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WO2006133634A1 - Tetrahydroindole derivatives and tetrahydroindazole derivatives, and use thereof - Google Patents

Tetrahydroindole derivatives and tetrahydroindazole derivatives, and use thereof Download PDF

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Publication number
WO2006133634A1
WO2006133634A1 PCT/CN2006/001281 CN2006001281W WO2006133634A1 WO 2006133634 A1 WO2006133634 A1 WO 2006133634A1 CN 2006001281 W CN2006001281 W CN 2006001281W WO 2006133634 A1 WO2006133634 A1 WO 2006133634A1
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Prior art keywords
oxo
trimethyl
benzamide
tetrahydrocarbazole
substituted
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PCT/CN2006/001281
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French (fr)
Chinese (zh)
Inventor
Min Xia
Tongxiang Zhang
Yifei Wang
Guowen Xing
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Beijing Gylongly Biodemtech Co., Ltd
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Publication of WO2006133634A1 publication Critical patent/WO2006133634A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to derivatives of tetrahydrofurfurones and derivatives of tetrahydrooxazolone and their use in the preparation of a medicament for the treatment of antitumor agents. Background technique
  • anticancer drugs have been considered to be less toxic and more efficient, such as inhibitors of various protein kinases (eg, Aurora kinase inhibitors, CDK inhibitors), and apoptosis inducers. .
  • inhibitors of various protein kinases eg, Aurora kinase inhibitors, CDK inhibitors
  • apoptosis inducers eg, apoptosis inducers.
  • U.S. Patent No. 6,759,427, U.S. Patent 6,727,270, U.S. Patent No. 6,407,261, and U.S. Patent No. 6,614,418 disclose the activity of the tetrahydroindolone with anti-protein kinase activity and other biological activities. among them:
  • U.S. Patent 6,759,427 discloses a compound substituted at the 1-position of an aniline carbonylethyltetrahydroindanone compound and its neurogenic effect.
  • Japanese Patent JP2004-137228 reports the preparation of tetrahydrofurfurones using 1, 3-dihydroxybenzene.
  • U.S. Patent No. 6,395,905 discloses the use of a tetrahydrooxazolone-3-carboxamide derivative as a ligand for the GABA-A receptor and its enhanced memory.
  • EU0101004 reports the preparation of a series of tetrahydrofurfurone compounds and their antiarrhythmic effects.
  • Another object of the present invention is to provide an application of the above derivative in the preparation of a medicament for the treatment of an antitumor.
  • the compound of the present invention has the following general formula (I):
  • n 0, 1 or 2;
  • X represents N or C-Rl;
  • Y represents N or CH;
  • Z represents N or C-R10;
  • R1, R2 select one of the following two combinations: (1) R1 represents H, Trifluoromethyl or fluorenyl, R2 represents H, trifluoromethyl or fluorenyl; (2) R1 and R2 together form an aromatic or substituted aromatic ring;
  • R3 represents H or fluorenyl, and R4 represents H or alkyl
  • R5 represents H or alkyl,
  • R6 represents H or alkyl,
  • R7 represents H or alkyl,
  • R8 represents H or alkyl;
  • R10, R11 are selected from the following two combinations: (1) R10 represents H, halogen, substituted Amino, heterocyclic or substituted heterocyclic ring, R11 represents carbamoyl, substituted carbamoyl or cyano; (2) R10 and R11 together form a heterocyclic or substituted heterocyclic
  • n is preferably 0 or 1;
  • Y, ⁇ is preferably one of the following three combinations: (1) ⁇ is C—R10; (2) ⁇ is ⁇ is CH (3) ⁇ is 01, ⁇ is C—R10; R3, R4, R7, R8 are preferably H; R5 is preferably H or d-C 3 fluorenyl, more preferably methyl or ethyl; R6 is preferably H or dC 3
  • the thiol group is more preferably a methyl group or an ethyl group.
  • R1 and R2 are selected as the first combination, R1 is preferably H or sulfhydryl, and Alkyl group is C, - ⁇ alkyl group, more preferably methyl or ethyl; R2 is preferably H, alkyl or trifluoromethyl group, and the alkyl group is d- C 3 alkyl, more preferably methyl or ethyl base.
  • one aromatic ring which may be formed together is preferably a benzene ring
  • a substituted aromatic ring which may be formed together is preferably a substituted benzene ring, more preferably trifluoro.
  • the R12 is preferably a halogen, more preferably C1 or Br.
  • R10 is preferably halogen, more preferably C1 or Br.
  • a heterocyclic ring which may be formed together is preferably a five-membered heterocyclic ring, more preferably a pyrazole, and a substituted heterocyclic ring which may be formed together is preferably substituted.
  • the substituted carbamoyl group represented by R11 is preferably N-(2-[1, 2, 3]triazinylcarbamoyl, N. - (2-(4-morpholine)ethylcarbamoyl, N-(4-hydroxycyclohexyl)carbamoyl, N-(4-acetoxycyclohexyl)carbamoyl, or N-(2-( 1-(4-Hydroxypiperidine)ethyl))carbamoyl.
  • R10 and R11 are selected as the first combination
  • R10 when R10 is selected as a substituted amino group, a decylamino group is preferred, a cycloguanylamidine group, a branched guanidino group or a linear alkylamino group is further preferred, and further preferably.
  • a monocyclic or bicyclic heterocyclic ring is preferred when R10 is selected as a heterocyclic ring, and a more preferred monoheterocyclic ring is piperazine or piperidine, and further preferred
  • the bicyclic heterocycle is quinoline; when R10 is selected as a substituted heterocycle, a substituted monoheterocycle or a substituted biheterocycle is preferred, and further preferably the substituted monoheterocycle is a substituted piperazine, a substituted pyrrolidinyl group, or a substituted Piperidine, still more preferably substituted monoheterocycles are 4-methylpiperazine, 4-(2-(4-morpholine)ethyl)piperazine, (4-cyclopentyl)piperazine, 4-( 2-hydroxyethyl) piperazine, or 4-(2-pyridyl) piperazine, is 3-hydroxypyrrole, 4-oxo-acrid
  • the first further preferred technical solution is: X selects N; Y, ⁇ selects the third combination; R1, R2 selects the first combination, and wherein R2 is preferably H, trifluoromethyl Or d-C 3 sulfhydryl; R10, Rll selects the first combination; R12 is preferably H or halogen.
  • the R 2 is preferably a C,-, fluorenyl group, more preferably a methyl group or an ethyl group;
  • R 5 is preferably a d-C 3 alkyl group, more preferably a methyl group or an ethyl group;
  • R6 is preferably C" ( 3 alkyl, more preferably methyl or ethyl;
  • R10 selected halogen is preferably C1 or Br;
  • R12 selected halogen is preferably C1 or Br.
  • the compound of the first further preferred embodiment of the invention is 2-chloro-4-(1-(3,6 6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide, 2-bromo-4-( 1-(3-methyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide, or 2-bromo-4-(1 -
  • R11 when R11 is selected as the substituted carbamoyl group, N-(2-[1,2,3]triazole ethylcarbamoyl, N-(2-( 4-morpholine)ethylcarbamoyl, N-(4-hydroxycyclohexyl)carbamoyl, N-(4-acetoxycyclohexyl)carbamoyl, or N-(2-(1-(4- Hydroxypiperidinyl)ethyl))carbamoyl.
  • the compound of the first preferred embodiment of the present invention is preferably N-(2-[1,2,3]triazoleethyl)-4- (1-(3,6,6)trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, N-(2-(4-morpholine)ethyl) - 4-(1-(3, 6, 6)trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, N-(4-hydroxycyclohexyl)-4 - ( 1- (3, 6, 6) trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) benzamide, N- (2 -
  • the R10 is preferably an alkylamino group, more preferably a cyclodecylamino group, a branched alkylamino group or a linear fluorenylamino group, and still more preferably a cyclohexylamino group or an ethylamino group.
  • the compound of the first preferred embodiment of the present invention is preferably 2-(2-diethylaminoethylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4). 5, 6, 7-tetrahydrocarbazole))benzamide, 2-cyclohexylamino-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7 - Tetrahydrocarbazole))benzamide, 2-(2-(1-piperidinyl)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6 , 7-tetrahydrocarbazole)) benzamide, 2-(2-(1-(3, 5-dimethylpiperidine))ethylamino)-4-(1-(3, 6, 6 - three Methyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(1,2,3)triazoleethylamin
  • R10 when the R10 is selected as a heterocyclic ring, a monoheterocyclic ring or a bicyclic heterocyclic ring is preferred, a further preferred monoheterocyclic ring is piperazine or piperidine, and a further preferred bicyclic heterocyclic ring is quinolin. Porphyrin.
  • the compound of the first preferred embodiment of the present invention is preferably 2-(1-piperazine)-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6) , 7-tetrahydrocarbazole))benzamide, or 2-(1-piperidine)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7 - Tetrahydrocarbazole)) Benzoylamide.
  • R10 when the R10 is selected as a substituted heterocyclic ring, a substituted monoheterocyclic ring or a substituted bicyclic heterocyclic ring is preferred, and a further preferred substituted monocyclic heterocyclic ring is a substituted piperazine, substituted.
  • Pyrrolidinyl, or substituted piperidine, a further preferred substituted monoheterocycle is 4-methylpiperazine, 4-(2-(4-morpholine)ethyl)piperazine, (4-cyclopentyl) Alkyl) piperazine, 4-(2-hydroxyethyl)piperazine, 4-(2-pyridine)piperazine, 3-light-pyrrole graft, 4-oxo-piperidine, 4-hydroxyacridine, 3 - hydroxypiperidine, 4-aminoacetoxypiperidine, 4-(4-morpholine)piperidine, 4-(1-pyrrolidinyl)piperidine, or 4-(2-(1-piperidine) Oxy) piperidine.
  • the compound of the first preferred embodiment of the present invention is preferably 2-(4-methylpiperazin)) 4-(1-(3,6,6-trimethyl-4-oxo-4) , 5, 6, 7 -tetrahydrocarbazole)) phenyl cyanide, 2-(1-(4-methylpiperazine))-4-(1-(3, 6, 6-trimethyl-4-oxygen) -4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2-(1-(4-cyclopentanyl)piperazine)-4-(1-(3,6,6-trimethyl) 4--4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-(2-(1-piperidine)ethoxy)piperidine)) 4-(1-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-oxo-piperidine) )
  • the substituted bicyclic heterocycle is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
  • the compound of the first further preferred embodiment of the present invention is 2-(2) - (6, 7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5 , 6, 7-tetrahydrocarbazole)) benzamide.
  • the second further preferred technical solution is: n selects 0; X selects N; Y, ⁇ selects the third combination; R1, R2 selects the first combination, and wherein R2 is preferably sulfhydryl More preferably, a methyl group; R5 is preferably ((: 3 fluorenyl group, more preferably methyl group, R6 is preferably ( 3 fluorenyl group, more preferably methyl group; R10, R11 are selected as the second combination, and R10 and R11 may together form One heterocyclic ring is preferably a pyrazole, and a substituted heterocyclic ring which can be formed together is preferably a 5-aminopyrazole; R12 is preferably H.
  • the compound of the second further preferred embodiment of the present invention is preferably 1-(6-(3- Amino-1H-carbazole)) - 3,6,6-trimethyl- 1,5,6,7-tetrahydrocarbazole-4-one.
  • a third further preferred technical solution is: n selects 0; X selects N; Y, ⁇ selects the first combination; R1, R2 selects the first combination, and wherein R2 is preferably sulfhydryl , more preferably methyl; R5 is preferably d-Cs alkyl, more preferably methyl, R6 is preferably Cr "C 3 Huan group, more preferably methyl; R10, R11 selecting the first combination, and R10 is preferably H, R11 Preferably, the carbamoyl group; R12 is preferably a substituted amino group, more preferably 4-hydroxylpiperidine or 4-(2-hydroxyethyl)piperazine.
  • the compounding step of the third further preferred embodiment of the present invention is preferably 4-(1) - (4-hydroxypiperidine))-6-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))nicotinamide, or 4_ ( 1-(4-(2-hydroxyethyl)piperazine))-6-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole) ) Nicotinamide.
  • the fourth further preferred technical solution is: X selects C_R1; Y, Z selects the third combination; R1, R2 selects the first combination, and wherein R1 is preferred! ! Or ⁇ -C : i of the alkyl group, R2 is preferably H or ( ⁇ _( 3 alkyl group; R10, R11 select the first combination.
  • the R1 is preferably a fluorenyl group of CrC 3 , more preferably a methyl group or an ethyl group
  • R 2 is preferably a fluorenyl group of C,-C 3 , more preferably a methyl group or an ethyl group
  • Preferred is an alkyl group of Cr C 3 , more preferably a methyl group or an ethyl group
  • R 6 is preferably an alkyl group of C 3 , more preferably a methyl group or an ethyl group
  • a halogen selected for R 10 is preferably C1 or Br
  • a halogen selected for R 12 is preferably C1 or Br.
  • the compound of the fourth further preferred embodiment of the present invention is preferably 2-bromo-4-(1-(4-oxo-4,5,6,7-tetrahydroindole)) phenyl cyanide, 2-bromo - 4- (1-(4-oxo-4,5,6,7-tetrahydroindole) methyl) phenyl cyanide, 2-bromo-4-(1-(3, 6, 6-trimethyl-) 4-oxo-4,5,6,7-tetrahydroindole)) phenyl cyanide, 2-bromo-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6 , 7-tetrahydro-indole) methyl) benzonitrile, 2-bromo --4- (BU (3, 6, 6-trimethyl - 4 - oxo-4, 5, 6, 7-- tetrahydroindole) Benzoylamide, 2-bromo-4-(1-(4-o
  • the R10 is preferably an alkylamino group, more preferably a cyclodecylamino group, a branched alkylamino group or a linear alkylamino group, and still more preferably a cyclohexylamino group or an ethylamino group.
  • 4-hydroxycyclohexylamino 4-aminoacetoxycyclohexylamino, 2-diethylaminoethylamino, 2-(4-morpholine)ethylamino, 2-(1,2,3)triazoleethylamino , 2-(1-(3,5-dimethylpiperidine))ethylamino, 2-(1-piperidine)ethylamino, 2-(1-pyrrolidinyl)ethylamino, or (2-tetrahydrofuran) Methylamino.
  • the compound of the fourth preferred embodiment of the present invention is preferably 2-(2-tetrahydrofuran)methylamino-4-(1-(3,6-6-trimethyl-4-oxo-4, 5) , 6, 7-tetrahydrofluorene)) benzamide, 2-cyclohexylamino-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-four Hydroquinone))benzamide, 2-(2-diethylaminoethylamino)- 4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7 - four Hydroquinone))benzamide, 2-(2-(4-morpholino)ethylamino)-4-(b (3,6,6-trimethyl-4-oxo-4, 5, 6, 7) - tetrahydroanthracene))benzamide, 2-(4-hydroxycyclohexylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6,
  • R10 when the R10 is selected as a heterocyclic ring, a monoheterocyclic ring or a bicyclic heterocyclic ring is preferred, a further preferred monoheterocyclic ring is piperazine or piperidine, and a further preferred bicyclic heterocyclic ring is quinolin. Porphyrin.
  • the compound of the fourth further preferred embodiment of the present invention is preferably 2-(1-piperidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6) , 7-tetrahydroanthracene)) phenyl cyanide, or 2-( 1 -piperidinyl) -4 - ( 1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7- Tetrahydropurine)) benzamide.
  • the R10 is a substituted heterocyclic ring, preferably a substituted monoheterocyclic ring or a substituted bicyclic heterocyclic ring, and further preferably the substituted monoheterocyclic ring is a substituted piperazine or a substituted pyrrole.
  • 'Mercapto or substituted piperidine still more preferably substituted monoheterocycle is 1-piperazine, 4-methylpiperazine, 4-(2-(4-morpholine)ethyl)piperazine, (4 -cyclopentyl)piperazine, 4-(2-hydroxyethyl)piperazine, or 4-(2-pyridyl)piperazine, 3-hydroxypyrrolidino, 4-oxo-piperidine, 4-hydroxypiperidin Pyridine, 3-hydroxypiperidine, 4-aminoacetoxypiperidine, 4-(4-morpholine)piperidine, 4-(1-pyrrolidinyl)piperidine, or 4-(2-(piperidine) ) Ethoxy) piperidine.
  • the compound of the fourth further preferred embodiment of the present invention is preferably 2-(1-(3-hydroxypyrrolidinyl)-4-yl,6,6-trimethyl-4-oxo-4,5. , 6, 7-tetrahydroanthracene)) phenyl cyanide, 2-(1 (3-hydroxypyrrolidinyl))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroanthracene))benzamide, 2-(1-(4-methylpiperazine))-4-(1-(3, 6, 6-trimethyl-4-oxo) -4, 5, 6, 7-tetrahydroindole)methyl)benzamide, 2-(1-(4-oxo-piperidine))- 4- (1-(3, 6, 6 - trimethyl) 4--4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(1-(4-hydroxypiperidinyl)-4-(1-(1-(
  • the substituted bicyclic heterocycle is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
  • the compound of the fourth further preferred embodiment of the present invention is 2-(2) - (6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5 , 6, 7-tetrahydroanthracene)) benzamide.
  • a fifth further preferred technical solution is: X selects C-R1; Y, ⁇ selects a third combination; R1, R2 selects a second combination, and R1 and R2 can form a common one.
  • the aromatic ring is preferably a benzene ring, and a substituted aromatic ring which may be formed together is preferably a trifluoromethyl-substituted benzene ring;
  • R5 is preferably an alkyl group of Cr C 3 , more preferably a methyl group; and
  • R 6 is preferably a C,-( 3 fluorenyl group, More preferably, the methyl group;
  • R10, R11, the first combination is selected, wherein R11 is preferably a carbamoyl group; R12 is preferably H.
  • the compound of the fifth further preferred embodiment of the present invention is preferably 2-(1-(4-hydroxylperyl) Acridine)) -4- (9-(2,2-dimethyl-4-oxo-1, 2,3,4_tetrahydrocarbazole))benzamide, 2-(4-hydroxycyclohexylamino) -4- (9-( 2 ,2-dimethyl-4-oxo-1,2,3,4-tetraoxazole))benzamide, 2- (1-(4-(2-hydroxyethyl) Piperazine)) -4- (9-(2,2-dimethyl- 4 -oxo-1,2,3,4-tetrahydrocarbazole))benzamide, 2 - ( 1- (4 - Methylpiperazine)) -4- (9-(2, 2 dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole))benzene Formamide, 2-(Bu(4-hydroxypiperidine))-4-(9-
  • a sixth further preferred technical solution is: n selects 0; X selects C-R1; Y, ⁇ selects the second combination; R1, R2 selects the first combination, wherein R1 is preferably an alkane group, more preferably methyl, wherein R2 is preferably H; R5 preferably d- alkyl, more preferably methyl; R6 preferably is d- C 3 alkyl, more preferably methyl; R10, R11 selecting the first combination, Wherein R11 is preferably a carbamoyl group; and R12 is preferably H.
  • a compound of a sixth preferred embodiment of the present invention is 5 : (1-(2,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))pyridine-2 - Formamide.
  • the seventh further preferred technical solution is: n selects 0; X selects C-R1; Y, ⁇ selects the third combination; R1, R2 selects the first combination, and wherein R1 is preferred H; R2 marry preferred group, more preferably methyl; R5 is preferably d- C 3 alkyl group, more preferably methyl; R6 preferably d- C 3 alkyl group, more preferably methyl; R10, R11 selected second combination And a heterocyclic ring which R10 and R11 may form together is preferably pyrazole, and a substituted heterocyclic ring which may be formed together is preferably 5-aminopyrazole; R12 is preferably H.
  • the compound of the seventh further preferred embodiment of the present invention is preferably 1-(6-(3-amino-1H-indazole))-3,6,6-trimethyl-1, 5, 6, 7-tetra Hydroquinone-4-ketone.
  • the eighth further preferred technical solution is: X selects N or C-R1; Y, ⁇ selects the third combination, that is, selects CH; ⁇ selects C-RIO; R1, R2 selects a combination, and where R1 Preferably H, methyl or ethyl, R2 is preferably H, methyl or ethyl; R5 is preferably H, methyl or ethyl; R6 is preferably H, methyl or ethyl; R10, R11 are selected for the first combination, and R10 Preference is given to H, halogen, substituted amino, heterocyclic or substituted heterocyclic ring; R11 is preferably carbamoyl or cyano; R12 is preferably H, C1 or Br.
  • the halogen selected for R10 is preferably C1 or Br; and the substituted amino group selected by R10 is preferably 2-diethylaminoethylamino, 2-(4-morpholine)ethylamino, 2- (1, 2, 3) triazole ethylamino, 2-(1-(3, 5-dimethylpiperidine))ethylamino, 2-(1-piperidinyl)ethylamino, 2-cyclopropenylamino
  • the preferred heterocyclic ring for R10 is 1-piperidine; the substituted heterocyclic ring selected for R10 is preferably 4-methylpiperazine, (4-cyclopentamethylene) piperazine, 4-hydroxypiperidine, 4-(1- Pyrrolidinyl) piperidine.
  • the compound of the eighth preferred embodiment of the present invention is preferably 2-bromo-4-(1-(4-oxo-4,5,6-7-tetrahydroindole)) phenyl cyanide, 2-bromo-4 - (1-(4-oxo-4,5,6,7-tetrahydroindole) methyl)benzonitrile, 2-bromo-4-(1-(3,6,6-trimethyl-4-) Oxygen - 4, 5, 6, 7-tetrahydroanthracene)) phenyl cyanide, 2-bromo-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7) -tetrahydroindole)methyl)benzonitrile, 2-bromo-4-(Bu(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzene Formamide, 2-bromo-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7
  • the compound of the above preferred embodiment is preferably 2-chloro-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide.
  • Benzoylamide 2-(1-(3-hydroxypyrrolidinyl))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro) ⁇ ))
  • Benzoic acid 2-(1-(3-hydroxypyrrolidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,
  • a further preferred compound among the preferred compounds of the above preferred embodiments is 2-(1-(3-hydroxypyrrolidinyl)-4-(1-(3,6,6-trimethyl-4-) Oxygen-4,5,6,7-tetrahydroindole))benzamide, 2_(piperidinyl)-4-(1-(3,6-6-trimethyl-4-oxo-4, 5 , 6, 7-tetrahydroanthracene))benzamide, 2-(2-diethylaminoethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5 , 6, 7-tetrahydroanthracene))benzamide, 2-(2-(4-morpholine)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo- 4, 5, 6, 7-tetrahydroanthracene)) benzamide, 2-(Bu(4-hydroxypiperidine))-4-(1-(3, 6, 6-trimethyl-4-o
  • the invention also includes pharmaceutically acceptable salts of the above compounds.
  • These salts are preferably sulfuric, hydrochloric, phosphoric, hydrobroraic, citric, maleic, and glycolic acid.
  • Another object of the present invention is the use of a preferred compound of the above-mentioned eighth preferred embodiment for the preparation of a medicament for the treatment of a tumor, the use of the compound of the above preferred embodiment for the preparation of a medicament for the treatment of a tumor, in particular A further preferred compound of the preferred embodiment is for use in the manufacture of a medicament for the treatment of a tumor. And the use of a compound of the above preferred embodiment in the preparation of a medicament for the treatment of a tumor in a pharmaceutically acceptable salt.
  • a method for synthesizing 2-cyclohexylamino-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzamide is the same as in Example 3. , yield 73%, melting point 158-160 ° C; 'Draw R (500 MHz, CDCL), ⁇ (ppm): 9.23 (b, IH) , 8.07-8.09 (d, IH), 7.12.
  • 2-(2-diethylaminoethylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide consists of 2 -Chloro-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 2-diethylamino Ethylamine was synthesized according to the synthesis method of Example 2, yield 38.5%, melting point 97-99 ° C; 3 ⁇ 4 NMR (500 MHz, CDC1 3 ), ⁇ (ppm): 7.76-7.78 (d, IH), 7.34 (s , IH), 7.05-7.07 (d, IH), 4.04 (b, IH), 3.29(t, 2H), 3.34 (t, 2H), 2.84 (s, 211), 2.63 (b, 4H), 2.55 ( s, 3H
  • 2-(4-hydroxycyclohexylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide consists of 2- Chloro-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 4-aminocyclohexanol It was synthesized according to the synthesis method of Example 2, and the yield was 51.6%, and the melting point was 105-107.
  • 2-(1-(4-(2-pyridine)piperazine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole) )) phenyl cyanide consists of 2-chloro-4_(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 4-(2-Pyridinyl)piperazine was synthesized according to the synthesis method of Example 2, yield: 69.4%, m.p.
  • 2,4-difluorophenyl cyanide (0.14 g, 1.0 mmol), DMFC 40 mL) and B0C-NHNH 2 (0.16 g, 1.2 mmol) were added to the reaction flask, and the reaction was stirred and heated to 150 ° C for 12 hours, and cooled. After that, it was extracted with methylene chloride, washed with water and dried over anhydrous magnesium sulfate, and the product was purified by silica gel column chromatography to give N-B0C-5-fluoro-2-cyano-benzoquinone, 0.20 g, yield 80%, melting point 79-81.
  • the synthesis method of 2-(4-hydroxycyclohexylamino)-4-(9-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole))benzamide is the same Example 46.
  • the first step is the reaction of 4-aminocyclohexanol with 2,4-difluorobenzene cyanide to give 4-fluoro-2-
  • the first step is the reaction of 4-(2-hydroxyethyl)piperazine with 2,4-difluorophenyl cyanide to give 4-fluoro-2-(1-(4-(2-hydroxyethyl'alkyl)piperazine) Benzoic acid (yield 58%)
  • the second step consists of 2,2-dimethyl-1,2,3,9-tetrahydrocarbazole-4-one and 4-fluoro-2-(1-(4-) (2-Hydroxyethyl) piperazine)) phenyl cyanide gives 2-(1-(4-(2-hydroxyethyl)piperazine))-4-(9-(2,2-dimethyl-) 4-oxo-1,2,3,4-tetrahydrocarbazole)) Benzoic acid (65.5% yield)
  • the last step is 2-(1-(4-(2-hydroxyethyl)piperazine)-4-(9-(2,2-dimethyl-4-oxo-)
  • Compound A2 was prepared according to Example 14 of U.S. Patent No. 6,716,856.
  • Examples 75 to 87 are the preparation of the hydrochloride salt of the compound of Examples 1 to 13 of the present invention, The preparation method was the same as in Example 74.
  • Examples 148 to 160 are the preparations of p-toluenesulfonate of the compounds of Examples 1 to 13 of the present invention, which were prepared in the same manner as in Example 147.
  • Example 221 to 233 The preparation of the tartrate salt of the compounds of Examples 1 to 13 of the present invention was carried out in the same manner as in Example 220.
  • Examples 294 to 306 are the preparations of the citrates of the compounds of Examples 1 to 13 of the present invention, which are prepared in the same manner as in Example 293.
  • Examples 307 to 365 are the preparations of the citrates of the compounds of Examples 15 to 73 of the present invention, which were prepared in the same manner as in Example 293.
  • Examples 380 to 438 The preparation of the succinate salt of the compound of Example 15 to Example 73 of the present invention was carried out in the same manner as in Example 366.
  • Examples 440 to 452 The preparation of the fumarate of the compounds of Examples 1 to 13 of the present invention was carried out in the same manner as in Example 439.
  • Examples 453 to 511 The preparation of the fumarate salt of the compound of Example 15 to Example 73 of the present invention was carried out in the same manner as in Example 439.
  • Example 12 2-(1-(4-oxo-piperidine)) 2-(4-0xo-piperidin-l- -4-( 1-(3, 6, 6-trimethylyl)-4-(3, 6, 6-trimethy base a 4-oxo-4, 5, 6, 7 - four l_4-oxo-4, 5, 6, 7-tetra
  • Example 39 0 2-(1-(4-(4- morpholine) 2-(4-Morpholin-4-yl-p piperidine)-4-(1- iperidin- 1- yl) - 4- ( 3, 6 (3, 6, 6-trimethyl-4-, 6-trimethyl-4-oxo-4, oxy-4, 5, 6, 7-tetrahydroindole 5, 6, 7-tetrahydro-inda
  • Structural Formula I 65 No. Structure Chinese name English name Example 71 N-(l-(4-(2-pyridine) N-(4-Pyridin-2-yl-pip piperazine)-4-( 1- (3, 6, erazin- 1-yl) -4- (3, 6, 6 6) trimethyl-4-oxo-4, 5, -triraethyl-4-oxo-4, 5,
  • the 73 compounds of the present invention (Compound 1-01 to Compound 1-73, see Table 1), Compound A1 and Compound A2, and the positive drug Vincristine to A549 were tested by microscopic observation of morphological changes of cells in combination with MTT assay.
  • Lung cancer MCF-7 (breast cancer), K562 (chronic blood cancer), HL60 (acute blood cancer), HT-29 (rectal cancer), HeLa (cervical cancer), HepG2 (liver cancer), PC3 (prostate cancer) and other cells toxicity.
  • Compound 1-01 to Compound 1-73, Compound A1 and Compound A2 The above compound 4-5 mg sample was weighed, dissolved in a small amount of DMS0, and added to a PBS concentration of 4-5 mg/mL.
  • Vincristine a positive control: Weigh 5. Omg of vincristine, dissolved in 1 mL of PBS to a final concentration of 5 mg/mL.
  • Cells A549 (lung cancer), MCF-7 (breast cancer), K562 (chronic blood cancer), HL60 (acute blood cancer), HT-29 (rectal cancer), Hela (cervical cancer), HepG2 (liver cancer), PC3 (prostate cancer) ).
  • Cell growth solution RPMI1640 medium containing 10% FBS.
  • Cell maintenance solution RPMI1640 medium containing 1% FBS.
  • a 96-well plate microcell culture method was used.
  • Monolayer cell preparation (pre-plate): The well-grown cells in the culture flask were routinely digested with digestive juice, and a cell suspension of 1.58 X 10 5 cell/mL was prepared using RPMI1640 growth solution, and added to a 96-well plate. In each well, ⁇ , placed at 37 ° C, incubated in a 5% CO 2 incubator for 24 h, grew into a uniform monolayer of cells.
  • A indicates that there is no significant difference between the blank saline group and the compound A1, the compound A2, P>0.05; **: represents the compound A1, the compound A2, the blank saline group and the compound 1-01 to the compound of the present invention.
  • 1-73 and the positive control drug vincristine have a significant difference between the two, P ⁇ 0.01.
  • the compound of the present invention is substituted with an aromatic ring (e.g., a benzene ring, a pyridine ring, etc.) at the 1-position of the tetrahydroindanone and the tetrahydrocarbazol, while being substituted on the aromatic ring with respect to the tetrahydrofurfurone substituent or
  • the paraxanyl substituent is substituted with a carbamoyl group (NH2C0-), a substituted carbamoyl group (R-NH-CO-) or a cyano group (CN), which is substituted with an alkylamino group at the meta position ( R-NH-, R2N-: R is a linear or branched fluorenyl group, cyclodecyl) or halogen (C1 or Br) substituted or unsubstituted with CI-C6.
  • an aromatic ring e.g., a benzene ring, a pyridine ring, etc

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Abstract

Compounds of formula (I) and salts thereof are provided, and the said compounds and salts are characterized in their activities of inhibiting the growth of tumor cells and malignant cells, such as breast carcinoma, pulmonary carcinoma, cervical carcinoma, rectal carcinoma, prostatic carcinoma, hepatic carcinoma and leucocythaemia and the like cancer cells.

Description

四氢吲哚酮的衍生物和四氢吲唑酮  Derivatives of tetrahydrofurfurones and tetrahydrooxazolone
的衍生物及它们的应用 技术领域  Derivatives and their applications
本发明涉及四氢吲哚酮的衍生物和四氢吲唑酮的衍生物以及它们在制备用于治疗 抗肿瘤药物中的应用。 背景技术  The present invention relates to derivatives of tetrahydrofurfurones and derivatives of tetrahydrooxazolone and their use in the preparation of a medicament for the treatment of antitumor agents. Background technique
最近十年来， 肿瘤治疗取得了很大进展， 每年都有新的抗肿瘤药物进入市场， 提高 了肿瘤患者的存活和生活质量。但是， 癌症仍是危害人们健康的头号杀手。 目前临床上 使用的抗癌药物存在毒性大、耐药性差等缺陷。其中很多药物是通过抑制 DNA合成来阻 止癌细胞生长。然而这些药物不仅对癌细胞有杀伤力，对正常细胞也有同样的杀伤作用。 结果这些药物对病人往往也造成不可逆转的毒性和副作用。  In the past decade, great progress has been made in cancer treatment. Every year, new anti-tumor drugs enter the market, improving the survival and quality of life of cancer patients. However, cancer is still the number one killer of people's health. Currently, anticancer drugs used clinically have defects such as high toxicity and poor drug resistance. Many of these drugs block cancer cell growth by inhibiting DNA synthesis. However, these drugs not only have a lethal effect on cancer cells, but also have the same killing effect on normal cells. As a result, these drugs often cause irreversible toxicity and side effects to patients.
近来一些新型的抗癌药物被认为具有低毒较高效的特点，如各种蛋白激酶 (protein kinases ) 的抑制剂（例如， Aurora kinase 抑制剂， CDK抑制剂）， 细胞死亡引发剂 (apoptosis inducers )。  Recently, some new anticancer drugs have been considered to be less toxic and more efficient, such as inhibitors of various protein kinases (eg, Aurora kinase inhibitors, CDK inhibitors), and apoptosis inducers. .
美国专利 US6759427、 US6727270、 US6407261以及 US6861418报道了四氢吲哚酮化 合物具有抗蛋白激酶的活性和其他生物活性。 其中：  U.S. Patent No. 6,759,427, U.S. Patent 6,727,270, U.S. Patent No. 6,407,261, and U.S. Patent No. 6,614,418 disclose the activity of the tetrahydroindolone with anti-protein kinase activity and other biological activities. among them:
US6407261提出了 1位取代的四氢吲哚衍生物， 作为 sPLA2抑制剂。 US 6,407,261 proposes a substituted monohydroquinone derivative as a sPLA 2 inhibitor.
US6759427提出的化合物在 1位取代的苯胺羰乙基四氢吲哚酮化合物及其神经剌激 作用。  U.S. Patent 6,759,427 discloses a compound substituted at the 1-position of an aniline carbonylethyltetrahydroindanone compound and its neurogenic effect.
US6727270提出的化合物在 1位取代的吡咯类衍生物及其 5— HT受体的亲和活性。 US6716856提出了 1位取代的四氢吲唑酮衍生物。  The affinity activity of the compound proposed in US 6,727,270 at the 1-substituted pyrrole derivative and its 5-HT receptor. U.S. Patent 6,716,856 teaches a substituted monohydrooxazolone derivative.
日本专利 JP2004-137228报道了用 1， 3—二羟基苯来制备四氢吲哚酮类化合物。 US6395905报道了四氢吲唑酮一 3—甲酰胺衍生物为 GABA-A受体的配合基及其增强 记忆力的用处。  Japanese Patent JP2004-137228 reports the preparation of tetrahydrofurfurones using 1, 3-dihydroxybenzene. U.S. Patent No. 6,395,905 discloses the use of a tetrahydrooxazolone-3-carboxamide derivative as a ligand for the GABA-A receptor and its enhanced memory.
EU0101004报道了一系列四氢吲哚酮化合物的制备及其抗心律不齐的作用。  EU0101004 reports the preparation of a series of tetrahydrofurfurone compounds and their antiarrhythmic effects.
此外， US3776923、 JP60- 32767、 JP60- 32768、 JP60- 116668、 JP59- 84863 以及 JP62-89660等专利都报道了一些独特的制备四氢吲哚酮化合物的制备方法。  Further, some of the unique preparation methods for preparing tetrahydrofurfurone compounds have been reported in the patents of US Pat. No. 3,778, 923, JP 60-32767, JP 60-32768, JP 60-116668, JP 59-84863, and JP 62-89660.
以上的背景技术中与本发明最接近的对比文件是 US6716856。 其中所涉及的化合物 虽然具有低毒的特点， 但对肿瘤细胞的杀伤效果并不十分显著， 仍需进一步的研究和提 髙。 这篇专利强调四氢吲唑酮母核的取代， 没有提到任何氨甲酰基（carbamyl ), 或氰 基 (cyano)取代的苯环结构或苯甲酰胺 （benzamide) 的结构。 发明内容 The closest document to the above background of the present invention is US6716856. Although the compounds involved have low toxicity, the killing effect on tumor cells is not very significant, and further research and improvement are still needed. This patent emphasizes the substitution of the tetrahydrocarbazolone core, without mentioning any carbamyl, or cyanide. The structure of a cyano substituted benzene ring structure or benzamide. Summary of the invention
本发明的目的在于提供四氢吲哚酮的衍生物和四氢吲唑酮的衍生物。  It is an object of the present invention to provide derivatives of tetrahydrofurfurone and derivatives of tetrahydrooxazolone.
本发明的另一目的在于提供上述衍生物在制备用于治疗抗肿瘤药物中的应用。  Another object of the present invention is to provide an application of the above derivative in the preparation of a medicament for the treatment of an antitumor.
实现本发明的其中一个目的的技术方案是： 本发明的化合物具有下述通式 （I ):  A technical solution for achieving one of the objects of the present invention is: The compound of the present invention has the following general formula (I):
Figure imgf000004_0001
其中： n表示 0, 1或 2; X表示 N或 C一 Rl ; Y表示 N或 CH; Z表示 N或 C一 R10; Rl、 R2选择下面两种组合之一： （1 ) R1表示 H、 三氟甲基或垸基， R2表示 H、 三氟甲 基或垸基； （2) R1和 R2共同形成一个芳香环或取代的芳香环； R3表示 H或垸基， R4 表示 H或烷基， R5表示 H或烷基， R6表示 H或烷基， R7表示 H或烷基， R8表示 H或烷 基； R10、 R11选择下面两种组合 一： ( 1 ) R10表示 H、 卤素、 取代的氨基、 杂环或取 代的杂环， R11表示氨甲酰基、 取代的氨甲酰基或氰基； （2) R10和 R11共同形成一个 杂环或取代的杂环； R12表示 H、 卤素或取代的氨基。
Figure imgf000004_0001
Wherein: n represents 0, 1 or 2; X represents N or C-Rl; Y represents N or CH; Z represents N or C-R10; R1, R2 select one of the following two combinations: (1) R1 represents H, Trifluoromethyl or fluorenyl, R2 represents H, trifluoromethyl or fluorenyl; (2) R1 and R2 together form an aromatic or substituted aromatic ring; R3 represents H or fluorenyl, and R4 represents H or alkyl R5 represents H or alkyl, R6 represents H or alkyl, R7 represents H or alkyl, R8 represents H or alkyl; R10, R11 are selected from the following two combinations: (1) R10 represents H, halogen, substituted Amino, heterocyclic or substituted heterocyclic ring, R11 represents carbamoyl, substituted carbamoyl or cyano; (2) R10 and R11 together form a heterocyclic or substituted heterocyclic ring; R12 represents H, halogen or substituted Amino group.
本发明优选的技术方案是， 在上述技术方案中： n优选 0或 1; Y、 Ζ优选下面三种 组合之一： （1 ) ¥为 Ζ为 C—R10; (2) ∑为 Υ为 CH; (3)丫为01， Ζ为 C—R10; R3、 R4、 R7、 R8优选 H; R5优选 H或 d- C3的垸基，更优选甲基或乙基； R6优选 H或 d-C3 的垸基， 更优选甲基或乙基。 In a preferred technical solution of the present invention, in the above technical solution: n is preferably 0 or 1; Y, Ζ is preferably one of the following three combinations: (1) Ζ is C—R10; (2) ∑ is Υ is CH (3) 丫 is 01, Ζ is C—R10; R3, R4, R7, R8 are preferably H; R5 is preferably H or d-C 3 fluorenyl, more preferably methyl or ethyl; R6 is preferably H or dC 3 The thiol group is more preferably a methyl group or an ethyl group.
上述优选技术方案中， 所述的 Rl、 R2选择第一种组合时， R1优选 H或浣基， 且该 烷基是 C,- ^的烷基，更优选甲基或乙基； R2优选 H、三氟甲基或烷基，且该烷基是 d- C3 的烷基， 更优选甲基或乙基。 In the above preferred technical solution, when R1 and R2 are selected as the first combination, R1 is preferably H or sulfhydryl, and Alkyl group is C, - ^ alkyl group, more preferably methyl or ethyl; R2 is preferably H, alkyl or trifluoromethyl group, and the alkyl group is d- C 3 alkyl, more preferably methyl or ethyl base.
上述优选技术方案中， 所述的 Rl、 R2选择第二种组合时， 其可以共同形成的一个 芳香环优选苯环，可共同形成的一个取代的芳香环优选取代的苯环，更优选三氟甲基取 代的苯环。  In the above preferred embodiment, when R1 and R2 are selected as the second combination, one aromatic ring which may be formed together is preferably a benzene ring, and a substituted aromatic ring which may be formed together is preferably a substituted benzene ring, more preferably trifluoro. A methyl substituted benzene ring.
上述优选技术方案中， 所述的 R12优选卤素， 更优选 C1或 Br。  In the above preferred embodiment, the R12 is preferably a halogen, more preferably C1 or Br.
上述优选技术方案中， 所述的 R10、 R11选择第一种组合时， 其中的 R10优选卤素， 更优选 C1或 Br。  In the above preferred embodiment, when R10 and R11 are selected as the first combination, R10 is preferably halogen, more preferably C1 or Br.
上述优选技术方案中， 所述的 R10、 R11选择第二种组合时， 其可以共同形成的一 个杂环优选五元杂环，更优选吡唑，可共同形成的一个取代的杂环优选取代的五元杂环， 更优选 5-氨基吡唑。  In the above preferred embodiment, when R10 and R11 are selected as the second combination, a heterocyclic ring which may be formed together is preferably a five-membered heterocyclic ring, more preferably a pyrazole, and a substituted heterocyclic ring which may be formed together is preferably substituted. A five-membered heterocyclic ring, more preferably 5-aminopyrazole.
上述优选技术方案中， 所述的 R10、 R11选择第一种组合时， R11表示的取代的氨 甲酰基优选 N- (2- [1， 2， 3]三氮 ^乙基氨甲酰基、 N- (2- (4-吗啉）乙基氨甲酰基、 N- (4- 羟基环己基)氨甲酰基、 N- (4-乙酰氧环己基)氨甲酰基、或 N- (2- (1- (4-羟基哌啶）乙基)） 氨甲酰基。  In the above preferred embodiment, when the first combination is selected for R10 and R11, the substituted carbamoyl group represented by R11 is preferably N-(2-[1, 2, 3]triazinylcarbamoyl, N. - (2-(4-morpholine)ethylcarbamoyl, N-(4-hydroxycyclohexyl)carbamoyl, N-(4-acetoxycyclohexyl)carbamoyl, or N-(2-( 1-(4-Hydroxypiperidine)ethyl))carbamoyl.
上述优选技术方案中， 所述的 R10、 R11选择第一种组合时， 当 R10选择为取代的 氨基时优选垸氨基， 进一步优选环垸氨基、支链垸氨基或直链烷氨基， 更进一步优选环 己氨基、 乙氨基、 4-羟基环己氨基、 4-氨基乙酰氧基环己氨基、 2-二乙氨基乙氨基、 2- (4-吗啉） 乙氨基、 2- ( 1 , 2， 3)三氮唑乙氨基、 2- ( 1- (3， 5-二甲基哌啶）） 乙氨 基、 2- ( 1-哌啶） 乙氨基、 2_ ( 1-吡咯烷基） 乙氨基、 或（2—四氢呋喃） 甲氨基。  In the above preferred embodiment, when R10 and R11 are selected as the first combination, when R10 is selected as a substituted amino group, a decylamino group is preferred, a cycloguanylamidine group, a branched guanidino group or a linear alkylamino group is further preferred, and further preferably. Cyclohexylamino, ethylamino, 4-hydroxycyclohexylamino, 4-aminoacetoxycyclohexylamino, 2-diethylaminoethylamino, 2-(4-morpholine)ethylamino, 2-(1, 2, 3) triazole ethylamino, 2-(1-(3, 5-dimethylpiperidine))ethylamino, 2-(1-piperidine)ethylamino, 2-(1-pyrrolidinyl)ethylamino, Or (2-tetrahydrofuran) methylamino.
上述优选技术方案中， 所述的 R10、 R11选择第一种组合时， 当 R10选择杂环时优 选单杂环或双杂环， 进一步优选的单杂环是哌嗪或哌啶， 进一步优选的双杂环是喹啉； 当 R10选择取代的杂环时优选取代的单杂环或取代的双杂环，进一步优选取代的单杂环 是取代的哌嗪、 取代的吡咯垸基、 或取代的哌啶， 更进一步优选取代的单杂环是 4 -甲 基哌嗪、 4- (2- (4-吗啉） 乙基） 哌嗪、 （4-环戊烷基） 哌嗪、 4- (2-羟乙基） 哌嗪、 或 4- (2-吡啶）哌嗪、 是 3-羟基吡咯烧基、 4-氧-昵啶、 4 -羟基哌啶、 3—羟基哌啶、 4 一氨基乙酰氧基哌啶、 4 (4-吗啉） 哌啶、 4- ( 1-吡咯烷基） 哌啶、 或 4- (2- ( 1 -哌 啶） 乙氧基）哌啶。 进一步优选取代的双杂环是取代的喹啉， 更进一步优选 6、 7-二甲 氧基- 1， 2， 3, 4-四氢异喹啉。  In the above preferred embodiment, when the first combination is selected for R10 and R11, a monocyclic or bicyclic heterocyclic ring is preferred when R10 is selected as a heterocyclic ring, and a more preferred monoheterocyclic ring is piperazine or piperidine, and further preferred The bicyclic heterocycle is quinoline; when R10 is selected as a substituted heterocycle, a substituted monoheterocycle or a substituted biheterocycle is preferred, and further preferably the substituted monoheterocycle is a substituted piperazine, a substituted pyrrolidinyl group, or a substituted Piperidine, still more preferably substituted monoheterocycles are 4-methylpiperazine, 4-(2-(4-morpholine)ethyl)piperazine, (4-cyclopentyl)piperazine, 4-( 2-hydroxyethyl) piperazine, or 4-(2-pyridyl) piperazine, is 3-hydroxypyrrole, 4-oxo-acridine, 4-hydroxypiperidine, 3-hydroxypiperidine, 4-amino group Acetoxypiperidine, 4 (4-morpholine) piperidine, 4-(1-pyrrolidinyl)piperidine, or 4-(2-(1-piperidinyl)ethoxy)piperidine. Further preferably, the substituted bicyclic heterocycle is a substituted quinoline, and further more preferably 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
上述优选的技术方案中， 第一种进一步优选的技术方案为： X选择 N; Y、 Ζ选择第 三种组合； Rl、 R2选择第一种组合，且其中的 R2优选 H、三氟甲基或 d- C3的垸基； R10、 Rll选择第一种组合； R12优选 H或卤素。 In the above preferred technical solution, the first further preferred technical solution is: X selects N; Y, Ζ selects the third combination; R1, R2 selects the first combination, and wherein R2 is preferably H, trifluoromethyl Or d-C 3 sulfhydryl; R10, Rll selects the first combination; R12 is preferably H or halogen.
上述第一种进一步优选的技术方案中， 所述的 R2优选 C,- ,的垸基， 更优选甲基或 乙基； R5优选 d- C3的烷基， 更优选甲基或乙基； R6优选 C「 ( 3的烷基， 更优选甲基或 乙基； R10选择的卤素优选 C1或 Br; R12选择的卤素优选 C1或 Br。这时本发明第一种 进一步优选的技术方案的化合物优选为 2-氯 -4- (1- (3, 6, 6-三甲基 -4-氧 -4, 5， 6, 7-四氢 吲唑)）苯氰、 2 -溴- 4- ( 1- (3-甲基- 4-氧- 4, 5, 6, 7-四氢吲唑））苯氰、 或 2 -溴- 4- ( 1 -In the above further preferred embodiment, the R 2 is preferably a C,-, fluorenyl group, more preferably a methyl group or an ethyl group; R 5 is preferably a d-C 3 alkyl group, more preferably a methyl group or an ethyl group; R6 is preferably C" ( 3 alkyl, more preferably methyl or ethyl; R10 selected halogen is preferably C1 or Br; R12 selected halogen is preferably C1 or Br. In this case, the compound of the first further preferred embodiment of the invention Preferred is 2-chloro-4-(1-(3,6 6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide, 2-bromo-4-( 1-(3-methyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide, or 2-bromo-4-(1 -
(3-甲基- 4-氧- 4， 5， 6， 7-四氢吲唑) 甲基）苯氰。 (3-Methyl-4-oxo-4,5,6,7-tetrahydrocarbazole) Methyl)benzonitrile.
上述第一种进一步优选的技术方案中， 所述的 R11 选择取代的氨甲酰基时优选 N- (2- [1, 2, 3]三氮唑乙基氨甲酰基、 N- (2- (4-吗啉）乙基氨甲酰基、 N- (4-羟基环己基） 氨甲酰基、 N- (4-乙酰氧环己基)氨甲酰基、 或 N- (2- (1- (4 -羟基哌啶）乙基)）氨甲酰基。 这时本发明第一种进一步优选'的技术方案的化合物优选为 N- (2- [1, 2， 3]三氮唑乙 基) - 4- ( 1- ( 3， 6， 6)三甲基 -4-氧- 4， 5， 6， 7 -四氢吲唑) )苯甲酰胺、 N - (2- (4- 吗啉）乙基) - 4- ( 1- (3， 6， 6)三甲基 -4-氧- 4， 5， 6， 7 -四氢吲唑) )苯甲酰胺、 N - (4- 羟基环己基) - 4- ( 1- (3, 6， 6)三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 N- (2 - In the above further preferred embodiment, when R11 is selected as the substituted carbamoyl group, N-(2-[1,2,3]triazole ethylcarbamoyl, N-(2-( 4-morpholine)ethylcarbamoyl, N-(4-hydroxycyclohexyl)carbamoyl, N-(4-acetoxycyclohexyl)carbamoyl, or N-(2-(1-(4- Hydroxypiperidinyl)ethyl))carbamoyl. In this case, the compound of the first preferred embodiment of the present invention is preferably N-(2-[1,2,3]triazoleethyl)-4- (1-(3,6,6)trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, N-(2-(4-morpholine)ethyl) - 4-(1-(3, 6, 6)trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, N-(4-hydroxycyclohexyl)-4 - ( 1- (3, 6, 6) trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) benzamide, N- (2 -
(1- (4-轻基哌啶）） 乙基) -4- ( 1- (3, 6, 6) 三甲基 -4-氧- 4, 5， 6， 7-四氢吲唑）） 苯甲酰胺、 N- (4-乙酰氧环己基 ) -4- ( 1- (3, 6， 6)三甲基 -4-氧- 4， 5, 6， 7-四氢吲 唑）） 苯甲酰胺、 或 Ν-α- (4- (2-吡啶） Β 嗪) -4- ( 1- (3， 6， 6)三甲基 -4-氧- 4， 5， 6， 7-四氢吲哇））苯甲酰胺。 (1-(4-Lightylpiperidine))ethyl)-4-(1-(3,6,6)trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) Benzoylamide, N-(4-acetoxycyclohexyl)-4-(1-(3,6,6)trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) Benzene Formamide, or Ν-α-(4-(2-pyridine) pyridazine)-4-(1-(3, 6, 6)trimethyl-4-oxo-4, 5, 6, 7 -tetrahydrogen吲 wow)) benzamide.
上述第一种进一步优选的技术方案中， 所述的 R10选择取代的氨基时优选烷氨基， 进一步优选环垸氨基、 支链烷氨基或直链垸氨基， 更进一步优选为环己氨基、 乙氨基、 4-羟基环己氨基、 4-氨基乙酰氧基环己氨基、 2-二乙氨基乙氨基、 2- (4-吗啉）乙氨基、 2- ( 1 , 2, 3 )三氮唑乙氨基、 2- ( 1- (3， 5-二甲基哌啶）） 乙氨基、 2- ( 1-哌啶） 乙 氨基、 2- ( 1-吡咯烷基） 乙氨基、 或（2—四氢呋喃） 甲氨基。 这时本发明第一种进一 步优选的技术方案的化合物优选为 2- (2-二乙氨基乙氨基） -4- ( 1- (3， 6, 6-三甲基- 4- 氧- 4， 5， 6， 7-四氢吲唑）)苯甲酰胺、 2 -环己氨基- 4- (1- (3, 6, 6-三甲基 -4-氧- 4, 5， 6, 7 -四氢吲唑)）苯甲酰胺、 2- (2- ( 1-哌啶）乙氨基）-4- ( 1-( 3， 6， 6_三甲基 -4-氧 -4， 5， 6, 7- 四氢吲唑）） 苯甲酰胺、 2- (2- ( 1- (3, 5-二甲基哌啶）） 乙氨基） -4- ( 1- (3， 6， 6 -三 甲基- 4-氧 -4， 5, 6， 7-四氢吲唑））苯甲酰胺、 2- (2- (1， 2, 3)三氮唑乙氨基 )-4- ( 1- (3， 6, 6- 三甲基 -4-氧- 4, 5， 6, 7-四氢吲唑））苯甲酰胺、 2-环丙垸氨基 -4- ( 1- (3， 6， 6-三甲基 -4- 氧- 4， 5, 6, 7-四氢吲唑））苯甲酰胺、 2- (2- (4-吗啉） 乙氨基） -4- ( 1- (3， 6, 6 -三甲 基 -4—氧—4, 5， 6， 7-四氢吲唑））苯甲酰胺、 2— (4-羟基环己氨基） -4- ( 1- (3, 6， 6— 三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑））苯甲酰胺、 2- (4-氨基乙酰氧基环己氨基） - 4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 2- (2- (1 -吡咯烷基) 乙氨基） -4- (1- (3, 6, 6-三甲基 -4-氧- 4, 5， 6, 7-四氢吲唑））苯甲酰胺、 2-环己氨基- 4- (9 -（2,2-二甲基 -4 -氧- 3-三氟甲基- 4， 5, 6， 7 四氢吲唑））苯甲酰胺、 2- (4-轻基环己 氨基） -4- (1- (6， 6_二甲基 -4-氧- 3-三氟甲基- 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 或 2- (2-四氢呋喃）甲氨基 -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5, 6, 7-四氢吲唑)）苯甲酰 胺。 In the above further preferred embodiment, the R10 is preferably an alkylamino group, more preferably a cyclodecylamino group, a branched alkylamino group or a linear fluorenylamino group, and still more preferably a cyclohexylamino group or an ethylamino group. , 4-hydroxycyclohexylamino, 4-aminoacetoxycyclohexylamino, 2-diethylaminoethylamino, 2-(4-morpholine)ethylamino, 2-(1,2,3)triazole Amino, 2-(1-(3,5-dimethylpiperidine))ethylamino, 2-(1-piperidine)ethylamino, 2-(1-pyrrolidinyl)ethylamino, or (2-tetrahydrofuran) ) methylamino. In this case, the compound of the first preferred embodiment of the present invention is preferably 2-(2-diethylaminoethylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4). 5, 6, 7-tetrahydrocarbazole))benzamide, 2-cyclohexylamino-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7 - Tetrahydrocarbazole))benzamide, 2-(2-(1-piperidinyl)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6 , 7-tetrahydrocarbazole)) benzamide, 2-(2-(1-(3, 5-dimethylpiperidine))ethylamino)-4-(1-(3, 6, 6 - three Methyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(1,2,3)triazoleethylamino)-4-(1-( 3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-cyclopropanylamino-4-(1-(3, 6, 6 -trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(4-morpholine)ethylamino)-4-(1-(3, 6, 6 - trimethyl --4 - O - 4, 5, 6, 7-tetrahydro-indazol)) benzamide, 2- (4-hydroxy-cyclohexylamino) -4- (l- (3, 6 , 6- Trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(4-aminoacetoxycyclohexylamino)-4- (1- (3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(1-pyrrolidinyl)ethylamino)-4-(1-( 3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) benzamide, 2-cyclohexylamino-4-(9-(2,2-dimethyl) 4--4-oxo-3-trifluoromethyl- 4, 5, 6, 7 tetrahydrocarbazole)) benzamide, 2-(4-light-cyclohexylamino)-4-(1-(6, 6-Dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydrocarbazole))benzamide, or 2-(2-tetrahydrofuran)methylamino-4- (1) - (3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide.
上述第一种进一步优选的技术方案中，所述的 R10选择杂环时，优选单杂环或双杂 环， 进一步优选的单杂环是哌嗪或哌啶， 进一步优选的双杂环是喹啉。这时本发明第一 种进一步优选的技术方案的化合物优选为 2- (1-哌嗪） -4- (1- (3,6,6-三甲基 -4 -氧 -4, 5, 6， 7-四氢吲唑））苯甲酰胺、或 2- (1-哌啶） - 4- (1- (3, 6， 6-三甲基 -4-氧- 4， 5， 6， 7- 四氢吲唑））苯甲酰胺。  In the above further preferred embodiment, when the R10 is selected as a heterocyclic ring, a monoheterocyclic ring or a bicyclic heterocyclic ring is preferred, a further preferred monoheterocyclic ring is piperazine or piperidine, and a further preferred bicyclic heterocyclic ring is quinolin. Porphyrin. In this case, the compound of the first preferred embodiment of the present invention is preferably 2-(1-piperazine)-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6) , 7-tetrahydrocarbazole))benzamide, or 2-(1-piperidine)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7 - Tetrahydrocarbazole)) Benzoylamide.
上述第一种进一步优选的技术方案中，所述的 R10选择取代的杂环时，优选取代的 单杂环或取代的双杂环， 进一步优选的取代的单杂环是取代的哌嗪、 取代的吡咯烷基、 或取代的哌啶， 更进一步优选的取代的单杂环是 4-甲基哌嗪、 4- (2- (4-吗啉） 乙基） 哌嗪、 （4-环戊烷基） 哌嗪、 4- (2-羟乙基） 哌嗪、 4- (2-吡啶） 哌嗪、 3-轻基吡咯嫁 基、 4 -氧-哌啶、 4-羟基呃啶、 3—羟基哌啶、 4一氨基乙酰氧基哌啶、 4- (4-吗啉） 哌 啶、 4- (1-吡咯垸基） 哌啶、 或 4- (2- (1-哌啶） 乙氧基） 哌啶。 这时本发明第一种 进一步优选的技术方案的化合物优选为 2 - -(4-甲基哌嗪)） - 4-(1- (3， 6， 6-三甲基- 4- 氧- 4, 5, 6， 7 -四氢吲唑））苯氰、 2- (1- (4-甲基哌嗪）） -4- (1- (3， 6， 6-三甲基 -4 -氧 -4， 5, 6， 7-四氢吲唑））苯甲酰胺、 2- (1- (4-环戊垸基） 哌嗪） - 4- (1- (3,6,6-三甲 基 -4-氧- 4, 5， 6， 7-四氢吲唑）)苯甲酰胺、 2- (1- (4- (2- (1-哌啶） 乙氧基） 哌啶）） -4- (1- (3， 6, 6-三甲基 -4-氧- 4,5,6,7-四氢吲唑））苯甲酰胺、 2- (1- (4-氧-哌啶）） -4- (1- (3， 6, 6_三甲基 -4-氧- 4， 5， 6, 7_四氢吲唑））苯甲酰胺、 2- (1- (4- (2 -羟乙基) 哌嗪）） -4- (1- (3, 6， 6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲唑））苯甲酰胺、 2- (1- (4- (1- 吡咯垸基) 哌啶）） -4- (1- (3,6,6-三甲基 -4-氧- 4， 5, 6， 7_四氢吲唑）)苯甲酰胺、 2- (1 - (4- (2- (4-吗啉） 乙基）哌嗪）） -4- (1- (3， 6, 6-三甲基 -4-氧- 4,5,6,7-四氢吲 唑））苯甲酰胺、 2- (1- (4 -羟基哌啶）) -4- (1- (3, 6, 6-三甲基 -4-氧- 4, 5， 6, 7-四氢 吲唑））苯甲酰胺、 2- (1- (4-氨基乙酰氧基哌啶））- 4- (1-(3, 6, 6-三甲基 -4-氧- 4， 5, 6, Ί- 四氢吲唑））苯甲酰胺、 2- (1- (3-羟基吡咯浣基））-4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5, 6, 7 - 四氢吲唑））苯甲酰胺、 2- (1-(4 （4-吗啉）哌啶））- 4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5, 6, 7- 四氢吲唑））苯甲酰胺、 2- ( 1- (3-羟基哌啶）） -4- ( 1- (3, 6， 6-三甲基 -4-氧 -4, 5, 6， 7- . 四氢吲唑）） 苯甲酰胺、 或 2- ( 1- (4- (2 -吡啶) 哌嗪）） -4- ( 1- (3, 6, 6-三甲基 -4- 氧- 4， 5, 6, 7-四氢吲唑））苯甲酰胺。 进一步优选取代的双杂环是 6、 7-二甲氧基- 1， 2， 3, 4-四氢异喹啉， 这时本发明第一种进一步优选的技术方案的化合物为 2- (2- (6, 7- 二甲氧基- 1， 2， 3, 4-四氢异喹啉）） -4- ( 1- (3, 6， 6-三甲基 -4-氧 -4, 5, 6， 7-四氢吲唑）) 苯甲酰胺。 In the above further preferred embodiment, when the R10 is selected as a substituted heterocyclic ring, a substituted monoheterocyclic ring or a substituted bicyclic heterocyclic ring is preferred, and a further preferred substituted monocyclic heterocyclic ring is a substituted piperazine, substituted. Pyrrolidinyl, or substituted piperidine, a further preferred substituted monoheterocycle is 4-methylpiperazine, 4-(2-(4-morpholine)ethyl)piperazine, (4-cyclopentyl) Alkyl) piperazine, 4-(2-hydroxyethyl)piperazine, 4-(2-pyridine)piperazine, 3-light-pyrrole graft, 4-oxo-piperidine, 4-hydroxyacridine, 3 - hydroxypiperidine, 4-aminoacetoxypiperidine, 4-(4-morpholine)piperidine, 4-(1-pyrrolidinyl)piperidine, or 4-(2-(1-piperidine) Oxy) piperidine. In this case, the compound of the first preferred embodiment of the present invention is preferably 2-(4-methylpiperazin)) 4-(1-(3,6,6-trimethyl-4-oxo-4) , 5, 6, 7 -tetrahydrocarbazole)) phenyl cyanide, 2-(1-(4-methylpiperazine))-4-(1-(3, 6, 6-trimethyl-4-oxygen) -4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2-(1-(4-cyclopentanyl)piperazine)-4-(1-(3,6,6-trimethyl) 4--4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-(2-(1-piperidine)ethoxy)piperidine)) 4-(1-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-oxo-piperidine) )) -4- (1-(3, 6, 6_Trimethyl-4-oxo-4, 5, 6, 7_tetrahydrocarbazole)) benzamide, 2- (1- (4- 2-hydroxyethyl) piperazine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2 - (1-(4-(1-pyrrolidinyl)piperidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7_tetrahydroindole) Oxazole))benzamide, 2-(1 - (4-(2-(4-morpholine)ethyl)piperazine))-4-(1-(3, 6, 6-trimethyl-4-) Oxygen - 4,5,6,7- Hydrocarbazole))benzamide, 2-(1-(4-hydroxypiperidine))-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7) -tetrahydrocarbazole))benzamide, 2-(1-(4-aminoacetoxypiperidine)) 4- (1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, Ί-tetrahydrocarbazole))benzamide, 2-(1-(3-hydroxypyrrolidino))-4-(1-(3, 6, 6-trimethyl-4-oxo) - 4, 5, 6, 7 - tetrahydrocarbazole))benzamide, 2-(1-(4 (4-morpholinyl)piperidine))- 4- (1- (3, 6, 6-three) Methyl-4-oxo-4, 5, 6, 7- Tetrahydrocarbazole))benzamide, 2-(1-(3-hydroxypiperidine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7- . Tetrahydrocarbazole)) Benzoylamide, or 2-(1-(4-(2-pyridine)piperazine))-4-(1-(3,6,6-trimethyl-4-) Oxygen-4,5,6,7-tetrahydrocarbazole))benzamide. Further preferably, the substituted bicyclic heterocycle is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, and the compound of the first further preferred embodiment of the present invention is 2-(2) - (6, 7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5 , 6, 7-tetrahydrocarbazole)) benzamide.
