CN1896060A - Tetrahydro-indolone and tetrahydro-indazolone derivatives and their use - Google Patents

Tetrahydro-indolone and tetrahydro-indazolone derivatives and their use Download PDF

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CN1896060A
CN1896060A CN 200610087495 CN200610087495A CN1896060A CN 1896060 A CN1896060 A CN 1896060A CN 200610087495 CN200610087495 CN 200610087495 CN 200610087495 A CN200610087495 A CN 200610087495A CN 1896060 A CN1896060 A CN 1896060A
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oxygen
trimethylammonium
benzamide
tetrahydrochysene indazole
heterocycle
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CN100575341C (en
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夏敏
张同祥
王一飞
邢国文
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Guangzhou Jinan Biomedical Research And Development Center
Guangzhou Kangqilai Precision Medical Technology Co ltd
Guangzhou Shaobo Holding Group Co ltd
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BEIJING GYLONGLY BIOMEDTECH Ltd
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Abstract

A tetrahydroindolone derivative and its use are disclosed. It can inhibit malignant tumor cell growth. It can be used for mammary gland cancer, lung cancer, uterus neck cancer, rectum cancer, liver cancer and blood cancer.

Description

The derivative of tetrahydro-indolone and the derivative of tetrahydro-indazolone and their application
Technical field
The present invention relates to the derivative of the derivative of tetrahydro-indolone and tetrahydro-indazolone and they and be used for the treatment of application in the antitumor drug in preparation.
Background technology
Last decade comes, and oncotherapy has obtained remarkable progress, and annual all have new antitumor drug to come into the market, and improved the survival and the quality of life of tumour patient.But cancer is still the No.1 killer of harm health of people.There are defectives such as toxicity is big, resistance difference in the cancer therapy drug that uses clinically at present.Wherein a lot of medicines are to synthesize by inhibition DNA to stop growth of cancer cells.Yet these medicines not only have lethality to cancer cells, and normal cell is also had same lethal effect.These medicines often also cause irreversible toxicity and side effect to patient as a result.
Recently some novel cancer therapy drugs are considered to have the characteristics of low toxicity more efficient, as the inhibitor of various protein kinases (proteinkinases) (for example, Aurora kinase inhibitor, the CDK inhibitor), necrocytosis initiator (apoptosis inducers).
U.S. Pat 6759427, US6727270, US6407261 and US6861418 have reported that the tetrahydro indole ketone compound has the activity and the other biological activity of anti-protein kinase.Wherein:
US6407261 has proposed the tetrahydro indole derivative of 1 replacement, as sPLA 2Inhibitor.
The compound that US6759427 proposes is at the aniline carbonyl ethyl tetrahydro indole ketone compound and the neural stimulation thereof of 1 replacement.
The compound that US6727270 proposes is in the affine activity of the pyrrole derivatives and the 5-HT acceptor thereof of 1 replacement.
US6716856 has proposed the tetrahydrochysene indazole ketone derivatives of 1 replacement.
Japanese Patent JP2004-137228 has reported that with 1 the 3-dihydroxy-benzene prepares the tetrahydro indole ketone compounds.
US6395905 has reported that tetrahydro-indazolone-3-carboxamides derivatives is the use of the ligand and the memory thereof of GABA-A acceptor.
EU0101004 has reported the preparation and the antiarrhythmic effect thereof of a series of tetrahydro indole ketone compounds.
In addition, patents such as US3776923, JP60-32767, JP60-32768, JP60-116668, JP59-84863 and JP62-89660 have all been reported the preparation method of the preparation tetrahydro indole ketone compound of some uniquenesses.
Be US6716856 with the immediate documents of the present invention in the above background technology.Though wherein related compound has the characteristics of low toxicity, very not remarkable to the fragmentation effect of tumour cell, still need further research and raising.This piece patent is emphasized the replacement of tetrahydro-indazolone parent nucleus, does not mention any carbamyl (carbamyl), or the benzene ring structure of cyano group (cyano) replacement or the structure of benzamide (benzamide).
Summary of the invention
The object of the present invention is to provide the derivative of tetrahydro-indolone and the derivative of tetrahydro-indazolone.
Another object of the present invention is to provide said derivative to be used for the treatment of application in the antitumor drug in preparation.
The technical scheme that realizes one of them purpose of the present invention is: compound of the present invention has following general formula (I):
Figure A20061008749500141
Wherein: n represents 0,1 or 2; X represents N or C-R1; Y represents N or CH; Z represents N or C-R10; R1, R2 select one of following two kinds of combinations: (1) R1 represents H, trifluoromethyl or alkyl, and R2 represents H, trifluoromethyl or alkyl; (2) the common aromatic nucleus that forms an aromatic nucleus or replacement of R1 and R2; R3 represents H or alkyl, and R4 represents H or alkyl, and R5 represents H or alkyl, and R6 represents H or alkyl, and R7 represents H or alkyl, and R8 represents H or alkyl; R10, R11 select one of following two kinds of combinations: (1) R10 represents the heterocycle of amino, heterocycle or the replacement of H, halogen, replacement, and R11 represents the carbamyl or the cyano group of carbamyl, replacement; (2) the common heterocycle that forms a heterocycle or replacement of R10 and R11; R12 represents the amino of H, halogen or replacement.
Optimized technical scheme of the present invention is, in technique scheme: n preferred 0 or 1; One of preferred following three kinds of combinations of Y, Z: (1) Y is N, and Z is C-R10; (2) Z is N, and Y is CH; (3) Y is CH, and Z is C-R10; R3, R4, the preferred H of R7, R8; Preferred H of R5 or C 1-C 3Alkyl, more preferably methyl or ethyl; Preferred H of R6 or C 1-C 3Alkyl, more preferably methyl or ethyl.
In the above-mentioned optimal technical scheme, when described R1, R2 select first kind of combination, preferred H of R1 or alkyl, and this alkyl is C 1-C 3Alkyl, more preferably methyl or ethyl; The preferred H of R2, trifluoromethyl or alkyl, and this alkyl is C 1-C 3Alkyl, more preferably methyl or ethyl.
In the above-mentioned optimal technical scheme, when described R1, R2 select second kind of combination, the preferred phenyl ring of aromatic nucleus that it can form jointly, the phenyl ring that the aromatic nucleus of a replacement that can form jointly preferably replaces, the more preferably phenyl ring of trifluoromethyl replacement.
In the above-mentioned optimal technical scheme, the preferred halogen of described R12, more preferably Cl or Br.
In the above-mentioned optimal technical scheme, when described R10, R11 select first kind of combination, the preferred halogen of R10 wherein, more preferably Cl or Br.
In the above-mentioned optimal technical scheme, when described R10, R11 select second kind of combination, the preferred five-membered ring of heterocycle, more preferably a pyrazoles that it can form jointly, the five-membered ring that the heterocycle of a replacement that can form jointly preferably replaces, more preferably 5-amino-pyrazol.
In the above-mentioned optimal technical scheme; when described R10, R11 select first kind of combination; preferred N-(the 2-[1 of the carbamyl of the replacement that R11 represents; 2,3] triazole ethyl carbamyl, N-(2-(4-morpholine) ethyl carbamyl, N-(4-hydroxy-cyclohexyl) carbamyl, N-(4-acetyl oxygen cyclohexyl) carbamyl or N-(2-(1-(4-hydroxy piperidine) ethyl)) carbamyl.
In the above-mentioned optimal technical scheme, described R10, when R11 selects first kind of combination, preferred alkylamino when R10 is chosen as replacement amino, further preferred naphthene amino, branched alkylamino or straight chain alkylamino, further preferred hexamethylene amino, ethylamino, 4-hydroxyl hexamethylene amino, oneself is amino for 4-glycyl oxygen basic ring, 2-diethylin ethylamino, 2-(4-morpholine) ethylamino, 2-(1,2,3) triazole ethylamino, 2-(1-(3, the 5-lupetidine)) ethylamino, 2-(1-piperidines) ethylamino, 2-(1-pyrrolidyl) ethylamino, or (2-tetrahydrofuran (THF)) methylamino-.
In the above-mentioned optimal technical scheme, when described R10, R11 select first kind of combination, preferred single heterocycle or two heterocycle when R10 selects heterocycle, further preferred single heterocycle is piperazine or piperidines, further preferred two heterocycles are quinoline; The single heterocycle that when R10 selects the heterocycle of replacement, preferably replaces or two heterocycles of replacement, the further preferred single heterocycle that replaces is the piperazine that replaces, the pyrrolidyl that replaces, or the piperidines that replaces, the further preferred single heterocycle that replaces is the 4-methylpiperazine, 4-(2-(4-morpholine) ethyl) piperazine, (4-pentamethylene base) piperazine, 4-(2-hydroxyethyl) piperazine, or 4-(2-pyridine) piperazine, it is 3-hydroxyl pyrrolidine base, 4-oxygen-piperidines, the 4-hydroxy piperidine, the 3-hydroxy piperidine, 4-glycyl oxygen phenylpiperidines, 4-(4-morpholine) piperidines, 4-(1-pyrrolidyl) piperidines, or 4-(2-(1-piperidines) oxyethyl group) piperidines.The quinoline that the further preferred two heterocycles that replace are replacements, further preferred 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
In the above-mentioned optimized technical scheme, first kind of further optimized technical scheme is: X selects N; Y, Z select the third combination; R1, R2 select first kind of combination, and the preferred H of R2 wherein, trifluoromethyl or C 1-C 3Alkyl; R10, R11 select first kind of combination; Preferred H of R12 or halogen.
In above-mentioned first kind of further optimized technical scheme, the preferred C of described R2 1-C 3Alkyl, more preferably methyl or ethyl; The preferred C of R5 1-C 3Alkyl, more preferably methyl or ethyl; The preferred C of R6 1-C 3Alkyl, more preferably methyl or ethyl; Preferred Cl of halogen or Br that R10 selects; Preferred Cl of halogen or Br that R12 selects.The compound of first kind of further optimized technical scheme of the present invention at this moment is preferably 2-chloro-4-, and (1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen, 2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen or 2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole) methyl) benzene cyanogen.
In above-mentioned first kind of further optimized technical scheme; preferred N-(2-[1 during carbamyl that described R11 selects to replace; 2,3] triazole ethyl carbamyl, N-(2-(4-morpholine) ethyl carbamyl, N-(4-hydroxy-cyclohexyl) carbamyl, N-(4-acetyl oxygen cyclohexyl) carbamyl or N-(2-(1-(4-hydroxy piperidine) ethyl)) carbamyl.The compound of first kind of further optimized technical scheme of the present invention at this moment is preferably that N-(2-[1,2,3] triazole ethyl)-(1-(3 for 4-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(4-morpholine) ethyl)-(1-(3,6 for 4-for N-, 6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, N-(4-hydroxy-cyclohexyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-(4-hydroxy piperidine)) ethyl)-(1-(3,6 for 4-for N-, 6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (4-acetyl oxygen cyclohexyl)-(1-(3 for 4-for N-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, or N-((4-(2-pyridine) piperazine)-(1-(3 for 4-for 1-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide.
In above-mentioned first kind of further optimized technical scheme, described R10 selects to replace preferred alkylamino when amino, further preferred naphthene amino, branched alkylamino or straight chain alkylamino, further be preferably hexamethylene amino, ethylamino, 4-hydroxyl hexamethylene amino, the own amino of 4-glycyl oxygen basic ring, 2-diethylin ethylamino, 2-(4-morpholine) ethylamino, 2-(1,2,3) triazole ethylamino, 2-(1-(3, the 5-lupetidine)) ethylamino, 2-(1-piperidines) ethylamino, 2-(1-pyrrolidyl) ethylamino or (2-tetrahydrofuran (THF)) methylamino-.The compound of first kind of further optimized technical scheme of the present invention at this moment is preferably 2-, and (2-diethylin ethylamino)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3 for 2-hexamethylene amino-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(2-(1-piperidines) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-(3, the 5-lupetidine)) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1 for 2-, 2,3) triazole ethylamino)-(1-(3,6 for 4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3 for 2-cyclopropane amino-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(4-morpholine) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(4-hydroxyl hexamethylene amino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (oneself is amino for 4-glycyl oxygen basic ring)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-pyrrolidyl) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (9-(2 for 2-hexamethylene amino-4-, 2-dimethyl-4-oxygen-3-trifluoromethyl-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (4-hydroxyl hexamethylene amino)-(1-(6 for 4-for 2-, 6-dimethyl-4-oxygen-3-trifluoromethyl-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, or 2-(2-tetrahydrofuran (THF)) methylamino--4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide.
In above-mentioned first kind of further optimized technical scheme, when described R10 selects heterocycle, preferred single heterocycle or two heterocycle, further preferred single heterocycle is piperazine or piperidines, further preferred two heterocycles are quinoline.The compound of first kind of further optimized technical scheme of the present invention at this moment is preferably that 2-(1-piperazine)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide or 2-(1-piperidines)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide.
In above-mentioned first kind of further optimized technical scheme, when described R10 selects the heterocycle of replacement, the preferred single heterocycle that replaces or two heterocycles of replacement, the further preferred single heterocycle that replaces is the piperazine that replaces, the pyrrolidyl that replaces, or the piperidines that replaces, the further preferred single heterocycle that replaces is the 4-methylpiperazine, 4-(2-(4-morpholine) ethyl) piperazine, (4-pentamethylene base) piperazine, 4-(2-hydroxyethyl) piperazine, 4-(2-pyridine) piperazine, 3-hydroxyl pyrrolidine base, 4-oxygen-piperidines, the 4-hydroxy piperidine, the 3-hydroxy piperidine, 4-glycyl oxygen phenylpiperidines, 4-(4-morpholine) piperidines, 4-(1-pyrrolidyl) piperidines, or 4-(2-(1-piperidines) oxyethyl group) piperidines.The compound of first kind of further optimized technical scheme of the present invention at this moment is preferably 2-, and (1-(4-methylpiperazine))-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen, (1-(4-methylpiperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-pentamethylene base) piperazine)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(2-(1-piperidines) oxyethyl group) piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(4-oxygen-piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(2-hydroxyethyl) piperazine))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(1-pyrrolidyl) piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(2-(4-morpholine) ethyl) piperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(4-hydroxy piperidine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-glycyl oxygen phenylpiperidines))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3-hydroxyl pyrrolidine base))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(4-morpholine) piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(3-hydroxy piperidine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, or 2-(1-(4-(2-pyridine) piperazine))-(1-(3,6 for 4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide.The further preferred two heterocycles that replace are 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, the compound of first kind of further optimized technical scheme of the present invention at this moment be 2-(2-(and 6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline))-(1-(3,6 for 4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide.
In the above-mentioned optimized technical scheme, second kind of further optimized technical scheme is: n selects 0; X selects N; Y, Z select the third combination; R1, R2 select first kind of combination, and R2 preferred alkyl wherein, more preferably methyl; The preferred C of R5 1-C 3Alkyl, more preferably methyl, the preferred C of R6 1-C 3Alkyl, more preferably methyl; R10, R11 select second kind of combination, and R10 and the R11 preferred pyrazoles of heterocycle that can form jointly, the preferred 5-amino-pyrazol of the heterocycle of a replacement that can form jointly; The preferred H of R12.The compound of second kind of further optimized technical scheme of the present invention is preferably 1-(6-(3-amino-1H-indazole))-3,6,6-trimethylammonium-1,5,6,7 tetrahydrochysene indazoles-4-ketone.
In the above-mentioned optimized technical scheme, the third further optimized technical scheme is: n selects 0; X selects N; Y, Z select first kind of combination; R1, R2 select first kind of combination, and R2 preferred alkyl wherein, more preferably methyl; The preferred C of R5 1-C 3Alkyl, more preferably methyl, the preferred C of R6 1-C 3Alkyl, more preferably methyl; R10, R11 select first kind of combination, and the preferred H of R10, the preferred carbamyl of R11; The amino that R12 preferably replaces, more preferably 4-hydroxy piperidine or 4-(2-hydroxyethyl) piperazine.The compound of the third further optimized technical scheme of the present invention is preferably 4-, and (1-(4-hydroxy piperidine))-(1-(3 for 6-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(4-(2-hydroxyethyl) piperazine))-(1-(3 for 6-for VITAMIN PP or 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) VITAMIN PP.
In the above-mentioned optimized technical scheme, the 4th kind of further optimized technical scheme is: X selects C-R1; Y, Z select the third combination; R1, R2 select first kind of combination, and wherein preferred H of R1 or C 1-C 3Alkyl, preferred H of R2 or C 1-C 3Alkyl; R10, R11 select first kind of combination.
In above-mentioned the 4th kind of further optimized technical scheme, the preferred C of described R1 1-C 3Alkyl, more preferably methyl or ethyl; The preferred C of R2 1-C 3Alkyl, more preferably methyl or ethyl; The preferred C of R5 1-C 3Alkyl, more preferably methyl or ethyl; The preferred C of R6 1-C 3Alkyl, more preferably methyl or ethyl; Preferred Cl of the selected halogen of R10 or Br, preferred Cl of halogen or Br that R12 selects.The compound of the 4th kind of further optimized technical scheme of the present invention at this moment is preferably 2-bromo-4-(1-(4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, 2-bromo-4-(1-(4-oxygen-4,5,6, the 7-tetrahydro indole) benzene cyanogen methyl), 2-bromo-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, (1-(3 for 2-bromo-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole) benzene cyanogen methyl), (1-(3 for 2-bromo-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, or 2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6, the 7-tetrahydro indole) methyl) benzene cyanogen.
In above-mentioned the 4th kind of further optimized technical scheme, described R10 selects to replace preferred alkylamino when amino, further preferred naphthene amino, branched alkylamino or straight chain alkylamino, further preferred hexamethylene amino, ethylamino, 4-hydroxyl hexamethylene amino, the own amino of 4-glycyl oxygen basic ring, 2-diethylin ethylamino, 2-(4-morpholine) ethylamino, 2-(1,2,3) triazole ethylamino, 2-(1-(3, the 5-lupetidine)) ethylamino, 2-(1-piperidines) ethylamino, 2-(1-pyrrolidyl) ethylamino or (2-tetrahydrofuran (THF)) methylamino-.The compound of the 4th kind of further optimized technical scheme of the present invention at this moment be preferably 2-(2-tetrahydrofuran (THF)) methylamino--4-(1-(and 3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(3 for 2-hexamethylene amino-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-diethylin ethylamino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-(4-morpholine) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(4-hydroxyl hexamethylene amino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, or 2-(2-(1,2,3) triazole ethylamino)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide.
In above-mentioned the 4th kind of further optimized technical scheme, when described R10 selects heterocycle, preferred single heterocycle or two heterocycle, further preferred single heterocycle is piperazine or piperidines, further preferred two heterocycles are quinoline.The compound of the 4th kind of further optimized technical scheme of the present invention at this moment is preferably that 2-(1-piperidines)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen or 2-(1-piperidines)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide.
In above-mentioned the 4th kind of further optimized technical scheme, described R10 selects the heterocycle of replacement, the preferred single heterocycle that replaces or two heterocycles of replacement, the further preferred single heterocycle that replaces is the piperazine that replaces, the pyrrolidyl that replaces, or the piperidines that replaces, the further preferred single heterocycle that replaces is the 1-piperazine, the 4-methylpiperazine, 4-(2-(4-morpholine) ethyl) piperazine, (4-pentamethylene base) piperazine, 4-(2-hydroxyethyl) piperazine, or 4-(2-pyridine) piperazine, 3-hydroxyl pyrrolidine base, 4-oxygen-piperidines, the 4-hydroxy piperidine, the 3-hydroxy piperidine, 4-glycyl oxygen phenylpiperidines, 4-(4-morpholine) piperidines, 4-(1-pyrrolidyl) piperidines, or 4-(2-(1-piperidines) oxyethyl group) piperidines.The compound of the 4th kind of further optimized technical scheme of the present invention at this moment be preferably 2-(1-(3-hydroxyl pyrrolidine base))-4-(1-(and 3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, (1-(3-hydroxyl pyrrolidine base))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-methylpiperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole) benzamide methyl), (1-(4-oxygen-piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(1-(4-hydroxy piperidine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-(4-morpholine) piperidines))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-(2-(4-morpholine) ethyl) piperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, or 2-(1-(4-(1-pyrrolidyl) piperidines))-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide.The further preferred two heterocycles that replace are 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, the compound of the 4th kind of further optimized technical scheme of the present invention at this moment be 2-(2-(and 6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline))-(1-(3,6 for 4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide.
In the above-mentioned optimized technical scheme, the 5th kind of further optimized technical scheme is: X selects C-R1; Y, Z select the third combination; R1, R2 select second kind of combination, and R1 and the R2 preferred phenyl ring of aromatic nucleus that can form jointly, the phenyl ring that the preferred trifluoromethyl of the aromatic nucleus of a replacement that can form jointly replaces; The preferred C of R5 1-C 3Alkyl, more preferably methyl; The preferred C of R6 1-C 3Alkyl, more preferably methyl; R10, R11 select first kind of combination, the preferred carbamyl of R11 wherein; The preferred H of R12.The compound of the 5th kind of further optimized technical scheme of the present invention is preferably 2-, and (1-(4-hydroxy piperidine))-(9-(2 for 4-, 2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-(4-hydroxyl hexamethylene amino)-4-(9-(2,2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-(1-(4-(2-hydroxyethyl) piperazine))-4-(9-(2,2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-(1-(4-methylpiperazine))-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-(1-(4-hydroxy piperidine))-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide, or 2-(4-hydroxyl hexamethylene amino)-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide.
In the above-mentioned optimized technical scheme, the 6th kind of further optimized technical scheme is: n selects 0; X selects C-R1; Y, Z select second kind of combination; R1, R2 select first kind of combination, R1 preferred alkyl wherein, more preferably methyl, the preferred H of R2 wherein; The preferred C of R5 1-C 3Alkyl, more preferably methyl; The preferred C of R6 1-C 3Alkyl, more preferably methyl; R10, R11 select first kind of combination, the preferred carbamyl of R11 wherein; The preferred H of R12.The compound of the 6th kind of further optimized technical scheme of the present invention is 5-(1-(2,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) pyridine-2-carboxamide.
In the above-mentioned optimized technical scheme, the 7th kind of further optimized technical scheme is: n selects 0; X selects C-R1; Y, Z select the third combination; R1, R2 select first kind of combination, and the preferred H of R1 wherein; R2 preferred alkyl, more preferably methyl; The preferred C of R5 1-C 3Alkyl, more preferably methyl; The preferred C of R6 1-C 3Alkyl, more preferably methyl; R10, R11 select second kind of combination, and R10 and the R11 preferred pyrazoles of heterocycle that can form jointly, the preferred 5-amino-pyrazol of the heterocycle of a replacement that can form jointly; The preferred H of R12.The 7th kind of compound that advances-go on foot optimized technical scheme of the present invention is preferably 1-(6-(3-amino-1H-indazole))-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone.
In the above-mentioned optimized technical scheme, the 8th kind of further optimized technical scheme is: X selects N or C-R1; Y, Z select the third combination, and promptly Y selects CH; Z selects C-R10; R1, R2 select first kind of combination, and the wherein preferred H of R1, methyl or ethyl, the preferred H of R2, methyl or ethyl; The preferred H of R5, methyl or ethyl; The preferred H of R6, methyl or ethyl; R10, R11 select first kind of combination, and the heterocycle of amino, heterocycle or the replacement of the preferred H of R10, halogen, replacement; Preferred carbamyl of R11 or cyano group; The preferred H of R12, Cl or Br.
