CN111491929A - 可用作tlr抑制剂的氨基吲哚化合物 - Google Patents
可用作tlr抑制剂的氨基吲哚化合物 Download PDFInfo
- Publication number
- CN111491929A CN111491929A CN201880081662.2A CN201880081662A CN111491929A CN 111491929 A CN111491929 A CN 111491929A CN 201880081662 A CN201880081662 A CN 201880081662A CN 111491929 A CN111491929 A CN 111491929A
- Authority
- CN
- China
- Prior art keywords
- dimethoxyphenyl
- isopropyl
- indol
- indole
- piperazin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003112 inhibitor Substances 0.000 title abstract description 10
- IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical class C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 151
- 150000003839 salts Chemical class 0.000 claims abstract description 47
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 24
- -1 dioxothiomorpholinyl Chemical group 0.000 claims description 218
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 58
- 150000003254 radicals Chemical class 0.000 claims description 58
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 52
- 201000006417 multiple sclerosis Diseases 0.000 claims description 49
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 45
- 229910052757 nitrogen Inorganic materials 0.000 claims description 37
- 125000002757 morpholinyl group Chemical group 0.000 claims description 35
- 125000004076 pyridyl group Chemical group 0.000 claims description 32
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 125000003386 piperidinyl group Chemical group 0.000 claims description 29
- 125000004193 piperazinyl group Chemical group 0.000 claims description 27
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 25
- 229910052801 chlorine Inorganic materials 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 150000001204 N-oxides Chemical class 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000005959 diazepanyl group Chemical group 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 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 16
- 125000003944 tolyl group Chemical group 0.000 claims description 15
- 239000003937 drug carrier Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 12
- 125000002393 azetidinyl group Chemical group 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 125000002948 undecyl 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])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 9
- JFNPNEAIJKWMSX-CYBMUJFWSA-N (3R)-N-[3-propan-2-yl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-indol-5-yl]pyrrolidine-3-carboxamide Chemical compound C(C)(C)C1=C(NC2=CC=C(C=C12)NC(=O)[C@H]1CNCC1)C1=C2C(=NC=C1)NN=C2 JFNPNEAIJKWMSX-CYBMUJFWSA-N 0.000 claims description 8
- KLBOVSWEOGCQSU-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-N,3-diethyl-N-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-indol-5-amine Chemical compound N1(CCC(N2CCC(N(C3=CC=C4NC(C5=CC(=C(C=C5)OC)OC)=C(C4=C3)CC)CC)CC2)CC1)C KLBOVSWEOGCQSU-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- VGQLXVMGALOXAO-UHFFFAOYSA-N 5-[4-(1,4-diazepan-1-yl)piperidin-1-yl]-2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indole Chemical compound N1(CCNCCC1)C1CCN(CC1)C=1C=C2C(=C(NC2=CC=1)C1=CC(=C(C=C1)OC)OC)C(C)C VGQLXVMGALOXAO-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- IULCIEBFFRMCDW-UHFFFAOYSA-N 1-[3-propan-2-yl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-indol-5-yl]imidazolidin-2-one Chemical compound CC(C)C1=C(NC2=CC=C(C=C12)N1CCNC1=O)C1=CC=NC2=C1C=NN2 IULCIEBFFRMCDW-UHFFFAOYSA-N 0.000 claims description 7
- YVLSNBJPFWCAGY-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-3-propan-2-yl-5-[4-(1-propan-2-ylazepan-4-yl)piperazin-1-yl]-1H-indole Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1C(C)C)N1CCN(CC1)C1CCN(CCC1)C(C)C YVLSNBJPFWCAGY-UHFFFAOYSA-N 0.000 claims description 7
- OQOYWPNIKQCROM-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-piperazin-1-yl-3-propan-2-yl-1H-indole Chemical class COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1C(C)C)N1CCNCC1 OQOYWPNIKQCROM-UHFFFAOYSA-N 0.000 claims description 7
- SPTACRJNTPNJSV-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-3-propan-2-yl-1H-indol-5-amine Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1C(C)C)NC1CC(N(C(C1)(C)C)C)(C)C SPTACRJNTPNJSV-UHFFFAOYSA-N 0.000 claims description 7
- WUJWTRGTVWUNAL-UHFFFAOYSA-N 3-[2-(dimethylamino)ethoxy]-1-[2-(2-methylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]pyrrolidin-2-one Chemical compound CN(CCOC1C(N(CC1)C=1C=C2C(=C(NC2=CC=1)C1=CC(=NC=C1)C)C(C)C)=O)C WUJWTRGTVWUNAL-UHFFFAOYSA-N 0.000 claims description 7
- LMTRLPVOFZQABZ-UHFFFAOYSA-N 3-[2-(methylamino)ethylamino]-1-[2-(2-methylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]pyrrolidin-2-one Chemical compound CNCCNC1CCN(C1=O)C1=CC=C2NC(=C(C(C)C)C2=C1)C1=CC(C)=NC=C1 LMTRLPVOFZQABZ-UHFFFAOYSA-N 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 7
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 7
- JFNPNEAIJKWMSX-ZDUSSCGKSA-N (3S)-N-[3-propan-2-yl-2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-indol-5-yl]pyrrolidine-3-carboxamide Chemical compound N1C[C@H](CC1)C(=O)NC=1C=C2C(=C(NC2=CC=1)C1=C2C(=NC=C1)NN=C2)C(C)C JFNPNEAIJKWMSX-ZDUSSCGKSA-N 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
- AHWHTNPWLYWPPW-UHFFFAOYSA-N 1-[2-(2,6-dimethylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]-3-(4-propan-2-ylpiperazin-1-yl)pyrrolidin-2-one Chemical compound CC(C)N1CCN(CC1)C1CCN(C1=O)C1=CC=C2NC(=C(C(C)C)C2=C1)C1=CC(C)=NC(C)=C1 AHWHTNPWLYWPPW-UHFFFAOYSA-N 0.000 claims description 6
- QXSBICPTEHJGIA-UHFFFAOYSA-N 1-[2-(2-methylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]imidazolidin-2-one Chemical compound CC(C)C1=C(NC2=CC=C(C=C12)N1CCNC1=O)C1=CC(C)=NC=C1 QXSBICPTEHJGIA-UHFFFAOYSA-N 0.000 claims description 6
- YWILYONFCMXQFM-UHFFFAOYSA-N 2-[4-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]piperazin-1-yl]-N-methylethanamine Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1C(C)C)N1CCN(CC1)CCNC YWILYONFCMXQFM-UHFFFAOYSA-N 0.000 claims description 6
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 6
- MNTFXNKPNNEWTE-UHFFFAOYSA-N 3-[2-aminoethyl(methyl)amino]-1-[2-(2-methylpyridin-4-yl)-3-propan-2-yl-1H-indol-5-yl]pyrrolidin-2-one Chemical compound NCCN(C1C(N(CC1)C=1C=C2C(=C(NC2=CC=1)C1=CC(=NC=C1)C)C(C)C)=O)C MNTFXNKPNNEWTE-UHFFFAOYSA-N 0.000 claims description 6
- ONXJEHLNFWIHQB-UHFFFAOYSA-N 5-[3-(1,4-diazepan-1-yl)azetidin-1-yl]-2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indole Chemical compound N1(CCNCCC1)C1CN(C1)C=1C=C2C(=C(NC2=CC=1)C1=CC(=C(C=C1)OC)OC)C(C)C ONXJEHLNFWIHQB-UHFFFAOYSA-N 0.000 claims description 6
- 125000003725 azepanyl group Chemical group 0.000 claims description 6
- 125000003566 oxetanyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 208000011580 syndromic disease Diseases 0.000 claims description 5
- UDSXCVPQTLSVMG-LJQANCHMSA-N (2R)-2-amino-N-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-4-methylpentanamide Chemical compound N[C@@H](C(=O)NC=1C=C2C(=C(NC2=CC=1)C1=CC(=C(C=C1)OC)OC)C(C)C)CC(C)C UDSXCVPQTLSVMG-LJQANCHMSA-N 0.000 claims description 4
- SOBYKXHXFDDVKA-IQMFZBJNSA-N (2R,3R)-2-amino-N-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-3-methylpentanamide Chemical compound N[C@@H](C(=O)NC=1C=C2C(=C(NC2=CC=1)C1=CC(=C(C=C1)OC)OC)C(C)C)[C@@H](CC)C SOBYKXHXFDDVKA-IQMFZBJNSA-N 0.000 claims description 4
- SCSASTCUJSMKTR-VWLOTQADSA-N (2S)-2-amino-N-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-2-phenylacetamide Chemical compound N[C@H](C(=O)NC=1C=C2C(=C(NC2=CC=1)C1=CC(=C(C=C1)OC)OC)C(C)C)C1=CC=CC=C1 SCSASTCUJSMKTR-VWLOTQADSA-N 0.000 claims description 4
- BVNWMNFUZIOOCE-KRWDZBQOSA-N (4S)-4-amino-5-[[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]amino]-5-oxopentanoic acid Chemical compound N[C@@H](CCC(=O)O)C(=O)NC=1C=C2C(=C(NC2=CC=1)C1=CC(=C(C=C1)OC)OC)C(C)C BVNWMNFUZIOOCE-KRWDZBQOSA-N 0.000 claims description 4
- IFGVYMZTDLYUAZ-UHFFFAOYSA-N 1-[1-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]piperidin-4-yl]-2-methyl-3,4-dihydro-1H-isoquinoline Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)N1CCC(CC1)C1N(C)CCC2=C1C=CC=C2 IFGVYMZTDLYUAZ-UHFFFAOYSA-N 0.000 claims description 4
- CPUGOFHESYXJFN-UHFFFAOYSA-N 1-[1-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]piperidin-4-yl]-4-hydroxypyrrolidin-2-one Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)N1CCC(CC1)N1CC(O)CC1=O CPUGOFHESYXJFN-UHFFFAOYSA-N 0.000 claims description 4
- RPZPVYMWEXBLOZ-UHFFFAOYSA-N 1-[1-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]piperidin-4-yl]-N,N-dimethylpiperidin-4-amine Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1C(C)C)N1CCC(CC1)N1CCC(CC1)N(C)C RPZPVYMWEXBLOZ-UHFFFAOYSA-N 0.000 claims description 4
- NLEFAIZNEZZBEX-UHFFFAOYSA-N 1-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-3-(dimethylamino)pyrrolidin-2-one Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1C(C)C)N1C(C(CC1)N(C)C)=O NLEFAIZNEZZBEX-UHFFFAOYSA-N 0.000 claims description 4
- XJCDJLUUGLGAIL-UHFFFAOYSA-N 1-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-4-[2-(dimethylamino)ethyl]-1,4-diazepan-5-one Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)N1CCN(CCN(C)C)C(=O)CC1 XJCDJLUUGLGAIL-UHFFFAOYSA-N 0.000 claims description 4
- DUGTVRQGEMFRRM-UHFFFAOYSA-N 1-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-N,N-dimethylpiperidin-4-amine Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)N1CCC(CC1)N(C)C DUGTVRQGEMFRRM-UHFFFAOYSA-N 0.000 claims description 4
- UIYZRMBWFPHGNR-UHFFFAOYSA-N 1-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-N,N-dimethylpyrrolidin-3-amine Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)N1CCC(C1)N(C)C UIYZRMBWFPHGNR-UHFFFAOYSA-N 0.000 claims description 4
- IVAJRYGUNZIMEY-UHFFFAOYSA-N 1-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]-N-(1-propan-2-ylpiperidin-4-yl)piperidin-4-amine Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)N1CCC(CC1)NC1CCN(CC1)C(C)C IVAJRYGUNZIMEY-UHFFFAOYSA-N 0.000 claims description 4
- DFUNYFUTZTYIRD-UHFFFAOYSA-N 1-[4-[1-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]piperidin-4-yl]-1,4-diazepan-1-yl]ethanone Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(=CC=C2N1)N1CCC(CC1)N1CCCN(CC1)C(C)=O DFUNYFUTZTYIRD-UHFFFAOYSA-N 0.000 claims description 4
- HVOSVHKJGADUCT-UHFFFAOYSA-N 1-[4-[1-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]piperidin-4-yl]piperazin-1-yl]ethanone Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1C(C)C)N1CCC(CC1)N1CCN(CC1)C(C)=O HVOSVHKJGADUCT-UHFFFAOYSA-N 0.000 claims description 4
- IGGAGOBKENGEDX-UHFFFAOYSA-N 1-[4-[4-[[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]amino]cyclohexyl]piperazin-1-yl]ethanone Chemical compound COC1=C(OC)C=C(C=C1)C1=C(C(C)C)C2=CC(NC3CCC(CC3)N3CCN(CC3)C(C)=O)=CC=C2N1 IGGAGOBKENGEDX-UHFFFAOYSA-N 0.000 claims description 4
- CFPBZGSPMQMLOU-UHFFFAOYSA-N 1-[4-[[1-[2-(3,4-dimethoxyphenyl)-3-propan-2-yl-1H-indol-5-yl]piperidin-4-yl]amino]piperidin-1-yl]ethanone Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1C(C)C)N1CCC(CC1)NC1CCN(CC1)C(C)=O CFPBZGSPMQMLOU-UHFFFAOYSA-N 0.000 claims description 4
- KFFUZFWIRNYSOD-UHFFFAOYSA-N 2-(2,6-dimethoxypyridin-4-yl)-3-ethyl-5-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-1H-indole Chemical compound COC1=NC(=CC(=C1)C=1NC2=CC=C(C=C2C=1CC)N1CCN(CC1)C1CCN(CC1)C)OC KFFUZFWIRNYSOD-UHFFFAOYSA-N 0.000 claims description 4
- IFMAKTASOPSASH-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-3-ethyl-5-(4-piperidin-4-yloxypiperidin-1-yl)-1H-indole Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1CC)N1CCC(CC1)OC1CCNCC1 IFMAKTASOPSASH-UHFFFAOYSA-N 0.000 claims description 4
- MMXZWEJCPTVPEN-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-3-ethyl-5-(4-piperidin-4-ylpiperidin-1-yl)-1H-indole Chemical compound N1(CCC(CC1)C1CCNCC1)C=1C=C2C(=C(NC2=CC=1)C1=CC(=C(C=C1)OC)OC)CC MMXZWEJCPTVPEN-UHFFFAOYSA-N 0.000 claims description 4
