CN113831325A - 新型吲哚类衍生物及其制备方法和应用 - Google Patents
新型吲哚类衍生物及其制备方法和应用 Download PDFInfo
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- CN113831325A CN113831325A CN202010578588.4A CN202010578588A CN113831325A CN 113831325 A CN113831325 A CN 113831325A CN 202010578588 A CN202010578588 A CN 202010578588A CN 113831325 A CN113831325 A CN 113831325A
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- CN
- China
- Prior art keywords
- ethynyl
- aminopyrimidin
- hydroxycyclohexyl
- indol
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title claims abstract description 57
- 150000002475 indoles Chemical class 0.000 title claims abstract description 20
- 229940054051 antipsychotic indole derivative Drugs 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 239000000651 prodrug Substances 0.000 claims abstract description 27
- 229940002612 prodrug Drugs 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 239000012453 solvate Substances 0.000 claims abstract description 25
- 150000004677 hydrates Chemical class 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 10
- -1 amino Chemical group 0.000 claims description 250
- 239000001257 hydrogen Substances 0.000 claims description 90
- 229910052739 hydrogen Inorganic materials 0.000 claims description 90
- 125000003118 aryl group Chemical group 0.000 claims description 65
- 150000003254 radicals Chemical class 0.000 claims description 45
- 229910052736 halogen Inorganic materials 0.000 claims description 38
- 150000002367 halogens Chemical class 0.000 claims description 38
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 125000001072 heteroaryl group Chemical group 0.000 claims description 30
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 30
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 29
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 23
- LSGKMZLPZFPAIN-UHFFFAOYSA-N 1h-indole-3-carboxamide Chemical compound C1=CC=C2C(C(=O)N)=CNC2=C1 LSGKMZLPZFPAIN-UHFFFAOYSA-N 0.000 claims description 20
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 125000001153 fluoro group Chemical group F* 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- 125000002883 imidazolyl group Chemical group 0.000 claims description 16
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 125000000335 thiazolyl group Chemical group 0.000 claims description 14
- 125000001544 thienyl group Chemical group 0.000 claims description 14
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 13
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 13
- 125000002971 oxazolyl group Chemical group 0.000 claims description 13
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000001041 indolyl group Chemical group 0.000 claims description 9
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 9
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 8
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 8
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 8
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 7
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 7
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 7
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 6
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 6
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 6
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 6
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
- 125000001931 aliphatic group Chemical group 0.000 claims description 5
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 5
- 229940043355 kinase inhibitor Drugs 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
- DWGRKURMWLQSNE-UHFFFAOYSA-N N-[[1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]indol-2-yl]methyl]benzamide Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C=C2CNC(C2=CC=CC=C2)=O)=N1 DWGRKURMWLQSNE-UHFFFAOYSA-N 0.000 claims description 4
- 150000001299 aldehydes Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000003909 protein kinase inhibitor Substances 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 3
- IOYNIRMQITUEKF-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]-N,N-dimethylindole-2-carboxamide Chemical compound CN(C)C(C(N(C1=C2)C3=NC(N)=NC=C3)=CC1=CC=C2C#CC1(CCCCC1)O)=O IOYNIRMQITUEKF-UHFFFAOYSA-N 0.000 claims description 3
- HLDRAWADLDXRKG-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]-N,N-dimethylindole-3-carboxamide Chemical compound CN(C)C(C(C(C1=C2)=CC=C2C#CC2(CCCCC2)O)=CN1C1=NC(N)=NC=C1)=O HLDRAWADLDXRKG-UHFFFAOYSA-N 0.000 claims description 3
- ZDSUUVAADDNIAJ-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]-N-(1,3-thiazol-2-yl)indole-3-carboxamide Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C(C(NC3=NC=CS3)=O)=C2)=N1 ZDSUUVAADDNIAJ-UHFFFAOYSA-N 0.000 claims description 3
- UFIRYJHDOAKMBB-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]-N-(1H-pyrazol-5-yl)indole-3-carboxamide Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C(C(NC3=NNC=C3)=O)=C2)=N1 UFIRYJHDOAKMBB-UHFFFAOYSA-N 0.000 claims description 3
- JNKNBLFMOCEEKR-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]-N-(2,2,2-trifluoroethyl)indole-3-carboxamide Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C(C(NCC(F)(F)F)=O)=C2)=N1 JNKNBLFMOCEEKR-UHFFFAOYSA-N 0.000 claims description 3
- PGCQNFAVMLPVHL-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]-N-(2-hydroxyethyl)indole-2-carboxamide Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C=C2C(NCCO)=O)=N1 PGCQNFAVMLPVHL-UHFFFAOYSA-N 0.000 claims description 3
- NPORJQKVDBTLGB-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]-N-(2-methoxyethyl)indole-2-carboxamide Chemical compound COCCNC(C(N(C1=C2)C3=CC=NC(N)=N3)=CC1=CC=C2C#CC1(CCCCC1)O)=O NPORJQKVDBTLGB-UHFFFAOYSA-N 0.000 claims description 3
- IZNJXMVRTFWIML-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]-N-(2-methoxyethyl)indole-3-carboxamide Chemical compound COCCNC(C(C(C1=C2)=CC=C2C#CC2(CCCCC2)O)=CN1C1=NC(N)=NC=C1)=O IZNJXMVRTFWIML-UHFFFAOYSA-N 0.000 claims description 3
- HGQLNIWPZCVTQE-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]-N-(3-methylphenyl)indole-2-carboxamide Chemical compound CC1=CC(NC(C(N(C2=C3)C4=NC(N)=NC=C4)=CC2=CC=C3C#CC2(CCCCC2)O)=O)=CC=C1 HGQLNIWPZCVTQE-UHFFFAOYSA-N 0.000 claims description 3
- OYDPYRPVOIQTJI-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]-N-(5-oxo-1,2-dihydropyrazol-3-yl)indole-3-carboxamide Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C(C(NC3=NNC(O)=C3)=O)=C2)=N1 OYDPYRPVOIQTJI-UHFFFAOYSA-N 0.000 claims description 3
- IQOFTPRAIUNPGX-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]-N-methylindole-3-carboxamide Chemical compound CNC(C(C(C1=C2)=CC=C2C#CC2(CCCCC2)O)=CN1C1=NC(N)=NC=C1)=O IQOFTPRAIUNPGX-UHFFFAOYSA-N 0.000 claims description 3
- YRTZAXIAPHUPHR-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]-N-pyridin-4-ylindole-2-carboxamide Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C=C2C(NC2=CC=NC=C2)=O)=N1 YRTZAXIAPHUPHR-UHFFFAOYSA-N 0.000 claims description 3
- XFPFHQWACDXOOH-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)-N-benzyl-6-[2-(1-hydroxycyclohexyl)ethynyl]indole-3-carboxamide Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C(C(NCC3=CC=CC=C3)=O)=C2)=N1 XFPFHQWACDXOOH-UHFFFAOYSA-N 0.000 claims description 3
- RJQNJVGXYCWPHS-UHFFFAOYSA-N 1-(2-aminopyrimidin-4-yl)-N-cyclopropyl-6-[2-(1-hydroxycyclohexyl)ethynyl]indole-2-carboxamide Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C=C2C(NC2CC2)=O)=N1 RJQNJVGXYCWPHS-UHFFFAOYSA-N 0.000 claims description 3
- AZYZRWDBPKYHMD-UHFFFAOYSA-N 3-[[4-[6-[2-(1-hydroxycyclohexyl)ethynyl]indol-1-yl]pyrimidin-2-yl]amino]benzonitrile Chemical compound N#CC1=CC(NC2=NC=CC(N3C4=CC(C#CC5(CCCCC5)O)=CC=C4C=C3)=N2)=CC=C1 AZYZRWDBPKYHMD-UHFFFAOYSA-N 0.000 claims description 3
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- DADSGHOHYQROCR-IBGZPJMESA-N [(3S)-3-aminopiperidin-1-yl]-[1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]indol-3-yl]methanone Chemical compound N[C@@H](CCC1)CN1C(C(C(C1=C2)=CC=C2C#CC2(CCCCC2)O)=CN1C1=NC(N)=NC=C1)=O DADSGHOHYQROCR-IBGZPJMESA-N 0.000 claims description 3
- SYJOLNGRHPSSMR-GOSISDBHSA-N [1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]indol-3-yl]-[(3R)-3-methylpiperazin-1-yl]methanone Chemical compound C[C@H](C1)NCCN1C(C(C(C1=C2)=CC=C2C#CC2(CCCCC2)O)=CN1C1=NC(N)=NC=C1)=O SYJOLNGRHPSSMR-GOSISDBHSA-N 0.000 claims description 3
- SYJOLNGRHPSSMR-SFHVURJKSA-N [1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]indol-3-yl]-[(3S)-3-methylpiperazin-1-yl]methanone Chemical compound C[C@H]1CN(CCN1)C(=O)C2=CN(C3=C2C=CC(=C3)C#CC4(CCCCC4)O)C5=NC(=NC=C5)N SYJOLNGRHPSSMR-SFHVURJKSA-N 0.000 claims description 3
- QDKVDNRMARPLSE-UHFFFAOYSA-N [1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]indol-3-yl]-[2-(2-hydroxyethyl)pyrrol-1-yl]methanone Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C(C(N3C(CCO)=CC=C3)=O)=C2)=N1 QDKVDNRMARPLSE-UHFFFAOYSA-N 0.000 claims description 3
- FFVCXUXWVNCSDZ-UHFFFAOYSA-N [1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]indol-3-yl]-[4-(2-hydroxyethyl)piperazin-1-yl]methanone Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C(C(N3CCN(CCO)CC3)=O)=C2)=N1 FFVCXUXWVNCSDZ-UHFFFAOYSA-N 0.000 claims description 3
- QWSJFAREKZMGNW-UHFFFAOYSA-N [1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]indol-3-yl]-morpholin-4-ylmethanone Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C(C(N3CCOCC3)=O)=C2)=N1 QWSJFAREKZMGNW-UHFFFAOYSA-N 0.000 claims description 3
- QFEPOIMWLJCSFW-UHFFFAOYSA-N [1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]indol-3-yl]-piperidin-1-ylmethanone Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C(C(N3CCCCC3)=O)=C2)=N1 QFEPOIMWLJCSFW-UHFFFAOYSA-N 0.000 claims description 3
- GCEHBQIPDGZXPR-UHFFFAOYSA-N [1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]indol-3-yl]-pyrrol-1-ylmethanone Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C(C(N3C=CC=C3)=O)=C2)=N1 GCEHBQIPDGZXPR-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- CYSIDCPBVCJYFF-UHFFFAOYSA-N N-[[1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]indol-2-yl]methyl]-1H-indole-2-carboxamide Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C=C2CNC(C2=CC3=CC=CC=C3N2)=O)=N1 CYSIDCPBVCJYFF-UHFFFAOYSA-N 0.000 claims description 2
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- ZBSPYKFWSRICMK-UHFFFAOYSA-N N-[[1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]indol-2-yl]methyl]-2-fluorobenzamide Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C=C2CNC(C(C=CC=C2)=C2F)=O)=N1 ZBSPYKFWSRICMK-UHFFFAOYSA-N 0.000 claims description 2
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- PHJCYAOVVVIZFC-UHFFFAOYSA-N N-[[1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]indol-2-yl]methyl]-3-methylbutanamide Chemical compound CC(C)CC(NCC(N(C1=C2)C3=NC(N)=NC=C3)=CC1=CC=C2C#CC1(CCCCC1)O)=O PHJCYAOVVVIZFC-UHFFFAOYSA-N 0.000 claims description 2
- UMYBFDKWJVRQNH-UHFFFAOYSA-N N-[[1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]indol-2-yl]methyl]-4-fluorobenzamide Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C=C2CNC(C(C=C2)=CC=C2F)=O)=N1 UMYBFDKWJVRQNH-UHFFFAOYSA-N 0.000 claims description 2
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- JUJBVXIQKXIGSD-UHFFFAOYSA-N N-[[1-(2-aminopyrimidin-4-yl)-6-[2-(1-hydroxycyclohexyl)ethynyl]indol-2-yl]methyl]-4-nitrobenzamide Chemical compound NC1=NC=CC(N2C3=CC(C#CC4(CCCCC4)O)=CC=C3C=C2CNC(C(C=C2)=CC=C2[N+]([O-])=O)=O)=N1 JUJBVXIQKXIGSD-UHFFFAOYSA-N 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000002393 azetidinyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 5