In above-mentioned the 8th kind of further optimized technical scheme, preferred Cl of the selected halogen of R10 or Br; The amino preferred 2-diethylin ethylamino of the selected replacement of R10,2-(4-morpholine) ethylamino, 2-(1,2,3) triazole ethylamino, 2-(1-(3, the 5-lupetidine)) ethylamino, 2-(1-piperidines) ethylamino, 2-cyclopropane amino; The preferred heterocycle of R10 institute is the 1-piperidines; The preferred 4-methylpiperazine of heterocycle, (4-pentamethylene base) piperazine, 4-hydroxy piperidine, 4-(1-pyrrolidyl) piperidines of the replacement that R10 selects.The compound of the 8th kind of further optimized technical scheme of the present invention is preferably 2-bromo-4-(1-(4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, 2-bromo-4-(1-(4-oxygen-4,5,6, the 7-tetrahydro indole) benzene cyanogen methyl), (1-(3 for 2-bromo-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, (1-(3,6 for 2-bromo-4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole) methyl) benzene cyanogen, (1-(3 for 2-bromo-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(3 for 2-bromo-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole) benzamide methyl), 2-(1-piperidines)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-diethylin ethylamino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(3 for 4-for 2-(2-(4-morpholine) ethylamino), 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-bromo-4-(1-(4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen, 2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole) methyl) benzene cyanogen, (1-(3,6 for 2-bromo-4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-diethylin ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-piperidines) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(4-methylpiperazine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-(3, the 5-lupetidine)) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1 for 2-, 2,3) triazole ethylamino)-(1-(3,6 for 4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-hydroxy piperidine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(1-pyrrolidyl) piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(4-pentamethylene base) piperazine)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, or 2-cyclopropane amino-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide.
Compound in the above-mentioned optimized technical scheme is preferably 2-chloro-4-, and (1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen, (1-(4-methylpiperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen, (1-(4-methylpiperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3-hydroxyl pyrrolidine base))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, (1-(3-hydroxyl pyrrolidine base))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(1-piperidines)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, 2-(1-piperidines)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-methylpiperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole) benzamide methyl), (1-(3 for 2-hexamethylene amino-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-diethylin ethylamino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-(4-morpholine) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-oxygen-piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(1-(4-hydroxy piperidine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (4-hydroxyl hexamethylene amino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-(4-morpholine) piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-(1 for 2-, 2,3) triazole ethylamino)-(1-(3,6 for 4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-(2-(4-morpholine) ethyl) piperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-(1-pyrrolidyl) piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(2-diethylin ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3,6 for 2-hexamethylene amino-4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-piperidines) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, ((1-(3 for 2-for 2-, the 5-lupetidine)) ethylamino)-and 4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1,2 for 2-, 3) triazole ethylamino)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(4-pentamethylene base) piperazine)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3,6 for 2-cyclopropane amino-4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(2-(1-piperidines) oxyethyl group) piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-oxygen-piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(4-(2-hydroxyethyl) piperazine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7 tetrahydrochysene indazoles)) benzamide, (2-(4-morpholine) ethylamino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6,7 tetrahydrochysene indazoles)) benzamide, (1-(4-(1-pyrrolidyl) piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(2-(4-morpholine) ethyl) piperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(4-hydroxy piperidine))-4-(1-(3,6,6-trimethylammonium 4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-glycyl oxygen phenylpiperidines))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (4-hydroxyl hexamethylene amino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (oneself is amino for 4-glycyl oxygen basic ring)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(2-(1-pyrrolidyl) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-piperazine)-(1-(3,6 for 4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3-hydroxyl pyrrolidine base))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(4-morpholine) piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(3-hydroxy piperidine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(2-(6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline))-(1-(3,6 for 4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(2-pyridine) piperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-piperidines)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 1-(6-(3-amino-1H-indazole))-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone, 1-(6-(3-amino-1H-indazole))-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone, 2 (1-(4-hydroxy piperidine))-(9-(2 for 4-, 2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, (4-hydroxyl hexamethylene amino)-(9-(2 for 4-for 2-, 2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, (1-(4-(2-hydroxyethyl) piperazine))-(9-(2 for 4-for 2-, 2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, (1-(4-methylpiperazine))-(9-(2 for 4-for 2-, 2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide, (1-(4-hydroxy piperidine))-(9-(2 for 4-for 2-, 2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide, (4-hydroxyl hexamethylene amino)-(9-(2 for 4-for 2-, 2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide, (9-(2 for 2-hexamethylene amino-4-, 2-dimethyl-4-oxygen-3-trifluoromethyl-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (4-hydroxyl hexamethylene amino)-(1-(6 for 4-for 2-, 6-dimethyl-4-oxygen-3-trifluoromethyl-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, N-(2[1,2,3] triazole ethyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(4-morpholine) ethyl)-(1-(3,6 for 4-for N-, 6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, N-(4-hydroxy-cyclohexyl)-(1-(3 for 4-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-(4-hydroxy piperidine)) ethyl)-(1-(3 for 4-for N-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 5-(1-(2,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) pyridine-2-carboxamide, 2-bromo-4-(1-(4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, 2-bromo-4-(1-(4-oxygen-4,5,6, the 7-tetrahydro indole) benzene cyanogen methyl), (1-(3 for 2-bromo-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, 2-bromo-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole) methyl) benzene cyanogen, (1-(3,6 for 2-bromo-4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, 2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6, the 7-tetrahydro indole) benzene cyanogen methyl), 2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen, 2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole) methyl) benzene cyanogen, (1-(4-(2-hydroxyethyl) piperazine))-(1-(3 for 6-for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) VITAMIN PP, (1-(4-hydroxy piperidine))-(1-(3 for 6-for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) VITAMIN PP, N-(4-acetyl oxygen cyclohexyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, ((4-(2-pyridine) piperazine)-(1-(3,6 for 4-for 1-for N-, 6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3 for 2-(2-tetrahydrofuran (THF)) methylamino--4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, or 2-(2-tetrahydrofuran (THF)) methylamino--4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide.
In the preferred compound in the above-mentioned optimized technical scheme further preferred compound be 2-(1-(3-hydroxyl pyrrolidine base))-4-(1-(and 3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(1-piperidines)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-diethylin ethylamino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(2-(4-morpholine) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-hydroxy piperidine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (4-hydroxyl hexamethylene amino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-(1,2,3) triazole ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-(2-(4-morpholine) ethyl) piperazine))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(2-diethylin ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3 for 2-hexamethylene amino-4,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-piperidines) ethylamino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-(3, the 5-lupetidine)) ethylamino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1,2,3) triazole ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3,6 for 2-cyclopropane amino-4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(4-(2-(1-piperidines) oxyethyl group) piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(2-hydroxyethyl) piperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(4-morpholine) ethylamino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(4-hydroxyl hexamethylene amino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (oneself is amino for 4-glycyl oxygen basic ring)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-pyrrolidyl) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-piperazine)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3-hydroxy piperidine))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 1-(6-(3-amino-1H-indazole))-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone, 1-(6-(3-amino-1H-indazole))-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone, 2-(1-(4-hydroxy piperidine))-4-(9-(2,2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-(4-hydroxyl hexamethylene amino)-4-(9-(2,2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-(1-(4-(2-hydroxyethyl) piperazine))-4-(9 (2,2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-(1-(4-hydroxy piperidine))-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-(4-hydroxyl hexamethylene amino)-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-(4-hydroxyl hexamethylene amino)-4-(1-(6,6-dimethyl-4-oxygen-3-trifluoromethyl-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, N-(2-[1,2,3] the triazole ethyl)-(1-(3 for 4-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(4-morpholine) ethyl)-(1-(3 for 4-for N-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, N-(4-hydroxy-cyclohexyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, or N-(2-(1-(4-hydroxy piperidine)) ethyl)-(1-(3,6 for 4-, 6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide.
The present invention comprises that also above-claimed cpd is at pharmacy acceptable salt.These salt are preferably vitriol (sulfuric), hydrochloride (hydrochloric), phosphoric acid salt (phosphoric), hydrobromate (hydrobromic), Citrate trianion (citric), maleate (maleic), mandelate (mandelic), succinate (succinic), fumarate (fumaric), acetate (acetic), lactic acid salt (lactic), nitrate (nitric), sulfonate (sulfonic), tosilate (p-toluene sulfonic), mesylate (methane sulfonic), benzoate (benzoic), tartrate (tartaric) or carbonate (carbonic acid).
Realize that another object of the present invention is the application of preferred compound in preparation medicine for treating tumor thing in above-mentioned the 8th kind of further optimized technical scheme, the application of compound in the above-mentioned optimized technical scheme in preparation medicine for treating tumor thing, the application of further preferred compound in preparation medicine for treating tumor thing in the particularly above-mentioned optimized technical scheme.And the compound in the above-mentioned optimized technical scheme is in the application of pharmacy acceptable salt in preparation medicine for treating tumor thing.
Beneficial effect of the present invention is: compound of the present invention is substituted with an aromatic nucleus (as phenyl ring on tetrahydro-indolone and tetrahydro-indazolone 1; pyridine ring etc.), simultaneously be substituted with carbamyl (NH on respect to tetrahydro-indolone substituting group or the substituent contraposition of tetrahydro-indazolone on the aromatic nucleus 2CO-), carbamyl of replacement (R-NH-CO-) or cyano group (CN) are substituted with alkylamino (R-NH-, R on a position 2N-:R is C 1-C 6The alkyl of the straight or branched that replaces or do not replace, cycloalkyl) or halogen (Cl or Br).The anti-tumor biological that has the compound of these groups by test comparison (seeing application examples) does not as can be known have the compound of substituted radical on the aromatic nucleus of tetrahydro-indolone and 1 replacement of tetrahydro-indazolone, and is substituted with carbamyl (NH in the contraposition as can be seen 2The activity of compound CO-) is higher than the compound that is substituted with cyano group (CN) again.
Embodiment
All synthetic related chemical feedstockss of The compounds of this invention, solvent all are to order from Beijing chemical reagents corporation, Beijing nine ancient cooking vessel Gao Ke company limiteds and Guangzhou reagent company and other places.All solid reagents all do not have directly to use through further handling.Liquid reagent all uses after overweight evaporate to dryness is dry.
One, the The compounds of this invention intermediate is synthetic.
Example 1
5, and 5-dimethyl-2-(2-oxygen-propyl group)-hydroresorcinol (5,5-dimethyl-2-(2-oxo-propyl)-cyclohexane-1,3-dione) synthetic.(intermediate compound I)
Figure A20061008749500261
In reaction flask, add 5,5-dimethyl-1, hydroresorcinol (5,5-dimethylcyclohexane-1,3-dione) (3.5g, 25mmol) be dissolved in THF (250mL) and sodium hydride (1g, 40mmol), under the ice bath cooling, chloroethene ketone (2.3g, 25mmol) be added drop-wise in the reaction flask, add entry (400mL) after stirring 2h under the room temperature, reaction product dichloromethane extraction, washing back anhydrous magnesium sulfate drying.After removing siccative, solvent removed by evaporation at reduced pressure obtains colourless liquid, 2.8g, and productive rate 57%, this compound need not purifying and can be used for following reaction.
Example 2
5, and 5-dimethyl-2-(2-propionic aldehyde base)-hydroresorcinol (5,5-dimethyl-2-(1-methyl-2-oxo-ethyl)-cyclohexane-1,3-dione) synthetic.(intermediate II)
In reaction flask, add 5,5-dimethyl-1, hydroresorcinol (5,5-dimethylcyclohexane-1,3-dione) (3.5g, 25mmol) be dissolved in THF (200mL) and 2N NaOH (15mL, 30mmol), under the ice bath cooling, 2-chlorine propionic aldehyde dimethyl acetal (2-chloro-1,1-dimethoxypropane) (3.5g, THF 25mmol) (50mL) is added drop-wise in the reaction flask, add 1N HCl (200mL) and stirred reaction product ethyl acetate extraction, saturated sodium-chloride water flushing back anhydrous sodium sulfate drying 1 hour after stirring 2h under the room temperature.After removing siccative, solvent removed by evaporation at reduced pressure obtains the 1.9g colourless liquid, and productive rate 39%, this compound need not purifying and can be used for following reaction.
Example 3
2-ethanoyl-5,5-dimethyl-hydroresorcinol (2-acetyl-5,5-dimethyl-cyclohexane-1,3-dione) synthetic.(intermediate III)
Acetyl Chloride 98Min. (8.8mL) is added drop-wise to contains 5, (16.8g is 120mmol) and in chloroform (400mL) solution of pyridine (9.2mL) for 5-dimethyl-hydroresorcinol.After dripping, reaction at room temperature continues to stir 1.5 hours.Reaction solution is with chloroform extraction, spend the night with 0.1N hydrochloric acid, water, saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water solution washing, dried over sodium sulfate.
After filtration, removing the colourless liquid crude product that obtains behind the solvent joins under 0 ℃ and contains Aluminum chloride anhydrous (32g is in chloroform 240mmol) (400mL) solution.After adding, reactant stirred 10 minutes at 0 ℃, at room temperature stirred then 2 hours.Reaction solution pour into contain in the ice and the beaker of concentrated hydrochloric acid (20mL), with chloroform extraction, saturated sodium-chloride water solution wash, anhydrous sodium sulfate drying.After filtration, remove and to obtain solid product 2-ethanoyl-5 after desolvating, 5-dimethyl-hydroresorcinol, 4.66 grams, productive rate 21.3% (two steps), product is not purified to be directly used in next step reaction.
Example 4
3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone (3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one) synthetic.(intermediate compound IV)
Add ethanol (50mL) and 5 in reaction flask, (1.6g, 8.2mmol), (0.63g 8.2mmol), was heated to 60 ℃ of stirring reactions 2 hours to 5-dimethyl-2-(2-propionic aldehyde base)-hydroresorcinol to add ammonium acetate after the dissolving again.Behind the solvent of decompression place to go, product ethyl acetate extraction, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying.Obtain faint yellow solid after filtering back removal of solvent under reduced pressure, drying, 0.95 gram, productive rate 73%; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.78 (b, 1H), 5.47 (b, 1H), 2.73 (s, 2H), 2.44 (s, 2H), 2.32 (s, 3H), 1.13 (s, 6H).
Example 5
3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone (3,6,6-trimethyl-1,5,6,7-tetrahydro-indazol-4-one) synthetic.(intermediate V)
Figure A20061008749500281
With 2-ethanoyl-5; 5-dimethyl-1; hydroresorcinol (2.33g, 12.8mmol), 90% hydrazine hydrate (1.95mL) and ethanol (29mL) mixture stir spend the night, removal of solvent under reduced pressure, resistates are dissolved in methylene dichloride, saturated sodium-chloride water solution wash drip, anhydrous sodium sulfate drying.After filtration, behind the removal of solvents, product with silica gel column chromatography separate, with methylene chloride (20: 1 to 12: 1) wash-out, obtain needle-like crystal, 1.108 restrain productive rate 48.6%; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.33 (s, 1H), 2.73 (s, 2H), 2.58 (s, 3H), 2.38 (s, 2H), 1.13 (s, 6H).
Example 6
2,2-dimethyl-1,2,3,9-tetrahydro carbazole-4-ketone (2,2-dimethyl-1,2,3,9-tetrahydro-carbazol-4-one) synthetic.(intermediate VI)
Figure A20061008749500282
In reaction flask, add 5, and 5-dimethyl-hydroresorcinol (2.8g, 20mmol), trifluoroacetic acid (20mL), toluene (20mL), (2.16g 20mmol), was heated to 100 ℃ of stirring reactions 12 hours to add phenylhydrazine after the dissolving again.Behind the solvent of decompression place to go, product dichloromethane extraction, saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying.Removal of solvent under reduced pressure, purification by silica gel column chromatography obtain white solid after filtering, 2.55 grams, productive rate 59.7%; 1HNMR (500MHz, CDCl3), δ (ppm): 9.95 (b, 1H), 6.95-7.20 (m, 4H), 2.79 (s, 2H), 2.54 (s, 2H), 1.14 (s, 6H).
Two, The compounds of this invention is synthetic.
Embodiment 1
2-chloro-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (2-chloro-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile) synthetic.(structural formula I-01)
Figure A20061008749500291
With 3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone (1.11g, 6.22mmol), DMF (90mL), and sodium hydride (299mg, 12.4mmol), join in the reaction flask, under the ice bath cooling, 2-chloro-4-fluorobenzene cyanogen (1.26g, 8.1mmol) join in the reaction flask, reaction was at room temperature stirred three hours.Reactant be poured in the frozen water and with ethyl acetate extraction, saturated sodium-chloride water solution wash droplet, anhydrous sodium sulfate drying.Thick product separates with silica gel column chromatography, and use hexane: ethyl acetate (1: 7 to 1: 3) wash-out obtains 2-chloro-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen, 0.75 gram, productive rate 38.5%, fusing point 88-90 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.81-7.83 (d, 2H), 7.56-7.58 (d, 1H) 2.89 (s, 2H), 2.56 (s, 3H), 2.45 (s, 2H), 1.16 (s, 6H).
Embodiment 2
(1-(4-methylpiperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen (2-(4-methyl-piperazin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile) synthetic.(structural formula I-02)
Under argon shield, in the exsiccant reaction flask, add 1,1 '-bis (diphenylphosphino) ferrocene (Dppf) (22.8mg, 0.036mmol); 2-chloro-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5; 6, the 7-tetrahydrochysene indazole)) benzene cyanogen (100mg, 0.32mmol), PdCl 2(7.8mg, 0.036mmol), Pd (OAc) 2(8.08mg, 0.036mmol), t-BuONa (50mg), and dry toluene (5ml).Reaction mixture is heated to 100 ℃ and stirs after 20 minutes, adds 4-methylpiperazine (0.1ml) and continue to stir 5.5 hours down at 100 ℃.After the cooling, the solids removed by filtration catalyzer is after the removal of solvent under reduced pressure, product separates with silica gel column chromatography, use methylene dichloride: methyl alcohol (50: 1 to 30: 1) wash-out obtain 2-(1-(4-methylpiperazine))-4-(1-(and 3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen, 61 milligrams, productive rate 50.5%, fusing point 95-97 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.67-7.69 (d, 1H), 7.25 (s, 1H), 7.07-7.09 (d, 1H), 3.42 (b, 4H), 2.84 (s, 2H), 2.77 (b, 4H), 2.56 (s, 3H), 2.47 (s, 3H), 2.44 (s, 2H), 1.14 (s, 6H).
Embodiment 3
(1-(4-methylpiperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(4-methyl-piperazin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-03)
Figure A20061008749500301
The reference of cyano group oxidation/be hydrolyzed into acid amides reaction is seen: (1) Bull.Chem.Soc.Jpn., 54,3,793-799,1981. (2) Synthesis, 12,949-950,1989. (3) Synthesis, 3,243-244,1980.
(61mg 0.16mmol) is dissolved in DMSO (0.3mL), adds dehydrated alcohol (2mL), KOH (30mg) with 2-(1-(4-methylpiperazine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen.Reactant at room temperature stirred 5 minutes, slowly dripped 30% hydrogen peroxide (0.15mL) then, and reaction solution continues at room temperature to stir 10 minutes.In reaction flask, add entry (50mL) and use ethyl acetate extraction, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying.Product separates with silica gel column chromatography, uses methylene dichloride: methyl alcohol (30: 1 to 20: 1) wash-out obtain 2-(1-(4-methylpiperazine))-4-(1-(and 3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 60 milligrams, productive rate 93.5%, fusing point 114-116 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.20 (b, 1H), 8.25-8.27 (d, 1H), 7.46 (s, 1H), 7.30 (s, 1H), 5.89 (b, 1H), 3.15 (b, 4H), 2.84 (s, 2H), 2.66 (b, 4H), 2.57 (s, 3H), 2.43 (s, 2H), 2.41 (s, 3H), 1.14 (s, 6H); 13CNMR (500MHz, CDCl 3), δ (ppm): 193.35,167.72,152.68,150.27,149.03,141.74,132.82,126.57,118.31,117.41,115.47,55.44,53.21,52.31,45.99,37.48,35.86,28.42,13.38; FAB-MS m/z:396.2 (M ++ 1); Ultimate analysis: calculated value C 66.81, H 7.39, and N 17.71; Measured value C 66.56, and H 6.98, and N 17.44.
Embodiment 4
(1-(3-hydroxyl pyrrolidine base))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen (2-(3-hydroxy-pyrrolidin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile) synthetic.(structural formula I-04)
Figure A20061008749500311
Adding 2-chloro-4-oil of mirbane cyanogen in reaction flask (0.5g, 2.7mmol), toluene (20mL) and 3-hydroxyl pyrrolidine (0.24g, 2.7mmol).Reactant was heated with stirring to 100 ℃ of reactions after 2 hours, and solvent is removed in cooling, uses chloroform extraction, saturated sodium-chloride water solution washing, anhydrous magnesium sulfate drying.Remove obtain behind siccative and the solvent product be dissolved in methyl alcohol (40mL) and add iron powder (0.45g, 8mmol) and glacial acetic acid (0.5mL).Reactant stirring and refluxing 2 hours, cooling is used ethyl acetate extraction in falling back, the saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying is through getting 0.31g, productive rate 52% behind the recrystallization purifying; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.46 (d, 1H), 6.72 (d, 1H), 6.43 (s, 1H), 3.96 (b, 2H), 3.43 (m, 1H), 3.05 (m, 2H), 2.96 (m, 2H), 1.85 (m, 2H).
5,5-dimethyl-2-(2-propionic aldehyde base)-hydroresorcinol (0.1g, 0.5mmol) be dissolved in toluene, be heated to 85 ℃, add 4-amino-2-(1-(3-hydroxyl pyrrolidine) benzene cyanogen (0.12g of above-mentioned preparation, 0.5mmol), temperature of reaction rises to 110 ℃, and stirs 1h.After the cooling, with removal of solvents, product obtains 2-(1-(3-hydroxyl pyrrolidine base))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen 0.16g, productive rate 44%, fusing point 79-81 ℃ after with purification by silica gel column chromatography; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.73 (d, 1H), 7.27 (d, 1H), 6.86 (s, 1H), 6.68 (s, 1H), 3.45 (m, 1H), 3.11 (m, 2H), 3.02 (m, 2H), 2.73 (s, 2H), 2.54 (s, 3H), 2.37 (s, 2H), 1.89 (m, 2H), 1.12 (s, 6H).
Embodiment 5
(1-(3-hydroxyl pyrrolidine base))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide (2-(3-hydroxy-pyrrolidin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide) synthetic.(structural formula I-05)
Synthetic method is with embodiment 3, productive rate 48%, fusing point 121-123 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.20 (b, 1H), 7.84-7.86 (d, 1H), 7.27 (d, 1H), 7.03-7.05 (s, 1H), 6.87 (s, 1H), 5.96 (b, 1H), 3.41 (m, 1H), 3.07 (m, 2H), 3.00 (m, 2H), 2.78 (s, 2H), 2.57 (s, 3H), 2.42 (s, 2H), 1.84 (m, 2H), 1.13 (s, 6H); FAB-MS m/z:382.2 (M ++ 1); Ultimate analysis: calculated value C 69.27, H 7.13, and N 11.02; Measured value C 69.05, and H 7.01, and N 11.13.
Embodiment 6
2-(1-piperidines)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen (2-piperidin-1-yl-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile synthetic.(structural formula I-06)
In reaction flask, add piperidines (8.5g, 0.1mol), DMF (150mL) and 2,4 difluorobenzene cyanogen (13.9g, 0.1mol).The reactant stirring heating refluxed 12 hours, cooling back removal of solvent under reduced pressure, and ethyl acetate extraction, washing, anhydrous sodium sulfate drying, product gets 14.8g through the cyclohexane/ethyl acetate recrystallization, productive rate 72.5%, 1HNMR (500MHz, CDCl 3), δ (ppm): 7.54-7.56 (d, 1H), 7.25 (d, 1H), 7.16 (s, 1H), 3.28 (b, 4H), 1.87 (m, 4H), 1.56 (m, 2H).
