CN114206870A - 三环akr1c3依赖性kars抑制剂 - Google Patents
三环akr1c3依赖性kars抑制剂 Download PDFInfo
- Publication number
- CN114206870A CN114206870A CN202080053804.1A CN202080053804A CN114206870A CN 114206870 A CN114206870 A CN 114206870A CN 202080053804 A CN202080053804 A CN 202080053804A CN 114206870 A CN114206870 A CN 114206870A
- Authority
- CN
- China
- Prior art keywords
- fluoro
- spiro
- piperidine
- quinoline
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 108010065942 Prostaglandin-F synthase Proteins 0.000 title claims abstract description 40
- 102000004602 Aldo-Keto Reductase Family 1 Member C3 Human genes 0.000 title claims abstract 5
- 230000001419 dependent effect Effects 0.000 title abstract description 26
- 239000003112 inhibitor Substances 0.000 title abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 645
- 238000000034 method Methods 0.000 claims abstract description 416
- 238000002360 preparation method Methods 0.000 claims abstract description 110
- 239000003814 drug Substances 0.000 claims abstract description 47
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 230000001404 mediated effect Effects 0.000 claims abstract description 14
- -1 4- ((6 '-fluoro-4' -oxo-3 ',4' -dihydro-1 'H-spiro [ piperidine-4, 2' -quinoline ] -1-carboxamido) methyl) phenyl Chemical group 0.000 claims description 218
- 125000000217 alkyl group Chemical group 0.000 claims description 173
- 150000003839 salts Chemical class 0.000 claims description 73
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 50
- 125000005843 halogen group Chemical group 0.000 claims description 42
- 206010028980 Neoplasm Diseases 0.000 claims description 40
- 108091007984 KARS Proteins 0.000 claims description 35
- 102100035529 Lysine-tRNA ligase Human genes 0.000 claims description 35
- 201000010099 disease Diseases 0.000 claims description 35
- 229940124597 therapeutic agent Drugs 0.000 claims description 35
- 201000011510 cancer Diseases 0.000 claims description 30
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- 238000011282 treatment Methods 0.000 claims description 23
- 229910052805 deuterium Inorganic materials 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 19
- 230000002265 prevention Effects 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 16
- 102100031701 Nuclear factor erythroid 2-related factor 2 Human genes 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- 125000005605 benzo group Chemical group 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 101000588302 Homo sapiens Nuclear factor erythroid 2-related factor 2 Proteins 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 238000006467 substitution reaction Methods 0.000 claims description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 102000004034 Kelch-Like ECH-Associated Protein 1 Human genes 0.000 claims description 10
- 108090000484 Kelch-Like ECH-Associated Protein 1 Proteins 0.000 claims description 10
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 10
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 claims description 10
- 230000014509 gene expression Effects 0.000 claims description 9
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 8
- 125000004429 atom Chemical group 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 206010060862 Prostate cancer Diseases 0.000 claims description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 7
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 6
- JOFCQZWOQLLRRF-UHFFFAOYSA-N 6-fluoro-N-(1,2-oxazol-5-ylmethyl)-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=CC=NO1)=O JOFCQZWOQLLRRF-UHFFFAOYSA-N 0.000 claims description 6
- FENXJYUIJWZXHS-UHFFFAOYSA-N 6-fluoro-N-[[4-fluoro-3-(2-hydroxyethylamino)phenyl]methyl]-1-methyl-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(N(C2=CC=1)C)CCN(CC3)C(=O)NCC1=CC(=C(C=C1)F)NCCO)=O FENXJYUIJWZXHS-UHFFFAOYSA-N 0.000 claims description 6
- RXZRSSHAUIGDJY-UHFFFAOYSA-N 6-fluoro-N-[[4-fluoro-3-[2-(2-oxopyrrolidin-1-yl)ethylamino]phenyl]methyl]-1-methyl-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(N(C2=CC=1)C)CCN(CC3)C(=O)NCC1=CC(=C(C=C1)F)NCCN1C(CCC1)=O)=O RXZRSSHAUIGDJY-UHFFFAOYSA-N 0.000 claims description 6
- 230000004913 activation Effects 0.000 claims description 6
- WILXKPUUUNCWJW-NSCUHMNNSA-N 1-[(E)-but-2-enyl]-6-fluoro-N-[(4-fluorophenyl)methyl]-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carboxamide Chemical compound C(\C=C\C)N1C2(CC(C3=CC(=CC=C13)F)=O)CCN(CC2)C(=O)NCC1=CC=C(C=C1)F WILXKPUUUNCWJW-NSCUHMNNSA-N 0.000 claims description 5
- OIHWXKWJYJDZSC-UHFFFAOYSA-N 1-ethyl-6-fluoro-N-[(4-fluorophenyl)methyl]-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carboxamide Chemical compound C(C)N1C2(CC(C3=CC(=CC=C13)F)=O)CCN(CC2)C(=O)NCC1=CC=C(C=C1)F OIHWXKWJYJDZSC-UHFFFAOYSA-N 0.000 claims description 5
- YZMWJEDIULFHRX-UHFFFAOYSA-N 1-ethyl-6-fluoro-N-[[4-fluoro-3-(2-hydroxyethylamino)phenyl]methyl]-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carboxamide Chemical compound C(C)N1C2(CC(C3=CC(=CC=C13)F)=O)CCN(CC2)C(=O)NCC1=CC(=C(C=C1)F)NCCO YZMWJEDIULFHRX-UHFFFAOYSA-N 0.000 claims description 5
- FDRYYQCQFLIPIY-UHFFFAOYSA-N 3-[2-fluoro-5-[[(6-fluoro-1-methyl-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carbonyl)amino]methyl]anilino]-2,2-dimethylpropanoic acid Chemical compound FC1=C(C=C(C=C1)CNC(=O)N1CCC2(N(C3=CC=C(C=C3C(C2)=O)F)C)CC1)NCC(C(=O)O)(C)C FDRYYQCQFLIPIY-UHFFFAOYSA-N 0.000 claims description 5
- ILVAMWYWJXZVBG-UHFFFAOYSA-N 6,8-difluoro-N-(furan-3-ylmethyl)-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=C(C=1)F)CCN(CC3)C(=O)NCC1=COC=C1)=O ILVAMWYWJXZVBG-UHFFFAOYSA-N 0.000 claims description 5
- PPGHIHYCIKVZQV-UHFFFAOYSA-N 6,8-difluoro-N-[(2-methoxypyridin-4-yl)methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=C(C=1)F)CCN(CC3)C(=O)NCC1=CC(=NC=C1)OC)=O PPGHIHYCIKVZQV-UHFFFAOYSA-N 0.000 claims description 5
- AJLZTCVWMUVWTP-UHFFFAOYSA-N 6,8-difluoro-N-[(2-methylfuran-3-yl)methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=C(C=1)F)CCN(CC3)C(=O)NCC1=C(OC=C1)C)=O AJLZTCVWMUVWTP-UHFFFAOYSA-N 0.000 claims description 5
- NVFUUXCXWSCALH-UHFFFAOYSA-N 6,8-difluoro-N-[(3-hydroxypyridin-2-yl)methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=C(C=1)F)CCN(CC3)C(=O)NCC1=NC=CC=C1O)=O NVFUUXCXWSCALH-UHFFFAOYSA-N 0.000 claims description 5
- HNRMFLGMCHCHEL-UHFFFAOYSA-N 6,8-difluoro-N-[(4-hydroxyphenyl)methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=C(C=1)F)CCN(CC3)C(=O)NCC1=CC=C(C=C1)O)=O HNRMFLGMCHCHEL-UHFFFAOYSA-N 0.000 claims description 5
- MEBQWURAVKNEKJ-UHFFFAOYSA-N 6,8-difluoro-N-[(5-methylthiophen-2-yl)methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=C(C=1)F)CCN(CC3)C(=O)NCC=1SC(=CC=1)C)=O MEBQWURAVKNEKJ-UHFFFAOYSA-N 0.000 claims description 5
- NFYUIXXRWLAGOP-UHFFFAOYSA-N 6,8-difluoro-N-[(6-fluoropyridin-3-yl)methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=C(C=1)F)CCN(CC3)C(=O)NCC=1C=NC(=CC=1)F)=O NFYUIXXRWLAGOP-UHFFFAOYSA-N 0.000 claims description 5
- FXXZVTGUUBWFQY-UHFFFAOYSA-N 6,8-difluoro-N-[[3-(1,3-oxazol-5-yl)phenyl]methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=C(C=1)F)CCN(CC3)C(=O)NCC1=CC(=CC=C1)C1=CN=CO1)=O FXXZVTGUUBWFQY-UHFFFAOYSA-N 0.000 claims description 5
- DLTMRJADLQKBPO-UHFFFAOYSA-N 6,8-difluoro-N-[[3-(hydroxymethyl)phenyl]methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=C(C=1)F)CCN(CC3)C(=O)NCC1=CC(=CC=C1)CO)=O DLTMRJADLQKBPO-UHFFFAOYSA-N 0.000 claims description 5
- GKUZLEIKYLPYKR-UHFFFAOYSA-N 6,8-difluoro-N-[[4-fluoro-3-(hydroxymethyl)phenyl]methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=C(C=1)F)CCN(CC3)C(=O)NCC1=CC(=C(C=C1)F)CO)=O GKUZLEIKYLPYKR-UHFFFAOYSA-N 0.000 claims description 5
- MUTXPYJCJPWLDX-UHFFFAOYSA-N 6-fluoro-1-methyl-N-[(5-methylfuran-2-yl)methyl]-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(N(C2=CC=1)C)CCN(CC3)C(=O)NCC=1OC(=CC=1)C)=O MUTXPYJCJPWLDX-UHFFFAOYSA-N 0.000 claims description 5
- KBICXKUPHXIHMV-UHFFFAOYSA-N 6-fluoro-4-oxo-N-[(3-sulfamoylphenyl)methyl]spiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=CC(=CC=C1)S(N)(=O)=O)=O KBICXKUPHXIHMV-UHFFFAOYSA-N 0.000 claims description 5
- FKFFREACDMRMBQ-UHFFFAOYSA-N 6-fluoro-4-oxo-N-[[2-(trifluoromethyl)furan-3-yl]methyl]spiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=C(OC=C1)C(F)(F)F)=O FKFFREACDMRMBQ-UHFFFAOYSA-N 0.000 claims description 5
- LSEJYNNMMVDSDU-UHFFFAOYSA-N 6-fluoro-N-(1,2-oxazol-3-ylmethyl)-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=NOC=C1)=O LSEJYNNMMVDSDU-UHFFFAOYSA-N 0.000 claims description 5
- OTLMBIUXYHVJKK-UHFFFAOYSA-N 6-fluoro-N-(1,2-oxazol-4-ylmethyl)-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC=1C=NOC=1)=O OTLMBIUXYHVJKK-UHFFFAOYSA-N 0.000 claims description 5
- MBDHNRIZEWPGHL-UHFFFAOYSA-N 6-fluoro-N-(1,3-oxazol-4-ylmethyl)-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC=1N=COC=1)=O MBDHNRIZEWPGHL-UHFFFAOYSA-N 0.000 claims description 5
- NXLXHTBFHYUFHP-UHFFFAOYSA-N 6-fluoro-N-[(1-methylpyrazol-4-yl)methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC=1C=NN(C=1)C)=O NXLXHTBFHYUFHP-UHFFFAOYSA-N 0.000 claims description 5
- PPHRIVJUFVOBOE-UHFFFAOYSA-N 6-fluoro-N-[(2-methylfuran-3-yl)methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=C(OC=C1)C)=O PPHRIVJUFVOBOE-UHFFFAOYSA-N 0.000 claims description 5
- JLPPUKLSPYGNRB-UHFFFAOYSA-N 6-fluoro-N-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=NC(=NO1)C)=O JLPPUKLSPYGNRB-UHFFFAOYSA-N 0.000 claims description 5
- FOKADWKBVVGPFG-UHFFFAOYSA-N 6-fluoro-N-[(4-fluoro-2-hydroxyphenyl)methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=C(C=C(C=C1)F)O)=O FOKADWKBVVGPFG-UHFFFAOYSA-N 0.000 claims description 5
- IRMXLYDFDWFBQZ-UHFFFAOYSA-N 6-fluoro-N-[(4-fluoro-2-methoxyphenyl)methyl]-1-methyl-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(N(C2=CC=1)C)CCN(CC3)C(=O)NCC1=C(C=C(C=C1)F)OC)=O IRMXLYDFDWFBQZ-UHFFFAOYSA-N 0.000 claims description 5
- INSJSEYDCIHRRG-UHFFFAOYSA-N 6-fluoro-N-[(4-fluoro-2-methoxyphenyl)methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=C(C=C(C=C1)F)OC)=O INSJSEYDCIHRRG-UHFFFAOYSA-N 0.000 claims description 5
- PESBKESWZSCILB-UHFFFAOYSA-N 6-fluoro-N-[(4-fluoro-3-methoxyphenyl)methyl]-1-methyl-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(N(C2=CC=1)C)CCN(CC3)C(=O)NCC1=CC(=C(C=C1)F)OC)=O PESBKESWZSCILB-UHFFFAOYSA-N 0.000 claims description 5
- PAOWPUJZOYULQR-UHFFFAOYSA-N 6-fluoro-N-[(4-fluoro-3-sulfamoylphenyl)methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=CC(=C(C=C1)F)S(N)(=O)=O)=O PAOWPUJZOYULQR-UHFFFAOYSA-N 0.000 claims description 5
- ZODRYECWZWJLJX-UHFFFAOYSA-N 6-fluoro-N-[(4-fluorophenyl)methyl]-1-(2-hydroxyethyl)-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(N(C2=CC=1)CCO)CCN(CC3)C(=O)NCC1=CC=C(C=C1)F)=O ZODRYECWZWJLJX-UHFFFAOYSA-N 0.000 claims description 5
- YZIHFCAFAGLLNH-UHFFFAOYSA-N 6-fluoro-N-[(4-fluorophenyl)methyl]-1-(2-methoxyethyl)-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(N(C2=CC=1)CCOC)CCN(CC3)C(=O)NCC1=CC=C(C=C1)F)=O YZIHFCAFAGLLNH-UHFFFAOYSA-N 0.000 claims description 5
- WVZQZRVDIMHSMC-UHFFFAOYSA-N 6-fluoro-N-[(4-fluorophenyl)methyl]-1-methyl-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(N(C2=CC=1)C)CCN(CC3)C(=O)NCC1=CC=C(C=C1)F)=O WVZQZRVDIMHSMC-UHFFFAOYSA-N 0.000 claims description 5
- MZIATKFUXPUFAI-UHFFFAOYSA-N 6-fluoro-N-[(4-hydroxyphenyl)methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=CC=C(C=C1)O)=O MZIATKFUXPUFAI-UHFFFAOYSA-N 0.000 claims description 5
- PUAGCJNOVIUTMH-UHFFFAOYSA-N 6-fluoro-N-[(5-methylfuran-2-yl)methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC=1OC(=CC=1)C)=O PUAGCJNOVIUTMH-UHFFFAOYSA-N 0.000 claims description 5
- WJHIIAJSTFBIHK-UHFFFAOYSA-N 6-fluoro-N-[[4-fluoro-2-(2,2,2-trifluoroethoxy)phenyl]methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=C(C=C(C=C1)F)OCC(F)(F)F)=O WJHIIAJSTFBIHK-UHFFFAOYSA-N 0.000 claims description 5
- JRENCXPQWFQBTF-UHFFFAOYSA-N 6-fluoro-N-[[4-fluoro-2-(2-hydroxyethylamino)phenyl]methyl]-1-methyl-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(N(C2=CC=1)C)CCN(CC3)C(=O)NCC1=C(C=C(C=C1)F)NCCO)=O JRENCXPQWFQBTF-UHFFFAOYSA-N 0.000 claims description 5
- UTTMXMULCDUQGC-UHFFFAOYSA-N 6-fluoro-N-[[4-fluoro-2-(2-methoxyethylamino)phenyl]methyl]-1-methyl-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(N(C2=CC=1)C)CCN(CC3)C(=O)NCC1=C(C=C(C=C1)F)NCCOC)=O UTTMXMULCDUQGC-UHFFFAOYSA-N 0.000 claims description 5
- RBFBBOIKZFSORM-UHFFFAOYSA-N 6-fluoro-N-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=C(C=C(C=C1)F)C(F)(F)F)=O RBFBBOIKZFSORM-UHFFFAOYSA-N 0.000 claims description 5
- IMJDEYGVMRSAPU-UHFFFAOYSA-N 6-fluoro-N-[[4-fluoro-3-(1,3-oxazol-5-yl)phenyl]methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=CC(=C(C=C1)F)C1=CN=CO1)=O IMJDEYGVMRSAPU-UHFFFAOYSA-N 0.000 claims description 5
- UKNQEBGLGBSODW-UHFFFAOYSA-N 6-fluoro-N-[[4-fluoro-3-(1-hydroxyethyl)phenyl]methyl]-1-methyl-4-oxospiro[3H-quinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(N(C2=CC=1)C)CCN(CC3)C(=O)NCC1=CC(=C(C=C1)F)C(C)O)=O UKNQEBGLGBSODW-UHFFFAOYSA-N 0.000 claims description 5
- ADMGUGQFYOJARP-UHFFFAOYSA-N 6-fluoro-N-[[4-fluoro-3-(1-hydroxyethyl)phenyl]methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=CC(=C(C=C1)F)C(C)O)=O ADMGUGQFYOJARP-UHFFFAOYSA-N 0.000 claims description 5
- WUYXLXHGKICOER-UHFFFAOYSA-N 6-fluoro-N-[[4-fluoro-3-(2,2,2-trifluoroethylcarbamoyl)phenyl]methyl]-4-oxospiro[1,3-dihydroquinoline-2,4'-piperidine]-1'-carboxamide Chemical compound FC=1C=C2C(CC3(NC2=CC=1)CCN(CC3)C(=O)NCC1=CC(=C(C=C1)F)C(NCC(F)(F)F)=O)=O WUYXLXHGKICOER-UHFFFAOYSA-N 0.000 claims description 5
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Abstract
本发明涉及作为AKR1C3依赖性KARS抑制剂的新型三环化合物、其制备方法、药物组合物、和含有它们的药剂、以及它们在由AKR1C3依赖性KARS抑制剂介导的疾病和障碍中的用途。
Description
技术领域
本发明涉及可用作AKR1C3依赖性KARS抑制剂的新型三环化合物。本发明还涉及用于制备所述化合物的方法、包含所述化合物的药物组合物、在多种疾病和障碍的治疗中使用所述化合物的方法、和含有它们的药剂、以及它们在由AKR1C3依赖性KARS抑制剂介导的疾病和障碍中的用途。
背景技术
NFE2L2/NRF2-KEAP1途径在癌症中具有强大的遗传基础。TCGA测序工作报告了在34%的肺鳞状细胞癌中此途径发生了改变(Hammerman PS等人Comprehensive genomiccharacterization of squamous cell lung cancers.[鳞状细胞肺癌的全面基因组表征]Nature[自然]489,519-525(2012))。另外,TCGA和其他组已报告了在其他实体瘤适应症(包括头颈鳞状细胞癌和肝细胞癌)中此途径的显著突变。NRF2途径的异常激活可能通过NRF2中的功能获得性遗传改变或KEAP1或CUL3中的功能丧失性遗传改变而发生,所述遗传改变导致NRF2的稳定及其靶基因的表达升高。这些靶基因的不受控转录为癌细胞赋予了优点,诸如恶化和针对氧化应激、化学疗法和放射疗法的保护(Jaramillo MC,Zhang DD.Theemerging role of the Nrf2-Keap1signaling pathway in cancer[Nrf2-Keap1信号传导途径在癌症中的新作用]Genes Dev.[基因与发育]27,2179-2191(2013))。肿瘤中NRF2活性加剧与预后不良相关(Shibata T,Ohta T,Tong KI,Kokubu A,Odogawa R,Tsuta K,Asamura H,Yamamoto M,Hirohashi S.Cancer related mutations in NRF2impair itsrecognition by Keap1-Cul3E3ligase and promote malignancy.[NRF2中的癌症相关突变损害其被Keap1-Cul3E3连接酶的识别并且促进恶化]Proc Natl Acad Sci USA[美国国家科学院院刊]105,13568-13573(2008))。据我们所知,当前没有获批的选择性靶向在NRF2/KEAP1途径中具有遗传改变的癌症的疗法,这因此代表未满足的医学需求。
醛酮还原酶1C3(AKR1C3)是转录因子NRF2的众多靶基因之一,其表达在NRF2/KEAP1突变癌症中上调(MacLeod AK,Acosta-Jimenez L,Coates PJ,McMahon M,Carey FA,Honda T,Henderson CJ和Wolf CR.Aldo-keto reductases are biomarkers ofNRF2activity and are coordinately overexpressed in non-small cell lungcancer.[醛酮还原酶是NRF2活性的生物标志物并且在非小细胞肺癌中协同过表达]Br JCancer[英国癌症期刊]115,1530-1539(2016))。AKR1C3(也称为2型3α(17β)-羟基类固醇脱氢酶)是NADP(H)依赖性酮类固醇还原酶,是醛酮还原酶(AKR)超家族的成员,其在类固醇激素代谢和信号传导以及异生物质解毒中起作用。AKR1C3的一些已知底物是内源性底物5α-二氢睾酮、Δ4-雄甾烯-3,17-二酮和孕酮(Penning TM,Burczynski ME,Jez JM,Hung CF,Lin HK,Ma H,Moore M,Palackal N,Ratnam K.Human 3α-hydroxysteroid dehydrogenaseisoforms(AKR1C1-AKR1C4)of the aldo-keto reductase superfamily:functionalplasticity and tissue distribution reveals roles in the inactivation andformation of male and female sex hormones.[醛酮还原酶超家族的人3α-羟基类固醇脱氢酶同种型(AKR1C1-AKR1C4):功能可塑性和组织分布揭示了在男性和女性性激素的失活和形成中的作用]Biochem.J.[生物化学期刊]351,67-77(2000))以及合成前药coumberone(Halim M,Yee DJ,Sames D.Imaging Induction of Cytoprotective Enzymesin Intact Human Cells:Coumberone,a Metabolic Reporter for Human AKR1C EnzymesReveals Activation by Panaxytriol,an Active Component of Red Ginseng[完整人细胞中细胞保护性酶的成像诱导:作为用于人AKR1C酶的代谢报告分子的Coumberone揭示了作为红参的活性组分的人参三醇的激活]J.Am.Chem.Soc.[美国化学学会期刊]130,14123-14128(2008))、PR104(Jamieson SM,Gu Y,Manesh DM,El-Hoss J,Jing D,Mackenzie KL,Guise CP,Foehrenbacher A,Pullen SM,Benito J,Smaill JB,Patterson AV,Mulaw MA,Konopleva M,Bohlander SK,Lock RB,Wilson WR.A novel fluorometric assay foraldo-keto reductase1C3predicts metabolic activation of the nitrogen mustardprodrug PR-104A in human leukaemia cells.[用于醛糖酮还原酶1C3的新型荧光测定预测了氮芥前药PR-104A在人白血病细胞中的代谢活化]Biochem Pharmacol.[生化药理学]88,36-45(2014))和TH3424/OBI3424(海槛制药公司(Threshold pharmaceuticals)WO2016/145092A1)。我们报告了在NADPH的存在下被AKR1C3转化为赖氨酸t-RNA合成酶(KARS)抑制剂的三环酮化合物的鉴定。赖氨酸t-RNA合成酶是蛋白质合成所必需的普遍存在的酶,所述酶是多-tRNA合成酶复合物的一部分。
AKR1C3依赖性KARS抑制剂提供了有吸引力的策略,用于选择性地治疗与正常组织相比过表达AKR1C3的肿瘤(诸如NRF2/KEAP1突变癌症和据报道过表达AKR1C3的其他类型癌症)(Guise CP,Abbattista MR,Singleton RS,Holford SD,Connolly J,Dachs GU,FoxSB,Pollock R,Harvey J,Guilford P,F,Wilson WR,Patterson AV.Thebioreductive prodrug PR-104A is activated under aerobic conditions by humanaldo-keto reductase 1C3.[生物还原性前药PR-104A在有氧条件下被人醛酮还原酶1C3激活]Cancer Res.[癌症研究]70,1573-1584(2010)),诸如乳腺癌(Lewis MJ,Wiebe JP,Heathcote JG.Expression of progesterone metabolizing enzyme genes(AKR1C1,AKR1C2,AKR1C3,SRD5A1,SRD5A2)is altered in human breast carcinoma.[孕酮代谢酶基因(AKR1C1、AKR1C2、AKR1C3、SRD5A1、SRD5A2)的表达在人乳腺癌中改变]BMC Cancer[BMC癌症]4,27(2004))和前列腺癌(Fung KM,Samara ENS,Wong C,Metwalli A,Krlin R,BaneB,Liu CZ等人Increased expression of type 2 3α-hydroxysteroid dehydrogenase/type 517β-hydroxysteroid dehydrogenase(AKR1C3)and its relationship withandrogen receptor in prostate carcinoma.[2型3α-羟基类固醇脱氢酶/5型17β-羟基类固醇脱氢酶(AKR1C3)的表达增加及其与前列腺癌中雄激素受体的关系]Endocr RelatCancer[内分泌相关癌症]13,169-180(2006))。
当前没有获批的可以选择性靶向NRF2/KEAP1改变的癌症或具有高的AKR1C3表达的癌症的疗法。因此,需要提供用于治疗癌症患者的新和/或替代治疗,包括选择性AKR1C3还原酶依赖性KARS抑制剂。
发明内容
AKR1C3依赖性KARS抑制剂为患有在NRF2/KEAP1途径中具有遗传改变的癌症的患者提供了新的治疗和疗法。本发明提供了化合物、其药学上可接受的盐、其药物组合物及其组合,所述化合物是AKR1C3依赖性KARS抑制剂,所述AKR1C3依赖性KARS抑制剂在NADPH的存在下被AKR1C3转化为赖氨酸t-RNA合成酶(KARS)抑制剂。赖氨酸t-RNA合成酶是蛋白质合成所必需的普遍存在的酶,所述酶是多-tRNA合成酶复合物的一部分。本发明进一步提供了治疗或预防与高AKR1C3表达或对KARS抑制敏感性相关的疾病和/或障碍的方法,所述方法包括向有需要的受试者施用有效量的AKR1C3依赖性KARS抑制剂。
本文描述了本发明的各种实施例。
在某些方面中,本文提供了式(I)的化合物或其药学上可接受的盐:
其中:
每个R1独立地选自由以下组成的组:(C1-C6)烷基、(C1-C6)烷氧基、(C0-C4)烷基N(R8)2、和卤基;
R2a和R2b各自独立地选自由以下组成的组:H、(C1-C6)烷基、和卤基;
每个R3独立地选自由以下组成的组:H、和卤基;
R4选自由以下组成的组:芳基,包含1、2、3、或4个独立地选自N、O和S的杂原子的5至6元杂芳基;和包含1、2、3、或4个独立地选自N、O和S的杂原子的9至10元稠合双环杂芳基;其中前述中的任一项任选地被一个或多个R6取代;
R5选自由以下组成的组:H;(C1-C6)烷基;(C2-C6)烯基;(C0-C4)烷基OR8;(C1-C4)烷基(C3-C10)环烷基;卤代(C1-C6)烷基;(C2-C3)炔基;(C1-C4)烷基N(R10)2;
每个R6独立地选自由以下组成的组:卤基;(C1-C6)烷基;(C1-C6)烷氧基;卤代(C1-C6)烷基;OH;芳基;3至6元杂环;5至6元杂芳基;(C0-C4)烷基S(O)m(C1-C6)烷基;卤代(C1-C6)烷氧基;(C0-C4)烷基S(O)mN(R8)2;(C0-C4)烷基N(R8)2;(C0-C4)烷基(CO)OR7;N(R8)S(O)m(C1-C6)烷基;N(R8)S(O)m(C3-C6)环烷基;OP(O)(OH)2;(C0-C3)烷基(CO)NHR11;(C0-C3)烷基OR7、和(C3-C10)环烷基;其中每个R6当不为卤基、OH、或OP(O)(OH)2时任选地被一至三个R9取代;或两个相邻的R6与它们所附接的原子一起形成5至7元杂环或(C5-C8)环烷基;
每个R7和R8独立地选自由以下组成的组:H或任选地被一至三个R9取代的(C1-C6)烷基;
每个R9独立地选自由以下组成的组:卤基;-OH;氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、OP(O)(OH)2;(C1-C6)烷基;(C1-C3)炔基;(C1-C6)烷氧基;卤代(C1-C6)烷基;(C0-C4)烷基S(O)m(C1-C6)烷基;卤代(C1-C6)烷氧基;任选地被氧代(=O)取代的3至6元杂环;(C0-C4)烷基S(O)mN(R10)2;(C0-C4)烷基(CO)R10;(C0-C4)烷基(CO)OR10;(C0-C4)烷基NR10S(O)m(C1-C6)烷基;(C0-C4)烷基OR10;(C0-C4)烷基N(R10)2;(C0-C4)烷基CN;(C0-C4)烷基N(R10)2;和(C0-C4)烷基(CO)N(R10)2;
每个R10独立地选自由以下组成的组:H、(C1-C6)烷基;或3至6元杂环,其中所述3至6元杂环任选地被以下中的一个或多个取代:(C1-C6)烷基;和氧代(=O);
每个R11选自由以下组成的组:H;任选地被一至四个R12取代的4至6元杂环;任选地被一至四个R12取代的(C3-C6)环烷基;任选地被卤基取代的(C0-C3)烷基(C3-C6)环烷基(C1-C3)烷基;任选地被一至三个R12取代的CH2-芳基;(C1-C6)烷基;(C2-C6)烯基;或(C2-C6)炔基,其中所述(C1-C6)烷基;(C2-C6)烯基;和(C2-C6)炔基中的每一个任选地被一个或多个R13取代;
每个R12独立地选自由以下组成的组:OH、(C1-C3)烷氧基、NH2;或任选地被一个或多个OH取代的(C1-C3)烷基;
每个R13独立地选自由以下组成的组:卤基、OH、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、(C1-C3)烷氧基;和C(O)-(C3-C8)环烷基;
m是0、1、或2;并且
n是0、1或2。
在另一个方面,本发明提供了一种药物组合物,所述药物组合物包含式(I)或其子式的化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体。
在另一个方面,本发明提供了一种组合、特别是药物组合,所述组合包含式(I)或其子式的化合物或其药学上可接受的盐以及一种或多种治疗剂。在某些情况下,将本发明的化合物与其他治疗剂组合,所述其他治疗剂诸如其他抗癌剂、抗恶心剂(或抗呕剂)、化学疗法、镇痛剂、细胞保护剂、及其组合。
考虑用于组合疗法的一般化学治疗剂包括阿那曲唑比卡鲁胺硫酸博来霉素白消安白消安注射液卡培他滨N4-戊氧羰基-5-脱氧-5-氟胞苷、卡铂卡莫司汀苯丁酸氮芥顺铂克拉屈滨环磷酰胺(或)、阿糖胞苷、胞嘧啶阿拉伯糖苷阿糖胞苷脂质体注射液达卡巴嗪更生霉素(放线菌素D、Cosmegan)、盐酸柔红霉素柠檬酸柔红霉素脂质体注射液地塞米松、多西他赛盐酸多柔比星 依托泊苷磷酸氟达拉滨5-氟尿嘧啶氟他胺替扎他滨(tezacitibine)、吉西他滨(二氟脱氧胞苷)、羟基脲伊达比星异环磷酰胺伊立替康L-天冬酰胺酶亚叶酸钙、美法仑6-巯基嘌呤甲氨蝶呤米托蒽醌麦罗塔、紫杉醇nab-紫杉醇phoenix(Yttrium90/MX-DTPA)、喷司他丁、聚苯丙生(polifeprosan)20与卡莫司汀的植入物枸橼酸他莫昔芬替尼泊苷6-硫代鸟嘌呤、噻替派、替拉扎明注射用盐酸托泊替康长春花碱长春新碱和长春瑞滨
在另一个方面,本发明提供了一种调节有需要的受试者中KARS活性的方法,所述方法包括向所述有需要的受试者施用式(I)或其子式的化合物或其药学上可接受的盐。
在另一个方面,本发明还提供了一种式(I)或其子式的化合物或其药学上可接受的盐,其用于治疗或预防癌症,其中所述癌症选自非小细胞肺癌(NSCLC)、肝癌、头颈癌、食道癌、子宫癌、乳腺癌、膀胱癌、子宫颈癌、结直肠癌、肾癌、黑素瘤、胃、去势抵抗性前列腺癌(CRPC)、T细胞急性成淋巴细胞性白血病(T-ALL)、急性髓性白血病(AML)、和骨髓增生异常综合征(MDS)。
在另一个方面,本发明还提供了一种式(I)或其子式的化合物或其药学上可接受的盐,其用于治疗或预防在基因NFE2L2、KEAP1、CUL3、AKR1C3中具有遗传或表观遗传改变的癌症或导致激活NRF2转录活性或AKR1C3基因表达的任何其他病症。
在另一个方面,本发明还提供了一种式(I)或其子式的化合物或其药学上可接受的盐,其用于治疗或预防AKR1C3过表达高于预定值的癌症。
附图说明
图1展示了在AKR1C3的存在下化合物40向化合物152的动力学转化
图2展示了化合物40在高AKR1C3表达的人肺癌异种移植物NCI-H1944中的剂量依赖性体内功效
图3展示了化合物40在KEAP1突变体和中度AKR1C3表达的人肺癌异种移植物NCI-H1944和NCI-H460中的剂量依赖性体内功效
具体实施方式
因此,本发明提供了一种式(I)的化合物:或其药学上可接受的盐:
其中:
每个R1独立地选自由以下组成的组:(C1-C6)烷基、(C1-C6)烷氧基、(C0-C4)烷基N(R8)2、和卤基;
R2a和R2b各自独立地选自由以下组成的组:H、(C1-C6)烷基、和卤基;
每个R3独立地选自由以下组成的组:H、和卤基;
R4选自由以下组成的组:芳基,包含1、2、3、或4个独立地选自N、O和S的杂原子的5至6元杂芳基;和包含1、2、3、或4个独立地选自N、O和S的杂原子的9至10元稠合双环杂芳基;其中前述中的任一项任选地被一个或多个R6取代;
R5选自由以下组成的组:H;(C1-C6)烷基;(C2-C6)烯基;(C0-C4)烷基OR8;(C1-C4)烷基(C3-C10)环烷基;卤代(C1-C6)烷基;(C2-C3)炔基;(C1-C4)烷基N(R10)2;
每个R6独立地选自由以下组成的组:卤基;(C1-C6)烷基;(C1-C6)烷氧基;卤代(C1-C6)烷基;OH;芳基;3至6元杂环;5至6元杂芳基;(C0-C4)烷基S(O)m(C1-C6)烷基;卤代(C1-C6)烷氧基;(C0-C4)烷基S(O)mN(R8)2;(C0-C4)烷基N(R8)2;(C0-C4)烷基(CO)OR7;N(R8)S(O)m(C1-C6)烷基;N(R8)S(O)m(C3-C6)环烷基;OP(O)(OH)2;(C0-C3)烷基(CO)NHR11;(C0-C3)烷基OR7、和(C3-C10)环烷基;其中每个R6当不为卤基、OH、或OP(O)(OH)2时任选地被一至三个R9取代;或两个相邻的R6与它们所附接的原子一起形成5至7元杂环或(C5-C8)环烷基;
每个R7和R8独立地选自由以下组成的组:H或任选地被一至三个R9取代的(C1-C6)烷基;
每个R9独立地选自由以下组成的组:卤基;-OH;氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、OP(O)(OH)2;(C1-C6)烷基;(C1-C3)炔基;(C1-C6)烷氧基;卤代(C1-C6)烷基;(C0-C4)烷基S(O)m(C1-C6)烷基;卤代(C1-C6)烷氧基;任选地被氧代(=O)取代的3至6元杂环;(C0-C4)烷基S(O)mN(R10)2;(C0-C4)烷基(CO)R10;(C0-C4)烷基(CO)OR10;(C0-C4)烷基NR10S(O)m(C1-C6)烷基;(C0-C4)烷基OR10;(C0-C4)烷基N(R10)2;(C0-C4)烷基CN;(C0-C4)烷基N(R10)2;和(C0-C4)烷基(CO)N(R10)2;
每个R10独立地选自由以下组成的组:H、(C1-C6)烷基;或3至6元杂环,其中所述3至6元杂环任选地被以下中的一个或多个取代:(C1-C6)烷基;和氧代(=O);
每个R11选自由以下组成的组:H;任选地被一至四个R12取代的4至6元杂环;任选地被一至四个R12取代的(C3-C6)环烷基;任选地被卤基取代的(C0-C3)烷基(C3-C6)环烷基(C1-C3)烷基;任选地被一至三个R12取代的CH2-芳基;(C1-C6)烷基;(C2-C6)烯基;或(C2-C6)炔基,其中所述(C1-C6)烷基;(C2-C6)烯基;和(C2-C6)炔基中的每一个任选地被一个或多个R13取代;
每个R12独立地选自由以下组成的组:OH、(C1-C3)烷氧基、NH2;或任选地被一个或多个OH取代的(C1-C3)烷基;
每个R13独立地选自由以下组成的组:卤基、OH、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、(C1-C3)烷氧基;和C(O)-(C3-C8)环烷基;
m是0、1、或2;并且
n是0、1或2。
定义
出于解释本说明书的目的,除非另有指定,否则将应用下面的定义,并且在适当时,以单数形式使用的术语还将包括复数形式,并且反之亦然。
必须注意的是,如本文和所附权利要求所用,单数形式“一种”、“一个”和“所述(the)”包括复数指示物,除非上下文另有明确规定。因此,例如,提及“所述化合物”包括提及一种或多种化合物;等。
如本文所用,术语“(C1-C6)烷基”是指仅由碳和氢原子组成的直链或支链烃链基团,所述基团不含有不饱和度,具有从一至六个碳原子,并且通过单键附接至分子的其余部分。术语“(C1-C4)烷基”应相应地进行解释。(C1-C6)烷基的实例包括但不限于甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基和1,1-二甲基乙基(叔丁基)。
如本文所用,术语“(C2-C6)烯基”是指仅由碳和氢原子组成的直链或支链烃链基团,所述基团含有至少一个双键,具有从二至六个碳原子,通过单键附接至分子的其余部分。术语“(C2-C4)烯基”应相应地进行解释。(C2-C6)烯基的实例包括但不限于乙烯基、丙-1-烯基、丁-1-烯基、戊-1-烯基、戊-4-烯基和戊-1,4-二烯基。
如本文所用,术语“(C2-C6)炔基”是指仅由碳和氢原子组成的直链或支链烃链基团,所述基团含有至少一个三键,具有从二至六个碳原子,并且通过单键附接至分子的其余部分。术语“(C2-C4)炔基”应相应地进行解释。(C2-C6)炔基的实例包括但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-炔基、戊-4-炔基和戊-1,4-二炔基。
如本文所用,术语“(C1-C6)烷氧基”是指式-ORa的基团,其中Ra是通常如上所定义的(C1-C6)烷基。(C1-C6)烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、戊氧基和己氧基。
如本文所用,术语“(C1-C6)烷氧基(C1-C6)烷基”是指式-Ra-O-Ra的基团,其中每个Ra独立地是如上所定义的(C1-C6)烷基。氧原子可以与任一烷基中的任何碳原子键合。(C1-C6)烷氧基(C1-C6)烷基的实例包括但不限于甲氧基-甲基、甲氧基-乙基、乙氧基-乙基、1-乙氧基-丙基和2-甲氧基-丁基。
如本文所用,术语“(C1-C4)烷基羰基”是指式-C(=O)-Ra的基团,其中Ra是如上所定义的(C1-C4)烷基。
如本文所用,术语“(C1-C6)烷基羰基(C1-C6)烷基”是指式-Ra-C(=O)-Ra的基团,其中每个Ra独立地是如上所定义的(C1-C6)烷基。羰基的碳原子可以与任一烷基中的任何碳原子键合。
如本文所用,术语“(C1-C6)烷氧基羰基”是指式-C(=O)-O-Ra的基团,其中Ra是如上所定义的(C1-C6)烷基。
如本文所用,术语“(C1-C6)烷氧基羰基(C1-C6)烷基”是指式-Ra-C(=O)-O-Ra的基团,其中每个Ra独立地是如上所定义的(C1-C6)烷基。
如本文所用,术语“(C1-C4)烷氧基羰基氨基”是指式-NH-C(=O)-O-Ra的基团,其中Ra是如上所定义的(C1-C4)烷基。
如本文所用,术语“羟基(C1-C6)烷基”是指如上所定义的(C1-C6)烷基,其中C1-6烷基的一个氢原子被OH替代。羟基(C1-C6)烷基的实例包括但不限于羟基-甲基、2-羟基-乙基、2-羟基-丙基、3-羟基-丙基和5-羟基-戊基。
如本文所用,术语“氨基(C1-C6)烷基”是指如上所定义的(C1-C6)烷基,其中(C1-C6)烷基的一个氢原子被伯氨基替代。氨基(C1-C6)烷基的代表性实例包括但不限于氨基-甲基、2-氨基-乙基、2-氨基-丙基、3-氨基-丙基、3-氨基-戊基和5-氨基-戊基。
如本文所用,术语“(C1-C4)烷基氨基”是指式-NH-Ra的基团,其中Ra是如上所定义的(C1-C4)烷基。
如本文所用,术语“(C1-C4)烷基氨基(C1-C6)烷基”是指式-Ra1-NH-Ra2的基团,其中Ra1是如上所定义的(C1-C6)烷基并且Ra2是如上所定义的(C1-C4)烷基。氮原子可以与任一烷基中的任何碳原子键合。
如本文所用,术语“二(C1-C4)烷基氨基”是指式-N(Ra)-Ra的基团,其中每个Ra是如上所定义的可以相同或不同的(C1-C4)烷基。
如本文所用,术语“二(C1-C4)烷基氨基(C1-C6)烷基”是指式-Ra1-N(Ra2)-Ra2的基团,其中Ra1是如上所定义的(C1-C6)烷基并且每个Ra2是如上所定义的可以相同或不同的(C1-C4)烷基。氮原子可以与任一烷基中的任何碳原子键合。
如本文所用,术语“氨基羰基”是指式-C(=O)-NH2的基团。
如本文所用,术语“氨基羰基C1-6烷基”是指式-Ra-C(=O)-NH2的基团,其中Ra是如上所定义的(C1-C6)烷基。
如本文所用,术语“(C1-C4)烷基氨基羰基”是指式-C(=O)-NH-Ra的基团,其中Ra是如上所定义的(C1-C4)烷基。