- 125000004432 carbon atom Chemical group C* 0.000 claims 4
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- 206010060862 Prostate cancer Diseases 0.000 claims 1
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- 208000029742 colonic neoplasm Diseases 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
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- 229940079593 drug Drugs 0.000 abstract description 6
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 168
- 238000005160 1H NMR spectroscopy Methods 0.000 description 84
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- 150000002431 hydrogen Chemical class 0.000 description 60
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
本发明属药物合成领域,涉及一类新型吲哚衍生物及其制备方法和应用,以及所述化合物的药学可接受的盐、水合物、溶剂化物或前药,它们的制备方法及其作为治疗剂特别是作为PAK抑制剂的用途。本发明的新型吲哚类衍生物,及其几何异构体或药学上可接受的盐、水合物、溶剂化物或前药如通式(I)所示,其中,各变量如权利要求书和说明书所述。
Description
技术领域
本发明属药物合成领域,涉及一类新型吲哚衍生物及其制备方法和应用,以及所述化合物的药学可接受的盐、水合物、溶剂化物或前药,它们的制备方法及其作为治疗剂特别是作为PAK抑制剂的用途。
背景技术
蛋白激酶是目前已知最大的超蛋白家族,自1954年发现蛋白激酶以来,目前已发现的蛋白激酶约有538种,其编码基因约占人类基因组的2%左右。蛋白激酶是一类磷酸转移酶,其作用是将ATP末端的γ磷酸基团转移到特定底物的氨基酸残基上,使其磷酸化,进而介导整个细胞进程。根据底物蛋白被磷酸化氨基酸残基的种类,可以将他们分为5类:丝氨酸/苏氨酸(Ser/Thr)蛋白激酶、酪氨酸(Tyr)蛋白激酶、组氨酸蛋白激酶、色氨酸蛋白激酶、天冬氨酸/谷氨酰胺蛋白激酶。蛋白激酶在信号转导中的主要作用有两个方面:其一是通过磷酸化作用调节蛋白的活性,在许多信号通路中磷酸化和被磷酸化是可逆激活的共同机制;其二是通过蛋白的逐级磷酸化,使信号逐级放大,引起细胞反应。研究表明,蛋白激酶对体内许多重要的生理过程起着关键性的调节作用,蛋白激酶磷酸化活性的异常会导致细胞调节发生紊乱,进而导致多种疾病的发生,如肿瘤、免疫性疾病、中枢神经系统疾病、糖尿病等。因此,蛋白激酶越来越成为治疗多种疾病的重要靶点。自2001年伊马替尼(Imatinib,STI571)获得FDA批准用于治疗慢性粒细胞白血病(CML),成为第一个上市的激酶抑制剂类抗肿瘤药以来,之后短短20年,已有52个蛋白激酶抑制剂上市。目前正在进行临床研究的170余个激酶抑制剂主要涉及约15-20种激酶靶标,约有50%的在研抑制剂是以已有上市药物的激酶作为靶标,从这个角度来说,对目前研究较少的激酶或尚无上市药物的激酶进行研究更容易产生突破性的进展,蛋白激酶抑制剂类药物的研究仍有巨大的发展空间。
p21活化激酶(PAKs,p21 activatedkinases)属于丝氨酸/苏氨酸家族,是Rho家族GTPases成员Cdc42(cell division cycle 42)和Rac的下游效应器,PAKs也是首个被发现的由Rho家族GTPase调节的激酶家族成员。PAKs通过N端的GTP酶结合域(GBD,GTPasebinding domain),也称作Cdc42/Rac结合域(CRIB),结合在Cdc42和Rac上并受其调控。根据其生化和结构特征,高等真核生物的PAKs被分为两类:I类PAKs(PAK1-PAK3),和II类PAKs(PAK4-PAK6)。
研究发现PAK能够与细胞内的多种蛋白产生相互作用,说明PAKs是一类多功能激酶,通过参与细胞内的多条信号通路,调节控制许多生物学功能,如细胞骨架重组、细胞迁移运动、细胞凋亡、有丝分裂等,除了参与调节细胞正常的生理活动外,PAK4还被发现与多种疾病的发生发展嘧切相关,特别是与恶性肿瘤的发生发展有嘧切的关系,因此,PAK4已经成为抗肿瘤药物研究的新的靶点。目前已经公开了一系列PAK4抑制剂,例如Staurosporine、PF3758309,KPT-9274、GNE-2861、CZH226等。尽管目前已经公开了一系列PAK4抑制剂,但是目前尚无PAK抑制剂药物上市,仍需要开发结构新颖的具有更好药效的化合物,经过不断努力,本发明设计具有通式(I)所示结构的化合物,并发现具有此类结构的化合物表现出较好的PAK4抑制活性并相对I类PAKs具有较好的选择性。
发明内容
本发明的目的在于提供一种通式为(I)的新型吲哚类衍生物,及其几何异构体或药学上可接受的盐、水合物、溶剂化物或前药:
其中:
W,X,Y,Z可以分别选自C或N。
R1选自:氢、C1-2烷基或-CH2-OH;
R2选自:氢、C1-6烷基、C3-6环烷基、6~10元芳基,5~10元杂芳基,且所述芳基或杂芳基可进一步被1~3个相同或不同的R2a取代;氢、卤素、氰基、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基或C1-4烷氧基;
或R1和R2连同他们所连接的碳原子一起形成一个C3-7环烷基或5-10元杂环烷基。所形成的环烷基可进一步被C1-2烷基或卤素所取代。
R3无取代,或R3选自:氢、卤素、氰基、C1-6烷基;
R4选自:氢、醛基、氰基、C1-6烷基、羰基、被-OH或氨基取代的C1-6烷基、-C1-6烷基氧基C1-4烷基、-C1-6烷基-C(=O)-N R4aR4b、-OC1-6烷基、被卤素取代的-OC1-6烷基、-C(=O)NR4aR4b、-NR4aR4b。其中R4a和R4b各自独立的选自氢、C1-4烷基、C2-4烷基氧基C1-4烷基、6~10元芳基,5~10元杂芳基;或R4a和R4b连同它们所连接的氮原子一起形成一个3-10元杂环基。且所述的芳基、杂芳基、杂环基可以任意地被1至3个氢、C1-4烷基、氨基、羟基、被一个羟基或氨基取代的C1-4烷基、或被一个或多个卤素取代的C1-4烷基、5~10元杂环基、6~10元芳基、5~10元芳杂基。
R5无取代,或R5选自:氢、氰基、C1-4醛基、C1-4酯基、C1-6烷基、C3-6环烷基、-C(=O)-NR5aR5b、-CNR5aR5b、NR5aR5b、6~10元芳环、5~10元杂环、被1~3个选自下组取代基取代的C1-6烷基:卤素、硝基、-OH、-OC1-4烷基、6~10元芳环以及5~10元杂环。R5a和R5b各自独立的选自下组:氢、C1-6烷基、C3-6环烷基、6~10元芳基、5~10元芳杂基。或R5a和R5b连同他们所连接的碳原子一起形成一个C3-7环烷基或5-10元杂环烷基。所形成的环烷基可进一步被C1-2烷基或卤素所取代。其中芳基和杂环可以任选的被1至3个选自以下各项的取代基取代:氢、羟基、氨基、卤素、氰基、C1-4烷基、C1-4烷氧基、被一个或多个卤素或羟基取代的C1-4烷基以及被一个或多个卤素或羟基取代的C1-4烷基氧基、5~10元杂环基、6~10元芳基、5~10元芳杂基。
R6选自:氢、C1-6烷基、C3-6的环烷基、C1-6亚烷基-C3-6环烷基、苯基、5-6元杂芳基、5-6元芳基或5-6元杂芳基取代的C1-6烷基、-C(=O)R6a,其中R6a选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C1-6杂烷基、3-6元环烷基、3-6元杂烷基、-(C1-6亚烷基)-(3-8元环烷基)、-(C1-6亚烷基)-(3-8元杂环烷基)、-(C1-6亚烷基)-(6元芳基)、(C1-6亚烷基)-(5-6元杂芳基)、苯基和5-6元杂芳基,所述的杂烷基、杂芳基含有1-3个N、O或S的杂原子。
其中R6的脂肪基和/或芳香基部分,可以任选的被1至多个选自下列的取代基取代:氢,羟基,卤素,硝基,氨基,氰基,游离的、成盐的、酯化的、酰胺化的羧基,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6烷基酰基,C1-6烷基亚磺酰基、磺酰基,氨基甲酰基,任选被羟基、氨基、卤代的C1-6烷基或C1-6烷氧基,被氢、羟基、氨基或游离的、成盐的、酯化的、酰胺化的羧基取代的C3-6环烷基或C3-6杂环烷基,被单或二(C1-6烷基)取代的胺基或C1-6烷基酰胺基,被单或二(C1-6烷基)取代的胺基甲酰基,被氢、羟基、氨基、烷基取代的5~10元杂芳基,其中所述杂环烷基与杂芳基分别含有1至3个选自O、N和S的杂原子。
R7选自:氢、氰基、氨基、C1-6烷基、C1-6烷氧基、C1-6烷基氨基。
本发明优选涉及通式(I)所示新型吲哚类衍生物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药,
其中:
W,X,Y,Z可以分别选自C或N。
R1选自:氢、C1-2烷基或-CH2-OH;
R2选自:氢、C1-6烷基、C3-6环烷基、6~10元芳基,5~10元杂芳基。所述芳基或杂芳基进一步被1~3个相同或不同的R2a取代;卤素、氰基、C1-4烷基、C1-4烷氧基、被一个或多个氟取代的C1-4烷基以及被一个或多个氟取代基取代的C1-4烷基氧基;
或R1和R2连同他们所连接的碳原子一起形成一个C3-7环烷基。所形成的环烷基可进一步被C1-2烷基或卤素所取代。
R3无取代,或R3选自:氢、卤素、氰基、C1-4烷基;
R4选自:氢、C1-4醛基、C1-4酯基、羰基、氰基、C1-6烷基、被一个-OH或氨基取代的C1-6烷基、-C1-6烷基氧基C1-4烷基、-C1-6烷基-C(=O)-NR4aR4b、-OC1-6烷基、被一个氟或多个氟取代基取代的C1-6烷氧基、-C(=O)NR4aR4b、-NR4aR4b。其中R4a和R4b各自独立的选自氢和C1-4烷基、C2-4烷基氧基C1-4烷基、6~10元芳基,5~10元杂芳基;或R4a和R4b连同它们所连接的氮原子一起形成一个3-10元杂环基。且芳基、杂芳基、杂环基这些基团各自可以任意地被1至3个C1-4烷基、氨基、羟基、被一个羟基或氨基取代基取代的C1-4烷基取代或被一个或多个氟取代基取代的C1-4烷基取代。
R5无取代,或R5选自:氢、氰基、C1-4醛基、C1-6烷基、C3-6环烷基、-C(=O)-NR5aR5b、-CNR5aR5b、NR5aR5b、苯基、5~6元杂环基、被1~3个如下取代基取代的C1-6烷基:卤素、-OH、C1-4烷氧基、6~10元芳基以及5~10元杂环基。R5a和R5b各自独立的选自:氢、C1-6烷基、C3-6环烷基、苯基、5~6元芳杂基。或R5a和R5b连同他们所连接的碳原子一起形成一个C3-10环烷基或5-10元杂环烷基。所形成的环烷基可进一步被C1-2烷基或氟所取代。
R5中所涉及的芳基和芳杂基主要包括:苯基、萘基、噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并噻吩基、苯并呋喃基、吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基。且芳基或杂环基可以任选的被1至3个选自以下各项的取代基取代:氢、羟基、氨基、卤素、氰基、C1-4烷基、C1-4烷氧基、被一个或多个氟取代的C1-4烷基以及被一个或多个氟取代基取代的C1-4烷基氧基。
R6选自:氢、C1-6烷基、C3-6的环烷基、C1-6亚烷基-C3-6环烷基、苯基、5-6元杂芳基、苯基取代的C1-6烷基、5-6元杂芳基取代的C1-6烷基、-C(=O)R6a,其中R6a选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C1-6杂烷基、3-6元环烷基、3-6元杂烷基、-(C1-6亚烷基)-(3-8元环烷基)、-(C1-6亚烷基)-(3-8元杂环烷基)、-(C1-6亚烷基)-(6元芳基)、(C1-6亚烷基)-(5-6元杂芳基)、6元芳基和5-6元杂芳基。其中芳基和芳杂基包括:噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并噻吩基、苯并呋喃基、吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基。
其中R6的脂肪基和/或芳香基部分,可以任选的被1至5个选自下列的取代基取代:氢,羟基,卤素,硝基,胺基,氰基,游离的、成盐的、酯化的、酰胺化的羧基,C1-6烷基,C1-6烯基,C1-6炔基,C1-6烷氧基,C1-6烷基酰基,C1-6烷基亚磺酰基、磺酰基,氨基甲酰基,任选被羟基、氨基、卤代的C1-6烷基或C1-6烷氧基,被氢、羟基、氨基或游离的、成盐的、酯化的、酰胺化的羧基取代的C3-6环烷基或C3-6杂环烷基,被单或二(C1-6烷基)取代的胺基或C1-6烷基酰胺基,被单或二(C1-6烷基)取代的胺基甲酰基,被氢、羟基、氨基、烷基取代的5~10元杂芳基,其中所述杂环烷基与杂芳基分别含有1至3个选自O、N和S的杂原子。
R7选自:氢、氰基、氨基、甲基、甲氧基、甲氨基。
本发明优选涉及通式(I)所示新型吲哚类衍生物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药,
其中:
W,Y,Z可以分别选自C或N;
X选自C;
R1和R2连同他们所连接的碳原子一起形成一个C3-7环烷基。所形成的环烷基可进一步被C1-2烷基或氟所取代。
R3选自:氢、卤素、氰基、甲基;
当Y为N时,R3无取代;
R4选自:氢、C1-4醛基、C1-4酯基、羰基、氰基、C1-4烷基、被一个-OH或氨基取代的C1-6烷基、-C(=O)NR4aR4b。其中R4a和R4b各自独立的选自氢、C1-4烷基、C2-4烷基氧基C1-4烷基、6-10元芳基,5~6元杂环基;或R4a和R4b连同它们所连接的氮原子一起形成一个3-10元杂环基。
所述的芳基或杂环基选自:苯基、萘基、哌啶基、哌嗪基、吗啉基、吡咯烷基、高哌嗪基、氮杂环丁烷基、咪唑基、吡唑基、四氢呋喃基、噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基以及吡嗪基。且芳基、杂环基各自可以任意地被1至3个氢、C1-4烷基、氨基、羟基、被一个羟基或氨基取代基取代的C1-4烷基取代或被一个或多个氟取代基取代的C1-4烷基取代。
R5选自:氢、氰基、醛基、C1-6烷基、C3-6环烷基、-C(=O)-NR5aR5b、-CNR5aR5b、NR5aR5b、6-10元芳基、5~6元杂环、被1~3个选自下组取代基取代的C1-6烷基:卤素、-OH、-OC1-4烷基、苯基以及5~6元杂环基。R5a和R5b各自独立的选自:氢、C1-6烷基、C3-6环烷基、6元芳基、5~6元芳杂基。或R5a和R5b连同他们所连接的碳原子一起形成一个C3-10环烷基或杂环烷基。所形成的环烷基可进一步被C1-2烷基和氟所取代。
所述的芳基或芳杂基主要包括:苯基、萘基、噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、哒嗪基、苯并噻吩基、吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并恶唑基。且芳基和杂环可以任选的被1至3个选自以下各项的取代基取代:氢、羟基、氨基、卤素、氰基、C1-4烷基、C1-4烷氧基、被一个或多个氟取代的C1-4烷基以及被一个或多个氟取代基取代的C1-4烷基氧基。
当W为N时,R5无取代;
R6选自:氢、C1-6烷基、C3-6的环烷基、C1-6亚烷基-C3-6环烷基、苯基、5-6元杂芳基、苯基取代的C1-6烷基、5-6元杂芳基取代的C1-6烷基-、-C(=O)R6a。其中R6a选自氢、C1-6烷基、C2-6链烯基、C1-6杂烷基、3-6元环烷基、3-6元杂烷基、-(C1-6亚烷基)-(3-8元环烷基)、-(C1-6亚烷基)-(3-8元杂环烷基)、-(C1-6亚烷基)-(6元芳基)、(C1-6亚烷基)-(5-6元杂芳基)、苯基和5-6元杂芳基。其中芳基和芳杂基包括:噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并噻吩基、苯并呋喃基、吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基。
其中R6的脂肪基和/或芳香基部分,可以任选的被1至5个选自下列的取代基取代:氢,羟基,卤素,硝基,胺基,氰基,游离的、成盐的、酯化的、酰胺化的羧基,C1-6烷基,C1-6烯基,C1-6炔基,C1-6烷氧基,C1-6烷基酰基,C1-6烷基亚磺酰基、磺酰基,氨基甲酰基,任选被羟基、氨基、卤代的C1-6烷基或C1-6烷氧基,被氢、羟基、氨基或游离的、成盐的、酯化的、酰胺化的羧基取代的C3-6环烷基或C3-6杂环烷基,被单或二(C1-6烷基)取代的胺基或C1-6烷基酰胺基,被单或二(C1-6烷基)取代的胺基甲酰基,被氢、羟基、氨基、烷基取代的5~10元杂芳基,其中所述杂环烷基与杂芳基分别含有1至3个选自O、N和S的杂原子。
R7选自:氢、氨基、甲基、甲氧基。
本发明优选涉及通式(I)所示新型吲哚类衍生物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药,
其中:
W,X,Y,Z分别选自C。
R1和R2连同他们所连接的碳原子一起形成一个C3-7环烷基。所形成的环烷基可进一步被C1-2烷基和氟所取代。
R3选自:氢、氟、氯。
R4选自:氢、C1-4醛基、氰基、-C(=O)NR4aR4b。其中R4a和R4b各自独立的选自氢和C1-3烷基、C2-4烷基氧基C1-4烷基、苯基,5~6元杂环基;或R4a和R4b连同它们所连接的氮原子一起形成一个3-10元杂环基。
所述的杂环基选自:哌啶基、哌嗪基、吗啉基、吡咯烷基、高哌嗪基、咪唑基、吡唑基、噻吩基、噻唑基、噁唑基、吡啶基。且所述的苯基、杂环基可以任意地被1至3个C1-4烷基、氨基、羟基、被一个羟基或氨基取代的C1-4烷基或被一个或多个氟取代的C1-4烷基。
R5选自:氢、氰基、C1-4醛基、C1-6烷基、C3-6环烷基、-C(=O)-NR5aR5b、-CNR5aR5b、NR5aR5b、苯基、5~6元杂环基、被1~3个如下取代基取代的C1-6烷基:-OH、-OC1-4烷基、苯基以及5~6元杂环。R5a和R5b各自独立的选自下组:氢、C1-4烷基、C3-6环烷基、苯基、5~6元芳杂基。
R5中所涉及的芳基和芳杂基主要包括:苯基、噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、吡啶基、吲哚基。且芳基和芳杂基可以任选的被1至3个选自以下各项的取代基取代:氢、羟基、氨基、卤素、氰基、C1-4烷基、C1-4烷氧基、被一个或多个氟取代的C1-4烷基以及被一个或多个氟取代基取代的C1-4烷基氧基。
R6选自:氢、C1-4烷基、C3-6的环烷基、C1-6亚烷基-C3-6环烷基、苯基、5-6元杂芳基、-C1-6亚烷基-6元芳基、C1-6亚烷基-5-6元杂芳基、-C(=O)R6a。其中R6a选自氢、C1-6烷基、C1-6杂烷基、3-6元环烷基、3-6元杂烷基、-(C1-6亚烷基)-(3-8元环烷基)、-(C1-6亚烷基)-(3-6元杂环烷基)、-(C1-6亚烷基)-(6元芳基)、(C1-6亚烷基)-(5-6元杂芳基)、苯基和5-6元杂芳基。其中芳基和芳杂基包括:噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、吡啶基、嘧啶基。
其中R6的脂肪基和/或芳香基部分,可以任选的被1至5个选自下列的取代基取代:氢,羟基,卤素,硝基,胺基,氰基,游离的、成盐的、酯化的、酰胺化的羧基,C1-6烷基,C1-6烯基,C1-6炔基,C1-6烷氧基,C1-6烷基酰基,C1-6烷基亚磺酰基、磺酰基,氨基甲酰基,任选被羟基、氨基、卤代的C1-6烷基或C1-6烷氧基,被氢、羟基、氨基或游离的、成盐的、酯化的、酰胺化的羧基取代的C3-6环烷基或C3-6杂环烷基,被单或二(C1-6烷基)取代的胺基或C1-6烷基酰胺基,被单或二(C1-6烷基)取代的胺基甲酰基,被氢、羟基、氨基、烷基取代的5~10元杂芳基,其中所述杂环烷基与杂芳基分别含有1至3个选自O、N和S的杂原子。
R7选自下组:氢、氨基、甲基、甲氧基。
本发明优选涉及通式(I)所示新型吲哚类衍生物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药,
其中:
W,X,Y,Z分别选自C。
R1和R2连同他们所连接的碳原子一起形成C3-7环烷基。
R3选自:氢、氟、氯。
R4选自:氢、C1-4醛基、氰基、-C(=O)NR4aR4b。其中R4a和R4b各自独立的选自氢和C1-3烷基、C2-4烷基氧基C1-4烷基、苯基、5~6元杂环基;或R4a和R4b连同它们所连接的氮原子一起形成一个3-10元杂环基。
所述的杂环基选自:苯基、哌啶基、哌嗪基、吗啉基、吡咯烷基、高哌嗪基、吡唑基、噻唑基。且所述的苯基、杂环基可以任意地被甲基、氨基、羟基、羟乙基、吗啉基取代。
R5选自:氢、氰基、C1-4醛基、-C(=O)-NR5aR5b、-CNR5aR5b、被1~3个如下取代基取代的C1-6烷基:-OH、C1-4烷氧基、6元芳环以及5~6元芳杂环。R5a和R5b各自独立的选自:氢、C1-3烷基、C3-6环烷基、苯基、5~6元芳杂基。
所述的芳基或芳杂基包括:苯基、噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、吡啶基、吲哚基。且芳基和芳杂环可以任选的被1至3个如下取代基取代:氢、羟基、氨基、氟、氯、氰基、硝基、甲基、甲氧基、三氟甲基、三氟甲氧基。
R6选自:氢、C1-3烷基、甲氧基乙基、C3-6的环烷基、苯基、5-6元杂芳基、(C1亚烷基)-(6元芳基)、-(C1亚烷基)-(5-6元杂芳基)。其中芳基和芳杂基包括:噻吩基、噻唑基、吡唑基、咪唑基、吡啶基、嘧啶基。且芳基和杂环可以任选的被1至3个选自以下各项的取代基取代:氢、羟基、氨基、氟、氯、氰基、硝基、甲基、甲氧基、三氟甲基、三氟甲氧基、磺酰氨基、甲基磺酰氨基。
R7选自:氢、氨基、甲基、甲氧基。
本发明优选涉及通式(I)所示新型吲哚类衍生物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药优选以下化合物,但这些化合物并不意味着对本发明的任何限制:
1-((1-(2-氨基嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-氨基嘧啶-4-基)-5-氟-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-氨基嘧啶-4-基)1H-吡咯[3,2-b]并吡啶-6-基)乙炔基)环己基-1-醇
1-((1-(2-氨基嘧啶-4-基)-1H-吲唑-6-基)乙炔基)环己基-1-醇
1-((2-氨基嘧啶-4-基)-1H-吡咯[2,3-b]并吡啶-6-基)乙炔基)环己基-1-醇
1-((2-氨基嘧啶-4-基)-1H-吡咯[3,2-c]并吡啶-6-基)乙炔基)环己基-1-醇
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(哌嗪-1-基)甲酮
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺
1-((1-(2,6-二氨基嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-(2-氨基嘧啶-4-基)-6-(1-羟基环己基)乙炔基)-1H-吲哚-3-甲醛
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(吡咯-1-基)甲酮
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(哌啶-1-基)甲酮
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N,N-二甲基-1H-吲哚-3-甲酰胺
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(吗啉基)甲酮
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-甲基哌嗪-1-基)甲酮
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-甲基-1H-吲哚-3-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(噻唑-2-基)-1H-吲哚-3-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-苯基-1H-吲哚-3-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲腈
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-甲氧乙基)-1H-吲哚-3-甲酰胺
1-(2-氨基嘧啶-4-基)-N-苄基-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-(2-羟乙基)哌嗪-1-基)甲酮
