TW201609657A - 作為bet溴域抑制劑之四氫喹啉組成物 - Google Patents
作為bet溴域抑制劑之四氫喹啉組成物 Download PDFInfo
- Publication number
- TW201609657A TW201609657A TW103139976A TW103139976A TW201609657A TW 201609657 A TW201609657 A TW 201609657A TW 103139976 A TW103139976 A TW 103139976A TW 103139976 A TW103139976 A TW 103139976A TW 201609657 A TW201609657 A TW 201609657A
- Authority
- TW
- Taiwan
- Prior art keywords
- methyl
- pyrazol
- tetrahydroquinoline
- tetrahydroquinolin
- oxy
- Prior art date
Links
- 102000001805 Bromodomains Human genes 0.000 title claims abstract description 17
- 108050009021 Bromodomains Proteins 0.000 title claims abstract description 16
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 title claims description 35
- 239000003112 inhibitor Substances 0.000 title abstract description 32
- 239000000203 mixture Substances 0.000 title description 94
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 24
- 201000011510 cancer Diseases 0.000 claims abstract description 17
- 208000008589 Obesity Diseases 0.000 claims abstract description 9
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 8
- 235000020824 obesity Nutrition 0.000 claims abstract description 8
- -1 C 1 -C 6 alkyl Chemical group 0.000 claims description 407
- 150000001875 compounds Chemical class 0.000 claims description 225
- 238000000034 method Methods 0.000 claims description 98
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 92
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 78
- 229910052794 bromium Inorganic materials 0.000 claims description 78
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 77
- 229910052739 hydrogen Inorganic materials 0.000 claims description 57
- 239000001257 hydrogen Substances 0.000 claims description 57
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 56
- 150000003839 salts Chemical class 0.000 claims description 56
- 125000003118 aryl group Chemical group 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 46
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 46
- 201000010099 disease Diseases 0.000 claims description 45
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
- 125000001072 heteroaryl group Chemical group 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 39
- 239000003814 drug Substances 0.000 claims description 37
- 239000008194 pharmaceutical composition Substances 0.000 claims description 37
- 239000000651 prodrug Substances 0.000 claims description 36
- 229940002612 prodrug Drugs 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 30
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 27
- 150000002431 hydrogen Chemical class 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 239000012453 solvate Substances 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 25
- 239000003937 drug carrier Substances 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 22
- 230000002401 inhibitory effect Effects 0.000 claims description 22
- 230000005764 inhibitory process Effects 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 18
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzenecarbonitrile Natural products N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 16
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 15
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 12
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 230000004968 inflammatory condition Effects 0.000 claims description 10
- 229940124597 therapeutic agent Drugs 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- 239000002583 male contraceptive agent Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 8
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 8
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 7
- JFFSQWHCQKPWTK-UHFFFAOYSA-N CC1CCC2=C(N1C(=O)OC)C=CC(=C2)C3=CN(N=C3)C4CCNCC4 Chemical compound CC1CCC2=C(N1C(=O)OC)C=CC(=C2)C3=CN(N=C3)C4CCNCC4 JFFSQWHCQKPWTK-UHFFFAOYSA-N 0.000 claims description 7
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 6
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 229960000473 altretamine Drugs 0.000 claims description 6
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 6
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 6
- 229960004562 carboplatin Drugs 0.000 claims description 6
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 claims description 6
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 claims description 6
- 229960001924 melphalan Drugs 0.000 claims description 6
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 6
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 6
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 6
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 claims description 6
- LCUMODKDHNQTRE-AWEZNQCLSA-N 1-[(2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC LCUMODKDHNQTRE-AWEZNQCLSA-N 0.000 claims description 5
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 5
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 5
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 5
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 5
- 229930012538 Paclitaxel Natural products 0.000 claims description 5
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 5
- 229960004630 chlorambucil Drugs 0.000 claims description 5
- 229960004316 cisplatin Drugs 0.000 claims description 5
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 5
- ZMWQMSTWRTUSRV-SFHVURJKSA-N cyclopropyl-[(2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=CC=C(C=C1)F)C ZMWQMSTWRTUSRV-SFHVURJKSA-N 0.000 claims description 5
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 5
- 229960001592 paclitaxel Drugs 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-N 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- MCSWKCGGMZLMNH-INIZCTEOSA-N 1-[(2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OCCC)C=1C=NN(C1)C1CCNCC1)C(C)=O MCSWKCGGMZLMNH-INIZCTEOSA-N 0.000 claims description 4
- UALZHMUXQIBCEV-HNNXBMFYSA-N 1-[(2S)-5-(1,3-benzoxazol-2-yloxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound O1C(=NC2=C1C=CC=C2)OC2=C1CC[C@@H](N(C1=CC=C2C=2C=NN(C2)C2CC2)C(C)=O)C UALZHMUXQIBCEV-HNNXBMFYSA-N 0.000 claims description 4
- SUTKOHJCPVMUFI-AWEZNQCLSA-N 1-[(2S)-5-(azetidin-3-ylmethoxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound N1CC(C1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(C)=O)C SUTKOHJCPVMUFI-AWEZNQCLSA-N 0.000 claims description 4
- HLOPTEVMYKPJHD-LBPRGKRZSA-N 1-[(2S)-5-cyclobutyloxy-6-(1-cyclopropylpyrazol-4-yl)-7,8-difluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C(=C1C=1C=NN(C1)C1CC1)F)F)C(C)=O)C HLOPTEVMYKPJHD-LBPRGKRZSA-N 0.000 claims description 4
- LGJJHRYMANXMLX-ZDUSSCGKSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(1H-pyrazolo[3,4-d]pyrimidin-6-yloxy)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC=C2C(=N1)NN=C2 LGJJHRYMANXMLX-ZDUSSCGKSA-N 0.000 claims description 4
- UIBYCDSFUICEEG-LBPRGKRZSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(2,2,2-trifluoroethoxy)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCC(F)(F)F UIBYCDSFUICEEG-LBPRGKRZSA-N 0.000 claims description 4
- LSZWBNPUINWAOT-ZDUSSCGKSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(3,3,3-trifluoropropoxy)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC(F)(F)F LSZWBNPUINWAOT-ZDUSSCGKSA-N 0.000 claims description 4
- BCBSJHKWYWHMRW-ZDUSSCGKSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-[4-(trifluoromethyl)pyrimidin-2-yl]oxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC=CC(=N1)C(F)(F)F BCBSJHKWYWHMRW-ZDUSSCGKSA-N 0.000 claims description 4
- AJHIFSQJGIGZFE-AWEZNQCLSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-pyrazin-2-yloxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC=CN=C1 AJHIFSQJGIGZFE-AWEZNQCLSA-N 0.000 claims description 4
- AAGLONFBXIQABR-INIZCTEOSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-quinazolin-2-yloxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC2=CC=CC=C2C=N1 AAGLONFBXIQABR-INIZCTEOSA-N 0.000 claims description 4
- VHUQWBASYKJWOF-ZDUSSCGKSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(2,2-difluoropropoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCC(C)(F)F VHUQWBASYKJWOF-ZDUSSCGKSA-N 0.000 claims description 4
- ZFNOOMOGFNZMIL-AWEZNQCLSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(2-fluoro-2-methylpropoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCC(C)(C)F ZFNOOMOGFNZMIL-AWEZNQCLSA-N 0.000 claims description 4
- QNECMOXXWJTIKD-HNNXBMFYSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(3-hydroxy-2,2-dimethylpropoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCC(CO)(C)C QNECMOXXWJTIKD-HNNXBMFYSA-N 0.000 claims description 4
- ZVZQNFZPGDSPKN-INIZCTEOSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(4,6-dimethylpyrimidin-2-yl)oxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC(=CC(=N1)C)C ZVZQNFZPGDSPKN-INIZCTEOSA-N 0.000 claims description 4
- ATZLIOSDBONBEN-KNVGNIICSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-[(2,2-difluorocyclopropyl)methoxy]-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCC1C(C1)(F)F ATZLIOSDBONBEN-KNVGNIICSA-N 0.000 claims description 4
- AAKQPHDWRBLDQW-AWEZNQCLSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-[(3-fluorooxetan-3-yl)methoxy]-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCC1(COC1)F AAKQPHDWRBLDQW-AWEZNQCLSA-N 0.000 claims description 4
- XZAMSSZITUNFPW-HNNXBMFYSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-[[3-(hydroxymethyl)oxetan-3-yl]methoxy]-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCC1(COC1)CO XZAMSSZITUNFPW-HNNXBMFYSA-N 0.000 claims description 4
- VZQNFGVIRDVDKJ-AWEZNQCLSA-N 1-[(2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-pyrimidin-2-yloxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC=CC=N1 VZQNFGVIRDVDKJ-AWEZNQCLSA-N 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- 102000004190 Enzymes Human genes 0.000 claims description 4
- 108090000790 Enzymes Proteins 0.000 claims description 4
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 claims description 4
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 4
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 claims description 4
- HAKIMTAQCNLQRE-KRWDZBQOSA-N [(2S)-5-(3-chloro-4-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound ClC=1C=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)C2CC2)C)C=CC1F HAKIMTAQCNLQRE-KRWDZBQOSA-N 0.000 claims description 4
- BWXSRPXVVGPGBM-SFHVURJKSA-N [(2S)-5-(3-chlorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound ClC=1C=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)C2CC2)C)C=CC1 BWXSRPXVVGPGBM-SFHVURJKSA-N 0.000 claims description 4
- MUPZVUJZDIZCLP-SFHVURJKSA-N [(2S)-5-(4-chlorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound ClC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)C2CC2)C)C=C1 MUPZVUJZDIZCLP-SFHVURJKSA-N 0.000 claims description 4
- YITSGRKDCGVZMF-AWEZNQCLSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(1-methylimidazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=CN(C1)C)C(=O)C1CC1)C YITSGRKDCGVZMF-AWEZNQCLSA-N 0.000 claims description 4
- UTBXLNNBINFQPM-AWEZNQCLSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C)C(=O)C1CC1)C UTBXLNNBINFQPM-AWEZNQCLSA-N 0.000 claims description 4
- XUCHRPWHTOGIOB-ZDUSSCGKSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=NN(C1)C)C(=O)C1CC1)C XUCHRPWHTOGIOB-ZDUSSCGKSA-N 0.000 claims description 4
- LEQDGABIQOLUTE-INIZCTEOSA-N [(2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NN(C1)C1CCNCC1)F)C(=O)C1CC1)C LEQDGABIQOLUTE-INIZCTEOSA-N 0.000 claims description 4
- ILSNWYPPPWRELM-INIZCTEOSA-N [(2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-5-(4-fluorophenoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)C1CC1)C)OC1=CC=C(C=C1)F ILSNWYPPPWRELM-INIZCTEOSA-N 0.000 claims description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- AHFVLWDAXQXZOP-INIZCTEOSA-N cyclopropyl-[(2S)-2-methyl-6-(1-methylimidazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=CN(C1)C)OC1=CC=CC=C1)C AHFVLWDAXQXZOP-INIZCTEOSA-N 0.000 claims description 4
- RAAZTPCWTNHLSQ-SFHVURJKSA-N cyclopropyl-[(2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-pyridin-2-yloxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=NC=CC=C1)C RAAZTPCWTNHLSQ-SFHVURJKSA-N 0.000 claims description 4
- AOISQTYQPOZYJR-KRWDZBQOSA-N cyclopropyl-[(2S)-5-(2,4-difluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=C(C=C(C=C1)F)F)C AOISQTYQPOZYJR-KRWDZBQOSA-N 0.000 claims description 4
- GLPXRBPDZRPKMY-KRWDZBQOSA-N cyclopropyl-[(2S)-5-(2,5-difluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=C(C=CC(=C1)F)F)C GLPXRBPDZRPKMY-KRWDZBQOSA-N 0.000 claims description 4
- DAEFOCWSVVRDQE-SFHVURJKSA-N cyclopropyl-[(2S)-5-(2-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=C(C=CC=C1)F)C DAEFOCWSVVRDQE-SFHVURJKSA-N 0.000 claims description 4
- WYWYLOKEHCZWRJ-SFHVURJKSA-N cyclopropyl-[(2S)-8-fluoro-2-methyl-5-phenoxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC(=C12)F)C=1C=NN(C1)C1CCNCC1)OC1=CC=CC=C1)C WYWYLOKEHCZWRJ-SFHVURJKSA-N 0.000 claims description 4
- 229960003957 dexamethasone Drugs 0.000 claims description 4
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 4
- 229960004679 doxorubicin Drugs 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 4
- 229960000908 idarubicin Drugs 0.000 claims description 4
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 4
- 229960001614 levamisole Drugs 0.000 claims description 4
- 229960004296 megestrol acetate Drugs 0.000 claims description 4
- AQPOAVOTGGLNEP-SFHVURJKSA-N methyl (2S)-5-(3-methoxyphenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound COC=1C=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC1 AQPOAVOTGGLNEP-SFHVURJKSA-N 0.000 claims description 4
- WXMPJWLOUXYXDP-NSHDSACASA-N methyl (2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NNC1)F)C(=O)OC)C WXMPJWLOUXYXDP-NSHDSACASA-N 0.000 claims description 4
- OLJKLNDGYFXLCY-KRWDZBQOSA-N methyl (2S)-8-fluoro-2-methyl-5-phenoxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C=C(C(=C2CC[C@@H](N(C12)C(=O)OC)C)OC1=CC=CC=C1)C=1C=NN(C1)C1CCNCC1 OLJKLNDGYFXLCY-KRWDZBQOSA-N 0.000 claims description 4
- 229960004857 mitomycin Drugs 0.000 claims description 4
- 229960001156 mitoxantrone Drugs 0.000 claims description 4
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N monoethyl amine Natural products CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 4
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 claims description 4
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 4
- 229960004618 prednisone Drugs 0.000 claims description 4
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 claims description 4
- 229960004641 rituximab Drugs 0.000 claims description 4
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims description 4
- 229960001278 teniposide Drugs 0.000 claims description 4
- 239000005460 tetrahydrofolate Substances 0.000 claims description 4
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 4
- POUHPXCCUUQHPD-KRWDZBQOSA-N 1-[(2S)-5-(2-chlorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound ClC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(C)=O)C)C=CC=C1 POUHPXCCUUQHPD-KRWDZBQOSA-N 0.000 claims description 3
- SPFFVZLZNRDNRJ-KRWDZBQOSA-N 1-[(2S)-5-(4-chlorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound ClC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(C)=O)C)C=C1 SPFFVZLZNRDNRJ-KRWDZBQOSA-N 0.000 claims description 3
- WBVMYKWDNRKTLG-KRWDZBQOSA-N 1-[(2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(C)=O)C)C=C1 WBVMYKWDNRKTLG-KRWDZBQOSA-N 0.000 claims description 3
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 claims description 3
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 claims description 3
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 3
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 claims description 3
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 3
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 claims description 3
- 102000014654 Aromatase Human genes 0.000 claims description 3
- 108010078554 Aromatase Proteins 0.000 claims description 3
- GOLCXWYRSKYTSP-UHFFFAOYSA-N Arsenious Acid Chemical compound O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 claims description 3
- OLCWFLWEHWLBTO-HSZRJFAPSA-N BMS-214662 Chemical compound C=1C=CSC=1S(=O)(=O)N([C@@H](C1)CC=2C=CC=CC=2)CC2=CC(C#N)=CC=C2N1CC1=CN=CN1 OLCWFLWEHWLBTO-HSZRJFAPSA-N 0.000 claims description 3
- 108010006654 Bleomycin Proteins 0.000 claims description 3
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 3