- UVSWLDHEJBSRBG-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-3-ethyl-5-[4-(1-ethylpiperidin-4-yl)oxypiperidin-1-yl]-1H-indole Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1CC)N1CCC(CC1)OC1CCN(CC1)CC UVSWLDHEJBSRBG-UHFFFAOYSA-N 0.000 claims description 4
- OSCCDFKDDWGOBU-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-3-ethyl-5-[4-(1-ethylpiperidin-4-yl)piperazin-1-yl]-1H-indole Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1CC)N1CCN(CC1)C1CCN(CC1)CC OSCCDFKDDWGOBU-UHFFFAOYSA-N 0.000 claims description 4
- GTEKYZATQIXIJN-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-3-ethyl-5-[4-(1-methylpiperidin-4-yl)-1,4-diazepan-1-yl]-1H-indole Chemical compound CCC1=C(NC2=CC=C(C=C12)N1CCCN(CC1)C1CCN(C)CC1)C1=CC(OC)=C(OC)C=C1 GTEKYZATQIXIJN-UHFFFAOYSA-N 0.000 claims description 4
- XNYBXVRQVWSJFO-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-3-ethyl-5-[4-(1-methylpiperidin-4-yl)oxypiperidin-1-yl]-1H-indole Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1CC)N1CCC(CC1)OC1CCN(CC1)C XNYBXVRQVWSJFO-UHFFFAOYSA-N 0.000 claims description 4
- CLHONIBDKRCCQH-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-3-ethyl-5-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-1H-indole Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1CC)N1CCN(CC1)C1CCN(CC1)C CLHONIBDKRCCQH-UHFFFAOYSA-N 0.000 claims description 4
- SGCYRZDGEZNDHE-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-3-ethyl-5-[4-(1-propan-2-ylpiperidin-4-yl)-1,4-diazepan-1-yl]-1H-indole Chemical compound CCC1=C(NC2=CC=C(C=C12)N1CCCN(CC1)C1CCN(CC1)C(C)C)C1=CC(OC)=C(OC)C=C1 SGCYRZDGEZNDHE-UHFFFAOYSA-N 0.000 claims description 4
- UIRUFGURZDZFAE-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-3-ethyl-5-[4-(1-propan-2-ylpiperidin-4-yl)oxypiperidin-1-yl]-1H-indole Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1CC)N1CCC(CC1)OC1CCN(CC1)C(C)C UIRUFGURZDZFAE-UHFFFAOYSA-N 0.000 claims description 4
- OETQUHWBCQUZFO-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-3-ethyl-5-[4-(1-propan-2-ylpiperidin-4-yl)piperazin-1-yl]-1H-indole Chemical compound COC=1C=C(C=CC=1OC)C=1NC2=CC=C(C=C2C=1CC)N1CCN(CC1)C1CCN(CC1)C(C)C OETQUHWBCQUZFO-UHFFFAOYSA-N 0.000 claims description 4
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- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 230000010472 type I IFN response Effects 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 235000016804 zinc Nutrition 0.000 description 1
Classifications
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
Abstract
公开式(I)化合物或其盐,其中G、R1、R5、R7、R8和n为本申请所定义。还公开使用这种化合物作为通过Toll样受体7或8或9的信号传导抑制剂的方法,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62/608,032的权益,其全部内容通过引用并入本申请。
描述
本发明总体上涉及氨基吲哚化合物,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。本申请提供了氨基吲哚化合物、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调节有关的病况,诸如炎症和自身免疫性疾病,以及抑制哺乳动物中TLR活性的方法。
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,NatureRev.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家族。作为模式识别受体,TLR抵抗外来分子,通过病原体相关分子模式(PAMP)激活,或保护受损组织,通过危险相关分子模式(DAMP)激活。已经鉴定了总共13个TLR家族成员,其中10个在人类中,这些家族成员跨越细胞表面或内体区室。TLR7/8/9属于内体定位的并且响应单链RNA(TLR7和TLR8)或含有胞嘧啶-磷酸-鸟嘌呤(CpG)基序的未甲基化单链DNA(TLR9)的集合。
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)。在自身免疫性病症的情况下,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的过度表达加剧了自身免疫性疾病,但发现小鼠中TLR7的敲除能够在易患狼疮的MRL/lpr小鼠中抵抗疾病。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,因此明显的是,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氨基吲哚化合物,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希望的稳定性、生物利用度、治疗指数和对其可药用性重要的毒性值的药物。
详述
本发明提供可用作通过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的式(I)的化合物,或其立体异构体、N-氧化物、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、代谢性、过敏性、自身免疫性和炎性疾病的方法,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,所述方法包括向需要其的哺乳动物给予至少一种式(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,其用于治疗。
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相关病况例如过敏性疾病、自身免疫性疾病、炎性疾病和增生性疾病。
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Toll样受体7、8或9相关病况。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过敏性疾病、自身免疫性疾病、炎性疾病和增生性疾病。
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-氧化物或盐,其中:
G为:
(iv)选自如下的9元杂环:
(v)选自如下的10元杂环:
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;条件为R2c和R2d之一为R2a,且R2c和R2d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;
R7为:
(i)R7a、-CH2R7a、-C(O)R7a、-C(O)CH(NH2)R7a、-C(O)(CH2)1-3NH2、-C(O)CH(NH2)(C1-4烷基)、-C(O)CH(NH2)(CH2)1-2C(O)OH、-C(O)CH(NH2)(CH2)2-4NH2或-C(O)CH(NH2)(CH2)1-3C(O)NH2;或
(ii)C3-6环烷基,其取代有一个选自如下的取代基:-NRx(CH2)2-3NRyRy、-NRx(甲基哌啶基)、-NRx(CH2)2-3(吗啉基)、二甲基氨基哌啶基和哌嗪基,其取代有选自如下的取代基:C1-4烷基、-C(O)CH3、-(CH2)1-2OCH3、-CH2(甲基苯基)、-(CH2)2-3(吡咯烷基)、C3-6环烷基、吡啶基和甲基哌啶基;
R7a为氮杂螺[3.5]壬基、C3-6环烷基、二氮杂螺[3.5]壬基、二氮杂螺[5.5]十一烷基、二氮杂环庚烷酮基(diazepanonyl)、二氮杂环庚烷基、吗啉基、苯基、哌嗪基、哌啶基、吡咯烷酮基、吡咯烷基或吡咯基,各自取代有0至1个选自如下的取代基:C1-3烷基、-NH2、甲基哌啶基、甲基吡咯烷基、-OCH2CH2(吡咯烷基)和-OCH2CH2NHCH2CH3;和0至4个选自-CH3的取代基;
R7b为:
(i)C1-4烷基、C1-3羟烷基、-(CH2)2-3C≡CH、-(CH2)1-2O(C1-2烷基)、-(CH2)1-2S(O)2(C1-2烷基)、-(CH2)0-3NRxRy、-CH2C(O)NRxRx、-NRx(C1-4羟烷基)、-NRy(C1-2氰基烷基)、-NRx(C1-2氟烷基)、-NRx(C2-4羟基氟烷基)、-NRx(CH2)1-2C(O)NRxRx、-NRx(CH2)1-3NRxRx、-NRxCH2CH2NRxRx、-NRxC(O)(CH2)1-2NRxRx、-O(CH2)1-3NRxRx、-C(O)CH2NRxRx、-(CH2)1-2R7d、-NHR7d、-NH(CH2)1-2R7d或-OR7d;或
(ii)氮杂环庚烷基、氮杂环丁烷基、二氮杂环庚烷基、二氧代硫代吗啉基、吗啉基、氧杂氮杂螺[3.3]庚基、氧杂环丁烷基、哌嗪酮基(piperazinonyl)、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基或四氢异喹啉基,各自取代有0至1个R8a和0至3个R8b;
每个R7c独立地为F、Cl、-CN、C1-2烷基、-CF3或-CH2CN;
R7d为氮杂螺[3.5]壬基、双环[1.1.1]戊基、C3-6环烷基、吗啉基、氧杂环丁烷基、苯基、哌啶基、吡唑基、吡咯烷基、四氢呋喃基或四氢吡喃基,各自取代有0至1个选自如下的取代基:C1-3烷基、-NRxRx、-C(O)CH3、甲基哌啶基、甲基吡咯烷基、四甲基哌啶基、-OCH2CH2(吡咯烷基)和-OCH2CH2NHCH2CH3;和0至4个选自-CH3的取代基;
R8为H或C1-3烷基;
或R7和R8与它们所连接的氮原子一起形成选自如下的杂环:氮杂环丁烷基、二氮杂环庚烷酮基、二氮杂环庚烷基、二氮杂螺[3.5]壬基、二氮杂螺[5.5]十一烷基、咪唑基、咪唑烷酮基、八氢-1H-吡咯并[3,4-b]吡啶基、哌嗪基、哌啶基、吡咯烷酮基、吡咯烷基和吡咯基,其中所述杂环取代有0至1个R7b和0至2个R7c;
R8a为-OH、C1-6烷基、C1-4氟烷基、C1-4羟烷基、-(CH2)1-2O(C1-3烷基)、-C(O)(C1-3烷基)、-(CH2)1-2(C3-6环烷基)、-(CH2)1-3(甲基苯基)、-(CH2)1-3(吡咯烷基)、-(CH2)1-3(甲基吡唑基)、-(CH2)1-3(噻吩基)、-NRxRx、C3-6环烷基、甲基哌啶基、吡啶基或嘧啶基;
每个R8b独立地为F、Cl、-CN、C1-3烷基或-CF3;
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 和R1、R2a、R2b、R2c、R2d、R5、R7、R8、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;和每个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;和每个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R1、R2、R5、R7、R8、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R1、R2、R5、R7、R8、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-氧化物或盐,其中G为:
(iv)和R1、R2、R2a、R2b、R5、R7、R8、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或-CH(CH3)2;每个R2独立地为Cl、-CH3或-OCH3;R2a为-CH3;
每个R2b独立地为H、Cl或-CH3;R7为:(i)-CH2(异丙基氮杂螺[3.5]壬基)、-CH2(甲基吡咯烷基)、-C(O)(CH2)1-3NH2、-C(O)CH(NH2)CH2CH2CH3、-C(O)CH(NH2)CH2CH(CH3)2、-C(O)CH(NH2)CH(CH3)CH2CH3、-C(O)CH(NH2)CH2CH2C(O)OH、-C(O)CH(NH2)(CH2)3-4NH2、-C(O)CH(NH2)(CH2)1-2C(O)NH2、-C(O)CH(NH2)(环己基)、-C(O)CH(NH2)(苯基)、-C(O)(氨基环己基)、-C(O)(吗啉基)、-C(O)(吡咯烷基)、五甲基哌啶基、甲基哌啶基-哌啶基、甲基吡咯烷基-吡咯烷基、或取代有-OCH2CH2(吡咯烷基)或-OCH2CH2NHCH2CH3的苯基;或(ii)环己基,所述环己基取代有-NRx(CH2)2-3N(CH3)2、-NHCH2CH2NHCH3、-NH(甲基哌啶基)、-NH(CH2)2-3(吗啉基)、二甲基氨基哌啶基,或哌嗪基,其取代有-CH3、-CH2CH3、-C(CH3)3、-CH2CH(CH3)2、-C(O)CH3、-CH2CH2OCH3、-CH2(甲基苯基)、-(CH2)2-3(吡咯烷基)、环戊基、吡啶基或甲基哌啶基;R8为H、-CH3或-CH2CH3;或R7和R8与它们所连接的氮原子一起形成选自如下的杂环:氮杂环丁烷基、二氮杂环庚烷酮基、二氮杂环庚烷基、二氮杂螺[3.5]壬基、二氮杂螺[5.5]十一烷基、咪唑烷酮基、八氢-1H-吡咯并[3,4-b]吡啶基、哌嗪基、哌啶基、吡咯烷酮基和吡咯烷基,其中所述杂环取代有0至1个R7b和0至2个R7c;R7b为:(i)-CH3、-CH(CH3)2、-C(CH3)2OH、-CH2CH2CH2C≡CH、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、-NRxRx、-NHCH2CH2NH(CH3)、-NHCH2CH2N(CH3)2、-N(CH3)CH2CH2NH2、-NRxCH2CH2CH2N(CH3)2、-OCH2CH2N(CH3)2、-CH2(苯基)、-CH2(甲基吡唑基)、-CH2CH2(吡咯烷基)、-NH(甲基哌啶基)、-NH(异丙基哌啶基)、-NH(五甲基哌啶基)、-NH(乙酰基哌啶基)、-NHCH2CH2(吗啉基)、-O(哌啶基)、-O(甲基哌啶基)、-O(乙基哌啶基)、-O(异丙基哌啶基)或-O(哌啶基)-(四甲基哌啶基);或(ii)氮杂环庚烷基、二氮杂环庚烷基、吗啉基、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基或四氢异喹啉基,各自取代有0至1个R8a和0至3个R8b;每个R7c独立地为-CH3或-CH2CN;R8a为-OH、-CH3、-CH2CH3、-CH(CH3)2、-C(CH3)3、-CH2CH(CH3)2、-CH2CH2OCH3、-CH2CH2CF3、-C(O)CH3、-CH2(环丙基)、-CH2(甲基苯基)、-(CH2)2-3(吡咯烷基)、-CH2(甲基吡唑基)、-CH2(噻吩基)、-NRxRx、环戊基、甲基哌啶基或吡啶基;每个R8b为-CH3;每个R5独立地为-CH3或-CH(CH3)2;每个Rx独立地为H或-CH3;n为0或1;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G、R5、R7、R8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或-CH(CH3)2。
一个实施方案提供式(I)化合物、其N-氧化物或盐,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G、R1、R5、R7、R8、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、C1-4烷氧基、-NRyRy、-C(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)、-S(O)2(C1-3烷基)、C3-6环烷基、吗啉基、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Cl、-CH3或-OCH3。另外,该实施方案中包括化合物,其中每个R2独立地为Cl、-CH3或-OCH3;和p为0、1、2或3。
一个实施方案提供式(I)化合物、其N-氧化物或盐,其中R7为-CH2R7a、-C(O)(CH2)1- 3NH2、-C(O)CH(NH2)(C1-4烷基)、-C(O)CH(NH2)(CH2)1-2C(O)OH、-C(O)CH(NH2)(CH2)2-4NH2、-C(O)CH(NH2)(CH2)1-3C(O)NH2、-C(O)CH(NH2)R7a、-C(O)R7a或R7a;R8为H或C1-3烷基;和G、R1、R5、R7a和n在第一方面中定义。该实施方案中包括化合物,其中R7为-CH2R7a、-C(O)(CH2)1-3NH2、-C(O)CH(NH2)(C1-4烷基)、-C(O)CH(NH2)(CH2)1-2C(O)OH、-C(O)CH(NH2)(CH2)2-4NH2、-C(O)CH(NH2)(CH2)1-3C(O)NH2、-C(O)CH(NH2)R7a、-C(O)R7a或R7a。该实施方案中还包括化合物,其中R7为-CH2(异丙基氮杂螺[3.5]壬基)、-CH2(甲基吡咯烷基)、-C(O)(CH2)1-3NH2、-C(O)CH(NH2)CH2CH2CH3、-C(O)CH(NH2)CH2CH(CH3)2、-C(O)CH(NH2)CH(CH3)CH2CH3、-C(O)CH(NH2)CH2CH2C(O)OH、-C(O)CH(NH2)(CH2)3-4NH2、-C(O)CH(NH2)(CH2)1-2C(O)NH2、-C(O)CH(NH2)(环己基)、-C(O)CH(NH2)(苯基)、-C(O)(氨基环己基)、-C(O)(吗啉基)、-C(O)(吡咯烷基)、五甲基哌啶基、甲基哌啶基-哌啶基、甲基吡咯烷基-吡咯烷基、或取代有-OCH2CH2(吡咯烷基)或-OCH2CH2NHCH2CH3的苯基;和R8为H或C1-2烷基。
一个实施方案提供式(I)化合物、其N-氧化物或盐,其中R7为C3-6环烷基,其取代有一个选自如下的取代基:-NRx(CH2)2-3NRyRy、-NRx(甲基哌啶基)、-NRx(CH2)2-3(吗啉基)、二甲基氨基哌啶基和哌嗪基,其取代有选自如下的取代基:C1-4烷基、-C(O)CH3、-(CH2)1-2OCH3、-CH2(甲基苯基)、-(CH2)2-3(吡咯烷基)、C3-6环烷基、吡啶基和甲基哌啶基;R8为H或C1-3烷基;和G、R1、R5、Rx、Ry和n在第一方面中定义。该实施方案中包括化合物,其中C3-6环烷基,其取代有一个选自如下的取代基:-NRx(CH2)2-3NRxRx、-NH(CH2)2-3NHCH3、-NH(甲基哌啶基)、-NH(CH2)2-3(吗啉基)、二甲基氨基哌啶基和哌嗪基,其取代有选自如下的取代基:C1-4烷基、-C(O)CH3、-(CH2)1-2OCH3、-CH2(甲基苯基)、-(CH2)2-3(吡咯烷基)、C3-6环烷基、吡啶基和甲基哌啶基。该实施方案中还包括化合物,其中R8为环己基,所述环己基取代有-NRx(CH2)2-3N(CH3)2、-NHCH2CH2NHCH3、-NH(甲基哌啶基)、-NH(CH2)2-3(吗啉基)、二甲基氨基哌啶基或哌嗪基,其取代有-CH3、-CH2CH3、-C(CH3)3、-CH2CH(CH3)2、-C(O)CH3、-CH2CH2OCH3、-CH2(甲基苯基)、-(CH2)2-3(吡咯烷基)、环戊基、吡啶基或甲基哌啶基;和R8为H或C1-2烷基。
一个实施方案提供式(I)化合物、其N-氧化物或盐,其中R7和R8与它们所连接的氮原子一起形成选自如下的杂环:氮杂环丁烷基、二氮杂环庚烷酮基、二氮杂环庚烷基、二氮杂螺[3.5]壬基、二氮杂螺[5.5]十一烷基、咪唑基、咪唑烷酮基、八氢-1H-吡咯并[3,4-b]吡啶基、哌嗪基、哌啶基、吡咯烷酮基、吡咯烷基和吡咯基,其中所述杂环取代有0至1个R7b和0至2个R7c;和G、R1、R5、R7b、R7c和n在第一方面中定义。该实施方案中包括化合物,其中R7和R8与它们所连接的氮原子一起形成选自如下的杂环:氮杂环丁烷基、二氮杂环庚烷酮基、二氮杂环庚烷基、二氮杂螺[3.5]壬基、二氮杂螺[5.5]十一烷基、咪唑烷酮基、八氢-1H-吡咯并[3,4-b]吡啶基、哌嗪基、哌啶基、吡咯烷酮基和吡咯烷基,其中所述杂环取代有0至1个R7b和0至2个R7c。该实施方案中还包括化合物,其中R7b为:(i)-CH3、-CH(CH3)2、-C(CH3)2OH、-CH2CH2CH2C≡CH、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、-NRxRx、-NHCH2CH2NH(CH3)、-NHCH2CH2N(CH3)2、-N(CH3)CH2CH2NH2、-NRxCH2CH2CH2N(CH3)2、-OCH2CH2N(CH3)2、-CH2(苯基)、-CH2(甲基吡唑基)、-CH2CH2(吡咯烷基)、-NH(甲基哌啶基)、-NH(异丙基哌啶基)、-NH(五甲基哌啶基)、-NH(乙酰基哌啶基)、-NHCH2CH2(吗啉基)、-O(哌啶基)、-O(甲基哌啶基)、-O(乙基哌啶基)、-O(异丙基哌啶基)或-O(哌啶基)-(四甲基哌啶基);或(ii)氮杂环庚烷基、二氮杂环庚烷基、吗啉基、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基或四氢异喹啉基,各自取代有0至1个R8a和0至3个R8b;和每个R7c独立地为-CH3或-CH2CN;和Rx、R8a和R8b在第一方面中定义。
一个实施方案提供式(I)化合物、其N-氧化物或盐,其中R7b为C1-4烷基、C1-3羟烷基、-(CH2)2-3C≡CH、-(CH2)0-3NRxRx、-NRx(CH2)1-3NRxRx、-N(CH3)CH2CH2NH2、-O(CH2)1-3NRxRx、-(CH2)1-2R7d、-NRxR7d、-NRx(CH2)1-2R7d或-OR7d;和G、R1、R5、R7、R8、R7d、Rx和n在第一方面中定义。该实施方案中包括化合物,其中R7b为C1-4烷基、C1-3羟烷基、-(CH2)2-3C≡CH、-(CH2)0-3NRxRx、-NRx(CH2)1-3NRxRx、-N(CH3)CH2CH2NH2、-O(CH2)1-3NRxRx、-(CH2)1-2R7d、-NHR7d、-NH(CH2)1-2R7d或-OR7d。该实施方案中还包括化合物,其中R7b为-CH3、-CH(CH3)2、-C(CH3)2OH、-CH2CH2CH2C≡CH、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、-NRxRx、-NHCH2CH2NH(CH3)、-NHCH2CH2N(CH3)2、-N(CH3)CH2CH2NH2、-NRxCH2CH2CH2N(CH3)2、-OCH2CH2N(CH3)2、-CH2(苯基)、-CH2(甲基吡唑基)、-CH2CH2(吡咯烷基)、-NH(甲基哌啶基)、-NH(异丙基哌啶基)、-NH(五甲基哌啶基)、-NH(乙酰基哌啶基)、-NHCH2CH2(吗啉基)、-O(哌啶基)、-O(甲基哌啶基)、-O(乙基哌啶基)、-O(异丙基哌啶基)或-O(哌啶基)-(四甲基哌啶基)。
一个实施方案提供式(I)化合物、其N-氧化物或盐,其中R7b为氮杂环庚烷基、二氮杂环庚烷基、吗啉基、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基或四氢异喹啉基,各自取代有0至1个R8a和0至3个R8b;每个R7c独立地为F、Cl、-CN、C1-2烷基、-CF3或-CH2CN;和G、R1、R5、R7、R8和n在第一方面中定义。该实施方案中包括化合物,其中R7b为氮杂环庚烷基、二氮杂环庚烷基、吗啉基、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基或四氢异喹啉基,各自取代有0至1个R8a和0至3个R8b;R8a为-OH、C1-4烷基、C1-3氟烷基、-(CH2)1-2O(C1-2烷基)、-C(O)(C1-2烷基)、-CH2(C3-6环烷基)、-(CH2)1-2(甲基苯基)、-(CH2)1-3(吡咯烷基)、-(CH2)1-2(甲基吡唑基)、-(CH2)1-2(噻吩基)、-NRxRx、C3-6环烷基、甲基哌啶基或吡啶基;每个R8b独立地为F或-CH3;和每个Rx独立地为H或-CH3。该实施方案中还包括化合物,其中R7b为氮杂环庚烷基、二氮杂环庚烷基、吗啉基、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基或四氢异喹啉基,各自取代有0至1个R8a和0至3个R8b。