上述优选的技术方案中， 第二种进一步优选的技术方案为： n选择 0; X选择 N; Y、 Ζ选择第三种组合； Rl、 R2选择第一种组合， 且其中的 R2优选垸基， 更优选甲基； R5 优选（ (：3的垸基， 更优选甲基， R6优选 ( 3的垸基， 更优选甲基； R10、 R11选择第 二种组合，且 R10和 R11可共同形成的一个杂环优选吡唑，可共同形成的一个取代的杂 环优选 5-氨基吡唑； R12优选 H。本发明第二种进一步优选的技术方案的化合物优选为 1- (6- (3 -氨基 -1H-吲唑）） - 3, 6， 6 -三甲基- 1， 5， 6， 7 -四氢吲唑- 4 -酮。 In the above preferred technical solution, the second further preferred technical solution is: n selects 0; X selects N; Y, Ζ selects the third combination; R1, R2 selects the first combination, and wherein R2 is preferably sulfhydryl More preferably, a methyl group; R5 is preferably ((: 3 fluorenyl group, more preferably methyl group, R6 is preferably ( 3 fluorenyl group, more preferably methyl group; R10, R11 are selected as the second combination, and R10 and R11 may together form One heterocyclic ring is preferably a pyrazole, and a substituted heterocyclic ring which can be formed together is preferably a 5-aminopyrazole; R12 is preferably H. The compound of the second further preferred embodiment of the present invention is preferably 1-(6-(3- Amino-1H-carbazole)) - 3,6,6-trimethyl- 1,5,6,7-tetrahydrocarbazole-4-one.
上述优选的技术方案中， 第三种进一步优选的技术方案为： n选择 0; X选择 N; Y、 Ζ选择第一种组合； Rl、 R2选择第一种组合， 且其中的 R2优选焼基， 更优选甲基； R5 优选 d-Cs的烷基， 更优选甲基， R6优选 Cr"C3的浣基， 更优选甲基； R10、 R11选择第 一种组合， 且 R10优选 H， R11优选氨甲酰基； R12优选取代的氨基， 更优选 4一羟基哌 啶或 4- (2-羟乙基）哌嗪。本发明第三种进一步优选的技术方案的化合驟优选为 4- ( 1 - (4羟基哌啶）） -6- ( 1- (3, 6, 6-三甲基 -4-氧 _4， 5， 6, 7-四氢吲唑））烟碱酰胺、 或 4_ ( 1- (4- (2 -羟乙基） 哌嗪）） -6- ( 1- (3, 6, 6-三甲基 -4-氧- 4, 5, 6, 7-四氢吲唑）)烟 碱酰胺。 In the above preferred technical solution, a third further preferred technical solution is: n selects 0; X selects N; Y, Ζ selects the first combination; R1, R2 selects the first combination, and wherein R2 is preferably sulfhydryl , more preferably methyl; R5 is preferably d-Cs alkyl, more preferably methyl, R6 is preferably Cr "C 3 Huan group, more preferably methyl; R10, R11 selecting the first combination, and R10 is preferably H, R11 Preferably, the carbamoyl group; R12 is preferably a substituted amino group, more preferably 4-hydroxylpiperidine or 4-(2-hydroxyethyl)piperazine. The compounding step of the third further preferred embodiment of the present invention is preferably 4-(1) - (4-hydroxypiperidine))-6-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))nicotinamide, or 4_ ( 1-(4-(2-hydroxyethyl)piperazine))-6-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole) ) Nicotinamide.
上述优选的技术方案中， 第四种进一步优选的技术方案为： X选择 C_R1 ; Y、 Z选 择第三种组合； Rl、 R2选择第一种组合， 且其中 R1优选！！或^- C:i的烧基， R2优选 H 或(^_( 3的烷基； R10、 R11选择第一种组合。 In the above preferred technical solution, the fourth further preferred technical solution is: X selects C_R1; Y, Z selects the third combination; R1, R2 selects the first combination, and wherein R1 is preferred! ! Or ^-C : i of the alkyl group, R2 is preferably H or (^_( 3 alkyl group; R10, R11 select the first combination.
上述第四种进一步优选的技术方案中， 所述的 R1优选 CrC3的焼基， 更优选甲基或 乙基； R2优选 C,- C3的垸基， 更优选甲基或乙基； R5优选 Cr C3的烷基， 更优选甲基或 乙基； R6优选 C3的烷基， 更优选甲基或乙基； R10所选择的卤素优选 C1或 Br， R12 选择的卤素优选 C1或 Br。这时本发明第四种进一步优选的技术方案的化合物优选为 2- 溴- 4- ( 1- (4 -氧- 4， 5， 6, 7-四氢吲哚）)苯氰、 2_溴- 4- ( 1- (4 -氧- 4, 5， 6， 7-四氢吲哚) 甲基） 苯氰、 2-溴- 4- ( 1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚））苯氰、 2 -溴- 4- ( 1- (3， 6， 6-三甲基 -4-氧 -4, 5, 6， 7-四氢吲哚) 甲基）苯氰、 2-溴- 4-（卜 (3， 6， 6-三甲 基一 4一氧一 4， 5, 6, 7 -四氢吲哚））苯甲酰胺、 2 -溴- 4- ( 1- (3-甲基- 4-氧- 4, 5, 6， 7-四氢吲 哚））苯氰、 或 2 -溴 _4- ( 1- (3 -甲基 -4-氧- 4, 5, 6, 7-四氢吲哚) 甲基）苯氰。 In a fourth further preferred embodiment, the R1 is preferably a fluorenyl group of CrC 3 , more preferably a methyl group or an ethyl group; R 2 is preferably a fluorenyl group of C,-C 3 , more preferably a methyl group or an ethyl group; Preferred is an alkyl group of Cr C 3 , more preferably a methyl group or an ethyl group; R 6 is preferably an alkyl group of C 3 , more preferably a methyl group or an ethyl group; a halogen selected for R 10 is preferably C1 or Br, and a halogen selected for R 12 is preferably C1 or Br. . At this time, the compound of the fourth further preferred embodiment of the present invention is preferably 2-bromo-4-(1-(4-oxo-4,5,6,7-tetrahydroindole)) phenyl cyanide, 2-bromo - 4- (1-(4-oxo-4,5,6,7-tetrahydroindole) methyl) phenyl cyanide, 2-bromo-4-(1-(3, 6, 6-trimethyl-) 4-oxo-4,5,6,7-tetrahydroindole)) phenyl cyanide, 2-bromo-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6 , 7-tetrahydro-indole) methyl) benzonitrile, 2-bromo --4- (BU (3, 6, 6-trimethyl - 4 - oxo-4, 5, 6, 7-- tetrahydroindole) Benzoylamide, 2-bromo-4-(1-(3-methyl-4-oxo-4,5,6,7-tetrahydroindole) 哚)) phenyl cyanide, or 2-bromo-4-(1-(3-methyl-4-oxo-4,5,6,7-tetrahydroindole)methyl)benzene cyanide.
上述第四种进一步优选的技术方案中， 所述的 R10选择取代的氨基时优选烷氨基， 进一步优选环垸氨基、支链烷氨基或直链烷氨基， 更进一步优选环己氨基、 乙氨基、 4 - 羟基环己氨基、 4-氨基乙酰氧基环己氨基、 2-二乙氨基乙氨基、 2- (4-吗啉） 乙氨基、 2- ( 1, 2, 3)三氮唑乙氨基、 2- ( 1- (3, 5 -二甲基哌啶）） 乙氨基、 2- ( 1-哌啶） 乙 氨基、 2- ( 1-吡咯烷基） 乙氨基、 或（2—四氢呋喃） 甲氨基。 这时本发明第四种迸一 步优选的技术方案的化合物优选为 2- (2-四氢呋喃）甲氨基 -4- (1- (3， 6, 6-三甲基 -4-氧 - 4， 5， 6, 7-四氢吲噪)）苯甲酰胺、 2-环己氨基- 4- (1- (3， 6， 6-三甲基 -4-氧 -4， 5， 6， 7-四氢吲哚)）苯甲酰胺、 2- (2-二乙氨基乙氨基）- 4- ( 1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6, 7 - 四氢吲哚））苯甲酰胺、 2- (2- (4-吗啉）乙氨基） - 4- (卜 (3, 6， 6-三甲基 -4-氧- 4， 5， 6， 7- 四氢吲哚））苯甲酰胺、 2- (4-羟基环己氨基） -4- ( 1- (3， 6， 6-三甲基 -4-氧- 4, 5， 6, 7 -四氢吲哚）) 苯甲酰胺、 或 2 - (2- (1，2, 3)三氮唑乙氨基 ) -4- ( 1- (3， 6， 6-三甲基 - 4 -氧- 4， 5, 6， 7-四氢吲哚））苯甲酰胺。  In a fourth preferred embodiment, the R10 is preferably an alkylamino group, more preferably a cyclodecylamino group, a branched alkylamino group or a linear alkylamino group, and still more preferably a cyclohexylamino group or an ethylamino group. 4-hydroxycyclohexylamino, 4-aminoacetoxycyclohexylamino, 2-diethylaminoethylamino, 2-(4-morpholine)ethylamino, 2-(1,2,3)triazoleethylamino , 2-(1-(3,5-dimethylpiperidine))ethylamino, 2-(1-piperidine)ethylamino, 2-(1-pyrrolidinyl)ethylamino, or (2-tetrahydrofuran) Methylamino. At this time, the compound of the fourth preferred embodiment of the present invention is preferably 2-(2-tetrahydrofuran)methylamino-4-(1-(3,6-6-trimethyl-4-oxo-4, 5) , 6, 7-tetrahydrofluorene)) benzamide, 2-cyclohexylamino-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-four Hydroquinone))benzamide, 2-(2-diethylaminoethylamino)- 4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7 - four Hydroquinone))benzamide, 2-(2-(4-morpholino)ethylamino)-4-(b (3,6,6-trimethyl-4-oxo-4, 5, 6, 7) - tetrahydroanthracene))benzamide, 2-(4-hydroxycyclohexylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7 - Tetrahydroindole)) Benzamide, or 2-(2-(1,2,3)triazole ethylamino)-4-(1-(3,6,6-trimethyl-4-ethoxy-) 4, 5, 6, 7-tetrahydroanthracene)) Benzamide.
上述第四种进一步优选的技术方案中，所述的 R10选择杂环时，优选单杂环或双杂 环， 进一步优选的单杂环是哌嗪或哌啶， 进一步优选的双杂环是喹啉。这时本发明第四 种进一步优选的技术方案的化合物优选为 2- ( 1-哌啶） -4- ( 1- (3， 6， 6-三甲基 -4-氧 _4， 5， 6, 7-四氢吲哚））苯氰、 或 2- ( 1 -哌啶) -4 - ( 1- (3， 6， 6-三甲基 -4 -氧- 4， 5， 6， 7- 四氢吲哚））苯甲酰胺。  In the above fourth preferred embodiment, when the R10 is selected as a heterocyclic ring, a monoheterocyclic ring or a bicyclic heterocyclic ring is preferred, a further preferred monoheterocyclic ring is piperazine or piperidine, and a further preferred bicyclic heterocyclic ring is quinolin. Porphyrin. At this time, the compound of the fourth further preferred embodiment of the present invention is preferably 2-(1-piperidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6) , 7-tetrahydroanthracene)) phenyl cyanide, or 2-( 1 -piperidinyl) -4 - ( 1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7- Tetrahydropurine)) benzamide.
上述第四种进一步优选的技术方案中，所述的 R10选择取代的杂环，优选取代的单 杂环或取代的双杂环， 进一步优选取代的单杂环是取代的哌嗪、取代的吡咯'垸基、或取 代的哌啶， 更进一步优选取代的单杂环是 1-哌嗪、 4-甲基哌嗪、 4- (2- (4-吗啉） 乙 基） 哌嗪、 （4-环戊烷基）哌嗪、 4- (2-羟乙基）哌嗪、 或 4- (2-吡啶）哌嗪、 3-羟基 吡咯垸基、 4-氧-哌啶、 4-羟基哌啶、 3—羟基哌啶、 4一氨基乙酰氧基哌啶、 4- (4 -吗 啉） 哌啶、 4- ( 1-吡咯垸基）哌啶、 或 4- (2- (卜哌啶） 乙氧基） 哌啶。 这时本发明 第四种进一步优选的技术方案的化合物优选为 2- (1- (3-羟基吡咯烷基 ))-4- 3， 6, 6- 三甲基 -4-氧- 4, 5, 6， 7-四氢吲哚））苯氰、 2- ( 1 (3 -羟基吡咯烷基）) -4- ( 1- (3, 6， 6- 三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚）)苯甲酰胺、 2- (1- (4 -甲基哌嗪）) -4- (1- (3, 6, 6- 三甲基 -4-氧 -4， 5, 6， 7-四氢吲哚）甲基）苯甲酰胺、 2 -（1- (4-氧-哌啶））- 4- ( 1-（3, 6， 6 - 三甲基 -4 -氧- 4, 5， 6， 7-四氢吲哚））苯甲酰胺、 2- (1- (4-羟基哌啶）） -4- ( 1- (3, 6, 6- 三甲基 -4-氧- 4， 5, 6， 7-四氢吲哚））苯甲酰胺、 2- ( 1- (4- (4-吗啉） 哌啶）） -4- ( 1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚））苯甲酰胺、 2- ( 1- (4- (2- (4-吗啉) 乙 基） 哌嗪）） -4- ( 1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚）)苯甲酰胺、 或 2 -（1- (4 - ( 1 -吡咯烷基)哌啶）） -4- ( 1- (3， 6, 6-三甲基 -4-氧 -4， 5, 6, 7-四氢吲哚）)苯甲 酰胺。 进一步优选取代的双杂环是 6、 7-二甲氧基- 1， 2， 3, 4-四氢异喹啉， 这时本发 明第四种进一步优选的技术方案的化合物为 2- (2- (6, 7-二甲氧基- 1， 2, 3， 4-四氢异喹 啉）） -4- ( 1- (3, 6, 6-三甲基 -4 -氧- 4， 5, 6， 7-四氢吲哚）)苯甲酰胺。 In a fourth further preferred embodiment, the R10 is a substituted heterocyclic ring, preferably a substituted monoheterocyclic ring or a substituted bicyclic heterocyclic ring, and further preferably the substituted monoheterocyclic ring is a substituted piperazine or a substituted pyrrole. 'Mercapto or substituted piperidine, still more preferably substituted monoheterocycle is 1-piperazine, 4-methylpiperazine, 4-(2-(4-morpholine)ethyl)piperazine, (4 -cyclopentyl)piperazine, 4-(2-hydroxyethyl)piperazine, or 4-(2-pyridyl)piperazine, 3-hydroxypyrrolidino, 4-oxo-piperidine, 4-hydroxypiperidin Pyridine, 3-hydroxypiperidine, 4-aminoacetoxypiperidine, 4-(4-morpholine)piperidine, 4-(1-pyrrolidinyl)piperidine, or 4-(2-(piperidine) ) Ethoxy) piperidine. In this case, the compound of the fourth further preferred embodiment of the present invention is preferably 2-(1-(3-hydroxypyrrolidinyl)-4-yl,6,6-trimethyl-4-oxo-4,5. , 6, 7-tetrahydroanthracene)) phenyl cyanide, 2-(1 (3-hydroxypyrrolidinyl))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroanthracene))benzamide, 2-(1-(4-methylpiperazine))-4-(1-(3, 6, 6-trimethyl-4-oxo) -4, 5, 6, 7-tetrahydroindole)methyl)benzamide, 2-(1-(4-oxo-piperidine))- 4- (1-(3, 6, 6 - trimethyl) 4--4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(1-(4-hydroxypiperidinyl)-4-(1-(3, 6, 6-) Trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(1-(4-(4-morpholinyl)piperidine)-4-(1- (3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(1-(4-(2-(4-morpholine)) B Base) piperazine)) -4- (1-(3, 6, 6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzamide, or 2-(1) - (4 - ( 1 -pyrrolidinyl) piperidine)) -4- ( 1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroanthracene)) Benzoylamide. Further preferably, the substituted bicyclic heterocycle is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, and the compound of the fourth further preferred embodiment of the present invention is 2-(2) - (6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5 , 6, 7-tetrahydroanthracene)) benzamide.
上述优选的技术方案中， 第五种进一步优选的技术方案为： X选择 C一 Rl ; Y、 Ζ 选择第三种组合； Rl、 R2选择第二种组合， 且 R1和 R2可以共同形成的一个芳香环优 选苯环， 可共同形成的一个取代的芳香环优选三氟甲基取代的苯环； R5优选 Cr C3的烷 基， 更优选甲基； R6优选 C,- ( 3的垸基， 更优选甲基； R10、 R11选择第一种组合， 其中 的 R11优选氨甲酰基； R12优选 H。 本发明第五种进一步优选的技术方案的化合物优选 为 2- ( 1- (4 -羟基哌啶）) -4- (9- (2, 2-二甲基 _4 -氧- 1， 2， 3, 4_四氢咔唑））苯甲酰胺、 2- (4-羟基环己氨基） -4- (9- (2，2-二甲基 - 4-氧- 1，2，3，4-四 咔唑））苯甲酰胺、 2- ( 1- (4- (2 -羟乙基) 哌嗪）） -4- (9- (2，2-二甲基 - 4 -氧- 1，2，3，4-四氢咔唑））苯甲 酰胺、 2 - ( 1- (4 -甲基哌嗪）) -4- (9- (2, 2 二甲基 -4 -氧- 6-三氟甲基- 1, 2, 3, 4 -四氢 咔唑））苯甲酰胺、 2- (卜 (4-羟基哌啶）） -4- (9- (2, 2-二甲基 -4-氧- 6-三氟甲基- 1， 2， 3, 4- 四氢咔唑）） 苯甲酰胺、 或 2- (4-羟基环己氨基） -4- (9- (2, 2-二甲基 -4-氧 6-三氟 甲基 _1， 2, 3， 4-四氢咔唑））苯甲酰胺。 In the above preferred technical solution, a fifth further preferred technical solution is: X selects C-R1; Y, Ζ selects a third combination; R1, R2 selects a second combination, and R1 and R2 can form a common one. The aromatic ring is preferably a benzene ring, and a substituted aromatic ring which may be formed together is preferably a trifluoromethyl-substituted benzene ring; R5 is preferably an alkyl group of Cr C 3 , more preferably a methyl group; and R 6 is preferably a C,-( 3 fluorenyl group, More preferably, the methyl group; R10, R11, the first combination is selected, wherein R11 is preferably a carbamoyl group; R12 is preferably H. The compound of the fifth further preferred embodiment of the present invention is preferably 2-(1-(4-hydroxylperyl) Acridine)) -4- (9-(2,2-dimethyl-4-oxo-1, 2,3,4_tetrahydrocarbazole))benzamide, 2-(4-hydroxycyclohexylamino) -4- (9-( 2 ,2-dimethyl-4-oxo-1,2,3,4-tetraoxazole))benzamide, 2- (1-(4-(2-hydroxyethyl) Piperazine)) -4- (9-(2,2-dimethyl- 4 -oxo-1,2,3,4-tetrahydrocarbazole))benzamide, 2 - ( 1- (4 - Methylpiperazine)) -4- (9-(2, 2 dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole))benzene Formamide, 2-(Bu(4-hydroxypiperidine))-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl- 1, 2, 3, 4- 4 Hydrocarbazole)) Benzamide, or 2-(4-hydroxycyclohexylamino)-4-(9-(2,2-dimethyl-4-oxo 6-trifluoromethyl_1, 2, 3 , 4-tetrahydrocarbazole)) benzamide.
上述优选的技术方案中，第六种进一步优选的技术方案为： n选择 0; X选择 C一 R1 ; Y、 Ζ选择第二种组合； Rl、 R2选择第一种组合， 其中的 R1优选烷基， 更优选甲基， 其 中的 R2优选 H; R5优选 d- 的烷基， 更优选甲基； R6优选 d- C3的烷基， 更优选甲基； R10、 R11选择第一种组合， 其中的 R11优选氨甲酰基； R12优选 H。 本发明第六种进一 步优选的技术方案的化合物为 5: ( 1- (2， 6， 6-三甲基 -4-氧- 4, 5, 6, 7-四氢吲哚））吡啶 - 2-甲酰胺。 In the above preferred technical solution, a sixth further preferred technical solution is: n selects 0; X selects C-R1; Y, Ζ selects the second combination; R1, R2 selects the first combination, wherein R1 is preferably an alkane group, more preferably methyl, wherein R2 is preferably H; R5 preferably d- alkyl, more preferably methyl; R6 preferably is d- C 3 alkyl, more preferably methyl; R10, R11 selecting the first combination, Wherein R11 is preferably a carbamoyl group; and R12 is preferably H. A compound of a sixth preferred embodiment of the present invention is 5 : (1-(2,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))pyridine-2 - Formamide.
上述优选的技术方案中，第七种进一步优选的技术方案为： n选择 0; X选择 C一 R1 ; Y、 Ζ选择第三种组合； Rl、 R2选择第一种组合， 且其中的 R1优选 H; R2优选嫁基， 更 优选甲基； R5优选 d- C3的烷基， 更优选甲基； R6优选 d- C3的烷基， 更优选甲基； R10、 R11选择第二种组合， 且 R10和 R11可共同形成的一个杂环优选吡唑， 可共同形成的一 个取代的杂环优选 5-氨基吡唑； R12优选 H。本发明第七种进一步优选的技术方案的化 合物优选为 1- (6- (3-氨基- 1H -吲唑）） -3, 6, 6-三甲基 -1, 5, 6, 7-四氢吲哚- 4 -酮。 In the above preferred technical solution, the seventh further preferred technical solution is: n selects 0; X selects C-R1; Y, Ζ selects the third combination; R1, R2 selects the first combination, and wherein R1 is preferred H; R2 marry preferred group, more preferably methyl; R5 is preferably d- C 3 alkyl group, more preferably methyl; R6 preferably d- C 3 alkyl group, more preferably methyl; R10, R11 selected second combination And a heterocyclic ring which R10 and R11 may form together is preferably pyrazole, and a substituted heterocyclic ring which may be formed together is preferably 5-aminopyrazole; R12 is preferably H. The compound of the seventh further preferred embodiment of the present invention is preferably 1-(6-(3-amino-1H-indazole))-3,6,6-trimethyl-1, 5, 6, 7-tetra Hydroquinone-4-ketone.
上述优选的技术方案中， 第八种进一步优选的技术方案为： X选择 N或 C一 Rl ; Y、 Ζ选择第三种组合， 即 Υ选择 CH; Ζ选择 C一 RIO; Rl、 R2选择第一种组合， 且其中 R1 优选 H、 甲基或乙基， R2优选 H、 甲基或乙基； R5优选 H、 甲基或乙基； R6优选 H、 甲 基或乙基； R10、 R11选择第一种组合， 且 R10优选 H、 卤素、 取代的氨基、 杂环或取代 的杂环； R11优选氨甲酰基或氰基； R12优选 H、 C1或 Br。 In the above preferred technical solution, the eighth further preferred technical solution is: X selects N or C-R1; Y, Ζ selects the third combination, that is, selects CH; Ζ selects C-RIO; R1, R2 selects a combination, and where R1 Preferably H, methyl or ethyl, R2 is preferably H, methyl or ethyl; R5 is preferably H, methyl or ethyl; R6 is preferably H, methyl or ethyl; R10, R11 are selected for the first combination, and R10 Preference is given to H, halogen, substituted amino, heterocyclic or substituted heterocyclic ring; R11 is preferably carbamoyl or cyano; R12 is preferably H, C1 or Br.
上述第八种进一步优选的技术方案中， R10所选择的卤素优选 C1或 Br; R10所选择 的取代的氨基优选 2-二乙氨基乙氨基、 2- (4-吗啉） 乙氨基、 2- (1， 2, 3)三氮唑乙 氨基、 2- (1- (3， 5-二甲基哌啶））乙氨基、 2- (1-哌啶）乙氨基、 2-环丙垸氨基； R10 所优选的杂环是 1-哌啶； R10选择的取代的杂环优选 4-甲基哌嗪、（4-环戊垸基）哌嗪、 4-羟基哌啶、 4- (1-吡咯烧基）哌啶。本发明第八种进一步优选的技术方案的化合物优 选为 2-溴- 4-（1- (4 -氧- 4， 5, 6, 7-四氢吲哚）)苯氰、 2 -溴 -4- (1- (4一氧一 4， 5， 6, 7 -四 氢吲哚） 甲基）苯氰、 2-溴- 4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚））苯氰、 2-溴- 4- (1-(3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7 -四氢吲哚)甲基）苯氰、 2 -溴- 4- (卜（3， 6， 6- 三甲基 -4-氧- 4， 5, 6， 7-四氢吲哚) )苯甲酰胺、 2 -溴- 4- (1- ( 3, 6, 6-三甲基 -4 -氧 -4, 5, 6, 7-四氢吲哚）甲基)苯甲酰胺、 2- (卜哌啶)- 4- (卜 (3, 6， 6-三甲基 -4-氧- 4， 5， 6, 7- 四氢吲哚））苯甲酰胺、 2- (2-二乙氨基乙氨基） -4- (1- (3， 6， 6-三甲基 -4 -氧 4， 5， 6, 7- 四氢吲哚））苯甲酰胺、 2- (2- (4 -吗啉）乙氨基） - 4- (1 -（3, 6, 6 -三甲基- 4-氧- 4, 5, 6， 7- 四氢吲哚））苯甲酰胺、 2 -溴 -4- (1- (4-氧- 4， 5, 6， 7-四氢吲唑）） 苯氰、 2-溴- 4- (1- In the above eighth preferred embodiment, the halogen selected for R10 is preferably C1 or Br; and the substituted amino group selected by R10 is preferably 2-diethylaminoethylamino, 2-(4-morpholine)ethylamino, 2- (1, 2, 3) triazole ethylamino, 2-(1-(3, 5-dimethylpiperidine))ethylamino, 2-(1-piperidinyl)ethylamino, 2-cyclopropenylamino The preferred heterocyclic ring for R10 is 1-piperidine; the substituted heterocyclic ring selected for R10 is preferably 4-methylpiperazine, (4-cyclopentamethylene) piperazine, 4-hydroxypiperidine, 4-(1- Pyrrolidinyl) piperidine. The compound of the eighth preferred embodiment of the present invention is preferably 2-bromo-4-(1-(4-oxo-4,5,6-7-tetrahydroindole)) phenyl cyanide, 2-bromo-4 - (1-(4-oxo-4,5,6,7-tetrahydroindole) methyl)benzonitrile, 2-bromo-4-(1-(3,6,6-trimethyl-4-) Oxygen - 4, 5, 6, 7-tetrahydroanthracene)) phenyl cyanide, 2-bromo-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7) -tetrahydroindole)methyl)benzonitrile, 2-bromo-4-(Bu(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzene Formamide, 2-bromo-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole)methyl)benzamide, 2-( Piperidine)- 4- (Bu (3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole)) benzamide, 2-(2-diethylamino) Ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(2-(4-) Phenanyl)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-bromo-4- (1-(4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide, 2-bromo - 4- (1-
(3 -甲基 -4-氧- 4, 5， 6， 7-四氢吲唑） 甲基） 苯氰、 2 -溴- 4-（1- (3, 6， 6-三甲基 -4 -氧 - 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 2- (2 -二乙氨基乙氨基） -4 (1- (3， 6， 6-三甲基 -4- 氧- 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 2- (2- (1-哌啶） 乙氨基） -4- (1- (3， 6， 6-三甲 基 -4 -氧- 4， 5， 6， 7-四氢吲唑）)苯甲酰胺、 2 (1- (4 -甲基哌嗪）) -4- (1- (3,6,6-三 甲基 -4-氧- 4,5,6,7-四氢吲唑））苯甲酰胺、 2- (2- (1- (3,5-二甲基哌啶）) 乙氨基） -4- (1- (3,6,6-三甲基 -4 -氧- 4， 5, 6, 7 -四氢吲唑））苯甲酰胺、 2- (2 -（1， 2， 3)三氮唑 乙氨基） -4- (1- (3， 6， 6-三甲基 -4-氧- 4,5,6,7-四氢吲唑）） 苯甲酰胺、 2- (1- (4 - 羟基哌啶）） -4- (1- (3, 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 2- (1- (4 -(3-methyl-4-oxo-4,5,6,7-tetrahydrocarbazole) methyl) phenyl cyanide, 2-bromo-4-(1-(3,6,6-trimethyl-4) -oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-diethylaminoethylamino)-4 (1-(3,6,6-trimethyl-4-) Oxygen-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(1-piperidine)ethylamino)-4-(1-(3,6,6-trimethyl) -4 -oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2 (1-(4-methylpiperazine))-4-(1-(3,6,6-three) Methyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(1-(3,5-dimethylpiperidine))ethylamino)-4 - (1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, 2-(2 -(1, 2, 3) three Azole, ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) benzamide, 2-(1-( 4-hydroxypiperidin))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2- (1 - (4 -
(1 -吡咯烷基)哌啶）） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑）)苯甲酰胺、 2- (1- (4 -环戊烷基)哌嗉） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑））苯甲 酰胺、 或 2-环丙'垸氨基 -4- (1- (3,6,6-三甲基 -4-氧- 4,5,6,7-四氢吲唑））苯甲酰胺。 (1 -pyrrolidinyl) piperidine)) -4- (1-(3, 6, 6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, 2-(1-(4-cyclopentyl)piperidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole) Benzoylamide, or 2-cyclopropanylamino-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) Amide.
上述优选的技术方案中的化合物优选为 2-氯- 4- (1-(3， 6， 6-三甲基 -4-氧 -4， 5， 6, 7- 四氢吲唑)）苯氰、 2- (1- (4 甲基哌嗪)） -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5, 6, 7-四氢吲唑)） 苯氰、 2- (1- (4-甲基哌嗪）） -4- (1- (3， 6， 6 -三甲基- 4-氧- 4, 5， 6， 7-四氢吲唑）)苯 甲酰胺、 2- (1- (3-羟基吡咯烷基）） -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚）） 苯氰、 2- (1- (3-羟基吡咯烷基）） -4- (1- (3,6,6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚）） 苯甲酰胺、 2- (1-哌啶） -4- (1- (3,6,6-三甲基 -4-氧- 4,5,6,7-四氢吲哚））苯氰、 2-The compound of the above preferred embodiment is preferably 2-chloro-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide. , 2-(1-(4methylpiperazine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) benzene Cyanide, 2-(1-(4-methylpiperazine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole) Benzoylamide, 2-(1-(3-hydroxypyrrolidinyl))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro)吲哚)) Benzoic acid, 2-(1-(3-hydroxypyrrolidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole) )) Benzamide, 2-(1-piperidine)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroanthracene))benzene Cyanide, 2-
(1 -哌啶) -4- (1- (3， 6， 6-三甲基 -4氧- 4, 5， 6, 7-四氢吲哚）)苯甲酰胺、 2- (1- (4- 甲基哌嗪）） -4- (1- (3, 6， 6-三甲基 -4-氧- 4, 5, 6， 7-四氢吲哚) 甲基） 苯甲酰胺、 2- 环己氨基- 4- (1- (3， 6, 6-三甲基 -4 -氧- 4， 5， 6， 7-四氢吲哚)）苯甲酰胺、 2- (2-二乙氨 基乙氨基） -4- (1- (3， 6， 6-三甲基 -4-氧- 4,5,6,7-四氢吲哚）)苯甲酰胺、 2- (2- (4- 吗啉） 乙氨基） -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚）)苯甲酰胺、 2- (1-(1 - piperidine) -4- (1-(3, 6, 6-trimethyl-4 oxo-4, 5, 6, 7-tetrahydroindole)) benzamide, 2- (1- ( 4-methylpiperazine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole) methyl)benzamide, 2 - Cyclohexylamino-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(2-diethyl) Aminoethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2- (2- (4) -morpholine)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2- (1 -
(4-氧-哌啶）） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲哚）)苯甲酰胺、 2- (1-(4-oxo-piperidine))-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzamide, 2- (1-
(4 -羟基哌啶）) -4- (1- (3, 6, 6 -三甲基- 4-氧 -4， 5， 6, 7 -四氢吲哚）)苯甲酰胺、 2- (4- 羟基环己氨基） -4 -（1- (3, 6， 6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲哚））苯甲酰胺、 2- (1- (4- (4-吗啉） 哌啶）） -4- (1- (3,6,6-三甲基 -4-氧- 4,5,6,7-四氢吲哚）)苯 甲酰胺、2- (2- (1, 2, 3)三氮唑乙氨基 )_4- (1- (3， 6， 6-三甲基 -4 -氧- 4， 5， 6, 7-四氢吲哚）） 苯甲酰胺、 2- (1- (4- (2- (4-吗啉）乙基)哌嗪））-4- (1-(3, 6, 6_三甲基 -4-氧- 4， 5， 6， 7- 四氢吲哚））苯甲酰胺、 2- (1- (4- (1 -吡咯垸基)哌啶）） -4一 (1- (3， 6， 6-三甲基 -4 - 氧- 4,5,6,7-四氢吲哚））苯甲酰胺、 2- (2 -二乙氨基乙氨基) -4- (1- (3,6,6-三甲基 - 4 -氧- 4， 5, 6， 7-四氢吲唑））苯甲酰胺、 2-环己氨基- 4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6, 7-四氢 Π 唑)）苯甲酰胺、 2- (2- (1 -哌啶) 乙氨基） -4_ (1- (3,6,6-三甲基 -4 -氧 - 4， 5， 6， 7-四氢吲唑）） 苯甲酰胺、 2- (2- (1- (3, 5 二甲基哌啶）） 乙氨基） -4- (1-(4-hydroxypiperidine))-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzamide, 2-( 4-hydroxycyclohexylamino) -4 -(1-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2- (1 - (4-(4-morpholine)piperidine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzene Formamide, 2-(2-(1, 2, 3)triazole ethylamino)_4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetra Hydroquinone)) Benzamide, 2-(1-(4-(2-(4-morpholinyl)ethyl)piperazine))-4-(1-(3, 6, 6-trimethyl- 4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(1-(4-(1-pyridinyl)piperidine))-4(1-(3, 6, 6-trimethyl-4 -oxy-4,5,6,7-tetrahydroanthracene))benzamide, 2-(2-diethylaminoethylamino)-4-(1-(3, 6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-cyclohexylamino-4-(1-(3, 6, 6-trimethyl) 4--4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(1-piperidyl)ethylamino)-4_(1-(3,6,6- Trimethyl-4-oxo-4 , 5, 6, 7-tetrahydrocarbazole))benzamide, 2-(2-(1-(3,5-dimethylpiperidine))ethylamino)-4-(1-
(3,6,6-三甲基 -4-氧 -4， 5, 6, 7-四氢吲唑）) 苯甲酰胺、 2- (2- (1, 2， 3)三氮唑乙氨基） -4- (1- (3， 6， 6-三甲基 -4-氧 -4, 5， 6， 7-四氢吲唑）)苯甲酰胺、 2- (1- (4-环戊烷基) 哌嗪） -4- (1- (3, 6， 6-三甲基- 4-氧- 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 2-环丙垸氨基- 4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) benzamide, 2-(2-(1, 2, 3)triazole ethylamino ) -4- (1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2-(1-(4-cyclopentyl) Alkyl) piperazine) -4- (1-(3, 6, 6-trimethyl-4-hydroxy- 4, 5, 6, 7-tetrahydrocarbazole)) benzamide, 2-cyclopropene Amino- 4-
(1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7_四氢吲唑））苯甲酰胺、 2- (1- (4- (2- (1-哌啶) 乙氧基）哌啶）） -4- (1- (3, 6, 6-三甲基 -4-氧- 4， 5, 6, 7-四氢吲唑）)苯甲酰胺、 2- (1-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7_tetrahydrocarbazole)) benzamide, 2- (1- (4- (2- (1-) Piperidine) ethoxy) piperidine)) -4- (1-(3, 6, 6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, twenty one-
(4 -氧-哌啶）) -4- (1- (3， 6， 6-三甲基 -4 -氧- 4， 5， 6， 7-四氢吲唑）)苯甲酰胺、 2- (1-(4-oxo-piperidine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2- (1-
(4- (2羟乙基） 哌嗪）） -4- (1- (3,6,6-三甲基 -4 -氧- 4,5,6,7-四氢吲唑）) 苯甲酰 胺、 2- (2- (4-吗啉） 乙氨基） -4- (1- (3, 6， 6-三甲基 -4-氧- 4, 5， 6， 7-四氢吲唑）)苯 甲酰胺、 2- (1- (4- (1-吡咯垸基) 哌啶）） -4 - (1 (3， 6， 6-三甲基 -4-氧- 4， 5, 6,7- 四氢吲唑））苯甲酰胺、 2- (1- (4- (2- (4-吗啉） 乙基） 哌嗪）） -4- (1- (3， 6， 6 -三 甲基- 4-氧- 4， 5, 6， 7-四氢吲唑）)苯甲酰胺、 2- (1- (4-羟基哌啶）)—4- (1 - (3， 6， 6- 三甲基- 4-氧- 4， 5, 6, 7-四氢吲唑））苯甲酰胺、 2- (1- (4-氨基乙酰氧基哌啶）） -4- (1-(4-(2-hydroxyethyl)piperazine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) Benzyl Amide, 2-(2-(4-morpholine)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole) Benzoylamide, 2-(1-(4-(1-pyrrolidino)piperidine)) -4 - (1 (3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2-(1-(4-(2-(4-morpholine)ethyl)piperazine))-4-(1-(3, 6, 6 -3) Methyl 4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-hydroxypiperidine))4-(1 - (3, 6, 6 - Trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-aminoacetoxypiperidine))-4-(1-
(3, 6, 6 -三甲基- 4-氧- 4， 5， 6, 7 -四氢吲唑）)苯甲酰胺、 2 (4-羟基环己氨基） -4- Clio (3, 6， 6 -三甲基- 4-氧- 4， 5, 6, 7-四氢吲唑）)苯甲酰胺、 2- (4 -氨基乙酰氧基环己 氨基） -4- (1- (3, 6， 6-三甲基 -4-氧- 4， 5， 6， 7 -四氢吲唑）)苯甲酰胺、 2- (2- (1- 吡咯垸基） 乙氨基） -4- (1- (3， 6, 6-三甲基 -4-氧 -4, 5， 6， 7-四氢吲唑））苯甲酰胺、 2-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2 (4-hydroxycyclohexylamino)-4- Clio (3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(4-aminoacetoxycyclohexylamino)-4- 1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, 2-(2-(1-pyrrolidinyl)ethylamino) -4- (1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2-
(1 -哌嗪) -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑））苯甲酰胺、 2- (1- (3- 羟基吡咯垸基）） -4- (1- (3, 6, 6-三甲基 -4-氧- 4, 5， 6, 7 -四氢吲唑）)苯甲酰胺、 2- (1-(1 - piperazine) -4- (1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) benzamide, 2- (1- (3-hydroxypyrrolidino))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, 2- (1-
(4- (4-吗啉）哌啶）） -4- (1- (3, 6， 6_三甲基 -4-氧 -4， 5， 6， 7-四氢吲唑）)苯甲酰胺、 2- (1- (3-羟基哌啶）） -4- (1- (3,6,6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲唑）)苯甲酰胺、 2- (2- (6, 7 -二甲氧基 _1， 2, 3, 4二四氢异喹啉）） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6, 7_ 四氢吲唑））苯甲酰胺、 2- (1 (4- (2-吡啶）哌嗪））-4- (1- (3， 6， 6-三甲基 -4-氧- 4, 5, 6, 7- 四氢吲唑））苯甲酰胺、 2- (1-哌啶) - 4- (1- (3， 6, 6-三甲基 -4氧- 4,5,6,7-四氢吲唑) ) 苯甲酰胺、 1- (6- (3 -氨基 -1H-吲唑）) - 3， 6， 6-三甲基 -1， 5， 6, 7-四氢吲哚- 4-酮、 1-(4-(4-morpholine)piperidine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) Amide, 2-(1-(3-hydroxypiperidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) Benzoylamide, 2-(2-(6,7-dimethoxy-1,2,3,4ditetrahydroisoquinoline)-4-(1-(3,6,6-trimethyl) -4-oxo-4, 5, 6, 7_tetrahydrocarbazole))benzamide, 2-(1 (4-(2-pyridine)piperazine)-4-(1-(3, 6, 6) -trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-piperidine)-4-(1-(3, 6, 6-trimethyl) Base-4 oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 1-(6-(3-amino-1H-carbazole))-3,6,6-trimethyl- 1, 5, 6, 7-tetrahydroindole-4-one, 1-
(6-（3 -氨基 -1H-吲唑）） - 3,6,6-三甲基 -1， 5， 6， 7-四氢吲唑 -4-酮、 2- (1- (4-羟基哌 啶）） -4- (9- (2， 2-二甲基 -4-氧- 1,2, 3， 4-四氢咔唑）)苯甲酰胺、 2- (4-羟基环己氨 基） -4- (9- (2， 2-二甲基 -4-氧 1,2， 3, 4-四氢咔唑））苯甲酰胺、 2- (1 -（4- (2-羟乙 基） 哌嗪）） -4- (9- (2， 2-二甲基 -4 -氧- 1,2， 3， 4-四氢咔唑））苯甲酰胺、 2- (1- (4- 甲基哌嗪）） -4- (9- (2,2-二甲基 -4-氧- 6-三氟甲基 -1,2， 3， 4-四氢咔唑）)苯甲酰胺、 2- (1- (4 -羟基呃啶）) -4- (9- (2,2-二甲基 -4 -氧- 6-三氟甲基 -1,2， 3， 4-四氢咔锉）) 苯甲酰胺、 2- (4 -羟基环己氨基) -4- (9- (2，2-二甲基 - 4-氧- 6-三氟甲基- 1，2，3，4_ 四氢咔唑））苯甲酰胺、 2-环己氨基- 4- (9- (2，2-二甲基 -4-氧- 3-三氟甲基- 4， 5， 6,7- 四氢吲唑）） 苯甲酰胺、 2- (4-羟基环己氨基） -4- (1- (6， 6-二甲基 -4-氧- 3-三氟甲 基- 4, 5， 6， 7-四氢吲唑））苯甲酰胺、 N- (2- [1， 2, 3]三氮唑乙基) -4- (1- (3， 6， 6) 三甲基 -4-氧- 4， 5, 6， 7-四氢吲唑））苯甲酰胺、 N- (2- (4-吗啉） 乙基) -4- (1- (3， 6， 6)三甲基 -4-氧- 4， 5， 6， 7 -四氢吲唑）)苯甲酰胺、 N- (4-羟基环己基) -4- (1- (3， 6， 6)三甲基 -4-氧 -4， 5， 6， 7-四氢吲唑））苯甲酰胺、 N- (2- (1- (4-羟基哌啶）） 乙 基)- 4- (1- (3， 6， 6)三甲基 -4-氧- 4， 5， 6， 7 -四氢吲唑）)苯甲酰胺、 5- (1- (2，6，6_ 三甲基 -4-氧- 4, 5, 6, 7-四氢吲哚））吡啶- 2-甲酰胺、 2-溴- 4- (1- (4-氧- 4， 5, 6, 7-四氢 吲哚））苯氰、 2 -溴 - 4- (1- (4-氧- 4, 5, 6， 7 -四氢吲哚)甲基）苯氰、 2 -溴- 4- (1- (3， 6, 6 - 三甲基 -4-氧- 4， 5, 6, 7-四氢吲哚））苯氰、 2-溴- 4- (1- (3， 6， 6-三甲基 -4-氧- 4, 5， 6， 7- 四氢吲哚） 甲基）苯氰、 2-溴- 4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚) )苯甲 酰胺、 2-溴- 4 - (1- (3-甲基- 4-氧- 4, 5， 6， 7-四氢吲哚）） 苯氰、 2-溴- 4 - (1- (3 -甲基 —4—氧—4， 5， 6, 7—四氢吲哚) 甲基） 苯氰、 2 -溴- 4- (卜 (3-甲基- 4-氧- 4， 5， 6， 7-四氢吲 唑））苯氰、 2-溴- 4- (1- (3-甲基- 4-氧- 4, 5, 6， 7-四氢吲唑） 甲基）苯氰、 4- (1- (4- (2 -羟乙基) 哌嗪）） -6- (1- (3,6,6-三甲基 -4 -氧 -4,5， 6， 7-四氢吲唑）)烟碱酰胺、 4- (1- (4-羟基哌啶）) -6- (1- (3,6,6-三甲基 -4 -氧- 4， 5, 6， 7-四氢吲唑））烟碱酰胺、 N- (4-乙酰氧环己基 )-4- (1- (3， 6, 6)三甲基 -4 -氧- 4， 5， 6， 7-四氢吲唑））苯甲酰 胺、 N-(l- (4- (2-吡啶）哌嗪） -4- (1- (3， 6， 6)三甲基 -4-氧- 4， 5， 6， 7-四氢吲 唑））苯甲酰胺、 2- (2-四氢呋喃）甲氨基 -4- (1- (3, 6， 6_三甲基 -4-氧- 4， 5, 6, 7 -四氢 吲哚)）苯甲酰胺、 或 2- (2-四氢呋喃）甲氨基 -4- (1- (3， 6， 6-三甲基 4-氧- 4， 5， 6， 7- 四氢吲唑)）苯甲酰胺。 (6-(3-amino-1H-carbazole)) - 3,6,6-trimethyl-1, 5, 6, 7-tetrahydrocarbazol-4-one, 2- (1- (4- Hydroxypiperidine))-4-(9-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole))benzamide, 2-(4-hydroxycyclohexane Amino)-4-(9-(2,2-dimethyl-4-oxo 1,2,3,4-tetrahydrocarbazole))benzamide, 2-(1 -(4-(2-hydroxy) Ethyl) piperazine))-4-(9-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole))benzamide, 2-(1-( 4-methylpiperazine))-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole)) Amide, 2-(1-(4-hydroxyacridinyl)-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3, 4-tetra Hydroquinone)) Benzamide, 2-(4-hydroxycyclohexylamino)-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl- 1,2,3 ,4_tetrahydrocarbazole))benzamide, 2-cyclohexylamino-4-(9-(2,2-dimethyl-4-oxo-3-trifluoromethyl-4, 5, 6,7) - tetrahydrocarbazole)) benzamide, 2-(4-hydroxycyclohexylamino)-4-(1-(6,6-dimethyl-4-oxo-3-trifluoromethyl- 4, 5 , 6, 7-four Carbazole))benzamide, N-(2-[1,2,3]triazolylethyl)-4-(1-(3, 6, 6) trimethyl-4-oxo-4, 5 , 6, 7-tetrahydrocarbazole))benzamide, N-(2-(4-morpholine)ethyl)-4-(1-(3, 6, 6)trimethyl-4-oxo- 4, 5, 6, 7-tetrahydrocarbazole)) benzamide, N-(4-hydroxycyclohexyl)-4-(1-(3, 6, 6)trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole))benzamide, N-(2-(1-(4-hydroxypiperidinyl))ethyl)- 4- (1-(3, 6, 6) trimethyl 4--4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 5-(1-(2,6,6-trimethyl-4-oxo-4, 5, 6, 7 -tetrahydroanthracene))pyridine-2-formamide, 2-bromo-4-(1-(4-oxo-4,5,6-7-tetrahydroindole)) phenyl cyanide, 2-bromo-4 - (1-(4-oxo-4,5,6,7-tetrahydroindole)methyl)benzonitrile, 2-bromo-4-(1-(3,6,6-trimethyl-4-) Oxygen - 4, 5, 6, 7-tetrahydroanthracene)) phenyl cyanide, 2-bromo-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7) - tetrahydroanthracene) methyl)benzonitrile, 2-bromo-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroanthracene)) Benzoylamide, 2-bromo-4-(1-(3-methyl-4-oxo-4,5,6,7-tetrahydroindole)) phenyl cyanide, 2-bromo-4-(1-(3-methyl) — 4 — Oxygen — 4 , 5 , 6 , 7 —Tetrahydroindole) Methyl)benzonitrile, 2 -bromo- 4- ( -(3-methyl-4-oxo-4, 5, 6, 7- Tetrahydropurine Acetone)) phenyl cyanide, 2-bromo-4-(1-(3-methyl-4-oxo-4,5,6,7-tetrahydrocarbazole)methyl)benzene cyanide, 4-(1-( 4-(2-hydroxyethyl) piperazine))-6-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))nicotine Amide, 4-(1-(4-hydroxypiperidinyl)-6-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) Nicotinamide, N-(4-acetoxycyclohexyl)-4-(1-(3, 6, 6)trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzene Formamide, N-(l-(4-(2-pyridine)piperazine)-4-(1-(3, 6, 6)trimethyl-4-oxo-4, 5, 6, 7-tetrahydrogen Carbazole))benzamide, 2-(2-tetrahydrofuran)methylamino-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole) )) benzamide, or 2-(2-tetrahydrofuran)methylamino-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) Benzoylamide.
上述优选的技术方案中的优选的化合物中更进一步优选的化合物为 2- (1- (3-羟基 吡咯烷基）） -4- (1- (3,6,6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚））苯甲酰胺、 2_ (卜哌 啶） -4- (1- ( 3， 6， 6_三甲基 -4-氧- 4， 5, 6， 7-四氢吲哚）)苯甲酰胺、 2- (2 -二乙氨基乙 氨基） -4- (1- (3, 6， 6-三甲基 -4-氧- 4, 5, 6， 7-四氢吲哚））苯甲酰胺、 2- (2- (4 -吗啉) 乙氨基） -4- (1- (3, 6, 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚）) 苯甲酰胺、 2- (卜 (4- 羟基哌啶）） -4- (1- (3, 6， 6_三甲基 -4-氧- 4， 5， 6， 7 -四氢吲哚））苯甲酰胺、 2- (4 -羟 基环己氨基 )- 4- ( 1_( 3， 6 , 6-三甲基 -4-氧 -4 ,5,6, 7-四氢吲哚））苯甲酰胺、 2- (2- (1， 2, 3) 三氮唑乙氨基 )-4- (1- (3， 6， 6-三甲基- 4-氧- 4， 5， 6， 7 -四氢吲哚）)苯甲酰胺、 2- (1- (4- (2- (4-吗琳) 乙基）哌嗪）） -4- (1- (3,6,6-三甲基 -4 -氧- 4， 5, 6, 7 -四氢吲哚）) 苯甲酰胺、 2- (2-二乙氨基乙氨基） -4- (1- (3, 6， 6-三甲基 -4-氧 -4， 5, 6, 7-四氢吲唑）） 苯甲酰胺、 2-环己氨基 4_(1- (3，6，6_三甲基 -4-氧- 4， 5， 6， 7 -四氢吲唑)）苯甲酰胺、 2 - (2- (1 -哌啶) 乙氨基） -4- (1- (3,6,6-三甲基 -4-氧- 4,5,6,7-四氢吲唑））苯甲酰 胺、 2- (2- (1-（3， 5-二甲基哌啶）） 乙氨基） -4- (1- (3， 6， 6 -三甲基- 4 -氧 _4， 5， 6， 7- 四氢吲唑）） 苯甲酰胺、 2- (2- (1,2,3)三氮唑乙氨基） -4- (1- (3, 6， 6-三甲基 -4 -氧 - 4, 5， 6, 7-四氢吲唑））苯甲酰胺、 2-环丙烷氨基- 4- (1- (3, 6， 6_三甲基 -4-氧- 4, 5, 6， 7- 四氢吲唑）） 苯甲酰胺、 2- (1- (4- (2- (1-哌啶） 乙氧基） 哌啶）） -4- (1- (3，6，6- 三甲基 -4-氧- 4, 5, 6, 7-四氢吲唑））苯甲酰胺、 2- (1- (4- (2 -羟乙基)哌嗪）） -4- (1 (3， 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 2- (2- (4-吗啉） 乙氨基） -4_ (1- (3, 6， 6-三甲基 -4 -氧- 4， 5， 6， 7 -四氢吲唑））苯甲酰胺、 2- (4 -羟基环己氨基) - 4- (1- (3, 6, 6_三甲基 -4-氧- 4， 5, 6, 7 -四氢吲唑）)苯甲酰胺、 2- (4-氨基乙酰氧基 环己氨基） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑））苯甲酰胺、 2- (2- (1 -吡咯焼基）乙氨基） -4- (1- (3， 6, 6-三甲基 -4-氧 -4， 5， 6, 7-四氢吲唑））苯甲酰胺、 2- (1 -哌嗪) -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑）） 苯甲酰胺、 2- (1- (3-羟基哌啶）) -4- ( 1- (3, 6， 6-三甲基 -4-氧- 4, 5， 6, 7-四氢吲唑））苯甲酰胺、 1- (6 - ( 3 -氨基 -1H-吲唑）) -3， 6, 6-三甲基 -1, 5， 6， 7-四氢吲哚- 4-酮、 1- (6- ( 3 -氨基 - 1H- 吲唑）） -3, 6, 6-三甲基 - 1, 5, 6, 7 -四氢吲唑- 4-酮、 2- (1- (4-羟基哌啶）） -4- (9- (2， 2- 二甲基 -4-氧- 1, 2, 3, 4-四氢咔唑））苯甲酰胺、 2- (4-羟基环己氨基) -4- (9- ( 2， 2- 二甲基 -4-氧- 1, 2， 3， 4-四氢咔唑））苯甲酰胺、 2- ( 1- (4- (2-羟乙基）哌嗪）） -4- (9 - (2， 2-二甲基 -4-氧- 1, 2， 3, 4-四氢咔唑）)苯甲酰胺、 2- ( 1- (4 -羟基哌啶）) -4- (9- (2， 2-二甲基 -4-氧- 6-三氟甲基- 1， 2, 3, 4-四氢咔唑））苯甲酰胺、 2- (4-羟基环己氨基） -4- (9- (2， 2-二甲基 -4-氧- 6-三氟甲基- 1, 2， 3， 4-四氢咔唑）)苯甲酰胺、 2- (4-羟基 环己氨基） -4- ( 1- (6, 6-二甲基 -4-氧- 3-三氟甲基- 4， 5， 6， 7-四氢吲唑））苯甲酰 胺、 N- (2- [1， 2， 3]三氮唑乙基) -4- ( 1- (3， 6, 6)三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑）） 苯甲酰胺、 N- (2- (4-吗啉) 乙基) -4- ( 1- (3， 6， 6)三甲基 -4-氧 _4， 5， 6, 7 -四氢 吲唑）） 苯甲酰胺、 N- (4羟基环己基）-4- ( 1- (3, 6, 6)三甲基 -4-氧- 4， 5， 6， 7 - 四氢吲唑））苯甲酰胺、 或 N- (2- ( 1- (4-羟基哌啶）） 乙基) -4- ( 1- (3, 6, 6)三甲 基 -4-氧- 4， 5， 6， 7-四氢吲唑））苯甲酰胺。 A further preferred compound among the preferred compounds of the above preferred embodiments is 2-(1-(3-hydroxypyrrolidinyl)-4-(1-(3,6,6-trimethyl-4-) Oxygen-4,5,6,7-tetrahydroindole))benzamide, 2_(piperidinyl)-4-(1-(3,6-6-trimethyl-4-oxo-4, 5 , 6, 7-tetrahydroanthracene))benzamide, 2-(2-diethylaminoethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5 , 6, 7-tetrahydroanthracene))benzamide, 2-(2-(4-morpholine)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo- 4, 5, 6, 7-tetrahydroanthracene)) benzamide, 2-(Bu(4-hydroxypiperidine))-4-(1-(3, 6, 6-trimethyl-4-oxo) - 4, 5, 6, 7 -tetrahydroanthracene))benzamide, 2-(4-hydroxycyclohexylamino)-4-(1_(3,6,6-trimethyl-4-oxo-4) ,5,6,7-tetrahydroindole))benzamide, 2-(2-(1, 2, 3) triazole ethylamino)-4-(1- (3, 6, 6-trimethyl) Base - 4-oxo-4, 5, 6, 7-tetrahydroindole))benzamide, 2-(1-(4-(2-(4-methyl)ethyl)piperazine)) -4 - (1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroanthracene) Benzoylamide, 2-(2-diethylaminoethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole) Benzoylamide, 2-cyclohexylamino 4_(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, 2 - ( 2-(1-Petidine)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(1-(3, 5-dimethylpiperidine))ethylamino)-4-(1-(3, 6, 6 -trimethyl- 4 -oxy_4, 5, 6, 7-tetrahydrocarbazole)) benzamide, 2-(2-(1,2,3)triazole ethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxyl) - 4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2-cyclopropanolamino-4-(1-(3, 6, 6_trimethyl-4-oxo-4, 5, 6 , 7-tetrahydrocarbazole)) benzamide, 2-(1-(4-(2-(1-piperidine)ethoxy) piperidine)) -4- (1- (3,6,6) - Trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-(2-hydroxyethyl)piperazine))-4- ( 1 (3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(4-morpholine)ethylamino) -4_ (1-(3, 6, 6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, 2-(4-hydroxycyclohexylamino)-4 - (1-(3, 6, 6_Trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2-(4-aminoacetoxycyclohexylamino) -4- (1-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(1-pyrrolidinyl) Ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-piperazine) ) -4- (1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) benzamide, 2- (1- (3-hydroxypiperidine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 1- ( 6 - (3-amino-1H-carbazole)) -3,6,6-trimethyl-1,5,6,7-tetrahydroindole-4-one, 1-(6-(3-amino) - 1H-carbazole)) -3, 6, 6-trimethyl-1, 5, 6, 7-tetrahydrocarbazole-4-one, 2-(1-(4-hydroxypiperidine))-4 - (9-(2,2-Dimethyl-4-oxo-1, 2,3,4-tetrahydrocarbazole))benzamide, 2-(4-hydroxycyclohexylamino)-4-(9 - ( 2, 2-dimethyl-4-oxo-1, 2, 3, 4-tetrahydrocarbazole))benzamide, 2-(1-(4-(2-hydroxyethyl)piperazine) -4- (9-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole))benzamide, 2-(1-(4-hydroxypiperidine) -4- (9-(2,2-Dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole))benzamide, 2- (4- Hydroxycyclohexylamino)-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole))benzamide, 2 - (4-Hydroxycyclohexylamino)-4-(1-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydrocarbazole))benzene Formamide N-(2- [1, 2, 3]triazolylethyl)-4-(1-(3, 6, 6)trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole Azole)) benzamide, N-(2-(4-morpholine)ethyl)-4-(1-(3, 6, 6)trimethyl-4-oxo_4, 5, 6, 7 - Tetrahydrocarbazole)) Benzamide, N-(4hydroxycyclohexyl)-4-( 1-(3, 6, 6)trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole Zinc), benzamide, or N-(2-(1-(4-hydroxypiperidinyl))ethyl)-4-(1-(3,6,6)trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) benzamide.
本发明还包括上述化合物在药学上可接受的盐。这些盐优选为硫酸盐（sulfuric)、 盐酸盐（hydrochloric )、 磷酸盐（phosphoric：)、氢溴酸盐（hydrobroraic)、柠檬酸盐 (citric), 马来酸盐 (maleic)、 笨乙醇酸盐 (mandelic), 琥珀酸盐 ( succinic), 富 马酸盐 (f画 ric)、 乙酸盐 (acetic；)、 乳酸盐 ( lactic), 硝酸盐 (nitric), 磺酸盐 ( sulfonic), 对甲苯磺酸盐（p_toluene sulfonic；)、 甲磺酸盐（methane sulfonic), 苯甲酸盐 （benzoic )、 酒石酸盐（tartaric)或碳酸盐 （carbonic acid)。  The invention also includes pharmaceutically acceptable salts of the above compounds. These salts are preferably sulfuric, hydrochloric, phosphoric, hydrobroraic, citric, maleic, and glycolic acid. Mandelic, succinic, fumarate, acetate, lactic, nitric, sulfonic, P-toluene sulfonic; (methane sulfonic), benzoic acid, tartaric or carbonic acid.
实现本发明的另一目的是上述第八种进一步优选的技术方案中优选的化合物在制 备治疗肿瘤药物中的应用，上述优选的技术方案中的化合物在制备治疗肿瘤药物中的应 用， 特别是上述优选的技术方案中进一步优选的化合物在制备治疗肿瘤药物中的应用。 以及上述优选的技术方案中的化合物在药学上可接受的盐在制备治疗肿瘤药物中的应 用。 具体实施方式  Another object of the present invention is the use of a preferred compound of the above-mentioned eighth preferred embodiment for the preparation of a medicament for the treatment of a tumor, the use of the compound of the above preferred embodiment for the preparation of a medicament for the treatment of a tumor, in particular A further preferred compound of the preferred embodiment is for use in the manufacture of a medicament for the treatment of a tumor. And the use of a compound of the above preferred embodiment in the preparation of a medicament for the treatment of a tumor in a pharmaceutically acceptable salt. detailed description
本发明化合物的合成所涉及的所有化学原料， 溶剂都是从北京化学试剂公司、 北 京九鼎高科有限公司和广州试剂公司等地订购。所有的固体试剂都没有经过进一步处理 而直接使用。 液体试剂都经过重蒸干燥后使用。  All chemical raw materials and solvents involved in the synthesis of the compounds of the present invention are ordered from Beijing Chemical Reagent Co., Ltd., Beijing Jiuding Hi-Tech Co., Ltd. and Guangzhou Reagent Co., Ltd. All solid reagents were used without further processing. The liquid reagents are all used after being re-distilled.
一、本发明化合物中间体的合成。 实例 1 1. Synthesis of intermediates of the compounds of the invention. Example 1
5, 5- 二 甲 基 一 2- ( 2 — 氧 一 丙 基 ） 一 1, 3 — 环 己 二 酮 (5, 5-dimethyl-2- (2-oxo-propyl) -cyclohexane-1, 3-dione) 的合成。 （中间体 I)
Figure imgf000016_0001
5, 5-dimethyl-2-(2-oxopropyl)-1,3-cyclohexanedione (5, 5-dimethyl-2-(2-oxo-propyl)-cyclohexane-1, 3- Synthesis of dione). (Intermediate I)
Figure imgf000016_0001
在 反 应 瓶 中 ， 加 入 5 ， 5- 二 甲 基 -1 , 3- 环 己 二 酮 (5, 5-dimethylcyclohexane-l, 3-dione) (3· 5g， 25匪 ol)溶解在 THF (250 mL)和氢 化钠 （1 g， 40 mmol ), 在冰浴冷却下， 氯乙酮（2. 3 g, 25 mmol)滴加到反应瓶中， 室 温下搅拌 2h后加入水 （400 mL)，反应产物用二氯甲垸萃取， 水洗后无水硫酸镁干燥。 除去干燥剂后， 减压蒸发除去溶剂得到无色液体， 2. 8 g, 产率 57%， 此化合物无需纯 化可用于以下反应。  In the reaction flask, 5,5-dimethylcyclohexane-l, 3-dione (3·5g, 25匪ol) was added to dissolve in THF (250 mL). And sodium hydride (1 g, 40 mmol), chloroethyl ketone (2.3 g, 25 mmol) was added dropwise to the reaction flask under ice-cooling. After stirring at room temperature for 2 h, water (400 mL) was added. The product was extracted with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. After removing the desiccant, the solvent was evaporated under reduced pressure to give a colorless liquid (yield: 57 g, yield: 57%).