In reaction flask, add 3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone (0.18g, 1mmol), DMF (25mL), NaH (0.036g, 1.5mmol).Behind the vigorous reaction, in reaction flask, added 2-(1-piperidines)-4 fluorobenzene cyanogen (0.21g 1mmol) and reflux 12 hours.After the cooling, removal of solvent under reduced pressure, product dichloromethane extraction, saturated sodium-chloride water solution washing, anhydrous magnesium sulfate drying.Product obtains 0.28g, productive rate 77.8%, fusing point 87-89 ℃ after with purification by silica gel column chromatography; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.44-7.46 (d, 1H), 7.14 (s, 1H), 7.01-7.03 (d, 1H), 6.67-6.69 (s, 1H), 3.25 (b, 4H), 2.84 (s, 2H), 2.55 (s, 3H), 2.42 (s, 2H), 1.78 (b, 4H), 1.53 (b, 2H), 1.14 (s, 6H).
Embodiment 7
2-(1-piperidines)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide (2-piperidin-1-yl-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide) synthetic.(structural formula I-07)
Synthetic method is with embodiment 3, productive rate 57.5%, fusing point 143-145 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.28 (b, 1H), 8.13-8.15 (d, 1H), 7.23 (s, 1H), 7.04-7.06 (d, 1H), 6.87 (s, 1H), 6.24 (b, 1H), 3.21 (b, 4H), 2.84 (s, 2H), 2.55 (s, 3H), 2.42 (s, 2H), 1.94 (b, 4H), 1.52 (b, 2H), 1.12 (s, 6H); FAB-MS m/z:380.2 (M ++ 1); Ultimate analysis: calculated value C 72.79, H 7.70, and N 11.07; Measured value C 72.46, and H 7.54, and N 10.83.
Embodiment 8
(1-(4-methylpiperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole) benzamide (2-(4-methyl-piperazin-1-yl)-4-(3 methyl), 6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-ylmethyl)-benzamide) synthetic.(structural formula I-08)
Figure A20061008749500332
Adding 2-bromo-methyl 4 methylbenzoate in reaction flask (2.29g, 10mmol), tetracol phenixin (60mL) and benzoyl hydroperoxide acid anhydride (0.35g, 0.4mmol).Reactant is heated with stirring to 90 ℃, and (1.78g is 10mmol) and 110 ℃ of following stirring reactions 2 hours to add NBS.After the cooling, solvent is removed in decompression, uses ethyl acetate extraction, 1N NaOH solution washing, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying.It is colorless oil 1.72g that removal siccative and solvent get 2-bromo-4-bromomethyl-benzoic acid methyl ester through purification by silica gel column chromatography, productive rate 56%. 1HNMR(500MHz，CDCl 3)，δ(ppm)：7.76-7.78(d，1H)，7.527.56(d，1H)，7.35-7.38(s，1H)，4.62(s，2H)，4.02(s，3H)。
With 3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone (1.0g, 5.5mmol), DMF (60mL), and sodium hydride (0.26g 11mmol) joins in the reaction flask, under the ice bath cooling, (1.72g 5.5mmol) joins in the reaction flask, and reaction was at room temperature stirred 2 hours with 2-bromo-4-bromomethyl-benzoic acid methyl ester.Reactant is poured in the frozen water and uses ethyl acetate extraction, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying.Thick product separates with silica gel column chromatography, and use hexanaphthene: ethyl acetate (4: 1 to 2: 1) wash-out obtains 2-bromo-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) methyl benzoate, 1.15 grams, productive rate 52%; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.75-7.78 (d, 1H), 7.42-7.45 (d, 1H), 7.26-7.29 (b, 1H), 6.21 (s, 1H), 5.26 (s, 2H), 3.91 (s, 3H), 2.78 (s, 2H), 2.13 (s, 3H), 2.35 (s, 2H), 1.13 (s, 6H).
According to the method for embodiment 2, with 2-bromo-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) methyl benzoate, Dppf, PdCl 2, t-BuONa, 4-methyl piperidine react in toluene and obtain 2-(1-(4-methyl piperidine))-4-(1-(3,6,6-trimethylammonium 4-oxygen-4,5,6,7-tetrahydro indole) methyl) methyl benzoate, productive rate 16%; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.69-7.73 (d, 1H), 7.48-7.52 (d, 2H), 6.11 (s, 1H), 5.19 (s, 2H), 3.44 (b, 4H), 2.81 (s, 2H), 2.73 (b, 4H), 2.16 (s, 3H), 2.33 (s, 3H), 2.34 (s, 2H), 1.12 (s, 6H).
(1-(4-methyl piperidine))-(1-(3 for 4-with 2-, 6,6-trimethylammonium 4-oxygen-4,5,6, the 7-tetrahydro indole) methyl) methyl benzoate (0.08g, 0.19mmol) be dissolved in the methanol solution of 2M ammonia, stirring at room went out to desolvate after 2 hours, and thick product separates with silica gel column chromatography, and use methylene dichloride: methyl alcohol (30: 1 to 20: 1) wash-out obtains 2-, and (1-(4-methylpiperazine))-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole) benzamide methyl), 45 milligrams, productive rate 58%, fusing point 125-127 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.23 (b, 1H), 7.31-8.34 (d, 1H), 7.25 (s, 1H), 7.10 (s, 1H), 6.04 (b, 1H), 5.26 (s, 2H), 3.42 (b, 4H), 2.81 (s, 2H), 2.65 (b, 4H), 2.34 (s, 2H), 2.31 (s, 3H), 2.14 (s, 3H), 1.13 (s, 6H); FAB-MS m/z:409.3 (M ++ 1); Ultimate analysis: calculated value C 70.56, H 7.90, N13.71; Measured value C 70.41, and H 7.76, and N 13.69.
Embodiment 9
2-hexamethylene amino-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide (2-cyclohexylamino-4-(3,6,6-trimethyl-4-oxo-4,5,6, synthetic (structural formula I-09) 7-tetrahydro-indol-1-yl)-benzamide)
The synthetic method of 2-hexamethylene amino-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen is with embodiment 6, productive rate 47%, fusing point 112-114 ℃; 1HNMR (500MHz, CDCl3), δ (ppm): 7.35-7.37 (d, 1H), 7.21 (s, 1H), and 6.94-6.96 (d, 1H), 6.59-6.61 (s, 1H), 4.12 (b, 1H), 2.83 (s, 2H), 2.64 (b, 1H), 2.54 (s, 3H), 2.39 (s, 2H), 1.73 (b, 4H), 1.40-1.50 (m, 6H), 1.13 (s, 6H).
The synthetic method of 2-hexamethylene amino-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide is with embodiment 3, productive rate 73%, fusing point 158-160 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.23 (b, 1H), 8.07-8.09 (d, 1H), 7.12 (s, 1H), 6.95-6.97 (d, 1H), 6.59 (s, 1H), 6.21 (b, 1H), 4.06 (b, 1H), 2.84 (s, 2H), 2.58 (b, 1H), 2.53 (s, 3H), 2.42 (s, 2H), 1.77 (b, 4H), 1.38-1.50 (m, 6H), 1.15 (s, 6H); FAB-MS m/z:394.2 (M ++ 1); Ultimate analysis: calculated value C 73.25, H, 7.94, N 10.68; Measured value C 73.32, and H 7.78, and N 10.46.
Embodiment 10
(2-diethylin ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide (2-(2-diethylamino-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide) synthetic.(structural formula I-10)
Figure A20061008749500351
The synthetic method of 2-(2-diethylin ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen is with embodiment 6, productive rate 56%, fusing point 142-144 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.53-7.55 (d, 1H), 7.27 (s, 1H), 7.02-7.04 (d, 1H), 6.54-6.56 (s, 1H), 4.07 (b, 1H), 3.45 (t, 2H), 3.28 (t, 2H), 2.84 (s, 2H), 2.65 (b, 4H), 2.56 (s, 3H), 2.42 (s, 2H), 1.22 (b, 4H), 1.14 (s, 6H).
The synthetic method of 2-(2-diethylin ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide is with embodiment 3, productive rate 61%, fusing point 172-174 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.21 (b, 1H), 7.84-8.86 (d, 1H), 7.31 (s, 1H), 6.87-6.89 (d, 1H), 6.64 (s, 1H), 6.23 (b, 1H), 4.03 (b, 1H), 3.37 (t, 2H), 3.30 (t, 2H), 2.85 (s, 2H), 2.68 (b, 4H), 2.54 (s, 3H), 2.432 (s, 2H), 1.17 (b, 4H), 1.13 (s, 6H); FAB-MS m/z:411.2 (M ++ 1); Ultimate analysis: calculated value C 70.21, H 8.35, and N 13.65; Measured value C 70.06, and H 7.98, and N 13.49.
Embodiment 11
(2-(4-morpholine) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide (2-(2-morpholin-4-yl-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide) synthetic.(structural formula I-11)
The synthetic method of 2-(2-(4-morpholine) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen is with embodiment 6, productive rate 45.8%, fusing point 117-119 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.75-7.77 (d, 1H), 7.43 (s, 1H), 6.95-6.97 (d, 1H), 6.62 (s, 1H), 4.05 (b, 1H), 3.86 (t, 4H), 3.37 (t, 2H), 3.23 (t, 2H), 2.84 (s, 2H), 2.63 (b, 4H), 2.54 (s, 3H), 2.43 (s, 2H), 1.13 (s, 6H).
The synthetic method of 2-(2-(4-morpholine) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide is with embodiment 3, productive rate 57%, fusing point 142-144 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.24 (b, 1H), 7.79-7.81 (d, 1H), 7.35 (s, 1H), 6.79-6.81 (d, 1H), 6.59 (s, 1H), 6.21 (b, 1H), 4.02 (b, 1H), 3.79 (t, 4H), 3.42 (t, 2H), 3.18 (t, 2H), 2.83 (s, 2H), 2.64 (b, 4H), 2.57 (s, 3H), 2.42 (s, 2H), 1.14 (s, 6H); FAB-MS m/z:407.2 (M ++ 1); Ultimate analysis: calculated value C 70.91, H 7.44, and N 13.78; Measured value C 70.78, and H 7.25, and N 13.52.
Embodiment 12
(1-(4-oxygen-piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide (2-(4-oxo-piperidin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6, synthetic (structural formula I-12) 7-tetrahydro-indol-1-yl)-benzamide)
Figure A20061008749500362
The synthetic method of 2-(1-(4-oxygen-piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen is with embodiment 4, productive rate 48%, fusing point 93-95 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.67-7.69 (d, 1H), 7.06 (s, 1H), 6.87-6.89 (d, 1H), 6.58 (s, 1H), 3.89 (b, 4H), 2.97 (b, 4H), 2.85 (s, 2H), 2.57 (s, 3H), 2.43 (s, 2H), 1.13 (s, 6H).
The synthetic method of 2-(1-(4-oxygen-piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide is with embodiment 3, productive rate 38,7%, fusing point 112-114 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.21 (b, 1H), 7.64-7.66 (d, 1H), 7.27 (s, 1H), 6.45-6.47 (d, 1H), 6.62 (s, 1H), 6.18 (b, 1H), 4.00 (b, 4H), 3.04 (b, 4H), 2.84 (s, 2H), 2.55 (s, 3H), 2.42 (s, 2H), 1.14 (s, 6H); FAB-MS m/z:376.2 (M ++ 1); Ultimate analysis: calculated value C 73.57, H 6.71, N11.19; Measured value C 73.43, and H 6.57, and N 11.52.
Embodiment 13
(1-(4-hydroxy piperidine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide (2-(4-hydroxy-piperidin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide) synthetic.(structural formula I-13)
The synthetic method of 2-(1-(4-hydroxy piperidine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen is with embodiment 6, productive rate 48%, fusing point 134-136 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.82-7.84 (d, 1H), 7.18 (s, 1H), 6.98-7.00 (d, 1H), 6.65 (s, 1H), 5.00-5.02 (m, 1H), and 3.57-3.59 (m, 2H), 3.24-3.26 (m, 2H), 2.83 (s, 2H), 2.57 (s, 3H), 2.42 (s, 2H), 2.12-2.16 (m, 2H), 1.86-1.88 (m, 2H), 1.14 (s, 6H).
The synthetic method of 2-(1-(4-hydroxy piperidine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide is with embodiment 3, productive rate 34%, fusing point 152-154 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.23 (b, 1H), 7.79-7.81 (d, 1H), 7.21 (s, 1H), 6.85-6.87 (d, 1H), 6.62 (s, 1H), 6.15 (b, 1H), 4.97-4.99 (m, 1H), 3.617-3.62 (m, 2H), 3.31-3.33 (m, 2H), 2.84 (s, 2H), 2.56 (s, 3H), 2.43 (s, 2H), 2.17-2.19 (m, 2H), 1.93-1.95 (m, 2H), 1.13 (s, 6H); FAB-MS m/z:396.2 (M ++ 1); Ultimate analysis: calculated value C 69.85, H 7.39, and N 10.62; Measured value C 69.57, and H 7.07, and N 10.39.
Embodiment 14
(4-hydroxyl hexamethylene amino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide (2-(4-hydroxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide) synthetic.(structural formula I-14)
Figure A20061008749500381
The synthetic method of 2-(4-hydroxyl hexamethylene amino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen is with embodiment 4, productive rate 36.7%, fusing point 146-148 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.42-7.44 (d, 1H), 6.87-6.89 (d, 1H), 6.81 (s, 1H), 6.69 (s, 1H), 4.07 (b, 1H), 3.68 (m, 1H), 3.02 (b, 1H), 2.73 (s, 2H), 2.54 (s, 3H), 2.46 (s, 2H), 1.73 (b, 4H), 1.62 (b, 4H), 1.13 (s, 6H).
The synthetic method of 2-(4-hydroxyl hexamethylene amino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide is with embodiment 3, productive rate 54%, fusing point 153-155 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 8.34 (b, 1H), 7.48-7.50 (d, 1H), 6.62 (s, 1H), 6.58 (s, 1H), 6.45 (d, 1H), 5.86 (b, 1H), 3.76 (b, 1H), 3.30 (b, 1H), 2.67 (s, 2H), 2.37 (s, 2H), 2.35 (s, 3H), 2.20 (b, 2H), 2.10 (b, 2H), 1.67 (b, 4H), 1.08 (s, 6H); FAB-MS m/z:410.2 (M ++ 1); Ultimate analysis: calculated value C 70.39, H 7.63, and N 10.26; Measured value C 70.06, and H 7.38, and N 10.32.
Embodiment 15
(1-(4-(4-morpholine) piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide (2-(4-morpholin-4-yl-piperidin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide) synthetic.(structural formula I-15)
Figure A20061008749500382
The synthetic method of 2-(1-(4-(4-morpholine) piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen is with embodiment 6, productive rate 62%, fusing point 141-143 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.97-7.99 (d, 1H), 7.43 (s, 1H), 7.18-7.20 (d, 1H), 6.58 (s, 1H), 3.84-3.86 (m, 4H), 2.89-2.91 (m, 4H), 2.84 (s, 2H), 2.65 (b, 4H), 2.55 (s, 3H), 2.43 (s, 2H), 1.52-1.54 (b, 4H), 1.14 (s, 6H).
The synthetic method of 2-(1-(4-(4-morpholine) piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide is with embodiment 3, productive rate 67%, fusing point 165-167 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.22 (b, 1H), 8.17-8.19 (d, 1H), 7.54 (s, 1H), 7.09-7.11 (d, 1H), 6.64 (s, 1H), 6.07 (b, 1H), 3.78-3.80 (b, 4H), 2.79-2.83 (m, 3H), 2.84 (s, 2H), 2.63 (b, 4H), 2.54 (s, 3H), 2.42 (s, 2H), 1.54-1.56 (b, 4H), 1.13 (s, 6H); FAB-MS m/z:465.3 (M ++ 1); Ultimate analysis: calculated value C 69.80, H 7.81, and N 12.06; Measured value C 69.64, and H 7.61, and N 11.87.
Embodiment 16
2-(2-[1,2,3] the triazole ethylamino)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide (2-(2-[1,2,3] triazol-1-yl-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide) synthetic.(structural formula I-16)
The synthetic method of 2-(2-[1,2,3] triazole ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen is with embodiment 4, productive rate 37.5%, fusing point 113-115 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 8.24-8.28 (d, 2H), 7.87-7.89 (d, 1H), 7.36 (s, 1H), 7.05-7.07 (d, 1H), 6.63 (s, 1H), 3.98-4.02 (m, 3H), 3.63 (t, 2H), 2.83 (s, 2H), 2.57 (s, 3H), 2.43 (s, 2H), 1.15 (s, 6H).
The synthetic method of 2-(2-[1,2,3] triazole ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide is with embodiment 3, productive rate 72%, fusing point 143-145 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.24 (b, 1H), 8.25-8.27 (d, 2H), 7.76-7.78 (d, 1H), 7.41 (s, 1H), 6.93-6.95 (d, 1H), 6.59 (s, 1H), 6.12 (b, 1H), 4.02-4.05 (b, 2H), 3.71 (t, 2H), 2.84 (s, 2H), 2.55 (s, 3H), 2.44 (s, 2H), 1.14 (s, 6H); FAB-MS m/z:407.2 (M ++ 1); Ultimate analysis: calculated value C 65.01, H 6.45, and N 20.68; Measured value C 64.82, and H 6.27, and N 20.53.
Embodiment 17
(1-(4-(2-(4-morpholine) ethyl) piperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide (2-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide) synthetic.(structural formula I-17)
Figure A20061008749500401
The synthetic method of 2-(1-(4-(2-(4-morpholine) ethyl) piperazine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen is with embodiment 4, productive rate 56%, fusing point 156-158 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.74-7.76 (d, 1H), 7.27 (s, 1H), 7.11-7.13 (d, 1H), 6.61 (s, 1H), 3.76-3.78 (t, 4H), and 3.41-3.43 (t, 4H), 2.95-2.98 (b, 4H), 2.84 (s, 2H), 2.68-2.70 (t, 4H), 2.57 (s, 3H), 2.54 (b, 4H), 2.43 (s, 2H), 1.13 (s, 6H).
The synthetic method of 2-(1-(4-(2-(4-morpholine) ethyl) piperazine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide is with embodiment 3, productive rate 58%, fusing point 168-170 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.22 (b, 1H), 8.328.34 (d, 1H), 7.54 (s, 1H), 7.18-7.20 (d, 1H), 6.64 (s, 1H), 5.98 (b, 1H), 3.84-3.86 (t, 4H), 3.27-3.29 (t, 4H), 2.88-2.90 (b, 4H), 2.85 (s, 2H), 2.59-2.61 (t, 4H), 2.57 (s, 3H), 2.53 (b, 4H), 2.44 (s, 2H), 1.14 (s, 6H); FAB-MS m/z:494.3 (M ++ 1); Ultimate analysis: calculated value C 68.13, H 7.96, and N 14.19; Measured value C 68.07, and H 7.72, and N 13.95.
Embodiment 18
(1-(4-(1-pyrrolidyl) piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide (2-(4-pyrrolidin-1-yl-piperidin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide) synthetic.(structural formula I-18)
Figure A20061008749500402
The synthetic method of 2-(1-(4-(1-pyrrolidyl) piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen is with embodiment 4, productive rate 42%, fusing point 121-123 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.73-7.75 (d, 1H), 7.16 (s, 1H), 6.96-6.98 (d, 1H), 6.62 (s, 1H), 3.01-3.03 (b, 4H), 2.84 (s, 2H), 2.68 (b, 4H), 2.57 (s, 3H), 2.45 (s, 2H), 1.90-2.03 (b, 8H), 1.14 (s, 6H).
The synthetic method of 2 (1-(4-(1-pyrrolidyl) piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide is with embodiment 3, productive rate 47%, fusing point 137-139 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.21 (b, 1H), 8.19-8.21 (d, 1H), 7.56 (s, 1H), 7.17-7.19 (d, 1H), 6.68 (s, 1H), 5.86 (b, 1H), 3.16-3.18 (d, 2H), 2.90-2.93 (m, 3H), 2.84 (s, 2H), 2.73 (b, 4H), 2.57 (s, 3H), 2.43 (s, 2H), 1.87-2.08 (b, 8H), 1.14 (s, 6H); FAB-MS m/z:449.3 (M ++ 1); Ultimate analysis: calculated value C 72.29, H 8.09, and N 12.49; Measured value C 72.08, and H 7.87, and N 12.26.
Embodiment 19
(2-diethylin ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(2-diethylamino-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-19)
Figure A20061008749500411
2-(2-diethylin ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 2-diethylamino-ethylamine obtain by the synthetic method of embodiment 2 is synthetic, productive rate 38.5%, fusing point 97-99 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.76-7.78 (d, 1H), 7.34 (s, 1H), 7.05-7.07 (d, 1H), 4.04 (b, 1H), 3.29 (t, 2H), 3.34 (t, 2H), 2.84 (s, 2H), 2.63 (b, 4H), 2.55 (s, 3H), 2.43 (s, 2H), 1.20 (t, 4H), 1.13 (s, 6H).
The synthetic method of 2-(2-diethylin ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 68%, fusing point 123-124 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.23 (b, 1H), 8.23-8.25 (d, 1H), 7.54 (s, 1H), 7.03-7.05 (d, 1H), 6.58 (s, 1H), 6.21 (b, 1H), 4.02 (b, 1H), 3.34-3.37 (t, 2H), 3.30-3.32 (t, 2H), 2.84 (s, 2H), 2.62 (b, 4H), 2.57 (s, 3H), 2.42 (s, 2H), 1.19 (b, 4H), 1.14 (s, 6H); FAB-MS m/z:412.3 (M ++ 1); Ultimate analysis: calculated value C 67.12, H 8.08, and N 17.02; Measured value C 67.08, and H 7.84, and N 16.79.
Embodiment 20
2-hexamethylene amino-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-cyclohexylamino-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-20)
Figure A20061008749500421
2-hexamethylene amino-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and hexahydroaniline obtain by the synthetic method of embodiment 2 is synthetic, productive rate 65%, fusing point 125-127 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.87-7.89 (d, 1H), 7.45 (s, 1H), 7.11-7.13 (d, 1H), 4.03 (b, 1H), 2.85 (s, 2H), 2.69 (b, 4H), 2.57 (s, 3H), 2.42 (s, 2H), 1.36-1.45 (m, 6H), 1.14 (s, 6H).
The synthetic method of 2-hexamethylene amino-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 73%, fusing point 164-166 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.22 (b, 1H), 8.01-8.03 (d, 1H), 7.24 (s, 1H), 6.87-6.89 (d, 1H), 6.65 (s, 1H), 6.18 (b, 1H), 4.02 (b, 1H), 2.84 (s, 2H), 2.58 (b, 1H), 2.53 (s, 3H), 2.42 (s, 2H), 1.77 (b, 4H), 1.38-1.45 (m, 6H), 1.15 (s, 6H); FAB-MS m/z:395.2 (M ++ 1); Ultimate analysis: calculated value C 70.02, H 7.66, and N 14.20; Measured value C 69.89, and H 7.53, and N 14.15.
Embodiment 21
(2-(1-piperidines) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(2-piperidin-1-yl-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-21)
Figure A20061008749500422
2-(2-(1-piperidines) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 2 (1-piperidines) ethamine obtain by the synthetic method of embodiment 2 is synthetic, productive rate 37%, fusing point 95-97 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.74-7.76 (d, 1H), 7.38 (s, 1H), 7.07-7.09 (d, 1H), 4.02 (b, 1H), 3.43-3.45 (t, 2H), 2.84 (s, 2H), 2.66 (b, 2H), 2.57 (s, 3H), 2.42 (s, 2H), 2.38-2.40 (t, 4H), 1.37-1.45 (m, 6H), 1.14 (s, 6H).
The synthetic method of 2-(2-(1-piperidines) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 73%, fusing point 131-133 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.21 (b, 1H), 8.01-8.03 (d, 1H), 7.43 (s, 1H), 6.95-6.97 (d, 1H), 6.62 (s, 1H), 6.15 (b, 1H), 4.05 (b, 1H), 3.51-3.53 (t, 2H), 2.84 (s, 2H), 2.65 (b, 2H), 2.54 (s, 3H), 2.43 (s, 2H), 2.37-2.39 (t, 4H), 1.38-1.46 (m, 6H), 1.14 (s, 6H); FAB-MS m/z:424.2 (M ++ 1); Ultimate analysis: calculated value C 68.06, H 7.85, and N 16.53; Measured value C 67.88, and H 7.67, and N 16.38.
