CN114980975A - 二氢环戊二烯并异喹啉磺酰胺衍生物 - Google Patents
二氢环戊二烯并异喹啉磺酰胺衍生物 Download PDFInfo
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- CN114980975A CN114980975A CN202080089663.9A CN202080089663A CN114980975A CN 114980975 A CN114980975 A CN 114980975A CN 202080089663 A CN202080089663 A CN 202080089663A CN 114980975 A CN114980975 A CN 114980975A
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- Prior art keywords
- amino
- cyclopropyl
- dihydro
- cyclopenta
- isoquinoline
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- 229940124530 sulfonamide Drugs 0.000 title description 3
- 150000003456 sulfonamides Chemical class 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 219
- 238000006243 chemical reaction Methods 0.000 claims abstract description 111
- 210000003630 histaminocyte Anatomy 0.000 claims abstract description 10
- 206010020751 Hypersensitivity Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 208000035475 disorder Diseases 0.000 claims abstract description 9
- 208000010668 atopic eczema Diseases 0.000 claims abstract description 7
- 230000000172 allergic effect Effects 0.000 claims abstract description 5
- 230000036647 reaction Effects 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- -1 C (O) OH Chemical group 0.000 claims description 400
- 150000001875 compounds Chemical class 0.000 claims description 236
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 159
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 78
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 48
- 229910052736 halogen Inorganic materials 0.000 claims description 47
- 150000002367 halogens Chemical class 0.000 claims description 47
- 125000001072 heteroaryl group Chemical group 0.000 claims description 44
- 125000004043 oxo group Chemical group O=* 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 38
- 229910052757 nitrogen Inorganic materials 0.000 claims description 38
- 125000003277 amino group Chemical group 0.000 claims description 35
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 24
- 239000000460 chlorine Substances 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 11
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 9
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 206010061218 Inflammation Diseases 0.000 claims description 7
- 208000024780 Urticaria Diseases 0.000 claims description 7
- 208000026935 allergic disease Diseases 0.000 claims description 7
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 230000004054 inflammatory process Effects 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 208000010216 atopic IgE responsiveness Diseases 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 6
- YBGWYLZJFWFYED-UHFFFAOYSA-N 3-cyclopropyl-9-[3-[(5-fluoropyridin-3-yl)amino]-1,2,4-triazol-4-yl]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)CCC3N1C(=NN=C1)NC=1C=NC=C(C=1)F YBGWYLZJFWFYED-UHFFFAOYSA-N 0.000 claims description 5
- CWCCDQHRSNJXNA-UHFFFAOYSA-N 3-cyclopropyl-N-(2-methylpropyl)-9-[3-[(2-methylpyrazol-3-yl)amino]-1,2,4-triazol-4-yl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)CCC3N1C(=NN=C1)NC=1N(N=CC=1)C CWCCDQHRSNJXNA-UHFFFAOYSA-N 0.000 claims description 5
- 230000007815 allergy Effects 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 5
- 125000005554 pyridyloxy group Chemical group 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 4
- 125000004144 cyclobuten-1-yl group Chemical group [H]C1=C(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 claims description 4
- 125000006379 fluoropyridyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- BFIWZEKPARJYJE-UHFFFAOYSA-N isoquinoline-5-sulfonamide Chemical compound N1=CC=C2C(S(=O)(=O)N)=CC=CC2=C1 BFIWZEKPARJYJE-UHFFFAOYSA-N 0.000 claims description 4
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 claims description 4
- KRCIPWHANHHPNF-UHFFFAOYSA-N 3-cyclopropyl-9-fluoro-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)CCC3F KRCIPWHANHHPNF-UHFFFAOYSA-N 0.000 claims description 3
- KQFWGHOLIXKSKX-UHFFFAOYSA-N 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(2-fluoropyridin-3-yl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)(C)F)C(CC3)C=1C(=NC=CC=1)F KQFWGHOLIXKSKX-UHFFFAOYSA-N 0.000 claims description 3
- ILCVTCFZENNORB-UHFFFAOYSA-N 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-9-pyridin-3-yloxy-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)(C)F)CCC3OC=1C=NC=CC=1 ILCVTCFZENNORB-UHFFFAOYSA-N 0.000 claims description 3
- ILIAZCOVXNJLJK-UHFFFAOYSA-N 3-cyclopropyl-N-(2-methylpropyl)-7-oxo-8,9-dihydrocyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)C(CC3)=O ILIAZCOVXNJLJK-UHFFFAOYSA-N 0.000 claims description 3
- CBYJZPPVTBHYKQ-UHFFFAOYSA-N 3-cyclopropyl-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]cinnoline-5-sulfonamide Chemical compound C1(CC1)C=1N=NC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)CCC3 CBYJZPPVTBHYKQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 3
- OJOBMXAQYISCJD-UHFFFAOYSA-N 7-cyclopropyl-N-(2-fluoro-2-methylpropyl)-3-hydroxy-2,3-dihydrofuro[3,2-h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)(C)F)C(CO3)O OJOBMXAQYISCJD-UHFFFAOYSA-N 0.000 claims description 3
- 208000032671 Allergic granulomatous angiitis Diseases 0.000 claims description 3
- JUNVJVSQPIZWDZ-UHFFFAOYSA-N C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)(C)F)C(CC3)(C=1C=NC=CC=1)O Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)(C)F)C(CC3)(C=1C=NC=CC=1)O JUNVJVSQPIZWDZ-UHFFFAOYSA-N 0.000 claims description 3
- OPEDORQBRUAVFX-UHFFFAOYSA-N C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)(C)F)C(CC3)NC=1C=NC=CC=1 Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)(C)F)C(CC3)NC=1C=NC=CC=1 OPEDORQBRUAVFX-UHFFFAOYSA-N 0.000 claims description 3
- DFXRNDPRFPVMAP-UHFFFAOYSA-N C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)(C)F)CCC3NC=1C=NC=CC=1 Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)(C)F)CCC3NC=1C=NC=CC=1 DFXRNDPRFPVMAP-UHFFFAOYSA-N 0.000 claims description 3
- SISDXSAXWUVQAM-UHFFFAOYSA-N C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)C(CC3)(C)O Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)C(CC3)(C)O SISDXSAXWUVQAM-UHFFFAOYSA-N 0.000 claims description 3
- RJMOFKQPEMEDDB-UHFFFAOYSA-N C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)CCC3(C)O Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)CCC3(C)O RJMOFKQPEMEDDB-UHFFFAOYSA-N 0.000 claims description 3
- LJARRUMQGGZYTN-UHFFFAOYSA-N C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)CCC3NCC=1C=NC=CC=1 Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)CCC3NCC=1C=NC=CC=1 LJARRUMQGGZYTN-UHFFFAOYSA-N 0.000 claims description 3
- 208000006344 Churg-Strauss Syndrome Diseases 0.000 claims description 3
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 claims description 3
- 208000038004 exacerbated respiratory disease Diseases 0.000 claims description 3
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 3
- 201000005962 mycosis fungoides Diseases 0.000 claims description 3
- YUWNYCDUOYZSAT-UHFFFAOYSA-N n,1,1-trifluoromethanimine Chemical group FN=C(F)F YUWNYCDUOYZSAT-UHFFFAOYSA-N 0.000 claims description 3
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- NKFOGCJWFKKJFS-UHFFFAOYSA-N 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-ethylthiourea Chemical compound C1(CC1)C=1N=CC2=C3C(=CC(=C2C=1)S(NCC(C)C)(=O)=O)C(CC3)NC(=S)NCC NKFOGCJWFKKJFS-UHFFFAOYSA-N 0.000 claims description 2
- RAFWNDZIMBZTLG-UHFFFAOYSA-N 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-[(2,5-dimethylpyrazol-3-yl)methyl]urea Chemical compound C1(CC1)C=1N=CC2=C3C(=CC(=C2C=1)S(NCC(C)C)(=O)=O)CCC3NC(=O)NCC=1N(N=C(C=1)C)C RAFWNDZIMBZTLG-UHFFFAOYSA-N 0.000 claims description 2
- JOZNDKMDQZSJNM-UHFFFAOYSA-N 1-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-pyridin-3-ylthiourea Chemical compound C1(CC1)C=1N=CC2=C3C(=CC(=C2C=1)S(NCC(C)C)(=O)=O)CCC3NC(=S)NC=1C=NC=CC=1 JOZNDKMDQZSJNM-UHFFFAOYSA-N 0.000 claims description 2
- BUILEPQIOHBPNB-UHFFFAOYSA-N 1-cyano-2-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-7-yl]-3-(4-methylphenyl)guanidine Chemical compound C(#N)N=C(NC1CCC=2C1=CC(=C1C=C(N=CC=21)C1CC1)S(NCC(C)C)(=O)=O)NC1=CC=C(C=C1)C BUILEPQIOHBPNB-UHFFFAOYSA-N 0.000 claims description 2
- JOJJSLWCPDHTLN-UHFFFAOYSA-N 1-cyano-2-[3-cyclopropyl-5-(2-methylpropylsulfamoyl)-8,9-dihydro-7H-cyclopenta[h]isoquinolin-9-yl]-3-(4-methylphenyl)guanidine Chemical compound C(#N)N=C(NC1CCC2=CC(=C3C=C(N=CC3=C21)C1CC1)S(NCC(C)C)(=O)=O)NC1=CC=C(C=C1)C JOJJSLWCPDHTLN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- FPKVTPCZTCDYJW-UHFFFAOYSA-N 3-cyclopropyl-5-[(2-fluoro-2-methylpropyl)sulfamoyl]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-7-carboxylic acid Chemical compound C1(CC1)C=1N=CC2=C3C(=CC(=C2C=1)S(NCC(C)(C)F)(=O)=O)C(CC3)C(=O)O FPKVTPCZTCDYJW-UHFFFAOYSA-N 0.000 claims description 2
- ZKVOGNGGNTVGIH-UHFFFAOYSA-N 3-cyclopropyl-7-[(4,4-dimethyl-3-oxocyclobuten-1-yl)amino]-N-(2-fluoro-2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)(C)F)C(CC3)NC1=CC(C1(C)C)=O ZKVOGNGGNTVGIH-UHFFFAOYSA-N 0.000 claims description 2
- LULINNJTFUVCKS-UHFFFAOYSA-N 3-cyclopropyl-7-[[3,4-dioxo-2-(pyridin-3-ylamino)cyclobuten-1-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)C(CC3)NC1=C(C(C1=O)=O)NC=1C=NC=CC=1 LULINNJTFUVCKS-UHFFFAOYSA-N 0.000 claims description 2
- VWCOAXIJOYGNNW-UHFFFAOYSA-N 3-cyclopropyl-7-[[4-(2,5-dimethylpyrazol-3-yl)-1,2,4-triazol-3-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)C(CC3)NC1=NN=CN1C=1N(N=C(C=1)C)C VWCOAXIJOYGNNW-UHFFFAOYSA-N 0.000 claims description 2
- KPDNIEFLTXXIBL-UHFFFAOYSA-N 3-cyclopropyl-9-(methanesulfonamido)-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)CCC3NS(=O)(=O)C KPDNIEFLTXXIBL-UHFFFAOYSA-N 0.000 claims description 2
- QLTYSKKCPHRRCE-UHFFFAOYSA-N 3-cyclopropyl-9-[(4-ethylimino-1,1-dioxo-1,2,5-thiadiazolidin-3-ylidene)amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)CCC3NC1=NS(N=C1NCC)(=O)=O QLTYSKKCPHRRCE-UHFFFAOYSA-N 0.000 claims description 2
- HKJQVVYUUUZDAT-UHFFFAOYSA-N 3-cyclopropyl-9-[[3,4-dioxo-2-(pyridin-3-ylamino)cyclobuten-1-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)CCC3NC1=C(C(C1=O)=O)NC=1C=NC=CC=1 HKJQVVYUUUZDAT-UHFFFAOYSA-N 0.000 claims description 2
- BNQXEAYUHOCCOB-UHFFFAOYSA-N 3-cyclopropyl-9-[[4-(5-fluoropyridin-3-yl)-1,2,4-triazol-3-yl]amino]-N-(2-methylpropyl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)C)CCC3NC1=NN=CN1C=1C=NC=C(C=1)F BNQXEAYUHOCCOB-UHFFFAOYSA-N 0.000 claims description 2
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- DNQYLJNMOJVXGI-UHFFFAOYSA-N 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-(7-methoxyimidazo[4,5-b]pyridin-3-yl)-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)(C)F)C(CC3)N1C=NC=2C1=NC=CC=2OC DNQYLJNMOJVXGI-UHFFFAOYSA-N 0.000 claims description 2
- ZIPXITHGRRWOBI-UHFFFAOYSA-N 3-cyclopropyl-N-(2-fluoro-2-methylpropyl)-7-[(1-methylpyrazolo[3,4-c]pyridin-4-yl)amino]-8,9-dihydro-7H-cyclopenta[h]isoquinoline-5-sulfonamide Chemical compound C1(CC1)C=1N=CC=2C3=C(C=C(C=2C=1)S(=O)(=O)NCC(C)(C)F)C(CC3)NC1=C2C(=CN=C1)N(N=C2)C ZIPXITHGRRWOBI-UHFFFAOYSA-N 0.000 claims description 2
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- WUOQXNWMYLFAHT-MRVPVSSYSA-N tert-butyl n-[(3r)-piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCNC1 WUOQXNWMYLFAHT-MRVPVSSYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- C07—ORGANIC CHEMISTRY
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- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
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- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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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
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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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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- C07D491/02—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 two hetero rings
- C07D491/04—Ortho-condensed systems
Abstract
本发明涉及式(I)的二氢环戊二烯并异喹啉衍生物,用于制备其的方法、含有其的药物组合物以及其在治疗由IgE引起的障碍(例如过敏反应、非过敏性肥大细胞反应或某些自身免疫反应),特别是由IgE与FcεRI受体相互作用引起的障碍中的用途。
Description
技术领域
本发明涉及式(I)的二氢环戊二烯并异喹啉衍生物、用于制备其的方法、含有其的药物组合物以及其在治疗由IgE引起的障碍(例如过敏反应、非过敏性肥大细胞反应或某些自身免疫反应),特别是由IgE与FcεRI受体的相互作用引起的障碍中的用途。
发明背景
IgE(免疫球蛋白E)是免疫球蛋白家族的成员,并且介导过敏反应,例如哮喘、食物过敏、1型超敏反应和常见的窦炎症。
IgE由B细胞分泌并在其表面表达。由B细胞合成的IgE通过跨膜结构域锚定在B细胞膜中,该跨膜结构域通过短的膜结合区与成熟的IgE序列连接。IgE还通过其Fc区与低亲和力IgE受体(FcεRII)结合而结合到B细胞(和单核细胞、嗜酸性粒细胞和血小板)。在哺乳动物暴露于过敏原后,B细胞被克隆扩增,其合成与过敏原结合的IgE。该IgE转而由B细胞释放到循环中,在此处其被B细胞(通过FcεRII)结合,并通过肥大细胞和嗜碱性粒细胞表面上存在的所谓高亲和力受体(FcεRI)被肥大细胞和嗜碱性粒细胞结合。这样的肥大细胞和嗜碱性粒细胞因此对过敏原敏感。下一次暴露于过敏原会使这些细胞上的FcεRI交叉关联(cross-link),从而激活它们释放组胺和其他导致临床超敏反应和过敏反应的因子。
目前,变应性疾病、荨麻疹和哮喘通常用以下药物中的一种或多种治疗:(1)抗组胺药和抗白三烯药,其拮抗炎症介质组胺和白三烯,(2)局部或全身(口服或注射)糖皮质激素或免疫抑制剂,其抑制广泛的炎症机制,(3)短效或长效支气管扩张药,其在哮喘中使收缩的气道的平滑肌松弛,或(4)肥大细胞稳定剂,其抑制通常由IgE在FcεRI处的结合触发的肥大细胞脱粒,(5)阻止IgE在FcεRI处结合的生物制品。也曾尝试使用调节IgE与FcεRI结合的肽。例如,WO96/01643描述了由4-50个氨基酸组成的肽来治疗速发型过敏反应。
然而,仍然需要确定在治疗或预防由IgE引起的障碍,特别是由IgE与FcεRI受体的相互作用引起的障碍中具有治疗效用的化合物。
发明内容
已发现式(I)的化合物及其药学上可接受的盐可用于此目的。
具体实施方案
本发明提供式(I)的化合物及其药学上可接受的盐:
其中:
X为C或N,
Y为C或O,
当Y为O时,R1为氢或羟基,R1’为氢且R2、R2’不存在;
R1表示
氢,
羟基;
氧代基;
氨基;
C1-6-烷基;
C1-6-烷基氨基;
C(O)OH;
C(O)NH-杂芳基;
-NH-C1-6-烷基-C3-6-环烷基;
-NH-C1-6-烷基-C(O)OH,任选地被氨基取代;
-NH-环烷基,任选地被一个或多个选自以下的基团取代:卤素;氧代基;C1-6-烷基;C1-6-烷基氨基;C1-6-烷基-C1-4-烷基氨基;C3-8-环烷基-C1-6-烷基氨基;杂芳基;任选地被一个或多个C1-6-烷基取代的杂芳基氨基;
杂芳基,任选地被一个或多个选自以下的基团取代:卤素;羟基;氧代基;氨基;氰基;-C(O)-C1-6-烷基;C1-6-烷基;C1-6-烷基氨基;C1-6-烷氧基;-NH-(C1-6-烷基)-杂环烷基;任选地被一个或多个C1-6-烷基取代的-NH-(C1-6-烷基)-杂芳基;-NH-C1-6-烷基-环烷基;-NH-C(O)-环烷基;被一个或多个C1-6-烷基取代的-NH-杂芳基;-NH-C1-6-烷基-C(O)OH;
被杂芳基氨基取代的杂芳基,所述杂芳基氨基任选地被以下基团取代:C1-6-烷基;C1-6-烷氧基;C3-6-环烷基;C1-6-卤代烷氧基;C1-6-卤代烷基;CN;卤素;C(O)OH;-C(O)O-C1-6-烷基;
-NH-C(S)-NH-Ra1;
-NH-SO2-Rb1;
-NH-杂芳基,任选地被一个或多个选自以下的基团取代:氧代基;C1-6-烷基;C1-6-烷基氨基;杂芳基,任选地被一个或多个氧代基、C1-6-烷基、-C(O)-NHNH-C(O)CH3、芳基、杂芳基氨基、C1-6-烷氧基、C3-6-环烷基、C1-6-卤代烷氧基、C1-6-卤代烷基、CN、卤素、C(O)OH、-C(O)O-C1-6-烷基取代;
-NH-杂环烷基,任选地被一个或多个选自以下的基团取代:卤素;C1-6-烷基;氧代基;杂芳基;C(O)ORb1;C1-6-烷基-NRb1Rb1;NHC(O)-芳基;NHC(O)-杂芳基;
被一个杂芳基取代的-NH-C1-6-烷基,所述杂芳基任选地被一个或多个选自以下的基团取代:C1-6-烷基;氨基;
-NH-C(O)O-Rb1;
-NH-C(NCN)-NH-Ra1;
-NH-C(NCN)-NH-杂芳基;
-NH-C(O)-C3-8-杂环烷基-C(O)O-Rb1;
-C(O)NH-C1-6-烷基;
-NH-C(O)NH-C1-6-烷基,任选地被一个或多个C3-8-杂环烷基取代;
-NH-C(O)NH-杂环烷基-C1-6-烷基;
-NH-C1-6-烷基-C(O)-C1-6-烷基氨基;
杂芳氧基;
-NH-C(O)-芳基;
-NH-C(O)-杂芳基;
-NH-C(O)-杂环烷基;
-NH-C(O)-C1-6-烷基,任选地被一个或多个氨基取代;
-NH-C(O)-C1-6-烷基-C(O)ORb1,任选地被选自以下的基团取代:氨基;-NH-C(O)ORb1;
杂环烷基,任选地被一个或多个选自以下的基团取代:氨基;-C(O)NH-Rb1;-C(O)ORb1;任选地被一个或多个C1-6-烷基取代的-NHC(O)-杂芳基;任选地被氨基取代的-NHC(O)-C1-6-烷基;-NHC(O)O-C1-6-烷基;-NH-C(O)Rb1;
-C2-6-烯基,任选地被一个或多个选自以下的基团取代:卤素;=NH基;
Ra1表示
C1-6-烷基;或
芳基,任选地被一个或多个C1-6-烷基取代;或
杂芳基,任选地被一个或多个C1-6-烷基取代;
Rb1表示
氢;或
C1-6-烷基;或
芳基,任选地被一个或多个卤素、C1-6-烷基、羟基取代;
R1’表示
氢;
羟基;
R2表示
氢;
卤素;
羟基;
氧代基;
C1-6-烷基;
C3-8-杂环烷基,任选地被一个或多个以下基团取代:羟基;卤素;氨基;氨基-C-1-6-烷基;C1-6-烷基;C(O)O-C1-6-烷基;C(O)NH2;
杂芳基,任选地被一个或多个选自以下的基团取代:C1-6-烷基氨基;任选地被一个或多个C1-6-烷基取代的杂芳基;卤素;
杂芳基,任选地被-NH-杂芳基取代,所述-NH-杂芳基任选地被一个或多个以下基团取代:C1-6-烷基;卤素;氰基;-C(O)OH;-C(O)O-C1-6-烷基;C1-6-卤代烷基;C1-6-烷氧基;C1-6-卤代烷氧基;C3-6-环烷基;
-NH-环烷基,任选地被一个或多个选自以下的基团取代:卤素;氧代基;C1-6-烷基;C1-6-烷基氨基;C1-6-烷基-C1-4-烷基氨基;C3-8-环烷基-C1-6-烷基氨基;芳基;杂芳基;任选地被一个或多个C1-6-烷基取代的杂芳基氨基;
-NH-杂芳基,任选地被一个或多个选自以下的基团取代:羟基;卤素;氧代基;C1-6-烷基;C1-6-烷氧基;杂芳基,任选地被一个或多个以下基团取代:羟基,卤素,氧代基,C1-6-烷基,C(O)O-C1-6-烷基,C(O)OH,C1-6-卤代烷基,C1-6-烷氧基,C1-6-卤代烷氧基,C3-6-环烷基,C1-6-烷基氨基,氰基,被一个或多个羟基、卤素、氧代基取代的杂环烷基;
被一个杂芳基取代的-NH-C1-6-烷基,所述杂芳基任选地被一个或多个选自C1-6-烷基的基团取代;
-NH-SO2-杂芳基,任选地被一个或多个选自卤素的基团取代;
-NHC(O)-C1-6-烷基,任选地被一个或多个以下基团取代:卤素;C1-6-烷氧基;氨基;C3-8-环烷基;C3-8-杂环烷基;杂芳基;
-NHC(O)-杂芳基,任选地被一个或多个选自以下的基团取代:卤素;羟基;氧代基;C1-6-烷基;杂芳基;C1-6-烷基氨基;S(O)2-C1-3-烷基;-NHC(O)-C1-6-烷基;
-NHC(O)-C3-8-杂环烷基,任选地被一个或多个氧代基、C1-6-烷基取代;
-NHC(O)O-C1-6-烷基;
-NHC(O)O-C1-6-烷基-Ra2;
-NHC(O)O-芳基;
-NHC(O)NH-Ra2;
-NHC(O)NH-C1-6-烷基-Ra2;
-NH-C(NCN)-NH-Ra1;
-NHC(O)-C3-8-环烷基;
-NH-SO2-Rb2;
-NH-C(S)-NH-Rb2;
-NH-C3-8-杂环烷基,任选地被一个或多个选自以下的基团取代:氧代基;C1-6-烷基;
芳氧基;
杂芳氧基;
Ra2表示
氢;
芳基,任选地被一个或多个选自以下的基团取代:卤素;羟基;氧代基;C1-6-烷基;
杂芳基,任选地被一个或多个选自以下的基团取代:卤素;羟基;氧代基;C1-6-烷基;
Rb2表示
C1-6-烷基;
杂芳基;
R2’表示
氢;
羟基;
R3表示选自以下的基团:
C1-6-烷基,任选地被一个或多个选自R3a的基团取代;
C1-3-亚烷基(alkanediyl)-C3-6-环烷基,任选地被一个或多个R3a取代;
C1-3-亚烷基-C3-6-杂环烷基,任选地被一个或多个R3a取代;
C3-6-杂环烷基,任选地被一个或多个R3a取代;
C3-6-环烷基,任选地被一个或多个R3a取代;
R3a表示选自以下的基团:氢;卤素;C1-2-烷基;羟基;C1-2-烷氧基;
R4表示选自以下的基团:
C3-6-环烷基,任选地被一个或多个R4a基团取代;或C1-6-亚烷基-C3-6-环烷基,任选地被一个或多个R4a基团取代;或C1-6-亚烷基-C3-6-杂环烷基,任选地被一个或多个R4a基团取代;
R4a表示选自以下的基团:羟基;卤素;C1-2-烷基。
R5表示
氢、甲基或卤素;
条件是:
-当R1’是羟基时,则R1选自吡啶基、C1-6-烷基;
-当R2’是羟基时,则R2选自吡啶基、C1-6-烷基;
-当R1不是氢时,则R2和R2’是氢;
-当R2不是氢时,则R1和R1’是氢;
-当R1是氧代基时,R1’不存在;
-当R2是氧代基时,R2’不存在;
式(I)的化合物可以含有一个或多个不对称碳原子。因此它们可以作为对映异构体或非对映异构体存在。这些对映异构体、非对映异构体及其混合物,包括外消旋混合物,构成本发明的一部分。
式(I)的化合物可以以碱的形式或以与酸的加成盐的形式存在。这样的加成盐是本发明的一部分。用药学上可接受的酸有利地制备这些盐。例如可用于纯化或分离式(I)的化合物的其他酸的盐也是本发明的一部分。
在本发明的范围内:
-Ct-z表示可具有t至z个碳原子的碳链,例如C1-7表示可具有1至7个碳原子的碳链;
-烷基是饱和的直链或支链的脂族基团;例如,C1-6-烷基表示1至6个碳原子的直链或支链的碳链,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基。烷基包括氘代基团,其中一个或多个氢原子被氘原子2H替代。
-烷基氨基是指在氨基上取代的一个或多个烷基。作为烷基氨基的实例,可以提及甲基氨基;乙基氨基;叔丁基氨基;二甲基氨基;
-酰基,烷基-C(O)-基团;
-羟基是-OH基团;
-烷氧基,-O-烷基;
-卤原子,氟、氯、溴或碘原子;
-卤代烷基是一个或多个氢原子被卤原子取代的烷基;
-卤代烷氧基是一个或多个氢原子被卤原子取代的烷氧基;
-氧代是显示双键的氧,例如=O;
-环烷基是指在基团中包含3至14个原子,优选3至9个原子的单环或双环饱和脂族基团。作为环烷基的实例,可以提及:环丙基;环丁基;环戊基;环己基;螺[2.2]戊基;螺十一烷基;
-杂环烷基是指在基团中包含3至14个原子,优选3至9个原子的单环或双环饱和基团,其可以包含双键而不具有芳香性,并且其中一个或多个碳原子被选自氮、氧、硫的原子替代。作为杂环烷基的实例,可以提及:氧杂环丙烷基;吡咯烷基;哌啶基;氧杂环丁烷基;氧杂螺-十一烷基;
-芳基是指包含6至14个碳原子的单环或双环芳基,其中该基团中至少一个环是芳基。作为芳基的实例,可以提及苯基或萘基;
-杂芳基是指包含5至14个原子的单环或双环基团,优选3至9个原子,其中该基团中至少一个环是芳族的,并且其中该基团中至少一个原子选自氮、氧、硫。作为杂芳基的实例,可以提及三唑基、呋喃基;吡咯基;色满基;异喹啉基;
-杂芳基氨基是指被杂芳基取代的氨基-NH2。杂芳基的实例可以是吡啶基氨基;
-芳氧基是指被氧基取代的芳基。作为芳氧基的一个实例,可以提及苯氧基。
-杂芳氧基是被氧基取代的杂芳基。作为杂芳氧基的一个实例,可以提及吡啶基氧基。
根据本发明的术语“药学上可接受的盐”包括式(I)的化合物与药学上可接受的酸或碱的盐,特别是酸加成盐。以其游离形式作为碱存在的式(I)的化合物的酸加成盐形式可以通过用诸如无机酸或有机酸的合适的酸处理游离碱来获得,所述无机酸为例如氢卤酸(如盐酸或氢溴酸)、硫酸、硝酸、磷酸等;所述有机酸为例如乙酸、三氟乙酸、草酸、羟基乙酸、丙酸、乳酸、丙酮酸、丙二酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环拉酸、水杨酸、对氨基水杨酸、扑酸等。
本发明还涉及式(I)的化合物或其混合物的诸如对映异构和非对映异构形式的所有立体异构形式(包括立体异构体的所有可能混合物,如外消旋物)。就本发明而言,提及一种或多种化合物旨在涵盖该化合物的每一种可能的异构体形式及其混合物,除非具体提及特定的异构体形式。
一些式(I)的化合物也可以以互变异构形式存在。这些形式虽然没有在上式中明确指出,但意在包括在本发明的范围内。
应当理解,存在于式(I)或本文描述的式中的每个单独的原子实际上可以以其任何天然存在的同位素的形式存在,其中最丰富的同位素是优选的。因此,举例来说,存在于式(I)或本文描述的式中的每个单独的氢原子可以作为1H、2H(氘)或3H(氚)原子存在,优选1H。类似地,举例来说,存在于式(I)或本文描述的式中的每个单独的碳原子可以作为12C、13C或14C原子存在,优选12C。
本发明在其范围内包括上述式(I)的化合物的溶剂化物。这样的溶剂化物可以与普通有机溶剂或水形成。
本发明在其范围内还包括上述式(I)的化合物的共晶。技术术语“共晶”用于描述中性分子组分以确定的化学计量比存在于结晶化合物内的情况。药物共晶的制备能够实现对药物活性成分的结晶形式进行修饰,进而可以改变其物理化学性质而不损害其预期的生物活性(参见Pharmaceutical Salts and Co-crystals,J.Wouters和L.Quere编,RSC出版,2012)。
根据本发明的化合物可以以不同的多晶型形式存在。尽管在上式中没有明确指出,但这些形式旨在包括在本发明的范围内。
本发明在其范围内还包括上述式(I)的化合物的前药。术语“前药”是指在体内代谢成本发明的化合物或其盐的化合物。前药可以通过将前药给予哺乳动物,例如大鼠、小鼠、猴或人,并确定例如血液或尿液中的化合物或其盐来确定。
本发明的另一个实施方案涉及药物组合物,其包含可检测量的式(I)的化合物或其药学上可接受的盐、溶剂化物或共晶以及药学上可接受的稀释剂或载体。
在另一个实施方案中,本发明涉及式(I)的化合物、其药学上可接受的盐、溶剂化物或共晶,其用作药物,特别是用于治疗或预防由IgE引起的障碍的方法中,所述障碍包括过敏、1型超敏反应、常见的窦炎症、荨麻疹或相关病症,例如哮喘中的气道收缩、湿疹中的局部炎症、过敏性鼻炎中的粘液分泌增加、血管通透性增加、嗜酸性肉芽肿伴多血管炎(也称为“Churg Strauss综合征”)、阿司匹林加重的呼吸系统疾病或皮肤T细胞淋巴瘤。
在另一个实施方案中,本发明涉及治疗或预防过敏、1型超敏反应、常见的窦炎症、荨麻疹或相关病症的方法,其包括以治疗有效量给予式(I)的化合物。
根据一个实施方案,本发明的化合物的特征在于下式(I),其中R4表示环丙基或螺[2.2]戊基;任选地被一个或多个独立地选自以下的基团取代:羟基;
氯、氟、溴;
甲基。
根据一个实施方案,本发明的化合物的特征在于式(I),其中R4表示环丙基。
根据一个实施方案,本发明的化合物的特征在于式(I),其中R1表示-杂芳基-NH-Ra1且R2表示任选地被一个或多个选自杂芳基、C1-6-烷基、-C(O)OH的基团取代的NH-杂芳基,其中Ra1为任选地被一个或多个C1-6-烷基取代的C1-6-烷基或杂芳基。
根据一个实施方案,本发明的化合物的特征在于式(I),其中:
R1表示:
氢;甲氧基咪唑并吡啶基;羧基;环丙基-甲基-氨基甲酰-氨基;吡啶-羰基氨基;羟基(吡啶基);[(氟碳亚胺酰基(carbonimidoyl))丙烯基];[(环丙基甲基氨基)咪唑基];[[(环丙基甲基)咪唑基]氨基];[(二甲基吡唑基)氨基硫代甲酰基(carbamothioyl)氨基];[[(二甲基吡唑基)-三唑基]氨基];(吡啶基氨基);(叔丁氧羰基氨基);氨基;[(环丙基甲基氨基)-三唑基];吡啶基氨基甲酰基;[(环丙烷羰基氨基)吡唑基];(氨基四唑基);[[(甲基四唑基)吡啶基]氨基];[(甲基吡唑并吡啶基)氨基];[[(甲基-噁二唑基)-吡啶基]氨基];氧代;羟基(甲基);乙基氨基硫代甲酰基氨基);[(乙基氨基)-三唑基];[[(乙基氨基)-二氧代-环丁烯基]氨基];[[(乙基氨基)-二氧代-噻二唑基]氨基];[[N'-氰基-N-(对甲苯基)氨基甲酰亚胺基(carbamimidoyl)]氨基];[(叔丁氧羰基氮杂环丁烷-羰基)氨基];[氨基哌啶基];[(甲基氨基甲酰基)吡咯烷基];[[(二甲基吡唑-羰基(arbonyl))氨基]氮杂环丁烷基];[(二甲基-氧代-环丁烯基)氨基];(吲哚基甲基氨基);甲磺酰氨基;[[二氧代(吡啶基氨基)环丁烯基]氨基];乙基氨基甲酰氨基;[[(二甲基吡唑基)氨基]-三唑基];[[(甲基-吡啶基)氨基]-三唑基];[[(吡啶基)-三唑基]氨基];[(吡啶基氨基)-三唑基];(苯并咪唑基氨基);吡啶基氧基;(吡啶基氨基硫代甲酰基氨基);
根据一个实施方案,本发明的化合物的特征在于式(I),其中:
R2表示:
氢;[(甲基苯并三唑基)-三唑基]甲基;[[(甲基吡唑基)-三唑基]氨基];[[(甲基吡唑基)氨基]-三唑基];[[(氟-吡啶基)-三唑基]氨基];[[(氟-吡啶基)氨基]-三唑基];(吡啶基甲基氨基);(吡啶基磺酰基氨基);[(氟-吲哚羰基)氨基];[(甲基苯并咪唑基)氨基];[(甲氧基羰基-吡啶基)氨基];[(羧基吡啶基)氨基];[(甲基-吡唑-羰基)氨基];(吡啶-羰基氨基);[(甲基环丙烷羰基)氨基];(嘧啶基氨基);[(氧代吲哚啉基)氨基];[(甲氧基吡啶基)氨基];(吡啶基氨基);[(甲基吡唑并吡啶基)氨基];苄氧基羰基氨基;[(溴苯基)氨基甲酰氨基];[(二甲基吡唑基)甲基氨基甲酰氨基];羟基;氧代;甲基;氟;[[(乙基氨基)-二氧代-噻二唑基]氨基];[(氰基甲基-吡唑基)氨基];(异喹啉基氨基);[[N'-氰基-N-(对甲苯基)氨基甲酰亚胺基]氨基];甲磺酰氨基;乙基氨基硫代甲酰基氨基;[(乙基氨基)-三唑基];[(乙基-三唑基)氨基];(吡啶基氨基硫代甲酰基氨基);[[(吡啶基)-三唑基]氨基];[[(甲基四唑基)-吡啶基]氨基];[[二氧代-(吡啶基氨基)环丁烯基]氨基];[[(乙基氨基)-二氧代-环丁烯基]氨基];(苯并咪唑基氨基);吡啶基氧基。
根据一个实施方案,本发明的化合物的特征在于式(I),其中:
R1表示:
氢;(7-甲氧基咪唑并[4,5-b]吡啶-3-基);羧基;环丙基-甲基-氨基甲酰-氨基;吡啶-3-羰基氨基;羟基(3-吡啶基);[1-(氟碳亚胺酰基)丙-1-烯基];[2-(环丙基甲基氨基)咪唑-1-基];[[1-(环丙基甲基)咪唑-2-基]氨基];[(2,5-二甲基吡唑-3-基)氨基硫代甲酰基氨基];[[4-(2,5-二甲基吡唑-3-基)-1,2,4-三唑-3-基]氨基];(3-吡啶基氨基);(叔丁氧羰基氨基);氨基;[3-(环丙基甲基氨基)-1,2,4-三唑-4-基];3-吡啶基氨基甲酰基;[5-(环丙烷羰基氨基)吡唑-1-基];(5-氨基四唑-1-基);[[6-(2-甲基四唑-5-基)-3-吡啶基]氨基];[(1-甲基吡唑并[3,4-c]吡啶-4-基)氨基];[[6-(5-甲基-1,3,4-噁二唑-2-基)-3-吡啶基]氨基];氧代;羟基(甲基);(乙基氨基硫代甲酰基氨基);[3-(乙基氨基)-1,2,4-三唑-4-基];[[2-(乙基氨基)-3,4-二氧代-环丁烯-1-基]氨基];[[4-(乙基氨基)-1,1-二氧代-1,2,5-噻二唑-3-基]氨基];[[N'-氰基-N-(对甲苯基)氨基甲酰亚胺基]氨基];[(1-叔丁氧羰基氮杂环丁烷-3-羰基)氨基];[3-氨基-1-哌啶基];[(2R)-2-(甲基氨基甲酰基)吡咯烷-1-基];[3-[(2,5-二甲基吡唑-3-羰基)氨基]氮杂环丁烷-1-基];[(4,4-二甲基-3-氧代-环丁烯-1-基)氨基];(1H-吲哚-2-基甲基氨基);甲磺酰氨基;[[3,4-二氧代-2-(3-吡啶基氨基)环丁烯-1-基]氨基];乙基氨基甲酰氨基;[3-[(2,5-二甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基];[3-[(5-甲基-3-吡啶基)氨基]-1,2,4-三唑-4-基];[[4-(3-吡啶基)-1,2,4-三唑-3-基]氨基];[3-(3-吡啶基氨基)-1,2,4-三唑-4-基];(1H-苯并咪唑-2-基氨基);3-吡啶基氧基;(3-吡啶基氨基硫代甲酰基氨基)。