实例 2  Example 2
5， 5 -二甲基一 2- ( 2—丙醛基） 一 1, 3—环己二酮 （5， 5-diraethyl-2- ( l—methyl- 2-0X0- ethyl ) -cyclohexane-1, 3-dione) 的合成。 （中间体 II)
Figure imgf000016_0002
5,5-Dimethyl- 2-(2-propanal)-1,3-cyclohexanedione (5,5-diraethyl-2-(l-methyl- 2-0X0-ethyl)-cyclohexane-1 , 3-dione). (Intermediate II)
Figure imgf000016_0002
向 反 应 瓶 中 加 入 5 ， 5- 二 甲 基 -1 ， 3 - 环 己 二 酮 (5, 5-dimethylcyclohexane-l, 3-dione) (3. 5 g, 25 mmol)溶解在 THF (200 mL) 和 To the reaction flask was added 5,5-dimethylcyclohexane-l, 3-dione (3.5 g, 25 mmol) dissolved in THF (200 mL) with
2N NaOH ( 15 mL, 30 mmol )， 在冰浴冷却下， 2-氯丙醛缩二 甲醇 (2-chloro-l, 1-dimethoxypropane) (3. 5 g, 25 匪 ol)的 THF (50 raL)滴加到反应瓶 中， 室温下搅拌 2h后加入 IN HC1 (200 raL) 并搅拌 1小时,反应产物用乙酸乙酯萃取， 饱和氯化钠水冲洗后无水硫酸钠干燥。 除去干燥剂后， 减压蒸发除去溶剂得到 1. 9 g无 色液体， 产率 39%， 此化合物无需纯化可用于以下反应。 2N NaOH (15 mL, 30 mmol), 2-chloro-l, 1-dimethoxypropane (3.5 g, 25 匪ol) in THF (50 raL) The mixture was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 2 h, then EtOAc (EtOAc) was evaporated. After the desiccant was removed, the solvent was evaporated under reduced pressure to give 1.9 g of a pale liquid, yield 39%.
实例 3  Example 3
2- 乙 酰 基 一 5, 5- 二 甲 基 一 1， 3 — 环 己  2-Acyl group 5, 5-Dimethyl group 1, 3 - ring
(2 - acetyl- 5， 5- dimethyl- cyclohexane- 1, 3-dione) 的合成。 （中间体 III )
Figure imgf000016_0003
将乙酰氯 (8.8 mL)滴加到含有 5, 5 -二甲基- 1, 3 -环己二酮 (16.8 g, 120 mmol) 和吡 啶 (9.2 mL)的氯仿 (400 mL)溶液中。 滴加完后， 反应在室温下继续搅拌 1.5小时。 反应 液用氯仿萃取、 用 0. IN盐酸、 水、 饱和碳酸氢钠水溶液、 饱和氯化钠水溶液洗涤、 硫 酸钠干燥过夜。 Synthesis of (2 - acetyl-5, 5-dimethyl-cyclohexane- 1, 3-dione). (Intermediate III)
Figure imgf000016_0003
Acetyl chloride (8.8 mL) was added dropwise to a solution of 5,5-dimethyl-1,3-cyclohexanedione (16.8 g, 120 mmol) and pyridine (9.2 mL) in chloroform (400 mL). After the dropwise addition was completed, the reaction was further stirred at room temperature for 1.5 hours. The reaction mixture was extracted with chloroform, washed with EtOAc EtOAc EtOAc.
经过滤、 去除溶剂后得到的无色液体粗产物在 0 °C下加入到含无水氯化铝 (32 g, 240画 ol)的氯仿 (400 mL)溶液中。 加完后， 反应物在 0。C搅拌 10分钟， 然后在室温 下搅拌 2小时。 反应液倒入含有冰和浓盐酸 (20 mL)的烧杯中、 用氯仿萃取、 饱和氯化 钠水溶液洗涤、 无水硫酸钠干燥。 经过滤、 除去溶剂后得到固体产物 2-乙酰基 -5， 5 -二 甲基- 1,3-环己二酮， 4.66克， 产率 21.3% (两步）， 产物不经纯化直接用于下一步反应。  The colorless liquid crude product obtained after filtration and solvent removal was added to a solution of anhydrous aluminum chloride (32 g, 240 s) in chloroform (400 mL) at 0 °C. After the addition is complete, the reactants are at 0. C was stirred for 10 minutes and then stirred at room temperature for 2 hours. The reaction mixture was poured into a beaker containing ice and concentrated hydrochloric acid (20 mL). After filtration and solvent removal, the solid product 2-acetyl-5,5-dimethyl-1,3-cyclohexanedione, 4.66 g, yield 21.3% (two steps), product was used without purification The next step is to react.
实例 4  Example 4
3, 6, 6- 三 甲 基 一 1,5， 6， 7 — 四 氢 吲 哚 一 4 一 酮 (3， 6， 6-trimethyl-l, 5, 6， 7- te rahydro- indol- 4- one) 的合成。 （中间体 iy)
Figure imgf000017_0001
3, 6, 6-trimethyl-1,5,6,7-tetrahydroindenyl 4-one (3, 6, 6-trimethyl-l, 5, 6, 7- te rahydro- indol- 4- The synthesis of one). (intermediate iy)
Figure imgf000017_0001
在反应瓶中加入乙醇（50 mL)和 5, 5-二甲基一 2- (2—丙醛基） 一 1， 3—环己二酮 (1.6 g, 8.2 mmol), 溶解后再加入乙酸铵 （0.63 g, 8.2 mmol) , 加热至 60。C搅 拌反应 2小时。减压去处溶剂后， 产物用乙酸乙酯萃取、饱和氯化钠水溶液洗涤、无水 硫酸钠干燥。 过滤后减压除去溶剂、 干燥后得到淡黄色固体， 0.95 克， 产率 73%; NMR(500MHz，CDCl3)， δ (ppm)： 7.78 (b, IH), 5.47 (b, IH), 2.73 (s, 2H)， 2.44(s, 2H): 2.32 (s, 3H), 1.13(s， 6H)。 Ethanol (50 mL) and 5,5-dimethyl- 2-(2-propanal)-1,3-cyclohexanedione (1.6 g, 8.2 mmol) were added to the reaction flask, and then acetic acid was added after dissolution. Ammonium (0.63 g, 8.2 mmol), heated to 60. The reaction was stirred for 2 hours. After the solvent was removed under reduced pressure, the product was evaporated, evaporated, evaporated After filtration, the solvent was removed under reduced pressure, and dried to give a pale yellow solid, 0.95 g, yield 73%; NMR (500MHz, CDCl 3), δ (ppm): 7.78 (b, IH), 5.47 (b, IH), 2.73 (s, 2H), 2.44(s, 2H) : 2.32 (s, 3H), 1.13(s, 6H).
实例 5  Example 5
3, 6， 6- 三 甲 基 一 1,5， 6， 7 — 四 氢 吲 唑 ― 4 ― 酮 (3, 6， 6-trimethyl-l, 5, 6， 7-tetrahydro- indazol- 4- one) 的合成。 （中间体 V)
Figure imgf000017_0002
3, 6, 6-trimethyl-1,5,6,7-tetrahydrocarbazole-4 ketone (3, 6, 6-trimethyl-l, 5, 6, 7-tetrahydro- indazol- 4- one ) Synthesis. (Intermediate V)
Figure imgf000017_0002
将 2-乙酰基 -5， 5-二甲基 - 1， 3-环己二酮（2.33 g， 12.8匪 ol)、90%水合肼（1.95 mL)、 和乙醇 （29 mL)混合物搅拌过夜、 减压除去溶剂、 残余物溶于二氯甲烷、 饱和氯化钠 水溶液洗滴、 无水硫酸钠干燥。 经过滤、 溶剂去除后、 产物用硅胶柱层析分离、 用二 氯甲垸 /甲醇 (20:1至 12:1)洗脱、 得到针状晶体， 1.108克， 产率 48.6%; ¾NMR(500 MHz, CDCla) , δ (ppra)： 9.33 (s, 1H), 2.73 (s, 2I.I)， 2.58 (s, 311) , 2.38 (s, 2H) , 1.13 (s,A mixture of 2-acetyl-5,5-dimethyl- 1, 3-cyclohexanedione (2.33 g, 12.8 匪ol), 90% hydrazine hydrate (1.95 mL), and ethanol (29 mL) was stirred overnight. The solvent was removed under reduced pressure, and the residue was evaporated, mjjjjjjj After filtration and solvent removal, the product was separated by silica gel column chromatography eluting with methylene chloride/methanol (20:1 to 12:1) to obtain needle crystals, 1.108 g, yield 48.6%; 3⁄4 NMR (500 MHz, CDCla), δ (ppra): 9.33 (s, 1H), 2.73 (s, 2I.I), 2.58 (s, 311), 2.38 (s, 2H), 1.13 (s,
6H)。 6H).
实例 6  Example 6
2,2- 二 甲 基 一 1,2,3,9 — 四 氢 咔 唑 一 4 - 酮 (2, 2- dimethyl- 1, 2, 3， 9- tetrahydro- carbazol- 4- one) 的合成。 （中间体 VI)  Synthesis of 2,2-dimethyl-1,2,3,9-tetrahydrocarbazol-4-yl. (2,2-dimethyl- 1, 2, 3, 9-tetrahydro-carbazol- 4-one). (Intermediate VI)
Figure imgf000018_0001
Figure imgf000018_0001
在反应瓶中加入 5, 5-二甲基 -1,3-环己二酮（2.8 g， 20 mraol) , 三氟乙酸 (20 mL)， 甲苯（20 mL), 溶解后再加入苯肼 （2.16 g, 20 mmol), 加热至 100 oC搅拌反应 12 小时。减压去处溶剂后， 产物用二氯甲烷萃取、饱和碳酸氢钠水溶液、饱和氯化钠水溶 液洗涤、无水硫酸钠干燥。 过滤后减压除去溶剂、硅胶柱层析纯化得到白色固体， 2.55 克， 产率 59.7%; 1HNMR(500 MHz, CDC13), δ (PPm)： 9.95(b, 1H)， 6.95-7.20 (m, 4H), 2.79 (s, 2H) , 2.54 (s, 2H)， 1.14(s， 6H)。 Add 5,5-dimethyl-1,3-cyclohexanedione (2.8 g, 20 mraol), trifluoroacetic acid (20 mL), toluene (20 mL) to the reaction flask, and then add benzoquinone after dissolution ( 2.16 g, 20 mmol), heat to 100 ° C and stir for 12 hours. After the solvent was removed under reduced pressure, the product was evaporated, evaporated, evaporated After filtration, the solvent was removed under reduced pressure, purified by silica gel column chromatography to give a white solid, 2.55 g, yield 59.7%; 1HNMR (500 MHz, CDC13), δ (PP m): 9.95 (b, 1H), 6.95-7.20 (m , 4H), 2.79 (s, 2H), 2.54 (s, 2H), 1.14 (s, 6H).
二、 本发明化合物的合成。  2. Synthesis of the compounds of the invention.
实施例 1  Example 1
2- 氯 - 4- (1- (3，6，6_ 三 甲 基 -4- 氧 -4， 5， 6， 7- 四 氢 吲 唑 ）） 苯 氰 ( 2-chloro - 4- (3， 6, 6-trimethyl_4_oxo- 4， 5， 6， 7-tetrahydro-indazol-l-yl)-benzon itrile) 的合成。 （结构式 1-01)  2-Chloro-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide (2-chloro - 4- (3, 6 Synthesis of 6-trimethyl_4_oxo- 4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzon itrile). (Structure 1-01)
Figure imgf000018_0002
Figure imgf000018_0002
将 3, 6,6-三甲基 -1,5， 6， 7-四氢吲唑- 4-酮 (1. llg, 6.22 mmol), DMF (90 mL), 和 氢化钠（299 mg, 12.4 mmol),加入到反应瓶中，在冰浴冷却下，将 2-氯- 4-氟苯氰（1.26g, 8.1 mmol) 加入到反应瓶中， 反应在室温下搅拌三个小时。 反应物倒入到冰水中并用 乙酸乙酯萃取、 饱和氯化钠水溶液洗滴、 无水硫酸钠干燥。 粗产品用硅胶柱层析分离， 用己烷： 乙酸乙酯（1: 7至 1: 3)洗脱得到 2-氯- 4- (1- (3,6,6-三甲基 -4-氧- 4， 5， 6,7 - 四氢吲唑)）苯氰， 0.75克， 产率 38.5%， 熔点 88— 90 °C; 'HNMR(500 MHz, CDC ) , 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)。 3,6,6-trimethyl-1,5,6,7-tetrahydrocarbazol-4-one (1.11 g, 6.22 mmol), DMF (90 mL), and sodium hydride (299 mg, 12.4) (mmol), was added to a reaction flask, and 2-chloro-4-fluorobenzonitrile (1.26 g, 8.1 mmol) was added to a reaction flask under ice-cooling, and the mixture was stirred at room temperature for three hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The crude product was purified by silica gel column chromatography eluting with hexane: ethyl acetate (1: 7 to 1: 3) to give 2-chloro-4-(4-(3,6,6-trimethyl-4-) Oxygen - 4, 5, 6, 7 - tetrahydrocarbazole)) phenyl cyanide, 0.75 g, yield 38.5%, melting point 88-90 ° C; 'HNMR (500 MHz, CDC), 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).
实施例 2  Example 2
2 -（1- (4-甲基哌嗪））- 4_(1- (3,6, 6 -三甲基- 4-氧- 4, 5, 6， 7-四氢吲唑））苯氰 (2- (4-methyl-piperazin-l-yl) -4- (3, 6, 6 - trimethyl-4-oxo-4, 5, 6, 7- tetrahydro- in dazol-l-yl) -benzonitrile)的合成。 （结构式 1-02)  2-(1-(4-Methylpiperazine))- 4_(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide (2-(4-methyl-piperazin-l-yl)-4-(3, 6, 6 - trimethyl-4-oxo-4, 5, 6, 7- tetrahydro- in dazol-l-yl) -benzonitrile) Synthesis. (Structure 1-02)
Figure imgf000019_0001
Figure imgf000019_0001
在 氩 气 保 护 下 ， 向 干 燥 的 反 应 瓶 中 加 入 1，1 ' -bis (diphenylphosphino) ferrocene (Dppf) (22.8 mg, 0.036 mmol) , 2 - 氯 -4-(l-(3, 6， 6 -三甲基- 4-氧- 4, 5， 6， 7-四氢吲唑））苯氰（100 mg, 0.32 mmol), PdCl2(7.8 mg, 0.036 mmol), Pd(0Ac)2(8.08 rag, 0.036 mmol), t-Bu0Na (50 rag)， 和无水甲苯 (5 ml)。 反应混合物加热至 100 °C搅拌 20分钟后， 加入 4-甲基哌嗪（0.1 ml) 并继续在 100 °C下搅捽 5.5小时。 冷却后， 过滤除去固体催化剂， 减压除去溶剂后， 产品用硅 胶柱层析分离， 用二氯甲垸： 甲醇 （50: 1 至 30: 1) 洗脱得到 2- (1- (4-甲基哌 嗪)） -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑)）苯氰， 61毫克，产率 50.5%,熔点 95-97 UC; 'HNMR(500MHz,CDCl3), δ (ppm) :7.67-7.69 (d, 1H)， 7.25 (s, 1H), 7.07-7.09 (d， IH), 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)。 Add 1,1 '-bis (diphenylphosphino) ferrocene (Dppf) (22.8 mg, 0.036 mmol), 2-chloro-4-(l-(3, 6, 6 -) to a dry reaction flask under argon. Trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide (100 mg, 0.32 mmol), PdCl 2 (7.8 mg, 0.036 mmol), Pd(0Ac) 2 (8.08 rag , 0.036 mmol), t-Bu0Na (50 rag), and anhydrous toluene (5 ml). After the reaction mixture was heated to 100 ° C and stirred for 20 minutes, 4-methylpiperazine (0.1 ml) was added and stirring was continued at 100 ° C for 5.5 hours. After cooling, the solid catalyst was removed by filtration, and after removing the solvent under reduced pressure, the product was separated by silica gel column chromatography and eluted with dichloromethane (50:1 to 30:1) to give 2-(1-(4-) Piperazine)) -4- (1-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide, 61 mg, yield 50.5% , melting point 95-97 U C; 'HNMR (500MHz, CDCl 3 ), δ (ppm): 7.67-7.69 (d, 1H), 7.25 (s, 1H), 7.07-7.09 (d, IH), 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).
实施例 3  Example 3
2- (1- (4-甲基哌嗪）） -4- (1- (3， 6， 6-三甲基 -4 -氧- 4， 5， 6， 7-四氢吲唑））苯甲酰胺 (2- (4-methyl-piperazin-l-yl) -4- (3, 6, 6_trimethyl- 4-oxo - 4， 5， 6, 7- tetrahydro- in dazol- 1- yl)- benzamide)的合成。 （结构式 I- 03)  2-(1-(4-Methylpiperazine)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzene Formamide (2-(4-methyl-piperazin-l-yl)-4-(3, 6, 6-trimethyl- 4-oxo-4, 5, 6, 7-tetrahydro- in dazol- 1-yl)- benzamide) Synthesis. (Structure I- 03)
Figure imgf000019_0002
将氤基氧化 /水解成酰胺反应的参考文献见： (1) Bull. Chem. Soc. Jpn. , 54， 3， 793-799, 1981. (2) Synthesis, 12, 949-950， 1989. (3) Synthesis, 3, 243-244， 1980.
Figure imgf000019_0002
References for the oxidation/hydrolysis of sulfhydryl groups to amides are described in: (1) Bull. Chem. Soc. Jpn., 54, 3, 793-799, 1981. (2) Synthesis, 12, 949-950, 1989. 3) Synthesis, 3, 243-244, 1980.
将 2- (1- (4-甲基哌嗪)） -4- (1- (3, 6， 6-三甲基 -4-氧- 4, 5， 6， 7_四氢吲唑)）苯氰（61 mg, 0.16 mmol)溶于 DMSO (0.3 mL), 加入无水乙醇（2 mL), KOH (30 mg)。 反应物 在室温下搅拌 5分钟， 然后慢慢滴加 30%过氧化氢 （0.15 mL), 反应液继续在室温下搅 拌 10分钟。 向反应瓶中加入水（50 mL)并用乙酸乙酯萃取， 饱和氯化钠水溶液洗涤， 无水硫酸钠干燥。 产品用硅胶柱层析分离， 用二氯甲垸： 甲醇（30: 1至 20: 1)洗脱 得到 2- (1- (4-甲基哌嗪)） -4-(1-(3, 6, 6-三甲基 -4 -氧- 4， 5, 6, 7-四氢吲唑)）苯甲酰胺， 60毫克，产率 93.5%， 熔点 114— 116。C; 'HNMR(500 MHz, CDC13), 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)； 1:!CNMR(500 MHz,CDCl3), 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++l)； 元素分析： 计算值 C66.81, H 7.39, N 17.71; 测定值 C 66.56， H 6.98, N 17.44。 2-(1-(4-Methylpiperazine)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) Benzoyl cyanide (61 mg, 0.16 mmol) was dissolved in DMSO (0.3 mL) and anhydrous ethanol (2 mL), KOH (30 mg). The reaction was stirred at room temperature for 5 minutes, then 30% hydrogen peroxide (0.15 mL) was slowly added dropwise and the mixture was stirred at room temperature for 10 min. Water (50 mL) was added to the reaction mixture and the mixture was evaporated. The product was separated by silica gel column chromatography eluting with dichloromethane (30:1 to 20:1) to give 2-(1-(4-methylpiperazine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 60 mg, yield 93.5%, m.p. 114-116. C; 'HNMR (500 MHz, CDC1 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); 1:! CNMR (500 MHz, 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, </ RTI> <RTIgt;</RTI><RTIgt;
施例 4  Example 4
2- (1- (3 -羟基吡咯烷基）) -4- (1- (3， 6， 6_三甲基 _4-氧- 4， 5, 6， 7-四氢吲哚）） 苯 氰 (2- (3- hydroxy - pyrrol i din- 1-yl) -4- (3, 6， 6- trimethyl- 4_oxo_4， 5, 6, 7- tetrahydro-indol-l-yl)-benzonitrile) 的合成。 （结构式 I- 04)  2-(1-(3-hydroxypyrrolidinyl))-4-(1-(3,6,6-trimethyl_4-oxo-4,5,6,7-tetrahydroindole)) benzene Synthesis of 2-(3-hydroxy-pyrrol i din- 1-yl) -4- (3, 6, 6- trimethyl- 4_oxo_4, 5, 6, 7- tetrahydro-indol-l-yl)-benzonitrile . (Structure I- 04)
Figure imgf000020_0001
Figure imgf000020_0001
在反应瓶中加入 2—氯一 4一硝基苯氰（0.5 g， 2.7 mmol), 甲苯（20 mL)和 3 -羟 基吡咯烷 (0.24 g, 2.7 mmol)。 反应物搅拌加热至 100 反应 2小时后， 冷却， 去除溶 剂， 用氯仿萃取， 饱和氯化钠水溶液洗涤， 无水硫酸镁干燥。 除去干燥剂和溶剂后得到 产物溶于甲醇（40 mL)并加入铁粉 (0.45 g, 8 mmol)和冰乙酸（0.5 mL)。 反应物搅 拌回流 2小时， 冷却后倒入水中， 用乙酸乙酯萃取， 饱和氯化钠水溶液洗涤， 无水硫酸 钠干燥， 经过重结晶纯化后得 0.31 g, 产率 52%； ¾NMR(500 MHz, CDC13) , 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)。 To the reaction flask were added 2-chloro-4-nitrophenyl cyanide (0.5 g, 2.7 mmol), toluene (20 mL) and 3-hydroxypyrrolidine (0.24 g, 2.7 mmol). The reaction mixture was stirred and heated to 100. After 2 hours, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. After removal of the desiccant and solvent, the product was dissolved in methanol (40 mL) and iron powder (0.45 g, 8 mmol) and glacial acetic acid (0.5 mL). The reaction mixture was stirred and refluxed for 2 hrs, then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,, , CDC1 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).
5,5-二甲基一2- (2—丙醛基） 一 1,3—环己二酮 （0.1 g, 0.5画 ol)溶于甲苯， 加 热至 85"C， 加入上述制备的 4-氨基- 2- (1- (3-羟基吡咯烷)苯氟 (0.12 g, 0.5瞧 ol), 反应温度升至 110 "C, 并搅拌 lh。 冷却后， 将溶剂去除， 产物用硅胶柱层析纯化后得 到 2- (1- (3-羟基吡咯烷基）) -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚）)苯 氰 0.16 g, 产率 44%， 熔点 79-81 °C; 画 R(500 MHz, CDC1,) , δ (ppm)： 7.73(d, 1H), 7.27 (d, 1H)， 6.86(s, 1H)， 6.68 (s, 1H)， 3.45 (m, 1H)， 3. ll(m, 2H) , 3.02 (m， 211) , 2.73 (s， 2H)， 2.54 (s, 3H) , 2.37 (s, 211)， 1.89(m, 2H), 1.12 (s, 6H)。  5,5-Dimethyl- 2-(2-propanal)-1,3-dicyclohexanedione (0.1 g, 0.5 liters ol) was dissolved in toluene, heated to 85"C, and added to 4- Amino-2-(1-(3-hydroxypyrrolidine)benzene fluoride (0.12 g, 0.5 瞧ol), the reaction temperature was raised to 110 ° C, and stirred for 1 h. After cooling, the solvent was removed and the product was purified by silica gel column chromatography. After purification, 2-(1-(3-hydroxypyrrolidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole) was obtained. )) phenyl cyanide 0.16 g, yield 44%, melting point 79-81 ° C; D (500 MHz, CDC1,), δ (ppm): 7.73 (d, 1H), 7.27 (d, 1H), 6.86 ( s, 1H), 6.68 (s, 1H), 3.45 (m, 1H), 3. ll(m, 2H) , 3.02 (m, 211), 2.73 (s, 2H), 2.54 (s, 3H), 2.37 (s, 211), 1.89 (m, 2H), 1.12 (s, 6H).
实施例 5  Example 5
2- (1- (3 -羟基吡咯垸基）) -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚）) 苯甲酰胺 （2 -（3— hydroxy— pyrrolidin-1-yl)—4- (3， 6， 6-trimethyl - 4—oxo— 4， 5, 6, 7_ tetrahydro-indol-l-yl)-benzamide) 的合成。 （结构式 1-05)  2-(1-(3-hydroxypyrrolidinyl))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole)) benzene Formamide (2-(3, hydroxy- pyrrolidin-1-yl) 4-(3, 6, 6-trimethyl - 4 -oxo-4, 5, 6, 7_ tetrahydro-indol-l-yl)-benzamide) Synthesis. (Structure 1-05)
Figure imgf000021_0001
Figure imgf000021_0001
合成方法同实施例 3, 产率 48 %， 熔点 121-123 °C; 1匪 R(500 MHz, CDC13) , δ (ppm) :9.20 (b, 1Η) , 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++l)； 元素分析： 计算值 C 69.27, H 7.13， N 11.02; 测定值 C 69.05， H 7.01， N 11.13。 The synthesis was carried out in the same manner as in Example 3, yield 48%, melting point 121-123 ° C; 1匪R (500 MHz, CDC1 3 ), δ (ppm): 9.20 (b, 1 Η), 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 + +l Elemental analysis: Calculated C 69.27, H 7.13, N 11.02; found C 69.05, H 7.01, N 11.13.
实施例 6  Example 6
2- ( 1-哌啶） _4- (1- (3, 6， 6-三甲基 -4-氧- 4, 5， 6, 7-四氢吲哚）） 苯氰 ( 2-piperidin-l-yl-4- (3, 6， 6-trimethyl-4-oxo-4, 5， 6, 7-tetrahydro-indol-l-yl) -benzonitrile的合成。 （结构式 1-06)
Figure imgf000022_0001
2-(1-piperidine) _4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole)) phenyl cyanide (2-piperidin-l Synthesis of -yl-4-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro-indol-l-yl)-benzonitrile (Structure 1-06)
Figure imgf000022_0001
向反应瓶中加入哌啶 (8.5g, 0. lmol), DMF(150mL)， 和 2， 4-二氟苯氰 (13.9 g, O. l moDo 反应物搅拌加热回流 12 小时， 冷却后减压除去溶剂， 乙酸乙酯萃取， 水洗， 无水硫酸钠干燥， 产物经环己垸 /乙酸乙酯重结晶得 14.8 g， 产率 72.5%， 刚 R(500 MHz, CDC13) , 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)„ To the reaction flask were added piperidine (8.5 g, 0.1 mol), DMF (150 mL), and 2, 4-difluorophenyl cyanide (13.9 g, O. l moDo reaction, heated under reflux for 12 hours, cooled and then decompressed. The solvent was removed, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The product was recrystallized from cyclohexane/ethyl acetate to yield 14.8 g, yield 72.5%, R (500 MHz, CDC1 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) „
在反应瓶中加入 3， 6， 6 -三甲基 -1， 5, 6， 7-四氢吲哚- 4-酮 (0.18 g， 1匪 ol) ， DMF Add 3,6,6-trimethyl-1,5,6,7-tetrahydroindol-4-one (0.18 g, 1 匪 ol) to the reaction flask, DMF
(25mL)， NaH (0.036 g, 1.5匪 ol)0 剧烈反应后， 向反应瓶中加入 2- (1 -哌啶) -4- 氟苯氰 （0.21 g 1 皿 ol) 并加热回流 12小时。 冷却后， 减压除去溶剂， 产物用二氯 甲烷萃取， 饱和氯化钠水溶液洗涤， 无水硫酸镁干燥。 产物用硅胶柱层析纯化后得到 0.28 g, 产率 77.8%， 熔点 87— 89 °C; ¾NMR(500 MHz, CDC13) , 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(25 mL), NaH (0.036 g, 1.5 匪ol) 0 After violent reaction, 2-(1-piperidine)-4-fluorobenzonitrile (0.21 g, 1 liter ol) was added to the reaction flask and heated to reflux for 12 hours. After cooling, the solvent was evaporated under reduced pressure. The product was purified by silica gel column chromatography to give 0.28 g, 77.8% yield, m.p. 87- 89 ° C; ¾NMR (500 MHz, CDC1 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. 2(s, 211), 1.78 (b, 4H)， 1·53('。， 2H) , 1.14 (s, 6H)。 (s, 2H), 2.55 (s, 3H), 2. 2(s, 211), 1.78 (b, 4H), 1·53 ('., 2H), 1.14 (s, 6H).
实施例 7  Example 7
2- (1 -哌啶） -4- (1- (3,6,6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚）） 苯甲酰胺 ( 2 - piperidin-1 - yl-4—(3， 6, 6- trimethyl- 4-oxo-4， 5, 6, 7-tetrahydro-indol-l-yl) - benzamide) 的合成。 （结构式 1-07)  2-(1-Petidine)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzamide (2-piperidin) Synthesis of -1 - yl-4-(3, 6, 6-trimethyl- 4-oxo-4, 5, 6, 7-tetrahydro-indol-l-yl) - benzamide). (Structure 1-07)
Figure imgf000022_0002
Figure imgf000022_0002
合成方法同实施例 3， 产率 57.5%, 熔点 143-145。C; '讓 R(500 MHz, CDC13) , δ (ppm) :9.28 (b， 1Η) , 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), 1.9 (b, 4H), 1.52(b, 2H), 1.12(s, 6H)； FAB-MS m/z: 380.2(^+1)； 元素分析： 计 算值 C 72.79， H 7.70， N 11.07； 测定值 C 72.46, H 7.54, N 10.83。 实施例 8 The synthesis was carried out in the same manner as in Example 3, yield 57.5%, melting point 143-145. C; 'Let R (500 MHz, CDC1 3 ), δ (ppm): 9.28 (b, 1Η), 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), 1.9 (b, 4H), 1.52 (b, 2H), 1.12(s, 6H); FAB-MS m/z: 380.2(^+1); Elemental analysis: Calculated C 72.79, H 7.70, N 11.07; Measured value C 72.46, H 7.54, N 10.83. Example 8
2- (1- (4 -甲基哌嗪）) -4- (1- (3,6,6-三甲基 -4-氧 -4， 5， 6， 7-四氢吲哚) 甲基） 苯 甲 酰 胺 （2_(4- methyl- piperazin-l-yl)-4-(3，6, 6- trimethyl- 4- oxo-4,5, 6， 7- tetrahydro-indol-l-ylmethyl)-benzaraide)的合成。 （结构式 1-08)  2-(1-(4-Methylpiperazine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole) methyl Benzoamide (2_(4-methyl-piperazin-l-yl)-4-(3,6, 6-trimethyl- 4- oxo-4,5, 6, 7- tetrahydro-indol-l-ylmethyl)- Synthesis of benzaraide). (Structure 1-08)
Figure imgf000023_0001
Figure imgf000023_0001
在反应瓶中加入 2—溴一 4一甲基苯甲酸甲酯（2.29 g, lOmmol)，四氯化碳（60mL)， 和过氧苯甲酸酐'（0.35 g, 0.4 mmoDo 反应物搅拌加热至 9(TC， 加入 NBS (1.78 g, 10 醒 ol)并在 110°C下搅拌反应 2 小时。冷却后，减压去除溶剂，用乙酸乙酯萃取， INNaOH 水溶液洗涤， 饱和氯化钠水溶液洗涤，无水硫酸钠干燥。去除干燥剂及溶剂经硅胶柱层 析纯化得 2—溴一 4一溴甲基苯甲酸甲酯为无色油状物 1.72 g， 产率 56%。 ¾NMR(500 MHz, CDC13) , δ (ppra) :7.76-7.78 (d, 1H)， 7.52-7.56 (d， 1H) , 7.35-7.38 (s, 1H)， 4.62 (s, 2H)， 4.02 (s, 3H)。 Add methyl 2-bromo-4-methylbenzoate (2.29 g, 10 mmol), carbon tetrachloride (60 mL), and peroxybenzoic anhydride' (0.35 g, 0.4 mmoDo reaction mixture to the reaction flask. 9 (TC, NBS (1.78 g, 10 awake ol) was added and the reaction was stirred at 110 ° C for 2 hours. After cooling, the solvent was evaporated under reduced pressure, extracted with ethyl acetate, washed with aq. Drying over anhydrous sodium sulfate. Removal of the desiccant and solvent was purified by silica gel column chromatography to yield ethyl 2-bromo-4-bromomethylbenzoate as a colorless oil 1.72 g, yield 56%. 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppra): 7.76-7.78 (d, 1H), 7.52-7.56 (d, 1H), 7.35-7.38 (s, 1H), 4.62 (s, 2H), 4.02 (s, 3H).
将 3, 6， 6-三甲基 -1， 5, 6, 7-四氢引哚- 4 -酮 (1.0 g, 5.5 nimol), DMF (60 mL), 和 氢化钠 （0.26 g, 11 mmol)加入到反应瓶中， 在冰浴冷却下， 将 2—溴一 4一溴甲基苯 甲酸甲酯 （1.72 g, 5.5 mmol)加入到反应瓶中， 反应在室温下搅拌 2个小时。 反应 物倒入到冰水中并用乙酸乙酯萃取、饱和氯化钠水溶液洗涤、无水硫酸钠干燥。粗产品 用硅胶柱层析分离， 用环己烷： 乙酸乙酯 (4： 1至 2: 1)洗脱得到 2-溴- 4- (1- (3, 6, 6 - 三甲基 -4-氧- 4，5， 6, 7-四氢吲哚））苯甲酸甲酯， 1.15 克， 产率 52%; 1麗 R(500 MHz, CDCI3) , 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)。 3,6,6-trimethyl-1,5,6,7-tetrahydroindole-4-enone (1.0 g, 5.5 nimol), DMF (60 mL), and sodium hydride (0.26 g, 11 mmol) It was added to a reaction flask, and methyl 2-bromo-4-bromomethylbenzoate (1.72 g, 5.5 mmol) was added to a reaction flask under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reactant was poured into ice water and extracted with ethyl acetate, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography eluting with EtOAc EtOAc (EtOAc (EtOAc) -oxo-4,5,6,7-tetrahydroindole)) methyl benzoate, 1.15 g, yield 52%; 1 R (500 MHz, CDCI3), δ (ppm): 7.75-7.78 (d (1,1H) 2.13 (s, 3H), 2.35 (s, 2H), 1.13(s, 6H).
照实施例 2的方法， 将 2 -溴- 4- (1- (3, 6, 6-三甲基 -4 -氧- 4， 5， 6, 7-四氢吲哚) )苯甲 酸甲酯， Dppf, PdCl2, t-Bu0Na, 4-甲基哌啶在甲苯中反应得到 2— （1— (4一甲基哌 啶）） -4- (1- (3， 6， 6—三甲基 4一氧一 4， 5， 6, 7—四氢吲哚） 甲基）苯甲酸甲 酯， 产率 16%; ¾NMR(500 MHz, CDC13), 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)。 将 2— （1— (4—甲基哌啶）） -4- (1- (3， 6， 6—三甲基 4—氧一 4， 5, 6， 7 一四氢吲哚） 甲基）苯甲酸甲酯（0.08 g， 0.19 ramol) 溶于 2M氨的甲醇溶液中， 室 温搅拌 2小时后出去溶剂，粗产品用硅胶柱层析分离，用二氯甲垸： 甲醇（30: 1至 20: 1)洗脱得到 2_(1- (4-甲基哌嗪)） - 4- (1- (3, 6, 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚）甲基） 苯甲酰胺， 45毫克， 产率 58%， 熔点 125— 127°C; Ή匪 R(500MHz,CDCl3)， δ (ppm) :9.23 (b, IH) , 7.31-8.34 (d, 1H)， 7.25 (s, 1H)， 7.10 (s, 1H)， 6.04 (b, IH)， 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 ra/z: 409.3(M++1); 元素分析： 计算值 C 70.56， H 7.90, N 13.71； 测定值 C 70.41, H 7.76, N 13.69。 ' 实施例 9 Methyl 2-bromo-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzoate as in Example 2 , Dppf, PdCl 2 , t-Bu0Na, 4-methylpiperidine is reacted in toluene to give 2-(1-(4-methylpiperidine))-4-(1-(3, 6, 6-trimethyl) Methyl 4-oxo-4,5,6,7-tetrahydroindole) methyl)benzoate, yield 16%; 3⁄4 NMR (500 MHz, CDC1 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). 2-(1-(4-methylpiperidine))-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7 tetrahydroanthracene)methyl Methyl benzoate (0.08 g, 0.19 ramol) was dissolved in 2M ammonia in methanol. After stirring at room temperature for 2 hrs, the solvent was evaporated. The crude product was separated by silica gel column chromatography using methylene chloride: methanol (30:1 20: 1) Elution gives 2_(1-(4-methylpiperazine)) 4- (1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-four Hydroquinone) methyl) benzamide, 45 mg, yield 58%, melting point 125-127 ° C; Ή匪R (500 MHz, CDCl 3 ), δ (ppm): 9.23 (b, IH), 7.31- 8.34 (d, 1H), 7.25 (s, 1H), 7.10 (s, 1H), 6.04 (b, IH), 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 ra/z: 409.3(M + +1) ; Analysis: Calculated C 70.56, H 7.90, N 13.71. Found C 70.41, H 7.76, N 13.69. 'Example 9
2-环己氨基- 4- (1- (3,6,6-三甲基 -4 -氧 4, 5， 6， 7-四氢吲哚））苯甲酰胺 ( 2 - cyclohexylamino- 4- (3， 6, 6-trimethyl-4-oxo-4, 5， 6, 7-tetrahydro - indol l - yl) -benzamide) 的合成 （结构式 1-09)  2-cyclohexylamino-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzamide (2-cyclohexylamino- 4- ( Synthesis of 3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro - indol l - yl) -benzamide) (Structure 1-09)
Figure imgf000024_0001
Figure imgf000024_0001
2 -环己氨基- 4- (1- (3， 6， 6-三甲基 -4-氧 -4， 5， 6， 7-四氢吲哚)）苯氰的合成方法同 实施例 6， 产率 47%,熔点 112-114 °C; 1應 R(500 MHz, CDC13)， δ (ppm) :7.35-7.37 (d, IH), 7.21 (s, IH), 6.94—6.96 (d, IH)， 6.59—6.61 (s， 1H)， 4.12(b, IH), 2.83 (s， 2H)， 2.64 (b, IH), 2.54 (s, 3H), 2.39 (s, 2H)， 1.73(b, 4H), 1.40- 1.50 (m， 6H)， 1.13 (s, 6H)。  The synthesis method of 2-cyclohexylamino-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydroanthracene))benzonitrile is the same as in Example 6, Yield 47%, melting point 112-114 °C; 1 should be R (500 MHz, CDC13), δ (ppm): 7.35-7.37 (d, IH), 7.21 (s, IH), 6.94-6.96 (d, IH ), 6.59—6.61 (s, 1H), 4.12(b, IH), 2.83 (s, 2H), 2.64 (b, IH), 2.54 (s, 3H), 2.39 (s, 2H), 1.73 (b, 4H), 1.40- 1.50 (m, 6H), 1.13 (s, 6H).
2 -环己氨基- 4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲哚)）苯甲酰胺的合成方 法同实施例 3, 产率 73%，熔点 158-160 °C; '画 R(500 MHz, CDCL)， δ (ppm) :9.23 (b, IH) , 8.07-8.09 (d, IH), 7.12. (s, IH), 6.95— 6.97 (d， IH), 6.59 (s, IH), 6.21 (b, 1H)， 4.06 (b, 1H)， 2.84 (s, 2H)， 2.58 (b, IH), 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)； 元素分析： 计算 值 C 73.25， H, 7.94， N 10.68; 测定值 C 73.32, H 7.78, N 10.46。 A method for synthesizing 2-cyclohexylamino-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzamide is the same as in Example 3. , yield 73%, melting point 158-160 ° C; 'Draw R (500 MHz, CDCL), δ (ppm): 9.23 (b, IH) , 8.07-8.09 (d, IH), 7.12. (s, IH ), 6.95— 6.97 (d, IH), 6.59 (s, IH), 6.21 (b, 1H), 4.06 (b, 1H), 2.84 (s, 2H), 2.58 (b, IH), 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); Elemental analysis Calcd for C 73.25, H, 7.94, N 10.68; found C 73.32, H 7.78, N 10.46.
实施例 10  Example 10
2- (2-二乙氨基乙氨基） -4- (1- (3， 6， 6-三甲基 -4-氧 -4, 5， 6， 7 -四氢吲哚））苯甲 酰 胺 ( 2-(2-diethylamino-ethylamino)-4 - (3， 6， 6 - trimethyl- 4-0X0-4， 5， 6， 7- ■tetrahydro- indol- l-yl)_benzamide) 的合成。 （结构式 I- 10) 2-(2-Diethylaminoethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole)) Benzyl Synthesis of 2-(2-diethylamino-ethylamino)-4 - (3,6,6-trimethyl- 4-0X0-4, 5, 6, 7- ■tetrahydro- indol-l-yl)-benzamide. (Structure I-10)
Figure imgf000025_0001
Figure imgf000025_0001
2- (2 -二乙氨基乙氨基) -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚）)苯氰 的合成方法同实施例 6， 产率 56%,熔点 142— 144 °C; ¾NMR(500 MHz, CDC13)， δ (ppm) :7.53-7.55 (d, IH), 7.27 (s, IH), 7.02-7.04 (d, IH) , 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)。 Synthesis of 2-(2-diethylaminoethylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole)) phenyl cyanide The same procedure as in Example 6, yield 56%, melting point 142-144 ° C; 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppm): 7.53-7.55 (d, IH), 7.27 (s, IH), 7.02- 7.04 (d, IH) , 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).
2- (2 -二乙氨基乙氨基) 4- (1- (3,6,6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚）)苯甲 酰胺的合成方法同实施例 3， 产率 61%， 熔点 172— 174 UC; 'HNMR(500 MHz, CDC1. , δ (ppm) :9.21 (b， IH)， 7.84-8.86 (d, 1H)， 7.31 (s, IH), 6.87-6.89 (d, IH), 6.64 (s, 1H)， 6.23 (b, 1H)， 4.03 (b, IH), 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); 元素分析： 计算值 C70.21, H8.35, N13.65; 测定值 C 70.06, H 7.98, 实施例 11 Synthesis of 2-(2-diethylaminoethylamino) 4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzamide The procedure was the same as in Example 3, yield 61%, melting point 172-174 U C; 'HNMR (500 MHz, CDC1., δ (ppm): 9.21 (b, IH), 7.84-8.86 (d, 1H), 7.31 ( s, IH), 6.87-6.89 (d, IH), 6.64 (s, 1H), 6.23 (b, 1H), 4.03 (b, IH), 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); Elemental analysis: Calculated C70.21, H8.35, N13.65; found C 70.06, H 7.98, Example 11
2- (2- (4-吗啉） 乙氨基） -4- (1- (3,6,6-三甲基 -4-氧- 4， 5, 6, 7-四氢吲哚））苯 甲 酰 胺 ( 2 (2-morpholin-4- yl-ethylamino)- 4-(3， 6， 6- trimethyl- 4-0X0- 4， 5， 6, 7 - tetrahydro- indol- 1 - yl)- benzamide) 的合成。 （结构式 1-11)  2-(2-(4-morpholine)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzene Formamide ( 2 (2-morpholin-4- yl-ethylamino) 4- (3, 6, 6- trimethyl- 4-0X0-4, 5, 6, 7 - tetrahydro- indol- 1 - yl)- benzamide) Synthesis. (Structure 1-11)
Figure imgf000025_0002
Figure imgf000025_0002
2- (2-（4 -吗啉） 乙氨基） -4- (1- (3， 6， 6-三甲基- 4 -氧- 4， 5， 6， 7-四氢吲哚）)苯 氰的合成方法同实施例 6， 产率 45.8%，熔点 117— 119 °C; ¾NMR(500 MHz, CDC13) , δ (ppm) :7.75-7.77 (d, IH), 7.43 (s, IH), 6.95—6.97 (d， IH)， 6.62 (s， IH), 4.05 (b, IH), 3.86 (t, 4H) , 3.37 (t, 2H)， 3.23 (t, 2H) , 2.84 (s, 2H)， 2.63 (b, 4H)， 2.54 (s,2-(2-(4-morpholine)ethylamino)-4-(1-(3,6,6-trimethyl- 4 -oxo-4,5,6,7-tetrahydroindole))benzene The synthesis of cyanide was the same as in Example 6, yield 45.8%, melting point 117-119 °C; 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppm): 7.75-7.77 (d, IH), 7.43 (s, IH) , 6.95—6.97 (d, IH), 6.62 (s, IH), 4.05 (b, IH), 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)。 3H), 2.43 (s, 2H), 1.13 (s, 6H).
2- (2- (4-吗啉） 乙氨基） -4- (1- (3,6,6-三甲基 -4-氧- 4,5,6,7-四氢吲哚））苯 甲酰胺的合成方法同实施例 3， 产率 57%， 熔点 142—144 °C; lHNMR(500丽 z， CDC13)， δ (ppm) :9.24 (b， IH)， 7.79-7.81 (d, IH), 7.35 (s, IH), 6.79- 6.81(d, 1H)， 6.59 (s， IH), 6.21(b, IH), 4.02 (b， IH), 3.79 (t， 4H), 3.42(t, 2H)， 3.18 (ΐ, 2H), 2.83 (s, 211), 2.64 (b, 4H)， 2.57 (s, 3H)， 2.42 (s, 2H) , 1.14 (s, 6H)； FAB-MS ra/z:2-(2-(4-morpholine)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzene Formamide was synthesized in the same manner as in Example 3, yield 57%, melting point 142-144 ° C; l HNMR (500 丽z, CDC1 3 ), δ (ppm): 9.24 (b, IH), 7.79-7.81 (d , IH), 7.35 (s, IH), 6.79- 6.81(d, 1H), 6.59 (s, IH), 6.21(b, IH), 4.02 (b, IH), 3.79 (t, 4H), 3.42 ( t, 2H), 3.18 (ΐ, 2H), 2.83 (s, 211), 2.64 (b, 4H), 2.57 (s, 3H), 2.42 (s, 2H), 1.14 (s, 6H); FAB-MS Ra/z:
407.2(M++1); 元素分析： 计算值 C 70.91， H7.44, N 13.78； 测定值 C 70.78， H 7.25，407.2(M + +1); Elemental analysis: Calculated C 70.91, H7.44, N 13.78; C 70.78, H 7.25,
N 13.52。 N 13.52.
实施例 12  Example 12
2- (1- (4 -氧-哌啶）) -4- (1- ( 3， 6， 6_三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚））苯甲酰 胺 ( 2- (4-oxo-piperidin-l-yl) -4- (3， 6， 6 - trimethyl-4-oxo- 4， 5, 6， 7-tetrahydro - indol- 1- yl)- benzamide) 的合.成 （结构式 I- 12)  2-(1-(4-oxo-piperidinyl)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzene Formamide ( 2-(4-oxo-piperidin-l-yl)-4-(3, 6, 6 - trimethyl-4-oxo-4, 5, 6, 7-tetrahydro - indol- 1-yl)- benzamide )合合成(Structure I-12)
Figure imgf000026_0001
Figure imgf000026_0001
2- (1- (4-氧-哌啶）） -4- (1- (3， 6, 6 -三甲基- 4-氧- 4,5,6,7-四氢吲哚）)苯氰的 合成方法同实施例 4， 产率 48%， 熔点 93— 95 °C; ¾NMR(500 MHz, CDCL) , δ (ppm) :7.67— 7.69 (d, IH), 7.06 (s, IH), 6.87—6.89 (d, IH)， 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)。  2-(1-(4-Oxo-piperidinyl)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzene The synthesis of cyanide is the same as in Example 4, yield 48%, melting point 93-95 ° C; 3⁄4 NMR (500 MHz, CDCL), δ (ppm): 7.67-7.69 (d, IH), 7.06 (s, IH), 6.87—6.89 (d, IH), 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).
2- (1- (4 -氧-哌啶）) -4- (1- (3, 6， 6_三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚）)苯甲酰 胺的合成方法同实施例 3， 产率 38,7%， 熔点 112— 114 UC; ¾NMR(500 MHz, CDC13) , δ (ppm) :9.21 (b, IH) , 7.64-7.66 (d, 1H)， 7.27 (s, IH), 6.45—6.47 (d， IH), 6.62 (s， IH), 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); 元素分析： 计算值 C 73.57， H 6.71， N 11.19; 测定值 C 73.43, H 6.57, N 11.52。 2-(1-(4-oxo-piperidinyl)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzene Formamide was synthesized in the same manner as in Example 3, yield 38, 7%, melting point 112-114 U C; 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppm): 9.21 (b, IH), 7.64-7.66 (d , 1H), 7.27 (s, IH), 6.45—6.47 (d, IH), 6.62 (s, IH), 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); Elemental analysis: Calculated C 73.57, H 6.71, N 11.19; Measured value C 73.43, H 6.57, N 11.52.
实施例 13  Example 13
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2- (4 -羟基环己氨基) -4- (1- (3, 6， 6-三甲基 -4-氧- 4， 5， 6, 7 -四氢吲哚）) 苯甲酰胺的合成方法同实施例 3, 产率 54 %， 熔点 153—155 °C; lHNMR(500MHz， CDC13)， δ (ppm)： 8.34(b, 1H)， 7.48-7.50 (d, 1H)， 6.62 (s, IH), 6.58 (s, IH), 6.45 (d, IH), 5.86(b， 1H)， 3.76 (b, 1H)， 3.30 (b, 1H)， 2.67(s, 211) , 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); 元素分析： 计算值 C 70.39， H 7.63, N 10.26; 测定值 C 70.06, H 7.38, N 10.32。 Synthesis of 2-(4-hydroxycyclohexylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole)) benzamide The same procedure as in Example 3, yield 54%, melting point 153-155 ° C; l HNMR (500 MHz, CDC1 3 ), δ (ppm): 8.34 (b, 1H), 7.48-7.50 (d, 1H), 6.62 ( s, IH), 6.58 (s, IH), 6.45 (d, IH), 5.86(b, 1H), 3.76 (b, 1H), 3.30 (b, 1H), 2.67(s, 211), 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) ; Elemental analysis: Calculated C 70.39, H 7.63, N 10.26; found C 70.06, H 7.38, N 10.32.
实施例 15  Example 15
2- (1- (4- (4 -吗啉)哌啶）） -4- (1- (3,6,6-三甲基 -4-氧- 4， 5， 6， 7 -四氢吲哚）) 苯 甲酰胺 ( 2 (4- morpholin- 4-yl piperidin_l-yl)-4_(3， 6, 6 trimethyl- 4-OXO- 4, 5, 6, 7-tetrahydro-indol-l-yl)-benzamide) 的合成。 （结构式 1-15)  2-(1-(4-(4-morpholine)piperidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole)哚)) Benzamide ( 2 (4- morpholin- 4-yl piperidin_l-yl)-4_(3, 6, 6 trimethyl- 4-OXO- 4, 5, 6, 7-tetrahydro-indol-l-yl) Synthesis of -benzamide). (Structure 1-15)
Figure imgf000028_0001
Figure imgf000028_0001
2- (1 - (4- (4-吗啉)呢啶）) -4- (1- (3， 6， 6-三甲基 -4 -氧 _4， 5, 6， 7-四氢吲哚）） 苯氰的合成方法同实施例 6， 产率 62%,熔点 141-143 °C; 1画 R(500 MHz, CDC13) , δ (ppm) :7.97- 7.99 (d, IH), 7.43(.s, 1H),7.18-7.20 (d， 1H)，6.58(s, IH), 3.84- 3.86 (m, 4H), 2.89-2.91 (ra, 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)。 2-(1 - (4-(4-morpholinyl) acyl)-4-(1-(3, 6, 6-trimethyl-4-oxo_4, 5, 6, 7-tetrahydroindole)哚)) The synthesis method of phenyl cyanide is the same as in Example 6, yield 62%, melting point 141-143 °C; 1 drawing R (500 MHz, CDC1 3 ), δ (ppm): 7.97- 7.99 (d, IH), 7.43 (.s, 1H), 7.18-7.20 (d, 1H), 6.58 (s, IH), 3.84- 3.86 (m, 4H), 2.89-2.91 (ra, 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).
2- (1- (4- (4-吗啉)哌啶）） -4- (1- (3， 6， 6-三甲基 -4 -氧- 4, 5, 6, 7-四氢吲哚）） 苯甲酰胺的合成方法同实施例 3, 产率 67%, 熔点 165-167 "C; 'HNMR (500 MHz, CDC13) , δ (ppm) :9.22 (b, IH) , 8.17-8.19 (d, 1H)， 7.54 (s, IH), 7.09- 7.11 (d， IH), 6.64 (s, IH), 6.07 (b, IH), 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 ra/z: 465.3(M++1)； 元素分析: 计算值 C 69.80, H 7.81， N 12.06; 测定值 C 69.64， H 7.61, N 11.87。 2-(1-(4-(4-morpholine)piperidinyl)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole)哚)) The synthesis of benzamide is the same as in Example 3, yield 67%, melting point 165-167 "C;'HNMR (500 MHz, CDC1 3 ), δ (ppm): 9.22 (b, IH), 8.17- 8.19 (d, 1H), 7.54 (s, IH), 7.09- 7.11 (d, IH), 6.64 (s, IH), 6.07 (b, IH), 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 ra/z: 465.3 (M + +1). Elemental analysis: Calculated C 69.80, H 7.81, N 12.06; calc. C 69.64, H 7.61, N 11.87.
实施例 16  Example 16
2- (2- [1， 2， 3]三氮唑乙氨基） -4- (1- (3, 6， 6_三甲基 -4 -氧- 4, 5， 6, 7 -四氢吲哚）) 苯 甲 酰胺 （2- (2_[l,2，3]triazo ■l-yl-ethylamino)-4-(3,6，6-trimethyl-4-oxo- 4， 5, 6, 7 tetrahydro - indol-l- yl)-benzamide)的合成。 （结构式 1-16)
Figure imgf000029_0001
2-(2- [1, 2, 3]triazole ethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole)哚)) Benzamide (2-(2_[l,2,3]triazo ■l-yl-ethylamino)-4-(3,6,6-trimethyl-4-oxo- 4, 5, 6, 7 tetrahydro - synthesis of indol-l-yl)-benzamide). (Structure 1-16)
Figure imgf000029_0001
2 - (2- [1,2, 3]三氮唑乙氨基) -4- (1- (3， 6， 6_三甲基 -4-氧- 4,5,6,7-四氢吲哚）) 苯氰的合成方法同实施例 4， 产率 37.5%，熔点 113— 115 °C; ¾NMR(500 MHz, CDC13)， 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, 211) , 1.15 (s 6H)。 2-(2-[1,2,3]triazolethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole哚)) The synthesis method of phenyl cyanide is the same as in Example 4, the yield is 37.5%, the melting point is 113-115 °C; 3⁄4 NMR (500 MHz, CDC1 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, 211), 1.15 (s 6H).
2- (2- [1， 2， 3]三氮唑乙氨基） -4- (1- (3, 6,6-三甲基 -4 -氧 -4， 5， 6， 7-四氢吲哚）) 苯甲酰胺的合成方法同实施例 3， 产率 72%，熔点 143— 145 ; 'HNMR(500MHz，CDCl3)， 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 (MM); 元素分析： 计算值 C 65.01, H 6.45, N 20.68; 测定值 C 64.82, H 6.27, N 20.53。 2-(2- [1, 2, 3]triazole ethylamino)-4-(1-(3, 6,6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole)哚)) The synthesis of benzamide is the same as in Example 3, yield 72%, melting point 143-145; 'HNMR (500 MHz, 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 (MM); Analysis: Calculated C 65.01, H 6.45, N 20.68; found C 64.82, H 6.27, N 20.53.
实施例 17  Example 17
2- (1- (4- (2- (4_吗啉) 乙基）哌嗪）） -4- (1- (3，6，6-三甲基 - 4 -氧- 4, 5，6，7- 四 氢 吲 哚 ） ） 苯 甲 酰 胺 （2- [4_(2- morpholin- 4 - yl-ethyl) -piperazin-1-yl] -4- (3, 6， 6-trimethyl 4- oxo- 4, 5， 6， 7-tetrahydro - indol-l - yl)-be nzamide)的合成。 （结构式 1-17) 2-(1-(4-(2-(4-morpholine)ethyl)piperazine))-4-(1-(3,6,6-trimethyl- 4 -oxy- 4, 5,6 ,7-tetrahydroanthracene))benzamide (2- [4_( 2 - morpholin- 4 - yl-ethyl) -piperazin-1-yl] -4- (3, 6, 6-trimethyl 4- oxo- Synthesis of 4, 5, 6, 7-tetrahydro - indol-l - yl)-be nzamide). (Structure 1-17)
Figure imgf000029_0002
Figure imgf000029_0002
2- (1- (4- (2- (4-吗啉） 乙基）哌嗪）） -4- (1- ( 3， 6， 6-三甲基 -4-氧- 4, 5,6， 7- 四氢吲哚）） 苯氰的合成方法同实施例 4， 产率 56%,熔点 156— 158 °C; ¾NMR(500 MHz, CDC13) , 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)， 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)。 2- (1- (4- (2- (4-吗啉) 乙基）哌嗪）） -4 (1- (3， 6, 6-三甲基 -4-氧- 4， 5,6, 7- 四氢吲哚））苯甲酰胺的合成方法同实施例 3， 产率 58%, 熔点 168— 17CTC; ¾NMR(500 MHz, CDC13)， δ (ppm) :9.22 (b, 1H) , 8.32-8.34 (d, 1H) , 7.54 (s， 1H)， 7.18—7.20 (d, 1H), 6.64(s,lH), 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 ra/z: 494.3(M÷+l); 元素分析： 计算值 C 68,13, H 7.96, N 14.19; 测定 值 C 68.07, H 7.72, N 13.95。 2-(1-(4-(2-(4-morpholine)ethyl)piperazine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5,6 , 7-tetrahydroanthracene)) Benzene cyanide was synthesized in the same manner as in Example 4, yield 56%, melting point 156-158 °C; 3⁄4 NMR (500 MHz, CDC1 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), 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). 2-(1-(4-(2-(4-morpholine)ethyl)piperazine)) -4 (1-(3, 6, 6-trimethyl-4-oxo-4, 5,6, The synthesis method of 7-tetrahydroanthracene))benzamide is the same as in Example 3, yield 58%, melting point 168-17 CTC; 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppm): 9.22 (b, 1H), 8.32-8.34 (d, 1H), 7.54 (s, 1H), 7.18—7.20 (d, 1H), 6.64(s,lH), 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 ra/z: 494.3 (M ÷ + l) ; Elemental analysis: Calculated C 68,13, H 7.96, N 14.19; Measured value C 68.07, H 7.72, N 13.95 .
实施例 18  Example 18
2- (1- (4- (1-吡咯垸基)哌啶）） -4- (1- (3,6,6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲 哚）） 苯甲酰胺 （2 -（4- pyrrolidin- l_yl - piperidin- 1- yl)- 4 -
Figure imgf000030_0001
2-(1-(4-(1-pyrrolidinyl)piperidine))-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro)吲哚)) Benzamide (2-(4- pyrrolidin- l_yl - piperidin- 1- yl)- 4 -
Figure imgf000030_0001
-oxo-A, 5， 6, 7- tetrahydro- indol- 1 - yl)_benzamide)的合成。 （结构式 1-18)  Synthesis of -oxo-A, 5, 6, 7-tetrahydro- indol- 1 - yl)_benzamide). (Structure 1-18)
Figure imgf000030_0002
Figure imgf000030_0002
2- (1- (4 -（1-吡咯烷基）哌啶）） -4- (1- (3， 6， 6 -三甲基- 4 -氧- 4， 5， 6， 7_四氢吲 哚））苯氰的合成方法同实施例 4， 产率 42%，熔点 121— 123 °C; ¾NMR(500 MHz, CDC13), 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)。 2-(1-(4-(1-pyrrolidinyl)piperidinyl)-4-(1-(3,6,6-trimethyl- 4 -oxo-4, 5, 6, 7-tetrahydro)吲哚)) The synthesis method of phenyl cyanide is the same as in Example 4, yield 42%, melting point 121-123 °C; 3⁄4 NMR (500 MHz, CDC1 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).
2- (1- (4- (1 -吡咯烷基)哌啶）） -4- (1- (3,6，6-三甲基 - 4-氧- 4，5,6，7_四氢吲 哚）） 苯甲酰胺的合成方法同实施例 3， 产率 47 %, 熔点 137— 139°C; ¾NMR(500 MHz, CDC13) , δ (ppm) :9.21 (b， 1Η)， 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++l)； 元素分析： 计算值 C 72.29, H 8.09, N 12.49; 测定值 C 72.08, H 7.87， N 12.26。 2-(1-(4-(1-pyrrolidinyl)piperidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro)吲哚)) The synthesis of benzamide is the same as in Example 3, yield 47%, melting point 137-139 ° C; 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppm): 9.21 (b, 1 Η), 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 + +l); Elemental analysis: Calculated C C.21.29, H 8.09, N 12.49; calc. C 72.08, H 7.87, N 12.26.
实施例 19  Example 19
2- (2-二乙氨基乙氨基） -4- (1- (3,6,6-三甲基 -4氧- 4， 5, 6， 7-四氢吲唑））苯甲 酰 胺 （2- (2-diethylamino-ethylamino) -4- (3, 6, 6- trimethyl- 4- 0x0- 4, 5, 6, 7- tetrahydro-indazol-l-yl)-benzamide)的合成。 （结构式 1-19) 2-(2-Diethylaminoethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide (2 - (2-diethylamino-ethylamino) -4- (3, 6, 6- trimethyl- 4- 0x0- 4, 5, 6, 7- Synthesis of tetrahydro-indazol-l-yl)-benzamide). (Structure 1-19)
Figure imgf000031_0001
Figure imgf000031_0001
2- (2-二乙氨基乙氨基） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑））苯氰 由 2-氯- 4-(1- (3, 6， 6_三甲基 -4 -氧- 4, 5， 6, 7-四氢吲唑)）苯氰（实施例 1)和 2-二乙氨基 乙胺按实施例 2 的合成方法合成得到， 产率 38.5%， 熔点 97— 99 °C; ¾NMR(500 MHz, CDC13) , δ (ppm) :7.76-7.78 (d, IH), 7.34 (s, IH), 7.05-7.07 (d， IH)， 4.04 (b, IH) , 3.29(t, 2H)， 3.34 (t, 2H)， 2.84 (s, 211)， 2.63 (b， 4H), 2.55 (s, 3H), 2.43 (s， 2H), 1.20(t, 4H), 1.13(s, 6H)。 2-(2-diethylaminoethylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide consists of 2 -Chloro-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 2-diethylamino Ethylamine was synthesized according to the synthesis method of Example 2, yield 38.5%, melting point 97-99 ° C; 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppm): 7.76-7.78 (d, IH), 7.34 (s , IH), 7.05-7.07 (d, IH), 4.04 (b, IH), 3.29(t, 2H), 3.34 (t, 2H), 2.84 (s, 211), 2.63 (b, 4H), 2.55 ( s, 3H), 2.43 (s, 2H), 1.20(t, 4H), 1.13(s, 6H).