Embodiment 22
(2-(1-(3, the 5-lupetidine)) ethylamino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (2-[2-(3 for benzamide, 5-dimethyl-piperidin-1-yl)-ethylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-22)
(2-(1-(3, the 5-lupetidine)) ethylamino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen by 2-chloro-4-(1-(and 3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 2-(1-along 3,5-lupetidine) ethamine obtains by the synthetic method of embodiment 2 is synthetic, productive rate 43%, fusing point 113-115 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.73-7.75 (d, 1H), 7.36 (s, 1H), 7.08-7.10 (d, 1H), 4.00 (b, 1H), 3.38-3.40 (t, 2H), 2.83 (s, 2H), 2.65 (b, 2H), 2.55 (s, 3H), 2.43 (s, 2H), 2.36-2.38 (t, 4H), 1.65 (m, 2H), 1.39-1.43 (m, 2H), 1.14 (s, 6H), 1.03-1.05 (d, 6H).
The synthetic method of 2-(2-(1-(3, the 5-lupetidine)) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 55%, fusing point 142-144 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.23 (b, 1H), 8.04-8.06 (d, 1H), 7.41 (s, 1H), 6.92-6.94 (d, 1H), 6.59 (s, 1H), 6.17 (b, 1H), 4.03 (b, 1H), 3.46-3.48 (t, 2H), 2.83 (s, 2H), 2.67 (b, 2H), 2.53 (s, 3H), 2.44 (s, 2H), 2.37-2.39 (t, 4H), 1.68 (m, 2H), 1.04-1.06 (m, 6H), 1.14 (s, 6H); FAB-MS m/z:452.3 (M ++ 1); Ultimate analysis: calculated value C 69.15, H 8.26, and N 15.51; Measured value C 68.94, and H 8.06, and N 15.35.
Embodiment 23
2-(2-[1,2,3] the triazole ethylamino)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(2-[1,2,3] triazol-1-yl-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazo-1-yl)-benzami de) synthetic.(structural formula I-23)
Figure A20061008749500441
2-(2-[1,2,3] the triazole ethylamino)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 2-[1,2,3] triazole ethamine obtains by the synthetic method of embodiment 2 is synthetic, productive rate 64%, fusing point 135-137 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 8.23-8.25 (d, 2H), 7.84-7.86 (d, 1H), 7.38 (s, 1H), 7.02-7.04 (d, 1H), 3.97-4.02 (m, 3H), 3.65 (t, 2H), 2.84 (s, 2H), 2.55 (s, 3H), 2.42 (s, 2H), 1.14 (s, 6H).
The synthetic method of 2-(2-[1,2,3] triazole ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 65%, fusing point 164-166 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.23 (b, 1H), 8.24-8.26 (d, 2H), 7.98-8.00 (d, 1H), 7.43 (s, 1H), 7.07-7.09 (d, 1H), 6.17 (b, 1H), 4.02-4.04 (m, 2H), 3.67 (t, 2H), 2.85 (s, 2H), 2.57 (s, 3H), 2.43 (s, 2H), 1.15 (s, 6H); FAB-MS m/z:408.2 (M ++ 1); Ultimate analysis: calculated value C 61.90, H 6.18, and N 24.06; Measured value C 61.74, and H 6.02, and N 23.88.
Embodiment 24
(1-(4-pentamethylene base) piperazine)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(4-cyclopentyl-piperazin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-24)
2-(1-(4-pentamethylene base) piperazine)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 4-pentamethylene base piperazine obtain by the synthetic method of embodiment 2 is synthetic, productive rate 55.8%, fusing point 141-143 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.83-7.85 (d, 1H), 7.31 (s, 1H), 7.06-7.08 (d, 1H), 3.38 (b, 4H), 2.83 (s, 2H), 2.74 (b, 4H), 2.67 (b, 1H), 2.55 (s, 3H), 2.43 (s, 2H), 1.68 (m, 4H), 1.58 (m, 4H), 1.14 (s, 6H).
The synthetic method of 2-(1-(4-pentamethylene base) piperazine)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 73%, fusing point 168-170 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.23 (b, 1H), 8.05-8.07 (d, 1H), 7.42 (s, 1H), 7.09-7.11 (d, 1H), 3.42 (b, 4H), 2.84 (s, 2H), 2.76 (b, 4H), 2.66 (b, 1H), 2.57 (s, 3H), 2.42 (s, 2H), 1.69 (m, 4H), 1.57 (m, 4H), 1.14 (s, 6H); FAB-MS m/z:450.3 (M ++ 1); Ultimate analysis: calculated value C 69.46, H 7.85, and N 15.58; Measured value C 69.18, and H 7.59, and N 15.62.
Embodiment 25
2-cyclopropane amino-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-cyclopropylamino-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-25)
2-cyclopropane amino-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and cyclopropylamine obtain by the synthetic method of embodiment 2 is synthetic, productive rate 38.5%, fusing point 87-89 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.74-7.76 (d, 1H), 7.32 (s, 1H), 7.03-7.05 (d, 1H), 4.01 (b, 1H), 2.84 (s, 2H), 2.55 (s, 3H), 2.43 (s, 2H), 2.38 (m, 1H), 1.14 (s, 6H), 0.55-0.84 (m4H).
The synthetic method of 2-cyclopropane amino-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 68%, fusing point 112-114 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.21 (b, 1H), 7.94-7.96 (d, 1H), 7.18 (s, 1H), 6.73-6.75 (d, 1H), 6.12 (b, 1H), 4.02 (b, 1H), 2.83 (s, 2H), 2.54 (s, 3H), 2.42 (s, 2H), 2.37 (m, 1H), 1.15 (s, 6H), 0.55-0.85 (m4H); FAB-MS m/z:353.2 (M ++ 1); Ultimate analysis: calculated value C 68.16, H 6.86, and N 15.90; Measured value C 67.87, and H 6.69, and N 15.78.
Embodiment 26
(1-(4-(2-(1-piperidines) oxyethyl group) piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-[4-(2-piperidin-1-yl-ethoxy)-piperidin-1-yl]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-26)
2-(1-(4-(2-(1-piperidines) oxyethyl group) piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen synthetic (1-(3,6 by 2-chloro-4-, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 4-(2-(1-piperidines) oxyethyl group) piperidines obtain by the synthetic method of embodiment 2 is synthetic, productive rate 63%, fusing point 126-128 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.84-7.86 (d, 1H), 7.37 (s, 1H), 6.89-6.91 (d, 1H), 3.77 (t, 2H), 3.02 (b, 1H), 2.83 (s, 2H), 2.76 (m, 4H), 2.64 (t, 2H), 2.56 (s, 3H), 2.46 (s, 2H), 2.38 (m, 4H), 1.73 (b, 4H), 1.68 (m, 4H), 1.48-1.54 (b, 6H), 1.13 (s, 6H).
The synthetic method of 2-(1-(4-(2-(1-piperidines) oxyethyl group) piperidines))-4-(1-(3,6,6-trimethylammonium 4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 75%, fusing point 146-147 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.21 (b, 1H), 8.08-8.10 (d, 1H), 7.54 (s, 1H), 7.05-7.07 (d, 1H), 3.86 (t, 2H), 3.09 (b, 1H), 2.84 (s, 2H), 2.74 (m, 4H), 2.68 (t, 2H), 2.57 (s, 3H), 2.43 (s, 2H), 2.41 (m, 4H), 1.78 (b, 4H), 1.69 (m, 4H), 1.48-1.54 (b, 6H), 1.14 (s, 6H); FAB-MS m/z:508.3 (M ++ 1); Ultimate analysis: calculated value C 68.61, H 8.14, N13.80; Measured value C 68.46, and H 7.87, and N 13.68.
Embodiment 27
2-(1-(4-oxygen-piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(4-oxo-piperidin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-27)
Figure A20061008749500471
2-(1-(4-oxygen-piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen synthetic (1-(3,6 by 2-chloro-4-, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 4-oxygen-piperidines obtain by the synthetic method of embodiment 2 is synthetic, productive rate 57%, fusing point 141-143 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.87-7.89 (d, 1H), 7.35 (s, 1H), 6.86-6.88 (d, 1H), 3.63 (t, 4H), 2.83 (s, 2H), 2.67 (t, 4H), 2.56 (s, 3H), 2.42 (s, 2H), 1.13 (s, 6H).
The synthetic method of 2-(1-(4-oxygen-piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 75%, fusing point 146-147 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.27 (b, 1H), 8.18-8.20 (d, 1H), 7.54 (s, 1H), 7.25-7.27 (d, 1H), 6.04 (b, 1H), 3.68 (t, 4H), 2.84 (s, 2H), 2.72 (t, 4H), 2.56 (s, 3H), 2.43 (s, 2H), 1.14 (s, 6H); FAB-MS m/z:395.2 (M ++ 1); Ultimate analysis: calculated value C 66.99, H 6.64, and N 14.20; Measured value C 66.74, and H 6.47, and N 14.05.
Embodiment 28
(1-(4-(2-hydroxyethyl) piperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-28)
Figure A20061008749500472
2-(1-(4-(2-hydroxyethyl) piperazine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 4-(2-hydroxyethyl) piperazine obtain by the synthetic method of embodiment 2 is synthetic, productive rate 63%, fusing point 127-129 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 8.01-8.03 (d, 1H), 7.48 (s, 1H), 7.18-7.20 (d, 1H), 3.86 (b, 2H), 3.58 (b, 4H), 2.83 (s, 2H), 2.63 (b, 4H), 2.56 (t, 2H), 2.565 (s, 3H), 2.43 (s, 2H), 1.14 (s, 6H).
The synthetic method of 2-(1-(4-(2-hydroxyethyl) piperazine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 60%, fusing point 155-157 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.22 (b, 1H), 8.22-8.24 (d, 1H), 7.57 (s, 1H), 7.29-7.31 (d, 1H), 6.21 (b, 1H), 3.93 (b, 2H), 3.68 (b, 4H), 2.84 (s, 2H), 2.72 (b, 4H), 2.64 (t, 2H), 2.56 (s, 3H), 2.43 (s, 2H), 1.14 (s, 6H); FAB-MS m/z:426.2 (M ++ 1); Ultimate analysis: calculated value C 64.92, H 7.34, and N 16.46; Measured value C 64.78, and H 7.17, and N 16.28.
Embodiment 29
(2-(4-morpholine) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(2-morpholin-4-yl-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-29)
Figure A20061008749500481
2-(2-(4-morpholine) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen synthetic (1-(3,6 by 2-chloro-4-, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 2-(4-morpholine) ethamine obtain by the synthetic method of embodiment 2 is synthetic, productive rate 68.5%, fusing point 132-134 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.72-7.74 (d, 1H), 7.34 (s, 1H), 7.08-7.09 (d, 1H), 4.02 (b, 1H), 3.76-3.78 (t, 4H), 3.36-3.38 (t, 2H), 2.88-2.90 (t, 4H), 2.84 (s, 2H), 2.58 (t, 2H), 2.54 (s, 3H), 2.43 (s, 2H), 1.13 (s, 6H).
The synthetic method of 2-(2-(4-morpholine) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 78%, fusing point 167-169 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.22 (b, 1H), 8.24-8.26 (d, 1H), 7.45 (s, 1H), 7.29-7.31 (d, 1H), 6.03 (b, 1H), 4.03 (b, 1H), 3.78-3.80 (t, 4H), 3.37-3.39 (t, 2H), 2.89-2.91 (t, 4H), 2.83 (s, 2H), 2.57 (t, 2H), 2.53 (s, 3H), 2.43 (s, 2H), 1.14 (s, 6H); FAB-MS m/z:426.2 (M ++ 1); Ultimate analysis: calculated value C 64.92, H 7.34, and N 16.46; Measured value C 64.75, and H 7.21, and N 16.28.
Embodiment 30
(1-(4-(1-pyrrolidyl) piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(4-pyrrolidin-1-yl-piperidin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-30)
Figure A20061008749500491
2-(1-(4-(1-pyrrolidyl) piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 4-(1-pyrrolidyl) piperidines obtain by the synthetic method of embodiment 2 is synthetic, productive rate 54.4%, fusing point 129-131 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.64-7.66 (d, 1H), 7.25 (s, 1H), 7.00-7.02 (d, 1H), 2.99-3.03 (b, 6H), 2.84 (s, 2H), 2.75 (b, 3H), 2.56 (s, 3H), 2.43 (s, 2H), 2.12 (b, 2H), 1.89 (b, 6H), 1.14 (s, 6H).
2-(1-(4-(1-pyrrolidyl) piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide synthetic method is with embodiment 3, productive rate 54%, fusing point 143-145 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.24 (b, 1H), 8.24-8.26 (d, 1H), 7.48 (s, 1H), 7.21-7.23 (d, 1H), 5.77 (b, 1H), and 3.32-3.35 (d, 2H), 2.86-2.91 (m, 3H), 2.85 (s, 2H), 2.69 (b, 4H), 2.58 (s, 3H), 2.43 (s, 2H), 2.15-2.22 (d, 2H), 1.82-1.88 (b, 6H), 1.14 (s, 6H); 13CNMR (500MHz, CDCl 3), δ (ppm): 193.42,167.51,153.21,150.32,149.10,141.64,132.78,126.62,117.90,117.42,115.59,60.99,52.64,52.36,51.74,37.55,35.89,32.08,28.43,23.22,13.41; FAB-MS m/z:450.3 (M ++ 1); Ultimate analysis: calculated value C 69.46; H 7.85; N 15.58; Measured value C 69.24, and H 7.58, and N 15.37.
Embodiment 31
(1-(4-(2-(4-morpholine) ethyl) piperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-31)
Figure A20061008749500501
2-(1-(4-(2-(4-morpholine) ethyl) piperazine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 4-(2-(4-morpholine) ethyl) piperazine obtain by the synthetic method of embodiment 2 is synthetic, productive rate 59.6%, fusing point 99-101 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.66-7.68 (d, 1H), 7.23 (s, 1H), 7.05-7.07 (d, 1H), 3.73-3.75 (t, 4H), 3.35-3.37 (t, 4H), 2.93 (b, 4H), 2.84 (s, 2H), 2.75-2.77 (t, 4H), 2.56 (s, 3H), 2.53 (b, 4H), 2.44 (s, 2H), 1.14 (s, 6H).
The synthetic method of 2-(1-(4-(2-(4-morpholine) ethyl) piperazine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 53.2%, fusing point 128-130 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.20 (b, 1H), 8.25-8.27 (d, 1H), 7.48 (s, 1H), 7.26-7.28 (d, 1H), 5.82 (b, 1H), 3.78 (b, 4H), 3.10-3.15 (b, 4H), 2.85 (s, 2H), 2.50-2.75 (b, 12H), 2.58 (s, 3H), 2.44 (s, 2H), 1.14 (s, 6H); 13CNMR (500MHz, CDCl 3), δ (ppm): 193.32,167.60,152.73,150.32,149.02,141.81,132.83,126.55,118.27,117.45,115.60,66.93,56.42,55.51,54.15,54.01,53.30,52.33,37.53,35.87,28.42,13.38; FAB-MS m/z:495.3 (M ++ 1); Ultimate analysis: calculated value C 65.56, H 7.74, and N 16.99; Measured value C 65.37, and H 7.54, and N 16.86.
Embodiment 32
(1-(4-hydroxy piperidine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(4-hydroxy-piperidin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-32)
Figure A20061008749500502
4-hydroxy piperidine acetic ester (piperidi-4-yl acetate) be according to document (J.Med.Chem., 2005,48, method 2577-2583) is synthesized gained, productive rate 45.8% (three step); 1HNMR (500MHz, CDCl 3), δ (ppm): 4.83-4.87 (m, 1H), 3.07-3.12 (q, 2H), 2.72-2.77 (q, 2H), 2.11 (s, 1H), 2.07 (s, 3H), 1.92-1.94 (m, 2H), 1.56-1.60 (m, 2H).
2-(1-(4-acetoxyl group piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 4-acetoxyl group piperidines obtain by the synthetic method of embodiment 2 is synthetic, productive rate 26.6%, fusing point (oily matter); 1HNMR (500MHz, CDCl 3), δ (ppm): 7.66-7.68 (d, 1H), 7.29 (s, 1H), 7.02-7.04 (d, 1H), 5.00-5.02 (m, 1H), 3.50-3.53 (m, 2H), 3.21-3.24 (m, 2H), 2.84 (s, 2H), 2.56 (s, 3H), 2.43 (s, 2H), 2.10-2.15 (m, 2H), 2.10 (s, 3H), 1.95-1.97 (m, 2H), 1.14 (s, 6H).
The synthetic method of 2-(1-(4-hydroxy piperidine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 35.8%, 100 ℃ of fusing points (decomposition); 1HNMR (500MHz, CDCl 3), δ (ppm): 9.31 (b, 1H), 8.25-8.27 (d, 1H), 7.52 (s, 1H), 7.24-7.26 (d, 1H), 6.01 (b, 1H), 3.97 (m, 1H), 3.30 (m, 2H), 2.96 (m, 2H), 2.85 (s, 2H), 2.57 (s, 3H), 2.43 (s, 2H), 2.11 (m, 2H), 1.82 (m, 2H), 1.14 (s, 6H); FAB-MS m/z:397.2 (M ++ 1); Ultimate analysis: calculated value C 66.64, H 7.12, and N 14.13; Measured value C 66.42, and H 6.89, and N 14.06.
Embodiment 33
(1-(4-glycyl oxygen phenylpiperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide 2-(4-Aminoacetyloxy-piperidin-1-yl)-4-(3,6,6-trimethyl4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-33)
Figure A20061008749500511
In reaction flask, add Compound I-32 (embodiment 32 prepares) (120mg, 0.3mmol), methylene dichloride (10mL), N, N-dipropyl ethamine (0.1mL), BOC-glycine-acyl chlorides (60mg, 0.3mmol).Reactant at room temperature stirs and spends the night.The product dichloromethane extraction, saturated sodium-chloride water solution washing, anhydrous magnesium sulfate drying.Filter and remove solid and solvent, residue is dissolved in methylene dichloride (20mL), adds trifluoroacetic acid (4mL), stirring at room 2 hours, and removal of solvent under reduced pressure is used dichloromethane extraction, saturated NaHCO 3The aqueous solution, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying, product obtains 2-behind silica gel column chromatography separating purification (1-(4-glycyl oxygen phenylpiperidines))-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide 86mg, productive rate 63%, 135137 ℃ of fusing points; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.24 (b, 1H), 8.03-8.05 (d, 1H), 7.21-7.23 (s, 1H), 6.92-6.94 (d, 1H), 6.00 (b, 1H), 4.04 (m, 1H), 3.64 (t, 2H), 2.93 (m, 2H), 2.83 (s, 2H), 2.57 (s, 3H), 2.45 (s, 2H), 1.86 (m, 2H), 1.78 (m, 2H), 1.13 (s, 6H); FAB-MS m/z:454.2 (M ++ 1); Ultimate analysis: calculated value C 63.56, H 6.89, and N 15.44; Measured value C 63.37, and H 6.77, and N 15.37.
Embodiment 34
(4-hydroxyl hexamethylene amino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(4-hydroxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-34)
Figure A20061008749500521
2-(4-hydroxyl hexamethylene amino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 4-Trans-4-Amino Cyclohexanol obtain by the synthetic method of embodiment 2 is synthetic, productive rate 51.6%, fusing point 105-107 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.45-7.47 (d, 1H), 7.12-7.14 (d, 1H), 6.93-6.95 (d, 1H), 3.06 (b, 1H), 3.67 (m, 1H), 2.83 (s, 2H), 2.55 (s, 3H), 2.44 (s, 2H), 1.73 (b, 4H), 1.59 (b, 4H), 1.13 (s, 6H).
2-(4-hydroxyl hexamethylene amino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide synthetic method is with embodiment 3, productive rate 63.8%, fusing point 118-120 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.22 (b, 1H), 7.61-7.63 (d, 1H), 7.17-7.19 (d, 1H), 6.96-6.98 (s, 1H), 6.03 (b, 1H), 4.07 (m, 1H), 3.95 (m, 1H), 2.89 (m, 1H), 2.83 (s, 2H), 2.55 (s, 3H), 2.44 (s, 2H), 1.74 (b, 4H), 1.62 (b, 4H), 1.13 (s, 6H); FAB-MS m/z:411.2 (M ++ 1); Ultimate analysis: calculated value C 67.29, H 7.37, and N 13.65; Measured value C 66.94, and H 7.13, and N 13.75.
Embodiment 35
(oneself is amino for 4-glycyl oxygen basic ring)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(4-aminoacetyloxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-35)
Figure A20061008749500531
2-(oneself is amino for 4-glycyl oxygen basic ring)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide synthetic (4-hydroxyl hexamethylene amino)-(1-(3,6 for 4-by 2-, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) it is synthetic that benzamide (embodiment 34) and BOC-glycine-acyl chlorides are pressed the method for embodiment 33, productive rate 75%, fusing point 173-175 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.22 (b, 1H), 8.20-8.22 (d, 1H), 7.45-7.47 (d, 1H), 7.24-7.26 (s, 1H), 6.03 (b, 1H), 4.04 (m, 1H), 3.76 (t, 2H), 3.44 (m, 1H), 2.88 (m, 1H), 2.84 (s, 2H), 2.56 (s, 3H), 2.43 (s, 2H), 1.73 (b, 4H), 1.64 (b, 4H), 1.14 (s, 6H); FAB-MS m/z:468.3 (M ++ 1); Ultimate analysis: calculated value C 64.22, H 7.11, and N 14.98; Measured value C 63.93, and H 6.97, and N 15.07.
Embodiment 36
(2-(1-pyrrolidyl) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(2-pyrrolidin-1-yl-ethylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-36)
2-(2-(1-pyrrolidyl) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 2-(1-pyrrolidyl) ethamine obtain by the synthetic method of embodiment 2 is synthetic, productive rate 53%, fusing point 112-113 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.78-7.80 (d, 1H), 7.41 (s, 1H), 7.12-7.14 (d, 1H), 4.03 (b, 1H), 3.47-3.49 (t, 2H), 2.84 (s, 2H), 2.68 (t, 2H), 2.55 (s, 3H), 2.42 (s, 2H), 2.33-2.35 (t, 4H), 1.63-1.65 (m, 4H), 1.14 (s, 6H).
The synthetic method of 2-(2-(1-pyrrolidyl) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 52%, fusing point 144-146 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.23 (b, 1H), 8.06-8.08 (d, 1H), 7.46 (s, 1H), 7.24-7.26 (d, 1H), 6.18 (b, 1H), 4.05 (b, 1H), 3.51-3.53 (t, 2H), 2.84 (s, 2H), 2.70 (t, 2H), 2.56 (s, 3H), 2.43 (s, 2H), 2.37-2.39 (t, 4H), 1.68-1.70 (m, 4H), 1.14 (s, 6H); FAB-MS m/z:410.2 (M ++ 1); Ultimate analysis: calculated value C 67.46, H 7.63, and N 17.10; Measured value C 67.29, and H 7.48, and N 16.98.
Embodiment 37
2-(1-piperazine)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-piperazin-1-yl-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-37)
Figure A20061008749500541
2-(1-piperazine)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 4-tertbutyloxycarbonyl (t-BOC) piperazine synthetic by the synthetic method of embodiment 2, obtain after removing t-BOC with trifluoroacetic acid again, productive rate 49%, fusing point 109-111 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 8.04-8.06 (d, 1H), 7.43 (s, 1H), 7.13-7.15 (d, 1H), 3.76-3.78 (b, 4H), 2.97-2.99 (m, 4H), 2.84 (s, 2H), 2.56 (s, 3H), 2.43 (s, 2H), 1.14 (s, 6H).