- ZFEHJOAFXIVHBN-UHFFFAOYSA-N COC(=O)N1C(CCC2=CC(=CC=C12)C=1C=NN(C1)C1CC1)C Chemical compound COC(=O)N1C(CCC2=CC(=CC=C12)C=1C=NN(C1)C1CC1)C ZFEHJOAFXIVHBN-UHFFFAOYSA-N 0.000 claims description 3
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims description 3
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims description 3
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 3
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 claims description 3
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 claims description 3
- 108010069236 Goserelin Proteins 0.000 claims description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 3
- 108010000817 Leuprolide Proteins 0.000 claims description 3
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 claims description 3
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 3
- WANNIOQKRZPMMR-KRWDZBQOSA-N [(2s)-5-cyclobutyloxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2h-quinolin-1-yl]-cyclopropylmethanone Chemical compound C([C@@H](N1C(=O)C2CC2)C)CC(C=2OC3CCC3)=C1C=CC=2C(=C1)C=NN1C1CCNCC1 WANNIOQKRZPMMR-KRWDZBQOSA-N 0.000 claims description 3
- 229960002932 anastrozole Drugs 0.000 claims description 3
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 claims description 3
- 229960001561 bleomycin Drugs 0.000 claims description 3
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 3
- 229960002092 busulfan Drugs 0.000 claims description 3
- 229960004117 capecitabine Drugs 0.000 claims description 3
- 125000002837 carbocyclic group Chemical group 0.000 claims description 3
- 229960005243 carmustine Drugs 0.000 claims description 3
- 229960004397 cyclophosphamide Drugs 0.000 claims description 3
- MUKBZXDFHGEPCZ-IBGZPJMESA-N cyclopropyl-[(2S)-5-(2-methoxyphenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=C(C=CC=C1)OC)C MUKBZXDFHGEPCZ-IBGZPJMESA-N 0.000 claims description 3
- 229960000684 cytarabine Drugs 0.000 claims description 3
- 229940127089 cytotoxic agent Drugs 0.000 claims description 3
- 239000002254 cytotoxic agent Substances 0.000 claims description 3
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 3
- 229960003901 dacarbazine Drugs 0.000 claims description 3
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 3
- 229960000975 daunorubicin Drugs 0.000 claims description 3
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 claims description 3
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 claims description 3
- 229960000452 diethylstilbestrol Drugs 0.000 claims description 3
- 229960003668 docetaxel Drugs 0.000 claims description 3
- 229940120655 eloxatin Drugs 0.000 claims description 3
- 229960001904 epirubicin Drugs 0.000 claims description 3
- 229930013356 epothilone Natural products 0.000 claims description 3
- 150000003883 epothilone derivatives Chemical class 0.000 claims description 3
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 claims description 3
- 229960001842 estramustine Drugs 0.000 claims description 3
- 229960005420 etoposide Drugs 0.000 claims description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 3
- 229960000255 exemestane Drugs 0.000 claims description 3
- 229960002949 fluorouracil Drugs 0.000 claims description 3
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 claims description 3
- 229960002074 flutamide Drugs 0.000 claims description 3
- 229960002258 fulvestrant Drugs 0.000 claims description 3
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 3
- 229960005277 gemcitabine Drugs 0.000 claims description 3
- 229940080856 gleevec Drugs 0.000 claims description 3
- 229960002913 goserelin Drugs 0.000 claims description 3
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 3
- 229960001101 ifosfamide Drugs 0.000 claims description 3
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 3
- 229960004768 irinotecan Drugs 0.000 claims description 3
- 229960003881 letrozole Drugs 0.000 claims description 3
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 claims description 3
- 229960002247 lomustine Drugs 0.000 claims description 3
- DHMTURDWPRKSOA-RUZDIDTESA-N lonafarnib Chemical compound C1CN(C(=O)N)CCC1CC(=O)N1CCC([C@@H]2C3=C(Br)C=C(Cl)C=C3CCC3=CC(Br)=CN=C32)CC1 DHMTURDWPRKSOA-RUZDIDTESA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229960002985 medroxyprogesterone acetate Drugs 0.000 claims description 3
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 claims description 3
- 229960001428 mercaptopurine Drugs 0.000 claims description 3
- 229960000485 methotrexate Drugs 0.000 claims description 3
- GBGGDSOFLRVEBJ-KRWDZBQOSA-N methyl (2S)-5-(3-chlorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC=1C=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC1 GBGGDSOFLRVEBJ-KRWDZBQOSA-N 0.000 claims description 3
- LVTZSHQYUZLQBU-SFHVURJKSA-N methyl (2S)-5-(3-cyanophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C=1C=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC1 LVTZSHQYUZLQBU-SFHVURJKSA-N 0.000 claims description 3
- ZSPJTUZZIRUVDB-INIZCTEOSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)OC)C ZSPJTUZZIRUVDB-INIZCTEOSA-N 0.000 claims description 3
- CVNJVTJDDJQMDU-HNNXBMFYSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-5-[[3-(hydroxymethyl)oxetan-3-yl]methoxy]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC1(COC1)CO CVNJVTJDDJQMDU-HNNXBMFYSA-N 0.000 claims description 3
- YKZYDUABWXPWAS-UHFFFAOYSA-N methyl 3,4-dihydro-2h-quinoline-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)CCCC2=C1 YKZYDUABWXPWAS-UHFFFAOYSA-N 0.000 claims description 3
- 229960004584 methylprednisolone Drugs 0.000 claims description 3
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 claims description 3
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 3
- 229960001756 oxaliplatin Drugs 0.000 claims description 3
- 108010092851 peginterferon alfa-2b Proteins 0.000 claims description 3
- 229940106366 pegintron Drugs 0.000 claims description 3
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 claims description 3
- 229960002340 pentostatin Drugs 0.000 claims description 3
- 229960003171 plicamycin Drugs 0.000 claims description 3
- 229960005205 prednisolone Drugs 0.000 claims description 3
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 3
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 claims description 3
- 229960000624 procarbazine Drugs 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 claims description 3
- 229960001052 streptozocin Drugs 0.000 claims description 3
- 229960001603 tamoxifen Drugs 0.000 claims description 3
- 229960004964 temozolomide Drugs 0.000 claims description 3
- 229960003604 testosterone Drugs 0.000 claims description 3
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 claims description 3
- 229960005026 toremifene Drugs 0.000 claims description 3
- 229960000575 trastuzumab Drugs 0.000 claims description 3
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 claims description 3
- 229960005294 triamcinolone Drugs 0.000 claims description 3
- 229960001055 uracil mustard Drugs 0.000 claims description 3
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 claims description 3
- 229960000653 valrubicin Drugs 0.000 claims description 3
- 229960003048 vinblastine Drugs 0.000 claims description 3
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 claims description 3
- 229960004355 vindesine Drugs 0.000 claims description 3
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 claims description 3
- 229960002066 vinorelbine Drugs 0.000 claims description 3
- UPCYLWBKVSCKIX-AWEZNQCLSA-N (2S)-1-(cyclopropanecarbonyl)-2-methyl-5-phenoxy-3,4-dihydro-2H-quinoline-6-carbonitrile Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C#N)OC1=CC=CC=C1)C UPCYLWBKVSCKIX-AWEZNQCLSA-N 0.000 claims description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 claims description 2
- RBPFUSJQPLOKCE-KRWDZBQOSA-N 1-[(2S)-2-methyl-5-(2-methylpropoxy)-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OCC(C)C)C=1C=NN(C1)C1CCNCC1)C(C)=O RBPFUSJQPLOKCE-KRWDZBQOSA-N 0.000 claims description 2
- JHEDDGHMUYENHJ-SFHVURJKSA-N 1-[(2S)-2-methyl-5-(6-methylpyridin-2-yl)oxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC(=CC=C1)C)C=1C=NN(C1)C1CCNCC1)C(C)=O JHEDDGHMUYENHJ-SFHVURJKSA-N 0.000 claims description 2
- WXZZTYZKGPFZHG-SFHVURJKSA-N 1-[(2S)-2-methyl-5-phenoxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=CC=CC=C1)C=1C=NN(C1)C1CCNCC1)C(C)=O WXZZTYZKGPFZHG-SFHVURJKSA-N 0.000 claims description 2
- FBBKDIBVHQAGDS-NSHDSACASA-N 1-[(2S)-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=CC(=C2CC1)OCCC)C(C)=O FBBKDIBVHQAGDS-NSHDSACASA-N 0.000 claims description 2
- HFEJIPGFSAJUMK-INIZCTEOSA-N 1-[(2S)-2-methyl-6-(1-methylsulfonyl-2,3-dihydroindol-5-yl)-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound CS(=O)(=O)N1CCC2=CC(=CC=C12)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC HFEJIPGFSAJUMK-INIZCTEOSA-N 0.000 claims description 2
- MZIVMRRAEYOKJC-AWEZNQCLSA-N 1-[(2S)-2-methyl-6-(1-methyltriazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=CC=CC=C1)C=1N=NN(C1)C)C(C)=O MZIVMRRAEYOKJC-AWEZNQCLSA-N 0.000 claims description 2
- TWGVMRJSXTXHNH-HNNXBMFYSA-N 1-[(2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[4-(trifluoromethyl)pyrimidin-2-yl]oxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=CC(=N1)C(F)(F)F)C=1C=NN(C1)C1CCNCC1)C(C)=O TWGVMRJSXTXHNH-HNNXBMFYSA-N 0.000 claims description 2
- YKMSDYGEPZFFRY-HNNXBMFYSA-N 1-[(2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]oxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=C(C=N1)C(F)(F)F)C=1C=NN(C1)C1CCNCC1)C(C)=O YKMSDYGEPZFFRY-HNNXBMFYSA-N 0.000 claims description 2
- VADWTACNHQATEH-KRWDZBQOSA-N 1-[(2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-pyridin-2-yloxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=CC=C1)C=1C=NN(C1)C1CCNCC1)C(C)=O VADWTACNHQATEH-KRWDZBQOSA-N 0.000 claims description 2
- KUSFFMFFJOZKME-HNNXBMFYSA-N 1-[(2S)-2-methyl-6-(3-methylsulfonylphenyl)-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound CS(=O)(=O)C=1C=C(C=CC1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC KUSFFMFFJOZKME-HNNXBMFYSA-N 0.000 claims description 2
- JOOWGADNHLOGPE-HNNXBMFYSA-N 1-[(2S)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC JOOWGADNHLOGPE-HNNXBMFYSA-N 0.000 claims description 2
- QFRWALIQWBOCIR-SFHVURJKSA-N 1-[(2S)-2-methyl-6-[3-(morpholine-4-carbonyl)phenyl]-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OCCC)C1=CC(=CC=C1)C(=O)N1CCOCC1)C(C)=O QFRWALIQWBOCIR-SFHVURJKSA-N 0.000 claims description 2
- UTBBSWDDIHMPIJ-HNNXBMFYSA-N 1-[(2S)-5-(1,3-benzoxazol-2-yloxy)-2-methyl-6-[1-(oxetan-3-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound O1C(=NC2=C1C=CC=C2)OC2=C1CC[C@@H](N(C1=CC=C2C=2C=NN(C2)C2COC2)C(C)=O)C UTBBSWDDIHMPIJ-HNNXBMFYSA-N 0.000 claims description 2
- GWHSFQQBHAMMBH-INIZCTEOSA-N 1-[(2S)-5-(2,5-difluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(C)=O)C)C=C(C=C1)F GWHSFQQBHAMMBH-INIZCTEOSA-N 0.000 claims description 2
- DTTKSRIOJHWICY-HNNXBMFYSA-N 1-[(2S)-5-(2-chlorophenoxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound ClC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CC2)C(C)=O)C)C=CC=C1 DTTKSRIOJHWICY-HNNXBMFYSA-N 0.000 claims description 2
- ZFOYSUPTLOPVJA-KRWDZBQOSA-N 1-[(2S)-5-(2-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(C)=O)C)C=CC=C1 ZFOYSUPTLOPVJA-KRWDZBQOSA-N 0.000 claims description 2
- SCDRXNIABNRNAY-INIZCTEOSA-N 1-[(2S)-5-(3,4-difluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC=1C=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(C)=O)C)C=CC1F SCDRXNIABNRNAY-INIZCTEOSA-N 0.000 claims description 2
- UIEWWOAISDVZIN-INIZCTEOSA-N 1-[(2S)-5-(4,6-dimethylpyrimidin-2-yl)oxy-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound CC1=NC(=NC(=C1)C)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCO)C(C)=O)C UIEWWOAISDVZIN-INIZCTEOSA-N 0.000 claims description 2
- QJHZUVWTLQSNOV-HNNXBMFYSA-N 1-[(2S)-5-(4-chlorophenoxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound ClC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CC2)C(C)=O)C)C=C1 QJHZUVWTLQSNOV-HNNXBMFYSA-N 0.000 claims description 2
- GFQGQZVRYNUZCE-KRWDZBQOSA-N 1-[(2S)-5-(5-cyclopropylpyrimidin-2-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)C=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(C)=O)C GFQGQZVRYNUZCE-KRWDZBQOSA-N 0.000 claims description 2
- JMYCPQOEEQJMIY-AWEZNQCLSA-N 1-[(2S)-5-(5-fluoropyrimidin-2-yl)oxy-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCS(=O)(=O)C)C(C)=O)C JMYCPQOEEQJMIY-AWEZNQCLSA-N 0.000 claims description 2
- KCCQVBOESYCIFZ-AWEZNQCLSA-N 1-[(2S)-5-(5-fluoropyrimidin-2-yl)oxy-6-[1-(1-hydroxy-2-methylpropan-2-yl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C(CO)(C)C)C(C)=O)C KCCQVBOESYCIFZ-AWEZNQCLSA-N 0.000 claims description 2
- GKGBSPGAOJJGKS-AWEZNQCLSA-N 1-[(2S)-5-(5-fluoropyrimidin-2-yl)oxy-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CC(C)(C)O)C(C)=O)C GKGBSPGAOJJGKS-AWEZNQCLSA-N 0.000 claims description 2
- AMZCDAKPLWMJBD-ZDUSSCGKSA-N 1-[(2S)-5-(5-fluoropyrimidin-2-yl)oxy-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCO)C(C)=O)C AMZCDAKPLWMJBD-ZDUSSCGKSA-N 0.000 claims description 2
- ILAFQIGTWMNTMB-KRWDZBQOSA-N 1-[(2S)-5-(6-cyclopropylpyrimidin-4-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)C1=CC(=NC=N1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(C)=O)C ILAFQIGTWMNTMB-KRWDZBQOSA-N 0.000 claims description 2
- LAEDXFNYOLXUKI-KRWDZBQOSA-N 1-[(2S)-5-(6-methoxypyridin-2-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound COC1=CC=CC(=N1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(C)=O)C LAEDXFNYOLXUKI-KRWDZBQOSA-N 0.000 claims description 2
- GBBHWMSRBRDSDA-HNNXBMFYSA-N 1-[(2S)-5-(cyclobutylmethoxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(C)=O)C GBBHWMSRBRDSDA-HNNXBMFYSA-N 0.000 claims description 2
- ANKYDNZTTKYKQE-KRWDZBQOSA-N 1-[(2S)-5-(cyclohexylmethoxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCCCC1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(C)=O)C ANKYDNZTTKYKQE-KRWDZBQOSA-N 0.000 claims description 2
- VLMBHXZMUPRNLP-ZDUSSCGKSA-N 1-[(2S)-5-(cyclopentylmethoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCCC1)COC1=C2CC[C@@H](N(C2=CC=C1)C(C)=O)C VLMBHXZMUPRNLP-ZDUSSCGKSA-N 0.000 claims description 2
- MHTQARHLWCDXFN-SFHVURJKSA-N 1-[(2S)-5-(cyclopentylmethoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCCC1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(C)=O)C MHTQARHLWCDXFN-SFHVURJKSA-N 0.000 claims description 2
- MWZFKILEASCUDR-KRWDZBQOSA-N 1-[(2S)-5-(cyclopentylmethoxy)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCCC1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCS(=O)(=O)C)C(C)=O)C MWZFKILEASCUDR-KRWDZBQOSA-N 0.000 claims description 2
- OZRJBVODBXTXOR-KRWDZBQOSA-N 1-[(2S)-5-(cyclopentylmethoxy)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCCC1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CC(C)(C)O)C(C)=O)C OZRJBVODBXTXOR-KRWDZBQOSA-N 0.000 claims description 2
- XPMASESZANMWJI-INIZCTEOSA-N 1-[(2S)-5-(cyclopentylmethoxy)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCCC1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCO)C(C)=O)C XPMASESZANMWJI-INIZCTEOSA-N 0.000 claims description 2
- NGQZQFZKOWQJTC-AWEZNQCLSA-N 1-[(2S)-5-(cyclopropylmethoxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCC1CC1 NGQZQFZKOWQJTC-AWEZNQCLSA-N 0.000 claims description 2
- IQPJOPZMWVPXGD-LXKVQUBZSA-N 1-[(2S)-5-[(E)-2-chloroethenoxy]-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound Cl/C=C/OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(C)=O)C IQPJOPZMWVPXGD-LXKVQUBZSA-N 0.000 claims description 2
- NUNROUNVEBUEKZ-SFHVURJKSA-N 1-[(2S)-5-anilino-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)NC1=CC=CC=C1)C=1C=NN(C1)C1CCNCC1)C(C)=O NUNROUNVEBUEKZ-SFHVURJKSA-N 0.000 claims description 2
- PHGBPFRCAYZQJH-HNNXBMFYSA-N 1-[(2S)-5-cyclobutyloxy-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCS(=O)(=O)C)C(C)=O)C PHGBPFRCAYZQJH-HNNXBMFYSA-N 0.000 claims description 2
- ROVUUBNJOXIYGB-AWEZNQCLSA-N 1-[(2S)-5-cyclobutyloxy-7,8-difluoro-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C(=C1C=1C=NN(C1)C1CCNCC1)F)F)C(C)=O)C ROVUUBNJOXIYGB-AWEZNQCLSA-N 0.000 claims description 2
- KLXUJHWSHXGDHK-NSHDSACASA-N 1-[(2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1N=NN(C1)C)F)C(C)=O)C KLXUJHWSHXGDHK-NSHDSACASA-N 0.000 claims description 2
- USMORCGYHHJWCN-HNNXBMFYSA-N 1-[(2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NN(C1)C1CCNCC1)F)C(C)=O)C USMORCGYHHJWCN-HNNXBMFYSA-N 0.000 claims description 2