2- (2 -二乙氨基乙氨基） -4- (1- (3,6，6-三甲基 - 4-氧 _4,5,6，7-四氢吲唑）)苯甲 酰胺的合成方法同实施例 3, 产率 68 %， 熔点 123-124。C; 1顯 MR(500 MHz, CDC13) , δ (ppm) :9.23 (b， IH) , 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， IH), 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. 2 (s, 2H)， 1.19 (b, 4H), 1.14(s， 6H)； FAB- MSm/z: 412.3(M++1);元素分析：计算值 C 67.12， H 8.08, N 17.02;测定值 C 67.08， H 7.84, N 16.79。 2-(2-diethylaminoethylamino)-4-(1-(3,6,6-trimethyl-4-oxo_4,5,6,7-tetrahydrocarbazole))benzamide The synthesis was carried out in the same manner as in Example 3, yield 68%, melting point 123-124. C; 1 display MR (500 MHz, CDC1 3 ), δ (ppm): 9.23 (b, IH), 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, IH), 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. 2 (s, 2H), 1.19 (b, 4H), 1.14(s, 6H); FAB- MSm/z: 412.3 (M + +1); Elemental analysis: Calculated C 67.12, H 8.08, N 17.02; found C 67.08, H 7.84, N 16.79.
实施例 20  Example 20
2 -环己氨基- 4- (1- (3， 6， 6_三甲基 -4-氧- 4, 5， 6， 7-四氢吲唑））苯甲酰胺 (2 - cyclohexylamino - 4- (3， 6, 6_trimethyl-4-oxo - 4， 5, 6, 7-tetrahydro-indazol-l-yl )-benzamide)的合成。 （结构式 1-20)  2-cyclohexylamino-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide (2-cyclohexylamino-4- Synthesis of (3, 6, 6_trimethyl-4-oxo-4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzamide). (Structure 1-20)
Figure imgf000031_0002
Figure imgf000031_0002
2 -环己氨基- 4- (1- (3,6,6-三甲基 -4-氧- 4， 5, 6， 7 -四氢吲唑））苯氰由 2-氯 - 4 -（1-(3， 6， 6-三甲基 -4-氧- 4, 5， 6, 7-四氢吲唑)）苯氰 (实施例 1)和环己胺按实施例 2 的合成方法合成得到， 产率 65%, 熔点 125— 127 °C; ¾丽 R(500 MHz, CDC13) , 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)。 2-cyclohexylamino-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide from 2-chloro-4-(() 1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and cyclohexylamine were synthesized according to the synthesis method of Example 2. Yield, yield 65%, melting point 125-127 °C; 3⁄4 Li R (500 MHz, CDC1 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).
2 -环己氨基- 4- (1- (3, 6， 6_三甲基 -4-氧- 4， 5, 6, 7-四氢吲唑)）苯甲酰胺的合成方 法同实施例 3, 产率 73%,熔点 164-166 °C; 1賺 R(500 MHz, CDC13)， 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); 元素分析： 计算 值 C 70.02, H 7.66， N 14.20； 测定值 C 69.89, H 7.53， N 14.15。 The synthesis method of 2-cyclohexylamino-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide is the same as in Example 3. , yield 73%, melting point 164-166 °C; 1 earn R (500 MHz, CDC1 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) ; Calcd for C 70.02, H 7.66, N 14.20; found C 69.89, H 7.53, N 14.15.
实施例 21  Example 21
2- (2- (1-哌啶） 乙氨基） - 4_ (1- (3， 6, 6-三甲基 _4-氧- 4, 5， 6， 7-四氢吲唑））苯 甲 酰 胺 (2- (2- piperidin - 1- yl-ethylamino) - 4 - (3， 6， 6_trimethyl- 4- OXO- 4， 5， 6, 7-tetrahydro-indazol-l-yl)-benzamide)的合成。 （结构式 1-21)  2-(2-(1-piperidinyl)ethylamino)-4_(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) Synthesis of amide (2-(2-piperidin - 1- yl-ethylamino) - 4 - (3, 6, 6-trimethyl- 4- OXO-4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzamide) . (Structure 1-21)
Figure imgf000032_0001
Figure imgf000032_0001
2- (2- (1 -哌啶) 乙氨基） -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲唑）)苯 氰由 2-氯- 4 -（1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑)）苯氰（实施例 1)和 2- (1 -哌 啶）乙胺按实施例 2 的合成方法合成得到， 产率 37%， 熔点 95— 97 °C; 'HNMR(500 MHz, CDC13) , δ (ppm) :7.74—7.76 (d， 1Η), 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)。 2-(2-(1-Petidine)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzene Cyanide from 2-chloro-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 2- (1 - piperidine) ethylamine was synthesized by the synthesis method of Example 2, yield 37%, melting point 95-97 ° C; 'HNMR (500 MHz, CDC1 3 ), δ (ppm): 7.74 - 7.76 (d , 1Η), 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).
2- (2- (1 -哌啶) 乙氨基） -4- (1- (3,6,6-三甲基 -4-氧- 4,5,6,7-四氢吲唑））苯 甲酰胺的合成方法同实施例 3， 产率 73°/0， 熔点 i31— 133 ¾NMR(500 MHz, CDC13) , δ (ppm) :9.21 (b, 1Η)， 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, 211)， 2.84 (s, 2H)， 2.65 (b, 2H), 2.54 (s, 3H), 2.43 (s， 2H)， 2.37-2.39 (ΐ, 4H), 1.38- 1.46 (m, 6H)， 1.14(s, 6H)； FAB-MS ra/z: 424.2 (M++l)； 元素分析： 计算值 C 68.06, H 7.85, N 16.53； 测定 值 C 67.88， H 7.67, N 16.38。 2-(2-(1-Pyridinyl)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzene Formamide was synthesized in the same manner as in Example 3, yield 73 ° / 0 , melting point i 31 - 133 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppm): 9.21 (b, 1 Η), 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, 211), 2.84 ( s, 2H), 2.65 (b, 2H), 2.54 (s, 3H), 2.43 (s, 2H), 2.37-2.39 (ΐ, 4H), 1.38- 1.46 (m, 6H), 1.14(s, 6H) FAB-MS: </ RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;
实施例 22 2- (2- (1- (3, 5-二甲基哌啶）) 乙氮基） -4- (1- ( 3， 6， 6-三甲基 -4-氧- 4, 5,6,7- 四氢吲唑）） 苯甲酰胺 (2- [2- (3, 5-dimethyl-piperidin-l-yl) -ethylamino] -4- (3, 6, 6-trimethyl-4-oxo-4, 5, 6， 7-tetrahydro-indazol-l-yl)-benzamide)的合成。 (结构式 1-22) Example 22 2-(2-(1-(3, 5-dimethylpiperidine))ethyl) -4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5,6 ,7-tetrahydrocarbazole))benzamide (2-[2-(3, 5-dimethyl-piperidin-l-yl)-ethylamino] -4- (3, 6, 6-trimethyl-4-oxo- Synthesis of 4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzamide). (Structure 1-22)
Figure imgf000033_0001
Figure imgf000033_0001
2 - (2- (1- (3, 5 -二甲基哌啶）） 乙氨基） -4- (1- (3， 6， 6_三甲基 -4-氧- 4， 5， 6,7- 四氢吲唑））苯氰由 2-氯 -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑)）苯氰 (实施例 1)和 2-(1-顺 3， 5-二甲基哌啶）乙胺按实施例 2的合成方法合成得到， 产率 43%， 熔点 113― 115 °C; ¾NMR(500 MHz, CDCla)， 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， 411) , 1.65 (m, 2H) , 1.39- 1.43 (m, 2H) ,2-(2-(1-(3,5-dimethylpiperidine))ethylamino)-4-(1-(3, 6, 6_trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) phenyl cyanide from 2-chloro-4-(1-(3, 6, 6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)benzene Cyanide (Example 1) and 2-(1-cis,3,5-dimethylpiperidine)ethylamine were synthesized according to the synthesis method of Example 2, yield 43%, melting point 113-115 ° C; 3⁄4 NMR (500 MHz, CDCl a ), 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, 411), 1.65 (m, 2H), 1.39- 1.43 ( m, 2H) ,
1.14(s, 6H), 1.03-1.05 (d, 6H)。 1.14(s, 6H), 1.03-1.05 (d, 6H).
2- (2- (1- (3, 5-二甲基哌啶）） 乙氨基） -4- (1- (3,6, 6-三甲基 - 4 -氧- 4，5，6, 7- 四氢 Π引唑））苯甲酰胺的合咸方法同实施例 3， 产率 55%， 瑢点 142— 144 °C; ¾NMR(500 MHz, CDC13) , δ (ppm) :9.23 (b， 1Η)， 8.04-8.06 (d, IH), 7.41 (s, 1H), 6.92-6.94 (d, 1H), 6.59 (s， IH), 6.17 (b, IH)， 4.03 (b, IH), 3.46-3.48 (t， 2H)， 2.83 (s, 2H)，2-(2-(1-(3, 5-dimethylpiperidine))ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6, 7-tetrahydroindole oxazole)) The salty method of benzamide is the same as in Example 3, the yield is 55%, 瑢 142-144 ° C; 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppm): 9.23 ( b, 1Η), 8.04-8.06 (d, IH), 7.41 (s, 1H), 6.92-6.94 (d, 1H), 6.59 (s, IH), 6.17 (b, IH), 4.03 (b, IH) , 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)；元素分析：计算值 C 69.15， H 8.26,2.67 (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); elemental analysis: calculated C 69.15, H 8.26,
N 15.51； 测定值 C 68.94， H 8.06， N 15.35。 N 15.51; Measured value C 68.94, H 8.06, N 15.35.
实施例 23  Example 23
2- (2- [1， 2， 3]三氮唑乙氨基) -4- (1- (3, 6, 6-三甲基 -4-氧- 4， 5, 6, 7-四氢吲唑）） 苯 甲 酰 胺 （2- (2-[l，2，3]triazol- 1- yl- ethylamino)- 4- (3，6，6- trimethyl-4- oxo-4, 5， 6， 7-tetrahydro-indazo-l-yl)-benzamide)的合成。 (结构式工- 23)  2-(2- [1, 2, 3]triazole ethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole) Oxazol)) Benzamide (2-(2-[l,2,3]triazol- 1- yl- ethylamino)- 4- (3,6,6- trimethyl-4- oxo-4, 5, 6, 7 Synthesis of -tetrahydro-indazo-l-yl)-benzamide). (Structural Workman - 23)
Figure imgf000033_0002
2- (2- [1,2， 3]三氮唑乙氨基） -4- (1- (3， 6， 6 -三甲基- 4-氧 -4， 5, 6, 7-四氢吲唑）） 苯氰由 2 -氯- 4- (1- (3,6,6-三甲基 -4-氧- 4，5，6, 7-四氢吲唑））苯氰（实施例 1)和 2- [1,2， 3]三氮唑乙胺按实施例 2 的合成方法合成得到， 产率 64%,熔点 135— 137 °C; 'HNMR(500 MHz, CDC1:)) , 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, 211) , 1.14 (s, 6H)。
Figure imgf000033_0002
2-(2- [1,2, 3]triazole ethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole) Azole)) Benzene cyanide from 2-chloro-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide (Example 1 And 2-[1,2,3]triazole ethylamine were synthesized according to the synthesis method of Example 2, yield 64%, melting point 135-137 °C; 'HNMR (500 MHz, CDC1 :) ), 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, 211), 1.14 (s, 6H).
2- (2- [1,2， 3]三氮唑乙氨基） -4- (1- (3， 6, 6-三甲基 -4 -氧- 4, 5， 6， 7-四氢吲唑）） 苯甲酰胺的合成方法同实施例 3， 产率 65%, 熔点 164-166 °C; ¾NMR(500 MHz, CDC13) , 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 (ra, 2H), 3.67(1:, 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)；元素分析：计算值 C61.90, H 6.18， N 24.06; 测定值 C 61.74, H 6.02, N 23.88。 2-(2- [1,2,3]triazole ethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole) The synthesis of benzamide is the same as in Example 3, yield 65%, melting point 164-166 ° C; 3⁄4 NMR (500 MHz, CDC1 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 (ra, 2H), 3.67 (1 :, 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); Elemental analysis: Calculated C 61.90, H 6.18, N 24.06; found C 61.74, H 6.02, N 23.88.
实施例 24  Example 24
2- (1- (4 -环戊烷基) 哌嗪） -4- (1- (3， 6,6-三甲基 _4-氧- 4， 5, 6， 7-四氢吲唑）） 苯 甲 酰 胺 ( 2-(4-cyclopentyl-piperazin-l-yl)-4-(3, 6, 6-trimethyl-4- oxo-4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzamide) 的合成。 (结构式 I - 24)  2-(1-(4-cyclopentyl)piperazine)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole) Benzoic acid (2-(4-cyclopentyl-piperazin-l-yl)-4-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro-indazol-l-yl) Synthesis of -benzamide). (Structure I - 24)
Figure imgf000034_0001
Figure imgf000034_0001
2- (1- (4 -环戊烷基)哌嗪） -4- (1- (3, 6， 6-三甲基 -4-氧 -4， 5， 6,7-四氢吲唑）) 苯氰由 2-氯 -4_(1- (3， 6， 6-三甲基 -4-氧- 4， 5, 6, 7-四氢吲唑)）苯氰（实施例 1)和 4环戊 垸基哌嗪按实施例 2的合成方法合成得到， 产率 55.8%， 熔点 141一 143 °C; ¾NMR(500 MHz, CDC13) , δ (ppm)： 7.83-7.85 (d, 1H)， 7.31 (s，lH), 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), 1.682-(1-(4-cyclopentyl)piperazine)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6,7-tetrahydrocarbazole) Benzoic acid from 2-chloro-4_(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 4 Cyclopentyl piperazine was synthesized according to the synthesis method of Example 2, yield 55.8%, melting point 141-143 ° C; 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppm): 7.83-7.85 (d, 1H) , 7.31 (s, lH), 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)。 (m, 4H), 1.58 (m, 4H), 1.14 (s, 6H).
2- (1- (4-环戊垸基）哌嗪） - 4 -（1- (3,6,6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑)） 苯甲酰胺的合成方法同实施例 3， 产率 73%， 熔点 168—170 °C; 醒 R (500丽2， CDC13) , 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, 611)； FAB-MS m/z: 450.3(M++1); 元素分析: 计算 值 C 69.46, H 7.85, N 15.58; 测定值 C 69.18, H 7.59, N 15.62。 2-(1-(4-Cyclopentyl)piperazine) - 4 -(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole) The synthesis method of benzamide is the same as in Example 3, the yield is 73%, the melting point is 168-170 °C; the wake R (500 Li 2 , CDC1 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, 611); FAB-MS m/z: 450.3 (M + +1); Elemental analysis: Calculated C 69.46, H 7.85, N 15.58; Value C 69.18, H 7.59, N 15.62.
实施例 25  Example 25
2-环丙烷氨基- 4- (1- (3,6,6-三甲基 -4-氧- 4, 5， 6, 7-四氢吲唑）） 苯甲酰胺 ( 2-cyclopropylamino-4- (3, 6， 6-trimethyl-4-oxo-4, 5, 6， 7-tetrahydro-indazol-l- yl)- benzamide) 的合成。 (结构式 1-25)  2-cyclopropanylamino-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide (2-cyclopropylamino-4- Synthesis of (3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro-indazol-l-yl)- benzamide). (Structure 1-25)
Figure imgf000035_0001
Figure imgf000035_0001
2 -环丙烷氨基- 4- (1- (3,6,6-三甲基 -4-氧- 4,5,6,7-四氢吲唑）) 苯氰由 2-氯 - 4 - (1- (3， 6， 6-三甲基 -4-氧- 4, 5， 6， 7-四氢吲唑)）苯氰 (实施例 1)和环丙胺按实施例 2 的合成方法合成得到， 产率 38.5%, 熔点 87-89 。C; 1匪 R(500 MHz, CDC13) , δ (ppm) :7.74-7.76 (d, 1Η)， 7.32 (s, 1Η)， 7.03-7.05 (d, 1Η) , 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 (m 4H) o 2-cyclopropanylamino-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide from 2-chloro-4-( 1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and cyclopropylamine were synthesized according to the synthesis method of Example 2. , yield 38.5%, melting point 87-89. C; 1匪R(500 MHz, CDC1 3 ) , δ (ppm): 7.74-7.76 (d, 1Η), 7.32 (s, 1Η), 7.03-7.05 (d, 1Η), 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 (m 4H) o
2 -环丙烷氨基 -4- (1- (3,6， 6_三甲基 -4-氧 4， 5， 6， 7-四氢吲唑））苯甲酰胺的合成 方法同实施例 3, 产率 68%，熔点 112-114 °C; ¾NMR(500 MHz, CDC13)， 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 (m 4H)； FAB-MS m/z: 353.2 (M++l)； 元素分析： 计算值 C 68.16， H 6.86， N 15.90; 测定 值 C 67.87， H 6.69， N 15.78。 The synthesis method of 2-cyclopropanylamino-4-(1-(3,6,6-trimethyl-4-oxo 4,5,6-7-tetrahydrocarbazole))benzamide is the same as in Example 3. Yield 68%, melting point 112-114 ° C; 3⁄4 NMR (500 MHz, CDC1 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), </ RTI> <RTIgt; 6.69, N 15.78.
实施例 26  Example 26
2- (1- (4- (2- (1 -哌啶）乙氧基）哌啶）） -4 -（1- (3， 6, 6-三甲基 -4-氧- 4, 5, 6， 7- 四氢吲唑）） 苯甲酰胺 （ 2- [4- (2- piperidin- 1- y卜 ethoxy)-piperidin-l-yl] - 4 - (3， 6， 6-trimethyl- 4-0X0-4, 5， 6， 7- tetrahydro- indazol- l-yl)-benzaraide)的合成。 (结构式 1-26)
Figure imgf000036_0001
2-(1-(4-(2-(1-piperidinyl)ethoxy)piperidine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) Benzamide (2- [4- (2-piperidin- 1- y ethoxy)-piperidin-l-yl] - 4 - (3, 6, 6-trimethyl- 4 Synthesis of -0X0-4, 5, 6, 7-tetrahydro- indazol-l-yl)-benzaraide). (Structure 1-26)
Figure imgf000036_0001
2- (1- (4- (2- (1 -哌啶)乙氧基）哌啶）） -4- (1- (3， 6， 6 -三甲基- 4-氧- 4， 5， 6, 7- 四氢吲唑））苯氰的合成由 2-氯- 4- (1- (3, 6， 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑)）苯氰 (实施例 1)和 4- (2- (1-哌啶） 乙氧基）哌啶按实施例 2的合成方法合成得到， 产率 63%, 熔点 126-128 °C; 丽（500 MHz, CDC1:)) , 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)。 2-(1-(4-(2-(1 -Piperidine)ethoxy)piperidine))-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) Synthesis of phenyl cyanide from 2-chloro-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole) Benzene)) phenyl cyanide (Example 1) and 4-(2-(1-piperidine)ethoxy) piperidine were synthesized according to the synthesis method of Example 2, yield 63%, melting point 126-128 ° C; Li (500 MHz, CDC1 :) ) , 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).
2- (1- (4- (2- (1 -哌啶)乙氧基）哌啶）） -4- (1- (3, 6， 6-三甲基 -4-氧- 4， 5, 6, 7 - 四氢吲唑））苯甲酰胺的合成方法同实施例 3， 产率 75%, 熔点 146— 147°C; ¾NMR(500 MHz, CDC13) , 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++l)； 元素分析： 计算值 C 68.61， H 8.14， N 13.80; 测定值 C 68.46, H 7.87， N 13,68。 2-(1-(4-(2-(1 -Piperidine)ethoxy)piperidine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7 - tetrahydrocarbazole)) benzamide was synthesized in the same manner as in Example 3, yield 75%, melting point 146-147 ° C; 3⁄4 NMR (500 MHz, CDC1 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 + +l); Elemental Analysis: Calculated C 68.61, H 8.14, N 13.80; Measured value C 68.46, H 7.87, N 13,68.
实施例 27  Example 27
2- (1- (4-氧-哌啶）) -4- (1- (3， 6, 6-三甲基 -4-氧 -4， 5, 6, 7-四氢吲唑））苯甲酰 胺 ( 2- (4 - 0X0- piperidin 1- yl)- 4- (3， 6, 6-trimethyl-4- oxo-4, 5, 6， 7-tetrahydro -indazol-l-yl)-benzamide) 的合成。 （结构式 1-27)  2-(1-(4-oxo-piperidinyl)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzene Formamide (2-(4 - 0X0-piperidin 1- yl)- 4- (3, 6, 6-trimethyl-4- oxo-4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzamide) Synthesis. (Structure 1-27)
Figure imgf000036_0002
Figure imgf000036_0002
2- (1- (4-氧-哌啶）） -4- (1- (3， 6， 6 -三甲基- 4 -氧 -4， 5, 6， 7-四氢吲唑）)苯氰的 合成由 2-氯- 4- (1- (3,6,6-三甲基 -4-氧- 4, 5， 6， 7-四氢吲唑)）苯氰 (实施例 1)和 4-氧- 哌啶按实施例 2 的合成方法合成得到， 产率 57%, 熔点 141一 143 °C; ¾NMR(500 MHz, CDCI3) , δ (ppm) :7.87-7.89 (d, IH), 7.35 (s， 1H)， 6.86-6.88 (d， IH) , 3.63(1, 4H)， 2.83 (s, 2H)， 2.67 (t， 4H), 2.56 (s, 3H), 2.42(s, 2H)， 1.13(s, 6H)。 2-(1-(4-oxo-piperidinyl)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzene The synthesis of cyanide consists of 2-chloro-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 4-oxo-piperidine was synthesized by the synthesis method of Example 2, yield 57%, melting point 141 - 143 ° C; 3⁄4 NMR (500 MHz, CDCI3), δ (ppm): 7.87-7.89 (d, IH), 7.35 (s, 1H), 6.86-6.88 (d, IH), 3.63 (1, 4H), 2.83 (s, 2H), 2.67 (t, 4H), 2.56 (s, 3H), 2.42 (s, 2H), 1.13 (s, 6H).
2- (1- (4-氧-哌啶）） -4- (1- (3,6,6-三甲基 _4-氧 -4, 5, 6, 7-四氢吲唑））苯甲酰 胺的合成方法同实施例 3, 产率 75 %, 熔点 146-147 "C; 1画 R(500 MHz, CDC13) , δ (ppm) :9.27 (b, IH)， 8.18- 8.20 (d, 1H)， 7.54 (s， 1H)， 7.25-7.27 (d, IH)， 6.04 (b, IH) , 3.68 (t, 4H), 2.84 (s，2H)， 2.72(1:, 4H), 2.56 (s, 3H) , 2.43 (s, 211) , 1.14(s, 6H); FAB - MS m/z: 395.2(M++1); 元素分析： 计算值 C66.99, H6.64， N 14.20; 测定值 C 66.74, H 6.47, N 14.05。 2-(1-(4-oxo-piperidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzene Formamide was synthesized in the same manner as in Example 3, yield 75%, melting point 146-147 "C; 1 draw R (500 MHz, CDC1 3 ), δ (ppm): 9.27 (b, IH), 8.18- 8.20 (d , 1H), 7.54 (s, 1H), 7.25-7.27 (d, IH), 6.04 (b, IH), 3.68 (t, 4H), 2.84 (s, 2H), 2.72 (1:, 4H), 2.56 (s, 3H), 2.43 (s, 211), 1.14(s, 6H); FAB - MS m/z: 395.2 (M++1); Elemental analysis: Calculated C66.99, H6.64, N 14.20 ; Measured value C 66.74, H 6.47, N 14.05.
实施例 28  Example 28
2- (1- (4- (2-羟乙基)哌嗪）） -4- (1- (3, 6, 6_三甲基 -4-氧 -4， 5， 6, 7_四氢吲唑）) 苯 甲 酰 胺 (2-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-4-(3, 6, 6-trimethyl- 4-0X0-4, 5， 6， 7-tetrahydro-indazol-l-yl)-benzamide) 的合成。 （结构式 1—28)  2-(1-(4-(2-Hydroxyethyl)piperazine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7_ tetrahydrogen) Carbazole)) Benzamide (2-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-4-(3, 6, 6-trimethyl- 4-0X0-4, 5, 6, 7 Synthesis of -tetrahydro-indazol-l-yl)-benzamide). (Structure 1-28)
Figure imgf000037_0001
Figure imgf000037_0001
2- (1- (4- (2 -羟乙基)哌嗪）） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5, 6, 7-四氢吲唑）） 苯氰由 2-氯- 4-(1- (3， 6, 6-三甲基 -4-氧- 4， 5, 6, 7-四氢吲唑)）苯氰（实施例 1)和 4- (2- 羟乙基）哌嗪按实施例 2的合成方法合成得到，产率 63%，熔点 127— 129 °C; ¾NMR(500 MHz, CDCI3) , δ (ppm)： 8.01-8.03 (d, IH)， 7.48 (s, 1H)， 7.18-7.20 (d, IH) , 3.86 (b, 2H) , 3.58 (b, 4H)， 2.83 (s， 21-1)， 2.63 (b, 4H), 2.56 (t, 2H)， 2.565 (s， 3H)， 2.43 (s, 2H)， 1.14(s， 6H)。  2-(1-(4-(2-hydroxyethyl)piperazine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro) Carbazole)) Benzene cyanide from 2-chloro-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 4-(2-hydroxyethyl)piperazine were synthesized according to the synthesis method of Example 2, yield 63%, melting point 127-129 °C; 3⁄4 NMR (500 MHz, CDCI3), δ (ppm): 8.01 -8.03 (d, IH), 7.48 (s, 1H), 7.18-7.20 (d, IH), 3.86 (b, 2H), 3.58 (b, 4H), 2.83 (s, 21-1), 2.63 (b , 4H), 2.56 (t, 2H), 2.565 (s, 3H), 2.43 (s, 2H), 1.14 (s, 6H).
2- (1- (4- (2 -羟乙基）哌嗪）） -4 - (1- (3， 6, 6 -三甲基- 4-氧- 4， 5, 6, 7-四氢吲唑）） 苯甲酰胺的合成方法同实施例 3， 产率 60%, 熔点 155-157 X； 1讓 R(500 MHz， CDC13)， δ (ppm) :9.22 (b， IH) , 8.22 - 8.24 (d, 1H)， 7.57 (s, IH), 7.29-7.31 (d, IH)， 6.21 (b， IH) , 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);元素分析：计算值 C 64.92， H 7.34, N 16.46； 测定值 C 64.78, H 7.17, N 16.28。 2-(1- (4-(2-hydroxyethyl)piperazine)) -4 - (1-(3, 6, 6 -trimethyl-4-oxo-4, 5, 6, 7-tetrahydro) Carbazole)) The synthesis of benzamide is the same as in Example 3, yield 60%, melting point 155-157 X; 1 let R (500 MHz, CDC1 3 ), δ (ppm): 9.22 (b, IH), 8.22 - 8.24 (d, 1H), 7.57 (s, IH), 7.29-7.31 (d, IH), 6.21 (b, IH), 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) ); elemental analysis: Calcd C 64.92, H 7.34, N 16.46 ; measured value C 64.78, H 7.17, N 16.28 .
实施例 29  Example 29
2- (2- (4-吗啉） 乙氨基） -4- (1- ( 3, 6， 6 -三甲基 _4 -氧- 4， 5, 6， 7 -四氢吲唑）)苯 甲 酰 胺 ( 2-(2-morpholin-4-yl-ethylamino)-4-(3, 6, 6-trimethyl-4-oxo- 4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzamide) 的合成。 （结构式 1-29) 2-(2-(4-morpholine)ethylamino)-4-(1-(3,6,6-trimethyl-4O-oxo-4,5,6-7-tetrahydrocarbazole))benzene Formamide (2-(2-morpholin-4-yl-ethylamino)-4-(3, 6, 6-trimethyl-4-oxo- 4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzamide ) Synthesis. (Structure 1-29)
Figure imgf000038_0001
Figure imgf000038_0001
2- (2- (4-吗啉） 乙氨基） -4- (1- (3， 6， 6-三甲基 _4_氧- 4， 5， 6， 7-四氢吲唑））苯 氰的合成由 2-氯 -4- (1- (3， 6, 6-三甲基 -4 -氧 -4， 5， 6， 7-四氢吲唑)）苯氰 (实施例 1)和 2 - 2-(2-(4-morpholine)ethylamino)-4-(1-(3,6,6-trimethyl_4_oxo-4,5,6,7-tetrahydrocarbazole))benzene The synthesis of cyanide consists of 2-chloro-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 2 -
(4-吗啉） 乙胺按实施例 2 的合成方法合成得到， 产率 68.5%，熔点 132— 134 °C; 'HNMR(500MHz, CDC13)， δ (ppm) :7.72-7.74 (d, IH), 7.34 (s， 1H)， 7.08-7.09 (d， IH)， 4.02(b， IH), 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)。 (4-morpholine) Ethylamine was synthesized according to the synthesis method of Example 2, yield 68.5%, melting point 132-134 ° C; 'HNMR (500 MHz, CDC1 3 ), δ (ppm): 7.72-7.74 (d, IH), 7.34 (s, 1H), 7.08-7.09 (d, IH), 4.02(b, IH), 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).
2- (2- (4-吗啉） 乙氨基）—4- (1- (3， 6, 6-三甲基 -4-氧- 4,5,6,7-四氢吲唑））苯 甲酰胺的合成方法同实施例 3, 产率 78%， 熔点 167—169 °C; 'HNMR(500顧 z, CDC13)， δ (ppm) :9.22 (b, IH) , 8.24-8.26 (d, IH), 7.45 (s, IH), 7.29-7.31 (d, IH), 6.03(b， IH), 4.03 (b, IH), 3.78-3.80 (t, 4H), 3.37-3.39 (t, 2H) , 2.89—2.91 (t， 4H), 2.832-(2-(4-morpholine)ethylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzene Formamide was synthesized in the same manner as in Example 3, yield 78%, melting point 167-169 °C; 'HNMR (500 Guz, CDC1 3 ), δ (ppm): 9.22 (b, IH), 8.24-8.26 (d , IH), 7.45 (s, IH), 7.29-7.31 (d, IH), 6.03(b, IH), 4.03 (b, IH), 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)； 元素分析： 计算值 C 64.92, H 7.34, N 16.46； 测定值 C 64.75， H 7.21, N 16.28。 - 实施例 30 (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); Analysis: Calculated C 64.92, H 7.34, N 16.46; found C 64.75, H 7.21, N 16.28. - Example 30
2-（1- (4- (1-吡咯垸基)哌啶)）- 4- (1- (3， 6， 6-三甲基 -4-氧- 4, 5， 6, 7_四氢吲唑)）苯 甲 酰 胺 (2- (4-pyrrolidin-l-yl-piperidin-l-yl)-4-(3, 6, 6-triraethyl-4- oxo-4, 5， 6, 7-tetrahydro-indazol-l-yl)-benzamide)的合成。 (结构式 1-30)  2-(1-(4-(1-pyrrolidino)piperidinyl))- 4- (1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro) Carbazole))benzamide (2-(4-pyrrolidin-l-yl-piperidin-l-yl)-4-(3, 6, 6-triraethyl-4-oxo-4, 5, 6, 7-tetrahydro Synthesis of -indazol-l-yl)-benzamide). (Structure 1-30)
Figure imgf000038_0002
Figure imgf000038_0002
2- (1- (4- (1-吡咯烷基）哌啶)）- 4- (1- (3, 6, 6-三甲基 -4-氧- 4， 5, 6, 7-四氢吲唑)）苯 氰由 2-氯- 4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7 -四氢吲唑)）苯氰 (实施例 1)和 4- (卜吡 咯烷基)哌啶按实施例 2的合成方法合成得到，产率 54.4%，熔点 129— 131 °C; ¾NMR(500 MHz，CDCl3), δ (ppm)： 7.64-7.66 (d, 1H)， 7.25 (s, IH), 7.00-7.02 (d, IH)， 2.99- 3.03 (b: 6H)， 2.84 (s, 211), 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-pyrrolidinyl)piperidinyl)) 4- (1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro) Carbazole)) benzene Cyanide consists of 2-chloro-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 4- (Byr pyrrolidinyl) piperidine was synthesized according to the synthesis method of Example 2, yield 54.4%, melting point 129-131 ° C; 3⁄4 NMR (500 MHz, CDCl 3 ), δ (ppm): 7.64-7.66 (d, 1H), 7.25 (s, IH), 7.00-7.02 (d, IH), 2.99-3.03 (b: 6H), 2.84 (s, 211), 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-吡咯烷基）哌啶)）-4_(l- (3， 6, 6 -三甲基- 4-氧- 4, 5， 6， 7-四氢吲唑)）苯 甲酰胺合成方法同实施例 3, 产率 54 %， 熔点 143-145。C; 1麵 R(500 MHz, CDC13) , δ (ppra) :9.24 (b, IH) , 8.24-8.26 (d, 1H)， 7.48 (s, IH), 7.21-7.23 (d, 1H)， 5.77 (b, IH)， 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(500 MHz, CDC13) , 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- MSm/z: 450.3 (M++l)； 元素分析: 计算值 C 69.46; H7.85; N 15.58; 测定值 C 69.24， H 7.58, N 15.37。 2-(1-(4-(1-pyrrolidinyl)piperidine))-4_(l-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole) The oxazole)) benzamide was synthesized in the same manner as in Example 3, yield 54%, melting point 143-145. C; 1 face R (500 MHz, CDC1 3 ), δ (ppra): 9.24 (b, IH), 8.24-8.26 (d, 1H), 7.48 (s, IH), 7.21-7.23 (d, 1H), 5.77 (b, IH), 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); 13 CNMR (500 MHz, CDC1 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- MSm/z: 450.3 (M + +l); Anal. Calcd. for C 69.46;
实施例 31  Example 31
2-(l-(4-(2- (4-吗啉）乙基）哌嗪)）-4- (1- (3, 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲 唑 ）） 苯 甲 酰 胺 （ 2- [4 -（2- morpholin- 4- yl- ethyl)- piperazin-卜 yl]-4 - (3, 6, 6-triraethy 1-4-0X0-4, 5, 6, 7-tetrahydro-indazol-l-yl) -benzamide ) 的合成。 (结构式 1-31)  2-(l-(4-(2-(4-morpholine)ethyl)piperazine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6 , 7-tetrahydrocarbazole)) Benzamide ( 2- [4 -(2- morpholin- 4- yl- ethyl)- piperazin- 卜 yl]-4 - (3, 6, 6-triraethy 1-4- Synthesis of 0X0-4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzamide). (Structure 1-31)
Figure imgf000039_0001
Figure imgf000039_0001
2 -（1- (4- (2—（4-吗啉）乙基）哌嗪)）-4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲 唑)）苯氰由 2-氯- 4-α-(3， 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑)）苯氰（实施例 1)和 4- (2- (4-吗啉） 乙基)哌嗪按实施例 2的合成方法合成得到， 产率 59.6%, 熔点 99一 101 °C; ¾NMR(500 MHZ)CDC13), δ (ppm) :7.66-7.68 (d, IH), 7.23 (s, IH), 7.05-7.07 (d, IH)， 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)。 2-(l-(4-(2- (4-吗啉）乙基)哌嗪)）-4- (1- (3, 6， 6-三甲基 -4-氧 -4， 5， 6， 7-四氢吲 唑））苯甲酰胺的合成方法同实施例 3, 产率 53.2 %， 熔点 128— 130 X； 'HNMR(500 MHz, CDCla)， 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, 311)， 2.44 (s, 2H) , 1.14 (s， 6H)； ,:iCNMR(500 MHz, CDC13) , 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); 元素分析： 计算值 C 65.56, H 7.74, N 16.99; 测定值 C 65.37, H 7.54, N 16.86。 2-(1-(4-(2-(4-morpholine)ethyl)piperazine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6 , 7-tetrahydrocarbazole)) phenyl cyanide from 2-chloro-4-α-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)benzene Cyanide (Example 1) and 4-(2-(4-morpholine)ethyl)piperazine were synthesized according to the synthesis method of Example 2, yield 59.6%, melting point 99-101 ° C; 3⁄4 NMR (500 MH Z ) CDC1 3), δ (ppm ): 7.66-7.68 (d, IH), 7.23 (s, IH), 7.05-7.07 (d, IH), 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). 2-(l-(4-(2-(4-morpholine)ethyl)piperazine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6 , 7-tetrahydrocarbazole)) benzamide was synthesized in the same manner as in Example 3, yield 53.2%, melting point 128-130 X; 'HNMR (500 MHz, CDCla), 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, 311), 2.44 (s, 2H), 1.14 (s, 6H); , :i CNMR(500 MHz, CDC1 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); elemental analysis: Calcd C 65.56, H 7.74, N 16.99 ; measured value C 65.37, H 7.54, N 16.86 .
实施例 32  Example 32
2- (1- (4 -羟基哌啶） ) -4- (1- (3, 6， 6-三甲基 -4-氧 _4, 5， 6， 7 -四氢吲唑））苯甲酰胺 (2- (4-hydroxy-piperidin-l-yl) -4- (3, 6， 6-trimethyl-4 0x0 - 4, 5, 6， 7-tetrahydro-i ndazol-l-yl) -benzaraide)的合成。 （结构式 1-32)  2-(1-(4-hydroxypiperidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide Amide (2-(4-hydroxy-piperidin-l-yl)-4-(3, 6, 6-trimethyl-4 0x0 - 4, 5, 6, 7-tetrahydro-i ndazol-l-yl) -benzaraide) Synthesis. (Structure 1-32)
Figure imgf000040_0001
Figure imgf000040_0001
4 -羟基哌啶乙酸酯（piperidi-4-yl acetate)是按照文献（J.Med. Chem.， 2005, 48, 2577-2583 ) 的方法合成所得， 产率 45.8% (三步）； 'HNMR OO MHZ, CDC13) , δ (ppm) :4.83-4.87(m, 1Η)， 3.07— 3.12(q， 2Η),2.72-2.77 (q, 2Η)， 2.11 (s, 1Η)， 2.07 (s, 3Η)， 1.92-1.94 (m, 2Η), 1.56-1.60 (m, 2H)。 4-piperidi-4-yl acetate was synthesized according to the method of the literature (J. Med. Chem., 2005, 48, 2577-2583), yield 45.8% (three steps); HNMR OO MHZ, CDC1 3 ) , δ (ppm): 4.83-4.87 (m, 1Η), 3.07— 3.12 (q, 2Η), 2.72-2.77 (q, 2Η), 2.11 (s, 1Η), 2.07 (s , 3Η), 1.92-1.94 (m, 2Η), 1.56-1.60 (m, 2H).
2 -（1- (4-乙酰氧基哌啶 )）- 4-(l- (3, 6， 6-三甲基 -4 -氧- 4, 5, 6, 7-四氢吲唑)）苯氰由 2 -氯 -4- (1_(3， 6, 6_三甲基 -4-氧- 4, 5， 6, 7-四氢吲唑)）苯氰 (实施例 1)和 4-乙酰氧基哌 啶按实施例 2的合成方法合成得到，产率 26.6%,熔点（油状物）； lHNMR(500 MHz, CDC13)， 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)。 2-(1-(4-acetoxypiperidine)) 4-(l-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) Benzene cyanide consists of 2-chloro-4-(1_(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 4- acetyloxy piperidine synthesized according to the method of Example 2 was synthesized, yield 26.6%, m.p. (oil); l HNMR (500 MHz, CDC1 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).
2-（1- (4-羟基哌啶)） - 4- (l-(3, 6， 6-三甲基 -4-氧- 4, 5, 6， 7-四氢吲唑)）苯甲酰胺的 合成方法同实施例 3, 产率 35.8%, 熔点 100 X (分解）； ¾NMR(500 MHz, CDC 1 ， 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 (ra, 2H)， 2.85 (s, 2H)， 2.57 (s, 311) , 2.43 (s, 2H) , 2.11 (m, 2H), 1.82(m, 211) , 1.14 (s, 6H)； FAB-MS m/z: 397.2(M++1); 元素分 析： 计算值 C 66.64, H 7.12， N 14.13; 测定值 C 66.42, H 6.89， N 14.06。 2-(1-(4-hydroxypiperidinyl)- 4-(l-(3, 6, 6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) The amide was synthesized in the same manner as in Example 3, yield 35.8%, melting point 100 X (decomposition); 3⁄4 NMR (500 MHz, CDC 1 , 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 (ra, 2H), 2.85 (s, 2H), 2.57 (s, 311), 2.43 (s, 2H), 2.11 (m, 2H) ), 1.82 (m, 211), 1.14 (s, 6H); FAB-MS m/z: 397.2 (M + +1) ; Elemental analysis: Calculated C 66.64, H 7.12, N 14.13; H 6.89, N 14.06.
实施例 33  Example 33
2-（1_(4-氨基乙酰氧基哌啶 )）- 4_(l-(3， 6， 6_三甲基 -4-氧- 4, 5， 6, 7-四氢吲唑)）苯 甲 酰 胺 2-(4-Aminoacetyloxy-piperidin-l-yl)-4-(3, 6, 6-trimethyl- 4-0X0-4, 5, 6， 7-tetrahydro-indazol-l-yl)-benzamide)的合成。 (结构式 1-33)  2-(1_(4-Aminoacetoxypiperidine))-4-(l-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzene 2-(4-Aminoacetyloxy-piperidin-l-yl)-4-(3, 6, 6-trimethyl- 4-0X0-4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzamide) Synthesis. (Structure 1-33)
Figure imgf000041_0001
Figure imgf000041_0001
在反应瓶中加入化合物 1-32 (实施例 32制备得到的） （120 mg， 0.3 mmol), 二氯 甲烷（10 mL)， N，N -二丙基乙胺（0.1 mL), B0C-甘氨酸 -酰氯 (60 mg， 0.3 mmol)。 反应 物在室温下搅拌过夜。产物用二氯甲烷萃取，饱和氯化钠水溶液洗涤，无水硫酸镁干燥。 过滤去除固体和溶剂， 残留物溶于二氯甲垸（20 mL), 加入三氟乙酸（4 mL), 室温搅 拌 2小时， 减压除去溶剂，用二氯甲垸萃取，饱和 NaHC03水溶液、饱和氯化钠水溶液洗 涤， 无水硫酸钠干燥， 产物经硅胶柱层析分离纯化后得到 2- (1-(4-氨基乙酰氧基哌 啶)） -4- (1- (3， 6， 6-三甲基 -4-氧- 4, 5， 6， 7-四氢吲唑)）苯甲酰胺 86 mg， 产率 63%，熔点 135-137 °C; ¾NMR(500 MHz, CDC13) , δ (ppm) :9.24 (b， 1Η) , 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(ra， 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); 元素分析： 计算值 C 63.56, H6.89, N15.44; 测定值 C 63.37, H 6.77， N 15.' 37。 Compound 1-32 (prepared in Example 32) (120 mg, 0.3 mmol), dichloromethane (10 mL), N,N-dipropylethylamine (0.1 mL), B0C-glycine - acid chloride (60 mg, 0.3 mmol). The reaction was stirred at room temperature overnight. The product was extracted with dichloromethane, washed with aq. The solid was removed by filtration and the solvent, the residue was dissolved in of dichloromethane (20 mL), trifluoroacetic acid (4 mL), stirred for 2 hours at room temperature, the solvent was removed under reduced pressure and extracted with of dichloromethane, saturated aqueous NaHC0 3, The mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide 86 mg, yield 63%, m.p. 135-137 °C; 3⁄4 NMR (500 MHz, CDC1 3 ) , δ (ppm): 9.24 (b, 1Η), 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(ra, 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) ; Elemental analysis: Calculated C 63.56, H6.89, N15.44; C 63.37, H 6.77, N 15.' 37.
实施例 34  Example 34
2- (4-羟基环己氨基） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑）） 苯甲酰胺 （ 2 -（4- hydroxy - cyclohexylamino) -4- (3， 6， 6- trimethyl-4- oxo- 4, 5， 6， 7- tetrahydro-indazol-l-yl) -benzamide ) 的合成。 (结构式 1—34)
Figure imgf000042_0001
2-(4-Hydroxycyclohexylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide (2 Synthesis of -(4-hydroxy-cyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-l-yl)-benzamide). (Structure 1 - 34)
Figure imgf000042_0001
2- (4 -羟基环己氨基) -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑）） 苯氰由 2-氯- 4- (1-(3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑)）苯氰 (实施例 1)和 4-氨基 环己醇按实施例 2 的合成方法合成得到， 产率 51.6%, 熔点 105-107。C; 1醒 R(500 MHz, CDC13) , 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),2-(4-hydroxycyclohexylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide consists of 2- Chloro-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 4-aminocyclohexanol It was synthesized according to the synthesis method of Example 2, and the yield was 51.6%, and the melting point was 105-107. C; 1 wake up R (500 MHz, CDC1 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)。 1.59 (b, 4H), 1.13 (s, 6H).
2- (4 -羟基环己氨基)—4- (1- (3, 6， 6 -三甲基- 4氧- 4， 5， 6， 7 -四氢吲唑）) 苯甲酰胺合成方法同实施例 3， 产率 63.8%， 熔点 118-120 X； ¾NMR(500 MHz, CDC13) , 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-(4-hydroxycyclohexylamino)-4-(1-(3,6-6-trimethyl-4-ethoxy-4,5,6-7-tetrahydrocarbazole)) benzamide Example 3, yield 63.8%, melting point 118-120 X; 3⁄4 NMR (500 MHz, CDC1 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); 元素分析: 计算值 C 67.29, H 7, 37, N 13.65; 测定值 C 66.94， H 7.13, N 13.75。 2.44 (s, 2H), 1.74 (b, 4H), 1.62 (b, 4H), 1.13(s, 6H); FAB-MS m/z: 411.2 (M + +1); Elemental analysis: Calculated C 67.29 , H 7, 37, N 13.65; found C 66.94, H 7.13, N 13.75.
实施例 35  Example 35
2- (4-氨基乙酰氧基环己氨基） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5, 6， 7-四氢 B引唑））苯甲酰胺（2- (4- aminoacetyloxy-cyclohexylamino)- 4- (3， 6， 6- triraethyl - 4 - 0X0-4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzamide) 的合成。 (结构式 1-35)  2-(4-Aminoacetoxycyclohexylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrob-butazole))benzene Synthesis of 2-(4-aminoacetyloxy-cyclohexylamino) 4- (3, 6, 6-triraethyl - 4 - 0X0-4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzamide). (Structure 1-35)
Figure imgf000042_0002
Figure imgf000042_0002
2- (4-氨基乙酰氧基环己氨基） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7 -四氢 吲唑））苯甲酰胺的合成由 2- (4-羟基环己氨基） -4- (1- (3, 6， 6-三甲基 -4-氧 -4， 5， 6， 7 -四氢吲唑））苯甲酰胺（实施例 34)和 B0C-甘氨酸-酰氯按实施例 33的方法合 成， 产率 75%, 熔点 173-175 °C; ¾NMR(500 MHz, CDC13) , S (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++l)； 元素分析： 计 算值 C 64.22, H 7.11, N 1498;测定值 C 63.93， H 6.97, N 15.07。 2-(4-Aminoacetoxycyclohexylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) Benzyl Synthesis of amide from 2-(4-hydroxycyclohexylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzene Formamide (Example 34) and BOC-Glycine-Acyl chloride were synthesized by the method of Example 33, yield 75%, melting point 173-175 °C; 3⁄4 NMR (500 MHz, CDC1 3 ), S (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 + +l); Elemental analysis: Calculated C 64.22, H 7.11, N 1498; measured value C 63.93, H 6.97, N 15.07.
实施例 36  Example 36
2- (2- (1 吡咯烷基)乙氨基） -4- (1- (3, 6， 6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲唑）） 苯 甲 酰 胺 （ 2- (2_pyrrolidin- 1- yl- ethylamino)- 4- (3,6，6- trimethyl-A- oxo- , 5, 6, 7-tetrahydro indazol-l - yl)-benzamide) 的合成。 (结构式 I - 36)  2-(2-(1pyrrolidinyl)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) benzene Synthesis of 2-(2_pyrrolidin- 1-yl-ethylamino) 4- (3,6,6-trimethyl-A- oxo- , 5, 6, 7-tetrahydro indazol-l - yl)-benzamide). (Structure I - 36)
Figure imgf000043_0001
Figure imgf000043_0001
2- (2- (1 -吡咯垸基）乙氨基） -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑）） 苯氰由 2-氯- 4- (1- (3, 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑)）苯氰（实施例 1)和 2- (1- 吡咯烷基）乙胺按实施例 2的合成方法合成得到，产率 53%，熔点 112— 113°C; ¾NMR(500 MHz, CDCl.,) , δ (ppm) :7.78-7.80 (d, 1Η)， 7.41 (s， 1Η)， 7.12-7.14 (d, 1Η)， 4.03 (b， 1H) , 3.47-3.49 (t， 2H) ， 2.84 (s, 2H), 2.68 (t, 2H)， 2.55(s, 311) , 2.42 (s, 2H)， 2.33-2.35 (t, 4H), 1.63-1.65 (m, 4H), 1.14(s, 6H)。  2-(2-(1-pyrrolidinyl)ethylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) Benzene cyanide consists of 2-chloro-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 2 -(1-Pyrrolidinyl)ethylamine was synthesized by the synthesis method of Example 2, yield 53%, melting point 112-113 ° C; 3⁄4 NMR (500 MHz, CDCl.,), δ (ppm): 7.78-7.80 (d, 1Η), 7.41 (s, 1Η), 7.12-7.14 (d, 1Η), 4.03 (b, 1H), 3.47-3.49 (t, 2H), 2.84 (s, 2H), 2.68 (t, 2H ), 2.55(s, 311), 2.42 (s, 2H), 2.33-2.35 (t, 4H), 1.63-1.65 (m, 4H), 1.14(s, 6H).
2 -（2- (1 -吡咯烷基)乙氨基） -4- (1- (3, 6, 6 -三甲基- 4-氧- 4， 5, 6， 7 -四氢吲唑）) 苯甲酰胺的合成方法同实施例 3， 产率 52%, 熔点 144—146 °C; ¾NMR(500顧 z, CDC13)， 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)； 元素分析： 计算值 C 67.46, H7.63, N 17.10； 测定值 C 67.29, H 7.48, N 16.98。 2-(2-(1-pyrrolidinyl)ethylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) The synthesis method of benzamide is the same as in Example 3, the yield is 52%, the melting point is 144-146 ° C; 3⁄4 NMR (500 Guz, CDC1 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 Elemental analysis: Calculated C 67.46, H7.63, N 17.10; found C 67.29, H 7.48, N 16.98.
实施例 37  Example 37
2 - (1 -哌嗪) -4- (1- ( 3， 6, 6^三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑）） 苯甲酰胺 ( 2-piperazin-l-yl-4- (3, 6， 6_trimethyl- 4- 0x0- 4, 5， 6， 7 tetrahydro- indazol-l- yl )- benzamide) 的合成。 （结构式 1-37)
Figure imgf000044_0001
2-(1-Piperazin)-4-(1-(3,6,6^trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide (2-piperazin) Synthesis of -l-yl-4-(3, 6, 6_trimethyl- 4- 0x0-4, 5, 6, 7 tetrahydro- indazol-l-yl )- benzamide). (Structures 1-37)
Figure imgf000044_0001
2- (1 -哌嗪) -4- (1- (3， 6， 6-三甲基 -4-氧- 4, 5， 6， 7-四氢吲唑）） 苯氰由 2 -氯 - 4_(1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑））苯氰（实施例 1)和 4-叔丁氧羰基 (t-BOC)哌嗪按实施例 2的合成方法合成、再用三氟乙酸除去 t- B0C后得到，产率 49%, 熔点 109-111 °C; 'HNMR(500 MHz, CDC13) , δ (ppm) :8· 04- 8.06 (d， 1H)， 7.43 (s, IH), 7.13-7.15 (d, IH) , 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)。 . 2-(1-Piperazin)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide from 2-chloro- 4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 4-tert-butoxycarbonyl (t- BOC) piperazine was synthesized according to the synthesis method of Example 2, and after removing t-B0C with trifluoroacetic acid, the yield was 49%, melting point 109-111 ° C; 'HNMR (500 MHz, CDC1 3 ) , δ (ppm) ) :8· 04- 8.06 (d, 1H), 7.43 (s, IH), 7.13-7.15 (d, IH), 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). .
2 -（1-哌嗪) - 4- (1_(3， 6， 6_三甲基 -4-氧 -4, 5， 6， 7-四氢吲唑)）苯甲酰胺的合成方法 同实施例 3， 产率 46%， 瑢点 144- 146 °C; 'HNMR(500 MHz, CDCl;i) , δ (ppm) :9.23 (b, IH), 8.23-8.25 (d, IH), 7.54(s, 1H)， 7.25-7.27 (d, IH), 6. ll(b， IH)， 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-MS m/z: 382.2(^+1)； 元素分析： 计算值 C 66.12， II 7.13, N 18.36； 测定值 C 65.93， H 6.86, N 18.25。 Synthesis of 2-(1-piperazine)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide Example 3, yield 46%, 瑢144-146 °C; 'HNMR (500 MHz, CDCl ; i ), δ (ppm): 9.23 (b, IH), 8.23-8.25 (d, IH), 7.54 ( s, 1H), 7.25-7.27 (d, IH), 6. ll(b, IH), 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-MS m/z: 382.2(^+1); Elemental analysis: Calculated C 66.12, II 7.13, N 18.36; 65.93, H 6.86, N 18.25.
实施例 38  Example 38
2- (1- (3 -羟基吡咯烷基）) -4 - (1- (3, 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑）) 苯甲酰胺 （ 2_(3- hydroxy- pyrrolidin-l-yl)- 4- (3， 6, 6 - trimethyl - 4 - oxo- 4, 5， 6， 7 -tetrahydro-indazol-l-yl) -bnzaraide ) 的合成。 （结构式 1-38)  2-(1-(3-hydroxypyrrolidinyl))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) benzene Formamide ( 2_(3- hydroxy- pyrrolidin-l-yl) 4- (3, 6, 6 - trimethyl - 4 - oxo- 4, 5, 6, 7 -tetrahydro-indazol-l-yl) -bnzaraide ) Synthesis. (Structure 1-38)
Figure imgf000044_0002
Figure imgf000044_0002
2 - (1- (3-羟基吡咯烷基） -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑）) 苯氰由 2-氯- 4- (1-(3， 6， 6-三甲基 -4-氧 -4， 5, 6, 7-四氢吲唑)）苯氰 (实施例 1)和 3-羟基 吡咯垸按实施例 2 的合成方法合成得到， 产率 78%， 熔点 137— 139 °C; ¾NMR(500 MHz, CDC13) , δ (ppm) :7.74-7.76 (d, IH), 7.38 (s, IH), 7.07-7.09 (d, IH)， 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)。 2-(1-(3-hydroxypyrrolidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide From 2-chloro-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 3-hydroxyl Pyrrole oxime was synthesized according to the synthesis method of Example 2, yield 78%, melting point 137-139 ° C; 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppm): 7.74-7.76 (d, IH), 7.38 (s , IH), 7.07-7.09 (d, IH), 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).
2- (1- (3 -羟基吡咯烷基）) -4- (1- (3, 6， 6-三甲基 _4-氧- 4， 5， 6， 7-四氢吲唑）) 苯甲酰胺的合成方法同实施例 3, 产率 57%, 熔点 169-171。C; 1顯 MR (500 MHz, CDCl^) , δ (ppm) :9.23 (b， IH)， 8.26-8.28 (d, IH), 7.52 (s， 1H)， 7.17-7.19 (d, IH), 6.20 (b, IH), 3.53 (m, IH)， 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 ra/z: 383.2 (M*+l)； 元 素分析: 计算值 C 65.95， H 6.85， N 14.65; 测定值 C 65.76, H 6.67， N 14.46。 2-(1-(3-hydroxypyrrolidinyl))-4-(1-(3,6,6-trimethyl_4-oxo-4,5,6,7-tetrahydrocarbazole)) benzene Formamide was synthesized in the same manner as in Example 3, yield 57%, melting point 169-171. C; 1 display MR (500 MHz, CDCl^), δ (ppm): 9.23 (b, IH), 8.26-8.28 (d, IH), 7.52 (s, 1H), 7.17-7.19 (d, IH), 6.20 (b, IH), 3.53 (m, IH), 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 ra/z: 383.2 (M*+l); Elemental analysis: Calculated C 65.95, H 6.85, N 14.65; C 65.76, H 6.67, N 14.46.
实施例 39  Example 39
2- (1- (4- (4 -吗啉)哌啶）） -4- (1- (3,6,6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑）） 苯 甲 醜 胺 (2- (4-raorpholin-4-yl-piperidin-l-yl) -4- (3, 6, 6-trimethyl-4-oxo- 4， 5， 6, 7 tetrahydro - indazol- l-yl)_benzainide) 的合成。 （结构式 1-39)  2-(1-(4-(4-morpholine)piperidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole) Azole)) 2-(4-raorpholin-4-yl-piperidin-l-yl)-4-(3, 6, 6-trimethyl-4-oxo- 4, 5, 6, 7 tetrahydro - Synthesis of indazol-l-yl)_benzainide). (Structure 1-39)
Figure imgf000045_0001
Figure imgf000045_0001
2 - (1- (4- (4 -吗啉)哌啶）） -4- (1- (3, 6， 6 -三甲基- 4 -氧- 4， 5, 6， 7 -四氢吲唑）) 苯氰由 2-氯- 4- (1- (3,6,6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑)）苯氰（实施例 1)和 4-(4- 吗啉)哌啶按实施例 2的合成方法合成得到， 产率 77%， 熔点 183— 184 °C; ¾NMR(500 MHz, CDC13) , δ (ppm)： 7.73-7.75 (d, IH) , 7.25(s, IH), 7.07-7.09 (d, IH)， 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)。 2-(1-(4-(4-morpholine)piperidinyl)-4-(1-(3, 6, 6-trimethyl- 4 -oxo-4, 5, 6, 7-tetrahydroindole) Oxazole)) Benzene cyanide from 2-chloro-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide (Example 1 And 4-(4-morpholine)piperidine were synthesized according to the synthesis method of Example 2, yield 77%, melting point 183-184 °C; 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppm): 7.73- 7.75 (d, IH), 7.25(s, IH), 7.07-7.09 (d, IH), 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).
2- (1- (4- (4-吗啉)哌啶）） -4- (1- (3,6,6-三甲基 -4-氧- 4,5， 6， 7_四氢吲唑）) 苯甲酰胺的合成方法同实施例 3， 产率 61%, 熔点 218—220°C; 'HNMR(500MHZ,CDC13)， δ (ppm) :9.22 (b， IH)， 8.24-8.26 (d, 1H)， 7.45 (s， 1H)， 7.25-7.27 (d, IH), 6.02(b, 1H),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, IH), 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); 元素分析： 计算值 C 67.07， H 7.58, N 15.04; 测定值 C 66.78， H 7.41, N 14.79。 2-(1-(4-(4-morpholine)piperidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7_tetrahydroindole) The synthesis of benzamide is the same as in Example 3, yield 61%, melting point 218-220 ° C; 'HNMR (500 MH Z , CDC1 3 ), δ (ppm): 9.22 (b, IH), 8.24- 8.26 (d, 1H), 7.45 (s, 1H), 7.25-7.27 (d, IH), 6.02(b, 1H), 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, IH), 2.57 (s, 3H), 2.43 (s, 2H), 1.73— 1.75 (m, 4H), 1.14 (s, 6H); </RTI><RTIID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;
实施例 40 2-（1 - (3 -轻基哌啶）) -4- (1- (3,6,6-三甲基 -4 -氧 -4， 5， 6， 7-四氢吲唑）） 苯甲 酰 胺 （ 2- (3- hydroxy- piperidin-1-yl) -4- (3， 6， 6- trimethyl- 4- oxo- 4, 5, 6， 7 - tetrahydro-indazol-l-yl) -benzamide ) 的合成。 (结构式 1-40) Example 40 2-(1-(3-light-piperidine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) benzene Formamide (2-(3- hydroxy-piperidin-1-yl) -4- (3, 6, 6- trimethyl- 4- oxo- 4, 5, 6, 7 - tetrahydro-indazol-l-yl) -benzamide ) Synthesis. (Structure 1-40)
Figure imgf000046_0001
Figure imgf000046_0001
2- (1- (3-羟基哌啶）) -4- (1- (3,6,6-三甲基 -4-氧 -4， 5, 6， 7-四氢吲唑））苯氰 由 2-氯- 4- (1-(3, 6, 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑)）苯氰 (实施例 1)和 3-羟基呃啶 按实施例 2的合成方法合成得到，产率 46.8%,熔点 142—144 °C; ¾NMR(500顧 z， CDCL)， 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(1, 2H)， 2.84 (s, 2H), 2.56 (s, 3H), 2.43 (s, 2H), 1.49-1.71 (m, 4H)， 1.14(s, 6H)。  2-(1-(3-Hydroxypiperidine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide From 2-chloro-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 3-hydroxyl Acridine was synthesized according to the synthesis method of Example 2, yield 46.8%, melting point 142-144 ° C; 3⁄4 NMR (500 g, CDCL), 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(1, 2H), 2.84 (s, 2H), 2.56 (s, 3H ), 2.43 (s, 2H), 1.49-1.71 (m, 4H), 1.14 (s, 6H).
2- (1- (3-羟基哌啶）) -4- (1- (3, 6， 6 -三甲基- 4-氧- 4， 5, 6, 7-四氢吲唑）) 苯甲 酰胺的合成方法同实施例 3, 产率 68%， 熔点 162— 164 °C; 'HNMR(500 MHz, CDC13) , δ (ppm) :9.21 (b, 1H) 5 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); 元素分析: 计算值 C 66.64, H 7.12， N 14.13; 测定值 C 66.57, H 6.87, N 13.93。 2-(1-(3-hydroxypiperidinyl)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) Benzyl The amide was synthesized in the same manner as in Example 3, yield 68%, melting point 162-164 ° C; 'HNMR (500 MHz, CDC1 3 ), δ (ppm): 9.21 (b, 1H) 5 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); Elemental analysis: Calculated C 66.64, H 7.12, N 14.13; found C 66.57, H 6.87, N 13.93.