The synthetic method of 2-(1-piperazine)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 46%, fusing point 144-146 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.23 (b, 1H), 8.23-8.25 (d, 1H), 7.54 (s, 1H), 7.25-7.27 (d, 1H), 6.11 (b, 1H), 3.80-3.82 (b, 4H), 2.96-2.98 (b, 4H), 2.84 (s, 2H), 2.57 (s, 3H), 2.44 (s, 2H), 1.15 (s, 6H); FAB-MSm/z:382.2 (M ++ 1); Ultimate analysis: calculated value C 66.12, H 7.13, and N 18.36; Measured value C 65.93, H6.86, and N 18.25.
Embodiment 38
(1-(3-hydroxyl pyrrolidine base))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(3-hydroxy-pyrrolidin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-bnzamide) synthetic.(structural formula I-38)
Figure A20061008749500551
2-(1-(3-hydroxyl pyrrolidine base))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 3-hydroxyl pyrrolidine obtain by the synthetic method of embodiment 2 is synthetic, productive rate 78%, fusing point 137-139 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.74-7.76 (d, 1H), 7.38 (s, 1H), 7.07-7.09 (d, 1H), 3.57 (m, 1H), 3.17-3.19 (b, 2H), 2.99-3.01 (t, 2H), 2.84 (s, 2H), 2.56 (s, 3H), 2.42 (s, 2H), 1.79-1.81 (t, 2H), 1.14 (s, 6H).
The synthetic method of 2-(1-(3-hydroxyl pyrrolidine base))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 57%, fusing point 169-171 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.23 (b, 1H), 8.26-8.28 (d, 1H), 7.52 (s, 1H), 7.17-7.19 (d, 1H), 6.20 (b, 1H), 3.53 (m, 1H), 3.23-3.25 (b, 2H), 3.01-3.03 (t, 2H), 2.84 (s, 2H), 2.57 (s, 3H), 2.43 (s, 2H), 1.80-1.82 (t, 2H), 1.15 (s, 6H); FAB-MS m/z:383.2 (M ++ 1); Ultimate analysis: calculated value C 65.95, H 6.85, and N 14.65; Measured value C 65.76, and H 6.67, and N 14.46.
Embodiment 39
(1-(4-(4-morpholine) piperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(4-morpholin-4-yl-piperidin-1-yl)-4-(3,6,6-trimethyl-4-oxo4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-39)
Figure A20061008749500552
2-(1-(4-(4-morpholine) piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 4-(4-morpholine) piperidines obtain by the synthetic method of embodiment 2 is synthetic, productive rate 77%, fusing point 183-184 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.73-7.75 (d, 1H), 7.25 (s, 1H), 7.07-7.09 (d, 1H), 3.76-3.78 (t, 4H), 3.28-3.30 (t, 4H), 2.87-2.89 (t, 4H), 2.84 (s, 2H), 2.67 (m, 1H), 2.56 (s, 3H), 2.43 (s, 2H), 1.73-1.75 (m, 4H), 1.14 (s, 6H).
The synthetic method of 2-(1-(4-(4-morpholine) piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 61%, fusing point 218-220 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.22 (b, 1H), 8.24-8.26 (d, 1H), 7.45 (s, 1H), 7.25-7.27 (d, 1H), 6.02 (b, 1H), and 3.78-3.80 (t, 4H), 3.31-3.33 (t, 4H), 2.89-2.91 (t, 4H), 2.83 (s, 2H), 2.67 (m, 1H), 2.57 (s, 3H), 2.43 (s, 2H), 1.73-1.75 (m, 4H), 1.14 (s, 6H); FAB-MS m/z:466.3 (M ++ 1); Ultimate analysis: calculated value C 67.07, H 7.58, and N 15.04; Measured value C 66.78, and H 7.41, and N 14.79.
Embodiment 40
(1-(3-hydroxy piperidine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(3-hydroxy-piperidin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-40)
Figure A20061008749500561
2-(1-(3-hydroxy piperidine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 3-hydroxy piperidine obtain by the synthetic method of embodiment 2 is synthetic, productive rate 46.8%, fusing point 142-144 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.75-7.77 (d, 1H), 7.41 (s, 1H), 7.04-7.06 (d, 1H), 3.46 (m, 1H), 3.14-3.16 (b, 2H), 2.93-2.95 (t, 2H), 2.84 (s, 2H), 2.56 (s, 3H), 2.43 (s, 2H), 1.49-1.71 (m, 4H), 1.14 (s, 6H).
The synthetic method of 2-(1-(3-hydroxy piperidine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 68%, fusing point 162-164 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.21 (b, 1H), 8.23-8.25 (d, 1H), 7.49 (s, 1H), 7.14-7.16 (d, 1H), 6.17 (b, 1H), 3.48 (m, 1H), 3.17-3.19 (b, 2H), 3.00-3.02 (t, 2H), 2.85 (s, 2H), 2.57 (s, 3H), 2.43 (s, 2H), 1.49-1.71 (m, 4H), 1.14 (s, 6H); FAB-MS m/z:397.2 (M ++ 1); Ultimate analysis: calculated value C 66.64, H 7.12, and N 14.13; Measured value C 66.57, and H 6.87, and N 13.93.
Embodiment 41
2-(2-(6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline))-and 4-(1-(3,6,6-trimethylammonium-4 oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (2-(6 for benzamide, 7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-and 4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-41)
2-(2-(6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline))-and 4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen by 2-chloro-4-(1-(and 3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline obtains productive rate 75%, fusing point 179-181 ℃ by the synthetic method of embodiment 2 is synthetic; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.87-7.89 (d, 1H), 7.47 (s, 1H), 7.11-7.13 (d, 1H), 6.58 (s, 1H), 6.65 (s, 1H), 4.72 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 3.66 (t, 2H), 2.92-2.94 (t, 2H), 2.84 (s, 2H), 2.56 (s, 3H), 2.43 (s, 2H), 1.14 (s, 6H).
The synthetic method of 2-(2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 84%, fusing point 222-224 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.26 (b, 1H), 8.27-8.29 (d, 1H), 7.53 (s, 1H), 7.24-7.26 (d, 1H), 6.67 (s, 1H), 6.62 (s, 1H), 6.21 (b, 1H), 4.76 (s, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.71 (t, 2H), 2.93-2.95 (t, 2H), 2.85 (s, 2H), 2.57 (s, 3H), 2.43 (s, 2H), 1.15 (s, 6H); FAB-MS m/z:489.2 (M ++ 1); Ultimate analysis: calculated value C 68.83, H 6.60, and N 11.47; Measured value C 68.75, and H 6.46, and N 11.35.
Embodiment 42
(1-(4-(2-pyridine) piperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-(4-pyridin-2-yl-piperazin-1-yl)-4-(3,6,6trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-42)
2-(1-(4-(2-pyridine) piperazine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) (1-(3,6 by 2-chloro-4-for benzene cyanogen, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and 4-(2-pyridine) piperazine obtain by the synthetic method of embodiment 2 is synthetic, productive rate 69.4%, fusing point 147-149 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 8.25 (d, 1H), 7.84 (d, 1H), 7.76-7.78 (d, 1H), 7.41 (s, 1H), 7.07-7.09 (d, 1H), 6.86 (d, 1H), 6.69 (d, 1H), 3.75-3.78 (t, 4H), 3.43-3.45 (t, 4H), 2.84 (s, 2H), 2.56 (s, 3H), 2.43 (s, 2H), 1.14 (s, 6H).
The synthetic method of 2-(1-(4-(2-pyridine) piperazine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 63%, fusing point 174-176 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.27 (b, 1H), 8.29-8.31 (d, 1H), 8.21-8.23 (d, 1H), 8.06-8.08 (d, 1H), 7.53 (s, 1H), 7.12-7.14 (d, 1H), 6.92 (d, 1H), 6.76 (d, 1H), 3.78-3.80 (t, 4H), 3.45-3.47 (t, 4H), 2.86 (s, 2H), 2.57 (s, 3H), 2.45 (s, 2H), 1.16 (s, 6H); FAB-MSm/z:459.2 (M ++ 1); Ultimate analysis: calculated value C 68.10, H 6.59, and N 18.33; Measured value C 67.88, H6.45, and N 18.27.
Embodiment 43
2-(1-piperidines)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-piperidin-1-yl-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-43)
2-(1-piperidines)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen synthetic (1-(3,6 by 2-chloro-4-, 6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen (embodiment 1) and piperidines obtain by the synthetic method of embodiment 2 is synthetic, productive rate 63.9%, fusing point 76-77 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.67-7.69 (d, 1H), 7.46 (s, 1H), 7.12-7.13 (d, 1H), 3.36 (b, 4H), 2.86 (s, 2H), 2.57 (s, 3H), 2.44 (s, 2H), 1.89 (b, 4H), 1.69 (b, 2H), 1.15 (s, 6H).
2-(1-piperidines)-4-(1-(3,6,6-trimethylammonium-4-oxygen 4,5,6,7-tetrahydrochysene indazole)) benzamide synthetic method is with embodiment 3, productive rate 49.4%, fusing point 122-124 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.40 (b, 1H), 8.19-8.21 (d, 1H), 7.42 (s, 1H), 7.18-7.20 (d, 1H), 6.33 (b, 1H), 2.97 (b, 4H), 2.82 (s, 2H), 2.51 (s, 3H), 2.37 (s, 2H), 1.75 (b, 4H), 1.59 (b, 2H), 1.08 (s, 6H); 13CNMR (500MHz, CDCl 3), δ (ppm): 193.46,167.83,154.20,150.15,149.14,141.64,132.58,126.52,117.80,117.32,116.09,54.84,52.33,37.43,35.86,28.36,26.46,23.50,13.38; FAB-MS m/z:381.2 (M ++ 1); Ultimate analysis: calculated value C 69.45, H 7.42, and N 14.73; Measured value C 69.40, and H 7.26, and N 14.61.
Embodiment 44
1-(6-(3-amino-1H-indazole))-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone (1-(3-amino-1H-indazol-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one) synthetic.(structural formula I-44)
Adding 2-chloro-4-oil of mirbane cyanogen in reaction flask (1.0g, 5.5mmol), toluene (40mL) and BOC-NHNH 2(0.92g, 7mmol).Reactant was heated with stirring to 100 ℃ of reactions after 2 hours, and solvent is removed in cooling, and residue was dissolved in the dioxane solution of 4N HCl (40mL) and reflux 1 hour.Reaction solution drips 20%NaOH solution and regulates pH=14 under the ice bath cooling, use chloroform extraction, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying.After removing siccative and solvent, residue be dissolved in THF (40mL) and add triethylamine (0.6mL) and (BOC) 2O (1.2g is 5.5mmol) at 0 ℃ of stirring reaction 2 hours to the room temperature.Removal of solvent under reduced pressure is used dichloromethane extraction, 1N NaOH solution washing, saturated sodium-chloride water solution washing, anhydrous magnesium sulfate drying.Removing and obtaining corresponding nitro indazole derivatives behind siccative and the solvent is yellow color solid (TLC shows＞85% purity), solid is dissolved in methyl alcohol (40mL) and add iron powder (0.92g, 17mmol) and glacial acetic acid (0.8mL).Reactant stirring and refluxing 2 hours, cooling is used ethyl acetate extraction in falling back, the saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying is through getting 0.18g, productive rate 13% (four steps) behind the recrystallization purifying. 1HNMR(500MHz，CDCl 3)，δ(ppm)：12.15(b，1H)，8.30(b，1H)，6.95-7.50(m，3H)，3.85(b，2H)，1.30(s，9H)。
(50mg 0.2mmol) joins 5 under 85 ℃, (40mg is in toluene 0.2mmol) (20mL) solution for 5-dimethyl-2-(2-propionic aldehyde base)-hydroresorcinol with above-mentioned products therefrom.Reactant under agitation is heated to 110 ℃ of reactions 1 hour, and solvent decompression is removed in cooling, and residue is dissolved in ethyl acetate (20mL) and adds trifluoroacetic acid (2mL) stirring reaction 2 hours at normal temperatures.Solvent is removed in decompression, product dichloromethane extraction, the 1N NaOH aqueous solution, saturated sodium-chloride water solution washing, anhydrous magnesium sulfate drying.Product after with purification by silica gel column chromatography 18mg, productive rate 29%, fusing point 153-155 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 12.35 (b, 1H), 7.45-7.90 (m, 3H), 6.28 (s, 1H), 4.15 (b, 2H), 2.82 (s, 2H), 2.56 (s, 3H), 2.44 (s, 2H), 1.13 (s, 6H); FAB-MS m/z:309.2 (M ++ 1); Ultimate analysis: calculated value C 70.11, H 6.54, and N 18.17; Measured value C 69.88, and H 6.47, and N 18.21.
Embodiment 45
1-(6-(3-amino-1H-indazole))-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone (1-(3-amino-1H-indazol-6-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indazolyl-4-one) synthetic.(structural formula I-45)
Figure A20061008749500601
Adding 2,4 difluorobenzene cyanogen in reaction flask (0.14g, 1.0mmol), DMF (40mL) and BOC-NHNH 2(0.16g, 1.2mmol), reactant is heated with stirring to 150 ℃ of reactions 12 hours, after the cooling, use dichloromethane extraction, water washing, anhydrous magnesium sulfate drying, product obtains N-BOC-5-fluoro-2-cyano group-phenylhydrazine with purification by silica gel column chromatography, 0.20g, productive rate 80%, fusing point 79-81 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 8.26 (b, 1H), 8.13 (s, 1H), 7.65-7.67 (d, 1H), 7.04-7.06 (d, 1H), 3.93 (b, 1H), 1.39 (s, 9H).
In reaction flask, add 3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone (95mg, 0.5mmol), DMF (15mL), NaH (24mg, 1mmol), reaction was at room temperature stirred 10 minutes, added N-BOC-5-fluoro-2-cyano group-phenylhydrazine (0.13mg of above-mentioned preparation, 0.5mmol), reactant reflux 4 hours is poured into frozen water (50mL) and uses dichloromethane extraction after the cooling, water washing, anhydrous magnesium sulfate drying, product obtains N-BOC-2-cyano group-5-(1-3 with purification by silica gel column chromatography, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole) phenylhydrazine, 0.125g, productive rate 61%, fusing point 136-138 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 8.19 (b, 1H), 7.96 (s, 1H), 7.68-7.69 (d, 1H), 7.09-7.11 (d, 1H), 4.03 (b, 1H), 2.84 (s, 2H), 2.55 (s, 3H), 2.42 (s, 2H), 1.39 (s, 9H), 1.14 (s, 6H).
(0.125g 0.3mmol) is dissolved in the dioxane solution of 4N HCl (20mL) and reflux 1 hour with N-BOC-2-cyano group-5-(1-3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole) phenylhydrazine.Reaction solution drips 20%NaOH solution and regulates pH=14 under the ice bath cooling, use chloroform extraction, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying.Remove solvent, product obtains 1-(6-(3-amino-1H-indazole)-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone, 36mg, productive rate 38.7%, fusing point 184-186 ℃ after with purification by silica gel column chromatography; 1HNMR (500MHz, CDCl 3), δ (ppm): 12.29 (b, 1H), 7.97-7.99 (d, 1H), 7.78-7.80 (b, 1H), 7.63-7.65 (d, 1H), 4.16 (b, 2H), 2.83 (s, 2H), 2.56 (s, 3H), 2.43 (s, 2H), 1.15 (s, 6H); FAB-MS m/z:310.2 (M ++ 1); Ultimate analysis: calculated value C 66.00, H 6.19, and N 22.64; Measured value C 65.76, and H 5.83, and N 22.43.
Embodiment 46
2-(1-(4-hydroxy piperidine))-4-(9-(2,2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide (4-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-2-(4-hydroxy-piperidin-1-yl)-benzamide) synthetic.(structural formula I-46)
According to the synthetic method of embodiment 6, and adding 4-hydroxy piperidine in reaction flask (1.01g, 0.01mol), DMF (100mL) and 2,4 difluorobenzene cyanogen (1.39g, 0.01mol).The reactant stirring heating refluxed 12 hours, cooling back removal of solvent under reduced pressure, and ethyl acetate extraction, washing, anhydrous sodium sulfate drying, product gets 4-fluoro-2-(1-(4-hydroxy piperidine)) benzene cyanogen 1.25g through the ethyl acetate/hexane recrystallization, productive rate 56.8%, 1HNMR (500MHz, CDCl 3), δ (ppm): 7.62-7.64 (d, 1H), 7.27 (b, 1H), 7.09 (d, 1H), 3.88 (m, 1H), 3.45-3.47 (b, 4H), 1.76 (m, 4H).
In reaction flask, add 2,2-dimethyl-1,2,3,9-tetrahydro carbazole-4-ketone (0.21g, 1mmol), DMF (25mL), NaH (0.036g, 1.5mmol).Behind the vigorous reaction, in reaction flask, add 4-fluoro-2-(1-(4-hydroxy piperidine)) benzene cyanogen (0.22g, 1mmol) and reflux 12 hours.After the cooling, removal of solvent under reduced pressure, product dichloromethane extraction, saturated sodium-chloride water solution washing, anhydrous magnesium sulfate drying.Product obtains 2-(1-(4-hydroxy piperidine))-4-(9-(2,2-dimethyl-4-oxygen-1,2,3,4-tetrahydro carbazole)) benzene cyanogen 0.31g, productive rate 75.6%, fusing point 154-156 ℃ after with purification by silica gel column chromatography; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.677.68 (d, 1H), 7.24 (s, 1H), 7.12-7.20 (m, 4H), 6.89-6.91 (d, 1H), 3.78 (m, 1H), 3.25-3.28 (t, 4H), 2.84 (s, 2H), 2.42 (s, 2H), 1.73 (b, 4H), 1.14 (s, 6H).
The synthetic method of 2-(1-(4-hydroxy piperidine))-4-(9-(2,2-dimethyl-4-oxygen-1,2,3,4-tetrahydro carbazole)) benzamide is with embodiment 3, productive rate 75%, fusing point 187-189 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.28 (b, 1H), 8.25-8.27 (d, 1H), 7.45 (s, 1H), 7.31 (d, 1H), 7.21-7.25 (m, 4H), 6.27 (b, 1H), 3.82 (m, 1H), 3.34-3.36 (t, 4H), 2.88 (s, 2H), 2.46 (s, 2H), 1.78 (b, 4H), 1.16 (s, 6H); FAB-MS m/z:451.2 (M ++ 1); Ultimate analysis: calculated value C 69.31, H 6.49, and N 9.33; Measured value C 69.16, and H 6.28, and N 9.16.
Embodiment 47
2-(4-hydroxyl hexamethylene amino)-4-(9-(2,2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide (4-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-2-(4-hydroxy-cyclohexylamino)-benzamide) synthetic.(structural formula I-47)
Figure A20061008749500621
The synthetic method of 2-(4-hydroxyl hexamethylene amino)-4-(9-(2,2-dimethyl-4-oxygen-1,2,3,4-tetrahydro carbazole)) benzamide is with embodiment 46.The first step is by 4-Trans-4-Amino Cyclohexanol and 2, the reaction of 4-two fluorobenzene cyanogen obtains 4-fluoro-2-(4-hydroxyl hexanaphthene amino) benzene cyanogen (productive rate 63%), second goes on foot by 2 2-dimethyl-1,2,3,9-tetrahydro carbazole-4-ketone and 4-fluoro-2-(4-hydroxyl hexanaphthene amino) benzene cyanogen reaction obtain 2-(4-hydroxyl hexamethylene amino)-4-(9-(and 2,2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzene cyanogen (productive rate 47.5%), final step with 2-(4-hydroxyl hexamethylene amino)-4-(9-(and 2,2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzene cyanogen and hydroperoxidation, (4-hydroxyl hexamethylene amino)-(9-(2 for 4-to obtain 2-behind purification by silica gel column chromatography, 2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, productive rate 86%, fusing point 202-204 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.26 (b, 1H), 8.24-8.26 (d, 1H), 7.47 (s, 1H), 7.28-7.30 (d, 1H), 7.19-7.24 (m, 4H), 6.22 (b, 1H), 4.04 (b, 1H), 3.78 (m, 1H), 3.16 (m, 1H), 2.87 (s, 2H), 2.47 (s, 2H), 1.73 (b, 4H), 1.64 (m, 4H), 1.16 (s, 6H); FAB-MS m/z:446.2 (M ++ 1); Ultimate analysis: calculated value C 72.78; H 7.01; N 9.43; Measured value C 72.65, and H 6.87, and N 9.22.
Embodiment 48
(1-(4-(2-hydroxyethyl) piperazine))-(9-(2 for 4-for 2-, 2 dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide (4-(and 2,2-Dimethyl-4-oxo-1,2,3,4-tetrahydro-carbazol-9-yl)-2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-benzamide) synthetic.(structural formula I-48)
Figure A20061008749500631
The synthetic method of 2-(1-(4-(2-hydroxyethyl) piperazine))-4-(9-(2,2-dimethyl-4-oxygen-1,2,3,4-tetrahydro carbazole)) benzamide is with embodiment 46.The first step is by 4-(2-hydroxyethyl) piperazine and 2, the reaction of 4-two fluorobenzene cyanogen obtains 4-fluoro-2-(1-(4-(2-hydroxyl ethane base) piperazine)) benzene cyanogen (productive rate 58%), second step is by 2,2-dimethyl-1,2,3,9-tetrahydro carbazole-4-ketone and 4-fluoro-2-(1-(4-(2-hydroxyl ethane base) piperazine)) benzene cyanogen reaction obtain 2-(1-(4-(2-hydroxyethyl) piperazine))-4-(9-(and 2,2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzene cyanogen (productive rate 65.5%), final step with 2-(1-(4-(2-hydroxyethyl) piperazine))-4-(9-(and 2,2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzene cyanogen and hydroperoxidation, (1-(4-(2-hydroxyethyl) piperazine))-(9-(2 for 4-to obtain 2-behind purification by silica gel column chromatography, 2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, productive rate 74.8%, fusing point 178-180 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.24 (b, 1H), 8.23-8.25 (d, 1H), 7.43 (s, 1H), 7.25-7.27 (d, 1H), 7.21-7.25 (m, 4H), 6.23 (b, 1H), 3.46 (t, 2H), 3.28 (m, 4H), 2.92-2.94 (t, 4H), 2.85 (s, 2H), 2.68 (t, 2H), 1.15 (s, 6H); FAB-MS m/z:461.3 (M ++ 1); Ultimate analysis: calculated value C 70.41, H 7.00, and N 12.16; Measured value C 70.27, and H 6.76, and N 11.94.
Embodiment 49
(1-(4-methylpiperazine))-(9-(2 for 4-for 2-, 2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide (4-(and 2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydro-carbazol-9-yl)-2-(4-methyl-piperazin-1-yl)-benzamide) synthetic.(structural formula I-49)
Figure A20061008749500632
2,2-dimethyl-6-Trifluoromethyl-1,2,3,9-tetrahydro carbazole-4-ketone (2,2-dimethyl-6-trifluoromethyl-1,2,3,9-tetrahydro-carbazol-4-one) according to the method for synthetic intermediate VI with right-trifluoromethyl phenyl hydrazine and 5,5-dimethyl hydroresorcinol is synthesized into, productive rate 64%, fusing point 152-153 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 10.23 (b, 1H), 7.13-7.27 (m, 3H), 2.82 (s, 2H), 2.57 (s, 2H), 1.14 (s, 6H).
By 4-fluoro-2-chlorobenzene cyanogen and 2,2-dimethyl-6-Trifluoromethyl-1,2,3,9-tetrahydro carbazole-4-ketone by the method for embodiment 1 synthetic obtain 2-chloro-4-(9-(and 2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzene cyanogen, productive rate 72%, fusing point 121-123 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.68-7.70 (d, 1H), 7.65-7.67 (s, 1H), 7.47-7.49 (d, 1H), 7.39-7.41 (d, 1H), 7.26-7.28 (s, 1H), 7.18-7.20 (d, 1H), 2.84 (s, 2H), 2.45 (b, 2H), 1.14 (s, 6H).