一个实施方案提供式(I)化合物、其N-氧化物或盐,其中每个R5独立地为F、Cl、-CN、C1-3烷基、-CF3或-OCH3;n为0、1或2;和G、R1、R7、R8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、C1-3烷基、-CF3或-OCH3。该实施方案中还包括化合物,其中每个R5独立地为-CH3或-CH(CH3)2。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-氧化物或盐,其中所述化合物为(R)-N-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)吡咯烷-3-甲酰胺(9);(S)-N-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)吡咯烷-3-甲酰胺(10);2-氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)乙酰胺(11);4-氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)丁酰胺(12);N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡咯烷-3-甲酰胺(13);(R)-2-氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)戊酰胺(14);N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吗啉-2-甲酰胺(15);(R)-2-氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-4-甲基戊酰胺(16);(2R,3R)-2-氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-3-甲基戊酰胺(17);(S)-2-氨基-N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)琥珀酰胺(18);(R)-2-氨基-N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)琥珀酰胺(19);(S)-2,5-二氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)戊酰胺(20);(1R,2S)-2-氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)环己烷-1-甲酰胺(21);(R)-2-氨基-N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)戊二酰胺(22);(S)-2,6-二氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)己酰胺(23);(S)-4-氨基-5-((2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)氨基)-5-氧代戊酸(24);(S)-2-氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-2-苯基乙酰胺(25);(S)-2-氨基-2-环己基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)乙酰胺(26);2-(3,4-二甲氧基苯基)-N,3-二乙基-N-(1'-甲基-1,4'-联哌啶-4-基)-1H-吲哚-5-胺(28);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(2-(甲基氨基)乙基)环己烷-1,4-二胺(30-31);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(2-(二甲基氨基)乙基)环己烷-1,4-二胺(32-33);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(4-甲基哌嗪-1-基)环己基)-1H-吲哚-5-胺(34);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(2-(二甲基氨基)乙基)-N4-甲基环己烷-1,4-二胺(35);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(3-(二甲基氨基)丙基)环己烷-1,4-二胺(36-37);2-(3,4-二甲氧基苯基)-N-(4-(4-乙基哌嗪-1-基)环己基)-3-异丙基-1H-吲哚-5-胺(38-39);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(1-甲基哌啶-4-基)环己烷-1,4-二胺(40-41);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(3-(二甲基氨基)丙基)-N4-甲基环己烷-1,4-二胺(42-43);1-(4-(4-((2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)氨基)环己基)哌嗪-1-基)乙烷-1-酮(44-45);2-(3,4-二甲氧基苯基)-N-(4-(4-(二甲基氨基)哌啶-1-基)环己基)-3-异丙基-1H-吲哚-5-胺(46);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(2-吗啉代乙基)环己烷-1,4-二胺(47-48);N-(4-(4-(叔丁基)哌嗪-1-基)环己基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-胺(49-50);2-(3,4-二甲氧基苯基)-N-(4-(4-异丁基哌嗪-1-基)环己基)-3-异丙基-1H-吲哚-5-胺(51-53);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(4-(2-甲氧基乙基)哌嗪-1-基)环己基)-1H-吲哚-5-胺(54);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(3-吗啉代丙基)环己烷-1,4-二胺(55-56);N-(4-(4-环戊基哌嗪-1-基)环己基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-胺(57-58);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(4-(吡啶-4-基)哌嗪-1-基)环己基)-1H-吲哚-5-胺(59-60);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)环己基)-1H-吲哚-5-胺(61-62);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(4-(2-(吡咯烷-1-基)乙基)哌嗪-1-基)环己基)-1H-吲哚-5-胺(63-64);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(4-(4-甲基苄基)哌嗪-1-基)环己基)-1H-吲哚-5-胺(65-66);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(4-(3-(吡咯烷-1-基)丙基)哌嗪-1-基)环己基)-1H-吲哚-5-胺(67);2-(3,4-二甲氧基苯基)-3-异丙基-N-(1,2,2,6,6-五甲基哌啶-4-基)-1H-吲哚-5-胺(103);2-(3,4-二甲氧基苯基)-3-异丙基-N-甲基-N-((1-甲基吡咯烷-2-基)甲基)-1H-吲哚-5-胺(104);2-(3,4-二甲氧基苯基)-N-(4-(2-(乙基氨基)乙氧基)苯基)-3-异丙基-1H-吲哚-5-胺(105);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吲哚-5-胺(106);2-(3,4-二甲氧基苯基)-3-乙基-N-((7-异丙基-7-氮杂螺[3.5]壬烷-2-基)甲基)-1H-吲哚-5-胺(124);或2-(3,4-二甲氧基苯基)-3-乙基-N-(1'-甲基-[1,4'-联哌啶]-4-基)-1H-吲哚-5-胺(125)。
在一个实施方案中,提供式(I)化合物或其盐,其中所述化合物为1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-3-((2-(甲基氨基)乙基)氨基)吡咯烷-2-酮(1);3-((2-氨基乙基)(甲基)氨基)-1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡咯烷-2-酮(2);1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-3-(二甲基氨基)吡咯烷-2-酮(3-4);1-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-3-(4-异丙基哌嗪-1-基)吡咯烷-2-酮(5-6);3-(2-(二甲基氨基)乙氧基)-1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡咯烷-2-酮(7);1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)咪唑烷-2-酮(8);1-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)咪唑烷-2-酮(27);5-(3-(1,4-二氮杂环庚烷-1-基)氮杂环丁烷-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(29);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(2,2,6,6-四甲基-1l2-哌啶-4-基)哌嗪-1-基)-1H-吲哚(68);2-(3,4-二甲氧基苯基)-3-乙基-6-异丙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚(69);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(吡咯烷-1-基)哌啶-1-基)-1H-吲哚(70);2-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-N,N-二甲基乙烷-1-胺(71);N1-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-N2-甲基乙烷-1,2-二胺(72);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(哌嗪-1-基)哌啶-1-基)-1H-吲哚(73);4-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)吗啉(74);N1-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-N2,N2-二甲基乙烷-1,2-二胺(75);N1-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-N3,N3-二甲基丙烷-1,3-二胺(76-77);2-(3,4-二甲氧基苯基)-5-(4-(4-乙基哌嗪-1-基)哌啶-1-基)-3-异丙基-1H-吲哚(78);1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(1-甲基哌啶-4-基)哌啶-4-胺(79);4-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-2,6-二甲基吗啉(80);N1-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-N1,N3,N3-三甲基丙烷-1,3-二胺(81);1-(4-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)哌嗪-1-基)乙烷-1-酮(82);1'-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N,N-二甲基-[1,4'-联哌啶]-4-胺(83);2-(3,4-二甲氧基苯基)-5-(4-(4-乙基-1,4-二氮杂环庚烷-1-基)哌啶-1-基)-3-异丙基-1H-吲哚(84);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-异丙基哌嗪-1-基)哌啶-1-基)-1H-吲哚(85);1-(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)哌啶-4-胺(86);5-(4-(4-(环丙基甲基)哌嗪-1-基)哌啶-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(87);1-(4-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-1,4-二氮杂环庚烷-1-基)乙烷-1-酮(88);1-(4-((1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)氨基)哌啶-1-基)乙烷-1-酮(89);5-(4-(4-(叔丁基)哌嗪-1-基)哌啶-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(90);2-(3,4-二甲氧基苯基)-5-(4-(4-异丁基哌嗪-1-基)哌啶-1-基)-3-异丙基-1H-吲哚(91);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-(2-甲氧基乙基)哌嗪-1-基)哌啶-1-基)-1H-吲哚(92);5-(4-(4-环戊基哌嗪-1-基)哌啶-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(93);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-(吡啶-4-基)哌嗪-1-基)哌啶-1-基)-1H-吲哚(94);N-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-1,2,2,6,6-五甲基哌啶-4-胺(95);2-(3,4-二甲氧基苯基)-3-异丙基-5-(1'-((1-甲基-1H-吡咯-2-基)甲基)-[4,4'-联哌啶]-1-基)-1H-吲哚(96);2-(3,4-二甲氧基苯基)-3-异丙基-5-(1'-(3,3,3-三氟丙基)-[4,4'-联哌啶]-1-基)-1H-吲哚(97);2-(3,4-二甲氧基苯基)-3-异丙基-5-(1'-(噻吩-3-基甲基)-[4,4'-联哌啶]-1-基)-1H-吲哚(98);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)哌啶-1-基)-1H-吲哚(99);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-(2-(吡咯烷-1-基)乙基)哌嗪-1-基)哌啶-1-基)-1H-吲哚(100);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-(4-甲基苄基)哌嗪-1-基)哌啶-1-基)-1H-吲哚(101);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-(3-(吡咯烷-1-基)丙基)哌嗪-1-基)哌啶-1-基)-1H-吲哚(102);1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-4-(2-(二甲基氨基)乙基)-1,4-二氮杂环庚烷-5-酮(107);1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N,N-二甲基哌啶-4-胺(108);2-(4-氨基-1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)乙腈(109);2-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)丙-2-醇(110);3-氯-5-(5-(4-(二甲基氨基)哌啶-1-基)-3-异丙基-1H-吲哚-2-基)-1,4-二甲基-1l4,2l5-吡啶-2-酮(111);2-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-4-(甲基氨基)哌啶-4-基)乙腈(112);2-(3,4-二甲氧基苯基)-3-异丙基-5-(2-(吡啶-4-基)哌啶-1-基)-1H-吲哚(113);2-((1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)氧基)-N,N-二甲基乙烷-1-胺(114);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(2-(吡咯烷-1-基)乙基)哌啶-1-基)-1H-吲哚(115);1-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-4-羟基吡咯烷-2-酮(116);4-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-4-甲基哌啶-4-基)吗啉(117);6-苄基-1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)八氢-1H-吡咯并[3,4-b]吡啶(118);1-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-2-甲基-1,2,3,4-四氢异喹啉(119);1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N,N-二甲基吡咯烷-3-胺(120);5-(4-(1,4-二氮杂环庚烷-1-基)哌啶-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(121);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(1-异丙基氮杂环庚烷-4-基)哌嗪-1-基)-1H-吲哚(122);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)哌啶-1-基)-1H-吲哚(123);2-(3,4-二甲氧基苯基)-3-异丙基-5-(哌嗪-1-基)-1H-吲哚,TFA盐(126);2-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌嗪-1-基)-N-甲基乙胺(127);4-(3-异丙基-5-(哌嗪-1-基)-1H-吲哚-2-基)-1H-吡咯并[2,3-b]吡啶(128);2-(2,6-二甲氧基吡啶-4-基)-3-乙基-5-(哌嗪-1-基)-1H-吲哚(129);4-(3-异丙基-6-甲基-5-(哌嗪-1-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(130);5-([4,4'-联哌啶]-1-基)-2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚(131);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(哌啶-4-基氧基)哌啶-1-基)-1H-吲哚(132);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(哌啶-4-基氧基)哌啶-1-基)-1H-吲哚(133);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-((1-甲基哌啶-4-基)氧基)哌啶-1-基)-1H-吲哚(134);6-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)八氢-1H-吡咯并[3,4-b]吡啶(135);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-2,6-二氮杂螺[3.5]壬烷(136);2-(4-(3-乙基-2-(2-甲氧基吡啶-4-基)-1H-吲哚-5-基)哌嗪-1-基)-N-甲基乙烷-1-胺(137);2-(4-(3-异丙基-2-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吲哚-5-基)哌嗪-1-基)-N-甲基乙烷-1-胺(138);3-乙基-5-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(139);2-(4-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)哌嗪-1-基)-N-甲基乙烷-1-胺(140);4-(3-甲基-5-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚-2-基)-1H-吡咯并[2,3-b]吡啶(141);3-乙基-5-(4-(1-乙基哌啶-4-基)哌嗪-1-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(142);3-乙基-2-(2-甲氧基吡啶-4-基)-5-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(143);2-(4-(2-(3,4-二甲氧基苯基)-3-乙基-6-甲基-1H-吲哚-5-基)哌嗪-1-基)-N-甲基乙烷-1-胺(144);4-(5-(4-(1-乙基哌啶-4-基)哌嗪-1-基)-3-甲基-1H-吲哚-2-基)-1H-吡咯并[2,3-b]吡啶(145);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(戊-4-炔-1-基)哌嗪-1-基)-1H-吲哚(146);3-乙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(147);3-乙基-5-(4-(1-乙基哌啶-4-基)哌嗪-1-基)-2-(2-甲氧基吡啶-4-基)-1H-吲哚(148);2-(3,4-二甲氧基苯基)-3-甲基-5-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(149);2-(4-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-3,3-二甲基哌嗪-1-基)-N-甲基乙烷-1-胺(150);4-(5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-3-甲基-1H-吲哚-2-基)-1H-吡咯并[2,3-b]吡啶(151);3-乙基-5-(4-(1-异丁基哌啶-4-基)哌嗪-1-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(152);3-乙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-2-(2-甲氧基吡啶-4-基)-1H-吲哚(153);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(154);2-(3,4-二甲氧基苯基)-5-(4-(1-乙基哌啶-4-基)哌嗪-1-基)-3-甲基-1H-吲哚(155);2-(2,6-二甲氧基吡啶-4-基)-3-乙基-5-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(156);4-(3-乙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚-2-基)-1H-吡咯并[2,3-b]吡啶(157);4-(5-(4-(1-异丁基哌啶-4-基)哌嗪-1-基)-3-甲基-1H-吲哚-2-基)-1H-吡咯并[2,3-b]吡啶(158);4-(3-乙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(159);3-乙基-5-(4-(1-异丁基哌啶-4-基)哌嗪-1-基)-2-(2-甲氧基吡啶-4-基)-1H-吲哚(160);3-乙基-2-(2-甲氧基吡啶-4-基)-5-(4-(2,2,6,6-四甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(161);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(162);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(1-乙基哌啶-4-基)哌嗪-1-基)-1H-吲哚(163);2-(3,4-二甲氧基苯基)-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-3-甲基-1H-吲哚(164);4-(3-乙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚-2-基)-1-甲基-1H-吡咯并[2,3-b]吡啶(165);4-(3-异丙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚-2-基)-1H-吡咯并[2,3-b]吡啶(166);4-(3-异丙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(167-168);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚(169);2-(3,4-二甲氧基苯基)-5-(4-(1-异丁基哌啶-4-基)哌嗪-1-基)-3-甲基-1H-吲哚(170);2-(3,4-二甲氧基苯基)-3-甲基-5-(4-(2,2,6,6-四甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