实施例 41  Example 41
2- (2- (6， 7-二甲氧基 1， 2， 3， 4-四氢异喹啉）) -4- (1- (3, 6, 6-三甲基 -4-氧 - 4， 5, 6， 7- 四 氢 吲 唑 ） ） 苯 甲 酰 胺 （ 2- (6，7- dimethoxy- 1,2, S - tetrahydroisoquinolin-^-yl)- 4-(3, 6, 6- trimethyl- 4-0X0 - 4, 5， 6, 7-tetrahydro-ind azol-l-yl) -benzamide) 的合成。 （结构式 1-41)  2-(2-(6, 7-Dimethoxy 1,2,3,4-tetrahydroisoquinoline))-4-(1-(3, 6, 6-trimethyl-4-oxo- 4, 5, 6, 7-tetrahydrocarbazole)) Benzamide (2-(6,7- dimethoxy- 1,2, S - tetrahydroisoquinolin-^-yl)- 4-(3, 6, 6- trimethyl - Synthesis of 4-0X0 - 4, 5, 6, 7-tetrahydro-ind azol-l-yl) -benzamide). (Structure 1-41)
Figure imgf000046_0002
Figure imgf000046_0002
2 - （2- (6, 7-二甲氧基- 1,2， 3,4-四氢异喹啉）） —4— (1— (3, 6， 6-三甲基 -4-氧 - 4， 5， 6, 7-四氢吲唑））苯氰由 2 -氯 -4-(1-（3， 6， 6-三甲基 -4-氧 -4, 5， 6, 7-四氢吲睡)）苯 氰 (实施例 1)和 6， 7-二甲氧基- 1， 2, 3， 4-四氢异喹啉按实施例 2的合成方法合成得到， 产率 75%, 熔点 179—181 "C; NMR(500 MHz, CDCl:i), δ (ppm)： 7.87-7.89 (d, IH), 7.47 (s, 1H)， 7.11-7.13 (d, IH)， 6.58 (s, IH), 6.65 (s, IH), 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, 311) , 2.43 (s, 2H) , 1.14 (s, 6H)。 2-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline))-4-(1-(3,6,6-trimethyl-4-oxo) - 4, 5, 6, 7-tetrahydrocarbazole)) phenyl cyanide consists of 2-chloro-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7- Tetrahydroguanidine)) phenyl cyanide (Example 1) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline were synthesized according to the synthesis method of Example 2, yield 75% , melting point 179-181 "C; NMR (500 MHz, CDCl :i ), δ (ppm): 7.87-7.89 (d, IH), 7.47 (s, 1H), 7.11-7.13 (d, IH), 6.58 ( s, IH), 6.65 (s, IH), 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, 311), 2.43 (s, 2H), 1.14 (s, 6H).
2- (2- (6,7-二甲氧基 1,2, 3, 4 -四氢异喹啉）） -4- (1- ( 3, 6, 6-三甲基 -4 -氧 - 4， 5， 6， 7-四氢吲唑））苯甲酰胺的合成方法同实施例 3， 产率 84%， 熔点 222— 224 °C; 1画 R(500 MHz，CDCl3)， δ (ppm) :9.26 (b, IH)， 8.27- 8.29(d， IH), 7.53 (s, IH), 7.24-7.26 (d, IH), 6.67 (s, IH), 6.62 (s, IH), 6.21(b， IH)， 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)； 元素分析： 计算值 C 68.83， H 6.60， N 11.47； 测定值 C 68.75， H 6.46, N 11.35。 2-(2-(6,7-Dimethoxy 1,2,3,4-tetrahydroisoquinoline))-4-(1-( 3, 6, 6-trimethyl-4-oxo- 4, 5, 6, 7-tetrahydrocarbazole)) benzamide was synthesized in the same manner as in Example 3, yield 84%, melting point 222-224 ° C; 1 draw R (500 MHz, CDCl 3 ), δ ( Ppm): 9.26 (b, IH), 8.27- 8.29 (d, IH), 7.53 (s, IH), 7.24-7.26 (d, IH), 6.67 (s, IH), 6.62 (s, IH), 6.21 (b, IH), 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); Elemental analysis: Calculated C 68.83, H 6.60, N 11.47; Measured value C 68.75, H 6.46, N 11.35.
实施例 42  Example 42
2 - (1- (4- (2 -吡啶)哌嗪）） -4- (1- (3,6,6-三甲基 -4-氧- 4, 5， 6， 7-四氢吲唑）） 苯 甲 酰 胺 ( 2- (4-pyridin-2-yl-piperazin-l-yl)-4-(3, 6, 6-trimethyl~4- oxo-4, 5, 6， 7-tetrahydro-indazol-l-yl)-benzamide) 的合成 <> (结构式 1-42)  2-(1-(4-(2-pyridine)piperazine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole) )) Benzamide (2-(4-pyridin-2-yl-piperazin-l-yl)-4-(3, 6, 6-trimethyl~4-oxo-4, 5, 6, 7-tetrahydro-indazol -l-yl)-benzamide) Synthesis <> (Structures 1-42)
Figure imgf000047_0001
Figure imgf000047_0001
2 - (1- (4- (2 -吡啶)哌嗪）） -4- (1- (3,6,6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑）） 苯氰由 2 -氯- 4_(1 - (3， 6, 6_三甲基 -4 -氧- 4, 5， 6， 7-四氢吲唑)）苯氰 (实施例 1)和 4 -（2- 吡啶）哌嗪按实施例 2的合成方法合成得到，产率 69.4%，熔点 147— 149 °C; 'HNMR(500 MHz,CDCl3), δ (ppm) :8.25(d, IH), 7.84 (d, IH), 7.76— 7.78(d， IH), 7.41 (s, IH), 7.07-7.09 (d, IH) , 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)。 2-(1-(4-(2-pyridine)piperazine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole) )) phenyl cyanide consists of 2-chloro-4_(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and 4-(2-Pyridinyl)piperazine was synthesized according to the synthesis method of Example 2, yield: 69.4%, m.p. 147-149 ° C; 'HNMR (500 MHz, CDCl 3 ), δ (ppm): 8.25 (d, IH), 7.84 (d, IH), 7.76— 7.78(d, IH), 7.41 (s, IH), 7.07-7.09 (d, IH), 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).
2 (1- (4- (2 -吡啶)哌嗪）） -4- (1- (3,6,6-三甲基 -4 -氧- 4， 5， 6， 7 四氢吲唑）） 苯甲酰胺的合成方法同实施例 3， 产率 63%, 熔点 174—176 C; ¾匪 R(500顧 z，CDCl3)， 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，lH)， 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-MS m/z: 459.2 (M++l)； 元素分析： 计算值 C 68.10, H 6.59， N 18.33; 测定值 C 67.88， H 6.45, N 18.27。 2 (1-(4-(2-pyridine)piperazine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7 tetrahydrocarbazole)) The synthesis method of benzamide is the same as that of Example 3, the yield is 63%, the melting point is 174-176 C; 3⁄4匪R (500 Guz, 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, lH), 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-MS m/z: 459.2 (M + +l); Elemental analysis: Calculated C 68.10, H 6.59, N 18.33; measured value C 67.88, H 6.45, N 18.27.
实施例 43  Example 43
2-(l-哌啶）-4- (1-(3， 6, 6-三甲基 -4-氧 -4， 5， 6， 7-四氢吲唑））苯甲酰胺 (2-piperidin-l-yl-4~ (3, 6， 6-trimethyl-4-oxo-4, 5, 6， 7-tetrahydro-indazol-l-yl) -benzamide)的合成。 （结构式 I- 43) 2-(l-piperidine)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide (2-piperidin) -l-yl-4~ Synthesis of (3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzamide). (Structure I- 4 4 )
Figure imgf000048_0001
Figure imgf000048_0001
2- -哌啶) - 4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲唑)）苯氰的合成由 2-氯 - 4 - (1- (3,6， 6_三甲基 _4-氧- 4, 5， 6， 7-四氢吲唑)）苯氰 (实施例 1)和哌啶按实施例 2的 合成方法合成得到， 产率 63.9% , 熔点 76 -77 。C； 'HNMR (500 MHz, CDC13)， 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. 4 (s, 2H), 1.89(b, 4H), 1.69 (b, 2H), 1.15(s， 6H)。 2-Piperidine) - 4-(1-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) Benzene cyanide synthesis from 2-chloro- Synthesis of 4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide (Example 1) and piperidine as in Example 2 The method was synthesized and the yield was 63.9%, and the melting point was 76-77. C; 'HNMR (500 MHz, CDC1 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. 4 (s, 2H), 1.89 (b, 4H), 1.69 (b, 2H), 1.15 (s, 6H).
2 -（1-哌啶) - 4_(1- (3， 6， 6-三甲基 -4-氧- 4， 5, 6, 7-四氢吲唑)）苯甲酰胺合成方法同 实施例 3, 产率 49.4%, 熔点 122-124。C; 1醒 R(500 MHz, CDC13)， 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(500 MHz,CDCl3)， δ (卯 m):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)； 元素分析： 计算值 C 69.45， H 7.42, N 14.73； 测定值 C 69.40, H 7.26， N 14.61。 Synthetic method of 2-(1-piperidine)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide 3, yield 49.4%, melting point 122-124. C; 1 wake up R (500 MHz, CDC1 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); 13 CNMR (500 MHz, CDCl 3 ), δ (卯m ): 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); Elemental analysis: Calculated C 69.45, H 7.42, N 14.73; C 69.40, H 7.26, N 14.61 .
实施例 44  Example 44
1- ( 6- ( 3-氨基 - 1H-吲唑）） -3, 6， 6-三甲基 -1， 5, 6， 7-四氢吲哚 -4 -酮 1-( 6-( 3-amino - 1H-carbazole) -3, 6, 6-trimethyl -1, 5, 6, 7-tetrahydroindole -4 -one
(1- (3-amino-lH-indazol-6-yl) -3, 6, 6-trimethyl-l, 5， 6, 7 - tetrahydro— indol - 4—one) 的合成。 （结构式 1-44)
Figure imgf000049_0001
Synthesis of (1-(3-amino-lH-indazol-6-yl)-3,6,6-trimethyl-l, 5, 6, 7-tetrahydro- indol - 4-one). (Structures 1-44)
Figure imgf000049_0001
在反应瓶中加入 2—氯一 4一硝基苯氰 （1.0 g, 5.5 mraol), 甲苯 （40 mL) 和 BOC-NHNH2(0.92 g, 7 mmol)。 反应物搅拌加热至 100"C反应 2小时后， 冷却， 去除溶剂， 残留物溶于 4N HC1的二氧六环溶液中 （40 mL)并加热回流 1小时。 反应液在冰浴冷却 下滴加 20%NaOH溶液调节 pH=14,用氯仿萃取， 饱和氯化钠水溶液洗漆， 无水硫酸钠干 燥。 除去干燥剂和溶剂后， 残留物溶于 THF (40 mL)并加入三乙胺（0.6mL)和 （B0C) 20(1.2g, 5.5 mmol)在 0°C至室温下搅拌反应 2小时。减压除去溶剂， 用二氯甲垸萃取， INNaOH水溶液洗涤， 饱和氯化钠水溶液洗涤， 无水硫酸镁干燥。 除去干燥剂和溶剂后 得到相应的硝基吲唑衍生物为黄颜色固体 (TLC显示〉 85%纯度），将固体溶于甲醇 (40 mL) 并加入铁粉（0.92 g, 17 mmol)和冰乙酸（0.8 mL)。 反应物搅拌回流 2小时， 冷却后 倒入水中， 用乙酸乙酯萃取， 饱和氯化钠水溶液洗涤， 无水硫酸钠干燥， 经过重结晶纯 化后得 0.18 g, 产率 13% (四步）。 1顧 R(500 MHz, CDC13) , δ (ppm)： 12.15 (b, IH), 8.30 (b, IH), 6.95-7.50 (ra, 3H), 3.85(b, 2H) , 1.30(s, 9H)。 To the reaction flask was added 2-chloro-4-nitrophenyl cyanide (1.0 g, 5.5 mraol), toluene (40 mL) and BOC-NHNH 2 (0.92 g, 7 mmol). The reaction was stirred and heated to 100 ° C for 2 hours. After cooling, the solvent was removed, and the residue was dissolved in 4N EtOAc (40 mL) and heated to reflux for 1 hr. 20% NaOH solution was adjusted to pH=14, extracted with chloroform, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After removing the desiccant and solvent, the residue was dissolved in THF (40 mL) and triethylamine (0.6) mL) and (B0C) 2 0 (1.2g, 5.5 mmol) the reaction was stirred at 0 ° C to room temperature for 2 hours. the solvent was removed under reduced pressure and extracted with of dichloromethane, washed with aqueous INNaOH, a saturated aqueous sodium chloride solution, Drying over anhydrous magnesium sulfate. After removing the desiccant and solvent, the corresponding nitrocarbazole derivative was obtained as a yellow solid (TLC showed > 85% purity), solid was dissolved in methanol (40 mL) and iron powder (0.92 g) was added. The reaction mixture was stirred and refluxed for 2 hrs. 0.18 g, yield 13% (four steps). 1 Gu R (500 MHz, CDC1 3 ) , δ (ppm): 12.15 (b, IH), 8.30 (b, IH), 6.95-7.50 (ra, 3H), 3.85(b, 2H), 1.30(s, 9H).
将上述所得产物 (50 mg, 0.2 mmol)在 85 °C下加入到 5, 5-二甲基一 2- (2—丙醛 基） 一 1， 3—环己二酮 （40 mg, .0.2 mmol) 的甲苯（20 mL)溶液中。 反应物在搅拌下 加热到 110 X反应 1小时， 冷却， 将溶剂减压去除， 残留物溶于乙酸乙酯 （20 mL) 并加入三氟乙酸（2mL)在常温下搅拌反应 2小时。 减压去除溶剂， 产物用二氯甲烷萃 取， INNaOH水溶液， 饱和氯化钠水溶液洗涤， 无水硫酸续干燥。 产品用硅胶柱层析纯 化后得 18mg， 产率 29%，熔点 153— 155 "C; 'Η應 R(500 MHz, CDC13)， δ (ppm): 12.35 (b, IH), 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); 元素分析： 计算值 C 70.11， H 6.54， N 18.17； 测定值 C 69.88， H 6.47， N 18.21。 The product obtained above (50 mg, 0.2 mmol) was added to 5,5-dimethyl- 2-(2-propanal)-1,3-cyclohexanedione (40 mg, .0.2) at 85 °C. Methyl) in toluene (20 mL). The reaction mixture was heated to 110 X for 1 hour under stirring, and the mixture was evaporated. The solvent was evaporated, evaporated, evaporated, evaporated. The solvent was removed under reduced pressure and the product was extracted with methylene chloride. The product was purified by silica gel column chromatography to give 18 mg, yield 29%, melting point 153 - 155 "C;' Η R R (500 MHz, CDC1 3 ), δ (ppm): 12.35 (b, IH), 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: </RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt;
实施例 45  Example 45
1- ( 6- ( 3-氨基 - IH-吲唑）） -3， 6， 6-三甲基 -1, 5， 6， 7-四氢吲唑 -4-酮 ( 1-(3 - amino-lH - indazol-6-yl)-3， 6， 6-trimethyl-l, 5， 6， 7-tetrahydro-indazolyl- 4-one) 的合成。 (结构式 1-45)
Figure imgf000050_0001
1-(6-(3-Amino-IH-carbazole))-3,6,6-trimethyl-1,5,6,7-tetrahydrocarbazol-4-one (1-(3-amino) -lH - indazol-6-yl)-3, 6, 6-trimethyl-l, 5, 6, 7-tetrahydro-indazolyl- 4-one). (Structures 1-45)
Figure imgf000050_0001
在反应瓶中加入 2, 4—二氟苯氰（0.14 g, 1.0 mmol), DMFC40 mL)和 B0C-NHNH2(0.16 g, 1.2 mmol), 反应物搅拌加热至 150°C反应 12小时， 冷却后， 用二氯甲烷萃取， 水 洗涤，无水硫酸镁干燥，产物用硅胶柱层析纯化得到 N- B0C-5-氟 -2-氰基-苯肼， 0.20 g， 产率 80%， 熔点 79—81。C; ¾NMR (500 MHz，CDCl ， 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)。 2,4-difluorophenyl cyanide (0.14 g, 1.0 mmol), DMFC 40 mL) and B0C-NHNH 2 (0.16 g, 1.2 mmol) were added to the reaction flask, and the reaction was stirred and heated to 150 ° C for 12 hours, and cooled. After that, it was extracted with methylene chloride, washed with water and dried over anhydrous magnesium sulfate, and the product was purified by silica gel column chromatography to give N-B0C-5-fluoro-2-cyano-benzoquinone, 0.20 g, yield 80%, melting point 79-81. C; 3⁄4 NMR (500 MHz, CDCl, 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).
在反应瓶中加入 3， 6， 6-三甲基一1, 5, 6， 7—四氢吲唑一 4一酮（95 mg, 0.5 mmol), DMF(15mL), NaH(24mg, 1議 ol)， 反应在室温下搅拌 10分钟，加入上述制备的 N-BOC- 5- 氟- 2-氰基-苯肼（0.13 mg, 0.5 mmol),反应物加热回流 4小时，冷却后倒入到冰水（50 mL)并用二氯甲烷萃取，水洗涤，无水硫酸镁干燥，产物用硅胶柱层析纯化得到 N-B0C - 2 - 氰基- 5- (1-3, 6, 6-三甲基 -4-氧- 4, 5， 6， 7-四氢吲唑）苯肼, 0.125 g， 产率 61%, 熔点 136-138 °C; 1顯 MR(500 MHz，CDCl3)， 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, 210,2.55 (s, 311) , 2.42(s, 2H), 1.39(s, 9H)， 1.14(s, 6H)。 Add 3,6,6-trimethyl-1,5,6-tetrahydrocarbazole-4-one (95 mg, 0.5 mmol), DMF (15 mL), NaH (24 mg, 1 Ol), the reaction was stirred at room temperature for 10 minutes, and N-BOC-5-fluoro-2-cyano-benzoquinone (0.13 mg, 0.5 mmol) prepared above was added, and the reaction was heated to reflux for 4 hr. Ice water (50 mL) was extracted with methylene chloride, washed with water, dried over anhydrous magnesium sulfate, and the product was purified by silica gel column chromatography to obtain N-B0C - 2 - cyano - 5- (1-3, 6, 6- Methyl-4-oxo-4,5,6,7-tetrahydrocarbazole)phenylhydrazine, 0.125 g, yield 61%, melting point 136-138 °C; 1 MR (500 MHz, 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, 210,2.55 (s, 311), 2.42(s, 2H), 1.39(s, 9H), 1.14(s, 6H).
将 N-B0C - 2-氰基 - 5-（1- 3， 6， 6-三甲基 -4-氧- 4, 5, 6, 7-四氢吲唑)苯肼（0.125 g, 0.3 mmol)溶于 4N HC1的二氧六环溶液中 （20 mL)并加热回流 1小时。 反应液在冰浴冷 却下滴加 20%NaOH溶液调节 pH=14,用氯仿萃取， 饱和氯化钠水溶液洗涤， 无水硫酸钠 干燥。 去除溶剂， 产物用硅胶柱层析纯化后得到 1- (6- (3-氨基 -1H-吲唑） -3， 6， 6 -三 甲基- 1, 5， 6， 7-四氢吲唑- 4-酮， 36 mg, 产率 38.7%, 熔点 184-186 V； 1醒 R(500 顧 z CDCl3), 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); 元素分析： 计算值 C 66.00, H 6.19, N 22.64； 测定 值 C 65.76, H 5.83， N 22.43。— N-B0C-2-cyano-5-(1- 3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)phenylhydrazine (0.125 g, 0.3 mmol) Dissolved in 4N HCl in dioxane (20 mL) and heated to reflux for 1 hour. The reaction solution was added dropwise with a 20% NaOH solution under ice-cooling to adjust pH=14, extracted with chloroform, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is removed and the product is purified by silica gel column chromatography to give 1-(6-(3-amino-1H-carbazole)-3,6,6-trimethyl-1,5,6,7-tetrahydrocarbazole - 4-ketone, 36 mg, yield 38.7%, melting point 184-186 V; 1 awake R (500 Gu z 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) ; Elemental analysis: Calculated C 66.00, H 6.19, N 22.64; calc. C 65.76, H 5.83, N 22.43.
实施例 46  Example 46
2- (1- (4-羟基哌啶）） -4- (9 - (2，2-二甲基 - 4-氧- 1，2, 3，4-四氢咔唑）)苯甲酰 胺 (4- (2， 2-diraethyl-4-oxo-l, 2, 3, 4-tetrahydro-carbazol-9-yl) - 2- (4-hydroxy- piperidin-l-yl) -benzamide) 的合成。 （结构式 1-46)
Figure imgf000051_0001
2-(1-(4-Hydroxypiperidinyl)-4-(9-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole))benzamide ( Synthesis of 4-(2,2-diraethyl-4-oxo-l, 2, 3, 4-tetrahydro-carbazol-9-yl)-2-(4-hydroxy-piperidin-l-yl)-benzamide). (Structures 1-46)
Figure imgf000051_0001
照实施例 6的合成方法，向反应瓶中加入 4-轻基哌啶（1.01 g， 0.01 mol), DMF(100 mL), 和 2， 4-二氟苯氰 （1.39 g， 0.01 mol)。 反应物搅拌加热回流 12 小时， 冷却后 减压除去溶剂， 乙酸乙酯萃取， 水洗， 无水硫酸钠干燥， 产物经乙酸乙酯 /己垸重结晶 得 4-氟- 2- (1- (4-羟基哌啶））苯氰 1.25 g, 产率 56.8%， 'HNMR(500 MHz, CDC13) , δ (ppm): 7.62-7.64 (d, 1H)， 7.27 (b, IH), 7.09 (d， IH), 3.88 (ra, 1H)， 3.45-3.47 (b, 4H), 1.76(m, 4H)。 According to the synthesis method of Example 6, 4-light piperidine (1.01 g, 0.01 mol), DMF (100 mL), and 2, 4-difluorophenyl cyanide (1.39 g, 0.01 mol) were added to the reaction flask. The reaction mixture was stirred and heated to reflux for 12 hr, then evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. -hydroxypiperidine)) phenyl cyanide 1.25 g, yield 56.8%, 'HNMR (500 MHz, CDC1 3 ), δ (ppm): 7.62-7.64 (d, 1H), 7.27 (b, IH), 7.09 (d , IH), 3.88 (ra, 1H), 3.45-3.47 (b, 4H), 1.76 (m, 4H).
在反应瓶中加入 2， 2-二甲基一 1,2， 3， 9一四氢咔唑一 4一酮 （0.21 g, 1 mmol) ， DMF (25 mL), NaH (0.036 g, 1.5腿 ol)。 剧烈反应后， 向反应瓶中加入 4 -氟- 2- (1- (4- 羟基哌啶））苯氰 （0.22 g, 1 mmol)并加热回流 12小时。 冷却后， 减压除去溶剂， 产物用二氯甲垸萃取， 饱和氯化钠水溶液洗涤， 无水硫酸镁干燥。产物用硅胶柱层析纯 化后得到 2- (1- (4 -羟基哌啶）) -4 (9- (2，2-二甲基 - 4 -氧- 1，2，3，4-四氢咔唑）)苯 氰 0.31 g， 产率 75.6%,熔点 154-156 °C; 'HN R(500 MHz, CDCl;i)， δ (ppm) :7.67-7.68 (d, IH), 7.24 (s, IH), 7.12-7.20 (ra, 4H), 6.89-6.91 (d， IH)， 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)。 Add 2,2-dimethyl-1,2,3,9-tetrahydrocarbazole-4-one (0.21 g, 1 mmol), DMF (25 mL), NaH (0.036 g, 1.5 leg) to the reaction flask. Ol). After vigorous reaction, 4-fluoro-2-(1-(4-hydroxypiperidine))benzonitrile (0.22 g, 1 mmol) was added to the reaction mixture and heated to reflux for 12 hr. After cooling, the solvent was evaporated under reduced pressure. The product was purified by silica gel column chromatography to give 2-(1-(4-hydroxypiperidine)) -4 (9-(2,2-dimethyl-4-ethoxy- 1,2,3,4-tetrahydro) Carbazole)) phenyl cyanide 0.31 g, yield 75.6%, melting point 154-156 °C; 'HN R (500 MHz, CDCl ; i ), δ (ppm): 7.67-7.68 (d, IH), 7.24 (s , IH), 7.12-7.20 (ra, 4H), 6.89-6.91 (d, IH), 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).
2 - （1- (4 -羟基哌啶）) -4- (9- (2,2-二甲基 -4-氧 -1， 2， 3， 4-四氢咔唑）)苯甲酰 胺的合成方法同实施例 3， 产率 75%, 熔点 187-189。C; 1薩 R(500 MHz, CDC13) , δ (ppm) :9.28 (b, IH)， 8.25-8.27 (d, IH), 7.45 (s, 1H)， 7.31(d， IH), 7.21-7.25 (m, 4H), 6.27 (b, 1H)， 3.82(m, IH), 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); 元素分析： 计算值 C 69.31， H 6.49， N 9.33； 测定值 C 69.16， H 6.28， N 9.16。 2-(1-(4-hydroxypiperidinyl)-4-(9-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole))benzamide The synthesis was carried out in the same manner as in Example 3, yield 75%, melting point 187-189. C; 1 Sa R (500 MHz, CDC1 3 ), δ (ppm): 9.28 (b, IH), 8.25-8.27 (d, IH), 7.45 (s, 1H), 7.31 (d, IH), 7.21- 7.25 (m, 4H), 6.27 (b, 1H), 3.82(m, IH), 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); elemental analysis: Calcd C 69.31, H 6.49, N 9.33 ; measured value C 69.16, H 6.28, N 9.16 .
实施例 47  Example 47
2- (4 -羟基环己氨基） -4- (9- (2，2-二甲基 - 4-氧- 1，2，3，4-四氢咔唑））苯甲酰胺 ( 4- (2, 2-dimethyl-4-oxo-l, 2, 3, 4-tetrahydro- carbazol - 9-yl) - 2 - (4 hydroxy- cyclohexylamino) -benzamide) 的合成。 （结构式 1-47)
Figure imgf000052_0001
2-(4-hydroxycyclohexylamino)-4-(9-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole))benzamide (4- Synthesis of 2,2-dimethyl-4-oxo-l, 2, 3, 4-tetrahydro-carbazol - 9-yl) - 2 - (4 hydroxy- cyclohexylamino) -benzamide). (Structures 1-47)
Figure imgf000052_0001
2- (4 -羟基环己氨基） -4- (9- (2，2-二甲基 - 4-氧- 1，2，3，4-四氢咔唑））苯甲酰胺 的合成方法同实施例 46。 第一步由 4-氨基环己醇和 2, 4-二氟苯氰反应得到 4-氟 -2- The synthesis method of 2-(4-hydroxycyclohexylamino)-4-(9-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole))benzamide is the same Example 46. The first step is the reaction of 4-aminocyclohexanol with 2,4-difluorobenzene cyanide to give 4-fluoro-2-
(4 -羟基环己烧氨基）苯氰（产率 63%),第二步由 2, 2-二甲基一 1, 2， 3， 9一四氢咔唑一 4一酮和 4-氟- 2- (4-羟基环己垸氨基）苯氰反应得到 2- (4-羟基环己氨基） -4- (9 -(4-hydroxycyclohexane amino) benzonitrile (yield 63%), the second step consists of 2,2-dimethyl-1,2,3,9-tetrahydrocarbazole-4-one and 4-fluoro - 2-(4-Hydroxycyclohexylamino)benzene cyanide gives 2-(4-hydroxycyclohexylamino)-4-(9-
(2, 2 -二甲基- 4-氧- 1, 2, 3， 4 -四氢咔唑）)苯氰（产率 47.5%), 最后一步将 2- (4 -羟基 环己氨基） -4- (9- (2，2-二甲基 - 4氧- 1，2,3，4-四氢咔唑））苯氰与过氧化氢反应， 经 硅胶柱层析纯化后得到 2- (4-羟基环己氨基） -4- (9- (2,2-二甲基 -4-氧- i， 2， 3， 4 -四 氢咔唑））苯甲酰胺，产率 86%，熔点 202—204 °C; 'HNMR(500 MHz, CDC13)， δ (ppm) :9.26(2,2-dimethyl-4-oxo-1, 2,3,4-tetrahydrocarbazole)) phenyl cyanide (yield 47.5%), the last step is 2-(4-hydroxycyclohexylamino)- 4-(9-(2,2-Dimethyl-4-ethoxy-1,2,3,4-tetrahydrocarbazole))benzonitrile is reacted with hydrogen peroxide and purified by silica gel column chromatography to give 2-( 4-hydroxycyclohexylamino)-4-(9-(2,2-dimethyl-4-oxo-i, 2,3,4-tetrahydrocarbazole))benzamide, yield 86%, m.p. 202-204 °C; 'HNMR (500 MHz, CDC1 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++l)； 元素分析： 计 算值 C 72.78； H 7.01; N 9,43; 测定值 C 72.65, H 6.87， 9.22。 (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 + +l); Elemental analysis: Calculated C. 72.78; H 7.01; N 9,43; calc. C 72.65, H 6.87, 9.22.
实施例 48  Example 48
2- (1- (4- (2 -羟乙基)哌嗪）） -4- (9- (2,2-二甲基 -4-氧- 1,2， 3， 4-四氢咔唑）） 苯 甲 酰 胺 （4-(2, 2_Dimethyl_4- oxo_l，2, 3，4-tetrahydro - carbazol - 9- yl)- 2 - [4- (2-hydroxy-ethyl)-pi erazin-l-yl]-benzamide) 的合成。 （结构式 I - 48)  2-(1-(4-(2-hydroxyethyl)piperazine))-4-(9-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole )) Benzamide (4-(2, 2_Dimethyl_4-oxo_l,2,3,4-tetrahydro-carbazol-9-yl)-2 - [4- (2-hydroxy-ethyl)-pi erazin-l-yl] Synthesis of -benzamide). (Structure I - 48)
Figure imgf000052_0002
Figure imgf000052_0002
2- (1- (4- (2 -羟乙基)哌嗪）） -4 (9- (2,2-二甲基 -4-氧- 1,2， 3, 4-四氢咔唑）） 苯甲酰胺的合成方法同实施例 46。 第一步由 4- (2-羟乙基）哌嗪和 2， 4 -二氟苯氰反 应得到 4-氟- 2- (1- (4- (2-羟基乙'烷基)哌嗪））苯氰（产率 58%), 第二步由 2, 2-二甲 基一 1,2， 3, 9—四氢咔唑一 4一酮和 4氟- 2- (1- (4- (2-羟基乙垸基）哌嗪）） 苯氰反应 得到 2- (1— (4- (2 -羟乙基)哌嗪）） -4- (9- (2，2-二甲基 - 4-氧- 1，2,3，4-四氢咔唑）) 苯氰 (产率 65.5%), 最后一步将 2- (1- (4- (2 -羟乙基) 哌嗪）） -4- (9- (2,2-二甲 基- 4-氧- 1， 2， 3， 4-四氢咔唑））苯氰与过氧化氢反应， 经硅胶柱层析纯化后得到 2- (1- (4 - (2-羟乙基)哌嗪）） -4- (9- (2,2-二甲基 -4-氧- 1,2, 3， 4-四氢咔唑））苯甲酰胺， 产率 74.8%, 熔点 178-180 。C; 蘭 R(500 MHz, CDC13) , δ (ppm) :9.24 (b， IH) , 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, IH), 3.46 (t, 2H), 3.28 (m, 4H), 2.92-2.94 (t, 4H), 2.85 (s， 2H)， 2.68 (t, 211) , 1.15 (s, 6H)； FAB-MS m/z: 461.3(M++1); 元素分析： 计算值 C 70.41, H 7.00, N 12.16； 测定 值 C 70.27, H 6.76, N 11.94。 2-(1-(4-(2-hydroxyethyl)piperazine))-4 (9-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole) The synthesis method of benzamide is the same as in Example 46. The first step is the reaction of 4-(2-hydroxyethyl)piperazine with 2,4-difluorophenyl cyanide to give 4-fluoro-2-(1-(4-(2-hydroxyethyl'alkyl)piperazine) Benzoic acid (yield 58%), the second step consists of 2,2-dimethyl-1,2,3,9-tetrahydrocarbazole-4-one and 4-fluoro-2-(1-(4-) (2-Hydroxyethyl) piperazine)) phenyl cyanide gives 2-(1-(4-(2-hydroxyethyl)piperazine))-4-(9-(2,2-dimethyl-) 4-oxo-1,2,3,4-tetrahydrocarbazole)) Benzoic acid (65.5% yield), the last step is 2-(1-(4-(2-hydroxyethyl)piperazine)-4-(9-(2,2-dimethyl-4-oxo-) 1, 2, 3, 4-tetrahydrocarbazole)) phenyl cyanide is reacted with hydrogen peroxide and purified by silica gel column chromatography to give 2-(1-(4-(2-hydroxyethyl)piperazine)) 4-(9-(2,2-Dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole))benzamide, yield 74.8%, mp 178-180. C; R (500 MHz, CDC1 3 ), δ (ppm): 9.24 (b, IH), 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, IH), 3.46 (t, 2H), 3.28 (m, 4H), 2.92-2.94 (t, 4H), 2.85 (s, 2H), 2.68 (t, 211 ), 1.15 (s, 6H) ; FAB-MS m / z: 461.3 (m + +1); elemental analysis: Calcd C 70.41, H 7.00, N 12.16 ; measured value C 70.27, H 6.76, N 11.94 .
实施例 49  Example 49
2- (1- (4 -甲基哌嗪）) -4- (9- (2， 2-二甲基 -4-氧- 6-三氟甲基 -1， 2， 3, 4-四氢咔 唑 ） ） 苯 甲 酰 胺 （ 4- (2，2_dimethyl- 4- 0X0- 6- trif!uoromethyl- 1，2，3, 4 - tetrahydro-carbazol-9-yl) - 2- (4-methyl-piperazin-l-yl) -benzamide )的合成。 (结 构式 1-49)  2-(1-(4-Methylpiperazine))-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1, 2, 3, 4-tetrahydrol) Carbazole)) Benzoic acid (4-(2,2_dimethyl- 4- 0X0- 6- trif!uoromethyl- 1,2,3, 4-tetrahydro-carbazol-9-yl) - 2- (4-methyl-piperazin -l-yl) -benzamide). (Structure 1-49)
Figure imgf000053_0001
Figure imgf000053_0001
2， 2- 二 甲 基 - 6- 三 氟 甲 基 - 1， 2， 3， 9 - 四 氢 咔 唑 -4- 酮 (2, 2-dimethyl-6-trifluoromethyl-l, 2, 3, 9-tetrahydro-carba_zol-4-one)按照合成 中间体 VI的方法用对-三氟甲基苯肼和 5， 5-二甲基 -1,3-环己二酮合成而得， 产率 64 %, 熔点 152— 153 X； 1麵 R(500 MHz, CDC1:,)， δ (ppm)： 10.23 (b， IH), 7.13-7.27 (m, 3H), 2.82 (s, 2H), 2.57 (s, 2H), 1.14 (s, 6H)。 2, 2-Dimethyl-6-trifluoromethyl-1, 2,3,9-tetrahydrocarbazol-4-one (2, 2-dimethyl-6-trifluoromethyl-l, 2, 3, 9- Tetrahydro-carba_zol-4-one) was synthesized by the method of the synthesis of intermediate VI using p-trifluoromethylphenylhydrazine and 5,5-dimethyl-1,3-cyclohexanedione in a yield of 64%. Melting point 152— 153 X; 1 side R (500 MHz, CDC1:,), δ (ppm): 10.23 (b, IH), 7.13-7.27 (m, 3H), 2.82 (s, 2H), 2.57 (s, 2H), 1.14 (s, 6H).
由 4-氟- 2-氯苯氰和 2， 2-二甲基 -6-三氟甲基 -1， 2, 3, 9一四氢咔唑- 4-酮按实施例 1 的方法合成得到 2 -氯- 4- (9- (2， 2-二甲基 -4 -氧- 6-三氟甲基 -1,2， 3, 4-四氢咔唑））苯 氰， 产率 72 %， 熔点 121-123。C; 1顯 MR (500 MHz, CDC13)， δ (ppm) :7.68-7.70 (d, 1H)， 7.65-7.67(s, 1H),7.47-7.49 (d， IH) , 7.39-7.41 (d, IH), 7.26-7.28(s, IH), 7.18-7.20 (d, 1H)， 2.84 (s, 2H) , 2.45 (b, 2H), 1.14(s, 6H)。 Synthesis of 4-fluoro-2-chlorobenzonitrile and 2,2-dimethyl-6-trifluoromethyl-1,2,3,9-tetrahydrocarbazole-4-one as in Example 1. 2-Chloro-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole)) phenyl cyanide, yield 72% , melting point 121-123. C; 1 display MR (500 MHz, CDC1 3 ), δ (ppm): 7.68-7.70 (d, 1H), 7.65-7.67 (s, 1H), 7.47-7.49 (d, IH), 7.39-7.41 (d , IH), 7.26-7.28(s, IH), 7.18-7.20 (d, 1H), 2.84 (s, 2H), 2.45 (b, 2H), 1.14(s, 6H).
由 2-氯- 4- (9- (2， 2-二甲基 -4-氧- 6-三氟甲基- 1， 2, 3, 4-四氢咔唑））苯氰和 4 -甲 基哌嗪按实施例 2的合成方法合成得到 2- (1- (4 甲基哌嗪）） -4- (9- (2， 2-二甲基 - 4 -氧 _6-三氟甲基- 1,2,3,4-四氢咔唑）） 苯氰， 产率 56.5%， 焙点 144—146 °C; ' MR (500 MHz, CDC1:,)， 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, 211), 2.52 (b， 4H)， 2.43 (b, 2H)， 2.3 (s, 3H), 1.13(s, 6H)。 From 2-chloro-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole)) phenyl cyanide and 4-methyl The piperidazine was synthesized according to the synthesis method of Example 2 to give 2-(1-(4methylpiperazine))-4-(9-(2,2-dimethyl) - 4 -oxo_6-trifluoromethyl- 1,2,3,4-tetrahydrocarbazole)) phenyl cyanide, yield 56.5%, baking point 144-146 ° C; ' MR (500 MHz, CDC1: ,), δ ( PP m) : 7.74 - 7.76 (d, 1H) , 7.58 (s, 1H), 7.07-7.38 (m, 4H), 3.44 (b, 4H), 2.83 (s, 211), 2.52 ( b, 4H), 2.43 (b, 2H), 2.3 (s, 3H), 1.13(s, 6H).
2- (1- (4-甲基哌嗪）） - 4- (9- (2,2-二甲基 -4-氧- 6-三氟甲基 -1,2, 3， 4-四氢咔 唑）） 苯甲酰胺的合成方法同实施例 3， 产率 47.6%， 熔点 165— 167 °C; ¾NMR(500 MHz, CDCla) , δ (ppra) :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)； 元素分析: 计 算值 C 65.05， H 5.86， N 11.24； 测定值 C 64.87, H 5.65, N 11.17。 2-(1-(4-Methylpiperazine)) 4- (9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrol) The synthesis of benzamide is the same as in Example 3, yield 47.6%, melting point 165-167 °C; 3⁄4 NMR (500 MHz, CDCla), δ (ppra): 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); Elemental analysis: calculated value C 65.05, H 5.86, N 11.24; found C 64.87, H 5.65, N 11.17.
实施例 50  Example 50
2- (1- (4-羟基哌啶）） - 4_ (9- (2,2-二甲基 -4-氧- 6-三氟甲基- 1， 2， 3,4-四氢咔 唑 ） ） 苯 甲 酰 胺 （ 4- (2，2- Dimethyl- 4- OXO-6- tri- fluoromethyl- 1，2，3，4 - tetrahydro-carbazol-9-yl) -2- (4-hydroxy-piperidin-l-yl) -benzamide)的合成。 (结 构式 1-50)  2-(1-(4-Hydroxypiperidine))-4_(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl- 1, 2, 3,4-tetrahydrocarbazole )) 4-(2-(2,2-Dimethyl- 4- OXO-6- tri-fluoromethyl- 1,2,3,4-tetrahydro-carbazol-9-yl) -2- (4-hydroxy-piperidin) -l-yl) -benzamide). (Structure 1-50)
Figure imgf000054_0001
Figure imgf000054_0001
2 - (1- (4 -羟基哌啶）) -4- (9- (2,2-二甲基 -4-氧- 6-三氟甲基- 1,2,3,4-四氢咔 唑））苯甲酰胺的合成方法同实施例 49。 将 2-氯- 4- (9- (2,2-二甲基 -4-氧- 6-三氟甲 基- 1， 2， 3， 4-四氢咔唑））苯氰 (实施例 49) (0. llg, 0.25醒 ol)， PdCl2(7.8 mg, 0.036 腿 ol)， Pd(0Ac)2(8.08 mg, 0.036讓 ol)， t- Bu0Na(50 mg)， 和无水甲苯 (5 mL)。 反 应混合物加热至 100 °C搅拌 20分钟后， 加入 4-羟基哌啶 （0.1 inL)并继续在 100 °C 下搅拌 5.5小时。 冷却后， 过滤除去固体催化剂， 减压除去溶剂后， 产品用硅胶柱层 析分离，得到 2- (1- (4-羟基哌啶）） -4- (9- (2, 2-二甲基 -4-氧- 6-三氟甲基- 1, 2, 3, 4 - 四氢咔唑））苯氰， 60 mg, 产率 50%; 将得到的 2- (1- (4 -羟基哌啶）) -4 (9- (2,2- 二甲基 -4-氧- 6-三氟甲基- 1， 2， 3， 4-四氢咔唑））苯氰在室温下溶于 DMS0 (1 mL)， 加入 无水乙醇（4 mL)， K0H (35 mg)。 反应物在室温下搅拌 10分钟， 然后慢慢滴加 30%过 氧化氢（0.15 mL), 反应液继续在室温下搅拌 120分钟。 向反应瓶中加入水 （50 mL) 并用二氯甲烷萃取， 饱和氯化钠水溶液洗涤， 无水硫酸钠干燥。产品用硅胶柱层析分离 得到 2- (1- (4 -羟基哌啶）) -4- (9- (2,2-二甲基 -4-氧 6-三氟甲基 -1,2， 3， 4-四氢咔 唑）） 苯甲酰胺， 36 mg， 产率 57.6%, 熔点 196-198 °C; 'HNMR(500 MHz, CDC13) , 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(ni, 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( ++1); 元素分析： 计算值 C 64.92, H 5.65， N 8.41； 测定值 C 64.68, H 5.47, N 8.23。 2-(1-(4-hydroxypiperidinyl)-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydroindole) The synthesis method of oxazole)) benzamide was the same as in Example 49. 2-Chloro-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole)) phenyl cyanide (Example 49 (0. llg, 0.25 awake ol), PdCl 2 (7.8 mg, 0.036 leg ol), Pd(0Ac) 2 (8.08 mg, 0.036 let ol), t-Bu0Na (50 mg), and anhydrous toluene (5) mL). After the reaction mixture was heated to 100 ° C and stirred for 20 minutes, 4-hydroxypiperidine (0.1 inL) was added and stirring was continued at 100 ° C for 5.5 hours. After cooling, the solid catalyst was removed by filtration. After removing the solvent under reduced pressure, the product was purified by silica gel column chromatography to give 2-(1-(4-hydroxypiperidine)-4-(9-(2,2-dimethyl) 4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole)) phenyl cyanide, 60 mg, yield 50%; 2-(1-(4-hydroxyl) Acridine)) -4 (9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole)) phenyl cyanide dissolved in DMS0 at room temperature (1 mL), add absolute ethanol (4 mL), K0H (35 mg). The reaction was stirred at room temperature for 10 minutes, then 30% hydrogen peroxide (0.15 mL) was slowly added dropwise and the mixture was stirred at room temperature for 120 min. Add water to the reaction flask (50 mL) It was extracted with dichloromethane, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The product was isolated by silica gel column chromatography to give 2-(1-(4-hydroxypiperidine)-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2, 3, 4-tetrahydrocarbazole)) benzamide, 36 mg, yield 57.6%, melting point 196-198 °C; 'HNMR (500 MHz, CDC1 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(ni, 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 ( + +1) ; Elemental analysis: Calculated C 64.92, H 5.65, N 8.41. Found C 64.68, H 5.47, N 8.23.
实施例 51  Example 51
2 (4-羟基环己氨基）_4- (9- (2， 2-二甲基 -4 -氧- 6 -三氟甲基 -1， 2, 3, 4-四氢咔唑）） 苯 甲 酰 胺 ( 4_(2， 2 - Dimethyl - 4- OXO- 6-trifluoromethyl— 1， 2， 3, 4- tetrahydro-carbazol-9-yl) -2- (4-hydroxy-cyclohexylamino) -benzamide ) 的合成。 (结构式 1-51)  2 (4-hydroxycyclohexylamino)_4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole)) Benzyl Synthesis of amide ( 4 —( 2, 2 -Dimethyl - 4- OXO-6-trifluoromethyl- 1, 2, 3, 4- tetrahydro-carbazol-9-yl) -2- (4-hydroxy-cyclohexylamino) -benzamide ). (Structure 1-51)
Figure imgf000055_0001
Figure imgf000055_0001
2 -（4-羟基环己氨基） 4- (9- (2， 2-二甲基 -4-氧- 6 -三氟甲基- 1， 2, 3， 4-四氢咔唑）） 苯甲酰胺的合成方法同实施例 50。2-氯- 4- (9- (2， 2-二甲基 -4-氧- 6-三氟甲基- 1， 2, 3， 4- 四氢咔唑））苯氰和 4-氨基环己醇反应得到 2- (4-羟基环己氨基） -4- (9- (2, 2-二甲 基- 4-氧- 6-三氟甲基 1,2,3,4-四氢咔唑））苯氰（产率 67.4%), 2- (4-羟基环己氨基） -4 - (9- (2， 2-二甲基 -4-氧 -6-三氟甲基- 1,2， 3, 4-四氢咔唑））苯氰和过氧化氢 /K0H反 应得到相应得 2- (4-轻基环己氨基） -4- (9- (2， 2-二甲基 -4-氧- 6-三氟甲基- 1, 2, 3, 4- 四氢咔唑））苯甲酰胺，产率 74%，熔点 174— 176 C; 'HNMR(500 MHz, CDC13), 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); 元素分析： 计 算值 C 65.49， H 5.89， N 8.18; 测定值 C 65.35, H 5.53， N 8.09。 2-(4-hydroxycyclohexylamino) 4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole) benzene The synthesis of formamide is the same as in Example 50. 2-Chloro-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl- 1, 2, 3, 4-tetrahydroindole) Oxazole)) benzonitrile and 4-aminocyclohexanol are reacted to give 2-(4-hydroxycyclohexylamino)-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl 1 , 2,3,4-tetrahydrocarbazole)) phenyl cyanide (yield 67.4%), 2-(4-hydroxycyclohexylamino)-4-(9-(2,2-dimethyl-4-oxo) -6-Trifluoromethyl-1,2,3,4-tetrahydrocarbazole))Benzene cyanide and hydrogen peroxide/K0H react to give 2-(4-light-cyclohexylamino)-4-(9 - (2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole)) benzamide, yield 74%, m.p. 174 - 176 C; 'HNMR (500 MHz, CDC1 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) ; Elemental analysis: Calculated C 65.49, H 5.89, N 8.18; calc. C 65.35, H 5.53, N 8.09.
实施例 52  Example 52
2 -环己氨基- 4- (9- (2,2-二甲基 -4-氧- 3-三氟甲基- 4， 5, 6, 7-四氢吲唑））苯甲酰 ( 2— cyclohexylamino- 4-(6， 6 - dimethyl- 4- oxo - 3- trifluoromethyl—4， 5， 6, 7— tetrahydro- indazol - l-yl)- benzamide) 的合成。 (结构式 1-52) 2-cyclohexylamino-4-(9-(2,2-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydrocarbazole))benzoyl (2 — cyclohexylamino- 4-(6, 6 - dimethyl- 4- oxo - 3- trifluoromethyl—4, 5, 6, 7— Synthesis of tetrahydro- indazol - l-yl)- benzamide). (Structures 1-52)
Figure imgf000056_0001
Figure imgf000056_0001
6， 6_二甲基 -3-三氟甲基- 1, 5， 6, 7-四氢吲唑- 4-酮的合成方法同中间体 V的合成方 法， 用三氟乙酸酐作为起始原料得到黄色粉状固体， 产率 51%， 熔点 115— 117 X； 'HNMR(500 MHz, CDC13) , δ (ppm)： 12.98 (b, 1H), 2.84(s, 2H) , 2.55 (s, 2H) , 1.12 (s,Synthesis of 6,6-dimethyl-3-trifluoromethyl-1,5,6,7-tetrahydrocarbazole-4-one The same as the synthesis of intermediate V, starting with trifluoroacetic anhydride The starting material gave a yellow powdery solid, yield 51%, m.p.: 115- 117 </ s;; HNMR (500 MHz, CDC1 3 ) , δ (ppm): 12.98 (b, 1H), 2.84 (s, 2H), 2.55 (s , 2H), 1.12 (s,
6H)。 6H).
向反应瓶重加入 6,6-二甲基 -3-三氟甲基- 1， 5, 6， 7-四氢吲唑 _4-酮 （0.23 g， 1 mmol), DMF (20 mL), NaH (36 mg, 1.5 mmol), 搅拌 10分钟， 再加入 4-氟- 2-环己烷 氨基苯氰（0.22 g， 1 mmol), 反应物加热回流 8小时， 冷却后将反应物倒入冰水中， 并用乙酸乙酯萃取， 饱和氯化钠水洗， 无水硫酸镁干燥， 产物经硅胶柱层析纯化后得到 2 -环己氨基- 4- (9- (2， 2-二甲基 -4-氧- 6 -三氟甲基- 1， 2, 3, 4-四氢咔唑））苯氰， 0.22 g, 产率 51%。 将所得产物 2-环己氨基- 4- (9- (2，2-二甲基 - 4-氧- 6-三氟甲基- 1，2，3,4 - 四氢昨唑）） 苯氰按实施例 3的方法得到 2-环己氨基- 4 (9- (2,2-二甲基 -4-氧- 6-三 氟甲基 -1， 2， 3， 4-四氢咔唑）） 苯甲酰胺， 产率 77%, 熔点 167-169 °C; 1匪 R(500 MHz, CDCla), 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)； 元素分析： 计算 值 C 61.60, H 6.07, N 12.49； 测定值 C 61.47， H 5.87, N 12.36。 To the reaction flask was added 6,6-dimethyl-3-trifluoromethyl-1,5,6,7-tetrahydrocarbazole-4-one (0.23 g, 1 mmol), DMF (20 mL). NaH (36 mg, 1.5 mmol), stirred for 10 min, then added 4-fluoro-2-cyclohexaneaminobenzonitrile (0.22 g, 1 mmol). The reaction was heated to reflux for 8 hr. The mixture was extracted with EtOAc. EtOAc (EtOAc)EtOAc. -Oxo-6-trifluoromethyl- 1,2,3,4-tetrahydrocarbazole)) phenyl cyanide, 0.22 g, yield 51%. The obtained product 2-cyclohexylamino-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydropyrazole)) phenyl cyanide 2-cyclohexylamino-4 (9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole) was obtained as in Example 3. Benzoylamide, yield 77%, melting point 167-169 °C; 1匪R (500 MHz, CDCla), 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); Elemental analysis: Calculated C 61.60, H 6.07, N 12.49 ; Measured value C 61.47, H 5.87, N 12.36.
实施例 53  Example 53
2- (4-羟基环己氨基） -4- (1- (6， 6-二甲基 _4 -氧- 3-三氟甲基- 4, 5， 6， 7 -四氢 H引 挫 ） ） 苯 甲 酰胺 (4-hydroxy- cyclohexylamino)-4 - (6， 6 - dimethyl - 4-OXO- 3- trifluoromethyl-4, 5, 6, 7 - tetrahydro- indazol- l-yl) - benzamide)的合成。 （结构式 1-53)
Figure imgf000057_0001
2-(4-Hydroxycyclohexylamino)-4-(1-(6,6-dimethyl-4-oxo-3-trifluoromethyl- 4, 5, 6, 7-tetrahydro-H) Synthesis of 4-hydroxy-cyclohexylamino-4 - (6, 6 - dimethyl - 4-OXO- 3-trifluoromethyl-4, 5, 6, 7 - tetrahydro- indazol- l-yl) - benzamide . (Structure 1-53)
Figure imgf000057_0001
4-氟- 2-氯苯氰和 6,6-二甲基 -3-三氟甲基- 1， 5, 6， 7-四氢吲唑- 4-酮按实施例 1 的 方法合成得到 2-氯- 4 - (1- (6, 6-二甲基 -4-氧- 3-三氟甲基- 4， 5， 6， 7-四氢吲唑）） 苯氰，产率 68 %，熔点 154-156 "C; 'HNMR(500 MHz, CDC13)， δ (ppra) :7.51-7· 53 (d， IH) , 7.43-7.45 (d， IH) , 7.34-7.36 (s, 1H)， 2.83 (s, 2H)， 2.42 (b, 2H)， 1.13 (s, 6H)。 4-fluoro-2-chlorobenzonitrile and 6,6-dimethyl-3-trifluoromethyl-1,5,6,7-tetrahydrocarbazole-4-one were synthesized as in Example 1 to obtain 2 -Chloro-4-(1-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide, yield 68%, Melting point 154-156 "C;'HNMR (500 MHz, CDC1 3 ), δ ( ppra ): 7.51-7· 53 (d, IH), 7.43-7.45 (d, IH), 7.34-7.36 (s, 1H) , 2.83 (s, 2H), 2.42 (b, 2H), 1.13 (s, 6H).
2- (4-轻基环己氨基） -4- (1- (6, 6-二甲基 -4-氧- 3-三氟甲基 _4, 5， 6， 7-四氢 吲唑））苯氰由 2-氯- 4- (1- (6, 6-二甲基 -4-氧- 3-三氟甲基- 4， 5， 6， 7_四氢吲唑）) 苯氰和 4-氨基环己醇按实施例 2的合成方法合成得到， 产率 42.6%， 熔点 173— 175 °C; ¾NMR(500 MHz, CDC1,)， δ (ppm) :7.68-7.70 (d, IH) , 7.12 (s， 1H)， 6.87-6.89 (d, IH)， 4.08 (b, IH), 3.68 (b， 1H)， 2.82 (s, 2H), 2.52 (ni， IH), 2.46 (b, 2H)， 1.74(m, 4H)， 1.62(ra, 4H)， 1.14(s， 6H)。 2-(4-Light-cyclohexylamino)-4-(1-(6,6-dimethyl-4-oxo-3-trifluoromethyl_4, 5, 6, 7-tetrahydrocarbazole) Benzoic acid from 2-chloro-4-(1-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide and 4-Aminocyclohexanol was synthesized by the synthesis method of Example 2, yield 42.6%, melting point 173-175 ° C; 3⁄4 NMR (500 MHz, CDC1,), δ (p pm ): 7.68-7.70 (d, IH ), 7.12 (s, 1H), 6.87-6.89 (d, IH), 4.08 (b, IH), 3.68 (b, 1H), 2.82 (s, 2H), 2.52 (ni, IH), 2.46 (b, 2H), 1.74 (m, 4H), 1.62 (ra, 4H), 1.14 (s, 6H).
2- (4-羟基环己氨基） -4- (1- (6， 6_二甲基 -4-氧- 3-三氟甲基 -4， 5， 6, 7-四氢 吲唑））苯甲酰胺的合成方法同实施例 3, 产率 56.4%， 焙点 149—151 °C; ¾NMR(500 MHz, CDC13) , δ (ppm) :9.21 (b, IH), 7.68-7.70 (d, IH)， 7.01(s, IH), 6.85-6.97 (d, 1H)， 5.97(b， IH), 4.02 (b, IH), 3.54 (b, 1H)， 2.84 (s， 2H), 2.53 (m, IH), 2.47(b, 2H)， 1.69 (m, 4H), 1.58 (111, 4H), 1.13 (s, 6H)； FAB-MS m/z: 465.2(M++1); 元素分 析： 计算值 C 59.47, H 5.86， N 12.06; 测定值 C 59.21, H 5.59， N 11.92。 2-(4-Hydroxycyclohexylamino)-4-(1-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydrocarbazole)) The synthesis of benzamide was the same as in Example 3, yield 56.4%, baking point 149-151 °C; 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppm): 9.21 (b, IH), 7.68-7.70 (d , IH), 7.01(s, IH), 6.85-6.97 (d, 1H), 5.97(b, IH), 4.02 (b, IH), 3.54 (b, 1H), 2.84 (s, 2H), 2.53 ( m, IH), 2.47(b, 2H), 1.69 (m, 4H), 1.58 (111, 4H), 1.13 (s, 6H); FAB-MS m/z: 465.2 (M + +1) ; Calcd for C 59.47, H 5.86, N 12.06; found C 59.21., H 5.59, N 11.92.
实施例 54  Example 54
N-(2- [1，2,3]三氮唑乙基) -4 -（1- (3, 6， 6)三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑）） 苯 甲 酰 胺 ( N- (2-[1, 2, 3] triazol-1-yl-ethyl) -4 -（3， 6, 6- trimethyl N-(2-[1,2,3]triazolylethyl)-4-(1-(3, 6, 6)trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole Azole)) benzamide ( N- (2-[1, 2, 3] triazol-1-yl-ethyl) -4 -(3, 6, 6- trimethyl
-4-0X0-4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzamide) 的合成。 （结构式 I 54) Synthesis of -4-0X0-4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzamide). (Structure I 54)
Figure imgf000057_0002
4 -肼基苯甲酸 (0.3 g， 2画 ol)在 85°C下加入到 2 -乙酰基一 5， 5 -二甲基一 1, 3- 环己二酮 （0.36 g， 2 誦 ol) 的甲苯 （20 mL)溶液中。 反应物在搅拌下加热到 110°C 反应 1小时， 冷却， 减压去除溶剂， 产物用二氯甲浣萃取， 饱和氯化钠水溶液洗漆， 无 水硫酸镁干燥。 产品用硅胶柱层析纯化后得 4- (1- (3， 6， 6-三甲基 4-氧- 4， 5， 6, 7-四氢吲唑）)苯甲酸 0.35 g, 产率 58%， 熔点 176— 177 X； '画 R(500 MHz, CDC1,), 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)。
Figure imgf000057_0002
4-Mercaptobenzoic acid (0.3 g, 2 liters ol) was added to 2-acetyl-5,5-dimethyl-1,3-trihexanedione (0.36 g, 2 诵ol) at 85 °C. In a solution of toluene (20 mL). The reaction mixture was heated to 110 ° C under stirring for 1 hour, cooled, and the solvent was evaporated under reduced pressure. The product was extracted with methylene chloride, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The product was purified by silica gel column chromatography to give 4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzoic acid 0.35 g, yield 58 %, melting point 176 - 177 X; 'Draw R (500 MHz, CDC1,), 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).
在冰浴冷却下， 向含有 1H[1， 2, 3]三氮唑 (0.7 g， 0.01 mol)和 THF (35 mL) 的反应瓶中加入 NaH(0.24 g, 0.01 mol)并在冰浴冷却下搅拌 15分钟， 然后在冰浴冷 却下加入溴代乙氰 (bromoacetonitrile) (1.2 g, 0.01 mol)。 反应在室温下搅拌 2小 时， 减压去处溶剂， 产物用二氯甲垸萃取， 饱和氯化钠水溶液洗涤， 无水硫酸镁干燥。 过滤， 减压去处溶剂， 真空干燥后得到油状产物 0.76 g。 将此产物溶于 THF (35 mL), 搅拌下慢慢加入 LiAl (0.38 g， 0.01 mol), 等剧烈反应过后， 反应混和物加热回流 1小时， 冷却后， 加入 IN NaOH(2 mL)和无水 N¾S04 (2 g)并搅拌 30分钟， 过滤， 滤 液减压抽千。 粗产物用硅胶柱层析纯化， 氯仿 /甲醇 /三乙胺 （7:3:0.1) 洗脱得到 2- (1,2, 3-三氮唑）乙胺 0.36 g, 产率 32% (两步）; '醒 R(500 MHz, CDC13) , 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)。 NaH (0.24 g, 0.01 mol) was added to a reaction flask containing 1H[1,2,3]triazole (0.7 g, 0.01 mol) and THF (35 mL) under ice-cooling and cooled in an ice bath. After stirring for 15 minutes, bromoacetonitrile (1.2 g, 0.01 mol) was added under ice cooling. The reaction was stirred at room temperature for 2 hours, and the solvent was evaporated to dryness. Filtration, the solvent was removed under reduced pressure and dried in vacuo. This product was dissolved in THF (35 mL), and LiAl (0.38 g, 0.01 mol) was slowly added with stirring. After vigorous reaction, the reaction mixture was heated to reflux for 1 hour. After cooling, IN NaOH (2 mL) and Water N3⁄4S0 4 (2 g) was stirred for 30 minutes, filtered, and the filtrate was depressurized. The crude product was purified by silica gel column chromatography eluting with chloroform / methanol / triethylamine (7:3:0.1) to give 2-(1,2,3-triazole)ethylamine 0.36 g, yield 32% Step); 'Wake up R (500 MHz, CDC1 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).
在反应瓶中加入 4- (1- (3， 6， 6-三甲基 4-氧- 4， 5， 6， 7-四氢吲唑））苯甲酸（0.3 g, 1 删 ol) ， 二氯甲垸（30 mL), 和二氯亚砜（5 mL)。 反应物在室温下搅拌 2小时， 去除溶剂得到相应的 4- (1- (3， 6, 6-三甲基 4-氧 -4， 5， 6， 7-四氢吲唑））苯甲酰氯 为深褐色液体 0.3 g, 产率 93%。  Add 4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzoic acid (0.3 g, 1 ol) to the reaction flask, Chloroformamidine (30 mL), and thionyl chloride (5 mL). The reaction was stirred at room temperature for 2 hours and the solvent was removed to give the corresponding 4-(1-(3,6-6-trimethyl 4-oxo-4,5,6-7-tetrahydrocarbazole))benzoyl chloride. It was 0.3 g of a dark brown liquid, and the yield was 93%.