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(2-(羟乙基)吡咯-1-基)甲酮
1-(2-氨基嘧啶-4-基)-N-(5-羟基-1H-吡唑-3-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺
(R)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-甲基哌嗪-1-基)甲酮
(S)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-甲基哌嗪-1-基)甲酮
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3,5-二甲基哌嗪-1-基)甲酮
(3-氨基-1H-吡唑-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(1H-吡唑-3-基)-1H-吲哚-3-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2,2,2-三氟乙基)-1H-吲哚-3-甲酰胺
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-吗啉基哌啶-1-基)甲酮
(R)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-羟基哌啶-1-基)甲酮
(S)-(3-氨基哌啶-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮
(S)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(哌啶-3-基)1H-吲哚-3-甲酰胺
(R)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(哌啶-3-基)1H-吲哚-3-甲酰胺
(R)-(3-氨基哌啶-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮
(S)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-氨基吡咯-1-基)甲酮
(S)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡咯-3-基)1H-吲哚-3-甲酰胺
(R)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡咯-3-基)1H-吲哚-3-甲酰胺
4-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-羰基)哌嗪-2-酮
1-((1-(2-苄胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-((噻吩-2-甲基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1-((1-(2-((2-氟苯基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1-((1-(2-((2-甲氧乙基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1-((1-(2-((2-氯苄基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1-((1-(2-((4-氟苯基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1-((1-(2-(苯胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔)环己基-1-醇
1-((1-(2-((3-氯苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔)环己基-1-醇
1-((1-(2-((3-氯-4-氟苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
3-((4-(6-((1-羟基环己基)乙炔基)-1H-吲哚-1-基)嘧啶-2-基)氨基)苯甲腈
1-((1-(2-((4-甲氧基苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-((3-硝基苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-(间甲基苯氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-((4-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-((2-(三氟甲基)苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-(邻甲基苯氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-((2-氟苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-((2-甲氧基乙基)氨基)嘧啶-4-基)-1H-吲哚-6基)乙炔基)环己基-1-醇
3-((4-(6-((1-羟基环己基)乙炔基)1H-吲哚-1-基)嘧啶-2-基)氨基)苯磺酰胺
1-((1-(2-(环己氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)苯甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-3-甲基苯甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-硝基苯甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-2-硝基苯甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-甲氧基苯甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-氟苯甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-2-氟苯甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-异戊酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-1H-吲哚-6-甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-1H-吲哚-2-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-苯基-1H-吲哚-2-甲酰胺
乙基1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-羧酸酯
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡啶-4-基)-1H-吲哚-2-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(间甲苯基)-1H-吲哚-2-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N,N-二甲基-1H-吲哚-2-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-甲氧基乙基)-1H-吲哚-2-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-羟基乙基)-1H-吲哚-2-甲酰胺
1-(2-氨基嘧啶-4-基)-N-环丙基-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺
N-烯丙基-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺
1-(2-氨基嘧啶-4-基)-N-乙基-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺
1-((1-(2-氨基嘧啶-4-基)-2-(2-羟丙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇的制备
1-((1-(2-氨基嘧啶-4-基)-2-(2-羟基-2-(噻吩-2-基)乙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-氨基嘧啶-4-基)-2-(2-羟基-2-苯乙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
而且,按照本发明所属领域的一些通常方法,本发明中通式(I)的衍生物可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐,与下列酸加成的盐是特别优选的:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
此外,本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式(I)的衍生物,它们自身可能具有较弱的活性甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明中“卤素”是指氟、氯、溴或碘代;“烷基”是指直链或支链的烷基;“亚烷基”是指直链或支链的亚烷基;“芳基”是指除去芳烃中的一个或不同位置的两个氢原子而得到的有机基团,如苯基、萘基;“杂芳基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系,该环状体系是指具有芳香性的,并且除去环状体系中的一个或不同位置的两个氢原子而得到的有机基团,如噻唑基,咪唑基、吡啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、呋喃基、噻吩基、吡咯基,吲哚基,苯并噻唑基,噁唑基,异噁唑基,萘基,喹啉基,异喹啉基,苯并咪唑基,苯并噁唑基等;杂环烷基是指含有一个或多个选自N、O、S的杂原子的单环的环状体系,如四氢吡咯烷基、吗啉基、哌嗪基、哌啶基、四氢吡唑烷基、四氢咪唑烷基和四氢噻唑啉基等。
本发明可以含有通式(I)的衍生物,及其药学上可接受的盐、水合物、溶剂化物或前药作为活性成份,与药学上可接受的载体或赋型剂混合制备成组合物,并制备成临床上可接受的剂型,上述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用,只要它们不产生其他不利的作用,例如过敏反应。
本发明的药用组合物可配制成若干种剂型,其中含有药物领域中一些常用的赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。
用于本发明药物组合物的载体是药物领域中可得到的常见类型,包括:粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防腐剂、加溶剂和基质等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下不稳定的,可将其配制成肠衣片剂。
本发明所述的化合物,及其药学上可接受的盐、水合物、溶剂化物或前药或其药物组合物可以作为蛋白激酶抑制剂,并用于制备抗肿瘤药物。
所述的蛋白激酶为二类PAK蛋白激酶。
本发明还包括所述的化合物,及其药学上可接受的盐、水合物、溶剂化物或前药或其药物组合物治疗由蛋白激酶活性介导的哺乳动物疾病状况的方法,它包含对哺乳动物施以可接受量的本发明的化合物、盐、水合物、溶剂合物或前药。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解,下述实例和制备例的范围并不以任何方式限制本发明的范围。按照本发明的式(I)的化合物,可按照以下路线1-7所示的方法制备得来,这些合成路线中应用的全部可变因数如权利要求中的定义。
制备式(I)化合物时,可能需要对中间体的远程官能团(例如伯胺或仲胺)进行保护。进行该保护的必要性取决于远程官能团的性质和制备方法的条件。适当的氨基保护包括乙酰基、三氟乙酰基、叔丁氧基羰基(Boc)、苄氧基羰基(CBz)和9-芴基甲氧基羰基(Fmoc)。
本发明的式(I)化合物可按照以下所提出来的流程来合成,其中“R”在每次出现时独立的代表非干扰取代基。
在此,‘Cs2CO3’意指碳酸铯,‘DCM’意指二氯甲烷,‘DMF’意指N,N-二甲基甲酰胺,‘DMSO’意指二甲亚砜,‘Et3N’意指三乙胺,‘EA’意指乙酸乙酯,‘HATU’意指六氟磷酸(二甲基氨基)-N,N-二甲基(3H-[1,2,3]三唑[4,5-b]吡啶-3-基氧基)甲亚基,‘MeOH’意指甲醇,‘THF’意指四氢呋喃,‘TFAA’意指三氟乙酸酐,‘HCl’意指盐酸,‘Boc’意指叔丁氧羰基。
路线1
路线1:示出了制备式(I)化合物的方法,其中W,X,Y,Z和R1-R7如权利要求书中所定义。可以在加热条件下DMF中,使用四(三苯基膦)钯(Pd(PPh)3)4、CuI以及碱(如Et3N)使式1的吲哚与炔基醇发生薗头偶合反应(Sonogashira coupling reaction),得到式(I)化合物。式炔基醇是可商业购买或通过合成方法制备。
路线2
路线2:将N杂吲哚A-1和2-氨基-4-氯嘧啶在碳酸铯条件下发生亲核反应得中间体A-2,然后通过路线1的方法将A-2发生Sonogashira反应,生成本发明的化合物。
路线3
路线3:将6-溴吲哚在三氟乙酸酐和氢氧化钠的处理下,得到中间体A-4的6-溴吲哚-3-羧酸,使用草酰氯和甲醇处理中间体A-5,得酯化中间体A-6;然后将中间体A-6和杂芳烃在适当亲核取代条件下(例如碳酸铯、碳酸钾、叔丁醇钾、氢化钠)相混合,已形成N-杂芳基化的吲哚;将化合物A-7与炔基醇在适当的Sonogashira型钯介导的偶联条件下相混合以得到化合物A-8(如路线1),最后在氢氧化钠条件下水解并与不同的伯胺或仲胺进行缩合以形成本发明化合物,例如化合物A-10。
路线4
路线4:将原料6-溴吲哚使用三氯氧磷处理以得到3-醛基取代吲哚,然后将中间体A-11和盐酸羟胺、醋酸钠、乙酸酐、乙酸混合加热处理得氰基取代中间体A-12,将A-11和A-12分别和芳杂烃在碱碳酸铯条件下相混合,得N-杂芳基化吲哚得A-13、A-14,再将A-14氧化的中间体A-15,最后可通过路线1的方法将A-13、A-14、A-15发生Sonogashira反应,生成本发明的化合物。
路线5
路线5:将吲哚B-1和双氯代杂芳烃在叔丁醇钾处理下得到N-杂芳烃B-2,然后在酸催化下和不同取代胺发生亲核反应得胺代中间体B-3,最后可通过路线1的方法将B-3发生Sonogashira反应,生成本发明的化合物。
路线6
路线6:本路线根据杂芳环起始原料的不同合成C-5的方法可分为两种,方法1:将5-溴-2-碘苯胺在酸催化下和杂芳环混合得中间体C-2,然后和不同炔基扣环得到中间体C-3,然后使用mCPBA氧化后进行亲核取代得中间体C-5。方法2:将5-溴-2-碘苯胺和杂芳环酸性条件下混合加热得中间体C-10,C-10和不同炔基环合得中间体C-5。然后根据炔基取代的不同分别处理,最后可通过路线1的方法将C-8和C-9发生Sonogashira反应,生成本发明的化合物。
路线7:
路线7:以4-溴-2-硝基甲苯为起始原料和草酸二乙酯在叔丁醇钾的作用下生成中间体C-12,然后在铁酸还原条件下进行还原环化得关键中间体吲哚C-13。氯代杂芳基在TMS溴的作用下生成溴代杂芳基,然后与C-13在碘化亚铜催化偶联条件下得N-杂芳烃,然后使用mCPBA氧化并使用不同氨基进行亲核取代得中间体C-17,中间体C-17在碱性条件下水解,然后做缩合反应得中间体C-19。最后可通过路线1的方法将C-19发生Sonogashira反应,生成本发明的化合物。
具体实施方式:
通过参考一下实施例可更充分的理解本发明。然而,他们不应该被解释成为对本发明范围的限制。这些实施例的目的不是限制本发明的范围,而是为熟练技术人员提供指导以制备和使用本发明化合物、组合物的方法。虽然描述了本发明的特定实施方案,但熟练的技术人员会意识到可进行各种改变和修饰而不偏离本发明的精神实质和范围。
实施例1:
1-((1-(2-氨基嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
4-(6-溴-1H-吲哚-1-基)嘧啶-2-胺的制备
步骤1:将化合物A-1(1.9g,9.8mmol)溶于20mL DMF中,再加入碳酸铯(6.4g,19.6mmol),常温搅拌10min,再加入2-氨基-4-氯嘧啶(1.34g,10.3mmol),升温至100℃反应5h后,将反应液冷却至室温后,倒入100mL的水中,有大量固体析出,洗涤,干燥得产品2.45g,产率86.7%。ESI-MS(m/z):289[M+H]+。
1-((1-(2-氨基嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇的制备
步骤2:将化合物A-2(1.25g,4.32mmol)加入20mL的无水DMF中,再在溶液中加入无水TEA(3mL,21.6mmol)和环己基炔醇(0.81g,6.48mmol),在氮气环境下超声,使溶液中的氧气排尽,再加入CuI(0.16g,0.86mmol),和四三苯基磷钯(0.25g,0.22mmol),在氮气保护下,升温至80℃反应6h。将反应液冷却至室温,然后倒入80mL的水中,再用EA(60*3mL)萃取,之后用饱和食盐水洗涤EA层,加入无水硫酸钠除水,再悬干EA层得化合物粗品。柱层析PE:EA=1:1,得淡黄色产品0.95g,产率66%。1H NMR(600MHz,DMSO-d6)δ8.66(d,J=1.2Hz,1H),8.30(d,J=5.6Hz,1H),8.09(d,J=3.6Hz,1H),7.60(d,J=8.1Hz,1H),7.22(dd,J=8.1,1.4Hz,1H),6.97–6.88(m,3H),6.79(d,J=3.5Hz,1H),5.36(s,1H),1.93–1.46(m,10H).ESI-MS(m/z):333.1740[M+H]+。
按照实施例1的方法,可与不同的N杂吲哚进行反应来进行实施例2-6的制备。
实施例2:1-((1-(2-氨基嘧啶-4-基)-5-氟-1H-吲哚-6-基)乙炔基)环己基-1-醇
1H NMR(600MHz,DMSO-d6)δ8.76(d,J=6.3Hz,1H),8.41(s,1H),8.19(d,J=3.6Hz,1H),7.50(d,J=9.6Hz,1H),7.10–6.90(m,3H),6.79(d,J=3.5Hz,1H),5.45(s,1H),1.98–1.43(m,10H).ESI-MS(m/z):351.1620[M+H]+。
实施例3:1-((1-(2-氨基嘧啶-4-基)1H-吡咯[3,2-b]并吡啶-6-基)乙炔基)环己基-1-醇
1H NMR(600MHz,DMSO-d6)δ9.02(d,J=1.6Hz,1H),8.50(s,1H),8.46(d,J=3.7Hz,1H),8.34(d,J=5.6Hz,1H),7.08(s,2H),7.02(d,J=5.6Hz,1H),6.93(d,J=3.6Hz,1H),5.47(s,1H),1.96–1.46(m,10H).ESI-MS(m/z):333.1667[M+H]+。
实施例4:1-((1-(2-氨基嘧啶-4-基)-1H-吲唑-6-基)乙炔基)环己基-1-醇
1H NMR(600MHz,DMSO-d6)δ8.89(s,1H),8.50(s,1H),8.32(d,J=5.5Hz,1H),7.89(d,J=8.2Hz,1H),7.36(dd,J=8.1,1.3Hz,1H),7.12(d,J=5.5Hz,1H),7.06(s,2H),5.48(s,1H),2.00–1.43(m,10H).ESI-MS(m/z):333.1667[M+H]+。
实施例5:1-((2-氨基嘧啶-4-基)-1H-吡咯[2,3-b]并吡啶-6-基)乙炔基)环己基-1-醇1H NMR(600MHz,DMSO-d6)δ8.42(d,J=5.2Hz,1H),8.40(d,J=4.0Hz,1H),8.10(d,J=5.0Hz,1H),8.08(d,J=2.4Hz,1H),7.39(d,J=8.0Hz,1H),6.82(s,2H),6.81(s,1H),5.60(s,1H),1.99–1.43(m,10H).ESI-MS(m/z):333.1667[M+H]+。
实施例6:1-((2-氨基嘧啶-4-基)-1H-吡咯[3,2-c]并吡啶-6-基)乙炔基)环己基-1-醇1H NMR(600MHz,DMSO-d6)δ8.86(d,J=1.1Hz,1H),8.62(t,J=0.9Hz,1H),8.34(d,J=5.5Hz,1H),8.20(d,J=3.6Hz,1H),7.07(s,2H),7.00(d,J=5.6Hz,1H),6.94(dd,J=3.6,0.8Hz,1H),5.46(s,1H),1.92–1.47(m,10H).ESI-MS(m/z):333.1667[M+H]+。
实施例7:
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(哌嗪-1-基)甲酮的制备
6-溴吲哚-3-羧酸的制备
步骤1:将6-溴吲哚(5g,25.5mmol),溶于30mL DMF中,在冰浴下,缓慢(10min左右)滴加三氟乙酸酐(4.3mL,30.6mmol),常温下反应1.5h。然后将反应液倒入100ml冰水中,析出类白色固体,抽滤得粗产品。
然后将上一步的粗品加入100mL的20%NaOH溶液中,加热至回流反应3h,将反应液冷却后,使用EA(50*3mL)萃取水层,然后弃去有机层。使用6M的盐酸调节pH到3-4,有大量固体析出,抽滤,然后使用水洗涤至pH为中性,干燥得产品5.2g,产率84.9%。ESI-MS(m/z):239[M-H]-。
6-溴-1H-吲哚-3-羧酸甲酯的制备
步骤2:将中间体A-4(3.7g,15.4mmol)加入25mL DCM中,化合物3并不全溶,此时可以在搅拌下加入3滴的DMF,然后将草酰氯(6.6mL,77.1mmol)溶于10mL的DCM中,缓慢滴加入化合物中,室温反应2h,将反应液减压蒸馏去除溶剂和多余草酰氯,然后将上述固体重新溶于20mL的DCM中,然后逐滴加入30mL无水甲醇和三乙胺(6mL,46.2mmol)的混合溶液中,反应1h。将反应液加圧蒸留除去溶剂,然后用水洗涤固体3次,干燥后得化合物A-63.85g,收率98.4%。ESI-MS(m/z):254[M+H]+。
1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-3-羧酸甲酯的制备
步骤3:将中间体A-6(2.5g,9.8mmol)溶于30mL DMF中,再加入碳酸铯(6.4g,19.6mmol),常温搅拌10min,再加入2-氨基-4-氯嘧啶(1.34g,10.3mmol),升温至100℃反应5h后,将反应液冷却至室温后,倒入100mL的水中,有大量固体析出,洗涤,干燥得产品2.95g,产率86.7%。ESI-MS(m/z):347[M+H]+。
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-羧酸甲酯的制备
步骤4:将中间体A-7(1.5g,4.32mmol)加入20mL的无水DMF中,再在溶液中加入无水TEA(3mL,21.6mmol)和环己基炔醇(0.81g,6.48mmol),在氮气环境下超声,使溶液中的氧气排尽,再加入CuI(0.16g,0.86mmol),和四三苯基磷钯(0.25g,0.22mmol),在氮气保护下,升温至80℃反应6h。将反应液冷却至室温,然后倒入80mL的水中,再用EA(60*3mL)萃取,之后用饱和食盐水洗涤EA层,加入无水硫酸钠除水,再将有机层干燥得化合物粗品。柱层析PE:EA=1:1,得淡黄色产品1.12g,产率66%。86.7%。ESI-MS(m/z):390[M+H]+。
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-羧酸的制备
步骤5:将中间体A-8(1g,2.56mmol)溶于30mL混合溶液(THF:H2O=1:1)中,再加入NaOH(0.41g,10.24mmol),升温至60℃反应。反应结束后加入20mL水,用EA多次萃取反应液,直至没有荧光为止,弃去有机层,用1M HCl调节水层PH至6-7,大量固体析出,抽滤,洗涤滤饼至中性,干燥得产品0.72g,产率75%。ESI-MS(m/z):375[M-H]-。
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(哌嗪-1-基)甲酮的制备
步骤6:将化合物A-9(0.2g,0.53mmol)溶于10mL DMF中,冰浴下加入HATU(0.22g,0.58mmol)和三乙胺(0.22mL,1.59mmol),搅拌10min,再加入哌嗪(94.8mg,1.1mmol),室温反应1h。反应结束后将反应液倒入40mL的水中,再用EA萃取至有机层无荧光,之后用饱和食盐水洗涤EA层,加入无水硫酸钠除水后,柱层析DCM:MeOH=5:1。1H NMR(400MHz,DMSO-d6)δ8.66(d,J=1.3Hz,1H),8.35–8.31(m,2H),7.65(d,J=8.2Hz,1H),7.29(dd,J=8.2,1.5Hz,1H),7.03(d,J=6.0Hz,3H),5.41(s,1H),3.58(t,J=4.9Hz,4H),2.77(t,J=5.0Hz,4H),1.92–1.48(m,11H).HRMS(ESI+)[M+H]+:445.2351.