(9-(2 by 2-chloro-4-, 2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3,4-tetrahydro carbazole)) benzene cyanogen and 4-methylpiperazine are by synthetic 2-(1-(4-methylpiperazine))-4-(9 (2 that obtains of the synthetic method of embodiment 2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzene cyanogen, productive rate 56.5%, fusing point 144-146 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.74-7.76 (d, 1H), 7.58 (s, 1H), 7.07-7.38 (m, 4H), 3.44 (b, 4H), 2.83 (s, 2H), 2.52 (b, 4H), 2.43 (b, 2H), 2.34 (s, 3H), 1.13 (s, 6H).
The synthetic method of 2-(1-(4-methylpiperazine))-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3,4-tetrahydro carbazole)) benzamide is with embodiment 3, productive rate 47.6%, fusing point 165-167 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.23 (b, 1H), 7.57-7.59 (d, 1H), 7.35-7.37 (m, 2H), 7.24 (s, 1H), 7.03-7.05 (m, 2H), 6.06 (b, 1H), 3.35 (b, 4H), 2.83 (s, 2H), 2.64 (b, 4H), 2.44 (s, 2H), 2.38 (s, 3H), 1.14 (s, 6H); FAB-MS m/z:499.2 (M ++ 1); Ultimate analysis: calculated value C 65.05, H 5.86, and N 11.24; Measured value C 64.87, and H 5.65, and N 11.17.
Embodiment 50
(1-(4-hydroxy piperidine))-(9-(2 for 4-for 2-, 2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide (4-(and 2,2-Dimethyl-4-oxo-6-tri-fluoromethyl-1,2,3,4-tetrahydro-carbazol-9-yl)-2-(4-hydroxy-piperidin-1-yl)-benzamide) synthetic.(structural formula I-50)
Figure A20061008749500641
The synthetic method of 2-(1-(4-hydroxy piperidine))-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3,4-tetrahydro carbazole)) benzamide is with embodiment 49.With 2-chloro-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3,4-tetrahydro carbazole)) benzene cyanogen (embodiment 49) (0.11g, 0.25mmol), PdCl 2(7.8mg, 0.036mmol), Pd (OAc) 2(8.08mg, 0.036mmol), t-BuONa (50mg), and dry toluene (5mL).Reaction mixture is heated to 100 ℃ and stirs after 20 minutes, adds 4-hydroxy piperidine (0.1mL) and continue to stir 5.5 hours down at 100 ℃.After the cooling, the solids removed by filtration catalyzer, after the removal of solvent under reduced pressure, product separates with silica gel column chromatography, obtain 2-(1-(4-hydroxy piperidine))-4-(9-(and 2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzene cyanogen, 60mg, productive rate 50%; 2-(1-(4-hydroxy piperidine))-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3,4-tetrahydro carbazole)) the benzene cyanogen that obtains at room temperature is dissolved in DMSO (1mL), adds dehydrated alcohol (4mL), KOH (35mg).Reactant at room temperature stirred 10 minutes, slowly dripped 30% hydrogen peroxide (0.15mL) then, and reaction solution continues at room temperature to stir 120 minutes.In reaction flask, add entry (50mL) and use dichloromethane extraction, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying.Product obtains 2-(1-(4-hydroxy piperidine))-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3,4-tetrahydro carbazole)) benzamide, 36mg, productive rate 57.6%, fusing point 196-198 ℃ with the silica gel column chromatography separation; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.25 (b, 1H), 7.74-7.76 (d, 1H), 7.32-7.34 (m, 2H), 7.22 (s, 1H), 7.04-7.06 (m, 2H), 6.10 (b, 1H), 3.78 (m, 1H), 3.34-3.36 (b, 4H), 2.85 (s, 2H), 2.45 (s, 2H), 1.76 (m, 4H), 1.15 (s, 6H); FAB-MS m/z:500.2 (M ++ 1); Ultimate analysis: calculated value C 64.92, H 5.65, and N 8.41; Measured value C 64.68, and H 5.47, and N 8.23.
Embodiment 51
(4-hydroxyl hexamethylene amino)-(9-(2 for 4-for 2-, 2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide (4-(and 2,2-Dimethyl-4-oxo 6-trifluoromethyl-1,2,3,4-tetrahydro-carbazol-9-yl)-2-(4-hydroxy-cyclohexylamino)-benzamide) synthetic.(structural formula I-51)
Figure A20061008749500651
The synthetic method of 2-(4-hydroxyl hexamethylene amino)-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3,4-tetrahydro carbazole)) benzamide is with embodiment 50.(9-(2 for 2-chloro-4-, 2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) reaction of benzene cyanogen and 4-Trans-4-Amino Cyclohexanol obtains 2-(4-hydroxyl hexamethylene amino)-(9-(2 for 4-, 2-dimethyl-4-oxygen-6 Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzene cyanogen (productive rate 67.4%), 2-(4-hydroxyl hexamethylene amino)-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzene cyanogen and hydrogen peroxide/KOH reaction obtain mutually deserved 2-(4-hydroxyl hexamethylene amino)-4-(9-(and 2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide, productive rate 74%, fusing point 174-176 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.25 (b, 1H), 7.87-7.89 (d, 1H), 7.43-7.45 (m, 2H), 7.25 (s, 1H), 7.07-7.09 (m, 2H), 6.13 (b, 1H), 4.04 (b, 1H), 3.72 (m, 1H), 2.85 (s, 2H), 2.74 (m, 1H), 2.45 (s, 2H), 1.72 (m, 4H), 1.65 (m, 4H), 1.15 (s, 6H); FAB-MS m/z:514.2 (M ++ 1); Ultimate analysis: calculated value C 65.49, H 5.89, and N 8.18; Measured value C 65.35, and H 5.53, and N 8.09.
Embodiment 52
(9-(2 for 2-hexamethylene amino-4-, 2-dimethyl-4-oxygen-3-trifluoromethyl-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (2-cyclohexylamino-4-(and 6,6-dimethyl-4-oxo-3-trifluoromethy1-4,5,6,7tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-52)
Figure A20061008749500661
6,6-dimethyl-3-Trifluoromethyl-1,5,6, the synthetic method of 7-tetrahydrochysene indazole-4-ketone obtains yellow powdery solid with trifluoroacetic anhydride as starting raw material with the synthetic method of intermediate V, productive rate 51%, fusing point 115-117 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 12.98 (b, 1H), 2.84 (s, 2H), 2.55 (s, 2H), 1.12 (s, 6H).
Heavily add 6 to reaction flask, 6-dimethyl-3-Trifluoromethyl-1,5,6, and 7-tetrahydrochysene indazole-4-ketone (0.23g, 1mmol), DMF (20mL), and NaH (36mg, 1.5mmol), stirred 10 minutes, add again 4-fluoro-2-hexanaphthene amino-benzene cyanogen (0.22g, 1mmol), reactant reflux 8 hours, after the cooling reactant is poured in the frozen water, and used ethyl acetate extraction, the saturated sodium-chloride washing, anhydrous magnesium sulfate drying, product behind purification by silica gel column chromatography, obtain 2-hexamethylene amino-4-(9-(and 2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzene cyanogen, 0.22g, productive rate 51%.(9-(2 with products therefrom 2-hexamethylene amino-4-, 2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3,4-tetrahydro carbazole)) benzene cyanogen obtains 2-hexamethylene amino-4-by the method for embodiment 3 (9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide, productive rate 77%, fusing point 167-169 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.23 (b, 1H), 7.78-7.80 (d, 1H), 7.14 (s, 1H), 6.95-6.97 (d, 1H), 6.05 (b, 1H), 4.01 (b, 1H), 3.37 (b, 1H), 2.85 (s, 2H), 2.47 (b, 2H), 1.66 (m, 4H), 1.43-1.52 (m, 6H), 1.14 (s, 6H); FAB-MS m/z:449.2 (M ++ 1); Ultimate analysis: calculated value C 61.60, H 6.07, and N 12.49; Measured value C 61.47, and H 5.87, and N 12.36.
Embodiment 53
(4-hydroxyl hexamethylene amino)-(1-(6 for 4-for 2-, 6-dimethyl-4-oxygen-3-trifluoromethyl-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (4-hydroxy-cyclohexylamino)-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-53)
Figure A20061008749500671
4-fluoro-2-chlorobenzene cyanogen and 6,6-dimethyl-3-Trifluoromethyl-1,5,6,7-tetrahydrochysene indazole-4-ketone by the method for embodiment 1 synthetic obtain 2-chloro-4-(1-(and 6,6-dimethyl-4-oxygen-3-trifluoromethyl-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen, productive rate 68%, fusing point 154-156 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.51-7.53 (d, 1H), 7.43-7.45 (d, 1H), 7.34-7.36 (s, 1H), 2.83 (s, 2H), 2.42 (b, 2H), 1.13 (s, 6H).
(4-hydroxyl hexamethylene amino)-(1-(6 for 4-for 2-, 6-dimethyl-4-oxygen-3-trifluoromethyl-4,5,6, the 7-tetrahydrochysene indazole)) (1-(6 by 2-chloro-4-for benzene cyanogen, 6-dimethyl-4-oxygen-3-trifluoromethyl-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen and 4-Trans-4-Amino Cyclohexanol obtain by the synthetic method of embodiment 2 is synthetic, productive rate 42.6%, fusing point 173-175 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.68-7.70 (d, 1H), 7.12 (s, 1H), 6.87-6.89 (d, 1H), 4.08 (b, 1H), 3.68 (b, 1H), 2.82 (s, 2H), 2.52 (m, 1H), 2.46 (b, 2H), 1.74 (m, 4H), 1.62 (m, 4H), 1.14 (s, 6H).
The synthetic method of 2-(4-hydroxyl hexamethylene amino)-4-(1-(6,6-dimethyl-4-oxygen-3-trifluoromethyl-4,5,6,7-tetrahydrochysene indazole)) benzamide is with embodiment 3, productive rate 56.4%, fusing point 149-151 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.21 (b, 1H), 7.68-7.70 (d, 1H), 7.01 (s, 1H), 6.85-6.97 (d, 1H), 5.97 (b, 1H), 4.02 (b, 1H), 3.54 (b, 1H), 2.84 (s, 2H), 2.53 (m, 1H), 2.47 (b, 2H), 1.69 (m, 4H), 1.58 (m, 4H), 1.13 (s, 6H); FAB-MS m/z:465.2 (M ++ 1); Ultimate analysis: calculated value C 59.47, H 5.86, and N 12.06; Measured value C 59.21, and H 5.59, and N 11.92.
Embodiment 54
N-(2-[1,2,3] the triazole ethyl)-(1-(3 for 4-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (N-(2-[1,2,3] triazol-1-yl-ethyl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-54)
(0.3g 2mmol) joins 2-ethanoyl-5 to the 4-hydrazino-benzoic acid under 85 ℃, (0.36g is in toluene 2mmol) (20mL) solution for 5-dimethyl-hydroresorcinol.Reactant under agitation is heated to 110 ℃ of reactions 1 hour, cooling, and solvent is removed in decompression, product dichloromethane extraction, saturated sodium-chloride water solution washing, anhydrous magnesium sulfate drying.Product after with purification by silica gel column chromatography 4-(1-(3,6,6-trimethylammonium 4-oxygen-4,5,6,7-tetrahydrochysene indazole)) phenylformic acid 0.35g, productive rate 58%, fusing point 176-177 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 11.05 (b, 1H), 7.89-7.92 (d, 2H), 7.54-7.56 (d, 2H), 2.86 (s, 2H), 2.57 (s, 3H), 2.41 (s, 2H), 1.14 (s, 6H).
Under the ice bath cooling, to containing 1H[1,2,3] triazole (0.7g, 0.01mol) and the reaction flask of THF (35mL) in add NaH (0.24g, 0.01mol) and under ice bath cooling, stirred 15 minutes, under the ice bath cooling, add then bromo second cyanogen (bromoacetonitrile) (1.2g, 0.01mol).Reaction was at room temperature stirred 2 hours, decompression place to go solvent, product dichloromethane extraction, saturated sodium-chloride water solution washing, anhydrous magnesium sulfate drying.Filter, decompression place to go solvent obtains oily product 0.76g after the vacuum-drying.This product is dissolved in THF (35mL), slowly adds LiAlH under stirring 4(0.38g 0.01mol), waits after the vigorous reaction, and reaction mixture reflux 1 hour after the cooling, adds 1N NaOH (2mL) and anhydrous Na 2SO 4(2g) and stirred 30 minutes, filter, filtrate decompression is drained.Crude product purification by silica gel column chromatography, chloroform/methanol/triethylamine (7: 3: 0.1) wash-out obtain 2-(1,2, the 3-triazole) ethamine 0.36g, productive rate 32% (two steps); 1HNMR (500MHz, CDCl 3), δ (ppm): 7.75-7.77 (d, 1H), 7.61-7.63 (d, 1H), 4.26-4.28 (b, 2H), 3.33 (m, 2H), 2.25 (b, 2H).
In reaction flask, add 4-(1-(3,6,6-trimethylammonium 4-oxygen 4,5,6,7-tetrahydrochysene indazole)) phenylformic acid (0.3g, 1mmol), methylene dichloride (30mL), and thionyl chloride (5mL).Reactant at room temperature stirred 2 hours, and it is Vandyke brown liquid 0.3g that the removal solvent obtains corresponding 4-(1-(3,6,6-trimethylammonium 4-oxygen-4,5,6,7-tetrahydrochysene indazole)) Benzoyl chloride, productive rate 93%.
The 4-of the above-mentioned preparation of adding in reaction flask (1-(3,6,6-trimethylammonium 4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) Benzoyl chloride (32mg, 0.1mmol), methylene dichloride (20mL), 2-(1,2, the 3-triazole) ethamine (12mg, 0.1mmol), triethylamine (0.1mL).Reaction was at room temperature stirred 1 hour, and product extracts with methylene dichloride (30mL), 1N NaOH washing, saturated sodium-chloride water solution washing, anhydrous magnesium sulfate drying.Thick product obtains N-(2-[1,2,3] triazole ethyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole) with purification by silica gel column chromatography) benzamide 25mg, productive rate 64%; Fusing point 143-145 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 8.12 (b, 1H), 7.94-7.96 (d, 2H), 7.71-7.73 (m, 2H), 7.47-7.49 (d, 2H), 4.47-4.49 (b, 2H), 3.66-3.68 (b, 2H), 2.83 (s, 2H), 2.54 (s, 3H), 2.39 (s, 2H), 1.13 (s, 6H); FAB-MSm/z:393.2 (M ++ 1); Ultimate analysis: calculated value C 64.27, H 6.16, and N 21.41; Measured value C 64.14, and H 5.87, and N 21.68.
Embodiment 55:
N (2-(4-morpholine) ethyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (N-(2-morpholin-4-yl-ethyl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-55)
Figure A20061008749500691
N-(2-(4-morpholine) ethyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) synthetic method of benzamide is with embodiment 54, productive rate 58%, fusing point 77-79 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 8.12 (b, 1H), 8.02-8.04 (d, 2H), 7.57-7.59 (m, 2H), 3.86-3.88 (m, 4H), 3.56 (t, 2H), 3.24 (t, 2H), 2.84 (s, 2H), 2.62 (b, 2H), 2.56 (s, 3H), 2.43 (s, 2H), 1.14 (s, 6H); FAB-MS m/z:411.2 (M ++ 1); Ultimate analysis: calculated value C 67.29, H 7.37, and N 13.65; Measured value C 67.11, and H 7.02, and N 13.52.
Embodiment 56
N-(4-hydroxy-cyclohexyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (N-(4-hydroxy-cyclohexyl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.(structural formula I-56)
Figure A20061008749500701
N-(4-hydroxy-cyclohexyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) synthetic method of benzamide is with embodiment 54, productive rate 66%, fusing point 89-91 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 8.08 (b, 1H), 7.92-7.94 (d, 2H), 7.62-7.64 (m, 2H), 3.68 (m, 1H), 3.46 (m, 1H), 2.85 (s, 2H), 2.57 (s, 3H), 2.43 (s, 2H), 1.86 (m, 4H), 1.68 (m, 4H), 1.14 (s, 6H); FAB-MS m/z:396.2 (M ++ 1); Ultimate analysis: calculated value C 69.85, H 7.39, and N 10.62; Measured value C 69.68, and H 7.15, and N 10.44.
Embodiment 57
(2-(1-(4-hydroxy piperidine)) ethyl)-(1-(3 for 4-for N-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide (N-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide) synthetic.
(structural formula I-57)
Figure A20061008749500702
N-(2-(1-(4-hydroxy piperidine)) ethyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) synthetic method of benzamide is with embodiment 54, productive rate 42%, fusing point (oily matter) ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 8.08 (b, 1H), 7.85-7.87 (d, 2H), 7.68-7.70 (m, 2H), 4.03 (m, 1H), 3.79-3.81 (b, 2H), 3.34 (m, 2H), 3.03 (m, 2H), 2.84 (s, 2H), 2.69 (b, 2H), 2.56 (s, 3H), 2.44 (s, 2H), 2.13 (m, 2H), 1.68 (m, 2H), 1.13 (s, 6H); FAB-MS m/z:425.3 (M ++ 1); Ultimate analysis: calculated value C 67.90, H 7.60, and N 13.20; Measured value C 67.72, and H 7.43, and N 13.02.
Embodiment 58
5-(1-(2,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) pyridine-2-carboxamide (5-(2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-pyridine-2-carboxylic acid amide) synthetic.(structural formula I-58)
Figure A20061008749500711
With 5, (0.1g 1mmol) is dissolved in toluene (20mL) to 5-dimethyl-2-(2-oxygen-propyl group)-hydroresorcinol, is heated to 85 ℃, adds 5-amino-2-cyanopyridine (0.12g, 1mmol)), and temperature of reaction rises to 110 ℃, and stirs 2h.After the cooling, with removal of solvents, product obtains 5-(1-(2,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole))-2-cyanopyridine, 0.13g, productive rate 46% with purification by silica gel column chromatography; Fusing point 63-65 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.12 (s, 1H), 8.54-8.56 (d, 1H), 8.318.33 (d, 1H), 6.45-6.47 (s, 1H), 2.84 (s, 2H), 2.56 (s, 3H), 2.43 (s, 2H), 1.14 (s, 6H).
The above-mentioned product that obtains handled by the synthetic method of embodiment 3 obtain 5-(1-(2,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) pyridine-2-carboxamide, productive rate 57.6%; Fusing point 87-89 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.22 (b, 1H), 8.87 (s, 1H), 8.61-8.63 (d, 1H), 8.35-8.37 (d, 1H), 6.31 (s, 1H), 5.97 (b, 1H), 2.83 (s, 2H), 2.55 (s, 3H), 2.44 (s, 2H), 1.14 (s, 6H); FAB-MS m/z:298.2 (M ++ 1); Ultimate analysis: calculated value C 68.67, H 6.44, and N 14.13; Measured value C 68.64, and H 6.07, and N 14.24.
Embodiment 59
2-bromo-4-(1-(4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen 2-Bromo-4-(4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitri le synthetic.(structural formula I-59)
Figure A20061008749500712
Synthetic method is with embodiment 1, productive rate 40%, fusing point 92-94 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.31-7.73 (m, 3H), 6.84 (d, 1H), 6.66 (d, 1H), 2.59 (t, 2H), 2.40 (t, 2H), 1.89 (m 2H).
Embodiment 60
2-bromo-4-(1-(4-oxygen-4,5,6,7-tetrahydro indole) methyl) benzene cyanogen 2-Bromo-4-(4-oxo-4,5,6,7-tetrahydro-indol-1-ylmethyl)-benzonitrile synthetic.(structural formula I-60)
Figure A20061008749500721
Synthetic method is with embodiment 1, productive rate 38%, fusing point 97-99 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.18-7.41 (m, 3H), 6.48 (d, 1H), 6.39 (d, 1H), 5.11 (s, 2H), 2.59 (t, 2H), 2.40 (t, 2H), 1.89 (m 2H).
Embodiment 61:
2-bromo-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen 2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile synthetic.
(structural formula I-61)
Figure A20061008749500722
Synthetic method is with embodiment 1, productive rate 45%, fusing point 87-89 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.30-7.45 (m, 3H), 6.50 (s, 1H), 2.51 (s, 2H), 2.32 (s, 2H), 2.05 (s, 3H), 1.11 (s 6H).
Embodiment 62
2-bromo-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole) methyl) benzene cyanogen 2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-ylmethyl)-benzonitrile (structural formula I-62)
Synthetic method is with embodiment 1, productive rate 35%, fusing point 85-87 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.18-7.41 (m, 3H), 6.05 (s, 1H), 5.11 (s, 2H), 2.52 (s, 2H), 2.32 (s, 2H), 2.05 (s, 3H), 1.14 (s 6H).
Embodiment 63
2-bromo-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide 2-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide synthetic.
(structural formula I-63)
Figure A20061008749500732
With Compound I-61 is raw material, and synthetic method is with embodiment 3, productive rate 85%, fusing point 96-98 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.41-7.80 (m, 3H), 6.50 (s, 1H), 2.52 (s, 2H), 2.33 (s, 2H), 2.04 (s, 3H), 1.16 (s 6H); FAB-MS m/z:374.1 (M ++ 1).
Embodiment 64
2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6,7-tetrahydro indole)) benzene cyanogen 2-Bromo-4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzonitrile synthetic.(structural formula I-64)
Figure A20061008749500733
Synthetic method is with embodiment 1, productive rate 45%, fusing point 86-88 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.40-7.61 (m, 3H), 6.50 (s, 1H), 2.59 (t, 2H), 2.40 (t, 2H), 2.05 (s, 3H), 1.89 (m 2H).
Embodiment 65
2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6,7-tetrahydro indole) methyl) benzene cyanogen 2-Bromo-4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-indol-1-ylmethyl)-benzonitrile synthetic.(structural formula I-65)
Synthetic method is with embodiment 1, productive rate 38%, fusing point 76-78 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.18-7.41 (m, 3H), 6.05 (s, 1H), 5.11 (s, 2H), 2.59 (t, 2H), 2.40 (t, 2H), 2.05 (s, 3H), 1.88 (m 2H).
Embodiment 66
2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzene cyanogen 2-Bromo-4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile synthetic.(structural formula I-66)
Synthetic method is with embodiment 1, productive rate 38%, fusing point 96-99 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.43-7.67 (m, 3H), 2.79 (s, 3H), 2.55 (t, 2H), 2.40 (t, 2H), 1.98 (m 2H).
Embodiment 67
2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6,7-tetrahydrochysene indazole) methyl) benzene cyanogen 2-Bromo-4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-ylmethyl)-benzonitrile synthetic.(structural formula I-67)
Synthetic method is with embodiment 1, productive rate 47%, fusing point 95-97 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 7.18-7.41 (m, 3H), 4.99 (s, 2H), 2.79 (s, 3H), 2.55 (t, 2H), 2.40 (t, 2H), 1.95 (m 2H).
Embodiment 68
(1-(4-(2-hydroxyethyl) piperazine))-(1-(3 for 6-for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) VITAMIN PP 4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-6-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-nicotinamide synthetic.(structural formula I-68)
Figure A20061008749500752
Synthetic method is with embodiment 3, productive rate 60%, oily matter; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.0 (s, 1H), 6.9 (s, 1H), 3.63 (t, 2H), 2.48-2.65 (m, 10H), 2.79 (s, 3H), 2.47 (s, 2H), 2.32 (s, 2H), 1.11 (s 6H); FAB-MS m/z:427.3 (M ++ 1); Ultimate analysis: calculated value C 61.95, H 7.09, and N 19.70; Measured value C 62.01, and H 7.20, and N 19.97.
Embodiment 69
(1-(4-hydroxy piperidine))-(1-(3 for 6-for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) VITAMIN PP 4-[4-Hydroxypiperidin-1-yl]-6--(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-nicotinamide synthetic.(structural formula I-69)
Figure A20061008749500753
Synthetic method is with embodiment 3, productive rate 65%, oily matter; 1HNMR (500MHz, CDCl 3), δ (ppm): 9.0 (s, 1H), 6.9 (s, 1H), 3.23 (m, 1H), 1.65-2.70 (m, 4H), 2.79 (s, 3H), 2.47 (s, 2H), 2.32 (s, 2H), 1.12 (s 6H); FAB-MS m/z:398.3 (M ++ 1); Ultimate analysis: calculated value C 63.46, H 6.85, and N 17.62; Measured value C 63.76, and H 6.98, and N 17.93.
