CN111491918B - 芳基和杂芳基取代的吲哚化合物 - Google Patents
芳基和杂芳基取代的吲哚化合物 Download PDFInfo
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- CN111491918B CN111491918B CN201880082778.8A CN201880082778A CN111491918B CN 111491918 B CN111491918 B CN 111491918B CN 201880082778 A CN201880082778 A CN 201880082778A CN 111491918 B CN111491918 B CN 111491918B
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- Prior art keywords
- isopropyl
- indol
- dimethoxyphenyl
- pyridin
- methylpyridin
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- 125000003118 aryl group Chemical group 0.000 title claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 title description 5
- 150000002475 indoles Chemical class 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 180
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 238000011282 treatment Methods 0.000 claims abstract description 41
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 26
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 17
- -1 pyrazolo [3,4-b]Pyridyl Chemical group 0.000 claims description 315
- 125000000217 alkyl group Chemical group 0.000 claims description 82
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 42
- 125000004076 pyridyl group Chemical group 0.000 claims description 42
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 41
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 38
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 33
- 125000002757 morpholinyl group Chemical group 0.000 claims description 27
- 201000006417 multiple sclerosis Diseases 0.000 claims description 24
- VAELWSLNTRVXQS-UHFFFAOYSA-N 1,3-oxazole-4-carboxamide Chemical compound NC(=O)C1=COC=N1 VAELWSLNTRVXQS-UHFFFAOYSA-N 0.000 claims description 20
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- FFNXULQHYCDQPJ-UHFFFAOYSA-N 2-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-5-piperidin-4-yl-1,3,4-oxadiazole Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)C1=NN=C(O1)C1CCNCC1 FFNXULQHYCDQPJ-UHFFFAOYSA-N 0.000 claims description 14
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 14
- 125000002393 azetidinyl group Chemical group 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 125000004193 piperazinyl group Chemical group 0.000 claims description 13
- 125000003386 piperidinyl group Chemical group 0.000 claims description 13
- STFWQJXPPQEYBY-UHFFFAOYSA-N 2-(1-azabicyclo[2.2.2]octan-3-yl)-5-[2-(2-methylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]-1,3,4-oxadiazole Chemical compound CC(C)C1=C(NC2=CC=C(C=C12)C1=NN=C(O1)C1CN2CCC1CC2)C1=CC(C)=NC=C1 STFWQJXPPQEYBY-UHFFFAOYSA-N 0.000 claims description 12
- DZFBSUZMGSCPHY-UHFFFAOYSA-N 2-(1-methylpiperidin-3-yl)-5-[2-(2-methylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]-1,3,4-oxadiazole Chemical compound CC(C)C1=C(NC2=CC=C(C=C12)C1=NN=C(O1)C1CCCN(C)C1)C1=CC(C)=NC=C1 DZFBSUZMGSCPHY-UHFFFAOYSA-N 0.000 claims description 12
- XDSJRGYPVBWTKW-UHFFFAOYSA-N 2-(2-methylpyridin-4-yl)-3-propan-2-yl-5-[5-(1-propan-2-ylpiperidin-3-yl)-1H-1,2,4-triazol-3-yl]-1H-indole Chemical compound CC(C)N1CCCC(C1)C1=NN=C(N1)C1=CC=C2NC(=C(C(C)C)C2=C1)C1=CC(C)=NC=C1 XDSJRGYPVBWTKW-UHFFFAOYSA-N 0.000 claims description 12
- WFURYHDRLAUOEZ-UHFFFAOYSA-N 2-(2-methylpyridin-4-yl)-5-(5-piperidin-3-yl-1H-1,2,4-triazol-3-yl)-3-propan-2-yl-1H-indole Chemical compound CC(C)C1=C(NC2=CC=C(C=C12)C1=NN=C(N1)C1CCCNC1)C1=CC(C)=NC=C1 WFURYHDRLAUOEZ-UHFFFAOYSA-N 0.000 claims description 12
- HXYGDWKXSUQLMI-UHFFFAOYSA-N 2-[3-(2,2-difluoroethyl)-2-(2,6-dimethylpyridin-4-yl)-1H-indol-5-yl]-5-(1-propan-2-ylpiperidin-3-yl)-1,3,4-oxadiazole Chemical compound CC(C)N1CCCC(C1)C1=NN=C(O1)C1=CC=C2NC(=C(CC(F)F)C2=C1)C1=CC(C)=NC(C)=C1 HXYGDWKXSUQLMI-UHFFFAOYSA-N 0.000 claims description 12
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 12
- SPFYEMLQPQAWKD-UHFFFAOYSA-N CC(C)N1CCCC(C1)C1=NN=C(N1)C1=CC=C2NC(=C(C(C)C)C2=C1)C1=CC(C)=NC(C)=C1 Chemical compound CC(C)N1CCCC(C1)C1=NN=C(N1)C1=CC=C2NC(=C(C(C)C)C2=C1)C1=CC(C)=NC(C)=C1 SPFYEMLQPQAWKD-UHFFFAOYSA-N 0.000 claims description 12
- SKXLZSFQKDJOHU-UHFFFAOYSA-N CC(C)N1CCCC(C1)C1=NN=C(O1)C1=CC=C2NC(=C(C(C)C)C2=C1)C1=CC(C)=NC=C1 Chemical compound CC(C)N1CCCC(C1)C1=NN=C(O1)C1=CC=C2NC(=C(C(C)C)C2=C1)C1=CC(C)=NC=C1 SKXLZSFQKDJOHU-UHFFFAOYSA-N 0.000 claims description 12
- 125000002883 imidazolyl group Chemical group 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 11
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 11
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 11
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 11
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 11
- IVLSZQUSIYBHEI-UHFFFAOYSA-N 2-(1-methylpiperidin-3-yl)-5-[3-propan-2-yl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-indol-5-yl]-1,3,4-oxadiazole Chemical compound CC(C)C1=C(NC2=CC=C(C=C12)C1=NN=C(O1)C1CCCN(C)C1)C1=CC=NC2=C1C=NN2 IVLSZQUSIYBHEI-UHFFFAOYSA-N 0.000 claims description 10
- LJXIIQAJLXYBPD-UHFFFAOYSA-N [3-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]phenyl]-piperazin-1-ylmethanone Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1C(C)C)C1=CC(=CC=C1)C(=O)N1CCNCC1 LJXIIQAJLXYBPD-UHFFFAOYSA-N 0.000 claims description 10
- 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 description 10
- 125000005959 diazepanyl group Chemical group 0.000 claims description 10
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 8
- VLJNHYLEOZPXFW-UHFFFAOYSA-N pyrrolidine-2-carboxamide Chemical compound NC(=O)C1CCCN1 VLJNHYLEOZPXFW-UHFFFAOYSA-N 0.000 claims description 8
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 8
- 125000001425 triazolyl group Chemical group 0.000 claims description 8
- RSDKJDOBUNCBMC-UHFFFAOYSA-N 1-[4-[5-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-1,3,4-oxadiazol-2-yl]piperidin-1-yl]-2-(dimethylamino)ethanone Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)C1=NN=C(O1)C1CCN(CC1)C(=O)CN(C)C RSDKJDOBUNCBMC-UHFFFAOYSA-N 0.000 claims description 7
- AEZQPNJAKOKBAC-UHFFFAOYSA-N 2-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-5-(1-propan-2-ylpiperidin-4-yl)-1,3,4-oxadiazole Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)C1=NN=C(O1)C1CCN(CC1)C(C)C AEZQPNJAKOKBAC-UHFFFAOYSA-N 0.000 claims description 7
- 125000005605 benzo group Chemical group 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 claims description 7
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 7
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims description 7
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 claims description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 6
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 125000001041 indolyl group Chemical group 0.000 claims description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 5
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 5
- ONWXDRJXHRQGNX-SFHVURJKSA-N (1S)-1-[3-[2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indol-5-yl]-1,2,4-oxadiazol-5-yl]butane-1,4-diamine Chemical compound CCC1=C(NC2=CC=C(C=C12)C1=NOC(=N1)[C@@H](N)CCCN)C1=CC(OC)=C(OC)C=C1 ONWXDRJXHRQGNX-SFHVURJKSA-N 0.000 claims description 4
- YMNONTDIURLAFH-IBGZPJMESA-N (1S)-1-[3-[2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indol-5-yl]-1,2,4-oxadiazol-5-yl]pentane-1,5-diamine Chemical compound CCC1=C(NC2=CC=C(C=C12)C1=NOC(=N1)[C@@H](N)CCCCN)C1=CC(OC)=C(OC)C=C1 YMNONTDIURLAFH-IBGZPJMESA-N 0.000 claims description 4
- WMCSKQDSUVJOSD-AWEZNQCLSA-N (1S)-1-[5-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-1,3,4-oxadiazol-2-yl]-N-methylethanamine Chemical compound CN[C@@H](C)C1=NN=C(O1)C1=CC=C2NC(=C(C(C)C)C2=C1)C1=CC(OC)=C(OC)C=C1 WMCSKQDSUVJOSD-AWEZNQCLSA-N 0.000 claims description 4
- LLMYATJVWYVQOJ-QGZVFWFLSA-N (3R)-N,N-dimethyl-1-[[5-[3-propan-2-yl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-indol-5-yl]-1,3,4-oxadiazol-2-yl]methyl]pyrrolidin-3-amine Chemical compound C(C)(C)C1=C(NC2=CC=C(C=C12)C1=NN=C(O1)CN1C[C@@H](CC1)N(C)C)C1=C2C(=NC=C1)NN=C2 LLMYATJVWYVQOJ-QGZVFWFLSA-N 0.000 claims description 4
- POLIEKCWHDWGLM-OAQYLSRUSA-N (3R)-N-[5-[2-(2-methylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]pyridin-2-yl]pyrrolidine-3-carboxamide Chemical compound C(C)(C)C1=C(NC2=CC=C(C=C12)C=1C=CC(=NC=1)NC(=O)[C@H]1CNCC1)C1=CC(=NC=C1)C POLIEKCWHDWGLM-OAQYLSRUSA-N 0.000 claims description 4
- HEJQVTCIFLAWTL-IBGZPJMESA-N (3S)-1-[2-[2-(2,6-dimethylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]-5,7-dihydro-4H-thieno[2,3-c]pyridin-6-yl]-3-hydroxybutan-1-one Chemical compound CC1=NC(=CC(=C1)C=1NC2=CC=C(C=C2C=1C(C)C)C1=CC2=C(CN(CC2)C(C[C@H](C)O)=O)S1)C HEJQVTCIFLAWTL-IBGZPJMESA-N 0.000 claims description 4
- POLIEKCWHDWGLM-NRFANRHFSA-N (3S)-N-[5-[2-(2-methylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]pyridin-2-yl]pyrrolidine-3-carboxamide Chemical compound C(C)(C)C1=C(NC2=CC=C(C=C12)C=1C=CC(=NC=1)NC(=O)[C@@H]1CNCC1)C1=CC(=NC=C1)C POLIEKCWHDWGLM-NRFANRHFSA-N 0.000 claims description 4
- PAQVZCQNCIYHKG-UHFFFAOYSA-N (4-hydroxypiperidin-1-yl)methanone Chemical compound OC1CCN([C]=O)CC1 PAQVZCQNCIYHKG-UHFFFAOYSA-N 0.000 claims description 4
- UCIIVQFJLGQJNI-UHFFFAOYSA-N 1-[2-[2-(2,6-dimethylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]-5,7-dihydro-4H-thieno[2,3-c]pyridin-6-yl]-2-(methylamino)ethanone Chemical compound CNCC(=O)N1CCC2=C(C1)SC(=C2)C1=CC=C2NC(=C(C(C)C)C2=C1)C1=CC(C)=NC(C)=C1 UCIIVQFJLGQJNI-UHFFFAOYSA-N 0.000 claims description 4
- BZZIMCWVYBBMFL-UHFFFAOYSA-N 1-[2-[2-(2,6-dimethylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]-5,7-dihydro-4H-thieno[2,3-c]pyridin-6-yl]-2-methylsulfonylethanone Chemical compound CC(C)C1=C(NC2=CC=C(C=C12)C1=CC2=C(CN(CC2)C(=O)CS(C)(=O)=O)S1)C1=CC(C)=NC(C)=C1 BZZIMCWVYBBMFL-UHFFFAOYSA-N 0.000 claims description 4
- HYLGLRDBCMHJOE-UHFFFAOYSA-N 1-[2-[2-(2,6-dimethylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridin-5-yl]ethanone Chemical compound CC(C)C1=C(NC2=CC=C(C=C12)C1=NC2=C(CN(CC2)C(C)=O)S1)C1=CC(C)=NC(C)=C1 HYLGLRDBCMHJOE-UHFFFAOYSA-N 0.000 claims description 4
- NFAQSSPNNFDSAC-UHFFFAOYSA-N 1-[4-[3-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-1H-1,2,4-triazol-5-yl]piperidin-1-yl]-2-(dimethylamino)ethanone Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)C1=NN=C(N1)C1CCN(CC1)C(=O)CN(C)C NFAQSSPNNFDSAC-UHFFFAOYSA-N 0.000 claims description 4
- YNNROVRZWGETIZ-UHFFFAOYSA-N 1-[4-[5-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-1,3,4-oxadiazol-2-yl]piperidin-1-yl]-2-(methylamino)ethanone Chemical compound CNCC(=O)N1CCC(CC1)C1=NN=C(O1)C1=CC=C2NC(=C(C(C)C)C2=C1)C1=CC(OC)=C(OC)C=C1 YNNROVRZWGETIZ-UHFFFAOYSA-N 0.000 claims description 4
- BESDKLAEOYEGBY-UHFFFAOYSA-N 1-[4-[5-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-1,3,4-oxadiazole-2-carbonyl]piperazin-1-yl]ethanone Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)C1=NN=C(O1)C(=O)N1CCN(CC1)C(C)=O BESDKLAEOYEGBY-UHFFFAOYSA-N 0.000 claims description 4
- PRUYEOAHQYHNPN-UHFFFAOYSA-N 1-[4-[5-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]pyridin-2-yl]piperazin-1-yl]ethanone Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)C1=CN=C(C=C1)N1CCN(CC1)C(C)=O PRUYEOAHQYHNPN-UHFFFAOYSA-N 0.000 claims description 4
- PWDPZSCYKDRDKD-UHFFFAOYSA-N 1-[4-[[5-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-1,3,4-oxadiazol-2-yl]methyl]-1,4-diazepan-1-yl]ethanone Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)C1=NN=C(CN2CCCN(CC2)C(C)=O)O1 PWDPZSCYKDRDKD-UHFFFAOYSA-N 0.000 claims description 4
- OHOARXVXRSCGBM-UHFFFAOYSA-N 1-[4-[[5-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-1,3,4-oxadiazol-2-yl]methyl]piperazin-1-yl]ethanone Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)C1=NN=C(CN2CCN(CC2)C(C)=O)O1 OHOARXVXRSCGBM-UHFFFAOYSA-N 0.000 claims description 4
- VTORUQHDOPFUGT-UHFFFAOYSA-N 1-[4-[[5-[3-propan-2-yl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-indol-5-yl]-1,3,4-oxadiazol-2-yl]methyl]-1,4-diazepan-1-yl]ethanone Chemical compound CC(C)C1=C(NC2=CC=C(C=C12)C1=NN=C(CN2CCCN(CC2)C(C)=O)O1)C1=CC=NC2=C1C=NN2 VTORUQHDOPFUGT-UHFFFAOYSA-N 0.000 claims description 4
- GWVLCUPAVAQENE-UHFFFAOYSA-N 1-[4-[[5-[3-propan-2-yl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-indol-5-yl]-1,3,4-oxadiazol-2-yl]methyl]piperazin-1-yl]ethanone Chemical compound CC(C)C1=C(NC2=CC=C(C=C12)C1=NN=C(CN2CCN(CC2)C(C)=O)O1)C1=CC=NC2=C1C=NN2 GWVLCUPAVAQENE-UHFFFAOYSA-N 0.000 claims description 4
- KWUYZZICVSXJOI-UHFFFAOYSA-N 1-[5-[2-(2-methylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]-1,3,4-oxadiazol-2-yl]propan-2-amine Chemical compound CC(N)CC1=NN=C(O1)C1=CC=C2NC(=C(C(C)C)C2=C1)C1=CC(C)=NC=C1 KWUYZZICVSXJOI-UHFFFAOYSA-N 0.000 claims description 4
- JWGHRFVWFSDRQX-UHFFFAOYSA-N 1-[5-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-1,3,4-oxadiazole-2-carbonyl]-N,N-diethylpiperidine-3-carboxamide Chemical compound CCN(CC)C(=O)C1CCCN(C1)C(=O)C1=NN=C(O1)C1=CC=C2NC(=C(C(C)C)C2=C1)C1=CC(OC)=C(OC)C=C1 JWGHRFVWFSDRQX-UHFFFAOYSA-N 0.000 claims description 4
- CGMQWNJXQODOJV-UHFFFAOYSA-N 1-[6-[3-propan-2-yl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-indol-5-yl]pyrimidin-4-yl]piperidin-4-amine Chemical compound CC(C)C1=C(NC2=CC=C(C=C12)C1=NC=NC(=C1)N1CCC(N)CC1)C1=CC=NC2=C1C=NN2 CGMQWNJXQODOJV-UHFFFAOYSA-N 0.000 claims description 4
- XAELYHRAARPUCD-UHFFFAOYSA-N 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl-[2-[2-(2-methylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]-1,3-oxazol-4-yl]methanone Chemical compound C1N(CC2C1CNC2)C(=O)C=1N=C(OC=1)C=1C=C2C(=C(NC2=CC=1)C1=CC(=NC=C1)C)C(C)C XAELYHRAARPUCD-UHFFFAOYSA-N 0.000 claims description 4
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- DZPQKGXQPZXTFF-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-[3-methyl-2-[4-(2-methylpropyl)piperazin-1-yl]imidazol-4-yl]-3-propan-2-yl-1H-indole Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1C(C)C)C1=CN=C(N1C)N1CCN(CC1)CC(C)C DZPQKGXQPZXTFF-UHFFFAOYSA-N 0.000 claims description 4
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- HDNUNOSVBOTUHW-GOSISDBHSA-N 2-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-5-[(3R)-piperidin-3-yl]-1,3,4-oxadiazole Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)C1=NN=C(O1)[C@@H]1CCCNC1 HDNUNOSVBOTUHW-GOSISDBHSA-N 0.000 claims description 4
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- FMYRAQUQDPYKAG-UHFFFAOYSA-N 2-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-5-[1-(1-propan-2-ylpiperidin-4-yl)piperidin-4-yl]-1,3,4-oxadiazole Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1C(C)C)C=1OC(=NN=1)C1CCN(CC1)C1CCN(CC1)C(C)C FMYRAQUQDPYKAG-UHFFFAOYSA-N 0.000 claims description 4
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- CCBGCVURXWOXQH-UHFFFAOYSA-N 2-[2-[2-(2,6-dimethylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridin-5-yl]-N,N-dimethylacetamide Chemical compound CC1=NC(=CC(=C1)C=1NC2=CC=C(C=C2C=1C(C)C)C=1SC=2CN(CCC=2N=1)CC(=O)N(C)C)C CCBGCVURXWOXQH-UHFFFAOYSA-N 0.000 claims description 4
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- QICRONCERRQVNS-UHFFFAOYSA-N 2-[3-propan-2-yl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-indol-5-yl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine Chemical compound CC(C)C1=C(NC2=CC=C(C=C12)C1=NN2CCNCC2=N1)C1=CC=NC2=C1C=NN2 QICRONCERRQVNS-UHFFFAOYSA-N 0.000 claims description 4
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- PUCJHGPKWZUSLG-UHFFFAOYSA-N 2-methyl-6-[5-(6-piperazin-1-ylpyridin-3-yl)-3-propan-2-yl-1H-indol-2-yl]imidazo[1,2-a]pyridine Chemical compound CC(C)C1=C(NC2=CC=C(C=C12)C1=CC=C(N=C1)N1CCNCC1)C1=CN2C=C(C)N=C2C=C1 PUCJHGPKWZUSLG-UHFFFAOYSA-N 0.000 claims description 4
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- SRKRCGGCHZGIIL-UHFFFAOYSA-N 3-[2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indol-5-yl]-5-(2-piperidin-4-ylethyl)-1,2,4-oxadiazole Chemical compound CCC1=C(NC2=CC=C(C=C12)C1=NOC(CCC2CCNCC2)=N1)C1=CC(OC)=C(OC)C=C1 SRKRCGGCHZGIIL-UHFFFAOYSA-N 0.000 claims description 4
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- ZUMZITXPOMLOTQ-INIZCTEOSA-N 3-[3-ethyl-2-(2-methylpyridin-4-yl)-1H-indol-5-yl]-5-[(3S)-pyrrolidin-3-yl]-1,2,4-oxadiazole Chemical compound CCC1=C(NC2=CC=C(C=C12)C1=NOC(=N1)[C@H]1CCNC1)C1=CC(C)=NC=C1 ZUMZITXPOMLOTQ-INIZCTEOSA-N 0.000 claims description 4
- MKKMILGFHQVFLW-UHFFFAOYSA-N 3-[3-ethyl-2-(2-methylpyridin-4-yl)-1H-indol-5-yl]-5-[2-(1-propan-2-ylpiperidin-4-yl)ethyl]-1,2,4-oxadiazole Chemical compound CCC1=C(NC2=CC=C(C=C12)C1=NOC(CCC2CCN(CC2)C(C)C)=N1)C1=CC(C)=NC=C1 MKKMILGFHQVFLW-UHFFFAOYSA-N 0.000 claims description 4
- OXDKJYLOOCWTKQ-UHFFFAOYSA-N 3-[3-ethyl-2-(2-methylpyridin-4-yl)-1H-indol-5-yl]-5-piperidin-3-yl-1,2,4-oxadiazole Chemical compound CCC1=C(NC2=CC=C(C=C12)C1=NOC(=N1)C1CCCNC1)C1=CC(C)=NC=C1 OXDKJYLOOCWTKQ-UHFFFAOYSA-N 0.000 claims description 4
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- BLLJEAWITIGAGI-UHFFFAOYSA-N 3-[5-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]pyridin-2-yl]oxy-N,N-dimethylpropan-1-amine Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1C(C)C)C=1C=CC(=NC=1)OCCCN(C)C BLLJEAWITIGAGI-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
本申请公开了式(I)化合物或其盐,其中A、G、R1、R5和n为本申请所定义。本申请还公开了使用这种化合物作为通过Toll样受体7或8或9的信号转导的抑制剂的方法,以及包含这种化合物的药物组合物。这些化合物可用于治疗炎性和自身免疫性疾病。