- XYBQHAOYYVXKGC-NSHDSACASA-N 1-[(2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NNC1)F)C(C)=O)C XYBQHAOYYVXKGC-NSHDSACASA-N 0.000 claims description 2
- OFAGZEZSSMAWQZ-HNNXBMFYSA-N 1-[(2S)-5-cyclopentyloxy-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(C)=O)C OFAGZEZSSMAWQZ-HNNXBMFYSA-N 0.000 claims description 2
- DGUDIYHRMWXESD-ZDUSSCGKSA-N 1-[(2S)-5-cyclopropyloxy-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(C)=O)C DGUDIYHRMWXESD-ZDUSSCGKSA-N 0.000 claims description 2
- WYRLFWQPXSEHLL-AWEZNQCLSA-N 1-[(2S)-6-(1,3-benzothiazol-2-yl)-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound S1C(=NC2=C1C=CC=C2)C=2C(=C1CC[C@@H](N(C1=CC2)C(C)=O)C)OCCC WYRLFWQPXSEHLL-AWEZNQCLSA-N 0.000 claims description 2
- NYXIKAKOGSOQSB-ZDUSSCGKSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(1,3-thiazol-2-yloxy)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC=1SC=CN1 NYXIKAKOGSOQSB-ZDUSSCGKSA-N 0.000 claims description 2
- RAGWBLCCUTVMGQ-INIZCTEOSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(1-propan-2-ylazetidin-3-yl)oxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1CN(C1)C(C)C RAGWBLCCUTVMGQ-INIZCTEOSA-N 0.000 claims description 2
- JNPHWZQATASSSC-HNNXBMFYSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(2-methylpropoxy)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCC(C)C JNPHWZQATASSSC-HNNXBMFYSA-N 0.000 claims description 2
- ZIAISUCYECNYQJ-INIZCTEOSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(4-methylpyridin-2-yl)oxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC=CC(=C1)C ZIAISUCYECNYQJ-INIZCTEOSA-N 0.000 claims description 2
- HSKZPKHOJSUPDZ-INIZCTEOSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(6-methylpyridin-2-yl)oxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC(=CC=C1)C HSKZPKHOJSUPDZ-INIZCTEOSA-N 0.000 claims description 2
- KUHLYBQYYZCVCJ-ZDUSSCGKSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(oxetan-3-yloxy)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1COC1 KUHLYBQYYZCVCJ-ZDUSSCGKSA-N 0.000 claims description 2
- UGRSRLVOWCKEQC-INIZCTEOSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(pyridin-3-ylmethoxy)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCC=1C=NC=CC1 UGRSRLVOWCKEQC-INIZCTEOSA-N 0.000 claims description 2
- YDNHTCNKNLQJLE-HNNXBMFYSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-[(1-methylpyrazol-3-yl)methoxy]-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCC1=NN(C=C1)C YDNHTCNKNLQJLE-HNNXBMFYSA-N 0.000 claims description 2
- JFLXYJQSGFPWEU-SFHVURJKSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-[1-[(E)-prop-1-enyl]benzimidazol-2-yl]oxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC2=C(N1C=CC)C=CC=C2 JFLXYJQSGFPWEU-SFHVURJKSA-N 0.000 claims description 2
- JKXVJSLBSOAHBN-RDJZCZTQSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-[[(3S)-pyrrolidin-3-yl]methoxy]-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC[C@@H]1CNCC1 JKXVJSLBSOAHBN-RDJZCZTQSA-N 0.000 claims description 2
- LGJMOUBUFCECFU-HNNXBMFYSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-pyridin-2-yloxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC=CC=C1 LGJMOUBUFCECFU-HNNXBMFYSA-N 0.000 claims description 2
- YVIOORPLBKMAMF-HNNXBMFYSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(1-ethylazetidin-3-yl)oxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1CN(C1)CC YVIOORPLBKMAMF-HNNXBMFYSA-N 0.000 claims description 2
- GNPRGSBLDAXCAE-HNNXBMFYSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=CC=C(C=C1)F GNPRGSBLDAXCAE-HNNXBMFYSA-N 0.000 claims description 2
- RRDVAKXMKLFFBP-HNNXBMFYSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-[2-(dimethylamino)ethoxy]-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCN(C)C RRDVAKXMKLFFBP-HNNXBMFYSA-N 0.000 claims description 2
- YYDHZVKHRKIXQQ-LBPRGKRZSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-methoxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC YYDHZVKHRKIXQQ-LBPRGKRZSA-N 0.000 claims description 2
- CNBICKCYAMPLMG-AWEZNQCLSA-N 1-[(2S)-6-(1H-benzimidazol-2-yl)-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound N1C(=NC2=C1C=CC=C2)C=2C(=C1CC[C@@H](N(C1=CC2)C(C)=O)C)OCCC CNBICKCYAMPLMG-AWEZNQCLSA-N 0.000 claims description 2
- VQTCVIROKDTIQB-HNNXBMFYSA-N 1-[(2S)-6-(1H-indol-2-yl)-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound N1C(=CC2=CC=CC=C12)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC VQTCVIROKDTIQB-HNNXBMFYSA-N 0.000 claims description 2
- FCHRZVZCROGEDK-ZDUSSCGKSA-N 1-[(2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]oxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC=C(C=N1)C(F)(F)F FCHRZVZCROGEDK-ZDUSSCGKSA-N 0.000 claims description 2
- RPZKGXIIYWXCQX-RDJZCZTQSA-N 1-[(2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-[[(3S)-pyrrolidin-3-yl]methoxy]-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC[C@@H]1CNCC1 RPZKGXIIYWXCQX-RDJZCZTQSA-N 0.000 claims description 2
- KHUSFTUVXQSMBE-ZDUSSCGKSA-N 1-[(2S)-8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC=1C=C(C(=C2CC[C@@H](N(C12)C(C)=O)C)OC1=CC=CC=C1)C=1C=NNC1 KHUSFTUVXQSMBE-ZDUSSCGKSA-N 0.000 claims description 2
- OPQIGPTVHCKZIU-ZDUSSCGKSA-N 1-[(2S)-8-fluoro-2-methyl-6-(1-methyltriazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC=1C=C(C(=C2CC[C@@H](N(C12)C(C)=O)C)OC1=CC=CC=C1)C=1N=NN(C1)C OPQIGPTVHCKZIU-ZDUSSCGKSA-N 0.000 claims description 2
- FYKRSWDVFVZSHA-UHFFFAOYSA-N 1-[2-methyl-6-(4-methylsulfonylphenyl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound CS(=O)(=O)C1=CC=C(C=C1)C=1C(=C2CCC(N(C2=CC1)C(C)=O)C)OC1=CC=CC=C1 FYKRSWDVFVZSHA-UHFFFAOYSA-N 0.000 claims description 2
- HCHKYSIOCVHDHF-UHFFFAOYSA-N 1-[6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CCC(N(C2=CC1)C(C)=O)C)OC1=CC=CC=C1 HCHKYSIOCVHDHF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- GCKMFJBGXUYNAG-UHFFFAOYSA-N 17alpha-methyltestosterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C)(O)C1(C)CC2 GCKMFJBGXUYNAG-UHFFFAOYSA-N 0.000 claims description 2
- ZYGPESHNXRHZQL-HNNXBMFYSA-N 2-[[(2S)-1-(cyclopropanecarbonyl)-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-5-yl]oxy]benzonitrile Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NN(C1)C)OC1=C(C#N)C=CC=C1)C ZYGPESHNXRHZQL-HNNXBMFYSA-N 0.000 claims description 2
- ZYUFRJJRKYWCIV-IBGZPJMESA-N 2-[[(2S)-1-(cyclopropanecarbonyl)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-5-yl]oxy]benzonitrile Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=C(C#N)C=CC=C1)C ZYUFRJJRKYWCIV-IBGZPJMESA-N 0.000 claims description 2
- VZPHJPKLPJZWIL-SFHVURJKSA-N 2-[[(2S)-1-(cyclopropanecarbonyl)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-5-yl]oxy]pyridine-3-carbonitrile Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=NC=CC=C1C#N)C VZPHJPKLPJZWIL-SFHVURJKSA-N 0.000 claims description 2
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 claims description 2
- AMQMSJWYNGZXKH-INIZCTEOSA-N C(=C)N1[C@H](CCC2=C(C(=CC=C12)C1=CC=C(C=C1)NS(=O)(=O)C)OCC(=O)N(C)C)C Chemical compound C(=C)N1[C@H](CCC2=C(C(=CC=C12)C1=CC=C(C=C1)NS(=O)(=O)C)OCC(=O)N(C)C)C AMQMSJWYNGZXKH-INIZCTEOSA-N 0.000 claims description 2
- NRZUYDZLNAKFEU-IBGZPJMESA-N C(=C)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OCC(=O)N1CCCC1)C Chemical compound C(=C)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OCC(=O)N1CCCC1)C NRZUYDZLNAKFEU-IBGZPJMESA-N 0.000 claims description 2
- FJAKYQMUXNUOTM-ZOWNYOTGSA-N C(=O)OC.C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](NC2=CC1)C)OCC1(COC1)F Chemical compound C(=O)OC.C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](NC2=CC1)C)OCC1(COC1)F FJAKYQMUXNUOTM-ZOWNYOTGSA-N 0.000 claims description 2
- AQMVLEKSMXUPPH-ZOWNYOTGSA-N C(=O)OC.C1(CCC1)OC1=C2CC[C@@H](NC2=CC=C1C=1N=C(SC1)C1(CNC1)OC)C Chemical compound C(=O)OC.C1(CCC1)OC1=C2CC[C@@H](NC2=CC=C1C=1N=C(SC1)C1(CNC1)OC)C AQMVLEKSMXUPPH-ZOWNYOTGSA-N 0.000 claims description 2
- GZZKUJCKOVNUMY-UQKRIMTDSA-N C(=O)OC.ClC1=CC=C(OC2=C3CC[C@@H](NC3=CC=C2C=2C=NN(C2)C2CC2)C)C=C1 Chemical compound C(=O)OC.ClC1=CC=C(OC2=C3CC[C@@H](NC3=CC=C2C=2C=NN(C2)C2CC2)C)C=C1 GZZKUJCKOVNUMY-UQKRIMTDSA-N 0.000 claims description 2
- UJJKSMRVUOSSGL-KRWDZBQOSA-N C(C)N1[C@H](CCC2=C(C(=CC=C12)C1CCN(CC1)C(=O)NCC)OCCC)C Chemical compound C(C)N1[C@H](CCC2=C(C(=CC=C12)C1CCN(CC1)C(=O)NCC)OCCC)C UJJKSMRVUOSSGL-KRWDZBQOSA-N 0.000 claims description 2
- PGLCZLBGFSUXSD-UEDXYCIISA-N C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCO1)C(=O)C1CC1)C Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCO1)C(=O)C1CC1)C PGLCZLBGFSUXSD-UEDXYCIISA-N 0.000 claims description 2
- RIMZHSBTSYRXSP-PVCZSOGJSA-N COC(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCO1)OC1CCC1)C Chemical compound COC(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCO1)OC1CCC1)C RIMZHSBTSYRXSP-PVCZSOGJSA-N 0.000 claims description 2
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 claims description 2
- 108010092160 Dactinomycin Proteins 0.000 claims description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 2
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 claims description 2
- YDNJHYJFVFAUJI-HNNXBMFYSA-N N-[4-[(2S)-5-cyclobutyloxy-1-(cyclopropanecarbonyl)-2-methyl-3,4-dihydro-2H-quinolin-6-yl]-2-cyclopropylpyrazol-3-yl]acetamide Chemical compound C(C)(=O)NC1=C(C=NN1C1CC1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)C1CC1)C)OC1CCC1 YDNJHYJFVFAUJI-HNNXBMFYSA-N 0.000 claims description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Natural products C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims description 2
- QYYOXQRTBWZVJA-KRWDZBQOSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(2-piperidin-4-ylpyrazol-3-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C1=CC=NN1C1CCNCC1)C(=O)C1CC1)C QYYOXQRTBWZVJA-KRWDZBQOSA-N 0.000 claims description 2
- YPVWYUYDYGSQRR-INIZCTEOSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(2-piperidin-4-yltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C1=NN(N=C1)C1CCNCC1)C(=O)C1CC1)C YPVWYUYDYGSQRR-INIZCTEOSA-N 0.000 claims description 2
- KLSGBMSNZZCPRP-LBPRGKRZSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(2H-triazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=NNC1)C(=O)C1CC1)C KLSGBMSNZZCPRP-LBPRGKRZSA-N 0.000 claims description 2
- BISLDUGWGNTUSM-INIZCTEOSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(5-piperidin-4-yl-1H-imidazol-2-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1NC(=CN1)C1CCNCC1)C(=O)C1CC1)C BISLDUGWGNTUSM-INIZCTEOSA-N 0.000 claims description 2
- JHOWLTMTDSTDPM-AWEZNQCLSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-pyrazol-1-yl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1N1N=CC=C1)C(=O)C1CC1)C JHOWLTMTDSTDPM-AWEZNQCLSA-N 0.000 claims description 2
- ISLBCWHIRDCQIS-AWEZNQCLSA-N [(2S)-5-cyclobutyloxy-6-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN2C1NCC2)C(=O)C2CC2)C ISLBCWHIRDCQIS-AWEZNQCLSA-N 0.000 claims description 2
- LCCZOUMIWDBYTE-HNNXBMFYSA-N [(2S)-5-cyclobutyloxy-6-[1-(1,1-dioxothietan-3-yl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CS(C1)(=O)=O)C(=O)C1CC1)C LCCZOUMIWDBYTE-HNNXBMFYSA-N 0.000 claims description 2
- PQCNGMKKAZYGBE-UIDQEFQQSA-N [(2S)-5-cyclobutyloxy-6-[1-[(3S,4R)-3-fluoropiperidin-4-yl]pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)[C@H]1[C@H](CNCC1)F)C(=O)C1CC1)C PQCNGMKKAZYGBE-UIDQEFQQSA-N 0.000 claims description 2
- QKTUWYNLUPWFSH-LBPRGKRZSA-N [(2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1N=NN(C1)C)F)C(=O)C1CC1)C QKTUWYNLUPWFSH-LBPRGKRZSA-N 0.000 claims description 2
- ZGQPEJSJOXVJHP-ZDUSSCGKSA-N [(2S)-6-(5-amino-1,3,4-thiadiazol-2-yl)-2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=NN=C(S1)N)OC1=CC=CC=C1)C ZGQPEJSJOXVJHP-ZDUSSCGKSA-N 0.000 claims description 2
- HNHSNVXCOUGUTN-NSHDSACASA-N [(2S)-6-(5-amino-1,3,4-thiadiazol-2-yl)-5-cyclobutyloxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C1=NN=C(S1)N)C(=O)C1CC1)C HNHSNVXCOUGUTN-NSHDSACASA-N 0.000 claims description 2
- HVNXFGPVWQMLEG-KRWDZBQOSA-N [(2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)C1CC1)C)OC1=CC=CC=C1 HVNXFGPVWQMLEG-KRWDZBQOSA-N 0.000 claims description 2
- QMDUWOKLJVVIMY-HNNXBMFYSA-N [(2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)C1CC1)C)OCCC QMDUWOKLJVVIMY-HNNXBMFYSA-N 0.000 claims description 2
- GJNJDTJJSGMTHN-HNNXBMFYSA-N [(2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-5-(2,4-difluorophenoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)C1CC1)C)OC1=C(C=C(C=C1)F)F GJNJDTJJSGMTHN-HNNXBMFYSA-N 0.000 claims description 2
- NGXOXBHCNSATAI-HNNXBMFYSA-N [(2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-5-(2,5-difluorophenoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)C1CC1)C)OC1=C(C=CC(=C1)F)F NGXOXBHCNSATAI-HNNXBMFYSA-N 0.000 claims description 2
- ICWMTYQCVNWEJM-HNNXBMFYSA-N [(2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-5-(3,4-difluorophenoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)C1CC1)C)OC1=CC(=C(C=C1)F)F ICWMTYQCVNWEJM-HNNXBMFYSA-N 0.000 claims description 2
- DXQBXMJGBLUZLJ-HNNXBMFYSA-N [(2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-5-(3,5-difluorophenoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)C1CC1)C)OC1=CC(=CC(=C1)F)F DXQBXMJGBLUZLJ-HNNXBMFYSA-N 0.000 claims description 2
- XYVXMOCAZZKZBV-INIZCTEOSA-N [(2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-5-(3-fluorophenoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)C1CC1)C)OC1=CC(=CC=C1)F XYVXMOCAZZKZBV-INIZCTEOSA-N 0.000 claims description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 claims description 2
- 229940009456 adriamycin Drugs 0.000 claims description 2
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 claims description 2
- 229960003437 aminoglutethimide Drugs 0.000 claims description 2
- 229960001220 amsacrine Drugs 0.000 claims description 2
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 claims description 2
- 229940120638 avastin Drugs 0.000 claims description 2
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 2
- 229960000997 bicalutamide Drugs 0.000 claims description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 claims description 2
- 229940112129 campath Drugs 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 229960002559 chlorotrianisene Drugs 0.000 claims description 2
- BFPSDSIWYFKGBC-UHFFFAOYSA-N chlorotrianisene Chemical compound C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 0.000 claims description 2
- RWLGNDGCLZPHHO-IBGZPJMESA-N cyclopropyl-[(2S)-2-methyl-5-(6-methylpyridin-2-yl)oxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=NC(=CC=C1)C)C RWLGNDGCLZPHHO-IBGZPJMESA-N 0.000 claims description 2
- STBYXWBVTUGCDB-IBGZPJMESA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(1-piperidin-4-ylpyrazol-3-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=NN(C=C1)C1CCNCC1)OC1=CC=CC=C1)C STBYXWBVTUGCDB-IBGZPJMESA-N 0.000 claims description 2
- LOBUYKMIGQVSFB-IBGZPJMESA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=CC=CC=C1)C LOBUYKMIGQVSFB-IBGZPJMESA-N 0.000 claims description 2
- HZXVMTRBKXQTNJ-HNNXBMFYSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NNC1)OC1=CC=CC=C1)C HZXVMTRBKXQTNJ-HNNXBMFYSA-N 0.000 claims description 2
- RFOCINPYVFGAPE-HNNXBMFYSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(1H-pyrazol-5-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=CC=NN1)OC1=CC=CC=C1)C RFOCINPYVFGAPE-HNNXBMFYSA-N 0.000 claims description 2
- LIGDASUINQIVIE-SFHVURJKSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(2-piperidin-4-yltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C1=NN(N=C1)C1CCNCC1)OC1=CC=CC=C1)C LIGDASUINQIVIE-SFHVURJKSA-N 0.000 claims description 2
- XQZOBJQIAOZYCD-AWEZNQCLSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(2H-triazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NNC1)OC1=CC=CC=C1)C XQZOBJQIAOZYCD-AWEZNQCLSA-N 0.000 claims description 2
- FNAIHNGWMZPVAA-IBGZPJMESA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(4-piperidin-4-ylpyrazol-1-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)N1N=CC(=C1)C1CCNCC1)OC1=CC=CC=C1)C FNAIHNGWMZPVAA-IBGZPJMESA-N 0.000 claims description 2
- VYLDWPJEORIWPH-INIZCTEOSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-prop-1-ynyl-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C#CC)OC1=CC=CC=C1)C VYLDWPJEORIWPH-INIZCTEOSA-N 0.000 claims description 2
- GBZZKMFTUFISMS-INIZCTEOSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-pyrazol-1-yl-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)N1N=CC=C1)OC1=CC=CC=C1)C GBZZKMFTUFISMS-INIZCTEOSA-N 0.000 claims description 2