如本文所用,术语“(C1-C4)烷基氨基羰基C1-6烷基”是指式-Ra1-C(=O)-NH-Ra2的基团,其中Ra1是如上所定义的(C1-C6)烷基并且Ra2是如上所定义的(C1-C4)烷基。
如本文所用,术语“二(C1-C4)烷基氨基羰基”是指式-C(=O)-N(Ra)-Ra的基团,其中每个Ra是如上所定义的可以相同或不同的(C1-C4)烷基。
如本文所用,术语“二(C1-C4)烷基氨基羰基C1-6烷基”是指式-Ra1-C(=O)-N(Ra2)-Ra2的基团,其中Ra1是如上所定义的C1-6烷基并且每个Ra2是如上所定义的可以相同或不同的(C1-C4)烷基。
如本文所用,术语“(C3-C8)环烷基(C0-C6)烷基”是指仅由碳和氢原子组成的稳定的单环饱和烃基团,所述基团具有从三至八个碳原子,并且通过单键或通过如上所定义的(C1-C6)烷基附接至分子的其余部分。(C3-C8)环烷基(C0-C6)烷基的实例包括但不限于环丙基、环丙基-甲基、环丁基、环丁基-乙基、环戊基、环戊基-丙基、环己基、环庚基和环辛基。
术语“芳基”是指6至10元芳族碳环部分,所述部分具有单环体系(例如苯基)或稠合环体系(例如萘)。典型的芳基是苯基。
如本文所用,术语“苯基(C0-C6)烷基”是指通过单键或通过如上所定义的(C1-C6)烷基附接至分子的其余部分的苯环。苯基(C0-C6)烷基的实例包括但不限于苯基和苄基。
如本文所用,术语“苯基(C0-C6)烷基氨基(C1-C6)烷基”是指式-Ra-NH-Rb的基团,其中Ra是如上所定义的(C1-C6)烷基并且Rb是如上所定义的苯基(C0-C6)烷基。
如本文所用,术语“苯基(C0-C6)烷基氨基((C1-C4)烷基)(C1-C6)烷基”是指式-Ra1-N(Ra2)-Rb的基团,其中Ra1是如上所定义的(C1-C6)烷基,Ra2是如上所定义的(C1-C4)烷基并且Rb是如上所定义的苯基(C0-C6)烷基。
如本文所用,卤基是指溴、氯、氟或碘。
如本文所用,术语“卤代(C1-C6)烷基”是指被如上所定义的一个或多个卤基取代的如上所定义的(C1-C6)烷基。卤素(C1-C6)烷基的实例包括但不限于三氟甲基、二氟甲基、氟甲基、三氯甲基、2,2,2-三氟乙基、1,3-二溴丙-2-基、3-溴-2-氟丙基和1,4,4-三氟丁-2-基。
术语“杂环基”是指饱和或部分饱和的(但非芳族的)环或环体系,其包括具有指定的环原子数目的单环、稠合环、桥环和螺环。例如,杂环基包括但不限于5至6元杂环基、4至10元杂环基、4至14元杂环基和5至14元杂环基。除非另有指定,否则杂环基含有1至7个、1至5个、1至3个或1至2个独立地选自由以下组成的组的杂原子作为环成员:氮、氧和硫,其中N和S也可以任选地被氧化成各种氧化态。杂环基团可以附接在杂原子或碳原子上。此类杂环基的实例包括但不限于氮杂环丁烷、氧杂环丁烷、哌啶、哌嗪、吡咯啉、吡咯烷、咪唑烷、咪唑啉、吗啉、四氢呋喃、四氢噻吩、四氢噻喃、四氢吡喃、1,4-二噁烷、1,4氧硫杂环己烷、六氢嘧啶基、3-氮杂双环[3.1.0]己烷、氮杂环庚烷、3-氮杂双环[3.2.2]壬烷、十氢异喹啉、2-氮杂螺[3.3]庚烷、2-氧杂-6-氮杂螺[3.3]庚烷、2,6-二氮杂螺[3.3]庚烷、8-氮杂-双环[3.2.1]辛烷、3,8-二氮杂双环[3.2.1]辛烷、3-氧杂-8-氮杂-双环[3.2.1]辛烷、8-氧杂-3-氮杂-双环[3.2.1]辛烷、2-氧杂-5-氮杂-双环[2.2.1]庚烷、2,5-二氮杂-双环[2.2.1]庚烷、1,4-二氧杂-8-氮杂-螺[4.5]癸烷、3-氧杂-1,8-二氮杂螺[4.5]癸烷、八氢吡咯并[3,2-b]吡咯等。
术语“稠合杂环基”是指与如上定义的芳基(例如苯基)或杂芳基稠合的如上定义的杂环基。此类稠合杂环基的实例包括但不限于1,2,3,4-四氢异喹啉、吲哚啉、异吲哚啉、1,2,3,4-四氢-2,7-萘啶、5,6,7,8-四氢-1,7-萘啶、1,2,3,4-四氢-2,6-萘啶、5,6,7,8-四氢-1,6-萘啶、2,3,4,5-四氢-1H-苯并[d]氮杂卓、1,2,3,4-四氢-1,4-表亚氨基萘、2,3-二氢苯并呋喃、5,6,7,8-四氢吡啶并[3,4-b]吡嗪等。如本文所用,术语“杂环基(C0-C6)烷基”是指如上所定义的杂环,所述杂环通过单键或通过如上所定义的(C1-C6)烷基附接至分子的其余部分。
术语“杂芳基”是指在5至10元芳族环体系内含有至少一个杂原子(例如,氧、硫、氮或其组合)的芳族部分(例如吡咯基、吡啶基、吡唑基、吲哚基、吲唑基、噻吩基、呋喃基、苯并呋喃基、噁唑基、异噁唑基、咪唑基、三唑基、四唑基、三嗪基、嘧啶基、吡嗪基、噻唑基、嘌呤基、苯并咪唑基、喹啉基、异喹啉基、喹喔啉基、苯并吡喃基、苯并噻吩基、苯并咪唑基、苯并噁唑基、1H-苯并[d][1,2,3]三唑基等)。杂芳族部分可以由单环或稠合环体系组成。典型的单杂芳基环是含有一至三个独立地选自氧、硫和氮的杂原子的5至6元环,并且典型的稠合杂芳基环体系是含有一至四个独立地选自氧、硫和氮的杂原子的9至10元环体系。稠合杂芳基环体系可以由稠合在一起的两个杂芳基环或稠合至芳基(例如苯基)的杂芳基组成。如本文所用,术语“杂芳基(C0-C6)烷基”是指如上所定义的杂芳基环,所述杂芳基环通过单键或通过如上所定义的(C1-C6)烷基附接至分子的其余部分。
除非另有指定,否则术语“本发明的化合物”是指式(I)及其子式的化合物(诸如如本文所定义的式(II)、(III)和(IV)的化合物)及其盐以及所有立体异构体(包括非对映异构体和对映异构体)、旋转异构体、互变异构体和同位素标记的化合物(包括氘取代物)以及固有形成的部分。术语“多种(本)发明化合物”或“一种(本)发明化合物”是指下文提及的任一个实施例中所定义的化合物。
在本文中描述了本发明的各种实施例,应认识到,每个实施例中指定的特征可以与其他指定特征组合以提供本发明的另外实施例。
在实施例1中,本发明提供了如上所描述的式(I)的化合物或其药学上可接受的盐。
在实施例2中,本发明提供了如实施例1所述的化合物,其中R4是任选地被一个或多个R6取代的苯基。
在实施例3中,本发明提供了如实施例1所述的化合物,其中R4是任选地被一个或多个R6取代的5至6元杂芳基。
在实施例4中,本发明提供了如实施例3所述的化合物,其中R4是吡啶基。
在实施例5中,本发明提供了如实施例3所述的化合物,其中R4选自由以下组成的组:呋喃基、噁唑基、吡唑基、异噁唑基、噻吩基、咪唑基、和噁二唑基。
在实施例6中,本发明提供了如实施例2所述的化合物,所述化合物具有式(II),
或其药学上可接受的盐。
在实施例7中,本发明提供了如实施例1所述的化合物,所述化合物具有式(III),
或其药学上可接受的盐,
其中环A是5元杂芳基,并且
u、v、w、和x各自独立地选自CH、O、S、N、和NH的组,条件是u、v、w、和x中的至少一个是O、S、N或NH。
在实施例8中,本发明提供了如实施例1、3、5、或7中任一项所述的化合物,
其中n是1或2;并且
R4是
其中R4任选地被一至三个R6取代。
在实施例9中,本发明提供了如实施例1-8中任一项所述的化合物,其中n是1或2,并且至少一个R1是卤基。
在实施例10中,本发明提供了如实施例1-9中任一项所述的化合物,其中n是1或2,并且至少一个R1是F。
在实施例11中,本发明提供了如实施例1-10中任一项所述的化合物,其中n是1。
在实施例12中,本发明提供了如实施例1-11中任一项所述的化合物,其中Z是O。
在实施例13中,本发明提供了如实施例1-12中任一项所述的化合物,其中R2a和R2b各自是H。
在实施例14中,本发明提供了如实施例1-13中任一项所述的化合物,其中R5是H;(C1-C6)烷基;(C2-C6)烯基;或(C0-C4)烷基OR8。
在实施例15中,本发明提供了如实施例1-14中任一项所述的化合物,其中R5是H或(C1-C2)烷基。
在实施例16中,本发明提供了如实施例1-15中任一项所述的化合物,其中R5是H。
在实施例17中,本发明提供了如实施例1-16中任一项所述的化合物,其中每个R3是H。
在实施例18中,本发明提供了如实施例1-17中任一项所述的化合物,其中每个R3是氘。
在实施例19中,本发明提供了如实施例1-18中任一项所述的化合物,其中每个R6独立地选自卤基和(C0-C4)烷基N(R8)2。
在实施例20中,本发明提供了如实施例1-19中任一项所述的化合物,其中R6是卤基。
在实施例21中,本发明提供了如实施例1所述的化合物,其中所述化合物选自:
6'-氟-N-((5-甲基呋喃-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-甲氧基苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(2-羟基乙氧基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
二氢磷酸4-((6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯酯;
N-(2,4-二氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
1'-乙基-6'-氟-N-(4-氟苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-1'-甲基-N-((5-甲基呋喃-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-甲氧基苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((2-甲基呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
6'-氟-N-((4-氟苯基)甲基-d2)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-1'-(2-甲氧基乙基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(噁唑-5-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-1'-(2-羟基乙基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-((2-甲氧基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((5-氯呋喃-2-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((1-甲基乙基)磺酰胺基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
1'-乙基-6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-2,4-二氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
二氢磷酸2-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)乙酯;
N-(3-氨基-4-氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-氨磺酰基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(((1,4-二噁烷-2-基)甲基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((4-(羟基甲基)苄基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-苄基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
N-((2,4-二甲基呋喃-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(3-(噁唑-5-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((1H-吡唑-4-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((4-氨基甲酰基呋喃-2-基)甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-2,4-二氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2,2-二甲基-3-(4-甲基哌嗪-1-基)-3-氧代丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(S)-N-(3-((2,3-二羟基丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(呋喃-3-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((1H-吡唑-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2,5-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(5-氨基-2,4-二氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-(2,2,2-三氟乙氧基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2-(乙基氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(苯并[d][1,3]二氧杂环戊烯-4-基甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(4-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(甲基磺酰胺基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2,3-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((2-甲基呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((3-羟基环丁基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
2-氟-5-((6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯甲酸甲酯;
N-(3-(2-氨基-2-氧代乙基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((3-羟基吡啶-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(甲基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3,5-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((6-(二甲基氨基)吡啶-2-基)甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-(三氟甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2-氯-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(2-羟基乙氧基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-(2-羟基乙氧基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((5-甲基-1H-吡唑-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-4-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-4'-氧代-N-(3-氨磺酰基苄基)-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-3-((2-羟基乙基)氨基)苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟-2-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2,6-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2-(二甲基氨基)乙基)氨基甲酰基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(E)-1'-(丁-2-烯-1-基)-6'-氟-N-(4-氟苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-((2-羟基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-氯苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-(2-氧代吡咯烷-1-基)乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-3-((2-羟基乙基)氨基)苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(1-羟基乙基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((4-氯-1-甲基-1H-吡唑-5-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(R)-6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-4'-氧代-N-((2-(三氟甲基)呋喃-3-基)甲基)-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基-2-甲基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2-环丙基-2-氧代乙基)氨基甲酰基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2,2,2-三氟乙基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(3-甲氧基氮杂环丁烷-1-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(2-氨基-2-氧代乙基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-(三氟甲基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(氧杂环丁烷-3-基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((3-乙基-5-甲基异噁唑-4-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(异噁唑-4-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-(二氟甲氧基)-3-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((2,5-二甲基呋喃-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-氯苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-(三氟甲基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2,2-二甲基-3-吗啉代-3-氧代丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-甲氧基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((2-甲氧基吡啶-4-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(S)-6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(异噁唑-3-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((1H-吲哚-6-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(((2-甲基噁唑-5-基)甲基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(E)-6'-氟-N-(4-氟-3-((4-羟基丁-2-烯-1-基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((5-甲基噻吩-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(异噁唑-5-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((6-氟吡啶-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(5-氨基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((5-甲基-2-(三氟甲基)呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(丙-2-炔-1-基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(1H-咪唑-2-基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(甲基磺酰胺基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(4-氟-3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(环丙烷磺酰胺基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((3-甲基-1,2,4-噁二唑-5-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(1-羟基乙基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((6-氨基吡啶-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2-氨基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(噁唑-4-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(2-羟基丙-2-基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
3-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)-2,2-二甲基丙酸;
N-(苯并[c][1,2,5]噁二唑-4-基甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-8'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(丙基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(1H-1,2,4-三唑-1-基)苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((1-甲基-1H-吡唑-4-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(((2-羟基乙基)氨基)甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(氨磺酰基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
3-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)丙酸;
(R)-N-(3-(1-氨基-2,2,2-三氟乙基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-(二氟甲氧基)苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(R)-6'-氟-N-(4-氟苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(S)-6'-氟-N-(4-氟苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(R)-6'-氟-N-(4-氟苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(S)-6'-氟-N-(4-氟苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(R)-6'-氟-N-(4-氟-2-羟基苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(S)-6'-氟-N-(4-氟-2-羟基苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6',8'-二氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-4-氟苄基)-6'-氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(羟基甲基)苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(2-氨基-2-氧代乙基)-4-氟苄基)-6'-氟-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((3-羟基环丁基)氨基甲酰基)苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(2-羟基乙氧基)苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(甲基磺酰胺基)苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-((2-甲氧基乙基)氨基)苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((R)-1-氨基-2,2,2-三氟乙基)-4-氟苄基)-6'-氟-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-甲氧基苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(R)-6'-氟-4'-羟基-N-((2-甲基呋喃-3-基)甲基)-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(R)-N-(4-氨基-3-氟苄基)-6'-氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;和
(S)-N-(4-氨基-3-氟苄基)-6'-氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
或其药学上可接受的盐。
在实施例22中,本发明提供了如实施例2所述的化合物,其中所述化合物选自:
6'-氟-N-(4-氟-2-甲氧基苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(2-羟基乙氧基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
二氢磷酸4-((6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯酯;
N-(2,4-二氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
1'-乙基-6'-氟-N-(4-氟苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-甲氧基苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((4-氟苯基)甲基-d2)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-1'-(2-甲氧基乙基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(噁唑-5-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-1'-(2-羟基乙基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-((2-甲氧基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((1-甲基乙基)磺酰胺基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
1'-乙基-6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-2,4-二氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
二氢磷酸2-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)乙酯;
N-(3-氨基-4-氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-氨磺酰基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(((1,4-二噁烷-2-基)甲基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((4-(羟基甲基)苄基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-苄基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(3-(噁唑-5-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-2,4-二氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2,2-二甲基-3-(4-甲基哌嗪-1-基)-3-氧代丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(S)-N-(3-((2,3-二羟基丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2,5-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(5-氨基-2,4-二氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-(2,2,2-三氟乙氧基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2-(乙基氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(苯并[d][1,3]二氧杂环戊烯-4-基甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(4-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(甲基磺酰胺基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2,3-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((3-羟基环丁基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
2-氟-5-((6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯甲酸甲酯;
N-(3-(2-氨基-2-氧代乙基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(甲基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3,5-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-(三氟甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2-氯-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(2-羟基乙氧基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-(2-羟基乙氧基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-4-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-4'-氧代-N-(3-氨磺酰基苄基)-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-3-((2-羟基乙基)氨基)苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟-2-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2,6-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2-(二甲基氨基)乙基)氨基甲酰基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺:
(E)-1'-(丁-2-烯-1-基)-6'-氟-N-(4-氟苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-((2-羟基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-氯苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-(2-氧代吡咯烷-1-基)乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-3-((2-羟基乙基)氨基)苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(1-羟基乙基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(R)-6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基-2-甲基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2-环丙基-2-氧代乙基)氨基甲酰基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2,2,2-三氟乙基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(3-甲氧基氮杂环丁烷-1-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(2-氨基-2-氧代乙基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-(三氟甲基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(氧杂环丁烷-3-基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-(二氟甲氧基)-3-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-氯苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-(三氟甲基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2,2-二甲基-3-吗啉代-3-氧代丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-甲氧基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(S)-6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(((2-甲基噁唑-5-基)甲基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(E)-6'-氟-N-(4-氟-3-((4-羟基丁-2-烯-1-基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(5-氨基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(丙-2-炔-1-基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(1H-咪唑-2-基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(甲基磺酰胺基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(4-氟-3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(环丙烷磺酰胺基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(1-羟基乙基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2-氨基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(2-羟基丙-2-基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
3-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)-2,2-二甲基丙酸;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-8'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(丙基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(1H-1,2,4-三唑-1-基)苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(((2-羟基乙基)氨基)甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(氨磺酰基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
R)-N-(3-(1-氨基-2,2,2-三氟乙基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;和
N-(4-(二氟甲氧基)苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
或其药学上可接受的盐。
在实施例23中,本发明提供了如实施例5所述的化合物,其中所述化合物选自:
6'-氟-N-((5-甲基呋喃-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-1'-甲基-N-((5-甲基呋喃-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((2-甲基呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((5-氯呋喃-2-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((2,4-二甲基呋喃-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((1H-吡唑-4-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((4-氨基甲酰基呋喃-2-基)甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(呋喃-3-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((1H-吡唑-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((2-甲基呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((3-羟基吡啶-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((6-(二甲基氨基)吡啶-2-基)甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((5-甲基-1H-吡唑-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((4-氯-1-甲基-1H-吡唑-5-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-4'-氧代-N-((2-(三氟甲基)呋喃-3-基)甲基)-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((3-乙基-5-甲基异噁唑-4-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(异噁唑-4-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((2,5-二甲基呋喃-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((2-甲氧基吡啶-4-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(异噁唑-3-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((1H-吲哚-6-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((5-甲基噻吩-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(异噁唑-5-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((6-氟吡啶-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((5-甲基-2-(三氟甲基)呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((3-甲基-1,2,4-噁二唑-5-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((6-氨基吡啶-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(噁唑-4-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(苯并[c][1,2,5]噁二唑-4-基甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;和
6'-氟-N-((1-甲基-1H-吡唑-4-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
或其药学上可接受的盐。
在实施例24中,本发明提供了一种药物组合物,所述药物组合物包含根据实施例1至23中任一项所述的化合物以及一种或多种药学上可接受的载体。
在实施例25中,本发明提供了一种药物组合,所述药物组合包含根据实施例1至23中任一项所述的化合物或其药学上可接受的盐以及一种或多种治疗剂。
在实施例26中,本发明提供了根据实施例1至23中任一项所述的化合物,所述化合物用作药剂,特别用于治疗或预防KARS介导的疾病或病症。
在实施例27中,本发明提供了根据实施例1至23中任一项所述的化合物,所述化合物用于治疗或预防癌症,其中所述方法包括向所述受试者施用根据实施例1至7中任一项所述的式(I)至(III)的化合物或其药学上可接受的盐。
在实施例28中,本发明提供了根据实施例23所述的化合物,其中所述癌症选自非小细胞肺癌(NSCLC)、肝癌、头颈癌、食道癌、子宫癌、乳腺癌、膀胱癌、子宫颈癌、结直肠癌、肾癌、黑素瘤、胃、去势抵抗性前列腺癌(CRPC)、T细胞急性成淋巴细胞性白血病(T-ALL)、急性髓性白血病(AML)、和骨髓增生异常综合征(MDS),其中所述方法包括向所述受试者施用根据实施例1至7中任一项所述的式(I)至(III)的化合物或其药学上可接受的盐。
在实施例29中,本发明提供了根据实施例28所述的化合物,其中所述非小细胞肺癌(NSCLC)选自腺癌、鳞状细胞癌、大细胞癌、大细胞神经内分泌癌、腺鳞癌、和肉瘤样癌。
在实施例30中,本发明提供了根据实施例1至23中任一项所述的化合物,所述化合物用于治疗或预防在基因NFE2L2、KEAP1、CUL3、AKR1C3中具有遗传或表观遗传改变的癌症或导致激活NRF2转录活性或AKR1C3基因表达的任何其他病症。
在实施例31中,本发明提供了如任何实施例1至23所述的化合物,所述化合物用于治疗或预防AKR1C3过表达高于预定值的癌症。
取决于起始材料和程序的选择,所述化合物可以以一种可能的立体异构体形式或作为其混合物(例如作为纯的光学异构体或作为立体异构体混合物,诸如外消旋体和非对映异构体混合物)存在,这取决于不对称碳原子的数目。本发明意在包括所有此类可能的立体异构体,包括外消旋混合物、非对映异构体混合物和光学纯的形式。光学活性(R)-和(S)-立体异构体可以使用手性合成子或手性试剂制备,或使用常规技术拆分。如果化合物含有双键,则取代基可以是(E)或(Z)构型。如果化合物含有二取代的环烷基,则环烷基取代基可以具有顺式或反式构型。也包括所有互变异构形式。
如本文所用,术语“一种盐”或“多种盐”是指本发明的化合物的酸加成盐或碱加成盐。“盐”特别地包括“药学上可接受的盐”。术语“药学上可接受的盐”是指保留本发明化合物的生物有效性和特性并且典型地不是生物学上或其他方面不希望的盐。在许多情况下,由于氨基和/或羧基或与其类似的基团的存在,本发明的化合物能够形成酸盐和/或碱盐。
可以用无机酸和有机酸形成药学上可接受的酸加成盐。
可以衍生出盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以衍生出盐的有机酸包括,例如乙酸、丙酸、乙醇酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、甲苯磺酸、磺基水杨酸等。
可以用无机碱和有机碱形成药学上可接受的碱加成盐。
可以衍生出盐的无机碱包括例如铵盐和来自元素周期表第I至XII列的金属。在某些实施例中,盐衍生自钠、钾、铵、钙、镁、铁、银、锌和铜;特别合适的盐包括铵盐、钾盐、钠盐、钙盐和镁盐。
可以衍生出盐的有机碱包括例如伯胺、仲胺和叔胺;取代的胺(包括天然存在的取代的胺);环胺;碱性离子交换树脂等。某些有机胺包括异丙胺、苄星、胆碱盐、二乙醇胺、二乙胺、赖氨酸、葡甲胺、哌嗪和氨丁三醇。
在另一个方面,本发明提供了呈以下形式的根据实施例1至5中任一项所述的式(I)至(IV)中任一项的化合物:乙酸盐、抗坏血酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、癸酸盐、氯化物/盐酸盐、氯脲鎓酸盐(chlortheophyllonate)、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、谷氨酸盐、戊二酸盐、乙醇酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、十二烷基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、粘酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八烷酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖醛酸盐、丙酸盐、癸二酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐三苯乙酸盐(trifenatate)、三氟乙酸盐、或昔萘酸盐。
在另一方面,本发明提供了呈以下形式的式(I)至(IV)中任一项的化合物:钠、钾、铵、钙、镁、铁、银、锌、铜、异丙胺、苄星、胆碱盐、二乙醇胺、二乙胺、赖氨酸、葡甲胺、哌嗪或氨丁三醇盐形式。
本文给出的任何式也旨在表示化合物的未标记形式以及同位素标记形式。同位素标记的化合物具有由本文给出的式描绘的结构,除了一个或多个原子被具有所选择的原子质量或质量数的原子替代。可以掺入本发明化合物中的同位素包括例如氢的同位素。
此外,掺入某些同位素,特别是氘(即2H或D)可以提供由更大代谢稳定性产生的某些治疗优点,例如增加的体内半衰期或减少的剂量要求或治疗指数或耐受性的改善。应理解,在此上下文中的氘被认为是式(I)的化合物的取代基。氘的浓度可以由同位素富集因子定义。如本文所用的术语“同位素富集因子”意指指定同位素的同位素丰度与天然丰度之间的比率。如果本发明化合物中的取代基指示氘,则此类化合物具有针对每个指定的氘原子的同位素富集因子为至少3500(在每个指定的氘原子上52.5%氘掺入)、至少4000(60%氘掺入)、至少4500(67.5%氘掺入)、至少5000(75%氘掺入)、至少5500(82.5%氘掺入)、至少6000(90%氘掺入)、至少6333.3(95%氘掺入)、至少6466.7(97%氘掺入)、至少6600(99%氘掺入)或至少6633.3(99.5%氘掺入)。应当理解,术语“同位素富集因子”可以与针对氘所描述的相同方式应用于任何同位素。
可以掺入本发明的化合物的同位素的其他实例包括氢、碳、氮、氧、磷、氟和氯的同位素,诸如分别是3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl、123I、124I、125I。因此,应理解,本发明包括掺入一种或多种任何前述同位素(包括例如放射性同位素(诸如3H和14C))的化合物,或其中存在非放射性同位素(诸如2H和13C)的化合物。此类同位素标记的化合物可用于代谢研究(用14C)、反应动力学研究(用例如2H或3H)、检测或成像技术(诸如正电子发射断层扫描(PET)或单光子发射计算机断层扫描(SPECT),包括药物或底物组织分布测定),或用于患者的放射性治疗。特别地,18F或标记的化合物可能对于PET或SPECT研究是特别希望的。同位素标记的式(I)的化合物通常可以通过本领域技术人员已知的常规技术或通过与所附实例和制备中描述的那些类似的方法使用适当的同位素标记的试剂代替先前使用的未标记的试剂来制备。
药物组合物
如本文所用,术语“药物组合物”是指呈适用于口服或肠胃外施用的形式的本发明化合物或其药学上可接受的盐以及至少一种药学上可接受的载体。
如本文所用,术语“药学上可接受的载体”是指可用于制备或使用药物组合物的物质,并且包括例如合适的稀释剂、溶剂、分散介质、表面活性剂、抗氧化剂、防腐剂、等渗剂、缓冲剂、乳化剂、吸收延迟剂、盐、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、润湿剂、甜味剂、矫味剂、染料以及它们的组合,如本领域技术人员已知的(参见例如Remington TheScience and Practice of Pharmacy[雷明顿:药物科学与实践],第22版,PharmaceuticalPress[药物出版社],2013,第1049至1070页)。
本发明化合物的术语“治疗有效量”是指将引起受试者的生物学或医学反应(例如酶或蛋白质活性的降低或抑制)或改善症状,减轻病症,减慢或延迟疾病进展,或预防疾病等的本发明化合物的量。在一个非限制性实施例中,术语“治疗有效量”是指这样的本发明化合物量,所述量当施用于受试者时有效地(1)至少部分地减轻,抑制,预防和/或改善(i)由KARS介导的、或(ii)对KARS抑制敏感的疾病、或(iii)特征为KARS的活性(正常或异常)的病症或障碍或疾病;或(2)减少或抑制对KARS抑制敏感的疾病。本发明进一步提供了治疗或预防与高AKR1C3表达或对KARS抑制敏感性相关的疾病和/或障碍的方法,所述方法包括向有需要的受试者施用有效量的AKR1C3依赖性KARS抑制剂。
如本文所用,术语“受试者”是指灵长类动物(例如,人(男性或女性))、猴、狗、兔、豚鼠、猪、大鼠和小鼠。在某些实施例中,受试者是灵长类动物。在又其他实施例中,受试者是人。
如本文所用,术语“抑制(inhibit、inhibition或inhibiting)”是指减少或抑制给定的病症、症状或障碍、或疾病,或在生物活性或过程的基线活性方面的显著降低。
如本文所用,术语任何疾病或障碍的“治疗(treat、treating或treatment)”是指减轻或改善疾病或障碍(即,减慢或阻止疾病或其至少一种临床症状的发展);或者减轻或改善与所述疾病或障碍相关联的至少一种物理参数或生物标志物,包括针对患者可能无法辨别的那些物理参数或生物标志物。
如本文所用,术语任何疾病或障碍的“预防(prevent、preventing或prevention)”是指疾病或障碍的预防性治疗;或延迟疾病或障碍的发作或进展
如本文所用,如果受试者将在生物学上、在医学上或在生活质量上从治疗中受益,则此类受试者是“需要”此类治疗的。
如本文所用,术语“一个”、“一种”、“所述(the)”以及在本发明的上下文中(尤其是在权利要求的上下文中)使用的类似术语应被解释为涵盖单数和复数二者,除非本文中另外指示或与上下文明显相矛盾。