实施例8:
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺的制备
6-溴-1H-吲哚-3-甲醛的制备
步骤1:将25mlDMF滴于50ml三颈瓶中,抽真空,用氮气加以保护。在零度冰浴下,向50ml三颈瓶缓慢滴加2.85ml的三氯氧磷,使其搅拌30分钟左右,溶液变为澄清透明。将6-溴吲哚(5.0g,25.5mmol)用15ml DMF溶解,滴入滴液漏斗中,嘧封,缓慢滴加,放置至室温搅拌1小时左右。检测反应完全后,将反应液逐滴加入5%NaOH(200ml)溶液中,加以淬灭。有大量白色固体析出,过滤,滤液可用乙酸乙酯萃取提高产率,得终产物5.2g,产率为91.2%。ESI-MS(m/z):224[M+H]+。
6-溴-1H-吲哚-3-甲腈的制备
步骤2:将中间体A-11(5.7g,25.45mM)溶于65mL冰醋酸中,然后依次加入醋酸钠(3.13g,38.17mM)、盐酸羟胺(7.1g,101.78mM),90℃反应1h,然后加入醋酐(5.2g,50.9mM),加热至回流反应4h。反应结束后,将反应液倒入150mL水中,然后分别用水,饱和碳酸氢钠,1N稀盐酸和饱和食盐水洗涤,并用无水硫酸钠干燥。加压干燥得暗红色粗产品2.8g(产率为50%)。ESI-MS(m/z):221[M+H]+。
1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-3-甲腈
将中间体A-12(2.73g,12.35mM)溶于50mL DMF中,加入碳酸铯(12g,37.5mM),室温搅拌30min后,加入2-氨基-4-氯嘧啶(1.68g,12.96mM),加热至80℃反应7h。将反应液倒入150mL水中,搅拌30min后抽滤,并用水洗涤、干燥,得产品3.41g(产率87.8%)。ESI-MS(m/z):314[M+H]+
1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-3-甲酰胺
将中间体A-14(2.19g,6.99mM)溶于15mL DMSO中,冰浴下加入碳酸钾(2g)和30%过氧化氢,将反应液加热至室温(反应中会有剧烈放热),10min后,稀释至150mL水中,冷却,将产物过滤收集,并使用30mL乙酸乙酯打浆处理,得淡黄色纯品2.0g(产率87.6%)。
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔)-1H-吲哚-3-甲酰胺
将中间体A-15(3.6g,10.85mM),乙炔基环己醇(2.7g,21.71mM),TEA(7.75mL,54.25mM)溶于40mL DMF中,超声除气泡,并使用氩气保护下,加入CuI(0.42g,2.17mM),四三苯基膦钯(0.63g,0.54mM),抽真空氮气保护,80℃温度下反应五小时,将反应液倒入水中,萃取,洗涤,干燥,然后柱层析(MeOH:DCM=1:50),得淡黄色粉末状产品2.5g(产率64.4%)。1H NMR(600MHz,DMSO-d6)δ8.78(s,1H),8.60(s,1H),8.46–8.35(m,1H),8.23(d,J=8.2Hz,1H),7.74(s,1H),7.35–7.29(m,1H),7.21(s,1H),7.10(s,2H),6.87(d,J=5.5Hz,1H),5.42(s,1H),1.99–1.41(m,10H).HRMS(ESI+)[M+H]+:375.4322.
按照实施例7和8的方法,可与适当的伯胺或仲胺进行反应来进行实施例9-39的制备。
实施例9:1-((1-(2,6-二氨基嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1H-NMR(600MHz,DMSO-d6,ppm)δ:1.48-1.60(m,6H),1.65-1.66(m,2H),1.86-1.89(m,2H),5.36(s,1H),5.93(s,1H),6.22(s,2H),6.50(s,2H),6.69(d,J=3.4Hz,1H),7.16(dd,J=1.02Hz,J=8.1Hz,1H),7.58(d,J=8.1Hz,1H),7.85(d,J=3.42Hz,1H),8.31(s,1H).HRMS(ESI+)[M+H]+:348.1829
实施例10:1-(2-氨基嘧啶-4-基)-6-(1-羟基环己基)乙炔基)-1H-吲哚-3-甲醛
1H NMR(600MHz,DMSO-d6)δ10.07(s,1H),9.03(s,1H),8.58(s,1H),8.47(s,1H),8.16(d,J=8.2Hz,1H),7.41(d,J=9.5Hz,1H),7.17(s,2H),7.06(d,J=5.2Hz,1H),5.42(s,1H),1.95–1.46(m,10H).HRMS(ESI+)[M+Na]+:383.1477.
实施例11:(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(吡咯-1-基)甲酮
1H NMR(600MHz,DMSO-d6)δ8.66(s,1H),8.40(s,1H),8.30(s,1H),7.62(d,J=8.2Hz,1H),7.32–7.27(m,1H),7.11–6.94(m,3H),5.39(s,1H),3.57(s,4H),1.90–1.51(m,14H).HRMS(ESI+)[M+Na]+:452.2075.
实施例12:(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(哌啶-1-基)甲酮
1H NMR(600MHz,DMSO-d6)δ8.62(s,1H),8.40(s,1H),8.36(s,1H),7.99(d,J=8.2Hz,1H),7.29(dd,J=8.3,1.2Hz,1H),7.05(s,1H),7.04(s,2H),5.39(s,1H),3.75(s,2H),3.54(s,2H),1.89(s,6H),1.74–1.43(m,8H).HRMS(ESI+)[M+Na]+:466.2223.
实施例13:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N,N-二甲基-1H-吲哚-3-甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.65(d,J=1.4Hz,1H),8.35(s,2H),7.73(d,J=8.3Hz,1H),7.29(dd,J=8.2,1.5Hz,1H),7.02(d,J=5.1Hz,3H),5.38(s,1H),3.09(d,J=12.8Hz,6H),1.92–1.52(m,10H).HRMS(ESI+)[M+Na]+:426.1921.
实施例14:(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(吗啉基)甲酮
1H NMR(600MHz,DMSO-d6)δ8.66(s,2H),8.35(s,1H),7.69(d,J=8.2Hz,1H),7.30(d,J=8.2Hz,1H),7.05(s,3H),5.38(s,1H),3.64(s,8H),1.94–1.43(m,10H).HRMS(ESI+)[M+Na]+:468.2018.
实施例15:(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-甲基哌嗪-1-基)甲酮
1H NMR(600MHz,DMSO-d6)δ8.66(s,1H),8.34(d,J=5.9Hz,1H),8.33(s,1H),7.65(d,J=8.2Hz,1H),7.30(dd,J=8.2,1.3Hz,1H),7.03(s,2H),7.02(s,1H),5.39(s,1H),3.63(s,4H),2.36(s,4H),2.22(s,3H),1.94–1.43(m,10H).HRMS(ESI+)[M+H]+:458.1877.
实施例16:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-甲基-1H-吲哚-3-甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.66(s,1H),8.58(d,J=1.3Hz,1H),8.39(d,J=5.5Hz,1H),8.20(dd,J=6.5,4.8Hz,2H),7.31(dd,J=8.2,1.4Hz,1H),7.08(s,2H),6.85(d,J=5.5Hz,1H),5.40(s,1H),2.81(d,J=4.5Hz,3H),1.95–1.42(m,10H).HRMS(ESI+)[M+Na]+:412.1744.
实施例17:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(噻唑-2-基)-1H-吲哚-3-甲酰胺
1H NMR(600MHz,DMSO-d6)δ12.42(s,1H),9.28(s,1H),8.65(s,1H),8.45(d,J=5.2Hz,1H),8.30(d,J=8.1Hz,1H),7.56(d,J=2.8Hz,1H),7.39(d,J=8.0Hz,1H),7.33–7.24(m,1H),7.17(s,2H),6.90(d,J=5.2Hz,1H),5.44(s,1H),1.95–1.45(m,10H).HRMS(ESI+)[M+Na]+:481.1420.
实施例18:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-苯基-1H-吲哚-3-甲酰胺
1H NMR(600MHz,DMSO-d6)δ10.04(s,1H),8.96(s,1H),8.60(s,1H),8.47(s,1H),8.24(d,J=8.2Hz,1H),7.77(d,J=8.0Hz,2H),7.37(q,J=8.9,8.3Hz,3H),7.12(d,J=12.5Hz,2H),7.09(d,J=7.3Hz,1H),6.96(d,J=5.1Hz,1H),5.42(s,1H),2.02–1.37(m,10H).HRMS(ESI+)[M+Na]+:474.1904.
实施例19:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲腈
1H NMR(600MHz,DMSO-d6)δ9.02(s,1H),8.68(s,1H),8.42(s,1H),7.74–7.68(m,1H),7.42(dd,J=8.2,1.4Hz,1H),7.19(s,2H),7.01(d,J=5.5Hz,1H),5.44(s,1H),1.95–1.42(m,10H).HRMS(ESI+)[M+Na]+:380.1479.
实施例20:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-甲氧乙基)-1H-吲哚-3-甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.77(s,1H),8.59(s,1H),8.47(d,J=31.0Hz,1H),8.30(t,J=5.2Hz,1H),8.22(d,J=8.2Hz,1H),7.31(dd,J=8.2,1.2Hz,1H),7.10(s,2H),6.88(d,J=3.2Hz,1H),5.41(s,1H),3.48(dq,J=9.7,5.2Hz,4H),3.30(s,3H),1.95–1.41(m,10H).HRMS(ESI+)[M+Na]+:456.2103.
实施例21:1-(2-氨基嘧啶-4-基)-N-苄基-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.81(s,1H),8.77(t,J=5.9Hz,1H),8.59(s,1H),8.41(s,1H),8.24(d,J=8.2Hz,1H),7.36(dt,J=15.2,7.5Hz,4H),7.33(dd,J=8.3,1.3Hz,1H),7.26(t,J=7.1Hz,1H),7.10(s,2H),6.86(d,J=5.5Hz,1H),5.41(s,1H),4.53(d,J=5.8Hz,2H),1.98–1.40(m,10H).HRMS(ESI+)[M+Na]+:488.2071.
实施例22:(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-(2-羟乙基)哌嗪-1-基)甲酮
1H NMR(400MHz,DMSO-d6)δ8.65(d,J=1.3Hz,1H),8.33(d,J=5.6Hz,1H),8.32(s,1H),7.65(d,J=8.3Hz,1H),7.30(dd,J=8.2,1.4Hz,1H),7.03(s,1H),7.02(s,2H),5.38(s,1H),4.43(t,J=5.3Hz,1H),3.62(t,J=4.8Hz,4H),3.52(q,J=5.8Hz,2H),2.45(dd,J=13.0,6.6Hz,6H),1.95–1.43(m,10H).HRMS(ESI+)[M+H]+:489.2625.
实施例23:(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(2-(羟乙基)吡咯-1-基)甲酮
1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.40(s,1H),8.35(d,J=5.6Hz,1H),7.93(s,1H),7.34–7.22(m,1H),7.02(s,3H),5.38(s,1H),4.83(t,J=5.6Hz,1H),4.26(t,J=5.6Hz,1H),3.83–3.57(m,3H),3.57–3.39(m,1H),2.05–1.18(m,16H).HRMS(ESI+)[M+Na]+:496.2334.
实施例24:1-(2-氨基嘧啶-4-基)-N-(5-羟基-1H-吡唑-3-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺
1H NMR(600MHz,DMSO-d6)δ10.44(s,1H),9.39(s,1H),8.47–8.44(m,2H),8.34(d,J=8.3Hz,1H),7.39(dd,J=8.3,1.4Hz,1H),7.16(s,2H),6.94(d,J=5.4Hz,1H),6.88(s,2H),5.41(s,1H),4.88(s,1H),1.91–1.49(m,15H).HRMS(ESI+)[M+Na]+:496.2334.
实施例25:(R)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-甲基哌嗪-1-基)甲酮
1H NMR(400MHz,DMSO-d6)δ8.66(d,J=1.3Hz,1H),8.41–8.32(m,2H),7.66(d,J=8.2Hz,1H),7.30(dd,J=8.2,1.5Hz,1H),7.03(d,J=5.5Hz,3H),5.76(s,1H),5.40(s,1H),4.16(s,2H),3.08–2.75(m,4H),1.93–1.45(m,10H),1.25(d,J=11.0Hz,1H),1.09(d,J=5.4Hz,3H).HRMS(ESI+)[M+H]+:459.2521.
