted by one or more substituents selected from the group consisting of: _, (1_6C) alkyl , (1_6C) alkoxy 'CN, N〇2, NH2, OH, COOH, COO alkyl, 20 CONH2, fluorenyl, trifluoromethyl or trifluoromethoxy; R1 and R2 or R8 and R9 or Ri〇 and R11 may form a 5- or 6-membered ring which may or may not contain a hetero atom such as hydrazine, S or n; and 畲R3 is a 6-membered nitrogen-containing heteroaryl or thiazolyl, imidazolyl or In the case of a carbazolyl group, at least one of R5 and R6 is an aryl group, which may be applied to a HS-based ladder (CNS) A4 specification (210x297 public 1345561 A7 B7). 24) or a plurality of substituents selected from the group consisting of halogen, CN 'N〇2, NH2, OH, 〇Rl〇' COOH, C(O)OR10, -0-C(0)R10, NR10R11, NHC ( O) R10, C(O)NR10Rll, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, SO2R10 , NHS02R1〇' 5 SO2NR10Rll, -0-S02R1〇, -so2-o-rio, aryl, heteroaryl, fluorenyl, tridecyl, trifluoromethoxy, and (1-6C)alkyl . Preferably, the present invention relates to an aminocarbazole derivative of the formula (1), a racemate, an enantiomer or a diastereomer thereof, a mixture thereof, a tautomer thereof and a pharmaceutically acceptable salt thereof as a medicament Uses thereof, wherein: 10 R3 is (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl, heteroaryl(KC)alkyl, and g-10G)cycloalkyl Fused penta- or heteroaryl, heterocyclic, heterocycloalkyl, pendant k-, adamantyl, poly-alkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, S02R1 or C(=NH) NR1 groups; such groups may be substituted with one or more substituents selected from 15 or less as follows: dentate, CN, N〇2, NH2, OH, OR1, COOH, C(0)ORl, -0- C(0)Rl, NR1R2, NHC(0)R1, C(0)NR1R2, SRI, S(0)R1, S02R1, NHSO2RI, S02NR1R2 'C(S)NR1R2, NHC(S)R1,-0-S02Rl ,-S02-0- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed R1 'aryl, heteroaryl, methionyl, oxo, trifluoromethyl, tri-l-20 alkylsulfanyl, trifluoromethyl Oxy or (1-6C)alkyl; R5 is aryl; R6 and R7 are independently halogen, methyl, cyclopropyl, CN, respectively OH, methoxy, trimethyl, ethylene, ethyl bromide, trimethylmethoxy, N〇2, NH2 or NMe2, -26- not paper grade applicable to China National Standard (CNS) A4 specification (210x297 Male «) --- 1345561 A7 B7 V. Description of the invention (25) R1 and R2 are each independently hydrogen '(1-6C)alkyl, aryl, alkenyl 'alkynyl or heteroaryl, which may itself be used as needed Substituted by one or more substituents selected from the group consisting of: phenyl, (1-6C)alkyl, (1-6C) alkoxy, CN, N02, NH2, OH, COOH, COO alkyl, CONH2, formamidine And oxo.5, trifluoromethyl or trifluoromethoxy; R1 and R2 may form a 5- or 6-membered ring which may optionally contain a hetero atom such as 0, S or N. The derivative of formula (I) can be prepared from the corresponding 3-amino derivative (V), the nitrogen of the 1-position being optionally protected by the group Pr. Γ is a trimethyl decyl ethoxy ethoxy 10 methyl group, a phenyl alcohol, a styrene or a benzyl group or as indicated in TW Greene, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1999) A known group that protects the NH group in the aromatic ring.

Ministry of Economic Affairs, Intellectual Property Bureau, Bayer Consumers Co., Ltd. Printed 20 formula (Π)3·Amino-1-indole carbazole can be prepared from 2-fluorophenyl cyanide and hydrazine hydrate or hydrochloride, according to RF Kaltenbach, Bioorg· Med .Chem Leu" 2(15), 2259-62 (1999), refluxing in ethanol or n-butanol for 2 to 18 hours: -27- This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 1345561 A7 ΒΊ V. INSTRUCTIONS (26) nh2nh2, h2o reflux alcohol (ethanol, butanol)

00 ; R5 and R6 in the compound are each independently selected from the group consisting of: halogen, 01^, :^02, position, 011, (:0011, (:(0)0118,-0- Ministry of Economic Affairs Intellectual Property Bureau) Employee Consumption Cooperatives print C(0)R8, NR8R9, NHC(0)R8, C(0)NR8R9, NHC(S)R8, 10 C(S)NR8R9, SR8, S(0)R8, S02R8, NHS02R8, S02NR8R9, -0-S02R8, -S02-0-R8, trifluoromethyl, trifluoromethoxy, (1-6C)-fluorenyl, (1-6C) alkoxy, aryl, aryl (1 -6C) alkyl, heteroaryl, heteroaryl (1-6C) alkyl, cycloalkyl, alkenyl, alkynyl or adamantyl; such groups may optionally be selected from one or more selected from the group consisting of Substituent 15 Substituted: halogen, CN, N〇2, NH2, OH, OR10, COOH, C(O)OR10, -〇-C(O)R10, NR10R11, NHC(O)R10, C(O)NR10Rll ' NHC(S)R10, C(S)NR10R11, SR10, S(O)R10, S02R1〇, NHSO2R10, SO2NR10Rll, -〇-SOzRlO, -SO2-O-RIO, aryl, heteroaryl 'carbamyl, In the case of a trifluoromethyl 20-, trifluoromethyl or (1-6C) alkyl group, the process for its preparation involves the chemical reaction of the corresponding halogenated derivative: Suzuki (A. Suzuki, Pure Appl. Chem., 63, 419-22 (1991), Stille (J. Stille, Angew. Chem" Int. Ed., 25, 508-24 (1986)), Heck (RF Heck, Org. React) 27, 345-90 (1982) )), Sonogashira (K. Sonogashira, -28- This paper size is suitable for China National Standard (CNS) A4 specification (210 x 297 public) 1345561 Α7 Α7 Β7 V. Invention description (27)

