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):
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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
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.