实施例26:(S)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-甲基哌嗪-1-基)甲酮
1H NMR(400MHz,DMSO-d6)δ8.66(d,J=1.3Hz,1H),8.41–8.32(m,2H),7.66(d,J=8.2Hz,1H),7.30(dd,J=8.2,1.5Hz,1H),7.03(d,J=5.5Hz,3H),5.76(s,1H),5.40(s,1H),4.16(s,2H),3.08–2.75(m,4H),1.93–1.45(m,10H),1.25(d,J=11.0Hz,1H),1.09(d,J=5.4Hz,3H).HRMS(ESI+)[M+H]+:459.2521.
实施例27:(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3,5-二甲基哌嗪-1-基)甲酮
1H NMR(400MHz,DMSO-d6)δ8.66(d,J=1.3Hz,1H),8.34(d,J=5.3Hz,2H),7.65(d,J=8.2Hz,1H),7.30(dd,J=8.2,1.4Hz,1H),7.07–6.97(m,3H),5.39(s,1H),4.18(s,2H),3.01–2.62(m,4H),1.95–1.43(m,10H),1.25(d,J=16.2Hz,1H),1.17–0.92(m,6H).HRMS(ESI+)[M+H]+:473.2670.
实施例28:(3-氨基-1H-吡唑-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮
1H NMR(400MHz,DMSO-d6)δ9.47(s,1H),8.47(d,J=1.3Hz,1H),8.45(d,J=5.4Hz,1H),8.34(d,J=8.2Hz,1H),8.25(d,J=2.9Hz,1H),7.40(dd,J=8.3,1.4Hz,1H),7.16(s,2H),7.00(d,J=5.5Hz,1H),6.01(d,J=2.9Hz,1H),5.72(s,2H),5.41(s,1H),1.94–1.44(m,10H).HRMS(ESI+)[M+Na]+:456.1809.
实施例29:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(1H-吡唑-3-基)-1H-吲哚-3-甲酰胺
1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.44(d,J=5.4Hz,1H),8.39(s,1H),8.36(d,J=8.4Hz,1H),7.54(d,J=1.7Hz,1H),7.42(d,J=8.4Hz,1H),7.17(s,2H),6.97(d,J=5.4Hz,1H),6.82(s,2H),5.44(d,J=1.8Hz,1H),5.41(s,1H),1.94–1.45(m,10H).HRMS(ESI+)[M+Na]+:456.1809.
实施例30:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2,2,2-三氟乙基)-1H-吲哚-3-甲酰胺
1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.92(d,J=6.4Hz,1H),8.57(d,J=1.3Hz,1H),8.41(d,J=5.5Hz,1H),8.20(d,J=8.2Hz,1H),7.33(dd,J=8.3,1.4Hz,1H),7.09(s,2H),6.90(d,J=5.6Hz,1H),5.39(s,1H),4.13(dh,J=14.3,5.6,4.9Hz,2H),1.94–1.40(m,10H).HRMS(ESI+)[M+Na]+:480.1614.
实施例31:(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-吗啉基哌啶-1-基)甲酮
1H NMR(400MHz,DMSO-d6)δ8.66(d,J=1.3Hz,1H),8.33(d,J=6.1Hz,2H),7.63(d,J=8.2Hz,1H),7.29(dd,J=8.3,1.4Hz,1H),7.07–6.97(m,3H),5.40(s,1H),4.23(s,2H),3.57(s,4H),3.00(s,2H),2.47(s,4H),1.94–1.34(m,14H).HRMS(ESI+)[M+Na]+:551.2754.
实施例32:(R)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-羟基哌啶-1-基)甲酮
1H NMR(400MHz,DMSO-d6)δ8.64(d,J=1.3Hz,1H),8.34(d,J=5.5Hz,1H),8.31(s,1H),7.63(d,J=8.2Hz,1H),7.29(dd,J=8.2,1.4Hz,1H),7.02(s,2H),6.99(d,J=5.6Hz,1H),5.38(s,1H),4.90(s,1H),4.00–3.46(m,3H),3.26(s,1H),3.07(s,1H),1.95–1.41(m,14H).HRMS(ESI+)[M+Na]+:482.2178.
实施例33:(S)-(3-氨基哌啶-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮
1H NMR(400MHz,DMSO-d6)δ8.65(d,J=1.3Hz,1H),8.33(d,J=5.6Hz,1H),8.31(s,1H),7.62(d,J=8.2Hz,1H),7.29(dd,J=8.2,1.5Hz,1H),7.01(s,2H),7.00(s,1H),5.38(s,1H),4.02(s,2H),3.00(t,J=11.9Hz,1H),2.68(td,J=21.0,16.2,9.9Hz,2H),2.03–1.37(m,16H).HRMS(ESI+)[M+H]+:459.2518.
实施例34:(S)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(哌啶-3-基)1H-吲哚-3-甲酰胺
1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.56(s,1H),8.39(d,J=5.6Hz,1H),8.20(d,J=8.2Hz,1H),7.92(d,J=7.9Hz,1H),7.30(d,J=8.2Hz,1H),7.06(s,2H),6.90(d,J=5.6Hz,1H),5.39(s,1H),3.84(d,J=10.4Hz,1H),3.09–2.95(m,1H),2.81(d,J=12.1Hz,1H),2.45–2.28(m,2H),1.95–1.35(m,15H).HRMS(ESI+)[M+H]+:459.2507.
实施例35:(R)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(哌啶-3-基)1H-吲哚-3-甲酰胺
1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.56(s,1H),8.39(d,J=5.6Hz,1H),8.20(d,J=8.2Hz,1H),7.92(d,J=7.9Hz,1H),7.30(d,J=8.2Hz,1H),7.06(s,2H),6.90(d,J=5.6Hz,1H),5.39(s,1H),3.84(d,J=10.4Hz,1H),3.09–2.95(m,1H),2.81(d,J=12.1Hz,1H),2.45–2.28(m,2H),1.95–1.35(m,15H).HRMS(ESI+)[M+H]+:459.2507.
实施例36:(R)-(3-氨基哌啶-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮
1H NMR(400MHz,DMSO-d6)δ8.65(d,J=1.3Hz,1H),8.33(d,J=5.6Hz,1H),8.31(s,1H),7.62(d,J=8.2Hz,1H),7.29(dd,J=8.2,1.5Hz,1H),7.01(s,2H),7.00(s,1H),5.38(s,1H),4.02(s,2H),3.00(t,J=11.9Hz,1H),2.68(td,J=21.0,16.2,9.9Hz,2H),2.03–1.37(m,16H).HRMS(ESI+)[M+H]+:459.2507.
实施例37:(S)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-氨基吡咯-1-基)甲酮
1H NMR(400MHz,DMSO-d6)δ8.61(d,J=1.4Hz,1H),8.39(s,1H),8.36(d,J=5.6Hz,1H),7.99(d,J=8.3Hz,1H),7.29(dd,J=8.3,1.5Hz,1H),7.04(d,J=5.7Hz,3H),5.38(s,1H),4.20(s,1H),3.91(s,1H),3.62(s,2H),3.42(s,2H),2.06(d,J=11.1Hz,1H),1.96–1.41(m,12H).HRMS(ESI+)[M+Na]+:469.2173.
实施例38:(S)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡咯-3-基)1H-吲哚-3-甲酰胺
1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.42(s,1H),8.37(d,J=5.6Hz,1H),8.18(s,1H),8.00(d,J=8.3Hz,1H),7.30(dd,J=8.3,1.5Hz,1H),7.09–7.00(m,3H),5.38(s,1H),3.80(d,J=45.6Hz,5H),2.31–2.19(m,1H),2.06(s,1H),1.94–1.44(m,11H).HRMS(ESI+)[M+Na]+:469.2173.
实施例39:(R)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡咯-3-基)1H-吲哚-3-甲酰胺
1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.42(s,1H),8.37(d,J=5.6Hz,1H),8.18(s,1H),8.00(d,J=8.3Hz,1H),7.30(dd,J=8.3,1.5Hz,1H),7.09–7.00(m,3H),5.38(s,1H),3.80(d,J=45.6Hz,5H),2.31–2.19(m,1H),2.06(s,1H),1.94–1.44(m,11H).HRMS(ESI+)[M+Na]+:469.2173.
实施例40:4-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-羰基)哌嗪-2-酮
1H NMR(600MHz,DMSO-d6)δ8.66(d,J=1.3Hz,1H),8.41(s,1H),8.35(d,J=5.5Hz,1H),8.16(d,J=2.7Hz,1H),7.73(d,J=8.2Hz,1H),7.30(dd,J=8.3,1.4Hz,1H),7.05(s,2H),7.03(d,J=5.6Hz,1H),5.40(s,1H),4.19(s,2H),3.81(t,J=5.4Hz,2H),3.31–3.27(m,2H),1.93–1.45(m,10H).HRMS(ESI+)[M+H]+:458.2068.
实施例41:
1-((1-(2-苄胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
6-溴-1-(2-氯嘧啶-4-基)-1H-吲哚的制备
步骤1:将6-溴吲哚(5g,25.5mM)溶于50mL THF中,冰浴至0℃,然后分批加入叔丁醇钾(3.15g,28.05mM),冰浴下搅拌30min,然后加入2,4-二氯嘧啶(4.18g,28.05mM),室温反应5h,将反应液倒入100mL水中,使用EA萃取(70*3mL),饱和食盐水洗涤,无水硫酸钠干燥,柱层析(PE:EA=10:1),得淡黄色产品3.2g(产率40.1%)。
4-(6-溴-1H-吲哚-1-基)-N-苯基嘧啶-2-胺的制备
步骤2:将6-溴-1-(2-氯嘧啶-4-基)-1H-吲哚(0.2g,0.648mM)和苯胺(63.4mg,0.68mM)加入耐压瓶中,然后加入4mL异丙醇和1d浓盐酸,嘧封,加热至120℃反应3h,将反应液充分冷却,结晶析出,抽滤,冷乙醇洗,水洗,干燥。得产品白色0.22g(产率92.6%)。ESI-MS(m/z):379[M+H]+。
1-((1-(2-苄胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇的制备
步骤3:该标题化合物通过调整实例1所述方法,将步骤2中的4-(6-溴-1H-吲哚-1-基)嘧啶-2-胺使用4-(6-溴-1H-吲哚-1-基)-N-苯基嘧啶-2-胺代替,反应在80℃下进行5个小时。得标题化合物1-((1-(2-苄胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇。1HNMR(600MHz,DMSO-d6)δ8.84(s,1H),8.35(s,1H),8.20–8.04(m,2H),7.60(d,J=8.0Hz,1H),7.45(s,2H),7.31(t,J=7.3Hz,2H),7.26–7.17(m,2H),7.00(s,1H),6.80(d,J=3.2Hz,1H),5.41(s,1H),4.63(s,2H),1.76–1.49(m,10H).HRMS(ESI+)[M+H]+:423.2182。
按照实施例41的方法,可与适当的伯胺或仲胺进行反应来进行实施例41-59的制备。
实施例42:1-((1-(2-((噻吩-2-甲基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1H NMR(600MHz,DMSO-d6)δ8.86(s,1H),8.40(s,1H),8.16(s,1H),8.13(s,1H),7.61(d,J=8.1Hz,1H),7.33(d,J=3.9Hz,1H),7.23(dd,J=8.1,1.2Hz,1H),7.13(s,1H),7.03(d,J=5.0Hz,1H),6.98–6.90(m,1H),6.82(d,J=3.5Hz,1H),5.39(s,1H),4.78(s,2H),2.04–1.30(m,10H).HRMS(ESI+)[M+H]+:429.1748。
实施例43:1-((1-(2-((2-氟苄基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1H NMR(600MHz,DMSO-d6)δ8.74(s,1H),8.36(s,1H),8.13(d,J=3.6Hz,1H),7.97(s,1H),7.61(d,J=8.1Hz,1H),7.45(s,1H),7.33–7.27(m,1H),7.22(d,J=7.6Hz,1H),7.21–7.16(m,1H),7.14(t,J=7.5Hz,1H),7.01(d,J=5.5Hz,1H),6.81(d,J=3.3Hz,1H),5.37(s,1H),4.69(s,2H),1.97–1.42(m,10H).HRMS(ESI+)[M+H]+:441.2089。
实施例44:1-((1-(2-((2-甲氧乙基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1H NMR(600MHz,DMSO-d6)δ8.77(s,1H),8.34(s,1H),8.14(s,1H),7.61(d,J=8.1Hz,1H),7.49(s,1H),7.23(d,J=8.0Hz,1H),6.97(d,J=5.5Hz,1H),6.81(d,J=3.2Hz,1H),5.41(s,1H),3.58(s,4H),3.29(s,3H),1.96–1.41(m,10H).HRMS(ESI+)[M+H]+:391.2136。
实施例45:1-((1-(2-((2-氯苄基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.33(d,J=5.4Hz,1H),8.13(d,J=3.3Hz,1H),8.07(t,J=6.0Hz,1H),7.60(d,J=8.1Hz,1H),7.46(s,2H),7.22(d,J=8.1Hz,1H),7.13(t,J=8.8Hz,2H),6.99(d,J=5.6Hz,1H),6.80(d,J=3.5Hz,1H),5.39(s,1H),4.61(d,J=5.2Hz,2H),1.85–1.41(m,10H).HRMS(ESI+)[M+H]+:457.1792。
实施例46:1-((1-(2-((4-氟苄基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.35(s,1H),8.22–8.09(m,1H),8.00(s,1H),7.61(d,J=8.1Hz,1H),7.53–7.44(m,1H),7.44(d,J=2.4Hz,1H),7.31(dd,J=7.8,2.3Hz,1H),7.29–7.26(m,1H),7.24(dd,J=12.2,5.1Hz,1H),7.00(d,J=5.6Hz,1H),6.81(d,J=3.5Hz,1H),5.33(s,1H),4.71(s,2H),2.10–1.23(m,10H).HRMS(ESI+)[M+H]+:441.2089。
实施例47:1-((1-(2-(苯胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔)环己基-1-醇
1H NMR(600MHz,DMSO-d6)δ9.87(s,1H),8.67(s,1H),8.53(d,J=5.6Hz,1H),8.18(d,J=3.6Hz,1H),7.78(s,1H),7.77(s,1H),7.63(d,J=8.1Hz,1H),7.37(t,J=7.9Hz,2H),7.25(dd,J=8.1,1.2Hz,1H),7.21(d,J=5.6Hz,1H),7.01(t,J=7.3Hz,1H),6.85(d,J=3.5Hz,1H),5.36(s,1H),1.92–1.42(m,10H).HRMS(ESI+)[M+H]+:409.2109。
实施例48:1-((1-(2-((3-氯苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔)环己基-1-醇
1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.63(s,1H),8.58(d,J=5.6Hz,1H),8.17(d,J=3.3Hz,1H),7.95(s,1H),7.74(d,J=8.0Hz,1H),7.64(d,J=8.0Hz,1H),7.37(t,J=8.1Hz,1H),7.26(t,J=6.4Hz,2H),7.03(d,J=7.6Hz,1H),6.86(d,J=3.1Hz,1H),5.32(s,1H),1.91–1.42(m,10H).HRMS(ESI+)[M+H]+:443.1628。
实施例49:1-((1-(2-((3-氯-4-氟苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.61(s,1H),8.57(d,J=5.7Hz,1H),8.16(d,J=3.6Hz,1H),8.09(dd,J=6.8,2.5Hz,1H),7.72(ddd,J=9.0,4.1,2.8Hz,1H),7.64(d,J=8.1Hz,1H),7.38(t,J=9.1Hz,1H),7.26(s,1H),7.26–7.23(m,1H),6.86(d,J=3.5Hz,1H),5.25(s,1H),1.91–1.41(m,10H).HRMS(ESI+)[M+Na]+:483.1362。
实施例50:3-((4-(6-((1-羟基环己基)乙炔基)-1H-吲哚-1-基)嘧啶-2-基)氨基)苯甲腈
1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.65–8.57(m,2H),8.26(t,J=1.9Hz,1H),8.19(d,J=3.7Hz,1H),8.07(ddd,J=8.5,2.3,1.1Hz,1H),7.64(d,J=8.1Hz,1H),7.56(t,J=8.0Hz,1H),7.43(dt,J=7.6,1.3Hz,1H),7.31(d,J=5.7Hz,1H),7.26(dd,J=8.1,1.4Hz,1H),6.87(d,J=3.6Hz,1H),5.33(s,1H),1.90–1.41(m,10H).HRMS(ESI+)[M+Na]+:456.1793。
实施例51:1-((1-(2-((4-甲氧基苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.60(s,1H),8.48(d,J=5.6Hz,1H),8.13(d,J=3.6Hz,1H),7.66(d,J=9.0Hz,2H),7.63(d,J=8.2Hz,1H),7.24(dd,J=8.1,1.2Hz,1H),7.13(d,J=5.6Hz,1H),6.93(d,J=9.0Hz,2H),6.84(d,J=3.5Hz,1H),5.30(s,1H),3.74(s,3H),1.92–1.38(m,10H).HRMS(ESI+)[M+Na]+:461.1852。