Synthesis, 777 (1977)), Buckwald (S. L. Buckwald, Ace. Chem. Re., 31, 805 (1998)). Therefore, reactive functional groups must be protected. It is therefore necessary to protect the OH, SH, COOH and NH2 functional groups prior to the coupling reaction. The protecting group 5 is introduced in any manner known to those skilled in the art, and is specifically described in TW Greene, "Protective groups in Organic Synthesis, J. Wiley-interscience Publication (1999)". It is preferably protected with a third butoxycarbonyl or anthracene derivative. It is preferred to use a third butyl dimethyl decyl group or a 10 isopropyl isopropyl group which can be removed by using a fluoride anion or acetic acid, and more specifically, a trimethyl decyl ethoxymethyl group which can be used as a tetrabutyl group. Fluorine is removed in a refluxing solvent (eg, hydrazine or dioxane) (JP Whitten, J. Org. Chem., 51, 1891 (1986); BH Lipshutz, Tetrahedron Lett., 4095 (1986)) Alternatively, it can be removed under reflux using 2N hydrochloric acid in methanol or ethanol. 15 1-position of the trimethyl decyl ethoxymethyl-protected derivative is prepared by the starting compound and trimethyl ethoxymethyloxyl in the presence of sodium hydride in a solvent (eg dimethyl Carbenamide), reacted at room temperature (JP Whitten, J. 〇rg. Chem., 51, 1891 (1986); Μ. Ρ. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative

Edwards’ Tetrahedron, 42, 3723 (1986)). 20 Similarly, the 1-indole nitrogen functional group of carbazole can be protected using, for example, a decyl derivative, a claudyl, an amine phthalate or a toluenesulfonyl group. For example, if palladium is required to be coupled with a functionalized derivative at the 6-position, the nitrogen at the 1-position must be protected as shown in Figure 1 below (X = Cb Br or I)· -29- This paper scale applies to China's sleepy standard (〇NS) A4 specification (210x297 public) 1345561 A7 B7 V. Invention description (28)

5 The removal of the protecting group is carried out in a manner known to those skilled in the art, as described in TW Greene, Protective Groups in Organic Synthesis, J. Wiley-Interscience Publication (1999). For example: if 1-position When the protecting group is a tridecyl ethoxylated oxime group, it can be reacted with tetrabutylammonium fluoride according to the following reaction scheme to remove the 10 group: ...r R3 15 HN I.1

Bi^NF.THF, reflux, removal protection

Tl Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 When one of the R5 or R6 groups involved in the use of palladium chemistry is inherently reactive, such as hydroxyl, amine, thiol, or acid When a hetero atom is usually included, it is also necessary to protect the latter before using the coupling reaction. Thus, for example, a phenolic functional group will be introduced from a gasified derivative in a protected form (e.g., 0-phenylhydrazine), and the nitrogen in the position is protected by the type previously described: -30- This paper scale is used VS embarrassing standard (CNS) A4 specification (210 X 297 public) 1345561 A7 B7 V. Invention description (29)

The methyl group is then removed by refluxing in acetonitrile using, for example, trimethoprim. It can also be protected with trimethyl decyl ethoxylated ruthenium, which can be removed using tetrabutylammonium fluoride in a refluxing solvent (eg tetrahydrofuran or the Ministry of Economic Affairs, Intellectual Property Office, Employees' Cooperatives Printing Institute) (J. P. Whitten, J. Org. Chem) 51, 1891 (1986); BH 10 LlPshutz, Tetrahedron Lett., 4095 (1986)) or by using 2N hydrochloric acid in methanol or ethanol under reflux. When R·5 and R6 are each independently an aryl group and a halogen, the aryl functional group green is introduced into the bromination position by a coupling reaction with it, and the nitrogen of the position is appropriately protected. Preferably, Pr Represents a tridecyl ethoxymethyl group, and Pri 15 represents a n-butylcarbonyl group, which forms a n-butyl amidoxime with nitrogen to remove a guanamine protecting group, and is refluxed in DMF for 1 week in the presence of ethanolamine. This cleavage reaction can also be carried out using stannous chloride in ethanol (RJ GRiffm, J. Chem. Soc. Perkin I, 1992, 181M819) or using methanol in methanol (Y. Furukawa, Chem. Pharm). Bull., 1968, 16, 1076) 20 or using any other alkoxide, in the corresponding alcohol.