Description
交叉引用
本申请要求2017年12月20日提交的美国临时申请序列号62/607,998的权益,其全部内容通过引用并入本申请。
技术领域
本发明总体上涉及芳基和杂芳基取代的吲哚化合物,其可用作通过Toll样受体7、8或9(TLR7、TLR8、TLR9)或其组合的信号传导的抑制剂。本申请提供了芳基和杂芳基取代的吲哚化合物、包含此类化合物的组合物、及其使用方法。本发明还涉及含有至少一种本发明化合物的药物组合物,其可用于治疗与TLR调节有关的病症,诸如炎性和自身免疫性疾病,以及抑制哺乳动物中TLR活性的方法。
背景技术
Toll/IL-1受体家族成员是炎症和宿主抗性的重要调节因子。Toll样受体家族识别衍生自传染性生物体(包括细菌、真菌、寄生虫和病毒)的分子模式(综述于Kawai,T.等人,Nature Immunol.,11:373-384(2010))。与受体结合的配体诱导衔接子分子的二聚化和募集到被称为Toll/IL-1受体(TIR)的受体的结构域中的保守细胞质基序。除TLR3外,所有TLR都募集衔接子分子MyD88。IL-1受体家族还含有细胞质TIR基序并且在配体结合时募集MyD88(综述于Sims,J.E.等人,Nature Rev.Immunol.,10:89-102(2010))。
Toll样受体(TLR)是参与第一线防御的进化上保守的跨膜天然免疫受体的家族。作为模式识别受体,TLR保护抵抗通过病原体相关分子模式(PAMP)激活的外来分子,或免于由危险相关分子模式(DAMP)激活的受损组织。已识别总计13个TLR家族成员,在人类中10个,所述成员跨细胞表面或内涵体腔。TLR7-9是在内涵体定位的集之中且对单股RNA响应(TLR7和TLR8)或对含有胞嘧啶-磷酸盐-尿嘌呤(CpG)基序的未甲基化的单股DNA响应(TLR9)。
TLR7/8/9的激活可引发多种炎性反应(细胞因子产生、B细胞激活和IgG产生,I型干扰素反应)。在自身免疫病症的情况下,TLR7/8/9的异常持续激活导致疾病状态恶化。虽然已显示小鼠中TLR7的过度表达加重了自身免疫性疾病,但发现小鼠中TLR7的敲除保护抵抗易发狼疮MRL/lpr小鼠的疾病。TLR7和9的双重敲除显示出进一步增强的保护。
由于许多病况可以通过涉及调节细胞因子、IFN产生和B细胞活性的治疗而受益,因此立即显而易见的是,能够调节TLR7和/或TLR8和/或TLR9的新化合物以及使用这些化合物的方法可以为多种多样的病人提供实质性的治疗益处。
本发明涉及一类新的芳基和杂芳基取代的吲哚化合物,发现这些化合物是通过TLR7/8/9的信号传导的有效抑制剂。提供的这些化合物可用作具有对其可药性(drugability)重要的期望稳定性、生物利用度、治疗指数和毒性值的药物。
发明内容
本发明提供式(I)化合物,或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其可用作通过Toll样受体7、8或9的信号传导的抑制剂并且可用于治疗增殖性疾病、过敏性疾病、自身免疫性疾病和炎性疾病。
本发明还提供药物组合物,该药物组合物包含药学上可接受的载体以及至少一种本发明的化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药。
本发明还提供用于抑制Toll样受体7、8或9的方法,包括向需要此类治疗的宿主给予治疗有效量的至少一种本发明化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药。
本发明还提供用于治疗增殖性疾病、代谢性疾病、过敏性疾病、自身免疫性疾病和炎性疾病的方法,包括向需要此类治疗的宿主给予治疗有效量的至少一种本发明化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药。
本发明还提供治疗与Toll样受体7、8或9活性有关的疾病或病症的方法,所述方法包括向有此需要的哺乳动物给药至少一种式(I)化合物或其盐、溶剂化物和前药。
本发明还提供用于制备式(I)化合物(包括其盐、溶剂化物和前药)的方法和中间体。
本发明还提供至少一种式(I)化合物或其盐、溶剂化物和前药,其用于疗法。
本发明还提供至少一种式(I)化合物或其盐、溶剂化物和前药在制备用于治疗或预防Toll样受体7、8或9相关病况的药物中的用途,所述Toll样受体7、8或9相关病况例如为过敏性疾病、自身免疫性疾病、炎性疾病和增殖性疾病。
式(I)化合物和包含式(I)化合物的组合物可用于治疗、预防或治愈各种与Toll样受体7、8或9相关的病况。包含这些化合物的药物组合物可用于治疗、预防或减缓在各种治疗领域中的疾病或病症的进展,所述疾病或病症例如为过敏性疾病、自身免疫性疾病、炎性疾病和增殖性疾病。
随着公开的继续,将以扩展形式阐述本发明的这些和其它特征。
具体实施方式
本发明的第一方面提供至少一种式(I)化合物:
其N-氧化物或其盐,其中:
(i)
(ii)
(iii)
(iv)选自如下的9元杂环:
或
(v)选自如下的10元杂环:
A为选自如下的芳族基团:[1,2,4]三唑并[1,5-a]吡啶基、咪唑并[1,2-a]吡啶基、咪唑基、吲唑基、异喹啉基、噁二唑基、噁唑基、苯基、吡嗪基、吡唑并[3,4-b]吡啶基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹啉酮基、喹啉基、喹喔啉基、四氢-[1,2,4]三唑并[1,5-a]吡嗪基、四氢咪唑并[1,2-a]吡嗪基、四氢异喹啉基、四氢噻唑并[5,4-c]吡啶基、四氢噻吩并[2,3-c]吡啶基、噻二唑基、噻唑基、硫代噁二唑基和三唑基,其各自取代有0至2个R14a和0至3个R14b;
R1为H、Cl、-CN、C1-4烷基、C1-3氟烷基、C1-3羟烷基、C1-3羟基-氟烷基、-CRv=CH2、C3-6环烷基、-CH2(C3-6环烷基)、-C(O)O(C1-3烷基)或四氢吡喃基;
每个R2独立地为卤素、-CN、-OH、-NO2、C1-4烷基、C1-2氟烷基、C1-2氰基烷基、C1-3羟烷基、C1-3氨基烷基、-O(CH2)1-2OH、-(CH2)0-4O(C1-4烷基)、C1-3氟烷氧基、-(CH2)1-4O(C1-3烷基)、-O(CH2)1-2OC(O)(C1-3烷基)、-O(CH2)1-2NRxRx、-C(O)O(C1-3烷基)、-(CH2)0-2C(O)NRyRy、-C(O)NRx(C1-5羟烷基)、-C(O)NRx(C2-6烷氧基烷基)、-C(O)NRx(C3-6环烷基)、-NRyRy、-NRy(C1-3氟烷基)、-NRy(C1-4羟烷基)、-NRxCH2(苯基)、-NRxS(O)2(C3-6环烷基)、-NRxC(O)(C1-3烷基)、-NRxCH2(C3-6环烷基)、-(CH2)0-2S(O)2(C1-3烷基)、-(CH2)0-2(C3-6环烷基)、-(CH2)0-2(苯基)、吗啉基、二氧代硫代吗啉基、二甲基吡唑基、甲基哌啶基、甲基哌嗪基、氨基-噁二唑基、咪唑基、三唑基或-C(O)(噻唑基);
R2a为C1-6烷基、C1-3氟烷基、C1-6羟烷基、C1-3氨基烷基、-(CH2)0-4O(C1-3烷基)、C3-6环烷基、-(CH2)1-3C(O)NRxRx、-CH2(C3-6环烷基)、-CH2(苯基)、四氢呋喃基、四氢吡喃基或苯基;
每个R2b独立地为H、卤素、-CN、-NRxRx、C1-6烷基、C1-3氟烷基、C1-3羟烷基、C1-3氟烷氧基、-(CH2)0-2O(C1-3烷基)、-(CH2)0-3C(O)NRxRx、-(CH2)1-3(C3-6环烷基)、-C(O)O(C1-3烷基)、-C(O)NRx(C1-3烷基)、-CRx=CRxRx或-CRx=CH(C3-6环烷基);
R2c为R2a或R2b;
R2d为R2a或R2b;条件是R2c和R2d中的一个为R2a,R2c和R2中的另一个为R2b;
每个R5独立地为F、Cl、-CN、C1-3烷基、C1-2氟烷基或-OCH3;
每个R14a独立地选自:
(i)H、卤素、-OH、C1-6烷基、C1-3氟烷基、C1-4羟烷基、-(CH2)0-2O(C1-3烷基)、-CRxRxNRyRy、-CRxRxNRx(C1-3氰基烷基)、-CRxRxNRx((CH2)1-2O(C1-2烷基))、-CRxRxN((CH2)1- 2OCH3)2、-CRxRxNRx(CH2C≡CRx)、-CRxRxNRx(CH2)1-3NRxRx、-(CRxRx)1-3CRxRxNRxRx、-CRx(NH2)(CH2)1-4NRxRx、-CRxRxNRx(CH2)1-2O(C1-3烷基)、-CRxRxNRx(CH2)1-2O(CH2)1-2OH、-CRxRxNRx(CH2)1-3S(O)2OH、-CRxRxC(O)NRxRx、-NRxRy、-NRx(CH2)1-3NRxRx、-NRxC(O)(C1-3烷基)、-NRxC(O)(C1-3氟烷基)、-NRxC(O)O(C1-3烷基)、-NRxC(O)(CH2)1-3NRxRx、-NRxCH2C(O)CH2NRxRx、-C(O)(C1-3烷基)、-C(O)(CRxRx)1-3OH、-C(O)CRxRxNRxRx、-C(O)NRxRx、-C(O)NRx(C1-2氰基烷基)、-C(O)NRx(CRxRx)1-3NRxRx、-C(O)N(CH2CH3)(CRxRx)1-3NRxRx、-C(O)NRx(CRxRx)1-2C(O)NRxRx、-C(O)NRx(CRxRx)1-3NRxC(O)(C1-2烷基)、-O(CRxRx)1-3NRxRx、-S(O)2NRxRx和-C(O)(CRxRx)1-2S(O)2(C1-2烷基);
(ii)8-氮杂双环[3.2.1]辛基、氮杂螺[3.5]壬基、氮杂环丁烷基、苯并[c][1,2,5]噁二唑基、环戊基、环己基、二氮杂环庚烷基、吗啉基、苯基、哌嗪基、哌啶基、吡唑基、吡啶基、吡咯烷酮基、喹啉基、奎宁环基、四氢异喹啉基、四氢吡啶基或噻唑烷基,其各自取代有0至2个取代基,所述取代基独立地选自C1-4烷基、C1-2氟烷基、C1-4羟烷基、-NRxRx、-(CH2)1- 2NRxRx、-C(O)(C1-2烷基)、-C(O)CH2NRxRx、-C(O)O(C1-3烷基)、-CH2C(O)NRxRx、C3-6环烷基、-CH2(苯基)、-CH2(吡咯基)、-CH2(吗啉基)、-CH2(甲基哌嗪基)、-CH2(硫代苯基)、甲基哌啶基、异丁基哌啶基和吡啶基;或
(iii)-L3-R14c;
每个R14b为F、Cl、-OH、-CH3或-OCH3;
L3为-(CRxRx)1-3-、-CH(NH2)-、-CRxRxNH-、-C(O)-、-C(O)NRx(CH2)0-4-、-NRx-、-NRxC(O)-、-NRxCH2-、-NRxCH2C(O)-或-O(CH2)0-2-;
R14c为金刚烷基、氮杂环庚烷基、氮杂环丁烷基、C3-7环烷基、二氮杂环庚烷基、咪唑基、吲哚基、吗啉基、八氢吡咯并[3,4-c]吡咯基、苯基、哌嗪酮基、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基、吡咯基、三唑基或四唑基,其各自取代有0至1个取代基,所述取代基选自F、-OH、C1-4烷基、C1-3羟烷基、-NRxRy、-NRxC(O)CH3、-C(O)(C1-2烷基)、-C(O)NRxRx、-C(O)N(CH2CH3)2、-C(O)(四氢呋喃基)、-C(O)O(C1-2烷基)、-CH2C(O)NRxRy、吗啉基、甲基哌啶基、吡嗪基、吡啶基和吡咯烷基;
Rv为H、C1-2烷基或C1-2氟烷基;
每个Rx独立地为H或-CH3;
每个Ry独立地为H或C1-6烷基;
n为0、1或2;和
p为0、1、2、3或4。
一个实施方案提供式(I)化合物或其盐,其中G为:A、R1、R5和n在第一方面中定义。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中G为: A、R1、R2、R5、n和p在第一方面中定义。
一个实施方案提供式(I)化合物或其盐,其中G为 A、R1、R2a、R2b、R2c、R2d、R5、n和p在第一方面中定义。该实施方案中包括化合物,其中R2a为C1-4烷基、C1-2氟烷基、C1-4羟烷基、-(CH2)1-3OCH3、C3-6环烷基、-CH2C(O)NRxRx、-CH2(C3-6环烷基)、-CH2(苯基)、四氢呋喃基或苯基;每个R2b独立地为H、F、Cl、-CN、-NRxRx、C1-6烷基、C1-2氟烷基、C1-3羟烷基、-(CH2)0-2O(C1-2烷基)、-(CH2)0-2C(O)NRxRx、-(CH2)1-3(环丙基)、-C(O)O(C1-2烷基)、-C(O)NRx(C1-3烷基)、-CRx=CH2或-CH=CH(C3-6环烷基)。该实施方案中还包括化合物,其中R2a为-CH3;每个R2b独立地为H、Cl或-CH3。
一个实施方案提供式(I)化合物或其盐,其中G为选自如下的9元杂环:
/>
/>
和A、R1、R2、R5、n和p在第一方面中定义。
一个实施方案提供式(I)化合物或其盐,其中G为选自如下的10元杂环:
和A、R1、R2、R5、n和p在第一方面中定义。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中A为选自如下的芳族基团:[1,2,4]三唑并[1,5-a]吡啶基、咪唑并[1,2-a]吡啶基、咪唑基、吲唑基、异喹啉基、噁二唑基、噁唑基、苯基、吡嗪基、吡唑并[3,4-b]吡啶基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹啉酮基、喹啉基、喹喔啉基、四氢-[1,2,4]三唑并[1,5-a]吡嗪基、四氢咪唑并[1,2-a]吡嗪基、四氢异喹啉基、四氢噻唑并[5,4-c]吡啶基、四氢噻吩并[2,3-c]吡啶基、噻二唑基、噻唑基、硫代噁二唑基和三唑基,其各自取代有0至2个R14a和0至3个R14b;R1为H、Cl、-CN、C1-4烷基、C1-2氟烷基、C1-2羟烷基或-C(O)O(C1-2烷基);每个R2独立地为F、Cl、-CN、-OH、C1-4烷基、C1-2氟烷基、C1-2氰基烷基、C1-3羟烷基、C1-3氨基烷基、-(CH2)0-2O(C1-4烷基)、-NRyRy、-(CH2)0- 2C(O)NRyRy、-C(O)NRx(C1-4羟烷基)、-C(O)NRx(C2-4烷氧基烷基)、-C(O)NRx(C3-6环烷基)、-(CH2)0-2S(O)2(C1-3烷基)、-(CH2)0-1(C3-6环烷基)、吗啉基、-(CH2)0-1(苯基)或二甲基吡唑基;R2a为C1-4烷基、C1-2氟烷基、C1-4羟烷基、-(CH2)1-3OCH3、C3-6环烷基、-CH2C(O)NRxRx、-CH2(C3-6环烷基)、-CH2(苯基)、四氢呋喃基或苯基;每个R2b独立地为H、F、Cl、-CN、-NRxRx、C1-6烷基、C1-2氟烷基、C1-3羟烷基、-(CH2)0-2O(C1-2烷基)、-(CH2)0-2C(O)NRxRx、-(CH2)1-3(环丙基)、-C(O)O(C1-2烷基)、-C(O)NRx(C1-3-烷基)、-CRx=CH2或-CH=CH(C3-6环烷基);每个R5独立地为F、Cl、-CN、C1-2烷基或-OCH3;每个R14a独立地选自:(i)H、F、Cl、-OH、C1-5烷基、C1-2氟烷基、C1-2羟烷基、-(CH2)0-2OCH3、-CHRxNRx(C1-5烷基)、-CHRxNRx(C1-2氰基烷基)、-CHRxNRx((CH2)1-2OCH3)、-CHRxN((CH2)1-2OCH3)2、-CH2NRx(CH2C≡CRx)、-CH2NRxCH2CH2NRxRx、-(CH2)1-3CRxRxNRxRx、-CH(NH2)(CH2)3-4NRxRx、-CH2NRx(CH2)1-2O(C1-3烷基)、-CH2NRx(CH2)1-2O(CH2)1-2OH、-CH2NH(CH2)1- 2S(O)2OH、-CH2C(O)NRxRx、-NRxRy、-NRx(CH2)2-3NRxRx、-NRxC(O)(C1-2烷基)、-NRxC(O)(C1-2氟烷基)、-NRxC(O)O(C1-3烷基)、-NRxC(O)(CH2)1-2NRxRx、-NRxCH2C(O)CH2NRxRx、-C(O)(C1-2烷基)、-C(O)CH2CRxRxOH、-C(O)CH2NRxRx、-C(O)NRxRx、-C(O)NRx(CH2CN)、-C(O)NRx(CRxRx)2-3NRxRx、-C(O)N(CH2CH3)(CRxRx)2-3NRxRx、-C(O)NRxCH2C(O)NRxRx、-C(O)NRxCH2CH2NRxC(O)CH3、-O(CRxRx)2-3NRxRx、-S(O)2NRxRx和-C(O)CH2S(O)2(C1-2烷基);(ii)8-氮杂双环[3.2.1]辛基、氮杂螺[3.5]壬基、氮杂环丁烷基、苯并[c][1,2,5]噁二唑基、环戊基、环己基、二氮杂环庚烷基、吗啉基、苯基、哌嗪基、哌啶基、吡唑基、吡啶基、吡咯烷酮基、喹啉基、奎宁环基、四氢异喹啉基、四氢吡啶基或噻唑烷基,其各自取代有0至2个取代基,所述取代基独立地选自C1-4烷基、C1-2氟烷基、C1-4羟烷基、-NRxRx、-(CH2)1-2NRxRx、-C(O)(C1-2烷基)、-C(O)CH2NRxRx、-C(O)O(C1-3烷基)、-CH2C(O)NRxRx、C3-6环烷基、-CH2(苯基)、-CH2(吡咯基)、-CH2(吗啉基)、-CH2(甲基哌嗪基)、-CH2(硫代苯基)、甲基哌啶基、异丁基哌啶基和吡啶基;或(iii)-L3-R14c;每个R14b为F、-CH3或-OCH3;L3为-(CRxRx)1-3-、-CH(NH2)-、-CRxRxNH-、-C(O)-、-C(O)NRx(CH2)0-4-、-NRx-、-NRxC(O)-、-NRxCH2-、-NRxCH2C(O)-、-O-或-O(CH2)1-2-;R14c为金刚烷基、氮杂环丁烷基、C3-6环烷基、二氮杂环庚烷基、咪唑基、吲哚基、吗啉基、八氢吡咯并[3,4-c]吡咯基、苯基、哌嗪酮基、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基或四唑基,其各自取代有0至1个取代基,所述取代基选自F、-OH、C1-4烷基、C1-3羟烷基、-NRxRy、-NRxC(O)CH3、-C(O)(C1-2烷基)、-C(O)NRxRx、-C(O)N(CH2CH3)2、-C(O)(四氢呋喃基)、-C(O)O(C1-2烷基)、-CH2C(O)NRxRy、吗啉基、甲基哌啶基、吡嗪基、吡啶基和吡咯烷基;n为0或1;p为0、1、2或3;和G在第一方面中定义。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中G为:(i)或
(ii)选自如下的9元杂环:
A、R1、R2、R5、n和p在第一方面中定义。该实施方案中包括化合物,其中R1为-CH3、-CH2CH3、-CH(CH3)2、-CH2CHF2或-CH2CF3;每个R2独立地为-CH3或-NH2;每个R14a独立地选自:(i)H、F、Cl、-OH、-CH3、-CH(CH3)2、-CH(CH3)(CH2CH3)、-CH2CH2CH2C(CH3)2、-CF3、-CH2CF3、-CH2OH、-OCH3、-CH2CH2OCH3、-CHRxNRx(CH3)、-CH2N(CH3)(CH(CH3)2)、-CH2NH(CH2C(CH3)3)、-CH2NH(CH2CN)、-CH2N(CH3)(CH2CH2OCH3)、-CH2N(CH2CH2OCH3)2、-CH2NRx(CH2C≡CH)、-CH2NHCH2CH2N(CH3)2、-CH2CH2NRx(CH3)、-CH2CRx(CH3)NH2、-CH2CH2CH2N(CH3)2、-CH2CH2CH2CH2NH2、-CH(NH2)(CH2)3-4NH2、-CH2NHCH2CH2O(C1-3烷基)、-CH2NHCH2CH2OCH2CH2OH、-CH2NHCH2CH2S(O)2OH、-CH2C(O)NRx(CH3)、-NRxRx、-NH(CH(CH3)2)、-NHCH2CH2NH(CH3)、-NHCH2CH2CH2N(CH3)2、-NHC(O)CH3、-NHC(O)CF3、-NHC(O)OC(CH3)3、-NHC(O)CH2N(CH3)2、-NHC(O)CH2CH2N(CH3)2、-NHCH2C(O)CH2NH(CH3)、-C(O)CH3、-C(O)CH2CH(CH3)OH、-C(O)CH2NRx(CH3)、-C(O)NRxRx、-C(O)NH(CH2CN)、-C(O)NHCH2CH2CH2NRxRx、-C(O)NHCH2CH(CH3)CH2NH2、-C(O)NHCH2C(O)NH2、-C(O)N(CH3)CH2CH2CH2N(CH3)2、-C(O)N(CH2CH3)CH2CH2N(CH3)2、-OCH2CH2CH2N(CH3)2、-C(O)NHCH2CH2NHC(O)CH3、-S(O)2NH2和-C(O)CH2S(O)2CH3;(ii)8-氮杂双环[3.2.1]辛基、氮杂螺[3.5]壬基、氮杂环丁烷基、苯并[c][1,2,5]噁二唑基、环戊基、环己基、二氮杂环庚烷基、吗啉基、苯基、哌嗪基、哌啶基、吡唑基、吡啶基、吡咯烷酮基、喹啉基、奎宁环基、四氢异喹啉基、四氢吡啶基或噻唑烷基,其各自取代有0至2个取代基,所述取代基独立地选自-CH3、-CH(CH3)2、-CH2CH(CH3)2、-CF3、-CH2CH2CF3、-CH2CH2OH、-CH2CH2CH(CH3)OH、-NH2、-CH2N(CH3)2、-CH2CH2NH(CH3)、-C(O)CH3、-C(O)CH2NH(CH3)、-C(O)CH2N(CH3)2、-C(O)O(C(CH3)3)、-CH2C(O)NRx(CH3)、环丁基、环戊基、-CH2(苯基)、-CH2(吡咯基)、-CH2(吗啉基)、-CH2(甲基哌嗪基)、-CH2(硫代苯基)、甲基哌啶基、异丁基哌啶基和吡啶基;或(iii)-L3-R14c;每个R14b为-CH3;L3为-(CH2)1-3-、-CH(CH3)-、-CH(NH2)-、-CH2NH-、-C(O)-、-C(O)NH(CH2)0-4-、-C(O)N(CH3)CH2CH2-、-NH-、-NHC(O)-、-NHCH2-、-NHCH2C(O)-、-O-或-OCH2CH2-;R14c为金刚烷基、氮杂环丁烷基、环丙基、环己基、二氮杂环庚烷基、咪唑基、吲哚基、吗啉基、八氢吡咯并[3,4-c]吡咯基、苯基、哌嗪酮基、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基或四唑基,其各自取代有0至1个取代基,所述取代基选自-OH、-CH3、-CH(CH3)2、-CH2CH(CH3)2、-C(CH3)2OH、-NH2、-N(CH3)2、-NH(C(CH3)2、-NHC(O)CH3、-C(O)CH3、-C(O)NH2、-C(O)N(CH2CH3)2、-C(O)(四氢呋喃基)、-C(O)OCH2CH3、-CH2C(O)NH(CH(CH3)2、吗啉基、甲基哌啶基、吡嗪基、吡啶基和吡咯烷基;n为0;和p为0、1、2或3。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中R1为H、Cl、-CN、C1-4烷基、C1-3氟烷基、C1-3羟烷基、C1-3羟基-氟烷基、C3-6环烷基、-CH2(C3-6环烷基)或-C(O)O(C1-3烷基);和A、G、R5和n在第一方面中定义。该实施方案中包括化合物,其中R1为H、Cl、-CN、C1-4烷基、C1-2氟烷基、C1-2羟烷基或-C(O)O(C1-2烷基)。该实施方案中还包括化合物,其中R1为-CH3、-CH2CH3、-CH(CH3)2、-CH2CHF2或-CH2CF3。另外,该实施方案中包括化合物,其中R1为-CH(CH3)2。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中每个R2独立地为F、Cl、Br、-CN、-OH、-NO2、C1-4烷基、C1-2氟烷基、C1-2氰基烷基、C1-3羟烷基、C1-3氨基烷基、-OCH2OH、-(CH2)0-2O(C1-4烷基)、C1-2氟烷氧基、-(CH2)1-2O(C1-3烷基)、-O(CH2)1-2OC(O)(C1-2烷基)、-O(CH2)1-2NRxRx,-C(O)O(C1-2烷基)、-C(O)NRyRy、-C(O)NRx(C1-5羟烷基)、-C(O)NRx(C2-6烷氧基烷基)、-C(O)NRx(C3-6环烷基)、-NRyRy、-NRy(C1-3氟烷基)、-NRy(C1-4羟烷基)、-NRxC(O)(C1-3烷基)、-S(O)2(C1-3烷基)、C3-6环烷基、苯基、吗啉基、二氧代硫代吗啉基、二甲基吡唑基、甲基哌啶基、甲基哌嗪基、氨基-噁二唑基、咪唑基或三唑基;和A、G、R1、R5、Rx、Ry、n和p在第一方面中定义。该实施方案中包括化合物,其中每个R2独立地为F、Cl、-CN、-OH、C1-4烷基、C1-2氟烷基、C1-2氰基烷基、C1-3羟烷基、C1-3氨基烷基、-(CH2)0-2O(C1-4烷基)、-NRyRy、-(CH2)0-2C(O)NRyRy、-C(O)NRx(C1-4羟烷基)、-C(O)NRx(C2-4烷氧基烷基)、-C(O)NRx(C3-6环烷基)、-(CH2)0-2S(O)2(C1-3烷基)、-(CH2)0-1(C3-6环烷基)、吗啉基、-(CH2)0-1(苯基)或二甲基吡唑基。该实施方案中还包括化合物,其中每个R2独立地为-CH3或-NH2。另外,该实施方案中包括化合物,其中每个R2独立地为-CH3;和p为0、1或2。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中每个R5独立地为F、Cl、-CN、C1-2烷基、C1-2氟烷基或-OCH3;和A、G、R1和n在第一方面中定义。该实施方案中包括化合物,其中每个R5独立地为F、Cl、-CN、C1-2烷基或-OCH3。该实施方案中还包括化合物,其中每个R5独立地为F或-CH3。该实施方案还包括化合物,其中n为0或1。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中A为苯基,其取代有0至1个R14a和0至3个R14b;和G、R1、R5、R14a、R14b和n在第一方面中定义。该实施方案中包括化合物,其中G为: 和R2和p在第一方面中定义。该实施方案中还包括化合物,其中A为苯基,其取代有0至1个R14a。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中A选自[1,2,4]三唑并[1,5-a]吡啶基、咪唑并[1,2-a]吡啶基、咪唑基、吲唑基、异喹啉基、噁二唑基、噁唑基、吡嗪基、吡唑并[3,4-b]吡啶基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹啉酮基、喹啉基、喹喔啉基、四氢-[1,2,4]三唑并[1,5-a]吡嗪基、四氢咪唑并[1,2-a]吡嗪基、四氢异喹啉基、四氢噻唑并[5,4-c]吡啶基、四氢噻吩并[2,3-c]吡啶基、噻二唑基、噻唑基、硫代噁二唑基和三唑基,其各自取代有0至2个R14a和0至3个R14b;和G、R1、R5、R14a、R14b和n在第一方面中定义。该实施方案中包括化合物,其中G为:
(i)或
(ii)选自如下的9元杂环:
和R2和p在第一方面定义。该实施方案中还包括化合物,其中G为:/>
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中A为噁二唑基,其取代有0至1个R14a和0至3个R14b;和G、R1、R5、R14a、R14b和n在第一方面中定义。该实施方案中包括化合物,其中G为: 和R2和p在第一方面中定义。该实施方案中还包括化合物,其中A为噁二唑基,其取代有0至1个R14a。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中A为噁唑基,其取代有0至1个R14a和0至3个R14b;和G、R1、R5、R14a、R14b和n在第一方面中定义。该实施方案中包括化合物,其中G为:和R2和p在第一方面中定义。该实施方案中还包括化合物,其中A为噁唑基,其取代有0至1个R14a。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中A为吡啶基或嘧啶基,其取代有0至1个R14a和0至3个R14b;和G、R1、R5、R14a、R14b和n在第一方面中定义。该实施方案中包括化合物,其中G为:和R2和p在第一方面中定义。该实施方案中还包括化合物,其中A为取代有0至1个R14a的吡啶基。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中A为三唑基,其取代有0至1个R14a和0至3个R14b;和G、R1、R5、R14a、R14b和n在第一方面中定义。该实施方案中包括化合物,其中G为: 和R2和p在第一方面中定义。该实施方案中还包括化合物,其中A为取代有0至1个R14a的三唑基。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中A为噻唑基或噻二唑基,其取代有0至1个R14a和0至3个R14b;和G、R1、R5、R14a、R14b和n在第一方面中定义。该实施方案中包括化合物,其中G为:和R2和p在第一方面中定义。该实施方案中还包括化合物,其中A为噻唑基,其取代有0至1个R14a。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中A为四氢噻吩并[2,3-c]吡啶基或四氢噻唑并[5,4-c]吡啶基,其取代有0至1个R14a和0至3个R14b;和G、R1、R5、R14a、R14b和n在第一方面中定义。该实施方案中包括化合物,其中G为:该实施方案中还包括化合物,其中A为四氢噻吩并[2,3-c]吡啶基或四氢噻唑并[5,4-c]吡啶基,其取代有0至1个R14a。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中每个R14a独立地选自H、卤素、-OH、C1-6烷基、C1-3氟烷基、C1-4羟烷基、-(CH2)0-2O(C1-3烷基)、-CRxRxNRyRy,-CRxRxNRx(C1-3氰基烷基)、-CRxRxNRx((CH2)1-2O(C1-2烷基))、-CRxRxN((CH2)1-2OCH3)2、-CRxRxNRx(CH2C≡CRx)、-CRxRxNRx(CH2)1-3NRxRx、-(CRxRx)1-3CRxRxNRxRx、-CRx(NH2)(CH2)1-4NRxRx、-CRxRxNRx(CH2)1-2O(C1-3烷基)、-CRxRxNRx(CH2)1-2O(CH2)1-2OH、-CRxRxNRx(CH2)1-3S(O)2OH、-CRxRxC(O)NRxRx、-NRxRy、-NRx(CH2)1-3NRxRx、-NRxC(O)(C1-3烷基)、-NRxC(O)(C1-3氟烷基)、-NRxC(O)O(C1-3烷基)、-NRxC(O)(CH2)1-3NRxRx、-NRxCH2C(O)CH2NRxRx、-C(O)(C1-3烷基)、-C(O)(CRxRx)1-3OH、-C(O)CRxRxNRxRx、-C(O)NRxRx、-C(O)NRx(C1-2氰基烷基)、-C(O)NRx(CRxRx)1-3NRxRx、-C(O)N(CH2CH3)(CRxRx)1-3NRxRx、-C(O)NRx(CRxRx)1-2C(O)NRxRx、-C(O)NRx(CRxRx)1-3NRxC(O)(C1-2烷基)、-O(CRxRx)1-3NRxRx、-S(O)2NRxRx和-C(O)(CRxRx)1-2S(O)2(C1-2烷基);和A、G、R1、R2、R5、Rx、n和p在第一方面中定义。该实施方案中包括化合物,其中每个R14a独立地选自H、F、Cl、-OH、C1-5烷基、C1-2氟烷基、C1-2羟烷基、-(CH2)0-2OCH3、-CHRxNRx(C1-5烷基)、-CHRxNRx(C1-2氰基烷基)、-CHRxNRx((CH2)1-2OCH3)、-CHRxN((CH2)1-2OCH3)2、-CH2NRx(CH2C≡CRx)、-CH2NRxCH2CH2NRxRx、-(CH2)1-3CRxRxNRxRx、-CH(NH2)(CH2)3-4NRxRx、-CH2NRx(CH2)1-2O(C1-3烷基)、-CH2NRx(CH2)1-2O(CH2)1-2OH、-CH2NH(CH2)1-2S(O)2OH、-CH2C(O)NRxRx、-NRxRy、-NRx(CH2)2- 3NRxRx、-NRxC(O)(C1-2烷基)、-NRxC(O)(C1-2氟烷基)、-NRxC(O)O(C1-3烷基)、-NRxC(O)(CH2)1- 2NRxRx、-NRxCH2C(O)CH2NRxRx、-C(O)(C1-2烷基)、-C(O)CH2CRxRxOH、-C(O)CH2NRxRx、-C(O)NRxRx、-C(O)NRx(CH2CN)、-C(O)NRx(CRxRx)2-3NRxRx、-C(O)N(CH2CH3)(CRxRx)2-3NRxRx、-C(O)NRxCH2C(O)NRxRx、-C(O)NRxCH2CH2NRxC(O)CH3、-O(CRxRx)2-3NRxRx、-S(O)2NRxRx和-C(O)CH2S(O)2(C1-2烷基)。该实施方案中还包括化合物,其中每个R14a独立地选自H、F、Cl、-OH、-CH3、-CH(CH3)2、-CH(CH3)(CH2CH3)、-CH2CH2CH2C(CH3)2、-CF3、-CH2CF3、-CH2OH、-OCH3、-CH2CH2OCH3、-CHRxNRx(CH3)、-CH2N(CH3)(CH(CH3)2)、-CH2NH(CH2C(CH3)3)、-CH2NH(CH2CN)、-CH2N(CH3)(CH2CH2OCH3)、-CH2N(CH2CH2OCH3)2、-CH2NRx(CH2C≡CH)、-CH2NHCH2CH2N(CH3)2、-CH2CH2NRx(CH3)、-CH2CRx(CH3)NH2、-CH2CH2CH2N(CH3)2、-CH2CH2CH2CH2NH2、-CH(NH2)(CH2)3-4NH2、-CH2NHCH2CH2O(C1-3烷基)、-CH2NHCH2CH2OCH2CH2OH、-CH2NHCH2CH2S(O)2OH、-CH2C(O)NRx(CH3)、-NRxRx、-NH(CH(CH3)2)、-NHCH2CH2NH(CH3)、-NHCH2CH2CH2N(CH3)2、-NHC(O)CH3、-NHC(O)CF3、-NHC(O)OC(CH3)3、-NHC(O)CH2N(CH3)2、-NHC(O)CH2CH2N(CH3)2、-NHCH2C(O)CH2NH(CH3)、-C(O)CH3、-C(O)CH2CH(CH3)OH、-C(O)CH2NRx(CH3)、-C(O)NRxRx、-C(O)NH(CH2CN)、-C(O)NHCH2CH2CH2NRxRx、-C(O)NHCH2CH(CH3)CH2NH2、-C(O)NHCH2C(O)NH2、-C(O)N(CH3)CH2CH2CH2N(CH3)2、-C(O)N(CH2CH3)CH2CH2N(CH3)2、-OCH2CH2CH2N(CH3)2、-C(O)NHCH2CH2NHC(O)CH3、-S(O)2NH2和-C(O)CH2S(O)2CH3。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中每个R14a独立地选自8-氮杂双环[3.2.1]辛基、氮杂螺[3.5]壬基、氮杂环丁烷基、苯并[c][1,2,5]噁二唑基、环戊基、环己基、二氮杂环庚烷基、吗啉基、苯基、哌嗪基、哌啶基、吡唑基、吡啶基、吡咯烷酮基、喹啉基、奎宁环基、四氢异喹啉基、四氢吡啶基或噻唑烷基,其各自取代有0至2个取代基,所述取代基独立地选自C1-4烷基、C1-2氟烷基、C1-4羟烷基、-NRxRx、-(CH2)1-2NRxRx、-C(O)(C1-2烷基)、-C(O)CH2NRxRx、-C(O)O(C1-3烷基)、-CH2C(O)NRxRx、C3-6环烷基、-CH2(苯基)、-CH2(吡咯基)、-CH2(吗啉基)、-CH2(甲基哌嗪基)、-CH2(硫代苯基)、甲基哌啶基、异丁基哌啶基和吡啶基;和A、G、R1、R2、R5、Rx、n和p在第一方面中定义。该实施方案中包括化合物,其中每个R14a独立地选自8-氮杂双环[3.2.1]辛基、氮杂螺[3.5]壬基、氮杂环丁烷基、苯并[c][1,2,5]噁二唑基、环戊基、环己基、二氮杂环庚烷基、吗啉基、苯基、哌嗪基、哌啶基、吡唑基、吡啶基、吡咯烷酮基、喹啉基、奎宁环基、四氢异喹啉基、四氢吡啶基或噻唑烷基,其各自取代有0至2个取代基,所述取代基独立地选自C1-4烷基、C1-2氟烷基、C1-4羟烷基、-NRxRx、-(CH2)1-2NRxRx、-C(O)(C1-2烷基)、-C(O)CH2NRxRx、-C(O)O(C1-3烷基)、-CH2C(O)NRxRx、C3-6环烷基、-CH2(苯基)、-CH2(吡咯基)、-CH2(吗啉基)、-CH2(甲基哌嗪基)、-CH2(硫代苯基)、甲基哌啶基、异丁基哌啶基和吡啶基。该实施方案中还包括化合物,其中每个R14a独立地选自8-氮杂双环[3.2.1]辛基、氮杂螺[3.5]壬基、氮杂环丁烷基、苯并[c][1,2,5]噁二唑基、环戊基、环己基、二氮杂环庚烷基、吗啉基、苯基、哌嗪基、哌啶基、吡唑基、吡啶基、吡咯烷酮基、喹啉基、奎宁环基、四氢异喹啉基、四氢吡啶基或噻唑烷基,其各自取代有0至2个取代基,所述取代基独立地选自-CH3、-CH(CH3)2、-CH2CH(CH3)2、-CF3、-CH2CH2CF3、-CH2CH2OH、-CH2CH2CH(CH3)OH、-NH2、-CH2N(CH3)2、-CH2CH2NH(CH3)、-C(O)CH3,、-C(O)CH2NH(CH3)、-C(O)CH2N(CH3)2、-C(O)O(C(CH3)3)、-CH2C(O)NRx(CH3)、环丁基、环戊基、-CH2(苯基)、-CH2(吡咯基)、-CH2(吗啉基)、-CH2(甲基哌嗪基)、-CH2(硫代苯基)、甲基哌啶基、异丁基哌啶基和吡啶基。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中每个R14a独立地选自-L3-R14c;和A、G、L3、R1、R2、R5、R14c、n和p在第一方面中定义。该实施方案中包括化合物,其中每个R14a独立地选自L3为-(CRxRx)1-3-、-CH(NH2)-、-CRxRxNH-、-C(O)-、-C(O)NRx(CH2)0-4-、-NRx-、-NRxC(O)-、-NRxCH2-、-NRxCH2C(O)-、-O-或-O(CH2)1-2-;R14c为金刚烷基、氮杂环丁烷基、C3-6环烷基、二氮杂环庚烷基、咪唑基、吲哚基、吗啉基、八氢吡咯并[3,4-c]吡咯基、苯基、哌嗪酮基、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基或四唑基,其各自取代有0至1个取代基,所述取代基选自F、-OH、C1-4烷基、C1-3羟烷基、-NRxRy、-NRxC(O)CH3、-C(O)(C1-2烷基)、-C(O)NRxRx、-C(O)N(CH2CH3)2、-C(O)(四氢呋喃基)、-C(O)O(C1-2烷基)、-CH2C(O)NRxRy、吗啉基、甲基哌啶基、吡嗪基、吡啶基和吡咯烷基;和每个Ry独立地为H或C1-6烷基。该实施方案中还包括化合物,其中L3为-(CH2)1-3-、-CH(CH3)-、-CH(NH2)-、-CH2NH-、-C(O)-、-C(O)NH(CH2)0-4-、-C(O)N(CH3)CH2CH2-、-NH-、-NHC(O)-、-NHCH2-、-NHCH2C(O)-、-O-或-OCH2CH2-;和R14c为金刚烷基、氮杂环丁烷基、环丙基、环己基、二氮杂环庚烷基、咪唑基、吲哚基、吗啉基、八氢吡咯并[3,4-c]吡咯基、苯基、哌嗪酮基、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基或四唑基,其各自取代有0至1个取代基,所述取代基选自-OH、-CH3、-CH(CH3)2、-CH2CH(CH3)2、-C(CH3)2OH、-NH2、-N(CH3)2、-NH(C(CH3)2、-NHC(O)CH3、-C(O)CH3、-C(O)NH2、-C(O)N(CH2CH3)2、-C(O)(四氢呋喃基)、-C(O)OCH2CH3、-CH2C(O)NH(CH(CH3)2、吗啉基、甲基哌啶基、吡嗪基、吡啶基和吡咯烷基。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中n为0或1;和A、G、R1和R5在第一方面中定义。该实施方案中包括化合物,其中n为0。