根据一个实施方案,本发明的化合物的特征在于式(I),其中:
R2表示:
氢;[4-(1-甲基苯并三唑-4-基)-1,2,4-三唑-3-基]甲基;[[4-(2-甲基吡唑-3-基)-1,2,4-三唑-3-基]氨基];[3-[(2-甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基];[[4-(5-氟-3-吡啶基)-1,2,4-三唑-3-基]氨基];[3-[(5-氟-3-吡啶基)氨基]-1,2,4-三唑-4-基];(3-吡啶基甲基氨基);(3-吡啶基磺酰基氨基);[(6-氟-1H-吲哚-3-羰基)氨基];[(1-甲基苯并咪唑-2-基)氨基];[(6-甲氧基羰基-3-吡啶基)氨基];[(6-羧基-3-吡啶基)氨基];[(5-甲基-1H-吡唑-3-羰基)氨基];(吡啶-3-羰基氨基);[(2-甲基环丙烷羰基)氨基];(嘧啶-5-基氨基);(2-氧代吲哚啉-5-基)氨基];[(5-甲氧基-3-吡啶基)氨基];(3-吡啶基氨基);[(1-甲基吡唑并[3,4-c]吡啶-4-基)氨基];苄氧基羰基氨基;[(4-溴苯基)氨基甲酰氨基];[(2,5-二甲基吡唑-3-基)甲基氨基甲酰氨基];羟基;氧代;甲基;氟;[[4-(乙基氨基)-1,1-二氧代-1,2,5-噻二唑-3-基]氨基];[(4-氰基-1-甲基-吡唑-3-基)氨基];(4-异喹啉基氨基);[[N'-氰基-N-(对甲苯基)氨基甲酰亚胺基]氨基];甲磺酰氨基;乙基氨基硫代甲酰基氨基;[3-(乙基氨基)-1,2,4-三唑-4-基];[(4-乙基-1,2,4-三唑-3-基)氨基];(3-吡啶基氨基硫代甲酰基氨基);[[4-(3-吡啶基)-1,2,4-三唑-3-基]氨基];[[6-(2-甲基四唑-5-基)-3-吡啶基]氨基];[[3,4-二氧代-2-(3-吡啶基氨基)环丁烯-1-基]氨基];[[2-(乙基氨基)-3,4-二氧代-环丁烯-1-基]氨基];(1H-苯并咪唑-2-基氨基);3-吡啶基氧基。
根据一个实施方案,本发明的化合物选自:
3-环丙基-N-(2-氟-2-甲基丙基)-7-(7-甲氧基咪唑并[4,5-b]吡啶-3-基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-异丁基-9-[[4-(1-甲基苯并三唑-4-基)-1,2,4-三唑-3-基]氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-异丁基-9-[[4-(2-甲基吡唑-3-基)-1,2,4-三唑-3-基]氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-异丁基-9-[3-[(2-甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-9-[[4-(5-氟-3-吡啶基)-1,2,4-三唑-3-基]氨基]-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-9-[3-[(5-氟-3-吡啶基)氨基]-1,2,4-三唑-4-基]-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-甲酸;
1-(环丙基甲基)-3-[(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]脲[*或S];
N-[(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]吡啶-3-甲酰胺[*或S];
3-环丙基-N-(2-氟-2-甲基丙基)-7-羟基-7-吡啶-3-基-8,9-二氢环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-7-(2-氟吡啶-3-基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
(7R*)-3-环丙基-7-[2-(环丙基甲基氨基)咪唑-1-基]-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
(7R*)-3-环丙基-7-[[1-(环丙基甲基)咪唑-2-基]氨基]-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
3-环丙基-N-(2-甲基丙基)-9-(吡啶-3-基甲基氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-甲基丙基)-9-(吡啶-3-基磺酰基氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
6-氟-N-[(9R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]-1H-吲哚-3-甲酰胺[*或S];
3-环丙基-N-(2-氟-2-甲基丙基)-9-[(1-甲基苯并咪唑-2-基)氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
5-[[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]氨基]吡啶-2-甲酸甲酯;
5-[[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]氨基]吡啶-2-甲酸;
5-甲基-N-[(9R*)-3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]-1H-吡唑-3-甲酰胺[*或S];
N-[(9R*)-3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]吡啶-3-甲酰胺[*或S];
3-环丙基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰胺;
1-[3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]噌啉-7-基]-3-(2,5-二甲基吡唑-3-基)硫脲;
3-环丙基-7-[[4-(2,5-二甲基吡唑-3-基)-1,2,4-三唑-3-基]氨基]-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰胺;
(7R*)-3-环丙基-7-[3-[(2,5-二甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基]-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰胺[*或S];
N-[3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]-2-甲基环丙烷-1-甲酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-(嘧啶-5-基氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-[(2-氧代-1,3-二氢吲哚-5-基)氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-[(5-甲氧基吡啶-3-基)氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-7-(吡啶-3-基氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-(吡啶-3-基氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
N-[3-环丙基-5-[(1,1-二氘-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]氨基甲酸叔丁酯;
7-氨基-3-环丙基-N-(1,1-二氘-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-7-[3-(环丙基甲基氨基)-1,2,4-三唑-4-基]-N-(1,1-二氘-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
7-环丙基-N-(2-氟-2-甲基丙基)-3-羟基-2,3-二氢呋喃并[3,2-h]异喹啉-5-磺酰胺;
(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-N-吡啶-3-基-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-甲酰胺[*或S];
N-[2-[3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]吡唑-3-基]环丙烷甲酰胺;
7-(5-氨基四唑-1-基)-3-环丙基-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-7-[[6-(2-甲基四唑-5-基)吡啶-3-基]氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-7-[(1-甲基吡唑并[3,4-c]吡啶-4-基)氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-7-[[6-(5-甲基-1,3,4-噁二唑-2-基)吡啶-3-基]氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-[(1-甲基吡唑并[3,4-c]吡啶-4-基)氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
N-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]氨基甲酸苄酯;
1-(4-溴苯基)-3-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]脲;
1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]-3-[(2,5-二甲基吡唑-3-基)甲基]脲;
3-环丙基-7-羟基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-甲基丙基)-7-氧代-8,9-二氢环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-7-羟基-7-甲基-N-(2-甲基丙基)-8,9-二氢环戊二烯并[h]异喹啉-5-磺酰胺;
7-氨基-3-环丙基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]-3-乙基硫脲;
(7R*)-3-环丙基-7-[3-(乙基氨基)-1,2,4-三唑-4-基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(*或S);
(7R*)-3-环丙基-7-[[2-(乙基氨基)-3,4-二氧代环丁烯-1-基]氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(*或S);
3-环丙基-7-[[4-(乙基氨基)-1,1-二氧代-1,2,5-噻二唑-3-基]氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
2-氰基-1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]-3-(4-甲基苯基)胍;
3-[[(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]氨基甲酰基]氮杂环丁烷-1-甲酸叔丁酯[*或S];
7-[(3R)-3-氨基哌啶-1-基]-3-环丙基-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
(2R)-1-[(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]-N-甲基吡咯烷-2-甲酰胺[*或S];
N-[1-[3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]氮杂环丁烷-3-基]-2,5-二甲基吡唑-3-甲酰胺;
3-环丙基-7-[(4,4-二甲基-3-氧代环丁烯-1-基)氨基]-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-7-(1H-吲哚-2-基甲基氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-9-羟基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-甲基丙基)-9-氧代-7,8-二氢环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-9-羟基-9-甲基-N-(2-甲基丙基)-7,8-二氢环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-9-氟-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-9-[[4-(乙基氨基)-1,1-二氧代-1,2,5-噻二唑-3-基]氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
9-[(4-氰基-1-甲基吡唑-3-基)氨基]-3-环丙基-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-(异喹啉-4-基氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
2-氰基-1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]-3-(4-甲基苯基)胍;
3-环丙基-9-(甲磺酰氨基)-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]-3-乙基硫脲;
3-环丙基-9-[3-(乙基氨基)-1,2,4-三唑-4-基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
(9R*)-3-环丙基-9-[(4-乙基-1,2,4-三唑-3-基)氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]-3-吡啶-3-基硫脲;
3-环丙基-N-(2-甲基丙基)-9-[(4-吡啶-3-基-1,2,4-三唑-3-基)氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-[[6-(5-甲基-1,3,4-噁二唑-2-基)吡啶-3-基]氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-[[6-(2-甲基四唑-5-基)吡啶-3-基]氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-9-[[3,4-二氧代-2-(吡啶-3-基氨基)环丁烯-1-基]氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
(9R*)-3-环丙基-9-[[2-(乙基氨基)-3,4-二氧代环丁烯-1-基]氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
(9R*)-9-(1H-苯并咪唑-2-基氨基)-3-环丙基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
3-环丙基-7-[3-(环丙基甲基氨基)-1,2,4-三唑-4-基]-N-(3,3-二氟环丁基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-7-[3-(环丙基甲基氨基)-1,2,4-三唑-4-基]-N-(3-氟环丁基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-7-(甲磺酰氨基)-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-7-[[3,4-二氧代-2-(吡啶-3-基氨基)环丁烯-1-基]氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
1-乙基-3-[(7R*)-3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]脲[*或S];
(7R*)-3-环丙基-7-[3-[(2,5-二甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基]-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
(7R*)-3-环丙基-7-[3-[(2,5-二甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
3-环丙基-7-[[4-(2,5-二甲基吡唑-3-基)-1,2,4-三唑-3-基]氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
(7R*)-3-环丙基-N-(2-甲基丙基)-7-[3-[(5-甲基吡啶-3-基)氨基]-1,2,4-三唑-4-基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
3-环丙基-N-(2-甲基丙基)-7-[(4-吡啶-3-基-1,2,4-三唑-3-基)氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-甲基丙基)-7-[3-(吡啶-3-基氨基)-1,2,4-三唑-4-基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
7-(1H-苯并咪唑-2-基氨基)-3-环丙基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-吡啶-3-基氧基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-7-吡啶-3-基氧基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
1-[3-环丙基-5-(异丁基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]-3-(3-吡啶基)硫脲。
以下实施例示出了如何合成式(I)所涵盖的化合物。提供它们仅出于说明目的,并不旨在也不应被解释为以任何方式限制本发明。本领域技术人员将理解,在不超出本发明的精神或范围的情况下,可以对以下实施例进行常规变化和修改。
实施例
缩写
DCM 二氯甲烷
MTBE 叔丁基甲基醚
Et2O 乙醚
THF 四氢呋喃
EtOAc 乙酸乙酯
MeCN 乙腈
MeOH 甲醇
broad s 宽单峰
M 质量或摩尔数
盐水 饱和氯化钠溶液
HPLC 高效液相色谱
LCMS 液相色谱-质谱
DIPEA N,N-二异丙基乙基胺
RT 保留时间
DMF N,N’-二甲基甲酰胺
NaOH 氢氧化钠
DMAP 4-二甲基氨基吡啶
TFA 三氟乙酸
DMSO 二甲基亚砜
TBTU 2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基铵四氟硼酸盐
EtOH 乙醇
sat. 饱和的
aq. 水性
BOC 叔丁氧羰基
tBuXPhos Pd G3 [(2-二叔丁基膦-2′,4′,6′-三异丙基-1,1′-联苯基)-2-(2′-氨基-1,1′-联苯)]钯(II)甲磺酸盐
HATU 1-[双(二甲氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐
Hrs 小时
IPA 异丙醇
conc. 浓
TBDMSCl 叔丁基二甲基氯硅烷
equiv. 当量
TBAB 四正丁基溴化铵
NBS N-溴代琥珀酰亚胺
NIS N-碘琥珀酰亚胺
SFC 超临界流体色谱法
LCMS方法
方法1:
方法2:
方法3:
方法4:
方法5:
方法6:
方法7:
方法8:
方法9:
方法10:
方法11:
方法12:
方法13:
方法14:
方法15:
方法16:
方法17:
通用程序
通用程序1:
将氯化汞(2当量)和甲酰肼(3当量)的无水N,N-二甲基甲酰胺(1mL)溶液加入到硫脲中间体中。加入三乙胺(3当量)并将反应加热至80℃,同时搅拌8h。通过硅藻土过滤反应,用MeCN(2-3mL)洗涤。在真空中除去溶剂,产物经柱色谱法纯化。
通用程序2:
向芳基氯(1当量)的1,4-二氧六环(20mL/g)溶液中加入环丙烷硼酸(3当量)、三环己基鏻四氟硼酸盐(2当量)和Pd(OAc)2(0.1当量)。混合物用N2气流脱气5min,然后加入K3PO4(1当量)。混合物用N2气流再脱气5min,密封并加热至110℃直到LCMS认为反应完成。将反应冷却并用EtOAc(20mL/g)稀释,并用饱和NaHCO3(20mL/g)水溶液洗涤。有机萃取物用Na2SO4干燥并真空浓缩。
通用程序3:
向胺(1当量)、叔丁醇钠(3当量)、芳基卤(2.5当量)和tBuXPhos Pd G3(0.15当量)的溶液中加入无水1,4-二氧六环(20mL/g)。用三个循环的真空/N2将混合物脱气,然后密封并在搅拌下加热至100℃,直到LCMS认为反应完成。用EtOAc(20mL/g)稀释反应,并用水(10mL/g)洗涤。水层用EtOAc(20mL/g)再次萃取,并将合并的有机萃取物用Na2SO4干燥并真空浓缩。
通用程序4:
向搅拌的相关的中间体(1当量)在二氯甲烷(40mL)中的悬浮液加入N,N-二异丙基乙胺(1.5当量)和相关的异硫氰酸酯(1.5当量),除非另有说明。将混合物在室温下搅拌1至3天。真空蒸发反应混合物并将残余物干法负载到硅胶上并通过柱色谱法纯化。
通用程序5:
向搅拌的相关的硫脲的N,N-二甲基甲酰胺(15mL)溶液中加入甲酰肼(~3当量),接着加入氯化汞(~2当量)。将混合物在室温下搅拌5分钟,然后加入三乙胺(~3当量)。所得的反应混合物在80℃下搅拌16小时。用乙腈稀释冷却的反应混合物,通过一层硅藻土过滤然后将其用乙腈(30mL x 3)洗涤。蒸发滤液,残余物通过柱色谱法纯化得到期望产物。
中间体
中间体1
3,6,7,8-四氢-2H-不对称引达省-1-酮
将3-茚满-5-基丙酸(100g,526mol,可从Angene商购,CAS号:23291-98-7)的多聚磷酸(320mL)溶液加热至140℃持续6分钟,然后冷却至10℃,并通过加入冰水(500mL)淬灭。所得混合物用DCM(25L,然后15L)萃取。合并的有机萃取物用Na2SO4干燥,过滤并真空浓缩。残余物通过SiO2柱色谱纯化得到标题化合物,为棕色固体(4.5g,5%产率)。δH(400MHz,CDCl3)7.42(m,1H),7.23(m,1H),3.21(m,2H),3.10(m,2H),2.94(m,2H),2.66(m,2H),2.14(m,2H).
中间体2
2-肟基-3,6,7,8-四氢-不对称引达省-1-酮
将中间体1(85g,493mmol)的MTBE(1.27L)溶液用HCl(12M的EtOH溶液,20.6mL)处理,冷却至0℃并用亚硝酸异戊酯(100mL,740mol)的乙醇(600mL)溶液处理[在5分钟内滴加]。将所得混合物在0℃下搅拌0.4h,然后通过过滤收集固体并用MTBE洗涤并干燥,得到标题化合物,为棕色固体(80g,81%产率)。MS m/z=202[M+H]+.δH(400MHz,DMSO-d6)7.55(d,1H),7.34(d,1H),3.70(s,2H),3.12(t,2H),2.86(t,2H),2.04-2.11(m,2H)[OH质子不可见].
中间体3
1,3-二氯-8,9-二氢-7H-环戊二烯并[h]异喹啉
将中间体2(83g,412.5mol)的POCl3(1.25L)溶液冷却至0℃并用PCl5(94.5g,454mol)处理。将所得混合物用HCl(气体)处理直至反应饱和并在65℃下搅拌1h。此后,混合物用另外的PCl5(34.4g,165mmol)处理并再搅拌15h。将混合物真空浓缩并用水处理,过滤收集所得固体并干燥得到标题化合物(80g,81%产率)。MS m/z=238[M+H]+.δH(400MHz,CDCl3)7.64-7.56(m,3H),3.75(m,2H),3.09(m,2H),2.19-2.26(m,2H).
中间体4
3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉
将中间体3(80g,336mol)的EtOAc(666mL)溶液用红磷(27.4g,806.4mmol)和HI(155mL,57重量%水溶液,1.18mol)处理,并在120℃下搅拌4h。将所得混合物趁热过滤并真空浓缩。将残余物溶解在水中,通过加入氨溶液碱化并通过过滤收集所得固体。将固体溶解在DCM中,用盐水洗涤,用Na2SO4干燥,浓缩并通过SiO2柱色谱法纯化得到标题化合物,为白色固体(38.5g,56%产率)。MS m/z=204[M+H]+.δH(400MHz,CDCl3)9.04(s,1H),7.70(s,1H),7.56-7.63(m,2H),3.34(m,2H),3.11(m,2H),2.34-2.27(m,2H).
中间体5
3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰氯
将中间体4(10g,49mmol)装入密封的250mL圆底压力烧瓶中,并加入氯磺酸(35mL,520mmol)(在加入时观察到氯化氢气体的产生)。将所得深红色/棕色溶液在氮气流下吹扫5分钟。将烧瓶密封并在80℃下加热3小时。将反应混合物用二氯甲烷(100mL)稀释,然后在45分钟内小心地加入搅拌的冰水(500mL)中。分离两相,水层进一步萃取到二氯甲烷(200mL x2)中,合并的有机萃取物用盐水(200mL)洗涤,用硫酸钠干燥并蒸发得到标题化合物(14.6g,98%产率)。1H NMR(300MHz,氯仿-d)δH 9.20(d,J=0.9Hz,1H),8.57(d,J=0.8Hz,1H),8.46(s,1H),3.48(tt,J=8.0,1.2Hz,2H),3.29–3.14(m,2H),2.50–2.32(m,2H).LCMS[M+H]+302/304,RT 1.33min(方法1)。
中间体6
3-氯-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
在氮气下向搅拌的中间体5(14.6g,48mmol)的无水DCM(125mL)溶液中滴加异丁胺(12mL,120mmol)(观察到气体逸出)。将反应混合物在室温下搅拌3天。将反应混合物用水(125mL)洗涤。分离水层并进一步萃取到二氯甲烷(125mL x 2)中,合并的有机萃取物用盐水(150mL)洗涤,用硫酸钠干燥并蒸发至干。粗品通过色谱法纯化(0%至100%乙酸乙酯/异己烷的梯度)得到标题化合物(10.7g,65%产率)。1H NMR(300MHz,氯仿-d)δH 9.14(d,J=0.9Hz,1H),8.48(d,J=0.9Hz,1H),8.36(s,1H),4.67(t,J=6.4Hz,1H),3.50–3.35(m,2H),3.18(t,J=7.4Hz,2H),2.78–2.65(m,2H),2.45–2.28(m,2H),1.69(dq,J=13.4,6.7Hz,1H),0.81(d,J=6.7Hz,6H).LCMS[M+H]+339/341,RT 1.26min(方法1)。
中间体7和8
7-溴-3-氯-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(7)
9-溴-3-氯-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(8)
向搅拌的中间体6(4.77g,14.1mmol)的EtOAc(250mL)溶液中加入2,2'-偶氮二(2-甲基丙腈)(240mg,1.4mmol)和N-溴代琥珀酰亚胺(3.3g,18mmol)。将反应混合物在黑暗中在90℃下搅拌2.5小时。蒸发反应混合物,得到标题化合物的1:1混合物的粗品(9.24g),其无需进一步纯化即可用于下一步骤。
中间体9和10
7-氨基-3-氯-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(9)
9-氨基-3-氯-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(10)
在圆底压力烧瓶中,将两批的中间体7和8的1:1混合物的粗品(2.31g,6mmol)溶于0.4M氨的THF溶液(400mL,200mmol)中。将密封的反应混合物在70℃下加热16小时。将两种反应混合物冷却并蒸发。使用一半量的氨的THF溶液将所得残余物重新置于上述反应条件下21小时。将反应混合物冷却,合并,并蒸发得到~1:1比例的标题化合物(4.7g),其无需进一步纯化即可用于下一步骤。
中间体11和12
N-[3-氯-5-(异丁基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]氨基 甲酸叔丁酯(11)
N-[3-氯-5-(异丁基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]氨基 甲酸叔丁酯(12)
向搅拌的中间体9和10的~1:1混合物(2.88g,8.14mmol)的二氯甲烷(60mL)溶液中加入二碳酸二叔丁酯(1.86g,8.52mmol),接着加入三乙胺(2.26mL,16.3mmol)。将反应混合物在室温下搅拌2小时。将反应混合物蒸发至干,粗产物通过柱色谱法纯化(0%至100%乙酸乙酯/异己烷的梯度)得到标题化合物。
中间体11(877mg,39%产率);LCMS[M+H]+454/456,RT 1.28min(方法1)。1H NMR(300MHz,氯仿-d)δH 9.15(d,J=0.8Hz,1H),8.51(d,J=0.9Hz,1H),8.42(s,1H),5.40(m,1H),4.88(m,1H),4.72(t,J=6.4Hz,1H),3.54(ddd,J=17.1,9.1,3.3Hz,1H),3.35–3.17(m,1H),2.95–2.63(m,3H),2.17–1.98(m,1H),1.77–1.66(m,1H),1.51(s,9H),0.83(dd,J=6.7,3.8Hz,6H).
中间体12(1.00g,46%产率);LCMS[M+H]+454/456,RT 1.31min(方法1)。1H NMR(300MHz,氯仿-d)δH 9.40(d,J=0.8Hz,1H),8.48(d,J=0.8Hz,1H),8.33(s,1H),5.86(s,1H),4.94(m,J=9.5Hz,1H),4.77(t,J=6.4Hz,1H),3.27(dt,J=15.8,7.6Hz,1H),3.07(ddd,J=16.8,9.0,4.6Hz,1H),2.85–2.65(m,3H),2.20(m,1H),1.76–1.67(m,1H),1.46(s,9H),0.83(dd,J=6.7,1.8Hz,6H).
中间体13
N-[3-环丙基-5-(异丁基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]
氨基甲酸叔丁酯
在氮气气氛下将中间体11(910mg,2.0mmol)、环丙基硼酸(540mg,6.0mmol)和碳酸铯(1.6g,4.9mmol)在1,4-二氧六环(20mL)中的混合物装入圆底压力烧瓶中。加入氯(η2-P,C-三(2,4-二叔丁基苯基)亚磷酸酯)(三环己基膦)钯(II)(210mg,0.20mmol),并将密封的反应混合物在100℃下加热17小时。蒸发冷却的反应混合物。将所得残余物分配在二氯甲烷(50mL)和水(25mL)之间。分离水层,并进一步萃取到二氯甲烷(50mL x 2)中,合并的有机萃取物用盐水(50mL)洗涤,用硫酸钠干燥并蒸发至干。粗品通过色谱法纯化(0%至100%乙酸乙酯/异己烷的梯度)得到标题化合物(694mg,75%产率)。1H NMR(300MHz,氯仿-d)δH9.21(d,J=0.9Hz,1H),8.34(s,1H),8.26(d,J=0.9Hz,1H),5.39(m,1H),4.85(m,1H),4.66(t,J=6.4Hz,1H),3.49(ddd,J=17.1,9.1,3.5Hz,1H),3.23(dt,J=16.8,8.1Hz,1H),2.93–2.62(m,3H),2.24(ddd,J=13.2,8.1,4.8Hz,1H),2.12–1.93(m,1H),1.72(m,1H),1.51(s,9H),1.18–1.01(m,4H),0.84(dd,J=6.7,4.4Hz,6H).LCMS[M+H]+460,RT 1.38min(方法1)。
中间体14
N-[7-环丙基-5-(异丁基氨磺酰基)-2,3-二氢-1H-环戊二烯并[a]萘-1-基]氨基
甲酸叔丁酯
将中间体12(500mg,1.10mmol)、环丙基硼酸(299mg,3.304mmol)和碳酸铯(906mg,2.753mmol)在无水1,4-二氧六环(5mL)中的混合物脱气并充入氮气。加入氯(η2-P,C-三(2,4-二叔丁基苯基)亚磷酸酯)(三环己基膦)钯(II)(117.6mg,0.11mmol),并将反应混合物在微波中在120℃下加热1.5h。减压浓缩反应混合物,然后分配在DCM和水之间。用盐水洗涤有机相,通过相分离筒并蒸发。粗品通过柱色谱法纯化(用20-70%EtOAc/异己烷(ipahexane)洗脱)得到标题化合物(332mg,66%产率)。LCMS[M+H-tBu]+404.0,RT 2.73(方法15)。LCMS[M+H-tBu]+404.0,RT 2.73min(方法3)。
中间体15
3-氯-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
向搅拌的中间体5(11.5g,38.1mmol)的DCM(200mL)溶液中加入2-氟-2-甲基-丙-1-胺盐酸盐(5.83g,45.7mmol),接着加入三乙胺(13.2mL,95.1mmol)。将反应混合物在室温下搅拌1h。用水(200mL)洗涤反应。分配有机层并用更多的水(200mL)洗涤。将有机层干燥并真空浓缩得到11.8g绿色/黑色固体。将其与热的IPA一起研磨并过滤得到标题化合物(10.4g,77%产率),为灰色粉末。1H NMR(300MHz,氯仿-d)δH9.14(d,J=0.9Hz,1H),8.46(d,J=0.8Hz,1H),8.34(s,1H),4.98(t,J=6.5Hz,1H),3.49–3.37(m,2H),3.17(t,J=7.5Hz,2H),3.04(dd,J=19.8,6.5Hz,2H),2.45–2.29(m,2H),1.31(d,J=21.4Hz,6H).LCMS[M+H]+357,RT 1.92min(方法2)。
中间体16和17
9-溴-3-氯-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰 胺(16)
7-溴-3-氯-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰 胺(17)
在氮气下向搅拌的中间体15(3.0g,8.4mmol)的乙酸乙酯(180mL)溶液中加入2,2'-偶氮二(2-甲基丙腈)(140mg,0.84mmol)和N-溴代琥珀酰亚胺(2.0g,11mmol)。将混合物在黑暗中在90℃下搅拌1.5小时。真空蒸发反应混合物得到粗产物,为标题化合物16(1.65g,44%产率)和标题化合物17(1.65g,44%产率)的1:1混合物。LCMS[M+H]+435/437/439,RT 1.56min(方法5)。
中间体18
N-[(3R)-1-[3-氯-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并
[h]异喹啉-7-基]-3-哌啶基]氨基甲酸叔丁酯
向中间体17(200mg,0.46mmol)的DMF(2mL)溶液中加入碳酸钾(128mg,0.92mmol),接着加入(R)-3-boc-氨基哌啶(190mg,0.95mmol)。将混合物搅拌18小时。将水(10mL)和EtOAc(20mL)加入混合物中。分离有机层并进一步用水(2x5mL)洗涤。将有机层通过相分离器并除去溶剂得到棕色油状物。油状物通过快速柱色谱法纯化,用0至100%EtOAc/庚烷梯度洗脱得到标题化合物,为棕色胶状物(240mg,94%产率)。LCMS[M+H]+555/557,RT 2.54分钟(方法4)。
中间体19
N-[(3R)-1-[3-环丙基-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二
烯并[h]异喹啉-7-基]-3-哌啶基]氨基甲酸叔丁酯
向中间体18(240mg,0.43mmol)在甲苯(2mL)和1,4-二氧六环(3mL)的混合物中的溶液中加入环丙基硼酸(117mg,1.30mmol),接着加入乙酸钯(II)(4.8mg,0.022mmol)。用氮气鼓泡通过混合物2分钟,然后加入三环己基鏻四氟硼酸盐(25mg,0.065mmol)和磷酸三钾(230mg,1.08mmol)。用氮气鼓泡通过其5分钟,然后将微波管加盖并在微波中在130℃下加热18小时。将饱和NaHCO3水溶液(10mL)和EtOAc(10mL)加入混合物中。分离有机层,通过相分离器并除去溶剂得到绿色油状物。油状物通过快速柱色谱法纯化,用0至100%EtOAc/庚烷梯度洗脱,接着用0至10%MeOH/EtOAc梯度洗脱得到标题化合物,为棕色胶状物(231mg,95%产率)。LCMS[M+H]+561,RT 2.63分钟(方法4)。
中间体20
向中间体17(100mg,0.23mmol)的DMF(2mL)溶液中加入碳酸钾(96.1mg,0.69mmol),接着加入(2R)-N-甲基吡咯烷-2-甲酰胺(59mg,0.46mmol)。将混合物静置18小时。将水(10mL)和EtOAc(20mL)加入混合物中。分离有机层并进一步用水(2x10mL)洗涤。将有机层通过相分离器并除去溶剂得到棕色油状物。油状物通过快速柱色谱法纯化,用0至100%EtOAc/庚烷梯度洗脱,接着用0-10%MeOH/EtOAc梯度洗脱得到标题化合物,为两种非对映异构体的混合物(96mg,87%产率)。LCMS[M+H]+483/485,RT 1.89和1.94分钟(方法4)。
中间体21
N-[1-[3-氯-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异
喹啉-7-基]氮杂环丁烷-3-基]氨基甲酸叔丁酯
向中间体17(160mg,0.37mmol)的DMF(2mL)溶液中加入3-N-Boc-氨基氮杂环丁烷(130mg,0.73mmol),接着加入碳酸钾(154mg,1.10mmol)。将混合物搅拌18小时。将乙酸乙酯(15mL)加入混合物中。用水(2x15mL)和盐水(15mL)洗涤悬浮液。然后将合并的有机层通过相分离器并减压浓缩。残余物通过快速柱色谱法纯化,用0-100%EtOAc/庚烷梯度洗脱,接着用0-20%MeOH/EtOAc梯度洗脱得到标题化合物,为浅棕色玻璃状物(119mg,61%产率)。LCMS[M+H]+527/529,RT 2.29分钟(方法4)。
中间体22
N-[1-[3-环丙基-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并
[h]异喹啉-7-基]氮杂环丁烷-3-基]氨基甲酸叔丁酯
将中间体21(119mg,0.23mmol)、环丙基硼酸(61mg,0.67mmol)、乙酸钯(II)(2.5mg,0.011mmol)、三环己基鏻四氟硼酸盐(13mg,0.034mmol)、磷酸三钾(120mg,0.57mmol)和水(20μL)的混合物悬浮在甲苯(2mL)中。用氮气吹扫混合物然后加热至120℃持续14小时。反应混合物用水(5mL)和DCM(10mL)稀释。将双相层分离,水层用DCM(2x10mL)萃取。将合并的有机层通过相分离器并减压浓缩得到油状物。油状物通过快速柱色谱法纯化,用0-100%EtOAc/异己烷梯度洗脱,接着用0-20%MeOH/EtOAc梯度洗脱得到标题化合物,为浅棕色玻璃状物(55mg,46%产率)。LCMS[M+H]+533,RT 1.96分钟(方法4)。
中间体23
7-(3-氨基氮杂环丁烷-1-基)-3-环丙基-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-
环戊二烯并[h]异喹啉-5-磺酰胺
向中间体22(47mg,0.088mmol)的DCM(2mL)溶液中加入TFA(2mL)。将溶液搅拌1小时。除去溶剂,使用DCM和异己烷的1:1混合物共沸过量的TFA。得到的棕色胶状物通过SCX柱色谱纯化,用0至100%7M氨的MeOH溶液梯度洗脱得到标题化合物,为浅棕色固体(36mg,94%产率)。LCMS[M+H]+433,RT 1.64分钟(方法4)。
中间体24
3-氯-N-(2-氟-2-甲基-丙基)-7-(1H-吲哚-2-基甲基氨基)-8,9-二氢-7H-环戊二
烯并[h]异喹啉-5-磺酰胺
向中间体17(100mg,0.23mmol)的DMF(2mL)溶液中加入碳酸钾(64mg,0.46mmol)接着加入(1H-吲哚-2-基甲基)胺(69mg,0.46mmol)。将混合物搅拌18小时。将水(5mL)和EtOAc(10mL)加入混合物中。分离有机层并用水(2x5mL)进一步洗涤。将有机层通过相分离器并除去溶剂得到绿色油状物。油状物通过快速柱色谱法纯化,用0至100%EtOAc/异己烷梯度洗脱得到标题化合物,为棕色泡沫状物(95mg,82%产率)。LCMS[M+H]+501/503,RT 2.46分钟(方法4)。
中间体25和26
3-氯-7-羟基-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(25)
3-氯-9-羟基-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(26)
向中间体7和8(1480mg,3.54mmol)在THF(6mL)/水(3mL)的混合物中加入碳酸银(1973mg,7.09mmol)。将反应剧烈搅拌18小时。通过硅藻土过滤混合物以除去银盐,用EtOAc(20mL)和水(5mL)洗涤。分离有机层并通过相分离器。除去溶剂得到棕色胶状物。胶状物通过快速柱色谱法纯化,用0至50%EtOAc/异己烷梯度洗脱得到中间体26(280mg,22%产率),中间体25(200mg,16%产率),以及中间体25和26的1:1混合物(113mg,9%产率).
中间体25;LCMS[M+H]+355,RT 2.10分钟(方法4)。
中间体26;LCMS[M+H]+355,RT 2.16分钟(方法4)。
中间体27
3-氯-9-氟-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
在0℃下向中间体26(48mg,0.14mmol)的DCM(2mL)溶液中加入DAST(44mg,0.27mmol)。混合物在0℃下搅拌10分钟,然后在室温下搅拌1小时。加入饱和NaHCO3水溶液(5mL),分离有机层并通过相分离器。除去溶剂得到胶状物。胶状物通过快速柱色谱法纯化,用0至50%EtOAc/异己烷梯度洗脱得到标题化合物,为白色固体(43mg,89%产率)。LCMS[M+H]+357,RT 2.41分钟(方法4)。
中间体28
7-[叔丁基(二甲基)甲硅烷基]氧基-3-氯-N-异丁基-8,9-二氢-7H-环戊二烯并
[h]异喹啉-5-磺酰胺
向中间体25(200mg,0.56mmol)的DMF(3mL)溶液中加入咪唑(78mg,1.13mmol)、4-二甲基氨基吡啶(3.4mg,0.028mmol)和TBDMSCl(127mg,0.85mmol)。将混合物搅拌6小时,加入4-二甲基氨基吡啶(0.1当量)并将反应在40℃下加热18小时。加入另一份TBDMSCl(127mg,0.85mmol)和咪唑(3.4mg,0.028mmol)并将混合物加热5小时。将水(10mL)和EtOAc(20mL)加入混合物中。分离有机层,用水(10mL)洗涤并通过相分离器。除去溶剂得到棕色胶状物。胶状物通过快速柱色谱法纯化,用0至20%EtOAc/异己烷梯度洗脱得到标题产物,为白色固体(190mg,72%产率)。LCMS[M+H]+469/471,RT 3.66分钟(方法4)。
中间体29
7-[叔丁基(二甲基)甲硅烷基]氧基-3-环丙基-N-异丁基-8,9-二氢-7H-环戊二烯
并[h]异喹啉-5-磺酰胺
在微波管中,将中间体28(135mg,0.29mmol)悬浮在1,4-二氧六环(3mL)中,加入碳酸铯(237mg,0.72mmol),接着加入环丙基硼酸(78mg,0.86mmol)。将烧瓶抽空并置于氮气气氛下5分钟。然后加入氯(η2-P,C-三(2,4-二叔丁基苯基)亚磷酸酯)(三环己基膦)钯(II)(31mg,0.029mmol)并将烧瓶再次抽空并置于氮气气氛下。然后将反应在120℃下加热2.5小时。除去溶剂,并将残余物分配在水(10mL)和EtOAc(15mL)之间。分离有机层并通过相分离器。除去溶剂得到棕色油状物。油状物通过快速柱色谱法纯化,用0至20%EtOAc/异己烷梯度洗脱得到标题产物,为灰白色固体(74mg,54%产率)。LCMS[M+H]+475,RT 3.68分钟(方法3)。
中间体30
3-氰基-2-苯基-1-(对甲苯基)异脲
N-氰基羰亚胺二苯酯(500mg,2.10mmol)和对甲苯胺(240mg,2.24mmol)溶于二氯甲烷(70mL)。加入N,N-二异丙基乙胺(397mg,3.15mmol)和2-丙醇(2mL)。将混合物在室温下搅拌过夜。蒸发溶剂。残余物与EtOAc一起研磨并过滤,用EtOAc洗涤三次,得到标题化合物,为白色固体(210mg,40%产率)。LCMS[M+H]+252,RT 1.90min(方法6)。
中间体31和32
9-氨基-3-氯-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺 酰胺(31)
7-氨基-3-氯-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺 酰胺(32)
将含有中间体16(1.65g,3.79mmol)和中间体17(1.65g,3.79mmol)的粗品混合物溶于四氢呋喃(200mL)中并将混合物装入密封的500mL圆底压力烧瓶中。将氨气鼓泡通过反应混合物5分钟。将密封的混合物在70℃下加热2天。将冷却的反应混合物真空蒸发得到包含标题化合物31(1.71g/定量产率,3.79mmol)和标题化合物32(1.71g/定量产率,3.79mmol)的1:1混合物的粗产物。LCMS[M+H]+372/374,RT 1.89和1.92分钟(方法6).