在反应瓶中加入上述制备的 4- (1- (3， 6， 6 -三甲基 4 -氧- 4， 5, 6， 7 -四氢吲唑）) 苯甲酰氯 （32 mg, 0.1 mraol) ， 二氯甲垸（20 mL)， 2- (1， 2， 3-三氮唑）乙胺 （12 mg， 0.1 腿 ol)，三乙胺 （0.1 mL)。 .反应在室温下搅拌 1 小时， 产物用二氯甲垸（30 mL) 萃取， IN NaOH洗涤， 饱和氯化钠水溶液洗涤， 无水硫酸镁干燥。 粗产品用硅胶柱层析 纯化得到 N- (2- [1， 2, 3]三氮唑乙基) -4- (1- (3, 6, 6)三甲基 -4-氧- 4， 5， 6, 7-四 氢吲唑））苯甲酰胺 25 mg, 产率 64%;熔点 143-145 "C; 'HNMR(500 MHz, CDC13)， 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-MS m/z: 393.2(M++1);元素分析：计算值 C 64.27， H 6.16, N 21.41;测定值 C 64.14, H 5.87, ff ·0Ι Ν 9Τ 'Ζ Η4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzoyl chloride prepared above (32 mg, 0.1 mraol) was added to the reaction flask. ), chloroform (20 mL), 2-(1,2,3-triazole)ethylamine (12 mg, 0.1 leg ol), triethylamine (0.1 mL). The reaction was stirred at room temperature for 1 hour. The product was extracted with dichloromethane (30 mL). The crude product was purified by silica gel column chromatography to afford N-(2-[1,2,3]triazolethyl)-4-(1-(3,6,6)trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) benzamide 25 mg, yield 64%; melting point 143-145 "C;'HNMR (500 MHz, CDC1 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-MS m/z: 393.2 (M + +1); Elemental analysis: Calculated C 64.27, H 6.16 , N 21.41; measured value C 64.14, H 5.87, Ff ·0Ι Ν 9Τ 'Ζ Η
'89 ·6931囊 s29 ·0ΐ Ν '6S *Ζ Η 'S8 ·693聽 4 峯^ : '96S： Vm SW-HVH'89 ·6931 s s 29 ·0ΐ Ν '6S *Ζ Η 'S8 ·693 听4 peak ^ : '96S: V m SW-HVH
： (H9 (s)W'T '(Η ¾) 89 '(m '«ι)98 · I '(Η2 '^)ZfZ '(HS 's)Z9 τ W, 's) 98 ^ (Ηΐ 'ω)9 ε '(HI 89 '(HZ <Vi 9 "Z-S9 "Z '(Η2 'Ρ)^6- -Ζ6 ' '(HI 'q) 80 '8: ( ) 9 ' CTOaO 'ZHW 009)HWNH, :3。ΐ6-68 '%99 ^ (f ^ ^导 ^翘綱 ώ¾ i 'WM-i '9 '9 - ¾ - ¾ ≡ (9 '9 'ε) -ΐ) (¾B E¾¾-^)-N : (H9 (s)W'T '(Η 3⁄4) 89 '(m '«ι)98 · I '(Η2 '^)ZfZ '(HS 's)Z9 τ W, 's) 98 ^ (Ηΐ ' ω)9 ε '(HI 89 '(HZ <Vi 9 "Z-S9 "Z '(Η2 'Ρ)^6- -Ζ6 ''(HI'q) 80 '8: ( ) 9 ' CTOaO ' Z HW 009)HWNH, :3.ΐ6-68 '%99 ^ ( f ^ ^导^翘ώ3⁄4 i 'WM-i '9 '9 - 3⁄4 - 3⁄4 ≡ (9 '9 'ε) -ΐ) (3⁄4B E3⁄43⁄4 -^)-N
Figure imgf000059_0001
Figure imgf000059_0001
(9s-i (9s-i
Figure imgf000059_0002
Figure imgf000059_0002
ώ¾ Ζ '9 '9 - -¾ 三 (9 '9 'ε) -I)
Figure imgf000059_0003
Ώ3⁄4 Ζ '9 '9 - -3⁄4 three (9 '9 'ε) -I)
Figure imgf000059_0003
99 W¾ 99 W3⁄4
29 ΈΙ N '20 -L H 'ΐΐ 'Ζ9 3f>¾29 ΈΙ N '20 -L H 'ΐΐ 'Ζ9 3f>3⁄4
Μ '· 9 \ Ν ΊΖ'ί Η <6Ζ· 93哥鴛 l>A^r :(1++W)S' :ζ/ω SW- SVd '· (H9Μ '· 9 \ Ν ΊΖ'ί Η <6Ζ· 93哥鸳l> A^r : (1+ + W)S' :ζ/ω SW- SVd '· (H9
's)^i '{ 's)z -z ((HS 's)9s's 'OK 'q)29 τ 'OK -z ' (i-iz 'ws '(nz ΐ)99 Έ '(Η ' )88Έ - 98Έ '(Η2 '^) 69 '(ΗΖ 'Ρ)Κ)·8- Ζ0·8 '(Ηΐ 'ς)ΖΓ8„ ' s )^i '{ 's)z -z ((HS 's)9s's 'OK 'q)29 τ 'OK -z ' (i-iz 'ws '(nz ΐ)99 Έ '(Η ' ) 88Έ - 98Έ '(Η2 '^) 69 '(ΗΖ 'Ρ)Κ)·8- Ζ0·8 '(Ηΐ 'ς)ΖΓ8„
'9 '9 ¾- 愛由三 (9 '9 'ε)— υ (#i¾u- -S)-N '9 '9 3⁄4- Love by three (9 '9 'ε) - υ (#i3⁄4u- -S)-N
-L '9 'S
Figure imgf000059_0004
-L '9 'S
Figure imgf000059_0004
((¾|&1霄 ffl- A '9 'S (9 '9 'S) -ΐ) (¾H¾a- ) -2)-N  ((3⁄4|&1霄 ffl- A '9 'S (9 '9 'S) -ΐ) (3⁄4H3⁄4a- ) -2)-N
T8Zl00/900iN3/X3d 1"f 9m/900Z OAV 实施例 57 T8Zl00/900iN3/X3d 1"f 9m/900Z OAV Example 57
N- (2- (1- (4-羟基哌啶）） 乙基) -4- (1- (3， 6, 6)三甲基 -4-氧- 4, 5， 6， 7-四 氢 吲 唑 ） ） 苯 甲 酰 胺 （ N- [2-(4-hydroxy- piperidin_l- y -ethyU- A-G, 6， 6-trimethyl-4-oxo-4, 5, 6， 7-tetrahydro-indazol l-yl)-benzaraide)的合成。 (结构式 1-57)  N-(2-(1-(4-hydroxypiperidinyl)ethyl)-4-(1-(3, 6, 6)trimethyl-4-oxo-4, 5, 6, 7-tetrahydro Carbazole)) Benzamide ( N- [2-(4-hydroxy-piperidin_l-y-ethyU-AG, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro-indazol l-yl )-benzaraide). (Structure 1-57)
Figure imgf000060_0001
Figure imgf000060_0001
N- (2- (1- (4-羟基哌啶）） 乙基 )- 4-（1- (3, 6， 6)三甲基 -4 -氧 -4， 5， 6, 7 -四 氢吲唑））苯甲酰胺的合成方法同实施例 54， 产率 42%， 熔点 （油状物） °C; ¾NMR(500 MHz, CDC13) , δ (ppm)： 8.08 (b, 1H), 7.85-7.87 (d, 2H), 7.68-7.70 (m, 2H), 4.03 (m, 1H), 3.79-3.8Kb, 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)； 元素分析： 计算值 C 67.90， H 7.60， N 13.20; 测定值 C 67.72, H 7.43， N 13.02。 N-(2-(1-(4-hydroxypiperidyl))ethyl)-4-(1-(3, 6, 6)trimethyl-4-oxo-4, 5, 6, 7-tetrahydrogen The oxazole)) benzamide was synthesized in the same manner as in Example 54, yield 42%, melting point (oil) °C; 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppm): 8.08 (b, 1H), 7.85 -7.87 (d, 2H), 7.68-7.70 (m, 2H), 4.03 (m, 1H), 3.79-3.8Kb, 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); Elemental analysis: Calculated C 67.90, H 7.60, N 13.20; found C 67.72, H 7.43, N 13.02.
实施例 58  Example 58
5 - （ 1- ( 2，6,6-三甲基 - 4-氧- 4，5，6，7-四氢吲哚）） 吡啶一 2-甲酰胺 (5- (2, 6， 6-trimethyl-4-oxo-4, '5, 6, 7-tetrahydro-indol-l-yl)-pyridine-2-carboxy lie acid amide) 的合成。 (结构式 1-58)  5-(1-( 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))pyridine-2-carboxamide (5-(2, 6, 6-) Synthesis of trimethyl-4-oxo-4, '5, 6, 7-tetrahydro-indol-l-yl)-pyridine-2-carboxy lie acid amide). (Structure 1-58)
Figure imgf000060_0002
Figure imgf000060_0002
将 5， 5-二甲基一 2- (2—氧一丙基） 一1,3—环己二酮（0.1 g， 1匪 ol)溶于甲苯 (20 mL), 加热至 85°C， 加入 5-氨基- 2-氰基吡啶（0.12g, lramol)), 反应温度升至 110 °C， 并搅拌 2h。 冷却后， 将溶剂去除， 产物用硅胶柱层析纯化得到 5- (1- (2,6,6-三甲基 - 4 -氧- 4,5,6,7-四氢吲哚）） -2-氰基吡啶， 0.13 g， 产率 46%; 熔点 63 - 65 °C; 1讓 R(500 腿 z,CDCl:,)， δ (ppm)： 9.12(s, 1H)， 8.54—8.56 (d， 1H)， 8.31- 8.33 (d， IH), 6.45-6.47 (s, IH) , 2.84 (s, 2H), 2.56 (s, 3H) , 2.43 (s, 2H), 1.14 (s, 6H)。 5,5-Dimethyl- 2-(2-oxopropyl)-1,3-cyclohexanedione (0.1 g, 1 匪ol) was dissolved in toluene (20 mL) and heated to 85 ° C. 5-Amino-2-cyanopyridine (0.12 g, lramol) was added, the reaction temperature was raised to 110 ° C, and stirred for 2 h. After cooling, the solvent was removed and the product was purified by silica gel column chromatography to yield 5-(1-(2,6,6-trimethyl) - 4 -oxo 4,5,6,7-tetrahydroindole))-2-cyanopyridine, 0.13 g, yield 46%; m.p. 63 - 65 ° C; 1 let R (500 leg z, CDCl :,), δ (ppm): 9.12(s, 1H), 8.54—8.56 (d, 1H), 8.31- 8.33 (d, IH), 6.45-6.47 (s, IH), 2.84 (s, 2H), 2.56 (s, 3H), 2.43 (s, 2H), 1.14 (s, 6H).
将上述得到的产物按实施例 3 的合成方法处理得到 5- (1- (2， 6, 6-三甲基 -4 -氧 -4， 5, 6， 7-四氢 Π引哚）） 吡啶一 2-甲酰胺， 产率 57.6%; 熔点 87-89 "C; ¾NMR(500 MHz, CDC13) , δ (ppm)： 9.22 (b, IH), 8.87(s, IH), 8.61-8.63 (d， IH), 8.35-8.37 (d, IH), 6.31 (s， IH), 5.97 (b， IH), 2.83 (s, 2H)， 2.55 (s, 3H), 2.44(s, 2H)， 1.14 (s, 6H)； FAB-MS m/z: 298.2(M++1)； 元素分析： 计算值 C 68.67， H 6.44， N 14.13; 测定值 C 68.64, H 6.07, N 14.24。 The product obtained above was treated in the same manner as in Example 3 to give 5-(1-(2,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole) pyridine. 2-formamide, yield 57.6%; melting point 87-89 "C; 3⁄4 NMR (500 MHz, CDC1 3 ), δ (ppm): 9.22 (b, IH), 8.87 (s, IH), 8.61-8.63 ( d, IH), 8.35-8.37 (d, IH), 6.31 (s, IH), 5.97 (b, IH), 2.83 (s, 2H), 2.55 (s, 3H), 2.44(s, 2H), 1.14 (s, 6H); FAB-MS m/z: 298.2 (M + +1); Elemental analysis: Calculated C 68.67, H 6.44, N 14.13; calc. C 68.64, H 6.07, N 14.24.
实施例 59  Example 59
2 -溴- 4_ (1- (4 -氧- 4,5,6,7-四氢吲哚）） 苯氰 2- Bromo- 4- (4-oxo_4, 5， 6, 7- tetrahydro-indol-l-yl)-benzonitrile 的合成。 (结构式 I - 59)  2-Bromo-4_(1-(4-oxo-4,5,6,7-tetrahydroindole)) phenyl cyanide 2- Bromo- 4-(4-oxo_4, 5, 6, 7- tetrahydro-indol- Synthesis of l-yl)-benzonitrile. (Structure I - 59)
Figure imgf000061_0001
Figure imgf000061_0001
合成方法同实施例 1， 产率 40%， 熔点 92- 94 C; 'HNMR (500MHz, CDC13)， S(ppm)：The synthesis was carried out in the same manner as in Example 1, yield 40%, melting point 92-94 C; 'HNMR (500 MHz, CDC1 3 ), S (ppm):
3一 7 (m， 3H), 6
Figure imgf000061_0002
(d (t, 2H) (t, 2H)3-7 (m, 3H), 6
Figure imgf000061_0002
(d (t, 2H) (t, 2H)
(m 2H) (m 2H)
实施例 60  Example 60
2-溴 -4- ( 1- ( 4-氧 -4， 5， 6， 7-四氢吲哚） 甲基） 苯氰 2- Bromo- 4- (4-0X0-4, 5， 6， 7-tetrahydro-indol-l-ylmethyl)-benzonitrile 的合成。 (结构式 1-60)  2-Bromo-4-(1-(4-oxo-4,5,6,7-tetrahydroindole)methyl) phenyl cyanide 2- Bromo- 4- (4-0X0-4, 5, 6, 7 Synthesis of -tetrahydro-indol-l-ylmethyl)-benzonitrile. (Structure 1-60)
Figure imgf000061_0003
Figure imgf000061_0003
合成方法同实施例 1， 产率 38%， 熔点 97-99 X； ¾匪 R (500MHz, CDC13)， 5(ppm)： 7.18-7.41 (m， 3H), 6.48 (d, IH), 6.39(d, 1H)， 5. ll(s, 2H)， 2.59 (t, 2H)， 2.40 (t, H), 1.89 (m 2H)。 The synthesis was carried out in the same manner as in Example 1, yield 38%, melting point 97-99 X; 3⁄4匪R (500MHz, CDC1 3 ), 5 (ppm): 7.18-7.41 (m, 3H), 6.48 (d, IH), 6.39 (d, 1H), 5. ll(s, 2H), 2.59 (t, 2H), 2.40 (t, H), 1.89 (m 2H).
实施例 61:  Example 61:
2-溴- 4- ( 1- (3,6， 6-三甲基 -4-氧- 4,5,6， 7-四氢吲哚）） 苯氰 2- Bromo- - (3, 6， 6-trimethy 1-4-0X0-4, 5， 6, 7-tetrahydro-indol-l-yl)-benzonitrile的合成。 (结构式 1-61)  2-Bromo-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole)) phenyl cyanide 2- Bromo- - (3, 6, Synthesis of 6-trimethy 1-4-0X0-4, 5, 6, 7-tetrahydro-indol-l-yl)-benzonitrile. (Structure 1-61)
Figure imgf000062_0001
Figure imgf000062_0001
合成方法同实施例 1， 产率 45%， 熔点 87- 89 °C; 1蘭 MR (500MHz， CDC13)， S(ppm)： 7.30-7.45 (ra, 3H), 6.50 (s, 1H)， 2.51 (s, 2H)， 2.32 (s， 2H)， 2.05 (s, 3H), 1.11 (s 6H)。 The synthesis was carried out in the same manner as in Example 1, yield 45%, melting point 87-89 ° C; 1 blue MR (500 MHz, CDC1 3 ), S (ppm): 7.30-7.45 (ra, 3H), 6.50 (s, 1H), 2.51 (s, 2H), 2.32 (s, 2H), 2.05 (s, 3H), 1.11 (s 6H).
实施例 62  Example 62
2-溴- 4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚) 甲基） 苯氰 2- Bromo- 4-(3， 6， 6-trimethyl-4-oxo-4, 5， 6, 7-tetrahydro-indol-l-ylmethyl) -benzonitrile ( 结抅式 1-62)  2-Bromo-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole) methyl) phenyl cyanide 2- Bromo- 4-(3 , 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro-indol-l-ylmethyl) -benzonitrile (saturated 1-62)
Figure imgf000062_0002
Figure imgf000062_0002
合成方法同实施例 1， 产率 35%， 熔点 85- 87 C; lHNMR (500MHz, CDC13)， 5(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)。 The synthesis was carried out in the same manner as in Example 1, yield 35%, melting point 85-87 C ; l HNMR (500 MHz, CDC1 3 ), 5 (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).
实施例 63  Example 63
2-溴- 4- (1- ( 3,6， 6_三甲基 -4-氧- 4, 5, 6， 7-四氢吲哚）） 苯甲酰胺 2- Bromo - 4- (3， 6, 6-trimethyl-4-oxo-4, 5， 6， 7- tetrahydro- indol - l_yl)-benzamide 的合成。 (结构式 1-63)
Figure imgf000063_0001
2-Bromo-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzamide 2- Bromo- 4- (3, Synthesis of 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro- indol-l_yl)-benzamide. (Structures 1-63)
Figure imgf000063_0001
以化合物 1-61 为原料， 合成方法同实施例 3， 产率 85%， 瑢点 96-98 °C; NMR (500MHz, CDC1:,)， S(ppm)： 7.41-7.80 (m, 3H)， 6.50 (s, 1H), 2.52 (s, 2H)， 2.33 (s, H)， 2.04 (s, 3H), 1.16 (s 6H)； FAB-MS m/z: 374.1 (M++l)。 Starting from compound 1-61, the synthesis method was the same as in Example 3, yield 85%, 瑢 96-98 ° C ; NMR (500 MHz, CDC1:,), S (ppm): 7.41-7.80 (m, 3H) , 6.50 (s, 1H), 2.52 (s, 2H), 2.33 (s, H), 2.04 (s, 3H), 1.16 (s 6H); FAB-MS m/z: 374.1 (M + +l).
实施例 64  Example 64
2-溴 -4- ( 1- ( 3-甲基 -4-氧 -4, 5， 6， 7-四氢吲哚）） 苯氰 2- Bromo- 4- (3- methyl- 4-OXO- 4, 5, 6, 7-tetrahydro-indol-l-yl)-benzonitrile的合成。 (结构式 1-64)  2-Bromo-4-(1-(3-methyl-4-oxo-4,5,6,7-tetrahydroindole)) phenyl cyanide 2- Bromo- 4- (3-methyl- 4-OXO- Synthesis of 4, 5, 6, 7-tetrahydro-indol-l-yl)-benzonitrile. (Structure 1-64)
Figure imgf000063_0002
Figure imgf000063_0002
合成方法同实施例 1， 产率 45%, 熔点 86-88。C; 'HNMR (500MHz, CDC13) , S(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)。 The synthesis was carried out in the same manner as in Example 1, yield 45%, melting point 86-88. C; 'HNMR (500MHz, CDC1 3 ) , S (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).
实施例 65  Example 65
2 -溴- 4- (1- (3-甲基- 4 -氧- 4， 5， 6， 7-四氢吲哚） 甲基） 苯氰 2- Bromo- 4- (3-methyl-4-oxo-4, 5, 6， 7 - tetrahydro-indol-l - ylmethyl)- benzonitrile的合成。 (结 构式 I - 65)  2-Bromo-4-(1-(3-methyl-4-oxo-4,5,6,7-tetrahydroindole) methyl) phenyl cyanide 2- Bromo- 4- (3-methyl-4- Synthesis of oxo-4, 5, 6, 7 - tetrahydro-indol-l - ylmethyl)- benzonitrile. (Structure I - 65)
Figure imgf000063_0003
Figure imgf000063_0003
合成方法同实施例 1， 产率 38%， 熔点 76-78。C; lHNMR (500MHz， CDC13)， S(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)。 The synthesis was carried out in the same manner as in Example 1, yield 38%, melting point 76-78. C; l HNMR (500MHz, CDC1 3 ), S (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).
实施例 66  Example 66
2-溴 -4- ( 1- ( 3-甲基 -4-氧 -4， 5， 6, 7-四氢吲唑）） 苯氰 2- Bromo- 4- (3-methyl-4-oxo-4, 5， 6， 7-tetrahydro-indazol-l-yl) -benzonitrile 的合成。 (结构 式 1-66)  2-bromo-4-(1-(3-methyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide 2- Bromo- 4- (3-methyl-4-oxo- Synthesis of 4, 5, 6, 7-tetrahydro-indazol-l-yl)-benzonitrile. (Structure 1-66)
Figure imgf000064_0001
Figure imgf000064_0001
合成方法同实施例 1, 产率 38%, 熔点 96-99。C; lHNMR (500MHz, CDC13) , 6(ppm)： 7.43-7.67 (m, 3H), 2.79 (s， 3H), 2.55 (t, 2H), 2.40 (t, 2H), 1.98 (ra 2H)。 The synthesis was carried out in the same manner as in Example 1, yield 38%, melting point 96-99. C; l HNMR (500MHz, CDC1 3 ) , 6 (ppm): 7.43-7.67 (m, 3H), 2.79 (s, 3H), 2.55 (t, 2H), 2.40 (t, 2H), 1.98 (ra 2H ).
实施例 67  Example 67
2 -溴- 4- (1- (3-甲基 _4-氧- 4， 5, 6, 7-四氢吲唑） 甲基） 苯氰 2- Bromo- 4- (3- methyl- 4-0X0 - 4, 5, 6, 7-tetrahydro-indazol-l-ylmethyl) -benzonitrile的合成。 (结构式 1-67)  2-Bromo-4-(1-(3-methyl_4-oxo-4,5,6,7-tetrahydrocarbazole)methyl) phenyl cyanide 2- Bromo- 4- (3-methyl- 4- 0X0 - 4, 5, 6, 7-tetrahydro-indazol-l-ylmethyl) Synthesis of -benzonitrile. (Structure 1-67)
Figure imgf000064_0002
Figure imgf000064_0002
合成方法同实施例 1， 产率 47%， 熔点 95-97。C; 'HNMR (500MHz, CDC13)， S(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 (ra 2H)。 The synthesis was carried out in the same manner as in Example 1, yield 47%, m.p. 95-97. C; 'HNMR (500MHz, CDC1 3 ), S (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 (ra 2H).
实施例 68  Example 68
4- α - (4- (2 -羟乙基)哌嗪）） -6- (1- (3, 6, 6 -三甲基- 4-氧- 4， 5， 6， 7_四氢吲唑）) 烟 碱 酰 胺 4- [4_(2- Hydroxy- ethyl)- piperazin- 1-yl]- 6- (3, 6， 6- trimethyl - 4-0X0-4, 5, 6, 7-tetrahydro-indazol-l-yl) -nicotinamide的合成。 (结构式 1-68)
Figure imgf000065_0001
4-α-(4-(2-hydroxyethyl)piperazine))-6-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7_tetrahydroindole) Oxazol)) Nicotinamide 4- [4_(2- Hydroxy-ethyl)-piperazin- 1-yl]- 6- (3, 6, 6- trimethyl - 4-0X0-4, 5, 6, 7-tetrahydro- Indazol-l-yl) Synthesis of -nicotinamide. (Structure 1-68)
Figure imgf000065_0001
合成方法同实施例 3， 产率 60%， 油状物； 'HNMR (500MHz, CDCL)， S(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( ++1); 元素分析： 计算值 C 61.95， H 7.09， N 19.70； 测定值 C 62.01， H 7.20, N 19.97。 Synthetic method was the same as in Example 3, yield 60%, oily; 'HNMR (500MHz, CDCL), S (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( + +1) ; Analysis: Calculated C 61.95, H 7.09, N 19.70; found C 62.01, H 7.20, N 19.97.
实施例 69  Example 69
4- (1- (4 -羟基哌啶）) -6- (1- (3,6,6-三甲基 -4 -氧- 4, 5， 6， 7-四氢吲唑））烟碱 酷 胺 4- [4- Hydroxypiperidin - 1 - yl]_6_(3， 6, 6-trimethyl-4-oxo-4， 5, 6, 7 - tetrahydro-indazol-l-yl) -nicotinamide的合成。 (结构式 1—69)  4-(1-(4-hydroxypiperidinyl)-6-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))nicotine - [4-Hydroxypiperidin - 1 - yl]_6_(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7 - tetrahydro-indazol-l-yl) - Synthesis of nicotinamide. (Structure 1 - 69)
Figure imgf000065_0002
Figure imgf000065_0002
合成方法同实施例 3，产率 65%，油状物； 1顯 MR (500MHz, CDC13)， 5(ppra)： 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); 元素分析： 计算值 C 63.46， H 6.85, N 17.62； 测定值 C 63.76， H 6.98, N 17.93。 The synthesis was carried out in the same manner as in Example 3, yield 65%, oily; 1 MR (500 MHz, CDC1 3 ), 5 (ppra): 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 ); elemental analysis: Calcd C 63.46, H 6.85, N 17.62 ; measured value C 63.76, H 6.98, N 17.93 .
实施例 70  Example 70
N- (4-乙酰氧环己基 )-4- (1- (3, 6， 6)三甲基 -4 -氧- 4， 5， 6, 7-四氢吲唑））苯 甲 酰 胺 N- (4-Acetyloxy-cyclohexyl) -4 -（3, 6, 6- trimethyl-4-oxo- 4, 5, 6， 7- tetrahydro-indazol-l-yl)-benzamide的合成。 (结构式 1-70)  N-(4-acetoxycyclohexyl)-4-(1-(3,6,6)trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide N- Synthesis of (4-Acetyloxy-cyclohexyl)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-indazol-l-yl)-benzamide. (Structure 1-70)
Figure imgf000065_0003
将 N- (4-羟基环己基) -4- (1- (3, 6， 6)三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑））苯 甲酰胺（1-56) 0.1 克溶于 1 毫升吡啶中， 缓慢滴加 0.5毫升醋酸酐后室温反应过夜。 除去溶剂后真空干燥得产物， 产率 98%， 熔点 73- 76°C; 'HNMR OOMH^CDCL), 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)； 元素分析：计算值 C 68.63， H 7.14, N 14.63； 测定值 C 68.78， H 7.35, N 14.44。
Figure imgf000065_0003
N-(4-Hydroxycyclohexyl)-4-(1-(3,6,6)trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide (1 -56) 0.1 g was dissolved in 1 ml of pyridine, and 0.5 ml of acetic anhydride was slowly added dropwise, and the reaction was allowed to proceed overnight at room temperature. The solvent was removed and dried in vacuo to give mp. 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); Elemental Analysis: Calculated C 68.63, H 7.14, N 14.63; C 68.78, H 7.35, N 14.44.
实施例 71  Example 71
N-(l- (4- (2-吡啶)哌嗪) -4- (1- (3， 6， 6)三甲基 - 4_氧- 4， 5， 6, 7-四氢吲 唑）） 苯甲酰胺 N- (4-Pyridin- 2- yl_piperazin-l- yl)-4- (3, 6， 6-trimethyl-4-oxo- 4, 5， 6， 7-tetrahydro-indazol-l-yl)-benzamide的合成。 (结构式 1-71)  N-(l-(4-(2-pyridine)piperazine)-4-(1-(3,6,6)trimethyl-4_oxo-4,5,6,7-tetrahydrocarbazole) Benzamide N-(4-Pyridin-2-yl_piperazin-l-yl)-4-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro-indazol-l-yl )-benzamide synthesis. (Structure 1-71)
Figure imgf000066_0001
Figure imgf000066_0001
合成方法同 N- (4-羟基环己基) -4- (1- (3， 6， 6)三甲基 -4-氧- 4, 5, 6， 7-四氢 吲唑）） 苯甲酰胺（1-56)， 产率 68%, 熔点 78_79。C; ¾丽 R(500 MHz, CDC13) , δ (ppm)： 8. ll(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)； 元素分析： 计算值 C 70.41， H 6.59， N 15.79； 测定值 C 70.70, H 6.35， N 15.49。 The synthesis method is the same as N-(4-hydroxycyclohexyl)-4-(1-(3, 6, 6)trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide (1-56), Yield 68%, mp 78-79. C; 3⁄4丽R(500 MHz, CDC1 3 ) , δ (ppm): 8. ll(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); Elemental analysis: Calculated C 70.41, H 6.59, N 15.79; , H 6.35, N 15.49.
实施例 72  Example 72
2- (2-四氢呋喃）甲氨基 _4-(l- (3， 6， 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚)）苯甲酰 胺 2- [ (Tetrahydro-furan-2-ylmethyl) -amino] -4- (3， 6， 6-trimethyl-4-oxo- 2-(2-tetrahydrofuran)methylamino_4-(l-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzamide 2- [ (Tetrahydro-furan-2-ylmethyl) -amino] -4- (3, 6, 6-trimethyl-4-oxo-
4, 5, 6， 7- tetrahydro- indol-l- yl)- benzamide的合成。 （结构式 1-72) Synthesis of 4, 5, 6, 7-tetrahydro- indol-l-yl)- benzamide. (Structure 1-72)
Figure imgf000066_0002
合成方法同实施例 3，产率 42%,熔点 122- 124°C; 'HNMR (500MHz, CDC13) , S(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); 元素分析： 计算值 C 69.85， H, 7.39， N 10.62; 测定值 C 69.97， H 7.56, N 10.45。
Figure imgf000066_0002
The synthesis was carried out in the same manner as in Example 3, yield 42%, melting point 122-124 ° C ; 'HNMR (500 MHz, CDC1 3 ), S (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), </ RTI><RTIgt;
实施例 73  Example 73
2 - (2-四氢呋喃）甲氨基 -4- (1_ (3， 6， 6_三甲基 -4-氧- 4, 5， 6， 7-四氢吲唑)）苯甲酰 胺 2-[(Tetrahydro-furan-2-ylmethyl) -amino] -4- (3, 6， 6 - trimethyi-4 oxo- 2-(2-tetrahydrofuran)methylamino-4-(1_(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide 2-[( Tetrahydro-furan-2-ylmethyl) -amino] -4- (3, 6, 6 - trimethyi-4 oxo-
4, 5， 6， 7-tetrahydro-indazol-l-yl) -benzami de的合成。 (结构式 I - 73) Synthesis of 4, 5, 6, 7-tetrahydro-indazol-l-yl) -benzami de. (Structure I - 73)
Figure imgf000067_0001
Figure imgf000067_0001
合成方法同实施例 3，产率 49%，熔点 107- 109 °C; 'HNMR (500MHz, CDC13)， 6(ppm)： 6.64-7.69 (m, 3H), 3.98 (m, 1H), 3.75(L, 2H)， 3.19 (d, 2H), 2.79 (s, 3H), 2.47(s, 2H)， 2.31(s, 2H)， 1.81-1.85 (ra, 4H), 1.13(s， 6H)； FAB- MS ra/z: 397.2 ； 元 素分析： 计算值 C 66.64， H， 7.12, N 14.13； 测定值 C 66.70, H 7.28, N 14.34。 The synthesis was carried out in the same manner as in Example 3, yield 49%, melting point 107-109 ° C; 'HNMR (500 MHz, CDC1 3 ), 6 (ppm): 6.64-7.69 (m, 3H), 3.98 (m, 1H), 3.75 (L, 2H), 3.19 (d, 2H), 2.79 (s, 3H), 2.47(s, 2H), 2.31(s, 2H), 1.81-1.85 (ra, 4H), 1.13(s, 6H); FAB-MS ra/z: 397.2; calcd for C 66.64, H, 7.12, N 14.13;
对比例 1  Comparative example 1
按照美国专利 US6716856中实施例 3制备的化合物 Al。  The compound Al prepared in accordance with Example 3 of U.S. Patent No. 6,716,856.
对比例 2  Comparative example 2
按照美国专利 US6716856中实施例 14制备的化合物 A2。  Compound A2 was prepared according to Example 14 of U.S. Patent No. 6,716,856.
三、 本发明化合物在药学上可接受的盐的制备方法。  3. A process for the preparation of a pharmaceutically acceptable salt of a compound of the invention.
实施例 74  Example 74
制备实施例 14的化合物 2- (4-羟基环己氨基） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚））苯甲酰胺的盐酸盐。  Preparation of the compound of Example 14 2-(4-hydroxycyclohexylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole) The hydrochloride salt of benzamide.
取 2_ (4-羟基环己氨基） -4- (1- (3， 6, 6-三甲基 -4-氧- 4, 5， 6， 7-四氢吲哚）） 苯甲酰胺 0.50克溶解于 70毫升乙酸乙酯中， 冰浴下通入干燥的盐酸气， 搅拌 5-20分 钟后除去溶剂得白色固体产物。  Take 2_(4-hydroxycyclohexylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzamide 0.50 g Dissolved in 70 ml of ethyl acetate, and dried with hydrochloric acid under ice-cooling. After stirring for 5-20 minutes, solvent was evaporated to give a white solid.
实施例 75至实施例 87为本发明的实施例 1至实施例 13的化合物的盐酸盐的制备， 制备方法同实施例 74。 Examples 75 to 87 are the preparation of the hydrochloride salt of the compound of Examples 1 to 13 of the present invention, The preparation method was the same as in Example 74.
实施例 88至实施例 146为本发明的实施例 15至实施例 73的化合物的盐酸盐的制 备， 制备方法同实施例 74。  Examples 88 to 146 The preparation of the hydrochloride salt of the compound of Example 15 to Example 73 of the present invention was carried out in the same manner as in Example 74.
实施例 147  Example 147
制备 2- (4 -羟基环己氨基) -4- ( 1- (3， 6， 6-三甲基 -4-氧- 4， 5, 6， 7 -四氢吲哚）) 苯甲酰胺对甲苯磺酸盐。  Preparation of 2-(4-hydroxycyclohexylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole)) benzamide Tosylate.
取 2- (4 -羟基环己氨基) -4- ( 1- ( 3, 6， 6 -三甲基- 4-氧- 4， 5, 6， 7_四氢吲哚）) 苯甲酰胺 0. 50克溶解于 75毫升乙酸乙酯中， 冰浴下加入 1一 2倍当量的对甲苯磺酸， 搅拌 5-20分钟后除去溶剂得白色固体产物。  Take 2-(4-hydroxycyclohexylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6,7_tetrahydroindole))benzamide 0 50 g was dissolved in 75 ml of ethyl acetate, and 1-2 times equivalent of p-toluenesulfonic acid was added in an ice bath. After stirring for 5-20 minutes, the solvent was removed to give a white solid product.
实施例 148至实施例 160为本发明的实施例 1至实施例 13的化合物的对甲苯磺酸 盐的制备， 制备方法同实施例 147。  Examples 148 to 160 are the preparations of p-toluenesulfonate of the compounds of Examples 1 to 13 of the present invention, which were prepared in the same manner as in Example 147.
实施例 161至实施例 219为本发明的实施例 15至实施例 73的化合物的对甲苯磺酸 盐的制备， 制备方法同实施例 147。  Examples 161 to 219 The preparation of p-toluenesulfonate of the compounds of Examples 15 to 73 of the present invention was carried out in the same manner as in Example 147.
实施例 220  Example 220
制备 2- (4-羟基环己氨基） -4- ( 1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6, 7 -四氢吲哚）) 苯甲酰胺酒石酸盐。  Preparation of 2-(4-hydroxycyclohexylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole)) benzamide tartaric acid salt.
取 2- (4-羟基环己氨基） -4- ( 1- (3, 6, 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚）） 苯甲酰胺 0. 55克溶解于 90毫升乙酸乙酯中， 冰浴下加入 1一 2倍当量的酒石酸， 搅拌 5-20分钟后除去溶剂得白色固体产物。  Take 2-(4-hydroxycyclohexylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide 0 55 g was dissolved in 90 ml of ethyl acetate, and 1-2 times equivalent of tartaric acid was added under ice bath. After stirring for 5-20 minutes, the solvent was removed to give a white solid product.
实施例 221至实施例 233为本发明的实施例 1至实施例 13的化合物的酒石酸盐的 制备， 制备方法同实施例 220。  Examples 221 to 233 The preparation of the tartrate salt of the compounds of Examples 1 to 13 of the present invention was carried out in the same manner as in Example 220.
实施例 234至实施例 292为本发明的实施例 15至实施例 73的化合物的酒石酸盐的 制备， 制备方法同实施例 220。  Examples 234 to 292 The preparation of the tartrate salt of the compound of Example 15 to Example 73 of the present invention was carried out in the same manner as in Example 220.
实施例 293  Example 293
制备 2- (4 -羟基环己氨基) -4- ( 1- ( 3, 6， 6-三甲基 -4-氧- 4， 5， 6， 7 -四氢吲哚）) 苯甲酰胺柠檬酸盐。 一  Preparation of 2-(4-hydroxycyclohexylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole)) benzamide lemon Acid salt. One
取 2-（4-羟基环己氨基） -4- ( 1- ( 3, 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚）） 苯甲酰胺 0. 50克溶解于 80毫升乙酸乙酯中， 冰浴下加入 1一 2倍当量的柠檬酸， 搅拌 5-20分钟后除去溶剂得白色固体产物。  Take 2-(4-hydroxycyclohexylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzamide0 50 g was dissolved in 80 ml of ethyl acetate, and 1-2 times equivalent of citric acid was added under ice bath. After stirring for 5-20 minutes, the solvent was removed to give a white solid product.
实施例 294至实施例 306为本发明的实施例 1至实施例 13的化合物的柠檬酸盐的 制备， 制备方法同实施例 293。 实施例 307至实施例 365为本发明的实施例 15至实施例 73的化合物的柠檬酸盐的 制备， 制备方法同实施例 293。 Examples 294 to 306 are the preparations of the citrates of the compounds of Examples 1 to 13 of the present invention, which are prepared in the same manner as in Example 293. Examples 307 to 365 are the preparations of the citrates of the compounds of Examples 15 to 73 of the present invention, which were prepared in the same manner as in Example 293.
实施例 366  Example 366
制备 2- (4 -羟基环己氨基） -4- ( 1- (3， 6, 6-三甲基 -4 -氧- 4, 5， 6， 7-四氢吲哚）） 苯甲酰胺琥珀酸盐。  Preparation of 2-(4-hydroxycyclohexylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole)) benzamide amber Acid salt.
取 2- (4 -羟基环己氨基) -4- ( 1- ( 3, 6， 6-三甲基 -4-氧- 4， 5, 6， 7_四氢吲哚）) 苯甲酰胺 0. 55克溶解于 70毫升乙酸乙酯中， 冰浴下加入 1一 2倍当量的琥珀酸， 搅拌 5-20分钟后除去溶剂得白色固体产物。  Take 2-(4-hydroxycyclohexylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzamide0 55 g was dissolved in 70 ml of ethyl acetate, and 1-2 times equivalent of succinic acid was added under ice bath. After stirring for 5-20 minutes, the solvent was removed to give a white solid product.
实施例 367至实施例 379为本发明的实施例 1至实施例 13的化合物的琥珀酸盐的 制备， 制备方法同实施例 366。  Examples 367 to 379 The preparation of the succinate salt of the compounds of Examples 1 to 13 of the present invention was carried out in the same manner as in Example 366.
实施例 380至实施例 438为本发明的实施例 15至实施例 73的化合物的琥珀酸盐的 制备， 制备方法同实施例 366。  Examples 380 to 438 The preparation of the succinate salt of the compound of Example 15 to Example 73 of the present invention was carried out in the same manner as in Example 366.
实施例 439  Example 439
制备 2- (4 -羟基环己氨基) -4- ( 1- ( 3， 6， 6-三甲基 _4 -氧- 4， 5， 6， 7_四氢吲哚）） 苯甲酰胺富马酸盐。 .  Preparation of 2-(4-hydroxycyclohexylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole)) benzamide rich Citrate. .
取 2- (4 -羟基环己氨基) -4- ( 1- (3, 6， 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚）） 苯甲酰胺 0. 48克溶解于 55毫升乙酸乙酯中， 冰浴下加入 1一 2倍当量的富马酸， 搅拌 5-20分钟后除去溶剂得白色固体产物。  Take 2-(4-hydroxycyclohexylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzamide0 48 g was dissolved in 55 ml of ethyl acetate, and 1 to 2 equivalents of fumaric acid were added in an ice bath. After stirring for 5-20 minutes, the solvent was removed to give a white solid.
实施例 440至实施例 452为本发明的实施例 1至实施例 13的化合物的富马酸盐的 制备， 制备方法同实施例 439。  Examples 440 to 452 The preparation of the fumarate of the compounds of Examples 1 to 13 of the present invention was carried out in the same manner as in Example 439.
实施例 453至实施例 511为本发明的实施例 15至实施例 73的化合物的富马酸盐的 制备， 制备方法同实施例 439。  Examples 453 to 511 The preparation of the fumarate salt of the compound of Example 15 to Example 73 of the present invention was carried out in the same manner as in Example 439.
实施例 1至实施例 73、 对比例 1以及对比例 2合成的化合物的化学结构、 中文名 称以及英文名称见表 1 序号 结构式 中文名 英文名 实施例 1 2-氯- 4- (1- (3， 6, 6- 2 - chloro- 4- (3, 6, 6-tri 三甲基 -4 -氧 methyl-4-oxo-4, 5， 6, 7- -4, 5, 6, 7-四氢吲 tetrahydro-indazol-1-
Figure imgf000070_0001
唑)）苯氰 yl) -benzonitrile 结构式 I - 01 实施例 2 2 -（1_ (4-甲基哌 2- (4-methyl-piperazin 嗪)） - 4- - (3， 6, 6- -l-yl) -4- (3, 6， 6-trirae 三甲基 -4-氧 thyl-4-oxo-4, 5, 6， 7- te -4, 5, 6， 7-四氢吲 trahydro-indazol-l-ylThe chemical structures, Chinese names and English names of the compounds synthesized in Examples 1 to 73, Comparative Example 1 and Comparative Example 2 are shown in Table 1. No. Structure Chinese name English name Example 1 2-Chloro-4-(1-(3, 6, 6- 2 - chloro- 4- (3, 6, 6-tri trimethyl-4-oxomethyl-4-) Oxo-4, 5, 6, 7- -4, 5, 6, 7-tetrahydroindoletetrahydro-indazol-1-
Figure imgf000070_0001
Oxazole)) phenyl cyanide yl) -benzonitrile Structural Formula I - 01 Example 2 2 -(1_(4-methylpipe2-(4-methyl-piperazinazine)) - 4- - (3, 6, 6- -l -yl) -4- (3, 6, 6-trirae trimethyl-4-oxothyl-4-oxo-4, 5, 6, 7- te -4, 5, 6, 7-tetrahydropurine-trahydro- Indazol-l-yl
0 唑)）苯氰 ) -benzonitrile 结构式 I - 02 0 azole)) phenyl cyanide ) -benzonitrile structural formula I - 02
实施例 3 2 -（1- (4 -甲基哌嗪）） 2- (4-Methyl-piperazin Example 3 2 -(1-(4-Methylpiperazine)) 2- (4-Methyl-piperazin
-4- ( 1- (3， 6， 6 -三甲 -l-yl) -4- (3, 6, 6-trime 基- 4-氧- 4， 5， 6， 7 -四 thy卜 4-oxo- 4， 5， 6, 7-te trahydro-indazol-l-yl -4- ( 1-(3, 6, 6 -trimethyl-l-yl) -4- (3, 6, 6-trimeyl - 4-oxo - 4, 5, 6, 7 - tetrathy 4-oxo - 4, 5, 6, 7-te trahydro-indazol-l-yl
0 氢吲唑））苯甲酰胺 0 hydrocarbazole)) benzamide
结构式 I - 03 ) -benzamide 实施例 4 2- ( 1- (3 -羟基吡咯 2- (3-hydroxy-pyrrol i d 烷基）） -4- ( 1- in-l-yl) -4- (3, 6, 6-tri Structural formula I - 03 ) -benzamide Example 4 2-(3-(3-hydroxy-pyrrolidide alkyl))-4-(1-in-l-yl)-4-(3 , 6, 6-tri
(3， 6， 6-三甲基- 4 - methyl - 4一 oxo—4, 5， 6， 7- 氧- 4， 5， 6， 7-四氢吲 tetrahydro - indol—l-yl(3, 6, 6-trimethyl- 4 - methyl - 4 - oxo-4, 5, 6, 7- oxy - 4, 5, 6, 7-tetrahydroindole tetrahydro - indol-l-yl
' 0 哚））苯氰 ) -benzonitrile 结构式 I - 04 ' 0 哚)) phenyl cyanide ) -benzonitrile structural formula I - 04
0丫 NHf  0丫 NHf
实施例 5 2- ( 1- (3-羟基吡咯 2- (3- Hydroxy- pyrrol id 垸基）） -4- ( 1- in- 1- yl) - 4- (3， 6， 6-triExample 5 2-(1-(3-Hydroxypyrrole 2-(3-Hydroxy- pyrrol id fluorenyl))-4-(1-in- 1-yl) - 4- (3, 6, 6-tri
(3， 6， 6-三甲基- 4- methyl— 4— oxo— 4， 5, 6, 7 - ' 0 氧- 4， 5， 6， 7-四氢吲 tetrahydro— indol—l—yl 结构式 I - 05 哚））苯甲酰胺 ) -benzamide
Figure imgf000071_0001
序号 结构式 中文名 英文名 实施例 11 2- (2- (4-吗啉） 乙 2- (2-Morpholin-4-yl-e 氨基） - 4- ( 1- (3， 6， 6- thylamino) -4- (3, 6, 6-t 三甲基 -4 -氧 riraethyl-4-oxo - 4， 5， 6， - 4, 5， 6， 7_四氢吲 7-tetrahydro-indol-l-
Figure imgf000072_0001
哚））苯甲酰胺 yl) -benzamide (3, 6, 6-trimethyl- 4-methyl-4-oxo-4, 5, 6, 7 - ' 0 oxo-4, 5, 6, 7-tetrahydroindoletetrahydro- indol-l-yl I - 05 哚)) benzoic acid amide) -benzamide
Figure imgf000071_0001
No. Structure Chinese name English name Example 11 2-(2-(4-morpholine)ethyl 2-(2-Morpholin-4-yl-e amino)-4-(1-(3, 6, 6- thylamino) -4- (3, 6, 6-t trimethyl-4 -oxyriraethyl-4-oxo - 4, 5, 6, - 4, 5, 6, 7_tetrahydroindole 7-tetrahydro-indol-l-
Figure imgf000072_0001
哚)) benzamide yl) -benzamide
结构式 I - 11  Structural formula I - 11
实施例 12 2 -（1- (4-氧-哌啶）） 2- (4-0xo-piperidin-l- -4- ( 1- (3, 6， 6 -三甲 yl) -4- (3, 6， 6-trimethy 基一4 -氧- 4， 5， 6， 7 -四 l_4-oxo-4， 5, 6, 7-tetraExample 12 2-(1-(4-oxo-piperidine)) 2-(4-0xo-piperidin-l- -4-( 1-(3, 6, 6-trimethylyl)-4-(3, 6, 6-trimethy base a 4-oxo-4, 5, 6, 7 - four l_4-oxo-4, 5, 6, 7-tetra
' 0 氢吲哚））苯甲酰胺 hydro-indol- 1 - yl) - ben 结构式 1-12 zamide 实施例 13 2-（1- (4-羟基哌啶）） 2- (4-Hydroxy-piperidi '0 hydroquinone)) benzamide hydro-indol- 1 - yl) - ben structural formula 1-12 zamide Example 13 2-(1-(4-hydroxypiperidinyl)) 2- (4-Hydroxy-piperidi
-4- ( 1- (3， 6, 6-三甲 n-l-yl) -4- (3, 6, 6- trim 基- 4-氧- 4， 5， 6， 7 -四 ethyl-4-oxo-4, 5， 6, 7-t  -4- ( 1-(3, 6, 6-trimethyl nl-yl) -4- (3, 6, 6-trimyl 4-oxo-4, 5, 6, 7 - tetraethyl-4-oxo- 4, 5, 6, 7-t
1 0 氢吲哚））苯甲酰胺 etrahydro-indol-l-yl) 结构式 1-13 -benzamide 实施例 14 2-（4-羟基环己氨基） 2- (4-Hydroxy-cyclohex 1 0 hydroquinone)) benzamide etrahydro-indol-l-yl) structural formula 1-13 -benzamide Example 14 2-(4-hydroxycyclohexylamino) 2- (4-Hydroxy-cyclohex
-4- ( 1- (3, 6， 6- ylamino) - 4 - (3， 6, 6-tri 三甲基 -4-氧 -4， 5， 6， methyl- 4- oxo-4, 5, 6， 7— 7 哚））苯甲酰 tetrahydro-indol-l-yl -4- ( 1-(3, 6, 6- ylamino) - 4 - (3, 6, 6-tri trimethyl-4-oxo-4, 5, 6, methyl- 4- oxo-4, 5, 6, 7-7 哚)) benzoyltetrahydro-indol-l-yl
1 0 -四氢吲 1 0 -tetrahydroanthracene
结构式 I - 14 胺 ) -benzamide 实施例 15 r? 2- ( 1- (4- (4-吗啉) 2- (4-Morpholin-4-yl-p 哌啶）） -4- ( 1- iperidin - 1- yl) - 4- (3， 6 Structural Formula I-14 Amine) -benzamide Example 15 r? 2-(1-(4-(4-morpholine) 2-(4-Morpholin-4-yl-p piperidine)-4-( 1- iperidin - 1- yl) - 4- (3, 6
(3， 6， 6-三甲基 - 4- ， 6-trimethyl-4-oxo-4, 氧- 4, 5, 6, 7-四氢吲 5, 6， 7-tetrahydro-indo(3, 6, 6-trimethyl-4-, 6-trimethyl-4-oxo-4, oxy-4, 5, 6, 7-tetrahydroindole 5, 6, 7-tetrahydro-indo
' 0 哚））苯甲酰胺 1-1- yl) -benzamide 结构式 I - 15
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
di ' 0 哚)) benzamide 1-1- yl) -benzamide Structural Formula I - 15
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Di
6, 7- - 4
Figure imgf000076_0001
序号 结构式 中文名 英文名 实施例 36 2_ (2_ ( 1 -吡咯烷基） 2- (2-Pyrrol idin-l-yl- 乙氨基） -4- ( 1- ethylamino) -4_ (3， 6, 6 - (3， 6， 6-三甲基 -4- trimethyl-4 - 0X0—4, 5, 6 氧- 4， 5， 6， 7-四氢吲 , 7-tetrahydro-indazol6, 7- - 4
Figure imgf000076_0001
No. Structure Chinese name English name Example 36 2_ (2_( 1 -pyrrolidinyl) 2- (2-Pyrrol idin-l-yl-ethylamino) -4- ( 1- ethylamino) -4_ (3, 6, 6 - (3, 6, 6-trimethyl-4-trimethyl-4 - 0X0-4, 5, 6 oxo-4, 5, 6, 7-tetrahydroindole, 7-tetrahydro-indazol
0 唑））苯甲酰胺 -1- yl) benzamide 结构式 I - 36 0 azole)) benzamide -1- yl) benzamide structural formula I - 36
实施例 37 2- ( 1-哌嗪） -4- ( 1- 2-Piperazin-l-yl-4- (3 Example 37 2-(1-Piperazin)-4-(1- 2-Piperazin-l-yl-4- (3
(3， 6， 6-三甲基 -4- , 6， 6— trimethyl_4_oxo- 氧- 4， 5， 6， 7_四氢吲 4， 5, 6， 7-tetrahydro-in  (3, 6, 6-trimethyl-4-, 6, 6-trimethyl_4_oxo-oxy- 4, 5, 6, 7_tetrahydroanthracene 4, 5, 6, 7-tetrahydro-in
0 唑）） 苯甲酰胺 dazol-l-yl) -benzamide 结构式 I - 37 实施例 38 0丫 ΝΗ2 2- ( 1- (3-羟基吡咯 2- (3-Hydroxy-pyrrolid 烷基）） -4- ( 1- in- 1- yl) - 4- (3, 6， 6- tri0 azole)) benzamide dazol-l-yl) -benzamide structure I - 37 Example 38 0 丫ΝΗ 2 2- (1-(3-hydroxypyrrole 2-(3-Hydroxy-pyrrolid alkyl)) -4 - ( 1- in- 1- yl) - 4- (3, 6, 6- tri
(3, 6， 6-三甲基 -4- methyl - 4一 oxo—4， 5, 6， 7 - 氧- 4, 5, 6, 7-四氢吲 tetrahydro-indazol-1- 0 唑））苯甲酰胺 yl) -benzamide 结构式 1-38 (3, 6, 6-trimethyl-4-methyl-4-oxo-4, 5, 6, 7-oxo-4, 5, 6, 7-tetrahydro-indazol-1- 0 azole)) Benzoyl yl) -benzamide Structural formula 1-38
实施例 39 0 2- ( 1- (4- (4 -吗啉) 2- (4-Morpholin-4-yl-p 哌啶）） -4- ( 1- iperidin- 1- yl) - 4- (3, 6 (3， 6， 6-三甲基 -4- , 6—trimethyl— 4—oxo— 4， 氧- 4, 5, 6， 7-四氢吲 5， 6, 7-tetrahydro-indaExample 39 0 2-(1-(4-(4- morpholine) 2-(4-Morpholin-4-yl-p piperidine)-4-(1- iperidin- 1- yl) - 4- ( 3, 6 (3, 6, 6-trimethyl-4-, 6-trimethyl-4-oxo-4, oxy-4, 5, 6, 7-tetrahydroindole 5, 6, 7-tetrahydro-inda
' 0 唑））苯甲酰胺 zol-l-yl) -benzamide 结构式 I - 39 '0 oxazole))benzamide zol-l-yl) -benzamide Structural Formula I - 39
实施例 40 2-（1- (3-羟基哌啶）） 2- (3-Hydroxy-piperidi Example 40 2-(1-(3-Hydroxypiperidine)) 2- (3-Hydroxy-piperidi
-4- ( 1- (3， 6, 6-三甲 n_l-yl) -4- (3， 6， 6 - trim 基- 4 -氧 -4， 5， 6， 7-四 ethyl-4-oxo-4, 5， 6， 7 - -4- ( 1-(3, 6, 6-trimethyl n_l-yl) -4- (3, 6, 6 - trim - 4 -oxy - 4 , 5, 6, 7-tetraethyl-4-oxo- 4, 5, 6, 7 -
0 氢吲唑））苯甲酰胺 etrahydro-indazol-l-y 结构式 1-40 1) -benzamide
Figure imgf000078_0001
0 hydrooxazole)) benzamide etrahydro-indazol-ly structural formula 1-40 1) -benzamide
Figure imgf000078_0001
Figure imgf000079_0001
序号 结构式 中文名 英文名 实施例 51 ΟγΝΗ2 2- (4-羟基环己氨基） 4- (2， 2- Dimethyl- 4- 0X0
Figure imgf000079_0001
No. Structure Chinese name English name Example 51 ΟγΝΗ 2 2- (4-hydroxycyclohexylamino) 4- (2, 2-Dimethyl- 4- 0X0
-4- (9 -（2, 2-二甲基 -6-trifluoromethyl-l, - 4 -氧 -6-三氟甲基 2, 3， 4-tetrahydro-carb -1, 2, 3, 4-四氢咔 azol-9-yl) -2- (4-hydro F3C ° 唑）） 苯甲酰胺 xy-cyclohexylamino) - b 结构式 1-51 enzamide -4- (9-(2,2-Dimethyl-6-trifluoromethyl-l, - 4 -oxy-6-trifluoromethyl 2, 3, 4-tetrahydro-carb -1, 2, 3, 4- Tetrahydropurine azol-9-yl) -2- (4-hydro F 3 C ° azole)) benzamide xy-cyclohexylamino) - b structural formula 1-51 enzamide
实施例 52 2-环己氨基 -4- (9- 2- Cyclohexylamino- 4- ( Example 52 2-Cyclohexylamino-4-(9- 2- Cyclohexylamino- 4- (
(2， 2_二甲基 -4 -氧 6， 6- dimethyl - 4- oxo-3— trifluoromethyl-4, 5, 6
Figure imgf000080_0001
-4, 5， 6， 7 -四氢吲 , 7-tetrahydro-indazol 结构式 1-52 唑））苯甲酰胺 -1-yl) -benzamide 实施例 53 2- (4-羟基环己氨基） 2- (4-Hydroxy-cyclohex (2, 2_Dimethyl-4-oxo 6,6- dimethyl - 4-oxo-3—trifluoromethyl-4, 5, 6
Figure imgf000080_0001
-4, 5, 6, 7 -tetrahydroindole, 7-tetrahydro-indazol, formula 1-52, azole)) benzamide-1-yl) -benzamide Example 53 2-(4-hydroxycyclohexylamino) 2- (4-Hydroxy-cyclohex
-4- ( 1- (6， 6-二甲 ylamino) -4— (6， 6- dimet 基- 4-氧- 3-三氟甲基 hyl-4-oxo-3~trifluoro
Figure imgf000080_0002
-4, 5， 6， 7-四氢 Β引 methyl -- 4， 5， 6, 7-tetrah 结构式 I - 53 唑））苯甲酰胺 ydro-indazol-l-yl) -be nzamide 实施例 54 Ν- (2- [1, 2， 3]三氮唑 N- (2- [l, 2, 3]Triazol-l 乙基) - 4 - ( 1- (3， 6， -yl-ethyl) -4- (3, 6, 6-t 6)三甲基 -4-氧- 4， 5， rimethyl-4 - oxo- 4， 5, 6， 6， 7-四氢吲唑））苯 7-tetrahydro-indazol-
Figure imgf000080_0003
甲酰胺 1-yl) -benzamide 结构式 I - 54 -4- ( 1-(6, 6-dimethylylamino) -4-(6, 6-dimetyl-4-oxo-3-trifluoromethylhyl-4-oxo-3~trifluoro
Figure imgf000080_0002
-4, 5, 6, 7-tetrahydroindole methyl - 4, 5, 6, 7-tetrah structural formula I - 53 oxazole)) benzamide ydro-indazol-l-yl) -be nzamide Example 54 Ν - (2- [1, 2, 3] Triazole N- (2- [l, 2, 3] Triazol-l ethyl) - 4 - ( 1- (3, 6, -yl-ethyl) -4 - (3, 6, 6-t 6) trimethyl-4-oxo-4, 5, rimethyl-4 - oxo- 4, 5, 6, 6, 7-tetrahydrocarbazole)) benzene 7-tetrahydro- Indazol-
Figure imgf000080_0003
Formamide 1-yl) -benzamide Structural Formula I - 54
实施例 55 Ν -（2- (4 -吗啉) 乙 N- (2- Morpholin- 4-yl - e 基) - 4- ( 1 -（3， 6， 6) thyl) -4- (3, 6, 6- trimet 三甲基 -4-氧- 4， 5， 6， hyl-4-oxo-4, 5, 6， 7-tet 7-四氢吲唑））苯甲酰 rahydro-indazol-l-yl)Example 55 Ν-(2-(4-morpholine)ethyl N-(2- Morpholin-4-yl-e-yl)-4- 4-(1 -(3, 6, 6) thyl)-4-(3, 6, 6- trimet trimethyl-4-oxo-4, 5, 6, hyl-4-oxo-4, 5, 6, 7-tet 7-tetrahydrocarbazole)) benzoyl rahydro-indazol-l -yl)
0 胺 -benzamide 0 amine -benzamide
结构式 I - 55 序号 结构式 中文名 英文名 实施例 56 N- (4-羟基环己 N- (4-Hydroxy-cyclohex Structural Formula I - 55 No. Structure Chinese name English name Example 56 N- (4-hydroxycyclohexene N- (4-Hydroxy-cyclohex
基)- 4- ( 1- (3， 6， 6) yl) - 4- (3， 6， 6-trimethy 三甲基 -4-氧 -4， 5， 6， l-4—oxo-4， 5， 6， 7- tetra 7 -四氢吲唑））苯甲酰 hydro-indazol-l-yl) - b Base)- 4- (1-(3, 6, 6) yl) - 4- (3, 6, 6-trimethy trimethyl-4-oxo-4, 5, 6, l-4-oxo-4, 5, 6, 7-tetra 7 -tetrahydrocarbazole))benzoyl hydro-indazol-l-yl) - b
0 胺 enzamide 0 amine enzamide
结构式 I - 56  Structural formula I - 56
实施例 57 N- (2- ( 1- (4-羟基哌 N-[2- (4- Hydroxy- pi per 啶）） 乙基) -4- ( 1- idin-l-yl) -ethyl] - 4- (Example 57 N-(2-(4-(Hydroxy-pi)-ethyl)-4-(1-idin-l-yl)-ethyl] - 4- (
(3， 6， 6)三甲基 _4 3， 6， 6-trimethyl-4"Oxo 氧- 4， 5, 6， 7 -四氢 - 4， 5， 6， 7-tetrahydro~i(3, 6, 6) trimethyl _4 3, 6, 6-trimethyl-4"Oxo Oxygen - 4, 5, 6, 7 - tetrahydro - 4, 5, 6, 7-tetrahydro~i
0 吲唑））苯甲酰胺 ndazol-l-yl) - benzamid 结构式 I - 57 e 0 carbazole)) benzamide ndazol-l-yl) - benzamid structural formula I - 57 e
实施例 58 5 -（1- (2， 6, 6 -三甲 5- (2， 6, 6- Trimethyl- 4- 基 -4-氧 -4， 5， 6， 7 -四 oxo-4, 5， 6， 7-tetrahydr 氢吲哚））吡啶- 2 -甲 o- indol- 1 - yl) -pyridin Example 58 5 -(1-(2, 6, 6 -Trimethyl 5-(2,6-6-Trimethyl-4-yl-4-oxo- 4 , 5, 6, 7-tetraoxo-4, 5, 6, 7-tetrahydr hydroquinone)) pyridine-2 - methyl- indol- 1 - yl) -pyridin
0 酰胺 e - 2— caxboxy 1 ic acid 结构式 I - 58 amide 0 amide e - 2— caxboxy 1 ic acid structural formula I - 58 amide
CN CN
实施例 59 2 -漠- 4- ( 1- ( 4-氧 2- Bromo- 4- (4-oxo- 4， 5， Example 59 2 - Desert - 4- ( 1- (4-oxo 2- Bromo- 4- (4-oxo- 4, 5,
-4, 5, 6， 7- 四 氢 吲 6， 7-tetrahydro-indol- p 哚））苯氰 1-yl) "benzonitrile -4, 5, 6, 7- tetrahydroanthracene 6, 7-tetrahydro-indol- p 哚)) phenyl cyanide 1-yl) "benzonitrile
0 0
结构式 1 59 实施例 60 Br 2 -溴- 4- ( 1- ( 4 -氧 2- Bromo- 4 - (4-oxo- 4， 5，  Structural Formula 1 59 Example 60 Br 2 -Bromo-4- (1-( 4 -oxy 2- Bromo- 4 - (4-oxo- 4, 5,
- 4， 5， 6, 7 -四氢吲哚) 6， 7—tetra ydro- indol- eg 甲基）苯氰 1- ylmethyl) -benzonitr o ile  - 4, 5, 6, 7 -tetrahydroanthracene) 6, 7-tetra ydro- indol-eg methyl) phenyl cyanide 1-ylmethyl) -benzonitr o ile
结构式 I - 60 序号 结构式 中文名 英文名 实施例 61 CN 2 -溴- 4- ( 1- (3, 6， 6- 2-Brorao-4- (3， 6, 6-trim 三 甲 基 -4- 氧 ethyl-4-oxo-4, 5, 6， 7—t - 4， 5, 6， 7- 四 氢 吲 etrahydro-indol-l-yl)Structural Formula I - 60 No. Structure Chinese name English name Example 61 CN 2 -Bromo-4- (1-(3, 6, 6- 2-Brorao-4-(3, 6, 6-trim trimethyl-4-oxoethyl-4) -oxo-4, 5, 6, 7-t - 4, 5, 6, 7-tetrahydroindole etrahydro-indol-l-yl)
0 哚)） 苯氰 -benzonitrile 结构式 1-61 实施例 62 ™ 2-溴- 4- ( 1- (3, 6， 6- 2- Bromo-4 -（3， 6, 6-trim 三 甲 基 -4- 氧 ethyl - 4 oxo - 4， 5， 6， 7 t -4， 5， 6， 7 -四氢吲哚) etrahydro-indol-l-ylm0 哚)) phenyl cyanide-benzonitrile Structural Formula 1-61 Example 62 TM 2-Bromo-4-(1-(3, 6, 6- 2- Bromo-4 -(3, 6, 6-trim trimethyl-) 4-oxoethyl - 4 oxo - 4, 5, 6, 7 t -4, 5, 6, 7 -tetrahydroanthracene) etrahydro-indol-l-ylm
0 甲基）苯氰 ethyl) -benzonitrile 结构式 I - 62 实施例 63 2 -溴- 4- (1- (3, 6, 6- 2- Bromo-4 - (3， 6， 6-trim 三甲基 -4 -氧 ethyl-4-oxo-4, 5， 6, 7-t -4, 5， 6, 7-四氢吲 etrahydro-indol-l-yl) 哚）） 苯甲酰胺 -benzamide 0 Methyl) phenyl cyanide ethyl) -benzonitrile Structural Formula I - 62 Example 63 2 -Bromo-4-(1-(3, 6, 6- 2- Bromo-4 - (3, 6, 6-trim trimethyl) -4 - oxoethyl-4-oxo-4, 5, 6, 7-t -4, 5, 6, 7-tetrahydroindole etrahydro-indol-l-yl) 哚)) benzamide-benzamide
0  0
结构式 I - 63  Structural Formula I - 63
实施例 64 CN 2 -溴- 4- ( 1- (3-甲基 2- Bromo-4- (3-methyl-4 Example 64 CN 2 -Bromo-4- (1-(3-methyl 2- Bromo-4-(3-methyl-4)
-4-氧- 4， 5， 6, 7 -四氢 —oxo-4， 5, 6, 7-tetrahyd 吲哚））苯氰 ro-indol 1-yl) -benzon itrile  -4-oxo-4, 5, 6, 7-tetrahydro-oxo-4, 5, 6, 7-tetrahyd 吲哚)) phenyl cyanide ro-indol 1-yl) -benzon itrile
0  0
结构式 1-64  Structure 1-64
实施例 65 Br 2 -溴- 4- ( 1- (3-甲基 2-Bromo-4- (3- methyl_4 Example 65 Br 2 -Bromo-4-(1-(3-methyl 2-Bromo-4-(3-methyl_4)
-4 -氧- 4, 5, 6, 7 -四氢 —oxo-4， 5， 6, 7-tetrahyd 吲哚） 甲基）苯氰 ro-indol-l-ylmethyl) - benzonitri le  -4 - Oxygen - 4, 5, 6, 7 - tetrahydro-oxo-4, 5, 6, 7-tetrahyd 吲哚) methyl) phenyl cyanide ro-indol-l-ylmethyl) - benzonitri le
0  0
结构式 I 65
Figure imgf000083_0001
序号 结构式 中文名 英文名 实施例 71 N- (l- (4- (2 -吡啶) N- (4-Pyridin-2-yl-pip 哌嗪) -4- ( 1- (3， 6， erazin-1-yl) -4- (3, 6， 6 6)三甲基 -4-氧 -4, 5， -triraethyl-4-oxo-4, 5，Structural Formula I 65
Figure imgf000083_0001
No. Structure Chinese name English name Example 71 N-(l-(4-(2-pyridine) N-(4-Pyridin-2-yl-pip piperazine)-4-( 1- (3, 6, erazin- 1-yl) -4- (3, 6, 6 6) trimethyl-4-oxo-4, 5, -triraethyl-4-oxo-4, 5,
1 0 6, 7-四氢吲唑))苯 6， 7-tetrahydro-indazo 结构式 1-71 甲酰胺 1-1-yl) -benzamide 实施例 72 2- (2-四氢呋喃）甲氨 2- [ (Tetrahydro-furan- 基- 4- (1 (3， 6， 6 -三 2- ylmethyl) -amino] -4- 甲基- 4-氧- 4， 5， 6， (3, 6, 6-trimethyl-4-ox 7-四氢吲哚)）苯甲酰 o-4, 5, 6， 7-tetrahydro- 结构式 I - 72 胺 indol - l-yl) -benzamide 实施例 73 2- (2-四氢呋喃）甲氨 2- [ (Tetrahydro-furan- 基- 4- (1- (3， 6, 6 -三 2- ylmethyl) -amino] - 4 - 甲基- 4-氧- 4， 5， 6， (3, 6， 6-trimethyl-4-ox 7 -四氢吲唑)）苯甲酰 o-4， 5， 6, 7-tetrahydro- 胺 indazol-l-yl) -benzami 结构式 1-73 de 1 0 6, 7-tetrahydrocarbazole)) benzene 6,7-tetrahydro-indazo Structural formula 1-71 Formamide 1-1-yl) -benzamide Example 72 2-(2-tetrahydrofuran)methylammonium 2- [ ( Tetrahydro-furan-yl- 4- (1,3,6-6-tri 2-ylmethyl)-amino]-4-methyl-4-oxo-4, 5, 6, (3, 6, 6-trimethyl- 4-ox 7-tetrahydroindole))benzoyl o-4, 5, 6, 7-tetrahydro- structural formula I - 72 amine indol - l-yl) -benzamide Example 73 2- (2-tetrahydrofuran) Ammonia 2- [(Tetrahydro-furan-yl- 4-(1-(3, 6, 6-tri 2-ylmethyl)-amino] - 4 - methyl-4-oxo-4, 5, 6, (3, 6, 6-trimethyl-4-ox 7 -tetrahydrocarbazole))benzoyl o-4, 5, 6, 7-tetrahydro-amine indazol-l-yl) -benzami Structural formula 1-73 de
对比例 1 p. 3， 6， 6-三甲基 - 1- (2- 3, 6， 6-Trimethyl-l-pyr 吡啶） - 1，5, 6， 7-四氢 idin-2-yl-l, 5， 6， 7-tet 吲唑- 4 -酮 rahydro-indazol-4-one  Comparative Example 1 p. 3, 6, 6-Trimethyl- 1-(2- 3, 6, 6-Trimethyl-l-pyr pyridine) - 1,5, 6, 7-tetrahydroidin-2-yl- l, 5, 6, 7-tet carbazole - 4 -one rahydro-indazol-4-one
0 0
化合物 Al 对比例 2 1- (3- 氨 基 苯 1- (3- Amino- phenyl) -3，  Compound Al Comparative Example 2 1- (3-Aminobenzene 1-(3-Amino-phenyl)-3,
基）- 3， 6, 6-三甲基 6， 6-trimethyl-l, 5， 6， 7 -1, 5, 6， 7 -四氢吲唑 -tetrahydro-indazol-4 Base)- 3, 6, 6-trimethyl 6, 6-trimethyl-l, 5, 6, 7 -1, 5, 6, 7-tetrahydrocarbazole -tetrahydro-indazol-4
0 - 4 -酮 -one 0 - 4 -ketone -one
化合物 A2 应用例：抗肿瘤生物活性 Compound A2 Application example: anti-tumor biological activity
以显微镜下观察细胞的形态变化结合 MTT法测试了本发明的 73个化合物（化合物 1-01至化合物 1-73，见表 1 )，化合物 A1和化合物 A2，以及阳性药物长春新碱对 A549 (肺 癌）， MCF-7 (乳腺癌）， K562 (慢性血癌）, HL60 (急性血癌）， HT-29 (直肠癌）， HeLa (宫颈癌）， HepG2 (肝癌）， PC3 (前列腺癌）等细胞的毒性。  The 73 compounds of the present invention (Compound 1-01 to Compound 1-73, see Table 1), Compound A1 and Compound A2, and the positive drug Vincristine to A549 were tested by microscopic observation of morphological changes of cells in combination with MTT assay. Lung cancer), MCF-7 (breast cancer), K562 (chronic blood cancer), HL60 (acute blood cancer), HT-29 (rectal cancer), HeLa (cervical cancer), HepG2 (liver cancer), PC3 (prostate cancer) and other cells toxicity.