- DKILLVRXOWPPJS-HNNXBMFYSA-N cyclopropyl-[(2S)-2-methyl-6-(1,2-oxazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NOC1)OC1=CC=CC=C1)C DKILLVRXOWPPJS-HNNXBMFYSA-N 0.000 claims description 2
- WFSCORJLUQLKFV-INIZCTEOSA-N cyclopropyl-[(2S)-2-methyl-6-(1-methylpyrazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C)OC1=CC=CC=C1)C WFSCORJLUQLKFV-INIZCTEOSA-N 0.000 claims description 2
- OMLDLZSYKWGEHW-KRWDZBQOSA-N cyclopropyl-[(2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[3-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=NC=CC=C1C(F)(F)F)C OMLDLZSYKWGEHW-KRWDZBQOSA-N 0.000 claims description 2
- TXIIDCQYXICUQI-KRWDZBQOSA-N cyclopropyl-[(2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[5-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=NC=C(C=C1)C(F)(F)F)C TXIIDCQYXICUQI-KRWDZBQOSA-N 0.000 claims description 2
- GUNJVTAVGFLBLO-AWEZNQCLSA-N cyclopropyl-[(2S)-2-methyl-6-(5-methyl-1,3,4-thiadiazol-2-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1SC(=NN1)C)OC1=CC=CC=C1)C GUNJVTAVGFLBLO-AWEZNQCLSA-N 0.000 claims description 2
- YDSNWUIMAAKNGD-ZDUSSCGKSA-N cyclopropyl-[(2S)-5-(2,5-difluorophenoxy)-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NN(C1)C)OC1=C(C=CC(=C1)F)F)C YDSNWUIMAAKNGD-ZDUSSCGKSA-N 0.000 claims description 2
- PMFYOQVPEQFJDZ-IBGZPJMESA-N cyclopropyl-[(2S)-5-(2,6-dimethylpyridin-3-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC=1C(=NC(=CC1)C)C)C PMFYOQVPEQFJDZ-IBGZPJMESA-N 0.000 claims description 2
- QYDUCSHUSJAWAI-AWEZNQCLSA-N cyclopropyl-[(2S)-5-(2-fluorophenoxy)-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NN(C1)C)OC1=C(C=CC=C1)F)C QYDUCSHUSJAWAI-AWEZNQCLSA-N 0.000 claims description 2
- UAPRHDLSCMAUPJ-ZDUSSCGKSA-N cyclopropyl-[(2S)-5-(3,4-difluorophenoxy)-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NN(C1)C)OC1=CC(=C(C=C1)F)F)C UAPRHDLSCMAUPJ-ZDUSSCGKSA-N 0.000 claims description 2
- HWYAUNXNSXUBKS-KRWDZBQOSA-N cyclopropyl-[(2S)-5-(3,4-difluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=CC(=C(C=C1)F)F)C HWYAUNXNSXUBKS-KRWDZBQOSA-N 0.000 claims description 2
- DLQMEQPHKMLKGO-KRWDZBQOSA-N cyclopropyl-[(2S)-5-(3,5-difluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=CC(=CC(=C1)F)F)C DLQMEQPHKMLKGO-KRWDZBQOSA-N 0.000 claims description 2
- PEYGWWFDSQICEG-AWEZNQCLSA-N cyclopropyl-[(2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NN(C1)C)OC1=CC=C(C=C1)F)C PEYGWWFDSQICEG-AWEZNQCLSA-N 0.000 claims description 2
- HFVHSOOIHPABCZ-IBGZPJMESA-N cyclopropyl-[(2S)-5-(4-methoxyphenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=CC=C(C=C1)OC)C HFVHSOOIHPABCZ-IBGZPJMESA-N 0.000 claims description 2
- CYDWMCYRONMHRX-SFHVURJKSA-N cyclopropyl-[(2S)-5-(6-methoxypyridin-2-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=NC(=CC=C1)OC)C CYDWMCYRONMHRX-SFHVURJKSA-N 0.000 claims description 2
- ODPGKYVCCDPOOD-INIZCTEOSA-N cyclopropyl-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-8-fluoro-2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC(=C12)F)C=1C=NN(C1)C1CC1)OC1=CC=CC=C1)C ODPGKYVCCDPOOD-INIZCTEOSA-N 0.000 claims description 2
- UCQVAPQEUNPGQF-KRWDZBQOSA-N cyclopropyl-[(2S)-6-[1-(1,1-dioxothietan-3-yl)pyrazol-4-yl]-2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CS(C1)(=O)=O)OC1=CC=CC=C1)C UCQVAPQEUNPGQF-KRWDZBQOSA-N 0.000 claims description 2
- CNGIHDFFZMVXFM-INIZCTEOSA-N cyclopropyl-[(2S)-6-[1-(1,1-dioxothietan-3-yl)pyrazol-4-yl]-5-(4-fluorophenoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CS(C1)(=O)=O)OC1=CC=C(C=C1)F)C CNGIHDFFZMVXFM-INIZCTEOSA-N 0.000 claims description 2
- NDSWOYYTVOZYEH-AWEZNQCLSA-N cyclopropyl-[(2S)-8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC(=C12)F)C=1C=NNC1)OC1=CC=CC=C1)C NDSWOYYTVOZYEH-AWEZNQCLSA-N 0.000 claims description 2
- CPWOBDURELDNNC-AWEZNQCLSA-N cyclopropyl-[(2S)-8-fluoro-2-methyl-6-(1-methyltriazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC(=C12)F)C=1N=NN(C1)C)OC1=CC=CC=C1)C CPWOBDURELDNNC-AWEZNQCLSA-N 0.000 claims description 2
- MHEIQLCZYXUDPY-UHFFFAOYSA-N cyclopropyl-[6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1C(CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CC1)OC1=CC=CC=C1)C MHEIQLCZYXUDPY-UHFFFAOYSA-N 0.000 claims description 2
- 229960000640 dactinomycin Drugs 0.000 claims description 2
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 claims description 2
- 229950004683 drostanolone propionate Drugs 0.000 claims description 2
- 229940082789 erbitux Drugs 0.000 claims description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 2
- 229960005304 fludarabine phosphate Drugs 0.000 claims description 2
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 claims description 2
- 229960001751 fluoxymesterone Drugs 0.000 claims description 2
- 229940022353 herceptin Drugs 0.000 claims description 2
- 229960001001 ibritumomab tiuxetan Drugs 0.000 claims description 2
- 150000002596 lactones Chemical class 0.000 claims description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 claims description 2
- 229960004338 leuprorelin Drugs 0.000 claims description 2
- 229960001786 megestrol Drugs 0.000 claims description 2
- VRUNSBGXRXNTHO-IBGZPJMESA-N methyl (2S)-2-methyl-5-(6-morpholin-4-ylpyrimidin-4-yl)oxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=NC(=C1)N1CCOCC1)C=1C=NN(C1)C1CCNCC1)C(=O)OC VRUNSBGXRXNTHO-IBGZPJMESA-N 0.000 claims description 2
- RVXVNBFIDKXTFK-SFHVURJKSA-N methyl (2S)-2-methyl-5-phenoxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=CC=CC=C1)C=1C=NN(C1)C1CCNCC1)C(=O)OC RVXVNBFIDKXTFK-SFHVURJKSA-N 0.000 claims description 2
- ZFSANWVXGOXOEE-SFHVURJKSA-N methyl (2S)-2-methyl-5-phenoxy-6-(4-piperazin-1-ylpyrazol-1-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=CC=CC=C1)N1N=CC(=C1)N1CCNCC1)C(=O)OC ZFSANWVXGOXOEE-SFHVURJKSA-N 0.000 claims description 2
- OUSVOXRCQUSQRN-AWEZNQCLSA-N methyl (2S)-2-methyl-6-(1-methyltriazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=CC=CC=C1)C=1N=NN(C1)C)C(=O)OC OUSVOXRCQUSQRN-AWEZNQCLSA-N 0.000 claims description 2
- VBESJGVEDCOYOB-HNNXBMFYSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[4-(trifluoromethyl)pyrimidin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=CC(=N1)C(F)(F)F)C=1C=NN(C1)C1CCNCC1)C(=O)OC VBESJGVEDCOYOB-HNNXBMFYSA-N 0.000 claims description 2
- BVTVGYKADOZPAO-INIZCTEOSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[5-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=C(C=C1)C(F)(F)F)C=1C=NN(C1)C1CCNCC1)C(=O)OC BVTVGYKADOZPAO-INIZCTEOSA-N 0.000 claims description 2
- OZSZZCZBEWKVBZ-HNNXBMFYSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=C(C=N1)C(F)(F)F)C=1C=NN(C1)C1CCNCC1)C(=O)OC OZSZZCZBEWKVBZ-HNNXBMFYSA-N 0.000 claims description 2
- QBGBWPYIAUZDIK-ROUUACIJSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[[(3S)-pyrrolidin-3-yl]methoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC[C@@H]1CNCC1)C=1C=NN(C1)C1CCNCC1)C(=O)OC QBGBWPYIAUZDIK-ROUUACIJSA-N 0.000 claims description 2
- CHMCQYHGEXFAGS-HNNXBMFYSA-N methyl (2S)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-5-[3-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=CC=C1C(F)(F)F CHMCQYHGEXFAGS-HNNXBMFYSA-N 0.000 claims description 2
- SEICFVOAUGADIY-HNNXBMFYSA-N methyl (2S)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-5-[5-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=C1)C(F)(F)F SEICFVOAUGADIY-HNNXBMFYSA-N 0.000 claims description 2
- MOOCCEDMGTWABG-HNNXBMFYSA-N methyl (2S)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-5-propoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCCC MOOCCEDMGTWABG-HNNXBMFYSA-N 0.000 claims description 2
- YLPGFIAZJPHQOX-KRWDZBQOSA-N methyl (2S)-5-(2-chloro-4-cyanophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC(=C1)C#N YLPGFIAZJPHQOX-KRWDZBQOSA-N 0.000 claims description 2
- KGWUUPAANRZEGI-KRWDZBQOSA-N methyl (2S)-5-(2-chlorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC=C1 KGWUUPAANRZEGI-KRWDZBQOSA-N 0.000 claims description 2
- WPYQALSRTIVPJC-HNNXBMFYSA-N methyl (2S)-5-(2-chlorophenoxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CC2)C(=O)OC)C)C=CC=C1 WPYQALSRTIVPJC-HNNXBMFYSA-N 0.000 claims description 2
- HKPICVGIBXKXNH-KRWDZBQOSA-N methyl (2S)-5-(2-cyano-3-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC=C1F HKPICVGIBXKXNH-KRWDZBQOSA-N 0.000 claims description 2
- NQEASFPKWSOVNS-INIZCTEOSA-N methyl (2S)-5-(3,5-difluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=C(C1)F NQEASFPKWSOVNS-INIZCTEOSA-N 0.000 claims description 2
- PCKGJVFGASZHDH-KRWDZBQOSA-N methyl (2S)-5-(3-chloro-2-cyanophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC=1C(=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC1)C#N PCKGJVFGASZHDH-KRWDZBQOSA-N 0.000 claims description 2
- SCDACDYMFHBSJB-INIZCTEOSA-N methyl (2S)-5-(3-cyanopyridin-2-yl)oxy-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C=1C(=NC=CC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CC(C)(C)O)C(=O)OC)C SCDACDYMFHBSJB-INIZCTEOSA-N 0.000 claims description 2
- CMXRILIORBROOC-SFHVURJKSA-N methyl (2S)-5-(4-chloro-2-cyanophenoxy)-2-methyl-6-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC1=CC(=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCN(CC2)C)C(=O)OC)C)C=C1)C#N CMXRILIORBROOC-SFHVURJKSA-N 0.000 claims description 2
- YHALVBHSAVYQSX-KRWDZBQOSA-N methyl (2S)-5-(4-cyano-2-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C1=CC(=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=C1)F YHALVBHSAVYQSX-KRWDZBQOSA-N 0.000 claims description 2
- SVTUQICDHSQQRH-XCUTYXLRSA-N methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-[(2S)-2-methylazetidin-3-yl]pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2[C@@H](NC2)C)C(=O)OC)C)C=C1 SVTUQICDHSQQRH-XCUTYXLRSA-N 0.000 claims description 2
- IHCFHRPBDCWKJY-SFHVURJKSA-N methyl (2S)-5-(4-methoxyphenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound COC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=C1 IHCFHRPBDCWKJY-SFHVURJKSA-N 0.000 claims description 2
- VNMQQWPAJSWGEH-INIZCTEOSA-N methyl (2S)-5-(5-cyclopropylpyrimidin-2-yl)oxy-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)C=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CC(C)(C)O)C(=O)OC)C VNMQQWPAJSWGEH-INIZCTEOSA-N 0.000 claims description 2
- DZYXHDSZIYXNJQ-HNNXBMFYSA-N methyl (2S)-5-(5-fluoropyrimidin-2-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)OC)C DZYXHDSZIYXNJQ-HNNXBMFYSA-N 0.000 claims description 2
- QOBMYCSXXLKSDA-AWEZNQCLSA-N methyl (2S)-5-(5-fluoropyrimidin-2-yl)oxy-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C=NC(=NC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCS(=O)(=O)C)C(=O)OC)C QOBMYCSXXLKSDA-AWEZNQCLSA-N 0.000 claims description 2
- ACALHZNVJQPIOY-ZDUSSCGKSA-N methyl (2S)-5-(azetidin-3-yloxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound N1CC(C1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(=O)OC)C ACALHZNVJQPIOY-ZDUSSCGKSA-N 0.000 claims description 2
- ADVNSCXXJFQVTE-INIZCTEOSA-N methyl (2S)-5-(cyclopentylmethoxy)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCCC1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCO)C(=O)OC)C ADVNSCXXJFQVTE-INIZCTEOSA-N 0.000 claims description 2
- DSVWTEUSCWEDIG-HNNXBMFYSA-N methyl (2S)-5-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C(=NC=C(C1)C(F)(F)F)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)OC)C DSVWTEUSCWEDIG-HNNXBMFYSA-N 0.000 claims description 2
- PJPCQWXJFCPKDV-ZDUSSCGKSA-N methyl (2S)-5-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C(=NC=C(C1)C(F)(F)F)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCO)C(=O)OC)C PJPCQWXJFCPKDV-ZDUSSCGKSA-N 0.000 claims description 2
- LHJAQGIVKJQOHV-INIZCTEOSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-(1-methyl-2-piperidin-4-ylimidazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(N(C1)C)C1CCNCC1)C(=O)OC)C LHJAQGIVKJQOHV-INIZCTEOSA-N 0.000 claims description 2
- ZDGAPQWSCPZGLE-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-(2-piperidin-4-yl-1H-imidazol-5-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(NC1)C1CCNCC1)C(=O)OC)C ZDGAPQWSCPZGLE-HNNXBMFYSA-N 0.000 claims description 2
- WHCYONWUXBGTDX-GGQJKKPXSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-[1-(2-methyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC2C(CN(C2)C)C1)C(=O)OC)C WHCYONWUXBGTDX-GGQJKKPXSA-N 0.000 claims description 2
- UMRNEJKPOLVZOP-CJUKTHODSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-[1-[(2S)-2-methylazetidin-3-yl]pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1[C@@H](NC1)C)C(=O)OC)C UMRNEJKPOLVZOP-CJUKTHODSA-N 0.000 claims description 2
- CKHGTCKQFMDPRV-XWFFHEKESA-N methyl (2S)-5-cyclobutyloxy-6-[1-(3-methoxy-1-methylpiperidin-4-yl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1C(CN(CC1)C)OC)C(=O)OC)C CKHGTCKQFMDPRV-XWFFHEKESA-N 0.000 claims description 2
- XLOUWFKVTYUTRQ-NSHDSACASA-N methyl (2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1-methyltriazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1N=NN(C1)C)F)C(=O)OC)C XLOUWFKVTYUTRQ-NSHDSACASA-N 0.000 claims description 2
- MACMCDJVWABJMX-INIZCTEOSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(1-propan-2-ylazetidin-3-yl)oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound COC(=O)N1[C@@H](C)CCC2=C1C=CC(C1=CN(N=C1)C1CC1)=C2OC1CN(C1)C(C)C MACMCDJVWABJMX-INIZCTEOSA-N 0.000 claims description 2
- LOVDMJFBWDGZJG-ZDUSSCGKSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(3,3,3-trifluoropropoxy)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCCC(F)(F)F LOVDMJFBWDGZJG-ZDUSSCGKSA-N 0.000 claims description 2
- ZGSCAGKCPWYLCN-HNNXBMFYSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(5-methylpyrimidin-2-yl)oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=N1)C ZGSCAGKCPWYLCN-HNNXBMFYSA-N 0.000 claims description 2
- XRPSXNKWWDWTDO-ZDUSSCGKSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=N1)C(F)(F)F XRPSXNKWWDWTDO-ZDUSSCGKSA-N 0.000 claims description 2
- JCWQWLWPBICAAF-ZDUSSCGKSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(1,3-difluoropropan-2-yloxy)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC(CF)CF JCWQWLWPBICAAF-ZDUSSCGKSA-N 0.000 claims description 2
- CXLHPDHBOYAKGX-LBPRGKRZSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(2,2-difluoroethoxy)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC(F)F CXLHPDHBOYAKGX-LBPRGKRZSA-N 0.000 claims description 2
- RIHNPVSHKSDELO-HNNXBMFYSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=CC=C(C=C1)F RIHNPVSHKSDELO-HNNXBMFYSA-N 0.000 claims description 2
- VJSBKESTWIYGCS-CFMCSPIPSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-5-[(2,2-difluorocyclopropyl)methoxy]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC1C(C1)(F)F VJSBKESTWIYGCS-CFMCSPIPSA-N 0.000 claims description 2
- MENJVDZGKKMBNV-INIZCTEOSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC(C)C)(C)C MENJVDZGKKMBNV-INIZCTEOSA-N 0.000 claims description 2
- RHDRFPNPXWRPFZ-INIZCTEOSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-(5-methylpyrimidin-2-yl)oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=N1)C)(C)C RHDRFPNPXWRPFZ-INIZCTEOSA-N 0.000 claims description 2
- ZAGONFXELSNOKP-HNNXBMFYSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=C1)C(F)(F)F)(C)C ZAGONFXELSNOKP-HNNXBMFYSA-N 0.000 claims description 2
- GXNDGIHQAINLMJ-HNNXBMFYSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-pyrazin-2-yloxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=CN=C1)(C)C GXNDGIHQAINLMJ-HNNXBMFYSA-N 0.000 claims description 2
- FHGWNUSCMPQQMR-HNNXBMFYSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-(2-methylpropoxy)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC(C)C FHGWNUSCMPQQMR-HNNXBMFYSA-N 0.000 claims description 2
- SJIWDCRHEXFYTJ-HNNXBMFYSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-[2-[methyl(methylsulfonyl)amino]ethoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCCN(S(=O)(=O)C)C SJIWDCRHEXFYTJ-HNNXBMFYSA-N 0.000 claims description 2
- BWRDDXFROXRDFG-AWEZNQCLSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=C1)C(F)(F)F BWRDDXFROXRDFG-AWEZNQCLSA-N 0.000 claims description 2
- DZXYELYSWMFYQS-ZDUSSCGKSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-[5-(trifluoromethyl)pyrimidin-2-yl]oxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=NC=C(C=N1)C(F)(F)F DZXYELYSWMFYQS-ZDUSSCGKSA-N 0.000 claims description 2
- FAUWOUSJWPFHHJ-HOTGVXAUSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-[[(3S)-pyrrolidin-3-yl]methoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC[C@@H]1CNCC1 FAUWOUSJWPFHHJ-HOTGVXAUSA-N 0.000 claims description 2
- RRHJNKNWTXBXCT-AWEZNQCLSA-N methyl (2S)-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-5-propoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OCCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCCC RRHJNKNWTXBXCT-AWEZNQCLSA-N 0.000 claims description 2