This paper scale applies to China Standard (CNS) A4 specification (210x297 mm) 1345561 A7 ______B7 ___ V. Description of invention (3〇) When R5 and R6 are independently aryl and halogen, respectively, the aryl functional group is The palladium coupling reaction is introduced to the bromination site to properly protect the nitrogen at the 1- and 3-positions. Preferably, Pr represents a tridecyl ethoxymethyl group, and Pr represents a n-butylcarboxy group which forms n-butyl decylamine with nitrogen. An electrophilic substitution reaction is carried out, for example, with a tetrafluoro 5 boric acid pin (no 2bf 4 ). A 5-position coupling reaction (Suzuki, Heck or Sonogashira coupling) was carried out using a palladium chemical reaction. The 7-position is functionalized with the desired substituent, such as: reduction of a halogenated introduction, or chemical reaction coupling (Suzuki, Heck or Sonogashira coupling) introduction of an aryl group, a heteroaryl group, an alkyl group, an alkenyl group, Alkyne 10 or acetylenic functional group. When the amine protecting group is removed, it is refluxed in DMF for 1 week in the presence of ethanolamine. This cleavage reaction can also be carried out using vaporized stannous 'in ethanol (RJ Griffin, J. Chem. Soc. Perkin I, 1992, 1811-1819) or using sodium methoxide in methanol (丫.1?111: 11]^\^,

Chem. Pharai. Bull" 1968, 16, 1076) or using any other alkanol 15 salt, in the corresponding alcohol. After removal of the protecting group at the 3-position, an NHz functional group is produced which can be associated with the desired group. The reaction is carried out to introduce the desired substituent to 3_, and the reaction is illustrated as follows:

-32- 1345561 A7 B7 V. DESCRIPTION OF THE INVENTION (3) The compound of formula (II) is the starting point for the preparation of various products, which are obtained by all general reaction of the 3-aminoimidazole mono-amine functional group according to the functional group, such as : alkylation, deuteration, reduction after reaction with a carbonyl derivative, sulfonation 'conversion to glandular or carbamate, arylation (castro.5 reacti〇n) or Buchwald reaction (Buchwald) Reaction)), etc. In the general formula (1), when Pr is a trimethyl decyl ethoxymethyl group, a derivative of R3 is hydrazine, and a boron derivative can be used for reductive amination, for example, using triethoxycarbonyl. Sodium borohydride, in dioxane methane, in the presence of an R1CH0 aldehyde, as described in Organic Reactions, Vol. 59, 1-714 (E. Baxter, 10 A. Reitz), or It is carried out by reducing the imine with other reducing agents and converting into a product, wherein R3 is (1-6Q alkyl, aryl (1-6C) alkyl, heteroaryl; ^(1-6C)alkyl, heterocycloalkyl , cycloalkyl hydrazine or polycyclic ν · - . alkyl, such groups may optionally be substituted by one or more substituents selected from the group consisting of halogen, CN, N02 , NH2, OH, OR1, COOH, 15 C(0)0R1, -〇-C(0)Rl, NR1R2 'NHC(0)R1, C(0)NR1R2 printed by the Ministry of Economic Affairs Intellectual Property Bureau SRI, S(0)R1, S02R1, NHS02R1, S02NR1R2, C(S)NR1R2, NHC(S)R1, -0-S02Rl, -S02-0-R1, aryl, heteroaryl, formazan, oxygen a substituent, a trifluoromethyl group, a trifluoromethylsulfanyl group, a trifluoromethoxy group or a (1-6C)alkyl group. 20 In the formula (I), R3 is a condensation reaction of a derivative of hydrazine with an OCNR1 type isocyanate. Specifically, it can be specifically described in the tetrahydro-β-flavor, according to the examples described in Comprehensive Organic Functional Group Transformations, Vol. 6 (Katritzky, Meth-Cohn, Rees 1995) to form a product in which R3 is CONR1R2 or CSNR1R2, R1 and R2 is independently -33- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) A7 1345561 V. Description of invention (32) Hydrogen, (1-6C) alkyl, aryl, alkenyl, An alkynyl or heteroaryl group, which may itself be substituted by one or more substituents selected from the group consisting of: a flavonoid, (1. 6 anthracenyl, (1-60) alkoxy, CN, oxime 2) ΝΗ2, OH, COOH, COO Group, CONH 2, Yue acyl, oxo '5-trifluoro-methoxy or trifluoromethyl group. The sulfonation method of the formula (I) wherein R3 is a derivative of ruthenium may be a sulfonium chloride of the type R1SC^Cl, in the presence of a base (specifically, a tertiary amine such as triethylamine or an aromatic amine, For example, pyridine) is carried out in a general solvent (for example, dichloromethane) to produce a product in which the rule 3 is s〇2R1, and R1 is 10 hydrogen, (1-6C) alkyl, aryl, alkenyl. , alkynyl or heteroaryl, which may itself be substituted by one or # substituents selected from the group consisting of: _, (1_6C) alkyl, (1-6C) alkane' CN, N〇2, NH2 , OH, COOH, COO alkyl, COiiH2, methyl, oxo, trifluoromethyl or trifluoromethoxy. The compound of the formula (1) can be isolated and purified by a generally known method, for example, crystallization, chromatography or extraction. Ministry of Economic Affairs Intellectual Property Bureau Bayer Consumer Cooperatives Printed formula (1) Compounds may be treated with inorganic or organic acids, and reacted with such acids in organic solvents (eg alcohols, ketones, ethers or gasification solvents) to form addition salts. . These salts also form part of the invention. 20 Examples of pharmaceutically acceptable salts may include the following salts: besylate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate 'gluconate, iodine Acid salt, maleate salt, isethionate, methanesulfonate, methylene dimethylnaphthalate, nitrate, oxalate, pamoate, phosphate, salicylate, Succinate, sulphate, tartrate, -34· The paper scale 赖 + ss - 1345561 V. Description of the invention (33) Theophylline acetate and the sulfonate sulfonate β compound (1) is a kinase inhibitor, so it is suitable For the prevention and treatment of neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, frontal and parietal dementia, cortical basal degeneration, Pick's disease, stroke, Gu 5 and spinal trauma and peripheral nerves Lesions, obesity, normal hypertension, arteriosclerotic cardiovascular disease, polycystic ovarian syndrome, sputum syndrome, immunodeficiency and cancer. The assay for activity measures the inhibition of the acidification of 7-protein in the cortical sections of adult rats. 10 Cortical sections of 30 μm μη thick were prepared from 8-10 weeks old male OFA rat (Iffa-Credo) by decapitation. In a 5 ml DI^IEM medium (containing pyruvate and glucose 4.5 g/1), it was maintained at 37 〇 for 4 minutes. The sections were then washed twice with medium and sub-packed into a microtest; (5 sputum contained in 500 μ ΐ medium with or without test compound), and cultured at 37 ° C. After 2 hours, the reaction was stopped by centrifugation. Sections were lysed, sonicated, and centrifuged at 8eC and 18300g for 15 minutes. The protein concentration in the supernatant was determined by the Lowry method using a commercial analysis method (bca protein assay, Pierce Pharmaceuticals). Printed samples from the Ministry of Economic Affairs' Intellectual Property Bureau's Beichi Consumer Cooperative were denaturing at 70 °C for 10 minutes and then separated on 4-12% Bis-tris vertical gel in the presence of MOPS-20 SDS buffer. 