在本文描述的所有方法能够以任何合适的顺序进行,除非本文中另外指示或另外与上下文明显矛盾。本文提供的任何和所有实例或示例性语言(例如“诸如”)的使用仅旨在更好地说明本发明,而不对另外要求保护的本发明范围做出限制。
本发明的一种或多种化合物的任何非对称原子(例如,碳等)可以以外消旋或对映异构体富集的形式存在,例如(R)-、(S)-或(R,S)-构型。在某些实施例中,每个非对称原子具有至少50%对映异构体过量、至少60%对映异构体过量、至少70%对映异构体过量、至少80%对映异构体过量、至少90%对映异构体过量、至少95%对映异构体过量、或至少99%对映异构体过量的(R)-或(S)-构型。如果可能,在具有不饱和双键的原子上的取代基可以以顺式-(Z)-或反式-(E)-形式存在。
因此,如本文所用,本发明的化合物可以呈可能的立体异构体、旋转异构体、阻转异构体、互变异构体或其混合物中的一种的形式,例如作为基本上纯的几何(顺式或反式)立体异构体、非对映异构体、光学异构体(对映体)、外消旋体或其混合物。
任何所得立体异构体混合物可以基于组分的物理化学差异例如通过色谱法和/或分级结晶被分离成纯的或基本上纯的几何或光学异构体、非对映异构体、外消旋体。
任何所得的终产物或中间体的外消旋体可以通过已知方法被拆分成光学对映体,例如通过分离用光学活性酸或碱获得的其非对映异构体盐并且释放出光学活性的酸性或碱性化合物。特别地,因此可以采用碱性化合物将本发明的化合物拆分成其光学对映体,例如通过用光学活性酸形成的盐的分级结晶,所述光学活性酸例如酒石酸、二苯甲酰基酒石酸、二乙酰基酒石酸、二-O,O'-对甲苯酰基酒石酸、扁桃酸、苹果酸或樟脑-10-磺酸。外消旋产物也可以通过手性色谱法(例如,使用手性吸附剂的高效液相色谱法(HPLC))拆分。
合成本发明化合物的方法
本发明化合物可以根据式(I)的化合物的定义通过以下方案或实例中描述的途径来制备。在本文描述的所有方法能够以任何合适的顺序进行,除非本文中另外指示或另外与上下文明显矛盾。本文提供的任何和所有实例或示例性语言(例如“诸如”)的使用仅旨在更好地说明本发明,而不对另外要求保护的本发明范围做出限制。
在以下通用方法中,R1、R2、R3、R4、R5、R6是如上定义或限于方案中的指定。除非另有说明,否则起始材料是可商购的或通过已知方法制备的。
通用合成方案
方案1
步骤(a)涉及在吡咯烷的存在下,在诸如DMSO的合适溶剂中,在诸如140℃的合适温度下,使取代的苯胺和N-Boc-4-氧代哌啶进行缩合反应。步骤(b)涉及在室温下在诸如DCM的合适溶剂中使用诸如TFA的试剂除去诸如Boc和PMB基团的N-保护基团。步骤(c)涉及在室温下使用在诸如DMF和MeCN的合适溶剂中的诸如CDI或三光气的试剂以及诸如Hunig碱的碱,与伯胺形成脲。任选地,在步骤(c)之后,可以通过诸如还原性胺化、烷基化、磺酰化、磷酸化、O-脱保护、酯水解和酰胺化的方法将R4基团的取代基进一步转化为新的取代基。
方案2
步骤(a)涉及螺-哌啶化合物和取代的异氰酸酯在诸如THF的合适溶剂中在诸如室温的合适温度下反应。
方案3
步骤(a)涉及在诸如室温的合适温度下使用诸如硼氢化钠的合适试剂并且在诸如乙醇的合适溶剂中进行将酮还原成相应的醇的反应。在某些情况下,通过色谱法使用手性柱分离醇的对映异构体。
此实施例的化合物可用于制备本发明的化合物,例如式(I)至(IV)的化合物或其药学上可接受的盐。
本发明进一步包括本发明方法的任何变型,其中将可在其任何阶段获得的中间体产物用作起始材料并且进行其余步骤,或其中起始材料在反应条件下原位形成,或其中将反应组分以其盐或光学纯的材料的形式使用。本发明化合物和中间体还可以根据本领域技术人员通常已知的方法彼此转化。
在另一方面,本发明提供了一种药物组合物,所述药物组合物包含本发明化合物或其药学上可接受的盐以及药学上可接受的载体。在另外的实施例中,所述组合物包含至少两种药学上可接受的载体,诸如本文所述的那些。所述药物组合物可以配制用于特定的施用途径,诸如口服施用、肠胃外施用(例如通过注射、输注、透皮或局部施用)、和直肠施用。局部施用也可以涉及吸入或鼻内应用。本发明的药物组合物可以以固体形式(包括但不限于胶囊、片剂、丸剂、颗粒、粉末或栓剂)、或以液体形式(包括但不限于溶液、悬浮液或乳液)制成。片剂可以根据本领域已知的方法进行薄膜包衣或肠溶包衣。典型地,药物组合物是包含活性成分及以下中的一种或多种的片剂或明胶胶囊:
a)稀释剂,例如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素和/或甘氨酸;
b)润滑剂,例如二氧化硅、滑石、硬脂酸、其镁或钙盐和/或聚乙二醇;对于片剂,还包含
c)粘合剂,例如硅酸铝镁、淀粉糊、明胶、黄芪胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;如果希望的话,
d)崩解剂,例如淀粉、琼脂、海藻酸或其钠盐、或泡腾混合物;和
e)吸附剂、着色剂、调味剂和甜味剂。
本发明的使用方法
呈游离形式或呈药学上可接受的盐形式的式(I)至(III)中任一项的化合物展现出有价值的药理学特性,例如IL-17调节特性(例如,如下一章节中提供的体外测试中所指示的),并且因此指示用于疗法或用作研究化学品,例如用作工具化合物。
本发明的化合物可以用于治疗或预防癌症,其中所述癌症选自非小细胞肺癌(NSCLC)、肝癌、头颈癌、食道癌、子宫癌、乳腺癌、膀胱癌、子宫颈癌、结直肠癌、肾癌、黑素瘤、胃、去势抵抗性前列腺癌(CRPC)、T细胞急性成淋巴细胞性白血病(T-ALL)、急性髓性白血病(AML)、和骨髓增生异常综合征(MDS)。
因此,作为另外的方面,本发明提供了式(I)、(II)或(III)的化合物,或根据任何前述实施例(即,根据实施例1至9e)的化合物,或其药学上可接受的盐在疗法中的用途。在另外的实施例中,所述疗法选自可以通过AKR1C3依赖性KARS抑制剂治疗的疾病。在另一个的实施例中,所述疾病选自前述列表,合适地选自癌症,特别地其中所述癌症选自非小细胞肺癌(NSCLC)、肝癌、头颈癌、食道癌、子宫癌、乳腺癌、膀胱癌、子宫颈癌、结直肠癌、肾癌、黑素瘤、胃、去势抵抗性前列腺癌(CRPC)、T细胞急性成淋巴细胞性白血病(T-ALL)、急性髓性白血病(AML)、和骨髓增生异常综合征(MDS)。
因此,作为另外的方面,本发明提供了式(I)至(III)中任一项的化合物,或根据任何前述实施例(即,根据实施例1至9e)的化合物,或其药学上可接受的盐,其用于疗法。在另外的实施例中,所述疗法选自可以通过AKR1C3依赖性KARS抑制剂治疗的疾病。在另一个的实施例中,所述疾病选自前述列表,合适地选自特别是癌症
在另一个方面,本发明提供了一种治疗或预防疾病的方法,所述疾病通过AKR1C3依赖性KARS抑制剂治疗,所述方法包括施用式(I)至(IV)中任一项的化合物,或根据任一项前述实施例(即,根据实施例1至5中任一项)的化合物,或其药学上可接受的盐。在另外的实施例中,所述疾病选自前述列表,合适地选自特别是癌症。
因此,作为另外的方面,本发明提供了式(I)至(IV)中任一项的化合物,或根据任一项前述实施例(即,根据实施例1至5中任一项),或其药学上可接受的盐的化合物用于制造药剂的用途。在另外的实施例中,所述药剂用于治疗或预防疾病,所述疾病可以通过AKR1C3依赖性KARS抑制剂治疗。在另一个的实施例中,所述疾病选自前述列表,合适地选自特别是癌症
对于约50-70kg的受试者,本发明的药物组合物或组合可以呈约1-1000mg一种或多种活性成分,或约1-500mg或约1-250mg或约1-150mg或约0.5-100mg或约1-50mg活性成分的单位剂量。化合物、药物组合物、或其组合的治疗有效剂量取决于受试者的物种,体重、年龄和个体状况,所治疗的障碍或疾病或其严重性。具有普通技能的医师、临床医生或兽医可以容易地确定预防、治疗或抑制障碍或疾病的进展所必需的每种活性成分的有效量。
有利地使用哺乳动物(例如,小鼠、大鼠、狗、猴)或其分离的器官、组织和制品使用体外和体内测试证明上述剂量特性。本发明化合物可以以溶液(例如水溶液)的形式体外应用,和例如以悬浮液或以水溶液的形式肠内、肠胃外、有利地静脉内体内应用。体外剂量的范围可以在约10-3摩尔浓度与10-9摩尔浓度之间。根据施用途径,体内治疗有效量的范围可以在约0.1-500mg/kg之间或在约1-100mg/kg之间。
本发明的组合产品和组合疗法
“组合”是指呈一种剂量单位形式的固定组合,或组合施用,其中本发明化合物与组合伴侣(例如,如下解释的另一种药物,也称为“治疗剂”或“共药剂”)可以同时独立地施用或在时间间隔内分开地施用,尤其地其中这些时间间隔允许组合伴侣显示出协作(例如协同)作应。单个组分可以包装在试剂盒中或分开包装。可以在施用之前将一种或两种组分(例如粉末或液体)重构或稀释至所希望的剂量。如本文所用的术语“共同施用”或“组合施用”等旨在涵盖将所选择的组合伴侣施用于有需要的单一受试者(例如患者),并且旨在包括其中药剂不一定通过相同的施用途径施用或同时施用的治疗方案。如本文所用,术语“药物组合”意指通过多于一种治疗剂的混合或组合而产生的产品,并且包括治疗剂的固定和非固定组合两者。术语“固定组合”意指治疗剂(例如,本发明化合物和组合伴侣)以单一实体或剂量的形式同时地施用于患者。术语“非固定组合”意指治疗剂(例如,本发明化合物和组合伴侣)作为单独的实体同时地、并行地或顺序地施用于患者(没有特定的时间限制),其中此类施用在患者体内提供治疗有效水平的两种化合物。后者也适用于鸡尾酒疗法,例如三种或更多种治疗剂的施用。
如本文所用的术语“药物组合”是指在一个剂量单位形式中的固定组合、或用于组合施用的非固定组合或成套试剂盒,其中两种或更多种治疗剂可以在同一时间独立地施用或在时间间隔内分别施用,尤其地其中这些时间间隔允许组合伴侣显示出协作(例如协同)作应。
术语“组合疗法”是指施用两种或更多种治疗剂以治疗在本披露中描述的治疗性病症或障碍。此类施用涵盖以基本上同时的方式共同施用这些治疗剂,诸如以具有固定比率的活性成分的单个胶囊施用。可替代地,此类施用涵盖在多个容器中或在每种活性成分的独立容器(例如,片剂、胶囊、粉末和液体)中共同施用。可以将粉末和/或液体在施用之前重构或稀释至所希望的剂量。此外,此类施用也涵盖在大致相同的时间或在不同的时间以依序方式使用每种类型的治疗剂。在任何一种情况下,治疗方案将在治疗本文描述的病症或障碍方面提供药物组合的有益作用。
本发明化合物可以与一种或多种其他治疗剂同时施用或者在其之前或之后施用。本发明化合物可以通过与其他药剂相同或不同的施用途径分开施用,或在相同的药物组合物中一起施用。治疗剂是例如化学化合物、肽、抗体、抗体片段或核酸,所述治疗剂当与本发明化合物组合施用于患者时具有治疗活性或增强治疗活性。
在一个实施例中,本发明提供了一种作为组合制剂的产品,所述产品包含式(I)、(II)、(III)或(IV)的化合物,或根据任一项前述实施例(即,根据实施例1至5中任一项)的化合物,或其药学上可接受的盐,以及至少一种其他治疗剂,用于在疗法中同时、分开或依序使用。
在一个实施例中,所述疗法是治疗或预防由AKR1C3依赖性KARS抑制剂介导的疾病或病症。作为组合制剂提供的产品包括组合物,所述组合物包含一起在同一药物组合物中的式(I)至(IV)中任一项的化合物或其药学上可接受的盐以及一种或多种其他治疗剂,或者呈分开的形式(例如呈试剂盒的形式)的式(I)至(IV)中任一项的化合物或其药学上可接受的盐以及一种或多种其他治疗剂。
在一个实施例中,本发明提供了一种药物组合,所述药物组合包含式(I)至(IV)中任一项的化合物,或根据任一项前述实施例(即,根据实施例1至5中任一项)的化合物,或其药学上可接受的盐,以及另一种或多种治疗剂。任选地,所述药物组合可以包含如上描述的药学上可接受的载体。
在一个实施例中,本发明提供了一种试剂盒,所述试剂盒包括两种或更多种单独的药物组合物,其中至少一种含有式(I)至(IV)中任一项的化合物,或根据任一项前述实施例(即,根据实施例1至5中任一项)的化合物,或其药学上可接受的盐。在一个实施例中,所述试剂盒包含用于单独地保留所述组合物的装置,诸如例如容器、分开的瓶、或分开的箔袋。此类试剂盒的实例是泡罩包装,如典型地用于包装片剂、胶囊等。
本发明试剂盒可以用于施用不同剂型(例如,口服和肠胃外),用于以不同剂量间隔施用单独的组合物,或用于相对彼此滴定单独的组合物。为了有助于依从性,本发明试剂盒典型地包括施用指导。
在本发明的组合疗法中,本发明化合物和其他治疗剂可以由相同或不同的制造商生产和/或配制。此外,可以将本发明的化合物和其他治疗剂一起形成组合疗法:(i)在向医师发布组合产品(例如,在包含本发明的化合物和其他治疗剂的试剂盒的情况下)之前进行;(ii)在施用前不久由医师本人(或在医师指导下)进行;(iii)在患者自身中,例如在依序施用本发明的化合物和其他治疗剂期间进行。
因此,本发明提供了式(I)至(IV)中任一项的化合物,或根据任一项前述实施例(即,根据实施例1至5中任一项)的化合物,或其药学上可接受的盐用于治疗或预防由AKR1C3依赖性KARS抑制剂介导的疾病或病症的用途,其中药剂被制备用于与另一种治疗剂一起施用。本发明还提供了另一种治疗剂用于治疗或预防由AKR1C3依赖性KARS抑制剂介导的疾病或病症的用途,其中将药剂与式(I)至(IV)中任一项的化合物或其药学上可接受的盐一起施用。
本发明还提供了式(I)至(IV)中任一项的化合物,或根据任一项前述实施例(即,根据实施例1至5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AKR1C3依赖性KARS抑制剂介导的疾病或病症的方法,其中式(I)、(II)、(III)或(IV)的化合物,或根据任一项前述实施例(即,根据实施例1至5中任一项)的化合物,或其药学上可接受的盐被制备用于与另一种治疗剂一起施用。本发明还提供了另一种治疗剂,所述治疗剂用于治疗或预防由AKR1C3依赖性KARS抑制剂介导的疾病或病症的方法,其中其他治疗剂被制备用于与式(I)、(II)、(III)或(IV)的化合物,或根据任一项前述实施例(即,根据实施例1至5中任一项)的化合物,或其药学上可接受的盐一起施用。本发明还提供了式(I)、(II)、(III)或(IV)的化合物,或根据任一项前述实施例(即,根据实施例1至5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AKR1C3依赖性KARS抑制剂介导的疾病或病症的方法,其中式(I)、(II)、(III)或(IV)的化合物,或根据任一项前述实施例(即,根据实施例1至5中任一项)的化合物,或其药学上可接受的盐与另一种治疗剂一起施用。本发明还提供了另一种治疗剂,所述治疗剂用于治疗或预防由AKR1C3依赖性KARS抑制剂介导的疾病或病症的方法,其中将其他治疗剂与式(I)、(II)、(III)或(IV)的化合物,或根据任一项前述实施例(即,根据实施例1至5中任一项)的化合物,或其药学上可接受的盐一起施用。
本发明还提供了式(I)至(IV)中任一项的化合物,或根据任一项前述实施例(即,根据实施例1至5中任一项)的化合物,或其药学上可接受的盐用于治疗或预防由AKR1C3介导的疾病或病症的用途,其中患者先前(例如在24小时内)已经用另一种治疗剂治疗。本发明还提供了另一种治疗剂用于治疗由AKR1C3依赖性KARS抑制剂介导的疾病或病症的用途,其中患者先前(例如在24小时内)已经用式(I)、(II)、(III)或(IV)的化合物,或根据任一项前述实施例(即,根据实施例1至5中任一项)的化合物,或其药学上可接受的盐治疗。
实例
本发明的实例
通过以下实例和合成方案进一步说明本披露,所述实例和合成方案不应解释为将本披露的范围或精神限制于本文描述的具体程序。应理解,所述实例被提供用来说明某些实施例,并且本披露的范围不旨被其限制。应进一步理解,在不脱离本披露的精神和/或所附权利要求的范围的情况下,可以采取可为本领域技术人员提出的各种其他实施例、修改和其等效物。
本披露的化合物可通过有机合成领域中已知的方法制备。在所有方法中,应理解,可以在必要时根据化学的一般原理使用针对敏感或反应性基团的保护基团。根据有机合成的标准方法(T.W.Green和P.G.M.Wuts(2014)Protective Groups in Organic Synthesis[有机合成中的保护基团],第5版,John Wiley&Sons[约翰威立父子出版公司])操作保护基团。使用对本领域技术人员显而易见的方法,在化合物合成的方便阶段除去这些基团。除非另有说明,否则使用如从商业供应商处收到的试剂和溶剂。
化学名称使用来自剑桥软件(CambridgeSoft)的ChemBioDraw Ultra产生。
温度以摄氏度给出。如本文所用,除非另外指定,否则术语“室温”或“环境温度”意指从15℃至30℃、诸如从20℃至30℃、诸如从20℃至25℃的温度。如果没有另外提及,所有蒸发均在减压下,典型地在约15mm Hg与100mm Hg(=20-133毫巴)之间进行。终产物、中间体和起始材料的结构通过标准分析方法(例如,微量分析和光谱特征(例如,MS、IR、NMR))来确认。所使用的缩写是本领域常规的那些缩写。
缩写
Ac 乙酰基
ACN 乙腈
AIBN 偶氮二异丁腈
app 明显的
ATP 5'-三磷酸腺苷
BINAP 外消旋2,2'-双(二苯基膦基)-1,1'-联萘
BOC 叔丁基羧基
br 宽
BSA 牛血清白蛋白
Bu 丁基
Cbz 碳苄氧基
CDI 羰基二咪唑
d 双重峰
DAST 二乙基氨基三氟化硫
dd 双双重峰
ddd 双双双重峰
DCE 二氯乙烷
DCM 二氯甲烷
DDQ 2,3-二氯-5,6-二氰基-1,4-苯醌
DIPEA 二异丙基乙胺
DMA 二甲基乙酰胺
DMAP 4-二甲基氨基吡啶
DME 1,4-二甲氧基乙烷
DMF N,N-二甲基甲酰胺
DMSO 二甲亚砜
dppf 1,1-双(二苯基膦基)二茂铁
dt 双三重峰
EDTA 乙二胺四乙酸
ESI 电喷雾电离
Et 乙基
EtOAc 乙酸乙酯
h 小时
HATU 1-[双(二甲基氨基)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
HBTU 1-[双(二甲基氨基)亚甲基]-1H-苯并三唑鎓六氟磷酸盐(1-)3-氧化物
HOBt 1-羟基-7-氮杂苯并三唑
HPLC 高压液相色谱法
HRMS 高分辨质谱法
LAH 氢化铝锂
LCMS 液相色谱法和质谱法
LHMDS 六甲基二硅叠氮化锂
MeCN 乙腈
MeOH 甲醇
MHz 兆赫兹
MTBE 甲基叔丁基醚
MS 质谱法
m 多重峰
mg 毫克
min 分钟
ml 毫升
mmol 毫摩尔
m/z 质荷比
NBS N-溴琥珀酰亚胺
NCS N-氯琥珀酰亚胺
NMR 核磁共振
P 对
PdCl2(dppf)-CH2Cl2 1,1’-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物
Pd(OAc)2 乙酸钯(II)
Pd/C 碳载钯
Ph 苯基
PMB 对甲氧基苄基
ppm 百万分率
PyBOP 苯并三唑-1-基氧基三吡咯烷基鏻六氟磷酸盐
q 四重峰
rac 外消旋的
RBF 圆底烧瓶
Rt 保留时间
RT 室温
s 单峰
sat. 饱和的
SCX 强阳离子交换吸附柱
SEM [2-(三甲基甲硅烷基)乙氧基]甲基
SFC 超临界液相色谱法
t 三重峰
TBAF 四丁基氟化铵
TBDMS 叔丁基二甲基甲硅烷基
TBDPS 叔丁基二苯基甲硅烷基
TBME 甲基叔丁基醚
tBu 叔丁基
td 三双重峰
tdt 三双三重峰
TEA 三乙胺
tert 叔
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层色谱法
TMS 三甲基甲硅烷基
Tris·HCl 氨基三(羟基甲基)甲烷盐酸盐
分析细节
仪器
实例的表征中使用的LCMS方法
使用带有Waters Micromass ZQ的安捷伦(Agilent)1100HPLC系统或者带有Waters SQ检测器或带有Waters 25ACQUITY Qda检测器的Waters ACQUITY UPLC记录LCMS数据。下面描述了用于获取所有LCMS数据的方法。
LCMS方法1
柱 Sunfire C18 3.0x30mm,3.5μm
柱温 40℃
洗脱液 A:含有0.05%TFA的H2O,B:MeCN
流速 2.0mL/min
梯度 在1.7min内5%至95%B,0.3min 95%B
LCMS方法2
柱 XBridge C18 3.0x30mm,3.5μm
柱温 40℃
洗脱液 A:H2O+5mM氢氧化铵,B:MeCN
流速 2.0mL/min
梯度 在1.7min内5%至95%B,0.3min 95%B
LCMS方法3
柱 AcQuity UPLC BEH C18 2.1x30mm,1.7μm
柱温 50℃
洗脱液 A:在水中的0.1%甲酸,B:在MeCN中的0.1%甲酸
流速 1.0mL/min
梯度 在1.5min内2%至98%B,0.3min 98%B
LCMS方法4
柱 AcQuity UPLC BEH C18 2.1x50mm,1.7μm
柱温 50℃
洗脱液 A:在水中的5mM NH4OH,B:在MeCN中的5mM NH4OH
流速 1.0mL/min
梯度 在1.5min内2%至98%B,0.3min 98%B
LCMS方法5
柱 AcQuity UPLC BEH C18 2.1x30mm,1.7μm
柱温 50℃
洗脱液 A:在水中的0.1%甲酸,B:在MeCN中的0.1%甲酸
流速 1.0mL/min
梯度 在1.4min内40%至98%B,0.65min 98%B
LCMS方法6
柱 AcQuity UPLC BEH C18 2.1x30mm,1.7μm
柱温 50℃
洗脱液 A:在水中的5mM NH4OH,B:在MeCN中的5mM NH4OH
流速 1.0mL/min
梯度 在1.2min内1%至30%B,在0.95min内30%至98%B
LCMS方法7
柱 Sunfire C18 3.0x30mm,3.5μm
柱温 40℃
洗脱液 A:含有0.05%TFA的H2O,B:MeCN
流速 2.0mL/min
梯度 在1.7min内40%至85%B,0.3min 95%B
LCMS方法8
柱 XBridge C18 3.0x30mm,3.5μm
柱温 40℃
洗脱液 A:H2O+5mM氢氧化铵,B:MeCN
流速 2.0mL/min
梯度 在1.2min内1%至30%B,在0.65min内30%至95%B,0.15min 95%B
LCMS方法9
柱 Acquity HSS T3 1.8μm 2.1x50mm
柱温 60℃
洗脱液 A:H2O+0.05%甲酸铵+3.75mM乙酸铵,B:MeCN+.04%甲酸
流速 1.0mL/min
梯度 在1.4min内5%至98%B
实例的表征中采用的NMR
用布鲁克傅里叶(Bruker Fourier)变换光谱仪在如下频率下操作获得1H NMR光谱:1H NMR:400MHz(布鲁克)。光谱数据按以下格式报告:化学位移(多重性,氢的数目)。化学位移在四甲基硅烷内标(δ单位,四甲基硅烷=0ppm)的低场中以ppm指定和/或参考溶剂峰,在1H NMR光谱中,在2.50ppm处出现CD3SOCD3,在3.31ppm处出现CD3OD,在1.94ppm处出现CD3CN,在4.79ppm处出现D2O,在5.32ppm处出现CD2Cl2,并且在7.26ppm ppm处出现CDCl3。
实例纯化中使用的方法
中间体和终产物的纯化通过正相色谱法、反相色谱法或超临界液相色谱法(SFC)来进行。正相色谱法使用预填充的SiO2小柱(例如来自特利丹蒂斯科公司(Teledyne Isco,Inc.)的Rf柱),用适当的溶剂体系的梯度洗脱(例如庚烷和乙酸乙酯;DCM和MeOH;或除非另外指示)来进行。使用下面描述的方法或除非实验部分中另有说明,进行反相制备型HPLC:
(1)基本方法:XBridge 5μm柱,在乙腈和水中的5mM NH4OH。
(2)TFA方法:Sunfire 5μm柱,在乙腈和水中的0.1%TFA。
(3)甲酸方法:XBridge 5μm柱;在乙腈和水中的0.1%甲酸。
所有以上三种HPLC方法从起始%乙腈至最终%乙腈的梯度来运行集中梯度。每个梯度的初始条件和最终条件如下:方法0:2%-12%乙腈;方法1:7.5%-20%乙腈;方法2:10%-30%乙腈;方法3:15%-40%乙腈;方法4:25%-50%乙腈;方法5:35%-60%乙腈;方法6:45%-70%乙腈;方法7:55%-80%乙腈;方法8:65%-95%乙腈;方法9:5%-95%乙腈;和方法10:10%-90%乙腈。
超临界液相色谱法(SFC)使用不同的柱和梯度/流动相(在实验部分中用“柱名称和流动相”指定)都用相同的流速(80g/分钟)、质量触发收集、柱箱温度40℃、背压120巴参数来进行。
使用以下条件,将手性制备型SFC用于分离醇对映异构体。
柱 AD-H 21x250mm
柱温 40℃
洗脱液 含10mM NH4OH的乙醇
流速 80mL/min
背压 125巴
中间体的合成
中间体1:(5-甲基呋喃-2-基)甲胺
将5-甲基-2-糠醛(1.5g,14mmol)、羟胺.HCl盐(1.89g,27.2mmol)、和乙酸钠(2.24g,27.2mmol)在MeOH(20mL)中的溶液在室温下搅拌18h。起始材料被消耗,并且以1:1的比率观察到两个新峰(LCMS:未观察到产物的m/z)。将混合物倒入饱和NaHCO3水溶液中并且用EtOAc(3x100mL)萃取。将合并的有机萃取物合并,用Na2SO4干燥,过滤,并且在真空中除去挥发物。将粗残余物通过硅胶色谱法(EtOAc/庚烷)纯化以给出呈白色固体的约1:1Z/E异构体的肟中间体(1.49g)。1H NMR(400MHz,DMSO-d6)δ1H NMR(400MHz,DMSO-d6)(两组信号)δ11.66(s,1H),11.07(s,1H),7.92(s,1H),7.44(s,1H),7.08(d,J=3.3Hz,1H),6.57(d,J=3.2Hz,1H),6.26(dt,J=3.2,0.9Hz,1H),6.18(dt,J=3.2,1.1Hz,1H),2.30(d,J=0.9Hz,3H),2.29(d,J=1.0Hz,3H)。将其吸收在THF(10mL)中,并且逐滴添加到在冰浴中的LiAlH4(在THF中2M,23.8mL,47.6mmol)在THF(20mL)中的溶液中。允许将混合物经18h温热至室温。起始材料被消耗,并且以1:1的比率观察到新峰(LCMS:未观察到产物的m/z)。将混合物用200mL DCM稀释,通过缓慢添加2g硫酸钠十水合物来淬灭,并且搅拌10min。添加过量的无水Na2SO4以除去痕量水。将混合物经硅藻土过滤并且在真空中除去挥发物。将粗产物不经纯化直接用于下一步骤,并且在下一步骤中确认此分子的身份为其衍生物(实例1)。
中间体2:6'-氟-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮
向1-(5-氟-2-((4-甲氧基苄基)氨基)苯基)乙-1-酮(从中间体3步骤1获得)(320mg,1.17mmol)在MeOH(10mL)中的搅拌溶液中添加4-氧代哌啶-1-甲酸叔丁酯(467mg,2.34mmol)和吡咯烷(0.194mL,2.34mmol)。将反应加热至回流持续15h。将混合物分配在EtOAc与水之间后,将合并的有机相经Na2SO4干燥并且浓缩。硅胶色谱法(庚烷/EtOAc,100/0至70/30)得到螺环产物(6'-氟-1'-(4-甲氧基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酸叔丁酯)(350mg),然后将其溶解在HCl(在二噁烷中4M,1.171mL,4.68mmol)中并且在室温下搅拌15h。沉淀出黄色固体,并且过滤以得到呈白色粉末的标题化合物(265mg,74%产率)。1H NMR(400MHz,DMSO-d6)δ7.24(ddd,J=18.5,9.2,3.1Hz,2H),7.07(dd,J=9.0,4.5Hz,1H),3.56(s,2H),3.31(d,J=11.1Hz,2H),3.09(d,J=9.5Hz,2H),1.83(ddt,J=20.3,14.1,7.5Hz,4H)。
也可以使用与中间体3步骤3类似的方法通过TFA代替HCl来完成PMB和Boc基团的除去。
中间体3:6'-氟-1'-甲基-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮
步骤1:1-(5-氟-2-((4-甲氧基苄基)氨基)苯基)乙-1-酮的制备
将1-(2-氨基-5-氟苯基)乙酮(1.5g,9.79mmol)添加到碳酸钾(2.71g,19.59mmol)在DMF(6mL)中溶液中。将反应在环境温度下搅拌30min。然后将1-(溴甲基)-4-甲氧基苯(2.166g,10.77mmol)逐滴添加到此溶液中并且将反应在80℃下加热18h。将反应用水淬灭,并且将水层用Et2O(3x100mL)萃取。将合并的有机层经Na2SO4干燥并且通过硅胶色谱法(烷/EtOAc=100/0至50/50)纯化以产生呈黄色油状物的标题化合物(501mg,18.72%产率)。1HNMR(400MHz,氯仿-d)δ9.07(t,J=5.6Hz,1H),7.45(dd,J=9.8,3.0Hz,1H),7.27(d,J=8.6Hz,2H),7.09(ddd,J=9.3,7.7,3.0Hz,1H),6.89(d,J=8.6Hz,2H),6.62(dd,J=9.3,4.5Hz,1H),4.39(d,J=5.4Hz,2H),3.82(s,3H),2.59(s,3H)。
步骤2:1-(5-氟-2-((4-甲氧基苄基)(甲基)氨基)苯基)乙-1-酮的制备
向步骤1的产物(125g,457mmol)和K2CO3(190g,137mmol)在DMF(1L)中的搅拌溶液中添加MeI(286mL,457mmol)。在配备有设定在5℃的冷冷凝器的4L热夹套反应器中,将反应在75℃下搅拌24h。将反应器冷却至室温并且添加另外的K2CO3(190g,137mmol)和MeI(200g,141mmol)。将反应加热至75℃持续24h。将混合物倒入水(7L)中并且用MTBE(3x2L)萃取。将有机萃取物合并,用5%LiCl水溶液洗涤,用Na2SO4干燥,过滤,并且在真空中除去挥发物。使粗残余物通过硅胶塞,用EtOAc洗脱。收集滤液,并且在真空中除去挥发物以给出约85%纯度的标题化合物(129g,83%产率)。LCMS:m/z 288.2(M+H)。
步骤3:1-(5-氟-2-(甲基氨基)苯基)乙-1-酮的制备
向在2L圆底烧瓶中的步骤2的产物(129g,382mmol)和三乙基硅烷(61.0ml,382mmol)的混合物中缓慢添加TFA(118mL,1526mmol)。为反应器皿配备有设定在5℃的冷冷凝器,并且将反应在70℃下搅拌18h。在真空中除去挥发物。将剩余的TFA使用10%Na2CO3水溶液淬灭至pH 10。将反应进一步用水(2L)稀释,并且转移至6L分液漏斗中。将混合物用EtOAc(3x1L)萃取。将有机物合并,用5%LiCl水溶液(1L)洗涤,用Na2SO4干燥,过滤,并且在真空中除去挥发物。将粗油状物负载到手动填充的硅胶干负载柱上并且通过硅胶色谱法使用750g柱(DCM/庚烷,20%至70%)纯化以给出约90%纯度的呈浅橙色油状物的标题化合物(57.3g,81%产率)。LCMS:m/z 168.1(M+H)。
步骤4:6'-氟-1'-甲基-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮的合成。
向步骤3的产物(57.3g,343mmol)和4-氧代哌啶-1-甲酸叔丁酯(137g,685mmol)在DMSO(300mL)中的溶液中添加吡咯烷(85mL,10mmol)。用设定在5℃的冷冷凝器,将反应在140℃下加热24h。将混合物倒入2L水中并且用EtOAc(3x750mL)萃取。将有机物合并,用盐水洗涤,用Na2SO4干燥,过滤,并且在真空中除去挥发物。然后将粗残余物通过硅胶色谱法(EtOAc/庚烷,4:6)纯化以给出6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酸叔丁酯。LCMS:m/z293.1(M-tBu)。将其溶解在DCM(300mL)中并且添加TFA(132mL,1714mmol)。将反应在室温下搅拌18h。在真空中除去挥发物。然后将残余物稀释在DCM中,并且将剩余的TFA通过缓慢添加10%K2CO3水溶液至pH约10来淬灭。将产物用DCM(2x750mL)萃取。将有机物合并,用Na2SO4干燥,过滤,并且在真空中除去挥发物。将粗残余物使用硅胶塞用MeOH/DCM(2:8)洗脱进行纯化以给出约95%纯度的呈棕色固体的标题化合物(45g,50.2%产率)。LCMS:m/z 249.2(M+H);1H NMR(400MHz,DMSO-d6)δ7.39-7.27(m,2H),6.98-6.89(m,1H),2.88(s,3H),2.87-2.76(m,4H),2.67-2.55(m,2H),1.76(td,J=12.5,4.7Hz,2H),1.56-1.44(m,2H)。
中间体4:4-(氨基甲基)-2-氟苯胺
步骤1:N-Boc 4-(氨基甲基)-2-氟苯胺的制备
向在冰浴中的4-氨基-3-氟苄腈(1.00g,7.35mmol)和氯化镍(II)(0.952g,7.35mmol)在MeOH(10mL)和THF(10mL)中的溶液中添加Boc-酸酐(3.21g,14.7mmol)在MeOH(2mL)中的溶液。分批添加硼氢化钠(0.834g,22.0mmol)并且将反应在0℃下搅拌72h。将反应混合物经硅藻土垫过滤,用DCM洗脱。将滤液转移至分液漏斗并且用饱和NaHCO3水溶液稀释。将混合物用DCM(3x75mL)萃取。将有机物合并,用Na2SO4干燥,过滤,并且在真空中除去挥发物。然后将粗残余物通过硅胶色谱法(EtOAc/庚烷)纯化以给出标题化合物。LCMS:m/z185.1(M+H-tBu);1H NMR(400MHz,DMSO-d6)δ7.21(t,J=6.2Hz,1H),6.83(dd,J=12.5,1.8Hz,1H),6.78-6.62(m,2H),4.97(s,2H),3.95(d,J=6.1Hz,2H),1.37(s,9H)。
步骤2:4-(氨基甲基)-2-氟苯胺的制备
将步骤1的产物溶解在DCM(10mL)中,并且添加三氟乙酸(5.63mL,73.5mmol)。将混合物在室温下搅拌2h。在真空中除去挥发物。将残余物溶解在4mL DCM中并且与10mL甲苯共沸以除去过量的TFA。将所得油状物溶解在二噁烷中并且在搅拌下逐滴添加4mL在二噁烷中的4M HCl。从溶液中沉淀出产物以形成灰白色固体。然后将固体过滤并且用二噁烷(3x20mL)洗涤。将固体溶解在MeOH中,在真空中除去挥发物,并且将样品置于高真空下2h。将粗产物不经纯化而用于下一步骤。1H NMR(400MHz,DMSO-d6)δ8.23(s,3H),7.22(dd,J=12.3,2.0Hz,1H),7.03(dd,J=8.2,1.9Hz,1H),6.87(dd,J=9.2,8.1Hz,1H),5.23(s,2H),3.86(q,J=5.8Hz,2H)。
中间体5:1'-乙基-6'-氟-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮。
步骤1:1-(2-(乙基氨基)-5-氟苯基)乙酮的制备
向1-(2-氨基-5-氟苯基)乙酮(1500mg,9.8mmol)和吡啶(2.75mL,34.0mmol)在二噁烷(200mL)中的溶液中添加Cu(OAc)2(4269mg,23.5mmol)。将混合物搅拌15min,然后添加乙基硼酸(1809mg,24.5mmol),并且将反应回流8h。允许将反应混合物冷却至室温,通过硅藻土过滤,并且在真空中除去挥发物。将粗油状物负载到手动填充的硅胶干负载柱上并且通过硅胶色谱法(EtOAc/庚烷0%至50%)纯化以得到>95%纯度的呈黄色油状物的标题化合物(301mg,17%产率)。LCMS:m/z 182.1(M+H);1H NMR(400MHz,氯仿-d)δ8.59(s,1H),7.43(dd,J=9.9,3.0Hz,1H),7.16(ddd,J=9.3,7.8,3.0Hz,1H),6.67(dd,J=9.3,4.5Hz,1H),3.24(dt,J=10.6,5.2Hz,2H),2.57(s,3H),1.33(t,J=7.2Hz,3H)。
步骤2:1'-乙基-6'-氟-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮的制备
通过与中间体3步骤4的制备类似的方法来制备标题化合物。LCMS:m/z 263.2(M+H);1H NMR(400MHz,甲醇-d4)δ7.39(ddt,J=8.4,5.4,2.7Hz,1H),7.29-7.16(m,1H),6.91(td,J=10.0,4.0Hz,1H),3.54-3.47(m,2H),3.20-3.10(m,2H),2.99-2.90(m,2H),2.42(t,J=6.3Hz,2H),2.02(td,J=13.5,4.4Hz,1H),1.90-1.75(m,1H),1.27(q,J=7.0Hz,3H)。
中间体6:5-(氨基甲基)-2-氟苯甲酰胺
步骤1:3-氨基甲酰基-4-氟苄基氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用5-氰基-2-氟苯甲酰胺代替4-氨基-3-氟苄腈来制备标题化合物。将粗残余物通过硅胶色谱法(EtOAc/庚烷)纯化以给出标题化合物(1.1g,95%产率)。LCMS:m/z 213.1(M+H-tBu)。
步骤2:5-(氨基甲基)-2-氟苯甲酰胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。使粗残余物通过SiliaPrepSPE小柱碳酸酯柱(产品编号:SPE-R66030B)(5x5g)以除去TFA以给出标题化合物(655mg,68%产率)。LCMS:m/z 169.1(M+H)。
中间体7:(4-氟苯基)甲-d2-胺
在室温下向NaBD4(311mg,7.43mmol)在干THF(10mL)中的悬浮液中经10min添加TFA(0.573mL,7.43mmol)在干THF(3mL)中的溶液。然后,添加4-氟苄腈(750mg,6.19mmol)在干THF(10mL)中的溶液并且将反应混合物搅拌过夜。通过添加D2O(3mL)将反应淬灭,然后添加水(20mL),并且在减压下除去THF。将水性悬浮液用碳酸氢钠水溶液中和并且用DCM萃取。将有机层合并,用水洗涤,并且然后用3N HCl溶液洗涤以进行反萃取。将有机层弃去,并且将酸水层用NaOH 1N溶液中和并且用DCM萃取。将此最终有机层干燥并且在减压下浓缩以给出呈淡黄色油状物的标题化合物(290mg,35%产率)。1H NMR(400MHz,氯仿-d)δ7.30(ddd,J=8.6,5.8,3.2Hz,2H),7.08-6.99(m,2H)。
中间体8:6'-氟-1'-(2-甲氧基乙基)-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮
步骤1:1-(5-氟-2-((2-甲氧基乙基)氨基)苯基)乙酮的制备
向微波小瓶中添加1-(2-氨基-5-氟苯基)乙-1-酮(200mg,1.3mmol)、DMF(3mL)、1-溴-2-甲氧基乙烷(0.617mL,6.53mmol)、KI(1084mg,6.53mmol)和DIPEA(1.140mL,6.53mmol)。将混合物在微波中在120℃下加热3.5h。然后将反应混合物用EtOAc稀释,用饱和碳酸氢钠水溶液洗涤,经Na2SO4干燥并且在减压下浓缩。将残余物通过硅胶色谱法(庚烷/EtOAc=100/0至50/50)纯化以产生呈黄色固体的标题化合物(110mg,40%产率)。LCMS:m/z212.0(M+H);1H NMR(400MHz,氯仿-d)δ8.72(s,1H),7.33(dd,J=9.8,3.0Hz,1H),7.04(ddd,J=9.3,7.8,3.0Hz,1H),6.59(dd,J=9.3,4.5Hz,1H),3.55(t,J=5.6Hz,2H),3.34(s,3H),3.30(d,J=4.9Hz,2H),2.47(s,3H)。
步骤2:6'-氟-1'-(2-甲氧基乙基)-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮的制备
向步骤12)的产物(110mg,0.521mmol)在EtOH(5mL)中的溶液中添加4-氧代哌啶-1-甲酸叔丁酯(135mg,0.677mmol)和吡咯烷(0.086mL,1.042mmol)。将反应在微波中在110℃下加热6h。然后将反应混合物用EtOAc稀释,用饱和碳酸氢钠水溶液洗涤,经Na2SO4干燥并且在减压下浓缩。将残余物通过硅胶色谱法(EtOAc/庚烷=0/100至30/70)纯化以产生Boc-保护的6'-氟-1'-(2-甲氧基乙基)-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮。然后将此Boc中间体溶解在DCM(1mL)中,并且添加TFA(0.120mL,1.562mmol)。将反应混合物在室温下搅拌2h并且在减压下浓缩。然后将反应混合物用EtOAc稀释,用饱和碳酸氢钠水溶液洗涤,经Na2SO4干燥并且在减压下浓缩以获得呈游离碱的标题化合物(55mg,28.2%产率)。LCMS:m/z293.1(M+H);1H NMR(400MHz,DMSO-d6)δ7.40-7.31(m,2H),6.99(dd,J=9.2,4.1Hz,1H),3.69-3.48(m,5H),3.32(s,3H),3.25-3.20(m,2H),3.11-2.95(m,4H),2.24(t,J=13.2Hz,2H),1.78(d,J=14.0Hz,2H)。
中间体9:(4-氟-3-(噁唑-5-基)苯基)甲胺
步骤1:4-氟-3-(噁唑-5-基)苄腈的制备
向(甲苯基磺酰基)甲基异氰化物(0.72g,3.688mmol)在MeOH(15mL)中的搅拌溶液中添加K2CO3(0.60g,4.359mmol)和2-氟-5-溴苯甲醛(0.5g,3.335mmol)。将反应混合物在室温下搅拌16h,然后在减压下浓缩。将残余物用DCM稀释,用饱和碳酸氢钠水溶液洗涤,经Na2SO4干燥并且在减压下浓缩。将残余物通过硅胶色谱法(己烷/EtOAc=100/0至40/60)纯化以产生呈白色固体的标题化合物(0.43g,68%产率)。LCMS:m/z 188.8(M+H)。
步骤2:(4-氟-3-(噁唑-5-基)苄基)氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用4-氟-3-(噁唑-5-基)苄腈代替4-氨基-3-氟苄腈来制备标题化合物。将产物通过硅胶色谱法(己烷/EtOAc=100/0至50/50)纯化以产生呈黄色液体的标题化合物(0.075g,48%产率)。LCMS:m/z 293.3(M+H)。
步骤3:(4-氟-3-(噁唑-5-基)苯基)甲胺的制备
通过与中间体4步骤2类似的方法使用(4-氟-3-(噁唑-5-基)苄基)氨基甲酸叔丁酯代替N-Boc 4-(氨基甲基)-2-氟苯胺来制备标题化合物。通过过滤获得呈TFA盐的产物(灰白色固体)(0.065g,83%产率)。LCMS:m/z 193.15(M+H)。
中间体10:5-(氨基甲基)-2,4-二氟-N-(2-甲氧基乙基)苯胺
步骤1:5-氨基-2,4-二氟苄腈的制备
向2,4-二氟-5-硝基苄腈(3g,16.30mmol)在MeOH(10mL)和THF(10mL)中的冰水冷却的溶液中添加NiCl2.6H2O(0.601g,4.07mmol),然后分批添加NaBH4(3.08g,81mmol)。30min后,将混合物用二亚乙基三胺(1.760mL,16.30mmol)淬灭并且搅拌16h。在真空中除去挥发物。将粗残余物溶解在EtOAc(30mL)中并且用水(2x20mL)洗涤。将有机萃取物合并,用水洗涤,然后用盐水(20mL)洗涤,用Na2SO4干燥,过滤,并且在真空中除去挥发物。将粗残余物通过制备型HPLC(碱,方法2)纯化以给出标题化合物(596mg,24%产率)。LCMS:m/z 153.1(M-H)。
步骤2:5-氨基-2,4-二氟苄基氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法来制备标题化合物。将粗残余物通过硅胶色谱法(EtOAc/庚烷)纯化以给出标题化合物(1.05g,25%产率)。LCMS:m/z 259.1(M-H)。
步骤3:(2,4-二氟-5-((2-甲氧基乙基)氨基)苄基)氨基甲酸叔丁酯的制备
向配备有搅拌棒的微波中添加步骤2的产物(330mg,2mmol)、DMF(2mL)、DIPEA(1.87mL,11mmol)、1-溴-2-甲氧基乙烷(1.01mL,11mmol)和碘化钾(3.37g,20.33mmol)。将微波小瓶加盖,并且在110℃下辐照10h。冷却后,将混合物倒入EtOAc(20mL)中并且用饱和氯化铵(2x20mL)洗涤,然后用饱和氯化铵(20mL)洗涤,用Na2SO4干燥,过滤,并且在真空中除去挥发物。将粗残余物通过硅胶色谱法(MeOH/DCM)纯化以给出标题化合物(520mg,40%产率)。LCMS:m/z 261.0(M+H-tBu)。
步骤4:5-(氨基甲基)-2,4-二氟-N-(2-甲氧基乙基)苯胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。将粗产物不经纯化进行至下一步骤(实例17)。LCMS:m/z 217.4(M+H)。
中间体11:2-(氨基甲基)-5-氟-N-(2-甲氧基乙基)苯胺
步骤1:2-氨基-4-氟苄基氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用2-氨基-4-氟苄腈代替4-氨基-3-氟苄腈来制备标题化合物。将粗残余物通过反相HPLC(碱,方法4)纯化以给出标题化合物(240mg,49.9%产率)。LCMS:m/z 184.9(M+H-tBu)。
步骤2:4-氟-2-((2-甲氧基乙基)氨基)苄基氨基甲酸叔丁酯的制备
通过与中间体10步骤3类似的方法来制备标题化合物。将粗残余物通过硅胶色谱法(庚烷/EtOAc)纯化以给出标题化合物(150mg,63.8%产率)。LCMS:m/z 299.2(M+H);1HNMR(400MHz,氯仿-d)δ7.03-6.91(m,1H),6.42-6.25(m,2H),4.20(d,J=6.2Hz,2H),3.62(t,J=5.6Hz,2H),3.40(s,3H),3.36-3.26(m,2H),1.45(s,10H)。
步骤3:2-氨基-4-氟苄基氨基甲酸叔丁酯的制备
通过与中间体4步骤2类似的方法来制备标题化合物。将粗产物不经纯化进行至下一步骤(实例20)。LCMS:m/z 197.2(M-H)。
中间体12:5-(氨基甲基)-2-氟-N-(2-甲氧基乙基)苯胺
步骤1:(3-氨基-4-氟苄基)氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用3-氨基-4-氟苄腈代替4-氨基-3-氟苄腈来制备标题化合物。将粗残余物通过硅胶色谱法(己烷/EtOAc=100/0至35/65)纯化以给出标题化合物(1810mg,51%产率)。LCMS:m/z 240.0(M+H);1H NMR(400MHz,氯仿-d)δ6.91(dd,J=10.9,8.3Hz,1H),6.71(d,J=8.5Hz,1H),6.64-6.49(m,1H),4.78(br s,1H),4.18(d,J=5.8Hz,2H),3.79-3.68(m,1H),3.65(s,J=2.8Hz,1H),1.45(s,9H)。
步骤2:4-氟-3-((2-甲氧基乙基)氨基)苄基氨基甲酸叔丁酯的制备
通过与中间体10步骤3类似的方法来制备标题化合物。将粗残余物通过硅胶色谱法(庚烷/EtOAc)纯化以给出标题化合物(505mg,61%产率)。1H NMR(400MHz,氯仿-d)δ6.91(dd,J=11.4,8.2Hz,1H),6.65(d,J=8.1Hz,1H),6.55(s,1H),4.22(d,J=5.7Hz,2H),3.68-3.58(m,2H),3.40(s,3H),3.31(t,J=5.2Hz,2H),1.46(s,9H)。
步骤3:5-(氨基甲基)-2-氟-N-(2-甲氧基乙基)苯胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。将粗产物不经纯化进行至下一步骤(实例21)。1H NMR(400MHz,氯仿-d)δ6.91(dd,J=11.4,8.2Hz,1H),6.69(ddd,J=18.1,8.4,1.9Hz,1H),6.60-6.51(m,1H),3.79(s,2H),3.72(s,0H),3.65-3.60(m,2H),3.40(d,J=2.0Hz,3H),3.33(dd,J=6.7,4.1Hz,2H)。
中间体13:3-(氨基甲基)-2,6-二氟苯胺
步骤1:3-氨基-2,4-二氟苄基氨基甲酸叔丁酯的制备
在0℃下向2,4-二氟-3-硝基苄腈(2g,10.86mmol)在干MeOH(120mL)中的搅拌溶液中经30min以小份添加Boc2O(3.78mL,16.30mmol)、NiCl2.6H2O(0.321g,2.173mmol)以及然后NaBH4(2.88g,76mmol)。允许将所得反应混合物温热至室温并且然后搅拌另外15h,此时添加二亚乙基三胺(1.174mL,10.86mmol)。允许将混合物搅拌2h,然后在硅藻土上过滤并且进行蒸发溶剂。将残余物溶解在EtOAc中,用饱和碳酸氢钠水溶液洗涤,经Na2SO4干燥并且在减压下浓缩以产生标题化合物(1.4g,50%产率)。LCMS:m/z 259.0(M+H)。
步骤2:3-(氨基甲基)-2,6-二氟苯胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物,获得呈灰白色固体的产物(TFA盐)(0.580g,100%产率)。此化合物的结构身份被确认为其衍生物(实例26)。
中间体14:1,4-二噁烷-2-甲醛
将(1,4-二噁烷-2-基)甲醇(70mg,0.59mmol)和戴斯-马丁氧化剂(Dess-Martinperiodinane)(261mg,0.615mmol)在DCM(2mL)中的混合物在室温下搅拌20h,通过二氧化硅垫(用DCM洗脱,然后用在DCM中的10%EtOAc洗脱)。不加热的情况下将滤液在真空(70mmHg)中浓缩。将粗产物直接用于下一步骤。在下一步骤中(实例31),产物的结构身份被确认为其衍生物。
中间体15:5-(氨基甲基)-N-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-2-氟苯胺
步骤1:(3-氨基-4-氟苄基)氨基甲酸苄酯的合成
在0℃下将氯甲酸苄酯(2.2ml,15mmol)缓慢添加到5-(氨基甲基)-2-氟苯胺(2.01g,14.34mmol)和三乙胺(4.00ml,28.7mmol)在THF(20mL)中的溶液中。将混合物在室温下搅拌30min并且分配在EtOAc与盐水之间。将合并的有机萃取物经MgSO4干燥并且浓缩。将粗产物通过硅胶柱色谱法(EtOAc/庚烷)纯化以给出呈白色固体的标题化合物(2.40g)。LCMS:m/z 275.3(M+H)。
步骤2:(3-((2-((叔丁基二甲基甲硅烷基)氧基)乙基)氨基)-4-氟苄基)氨基甲酸苄酯的合成
将步骤1的产物(2.00g,7.29mmol)、2-(叔丁基二甲基甲硅烷氧基)乙醛(1.35g,7.74mmol)和三乙酰氧基硼氢化钠(1.52g,7.17mmol)在DCM(40mL)中的混合物在室温下搅拌62h。将混合物浓缩并且分配在EtOAc与NH4Cl水溶液之间。将合并的有机萃取物经MgSO4干燥,浓缩并且通过硅胶色谱法(EtOAc/庚烷)纯化以给出呈无色油状物的标题化合物(2.33g)。LCMS:m/z 433.4(M+H)。
步骤3:5-(氨基甲基)-N-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-2-氟苯胺的合成
将步骤2的产物(2.33g,5.39mmol)和10%Pd/C(0.12g)在EtOH(30mL)中的混合物在气球压力下并且在室温下氢化15min,并且通过硅藻土过滤,并且将滤液浓缩以给出粗产物。通过硅胶色谱法(DCM/MeOH)纯化给出呈浅黄色油状物的标题化合物(1.46g)。LCMS:m/z299.4(M+H)。
中间体16:(S)-5-(氨基甲基)-N-((2,2-二甲基-1,3-二氧戊环-4-基)甲基)-2-氟苯胺
通过与中间体15的制备类似的方法在步骤2中使用(R)-2,2-二甲基-1,3-二氧戊环-4-甲醛代替2-(叔丁基二甲基甲硅烷氧基)乙醛来制备标题化合物。LCMS:m/z 255.3(M+H)。
中间体17:4-(氨基甲基)-2,5-二氟苯胺
步骤1:(4-氨基-2,5-二氟苄基)氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用4-氨基-2,5-二氟苄腈代替4-氨基-3-氟苄腈来制备标题化合物。LCMS:m/z 203.1(M+H-tBu)。
步骤2:4-(氨基甲基)-2,5-二氟苯胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。没有观察到产物的m/z(LCMS)。在下一步骤中(实例49),结构的身份被确认为其衍生物。
中间体18:2-(氨基甲基)-N-乙基-5-氟苯胺
步骤1:2-(乙基氨基)-4-氟苄基氨基甲酸叔丁酯的制备
向微波小瓶中添加来自中间体11步骤1的产物(135mg,0.562mmol)、DMF(8mL)、溴乙烷(306mg,2.81mmol)、KI(466mg,2.81mmol)和DIPEA(0.491mL,2.81mmol)。将混合物在微波中在110℃下加热10h。然后将混合物用EtOAc稀释,用饱和碳酸氢钠水溶液洗涤,经Na2SO4干燥并且在减压下浓缩。将残余物通过硅胶色谱法(庚烷/EtOAc)纯化以产生呈黄色油状物的标题化合物(0.030g,20%产率)。LCMS:m/z 267.2(M-H)。
步骤2:2-(氨基甲基)-N-乙基-5-氟苯胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。分离出呈游离碱的标题化合物(0.062g,61%产率)。LCMS:m/z 167.1(M-H)。中间体19:(4-氟-3-(2-甲氧基乙氧基)苯基)甲胺
步骤1:4-氟-3-(2-甲氧基乙氧基)苄腈的合成
向微波小瓶中添加4-氟-3-羟基苄腈(1g,7.29mmol)、DMF、1-溴-2-甲氧基乙烷(3.42ml,36.5mmol)、KI(6.05g,36.5mmol)和DIPEA(6.37ml,36.5mmol)。将混合物在微波中在110℃下加热10h。将混合物用EtOAc稀释,用饱和碳酸氢钠水溶液洗涤,经Na2SO4干燥,并且在减压下浓缩到硅藻土床上。将残余物通过硅胶色谱法(EtOAc/庚烷)纯化以得到呈澄清油状物的标题化合物(1.2g,84%产率)。LCMS:m/z 198.9(M+H);1H NMR(400MHz,氯仿-d)δ7.31-7.26(m,3H),7.18(dd,J=10.7,8.7Hz,1H),4.26-4.20(m,2H),3.84-3.78(m,2H),3.48(s,3H)。
步骤2:4-氟-3-(2-甲氧基乙氧基)苄基氨基甲酸叔丁酯的合成
通过与中间体4步骤1类似的方法来制备标题化合物。将产物通过硅胶色谱法(EtOAc/庚烷)纯化以给出呈澄清油状物的标题化合物(1.356g,73.7%产率)。LCMS:m/z243.3(M+H(-叔丁基));1H NMR(400MHz,氯仿-d)δ7.03(dd,J=11.1,8.3Hz,1H),6.95(dd,J=8.1,2.1Hz,1H),6.83(ddd,J=8.3,4.3,2.2Hz,1H),4.26(d,J=5.5Hz,2H),4.23-4.18(m,2H),3.81-3.75(m,2H),3.48(s,3H),1.48(s,9H)。
步骤3:(4-氟-3-(2-甲氧基乙氧基)苯基)甲胺的合成
通过与中间体4步骤2类似的方法来制备标题化合物。将混合物浓缩并且使残余物通过SCX柱以用在MeOH中的7N NH3除去TFA。除去溶剂后,获得呈棕色油状物的标题化合物(166mg,99%产率)。LCMS:m/z 200.2(M+H)。