- LNDKYLDOJZCWKN-AWEZNQCLSA-N methyl (2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-5-(2,4-difluorophenoxy)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=C(C=C(C=C1)F)F LNDKYLDOJZCWKN-AWEZNQCLSA-N 0.000 claims description 2
- PTYBTYNBNMRSSE-AWEZNQCLSA-N methyl (2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-5-(2,5-difluorophenoxy)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=C(C=CC(=C1)F)F PTYBTYNBNMRSSE-AWEZNQCLSA-N 0.000 claims description 2
- LQTYPLHNKDSHBL-HNNXBMFYSA-N methyl (2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-5-(4-fluorophenoxy)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=CC=C(C=C1)F LQTYPLHNKDSHBL-HNNXBMFYSA-N 0.000 claims description 2
- PPKNUWOYANVMPR-ZDUSSCGKSA-N methyl (2S)-6-cyano-2-methyl-5-phenoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=CC=CC=C1 PPKNUWOYANVMPR-ZDUSSCGKSA-N 0.000 claims description 2
- GJLJHYYCLGCERJ-UHFFFAOYSA-N methyl 2-methyl-3,4-dihydro-2h-quinoline-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)C(C)CCC2=C1 GJLJHYYCLGCERJ-UHFFFAOYSA-N 0.000 claims description 2
- KOTNKQVSRSPRQI-UHFFFAOYSA-N methyl 6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-phenoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CCC(N(C2=CC1)C(=O)OC)C)OC1=CC=CC=C1 KOTNKQVSRSPRQI-UHFFFAOYSA-N 0.000 claims description 2
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- 229960001566 methyltestosterone Drugs 0.000 claims description 2
- 229960000350 mitotane Drugs 0.000 claims description 2
- 235000005152 nicotinamide Nutrition 0.000 claims description 2
- 239000011570 nicotinamide Substances 0.000 claims description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinic acid amide Natural products NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 2
- 229940063683 taxotere Drugs 0.000 claims description 2
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 claims description 2
- 229960005353 testolactone Drugs 0.000 claims description 2
- 229960001196 thiotepa Drugs 0.000 claims description 2
- 229960003087 tioguanine Drugs 0.000 claims description 2
- 229950009158 tipifarnib Drugs 0.000 claims description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 2
- 229960000303 topotecan Drugs 0.000 claims description 2
- 229960005267 tositumomab Drugs 0.000 claims description 2
- 229950001353 tretamine Drugs 0.000 claims description 2
- 229940086984 trisenox Drugs 0.000 claims description 2
- 229940099039 velcade Drugs 0.000 claims description 2
- 229940053867 xeloda Drugs 0.000 claims description 2
- STODOJZJIXRDTC-SFHVURJKSA-N methyl (2S)-5-(cyclopentylmethoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCCC1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)OC)C STODOJZJIXRDTC-SFHVURJKSA-N 0.000 claims 6
- JFPBTWVGOUKYPF-KRWDZBQOSA-N 1-[(2S)-8-fluoro-2-methyl-5-phenoxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound FC=1C=C(C(=C2CC[C@@H](N(C12)C(C)=O)C)OC1=CC=CC=C1)C=1C=NN(C1)C1CCNCC1 JFPBTWVGOUKYPF-KRWDZBQOSA-N 0.000 claims 2
- AVALAFKCUACXBX-HNNXBMFYSA-N cyclopropyl-[(2S)-2-methyl-6-(1-methyltriazol-4-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1N=NN(C1)C)OC1=CC=CC=C1)C AVALAFKCUACXBX-HNNXBMFYSA-N 0.000 claims 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 2
- CALYTWFVCCZBPJ-INIZCTEOSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-propoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OCCC)C=1C=NN(C1)C1CCNCC1)C(=O)OC CALYTWFVCCZBPJ-INIZCTEOSA-N 0.000 claims 2
- PBSJLGYCWCUXLV-UHFFFAOYSA-N methyl 2h-quinoline-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)CC=CC2=C1 PBSJLGYCWCUXLV-UHFFFAOYSA-N 0.000 claims 2
- QBNLOOFPJGMLIC-KRWDZBQOSA-N (2S)-2-methyl-5-phenoxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylic acid Chemical compound C[C@H]1CCc2c(Oc3ccccc3)c(ccc2N1C(O)=O)-c1cnn(c1)C1CCNCC1 QBNLOOFPJGMLIC-KRWDZBQOSA-N 0.000 claims 1
- BJFGZJXPDIVFRK-PNDGYVOYSA-N (2S)-5-(4-fluorophenoxy)-6-[1-[(3R,4R)-3-fluoropiperidin-4-yl]pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid Chemical compound C[C@H]1CCc2c(Oc3ccc(F)cc3)c(ccc2N1C(O)=O)-c1cnn(c1)[C@@H]1CCNC[C@H]1F BJFGZJXPDIVFRK-PNDGYVOYSA-N 0.000 claims 1
- IKJMHOUZIGEYMT-BLMAQRGESA-N (8S,9S,10R,13S,14S,17R)-17-acetyl-16-hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC(O)[C@H](C(=O)C)[C@@]1(C)CC2.C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC(O)[C@H](C(=O)C)[C@@]1(C)CC2 IKJMHOUZIGEYMT-BLMAQRGESA-N 0.000 claims 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims 1
- FHPPCNHAICXZHK-UHFFFAOYSA-N 1-(2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl)ethanone Chemical compound CC1N(C2=CC=CC(=C2CC1)OC1=CC=CC=C1)C(C)=O FHPPCNHAICXZHK-UHFFFAOYSA-N 0.000 claims 1
- CBKMNAXABMOMPW-HNNXBMFYSA-N 1-[(2S)-2-methyl-6-(4-methylsulfonylphenyl)-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound CS(=O)(=O)C1=CC=C(C=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC CBKMNAXABMOMPW-HNNXBMFYSA-N 0.000 claims 1
- TVBDWGYLBWHCJB-AWEZNQCLSA-N 1-[(2S)-2-methyl-6-piperidin-4-yl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OCCC)C1CCNCC1)C(C)=O TVBDWGYLBWHCJB-AWEZNQCLSA-N 0.000 claims 1
- KSNBPCKLFGCBEP-HNNXBMFYSA-N 1-[(2S)-5-cyclobutyloxy-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CC(C)(C)O)C(C)=O)C KSNBPCKLFGCBEP-HNNXBMFYSA-N 0.000 claims 1
- QNEITEOEALJAKN-AWEZNQCLSA-N 1-[(2S)-5-cyclobutyloxy-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CCO)C(C)=O)C QNEITEOEALJAKN-AWEZNQCLSA-N 0.000 claims 1
- HNMSVNSXVDSVGO-AWEZNQCLSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-[(5-methyl-1,3-oxazol-2-yl)methoxy]-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCC=1OC(=CN1)C HNMSVNSXVDSVGO-AWEZNQCLSA-N 0.000 claims 1
- HKGQEALZVIZMIR-HNNXBMFYSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(2-fluorophenoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=C(C=CC=C1)F HKGQEALZVIZMIR-HNNXBMFYSA-N 0.000 claims 1
- QMFHTBFSXPWNHN-INIZCTEOSA-N 1-[(2S)-6-(4-ethylsulfonylphenyl)-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C(C)S(=O)(=O)C1=CC=C(C=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC QMFHTBFSXPWNHN-INIZCTEOSA-N 0.000 claims 1
- XXUZWVAQEYVSQG-SFHVURJKSA-N 1-[(2S)-6-[4-[2-(dimethylamino)ethoxy]phenyl]-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound CN(CCOC1=CC=C(C=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC)C XXUZWVAQEYVSQG-SFHVURJKSA-N 0.000 claims 1
- CAHHPUQFIZIJCA-UHFFFAOYSA-N 2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylic acid Chemical compound CC1CCC2=C(N1C(=O)O)C=CC(=C2)C3=CN(N=C3)C4CCNCC4 CAHHPUQFIZIJCA-UHFFFAOYSA-N 0.000 claims 1
- BZFKSWOGZQMOMO-UHFFFAOYSA-N 3-chloropropan-1-amine Chemical compound NCCCCl BZFKSWOGZQMOMO-UHFFFAOYSA-N 0.000 claims 1
- AEBRKQOHGXNBNI-SFHVURJKSA-N 4-[[(2S)-1-(cyclopropanecarbonyl)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-5-yl]oxy]-3-fluorobenzonitrile Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=C(C=C(C#N)C=C1)F)C AEBRKQOHGXNBNI-SFHVURJKSA-N 0.000 claims 1
- MBYMPPWWIWEPLF-NTISSMGPSA-N C(=O)OC.C(#N)C=1C(=NC=CC1)OC1=C2CC[C@@H](NC2=CC=C1C=1C=NN(C1)C1CCNCC1)C Chemical compound C(=O)OC.C(#N)C=1C(=NC=CC1)OC1=C2CC[C@@H](NC2=CC=C1C=1C=NN(C1)C1CCNCC1)C MBYMPPWWIWEPLF-NTISSMGPSA-N 0.000 claims 1
- DUCPFDXDCHSBAO-RSAXXLAASA-N C(=O)OC.ClC=1C=C(OC2=C3CC[C@@H](NC3=CC=C2C=2C=NN(C2)C2CCNCC2)C)C=CC1F Chemical compound C(=O)OC.ClC=1C=C(OC2=C3CC[C@@H](NC3=CC=C2C=2C=NN(C2)C2CCNCC2)C)C=CC1F DUCPFDXDCHSBAO-RSAXXLAASA-N 0.000 claims 1
- TZNOKBAXQOOEAM-INIZCTEOSA-N CCCOC1=C(C=CC2=C1CC[C@@H](N2CC)C)C3CCN(CC3)C(=O)OC Chemical compound CCCOC1=C(C=CC2=C1CC[C@@H](N2CC)C)C3CCN(CC3)C(=O)OC TZNOKBAXQOOEAM-INIZCTEOSA-N 0.000 claims 1
- 229920000877 Melamine resin Polymers 0.000 claims 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims 1
- UNDMNKBTPGAXDS-UHFFFAOYSA-N N1(CCCC2CC=CC=C12)C(=O)OC Chemical compound N1(CCCC2CC=CC=C12)C(=O)OC UNDMNKBTPGAXDS-UHFFFAOYSA-N 0.000 claims 1
- XZXSOJYSPUKOHO-SFHVURJKSA-N [(2S)-5-(2-chlorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound ClC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)C2CC2)C)C=CC=C1 XZXSOJYSPUKOHO-SFHVURJKSA-N 0.000 claims 1
- AVBOMLHAAZPIFO-HNNXBMFYSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(1-methylsulfonyl-2,3-dihydroimidazo[1,2-b]pyrazol-7-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN2C1N(CC2)S(=O)(=O)C)C(=O)C2CC2)C AVBOMLHAAZPIFO-HNNXBMFYSA-N 0.000 claims 1
- OXSFTLNJAWYQGF-INIZCTEOSA-N [(2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-5-(3-chlorophenoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)C1CC1)C)OC1=CC(=CC=C1)Cl OXSFTLNJAWYQGF-INIZCTEOSA-N 0.000 claims 1
- 229910052785 arsenic Inorganic materials 0.000 claims 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 claims 1
- 230000037429 base substitution Effects 0.000 claims 1
- 229940125782 compound 2 Drugs 0.000 claims 1
- SLKVXPXVZHCEIO-SFHVURJKSA-N cyclopropyl-[(2S)-5-(3-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=CC(=CC=C1)F)C SLKVXPXVZHCEIO-SFHVURJKSA-N 0.000 claims 1
- VHVMGVCBNABLSJ-SFHVURJKSA-N cyclopropyl-[(2S)-8-fluoro-5-(3-methoxyphenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC(=C12)F)C=1C=NN(C1)C1CCNCC1)OC1=CC(=CC=C1)OC)C VHVMGVCBNABLSJ-SFHVURJKSA-N 0.000 claims 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims 1
- 229960004961 mechlorethamine Drugs 0.000 claims 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims 1
- JDSHMPZPIAZGSV-UHFFFAOYSA-N melamine Chemical compound NC1=NC(N)=NC(N)=N1 JDSHMPZPIAZGSV-UHFFFAOYSA-N 0.000 claims 1
- DMQLCGUTBZIOEE-KRWDZBQOSA-N methyl (2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-pyridin-2-yloxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=CC=C1)C=1C=NN(C1)C1CCNCC1)C(=O)OC DMQLCGUTBZIOEE-KRWDZBQOSA-N 0.000 claims 1
- XVOINJTYRNIAPF-SFHVURJKSA-N methyl (2S)-2-methyl-6-(4-morpholin-4-ylpyrazol-1-yl)-5-phenoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=CC=CC=C1)N1N=CC(=C1)N1CCOCC1)C(=O)OC XVOINJTYRNIAPF-SFHVURJKSA-N 0.000 claims 1
- UIBMHSADAQPXFA-SFHVURJKSA-N methyl (2S)-5-(2-methoxyphenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound COC1=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC=C1 UIBMHSADAQPXFA-SFHVURJKSA-N 0.000 claims 1
- VTHVYYMEDOOPNK-KRWDZBQOSA-N methyl (2S)-5-(3-cyano-4-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C=1C=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC1F VTHVYYMEDOOPNK-KRWDZBQOSA-N 0.000 claims 1
- FMSMFEQJWRERDO-KRWDZBQOSA-N methyl (2S)-5-(3-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC1 FMSMFEQJWRERDO-KRWDZBQOSA-N 0.000 claims 1
- GTYZIOUKGUPXDG-KRWDZBQOSA-N methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=C1 GTYZIOUKGUPXDG-KRWDZBQOSA-N 0.000 claims 1
- UOBQCJGAKCYHID-XFXRKFMASA-N methyl (2S)-5-(4-fluorophenoxy)-6-[1-(3-methoxy-1-methylpiperidin-4-yl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2C(CN(CC2)C)OC)C(=O)OC)C)C=C1 UOBQCJGAKCYHID-XFXRKFMASA-N 0.000 claims 1
- AXLJVHWCUNJUHM-IGUJJWBZSA-N methyl (2S)-5-(4-fluorophenoxy)-6-[1-[(3R,4S)-3-fluoropiperidin-4-yl]pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)[C@@H]2[C@@H](CNCC2)F)C(=O)OC)C)C=C1 AXLJVHWCUNJUHM-IGUJJWBZSA-N 0.000 claims 1
- AXLJVHWCUNJUHM-DQLWACAZSA-N methyl (2S)-5-(4-fluorophenoxy)-6-[1-[(3S,4S)-3-fluoropiperidin-4-yl]pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)[C@@H]2[C@H](CNCC2)F)C(=O)OC)C)C=C1 AXLJVHWCUNJUHM-DQLWACAZSA-N 0.000 claims 1
- AQNOXIQFFQEXJG-AWEZNQCLSA-N methyl (2S)-5-(azetidin-3-ylmethoxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound N1CC(C1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(=O)OC)C AQNOXIQFFQEXJG-AWEZNQCLSA-N 0.000 claims 1
- OEWLRHLCQDGMPR-MYJWUSKBSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-(1-pyrrolidin-3-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CNCC1)C(=O)OC)C OEWLRHLCQDGMPR-MYJWUSKBSA-N 0.000 claims 1
- QWQCGYMXXFHKGO-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-(2-piperazin-1-yl-1,3-thiazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(SC1)N1CCNCC1)C(=O)OC)C QWQCGYMXXFHKGO-HNNXBMFYSA-N 0.000 claims 1
- IGEPYXYBHMRMID-GJULWVSJSA-N methyl (2S)-5-cyclobutyloxy-6-[1-[(3S,4R)-3-fluoropiperidin-4-yl]pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)[C@H]1[C@H](CNCC1)F)C(=O)OC)C IGEPYXYBHMRMID-GJULWVSJSA-N 0.000 claims 1
- GJXLRMCHGJLIOF-ZDUSSCGKSA-N methyl (2S)-5-cyclobutyloxy-6-[2-(3-hydroxyazetidin-3-yl)-1,3-thiazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(SC1)C1(CNC1)O)C(=O)OC)C GJXLRMCHGJLIOF-ZDUSSCGKSA-N 0.000 claims 1
- SZRQAJHPJSCYFZ-KRWDZBQOSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(2-oxo-2-piperidin-1-ylethoxy)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC(N1CCCCC1)=O SZRQAJHPJSCYFZ-KRWDZBQOSA-N 0.000 claims 1
- XCFWGMQFWWSDSQ-LBPRGKRZSA-N methyl (2S)-6-(2-acetamido-1,3-thiazol-4-yl)-5-cyclobutyloxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(SC1)NC(C)=O)C(=O)OC)C XCFWGMQFWWSDSQ-LBPRGKRZSA-N 0.000 claims 1
- KRQIXVBFNUKQFW-INIZCTEOSA-N methyl (2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-2-methyl-5-phenoxy-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=CC=CC=C1 KRQIXVBFNUKQFW-INIZCTEOSA-N 0.000 claims 1
- VHBGPJAFEZLOQJ-AWEZNQCLSA-N methyl (2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-5-(3-chloro-4-fluorophenoxy)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=CC(=C(C=C1)F)Cl VHBGPJAFEZLOQJ-AWEZNQCLSA-N 0.000 claims 1
- BZQPKAMWHPKYRS-ZDUSSCGKSA-N methyl (2S)-8-fluoro-2-methyl-5-phenoxy-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC=1C=C(C(=C2CC[C@@H](N(C12)C(=O)OC)C)OC1=CC=CC=C1)C=1C=NNC1 BZQPKAMWHPKYRS-ZDUSSCGKSA-N 0.000 claims 1
- 229960000952 pipobroman Drugs 0.000 claims 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 claims 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 abstract description 3
- 208000027866 inflammatory disease Diseases 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 248
- 235000019439 ethyl acetate Nutrition 0.000 description 122
- 150000001768 cations Chemical class 0.000 description 107
- 239000000243 solution Substances 0.000 description 94
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 81
- 235000002639 sodium chloride Nutrition 0.000 description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 239000011541 reaction mixture Substances 0.000 description 51
- 239000000543 intermediate Substances 0.000 description 50
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 27
- 239000002904 solvent Substances 0.000 description 23
- 239000007787 solid Substances 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 108090000623 proteins and genes Proteins 0.000 description 20
- 230000002829 reductive effect Effects 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 235000018102 proteins Nutrition 0.000 description 18
- 102000004169 proteins and genes Human genes 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000000546 pharmaceutical excipient Substances 0.000 description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 14
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 230000002265 prevention Effects 0.000 description 14
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 13
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 12
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 239000006188 syrup Substances 0.000 description 12
- 235000020357 syrup Nutrition 0.000 description 12
- 108091005625 BRD4 Proteins 0.000 description 11
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 230000008030 elimination Effects 0.000 description 10
- 238000003379 elimination reaction Methods 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000002585 base Substances 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 150000004677 hydrates Chemical class 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
- 241000124008 Mammalia Species 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 230000001154 acute effect Effects 0.000 description 8
- 150000001499 aryl bromides Chemical class 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 150000002500 ions Chemical class 0.000 description 8
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 235000015424 sodium Nutrition 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 235000000346 sugar Nutrition 0.000 description 8
- BFYHFIAUSLGNEW-QMMMGPOBSA-N (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline Chemical compound COC1=C2CC[C@@H](NC2=CC=C1)C BFYHFIAUSLGNEW-QMMMGPOBSA-N 0.000 description 7
- SLAMMQHWLFJDLB-UHFFFAOYSA-N 2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline Chemical compound CC1NC2=CC=CC(=C2CC1)OC1=CC=CC=C1 SLAMMQHWLFJDLB-UHFFFAOYSA-N 0.000 description 7