中间体33和34
N-[3-氯-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹 啉-9-基]氨基甲酸叔丁酯(33)
N-[3-氯-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹 啉-7-基]氨基甲酸叔丁酯(34)
向搅拌的中间体31(3.79mmol)和中间体32(3.79mmol)在二氯甲烷(100mL)中的粗品混合物中加入二碳酸二叔丁酯(2.1g,9.5mmol),接着加入三乙胺(2.5mL,18mmol)。将混合物在室温下在氮气下搅拌3小时。真空蒸发反应混合物并通过柱色谱法纯化,使用0–40%乙酸乙酯/异己烷梯度。
中间体33(1.2g,85%纯度,2.16mmol,57%产率)分离为黄色泡沫状物。δH(300MHz,d-氯仿)9.40(d,J=0.8Hz,1H),8.46(d,J=0.9Hz,1H),8.31(s,1H),5.86(m,1H),5.01(t,J=6.4Hz,1H),4.98–4.88(m,1H),3.34–3.19(m,1H),3.06(m,3H),2.87–2.66(m,1H),2.21(ddt,J=13.7,8.9,4.0Hz,1H),1.48(s,9H),1.36(d,J=6.0Hz,3H),1.31–1.27(m,3H).LCMS[M+H]+472/474,RT 2.55min(方法6)。
中间体34(877mg,1.86mmol,49%产率)分离为黄色固体。δH(300MHz,d-氯仿)9.15(d,J=0.9Hz,1H),8.49(d,J=0.8Hz,1H),8.41(s,1H),5.41(m,1H),5.03(t,J=6.4Hz,1H),4.89(d,J=8.9Hz,1H),3.54(ddd,J=17.1,9.2,3.2Hz,1H),3.37–2.79(m,4H),2.15–1.98(m,1H),1.51(s,9H),1.41–1.23(m,6H).LCMS[M+H]+472/474,RT 2.52min(方法6)。
中间体35
N-[3-环丙基-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]
异喹啉-7-基]氨基甲酸叔丁酯
将中间体34(870mg,1.8mmol)、环丙基硼酸(500mg,5.5mmol)和碳酸铯(1.5g,4.6mmol)在无水1,4-二氧六环(20mL)中的混合物装入50mL压力烧瓶中并在氮气流下吹扫5分钟。加入氯(η2-P,C-三(2,4-二叔丁基苯基)亚磷酸酯)(三环己基膦)钯(II)(200mg,0.19mmol)并将密封的混合物在100℃下加热16小时。真空蒸发冷却的反应混合物,并将所得残余物分配于二氯甲烷(100mL)和水(50mL)之间。分离水层并进一步萃取到二氯甲烷中(2x100mL),将合并的有机萃取物用盐水(100mL)洗涤,用硫酸钠干燥并真空蒸发。残余物通过柱色谱法纯化,使用0–80%乙酸乙酯/异己烷梯度得到标题化合物(571mg,65%产率)。δH(300MHz,d-氯仿)9.22(d,J=0.9Hz,1H),8.33(s,1H),8.23(d,J=1.0Hz,1H),5.39(m,1H),4.95(t,J=6.5Hz,1H),4.84(d,J=8.9Hz,1H),3.50(ddd,J=17.1,9.1,3.4Hz,1H),3.23(dt,J=17.0,8.3Hz,1H),3.13–2.76(m,3H),2.25(ddd,J=13.3,8.2,4.9Hz,1H),2.08–1.98(m,1H),1.51(s,9H),1.43–1.24(m,6H),1.13(m,4H).LCMS[M+H]+478,RT 1.23min(方法1)。
中间体36
7-氨基-3-环丙基-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-
5-磺酰胺
将中间体35(570mg,1.2mmol)在4M盐酸的二氧六环溶液(15mL)中的溶液在室温下搅拌1小时。真空蒸发反应混合物,残余物通过SCX柱纯化,用100%甲醇接着用7N氨的甲醇溶液洗脱得到标题化合物(438mg,97%产率)。δH(300MHz,d-氯仿)9.21(s,1H),8.38(s,1H),8.21(s,1H),5.05(m,1H),4.60(m,1H),3.59-3.51(m,1H),3.29–3.12(m,1H),3.03(m,2H),2.76(m,1H),2.22(m,1H),1.94(m,1H),1.38–1.23(m,6H),1.10(m,4H).缺少NH2质子.LCMS[M+H]+378,RT 1.31min(方法5)。
中间体37和38
(7R)-7-氨基-3-环丙基-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异
喹啉-5-磺酰胺
(7S)-7-氨基-3-环丙基-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异
喹啉-5-磺酰胺
通过用手性HPLC分离中间体36得到标题化合物,使用以下条件:LUX Cellulose-4,250x21.2mm,5μM柱,流速10mL/min.柱温:40℃,流动相:MeOH+0.1%NH4OH.运行时间:20mins
注:中间体37和38中,一个是R-对映异构体,另一个是S-对映异构体,我们没有指定哪个对映异构体是哪个中间体。
中间体37:手性RT**=2.50min;LCMS[M+H]+378.2,RT 1.67min(方法3)。
中间体38:手性RT**=2.77min;LCMS[M+H]+378.2,RT 1.74min(方法3)。
**手性分析在极性有机模式下进行,在Agilent 1100UV导向系统上使用LuxCellulose-4 4.6x150mm,3μm柱,流速1mL/min,用甲醇(0.1%氢氧化铵)洗脱,使用10min运行时间。
中间体39
9-氨基-3-环丙基-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺盐酸
盐
9-氨基-3-环丙基-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将中间体14(1.81g,3.47mmol)溶于4M盐酸的二氧六环溶液(20mL)中,并在环境温度下搅拌30min。真空浓缩反应得到盐酸盐形式的标题化合物。然后将其溶解在MeOH(10mL)中,并吸附到SCX柱上,首先用MeOH(50mL)洗脱,然后用7N NH3的MeOH溶液(75mL)洗脱。真空除去甲醇氨得到游离碱形式的标题化合物(1.18g,95%产率)。δH(300MHz,d-甲醇)9.47(s,1H),8.37(d,J=0.9Hz,1H),8.28(s,1H),5.05(dd,J=7.5,2.5Hz,1H),3.43–3.32(m,1H),3.03(ddd,J=16.4,9.0,3.1Hz,1H),2.68–2.50(m,3H),2.30(tt,J=7.9,5.3Hz,1H),2.12(ddt,J=13.6,8.1,2.8Hz,1H),1.62(dp,J=13.4,6.7Hz,1H),1.18–1.01(m,4H),0.78(d,J=6.7Hz,6H).
中间体40-42
根据以下程序合成中间体40-42:向中间体39(50mg,0.14mmol)在DCM(1mL)和THF(1mL)的溶液中加入异硫氰酸酯(1.2当量)。将反应在环境温度下搅拌过夜,真空浓缩,然后使用柱色谱法纯化得到标题化合物。使用方法5获得下表中给出的LCMS数据。
中间体43
3-(6-碘茚满-5-基)丙酸
在0–10℃下向3-茚满-5-基丙酸(5.14kg,27mol)和TFA(6.9L)在DCM(26L)的混合物中加入N-碘琥珀酰亚胺(1.0当量)。将溶液在10–15℃下搅拌20小时,然后倒到冰上。用DCM萃取该水性混合物,并用10%Na2S2O3水溶液洗涤。该二氯甲烷溶液直接用于随后的步骤。假定为定量产率(8.5kg,mw=315.1).
中间体44
4-碘-3,6,7,8-四氢-2H-不对称引达省-1-酮
在0℃下将中间体43(8.5kg,27mol)的DCM(127L)溶液用DMF处理,接着用草酰氯(6.8kg,54mol)处理,并将反应混合物在10-15℃下搅拌3小时。将混合物真空浓缩,溶解在DCM(127L)中,冷却至0℃并用AlCl3(10.8kg,81mol)处理。将混合物在0℃下搅拌2小时,然后通过加入冰水(85L)淬灭,并用DCM(85L)萃取。将有机萃取物真空浓缩并通过柱色谱法纯化得到标题化合物(大约750g,~12%产率)。δH(300MHz,DMSO-d6)7.92(s,1H),3.03(t,J=7.5Hz,2H)2.85(t,J=5.8Hz,4H),2.69–2.56(m,2H),2.04(p,J=7.5Hz,2H).LCMS[M+H]+299,RT 2.51min(方法3)。
中间体45
2-肟基-4-碘-3,6,7,8-四氢-不对称引达省-1-酮
将中间体44(100g,335mmol)悬浮在Et2O(800mL)和EtOH(100mL)的混合物中。在室温下加入HCl(4mol/L)的1,4-二氧六环溶液(16mL),接着在0℃下加入亚硝酸丁酯(58mL,471mmol)。除去冰浴,并将反应混合物搅拌下升温过夜。过滤收集白色固体沉淀物,用MeOH和EtOAc漂洗并真空干燥得到标题化合物(109g,99%产率)。1H NMR(300MHz,DMSO-d6)δ12.69(s,1H),7.99(d,J=0.9Hz,1H),3.50(s,2H),3.10(t,J=7.5Hz,2H),2.88(t,J=7.5Hz,2H),2.07(p,J=7.6Hz,2H).LCMS[M+H]+328,RT 1.13min(方法1)。
中间体46
3-氯-5-碘-8,9-二氢-7H-环戊二烯并[h]异喹啉
使用以下两个步骤得到标题化合物:
步骤1:在室温下向中间体45(50g,152mmol)在三氯氧磷(280mL,3010mmol)中的悬浮液中加入五氯化磷(36g,172mmol)。几分钟后,反应混合物中的大部分沉淀物已溶解,得到深橙色悬浮液(注意到有少量气体逸出)。将反应混合物保持在室温下,将HCl(通过将硫酸逐步添加到NaCl中原位产生)鼓泡通过反应混合物30min。然后将混合物加热至80℃。注意到缓慢但稳定的气体逸出。15分钟后气体停止逸出。注:加热第一小时后,添加更多五氯化磷(6g,28.8mmol)。总共加热约4小时后,将减压浓缩混合物。将残余物(绿色固体)在冰/水浴中冷却并用水(~80mL)处理。过滤收集灰色沉淀。
步骤2:向上述步骤1的灰色沉淀物(50g,137mmol)的AcOH溶液中加入HCl(70mL,514mmol,57质量%),接着加入红磷(9.5g,310mmol)。将混合物加热至110℃持续约15小时。蒸发挥发物,将粗品悬浮在水中。添加浓氢氧化铵溶液以将pH调节至8-9。将DCM和水添加到浆液中并分离各层。用硫酸钠干燥有机物并蒸发,得到标题化合物(33g,62%产率)1H NMR(300MHz,氯仿-d)δ8.95(d,J=0.8Hz,1H),8.20(s,1H),7.95(d,J=0.7Hz,1H),3.34(t,J=7.5Hz,2H),3.11(t,J=7.5Hz,2H),2.39–2.22(m,2H).LCMS[M+H]+330,RT 3.08min(方法4)。
中间体47和48
3-氯-5-碘-7,8-二氢环戊二烯并[h]异喹啉-9-酮(47)
3-氯-5-碘-8,9-二氢环戊二烯并[h]异喹啉-7-酮(48)
将中间体46(47mmol,15.5g)悬浮于DCM(500mL)中。在室温下加入氧化铬(VI)(5mmol,500mg)和70%叔丁基过氧化氢水溶液(930mmol,120mL)并将反应剧烈搅拌过夜。然后在0℃下用饱和Na2S2O5水溶液淬灭反应混合物。然后分离两层,并将有机层用水洗涤,用硫酸钠干燥并蒸发至干。将所得残余物干法负载到硅胶上并通过柱色谱法纯化,用0至20%EtOAc/甲苯梯度洗脱得到标题化合物:
中间体47(5.9g,37%产率);1H NMR(300MHz,氯仿-d)δ10.19(d,J=0.9Hz,1H),8.46(s,1H),8.03(d,J=0.8Hz,1H),3.41–3.16(m,2H),3.04–2.73(m,2H).LCMS[M+H]+344,RT 1.47min(方法5)。
中间体48(3.4g,21%产率);1H NMR(300MHz,氯仿-d)δ9.22(d,J=0.8Hz,1H),8.54(s,1H),8.10(d,J=0.7Hz,1H),3.77–3.36(m,2H),3.21–2.74(m,2H).LCMS[M+H]+344,RT 1.43min(方法5)。
中间体49
3-氯-5-碘-7-(3-吡啶基)-8,9-二氢环戊二烯并[h]异喹啉-7-醇
在N2气氛下在-78℃下向搅拌的3-溴吡啶(0.1g,0.63mmol)的无水THF(2mL)溶液中加入2.5M正丁基锂的己烷溶液(0.30mL,0.75mmol)。将反应混合物在-78℃下搅拌20min然后在10min内滴加中间体48(217mg,0.63mmol)的无水THF(3mL)的溶液。加完后,移走冷浴,将反应升温至环境温度过夜。通过加入饱和水NH4Cl(3mL)淬灭反应并用水(5mL)和EtOAc(5mL)的混合物稀释。分配有机层,用Na2SO4干燥并真空浓缩。粗产物通过柱色谱法纯化得到标题化合物(53mg,20%产率)。LCMS[M+H]+423/425,RT 1.09min(方法1)。
中间体50
3-氯-N-(2-氟-2-甲基-丙基)-7-羟基-7-(3-吡啶基)-8,9-二氢环戊二烯并[h]异
喹啉-5-磺酰胺
将中间体49(53mg,0.12mmol)、1,4-二氮杂双环[2.2.2]辛烷双(二氧化硫)加合物(19mg,0.08mmol)、乙酸钯(II)(1.5mg,0.006mmol)和丁基二-1-金刚烷基膦(3.4mg,0.009mmol)装入密封管中。加入三乙胺(52μL,0.38mmol)和无水IPA(2mL),将反应密封并加热至75℃过夜。将反应用2-氟-2-甲基丙-1-胺HCl(51mg,0.38mmol)和次氯酸钠水溶液(0.16mL,0.25mmol)处理,并在环境温度下搅拌3h。将反应用EtOAc(5mL)稀释并用水(5mL)洗涤。有机相用Na2SO4干燥并真空浓缩。粗产物通过柱色谱法纯化得到标题化合物(11mg,10%产率)。LCMS[M+H]+450/452,RT 0.98min(方法1)。
中间体51
3-氯-5-碘-7-三甲基甲硅烷基氧基-8,9-二氢环戊二烯并[h]异喹啉-7-甲腈
向中间体48(1.2g,3.5mmol)在甲苯(20mL)和乙腈(10mL)的溶液中加入碘化锌(110mg,0.35mmol)和三甲基氰硅烷(1.3mL,10mmol)。将反应加热至75℃并搅拌过夜,然后用三甲基氰硅烷(2.0mL)处理并在75℃下加热4.5小时。将反应冷却,用饱和NaHCO3水溶液淬灭(25mL)并用EtOAc(100mL)萃取。分配有机相,用Na2SO4干燥并真空浓缩。经柱色谱纯化得到标题化合物(694mg,45%产率)。1H NMR(300MHz,氯仿-d)δ9.02(d,J=0.8Hz,1H),8.35(s,1H),8.03(d,J=0.8Hz,1H),3.62–3.31(m,2H),3.02(ddd,J=13.5,7.8,4.6Hz,1H),2.61(ddd,J=13.5,8.3,6.3Hz,1H),0.32(s,9H).
中间体52
3-氯-5-碘-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-甲酸
将氯化亚锡(1.69g,8.70mmol)加入中间体51(967mg,2.18mmol)中,接着加入冰乙酸(4.0mL),然后加入浓盐酸(4.0mL)。将反应容器密封并置于预加热模块(140℃)中2.5小时,同时剧烈搅拌。冷却反应,用水(10mL)稀释并用10%MeOH/DCM(3x20mL)萃取。将合并的有机萃取物用Na2SO4干燥并真空浓缩得到标题化合物(0.58g,50%产率)。LCMS[M+H]+374,RT 1.39min(方法1)。
中间体53
3-氯-5-碘-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-甲酸甲酯
向冰冷的中间体52(0.58g,0.93mmol)在甲醇(10mL)中的悬浮液中滴加二氯亚砜(0.14mL,1.9mmol)。加完后,除去冰浴,将反应升温至环境温度下2小时。真空浓缩反应,粗产物通过柱色谱法纯化得到标题化合物(125mg,35%产率)。1H NMR(300MHz,氯仿-d)δ8.95(d,J=0.8Hz,1H),8.31(s,1H),7.96(d,J=0.7Hz,1H),4.23(dd,J=8.7,5.8Hz,1H),3.78(s,3H),3.59–3.42(m,1H),3.40–3.23(m,1H),2.76–2.47(m,2H).LCMS[M+H]+388/390,RT1.36min(方法1)。
中间体54
5-苄硫基-3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-甲酸甲酯
将中间体53(125mg,0.32mmol)、4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(23mg,0.039mmol)、三(二亚苄基丙酮)二钯(0)(18mg,0.019mmol)和N,N-二异丙基乙胺(135μL,0.77mmol)在1,4-二氧六环(2mL)中的混合物用氮气吹扫5分钟,然后加入苄硫醇(61mg,0.48mmol)。将混合物加热至85℃,同时搅拌1.5小时。将混合物冷却,用DCM(10mL)稀释并用饱和NaHCO3(5mL)水溶液洗涤。将有机层通过相分离器并在真空中除去挥发物。粗产物通过柱色谱法纯化得到标题化合物(102mg,76%产率);1H NMR(300MHz,氯仿-d)δ9.02(d,J=0.8Hz,1H),8.18(d,J=0.8Hz,1H),7.74(s,1H),7.25–7.10(m,5H),3.71(s,3H),3.59–3.42(m,1H),3.40–3.23(m,1H),2.74–2.44(m,2H),2.04(s,3H).
中间体55
3-氯-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-
7-甲酸甲酯
向中间体54(350mg,0.87mmol)在乙腈(6mL)、水(0.100mL)和乙酸(0.06mL)的混合物的冰冷溶液中加入1,3-二氯-5,5-二甲基乙内酰脲(380mg,1.93mmol),并将反应搅拌10min。加入2-氟-2-甲基-丙-1-胺盐酸盐(232mg,1.82mmol),接着加入N,N-二异丙基乙胺(0.60mL,3.5mmol)。将混合物在环境温度下搅拌15min然后真空浓缩。粗品残余物通过柱色谱法纯化得到标题产物(160mg,42%产率)。LCMS[M+H]+415,RT 1.49min(方法5)。
中间体56
3-环丙基-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹
啉-7-甲酸甲酯
向中间体55(65mg,0.16mmol)在1,4-二氧六环(1mL)的溶液中加入环丙基硼酸(42mg,0.47mmol)、氯(η2-P,C-三(2,4-二叔丁基苯基)亚磷酸酯)(三环己基膦)钯(II)(17mg,0.016mmol)和碳酸铯(128mg,0.39mmol)。将混合物在N2气流下脱气5min,密封并加热至120℃持续2小时。反应用EtOAc(5mL)稀释并用饱和NaHCO3水溶液(2.5mL)洗涤。有机层用Na2SO4干燥并真空浓缩。粗产物通过快速色谱法纯化得到标题产物(3mg,4.5%产率)。1HNMR(400MHz,氯仿-d)δ9.21(d,J=1.0Hz,1H),8.38(s,1H),8.23(d,J=1.0Hz,1H),4.96(t,J=6.5Hz,1H),4.32–4.21(m,1H),3.71(s,3H),3.63–3.47(m,1H),3.38(ddd,J=17.0,9.0,5.9Hz,1H),3.03(ddd,J=19.7,6.6,2.0Hz,2H),2.80–2.55(m,2H),2.24(tt,J=8.1,4.8Hz,1H),1.29(d,J=3.4Hz,6H),0.73–0.36(m,4H).
中间体57
1-(环丙基甲基)-1-[(2,4-二甲氧基苯基)甲基]-3-[(7S*)-3-环丙基-5-[(2-氟- 2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]硫脲[*或R]
向搅拌的中间体38(75mg,0.20mmol)的二氯甲烷(1mL)溶液中加入1,1'-硫代羰基二咪唑(43mg,0.22mmol)。将反应混合物在室温下搅拌1.5小时。然后加入N-(环丙基甲基)-1-(2,4-二甲氧基苯基)甲胺(66mg,0.30mmol)并将反应再搅拌一小时。反应混合物用DCM(1mL)稀释并用饱和NH4Cl水溶液(1mL)和0.5M HCl水溶液(1mL)洗涤得到标题化合物(168mg,60%纯度,79%).LCMS[M+H]+641,RT 2.95min(方法7)。
中间体58
3-氯-N-异丁基-7-(甲磺酰氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
向搅拌的中间体9(330mg,0.61mmol,65%)的无水DCM(10mL)溶液中加入DIPEA(0.32mL,1.87mmol)和甲磺酰氯(87.2μL,1.12mmol)。将反应混合物在室温下搅拌15小时。然后将反应混合物用水(10mL)和盐水(10mL)洗涤,干燥(MgSO4),过滤并真空浓缩。粗物质通过柱色谱法纯化,使用2-20%MeOH/DCM梯度,得到标题化合物(0.26g,62%产率),为米色泡沫状物。LCMS[M+H]+432,RT 1.10min(方法17)。
中间体59和60
3-氯-N-(2-氟-2-甲基-丙基)-7-氧代-8,9-二氢环戊二烯并[h]异喹啉-5-磺酰胺 (59)
3-氯-N-(2-氟-2-甲基-丙基)-9-氧代-7,8-二氢环戊二烯并[h]异喹啉-5-磺酰胺 (60)
向四氯金(III)酸钾(2.6mg,7.0μmol)的吡啶(0.2mL,2mmol)溶液中加入中间体15(50mg,0.14mmol),接着加入叔丁基过氧化氢(0.05mL,0.28mmol)。将反应密封并加热至90℃同时搅拌1小时。将反应冷却并通过柱色谱法纯化得到标题化合物:
中间体59(15mg,29%产率):1H NMR(300MHz,氯仿-d)δ9.39(d,J=0.8Hz,1H),8.63–8.56(m,2H),5.40(t,J=6.4Hz,1H),3.69–3.61(m,2H),3.12(dd,J=20.2,6.4Hz,2H),2.99–2.91(m,2H),1.32(d,J=21.4Hz,6H).
中间体60(15mg,29%产率):1H NMR(300MHz,氯仿-d)δ10.30(d,J=0.9Hz,1H),8.52–8.45(m,2H),5.53(t,J=6.3Hz,1H),3.38–3.31(m,2H),3.15(dd,J=20.0,6.4Hz,2H),2.96–2.89(m,2H),1.32(d,J=21.4Hz,6H).
中间体61
3-氯-N-(2-氟-2-甲基-丙基)-7-(2-氟-3-吡啶基)-8,9-二氢-7H-环戊二烯并[h]
异喹啉-5-磺酰胺
将中间体59(270mg,0.73mmol)和4-甲基苯磺酰肼(140mg,0.73mmol)悬浮在无水1,4-二氧六环(7.0mL)中,并将混合物加热至80℃持续45min。加入碳酸钾(251mg,1.82mmol)和2-氟吡啶-3-硼酸水合物(177mg,1.09mmol)并继续在110℃下加热4小时。冷却反应,用EtOAc(25mL)稀释并用饱和NaHCO3水溶液(25mL)洗涤。水相用EtOAc(25mL)萃取,合并的有机萃取物用Na2SO4干燥并真空浓缩。通过柱色谱纯化得到标题化合物(122mg,32%产率);1HNMR(300MHz,氯仿-d)δ9.23(d,J=0.9Hz,1H),8.51(d,J=0.9Hz,1H),8.17(dt,J=4.8,1.5Hz,1H),8.07(s,1H),7.44(ddd,J=9.7,7.4,2.0Hz,1H),7.17(ddd,J=7.1,4.9,1.8Hz,1H),4.94(t,J=6.4Hz,1H),4.83(t,J=8.2Hz,1H),3.74–3.59(m,1H),3.55–3.39(m,1H),3.13–2.86(m,3H),2.52–2.26(m,1H),1.27(dd,J=21.4,5.0Hz,6H).
中间体62
N-[3-环丙基-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]
异喹啉-9-基]氨基甲酸叔丁酯
将中间体33(1140mg,2.41mmol)、环丙基硼酸(652mg,7.214mmol)和乙酸钯(II)(27mg,0.120mmol)在甲苯(10mL)中的混合物脱气并置于氮气气氛下。加入三环己基鏻四氟硼酸盐(137mg,0.361mmol)和磷酸三钾(1280mg,6.01mmol)的水(1mL)溶液,将混合物脱气并置于氮气气氛下。将反应混合物在微波中在120℃下加热2小时。将反应混合物冷却,然后用EtOAc稀释,用水洗涤,然后盐水洗涤,通过相分离器并蒸发。粗物质通过快速色谱法纯化,用10-60%EtOAc/己烷梯度洗脱得到标题化合物,为灰白色固体(938mg,82%产率)。LCMS[M+H]+478,RT 2.70min(方法3)。
中间体63和64
N-[(9R)-3-环丙基-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯
并[h]异喹啉-9-基]氨基甲酸叔丁酯
N-[(9S)-3-环丙基-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯
并[h]异喹啉-9-基]氨基甲酸叔丁酯
通过分离中间体62得到标题化合物,使用手性SFC,用以下条件:柱-Chir AS265x50mm,5μM.流速-360mL/min,柱温-30℃,流动相-10%EtOH的CO2溶液,运行时间-10mins.
注:中间体63和64中,一个是R-对映异构体,另一个是S-对映异构体,我们没有指定哪个对映异构体是哪个中间体。
中间体63:手性RT**=2.55min;1H NMR(300MHz,氯仿-d)δ9.44(d,J=0.9Hz,1H),8.24(s,1H),8.20(d,J=0.9Hz,1H),5.86–5.71(m,1H),4.96(t,J=6.5Hz,1H),4.86(d,J=8.9Hz,1H),3.32–3.16(m,1H),3.11–2.93(m,3H),2.80–2.62(m,1H),2.29–2.14(m,2H),1.47(s,9H),1.33(dd,J=21.5,6.9Hz,6H),1.21–1.03(m,4H).
中间体64:手性RT**1.92min;1H NMR(300MHz,氯仿-d)δ9.43(d,J=0.9Hz,1H),8.24(s,1H),8.20(d,J=0.9Hz,1H),5.89–5.67(m,1H),4.97(t,J=6.5Hz,1H),4.86(d,J=9.0Hz,1H),3.34–3.18(m,1H),3.13–2.93(m,3H),2.82–2.62(m,1H),2.31–2.13(m,2H),1.47(s,9H),1.33(dd,J=21.5,6.9Hz,6H),1.21–0.99(m,4H).
**手性分析在正相(Normal Phase)中进行,在Agilent 1290Infinity UV导向系统上,使用Lux Cellulose-2,4.6x150mm,3μm柱,流速1.5mL/min,用50%乙醇:50%正庚烷(+0.1%二乙胺)洗脱,使用8min运行时间。
中间体65
(9R*)-9-氨基-3-环丙基-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h] 异喹啉-5-磺酰胺[*或S]
将中间体63(200mg,0.42mmol)溶于二氯甲烷(2.0mL)中并加入三氟乙酸(1.0mL)。将反应在环境温度下搅拌过夜,真空浓缩,然后溶解于MeOH(1.5mL)并吸附到SCX柱上。用MeOH(10mL)洗涤柱,用7N MeOH的氨溶液(10mL)洗脱产物。真空除去甲醇/氨,得到标题化合物(155mg,93%产率)。1H NMR(300MHz,氯仿-d)δ9.68(s,1H),8.37–8.34(m,2H),8.14(s,1H),4.93(dd,J=7.6,3.7Hz,1H),3.25(d,J=41.9Hz,2H),3.00–2.83(m,4H),2.56–2.40(m,1H),2.28(tt,J=7.7,5.8Hz,1H),1.93(ddt,J=12.7,8.3,4.2Hz,1H),1.23(d,J=21.4Hz,6H),1.09–0.98(m,4H).
中间体66
3-氯-N-(2-氟-2-甲基-丙基)-9-[(1-甲基苯并咪唑-2-基)氨基]-8,9-二氢-7H-
环戊二烯并[h]异喹啉-5-磺酰胺
将中间体16(50mg,0.12mmol)和2-氨基-1-甲基苯并咪唑(36mg,0.24mmol)悬浮在无水甲苯(1mL)中,并将混合物加热至70℃下过夜。将反应冷却并用EtOAc(2mL)稀释,并用饱和NaHCO3水溶液(1mL)洗涤。有机相用Na2SO4干燥并真空浓缩。所得粗产物通过柱色谱法得到标题化合物(13mg,23%产率);1H NMR(400MHz,氯仿-d)δ9.39(s,1H),8.34(d,J=4.0Hz,2H),7.49(d,J=7.4Hz,1H),7.15–7.00(m,3H),6.35(td,J=8.1,3.9Hz,1H),5.51-5.10(m,1H),4.81(s,1H),3.46(s,3H),3.34(dt,J=15.7,7.4Hz,1H),3.24–2.91(m,4H),2.37(ddt,J=13.3,8.8,4.4Hz,1H),1.43–1.26(m,6H).
中间体67和68
(9S)-9-氨基-3-环丙基-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰
胺
(9R)-9-氨基-3-环丙基-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰
胺
通过使用手性SFC用以下条件分离中间体39得到标题化合物:柱-Chiralcel OJ-H250x20mm,5μM.流速-100mL/min.柱温-40℃.流动相-10-25%MeOH的梯度+0.1%NH4OH的CO2溶液.运行时间-6min.
注:中间体67和68中,一个是R-对映异构体,另一个是S-对映异构体,我们没有指定哪个对映异构体是哪个中间体。
中间体67:手性SFC RT**=2.28min
中间体68:手性SFC RT**=3.23min
**手性分析通过SFC进行,在Waters UPC2-SQD系统上,使用Chiralcel OJ-34.6x150mm,3μm柱,流速3.5mL/min,用10-25%甲醇(0.1%氢氧化铵)洗脱,用6min运行时间。
中间体69
1-(4-氨基茚满-5-基)-2-氯-乙酮
在5min内向三氯化硼-二甲硫醚络合物(25.4g,140mmol)在1,2-二氯乙烷(400mL)的冰冷溶液中滴加茚满-4-胺(17g,128mmol)。将溶液在0℃下搅拌10min。加入氯乙腈(10mL,160mmol)和氯化铝(18.7g,140mmol)并在10min内将反应升温至环境温度,然后回流2小时。将反应冷却至环境温度,分批加入2M HCl(300mL)。将淬灭物加热至80℃持续20min,冷却并用DCM(250mL)稀释。分配有机相,水相用DCM(2x250mL)萃取。合并的有机萃取物用Na2SO4干燥,并真空除去溶剂。将固体与EtOAc一起研磨并干燥得到标题化合物(7.13g,27%产率)。1H NMR(400MHz,氯仿-d)δ7.50(d,J=8.2Hz,1H),6.62(d,J=8.2Hz,1H),4.68(s,2H),3.01–2.83(m,2H),2.74(t,J=7.4Hz,2H),2.15(p,J=7.6Hz,2H).NH2质子不可见。
中间体70
4-氯-8,9-二氢-7H-环戊二烯并[h]噌啉-3-酚
将中间体69(7100mg,34mmol)溶于乙酸(35mL)和盐酸水溶液(1.2M,35mL)中,并在冰浴中冷却,然后分批加入亚硝酸钠(12g,170mmol)。加完后,将反应在0℃下搅拌5min然后在环境温度下搅拌2小时。在环境温度下加入亚硝酸钠(5.4g,78.4mmol),并继续搅拌30min。将反应用水(50mL)稀释,并用1:1CHCl3:IPA(3x100mL)萃取。将合并的有机萃取物干燥(Na2SO4)并真空浓缩。产物通过柱色谱法纯化接着与EtOAc一起研磨得到标题化合物(0.96g,13%产率);1H NMR(400MHz,DMSO-d6)δ7.92(d,J=8.2Hz,1H),7.40(d,J=8.3Hz,1H),3.11(t,J=7.5Hz,2H),3.03(t,J=7.5Hz,2H),2.19(p,J=7.6Hz,2H).OH质子不可见。
中间体71
3,4-二氯-8,9-二氢-7H-环戊二烯并[h]噌啉
将中间体70(3.6g,16.3mmol)在磷酰氯(127mmol,12.0mL)中的浆液在75℃下搅拌45min。然后将反应混合物冷却并真空浓缩,将残余物溶于DCM(100mL)并用饱和NaHCO3水溶液(100mL)洗涤。分配有机层,水层用DCM萃取(50mL)。合并的有机萃取物用Na2SO4干燥并真空除去溶剂得到标题化合物(3.29g,80%产率);1H NMR(300MHz,氯仿-d)δ8.07–7.90(m,1H),7.78(d,J=8.6Hz,1H),3.78–3.57(m,2H),3.20(t,J=7.4Hz,2H),2.37(p,J=7.7Hz,2H).
中间体72
3-氯-8,9-二氢-7H-环戊二烯并[h]噌啉
将中间体71(3.29g,13.8mmol)溶于氯仿(50mL)中并加入4-甲基苯磺酰肼(5280mg,27.5mmol)。将反应在60℃下加热过夜,然后冷却并真空浓缩。将残余物溶解于水(150mL)和1,4-二氧六环(15mL)的混合物中。加入碳酸钠(13.1g,124mmol)并将反应物加热至95℃并剧烈搅拌3h。将反应冷却并用DCM(4x150mL)萃取。合并的有机萃取物用Na2SO4干燥并真空除去溶剂得到棕色固体,将其与Et2O(20mL)一起研磨,过滤并干燥得到标题化合物(1.63g,49%产率);1H NMR(300MHz,氯仿-d)δ7.89(s,1H),7.69(d,J=8.4Hz,1H),7.59(d,J=8.3Hz,1H),3.65(t,J=7.6Hz,2H),3.18(t,J=7.6Hz,2H),2.35(p,J=7.6Hz,2H).
中间体73
3-氯-N-异丁基-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰胺
将中间体72(225mg,1.1mmol)加入密封管中,然后加入氯磺酸(1.94g,16.5mmol)。将反应密封并加热至120℃,同时搅拌6小时。将反应缓慢倒入冰和DCM(100mL)的混合物中,并用DCM和盐水(100mL)的混合物稀释。有机相用Na2SO4干燥,用2-甲基丙-1-胺(1608mg,21.99mmol)处理并在室温下搅拌15min。真空浓缩反应,粗产物通过柱色谱法纯化得到标题化合物(77mg,21%产率)。1H NMR(400MHz,氯仿-d)δ8.69(s,1H),8.40(s,1H),4.68(t,J=6.4Hz,1H),3.78–3.65(m,2H),3.31–3.17(m,2H),2.76(t,J=6.6Hz,2H),2.41(p,J=7.7Hz,2H),1.70(dp,J=13.4,6.7Hz,1H),0.83(d,J=6.7Hz,6H).
中间体74
3-氯-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰胺
向密封的压力管中加入中间体72(1.63g,7.96mmol),接着加入氯磺酸(8.03mL,119mmol)。将烧瓶密封并在120℃下加热过夜。反应混合物用二氯甲烷(200mL)稀释,然后在25分钟内加入搅拌的冰水(200mL)中。有机层用Na2SO4干燥,真空浓缩,然后溶于DCM(100mL)中。加入2-氟-2-甲基丙-1-胺HCl(1.28g,9.56mmol),接着滴加三乙胺(2.01g,19.9mmol)。将反应混合物在室温下搅拌1小时,用水(100mL)洗涤并分配有机层。水相用DCM(50mL)萃取,合并的有机萃取物用Na2SO4干燥。真空除去溶剂,粗产物通过柱色谱法纯化得到标题化合物(480mg,17%产率);1H NMR(300MHz,氯仿-d)δ8.67(s,1H),8.38(s,1H),5.23(t,J=6.4Hz,1H),3.71(tt,J=8.4,1.5Hz,2H),3.31–3.18(m,2H),3.09(dd,J=19.8,6.5Hz,2H),2.41(p,J=7.7Hz,2H),1.31(d,J=21.4Hz,6H).
中间体75和76
7-溴-3-氯-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰胺 (75)
9-溴-3-氯-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰胺 (76)
在环境温度下向搅拌的中间体74(455mg,1.27mmol)的EtOAc(10mL)溶液中加入N-溴代琥珀酰亚胺(294mg,1.65mmol),接着加入2,2'-偶氮二(2-甲基丙腈)(21mg,0.13mmol)。将反应密封并加热至70℃持续1小时,然后冷却并真空浓缩得到标题化合物中间体75和76的混合物,无需进一步纯化即可用于下一步。LCMS[M+H]+436/438RT 2.41和2.45min(方法6)。
中间体77和78
7-氨基-3-氯-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰 胺(77)
9-氨基-3-氯-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰 胺(78)
将中间体75和76的粗品混合物(460mg,0.53mmol)溶于氨(100mL,THF的饱和溶液)中。将反应混合物密封并在70℃下加热。将反应冷却并真空浓缩得到标题化合物中间体77和78的混合物(390mg),将其用于下一步。LCMS[M+H]+373/375,RT 1.72和1.74min(方法6)。
中间体79和80
N-[3-氯-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]噌啉- 7-基]氨基甲酸叔丁酯(79)
N-[3-氯-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]噌啉- 9-基]氨基甲酸叔丁酯(80)
向搅拌的中间体77和78的混合物(390mg,0.52mmol)在DCM(25mL)的溶液中加入二碳酸二叔丁酯(240mg,1.1mmol),接着加入三乙胺(0.29mL,2.1mmol)。将反应混合物在室温下搅拌过夜然后用DCM(50mL)和水(50mL)稀释。分配水相并用DCM(50mL)萃取。合并的有机萃取物用Na2SO4干燥并真空浓缩。粗品残余物通过柱色谱法纯化得到标题化合物:
中间体79(58mg,23%产率);1H NMR(300MHz,氯仿-d)δ8.69(s,1H),8.45(s,1H),5.56–5.38(m,1H),5.16(t,J=6.4Hz,1H),4.95(d,J=8.8Hz,1H),3.95–3.79(m,1H),3.59–3.40(m,1H),3.29–2.98(m,2H),2.98–2.83(m,1H),2.19–2.06(m,1H),1.51(s,9H),1.42–1.26(m,6H).LCMS[M+H]+473/475RT 2.34min(方法6)。
中间体80(57mg,23%产率);1H NMR(300MHz,氯仿-d)δ8.67(s,1H),8.37(s,1H),5.90–5.78(m,1H),5.78–5.63(m,1H),5.24(t,J=6.6Hz,1H),3.46–3.32(m,1H),3.23–3.02(m,3H),2.96–2.79(m,1H),2.52–2.33(m,1H),1.42(s,9H),1.36–1.26(m,6H).LCMS[M+H]+473/475RT2.38min(方法6)。
中间体81
N-[3-环丙基-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]
噌啉-7-基]氨基甲酸叔丁酯
将中间体79(58mg,0.13mmol)、环丙基硼酸(33mg,0.37mmol)和乙酸钯(II)(1.4mg,6.1μmol)在甲苯(1mL)中的浆液在氮气流下脱气5分钟。加入三环己基鏻四氟硼酸盐(7mg,0.018mmol)和磷酸三钾(65mg,0.31mmol)并继续脱气5min。将反应密封并在微波辐射下在115℃下加热1小时。将反应用水(2mL)和EtOAc(2mL)稀释。分配有机相,水相用EtOAc(2mL)萃取。合并的有机萃取物用Na2SO4干燥并真空浓缩。粗产物通过柱色谱法纯化得到标题化合物(51mg,87%产率);1H NMR(300MHz,氯仿-d)δ8.37(d,J=3.2Hz,2H),5.58–5.35(m,1H),5.09(t,J=6.5Hz,1H),4.92(d,J=9.0Hz,1H),3.83(ddd,J=18.4,9.5,3.3Hz,1H),3.56–3.35(m,1H),3.25–2.76(m,2H),2.44–2.26(m,1H),2.16–1.95(m,1H),1.51(s,9H),1.44–1.23(m,7H),0.93–0.79(m,2H),0.75–0.48(m,2H).