实施例52:1-((1-(2-((3-硝基苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.83(t,J=2.1Hz,1H),8.62(d,J=5.7Hz,2H),8.21(d,J=3.6Hz,1H),8.18–8.13(m,1H),7.85(dd,J=8.1,2.1Hz,1H),7.68–7.61(m,2H),7.33(d,J=5.7Hz,1H),7.25(dd,J=8.1,1.2Hz,1H),6.88(d,J=3.6Hz,1H),5.30(s,1H),1.88–1.37(m,10H).HRMS(ESI+)[M+Na]+:476.1658。
实施例53:1-((1-(2-(间甲基苯氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.64(s,1H),8.52(d,J=5.6Hz,1H),8.16(d,J=3.6Hz,1H),7.70–7.60(m,2H),7.54(d,J=8.1Hz,1H),7.30–7.21(m,2H),7.19(d,J=5.6Hz,1H),6.85(d,J=3.5Hz,1H),6.82(d,J=7.5Hz,1H),5.31(s,1H),2.30(s,3H),1.91–1.39(m,10H).HRMS(ESI+)[M+Na]+:445.2007。
实施例54:1-((1-(2-((4-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.62(s,1H),8.56(d,J=5.6Hz,1H),8.17(d,J=3.6Hz,1H),7.92(d,J=2.0Hz,1H),7.90(d,J=2.0Hz,1H),7.64(d,J=8.1Hz,1H),7.33(d,J=8.8Hz,2H),7.28–7.23(m,2H),6.86(d,J=3.6Hz,1H),5.33(s,1H),1.92–1.40(m,10H).HRMS(ESI+)[M+Na]+:493.1848。
实施例55:1-((1-(2-((2-(三氟甲基)苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.64(d,J=1.3Hz,1H),8.62(d,J=5.7Hz,1H),8.19(d,J=3.7Hz,1H),8.03(d,J=1.9Hz,1H),8.01(d,J=2.1Hz,1H),7.79–7.73(m,2H),7.65(d,J=8.1Hz,1H),7.35(d,J=5.7Hz,1H),7.27(dd,J=8.1,1.4Hz,1H),6.88(dd,J=3.6,0.8Hz,1H),5.32(s,1H),1.92–1.40(m,10H).HRMS(ESI+)[M+Na]+:499.1718。
实施例56:1-((1-(2-(邻甲基苯氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.45(s,1H),8.37(s,1H),8.11(d,J=3.7Hz,1H),7.57(d,J=8.1Hz,1H),7.55–7.45(m,1H),7.32(t,J=7.7Hz,2H),7.25–7.06(m,3H),6.80(d,J=3.5Hz,1H),5.36(s,1H),2.29(s,3H),1.99–1.43(m,10H).HRMS(ESI+)[M+H]+:423.2190。
实施例57:1-((1-(2-((2-氟苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.46(d,J=20.5Hz,2H),8.24–8.05(m,1H),7.79–7.54(m,2H),7.51–7.10(m,5H),6.81(s,1H),5.38(s,1H),2.06–1.32(m,10H).HRMS(ESI+)[M+Na]+:449.1744。
实施例58:3-((4-(6-((1-羟基环己基)乙炔基)1H-吲哚-1-基)嘧啶-2-基)氨基)苯磺酰胺
1H NMR(600MHz,DMSO-d6)δ10.22(s,1H),8.64(s,1H),8.58(d,J=5.6Hz,1H),8.28(t,J=2.0Hz,1H),8.21(d,J=3.7Hz,1H),8.09(dd,J=8.2,2.1Hz,1H),7.64(d,J=8.1Hz,1H),7.57(t,J=8.0Hz,1H),7.47(dt,J=7.7,1.2Hz,1H),7.35(s,2H),7.30(d,J=5.7Hz,1H),7.27(dd,J=8.1,1.4Hz,1H),6.86(d,J=3.5Hz,1H),5.37(s,1H),1.95–1.42(m,10H).HRMS(ESI+)[M+Na]+:510.1572。
实施例59:1-((1-(2-(环己氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1H NMR(600MHz,DMSO-d6)δ8.79(s,1H),8.38–8.25(m,1H),8.15(s,1H),7.61(d,J=8.0Hz,1H),7.36(d,J=7.7Hz,1H),7.24(d,J=8.2Hz,1H),6.93(d,J=5.4Hz,1H),6.81(d,J=3.5Hz,1H),5.35(s,1H),3.80(tdt,J=11.0,7.5,3.8Hz,1H),2.02(d,J=14.3Hz,2H),1.90–1.44(m,15H),1.32(dtd,J=23.0,11.4,10.4,4.8Hz,3H).HRMS(ESI+)[M+H]+:415.2502。
实施例60:N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)苯甲酰胺
N-(5-溴-2-碘苯基)-2-(甲硫基)嘧啶-4-胺的制备
步骤1:将5-溴-2-碘苯胺(1g,3.357mmol)和2-甲硫基嘧啶(0.4ml,0.3439mmol)溶于10ml异丙醇中,加入浓盐酸2d,将反应加热至60℃反应20h,Tlc检测反应结束。将反应液倾入50ml冰水中,用20%的氢氧化钠溶液调PH至8左右,抽滤,洗涤,干燥得类白色固体1.18g。产率83.2%。ESI-MS(m/z):422[M+H]+。
N-Boc(6-溴-1-(2-(甲硫基)嘧啶-4-基)1H-吲哚-2-基)甲胺的制备
步骤2:将N-(5-溴-2-碘苯基)-2-(甲硫基)嘧啶-4-胺(1g,2.37mmol),N-Boc氨基丙炔(0.4g,2.61mmol),TEA(1ml,7.11mmol),加入10ml DMF中,超声除气泡,并抽真空氮气保护,然后加入CuI(0.09g,0.474mmol),双三苯基膦二氯化钯(83mg,0.12mmol)室温反应,大约2h后,补加0.8eq CuI,加热至70℃反应8h,TLC检测反应结束。将反应液倒入50ml水中使用EA 30 ml*3萃取,饱和食盐水洗涤,干燥,然后进行柱层析分离(EA:PE=1:10),最后得白色絮状固体0.81g,产率75%。ESI-MS(m/z):448[M+H]-。
N-Boc(6-溴-1-(2-(甲磺酰基)嘧啶-4-基)1H-吲哚-2-基)甲胺的制备
步骤3:将N-Boc(6-溴-1-(2-(甲硫基)嘧啶-4-基)1H-吲哚-2-基)甲胺(6.4g,14.24mmol),溶于DCM中,然后于冷阱中降温至零下4℃,再分批加入mCPBA,并于此温度下反应5h后检测,反应完毕。将反应液使用饱和硫代硫酸钠淬灭,然后用饱和碳酸氢钠洗涤,再用饱和食盐水干燥,减压蒸出溶剂,直接投下一步。ESI-MS(m/z):481[M+H]+。
N-Boc(1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-2-基)甲胺的制备
步骤4:将N-Boc(6-溴-1-(2-(甲磺酰基)嘧啶-4-基)1H-吲哚-2-基)甲胺(10g),分别加入氨水(15ml),氯化铵(2g)(氨水和氯化铵都为大过量),异丙醇(50ml),封管60度反应,1.5h后反应结束,柱层析(PE:EA=1.5:1)得淡黄色固体,产率41%。ESI-MS(m/z):418[M+H]+。
4-(2-(氨甲基)-6-溴-1H-吲哚-1-基)嘧啶-2-胺盐酸盐的制备
步骤5:将N-Boc(1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-2-基)甲胺(2g,4.78mmol)溶于二氧六环的盐酸溶液(1N),室温反应3h,直接抽滤得暗黄色粉末1.6g,产率91%。
N-((1-(2-氨基嘧啶-4-基)6-溴-1H-吲哚-2-基)甲基)苯甲酰胺的制备
步骤6:将4-(2-氨甲基)-6-溴-1H-吲哚-1-基)嘧啶-2-胺盐酸盐(0.2g,0.564mmol),溶于3ml DMF中,然后加入0.12ml三乙胺,室温搅拌,溶液由浑浊变为澄清后复现浑浊。再将HATU(0.257g,0.67mmol)和苯甲酸(0.083mg,0.67mmol)溶于3ml DMF中,加入0.12ml三乙胺,搅拌10min后滴入上述反应液,室温反应1h反应结束,将反应液倾入30ml水中,使用EA 20 ml*3进行萃取,然后使用饱和碳酸氢钠和饱和食盐水洗涤,干燥,蒸出溶剂,直接用于下一部反应。ESI-MS(m/z):422[M+H]+。
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)苯甲酰胺的制备
步骤7:该标题化合物通过调整实例1所述方法,将步骤2中的4-(6-溴-1H-吲哚-1-基)嘧啶-2-胺使用N-((1-(2-氨基嘧啶-4-基)6-溴-1H-吲哚-2-基)甲基)苯甲酰胺代替,反应在80℃下进行5个小时。得标题化合物N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)苯甲酰胺。1H NMR(600MHz,DMSO-d6)δ9.04(t,J=5.7Hz,1H),8.45(d,J=5.2Hz,1H),7.87(s,1H),7.86(s,1H),7.61(s,1H),7.54(d,J=7.8Hz,2H),7.48(t,J=7.6Hz,2H),7.15(d,J=8.0Hz,1H),7.02(s,2H),6.85(d,J=5.2Hz,1H),6.60(s,1H),5.38(s,1H),4.80(d,J=5.5Hz,2H),1.89–1.42(m,10H).HRMS(ESI+)[M+Na]+:488.2060。
按照实施例60的方法,可与适当的伯胺或仲胺或者醇进行反应来进行实施例61-69的制备。
实施例61:N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-3-甲基苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ9.10–9.00(m,1H),8.45(d,J=5.2Hz,1H),7.69(s,1H),7.67(s,1H),7.61(s,1H),7.54(d,J=8.1Hz,1H),7.36(d,J=5.1Hz,2H),7.15(d,J=8.1Hz,1H),7.03(s,2H),6.85(d,J=5.2Hz,1H),6.60(s,1H),5.39(s,1H),4.79(d,J=5.5Hz,2H),2.37(s,3H),1.88–1.44(m,10H).HRMS(ESI+)[M+Na]+:502.2232。
实施例62:N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-硝基苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ9.50(d,J=5.0Hz,1H),8.45(d,J=5.2Hz,1H),8.33(s,1H),8.32(s,1H),8.13(s,1H),8.11(s,1H),7.60(s,1H),7.55(d,J=8.1Hz,1H),7.15(d,J=8.0Hz,1H),7.03(s,2H),6.85(d,J=5.2Hz,1H),6.65(s,1H),5.40(s,1H),4.84(d,J=5.4Hz,2H),1.91–1.42(m,10H).HRMS(ESI+)[M+Na]+:533.1914。
实施例63:N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-2-硝基苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ9.33(s,1H),8.46(s,1H),8.05(d,J=6.6Hz,1H),7.81(s,1H),7.71(s,1H),7.61(s,2H),7.58(d,J=7.0Hz,1H),7.17(d,J=6.4Hz,1H),7.05(s,2H),6.85(s,1H),6.75(s,1H),5.41(s,1H),4.78(s,2H),1.92–1.41(m,10H).HRMS(ESI+)[M+Na]+:533.1918。
实施例64:N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-甲氧基苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.94(t,J=5.7Hz,1H),8.45(d,J=5.2Hz,1H),7.88(s,1H),7.86(s,1H),7.60(s,1H),7.54(d,J=8.1Hz,1H),7.14(d,J=8.1Hz,1H),7.02(s,2H),7.02(s,1H),7.00(s,1H),6.85(d,J=5.2Hz,1H),6.58(s,1H),5.39(s,1H),4.77(d,J=5.5Hz,2H),3.82(s,3H),1.89–1.40(m,10H).HRMS(ESI+)[M+Na]+:518.2179。
实施例65:N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-氟苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ9.11(t,J=5.7Hz,1H),8.44(d,J=5.2Hz,1H),7.93–7.85(m,2H),7.60(s,1H),7.56(d,J=1.9Hz,1H),7.55(d,J=8.3Hz,2H),7.15(dd,J=8.1,1.3Hz,1H),7.02(s,2H),6.84(d,J=5.2Hz,1H),6.61(s,1H),5.38(s,1H),4.80(d,J=5.5Hz,2H),1.94–1.39(m,10H).HRMS(ESI+)[M+K]+:522.1668。
实施例66:N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-2-氟苯甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.89(dt,J=5.6,2.8Hz,1H),8.45(d,J=5.2Hz,1H),7.64–7.59(m,2H),7.57(d,J=8.1Hz,1H),7.56–7.52(m,1H),7.34–7.30(m,1H),7.30–7.27(m,1H),7.16(dd,J=8.1,1.3Hz,1H),7.02(s,2H),6.85(d,J=5.3Hz,1H),6.67–6.63(m,1H),5.38(s,1H),4.80(d,J=5.7Hz,2H),1.89–1.44(m,10H).HRMS(ESI+)[M+Na]+:506.1974。
实施例67:N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-异戊酰胺
1H NMR(600MHz,DMSO-d6)δ8.45(d,J=5.4Hz,1H),8.34(t,J=5.4Hz,1H),7.61(s,1H),7.56(d,J=8.1Hz,1H),7.27(s,2H),7.16(d,J=8.0Hz,1H),6.86(d,J=5.4Hz,1H),6.59(s,1H),5.38(s,1H),4.59(d,J=5.5Hz,2H),2.03(d,J=7.0Hz,2H),1.97(tt,J=13.8,6.5Hz,1H),1.87–1.45(m,10H),0.86(d,J=6.5Hz,6H).HRMS(ESI+)[M+Na]+:468.2383。
实施例68:N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-1H-吲哚-6-甲酰胺
1H NMR(600MHz,DMSO-d6)δ11.41(s,1H),8.95(t,J=5.7Hz,1H),8.47(d,J=4.8Hz,1H),8.00(s,1H),7.63(s,1H),7.60(d,J=8.3Hz,1H),7.58–7.56(m,1H),7.54(d,J=8.1Hz,1H),7.52(t,J=2.7Hz,1H),7.18–7.13(m,1H),7.04(s,2H),6.87(d,J=5.2Hz,1H),6.60(s,1H),6.50(s,1H),5.39(s,1H),4.82(d,J=5.5Hz,2H),1.89–1.42(m,10H).HRMS(ESI+)[M+Na]+:527.2182。
实施例69:N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-1H-吲哚-2-甲酰胺
1H NMR(600MHz,DMSO-d6)δ11.66(s,1H),9.08(t,J=5.8Hz,1H),8.47(d,J=5.1Hz,1H),7.63(t,J=3.9Hz,2H),7.55(d,J=8.1Hz,1H),7.45(d,J=8.3Hz,1H),7.25–7.21(m,1H),7.19(t,J=7.6Hz,1H),7.16(d,J=8.1Hz,1H),7.09–7.02(m,3H),6.88(d,J=5.2Hz,1H),6.64(s,1H),5.40(s,1H),4.86(d,J=5.7Hz,2H),1.90–1.43(m,10H).HRMS(ESI+)[M+Na]+:527.2164。
实施例70:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-苯基-1H-吲哚-2-甲酰胺
6-溴吲哚-2-甲酸乙酯的制备:
步骤1:在Ar气氛保护下,在室温、搅拌下,分批的向乙醇(25mL)中加入叔丁醇钾(22.44g,0.2mol)。当所得的粘稠溶液进行充分冷却后加入乙醚(300Ml),随后加入草酸二乙酯(27.2mL,0.2mol)。搅拌10分钟后加入4-溴-2-硝基甲苯(21.5g,0.1mol),此时的现象为黄色溶液变成深红色溶液,再将反应混合物转移到锥形瓶中,塞好瓶塞并在室温下放置4h,然后在冰箱中放置1小时,之后进行过滤收集反应生成的固体,将所得到的固体用乙醚洗至滤液流无色并抽干15分钟,分离出的产物为25.8g,产率为73.0%,可以不经进一步纯化直接使用。
将上述产物(17.7g,0.05mol)中加入乙酸(250mL)溶液,再加入加入铁粉(8.4g,0.15mol)并进行加热使混合物到90℃。此时混合物变成浅粽色悬浮液。在90℃下反应过3小时后将反应混合物冷却至45℃,然后倒入冰水(500mL)中。将该混合物用乙醚(3×400mL)进行萃取,收集乙醚层进行合并,将萃取液用饱和的碳酸氢钠水溶液进行反复洗涤,直到停止冒泡、再用水(400mL)和1NHC1(2×300mL)进行洗涤,有机萃取液经过(硫酸镁)干燥并且在真空环境下除去溶剂得到类白色固体粗产品10.1g,产率为76%,将所得的粗产品使用甲苯进行重结晶,得7.1g产品,产率为70%。1H NMR(600MHz,DMSO-d6)δ12.03(s,1H),δ7.63(d,J=8.52Hz,1H),δ7.61(m,J=0.72Hz,1H),δ7.22(dd,J=1.8Hz,1H),δ7.17(m,J=0.9Hz,1H),δ4.35(dd,J=7.08Hz,2H),δ1.34(t,J=7.14Hz,3H)。
6-溴-1-(2-(甲基硫醚)嘧啶-4-基)-1H-吲哚-2-羧酸乙酯的制备
步骤2:将6-溴吲哚-2-甲酸乙酯(0.5g,1.86mmol)和2-甲硫基-4-溴嘧啶(0.46g,2.24mmol)溶于10mL干燥甲苯中,然后分别加入无水磷酸钾(1.18g,5.58mmol)、碘化亚铜(0.36g,1.86mmol)以及配体1,2-二氨基环己烷(0.43g,3.72mmol),加热至回流反映,反应10h完毕后,将反应液使用30mL乙酸乙酯进行稀释,通过硅藻土滤除不溶物后进行柱层析(PE:EA=5:1)得白色纯品0.57g,产率为78%。
6-溴-1-(2-(甲磺酰基)嘧啶-4-基)-1H-吲哚-2-羧酸乙酯的制备
步骤3:将6-溴-1-(2-(甲基硫醚)嘧啶-4-基)-1H-吲哚-2-羧酸乙酯(5.58g,14.24mmol),溶于DCM中,然后于冷阱中降温至零下4℃,再分批加入mCPBA,并于此温度下反应5h后检测,反应完毕。将反应液使用饱和硫代硫酸钠淬灭,然后用饱和碳酸氢钠洗涤,再用饱和食盐水干燥,减压蒸出溶剂,直接投下一步。ESI-MS(m/z):423[M-H]-。