(171);2-(3,4-二甲氧基苯基)-5-(2,2-二甲基-4-(1-甲基哌啶-4-基)哌嗪-1-基)-3-乙基-1H-吲哚(172);2-(2,6-二甲氧基吡啶-4-基)-3-乙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚(173-174);4-(3-异丙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-6-甲基-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(175);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(2,2,6,6-四甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(176);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(1-异丁基哌啶-4-基)哌嗪-1-基)-1H-吲哚(177);2-(4-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,4-二氮杂环庚烷-1-基)-N-甲基乙烷-1-胺(178);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(1-甲基哌啶-4-基)-1,4-二氮杂环庚烷-1-基)-1H-吲哚(179);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(1-异丙基哌啶-4-基)-1,4-二氮杂环庚烷-1-基)-1H-吲哚(180);3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-9-甲基-3,9-二氮杂螺[5.5]十一烷(181);3-乙基-5-(4-((1-异丙基哌啶-4-基)氧基)哌啶-1-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(182);3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-9-异丙基-3,9-二氮杂螺[5.5]十一烷(183);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-1H-吲哚(184);4-(3-乙基-5-(4-((1-异丙基哌啶-4-基)氧基)哌啶-1-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(185);3-(2-(3,4-二甲氧基苯基)-3-乙基-6-甲基-1H-吲哚-5-基)-9-异丙基-3,9-二氮杂螺[5.5]十一烷(186);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-((1-甲基哌啶-4-基)氧基)哌啶-1-基)-1H-吲哚(187);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-((1-乙基哌啶-4-基)氧基)哌啶-1-基)-1H-吲哚(188);3-((1-甲基-1H-吡咯-2-基)甲基)-9-(3-甲基-2-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吲哚-5-基)-3,9-二氮杂螺[5.5]十一烷(189);2-(3,4-二甲氧基苯基)-5-(4-((1-乙基哌啶-4-基)氧基)哌啶-1-基)-3-异丙基-1H-吲哚(190);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-((1-异丙基哌啶-4-基)氧基)哌啶-1-基)-1H-吲哚(191);1-(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)哌啶-4-胺(192);或2-(3,4-二甲氧基苯基)-3-乙基-5-(4-((2',2',6',6'-四甲基-[1,4'-联哌啶]-4-基)氧基)哌啶-1-基)-1H-吲哚(193)。
在不脱离本发明的精神或本质属性的情况下,本发明可以其他特定形式实施。本发明包括本申请提到的发明的方面和/或实施方案的所有组合。应理解,可以采用本发明的任何和所有实施方案结合任何其他一个或多个实施方案来描述另外的实施方案。还应理解,这些实施方案中的每个单独要素意在与来自任何实施方案中的任何和所有其他要素组合来描述另外的实施方案。
定义
在阅读下面详细描述时,本领域普通技术人员可以更容易地理解本发明的特征和优点。应当理解,为了清楚起见,在单独的实施方案的背景下,上面和下面描述的本发明的某些特征也可以组合以形成单个实施方案。相反,出于简洁性原因而在单个实施方案的上下文中描述的本发明的各种特征还可以组合以形成其子组合。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/一种或者一个/一种或多个/多种。
如本申请所用,短语“化合物”是指至少一种化合物。例如,式(I)的化合物包括一种式(I)的化合物以及两种或更多种式(I)的化合物。
除非另外指明,否则假定具有不满足的化合价的任何杂原子具有足以满足化合价的氢原子。
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。这些定义适用于在整个说明书中单独使用或者作为较大基团的一部分使用时的术语(除非它们在特定情况下另有限制)。
在整个说明书中,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”意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”意在包括被一个或多个氟原子取代的C1、C2、C3和C4烷基。氟烷基的代表性实例包括但不限于-CF3和-CH2CF3。
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去除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连接的烷基,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。
如本申请所用的术语“烷氧基烷基”是指通过氧原子与烷基连接的烷氧基,其与母体分子部分进行连接,例如,甲氧基甲基(-CH2OCH3)。例如,“C2-4烷氧基烷基”指代具有2至4个碳原子的烷氧基烷基,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)的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式(I)的化合物为无定形固体。
还应当理解,式(I)的化合物的溶剂化物(例如,水合物)也在本发明的范围内。术语“溶剂化物”意指式(I)的化合物与一个或多个溶剂分子(无论是有机的还是无机的)的物理缔合物。这种物理缔合物包括氢键合。在某些情况下,溶剂化物将能够分离,例如当一个或多个溶剂分子掺入结晶固体的晶格中时。“溶剂化物”包括溶液相和可分离溶剂化物两者。示例性溶剂化物包括水合物、乙醇化物、甲醇化物、异丙醇化物、乙腈溶剂化物和乙酸乙酯溶剂化物。溶剂化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,可以分离并且纯化式(I)的化合物(在其制备之后),以获得含有按重量计等于或大于99%的量的式(I)的化合物(“基本上纯的”)的组分,该组分然后如本申请所描述而使用或配制。此类“基本上纯的”式(I)的化合物在本申请中也被考虑作为是本发明的一部分。
“稳定的化合物”和“稳定的结构”意在指示足够稳固以经受以有用纯度程度从反应混合物中分离并且配制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量,这些活性成分有效充当TLR7/8/9的抑制剂,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(MS)和肖格伦综合征,以及类风湿性关节炎。
如本申请所用,“治疗”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倾向于患该疾病状态,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)缓解该疾病状态,即引起该疾病状态的消退。
本发明的化合物旨在包括在本发明化合物中存在的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。通过一般举例而非限制的方式,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的化合物通常可以通过本领域技术人员已知的常规技术或通过与本申请所述的那些类似的方法,使用适当的同位素标记的试剂代替以其他方式使用的未标记的试剂来制备。例如,甲基(-CH3)还包括氘代甲基,诸如-CD3。
效用
人类免疫系统已经进化使身体抵御可能导致感染、疾病或死亡的微生物、病毒和寄生虫。复杂的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,同时不会对个体造成永久性或显著损害。虽然此时尚未充分理解起始事件,但在自身免疫性疾病状态中,免疫系统将其炎症反应引导至遭受痛苦的个体中的靶器官。不同的自身免疫疾病典型地以主要或初始靶器官或受影响组织为特征;诸如类风湿性关节炎情况下的关节、桥本氏甲状腺炎情况下的甲状腺、多发性硬化情况下的中枢神经系统、I型糖尿病情况下的胰腺以及炎性肠病情况下的肠。
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)的化合物具有治疗与通过TLR7、TLR8或TLR9中的一种或多种的信号传导的抑制相关的病况的效用。此类病况包括TLR7、TLR8或TLR9受体相关的疾病,其中细胞因子水平因细胞内信号传导而被调节。
如本申请所用,术语“治疗”涵盖对哺乳动物(特别是人类)中疾病状态的治疗,并且包括:(a)预防或延迟哺乳动物中疾病状态的发生,特别是当这种哺乳动物倾向于患该疾病状态但尚未被诊断为具有该疾病状态时;(b)抑制该疾病状态,即,阻止其发展;和/或(c)实现症状或疾病状态的完全或部分缓解,和/或减轻、改善、减小或治愈疾病或病症和/或其症状。
鉴于它们作为TLR7、TLR8或TLR9的选择性抑制剂的活性,式(I)的化合物可分别用于治疗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、溃疡性结肠炎、哮喘、移植物抗宿主病、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、类风湿性关节炎、系统性红斑狼疮、狼疮肾炎、皮肤狼疮、银屑病;自身炎性疾病,包括Cryopyrin相关的周期性综合征(CAPS)、TNF受体相关的周期性综合征(TRAPS)、家族性地中海热(FMF)、成人斯蒂尔病、全身性发作的幼年特发性关节炎、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(destructive bonedisorder),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;增殖性疾病,诸如急性骨髓性白血病、慢性骨髓性白血病;血管生成疾病,诸如包括实体瘤、眼部新生血管和婴儿血管瘤的血管生成疾病;感染性疾病,诸如败血症、败血性休克和志贺氏菌病;神经变性疾病,诸如阿尔茨海默病、帕金森病、由创伤性损伤引起的脑缺血或神经变性疾病;肿瘤疾病和病毒性疾病,诸如转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤和HIV感染及CMV视网膜炎、AIDS。
更具体地,可用本发明化合物治疗的具体病况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、痛风性关节炎和其他关节炎病症、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;血管生成疾病,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相关的病况、以及寻常型天疱疮。该实施方案中包括其中病况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。还包括其中病况选自缺血再灌注损伤的治疗方法,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况是多发性骨髓瘤的方法。
在一个实施方案中,式(I)的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相关的病况包括水肿、镇痛、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况的方法,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)的化合物或其盐。“治疗有效量”旨在包括当单独或组合给予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相关的病况的方法可以包括单独或彼此组合和/或与用于治疗此类病况的其他合适治疗剂组合给予式(I)的化合物。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。
此类其他治疗剂的例子包括皮质类固醇、咯利普兰、钙磷酸蛋白C、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、一氧化氮和其他免疫抑制剂;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使用时,以上其他治疗剂可以例如以Physicians’DeskReference(PDR)中指示的或者如在其他方面由本领域普通技术人员确定的那些量使用。在本发明的方法中,此类其他一种或多种治疗剂可在本发明化合物之前、同时或之后给予。本发明还提供了能够治疗TLR7/8/9受体相关的病况的药物组合物,包括如上所描述的IL-1家族受体介导的疾病。
本发明的组合物可以含有如上所描述的其他治疗剂,并且可以例如通过使用常规的固体或液体媒介物或稀释剂以及适合于所希望的给予方式的类型的药物添加剂(例如,赋形剂、粘合剂、防腐剂、稳定剂、调味剂等)根据药物配制领域熟知的那些技术来配制。
因此,本发明还包括含有一种或多种式(I)的化合物和药学上可接受的载体的组合物。
“药学上可接受的载体”是指本领域通常接受用于将生物活性剂递送至动物、特别是哺乳动物的介质。药学上可接受的载体根据本领域普通技术人员认知范围内的许多因素来配制。这些包括但不限于所配制的活性剂的类型和性质;待被给予含有药剂的组合物的受试者;给予该组合物的预期途径;以及所针对的治疗适应症。药学上可接受的载体包括水性和非水性液体介质两者,以及多种固体和半固体剂型。此类载体还可包括除活性剂之外的许多不同的成分和添加剂,此类另外的成分出于本领域普通技术人员熟知的多种原因(例如,活性剂、粘合剂等的稳定化)被包括在配制品中。合适的药学上可接受的载体及其选择中涉及的因素的描述在多种可容易获得的来源(例如Remington’s PharmaceuticalSciences,第17版(1985))中找到,将其通过引用以其全文并入本申请。
根据式(I)的化合物可以通过适用于待治疗病况的任何手段给予,这可取决于位点特异性治疗或待递送的式(I)的化合物的量的需要。
本发明中还包括一类药物组合物,其包含式(I)的化合物和一种或多种无毒的药学上可接受的载体和/或稀释剂和/或佐剂(在本申请中统称为“载体”材料),以及(如果希望)其他活性成分。式(I)的化合物可以通过任何合适的途径、优选以适于此类途径的药物组合物的形式,并且以对于预期治疗有效的剂量给予。本发明的化合物和组合物可以例如经口服、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)以含有常规药学上可接受的载体、佐剂和媒介物的剂量单位配制品给予。例如,该药物载体可含有甘露醇或乳糖和微晶纤维素的混合物。该混合物可含有另外的组分,诸如润滑剂(例如,硬脂酸镁)和崩解剂(诸如交聚维酮)。载体混合物可以填充到明胶胶囊中或压缩成片剂。例如,该药物组合物可以作为口服剂型或输注给予。
对于口服给予,该药物组合物可以呈例如片剂、胶囊剂、液体胶囊剂、悬浮液或液体的形式。该药物组合物优选地以含有特定量活性成分的剂量单位的形式制备。例如,该药物组合物可以提供为片剂或胶囊剂,该片剂或胶囊剂包含在约0.1至1000mg、优选约0.25至250mg、并且更优选约0.5至100mg范围内的量的活性成分。对于人或其他哺乳动物,合适的日剂量可以根据患者的状况和其他因素而广泛变化,但是可以使用常规方法来确定。
本申请预期的任何药物组合物可以例如通过任何可接受且合适的口服制剂口服递送。示例性的口服制剂包括但不限于例如片剂、锭剂、糖锭剂、水性和油性悬浮液、可分散粉剂或颗粒剂、乳剂、硬和软胶囊剂、液体胶囊剂、糖浆剂和酏剂。旨在用于口服给予的药物组合物可根据本领域已知的用于制备旨在用于口服给予的药物组合物的任何方法来制备。为了提供药学上可口的制剂,根据本发明的药物组合物可以含有至少一种选自甜味剂、调味剂、着色剂、缓和剂、抗氧化剂和防腐剂的药剂。
片剂可以例如通过将至少一种式(I)的化合物与至少一种适用于制造片剂的无毒的药学上可接受的赋形剂混合来制备。示例性的赋形剂包括但不限于例如惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙和磷酸钠;制粒剂和崩解剂,例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉和海藻酸;粘合剂,例如淀粉、明胶、聚乙烯吡咯烷酮和阿拉伯胶;以及润滑剂,例如硬脂酸镁、硬脂酸和滑石。另外,片剂可以是未包衣的,或通过已知技术包衣,以掩盖尝起来令人不快的药物的不良味道,或延迟胃肠道中活性成分的崩解和吸收,从而维持活性成分的作用持续更长时间。示例性的水溶性味道掩蔽材料包括但不限于羟丙基甲基纤维素和羟丙基纤维素。示例性的延时材料包括但不限于乙基纤维素和乙酸丁酸纤维素。
硬明胶胶囊剂可以例如通过将至少一种式(I)的化合物与至少一种惰性固体稀释剂(例如碳酸钙;磷酸钙;和高岭土)混合来制备。
软明胶胶囊剂可以例如通过将至少一种式(I)的化合物与至少一种水溶性载体(例如聚乙二醇)和至少一种油介质(例如花生油、液体石蜡和橄榄油)混合来制备。
水性悬浮液可以例如通过将至少一种式(I)的化合物与至少一种适合于制造水性悬浮液的赋形剂混合来制备。适合于生产水性悬浮液的示例性的赋形剂包括但不限于例如悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、海藻酸、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶;分散剂或润湿剂,例如天然存在的磷脂,例如卵磷脂;环氧烷与脂肪酸的缩合产物,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,例如十七烷乙烯-氧基鲸蜡醇;环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物,例如聚氧乙烯山梨糖醇单油酸酯;以及环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物,例如聚乙烯脱水山梨糖醇单油酸酯。水性悬浮液还可以含有至少一种防腐剂,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。
油性悬浮液可以例如通过将至少一种式(I)的化合物悬浮在植物油(例如花生油;橄榄油;芝麻油;和椰子油)或矿物油(例如,液体石蜡)中来制备。油性悬浮液还可以包含至少一种增稠剂,例如蜂蜡、硬石蜡和鲸蜡醇。为提供可口的油性悬浮液,可以将至少一种上文已经描述的甜味剂和/或至少一种调味剂添加至该油性悬浮液中。油性悬浮液还可以含有至少一种防腐剂,包括但不限于例如抗氧化剂,例如丁基化羟基茴香醚和α-生育酚。
可分散粉剂和颗粒剂可以例如通过将至少一种式(I)的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来制备。合适的分散剂、润湿剂和悬浮剂是如上已描述的。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,可分散粉剂和颗粒剂还可以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)的化合物的乳剂可以例如制备为水包油乳剂。包含式(I)的化合物的乳剂的油相可以已知方式由已知成分构成。油相可以通过但不限于例如植物油(例如橄榄油和花生油)、矿物油(例如液体石蜡)及其混合物来提供。虽然该相可以仅包含乳化剂,但是它可以包含至少一种乳化剂与脂肪或油或与脂肪和油两者的混合物。合适的乳化剂包括但不限于例如天然存在的磷脂,例如大豆卵磷脂;衍生自脂肪酸和己糖醇酐的酯或偏酯,例如脱水山梨糖醇单油酸酯;以及偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨糖醇单油酸酯。优选地,亲水性乳化剂与亲脂性乳化剂一起被包括,所述亲脂性乳化剂用作稳定剂。还优选的是包括油和脂肪两者。乳化剂与或不与稳定剂一起构成所谓的乳化蜡,并且蜡与油和脂肪一起构成所谓的乳化软膏基质,其形成乳膏配制品的油性分散相。乳剂还可以含有甜味剂、调味剂、防腐剂和/或抗氧化剂。适用于本发明配制品的乳化剂和乳剂稳定剂包括吐温60、司盘80、十六十八醇、肉豆蔻醇、单硬脂酸甘油酯、十二烷基硫酸钠、单独或与蜡一起的二硬脂酸甘油酯、或本领域熟知的其他材料。
例如,式(I)的化合物还可以经由任何药学上可接受且合适的可注射形式经静脉内、皮下和/或肌肉内递送。示例性的可注射形式包括但不限于例如无菌水溶液,其包含可接受的媒介物和溶剂,例如水、林格氏溶液和等渗氯化钠溶液;无菌水包油微乳剂;以及水性或油性悬浮液。
用于肠胃外给予的配制品可以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以使用提及的用于在供口服给予的配制品中使用的一种或多种载体或稀释剂或者通过使用其他合适的分散剂或润湿剂和悬浮剂由无菌粉剂或颗粒剂制备。可以将化合物溶于水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苯甲醇、氯化钠溶液、黄蓍胶和/或各种缓冲剂中。其他佐剂和给药方式在制药领域中是众所周知的。活性成分也可以通过注射作为与合适的载体(包括盐水、右旋糖或水)或与环糊精(即Captisol)、共溶剂增溶(即丙二醇)或胶束增溶(即吐温80)的组合物来给予。
无菌可注射制剂还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如作为在1,3-丁二醇中的溶液。可以使用的可接受的媒介物和溶剂是水、林格氏溶液和等渗氯化钠溶液。此外,无菌的固定油通常用作溶剂或悬浮介质。为了这个目的,可以使用任何温和的固定油,包括合成的甘油单酯或甘油二酯。此外,脂肪酸诸如油酸可用于制备可注射剂。
无菌可注射水包油微乳剂可以例如通过以下方式来制备:1)将至少一种式(I)的化合物溶于油相(例如大豆油和卵磷脂的混合物)中;2)将含式(I)的油相与水和甘油混合物组合;和3)加工该组合以形成微乳剂。
可以根据本领域已知的方法制备无菌水性或油性悬浮液。例如,可以用无毒的肠胃外可接受的稀释剂或溶剂(例如1,3-丁二醇)制备无菌水溶液或悬浮液;并且可以用无菌无毒可接受溶剂或悬浮介质(例如无菌固定油,例如合成的甘油单酯或甘油二酯;和脂肪酸,例如油酸)制备无菌油性悬浮液。
可用于本发明的药物组合物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,用于药物剂型的表面活性剂诸如吐温类,聚乙氧基化蓖麻油诸如CREMOPHOR表面活性剂(BASF),或其他类似的聚合物递送基质,血清蛋白诸如人血清白蛋白,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,基于纤维素的物质,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。环糊精诸如α-、β-和γ-环糊精,或化学改性的衍生物诸如羟烷基环糊精,包括2-和3-羟丙基-环糊精,或者其他溶解的衍生物也可有利地用于增强本申请所描述的式的化合物的递送。
可根据常规药学方法加工本发明的药物活性化合物,以生产用于给予患者(包括人类和其他哺乳动物)的医药剂。该药物组合物可以经受诸如灭菌的常规制药操作和/或可以含有常规佐剂,如防腐剂、稳定剂、润湿剂、乳化剂、缓冲剂等。片剂和丸剂可以另外用肠溶衣制备。此类组合物还可以包含佐剂,如润湿剂、甜味剂、调味剂和芳香剂。
所给予的化合物的量和用于用本发明的化合物和/或组合物治疗病状的剂量方案取决于多种因素,包括受试者的年龄、重量、性别、医学状况,疾病类型,疾病的严重程度,给予途径和频率,以及所使用的具体化合物。因此,剂量方案可以广泛变化,但可以使用标准方法常规确定。约0.001至100mg/kg体重、优选约0.0025至约50mg/kg体重以及最优选约0.005至10mg/kg体重的日剂量可能是适当的。日剂量能以每天一至四剂给予。其他给药方案包括每周一剂和每两天一剂的循环。
出于治疗目的,本发明的活性化合物通常与一种或多种适合于所指示的给予途径的佐剂组合。如果口服给予,可将化合物与乳糖、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、磷酸和硫酸的钠和钙盐、明胶、阿拉伯树胶、海藻酸钠、聚乙烯吡咯烷酮和/或聚乙烯醇混合,然后压片或胶囊化以方便给予。此类胶囊剂或片剂可以含有控释配制品,其可以在活性化合物在羟丙基甲基纤维素中的分散体中提供。
本发明的药物组合物包含至少一种式(I)的化合物以及任选地选自任何药学上可接受的载体、佐剂和媒介物的另外的试剂。本发明的替代组合物包含本申请所描述的式(I)的化合物或其前药,和药学上可接受的载体、佐剂或媒介物。
本发明还包括制品。如本申请所用,制品旨在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)位于该第一容器内的药物组合物,其中该组合物包含:第一治疗剂,其包含:本发明的化合物或其药学上可接受的盐形式;以及(c)包装说明书,其说明该药物组合物可用于治疗炎性疾病和/或自身免疫性疾病(如前所定义的)。在另一个实施方案中,该包装说明书指出该药物组合物可以与第二治疗剂组合使用(如前所定义的)以治疗炎性疾病和/或自身免疫性疾病。该制品可进一步包含:(d)第二容器,其中组分(a)和(b)位于该第二容器内,并且组分(c)位于该第二容器内或外侧。位于该第一容器和第二容器内意味着相应的容器将物品容纳在其边界内。