'Electric transfer to the cellulose substrate. Immunolabeling was performed using the monoclonal antibody AD2, which specifically recognizes the Ser396/404 phosphorylation epitope of the 7-protein. Add secondary antibody to mouse IgGs and peroxidase coupling and coupling with chemiluminescent substrate, so that the immuno-35- paper scale is applicable to China National Standard (CNS) A4 specification (210 297 297 mm) 1345561 A7 B7 DESCRIPTION OF THE INVENTION (34) The reactive protein can be measured visually. The resulting autoradiogram finally uses the 'GeneTools' software (Syngene (GeneGnome, Ozyme)) to determine the IC5 〇 value. The compound of formula (I) has a very advantageous activity, especially that some compounds have an IC50 of less than 100 μΜ. The following examples illustrate the invention without limitation. The LC/MS analysis of the product was carried out by measuring the LC fraction on a Waters Alliance 2695 apparatus and measuring the mass fraction on a Waters-Micromass Platform II. 10 Method for the preparation of intermediate products 6,7-difluoro-11!-carbazole 3-脍: Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed 0.32 cm3 肼 monohydrate to 0.46 cm3 2,3,4-three Fluorophenyl cyanide in 10 cm3 absolute ethanol. After the reaction medium was heated at about 75 t for 17 hours, 10 cm 3 of ethyl acetate, 5 cm 3 of tetrahydrofuran and 5 cm 3 of steam were added. After the phases were separated, the organic phase was separated, washed with 1 〇 cm 3 of distilled water, and then washed with a saturated aqueous solution of 10 cm 3 of sodium sulphate. After the phases were separated, the organic phase was separated, dried over magnesium sulfate, filtered and concentrated to dryness (2 kPa; 5 ° C). The residue obtained was purified by hydrazine column chromatography (particle size 40-60 μπι; diameter 1.5 cm) under argon pressure of 50 kPa, and dissolved in a cyclohexane/ethyl acetate mixture (50/50 by volume). The dissolved fractions containing the desired product were combined to evaporate under reduced pressure (2 1 ^; 40 〇; after drying (90?3; 40. (:), 1 〇〇mg6,7-difluoro-1Η-»丨Sodium-3-amine' is a white solid with a bright spot of 183. 〇 NMR spectrum (3 〇〇 MHz, (CD3) 2 SOd6, Sppm): 5.57 (unresolved complex: 2 Η); 6·93 (mt MH) 7.52 (ddd, J = 8.5-4.5 and 1Hz: -36- This paper scale applies to the national standard year (cns) A4 specification (21 297 public love 1345561 A7 B7 5. Invention description (35) 10 15 1H ; 12.01 (unresolved complex: 1H). N-(6,7-difluoro-1H-indazol-3-yl) butyl sulphate · Add 0.61 cm3 of butyl hydrazine to ig containing the above 6,7-two After cooling to about 3 ° C in 15 cm 3 pyridine of fluoro-1HH 3-amine, the mixture was allowed to stand at room temperature for 76 hours. The reaction medium was concentrated under reduced pressure (2 kPa; 40 ° C), and the residue was dissolved in 25 cm of ethyl acetate. 25 cm3 of water. The organic phase was washed sequentially with 25 cm3 of steamed residual water and 25 cm3 of saturated sodium carbonated aqueous solution. After the magnesium sulfate is dehydrated, it is filtered and concentrated under reduced pressure (2 kPa; 40 ° C), and the residue is purified under a argon pressure of 50 kPa by particle chromatography (particle size 40-60 / wn; straight 3 Cm) 'Dissolved in a dichloromethane/sterol mixture (98/2 by volume). The fractions containing the desired product were combined and evaporated under reduced pressure (2 kPa; 40 〇; after drying (90 Pa; 40 ° C) Obtained 59611^> 1-(6,7-difluoro-111-oxazol-3-yl)butanamine as a white solid, m.p. 191. 4 NMR spectrum (300 MHz, (CD3) 2SO < 16, δρρπι) : 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 (width dd, J = 9 and 4.5 Hz : 1H) ; 10.47 (wide unresolved complex: 1H); 13.35 (wide unresolved complex · · 1H) β fluoro-1-ΓΓ2-(tricalite) school, US, argon-based r- Its 1-m-test 丨 Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί Ί - ° 丨 丨 -3--3-yl) butanamine iso cm 3 dimethyl decylamine solution to contain 1.65 g of sodium hydride (containing 6 〇 0 / 〇 oil) 50 cm 3 dimethyl Acyl amine. The reaction medium is concentrated to dryness under reduced pressure, dissolved in 250 cm3 of ethyl acetate and 200 cm3 of water; after stratification, the 'isolated organic phase' is washed with 15 〇cm3 of water, and is applied to the paper scale. Standard (CNS) A4 specification (21〇χ 297 mm j