1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-2-羧酸乙酯的制备
步骤4:将上述中间体6-溴-1-(2-(甲磺酰基)嘧啶-4-基)-1H-吲哚-2-羧酸乙酯,分别加入氨水(10mL),氯化铵(2g)(氨水和氯化铵都为大过量),异丙醇(50mL),封管60℃反应,1.5h后反应结束,柱层析(PE:EA=1.5:1)得淡黄色固体,产率41%。ESI-MS(m/z):362[M+H]+。
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-羧酸乙酯的制备
步骤5:该标题化合物通过调整实例1所述方法,将步骤2中的4-(6-溴-1H-吲哚-1-基)嘧啶-2-胺使用1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-2-羧酸乙酯替换,得标题化合物。ESI-MS(m/z):405[M+H]+。
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-羧酸的制备
步骤6:该标题化合物通过调整实例7所述方法,将步骤5中的1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-羧酸甲酯用1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-羧酸乙酯代替,得标题化合物。ESI-MS(m/z):375[M-H]-。
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-苯基-1H-吲哚-2-甲酰胺的制备
步骤7:该标题化合物通过调整实例7所述方法,在步骤6中用1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-羧酸代替1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-羧酸来与不同的取代胺进行反应,反应在常温下进行,得标题化合物。1H NMR(600MHz,DMSO-d6)δ10.66(s,1H),8.35(d,J=5.2Hz,1H),7.80–7.74(m,2H),7.71(d,J=8.0Hz,2H),7.40(s,1H),7.34(t,J=7.8Hz,2H),7.26(dd,J=8.1,1.4Hz,1H),7.10(t,J=7.4Hz,1H),6.96(s,2H),6.58(d,J=5.2Hz,1H),5.43(s,1H),1.89–1.45(m,10H).HRMS(ESI+)[M+Na]+:474.1911。
按照实施例70的方法,可与适当的伯胺或仲胺或者醇进行反应来进行实施例71-80的制备。
实施例71:乙基1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-羧酸酯
1H NMR(600MHz,DMSO-d6)δ8.42(d,J=5.2Hz,1H),7.76(d,J=8.2Hz,1H),7.57(s,1H),7.45(s,1H),7.25(dd,J=8.2,1.3Hz,1H),7.00(s,2H),6.74(d,J=5.2Hz,1H),5.43(s,1H),4.22(q,J=7.1Hz,2H),1.86–1.45(m,10H),1.19(t,J=7.1Hz,3H).HRMS(ESI+)[M+Na]+:405.1923。
实施例72:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡啶-4-基)-1H-吲哚-2-甲酰胺
1H NMR(600MHz,DMSO-d6)δ11.65(s,1H),8.48(s,2H),8.30(d,J=5.2Hz,1H),8.01–7.89(m,2H),7.70(d,J=8.2Hz,1H),7.66(s,1H),7.59(s,1H),7.22–7.16(m,1H),6.89(s,2H),6.60(d,J=5.2Hz,1H),5.38(s,1H),1.82–1.31(m,10H).HRMS(ESI+)[M+H]+:453.2036。
实施例73:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(间甲苯基)-1H-吲哚-2-甲酰胺
1H NMR(600MHz,DMSO-d6)δ10.59(s,1H),8.36(d,J=5.2Hz,1H),7.76(d,J=8.7Hz,1H),7.75(s,1H),7.59(s,1H),7.49(d,J=8.1Hz,1H),7.40(s,1H),7.26(dd,J=8.2,1.1Hz,1H),7.22(t,J=7.8Hz,1H),6.97(s,2H),6.92(d,J=7.5Hz,1H),6.58(d,J=5.2Hz,1H),5.43(s,1H),2.30(s,3H),1.92–1.41(m,10H).HRMS(ESI+)[M+Na]+:488.2071。
实施例74:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-异丙基-1H-吲哚-2-甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.55(d,J=7.8Hz,1H),8.33(d,J=5.2Hz,1H),7.77(s,1H),7.68(d,J=8.2Hz,1H),7.26–7.19(m,1H),7.13(s,1H),6.93(s,2H),6.44(d,J=5.2Hz,1H),5.41(s,1H),4.04–3.92(m,J=6.7Hz,1H),1.90–1.41(m,10H),1.16(d,J=6.6Hz,6H).HRMS(ESI+)[M+Na]+:440.2073。
实施例75:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N,N-二甲基-1H-吲哚-2-甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.35(d,J=5.3Hz,1H),7.90(s,1H),7.65(d,J=8.1Hz,1H),7.24(dd,J=8.1,1.2Hz,1H),6.92(d,J=4.5Hz,3H),6.58(d,J=5.3Hz,1H),5.42(s,1H),3.09(s,3H),2.98(s,3H),1.95–1.43(m,10H).HRMS(ESI+)[M+Na]+:426.1913。
实施例76:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-甲氧基乙基)-1H-吲哚-2-甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.78(t,J=5.7Hz,1H),8.34(d,J=5.2Hz,1H),7.78(s,1H),7.70(d,J=8.1Hz,1H),7.23(dd,J=8.2,1.2Hz,1H),7.15(s,1H),6.96(s,2H),6.48(d,J=5.2Hz,1H),5.42(s,1H),3.47(t,J=5.8Hz,2H),3.43–3.38(m,2H),3.29(s,3H),1.95–1.41(m,10H).HRMS(ESI+)[M+Na]+:456.2026。
实施例77:1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-羟基乙基)-1H-吲哚-2-甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.71(t,J=5.7Hz,1H),8.32(d,J=5.3Hz,1H),7.75(s,1H),7.69(d,J=8.1Hz,1H),7.22(d,J=8.1Hz,1H),7.16(s,1H),6.94(s,2H),6.49(d,J=5.3Hz,1H),5.41(s,1H),4.82–4.77(m,1H),3.51(q,J=6.1Hz,2H),3.28(q,J=6.1Hz,2H),1.89–1.42(m,10H).HRMS(ESI+)[M+Na]+:442.1869。
实施例78:1-(2-氨基嘧啶-4-基)-N-环丙基-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.72(d,J=4.1Hz,1H),8.34(d,J=5.2Hz,1H),7.73(s,1H),7.68(d,J=8.1Hz,1H),7.21(dd,J=8.2,1.2Hz,1H),7.11(s,1H),6.95(s,2H),6.46(d,J=5.2Hz,1H),5.40(s,1H),2.77(tq,J=7.8,4.0Hz,1H),1.89–1.43(m,10H),0.69(td,J=7.0,4.9Hz,2H),0.61–0.55(m,2H).HRMS(ESI+)[M+Na]+:438.1914。
实施例79:N-烯丙基-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.90(t,J=5.7Hz,1H),8.33(d,J=5.2Hz,1H),7.72(s,1H),7.70(d,J=8.2Hz,1H),7.22(d,J=9.2Hz,1H),7.20(s,1H),6.94(s,2H),6.47(d,J=5.2Hz,1H),5.88(ddt,J=15.5,10.3,5.1Hz,1H),5.41(s,1H),5.28–5.19(m,1H),5.16–5.06(m,1H),3.85(t,J=5.3Hz,2H),1.89–1.43(m,10H).HRMS(ESI+)[M+Na]+:438.1903。
实施例80:1-(2-氨基嘧啶-4-基)-N-乙基-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺
1H NMR(600MHz,DMSO-d6)δ8.70(t,J=5.6Hz,1H),8.32(d,J=5.2Hz,1H),7.74(s,1H),7.68(d,J=8.2Hz,1H),7.22(dd,J=8.2,1.1Hz,1H),7.13(s,1H),6.94(s,2H),6.45(d,J=5.2Hz,1H),5.40(s,1H),3.28–3.18(m,2H),1.92–1.41(m,10H),1.12(t,J=7.2Hz,3H).HRMS(ESI+)[M+H]+:404.2083。
实施例81:1-((1-(2-氨基嘧啶-4-基)-2-(2-羟丙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇的制备
N-(5-溴-2-碘苯基)-2-(甲硫基)嘧啶-4-胺的合成的制备
步骤1:将5-溴-2-碘苯胺(1g,3.357mmol)和2-甲硫基嘧啶(0.4ml,0.3439mmol)溶于10ml异丙醇中,加入浓盐酸2d,将反应加热至60℃反应20h,Tlc检测反应结束。将反应液倾入50ml冰水中,用20%的氢氧化钠溶液调PH至8左右,抽滤,洗涤,干燥得类白色固体1.18g。产率83.2%。ESI-MS(m/z):422[M-H]-。
1-(6-溴-1-(2-(甲硫基)嘧啶-4-基)1H-吲哚-2-基)丙基-2醇的制备
步骤2:将N-(5-溴-2-碘苯基)-2-(甲硫基)嘧啶-4-胺(1g,2.37mmol),4-戊炔-2-醇(0.22g,2.61mmol),TEA(1ml,7.11mmol),加入10ml DMF中,超声除气泡,并抽真空氮气保护,然后加入CuI(0.09g,0.474mmol),双三苯基膦二氯化钯(83mg,0.12mmol)室温反应,大约2h后,补加0.8eq CuI,加热至70℃反应8h,TLC检测反应结束。将反应液倒入50ml水中使用EA30 ml*3萃取,饱和食盐水洗涤,干燥,然后进行柱层析分离(EA:PE=2:1),最后得白色絮状固体0.81g,产率75%。ESI-MS(m/z):378[M-H]-。
1-(6-溴-1-(2-(甲磺酰基)嘧啶-4-基)1H-吲哚-2-基)丙基-2-醇的制备
步骤3:1-(6-溴-1-(2-(甲硫基)嘧啶-4-基)1H-吲哚-2-基)丙基-2醇(0.8g,1.9mmol),溶于DCM中,然后于冷阱中降温至零下4℃,再分批加入mCPBA(1.01g,5.85mmol),并于此温度下反应5h后检测,反应完毕。将反应液使用饱和硫代硫酸钠淬灭,然后用饱和碳酸氢钠洗涤,再用饱和食盐水干燥,减压蒸出溶剂,直接投下一步。ESI-MS(m/z):410[M-H]-。
1-(1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-2-基)丙基-2-醇的制备
步骤4:将1-(6-溴-1-(2-(甲磺酰基)嘧啶-4-基)1H-吲哚-2-基)丙基-2-醇溶于20mL异丙醇中,加入氨水(2ml),氯化铵(0.5g)(氨水和氯化铵都为大过量),封管80度反应,1.5h后反应结束,柱层析(DCM:MeOH=50:1)得淡黄色固体,产率41%。ESI-MS(m/z):348[M+H]+。
1-((1-(2-氨基嘧啶-4-基)-2-(2-羟丙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇的制备
步骤5:该标题化合物通过调整实施例1所述方法,将步骤2中的4-(6-溴-1H-吲哚-1-基)嘧啶-2-胺使用1-(1-(2-氨基嘧啶-4-基)-6-溴-1H-吲哚-2-基)丙基-2-醇代替,反应在80℃下进行5个小时,得标题化合物1-((1-(2-氨基嘧啶-4-基)-2-(2-羟丙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇。1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),7.97(d,J=1.6Hz,1H),7.87(d,J=5.9Hz,1H),7.36(d,J=8.0Hz,1H),7.06(dd,J=7.9,1.7Hz,1H),6.52(s,2H),6.16(d,J=5.9Hz,1H),5.43(s,1H),5.02(d,J=4.9Hz,1H),3.84(hept,J=6.0Hz,1H),2.54(d,J=5.1Hz,2H),1.90–1.43(m,10H),1.15(d,J=6.2Hz,3H).HRMS(ESI+)[M+H]+:391.2135。
按照实施例81的方法,可与适当的端炔进行反应来进行实施例82和83的制备。
实施例82:1-((1-(2-氨基嘧啶-4-基)-2-(2-羟基-2-(噻吩-2-基)乙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1H NMR(600MHz,DMSO-d6)δ8.29(s,1H),8.13(s,1H),7.88(d,J=5.7Hz,1H),7.39(d,J=5.0Hz,1H),7.31(d,J=8.0Hz,1H),7.05(d,J=3.4Hz,1H),7.01(d,J=7.9Hz,1H),6.95(t,J=4.3Hz,1H),6.34(s,2H),6.16(d,J=4.9Hz,1H),6.14(d,J=5.8Hz,1H),5.41(s,1H),5.10(q,J=5.6Hz,1H),2.98–2.88(m,2H),1.89–1.45(m,10H).HRMS(ESI+)[M+H]+:459.1868。
实施例83:1-((1-(2-氨基嘧啶-4-基)-2-(2-羟基-2-苯乙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1H NMR(400MHz,DMSO-d6)δ8.29(s,1H),8.11(d,J=1.6Hz,1H),7.89(d,J=5.7Hz,1H),7.52–7.39(m,2H),7.36–7.20(m,4H),7.00(dd,J=7.9,1.7Hz,1H),6.33(s,2H),6.14(d,J=5.8Hz,1H),5.79(d,J=4.6Hz,1H),5.41(s,1H),4.84(q,J=5.7Hz,1H),2.85(d,J=6.1Hz,2H),1.89–1.45(m,10H).HRMS(ESI+)[M+H]+:453.2294。
实施例84:本发明部分产物的体外酶抑制活性研究
实验材料:多功能酶标仪(Tecan,Infinite F500),HTRF KinEASE-STK S2 Kit(CisBio),Kit中包括:STK Substrate 2-biotin,Streptavidin-XL-665,STKAntibody-Cryptate,5x Enzymatic buffer,HTRF Detection buffer。PAK4蛋白(Full-length,Carna),二硫苏糖醇(DL-Dithiothreitol,DTT),ATP等。
实验方法:本实验采用KinEASETM-STK激酶测试方法。操作步骤包括酶促反应和检测反应。具体操作如下:按照试剂盒说明,配制Kinase buffer;先将待测试化合物用DMSO配制成8000μM的储备液,后用Kinase buffer稀释至25.0μM,接着依次3倍稀释至0.4nM,共11个浓度。将待测试化合物(4μL)、STK Substrate 2和ATP(Km浓度)的混合液(4μL)、PAK4蛋白(Full-length)(2μL)混合,高速离心后,25℃孵育1.0h。用Detection buffer稀释Streptavidin-XL-665和STK Antibody-Cryptate配制Detection reagents,将10μLDetection reagents加到上述1.0h孵育后的反应液中,高速离心,25℃孵育1.0h后利用多功能酶标仪(Tecan,Infinite F500)测定Cryptate(620nm)和XL-665(665nm)在340nm波长激发光照射下的散射光强度,计算665/620比值。使用GraphPad Prism 6软件的四参数逻辑回归法做抑制曲线,得到待测化合物对于PAK4的IC50。
实施例85:本发明部分产物的体外A549细胞迁移活性研究
人源A549肿瘤细胞接种于含10%胎牛血清,100U/mL青霉素,100μg/mL链霉素的RPMI-1640培养基中,将培养瓶置于37℃,5%CO2饱和湿度培养箱培养,每1-2天换培养液一次。当细胞生长到足以覆盖瓶底壁的大部分表面时,贴壁细胞用0.25%胰蛋白酶消化,传代。
对数生长期细胞培养于6孔培养板内,在6孔板背面使用marker笔画线,间隔1厘米左右,线尽量均匀,横穿过孔,每个孔约画5至7条线。细胞计数,在6孔板中每孔加入70000-120000左右个A549细胞,然后将6孔板放入培养箱孵育至形成均匀单层细胞。次日,取出6孔板,每个孔用PBS洗3次,用枪头比着直尺,垂直于6孔板底部的横线划痕。之后每孔再用PBS洗三次,去除划下的细胞。对照组加入与给药组等体积的溶剂,置37℃,5%CO2温箱中培养。。放入培养箱培养。按照72h取样,拍照测量。
表1部分实施例化合物在1μM、10μM浓度下体外PAK4抑制活性百分比
本发明中通式(I)的化合物可单独施用,但通常是和药用载体混合物给予,所述药用载体的选择要根据所需用药途径和标准药物实践,下面分别用该类化合物的各种药物剂型,例如片剂、胶囊剂、注射剂、气雾剂、栓剂、膜剂、滴丸剂、外用搽剂和软膏剂的制备方法,说明其在制药领域中的新应用。
实施例86:片剂
用含有权利要求1中化合物的化合物(以实施例8化合物为例)10g,按照药剂学一般压片法加辅料20g混匀后,压制成100片,每片重300mg。
实施例87:胶囊剂
用含有权利要求1中化合物的化合物(以实施例8化合物为例)10g,按照药剂学胶囊剂的要求将辅料20g混匀后,装入空心胶囊,每个胶囊重300mg。
实施例88:注射剂
用含有权利要求1中化合物的化合物(以实施例8化合物为例)10g,按照药剂学常规方法,进行活性炭吸附,经0.65μm微孔滤膜过滤后,填入氮气罐制成水针制剂,每只装2mL,共灌装100瓶。
实施例89:气雾剂
用含有权利要求1中化合物的化合物(以实施例8化合物为例)10g,用适量丙二醇溶解后,加入蒸馏水及其他辐料后,制成500mL的澄清溶液即得。
实施例90:栓剂
用含有权利要求1中化合物的化合物(以实施例8化合物为例)10g,将之研细加入甘油适量,研匀后加入已熔化的甘油明胶,研磨均匀,倾入已涂润滑剂的模型中,制得栓剂50颗
实施例91:膜剂
用含有权利要求1中化合物的化合物(以实施例8化合物为例)10g,将聚乙烯醇、药用甘油、水等搅拌膨胀后加热溶解,80目筛网过滤,再将实施例18化合物加入到滤液中搅拌溶解,涂膜机制膜100片。
实施例92:滴丸剂
用含有权利要求1中化合物的化合物(以实施例35化合物为例)10g,与明胶等基质50g加热熔化混匀后,滴入低温液体石蜡中,共制得滴丸1000丸。
实施例93:外用搽剂
用含有权利要求1中化合物的化合物(以实施例8化合物为例)10g,按照常规药剂学方法与乳化剂等辅料2.5g混合研磨,再加蒸馏水至200mL制得。
实施例94:软膏剂
用含有权利要求1中化合物的化合物(以实施例35化合物为例)10g,研细后与凡士林等油性基质500g研匀制得。
尽管已经通过特定实施方案描述了本发明,但修改和等价变化对于精通此领域的技术人员而言是显见的,且它们都包含在本发明范围。
Claims (10)