- 102100033641 Bromodomain-containing protein 2 Human genes 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 7
- 108010010803 Gelatin Proteins 0.000 description 7
- 101000871850 Homo sapiens Bromodomain-containing protein 2 Proteins 0.000 description 7
- 239000002202 Polyethylene glycol Substances 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000000654 additive Substances 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 125000003277 amino group Chemical group 0.000 description 7
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 239000001913 cellulose Substances 0.000 description 7
- 229950011148 cyclopropane Drugs 0.000 description 7
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 7
- 239000008273 gelatin Substances 0.000 description 7
- 229920000159 gelatin Polymers 0.000 description 7
- 235000019322 gelatine Nutrition 0.000 description 7
- 235000011852 gelatine desserts Nutrition 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 210000000056 organ Anatomy 0.000 description 7
- 229960003742 phenol Drugs 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 6
- AKEQSUAAGDGHLQ-ZETCQYMHSA-N 1-[(2S)-6-bromo-5-hydroxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound BrC=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)O AKEQSUAAGDGHLQ-ZETCQYMHSA-N 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
- 102100029894 Bromodomain testis-specific protein Human genes 0.000 description 6
- 102100033642 Bromodomain-containing protein 3 Human genes 0.000 description 6
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 6
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 6
- 101000794028 Homo sapiens Bromodomain testis-specific protein Proteins 0.000 description 6
- 101000871851 Homo sapiens Bromodomain-containing protein 3 Proteins 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 6
- 125000002947 alkylene group Chemical group 0.000 description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000004359 castor oil Substances 0.000 description 6
- 235000019438 castor oil Nutrition 0.000 description 6
- 229910000420 cerium oxide Inorganic materials 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000011161 development Methods 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- 125000000524 functional group Chemical group 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 6
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 6
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- 235000010356 sorbitol Nutrition 0.000 description 6
- 239000000600 sorbitol Substances 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 5
- DSIUGJOGYJLEHL-UHFFFAOYSA-N 6-bromo-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline Chemical compound BrC=1C(=C2CCC(NC2=CC1)C)OC1=CC=CC=C1 DSIUGJOGYJLEHL-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 206010040047 Sepsis Diseases 0.000 description 5
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 5
- JSQMPYVPDOFZAH-QMMMGPOBSA-N [(2S)-6-bromo-5-hydroxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound BrC=1C(=C2CC[C@@H](N(C2=CC1)C(=O)C1CC1)C)O JSQMPYVPDOFZAH-QMMMGPOBSA-N 0.000 description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 229920000609 methyl cellulose Polymers 0.000 description 5
- 235000010981 methylcellulose Nutrition 0.000 description 5
- 239000001923 methylcellulose Substances 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 5
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- NLWYVKHISUTBMY-UHFFFAOYSA-N 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN(C2CC2)N=C1 NLWYVKHISUTBMY-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 208000001344 Macular Edema Diseases 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 description 4
- 208000036142 Viral infection Diseases 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 239000000440 bentonite Substances 0.000 description 4
- 229910000278 bentonite Inorganic materials 0.000 description 4
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 4
- 229940076134 benzene Drugs 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- CNBNMRZLQSRNMB-VIFPVBQESA-N cyclopropyl-[(2S)-5-hydroxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC=2C(=CC=CC12)O)C CNBNMRZLQSRNMB-VIFPVBQESA-N 0.000 description 4
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 4
- 239000008121 dextrose Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229960001484 edetic acid Drugs 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 235000003599 food sweetener Nutrition 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000007937 lozenge Substances 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 235000013772 propylene glycol Nutrition 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 230000000087 stabilizing effect Effects 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 229960004793 sucrose Drugs 0.000 description 4
- 239000003765 sweetening agent Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 229940033134 talc Drugs 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 4
- CTSVHCXSQCYTDL-SECBINFHSA-N (2R)-4-[2-(methoxymethoxy)-6-nitrophenyl]but-3-yn-2-ol Chemical compound COCOC1=C(C(=CC=C1)[N+](=O)[O-])C#C[C@@H](C)O CTSVHCXSQCYTDL-SECBINFHSA-N 0.000 description 3
- GUWRNJQUTBXHPM-SECBINFHSA-N (2R)-4-[2-amino-6-(methoxymethoxy)phenyl]butan-2-ol Chemical compound COCOC1=CC=CC(N)=C1CC[C@@H](C)O GUWRNJQUTBXHPM-SECBINFHSA-N 0.000 description 3
- PPTBPZWDAKWBIF-QRPNPIFTSA-N (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline hydrochloride Chemical compound Cl.COC1=C2CC[C@@H](NC2=CC=C1)C PPTBPZWDAKWBIF-QRPNPIFTSA-N 0.000 description 3
- JNCIYEAJQKNGIP-JTQLQIEISA-N 1-[(2S)-6-bromo-2-methyl-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound BrC=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC JNCIYEAJQKNGIP-JTQLQIEISA-N 0.000 description 3
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- JNKYUDNDIHOZFA-UHFFFAOYSA-N 2-iodo-1-(methoxymethoxy)-3-nitrobenzene Chemical compound IC1=C(C=CC=C1[N+](=O)[O-])OCOC JNKYUDNDIHOZFA-UHFFFAOYSA-N 0.000 description 3
- BFXOSMOZBIBXHU-UHFFFAOYSA-N 2-iodo-3-nitrophenol Chemical compound OC1=CC=CC([N+]([O-])=O)=C1I BFXOSMOZBIBXHU-UHFFFAOYSA-N 0.000 description 3
- KQDJTBPASNJQFQ-UHFFFAOYSA-N 2-iodophenol Chemical compound OC1=CC=CC=C1I KQDJTBPASNJQFQ-UHFFFAOYSA-N 0.000 description 3
- XLESFKNMUADITH-UHFFFAOYSA-N 2-methyl-5-phenoxyquinoline Chemical compound CC1=NC2=CC=CC(=C2C=C1)OC1=CC=CC=C1 XLESFKNMUADITH-UHFFFAOYSA-N 0.000 description 3
- GUQUYKTWVBJKFL-UHFFFAOYSA-N 4,5-dibromo-2h-triazole Chemical compound BrC1=NNN=C1Br GUQUYKTWVBJKFL-UHFFFAOYSA-N 0.000 description 3
- OQPWQOOLGQWRAL-UHFFFAOYSA-N 5-methoxy-2-methylquinoline Chemical compound CC1=CC=C2C(OC)=CC=CC2=N1 OQPWQOOLGQWRAL-UHFFFAOYSA-N 0.000 description 3
- LEHFDVYXPCSLJT-UHFFFAOYSA-N 8-chloro-5-methoxy-2-methylquinoline;hydrochloride Chemical compound Cl.CC1=CC=C2C(OC)=CC=C(Cl)C2=N1 LEHFDVYXPCSLJT-UHFFFAOYSA-N 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 3
- 241000490494 Arabis Species 0.000 description 3
- 241000416162 Astragalus gummifer Species 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 108010077544 Chromatin Proteins 0.000 description 3
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 3
- 239000004375 Dextrin Substances 0.000 description 3
- 229920001353 Dextrin Polymers 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- 102000003893 Histone acetyltransferases Human genes 0.000 description 3
- 108090000246 Histone acetyltransferases Proteins 0.000 description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 206010033645 Pancreatitis Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 206010057190 Respiratory tract infections Diseases 0.000 description 3
- 235000021355 Stearic acid Nutrition 0.000 description 3
- 229920001615 Tragacanth Polymers 0.000 description 3
- 206010047115 Vasculitis Diseases 0.000 description 3
- QIRUHBCHFJFGTL-KRWDZBQOSA-N [(2S)-5-(6-chloropyridin-2-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound ClC1=CC=CC(=N1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(=O)C1CC1)C QIRUHBCHFJFGTL-KRWDZBQOSA-N 0.000 description 3
- MDBGQOVYYAVSMJ-AWEZNQCLSA-N [(2S)-5-cyclobutyloxy-6-(1-cyclopropylpyrazol-4-yl)-8-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NN(C1)C1CC1)F)C(=O)C1CC1)C MDBGQOVYYAVSMJ-AWEZNQCLSA-N 0.000 description 3
- XJLNSJPUSIWMKZ-LBPRGKRZSA-N [(2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NNC1)F)C(=O)C1CC1)C XJLNSJPUSIWMKZ-LBPRGKRZSA-N 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000000205 acacia gum Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 239000000783 alginic acid Substances 0.000 description 3
- 229960001126 alginic acid Drugs 0.000 description 3
- 150000004781 alginic acids Chemical class 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000001099 ammonium carbonate Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000004305 biphenyl Chemical group 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical group CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 3
- 210000003483 chromatin Anatomy 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 235000005687 corn oil Nutrition 0.000 description 3
- 239000002285 corn oil Substances 0.000 description 3
- MLUCVPSAIODCQM-NSCUHMNNSA-N crotonaldehyde Chemical compound C\C=C\C=O MLUCVPSAIODCQM-NSCUHMNNSA-N 0.000 description 3
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 3
- FBICOVZOJBJVSU-KRWDZBQOSA-N cyclopropyl-[(2S)-5-(6-fluoropyridin-2-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=NC(=CC=C1)F)C FBICOVZOJBJVSU-KRWDZBQOSA-N 0.000 description 3
- 235000019425 dextrin Nutrition 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 229960003750 ethyl chloride Drugs 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 235000001727 glucose Nutrition 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 125000002971 oxazolyl group Chemical group 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 3
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- 235000011007 phosphoric acid Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 3
- 229920003124 powdered cellulose Polymers 0.000 description 3
- 235000019814 powdered cellulose Nutrition 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 229940083037 simethicone Drugs 0.000 description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 3
- 235000010234 sodium benzoate Nutrition 0.000 description 3
- 239000004299 sodium benzoate Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000008117 stearic acid Substances 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- UTUVUXYKFFKIKP-UHFFFAOYSA-N tert-butyl 4-(1h-imidazol-2-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC=CN1 UTUVUXYKFFKIKP-UHFFFAOYSA-N 0.000 description 3
- GSXXBWGSODTJIY-UHFFFAOYSA-N tert-butyl 4-(4,5-dibromotriazol-1-yl)piperidine-1-carboxylate Chemical compound BrC=1N=NN(C1Br)C1CCN(CC1)C(=O)OC(C)(C)C GSXXBWGSODTJIY-UHFFFAOYSA-N 0.000 description 3
- SSLPKQOFGJZOOU-UHFFFAOYSA-N tert-butyl 4-(4-bromotriazol-1-yl)piperidine-1-carboxylate Chemical compound BrC=1N=NN(C1)C1CCN(CC1)C(=O)OC(C)(C)C SSLPKQOFGJZOOU-UHFFFAOYSA-N 0.000 description 3
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 235000010487 tragacanth Nutrition 0.000 description 3
- 239000000196 tragacanth Substances 0.000 description 3
- 229940116362 tragacanth Drugs 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 3
- 229960004528 vincristine Drugs 0.000 description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- AHERXIIRKSQMRH-FJXQXJEOSA-N (2S)-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol hydrobromide Chemical compound Br.C[C@@H]1NC=2C=CC=C(C2CC1)O AHERXIIRKSQMRH-FJXQXJEOSA-N 0.000 description 2
- KXLFJEYUHFXYAJ-ZETCQYMHSA-N (2S)-6-bromo-5-cyclobutyloxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline Chemical compound BrC=1C(=C2CC[C@@H](NC2=C(C1F)F)C)OC1CCC1 KXLFJEYUHFXYAJ-ZETCQYMHSA-N 0.000 description 2
- GKPOMITUDGXOSB-SCSAIBSYSA-N (2r)-but-3-yn-2-ol Chemical compound C[C@@H](O)C#C GKPOMITUDGXOSB-SCSAIBSYSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 2
- OMJKFYKNWZZKTK-POHAHGRESA-N (5z)-5-(dimethylaminohydrazinylidene)imidazole-4-carboxamide Chemical compound CN(C)N\N=C1/N=CN=C1C(N)=O OMJKFYKNWZZKTK-POHAHGRESA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical class OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 2
- QXRICMUAQZKMBX-AWEZNQCLSA-N 1-[(2S)-5-(3-chloropyridin-2-yl)oxy-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound ClC=1C(=NC=CC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(C)=O)C QXRICMUAQZKMBX-AWEZNQCLSA-N 0.000 description 2
- CDOZHZLYYZIOCE-ZDUSSCGKSA-N 1-[(2S)-5-(azetidin-3-yloxy)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound N1CC(C1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC1)C(C)=O)C CDOZHZLYYZIOCE-ZDUSSCGKSA-N 0.000 description 2
- PCJBTYSVCNCNKO-JTQLQIEISA-N 1-[(2S)-5-(methoxymethoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound COCOC1=C2CC[C@@H](N(C2=CC=C1)C(C)=O)C PCJBTYSVCNCNKO-JTQLQIEISA-N 0.000 description 2
- GJSIDODCRAYPJG-ZDUSSCGKSA-N 1-[(2S)-5-cyclobutyloxy-6-(1-cyclopropylpyrazol-4-yl)-8-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NN(C1)C1CC1)F)C(C)=O)C GJSIDODCRAYPJG-ZDUSSCGKSA-N 0.000 description 2
- RRMGHAYLUDKIMV-QMMMGPOBSA-N 1-[(2S)-5-hydroxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound OC1=C2CC[C@@H](N(C2=CC=C1)C(C)=O)C RRMGHAYLUDKIMV-QMMMGPOBSA-N 0.000 description 2
- YYRAEWKQJGPMGR-HNNXBMFYSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(5-methylpyrimidin-2-yl)oxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC=C(C=N1)C YYRAEWKQJGPMGR-HNNXBMFYSA-N 0.000 description 2
- FUVIFAJXYXRZEH-HNNXBMFYSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-[2-(oxetan-3-yl)ethoxy]-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCC1COC1 FUVIFAJXYXRZEH-HNNXBMFYSA-N 0.000 description 2
- XIQPZCMSPYQKET-ZDUSSCGKSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-[2-(trifluoromethyl)pyrimidin-4-yl]oxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC(=NC=C1)C(F)(F)F XIQPZCMSPYQKET-ZDUSSCGKSA-N 0.000 description 2
- URCUTIYENVIWQB-AWEZNQCLSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-[3-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC=CC=C1C(F)(F)F URCUTIYENVIWQB-AWEZNQCLSA-N 0.000 description 2
- FZNTXSHCZYARCZ-ZDUSSCGKSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(1,3-difluoropropan-2-yloxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC(CF)CF FZNTXSHCZYARCZ-ZDUSSCGKSA-N 0.000 description 2
- GOIIOBYDFGXLEM-LBPRGKRZSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(2,2-difluoroethoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCC(F)F GOIIOBYDFGXLEM-LBPRGKRZSA-N 0.000 description 2
- FVHOVPUMOQTDPS-ZDUSSCGKSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(2-fluoroethoxy)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCCF FVHOVPUMOQTDPS-ZDUSSCGKSA-N 0.000 description 2
- MRALGGFJIQZAOO-ZDUSSCGKSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(3,3-difluorocyclobutyl)oxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1CC(C1)(F)F MRALGGFJIQZAOO-ZDUSSCGKSA-N 0.000 description 2
- SEZUWJKMJIIVCC-LBPRGKRZSA-N 1-[(2S)-6-bromo-2-methyl-5-quinazolin-2-yloxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound BrC=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC2=CC=CC=C2C=N1 SEZUWJKMJIIVCC-LBPRGKRZSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- DBPWSSGDRRHUNT-CEGNMAFCSA-N 17α-hydroxyprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DBPWSSGDRRHUNT-CEGNMAFCSA-N 0.000 description 2
- UHGVHUUHCKECKJ-UHFFFAOYSA-N 2,3-difluoro-5-hydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC(F)=C1F UHGVHUUHCKECKJ-UHFFFAOYSA-N 0.000 description 2
- MKEJZKKVVUZXIS-UHFFFAOYSA-N 2,4-dibromo-1,3-thiazole Chemical compound BrC1=CSC(Br)=N1 MKEJZKKVVUZXIS-UHFFFAOYSA-N 0.000 description 2
- OIALAIQRYISUEV-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]e Polymers CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO OIALAIQRYISUEV-UHFFFAOYSA-N 0.000 description 2
- KUCWUAFNGCMZDB-UHFFFAOYSA-N 2-amino-3-nitrophenol Chemical compound NC1=C(O)C=CC=C1[N+]([O-])=O KUCWUAFNGCMZDB-UHFFFAOYSA-N 0.000 description 2
- AXHRGVJWDJDYPO-UHFFFAOYSA-N 2-bromo-1h-imidazole Chemical compound BrC1=NC=CN1 AXHRGVJWDJDYPO-UHFFFAOYSA-N 0.000 description 2
- GBOUQGUQUUPGLO-UHFFFAOYSA-N 2-chloro-5-methoxyaniline Chemical compound COC1=CC=C(Cl)C(N)=C1 GBOUQGUQUUPGLO-UHFFFAOYSA-N 0.000 description 2