1345561 A7 B7 V. INSTRUCTIONS (36) Dehydration of magnesium sulfate, filtration and concentration under reduced pressure to dryness (2 kPa; 50 ° C). The crude product was purified by hydrazine gel column chromatography (particle size 40-60 spleen; diameter 6 cm) under a argon pressure of 50 kPa to dissolve in a cyclohexane/ethyl acetate mixture (8 〇/2 〇 by volume). The fractions containing the desired product were combined and evaporated under reduced pressure (2 kPa; 5 50 ° C) to yield 7.3 g of N-[6,7-dis-l-[[2-(trimethyldecyl)ethoxy]曱基]-1Η-0 cited. Sitting on _3_base] butylamine, a yellow oil. H NMR spectrum (300 MHz, (CD3) 2SO <16, δρρπι): · 〇, 〇9 (s : 9Η) · 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 : 10 2H); 7.22 (ddd, J = 11- 9 and 7 Hz : 1H) ; 7.69 (width dd, J= 9 and 4.5 Hz : 1H}; ΙΟ·6” (unresolved complex: ih) Mass spectrometry: M=369 M-『5-清-6, 7·Difluoro-1-|72-(三甲石夕烧基)乙童基1甲一引峻_ k-base 1-butyramine 15 Add 0.87cm3 pyridine to lg containing the above prepared N-[6,7 -Difluoro-1-Issued by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives [[2-(Ximenyuan))ethoxy]methyl]-1HH3-yl] butylamine 3〇cm3 in the imitation ' Then, 0 56 cm3 of bromine was added, and the mixture was refluxed overnight. 50 cm3 of dichloromethane and 50 cm3 of a 1% by weight aqueous solution of sodium thiosulfate were added to the reaction medium. After stirring for 10 minutes, the insoluble 20 was removed by filtration through a frit glass. The organic phase was washed with 50 cm3 of water and 50 〇 1113 saturated sodium carbonate solution. After phase separation, the organic phase was separated, dried over magnesium sulfate, filtered and concentrated to dryness (2 kPa; The crude product (l.lg) was purified by hydrazine column chromatography under a argon pressure of 50 kPa (particle size 40-60 μπι; diameter 3 cm), with a mixture of cyclohexane/ethyl acetate (90/10 volume). The mixture contains the desired -38-1345561 A7 V. Description of the invention (37 Dissolved product, evaporated under reduced pressure (2 kPa; 50. 〇. After drying (90 Pa; 45 ° C)') 230 mg N- [5-Dimethyl-6,7-difluoro-1-[[2-(trimethyldecyl)ethoxy]methyl]indazol-3-yl]butanamine as a colorless oil. 4 NMR spectrum (300 MHz, (CD3)2SO d6, δρριη) : - 0.08 (s : 5 10 9Η) ; 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) ; (Unresolved complex: 1H). Mass spectrometry: Μ = 447 ίίι!·6,.7-difluoro-5-phenyl-1-indole [2·(三甲石夕烧一) 氪 氪 1 1 its m蛘丨° sitting -3-1 - Ding Hao Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed with 469 mg phenyl dihydroxyboric acid, 760 mg carbonic acid 3 〇 cm 3 water and 379 mg lanthanum (triphenyl phosphine) to yttrium 15 g prepared above N- [5_ _6,7-Difluorodecylalkyl)ethoxy]methyl]1Hoxazolidine] 15 Butylamine in 15 〇 cm 3 of dioxane, the mixture was refluxed for 4 hr. The reaction medium was diluted with 100 cm3 of ethyl acetate and 75 cm3 of water, and filtered through a fritted glass filled with strontium salt. After phase separation, the organic phase was separated, washed with 75 cm3 of water and 75 cm3 of saturated sodium chloride solution, dehydrated over magnesium sulfate, filtered and decompressed to dryness (2 kPa; 50 〇, yielding 2 g of crude product, It is a black oily 20 substance β crude product purified under a argon pressure of 50 kPa by means of Shixi rubber column chromatography (particle size 40-60 μιη; diameter 3.5 cm), with cyclohexane/ethyl acetate mixture (85/ 15 volume ratio) Dissolve. Combine the fractions containing the desired product and evaporate under reduced pressure (2 &3; 50. 〇 and dry (9 〇 3, 45 〇, yield 1.4^[6,7-difluoro_ 5-phenyl-1-[[2-(三曱石夕) ethoxy]methyl]_今坐_3·基] -39- Moderate ruler paper