中间体82
7-氨基-3-环丙基-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-
磺酰胺盐酸盐
向搅拌的中间体81(51mg,0.11mmol)的DCM(0.5mL)溶液中加入盐酸(4mol/L)的1,4-二氧六环溶液(0.11mL),并将反应在环境温度下搅拌2.5小时。真空浓缩反应得到HCl盐形式的标题化合物(44mg,定量);LCMS[M+H]+379,RT 1.01min(方法1)。
中间体83
3-环丙基-N-(2-氟-2-甲基-丙基)-7-[(4-甲氧基-3-硝基-2-吡啶基)氨基]-8,9-
二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将中间体36(0.42mmol)悬浮在CH3CN(4mL)中,用DIPEA(0.183mL,1.05mmol)处理并在室温下搅拌。然后用2-氯-4-甲氧基-3-硝基吡啶(80mg,0.42mmol)处理混合物,并将反应在室温下搅拌过夜。然后用DIPEA(0.18mL,1.05mmol)和2-氯-4-甲氧基-3-硝基吡啶(80mg,0.42mmol)处理反应,并加热至100℃持续24小时。将反应混合物冷却至室温,干法负载到硅胶上并通过柱色谱法纯化,使用乙酸乙酯/异己烷梯度,得到标题化合物(34mg(LCMS纯度81%),0.052mmol,12%);δH(400MHz,d4-甲醇)9.23(d,J=1.0Hz,1H),8.39(d,J=0.9Hz,1H),8.25(s,1H),8.19(d,J=5.9Hz,1H),6.62(d,J=5.9Hz,1H),6.04(t,J=7.6Hz,1H),3.97(d,J=2.8Hz,3H),3.69–3.54(m,1H),3.36(dd,J=15.0,6.9Hz,1H),3.06(dd,J=19.9,6.5Hz,1H),2.97(d,J=19.6Hz,2H),2.93–2.81(m,1H),2.42–2.29(m,1H),2.27–2.15(m,1H),1.27–1.21(m,4H),1.20–1.14(m,3H),1.15–1.05(m,2H).LCMS[M+H]+530,RT1.23min(方法1)。
中间体84
9-氨基-3-环丙基-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-
5-磺酰胺
将HCl的1,4-二氧六环溶液(4mol/L,24mL,96mmol)加入中间体62(2g,4.18mmol)中。然后加入MeOH(8mL,198mmol),并将所得溶液在环境温度下搅拌。1小时后,减压浓缩混合物得到黄色固体,然后将其溶解在MeOH(20mL)中并从SCX柱通过,首先用甲醇洗脱,然后用7N NH3的甲醇溶液洗脱。减压浓缩甲醇氨溶液,并将所得固体与乙醚一起研磨得到标题化合物,为白色固体(1.3g,82%产率);1H NMR(300MHz,DMSO-d6)δ9.52(s,1H),8.43(d,J=0.9Hz,1H),8.27(s,1H),5.44(d,J=7.4Hz,1H),3.17(s,1H),3.14–3.06(m,1H),3.02(s,1H),2.95(s,1H),2.34(dd,J=12.2,6.4Hz,3H),1.27(d,J=2.1Hz,3H),1.19(d,J=2.1Hz,4H),1.07(p,J=5.0Hz,6H).LCMS[M+H]+378,RT 0.95min(方法1)。
中间体85
3-环丙基-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹
啉-7-甲酸
将中间体56(145mg,0.33mmol)溶于THF(3mL)和水(2mL)中,并加入氢氧化锂一水合物(27mg,0.64mmol)。将反应混合物在室温下搅拌过夜,然后减压浓缩并将所得残余物用水和乙醚稀释。分配水层,酸化至pH 1并用EtOAc萃取。将有机层干燥并蒸发得到标题化合物,为白色固体(139mg,定量)。LCMS[M+H]+407,RT 0.77min(方法5)。
中间体86
3-氯-N-(2-氟-2-甲基-丙基)-7-肼基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺
酰胺
将中间体17(320mg,0.73mmol)和肼的THF溶液(1mol/L,15mL,15mmol)在70℃下加热搅拌20min。真空除去溶剂并将残余物负载到SCX柱上,用MeOH洗脱,接着用4N氨的MeOH溶液洗脱得到标题化合物(298mg,定量)。LCMS[M+H]+387,RT 1.40min(方法1)。
中间体87
7-(5-氨基吡唑-1-基)-3-氯-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并
[h]异喹啉-5-磺酰胺
将中间体86(190mg,0.49mmol)和3,3-二甲氧基丙腈(0.06mL,0.5mmol)的混合物溶于EtOH(6mL)中并加入HCl(0.2mL,2mmol;37质量%)。将反应混合物在密封管中在80℃下加热过夜。将挥发物蒸发,将所得残余物用DCM稀释并用水洗涤。将有机物干燥并蒸发得到固体,将其与己烷一起研磨并通过反相柱色谱法纯化(碱性条件)得到标题化合物(134mg,62%产率),为白色固体。LCMS[M+H]+438,RT 1.67min(方法4)。
中间体88
N-[2-[3-氯-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异
喹啉-7-基]吡唑-3-基]环丙烷甲酰胺
将中间体87(135mg,0.30mmol)溶于吡啶(5mL)中并加入环丙烷甲酰氯(0.030mL,0.32mmol),接着加入DMAP(5mg,0.040mmol)。将反应混合物在室温下搅拌过夜,然后用的DCM和饱和NaHCO3水溶液的混合物稀释。有机层用硫酸钠干燥并减压浓缩。将所得残余物通过柱色谱法纯化,用0-50%EtOAc/己烷梯度洗脱,接着用0-2%MeOH/DCM梯度洗脱得到标题化合物(105mg,67%产率);1H NMR(300MHz,氯仿-d)δ9.21(s,1H),8.53(s,1H),8.16(s,1H),7.46(s,1H),7.33(s,1H),6.17(s,1H),5.94(s,1H),5.10(s,1H),3.77(d,J=12.5Hz,1H),3.48–3.36(m,1H),3.13–2.84(m,3H),2.74(s,1H),1.30(dd,J=21.4,14.2Hz,6H),1.14(m,2H),1.01–0.81(m,3H).LCMS[M+H]+506,RT 1.96min(方法4)。
中间体89
7-(氰基氨基)-3-环丙基-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]
异喹啉-5-磺酰胺
将中间体36(140mg,0.37mmol)溶于THF(10mL)中并加入N,N-二异丙基乙胺(0.130mL,0.74mmol),接着加入溴化氰(51mg,0.48mmol)。在室温下搅拌30min后,将反应混合物用饱和NaHCO3水溶液洗涤[注:通过LCMS观察到部分分解]。由于怀疑不稳定,反应混合物无需进一步纯化即可用于下一步。LCMS[M+H]+403,RT 0.97min(方法1)。
中间体90
3-氯-N-(2-氟-2-甲基-丙基)-7-(3-吡啶基氧基)-8,9-二氢-7H-环戊二烯并[h]
异喹啉-5-磺酰胺
向中间体17(95mg,0.22mmol)的无水DMF(5mL)溶液中加入3-羟基吡啶(25mg,0.26mmol)和碳酸钠(28mg,0.26mmol),并将所得溶液在室温下搅拌。2小时后,加入3-羟基吡啶(25mg,0.26mmol)接着加入碳酸钠(28mg,0.26mmol)。再1小时后,真空浓缩反应混合物并通过柱色谱法纯化,用0-100%EtOAc/异己烷梯度洗脱得到标题化合物(25mg,26%产率)。LCMS[M+H]+450,RT 1.12分钟(方法1)。
中间体91
3-氯-N-(2-氟-2-甲基-丙基)-9-(3-吡啶基氧基)-8,9-二氢-7H-环戊二烯并[h]
异喹啉-5-磺酰胺
使用中间体16(95mg,0.22mmol)和相当化学计量的试剂,以与中间体90相同的方式合成。通过柱色谱法纯化,用0-100%EtOAc/异己烷梯度洗脱得到标题化合物(37mg,38%产率)。LCMS[M+H]+450,RT1.13分钟(方法1)。
中间体92
3-氯-N-(1,1-二氘-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰
胺
向中间体5(3.45g,11.4mmol)的二氯甲烷(25mL)溶液中加入1,1-二氘-2-甲基-丙-1-胺盐酸盐(1.34g,12.0mmol),接着加入三乙胺(6.4mL,46mmol)。30分钟后,将悬浮液用水(50mL)和二氯甲烷(20mL)稀释。水层用二氯甲烷(2x40mL)萃取。合并的有机物用盐水(50mL)洗涤,从疏水烧结漏斗(frit)通过并减压浓缩。通过快速色谱法纯化得到标题化合物,为膏状固体(3.15g,81%产率)。δH(300MHz,氯仿-d)9.15(d,J=0.9Hz,1H),8.49(d,J=0.8Hz,1H),8.38(s,1H),4.66(s,1H),3.44(t,J=7.6Hz,2H),3.19(t,J=7.5Hz,2H),2.39(app.p,J=7.7Hz,2H),1.68(hept,J=6.7,1H),0.83(d,J=6.7Hz,6H);LCMS[M+H]+341/343,RT2.40min(方法6)。
中间体93和94
7-溴-3-氯-N-(1,1-二氘-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5- 磺酰胺(93)
9-溴-3-氯-N-(1,1-二氘-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5- 磺酰胺(94)
向中间体92(3.15g,9.24mmol)的乙酸乙酯(200mL)溶液中加入2,2'-偶氮二(2-甲基丙腈)(152mg,0.92mmol)和N-溴代琥珀酰亚胺(从水中重结晶并干燥)(1.9g,11mmol)。在避光的情况下将混合物加热至90℃。1.5小时后,减压浓缩混合物得到标题化合物,为棕色固体,其以粗品用于下一步。LCMS[M+H]+419/421/423,RT 2.44min(方法6)。
中间体95和96
7-氨基-3-氯-N-(1,1-二氘-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉- 5-磺酰胺(95)
9-氨基-3-氯-N-(1,1-二氘-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉- 5-磺酰胺(96)
向中间体93的94的粗品混合物中加入四氢呋喃(200mL)。将氨气通过溶液20分钟,然后在密封的容器中将混合物加热至70℃持续16小时。减压浓缩混合物,得到标题化合物的混合物,为绿色/棕色固体,其作为粗品用于下一步。LCMS[M+H]+356/358,RT 1.80and1.87分钟(方法6).
中间体97和98
N-[3-氯-5-[(1,1-二氘-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h] 异喹啉-7-基]氨基甲酸叔丁酯(97)
N-[3-氯-5-[(1,1-二氘-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h] 异喹啉-9-基]氨基甲酸叔丁酯(98)
向中间体95和96的粗品混合物中加入二氯甲烷(150mL)、三乙胺(3.2mL,23mmol)和二碳酸二叔丁酯(3.0g,14mmol)。72小时后,将混合物用饱和氯化铵溶液(80mL)洗涤,通过疏水烧结漏斗,并通过快速色谱法纯化得到标题化合物,为膏状固体。
中间体97(1.24g,29%产率);δH(400MHz,氯仿-d)9.15(s,1H),8.51(s,1H),8.42(s,1H),5.47–5.35(m,1H),5.09–4.95(m,2H),3.55(ddd,J=17.2,9.2,3.3Hz,1H),3.33–3.22(m,1H),2.96–2.83(m,1H),2.17–2.03(m,1H),1.76–1.67(m,1H),1.52(s,9H),0.89–0.80(m,6H);LCMS[M+H]+456/458,RT 2.42min(方法6)。
中间体98(66%w/w纯度,2.0g,32%产率);δH(300MHz,氯仿-d)9.38(d,J=0.8Hz,1H),8.49(d,J=0.9Hz,1H),8.31(s,1H),5.90–5.79(m,1H),5.32(s,1H),5.03(d,J=9.6Hz,1H),3.33–3.20(m,1H),3.12–3.00(m,1H),2.84–2.67(m,1H),2.25–2.12(m,1H),1.74–1.66(m,1H),1.47(s,9H),0.85–0.80(m,6H);LCMS[M+H]+456,458,RT 2.47min(方法6)。
中间体99
3-甲氧基-4-(3-吡啶基氨基)环丁-3-烯-1,2-二酮
向3-氨基吡啶(500mg,5.26mmol)的DCM(20mL)溶液中加入3,4-二甲氧基-3-环丁烯-1,2-二酮(822mg,5.79mmol)和N,N-二异丙基乙胺(1020mg,7.89mmol)。将混合物在室温下搅拌过夜。将所得沉淀物过滤掉,并蒸发滤液。将残余物与5%MeOH/DCM一起研磨并过滤沉淀物,用DCM洗涤得到标题化合物,为黄色固体(382mg,36%产率)。LCMS[M+H]+205,RT0.57min(方法3)。
中间体100
4-(5-溴-3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基)-N-(环丙基甲基)-N-
[(2,4-二甲氧基苯基)甲基]-1,2,4-三唑-3-胺
将中间体137(480mg,0.83mmol)溶于干燥DMF(8mL)中。加入甲酸肼(149.5mg,2.49mmol)和二氯化汞(676mg,2.49mmol),并将反应搅拌5分钟。加入三乙胺(0.34mL,2.49mmol)并将反应加热至90℃,同时搅拌2小时,得到黑色悬浮液。一旦在室温下,用DCM(20mL)稀释反应并加入硅藻土,将混合物搅拌5分钟,然后通过硅藻土塞过滤,用DCM洗涤。真空浓缩滤液,将残余物溶于乙酸乙酯(50mL)中。将溶液用饱和NH4Cl(30mL)、水(30mL)和盐水(30mL)洗涤,干燥(硫酸钠)并真空浓缩。通过柱色谱法纯化,使用0-10%MeOH/DCM梯度,得到标题化合物(295mg,57%产率),为黑色固体。LCMS[M+H]+568/570,RT 2.03min(方法9)。
中间体101
3-环丙基-7-[3-[环丙基甲基-[(2,4-二甲氧基苯基)甲基]氨基]-1,2,4-三唑-4-
基]-N-(1,1-二氘-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
向实施例34(420mg,1.16mmol)在二氯甲烷(20mL)的悬浮液中加入1,1'-硫代羰基二咪唑(230mg,1.16mmol)。3小时后,以二氯甲烷(5mL)溶液形式加入N-(环丙基甲基)-1-(2,4-二甲氧基苯基)甲胺(280mg,1.26mmol)。90分钟后,用二氯甲烷(20mL)稀释混合物并依次用水(20mL)、10%氯化铵溶液(40mL)、水(40mL)和盐水(40mL)洗涤。减压浓缩后,将残余物溶于N,N-二甲基甲酰胺(15mL)中。加入甲酰肼(210mg,3.50mmol)和氯化汞(630mg,2.32mmol)。5分钟后,加入三乙胺(0.5mL,4mmol)并将混合物加热至80℃。2小时20分钟后,将混合物冷却,通过硅藻土过滤并减压浓缩。将残余物溶于乙酸乙酯(80mL),用10%氯化铵溶液(2x40mL)和盐水(50mL)洗涤,通过疏水烧结漏斗并减压浓缩。通过快速色谱法纯化得到标题化合物,为黄色玻璃状物(407mg,55%产率)。δH(300MHz,氯仿-d)9.27(d,J=1.0Hz,1H),8.31(d,J=1.0Hz,1H),7.73(s,1H),7.56(s,1H),7.14(d,J=8.9Hz,1H),6.47–6.39(m,2H),5.93(t,J=7.4Hz,1H),4.88(s,1H),4.40–4.23(m,2H),3.82(s,3H),3.72(s,3H),3.67–3.54(m,1H),3.43–3.27(m,1H),3.23–3.05(m,2H),2.85–2.66(m,1H),2.33–2.19(m,1H),2.18–2.07(m,1H),1.74–1.55(m,2H),1.21–1.02(m,4H),0.86–0.74(m,6H),0.60–0.44(m,2H),0.22–0.10(m,2H);LCMS[M+H]+633,RT 2.67min(方法6)。
中间体102
2-肟基-7-甲氧基-茚满-1-酮
在0℃下向7-甲氧基-1-茚满酮(4.5g,28mmol)在乙醚(80mL)的悬浮液中加入盐酸(4mol/L)的1,4-二氧六环(1.7mL)溶液,接着滴加10-20%亚硝酸乙酯的乙醇溶液(25mL,39.6mmol)。5分钟后,将混合物升温至环境温度。2小时后,加入10-20%亚硝酸乙酯的乙醇溶液(5mL,7.9mmol)。30分钟后,加入乙醚(50mL)并在烧结漏斗(sinter)上回收灰白色沉淀物。得到标题化合物,为灰白色固体(3.90g,72%产率)。δH(300MHz,DMSO-d6)12.40(s,1H),7.66(dd,J=8.3,7.5Hz,1H),7.10(dd,J=7.5,0.8Hz,1H),7.02(dd,J=8.4,0.8Hz,1H),3.88(s,3H),3.69(s,2H);LCMS[M+H]+192,RT 1.04min(方法6)。
中间体103
3-氯-8-甲氧基-异喹啉
在0℃下向中间体102(5.2g,27mmol)在磷酰氯(63mL,680mmol)的悬浮液中加入五氯化磷(6.5g,31mmol)。5分钟后,将氯化氢鼓泡通过混合物20分钟。3小时后,将混合物冷却至环境温度,用五氯化磷(2.2g,11mmol)处理并加热至80℃持续16小时。减压浓缩混合物。将残余物悬浮于水(60mL)中,加入氢氧化铵以调节pH至8-9。加入二氯甲烷(150mL)并通过硅藻土过滤悬浮液。使用疏水烧结漏斗分离滤液并减压浓缩有机物。残余物通过快速柱色谱法纯化得到标题化合物,为膏状固体(3.0g,58%产率)。δH(300MHz,DMSO-d6)9.29(t,J=0.9Hz,1H),7.98(d,J=0.8Hz,1H),7.82–7.69(m,1H),7.55–7.42(m,1H),7.19–7.00(m,1H),4.02(s,3H);LCMS[M+H]+194/196RT 1.19min(方法1)。
中间体104
5-溴-3-氯-8-甲氧基-异喹啉
在0℃下将中间体103(1g,5.16mmol)分批加入到硫酸(15mL)中。然后将混合物进一步冷却至-20℃,然后在5分钟内用N-溴代琥珀酰亚胺(920mg,5.17)分批处理。30分钟后,加入冰(30g)和二氯甲烷(50mL)。用氢氧化铵溶液将pH调至7-8。水层用二氯甲烷(2x50mL)萃取。将合并的有机物通过疏水烧结漏斗,浓缩并将残余物通过快速色谱法纯化得到标题化合物,为浅粉色固体(1.02g,70%产率)。δH(400MHz,DMSO-d6)9.33(d,J=0.8Hz,1H),8.09(d,J=8.4Hz,1H),7.87(d,J=0.7Hz,1H),7.11(d,J=8.4Hz,1H),4.03(s,3H);LCMS[M+H]+272/274/276,RT 1.41min(方法1)。
中间体105
3-氯-7-[3-[环丙基甲基-[(2,4-二甲氧基苯基)甲基]氨基]-1,2,4-三唑-4-基]-
N-(3-氟环丁基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
在密封管中装入中间体100(75mg,0.013mmol)、焦亚硫酸钾(58mg,0.26mmol)、TBAB(46.7mg,0.14mmol)、甲酸钠(19.7mg,0.29mmol)、Pd(OAc)2(1.48mg,0.007mmol)、三苯基膦(5.18mg,0.02mmol)和1,10-菲咯啉(3.56mg,0.02mmol)。加入DMSO(1.0mL)并将悬浮液脱气并置于氮气气氛下。将管密封并加热至70℃持续3小时。一旦在室温下,加入3-氟环丁烷-1-胺盐酸盐(33.1mg,0.26mmol)和三乙胺(36.6μL,0.26mmol)在THF(1.5mL)中的混合物并将反应冷却至0℃。然后滴加NBS(46.9mg,0.26mmol)的THF(2mL)溶液。然后将反应混合物搅拌1小时,同时将反应升温至室温。混合物用乙酸乙酯(20mL)和水(15mL)稀释。有机层用水(15mL)和盐水(10mL)洗涤,干燥(硫酸镁)并减压浓缩。经柱色谱纯化得到标题化合物(65mg,38%产率),为浅黄色胶状物。LCMS[M+H]+641,RT 3.06min(方法8)。
中间体106
2-[(5-溴-3-氯-8-异喹啉基)氧基]乙酸甲酯
向-40℃的中间体104(200mg,0.55mmol)的二氯甲烷(5mL)溶液中滴加三溴化硼的二氯甲烷溶液(1mol/L,2.2mL,2.2mmol)。将混合物升温至环境温度。18小时后,加入三溴化硼的二氯甲烷溶液(1mol/L,0.5mL,0.5mmol)。再过24小时后,在0℃下将甲醇(3mL)加入溶液中。减压浓缩混合物得到黄色固体,将其溶解于N,N-二甲基甲酰胺(4mL)中。加入碳酸钾(230mg,1.74mmol),接着加入溴乙酸甲基(75μL,0.77mmol)。20小时后,用乙酸乙酯(20mL)和水(20mL)稀释混合物。有机物用盐水洗涤,通过疏水烧结漏斗并减压浓缩。残余物通过快速柱色谱法纯化得到白色固体(220mg,定量)。δH(400MHz,DMSO-d6)9.41(d,J=0.8Hz,1H),8.10(d,J=8.5Hz,1H),7.93(d,J=0.7Hz,1H),7.12(d,J=8.5Hz,1H),5.15(s,2H),3.74(s,3H);LCMS[M+H]+330/332/334,RT 1.30min(方法1)。
中间体107
2-[(5-溴-3-氯-8-异喹啉基)氧基]乙酸
向中间体106(580mg,1.54mmol)的四氢呋喃(10mL)悬浮液中加入氢氧化锂(120mg,5.010mmol),接着加入水(1mL)。4小时后,使用2M HCl将混合物酸化至pH 2-3。用乙酸乙酯萃取混合物。将有机物减压浓缩得到标题化合物粗品,为白色固体(600mg,定量产率)。LCMS[M+H]+316/318/320,RT 0.85min(方法1)。
中间体108和109
(7R*)-3-环丙基-7-[3-[环丙基甲基-[(2,4-二甲氧基苯基)甲基]氨基]-1,2,4- 三唑-4-基]-N-(2-氟-2-甲基-丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S](108)
N-(环丙基甲基)-N-[(2,4-二甲氧基苯基)甲基]-N'-[(7R*)-3-环丙基-5-[(2- 氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]咪唑-1-甲脒[*或S](109)
根据通用程序1制备标题化合物,使用中间体57(60mg(50%纯度),0.047mmol)。使用碱性反相柱色谱法纯化产物得到:
中间体108(7mg,23%产率);1H NMR(300MHz,氯仿-d)δ9.24(d,J=0.9Hz,1H),8.28(d,J=1.0Hz,1H),7.68(s,1H),7.55(s,1H),7.16–7.06(m,1H),6.46–6.39(m,2H),5.95–5.85(m,1H),4.37–4.20(m,2H),3.79(s,3H),3.70(s,3H),3.66–3.53(m,1H),3.42–3.26(m,1H),3.21–2.93(m,5H),2.82–2.67(m,1H),2.35–2.21(m,1H),2.19–2.02(m,1H),1.28(dd,J=21.4,12.7Hz,7H),1.19–0.95(m,4H),0.56–0.41(m,2H),0.22–0.05(m,2H).
中间体109(12mg,38%产率);1H NMR(300MHz,氯仿-d)δ9.14(d,J=0.9Hz,1H),8.20(d,J=0.9Hz,1H),8.05(s,1H),7.64(s,1H),7.16(d,J=1.1Hz,1H),7.12–7.01(m,2H),6.49–6.37(m,2H),4.57–4.23(m,2H),3.89–3.69(m,7H),3.58–3.41(m,1H),3.19–3.02(m,1H),3.02–2.84(m,3H),2.55–2.36(m,1H),2.27–2.07(m,2H),1.24(dd,J=21.5,7.2Hz,6H),1.16–0.90(m,5H),0.59–0.35(m,2H),0.21–-0.04(m,2H).
中间体110
5-溴-7-氯-2,3-二氢呋喃并[3,2-h]异喹啉-3-醇
向中间体107(450mg,1.35mmol)的1,2-二氯乙烷(4mL)悬浮液中加入二氯亚砜(8mL)。将混合物加热至60℃持续3小时然后减压浓缩。将1,2-二氯乙烷(9mL)加入残余物中并冷却至0℃。用氯化铝(660mg,4.95mmol)处理悬浮液。1.5小时后,加入氯化铝(50mg,0.37mmol)并将混合物加热至45℃。15分钟后,在冰/水浴中冷却混合物,用二氯甲烷(50mL)稀释并用冰(10g)淬灭。加入饱和的罗谢尔盐(Rochelle’s salt)溶液(20mL)和水(20mL)。使用疏水烧结漏斗分离并减压浓缩有机物,得到米黄色固体(406mg)。加入甲醇(8mL)和二氯甲烷(8mL)并将悬浮液冷却至-20℃。加入硼氢化钠(50mg,1.59mmol)。30分钟后,将混合物升温至环境温度并用水(10mL)淬灭反应。混合物用二氯甲烷(20mL)稀释,水层用乙酸乙酯(2x10mL)萃取。将合并的有机物减压浓缩并通过快速色谱法纯化得到标题化合物,为灰白色固体(189mg,44%产率)。δH(300MHz,DMSO-d6)9.23(d,J=0.8Hz,1H),8.16(s,1H),7.94(d,J=0.8Hz,1H),5.91(d,J=5.9Hz,1H),5.55–5.41(m,1H),4.86(dd,J=10.4,7.0Hz,1H),4.58(dd,J=10.4,3.0Hz,1H);LCMS[M+H]+300/302/304,RT 1.16min(方法1)。
中间体111
(5-溴-7-氯-2,3-二氢呋喃并[3,2-h]异喹啉-3-基)氧基-叔丁基-二甲基-硅烷
向中间体110(189mg,0.6mmol)的N,N-二甲基甲酰胺(4mL)溶液中加入咪唑(82mg,1.2mmol)和叔丁基二甲基氯硅烷(126mg,0.84),并将混合物在环境温度下搅拌18小时。加入咪唑(50mg,0.74mmol)和叔丁基二甲基氯硅烷(50mg,0.33)。再1小时后,用乙酸乙酯(20mL)和水(20mL)稀释混合物。有机物用盐水洗涤,然后通过疏水烧结漏斗并减压浓缩。残余物通过快速柱色谱法纯化得到标题化合物,为白色固体(250mg,97%产率)。δH(300MHz,DMSO-d6)9.24(d,J=0.8Hz,1H),8.07(d,J=0.4Hz,1H),7.95(d,J=0.8Hz,1H),5.70(dd,J=6.7,2.6Hz,1H),4.90(dd,J=10.5,6.7Hz,1H),4.59(dd,J=10.5,2.6Hz,1H),0.87(s,9H),0.17(s,6H);LCMS[M+H]+414/416/418,RT 1.77min(方法1)。
中间体112
(5-苄硫基-7-氯-2,3-二氢呋喃并[3,2-h]异喹啉-3-基)氧基-叔丁基-二甲基-硅
烷
向氮气吹扫的中间体111(250mg,0.58mmol)、4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽(42mg,0.07mmol)、三(二亚苄基丙酮)二钯(0)(32mg,0.035mmol)和N,N-二异丙基乙胺(0.24mL,1.4mmol)在1,4-二氧六环(3mL)的溶液中加入苄硫醇(103μL,0.87mmol)。将混合物加热至85℃持续3.5小时,冷却并通过硅藻土过滤,用乙酸乙酯洗涤然后减压浓缩。通过快速色谱法纯化得到期望化合物,为橙色油状物(305mg,79%产率)。LCMS[M+H]+458/460,RT 4.12min(方法6)。
中间体113
3-环丙基-7-[3-[环丙基甲基-[(2,4-二甲氧基苯基)甲基]氨基]-1,2,4-三唑-4-
基]-N-(3-氟环丁基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将甲苯(5mL)和水(0.075mL)加入中间体105(65mg,0.101mmol)、环丙基硼酸(21.7mg,0.25mmol)、Pd(OAc)2(1.1mg,5.0μmol)、P(Cy)3.HBF4(5.6mg,15.2μmol)和K3PO4(53.8mg,0.25mmol)的混合物中。双相溶液在120℃下加热5小时。然后将反应混合物用DCM(20mL)稀释,干燥(MgSO4)并通过硅藻土过滤(用DCM洗涤)。减压浓缩滤液并通过柱色谱法纯化,用0%至10%MeOH/DCM梯度洗脱得到标题化合物(46mg,33%产率),为浅黄色胶状物.LCMS[M+H]+647,RT3.15min(方法8)。
中间体114
3-[叔丁基(二甲基)甲硅烷基]氧基-7-氯-N-(2-氟-2-甲基-丙基)-2,3-二氢呋喃
并[3,2-h]异喹啉-5-磺酰胺
在-20℃下向中间体112(305mg,0.46mmol)在乙腈(5mL)、乙酸(30μL,0.52mmol)、水(60μL,3.3mmol)和二氯甲烷(2mL)的混合物中的溶液中分批加入1,3-二氯-5,5-二甲基乙内酰脲(181mg,0.92mmol)。35分钟后,加入1,3-二氯-5,5-二甲基乙内酰脲(25mg,0.13mmol)。再过15分钟后,加入氟异丁胺盐酸盐(120mg,0.94)在N,N-二异丙基乙胺(0.4mL,2mmol)、乙腈(1mL)和二氯甲烷(0.2mL)中的混合物。20分钟后,用水(10mL)和二氯甲烷(20mL)稀释混合物。使用疏水烧结漏斗分离有机物并减压浓缩得到油状物。向残余物中加入N,N-二甲基甲酰胺(3mL)、咪唑(63mg,0.91mmol)和叔丁基二甲基氯硅烷(97mg,0.64)。2小时后,用乙酸乙酯(20mL)和水(10mL)稀释混合物。有机物用盐水洗涤,通过疏水烧结漏斗并减压浓缩。通过快速色谱法纯化得到标题化合物,为白色胶状物(134mg,57%产率)。LCMS[M+H]+489/491,RT3.14min(方法6)。
中间体115
5-溴-3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉
在0℃下将中间体4(1.0g,0.98mmol)分批加入硫酸(4.09mL)和DCM(50mL)的混合物中。在-10℃下冷却反应混合物,分批加入NBS(961mg,5.4mmol)。将反应混合物在-10℃下搅拌2小时。加入NBS(0.2当量)并将反应将混合物在室温下搅拌1小时。反应混合物用冰水(50mL)稀释并用浓氢氧化铵将pH调至8-10。用DCM(2×50mL)萃取所得溶液,将合并的有机层干燥(硫酸钠)并减压浓缩。残余物通过柱色谱法纯化,用0%至20%EtOAc/庚烷梯度洗脱得到标题化合物(1.26g,75%产率),为灰白色固体。LCMS[M+H]+282/284,RT 2.13min(方法9)。
中间体116
1-[3-环丙基-5-[(2-氟-2-甲基-丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]
异喹啉-7-基]-3-(2,5-二甲基吡唑-3-基)硫脲
根据通用程序4,用中间体36(378mg,1.00mmol)、5-异硫氰酸基-1,3-二甲基-1H-吡唑(250mg,1.6mmol)、N,N-二异丙基乙胺(0.26mL,1.5mmol)和二氯甲烷(40mL)制备标题化合物。通过柱色谱法纯化,使用0–100%乙酸乙酯/异己烷梯度,接着1–30%甲醇/乙酸乙酯梯度,得到标题化合物(416mg,78%产率)。δH(300MHz,d6-DMSO)9.34(s,1H),9.29(s,1H),8.52–8.31(m,2H),8.23(s,1H),6.17(m,1H),5.93(s,1H),3.54(m,4H),3.25(m,2H),3.01–2.82(m,2H),2.80–2.63(m,1H),2.29(q,J=6.2Hz,1H),2.07(m,4H),1.26(d,J=7.3Hz,3H),1.19(d,J=7.3Hz,3H),1.06(m,4H).LCMS[M+H]+531,RT 1.17min(方法1)。
中间体117
1-[3-环丙基-5-(异丁基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]-
3-(2,5-二甲基吡唑-3-基)硫脲
根据通用程序4,用实施例50(100mg,0.28mmol)、5-异硫氰酸基-1,3-二甲基-1H-吡唑(0.05mL,0.4mmol)、N,N-二异丙基乙胺(0.07mL,0.4mmol)和二氯甲烷(10mL)制备标题化合物。通过柱色谱法纯化,使用0–100%乙酸乙酯/异己烷梯度,接着1-30%甲醇/乙酸乙酯梯度,得到标题化合物(147mg,100%产率)。δH(300MHz,d6-DMSO)9.36(s,1H),9.28(d,J=1.0Hz,1H),8.43(d,J=8.2Hz,1H),8.34(d,J=1.0Hz,1H),8.23(s,1H),8.07(t,J=5.9Hz,1H),6.18(m,1H),5.92(s,1H),3.55(s,3H),3.52–3.42(m,1H),3.28–3.15(m,1H),2.70(m,1H),2.55(m,2H),2.29(p,J=6.5Hz,1H),2.08(m,4H),1.59(dq,J=13.2,6.7Hz,1H),1.05(m,4H),0.76(dd,J=6.6,1.2Hz,6H).LCMS[M+H]+513,RT 1.19min(方法1)。
中间体118
1-[3-环丙基-5-(异丁基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]-
3-(5-甲基-3-吡啶基)硫脲
根据通用程序4,用实施例50(100mg,0.28mmol)、3-异硫氰酸基-5-甲基-吡啶(63mg,0.42mmol)、N,N-二异丙基乙胺(0.07mL,0.4mmol)和二氯甲烷(10mL)制备标题化合物。通过柱色谱法纯化,使用0–100%乙酸乙酯/异己烷梯度,接着1–20%甲醇/乙酸乙酯梯度,得到标题化合物(140mg,99%产率)。δH(300MHz,d-氯仿)9.12(d,J=1.0Hz,1H),8.92(s,1H),8.35(s,1H),8.31(d,J=2.3Hz,1H),8.18(d,J=0.9Hz,1H),8.15–8.01(m,2H),7.33(d,J=8.1Hz,1H),6.23(q,J=7.7Hz,1H),5.56(m,1H),3.50–3.36(m,1H),3.20(dt,J=16.8,8.2Hz,1H),3.06–2.90(m,1H),2.81(m,1H),2.71–2.62(m,1H),2.31(s,3H),2.20(td,J=9.0,8.4,4.0Hz,1H),2.15–2.05(m,1H),1.67(dq,J=13.4,6.7Hz,1H),1.17–1.03(m,4H),0.79(m,6H).LCMS[M+H]+510,RT 1.35min(方法1)。
中间体119
3-环丙基-7-[3-[环丙基甲基-[(2,4-二甲氧基苯基)甲基]氨基]-1,2,4-三唑-4-
基]-N-(3,3-二氟环丁基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将中间体131(51mg,0.077mmol)、环丙基硼酸(16.6mg,0.19mmol)、Pd(OAc)2(0.87mg,3.8μmol)、P(Cy)3.HBF4(4.27mg,11.6μmol)和K3PO4(41.0mg,0.19mmol)在甲苯(5mL)和水(0.075mL)的两相溶液中的混合物在120℃下加热5小时。反应混合物用DCM(20mL)稀释,干燥(MgSO4)并通过硅藻土过滤(用DCM洗涤)。减压浓缩滤液并通过柱色谱法纯化,用0%至10%MeOH/DCM梯度洗脱得到标题化合物(35mg,55%产率),为浅黄色胶状物。LCMS[M+H]+665,RT 1.93min(方法9)。
中间体120
3-环丙基-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将中间体6(300mg,0.886mmol)、环丙基硼酸(240mg,2.66mmol)和碳酸铯(729mg,2.21mmol)在1,4-二氧六环(5mL)中的混合物脱气并置于N2气氛下。加入氯(η2-P,C-三(2,4-二叔丁基苯基)亚磷酸酯)(三环己基膦)钯(II)(95mg,0.0886mmol)并将反应混合物在微波中在120℃下加热90min。蒸发溶剂,并将残余物分配于DCM和水之间。将有机相用盐水洗涤,通过相分离器并蒸发。粗物质通过快速色谱法纯化,用20-70%EtOAc/己烷梯度洗脱,得到标题产物,为灰白色固体(214mg,70%产率)。LCMS[M+H]+345,RT 2.60min(方法3)。
中间体121和122
9-溴-3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉(121)
7-溴-3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉(122)
将中间体4(2.5g,12.2mmol)溶于EtOAc(150mL)中并加入NBS(2.4g,13.5mmol)。将反应混合物用光照射1小时。除去溶剂,标题产物混合物粗品(4.9g)无需进一步纯化即可用于下一阶段。LCMS[M+H,-Br,+OH]+220,RT 2.04和2.18分钟(方法8)
中间体123和124
3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-胺(123)
3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-胺(124)
在压力烧瓶中,将中间体121和122(3.46g,12.25mmol)的混合物溶于THF(160mL)中。将氨气鼓泡通过5min,然后将反应混合物在60℃下搅拌3小时然后在室温下搅拌16小时。将氨气鼓泡通过~5min并将反应混合物在60℃下加热5小时然后在室温下16小时。真空除去溶剂得到标题化合物混合物(3.4g),为黑色胶状物。该物质无需进一步纯化即可用于下一阶段。LCMS[M+H]+219,RT 1.17和1.29分钟(方法8)。
中间体125和126
N-(3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基)氨基甲酸叔丁酯(125)
N-(3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基)氨基甲酸叔丁酯(126)
向搅拌的中间体123和124(2.6g,11.8mmol)在DCM(100mL)的混合物中加入二碳酸二叔丁酯(2.8g,13.0mmol),接着加入三乙胺(3.31mL,23.7mmol)。将反应混合物在室温下搅拌16小时。用DCM(100mL)稀释反应混合物,并用水(100mL)洗涤。有机层用硫酸钠干燥并真空浓缩。通过柱色谱法纯化,用0-50%乙酸乙酯/庚烷洗脱得到标题化合物:
中间体125(940mg,24%产率);δH(500MHz,氯仿-d)9.27(s,1H),7.73(s,1H),7.67(d,J=8.4Hz,1H),7.59(d,J=8.4Hz,1H),5.86-5.74(m,1H),4.85(d,J=8.0Hz,1H),3.27-3.14(m,1H),3.06-2.95(m,1H),2.78-2.65(m,1H),2.19-2.09(m,1H),1.48(s,9H).LCMS[M+H]+319,RT 3.03min(方法8)。