中间体20:4-(氨基甲基)-2,3-二氟苯胺
步骤1:(4-氨基-2,3-二氟苄基)氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用4-氨基-2,5-二氟苄腈代替4-氨基-3-氟苄腈来制备标题化合物。LCMS:m/z 203.1(M+H-tBu)。
步骤2:4-(氨基甲基)-2,3-二氟苯胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。没有观察到产物的m/z(LCMS)。在下一步骤中(实例57),结构的身份被确认为其衍生物。
中间体21:5-(氨基甲基)-2-氟苯甲酸甲酯
步骤1:5-(((叔丁氧基羰基)氨基)甲基)-2-氟苯甲酸甲酯的制备
通过与中间体4步骤1类似的方法来制备标题化合物。将产物通过硅胶色谱法(EtOAc/庚烷)纯化以给出呈澄清粘性油状物的标题化合物(1.26g,4.45mmol,39.8%产率)。LCMS:m/z 228.1(M+H-tBu)。
步骤2:5-(氨基甲基)-2-氟苯甲酸甲酯的制备
通过与中间体4步骤2类似的方法来制备标题化合物。LCMS:m/z184.2(M+H)。
中间体22:2-(5-(氨基甲基)-2-氟苯基)乙酰胺
步骤1:2-(2-氟-5-甲基苯基)乙酸甲酯的制备
在0℃下向2-(2-氟-5-甲基苯基)乙酸(0.5g,2.97mmol)在MeOH(10mL)中的搅拌溶液中添加亚硫酰氯(0.3mL,5.94mmol)。将混合物在室温下搅拌2h。通过TLC监测反应的完成。将混合物在真空中浓缩。将粗残余物用水稀释并且用EtOAc萃取。将有机萃取物合并,用饱和NaCl洗涤,经Na2SO4干燥,过滤,并且在真空中浓缩以给出呈黄色液体的标题化合物(0.5g,92%产率)。将粗产物不经纯化进行至下一步骤。
步骤2:2-(5-(溴甲基)-2-氟苯基)乙酸甲酯的制备
在0℃下向步骤1的产物(0.5g,2.74mmol)在CCl4(10mL)中的搅拌溶液中添加NBS(0.51g,2.88mmol)和AIBN(0.067g,0.41mmol)。将混合物在回流下搅拌3h。将混合物在真空中浓缩。将粗残余物用水稀释并且用DCM萃取。将有机萃取物合并,用水洗涤,并且用饱和NaCl洗涤,经Na2SO4干燥,过滤,并且在真空中浓缩。将粗残余物通过硅胶色谱法(EtOAc/庚烷=1/9)纯化以给出呈无色液体的标题化合物(261mg,70%产率)。
步骤3:2-(5-(叠氮基甲基)-2-氟苯基)乙酸甲酯的制备
向步骤2的产物(0.5g,1.915mmol)在DMF(5mL)中的搅拌溶液中添加叠氮化钠(0.136g,2.106mmol)。将混合物在室温下搅拌2h。将混合物在真空中浓缩。将混合物用水稀释并且用醚萃取。将有机萃取物合并,用水洗涤,并且用饱和NaCl洗涤,经Na2SO4干燥,过滤,并且在真空中浓缩。将粗产物不经纯化进行至下一步骤。(0.3g,71%产率)。LCMS:m/z196.1(M+H-N2)。
步骤4:2-(5-(叠氮基甲基)-2-氟苯基)乙酸的制备
向步骤3的产物(0.5g,2.24mmol)在THF(2mL)、MeOH(2mL)和水(2mL)中的搅拌溶液中添加LiOH.H2O(0.18g,4.48mmol)。将混合物在室温下搅拌2h。将混合物在真空中浓缩。将粗混合物用3N HCl水溶液酸化。从溶液中沉淀出产物以形成灰白色固体。然后将固体在真空下过滤。将粗产物不经纯化进行至下一步骤。(0.41g,89%产率)。
步骤5:2-(5-(叠氮基甲基)-2-氟苯基)乙酰胺的制备
向步骤4的产物(0.41g,1.96mmol)在DMF(10mL)中的搅拌溶液中添加吡啶(0.31g,3.92mmol),然后添加二碳酸二叔丁酯(1.32g,6.07mmol)和NH4HCO3(0.48g,6.07mmol)。将混合物在室温下搅拌16h。将混合物用饱和NH4Cl稀释并且用EtOAc萃取。将有机萃取物合并,用水洗涤,并且用饱和NaCl洗涤,经Na2SO4干燥,过滤,并且在真空中浓缩。将粗残余物通过硅胶色谱法(EtOAc/DCM=45/55)纯化以给出呈白色固体的标题化合物(350mg,87%产率)。LCMS:m/z 209.9(M+H)
步骤6:2-(5-(氨基甲基)-2-氟苯基)乙酰胺
在N2气体下向步骤5的产物(0.2g,0.96mmol)在乙醇(10mL)中的搅拌溶液中添加湿Pd/C 10%(0.05g)和1N水溶液HCl(2滴)。将混合物在室温下氢化2h。将反应混合物经硅藻土垫过滤并且用乙醇洗脱。将滤液在真空中浓缩以给出呈灰白色固体的标题化合物(160mg,76%产率)。将粗产物不经纯化进行至下一步骤(实例62)。
中间体23:5-(氨基甲基)-2-氟-N-甲基苯甲酰胺
步骤1:5-氰基-2-氟-N-甲基苯甲酰胺的制备
向5-氰基-2-氟苯甲酸(1000mg,6.06mmol)在DCM(5mL)中的溶液中添加草酰氯(1.060mL,12.11mmol),然后添加1滴DMF。将混合物在室温下搅拌1.5h。将混合物在真空中浓缩,并且将所得残余物溶解在DCM(3mL)中并且冷却至0℃。添加在THF(2mL)中的甲基胺(16.65mL,33.3mmol)并且允许将反应在0℃下搅拌0.5h。将反应混合物用水淬灭并且将粗残余物在真空中浓缩。将粗残余物用水稀释,并且将所得固体过滤,用水冲洗,并且在真空下干燥。将粗产物不经纯化进行至下一步骤。LCMS:m/z 179.1(M+H);1H NMR(400MHz,甲醇-d4)δ8.08(dd,1H),7.91(ddd,J=8.7,4.6,2.2Hz,1H),7.41(dd,J=10.2,8.7Hz,1H),2.93(s,3H)。
步骤2和步骤3:4-氟-3-(甲基氨基甲酰基)苄基氨基甲酸叔丁酯的制备
通过与中间体4类似的方法来制备标题化合物。LCMS:m/z 183.2(M+H);1H NMR(400MHz,甲醇-d4)δ8.09(dd,J=6.5,2.2Hz,1H),7.91(ddd,J=8.6,4.6,2.2Hz,1H),7.42(dd,J=10.2,8.7Hz,1H),2.93(s,3H)。
中间体24:4-(氨基甲基)-2,6-二氟苯胺
步骤1:(4-氨基-2,6-二氟苄基)氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用4-氨基-2,6-二氟苄腈代替4-氨基-3-氟苄腈来制备标题化合物。LCMS:m/z 203.2(M+H-tBu)。
步骤2:4-(氨基甲基)-2,6-二氟苯胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。没有观察到产物的m/z(LCMS)。在下一步骤中(实例65),结构的身份被确认为其衍生物。
中间体25:(2,4-二氟-5-(2-甲氧基乙氧基)苯基)甲胺
步骤1:2-(2,4-二氟-5-甲基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷的制备
向双频哪醇合二硼(1.2g,4.83mmol)和1-溴-2,4-二氟-5-甲基苯(1.0g,4.83mmol)在二噁烷(10mL)中的脱气溶液中添加KOAc(1.0g,9.66mmol)和PdCl2(dppf)(0.39g,0.483mmol)。将反应混合物在密封管中在100℃下搅拌16h,然后通过硅藻土床过滤。将滤液浓缩,然后用DCM稀释并且用水洗涤。将有机相经Na2SO4干燥并且在减压下浓缩。将残余物通过硅胶色谱法(庚烷/EtOAc=100/0至90/10)纯化以产生标题化合物(0.7g,2.75mmol,57%产率)。
步骤2:2,4-二氟-5-甲基苯酚的制备
在0℃下向步骤1的产物(600mg,2.36mmol)在MeOH(5mL)中的溶液中添加脲-过氧化氢加合物(266mg,2.83mmol)。在室温下将反应混合物搅拌12h,然后浓缩并且用DCM稀释并且用水洗涤。将有机相经Na2SO4干燥并且在减压下浓缩以产生标题中间体(700mg),将其作为粗产物直接接入下一反应。
步骤3:1,5-二氟-2-(2-甲氧基乙氧基)-4-甲基苯的制备
通过与中间体19类似的方法使用步骤2的产物代替4-氟-3-羟基苄腈来制备标题化合物以产生标题化合物(380mg,38%产率)。
步骤4:1-(溴甲基)-2,4-二氟-5-(2-甲氧基乙氧基)苯的制备
在室温下向步骤3的产物在CCl4(5mL)中的溶液中添加NBS(245mg,1.39mmol)和AIBN(22mg,0.138mmol)。在室温下将反应混合物搅拌1h并且然后温热至50℃持续2h并且温热至80℃持续12h。然后将混合物浓缩,用DCM稀释并且用水洗涤。将有机相经Na2SO4干燥并且在减压下浓缩。将残余物通过硅胶色谱法(己烷/EtOAc=100/0至80/20)纯化以产生呈无色油状物的标题化合物(150mg,38%产率)。
步骤5:1-(叠氮基甲基)-2,4-二氟-5-(2-甲氧基乙氧基)苯的制备
向步骤4的产物(150mg,0.533mmol)在DMF(5mL)中的溶液中添加叠氮化钠(69mg)。将反应混合物在室温下搅拌16h,然后用EtOAc和水稀释。将有机层经Na2SO4干燥并且在减压下浓缩。将粗产物直接接入下一反应步骤。
步骤6:(2,4-二氟-5-(2-甲氧基乙氧基)苯基)甲胺的制备
向步骤5的产物(60mg,0.246mmol)在EtOH(20mL)中的脱气溶液中添加Pd/C(10mg),并且将反应混合物在H2气球下搅拌8h。然后将反应通过硅藻土垫过滤,并且将滤液在减压下浓缩以产生标题化合物(28mg,52%产率)。LCMS:m/z 218(M+H)。
中间体26:6',8'-二氟-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮
步骤1:1-(3,5-二氟-2-((4-甲氧基苄基)氨基)苯基)乙-1-酮的制备
向1-(2,3,5-三氟苯基)乙-1-酮(12.0g,69.0mmol)在DMSO(12mL)中的搅拌溶液中添加对甲氧基苄胺(11.6mL,88.9mmol)和TEA(12mL,82.7mmol)。在室温下将反应混合物搅拌10min,然后加热至150℃持续4h。然后将反应混合物用水淬灭,用EtOAc萃取并且用水和盐水溶液洗涤,并且经Na2SO4干燥并且浓缩。将粗油状物通过硅胶色谱法(EtOAc/己烷0%至10%)纯化并且在正戊烷中重结晶以得到呈黄色油状物的标题化合物(1.3g,6%产率)。
步骤2:6',8'-二氟-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮的制备
通过与中间体2的制备类似的方法来制备标题化合物并且以黄色固体分离(0.69g,59%产率)。LCMS:m/z 253(M+H);1H NMR(300MHz,DMSO-d6):δ7.46-7.38(1H,m),7.13-7.10(1H,d),6.37(1H,s),2.82-2.77(2H,m),2.72(2H,s),2.63-2.49(2H,m),1.64-1.60(4H,m)。
中间体27:3-(氨基甲基)苯磺酰胺
步骤1:3-氰基苯磺酰胺的制备
在0℃下向3-氰基苯磺酰氯(0.5g,2.47mmol)在THF(5mL)中的搅拌溶液中添加NH325%水溶液(4.95mmol),并且将反应混合物在室温下搅拌16h。然后将反应浓缩,并且用EtOAc和水稀释。将有机层经Na2SO4干燥并且在减压下浓缩以得到呈白色固体的标题化合物(0.4g,88%产率)。
步骤2:(3-氨磺酰基苄基)氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用3-氰基苯磺酰胺代替4-氨基-3-氟苄腈来制备标题化合物。将产物通过硅胶色谱法(己烷/EtOAc=70/30至55/45)纯化以产生呈白色固体的标题化合物(0.15g,65%产率)。LCMS:m/z 248.9(M-H)。
步骤3:3-(氨基甲基)苯磺酰胺的制备
通过与中间体4步骤2类似的方法使用(3-氨磺酰基苄基)氨基甲酸叔丁酯代替N-Boc 4-(氨基甲基)-2-氟苯胺来制备标题化合物。通过过滤获得呈灰白色固体的产物(0.11g,90%产率)。LCMS:m/z 187.3(M+H)。
中间体28:3-(氨基甲基)-2,6-二氟-N-(2-甲氧基乙基)苯胺
步骤1:2,4-二氟-3-((2-甲氧基乙基)氨基)苄基氨基甲酸叔丁酯的制备
通过与中间体18步骤1类似的方法使用3-氨基-2,4-二氟苄基氨基甲酸叔丁酯(中间体13,步骤1)代替(2-氨基-4-氟苄基)氨基甲酸叔丁酯并且使用1-溴-2-甲氧基乙烷代替溴乙烷来制备标题化合物。将产物通过硅胶色谱法(庚烷/EtOAc=100/0至50/50)纯化以产生标题化合物(0.345g,63%产率)。LCMS:m/z 317.1(M+H)。
步骤2:3-(氨基甲基)-2,6-二氟-N-(2-甲氧基乙基)苯胺的制备
通过与中间体4步骤2类似的方法使用2,4-二氟-3-((2-甲氧基乙基)氨基)苄基氨基甲酸叔丁酯代替N-Boc 4-(氨基甲基)-2-氟苯胺来制备标题化合物。分离出呈TFA盐的标题化合物(0.650g,100%产率)。LCMS:m/z 217.2(M+H)。
中间体29:3-(氨基甲基)-6-氟-2-甲基苯甲酰胺
步骤1:2-(2-氟-5-甲基苯基)乙酸甲酯的制备
向在0℃下的2-氟-6-甲基苯甲酸(2g,12.97mmol)在浓H2SO4(60mL)中的搅拌溶液中添加NBS(2.41g,13.62mmol)。在0℃下将混合物在室温下搅拌3h。使混合物达到室温并且搅拌16h。将混合物倒入冰水中并且用醚萃取。将有机萃取物合并,用水和盐水洗涤,经Na2SO4干燥,过滤,并且在真空中浓缩以给出呈灰白色固体的标题化合物(2.3g,76%产率)。将粗产物不经纯化进行至下一步骤。LCMS:m/z 231(M-2H)。
步骤2:3-溴-6-氟-2-甲基苯甲酸甲酯的制备
向步骤1的产物(1g,4.29mmol)在DMF(10mL)中的搅拌溶液中添加NaHCO3(1.08g,12.87mmol)。将混合物在室温下搅拌15min,然后添加MeI(1.21g,8.58mmol)。将混合物在室温下搅拌16h。将混合物倒入冰水中并且用EtOAc萃取。将有机萃取物合并,用水和盐水洗涤,经Na2SO4干燥,过滤,并且在真空中浓缩以得到呈黄色液体的标题化合物(0.85g,85%产率)。将粗产物不经纯化进行至下一步骤。
步骤3:3-氰基-6-氟-2-甲基苯甲酸甲酯的制备
向步骤2的产物(1g,4.04mmol)在DMA(10mL)中的搅拌溶液中,六氰基高铁(II)酸钾三水合物(0.43g,1.01mmol)、Pd(OAc)2(45mg,0.2mmol)、和Na2CO3。将混合物用氩气吹扫并且在140℃下搅拌16h。将混合物用EtOAc(20mL)稀释,并且在硅藻土垫上过滤。向滤液中添加水和EtOAc。将有机层分离并且用盐水洗涤,经Na2SO4干燥,过滤,并且在真空中浓缩。将粗残余物通过ICO硅胶色谱法(EtOAc/己烷=3:7)纯化,纯化以给出呈灰白色固体的标题化合物(0.35g,44%产率)。
步骤4:3-氰基-6-氟-2-甲基苯甲酸的制备
通过与中间体22步骤4类似的方法分别使用步骤3的产物(0.35g,1.911mmol)和氢氧化钠(0.144g,3.623mmol)代替对于中间体22步骤3获得的产物和氢氧化锂来制备标题化合物。将混合物在真空中浓缩浓缩并且萃取在EtOAc中。将有机层弃去,并且将水层用3NHCl溶液酸化并且萃取在DCM中。将有机层经Na2SO4干燥,过滤,在真空中浓缩以给出呈灰白色固体的标题化合物(0.3g,90%产率)。将粗产物不经纯化进行至下一步骤。LCMS:m/z177.9(M-H)。
步骤5:3-氰基-6-氟-2-甲基苯甲酰胺的制备
通过与中间体22步骤5类似的方法使用步骤4的产物来制备标题化合物。将粗残余物通过硅胶色谱法(EtOAc/DCM=45/55)纯化以给出呈灰白色固体的标题化合物(80mg,75%产率)。
步骤6:2-(3-氨基甲酰基-4-氟-2-甲基苯基)乙酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用3-氰基-6-氟-2-甲基苯甲酰胺代替4-氨基-3-氟苄腈来制备标题化合物。然后将粗残余物通过硅胶色谱法(MeOH/DCM=1/9)纯化以给出呈灰白色固体的标题化合物(75mg,0.265mmol,59%)。
步骤7:3-(氨基甲基)-6-氟-2-甲基苯甲酰胺的制备
通过与中间体4步骤2类似的方法使用2-(3-氨基甲酰基-4-氟-2-甲基苯基)乙酸叔丁酯代替N-Boc 4-(氨基甲基)-2-氟苯胺来制备标题化合物。将混合物在真空中浓缩。将获得的固体过滤并且在真空下干燥以给出呈灰白色固体的标题化合物(55mg,95%产率)。将粗产物不经纯化进行至下一步骤。LCMS:m/z 183(M+H)。
中间体30:4-(氨基甲基)-3,5-二氟苯胺
步骤1:(4-氨基-2,6-二氟苄基)氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用4-氨基-2,6-二氟苄腈代替4-氨基-3-氟苄腈来制备标题化合物。LCMS:m/z 203.2(M+H-tBu)。
步骤2:4-(氨基甲基)-3,5-二氟苯胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。没有观察到产物的m/z(LCMS)。在下一步骤中(实例80),结构的身份被确认为其衍生物。
中间体31:(E)-1'-(丁-2-烯-1-基)-6'-氟-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮
步骤1:(E)-1-(2-(丁-2-烯-1-基氨基)-5-氟苯基)乙酮的制备
将1-(2-氨基-5-氟苯基)乙酮(250mg,1.632mmol)添加到Cs2CO3(532mg,1.632mmol)在DMF(15mL)中的溶液中。将反应混合物在室温下搅拌30min。然后将(E)-1-溴丁-2-烯(0.237mL,2.285mmol)逐滴添加到此溶液中并且将反应在80℃下加热48h。将反应用水淬灭,并且将水层用Et2O(3x20mL)萃取。将合并的有机层经Na2SO4干燥并且通过硅胶色谱法(烷/EtOAc=100/0至70/30)纯化以产生呈黄色固体的标题化合物(280mg,79%产率)。1HNMR(400MHz,DMSO-d6)δ7.65(dt,J=10.3,3.3Hz,1H),7.35-7.25(m,1H),6.75(dd,J=9.4,4.7Hz,1H),5.72-5.62(m,1H),5.59-5.47(m,1H),3.85-3.75(m,2H),2.53(s,3H),1.71-1.64(m,3H)。
步骤2:(E)-1'-(丁-2-烯-1-基)-6'-氟-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮的制备
向步骤1的产物(280mg,1.284mmol)在MeOH(10mL)中的搅拌溶液中添加4-氧代哌啶-1-甲酸叔丁酯(558mg,2.80mmol)和吡咯烷(0.231mL,2.80mmol)。将反应经72h加热至回流。然后将反应混合物用EtOAc稀释,用饱和碳酸氢钠水溶液洗涤,经Na2SO4干燥并且在减压下浓缩。将残余物通过硅胶色谱法(庚烷/EtOAc=100/0至70/30)纯化以得到Boc-保护的(E)-1'-(丁-2-烯-1-基)-6'-氟-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮(370mg)。然后将此Boc中间体溶解于在二噁烷中的HCl4N(1.399mL,5.60mmol)并且在室温下搅拌15h。沉淀出所希望的化合物的HCl盐并且通过过滤分离为黄色粉末(240mg,42%产率)。此产物的结构身份被确认为其衍生物(实例85)。
中间体32:4-(氨基甲基)-2-氯苯胺
步骤1:(4-氨基-3-氯苄基)氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用4-氨基-3-氯苄腈代替4-氨基-3-氟苄腈来制备标题化合物。LCMS:m/z 201.1(M+H-tBu)。
步骤2:4-(氨基甲基)-2-氯苯胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。没有观察到产物的m/z(LCMS)。在下一步骤中(实例87),结构的身份被确认为其衍生物。
中间体33:2-(2-氧代吡咯烷-1-基)乙醛
将1-(2-羟基乙基)吡咯烷-2-酮(67mg,0.52mmol)和戴斯-马丁氧化剂(280mg,0.660mmol)在DCM(2mL)中的混合物在室温下搅拌3h,通过二氧化硅垫(用DCM、然后用在DCM中的10%EtOAc洗脱)。不加热的情况下将滤液通过旋转蒸发器(70mmHg)浓缩。将粗产物直接用于下一步骤(实例90)。
中间体34:4-(氨基甲基)-3-(三氟甲基)苯胺
步骤1:(4-氨基-2-三氟甲基苄基)氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用4-氨基-2-(三氟甲基)苄腈代替4-氨基-3-氟苄腈来制备标题化合物。LCMS:m/z 235.2(M+H-tBu)。
步骤2:4-(氨基甲基)-3-(三氟甲基)苯胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。没有观察到产物的m/z(LCMS)。在下一步骤中(实例104),结构的身份被确认为其衍生物。
中间体35:4-(氨基甲基)-3-氯苯胺
步骤1:(4-氨基-2-氯苄基)氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用4-氨基-2-氯苄腈代替4-氨基-3-氟苄腈来制备标题化合物。LCMS:m/z 201.2(M+H-tBu)。
步骤2:4-(氨基甲基)-3-氯苯胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。没有观察到产物的m/z(LCMS)。在下一步骤中(实例111),结构的身份被确认为其衍生物。
中间体36:4-(氨基甲基)-2-(三氟甲基)苯胺
步骤1:(4-氨基-3-三氟甲基苄基)氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用4-氨基-3-(三氟甲基)苄腈代替4-氨基-3-氟苄腈来制备标题化合物。LCMS:m/z 190.1(M-Boc)。
步骤2:4-(氨基甲基)-2-(三氟甲基)苯胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。LCMS:m/z190.1(M)。
中间体37:4-(氨基甲基)-3-甲基苯胺
步骤1:(4-氨基-3-三氟甲基苄基)氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用4-氨基-2-甲基苄腈代替4-氨基-3-氟苄腈来制备标题化合物。LCMS:未观察到m/z。
步骤2:4-(氨基甲基)-2-(三氟甲基)苯胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。没有观察到产物的m/z(LCMS)。在下一步骤中(实例116),结构的身份被确认为其衍生物。
中间体38:4-(氨基甲基)-2-甲基苯胺
步骤1:(4-氨基-3-三氟甲基苄基)氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用4-氨基-3-甲基苄腈代替4-氨基-3-氟苄腈来制备标题化合物。LCMS:m/z 181.2(M+H-tBu)。
步骤2:4-(氨基甲基)-2-(三氟甲基)苯胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。没有观察到产物的m/z(LCMS)。在下一步骤中(实例119),结构的身份被确认为其衍生物。
中间体39:N-(5-(氨基甲基)-2-氟苯基)甲烷磺酰胺
步骤1:N-(5-氰基-2-氟苯基)甲烷磺酰胺的制备
向3-氨基-4-氟苄腈(500mg,3.67mmol)在吡啶(8162μl)中的冰冷溶液中逐滴添加甲基磺酰氯(256μl,3.31mmol)。将反应在室温下搅拌过夜。将反应浓缩,并且将残余物分配在1N HCl水溶液与EtOAc之间。将有机层用盐水洗涤,经MgSO4干燥并且过滤。将滤液浓缩以给出呈淡粉色固体的标题化合物(708mg,90%产率)。HRMS:m/z 215.0292(M+H)。
步骤2:4-氟-3-(甲基磺酰胺基)苄基氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法来制备标题化合物。LCMS:m/z317.0(M-H)。
步骤3:N-(5-(氨基甲基)-2-氟苯基)甲烷磺酰胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。将混合物通过SCX柱使用在甲醇中的7N NH3过滤。将洗脱液浓缩以得到呈白色固体的标题化合物(50mg,72.9%产率)。LCMS:m/z 218.1(M+H)。
中间体40:2,2-二甲基-3-氧代丙酸甲酯
通过与中间体33类似的方法使用3-羟基-2,2-二甲基丙酸甲酯代替1-(2-羟基乙基)吡咯烷-2-酮来制备标题化合物。将粗产物直接用于下一步骤(实例140)。
中间体41:(4-氟-3-((2-甲氧基乙氧基)甲基)苯基)甲胺
步骤1:4-氟-3-((2-甲氧基乙氧基)甲基)苄基氨基甲酸叔丁酯的制备
通过与中间体4步骤1类似的方法使用4-氟-3-((2-甲氧基乙氧基)甲基)苄腈代替4-氨基-3-氟苄腈来制备标题化合物。LCMS:m/z 214.0(M+H-Boc)。
步骤2:(4-氟-3-((2-甲氧基乙氧基)甲基)苯基)甲胺的制备
通过与中间体4步骤2类似的方法来制备标题化合物。将混合物通过SCX柱使用在甲醇中的7N NH3过滤。将洗脱液浓缩以得到呈黄色油状物的标题化合物(95mg,78%产率)。LCMS:m/z 214.0(M+H)。
中间体42:3-(氨基甲基)-2,6-二氟苯甲酰胺
步骤1:2,6-二氟-3-甲基苯甲酸甲酯的制备
在0℃下向2,6-二氟-3-甲基苯甲酸(1.0g,5.81mmol)在MeOH(10mL)中的溶液中缓慢添加H2SO4(2mL)。允许将反应混合物在70℃下搅拌16h,然后在减压下浓缩。然后将残余物用冷水稀释,用饱和NaHCO3溶液碱化,并且用DCM萃取。将有机层用盐水溶液洗涤,并且经Na2SO4干燥并且然后在减压下浓缩以得到呈无色油状物的粗产物(600mg,55%产率),将其直接接入下一反应步骤。
步骤2:3-(溴甲基)-2,6-二氟苯甲酸甲酯的制备
通过与中间体25步骤4类似的方法使用2,6-二氟-3-甲基苯甲酸甲酯代替1,5-二氟-2-(2-甲氧基乙氧基)-4-甲基苯来获得标题化合物。将产物通过硅胶色谱法(己烷/EtOAc=100/0至90/10)纯化以产生呈白色固体的标题化合物(310mg,36%产率)。
步骤3:3-(叠氮基甲基)-2,6-二氟苯甲酸甲酯的制备
通过与中间体25步骤5类似的方法使用3-(溴甲基)-2,6-二氟苯甲酸甲酯代替1-(溴甲基)-2,4-二氟-5-(2-甲氧基乙氧基)苯来获得标题化合物。将粗产物(250mg,95%产率)直接接入下一反应步骤。
步骤4:3-(叠氮基甲基)-2,6-二氟苯甲酸的制备
向3-(叠氮基甲基)-2,6-二氟苯甲酸甲酯(250mg,1.10mmol)在THF(8mL)和MeOH(2mL)中的溶液中添加LiOH.H2O(230mg,5.50mmol)和水(1.5mL)。允许将反应混合物在室温下搅拌16h,然后在减压下浓缩。将残余物用2N HCl溶液酸化并且用EtOAc萃取。将分离的有机层用盐水溶液洗涤,经Na2SO4干燥并且然后在减压下浓缩以提供粗产物(200mg,0.93mmol),将其直接接入下一反应步骤。LCMS:m/z 211.8(M-H)。
步骤5:3-(叠氮基甲基)-2,6-二氟苯甲酰胺的制备
向3-(叠氮基甲基)-2,6-二氟苯甲酸(200mg,0.93mmol)在DMF(10mL)中的搅拌溶液中添加吡啶(0.159mL,1.87mmol),然后添加(Boc)2O(0.63g,2.90mmol)和NH4HCO3(230mg,2.90mmol)。将反应物质在室温下搅拌16h。然后将反应混合物用饱和NH4Cl溶液淬灭并且用EtOAc萃取。将分离的有机层用盐水溶液洗涤,经Na2SO4干燥并且然后在减压下浓缩。将残余物通过硅胶色谱法(己烷/EtOAc=100/0至50/50)纯化以给出标题产物(120mg,63%产率,呈白色固体)。LCMS:m/z 212.9(M+H)。
步骤6:3-(氨基甲基)-2,6-二氟苯甲酰胺的制备
通过与中间体25步骤6类似的方法使用3-(叠氮基甲基)-2,6-二氟苯甲酰胺代替11-(叠氮基甲基)-2,4-二氟-5-(2-甲氧基乙氧基)苯来获得标题化合物。分离出呈黄色固体的粗产物(120mg,69%产率)。LCMS:m/z 187.0(M+H)。
中间体43:2-(5-(氨基甲基)-2-氟苯基)丙-2-醇
步骤1:2-(5-(溴甲基)-2-氟苯基)丙-2-醇的制备
在0℃下向5-(溴甲基)-2-氟苯甲酸甲酯(2.5g,10.12mmol)在Et2O(100mL)中的溶液中添加在Et2O中的MeMgBr 3.0M溶液(10.7mL,32.3mmol)。将反应混合物在室温下搅拌3h,然后冷却至0℃并且用NH4Cl溶液和EtOAc处理。15min搅拌后,将有机层分离,用盐水洗涤,经Na2SO4干燥,并且在减压下浓缩。将粗化合物通过硅胶色谱法(己烷/EtOAc=70/30)纯化以得到呈黄色液体的所希望的产物(1.5g,60%产率)。
步骤2:2-(5-(叠氮基甲基)-2-氟苯基)丙-2-醇的制备
通过与中间体25步骤5类似的方法使用2-(5-(溴甲基)-2-氟苯基)丙-2-醇来获得标题化合物。将粗产物(1.1g,59%产率)直接接入下一步反应。
步骤3:2-(5-(氨基甲基)-2-氟苯基)丙-2-醇的制备
通过与中间体25步骤6类似的方法使用2-(5-(叠氮基甲基)-2-氟苯基)丙-2-醇来获得标题化合物。将粗产物通过硅胶色谱法(DCM/MeOH=97/3)纯化以得到标题化合物(0.27g,28%产率)。
中间体44:6'-氟-8'-甲基-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮
步骤1:1-(2-氨基-5-氟-3-甲基苯基)乙-1-酮的制备
在室温下在氩气下向2-溴-4-氟-6-甲基苯胺(1.0g,4.90mmol)在DMF(20mL)中的溶液中添加乙氧基乙烯基三丁基锡(2.6g,7.35mmol)和Pd(PPh3)4(57mg,0.05mmol)。将反应混合物在密封管中在110℃下搅拌15h。然后将反应混合物用20%HCl溶液搅拌2h,用水稀释并且用EtOAc(2x50mL)萃取。将合并的有机层经Na2SO4干燥并且在减压下浓缩。将残余物通过硅胶色谱法(己烷/EtOAc=100/0至30/70)纯化以产生标题化合物(600mg,73%产率)。
步骤2:6'-氟-8'-甲基-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮的制备
向1-(2-氨基-5-氟-3-甲基苯基)乙-1-酮(600mg,3.59mmol)在EtOH(50mL)中的溶液中添加4-氧代哌啶-1-甲酸叔丁酯(1.07g,5.38mmol)和吡咯烷(0.44mL,7.18mmol)。将反应混合物在密封管中在120℃下搅拌48h,然后浓缩并且用水稀释并且用EtOAc萃取。将有机层经Na2SO4干燥并且在减压下浓缩。将残余物通过硅胶色谱法(己烷/EtOAc=100/0至30/70)纯化以产生Boc-保护的6'-氟-8'-甲基-1'H-螺[哌啶-4,2'-喹啉]-4'(3'H)-酮(380mg)。将Boc中间体稀释在二噁烷(4mL)中并且添加2mL在二噁烷中的HCl 4N。将反应混合物在室温下搅拌16h,在减压下浓缩,并且将获得的固体用醚洗涤,并且在真空下干燥以得到呈HCl盐的标题化合物(300mg,34%产率,黄色固体)。LCMS:m/z249.1(M+H)。
中间体45:1-(5-(氨基甲基)-2-氟苯基)乙醇
使在甲醇(10mL)溶液中的4-氟-3-(1-羟基乙基)苄腈(320mg,1.973mmol)通过雷尼Ni在20℃下用50巴H2压力(1mL/min)持续1h来运行H-cube PROTM。在真空中除去挥发物。将粗残余物通过制备型HPLC(碱,方法2)纯化以给出标题化合物(120mg,37%产率)。LCMS:m/z 170.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.52-7.45(m,1H),7.28-7.19(m,1H),6.99(dd,J=10.4,8.4Hz,1H),5.11(q,J=6.4Hz,1H),3.79(s,2H),1.43(d,J=6.5Hz,3H)。
中间体46:(R)-1-(5-(氨基甲基)-2-氟苯基)-2,2,2-三氟乙胺
使(R)-3-(1-氨基-2,2,2-三氟乙基)-4-氟苄腈(218mg,1mmol)在甲醇(20mL)中的溶液通过Pd/C在20℃下用1巴的H2压力以1mL/min的流速持续1h来运行H-cubePROTM。将粗混合物倒入2x5g SCX柱中。将柱用MeOH(4x10mL)冲洗。使用7N甲醇氨溶液(2x20mL)从柱中洗脱出产物。在真空中除去挥发物以给出标题化合物(178mg,80%产率)。LCMS:m/z 223.3(M+H)。将粗产物不经纯化进行至下一步骤。
中间体47:(2-(三氟甲基)呋喃-3-基)甲胺
使2-(三氟甲基)呋喃-3-甲腈(150mg,0.931mmol)在甲醇(10mL)中的溶液通过Pd/C在25℃下用1巴H2压力以1mL/min的流速持续1h,在20℃下用50巴H2压力运行H-cube PROTM。在真空中除去挥发物以给出标题化合物(60mg,39%产率)。LCMS:m/z 166.1(M+H)。将粗产物不经进一步纯化进行至下一步骤。
中间体48:(4-氟-3-(3-甲氧基氮杂环丁烷-1-基)苯基)甲胺
步骤1:4-氟-3-(3-甲氧基氮杂环丁烷-1-基)苄腈的制备
通过参考以下来制备标题化合物:Angew.Chem.Int.Ed.[应用化学国际版]2011,50,8325-8328。向冷却至-40℃的烘箱干燥的烧瓶中添加异丙基氯化镁氯化锂(3846μl,5.00mmol)的1.3M THF溶液和3-溴-4-氟苄腈(1g,5.00mmol)。将混合物在-40℃下搅拌3h,并且然后然后用碘滴定。在N2下向烘箱干燥的10mL小瓶中,将3-甲氧基氮杂环丁烷(0.247g,2mmol)和N-氯琥珀酰亚胺(0.668g,5.00mmol)搅拌到甲苯(5mL)中。20min后,在-40℃下在N2下向单独的烘箱干燥的10mL小瓶中添加甲苯(5mL)、和(5-氰基-2-氟苯基)溴化镁在THF中的0.7M溶液、以及异丙醇钛(1.421g,5.00mmol),同时搅拌。另外5min后,将N-氯苯胺冷却至-40℃,并且通过注射器添加-40℃溶液。使浴温经1h缓慢达到室温。3h后,将混合物用K2CO3的饱和水溶液(10mL)淬灭。将固化的混合物用EtOAc(50mL)稀释并且过滤。将水层进一步用EtOAc(2x50mL)萃取。将有机萃取物合并,用Na2SO4干燥,过滤,并且在真空中浓缩。使用硅胶色谱法用从纯净己烷至(85:15)己烷/EtOAc的梯度进行纯化。然后将粗残余物通过硅胶色谱法(EtOAc/庚烷,85/15)纯化以给出标题化合物(0.728g,85%产率)。LCMS:MS m/z 207.3(M+H)。
步骤2和步骤3:(4-氟-3-(3-甲氧基氮杂环丁烷-1-基)苯基)甲胺的制备
制备标题化合物,通过与中间体4类似的方法使用4-氟-3-(3-甲氧基氮杂环丁烷-1-基)苄腈代替4-氨基-3-氟苄腈代替4-氨基-3-氟苄腈给出呈无色油状物的标题化合物(33mg,28%产率,经2步骤)。LCMS:m/z211.2(M+H)。
中间体49:5-(氨基甲基)-2,4-二氟苯胺
步骤1:5-氨基-2,4-二氟苄腈的制备
在N2气体下向2,4-二氟-5-硝基苄腈(1.94g,10.56mmol)在MeOH(40mL)中的搅拌溶液中添加湿Pd/C 10%(0.112g,1.056mmol)。将混合物在室温下氢化16h。将反应混合物经硅藻土垫过滤并且用MeOH洗脱。将滤液在真空中浓缩,然后在真空下浓缩后通过硅胶色谱法(庚烷/EtOAc=100/0至50/50)纯化以给出标题化合物(1.21g,74%产率)。LCMS:m/z153.1(M-H);1H NMR(400MHz,DMFS-d6)δ7.44(dd,J=11.3,9.5Hz,1H),7.08(dd,J=9.3,6.6Hz,1H),5.56(s,2H)。
步骤2:5-(氨基甲基)-2,4-二氟苯胺的制备
向步骤1的产物(1.2g,7.84mmol)在甲醇(50mL)中的溶液中添加氯化钴(II)六水合物(CoCl2.6H2O)(1.87g,7.84mmol),然后在0℃下分批添加NaBH4(0.89g,23.53mmol)。使混合物达到室温并且搅拌另外12h。通过用氢氧化铵将pH调节至13将混合物淬灭,并且用EtOAc(3x50mL)萃取。将合并的有机层用盐水洗涤,经Na2SO4干燥,并且在真空中浓缩。将粗品通过制备型反相HPLC(TFA,方法0)纯化以给出标题化合物(564mg,46%产率)。LCMS:m/z159.01(M-H);1H NMR(400MHz,DMF-d7)δ7.07-6.91(m,1H),6.82(dd,J=10.0,7.8Hz,1H),3.72(s,2H)。
中间体50:苯并[c][1,2,5]噁二唑-4-基甲胺
步骤1:(苯并[c][1,2,5]噁二唑-4-基甲基)氨基甲酸叔丁酯的制备
在室温下向苯并[c][1,2,5]噁二唑-4-甲醛(0.5g,3.37mmol)在乙腈(20mL)中的搅拌溶液中添加氨基甲酸叔丁酯(1.18g,10.13mmol)、三乙基硅烷(1.61mL,10.13mmol)、和TFA(0.5mL)。将混合物在室温下搅拌16h。将混合物倒入饱和NaHCO3水溶液,并且用EtOAc萃取。将有机层用饱和氯化铵洗涤,并且经Na2SO4干燥,过滤,并且在真空中浓缩以给出粗标题产物(450mg,53%产率),将其不经纯化进行至下一步骤。LCMS:m/z 250.1(M+H)。
步骤2:苯并[c][1,2,5]噁二唑-4-基甲胺的制备
将步骤1的粗残余物在TFA(3mL)中的溶液在室温下搅拌1h。在真空中除去挥发物后,并且将粗残余物用戊烷(10mL)和乙醚(10mL)一起磨碎,在真空中干燥以给出粗标题产物(322mg)。将粗产物不经纯化进行至下一步骤。LCMS:m/z 150.1(M+H)。
中间体51:(5-(氨基甲基)-2-氟苯基)甲烷磺酰胺
使在甲醇(15mL)溶液中的(5-氰基-2-氟苯基)甲烷磺酰胺(480mg,2.241mmol)通过Pd/C 在40℃下用30巴H2压力以1mL/min的流速持续1h来运行H-cube PROTM。将粗混合物倒入2x5g SCX柱中。将柱用MeOH(4x10mL)冲洗。使用7N甲醇氨溶液(2x20mL)从柱中洗脱出产物。在真空中除去挥发物以给出标题化合物(484mg,99%产率)。LCMS:m/z219.0(M+H)。1H NMR(400MHz,甲醇-d4)δ7.46(dd,J=7.0,2.1Hz,1H),7.37(ddd,J=7.4,4.9,2.3Hz,1H),7.17-7.07(m,1H),4.40(d,J=3.1Hz,2H),3.82(s,2H)。
实例的合成
实例1:6'-氟-N-((5-甲基呋喃-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
向在冰浴中的(5-甲基呋喃-2-基)甲胺(中间体1)(50mg,0.23mmol)在DMF(1mL)和乙腈(2mL)的混合物中的溶液中添加CDI(40mg,0.25mmol)。然后添加Hunig碱(0.079mL,0.45mmol),并且将混合物在此温度下搅拌30min。在单独的烧瓶中,将呈HCl盐的中间体2(69mg,0.20mmol)和Hunig碱(0.079mL,0.45mmol)在DMF(1mL)和乙腈(1mL)中的溶液在室温下搅拌5min。然后将混合物添加到以上中间体1和CDI的冷反应混合物中。将混合物在40℃下加热18h。将混合物倒入饱和NaHCO3水溶液中,并且将产物用EtOAc萃取。将合并的有机萃取物经Na2SO4干燥,过滤,并且在真空中浓缩。将粗残余物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(18mg,21%产率)。LCMS:m/z 372.4(M+H);1H NMR(400MHz,DMSO-d6)δ7.28-7.16(m,2H),6.96(t,J=5.5Hz,1H),6.93-6.86(m,1H),6.80(s,1H),6.01(d,J=3.0Hz,1H),5.99-5.91(m,1H),4.14(d,J=5.5Hz,2H),3.50-3.26(m,4H),2.60(s,2H),2.21(s,3H),1.66-1.46(m,4H)。
实例2:6'-氟-N-(4-氟-2-甲氧基苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
在-20℃下向(4-氟-2-甲氧基苯基)甲胺(60mg,0.39mmol)在THF(7.5mL)中的溶液中添加三光气(34.4mg,0.116mmol)和DIPEA(0.135mL,0.773mmol),并且在-20℃下将反应混合物搅拌1h。然后向其中添加在-20℃下的中间体3(110mg,0.387mmol)和DIPEA(0.081mL,0.464mmol)在5mL THF中的溶液,并且允许将混合物温热至室温并且搅拌过夜。将反应混合物用饱和NaHCO3水溶液淬灭,并且将产物用EtOAc萃取。将EtOAc层浓缩,并且通过反相HPLC(碱,方法4)纯化以给出标题化合物(82.6mg,50%产率)。LCMS:m/z 429.9(M);1H NMR(400MHz,DCM-d2)δ1.61(d,J=12.4Hz,2H),1.79(td,J=12.9,4.6Hz,2H),2.77(d,J=17.1Hz,5H),2.84-2.96(m,2H),3.73(d,J=6.6Hz,5H),4.21(d,J=5.5Hz,2H),4.95(s,1H),6.42-6.62(m,2H),6.70(dd,J=9.3,4.0Hz,1H),7.01-7.21(m,2H),7.39(dd,J=8.6,3.2Hz,1H)。
实例3:6'-氟-N-(4-氟-3-(2-羟基乙氧基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
步骤1:6'-氟-N-(4-氟-3-(2-甲氧基乙氧基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例1类似的方法分别使用中间体19和中间体3代替中间体1和2来制备标题化合物。将产物通过硅胶色谱法(MeOH/DCM)纯化以在冻干后给出呈黄色固体的标题化合物(200mg,70%产率)。LCMS:m/z 474.2(M+H)。
步骤2:6'-氟-N-(4-氟-3-(2-羟基乙氧基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
向在0℃下的步骤1的产物(200mg,0.422mmol)在DCM(4mL)中的冷却溶液中缓慢添加BBr3(在THF中1M,1267μL,1.267mmol)。将反应混合物在0℃下搅拌1h并且然后通过饱和NH4Cl水溶液(15mL)淬灭并且用DCM(2x5mL)萃取。将有机层经硫酸钠干燥并且在减压下浓缩。将残余物通过HPLC(碱,方法4)纯化以得到呈黄色固体的标题化合物(100mg,51%产率)。LCMS:m/z 460.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.43(dd,J=8.7,3.2Hz,1H),7.24(ddd,J=9.3,7.9,3.3Hz,1H),7.09-6.97(m,2H),6.94(dd,J=9.3,4.0Hz,1H),6.85(ddd,J=8.3,4.3,2.0Hz,1H),4.29(s,2H),4.10(dd,J=5.3,4.3Hz,2H),3.95(d,J=13.9Hz,2H),3.88(dd,J=5.4,4.3Hz,2H),3.12-3.01(m,2H),2.94(s,3H),2.93(s,2H),1.93(td,J=12.8,4.7Hz,2H),1.72(d,J=13.2Hz,2H)。
实例4:二氢磷酸4-((6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯酯
通过与实例28类似的方法使用化合物实例39代替化合物实例36来制备标题化合物。将产物通过反相HPLC(碱,方法0)纯化以给出呈黄色固体的标题化合物(4mg,15%产率)。LCMS:m/z 464.2(M+H);1H NMR(400MHz,甲醇-d4)δ7.29(dd,J=9.0,3.1Hz,1H),7.26-7.07(m,5H),6.86(dd,J=9.0,4.3Hz,1H),4.29(s,2H),3.57-3.42(m,4H),2.66(s,2H),1.82-1.62(m,4H)。
实例5:N-(2,4-二氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法使用(2,4-二氟苯基)甲胺代替(4-氟-2-甲氧基苯基)甲胺来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法5)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(120mg,22%产率)。LCMS:m/z 418.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.47-7.31(m,2H),7.30-7.20(m,1H),6.99-6.85(m,3H),4.36(s,2H),3.99-3.90(m,2H),3.11-3.00(m,2H),2.97-2.90(m,5H),1.93(td,J=13.0,4.6Hz,2H),1.76-1.67(m,2H)。
实例6:1'-乙基-6'-氟-N-(4-氟苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用(4-氟苯基)甲胺和中间体5代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过SFC(柱:Phenomenex Kinetex联苯21.2x150mm 5μm;流动相:MeOH)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(65mg,51%产率)。LCMS:m/z 414.3(M+H);1H NMR(400MHz,甲醇-d4)δ7.40(dd,J=8.7,3.3Hz,1H),7.36-7.28(m,2H),7.28-7.21(m,1H),7.07-6.99(m,2H),6.90(dd,J=9.4,4.0Hz,1H),4.32(s,2H),4.00(dd,J=11.8,2.4Hz,2H),3.44(q,J=7.1Hz,2H),3.08-2.97(m,2H),2.91(s,2H),1.90(td,J=13.0,4.8Hz,2H),1.78(d,J=13.5Hz,2H),1.24(t,J=7.1Hz,3H)。
实例7:6'-氟-1'-甲基-N-((5-甲基呋喃-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体3代替中间体2来制备标题化合物。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(12mg,11%产率)。LCMS:m/z 386.4(M+H);1H NMR(400MHz,DMSO-d6)δ7.46-7.25(m,2H),7.06-6.86(m,2H),6.02(d,J=3.0Hz,1H),5.99-5.91(m,1H),4.14(d,J=5.3Hz,2H),3.99-3.77(m,2H),3.00-2.76(m,7H),2.21(s,3H),1.78-1.72(m,2H),1.62-1.48(m,2H)。
实例8:6'-氟-N-(4-氟-3-甲氧基苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法使用(4-氟-3-甲氧基苯基)甲胺代替中间体1来制备标题化合物。将产物通过硅胶色谱法(DCM/MeOH=100/0至95/5)、然后通过SFC(柱:PrincetonDIOL 20x150mm 5μm;流动相:MeOH)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(40mg,29%产率)。LCMS:m/z 430.4(M+H);1H NMR(400MHz,甲醇-d4)δ7.43(dd,J=8.6,3.2Hz,1H),7.25(ddd,J=9.3,7.9,3.3Hz,1H),7.06-6.90(m,3H),6.83(ddd,J=8.2,4.3,2.0Hz,1H),4.30(s,2H),4.01-3.91(m,2H),3.85(s,3H),3.06(td,J=14.3,13.2,2.7Hz,2H),2.93(d,J=3.0Hz,5H),1.93(td,J=13.0,4.7Hz,2H),1.72(d,J=12.7Hz,2H)。
实例9:6'-氟-N-(4-氟苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法使用(4-氟苯基)甲胺代替(4-氟-2-甲氧基苯基)甲胺来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法6)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(42mg,12%产率)。LCMS:m/z 400.2(M+H);1H NMR(400MHz,DMSO-d6)δ7.40-7.31(m,2H),7.31-7.23(m,2H),7.17-7.06(m,3H),7.00-6.92(m,1H),4.20(d,J=5.7Hz,2H),3.93-3.85(m,2H),2.95-2.82(m,7H),1.75(dt,J=12.7,6.5Hz,2H),1.60-1.52(m,2H)。
实例10:6',8'-二氟-N-((2-甲基呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别使用(2-甲基呋喃-3-基)甲胺和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 390.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.26-7.12(m,3H),6.32(s,1H),4.12(s,2H),3.69-3.63(m,2H),3.36-3.29(m,2H),2.81(s,2H),2.27(s,3H),1.82-1.73(m,4H)。
实例11:N-(3-氨基甲酰基-4-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体6和26(游离碱)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(57mg,32%产率)。LCMS:m/z 477.2(M+H);1H NMR(400MHz,甲醇-d4)δ7.75(dd,J=7.1,2.3Hz,1H),7.47(ddd,J=7.4,4.8,2.4Hz,1H),7.25-7.10(m,3H),4.36(s,2H),3.70(dt,J=14.2,5.1Hz,2H),3.41-3.33(m,2H),2.81(s,2H),1.87-1.73(m,4H)。
实例12:6'-氟-N-((4-氟苯基)甲基-d2)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体7和2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过制备型HPLC(碱,方法5)、然后通过SFC(柱:Princeton DIOL 20x150mm5μm;流动相:MeOH)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(29mg,31%产率)。LCMS:m/z 388.3(M+H);1H NMR(400MHz,甲醇-d4)δ7.33-7.26(m,3H),7.12(ddd,J=9.0,8.2,3.1Hz,1H),7.05-6.98(m,2H),6.85(dd,J=9.1,4.3Hz,1H),3.57-3.45(m,4H),3.33(d,J=1.7Hz,1H),2.66(s,2H),1.72(tdt,J=13.3,7.7,4.6Hz,4H)。
实例13:N-(3-氨基甲酰基-4-氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体6和5代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(55mg,26%产率)。LCMS:m/z 477.2(M+H);1H NMR(400MHz,甲醇-d4)δ7.76(dd,J=7.1,2.3Hz,1H),7.48(dd,J=6.0,2.4Hz,1H),7.41(dd,J=8.7,3.2Hz,1H),7.24(ddd,J=9.4,7.9,3.3Hz,1H),7.17(dd,J=10.9,8.5Hz,1H),6.91(dd,J=9.3,4.0Hz,1H),4.36(s,2H),4.01(d,J=13.8Hz,2H),3.45(q,J=7.1Hz,2H),3.03(t,J=11.9Hz,2H),2.92(s,2H),1.99-1.72(m,4H),1.25(t,J=7.1Hz,3H)。
实例14:6'-氟-N-(4-氟苄基)-1'-(2-甲氧基乙基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用(4-氟苯基)甲胺和中间体8代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过制备型HPLC(碱,方法5)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(14mg,21%产率)。LCMS:m/z 444.3(M+H);1H NMR(400MHz,甲醇-d4)δ7.41(dd,J=8.6,3.3Hz,1H),7.35-7.27(m,2H),7.23(ddd,J=9.4,7.9,3.3Hz,1H),7.05-7.00(m,2H),6.96(dd,J=9.4,4.0Hz,1H),4.32(s,2H),3.97(d,J=14.0Hz,2H),3.61-3.50(m,4H),3.33(s,3H),3.08-2.98(m,2H),2.92(s,2H),1.93(td,J=13.0,4.7Hz,2H),1.76(d,J=13.6Hz,2H)。
实例15:6'-氟-N-(4-氟-3-(噁唑-5-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体9(TFA盐)和2(HCl盐)代替(4-氟苯基)甲胺和中间体3来制备标题化合物。将产物在制备型TLC板使用作为流动相的在DCM中的5%MeOH纯化以给出呈黄色固体的标题化合物(49mg,44%产率)。LCMS:m/z 452.9(M+H);1HNMR(400MHz,DMSO-d6)δ8.56(1H,s),7.69-7.67(1H,d),7.54-7.53(1H,d),7.33-7.31(2H,m),7.24-7.20(2H,m),6.92-6.90(1H,m),6.82(1H,s),4.26-4.25(2H,d),3.46-3.38(4H,m),2.61(2H,s),1.59-1.55(4H,m)。