- JTFKLSFOJWYTIW-UHFFFAOYSA-N 2-chloro-5-phenoxyaniline Chemical compound C1=C(Cl)C(N)=CC(OC=2C=CC=CC=2)=C1 JTFKLSFOJWYTIW-UHFFFAOYSA-N 0.000 description 2
- ZTQNUTNKGQGWCM-UHFFFAOYSA-N 2-methoxyquinoline Chemical compound C1=CC=CC2=NC(OC)=CC=C21 ZTQNUTNKGQGWCM-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- FWUALUHYKLDYAN-UHFFFAOYSA-N 3-amino-4-chlorophenol Chemical compound NC1=CC(O)=CC=C1Cl FWUALUHYKLDYAN-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- MKTXODCMRKPJDI-UHFFFAOYSA-N 5-cyclobutyloxy-2,3-difluoroaniline hydrochloride Chemical compound Cl.C1(CCC1)OC=1C=C(C(=C(N)C1)F)F MKTXODCMRKPJDI-UHFFFAOYSA-N 0.000 description 2
- LQVNLBFEOYHPQS-UHFFFAOYSA-N 5-cyclobutyloxy-2,3-difluorobenzoic acid Chemical compound C1(CCC1)OC=1C=C(C(=C(C(=O)O)C1)F)F LQVNLBFEOYHPQS-UHFFFAOYSA-N 0.000 description 2
- ILMIQZXLNRZIPI-UHFFFAOYSA-N 8-chloro-2-methyl-5-phenoxyquinoline Chemical compound ClC=1C=CC(=C2C=CC(=NC12)C)OC1=CC=CC=C1 ILMIQZXLNRZIPI-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical class CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 208000009304 Acute Kidney Injury Diseases 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000282693 Cercopithecidae Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 206010058202 Cystoid macular oedema Diseases 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- 208000007465 Giant cell arteritis Diseases 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 108010033040 Histones Proteins 0.000 description 2
- 102000006947 Histones Human genes 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- 206010025415 Macular oedema Diseases 0.000 description 2
- 235000006679 Mentha X verticillata Nutrition 0.000 description 2
- 235000002899 Mentha suaveolens Nutrition 0.000 description 2
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- OKLUZMUKXYWEGD-UHFFFAOYSA-N N-bromobutan-1-imine Chemical compound CCCC=NBr OKLUZMUKXYWEGD-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 229920001219 Polysorbate 40 Polymers 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- 206010038910 Retinitis Diseases 0.000 description 2
- 206010040070 Septic Shock Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 2
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 235000007423 Tolu balsam tree Nutrition 0.000 description 2
- 244000007731 Tolu balsam tree Species 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 235000009499 Vanilla fragrans Nutrition 0.000 description 2
- 244000263375 Vanilla tahitensis Species 0.000 description 2
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 2
- VWQNDJADSJOLOJ-ZDUSSCGKSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(1H-pyrazol-5-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C1=CC=NN1)C(=O)C1CC1)C VWQNDJADSJOLOJ-ZDUSSCGKSA-N 0.000 description 2
- WZPGASAWHJRXSW-HNNXBMFYSA-N [(2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-5-cyclobutyloxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)C1CC1)C)OC1CCC1 WZPGASAWHJRXSW-HNNXBMFYSA-N 0.000 description 2
- VHPVYJWSANMMHN-NSHDSACASA-N [(2S)-6-bromo-5-cyclobutyloxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound BrC=1C(=C2CC[C@@H](N(C2=CC1)C(=O)C1CC1)C)OC1CCC1 VHPVYJWSANMMHN-NSHDSACASA-N 0.000 description 2
- 229940022663 acetate Drugs 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003463 adsorbent Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 235000012501 ammonium carbonate Nutrition 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 2
- 229960000723 ampicillin Drugs 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000001502 aryl halides Chemical class 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- 229940050390 benzoate Drugs 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- KXVUSQIDCZRUKF-UHFFFAOYSA-N bromocyclobutane Chemical compound BrC1CCC1 KXVUSQIDCZRUKF-UHFFFAOYSA-N 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- BQWQGEBNCNNFCI-UHFFFAOYSA-N butan-2-yl methanesulfonate Chemical compound CCC(C)OS(C)(=O)=O BQWQGEBNCNNFCI-UHFFFAOYSA-N 0.000 description 2
- 239000001273 butane Substances 0.000 description 2
- 125000006309 butyl amino group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229940095672 calcium sulfate Drugs 0.000 description 2
- 235000011132 calcium sulphate Nutrition 0.000 description 2
- 229960001631 carbomer Drugs 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 229940113118 carrageenan Drugs 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 230000006369 cell cycle progression Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 229920002301 cellulose acetate Polymers 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 239000002385 cottonseed oil Substances 0.000 description 2
- MLUCVPSAIODCQM-UHFFFAOYSA-N crotonaldehyde Natural products CC=CC=O MLUCVPSAIODCQM-UHFFFAOYSA-N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 2
- FYZTXISZLQSYRF-UHFFFAOYSA-N cyclobutyl 5-cyclobutyloxy-2,3-difluorobenzoate Chemical compound C1(CCC1)OC=1C=C(C(=C(C(=O)OC2CCC2)C1)F)F FYZTXISZLQSYRF-UHFFFAOYSA-N 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- YZNGNKSOITUUSS-JTQLQIEISA-N cyclopropyl-[(2S)-5-methoxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C=CC=C12)OC)C YZNGNKSOITUUSS-JTQLQIEISA-N 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 125000004663 dialkyl amino group Chemical group 0.000 description 2
- IYYZUPMFVPLQIF-UHFFFAOYSA-N dibenzothiophene Chemical compound C1=CC=C2C3=CC=CC=C3SC2=C1 IYYZUPMFVPLQIF-UHFFFAOYSA-N 0.000 description 2
- ZOCHARZZJNPSEU-UHFFFAOYSA-N diboron Chemical compound B#B ZOCHARZZJNPSEU-UHFFFAOYSA-N 0.000 description 2
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 239000008387 emulsifying waxe Substances 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- CBOQJANXLMLOSS-UHFFFAOYSA-N ethyl vanillin Chemical compound CCOC1=CC(C=O)=CC=C1O CBOQJANXLMLOSS-UHFFFAOYSA-N 0.000 description 2
- SKEHVMZPBBGBAO-UHFFFAOYSA-N ethylhydrazine;hydrochloride Chemical compound Cl.CCNN SKEHVMZPBBGBAO-UHFFFAOYSA-N 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 229920000591 gum Polymers 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 2
- ACCCMOQWYVYDOT-UHFFFAOYSA-N hexane-1,1-diol Chemical compound CCCCCC(O)O ACCCMOQWYVYDOT-UHFFFAOYSA-N 0.000 description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 229960002899 hydroxyprogesterone Drugs 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 208000002780 macular degeneration Diseases 0.000 description 2
- 201000010230 macular retinal edema Diseases 0.000 description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 2
- 239000001095 magnesium carbonate Substances 0.000 description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 2
- 235000014380 magnesium carbonate Nutrition 0.000 description 2
- 239000004337 magnesium citrate Substances 0.000 description 2
- 235000002538 magnesium citrate Nutrition 0.000 description 2
- 229960005336 magnesium citrate Drugs 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- IVKYKUBOJNKTGN-HFCFLWKCSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-[1-(2-methylpiperidin-4-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC(NCC1)C)C(=O)OC)C IVKYKUBOJNKTGN-HFCFLWKCSA-N 0.000 description 2
- YOERJIWOGVRLDQ-AWEZNQCLSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-5-[(3-fluorooxetan-3-yl)methoxy]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OCC1(COC1)F YOERJIWOGVRLDQ-AWEZNQCLSA-N 0.000 description 2
- WDPKPMSORFKRKR-ZETCQYMHSA-N methyl (2S)-6-bromo-5-hydroxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound BrC=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)O WDPKPMSORFKRKR-ZETCQYMHSA-N 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000001673 myroxylon balsanum l. absolute Substances 0.000 description 2
- 201000008383 nephritis Diseases 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000010651 palladium-catalyzed cross coupling reaction Methods 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 2
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 2
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 2
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 2
- 229940068977 polysorbate 20 Drugs 0.000 description 2
- 229940101027 polysorbate 40 Drugs 0.000 description 2
- 229940113124 polysorbate 60 Drugs 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 230000002980 postoperative effect Effects 0.000 description 2
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000012041 precatalyst Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 2
- 230000002207 retinal effect Effects 0.000 description 2
- 208000004644 retinal vein occlusion Diseases 0.000 description 2
- 235000019204 saccharin Nutrition 0.000 description 2
- 229940081974 saccharin Drugs 0.000 description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 229960003885 sodium benzoate Drugs 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 2
- 239000001570 sorbitan monopalmitate Substances 0.000 description 2
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 2
- 235000011076 sorbitan monostearate Nutrition 0.000 description 2
- 239000001587 sorbitan monostearate Substances 0.000 description 2
- 229940035048 sorbitan monostearate Drugs 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 229940114926 stearate Drugs 0.000 description 2
- 229960004274 stearic acid Drugs 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- 206010043207 temporal arteritis Diseases 0.000 description 2
- VXESIQITZBRNNA-UHFFFAOYSA-N tert-butyl 4-(1h-imidazol-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(C=2NC=CN=2)=C1 VXESIQITZBRNNA-UHFFFAOYSA-N 0.000 description 2
- WOEQSXAIPTXOPY-UHFFFAOYSA-N tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1 WOEQSXAIPTXOPY-UHFFFAOYSA-N 0.000 description 2
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 2
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 description 2
- 125000003396 thiol group Chemical class [H]S* 0.000 description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 2
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 235000010384 tocopherol Nutrition 0.000 description 2
- 229930003799 tocopherol Natural products 0.000 description 2
- 229960001295 tocopherol Drugs 0.000 description 2
- 239000011732 tocopherol Substances 0.000 description 2
- 229940088660 tolu balsam Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 229940078499 tricalcium phosphate Drugs 0.000 description 2
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 description 2
- 239000002691 unilamellar liposome Substances 0.000 description 2
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- MPPMDFKHJFMDNK-INIZCTEOSA-N (2S)-5-(2-cyano-4-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylic acid Chemical compound C[C@H]1CCc2c(ccc(-c3cnn(c3)C3CCNCC3)c2Oc2ccc(F)cc2C#N)N1C(O)=O MPPMDFKHJFMDNK-INIZCTEOSA-N 0.000 description 1
- YVERODGYESMAJX-QMMMGPOBSA-N (2S)-5-cyclobutyloxy-7,8-difluoro-2-methyl-1,2,3,4-tetrahydroquinoline Chemical compound C1(CCC1)OC1=C2CC[C@@H](NC2=C(C(=C1)F)F)C YVERODGYESMAJX-QMMMGPOBSA-N 0.000 description 1
- GQEVQJMZFCFNHK-ZETCQYMHSA-N (2S)-8-fluoro-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline Chemical compound FC=1C=CC(=C2CC[C@@H](NC12)C)OC GQEVQJMZFCFNHK-ZETCQYMHSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- PAORVUMOXXAMPL-SECBINFHSA-N (2s)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride Chemical compound CO[C@](C(Cl)=O)(C(F)(F)F)C1=CC=CC=C1 PAORVUMOXXAMPL-SECBINFHSA-N 0.000 description 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UDVPQRRWUGKGQY-XQHVRGAUSA-N (e)-but-2-enal Chemical compound C\C=C\C=O.C\C=C\C=O UDVPQRRWUGKGQY-XQHVRGAUSA-N 0.000 description 1
- VTWKXBJHBHYJBI-VURMDHGXSA-N (nz)-n-benzylidenehydroxylamine Chemical compound O\N=C/C1=CC=CC=C1 VTWKXBJHBHYJBI-VURMDHGXSA-N 0.000 description 1
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- JCIIKRHCWVHVFF-UHFFFAOYSA-N 1,2,4-thiadiazol-5-amine;hydrochloride Chemical compound Cl.NC1=NC=NS1 JCIIKRHCWVHVFF-UHFFFAOYSA-N 0.000 description 1
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical class NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 1
- KQDQZEZWWRPNQH-UHFFFAOYSA-N 1,3-diazabicyclo[2.2.2]octane Chemical compound C1CC2CCN1CN2 KQDQZEZWWRPNQH-UHFFFAOYSA-N 0.000 description 1
- HKIPCXRNASWFRU-UHFFFAOYSA-N 1,3-difluoropropan-2-one Chemical compound FCC(=O)CF HKIPCXRNASWFRU-UHFFFAOYSA-N 0.000 description 1
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical compound C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 1
- VAYTZRYEBVHVLE-UHFFFAOYSA-N 1,3-dioxol-2-one Chemical compound O=C1OC=CO1 VAYTZRYEBVHVLE-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- QDVBKXJMLILLLB-UHFFFAOYSA-N 1,4'-bipiperidine Chemical group C1CCCCN1C1CCNCC1 QDVBKXJMLILLLB-UHFFFAOYSA-N 0.000 description 1
- 125000005960 1,4-diazepanyl group Chemical group 0.000 description 1
- LMQPNTPBOAOKLO-UHFFFAOYSA-N 1,5,6,7,8,9-hexahydropyrazolo[1,2-a]diazepine Chemical compound C1CCCCN2CC=CN21 LMQPNTPBOAOKLO-UHFFFAOYSA-N 0.000 description 1
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 1
- HSNHHAIGXZWNEI-UHFFFAOYSA-N 1-N'-bromobutane-1,1-diamine Chemical compound BrNC(CCC)N HSNHHAIGXZWNEI-UHFFFAOYSA-N 0.000 description 1
- SVCWQWNEJXTCEO-KRWDZBQOSA-N 1-[(2S)-2-methyl-5-(5-methylpyrimidin-2-yl)oxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=C(C=N1)C)C=1C=NN(C1)C1CCNCC1)C(C)=O SVCWQWNEJXTCEO-KRWDZBQOSA-N 0.000 description 1
- PMDLIKFTDZRJNX-HNNXBMFYSA-N 1-[(2S)-2-methyl-6-(1-methylsulfonylpiperidin-4-yl)-5-propoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OCCC)C1CCN(CC1)S(=O)(=O)C)C(C)=O PMDLIKFTDZRJNX-HNNXBMFYSA-N 0.000 description 1
- WWYSORCZNAMJSU-INIZCTEOSA-N 1-[(2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-[3-(trifluoromethyl)pyridin-2-yl]oxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=CC=C1C(F)(F)F)C=1C=NN(C1)C1CCNCC1)C(C)=O WWYSORCZNAMJSU-INIZCTEOSA-N 0.000 description 1
- YHWCATDRZANJSR-INIZCTEOSA-N 1-[(2S)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-5-pyrazin-2-yloxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC=CN=C1)C=1C=NN(C1)C1CCNCC1)C(C)=O YHWCATDRZANJSR-INIZCTEOSA-N 0.000 description 1
- TYBOACRAUTWZGZ-INIZCTEOSA-N 1-[(2S)-5-(3-chloropyridin-2-yl)oxy-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound ClC=1C(=NC=CC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCNCC1)C(C)=O)C TYBOACRAUTWZGZ-INIZCTEOSA-N 0.000 description 1
- DSBBIXIIUPWBAC-AWEZNQCLSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(1,3-thiazol-5-ylmethoxy)-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OCC1=CN=CS1 DSBBIXIIUPWBAC-AWEZNQCLSA-N 0.000 description 1
- PEDMCUZTWXKKLX-INIZCTEOSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-2-methyl-5-(5-methylpyridin-2-yl)oxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC=C(C=C1)C PEDMCUZTWXKKLX-INIZCTEOSA-N 0.000 description 1
- NUPAKVHXTOPKGD-KRWDZBQOSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-5-isoquinolin-1-yloxy-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(C)=O)C)OC1=NC=CC2=CC=CC=C12 NUPAKVHXTOPKGD-KRWDZBQOSA-N 0.000 description 1
- BWSLNVFQPLKPPB-HNNXBMFYSA-N 1-[(2S)-6-(1-cyclopropylpyrazol-4-yl)-8-fluoro-2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=C(C1)F)C(C)=O)C)OC1=CC=CC=C1 BWSLNVFQPLKPPB-HNNXBMFYSA-N 0.000 description 1
- IAGCGIMNCSMBBT-QMMMGPOBSA-N 1-[(2S)-6-bromo-5-cyclobutyloxy-7,8-difluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl]ethanone Chemical compound BrC=1C(=C2CC[C@@H](N(C2=C(C1F)F)C(C)=O)C)OC1CCC1 IAGCGIMNCSMBBT-QMMMGPOBSA-N 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- VUQPJRPDRDVQMN-UHFFFAOYSA-N 1-chlorooctadecane Chemical compound CCCCCCCCCCCCCCCCCCCl VUQPJRPDRDVQMN-UHFFFAOYSA-N 0.000 description 1
- OUUCZGCOAXRCHN-UHFFFAOYSA-N 1-hexadecoxyoctadecane Chemical compound CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC OUUCZGCOAXRCHN-UHFFFAOYSA-N 0.000 description 1
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- HFZLSTDPRQSZCQ-UHFFFAOYSA-N 1-pyrrolidin-3-ylpyrrolidine Chemical group C1CCCN1C1CNCC1 HFZLSTDPRQSZCQ-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- AWBOSXFRPFZLOP-UHFFFAOYSA-N 2,1,3-benzoxadiazole Chemical compound C1=CC=CC2=NON=C21 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- IEJPPSMHUUQABK-UHFFFAOYSA-N 2,4-diphenyl-4h-1,3-oxazol-5-one Chemical compound O=C1OC(C=2C=CC=CC=2)=NC1C1=CC=CC=C1 IEJPPSMHUUQABK-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 description 1
- HNLXNOZHXNSSPN-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CC(C)(C)CC(C)(C)C1=CC=C(OCCOCCOCCOCCOCCOCCOCCO)C=C1 HNLXNOZHXNSSPN-UHFFFAOYSA-N 0.000 description 1