中间体126(1.28g,32%产率);δH(500MHz,氯仿-d)9.06(s,1H),7.73(s,1H),7.70(d,J=8.4Hz,1H),7.64(d,J=8.5Hz,1H),5.44-5.33(m,1H),4.88-4.75(m,1H),3.51-3.39(m,1H),3.26-3.14(m,1H),2.87-2.76(m,1H),2.05-1.93(m,1H),1.50(s,9H).LCMS[M+H]+319,RT 3.03min(方法8)。
中间体127
3-氯-5-碘-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-胺
在0℃下将中间体126(1.0g,3.13mmol)分批加入硫酸(2.6mL)的DCM(50mL)溶液中。在-10℃下冷却反应混合物,分批加入NIS(847mg,3.76mmol)。将反应混合物在-10℃下搅拌2小时,然后在室温下搅拌16小时。然后,在32小时期间内加入2批NIS(每批2当量)。反应混合物用冰水(750mL)稀释,并用浓氢氧化铵将pH调至8-10。所得溶液用DCM(2×70mL)萃取,合并的有机层用硫代硫酸钠洗涤,干燥(硫酸钠)并减压浓缩。标题化合物粗品(650mg)无需进一步纯化即可用于下一阶段。LCMS[M+H]+345,RT 0.93min(方法17)。
中间体128
N-(环丙基甲基)-1-(2,4-二甲氧基苯基)甲胺
将2,4-二甲氧基苯甲醛(2.0g,12.04mmol)和MgSO4(400mg)加入1-环丙基甲胺(0.85g,12.04mmol)的乙醇(10mL)溶液中。将反应混合物在78℃下搅拌4h。然后将反应混合物冷却至室温并将硼氢化钠(0.50g,13.24mmol)加入反应混合物中。将反应混合物在室温下搅拌过夜,然后真空浓缩。将残余物溶于EtOAc(50mL)中,用饱和NH4Cl水溶液、水和盐水(各30mL)洗涤。有机层用MgSO4干燥并真空浓缩。通过快速柱色谱法纯化,用0%至20%MeOH/DCM梯度洗脱得到标题化合物(2.1g,72%产率),为无色油状物。LCMS[M+H]+222,RT0.83min(方法17)。
中间体129
3-(3-氯-5-碘-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基)-1-(环丙基甲基)-1-
[(2,4-二甲氧基苯基)甲基]硫脲
在0℃下将中间体127(650mg,1.64mmol,87%纯度)和三乙胺(0.68mL,4.9mmol)在DCM(15mL)的混合物滴加到搅拌着的硫代氯甲酸苯酯(0.25mL,1.8mmol)的DCM(15mL)溶液中。将反应在0℃下搅拌30分钟。然后在0℃下加入中间体128(626mg,2.83mmol)的DCM(15mL)溶液。将反应混合物升温至室温并搅拌20小时。反应用DCM(30mL)稀释并用水(30mL)接着用饱和NaHCO3水溶液(30mL)洗涤。有机层用硫酸钠干燥并真空浓缩。通过柱色谱法纯化,使用0-50%乙酸乙酯/庚烷梯度得到标题化合物(305mg,29%产率),为浅棕色固体。LCMS[M+H]+608,RT 2.26min(方法9)。
中间体130
4-(3-氯-5-碘-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基)-N-(环丙基甲基)-N-
[(2,4-二甲氧基苯基)甲基]-1,2,4-三唑-3-胺
将中间体129(305mg,0.48mmol)溶于干燥DMF(7mL)中。加入甲酸肼(87.6mg,1.46mmol)和二氯化汞(396.3mg,1.46mmol)并将反应搅拌5分钟。加入三乙胺(0.20mL,1.46mmol)并将反应加热至90℃同时搅拌4小时,得到黑色悬浮液。一旦在室温下,反应用DCM(20mL)稀释并加入硅藻土,将混合物搅拌5分钟,然后通过硅藻土塞过滤,用DCM洗涤。真空浓缩滤液,并将残余物溶于中乙酸乙酯(50mL)中。有机层用饱和NH4Cl(30mL)、水(30mL)和盐水(30mL)洗涤,然后干燥(硫酸钠)并真空浓缩。通过柱色谱法纯化,使用0-10%MeOH/DCM梯度,得到标题化合物(175mg,54%产率),为灰色固体。LCMS[M+H]+616,RT 2.05min(方法9)。
中间体131
3-氯-7-[3-[环丙基甲基-[(2,4-二甲氧基苯基)甲基]氨基]-1,2,4-三唑-4-基]-
N-(3,3-二氟环丁基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
在密封管中装入中间体130(90mg,0.14mmol)、焦亚硫酸钾(64.9mg,0.29mmol)、TBAB(51.8mg,0.16mmol)、甲酸钠(21.8mg,0.32mmol)、Pd(OAc)2(1.6mg,0.007mmol)、三苯基膦(5.7mg,0.022mmol)和1,10-菲咯啉(3.9mg,0.022mmol)。将混合物悬浮在DMSO(1.0mL)中,脱气并置于氮气气氛下。将管密封并加热至70℃持续2小时。一旦在室温下,加入3,3-二氟环丁烷-1-胺盐酸盐(41.9mg,0.29mmol)和三乙胺(40.5mL,0.29mmol)的THF(1.5mL)溶液并将反应冷却至0℃。滴加NBS(52.0mg,0.29mmol)的THF(2mL)的溶液,并将反应升温至室温。1小时后,用乙酸乙酯(20mL)和水(15mL)稀释混合物。有机层用水(15mL)和盐水(10mL)洗涤,干燥(硫酸镁)并减压浓缩。通过快速柱色谱法纯化得到标题化合物(51mg,50%)为薄膜状物。LCMS[M+H]+659,RT 1.94min(方法9)。
中间体132和133
5,9-二溴-3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉(132)
5,7-二溴-3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉(133)
将中间体115(200mg,0.70mmol)溶于EtOAc(13mL)中,加入NBS(132.2mg,0.74mmol)接着加入偶氮二异丁腈(11.6mg,0.07mmol)。将反应混合物用光照射1小时。由于怀疑产物不稳定,除去溶剂,且标题化合物粗品(310mg)无需进一步纯化即用于下一阶段。LCMS[M+H]+362,RT 3.18min(方法8)。
中间体134和135
5-溴-3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-胺(134)
5-溴-3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-胺(135)
在密封管中将中间体132和133(1.61g,4.4mmol)的混合物溶于THF(95mL)中。将氨气鼓泡通过5min并将反应混合物在60℃下搅拌16小时。除去溶剂,标题化合物粗品(1.6g)无需进一步纯化即用于下一阶段。LCMS[M+H]+297/299,RT 1.87and 2.00min(方法8)
中间体136和137
3-(5-溴-3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基)-1-(环丙基甲基)-1- [(2,4-二甲氧基苯基)甲基]硫脲(136)
3-(5-溴-3-氯-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基)-1-(环丙基甲基)-1- [(2,4-二甲氧基苯基)甲基]硫脲(137)
在0℃下将中间体134和135(788mg,2.64mmol)和三乙胺(1.10mL,7.94mmol)在DCM(20mL)中的混合物滴加到搅拌的硫代氯甲酸苯酯(0.404mL,2.91mmol)的DCM(20mL)溶液中。将反应在0℃下搅拌30分钟。然后加入中间体128(879mg,3.92mmol)的DCM(20mL)溶液并将反应混合物升温至室温。20小时后,用DCM(30mL)稀释反应并用水(30mL)和饱和NaHCO3水溶液(30mL)洗涤,用硫酸钠干燥并真空浓缩。通过柱色谱法纯化,使用0-50%乙酸乙酯/庚烷梯度得到标题化合物:
中间体136(770mg,52%产率);LCMS[M+H]+560/562,RT 3.85min(方法8)。
中间体137(480mg,31%产率);LCMS[M+H]+560/562,RT 3.90min(方法8)。
实施例
实施例1
3-环丙基-N-(2-氟-2-甲基丙基)-7-(7-甲氧基咪唑并[4,5-b]吡啶-3-基)-8,9-
二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将中间体83(34mg 0.052mmol)溶于乙酸(0.5mL)中并用铁粉(25mg,0.44mmol)处理。将所得混合物在室温下搅拌1小时。然后加入乙酸(0.5mL)、MeOH(1mL)和第二批铁粉(25mg,0.44mol)并将混合物在80℃下加热8小时。加入第三批铁粉(35mg,0.63mmol)并将反应在80℃下加热3小时。将反应用水(20mL)和EtOAc(30mL)稀释,分离各层,水层用EtOAc萃取。将合并的有机层用饱和水溶液NaHCO3洗涤,干燥(Na2SO4),过滤并真空浓缩。通过柱色谱法纯化,用乙酸乙酯/异己烷梯度得到标题化合物(4mg);δH(300MHz,d4-甲醇)9.33(d,J=0.9Hz,1H),8.42(d,J=0.9Hz,1H),8.24(d,J=5.7Hz,1H),8.13(s,1H),7.98(s,1H),6.93(d,J=5.7Hz,1H),6.55–6.46(m,1H),4.10(s,3H),3.93–3.79(m,1H),3.64–3.49(m,1H),3.19–3.01(m,1H),2.87(dd,J=19.8,10.3Hz,2H),2.79–2.67(m,1H),2.39–2.28(m,1H),1.17–1.04(m,10H).LCMS[M+H]+510,RT 2.22min(方法4)。
实施例2
3-环丙基-N-异丁基-9-[[4-(1-甲基苯并三唑-4-基)-1,2,4-三唑-3-基]氨基]-
8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
通用程序1使用中间体40(71mg)得到标题化合物(13mg,19%产率)。1H NMR(300MHz,甲醇-d4)δ9.38(d,J=0.9Hz,1H),8.42(s,1H),8.30(d,J=1.0Hz,1H),8.22(s,1H),7.76(dd,J=8.4,0.9Hz,1H),7.66–7.50(m,1H),7.46(dd,J=7.4,0.8Hz,1H),5.99(dd,J=7.9,3.6Hz,1H),4.30(s,3H),3.29–3.21(m,1H),3.17–3.00(m,1H),2.95–2.77(m,1H),2.63(dd,J=6.9,2.7Hz,2H),2.52–2.35(m,1H),2.32–2.15(m,1H),1.63(dt,J=13.5,6.8Hz,1H),1.11–1.01(m,4H),0.78(dd,J=6.7,2.6Hz,6H).LCMS[M+H]+558,RT 1.89min(方法3)。
实施例3和4
3-环丙基-N-异丁基-9-[[4-(2-甲基吡唑-3-基)-1,2,4-三唑-3-基]氨基]-8,9- 二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(3)
3-环丙基-N-异丁基-9-[3-[(2-甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基]-8,9- 二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(4)
通用程序1使用中间体41(30mg)得到标题化合物:
实施例3(5mg,16%产率);1H NMR(300MHz,甲醇-d4)δ9.33(d,J=0.9Hz,1H),8.55(s,1H),8.38(d,J=1.0Hz,1H),8.27(s,1H),8.22(s,1H),7.49(d,J=2.1Hz,1H),6.45(d,J=2.1Hz,1H),5.96(dd,J=8.2,3.9Hz,1H),3.61(s,3H),3.29–3.21(m,1H),3.17–3.01(m,1H),2.93–2.75(m,1H),2.62(d,J=6.9Hz,2H),2.34–2.17(m,2H),1.61(dq,J=13.4,6.8Hz,1H),1.08(d,J=7.0Hz,4H),0.79(dd,J=6.7,1.1Hz,6H).LCMS[M+H]+507.2RT1.76min(方法3)。
实施例4(7.5mg,25%产率);1H NMR(300MHz,甲醇-d4)δ9.27–8.68(m,1H),8.43(s,1H),8.39(s,1H),7.77–7.57(m,1H),7.56–7.28(m,1H),6.67–6.32(m,1H),6.30–5.82(m,1H),3.80–3.67(m,3H),3.61–3.43(m,1H),3.29–3.21(m,1H),3.06–2.89(m,1H),2.70(d,J=6.9Hz,2H),2.52–2.37(m,1H),2.34–2.21(m,1H),1.64(dp,J=13.4,6.7Hz,1H),1.13–0.99(m,4H),0.79(d,J=6.7Hz,6H).LCMS[M+H]+507.2RT 1.74min(方法3)。
实施例5和6
3-环丙基-9-[[4-(5-氟-3-吡啶基)-1,2,4-三唑-3-基]氨基]-N-异丁基-8,9-二 氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(5)
3-环丙基-9-[3-[(5-氟-3-吡啶基)氨基]-1,2,4-三唑-4-基]-N-异丁基-8,9-二 氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(6)
通用程序1使用中间体42(15mg)得到标题化合物:
实施例5(5mg,33%产率)。1H NMR(300MHz,甲醇-d4)δ9.40(d,J=0.9Hz,1H),8.56–8.49(m,2H),8.38(d,J=1.0Hz,1H),8.33(s,1H),8.26(s,1H),8.07(s,1H),7.85(dt,J=8.9,2.3Hz,1H),5.96(dd,J=8.1,3.9Hz,1H),3.29–3.22(m,1H),3.19–3.03(m,1H),2.94–2.78(m,1H),2.62(d,J=6.9Hz,2H),2.35–2.19(m,2H),1.62(dp,J=13.7,6.8Hz,1H),1.14–1.04(m,4H),0.78(dd,J=6.7,1.0Hz,6H).LCMS[M+H]+522,RT 1.86min(方法3)
实施例6(4mg,27%产率)。1H NMR(300MHz,甲醇-d4)δ8.79(d,J=1.0Hz,1H),8.48–8.44(m,1H),8.43(d,J=0.9Hz,1H),8.40(s,1H),8.06(s,2H),7.92(dt,J=11.1,2.4Hz,1H),7.82(s,1H),6.52(dd,J=8.5,3.4Hz,1H),3.60–3.41(m,1H),3.28–3.23(m,1H),3.10–2.96(m,1H),2.71(d,J=6.9Hz,2H),2.53–2.36(m,1H),2.36–2.19(m,1H),1.73–1.57(m,1H),1.12–0.96(m,4H),0.80(dd,J=6.7,1.0Hz,6H).LCMS[M+H]+522,RT 1.88min(方法3)
实施例7
3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹
啉-7-甲酸
将中间体56(3mg,7.1μmol)溶于四氢呋喃(1.0mL)和水(0.5mL)的混合物中。加入氢氧化锂(5mg,21.4μmol)并将反应在环境温度下搅拌1小时。浓缩反应以除去有机溶剂并用Et2O(2mL)稀释。将乙醚层分配并弃去,使用HCl水溶液(0.5M)将水层的pH调至1。用EtOAc(2mL)萃取酸性水层。真空除去有机溶剂得到标题化合物(0.8mg,30%产率)。1H(400MHz,甲醇-d4)δ9.22(d,J=0.9Hz,1H),8.44(s,1H),8.42(d,J=0.9Hz,1H),4.44–4.17(m,1H),3.68–3.36(m,2H),3.03(d,J=19.2Hz,2H),2.64(q,J=7.5Hz,2H),2.33(tt,J=8.1,5.2Hz,1H),1.23(dd,J=21.1,7.4Hz,6H),1.12(tt,J=8.2,2.5Hz,4H).
实施例8
1-(环丙基甲基)-3-[(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二 氢-7H-环戊二烯并[h]异喹啉-7-基]脲[*或S]
将中间体109(12mg,0.018mmol)溶于二氯甲烷(0.225mL)中,加入三氟乙酸(0.025mL,0.32mmol)并将反应在环境温度下搅拌过夜。真空浓缩反应,使用反相柱(酸性条件)纯化粗产物得到标题化合物(1.4mg,17%产率)。1H(300MHz,甲醇-d4)δ9.20(d,J=1.0Hz,1H),8.39(d,J=1.0Hz,1H),8.29(s,1H),5.45(t,J=7.7Hz,1H),3.62-3.44(m,1H),3.28-3.18(m,1H),3.13–2.93(m,4H),2.86–2.70(m,1H),2.32(tt,J=7.9,5.3Hz,1H),2.07–1.96(m,1H),1.30–1.15(m,6H),1.14–1.05(m,4H),1.06–0.93(m,1H),0.54–0.45(m,2H),0.22(td,J=5.6,4.2Hz,2H).LCMS[M+H]+475,RT 2.08min(方法3)。
实施例9
N-[(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯 并[h]异喹啉-7-基]吡啶-3-甲酰胺[*或S]
向搅拌的中间体38(50mg,0.13mmol)、烟酸(20mg,0.16mmol)和N,N-二异丙基乙胺(69μl,0.40mmol)的无水N,N-二甲基甲酰胺(1mL)溶液中加入HATU(78mg,0.199mmol)。将反应混合物在室温下搅拌过夜。反应混合物通过柱色谱法纯化,得到标题化合物(35mg,55%).1H(300MHz,DMSO-d6)δ9.32(d,J=0.9Hz,1H),9.15(d,J=8.1Hz,1H),9.06(dd,J=2.3,0.9Hz,1H),8.72(dd,J=4.9,1.7Hz,1H),8.45–8.34(m,1H),8.25(dt,J=8.0,1.9Hz,1H),8.15(s,1H),7.52(ddd,J=8.0,4.8,0.8Hz,1H),5.77(q,J=7.6Hz,1H),3.67–3.49(m,1H),3.38–3.24(m,1H),2.95(t,J=5.3Hz,1H),2.92–2.83(m,1H),2.80–2.64(m,1H),2.37–2.25(m,1H),2.25–2.11(m,1H),1.19(dd,J=21.4,6.7Hz,6H),1.06(d,J=6.5Hz,4H).LCMS[M+H]+483,RT 1.92min(方法3)。
实施例10
3-环丙基-N-(2-氟-2-甲基丙基)-7-羟基-7-吡啶-3-基-8,9-二氢环戊二烯并[h]
异喹啉-5-磺酰胺
通用程序2使用中间体50(10mg,0.011mmol)和反相HPLC(碱性条件)用于纯化产物,得到标题化合物(0.3mg,6%产率)。1H(400MHz,甲醇-d4)δ9.32(d,J=1.0Hz,1H),8.59(dd,J=2.4,0.8Hz,1H),8.46(dd,J=4.9,1.6Hz,1H),8.43(d,J=1.0Hz,1H),7.99(s,1H),7.82(ddd,J=8.1,2.3,1.6Hz,1H),7.43(ddd,J=8.1,4.9,0.9Hz,1H),3.74–3.49(m,2H),3.09–2.81(m,2H),2.73(dd,J=7.5,6.3Hz,2H),2.40–2.28(m,1H),1.25–1.05(m,10H).LCMS[M+H]+456,RT 1.75min(方法3)。
实施例11
3-环丙基-N-(2-氟-2-甲基丙基)-7-(2-氟吡啶-3-基)-8,9-二氢-7H-环戊二烯并
[h]异喹啉-5-磺酰胺
通用程序2使用中间体61(110mg,0.24mmol)和反相HPLC(碱性条件)用于纯化产物得到标题化合物(40mg,36%产率)。1H NMR(400MHz,DMSO-d6)δ9.38–9.32(m,1H),8.64–8.36(m,1H),8.21–8.13(m,1H),7.97-7.82(m,1H),7.72–7.60(m,1H),7.35–7.27(m,1H),4.94–4.76(m,1H),3.70–3.55(m,1H),3.52–3.36(m,1H),2.98–2.74(m,3H),2.36–2.27(m,1H),2.26–2.15(m,1H),1.20–1.09(m,6H),1.09–0.99(m,4H).LCMS[M+H]+458,RT 2.42min(方法3)。
实施例12和13
(7R*)-3-环丙基-7-[2-(环丙基甲基氨基)咪唑-1-基]-N-(2-氟-2-甲基丙基)-8, 9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S](12)
(7R*)-3-环丙基-7-[[1-(环丙基甲基)咪唑-2-基]氨基]-N-(2-氟-2-甲基丙基)- 8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S](13)
向搅拌的中间体57(134mg,0.21mmol)的DMF(1.0mL)溶液中加入氨基乙醛二乙缩醛(84mg,0.63mmol),接着加入氯化汞(113.5mg,0.42mmol)。将混合物在室温下搅拌5分钟,然后加入三乙胺(63mg,0.63mmol)。将所得的反应混合物在80℃下搅拌1h。
用EtOAc(5mL)稀释反应,并用饱和NaHCO3水溶液(3mL)洗涤。用EtOAc(3mL)再萃取水相,将合并的有机萃取物通过硅藻土和Na2SO4垫过滤。在真空中除去溶剂得到粗物质,对其进行反相HPLC(碱性条件)纯化得到标题化合物:
实施例12(5mg,5%产率);1H(400MHz,甲醇-d4)δ9.27(d,J=0.9Hz,1H),8.42(d,J=0.9Hz,1H),8.03(s,1H),6.54(d,J=1.8Hz,1H),6.25(d,J=1.8Hz,1H),6.03–5.79(m,1H),3.75–3.59(m,1H),3.48–3.36(m,1H),3.25–3.13(m,2H),3.01–2.89(m,3H),2.39–2.25(m,2H),1.23–1.07(m,11H),0.58–0.47(m,2H),0.33–0.23(m,2H).
实施例13(4mg,4%产率);1H(400MHz,甲醇-d4)δδ9.22(d,J=1.0Hz,1H),8.39(d,J=1.1Hz,1H),8.33(s,1H),6.76(d,J=1.7Hz,1H),6.62(d,J=1.7Hz,1H),5.48(t,J=7.4Hz,1H),3.61(d,J=6.9Hz,2H),3.60–3.52(m,1H),3.06–2.83(m,4H),2.37–2.25(m,1H),2.22–2.07(m,1H),1.22(dd,J=21.1,15.2Hz,6H),1.17–1.02(m,5H),0.64–0.50(m,2H),0.42–0.14(m,2H).
实施例14
3-环丙基-N-(2-甲基丙基)-9-(吡啶-3-基甲基氨基)-8,9-二氢-7H-环戊二烯并
[h]异喹啉-5-磺酰胺
将盐酸盐形式的中间体39(50mg,0.13mmol)悬浮在1,2-二氯乙烷(1mL)中,然后加入N,N-二异丙基乙胺(44μL,0.25mmol)、3-吡啶甲醛(14mg,0.13mmol)和乙酸(1滴)。将反应在环境温度下搅拌1小时。加入硼氢化钠(48mg,1.26mmol)和几滴MeOH并将反应在环境温度下搅拌过夜。用MeOH(1mL)和饱和NaHCO3水溶液(2mL)稀释反应。分离有机层,水层用DCM(2mL)萃取。合并的有机萃取物用Na2SO4干燥并真空浓缩。使用反相HPLC(碱性条件)纯化产物得到标题化合物(8mg,14%产率);1H(300MHz,DMSO-d6)δ9.64(d,J=0.9Hz,1H),8.56(d,J=2.2Hz,1H),8.43(dd,J=4.8,1.7Hz,1H),8.31(d,J=0.9Hz,1H),8.15(s,1H),8.02(s,1H),7.77(dt,J=7.8,2.0Hz,1H),7.34(dd,J=7.9,4.6Hz,1H),4.85(dd,J=7.6,3.7Hz,1H),3.83(s,2H),3.27–3.13(m,1H),3.06–2.90(m,1H),2.59–2.53(m,2H),2.46–2.32(m,1H),2.30–2.10(m,2H),1.59(dt,J=13.4,6.7Hz,1H),1.10–0.99(m,4H),0.75(dd,J=6.7,1.0Hz,6H).
实施例15
3-环丙基-N-(2-甲基丙基)-9-(吡啶-3-基磺酰基氨基)-8,9-二氢-7H-环戊二烯
并[h]异喹啉-5-磺酰胺
将中间体39(50mg,0.14mmol)溶于二氯甲烷(2mL)和N,N-二异丙基乙胺(45mg,0.3477mmol)中。加入吡啶-3-磺酰氯(34mg,0.18mmol)并将反应在室温下搅拌2小时。用DCM(2mL)和MeOH(1mL)稀释反应,并用水(2mL)洗涤。真空除去溶剂,通过反相HPLC(碱性条件)纯化产物得到标题化合物(21mg,30%产率);1H(300MHz,DMSO-d6)δ9.48(d,J=0.9Hz,1H),9.02(dd,J=2.4,0.8Hz,1H),8.85(dd,J=4.8,1.6Hz,1H),8.56(s,1H),8.34(d,J=0.9Hz,1H),8.24(dt,J=8.1,1.8Hz,1H),8.15(s,1H),8.09(t,J=5.9Hz,1H),7.66(ddd,J=8.0,4.9,0.8Hz,1H),5.58(d,J=7.6Hz,1H),3.21–3.02(m,1H),2.96–2.77(m,1H),2.55(t,J=6.2Hz,2H),2.34–2.09(m,2H),1.59(dp,J=12.2,6.2,5.5Hz,2H),1.14–1.00(m,4H),0.75(dd,J=6.7,1.2Hz,6H).
实施例16
6-氟-N-[(9R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊 二烯并[h]异喹啉-9-基]-1H-吲哚-3-甲酰胺[*或S]
将6-氟-1H-吲哚-3-甲酸(12mg,0.064mmol)溶于包含N,N-二异丙基乙胺(0.13mmol,0.023mL)和N,N,N′,N′-四甲基-O-(1H-苯并三唑-1-基)脲鎓六氟磷酸盐、O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐(31mg,0.079mmol)的DMF(0.25mL)溶液中。将反应搅拌10min,然后加入中间体65(20mg,0.053mmol)的DMF(0.25mL)溶液。将反应在环境温度下搅拌过夜,用水(2mL)稀释并用EtOAc(2x2mL)萃取。将合并的有机萃取物用Na2SO4干燥并真空浓缩。反相HPLC(碱性条件)纯化产物得到标题化合物(4mg,14%产率);1H(300MHz,甲醇-d4)δ9.41(d,J=0.9Hz,1H),8.41(d,J=1.0Hz,1H),8.32(s,1H),8.16(dd,J=8.8,5.4Hz,1H),7.82(s,1H),7.15–7.07(m,1H),6.94(ddd,J=9.7,8.8,2.4Hz,1H),6.33(dd,J=8.6,4.5Hz,1H),3.47–3.33(m,1H),3.20–3.08(m,1H),3.02(d,J=19.4Hz,2H),2.93–2.77(m,1H),2.34–2.20(m,2H),1.24(dd,J=21.1,5.8Hz,6H),1.09–0.99(m,4H).LCMS[M+H]+539,RT 2.23min(方法3)。
实施例17
3-环丙基-N-(2-氟-2-甲基丙基)-9-[(1-甲基苯并咪唑-2-基)氨基]-8,9-二氢-
7H-环戊二烯并[h]异喹啉-5-磺酰胺
通用程序2使用中间体66(13mg,0.026mmol)和反相柱色谱法(碱性条件)得到标题化合物(0.5mg,4%产率)。1H(400MHz,甲醇-d4)δ9.35(d,J=0.9Hz,1H),8.43(d,J=0.9Hz,1H),8.34(s,1H),7.45–7.35(m,1H),7.22–7.15(m,1H),7.14–7.03(m,2H),6.20(dd,J=8.2,4.3Hz,1H),3.47(s,3H),3.46–3.32(m,1H),3.20–3.10(m,1H),3.03(d,J=19.4Hz,2H),2.91(dtd,J=14.5,8.7,6.2Hz,1H),2.37–2.22(m,2H),1.25(dd,J=21.1,8.4Hz,6H),1.12–0.99(m,4H).LCMS[M+H]+508,RT 2.26min(方法7)。
实施例18
5-[[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-
9-基]氨基]吡啶-2-甲酸甲酯
通用程序3使用中间体39(50mg,0.14mmol)、5-溴吡啶-2-甲酸甲酯(77mg,0.35mmol)和用于纯化的柱色谱法得到标题化合物(28mg,39%产率);1H(400MHz,DMSO-d6)δ9.21(s,1H),8.37(d,J=0.9Hz,1H),8.25(s,1H),8.15–8.07(m,2H),7.88(d,J=8.7Hz,1H),7.30(d,J=8.2Hz,1H),7.18(dd,J=8.8,2.8Hz,1H),5.86–5.76(m,1H),3.79(s,3H),3.30–3.20(m,1H),3.17–3.04(m,1H),2.72–2.61(m,1H),2.58(t,J=6.5Hz,2H),2.32–2.20(m,1H),2.14–1.99(m,1H),1.62(hept,J=6.7Hz,1H),1.07–0.91(m,4H),0.78(dd,J=6.7,4.4Hz,6H).LCMS[M+H]+495,RT2.09min(方法7)。
实施例19
5-[[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-
9-基]氨基]吡啶-2-甲酸
将实施例18(26mg,0.053mmol)溶于四氢呋喃(0.75mL)和水(0.5mL)的混合物中。加入氢氧化锂一水合物(8.5mg,0.20mmol)并将反应在50℃下加热并搅拌1小时。冷却反应并真空浓缩,粗品残余物通过碱性反相柱色谱法纯化得到标题化合物(11mg,45%产率);1H(400MHz,DMSO-d6)δ12.06(s,1H),9.26–9.16(m,1H),8.37(d,J=0.9Hz,1H),8.25(s,1H),8.16–8.05(m,2H),7.87(d,J=8.6Hz,1H),7.23(d,J=8.2Hz,1H),7.19(dd,J=8.8,2.8Hz,1H),5.86–5.73(m,1H),3.28–3.21(m,1H),3.15–3.04(m,1H),2.73–2.61(m,1H),2.61–2.55(m,2H),2.31–2.22(m,1H),2.12–2.00(m,1H),1.62(hept,J=6.7Hz,1H),1.11–0.92(m,4H),0.78(dd,J=6.7,4.5Hz,6H).LCMS[M+H]+481,RT 1.58min(方法7)。
实施例20
5-甲基-N-[(9R*)-3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯 并[h]异喹啉-9-基]-1H-吡唑-3-甲酰胺[*或S]
将HATU(82mg,0.21mmol)加入搅拌的中间体39的盐酸盐形式(50mg,0.14mmol)、5-甲基-1h-吡唑-3-甲酸(21mg,0.167mmol)和N,N-二异丙基乙胺(54mg,0.42mmol)的无水N,N-二甲基甲酰胺(1mL)溶液中。将反应混合物在室温下搅拌45min。然后将反应混合物用反相柱色谱法(酸性条件)接着用反相HPLC(碱性条件)纯化得到标题化合物(39mg,60%产率),为对映异构体的混合物;使用手性SFC分离混合物得到标题化合物,为单一异构体(2mg);手性SFC RT**=2.31min.1H(300MHz,DMSO-d6)δ12.89(s,1H),9.27(s,1H),8.87–8.68(m,1H),8.34(d,J=0.9Hz,1H),8.18(s,1H),8.06(s,1H),6.52–6.34(m,1H),6.14(td,J=9.0,4.2Hz,1H),3.44–3.35(m,1H),3.10–2.90(m,1H),2.75–2.53(m,3H),2.31–2.04(m,5H),1.62(dp,J=13.5,6.7Hz,1H),1.09–0.90(m,4H),0.78(dd,J=6.7,2.1Hz,6H).LCMS[M+H]+468,RT 2.07min(方法7)。
**手性分析通过SFC在Waters UPC2–SQD2系统上进行,使用Chiralcel OJ-3150x4.6mm,3μM柱,流速3.5mL/min,用10-25%MeOH(+0.1%NH4OH)洗脱,用6min运行时间.
实施例21
N-[(9R*)-3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异 喹啉-9-基]吡啶-3-甲酰胺[*或S]
将HATU(16mg,0.042mmol)加入搅拌的中间体67(10mg,0.028mmol)、烟酸(4mg,0.033mmol)和N,N-二异丙基乙胺(15μL,0.084mmol)的无水N,N-二甲基甲酰胺(0.2mL,3mmol)溶液中。将反应混合物在室温下搅拌1小时。然后通过碱性反相柱色谱法纯化得到标题化合物(8mg,60%产率);1H(300MHz,DMSO-d6)δ9.33–9.21(m,2H),9.00(dd,J=2.3,0.9Hz,1H),8.69(dd,J=4.8,1.7Hz,1H),8.35(d,J=0.9Hz,1H),8.23(s,1H),8.20(dt,J=8.0,2.0Hz,1H),8.15–8.03(m,1H),7.49(ddd,J=8.0,4.8,0.9Hz,1H),6.21(dt,J=8.5,4.4Hz,1H),3.45–3.33(m,1H),3.16–3.00(m,1H),2.78–2.53(m,2H),2.31–2.07(m,3H),1.63(dt,J=13.4,6.7Hz,1H),1.07–0.90(m,4H),0.78(dd,J=6.7,2.5Hz,6H).LCMS[M+H]+465,RT 2.11min(方法4)。
实施例22
3-环丙基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰胺
将中间体73(77mg,0.23mmol)、环丙基硼酸(61mg,0.68mmol)和碳酸铯(186mg,0.57mmol)在无水1,4-二氧六环(1.5mL)中的混合物用氮气吹扫5分钟。加入氯(η2-P,C-三(2,4-二叔丁基苯基)亚磷酸酯)(三环己基膦)钯(II)(24mg,0.023mmol)并将反应混合物在微波中在120℃下加热1小时。反应用DCM(3mL)稀释并用水(1mL)洗涤。有机相用Na2SO4干燥并真空浓缩。产物通过柱色谱法纯化得到标题化合物(21mg,27%产率)。1H(400MHz,氯仿-d)δ8.39(s,1H),8.32(s,1H),4.69(t,J=6.4Hz,1H),3.69(t,J=7.6Hz,2H),3.21(t,J=7.5Hz,2H),2.74(t,J=6.6Hz,2H),2.45–2.30(m,3H),1.68(dh,J=13.2,6.6Hz,1H),1.46–1.38(m,2H),1.27–1.17(m,2H),0.82(d,J=6.7Hz,6H).LCMS[M+H]+346,RT 2.41min(方法3)。
实施例23
1-[3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]噌
啉-7-基]-3-(2,5-二甲基吡唑-3-基)硫脲
向搅拌的中间体82(42mg,0.10mmol)的二氯甲烷(2mL)悬浮液加入N,N-二异丙基乙胺(26mg,0.20mmol)和5-异硫氰酸基-1,3-二甲基-1h-吡唑(24mg,0.15mmol)。将反应混合物在室温下搅拌1小时,用MeOH稀释并真空浓缩。粗产物通过柱色谱法纯化得到标题化合物(41mg,76%产率)。1H NMR(300MHz,DMSO-d6)δ9.43(s,1H),8.58–8.43(m,3H),8.29(s,1H),6.36–6.16(m,1H),5.94(s,1H),3.81–3.60(m,1H),3.55(s,3H),3.49–3.33(m,1H),3.02–2.89(m,2H),2.82–2.70(m,1H),2.24–1.99(m,4H),1.33–1.12(m,11H).LCMS[M+H]+532.1RT 2.17min(方法3)。
实施例24和25
3-环丙基-7-[[4-(2,5-二甲基吡唑-3-基)-1,2,4-三唑-3-基]氨基]-N-(2-氟-2- 甲基丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰胺(24)
(7R*)-3-环丙基-7-[3-[(2,5-二甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基]-N- (2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰胺[*或S](25)
通用程序1使用实施例23(50mg,0.094mmol)和用于纯化的柱色谱法得到实施例24(21mg,41%产率)和实施例25的外消旋混合物(14mg,28%产率)。实施例25的外消旋混合物用手性HPLC(柱:LUX Cullulose-2 250x21.2mm,5uM,流速10mL/min,柱温40℃。流动相:MeOH+0.1%NH4OH.运行时间:20mins)纯化得到实施例25,为第一洗脱峰。
实施例24 1H NMR(300MHz,DMSO-d6)δ8.56(s,1H),8.45(s,1H),8.26–8.17(m,2H),6.88(d,J=8.5Hz,1H),6.29(s,1H),5.54(q,J=7.7Hz,1H),3.78–3.58(m,1H),3.51(s,3H),3.47–3.37(m,1H),2.94–2.67(m,3H),2.30–2.16(m,1H),2.15(s,3H),1.32–1.08(m,11H).LCMS[M+H]+540RT 1.73min(方法7)。
实施例25手性RT**=2.93分钟.1H NMR(300MHz,甲醇-d4)δ8.75–8.47(m,1H),8.36–8.12(m,1H),8.08–7.89(m,1H),6.11(t,J=7.0Hz,1H),5.87(s,1H),4.11–3.82(m,1H),3.78–3.47(m,4H),3.18–2.86(m,3H),2.72–2.42(m,2H),2.18(s,3H),1.53–1.24(m,4H),1.24–0.95(m,6H).LCMS[M+H]+540,RT 1.65min(方法7)。
**手性分析在Agilent 1100UV导向系统上在极性有机模式下进行,使用LuxCellulose-2 4.6x150mm,3μm柱,流速1mL/min,用甲醇(0.1%氢氧化铵)洗脱,用10min运行时间。
实施例26
N-[3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异
喹啉-9-基]-2-甲基环丙烷-1-甲酰胺
用2-甲基环丙烷甲酸(5.2mg,0.05mmol)处理中间体84(19mg,0.05mmol)的DMF(0.4mL)溶液。然后加入TBTU(19mg,0.05mmol)的DMF(416μL)溶液,接着加入DIPEA(9μL,0.05mmol)的DMF(50μL)溶液。将所得混合物在环境温度下搅拌18小时,然后通过制备型HPLC纯化得到标题化合物(12.4mg,53%产率)。LCMS[M+H]+460.5,RT1.44分钟(方法13)。HRMS[M+H]+实测值460.2055,计算值C24H31FN3O3S1 460.207.