一个实施方案提供式(I)化合物、其N-氧化物或其盐,其中所述化合物为2-(3,4-二甲氧基苯基)-5-[3-(哌嗪-1-羰基)苯基]-3-(丙烷-2-基)-1H-吲哚(1);2-(3,4-二甲氧基苯基)-5-[5-(哌啶-4-基)-1,3,4-噁二唑-2-基]-3-(丙烷-2-基)-1H-吲哚(2);1-(4-{5-[2-(3,4-二甲氧基苯基)-3-(丙烷-2-基)-1H-吲哚-5-基]-1,3,4-噁二唑-2-基}哌啶-1-基)-2-(二甲基氨基)乙烷-1-酮(3);2-(3,4-二甲氧基苯基)-3-(丙烷-2-基)-5-{5-[1-(丙烷-2-基)哌啶-4-基]-1,3,4-噁二唑-2-基}-1H-吲哚(4);(3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)(4-甲基-1,4-二氮杂环庚烷-1-基)甲酮(5);N-((1r,4r)-4-氨基环己基)-3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯甲酰胺(6);3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-((1r,4r)-4-(2-羟基丙烷-2-基)环己基)苯甲酰胺(7);3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)苯甲酰胺(8);(3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(9);(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)(4-甲基-1,4-二氮杂环庚烷-1-基)甲酮(10);4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)吡啶甲酰胺(11);N-(4-氨基环己基)-4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡啶甲酰胺(12);4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-((1r,4r)-4-(2-羟基丙烷-2-基)环己基)吡啶甲酰胺(13);(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)(哌嗪-1-基)甲酮(14);(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(3-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)苯基)甲酮(15);3-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)苯甲酰胺(16);2-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N,N-二甲基乙酰胺(17);1-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-2-(甲基氨基)乙烷-1-酮(18);叔丁基4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-甲酸酯(19);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(1-甲基哌啶-4-基)-1,3,4-噁二唑(20);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(1'-甲基-[1,4'-联哌啶]-4-基)-1,3,4-噁二唑(21);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(1'-异丙基-[1,4'-联哌啶]-4-基)-1,3,4-噁二唑(22);2-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N-甲基乙酰胺(23);2-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N-甲基乙烷-1-胺(24);3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)-N-(2-(1-甲基吡咯烷-2-基)乙基)苯甲酰胺(25);N-(2-乙酰氨基乙基)-3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯甲酰胺(26);N-(氰基甲基)-3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯甲酰胺(27);N-(2-氨基-2-氧代乙基)-3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯甲酰胺(28);3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)-N-(2-吗啉代乙基)苯甲酰胺(29);2-(4-(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯甲酰基)哌嗪-1-基)-N-异丙基乙酰胺(30);(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯基)(4-羟基哌啶-1-基)甲酮(31);(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯基)(2-甲基吡咯烷-1-基)甲酮(32);(4-(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯甲酰基)哌嗪-1-基)(四氢呋喃-2-基)甲酮(33);(R)-(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯基)(3-羟基吡咯烷-1-基)甲酮(34);3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)-N-甲基-N-(2-(吡啶-2-基)乙基)苯甲酰胺(35);(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯基)(4-(吡啶-4-基)哌嗪-1-基)甲酮(36);(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯基)(4-(1-甲基哌啶-4-基)哌嗪-1-基)甲酮(37);5-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-N,N-二甲基-1,3,4-噁二唑-2-甲酰胺(38);5-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噁二唑-2-甲酰胺(39);(5-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(40);5-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-甲酰胺(41);(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(42);2-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N,N-二甲基乙烷-1-胺(43);1-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N,N-二甲基甲胺(44);2-((1H-咪唑-4-基)甲基)-5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑(45);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(1-甲基哌啶-3-基)-1,3,4-噁二唑(46);2-(2-(1H-咪唑-1-基)乙基)-5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑(47);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(吡咯烷-3-基)-1,3,4-噁二唑(48);(S)-1-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N-甲基乙烷-1-胺(49);(S)-2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-2-基甲基)-1,3,4-噁二唑(50);(S)-2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(吡咯烷-2-基甲基)-1,3,4-噁二唑(51);(S)-2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(52);2-(氮杂环丁烷-3-基)-5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑(53);(R)-2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-2-基甲基)-1,3,4-噁二唑(54);(R)-2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(55);(R)-2-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(56);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噁二唑-2-甲酰胺(58);5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噁二唑-2-甲酰胺(59);(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲酮(60);(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(61);2-(二甲基氨基)-1-(4-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)乙烷-1-酮(62);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-甲基-1,3,4-噁二唑(63);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(2,2,2-三氟乙基)-1,3,4-噁二唑(64);2-(4-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N,N-二甲基乙酰胺(65);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-4-基)-1,3,4-噁二唑(66);2-(4-(5-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N-甲基乙烷-1-胺(67);(R)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(噻唑烷-4-基)-1,3,4-噁二唑(68);(S)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(69);2-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)吗啉(70);(S)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-2-基甲基)-1,3,4-噁二唑(71);(R)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1,2,3,4-四氢异喹啉-3-基)-1,3,4-噁二唑(72);2-((1H-吲哚-3-基)甲基)-5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑(73);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡啶-3-基甲基)-1,3,4-噁二唑(74);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(2,2,2-三氟乙基)-1,3,4-噁二唑(75);2-((1H-四唑-5-基)甲基)-5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑(76);3-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N,N-二甲基丙烷-1-胺(77);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(4-(三氟甲基)环己基)-1,3,4-噁二唑(78);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-((4-甲基哌嗪-1-基)甲基)-1,3,4-噁二唑(79);(R)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(80);(S)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1,2,3,4-四氢异喹啉-3-基)-1,3,4-噁二唑(81);(S)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(噻唑烷-4-基)-1,3,4-噁二唑(82);2-(4-(5-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N,N-二甲基乙酰胺(83);5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噁二唑-2-甲酰胺(84);(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲酮(85);2-(二甲基氨基)-1-(4-(5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)乙烷-1-酮(86);2-(4-(5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N,N-二甲基乙酰胺(87);2-(4-(5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N-甲基乙酰胺(88);1-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-羰基)-N,N-二乙基哌啶-3-甲酰胺(89);5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(2-(二甲基氨基)乙基)-1,3,4-噁二唑-2-甲酰胺(90);(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(4-羟基哌啶-1-基)甲酮(91);1-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-羰基)哌嗪-1-基)乙烷-1-酮(92);(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(4-甲基-1,4-二氮杂环庚烷-1-基)甲酮(93);5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-甲基-N-(2-(吡啶-2-基)乙基)-1,3,4-噁二唑-2-甲酰胺(94);(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(4-(吡咯烷-1-基)哌啶-1-基)甲酮(95);5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(3-(二甲基氨基)丙基)-N-甲基-1,3,4-噁二唑-2-甲酰胺(96);(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(4-(吡嗪-2-基)哌嗪-1-基)甲酮(97);(S)-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(3-(二甲基氨基)吡咯烷-1-基)甲酮(98);(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(3-吗啉代吡咯烷-1-基)甲酮(99);N-(2-乙酰氨基乙基)-5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-甲酰胺(100);N-(3-(1H-咪唑-1-基)丙基)-5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-甲酰胺(101);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-4-基)-1,3,4-噁二唑(102);(R)-2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(103);(S)-2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-2-基甲基)-1,3,4-噁二唑(104);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(哌嗪-1-基)-1,3,4-噁二唑(105);5-(5-(1-苄基哌啶-4-基)-4H-1,2,4-三唑-3-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(106);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-((六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲基)-1,3,4-噁二唑(107);N-(2-(((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)氨基)乙基)乙酰胺(108);N-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-2-甲氧基乙烷-1-胺(109);N-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)丙-2-炔-1-胺(110);N-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-2-乙氧基乙烷-1-胺(111);2-(2-(((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)氨基)乙氧基)乙烷-1-醇(112);2-(((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)氨基)乙烷-1-磺酸(113);N-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-2-异丙氧基乙烷-1-胺(114);4-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)吗啉(115);1-(4-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)哌嗪-1-基)乙烷-1-酮(116);(S)-N-(1-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)吡咯烷-3-基)乙酰胺(117);N-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-2-甲氧基-N-(2-甲氧基乙基)乙烷-1-胺(118);1-(4-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-1,4-二氮杂环庚烷-1-基)乙烷-1-酮(119);4-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)哌嗪-2-酮(120);N-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-2-甲氧基-N-甲基乙烷-1-胺(121);(S)-1-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)吡咯烷-2-甲酰胺(122);N-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-N-甲基丙-2-炔-1-胺(123);2-(3,4-二甲氧基苯基)-3-异丙基-5-(5-(哌啶-4-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(124);(5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(4-甲基-1,4-二氮杂环庚烷-1-基)甲酮(125);(S)-2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(126);(2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)噁唑-4-基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(127);2-(3-异丙基-2-(2H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-1-基甲基)-1,3,4-噁二唑(128);2-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)-N,N-二甲基乙酰胺(129);2-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)-N-甲基乙酰胺(130);1-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)-2-(二甲基氨基)乙烷-1-酮(131);1-(5-(3-异丙基-2-(2H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N-甲基甲胺(132);N-(2-(二甲基氨基)乙基)-5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噻二唑-2-甲酰胺(133);N1-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-N2,N2-二甲基乙烷-1,2-二胺(134);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噻二唑-2-甲酰胺(135);6-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,2,3,4-四氢异喹啉(136);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-(吡咯烷-3-基)-1,3,4-噻二唑-2-甲酰胺(137);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-2-基甲基)-1,3,4-噁二唑(138);(R)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-3-基)-1,3,4-噁二唑(139);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(哌嗪-1-基甲基)-1,3,4-噁二唑(140);2-((1H-咪唑-1-基)甲基)-5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑(141);2-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N-甲基乙烷-1-胺(142);2-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N,N-二甲基乙烷-1-胺(143);2-((1H-咪唑-4-基)甲基)-5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑(144);(R)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-2-基甲基)-1,3,4-噁二唑(145);(S)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-3-基)-1,3,4-噁二唑(146);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)噻唑-4-甲酰胺(147);N-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)环丙胺(148);N-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-2,2-二甲基丙烷-1-胺(149);2-(((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)氨基)乙腈(150);N-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)金刚烷-1-胺(151);4-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)吗啉(152);1-(4-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)哌嗪-1-基)乙烷-1-酮(153);N-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-N-甲基丙烷-2-胺(154);1-(4-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-1,4-二氮杂环庚烷-1-基)乙烷-1-酮(155);4-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)哌嗪-2-酮(156);(R)-1-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-N,N-二甲基吡咯烷-3-胺(157);(S)-1-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)吡咯烷-2-甲酰胺(158);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-甲基哌啶-3-基)-1,3,4-噁二唑(159);2-(2-(2-氨基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)噁唑-4-甲酰胺(160);7-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,2,3,4-四氢喹啉(161);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(1-甲基哌啶-3-基)-1,3,4-噁二唑(162);5-(5-(1-苄基哌啶-4-基)-4H-1,2,4-三唑-3-基)-3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚(163);3-异丙基-2-(2-甲基吡啶-4-基)-5-(5-(哌啶-3-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(164);2-(3,4-二甲氧基苯基)-5-(1H-咪唑-2-基)-3-异丙基-1H-吲哚(165);5-(2-(2-氨基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N,N-二甲基-1,3,4-噁二唑-2-甲酰胺(166);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(1-甲基哌啶-3-基)-1,3,4-噁二唑(167);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(1-甲基哌啶-3-基)-1,3,4-噁二唑(168);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-甲基哌啶-3-基)-1,3,4-噁二唑(169);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-甲基哌啶-3-基)-1,3,4-噁二唑(170);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)噻唑(171);(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)噁唑-4-基)甲酮(172);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)噁唑-4-甲酰胺(173);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-胺(174);2-(3-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)-N-甲基乙酰胺(175);2-(二甲基氨基)-1-(3-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)乙烷-1-酮(176);4,4'-(3-异丙基-1H-吲哚-2,5-二基)双(1H-吡唑并[3,4-b]吡啶)(177);3-异丙基-2-(2-甲基吡啶-4-基)-5-(5-(哌啶-3-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(178);3-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)环己烷-1-胺(179);2-(3-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)-N,N-二甲基乙酰胺(180);2-(3-异丙基-2-(2H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)噻唑(181);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基甲基)-1,3,4-噁二唑(182);2-(3-异丙基-2-(2H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)噁唑-4-甲酰胺(183);3-异丙基-2-(2-甲基吡啶-4-基)-5-(5-(哌啶-3-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(184);2-(4-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)-N,N-二甲基乙酰胺(185);2-(二甲基氨基)-1-(4-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)乙烷-1-酮(186);3-异丙基-5-(5-(1-异丙基哌啶-4-基)-4H-1,2,4-三唑-3-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(187);3-异丙基-5-(5-(1-异丙基哌啶-3-基)-4H-1,2,4-三唑-3-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(188);3-异丙基-2-(2-甲基吡啶-4-基)-5-(4-(哌啶-4-基)-1H-咪唑-2-基)-1H-吲哚(189);2-(二甲基氨基)-N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)乙酰胺(190);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-5-甲基噁唑-4-甲酰胺(191);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4-甲基噻唑(192);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)嘧啶-2-胺(193);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-甲基-N-(吡咯烷-3-基甲基)噁唑-4-甲酰胺(194);N-(2-(二甲基氨基)乙基)-5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噻二唑-2-甲酰胺(195);3-异丙基-2-(2-甲基吡啶-4-基)-5-(5-(哌啶-4-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(196);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-(吡咯烷-3-基甲基)噁唑-4-甲酰胺(197);2-(二甲基氨基)-N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)乙酰胺(198);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-2-(哌啶-4-基)噻唑(199);4-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-胺(200);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4-甲基-2-(哌啶-4-基)噻唑(201);N1-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)-N2-甲基乙烷-1,2-二胺(202);5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噻二唑-2-甲酰胺(203);3-异丙基-5-(5-(1-异丙基哌啶-3-基)-4H-1,2,4-三唑-3-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(204);3-异丙基-5-(5-(1-异丙基哌啶-3-基)-4H-1,2,4-三唑-3-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(205);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[1,5-a]吡嗪(206);(S)-N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)吡咯烷-3-甲酰胺(207);1-(6-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)嘧啶-4-基)哌啶-4-胺(208);(R)-N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)吡咯烷-3-甲酰胺(209);N1-(4-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)-N2-甲基乙烷-1,2-二胺(210);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-7-(1-异丙基哌啶-4-基)-5,6,7,8-四氢-[1,2,4]三唑并[1,5-a]吡嗪(211);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-甲基-N-(吡咯烷-3-基甲基)噁唑-4-甲酰胺(212);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(奎宁环-3-基)-1,3,4-噁二唑(213);N-(1-异丁基哌啶-4-基)-5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-甲酰胺(214);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-甲酰胺(215);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-甲酰胺(216);2-(2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5,6-二氢-[1,2,4]三唑并[1,5-a]吡嗪-7(8H)-基)-N-甲基乙烷-1-胺(217);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(2-(甲基氨基)乙基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-甲酰胺(218);