该第一容器是用于容纳药物组合物的接收容器。此容器可用于制造、储存、运输和/或单独/批量销售。第一容器旨在涵盖瓶、罐、小瓶、烧瓶、注射器、管(例如,用于乳膏制剂),或用于制造、容纳、储存或分布药物产品的任何其他容器。
该第二容器是用于容纳该第一容器和任选地包装说明书的容器。该第二容器的例子包括但不限于盒(例如,纸板或塑料)、板条箱、纸箱、袋(例如,纸或塑料袋)、小袋和包。该包装说明书可以通过胶带、胶水、订书钉或其他附接方法物理地附接到该第一容器的外侧,或者它可以放置在该第二容器内侧而无需与该第一容器附接的任何物理装置。可替代地,该包装说明书位于该第二容器的外侧。当位于该第二容器外侧时,优选的是,该包装说明书通过胶带、胶水、订书钉或其他附接方法物理地附接。可替代地,它可以与该第二容器外侧相邻或接触,而不是物理附接。
该包装说明书是标签、签条、标记等,其列举了涉及位于该第一容器内的药物组合物的信息。所列举的信息将通常由管理其中销售制品的地区的管理机构(例如,美国食品和药物管理局)来确定。在一个实施方案中,该包装说明书具体列举了已批准药物组合物所针对的适应症。该包装说明书可以由人可以阅读其中或其上所含信息的任何材料制成。例如,该包装说明书是可印刷材料(例如,纸、塑料、纸板、箔、粘合剂背衬的纸或塑料等),其上已形成(例如,印刷或施加)所希望的信息。
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引用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明显的,并且可以使用替代方法。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(Protective Groups In Organic Synthesis,第三版,Wileyand Sons,1999)。
实施例
下列实施例说明了本发明的特定和优选的实施方案,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。上文定义了本申请中的实施例和其它地方使用的另外缩写。常见的中间体通常可用于制备一个以上的实施例,依次进行识别(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实施例和制备步骤进行识别(例如,“1-A”表示实施例1,步骤A)或仅在化合物为实施例的标题化合物的情况下通过实施例进行标识(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。基于一个或多个考虑因素,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、易于催化、避免有毒的试剂、专用仪器的可获得性、线性步骤的数量减少等,合成领域的化学人员通常可以设计出可期望的替代制备方法。描述替代制备方法的目的是进一步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中的一些官能团可以通过本领域已知的众所周知的生物电子等排取代进行替代,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. 含水
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 钯炭
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
保留时间 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 C18,2.1x 50mm,1.7μm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;流速:1.0mL/min;检测:在220nm下的UV。
QC-ACN-TFA-XB:柱:Waters Acquity UPLC BEH C18,2.1x 50mm,1.7μm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;流速:1.0mL/min;检测:在220nm下的UV。
方法A1:L3 Acquity:柱:(LCMS)UPLC BEH C18,2.1x 50mm,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 C18,2.1x 50mm,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 C18,2.1x 50mm,1.7μm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 C18,2.1x 50mm,1.7μm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 C18,19x 200mm,5μm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 C18,19x 200mm,5μm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 4.6x 50mm 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 1.7μm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(50x 2.1mm-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,流速=1mL/min。
(B)Waters Acquity BEH C18(2.1x 50mm)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%,流速:0.8mL/min。
(C)柱-Ascentis Express C18(50x 2.1mm-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(75x 3mm)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(50x 2.1mm),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;流速:1.1ml/min。
(F)柱:Ascentis Express C18(50x 2.1mm),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;流速:1.1mL/min。
(G)柱:Waters Acquity UPLC BEH C18(2.1x 50mm),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(50x 2.1mm)1.7μm,Acentis C8 NH4COOH 5min。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);流速:1mL/min。
(I)柱:Sunfire C18(4.6x 150)mm,3.5μm;流动相A:5:95乙腈:含有0.05%TFA的水;流动相B:95:5乙腈:含有0.05%TFA的水;温度:50℃;梯度:10-100%B,经12分钟;流速:1mL/min。
(J)柱:Sunfire C18(4.6x 150)mm,3.5μm;流动相A:5:95乙腈:含有0.05%TFA的水;流动相B:95:5乙腈:含有0.05%TFA的水。
(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;流速: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(3.0x 50mm)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;流速:0.7mL/min;检测:检测器1:UV,在220nm;检测器2:MS(ES+)。
(M):Kinetex SBC18(4.6x 50mm)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);流速:1.5mL/min;检测:在220nm下的UV。
(N):柱-Ascentis Express C18(50x 2.1mm-2.7μm)流动相A:10mM NH4COOH在水中:ACN(98:02);流动相B:10mM NH4COOH在水:ACN(02:98)中,梯度:0-100%B(0-1.7分钟);100%B(1.7-3.4分钟)。流速=1mL/min。
(O)Waters Acquity SDS柱BEH C18(2.1x 50mm)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);流速=0.8mL/min。
模板1
5-溴-3-异丙基-1H-吲哚
向250mL圆底烧瓶中加入三乙基硅烷(8.90g,77mmol)、三氯乙酸(6.25g,38.3mmol)和甲苯(50mL)。将溶液加热至70℃。通过滴液漏斗滴加5-溴-1H-吲哚(5.0g,25.5mmol)和丙酮(2.247mL,30.6mmol)在甲苯(30mL)中的溶液。在70℃加热所得棕色溶液1.5h。将溶液冷却至10℃。通过加入10%碳酸氢钠淬灭反应。将溶液用乙醚稀释。分离有机层,干燥,在真空下浓缩,得到粗制化合物。粗制物质使用硅胶色谱以5%乙酸乙酯的己烷溶液洗脱进行纯化,得到5-溴-3-异丙基-1H-吲哚(5.5g,23.10mmol 95%收率),其为油状物。LC保留时间1.42min[D]。MS m/z:238.2(M+H)。1H NMR(400MHz,DMSO-d6)δ11.03-10.90(m,1H),7.75-7.64(m,1H),7.33-7.28(m,1H),7.19-7.13(m,2H),3.19-3.04(m,1H),1.31-1.26(m,6H)。
模板2
5-溴-2-碘-3-异丙基-1H-吲哚
向5-溴-3-异丙基-1H-吲哚(500mg,2.100mmol)在THF(10mL)中的搅拌溶液中加入三氟甲磺酸银(647mg,2.52mmol)。溶液搅拌2min。接着,加入在THF(10mL)中的I2(533mg,2.100mmol),反应混合物在室温搅拌30min。通过加入Na2S2O3水溶液淬灭反应。溶液用EtOAc萃取,经硫酸钠干燥,浓缩,得到粗制物质。粗制物质通过硅胶柱色谱纯化,得到5-溴-2-碘-3-异丙基-1H-吲哚(500mg,1.374mmol,65.4%收率)。LCMS保留时间1.62min[B]。1H NMR(400MHz,DMSO-d6)δppm 11.6(s,1H),7.77(br.s.1H),7.2-7.3(m,1H),7.1-7.2(m,1H),3.33(br s,3H),2.50(br s,6H)。
模板3
5-溴-3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚
向带有减压隔片的4打兰小瓶中加入5-溴-2-碘-3-异丙基-1H-吲哚(100mg,0.275mmol)、(2-甲基吡啶-4-基)硼酸(37.6mg,0.275mmol)、PdCl2(dppf)-CH2Cl2加合物(22.43mg,0.027mmol)和THF(1mL)。将小瓶抽真空,用N2吹扫几次。接着,加入磷酸三钾(0.275mL,0.824mmol)。将小瓶抽真空,用N2吹扫几次,加热至65℃。3小时后,LCMS表明存在起始原料。在室温持续反应过夜。LCMS表明反应不完全。加入另外的(2-甲基吡啶-4-基)硼酸(37.6mg,0.275mmol)和PdCl2(dppf)-CH2Cl2加合物(22.43mg,0.027mmol),反应混合物加热至90℃。3小时后,LCMS表明反应完全。反应混合物用水稀释,用EtOAc(3x15 mL)萃取。合并有机相,经硫酸钠干燥,过滤,浓缩,得到黄色油状物,将其通过硅胶柱色谱在(Isco 12g二氧化硅,100%己烷-100%EtOAc)上纯化。合并类似级分,浓缩,得到5-溴-3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚(45mg,0.137mmol,49.8%收率)。LCMS保留时间0.83min[B1]。MS m/z:329,331(M+H)。
模板4
3-溴-1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡咯烷-2-酮
中间体T-4A:(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)氨基甲酸叔丁酯
在环境温度向5-溴-3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚(0.5g,1.519mmol)和氨基甲酸叔丁酯(0.213g,1.822mmol)在甲苯(15mL)中的溶液中加入叔丁醇钠(0.292g,3.04mmol)。将混合物用氮气脱气10分钟,加入Pd2(dba)3(0.139g,0.152mmol),随后加入2-(二叔丁基膦基)联苯(0.023g,0.076mmol),进一步脱气5min。在90℃搅拌所得混合物3h。反应混合物用乙酸乙酯(100mL)稀释,用水(2x 50mL)、盐水(20mL)洗涤,经硫酸钠干燥,浓缩,得到粗制产物。粗制物质通过柱色谱使用40g硅胶柱纯化,化合物用4%在氯仿中的甲醇洗脱,收集级分,浓缩,得到(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)氨基甲酸叔丁酯(0.3g,0.821mmol,54%收率),其为黄色固体。LCMS保留时间3.55min[D]。MS m/z:366.2(M+H)。
中间体T-4B:3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-胺
在环境温度向(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)氨基甲酸叔丁酯(0.3g,0.821mmol)在DCM(2mL)中的溶液中加入4M在二噁烷(1.231mL,4.93mmol)中的HCl。在相同温度搅拌混合物3h。浓缩反应混合物,得到3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-胺(0.21g,96%收率),其为浅黄色固体。LCMS保留时间1.75min[D]。MS m/z:266.1(M+H)。
中间体T-4C:2,4-二溴-N-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)丁酰胺
在0℃向3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-胺(0.21g,0.791mmol)在DCM(5mL)中的溶液中逐滴加入2,4-二溴丁酰氯(0.105mL,0.791mmol)。在环境温度搅拌反应混合物4h。反应混合物用DCM(50mL)稀释,用水(50mL)洗涤,经硫酸钠干燥,浓缩,得到粗制产物。粗制物质通过柱色谱使用24g硅胶柱进行纯化。将产物用4.5%在氯仿中的MeOH洗脱,收集级分,浓缩,得到2,4-二溴-N-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)丁酰胺(0.28g,0.568mmol,72%收率),其为黄色固体。LCMS保留时间2.83min[D]。MS m/z:492.2(M+2H)。
模板4:
向2,4-二溴-N-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)丁酰胺(0.28g,0.568mmol)在DCM(10mL)中的溶液中逐滴加入含水NaOH(0.091g,2.271mmol)(50%水溶液)。在环境温度搅拌混合物2h。用冰水(50mL)淬灭反应。反应物质用DCM(2X 50mL)萃取。有机层经硫酸钠干燥,浓缩,得到粗制产物。粗制物质通过柱色谱使用24g硅胶柱进行纯化。将产物用60-80%在石油醚中的乙酸乙酯洗脱,收集级分,浓缩,得到3-溴-1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡咯烷-2-酮(0.15g,0.364mmol,64%收率),其为黄色固体。LCMS保留时间2.38min[D]。MS m/z:412.2(M+2H)。
以下模板根据模板1-4中描述的一般步骤来制备:
表1
实施例1和2
1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-3-((2-(甲基氨基)乙基)氨基)吡咯烷-2-酮(1)和3-((2-氨基乙基)(甲基)氨基)-1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡咯烷-2-酮(2)
向3-溴-1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡咯烷-2-酮(0.1g,0.243mmol)和K2CO3(0.034g,0.243mmol)在THF(1mL)和水(0.1mL)中的溶液中加入N1-甲基乙烷-1,2-二胺(0.018g,0.243mmol)。在90℃加热所得反应混合物24h。在真空下浓缩反应物质,得到粗制产物。粗制样品通过手性色谱使用如下进行纯化:柱:Chiralpak-IC(250X4.6mm)5μm,注入体积:10,0.2%在甲醇中的DEA作为共溶剂。收集级分,浓缩,冻干,得到1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-3-((2-(甲基氨基)乙基)氨基)吡咯烷-2-酮(7mg,7%收率)和3-((2-氨基乙基)(甲基)氨基)-1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡咯烷-2-酮(7mg,7%收率),其为浅色固体。
实施例1:LCMS保留时间1.25min[C1]。MS m/z:406.2(M+H)。1H NMR(400MHz,DMSO-d6)δppm 11.83(s,1H),8.94(d,J=5.6Hz,1H),8.35(d,J=1.7Hz,1H),7.95-7.84(m,1H),7.76-7.67(m,2H),7.53-7.23(m,1H),4.27-4.20(m,2H),3.72-3.66(m,3H),3.54(d,J=6.4Hz,3H),2.96-2.90(m,6H),2.88-2.83(m,3H),2.48(d,J=10.3Hz,2H),1.72(dd,J=7.1,5.4Hz,6H)。
实施例2:LCMS保留时间1.32min[C1]。MS m/z:406.2(M+H)。1H NMR(400MHz,DMSO-d6)δppm 11.96(s,1H),9.00(d,J=5.9Hz,1H),8.33(s,1H),8.23(br.s.,2H),8.07(s,1H),8.02(d,J=5.9Hz,1H),7.78-7.69(m,2H),7.58-7.30(m,1H),4.19-4.13(m,3H),3.71(dt,J=14.0,7.1Hz,2H),3.38(br.s.,4H),3.02-2.97(m,3H),2.93(br.s.,3H),2.72-2.65(m,1H),2.54-2.44(m,2H),1.73(dd,J=7.1,2.7Hz,6H)。
以下实施例根据实施例1和2的制备中使用的一般步骤来制备。
表2
实施例5和6
1-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-3-(4-异丙基哌嗪-1-基)吡咯烷-2-酮(5-6)
中间体5A:4-(1-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-2-氧代吡咯烷-3-基)哌嗪-1-甲酸叔丁酯
向3-溴-1-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)吡咯烷-2-酮(0.15g,0.352mmol)和K2CO3(0.049g,0.352mmol)在THF(3mL)和水(0.5mL)中的溶液中加入哌嗪-1-甲酸叔丁酯(0.066g,0.352mmol)。在90℃加热所得反应混合物24h。反应物质用水(20mL)淬灭,用乙酸乙酯(3X 10mL)萃取。有机层经硫酸钠干燥,过滤,浓缩,得到4-(1-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-2-氧代吡咯烷-3-基)哌嗪-1-甲酸叔丁酯(0.14g,75%),其为褐色固体。LCMS保留时间1.33min[F],MS m/z:532.2(M+H)。
中间体5B:1-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-3-(哌嗪-1-基)吡咯烷-2-酮
在环境温度向4-(1-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-2-氧代吡咯烷-3-基)哌嗪-1-甲酸叔丁酯(0.12g,0.226mmol)在DCM(2mL)中的溶液中加入4M在二噁烷(0.339mL,1.354mmol)中的HCl。在相同温度搅拌混合物3h。浓缩反应混合物,得到1-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-3-(哌嗪-1-基)吡咯烷-2-酮(0.095g,97%收率),其为浅黄色固体。LCMS保留时间2.99min[F]。MS m/z:432.4(M+H)。
实施例5和6:
向1-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-3-(哌嗪-1-基)吡咯烷-2-酮(0.095g,0.220mmol)和丙酮(0.048mL,0.660mmol)在甲醇(4mL)中的溶液中逐滴加入异丙醇钛(IV)(0.077mL,0.264mmol)。在氮气下于25℃搅拌所得淡黄色溶液4h。接着,加入氰基硼氢化钠(0.014g,0.220mmol),在环境温度搅拌混合物12h。反应物质用水(10mL)淬灭,用DCM(2X 10mL)萃取。分离的有机层经硫酸钠干燥,过滤,浓缩。粗制样品通过手性色谱使用如下进行纯化:柱:Luxcellulose-4(250X 4.6)mm,5μ,注入体积:10,0.2%在甲醇中的DEA作为共溶剂,得到1-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-3-(4-异丙基哌嗪-1-基)吡咯烷-2-酮(0.012g,12%)(手性RT:5.72),其为浅黄色固体,和1-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-3-(4-异丙基哌嗪-1-基)吡咯烷-2-酮(0.011g,11%)(手性RT:11.97),其为浅黄色固体。
实施例5:LCMS保留时间1.62min[E]。MS m/z:474.4(M+H)。手性RT:5.72min。1HNMR(400MHz,DMSO-d6)δppm 11.18(s,1H),7.95(s.,1H),7.34(s,2H),7.16(s,2H),3.78-3.52(m,2H),3.50(s,3H),2.87(m,3H),2.66(s,2H),2.59-2.53(m,6),2.33(s,1H),2.07(s,2H),1.79(m,2H),1.42-1.39(m,6H),0.97-0.95(m,6H)。
实施例6:LCMS保留时间1.62min[E]。MS m/z:474.4(M+H)。手性RT:11.97min。1HNMR(400M Hz,DMSO-d6)δppm 11.18(s,1H),7.95(s.,1H),7.34(s,2H),7.16(s,2H),3.78-3.52(m,2H),3.50(s,3H),2.87(m,3H),2.66(s,2H),2.59-2.53(m,6),2.33(s,1H),2.07(s,2H),1.79(m,2H),1.42-1.39(m,6H),0.97-0.95(m,6H)。
实施例7
3-(2-(二甲基氨基)乙氧基)-1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡咯烷-2-酮
中间体7A:3-羟基-1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡咯烷-2-酮
将5-溴-3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚(0.5g,1.519mmol)、3-羟基吡咯烷-2-酮(0.184g,1.822mmol)、碳酸铯(1.237g,3.80mmol)和N,N’-二甲基乙二胺(0.054g,0.607mmol)在二噁烷(5mL)溶剂中的溶液进行脱气,在130℃加热18h。反应混合物用DCM(50mL)稀释,用水(50mL)洗涤,经硫酸钠干燥,浓缩,得到粗制产物。粗制物质通过柱色谱使用24g硅胶柱进行纯化。将化合物用4%在氯仿中的MeOH洗脱,收集级分,浓缩,得到3-羟基-1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡咯烷-2-酮(0.4g,1.145mmol,75%收率),其为褐色固体。LCMS保留时间1.58min[D]。MS m/z:350.2(M+H)。
中间体7B:三氟甲磺酸1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-2-氧代吡咯烷-3-基酯
在0℃,向3-羟基-1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡咯烷-2-酮(0.05g,0.143mmol)在DCM(2mL)中的溶液中加入吡啶(0.012mL,0.143mmol),随后加入三氟甲磺酸酐(0.024mL,0.143mmol)。在25℃搅拌反应混合物2h。TLC显示形成非极性斑点,不存在起始原料。反应物质用水(20mL)淬灭,用乙酸乙酯(3X 20mL)萃取。有机层经硫酸钠干燥,过滤,浓缩,得到三氟甲磺酸1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-2-氧代吡咯烷-3-基酯(0.04g,58%),其为黄色固体。
实施例7:
三氟甲磺酸1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-2-氧代吡咯烷-3-基酯(0.04g,0.083mmol)、2-(二甲基氨基)乙醇(0.022g,0.249mmol)和K2CO3(0.011g,0.083mmol)在乙腈(2mL)溶剂中的溶液在室温搅拌12h。用水(10mL)淬灭反应。反应混合物用乙酸乙酯(3X 10mL)萃取。分离的有机层经硫酸钠干燥,过滤,浓缩,得到粗制产物。粗制物质通过制备型LCMS在以下条件下纯化:Waters Xbridge C18,19x150 mm,5μm;保护柱:Waters XBridge C18,19x10 mm,5μm;流动相A:5:95甲醇:含有10mM NH4OAc的水;流动相B:95:5甲醇:含有10mM NH4OAc的水;梯度:15-65%B,经25分钟,随后在65%B保持10分钟,在100%B保持5分钟;流速:15ml/min。收集级分,浓缩,冻干,得到3-(2-(二甲基氨基)乙氧基)-1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡咯烷-2-酮(11.1mg,32%),其为浅黄色固体。LCMS保留时间1.27min[E]。MS m/z:421.1(M+H)。1H NMR(400MHz,DMSO-d6)δppm 11.67(s,1H),8.82(d,J=5.1Hz,1H),8.28(d,J=1.7Hz,1H),7.67(t,J=8.4Hz,2H),7.62-7.55(m,2H),5.17(t,J=9.7Hz,1H),4.25-4.13(m,4H),4.05-4.00(m,3H),3.55(s,4H),2.82(s,4H),1.84(s,2H),1.70(dd,J=7.0,4.3Hz,6H)。
实施例8
1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)咪唑烷-2-酮
实施例8根据中间体7A中描述的一般方法来制备。LCMS保留时间1.50min[E]。MSm/z:335.3(M+H)。
实施例9
(R)-N-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)吡咯烷-3-甲酰胺
中间体9A:4-(5-溴-3-异丙基-1H-吲哚-2-基)-1-三苯甲基-1H-吡唑并[3,4-b]吡啶:
将5-溴-2-碘-3-异丙基-1H-吲哚(2.0g,5.49mmol)、K2CO3(3.50g,16.48mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1-三苯甲基-1H-吡唑并[3,4-b]吡啶(2.68g,5.49mmol)在THF(80mL)和水(10mL)溶剂混合物中的溶液在氮气下脱气5min。接着,加入PdCl2(dppf)-CH2Cl2加合物(0.449g,0.549mmol),在80℃搅拌所得反应混合物6h。反应混合物用过量乙酸乙酯稀释,用水、盐水洗涤,经硫酸钠干燥,浓缩,得到粗制产物。粗制物质通过柱色谱使用40g硅胶柱纯化,将化合物用80%在石油醚中的乙酸乙酯洗脱,收集级分,浓缩,得到4-(5-溴-3-异丙基-1H-吲哚-2-基)-1-三苯甲基-1H-吡唑并[3,4-b]吡啶(2.2g,3.68mmol,67.0%收率),其为浅棕色固体。LCMS保留时间4.423min[D],MS m/z:597.2(M+H)。
中间体9B:(3-异丙基-2-(1-三苯甲基-1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)氨基甲酸叔丁酯
在室温向4-(5-溴-3-异丙基-1H-吲哚-2-基)-1-三苯甲基-1H-吡唑并[3,4-b]吡啶(1.5g,2.51mmol)和氨基甲酸叔丁酯(0.353g,3.01mmol)在甲苯(15mL)中的溶液中加入NaOtBu(0.482g,5.02mmol)。将混合物用氮气脱气10min。接着,加入Pd2dba3(0.230g,0.251mmol),随后加入2-(二叔丁基膦基)联苯(0.037g,0.126mmol)。溶液再次脱气5min。在90℃将所得混合物搅拌3h。反应混合物用乙酸乙酯(100mL)稀释,用水(2x 50mL)、盐水(20mL)洗涤,经硫酸钠干燥,浓缩,得到粗制产物。粗制物质通过柱色谱使用40g硅胶柱纯化,将化合物用14%在己烷中的乙酸乙酯洗脱,收集级分,浓缩,得到(3-异丙基-2-(1-三苯甲基-1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)氨基甲酸叔丁酯(1.5g,2.51mmol,94%收率),其为黄色固体。LCMS保留时间1.63min[D]。MS m/z:634.2(M+H)。
中间体9C:3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-胺
在室温向(3-异丙基-2-(1-三苯甲基-1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)氨基甲酸叔丁酯(1.5g,2.367mmol)在DCM(5mL)中的溶液中加入4M在二噁烷(3.55mL,14.20mmol)中的HCl。在相同温度搅拌混合物3h。浓缩反应混合物,得到3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-胺(0.67mg,99%收率),其为浅黄色固体。LCMS保留时间1.46min[E]。MS m/z:291.1(M+H)。
中间体9D:(R)-3-((3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)氨基甲酰基)吡咯烷-1-甲酸叔丁酯
在室温向3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-胺(0.025g,0.086mmol)和(R)-1-(叔丁氧基羰基)吡咯烷-3-甲酸(0.020g,0.094mmol)在DMF(2mL)中的溶液中加入DIPEA(0.045mL,0.257mmol)和HATU(0.065g,0.172mmol)。在相同温度搅拌反应混合物3h。反应混合物用DCM(10mL)稀释,用水(10mL)洗涤,经硫酸钠干燥,浓缩,得到(R)-3-((3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)氨基甲酰基)吡咯烷-1-甲酸叔丁酯(0.03g,0.061mmol),其为黄色固体。LCMS保留时间2.29min[D]。MS m/z:489.2(M+H)。
实施例9:
在室温向(R)-3-((3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)氨基甲酰基)吡咯烷-1-甲酸叔丁酯(0.03g,0.061mmol)在DCM(2mL)的溶液中加入4M在二噁烷(0.090mL,0.368mmol)中的盐酸。在相同温度搅拌反应混合物1h。浓缩反应物质,得到粗制产物。产物通过制备型LCMS在以下条件下纯化:Waters Xbridge C18,19x150 mm,5μm;保护柱:Waters XBridge C18,19x10 mm,5μm;流动相A:5:95甲醇:含有10mM NH4OAc的水;流动相B:95:5甲醇:含有10mM NH4OAc的水;梯度:15-65%B,经25分钟,随后在65%B保持10分钟,在100%B保持5分钟;流速:15ml/min。收集级分,浓缩,冻干,得到(R)-N-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)吡咯烷-3-甲酰胺(4.5mg,19%),其为浅黄色固体。LCMS保留时间1.14min[C1]。MS m/z:389.1(M+H);1H NMR(400MHz,DMSO-d6)δppm13.80(br.s.,1H),11.27(s,1H),10.09(s,1H),8.65-8.56(m,1H),8.26(d,J=1.5Hz,1H),8.18-8.11(m,1H),7.42-7.28(m,2H),7.22(d,J=4.5Hz,1H),3.27-3.14(m,4H),2.89(s,1H),2.28-2.19(m,2H),2.15-2.05(m,1H),1.51-1.39(m,6H)。
实施例10
(S)-N-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)吡咯烷-3-甲酰胺
实施例10根据实施例9中描述的一般步骤来制备。LCMS保留时间2.29min[D]。MSm/z:489.2(M+H)。
以下实施例根据实施例9中描述的一般步骤来制备:
表3
实施例27
1-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)咪唑烷-2-酮
中间体27A:1-(3-异丙基-2-(1-三苯甲基-1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)咪唑烷-2-酮
将4-(5-溴-3-异丙基-1H-吲哚-2-基)-1-三苯甲基-1H-吡唑并[3,4-b]吡啶(0.500g,0.837mmol)、咪唑烷-2-酮(0.108g,1.255mmol)和Cs2CO3(0.545g,1.674mmol)在二噁烷(25mL)中的溶液脱气3min。接着,加入碘化亚铜(I)(0.080g,0.418mmol)和N,N’-二甲基乙二胺(0.074g,0.837mmol)。在130℃加热所得反应混合物16h。反应混合物用DCM(100mL)稀释,用水(50mL)洗涤,经硫酸钠干燥,浓缩,得到粗制产物。粗制物质通过柱色谱使用24g硅胶柱纯化,将化合物用45%在石油醚中的乙酸乙酯洗脱,收集级分,浓缩,得到1-(3-异丙基-2-(1-三苯甲基-1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)咪唑烷-2-酮(0.270g,0.448mmol,53.5%收率),其为淡黄色固体。LCMS保留时间1.10min。[D],MS m/z:603.3(M+H)。
中间体27B:1-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)咪唑烷-2-酮
在10℃向1-(3-异丙基-2-(1-三苯甲基-1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)咪唑烷-2-酮(0.050g,0.083mmol)在二噁烷(2.0mL)中的溶液中加入4M在二噁烷(0.518mL,2.074mmol)中的HCl。在相同温度搅拌混合物4h。浓缩反应混合物质,得到粗制产物。粗制产物通过制备型LCMS在以下条件下纯化:Waters Xbridge C18,19x150 mm,5μm;保护柱:Waters XBridge C18,19x10 mm,5μm;流动相A:5:95乙腈:含有10mM NH4OAc的水;流动相B:95:5乙腈:含有10mM NH4OAc的水;梯度:10-30%B,经25分钟,随后在30%B保持10分钟,在100%B保持5分钟;流速:15ml/min。合并包含产物的级分,使用Genevac离心式蒸发器干燥,得到1-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)咪唑烷-2-酮(6.9mg,23%),其为浅黄色固体。LCMS保留时间1.381min[E]。MS m/z:361.1(M+H);1H NMR(400MHz,DMSO-d6)δppm 14.13-13.99(m,1H),11.59-11.35(m,1H),8.86(d,J=4.9Hz,1H),8.41(s,1H),8.14-8.01(m,1H),7.86-7.61(m,2H),7.47(s,1H),7.10-6.91(m,1H),4.29-4.11(m,2H),3.74-3.59(m,3H),1.70(d,J=7.1Hz,6H)。
实施例28
2-(3,4-二甲氧基苯基)-N,3-二乙基-N-(1'-甲基-1,4'-联哌啶-4-基)-1H-吲哚-5-胺
中间体28A:5-(1-(叔丁氧基羰基)哌啶-4-基氨基)-2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-1-甲酸叔丁酯
向2打兰反应小瓶中加入在二噁烷(2mL)中的5-氯-2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-1-甲酸叔丁酯(0.100g,0.240mmol)、碳酸铯(0.235g,0.721mmol)、第二代XPhos预催化剂(0.019g,0.024mmol)和4-氨基哌啶-1-甲酸叔丁酯(0.144g,0.721mmol)。将小瓶盖上特氟隆衬里的盖,用氮气泵送/吹扫三次。使混合物在100℃加热2小时。将反应混合物冷却至室温,在氮气流下浓缩至干燥,用乙酸乙酯和水稀释。将内容物转移至分液漏斗,分离各层。将有机物用盐水洗涤,经无水硫酸钠干燥,过滤,通过旋转蒸发浓缩。残留物通过硅胶色谱纯化,然后浓缩类似级分,5-((1-(叔丁氧基羰基)哌啶-4-基)氨基)-2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-1-甲酸叔丁酯(0.106g,0.183mmol,76%收率)收集为棕褐色固体。LCMS保留时间1.05min[F1]。MS m/z:580.4(M+H)。
中间体28B:5-((1-(叔丁氧基羰基)哌啶-4-基)(乙基)氨基)-2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-1-甲酸叔丁酯
向2打兰小瓶中加入5-((1-(叔丁氧基羰基)哌啶-4-基)氨基)-2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-1-甲酸叔丁酯(0.029g,0.050mmol)、碳酸铯(0.049g,0.150mmol)、丙酮(1mL)和碘乙烷(0.078g,0.500mmol)。在室温搅拌反应混合物2小时,然后,通过硅藻土过滤,用丙酮冲洗。在氮气流下去除挥发物,收集5-((1-(叔丁氧基羰基)哌啶-4-基)(乙基)氨基)-2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-1-甲酸叔丁酯(0.03g,0.050mmol,99%收率)。LCMS保留时间1.24min[B]。MS m/z:608.4(M+H)。
中间体28C:2,2,2-三氟乙酸2-(3,4-二甲氧基苯基)-N,3-二乙基-N-(哌啶-4-基)-1H-吲哚-5-胺
向2-打兰小瓶中加入5-((1-(叔丁氧基羰基)哌啶-4-基)(乙基)氨基)-2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-1-甲酸叔丁酯(0.03g,0.050mmol)、DCM(0.5mL)和2,2,2-三氟乙酸(0.057g,0.500mmol)。在室温搅拌反应混合物20分钟,浓缩至干燥。收集2,2,2-三氟乙酸2-(3,4-二甲氧基苯基)-N,3-二乙基-N-(哌啶-4-基)-1H-吲哚-5-胺。LCMS保留时间0.73min[B]。MS m/z:408.2(M+H)。
实施例28:
向2,2,2-三氟乙酸2-(3,4-二甲氧基苯基)-N,3-二乙基-N-(哌啶-4-基)-1H-吲哚-5-胺(0.025g)中加入DMF(1.0mL)、TEA(0.035mL,0.250mmol)、乙酸(0.01mL)和1-甲基哌啶-4-酮(0.017g,0.150mmol)。在室温搅拌15分钟后,加入氰基硼氢化钠(9.43mg,0.150mmol),将混合物搅拌14小时。加入MeOH(0.5mL),在氮气流下浓缩混合物。该残留物用DMF(2.0mL)稀释,通过注射器过滤器过滤,通过制备型HPLC纯化,得到2-(3,4-二甲氧基苯基)-N,3-二乙基-N-(1'-甲基-1,4'-联哌啶-4-基)-1H-吲哚-5-胺。HPLC保留时间1.46min[方法C]。MS m/z:505.4(M+H)。HPLC保留时间1.00min[方法D]。MS m/z:505.3(M+H)。1H NMR(500MHz,DMSO-d6)δ11.71-11.39(m,1H),7.94(s,1H),7.75(br s,1H),7.52(d,J=8.8Hz,1H),7.32(s,1H),7.28-7.07(m,2H),3.99(br s,1H),3.83(d,J=11.8Hz,8H),3.76(br d,J=4.0Hz,1H),3.66-3.49(m,1H),3.37(br s,1H),3.13-2.93(m,2H),2.92-2.81(m,4H),2.74(br d,J=12.5Hz,5H),2.22(br d,J=11.1Hz,2H),1.83(br d,J=11.1Hz,4H),1.27(t,J=7.6Hz,4H),1.00(br t,J=6.9Hz,4H)。
实施例29
5-(3-(1,4-二氮杂环庚烷-1-基)氮杂环丁烷-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚
向Bohdan Miniblock XT中的反应管中溶解在二噁烷(0.550mL)中的5-氯-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-1-甲酸叔丁酯(13.5mg,0.031mmol)。加入碳酸铯(30.7mg,0.094mmol)和第二代XPhos预催化剂(0.0024mg,0.0031mmol)。接着,加入4-(氮杂环丁烷-3-基)-1,4-二氮杂环庚烷-1-甲酸叔丁酯(0.012g,0.047mmol)。将反应管盖上盖,通过泵脱气/用氮气吹扫。反应混合物在100℃加热2小时。将反应混合物冷却至室温,在氮气流下浓缩至干燥。将混合物用4M在二噁烷(0.5mL)中的HCl稀释,在室温搅拌1小时,通过氮气流浓缩。残留物通过制备型HPLC纯化,得到5-(3-(1,4-二氮杂环庚烷-1-基)氮杂环丁烷-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(0.106g,0.183mmol,76%收率)。HPLC保留时间1.36min[方法C]。MS m/z:449.4(M+H)。HPLC保留时间1.11min[方法D]。MS m/z:449.4(M+H)。1H NMR(500MHz,DMSO-d6)δ10.79-10.62(m,1H),7.96(s,1H),7.22(d,J=8.8Hz,1H),7.16-6.95(m,3H),6.43(br d,J=8.4Hz,1H),4.14-4.03(m,2H),3.88-3.71(m,7H),3.40-3.18(m,3H),3.09-2.98(m,1H),2.90(s,4H),2.74(s,4H),2.03(br s,2H),1.48-1.34(m,6H)。
实施例30
N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(2-(甲基氨基)乙基)环己烷-1,4-二胺
中间体30A:2-(3,4-二甲氧基苯基)-3-异丙基-N-(1,4-二氧杂螺[4.5]癸烷-8-基)-1H-吲哚-5-胺
向2打兰反应小瓶中加入在二噁烷(3mL)中的5-氯-2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-1-甲酸叔丁酯(0.310g,0.721mmol)、碳酸铯(0.705g,2.16mmol)、第二代XPhos预催化剂(0.057g,0.072mmol)和1,4-二氧杂螺[4.5]癸烷-8-胺(227mg,1.442mmol)。将小瓶盖上特氟隆衬里的盖,用氮气泵送/吹扫三次。混合物在100℃加热16小时。将反应混合物冷却至室温,在氮气流下浓缩至干燥,用DCM和水稀释。将内容物转移至分液漏斗,分离各层。将有机物用盐水洗涤,经无水硫酸钠干燥,过滤,通过旋转蒸发浓缩。残留物通过硅胶色谱纯化,然后浓缩类似级分,收集到2-(3,4-二甲氧基苯基)-3-异丙基-N-(1,4-二氧杂螺[4.5]癸烷-8-基)-1H-吲哚-5-胺(0.200g,0.363mmol,50%收率)。LCMS保留时间1.20min[F1]。MS m/z:450.4(M+H)。
中间体30B:4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基氨基)环己酮
向在DCM(0.5mL)中的5-(1,4-二氧杂螺[4.5]癸烷-8-基氨基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-1-甲酸叔丁酯(0.053g,0.096mmol)加入TFA(1000μl,12.98mmol)。反应小瓶盖上盖。在90℃搅拌反应混合物7小时。在氮气流下除去挥发物,得到4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基氨基)环己酮(0.040g,0.099mmol,100%收率)。LCMS保留时间0.988min[F1]。MS m/z:407.4(M+H)。
实施例30:
向在反应小瓶中的4-((2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)氨基)环己酮(0.018g,0.044mmol)中加入DCM(1mL)、(2-氨基乙基)(甲基)氨基甲酸叔丁酯(0.023g,0.133mmol)和乙酸(2.53μl,0.044mmol)。将反应混合物在室温搅拌15分钟,然后加入氰基硼氢化钠(8.35mg,0.133mmol)。在相同温度继续搅拌1小时。样品浓缩至干燥,然后加入DCM(1mL)和TFA(1mL)。将反应混合物搅拌15分钟,浓缩至干燥。将残留物用DMF稀释,通过制备型HPLC纯化,得到N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(2-(甲基氨基)乙基)环己烷-1,4-二胺吲哚(0.0013g,0.0015mmol,3.50%收率)。HPLC保留时间1.21min[方法C]。MS m/z:465.4(M+H)。HPLC保留时间0.95min[方法D]。MS m/z:465.3(M+H)。1H NMR(500MHz,DMSO-d6)位移11.49-11.31(m,1H),7.82(br s,1H),7.48(d,J=8.4Hz,1H),7.25-7.00(m,4H),3.83(d,J=7.7Hz,6H),3.58-3.42(m,1H),3.41-3.31(m,1H),3.24(br d,J=9.8Hz,4H),3.13(br s,1H),2.64(s,3H),2.20-2.00(m,4H),1.55(br d,J=12.8Hz,2H),1.47-1.34(m,8H)。
以下实施例根据上述实施例中描述的一般方法来制备:
表4
实施例103
2-(3,4-二甲氧基苯基)-3-异丙基-N-(1,2,2,6,6-五甲基哌啶-4-基)-1H-吲哚-5-胺
向2打兰反应小瓶中加入5-氯-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-1-甲酸叔丁酯(0.018g,0.042mmol)、碳酸铯(0.041g,0.126mmol)、第二代XPhos预催化剂(3.29mg,4.19μmol)、1,2,2,6,6-五甲基哌啶-4-胺(7.13mg,0.042mmol)和二噁烷(1mL)。将混合物用特氟隆衬里的盖盖上,用氮气泵送/吹扫三次。使混合物在100℃加热2小时。冷却至室温后,将混合物浓缩,用DCM/MeOH(3.0mL)稀释,通过注射器过滤器过滤。将滤液浓缩至褐色残留物。向残留物中加入4M HCl/二噁烷(1.0mL)。在室温将反应混合物搅拌1小时。将混合物在氮气流下浓缩至干燥,然后用DMSO(2.0mL)稀释,通过制备型HPLC纯化,得到2-(3,4-二甲氧基苯基)-3-异丙基-N-(1,2,2,6,6-五甲基哌啶-4-基)-1H-吲哚-5-胺(0.0029g,0.0060mmol,14.3%收率)。HPLC保留时间1.44min[方法C]。MS m/z:464.4(M+H)。HPLC保留时间1.14min[方法D]。MS m/z:464.5(M+H)。1H NMR(500MHz,DMSO-d6)δ11.05-10.72(m,1H),8.48-8.17(m,1H),7.96(s,1H),7.37-7.19(m,1H),7.16-6.96(m,4H),4.05-3.93(m,1H),3.82(d,J=8.8Hz,3H),3.49-3.40(m,1H),3.37-3.26(m,1H),2.90(s,2H),2.80-2.68(m,4H),2.56(t,J=5.6Hz,2H),2.14(br d,J=12.1Hz,2H),1.73(br s,2H),1.50-1.17(m,15H)。
表5中的实施例根据实施例103中公开的一般步骤来制备。
表5
实施例121
5-(4-(1,4-二氮杂环庚烷-1-基)哌啶-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚
中间体121A:2-(3,4-二甲氧基苯基)-3-异丙基-5-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)-1H-吲哚-1-甲酸叔丁酯
向在二噁烷(10mL)中的5-氯-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-1-甲酸叔丁酯(1.040g,2.419mmol)、碳酸铯(2.364g,7.26mmol)加入第二代Xphos预催化剂(0.190g,0.242mmol)和1,4-二氧杂-8-氮杂螺[4.5]癸烷(0.693g,4.84mmol)。将反应容器用特氟隆衬里的盖盖上,用氮气泵送/吹扫三次。反应混合物在100℃加热1小时。将反应混合物冷却至室温,在氮气流下浓缩至干燥,用DCM和水稀释。将内容物转移至分液漏斗,分离各层。将有机物用盐水洗涤,经无水硫酸钠干燥,过滤,通过旋转蒸发浓缩,得到2-(3,4-二甲氧基苯基)-3-异丙基-5-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)-1H-吲哚-1-甲酸叔丁酯(1.30g,2.422mmol,100%收率)。LCMS保留时间1.205min[F1]。MS m/z:537.5(M+H)。
中间体121B:1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-酮
向2打兰反应小瓶中加入2-(3,4-二甲氧基苯基)-3-异丙基-5-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)-1H-吲哚-1-甲酸叔丁酯(0.175g,0.326mmol)、DCM(2.0mL)和TFA(4000μl,51.9mmol)。将小瓶盖上,在90℃搅拌反应混合物7小时。将混合物冷却至室温,在氮气流下浓缩至干燥,得到粗制品1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-酮(0.135g,0.344mmol,100%收率)。LCMS保留时间0.995min[F1]。MS m/z:393.0(M+H)。
实施例121:
向在反应小瓶中的1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-酮(0.025g,0.064mmol)中加入DCM(1mL)、1,4-二氮杂环庚烷-1-甲酸叔丁酯(0.038g,0.191mmol)和乙酸(3.63μl,0.064mmol)。反应混合物在室温搅拌15分钟,然后加入氰基硼氢化钠(0.012g,0.191mmol)。在相同温度继续搅拌1小时。将样品浓缩至干燥。接着,加入DCM(1mL)和TFA(1mL)。将反应混合物搅拌15分钟,浓缩至干燥。将残留物用DMF稀释,通过制备型HPLC纯化,得到5-(4-(1,4-二氮杂环庚烷-1-基)哌啶-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(0.0043g,0.009mmol,14%收率)。HPLC保留时间1.36min[方法C]。MS(E-)m/z:477.3(M+H)。HPLC保留时间0.98min[方法D]。MS m/z:477.3(M+H)。1H NMR(500MHz,DMSO-d6)δ11.24-11.01(m,1H),7.65(br s,1H),7.38(br d,J=8.8Hz,1H),7.28(s,1H),7.21-7.00(m,4H),3.83(d,J=8.1Hz,8H),3.71(br d,J=11.4Hz,3H),3.58-3.43(m,1H),3.39-3.25(m,3H),3.18(s,1H),2.27-1.97(m,7H),1.42(br d,J=6.7Hz,8H),0.84-0.84(m,1H)。
实施例122
2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(1-异丙基氮杂环庚烷-4-基)哌嗪-1-基)-1H-吲哚
中间体122A:5-(4-(叔丁氧基羰基)哌嗪-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-1-甲酸叔丁酯
向2-打兰小瓶中加入在二噁烷(3.0mL)中的5-氯-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-1-甲酸叔丁酯(0.215g,0.500mmol)、碳酸铯(0.489g,1.500mmol)、第二代XPhos预催化剂(0.039g,0.050mmol)和哌嗪-1-甲酸叔丁酯(0.279g,1.500mmol)。将混合物用特氟隆衬里的盖盖上,用氮气泵送/吹扫三次。混合物在100℃加热48小时。将反应混合物冷却至室温,在氮气流下浓缩至干燥,用乙酸乙酯和水稀释。将内容物转移至分液漏斗,分离各层。将有机物用盐水洗涤,经无水硫酸钠干燥,过滤,通过旋转蒸发浓缩。残留物通过硅胶色谱纯化,然后浓缩类似级分,收集到5-(4-(叔丁氧基羰基)哌嗪-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-1-甲酸叔丁酯(0.225g,0.322mmol,78%收率)。LCMS保留时间1.10min[B1]。MS m/z:580.4(M+H)。
中间体122B:2-(3,4-二甲氧基苯基)-3-异丙基-5-(哌嗪-1-基)-1H-吲哚,TFA盐
向2打兰反应小瓶中加入5-(4-(叔丁氧基羰基)哌嗪-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-1-甲酸叔丁酯(0.055g,0.095mmol)、DCM(0.5mL)和TFA(0.073mL,0.949mmol)。反应混合物在室温搅拌30分钟,然后在氮气流下浓缩,得到2-(3,4-二甲氧基苯基)-3-异丙基-5-(哌嗪-1-基)-1H-吲哚TFA盐(0.045g,0.95mmol,100%收率),其为淡黄色残留物。LCMS保留时间1.16min[D]。MS m/z:380.3(M+H)。
中间体122C:5-(4-(氮杂环庚烷-4-基)哌嗪-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚,2TFA
向2打兰小瓶中加入2-(3,4-二甲氧基苯基)-3-异丙基-5-(哌嗪-1-基)-1H-吲哚2,2,2-三氟乙酸盐(0.030g,0.061mmol)和DMF(1mL)。接着,加入TEA(0.042mL,0.304mmol)、4-氧代氮杂环庚烷-1-甲酸叔丁酯(0.026g,0.122mmol)和乙酸(0.010mL)。在室温将反应混合物搅拌1小时,加入氰基硼氢化钠(0.011g,0.182mmol)。在室温将反应混合物搅拌16小时,然后用水稀释(0.5mL),浓缩。加入DCM(0.5mL)和TFA(0.5mL),搅拌20分钟。将其浓缩,所得淡黄色残留物为5-(4-(氮杂环庚烷-4-基)哌嗪-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚,2TFA。LCMS保留时间1.09min[C]。MS m/z:477.4(M+H)。
实施例122:
向2打兰小瓶中加入5-(4-(氮杂环庚烷-4-基)哌嗪-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚二(2,2,2-三氟乙酸盐)(0.020g,0.028mmol)和DMF(1mL)。接着,加入TEA(0.020mL,0.142mmol)、丙烷-2-酮(4.95mg,0.085mmol)和乙酸(0.010mL)。在室温将反应混合物搅拌1小时,加入氰基硼氢化钠(5.35mg,0.085mmol)。在室温将反应混合物搅拌16小时,用水(0.1mL)和MeOH(1.0mL)稀释。滤出固体,通过制备型HPLC纯化所得溶液,得到2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(1-异丙基氮杂环庚烷-4-基)哌嗪-1-基)-1H-吲哚(0.0042g,0.0077mmol,27%收率)。HPLC保留时间1.39min[方法C]。MS m/z:519.4(M+H)。HPLC保留时间1.14min[方法D]。MS m/z:519.5(M+H)。1H NMR(500MHz,DMSO-d6)δ10.71(brs,1H),7.18(br d,J=8.4Hz,1H),7.10(br s,1H),7.04-6.90(m,3H),6.81(br d,J=8.1Hz,1H),3.75(d,J=9.1Hz,8H),3.38(br s,1H),3.32-3.21(m,1H),3.20-3.01(m,3H),2.83(s,2H),2.67(s,2H),2.25-1.58(m,8H),1.34(br d,J=7.1Hz,6H),1.18(br d,J=5.7Hz,8H)。
表6中的实施例根据以上实施例中公开的一般步骤来制备。
表6
实施例126
2-(3,4-二甲氧基苯基)-3-异丙基-5-(哌嗪-1-基)-1H-吲哚,TFA盐
向2打兰反应小瓶中加入5-(4-(叔丁氧基羰基)哌嗪-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-1-甲酸叔丁酯(0.055g,0.095mmol)、DCM(0.5mL)和TFA(0.073mL,0.949mmol)。反应混合物在室温搅拌30分钟,然后在氮气流下浓缩,得到淡黄色残留物。将残留物用DMF稀释,通过制备型HPLC纯化,得到2-(3,4-二甲氧基苯基)-3-异丙基-5-(哌嗪-1-基)-1H-吲哚(0.0076g,0.019mmol,20%收率)。HPLC保留时间1.17min[方法C]。MS m/z:380.3(M+H)。HPLC保留时间1.16min[方法D]。MS m/z:380.3(M+H)。1H NMR(500MHz,DMSO-d6)δ10.86-10.74(m,1H),8.73(br s,1H),7.95(s,1H),7.27(d,J=8.8Hz,1H),7.19(s,1H),7.12-6.98(m,3H),6.88(br d,J=8.8Hz,1H),3.82(d,J=8.8Hz,6H),3.57-3.44(m,2H),3.38-3.20(m,3H),2.89(s,2H),2.74(s,2H),1.41(br d,J=7.1Hz,6H)。
实施例127
2-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌嗪-1-基)-N-甲基乙胺
向2打兰反应小瓶中加入2-(3,4-二甲氧基苯基)-3-异丙基-5-(哌嗪-1-基)-1H-吲哚、2,2,2-三氟乙酸盐(0.015g,0.030mmol)和DMF(1mL)。接着,加入TEA(0.021mL,0.152mmol)、甲基(2-氧代乙基)氨基甲酸叔丁酯(0.011g,0.061mmol)和乙酸(0.010mL)。在室温将反应混合物搅拌1小时,加入氰基硼氢化钠(5.73mg,0.091mmol)。反应混合物在室温搅拌过夜。反应混合物用水(0.5mL)稀释,在氮气流下浓缩。该残留物用DCM(0.5mL)和TFA(0.5mL)稀释,在室温搅拌30分钟。将样品浓缩,用DMF(2.0mL)稀释,过滤,通过制备型HPLC纯化,得到2-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌嗪-1-基)-N-甲基乙胺吲哚(0.013g,0.0080mmol,27%收率)。HPLC保留时间1.62min[方法C]。MS m/z:519.4(M+H)。HPLC保留时间1.15min[方法D]。MS m/z:519.5(M+H)。1H NMR(500MHz,DMSO-d6)δ11.06-10.85(m,1H),7.31(br d,J=8.4Hz,1H),7.27(s,1H),7.13-6.95(m,4H),3.82(d,J=8.4Hz,6H),3.46(br s,1H),3.51-3.40(m,1H),3.37-3.28(m,1H),3.23(br s,2H),3.14-2.93(m,3H),2.90(s,1H),2.74(s,1H),2.64(s,4H),1.71-1.47(m,1H),1.48-1.18(m,7H),1.37-1.18(m,1H)。
表7中的实施例根据以上实施例中公开的相同方法来制备。
表7
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
过表达人TLR7、TLR8或TLR9受体的HEK-BlueTM-细胞(Invivogen)用于通过在与五个NF-κB和AP-1结合位点融合的IFN-β最小启动子的控制下,使用诱导型SEAP(分泌型胚胎碱性磷酸酶)报告基因来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),然后在DMSO中用测试化合物处理,以产生0.05nM–50μM的最终剂量反应浓度范围。在室温进行30分钟的化合物预处理后,用TLR7配体(gardiquimod,终浓度为7.5μM)、TLR8配体(R848,终浓度为15.9μM)或TLR9配体(ODN2006,终浓度为5nM)刺激细胞,以激活NF-κB和AP-1,从而诱导SEAP的产生。在37℃、5%CO2孵育22小时后,根据制造商的说明,通过添加HEK-BlueTM检测试剂(Invivogen)来确定SEAP水平,HEK-BlueTM检测试剂是使得检测SEAP的细胞培养基。抑制百分比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信号减少的百分比。
表8
TLR7/8/9报告基因分析数据
(NT=未测试)
Claims (12)
1.式(I)化合物
其N-氧化物或盐,其中:
G为:
(iv)选自如下的9元杂环:
(v)选自如下的10元杂环:
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;条件为R2c和R2d之一为R2a,且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;
R7为:
(i)R7a、-CH2R7a、-C(O)R7a、-C(O)CH(NH2)R7a、-C(O)(CH2)1-3NH2、-C(O)CH(NH2)(C1-4烷基)、-C(O)CH(NH2)(CH2)1-2C(O)OH、-C(O)CH(NH2)(CH2)2-4NH2或-C(O)CH(NH2)(CH2)1-3C(O)NH2;或
(ii)C3-6环烷基,所述C3-6环烷基取代有一个选自如下的取代基:-NRx(CH2)2-3NRyRy、-NRx(甲基哌啶基)、-NRx(CH2)2-3(吗啉基)、二甲基氨基哌啶基和哌嗪基,其取代有选自如下的取代基:C1-4烷基、-C(O)CH3、-(CH2)1-2OCH3、-CH2(甲基苯基)、-(CH2)2-3(吡咯烷基)、C3-6环烷基、吡啶基和甲基哌啶基;
R7a为氮杂螺[3.5]壬基、C3-6环烷基、二氮杂螺[3.5]壬基、二氮杂螺[5.5]十一烷基、二氮杂环庚烷酮基、二氮杂环庚烷基、吗啉基、苯基、哌嗪基、哌啶基、吡咯烷酮基、吡咯烷基或吡咯基,各自取代有0至1个选自如下的取代基:C1-3烷基、-NH2、甲基哌啶基、甲基吡咯烷基、-OCH2CH2(吡咯烷基)和-OCH2CH2NHCH2CH3;和0至4个选自-CH3的取代基;
R7b为:
(i)C1-4烷基、C1-3羟烷基、-(CH2)2-3C≡CH、-(CH2)1-2O(C1-2烷基)、-(CH2)1-2S(O)2(C1-2烷基)、-(CH2)0-3NRxRy、-CH2C(O)NRxRx、-NRx(C1-4羟烷基)、-NRy(C1-2氰基烷基)、-NRx(C1-2氟烷基)、-NRx(C2-4羟基氟烷基)、-NRx(CH2)1-2C(O)NRxRx、-NRx(CH2)1-3NRxRx、-NRxCH2CH2NRxRx、-NRxC(O)(CH2)1-2NRxRx、-O(CH2)1-3NRxRx、-C(O)CH2NRxRx、-(CH2)1-2R7d、-NHR7d、-NH(CH2)1-2R7d或-OR7d;或
(ii)氮杂环庚烷基、氮杂环丁烷基、二氮杂环庚烷基、二氧代硫代吗啉基、吗啉基、氧杂氮杂螺[3.3]庚基、氧杂环丁烷基、哌嗪酮基、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基或四氢异喹啉基,各自取代有0至1个R8a和0至3个R8b;
每个R7c独立地为F、Cl、-CN、C1-2烷基、-CF3或-CH2CN;
R7d为氮杂螺[3.5]壬基、双环[1.1.1]戊基、C3-6环烷基、吗啉基、氧杂环丁烷基、苯基、哌啶基、吡唑基、吡咯烷基、四氢呋喃基或四氢吡喃基,各自取代有0至1个选自如下的取代基:C1-3烷基、-NRxRx、-C(O)CH3、甲基哌啶基、甲基吡咯烷基、四甲基哌啶基、-OCH2CH2(吡咯烷基)和-OCH2CH2NHCH2CH3;和0至4个选自-CH3的取代基;
R8为H或C1-3烷基;
或R7和R8与它们所连接的氮原子一起形成选自如下的杂环:氮杂环丁烷基、二氮杂环庚烷酮基、二氮杂环庚烷基、二氮杂螺[3.5]壬基、二氮杂螺[5.5]十一烷基、咪唑基、咪唑烷酮基、八氢-1H-吡咯并[3,4-b]吡啶基、哌嗪基、哌啶基、吡咯烷酮基、吡咯烷基和吡咯基,其中所述杂环取代有0至1个R7b和0至2个R7c;
R8a为-OH、C1-6烷基、C1-4氟烷基、C1-4羟烷基、-(CH2)1-2O(C1-3烷基)、-C(O)(C1-3烷基)、-(CH2)1-2(C3-6环烷基)、-(CH2)1-3(甲基苯基)、-(CH2)1-3(吡咯烷基)、-(CH2)1-3(甲基吡唑基)、-(CH2)1-3(噻吩基)、-NRxRx、C3-6环烷基、甲基哌啶基、吡啶基或嘧啶基;
每个R8b独立地为F、Cl、-CN、C1-3烷基或-CF3;
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。
2.根据权利要求1所述的化合物、其N-氧化物或盐,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);
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;
R7为:
(i)R7a、-CH2R7a、-C(O)R7a、-C(O)CH(NH2)R7a、-C(O)(CH2)1-3NH2、-C(O)CH(NH2)(C1-4烷基)、-C(O)CH(NH2)(CH2)1-2C(O)OH、-C(O)CH(NH2)(CH2)2-4NH2或-C(O)CH(NH2)(CH2)1-3C(O)NH2;或
(ii)C3-6环烷基,所述C3-6环烷基取代有一个选自如下的取代基:-NRx(CH2)2-3NRxRx、-NH(CH2)2-3NHCH3、-NH(甲基哌啶基)、-NH(CH2)2-3(吗啉基)、二甲基氨基哌啶基和哌嗪基,其取代有选自如下的取代基:C1-4烷基、-C(O)CH3、-(CH2)1-2OCH3、-CH2(甲基苯基)、-(CH2)2-3(吡咯烷基)、C3-6环烷基、吡啶基和甲基哌啶基;
R7b为:
(i)C1-4烷基、C1-3羟烷基、-(CH2)2-3C≡CH、-(CH2)1-2O(C1-2烷基)、-(CH2)1-2S(O)2(C1-2烷基)、-(CH2)0-3NRxRy、-CH2C(O)NRxRx、-NRx(C1-4羟烷基)、-NRy(C1-2氰基烷基)、-NRx(C1-2氟烷基)、-NRx(C2-4羟基氟烷基)、-NRx(CH2)1-2C(O)NRxRx、-NRx(CH2)1-3NRxRx、-NRxCH2CH2NRxRx、-NRxC(O)(CH2)1-2NRxRx、-O(CH2)1-3NRxRx、-C(O)CH2NRxRx、-(CH2)1-2R7d、-NHR7d、-NH(CH2)1-2R7d或-OR7d;或
(ii)氮杂环庚烷基、氮杂环丁烷基、二氮杂环庚烷基、二氧代硫代吗啉基、吗啉基、氧杂氮杂螺[3.3]庚基、氧杂环丁烷基、哌嗪酮基、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基或四氢异喹啉基,各自取代有0至1个R8a和0至3个R8b;
每个R7c独立地为F、-CH3或-CH2CN;
R7d为氮杂螺[3.5]壬基、双环[1.1.1]戊基、C3-6环烷基、吗啉基、氧杂环丁烷基、苯基、哌啶基、吡唑基、吡咯烷基、四氢呋喃基或四氢吡喃基,各自取代有0至1个选自如下的取代基:C1-3烷基、-NH2、-C(O)CH3、甲基哌啶基、甲基吡咯烷基、四甲基哌啶基、-OCH2CH2(吡咯烷基)和-OCH2CH2NHCH2CH3;和0至4个选自-CH3的取代基;
R8为H或C1-2烷基;
或R7和R8与它们所连接的氮原子一起形成选自如下的杂环:氮杂环丁烷基、二氮杂环庚烷酮基、二氮杂环庚烷基、二氮杂螺[3.5]壬基、二氮杂螺[5.5]十一烷基、咪唑基、咪唑烷酮基、八氢-1H-吡咯并[3,4-b]吡啶基、哌嗪基、哌啶基、吡咯烷酮基、吡咯烷基和吡咯基,其中所述杂环取代有0至1个R7b和0至2个R7c;
R8a为-OH、C1-4烷基、C1-3氟烷基、-(CH2)1-2O(C1-2烷基)、-C(O)(C1-2烷基)、-CH2(C3-6环烷基)、-(CH2)1-2(甲基苯基)、-(CH2)1-3(吡咯烷基)、-(CH2)1-2(甲基吡唑基)、-(CH2)1-2(噻吩基)、-NRxRx、C3-6环烷基、甲基哌啶基或吡啶基;和
每个R8b独立地为F或-CH3。
4.根据权利要求1所述的化合物、其N-氧化物或盐,其中:
G为:
R1为-CH3、-CH2CH3或-CH(CH3)2;
每个R2独立地为Cl、-CH3或-OCH3;
R2a为-CH3;
每个R2b独立地为H、Cl或-CH3;
每个R5独立地为-CH3或-CH(CH3)2;
R7为:
(i)-CH2(异丙基氮杂螺[3.5]壬基)、-CH2(甲基吡咯烷基)、-C(O)(CH2)1-3NH2、-C(O)CH(NH2)CH2CH2CH3、-C(O)CH(NH2)CH2CH(CH3)2、-C(O)CH(NH2)CH(CH3)CH2CH3、-C(O)CH(NH2)CH2CH2C(O)OH、-C(O)CH(NH2)(CH2)3-4NH2、-C(O)CH(NH2)(CH2)1-2C(O)NH2、-C(O)CH(NH2)(环己基)、-C(O)CH(NH2)(苯基)、-C(O)(氨基环己基)、-C(O)(吗啉基)、-C(O)(吡咯烷基)、五甲基哌啶基、甲基哌啶基-哌啶基、甲基吡咯烷基-吡咯烷基、或取代有-OCH2CH2(吡咯烷基)或-OCH2CH2NHCH2CH3的苯基;或
(ii)环己基,所述环己基取代有-NRx(CH2)2-3N(CH3)2、-NHCH2CH2NHCH3、-NH(甲基哌啶基)、-NH(CH2)2-3(吗啉基)、二甲基氨基哌啶基或哌嗪基,其取代有-CH3、-CH2CH3、-C(CH3)3、-CH2CH(CH3)2、-C(O)CH3、-CH2CH2OCH3、-CH2(甲基苯基)、-(CH2)2-3(吡咯烷基)、环戊基、吡啶基或甲基哌啶基;
R8为H、-CH3或-CH2CH3;
或R7和R*与它们所连接的氮原子一起形成选自如下的杂环:氮杂环丁烷基、二氮杂环庚烷酮基、二氮杂环庚烷基、二氮杂螺[3.5]壬基、二氮杂螺[5.5]十一烷基、咪唑烷酮基、八氢-1H-吡咯并[3,4-b]吡啶基、哌嗪基、哌啶基、吡咯烷酮基和吡咯烷基,其中所述杂环取代有0至1个R7b和0至2个R7c;
R7b为:
(i)-CH3、-CH(CH3)2、-C(CH3)2OH、-CH2CH2CH2C≡CH、-CH2CH2NH(CH3)、-CH2CH2N(CH3)2、-NRxRx、-NHCH2CH2NH(CH3)、-NHCH2CH2N(CH3)2、-N(CH3)CH2CH2NH2、-NRxCH2CH2CH2N(CH3)2、-OCH2CH2N(CH3)2、-CH2(苯基)、-CH2(甲基吡唑基)、-CH2CH2(吡咯烷基)、-NH(甲基哌啶基)、-NH(异丙基哌啶基)、-NH(五甲基哌啶基)、-NH(乙酰基哌啶基)、-NHCH2CH2(吗啉基)、-O(哌啶基)、-O(甲基哌啶基)、-O(乙基哌啶基)、-O(异丙基哌啶基)或-O(哌啶基)-(四甲基哌啶基);或
(ii)氮杂环庚烷基、二氮杂环庚烷基、吗啉基、哌嗪基、哌啶基、吡啶基、吡咯烷酮基、吡咯烷基或四氢异喹啉基,各自取代有0至1个R8a和0至3个R8b;
每个R7c独立地为-CH3或-CH2CN;
R8a为-OH、-CH3、-CH2CH3、-CH(CH3)2、-C(CH3)3、-CH2CH(CH3)2、-CH2CH2OCH3、-CH2CH2CF3、-C(O)CH3、-CH2(环丙基)、-CH2(甲基苯基)、-(CH2)2-3(吡咯烷基)、-CH2(甲基吡唑基)、-CH2(噻吩基)、-NRxRx、环戊基、甲基哌啶基或吡啶基;
每个R8b为-CH3;
每个Rx独立地为H或-CH3;
n为0或1;和
p为0、1、2或3。
5.根据权利要求1所述的化合物、其N-氧化物或盐,其中R7为-CH2R7a、-C(O)(CH2)1- 3NH2、-C(O)CH(NH2)(C1-4烷基)、-C(O)CH(NH2)(CH2)1-2C(O)OH、-C(O)CH(NH2)(CH2)2-4NH2、-C(O)CH(NH2)(CH2)1-3C(O)NH2、-C(O)CH(NH2)R7a、-C(O)R7a或R7a。
6.根据权利要求1所述的化合物、其N-氧化物或盐,其中R7为C3-6环烷基,所述C3-6环烷基取代有一个选自如下的取代基:-NRx(CH2)2-3NRyRy、-NRx(甲基哌啶基)、-NRx(CH2)2-3(吗啉基)、二甲基氨基哌啶基和哌嗪基,其取代有选自如下的取代基:C1-4烷基、-C(O)CH3、-(CH2)1-2OCH3、-CH2(甲基苯基)、-(CH2)2-3(吡咯烷基)、C3-6环烷基、吡啶基和甲基哌啶基。
7.根据权利要求1所述的化合物、其N-氧化物或盐,其中R7和R8与它们所连接的氮原子一起形成选自如下的杂环:氮杂环丁烷基、二氮杂环庚烷酮基、二氮杂环庚烷基、二氮杂螺[3.5]壬基、二氮杂螺[5.5]十一烷基、咪唑基、咪唑烷酮基、八氢-1H-吡咯并[3,4-b]吡啶基、哌嗪基、哌啶基、吡咯烷酮基、吡咯烷基和吡咯基,其中所述杂环取代有0至1个R7b和0至2个R7c。