实施例27
3-环丙基-4-氟-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将中间体120(22mg,0.064mmol)、N-氟苯磺酰胺(63mg,0.2mmol)和碳酸锂(6mg,0.08mmol)在MeCN(0.3mL)中的悬浮液在氩气气氛下加热至75℃持续3天,该时间后将混合物过滤,滤液通过制备型HPLC纯化得到标题化合物(1.2mg,5%产率)。δH(500MHz,DMSO-d6)9.09(s,1H),8.27(s,1H),7.62(s,1H),3.41–3.35(m,2H),3.13(t,J=7.5Hz,2H),2.76(t,J=5.9Hz,2H),2.24(p,J=7.7Hz,2H),1.69(hept,J=6.7Hz,1H),1.14–1.07(m,5H),0.80(d,J=6.7Hz,6H).LCMS[M+H]+363,RT 3.27min(方法15)。
实施例28、29、30
程序
将中间体84(18.9mg,0.05mmol)和tBuXPhos Pd G3(6.2mg,0.0075mmol)的二氧六环(0.5mL)溶液用叔丁醇钠(14.4mg,0.15mmol)和合适的芳基溴(0.072mmol,见下表)处理,并将所得混合物在氩气下加热至100℃持续18小时。产物通过制备型HPLC分离并用LCMS方法13(**)或14(***)分析。
实施例31
3-环丙基-N-(2-氟-2-甲基丙基)-7-(吡啶-3-基氨基)-8,9-二氢-7H-环戊二烯并
[h]异喹啉-5-磺酰胺
将中间体36(36.0mg,0.0954mmol)、3-溴吡啶(20μL,0.21mmol)、叔丁醇钠(18.0mg,0.187mmol)、(+/-)-2,2'-双(二苯基膦基)-1,1'-联萘(18.0mg,0.0280mmol)和乙酸钯(II)(2.8mg,0.012mmol)置于烧瓶中并悬浮于甲苯(1.5mL)中。将烧瓶密封,脱气并置于氮气气氛下。将密封的反应在80℃下搅拌18小时。将反应冷却至室温,然后用5%MeOH/DCM(20mL)和饱和NaHCO3水溶液(20mL)稀释。分离各层,水层用5%MeOH/DCM(2x20mL)萃取。将合并的有机层通过相分离器并真空浓缩得到粗产物,将其通过碱性制备型HPLC纯化得到标题化合物(1mg,2%产率)。LCMS[M+H]+455,RT 2.02min(方法3)。
实施例32
3-环丙基-N-(2-氟-2-甲基丙基)-9-(吡啶-3-基氨基)-8,9-二氢-7H-环戊二烯并
[h]异喹啉-5-磺酰胺
将中间体84(50.0mg,0.132mmol)、3-溴吡啶(0.020mL,0.21mmol)、叔丁醇钠(27.5mg,0.286mmol)、(+/-)-2,2'-双(二苯基膦基)-1,1'-联萘(17.0mg,0.0265mmol)和乙酸钯(II)(3.5mg,0.016mmol)置于烧瓶中并悬浮于甲苯(1.7mL)中。将烧瓶密封,脱气并置于氮气气氛下。将密封的反应在70℃下搅拌18小时。将反应冷却至室温,然后用5%MeOH/DCM(20mL)和饱和NaHCO3水溶液(20mL)稀释。分离各层,水层用5%MeOH/DCM(2x20mL)萃取。将合并的有机层通过相分离器并真空浓缩得到粗产物,将其通过快速硅胶柱色谱法纯化(用0%至100%EtOAc/异己烷梯度洗脱),然后用碱性制备型HPLC纯化,得到标题化合物(7mg,12%产率)。1H NMR(300MHz,DMSO-d6)δ9.27(s,1H),9.27(d,J=0.9Hz,1H),8.46–8.37(m,2H),8.22(s,1H),8.09(dd,J=2.5,1.1Hz,1H),7.83(dd,J=4.0,1.9Hz,1H),7.18–7.08(m,2H),6.40(d,J=8.6Hz,1H),5.68(dt,J=7.9,4.2Hz,1H),3.28–3.16(m,1H),3.13–3.01(m,1H),2.96(d,J=19.8Hz,2H),2.67–2.53(m,1H),2.28(p,J=6.6Hz,1H),2.11–1.98(m,1H),1.24(dd,J=21.4,2.4Hz,6H),1.08–0.94(m,4H).LCMS[M+H]+455,RT 2.09min(方法3)。
实施例33
N-[3-环丙基-5-[(1,1-二氘-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并
[h]异喹啉-7-基]氨基甲酸叔丁酯
向中间体97(1.2g,2.6mmol)在甲苯(15mL)的悬浮液中加入环丙基硼酸(710mg,7.9mmol)、磷酸三钾(1400mg,6.6mmol)、三环己基鏻四氟硼酸盐(150mg,0.39mmol)、乙酸钯(II)(30mg,0.13mmol)和水(0.15mL)。用氮气吹扫混合物然后在微波中加热至115℃持续2小时。混合物用二氯甲烷(20mL)稀释并用水(30mL)洗涤。水层用二氯甲烷(2x10mL)萃取。将合并的有机物通过疏水烧结漏斗并通过快速色谱法纯化得到标题化合物,为膏状固体(1.05g,2.27mmol,86%).δH(300MHz,氯仿-d)δ9.21(d,J=0.9Hz,1H),8.33(s,1H),8.25(d,J=0.9Hz,1H),5.39(d,J=8.4Hz,1H),4.85(d,J=8.9Hz,1H),4.66(s,1H),3.49(ddd,J=17.1,9.1,3.5Hz,1H),3.22(dt,J=16.8,8.2Hz,1H),2.83(dd,J=12.6,7.2Hz,1H),2.29–2.17(m,1H),2.13–1.95(m,1H),1.73–1.62(m,1H),1.51(s,9H),1.19–1.02(m,4H),0.93–0.75(m,6H);LCMS[M+H]+462,RT 2.64min(方法3)。
实施例34
7-氨基-3-环丙基-N-(1,1-二氘-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹
啉-5-磺酰胺
向实施例33(15mg,0.032mmol)中加入盐酸(4mol/L)的1,4-二氧六环溶液(0.2mL,0.8mmol)。30分钟后加入盐酸(4mol/L)的1,4-二氧六环溶液(0.2mL,0.8mmol)和甲醇(50μL)。20分钟后,减压浓缩混合物,残余物通过反相快速色谱法纯化得到标题化合物,为白色固体(8mg,68%).δH(300MHz,DMSO-d6)δ9.24(d,J=0.9Hz,1H),8.38–8.26(m,2H),7.96(s,1H),4.39(t,J=7.5Hz,1H),3.50–3.37(m,1H),3.18–3.02(m,1H),2.64–2.54(m,1H),2.33–2.22(m,1H),2.15(br.s,2H),1.85–1.69(m,1H),1.64–1.51(m,1H),1.04(d,J=6.5Hz,4H),0.75(dd,J=6.7,1.6Hz,6H).LCMS[M+H]+362,RT 1.91min(方法3)。
实施例35
3-环丙基-7-[3-(环丙基甲基氨基)-1,2,4-三唑-4-基]-N-(1,1-二氘-2-甲基丙
基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
向在冰/水浴中冷却的中间体101(407mg,0.611mmol)的二氯甲烷(50mL,780mmol)溶液中加入三氟乙酸(5mL)。20分钟后,将饱和碳酸氢钠溶液(20mL)和水(10mL)加入混合物中。水层用二氯甲烷(4x20mL)和二氯甲烷:甲醇5:1(3x10mL)萃取。将合并的萃取物通过疏水烧结漏斗,浓缩并通过反相快速色谱法纯化残余物得到标题化合物,为白色固体(173mg,0.36mmol,58%).δH(300MHz,DMSO-d6)δ9.36(d,J=0.9Hz,1H),8.36(d,J=1.0Hz,1H),8.07(s,1H),7.96(s,1H),6.26(t,J=5.7Hz,1H),5.92–5.85(m,1H),3.75–3.61(m,1H),3.46–3.36(m,1H),3.18–3.10(m,2H),2.93–2.79(m,1H),2.37–2.23(m,3H),1.51(p,J=6.6Hz,1H),1.24–1.11(m,1H),1.11–1.02(m,4H),0.71(d,J=3.6Hz,3H),0.69(d,J=3.6Hz,3H),0.52–0.44(m,2H),0.30–0.22(m,2H);LCMS[M+H]+483,RT 2.02min(方法3)。
实施例36
7-环丙基-N-(2-氟-2-甲基丙基)-3-羟基-2,3-二氢呋喃并[3,2-h]异喹啉-5-磺
酰胺
将甲苯(0.2mL)加入中间体114(9mg,0.016mmol)中,接着加入乙酸钯(II)(0.4mg,0.002mmol)、三环己基鏻四氟硼酸盐(1.8mg,0.005mmol)和磷酸三钾(17mg,0.08mmol)、环丙基硼酸(9mg,0.1mmol)和水(2μL)。将混合物在微波中加热至115℃。冷却后,通过硅藻土过滤,减压浓缩,加入四氢呋喃(1mL)和1M四丁基氟化铵的四氢呋喃溶液(24μL,0.024mmol,1mol/L)。2.5小时后,浓缩混合物,用乙酸乙酯(10mL)稀释并用10%氯化铵溶液(2x5mL)和水(5mL)洗涤。减压浓缩后,通过柱色谱法纯化得到标题化合物,为白色固体(6.5mg,43%)。δH(300MHz,氯仿-d)δ9.40(d,J=0.9Hz,1H),8.44(s,1H),8.19(d,J=1.0Hz,1H),5.63(td,J=7.0,2.7Hz,1H),4.98–4.84(m,2H),4.81(dd,J=11.0,2.8Hz,1H),3.03(dd,J=19.9,6.6Hz,2H),2.29–2.19(m,1H),2.15(d,J=7.1Hz,1H),1.34(d,J=21.5Hz,6H),1.23–1.08(m,4H);LCMS[M+H]+381,RT 1.97min(方法16)。
实施例37
(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-N-吡啶-3-基-8,9-二氢-7H- 环戊二烯并[h]异喹啉-7-甲酰胺[*或S]
将中间体85(70mg,0.17mmol)溶于DCM(3mL)中并加入HATU(81mg,0.20mmol),接着加入三乙胺(0.1mL,0.7mmol)。反应混合物在室温下搅拌5min,然后加入3-氨基吡啶(33mg,0.34mmol)。约1小时后,粗品用EtOAc稀释并将有机层用水和盐水洗涤。通过柱色谱法纯化,用0至100%EtOAc/己烷梯度,接着用0至10%MeOH/DCM梯度,得到标题化合物,为对映异构体的混合物(34mg,41%产率)。使用手性HPLC(Waters UV制备系统,配备2996PDA.LuxCellulose-1 21.2x250mm 5μm柱,流速10mL/min)分离外消旋物,得到标题化合物(7mg);手性RT**=2.39min.1H NMR(300MHz,氯仿-d)δ9.20(s,1H),8.59(d,J=2.6Hz,1H),8.34(s,2H),8.23(s,1H),8.14(d,J=8.6Hz,1H),7.24(dd,J=8.4,4.8Hz,1H),5.54(s,1H),4.30–4.07(m,1H),3.62(dt,J=15.4,7.1Hz,1H),3.39–3.24(m,1H),3.05(dd,J=20.2,6.1Hz,2H),2.68(q,J=6.8Hz,2H),2.29–2.17(m,1H),1.40–1.26(m,8H),1.31–1.05(m,3H).LCMS[M+H]+483,RT 1.78min(方法4)。
**手性分析在Lux Cellulose-1 4.6x150mm,3μm柱上使用100%MeOH(+0.1%NH4OH)等度方法,流速1mL/min.
实施例38
N-[2-[3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并
[h]异喹啉-7-基]吡唑-3-基]环丙烷甲酰胺
将中间体88(105mg,0.20mmol)、环丙烷硼酸(56mg,0.61mmol)和乙酸钯(II)(2.3mg,0.010mmol)在1,4-二氧六环(3mL)中的混合物用氮气吹扫5分钟。加入三环己基鏻四氟硼酸盐(12mg,0.031mmol)和磷酸三钾(110mg,0.51mmol)并将反应混合物用氮气吹扫5min。然后将反应在120℃下加热2小时。然后将其通过硅藻土过滤并减压浓缩溶剂。经柱色谱纯化得到标题化合物(38mg,36%产率)。1H NMR(300MHz,氯仿-d)δ9.27(s,1H),8.28(s,1H),8.07(s,1H),7.45(s,1H),6.19(s,1H),5.93(s,1H),5.06(s,1H),3.72(s,1H),3.37(s,1H),3.09–2.81(m,3H),2.70(s,1H),2.28(s,1H),1.30(dd,J=21.5,15.1Hz,6H),1.24–1.07(m,7H),0.94(s,3H).LCMS[M+H]+512,RT 2.02min(方法4)。
实施例39
7-(5-氨基四唑-1-基)-3-环丙基-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯
并[h]异喹啉-5-磺酰胺
将中间体89(160mg,0.31mmol)溶于DMF(5mL)中。加入氯化铵(42mg,0.78mmol),接着加入叠氮化钠(52mg,0.80mmol),并将所得混合物在80℃下加热过夜。蒸发挥发物然后进行DCM/水萃取。将有机物用硫酸钠干燥并蒸发。粗品残余物用反相柱色谱法使用碱性条件纯化,得到标题化合物(45mg,32%产率)。1H NMR(400MHz,氯仿-d)δ9.32(d,J=0.9Hz,1H),8.29(d,J=1.0Hz,1H),8.11(s,1H),6.09(dd,J=8.5,5.6Hz,1H),5.07(t,J=6.4Hz,1H),4.47(s,2H),3.81(ddd,J=17.6,9.3,4.9Hz,1H),3.65–3.35(m,1H),3.14–2.84(m,3H),2.66(ddt,J=14.5,9.0,5.9Hz,1H),2.28(td,J=8.1,4.1Hz,1H),1.39–1.24(m,10H).LCMS[M+H]+446,RT 1.64min(方法3)。
实施例40
3-环丙基-N-(2-氟-2-甲基丙基)-7-[[6-(2-甲基四唑-5-基)吡啶-3-基]氨基]-
8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
在氮气下将中间体36(35mg,0.09272mmol)和5-溴-2-(2-甲基-2H-四唑-5-基)-吡啶(45mg,0.1875mmol)溶于无水1,4-二氧六环(2mL)中。然后加入叔丁醇钠(27mg,0.28mmol)和tBuXphos-Pd-G3(6mg,0.007mmol)并将反应容器在室温下搅拌过夜。然后向反应混合物中加入叔丁醇钠(27mg,0.2 8mmol)和tBuXphos-Pd-G3(6mg,0.007mmol)并将反应混合物加热至80℃持续4小时。将反应冷却至室温,然后真空浓缩并通过柱色谱法纯化得到标题化合物(21mg).δH(400MHz,d6-DMSO)9.27(s,1H),8.50(s,1H),8.25(d,J=2.8Hz,1H),8.12(s,1H),7.89(d,J=8.6Hz,1H),7.27(dd,J=8.7,2.8Hz,1H),6.93(d,J=8.4Hz,1H),5.35(d,J=7.7Hz,1H),4.40(s,3H),3.51(s,1H),3.31(d,J=4.7Hz,1H),2.80(s,3H),2.27(s,1H),2.03(tt,J=14.8,7.3Hz,1H),1.24(s,1H),1.16(d,J=21.5Hz,6H),1.05(d,J=6.7Hz,4H).LCMS[M+H]+537.0,RT 2.07min(方法3)。
实施例41
3-环丙基-N-(2-氟-2-甲基丙基)-7-[(1-甲基吡唑并[3,4-c]吡啶-4-基)氨基]-
8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
如实施例40描述的方法,使用中间体36(0.093mmol)和4-溴-1-甲基-1H-吡唑并[3,4-c]吡啶(41mg,0.1854mmol),得到标题化合物(13mg,0.026mmol).δH(400MHz,d4-甲醇)9.26(d,J=0.9Hz,1H),8.41(d,J=1.0Hz,1H),8.33(d,J=0.8Hz,1H),8.31(s,1H),8.21(d,J=0.9Hz,1H),7.70(s,1H),5.58(t,J=7.0Hz,1H),4.13(s,3H),3.69–3.60(m,1H),3.46–3.36(m,1H),3.01–2.85(m,3H),2.38–2.23(m,2H),1.21(d,J=5.9Hz,3H),1.16(d,J=5.8Hz,3H),1.15–1.07(m,4H).LCMS[M+H]+509.0,RT1.96min(方法3)。
实施例42
3-环丙基-N-(2-氟-2-甲基丙基)-7-[[6-(5-甲基-1,3,4-噁二唑-2-基)吡啶-3-
基]氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
如实施例40描述的方法,使用中间体36(0.093mmol)和2-(5-溴-2-吡啶基)-5-甲基-1,3,4-噁二唑(46mg,0.19mmol),得到标题化合物(13mg,0.024mmol).δH(400MHz,d4-甲醇)9.26(d,J=1.0Hz,1H),8.42(d,J=1.0Hz,1H),8.30(s,1H),8.19(d,J=2.7Hz,1H),7.97(d,J=9.0Hz,1H),7.32(dd,J=8.8,2.9Hz,1H),5.42(t,J=6.9Hz,1H),3.68–3.57(m,1H),3.46–3.36(m,1H),2.97(d,J=19.4Hz,2H),2.94–2.85(m,1H),2.62(s,3H),2.38–2.30(m,1H),2.24–2.13(m,1H),1.23(s,3H),1.17(s,3H),1.16–1.07(m,4H).LCMS[M+H]+537.0,RT 1.98min(方法3)。
实施例43
3-环丙基-N-(2-氟-2-甲基丙基)-9-[(1-甲基吡唑并[3,4-c]吡啶-4-基)氨基]-
8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
如实施例40描述的方法,使用中间体84(0.093mmol)和4-溴-1-甲基-1H-吡唑并[3,4-C]吡啶(41mg,0.185mmol),得到标题化合物(18mg,0.032mmol).δH(400MHz,d4-甲醇)9.33(d,J=0.9Hz,1H),8.44(d,J=1.0Hz,1H),8.36(s,1H),8.34(d,J=0.8Hz,1H),8.12(d,J=0.8Hz,1H),7.73(s,1H),5.97(dd,J=7.8,3.7Hz,1H),4.12(s,3H),3.42–3.32(m,1H),3.23–3.13(m,1H),3.08–2.97(m,2H),2.89–2.77(m,1H),2.38–2.25(m,2H),1.33–1.27(m,3H),1.24(d,J=5.0Hz,3H),1.07–1.02(m,4H).LCMS[M+H]+509.0,RT 1.99min(方法3)。
实施例44
N-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-
基]氨基甲酸苄酯
将中间体39(25mg,0.07mmol)溶于DCM(1mL)中并在室温下用DIPEA(25μL,0.143mmol)处理,然后滴加氯甲酸苄酯(12μL,0.082mmol)。将反应在室温下搅拌过夜。将反应混合物用MeOH(0.5mL)和NaOH(4N水溶液,0.5mL)稀释并在室温下剧烈搅拌72小时。然后将混合物升温至48℃持续5小时。反应混合物用水(5mL)和DCM(5mL)稀释,剧烈搅拌并通过相分离器分离各层。水层用DCM(x2)萃取,将合并的有机层干燥并真空浓缩。通过柱色谱法以甲醇/DCM梯度纯化,得到标题化合物(31mg,0.026mmol).δH(400MHz,d6-DMSO)9.31(d,J=0.9Hz,1H),8.34(d,J=0.9Hz,1H),8.17(s,1H),8.06(t,J=6.1Hz,1H),8.03(d,J=9.3Hz,1H),7.36–7.32(m,5H),5.72(td,J=8.6,3.6Hz,1H),5.16–5.01(m,2H),3.26–3.17(m,1H),3.03–2.92(m,1H),2.64–2.53(m,3H),2.27(p,J=6.8Hz,1H),2.10–1.97(m,1H),1.68–1.53(m,1H),1.11–0.96(m,4H),0.77(d,J=2.5Hz,3H),0.75(d,J=2.4Hz,3H).LCMS[M+H]+494.0RT 2.65min(方法3)。
实施例45
1-(4-溴苯基)-3-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯
并[h]异喹啉-9-基]脲
在室温下将中间体39(25mg,0.07mmol)溶于DCM(1mL)中,并用DIPEA(25μL,0.143mmol)和4-溴苯基-异氰酸酯(16mg,0.081mmol)处理。将反应在室温下搅拌过夜。真空浓缩反应混合物,粗残余物通过柱色谱法用甲醇/DCM的梯度纯化得到标题化合物(32mg,0.05mmol).δH(400MHz,d6-DMSO)9.36(d,J=0.9Hz,1H),8.46(s,1H),8.35(d,J=1.0Hz,1H),8.20(s,1H),8.08(t,J=6.0Hz,1H),7.40(s,4H),6.95(d,J=8.7Hz,1H),5.87(td,J=8.5,3.8Hz,1H),3.24(dt,J=15.7,7.5Hz,1H),3.03(ddd,J=16.5,9.0,4.4Hz,1H),2.69–2.59(m,1H),2.56(t,J=6.4Hz,2H),2.30–2.21(m,1H),2.13–2.03(m,1H),1.61(hept,J=6.7Hz,1H),1.02(dt,J=8.6,3.3Hz,4H),0.77(dd,J=6.7,2.6Hz,6H).LCMS[M+H]+557/559,RT 2.66min(方法3)。
实施例46
1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-
基]-3-[(2,5-二甲基吡唑-3-基)甲基]脲
在氮气下向(1,3-二甲基-1H-吡唑-5-基)甲基胺(10mg,0.08mmol)的乙腈(1mL,19.1mmol)溶液中加入三乙胺(22μL,0.16mmol),接着加入1,1'-羰基-二咪唑(12mg,0.074mmol)。将混合物在室温下搅拌1小时,然后加入中间体39(25mg,0.07mmol)。将所得混合物在室温下搅拌36小时。将反应混合物浓缩并通过柱色谱法以甲醇/乙酸乙酯的梯度纯化得到标题化合物(20mg,0.28mmol).δH(400MHz,d6-DMSO)δ9.36(d,J=0.9Hz,1H),8.34(d,J=1.0Hz,1H),8.17(s,1H),8.06(t,J=5.9Hz,1H),6.69(d,J=8.9Hz,1H),6.15(t,J=5.9Hz,1H),5.88–5.77(m,2H),4.33–4.15(m,2H),3.65(s,3H),3.26–3.12(m,1H),3.06–2.90(m,1H),2.63–2.53(m,3H),2.31–2.20(m,1H),2.06(s,3H),2.03–1.92(m,1H),1.66–1.54(m,1H),1.07–1.01(m,4H),0.77(d,J=2.6Hz,3H),0.75(d,J=2.7Hz,3H).LCMS[M+H]+511.2RT 1.91min(方法3)。
实施例47
3-环丙基-7-羟基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰
胺
在0℃下向中间体29(73mg,0.15mmol)的THF(3mL)溶液中加入1M四丁基氯化铵的THF溶液(0.22mL,0.22mmol)。将溶液在0℃下搅拌5分钟然后在室温下搅拌90分钟。用水(10mL)和EtOAc(15mL)稀释溶液。分离有机层并用盐水洗涤,通过相分离器烧结漏斗(frit)。除去溶剂得到棕色油状物,将其通过快速柱色谱法纯化(用0至70%的EtOAc/异己烷梯度洗脱)得到标题产物,为白色固体(53mg,96%产率)。LCMS[M+H]+361,RT 2.19分钟(方法3)。
实施例48
3-环丙基-N-(2-甲基丙基)-7-氧代-8,9-二氢环戊二烯并[h]异喹啉-5-磺酰胺
在0℃下向实施例47(60mg,0.17mmol)的DCM(4mL)溶液中加入Dess-Martin高价碘化物(109mg,0.25mmol)。将混合物搅拌2.5小时。加入饱和硫代硫酸钠水溶液和饱和水NaHCO3溶液的1:1混合物(10mL),并将混合物剧烈搅拌15分钟。分离有机层并进一步用饱和NaHCO3水溶液(10mL)洗涤,然后通过相分离器烧结漏斗。除去溶剂得到固体,将其通过快速柱色谱法纯化(用0至70%的EtOAc/异己烷梯度洗脱)得到标题产物,为白色固体(56mg,94%产率)。δH(400MHz,氯仿)9.45(d,J=0.9Hz,1H),8.58(s,1H),8.40(d,J=1.0Hz,1H),4.74(t,J=6.4Hz,1H),3.58-3.66(m,2H),2.90-2.98(m,2H),2.82(t,J=6.6Hz,2H),2.31(tt,J=8.0,4.8Hz,1H),1.75(dt,J=13.4,6.7Hz,1H),1.33-1.22(m,4H),0.87(d,J=6.7Hz,6H).LCMS[M+H]+359,RT 2.12分钟(方法3)。
实施例49
3-环丙基-7-羟基-7-甲基-N-(2-甲基丙基)-8,9-二氢环戊二烯并[h]异喹啉-5-
磺酰胺
在0℃下向实施例48(10.5mg,0.12mmol)的THF(1mL)溶液中加入1M甲基锂的THF溶液(0.349mL,0.35mmol)。将混合物在0℃下搅拌10分钟然后在室温下搅拌1小时。除去THF并将残余物分配在EtOAc(10mL)和水(5mL)之间。将有机层通过相分离器并除去溶剂得到胶状物,将其通过快速柱色谱法纯化(用0至70%的EtOAc/异己烷梯度洗脱)得到标题产物,为白色固体(10mg,90%产率)。δH(400MHz,氯仿)9.26(d,J=1.0Hz,1H),8.40(s,1H),8.27(d,J=1.0Hz,1H),4.66(t,J=6.4Hz,1H),3.45-3.60(m,1H),3.20-3.40(m,1H),2.65-2.87(m,2H),2.35-2.59(m,2H),2.20-2.32(m,1H),1.68-1.83(m,4H),1.04-1.29(m,4H),0.80-1.00(m,6H).LCMS[M+H]+375,RT 2.08分钟(方法3)。
实施例50
7-氨基-3-环丙基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰
胺
将中间体13(308mg,0.78mmol)悬浮在4M HCl的二氧六环溶液(5mL,0.02mmol)中并将混合物搅拌2小时。除去溶剂得到固体。通过SCX柱色谱法纯化,用0至100%NH3甲醇溶液梯度洗脱得到标题产物,为棕色固体(279mg,定量)。δH(300MHz,DMSO-d6)9.25(d,J=0.9Hz,1H),8.29-8.37(m,2H),7.98(s,1H),4.42(t,J=7.4Hz,1H),3.40-3.55(m,1H),3.11(dt,J=16.9,8.5,1H),2.62-2.86(m,2H),2.51-2.67(m,1H),2.28(p,J=6.4Hz,1H),1.73-1.90(m,1H),1.59(dt,J=13.4,6.7Hz,1H),1.04(d,J=6.4Hz,4H),0.75(dd,J=6.7,1.6Hz,6H).LCMS[M+H]+360,RT2.17分钟(方法3)。
实施例51
1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-
基]-3-乙基硫脲
将实施例50(120mg,0.33mmol)悬浮在DCM(5mL)和THF(5mL)的混合物中。向该悬浮液中加入DIPEA(0.089mL,0.50mmol)和异硫氰酸乙酯(0.044mL,0.50mmol)。将反应搅拌18小时。除去溶剂得到标题产物,为白色固体(130mg,87%产率)。δH(300MHz,甲醇-d4)9.21(d,J=1.0Hz,1H),8.38(s,2H),6.23(s,1H),3.45-3.70(m,1H),3.55(s,3H),2.80-2.90(m,1H),2.65-2.75(m,2H),2.31(tt,J=7.6,5.5,1H),1.99-2.20(m,1H),1.64(dq,J=13.4,6.7Hz,1H),1.03-1.35(m,7H),0.81(dd,J=6.7,1.9Hz,6H).LCMS[M+H]+447,RT 2.34分钟(方法3)。
实施例52
(7R*)-3-环丙基-7-[3-(乙基氨基)-1,2,4-三唑-4-基]-N-(2-甲基丙基)-8,9-二 氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(*或S)
向实施例51(118mg,0.26mmol)的DMF(5mL)溶液中加入甲酰肼(40mg,0.67mmol),接着加入氯化汞(181mg,0.67mmol)。将混合物搅拌2分钟,然后加入三乙胺(0.093mL,0.67mmol),并将混合物在80℃下加热18小时。将反应冷却并将CH3CN(10mL)加入混合物中然后将其通过硅藻土过滤,用过量的CH3CN(25mL)洗涤。除去溶剂得到棕色油状物。通过快速柱色谱法接着反相色谱法纯化,得到外消旋产物,为白色固体(9mg,6%产率)。外消旋物通过手性SFC纯化得到标题化合物,为白色固体(2mg,1.6%产率)。手性SFC RT**6.34分钟(实测质量为[M+H]+455).
**手性分析在Waters UPC2–SQD2系统上通过SFC进行,使用Chiralcel OJ-34.6x150mm,3μm柱,流速3.5mL/min,用10-25%甲醇洗脱,用8min运行时间。
实施例53
(7R*)-3-环丙基-7-[[2-(乙基氨基)-3,4-二氧代环丁烯-1-基]氨基]-N-(2-甲基 丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(*或S)
向实施例50(45mg,0.13mmol)的DCM(5mL)悬浮液中加入DIPEA(0.033mL,0.19mmol)和3,4-二甲氧基-3-环丁烯-1,2-二酮(27mg,0.19mmol)。将混合物搅拌18小时。将残余物溶于DCM(5mL)中并加入2M乙胺的THF溶液(3mL)。将混合物搅拌1小时。除去溶剂,将固体与DCM(3mL)一起研磨并过滤得到外消旋产物,为白色固体(50mg,83%产率)。外消旋物通过手性SFC分离得到标题产物,为白色固体(10mg,21%产率)。LCMS[M+H]+483,RT 2.12分钟(方法10)。手性SFC RT**=3.52分钟.
**手性分析在Waters UPC2–SQD2系统上通过SFC进行,使用Chiralcel OJ-34.6x150mm,3μm柱,流速3.5mL/min,用5-20%甲醇(+0.1%NH4OH)洗脱,用6min运行时间.
实施例54
3-环丙基-7-[[4-(乙基氨基)-1,1-二氧代-1,2,5-噻二唑-3-基]氨基]-N-(2-甲
基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
向实施例50(31mg,0.086mmol)的DCM(10mL)溶液中加入DIPEA(0.023mL,0.13mmol)和3,4-二乙氧基-1,2,5-噻二唑-1,1-二氧化物(0.027mL,0.13mmol)。将溶液搅拌3小时。将2M乙胺的THF溶液(0.085mL,0.17mmol)加入溶液中并将该溶液搅拌18小时。除去溶剂,将所得残余物通过快速柱色谱法纯化(用0至100%的EtOAc/异己烷梯度然后0至10%甲醇/乙酸乙酯梯度洗脱)得到标题产物,为白色固体(35mg,80%产率)。δH(300MHz,DMSO-d6)9.35(s,1H),8.98(d,J=7.2Hz,1H),8.48(d,J=5.4Hz,1H),8.38(d,J=1.0Hz,1H),8.25(s,1H),8.07(t,J=5.9Hz,1H),5.51(d,J=6.5Hz,1H),3.48-3.63(m,1H),3.29-3.48(m,3H),2.70-2.90(m,1H),2.50-2.70(m,2H),2.05-2.40(m,2H),1.60(dt,J=13.3,6.7Hz,1H),1.18(t,J=7.3Hz,3H),1.07(d,J=6.7,4H),0.76(dd,J=6.7,5.1Hz,6H).LCMS[M+H]+519,RT 2.09分钟(方法3)。
实施例55
2-氰基-1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异
喹啉-7-基]-3-(4-甲基苯基)胍
向实施例50(45mg,0.13mmol)在DCM(10mL)和THF(5mL)的混合物中的悬浮液中加入DIPEA(0.058mL,0.19mmol)和中间体30(47mg,0.19mmol)。将混合物搅拌18小时。除去溶剂得到残余物,将其通过快速柱色谱法纯化(用0至90%的EtOAc/异己烷梯度洗脱)得到标题产物,为无色胶状物(28mg,43%产率)。δH(300MHz,氯仿-d)9.17(s,1H),8.28(s,1H),8.26(s,1H),7.40(s,1H),7.20(d,J=7.4Hz,2H),7.15(d,J–7.4Hz,2H),5.70(q,J=7.2Hz,1H),5.05(d,J=3.1Hz,1H),4.00-4.20(m,1H),3.40-3.55(m,1H),3.15-3.35(m,1H),2.65-2.95(m,3H),2.30(s,3H),2.20-2.30(m,1H),1.90-2.05(m,1H),1.50-1.80(m,1H),1.10-1.25(m,3H),0.77-1.00(m,6H).LCMS[M+H]+517,RT 2.51分钟(方法3)。
实施例56
3-[[(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯 并[h]异喹啉-7-基]氨基甲酰基]氮杂环丁烷-1-甲酸叔丁酯[*或S]
向中间体38(33mg,0.087mmol)的DMF(2mL)溶液中加入DIPEA(0.046mL,0.26mmol)接着加入1-Boc-氮杂环丁烷-3-甲酸(21.7mg,0.105mmol)和HATU(41mg,0.10mmol)。将混合物搅拌18小时。然后加入水(10mL)和EtOAc(15mL)。分离有机层并用水(2x10mL)和盐水(10mL)洗涤,然后通过相分离器,除去溶剂得到棕色油状物。通过快速柱色谱法纯化,用0至100%EtOAc/异己烷接着0至10%甲醇/DCM梯度洗脱,得到标题产物,为白色固体(49mg,100%产率)。δH(400MHz,氯仿-d)9.19(d,J=0.9Hz,1H),8.21(t,J=1.1,2H),6.03(d,J=8.6Hz,1H),5.74(q,J=7.9Hz,1H),5.08(t,J=6.5Hz,1H),4.04-4.28(m,3H),3.45-3.60(m,1H),3.20-3.35(m,2H),3.10-3.20(m,1H),2.84-3.01(m,2H),2.25(tt,J=8.1,4.8Hz,1H),1.98-2.14(m,1H),1.60(s,9H),1.47(s,3H),1.05-1.35(m,6H).LCMS[M+H]+561,RT2.29分钟(方法3)。
实施例57
7-[(3R)-3-氨基哌啶-1-基]-3-环丙基-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环
戊二烯并[h]异喹啉-5-磺酰胺
向中间体19(216mg,0.39mmol)的DCM(2mL)溶液中加入TFA(2mL)。将溶液搅拌1小时。除去溶剂,使用1:1DCM/异己烷(2x10mL)共沸过量的TFA。得到的棕色胶状物通过SCX柱色谱纯化,用0至100%氨甲醇溶液梯度洗脱得到棕色胶状物。进一步通过反相柱色谱法纯化得到标题产物,为白色固体(17mg,10%产率)。δH(300MHz,氯仿-d)9.20(s,1H),8.41(d,J=12.4Hz,1H),8.31(d,J=14.7Hz,1H),4.45-4.68(m,1H),2.93-3.51(m,5H),2.06-2.81(m,10H),1.49-2.01(m,3H),1.25-1.40(m,6H),1.00-1.23(m,4H).LCMS[M+H]+461,RT 1.72分钟(方法3)。
实施例58
(2R)-1-[(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊 二烯并[h]异喹啉-7-基]-N-甲基吡咯烷-2-甲酰胺[*或S]
向中间体20(96mg,0.20mmol)在1,4-二氧六环(3mL)和甲苯(2mL)的混合物的溶液中加入环丙基硼酸(54mg,0.60mmol),接着加入乙酸钯(II)(2.2mg,0.010mmol)。用氮气鼓泡通过混合物2分钟,然后加入三环己基鏻四氟硼酸盐(11mg,0.030mmol)和磷酸三钾(106mg,0.50mmol)。用氮气鼓泡通过5分钟,然后将微波管加盖并在130℃下加热18小时。将饱和水Na2CO3溶液(10mL)和EtOAc(10mL)加入混合物中。通过硅藻土过滤混合物以除去Pd残余物。分离有机层并用饱和Na2CO3水溶液(15mL)和盐水(10mL)进一步洗涤,然后将溶液通过相分离器。除去溶剂得到棕色油状物。通过快速柱色谱法纯化,用0至100%的EtOAc/异己烷梯度,然后用0至10%甲醇/DCM梯度洗脱得到产物,为非对映异构体的混合物(42mg,43%产率)。混合物通过SFC分离得到标题化合物,为单一非对映异构体(4mg,13%产率)。δH(400MHz,DMSO-d6)9.25(d,J=0.9Hz,1H),8.39(d,J=1.0Hz,1H),8.33(d,J=4.0Hz,2H),7.81(d,J=4.9Hz,1H),4.60(t,J=6.5Hz,1H),3.37-3.51(m,1H),3.20-3.30(m,1H),2.96(2x s,2H),2.55-2.67(m,4H),1.98-2.46(m,6H),1.61-1.81(m,3H),1.25(s,3H),1.17(s,3H),1.05(d,J=6.4Hz,4H).LCMS[M+H]+489,RT 2.06分钟(方法11).