实例16:N-(2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用(2,4-二氟苯基)甲胺和中间体2(HCl盐)代替(4-氟苯基)甲胺和中间体3来制备标题化合物。将产物通过制备型SFC(柱:Princeton DIOL20x150mm 5μm;流动相:MeOH)纯化以给出呈黄色固体的标题化合物(35mg,36%产率)。LCMS:m/z404.3(M+H);1H NMR(400MHz,MeOH-d4)δ7.40-7.26(m,2H),7.12(ddd,J=9.0,8.2,3.1Hz,1H),6.96-6.81(m,3H),4.36(s,2H),3.57-3.46(m,4H),2.66(s,2H),1.72(tdt,J=13.3,7.8,4.6Hz,4H)。
实例17:N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
步骤1:N-(2,4-二氟-5-((2-甲氧基乙基)氨基)苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例2类似的方法使用中间体10代替(4-氟-2-甲氧基苯基)甲胺来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(48mg,16.2%产率)。LCMS:m/z 491.2(M+H)。
步骤2:N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例3步骤2类似的方法来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以得到呈黄色固体的标题化合物(22mg,44.8%产率)。HRMS:m/z 477.2110(M+H);1H NMR(400MHz,甲醇-d4)δ7.43(dd,J=8.6,3.2Hz,1H),7.30-7.19(m,1H),6.98-6.90(m,1H),6.81(dd,J=11.4,9.7Hz,1H),6.75(dd,J=9.6,7.4Hz,1H),4.32(s,2H),3.99-3.90(m,2H),3.73(t,J=5.7Hz,2H),3.23(t,J=5.7Hz,3H),3.11-3.00(m,2H),2.93(s,3H),2.93(s,2H),1.92(td,J=13.0,4.6Hz,2H),1.75-1.65(m,2H)。
实例18:N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
步骤1:N-(2,4-二氟-5-((2-甲氧基乙基)氨基)苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例2类似的方法分别使用中间体10和5代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型SFC(柱:Princeton DEAP 20x150mm 5μm;流动相:MeOH)纯化以给出标题化合物。HRMS:m/z 505.2423(M+H)。
步骤2:N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例3步骤2类似的方法来制备标题化合物。然后将产物通过制备型SFC(柱:Princeton DEAP 20x150mm 5μm;流动相:MeOH)纯化以得到呈黄色固体的标题化合物(5mg,27.1%产率)。HRMS:m/z 491.2265(M+H);1H NMR(400MHz,甲醇-d4)δ7.38(dd,J=8.7,3.3Hz,1H),7.22(m,J=9.4,7.9,3.3Hz,1H),6.88(dd,J=9.4,4.0Hz,1H),6.85-6.61(m,2H),4.31(s,2H),4.04-3.92(m,2H),3.71(t,J=5.7Hz,2H),3.42(q,J=7.0Hz,2H),3.22(t,J=5.7Hz,2H),3.04-2.94(m,2H),2.90(s,2H),1.89(td,J=13.0,4.8Hz,2H),1.76(d,J=13.5Hz,2H),1.22(t,J=7.1Hz,3H)。
实例19:6'-氟-N-(4-氟苄基)-1'-(2-羟基乙基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
向在0℃下的实例14(65mg,0.147mmol)在干DCM(2mL)中的溶液中缓慢添加在DCM中的三溴硼烷1M(0.293mL,0.293mmol)。将反应混合物在0℃下搅拌30min,然后通过饱和NH4Cl水溶液淬灭并且用DCM和EtOAc萃取。将合并的有机层经Na2SO4干燥并且在减压下浓缩。将残余物通过制备型SFC(柱:Princeton DEAP 20x150mm 5μm;流动相:MeOH)纯化纯化以产生呈黄色固体的标题化合物(35mg,53%产率)。LCMS:m/z 430.3(M+H);1H NMR(400MHz,氯仿-d)δ7.56(dd,J=8.3,3.2Hz,1H),7.31-7.27(m,2H),7.20(td,J=8.4,7.6,3.2Hz,1H),7.02(t,J=8.7Hz,3H),4.39(s,2H),3.96-3.79(m,4H),3.53(t,J=6.1Hz,2H),3.04(t,J=11.9Hz,2H),2.91(s,2H),2.15-2.05(m,2H),1.83(d,J=13.3Hz,2H)。
实例20:6'-氟-N-(4-氟-2-((2-甲氧基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法使用中间体11代替(4-氟-2-甲氧基苯基)甲胺来制备标题化合物。将粗残余物通过HPLC(碱,方法5)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(40mg,93%产率)。LCMS:m/z 473.0(M+H);1H NMR(400MHz,甲醇-d4)δ7.42(dd,J=8.6,3.2Hz,1H),7.25(ddd,J=9.3,7.9,3.3Hz,1H),7.03(dd,J=8.2,6.8Hz,1H),6.94(dd,J=9.4,4.1Hz,1H),6.33(dd,J=12.1,2.5Hz,1H),6.26(td,J=8.4,2.5Hz,1H),4.24(s,2H),3.94(d,J=13.9Hz,2H),3.61(t,J=5.5Hz,2H),3.38(s,3H),3.26(t,J=5.5Hz,2H),3.11-2.98(m,2H),2.92(d,J=4.5Hz,5H),1.92(td,J=12.7,4.7Hz,2H),1.70(d,J=13.3Hz,2H)。
实例21:6'-氟-N-(4-氟-3-(2-甲氧基乙氧基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法使用中间体12代替(4-氟-2-甲氧基苯基)甲胺来制备标题化合物。将产物通过硅胶色谱法(DCM/MeOH=100/0至90/10)、然后通过制备型HPLC(碱,方法5)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(156mg,40%产率)。LCMS:m/z473.3(M+H);1H NMR(400MHz,DMSO-d6)δ7.36(ddd,J=10.5,4.9,2.6Hz,2H),7.10-6.81(m,3H),6.64(dd,J=8.7,1.9Hz,1H),6.51-6.32(m,1H),5.23(s,1H),4.13(d,J=5.5Hz,2H),3.91(d,J=13.8Hz,2H),3.49(d,J=6.0Hz,2H),3.26(s,3H),3.22(d,J=4.9Hz,2H),2.90(d,J=10.2Hz,3H),2.84(s,3H),1.75(td,J=12.9,4.5Hz,2H),1.56(d,J=12.9Hz,2H)。
实例22:N-((5-氯呋喃-2-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用(5-氯呋喃-2-基)甲胺(根据J.Med.Chem.[药物化学期刊]2016,59,3471制备)代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(27mg,25%产率)。LCMS:m/z 392.3(M+H);1H NMR(400MHz,DMSO-d6)δ7.27-7.17(m,2H),7.06(t,J=5.6Hz,1H),6.97-6.85(m,1H),6.80(s,1H),6.36(d,J=3.3Hz,1H),6.26(d,J=3.2Hz,1H),4.16(d,J=5.4Hz,2H),3.52-3.28(m,4H),2.60(s,2H),1.69-1.45(m,4H)。
实例23:6'-氟-N-(4-氟-3-((1-甲基乙基)磺酰胺基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
向实例95(35mg,0.087mmol)在DCM(437μL)和吡啶(437μL)中的搅拌溶液中添加2-丙烷磺酰氯(9.81μL,0.087mmol)。允许将反应在50℃下搅拌。将粗材料通过HPLC(碱,方法3)纯化以得到呈黄色固体的标题化合物(7.3mg,16%产率)。LCMS:m/z 507.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.52(d,J=7.0Hz,1H),7.32(dd,J=9.0,3.0Hz,1H),7.18-7.07(m,3H),6.88(dd,J=9.1,4.3Hz,1H),4.34(s,2H),3.54(t,J=5.5Hz,4H),3.30-3.24(m,1H),2.71(s,2H),1.78(h,J=7.6,7.0Hz,4H),1.38(s,3H),1.36(s,3H)。
实例24:N-(3-氨基甲酰基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体6和2(游离碱)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗产物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(110mg,39%产率)。LCMS:m/z 429.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.75(dd,J=7.1,2.4Hz,1H),7.47(m,J=7.3,4.8,2.4Hz,1H),7.30(dd,J=9.0,3.0Hz,1H),7.22-7.08(m,2H),6.88(dd,J=9.1,4.3Hz,1H),4.36(s,2H),3.52(t,J=5.7Hz,4H),2.68(s,2H),1.82-1.68(m,4H)。
实例25:1'-乙基-6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
步骤1:1'-乙基-6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例2类似的方法分别使用中间体12和5代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过制备型HPLC(碱,方法5)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(15mg,13%产率)。LCMS:m/z 487.3(M+H)。
步骤2:1'-乙基-6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例19类似的方法使用步骤1的产物代替实例14来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(3mg,31%产率)。LCMS:m/z 473.3(M+H);1H NMR(400MHz,DMSO-d6)δ7.38-7.27(m,2H),7.06(t,J=5.8Hz,1H),6.95-6.85(m,2H),6.64(dd,J=8.7,1.8Hz,1H),6.43(ddd,J=8.0,4.5,2.0Hz,1H),5.16(q,J=3.6Hz,1H),4.77(s,1H),4.13(d,J=5.7Hz,2H),3.94(d,J=13.8Hz,2H),3.57(t,J=5.8Hz,2H),3.39(s,2H),3.11(q,J=6.0Hz,2H),2.87(d,J=11.5Hz,4H),1.81-1.56(m,4H),1.14(t,J=7.0Hz,3H)。
实例26:N-(3-氨基-2,4-二氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体13和5代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(5mg,5%产率)。LCMS:m/z 447.3(M+H);1H NMR(400MHz,氯仿-d)δ7.51(dd,J=8.5,3.3Hz,1H),7.16(ddd,J=9.3,7.7,3.2Hz,1H),6.81-6.73(m,2H),6.71-6.63(m,1H),4.83(s,1H),4.40(d,J=4.4Hz,2H),3.90(d,J=13.6Hz,2H),3.49(s,1H),3.37(q,J=7.1Hz,2H),3.05-2.93(m,2H),2.84(s,2H),1.90(dt,J=12.6,6.7Hz,2H),1.79(d,J=13.2Hz,3H),1.25(d,J=7.1Hz,3H)。
实例27:N-(3-氨基-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法使用5-(氨基甲基)-2-氟苯胺代替(4-氟-2-甲氧基苯基)甲胺来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(110mg,37%产率)。LCMS:m/z 415.3(M+H);1H NMR(400MHz,甲醇-d4)δ7.43(dd,J=8.7,3.2Hz,1H),7.25(ddd,J=9.3,8.0,3.3Hz,1H),6.94(dd,J=9.4,4.1Hz,1H),6.86(dd,J=11.2,8.3Hz,1H),6.77(dd,J=8.6,2.1Hz,1H),6.60-6.51(m,1H),4.22(d,J=4.2Hz,2H),3.95(d,J=13.9Hz,2H),3.10-3.00(m,2H),2.94(s,3H),2.93(s,2H),1.99-1.86(m,2H),1.71(d,J=12.8Hz,2H)。
实例28:6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
向在冰浴中的实例36(300mg,0.654mmol)和三乙胺(0.547mL,3.93mmol)在THF(5mL)中的溶液中逐滴添加三氯氧磷(0.122mL,1.309mmol)。5min后,将反应混合物从冰浴中移出并且允许经30min温热至室温。将混合物用H2O缓慢淬灭并且转移至分液漏斗。将水层用EtOAc/THF(1:1)(3x100mL)萃取。将有机萃取物合并,并且在真空中浓缩。将粗残余物通过反相HPLC(碱,方法1)纯化以在冻干后给出呈黄色固体的标题化合物(222mg,60.5%产率)。LCMS:m/z 539.2(M+H);1H NMR(400MHz,甲醇-d4)δ7.42(dd,J=8.7,3.2Hz,1H),7.24(ddd,J=9.3,7.9,3.3Hz,1H),6.95(dd,J=9.4,4.0Hz,1H),6.85(dd,J=11.7,8.2Hz,1H),6.75(dd,J=8.4,2.1Hz,1H),6.52(ddd,J=8.2,4.5,2.1Hz,1H),4.26(s,2H),4.10-4.01(m,2H),4.01-3.92(m,2H),3.38(t,J=5.7Hz,2H),3.11-3.00(m,2H),2.98-2.87(m,5H),1.93(td,J=12.8,4.7Hz,2H),1.79-1.64(m,2H)。
实例29:N-(3-氨基-4-氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用5-(氨基甲基)-2-氟苯胺和中间体5代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过硅胶色谱法(DCM/MeOH=100/0至90/10)、然后通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(19mg,19%产率)。LCMS:m/z 429.3(M+H);1H NMR(400MHz,MeOH-d4)δ7.40(dd,J=8.7,3.3Hz,1H),7.23(ddd,J=9.4,7.9,3.3Hz,1H),6.96-6.83(m,2H),6.78(dd,J=8.7,2.1Hz,1H),6.56(ddd,J=8.2,4.4,2.2Hz,1H),4.22(s,2H),4.06-3.92(m,2H),3.44(q,J=7.0Hz,2H),3.08-2.95(m,2H),2.91(s,2H),1.91(td,J=13.0,4.8Hz,2H),1.78(d,J=13.6Hz,2H),1.24(t,J=7.1Hz,3H)。
实例30:6'-氟-N-(4-氟-3-氨磺酰基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用5-(氨基甲基)-2-氟苯磺酰胺和中间体2(游离碱)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(110mg,37%产率)。LCMS:MS m/z 465.2(M+H);1H NMR(400MHz,甲醇-d4)δ7.70(dd,J=7.0,2.4Hz,1H),7.49-7.41(m,1H),7.31(dd,J=8.9,3.0Hz,1H),7.20-7.08(m,2H),6.91-6.83(m,1H),4.35(s,2H),3.76-3.68(m,2H),3.54-3.51(m,4H),2.68(s,2H),1.82-1.67(m,4H)。
实例31:N-(3-(((1,4-二噁烷-2-基)甲基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
将实例27(50mg,0.121mmol)、中间体14(粗材料)和NaBH(OAc)3(52mg,0.25mmol)在DCM(5mL)中的混合物在室温下搅拌16h,分配在DCM与NH4Cl水溶液之间。将合并的有机萃取物经MgSO4干燥,浓缩,并且通过反相HPLC(碱,方法4)纯化以给出呈黄色固体的标题化合物(9mg,14%产率)。LCMS:m/z 515.4(M+H);1H NMR(400MHz,甲醇-d4)δ7.43(dd,J=8.7,3.2Hz,1H),7.27-7.22(m,1H),6.94(dd,J=9.4,4.1Hz,1H),6.86(dd,J=11.7,8.2Hz,1H),6.70(dd,J=8.5,1.9Hz,1H),6.56-6.50(m,1H),4.25(s,2H),3.99-3.91(m,2H),3.84-3.75(m,3H),3.73-3.65(m,2H),3.62-3.53(m,1H),3.42-3.35(m,1H),3.21(dd,J=13.4,4.9Hz,1H),3.13(dd,J=13.4,6.6Hz,1H),3.10-3.01(m,2H),2.94(s,3H),2.92(s,2H),1.93(td,J=13.1,4.7Hz,2H),1.76-1.67(m,2H)。
实例32:6'-氟-N-(4-氟-3-((4-(羟基甲基)苄基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
步骤1:2-氟-5-((6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-基甲酰胺基)甲基)苯甲酸的合成
向在THF(10mL)和水(10mL)中的实例61(5.93g,13.37mmol)中添加LiOH(0.641g,26.7mmol)。将反应混合物在室温下搅拌16h。在真空中浓缩挥发物。将粗残余物与MeOH/DCM一起磨碎,过滤,并且在真空烘箱中干燥16h以获得标题化合物。LCMS:m/z 430.2(M+H);1HNMR(400MHz,甲醇-d4)δ1H NMR(400MHz,甲醇-d4)δ7.63(dd,J=6.9,2.4Hz,1H),7.36-7.26(m,2H),7.17-7.08(m,1H),7.07-6.98(m,1H),6.91-6.83(m,1H),4.33(s,2H),3.51(t,J=5.8Hz,4H),2.68(s,2H),1.82-1.66(m,4H)。
步骤2:6'-氟-N-(4-氟-3-((4-(羟基甲基)苄基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
向步骤1的产物(0.080g,0.180mmol)在DMF(1mL)中的无水溶液中添加DIPEA(0.047mL,0.271mmol),然后添加HATU(0.103g,0.271mmol)。将混合物在室温下搅拌15min,并且添加(4-(氨基甲基)苯基)甲醇(0.025g,0.18mmol)。将反应混合物在室温下搅拌18h。将混合物用EtOAc(5mL)稀释并且用饱和氯化铵(2x5mL)和饱和NaCl(1x5mL)洗涤。将有机层用Na2SO4干燥,过滤,并且在真空中浓缩挥发物。将粗残余物溶解在MeOH中并且通过制备型反相HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(63mg,58%产率)。HRMS:m/z 549.2341(M+H);1H NMR(400MHz,甲醇-d4)δ7.65(dd,J=6.9,2.4Hz,1H),7.49-7.40(m,1H),7.40-7.26(m,5H),7.21-7.07(m,2H),6.90-6.79(m,1H),4.62-4.56(m,4H),4.35(s,2H),3.51(t,J=5.8Hz,4H),2.67(s,2H),1.82-1.66(m,4H)。
实例33:N-苄基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用苄胺和中间体2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过硅胶色谱法(DCM/EtOAc=60/40至20/80)纯化以给出呈黄色固体的标题化合物(74mg,35%产率)。LCMS:m/z 368.05(M+H);1HNMR(400MHz,DMSO-d6)δ7.31-7.27(2H,m),7.24-7.20(5H,m),7.12-7.08(1H,m),6.92-6.90(1H,m),6.80(1H,s),4.23-4.22(2H,m),3.46-3.40(4H,m),2.61(2H,s),1.60-1.55(4H,m)。
实例34:N-((2,4-二甲基呋喃-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用(2,4-二甲基呋喃-3-基)甲胺代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过HPLC(甲酸,方法3)纯化以给出呈黄色固体的标题化合物(29mg,27%产率)。LCMS:m/z 386.3(M+H);1H NMR(400MHz,DMSO-d6)δ7.29-7.10(m,3H),6.94-6.85(m,1H),6.79(s,1H),6.64(t,J=5.3Hz,1H),3.95(d,J=5.1Hz,2H),3.56-3.21(m,4H),2.59(s,2H),2.20(s,3H),1.89(s,3H),1.64-1.44(m,4H)。
实例35:6',8'-二氟-N-(3-(噁唑-5-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别使用(3-(噁唑-5-基)苯基)甲胺和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 453.2(M+H)。
实例36:6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
步骤1:N-(3-((2-((叔丁基二甲基甲硅烷基)氧基)乙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例1类似的方法分别使用中间体15和中间体3代替中间体1和中间体2来制备标题化合物。LCMS:m/z 573.6(M+H)。
步骤2:6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
将步骤1的产物吸收在THF(20mL)中。向其中添加TBAF(1M THF溶液,6.70mL,6.70mmol)。将混合物在室温下搅拌2h并且分配在NH4Cl水溶液与EtOAc之间。将合并的有机萃取物经Na2SO4干燥并且浓缩。将粗产物通过硅胶色谱法(MeOH/DCM)纯化以给出呈黄色固体的标题化合物(1.33g,86%产率)。LCMS:m/z 459.5(M+H);1H NMR(400MHz,DMSO-d6)δ7.44-7.28(m,2H),7.03(t,J=5.9Hz,1H),7.00-6.87(m,2H),6.63(dd,J=8.7,2.0Hz,1H),6.42(ddd,J=8.1,4.5,2.0Hz,1H),5.24-5.07(m,1H),4.77(t,J=5.5Hz,1H),4.13(d,J=5.6Hz,2H),4.01-3.81(m,2H),3.57(q,J=5.9Hz,2H),3.12(q,J=5.9Hz,2H),2.98-2.79(m,7H),1.76(td,J=12.8,4.6Hz,2H),1.64-1.49(m,2H)。
实例37:N-((1H-吡唑-4-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用(1H-吡唑-4-基)甲胺代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(DCM/MeOH)、然后通过HPLC(碱,方法3)纯化以给出呈黄色固体的标题化合物(29mg,36%产率)。LCMS:m/z 358.3(M+H);1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),7.45(s,2H),7.30-7.12(m,2H),6.95-6.85(m,1H),6.86-6.73(m,2H),4.07(d,J=5.4Hz,2H),3.53-3.19(m,4H),2.60(s,2H),1.65-1.42(m,4H)。
实例38:N-((4-氨基甲酰基呋喃-2-基)甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别使用5-(氨基甲基)呋喃-3-甲酰胺和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 418.9(M+H)。
实例39:6'-氟-N-(4-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用4-羟基苄基胺代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法3)纯化以给出呈黄色固体的标题化合物(17mg,8%产率)。LCMS:m/z 384.3(M+H)。1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),7.28-7.16(m,2H),7.09-7.00(m,2H),6.97(t,J=5.8Hz,1H),6.94-6.86(m,1H),6.80(s,1H),6.71-6.63(m,2H),4.10(d,J=5.8Hz,2H),3.49-3.28(m,4H),2.60(s,2H),1.66-1.46(m,4H)。
实例40:6'-氟-N-(异噁唑-5-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
向异氰酸4-氟苄酯(0.709g,4.69mmol)在THF(1mL)中的溶液中添加呈TFA盐的中间体2(1.42g,4.08mmol)和Hunig碱(2.136mL,12.23mmol)在THF(1mL)中的溶液。将混合物在室温下搅拌18h。将反应倒入饱和NaHCO3水溶液中并且用EtOAc萃取。将有机物合并,用Na2SO4干燥,过滤,并且在真空中浓缩挥发物。使粗残余物通过硅胶塞用MeOH/DCM(5/95)洗脱。在真空中浓缩溶剂并且将固体与乙醚一起磨碎以给出标题化合物(1.1g,69%产率)。LCMS:m/z 386.2(M+H);1H NMR(400MHz,甲醇-d4)δ7.32-7.25(m,3H),7.12(ddd,J=9.2,8.0,3.0Hz,1H),7.05-6.98(m,2H),6.85(dd,J=9.1,4.3Hz,1H),4.31(s,2H),3.57-3.43(m,4H),2.66(s,2H),1.80-1.63(m,4H)。
实例41:N-(3-氨基甲酰基-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法分别使用中间体6和3代替中间体1和2来制备标题化合物。将粗残余物通过硅胶色谱法(MeOH/DCM=1:9)、然后通过制备型反相HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(656mg,48%产率)。HRMS:m/z 443.1886(M+H);1H NMR(400MHz,甲醇-d4)δ7.80-7.73(m,1H),7.53-7.41(m,2H),7.32-7.22(m,1H),7.22-7.13(m,1H),7.01-6.92(m,1H),4.37(s,2H),4.03-3.93(m,2H),3.14-3.04(m,2H),2.97(s,3H),2.95(s,2H),2.03-1.91(m,2H),1.78-1.70(m,2H)。
实例42:N-(3-氨基-2,4-二氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法使用中间体13代替(4-氟-2-甲氧基苯基)甲胺来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(15mg,22%产率)。LCMS:m/z 433.3(M+H)。
实例43:6'-氟-N-(4-氟-2-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
在室温下在氮气气氛下向实例114(900mg,2.15mmol)在DCM(15mL)中的搅拌溶液中添加BBr3(0.6mL,6.47mmol)并且将反应在室温下搅拌4h。将反应冷却至0℃并且用MeOH淬灭,然后用EtOAc稀释并且用水洗涤,经Na2SO4干燥并且在减压下浓缩。将产物通过硅胶色谱法(DCM/MeOH=100/0至90/10)纯化以给出呈黄色固体的标题化合物(500mg,58%产率)。LCMS:m/z 402.3(M+H);1H NMR(400MHz,DMSO-d6)δ:10.5(1H,s),7.24-7.19(3H,m),7.09-7.05(1H,t),6.90-6.87(1H,m),6.79(1H,s),6.59-6.52(2H,m),4.11-4.10(2H,d),3.45-3.32(4H,m),2.60(2H,m),1.58-1.55(4H,m)。
实例44:N-(3-((2,2-二甲基-3-(4-甲基哌嗪-1-基)-3-氧代丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过水解如实例140步骤1中描述的相应的甲酯(43mg,0.081mmol)来制备化合物实例140。将粗羧酸产物(实例140)吸收在DMF(6mL)中,并且分离到相等体积的两个小瓶中。向一个小瓶中添加HATU(145mg,0.381mmol)和N-Me哌嗪(150μL,1.35mmol)。将混合物在室温下搅拌2h,分配在EtOAc与NH4Cl水溶液之间。将合并的有机萃取物经MgSO4干燥,浓缩并且通过反相HPLC(碱,方法5)纯化以给出呈黄色固体的标题化合物(11mg,44%产率)。LCMS:m/z597.4(M+H);1H NMR(400MHz,甲醇-d4)δ7.42(dd,J=8.6,3.2Hz,1H),7.27-7.21(m,1H),6.93(dd,J=9.4,4.0Hz,1H),6.85(dd,J=11.7,8.2Hz,1H),6.76(dd,J=8.5,1.9Hz,1H),6.54-6.45(m,1H),4.24(s,2H),4.00-3.90(m,2H),3.75-3.64(m,4H),3.27(s,2H),3.11-2.99(m,2H),2.93(s,3H),2.92(s,2H),2.49-2.39(m,4H),2.29(s,3H),1.92(td,J=13.0,4.6Hz,2H),1.75-1.66(m,2H),1.35(s,6H)。
实例45:(S)-N-(3-((2,3-二羟基丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
步骤1:(S)-N-(3-(((2,2-二甲基-1,3-二氧戊环-4-基)甲基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例1类似的方法分别使用中间体16和中间体3代替中间体1和中间体2来制备标题化合物。将产物通过硅胶色谱法(EtOAc)纯化以给出呈黄色油状物的标题化合物(320mg)。LCMS:m/z 529.4(M+H)。
步骤2:(S)-N-(3-((2,3-二羟基丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
将HCl水溶液(3M,5mL,15mmol)添加到步骤1的产物(318mg,0.602mmol)在THF(5mL)中的溶液中。将混合物在室温下搅拌20min,浓缩,并且分配在EtOAc与K2CO3水溶液之间。将合并的有机萃取物经MgSO4干燥,浓缩,并且通过硅胶色谱法(DCM/MeOH)纯化以给出呈黄色固体的标题化合物(101mg,34%产率,经2步骤)。LCMS:m/z489.3(M+H);1H NMR(400MHz,甲醇-d4)δ7.42(dd,J=8.7,3.2Hz,1H),7.27-7.22(m,1H),6.94(dd,J=9.4,4.1Hz,1H),6.86(dd,J=11.7,8.2Hz,1H),6.74(dd,J=8.5,2.1Hz,1H),6.52(ddd,J=8.2,4.5,2.2Hz,1H),4.25(s,2H),3.99-3.92(m,2H),3.87-3.79(m,1H),3.61-3.53(m,2H),3.37-3.33(m,1H),3.17-3.00(m,3H),2.94(s,3H),2.92(s,2H),1.96-1.87(m,2H),1.77-1.61(m,2H)。
实例46:6',8'-二氟-N-(呋喃-3-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别使用呋喃-3-基甲胺和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 376.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.32(s,1H),7.11-7.03(m,2H),6.29(s,2H),4.07(d,J=8Hz,3H),3.59-3.53(m,2H),3.23(s,1H),2.68(s,2H),1.72-1.63(m,4H)。
实例47:N-((1H-吡唑-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用(1H-吡唑-3-基)甲基胺代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法2)纯化以在冻干后给出呈白色固体的标题化合物(39mg,42%产率)。LCMS:m/z 358.4(M+H)。1H NMR(400MHz,DMSO-d6)δ12.49(s,1H),7.58(s,1H),7.30-7.14(m,2H),7.03-6.85(m,2H),6.81(s,1H),6.08(s,1H),4.21(d,J=5.5Hz,2H),3.54-3.25(m,4H),2.60(s,2H),1.71-1.43(m,4H)。
实例48:6'-氟-N-(4-氟-3-((2-羟基乙基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例32步骤2类似的方法来制备标题化合物。将粗残余物通过硅胶色谱法(MeOH/DCM=1:9)、然后通过制备型反相HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(656mg,48%产率)。HRMS:m/z 473.2002(M+H);1H NMR(400MHz,甲醇-d4)δ7.59(dd,J=7.0,2.3Hz,1H),7.45-7.25(m,1H),7.20(dd,J=8.9,3.0Hz,1H),7.13-6.94(m,2H),6.83-6.68(m,1H),4.25(s,2H),3.61(t,J=5.8Hz,2H),3.52-3.34(m,6H),2.57(s,2H),1.79-1.56(m,4H)。
实例49:N-(4-氨基-2,5-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体17代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(35mg,50%产率)。LCMS:m/z=441.3(M+Na)。1H NMR(400MHz,DMSO-d6)δ7.30-7.15(m,2H),6.96-6.84(m,3H),6.78(s,1H),6.47(dd,J=11.6,7.5Hz,1H),5.28(s,2H),4.08(d,J=5.4Hz,2H),3.49-3.32(m,4H),2.60(s,2H),1.67-1.47(m,4H)。
实例50:N-(5-氨基-2,4-二氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用(2,4-二氟苯基)甲胺和中间体5代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(6mg,4%产率)。HRMS:m/z 447.2004(M+H);1H NMR(400MHz,氯仿-d)δ7.50(d,1H),7.20-7.10(m,1H),6.89-6.80(m,1H),6.80-6.73(m,1H),6.73-6.67(m,1H),4.34(d,J=5.6Hz,2H),3.94-3.85(m,2H),3.36(q,J=7.1Hz,2H),3.04-2.92(m,2H),2.83(s,2H),1.93-1.74(m,4H),1.25-1.19(m,3H)。
实例51:6'-氟-N-(4-氟-2-(2,2,2-三氟乙氧基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
向实例43(50mg,0.124mmol)在DMF(1.2mL)中的溶液中添加1,1,1-三氟-2-碘乙烷(34mg,0.16mmol)和碳酸铯(60.8mg,0.186mmol)。将反应混合物加热至70℃过夜。将反应混合物用水稀释,并且用EtOAc萃取。将EtOAc层浓缩,并且用HPLC(碱,方法5)、然后用硅胶柱色谱法(庚烷/EtOAc)纯化以给出标题化合物(8mg,6%产率)。LCMS:m/z 484.1(M+H);1HNMR(400MHz,DCM-d2)δ1.83(m,4H),2.71(s,2H),3.30-3.52(m,4H),4.40(s,2H),4.46(q,J=8.1Hz,2H),6.64(dd,J=10.2,2.4Hz,1H),6.70-6.82(m,2H),7.09-7.17(m,1H),7.36(dd,J=8.3,6.7Hz,1H),7.44(dd,J=8.9,3.0Hz,1H)。未观察到NH质子。
实例52:N-(2-(乙基氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法使用中间体18代替(4-氟-2-甲氧基苯基)甲胺来制备标题化合物。将产物通过SFC(柱:Phenomenex Kinetex联苯21.2x150mm 5μm;流动相:MeOH)、然后通过制备型HPLC(碱,方法6)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(10mg,17%产率)。LCMS:m/z 443.3(M+H)。1H NMR(400MHz,DMSO-d6)δ7.34(ddd,J=8.9,6.7,3.2Hz,2H),7.10-6.86(m,3H),6.29-6.21(m,2H),6.10(s,1H),4.09(d,J=5.6Hz,2H),3.88(d,J=13.6Hz,2H),3.01(dt,J=12.1,6.1Hz,2H),2.87(d,J=27.5Hz,7H),1.75(td,J=12.6,4.0Hz,2H),1.56(d,J=12.8Hz,2H),1.17(t,J=7.1Hz,3H)。
实例53:N-(苯并[d][1,3]二氧杂环戊烯-4-基甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别使用苯并[d][1,3]二氧杂环戊烯-4-基甲胺和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 429.9(M+H)。
实例54:6',8'-二氟-N-(4-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别使用4-(氨基甲基)苯酚和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z402.1(M+H)。
实例55:6'-氟-N-(4-氟-3-(甲基磺酰胺基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
向实例27(17mg,0.041mmol)在DCM(300μL)中的搅拌溶液中添加吡啶(3.32μl,0.041mmol)和甲磺酰氯(3.24μl,0.041mmol)。将反应在50℃下加热2h。将材料通过反相HPLC(碱,方法2)纯化以得到呈黄色固体的标题化合物(8mg,39.2%产率)。LCMS:m/z 493.1(M+H)。1H NMR(400MHz,甲醇-d4)δ7.33(dd,J=8.6,3.2Hz,2H),7.15(ddd,J=9.3,8.0,3.2Hz,1H),6.99(dd,J=7.9,1.5Hz,2H),6.85(dd,J=9.3,4.0Hz,1H),4.22(s,2H),3.87(d,J=14.0Hz,2H),3.02-2.93(m,3H),2.87(s,3H),2.86(s,3H),2.84(s,1H),1.87(td,J=13.1,4.8Hz,2H),1.62(d,J=12.2Hz,2H)。
实例56:N-(4-氨基-3-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体4代替中间体1来制备标题化合物。中间体2是TFA盐。将产物通过硅胶色谱法(MeOH/DCM)纯化,然后在水/乙腈(95/5v/v)中重结晶以给出呈结晶黄色固体的标题化合物(331mg,35%产率)。LCMS:m/z 401.2(M+H)。1H NMR(400MHz,DMSO-d6)δ7.27-7.17(m,2H),6.96(t,J=5.8Hz,1H),6.94-6.82(m,2H),6.80(s,1H),6.76(dd,J=8.1,1.9Hz,1H),6.67(dd,J=9.3,8.1Hz,1H),4.97(s,2H),4.06(d,J=5.5Hz,2H),3.51-3.26(m,4H),2.60(s,2H),1.66-1.47(m,4H)。
实例57:N-(4-氨基-2,3-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体20代替中间体1来制备标题化合物。中间体2是TFA盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(25mg,37%产率)。LCMS:m/z 419.3(M+H);1H NMR(400MHz,DMSO-d6)δ7.30-7.15(m,2H),6.99-6.86(m,2H),6.85-6.72(m,2H),6.49(td,J=8.4,1.7Hz,1H),5.34(s,2H),4.12(d,J=5.3Hz,2H),3.49-3.27(m,4H),2.60(s,2H),1.65-1.45(m,4H)。
实例58:6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
步骤1:2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯甲酸甲酯的合成
通过与实例1类似的方法分别使用中间体21和3代替中间体1和2来制备标题化合物。将粗残余物通过硅胶色谱法(EtOAc/庚烷=3/7)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(1.2g,30%产率)。LCMS:m/z 458.5(M+H)。
步骤2:2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯甲酸的合成
向在THF(10mL)和水(5mL)中的步骤1的产物(1.2g,2.62mmol)中添加6N NaOH溶液(2mL,12mmol)。将反应混合物在室温下搅拌3h。在真空中浓缩挥发物。在搅拌下向粗残余物中逐滴添加3N HCl水溶液。从溶液中沉淀出产物,过滤,并且在真空烘箱中干燥16h以获得标题化合物。(0.3g,27%产率)。LCMS m/z 444.3(M+H);1H NMR(300MHz,DMSO-d6)δ7.76-7.73(1H,m),7.49(1H,m),7.37-7.20(4H,m),6.97-6.92(1H,m),4.23-4.21(2H,d),3.91-3.87(2H,d),2.91(3H,s),2.84(3H,s),1.80-1.73(2H,m),1.58-1.54(2H,d)。
步骤3:6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例32步骤2类似的方法来制备标题化合物。将粗残余物通过硅胶色谱法(MeOH/DCM=1:9)、然后通过制备型反相HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(45mg,66%产率)。HRMS:m/z 501.2364(M+H);1H NMR(400MHz,甲醇-d4)δ7.69(dd,J=7.0,2.3Hz,1H),7.51-7.41(m,2H),7.32-7.22(m,1H),7.22-7.12(m,1H),6.97(dd,J=9.4,4.0Hz,1H),4.37(s,2H),4.02-3.93(m,2H),3.58(s,4H),3.40(s,3H),3.14-3.04(m,2H),2.99-2.93(m,5H),2.03-1.90(m,2H),1.78-1.70(m,2H)。
实例59:6'-氟-N-((2-甲基呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体1的(2-甲基呋喃-3-基)甲胺来制备标题化合物。中间体2是游离碱。将粗残余物通过制备型反相HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(656mg,48%产率)。HRMS:m/z 372.1728(M+H);1H NMR(400MHz,甲醇-d4)δ7.25-7.10(m,2H),7.06-6.96(m,1H),6.74(dd,J=9.1,4.2Hz,1H),6.19(d,J=1.9Hz,1H),4.00(s,2H),3.44-3.29(m,4H),2.54(s,2H),2.14(s,3H),1.70-1.52(m,4H)。
实例60:6'-氟-N-(4-氟-3-((3-羟基环丁基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例32步骤2类似的方法使用3-氨基环丁醇代替(4-(氨基甲基)苯基)甲醇来制备标题化合物。将粗残余物通过制备型反相HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(88mg,98%产率)。HRMS:m/z 499.2166(M+H);1H NMR(400MHz,甲醇-d4)δ7.50-7.42(m,1H),7.36-7.28(m,1H),7.20(dd,J=9.1,3.1Hz,1H),7.08-6.98(m,2H),6.80-6.72(m,1H),4.24(s,2H),3.98-3.85(m,2H),3.47-3.37(m,4H),2.72-2.59(m,2H),2.57(s,2H),1.90-1.78(m,2H),1.72-1.55(m,4H)。
实例61:2-氟-5-((6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯甲酸甲酯
通过与实例2类似的方法分别使用中间体21和2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过反相HPLC(碱,方法4)纯化以得到标题化合物(158mg,17.22%产率)。LCMS:m/z 444.1(M+H)。1H NMR(400MHz,甲醇-d4)δ7.86(dd,J=6.9,2.4Hz,1H),7.57-7.50(m,1H),7.32(dd,J=9.0,3.1Hz,1H),7.21-7.11(m,2H),6.87(dd,J=9.1,4.3Hz,1H),4.36(s,2H),3.92(s,3H),3.59-3.50(m,4H),2.68(s,2H),1.81-1.68(m,4H)。
实例62:N-(3-(2-氨基-2-氧代乙基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法使用中间体22代替(4-氟-2-甲氧基苯基)甲胺来制备标题化合物。将粗残余物通过制备型HPLC纯化以在冻干后给出呈蓬松黄色固体的标题化合物(180mg,75%产率)。LCMS:m/z 457.3(M+H);1H NMR(300MHz,DMSO-d6)δ7.48(1H,s),7.37-7.32(2H,m),7.18-7.05(4H,m),7.03-6.94(2H,m),4.18-4.17(2H,d),3.92-3.88(2H,m),3.40(3H,s),2.91(3H,s),2.85(3H,s),1.77-1.74(2H,m),1.58-1.54(2H,m)。
实例63:6',8'-二氟-N-((3-羟基吡啶-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别使用2-(氨基甲基)吡啶-3-酚和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 403.1(M+H)。
实例64:6'-氟-N-(4-氟-3-(甲基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法使用中间体23代替(4-氟-2-甲氧基苯基)甲胺来制备标题化合物。中间体2是游离碱。将粗残余物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(35mg,15%产率)。LCMS:m/z 443.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.67(dd,J=7.1,2.4Hz,1H),7.48-7.39(m,1H),7.31(dd,J=9.0,3.0Hz,1H),7.21-7.06(m,2H),6.92-6.81(m,1H),4.35(s,2H),3.52(t,J=5.7Hz,4H),2.94(s,3H),2.68(s,2H),1.84-1.65(m,4H)。
实例65:N-(4-氨基-3,5-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体24代替中间体1来制备标题化合物。中间体2是TFA盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(18mg,27%产率)。LCMS:m/z 419.3(M+H);1H NMR(400MHz,DMSO-d6)δ7.27-7.16(m,2H),7.03(t,J=5.7Hz,1H),6.90(ddd,J=8.3,4.5,1.3Hz,1H),6.85-6.71(m,3H),5.03(s,2H),4.07(d,J=5.7Hz,2H),3.50-3.25(m,4H),2.61(s,2H),1.66-1.48(m,4H)。
实例66:N-((6-(二甲基氨基)吡啶-2-基)甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别使用6-(氨基甲基)-N,N-二甲基吡啶-2-胺和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 430.3(M+H)。
实例67:6'-氟-N-(4-氟-2-(三氟甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用(4-氟-3-(三氟甲基)苯基)甲胺和中间体2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(5mg,4%产率)。HRMS:m/z 454.1537(M+H);1H NMR(400MHz,甲醇-d4)δ7.57-7.49(m,1H),7.47-7.39(m,1H),7.39-7.32(m,1H),7.30(dd,J=9.0,3.1Hz,1H),7.12(ddd,J=9.2,8.1,3.1Hz,1H),6.90-6.82(m,1H),4.52(s,2H),3.61-3.46(m,4H),2.67(s,2H),1.83-1.67(m,4H)。
实例68:N-(2-氯-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用(2-氯-4-氟苯基)甲胺和中间体2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(5mg,4%产率)。HRMS:m/z420.1313(M+H);1H NMR(400MHz,甲醇-d4)δ7.40-7.27(m,2H),7.21(dd,J=8.6,2.6Hz,1H),7.14(ddd,J=9.2,8.1,3.1Hz,1H),7.06(td,J=8.4,2.6Hz,1H),6.87(dd,J=9.1,4.3Hz,1H),4.41(s,2H),3.62-3.45(m,4H),2.68(s,2H),1.84-1.67(m,4H)。