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-甲基-5-(2-(甲基氨基)乙基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-甲酰胺(219);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(奎宁环-3-基)-1,3,4-噁二唑(220);5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噁二唑-2-甲酰胺(221);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(奎宁环-3-基)-1,3,4-噁二唑(222);N-(2-(二甲基氨基)乙基)-5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-甲酰胺(223);N-(3-(二甲基氨基)丙基)-5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-甲酰胺(224);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶(225);2-(5-(2-([1,2,4]三唑并[1,5-a]吡啶-6-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N-甲基乙烷-1-胺(226);(R)-2-(2-([1,2,4]三唑并[1,5-a]吡啶-6-基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(227);6-异丙基-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶(228);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶(229);(4-氨基哌啶-1-基)(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲酮(230);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(奎宁环-3-基)-1,3,4-噁二唑(231);(R)-2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(232);(2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)噁唑-4-基)(4-甲基-1,4-二氮杂环庚烷-1-基)甲酮(233);N-(2-(二甲基氨基)乙基)-2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)噁唑-4-甲酰胺(234);5-(6-氯吡啶-3-基)-3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚(235);5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶-2-胺(236);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-胺(237);2-(二甲基氨基)-N-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)乙酰胺(238);N1-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)-N2-甲基乙烷-1,2-二胺(239);(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(4-(异丙基氨基)哌啶-1-基)甲酮(240);5-(2-(咪唑并[1,2-a]吡啶-6-基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噁二唑-2-甲酰胺(241);N-(2-(二甲基氨基)乙基)-5-(2-(咪唑并[1,2-a]吡啶-6-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-甲酰胺(242);(R)-2-(3-(2,2-二氟乙基)-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(243);(R)-2-(2-(咪唑并[1,2-a]吡啶-6-基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(244);(R)-2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-5-(1-异丙基哌啶-3-基)-1,3,4-噁二唑(245);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N,N-二甲基吡啶-2-胺(246);N-异丙基-5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-胺(247);5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-异丙基吡啶-2-胺(248);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)噁唑-4-甲酰胺(249);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-5-(奎宁环-3-基)-1,3,4-噁二唑(250);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶(251);1-(2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-2-(甲基氨基)乙烷-1-酮(252);3-异丙基-5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(253);3-异丙基-2-(2-甲基吡啶-4-基)-5-(2-(哌啶-4-基)-1H-咪唑-5-基)-1H-吲哚(254);3-异丙基-2-(2-甲基吡啶-4-基)-5-(6-(哌嗪-1-基)吡啶-3-基)-1H-吲哚(255);N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)乙酰胺(256);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(6-(哌嗪-1-基)吡啶-3-基)-1H-吲哚(257);5-(2-(1H-吡唑-4-基)吡啶-4-基)-3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚(258);1-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)丙烷-2-胺(259);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(2-(哌啶-1-基)乙基)-1,3,4-噁二唑(260);(S)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-2-基)-1,3,4-噁二唑(261);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(2-(吡啶-3-基)乙基)-1,3,4-噁二唑(262);2-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)丙烷-1-胺(263);4-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)丁烷-1-胺(264);1-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-2-甲基丙烷-2-胺(265);(1S,2R)-2-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)环己烷-1-胺(266);(1S,2R)-2-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)环戊烷-1-胺(267);(S)-环丙基(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲胺(268);3-异丙基-5-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(269);2-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N,N-二甲基乙烷-1-胺(270);3-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N,N-二甲基丙烷-1-胺(271);3-异丙基-5-(2-(1-异丙基哌啶-4-基)吡啶-4-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(272);3-异丙基-2-(2-甲基吡啶-4-基)-5-(2-(哌嗪-1-基)吡啶-4-基)-1H-吲哚(273);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(2-(哌啶-1-基)乙基)噁唑-4-甲酰胺(274);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(3-(哌啶-1-基)丙基)噁唑-4-甲酰胺(275);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(吡咯烷-3-基甲基)噁唑-4-甲酰胺(276);N-(3-氨基-2-甲基丙基)-2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)噁唑-4-甲酰胺(277);N-(3-氨基丙基)-2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)噁唑-4-甲酰胺(278);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(3-(甲基氨基)丙基)噁唑-4-甲酰胺(279);N-(3-(二甲基氨基)丙基)-2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)噁唑-4-甲酰胺(280);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(2-吗啉代乙基)噁唑-4-甲酰胺(281);N-((1r,4r)-4-氨基环己基)-2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)噁唑-4-甲酰胺(282);乙基4-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)噁唑-4-甲酰氨基)哌啶-1-甲酸酯(283);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(3-(吡咯烷-1-基)丙基)噁唑-4-甲酰胺(284);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(4-(吡咯烷-1-基)butyl)噁唑-4-甲酰胺(285);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(3-(4-甲基哌嗪-1-基)丙基)噁唑-4-甲酰胺(286);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(哌啶-2-基甲基)噁唑-4-甲酰胺(287);N-(氮杂环丁烷-3-基甲基)-2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)噁唑-4-甲酰胺(288);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(2-甲基-2-吗啉代丙基)噁唑-4-甲酰胺(289);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(哌啶-3-基)噁唑-4-甲酰胺(290);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(2-(吡咯烷-2-基)乙基)噁唑-4-甲酰胺(291);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-异丙基哌啶-3-基)-1,3,4-噁二唑(292);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-甲基吡啶-2-胺(293);3-(二甲基氨基)-N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)丙酰胺(294);2,2,2-三氟-N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)乙酰胺(295);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-5-(奎宁环-3-基)-1,3,4-噁二唑(296-297);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-异丙基哌啶-3-基)-1,3,4-噁二唑(298);3-异丙基-5-(2-(4-异丙基哌嗪-1-基)吡啶-4-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(299);N-(2-(二甲基氨基)乙基)-5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-乙基-1,3,4-噁二唑-2-甲酰胺(300);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吲哚(301);3-异丙基-5-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(302);叔丁基(6-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-8-基)氨基甲酸酯(303);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(吡啶-3-基)-1H-吲哚(304);2-(二甲基氨基)-1-(2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)乙烷-1-酮(305);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)-1H-吲哚(306);5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡嗪-2-胺(307);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,5,6,7-四氢噻唑并[5,4-c]吡啶(308);2-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-6,7-二氢噻唑并[5,4-c]吡啶-5(4H)-基)-N,N-二甲基乙酰胺(309);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,5,6,7-四氢噻唑并[4,5-c]吡啶(310);2-(2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-N,N-二甲基乙酰胺(311);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-异丙基哌啶-3-基)-1,3,4-噁二唑(312);(4-(二甲基氨基)哌啶-1-基)(4-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)苯基)甲酮(313);2-(3-(2,2-二氟乙基)-2-(2,6-二甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-异丙基哌啶-3-基)-1,3,4-噁二唑(314);2-(2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-N-甲基乙酰胺(315);5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-甲基吡啶甲酰胺(316);5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶甲酰胺(317);5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-胺(318);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吲哚(319);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(2-(哌嗪-1-基)吡啶-4-基)-1H-吲哚(320);(4-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)苯基)(4-(异丙基氨基)哌啶-1-基)甲酮(321);(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)甲醇(322);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(5-(哌啶-3-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(323);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶(324);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-6-异丙基-4,5,6,7-四氢噻吩并[2,3-c]吡啶(325);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(2-(4-异丙基哌嗪-1-基)吡啶-4-基)-1H-吲哚(326);2-(3-(2,2-二氟乙基)-2-(2,6-二甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-异丙基哌啶-3-基)-1,3,4-噁二唑(327);2-(3-(2,2-二氟乙基)-2-(2,6-二甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-异丙基哌啶-3-基)-1,3,4-噁二唑(328);2-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-6,7-二氢噻唑并[4,5-c]吡啶-5(4H)-基)-N,N-二甲基乙酰胺(329);2-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-N-甲基乙酰胺(330);1-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-2-(甲基氨基)乙烷-1-酮(331);N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)-1-甲基-5-氧代吡咯烷-3-甲酰胺(332);6-(3-异丙基-5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吲哚-2-基)-2-甲基咪唑并[1,2-a]吡啶(333);6-(3-异丙基-5-(6-(哌嗪-1-基)吡啶-3-基)-1H-吲哚-2-基)-2-甲基咪唑并[1,2-a]吡啶(334);4-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)-2,6-二甲基吗啉(335);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(6-(吡咯烷-1-基)吡啶-3-基)-1H-吲哚(336);1-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)-N,N-二甲基哌啶-4-胺(337);5-(6-(氮杂环丁烷-1-基)吡啶-3-基)-2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚(338);2-(4-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)哌嗪-1-基)乙烷-1-醇(339);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(5-(1-异丙基哌啶-3-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(340);2-(二甲基氨基)-1-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)乙烷-1-酮(341);2-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-N,N-二甲基乙酰胺(342);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-6-((2-甲基-1H-咪唑-4-基)甲基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶(343);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(2-(哌啶-4-基)吡啶-4-基)-1H-吲哚(344);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(2-(1-异丙基哌啶-4-基)吡啶-4-基)-1H-吲哚(345);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-甲基-1,3,4-噁二唑-2-胺(346);6-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-2,7-二甲基咪唑并[1,2-a]吡啶(347);6-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-7-氟-2-甲基咪唑并[1,2-a]吡啶(348);6-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)哒嗪-3-胺(349);4-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-2-(哌啶-1-基)噻唑(350);(S)-1-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-3-羟基丁烷-1-酮(351);4-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-6-羰基)-1-甲基吡咯烷-2-酮(352);1-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-2-(甲基磺酰基)乙烷-1-酮(353);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡嗪(354);7-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-8-甲基-[1,2,4]三唑并[1,5-a]吡啶(355);N-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡嗪-2-基)-2-(甲基氨基)乙酰胺(356);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(5-(1-异丙基哌啶-3-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(357);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(5-(1-异丙基哌啶-3-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(358);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡嗪-2-胺(359);6-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)哒嗪-3-胺(360);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶(361);1-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-6,7-二氢噻唑并[5,4-c]吡啶-5(4H)-基)乙烷-1-酮(362);2-(二甲基氨基)-1-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-6,7-二氢噻唑并[5,4-c]吡啶-5(4H)-基)乙烷-1-酮(363);4-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,5,6,7-四氢噻唑并[5,4-c]吡啶-5-羰基)-1-甲基吡咯烷-2-酮(364);2-(二甲基氨基)-N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡嗪-2-基)乙酰胺(365);6-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-8-氟-2-甲基咪唑并[1,2-a]吡啶(366);2-(3-异丙基-2-(8-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)-5-(1-甲基哌啶-4-基)-1,3,4-噁二唑(367);2-(3,4-二甲氧基苯基)-3-乙基-5-(3-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲哚(368);2-(3,4-二甲氧基苯基)-3-异丙基-5-(3-(4-甲基哌嗪-1-基)苯基)-1H-吲哚(369);2-(3,4-二甲氧基苯基)-3-异丙基-5-(3-(4-异丙基哌嗪-1-基)苯基)-1H-吲哚(370);2-(3,4-二甲氧基苯基)-5-(3-(4-异丁基哌嗪-1-基)苯基)-3-异丙基-1H-吲哚(371);4-(1-(4-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)苯基)乙基)吗啉(372);2-(3,4-二甲氧基苯基)-3-异丙基-5-(3'-((4-甲基哌嗪-1-基)甲基)-[1,1'-联苯基]-4-基)-1H-吲哚(373);1-(4'-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-[1,1'-联苯基]-3-基)-N,N-二甲基甲胺(374);2-(3,4-二甲氧基苯基)-5-(4-(1-(1-异丁基哌啶-4-基)-1,2,3,6-四氢吡啶-4-基)苯基)-3-甲基-1H-吲哚(375);2-(3,4-二甲氧基苯基)-3-甲基-5-(4-(1-甲基-1,2,3,6-四氢吡啶-4-基)苯基)-1H-吲哚(376);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(2,2,6,6-四甲基-1,2,3,6-四氢吡啶-4-基)苯基)-1H-吲哚(377);4-(3-异丙基-5-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(378);2-(4-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)-1,4-二氮杂环庚烷-1-基)乙烷-1-醇(379);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯基)-1H-吲哚(380);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲哚(381);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-异丙基哌嗪-1-基)苯基)-1H-吲哚(382);(R)-2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(3-甲基哌嗪-1-基)苯基)-1H-吲哚(383);4-(3-乙基-5-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(384);N-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)-1-异丙基哌啶-4-胺(385);4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-((1-甲基吡咯烷-3-基)甲基)苯胺(386);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-((1-甲基哌啶-4-基)氧基)苯基)-1H-吲哚(387);2-(3,4-二甲氧基苯基)-5-(4-((1-异丁基哌啶-4-基)氧基)苯基)-3-异丙基-1H-吲哚(388);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-((1-异丙基哌啶-4-基)氧基)苯基)-1H-吲哚(389);1-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)哌嗪-1-基)乙烷-1-酮(390);2-(3,4-二甲氧基苯基)-5-(6-(4-异丁基哌嗪-1-基)吡啶-3-基)-3-异丙基-1H-吲哚(391);2-(3,4-二甲氧基苯基)-3-异丙基-5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吲哚(392);2-(3,4-二甲氧基苯基)-3-异丙基-5-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)-1H-吲哚(393);4-羟基-6-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)喹啉-2(1H)-酮(394);4-(3-异丙基-5-(1-甲基-1H-吲唑-5-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(395);4-((3'-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-[1,1'-联苯基]-3-基)甲基)吗啉(396);1-(3'-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-[1,1'-联苯基]-3-基)-N,N-二甲基甲胺(397);4-(3-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)丙基)吗啉(398);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(哌嗪-1-基)苯基)-1H-吲哚(399);N1-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)-N3,N3-二甲基丙烷-1,3-二胺(400);4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(2-吗啉代乙基)苯胺(401);N-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)哌啶-3-胺(402);5-(4-(4-环戊基哌嗪-1-基)苯基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(403);N1-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)-N2-甲基乙烷-1,2-二胺(404);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-(吡啶-4-基)哌啶-1-基)苯基)-1H-吲哚(405);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(吡啶-3-基)苯基)-1H-吲哚(406);4-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)异喹啉(407);2-(3,4-二甲氧基苯基)-3-甲基-5-(4-(1,2,3,6-四氢吡啶-4-基)苯基)-1H-吲哚(408);5-(3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)苯并[c][1,2,5]噁二唑(409);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(哌啶-4-yl氧基)苯基)-1H-吲哚(410);2-(3,4-二甲氧基苯基)-3-异丙基-5-(3-(哌嗪-1-基)苯基)-1H-吲哚(411);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吲哚(412);4-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苄基)吗啉(413);(3-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)苯基)甲醇(414);3-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)苯磺酰胺(415);4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)吗啉(416);2-(3,4-二甲氧基苯基)-3-异丙基-5-(6-(哌嗪-1-基)吡啶-3-基)-1H-吲哚(417);2-(3,4-二甲氧基苯基)-5-(6-(4-异丁基哌嗪-1-基)-4-甲基吡啶-3-基)-3-异丙基-1H-吲哚(418);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-甲基-6-(哌嗪-1-基)吡啶-3-基)-1H-吲哚(419);2-(3,4-二甲氧基苯基)-3-异丙基-5-(6-(4-异丙基哌嗪-1-基)-4-甲基吡啶-3-基)-1H-吲哚(420);3-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)氧基)-N,N-二甲基丙烷-1-胺(421);4-(3-异丙基-5-(6-甲氧基吡啶-3-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(422);2-(3,4-二甲氧基苯基)-3-异丙基-5-(2-(4-(噻吩-3-基甲基)哌嗪-1-基)吡啶-4-基)-1H-吲哚(423);2-(3,4-二甲氧基苯基)-3-异丙基-5-(2-(4-(3,3,3-三氟丙基)哌嗪-1-基)吡啶-4-基)-1H-吲哚(424);4-(4-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)哌嗪-1-基)丁烷-2-醇(425);5-(2-(4-环戊基哌嗪-1-基)吡啶-4-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(426);5-(2-(4-环丁基哌嗪-1-基)吡啶-4-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(427);4-(3-异丙基-5-(1-甲基-1H-吡唑-5-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(428);2-(3,4-二甲氧基苯基)-3-异丙基-5-(2-(4-(噻吩-3-基甲基)哌嗪-1-基)嘧啶-5-基)-1H-吲哚(429);2-(3,4-二甲氧基苯基)-3-异丙基-5-(2-(4-((1-甲基-1H-吡咯-2-基)甲基)哌嗪-1-基)嘧啶-5-基)-1H-吲哚(430);4-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)嘧啶-2-基)哌嗪-1-基)丁烷-2-醇(431);2-(3,4-二甲氧基苯基)-3-异丙基-5-(2-(4-甲基哌嗪-1-基)嘧啶-5-基)-1H-吲哚(432);2-(3,4-二甲氧基苯基)-5-(2-(4-异丁基哌嗪-1-基)-1-甲基-1H-咪唑-5-基)-3-异丙基-1H-吲哚(433);4-(5-(5,6-二甲氧基吡啶-3-基)-3-异丙基-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(434);5-(2-(4-环戊基哌嗪-1-基)嘧啶-5-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(435);5-(2-(4-环丁基哌嗪-1-基)嘧啶-5-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(436);5-(2-氯-1-甲基-1H-咪唑-5-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(437);4-(3-异丙基-5-(3-(三氟甲基)-1H-吡唑-4-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(438);(S)-3-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-2-基甲基)-1,2,4-噁二唑(439);(S)-1-(3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)-2-(1H-咪唑-4-基)乙烷-1-胺(440);4-(3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)-1-甲基吡咯烷-2-酮(441);(1R,2S)-2-(3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)-1-甲基环戊烷-1-胺(442);5-(1-苄基吡咯烷-3-基)-3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑(443);5-(1-苄基哌啶-4-基)-3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑(444);3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-5-(1-异丙基哌啶-4-基)-1,2,4-噁二唑(445);2-(二甲基氨基)-1-(4-(3-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)哌啶-1-基)乙烷-1-酮(446);3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-5-(2-(哌啶-4-基)乙基)-1,2,4-噁二唑(447);3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(2-(哌啶-4-基)乙基)-1,2,4-噁二唑(448);3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(2-(1-异丙基哌啶-4-基)乙基)-1,2,4-噁二唑(449);3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-5-(吡咯烷-3-基)-1,2,4-噁二唑(450);3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-5-(2-甲氧基乙基)-1,2,4-噁二唑(451);5-((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑(452);1-(3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)-N,N-二甲基甲胺(453);2-(3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)-N,N-二甲基乙烷-1-胺(454);(S)-3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-3-基)-1,2,4-噁二唑(455);3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-3-基)-1,2,4-噁二唑(456);3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,2,4-噁二唑(457);5-(氮杂环丁烷-3-基)-3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,2,4-噁二唑(458);3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-5-(哌啶-4-基)-1,2,4-噁二唑(459);2-(3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)-N-甲基乙烷-1-胺(460);3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(7-氮杂螺[3.5]壬烷-2-基)-1,2,4-噁二唑(461);(R)-3-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,2,4-噁二唑(462);(S)-1-(3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)丁烷-1,4-二胺(463);(S)-1-(3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)戊烷-1,5-二胺(464);2-(3,4-二甲氧基苯基)-3-异丙基-5-(1H-吡咯-3-基)-1H-吲哚(465);2-(3,4-二甲氧基苯基)-3-乙基-5-(吡啶-3-基)-1H-吲哚(466);4-(3-异丙基-5-(吡啶-3-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(467);6-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)喹喔啉(468);6-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)喹啉(469);5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)异喹啉(470);或2-(3,4-二甲氧基苯基)-3-乙基-5-(吡啶-4-基)-1H-吲哚(471)。