1. 试验目的  Test purpose
测定化合物 1-01至化合物 1-73总共 73个样品对 Λ549, MCF-7, K562, HL60, HT-29, Hela, HepG2, PC3细胞的毒性。  The toxicity of a total of 73 samples of compound 1-01 to compound 1-73 against Λ549, MCF-7, K562, HL60, HT-29, Hela, HepG2, PC3 cells was determined.
2. 样品的溶解  2. Dissolution of the sample
化合物 1-01至化合物 1-73、化合物 A1以及化合物 A2:分别称取上述化合物 4-5 mg 样品， 用少量的 DMS0溶解， 再加 PBS使其浓度为 4-5 mg/mL。  Compound 1-01 to Compound 1-73, Compound A1 and Compound A2: The above compound 4-5 mg sample was weighed, dissolved in a small amount of DMS0, and added to a PBS concentration of 4-5 mg/mL.
阳性对照药长春新碱： 称取 5. Omg长春新碱， 溶于 1 mL PBS终浓度为 5 mg/mL。 Vincristine, a positive control: Weigh 5. Omg of vincristine, dissolved in 1 mL of PBS to a final concentration of 5 mg/mL.
3. 试验材料 3. Test materials
细胞： A549 (肺癌）， MCF-7 (乳腺癌）， K562 (慢性血癌）， HL60 (急性血癌）， HT-29 (直肠癌）， Hela (宫颈癌）， HepG2 (肝癌）， PC3 (前列腺癌）。  Cells: A549 (lung cancer), MCF-7 (breast cancer), K562 (chronic blood cancer), HL60 (acute blood cancer), HT-29 (rectal cancer), Hela (cervical cancer), HepG2 (liver cancer), PC3 (prostate cancer) ).
细胞生长液： 含 10%FBS的 RPMI1640培养液。  Cell growth solution: RPMI1640 medium containing 10% FBS.
细胞维持液： 含 1 %FBS的 RPMI1640培养液 。  Cell maintenance solution: RPMI1640 medium containing 1% FBS.
阳性药物： 长春新碱  Positive drug: vincristine
4. 试验方法  4. Test method
采用 96孔板微量细胞培养法。  A 96-well plate microcell culture method was used.
4. 1 单层细胞制备 （预板）： 将培养瓶中生长良好的细胞用消化液常规消化， 用 RPMI1640生长液制成 1. 58 X 105cell/mL的细胞悬液， 加入 96孔板中， 每孔 ΙΟΟμί, 置 37°C， 5%C02培养箱中孵育 24h， 生长成均勾一致的单层细胞。 4. 1 Monolayer cell preparation (pre-plate): The well-grown cells in the culture flask were routinely digested with digestive juice, and a cell suspension of 1.58 X 10 5 cell/mL was prepared using RPMI1640 growth solution, and added to a 96-well plate. In each well, ΙΟΟμί, placed at 37 ° C, incubated in a 5% CO 2 incubator for 24 h, grew into a uniform monolayer of cells.
4. 2药物稀释： 将各个样品的母液分别用细胞维持液做 10倍、 100倍、 500倍、 1000倍、 5000倍、 10000倍、 100000倍稀释， 得 7个工作浓度梯度。  4. 2 Drug dilution: The mother liquor of each sample was diluted 10 times, 100 times, 500 times, 1000 times, 5000 times, 10000 times, 100,000 times with the cell maintenance solution, and 7 working concentration gradients were obtained.
4. 3加样： 弃微孔中生长液， 加入上述已稀释好的样品溶液， 每孔 ΙΟΟμί, 每个 浓度设 3个复孔， 同时设 Η行为正常细胞对照 （加入无药细胞维持液 ΙΟΟμΐν孔）组， 置 37°C， 5 %C02培养箱中继续培养。 4. 3 Adding the sample: Discard the growth solution in the microwell, add the above diluted sample solution, ΙΟΟμί per well, set 3 replicate wells per concentration, and set the normal cell control for Η behavior (add the drug-free cell maintenance solution ΙΟΟμΐν The wells were placed in a 37 ° C, 5 % CO 2 incubator for further culture.
4. 4结果观察： 每天观察细胞生长情况， 连续观察 48h。  4. 4 Results observation: Cell growth was observed every day for 48 hours.
4. 5 MTT法： 48小时后， 加入 5%的 MTT， 每孔 10 μί， 于 37°C， 5%C02培养箱中 继续培养， 4h后， 弃上清， 加入 10%的 SDS, 每孔 ΙΟΟ μί, 过夜， 酶标读数仪比色（λ =570nm), 测吸光度 A值并计算药物对被筛选细胞的抑制率。 被筛选细胞存活率 (%) = (药物组 A值 /细胞对照组 A值) X100%， 抑制率（％) =1—存活率。 按 Reed-Muench方 法计算细胞的半数抑制浓度（IC5„)。 4. 5 MTT method: After 48 hours, add 5% MTT, 10 μί per well, continue to culture at 37 ° C, 5% CO 2 incubator, 4 h, discard the supernatant, add 10% SDS, each ΙΟΟμί, overnight, microbimetric reader colorimetric (λ = 570 nm), absorb the absorbance A value and calculate the inhibition rate of the drug on the screened cells. Screened cell viability (%) = (drug group A value / cell control group A value) X100%, inhibition rate (%) =1 - survival rate. The half-inhibitory concentration (IC 5 „) of the cells was calculated according to the Reed-Muench method.
5. 实验结果  5. Experimental results
(1)按试验方法 4测定的结果显示本发明化合物 1-01至 1-73和阳性对照药长春 新碱对被筛选的肿瘤细胞有显著的抑制生长活性； 但两者之间的效果比较有显著差异 P〈0.05， 说明化合物 1-01至 1-73的抗肿瘤细胞毒性明显高于长春新碱。 结果见表 2， 表 2为本专利化合物（I一 01至 I一 73)对被筛选的肿瘤细胞抑制生长活性的实验数据。  (1) The results of the test method 4 showed that the compounds of the present invention 1-01 to 1-73 and the positive control drug vincristine have significant growth inhibitory activity on the screened tumor cells; Significant difference P < 0.05, indicating that the anti-tumor cytotoxicity of compounds 1-01 to 1-73 was significantly higher than vincristine. The results are shown in Table 2, and Table 2 is the experimental data of the compounds of the present invention (I-01 to I-73) for inhibiting the growth activity of the selected tumor cells.
(2)我们从专利 US6716856中选择了它的实施例 3和实施例 14制备的化合物 A1 和化合物 A2与本专利化合物 1-01至化合物 1-73化合物和阳性药物长春新碱进行了 抗肿瘤细胞毒试验比较两者有显著差异， P<0.01,而且与空白生理盐水组比较两者没有 显著性差异， P〉0.05; 说明化合物 A1和化合物 A2的抗肿瘤细胞活性极低， 和本专利的 化合物相比， 几乎无活性存在。 结果见表 2。  (2) We selected compound A1 and compound A2 prepared in Example 3 and Example 14 from the patent US Pat. No. 6,716,856, and antitumor cells were reacted with the compound of this patent compound 1-01 to compound 1-73 and the positive drug vincristine. The toxicity test showed significant difference between the two, P<0.01, and there was no significant difference between the two groups compared with the blank saline group, P>0.05; indicating that the anti-tumor activity of compound A1 and compound A2 is extremely low, and the compound of this patent In comparison, almost no activity exists. The results are shown in Table 2.
表 2 化合物 IC5n, nM Table 2 Compound IC 5 n, nM
A549 MCF-7 562 HL60 H-29 HeLa HepG2 PC3 实施例 1的  A549 MCF-7 562 HL60 H-29 HeLa HepG2 PC3 Example 1
321 452 257 345 501 356 378 398 化合物 I - 01  321 452 257 345 501 356 378 398 Compound I - 01
实施例 2的  Example 2
356 503 432 357 267 210 421 126 化合物 I - 02  356 503 432 357 267 210 421 126 Compound I - 02
实施例 3的  Example 3
126 145 99.4 105 104 157 102 169 化合物 1-03  126 145 99.4 105 104 157 102 169 Compound 1-03
实施例 4的  Example 4
125 214 89.1 216 168 175 231 157 化合物 1-04  125 214 89.1 216 168 175 231 157 Compound 1-04
实施例 5的  Example 5
16.5 19.6 100 11.5 24.3 88.0 29.1 97 化合物 1-05  16.5 19.6 100 11.5 24.3 88.0 29.1 97 Compound 1-05
实施例 6的  Example 6
123 156 167 39.9 101 21.9 99.6 231 化合物 1-06  123 156 167 39.9 101 21.9 99.6 231 Compound 1-06
实施例 7的  Example 7
551 271 128 125 98.5 97.2 124 183 化合物 1-07  551 271 128 125 98.5 97.2 124 183 Compound 1-07
实施例 8的  Example 8
163 68.8 216 237 194 59.2 67.0 153 化合物 1-08  163 68.8 216 237 194 59.2 67.0 153 Compound 1-08
实施例 9的  Example 9
127 102 16.4 17.2 47.4 83.2 102 285 化合物 1-09  127 102 16.4 17.2 47.4 83.2 102 285 Compound 1-09
实施例 10的 Example 10
167 128 114 18.2 15.1 14.7 195 174 化合物 1-10  167 128 114 18.2 15.1 14.7 195 174 Compound 1-10
实施例 11的 Example 11
127 98 126 23.5 17.6 98.9 125 176 化合物 1-11 ICso, nM 127 98 126 23.5 17.6 98.9 125 176 Compound 1-11 ICso, nM
化合物  Compound
A549 MCF-7 K562 HL60 H-29 HeLa HepG2 PC3 实施例 12的  A549 MCF-7 K562 HL60 H-29 HeLa HepG2 PC3 Example 12
162 149 22.5 98.3 114 18.5 178 194 化合物 [- 12  162 149 22.5 98.3 114 18.5 178 194 Compound [- 12
实施例 13的 Example 13
125 89.5 14.8 10.0 95.5 12.5 80.9 100 化合物 .1-1.3  125 89.5 14.8 10.0 95.5 12.5 80.9 100 Compounds .1-1.3
实施例 14的 Example 14
159 88.4 78.5 92.1 13.9 18.0 45.1 101 化合物 1-14  159 88.4 78.5 92.1 13.9 18.0 45.1 101 Compound 1-14
实施例 15的 Example 15
23.5 13.0 12.2 87.6 58 108 90 71 化合物 1-15  23.5 13.0 12.2 87.6 58 108 90 71 Compound 1-15
实施例 16的 Example 16
135 137 94 34.9 98 .2 89.2 100 54.6 化合物 I - 16  135 137 94 34.9 98 .2 89.2 100 54.6 Compound I - 16
实施例 17的 Example 17
103 25.6 12.4 13.4 18.9 10.9 35.6 70.6 化合物 1-17  103 25.6 12.4 13.4 18.9 10.9 35.6 70.6 Compound 1-17
实施例 18的 Example 18
188 116 275 135 176 99 90 89.9 化合物 1-18  188 116 275 135 176 99 90 89.9 Compound 1-18
实施例 19的 Example 19
35.8 25.6 19.9 18.9 95.9 16.0 77 99 化合物 1-19  35.8 25.6 19.9 18.9 95.9 16.0 77 99 Compound 1-19
实施例 20的 Example 20
31.9 35 .9 75.5 21.8 97.4 102 89.1 105 化合物 I - 20  31.9 35 .9 75.5 21.8 97.4 102 89.1 105 Compound I - 20
实施例 21的 Example 21
53.3 16.9 29.2 12.7 94.7 20.4 11.9 12.1 化合物 1-21  53.3 16.9 29.2 12.7 94.7 20.4 11.9 12.1 Compound 1-21
实施例 22的 Example 22
37.3 21.9 13.6 101 23.3 22.7 12.9 107 化合物 1-22  37.3 21.9 13.6 101 23.3 22.7 12.9 107 Compound 1-22
实施例 23的 Example 23
128 24.5. 15.7 90.6 12.3 19.6 99.2 81.9 化合物 I - 23  128 24.5. 15.7 90.6 12.3 19.6 99.2 81.9 Compound I - 23
实施例 24的 Example 24
125 156 155 165 83 146 119 99.1 化合物 1-24  125 156 155 165 83 146 119 99.1 Compound 1-24
实施例 25的 Example 25
56 104 33.5 15.9 96.9 56.8 107 92.6 化合物 1-25  56 104 33.5 15.9 96.9 56.8 107 92.6 Compound 1-25
实施例 26的 Example 26
15.5 109 15.3 16.9 89.5 154 25.9 91.2 化合物 1-26  15.5 109 15.3 16.9 89.5 154 25.9 91.2 Compound 1-26
实施例 27的 Example 27
164 150 185 166 90.8 175 106 51.8 化合物 I - 27  164 150 185 166 90.8 175 106 51.8 Compound I - 27
实施例 28的 Example 28
108 25.6 28. 16.7 99.5 99.6 87.1 98.5 化合物 1-28  108 25.6 28. 16.7 99.5 99.6 87.1 98.5 Compound 1-28
实施例 29的 Example 29
64 151 134 18.5 11.5 13.8 20.6 208 化合物 1-29  64 151 134 18.5 11.5 13.8 20.6 208 Compound 1-29
实施例 30的 Example 30
130 128 129 145 100 175 98.2 123 化合物 1-30  130 128 129 145 100 175 98.2 123 Compound 1-30
实施例 31的 Example 31
167 215 23.4 198 151 121 100 103 化合物 1-31  167 215 23.4 198 151 121 100 103 Compound 1-31
实施例 32的 Example 32
189 25.6 145 27.9 24.5 43.8 107 158 化合物 I - 32  189 25.6 145 27.9 24.5 43.8 107 158 Compound I - 32
实施例 33的 Example 33
212 135 108 103 99.1 216 154 95.2 化合物 1-33 ICso, nM 212 135 108 103 99.1 216 154 95.2 Compound 1-33 ICso, nM
化合物  Compound
Λ549 MCF-7 K562 HL60 H-29 HeLa HepG2 PC3 实施例 34的  Λ549 MCF-7 K562 HL60 H-29 HeLa HepG2 PC3 Example 34
17.6 25.1 15.0 58.9 88.3 18.9 28.4 18.9 化合物 1-34  17.6 25.1 15.0 58.9 88.3 18.9 28.4 18.9 Compound 1-34
实施例 35的 Example 35
15.2 18.5 26.5 20.2 10.5 22.1 13.2 16.9 化合物 1-35  15.2 18.5 26.5 20.2 10.5 22.1 13.2 16.9 Compound 1-35
实施例 36的 Example 36
82.3 22.2 28.6 113 25.8 100 91.67 115 化合物 1-36  82.3 22.2 28.6 113 25.8 100 91.67 115 Compound 1-36
实施例 37的 Example 37
14.5 12.6 - 98.2 21.6 11.3 16.9 110 109 化合物 I - 37  14.5 12.6 - 98.2 21.6 11.3 16.9 110 109 Compound I - 37
实施例 38的 Example 38
154 161 168 125 157 143 90.39 196 化合物 1-38  154 161 168 125 157 143 90.39 196 Compound 1-38
实施例 39的 Example 39
97.2 34.8 67.5 123 58.6 58.3 92.5 82.7 化合物 1-39  97.2 34.8 67.5 123 58.6 58.3 92.5 82.7 Compound 1-39
实施例 40的 Example 40
98.6 36.7 53.9 14.9 67.7 20.7 91.5 63.2 化合物 1-40  98.6 36.7 53.9 14.9 67.7 20.7 91.5 63.2 Compound 1-40
实施例 41的 Example 41
53.3 157 177 75.3 38.7 22.9 81.4 156 化合物 1-41  53.3 157 177 75.3 38.7 22.9 81.4 156 Compound 1-41
实施例 42的 Example 42
85.2 167 35.6 76.1 56.9 95.2 63.8 179 化合物 1-42  85.2 167 35.6 76.1 56.9 95.2 63.8 179 Compound 1-42
实施例 43的 Example 43
176 182 159 145 176 195 98 123 化合物 I - 43  176 182 159 145 176 195 98 123 Compound I - 43
实施例 44的 Example 44
24.5 25 .4 . 17.8 98.6 23.8 33.8 121 101 化合物 1-44  24.5 25 .4 . 17.8 98.6 23.8 33.8 121 101 Compound 1-44
实施例 45的 Example 45
35.4 26.7 45.9 48.2 89.6 57.4 81.57 18.2 化合物 1-45  35.4 26.7 45.9 48.2 89.6 57.4 81.57 18.2 Compound 1-45
实施例 46的 Example 46
75.1 10.5 15.7 48.8 49.3 37.6 100 19.1 化合物 1-46  75.1 10.5 15.7 48.8 49.3 37.6 100 19.1 Compound 1-46
实施例 47的 Example 47
107 65 59.6 90.1 10.1 54.9 102 103 化合物 1-47  107 65 59.6 90.1 10.1 54.9 102 103 Compound 1-47
实施例 48的 Example 48
42.4 102 105 46.7 95.1 115 90.8 109 化合物 1-48  42.4 102 105 46.7 95.1 115 90.8 109 Compound 1-48
实施例 49的 Example 49
34.7 35.4 95 36.8 59.2 109 71.8 82.8 化合物 1-49  34.7 35.4 95 36.8 59.2 109 71.8 82.8 Compound 1-49
实施例 50的 Example 50
16.8 36.4 15.8 45.5 34.8 81.5 103. 62.6 化合物 1-50  16.8 36.4 15.8 45.5 34.8 81.5 103. 62.6 Compound 1-50
实施例 51的 Example 51
82.2 82.1 218 71.3 87.5 102 93.2 88.4 化合物 1-51  82.2 82.1 218 71.3 87.5 102 93.2 88.4 Compound 1-51
实施例 52的 Example 52
27.3 91.2 48.2 96.2 101 71.7 61.9 90.3 化合物 1-52  27.3 91.2 48.2 96.2 101 71.7 61.9 90.3 Compound 1-52
实施例 53的 Example 53
12.3 34.8 86.4 91.6 81.2 75.3 71.7 89.6 化合物 1-53  12.3 34.8 86.4 91.6 81.2 75.3 71.7 89.6 Compound 1-53
实施例 54的 Example 54
32.4 38.6 63.1 35.7 62.9 85 82.9 100 化合物 1-54  32.4 38.6 63.1 35.7 62.9 85 82.9 100 Compound 1-54
实施例 55的 Example 55
28.9 35.7 67.2 91.2 67.8 112 89.7 23.8 化合物 1-55 化合物 28.9 35.7 67.2 91.2 67.8 112 89.7 23.8 Compound 1-55 Compound
Λ549 MCF-7 Κ562 HL60 II- 29 HeLa HepG2 PC3 实施例 56的  Λ549 MCF-7 Κ562 HL60 II- 29 HeLa HepG2 PC3 Example 56
12.4 102 85.6 38.8 86.4 59.6 92.7 16.3 化合物 1-56  12.4 102 85.6 38.8 86.4 59.6 92.7 16.3 Compound 1-56
实施例 57的 Example 57
76.5 50.7 94.3 42.3 69.7 99.3 90.6 28.5 化合物 1-57  76.5 50.7 94.3 42.3 69.7 99.3 90.6 28.5 Compound 1-57
实施例 58的 Example 58
204 38.9 38.8 125 65.8 55.4 68.5 103 化合物 1-58  204 38.9 38.8 125 65.8 55.4 68.5 103 Compound 1-58
实施例 59的 Example 59
102 110 231 212 109 400 412 231 化合物 I - 59  102 110 231 212 109 400 412 231 Compound I - 59
实施例 60的 Example 60
256 468 456 489 345 412 234 356 化合物 1-60  256 468 456 489 345 412 234 356 Compound 1-60
实施例 61的 Example 61
561 595 196 642 472 450 680 674 化合物 1-61  561 595 196 642 472 450 680 674 Compound 1-61
实施例 62的 Example 62
950 178 210 174 339 117 240 385 化合物 1-62  950 178 210 174 339 117 240 385 Compound 1-62
实施例 63的 Example 63
232 65.8 98.4 247 172 278 176 258 化合物 1-63  232 65.8 98.4 247 172 278 176 258 Compound 1-63
实施例 64的 Example 64
241 128 121 97.4 98.5 248 127 268 化合物 1-64  241 128 121 97.4 98.5 248 127 268 Compound 1-64
实施例 65的 Example 65
671 145 125 103 184 255 128 274 化合物 1-65  671 145 125 103 184 255 128 274 Compound 1-65
实施例 66的 Example 66
187 165 127 93.4 146 138 203 110.36 化合物 1-66  187 165 127 93.4 146 138 203 110.36 Compound 1-66
实施例 67的 Example 67
199 125 138 154 103 204 186 145 化合物 1-67  199 125 138 154 103 204 186 145 Compound 1-67
实施例 68的 Example 68
123 201 35.8 98.1 102 132 122 198 化合物 I - 68  123 201 35.8 98.1 102 132 122 198 Compound I - 68
实施例 69的 Example 69
23 123 164 99.3 111 109 104 156 化合物 1 69  23 123 164 99.3 111 109 104 156 Compound 1 69
实施例 70的 Example 70
137 38.6 97.5 57.8 97.7 63.4 81.8 75.6 化合物 1-70  137 38.6 97.5 57.8 97.7 63.4 81.8 75.6 Compound 1-70
实施例 71的 Example 71
124 87.6 93.9 68.7 112 72.5 58.2 196 化合物 I - 71  124 87.6 93.9 68.7 112 72.5 58.2 196 Compound I - 71
实施例 72的 Example 72
235 98.6 69.3 167 234 69.9 93.6 235 化合物 1-72  235 98.6 69.3 167 234 69.9 93.6 235 Compound 1-72
实施例 73的 Example 73
346 94.9 245 198 321 98.5 389 145 化合物 I - 73  346 94.9 245 198 321 98.5 389 145 Compound I - 73
对比例 1的 ** ** ** 树 ** ** ** of the comparison 1 ** ** tree ** **
〉1000 768 894 〉1000 985 >1000 >1000 >1000 化合物 A1  〉1000 768 894 〉1000 985 >1000 >1000 >1000 Compound A1
对比例 2的 ** ** ** ** ** ** ** **  Comparative Example 2 ** ** ** ** ** ** ** **
>1000 854 >1000 >1000 743 >1000 >1000 >1000 化合物 A2  >1000 854 >1000 >1000 743 >1000 >1000 >1000 Compound A2
阳性对照药 Δ Δ Δ Δ Δ Δ  Positive control drug Δ Δ Δ Δ Δ Δ
340 365Δ 287 226 297 268 269 △ 340 365 Δ 287 226 297 268 269 △
245 长春新碱  245 vincristine
空白生理盐  Blank physiological salt
>ιοοοΑ >ιοοοΑ >ιοοοΑ >ιοοοΑ >ιοοοΑ >ιοοοΑ >ιοοοΑ >ιοοοΑ 水 表 2中 >ιοοο Α >ιοοο Α >ιοοο Α >ιοοο Α >ιοοο Α >ιοοο Α >ιοοο Α >ιοοο Α水 In Table 2
A: 表示空白生理盐水组与化合物 Al、 化合物 A2比较两者没有显著性差异， P>0. 05; **: 表示化合物 Al、 化合物 A2、 空白生理盐水组与本发明化合物 1-01至化合物 1-73 和阳性对照药长春新碱的效果比较两者有显著性差异， P<0. 01；  A: indicates that there is no significant difference between the blank saline group and the compound A1, the compound A2, P>0.05; **: represents the compound A1, the compound A2, the blank saline group and the compound 1-01 to the compound of the present invention. 1-73 and the positive control drug vincristine have a significant difference between the two, P <0.01.
表示化合物 1-01至化合物 1-73与阳性对照药长春新碱效果比较两者有显著性差异， P<0. 05  There is a significant difference between the compounds 1-01 to the compound 1-73 and the positive control drug vincristine, P<0.05
实验中， 所有化合物采用的都是其盐酸盐的形式。 显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本 发明的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可 以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而这 些属于本发明的精神所引伸出的显而易见的变化或变动仍处于本发明的保护范围之中。 工业实用性  In the experiment, all compounds were in the form of their hydrochloride. It is apparent that the above-described embodiments of the present invention are merely illustrative of the present invention and are not intended to limit the embodiments of the present invention. Other variations or modifications of the various forms may be made by those skilled in the art in light of the above description. There is no need and no way to exhaust all of the implementations. It is to be understood that the obvious changes or modifications which come within the spirit of the invention are still within the scope of the invention. Industrial applicability
本发明的化合物在四氢吲哚酮和四氢吲唑酮的 1位上取代有一个芳香环 （如苯环， 吡啶环等)， 同时在芳香环上相对于四氢吲哚酮取代基或四氢吲唑酮取代基的对位上取 代有氨甲酰基（NH2C0-), 取代的氨甲酰基（R-NH- CO- )或氰基（CN)， 在间位上取代有 烷氨基（R- NH-， R2N-: R是 CI- C6取代或不取代的直链或支链的浣基， 环浣基） 或卤 素（C1或 Br)。通过试验比较（见应用例）可知带有这些基团的化合物的抗肿瘤生物活 性明显高于四氢吲哚酮和四氢吲唑酮 1位取代的芳香环上没有取代基团的化合物，并且 还可以看出对位上取代有氨甲酰基（NH2C0-)的化合物的活性又要高于取代有氰基 (CN) 的化合物。  The compound of the present invention is substituted with an aromatic ring (e.g., a benzene ring, a pyridine ring, etc.) at the 1-position of the tetrahydroindanone and the tetrahydrocarbazol, while being substituted on the aromatic ring with respect to the tetrahydrofurfurone substituent or The paraxanyl substituent is substituted with a carbamoyl group (NH2C0-), a substituted carbamoyl group (R-NH-CO-) or a cyano group (CN), which is substituted with an alkylamino group at the meta position ( R-NH-, R2N-: R is a linear or branched fluorenyl group, cyclodecyl) or halogen (C1 or Br) substituted or unsubstituted with CI-C6. By experimental comparison (see application examples), it is known that the antitumor biological activity of the compound having these groups is significantly higher than that of the compound having no substituent group on the aromatic ring of the tetrahydroindanone and the tetrahydrocarbazolone, and It can also be seen that the compound substituted with a carbamoyl group (NH2C0-) in the para position is more active than the compound substituted with a cyano group (CN).

Claims

权利要求 Rights request
1、 一种化合物， 具有下述通式（I ): A compound having the following general formula (I):
Figure imgf000091_0001
其中：
Figure imgf000091_0001
among them:
n表示 0， 1或 2; X表示 N或 C一 Rl ; Y表示 N或 CH; Z表示 N或 C一 R10;  n represents 0, 1 or 2; X represents N or C-Rl; Y represents N or CH; Z represents N or C-R10;
Rl、 R2选择下面两种组合之一： （1 ) R1表示 H、 三氟甲基或烷基， R2表示 H、 三 氟甲基或烷基； （2) R1和 R2共同形成一个芳香环或取代的芳香环；  R1, R2 are selected from one of the following two combinations: (1) R1 represents H, trifluoromethyl or alkyl, R2 represents H, trifluoromethyl or alkyl; (2) R1 and R2 together form an aromatic ring or Substituted aromatic ring;
R3表示 H或烷基， R4表示 H或烷基， R5表示 H或垸基， R6表示 H或烷基， R7表 示 H或垸基， R8表示 H或烷基；  R3 represents H or an alkyl group, R4 represents H or an alkyl group, R5 represents H or a fluorenyl group, R6 represents H or an alkyl group, R7 represents H or a fluorenyl group, and R8 represents H or an alkyl group;
R10、 Rli选择下面两种组合之一： （1 ) R10表示 H、 卤素、 取代的氨基、 杂环或取 代的杂环， R11表示氨甲酰基、 取代的氨甲酰基或氰基； （2) R10和 R11共同形成一个 杂环或取代的杂环；  R10, Rli select one of the following two combinations: (1) R10 represents H, halogen, substituted amino, heterocyclic or substituted heterocyclic ring, R11 represents carbamoyl, substituted carbamoyl or cyano; (2) R10 and R11 together form a heterocyclic ring or a substituted heterocyclic ring;
R12表示 H、 卤素或取代的氨基。  R12 represents H, halogen or substituted amino.
2、 根据权利要求 1所述化合物， 其特征在于： 通式中： n表示 0或 1 ; Y、 Z选择 下面三种组合之一： （1 ) Υ为 Ν， Ζ为 C一 RIO; (2) Y为 CH, Z为 N; (3) ¥为(31， Z为 C— RIO; R3、 R4、 R7、 R8表示 H; R5表示 H或 d- C3的垸基， R6表示 H或 d- C3的院基。 2. A compound according to claim 1, wherein: n represents 0 or 1; Y, Z selects one of the following three combinations: (1) Υ is Ν, Ζ is C-RIO; Y is CH, Z is N; (3) ¥ is (31, Z is C-RIO; R3, R4, R7, R8 are H; R5 is H or d-C 3 thiol, R6 is H or d - C 3 's yard base.
3、 根据权利要求 2所述化合物， 其特征在于： Rl、 R2选择第一种组合； R1表示 H 或垸基， 且该烷基是 CrC3的浣基； R2表示 H、 三氟甲基或垸基， 且该垸基是 d- C3的烷 基。 3. The compound according to claim 2, wherein: Rl, R2 selecting a first composition; Rl represents H or alkyl with, and the alkyl group is 3 CrC Huan group; R2 represents H, methyl or trifluoromethyl Sulfhydryl group, and the fluorenyl group is a d-C 3 alkane Base.
4、 根据权利要求 3所述的化合物， 其特征在于： R1表示 Cr 的烷基， 且该 d-C^ 的烷基是甲基或乙基， R2表示 烷基， 且该 d- (3的垸基是甲基或乙基； R10、 R11 选择第一种组合， 其中的 R10表示卤素， 且 R10所表示的卤素是 C1或 Br; R12表示卤 素， 且 R12所表示的卤素是 C1或 Br。 The compound according to claim 3, wherein R1 represents an alkyl group of Cr, and the alkyl group of the dC^ is a methyl group or an ethyl group, R2 represents an alkyl group, and the d-( 3 fluorenyl group) Is a methyl group or an ethyl group; R10, R11 are the first combination selected, wherein R10 represents a halogen, and the halogen represented by R10 is C1 or Br; R12 represents a halogen, and the halogen represented by R12 is C1 or Br.
5、 根据权利要求 2所述的化合物， 其特征在于： Rl、 R2选择第二种组合， R1和 2可以共同形成的一个芳香环是苯环， 可共同形成的一个取代的芳香环是取代的苯环。  The compound according to claim 2, wherein: R1 and R2 are selected from the second combination, and an aromatic ring which R1 and 2 can form together is a benzene ring, and a substituted aromatic ring which can be formed together is substituted. Benzene ring.
6、 根据权利要求 5所述的化合物， 其特征在于： R1和 R2共同形成一个取代的芳 香环， 且该取代的芳香环是三氟甲基取代的苯环。  The compound according to claim 5, wherein R1 and R2 together form a substituted aromatic ring, and the substituted aromatic ring is a trifluoromethyl-substituted benzene ring.
7、 根据权利要求 2所述的化合物， 其特征在于： R10、 R11选择第二种组合， R10 和 R11可以共同形成的一个杂环是五元杂环，可共同形成的一个取代的杂环是取代的五 元杂环。  7. The compound according to claim 2, wherein R10 and R11 are selected from the second combination, and a heterocyclic ring which R10 and R11 may form together is a five-membered heterocyclic ring, and a substituted heterocyclic ring which can be formed together is Substituted five-membered heterocyclic ring.
8、 根据权利要求 7所述的化合物， 其特征在于： R10和 R11可以共同形成的一个 五元杂环是吡唑， 可以共同形成的一个取代的五元杂环是 5-氨基吡唑。  The compound according to claim 7, wherein a five-membered heterocyclic ring which R10 and R11 may form together is a pyrazole, and a substituted five-membered heterocyclic ring which may be formed together is a 5-aminopyrazole.
9、 根据权利要求 2所述的化合物， 其特征在于： R10、 R11选择第一种组合， R11 表示取代的氨甲酰基， 该氨甲酰基是 N- (2- [1, 2， 3]三氮唑乙基氨甲酰基、 N- (2- (4 -吗 啉-)乙基氨甲酰基、 N- (4-羟基环己基)氨甲酰基、 N- (4-乙酰氧环己基)氨甲酷基、 或 N (2- (1- (4-羟基哌啶）乙基)）氨甲酰基。  The compound according to claim 2, wherein R10 and R11 are the first combination selected, and R11 represents a substituted carbamoyl group which is N-(2-[1, 2, 3] three Azole ethylcarbamoyl, N-(2-(4-morpholine-)ethylcarbamoyl, N-(4-hydroxycyclohexyl)carbamoyl, N-(4-acetoxycyclohexyl)ammonia Mercapto, or N(2-(1-(4-hydroxypiperidinyl)ethyl))carbamoyl.
10、 根据权利要求 2所述的化合物， 其特征在于： R10、 R11选择第一种组合， R10 表示取代的氨基， 该取代的氨基是烷氨基。  The compound according to claim 2, wherein R10 and R11 are the first combination selected, R10 represents a substituted amino group, and the substituted amino group is an alkylamino group.
11、 根据权利要求 10所述的化合物， 其特征在于： R10所表示的烷氨基是环垸氨 基、 支链烷氨基或直链烷氨基。  The compound according to claim 10, wherein the alkylamino group represented by R10 is a cyclodecylamino group, a branched alkylamino group or a linear alkylamino group.
12、 根据权利要求 11所述的化合物， 其特征在于： R10所表示的烷氨基是环己氨 基、 乙氨基、 4-羟基环己氨基、 4-氨基乙酰氧基环己氨基、 2-二乙氨基乙氨基、 2- (4- 吗啉） 乙氨基、 2- ( 1， 2， 3 )三氮唑乙氨基、 2- ( 1- (3, 5-二甲基哌啶）） 乙氨基、 2- ( 1-哌啶） 乙氨基、 2- (卜吡咯院基） 乙氨基、 或（2—四氢呋喃） 甲氨基。  The compound according to claim 11, wherein the alkylamino group represented by R10 is cyclohexylamino group, ethylamino group, 4-hydroxycyclohexylamino group, 4-aminoacetoxycyclohexylamino group, 2-diethyl group. Aminoethylamino, 2-(4-morpholine)ethylamino, 2-(1,2,3)triazoleethylamino, 2-(1-(3,5-dimethylpiperidine))ethylamino, 2-(1-piperidinyl)ethylamino, 2-(bupyrrole)ethylamino, or (2-tetrahydrofuran)methylamino.
13、 根据权利要求 2所述的化合物， 其特征在于： R10、 R11选择第一种组合， R10 表示杂环或取代的杂环，所述的该杂环是单杂环或双杂环，所述的该取代的杂环是取代 的单杂环或取代的双杂环。  The compound according to claim 2, wherein R10 and R11 are the first combination selected, R10 represents a heterocyclic ring or a substituted heterocyclic ring, and the heterocyclic ring is a monoheterocyclic ring or a bicyclic heterocyclic ring. The substituted heterocyclic ring is a substituted monoheterocyclic ring or a substituted bicyclic heterocyclic ring.
14、 根据权利要求 13所述的化合物， 其特征在于： R10表示杂环, 且该杂环是单 杂环或双杂环， 所述的该单杂环是哌嗪或哌啶， 所述的该双杂环是喹啉。 The compound according to claim 13, wherein R10 represents a heterocyclic ring, and the heterocyclic ring is a monoheterocyclic ring or a bicyclic heterocyclic ring, and the monoheterocyclic ring is piperazine or piperidine, The bicyclic heterocycle is quinoline.
15、 根据权利要求 13所述的化合物， 其特征在于： R10表示取代的杂环， 且该取 代的杂环是取代的单杂环或取代的双杂环，所述的该取代的单杂环是取代的哌嗪、取代 的吡咯垸基、 或取代的哌啶， 所述的该取代的双杂环是 6、 7-二甲氧基- 1， 2， 3, 4 -四 氢异喹啉。 The compound according to claim 13, wherein R10 represents a substituted heterocyclic ring, and the substituted heterocyclic ring is a substituted monoheterocyclic ring or a substituted diheterocyclic ring, said substituted monoheterocyclic ring. Is a substituted piperazine, a substituted pyrrolidinyl group, or a substituted piperidine, and the substituted bicyclic heterocycle is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. .
16、 根据权利要求 15所述的化合物， 其特征在于： R10表示的取代的单杂环， 且 该取代的单杂环是取代的哌嗪、取代的吡咯烷基、或取代的哌啶， 所述的该取代的哌嗪 是 4-甲基哌嗪、 4- (2- (4-吗啉） 乙基） 哌嗪、 （4-环戊垸基） 哌嗪、 4- (2-羟乙基） 哌嗪、 或 4- (2-吡啶） 哌嗪， 所述的该取代的吡咯烷基是 3-羟基吡咯烧基， 所述的该 取代的哌啶是 4-氧-哌啶、 4-羟基哌啶、 3—羟基哌啶、 4一氨基乙酰氧基哌啶、 4- (4- 吗啉）哌啶、 4- ( 1-吡咯烷基） 哌啶、 或 4- (2- ( 1-哌啶） 乙氧基） 哌啶。  The compound according to claim 15, wherein R10 represents a substituted monoheterocyclic ring, and the substituted monoheterocyclic ring is a substituted piperazine, a substituted pyrrolidinyl group or a substituted piperidine. The substituted piperazines are 4-methylpiperazine, 4-(2-(4-morpholine)ethyl)piperazine, (4-cyclopentamyl)piperazine, 4-(2-hydroxyethyl) a piperazine, or 4-(2-pyridine) piperazine, the substituted pyrrolidinyl group is a 3-hydroxypyrrole group, and the substituted piperidine is 4-oxo-piperidine, 4 -hydroxypiperidine, 3-hydroxypiperidine, 4-aminoacetoxypiperidine, 4-(4-morpholine)piperidine, 4-(1-pyrrolidinyl)piperidine, or 4-(2-( 1-piperidine) ethoxy) piperidine.
17、 根据权利要求 2所述的化合物， 其特征在于， 通式中： X表示 N; Y、 Ζ选择第 三种组合； Rl、 R2选择第一种组合，且其中的 R2表示 H、三氟甲基或 CrC3的烷基； R10、 R11选择第一种组合； R12表示 H或卤素。 The compound according to claim 2, wherein: X represents N; Y, Ζ selects a third combination; R1, R2 selects the first combination, and wherein R2 represents H, trifluoro Methyl or CrC 3 alkyl; R10, R11 select the first combination; R12 represents H or halogen.
18、根据权利要求 17所述的化合物，其特征在于： R2表示 d- C3的烷基，且该 Cr"C3 的烷基是甲基或乙基； R5、 R6均表示 C「C3的烷基， 且 R5所表示的 C「 C3的焼基是甲基 或乙基， R6所表示的 d- C3的焼基是甲基或乙基； R10表示卤素， 且该卤素是 C1或 Br; R12表示卤素， 且该卤素是 C1或 Br -。 The compound according to claim 17, wherein R 2 represents an alkyl group of d-C 3 and the alkyl group of Cr "C 3 is a methyl group or an ethyl group; and R 5 and R 6 each represent C "C 3 " alkyl, and C "represented by R5 firing group C 3 are methyl or ethyl, d- C R6 firing group represented by 3 are methyl or ethyl; R10 represents halogen, and the halogen is C1 Or Br; R12 represents a halogen, and the halogen is C1 or Br-.
19、 根据权利要求 18 所述的化合物， 其特征在于： 所述的化合物为 2 -氯 - 4 -（1 -（3， 6, 6-三甲基 -4 -氧- 4, 5, 6, 7 -四氢吲唑））苯氰、 2 -溴 4- ( 1- ( 3 -甲基 -4 -氧 -4, 5， 6， 7-四氢吲唑））苯氰、或 2 -溴- 4- ( 1- (3-甲基 -4-氧- 4, 5， 6， 7-四氢吲唑）甲基） 苯氰。  The compound according to claim 18, wherein the compound is 2-chloro-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) phenyl cyanide, 2-bromo 4-(1-(3-methyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) phenyl cyanide, or 2-bromo - 4-(1-(3-methyl-4-oxo-4,5,6,7-tetrahydrocarbazole)methyl)benzonitrile.
20、 根据权利要求 17所述的化合物， 其特征在于： R11表示取代的氨甲酰基， 该 取代的氨甲酰基是 N- (2- [1, 2， 3]三氮唑乙基氨甲酰基、 N- (2- (4-吗啉）乙基氨甲酰基、 N- (4-羟基环己基)氨甲酰基、 N- (4-乙酰氧环己基)氨甲酰基、或 N- (2- (1- (4-羟基哌啶） 乙基)）氨甲酰基。  The compound according to claim 17, wherein R11 represents a substituted carbamoyl group, and the substituted carbamoyl group is N-(2-[1, 2, 3]triazole ethylcarbamoyl group. , N-(2-(4-morpholine)ethylcarbamoyl, N-(4-hydroxycyclohexyl)carbamoyl, N-(4-acetoxycyclohexyl)carbamoyl, or N- (2 - (1-(4-Hydroxypiperidine)ethyl))carbamoyl.
21、 根据权利要求 20所述的化合物， 其特征在于： 所述的化合物为 N- (2- [1， 2, 3] 三氮唑乙基) -4- ( 1- (3， 6， 6)三甲基 -4-氧- 4， 5， 6， 7 -四氢吲唑) )苯甲酰胺、 N- (2- The compound according to claim 20, wherein the compound is N-(2-[1, 2, 3]triazole ethyl)-4-(1-(3, 6, 6) Trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, N-(2-
(4-吗啉） 乙基) 4- ( 1- (3， 6， 6)三甲基 -4-氧- 4， 5， 6， 7 -四氢吲唑））苯甲酰胺、 N- (4-羟基环己基) -4- ( 1- (3， 6， 6)三甲基 -4-氧- 4， 5， 6， 7 -四氢吲唑）)苯甲酰胺、 N- (2- ( 1- (4 -羟基哌啶）) 乙基) - 4- ( 1- (3， 6, 6)三甲基 -4-氧- 4， 5， 6, 7-四氢吲 唑）） 苯甲酰胺、 N- (4-乙酰氧环己基 ) -4- ( 1- (3, 6， 6)三甲基 -4-氧- 4， 5， 6, 7- 四氢吲唑））苯甲酰胺、 或 N -（1- (4- (2-吡啶) 哌嗪） -4- (1- (3， 6， 6)三甲基 -4- 氧- 4， 5， 6， 7 -四氢吲唑) )苯甲酰胺。 (4-morpholine) ethyl) 4-(1-(3, 6, 6)trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, N- ( 4-hydroxycyclohexyl)-4-(1-(3,6,6)trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, N-(2- (1-(4-hydroxypiperidine))ethyl)-4-(1-(3,6,6)trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) Benzene Formamide, N-(4-acetoxycyclohexyl)-4-(1-(3, 6, 6)trimethyl-4-oxo-4, 5, 6, 7- Tetrahydrocarbazole))benzamide, or N-(1-(4-(2-pyridine)piperazine)-4-(1-(3,6,6)trimethyl-4-oxo-4, 5, 6, 7 -tetrahydrocarbazole)) benzamide.
22、 根据权利要求 17所述的化合物， 其特征在于： R10表示取代的氨基， 该取代 的氨基是烷氨基。  The compound according to claim 17, wherein R10 represents a substituted amino group, and the substituted amino group is an alkylamino group.
23、 根据权利要求 22所述的化合物， 其特征在于： R10所表示的烷氨基是环烷氨 基、 支链垸氨基或直链烷氨基。  The compound according to claim 22, wherein the alkylamino group represented by R10 is a cycloalkylamino group, a branched europium group or a linear alkylamino group.
24、 根据权利要求 23所述的化合物， 其特征在于： R10所表示的垸氨基是环己氨 基、 乙氨基、 4-羟基环己氨基、 4-氨基乙酰氧基环己氨基、 2 -二乙氨基乙氨基、 2- (4 - 吗啉） 乙氨基、 2- (1， 2, 3)三氮唑乙氨基、 2- (1- (3， 5-二甲基哌啶）） 乙氨基、 2- (1-哌啶） 乙氨基、 2- (1-吡咯烷基） 乙氨基、 或（2—四氢呋喃） 甲氨基。  The compound according to claim 23, wherein the oxime amino group represented by R10 is cyclohexylamino group, ethylamino group, 4-hydroxycyclohexylamino group, 4-aminoacetoxycyclohexylamino group, 2-diethyl group. Aminoethylamino, 2-(4-morpholine)ethylamino, 2-(1,2,3)triazoleethylamino, 2-(1-(3,5-dimethylpiperidine))ethylamino, 2-(1-Piperidine)ethylamino, 2-(1-pyrrolidinyl)ethylamino, or (2-tetrahydrofuran)methylamino.
25、 根据权利要求 24所述的化合物， 其特征在于： 所述的化合物为 2- (2-二乙氨 基乙氨基） -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑）)苯甲酰胺、 2 -环己氨基 - 4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7 -四氢吲唑)）苯甲酰胺、 2- (2- (1 -哌啶) 乙氨 基） -4- (1- (3,6,6-三甲基 -4-氧- 4， 5， 6, 7 -四氢吲唑）)苯甲酰胺、 2- (2-（1- (3，5- 二甲基哌啶）） 乙氨基） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲唑）)苯甲酰胺、 2- (2 -（1， 2, 3)三氮唑乙氨基) -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5, 6, 7-四氢吲唑）)苯 甲酰胺、 2-环丙烷氨基- 4- (1- (3， 6， 6-三甲基 -4-氧- 4,5,6,7-四氢吲唑））苯甲酰胺、 2- (2- (4-吗啉) 乙氨基） -4- (1- (3,6,6-三甲基 -4-氧- 4,5,6,7-四氢吲唑）)苯甲酰 胺、 2- (4-羟基环己氨基） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑）） 苯甲酰胺、 2- (4-氨基乙酰氧基环己氨基） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑）)苯甲酰胺、 2- (2 - (1 -吡咯烷基) 乙氨基） -4- (1- (3,6,6-三甲基 -4- 氧 -4， 5, 6, 7-四氢吲唑））苯甲酰胺、 2-环己氨基- 4- (9- (2， 2_二甲基 -4-氧- 3-三氟甲 基- 4， 5, 6， 7-四氢吲唑）)苯甲酰胺、 2 - (4 -羟基环己氨基) -4- (1- (6， 6-二甲基- 4- 氧 -3-三氟甲基- 4， 5， 6， 7-四氢吲唑）） 苯甲酰胺、 或 2- (2-四氢呋喃）甲氨基 -4-（1-(3，6，6-三甲基-4-氧-4， 5, 6， 7-四氢吲唑)）苯甲酰胺。  The compound according to claim 24, wherein the compound is 2-(2-diethylaminoethylamino)-4-(1-(3,6,6-trimethyl-4-) Oxygen-4,5,6,7-tetrahydrocarbazole))benzamide, 2-cyclohexylamino-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2-(2-(1-piperidyl)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4 , 5, 6, 7 -tetrahydrocarbazole))benzamide, 2-(2-(1-(3,5-dimethylpiperidine))ethylamino)-4-(1-(3, 6 , 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(1,2,3)triazoleethylamino)-4- (1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-cyclopropanylamino-4-(1-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(4-morpholine)ethylamino)-4-(1- (3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(4-hydroxycyclohexylamino)-4-(1-( 3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) benzene Formamide, 2-(4-aminoacetoxycyclohexylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole) Benzoylamide, 2-(2-(1-pyrrolidinyl)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7-four Hydrocarbazole))benzamide, 2-cyclohexylamino-4-(9-(2,2-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro) Carbazole))benzamide, 2-(4-hydroxycyclohexylamino)-4-(1-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4, 5, 6, 7-tetrahydrocarbazole)) benzamide, or 2-(2-tetrahydrofuran)methylamino-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7) - tetrahydrocarbazole)) benzamide.
26、 根据权利要求 17所述的化合物， 其特征在于： R10表示杂环或取代的杂环， 所述的该杂环是单杂环或双杂环， 所述的该取代的杂环是取代的单杂环或取代的双杂 环。  The compound according to claim 17, wherein R10 represents a heterocyclic ring or a substituted heterocyclic ring, and the heterocyclic ring is a monoheterocyclic ring or a bicyclic heterocyclic ring, and the substituted heterocyclic ring is substituted. Monoheterocyclic or substituted bicyclic heterocycles.
27、 根据权利要求 26所述的化合物， 其特征在于： R10表示杂环， 且该杂环是单 杂环或双杂环， 所述的该单杂环是哌唪或哌啶， 所述的该双杂环是喹啉。  The compound according to claim 26, wherein R10 represents a heterocyclic ring, and the heterocyclic ring is a monoheterocyclic ring or a bicyclic heterocyclic ring, and the monoheterocyclic ring is piperidine or piperidine, The bicyclic heterocycle is quinoline.
28、 根据权利要求 27所述的化合物， 其特征在于： 所述的化合物为 2- (1-哌嗪） -4- ( 1- (3， 6， 6_三甲基 -4 -氧- 4, 5， 6, 7-四氢吲唑））苯甲酰胺、 或 2- (1 -哌啶 ) - 4- (1- (3， 6， 6-三甲基 _4 -氧- 4, 5， 6， 7 -四氢吲唑) )苯甲酰胺。 The compound according to claim 27, wherein the compound is 2-(1-piperazine) -4- ( 1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) benzamide, or 2-(1-piperidine)-4 - (1-(3, 6, 6-trimethyl_4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) benzamide.
29、 根据权利要求 26所述的化合物， 其特征在于： R10表示取代的杂环， 且该取 代的杂环是取代的单杂环或取代的双杂环，所述的该取代的单杂环是取代的哌嗪、取代 的吡咯垸基、 或取代的哌啶， 所述的该取代的双杂环是 6、 7-二甲氧基 -1， 2, 3, 4-四 氢异喹啉、从而相应的化合物是 2- (2- (6, 7-二甲氧基- 1, 2， 3, 4-四氢异喹啉）） -4- ( 1- The compound according to claim 26, wherein R10 represents a substituted heterocyclic ring, and the substituted heterocyclic ring is a substituted monoheterocyclic ring or a substituted diheterocyclic ring, said substituted monoheterocyclic ring. Is a substituted piperazine, a substituted pyrrolidinyl group, or a substituted piperidine, and the substituted bicyclic heterocycle is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. The corresponding compound is 2-(2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline)-4-(1-
(3， 6, 6 -三甲基- 4-氧 -4, 5, 6, 7-四氢吲唑）） 苯甲酰胺。 (3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) Benzamide.
30、 根据权利要求 29所述的化合物， 其特征在于： R10表示取代的单杂环， 且该 取代的单杂环是取代的哌嗪、取代的吡咯浣基、或取代的哌啶， 所述的该取代的哌嗪是 4 -甲基哌嗪、 4- (2- (4-吗啉） 乙基） 哌嗪、 （4-环戊烷基） 哌嗪、 4- (2羟乙基） 哌 嗪、 或 4- (2-吡啶） 哌嗪， 所述的该取代的吡咯烷基是 3-羟基吡咯垸基， 所述的该取 代的哌啶是 4-氧-哌啶、 4-羟基哌啶、 3—羟基哌啶、 4一氨基乙酰氧基哌啶、 4- (4 -吗 啉） 哌啶、 4- ( 1-吡咯烧基） 哌啶、 或 4_ (2- ( 1-哌啶） 乙氧基） 哌啶。  30. The compound according to claim 29, wherein: R10 represents a substituted monoheterocyclic ring, and the substituted monoheterocyclic ring is a substituted piperazine, a substituted pyrrolidinyl group, or a substituted piperidine, The substituted piperazine is 4-methylpiperazine, 4-(2-(4-morpholine)ethyl)piperazine, (4-cyclopentyl)piperazine, 4-(2-hydroxyethyl) Piperazine, or 4-(2-pyridine) piperazine, the substituted pyrrolidinyl group is a 3-hydroxypyrrole group, and the substituted piperidine is 4-oxo-piperidine, 4-hydroxyl Piperidine, 3-hydroxypiperidine, 4-aminoacetoxypiperidine, 4-(4-morpholine)piperidine, 4-(1-pyrrolidinyl)piperidine, or 4-(2-(1-pipeper) Acridine) Ethoxy) piperidine.
31、 根据权利要求 30所述的化合物， 其特征在于： 所述的化合物为 2- (1- (4-甲基 哌嗪)）-4- (1- (3， 6， 6-三甲基 -4 -氧- 4， 5， 6， 7_四氢吲唑)）苯氰、 2- ( 1- (4-甲基哌嗪）） -4- (1- (3， 6， 6-三甲基 -4 -氧- 4, 5， 6, 7 -四氢吲唑））苯甲酰胺、 2- ( 1- (4-环戊烷基） 哌嗪） -4- ( 1- (3， 6， 6-三甲基 -4-氧 -4, 5， 6, 7 四氢吲唑）)苯甲酰胺、 2- ( 1-（4- (2- The compound according to claim 30, wherein the compound is 2-(1-(4-methylpiperazine)-4-(1-(3,6,6-trimethyl). -4 -oxo-4, 5, 6, 7_tetrahydrocarbazole)) phenyl cyanide, 2-(1-(4-methylpiperazine))-4-(1-(3, 6, 6-three Methyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-cyclopentanyl)piperazine)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7 tetrahydrocarbazole)) benzamide, 2- ( 1-(4- (2-
( 1 -哌啶） 乙氧基） 哌啶）） -4- ( 1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑）)苯甲 酰胺、 2- ( 1- (4-氧-哌啶）） -4- ( 1- (3, 6, 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑）)苯甲 酰胺、 2- ( 1- (4- (2-羟乙基)哌嗪）） -4- ( 1- ( 3， 6， 6_三甲基 -4 -氧- 4, 5， 6， 7-四氢吲 唑））苯甲酰胺、 2_ α- ( 4- ( 1-吡咯烷基 )哌啶）） - 4- ( 1- ( 3, 6， 6 -三甲基- 4-氧- 4, 5， 6， 7 - 四氢吲唑））苯甲酰胺、 2- ( 1- (4- (2- (4-吗啉） 乙基） 哌嗪）） -4- ( 1- (3， 6， 6-三 甲基- 4-氧- 4， 5， 6, 7-四氢吲唑））苯甲酰胺、 2- ( 1- (4-羟基哌啶）） -4- ( 1- (3，6，6_ 三甲基 -4-氧- 4, 5, 6, 7-四氢吲唑））苯甲酰胺、 2- ( 1- (4-氨基乙酰氧基哌啶）） -4- ( 1-(1 - piperidine) ethoxy) piperidine)) -4- ( 1-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzene Formamide, 2-(1-(4-oxo-piperidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole) )) benzamide, 2-(1-(4-(2-hydroxyethyl)piperazine))-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2_α-(4-(1-pyrrolidinyl)piperidine)) 4- (1-( 3, 6, 6 -trimethyl- 4- Oxygen-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-(2-(4-morpholine)ethyl)piperazine))-4- ( 1- (3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-hydroxypiperidinyl)-4-( 1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-aminoacetoxypiperidine)) -4- ( 1-
(3, 6， 6 -三甲基- 4-氧- 4, 5， 6， 7-四氢吲唑））苯甲酰胺、 2- ( 1- (3 -羟基吡咯垸基）) - 4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(3-hydroxypyrrolidinyl))-4-
( 1- (3， 6， 6-三甲基 -4 -氧- 4, 5， 6, 7-四氢吲唑）)苯甲酰胺、 2 - ( 1- (4- (4-吗啉） 哌 啶）） -4- ( 1- (3, 6, 6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲唑））苯甲酰胺、 2- ( 1- (3 -羟基 哌啶）） -4- ( 1- (3， 6， 6 -三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑）)苯甲酰胺、 或 2- ( 1- (4 -(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-(4-morpholine) Piperidine)) -4- (1-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2- (1- (3) -hydroxypiperidine))-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, or 2-(1 - (4 -
(2 -吡啶) 哌嗪）） -4- ( 1- (3， 6， 6-三甲基 -4-氧- 4, 5， 6， 7-四氢吲唑））苯甲酰胺。 (2-pyridine) piperazine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide.