Male 97 2 X 10 2 (Regular) A4 s) CN 1345561 A7 B7 V. Description of the Invention (38) - Butanamine 'is a yellow oil. 4 NMR spectrum (3 〇〇 MHz, (CD3) 2S 〇牴 δρριη): _ 〇〇 5 (s : 9H); 0.84 (t, J = 8 Hz: 2H); 0.95 (t, j = 7.5 Hz: 3H ); 1.66 (mt: 2H); 2.43 (t, J = 7 Hz: 2H); 3.59 (t, J = 8 Hz: 2H); 5.69 (s: 5 2H), from 7.40 to 7.65 (mt: 5H) ; 7.82 (width d, J = 7 Hz : 1H); 10.64 (unresolved complex: 1H) e mass spectrum: M = 445 phenyl-l-『[2-(三基)乙负.幻methyl卜1Η_ι Zyrazin-3-amine 10 sequentially added il cm3 ethanolamine and 1.50 g of potassium carbonate to contain N 6g. N-[6,7-difluoro-5-phenyl trimethoate prepared by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative In a 50 cm 3 dimethylformamide of decyl)ethyl]methyl]-1H-"bendan-3-yl]-butylamine, the mixture was refluxed for one week. The reaction medium was concentrated to dryness under reduced pressure. The organic phase was separated and washed with 75 15 cm of water and 50 cm3 of brine. kPa; 50 ° C). The crude oily product obtained was purified by hydrazine column chromatography under argon pressure of 50 kPa (particle size 40-60 / mi; diameter 4 cm) Dissolve in a mixture of cyclohexane/ethyl acetate (8 〇 / 2 〇 by volume). Combine the fractions containing the desired product, and evaporate under reduced pressure (2 kPa; 50 ° C). After drying 20 (9 〇 Pa; 45 〇, obtained 0.32 g of 6,7-difluoro-5-phenyl-1-[[2-(tridecyl)ethoxy]methyl]-1H-indazol-3-amine fluoro·5 ·笑一-1H-碎丨.Φ-3·face· Add 1.1ml 2Ν HC1 to 661mg 6,7-difluoro-5-phenyl (dimethylglycol) ethoxy]methyl]- 1Η-β丨丨. Sitting in 15ml of sterol in 3-amine. -40-This paper scale applies to the National Standard (CNS) A4 specification (210x297 mm) 1345561 B7 V. Description of invention (39) Reaction Treated in a microwave oven at 140 ° C for 3 minutes 'after saturation Κ ί ί ί 〇 容 容 容 容 容 容 容 容 容 容 水解 ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' 7-Difluoro·5_stupyl·1H-% oxazol-3-amine. 5 Suitable M__L: hexahydro.bipyridine-1-carboxylic acid (.-Working fluorine: stupid sylvestre "Tyrazole winter base"-醯Amine step 1 sequentially add 131/U " than bite with 154 private 1 gas formic acid ethyl vinegar to contain 10 387.8mg (6,7-difluoro-5-phenyl-1-[[2-(三曱梦烧Ethyloxy]曱基]_ 1H-® induces salino-3-amination to make #8 ml one. After 7 minutes, the reaction was completed. After hydrolysis, extraction and evaporation, 840 mg of crude (6,7-difluoro-5-phenyl-indole-indazol-3-yl)urethane was obtained. Step 2 15 Add 184 mg of hexahydroacridine to 161 mg of crude product (6,7-difluoro-5-Industrial Intelligence Co., Ltd., ICP-1H-carbazol-3-yl)amine formate B The ester was added to 2.5 ml of trifluorotoluene and the reaction was carried out in a microwave oven at 200 ° C for 20 minutes. After purification by preparative LC/MS (acetonitrile/pH 9 buffer), '80 mg of hexahydro" pyridine-1-carboxylic acid (6,7-difluoro-5-phenyl-1-[[2-( Trimethyldecyl)ethoxy]methyl]-1H-indazol-3-yl) 20 decylamine. Step 3: Containing 80 mg of hexahydropyridine carboxylic acid (6,7-difluoro-5-phenyl][[2-(trimethyldecyl)-ethoxy]methyl]-1H-indazol-3-yl 2.5 ml of decylamine was treated with 0.82 ml of 2N HCl under reflux for 1 hour. After evaporation, the prepared -41- paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1345561 A7 V. Inventive Note (40) LC/'MS (acetonitrile/pH 9 buffer) purification , get llmg hexahydro 8 than 1 - rebellious S 夂 (6,7 · fluoro-5-stupyl-1 Η-〇 5 | ° sit-3-yl) brewing amine. Mass spectrometry: residence time: 3.99; 357 = [M+H]+ 'IH NMR spectrum (3 〇〇 MHz, (DMSO-d6, 5 ppm): 1.50 (m, 5 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-1Η-β-conoxazol-3-yl)-decylamine 10 Step 1 Add 154 mg "bibrine to I61mg (6,7d54*-lH-indazol-3-yl)amine decanoic acid Ethyl acetate in 2.5 ml of trifluorotoluene, the reaction was carried out in a microwave oven at 200 ° C for 20 minutes. The product was purified by a silica gel column to give 75 mg of pyrrolidine small carboxylic acid (6,7-difluoro-5-phenyl- 1-[[2-(Trimethyl decyl) ethoxy 15-yl] hydrazino]-1H·0 丨 丨 -3- 基 基 酿 酿 酿 步骤 步骤 步骤 Step Step Step Step 2 Department of the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 75mg of pyrrole 3 ml of pyridine-1-carboxylic acid (6,7-difluoro-5-phenyl-H[2-(trimethyldecyl)-ethoxy]methyl]-1H-indazol-3-yl) decylamine The methanol was treated with 0-82 ml of 2N HCl for 1 hour under reflux. After evaporation, purified by preparative 20 LC/MS (acetonitrile/pH 9 buffer) afforded 36 mg of pyrrolidine-1-carboxylic acid (6,7-difluoro- 5-phenyl-1H-carbazole-3·yl)guanamine. Mass spectrometry: residence time 3. 72 min; 343 = [M+H] + 4 NMR spectrum (300 MHz, (DMSO-d6, δ ppm): 1.86 (m, 4H); 3.40 (m, 4H); 7.42 (m, 1H); To 7.54 (m, 4H); -42- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 1345561 A7 B7 Five 'Invention Description (4!) 7.63 (bd, J= 7 Hz, 1H) ; 8.84 (s, 1H); 13.20 (bs, 1H). Mysterious Example 3. In the manner of Example 2, starting with 3-(4-methylhexahydro. 1,4-丨_yl)propylamine Carry out the reaction 'produces 1_(6,7-difluoro_5-phenyl·5 】^吲° sits _3_yl)-3-[3-(4-methyl-hexahydro- 0-till-1-yl Propyl] gland. H NMR spectrum (300 MHz, (DMSO-d6, δρρπι): 1.92 (m 2H); 2.82 (s, 3H); from 3.01 to 3.75 (m, partially obscured, 12 η); 7.43 (m,1Η); from 7.47 to 7.56 (m, 4Η); 7.71 (t, J=7 Hz, 10 1H); 8.05 (dd, J=1.5 -7 Hz, 1H); 9.61 (s,lH) mass spectrum: retention time of .57 minutes; 429 [M+H;!+ according to the invention the pharmaceutical composition is a pure substance from the compound of formula (1) or the salt of such compounds. Other inert or physiologically active pharmaceutically compatible active ingredients The composition is synthesized. According to the invention, the medicine can be administered by 15-port, parenteral administration, rectal or topical administration. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives. The solid dosage form for oral administration can be used as a tablet, a pill, a powder (hard gelatin capsule, a drug pack) or a granule. In such compositions, the active ingredient according to the invention is mixed with one or more inert diluents, such as powder, cellulose, curtain sugar, lactose or smectite, under a stream of argon. These compositions may also contain substances other than 20, such as one or more lubricants such as stearic acid or talc, a coloring agent, a coating (sugar ingot) or a brightening agent. The liquid composition for oral administration can be formulated into pharmaceutically acceptable solutions, suspensions, emulsions, sugars and granules containing inert diluents such as water, ethanol, glycerol, vegetable oil or liquid stone. These conjugates may contain a diluent-43- This paper size applies to the 囲® Family Standard (CNS) A4 specification (210 X 297 ***) - 1345561 B7 5. Other than the invention description (42)* For example: Humidifier, sweetener stabilizer. Thickeners, Flavouring Agents, or the Ministry of Economics, the Bureau of Labor, and the Consumers' Co., Ltd.. The parenteral sterile composition is preferably an aqueous or non-aqueous suspension or emulsion. As the solvent or vehicle, water, propylene glycol, vegetable oil, in particular, eucalyptus oil, organic substance for injection: for example, oleic acid vinegar, or other suitable organic solvent can be used. These compositions comprise adjuvants, in particular moisturizers, isotonic agents, emulsifiers, and stabilizers. There are several methods of sterilization, such as: sterile, add fungicides to the group 'irradiation or heating. It can also be prepared in the form of a sterile solid composition 10 which is dissolved in sterile water or any other sterile form for injection. The composition for rectal administration is a test or rectal capsule containing, in addition to the active product, an excipient such as: cocoa butter <semi-synthetic: oleyl ester or polyethylene glycol. The topical pharmaceutical composition can be, for example, a cream, lotion, ophthalmic drip, mouthwash, nasal drop or aerosol. The subject of the present invention is an aminoguanazole compound of the formula (1), and a pharmaceutically acceptable salt thereof, and the use thereof for the preparation of a pharmaceutical composition for preventing and treating diseases caused by abnormal kinase activity, for example, Degenerative disease 20 'Alzheimer's disease, Parkinson's disease, frontal and parietal dementia, cortical basal degeneration, Pick, sdisease, stroke, cranial and spinal trauma and peripheral neuropathy' obesity Metabolic disease, type H diabetes, essential hypertension, arteriosclerotic cardiovascular disease, polycystic ovarian syndrome, X syndrome, immunodeficiency and cancer.