1.通式(I)的新型吲哚类衍生物,及其几何异构体或药学上可接受的盐、水合物、溶剂化物或前药:
其中:
W,X,Y,Z可以分别选自C或N。
R1选自:氢、C1-2烷基或-CH2-OH;
R2选自:氢、C1-6烷基、C3-6环烷基、6~10元芳基,5~10元杂芳基,且所述芳基或杂芳基可进一步被1~3个相同或不同的R2a取代;氢、卤素、氰基、C1-4烷基、C1-4烷氧基、卤素取代的C1-4烷基或C1-4烷氧基;
或R1和R2连同他们所连接的碳原子一起形成一个C3-7环烷基或5-10元杂环烷基,所形成的环烷基可进一步被C1-2烷基或卤素所取代。
R3无取代,或R3选自:氢、卤素、氰基、C1-6烷基;
R4选自:氢、醛基、氰基、C1-6烷基、羰基、被-OH或氨基取代的C1-6烷基、-C1-6烷基氧基C1-4烷基、-C1-6烷基-C(=O)-N R4aR4b、-OC1-6烷基、被卤素取代的-OC1-6烷基、-C(=O)NR4aR4b、-NR4aR4b。其中R4a和R4b各自独立的选自氢、C1-4烷基、C2-4烷基氧基C1-4烷基、6~10元芳基,5~10元杂芳基;或R4a和R4b连同它们所连接的氮原子一起形成一个3-10元杂环基。且所述的芳基、杂芳基、杂环基可以任意地被1至3个氢、C1-4烷基、氨基、羟基、被一个羟基或氨基取代的C1-4烷基、或被一个或多个卤素取代的C1-4烷基、5~10元杂环基、6~10元芳基、5~10元芳杂基;
R5无取代,或R5选自:氢、氰基、C1-4醛基、C1-4酯基、C1-6烷基、C3-6环烷基、-C(=O)-NR5aR5b、-CNR5aR5b、NR5aR5b、6~10元芳环、5~10元杂环、被1~3个选自下组取代基取代的C1-6烷基:卤素、硝基、-OH、-OC1-4烷基、6~10元芳环以及5~10元杂环。R5a和R5b各自独立的选自下组:氢、C1-6烷基、C3-6环烷基、6~10元芳基、5~10元芳杂基。或R5a和R5b连同他们所连接的碳原子一起形成一个C3-7环烷基或5-10元杂环烷基。所形成的环烷基可进一步被C1-2烷基或卤素所取代。其中芳基和杂环可以任选的被1至3个选自以下各项的取代基取代:氢、羟基、氨基、卤素、氰基、C1-4烷基、C1-4烷氧基、被一个或多个卤素或羟基取代的C1-4烷基以及被一个或多个卤素或羟基取代的C1-4烷基氧基、5~10元杂环基、6~10元芳基、5~10元芳杂基;
R6选自:氢、C1-6烷基、C3-6的环烷基、C1-6亚烷基-C3-6环烷基、苯基、5-6元杂芳基、5-6元芳基或5-6元杂芳基取代的C1-6烷基、-C(=O)R6a,其中R6a选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C1-6杂烷基、3-6元环烷基、3-6元杂烷基、-(C1-6亚烷基)-(3-8元环烷基)、-(C1-6亚烷基)-(3-8元杂环烷基)、-(C1-6亚烷基)-(6元芳基)、(C1-6亚烷基)-(5-6元杂芳基)、苯基和5-6元杂芳基,所述的杂烷基、杂芳基含有1-3个N、O或S的杂原子;
其中R6的脂肪基和/或芳香基部分,可以任选的被1至多个选自下列的取代基取代:氢,羟基,卤素,硝基,氨基,氰基,游离的、成盐的、酯化的、酰胺化的羧基,C1-6烷基,C2-6烯基,C2-6炔基,C1-6烷氧基,C1-6烷基酰基,C1-6烷基亚磺酰基、磺酰基,氨基甲酰基,任选被羟基、氨基、卤代的C1-6烷基或C1-6烷氧基,被氢、羟基、氨基或游离的、成盐的、酯化的、酰胺化的羧基取代的C3-6环烷基或C3-6杂环烷基,被单或二(C1-6烷基)取代的胺基或C1-6烷基酰胺基,被单或二(C1-6烷基)取代的胺基甲酰基,被氢、羟基、氨基、烷基取代的5~10元杂芳基,其中所述杂环烷基与杂芳基分别含有1至3个选自O、N和S的杂原子;
R7选自:氢、氰基、氨基、C1-6烷基、C1-6烷氧基、C1-6烷基氨基。
2.权利要求1的通式(I)化合物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药,
其中:
R1和R2连同他们所连接的碳原子一起形成环戊基、环己基,所形成的环戊基、环己基可进一步被C1-2烷基和氟所取代。
3.权利要求1或2任何一项的通式(I)化合物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药,
其中:
R4选自:氢、C1-4醛基、C1-4酯基、羰基、氰基、C1-4烷基、被一个-OH或氨基取代的C1-6烷基、-C(=O)NR4aR4b,其中R4a和R4b各自独立的选自氢、C1-4烷基、C2-4烷基氧基C1-4烷基、6-10元芳基,5~6元杂环基;或R4a和R4b连同它们所连接的氮原子一起形成一个3-10元杂环基;
所述的芳基或杂环基选自:苯基、萘基、哌啶基、哌嗪基、吗啉基、吡咯烷基、高哌嗪基、氮杂环丁烷基、咪唑基、吡唑基、四氢呋喃基、噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基以及吡嗪基,且芳基、杂环基各自可以任意地被1至3个氢、C1-4烷基、氨基、羟基、被一个羟基或氨基取代基取代的C1-4烷基取代或被一个或多个氟取代基取代的C1-4烷基取代。
4.权利要求1-3任何一项的通式(I)化合物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药,
其中,
R5选自:氢、氰基、醛基、C1-6烷基、C3-6环烷基、-C(=O)-NR5aR5b、-CNR5aR5b、NR5aR5b、6元芳环、5~6元杂环、被1~3个选自如下取代基取代的C1-6烷基:卤素、-OH、-OC1-4烷基、6~10元芳基以及5~10元杂基,R5a和R5b各自独立的选自:氢、C1-6烷基、C3-6环烷基、苯基、5~6元芳杂基,或R5a和R5b连同他们所连接的碳原子一起形成一个C3-10环烷基或杂环烷基,所形成的环烷基可进一步被C1-2烷基和氟所取代。
R5中所涉及的芳基和芳杂基主要包括:苯基、萘基、噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并噻吩基、苯并呋喃基、吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基,且芳基和杂环基可以任选的被1至3个选自以下各项的取代基取代:氢、羟基、氨基、卤素、氰基、C1-4烷基、C1-4烷氧基、被一个或多个氟取代的C1-4烷基以及被一个或多个氟取代基取代的C1-4烷基氧基。
5.权利要求1-4任何一项的通式(I)化合物,及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药,
其中,
R6选自:氢、C1-6烷基、C3-6的环烷基、C1-6亚烷基-C3-6环烷基、苯基、5-6元杂芳基、-C1-6亚烷基-6元芳基、C1-6亚烷基-5-6元杂芳基、-C(=O)R6a,其中R6a选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C1-6杂烷基、3-6元环烷基、3-6元杂烷基、-(C1-6亚烷基)-(3-8元环烷基)、-(C1-6亚烷基)-(3-8元杂环烷基)、-(C1-6亚烷基)-(6元芳基)、(C1-6亚烷基)-(5-6元杂芳基)、苯基和5-6元杂芳基,其中芳基和芳杂基包括:噻吩基、噻唑基、吡咯基、噁唑基、吡唑基、咪唑基、异恶唑基、异噻唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、苯并噻吩基、苯并呋喃基、吲哚基、苯并咪唑基、苯并吡唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基;
其中R6的脂肪族和/或芳香族部分,可以任选的被1至5个选自下列的取代基取代:氢,羟基,卤素,硝基,胺基,氰基,游离的、成盐的、酯化的、酰胺化的羧基,C1-6烷基,C1-6烯基,C1-6炔基,C1-6烷氧基,C1-6烷基酰基,C1-6烷基亚磺酰基、磺酰基,氨基甲酰基,任选被羟基、氨基、卤代的C1-6烷基或C1-6烷氧基,被氢、羟基、氨基或游离的、成盐的、酯化的、酰胺化的羧基取代的C3-6环烷基或C3-6杂环烷基,被单或二(C1-6烷基)取代的胺基或C1-6烷基酰胺基,被单或二(C1-6烷基)取代的胺基甲酰基,被氢、羟基、氨基、烷基取代的5~10元杂芳基,其中所述杂环烷基与杂芳基分别含有1至3个选自O、N和S的杂原子。
6.通式(I)的新型吲哚类衍生物,及其几何异构体或药学上可接受的盐、水合物、溶剂化物或前药,选自:
1-((1-(2-氨基嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-氨基嘧啶-4-基)-5-氟-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-氨基嘧啶-4-基)1H-吡咯[3,2-b]并吡啶-6-基)乙炔基)环己基-1-醇
1-((1-(2-氨基嘧啶-4-基)-1H-吲唑-6-基)乙炔基)环己基-1-醇
1-((2-氨基嘧啶-4-基)-1H-吡咯[2,3-b]并吡啶-6-基)乙炔基)环己基-1-醇
1-((2-氨基嘧啶-4-基)-1H-吡咯[3,2-c]并吡啶-6-基)乙炔基)环己基-1-醇
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(哌嗪-1-基)甲酮
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺
1-((1-(2,6-二氨基嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-(2-氨基嘧啶-4-基)-6-(1-羟基环己基)乙炔基)-1H-吲哚-3-甲醛
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(吡咯-1-基)甲酮
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(哌啶-1-基)甲酮
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N,N-二甲基-1H-吲哚-3-甲酰胺
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(吗啉基)甲酮
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-甲基哌嗪-1-基)甲酮
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-甲基-1H-吲哚-3-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(噻唑-2-基)-1H-吲哚-3-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-苯基-1H-吲哚-3-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲腈
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-甲氧乙基)-1H-吲哚-3-甲酰胺
1-(2-氨基嘧啶-4-基)-N-苄基-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-(2-羟乙基)哌嗪-1-基)甲酮
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(2-(羟乙基)吡咯-1-基)甲酮
1-(2-氨基嘧啶-4-基)-N-(5-羟基-1H-吡唑-3-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-甲酰胺
(R)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-甲基哌嗪-1-基)甲酮
(S)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-甲基哌嗪-1-基)甲酮
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3,5-二甲基哌嗪-1-基)甲酮
(3-氨基-1H-吡唑-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(1H-吡唑-3-基)-1H-吲哚-3-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2,2,2-三氟乙基)-1H-吲哚-3-甲酰胺
(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(4-吗啉基哌啶-1-基)甲酮
(R)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-羟基哌啶-1-基)甲酮
(S)-(3-氨基哌啶-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮
(S)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(哌啶-3-基)1H-吲哚-3-甲酰胺
(R)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(哌啶-3-基)1H-吲哚-3-甲酰胺
(R)-(3-氨基哌啶-1-基)(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)甲酮
(S)-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-基)(3-氨基吡咯-1-基)甲酮
(S)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡咯-3-基)1H-吲哚-3-甲酰胺
(R)-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡咯-3-基)1H-吲哚-3-甲酰胺
4-(1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-3-羰基)哌嗪-2-酮
1-((1-(2-苄胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-((噻吩-2-甲基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1-((1-(2-((2-氟苯基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1-((1-(2-((2-甲氧乙基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1-((1-(2-((2-氯苄基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1-((1-(2-((4-氟苯基)氨基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己烷-1-醇
1-((1-(2-(苯胺)嘧啶-4-基)-1H-吲哚-6-基)乙炔)环己基-1-醇
1-((1-(2-((3-氯苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔)环己基-1-醇
1-((1-(2-((3-氯-4-氟苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
3-((4-(6-((1-羟基环己基)乙炔基)-1H-吲哚-1-基)嘧啶-2-基)氨基)苯甲腈
1-((1-(2-((4-甲氧基苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-((3-硝基苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-(间甲基苯氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-((4-(三氟甲氧基)苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-((2-(三氟甲基)苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-(邻甲基苯氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-((2-氟苯基)氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-((2-甲氧基乙基)氨基)嘧啶-4-基)-1H-吲哚-6基)乙炔基)环己基-1-醇
3-((4-(6-((1-羟基环己基)乙炔基)1H-吲哚-1-基)嘧啶-2-基)氨基)苯磺酰胺
1-((1-(2-(环己氨基)嘧啶-4-基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)苯甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-3-甲基苯甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-硝基苯甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-2-硝基苯甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-甲氧基苯甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-4-氟苯甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-2-氟苯甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-异戊酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-1H-吲哚-6-甲酰胺
N-((1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-基)甲基)-1H-吲哚-2-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-苯基-1H-吲哚-2-甲酰胺
乙基1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-羧酸酯
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(吡啶-4-基)-1H-吲哚-2-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(间甲苯基)-1H-吲哚-2-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N,N-二甲基-1H-吲哚-2-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-甲氧基乙基)-1H-吲哚-2-甲酰胺
1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-N-(2-羟基乙基)-1H-吲哚-2-甲酰胺
1-(2-氨基嘧啶-4-基)-N-环丙基-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺
N-烯丙基-1-(2-氨基嘧啶-4-基)-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺
1-(2-氨基嘧啶-4-基)-N-乙基-6-((1-羟基环己基)乙炔基)-1H-吲哚-2-甲酰胺
1-((1-(2-氨基嘧啶-4-基)-2-(2-羟丙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇的制备
1-((1-(2-氨基嘧啶-4-基)-2-(2-羟基-2-(噻吩-2-基)乙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
1-((1-(2-氨基嘧啶-4-基)-2-(2-羟基-2-苯乙基)-1H-吲哚-6-基)乙炔基)环己基-1-醇
7.一种药用组合物,包含权利要求1至6中任何一项的化合物及其药学上可接受的盐、水合物、溶剂化物或前药作为活性成分以及药学上可接受的赋形剂。
8.权利要求1-6任何一项的化合物及其药学上可接受的盐、水合物、溶剂化物或前药或权利要求7所述的药物组合物在制备PAK蛋白激酶抑制剂中的应用。
9.权利要求1-6任何一项的化合物及其药学上可接受的盐、水合物、溶剂化物或前药或权利要求7所述的药物组合物在制备抗肿瘤的药物中的应用。
10.权利要求9所述的应用,其特征在于,所述的肿瘤为肺癌、乳腺癌、胰腺癌、结肠癌、胃癌、卵巢癌、口腔鳞状细胞癌、前列腺癌、黑色素瘤、白血病、非霍奇金性淋巴瘤。
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