实施例59
N-[1-[3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并
[h]异喹啉-7-基]氮杂环丁烷-3-基]-2,5-二甲基吡唑-3-甲酰胺
向中间体23(15mg,0.035mmol)的DMF(1mL)溶液中加入DIPEA(0.018mL,0.10mmol)接着加入1,3-二甲基-1H-吡唑-5-甲酸(5.5mg,0.042mmol)和HATU(16.31mg,0.042mmol)。将反应将混合物搅拌2小时,将水(10mL)和EtOAc(15mL)加入混合物中。将有机层分离,用水(2x10mL)和盐水(10mL)进一步洗涤,然后通过相分离器。除去溶剂得到棕色油状物。通过快速柱色谱法纯化,用0至10%甲醇(含有7M NH3)/乙酸乙酯梯度洗脱得到标题产物,为白色固体(7.7mg,40%产率)。δH(400MHz,DMSO-d6)9.27(s,1H),8.70(d,J=6.8Hz,1H),8.38(s,2H),8.15(s,1H),6.66(s,1H),4.40(d,J=7.1Hz,2H),4.16(s,1H),3.93(s,3H),3.54(d,J=6.7Hz,2H),3.39(d,J=8.6Hz,1H),3.12(s,1H),2.80-2.95(m,2H),2.22-2.38(m,3H),2.15(s,4H),1.23(s,3H),1.16(s,3H),1.05(d,J=6.4Hz,4H).LCMS[M+H]+555,RT 1.76分钟(方法3)。
实施例60
3-环丙基-7-[(4,4-二甲基-3-氧代环丁烯-1-基)氨基]-N-(2-氟-2-甲基丙基)-
8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
向中间体36(90mg,0.24mmol)的THF溶液(3mL)溶液中加入DIPEA(0.062mL,0.36mmol),接着加入2,2-二甲基环丁烷-1,3-二酮(40mg,0.36mmol)。将混合物在70℃下搅拌18小时。除去溶剂得到棕色胶状物。通过快速柱色谱法纯化,用0至100%的EtOAc/异己烷梯度,然后用0至10%甲醇/DCM梯度洗脱得到标题产物,为浅棕色固体(68mg,60%产率)。δH(400MHz,氯仿-d)9.23(d,J=1.0Hz,1H),8.21-8.31(m,2H),5.79(d,J=8.0Hz,1H),5.00-5.20(m,2H),4.55(s,1H),3.55-3.65(m,1H),3.25-3.40(m,1H),2.83-3.16(m,3H),2.15-2.40(m,2H),1.25-1.43(m,12H),1.06-1.22(m,4H).LCMS[M+H]+472,RT 1.88分钟(方法3)。
实施例61
3-环丙基-N-(2-氟-2-甲基丙基)-7-(1H-吲哚-2-基甲基氨基)-8,9-二氢-7H-环
戊二烯并[h]异喹啉-5-磺酰胺
向中间体24(95mg,0.19mmol)在1,4-二氧六环(3mL)和甲苯(2mL)的混合物的溶液中加入环丙基硼酸(51mg,0.57mmol),接着加入乙酸钯(II)(2.1mg,0.0095mmol)。用氮气鼓泡通过混合物2分钟,然后加入三环己基鏻四氟硼酸盐(11mg,0.028mmol)和磷酸三钾(101mg,0.47mmol)。用氮气鼓泡通过5分钟,然后将微波管加盖并在微波中在130℃下加热18小时。将饱和NaHCO3水溶液(10mL)和EtOAc(10mL)加入混合物中。分离有机层并通过相分离器,除去溶剂得到绿色油状物。通过快速柱色谱法纯化,用0至100%EtOAc/异己烷梯度洗脱得到标题产物,为棕色胶状物(45mg,47%产率)。δH(400MHz,DMSO-d6)10.98-11.04(m,1H),9.25-9.30(m,1H),8.31-8.44(m,3H),7.45(d,J=7.7Hz,1H),7.31-7.38(m,1H),6.90-7.07(m,2H),6.35(s,1H),4.35-4.50(m,1H),3.90-4.05(m,2H),3.45-3.55(m,1H),3.15-3.25(m,1H),2.85-3.00(m,2H),2.70-2.85(m,1H),2.30(q,J=6.5Hz,1H),1.95-2.08(m,1H),1.10-1.30(m,6H),1.00-1.10(m,4H).LCMS[M+H]+507,RT 2.58分钟(方法3)。
实施例62
3-环丙基-9-羟基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰
胺
在微波管中,将中间体26(53mg,0.15mmol)溶于1,4-二氧六环(2.5mL)中,并加入碳酸铯(123mg,0.37mmol)和环丙基硼酸(41mg,0.45mmol)。将烧瓶抽空并置于氮气气氛下5分钟。然后加入氯(η2-P,C-三(2,4-二叔丁基苯基)亚磷酸酯)(三环己基膦)钯(II)(16mg,0.015mmol),并将烧瓶再次抽空并置于氮气气氛下。然后将反应在微波中在120℃下加热3小时。混合物用EtOAc(10mL)稀释并通过硅藻土过滤。通过快速柱色谱法纯化,用0至50%的EtOAc/异己烷梯度洗脱得到标题产物,为白色固体(5mg,9%产率)。δH(400MHz,氯仿-d)9.70(s,1H),8.34(s,1H),8.29(s,1H),5.92(dd,J=7.3,4.2Hz,1H),4.74(t,J=6.5Hz,1H),3.27-3.39(m,1H),2.99-3.12(m,1H),2.74(dq,J=9.4,6.2Hz,3H),2.25-2.40(m,1H),1.72(h,J=6.7Hz,1H),1.16-1.30(m,3H),1.09-1.21(m,2H),0.86(dd,J=5.5,1.1Hz,6H).LCMS[M+H]+361,RT 2.35分钟(方法3)。
实施例63
3-环丙基-N-(2-甲基丙基)-9-氧代-7,8-二氢环戊二烯并[h]异喹啉-5-磺酰胺
在0℃下向实施例62(44mg,0.12mmol)的DCM(4mL)的悬浮液中加入Dess-Martin高价碘化物(160mg,0.37mmol)。将混合物搅拌18小时。加入饱和硫代硫酸钠水溶液和饱和NaHCO3水溶液的1:1混合物(10mL),并将该混合物剧烈搅拌15分钟。分离有机层并用饱和NaHCO3水溶液(10mL)进一步洗涤,然后通过相分离器烧结漏斗。除去溶剂得到固体。通过快速柱色谱法纯化,用0至50%的EtOAc/异己烷梯度洗脱得到标题产物,为黄色固体(28mg,64%产率)。δH(400MHz,氯仿-d)10.40(d,J=0.9Hz,1H),8.45(s,1H),8.28(d,J=1.0Hz,1H),4.91(t,J=6.4Hz,1H),3.29-3.37(m,2H),2.87-2.95(m,2H),2.79(t,J=6.6Hz,2H),2.24(tt,J=8.2,4.8Hz,1H),1.73(dt,J=13.4,6.7Hz,1H),1.17-1.32(m,2H),1.04-1.14(m,2H),0.86(d,J=6.7Hz,6H).LCMS[M+H]+359,RT2.25分钟(方法3)。
实施例64
3-环丙基-9-羟基-9-甲基-N-(2-甲基丙基)-7,8-二氢环戊二烯并[h]异喹啉-5-
磺酰胺
在0℃下向实施例63(18mg,0.050mmol)的THF溶液(1mL)溶液中加入1M甲基锂的THF溶液(0.151mL,0.15mmol)。将混合物搅拌2小时。除去溶剂,并将残余物分配在H2O(3mL)和EtOAc(10mL)之间。产物进入有机层,然后通过相分离器烧结漏斗。除去溶剂得到黄色胶状物。通过快速柱色谱法纯化,用0至50%的EtOAc/异己烷梯度洗脱得到标题产物,为白色固体(4mg,21%产率)。δH(400MHz,氯仿-d)10.02(s,1H),8.22-8.29(m,2H),4.65(t,J=6.4Hz,1H),3.08-3.19(m,1H),2.95-3.05(m,1H),2.65-2.82(m,2H),2.50-2.60(m,1H),2.16-2.43(m,3H),1.46-1.93(m,4H),1.08-1.33(m,3H),1.10(t,J=3.1Hz,1H),0.83-0.98(m,6H).LCMS[M+H]+375,RT 2.14分钟(方法3)。
实施例65
3-环丙基-9-氟-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
在微波管中,将中间体27(43mg,0.12mmol)悬浮在甲苯(3mL)中并加入环丙基硼酸(33mg,0.36mmol)和磷酸三钾(64mg,0.30mmol)。将烧瓶抽空并置于氮气气氛下5分钟。然后加入三环己基鏻四氟硼酸盐(6.8mg,0.018mmol)和乙酸钯(II)(1.35mg,0.006mmol),并将烧瓶再次抽空并置于氮气气氛下。然后将反应在微波中在110℃下加热1小时15分钟。混合物再用环丙基硼酸(33mg,0.36mmol)和磷酸三钾(64mg,0.30mmol)、三环己基鏻四氟硼酸盐(6.8mg,0.018mmol)和乙酸钯(II)(1.35mg,0.006mmol)处理。将混合物用氮气吹扫并在110℃下加热2小时。除去溶剂得到残余物。通过快速柱色谱法纯化,用0至20%的EtOAc/异己烷梯度洗脱得到标题产物,为灰白色固体(13mg,30%产率)。δH(300MHz,氯仿-d)9.47(s,1H),8.34(d,J=1.4Hz,1H),8.27(d,J=1.0Hz,1H),6.63(ddd,J=56.6,6.9,2.9Hz,1H),4.68(t,J=6.4Hz,1H),3.24-3.53(m,1H),3.00-3.20(m,1H),2.44-2.84(m,3H),2.20-2.35(m,1H),1.65-1.80(m,1H),1.02-1.29(m,4H),0.85(dd,J=6.7,1.7Hz,6H).LCMS[M+H]+363,RT2.48分钟(方法3)。
实施例66
3-环丙基-9-[[4-(乙基氨基)-1,1-二氧代-1,2,5-噻二唑-3-基]氨基]-N-(2-甲
基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将中间体39(55mg,0.139mmol)溶于二氯甲烷(5mL)和N,N-二异丙基乙胺(54mg,0.417mmol)的混合物中。加入3,4-二乙氧基-1,2,5-噻二唑-1,1-二氧化物(45mg,0.208mmol)并将混合物在室温下搅拌2小时。再加入3,4-二乙氧基-1,2,5-噻二唑-1,1-二氧化物(14mg,0.070mmol)和N,N-二异丙基乙基胺(18mg,0.139mmol)。将混合物在室温下再搅拌1小时。加入乙胺溶液(2M的THF溶液)(2.8mL,5.56mmol)并将混合物在室温下搅拌1小时。蒸发溶剂,粗物质通过快速色谱法纯化(用75-100%EtOAc/己烷接着0-15%MeOH/EtOAc洗脱)得到标题化合物(63mg,87%产率)。δH(300MHz,d-DMSO),9.18(s,1H),8.93(d,J=7.5Hz,1H),8.39(s,1H),8.35–8.31(m,1H),8.29(s,1H),8.18–8.10(m,1H),5.98–5.90(m,1H),3.74–3.63(m,1H),3.53–3.43(m,1H),3.28–3.22(m,1H),3.20–3.08(m,1H),2.74–2.62(m,1H),2.58(t,J=6.3Hz,2H),2.34–2.21(m,2H),1.71–1.54(m,1H),1.13(t,J=7.3Hz,3H),1.05(d,J=6.5Hz,4H),0.79(dd,J=6.7,4.0Hz,6H).LCMS[M+H]+519,RT 2.14min(方法3)。
实施例67
9-[(4-氰基-1-甲基吡唑-3-基)氨基]-3-环丙基-N-(2-氟-2-甲基丙基)-8,9-二
氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将中间体84(50mg,0.132mmol)、3-溴-1-甲基-1H-吡唑-4-甲腈(37mg,0.198mmol)和叔丁醇钠(40mg,0.413mmol)在无水1,4-二氧六环(2mL)中的混合物真空脱气/氮气吹扫(x3)。加入tBuXPhos Pd G3(17mg,0.021mmol)并将混合物再次真空脱气/氮气吹扫(x3)。反应混合物在70℃下加热16小时,然后冷却至室温并通过硅藻土过滤,用二氧六环洗涤。蒸发溶剂,粗物质通过柱色谱法纯化得到标题化合物(23mg,36%产率)。δH(300MHz,d-DMSO),9.31(s,1H),8.44–8.35(m,2H),8.21–8.14(m,2H),6.82(d,J=8.9Hz,1H),5.76(td,J=8.5,3.8Hz,1H),3.73(s,3H),3.63–3.39(m,1H),3.31–3.11(m,1H),3.06–2.89(m,2H),2.66–2.54(m,1H),2.27(q,J=6.4Hz,1H),2.17–2.04(m,1H),1.32–1.18(m,6H),1.08–0.97(m,4H).LCMS[M-H]-481,RT 2.06min(方法10)。
实施例68
3-环丙基-N-(2-氟-2-甲基丙基)-9-(异喹啉-4-基氨基)-8,9-二氢-7H-环戊二烯
并[h]异喹啉-5-磺酰胺
将中间体84(50mg,0.132mmol)、4-溴异喹啉(41mg,0.198mmol)和叔丁醇钠(40mg,0.413mmol)在无水1,4-二氧六环(2mL)中的混合物真空脱气/氮气吹扫(x3)。加入tBuXPhosPd G3(17mg,0.021mmol)并将混合物再次真空脱气/氮气吹扫(x3)。将反应混合物在70℃下加热16小时,然后冷却至室温并通过硅藻土过滤,用二氧六环洗涤。蒸发溶剂,粗物质通过快速柱色谱法纯化得到标题化合物(25mg,37%产率)。δH(300MHz,d-DMSO),9.32(d,J=0.9Hz,1H),8.64(s,1H),8.47–8.39(m,2H),8.27(s,1H),8.20–8.07(m,2H),8.03–7.94(m,1H),7.66–7.54(m,2H),6.74(d,J=8.6Hz,1H),5.97(td,J=8.2,4.0Hz,1H),3.28(d,J=10.3Hz,1H),3.19–3.06(m,1H),3.00(dd,J=19.9,6.5Hz,2H),2.87–2.71(m,1H),2.34–2.13(m,2H),1.35–1.18(m,6H),1.03–0.93(m,4H).LCMS[M-H]-503,RT 1.71min(方法10)。
实施例69
2-氰基-1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异
喹啉-9-基]-3-(4-甲基苯基)胍
将中间体39(43mg,0.109mmol)溶于二氯甲烷(10mL)和N,N-二异丙基乙胺(42mg,0.326mmol)的混合物中。然后加入中间体30(41mg,0.163mmol)并将混合物在微波中在120℃下搅拌4小时。蒸发溶剂,粗物质通过快速柱色谱法纯化得到标题化合物(28mg,50%产率)。δH(300MHz,d-DMSO),9.32(d,J=0.9Hz,1H),9.16(s,1H),8.35(d,J=1.1Hz,1H),8.15(s,1H),8.07(t,J=5.9Hz,1H),7.75(d,J=8.7Hz,1H),7.08(d,J=8.3Hz,2H),7.02(d,J=8.4Hz,2H),6.04(td,J=8.6,4.1Hz,1H),3.27–3.12(m,1H),3.04–2.90(m,1H),2.70–2.53(m,3H),2.35–2.25(m,1H),2.22(s,3H),2.19–2.02(m,1H),1.66–1.54(m,1H),1.12–0.99(m,4H),0.80–0.72(m,6H).LCMS[M+H]+517,RT 2.53min(方法3)。
实施例70
3-环丙基-9-(甲磺酰氨基)-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹
啉-5-磺酰胺
将中间体39(16mg,0.040mmol)溶于二氯甲烷(2mL)和N,N-二异丙基乙胺(68mg,0.527mmol)中。加入甲磺酰氯(31mg,0.274mmol)。将混合物在室温下搅拌1小时。粗物质通过快速色谱法纯化(用30-100%EtOAc/己烷洗脱)得到标题化合物(8.5mg,48%产率)。δH(300MHz,d-DMSO),9.59(d,J=0.9Hz,1H),8.35(d,J=0.9Hz,1H),8.18(s,1H),8.11–8.01(m,1H),7.82–7.65(m,1H),5.59–5.43(m,1H),3.29–3.17(m,1H),3.10(s,3H),3.07–2.91(m,1H),2.75–2.61(m,1H),2.56(d,J=6.9Hz,2H),2.33–2.11(m,2H),1.68–1.51(m,1H),1.10–0.98(m,4H),0.80–0.68(m,6H).LCMS[M+H]+438,RT 2.11min(方法3)。
实施例71
1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-
基]-3-乙基硫脲
将中间体39(129mg,0.326mmol)溶于二氯甲烷(5mL)和N,N-二异丙基乙胺(63mg,0.489mmol)的混合物中。加入异硫氰酸乙酯(86mg,0.978mmol)并将混合物在室温下搅拌20小时,然后在45℃下搅拌2小时。粗物质通过快速色谱法纯化(用30-100%EtOAc/己烷然后用0-10%MeOH/EtOAc洗脱)得到标题化合物(93mg,64%产率)。δH(300MHz,d-DMSO),9.33(s,1H),8.35(d,J=1.0Hz,1H),8.19(s,1H),8.10–8.03(m,1H),7.98(d,J=9.0Hz,1H),7.49–7.10(m,1H),6.71–6.52(m,1H),3.54–3.33(m,2H),3.28–3.14(m,1H),3.09–2.94(m,1H),2.70–2.53(m,3H),2.33–2.19(m,1H),2.07–1.91(m,1H),1.69–1.54(m,1H),1.10–0.97(m,7H),0.81–0.72(m,6H).LCMS[M-H]-445,RT 2.29min(方法10)。
实施例72和73
3-环丙基-9-[3-(乙基氨基)-1,2,4-三唑-4-基]-N-(2-甲基丙基)-8,9-二氢-7H- 环戊二烯并[h]异喹啉-5-磺酰胺(72)
(9R*)-3-环丙基-9-[(4-乙基-1,2,4-三唑-3-基)氨基]-N-(2-甲基丙基)-8,9-二 氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S](73)
将实施例71(105mg,0.235mmol)溶于N,N-二甲基甲酰胺(5mL)中。加入甲酰肼(47mg,0.705mmol)和氯化汞(128mg,0.470mmol)。将混合物在室温下搅拌5min。然后加入三乙胺(72mg,0.705mmol)并将混合物在90℃下搅拌3h。反应混合物用MeCN(10mL)稀释并通过硅藻土垫过滤,用MeCN(3x10mL)洗涤。蒸发滤液,粗物质通过快速柱色谱法纯化,接着通过SFC纯化,得到实施例72和实施例73的外消旋混合物。
实施例72(11mg,10%产率)。δH(400MHz,d-DMSO),8.79(d,J=0.9Hz,1H),8.39(d,J=0.9Hz,1H),8.28(s,1H),8.18–8.08(m,1H),7.48(s,1H),6.35(t,J=5.5Hz,1H),6.24(dd,J=8.6,3.7Hz,1H),3.47–3.34(m,3H),3.21–3.10(m,1H),2.86–2.73(m,1H),2.66–2.55(m,2H),2.30–2.22(m,1H),2.21–2.10(m,1H),1.65–1.54(m,1H),1.26(t,J=7.2Hz,3H),1.06–0.95(m,4H),0.80–0.70(m,6H).
使用手性SFC分离实施例73的外消旋混合物(38mg,36%产率),得到标题化合物,为单一异构体(11mg,29%产率)。手性SFC RT**=2.24分钟;δH(400MHz,d-DMSO),9.38(s,1H),8.37(s,1H),8.20(s,1H),8.13–8.04(m,1H),8.03(s,1H),6.65(d,J=8.8Hz,1H),5.93–5.84(m,1H),3.72(q,J=7.2Hz,2H),3.31–3.21(m,1H),3.08–2.98(m,1H),2.73–2.62(m,1H),2.59–2.54(m,2H),2.25(p,J=6.5Hz,1H),2.19–2.10(m,1H),1.63(hept,J=6.8Hz,1H),1.16(t,J=7.2Hz,3H),1.06–0.94(m,4H),0.83–0.73(m,6H).LCMS[M+H]+455,RT 2.08min(方法16)。
**手性分析通过SFC在Waters UPC2–SQD2系统上进行,使用Chiralcel OJ-34.6x150mm,3μm柱,流速3.5mL/min,用10%甲醇等度洗脱方法,用5min运行时间。
实施例74
1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-
基]-3-吡啶-3-基硫脲
将中间体39(100mg,0.278mmol)溶于二氯甲烷(5mL)和N,N-二异丙基乙胺(54mg,0.417mmol)的混合物中。加入3-吡啶基异硫氰酸酯(60mg,0.417mmol)并将混合物在室温下搅拌过夜。粗物质通过快速色谱法纯化,用60-100%EtOAc/己烷然后用0-20%MeOH/EtOAc洗脱,得到标题化合物(104mg,75%产率)。δH(400MHz,d-DMSO),9.54(s,1H),9.37(s,1H),8.68(d,J=8.6Hz,1H),8.54(s,1H),8.38(d,J=1.0Hz,1H),8.29(d,J=4.8Hz,1H),8.22(s,1H),8.10(t,J=6.0Hz,1H),7.95(dt,J=8.2,2.1Hz,1H),7.34(dd,J=8.2,4.7Hz,1H),6.72–6.63(m,1H),3.29–3.21(m,1H),3.12–3.02(m,1H),2.74–2.67(m,1H),2.58(t,J=6.4Hz,2H),2.32–2.23(m,1H),2.18–2.08(m,1H),1.68–1.57(m,1H),1.10–0.99(m,4H),0.81–0.73(m,6H).LCMS[M+H]+496,RT 2.39min(方法3)。
实施例75
3-环丙基-N-(2-甲基丙基)-9-[(4-吡啶-3-基-1,2,4-三唑-3-基)氨基]-8,9-二
氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将实施例74(102mg,0.206mmol)溶于N,N-二甲基甲酰胺(5mL)中。加入甲酰肼(41mg,0.618mmol)和氯化汞(112mg,0.412mmol)。将混合物在室温下搅拌5min。加入三乙胺(63mg,0.618mmol)。将混合物在90℃下搅拌5小时,然后冷却至室温。然后将反应混合物用MeCN(10mL)稀释并通过硅藻土垫过滤,用MeCN(3x10mL)洗涤。蒸发滤液。粗物质通过反相快速柱色谱法纯化得到标题化合物(9mg,9%产率)。δH(400MHz,d-DMSO),9.44(d,J=0.9Hz,1H),8.63(d,J=2.5Hz,1H),8.60(dd,J=4.8,1.5Hz,1H),8.35–8.30(m,2H),8.17(s,1H),8.10–8.03(m,1H),7.87(ddd,J=8.2,2.6,1.5Hz,1H),7.53(dd,J=8.1,4.8Hz,1H),6.85(d,J=8.7Hz,1H),5.96–5.89(m,1H),3.29–3.20(m,1H),3.06–2.95(m,1H),2.74–2.62(m,1H),2.61–2.54(m,2H),2.31–2.15(m,2H),1.67–1.57(m,1H),1.07–0.99(m,4H),0.82–0.73(m,6H).LCMS[M+H]+504,RT 1.48min(方法10)。
实施例76
3-环丙基-N-(2-氟-2-甲基丙基)-9-[[6-(5-甲基-1,3,4-噁二唑-2-基)吡啶-3-
基]氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将中间体84(52mg,0.138mmol)、2-(5-溴-2-吡啶基)-5-甲基-1,3,4-噁二唑(50mg,0.207mmol)和叔丁醇钠(40mg,0.413mmol)在无水1,4-二氧六环(2mL)中的混合物真空脱气/氮气吹扫(x3)。加入tBuXPhos Pd G3(17mg,0.021mmol)并将混合物再次真空脱气/氮气吹扫(x3)。将反应混合物在70℃下加热16小时。冷却至室温,通过硅藻土过滤,用二氧六环洗涤。蒸发溶剂,粗物质通过快速柱色谱法纯化得到标题化合物(11mg,15%产率)。δH(300MHz,d-DMSO),9.25(d,J=0.8Hz,1H),8.50–8.40(m,2H),8.26(s,1H),8.20(d,J=2.7Hz,1H),7.92(d,J=8.7Hz,1H),7.29(dd,J=8.8,2.8Hz,1H),7.21(d,J=8.2Hz,1H),5.87–5.76(m,1H),3.29–3.20(m,1H),3.18–3.04(m,1H),3.02(d,J=6.4Hz,1H),2.96(d,J=6.4Hz,1H),2.76–2.61(m,1H),2.57(s,3H),2.36–2.22(m,1H),2.15–2.02(m,1H),1.32–1.18(m,6H),1.03(d,J=7.5Hz,4H).LCMS[M+H]+537,RT 1.97min(方法3)。
实施例77
3-环丙基-N-(2-氟-2-甲基丙基)-9-[[6-(2-甲基四唑-5-基)吡啶-3-基]氨基]-
8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将中间体84(52mg,0.138mmol)、5-溴-2-(2-甲基-2H-四唑-5-基)-吡啶(50mg,0.207mmol)和叔丁醇钠(40mg,0.413mmol)在无水1,4-二氧六环(2mL)中的混合物真空脱气/氮气吹扫(x3)。加入tBuXPhos Pd G3(17mg,0.021mmol)并将混合物再次真空脱气/氮气吹扫(x3)。将反应混合物在70℃下加热16小时,然后冷却至室温并通过硅藻土过滤,用二氧六环洗涤。蒸发溶剂,粗物质通过快速柱色谱法纯化得到标题化合物(16mg,22%产率)。δH(300MHz,d-DMSO),9.28(d,J=0.9Hz,1H),8.48–8.40(m,2H),8.26(s,1H),8.21(d,J=2.7Hz,1H),7.92(d,J=8.6Hz,1H),7.28(dd,J=8.7,2.8Hz,1H),6.96(d,J=8.3Hz,1H),5.86–5.74(m,1H),4.41(s,3H),3.31–3.19(m,1H),3.17–3.05(m,1H),3.02(d,J=6.4Hz,1H),2.96(d,J=6.4Hz,1H),2.75–2.59(m,1H),2.29(p,J=6.6Hz,1H),2.15–2.03(m,1H),1.32–1.18(m,6H),1.07–0.97(m,4H).LCMS[M+H]+537,RT 2.09min(方法3)。
实施例78
3-环丙基-9-[[3,4-二氧代-2-(吡啶-3-基氨基)环丁烯-1-基]氨基]-N-(2-甲基
丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将3-甲氧基-4-(3-吡啶基氨基)环丁-3-烯-1,2-二酮(43mg,0.209mmol)悬浮在二氯甲烷(3mL)中。加入N,N-二异丙基乙胺(27mg,0.209mmol)和甲醇(2mL)。然后加入中间体39(50mg,0.139mmol)并将混合物在室温下搅拌18小时。将形成的沉淀物滤出,并用DCM洗涤得到标题化合物(5.7mg,8%产率)。δH(400MHz,d-DMSO),9.54(s,1H),9.33(s,1H),8.51(d,J=2.8Hz,1H),8.41(s,1H),8.30(s,1H),8.25–8.12(m,3H),7.94–7.85(m,1H),7.36(dd,J=8.4,4.7Hz,1H),6.35–6.25(m,1H),3.36–3.27(m,1H),3.20–3.09(m,1H),2.80–2.70(m,1H),2.63–2.55(m,2H),2.37–2.23(m,2H),1.68–1.57(m,1H),1.09–1.01(m,4H),0.82–0.74(m,6H).LCMS[M+H]+532,RT 2.07min(方法3)。
实施例79
(9R*)-3-环丙基-9-[[2-(乙基氨基)-3,4-二氧代环丁烯-1-基]氨基]-N-(2-甲基 丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S]
将中间体39(43mg,0.109mmol)溶于二氯甲烷(10mL)和N,N-二异丙基乙胺(21mg,0.163mmol)的混合物中。加入3,4-二甲氧基-3-环丁烯-1,2-二酮(23mg,0.163mmol)并将混合物在室温下搅拌16小时。加入乙胺溶液(2M的THF溶液,2.17mL,4.34mmol)并将混合物在室温下搅拌1小时。蒸发溶剂,粗物质通过快速柱色谱法纯化得到标题化合物,为外消旋混合物(26.5mg,51%产率)。使用手性HPLC在极性有机模式下分离外消旋物得到标题化合物,为单一异构体(6.2mg,23%产率)。δH(300MHz,d-DMSO),9.26(s,1H),8.39(d,J=0.9Hz,1H),8.25(s,1H),8.17–8.09(m,1H),8.07–7.85(brs,1H),7.30–7.00(brs,1H),6.24(s,1H),3.50(s,3H),3.29–3.19(m,1H),3.14–3.01(m,1H),2.72–2.62(m,1H),2.60–2.53(m,2H),2.33–2.12(m,1H),1.67–1.54(m,1H),1.12(t,J=7.1Hz,3H),1.08–0.97(m,4H),0.81–0.70(m,6H).LCMS[M+H]+483,RT1.94min(方法3)。手性RT**=2.76分钟(峰2).
**在UV导向Agilent 1100系统上,在极性有机模式下进行分析,使用LuxCellulose-4,4.6x150mm,3μm柱,流速1mL/min,用100%甲醇洗脱,用10min运行时间。
实施例80
(9R*)-9-(1H-苯并咪唑-2-基氨基)-3-环丙基-N-(2-甲基丙基)-8,9-二氢-7H-环 戊二烯并[h]异喹啉-5-磺酰胺[*或S]
将中间体39(50mg,0.139mmol)、2-氯苯并咪唑(32mg,0.209mmol)和1-丁醇(3mL)装入微波管中。加入4M盐酸的二氧六环溶液(0.03mL,0.14mmol)。将密封的反应混合物在微波中在160℃下加热4.5小时并冷却至室温。蒸发溶剂,将残余物分配于DCM和饱和NaHCO3水溶液之间。有机相用盐水洗涤,通过相分离筒并蒸发。粗物质通过快速柱色谱法纯化得到标题化合物,为外消旋混合物(26mg,39%产率)。然后通过手性SFC分离外消旋物(20mg),得到标题化合物,为单一异构体(4mg,20%产率,来自手性分离,峰1).手性SFC RT**=6.36分钟;δH(300MHz,d-DMSO),10.85–10.65(m,1H),9.37(s,1H),8.36(s,1H),8.21(s,1H),8.15–8.00(m,1H),7.41–7.32(m,1H),7.27–7.10(m,2H),6.98–6.83(m,2H),6.17–6.06(m,1H),3.31–3.22(m,1H),3.11–2.97(m,1H),2.78–2.63(m,1H),2.57(d,J=6.9Hz,2H),2.30–2.09(m,2H),1.69–1.55(m,1H),1.03–0.91(m,4H),0.81–0.73(m,6H).LCMS[M+H]+476,RT2.50min(方法16)。
**手性分析通过SFC在Waters UPC2–SQD2系统上进行,使用Chiralcel OJ-34.6x150mm,3μm柱,流速3.5mL/min,用5-15%甲醇(+0.1%NH4OH)洗脱,用9min运行时间。
实施例81
3-环丙基-7-[3-(环丙基甲基氨基)-1,2,4-三唑-4-基]-N-(3,3-二氟环丁基)-8,
9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将中间体119(35mg,0.026mmol,50%纯度)在DCM(3mL)中搅拌并加入TFA(30.2μL,0.39mmol)。将反应在室温下搅拌30分钟。用饱和NaHCO3水溶液(10mL)淬灭有机悬浮液,分离有机层,水层用另外的DCM(3x20mL)萃取。合并有机层,用硫酸钠干燥并真空浓缩。橙色残余物通过酸性制备型HPLC纯化得到标题化合物(1mg,7%产率),为白色固体。δH(500MHz,甲醇-d4)9.31(s,1H),8.41(s,1H),8.12(s,1H),7.79(s,1H),5.96-5.90(m,1H),3.80-3.71(m,1H),3.59-3.46(m,2H),3.28-3.19(m,2H),3.06-2.95(m,1H),2.66-2.51(m,2H),2.47-2.38(m,1H),2.37-2.25(m,3H),1.25-1.19(m,1H),1.18-1.10(m,4H),0.60-0.53(m,2H),0.34-0.26(m,2H).LCMS[M+H]+515,RT 2.20min(方法12)。
实施例82
3-环丙基-7-[3-(环丙基甲基氨基)-1,2,4-三唑-4-基]-N-(3-氟环丁基)-8,9-二
氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
将中间体113(46mg,0.034mmol)在DCM(4mL)中搅拌并加入TFA(39μL,0.51mmol)。将反应在室温下搅拌30分钟。有机悬浮液用饱和NaHCO3水溶液(15mL)淬灭,分离有机层,水层用另外的DCM(3x20mL)萃取。合并有机层,用硫酸钠干燥并真空浓缩。橙色残余物通过HPLC纯化(碱性条件)得到标题产物(4.1mg,24%产率),为非对映异构体的约7:3的混合物(通过NMR观察).δH(500MHz,甲醇-d4)9.31(s,1H),8.41-8.37(m,1H),8.12(s,1H,异构体2),8.10(s,1H,异构体1),7.79(s,1H),5.98-5.89(m,1H),5.08-4.87(m,1H,异构体2),4.67-4.44(m,1H,异构体1),3.96-3.85(m,1H,异构体2),3.83-3.70(m,1H),3.60-3.43(m,1H),3.29-3.15(m,2H+异构体1,1H),3.08-2.92(m,1H),2.54-2.01(m,5H),1.99-1.77(m,1H),1.28-1.19(m,1H),1.18-1.06(m,4H),0.62-0.52(m,2H),0.36-0.23(m,2H).LCMS[M+H]+497,RT 2.13min(方法12)。
实施例83
3-环丙基-7-(甲磺酰氨基)-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹
啉-5-磺酰胺
将中间体58(255mg,0.59mmol)、环丙基硼酸(152mg,1.77mmol)和碳酸铯(385mg,1.18mmol)在无水1,4-二氧六环(1.5mL)中的混合物在氮气流下超声脱气5分钟。然后加入Bedford催化剂:(2-{[双(2,4-二-叔丁基苯氧基)膦基]氧基}-3,5-二叔丁基苯基)(氯)钯-三环己基膦(1:1)(63.06mg,0.06mmol),将管密封并将混合物在微波反应器中加热至120℃并搅拌2h。然后加入更多的Bedford催化剂(63.06mg,0.06mmol)和环丙基硼酸(152mg,1.77mmol),将混合物密封并在微波反应器中再加热至120℃并搅拌1小时以上。然后真空浓缩混合物。将所得残余物溶于EtOAc(5mL),并用水(5mL)洗涤。形成乳液,将混合物通过硅藻土塞。用EtOAc(5mL)洗涤除去的固体。将存在于滤液中的两相分离并用EtOAc(5mL)萃取水相。合并的有机萃取物用盐水洗涤(5mL),用MgSO4干燥,过滤并真空浓缩。粗物质通过制备型HPLC在碱性条件下纯化得到标题化合物(28mg,16.3%产率),为白色固体。δH(500MHz,氯仿-d)9.23(s,1H),8.39(s,1H),8.28(s,1H),5.20(app.q,J=7.6Hz,1H),4.76–4.62(m,2H),3.55(ddd,J=17.0,8.9,3.3Hz,1H),3.32–3.21(m,1H),3.15(s,3H),2.98–2.90(m,1H),2.84–2.72(m,2H),2.31–2.23(m,1H),2.23–2.15(m,1H),1.77–1.68(m,1H),1.20–1.15(m,2H),1.14–1.07(m,2H),0.86(dd,J=6.7,3.5Hz,6H).LCMS[M+H]+438,RT2.90min(方法12)。
实施例84
3-环丙基-7-[[3,4-二氧代-2-(吡啶-3-基氨基)环丁烯-1-基]氨基]-N-(2-甲基
丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺
向搅拌的中间体99(45mg,0.22mmol)在二氯甲烷(3mL)的悬浮液中加入N,N-二异丙基乙胺(0.04mL,0,2mmol),接着加入甲醇(2mL)以溶解混合物。加入实施例50(50mg,0.14mmol)并将所得混合物在室温下搅拌17小时。真空蒸发反应混合物,并将残余物通过柱色谱法纯化,使用0–100%乙酸乙酯/异己烷梯度,接着用1–20%甲醇/乙酸乙酯梯度,得到标题化合物(62mg,84%产率)。δH(300MHz,d6-DMSO)9.77(s,1H),9.35(d,J=0.9Hz,1H),8.55(d,J=2.8Hz,1H),8.37(d,J=0.9Hz,1H),8.25–8.21(m,1H),8.20(s,1H),8.11(m,1H),7.91(m,1H),7.37(dd,J=8.4,4.7Hz,1H),5.83(m,1H),3.59(m,1H),2.83(m,1H),2.54(m,2H),2.25(m,2H),1.56(dq,J=13.5,6.7Hz,1H),1.14–0.98(m,4H),0.73(dd,J=6.7,4.7Hz,6H).一个CH2被水峰掩盖。缺少一个NH2质子。LCMS[M+H]+532,RT 2.12min(方法16)。
实施例85
1-乙基-3-[(7R*)-3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯 并[h]异喹啉-7-基]脲[*或S]
将实施例50(60mg,0.15mmol)和异氰酸乙酯(33μL,0.41mmol)在二氯甲烷(3mL)中的混合物在室温下搅拌3小时。通过加入甲醇(1.5mL)淬灭反应混合物并真空蒸发。残余物通过柱色谱法纯化,使用0–100%乙酸乙酯/异己烷梯度得到产物(51mg),为对映异构体混合物。通过手性色谱法纯化得到标题化合物(14mg,29%产率)。手性SFC*RT=4.01min.δH(300MHz,d6-DMSO)9.26(d,J=0.9Hz,1H),8.34(s,1H),8.12(s,1H),8.02(s,1H),6.39(d,J=8.4Hz,1H),5.85(t,J=5.6Hz,1H),5.32(q,J=8.0Hz,1H),3.57–3.38(m,1H),3.25–3.00(m,3H),2.61(m,1H),2.56–2.52(m,2H),2.27(m,1H),1.90(m,1H),1.58(m,1H),1.09–0.99(m,7H),0.75(m,6H).LCMS[M+H]+431,RT 2.25min(方法16)。
*在Waters UPC2–SQD2系统上进行手性分析,使用Chiralpak IB-3 4.6x150mm,3μm柱,流速3.5mL/min,用10–25%甲醇(0.1%氢氧化铵)洗脱,用6min运行时间.