-44-

The kinase activity of iso-% can be mentioned, for example, Ρί3κ, AkT < abnormal activity of GSK Qiu, abnormal activity of CDKs, etc. In β human therapy, the compound according to the present invention is particularly suitable for treating/preventing neurodegenerative diseases, Azhai Mohs disease, Parkinson's disease, frontal bone and parietal dementia, cortical basal degeneration, Pickisdisease, stroke, cranial and spinal trauma and peripheral neuropathy, obesity, metabolic disease, π-type diabetes , normal hypertension, arteriosclerotic cardiovascular disease, polycystic ovary syndrome, X syndrome, immunodeficiency and cancer. The dosage 1: depends on the desired effect, the length of the treatment period and the route of administration used; the daily oral dose for adults is usually between 5 mg and i〇〇〇mg, and the unit dosage is from 1 mg to 250. Mg active ingredient. Usually, the physician will determine the dosage according to the age, weight and all other specific factors of the patient being treated. The following examples illustrate the compositions according to the invention: 15 Example 2 A hard alum sac is prepared according to the general technique at a dose of 50 mg of the active ingredient, the composition of which is as follows: - Compound of formula (1) 50 mg Printed by the Ministry of Economy, Intellectual Property Office, Staff Consumer Cooperative - Cellulose 18 mg 20 -Lactose 55 mg - Colloidal vermiculite 1 mg - Sodium carboxymethyl starch 10 mg - Talc 10 mg - Stearic acid cake 1 mg -45- ^ Paper scale applicable to the home standard (CNS > A4 Specifications (210 x 297 public) 1345561 A7 B7 V. Description of invention (44) Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printing Example B A tablet is prepared according to the general technique at a dose of 50 mg of active ingredient, the composition of which is as follows: 5 - (I) Compound 50 mg - Lactose 104 mg - Cellulose 40 mg - Polyvinylpyrrolidone 10 mg - Carboxymethyl starch sodium 22 mg 10 - Talc 10 mg - Stearic acid 2 mg - Colloidal vermiculite 2 mg - Hydroxymethyl a mixture of cellulose, glycerin and titanium oxide: (72/3.5/24.5) appropriate amount, so that a finished coating 15 tablets equivalent to 245mg Example C is prepared according to the general technique, the dosage is l〇mg active ingredient, Group As follows: 20 - Compound of formula (I) 10 mg - Benzoic acid 80 mg - Benzohydrin 0.06 ml - Sodium benzoate 80 mg - 95% ethanol 0.4 ml -46- This paper scale applies to China National Standard (CNS) A4 specification ( 210x297 mm) 1345561 A7 B7 V. INSTRUCTIONS (45) -Sodium Hydroxide-Propylene Glycol-Water Ministry of Energy Intellectual Property Office Staff Cooperatives Printed 24 mg 1.6 ml Appropriate amount, added to 4 ml The invention relates to prevention and treatment involving τ a method for the disease of a phosphorylation reaction of a protein, which is a compound of the formula (I) and a pharmaceutically acceptable salt thereof. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 x 297 mm).

Claims (1)

Six·, -------- two _«· application for patent ~ scope, patent application No. 92124409 ROC Patent Appln. No.92124409 After the amendment, no application for the line, Chunli Fangu Chinese text - attachment (two Amended Claims in Chinese - Encl (II) (Submitted on December 6, 2010) Compound (i) 0) 10 15 Ministry of Finance, Intellectual Property Bureau, Staff Consumer Cooperatives, 20 of which are CONR1R2 groups; phenyl; R7 is halogen; and R2 is independently hydrogen, or hexahydrogen port _ (1_6C) An alkyl group, wherein the hexahydrohydrogen is required to be substituted by an (i_6C) alkyl group; the phantom and R2 may form a pyrrolidinyl group or a hexahydropyridinyl group, the racemate, enantiomer or non-pair And mixtures thereof, tautomers thereof and pharmaceutically acceptable salts thereof. = The compound of the scope of application for the scope of the patent i is selected from the following: Hydrogen ratio bite-1-repulsive acid (6,7-difluoro_5_phenyl_1H_〇5|〇坐_3_ base) Amines are more than serotonin-1-acids (6,7-digas-5_phenyl H_. 弓3_基_基) guanamine 1 I 7-difluoro_5_phenyl_1H to sit _ 3_yl)-3_[3 (4methylhexaazinium)-1-yl)propyl]urea its tautomer and its pharmaceutically acceptable salt. 3. A compound according to any one of the items in the scope of the patent application, which is used for the preparation of a medicament. 2, -4 8 - The paper size ^ Specification r21Qx297 J6 Order 1345561 A8 B8 C8 D8 VI. Patent scope 4. A pharmaceutical composition for treating diseases caused by abnormal kinase activity, which is pharmaceutically acceptable The medium contains a compound as defined in any one of claims 1-2 to 2. 5. The pharmaceutical composition according to claim 4, comprising at least 5 compounds according to any one of claims 1 and 2, for medical use, for the treatment of tau-protein phosphate Disease. 6. The pharmaceutical composition according to claim 4, comprising at least one compound according to any one of claims 1 and 2, for use in medical treatment for treating neurodegenerative diseases, stroke, Cranial and spinal trauma and peripheral neuropathy, obesity, metabolic diseases, type 2 diabetes, essential hypertension, arteriosclerotic cardiovascular disease, polycystic ovarian syndrome, X syndrome, immunodeficiency and cancer. 15 7. The pharmaceutical composition according to claim 6 wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, frontal and parietal dementia, cortical basal degeneration or Pick's disease. ). Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives. 8. A method for preparing a compound of the formula (I) as defined in claim 1 of the patent application, which is represented by OCNR1 and R3 in formula (I) as a derivative of hydrogen 20 The reaction is carried out in tetrahydrofuran, and the resulting product can be converted into a pharmaceutically acceptable salt as needed. 9. An intermediate product: N-(6,7-difluoro-1H-indazol-3-yl)butanamine N-[6,7-difluoro-1-[[2-(tris) Ethoxy]methyl]-1H-carbazole - 49 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1345561 A8 B8 C8 _D8_ * VI. Patent application scope - 3-base] Butylamine, N-[5-bromo-6,7-difluoro-1-[[2-(trimethyldecyl)ethoxy]methyl]-1H-indazol-3-yl]-butanamine N-[6,7-Difluoro-5-phenyl-1-[[2-(tridecyl)ethoxy]methyl]-5 1H-indazol-3-yl]butanamine 6.7- Difluoro-5-phenylsucci[[2-(tridecyl)ethoxy]methyl]-1H-indazol-3-amine 6.7-difluoro-5-phenyl-1H-carbazole-3 -amine. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. This paper scale applies the Chinese National Standard (CNS) A4 specification (210x297 mm).