在不脱离本发明的精神或基本属性的情况下,本发明可以其他特定形式实施。本发明包括本申请所指出的本发明的方面和/或实施方案的所有组合。应理解,本发明的任何和所有实施方案可与任何其他实施方案结合以描述额外实施方案。还应理解,意欲将该实施方案的个别要素与来自任何实施方案的任何和所有其他要素组合以描述额外实施方案。
定义
本发明的特征和优点可由本领域普通技术人员阅读下列详细描述后更容易理解。应了解,出于清楚原因,在分开实施方案的背景下,上述和下述本发明的某些特征还可经组合以形成单个实施方案。相反,出于简洁原因,在单个实施方案的背景下所述的本发明的各种特征还可经组合以便形成其子组合。本申请中标识为示例性或优选的实施方案旨在是说明性的而非限制性的。
除非本申请另有明确说明,否则以单数形式作出的引用也可以包括复数形式。例如,“一个”和“一种”可以指代一个或一或多个。
如本申请所用,短语“化合物”是指至少一种化合物。例如,式(I)化合物包括一种式(I)化合物以及两种或更多种式(I)化合物。
除非另外指明,否则具有未满足价的任何杂原子假定具有足以满足价的氢原子。
本申请所陈述的定义优先于在通过引用并入本申请的任何专利、专利申请和/或专利申请公开物中所陈述的定义。
下文列出了用于描述本发明的各种术语的定义。在整篇说明书个别地或作为更大基团的一部分使用术语(除非在特定情况下以其他方式受限)时,这些定义适用于所述术语。
在整篇说明书中,本领域技术人员可以选择其基团和取代基以提供稳定的部分和化合物。
根据本领域中使用的惯例,本申请的结构式中使用来描绘作为部分或取代基与核心或骨架结构的连接点的键。
如本申请所用的术语“卤代”和“卤素”是指F、Cl、Br和I。
术语“氰基”是指基团-CN。
术语“氨基”是指基团-NH2。
术语“氧代”是指基团=O。
如本申请所用的术语“烷基”是指含有例如从1至12个碳原子、从1至6个碳原子和从1至4个碳原子的支链和直链饱和脂族烃基两者。烷基的例子包括但不限于甲基(Me)、乙基(Et)、丙基(例如,正丙基和异丙基)、丁基(例如,正丁基、异丁基、仲丁基和叔丁基)和戊基(例如,正戊基、异戊基、新戊基)、正己基、2-甲基戊基、2-乙基丁基、3-甲基戊基和4-甲基戊基。当符号“C”后面的下标中出现数字时,该下标更具体地定义了特定基团可能含有的碳原子的数量。例如,“C1-6烷基”表示具有1至6个碳原子的直链和支链烷基。
如本申请所用的术语“氟烷基”旨在包括被一个或多个氟原子取代的支链和直链饱和脂族烃基两者。例如,“C1-4氟烷基”旨在包括被一个或多个氟原子取代的C1、C2、C3和C4烷基。氟烷基的代表性例子包括但不限于-CF3和-CH2CF3。
如本申请所用的术语“氯烷基”旨在包括被一个或多个氯原子取代的支链和直链饱和脂族烃基两者。例如,“C1-4氯烷基”旨在包括被一个或多个氯原子取代的C1、C2、C3和C4烷基。氟烷基的代表性例子包括但不限于-CCl3和-CH2CCl3。
术语“氰基烷基”包括被一个或多个氰基取代的支链和直链饱和烷基两者。例如,“氰基烷基”包括-CH2CN、-CH2CH2CN和C1-4氰基烷基。
术语“氨基烷基”包括被一个或多个胺基团取代的支链和直链饱和烷基两者。例如,“氨基烷基”包括-CH2NH2、-CH2CH2NH2和C1-4氨基烷基。
术语“羟烷基”包括被一个或多个羟基取代的支链和直链饱和烷基两者。例如,“羟烷基”包括-CH2OH、-CH2CH2OH、和C1-4羟烷基。
术语“羟基-氟烷基”包括被一个或多个羟基和一个或多个氟原子取代的支链和直链饱和烷基两者。例如,“羟基-氟烷基”包括-CHFCH2OH、-CH2CHFC(CH3)2OH和C1-4羟基-氟烷基。
如本申请所用的术语“环烷基”是指通过从饱和环碳原子上除去一个氢原子而衍生自非芳族单环或多环烃分子的基团。环烷基的代表性例子包括但不限于环丙基、环戊基和环己基。当数字出现在符号“C”之后的下标中时,下标更具体地定义了特定环烷基可能包含的碳原子的数目。例如,“C3-C6环烷基”表示具有3至6个碳原子的环烷基。
如本申请所用的术语“烷氧基”是指通过氧原子与母体分子部分附接的烷基,例如,甲氧基(-OCH3)。例如,“C1-3烷氧基”表示具有1至3个碳原子的烷氧基。
术语“氟烷氧基”和“-O(氟烷基)”表示通过氧键联(-O-)附接的如上定义的氟烷基。例如,“C1-4氟烷氧基”旨在包括C1、C2、C3和C4氟烷氧基。
如本申请所用的术语“烷氧基烷基”表示通过其氧原子与烷基相连的烷氧基,所述烷基与母体分子部分相连,例如甲氧基甲基基团(-CH2OCH3)。例如,“C2-4烷氧基烷基”表示具有2至4个碳原子的烷氧基烷基基团,例如-CH2OCH3、-CH2CH2OCH3、-CH2OCH2CH3和-CH2CH2OCH2CH3。
本申请采用短语“药学上可接受的”是指在合理医学判断范围内适合于与人和动物组织接触使用而没有过多的毒性、刺激、过敏反应或其他问题或并发症,与合理的效益/风险比相称的那些化合物、材料、组合物和/或剂型。
式(I)化合物可以作为无定形固体或结晶固体来提供。可以使用冻干来提供作为无定形固体的式(I)化合物。
还应当理解,式(I)化合物的溶剂合物(例如,水合物)也在本发明的范围内。术语“溶剂合物”意指式(I)化合物与一个或多个溶剂分子(无论是有机的还是无机的)的物理缔合。这种物理缔合包括氢键。在某些情况下,溶剂合物将能够分离,例如当一个或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液相和可分离溶剂合物两者。示例性溶剂合物包括水合物、乙醇化物、甲醇化物、异丙醇化物、乙腈溶剂合物、和乙酸乙酯溶剂合物。溶剂化作用的方法在本领域中是已知的。
各种形式的前药在本领域中是公知的并且描述于:
a)The Practice of Medicinal Chemistry,Camille G.Wermuth等人,第31章,(Academic Press,1996);
b)Design of Prodrugs,由H.Bundgaard编辑,(Elsevier,1985);
c)A Textbook of Drug Design and Development,P.Krogsgaard–Larson和H.Bundgaard编辑第5章,第113-191页(Harwood Academic Publishers,1991);以及
d)Hydrolysis in Drug and Prodrug Metabolism,Bernard Testa和JoachimM.Mayer,(Wiley-VCH,2003)。
此外,式(I)化合物可在其制备后经分离和纯化以获得含有以重量计等于或大于99%式(I)化合物的量的组合物(“实质上纯”),然后如本文中所述使用或调配。本文中还意欲将此类“实质上纯”的式(I)化合物作为本发明的一部分。
“稳定的化合物”和“稳定的结构”意指足够稳健地经受自反应混合物分离至有用纯度且调配成有效治疗剂的化合物。本发明旨在实施稳定的化合物。
“治疗有效量”旨在包括单独的本发明化合物的量,或所要求保护的多种化合物的组合的量,或本发明化合物与其他活性成分组合的量,其有效充当TLR7/8/9抑制剂或有效治疗或预防自身免疫性和/或炎性疾病状态(诸如SLE、IBD、多发性硬化症(MS)和干燥综合征(syndrome)和类风湿性关节炎)。
如本申请所用的,“治疗(treating/treatment)”涵盖哺乳动物(特别是人)的疾病状态的治疗,并且包括:(a)防止该疾病状态在哺乳动物中发生,特别是当这种哺乳动物易患该疾病状态,但尚未被诊断为患有该疾病状态时;(b)抑制该疾病状态,即阻止其发展;和/或(c)减轻该疾病状态,即引起该疾病状态的消退。
本发明化合物意欲包括本发明化合物中出现的原子的所有同位素。同位素包括具有相同原子数但是不同质量数的那些原子。举一般实例而言且非限制性,氢的同位素包括氘(D)和氚(T)。碳的同位素包括13C和14C。本发明的同位素标记化合物一般可通过本领域技术人员已知的常规技术或通过与本文中所述那些类似的方法,使用适宜同位素标记试剂代替原本采用的非标记试剂制备。例如,甲基(-CH3)还包括氘化甲基基团,诸如-CD3。
效用
人类免疫系统已进化至使身体防御可造成感染、疾病或死亡的微生物、病毒和寄生虫。复杂调节机制确保免疫系统的各种细胞组分靶向外来物质或生物体,同时不对个体造成永久或显著损伤。虽然此时未充分了解自身免疫性疾病状态中的引发事件,免疫系统指导其炎症反应以靶向患病个体的器官。不同自身免疫性疾病的特征通常在于受影响的占优势或初始靶器官或组织;诸如在类风湿性关节炎的情况下为关节,在桥本甲状腺炎的情况下为甲状腺,在多发性硬化症的情况下为中枢神经系统,在I型糖尿病的情况下为胰,且在炎性肠病的情况下为肠。
本发明化合物抑制通过Toll样受体7或8或9(TLR7、TLR8、TLR9)或其组合的信号传导。因此,式(I)化合物具有治疗与抑制通过TLR7、TLR8或TLR9中的一或多个的信号传导相关的病状的效用。此类病状包括TLR7、TLR8或TLR9受体相关疾病,其中细胞因子水平作为细胞内信号传导的结果而调节。
如本文中所用,术语“治疗(treating/treatment)”涵盖哺乳动物(具体而言,人类)的疾病状态的治疗且包括:(a)防止或延迟该疾病状态在哺乳动物中发生,具体而言,当此哺乳动物易患该疾病状态但是尚未诊断为患有该疾病状态时;(b)抑制该疾病状态,即,阻止其发展;和/或(c)达成症状或疾病状态的完全或部分减少,和/或减轻、改善、减少或治愈疾病或病症和/或其症状。
鉴于其作为TLR7、TLR8或TLR9的选择性抑制剂的活性,式(I)化合物可用于治疗TLR7、TLR8或TLR9家族受体相关疾病,但不限于炎性疾病,诸如克罗恩病(Crohn'sdisease)、溃疡性结肠炎、哮喘、移植物抗宿主疾病、同种异体移植排斥、慢性阻塞性肺病;自身免疫性疾病,诸如格雷夫斯病(Graves'disease)、类风湿性关节炎、系统性红斑狼疮、狼疮性肾炎、皮肤狼疮、牛皮癣;自身炎性疾病,包括冷吡啉(Cryopyrin)相关周期性综合征(CAPS)、TNF受体相关周期性综合征(TRAPS)、家族性地中海热(FMF)、成人发作性斯蒂尔病(adult onset stills)、全身发作性幼年特发性关节炎、痛风、痛风性关节炎;代谢疾病,包括2型糖尿病、动脉粥样硬化、心肌梗塞、破坏性骨病,诸如骨吸收疾病、骨关节炎、骨质疏松症、多发性骨髓瘤相关骨病;增殖性病症,诸如急性骨髓性白血病、慢性骨髓性白血病;血管生成障碍,诸如包括实体肿瘤、眼部新血管生成和婴儿血管瘤的血管生成障碍;传染性疾病,诸如败血症、败血性休克和志贺菌病(Shigellosis);神经变性疾病,诸如阿尔茨海默病(Alzheimer's disease)、帕金森病(Parkinson's disease)、脑缺血或由创伤性损伤造成的神经变性疾病,肿瘤性和病毒性疾病,诸如转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤和HIV感染和CMV视网膜炎、AIDS。
更具体地,可用本发明化合物治疗的具体病症或疾病包括但不限于胰腺炎(急性或慢性)、哮喘、过敏、成人呼吸窘迫综合征、慢性阻塞性肺病、肾小球肾炎、类风湿性关节炎、系统性红斑狼疮、硬皮病、慢性甲状腺炎、格雷夫斯病、自身免疫性胃炎、糖尿病、自身免疫性溶血性贫血、自身免疫性中性粒细胞减少症、血小板减少症、特应性皮炎、慢性活动性肝炎、重症肌无力、多发性硬化、炎性肠病、溃疡性结肠炎、克罗恩病、银屑病、移植物抗宿主病、内毒素诱导的炎症反应、肺结核、动脉粥样硬化、肌肉退化、恶病质、银屑病关节炎、莱特尔氏综合征(Reiter’s syndrome)、痛风、创伤性关节炎、风疹性关节炎、急性滑膜炎、胰腺β细胞病;以大量嗜中性粒细胞浸润为特征的疾病;类风湿性脊椎炎、痛风性关节炎和其它关节炎病症、脑型疟疾、慢性肺部炎性疾病、矽肺病、肺结节病、骨吸收疾病、同种异体移植排斥、感染引起的发热和肌痛、继发于感染的恶病质、瘢痕疙瘩形成、瘢痕组织形成、溃疡性结肠炎、热病(pyresis)、流感、骨质疏松症、骨关节炎、急性骨髓性白血病、慢性骨髓性白血病、转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤、败血症、败血性休克和志贺氏菌病;阿尔茨海默病、帕金森病、创伤性损伤引起的脑缺血或神经变性疾病;血管生成障碍,包括实体瘤、眼部新生血管和婴儿血管瘤;病毒性疾病,包括急性肝炎感染(包括甲型肝炎、乙型肝炎和丙型肝炎)、HIV感染和CMV视网膜炎、AIDS、ARC或恶性肿瘤和疱疹;中风、心肌缺血、中风心脏病发作中的局部缺血、器官缺氧、血管增生、心脏和肾脏再灌注损伤、血栓形成、心脏肥大、凝血酶诱导的血小板聚集、内毒素血症和/或中毒性休克综合征、与前列腺素内过氧化酶合酶-2相关的病症、以及寻常型天疱疮。该实施方案中包括其中病症选自包括狼疮肾炎和系统性红斑狼疮(SLE)在内的狼疮、克罗恩病、溃疡性结肠炎、同种异体移植物排斥、类风湿性关节炎、牛皮癣、强直性脊柱炎、牛皮癣性关节炎和寻常型天疱疮的治疗方法。还包括其中病症选自缺血再灌注损伤的治疗方法,该缺血再灌注损伤包括由中风引起的脑缺血再灌注损伤和由心肌梗塞引起的心肌缺血再灌注损伤。另一种治疗方法是其中病症是多发性骨髓瘤的方法。
在一个实施方案中,式(I)化合物可用于治疗癌症,包括瓦尔登斯特伦氏巨球蛋白血症(Waldenstrom’s Macroglobulinemia,WM)、弥漫性大B细胞淋巴瘤(DLBCL)、慢性淋巴细胞白血病(CLL)、皮肤弥漫性大B细胞淋巴瘤、和原发性CNS淋巴瘤。
此外,本发明的TLR7、TLR8或TLR9抑制剂会抑制诱导型促炎蛋白的表达,该诱导型促炎蛋白诸如前列腺素内过氧化物合酶-2(PGHS-2),也称为环氧合酶-2(COX-2)、IL-1、IL-6、IL-18、趋化因子。因此,另外的TLR7/8/9相关的病症包括水肿、痛觉缺失、发热和疼痛(诸如神经肌肉疼痛、头痛、由癌症引起的疼痛、牙痛和关节炎疼痛)。本发明化合物还可用于治疗兽医病毒感染,诸如慢病毒感染,包括但不限于马传染性贫血病毒;或逆转录病毒感染,包括猫免疫缺陷病毒、牛免疫缺陷病毒、和犬免疫缺陷病毒。
因此,本发明提供了用于治疗此类病症的方法,包括向对其有需要的受试者给予治疗有效量的至少一种式(I)化合物或其盐。“治疗有效量”旨在包括当单独或组合给药时有效抑制自身免疫性疾病或慢性炎性疾病的本发明化合物的量。
治疗TLR7、TLR8或TLR9相关的病症的方法可以包括单独或与彼此和/或用于治疗此类病症的其它合适治疗剂组合地给予式(I)化合物。因此,“治疗有效量”还旨在包括有效抑制TLR7、TLR8或TLR9和/或治疗与TLR7、TLR8或TLR9相关的疾病的所要求保护的化合物的组合的量。
此类其它治疗剂的例子包括皮质类固醇、咯利普兰、卡弗他丁(calphostin)、细胞因子抑制性抗炎药(CSAID)、白细胞介素-10、糖皮质激素、水杨酸盐、一氧化氮和其它免疫抑制剂;核易位抑制剂诸如脱氧精胍菌素(DSG);非甾体抗炎药(NSAID),诸如布洛芬、塞来昔布和罗非昔布;类固醇诸如泼尼松或地塞米松;抗病毒药剂诸如阿巴卡韦;抗增殖剂,诸如甲氨蝶呤、来氟米特、FK506(他克莫司,);抗疟药诸如羟氯喹;细胞毒性药物,诸如硫唑嘌呤(azathiprine)和环磷酰胺;TNF-α抑制剂,诸如替尼达普、抗TNF抗体或可溶性TNF受体和雷帕霉素(西罗莫司或/>),或其衍生物。
当与本发明化合物组合采用时,可(例如)以Physicians'Desk Reference(PDR)中所指示或如由本领域普通技术人员原本确定的那些量使用以上其他治疗剂。在本发明的方法中,可在给药本发明化合物之前、同时或之后给药一或多种此类其他治疗剂。本发明还提供能治疗TLR7/8/9受体相关病状(包括如上所述的IL-1家族受体介导的疾病)的药物组合物。
本发明组合物可含有如上所述的其他治疗剂且可(例如)根据诸如药物制剂领域中熟知的那些的技术,通过采用常规固体或液体媒介物或稀释剂以及一种适于期望给药模式的药物添加剂(例如,赋形剂、粘合剂、防腐剂、稳定剂、调味剂等)来调配。
因此,本发明进一步包括组合物,其包含一或多种式(I)化合物和药学上可接受的载体。
“药学上可接受的载体”是指在向给动物(具体而言,哺乳动物)递送生物活性剂的领域中一般公认的介质。根据完全在本领域普通技术人员的范围内的许多因素调配药学上可接受的载体。这些包括(但不限于)在调配的活性剂的类型和性质、待给药含有药剂的组合物的受试者、组合物的预期给药途径和所靶向的治疗适应症。药学上可接受的载体包括水性和非水性液体介质,以及各种固体和半固体剂型。此类载体可包括除了活性剂外的许多不同成分并添加剂,出于本领域普通技术人员熟知的各种原因(例如,活性剂、粘合剂等的稳定),此类额外成分包含于制剂中。适宜药学上可接受的载体的描述和涉及其选择的因素见于各种易得资源,诸如例如,Remington's Pharmaceutical Sciences,第17版(1985),其全文以引用的方式并入本文中。
可通过适用于所治疗病状的任何方式给药式(I)化合物,其可取决于位点-特异性治疗的需要或待递送的式(I)化合物的量。
本发明还包括一类药物组合物,其包含式(I)化合物和一或多种无毒、药学上可接受的载体和/或稀释剂和/或佐剂(本文中统称作“载体”物质)及(若需要)其他活性成分。式(I)化合物可通过任何适宜途径,优选地呈适于此途径的药物组合物的形式且以有效用于预期治疗的剂量给药。本发明化合物和组合物可(例如)呈含有常规药学上可接受的载体、佐剂和媒介物的单位剂量制剂口服、经粘膜或肠胃外(包括血管内、静脉内、腹膜内、皮下、肌肉内和胸骨内)给药。例如,药物载体可含有甘露醇或乳糖和微晶纤维素的混合物。该混合物可含有额外组分,诸如润滑剂(例如,硬脂酸镁)和崩解剂(诸如交联聚乙烯吡咯烷酮)。可将载体混合物填充至明胶胶囊中或压制成片剂。例如,药物组合物可呈口服剂型或输注给药。
针对口服给药,药物组合物可呈(例如)片剂、胶囊、液体胶囊、悬浮液或液体的形式。药物组合物优选地呈含有特定量的活性成分的单位剂型制备。例如,药物组合物可呈包含以下范围的活性成分的量的片剂或胶囊提供:约0.1至1000mg,优选地约0.25至250mg,和更优选地约0.5至100mg。针对人类或其他哺乳动物的适宜每日剂量可取决于患者的病状及其他因素广泛变化,但是可使用常规方法确定。
本文中涵盖的任何药物组合物可(例如)经由任何可接受且适宜口服制剂口服递送。示例性口服制剂包括(但不限于)例如,片剂、糖锭、锭剂、水性和油性悬浮液、可分散粉末或颗粒、乳液、硬和软胶囊、液体胶囊、糖浆和酏剂。意欲用于口服给药的药物组合物可根据制造意欲用于口服给药的药物组合物的技术中已知的任何方法制备。为提供药学上适口的制剂,本发明的药物组合物可含有选自甜味剂、调味剂、着色剂、缓和剂、抗氧化剂和防腐剂的至少一种试剂。
片剂可(例如)通过至少一种式(I)化合物与适用于制造片剂的至少一种无毒药学上可接受的赋形剂混合制备。示例性赋形剂包括(但不限于)例如,惰性稀释剂,诸如,例如,碳酸钙、碳酸钠、乳糖、磷酸钙和磷酸钠;造粒剂和崩解剂,诸如,例如,微晶纤维素、交联羧甲基纤维素钠、玉米淀粉和藻酸;粘合剂,诸如,例如,淀粉、明胶、聚乙烯吡咯烷酮和阿拉伯胶;和润滑剂,诸如,例如,硬脂酸镁、硬脂酸和滑石。此外,片剂可未经包衣或通过已知技术包衣以掩盖不愉快尝药的坏的味道,或延迟胃肠道中的活性成分的崩解和吸收从而使活性成分的效果持续更长时间。示例性水溶性味觉掩盖物质包括(但不限于)羟丙基甲基纤维素和羟丙基纤维素。示例性时间延迟物质包括(但不限于)乙基纤维素和乙酸丁酸纤维素。
硬明胶胶囊可(例如)通过至少一种式(I)化合物与至少一种惰性固体稀释剂(诸如,例如,碳酸钙、磷酸钙和高岭土)混合制备。
软明胶胶囊可(例如)通过至少一种式(I)化合物与至少一种水溶性载体(诸如,例如,聚乙二醇)和至少一种油介质(诸如,例如,花生油、液体石蜡和橄榄油)混合制备。
水性悬浮液可(例如)通过至少一种式(I)化合物与至少一种适用于制造水性悬浮液的赋形剂混合制备。适用于制造水性悬浮液的示例性赋形剂包括(但不限于)例如,悬浮剂,诸如,例如,羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、藻酸、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯胶;分散剂或润湿剂,诸如,例如,天然磷脂,例如,卵磷脂;烯化氧与脂肪酸的缩合产物,诸如,例如,聚氧乙烯硬脂酸酯;环氧乙烷与长链脂族醇的缩合产物,诸如,例如,十七烯-氧鲸蜡醇;环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物,诸如,例如,聚氧乙烯山梨醇单酸油酸酯;和环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物,诸如,例如,聚乙烯山梨醇酐单酸油酸酯。水性悬浮液还可含有至少一种防腐剂,诸如,例如,对羟基苯甲酸乙酯和对羟基苯甲酸正丙酯;至少一种着色剂;至少一种调味剂;和/或至少一种甜味剂,包括(但不限于)例如,蔗糖、糖精和阿斯巴甜(aspartame)。
油性悬浮液可(例如)通过将至少一种式(I)化合物悬浮于植物油(诸如,例如,花生油、橄榄油、芝麻油和椰子油)或矿物油(诸如,例如,液体石蜡)中制备。油性悬浮液还可含有至少一种增稠剂,诸如,例如,蜂蜡、硬石蜡和鲸蜡醇。为提供适口的油性悬浮液,可将至少一种上文中已述甜味剂和/或至少一种调味剂添加至油性悬浮液中。油性悬浮液可进一步含有至少一种防腐剂,包括(但不限于)例如,抗氧化物,诸如,例如,丁基化羟基苯甲醚和α-生育酚。
可分散粉末和颗粒可(例如)通过至少一种式(I)化合物与至少一种分散剂和/或润湿剂、至少一种悬浮剂、和/或至少一种防腐剂混合制备。适宜分散剂、润湿剂和悬浮剂系如上已述。示例性防腐剂包括(但不限于)例如,抗氧化剂,例如,抗坏血酸。此外,可分散粉末和颗粒还可含有至少一种赋形剂,包括(但不限于)例如,甜味剂、调味剂和着色剂。
其至少一种式(I)化合物的乳液可(例如)呈水包油乳液制备。包含式(I)化合物的乳液的油性相可由已知成分以已知方式构成。可通过但不限于以下提供油相:例如,植物油,诸如,例如,橄榄油和花生油;矿物油,诸如,例如,液体石蜡;及其混合物。虽然该相可仅包含乳化剂,但是其可包含至少一种乳化剂与脂肪或油或与脂肪和油二者的混合物。适宜乳化剂包括(但不限于)例如,天然磷脂,例如,大豆卵磷脂;衍生自脂肪酸和己糖醇酐的酯或偏酯,诸如,例如,山梨醇酐单酸油酸酯;和偏酯与环氧乙烷的缩合产物,诸如,例如,聚氧乙烯山梨醇酐单酸油酸酯。优选地,包含亲水性乳化剂连同充当稳定剂的亲脂性乳化剂。还优选地包含油和脂肪二者。同时,含有或不含稳定剂的乳化剂组成所谓乳化蜡,及该蜡与油和脂肪一起组成所谓乳化软膏基,其形成乳膏制剂的油性分散相。乳液还可含有甜味剂、调味剂、防腐剂和/或抗氧化剂。适用于本发明制剂中的乳化剂和乳液稳定剂包括Tween60、Span 80、鲸蜡硬脂醇、肉豆蔻醇、单硬脂酸甘油酯、十二烷基硫酸钠、二硬脂酸甘油酯(单独或与蜡)、或本领域中熟知的其他物质。
式(I)化合物还可(例如)经静脉内、皮下和/或肌肉内经由任何药学上可接受且适宜可注射形式递送。示例性可注射形式包括(但不限于)例如,包含可接受媒介物和溶剂(诸如,例如,水、林格溶液和等渗氯化钠溶液)的无菌水溶液;无菌水包油微乳液;和水性或油性悬浮液。
用于肠胃外给药的制剂可呈水性或非水性等渗无菌注射溶液或悬浮液的形式。这些溶液和悬浮液可自无菌粉末或颗粒使用一或多种用于口服给药的制剂所提及的载体或稀释剂或通过使用其他适宜分散或润湿剂和悬浮剂制备。所述化合物可溶解于水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苄醇、氯化钠溶液、黄蓍胶和/或各种缓冲剂。其他佐剂和给药模式是药学领域中广为人知的。活性成分还可呈含有适宜载体(包括盐水、右旋糖或水)、或含有环糊精(即,Captisol)、助溶剂增溶(即,丙二醇)或胶束增溶(即,Tween 80)的组合物通过注射给药。
无菌可注射制剂还可为含于无毒肠胃外可接受稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如,呈含于1,3-丁二醇中的溶液。可采用的可接受媒介物和溶剂为水、林格溶液和等渗氯化钠溶液。此外,常规采用无菌固定油作为溶剂或悬浮介质。出于此目的,可采用任何温和固定油,包括合成单酸甘油酯或二酸甘油酯。此外,发现脂肪酸(诸如油酸)用于制备可注射剂。
无菌可注射水包油微乳液可(例如)通过以下制备:1)将至少一种式(I)化合物溶解于油性相(诸如,例如,大豆油和卵磷脂的混合物)中;2)将含有油相的式(I)与水和甘油混合物组合;和3)处理该组合以形成微乳液。
无菌水性或油性悬浮液可根据本领域中已知方法制备。例如,无菌水性溶液或悬浮液可利用无毒肠胃外可接受稀释剂或溶剂(诸如,例如,1,3-丁二醇)制备;和无菌油性悬浮液可利用无菌无毒可接受溶剂或悬浮介质(诸如,例如,无菌固定油,例如,合成单酸甘油酯或二酸甘油酯;和脂肪酸,诸如,例如,油酸)制备。
可用于本发明药物组合物中的药学上可接受的载体、佐剂和媒介物包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、自乳化药物递送系统(SEDDS)(诸如d-α-生育酚聚乙二醇1000琥珀酸酯)、呈药物剂型使用的表面活性剂(诸如Tween、聚乙氧基化蓖麻油(诸如CREMOPHOR表面活性剂(BASF)或其他类似聚合递送基质)、血清蛋白(诸如人类血清白蛋白)、缓冲物质(诸如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(诸如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐))、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素基物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇和羊毛脂。还可有利地使用环糊精(诸如,α-、β-和γ-环糊精,或化学修饰衍生物(诸如羟基烷基环糊精,包括2-和3-羟丙基环糊精),或其他可溶性衍生物)以增强本文中所述式的化合物的递送。
本发明的药学活性化合物可根据常规药学方法处理以产生对患者(包括人类和其他哺乳动物)给药的药剂。药物组合物可接受常规药学操作(诸如杀菌)和/或可含有常规佐剂(诸如防腐剂、稳定剂、润湿剂、乳化剂、缓冲剂等)。此外,可利用肠包衣制备片剂和丸剂。此类组合物还可包含佐剂,诸如润湿剂、甜味剂、调味剂和芳香剂。
给药化合物的量和利用本发明化合物和/或组合物治疗疾病状的剂量方案取决于各种因素,包括受试者的年龄、体重、性别、医疗状况、疾病类型、疾病的严重度、给药途径和频率及采用的特定化合物。因此,剂量方案可广泛变化,但是可使用标准方法常规确定。可适用约0.001至100mg/kg体重,优选地约0.0025至约50mg/kg体重且最优选地约0.005至10mg/kg体重的每日剂量。每日剂量可以1至4个剂量/天给药。其他给药方案包括1个剂量/周和一个剂量/两天循环。
出于治疗目的,本发明的活性化合物通常与适于指示给药途径的一或多种佐剂组合。若口服给药,则化合物可与以下混合:乳糖、蔗糖、淀粉粉末、烷酸的纤维素酯、纤维素烷基酯、滑石、硬脂酸、硬脂酸镁、氧化镁、磷酸和硫酸的钠盐和钙盐、明胶、阿拉伯胶、藻酸钠、聚乙烯吡咯烷酮和/或聚乙烯醇,然后制成片剂或胶囊用于方便给药。此类胶囊或片剂可含有如可以在活性化合物于羟丙基甲基纤维素中的分散剂提供的可控释放制剂。
本发明的药物组合物包含至少一种式(I)化合物和任选的选自任何药学上可接受的载体、佐剂和媒介物的额外试剂。本发明的替代组合物包含本文中所述式(I)化合物或其前药和药学上可接受的载体、佐剂或媒介物。
本发明还涵盖一种制品。如本文中所用,制品意欲包括(但不限于)试剂盒和包装。本发明的制品包含:(a)第一容器;(b)位于第一容器内的药物组合物,其中该组合物包含:第一治疗剂,包含:本发明化合物或其药学上可接受的盐形式;和(c)指明药物组合物可用于治疗炎性病症和/或自身免疫性疾病(如先前所定义)的包装插页。在另一个实施方案中,包装插页指明药物组合物可用于与第二治疗剂的组合(如先前所定义)中以治疗炎性病症和/或自身免疫性疾病。制品可进一步包含:(d)第二容器,其中组分(a)和(b)位于第二容器内且组分(c)位于第二容器内或外面。位于第一和第二容器内意指各自容器将物品保持在其边界内。
第一容器为用于保持药物组合物的容器。该容器可用于制造、储存、运送和/或零售/批发。第一容器意欲涵盖瓶、罐、小瓶、烧瓶、注射器、管(例如,用于乳膏制备)或用于制造、保持、储存或分配药物产品的任何其他容器。
第二容器为用于保持第一容器和任选的包装插页的容器。第二容器的实例包括(但不限于)盒(例如,纸板箱或塑料)、板条箱、纸盒、袋(例如,纸或塑料袋)、小袋和麻袋。包装插页可经由胶带、胶水、订书钉或另一种连接方法物理连接至第一容器的外面,或其可停留在第二容器内部而没有与第一容器的任何物理连接方式。或者,包装插页位于第二容器的外面。当位于第二容器的外面时,优选包装插页经由胶带、胶水、订书钉或另一种连接方法物理连接。或者,其可邻近或接触第二容器的外面而未经物理连接。
包装插页为详述与位于第一容器内的药物组合物相关的信息的标签(label)、标记(tag)、标志物等。详述的信息通常将由管理待售制品的区域的管理机构(例如,美国食品和药物管理局)确定。在一个实施方案中,包装插页具体而言详述已批准药物组合物的适应症。包装插页可由任何材料制得,在该材料上人们可阅读其中或其上含有的信息。例如,包装插页为可印刷材料(例如,纸、塑料、纸板、箔、胶背纸或塑料等),在其上已形成所需信息(例如,印刷或施覆)。
制备方法
本发明的化合物可以通过有机合成领域的技术人员熟知的多种方式制备。本发明的化合物可以使用下面所描述的方法,连同合成有机化学领域中已知的合成方法或如本领域技术人员所理解的其变化来合成。优选的方法包括但不限于以下所描述的那些。将本申请列举的所有参考文献通过援引方式以其全文并入本申请。
可以使用本部分中所描述的反应和技术来制备本发明的化合物。这些反应在适合于所用试剂和材料的溶剂中进行,并且适用于所进行的转化。此外,在以下描述的合成方法的描述中,应当理解,所有提出的反应条件,包括溶剂的选择、反应气氛、反应温度、实验的持续时间和后处理程序,被选择为对于所述反应为标准的条件,本领域技术人员应该容易认识到这一点。有机合成领域的技术人员应理解,分子各部分上存在的官能团必须与所提出的试剂和反应相容。对于与这些反应条件相容的取代基的此类限制将对于本领域技术人员而言是显而易见的,并且于是必须使用替代方法。这将有时需要做出判断来修改合成步骤的顺序或选择一种特定的工艺方案而不是另一种,以便获得所希望的本发明化合物。还将认识到,在该领域的任何合成途径的规划中的另一个主要考虑因素是明智地选择用于保护本发明中所述化合物中存在的反应性官能团的保护基团。描述受过培训的从业者的许多替代方案的权威解释是Greene和Wuts的(Protective Groups In Organic Synthesis,第三版,Wiley and Sons,1999)。
实施例
以下实施例说明了本发明的特定和优选实施方案,并不限制本发明的范围。除非另有说明,否则化学缩写和符号以及科学缩写和符号具有其通常和惯常的含义。上面定义了实施例和本申请中其它地方使用的其它缩写。常见的中间体通常可用于制备一种以上的实施例,进行顺序确定(例如,中间体1、中间体2等),并且缩写为Int.1或I1、Int.2或I2等。实施例的化合物通过如下确定:实施例及其制备步骤(例如“1-A”表示实施例1、步骤A)或其中仅化合物为实施例的标题化合物的实施例(例如,“1”表示实施例1的标题化合物)。在一些情况下,描述了中间体或实施例的替代制备。基于一种或多种考虑因素,合成领域的技术人员通常可以设计出可期望的替代制备,所述考虑因素例如较短的反应时间、较便宜的起始原料、易于操作或分离、提高的收率、适于催化、避免有毒试剂、专用仪器的可获得性以及线性步骤数目的减少等。描述替代制备的目的是进一步使得能够制备本发明的实施例。在一些情况下,概述的实施例和权利要求书中的一些官能团可以用本领域已知的众所周知的生物电子等排取代替代,例如,用四唑或磷酸酯部分替代羧酸基团。
缩写
Ac 乙酰基
ACN 乙腈
AcOH 乙酸
anhyd. 无水
aq. 水性的
Bn 苄基
Bu 丁基
Boc 叔丁氧基羰基
CV 柱体积
DCE 二氯乙烷
DCM 二氯甲烷
DMAP 二甲基氨基吡啶
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
EDC 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐
EtOAc 乙酸乙酯
Et 乙基
EtOH 乙醇
H或H2 氢
h、hr或hrs 小时
HCTU O-(6-氯苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐
hex 己烷
i 异
IPA 异丙醇
HOAc 乙酸
HCl 盐酸
HPLC 高压液相色谱法
LC 液相色谱法
M 摩尔浓度
mM 毫摩尔浓度
Me 甲基
MeOH 甲醇
MHz 兆赫
min. 分钟
mins 分钟
M+1 (M+H)+
MS 质谱法
n或N 正
NBS 正溴琥珀酰亚胺
nm 纳米
nM 纳摩尔浓度
NMP N-甲基吡咯烷
Pd/C 钯碳
PdCl2(dppf)2 [1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)
Pd(PPh3)4 四(三苯基膦)钯
Ph 苯基
PPh3 三苯基膦
Pr 丙基
PSI 磅/平方英寸
PyBOP 三吡咯烷基溴化鏻六氟磷酸盐(bromotripyrrolidinophosphoniumhexafluorophosphate)
Ret Time 保留时间
sat. 饱和的
SFC 超临界流体色谱法
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
分析和制备型HPLC条件:
QC-ACN-AA-XB:柱:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm颗粒;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B下保持0.75分钟;流量:1.0mL/min;检测:在220nm下的UV。