32、 根据权利要求 2所述的化合物， 其特征在于， 通式中： η表示 0; X表示 Ν; Υ、 Ζ选择第三种组合； Rl、 R2选择第一种组合， 且其中的 R2表示垸基、 该垸基为甲基； R5、 R6均表示 C,- 0；3的烷基， 且 R5、 R6均为甲基； R10、 Rll选择第二种组合， 且 R10 和 R11可共同形成的一个杂环是吡唑， 可共同形成的一个取代的杂环是 5-氨基吡唑； R12表示 Ho 32. The compound according to claim 2, wherein: η represents 0; X represents Ν; Υ, Ζ selects a third combination; R1, R2 selects a first combination, and wherein R2 represents a mercapto group, the mercapto group being a methyl group; R5, R6 each represent C, - 0; 3 alkyl, and R5, R6 are all methyl; R10, Rll select the second combination, and a heterocyclic ring which R10 and R11 can form together is pyrazole, which can be One substituted heterocyclic ring formed is 5-aminopyrazole; R12 represents Ho
33、 根据权利要求 32所述的化合物， 其特征在于:所述的化合物为 1- (6- (3-氨 基- 1H -吲唑）） _3， 6， 6-三甲基 - 1, 5， 6， 7-四氢吲唑- 4-酮。  33. The compound according to claim 32, wherein the compound is 1-(6-(3-amino-1H-indazole))_3,6,6-trimethyl- 1, 5, 6, 7-tetrahydrocarbazole-4-one.
34、 根据权利要求 2所述的化合物， 其特征在于， 通式中： n表示 0; X示表 N; Y、 Ζ选择第一种组合； Rl、 R2选择第一种组合， 且其中的 R2表示烷基、且该垸基为甲基； R5、 R6均表示 Cr C3的浣基， 且 R5、 R6均为甲基； R10、 Rll选择第一种组合， 且 R10 表示 H， Rll表示氨甲酰基； R12表示取代的氨基。 The compound according to claim 2, wherein: n represents 0; X represents Table N; Y, Ζ selects the first combination; R1, R2 selects the first combination, and wherein R2 Represents an alkyl group, and the fluorenyl group is a methyl group; R5 and R6 each represent a fluorenyl group of C r C 3 , and R 5 and R 6 are both methyl groups; R 10 and R ll are selected as the first combination, and R 10 represents H, and R 11 represents Carbamoyl; R12 represents a substituted amino group.
35、 根据权利要求 34所述的化合物， 其特征在于： R12所表示的取代的氨基是 4 一羟基哌啶或 4- (2-羟乙基） 哌嗪， 从而相应的化合物是 4- ( 1- (4-羟基哌啶）） -6- The compound according to claim 34, wherein the substituted amino group represented by R12 is 4-hydroxypiperidine or 4-(2-hydroxyethyl)piperazine, whereby the corresponding compound is 4-(1) - (4-hydroxypiperidine)) -6-
( 1- (3, 6, 6-三甲基 -4 -氧- 4， 5， 6， 7-四氢吲唑）)烟碱酰胺、或 4- ( 1- (4- (2 -羟乙基) 哌嗪）） -6- ( 1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑）)烟碱酰胺。 ( 1- (3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) Nicotinamide, or 4-(1-(4-(2-hydroxyl) Base) Piperazine)) -6- (1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) Nicotinamide.
36、 根据权利要求 2所述的化合物， 其特征在于， 通式中： X表示 C一 Rl ; Y、 Ζ选 择第三种组合； Rl、 R2选择第一种组合， 且其中 R1表示 H或 C,- C:i ½院基， R2表示 H 或 (：1-(3的烷基； R10、 Rll选择第一种组合。 36. The compound according to claim 2, wherein: X represents C-R1; Y, Ζ selects a third combination; R1, R2 selects the first combination, and wherein R1 represents H or C , - C : i 1⁄2 yard base, R2 represents H or (: 1-( 3 alkyl; R10, Rll choose the first combination.
37、 根据权利要求 36所述的化合物， 其特征在于： Rl、 R2、 R5、 R6均表示 d-C3 的烷基， 且 Rl所表示的(^- C3的垸基是甲基或乙基， R2所表示的(^- C3的烷基是甲基或 乙基， R5所表示 d- C3的烷基是甲基或乙基， R6所表示的(「 C3的烷基是甲基或乙基； R10、 R12均表示卤素， R10所表示的卤素是 C1或 Br， R12所表示的卤素是 C1或 Br。 The compound according to claim 36, wherein R1, R2, R5 and R6 each represent an alkyl group of dC 3 , and the fluorenyl group of (^-C 3 represented by R1 is a methyl group or an ethyl group, The alkyl group of (^-C 3 represented by R2 is a methyl group or an ethyl group, and the alkyl group of d-C 3 represented by R5 is a methyl group or an ethyl group, and is represented by R6 ("C 3 alkyl group is a methyl group) Or ethyl; R10, R12 each represent a halogen, the halogen represented by R10 is C1 or Br, and the halogen represented by R12 is C1 or Br.
38、 根据权利要求 36所述的化合物， 其特征在于： 所述的化合物为 2-溴 -4- ( 1- (4 -氧- 4， 5， 6， 7_四氢吲哚））苯氰、 2-溴 -4- ( 1- (4-氧- 4， 5, 6， 7-四氢吲哚） 甲基）苯 氰、 2-溴- 4- ( 1- (3, 6, 6-三甲基 -4-氧- 4， 5, 6, 7-四氢吲哚））苯氰、 2-溴- 4- ( 1- (3， 6, 6- 三甲基 -4-氧- 4, 5， 6， 7-四氢吲哚） 甲基） 苯氰、 2 -溴- 4- (1- ( 3, 6, 6-三甲基 -4-氧 -4， 5， 6， 7-四氢吲哚））苯甲酰胺、 2-溴 -4- ( 1- (3-甲基 -4-氧- 4， 5， 6， 7-四氢吲哚））苯 氰、 或 2-溴- 4- ( 1- (3 -甲基 -4 -氧- 4， 5， 6， 7 -四氢吲哚） 甲基）苯氰。  The compound according to claim 36, wherein the compound is 2-bromo-4-(1-(4-oxo-4,5,6-7-tetrahydroindole)) phenyl cyanide. , 2-bromo-4-(1-(4-oxo-4,5,6,7-tetrahydroindole)methyl)phenyl cyanide, 2-bromo-4-(1-(3, 6, 6-) Trimethyl-4-oxo-4,5,6,7-tetrahydroindole)) phenyl cyanide, 2-bromo-4-(1-(3, 6, 6-trimethyl-4-oxo-4) , 5, 6, 7-tetrahydroindole) methyl) phenyl cyanide, 2-bromo-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7- Tetrahydroindole))benzamide, 2-bromo-4-(1-(3-methyl-4-oxo-4,5,6-7-tetrahydroindole)) phenyl cyanide, or 2-bromo - 4-(1-(3-Methyl-4-oxo-4,5,6-7-tetrahydroindole)methyl)benzonitrile.
39、 根据权利要求 36所述的化合物， 其特征在于： R10表示取代的氨基， 且该取 代的氨基是烷氨基。  39. The compound according to claim 36, wherein R10 represents a substituted amino group, and the substituted amino group is an alkylamino group.
40、 根据权利要求 39所述的化合物， 其特征在于： R10所表示的烷氨基是环烷氨 基、 支链烷氨基或直链垸氨基。  The compound according to claim 39, wherein the alkylamino group represented by R10 is a cycloalkylamino group, a branched alkylamino group or a linear decylamino group.
41、 根据权利要求 40所述的化合物， 其特征在于： R10所表示的浣氨基是环己氨 基、 乙氨基、 4-羟基环己氨基、 4-氨基乙酰氧基环己氨基、 2-二乙氨基乙氨基、 2- (4 - 吗啉） 乙氨基、 2- ( 1， 2, 3 )三氮唑乙氨基、 2- ( 1- (3， 5-二甲基哌啶）） 乙氨基、 2- ( 1-哌啶） 乙氨基、 2_ ( 1-吡咯烷基） 乙氨基、 或（2—四氢呋喃） 甲氨基。 The compound according to claim 40, wherein the oxime amino group represented by R10 is cyclohexylamine. Base, ethylamino, 4-hydroxycyclohexylamino, 4-aminoacetoxycyclohexylamino, 2-diethylaminoethylamino, 2-(4-morpholine)ethylamino, 2-(1,2,3) Triazole ethylamino, 2-(1-(3, 5-dimethylpiperidine))ethylamino, 2-(1-piperidine)ethylamino, 2-(1-pyrrolidinyl)ethylamino, or 2-tetrahydrofuran) methylamino.
42、 根据权利要求 41所述的化合物， 其特征在于： 所述的化合物为 2- (2_四氢呋 喃）甲氨基 - 4- (1- (3, 6, 6-三甲基 - 4 -氧- 4， 5， 6， 7-四氢吲哚)）苯甲酰胺、 2-环己氨基 -4_ (1- (3，6，6_三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚)）苯甲酰胺、 2_ (2 -二乙氨基乙氨基） -4- ( 1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚））苯甲酰胺、 2- (2- (4-吗啉） 乙氨 基） -4- ( 1- (3， 6， 6_三甲基 -4-氧- 4, 5, 6, 7-四氢吲哚）)苯甲酰胺、 2- (4-羟基环己氨 基）- 4- ( 1- (3, 6， 6-三甲基 -4 -氧- 4， 5， 6， 7-四氢吲哚））苯甲酰胺、或 2- (2- (1， 2， 3) 三氮唑乙氨基 ) -4- ( 1- (3， 6， 6-三甲基 -4-氧 4, 5, 6， 7_四氢吲哚））苯甲酰胺。  The compound according to claim 41, wherein the compound is 2-(2-tetrahydrofuran)methylamino-4-(1-(3,6,6-trimethyl-4-oxy-)- 4, 5, 6, 7-tetrahydroanthracene))benzamide, 2-cyclohexylamino-4_ (1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7 -tetrahydroanthracene))benzamide, 2_(2-diethylaminoethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7- Tetrahydroindole))benzamide, 2-(2-(4-morpholine)ethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6 , 7-tetrahydroanthracene))benzamide, 2-(4-hydroxycyclohexylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroanthracene))benzamide, or 2-(2-(1,2,3)triazoleethylamino)-4-(1-(3,6,6-trimethyl-4-) Oxygen 4, 5, 6, 7_tetrahydroindole)) benzamide.
43、 根据权利要求 36所述的化合物， 其特征在于： R10表示杂环或取代的杂环， 所述的该杂环是单杂环或双杂环， 所述的该取代的杂环是取代的单杂环或取代的双杂 环。  The compound according to claim 36, wherein R10 represents a heterocyclic ring or a substituted heterocyclic ring, said heterocyclic ring is a monoheterocyclic ring or a bicyclic heterocyclic ring, and said substituted heterocyclic ring is substituted. Monoheterocyclic or substituted bicyclic heterocycles.
44、 根据权利要求 43所述的化合物， 其特征在于： R10表示杂环， 且该杂环是单 杂环或双杂环， 所述的该单杂环是哌嗪或哌啶， 所述的该双杂环是喹啉。  44. The compound according to claim 43, wherein R10 represents a heterocyclic ring, and the heterocyclic ring is a monoheterocyclic ring or a bicyclic heterocyclic ring, and the monoheterocyclic ring is piperazine or piperidine, The bicyclic heterocycle is quinoline.
45、 根据权利要求 44所述的化合物， 其特征在于： 所述的化合物为 2- ( 1-哌啶） - 4-（1- (3， 6， 6-三甲基 -4-氧- 4, 5， 6, 7-四氢吲哚））苯氰、或 2- ( 1-哌啶） -4- ( 1 -（3， 6, 6- 三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚））苯甲酰胺。  The compound according to claim 44, wherein the compound is 2-(1-piperidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4) , 5, 6, 7-tetrahydroindole)) phenyl cyanide, or 2-(1-piperidine)-4-( 1 -(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroanthracene)) benzamide.
46、 根据权利要求 43所述的化合物， 其特征在于： R10表示取代的杂环， 且该取 代的杂环是取代的单杂环或取代的双杂环，所述的该取代的单杂环是取代的哌嗪、取代 的吡咯烧基、 或取代的哌啶， 所述的该取代的双杂环是 6、 7-二甲氧基- 1， 2, 3, 4-四 氢异喹啉。  The compound according to claim 43, wherein R10 represents a substituted heterocyclic ring, and the substituted heterocyclic ring is a substituted monoheterocyclic ring or a substituted diheterocyclic ring, said substituted monoheterocyclic ring. Is a substituted piperazine, a substituted pyrrolidinyl group, or a substituted piperidine, and the substituted bicyclic heterocycle is 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. .
47、 根据权利要求 46所述的化合物， 其特征在于： R10表示取代的单杂环， 且该 取代的单杂环是取代的哌嗪、取代的吡咯烷基、或取代的哌啶， 所述的该取代的哌嗪是 1-呢嗪、 4-甲基哌嗪、 4- (2- (4-吗啉） 乙基） 哌嗪、 （4-环戊垸基）哌嗪、 4_ (2 -羟 乙基） 哌嗪、 或 4- (2-吡啶） 哌嗪， 所述的该取代的吡咯烷基是 3-羟基吡咯浣基， 所 述的该哌啶是 4-氧-哌啶、 4-羟基哌啶、 3—羟基哌啶、 4一氨基乙酰氧基哌啶、 4- (4- 吗啉） 哌啶、 4- ( 1-吡咯烷基） 哌啶、 或 4- (2- ( 1-哌啶） 乙氧基） 哌啶。  47. The compound according to claim 46, wherein: R10 represents a substituted monoheterocyclic ring, and the substituted monoheterocyclic ring is a substituted piperazine, a substituted pyrrolidinyl group, or a substituted piperidine, The substituted piperazine is 1-oxazine, 4-methylpiperazine, 4-(2-(4-morpholine)ethyl)piperazine, (4-cyclopentamethylene)piperazine, 4_ (2 - hydroxyethyl) piperazine, or 4-(2-pyridine) piperazine, the substituted pyrrolidinyl group is a 3-hydroxypyrrole group, the piperidine is 4-oxo-piperidine, 4-hydroxypiperidine, 3-hydroxypiperidine, 4-aminoacetoxypiperidine, 4-(4-morpholine)piperidine, 4-(1-pyrrolidinyl)piperidine, or 4-(2- (1-piperidine) ethoxy) piperidine.
48、 根据权利要求 47所述的化合物， 其特征在于： 所述的化合物为 2- ( 1- (3 -羟 基吡咯垸基）） -4- ( 1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚））苯氰、 2- ( 1- (3 - 羟基吡咯垸基）） 4- (1- (3, 6， 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚））苯甲酰胺、 2- ( 1- (4 -甲基哌嗪）) -4- ( 1- (3， 6， 6-三甲基 -4-氧- 4, 5， 6, 7 -四氢吲哚) 甲基）苯甲酰胺、 2- ( 1- (4-氧-哌啶）） -4- ( 1- (3, 6, 6-三甲基 -4-氧- 4, 5， 6, 7-四氢吲哚）)苯甲酰胺、 2 - ( 1- (4 -羟基哌啶）) -4- ( 1- (3, 6, 6-三甲基 _4 -氧 -4， 5， 6, 7-四氢吲哚）)苯甲酰胺、 2- ( 1- (4- (4-吗啉) 哌啶）） -4- ( 1- (3, 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚）)苯 甲酰胺、 2- C 1- (4- (2- (4-吗啉)乙基）呢嗪）） - 4- ( 1- (3, 6, 6-三甲基 -4-氧- 4， 5， 6， 7- 四氢吲哚））苯甲酰胺、 或 2- ( 1- (4- ( 1 -吡咯烷基)哌啶）） -4- ( 1- (3， 6， 6-三甲基 -4 -氧- 4， 5， 6， 7-四氢吲哚））苯甲酰胺。 The compound according to claim 47, wherein the compound is 2-(1-(3-hydroxypyrrolidino))-4-(1-(3,6,6-trimethyl) -4-oxo-4,5,6,7-tetrahydroindole)) phenyl cyanide, 2-(1-(3-hydroxypyrrolidinyl)) 4- (1-(3, 6, 6-trimethyl) 4--4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2- ( 1- (4-methylpiperazine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole)methyl)benzamide, 2-(1-(4-oxo-piperidinyl)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))benzene Formamide, 2-(1-(4-hydroxypiperidine))-4-(1-(3, 6, 6-trimethyl_4-oxo-4, 5, 6, 7-tetrahydroanthracene) Benzoylamide, 2-(1-(4-(4-morpholinyl)piperidine)-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroanthracene))benzamide, 2- C 1-(4-(2-(4-morpholine)ethyl)histazine)) - 4- ( 1- (3, 6, 6-three) Methyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, or 2-(1-(4-(1-pyrrolidinyl)piperidinyl)-4-(1) - (3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide.
49、 根据权利要求 2所述的化合物， 其特征在于， 通式中： X表示 C一 Rl; Y、 Ζ选 择第三种组合； Rl、 R2选择第二种组合， 且 R1和 R2可以共同形成的一个芳香环是苯 环， 可共同形成的一个取代的芳香环是三氟甲基取代的苯环； R5、 R6均表示 d- C3的烷 基， 且该 d-C3的浣基均为甲基； R10、 R11选择第一种组合，其中的 R11表示氨甲酰基； R12表示 H。 49. The compound according to claim 2, wherein: X represents C-R1; Y, Ζ selects a third combination; R1, R2 selects a second combination, and R1 and R2 can form together One aromatic ring is a benzene ring, and a substituted aromatic ring which can be formed together is a trifluoromethyl-substituted benzene ring; R5 and R6 each represent a d-C 3 alkyl group, and the dC 3 fluorenyl group is a The first combination is selected from R10 and R11, wherein R11 represents a carbamoyl group; and R12 represents H.
50、 根据权利要求 49所述的化合物， 其特征在于： 所述的化合物为 2- ( 1- (4 -羟 基哌啶）） -4- (9- (2， 2-二甲基 -4-氧 -1， 2， 3， 4-四氢咔唑）)苯甲酰胺、 2- (4-羟基环 己氨基） -4- (9- (2，2-二甲基 - 4 -氧- 1，2, 3，4-四氢咔唑）)苯甲酰胺、 2- ( 1- (4- (2- 羟乙基） 哌嗪）） -4- (9- (2， 2-二甲基 -4 -氧- 1， 2， 3， 4-四氢咔唑）)苯甲酰胺、 2- ( 1 - The compound according to claim 49, wherein the compound is 2-(1-(4-hydroxypiperidinyl)-4-(9-(2,2-dimethyl-4-) Oxy-1,2,3,4-tetrahydrocarbazole))benzamide, 2-(4-hydroxycyclohexylamino)-4-(9-(2,2-dimethyl-4-oxo-1) , 2,3,4-tetrahydrocarbazole))benzamide, 2-(1-(4-(2-hydroxyethyl)piperazine))-4-(9-(2,2-dimethyl) -4 -oxy-1, 2, 3, 4-tetrahydrocarbazole)) benzamide, 2- (1 -
(4-甲基哌嗪）） -4- (9- (2， 2-二甲基 -4-氧- 6-三氟甲基- 1, 2， 3, 4-四氢^唑））苯甲酰 胺、 2- ( 1- (4 -羟基哌啶）) -4- (9- (2, 2-二甲基 _4 -氧- 6-三氟甲基- 1, 2， 3， 4-四氢咔 唑）)苯甲酰胺、或 2- (4-羟基环己氨基 )-4- (9- (2， 2-二甲基 -4-氧- 6-三氟甲基- 1, 2， 3, 4- 四氢咔唑））苯甲酰胺。 ' (4-methylpiperazine))-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydroxazole))benzene Formamide, 2-(1-(4-hydroxypiperidine))-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl- 1, 2, 3, 4- Tetrahydrocarbazole))benzamide, or 2-(4-hydroxycyclohexylamino)-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl- 1, 2 , 3, 4-tetrahydrocarbazole)) benzamide. '
51、根据权利要求 2所述的化合物，其特征在于，通式中： n表示 0; X表示 C一 R1; Y、 Ζ选择第二种组合； Rl、 R2选择第一种组合，其中的 R1表示浣基，且该烷基为甲基， 其中的 R2表示 H; R5、 R6均表示 C「 C3的垸基， 且该 C,- C3的烷基均为甲基； R10、 R11 选择第一种组合， 其中的 R11表示氨甲酰基； R12表示 H， 从而相应的化合物是 5- ( 1-The compound according to claim 2, wherein: n represents 0; X represents C-R1; Y, Ζ selects the second combination; and R1, R2 selects the first combination, wherein R1 Huan represents a group, and the alkyl is methyl, wherein R2 represents H; R5, R6 represent C "3 alkyl with C, and the C, - C 3 alkyl are methyl; R10, R11 selected The first combination, wherein R11 represents a carbamoyl group; R12 represents H, and the corresponding compound is 5-(1-
(2, 6， 6 -三甲基- 4-氧- 4， 5， 6， 7-四氢吲哚）） 吡啶- 2-甲酰胺。 (2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole)) Pyridine-2-formamide.
52、根据权利要求 2所述的化合物，其特征在于，通式中： n表示 0; X表示 C一 R1 ; Y、 Ζ选择第三种组合； Rl、 R2选择第一种组合， 且其中的 R1表示 H, R2表示烷基、该 垸基为甲基； R5、 R6均表示 d- C3的烷基， 且 R5、 R6均为甲基； R10、 R11选择第二种 组合， 且 R10和 R11可共同形成的一个杂环是吡唑， 可共同形成的一个取代的杂环是 5-氨基吡唑; R12表示 H。 52. The compound of claim 2, wherein: n represents 0; X represents C-R1; Y, Ζ selects a third combination; Rl, R2 selects a first combination, and wherein R1 represents H, R2 represents an alkyl group, the embankment is methyl; R5, R6 each represents d- C 3 alkyl group, and R5, R6 are methyl; R10, R11 selected second combination, and R10 and One heterocyclic ring which R11 can form together is pyrazole, and a substituted heterocyclic ring which can be formed together is 5-aminopyrazole; R12 represents H.
53、 根据权利要求 52所述的化合物， 其特征在于： 所述的化合物为 1- (6- (3-氨 基- 1H-吲唑）） -3, 6, 6_三甲基 - 1, 5， 6, 7 -四氢吲哚- 4-酮。 53. The compound of claim 52, wherein: the compound is 1-(6-(3-ammonium) Base-1H-carbazole)) -3,6,6-trimethyl- 1,5,6,7-tetrahydroindole-4-one.
54、 根据权利要求 2所述的化合物， 其特征在于， 通式中： X表示 N或 C一 Rl ; Y、 Ζ选择第三种组合， 即 Υ表示 CH; Ζ表示 C一 RIO; Rl、 R2选择第一种组合， 且其中 R1 表示 H、 甲基或乙基， R2表示 H、 甲基或乙基； R5表示 H、 甲基或乙基； R6表示 H、 甲 基或乙基； R10、 R11选择第一种组合， 且 R10表示 H、 卤素、 取代的氨基、 杂环或取代 的杂环； R11表示氨甲酰基或氰基； R12表示 H、 C1或 Br。  54. The compound according to claim 2, wherein: X represents N or C-R1; Y, Ζ selects a third combination, that is, Υ represents CH; Ζ represents C-RIO; Rl, R2 Select the first combination, and wherein R1 represents H, methyl or ethyl, R2 represents H, methyl or ethyl; R5 represents H, methyl or ethyl; R6 represents H, methyl or ethyl; R10, R11 selects the first combination, and R10 represents H, halogen, substituted amino, heterocyclic or substituted heterocyclic ring; R11 represents carbamoyl or cyano; and R12 represents H, C1 or Br.
55、 根据权利要求 54所述的化合物， 其特征在于： R10所表示的卤素是 C1或 Br; R10所表示的取代的氨基是 2-二乙氨基乙氨基、 2- (4-吗啉） 乙氨基、 2- ( 1， 2， 3) 三氮唑乙氨基、 2- ( 1 (3， 5-二甲基哌啶）) 乙氨基、 2- ( 1 哌啶) 乙氨基、 2-环丙垸 氨基； R10所表示的杂环是 1_哌啶； R10所表示的取代的杂环是 4-甲基哌嗪、 （4-环戊 烷基） 哌嗪、 4-羟基哌啶、 4- ( 1 -吡咯烷基）哌啶。  55. The compound according to claim 54, wherein the halogen represented by R10 is C1 or Br; and the substituted amino group represented by R10 is 2-diethylaminoethylamino, 2-(4-morpholine) Amino, 2-( 1, 2, 3) triazole ethylamino, 2-(1 (3, 5-dimethylpiperidine)) ethylamino, 2-(1 piperidine) ethylamino, 2-cyclopropyl Amidino group; the heterocyclic ring represented by R10 is 1-piperidinyl; the substituted heterocyclic ring represented by R10 is 4-methylpiperazine, (4-cyclopentyl) piperazine, 4-hydroxypiperidine, 4- (1-pyrrolidinyl) piperidine.
56、 根据权利要求 55所述的化合物， 其特征在于： 所述的化合物为 2-溴 -4- ( 1 - (4-氧- 4， 5， 6， 7-四氢吲哚）)苯氰、 2-溴- 4- ( 1- (4-氧- 4， 5， 6, 7-四氢吲哚） 甲基）苯 氰、 2-溴- 4- ( 1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲哚））苯氰、 2-溴- 4- ( 1- (3， 6, 6- 三甲基 -4-氧- 4, 5, 6， 7-四氢吲哚） 甲基） 苯氰、 2-溴 -4- (1- ( 3， 6, 6-三甲基 -4 -氧 -4, 5， 6， 7 -四氢吲哚) )苯甲酰胺、 2 -溴- 4 - ( 1- (3, 6, 6 -三甲基- 4 -氧- 4, 5, 6, 7 -四氢吲 哚）甲基）苯甲蹴胺、 2- ( 1 -哌啶） -4- ( 1- (3, 6， 6-三甲基 -4-氧- 4, 5, 6, 7-四氢吲哚）） 苯甲酰胺、 2- (2-二乙氨基乙氨基） -4- ( 1- (3, 6, 6-三甲基 -4-氧- 4， 5, 6, 7-四氢吲哚）） 苯甲酰胺、 2- (2- (4-吗啉) 乙氨基） -4- ( 1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲 哚）） 苯甲酰胺、 2 -溴- 4- ( 1- (4-氧- 4, 5, 6， 7-四氢吲唑））苯氰、 2-溴- 4- ( 1- (3 -甲 基- 4-氧- 4， 5， 6， 7-四氢吲唑） 甲基）苯氰、 2-溴- 4- (1- (3， 6， 6-三甲基 -4-氧 4， 5， 6， 7- 四氢吲唑））苯甲酰胺、 2- (2-二乙氨基乙氨基） -4- ( 1- (3， 6， 6-三甲基 -4-氧- 4, 5, 6， 7- 四氢吲唑））苯甲酰胺、 2- (2- ( 1-哌啶)乙氨基）-4- ( 1- (3， 6， 6 -三甲基- 4 -氧- 4， 5, 6， 7_ 四氢吲唑））苯甲酰胺、 2- ( 1 - (4-甲基哌嗪）) -4 - ( 1- (3， 6, 6-三甲基 -4-氧- 4， 5, 6, 7- 四氢吲唑））苯甲酰胺、 2- (2- ( 1- (3， 5-二甲基哌啶）） 乙氨基） -4- ( 1- (3, 6, 6 -三 甲基- 4-氧- 4， 5， 6, 7-四氢吲唑）)苯甲酰胺、 2- (2- (1， 2， 3)三氮唑乙氨基 )-4- ( 1- (3, 6, 6- 三甲基 -4-氧- 4, 5, 6, 7 -四氢吲唑）)苯甲酰胺、 2- ( 1- (4 -羟基哌啶）) -4- ( 1- (3， 6， 6- 三甲基 -4-氧- 4, 5， 6， 7-四氢吲唑））苯甲酰胺、 2- ( 1- (4- ( 1-吡咯垸基) 哌啶）） - 4- ( 1- (3， 6, 6-三甲基 -4 -氧- 4， 5, 6， 7_四氢吲唑）)苯甲酰胺、 2- ( 1- (4 -环戊烷基) 哌 嗪） -4- ( 1- (3， 6， 6-三甲基 -4 -氧- 4， 5， 6， 7 -四氢吲唑）)苯甲酰胺、 或 2 -环丙烷氨基 -4-（1- (3, 6， 6 -三甲基- 4-氧- 4, 5， 6， 7-四氢吲唑））苯甲酰胺。 56. The compound according to claim 55, wherein: the compound is 2-bromo-4-(1-(4-oxo-4,5,6-7-tetrahydroindole)) phenyl cyanide. , 2-bromo-4-(1-(4-oxo-4,5,6,7-tetrahydroindole)methyl)benzonitrile, 2-bromo-4-(1-(3, 6, 6-) Trimethyl-4-oxo-4,5,6,7-tetrahydroindole)) phenyl cyanide, 2-bromo-4-(1-(3, 6, 6-trimethyl-4-oxo-4) , 5, 6, 7-tetrahydroindole) methyl) phenyl cyanide, 2-bromo-4-(1-( 3, 6, 6-trimethyl-4 -oxy-4, 5, 6, 7 - Tetrahydroindole))benzamide, 2-bromo-4-(1-(3,6-6-trimethyl-4-ethoxy- 4,5,6-7-tetrahydroindole)methyl) Benzylamine, 2-(1-piperidine)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole)) Benzyl Amide, 2-(2-diethylaminoethylamino)-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole)) Benzyl Amide, 2-(2-(4-morpholine)ethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroanthracene) Benzoylamide, 2-bromo-4-(1-(4-oxo-4,5,6,7-tetrahydrocarbazole)) phenyl cyanide, 2- - 4- (1-(3-methyl-4-oxo-4,5,6,7-tetrahydrocarbazole) methyl)benzonitrile, 2-bromo-4-(1-(3, 6, 6) -trimethyl-4-oxo 4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-diethylaminoethylamino)-4-(1-(3, 6, 6- Trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(1-piperidinyl)ethylamino)-4-(1-(3, 6 , 6-trimethyl- 4 -oxy-4, 5, 6, 7_ tetrahydrocarbazole)) benzamide, 2-( 1 - (4-methylpiperazine)) -4 - ( 1- (3 , 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2-(2-(1-(3, 5-dimethylpiperidine)) Ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2- (2- (1) , 2, 3) triazole ethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, 2-(1-(4-hydroxypiperidinyl)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole)) benzoate Amide, 2-(1-(4-(1-pyrrolidinyl)piperidine)) 4- (1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6 7_tetrahydrocarbazole))benzamide, 2-(1-(4-cyclopentanyl)piperazine)-4-(1-(3,6,6-trimethyl-4-oxo-4) , 5, 6, 7 -tetrahydrocarbazole))benzamide, or 2-cyclopropanylamino-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) benzamide.
57、 根据权利要求 2 所述的化合物， 其特征在于： 所述的化合物为 2-氯 -4 -（1 - (3, 6， 6-三甲基 - 4-氧 -4, 5, 6， 7-四氢吲唑）) 苯氰、 2- (1- (4-甲基哌 嗪)） -4-（1- (3, 6， 6 -三甲基- 4 -氧- 4， 5， 6， 7-四氢吲唑)）苯氰、 2- (1- (4-甲基哌嗪）） -4_The compound according to claim 2, wherein the compound is 2-chloro-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) phenyl cyanide, 2-(1-(4-methylpiperazine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) phenyl cyanide, 2-(1-(4-methylpiperazine)) -4_
(1- (3， 6， 6 -三甲基- 4-氧 -4， 5, 6， 7_四氢吲唑）)苯甲酰胺、 2- (1- (3 -羟基吡咯烷基）) - 4 -（1- (3,6,6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚））苯氰、 2- (1- (3 -羟基吡咯烷基）) -4- (1- (3， 6, 6-三甲基 -4 -氧- 4， 5, 6, 7-四氢吲哚）)苯甲酰胺、 2- (1 -哌啶) -4- (1-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(3-hydroxypyrrolidinyl)) - 4 -(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole)) phenyl cyanide, 2-(1-(3-hydroxypyrrolidinyl) )) -4- (1-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(1-piperidine)- 4- (1-
(3， 6， 6-三甲基 -4 -氧- 4,5， 6， 7-四氢吲哚）)苯氰、 2- (1 -哌啶） -4- (1 -（3， 6， 6 -三甲 基- 4-氧- 4, 5, 6， 7-四氢吲哚））苯甲酰胺、 2- (1- (4-甲基哌嗪）） -4- (1- (3， 6， 6 -三 甲基- 4-氧- 4, 5, 6, 7-四氢吲哚）甲基）苯甲酰胺、 2-环己氨基- 4- (1- (3， 6,6-三甲基 _4- 氧- 4, 5， 6, 7 -四氢吲哚)）苯甲酰胺、 2- (2 -二乙氨基乙氨基) -4- (1- (3， 6， 6 -三甲 基- 4 -氧- 4, 5, 6, 7 -四氢吲哚））苯甲酰胺、 2- (2- (4 -吗啉) 乙氨基） -4- (1 -（3,6,6- 三甲基 -4-氧- 4， 5, 6， 7-四氢吲哚））苯甲酰胺、 2- (1- (4-氧-哌啶）） -4- (1- (3,6,6- 三甲基 -4-氧- 4， 5, 6， 7-四氢吲哚））苯甲酰胺、 2- (1- (4 -羟基呢啶）) -4- (1- (3, 6， 6- 三甲基 -4-氧- 4,5,6,7-四氢吲哚））苯甲酰胺、 2- (4 -羟基环己氨基) -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲哚））苯甲酰胺、 2- (1- (4- (4 -吗啉)哌啶）） - 4 -(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole)) phenyl cyanide, 2-(1-piperidinyl)-4-(1 -(3, 6 , 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole))benzamide, 2-(1-(4-methylpiperazine))-4-(1-( 3, 6, 6 -trimethyl-4-oxo-4,5,6,7-tetrahydroindole)methyl)benzamide, 2-cyclohexylamino-4-(1-(3, 6, 6-trimethyl_4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(2-diethylaminoethylamino)-4-(1-(3, 6, 6-trimethyl- 4 -ethoxy- 4, 5, 6, 7-tetrahydroindole)) benzamide, 2-(2-(4-morpholine)ethylamino)-4-(1 -(3 ,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(1-(4-oxo-piperidine))-4- (1 - (3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(1-(4-hydroxyoctyl))-4- (1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(4-hydroxycyclohexylamino)-4-( 1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(1-(4-(4- morpholine)piperidin Acridine)) - 4 -
(1- (3， 6， 6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲哚）)苯甲酰胺、 2-(2- (1， 2， 3)三氮唑乙氨 基)- 4- (1- (3， 6， 6-三甲基 _4_氧- 4， 5, 6， 7_四氢吲哚）)苯甲酰胺、 2- (1- (4- (2- (4- 吗啉） 乙基） 哌嗪）） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5， 6， 7 -四氢吲哚）)苯甲酰胺、 2- (1- (4- (1 -吡咯垸基)哌啶）） -4- (1- (3,6,6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚）) 苯甲酰胺、 2- (2-二乙氨基乙氨基） -4- (1- (3, 6, 6-三甲基 -4-氧- 4, 5, 6, 7_四氢吲唑）） 苯甲酰胺、 2-环己氨基- 4- (1- (3,6,6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑)）苯甲酰胺、 2- (2- (1 -哌啶) 乙氨基） -4- (1- (3,6,6-三甲基 _4 -氧- 4, 5, 6， 7-四氢吲唑））苯甲酰 胺、 2- (2- (1- (3， 5-二甲基哌啶）) 乙氨基） -4 - (1- (3， 6， 6-三甲基 -4-氧- 4, 5,6,7- 四氢吲唑）） 苯甲酰胺、 2- (2_(1，2，3)三氮唑乙氨基） -4- (1- (3， 6， 6-三甲基 -4 -氧 -4,5,6,7-四氢吲唑）)苯甲酰胺、 2- (1- (4-环戊垸基) 哌嗪） -4- (1- (3， 6， 6-三甲 基- 4-氧- 4,5,6,7-四氢吲唑））苯甲酰胺、 2-环丙烷氨基- 4- (1- (3， 6， 6-三甲基 -4 -氧 - 4，5，6，7-四氢吲唑））苯甲酰胺、 2- (1- (4- (2- (1 -哌啶) 乙氧基）哌啶）） -4- (1-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(2-(1, 2, 3)trinitrogen Oxazideethylamino)- 4- (1-(3, 6, 6-trimethyl_4_oxo-4, 5, 6, 7_tetrahydroindole)) benzamide, 2- (1- (4) - (2-(4-morpholine)ethyl)piperazine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole) ))benzamide, 2-(1-(4-(1-pyrrolidinyl)piperidine))-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroanthracene)) benzamide, 2-(2-diethylaminoethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7_tetrahydrocarbazole)) benzamide, 2-cyclohexylamino-4-(1-(3,6,6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro) Carbazole))benzamide, 2-(2-(1-piperidinyl)ethylamino)-4-(1-(3,6,6-trimethyl_4-oxo-4, 5, 6, 7 -tetrahydrocarbazole))benzamide, 2-(2-(1-(3,5-dimethylpiperidine))ethylamino) -4 - (1-(3, 6, 6-trimethyl) -4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2_(1,2,3)triazoleethylamino)-4-(1-(3, 6 , 6-trimethyl -4 -oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-cyclopentanyl)piperazine)-4- (1- (3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-cyclopropanylamino-4-(1-(3,6,6-trimethyl-) 4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-(2-(1-piperidine)ethoxy)piperidine))-4- (1-
(3, 6,6-三甲基 -4-氧 4， 5, 6, 7-四氢吲唑））苯甲酰胺、 2- (1- (4 -氧-哌啶；)) -4- (1-(3,6,6-trimethyl-4-oxo 4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-oxo-piperidine))-4- (1-
(3, 6, 6 -三甲基- 4-氧- 4， 5, 6, 7 -四氢吲唑）)苯甲酰胺、 2- (1- (4- (2 -羟乙基）哌嗪）） —4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲唑））苯甲酰胺、 2- (2- (4-吗啉） 乙氨 基） -4- (1— (3， 6, 6 -三甲基- 4-氧- 4, 5， 6,7-四氢吲唑）) 苯甲酰胺、 2- (1- (4- (1- 吡咯烷基） 哌啶）） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5, 6, 7-四氢吲唑）)苯甲酰胺、 2- (1- (4- (2- (4-吗啉) 乙基）哌嗪）） -4- (1- (3, 6, 6-三甲基 -4-氧- 4, 5, 6， 7-四氢吲 唑））苯甲酰胺、 2- (1- (4-羟基哌啶）) -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5, 6， 7-四氢 吲唑））苯甲酰胺、 2- (1- (4-氨基乙酰氧基哌啶））-4- (1- (3， 6， 6_三甲基 -4-氧- 4， 5, 6, 7- 四氢吲唑））苯甲酰胺、 2- (4-羟基环己氨基） -4- (1- (3， 6， 6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲唑））苯甲酰胺、 2- (4-氨基乙酰氧基环己氨基） -4- (1- (3, 6, 6 -三甲 基- 4-氧- 4, 5， 6， 7-四氢吲唑）） 苯甲酰胺、 2- (2- (1-吡咯烷基） 乙氨基） -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 2- (1 -哌嗪) -4- (1- (3,6,6- 三甲基 -4-氧- 4, 5, 6， 7-四氢吲唑））苯甲酰胺、 2_(1- (3-羟基吡咯垸基）） 4-(1- (3, 6， 6 - 三甲基 -4-氧- 4， 5， 6， 7_四氢吲唑）)苯甲酰胺、 2- (1- (4- (4-吗啉） 哌啶）） -4- (1- (3, 6， 6 -三甲基- 4 -氧- 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 2- (1- (3-羟基哌啶）） -4- (1- (3, 6, 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲唑））苯甲酰胺、 2- (2- (6, 7 -二甲氧基- 1, 2, 3, 4- 四氢异喹啉）） -4- (1- (3, 6， 6 -三甲基- 4-氧- 4， 5， 6， 7_四氢吲唑）） 苯甲酰胺、 2- (1- (4- (2 -吡啶)哌嗪）） -4- (1- (3, 6， 6_三甲基 -4 -氧- 4, 5, 6， 7-四氢吲唑）)苯甲酰胺、 2-（1-哌啶) - 4- (1- (3， 6, 6 -三甲基- 4 -氧- 4,5,6,7-四氢吲唑) )苯甲酰胺、 卜 (6-（3- 氨基- 1H-吲唑）） -3， 6, 6-三甲基 -1,5， 6, 7 -四氢吲哚- 4-酮、 1- (6- (3-氨基- 1H-吲唑）） -3， 6, 6-三甲基 -1, 5， 6, 7-四氢! 3引唑- 4-酮、 2- (1- (4-羟基哌啶）） -4- (9- (2， 2-二甲 基- 4-氧- 1， 2， 3， 4-四氢咔唑））苯甲酰胺、 2- (4-羟基环己氨基) 4- (9- (2,2-二甲基 - 4 -氧- 1， 2， 3, 4-四氢咔唑））苯甲酰胺、 2- (1- (4- (2-羟乙基）哌嗪）） -4— (9- (2,2- 二甲基 -4-氧- 1,2, 3， 4_四氢咔唑））苯甲酰胺、 2- (1- (4-甲基哌嗪）） -4— (9- (2,2- 二甲基 -4-氧- 6-三氟甲基- 1， 2， 3, 4-四氢咔唑））苯甲酰胺、 2- (1- (4-羟基哌啶）） - 4- (9- (2,2-二甲基 -4-氧- 6-三氟甲基- 1,2,3,4-四氢咔唑））苯甲酰胺、 2- (4-羟基环己 氨基） -4- (9- (2,2-二甲基 -4-氧- 6-三氟甲基- 1， 2, 3, 4-四氢咔唑））苯甲酰胺、 2-环 己氨基 -4- (9- (2， 2_二甲基 -4-氧- 3-三氟甲基 -4， 5， 6, 7-四氢吲唑））苯甲酰胺、 2- (4- 羟基环己氨基） -4- (1- (6， 6_二甲基 -4-氧 -3 -三氟甲基- 4， 5， 6， 7-四氢吲唑））苯 甲酰胺、 N- (2- [1， 2， 3]三氮唑乙基) -4- (1- (3， 6， 6)三甲基 -4-氧- 4， 5， 6, 7 -四氢 吲唑）） 苯甲酰胺、 N-(2- (4 吗啉） 乙基) -4- (1- (3, 6， 6)三甲基 -4-氧 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 N- (4-羟基环己基) -4- (1- (3， 6, 6)三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 N- (2- (1- (4 -羟基哌啶）） 乙基) -4- (1- (3, 6， 6)三甲基 - 4 -氧- 4， 5， 6， 7 -四氢吲唑）)苯甲酰胺、 5- (1- (2,6,6-三甲基 -4-氧- 4， 5， 6, 7-四氢 吲哚））吡啶- 2-甲酰胺、 2-溴- 4- (1- (4-氧- 4， 5， 6， 7-四氢吲哚））苯氰、 2-溴- 4- (1- (4 -氧- 4,5,6,7-四氢吲哚） 甲基）苯氰、 2-溴- 4- (1- (3， 6, 6-三甲基 -4-氧- 4, 5, 6， 7- 四氢吲哚））苯氰、 2 -溴- 4- (1- (3， 6, 6-三甲基 -4-氧 -4, 5， 6, 7 -四氢吲哚)甲基）笨氰、 2-溴- 4- (1- (3， 6， 6-三甲基 -4-氧- 4,5,6,7-四氢吲哚) )苯甲酰胺、 2-溴- 4- (1- (3- 甲基- 4 -氧 -4， 5， 6, 7-四氢吲哚））苯氰、 2-溴- 4- (1- (3-甲基- 4-氧- 4， 5, 6, 7-四氢吲哚） 甲基）苯氰、 2-溴- 4- (1- (3-甲基- 4-氧- 4, 5， 6， 7-四氢吲唑））苯氰、 2 -溴- 4- (1- (3- 甲基- 4-氧- 4, 5， 6， 7-四氢吲唑） 甲基）苯氰、 4- (卜 (4- (2 -羟乙基)哌嗪）） - 6- (1 - (3， 6， 6-三甲基 -4-氧 -4， 5， 6, 7-四氢吲唑）)烟碱酰胺、 4- (1- (4 -羟基哌啶）) -6- (1- (3， 6， 6-三甲基 _4 -氧- 4， 5， 6， 7-四氢吲唑）) 烟碱酰胺、 Ν- (4-乙酰氧环己基 )-4- (1- (3， 6, 6)三甲基 -4 -氧- 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 Ν- (1- (4- (2 -吡啶)哌 嗪） -4- (1- (3， 6， 6)三甲基 -4-氧- 4， 5, 6， 7-四氢吲唑））苯甲酰胺、 2- (2 -四氢 呋喃）甲氨基 -4- (1- (3, 6, 6-三甲基 -4 -氧- 4， 5, 6， 7-四氢吲哚)）苯甲酰胺、 或 2- (2- 四氢呋喃）甲氨基 -4- (1- (3， 6, 6-Η甲基- 4-氧- 4， 5， 6， 7-四氢吲唑)）苯甲酰胺。 (3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-(2-hydroxyethyl)piperazine) )) 4-(1-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(4-? Ethyl) Ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-( 4- (1- Pyrrolidinyl) piperidine)) -4- (1-(3, 6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2- ( 1-(4-(2-(4-morpholine)ethyl)piperazine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7- Tetrahydrocarbazole))benzamide, 2-(1-(4-hydroxypiperidine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2-(1-(4-aminoacetoxypiperidine))-4-(1-(3,6,6-trimethyl-4-oxo-4) , 5, 6, 7-tetrahydrocarbazole))benzamide, 2-(4-hydroxycyclohexylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2-(4-aminoacetoxycyclohexylamino)-4-(1-(3,6,6-trimethyl-4-oxo-) 4, 5, 6, 7-tetrahydrocarbazole)) benzamide, 2-(2-(1-pyrrolidinyl)ethylamino)-4-(1-(3, 6, 6-trimethyl-) 4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-piperazin)-4-(1-(3,6,6-trimethyl-4-oxo) - 4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2_(1-(3-hydroxypyrrolidino)) 4-(1-(3, 6, 6 - trimethyl) 4--4-oxo-4,5,6,7_tetrahydrocarbazole))benzamide, 2-(1-(4-(4-morpholinyl)piperidine))-4- (1- (3) , 6, 6 -trimethyl-4-ethoxy- 4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2-(1-(3-hydroxypiperidinyl)-4-(1- (3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(6,7-dimethoxy-1) 2, 3, 4-tetrahydroisoquinoline)) -4- (1-(3, 6, 6 -trimethyl-4-hydroxy- 4, 5, 6, 7-tetrahydrocarbazole)) Benzyl Amide, 2-(1-(4-(2-pyridine)piperazine))-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro) Carbazole))benzamide, 2-(1-piperidine)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole) Benzoylamide, b (6-(3-amino-1H-carbazole))-3,6,6-trimethyl-1,5,6,7-tetrahydroindole-4-one, 1- (6-(3-Amino- 1H-carbazole)) -3, 6, 6-trimethyl-1, 5, 6, 7-tetrahydro! 3 azole- 4-one, 2- (1- ( 4-hydroxypiperidine))-4-(9-(2,2-dimethyl-4-oxo-1, 2,3,4-tetrahydrocarbazole))benzamide, 2-(4-hydroxyl Cyclohexylamino) 4- (9- (2,2 -Dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole))benzamide, 2-(1-(4-(2-hydroxyethyl)piperazine))-4- ( 9-(2,2-Dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole))benzamide, 2-(1-(4-methylpiperazine))-4 (9-(2,2-Dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole))benzamide, 2-(1-(4-hydroxyl) Piperidine)) - 4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole))benzamide, 2- (4-hydroxycyclohexylamino)-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole)) Benzyl Amide, 2-cyclohexylamino-4-(9-(2,2-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydrocarbazole))benzamide , 2-(4-Hydroxycyclohexylamino)-4-(1-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydrocarbazole) )benzamide, N-(2-[1,2,3]triazolylethyl)-4-(1-(3, 6, 6)trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) benzamide, N-(2-(4 morpholine)ethyl)-4-(1-(3, 6, 6)trimethyl-4-oxo 4, 5, 6 , 7-four Hydrocarbazole))benzamide, N-(4-hydroxycyclohexyl)-4-(1-(3,6,6)trimethyl-4-oxo-4,5,6,7-tetrahydroindole Oxazol))benzamide, N-(2-(1-(4-hydroxypiperidine))ethyl)-4-(1-(3, 6, 6)trimethyl-4-oxo-4, 5 , 6, 7 -tetrahydrocarbazole))benzamide, 5-(1-(2,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydroindole))pyridine 2-formamide, 2-bromo-4-(1-(4-oxo-4,5,6-7-tetrahydroindole))benzonitrile, 2-bromo-4-(1- (4-oxo-4,5,6,7-tetrahydroindole) methyl)benzonitrile, 2-bromo-4-(1-(3,6-6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroanthracene)) phenyl cyanide, 2-bromo-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole)哚)methyl)cyanate, 2-bromo-4-(1-(3,6-6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-bromo-4-(1-(3-methyl-4-oxo-4,5,6,7-tetrahydroindole)) phenyl cyanide, 2-bromo-4-(1-(3-methyl) - 4-oxo-4, 5, 6, 7-tetrahydroindole) methyl)benzonitrile, 2-bromo-4-(1-(3-methyl-4-oxo-4, 5, 6, 7) -tetrahydrocarbazole)) phenyl cyanide, 2-bromo-4-(1-(3-methyl-4-oxo-4,5,6,7-tetrahydrocarbazole)methyl)benzene cyanide, 4- (Bu (4-(2-hydroxyethyl) piperazine)) - 6- (1 - (3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole) Nicotinamide, 4-(1-(4-hydroxypiperidine))-6-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindole) Oxazole)) Nicotinamide, Ν-(4-acetoxycyclohexyl)-4-(1-(3, 6, 6)trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole ))benzamide, Ν-(1-(4-(2-pyridine)) Piperazine)-4-(1-(3,6,6)trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-tetrahydrofuran) Amino-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, or 2-(2-tetrahydrofuran)methylamino 4-(1-(3, 6, 6-fluorenylmethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide.
58、 根据权利要求 57所述的化合物， 其特征在于： 所述的化合物为 2- (1- (3 -羟 基吡咯垸基）） -4- (1- (3, 6， 6-三甲基 -4-氧- 4, 5， 6， 7-四氢吲哚）) 苯甲酰胺、 2- (1- 哌啶） -4- (1- (3， 6， 6-三甲基 -4-氧 _4， 5， 6， 7-四氢吲哚）)苯甲酰胺、 2- (2 -二乙氨基 乙氨基） -4- (1- (3， 6, 6-三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚）)苯甲酰胺、 2- (2- (4- 吗啉） 乙氨基） -4- (1- ( 3， 6， 6_三甲基 -4-氧 -4， 5, 6, 7-四氢吲哚）)苯甲酰胺、 2- (1- (4-羟基哌啶）) 4- (1- (3， 6， 6-三甲基 _4 -氧 -4， 5, 6， 7 -四氢吲哚）)苯甲酰胺、 2- (4- 羟基环己氨基） -4- (1- (3， 6， 6_三甲基 -4-氧- 4， 5， 6, 7-四氢吲哚））苯甲酰胺、 2_ (2- (1,2, 3)三氮唑乙氨基 )-4- (1- (3， 6， 6-三甲基 -4-氧- 4,5,6,7-四氢吲哚）） 苯甲 酰胺、 2- (1- (4- (2- (4-吗啉）乙基）哌嗪）） -4- (1- (3, 6, 6-三甲基 -4-氧- 4， 5， 6， 7- 四氢吲哚））苯甲酰胺、 2- (2-二乙氨基乙氨基） -4- (1- (3, 6， 6-三甲基 -4-氧- 4， 5， 6， 7- 四氢吲唑））苯甲酰胺、 2 -环己氨基- 4 -（1- (3，6，6-三甲基 _4 -氧- 4， 5, 6， 7-四氢吲唑)) 苯甲酰胺、 2- (2- (1 -哌啶) 乙氨基） -4- (1- (3, 6,6-三甲基 -4-氧- 4,5， 6， 7_四氢吲 唑））苯甲酰胺、 2- (2- (1- (3,5-二甲基哌啶）） 乙氨基） -4- (1- (3，6,6_三甲基-4- 氧- 4， 5, 6， 7-四氢吲唑）) 苯甲酰胺、 2- (2 -（1， 2， 3)三氮唑乙氨基) -4- (1- (3,6,6- 三甲基 -4-氧- 4, 5, 6, 7-四氢吲唑））苯甲酰胺、 2-环丙垸氨基 -4- (1- (3， 6, 6-三甲基 - 4- 氧- 4， 5， 6， 7-四氢吲唑）） 苯甲酰胺、 2- (1- (4- (2- (1-哌啶） 乙氧基） 哌啶）） - 4- The compound according to claim 57, wherein the compound is 2-(1-(3-hydroxypyrrolidino))-4-(1-(3,6,6-trimethyl). -4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(1-piperidine)-4-(1-(3,6,6-trimethyl-4-) Oxygen-4,5,6,7-tetrahydroindole))benzamide, 2-(2-diethylaminoethylamino)-4-(1-(3,6,6-trimethyl-4-) Oxygen-4,5,6,7-tetrahydroindole))benzamide, 2-(2-(4-morpholine)ethylamino)-4-(1-(3,6,6-trimethyl) -4-oxo-4, 5, 6, 7-tetrahydroindole))benzamide, 2-(1-(4-hydroxypiperidine)) 4- (1-(3, 6, 6-trimethyl) Base _4-oxo-4, 5, 6, 7-tetrahydroanthracene))benzamide, 2-(4-hydroxycyclohexylamino)-4-(1-(3,6,6-trimethyl) -4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2_(2-(1,2,3)triazoleethylamino)-4-(1- (3, 6 , 6-trimethyl-4-oxo-4,5,6,7-tetrahydroindole))benzamide, 2-(1-(4-(2-(4-morpholine)ethyl)piperidin Oxide)) -4- (1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydroanthracene))benzamide, 2-(2-diethylaminoethylamino)-4-(1-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole))benzamide, 2-cyclohexylamino-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole) )) Benzamide, 2-(2-(1-piperidyl)ethylamino)-4-(1-(3, 6,6-trimethyl-4-oxo-4,5, 6, 7_4 Hydrocarbazole))benzamide, 2-(2-(1-(3,5-dimethylpiperidine))ethylamino)-4-(1-(3,6,6-trimethyl-4) - Oxygen-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(2-(1,2,3)triazoleethylamino)-4-(1-(3,6, 6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-cyclopropylamino-4-(1-(3,6,6-trimethyl) - 4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-(2-(1-piperidinyl)ethoxy)piperidine))-4 -
(1- (3， 6, 6-三甲基 -4-氧- 4, 5, 6， 7-四氢吲唑）)苯甲酰胺、 2- (1- (4- (2-羟乙基） 哌嗪）） -4- (1 (3， 6, 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 2- (2- (4 -吗 啉） 乙氨基）—4— (1- (3,6,6-三甲基 -4-氧- 4, 5， 6， 7-四氢吲唑）） 苯甲酰胺、 2- (4- 羟基环己氨基） -4- (1- (3, 6， 6-三甲基 -4-氧 -4， 5， 6， 7-四氢吲唑））苯甲酰胺、 2- (4 -氨基乙酰氧基环己氨基) -4- (1- (3, 6， 6-三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑）） 苯甲酰胺、 2- (2- (1 -吡咯烷基) 乙氨基） -4- (1- (3， 6, 6 -三甲基- 4 -氧- 4， 5， 6， 7-四 氢吲唑））苯甲酰胺、 2- (1-哌嗪) -4- (1- (3,6,6-三甲基 -4-氧- 4， 5, 6， 7-四氢吲唑）） 苯甲酰胺、 2- (1 (3 -羟基哌啶）) -4- (1- (3,6,6-三甲基 -4-氧- 4,5， 6， 7_四氢吲唑）） 苯甲酰胺、 1- (6- (3 -氨基 -1H-吲唑）) - 3,6， 6_三甲基 -1， 5， 6， 7-四氢吲哚- 4-酮、 1-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-(4-(2-hydroxyethyl) Piperazine)) -4- (1 (3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) benzamide, 2- (2- (4) -morpholine)ethylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, 2- (4 - Hydroxycyclohexylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(4-amino Acetoxycyclohexylamino)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole)) benzamide, 2- (2 - (1 -pyrrolidinyl)ethylamino)-4-(1-(3,6,6-trimethyl- 4 -oxo-4,5,6,7-tetrahydrocarbazole))benzamide, 2-(1-piperazine)-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, 2-( 1 (3-hydroxypiperidine))-4-(1-(3,6,6-trimethyl-4-oxo-4,5,6-7-tetrahydrocarbazole))benzamide, 1- (6-(3-amino-1H-carbazole)) - 3,6,6-trimethyl-1,5,6,7-tetrahydroindole-4-one, 1-
(6- (3-氨基- 1H-吲唑）） -3, 6,6-三甲基 -1,5， 6, 7-四氢吲唑- 4 -酮、 2- (1- (4-羟基哌 啶）） -4- (9- (2，2-二甲基 - 4-氧- 1,2,3，4_四氢咔唑））苯甲酰胺、 2- (4-羟基环己氨 基） -4- (9- (2,2-二甲基 -4-氧- 1,2， 3, 4-四氢咔唑））苯甲酰胺、 2- (1- (4- (2-羟乙 基） 哌嗪）） -4- (9- (2， 2-二甲基 -4-氧- 1,2,3,4-四氢咔唑）） 苯甲酰胺、 2- (1- (4- 羟基哌啶）） -4- (9- (2， 2_二甲基 -4 -氧- 6 -三氟甲基 _1， 2,3， 4_四氢咔唑））苯甲酰胺、 2- (4-羟基环己氨基） -4- (9- (2,2-二甲基 -4-氧- 6-三氟甲基 -1,2, 3， 4-四氢咔唑）） 苯甲酰胺、 2- (4-羟基环己氨基） -4- (1- (6， 6-二甲基 -4-氧- 3-三氟甲基- 4， 5， 6， 7-四氢吲唑）)苯甲酰胺、 N- (2- [1， 2， 3]三氮唑乙基) -4- (1- (3， 6， 6)三甲基 -4 -氧 - 4， 5， 6， 7-四氢吲唑））苯甲酰胺、 N- (2- (4-吗啉） 乙基) -4- (1- (3， 6， 6)三甲 基- 4 -氧- 4， 5， 6, 7-四氢吲唑）)苯甲酰胺、 N- (4-羟基环己基) -4- (1- (3， 6， 6)三 甲基 -4-氧- 4， 5， 6， 7 -四氢吲唑）)苯甲酰胺、或 N- (2- (1- (4 -羟基哌啶）)乙基) -4 -(6-(3-Amino-1H-carbazole))-3,6,6-trimethyl-1,5,6,7-tetrahydrocarbazole-4-enone, 2-(1- (4- Hydroxypiperidine))-4-(9-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole))benzamide, 2-(4-hydroxycyclohexane Amino)-4-(9-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole))benzamide, 2- (1- (4- (2- Hydroxyethyl) piperazine)) -4- (9-(2,2-dimethyl-4-oxo-1,2,3,4-tetrahydrocarbazole)) benzamide, 2- (1- (4-hydroxypiperidine))-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole)) Amide, 2-(4-hydroxycyclohexylamino)-4-(9-(2,2-dimethyl-4-oxo-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazole )) Benzamide, 2-(4-hydroxycyclohexylamino)-4-(1-(6, 6-dimethyl-4-oxo-3-trifluoromethyl- 4, 5, 6, 7- Tetrahydrocarbazole))benzamide, N-(2-[1,2,3]triazolylethyl)-4-(1-(3, 6, 6)trimethyl-4-oxo-4 , 5, 6, 7-tetrahydrocarbazole))benzamide, N-(2-(4-morpholine)ethyl)-4-(1-(3, 6, 6)trimethyl- 4 - Oxygen - 4, 5, 6, 7-tetrahydrocarbazole))benzamide, N-(4-hydroxycyclohexyl)-4-(1-(3, 6, 6)trimethyl-4-oxo-4, 5, 6, 7-tetrahydrocarbazole)) benzamide, or N-(2-(1-(4-hydroxypiperidinyl))ethyl)-4
(1-（3， 6， 6)三甲基 -4-氧- 4， 5， 6， 7-四氢吲唑））苯甲酰胺。 (1-(3, 6, 6) Trimethyl-4-oxo-4,5,6,7-tetrahydrocarbazole))benzamide.
59、 一种权利要求 1至 58之一所述的化合物在药学上可接受的盐。  59. A pharmaceutically acceptable salt of a compound of any one of claims 1 to 58.
60、 根据权利要求 59所述的化合物在药学上可接受的盐， 其特征在于： 所述的盐 为硫酸盐、盐酸盐、磷酸盐、氢溴酸盐、柠檬酸盐、马来酸盐、苯乙醇酸盐、琥珀酸盐、 富马酸盐、 乙酸盐、 乳酸盐、 硝酸盐、 磺酸盐、 对甲苯磺酸盐、 甲磺酸盐、 苯甲酸盐、 酒石酸盐或碳酸盐。  The pharmaceutically acceptable salt of the compound according to claim 59, wherein the salt is a sulfate, a hydrochloride, a phosphate, a hydrobromide, a citrate or a maleate. , phenate, succinate, fumarate, acetate, lactate, nitrate, sulfonate, p-toluenesulfonate, methanesulfonate, benzoate, tartrate or carbon Acid salt.
61、 权利要求 56所述的化合物在制备治疗肿瘤药物中的应用。  61. Use of a compound of claim 56 in the manufacture of a medicament for the treatment of tumors.
62、 权利要求 57所述的化合物在制备治疗肿瘤药物中的应用。  62. Use of a compound of claim 57 in the manufacture of a medicament for the treatment of tumors.
63、 权利要求 58所述的化合物在制备治疗肿瘤药物中的应用。  63. Use of a compound of claim 58 in the manufacture of a medicament for the treatment of tumors.
64、权利要求 60所述的化合物在药学上可接受的盐在制备治疗肿瘤药物中的应用。 摘要 本发明公开了一种具有通式 （I ) 的化合物及其盐， 本发明的化合物及其盐具有抑 制肿瘤细胞及恶性细胞生长的特点， 如乳腺癌、肺癌、 宫颈癌、直肠癌、 前列腺癌、 肝 癌、 血癌等癌细胞。 64. Use of a pharmaceutically acceptable salt of a compound of claim 60 in the manufacture of a medicament for the treatment of a tumor. SUMMARY OF THE INVENTION The present invention discloses a compound of the general formula (I) and a salt thereof, and the compound of the present invention and a salt thereof have the characteristics of inhibiting the growth of tumor cells and malignant cells, such as breast cancer, lung cancer, cervical cancer, rectal cancer, and prostate. Cancer cells such as cancer, liver cancer, and blood cancer.
Figure imgf000104_0001
Figure imgf000104_0001
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