实施例86
(7R*)-3-环丙基-7-[3-[(2,5-二甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基]-N- (2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S]
根据通用程序2制备标题化合物,使用中间体116(410mg,0.77mmol)、甲酰肼(150mg,2.2mmol)、氯化汞(420mg,1.5mmol)、N,N-二甲基甲酰胺(15mL)和三乙胺(0.32mL,2.3mmol)。通过色谱法使用0–15%甲醇/二氯甲烷梯度纯化,接着通过反相柱色谱法使用0–100%乙腈/水(+0.1%氨)梯度纯化,得到标题化合物(229mg),为对映异构体混合物。通过手性SFC纯化样品得到标题化合物,为单一异构体(8mg).手性SFC RT**=6.62min.δH(300MHz,d6-DMSO)9.34(s,1H),8.55(s,0.5H,旋转异构),8.43(s,1H),8.03(s,1H),7.92(s,1H),6.08–5.93(m,1H),5.83(s,1H),3.66(m,1H),3.41(m,4H),2.87(m,1.5H,旋转异构),2.80(m,1.5H,旋转异构),2.36–2.24(m,2H),2.05(s,3H),1.17(d,J=2.5Hz,3H),1.10(d,J=2.5Hz,3H),1.06(m,4H).化合物是部分旋转异构的。缺少旋转异构的0.5个质子。缺少一个NH质子。LCMS[M+H]+539,RT 1.92min(方法6)。
**手性分析通过SFC在Waters UPC2–SQD2系统进行,使用Chiralcel OJ-34.6x150mm,3μm柱,流速3.5mL/min,用5–15%甲醇(0.1%氢氧化铵)洗脱,使用8min运行时间。
实施例87和88
(7R*)-3-环丙基-7-[3-[(2,5-二甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基]-N- (2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S](87)
3-环丙基-7-[[4-(2,5-二甲基吡唑-3-基)-1,2,4-三唑-3-基]氨基]-N-(2-甲基 丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(88)
根据通用程序5制备标题化合物,使用中间体117(145mg,0.28mmol)、甲酰肼(60mg,0.90mmol)、氯化汞(155mg,0.57mmol)、N,N-二甲基甲酰胺(5mL)和三乙胺(0.12mL,0.86mmol)。通过反相柱色谱法使用0–100%乙腈/水(+0.1%甲酸)梯度纯化,接着通过柱色谱法使用0–100%乙酸乙酯/异己烷然后1–50%甲醇/乙酸乙酯梯度纯化得到标题化合物。
得到实施例87(23mg),为对映异构体的混合物,将其通过手性色谱法分离得到标题化合物(6mg),为单一异构体。手性HPLC RT**=2.60min.δH(300MHz,d6-DMSO)9.36(d,J=0.9Hz,1H),8.36(d,J=0.9Hz,1H),8.02(m,3H),6.09–5.94(m,1H),5.82(s,1H),3.81–3.63(m,1H),3.45(m,4H),2.86(m,1H),2.46(m,3H部分被DMSO掩盖),2.35–2.24(m,1H),2.06(s,3H),1.49(dt,J=13.3,6.7Hz,1H),1.12–1.02(m,4H),0.67(dd,J=6.6,2.3Hz,6H).缺少一个NH质子。LCMS[M-H]-519,RT1.84min(方法3)。
**在Agilent 1100UV导向系统上通过极性有机模式进行手性分析,使用LuxCellulose-2 4.6x150mm,3μm柱,流速1mL/min,用甲醇(0.1%氢氧化铵)洗脱,用10min运行时间。
实施例88(34mg,23%产率);δH(300MHz,d6-DMSO)9.28(d,J=0.9Hz,1H),8.39(s,1H),8.32(d,J=0.9Hz,1H),8.22(s,1H),8.18(s,1H),6.81(d,J=8.5Hz,1H),6.28(s,1H),5.46(q,J=7.7Hz,1H),3.54(m,1H部分被水掩盖),3.50(s,3H部分被水掩盖),3.46(m,1H部分被水掩盖),3.26(m,2H部分被水掩盖),2.70(m,1H),2.32–2.23(m,1H),2.15(m,4H),1.56(dq,J=13.4,6.7Hz,1H),1.05(m,4H),0.74(dd,J=6.6,2.0Hz,6H).LCMS[M+H]+521,RT2.22min(方法16)。
实施例89
(7R*)-3-环丙基-N-(2-甲基丙基)-7-[3-[(5-甲基吡啶-3-基)氨基]-1,2,4-三 唑-4-基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S]
根据通用程序5制备标题化合物,使用中间体118(135mg,0.26mmol)、甲酰肼(55mg,0.82mmol)、氯化汞(145mg,0.53mmol)、N,N-二甲基甲酰胺(5mL)和三乙胺(0.11mL,0.79mmol)。通过反相柱色谱法使用0–100%乙腈/水(+0.1%甲酸)梯度纯化,得到标题化合物(61mg),为对映异构体混合物。通过手性色谱法纯化得到标题化合物,为单一异构体(17mg).手性HPLC RT**=2.13min.δH(300MHz,d6-DMSO)9.38(d,J=0.9Hz,1H),9.04(s,1H),8.54(d,J=2.5Hz,1H),8.37(d,J=0.9Hz,1H),8.08(t,J=5.9Hz,1H),8.02(s,1H),8.00(s,1H),7.97(d,J=1.9Hz,1H),7.94(t,J=2.1Hz,1H),6.18–6.06(m,1H),3.81–3.64(m,1H),3.52–3.37(m,1H),3.03–2.85(m,1H),2.48–2.39(m,2H),2.38–2.24(m,5H),1.51(dq,J=13.4,6.6Hz,1H),1.08(m,4H),0.68(dd,J=6.7,3.4Hz,6H).LCMS[M+H]+518,RT2.14min(方法16)。
**在Agilent 1100UV导向系统上通过极性有机模式进行手性分析,使用LuxCellulose-2 4.6x150mm,3μm柱,流速1mL/min,用甲醇洗脱,用10min运行时间。
实施例90和91
3-环丙基-N-(2-甲基丙基)-7-[(4-吡啶-3-基-1,2,4-三唑-3-基)氨基]-8,9-二 氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(90)
3-环丙基-N-(2-甲基丙基)-7-[3-(吡啶-3-基氨基)-1,2,4-三唑-4-基]-8,9-二 氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(91)
根据通用程序5制备标题化合物,使用实施例95(105mg,0.21mmol)、甲酰肼(42mg,0.63mmol)、氯化汞(115mg,0.42mmol)、N,N-二甲基甲酰胺(5mL)和三乙胺(0.09mL,0.60mmol)。通过反相柱色谱法,使用0–100%乙腈/水(+0.1%氨)梯度纯化得到产物(115mg),为混合物。通过SFC纯化样品得到标题化合物:
实施例90(4mg);δH(300MHz,d6-DMSO)9.28(s,1H),8.71(dd,J=2.6,0.7Hz,1H),8.64(dd,J=4.8,1.5Hz,1H),8.36(s,1H),8.34(s,1H),8.26(s,1H),8.10–7.87(m,2H),7.57(ddd,J=8.2,4.8,0.8Hz,1H),6.71(d,J=8.5Hz,1H),5.46(q,J=7.7Hz,1H),3.50(m,1H),3.23(m,1H),2.84–2.64(m,1H),2.35–2.09(m,2H),1.56(dq,J=13.7,6.9Hz,1H),1.04(m,4H),0.74(dd,J=6.6,3.7Hz,6H).两个CH2质子掩盖在DMSO峰下。LCMS[M+H]+504,RT2.04min(方法16)。
实施例91(10mg);δH(300MHz,d6-DMSO)9.38(d,J=0.9Hz,1H),9.20–8.99(m,1H),8.81–8.71(m,1H),8.37(d,J=0.9Hz,1H),8.18–8.03(m,3H),8.01(d,J=2.4Hz,2H),7.33(ddd,J=8.4,4.7,0.7Hz,1H),6.20–6.05(m,1H),3.81–3.62(m,1H),3.53–3.36(m,1H),3.03–2.86(m,1H),2.59–2.51(m,1H),2.34(m,3H),1.50(dt,J=13.4,6.7Hz,1H),1.13–1.03(m,4H),0.68(dd,J=6.7,3.3Hz,6H).LCMS[M+H]+504,RT 2.11min(方法16)。
实施例92
7-(1H-苯并咪唑-2-基氨基)-3-环丙基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯
并[h]异喹啉-5-磺酰胺
将实施例50(50mg,0.14mmol)、2-氯苯并咪唑(32mg,0.21mmol)和1-丁醇(3mL)装入微波管中。加入4M盐酸的二氧六环溶液(0.03mL,0.1mmol)并将密封的混合物在微波中在160℃下加热2小时。再加入2-氯苯并咪唑(10mg,0.07mmol)和4M盐酸的二氧六环溶液(2滴)并将混合物在微波中在160℃下加热1小时。冷却的反应混合物用25%氨水溶液(2mL)淬灭,分配于二氯甲烷(10mL)和饱和碳酸氢钠溶液(10mL)之间。分离水层并进一步萃取到二氯甲烷(10mL)中,合并的有机萃取物用盐水(10mL)洗涤,用硫酸钠干燥并真空蒸发。残余物通过柱色谱法,用0–100%乙酸乙酯/异己烷梯度接着1–30%甲醇/乙酸乙酯梯度纯化,然后通过反相柱色谱法使用0–100%乙腈/水(+0.1%氨)梯度纯化,得到标题化合物(12mg,18%产率)。δH(300MHz,d6-DMSO)11.72(broad s,1H),9.33(d,J=0.9Hz,1H),8.35(d,J=0.9Hz,1H),8.26(s,1H),8.04(t,J=6.0Hz,1H),7.25(m,2H),7.02(m,2H),5.58(q,J=7.8Hz,1H),3.67–3.48(m,1H),3.26(m,1H),2.93–2.73(m,1H),2.51(m,2H),2.37–2.24(m,1H),2.16(dq,J=15.6,7.8Hz,1H),1.54(dt,J=13.4,6.7Hz,1H),1.06(m,4H),0.70(dd,J=6.7,2.6Hz,6H).一个NH质子部分可观察到。LCMS[M+H]+476,RT 2.43min(方法16)。
实施例93
3-环丙基-N-(2-氟-2-甲基丙基)-9-吡啶-3-基氧基-8,9-二氢-7H-环戊二烯并
[h]异喹啉-5-磺酰胺
使用中间体91(36mg,0.08mmol)和相当化学计量的试剂,以与实施例94相同的方式合成。通过反相HPLC(碱性条件)纯化得到标题化合物(0.4mg,1%产率)。δH(400MHz,甲醇-d4)9.22(d,J=1.0Hz,1H),8.45(d,J=1.0Hz,1H),8.37–8.34(m,2H),8.23(dd,J=4.6,1.2Hz,1H),7.64(ddd,J=8.6,3.0,1.2Hz,1H),7.47(dd,J=8.5,4.8Hz,1H),6.59(dd,J=7.1,2.9Hz,1H),3.42–3.32(m,1H),3.20(ddd,J=16.8,9.0,4.2Hz,1H),3.06(d,J=19.6Hz,2H),2.95–2.83(m,1H),2.45–2.28(m,2H),1.24(dd,J=21.1,1.6Hz,6H),1.12–1.05(m,4H).LCMS[M+H]+456,RT 2.14分钟(方法3)。
实施例94
3-环丙基-N-(2-氟-2-甲基丙基)-7-吡啶-3-基氧基-8,9-二氢-7H-环戊二烯并
[h]异喹啉-5-磺酰胺
向中间体90(25mg,0.056mmol)在1,4-二氧六环(2mL)的溶液中加入环丙基硼酸(22mg,0.2433mmol)和碳酸铯(66mg,0.20mmol)。将混合物脱气,加入氯(η2-P,C-三(2,4-二叔丁基苯基)亚磷酸酯)(三环己基膦)钯(II)(9mg,0.01mmol),然后用N2吹扫5min。将所得混合物在100℃下加热10小时。然后将反应混合物通过硅藻土过滤(30mL DCM洗涤)。用H2O(50mL)稀释溶液并分离各相。用DCM(2x30mL)萃取水相,合并的有机物干燥(相分离器)并真空浓缩。通过反相HPLC(碱性条件)纯化得到标题化合物(0.6mg,2%产率)。δH(400MHz,甲醇-d4)9.28(d,J=1.0Hz,1H),8.44(d,J=1.0Hz,1H),8.38–8.33(m,2H),8.20(d,J=4.4Hz,1H),7.63(ddd,J=8.6,3.0,1.3Hz,1H),7.44(dd,J=8.5,4.8Hz,1H),6.14(dd,J=6.9,3.6Hz,1H),3.69–3.59(m,1H),3.53–3.42(m,1H),3.00(dd,J=19.4,1.3Hz,2H),2.95–2.86(m,1H),2.37(dddd,J=15.6,13.3,8.7,4.8Hz,2H),1.28–1.18(m,6H),1.17–1.08(m,4H).LCMS[M+H]+456,RT 2.14分钟(方法3)。
实施例95
1-[3-环丙基-5-(异丁基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]-
3-(3-吡啶基)硫脲
根据通用程序4制备标题化合物,使用实施例50(100mg,0.28mmol)、3-吡啶基异硫氰酸酯(0.05mL,0.42mmol)、N,N-二异丙基乙胺(0.07mL,0.4mmol)和二氯甲烷(10mL)。通过柱色谱法使用0–100%乙酸乙酯/异己烷梯度接着1–20%甲醇/乙酸乙酯梯度纯化,得到标题化合物(120mg,87%产率)。δH(300MHz,d6-DMSO)9.70(s,1H),9.30(d,J=0.9Hz,1H),8.66–8.49(m,2H),8.35(d,J=0.9Hz,1H),8.30(m,2H),8.08(t,J=5.9Hz,1H),7.97(ddd,J=8.3,2.6,1.5Hz,1H),7.36(ddd,J=8.2,4.7,0.7Hz,1H),6.17(m,1H),3.53(dd,J=16.4,7.9Hz,1H),3.30–3.18(m,1H),2.76(dq,J=12.7,4.6,4.1Hz,1H),2.61–2.53(m,2H),2.29(p,J=6.5Hz,1H),2.11(m,1H),1.60(dq,J=13.2,6.6Hz,1H),1.11–0.99(m,4H),0.76(dd,J=6.6,3.3Hz,6H).LCMS[M+H]+496,RT 2.40min(方法16)。
体外生化试验:
用于制备IgE-Tb试剂的方案
将86纳摩尔IgE-Fc(N265Q,N371Q)(Young等,1995)以在100mM pH 9.5的NaHCO3中172μM添加到1mg LanthaScreenTM胺反应性Tb螯合物(ThermoFisher产品编号PV3583)中,并在20℃下孵育16小时。然后将该物质缓冲交换到磷酸盐缓冲盐水(即,137mM NaCl,2.7mMKCl,10mM Na2HPO4,1.8mM K2HPO4,pH 7.4)中,并通过测量280nm和343nm处的吸收来定量物质和确定Tb结合程度。
在S200 HR 10x300柱(GE Healthcare)上通过分析尺寸排阻色谱法确定结合的物质的完整性。典型的结合比为4:1Tb:IgE-Fc。
Young RJ.,Owens,RJ.,MacKay GA.,Chan CMW.,Shi J.,Hide M.,Francis DM.,Henry AJ.,Sutton BJ.,and Gould HJ(1995)Protein Engineering 8:193-199。
用于制备SFcεR1α-Y131A-AF488试剂的方案
400纳摩尔的FcεR1α(Y131A突变体)(Cook等,1997)以在100mM pH 5.5的NaOAc中400μM与1mM终浓度的高碘酸钠(在100mM pH5.5的NaOAc中)在22℃下反应60分钟。通过添加40μL乙二醇淬灭氧化,并在22℃下孵育60分钟。将蛋白质缓冲交换到结合缓冲液(50mMNaHCO3,150mM NaCl,pH 9.5)中,并浓缩至750μM。
将175纳摩尔的蛋白质添加到1mg的Alexa FluorTM 488酰肼(Invitrogen)中,并在22℃下孵育16小时。加入氰基硼氢化钠(在结合缓冲液中为100mM)至终浓度为1mM,并在冰上孵育60分钟。将蛋白质缓冲交换到磷酸盐缓冲盐水(即,137mM NaCl,2.7mM KCl,10mMNa2HPO4,1.8mM K2HPO4,pH 7.4)中,然后通过测量280nm和495nm下的吸收来定量物质并确定Alexa FluorTM 488结合程度。
在S200 HR 10x300柱(GE Healthcare)上通过分析尺寸排阻色谱法确定结合材料的完整性。典型的结合比为2:1Alexa FluorTM488:sFcεR1α。
Cook JPD.,Henry AJ.,McDonnell JM.,Owens RJ.,Sutton BJ.,和Gould HJ(1997)Biochemistry 36:15579-15588。
目的是使用体外荧光共振能量转移(FRET)试验来测量IgE-Tb与受体的结合,以及化合物对其的抑制作用。
试剂
使用的FRET试剂是用铽(FRET给体)标记的IgE和用Alexa FluorTM488(FRET受体)标记的具有Y131A突变的可溶性IgE受体FcεRIα。未标记的FcεRIα也用于生成背景对照。试验缓冲液由20mM pH7.2的Tris、150mM NaCl、0.002%Tween和1%DMSO组成。
试验反应
根据以下进行试验:在384孔半体积板中以25μl的体积进行每个试验反应。在DMSO中产生10点化合物连续稀释液(3倍),浓度为最终试验浓度(FAC)的50倍。然后通过在试验缓冲液中10倍稀释IgE-Tb来制备化合物溶液。对于该试验,将5μl的稀释的化合物添加到10μl的IgE-Tb中,然后添加10μl的FcεRIα-Y131A-AF488。FRET试剂的FAC为5nM IgE-Tb、25nMFcεRIα-Y131A-AF488。通常试验中化合物的最高FAC为10μM。最终的DMSO浓度为2%。通过向FRET试剂中添加5μl的未标记的1μM的FcεRIα(FAC=200nM)来测量最小信号(MIN)。在含有FRET试剂但不含化合物的孔中测量到最大FRET信号(MAX)。
将该试验在室温下孵育2小时,避光并避免蒸发,同时温和搅拌。
FRET测量
通过在330nm处激发并使用Envision读板器(Perkin Elmer)在495/520nm处测量发射来进行每个孔的FRET测量。FRET比计算如下:
520处的发射/495处的发射x 1000。
FRET比用于数据分析。
数据分析
Z’计算如下(σ=标准偏差,μ=平均值):
1-((3xσMAX)+(3xσMIN))/(μMAX–μMIN)
Z’高于0.5被认为是良好的试验。
从所有孔中扣除背景信号(MIN)。使用扣除背景的值,每个测试孔中化合物的抑制百分比计算如下:
100–测试孔FRET比/最大FRET比x 100.
将抑制百分比对化合物浓度作图。使用XLFIT5软件包使用四参数逻辑拟合模型确定每种化合物的IC50值。
化合物显示范围为4n M至3602nM的IC50值。
下表显示了每个实施例的IC50值范围:
Claims (18)
1.通式(I)的化合物或其药学上可接受的盐,
其中:
X为C或N,
Y为C或O,
当Y为O时,R1为氢或羟基,R1’为氢且R2、R2’不存在;
R1表示
氢,
羟基;
氧代基;
氨基;
C1-6-烷基;
C1-6-烷基氨基;
C(O)OH;
C(O)NH-杂芳基;
-NH-C1-6-烷基-C3-6-环烷基;
-NH-C1-6-烷基-C(O)OH,任选地被氨基取代;
-NH-环烷基,任选地被一个或多个选自以下的基团取代:卤素;氧代基;C1-6-烷基;C1-6-烷基氨基;C1-6-烷基-C1-4-烷基氨基;C3-8-环烷基-C1-6-烷基氨基;杂芳基;任选地被一个或多个C1-6-烷基取代的杂芳基氨基;
杂芳基,任选地被一个或多个选自以下的基团取代:卤素;羟基;氧代基;氨基;氰基;-C(O)-C1-6-烷基;C1-6-烷基;C1-6-烷基氨基;C1-6-烷氧基;-NH-(C1-6-烷基)-杂环烷基;任选地被一个或多个C1-6-烷基取代的-NH-(C1-6-烷基)-杂芳基;-NH-C1-6-烷基-环烷基;-NH-C(O)-环烷基;被一个或多个C1-6-烷基取代的-NH-杂芳基;-NH-C1-6-烷基-C(O)OH;
被杂芳基氨基取代的杂芳基,所述杂芳基氨基任选地被以下基团取代:C1-6-烷基;C1-6-烷氧基;C3-6-环烷基;C1-6-卤代烷氧基;C1-6-卤代烷基;CN;卤素;C(O)OH;-C(O)O-C1-6-烷基;
-NH-C(S)-NH-Ra1;
-NH-SO2-Rb1;
-NH-杂芳基,任选地被一个或多个选自以下的基团取代:氧代基;C1-6-烷基;C1-6-烷基氨基;杂芳基,任选地被一个或多个氧代基、C1-6-烷基、-C(O)-NHNH-C(O)CH3、芳基、杂芳基氨基、C1-6-烷氧基、C3-6-环烷基、C1-6-卤代烷氧基、C1-6-卤代烷基、CN、卤素、C(O)OH、-C(O)O-C1-6-烷基取代;
-NH-杂环烷基,任选地被一个或多个选自以下的基团取代:卤素;C1-6-烷基;氧代基;杂芳基;C(O)ORb1;C1-6-烷基-NRb1Rb1;NHC(O)-芳基;NHC(O)-杂芳基;
被一个杂芳基取代的-NH-C1-6-烷基,所述杂芳基任选地被一个或多个选自以下的基团取代:C1-6-烷基;氨基;
-NH-C(O)O-Rb1;
-NH-C(NCN)-NH-Ra1;
-NH-C(NCN)-NH-杂芳基;
-NH-C(O)-C3-8-杂环烷基-C(O)O-Rb1;
-C(O)NH-C1-6-烷基;
-NH-C(O)NH-C1-6-烷基,任选地被一个或多个C3-8-杂环烷基取代;
-NH-C(O)NH-杂环烷基-C1-6-烷基;
-NH-C1-6-烷基-C(O)-C1-6-烷基氨基;
杂芳氧基;
-NH-C(O)-芳基;
-NH-C(O)-杂芳基;
-NH-C(O)-杂环烷基;
-NH-C(O)-C1-6-烷基,任选地被一个或多个氨基取代;
-NH-C(O)-C1-6-烷基-C(O)ORb1,任选地被选自以下的基团取代:氨基;-NH-C(O)ORb1;
杂环烷基,任选地被一个或多个选自以下的基团取代:氨基;-C(O)NH-Rb1;-C(O)ORb1;任选地被一个或多个C1-6-烷基取代的-NHC(O)-杂芳基;任选地被氨基取代的-NHC(O)-C1-6-烷基;-NHC(O)O-C1-6-烷基;-NH-C(O)Rb1;
-C2-6-烯基,任选地被一个或多个选自以下的基团取代:卤素;=NH基;
Ra1表示
C1-6-烷基;或
芳基,任选地被一个或多个C1-6-烷基取代;或
杂芳基,任选地被一个或多个C1-6-烷基取代;
Rb1表示
氢;或
C1-6-烷基;或
芳基,任选地被一个或多个卤素、C1-6-烷基、羟基取代;
R1’表示
氢;
羟基;
R2表示
氢;
卤素;
羟基;
氧代基;
C1-6-烷基;
C3-8-杂环烷基,任选地被一个或多个以下基团取代:羟基;卤素;氨基;氨基-C-1-6-烷基;C1-6-烷基;C(O)O-C1-6-烷基;C(O)NH2;
杂芳基,任选地被一个或多个选自以下的基团取代:C1-6-烷基氨基;任选地被一个或多个C1-6-烷基取代的杂芳基;卤素;
杂芳基,任选地被-NH-杂芳基取代,所述-NH-杂芳基任选地被一个或多个以下基团取代:C1-6-烷基;卤素;氰基;-C(O)OH;-C(O)O-C1-6-烷基;C1-6-卤代烷基;C1-6-烷氧基;C1-6-卤代烷氧基;C3-6-环烷基;
-NH-环烷基,任选地被一个或多个选自以下的基团取代:卤素;氧代基;C1-6-烷基;C1-6-烷基氨基;C1-6-烷基-C1-4-烷基氨基;C3-8-环烷基-C1-6-烷基氨基;芳基;杂芳基;任选地被一个或多个C1-6-烷基取代的杂芳基氨基;
-NH-杂芳基,任选地被一个或多个选自以下的基团取代:羟基;卤素;氧代基;C1-6-烷基;C1-6-烷氧基;杂芳基,任选地被一个或多个以下基团取代:羟基,卤素,氧代基,C1-6-烷基,C(O)O-C1-6-烷基,C(O)OH,C1-6-卤代烷基,C1-6-烷氧基,C1-6-卤代烷氧基,C3-6-环烷基,C1-6-烷基氨基,氰基,被一个或多个羟基、卤素、氧代基取代的杂环烷基;
被一个杂芳基取代的-NH-C1-6-烷基,所述杂芳基任选地被一个或多个选自C1-6-烷基的基团取代;
-NH-SO2-杂芳基,任选地被一个或多个选自卤素的基团取代;
-NHC(O)-C1-6-烷基,任选地被一个或多个以下基团取代:卤素;C1-6-烷氧基;氨基;C3-8-环烷基;C3-8-杂环烷基;杂芳基;
-NHC(O)-杂芳基,任选地被一个或多个选自以下的基团取代:卤素;羟基;氧代基;C1-6-烷基;杂芳基;C1-6-烷基氨基;S(O)2-C1-3-烷基;-NHC(O)-C1-6-烷基;
-NHC(O)-C3-8-杂环烷基,任选地被一个或多个氧代基、C1-6-烷基取代;
-NHC(O)O-C1-6-烷基;
-NHC(O)O-C1-6-烷基-Ra2;
-NHC(O)O-芳基;
-NHC(O)NH-Ra2;
-NHC(O)NH-C1-6-烷基-Ra2;
-NH-C(NCN)-NH-Ra1;
-NHC(O)-C3-8-环烷基;
-NH-SO2-Rb2;
-NH-C(S)-NH-Rb2;
-NH-C3-8-杂环烷基,任选地被一个或多个选自以下的基团取代:氧代基;C1-6-烷基;
芳氧基;
杂芳氧基;
Ra2表示
氢;
芳基,任选地被一个或多个选自以下的基团取代:卤素;羟基;氧代基;C1-6-烷基;
杂芳基,任选地被一个或多个选自以下的基团取代:卤素;羟基;氧代基;C1-6-烷基;
Rb2表示
C1-6-烷基;
杂芳基;
R2’表示
氢;
羟基;
R3表示选自以下的基团:
C1-6-烷基,任选地被一个或多个选自R3a的基团取代;
C1-3-亚烷基-C3-6-环烷基,任选地被一个或多个R3a取代;
C1-3-亚烷基-C3-6-杂环烷基,任选地被一个或多个R3a取代;
C3-6-杂环烷基,任选地被一个或多个R3a取代;
C3-6-环烷基,任选地被一个或多个R3a取代;
R3a表示选自以下的基团:氢;卤素;C1-2-烷基;羟基;C1-2-烷氧基;
R4表示选自以下的基团:
C3-6-环烷基,任选地被一个或多个R4a基团取代;或C1-6-亚烷基-C3-6-环烷基,任选地被一个或多个R4a基团取代;或C1-6-亚烷基-C3-6-杂环烷基,任选地被一个或多个R4a基团取代;
R4a表示选自以下的基团:羟基;卤素;C1-2-烷基。
R5表示
氢、甲基或卤素;
条件是:
-当R1’是羟基时,则R1选自吡啶基、C1-6-烷基;
-当R2’是羟基时,则R2选自吡啶基、C1-6-烷基;
-当R1不是氢时,则R2和R2’是氢;
-当R2不是氢时,则R1和R1’是氢;
-当R1是氧代基时,R1’不存在;
-当R2是氧代基时,R2’不存在;
2.根据权利要求1的通式(I)的化合物,其中R4表示环丙基或螺[2.2]戊基;任选地被一个或多个独立地选自以下的基团取代:羟基;氯;氟;溴;甲基。
3.根据前述权利要求中任一项的通式(I)的化合物,其中R4表示环丙基。
4.根据前述权利要求中任一项的通式(I)的化合物,其中R1表示:
氢;甲氧基咪唑并吡啶基;羧基;环丙基-甲基-氨基甲酰-氨基;吡啶-羰基氨基;羟基(吡啶基);[(氟碳亚胺酰基)丙烯基];[(环丙基甲基氨基)咪唑基];[[(环丙基甲基)咪唑基]氨基];[(二甲基吡唑基)氨基硫代甲酰基氨基];[[(二甲基吡唑基)-三唑基]氨基];(吡啶基氨基);(叔丁氧羰基氨基);氨基;[(环丙基甲基氨基)-三唑基];吡啶基氨基甲酰基;[(环丙烷羰基氨基)吡唑基];(氨基四唑基);[[(甲基四唑基)吡啶基]氨基];[(甲基吡唑并吡啶基)氨基];[[(甲基-噁二唑基)-吡啶基]氨基];氧代;羟基(甲基);乙基氨基硫代甲酰基氨基);[(乙基氨基)-三唑基];[[(乙基氨基)-二氧代-环丁烯基]氨基];[[(乙基氨基)-二氧代-噻二唑基]氨基];[[N'-氰基-N-(对甲苯基)氨基甲酰亚胺基]氨基];[(叔丁氧羰基氮杂环丁烷-羰基)氨基];[氨基哌啶基];[(甲基氨基甲酰基)吡咯烷基];[[(二甲基吡唑-羰基)氨基]氮杂环丁烷基];[(二甲基-氧代-环丁烯基)氨基];(吲哚基甲基氨基);甲磺酰氨基;[[二氧代(吡啶基氨基)环丁烯基]氨基];乙基氨基甲酰氨基;[[(二甲基吡唑基)氨基]-三唑基];[[(甲基-吡啶基)氨基]-三唑基];[[(吡啶基)-三唑基]氨基];[(吡啶基氨基)-三唑基];(苯并咪唑基氨基);吡啶基氧基;(吡啶基氨基硫代甲酰基氨基)。
5.根据前述权利要求中任一项的通式(I)的化合物,其中R2表示:
氢;[(甲基苯并三唑基)-三唑基]甲基;[[(甲基吡唑基)-三唑基]氨基];[[(甲基吡唑基)氨基]-三唑基];[[(氟-吡啶基)-三唑基]氨基];[[(氟-吡啶基)氨基]-三唑基];(吡啶基甲基氨基);(吡啶基磺酰基氨基);[(氟-吲哚羰基)氨基];[(甲基苯并咪唑基)氨基];[(甲氧基羰基-吡啶基)氨基];[(羧基吡啶基)氨基];[(甲基-吡唑-羰基)氨基];(吡啶-羰基氨基);[(甲基环丙烷羰基)氨基];(嘧啶基氨基);[(氧代吲哚啉基)氨基];[(甲氧基吡啶基)氨基];(吡啶基氨基);[(甲基吡唑并吡啶基)氨基];苄氧基羰基氨基;[(溴苯基)氨基甲酰氨基];[(二甲基吡唑基)甲基氨基甲酰氨基];羟基;氧代;甲基;氟;[[(乙基氨基)-二氧代-噻二唑基]氨基];[(氰基甲基-吡唑基)氨基];(异喹啉基氨基);[[N'-氰基-N-(对甲苯基)氨基甲酰亚胺基]氨基];甲磺酰氨基;乙基氨基硫代甲酰基氨基;[(乙基氨基)-三唑基];[(乙基-三唑基)氨基];(吡啶基氨基硫代甲酰基氨基);[[(吡啶基)-三唑基]氨基];[[(甲基四唑基)-吡啶基]氨基];[[二氧代-(吡啶基氨基)环丁烯基]氨基];[[(乙基氨基)-二氧代-环丁烯基]氨基];(苯并咪唑基氨基);吡啶基氧基。
6.根据前述权利要求中任一项的通式(I)的化合物,其中R1表示:
氢;(7-甲氧基咪唑并[4,5-b]吡啶-3-基);羧基;环丙基-甲基-氨基甲酰-氨基;吡啶-3-羰基氨基;羟基(3-吡啶基);[1-(氟碳亚胺酰基)丙-1-烯基];[2-(环丙基甲基氨基)咪唑-1-基];[[1-(环丙基甲基)咪唑-2-基]氨基];[(2,5-二甲基吡唑-3-基)氨基硫代甲酰基氨基];[[4-(2,5-二甲基吡唑-3-基)-1,2,4-三唑-3-基]氨基];(3-吡啶基氨基);(叔丁氧羰基氨基);氨基;[3-(环丙基甲基氨基)-1,2,4-三唑-4-基];3-吡啶基氨基甲酰基;[5-(环丙烷羰基氨基)吡唑-1-基];(5-氨基四唑-1-基);[[6-(2-甲基四唑-5-基)-3-吡啶基]氨基];[(1-甲基吡唑并[3,4-c]吡啶-4-基)氨基];[[6-(5-甲基-1,3,4-噁二唑-2-基)-3-吡啶基]氨基];氧代;羟基(甲基);(乙基氨基硫代甲酰基氨基);[3-(乙基氨基)-1,2,4-三唑-4-基];[[2-(乙基氨基)-3,4-二氧代-环丁烯-1-基]氨基];[[4-(乙基氨基)-1,1-二氧代-1,2,5-噻二唑-3-基]氨基];[[N'-氰基-N-(对甲苯基)氨基甲酰亚胺基]氨基];[(1-叔丁氧羰基氮杂环丁烷-3-羰基)氨基];[3-氨基-1-哌啶基];[(2R)-2-(甲基氨基甲酰基)吡咯烷-1-基];[3-[(2,5-二甲基吡唑-3-羰基)氨基]氮杂环丁烷-1-基];[(4,4-二甲基-3-氧代-环丁烯-1-基)氨基];(1H-吲哚-2-基甲基氨基);甲磺酰氨基;[[3,4-二氧代-2-(3-吡啶基氨基)环丁烯-1-基]氨基];乙基氨基甲酰氨基;[3-[(2,5-二甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基];[3-[(5-甲基-3-吡啶基)氨基]-1,2,4-三唑-4-基];[[4-(3-吡啶基)-1,2,4-三唑-3-基]氨基];[3-(3-吡啶基氨基)-1,2,4-三唑-4-基];(1H-苯并咪唑-2-基氨基);3-吡啶基氧基;(3-吡啶基氨基硫代甲酰基氨基)。
7.根据前述权利要求中任一项的通式(I)的化合物,其中R2表示:
氢;[4-(1-甲基苯并三唑-4-基)-1,2,4-三唑-3-基]甲基;[[4-(2-甲基吡唑-3-基)-1,2,4-三唑-3-基]氨基];[3-[(2-甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基];[[4-(5-氟-3-吡啶基)-1,2,4-三唑-3-基]氨基];[3-[(5-氟-3-吡啶基)氨基]-1,2,4-三唑-4-基];(3-吡啶基甲基氨基);(3-吡啶基磺酰基氨基);[(6-氟-1H-吲哚-3-羰基)氨基];[(1-甲基苯并咪唑-2-基)氨基];[(6-甲氧基羰基-3-吡啶基)氨基];[(6-羧基-3-吡啶基)氨基];[(5-甲基-1H-吡唑-3-羰基)氨基];(吡啶-3-羰基氨基);[(2-甲基环丙烷羰基)氨基];(嘧啶-5-基氨基);(2-氧代吲哚啉-5-基)氨基];[(5-甲氧基-3-吡啶基)氨基];(3-吡啶基氨基);[(1-甲基吡唑并[3,4-c]吡啶-4-基)氨基];苄氧基羰基氨基;[(4-溴苯基)氨基甲酰氨基];[(2,5-二甲基吡唑-3-基)甲基氨基甲酰氨基];羟基;氧代;甲基;氟;[[4-(乙基氨基)-1,1-二氧代-1,2,5-噻二唑-3-基]氨基];[(4-氰基-1-甲基-吡唑-3-基)氨基];(4-异喹啉基氨基);[[N'-氰基-N-(对甲苯基)氨基甲酰亚胺基]氨基];甲磺酰氨基;乙基氨基硫代甲酰基氨基;[3-(乙基氨基)-1,2,4-三唑-4-基];[(4-乙基-1,2,4-三唑-3-基)氨基];(3-吡啶基氨基硫代甲酰基氨基);[[4-(3-吡啶基)-1,2,4-三唑-3-基]氨基];[[6-(2-甲基四唑-5-基)-3-吡啶基]氨基];[[3,4-二氧代-2-(3-吡啶基氨基)环丁烯-1-基]氨基];[[2-(乙基氨基)-3,4-二氧代-环丁烯-1-基]氨基];(1H-苯并咪唑-2-基氨基);3-吡啶基氧基。
8.根据权利要求1的通式(I)的化合物,其选自:
3-环丙基-N-(2-氟-2-甲基丙基)-7-(7-甲氧基咪唑并[4,5-b]吡啶-3-基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-异丁基-9-[[4-(1-甲基苯并三唑-4-基)-1,2,4-三唑-3-基]氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-异丁基-9-[[4-(2-甲基吡唑-3-基)-1,2,4-三唑-3-基]氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-异丁基-9-[3-[(2-甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-9-[[4-(5-氟-3-吡啶基)-1,2,4-三唑-3-基]氨基]-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-9-[3-[(5-氟-3-吡啶基)氨基]-1,2,4-三唑-4-基]-N-异丁基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-甲酸;
1-(环丙基甲基)-3-[(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]脲[*或S];
N-[(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]吡啶-3-甲酰胺[*或S];
3-环丙基-N-(2-氟-2-甲基丙基)-7-羟基-7-吡啶-3-基-8,9-二氢环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-7-(2-氟吡啶-3-基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
(7R*)-3-环丙基-7-[2-(环丙基甲基氨基)咪唑-1-基]-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
(7R*)-3-环丙基-7-[[1-(环丙基甲基)咪唑-2-基]氨基]-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
3-环丙基-N-(2-甲基丙基)-9-(吡啶-3-基甲基氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-甲基丙基)-9-(吡啶-3-基磺酰基氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
6-氟-N-[(9R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]-1H-吲哚-3-甲酰胺[*或S];
3-环丙基-N-(2-氟-2-甲基丙基)-9-[(1-甲基苯并咪唑-2-基)氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
5-[[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]氨基]吡啶-2-甲酸甲酯;
5-[[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]氨基]吡啶-2-甲酸;
5-甲基-N-[(9R*)-3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]-1H-吡唑-3-甲酰胺[*或S];
N-[(9R*)-3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]吡啶-3-甲酰胺[*或S];
3-环丙基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰胺;
1-[3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]噌啉-7-基]-3-(2,5-二甲基吡唑-3-基)硫脲;
3-环丙基-7-[[4-(2,5-二甲基吡唑-3-基)-1,2,4-三唑-3-基]氨基]-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰胺;
(7R*)-3-环丙基-7-[3-[(2,5-二甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基]-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]噌啉-5-磺酰胺[*或S];
N-[3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]-2-甲基环丙烷-1-甲酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-(嘧啶-5-基氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-[(2-氧代-1,3-二氢吲哚-5-基)氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-[(5-甲氧基吡啶-3-基)氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-7-(吡啶-3-基氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-(吡啶-3-基氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
N-[3-环丙基-5-[(1,1-二氘-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]氨基甲酸叔丁酯;
7-氨基-3-环丙基-N-(1,1-二氘-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-7-[3-(环丙基甲基氨基)-1,2,4-三唑-4-基]-N-(1,1-二氘-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
7-环丙基-N-(2-氟-2-甲基丙基)-3-羟基-2,3-二氢呋喃并[3,2-h]异喹啉-5-磺酰胺;
(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-N-吡啶-3-基-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-甲酰胺[*或S];
N-[2-[3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]吡唑-3-基]环丙烷甲酰胺;
7-(5-氨基四氮唑-1-基)-3-环丙基-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-7-[[6-(2-甲基四氮唑-5-基)吡啶-3-基]氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-7-[(1-甲基吡唑并[3,4-c]吡啶-4-基)氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-7-[[6-(5-甲基-1,3,4-噁二唑-2-基)吡啶-3-基]氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-[(1-甲基吡唑并[3,4-c]吡啶-4-基)氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
N-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]氨基甲酸苄酯;
1-(4-溴苯基)-3-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]脲;
1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]-3-[(2,5-二甲基吡唑-3-基)甲基]脲;
3-环丙基-7-羟基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-甲基丙基)-7-氧代-8,9-二氢环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-7-羟基-7-甲基-N-(2-甲基丙基)-8,9-二氢环戊二烯并[h]异喹啉-5-磺酰胺;
7-氨基-3-环丙基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]-3-乙基硫脲;
(7R*)-3-环丙基-7-[3-(乙基氨基)-1,2,4-三唑-4-基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(*或S);
(7R*)-3-环丙基-7-[[2-(乙基氨基)-3,4-二氧代环丁烯-1-基]氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺(*或S);
3-环丙基-7-[[4-(乙基氨基)-1,1-二氧代-1,2,5-噻二唑-3-基]氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
2-氰基-1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]-3-(4-甲基苯基)胍;
3-[[(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]氨基甲酰]氮杂环丁烷-1-甲酸叔丁酯[*或S];
7-[(3R)-3-氨基哌啶-1-基]-3-环丙基-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
(2R)-1-[(7R*)-3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]-N-甲基吡咯烷-2-甲酰胺[*或S];
N-[1-[3-环丙基-5-[(2-氟-2-甲基丙基)氨磺酰基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]氮杂环丁烷-3-基]-2,5-二甲基吡唑-3-甲酰胺;
3-环丙基-7-[(4,4-二甲基-3-氧代环丁烯-1-基)氨基]-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-7-(1H-吲哚-2-基甲基氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-9-羟基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-甲基丙基)-9-氧代-7,8-二氢环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-9-羟基-9-甲基-N-(2-甲基丙基)-7,8-二氢环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-9-氟-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-9-[[4-(乙基氨基)-1,1-二氧代-1,2,5-噻二唑-3-基]氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
9-[(4-氰基-1-甲基吡唑-3-基)氨基]-3-环丙基-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-(异喹啉-4-基氨基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
2-氰基-1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]-3-(4-甲基苯基)胍;
3-环丙基-9-(甲磺酰氨基)-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]-3-乙基硫脲;
3-环丙基-9-[3-(乙基氨基)-1,2,4-三唑-4-基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
(9R*)-3-环丙基-9-[(4-乙基-1,2,4-三唑-3-基)氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
1-[3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-9-基]-3-吡啶-3-基硫脲;
3-环丙基-N-(2-甲基丙基)-9-[(4-吡啶-3-基-1,2,4-三唑-3-基)氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-[[6-(5-甲基-1,3,4-噁二唑-2-基)吡啶-3-基]氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-[[6-(2-甲基四氮唑-5-基)吡啶-3-基]氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-9-[[3,4-二氧代-2-(吡啶-3-基氨基)环丁烯-1-基]氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
(9R*)-3-环丙基-9-[[2-(乙基氨基)-3,4-二氧代环丁烯-1-基]氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
(9R*)-9-(1H-苯并咪唑-2-基氨基)-3-环丙基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
3-环丙基-7-[3-(环丙基甲基氨基)-1,2,4-三唑-4-基]-N-(3,3-二氟环丁基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-7-[3-(环丙基甲基氨基)-1,2,4-三唑-4-基]-N-(3-氟环丁基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-7-(甲磺酰氨基)-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-7-[[3,4-二氧代-2-(吡啶-3-基氨基)环丁烯-1-基]氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
1-乙基-3-[(7R*)-3-环丙基-5-(2-甲基丙基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]脲[*或S];
(7R*)-3-环丙基-7-[3-[(2,5-二甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基]-N-(2-氟-2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
(7R*)-3-环丙基-7-[3-[(2,5-二甲基吡唑-3-基)氨基]-1,2,4-三唑-4-基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
3-环丙基-7-[[4-(2,5-二甲基吡唑-3-基)-1,2,4-三唑-3-基]氨基]-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
(7R*)-3-环丙基-N-(2-甲基丙基)-7-[3-[(5-甲基吡啶-3-基)氨基]-1,2,4-三唑-4-基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺[*或S];
3-环丙基-N-(2-甲基丙基)-7-[(4-吡啶-3-基-1,2,4-三唑-3-基)氨基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-甲基丙基)-7-[3-(吡啶-3-基氨基)-1,2,4-三唑-4-基]-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
7-(1H-苯并咪唑-2-基氨基)-3-环丙基-N-(2-甲基丙基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-9-吡啶-3-基氧基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
3-环丙基-N-(2-氟-2-甲基丙基)-7-吡啶-3-基氧基-8,9-二氢-7H-环戊二烯并[h]异喹啉-5-磺酰胺;
1-[3-环丙基-5-(异丁基氨磺酰基)-8,9-二氢-7H-环戊二烯并[h]异喹啉-7-基]-3-(3-吡啶基)硫脲.
9.根据权利要求1至8中任一项的化合物或其药学上可接受的盐,其用于治疗用途。
10.根据权利要求1至8中任一项的化合物或其药学上可接受的盐,其用于治疗或预防由IgE引起的障碍的方法中。
11.根据权利要求1至8中任一项的化合物或其药学上可接受的盐,其用于治疗或预防过敏、非过敏性肥大细胞反应、1型超敏反应、荨麻疹或常见的窦炎症的方法中。
12.根据权利要求1至8中任一项的化合物或其药学上可接受的盐,其用于治疗或预防哮喘中的气道收缩、湿疹中的局部炎症、过敏性鼻炎中的粘液分泌增加、荨麻疹或血管通透性增加的方法中。
13.根据权利要求1至8中任一项的化合物或其药学上可接受的盐,其用于治疗或预防嗜酸性肉芽肿伴多血管炎(也称为“Churg Strauss综合征”)、阿司匹林加重的呼吸系统疾病或皮肤T细胞淋巴瘤的方法中。
14.一种药物组合物,其包含根据权利要求1至8的式(I)的化合物或其药学上可接受的盐以及药学上可接受的载体。
15.根据权利要求1至8中任一项的化合物或其药学上可接受的盐在制备药物中的用途。
16.根据权利要求1至9中任一项的化合物或其药学上可接受的盐在制备用于治疗和/或预防由IgE引起的障碍的药物中的用途。
17.根据权利要求1至8中任一项的化合物或其药学上可接受的盐在制备用于治疗和/或预防过敏、非过敏性肥大细胞反应、1型超敏反应、荨麻疹或常见的窦炎症的药物中的用途。
18.一种治疗或预防过敏、非过敏性肥大细胞反应、1型超敏反应、荨麻疹、常见的窦炎症、嗜酸性肉芽肿伴多血管炎(也称为“Churg Strauss综合征”)、阿司匹林加重的呼吸系统疾病或皮肤T细胞淋巴瘤的方法,其包括给予患者治疗有效量的根据权利要求1至8中任一项的化合物或其药学上可接受的盐。
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- 2020-12-22 JP JP2022538869A patent/JP2023508384A/ja active Pending
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CN115417816B (zh) * | 2022-09-05 | 2024-01-26 | 江苏南大光电材料股份有限公司 | 一种3,6-二溴-1-氯-异喹啉的制备方法 |
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