8.根据权利要求1所述的化合物、其N-氧化物或盐,其中所述化合物为:(R)-N-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)吡咯烷-3-甲酰胺(9);(S)-N-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)吡咯烷-3-甲酰胺(10);2-氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)乙酰胺(11);4-氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)丁酰胺(12);N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吡咯烷-3-甲酰胺(13);(R)-2-氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)戊酰胺(14);N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)吗啉-2-甲酰胺(15);(R)-2-氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-4-甲基戊酰胺(16);(2R,3R)-2-氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-3-甲基戊酰胺(17);(S)-2-氨基-N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)琥珀酰胺(18);(R)-2-氨基-N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)琥珀酰胺(19);(S)-2,5-二氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)戊酰胺(20);(1R,2S)-2-氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)环己烷-1-甲酰胺(21);(R)-2-氨基-N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)戊二酰胺(22);(S)-2,6-二氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)己酰胺(23);(S)-4-氨基-5-((2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)氨基)-5-氧代戊酸(24);(S)-2-氨基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-2-苯基乙酰胺(25);(S)-2-氨基-2-环己基-N-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)乙酰胺(26);2-(3,4-二甲氧基苯基)-N,3-二乙基-N-(1'-甲基-1,4'-联哌啶-4-基)-1H-吲哚-5-胺(28);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(2-(甲基氨基)乙基)环己烷-1,4-二胺(30-31);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(2-(二甲基氨基)乙基)环己烷-1,4-二胺(32-33);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(4-甲基哌嗪-1-基)环己基)-1H-吲哚-5-胺(34);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(2-(二甲基氨基)乙基)-N4-甲基环己烷-1,4-二胺(35);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(3-(二甲基氨基)丙基)环己烷-1,4-二胺(36-37);2-(3,4-二甲氧基苯基)-N-(4-(4-乙基哌嗪-1-基)环己基)-3-异丙基-1H-吲哚-5-胺(38-39);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(1-甲基哌啶-4-基)环己烷-1,4-二胺(40-41);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(3-(二甲基氨基)丙基)-N4-甲基环己烷-1,4-二胺(42-43);1-(4-(4-((2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)氨基)环己基)哌嗪-1-基)乙烷-1-酮(44-45);2-(3,4-二甲氧基苯基)-N-(4-(4-(二甲基氨基)哌啶-1-基)环己基)-3-异丙基-1H-吲哚-5-胺(46);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(2-吗啉代乙基)环己烷-1,4-二胺(47-48);N-(4-(4-(叔丁基)哌嗪-1-基)环己基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-胺(49-50);2-(3,4-二甲氧基苯基)-N-(4-(4-异丁基哌嗪-1-基)环己基)-3-异丙基-1H-吲哚-5-胺(51-53);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(4-(2-甲氧基乙基)哌嗪-1-基)环己基)-1H-吲哚-5-胺(54);N1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N4-(3-吗啉代丙基)环己烷-1,4-二胺(55-56);N-(4-(4-环戊基哌嗪-1-基)环己基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-胺(57-58);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(4-(吡啶-4-基)哌嗪-1-基)环己基)-1H-吲哚-5-胺(59-60);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)环己基)-1H-吲哚-5-胺(61-62);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(4-(2-(吡咯烷-1-基)乙基)哌嗪-1-基)环己基)-1H-吲哚-5-胺(63-64);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(4-(4-甲基苄基)哌嗪-1-基)环己基)-1H-吲哚-5-胺(65-66);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(4-(3-(吡咯烷-1-基)丙基)哌嗪-1-基)环己基)-1H-吲哚-5-胺(67);2-(3,4-二甲氧基苯基)-3-异丙基-N-(1,2,2,6,6-五甲基哌啶-4-基)-1H-吲哚-5-胺(103);2-(3,4-二甲氧基苯基)-3-异丙基-N-甲基-N-((1-甲基吡咯烷-2-基)甲基)-1H-吲哚-5-胺(104);2-(3,4-二甲氧基苯基)-N-(4-(2-(乙基氨基)乙氧基)苯基)-3-异丙基-1H-吲哚-5-胺(105);2-(3,4-二甲氧基苯基)-3-异丙基-N-(4-(2-(吡咯烷-1-基)乙氧基)苯基)-1H-吲哚-5-胺(106);2-(3,4-二甲氧基苯基)-3-乙基-N-((7-异丙基-7-氮杂螺[3.5]壬烷-2-基)甲基)-1H-吲哚-5-胺(124);或2-(3,4-二甲氧基苯基)-3-乙基-N-(1'-甲基-[1,4'-联哌啶]-4-基)-1H-吲哚-5-胺(125)。
9.根据权利要求1所述的化合物或其盐,其中所述化合物为:1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)-3-((2-(甲基氨基)乙基)氨基)吡咯烷-2-酮(1);3-((2-氨基乙基)(甲基)氨基)-1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡咯烷-2-酮(2);1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-3-(二甲基氨基)吡咯烷-2-酮(3-4);1-(2-(2,6-二甲基吡啶-4-基)-3-异丙基-1H-吲哚-5-基)-3-(4-异丙基哌嗪-1-基)吡咯烷-2-酮(5-6);3-(2-(二甲基氨基)乙氧基)-1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)吡咯烷-2-酮(7);1-(3-异丙基-2-(2-甲基吡啶-4-基)-1H-吲哚-5-基)咪唑烷-2-酮(8);1-(3-异丙基-2-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吲哚-5-基)咪唑烷-2-酮(27);5-(3-(1,4-二氮杂环庚烷-1-基)氮杂环丁烷-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(29);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(2,2,6,6-四甲基-1l2-哌啶-4-基)哌嗪-1-基)-1H-吲哚(68);2-(3,4-二甲氧基苯基)-3-乙基-6-异丙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚(69);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(吡咯烷-1-基)哌啶-1-基)-1H-吲哚(70);2-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-N,N-二甲基乙烷-1-胺(71);N1-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-N2-甲基乙烷-1,2-二胺(72);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(哌嗪-1-基)哌啶-1-基)-1H-吲哚(73);4-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)吗啉(74);N1-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-N2,N2-二甲基乙烷-1,2-二胺(75);N1-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-N3,N3-二甲基丙烷-1,3-二胺(76-77);2-(3,4-二甲氧基苯基)-5-(4-(4-乙基哌嗪-1-基)哌啶-1-基)-3-异丙基-1H-吲哚(78);1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N-(1-甲基哌啶-4-基)哌啶-4-胺(79);4-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-2,6-二甲基吗啉(80);N1-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-N1,N3,N3-三甲基丙烷-1,3-二胺(81);1-(4-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)哌嗪-1-基)乙烷-1-酮(82);1'-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N,N-二甲基-[1,4'-联哌啶]-4-胺(83);2-(3,4-二甲氧基苯基)-5-(4-(4-乙基-1,4-二氮杂环庚烷-1-基)哌啶-1-基)-3-异丙基-1H-吲哚(84);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-异丙基哌嗪-1-基)哌啶-1-基)-1H-吲哚(85);1-(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)哌啶-4-胺(86);5-(4-(4-(环丙基甲基)哌嗪-1-基)哌啶-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(87);1-(4-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-1,4-二氮杂环庚烷-1-基)乙烷-1-酮(88);1-(4-((1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)氨基)哌啶-1-基)乙烷-1-酮(89);5-(4-(4-(叔丁基)哌嗪-1-基)哌啶-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(90);2-(3,4-二甲氧基苯基)-5-(4-(4-异丁基哌嗪-1-基)哌啶-1-基)-3-异丙基-1H-吲哚(91);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-(2-甲氧基乙基)哌嗪-1-基)哌啶-1-基)-1H-吲哚(92);5-(4-(4-环戊基哌嗪-1-基)哌啶-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(93);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-(吡啶-4-基)哌嗪-1-基)哌啶-1-基)-1H-吲哚(94);N-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-1,2,2,6,6-五甲基哌啶-4-胺(95);2-(3,4-二甲氧基苯基)-3-异丙基-5-(1'-((1-甲基-1H-吡咯-2-基)甲基)-[4,4'-联哌啶]-1-基)-1H-吲哚(96);2-(3,4-二甲氧基苯基)-3-异丙基-5-(1'-(3,3,3-三氟丙基)-[4,4'-联哌啶]-1-基)-1H-吲哚(97);2-(3,4-二甲氧基苯基)-3-异丙基-5-(1'-(噻吩-3-基甲基)-[4,4'-联哌啶]-1-基)-1H-吲哚(98);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-(1-甲基哌啶-4-基)哌嗪-1-基)哌啶-1-基)-1H-吲哚(99);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-(2-(吡咯烷-1-基)乙基)哌嗪-1-基)哌啶-1-基)-1H-吲哚(100);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-(4-甲基苄基)哌嗪-1-基)哌啶-1-基)-1H-吲哚(101);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-(3-(吡咯烷-1-基)丙基)哌嗪-1-基)哌啶-1-基)-1H-吲哚(102);1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-4-(2-(二甲基氨基)乙基)-1,4-二氮杂环庚烷-5-酮(107);1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N,N-二甲基哌啶-4-胺(108);2-(4-氨基-1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)乙腈(109);2-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)丙-2-醇(110);3-氯-5-(5-(4-(二甲基氨基)哌啶-1-基)-3-异丙基-1H-吲哚-2-基)-1,4-二甲基-1l4,2l5-吡啶-2-酮(111);2-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-4-(甲基氨基)哌啶-4-基)乙腈(112);2-(3,4-二甲氧基苯基)-3-异丙基-5-(2-(吡啶-4-基)哌啶-1-基)-1H-吲哚(113);2-((1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)氧基)-N,N-二甲基乙烷-1-胺(114);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(2-(吡咯烷-1-基)乙基)哌啶-1-基)-1H-吲哚(115);1-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-4-羟基吡咯烷-2-酮(116);4-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-4-甲基哌啶-4-基)吗啉(117);6-苄基-1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)八氢-1H-吡咯并[3,4-b]吡啶(118);1-(1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌啶-4-基)-2-甲基-1,2,3,4-四氢异喹啉(119);1-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-N,N-二甲基吡咯烷-3-胺(120);5-(4-(1,4-二氮杂环庚烷-1-基)哌啶-1-基)-2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚(121);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(1-异丙基氮杂环庚烷-4-基)哌嗪-1-基)-1H-吲哚(122);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)哌啶-1-基)-1H-吲哚(123);2-(3,4-二甲氧基苯基)-3-异丙基-5-(哌嗪-1-基)-1H-吲哚,TFA盐(126);2-(4-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)哌嗪-1-基)-N-甲基乙胺(127);4-(3-异丙基-5-(哌嗪-1-基)-1H-吲哚-2-基)-1H-吡咯并[2,3-b]吡啶(128);2-(2,6-二甲氧基吡啶-4-基)-3-乙基-5-(哌嗪-1-基)-1H-吲哚(129);4-(3-异丙基-6-甲基-5-(哌嗪-1-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(130);5-([4,4'-联哌啶]-1-基)-2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚(131);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(哌啶-4-基氧基)哌啶-1-基)-1H-吲哚(132);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(哌啶-4-基氧基)哌啶-1-基)-1H-吲哚(133);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-((1-甲基哌啶-4-基)氧基)哌啶-1-基)-1H-吲哚(134);6-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)八氢-1H-吡咯并[3,4-b]吡啶(135);2-(2-(3,4-二甲氧基苯基)-3-异丙基-1H-吲哚-5-基)-2,6-二氮杂螺[3.5]壬烷(136);2-(4-(3-乙基-2-(2-甲氧基吡啶-4-基)-1H-吲哚-5-基)哌嗪-1-基)-N-甲基乙烷-1-胺(137);2-(4-(3-异丙基-2-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吲哚-5-基)哌嗪-1-基)-N-甲基乙烷-1-胺(138);3-乙基-5-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(139);2-(4-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)哌嗪-1-基)-N-甲基乙烷-1-胺(140);4-(3-甲基-5-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚-2-基)-1H-吡咯并[2,3-b]吡啶(141);3-乙基-5-(4-(1-乙基哌啶-4-基)哌嗪-1-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(142);3-乙基-2-(2-甲氧基吡啶-4-基)-5-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(143);2-(4-(2-(3,4-二甲氧基苯基)-3-乙基-6-甲基-1H-吲哚-5-基)哌嗪-1-基)-N-甲基乙烷-1-胺(144);4-(5-(4-(1-乙基哌啶-4-基)哌嗪-1-基)-3-甲基-1H-吲哚-2-基)-1H-吡咯并[2,3-b]吡啶(145);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(戊-4-炔-1-基)哌嗪-1-基)-1H-吲哚(146);3-乙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(147);3-乙基-5-(4-(1-乙基哌啶-4-基)哌嗪-1-基)-2-(2-甲氧基吡啶-4-基)-1H-吲哚(148);2-(3,4-二甲氧基苯基)-3-甲基-5-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(149);2-(4-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-3,3-二甲基哌嗪-1-基)-N-甲基乙烷-1-胺(150);4-(5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-3-甲基-1H-吲哚-2-基)-1H-吡咯并[2,3-b]吡啶(151);3-乙基-5-(4-(1-异丁基哌啶-4-基)哌嗪-1-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(152);3-乙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-2-(2-甲氧基吡啶-4-基)-1H-吲哚(153);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(154);2-(3,4-二甲氧基苯基)-5-(4-(1-乙基哌啶-4-基)哌嗪-1-基)-3-甲基-1H-吲哚(155);2-(2,6-二甲氧基吡啶-4-基)-3-乙基-5-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(156);4-(3-乙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚-2-基)-1H-吡咯并[2,3-b]吡啶(157);4-(5-(4-(1-异丁基哌啶-4-基)哌嗪-1-基)-3-甲基-1H-吲哚-2-基)-1H-吡咯并[2,3-b]吡啶(158);4-(3-乙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(159);3-乙基-5-(4-(1-异丁基哌啶-4-基)哌嗪-1-基)-2-(2-甲氧基吡啶-4-基)-1H-吲哚(160);3-乙基-2-(2-甲氧基吡啶-4-基)-5-(4-(2,2,6,6-四甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(161);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(162);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(1-乙基哌啶-4-基)哌嗪-1-基)-1H-吲哚(163);2-(3,4-二甲氧基苯基)-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-3-甲基-1H-吲哚(164);4-(3-乙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚-2-基)-1-甲基-1H-吡咯并[2,3-b]吡啶(165);4-(3-异丙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚-2-基)-1H-吡咯并[2,3-b]吡啶(166);4-(3-异丙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(167-168);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚(169);2-(3,4-二甲氧基苯基)-5-(4-(1-异丁基哌啶-4-基)哌嗪-1-基)-3-甲基-1H-吲哚(170);2-(3,4-二甲氧基苯基)-3-甲基-5-(4-(2,2,6,6-四甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(171);2-(3,4-二甲氧基苯基)-5-(2,2-二甲基-4-(1-甲基哌啶-4-基)哌嗪-1-基)-3-乙基-1H-吲哚(172);2-(2,6-二甲氧基吡啶-4-基)-3-乙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-1H-吲哚(173-174);4-(3-异丙基-5-(4-(1-异丙基哌啶-4-基)哌嗪-1-基)-6-甲基-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(175);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(2,2,6,6-四甲基哌啶-4-基)哌嗪-1-基)-1H-吲哚(176);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(1-异丁基哌啶-4-基)哌嗪-1-基)-1H-吲哚(177);2-(4-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-1,4-二氮杂环庚烷-1-基)-N-甲基乙烷-1-胺(178);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(1-甲基哌啶-4-基)-1,4-二氮杂环庚烷-1-基)-1H-吲哚(179);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-(1-异丙基哌啶-4-基)-1,4-二氮杂环庚烷-1-基)-1H-吲哚(180);3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-9-甲基-3,9-二氮杂螺[5.5]十一烷(181);3-乙基-5-(4-((1-异丙基哌啶-4-基)氧基)哌啶-1-基)-2-(2-甲基吡啶-4-基)-1H-吲哚(182);3-(2-(3,4-二甲氧基苯基)-3-乙基-1H-吲哚-5-基)-9-异丙基-3,9-二氮杂螺[5.5]十一烷(183);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-(4-甲基哌嗪-1-基)哌啶-1-基)-1H-吲哚(184);4-(3-乙基-5-(4-((1-异丙基哌啶-4-基)氧基)哌啶-1-基)-1H-吲哚-2-基)-1H-吡唑并[3,4-b]吡啶(185);3-(2-(3,4-二甲氧基苯基)-3-乙基-6-甲基-1H-吲哚-5-基)-9-异丙基-3,9-二氮杂螺[5.5]十一烷(186);2-(3,4-二甲氧基苯基)-3-异丙基-5-(4-((1-甲基哌啶-4-基)氧基)哌啶-1-基)-1H-吲哚(187);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-((1-乙基哌啶-4-基)氧基)哌啶-1-基)-1H-吲哚(188);3-((1-甲基-1H-吡咯-2-基)甲基)-9-(3-甲基-2-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吲哚-5-基)-3,9-二氮杂螺[5.5]十一烷(189);2-(3,4-二甲氧基苯基)-5-(4-((1-乙基哌啶-4-基)氧基)哌啶-1-基)-3-异丙基-1H-吲哚(190);2-(3,4-二甲氧基苯基)-3-乙基-5-(4-((1-异丙基哌啶-4-基)氧基)哌啶-1-基)-1H-吲哚(191);1-(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)哌啶-4-胺(192);或2-(3,4-二甲氧基苯基)-3-乙基-5-(4-((2',2',6',6'-四甲基-[1,4'-联哌啶]-4-基)氧基)哌啶-1-基)-1H-吲哚(193)。
10.药物组合物,其包含根据权利要求1-9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。
11.根据权利要求1-10中任一项所述的化合物或其药学上可接受的盐,其用于治疗自身免疫性疾病或慢性炎性疾病的疗法中。
12.根据权利要求所述的化合物11或其药学上可接受的盐,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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