实例69:N-(3-氨基甲酰基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用3-(氨基甲基)苯甲酰胺和中间体2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(58mg,25%产率)。HRMS:m/z411.1833(M+H);1H NMR(400MHz,甲醇-d4)δ7.81-7.76(m,1H),7.76-7.68(m,1H),7.50-7.44(m,1H),7.44-7.35(m,1H),7.29(dd,J=9.0,3.1Hz,1H),7.12(ddd,J=9.0,8.2,3.1Hz,1H),6.90-6.81(m,1H),4.39(s,2H),3.52(t,J=5.8Hz,4H),2.66(s,2H),1.82-1.65(m,4H)。
实例70:6'-氟-N-(4-氟-3-(2-羟基乙氧基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
步骤1:6'-氟-N-(4-氟-3-(2-甲氧基乙氧基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例2类似的方法分别使用中间体19和中间体2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过反相HPLC(碱,方法2)纯化以给出呈黄色固体的标题化合物(13mg,13%产率)。LCMS:m/z 460.1(M+H)。
步骤2:6'-氟-N-(4-氟-3-(2-羟基乙氧基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例3步骤2类似的方法来制备标题化合物。将产物通过反相HPLC(碱,方法3)纯化以得到呈黄色固体的标题化合物(3.1mg,23%产率)。LCMS:m/z 446.1(M+H);1H NMR(400MHz,MeOH-d4):δ7.30(dd,J=8Hz,1H),7.12(td,J=8Hz,1H),7.05-6.98(m,2H),6.86-6.82(m,2H),4.29(s,2H),4.10(t,J=4Hz,2H),3.88(t,J=4Hz,2H),3.53-3.48(m,4H),2.65(s,2H)1.79-1.66(m,4H)。
实例71:N-(2,4-二氟-5-(2-羟基乙氧基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
步骤1:N-(2,4-二氟-5-(2-甲氧基乙氧基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例2类似的方法分别使用中间体25和中间体2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物不经纯化直接接入下一步骤。LCMS:m/z478.0(M+H)。
步骤2:1'-乙基-6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例19类似的方法来制备标题化合物。将产物通过制备型HPLC(柱:GeminiNX 5μC18 21.2mm x 150mm;流动相:在水/ACN中的0.05%氢氧化铵)纯化以给出呈黄色固体的标题化合物(18mg,22%产率)。LCMS:m/z 464(M+H)。1H NMR(400MHz,氯仿-d)δ7.47-7.44(1H,m)7.25-7.05(2H,m),6.86-6.81(1H,t),6.64-6.61(1H,m),4.89-4.86(2H,br s),4.38-4.37(2H,d),4.31(1H,s),3.96-3.93(2H,br),3.40-3.39(3H,m),2.68(1H,s),2.13(1H,t),1.83-1.74(4H,m)。
实例72:6'-氟-N-((5-甲基-1H-吡唑-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用(5-甲基-1H-吡唑-3-基)甲胺代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(21mg,31%产率)。LCMS:m/z 372.3(M+H)。1H NMR(400MHz,DMSO-d6)δ12.10(s,1H),7.30-7.13(m,2H),6.95-6.83(m,2H),6.80(s,1H),5.83(s,1H),4.12(d,J=5.5Hz,2H),3.51-3.21(m,4H),2.60(s,2H),2.15(s,3H),1.65-1.45(m,4H)。
实例73:N-(3-氨基-4-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用5-(氨基甲基)-2-氟苯胺和中间体26(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过硅胶色谱法(DCM/MeOH=100/0至90/10)、然后通过制备型HPLC(碱,方法4)纯化以给出呈黄色固体的标题化合物(44mg,34%产率)。LCMS:m/z 419.2(M+H);1H NMR(400MHz,DMSO-d6)δ7.44(ddd,J=11.4,8.5,2.9Hz,1H),7.22-7.05(m,1H),7.00(t,J=5.8Hz,1H),6.87(dd,J=11.5,8.2Hz,1H),6.64(dd,J=8.9,2.0Hz,1H),6.48(s,1H),6.38(ddd,J=8.0,4.4,2.1Hz,1H),5.06(s,2H),4.07(d,J=5.6Hz,2H),3.78-3.50(m,2H),3.08(dt,J=13.4,6.3Hz,2H),2.79(s,2H),1.79-1.54(m,4H)。
实例74:6'-氟-4'-氧代-N-(3-氨磺酰基苄基)-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体27和2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过制备型TLC(己烷/EtOAc=20/80)纯化以给出呈黄色固体的标题化合物(60mg,60%产率)。LCMS:m/z 447.05(M+H);1H NMR(400MHz,DMSO-d6)δ:7.67-7.65(2H,d),7.51-7.44(2H,m),7.23-7.19(2H,d),6.91-6.89(1H,m),4.26(2H,s),3.63-3.42(4H,m),2.6(2H,s),1.60-1.55(4H,m)。
实例75:N-(2,4-二氟-3-((2-羟基乙基)氨基)苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
步骤1:N-(2,4-二氟-3-((2-甲氧基乙基)氨基)苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例2类似的方法分别使用中间体28和5代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(11mg,11%产率)。LCMS:m/z 505.3(M+H)。
步骤2:N-(2,4-二氟-3-((2-羟基乙基)氨基)苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例19类似的方法来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(4mg,41%产率)。LCMS:m/z 491.3(M+H)。1H NMR(400MHz,DMSO-d6)δ7.40(dd,J=8.7,3.3Hz,1H),7.23(ddd,J=9.4,7.9,3.3Hz,1H),6.90(dd,J=9.4,4.0Hz,1H),6.86-6.76(m,1H),6.69(td,J=8.2,5.9Hz,1H),4.34(s,2H),4.00(d,J=14.1Hz,2H),3.67(t,J=5.6Hz,2H),3.49-3.37(m,4H),3.08-2.96(m,2H),2.91(s,2H),1.98-1.70(m,4H),1.25(t,J=7.1Hz,3H)。
实例76:N-(4-氨基苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法分别使用4-(氨基甲基)苯胺和中间体3代替中间体1和中间体2来制备标题化合物。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(42mg,32%产率)。LCMS:m/z 419.2(M+Na);1H NMR(400MHz,DMSO-d6)δ7.41-7.29(m,2H),7.01-6.84(m,4H),6.53-6.42(m,2H),4.90(s,2H),4.05(d,J=5.6Hz,2H),3.96-3.83(m,2H),2.95-2.80(m,7H),1.75(td,J=12.8,4.6Hz,2H),1.62-1.48(m,2H)。
实例77:N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
步骤1:N-(2,4-二氟-5-((2-甲氧基乙基)氨基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例2类似的方法分别使用中间体10和2(游离碱)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法3)纯化以给出标题化合物。HRMS:m/z 477.2118(M+H)。
步骤2:N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例3步骤2类似的方法来制备标题化合物。将产物通过制备型SFC(柱:Princeton氨基20x150mm 5μm;流动相:MeOH)纯化以得到呈黄色的标题化合物(22mg,41%产率)。HRMS:m/z 462.1879(M+H);1H NMR(400MHz,甲醇-d4)δ7.29(dd,J=9.0,3.0Hz,1H),7.15-7.08(m,1H),6.88-6.69(m,3H),4.31(s,2H),3.73(t,J=5.7Hz,2H),3.50(h,J=9.5Hz,4H),3.23(t,J=5.7Hz,2H),2.65(s,2H),1.71(tdt,J=13.3,7.4,4.6Hz,4H)。
实例78:6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例19类似的方法来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(8mg,13%产率)。LCMS:m/z 445.3(M+H)。1H NMR(400MHz,MeOH-d4)δ7.29(dd,J=9.0,3.0Hz,1H),7.12(ddd,J=9.0,8.2,3.1Hz,1H),6.94-6.78(m,2H),6.71(dd,J=8.5,2.0Hz,1H),6.52(ddd,J=8.1,4.5,2.1Hz,1H),4.25(s,2H),3.73(t,J=5.7Hz,2H),3.59-3.44(m,5H),3.25(d,J=5.7Hz,2H),2.65(s,2H),1.72(tdt,J=13.3,7.8,4.6Hz,4H)。
实例79:N-(3-氨基甲酰基-4-氟-2-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体29代替中间体1来制备标题化合物。中间体2是HCl盐。将粗材料在制备型TLC板上使用流动相在DCM中的7%甲醇作为洗脱液进行纯化以得到得到标题化合物(65gm,059%产率)。LCMS:m/z 443.9(M+H)。1H NMR(400MHz,DMSO-d6)δ7.93(1H,s),7.65(1H,d),7.24-7.18(3H,m),7.03-6.98(2H,m),6.92-6.89(1H,m),6.80(1H,m),4.18(2H,d),3.44-3.38(4H,m),2.61(2H,s),2.22(3H,s),1.59-1.55(4H,m)
实例80:N-(4-氨基-2,6-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体30代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(14mg,21%产率)。LCMS:m/z 419.3(M+H)。1H NMR(400MHz,DMSO-d6)δ7.28-7.14(m,2H),6.97-6.84(m,1H),6.76(s,1H),6.55(t,J=4.9Hz,1H),6.21-6.07(m,2H),5.60(s,2H),4.08(d,J=4.9Hz,2H),3.44-3.23(m,4H),2.58(s,2H),1.65-1.41(m,4H)。
实例81:N-(3-((2-(二甲基氨基)乙基)氨基甲酰基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例32步骤2类似的方法使用N1,N1-二甲基乙烷-1,2-二胺代替(4-(氨基甲基)苯基)甲醇来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以给出标题化合物(135mg,97%产率)。HRMS:m/z 500.2529(M+H);1H NMR(400MHz,甲醇-d4)δ7.68(dd,J=7.0,2.4Hz,1H),7.43(ddd,J=8.4,4.9,2.4Hz,1H),7.29(dd,J=8.9,3.1Hz,1H),7.18-7.06(m,2H),6.90-6.81(m,1H),4.34(s,2H),3.57-3.44(m,6H),2.66(s,2H),2.57(t,J=6.9Hz,2H),2.31(s,6H),1.82-1.65(m,4H)。
实例82:6'-氟-N-(4-氟-3-((2-羟基乙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例32步骤2类似的方法使用2-氨基乙醇HCl盐代替(4-(氨基甲基)苯基)甲醇来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法4)纯化以给出标题化合物(45mg,81%产率)。HRMS:m/z 487.2182;1H NMR(400MHz,甲醇-d4)δ7.69(dd,J=7.1,2.3Hz,1H),7.49-7.39(m,2H),7.30-7.21(m,1H),7.15(dd,J=10.9,8.4Hz,1H),6.97-6.90(m,1H),4.34(s,2H),3.99-3.91(m,2H),3.70(t,J=5.8Hz,2H),3.51(t,J=5.8Hz,2H),3.13-3.01(m,2H),2.94(s,3H),2.93(s,2H),2.00-1.88(m,2H),1.76-1.68(m,2H)。
实例83:6'-氟-N-(4-氟-3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用(5-(氨基甲基)-2-氟苯基)甲醇和中间体2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(60mg,35.7%产率)。HRMS:m/z416.1780(M+H);1H NMR(400MHz,甲醇-d4)δ7.44-7.36(m,1H),7.30(dd,J=9.0,3.0Hz,1H),7.26-7.18(m,1H),7.18-7.08(m,1H),7.05-6.96(m,1H),6.91-6.82(m,1H),4.65(s,2H),4.33(s,2H),3.60-3.43(m,4H),2.67(s,2H),1.82-1.65(m,4H)。
实例84:N-(3-氨基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体13和2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以给出呈黄色固体的标题化合物(10mg,12%产率)。LCMS:m/z 419.2(M+H);1H NMR(400MHz,DMSO-d6)δ7.29-7.16(m,2H),6.99(t,J=5.7Hz,1H),6.95-6.88(m,1H),6.86-6.74(m,2H),6.53-6.36(m,1H),5.12(s,2H),4.18(d,J=5.4Hz,2H),3.46-3.35(m,4H),2.61(s,2H),1.56(qq,J=7.8,3.8Hz,4H)。
实例85:(E)-1'-(丁-2-烯-1-基)-6'-氟-N-(4-氟苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用(4-氟苯基)甲胺和中间体31代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过制备型HPLC(碱,方法5)纯化以给出呈黄色固体的标题化合物(21mg,21%产率)。LCMS:m/z 440.2(M+H);1H NMR(400MHz,MeOH-d4)δ:7.39(dd,J=8.7,3.2Hz,1H),7.31(dd,J=8.7,5.4Hz,2H),7.20(ddd,J=9.4,7.9,3.3Hz,1H),7.07-6.97(m,2H),6.82(dd,J=9.4,4.0Hz,1H),5.84-5.71(m,1H),5.56(dtd,J=15.3,4.5,1.6Hz,1H),4.32(s,2H),4.05-3.90(m,4H),3.06-2.96(m,2H),2.95(s,2H),1.89(td,J=13.1,4.8Hz,2H),1.78-1.67(m,5H)。
实例86:6'-氟-N-(4-氟-2-((2-羟基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例19类似的方法来制备标题化合物。将产物通过制备型SFC(柱:Princeton氨基20x150mm 5μm;流动相:MeOH)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(10mg,39%产率)。LCMS:m/z 459.2(M+H);1H NMR(400MHz,氯仿-d)δ7.53(dd,J=8.5,3.2Hz,1H),7.17(ddd,J=9.2,7.7,3.2Hz,1H),7.02(t,J=7.2Hz,1H),6.76(dd,J=9.3,4.0Hz,1H),6.42(d,J=18.3Hz,2H),5.01(s,1H),4.35(d,J=4.2Hz,2H),3.94(d,J=4.4Hz,2H),3.81(d,J=13.2Hz,2H),3.30-3.18(m,2H),3.04(t,J=11.5Hz,2H),2.88(s,3H),2.83(s,2H),1.89(td,J=13.1,4.4Hz,2H),1.73(d,J=13.2Hz,2H)。
实例87:N-(4-氨基-3-氯苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体32代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(13mg,19%产率)。LCMS:m/z 439.2(M+Na);1H NMR(400MHz,DMSO-d6)δ7.26-7.17(m,2H),7.07(d,J=1.9Hz,1H),6.98-6.87(m,3H),6.78(s,1H),6.71(d,J=8.2Hz,1H),5.16(s,2H),4.05(d,J=5.6Hz,2H),3.49-3.32(m,4H),2.60(s,2H),1.66-1.47(m,4H)。
实例88:6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例32步骤2类似的方法使用3-氨基丙-2-醇代替(4-(氨基甲基)苯基)甲醇来制备标题化合物。将产物通过反相HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题外消旋体化合物(20mg,44%产率)。LCMS:m/z 501.3(M+H);1H NMR(400MHz,DMSO-d6)δ8.10(td,J=5.9,3.4Hz,1H),7.53(dd,J=7.4,2.2Hz,1H),7.36(qd,J=7.9,4.9Hz,3H),7.25-7.13(m,2H),7.01-6.91(m,1H),4.75(d,J=4.8Hz,1H),4.22(d,J=5.7Hz,2H),3.90(dt,J=13.4,3.4Hz,2H),3.76(p,J=5.8Hz,1H),3.20(t,J=5.9Hz,2H),2.88(d,J=23.4Hz,7H),1.77(dt,J=12.7,6.4Hz,2H),1.57(d,J=12.8Hz,2H),1.07(d,J=6.2Hz,3H)。
实例89:N-(4-氨基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用4-氨基苄基胺代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(23mg,32%产率)。LCMS:m/z 383.4(M+H);1H NMR(400MHz,DMSO-d6)δ7.29-7.14(m,2H),6.97-6.83(m,4H),6.80(s,1H),6.53-6.42(m,2H),4.90(s,2H),4.05(d,J=5.6Hz,2H),3.48-3.27(m,4H),2.60(s,2H),1.65-1.46(m,4H)。
实例90:6'-氟-N-(4-氟-3-((2-(2-氧代吡咯烷-1-基)乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例31类似的方法使用中间体33代替中间体14来制备标题化合物。将产物通过硅胶色谱法(DCM/MeOH)、然后通过反相HPLC(碱,方法4)纯化以给出标题化合物(7mg,5%产率)。LCMS:m/z526.3(M+H)。1H NMR(400MHz,甲醇-d4)δ7.43(dd,J=8.6,3.2Hz,1H),7.28-7.21(m,1H),6.94(dd,J=9.4,4.0Hz,1H),6.86(dd,J=11.7,8.2Hz,1H),6.74(dd,J=8.5,1.9Hz,1H),6.56-6.47(m,1H),4.25(s,2H),4.00-3.89(m,2H),3.54-3.47(m,4H),3.39-3.33(m,2H),3.11-3.01(m,2H),2.93(s,3H),2.92(s,2H),2.34(t,J=8.1Hz,2H),2.04-1.87(m,4H),1.75-1.67(m,2H)。
实例91:N-(2,4-二氟-3-((2-羟基乙基)氨基)苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
步骤1:N-(2,4-二氟-3-((2-甲氧基乙基)氨基)苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例2类似的方法使用中间体28代替(4-氟-2-甲氧基苯基)甲胺来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(30mg,43%产率)。LCMS:m/z 491.3(M+H)。
步骤2:N-(2,4-二氟-3-((2-羟基乙基)氨基)苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例19类似的方法来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(12mg,52%产率)。LCMS:m/z 477.2(M+H);1H NMR(400MHz,DMSO-d6)δ7.40-7.28(m,2H),7.08-6.93(m,2H),6.88(ddd,J=11.7,8.6,1.5Hz,1H),6.57(td,J=8.2,6.1Hz,1H),4.82(dt,J=6.3,3.3Hz,1H),4.73(t,J=5.3Hz,1H),4.19(d,J=5.4Hz,2H),3.90(d,J=13.7Hz,2H),3.50(q,J=5.7Hz,2H),3.27(q,J=6.0Hz,2H),2.88(d,J=23.3Hz,7H),1.77(td,J=12.8,4.5Hz,2H),1.57(d,J=12.9Hz,2H)。
实例92:6'-氟-N-(4-氟-3-(1-羟基乙基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法使用中间体46代替(4-氟-2-甲氧基苯基)甲胺来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法5)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(52mg,41%产率)。LCMS:MS m/z 444.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.50-7.40(m,2H),7.31-7.22(m,1H),7.22-7.15(m,1H),7.02-6.91(m,2H),5.11(q,J=6.5Hz,1H),4.34(s,2H),4.01-3.93(m,2H),3.13-3.03(m,2H),2.96(s,3H),2.94(s,2H),2.01-1.89(m,2H),1.77-1.69(m,2H),1.43(d,J=6.5Hz,3H)。
实例93:N-((4-氯-1-甲基-1H-吡唑-5-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用(4-氯-1-甲基-1H-吡唑-5-基)甲胺代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法3)纯化以在冻干后给出呈白色固体的标题化合物(26mg,39%产率)。LCMS:m/z406.4(M+H);1H NMR(400MHz,DMSO-d6)δ7.44(s,1H),7.26-7.17(m,2H),7.01(t,J=5.1Hz,1H),6.90(ddd,J=8.5,4.5,1.1Hz,1H),6.79(s,1H),4.25(d,J=5.1Hz,2H),3.80(s,3H),3.50-3.26(m,4H),2.60(s,2H),1.65-1.45(m,4H)。
实例94:(R)-6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例32步骤2类似的方法使用(R)-1-氨基丙-2-醇代替(4-(氨基甲基)苯基)甲醇来制备标题化合物。将粗残余物通过制备型反相HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(43mg,71%产率)。LCMS:m/z 501.4(M+H);1H NMR(400MHz,甲醇-d4)δ7.69(dd,J=7.0,2.3Hz,1H),7.51-7.41(m,2H),7.32-7.22(m,1H),7.22-7.12(m,1H),6.97(dd,J=9.4,4.0Hz,1H),4.37(s,2H),4.02-3.93(m,2H),3.58(s,4H),3.40(s,3H),3.14-3.04(m,2H),2.99-2.93(m,5H),2.03-1.90(m,2H),1.78-1.70(m,2H)。
实例95:N-(3-氨基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用5-(氨基甲基)-2-氟苯胺和中间体2(游离碱)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(140mg,37%产率)。HRMS:m/z 401.1785(M+H);1H NMR(400MHz,甲醇-d4)δ7.30(dd,J=9.0,3.0Hz,1H),7.18-7.08(m,1H),6.92-6.82(m,2H),6.77(dd,J=8.6,2.1Hz,1H),6.61-6.53(m,1H),4.23(s,2H),3.50(dq,J=14.4,5.1,4.1Hz,4H),2.67(s,2H),1.82-1.65(m,4H)。
实例96:6'-氟-4'-氧代-N-((2-(三氟甲基)呋喃-3-基)甲基)-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体47代替中间体1来制备标题化合物。中间体2是游离碱。将粗残余物通过制备型反相HPLC(碱,方法2)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(20.8mg,10%产率)。HRMS:m/z 426.1465(M+H);1H NMR(400MHz,甲醇-d4)δ7.63(d,J=1.9Hz,1H),7.32(dd,J=9.1,3.1Hz,1H),7.19-7.09(m,1H),6.87(dd,J=9.0,4.3Hz,1H),6.58(s,1H),4.35(d,J=1.7Hz,2H),3.60-3.44(m,4H),2.68(s,2H),1.83-1.66(m,4H)。
实例97:6'-氟-N-(4-氟-3-((2-羟基-2-甲基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例32步骤2类似的方法使用1-氨基-2-甲基丙-2-醇代替(4-(氨基甲基)苯基)甲醇来制备标题化合物。将产物通过反相HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(15mg,35%产率)。LCMS:m/z 515.3(M+H);1H NMR(400MHz,DMSO-d6)δ7.97(d,J=4.5Hz,1H),7.54(dd,J=7.1,2.4Hz,1H),7.43-7.27(m,3H),7.27-7.12(m,2H),7.04-6.87(m,1H),4.55(s,1H),4.22(d,J=5.6Hz,2H),3.90(d,J=13.4Hz,2H),3.24(d,J=5.9Hz,2H),2.88(d,J=23.5Hz,7H),1.77(td,J=12.7,4.5Hz,2H),1.57(d,J=12.9Hz,2H),1.11(s,6H)。
实例98:N-(4-氨基-2-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用4-(氨基甲基)-3-氟苯胺代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(甲酸,方法3)纯化以在冻干后给出呈黄色固体的标题化合物(17mg,23%产率)。LCMS:m/z 401.4(M+H);1H NMR(400MHz,DMSO-d6)δ7.31-7.14(m,2H),7.02-6.85(m,2H),6.85-6.72(m,2H),6.32(dd,J=8.2,2.2Hz,1H),6.26(dd,J=12.7,2.2Hz,1H),5.22(s,2H),4.09(d,J=5.4Hz,2H),3.52-3.24(m,4H),2.60(s,2H),1.67-1.46(m,4H)。
实例99:6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
向微波小瓶中添加实例95(25mg,0.062mmol)、DMF(5mL)、1-溴-2-甲氧基乙烷(0.029mL,0.31mmol)、KI(51.8mg,0.312mmol)和DIPEA(0.055mL,0.31mmol)。将混合物在微波中在110℃下加热10h。然后将混合物用EtOAc稀释,用饱和碳酸氢钠水溶液洗涤,经Na2SO4干燥,过滤,并且在减压下浓缩。将残余物通过HPLC(碱,方法4)纯化以给出标题目标化合物(8.9mg,30.8%产率)。LCMS:m/z459.2(M+H);1H NMR(400MHz,甲醇-d4)δ7.29(dd,J=9.0,3.0Hz,1H),7.16-7.07(m,1H),6.91-6.82(m,2H),6.71(dd,J=8.5,1.9Hz,1H),6.56-6.49(m,1H),4.25(s,2H),3.59(t,J=5.6Hz,2H),3.55-3.46(m,4H),3.38(s,3H),2.65(s,2H),1.72(dtt,J=13.5,8.6,3.8Hz,4H),1.33(dd,J=6.7,4.8Hz,1H),1.11(d,J=6.6Hz,2H)
实例100:N-(3-((2-环丙基-2-氧代乙基)氨基甲酰基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
在与实例32步骤2类似的方法中制备标题化合物。将产物通过反相HPLC(碱,方法10)纯化以在冻干后给出呈固体的标题化合物(7.3mg,28%产率)。LCMS:m/z 511.2(M+H)。
实例101:6'-氟-N-(4-氟-3-((2,2,2-三氟乙基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例32步骤2类似的方法使用2,2,2-三氟乙胺代替(4-(氨基甲基)苯基)甲醇来制备标题化合物。将产物通过反相HPLC(碱,方法4)纯化以给出呈黄色固体的标题化合物(31mg,36%产率)。LCMS:m/z571.4(M+H);1H NMR(400MHz,DMSO-d6)δ8.94(td,J=6.3,2.0Hz,1H),7.50(dd,J=6.9,2.4Hz,1H),7.42(ddd,J=7.7,5.0,2.3Hz,1H),7.31-7.11(m,4H),6.98-6.86(m,1H),6.79(s,1H),4.23(d,J=5.8Hz,2H),4.08(dddd,J=16.0,9.7,6.1,3.2Hz,2H),3.49-3.32(m,4H),2.61(s,2H),1.58(qdd,J=13.2,9.3,4.4Hz,4H)。
实例102:6'-氟-N-(4-氟-3-(3-甲氧基氮杂环丁烷-1-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体48(44mg,0.209mmol)和2(游离碱)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法5)、然后通过SFC(柱:Princeton DIOL 20x150mm 5μm;流动相:MeOH)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(20mg,20%产率)。LCMS:m/z 470.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.29(dd,J=8.9,3.0Hz,1H),7.12(ddd,J=9.2,8.2,3.1Hz,1H),6.93-6.81(m,2H),6.69-6.61(m,1H),6.50(dd,J=8.8,2.3Hz,1H),4.35-4.26(m,1H),4.24(s,2H),4.20-4.11(m,2H),3.73-3.65(m,2H),3.58-3.41(m,4H),3.32(s,3H),2.65(s,2H),1.81-1.63(m,4H)。
实例103:N-(3-(2-氨基-2-氧代乙基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体22和2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过硅胶色谱法(DCM/MeOH=100/0至85/15)纯化以给出呈黄色固体的标题化合物(27mg,12%产率)。LCMS:m/z 442.9(M+H);1H NMR(400MHz,DMSO-d6)δ:7.49(1H,s),7.24-7.04(6H,m),6.96(1H,s),6.92-6.88(1H,m),6.79(1H,s),4.18-4.12(2H,d),3.44-3.38(5H,m),2.66(2H,s),1.61-1.53(4H,m)。
实例104:N-(4-氨基-2-(三氟甲基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体34代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(甲酸,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(17mg,23%产率)。LCMS:m/z=451.4(M+H)。1H NMR(400MHz,DMSO-d6)δ7.27-7.17(m,2H),7.11(d,J=8.5Hz,1H),6.96-6.87(m,2H),6.87-6.83(m,1H),6.80(s,1H),6.75(dd,J=8.5,2.3Hz,1H),5.38(s,2H),4.24(d,J=5.3Hz,2H),3.50-3.37(m,4H),2.62(s,2H),1.68-1.50(m,4H)。
实例105:6'-氟-N-(4-氟-3-(氧杂环丁烷-3-基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例32步骤2类似的方法使用氧杂环丁烷-3-胺代替(4-(氨基甲基)苯基)甲醇)来制备标题化合物。将粗残余物通过硅胶色谱法(EtOAc/己烷=0/100至50/50)、然后通过制备型反相HPLC(碱,方法3)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(90mg,97%产率)。LCMS:m/z 485.0(M+H);1H NMR(400MHz,甲醇-d4)δ7.64-7.57(m,1H),7.49-7.40(m,1H),7.29(dd,J=8.9,3.1Hz,1H),7.20-7.07(m,2H),6.85(dd,J=9.1,4.3Hz,1H),5.12(ddt,J=8.2,7.4,6.1Hz,1H),4.97-4.90(m,2H),4.68(t,J=6.5Hz,2H),4.34(s,2H),3.58-3.45(m,4H),2.66(s,2H),1.81-1.69(m,4H)。
实例106:N-((3-乙基-5-甲基异噁唑-4-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
在与实例1类似的方法中使用(3-乙基-5-甲基异噁唑-4-基)甲胺代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过反相HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 401.4(M+H)。
实例107:6'-氟-N-(异噁唑-4-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用4-氨基甲基异噁唑.HCl盐代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过反相HPLC(甲酸,方法3)纯化以给出呈黄色固体的标题化合物(22mg,28%产率)。LCMS:m/z 359.4(M+H);1H NMR(400MHz,甲醇-d4)δ8.54(s,1H),8.36(s,1H),7.30(dd,J=12,4Hz,1H),7.15-7.08(m,1H),6.84(dd,J=12,4Hz,1H),4.20(s,2H),3.57-3.39(m,4H),2.65(s,2H),1.79-1.60(m,4H)。
实例108:N-(4-(二氟甲氧基)-3-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别使用(4-(二氟甲氧基)-3-氟苯基)甲胺和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 470.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.23-7.20(m,5H),6.61(s,1H),4.34(s,2H),3.74-3.68(m,2H),3.40-3.33(m,2H),2.81(s,2H),1.83-1.80(m,4H)。
实例109:N-(3-氨基甲酰基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体42和2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过硅胶色谱法(DCM/MeOH=100/0至90/10)、然后通过制备型反相HPLC(柱:Zorbax xdb C18 5μ21.2mm x 150mm;流动相:水/MeCN)纯化以给出呈黄色固体的标题化合物(29mg,20%产率)。LCMS:m/z 446.95(M+H);1H NMR(400MHz,氯仿-d)δ7.48-7.43(2H,m),7.08-7.07(1H,d),6.91(1H,m),6.67-6.63(1H,m),5.94(1H,br,s),5.11(1H,br,s),4.42-4.37(3H,m),3.49-3.48(1H,d),3.41-3.38(4H,m),2.67(2H,s)1.79-1.59(4H,m)。
实例110:N-((2,5-二甲基呋喃-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用(2,5-二甲基呋喃-3-基)甲胺代替中间体1来制备标题化合物。将产物通过反相HPLC(碱,方法5)、然后通过SFC(柱:Princeton DIOL 20x150mm5μM;流动相:MeOH)纯化以给出呈黄色固体的标题化合物(15.6mg,10%产率)。LCMS:m/z384.2(M+H);1H NMR(400MHz,甲醇-d4)δ7.29(dd,J=8.9,3.1Hz,1H),7.11(ddd,J=9.1,8.2,3.1Hz,1H),6.84(dd,J=9.1,4.3Hz,1H),5.86(d,J=1.2Hz,1H),4.03(d,J=4.6Hz,2H),3.50-3.43(m,4H),2.64(s,2H),2.17(d,J=10.8Hz,6H),1.70(qdd,J=13.3,9.1,4.8Hz,4H)。
实例111:N-(4-氨基-2-氯苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体35代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(28mg,41%产率)。LCMS:m/z 439.3(M+Na);1H NMR(400MHz,DMSO-d6)δ7.26-7.17(m,2H),7.00-6.88(m,2H),6.84(t,J=5.5Hz,1H),6.79(s,1H),6.58(d,J=2.2Hz,1H),6.47(dd,J=8.3,2.2Hz,1H),5.21(s,2H),4.14(d,J=5.5Hz,2H),3.51-3.34(m,4H),2.61(s,2H),1.69-1.48(m,4H)。
实例112:N-(4-氨基-3-(三氟甲基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体36代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(8mg,13%产率)。LCMS:m/z 489.3(M+39);1H NMR(400MHz,DMSO-d6)δ7.27-7.16(m,2H),7.04-6.86(m,4H),6.79(s,1H),6.74(d,J=8.2Hz,1H),5.19(s,2H),4.07(d,J=5.6Hz,2H),3.50-3.32(m,4H),2.59(s,2H),1.67-1.46(m,4H)。
实例113:6'-氟-N-(4-氟-3-((2-(2-氧代吡咯烷-1-基)乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例44类似的方法使用吗啉代替N-Me哌嗪来制备标题化合物。将产物通过反相HPLC(碱,方法5)纯化以给出呈黄色固体的标题化合物(9mg)。LCMS:m/z 584.4(M+H);1H NMR(400MHz,甲醇-d4)δ7.42(dd,J=8.6,3.2Hz,1H),7.27-7.21(m,1H),6.93(dd,J=9.4,4.0Hz,1H),6.85(dd,J=11.7,8.2Hz,1H),6.76(dd,J=8.4,1.8Hz,1H),6.54-6.46(m,1H),4.24(s,2H),3.99-3.90(m,2H),3.71-3.59(m,8H),3.27(s,2H),3.10-3.01(m,2H),2.93(s,3H),2.92(s,2H),1.92(td,J=12.9,4.7Hz,2H),1.74-1.66(m,2H),1.35(s,6H)。
实例114:6'-氟-N-(4-氟-2-甲氧基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用(4-氟-2-甲氧基苯基)甲胺和中间体2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法5)、然后通过SFC(柱:Princeton DIOL 20x150mm 5μm;流动相:MeOH)纯化以在冻干后给出呈黄色固体的标题化合物(15mg,15%产率)。LCMS:MS m/z 416.2(M+H);1H NMR(400MHz,甲醇-d4)δ7.30(dd,J=9.0,3.0Hz,1H),7.21-7.08(m,2H),6.86(dd,J=9.1,4.3Hz,1H),6.73(dd,J=11.1,2.4Hz,1H),6.61(td,J=8.4,2.4Hz,1H),4.30(s,2H),3.84(s,3H),3.56-3.46(m,4H),2.66(s,2H),1.72(tdt,J=13.2,7.7,4.6Hz,4H)。
实例115:6',8'-二氟-N-((2-甲氧基吡啶-4-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别使用(2-甲氧基吡啶-4-基)甲胺和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 417.1(M+H)。
实例116:N-(4-氨基-2-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体37代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(28mg,38%产率)。LCMS:m/z 397.4(M+H);1H NMR(400MHz,DMSO-d6)δ7.29-7.14(m,2H),6.95-6.87(m,1H),6.85(d,J=7.9Hz,1H),6.78(s,1H),6.64(t,J=5.3Hz,1H),6.39-6.28(m,2H),4.81(s,2H),4.05(d,J=5.3Hz,2H),3.50-3.25(m,4H),2.60(s,2H),2.13(s,3H),1.68-1.44(m,4H)。
实例117:(S)-6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例32步骤2类似的方法使用来自实例58步骤2的产物和(S)-1-氨基丙-2-醇来制备标题化合物。将产物通过反相HPLC(碱,方法3)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(20mg,34%产率)。LCMS:m/z 501.4(M+H);1H NMR(400MHz,DMSO-d6)δ8.10(td,J=5.6,3.3Hz,1H),7.53(dd,J=7.2,2.4Hz,1H),7.46-7.29(m,3H),7.28-7.12(m,2H),7.04-6.88(m,1H),4.74(d,J=4.8Hz,1H),4.22(d,J=5.6Hz,2H),3.90(dt,J=13.5,3.8Hz,2H),3.76(qd,J=6.2,4.9Hz,1H),3.20(t,J=5.9Hz,2H),2.88(d,J=23.3Hz,7H),1.77(td,J=12.8,4.5Hz,2H),1.57(d,J=12.7Hz,2H),1.07(d,J=6.3Hz,3H)。
实例118:6'-氟-N-(异噁唑-3-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用3-氨基甲基异噁唑.HCl盐代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(EtOAc)、然后通过反相HPLC(TFA,方法3)纯化。浓缩后,将产物吸收在MeOH中并且通过小柱以除去TFA以给出呈黄色固体的标题化合物(45mg,56%产率)。LCMS:m/z 359.4(M+H);1H NMR(400MHz,甲醇-d4)δ8.56(d,J=1.6Hz,1H),7.29(dd,J=12,4Hz,1H),7.17-7.07(m,1H),6.85(dd,J=12,4Hz,1H),6.42(d,J=1.6Hz,1H),4.42(s,2H),3.58-3.43(m,4H),2.65(s,2H),1.80-1.65(m,4H)。
实例119:N-(4-氨基-3-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用中间体38代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法3)纯化以在冻干后给出呈黄色固体的标题化合物(5mg,7%产率)。LCMS:m/z 419.3(M+Na);1H NMR(400MHz,DMSO-d6)δ7.27-7.16(m,2H),6.95-6.86(m,1H),6.86-6.72(m,4H),6.51(d,J=7.9Hz,1H),4.65(s,2H),4.03(d,J=5.6Hz,2H),3.48-3.33(m,4H),2.59(s,2H),2.02(s,3H),1.66-1.46(m,4H)。
实例120:N-((1H-吲哚-6-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用6-(氨基甲基)吲哚代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法4)纯化以在冻干后给出呈黄色固体的标题化合物(32mg,33%产率)。LCMS:m/z 407.4(M+H);1HNMR(400MHz,DMSO-d6)δ11.00(s,1H),7.43(d,J=8.1Hz,1H),7.31-7.17(m,4H),7.08(t,J=5.7Hz,1H),6.96-6.87(m,2H),6.81(s,1H),6.39-6.31(m,1H),4.31(d,J=5.7Hz,2H),3.56-3.26(m,4H),2.61(s,2H),1.67-1.46(m,4H)。
实例121:6'-氟-N-(4-氟-3-(((2-甲基噁唑-5-基)甲基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
在与实例32步骤2类似的方法中制备标题化合物。将产物通过反相HPLC(碱,方法10)纯化以在冻干后给出呈固体的标题化合物(7.5mg,28%产率)。LCMS:m/z 524.2(M+H)。
实例122:(E)-6'-氟-N-(4-氟-3-((4-羟基丁-2-烯-1-基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
在与实例32步骤2类似的方法中制备标题化合物。将产物通过反相HPLC(碱,方法10)纯化以在冻干后给出呈固体的标题化合物(12.1mg,48%产率)。LCMS:m/z 499.2(M+H)。
实例123:6',8'-二氟-N-((5-甲基噻吩-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别使用(5-甲基噻吩-2-基)甲胺和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 406.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.24-7.15(m,2H),7.15(dd,J=4Hz,1H),6.57(dd,J=4Hz,1.2Hz,1H),4.41(s,2H),3.70-3.64(m,2H),3.37-3.33(m,2H),2.80(s,2H),2.42(s,3H),1.84-1.74(m,4H)。
实例124:6'-氟-N-(异噁唑-5-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用异噁唑-5-基甲胺代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过HPLC(甲酸,方法3)纯化以给出呈黄色固体的标题化合物(65mg,66%产率)。LCMS:m/z359.5(M+H);1H NMR(400MHz,甲醇-d4)δ8.28(br s,1H),7.29(dd,J=8,4Hz,1H),7.19-7.06(m,1H),6.85(dd,J=8,4Hz,1H),6.24(br s,1H),4.47(s,2H),3.60-3.40(m,4H),2.66(s,2H),1.84-1.63(m,4H)。
实例125:6',8'-二氟-N-((6-氟吡啶-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别使用(6-氟吡啶-3-基)甲胺和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 405.2(M+H)。
实例126:N-(5-氨基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体49和2(游离碱)代替(5-(氨基甲基)-2,4-二氟苯胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(甲酸,方法4)、然后通过SFC(柱:Princeton DEAP20x150mm 5μm;流动相:MeOH)纯化以在冻干后给出呈黄色固体的标题化合物(33mg,1%产率)。HRMS:m/z 419.1689(M+H);1H NMR(400MHz,甲醇-d4)δ7.31(dd,J=9.0,3.1Hz,1H),7.19-7.08(m,1H),6.91-6.77(m,3H),4.30(s,2H),3.60-3.42(m,4H),2.67(s,2H),1.73(tdt,J=13.2,7.6,4.4Hz,4H)。
实例127:6'-氟-N-((5-甲基-2-(三氟甲基)呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用(5-甲基-2-(三氟甲基)呋喃-3-基)甲胺代替中间体1来制备标题化合物。将产物通过HPLC(碱,方法5)纯化以给出呈黄色固体的标题化合物(48mg,39%产率)。LCMS:m/z 440.2(M+H);1H NMR(400MHz,甲醇-d4)δ7.29(dd,J=9.0,3.1Hz,1H),7.11(ddd,J=9.2,8.1,3.1Hz,1H),6.85(dd,J=9.1,4.3Hz,1H),6.15(d,J=1.4Hz,1H),4.27(q,J=1.6Hz,2H),3.54-3.43(m,4H),2.65(s,2H),2.29(t,J=1.1Hz,3H),1.80-1.64(m,4H)。
实例128:6'-氟-N-(4-氟-3-(丙-2-炔-1-基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