Embodiment 70
N-(4-acetyl oxygen cyclohexyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide N-(4-Acetyloxy-cyclohexyl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide synthetic.(structural formula I-70)
Figure A20061008749500761
With N-(4-hydroxy-cyclohexyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide (I-56) 0.1 gram is dissolved in 1 milliliter of pyridine, slowly drip 0.5 milliliter of acetic anhydride after room temperature reaction spend the night.Remove dry product, productive rate 98%, fusing point 73-76 ℃ of getting of the final vacuum that desolvates; 1HNMR (500MHz, CDCl 3), δ (ppm): 8.08 (b, 1H), 7.92-7.94 (d, 2H), 7.62-7.64 (m, 2H), 3.68 (m, 1H), 3.46 (m, 1H), 2.85 (s, 2H), 2.57 (s, 3H), 2.43 (s, 2H), 2.01 (s, 3H), 1.86 (m, 4H), 1.68 (m, 4H), 1.14 (s, 6H); FAB-MS m/z:438.2 (M ++ 1); Ultimate analysis: calculated value C 68.63, H 7.14, and N 14.63; Measured value C 68.78, and H 7.35, and N 14.44.
Embodiment 71
((4-(2-pyridine) piperazine)-(1-(3 for 4-for 1-for N-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide N-(4-Pyridin-2-yl-piperazin-1-yl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide synthetic.(structural formula I-71)
Figure A20061008749500762
The same N-of synthetic method (4-hydroxy-cyclohexyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6,7-tetrahydrochysene indazole)) benzamide (I-56), productive rate 68%, fusing point 78-79 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 8.11 (m, 1H), 8.08 (b, 1H), 7.92-7.94 (d, 2H), 7.62-7.64 (m, 2H), 7.44 (m, 1H), 6.60-6.70 (m, 2H), 3.68 (m, 1H), 3.46 (m, 1H), 3.32 (m, 4H), 2.85 (m, 6H), 2.57 (s, 3H), 2.43 (s, 2H), 1.12 (s, 6H); FAB-MS m/z:444.2 (M ++ 1); Ultimate analysis: calculated value C70.41, H 6.59, and N 15.79; Measured value C 70.70, and H 6.35, and N 15.49.
Embodiment 72
(1-(3 for 2-(2-tetrahydrofuran (THF)) methylamino--4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide 2-[(Tetrahydro-furan-2-ylmethyl)-amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indol-1-yl)-benzamide synthetic.(structural formula I-72)
Figure A20061008749500771
Synthetic method is with embodiment 3, productive rate 42%, fusing point 122-124 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 6.68-7.67 (m, 3H), 6.50 (s, 1H), 3.98 (m, 1H), 3.75 (t, 2H), 3.19 (d, 2H), 2.51 (s, 2H), 2.32 (s, 2H), 2.05 (s, 3H), 1.81-1.85 (m, 4H), 1.11 (s, 6H); FAB-MS m/z:396.2 (M ++ 1); Ultimate analysis: calculated value C 69.85, H, 7.39, N 10.62; Measured value C 69.97, and H 7.56, N10.45.
Embodiment 73
(1-(3 for 2-(2-tetrahydrofuran (THF)) methylamino--4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide 2-[(Tetrahydro-furan-2-ylmethyl)-amino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-1-yl)-benzamide synthetic.(structural formula I-73)
Synthetic method is with embodiment 3, productive rate 49%, fusing point 107-109 ℃; 1HNMR (500MHz, CDCl 3), δ (ppm): 6.64-7.69 (m, 3H), 3.98 (m, 1H), 3.75 (t, 2H), 3.19 (d, 2H), 2.79 (s, 3H), 2.47 (s, 2H), 2.31 (s, 2H), 1.81-1.85 (m, 4H), 1.13 (s, 6H); FAB-MS m/z:397.2 (M ++ 1); Ultimate analysis: calculated value C 66.64, H, 7.12, N 14.13; Measured value C 66.70, and H 7.28, and N 14.34.
Comparative Examples 1
Compd A 1 according to 3 preparations of embodiment in the U.S. Pat 6716856.
Comparative Examples 2
Compd A 2 according to 14 preparations of embodiment in the U.S. Pat 6716856.
Three, The compounds of this invention is in the preparation method of pharmacy acceptable salt.
Embodiment 74
The hydrochloride of compound 2-(4-hydroxyl hexamethylene amino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide of preparation embodiment 14.
Get 2-(4-hydroxyl hexamethylene amino)-4-(1-(and 3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide 0.50 gram is dissolved in 70 milliliters of ethyl acetate, ice bath feeds down the exsiccant hydrogen chloride gas, stirs after 5-20 minute except that desolvate white solid product.
Embodiment 75 to embodiment 87 is the preparation of hydrochloride of the compound of embodiments of the invention 1 to embodiment 13, and the preparation method is with embodiment 74.
Embodiment 88 to embodiment 146 is the preparation of hydrochloride of the compound of embodiments of the invention 15 to embodiment 73, and the preparation method is with embodiment 74.
Embodiment 147
Preparation 2-(4-hydroxyl hexamethylene amino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide tosilate.
Get 2-(4-hydroxyl hexamethylene amino)-4-(1-(and 3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide 0.50 gram is dissolved in 75 milliliters of ethyl acetate, ice bath adds down the doubly normal tosic acid of 1-2, stirs after 5-20 minute except that desolvate white solid product.
Embodiment 148 to embodiment 160 is the preparation of tosilate of the compound of embodiments of the invention 1 to embodiment 13, and the preparation method is with embodiment 147.
Embodiment 161 to embodiment 219 is the preparation of tosilate of the compound of embodiments of the invention 15 to embodiment 73, and the preparation method is with embodiment 147.
Embodiment 220
Preparation 2-(4-hydroxyl hexamethylene amino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide tartrate.
Get 2-(4-hydroxyl hexamethylene amino)-4-(1-(and 3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide 0.55 gram is dissolved in 90 milliliters of ethyl acetate, ice bath adds down the doubly normal tartrate of 1-2, stirs after 5-20 minute except that desolvate white solid product.
Embodiment 221 to embodiment 233 is the preparation of tartrate of the compound of embodiments of the invention 1 to embodiment 13, and the preparation method is with embodiment 220.
Embodiment 234 to embodiment 292 is the preparation of tartrate of the compound of embodiments of the invention 15 to embodiment 73, and the preparation method is with embodiment 220.
Embodiment 293
Preparation 2-(4-hydroxyl hexamethylene amino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide Citrate trianion.
Get 2-(4-hydroxyl hexamethylene amino)-4-(1-(and 3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide 0.50 gram is dissolved in 80 milliliters of ethyl acetate, ice bath adds down the doubly normal citric acid of 1-2, stirs after 5-20 minute except that desolvate white solid product.
Embodiment 294 to embodiment 306 is the preparation of Citrate trianion of the compound of embodiments of the invention 1 to embodiment 13, and the preparation method is with embodiment 293.
Embodiment 307 to embodiment 365 is the preparation of Citrate trianion of the compound of embodiments of the invention 15 to embodiment 73, and the preparation method is with embodiment 293.
Embodiment 366
Preparation 2-(4-hydroxyl hexamethylene amino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide succinate.
Get 2-(4-hydroxyl hexamethylene amino)-4-(1-(and 3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide 0.55 gram is dissolved in 70 milliliters of ethyl acetate, ice bath adds down the doubly normal succsinic acid of 1-2, stirs after 5-20 minute except that desolvate white solid product.
Embodiment 367 to embodiment 379 is the preparation of succinate of the compound of embodiments of the invention 1 to embodiment 13, and the preparation method is with embodiment 366.
Embodiment 380 to embodiment 438 is the preparation of succinate of the compound of embodiments of the invention 15 to embodiment 73, and the preparation method is with embodiment 366.
Embodiment 439
Preparation 2-(4-hydroxyl hexamethylene amino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide fumarate.
Get 2-(4-hydroxyl hexamethylene amino)-4-(1-(and 3,6,6-trimethylammonium-4-oxygen-4,5,6,7-tetrahydro indole)) benzamide 0.48 gram is dissolved in 55 milliliters of ethyl acetate, ice bath adds down the doubly normal fumaric acid of 1-2, stirs after 5-20 minute except that desolvate white solid product.
Embodiment 440 to embodiment 452 is the preparation of fumarate of the compound of embodiments of the invention 1 to embodiment 13, and the preparation method is with embodiment 439.
Embodiment 453 to embodiment 511 is the preparation of fumarate of the compound of embodiments of the invention 15 to embodiment 73, and the preparation method is with embodiment 439.
Chemical structure, Chinese and the English name of embodiment 1 to embodiment 73, Comparative Examples 1 and Comparative Examples 2 synthetic compounds see Table 1
Table 1
Figure A20061008749500811
Figure A20061008749500831
Figure A20061008749500841
Figure A20061008749500851
Figure A20061008749500861
Figure A20061008749500891
Figure A20061008749500921
Figure A20061008749500931
Application examples: anti-tumor biological
(Compound I-01 is to Compound I-73 to have tested 73 compounds of the present invention with the metamorphosis of microscopically observation of cell in conjunction with mtt assay, see Table 1), compd A 1 and compd A 2, and the positive drug vincristine(VCR) is to A549 (lung cancer), MCF-7 (mammary cancer), K562 (chronic leukemia), HL60 (acute leukemia), HT-29 (rectum cancer), HeLa (cervical cancer), HepG2 (liver cancer), the isocellular toxicity of PC3 (prostate cancer).
1. test objective
Measure Compound I-01 to Compound I-73 altogether 73 samples to A549, MCF-7, K562, HL60, HT-29, Hela, HepG2, the toxicity of PC3 cell.
2. the dissolving of sample
Compound I-01 is to Compound I-73, compd A 1 and compd A 2: take by weighing above-claimed cpd 4-5mg sample respectively, with a spot of DMSO dissolving, adding PBS again, to make its concentration be 4-5mg/mL.
The positive control drug vincristine(VCR): take by weighing the 5.0mg vincristine(VCR), being dissolved in 1mL PBS final concentration is 5mg/mL.
3. test materials
Cell: A549 (lung cancer), MCF-7 (mammary cancer), K562 (chronic leukemia), HL60 (acute leukemia), HT-29 (rectum cancer), Hela (cervical cancer), HepG2 (liver cancer), PC3 (prostate cancer).
Cell growth medium: the RPMI1640 nutrient solution that contains 10%FBS.
Cell maintenance medium: the RPMI1640 nutrient solution that contains 1%FBS.
Positive drug: vincristine(VCR)
4. test method
Adopt 96 orifice plates trace cell culture method.
4.1 monolayer cell preparation (pre-plate): well-grown cell in the culturing bottle with the conventional digestion of Digestive system, is made 1.58 * 10 with the RPMI1640 growth media 5The cell suspension of cell/mL adds in 96 orifice plates, and every hole 100 μ L put 37 ℃, 5%CO 2Hatch 24h in the incubator, grow into the monolayer cell of uniformity.
4.2 drug dilution: the mother liquor of each sample is done 10 times, 100 times, 500 times, 1000 times, 5000 times, 10000 times, 100000 times dilutions with cell maintenance medium respectively, get 7 working concentration gradients.
4.3 application of sample: abandon growth media in the micropore, add the above-mentioned good sample solution that diluted, every hole 100 μ L, each concentration is established 3 multiple holes, establishes H behavior normal cell contrast (adding no medicine cell maintenance medium 100 μ L/ holes) group simultaneously, puts 37 ℃, 5%CO 2Continue in the incubator to cultivate.
4.4 the result observes: every day the observation of cell growing state, observe 48h continuously.
4.5MTT method: after 48 hours, add 5% MTT, every hole 10 μ L, in 37 ℃, 5%CO 2Continue in the incubator to cultivate, behind the 4h, abandon supernatant, add 10% SDS, every hole 100 μ L spend the night, elisa reading instrument colorimetric (λ=570nm), survey the absorbance A value and calculate medicine to screened cell inhibiting rate.Screened cell survival rate (%)=(medicine group A value/cell control group A value) * 100%, inhibiting rate (%)=1-survival rate.Press the half-inhibition concentration (IC that the Reed-Muench method is calculated cell 50).
5. experimental result
(1) result who measures by test method 4 shows that The compounds of this invention I-01 to I-73 and positive control drug vincristine(VCR) have significant inhibition growth activity to screened tumour cell; But relatively there were significant differences P＜0.05 of effect between the two, illustrate Compound I-01 to the antitumor cell toxicity of I-73 apparently higher than vincristine(VCR).The results are shown in Table 2, table 2 is this patent compound (I-01 to I-73) suppresses growth activity to screened tumour cell a experimental data.
(2) we from patent US6716856, selected it embodiment 3 and the compd A 1 of embodiment 14 preparation and compd A 2 and this patent Compound I-01 to Compound I-73 compound and positive drug vincristine(VCR) carried out the test of antitumor cell poison relatively both there were significant differences, P＜0.01, and there is not significant difference, P＞0.05 with the comparison of blank physiological saline group; The antitumor cell activity that compd A 1 and compd A 2 are described is extremely low, compares with the compound of this patent, and almost non-activity exists.The results are shown in Table 2.
Table 2
Compound IC 50，nM
A549 MCF-7 K562 HL60 H-29 HeLa HepG2 PC3
The Compound I of embodiment 1-01 321 452 257 345 501 356 378 398
The Compound I of embodiment 2-02 356 503 432 357 267 210 421 126
The Compound I of embodiment 3-03 126 145 99.4 105 104 157 102 169
The Compound I of embodiment 4-04 125 214 89.1 216 168 175 231 157
The Compound I of embodiment 5-05 16.5 19.6 100 11.5 24.3 88.0 29.1 97
The Compound I of embodiment 6-06 123 156 167 39.9 101 21.9 99.6 231
The Compound I of embodiment 7-07 551 271 128 125 98.5 97.2 124 183
The Compound I of embodiment 8-08 163 68.8 216 237 194 59.2 67.0 153
The Compound I of embodiment 9-09 127 102 16.4 17.2 47.4 83.2 102 285
The Compound I of embodiment 10-10 167 128 114 18.2 15.1 14.7 195 174
The Compound I of embodiment 11-11 127 98 126 23.5 17.6 98.9 125 176
Compound IC 50，nM
A549 MCF-7 K562 HL60 H-29 HeLa HepG2 PC3
The Compound I of embodiment 12-12 162 149 22.5 98.3 114 18.5 178 194
The Compound I of embodiment 13-13 125 89.5 14.8 10.0 95.5 12.5 80.9 100
The Compound I of embodiment 14-14 159 88.4 78.5 92.1 13.9 18.0 45.1 101
The Compound I of embodiment 15-15 23.5 13.0 12.2 87.6 58 108 90 71
The Compound I of embodiment 16-16 135 137 94 34.9 98.2 89.2 100 54.6
The Compound I of embodiment 17-17 103 25.6 12.4 13.4 18.9 10.9 35.6 70.6
The Compound I of embodiment 18-18 188 116 275 135 176 99 90 89.9
The Compound I of embodiment 19-19 35.8 25.6 19.9 18.9 95.9 16.0 77 99
The Compound I of embodiment 20-20 31.9 35.9 75.5 21.8 97.4 102 89.1 105
The Compound I of embodiment 21-21 53.3 16.9 29.2 12.7 94.7 20.4 11.9 12.1
The Compound I of embodiment 22-22 37.3 21.9 13.6 101 23.3 22.7 12.9 107
The Compound I of embodiment 23-23 128 24.5. 15.7 90.6 12.3 19.6 99.2 81.9
The Compound I of embodiment 24-24 125 156 155 165 83 146 119 99.1
The Compound I of embodiment 25-25 56 104 33.5 15.9 96.9 56.8 107 92.6
The Compound I of embodiment 26-26 15.5 109 15.3 16.9 89.5 154 25.9 91.2
The Compound I of embodiment 27-27 164 150 185 166 90.8 175 106 51.8
The Compound I of embodiment 28-28 108 25.6 28. 16.7 99.5 99.6 87.1 98.5
The Compound I of embodiment 29-29 64 151 134 18.5 11.5 13.8 20.6 208
The Compound I of embodiment 30-30 130 128 129 145 100 175 98.2 123
The Compound I of embodiment 31-31 167 215 23.4 198 151 121 100 103
The Compound I of embodiment 32-32 189 25.6 145 27.9 24.5 43.8 107 158
The Compound I of embodiment 33-33 212 135 108 103 99.1 216 154 95.2
Compound IC 50，nM
A549 MCF-7 K562 HL60 H-29 HeLa HepG2 PC3
The Compound I of embodiment 34-34 17.6 25.1 15.0 58.9 88.3 18.9 28.4 18.9
The Compound I of embodiment 35-35 15.2 18.5 26.5 20.2 10.5 22.1 13.2 16.9
The Compound I of embodiment 36-36 82.3 22.2 28.6 113 25.8 100 91.67 115
The Compound I of embodiment 37-37 14.5 12.6 98.2 21.6 11.3 16.9 110 109
The Compound I of embodiment 38-38 154 161 168 125 157 143 90.39 196
The Compound I of embodiment 39-39 97.2 34.8 67.5 123 58.6 58.3 92.5 82.7
The Compound I of embodiment 40-40 98.6 36.7 53.9 14.9 67.7 20.7 91.5 63.2
The Compound I of embodiment 41-41 53.3 157 177 75.3 38.7 22.9 81.4 156
The Compound I of embodiment 42-42 85.2 167 35.6 76.1 56.9 95.2 63.8 179
The Compound I of embodiment 43-43 176 182 159 145 176 195 98 123
The compound of embodiment 44-44 24.5 25.4 17.8 98.6 23.8 33.8 121 101
The Compound I of embodiment 45-45 35.4 26.7 45.9 48.2 89.6 57.4 81.57 18.2
The Compound I of embodiment 46-46 75.1 10.5 15.7 48.8 49.3 37.6 100 19.1
The Compound I of embodiment 47-47 107 65 59.6 90.1 10.1 54.9 102 103
The Compound I of embodiment 48-48 42.4 102 105 46.7 95.1 115 90.8 109
The Compound I of embodiment 49-49 34.7 35.4 95 36.8 59.2 109 71.8 82.8
The Compound I of embodiment 50-50 16.8 36.4 15.8 45.5 34.8 81.5 103. 62.6
The Compound I of embodiment 51-51 82.2 82.1 218 71.3 87.5 102 93.2 88.4
The Compound I of embodiment 52-52 27.3 91.2 48.2 96.2 101 71.7 61.9 90.3
The Compound I of embodiment 53-53 12.3 34.8 86.4 91.6 81.2 75.3 71.7 89.6
The Compound I of embodiment 54-54 32.4 38.6 63.1 35.7 62.9 85 82.9 100
The Compound I of embodiment 55-55 28.9 35.7 67.2 91.2 67.8 112 89.7 23.8
Compound IC 50，nM
A549 MCF-7 K562 HL60 H-29 HeLa HepG2 PC3
The Compound I of embodiment 56-56 12.4 102 85.6 38.8 86.4 59.6 92.7 16.3
The Compound I of embodiment 57-57 76.5 50.7 94.3 42.3 69.7 99.3 90.6 28.5
The Compound I of embodiment 58-58 204 38.9 38.8 125 65.8 55.4 68.5 103
The Compound I of embodiment 59-59 102 110 231 212 109 400 412 231
The Compound I of embodiment 60-60 256 468 456 489 345 412 234 356
The Compound I of embodiment 61-61 561 595 196 642 472 450 680 674
The Compound I of embodiment 62-62 950 178 210 174 339 117 240 385
The Compound I of embodiment 63-63 232 65.8 98.4 247 172 278 176 258
The Compound I of embodiment 64-64 241 128 121 97.4 98.5 248 127 268
The Compound I of embodiment 65-65 671 145 125 103 184 255 128 274
The Compound I of embodiment 66-66 187 165 127 93.4 146 138 203 110.36
The Compound I of embodiment 67-67 199 125 138 154 103 204 186 145
The Compound I of embodiment 68-68 123 201 35.8 98.1 102 132 122 198
The Compound I of embodiment 69-69 23 123 164 99.3 111 109 104 156
The Compound I of embodiment 70-70 137 38.6 97.5 57.8 97.7 63.4 81.8 75.6
The Compound I of embodiment 71-71 124 87.6 93.9 68.7 112 72.5 58.2 196
The Compound I of embodiment 72-72 235 98.6 69.3 167 234 69.9 93.6 235
The Compound I of embodiment 73-73 346 94.9 245 198 321 98.5 389 145
The compd A 1 of Comparative Examples 1 ＞1000 ** 768 ** 894 ** ＞1000 ** 985 ** ＞1000 ** ＞1000 ** ＞1000 **
The compd A 2 of Comparative Examples 2 ＞1000 ** 854 ** ＞1000 ** ＞1000 ** 743 ** ＞1000 ** ＞1000 ** ＞1000 **
The positive control drug vincristine(VCR) 340 △ 365 △ 287 △ 226 △ 297 △ 268 △ 269 △ 245 △
Blank physiological saline ＞1000 ▲ ＞1000 ▲ ＞1000 ▲ ＞1000 ▲ ＞1000 ▲ ＞1000 ▲ ＞1000 ▲ ＞1000 ▲
In the table 2
▲: represent that relatively both do not have significant difference, P＞0.05 for blank physiological saline group and compd A 1, compd A 2;
*: expression compd A 1, compd A 2, blank physiological saline group and The compounds of this invention I-01 have significant difference, P＜0.01 to the effect comparison of Compound I-73 and positive control drug vincristine(VCR);
△: expression Compound I-01 to Compound I-73 and the comparison of positive control drug vincristine(VCR) effect has significant difference, P＜0.05
In the experiment, what all compounds adopted all is the form of its hydrochloride.
Obviously, the above embodiment of the present invention only is for example of the present invention clearly is described, and is not to be qualification to embodiments of the present invention.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.Here need not also can't give exhaustive to all embodiments.And these belong to conspicuous variation or the change that spirit of the present invention extended out and still are among protection scope of the present invention.

Claims (52)

1, a kind of compound has following general formula (I):
Wherein:
N represents 0,1 or 2; X represents N or C-R1; Y represents N or CH; Z represents N or C-R10;
R1, R2 select one of following two kinds of combinations: (1) R1 represents H, trifluoromethyl or alkyl, and R2 represents H, trifluoromethyl or alkyl; (2) the common aromatic nucleus that forms an aromatic nucleus or replacement of R1 and R2;
R3 represents H or alkyl, and R4 represents H or alkyl, and R5 represents H or alkyl, and R6 represents H or alkyl, and R7 represents H or alkyl, and R8 represents H or alkyl;
R10, R11 select one of following two kinds of combinations: (1) R10 represents the heterocycle of amino, heterocycle or the replacement of H, halogen, replacement, and R11 represents the carbamyl or the cyano group of carbamyl, replacement; (2) the common heterocycle that forms a heterocycle or replacement of R10 and R11;
R12 represents the amino of H, halogen or replacement.
2, according to the described compound of claim 1, it is characterized in that: in the general formula: n represents 0 or 1; Y, Z select one of following three kinds of combinations: (1) Y is N, and Z is C-R10; (2) Y is CH, and Z is N; (3) Y is CH, and Z is C-R10; R3, R4, R7, R8 represent H; R5 represents H or C 1-C 3Alkyl, R6 represents H or C 1-C 3Alkyl.
3, according to the described compound of claim 2, it is characterized in that: R1, R2 select first kind of combination; R1 represents H or alkyl, and this alkyl is the alkyl of C1-C3; R2 represents H, trifluoromethyl or alkyl, and this alkyl is C 1-C 3Alkyl.