QC-ACN-TFA-XB:柱:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm颗粒;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:经3分钟0-100%B,然后在100%B下保持0.75分钟;流量:1.0mL/min;检测:在220nm下的UV。
方法A1:L3 Acquity:柱:(LCMS)UPLC BEH C18,2.1x50mm,1.7μm颗粒;流动相:(A)水;(B)乙腈;缓冲液:0.05%TFA;梯度范围:2%-98%B(0至1min)98%B(至1.5min)98%-2%B(至1.6min);梯度时间:1.6min;流速:0.8mL/min;分析时间:2.2min;检测:检测器1:在220nm下的UV;检测器2:MS(ESI+)。
方法B1:L2 Acquity;柱:(LCMS)UPLC BEH C18,2.1x50mm,1.7μm颗粒;流动相:(A)水;(B)乙腈;缓冲液:0.05%TFA;梯度范围:2%-98%B(0至1min),98%-2%B(至1.5min);梯度时间:1.8min;流速:0.8mL/min;分析时间:2.2min;检测:检测器1:在220nm下的UV;检测器2:MS(ESI+)。
方法C1 SCP:柱:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm颗粒;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水。温度:50℃;梯度:0-100%B(经3分钟),然后以100%B保持0.75分钟;流速:1.11mL/min;检测:在220nm下的UV。
方法D1 SCP:柱:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm颗粒;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:0-100%B(经3分钟),然后以100%B保持0.75分钟;流速:1.11mL/min;检测:在220nm下的UV。
方法D2 SCP:柱:XBridge C18,19x200mm,5-μm颗粒;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水;梯度:10-50%B(经20分钟),然后以100%B保持5分钟;流速:20mL/min。检测:在220nm下的UV。
方法D3 SCP:柱:XBridge C18,19x200mm,5-μm颗粒;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;梯度:6-46%B(经20分钟),然后以100%B保持4分钟;流速:20mL/min。检测:在220nm下的UV。
方法E1 iPAC:柱:Waters Xbridge C18 4.6x50mm 5um颗粒;流动相A:5:95乙腈:含10mM乙酸铵的水;流动相B:95:5乙腈:含10mM乙酸铵的水。温度:50℃;梯度:0-100%B(经1分钟);流速:4mL/min;检测:在220nm下的UV。
方法F1 iPAC:柱:Waters Acquity BEH C18 2.1x50 mm 1.7-μm颗粒;流动相A:5:95乙腈:含0.1%三氟乙酸的水;流动相B:95:5乙腈:含0.1%三氟乙酸的水;温度:50℃;梯度:0-100%B(经2.20分钟);流速:0.800mL/min;检测:在220nm下的UV。
(A)柱-Ascentis Express C18(50x2.1mm-2.7μm)流动相A:在水中的10mMNH4COOH:ACN(98:02);流动相B:在水中的10mM NH4COOH:ACN(02:98),梯度:经3分钟0-100%B,流量=1mL/min。
(B)Waters Acquity BEH C18(2.1x50mm)1.7微米;缓冲剂:经HCOOH调节至pH 5的5mM乙酸铵,溶剂A:缓冲剂:ACN(95:5),溶剂B:缓冲剂:ACN(5:95),方法:%B:0min-5%:1.1min-95%:1.7min-95%,流量:0.8mL/min。
(C)柱-Ascentis Express C18(50x2.1mm-2.7μm)流动相A:在水中的0.1%HCOOH流动相B:ACN。温度:50℃;梯度:经3分钟0-100%B;流速:1.0mL/min。
(D)Kinetex XB-C18(75x3mm)2.6微米;溶剂A:在水中的10mM甲酸铵:乙腈(98:02);流动相B:在水中的10mM甲酸铵:乙腈(02:98);温度:50℃;梯度:经3分钟0-100%B;流速:1.1mL/min;检测:在220nm下的UV。
(E)柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:含10mMNH4OAc的水;流动相B:95:5乙腈:含10mM NH4OAc的水;温度:50℃;梯度:经3分钟0-100%B;流量:1.1ml/min。
(F)柱:Ascentis Express C18(50x2.1)mm,2.7μm;流动相A:5:95乙腈:含0.1%TFA的水;流动相B:95:5乙腈:含0.1%TFA的水;温度:50℃;梯度:经3分钟0-100%B;流量:1.1mL/min。
(G)柱:Waters Acquity UPLC BEH C18(2.1x50mm),1.7微米;溶剂A=含0.05%TFA的100%水;溶剂B=含0.05%TFA的100%乙腈;梯度=经1分钟2%-98%B,然后在98%B下保持0.5分钟;流速:0.8mL/min;检测:在220nm下的UV。
(H)柱:Acentis Express C18(50x2.1mm)1.7μm,Acentis C8 NH4COOH5min。流动相A:10mM甲酸铵:ACN(98:2),流动相B:10mM甲酸铵:ACN(2:98),梯度:20%-100%B(0-4min);100%B(4-4.6min);流量:1mL/min。
(I)柱:Sunfire C18(4.6x150)mm,3.5μm;流动相A:5:95乙腈:含0.05%TFA的水;流动相B:95:5乙腈:含0.05%TFA的水;温度:50℃;梯度:10-100%B,经12分钟;流量:1mL/min。
(J)柱:Sunfire C18(4.6x150)mm,3.5μm;流动相A:5:95乙腈:水与0.05%TFA;流动相B:95:5乙腈:水与0.05%TFA。
(K)Waters Acquity SDS流动相:A:水,B:ACN;5%-95%B,在1min内;梯度范围:50%-98%B(0-0.5min);98%B(0.5min-1min);98%-2%B(1-1.1min);运行时间:1.2min;流率:0.7mL/min;分析时间:1.7min;检测:检测器1:UV,在220nm;检测器2:MS(ES+)。
(L)Acquity UPLC BEH C18(3.0x50mm)1.7μm。缓冲液:5mM乙酸铵;流动相A:缓冲液:ACN(95:5);流动相B:缓冲液:ACN(5:95)方法:%B:0min-20%:1.1min-90%:1.7min-90%。运行时间:2.25min;流率:0.7mL/min;检测:检测器1:UV,在220nm;检测器2:MS(ES+)。
(M)Kinetex SBC18(4.6x50mm)5微米;溶剂A:10mM甲酸铵,在水:乙腈(98:02)中;流动相B:10mM甲酸铵,在水:乙腈(02:98)中;温度:50℃;梯度:30-100%B(0-4min),100%B(4-4.6min),100-30%B(4.6-4.7min),30%B(4.7-5.0min);流率:1.5mL/min;检测:UV,在220nm。
(N)柱-Ascentis Express C18(50x2.1mm-2.7μm)流动相A:10mM NH4COOH在水中:ACN(98:02);流动相B:10mM NH4COOH在水中:ACN(02:98),梯度:0-100%B(0-1.7分钟);100%B(1.7-3.4分钟)。流量=1mL/min。
(O)Waters Acquity SDS柱BEH C18(2.1x50mm)1.7μm。相A:在水中的缓冲液;流动相B:在ACN中的缓冲液,梯度:20-98%B(0-1.25分钟);98%B(1.25-1.70分钟);98%-2%B(1.70-1.75分钟);流量=0.8mL/min。
实施例1
2-(3,4-二甲氧基苯基)-5-[3-(哌嗪-1-羰基)苯基]-3-(丙烷-2-基)-1H-吲哚
中间体1A:3-(3-异丙基-1H-吲哚-5-基)苯甲酸乙酯
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将5-溴-3-异丙基-1H-吲哚(1.00g,4.20mmol)、(3-(乙氧基羰基)苯基)硼酸(0.978g,5.04mmol)和磷酸三钾(2.67g,12.60mmol)在THF(20mL)和水(4mL)中的混合物用氮气脱气10min。接着,加入PdCl2(dppf)-CH2Cl2加合物(0.086g,0.105mmol),在75℃搅拌混合物16h。将反应混合物用EtOAc(50mL)稀释,用水(30mL)、盐水(10mL)洗涤,干燥(Na2SO4),浓缩,得到粗制物质。粗制物质通过使用24g硅胶柱的硅胶色谱(ISCO)纯化,将化合物用10%在己烷中的EtOAc洗脱,收集级分,浓缩,得到3-(3-异丙基-1H-吲哚-5-基)苯甲酸乙酯(1.021g,3.32mmol,79%收率),其为浅黄色固体。LCMS保留时间1.21min[B]。MS m/z:308(M+H)。
中间体1B:3-(2-溴-3-异丙基-1H-吲哚-5-基)苯甲酸乙酯
在室温向3-(3-异丙基-1H-吲哚-5-基)苯甲酸乙酯(0.880g,2.86mmol)在DCE(16mL)中的溶液中加入NBS(0.510g,2.86mmol)。在相同温度搅拌混合物30min。反应用水(10mL)淬灭。反应混合物用DCM(2x30mL)萃取,用盐水(5ml)洗涤,干燥(Na2SO4),浓缩,得到粗制化合物。粗制物质通过使用24g硅胶柱的硅胶色谱(ISCO)纯化,将化合物用10%在己烷中的EtOAc洗脱,收集级分,浓缩,得到3-(2-溴-3-异丙基-1H-吲哚-5-基)苯甲酸乙酯(1.08g,2.80mmol,88%收率),其为橙色固体。LCMS保留时间1.24min[B]。MS m/z:388(M+2H)。
中间体1C:3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯甲酸乙酯
将3-(2-溴-3-异丙基-1H-吲哚-5-基)苯甲酸乙酯(0.640g,1.657mmol)、(3,4-二甲氧基苯基)硼酸(0.633g,3.48mmol)和碳酸铯(1.619g,4.97mmol)在二噁烷(12.00mL)和水(3.00mL)中的溶液脱气30min。接着,加入Pd(Ph3P)4(0.191g,0.166mmol)。在90℃将反应混合物搅拌16h。将反应用水(5ml)淬灭。反应混合物用EtOAc(2X30ml)萃取,合并的有机萃取物用盐水(5ml)洗涤,干燥(Na2SO4),浓缩,得到粗制物质。粗制物质通过使用24g硅胶柱的硅胶色谱(ISCO)纯化,化合物用30%在己烷中的EtOAc洗脱,收集级分,浓缩,得到3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯甲酸乙酯(0.615g,1.387mmol,84%收率),其为灰白色固体。LCMS保留时间1.23min[B]。MS m/z:444.4(M+H)。
中间体1D:3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯甲酸
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在室温向3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯甲酸乙酯(0.600g,1.353mmol)在THF(8.00mL)、MeOH(4.00mL)和水(2.000mL)溶剂混合物中的溶液中加入氢氧化锂(0.162g,6.76mmol)。在相同温度将反应混合物搅拌3h。将反应物质浓缩,残留物溶解在水(5mL)中,用1.5N HCl酸化。将固体过滤,在真空下干燥,得到粗制化合物。粗制化合物通过使用12g硅胶柱的硅胶色谱(ISCO)纯化,化合物用50%在己烷中的EtOAc洗脱,收集级分,浓缩,得到3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯甲酸(0.410g,0.987mmol,72.9%收率),其为灰白色固体。LCMS保留时间1.01min[B]。MS m/z:416.2(M+H)。
中间体1E:4-(3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯甲酰基)哌嗪-1-甲酸叔丁酯
在室温向3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯甲酸(0.073g,0.176mmol)在DCM(1.00mL)和DMF(1.00mL)中的溶液中分别加入1-boc-哌嗪(0.039g,0.211mmol)和EDC(0.051g,0.264mmol)。在相同温度搅拌混合物3h。加入水(5mL)以淬灭反应。混合物用10%在CH2Cl2(2x10mL)中的MeOH萃取。合并的有机萃取物用水(10mL)、盐水(5mL)洗涤,干燥(Na2SO4),浓缩,得到粗制的4-(3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯甲酰基)哌嗪-1-甲酸叔丁酯(0.106g,0.153mmol,87%收率)。LCMS保留时间1.14min[B]。MS m/z:528(M+H-tBu)。
实施例1:
在室温将在二噁烷(2.00mL)中的4-(3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯甲酰基)哌嗪-1-甲酸叔丁酯(0.099g,0.17mmol)加入至4M的在二噁烷(0.085mL,0.340mmol)中的盐酸中。在相同温度将反应混合物搅拌4h。浓缩反应混合物,得到粗制化合物。粗制化合物通过制备型LCMS使用方法D2来纯化,合并包含所需产物的级分,使用Genevac离心蒸发仪干燥,得到(3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)(哌嗪-1-基)甲酮(0.0181g,0.034mmol,20%收率),其为浅黄色固体。LCMS保留时间1.52min[E]。MS m/z:484.2(M+H-tBu)。1H NMR(400MHz,DMSO-d6)δppm 11.08(s,1H),7.91(s,1H),7.75(d,J=8.4Hz,1H),7.61(s,1H),7.51(d,J=7.2Hz,1H),7.45-7.36(m,2H),7.32-7.27(m,1H),7.13-7.04(m,3H),3.85(s,3H),3.84(s,3H),3.35-3.33(m,4H),2.81-2.63(m,4H),1.48(s,3H),1.46(s,3H)。
实施例2
2-(3,4-二甲氧基苯基)-5-[5-(哌啶-4-基)-1,3,4-噁二唑-2-基]-3-(丙烷-2-基)-1H-吲哚
中间体2A:3-异丙基-1H-吲哚-5-甲酸甲酯
向5-溴-3-异丙基-1H-吲哚(4.00g,16.80mmol)在MeOH(80.00mL)和DMF(80.00mL)中的溶液中加入乙酸钯(II)(0.754g,1.119mmol)和DPPF(2.79g,5.04mmol)。反应混合物用氮气脱气5min,然后加入TEA(7.02mL,50.4mmol),将反应混合物在高压釜中在100℃、5kg压力在CO气体存在下搅拌16h。粗制的LCMS显示形成产物并且没有起始原料。将反应物质浓缩,然后残留物溶解在EtOAc(50mL)中,将固体过滤,用EtOAc(2X30mL)洗涤,收集合并的滤液,浓缩,得到粗制化合物。粗制化合物通过使用120g硅胶柱的硅胶色谱(ISCO)纯化,化合物用35%在己烷中的EA洗脱,收集级分,浓缩,得到3-异丙基-1H-吲哚-5-甲酸甲酯(3.42g,15.74mmol,94%收率),其为油状物。LCMS保留时间0.96min[G]。MS m/z:218.6[M+H]+。
中间体2B:2-溴-3-异丙基-1H-吲哚-5-甲酸甲酯
在室温向3-异丙基-1H-吲哚-5-甲酸甲酯(0.790g,2.69mmol)在DCE(20mL)中的溶液中加入NBS(0.479g,2.69mmol)。接着,在相同温度将反应混合物搅拌10min。粗制的LCMS显示形成产物并且没有起始原料。加入水(5mL)以淬灭反应。反应混合物用DCM(2X20mL)萃取,合并的有机萃取物用盐水(5mL)洗涤,干燥(Na2SO4),浓缩,得到粗制化合物。粗制化合物通过使用24g硅胶柱的硅胶色谱(ISCO)纯化,化合物用15%在己烷中的EtOAc洗脱,收集级分,浓缩,得到2-溴-3-异丙基-1H-吲哚-5-甲酸甲酯(0.582g,1.965mmol,73.0%收率),其为浅棕色固体。LCMS保留时间1.05min[G]。MS m/z:298[M+2H]+。
中间体2C:2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-甲酸甲酯
将2-溴-3-异丙基-1H-吲哚-5-甲酸甲酯(0.570g,1.925mmol)、(3,4-二甲氧基苯基)硼酸(0.736g,4.04mmol)和碳酸铯(1.881g,5.77mmol)在二噁烷(12.00mL)和水(3.00mL)中的溶液脱气30min。接着,加入Pd(Ph3P)4(0.222g,0.192mmol),在90℃将反应混合物搅拌4h。粗制的LCMS显示形成产物并且没有起始原料。反应用水(5mL)淬灭。反应混合物用EtOAc(2X30mL)萃取,合并的有机萃取物用盐水(10mL)洗涤,干燥(Na2SO4),,浓缩,得到粗制化合物。粗制化合物通过使用24g硅胶柱的硅胶色谱(ISCO)纯化,化合物在15%的在己烷中的EtOAc中洗脱,收集级分,浓缩,得到2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-甲酸甲酯(0.520g,1.471mmol,76%收率),其为淡橙色固体。LCMS保留时间1.13min[G]。MSm/z:354[M+H]+。
中间体2D:2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-碳酰肼
在室温向2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-甲酸甲酯(0.200g,0.566mmol)在EtOH(4.00mL)中的溶液中加入水合肼(0.553mL,11.32mmol)。在100℃将反应混合物搅拌24h。将反应混合物冷却至室温。将沉淀出的固体过滤,用己烷洗涤,得到2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-碳酰肼(0.190g,0.538mmol,95%收率),其为白色固体。LCMS保留时间0.73min[G]。MS m/z:354.6[M+H]+。
实施例2:
在90℃将在POCl3(3.00ml,32.2mmol)中的2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-碳酰肼(0.125g,0.354mmol)和1-(叔丁氧基羰基)哌啶-4-甲酸(0.105g,0.460mmol)的混合物搅拌4h。将反应物质浓缩。将浆料在乙醚(10mL)中搅拌,将所得沉淀的固体过滤,得到粗制的2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-4-基)-1,3,4-噁二唑(0.164g,0.283mmol,80%收率),其为粘性固体。将一部分粗制化合物通过制备型LCMS使用方法D2进一步纯化,合并包含产物的级分,使用Genevac离心蒸发仪干燥,得到2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-4-基)-1,3,4-噁二唑(3mg),其为浅黄色固体。LCMS保留时间1.238min[G]。MS m/z:354.6[M+H]+;1H NMR(400MHz,DMSO-d6)δppm 11.46(s,1H),8.30(s,1H),7.71(dd,J=8.4,1.6Hz,1H),7.51(d,J=8.4Hz,1H),7.14-7.06(m,3H),3.85(s,3H),3.83(s,3H),3.46-3.21(m,5H),2.96-2.89(m,2H),2.22-2.14(m,2H),1.93-1.87(m,2H),1.45(d,J=6.8Hz,6H)。
实施例3
1-(4-{5-[2-(3,4-二甲氧基苯基)-3-(丙烷-2-基)-1H-吲哚-5-基]-1,3,4-噁二唑-2-基}哌啶-1-基)-2-(二甲基氨基)乙烷-1-酮
在室温向2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-4-基)-1,3,4-噁二唑盐酸盐(0.050g,0.104mmol)和2-(二甲基氨基)乙酸(0.021g,0.207mmol)在DMF(2.00mL)中的溶液中加入TEA(0.144mL,1.035mmol)。将反应混合物搅拌5min,然后加入HATU(0.039g,0.104mmol)。持续搅拌过夜。反应用水淬灭。反应混合物用10%的在DCM中MeOH(2X10mL)萃取,合并的有机萃取物用盐水(5mL)洗涤,干燥(Na2SO4),浓缩,得到粗制化合物。粗制化合物通过制备型LCMS使用方法D2来纯化,合并包含所需产物的级分,使用Genevac离心蒸发仪干燥,得到1-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-2-(二甲基氨基)乙酮(0.008g,0.014mmol,14%收率),其为浅黄色固体。LCMS保留时间1.427min[E]。MS m/z:532.4[M+H]+;1H NMR(400MHz,DMSO-d6)δppm11.44(s,1H),8.30(s,1H),7.71(dd,J=8.4Hz,1.6Hz,1H),7.50(d,J=8.8Hz,1H),7.13-7.07(m,3H),4.35-4.28(m,1H),4.07-4.01(m,1H),3.85(s,3H),3.83(s,3H),3.42-3.33(m,5H),2.95-2.89(m,1H),2.33(s 6H),2.16-2.12(m,2H),1.88-1.78(m,1H),1.71-1.62(m,1H),1.45(d,J=6.8Hz,6H)。
实施例4
2-(3,4-二甲氧基苯基)-3-(丙烷-2-基)-5-{5-[1-(丙烷-2-基)哌啶-4-基]-1,3,4-噁二唑-2-基}-1H-吲哚
在0℃向2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-4-基)-1,3,4-噁二唑盐酸盐(0.030g,0.062mmol)在MeOH(3.00mL)中的溶液中加入丙酮(0.1ml,1.362mmol)和TEA(0.15mL,1.076mmol)。在室温将反应混合物搅拌2h。将反应混合物冷却至0℃,加入乙酸(0.20ml,3.49mmol)。在室温将反应混合物搅拌3h。将反应混合物重新冷却至0℃,加入氰基硼氢化钠(0.020g,0.311mmol),然后在室温将反应混合物搅拌16h。反应用水(1mL)淬灭。浓缩反应混合物,残留物通过制备型LCMS使用方法D2纯化。合并包含所需产物的级分,使用Genevac离心蒸发仪干燥,得到2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(1-异丙基哌啶-4-基)-1,3,4-噁二唑(0.002g,3.99μmol,6%收率),其为浅黄色固体。LCMS保留时间1.524min[E]。MS m/z:489.4[M+H]+;1H NMR(400MHz,CD3OD)δppm8.43(d,J=1.2Hz,1H),7.76(dd,J=8.4,1.6Hz,1H),7.49(d,J=8.8Hz,1H),7.13-7.08(m,3H),3.91(s,3H),3.90(s,3H),3.45-3.39(m,1H),3.24-3.14(m,3H),2.78-2.61(m,3H),2.44-2.36(m,2H),2.11-2.01(m,2H),1.51(d,J=7.2Hz,6H),1.21(d,J=6.4Hz,6H)。
以下实施例根据实施例1-4中描述的一般步骤来制备。
表1
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以下实施例以与实施例1-4的产物类似的方式来制备。
表2
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生物学测定
本发明化合物的药理性质可以通过许多生物学测定法来证实。随后的示例性生物学测定已用本发明的化合物进行。
TLR7/8/9抑制报告基因分析
使用过表达人TLR7、TLR8或TLR9受体的HEK-BlueTM-细胞(Invivogen)来使用诱导型SEAP(分泌胚胎碱性磷酸酶)报告基因在融合至5个NF-κB和AP-1结合位点的IFN-β最小启动子的控制下筛选这些受体的抑制剂。简而言之,将细胞接种到Greiner 384孔板中(对于TLR7每孔15000个细胞,对于TLR8每孔20,000个细胞,对于TLR9每孔25,000个细胞),然后用在DMSO中的测试化合物处理,以产生0.05nM–50μM的最终剂量响应浓度范围。在室温进行30分钟的化合物预处理后,然后用TLR7配体(Gardiquimod,最终浓度为7.5μM)、TLR8配体(R848,最终浓度为15.9μM)或TLR9配体(ODN2006,最终浓度为5nM)刺激细胞,以激活NF-κB和AP-1,其诱导SEAP的产生。在37℃、5%CO2孵育22小时后,根据制造商的说明书,通过添加HEK-BlueTM检测试剂(Invivogen)(允许检测SEAP的细胞培养基)来确定SEAP水平。百分比抑制被确定为与用已知抑制剂处理的孔相比,单独用激动剂加DMSO处理的孔中存在的HEK-Blue信号的%降低。
表3
TLR7/8/9报告基因分析数据
(NT=未测试)
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Claims (9)
1.式(I)化合物
或其盐,其中:
G为:
(i)(ii)/>或
(iii)选自如下的9元杂环:
R1为-CH3、-CH2CH3、-CH(CH3)2、-CH2CHF2或-CH2CF3;
每个R2独立地为-CH3或-NH2;
A为选自如下的芳族基团:[1,2,4]三唑并[1,5-a]吡啶基、咪唑并[1,2-a]吡啶基、咪唑基、吲唑基、异喹啉基、噁二唑基、噁唑基、苯基、吡嗪基、吡唑并[3,4-b]吡啶基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹啉酮基、喹啉基、喹喔啉基、四氢-[1,2,4]三唑并[1,5-a]吡嗪基、四氢咪唑并[1,2-a]吡嗪基、四氢异喹啉基、四氢噻唑并[5,4-c]吡啶基、四氢噻吩并[2,3-c]吡啶基、噻二唑基、噻唑基、硫代噁二唑基和三唑基,其各自取代有0至2个R14a和0至3个R14b;
每个R14a独立地选自:
(i)H、F、Cl、-OH、-CH3、-CH(CH3)2、-CH(CH3)(CH2CH3)、-CH2CH2CH2C(CH3)2、-CF3、-CH2CF3、-CH2OH、-OCH3、-CH2CH2OCH3、-CHRxNRx(CH3)、-CH2N(CH3)(CH(CH3)2)、-CH2NH(CH2C(CH3)3)、-CH2NH(CH2CN)、-CH2N(CH3)(CH2CH2OCH3)、-CH2N(CH2CH2OCH3)2、-CH2NRx(CH2C≡CH)、-CH2NHCH2CH2N(CH3)2、-CH2CH2NRx(CH3)、-CH2CRx(CH3)NH2、-CH2CH2CH2N(CH3)2、-CH2CH2CH2CH2NH2、-CH(NH2)(CH2)3-4NH2、-CH2NHCH2CH2O(C1-3烷基)、-CH2NHCH2CH2OCH2CH2OH、-CH2NHCH2CH2S(O)2OH、-CH2C(O)NRx(CH3)、-NRxRx、-NH(CH(CH3)2)、-NHCH2CH2NH(CH3)、-NHCH2CH2CH2N(CH3)2、-NHC(O)CH3、-NHC(O)CF3、-NHC(O)OC(CH3)3、-NHC(O)CH2N(CH3)2、-NHC(O)CH2CH2N(CH3)2、-NHCH2C(O)CH2NH(CH3)、-C(O)CH3、-C(O)CH2CH(CH3)OH、-C(O)CH2NRx(CH3)、-C(O)NRxRx、-C(O)NH(CH2CN)、-C(O)NHCH2CH2CH2NRxRx、-C(O)NHCH2CH(CH3)CH2NH2、-C(O)NHCH2C(O)NH2、-C(O)N(CH3)CH2CH2CH2N(CH3)2、-C(O)N(CH2CH3)CH2CH2N(CH3)2、-OCH2CH2CH2N(CH3)2、-C(O)NHCH2CH2NHC(O)CH3、-S(O)2NH2和-C(O)CH2S(O)2CH3;
(ii)8-氮杂双环[3.2.1]辛基、氮杂螺[3.5]壬基、氮杂环丁烷基、苯并[c][1,2,5]噁二唑基、环戊基、环己基、二氮杂环庚烷基、吗啉基、苯基、哌嗪基、哌啶基、吡唑基、吡啶基、吡咯烷酮基、喹啉基、奎宁环基、四氢异喹啉基、四氢吡啶基或噻唑烷基,其各自取代有0至2个独立地选自以下的取代基:-CH3、-CH(CH3)2、-CH2CH(CH3)2、-CF3、-CH2CH2CF3、-CH2CH2OH、-CH2CH2CH(CH3)OH、-NH2、-CH2N(CH3)2、-CH2CH2NH(CH3)、-C(O)CH3、-C(O)CH2NH(CH3)、-C(O)CH2N(CH3)2、-C(O)O(C(CH3)3)、-CH2C(O)NRx(CH3)、环丁基、环戊基、-CH2(苯基)、-CH2(吡咯基)、-CH2(吗啉基)、-CH2(甲基哌嗪基)、-CH2(硫代苯基)、甲基哌啶基、异丁基哌啶基和吡啶基;或
(iii)-L3-R14c;
每个R14b为-CH3;
L3为-(CH2)1-3-、-CH(CH3)-、-CH(NH2)-、-CH2NH-、-C(O)-、-C(O)NH(CH2)0-4-、-C(O)N(CH3)CH2CH2-、-NH-、-NHC(O)-、-NHCH2-、-NHCH2C(O)-、-O-或-OCH2CH2-;
R14c为金刚烷基、氮杂环丁烷基、环丙基、环己基、二氮杂环庚烷基、咪唑基、吲哚基、吗啉基、八氢吡咯并[3,4-c]吡咯基、苯基、哌嗪酮基、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基或四唑基,其各自取代有0至1个选自以下的取代基:OH、-CH3、-CH(CH3)2、-CH2CH(CH3)2、-C(CH3)2OH、-NH2、-N(CH3)2、-NH(C(CH3)2、-NHC(O)CH3、-C(O)CH3、-C(O)NH2、-C(O)N(CH2CH3)2、-C(O)(四氢呋喃基)、-C(O)OCH2CH3、-CH2C(O)NH(CH(CH3)2、吗啉基、甲基哌啶基、吡嗪基、吡啶基和吡咯烷基;
每个R5独立地为F、Cl、-CN、C1-3烷基、C1-2氟烷基或-OCH3;
每个Rx独立地为H或-CH3;
n为0;和
p为0、1、2或3。
2.根据权利要求1所述的化合物或其盐,其中A为苯基。
3.根据权利要求2所述的化合物或其盐,其中A为噁唑基或噁二唑基。
4.根据权利要求1所述的化合物或其盐,其中A为吡啶基、吡嗪基或哒嗪基。
5.根据权利要求1所述的化合物或其盐,其中A为[1,2,4]三唑并[1,5-a]吡啶基、咪唑并[1,2-a]吡啶基、吡唑并[3,4-b]吡啶基、喹啉酮基、喹啉基、喹喔啉基、四氢-[1,2,4]三唑并[1,5-a]吡嗪基、四氢咪唑并[1,2-a]吡嗪基、四氢异喹啉基、四氢噻唑并[5,4-c]吡啶基或四氢噻吩并[2,3-c]吡啶基。
6.根据权利要求1所述的化合物或其盐,其中所述化合物为2-(3,4-二甲氧基苯基)-5-[3-(哌嗪-1-羰基)苯基]-3-(丙烷-2-基)-1H-吲哚(1);2-(3,4-二甲氧基苯基)-5-[5-(哌啶-4-基)-1,3,4-噁二唑-2-基]-3-(丙烷-2-基)-1H-吲哚(2);1-(4-{5-[2-(3,4-二甲氧基苯基)-3-(丙烷-2-基)-1H-吲哚-5-基]-1,3,4-噁二唑-2-基}哌啶-1-基)-2-(二甲基氨基)乙烷-1-酮(3);2-(3,4-二甲氧基苯基)-3-(丙烷-2-基)-5-{5-[1-(丙烷-2-基)哌啶-4-基]-1,3,4-噁二唑-2-基}-1H-吲哚(4);(3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)(4-甲基-1,4-二氮杂环庚烷-1-基)甲酮(5);N-((1r,4r)-4-氨基环己基)-3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯甲酰胺(6);3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-((1r,4r)-4-(2-羟基丙烷-2-基)环己基)苯甲酰胺(7);3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)苯甲酰胺(8);(3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(9);(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)(4-甲基-1,4-二氮杂环庚烷-1-基)甲酮(10);4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)吡啶甲酰胺(11);N-(4-氨基环己基)-4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡啶甲酰胺(12);4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-((1r,4r)-4-(2-羟基丙烷-2-基)环己基)吡啶甲酰胺(13);(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)(哌嗪-1-基)甲酮(14);(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(3-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)苯基)甲酮(15);3-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)苯甲酰胺(16);2-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N,N-二甲基乙酰胺(17);1-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-2-(甲基氨基)乙烷-1-酮(18);4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-甲酸叔丁酯(19);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(1-甲基哌啶-4-基)-1,3,4-噁二唑(20);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(1'-甲基-[1,4'-联哌啶]-4-基)-1,3,4-噁二唑(21);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(1'-异丙基-[1,4'-联哌啶]-4-基)-1,3,4-噁二唑(22);2-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N-甲基乙酰胺(23);2-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N-甲基乙烷-1-胺(24);3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)-N-(2-(1-甲基吡咯烷-2-基)乙基)苯甲酰胺(25);N-(2-乙酰氨基乙基)-3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯甲酰胺(26);N-(氰基甲基)-3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯甲酰胺(27);N-(2-氨基-2-氧代乙基)-3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯甲酰胺(28);3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)-N-(2-吗啉代乙基)苯甲酰胺(29);2-(4-(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯甲酰基)哌嗪-1-基)-N-异丙基乙酰胺(30);(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯基)(4-羟基哌啶-1-基)甲酮(31);(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯基)(2-甲基吡咯烷-1-基)甲酮(32);(4-(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯甲酰基)哌嗪-1-基)(四氢呋喃-2-基)甲酮(33);(R)-(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯基)(3-羟基吡咯烷-1-基)甲酮(34);3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)-N-甲基-N-(2-(吡啶-2-基)乙基)苯甲酰胺(35);(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯基)(4-(吡啶-4-基)哌嗪-1-基)甲酮(36);(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯基)(4-(1-甲基哌啶-4-基)哌嗪-1-基)甲酮(37);5-