在与实例32步骤2类似的方法中制备标题化合物。将产物通过反相HPLC(碱,方法10)纯化以在冻干后给出呈固体的标题化合物(3.9mg,16%产率)。LCMS:m/z 467.2(M+H)。
实例129:6',8'-二氟-N-(3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别使用(3-(氨基甲基)苯基)甲醇和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 416.0(M+H)。
实例130:N-(3-(1H-咪唑-2-基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用(3-(1H-咪唑-2-基)苯基)甲胺代替中间体1来制备标题化合物。中间体2是游离碱。将粗残余物通过制备型反相HPLC(碱,方法3)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(44mg,3%产率)。HRMS:m/z 372.1728(M+H);1H NMR(400MHz,甲醇-d4)δ7.80-7.76(m,1H),7.71(dt,J=7.7,1.5Hz,1H),7.40(t,J=7.7Hz,1H),7.35-7.26(m,2H),7.17-7.07(m,3H),6.85(dd,J=9.1,4.2Hz,1H),4.41(s,2H),3.61-3.48(m,4H),2.66(s,2H),1.83-1.66(m,4H)。
实例131:6'-氟-N-(4-氟-3-(甲基磺酰胺基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体39和中间体2代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过反相HPLC(碱,方法2)纯化以给出呈黄色固体的标题化合物(23.5mg,21%产率)。LCMS:m/z 479.3(M+H);1H NMR(400MHz,甲醇-d4)δ7.44(d,J=8Hz,1H),7.30(dd,J=8Hz,1H),7.15-7.09(m,3H),6.85(dd,J=4Hz,1H),4.32(s,2H),3.51(t,J=8Hz,4H),2.99(s,3H),2.68(s,2H),1.79-1.70(m,4H)。
实例132:6',8'-二氟-N-(4-氟-3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用(5-(氨基甲基)-2-氟苯基)甲醇HCl盐和中间体26(HCl盐)代替中间体1和2来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以给出呈黄色蓬松固体的标题化合物(85mg,40%产率)。HRMS:m/z 434.1700(M+H);1H NMR(400MHz,甲醇-d4)δ7.40(dd,J=7.1,2.3Hz,1H),7.26-7.18(m,2H),7.18-7.09(m,1H),6.99(dd,J=10.0,8.3Hz,1H),4.65(s,2H),4.33(s,2H),3.73-3.63(m,2H),3.40-3.32(m,2H),2.79(s,2H),1.86-1.72(m,4H)。
实例133:N-(3-(环丙烷磺酰胺基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
向实例95(35mg,0.087mmol)在THF(874μL)中的搅拌溶液中添加K2CO3(18.12mg,0.131mmol),然后添加环丙烷磺酰氯(8.9μL,0.087mmol)。将反应混合物在室温下搅拌。3h后,添加另外的环丙烷磺酰氯(26.7μL,0.261mmol)和K2CO3(54.36mg,0.393mmol)。过夜揭示出未消耗SM,因此然后将反应过滤以除去K2CO3,浓缩并且在DCM:吡啶(900μL,1:1v/v比率)中重构。将反应加热至50℃并且允许搅拌5h。将材料浓缩至胶状油状物,重悬在DMSO中并且通过HPLC(碱,方法2)、然后通过SFC(柱:Phenomenex Kinetex联苯,21.2x150mm 5μm;流动相:MeOH)纯化以得到呈黄色固体的标题化合物。(7.7mg,17%产率)。LCMS:m/z 503.1(M-H);1H NMR(400MHz,甲醇-d4)δ7.46(d,J=8.2Hz,1H),7.29(dd,J=9.0,3.0Hz,1H),7.15-7.09(m,3H),6.85(dd,J=9.1,4.3Hz,1H),4.32(s,2H),3.52(t,J=5.7Hz,5H),2.68(s,2H),2.57(ddd,J=12.9,8.0,4.8Hz,1H),1.75(h,J=8.0,7.5Hz,4H),1.05-0.99(m,2H),0.99-0.89(m,2H)。
实例134:6'-氟-N-((3-甲基-1,2,4-噁二唑-5-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用(3-甲基-1,2,4-噁二唑-5-基)甲基胺盐酸盐代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(甲酸,方法3)纯化以在冻干后给出呈黄色固体的标题化合物(32mg,36%产率)。LCMS:m/z 374.4(M+H);1H NMR(400MHz,DMSO-d6)δ7.39(t,J=5.5Hz,1H),7.27-7.17(m,2H),6.91(ddd,J=8.4,4.5,1.2Hz,1H),6.83(s,1H),4.41(d,J=5.5Hz,2H),3.53-3.21(m,4H),2.61(s,2H),2.30(s,3H),1.72-1.47(m,4H)。
实例135:6'-氟-N-(4-氟-3-(1-羟基乙基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体45和2(游离碱)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(65mg,48%产率)。LCMS:m/z 412.3(M-OH);1H NMR(400MHz,甲醇-d4)δ7.46(d,J=7.2Hz,1H),7.30(dd,J=9.0,3.0Hz,1H),7.21-7.08(m,2H),7.02-6.92(m,1H),6.86(dd,J=9.1,4.3Hz,1H),5.11(q,J=6.5Hz,1H),4.34(s,2H),3.59-3.48(m,4H),2.67(s,2H),1.82-1.67(m,4H),1.43(d,J=6.5Hz,3H)。
实例136:N-((6-氨基吡啶-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用5-(氨基甲基)吡啶-2-胺代替中间体1来制备标题化合物。中间体2是游离碱。将粗残余物通过制备型反相HPLC(碱,方法2)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(75mg,62%产率)。LCMS:m/z 384.2(M+H);1H NMR(400MHz,甲醇-d4)δ7.81(d,J=2.3Hz,1H),7.43(dd,J=8.7,2.4Hz,1H),7.29(dd,J=9.0,3.1Hz,1H),7.16-7.06(m,1H),6.84(dd,J=9.1,4.3Hz,1H),6.54(d,J=8.5Hz,1H),4.17(s,2H),3.56-3.38(m,4H),2.64(s,2H),1.81-1.62(m,4H)。
实例137:N-(2-氨基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用2-(氨基甲基)-5-氟苯胺和中间体2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过SFC(柱:Princeton DEAP 20x150mm 5μm;流动相:MeOH)纯化以在真空中浓缩后给出呈黄色固体的标题化合物(29mg,9%产率)。LCMS:m/z 401.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.46(d,J=7.2Hz,1H),7.30(dd,J=9.0,3.0Hz,1H),7.21-7.08(m,2H),7.02-6.92(m,1H),6.86(dd,J=9.1,4.3Hz,1H),5.11(q,J=6.5Hz,1H),4.34(s,2H),3.59-3.48(m,4H),2.67(s,2H),1.82-1.67(m,4H),1.43(d,J=6.5Hz,3H)。
实例138:6'-氟-N-(噁唑-4-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用噁唑-4-基甲胺和中间体2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过制备型TLC(DCM/MeOH=90/10)纯化以给出呈黄色固体的标题化合物(85mg,48%产率)。LCMS:m/z 358.95(M+H);1HNMR(400MHz,DMSO-d6)δ:8.24(1H,s),7.78(1H,m),7.21-7.16(2H,m),6.95-6.92(1H,m),6.88-6.85(1H,m),6.76(1H,s),4.08-4.07(2H,d),3.39-3.35(4H,m),2.57(2H,s),1.57-1.50(4H,m)。
实例139:6'-氟-N-(4-氟-3-(2-羟基丙-2-基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法使用中间体43代替(4-氟-2-甲氧基苯基)甲胺来制备标题化合物。将产物通过制备型HPLC(柱:Gemini NX 5μC1821.2mm x 150mm;流动相:在水/ACN中的0.01%氢氧化铵)纯化以给出呈黄色固体的标题化合物(35mg,19%产率)。LCMS:m/z 458.1(M+H-18);1H NMR(400MHz,MeOH-d)δ:7.54-7.52(1H,m),7.42-7.39(1H,m),7.23-7.26(1H,m),7.14-(1H,m),6.96-6.91(2H,m),4.31-4.30(2H,m),3.95-3.92(2H,m),3.07-3.01(2H,t),3.04-2.91(5H,m),1.92-1.97(2H,m),1.71-1.53(2H,d),1.68-1.53(6H,s)。
实例140:3-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)-2,2-二甲基丙酸
步骤1:3-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)-2,2-二甲基丙酸甲酯的合成
将化合物实例27(153mg,0.369mmol)、中间体40(粗材料)和NaBH(OAc)3(120mg,0.566mmol)在DCM(5mL)中的混合物在室温下搅拌24h,分配在DCM与NH4Cl水溶液之间。将合并的有机萃取物经MgSO4干燥,浓缩并且通过硅胶柱色谱法(EtOAc)纯化以给出标题化合物。LCMS:m/z 529.3(M+H)。
步骤2:3-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)-2,2-二甲基丙酸的合成
将KOH水溶液(KOH 150mg,2.67mmol,溶解在2mL水中)添加到步骤1的产物在甲醇(2mL)中的溶液中。将混合物在60℃下加热2h,冷却至室温,并且分配在EtOAc与1M HCl水溶液之间。将合并的有机萃取物经MgSO4干燥,浓缩并且通过反相HPLC(甲酸,方法5)纯化以给出呈黄色固体的标题化合物(17mg,9%产率,经2步骤)。LCMS:m/z 515.4(M+H);1H NMR(400MHz,甲醇-d4)δ7.42(dd,J=8.6,3.2Hz,1H),7.27-7.21(m,1H),6.93(dd,J=9.4,4.0Hz,1H),6.85(dd,J=11.7,8.2Hz,1H),6.78(dd,J=8.4,1.6Hz,1H),6.53-6.46(m,1H),4.24(s,2H),4.00-3.90(m,2H),3.28(s,2H),3.11-2.99(m,2H),2.93(s,3H),2.92(s,2H),1.91(td,J=12.5,4.2Hz,2H),1.76-1.65(m,2H),1.24(s,6H)。
实例141:N-(苯并[c][1,2,5]噁二唑-4-基甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体50和2(HCl盐)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC纯化以在冻干后给出呈黄色固体的标题化合物(18mg,12%产率)。LCMS:m/z 410.0(M+H);1H NMR(300MHz,CDCl3)δ7.467.92-7.89(1H,d),7.62-7.51(1H,m),7.34-7.20(4H,m),6.94-6.90(1H,m),6.83(1H,s),4.61-4.59(2H,d),3.51-3.34(4H,m),1.61(4H,m)
实例142:N-(3-氨基甲酰基-4-氟苄基)-6'-氟-8'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体6和44代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过制备型TLC(DCM/MeOH=90/10)纯化以给出呈黄色固体的标题化合物(18mg,10%产率)。LCMS:m/z 442.95(M+H);1H NMR(400MHz,DMSO-d6)δ:7.65(bs,1H),7.56-7.54(m,1H),7.37(m,1H),7.22-7.10(m,3H),5.52(m,1H),4.22-4.21(d,2H),3.65-3.63(m,1H),3.12(m,1H),2.72(s,1H),2.17(s,2H),1.71-1.66(m,3H)。
实例143:6'-氟-N-(4-氟-3-(丙基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例32步骤2类似的方法使用丙胺代替(4-(氨基甲基)苯基)甲醇来制备标题化合物。将产物通过反相HPLC(碱,方法4)纯化以给出呈黄色固体的标题化合物(33mg,41%产率)。LCMS:m/z 471.3(M+H);1H NMR(400MHz,DMSO-d6)δ8.25(q,J=5.2Hz,1H),7.47(dd,J=6.9,2.3Hz,1H),7.36(ddd,J=7.6,4.9,2.4Hz,1H),7.31-7.11(m,4H),6.98-6.86(m,1H),6.79(s,1H),4.21(d,J=5.7Hz,2H),3.49-3.33(m,4H),3.20(q,J=6.9Hz,2H),2.61(s,2H),1.67-1.42(m,6H),0.89(t,J=7.4Hz,3H)。
实例144:N-(3-(1H-1,2,4-三唑-1-基)苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别(3-(1H-1,2,4-三唑-1-基)苯基)甲胺和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 453.2(M+H)。
实例145:6'-氟-N-((1-甲基-1H-吡唑-4-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法使用(1-甲基-1H-吡唑-4-基)甲基胺代替中间体1来制备标题化合物。中间体2是HCl盐。将产物通过硅胶色谱法(MeOH/DCM)、然后通过反相HPLC(碱,方法3)纯化以在冻干后给出呈白色固体的标题化合物(26mg,39%产率)。LCMS:m/z 372.4(M+H);1H NMR(400MHz,DMSO-d6)δ7.49(s,1H),7.26(s,1H),7.25-7.18(m,2H),6.95-6.86(m,1H),6.86-6.75(m,2H),4.02(d,J=5.4Hz,2H),3.76(s,3H),3.49-3.21(m,4H),2.60(s,2H),1.65-1.42(m,4H)。
实例146:6'-氟-N-(4-氟-3-(((2-羟基乙基)氨基)甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
步骤1:6'-氟-N-(4-氟-3-((2-甲氧基乙氧基)甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例2类似的方法分别使用中间体41和中间体2代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将产物通过反相HPLC(碱,方法4)纯化以给出呈黄色固体的标题化合物(38mg,18%产率)。LCMS:m/z 474.2(M+H)。
步骤2:N-(3-(溴甲基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
通过与实例70步骤2类似的方法来制备标题化合物。将产物通过反相HPLC(碱,方法5)纯化以给出呈黄色固体的标题化合物(38mg,99%产率)。LCMS:m/z 479.2(M+H)。
步骤3:6'-氟-N-(4-氟-3-(((2-羟基乙基)氨基)甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺的合成
向步骤2的产物(38mg,0.079mmol)在乙腈(397μL)中的溶液中添加乙醇胺(14μL,0.24mmol)。将反应混合物在室温下搅拌3h。将反应用盐水淬灭并且用DCM(2x5mL)萃取。将有机层经硫酸钠干燥并且在减压下浓缩。然后将残余物通过HPLC(碱,方法5)纯化以得到呈白色固体的标题化合物(15mg,40.8%产率)。LCMS:m/z 459.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.28-7.21(m,2H),7.16(ddd,J=7.5,5.0,2.3Hz,1H),7.05(ddd,J=9.0,8.2,3.1Hz,1H),6.96(dd,J=9.9,8.5Hz,1H),6.78(dd,J=9.1,4.3Hz,1H),4.25(s,2H),3.77(s,2H),3.64-3.58(m,2H),3.49-3.38(m,4H),2.67(t,J=5.5Hz,2H),2.59(s,2H),1.75-1.58(m,4H)。
实例147:6'-氟-N-(4-氟-3-(氨磺酰基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例2类似的方法分别使用中间体51和中间体2(游离碱)代替(4-氟-2-甲氧基苯基)甲胺和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法4)纯化以在真空中浓缩后给出呈黄色固体的标题化合物(85mg,34%产率)。LCMS:m/z 479.1(M+H);1H NMR(400MHz,甲醇-d4)δ7.51-7.38(m,1H),7.34-7.26(m,2H),7.18-7.05(m,2H),6.94-6.79(m,1H),4.40(s,2H),4.33(s,2H),3.56-3.46(m,4H),2.69(s,2H),1.79-1.70(m,4H)。
实例148:3-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)丙酸
步骤1:3-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)丙酸乙酯的合成
将实例27(110mg,0.265mmol)、3-溴丙酸乙酯(250mg,1.381mmol)和碳酸钾(120mg,0.868mmol)在DMF(3mL)中的混合物在90℃下加热16h,冷却至室温并且分配在EtOAc与盐水之间。将合并的有机萃取物经MgSO4干燥并且浓缩。将残余粗产物直接用于下一步骤。LCMS:m/z 515.4(M+H)。
步骤2:3-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)丙酸的合成
将氢氧化钾(520mg,9.27mmol)在水(2mL)中的溶液添加到步骤1的产物在MeOH(2mL)中的溶液中。将混合物在室温下搅拌30min,并且在真空中除去大部分MeOH。将粗反应混合物分配在EtOAc与0.5M HCl水溶液之间。将合并的有机萃取物经MgSO4干燥,浓缩并且通过反相HPLC(甲酸,方法4)纯化以给出呈黄色固体的标题化合物(8mg,6%产率,经2步骤)。LCMS:m/z 487.3(M+H);1H NMR(400MHz,甲醇-d4)δ7.45(dd,J=8.7,3.2Hz,1H),7.27-7.25(m,1H),6.96(dd,J=9.4,4.1Hz,1H),6.88(dd,J=11.7,8.2Hz,1H),6.75(dd,J=8.4,2.0Hz,1H),6.59-6.50(m,1H),4.28(s,2H),4.04-3.91(m,2H),3.46(t,J=6.8Hz,2H),3.13-3.04(m,2H),2.96(s,3H),2.95(s,2H),2.62(t,J=6.8Hz,2H),1.95(td,J=13.1,4.6Hz,2H),1.79-1.68(m,2H)。
实例149:(R)-N-(3-(1-氨基-2,2,2-三氟乙基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例1类似的方法分别使用中间体46和中间体3代替中间体1和2来制备标题化合物。将粗残余物通过制备型反相HPLC(碱,方法4)纯化以在冻干后给出呈蓬松黄色固体的标题化合物(94mg,58%产率)。LCMS:m/z 497.3(M+H);1H NMR(400MHz,甲醇-d4)δ7.56-7.50(m,1H),7.44(dd,J=8.7,3.2Hz,1H),7.39-7.30(m,1H),7.30-7.20(m,1H),7.14-7.05(m,1H),6.95(dd,J=9.3,4.0Hz,1H),4.77(q,J=7.6Hz,1H),4.35(s,2H),4.01-3.91(m,2H),3.13-3.01(m,2H),2.95(s,3H),2.94(s,2H),2.00-1.88(m,2H),1.77-1.68(m,2H)。
实例150:N-(4-(二氟甲氧基)苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
使用与实例2类似的方法分别用((4-(二氟甲氧基)苯基)甲胺和中间体26代替(4-氟-2-甲氧基苯基)甲胺)和中间体3来制备标题化合物。将粗残余物通过制备型HPLC(碱,方法10)纯化以给出标题化合物。LCMS:m/z 452.2(M+H);1H NMR(400MHz,甲醇-d4)δ7.34-7.32(d,J=8Hz,2H),7.23-7.21(d,J=8Hz,1H),7.15-7.08(m,3H),6.97(s,1H),4.37-4.34(s,2H),3.73-3.67(m,2H),3.39-3.30(m,2H),2.81(s,2H),1.84-1.77(m,4H)。
实例151a:(R)-6'-氟-N-(4-氟苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
实例151b:(S)-6'-氟-N-(4-氟苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例152和实例153类似的方法使用实例9代替实例40来制备标题化合物。将产物通过制备型手性SFC纯化以得到呈白色固体的实例151a(49mg,21%产率,手性SFC分离中的峰2,保留时间=4.8min)和实例151b(52mg,22%产率,手性SFC分离中的峰1,保留时间=3.1min)。
实例151a:LCMS:m/z 402.3(M+H);1H NMR(400MHz,MeOH-d4)δ7.39-7.23(m,2H),7.13-6.96(m,3H),6.84(td,J=8.6,3.1Hz,1H),6.64(dd,J=9.0,4.5Hz,1H),4.63(dd,J=10.0,5.0Hz,1H),4.33(s,2H),4.02-3.84(m,2H),3.24-3.01(m,2H),2.76(s,3H),2.48(dd,J=13.1,5.1Hz,1H),2.09-1.85(m,2H),1.72-1.37(m,3H)。
实例151b:LCMS:m/z 384.3(M+H-H2O);1H NMR(400MHz,DMSO-d6)δ7.33-7.25(m,2H),7.18-7.09(m,3H),7.04(dd,J=9.4,2.5Hz,1H),6.87(td,J=8.7,3.2Hz,1H),6.54(dd,J=9.0,4.6Hz,1H),5.39(d,J=5.9Hz,1H),4.48(dt,J=10.4,5.2Hz,1H),4.21(d,J=5.7Hz,2H),3.91(d,J=13.7Hz,2H),2.91(dt,J=39.7,11.9Hz,2H),2.67(s,3H),2.48-2.43(m,1H),1.81(dtd,J=57.6,12.7,4.5Hz,2H),1.38(dd,J=64.9,12.8Hz,3H)。
实例151a的手性通过与KARS的共晶结构来确定。
实例152:(R)-6'-氟-N-(4-氟苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺和
实例153:(S)-6'-氟-N-(4-氟苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
在室温下向实例40(80mg,0.208mmol)在(乙醇(5mL)中的搅拌溶液中分批添加硼氢化钠(20mg,0.519mmol)。将反应混合物在室温下搅拌过夜,然后用水(30mL)稀释并且用EtOAc(2×20mL)萃取。蒸发溶剂,并且将获得的残余物通过制备型HPLC(碱,方法4)纯化。将所希望的级分合并并且冻干以给出呈白色固体的(R)和(S)醇的外消旋混合物。然后将外消旋混合物通过手性SFC分离以得到呈白色固体的实例152(17.5mg,21%产率,手性SFC分离中的峰2,保留时间=3.62min)和实例153(8.5mg,10%产率,手性SFC分离中的峰1,保留时间=2.40min)。实例152:LCMS:m/z 370.2(M+H-18);1H NMR(400MHz,DMSO-d6)δ7.27(ddd,J=8.5,5.4,2.4Hz,2H),7.16-7.08(m,3H),6.98(dd,J=9.9,3.0Hz,1H),6.76(td,J=8.7,3.1Hz,1H),6.56(dd,J=8.8,5.0Hz,1H),5.74(s,1H),5.22(d,J=6.2Hz,1H),4.62-4.54(m,1H),4.20(d,J=5.7Hz,2H),3.49-3.35(m,3H),3.33-3.28(m,1H),1.97(dd,J=12.8,5.7Hz,1H),1.61-1.39(m,5H)。实例153:LCMS:m/z 370.2(M+H-18);1H NMR(400MHz,DMSO-d6)δ7.31-7.25(m,2H),7.15-7.09(m,3H),6.98(dd,J=10.0,3.0Hz,1H),6.75(td,J=8.7,3.1Hz,1H),6.56(dd,J=8.8,4.9Hz,1H),5.75(s,1H),5.24(d,J=6.2Hz,1H),4.59(dd,J=8.8,4.5Hz,1H),4.20(d,J=5.6Hz,2H),3.42(q,J=6.4,5.8Hz,3H),3.33(s,1H),1.96(dd,J=12.7,5.9Hz,1H),1.63-1.36(m,5H)。
实例152的手性通过与KARS的共晶结构来确定。
实例154a:(R)-6'-氟-N-(4-氟-2-羟基苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
实例154b:(S)-6'-氟-N-(4-氟-2-羟基苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例152和实例153类似的方法使用实例43代替实例40来制备标题化合物。将产物通过硅胶色谱法(DCM/MeOH=97/3)纯化。然后将外消旋混合物通过手性SFC分离以得到呈白色固体的实例154a(69mg,19%产率,手性SFC分离中的峰2)和实例154b(70mg,19%产率,手性SFC分离中的峰1)。
实例154a:LCMS:m/z 404.1(M+H);1H NMR(400MHz,氯仿-d)δ10.66(1H,s),7.25-7.22(1H,m),7.11-7.07(1H,t),6.99-6.96(1H,dd),6.78-6.73(1H,t),6.60-6.53(3H,m),5.73(1H,s),5.22-5.20(1H,m),4.61-4.52(1H,m),4.12-4.11(2H,m),3.45-3.35(4H,m),1.99-1.94(1H,m),1.60-1.44(5H,m)。
实例154b:LCMS:m/z 404.4(M+H);1H NMR(400MHz,氯仿-d)δ10.66(1H,s),7.25-7.22(1H,m),7.10-7.07(1H,t),6.99-6.96(1H,dd),6.78-6.73(1H,t),6.60-6.53(3H,m),5.73(1H,s),5.22-5.20(1H,m),4.59-4.57(1H,m),4.12-4.11(2H,m),3.47-3.34(4H,m),1.99-1.94(1H,m),1.58-1.44(5H,m)。
实例155:(R)-6'-氟-N-(4-氟苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例152类似的方法使用实例41代替实例40来制备标题化合物。将产物通过制备型手性SFC纯化以给出呈白色固体的标题化合物(15mg,98%产率,手性SFC分离中的峰2)。LCMS:m/z 443.4(M+H);1H NMR(400MHz,MeOH-d4)δ7.66(dd,J=7.3,2.4Hz,1H),7.38(ddd,J=7.3,4.9,2.4Hz,1H),7.06(dd,J=10.9,8.4Hz,1H),6.97(dd,J=9.3,3.1Hz,1H),6.74(td,J=8.7,3.2Hz,1H),6.54(dd,J=8.9,4.5Hz,1H),4.54(dd,J=10.0,5.1Hz,1H),4.27(s,2H),3.83(dq,J=12.0,3.4Hz,2H),3.13-2.94(m,2H),2.67(s,3H),2.38(dd,J=13.1,5.2Hz,1H),1.99-1.90(m,1H),1.87-1.76(m,1H),1.57(dd,J=13.1,10.0Hz,1H),1.52-1.32(m,2H)。
实例156:N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例165类似的方法使用实例17代替实例36来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以给出呈白色固体的外消旋标题化合物(5mg,79%产率)。HRMS:m/z 461.2162(M+H-O);1H NMR(400MHz,MeOH-d4)δ7.10-7.02(m,1H),6.88-6.71(m,3H),6.64(dd,J=9.0,4.5Hz,1H),4.63(dd,J=10.0,5.1Hz,1H),4.33(s,2H),3.97-3.88(m,2H),3.73(t,J=5.7Hz,2H),3.24(t,J=5.7Hz,2H),3.21-3.04(m,2H),2.76(s,3H),2.47(dd,J=13.1,5.1Hz,1H),2.02(td,J=12.5,4.5Hz,1H),1.90(td,J=12.7,4.5Hz,1H),1.65(dd,J=12.9,10.2Hz,1H),1.60-1.51(m,1H),1.45(d,J=13.3Hz,1H)。
实例157:N-(3-氨基甲酰基-4-氟苄基)-6',8'-二氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例165类似的方法使用实例11代替实例36来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以给出呈白色固体的外消旋标题化合物(12mg,90%产率)。HRMS:m/z 431.2525(M+H-O);1H NMR(400MHz,MeOH-d4)δ7.75(d,J=6.9Hz,1H),7.57-7.41(m,1H),7.24-7.09(m,1H),7.00-6.85(m,1H),6.73(t,J=10.0Hz,1H),4.81-4.73(m,1H),4.35(s,2H),3.69-3.38(m,4H),2.31-2.10(m,1H),1.92-1.51(m,5H)。
实例158:N-(3-氨基-4-氟苄基)-6'-氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例165类似的方法使用实例95代替实例36来制备标题化合物。将产物通过制备型HPLC(碱,方法5)纯化以给出呈白色固体的外消旋标题化合物(6mg,57%产率)。LCMS:m/z 385.2(M+H-18);1H NMR(400MHz,DMSO-d6)δ7.02-6.93(m,2H),6.87(dd,J=11.5,8.2Hz,1H),6.76(td,J=8.7,3.0Hz,1H),6.65(dd,J=8.9,2.0Hz,1H),6.55(dd,J=8.8,5.0Hz,1H),6.38(ddd,J=8.1,4.4,2.1Hz,1H),5.72(s,1H),5.21(d,J=5.3Hz,1H),5.07(s,2H),4.65-4.51(m,1H),4.07(d,J=5.6Hz,2H),3.41(dt,J=10.0,4.4Hz,3H),3.32(d,J=4.8Hz,1H),1.97(dd,J=12.7,5.7Hz,1H),1.50(ddt,J=35.0,16.2,5.8Hz,5H)。
实例159:6'-氟-N-(4-氟-3-(羟基甲基)苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例165类似的方法使用实例83代替实例36来制备标题化合物。将产物通过制备型HPLC(碱,方法5)纯化以给出呈白色固体的外消旋标题化合物(6.2mg,76%产率)。LCMS:m/z 400.4(M+H-O);1NMR(400MHz,甲醇-d4)δ7.40(dd,J=7.1,2.1Hz,1H),7.26-7.17(m,1H),7.06-6.95(m,2H),6.74(td,J=8.6,2.9Hz,1H),6.60(dd,J=8.8,4.8Hz,1H),4.76(dd,J=8.8,5.9Hz,1H),4.65(s,2H),4.33(s,2H),3.62-3.43(m,4H),2.09(dd,J=13.0,5.9Hz,1H),1.81-1.70(m,2H),1.70-1.52(m,3H)。
实例160:N-(3-氨基甲酰基-4-氟苄基)-6'-氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例165类似的方法使用实例24代替实例36来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以给出呈白色固体的外消旋标题化合物(19.1mg,93%产率)。HRMS:m/z 431.2525(M+H-O);1H NMR(400MHz,MeOH-d4)δ7.71(dd,J=7.1,2.2Hz,1H),7.43(td,J=5.2,2.5Hz,1H),7.12(dd,J=10.9,8.6Hz,1H),6.98(dd,J=9.6,2.8Hz,1H),6.70(td,J=8.6,2.9Hz,1H),6.57(dd,J=8.8,4.8Hz,1H),4.72(dd,J=8.7,6.0Hz,1H),4.32(s,2H),3.53-3.39(m,4H),2.12-1.97(m,1H),1.78-1.67(m,2H),1.59(ddt,J=18.3,13.6,6.9Hz,3H)。
实例161:N-(3-(2-氨基-2-氧代乙基)-4-氟苄基)-6'-氟-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例165类似的方法使用实例62代替实例36来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以给出呈白色固体的外消旋标题化合物(30.5mg,0.066mmol,38%产率)。LCMS:m/z 459.1(M+H);1H NMR(300MHz,CD3OD)δ7.25-7.19(2H,m),7.07-7.69(3H,m),6.86-6.79(1H,m),6.65-6.60(1H,m),4.65-4.32(1H,m),4.30-3.93(2H,d),3.89-3.67(2H,m),3.30(2H,s),3.19-2.76(2H,m),2.53(3H,s),2.50-2.14(1H,m),2.07-1.85(2H,m),1.68-1.42(3H,m)。
实例162:6'-氟-N-(4-氟-3-((3-羟基环丁基)氨基甲酰基)苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例165类似的方法使用实例60代替实例36来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以给出呈白色固体的外消旋标题化合物(2mg,3.96μmol,25%产率)。HRMS:m/z 483.2224(M+H-O);1H NMR(400MHz,MeOH-d4)δ7.50-7.44(m,1H),7.37-7.29(m,1H),7.05(dd,J=9.7Hz,1H),6.96-6.87(m,1H),6.71-6.60(m,1H),6.54-6.45(m,1H),4.69-4.64(m,1H),4.25(s,2H),3.98-3.86(m,2H),3.41(d,J=18.8Hz,4H),2.71-2.61(m,2H),2.09-1.82(m,3H),1.73-1.46(m,5H)。
实例163:6’-氟-N-(4-氟-3-(2-羟基乙氧基(苄基)-4’-羟基-1’-甲基-3’,4’-二氢-1’J-螺[哌啶-4,2’-喹啉]-1-甲酰胺
通过与实例165类似的方法使用实例3代替实例36来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以给出呈白色固体的外消旋标题化合物(3.8mg,54%产率)。LCMS:m/z 460.3(M-H);1H NMR(400MHz,MeOH-d4)δ7.09-6.99(m,3H),6.88-6.80(m,2H),6.64(dd,J=9.0,4.5Hz,1H),4.63(dd,J=10.0,5.1Hz,1H),4.30(s,2H),4.11(dd,J=5.3,4.3Hz,2H),3.96-3.86(m,4H),3.23-3.05(m,2H),2.76(s,3H),2.47(dd,J=13.1,5.2Hz,1H),1.97(dtd,J=46.6,12.4,4.5Hz,2H),1.70-1.41(m,3H)。
实例164:6'-氟-N-(4-氟-3-(甲基磺酰胺基)苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例165类似的方法使用实例131代替实例36来制备标题化合物。将产物通过制备型HPLC(碱,方法2)纯化以给出呈白色固体的外消旋标题化合物(3.3mg,33%产率)。LCMS:m/z 481.1(M+H);1H NMR(400MHz,MeOH-d4)δ7.43(d,J=8Hz,1H),7.10-7.07(m,1H),7.01(dd,J=8Hz,3H),6.76-6.71(m,1H),6.60(q,J=8Hz,1H)4.32(s,2H),3.55-3.48(m,J=8Hz,4H),2.97(s,3H),2.15-2.10(m,1H),1.78-1.73(m,2H),1.67-1.59(m,4H)。
实例165:6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
在室温下向实例36(14mg,0.031mmol)在EtOH(5mL)中的搅拌溶液中分批添加硼氢化钠(3.5mg,0.092mmol)。将反应混合物在室温下搅拌过夜,在减压下浓缩,然后用水(10mL)稀释并且用EtOAc(2×10mL)萃取。蒸发溶剂,并且将残余物通过制备型HPLC(碱,方法4)纯化以给出呈白色固体的标题化合物(9mg,63%产率)。LCMS:m/z 443.3(M+H-18);1HNMR(400MHz,DMSO-d6)δ7.04(dd,J=9.2,3.3Hz,2H),6.98-6.81(m,2H),6.64(dd,J=8.7,1.8Hz,1H),6.54(dd,J=9.0,4.6Hz,1H),6.43(ddd,J=7.9,4.5,1.9Hz,1H),5.39(s,1H),5.16(q,J=3.6Hz,1H),4.77(s,1H),4.48(d,J=6.0Hz,1H),4.14(d,J=5.7Hz,2H),3.92(d,J=13.6Hz,2H),3.57(t,J=5.8Hz,2H),3.12(q,J=5.9Hz,2H),2.90(dt,J=39.8,11.8Hz,2H),2.67(s,3H),2.48-2.43(m,1H),1.81(dtd,J=58.4,12.6,4.4Hz,2H),1.49-1.41(m,2H),1.29(d,J=11.6Hz,1H)。
实例166:6'-氟-N-(4-氟-2-((2-甲氧基乙基)氨基)苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例165类似的方法使用实例20代替实例36来制备标题化合物。将产物通过制备型HPLC(碱,方法5)纯化以给出呈白色固体的外消旋标题化合物(10mg,0.020mmol,63%产率)。LCMS:m/z 475.3(M+H);1H NMR(400MHz,MeOH-d4)δ7.13-6.96(m,2H),6.83(td,J=8.6,3.0Hz,1H),6.63(dd,J=9.0,4.5Hz,1H),6.38-6.20(m,2H),4.62(dd,J=10.0,5.0Hz,1H),4.25(s,2H),3.98-3.80(m,2H),3.61(t,J=5.5Hz,2H),3.39(s,3H),3.27(t,J=5.5Hz,2H),3.19-3.01(m,2H),2.75(s,3H),2.46(dd,J=13.1,5.1Hz,1H),2.12-1.78(m,2H),1.72-1.34(m,3H)。
实例167:N-(3-((R)-1-氨基-2,2,2-三氟乙基)-4-氟苄基)-6'-氟-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例165类似的方法使用实例149代替实例36来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以给出呈白色固体的外消旋标题化合物(9mg,85%产率)。HRMS:m/z 481.1548(M+H-O);1H NMR(400MHz,甲醇-d4)δ7.47-7.40(m,1H),7.29-7.20(m,1H),7.05-6.93(m,2H),6.74(td,J=8.7,3.2Hz,1H),6.54(dd,J=9.0,4.5Hz,1H),4.66(q,J=7.6Hz,1H),4.54(dd,J=9.9,5.3Hz,1H),4.26(s,2H),3.89-3.76(m,2H),3.14-2.94(m,2H),2.67(s,3H),2.37(dd,J=13.1,5.3Hz,1H),1.99-1.87(m,1H),1.87-1.75(m,1H),1.57(dd,J=13.0,10.0Hz,1H),1.51-1.42(m,1H),1.42-1.31(m,1H)。
实例168:6'-氟-N-(4-氟-2-甲氧基苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例165类似的方法使用实例114代替实例36来制备标题化合物。将产物通过制备型HPLC(碱,方法4)纯化以给出呈白色固体的外消旋标题化合物(5mg,47%产率)。LCMS:m/z 418.3(M+H);1H NMR(400MHz,MeOH-d4)δ7.18(dd,J=8.3,6.8Hz,1H),7.02(dd,J=9.7,2.5Hz,1H),6.77-6.70(m,2H),6.65-6.57(m,2H),4.76(dd,J=8.9,5.9Hz,1H),4.31(s,2H),3.84(s,3H),3.62-3.41(m,4H),2.09(dd,J=13.0,5.9Hz,1H),1.75(ddd,J=13.4,8.6,4.7Hz,2H),1.69-1.54(m,3H)。
实例169:(R)-6'-氟-4'-羟基-N-((2-甲基呋喃-3-基)甲基)-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例152类似的方法使用实例59代替实例40来制备标题化合物。将产物通过制备型手性SFC纯化以得到呈白色固体的标题化合物(57.8mg,24.5%产率,手性SFC分离中的峰2,保留时间=3.83min)。LCMS:m/z 372.5(M-H);1H NMR(400MHz,MeOH-d4)δ7.26(d,J=1.9Hz,1H),7.03(dd,J=9.5,2.9Hz,1H),6.75(td,J=8.6,3.0Hz,1H),6.61(dd,J=8.8,4.8Hz,1H),6.32(d,J=1.9Hz,1H),4.77(dd,J=9.0,5.9Hz,1H),4.12(s,2H),3.58-3.45(m,4H),2.27(s,3H),2.09(dd,J=13.0,5.9Hz,1H),1.80-1.70(m,2H),1.63(ddt,J=16.4,12.5,5.7Hz,3H)。
实例170a:(R)-N-(4-氨基-3-氟苄基)-6'-氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
实例170b:(S)-N-(4-氨基-3-氟苄基)-6'-氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
通过与实例152和153类似的方法使用实例56代替实例40来制备标题化合物。将产物通过手性SFC纯化以得到呈白色固体的实例170a(5mg,20%产率,手性SFC分离中的峰2)和实例170b(5mg,20%产率,手性SFC分离中的峰1)。
实例170a:LCMS:m/z 425.1(M+H+Na);1H NMR(400MHz,DMSO-d6)δ7.02-6.90(m,2H),6.86(dd,J=12.5,1.8Hz,1H),6.80-6.71(m,2H),6.67(dd,J=9.3,8.0Hz,1H),6.60-6.50(m,1H),5.73(s,1H),5.22(d,J=6.2Hz,1H),4.97(s,2H),4.64-4.52(m,1H),4.06(d,J=5.6Hz,2H),3.48-3.24(m,4H),1.96(dd,J=12.8,5.7Hz,1H),1.64-1.31(m,5H)。
实例 170b:LCMS:m/z 425.1(M+H+Na);1H NMR(400MHz,DMSO-d6)δ7.02-6.90(m,2H),6.86(dd,J=12.5,1.8Hz,1H),6.81-6.71(m,2H),6.67(dd,J=9.3,8.0Hz,1H),6.60-6.51(m,1H),5.73(s,1H),5.22(d,J=6.1Hz,1H),4.97(s,2H),4.65-4.51(m,1H),4.06(d,J=5.6Hz,2H),3.49-3.25(m,4H),1.96(dd,J=12.7,5.7Hz,1H),1.63-1.31(m,5H)。
生物学测定和数据
根据本发明的化合物的活性可以通过以下体外方法进行评估。式(I)的化合物或其药学上可接受的盐展现出有价值的药理学特性(例如,如下一章节中提供的测试中所指示的),并且因此被指示用于与AKR1C3依赖性KARS抑制剂相关的疗法。
评估在H460(具有高AKR1C3表达的NRF2途径突变体细胞系)和Hara(具有低AKR1C3表达的NRF2途径野生型细胞系)中的化合物活性的细胞增殖测定。
细胞系A549和H460是NRF2途径突变体并且在KEAP1中特异地含有遗传改变(A549:G333C,H460:D236H)(Singh A.等人,2006 PLoS Medicine[公共科学图书馆·医学]3(10)e420)。在这些细胞系中,NRF2途径具有组成性活性,并且这些细胞表达出高水平的NRF2蛋白和NRF2途径靶基因AKR1C3。Hara细胞在NRF2途径中没有任何已知的遗传改变,并且被归类为野生型。它们具有低的AKR1C3表达。在化合物处理后监测H460和Hara细胞系的体外增殖,以鉴定特异性抑制H460系增殖的化合物。
体外细胞增殖测定
在第1天,将对于H460 800个细胞/孔或40μL 2x104个细胞/mL以及对于Hara 2000个细胞/孔或40μL 5x104个细胞/mL培养基(补充有10%胎牛血清和1%青霉素/链霉素的RPMI-1640)接种到384孔组织培养板中。在第2天,将化合物按1:5连续稀释以产生8点剂量反应曲线,并且添加到细胞中,最终最高浓度为10μM。将DMSO(1%)对照和MG132(30μM)对照分别添加到每个板上的第23和24列,以用于阳性和阴性对照。在37℃/5%CO2下孵育3天后,添加30μl CellTiter-Glo试剂(Promega)并且将板在振摇器上孵育10min。使用PerkinElmer Envision读板器来确定发光量。使用被DMSO和MG132对照处理的细胞的CellTiter-Glo发光值来归一化数据并且使用Helios软件套件计算化合物的百分比活性和AC50。
评估在57种NRF2途径突变体肺癌细胞系和野生型肺癌细胞系的扩增面板中的化合物活性的细胞增殖测定。
运行NRF2途径突变体肺癌细胞系和野生型肺癌细胞系的扩增面板以进一步证明在具有不同水平的AKR1C3mRNA表达的细胞系中化合物的选择性特征曲线。将PrestoBlue细胞活力试剂和Cell Titer Glo两者多重复用在一起,作为最终测定读数。PrestoBlue是基于细胞渗透性刃天青的溶液,所述溶液利用活细胞的还原能力来定量测量其增殖。CellTiter Glo测量存在的ATP的量,ATP是代谢活性细胞的指标。
扩增的肺癌细胞系增殖测定概述、分析和剖析结果
使用Thermo Scientific Matrix WellMate微板分配器和Thermo ScientificMatrix WellMate小孔径一次性管筒(目录号201-30002)将细胞接种到384孔测定板(Greiner Bio-One,目录号781080)中到30μl生长培养基(补充有10%胎牛血清和1%青霉素/链霉素的RPMI-1640)/孔(1000至2000个细胞/孔,取决于倍增时间)中。细胞铺板后,将测定板放置到组织培养箱中在37℃/5%CO2下过夜。在下一天,将一个用于每种细胞系的测定板用于第0天Cell Titer Glo和PrestoBlue读数。将3μl PrestoBlue细胞活力试剂(Thermo Scientific,目录号A13262)添加到每个孔中并且然后将测定板在37℃/5%CO2下孵育30分钟,在EnVision 2105多模式读板器(Perkin Elmer)上进行荧光读数。在PrestoBlue读数后,然后将18μl Cell Titer Glo(Promega,目录号G7572)添加到每个孔中,允许将板在室温下孵育10分钟,然后在EnVision上进行发光读数。然后使用LabcyteInc Echo 555声学液体处理器将化合物添加到剩余的测定板(每个细胞系一式三份地运行)中。将化合物排列到Labcyte Inc Echo合格384孔LDV微板(目录号LP-0200-GNF10)中。将化合物按1:3.16连续稀释以产生8点剂量反应,最终最高浓度为1μM。将DMSO(0.3%)用作中性对照(NC),并且将MG132(30μM)用作活性对照(AC)。使用Labcyte Inc Echo 555声学液体处理器将90nl化合物添加到30μl细胞中,最终DMSO测定浓度为0.3%。在化合物添加后,将测定板在台式离心机中以500rpm旋转1分钟并且然后放置到组织培养箱中在37℃/5%CO2下72h。在72h孵育后,使用PrestoBlue和Cell Titer Glo使用先前针对第0天读数描述的相同条件将所有测定板读数。使用第0天的读数(未处理的细胞)以与在每个测定板上的72h DMSO处理的样品比较,作为跟踪每个细胞系的倍数生长的方式。将基于NC1对照的归一化用于Helios中的数据分析,其结合了DMSO中性对照(NC)和MG132活性对照(AC)以产生剂量响应曲线,所述剂量响应曲线然后用于计算对于每种化合物和细胞系的绝对合格AC50要求(call)。
NC1归一化计算模型:NC1:xn=±100(x-NC)/(AC-NC)
+/-由抑制类型参数设置来设置,其中NC和AC是相应的NC和AC孔值的平均值(均值或中值)。化合物36和化合物40的合格绝对AC50值在下表中列出并且表示为PrestoBlue和Cell Titer Glo测定读数两者的平均活性。
下面列出的绝对合格AC50值是呈PrestoBlue和Cell Titer Glo测定读数两者的每种化合物的平均活性。
*转录物/千碱基百万
测量KARS酶活性的抑制的KARS AMP Transcreener FP测定
赖氨酸-tRNA合成酶(KARS)是催化ATP、L-赖氨酸、和tRNA(Lys)的反应以形成AMP、二磷酸、和L-赖氨酰基-tRNA(Lys)的酶。
AMP/GMP(贝尔布鲁克实验室公司(BellBrook Labs),麦迪逊,威斯康星州,美国)是基于作为tRNA的氨基酰化产物之一的AMP的检测的远红竞争荧光偏振(FP)免疫测定。在此测定中,使用荧光标记的AMP(AMP Alexa Fluor 633)作为可以被特异性抗体识别的示踪剂。在不存在AMP的情况下,所有示踪剂分子都与抗体结合,从而导致大的偏振。通过酶反应产生的AMP产物将与示踪剂竞争与抗体的结合,所述结合导致偏振降低。因此,酶活性与FP值成反比。
测定方案
使用与文献(Crystal structure of tetrameric form of human lysyl-tRNAsynthetase:Implications for multisynthetase complex formation[人赖氨酰基-tRNA合成酶的四聚体形式的晶体结构:多合成酶复合物形成的意义]Guo,M.,Ignatov,M.,Musier-Forsyth,K.,Schimmel,P.,Yang,X.L.(2008)Proc.Natl.Acad.Sci.Usa[美国国家科学院院刊]105:2331-2336)中描述的方案类似的方案表达并且纯化人KARS蛋白(残基70-584)。
在10μL最终体积/Corning Costar 384孔板平底黑色未处理板的孔中进行KARS酶测定。最终测定浓度为20mM HEPES pH 7.5、1mM DTT、50nM人KARS、20μM ATP、50μM L-赖氨酸、1μM tRNA和8mM MgCl2。