4, compound according to claim 3, it is characterized in that: R1 represents C 1-C 3Alkyl, and this C 1-C 3Alkyl be methyl or ethyl, R2 represents C 1-C 3Alkyl, and this C 1-C 3Alkyl be methyl or ethyl; R10, R11 select first kind of combination, and R10 wherein represents halogen, and the represented halogen of R10 is Cl or Br; R12 represents halogen, and the represented halogen of R12 is Cl or Br.
5, compound according to claim 2 is characterized in that: R1, R2 select second kind of combination, and the aromatic nucleus that R1 and R2 can form jointly is a phenyl ring, and the aromatic nucleus of a replacement that can form jointly is the phenyl ring that replaces.
6, compound according to claim 5 is characterized in that: the common aromatic nucleus that forms a replacement of R1 and R2, and the aromatic nucleus of this replacement is the phenyl ring that trifluoromethyl replaces.
7, compound according to claim 2 is characterized in that: R10, R11 select second kind of combination, and the heterocycle that R10 and R11 can form jointly is a five-membered ring, and the heterocycle of a replacement that can form jointly is the five-membered ring that replaces.
8, compound according to claim 7 is characterized in that: the five-membered ring that R10 and R11 can form jointly is a pyrazoles, and the five-membered ring of a replacement that can form jointly is the 5-amino-pyrazol.
9, compound according to claim 2; it is characterized in that: R10, R11 select first kind of combination; R11 represents the carbamyl that replaces; this carbamyl is N-(2-[1; 2,3] triazole ethyl carbamyl, N-(2-(4-morpholine) ethyl carbamyl, N-(4-hydroxy-cyclohexyl) carbamyl, N-(4-acetyl oxygen cyclohexyl) carbamyl or N-(2-(1-(4-hydroxy piperidine) ethyl)) carbamyl.
10, compound according to claim 2 is characterized in that: R10, R11 select first kind of combination, and R10 represents the amino that replaces, and the amino of this replacement is alkylamino.
11, compound according to claim 10 is characterized in that: the represented alkylamino of R10 is naphthene amino, branched alkylamino or straight chain alkylamino.
12, compound according to claim 11, it is characterized in that: the represented alkylamino of R10 is hexamethylene amino, ethylamino, 4-hydroxyl hexamethylene amino, the own amino of 4-glycyl oxygen basic ring, 2-diethylin ethylamino, 2-(4-morpholine) ethylamino, 2-(1,2,3) triazole ethylamino, 2-(1-(3, the 5-lupetidine)) ethylamino, 2-(1-piperidines) ethylamino, 2-(1-pyrrolidyl) ethylamino or (2-tetrahydrofuran (THF)) methylamino-.
13, compound according to claim 2, it is characterized in that: R10, R11 select first kind of combination, R10 represents the heterocycle of heterocycle or replacement, and described this heterocycle is single heterocycle or two heterocycle, and the heterocycle of described this replacement is single heterocycle of replacement or two heterocycles of replacement.
14, compound according to claim 13, it is characterized in that: R10 represents heterocycle, and this heterocycle is single heterocycle or two heterocycle, and described should the list heterocycle be piperazine or piperidines, and described this pair heterocycle is a quinoline.
15, compound according to claim 13, it is characterized in that: R10 represents the heterocycle that replaces, and the heterocycle of this replacement is single heterocycle of replacement or two heterocycles of replacement, single heterocycle of described this replacement is the piperazine that replaces, the pyrrolidyl of replacement or the piperidines that replaces, two heterocycles of described this replacement are 6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline.
16, compound according to claim 15, it is characterized in that: single heterocycle of the replacement that R10 represents, and single heterocycle of this replacement is the piperazine that replaces, the pyrrolidyl that replaces, or the piperidines that replaces, the piperazine of described this replacement is the 4-methylpiperazine, 4-(2-(4-morpholine) ethyl) piperazine, (4-pentamethylene base) piperazine, 4-(2-hydroxyethyl) piperazine, or 4-(2-pyridine) piperazine, the pyrrolidyl of described this replacement is a 3-hydroxyl pyrrolidine base, and the piperidines of described this replacement is 4-oxygen-piperidines, the 4-hydroxy piperidine, the 3-hydroxy piperidine, 4-glycyl oxygen phenylpiperidines, 4-(4-morpholine) piperidines, 4-(1-pyrrolidyl) piperidines, or 4-(2-(1-piperidines) oxyethyl group) piperidines.
17, compound according to claim 2 is characterized in that, in the general formula: X represents N; Y, Z select the third combination; R1, R2 select first kind of combination, and R2 wherein represents H, trifluoromethyl or C 1-C 3Alkyl; R10, R11 select first kind of combination; R12 represents H or halogen.
18, compound according to claim 17, it is characterized in that: R2 represents C 1-C 3Alkyl, and this C 1-C 3Alkyl be methyl or ethyl; R5, R6 all represent C 1-C 3Alkyl, and the represented C of R5 1-C 3Alkyl be methyl or ethyl, the C that R6 is represented 1-C 3Alkyl be methyl or ethyl; R10 represents halogen, and this halogen is Cl or Br; R12 represents halogen, and this halogen is Cl or Br.
19, compound according to claim 17; it is characterized in that: R11 represents the carbamyl that replaces; the carbamyl of this replacement is N-(2-[1; 2,3] triazole ethyl carbamyl, N-(2-(4-morpholine) ethyl carbamyl, N-(4-hydroxy-cyclohexyl) carbamyl, N-(4-acetyl oxygen cyclohexyl) carbamyl or N-(2-(1-(4 hydroxy piperidine) ethyl)) carbamyl.
20, compound according to claim 17 is characterized in that: R10 represents the amino that replaces, and the amino of this replacement is alkylamino.
21, compound according to claim 20 is characterized in that: the represented alkylamino of R10 is naphthene amino, branched alkylamino or straight chain alkylamino.
22, compound according to claim 21, it is characterized in that: the represented alkylamino of R10 is hexamethylene amino, ethylamino, 4-hydroxyl hexamethylene amino, the own amino of 4-glycyl oxygen basic ring, 2-diethylin ethylamino, 2-(4-morpholine) ethylamino, 2-(1,2,3) triazole ethylamino, 2-(1-(3, the 5-lupetidine)) ethylamino, 2-(1-piperidines) ethylamino, 2-(1-pyrrolidyl) ethylamino or (2-tetrahydrofuran (THF)) methylamino-.
23, compound according to claim 17 is characterized in that: R10 represents the heterocycle of heterocycle or replacement, and described this heterocycle is single heterocycle or two heterocycle, and the heterocycle of described this replacement is single heterocycle of replacement or two heterocycles of replacement.
24, compound according to claim 23, it is characterized in that: R10 represents heterocycle, and this heterocycle is single heterocycle or two heterocycle, and described should the list heterocycle be piperazine or piperidines, and described this pair heterocycle is a quinoline.
25, compound according to claim 23, it is characterized in that: R10 represents the heterocycle that replaces, and the heterocycle of this replacement is single heterocycle of replacement or two heterocycles of replacement, single heterocycle of described this replacement is the piperazine that replaces, the pyrrolidyl of replacement or the piperidines that replaces, two heterocycles of described this replacement are 6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline.
26, compound according to claim 25, it is characterized in that: R10 represents single heterocycle of replacing, and single heterocycle of this replacement is the piperazine that replaces, the pyrrolidyl that replaces, or the piperidines that replaces, the piperazine of described this replacement is the 4-methylpiperazine, 4-(2-(4-morpholine) ethyl) piperazine, (4-pentamethylene base) piperazine, 4-(2-hydroxyethyl) piperazine, or 4-(2-pyridine) piperazine, the pyrrolidyl of described this replacement is a 3-hydroxyl pyrrolidine base, and the piperidines of described this replacement is 4-oxygen-piperidines, the 4-hydroxy piperidine, the 3-hydroxy piperidine, 4-glycyl oxygen phenylpiperidines, 4-(4-morpholine) piperidines, 4-(1-pyrrolidyl) piperidines, or 4-(2-(1-piperidines) oxyethyl group) piperidines.
27, compound according to claim 2 is characterized in that, in the general formula: n represents 0; X represents N; Y, Z select the third combination; R1, R2 select first kind of combination, and R2 wherein represents that alkyl, this alkyl are methyl; R5, R6 all represent C 1-C 3Alkyl, and R5, R6 are methyl; R10, R11 select second kind of combination, and the heterocycle that R10 and R11 can form jointly is pyrazoles, and the heterocycle of a replacement that can form jointly is the 5-amino-pyrazol; R12 represents H.
28, compound according to claim 2 is characterized in that, in the general formula: n represents 0; X shows table N; Y, Z select first kind of combination; R1, R2 select first kind of combination, and R2 wherein represents that alkyl and this alkyl are methyl; R5, R6 all represent C 1-C 3Alkyl, and R5, R6 are methyl; R10, R11 select first kind of combination, and R10 represents H, and R11 represents carbamyl; R12 represents the amino that replaces.
29, compound according to claim 28 is characterized in that: the amino of the replacement that R12 is represented is 4-hydroxy piperidine or 4-(2-hydroxyethyl) piperazine.
30, compound according to claim 2 is characterized in that, in the general formula: X represents C-R1; Y, Z select the third combination; R1, R2 select first kind of combination, and wherein R1 represents H or C 1-C 3Alkyl, R2 represents H or C 1-C 3Alkyl; R10, R11 select first kind of combination.
31, compound according to claim 30 is characterized in that: R1, R2, R5, R6 all represent C 1-C 3Alkyl, and the represented C of R1 1-C 3Alkyl be methyl or ethyl, the C that R2 is represented 1-C 3Alkyl be methyl or ethyl, the C that R5 is represented 1-C 3Alkyl be methyl or ethyl, the C that R6 is represented 1-C 3Alkyl be methyl or ethyl; R10, R12 all represent halogen, and the represented halogen of R10 is Cl or Br, and the represented halogen of R12 is Cl or Br.
32, compound according to claim 30; it is characterized in that: R11 represents the carbamyl that replaces; and the carbamyl of this replacement is N-(2-[1; 2,3] triazole ethyl carbamyl, N-(2-(4-morpholine) ethyl carbamyl, N-(4-hydroxy-cyclohexyl) carbamyl, N-(4-acetyl oxygen cyclohexyl) carbamyl or N-(2-(1-(4-hydroxy piperidine) ethyl)) carbamyl.
33, compound according to claim 30 is characterized in that: R10 represents the amino that replaces, and the amino of this replacement is alkylamino.
34, compound according to claim 33 is characterized in that: the represented alkylamino of R10 is naphthene amino, branched alkylamino or straight chain alkylamino.
35, compound according to claim 33, it is characterized in that: the represented alkylamino of R10 is hexamethylene amino, ethylamino, 4-hydroxyl hexamethylene amino, the own amino of 4-glycyl oxygen basic ring, 2-diethylin ethylamino, 2-(4-morpholine) ethylamino, 2-(1,2,3) triazole ethylamino, 2-(1-(3, the 5-lupetidine)) ethylamino, 2-(1-piperidines) ethylamino, 2-(1-pyrrolidyl) ethylamino or (2-tetrahydrofuran (THF)) methylamino-.
36, compound according to claim 30 is characterized in that: R10 represents the heterocycle of heterocycle or replacement, and described this heterocycle is single heterocycle or two heterocycle, and the heterocycle of described this replacement is single heterocycle of replacement or two heterocycles of replacement.
37, compound according to claim 36, it is characterized in that: R10 represents heterocycle, and this heterocycle is single heterocycle or two heterocycle, and described should the list heterocycle be piperazine or piperidines, and described this pair heterocycle is a quinoline.
38, compound according to claim 36, it is characterized in that: R10 represents the heterocycle that replaces, and the heterocycle of this replacement is single heterocycle of replacement or two heterocycles of replacement, single heterocycle of described this replacement is the piperazine that replaces, the pyrrolidyl of replacement or the piperidines that replaces, two heterocycles of described this replacement are 6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline.
39, according to the described compound of claim 38, it is characterized in that: R10 represents single heterocycle of replacing, and single heterocycle of this replacement is the piperazine that replaces, the pyrrolidyl that replaces, or the piperidines that replaces, the piperazine of described this replacement is the 1-piperazine, the 4-methylpiperazine, 4-(2-(4-morpholine) ethyl) piperazine, (4-pentamethylene base) piperazine, 4-(2-hydroxyethyl) piperazine, or 4-(2-pyridine) piperazine, the pyrrolidyl of described this replacement is a 3-hydroxyl pyrrolidine base, and described this piperidines is 4-oxygen-piperidines, the 4-hydroxy piperidine, the 3-hydroxy piperidine, 4-glycyl oxygen phenylpiperidines, 4-(4-morpholine) piperidines, 4-(1-pyrrolidyl) piperidines, or 4-(2-(1-piperidines) oxyethyl group) piperidines.
40, compound according to claim 2 is characterized in that, in the general formula: X represents C-R1; Y, Z select the third combination; R1, R2 select second kind of combination, and the aromatic nucleus that R1 and R2 can form jointly is phenyl ring, and the aromatic nucleus of a replacement that can form jointly is the phenyl ring that trifluoromethyl replaces; R5, R6 all represent C 1-C 3Alkyl, and this C 1-C 3Alkyl be methyl; R10, R11 select first kind of combination, and R11 wherein represents carbamyl; R12 represents H.
41, compound according to claim 2 is characterized in that, in the general formula: n represents 0; X represents C-R1; Y, Z select second kind of combination; R1, R2 select first kind of combination, and R1 wherein represents alkyl, and this alkyl is methyl, and R2 wherein represents H; R5, R6 all represent C 1-C 3Alkyl, and this C 1-C 3Alkyl be methyl; R10, R11 select first kind of combination, and R11 wherein represents carbamyl; R12 represents H.
42, compound according to claim 2 is characterized in that, in the general formula: n represents 0; X represents C-R1; Y, Z select the third combination; R1, R2 select first kind of combination, and R1 wherein represents H, and R2 represents that alkyl, this alkyl are methyl; R5, R6 all represent C 1-C 3Alkyl, and R5, R6 are methyl; R10, R11 select second kind of combination, and the heterocycle that R10 and R11 can form jointly is pyrazoles, and the heterocycle of a replacement that can form jointly is the 5-amino-pyrazol; R12 represents H.
43, compound according to claim 2 is characterized in that, in the general formula:
X represents N or C-R1; Y, Z select the third combination, and promptly Y represents CH; Z represents C-R10; R1, R2 select first kind of combination, and wherein R1 represents H, methyl or ethyl, and R2 represents H, methyl or ethyl; R5 represents H, methyl or ethyl; R6 represents H, methyl or ethyl; R10, R11 select first kind of combination, and R10 represents the heterocycle of amino, heterocycle or the replacement of H, halogen, replacement; R11 represents carbamyl or cyano group; R12 represents H, Cl or Br.
44, according to the described compound of claim 43, it is characterized in that: the represented halogen of R10 is Cl or Br; The amino of the replacement that R10 is represented is 2-diethylin ethylamino, 2-(4-morpholine) ethylamino, 2-(1,2,3) triazole ethylamino, 2-(1-(3, the 5-lupetidine)) ethylamino, 2-(1-piperidines) ethylamino, 2-cyclopropane amino; The represented heterocycle of R10 is the 1-piperidines; The heterocycle of the replacement that R10 is represented is 4-methylpiperazine, (4-pentamethylene base) piperazine, 4-hydroxy piperidine, 4-(1-pyrrolidyl) piperidines.
45, according to the described compound of claim 44, it is characterized in that: described compound is a 2-bromo-4-(1-(4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, 2-bromo-4-(1-(4-oxygen-4,5,6, the 7-tetrahydro indole) benzene cyanogen methyl), (1-(3 for 2-bromo-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, (1-(3 for 2-bromo-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole) benzene cyanogen methyl), 2-bromo-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(3,6 for 2-bromo-4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole) methyl) benzamide, 2-(1-piperidines)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-diethylin ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(2-(4-morpholine) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-bromo-4-(1-(4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen, 2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole) benzene cyanogen methyl), (1-(3 for 2-bromo-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(2-diethylin ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-piperidines) ethylamino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-methylpiperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, ((1-(3 for 2-for 2-, the 5-lupetidine)) ethylamino)-and 4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1,2 for 2-, 3) triazole ethylamino)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(4-hydroxy piperidine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(1-pyrrolidyl) piperidines))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-pentamethylene base) piperazine)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, or 2-cyclopropane amino-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide.
46, compound according to claim 2, it is characterized in that: described compound is that (1-(3 for 2-chloro-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen, (1-(4-methylpiperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen, (1-(4-methylpiperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3-hydroxyl pyrrolidine base))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, (1-(3-hydroxyl pyrrolidine base))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(1-piperidines)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, 2-(1-piperidines)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-methylpiperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole) benzamide methyl), (1-(3 for 2-hexamethylene amino-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-diethylin ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(2-(4-morpholine) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-oxygen-piperidines))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-hydroxy piperidine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2 (4-hydroxyl hexamethylene amino)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(1-(4-(4-morpholine) piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-(1,2 for 2-, 3) triazole ethylamino)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(1-(4-(2-(4-morpholine) ethyl) piperazine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-(1-pyrrolidyl) piperidines))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-diethylin ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3 for 2-hexamethylene amino-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(2-(1-piperidines) ethylamino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3 for 2-(2-(1-(3, the 5-lupetidine)) ethylamino)-4,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1 for 2-, 2,3) triazole ethylamino)-(1-(3,6 for 4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-pentamethylene base) piperazine)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3 for 2-cyclopropane amino-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(4-(2-(1-piperidines) oxyethyl group) piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-oxygen-piperidines))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(2-hydroxyethyl) piperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(4-morpholine) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(4-(1-pyrrolidyl) piperidines))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(2-(4-morpholine) ethyl) piperazine))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-hydroxy piperidine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-glycyl oxygen phenylpiperidines))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(4-hydroxyl hexamethylene amino)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (oneself is amino for 4-glycyl oxygen basic ring)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-pyrrolidyl) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-piperazine)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(3-hydroxyl pyrrolidine base))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(4-morpholine) piperidines))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3-hydroxy piperidine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(6 for 2-, 7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline))-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(4-(2-pyridine) piperazine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-piperidines)-(1-(3,6 for 4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 1-(6-(3-amino-1H-indazole))-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone, 1-(6-(3-amino-1H-indazole))-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone, 2-(1-(4-hydroxy piperidine))-4-(9-(2,2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-(4-hydroxyl hexamethylene amino)-4-(9-(2,2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-(1-(4-(2-hydroxyethyl) piperazine))-4-(9-(2,2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-(1-(4-methylpiperazine))-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-(1-(4-hydroxy piperidine))-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-(4-hydroxyl hexamethylene amino)-4-(9-(2,2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide, 2-hexamethylene amino-4-(9-(2,2-dimethyl-4-oxygen-3-trifluoromethyl-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(4-hydroxyl hexamethylene amino)-4-(1-(6,6-dimethyl-4-oxygen-3-trifluoromethyl-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, N-(2-[1,2,3] the triazole ethyl)-(1-(3 for 4-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(4-morpholine) ethyl)-(1-(3 for 4-for N-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, N-(4-hydroxy-cyclohexyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-(4-hydroxy piperidine)) ethyl)-(1-(3,6 for 4-for N-, 6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(2 for 5-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) pyridine-2-carboxamide, 2-bromo-4-(1-(4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, 2-bromo-4-(1-(4-oxygen-4,5,6, the 7-tetrahydro indole) methyl) benzene cyanogen, (1-(3,6 for 2-bromo-4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, (1-(3 for 2-bromo-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole) benzene cyanogen methyl), (1-(3 for 2-bromo-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzene cyanogen, 2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6, the 7-tetrahydro indole) methyl) benzene cyanogen, 2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzene cyanogen, 2-bromo-4-(1-(3-methyl-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole) benzene cyanogen methyl), 4-(1-(4-(2-hydroxyethyl) piperazine))-6-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) VITAMIN PP, (1-(4-hydroxy piperidine))-(1-(3,6 for 6-for 4-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) VITAMIN PP, (4-acetyl oxygen cyclohexyl)-(1-(3 for 4-for N-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, ((4-(2-pyridine) piperazine)-(1-(3 for 4-for 1-for N-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(2-tetrahydrofuran (THF)) methylamino--4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, or 2-(2-tetrahydrofuran (THF)) methylamino--4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide.
47, according to the described compound of claim 46, it is characterized in that: described compound is that (1-(3-hydroxyl pyrrolidine base))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(1-piperidines)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-diethylin ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6,7 tetrahydro indoles)) benzamide, (2-(4-morpholine) ethylamino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, 2-(1-(4-hydroxy piperidine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (4-hydroxyl hexamethylene amino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-(1,2 for 2-, 3) triazole ethylamino)-and 4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (1-(4-(2-(4-morpholine) ethyl) piperazine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydro indole)) benzamide, (2-diethylin ethylamino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-hexamethylene amino-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-piperidines) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-(3, the 5-lupetidine)) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1,2 for 2-, 3) triazole ethylamino)-and 4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3 for 2-cyclopropane amino-4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(4-(2-(1-piperidines) oxyethyl group) piperidines))-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-(4-(2-hydroxyethyl) piperazine))-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(4-morpholine) ethylamino)-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (4-hydroxyl hexamethylene amino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(oneself is amino for 4-glycyl oxygen basic ring)-4-(1-(3,6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(1-pyrrolidyl) ethylamino)-(1-(3,6 for 4-for 2-, 6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 2-(1-piperazine)-(1-(3 for 4-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (1-(3-hydroxy piperidine))-(1-(3 for 4-for 2-, 6,6-trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, 1-(6-(3-amino-1H-indazole))-3,6,6-trimethylammonium-1,5,6,7-tetrahydro indole-4-ketone, 1-(6-(3-amino-1H-indazole))-3,6,6-trimethylammonium-1,5,6,7-tetrahydrochysene indazole-4-ketone, (1-(4-hydroxy piperidine))-(9-(2 for 4-for 2-, 2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, (4-hydroxyl hexamethylene amino)-(9-(2 for 4-for 2-, 2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, (1-(4-(2-hydroxyethyl) piperazine))-(9-(2 for 4-for 2-, 2-dimethyl-4-oxygen-1,2,3, the 4-tetrahydro carbazole)) benzamide, (1-(4-hydroxy piperidine))-(9-(2 for 4-for 2-, 2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide, (4-hydroxyl hexamethylene amino)-(9-(2 for 4-for 2-, 2-dimethyl-4-oxygen-6-Trifluoromethyl-1,2,3, the 4-tetrahydro carbazole)) benzamide, (4-hydroxyl hexamethylene amino)-(1-(6 for 4-for 2-, 6-dimethyl-4-oxygen-3-trifluoromethyl-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, N-(2-[1,2,3] triazole ethyl)-4-(1-(3,6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, (2-(4-morpholine) ethyl)-(1-(3,6 for 4-for N-, 6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, N-(4-hydroxy-cyclohexyl)-(1-(3 for 4-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide, or N-(2-(1-(4-hydroxy piperidine)) ethyl)-(1-(3 for 4-, 6,6) trimethylammonium-4-oxygen-4,5,6, the 7-tetrahydrochysene indazole)) benzamide.
48, the described compound of one of a kind of claim 1 to 47 is at pharmacy acceptable salt.
49, according to the described compound of claim 48 at pharmacy acceptable salt, it is characterized in that: described salt is vitriol, hydrochloride, phosphoric acid salt, hydrobromate, Citrate trianion, maleate, mandelate, succinate, fumarate, acetate, lactic acid salt, nitrate, sulfonate, tosilate, mesylate, benzoate, tartrate or carbonate.
50, the application of the described compound of claim 46 in preparation medicine for treating tumor thing.
51, the application of the described compound of claim 47 in preparation medicine for treating tumor thing.
52, the described compound of claim 49 is in the application of pharmacy acceptable salt in preparation medicine for treating tumor thing.
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