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-N,N-二甲基-1,3,4-噁二唑-2-甲酰胺(38);5-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噁二唑-2-甲酰胺(39);(5-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(40);5-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-甲酰胺(41);(3-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)苯基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(42);2-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N,N-二甲基乙烷-1-胺(43);1-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N,N-二甲基甲胺(44);2-((1H-咪唑-4-基)甲基)-5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑(45);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(1-甲基哌啶-3-基)-1,3,4-噁二唑(46);2-(2-(1H-咪唑-1-基)乙基)-5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑(47);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(吡咯烷-3-基)-1,3,4-噁二唑(48);(S)-1-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N-甲基乙烷-1-胺(49);(S)-2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-2-基甲基)-1,3,4-噁二唑(50);(S)-2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(吡咯烷-2-基甲基)-1,3,4-噁二唑(51);(S)-2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(52);2-(氮杂环丁烷-3-基)-5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑(53);(R)-2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-2-基甲基)-1,3,4-噁二唑(54);(R)-2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(55);(R)-2-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(56);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噁二唑-2-甲酰胺(58);5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噁二唑-2-甲酰胺(59);(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲酮(60);(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(61);2-(二甲基氨基)-1-(4-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)乙烷-1-酮(62);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-甲基-1,3,4-噁二唑(63);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(2,2,2-三氟乙基)-1,3,4-噁二唑(64);2-(4-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N,N-二甲基乙酰胺(65);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-4-基)-1,3,4-噁二唑(66);2-(4-(5-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N-甲基乙烷-1-胺(67);(R)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(噻唑烷-4-基)-1,3,4-噁二唑(68);(S)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(69);2-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)吗啉(70);(S)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-2-基甲基)-1,3,4-噁二唑(71);(R)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1,2,3,4-四氢异喹啉-3-基)-1,3,4-噁二唑(72);2-((1H-吲哚-3-基)甲基)-5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑(73);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡啶-3-基甲基)-1,3,4-噁二唑(74);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(2,2,2-三氟乙基)-1,3,4-噁二唑(75);2-((1H-四唑-5-基)甲基)-5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑(76);3-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N,N-二甲基丙烷-1-胺(77);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(4-(三氟甲基)环己基)-1,3,4-噁二唑(78);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-((4-甲基哌嗪-1-基)甲基)-1,3,4-噁二唑(79);(R)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(80);(S)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1,2,3,4-四氢异喹啉-3-基)-1,3,4-噁二唑(81);(S)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(噻唑烷-4-基)-1,3,4-噁二唑(82);2-(4-(5-(2-(3,4-二甲氧基苯基)-3-(2,2,2-三氟乙基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N,N-二甲基乙酰胺(83);5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噁二唑-2-甲酰胺(84);(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲酮(85);2-(二甲基氨基)-1-(4-(5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)乙烷-1-酮(86);2-(4-(5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N,N-二甲基乙酰胺(87);2-(4-(5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)哌啶-1-基)-N-甲基乙酰胺(88);1-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-羰基)-N,N-二乙基哌啶-3-甲酰胺(89);5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(2-(二甲基氨基)乙基)-1,3,4-噁二唑-2-甲酰胺(90);(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(4-羟基哌啶-1-基)甲酮(91);1-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-羰基)哌嗪-1-基)乙烷-1-酮(92);(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(4-甲基-1,4-二氮杂环庚烷-1-基)甲酮(93);5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-甲基-N-(2-(吡啶-2-基)乙基)-1,3,4-噁二唑-2-甲酰胺(94);(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(4-(吡咯烷-1-基)哌啶-1-基)甲酮(95);5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(3-(二甲基氨基)丙基)-N-甲基-1,3,4-噁二唑-2-甲酰胺(96);(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(4-(吡嗪-2-基)哌嗪-1-基)甲酮(97);(S)-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(3-(二甲基氨基)吡咯烷-1-基)甲酮(98);(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(3-吗啉代吡咯烷-1-基)甲酮(99);N-(2-乙酰氨基乙基)-5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-甲酰胺(100);N-(3-(1H-咪唑-1-基)丙基)-5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-甲酰胺(101);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-4-基)-1,3,4-噁二唑(102);(R)-2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(103);(S)-2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-2-基甲基)-1,3,4-噁二唑(104);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-(哌嗪-1-基)-1,3,4-噁二唑(105);5-(5-(1-苄基哌啶-4-基)-4H-1,2,4-三唑-3-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(106);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-5-((六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲基)-1,3,4-噁二唑(107);N-(2-(((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)氨基)乙基)乙酰胺(108);N-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-2-甲氧基乙烷-1-胺(109);N-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)丙-2-炔-1-胺(110);N-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-2-乙氧基乙烷-1-胺(111);2-(2-(((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)氨基)乙氧基)乙烷-1-醇(112);2-(((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)氨基)乙烷-1-磺酸(113);N-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-2-异丙氧基乙烷-1-胺(114);4-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)吗啉(115);1-(4-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)哌嗪-1-基)乙烷-1-酮(116);(S)-N-(1-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)吡咯烷-3-基)乙酰胺(117);N-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-2-甲氧基-N-(2-甲氧基乙基)乙烷-1-胺(118);1-(4-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-1,4-二氮杂环庚烷-1-基)乙烷-1-酮(119);4-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)哌嗪-2-酮(120);N-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-2-甲氧基-N-甲基乙烷-1-胺(121);(S)-1-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)吡咯烷-2-甲酰胺(122);N-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-N-甲基丙-2-炔-1-胺(123);2-(3,4-二甲氧基苯基)-3-异丙基-5-(5-(哌啶-4-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(124);(5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(4-甲基-1,4-二氮杂环庚烷-1-基)甲酮(125);(S)-2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(126);(2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)噁唑-4-基)(六氢吡咯并[3,4-c]吡咯-2(1H)-基)甲酮(127);2-(3-异丙基-2-(2H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-1-基甲基)-1,3,4-噁二唑(128);2-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)-N,N-二甲基乙酰胺(129);2-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)-N-甲基乙酰胺(130);1-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)-2-(二甲基氨基)乙烷-1-酮(131);1-(5-(3-异丙基-2-(2H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N-甲基甲胺(132);N-(2-(二甲基氨基)乙基)-5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噻二唑-2-甲酰胺(133);N1-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-N2,N2-二甲基乙烷-1,2-二胺(134);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噻二唑-2-甲酰胺(135);6-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,2,3,4-四氢异喹啉(136);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-(吡咯烷-3-基)-1,3,4-噻二唑-2-甲酰胺(137);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-2-基甲基)-1,3,4-噁二唑(138);(R)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-3-基)-1,3,4-噁二唑(139);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(哌嗪-1-基甲基)-1,3,4-噁二唑(140);2-((1H-咪唑-1-基)甲基)-5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑(141);2-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N-甲基乙烷-1-胺(142);2-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N,N-二甲基乙烷-1-胺(143);2-((1H-咪唑-4-基)甲基)-5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑(144);(R)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-2-基甲基)-1,3,4-噁二唑(145);(S)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-3-基)-1,3,4-噁二唑(146);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)噻唑-4-甲酰胺(147);N-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)环丙胺(148);N-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-2,2-二甲基丙烷-1-胺(149);2-(((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)氨基)乙腈(150);N-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)金刚烷-1-胺(151);4-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)吗啉(152);1-(4-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)哌嗪-1-基)乙烷-1-酮(153);N-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-N-甲基丙烷-2-胺(154);1-(4-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-1,4-二氮杂环庚烷-1-基)乙烷-1-酮(155);4-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)哌嗪-2-酮(156);(R)-1-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)-N,N-二甲基吡咯烷-3-胺(157);(S)-1-((5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲基)吡咯烷-2-甲酰胺(158);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-甲基哌啶-3-基)-1,3,4-噁二唑(159);2-(2-(2-氨基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)噁唑-4-甲酰胺(160);7-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-1,2,3,4-四氢喹啉(161);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(1-甲基哌啶-3-基)-1,3,4-噁二唑(162);5-(5-(1-苄基哌啶-4-基)-4H-1,2,4-三唑-3-基)-3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚(163);3-异丙基-2-(2-甲基吡啶-4-基)-5-(5-(哌啶-3-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(164);2-(3,4-二甲氧基苯基)-5-(1H-咪唑-2-基)-3-异丙基-1H-吲哚(165);5-(2-(2-氨基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N,N-二甲基-1,3,4-噁二唑-2-甲酰胺(166);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(1-甲基哌啶-3-基)-1,3,4-噁二唑(167);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(1-甲基哌啶-3-基)-1,3,4-噁二唑(168);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-甲基哌啶-3-基)-1,3,4-噁二唑(169);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-甲基哌啶-3-基)-1,3,4-噁二唑(170);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)噻唑(171);(六氢吡咯并[3,4-c]吡咯-2(1H)-基)(2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)噁唑-4-基)甲酮(172);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)噁唑-4-甲酰胺(173);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-胺(174);2-(3-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)-N-甲基乙酰胺(175);2-(二甲基氨基)-1-(3-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)乙烷-1-酮(176);4,4'-(3-异丙基-1H-吲哚-2,5-二基)双(1H-吡唑并[3,4-b]吡啶)(177);3-异丙基-2-(2-甲基吡啶-4-基)-5-(5-(哌啶-3-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(178);3-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)环己烷-1-胺(179);2-(3-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)-N,N-二甲基乙酰胺(180);2-(3-异丙基-2-(2H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)噻唑(181);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基甲基)-1,3,4-噁二唑(182);2-(3-异丙基-2-(2H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)噁唑-4-甲酰胺(183);3-异丙基-2-(2-甲基吡啶-4-基)-5-(5-(哌啶-3-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(184);2-(4-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)-N,N-二甲基乙酰胺(185);2-(二甲基氨基)-1-(4-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4H-1,2,4-三唑-3-基)哌啶-1-基)乙烷-1-酮(186);3-异丙基-5-(5-(1-异丙基哌啶-4-基)-4H-1,2,4-三唑-3-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(187);3-异丙基-5-(5-(1-异丙基哌啶-3-基)-4H-1,2,4-三唑-3-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(188);3-异丙基-2-(2-甲基吡啶-4-基)-5-(4-(哌啶-4-基)-1H-咪唑-2-基)-1H-吲哚(189);2-(二甲基氨基)-N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)乙酰胺(190);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-5-甲基噁唑-4-甲酰胺(191);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4-甲基噻唑(192);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)嘧啶-2-胺(193);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-甲基-N-(吡咯烷-3-基甲基)噁唑-4-甲酰胺(194);N-(2-(二甲基氨基)乙基)-5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噻二唑-2-甲酰胺(195);3-异丙基-2-(2-甲基吡啶-4-基)-5-(5-(哌啶-4-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(196);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-(吡咯烷-3-基甲基)噁唑-4-甲酰胺(197);2-(二甲基氨基)-N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)乙酰胺(198);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-2-(哌啶-4-基)噻唑(199);4-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-胺(200);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4-甲基-2-(哌啶-4-基)噻唑(201);N1-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)-N2-甲基乙烷-1,2-二胺(202);5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噻二唑-2-甲酰胺(203);3-异丙基-5-(5-(1-异丙基哌啶-3-基)-4H-1,2,4-三唑-3-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(204);3-异丙基-5-(5-(1-异丙基哌啶-3-基)-4H-1,2,4-三唑-3-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(205);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5,6,7,8-四氢-[1,2,4]三唑并[1,5-a]吡嗪(206);(S)-N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)吡咯烷-3-甲酰胺(207);1-(6-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)嘧啶-4-基)哌啶-4-胺(208);(R)-N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)吡咯烷-3-甲酰胺(209);N1-(4-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)-N2-甲基乙烷-1,2-二胺(210);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-7-(1-异丙基哌啶-4-基)-5,6,7,8-四氢-[1,2,4]三唑并[1,5-a]吡嗪(211);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-甲基-N-(吡咯烷-3-基甲基)噁唑-4-甲酰胺(212);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(奎宁环-3-基)-1,3,4-噁二唑(213);N-(1-异丁基哌啶-4-基)-5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-甲酰胺(214);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-甲酰胺(215);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-甲酰胺(216);2-(2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5,6-二氢-[1,2,4]三唑并[1,5-a]吡嗪-7(8H)-基)-N-甲基乙烷-1-胺(217);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(2-(甲基氨基)乙基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-甲酰胺(218);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-甲基-5-(2-(甲基氨基)乙基)-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-甲酰胺(219);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(奎宁环-3-基)-1,3,4-噁二唑(220);5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噁二唑-2-甲酰胺(221);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(奎宁环-3-基)-1,3,4-噁二唑(222);N-(2-(二甲基氨基)乙基)-5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-甲酰胺(223);N-(3-(二甲基氨基)丙基)-5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-甲酰胺(224);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶(225);2-(5-(2-([1,2,4]三唑并[1,5-a]吡啶-6-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N-甲基乙烷-1-胺(226);(R)-2-(2-([1,2,4]三唑并[1,5-a]吡啶-6-基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(227);6-异丙基-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶(228);2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶(229);(4-氨基哌啶-1-基)(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲酮(230);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(奎宁环-3-基)-1,3,4-噁二唑(231);(R)-2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(232);(2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)噁唑-4-基)(4-甲基-1,4-二氮杂环庚烷-1-基)甲酮(233);N-(2-(二甲基氨基)乙基)-2-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)噁唑-4-甲酰胺(234);5-(6-氯吡啶-3-基)-3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚(235);5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶-2-胺(236);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-胺(237);2-(二甲基氨基)-N-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)乙酰胺(238);N1-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)-N2-甲基乙烷-1,2-二胺(239);(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)(4-(异丙基氨基)哌啶-1-基)甲酮(240);5-(2-(咪唑并[1,2-a]吡啶-6-基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)-1,3,4-噁二唑-2-甲酰胺(241);N-(2-(二甲基氨基)乙基)-5-(2-(咪唑并[1,2-a]吡啶-6-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-甲酰胺(242);(R)-2-(3-(2,2-二氟乙基)-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(243);(R)-2-(2-(咪唑并[1,2-a]吡啶-6-基)-3-异丙基-1H-吲哚-5-基)-5-(哌啶-3-基)-1,3,4-噁二唑(244);(R)-2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-5-(1-异丙基哌啶-3-基)-1,3,4-噁二唑(245);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N,N-二甲基吡啶-2-胺(246);N-异丙基-5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-胺(247);5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-异丙基吡啶-2-胺(248);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(1-异丙基哌啶-4-基)噁唑-4-甲酰胺(249);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-5-(奎宁环-3-基)-1,3,4-噁二唑(250);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶(251);1-(2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-2-(甲基氨基)乙烷-1-酮(252);3-异丙基-5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(253);3-异丙基-2-(2-甲基吡啶-4-基)-5-(2-(哌啶-4-基)-1H-咪唑-5-基)-1H-吲哚(254);3-异丙基-2-(2-甲基吡啶-4-基)-5-(6-(哌嗪-1-基)吡啶-3-基)-1H-吲哚(255);N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)乙酰胺(256);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(6-(哌嗪-1-基)吡啶-3-基)-1H-吲哚(257);5-(2-(1H-吡唑-4-基)吡啶-4-基)-3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚(258);1-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)丙烷-2-胺(259);