将化合物按1:3连续稀释在主板中的DMSO中以产生10浓度点剂量反应,最大浓度为10mM。将来自化合物主板中的50nL点入384黑色板(Corning 3573)的每个孔中,并且添加5μL含有稀释在测定缓冲液(20mM HEPES pH 7.5和1mM DTT)中的100nM KARS的酶混合物。通过添加5μL含有稀释在测定缓冲液(20mM HEPES pH 7.5和1mM DTT)中的40μM ATP(最终20μM ATP)、100μM L-赖氨酸(最终50μM)、2μM tRNA(最终1μM)、16mM MgCl2(最终8mM MgCl2)的底物混合物开始反应。将混合物混合并且在室温下孵育2h,然后终止反应。
制备停止缓冲液和检测缓冲液(1X停止缓冲液[最终:0.5X]、2nM示踪剂[最终:1nM]和5μg/ml抗AMP抗体[最终:2.5μg/ml],在去离子水中),并且将10μL停止和检测混合物添加到反应孔中,混合一分钟,并且以1000rpm离心10秒。在室温下孵育30-60min后使用M1000用以下设置读取板:激发波长:635nm;发射波长:680nm。将DMSO对照的FP值用于归一化数据并且使用Helios软件套件计算化合物的IC50。
通过纯化的人AKR1C3酶转化AKR1C3依赖性KARS抑制剂
醛酮还原酶1C3(AKR1C3),也称为5型17β-羟基类固醇脱氢酶(17β-HSD5)或前列腺素F合酶(PGFS),是醛酮还原酶(AKR)超家族的成员。此酶充当NADP(H)-依赖性3-、17-和20-酮类固醇还原酶并且在类固醇激素代谢以及异生物质(包括多环芳族烃)的代谢中起中心作用。使用纯化的人AKR1C3酶和LC-MS作为读数来测量化合物40向化合物152转化的动力学。图1展示了动力学转化。
人AKR1C3蛋白纯化
通过GeneArt(赛默飞世尔科技公司(Thermo Fisher scientific))合成全长人AKR1C3DNA序列,并且使用聚合酶不完全引物延伸(PIPE)克隆将其克隆到pSpeed-ET载体中(Methods Mol Biol.[分子生物学方法]2009;498:91-103)。通过质粒在大肠杆菌菌株BL21-CODONPLUS(DE3)-RIL(安捷伦230245)中表达来获得N-末端His标记的蛋白。在摇动下使单个菌落在30℃的25ml含有50μg/ml卡那霉素的溶菌性肉汤培养物中生长过夜。将此培养物转移到含有50μg/ml卡那霉素的极品肉汤(Terrific Broth)中并且在摇动下在37℃下生长直到0.6-1的OD。然后将培养物放置在18℃培养箱中45min,用1mM IPTG(对于Cyno)或0.2%阿拉伯糖(对于人)诱导,并且在18℃下生长过夜。
通过离心(7000rpm,持续10分钟)使细菌培养物沉淀。将沉淀物用锤子压碎,并且重悬于40ml根据凯杰(Qiagen)方案(凯杰37900)用20mM咪唑和蛋白酶抑制剂片剂(罗氏(Roche)05056489001)制备的Q-蛋白质组缓冲液中。将裂解物在旋转下在4℃下孵育30min,并且然后以24,000g旋转30min。将上清液在0.45μm过滤器上过滤并且负载到1ml HisTrap柱(通用医疗(GE Healthcare)17-5319-01)上,使用AktaXpress色谱法系统,并且用以下缓冲液洗脱:
洗液I(50mM Tris、500mM NaCl、20mM咪唑、10%甘油)
洗液II(50mM Tris、500mM NaCl、30mM咪唑、10%甘油)
洗脱缓冲液(50mM Tris、150mM NaCl、300mM咪唑、10%甘油)
将峰级分合并,并且负载到用洗脱缓冲液(50mM Tris、200mM NaCl、5%甘油)预先平衡的16/60Superdex 200凝胶过滤柱(通用医疗28989335)上。收集洗脱级分,并且将含有正确大小的蛋白质的峰级分合并并且使用Amicon 10k截止浓度装置(密理博(Millipore)UFC901024)浓缩至>1mg/ml最终浓度
酶动力学测定方案
使用与文献(Crystal structures of three classes of non-steroidal anti-inflammatory drugs in complex with aldo-keto reductase 1C3.[三类非甾体抗炎药物与醛酮还原酶1C3的复合物的晶体结构]Flanagan,J.U.,Yosaatmadja,Y.,Teague,R.M.,Chai,M.Z.,Turnbull,A.P.,Squire,C.J.(2012)Plos One[公共科学图书馆·综合]7:e43965-e43965)中描述的方案类似的方案表达并且纯化人AKR1C3蛋白。
在37℃下在含有NADPH(50μM)的pH 7.4缓冲液(10mM磷酸盐、130mM NaCl、1mMDTT、0.01%Triton)中进行反应。将底物化合物40制成所希望的浓度,最终DMSO浓度为1%。AKR1C3浓度是0.25μM(对于含有100、50和25μM底物的反应)或0.5μM(对于含有12.5、6.25和3.12μM底物的反应)。在所希望的时间点,将反应用ACN:MeOH(3:1)淬灭,并且通过LC-MS/MS来确定产物和底物的浓度两者。分析反应速率,并且使用GraphPad Prism拟合至Michaelis-Menten方程,并且计算动力学常数。
LC-MS/MS方案
通过质谱法在AB Sciex 6500 Q-Trap仪器上分析样品。通过梯度HPLC(CTC PAL/安捷伦1260)使用分别均含有0.1%甲酸的水和乙腈的流动相A和B以0.7mL/min的流速在ACE C18-AR柱(30x2.1mm,3μm)上经2.5分钟实现非手性色谱分离。使用格列本脲作为内标。
通过等度HPLC(岛津公司(Shimadzu))在Daicel Chiralpak AGP柱(150x4mm,5μm)上使用含有90%的含有0.1%甲酸(用氢氧化铵:乙腈调节至pH 7)的90:10 10mM乙酸铵和10%甲醇的流动相以0.6mL/min的流速经7分钟实现手性色谱分离。使用卡马西平作为内标。
实例1
在表达人肺癌异种移植物NCI-H1944的KEAP1突变体AKR1C3中的化合物40剂量依
赖性药代动力学和药效学(PK/PD)变化
在具有建立的皮下NCI-H1944(KEAP1突变体,表达AKR1C3)细胞系衍生的肺癌异种移植物的裸小鼠中评估化合物40的PK/PD关系(图2)。单次口服施用化合物40后,收集血液和肿瘤以探索在血液和肿瘤中化合物40水平的PK特征曲线。还在肿瘤和血液中测量抑制KARS的化合物152(前药化合物40的活性代谢物)。将PK数据与DDIT3和EGR1mRNA诱导的肿瘤PD标志物读数(KARS抑制的下游转录读数)比较。DDIT3以及尤其是EGR1mRNA水平的诱导的持续时间随着剂量递增而增加,这涉及前药化合物40的PK以及活性抑制剂化合物152的肿瘤水平的持续时间。尽管呈剂量依赖性方式,但是PD标志物在给药后24小时内仍然升高,因此在此模型中评估每日一次给药的抗肿瘤功效。
实例2
在表达人肺癌异种移植物NCI-H1944的高AKR1C3中化合物40的剂量依赖性体内功效
在表达高水平AKR1C3的小鼠中的NCI-H1944人肺癌异种移植模型中评估化合物40的抗癌功效。通过皮下注射肿瘤细胞在裸雌性小鼠中建立NCI-H1944肿瘤。在第16天,当肿瘤达到大约200mm3时,根据肿瘤体积将小鼠随机分配到治疗组(n=8只/组)。以表1和图3所指示的剂量水平、途径和时间表施用测试剂。
在所有剂量水平下均具有功效益处,在高于75mg/kg的每日一次口服(qd,po)化合物40给药的剂量水平下有深度肿瘤消退。在75mg/kg qd剂量水平下观察到肿瘤停滞,其中%ΔT/ΔC为4.9%(ΔT/ΔC=治疗肿瘤体积的变化/对照肿瘤体积的变化)。
表1:在第44天,NCI-H1944肺癌异种移植物模型中的化合物40剂量反应功效。呈现
了治疗对肿瘤体积的作用。
实例3
在表达人肺癌异种移植物NCI-H460的KEAP1突变体和中度AKR1C3中的化合物40剂
量依赖性体内功效
在表达中度水平AKR1C3的小鼠中的NCI-H460人肺癌异种移植模型中评估化合物40的抗癌功效。通过皮下注射肿瘤细胞在裸雌性小鼠中建立NCI-H460肿瘤。在第8天,当肿瘤达到大约200mm3时,根据肿瘤体积将小鼠随机分配到治疗组(n=7只/组)。以表2和图3所指示的剂量水平、途径和时间表施用测试剂。
观察到剂量依赖性功效。在300mg/kg qd下看到肿瘤停滞,并且在150mg/kg qd下功效有一些降低。在75mg/kg qd治疗的情况下存在明显的功效降低。
表2:在第18天,NCI-H460肺癌异种移植物模型中的化合物40剂量反应功效。呈现
了治疗对肿瘤体积的作用。
Claims (31)
1.一种式(I)的化合物:
或其药学上可接受的盐,
其中:
每个R1独立地选自由以下组成的组:(C1-C6)烷基、(C1-C6)烷氧基、(C0-C4)烷基N(R8)2、和卤基;
R2a和R2b各自独立地选自由以下组成的组:H、(C1-C6)烷基、和卤基;
每个R3独立地选自由以下组成的组:H、和卤基;
R4选自由以下组成的组:芳基,包含1、2、3、或4个独立地选自N、O和S的杂原子的5至6元杂芳基;和包含1、2、3、或4个独立地选自N、O和S的杂原子的9至10元稠合双环杂芳基;其中前述中的任一项任选地被一个或多个R6取代;
R5选自由以下组成的组:H;(C1-C6)烷基;(C2-C6)烯基;(C0-C4)烷基OR8;(C1-C4)烷基(C3-C10)环烷基;卤代(C1-C6)烷基;(C2-C3)炔基;(C1-C4)烷基N(R10)2;
每个R6独立地选自由以下组成的组:卤基;(C1-C6)烷基;(C1-C6)烷氧基;卤代(C1-C6)烷基;OH;芳基;3至6元杂环;5至6元杂芳基;(C0-C4)烷基S(O)m(C1-C6)烷基;卤代(C1-C6)烷氧基;(C0-C4)烷基S(O)mN(R8)2;(C0-C4)烷基N(R8)2;(C0-C4)烷基(CO)OR7;N(R8)S(O)m(C1-C6)烷基;N(R8)S(O)m(C3-C6)环烷基;OP(O)(OH)2;(C0-C3)烷基(CO)NHR11;(C0-C3)烷基OR7、和(C3-C10)环烷基;其中每个R6当不为卤基、OH、或OP(O)(OH)2时任选地被一至三个R9取代;或两个相邻的R6与它们所附接的原子一起形成5至7元杂环或(C5-C8)环烷基;
每个R7和R8独立地选自由以下组成的组:H或任选地被一至三个R9取代的(C1-C6)烷基;
每个R9独立地选自由以下组成的组:卤基;-OH;氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、OP(O)(OH)2;(C1-C6)烷基;(C1-C3)炔基;(C1-C6)烷氧基;卤代(C1-C6)烷基;(C0-C4)烷基S(O)m(C1-C6)烷基;卤代(C1-C6)烷氧基;任选地被氧代(=O)取代的3至6元杂环;(C0-C4)烷基S(O)mN(R10)2;(C0-C4)烷基(CO)R10;(C0-C4)烷基(CO)OR10;(C0-C4)烷基NR10S(O)m(C1-C6)烷基;(C0-C4)烷基OR10;(C0-C4)烷基N(R10)2;(C0-C4)烷基CN;(C0-C4)烷基N(R10)2;和(C0-C4)烷基(CO)N(R10)2;
每个R10独立地选自由以下组成的组:H、(C1-C6)烷基;或3至6元杂环,其中所述3至6元杂环任选地被以下中的一个或多个取代:(C1-C6)烷基;和氧代(=O);
每个R11选自由以下组成的组:H;任选地被一至四个R12取代的4至6元杂环;任选地被一至四个R12取代的(C3-C6)环烷基;任选地被卤基取代的(C0-C3)烷基(C3-C6)环烷基(C1-C3)烷基;任选地被一至三个R12取代的CH2-芳基;(C1-C6)烷基;(C2-C6)烯基;或(C2-C6)炔基,其中所述(C1-C6)烷基;(C2-C6)烯基;和(C2-C6)炔基中的每一个任选地被一个或多个R13取代;
每个R12独立地选自由以下组成的组:OH、(C1-C3)烷氧基、NH2;或任选地被一个或多个OH取代的(C1-C3)烷基;
每个R13独立地选自由以下组成的组:卤基、OH、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、(C1-C3)烷氧基;和C(O)-(C3-C8)环烷基;
m是0、1、或2;并且
n是0、1或2。
2.如权利要求1所述的化合物,其中R4任选地被一个或多个R6取代的苯基。
3.如权利要求1所述的化合物,其中R4是任选地被一个或多个R6取代的5至6元杂芳基。
4.如权利要求3所述的化合物,其中R4是吡啶基。
5.如权利要求3所述的化合物,其中R4选自由以下组成的组:呋喃基、噁唑基、吡唑基、异噁唑基、噻吩基、咪唑基、和噁二唑基。
9.如权利要求1-8中任一项所述的化合物,其中n是1或2,并且至少一个R1是卤基。
10.如权利要求1-9中任一项所述的化合物,其中n是1或2,并且至少一个R1是F。
11.如权利要求1-10中任一项所述的化合物,其中n是1。
12.如权利要求1-11中任一项所述的化合物,其中Z是O。
13.如权利要求1-12中任一项所述的化合物,其中R2a和R2b各自是H。
14.如权利要求1-13中任一项所述的化合物,其中R5是H;(C1-C6)烷基;(C2-C6)烯基;或(C0-C4)烷基OR8。
15.如权利要求1-14中任一项所述的化合物,其中R5是H或(C1-C2)烷基。
16.如权利要求1-15中任一项所述的化合物,其中R5是H。
17.如权利要求1-16中任一项所述的化合物,其中每个R3是H。
18.如权利要求1-17中任一项所述的化合物,其中每个R3是氘。
19.如权利要求1-18中任一项所述的化合物,其中每个R6独立地选自卤基和(C0-C4)烷基N(R8)2。
20.如权利要求1-19中任一项所述的化合物,其中R6是卤基。
21.如权利要求1所述的化合物,其中所述化合物选自:
6'-氟-N-((5-甲基呋喃-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-甲氧基苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(2-羟基乙氧基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
二氢磷酸4-((6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯酯;
N-(2,4-二氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
1'-乙基-6'-氟-N-(4-氟苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-1'-甲基-N-((5-甲基呋喃-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-甲氧基苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((2-甲基呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
6'-氟-N-((4-氟苯基)甲基-d2)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-1'-(2-甲氧基乙基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(噁唑-5-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-1'-(2-羟基乙基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-((2-甲氧基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((5-氯呋喃-2-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((1-甲基乙基)磺酰胺基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
1'-乙基-6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-2,4-二氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
二氢磷酸2-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)乙酯;
N-(3-氨基-4-氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-氨磺酰基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(((1,4-二噁烷-2-基)甲基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((4-(羟基甲基)苄基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-苄基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺
N-((2,4-二甲基呋喃-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(3-(噁唑-5-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((1H-吡唑-4-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((4-氨基甲酰基呋喃-2-基)甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-2,4-二氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2,2-二甲基-3-(4-甲基哌嗪-1-基)-3-氧代丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(S)-N-(3-((2,3-二羟基丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(呋喃-3-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((1H-吡唑-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2,5-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(5-氨基-2,4-二氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-(2,2,2-三氟乙氧基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2-(乙基氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(苯并[d][1,3]二氧杂环戊烯-4-基甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(4-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(甲基磺酰胺基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2,3-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((2-甲基呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((3-羟基环丁基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
2-氟-5-((6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯甲酸甲酯;
N-(3-(2-氨基-2-氧代乙基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((3-羟基吡啶-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(甲基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3,5-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((6-(二甲基氨基)吡啶-2-基)甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-(三氟甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2-氯-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(2-羟基乙氧基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-(2-羟基乙氧基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((5-甲基-1H-吡唑-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-4-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-4'-氧代-N-(3-氨磺酰基苄基)-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-3-((2-羟基乙基)氨基)苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟-2-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2,6-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2-(二甲基氨基)乙基)氨基甲酰基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(E)-1'-(丁-2-烯-1-基)-6'-氟-N-(4-氟苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-((2-羟基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-氯苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-(2-氧代吡咯烷-1-基)乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-3-((2-羟基乙基)氨基)苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(1-羟基乙基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((4-氯-1-甲基-1H-吡唑-5-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(R)-6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-4'-氧代-N-((2-(三氟甲基)呋喃-3-基)甲基)-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基-2-甲基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2-环丙基-2-氧代乙基)氨基甲酰基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2,2,2-三氟乙基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(3-甲氧基氮杂环丁烷-1-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(2-氨基-2-氧代乙基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-(三氟甲基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(氧杂环丁烷-3-基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((3-乙基-5-甲基异噁唑-4-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(异噁唑-4-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-(二氟甲氧基)-3-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((2,5-二甲基呋喃-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-氯苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-(三氟甲基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2,2-二甲基-3-吗啉代-3-氧代丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-甲氧基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((2-甲氧基吡啶-4-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(S)-6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(异噁唑-3-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((1H-吲哚-6-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(((2-甲基噁唑-5-基)甲基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(E)-6'-氟-N-(4-氟-3-((4-羟基丁-2-烯-1-基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((5-甲基噻吩-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(异噁唑-5-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((6-氟吡啶-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(5-氨基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((5-甲基-2-(三氟甲基)呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(丙-2-炔-1-基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(1H-咪唑-2-基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(甲基磺酰胺基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(4-氟-3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(环丙烷磺酰胺基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((3-甲基-1,2,4-噁二唑-5-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(1-羟基乙基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((6-氨基吡啶-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2-氨基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(噁唑-4-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(2-羟基丙-2-基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
3-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)-2,2-二甲基丙酸;
N-(苯并[c][1,2,5]噁二唑-4-基甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-8'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(丙基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(1H-1,2,4-三唑-1-基)苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((1-甲基-1H-吡唑-4-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(((2-羟基乙基)氨基)甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(氨磺酰基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
3-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)丙酸;
(R)-N-(3-(1-氨基-2,2,2-三氟乙基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-(二氟甲氧基)苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(R)-6'-氟-N-(4-氟苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(S)-6'-氟-N-(4-氟苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(R)-6'-氟-N-(4-氟苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(S)-6'-氟-N-(4-氟苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(R)-6'-氟-N-(4-氟-2-羟基苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(S)-6'-氟-N-(4-氟-2-羟基苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6',8'-二氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-4-氟苄基)-6'-氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(羟基甲基)苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(2-氨基-2-氧代乙基)-4-氟苄基)-6'-氟-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((3-羟基环丁基)氨基甲酰基)苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(2-羟基乙氧基)苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(甲基磺酰胺基)苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-((2-甲氧基乙基)氨基)苄基)-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((R)-1-氨基-2,2,2-三氟乙基)-4-氟苄基)-6'-氟-4'-羟基-1'-甲基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-甲氧基苄基)-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(R)-6'-氟-4'-羟基-N-((2-甲基呋喃-3-基)甲基)-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(R)-N-(4-氨基-3-氟苄基)-6'-氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;和
(S)-N-(4-氨基-3-氟苄基)-6'-氟-4'-羟基-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
或其药学上可接受的盐。
22.如权利要求2所述的化合物,其中所述化合物选自:
6'-氟-N-(4-氟-2-甲氧基苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(2-羟基乙氧基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
二氢磷酸4-((6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯酯;
N-(2,4-二氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
1'-乙基-6'-氟-N-(4-氟苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-甲氧基苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((4-氟苯基)甲基-d2)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-1'-(2-甲氧基乙基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(噁唑-5-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-1'-(2-羟基乙基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-((2-甲氧基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((1-甲基乙基)磺酰胺基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
1'-乙基-6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-2,4-二氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
二氢磷酸2-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)乙酯;
N-(3-氨基-4-氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-氨磺酰基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(((1,4-二噁烷-2-基)甲基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((4-(羟基甲基)苄基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-苄基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(3-(噁唑-5-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-2,4-二氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2,2-二甲基-3-(4-甲基哌嗪-1-基)-3-氧代丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(S)-N-(3-((2,3-二羟基丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2,5-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(5-氨基-2,4-二氟苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-(2,2,2-三氟乙氧基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2-(乙基氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(苯并[d][1,3]二氧杂环戊烯-4-基甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(4-羟基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(甲基磺酰胺基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2,3-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((3-羟基环丁基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
2-氟-5-((6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯甲酸甲酯;
N-(3-(2-氨基-2-氧代乙基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(甲基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3,5-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-(三氟甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2-氯-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(2-羟基乙氧基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-(2-羟基乙氧基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-4-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-4'-氧代-N-(3-氨磺酰基苄基)-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-3-((2-羟基乙基)氨基)苄基)-1'-乙基-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-5-((2-羟基乙基)氨基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-4-氟-2-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2,6-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2-(二甲基氨基)乙基)氨基甲酰基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基乙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺:
(E)-1'-(丁-2-烯-1-基)-6'-氟-N-(4-氟苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-((2-羟基乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-氯苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-(2-氧代吡咯烷-1-基)乙基)氨基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2,4-二氟-3-((2-羟基乙基)氨基)苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(1-羟基乙基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(R)-6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-羟基-2-甲基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2-甲氧基乙基)氨基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2-环丙基-2-氧代乙基)氨基甲酰基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-((2,2,2-三氟乙基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(3-甲氧基氮杂环丁烷-1-基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(2-氨基-2-氧代乙基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-(三氟甲基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(氧杂环丁烷-3-基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-(二氟甲氧基)-3-氟苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-氨基甲酰基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-氯苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-(三氟甲基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-((2,2-二甲基-3-吗啉代-3-氧代丙基)氨基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-2-甲氧基苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-2-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(S)-6'-氟-N-(4-氟-3-((2-羟基丙基)氨基甲酰基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(4-氨基-3-甲基苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(((2-甲基噁唑-5-基)甲基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
(E)-6'-氟-N-(4-氟-3-((4-羟基丁-2-烯-1-基)氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(5-氨基-2,4-二氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(丙-2-炔-1-基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(1H-咪唑-2-基)苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(甲基磺酰胺基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(4-氟-3-(羟基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(环丙烷磺酰胺基)-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(1-羟基乙基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(2-氨基-4-氟苄基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(2-羟基丙-2-基)苄基)-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
3-((2-氟-5-((6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺基)甲基)苯基)氨基)-2,2-二甲基丙酸;
N-(3-氨基甲酰基-4-氟苄基)-6'-氟-8'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(丙基氨基甲酰基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(3-(1H-1,2,4-三唑-1-基)苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(((2-羟基乙基)氨基)甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(4-氟-3-(氨磺酰基甲基)苄基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
R)-N-(3-(1-氨基-2,2,2-三氟乙基)-4-氟苄基)-6'-氟-1'-甲基-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;和
N-(4-(二氟甲氧基)苄基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
或其药学上可接受的盐。
23.如权利要求5所述的化合物,其中所述化合物选自:
6'-氟-N-((5-甲基呋喃-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-1'-甲基-N-((5-甲基呋喃-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((2-甲基呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((5-氯呋喃-2-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((2,4-二甲基呋喃-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((1H-吡唑-4-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((4-氨基甲酰基呋喃-2-基)甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-(呋喃-3-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((1H-吡唑-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((2-甲基呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((3-羟基吡啶-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((6-(二甲基氨基)吡啶-2-基)甲基)-6',8'-二氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((5-甲基-1H-吡唑-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((4-氯-1-甲基-1H-吡唑-5-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-4'-氧代-N-((2-(三氟甲基)呋喃-3-基)甲基)-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((3-乙基-5-甲基异噁唑-4-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(异噁唑-4-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((2,5-二甲基呋喃-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((2-甲氧基吡啶-4-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(异噁唑-3-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((1H-吲哚-6-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((5-甲基噻吩-2-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(异噁唑-5-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6',8'-二氟-N-((6-氟吡啶-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((5-甲基-2-(三氟甲基)呋喃-3-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-((3-甲基-1,2,4-噁二唑-5-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-((6-氨基吡啶-3-基)甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
6'-氟-N-(噁唑-4-基甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
N-(苯并[c][1,2,5]噁二唑-4-基甲基)-6'-氟-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;和
6'-氟-N-((1-甲基-1H-吡唑-4-基)甲基)-4'-氧代-3',4'-二氢-1'H-螺[哌啶-4,2'-喹啉]-1-甲酰胺;
或其药学上可接受的盐。
24.一种药物组合物,所述药物组合物包含如权利要求1至23中任一项所述的化合物,以及一种或多种药学上可接受的载体。
25.一种药物组合,所述药物组合包含如权利要求1至23中任一项所述的化合物或其药学上可接受的盐,以及一种或多种治疗剂。
26.如权利要求1至23中任一项所述的化合物,所述化合物用作药剂,特别用于治疗或预防KARS介导的疾病或病症。
27.如权利要求1至23中任一项所述的化合物,所述化合物用于治疗或预防癌症,其中所述方法包括向所述受试者施用如权利要求1至7中任一项所述的式(I)至(III)的化合物或其药学上可接受的盐。
28.如权利要求27所述的用途,其中所述癌症选自非小细胞肺癌(NSCLC)、肝癌、头颈癌、食道癌、子宫癌、乳腺癌、膀胱癌、子宫颈癌、结直肠癌、肾癌、黑素瘤、胃、去势抵抗性前列腺癌(CRPC)、T细胞急性成淋巴细胞性白血病(T-ALL)、急性髓性白血病(AML)、和骨髓增生异常综合征(MDS),其中所述方法包括向所述受试者施用根据实施例1至7中任一项所述的式(I)至(III)的化合物或其药学上可接受的盐。
29.如权利要求28所述的用途,其中所述非小细胞肺癌(NSCLC)选自腺癌、鳞状细胞癌、大细胞癌、大细胞神经内分泌癌、腺鳞癌、和肉瘤样癌。
30.如权利要求1至23中任一项所述的化合物,所述化合物用于治疗或预防在基因NFE2L2、KEAP1、CUL3、AKR1C3中具有遗传或表观遗传改变的癌症或导致激活NRF2转录活性或AKR1C3基因表达的任何其他病症。
31.如权利要求1至23中任一项所述的化合物,所述化合物用于治疗或预防AKR1C3过表达高于预定值的癌症。
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CN113135878A (zh) * | 2021-04-09 | 2021-07-20 | 新沂市凯美斯特医药科技有限公司 | 一种以呋喃为原料合成3-氨基甲基四氢呋喃的方法 |
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CN115403579A (zh) * | 2021-05-27 | 2022-11-29 | 上海拓界生物医药科技有限公司 | 一种新的螺环衍生物及其用途 |
WO2023174319A1 (zh) * | 2022-03-15 | 2023-09-21 | 深圳艾欣达伟医药科技有限公司 | 治疗brca突变癌症患者的方法 |
WO2024023659A1 (en) | 2022-07-26 | 2024-02-01 | Novartis Ag | Pharmaceutical compositions of tricyclic akr1c3 dependent kars inhibitor and methods for making same |
WO2024023641A1 (en) | 2022-07-26 | 2024-02-01 | Novartis Ag | Methods of tricyclic akr1c3 dependent kars inhibitor dosing field of the invention |
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