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(2-(哌啶-1-基)乙基)-1,3,4-噁二唑(260);(S)-2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-2-基)-1,3,4-噁二唑(261);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(2-(吡啶-3-基)乙基)-1,3,4-噁二唑(262);2-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)丙烷-1-胺(263);4-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)丁烷-1-胺(264);1-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-2-甲基丙烷-2-胺(265);(1S,2R)-2-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)环己烷-1-胺(266);(1S,2R)-2-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)环戊烷-1-胺(267);(S)-环丙基(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)甲胺(268);3-异丙基-5-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(269);2-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N,N-二甲基乙烷-1-胺(270);3-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-基)-N,N-二甲基丙烷-1-胺(271);3-异丙基-5-(2-(1-异丙基哌啶-4-基)吡啶-4-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(272);3-异丙基-2-(2-甲基吡啶-4-基)-5-(2-(哌嗪-1-基)吡啶-4-基)-1H-吲哚(273);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(2-(哌啶-1-基)乙基)噁唑-4-甲酰胺(274);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(3-(哌啶-1-基)丙基)噁唑-4-甲酰胺(275);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(吡咯烷-3-基甲基)噁唑-4-甲酰胺(276);N-(3-氨基-2-甲基丙基)-2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)噁唑-4-甲酰胺(277);N-(3-氨基丙基)-2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)噁唑-4-甲酰胺(278);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(3-(甲基氨基)丙基)噁唑-4-甲酰胺(279);N-(3-(二甲基氨基)丙基)-2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)噁唑-4-甲酰胺(280);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(2-吗啉代乙基)噁唑-4-甲酰胺(281);N-((1r,4r)-4-氨基环己基)-2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)噁唑-4-甲酰胺(282);4-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)噁唑-4-甲酰氨基)哌啶-1-甲酸乙酯(283);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(3-(吡咯烷-1-基)丙基)噁唑-4-甲酰胺(284);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(4-(吡咯烷-1-基)butyl)噁唑-4-甲酰胺(285);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(3-(4-甲基哌嗪-1-基)丙基)噁唑-4-甲酰胺(286);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(哌啶-2-基甲基)噁唑-4-甲酰胺(287);N-(氮杂环丁烷-3-基甲基)-2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)噁唑-4-甲酰胺(288);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(2-甲基-2-吗啉代丙基)噁唑-4-甲酰胺(289);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(哌啶-3-基)噁唑-4-甲酰胺(290);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-(2-(吡咯烷-2-基)乙基)噁唑-4-甲酰胺(291);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-异丙基哌啶-3-基)-1,3,4-噁二唑(292);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-甲基吡啶-2-胺(293);3-(二甲基氨基)-N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)丙酰胺(294);2,2,2-三氟-N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)乙酰胺(295);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-5-(奎宁环-3-基)-1,3,4-噁二唑(296-297);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-异丙基哌啶-3-基)-1,3,4-噁二唑(298);3-异丙基-5-(2-(4-异丙基哌嗪-1-基)吡啶-4-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(299);N-(2-(二甲基氨基)乙基)-5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-乙基-1,3,4-噁二唑-2-甲酰胺(300);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吲哚(301);3-异丙基-5-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(302);(6-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)咪唑并[1,2-a]吡啶-8-基)氨基甲酸叔丁酯(303);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(吡啶-3-基)-1H-吲哚(304);2-(二甲基氨基)-1-(2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)乙烷-1-酮(305);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)-1H-吲哚(306);5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡嗪-2-胺(307);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,5,6,7-四氢噻唑并[5,4-c]吡啶(308);2-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-6,7-二氢噻唑并[5,4-c]吡啶-5(4H)-基)-N,N-二甲基乙酰胺(309);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,5,6,7-四氢噻唑并[4,5-c]吡啶(310);2-(2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-N,N-二甲基乙酰胺(311);2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-异丙基哌啶-3-基)-1,3,4-噁二唑(312);(4-(二甲基氨基)哌啶-1-基)(4-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)苯基)甲酮(313);2-(3-(2,2-二氟乙基)-2-(2,6-二甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-异丙基哌啶-3-基)-1,3,4-噁二唑(314);2-(2-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-N-甲基乙酰胺(315);5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-N-甲基吡啶甲酰胺(316);5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶甲酰胺(317);5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-1,3,4-噁二唑-2-胺(318);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(2-(4-甲基哌嗪-1-基)吡啶-4-基)-1H-吲哚(319);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(2-(哌嗪-1-基)吡啶-4-基)-1H-吲哚(320);(4-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)苯基)(4-(异丙基氨基)哌啶-1-基)甲酮(321);(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)甲醇(322);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(5-(哌啶-3-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(323);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶(324);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-6-异丙基-4,5,6,7-四氢噻吩并[2,3-c]吡啶(325);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(2-(4-异丙基哌嗪-1-基)吡啶-4-基)-1H-吲哚(326);2-(3-(2,2-二氟乙基)-2-(2,6-二甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-异丙基哌啶-3-基)-1,3,4-噁二唑(327);2-(3-(2,2-二氟乙基)-2-(2,6-二甲基吡啶-4-基)-1H-吲哚-5-基)-5-(1-异丙基哌啶-3-基)-1,3,4-噁二唑(328);2-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-6,7-二氢噻唑并[4,5-c]吡啶-5(4H)-基)-N,N-二甲基乙酰胺(329);2-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-N-甲基乙酰胺(330);1-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-2-(甲基氨基)乙烷-1-酮(331);N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡啶-2-基)-1-甲基-5-氧代吡咯烷-3-甲酰胺(332);6-(3-异丙基-5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吲哚-2-基)-2-甲基咪唑并[1,2-a]吡啶(333);6-(3-异丙基-5-(6-(哌嗪-1-基)吡啶-3-基)-1H-吲哚-2-基)-2-甲基咪唑并[1,2-a]吡啶(334);4-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)-2,6-二甲基吗啉(335);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(6-(吡咯烷-1-基)吡啶-3-基)-1H-吲哚(336);1-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)-N,N-二甲基哌啶-4-胺(337);5-(6-(氮杂环丁烷-1-基)吡啶-3-基)-2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚(338);2-(4-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)哌嗪-1-基)乙烷-1-醇(339);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(5-(1-异丙基哌啶-3-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(340);2-(二甲基氨基)-1-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)乙烷-1-酮(341);2-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-N,N-二甲基乙酰胺(342);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-6-((2-甲基-1H-咪唑-4-基)甲基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶(343);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(2-(哌啶-4-基)吡啶-4-基)-1H-吲哚(344);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(2-(1-异丙基哌啶-4-基)吡啶-4-基)-1H-吲哚(345);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-N-甲基-1,3,4-噁二唑-2-胺(346);6-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-2,7-二甲基咪唑并[1,2-a]吡啶(347);6-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-7-氟-2-甲基咪唑并[1,2-a]吡啶(348);6-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)哒嗪-3-胺(349);4-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-2-(哌啶-1-基)噻唑(350);(S)-1-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-3-羟基丁烷-1-酮(351);4-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,5,6,7-四氢噻吩并[2,3-c]吡啶-6-羰基)-1-甲基吡咯烷-2-酮(352);1-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,7-二氢噻吩并[2,3-c]吡啶-6(5H)-基)-2-(甲基磺酰基)乙烷-1-酮(353);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-5,6,7,8-四氢咪唑并[1,2-a]吡嗪(354);7-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-8-甲基-[1,2,4]三唑并[1,5-a]吡啶(355);N-(5-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡嗪-2-基)-2-(甲基氨基)乙酰胺(356);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(5-(1-异丙基哌啶-3-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(357);2-(2,6-二甲基吡啶-4-基)-3-异丙基-5-(5-(1-异丙基哌啶-3-基)-4H-1,2,4-三唑-3-基)-1H-吲哚(358);5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡嗪-2-胺(359);6-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)哒嗪-3-胺(360);2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-6-甲基-4,5,6,7-四氢噻吩并[2,3-c]吡啶(361);1-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-6,7-二氢噻唑并[5,4-c]吡啶-5(4H)-基)乙烷-1-酮(362);2-(二甲基氨基)-1-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-6,7-二氢噻唑并[5,4-c]吡啶-5(4H)-基)乙烷-1-酮(363);4-(2-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-4,5,6,7-四氢噻唑并[5,4-c]吡啶-5-羰基)-1-甲基吡咯烷-2-酮(364);2-(二甲基氨基)-N-(5-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡嗪-2-基)乙酰胺(365);6-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-8-氟-2-甲基咪唑并[1,2-a]吡啶(366);2-(3-异丙基-2-(8-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-1H-吲哚-5-基)-5-(1-甲基哌啶-4-基)-1,3,4-噁二唑(367);2-(3,4-二甲氧基苯基)-3-乙基-5-(3-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲哚(368);2-(3,4-二甲氧基苯基)-3-异丙基-5-(3-(4-甲基哌嗪-1-基)苯基)-1H-吲哚(369);2-(3,4-二甲氧基苯基)-3-异丙基-5-(3-(4-异丙基哌嗪-1-基)苯基)-1H-吲哚(370);2-(3,4-二甲氧基苯基)-5-(3-(4-异丁基哌嗪-1-基)苯基)-3-异丙基-1H-吲哚(371);4-(1-(4-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)苯基)乙基)吗啉(372);2-(3,4-二甲氧基苯基)-3-异丙基-5-(3'-((4-甲基哌嗪-1-基)甲基)-[1,1'-联苯基]-4-基)-1H-吲哚(373);1-(4'-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-[1,1'-联苯基]-3-基)-N,N-二甲基甲胺(374);2-(3,4-二甲氧基苯基)-5-(4-(1-(1-异丁基哌啶-4-基)-1,2,3,6-四氢吡啶-4-基)苯基)-3-甲基-1H-吲哚(375);2-(3,4-二甲氧基苯基)-3-甲基-5-(4-(1-甲基-1,2,3,6-四氢吡啶-4-基)苯基)-1H-吲哚(376);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(2,2,6,6-四甲基-1,2,3,6-四氢吡啶-4-基)苯基)-1H-吲哚(377);4-(3-异丙基-5-(4-((4-甲基哌嗪-1-基)甲基)苯基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(378);2-(4-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)-1,4-二氮杂环庚烷-1-基)乙烷-1-醇(379);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-甲基-1,4-二氮杂环庚烷-1-基)苯基)-1H-吲哚(380);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲哚(381);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-异丙基哌嗪-1-基)苯基)-1H-吲哚(382);(R)-2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(3-甲基哌嗪-1-基)苯基)-1H-吲哚(383);4-(3-乙基-5-(4-(4-甲基哌嗪-1-基)苯基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(384);N-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)-1-异丙基哌啶-4-胺(385);4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-((1-甲基吡咯烷-3-基)甲基)苯胺(386);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-((1-甲基哌啶-4-基)氧基)苯基)-1H-吲哚(387);2-(3,4-二甲氧基苯基)-5-(4-((1-异丁基哌啶-4-基)氧基)苯基)-3-异丙基-1H-吲哚(388);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-((1-异丙基哌啶-4-基)氧基)苯基)-1H-吲哚(389);1-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)哌嗪-1-基)乙烷-1-酮(390);2-(3,4-二甲氧基苯基)-5-(6-(4-异丁基哌嗪-1-基)吡啶-3-基)-3-异丙基-1H-吲哚(391);2-(3,4-二甲氧基苯基)-3-异丙基-5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)-1H-吲哚(392);2-(3,4-二甲氧基苯基)-3-异丙基-5-(6-(4-异丙基哌嗪-1-基)吡啶-3-基)-1H-吲哚(393);4-羟基-6-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)喹啉-2(1H)-酮(394);4-(3-异丙基-5-(1-甲基-1H-吲唑-5-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(395);4-((3'-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-[1,1'-联苯基]-3-基)甲基)吗啉(396);1-(3'-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-[1,1'-联苯基]-3-基)-N,N-二甲基甲胺(397);4-(3-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)丙基)吗啉(398);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(哌嗪-1-基)苯基)-1H-吲哚(399);N1-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)-N3,N3-二甲基丙烷-1,3-二胺(400);4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(2-吗啉代乙基)苯胺(401);N-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)哌啶-3-胺(402);5-(4-(4-环戊基哌嗪-1-基)苯基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(403);N1-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)-N2-甲基乙烷-1,2-二胺(404);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-(吡啶-4-基)哌啶-1-基)苯基)-1H-吲哚(405);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(吡啶-3-基)苯基)-1H-吲哚(406);4-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)异喹啉(407);2-(3,4-二甲氧基苯基)-3-甲基-5-(4-(1,2,3,6-四氢吡啶-4-基)苯基)-1H-吲哚(408);5-(3-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苯基)苯并[c][1,2,5]噁二唑(409);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(哌啶-4-yl氧基)苯基)-1H-吲哚(410);2-(3,4-二甲氧基苯基)-3-异丙基-5-(3-(哌嗪-1-基)苯基)-1H-吲哚(411);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吲哚(412);4-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)苄基)吗啉(413);(3-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)苯基)甲醇(414);3-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)苯磺酰胺(415);4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)吗啉(416);2-(3,4-二甲氧基苯基)-3-异丙基-5-(6-(哌嗪-1-基)吡啶-3-基)-1H-吲哚(417);2-(3,4-二甲氧基苯基)-5-(6-(4-异丁基哌嗪-1-基)-4-甲基吡啶-3-基)-3-异丙基-1H-吲哚(418);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-甲基-6-(哌嗪-1-基)吡啶-3-基)-1H-吲哚(419);2-(3,4-二甲氧基苯基)-3-异丙基-5-(6-(4-异丙基哌嗪-1-基)-4-甲基吡啶-3-基)-1H-吲哚(420);3-((5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)氧基)-N,N-二甲基丙烷-1-胺(421);4-(3-异丙基-5-(6-甲氧基吡啶-3-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(422);2-(3,4-二甲氧基苯基)-3-异丙基-5-(2-(4-(噻吩-3-基甲基)哌嗪-1-基)吡啶-4-基)-1H-吲哚(423);2-(3,4-二甲氧基苯基)-3-异丙基-5-(2-(4-(3,3,3-三氟丙基)哌嗪-1-基)吡啶-4-基)-1H-吲哚(424);4-(4-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡啶-2-基)哌嗪-1-基)丁烷-2-醇(425);5-(2-(4-环戊基哌嗪-1-基)吡啶-4-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(426);5-(2-(4-环丁基哌嗪-1-基)吡啶-4-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(427);4-(3-异丙基-5-(1-甲基-1H-吡唑-5-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(428);2-(3,4-二甲氧基苯基)-3-异丙基-5-(2-(4-(噻吩-3-基甲基)哌嗪-1-基)嘧啶-5-基)-1H-吲哚(429);2-(3,4-二甲氧基苯基)-3-异丙基-5-(2-(4-((1-甲基-1H-吡咯-2-基)甲基)哌嗪-1-基)嘧啶-5-基)-1H-吲哚(430);4-(4-(5-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)嘧啶-2-基)哌嗪-1-基)丁烷-2-醇(431);2-(3,4-二甲氧基苯基)-3-异丙基-5-(2-(4-甲基哌嗪-1-基)嘧啶-5-基)-1H-吲哚(432);2-(3,4-二甲氧基苯基)-5-(2-(4-异丁基哌嗪-1-基)-1-甲基-1H-咪唑-5-基)-3-异丙基-1H-吲哚(433);4-(5-(5,6-二甲氧基吡啶-3-基)-3-异丙基-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(434);5-(2-(4-环戊基哌嗪-1-基)嘧啶-5-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(435);5-(2-(4-环丁基哌嗪-1-基)嘧啶-5-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(436);5-(2-氯-1-甲基-1H-咪唑-5-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(437);4-(3-异丙基-5-(3-(三氟甲基)-1H-吡唑-4-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(438);(S)-3-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-2-基甲基)-1,2,4-噁二唑(439);(S)-1-(3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)-2-(1H-咪唑-4-基)乙烷-1-胺(440);4-(3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)-1-甲基吡咯烷-2-酮(441);(1R,2S)-2-(3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)-1-甲基环戊烷-1-胺(442);5-(1-苄基吡咯烷-3-基)-3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑(443);5-(1-苄基哌啶-4-基)-3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑(444);3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-5-(1-异丙基哌啶-4-基)-1,2,4-噁二唑(445);2-(二甲基氨基)-1-(4-(3-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)哌啶-1-基)乙烷-1-酮(446);3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-5-(2-(哌啶-4-基)乙基)-1,2,4-噁二唑(447);3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(2-(哌啶-4-基)乙基)-1,2,4-噁二唑(448);3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(2-(1-异丙基哌啶-4-基)乙基)-1,2,4-噁二唑(449);3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-5-(吡咯烷-3-基)-1,2,4-噁二唑(450);3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-5-(2-甲氧基乙基)-1,2,4-噁二唑(451);5-((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑(452);1-(3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)-N,N-二甲基甲胺(453);2-(3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)-N,N-二甲基乙烷-1-胺(454);(S)-3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-3-基)-1,2,4-噁二唑(455);3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(吡咯烷-3-基)-1,2,4-噁二唑(456);3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,2,4-噁二唑(457);5-(氮杂环丁烷-3-基)-3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-1,2,4-噁二唑(458);3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-5-(哌啶-4-基)-1,2,4-噁二唑(459);2-(3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)-N-甲基乙烷-1-胺(460);3-(3-乙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-5-(7-氮杂螺[3.5]壬烷-2-基)-1,2,4-噁二唑(461);(R)-3-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)-5-(哌啶-3-基)-1,2,4-噁二唑(462);(S)-1-(3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)丁烷-1,4-二胺(463);(S)-1-(3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,2,4-噁二唑-5-基)戊烷-1,5-二胺(464);2-(3,4-二甲氧基苯基)-3-异丙基-5-(1H-吡咯-3-基)-1H-吲哚(465);2-(3,4-二甲氧基苯基)-3-乙基-5-(吡啶-3-基)-1H-吲哚(466);4-(3-异丙基-5-(吡啶-3-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(467);6-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)喹喔啉(468);6-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)喹啉(469);5-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)异喹啉(470);或2-(3,4-二甲氧基苯基)-3-乙基-5-(吡啶-4-基)-1H-吲哚(471)。
7.药物组合物,其包含根据权利要求1-6中任一项所述的化合物或其药学上可接受的盐;和药学上可接受的载体。
8.根据权利要求1-6中任一项所述的化合物或其药学上可接受的盐在制备用于治疗自身免疫性疾病或慢性炎性疾病的药物中的用途。
9.根据权利要求8所述的用途,其中所述自身免疫性疾病或慢性炎性疾病选自系统性红斑狼疮(SLE)、类风湿性关节炎、多发性硬化(MS)和肖格伦综合征。
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CN111491918A (zh) | 2020-08-04 |
WO2019126253A1 (en) | 2019-06-27 |
SG11202005695PA (en) | 2020-07-29 |
JP7291707B2 (ja) | 2023-06-15 |
BR112020011981A2 (pt) | 2020-11-17 |
EP3728188B1 (en) | 2023-10-11 |
EA202091479A1 (ru) | 2020-11-24 |
AU2018393003A1 (en) | 2020-08-06 |
KR20200101400A (ko) | 2020-08-27 |
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