- QEHDAUWYRNEWBF-UHFFFAOYSA-N 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethanol Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN(CCO)N=C1 QEHDAUWYRNEWBF-UHFFFAOYSA-N 0.000 description 1
- VDSGBPKUOUCVBD-SFHVURJKSA-N 2-[[(2S)-1-(cyclopropanecarbonyl)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-5-yl]oxy]-6-fluorobenzonitrile Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=C(C#N)C(=CC=C1)F)C VDSGBPKUOUCVBD-SFHVURJKSA-N 0.000 description 1
- BANOTGHIHYMTDL-UHFFFAOYSA-N 2-bromo-1-methylimidazole Chemical compound CN1C=CN=C1Br BANOTGHIHYMTDL-UHFFFAOYSA-N 0.000 description 1
- YFBQXUGQIFAFMM-UHFFFAOYSA-N 2-chloro-n-methylethanamine Chemical compound CNCCCl YFBQXUGQIFAFMM-UHFFFAOYSA-N 0.000 description 1
- NFIHXTUNNGIYRF-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate Chemical compound CCCCCCCCCC(=O)OCC(C)OC(=O)CCCCCCCCC NFIHXTUNNGIYRF-UHFFFAOYSA-N 0.000 description 1
- RUTKJXMYXZFXPQ-UHFFFAOYSA-N 2-fluoro-5-methoxyaniline Chemical compound COC1=CC=C(F)C(N)=C1 RUTKJXMYXZFXPQ-UHFFFAOYSA-N 0.000 description 1
- GHHURQMJLARIDK-UHFFFAOYSA-N 2-hydroxypropyl octanoate Chemical compound CCCCCCCC(=O)OCC(C)O GHHURQMJLARIDK-UHFFFAOYSA-N 0.000 description 1
- FLMTWGIMWGBMGB-UHFFFAOYSA-N 2-methoxy-3,4-dihydro-2H-quinoline-1-carboxylic acid Chemical compound COC1N(C2=CC=CC=C2CC1)C(=O)O FLMTWGIMWGBMGB-UHFFFAOYSA-N 0.000 description 1
- JZICUKPOZUKZLL-UHFFFAOYSA-N 2-methyl-1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2NC(C)CCC2=C1 JZICUKPOZUKZLL-UHFFFAOYSA-N 0.000 description 1
- WWAJCVIKMVMFIS-UHFFFAOYSA-N 2-methyl-1,2,3,4-tetrahydroquinoline;hydrochloride Chemical compound Cl.C1=CC=C2NC(C)CCC2=C1 WWAJCVIKMVMFIS-UHFFFAOYSA-N 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- LNCCBHFAHILMCT-UHFFFAOYSA-N 2-n,4-n,6-n-triethyl-1,3,5-triazine-2,4,6-triamine Chemical compound CCNC1=NC(NCC)=NC(NCC)=N1 LNCCBHFAHILMCT-UHFFFAOYSA-N 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical compound BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- DXFBKDSQMUFYLD-UHFFFAOYSA-N 2-pyrazol-1-ylethanol Chemical compound OCCN1C=CC=N1 DXFBKDSQMUFYLD-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- CXIISRLRZRAKST-UHFFFAOYSA-N 29‐(4‐nonylphenoxy)‐3,6,9,12,15,18,21,24,27‐ nonaoxanonacosan‐1‐ol Chemical compound CCCCCCCCCC1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1 CXIISRLRZRAKST-UHFFFAOYSA-N 0.000 description 1
- BNPWVUJOPCGHIK-UHFFFAOYSA-N 3,4-difluorophenol Chemical compound OC1=CC=C(F)C(F)=C1 BNPWVUJOPCGHIK-UHFFFAOYSA-N 0.000 description 1
- IDUSJBBWEKNWAK-UHFFFAOYSA-N 3,4-dihydro-2h-1,2-benzothiazine Chemical compound C1=CC=C2SNCCC2=C1 IDUSJBBWEKNWAK-UHFFFAOYSA-N 0.000 description 1
- GYLMCBOAXJVARF-UHFFFAOYSA-N 3-azabicyclo[2.2.1]heptane Chemical compound C1C2CCC1NC2 GYLMCBOAXJVARF-UHFFFAOYSA-N 0.000 description 1
- IHXLTTGASCITSD-UHFFFAOYSA-N 3-benzyl-2-methylquinoline Chemical compound CC1=NC2=CC=CC=C2C=C1CC1=CC=CC=C1 IHXLTTGASCITSD-UHFFFAOYSA-N 0.000 description 1
- XSEKMFLQQOEVTJ-UHFFFAOYSA-N 3-bromothietane 1,1-dioxide Chemical compound BrC1CS(=O)(=O)C1 XSEKMFLQQOEVTJ-UHFFFAOYSA-N 0.000 description 1
- KRKAHVGIXIYIGB-UHFFFAOYSA-N 3-chloro-2,2-dimethyldecane Chemical compound CCCCCCCC(Cl)C(C)(C)C KRKAHVGIXIYIGB-UHFFFAOYSA-N 0.000 description 1
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- TVOJIBGZFYMWDT-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CNN=C1 TVOJIBGZFYMWDT-UHFFFAOYSA-N 0.000 description 1
- RQXAQBBPEUPYMU-UHFFFAOYSA-N 4-(5-bromopyrazol-1-yl)piperidine Chemical compound BrC1=CC=NN1C1CCNCC1 RQXAQBBPEUPYMU-UHFFFAOYSA-N 0.000 description 1
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
- QJPQUNWGOHADOB-UHFFFAOYSA-N 4-bromo-1,3-thiazol-2-amine Chemical compound NC1=NC(Br)=CS1 QJPQUNWGOHADOB-UHFFFAOYSA-N 0.000 description 1
- VDTIGYKLTROQAH-UHFFFAOYSA-N 4-bromo-1,3-thiazole Chemical compound BrC1=CSC=N1 VDTIGYKLTROQAH-UHFFFAOYSA-N 0.000 description 1
- BZULRTZCBCPPKA-UHFFFAOYSA-N 4-bromo-1,3-thiazole-2-carboxamide Chemical compound NC(=O)C1=NC(Br)=CS1 BZULRTZCBCPPKA-UHFFFAOYSA-N 0.000 description 1
- OSWSSZXHGBDQIH-UHFFFAOYSA-N 4-bromothiane 1,1-dioxide Chemical compound BrC1CCS(=O)(=O)CC1 OSWSSZXHGBDQIH-UHFFFAOYSA-N 0.000 description 1
- JUIKCULGDIZNDI-UHFFFAOYSA-N 4-chloro-3-nitrophenol Chemical compound OC1=CC=C(Cl)C([N+]([O-])=O)=C1 JUIKCULGDIZNDI-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- XHZWFUVEKDDQPF-UHFFFAOYSA-N 5-bromo-1h-pyrazole Chemical compound BrC1=CC=NN1 XHZWFUVEKDDQPF-UHFFFAOYSA-N 0.000 description 1
- IEGAJKFNCPLAQH-UHFFFAOYSA-N 5-cyclobutyloxy-7,8-difluoro-2-methylquinoline Chemical compound C1(CCC1)OC1=C2C=CC(=NC2=C(C(=C1)F)F)C IEGAJKFNCPLAQH-UHFFFAOYSA-N 0.000 description 1
- GZWQWDSVTVADEP-UHFFFAOYSA-N 5-cyclobutyloxy-7,8-difluoro-2-methylquinoline hydrochloride Chemical compound Cl.C1(CCC1)OC1=C2C=CC(=NC2=C(C(=C1)F)F)C GZWQWDSVTVADEP-UHFFFAOYSA-N 0.000 description 1
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- 125000005941 7-oxabicyclo[2.2.1]heptyl group Chemical group 0.000 description 1
- UNPLQAGUEXIURZ-UHFFFAOYSA-N 8-fluoro-5-methoxy-2-methylquinoline Chemical compound FC=1C=CC(=C2C=CC(=NC12)C)OC UNPLQAGUEXIURZ-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- 244000144730 Amygdalus persica Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 241001474374 Blennius Species 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 244000056139 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 108091005575 Bromodomain-containing proteins Proteins 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- YKZRTKCHXWQOHV-KRWDZBQOSA-N C[C@H]1CCC2=C(N1)C=CC(=C2OCC(=O)N3CCCC3)C4=CN(N=C4)C5CCNCC5 Chemical compound C[C@H]1CCC2=C(N1)C=CC(=C2OCC(=O)N3CCCC3)C4=CN(N=C4)C5CCNCC5 YKZRTKCHXWQOHV-KRWDZBQOSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 239000001736 Calcium glycerylphosphate Substances 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 102000011632 Caseins Human genes 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 241000283153 Cetacea Species 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 208000002691 Choroiditis Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 244000241257 Cucumis melo Species 0.000 description 1
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- XMSXQFUHVRWGNA-UHFFFAOYSA-N Decamethylcyclopentasiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O1 XMSXQFUHVRWGNA-UHFFFAOYSA-N 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 239000001692 EU approved anti-caking agent Substances 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000037487 Endotoxemia Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 1
- 240000006927 Foeniculum vulgare Species 0.000 description 1
- 235000004204 Foeniculum vulgare Nutrition 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical class [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 229930191892 Formycin Natural products 0.000 description 1
- KBHMEHLJSZMEMI-UHFFFAOYSA-N Formycin A Natural products N1N=C2C(N)=NC=NC2=C1C1OC(CO)C(O)C1O KBHMEHLJSZMEMI-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010061172 Gastrointestinal injury Diseases 0.000 description 1
- 241000237858 Gastropoda Species 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 208000013875 Heart injury Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 241000701806 Human papillomavirus Species 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 206010022941 Iridocyclitis Diseases 0.000 description 1
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Natural products CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 1
- 206010023125 Jarisch-Herxheimer reaction Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 208000011200 Kawasaki disease Diseases 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 208000004852 Lung Injury Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000005777 Lupus Nephritis Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- 208000035719 Maculopathy Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 208000001940 Massive Hepatic Necrosis Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 208000010718 Multiple Organ Failure Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 208000005647 Mumps Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- 208000003926 Myelitis Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 208000005890 Neuroma Diseases 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108010089610 Nuclear Proteins Proteins 0.000 description 1
- 102000007999 Nuclear Proteins Human genes 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 208000003435 Optic Neuritis Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- YYVFXSYQSOZCOQ-UHFFFAOYSA-N Oxyquinoline sulfate Chemical compound [O-]S([O-])(=O)=O.C1=C[NH+]=C2C(O)=CC=CC2=C1.C1=C[NH+]=C2C(O)=CC=CC2=C1 YYVFXSYQSOZCOQ-UHFFFAOYSA-N 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- 206010033647 Pancreatitis acute Diseases 0.000 description 1
- 241000282520 Papio Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 208000003971 Posterior uveitis Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- HDSBZMRLPLPFLQ-UHFFFAOYSA-N Propylene glycol alginate Chemical compound OC1C(O)C(OC)OC(C(O)=O)C1OC1C(O)C(O)C(C)C(C(=O)OCC(C)O)O1 HDSBZMRLPLPFLQ-UHFFFAOYSA-N 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000006311 Pyoderma Diseases 0.000 description 1
- WHBMMWSBFZVSSR-UHFFFAOYSA-N R3HBA Natural products CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 206010038848 Retinal detachment Diseases 0.000 description 1
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 1
- 239000008156 Ringer's lactate solution Substances 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 206010039705 Scleritis Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 239000004288 Sodium dehydroacetate Substances 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 1
- ZIJKGAXBCRWEOL-SAXBRCJISA-N Sucrose octaacetate Chemical compound CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@@]1(COC(C)=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1 ZIJKGAXBCRWEOL-SAXBRCJISA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 208000001106 Takayasu Arteritis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010043189 Telangiectasia Diseases 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N Tetrahydrothiophene-1,1-dioxide, Natural products O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- 239000005844 Thymol Substances 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- 206010044248 Toxic shock syndrome Diseases 0.000 description 1
- 231100000650 Toxic shock syndrome Toxicity 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- 206010069363 Traumatic lung injury Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 241000009298 Trigla lyra Species 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 240000001717 Vaccinium macrocarpon Species 0.000 description 1
- 235000012545 Vaccinium macrocarpon Nutrition 0.000 description 1
- 235000002118 Vaccinium oxycoccus Nutrition 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 206010047642 Vitiligo Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- BIIDBUHYULVVIZ-ZDUSSCGKSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(1,2-oxazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NOC1)C(=O)C1CC1)C BIIDBUHYULVVIZ-ZDUSSCGKSA-N 0.000 description 1
- GDCFAPBNSIQTAA-INIZCTEOSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(1-piperidin-4-yltriazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=NN(C1)C1CCNCC1)C(=O)C1CC1)C GDCFAPBNSIQTAA-INIZCTEOSA-N 0.000 description 1
- VOTDBTSNDCQSQA-ZDUSSCGKSA-N [(2S)-5-cyclobutyloxy-2-methyl-6-(triazol-2-yl)-3,4-dihydro-2H-quinolin-1-yl]-cyclopropylmethanone Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1N1N=CC=N1)C(=O)C1CC1)C VOTDBTSNDCQSQA-ZDUSSCGKSA-N 0.000 description 1
- 239000001344 [(2S,3S,4R,5R)-4-acetyloxy-2,5-bis(acetyloxymethyl)-2-[(2R,3R,4S,5R,6R)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxyoxolan-3-yl] acetate Substances 0.000 description 1
- UJQAHAANAPEYLR-UHFFFAOYSA-N [2-chloro-6-[2,4,6-tri(propan-2-yl)phenyl]phenyl]-dicyclohexylphosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(Cl)=C1P(C1CCCCC1)C1CCCCC1 UJQAHAANAPEYLR-UHFFFAOYSA-N 0.000 description 1
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 description 1
- MJMXSNHYUJBWKG-UHFFFAOYSA-N [Cl-].[SH3+].C Chemical compound [Cl-].[SH3+].C MJMXSNHYUJBWKG-UHFFFAOYSA-N 0.000 description 1
- GUWTXVUFNXVQMT-UHFFFAOYSA-N [N]1C=2N(CCC1)C=CC2 Chemical compound [N]1C=2N(CCC1)C=CC2 GUWTXVUFNXVQMT-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
- 108091005646 acetylated proteins Proteins 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 239000002535 acidifier Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229920006243 acrylic copolymer Polymers 0.000 description 1
- 208000009621 actinic keratosis Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 206010069351 acute lung injury Diseases 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 229920013820 alkyl cellulose Polymers 0.000 description 1
- 125000005466 alkylenyl group Chemical group 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 125000002431 aminoalkoxy group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229920000469 amphiphilic block copolymer Polymers 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 201000004612 anterior uveitis Diseases 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- BTFJIXJJCSYFAL-UHFFFAOYSA-N arachidyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCO BTFJIXJJCSYFAL-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 206010069664 atopic keratoconjunctivitis Diseases 0.000 description 1
- AXMNGEUJXLXFRY-UHFFFAOYSA-N azaspirodecane Chemical compound C1CCCC21CCNCC2 AXMNGEUJXLXFRY-UHFFFAOYSA-N 0.000 description 1
- 125000003725 azepanyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- 229940095076 benzaldehyde Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- YYMVPVZYUYQSJE-UHFFFAOYSA-N benzyl-[2-(2,6-dimethylanilino)-2-oxoethyl]-diethylazanium;benzoate;hydrate Chemical compound O.[O-]C(=O)C1=CC=CC=C1.C=1C=CC=CC=1C[N+](CC)(CC)CC(=O)NC1=C(C)C=CC=C1C YYMVPVZYUYQSJE-UHFFFAOYSA-N 0.000 description 1
- XKXHCNPAFAXVRZ-UHFFFAOYSA-N benzylazanium;chloride Chemical compound [Cl-].[NH3+]CC1=CC=CC=C1 XKXHCNPAFAXVRZ-UHFFFAOYSA-N 0.000 description 1
- 150000005347 biaryls Chemical class 0.000 description 1
- GPRLTFBKWDERLU-UHFFFAOYSA-N bicyclo[2.2.2]octane Chemical compound C1CC2CCC1CC2 GPRLTFBKWDERLU-UHFFFAOYSA-N 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 235000010338 boric acid Nutrition 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 208000025698 brain inflammatory disease Diseases 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229940125763 bromodomain inhibitor Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 208000019748 bullous skin disease Diseases 0.000 description 1
- 229940057971 butane Drugs 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 229940038926 butyl chloride Drugs 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229940067596 butylparaben Drugs 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- FNAQSUUGMSOBHW-UHFFFAOYSA-H calcium citrate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FNAQSUUGMSOBHW-UHFFFAOYSA-H 0.000 description 1
- 239000001354 calcium citrate Substances 0.000 description 1
- UHHRFSOMMCWGSO-UHFFFAOYSA-L calcium glycerophosphate Chemical compound [Ca+2].OCC(CO)OP([O-])([O-])=O UHHRFSOMMCWGSO-UHFFFAOYSA-L 0.000 description 1
- 229940095618 calcium glycerophosphate Drugs 0.000 description 1
- 235000019299 calcium glycerylphosphate Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
- 239000001527 calcium lactate Substances 0.000 description 1
- 235000011086 calcium lactate Nutrition 0.000 description 1
- 229960002401 calcium lactate Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- LNMAXKMUGYXKPJ-UHFFFAOYSA-L calcium;1,1-dioxo-1,2-benzothiazol-2-id-3-one Chemical compound [Ca+2].C1=CC=C2C([O-])=NS(=O)(=O)C2=C1.C1=CC=C2C([O-])=NS(=O)(=O)C2=C1 LNMAXKMUGYXKPJ-UHFFFAOYSA-L 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- LDVVMCZRFWMZSG-UHFFFAOYSA-N captan Chemical compound C1C=CCC2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C21 LDVVMCZRFWMZSG-UHFFFAOYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- GVFJQKOCPYMYKI-UHFFFAOYSA-N carbonyl dichloride;propane Chemical compound CCC.ClC(Cl)=O GVFJQKOCPYMYKI-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 230000009787 cardiac fibrosis Effects 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 229940082483 carnauba wax Drugs 0.000 description 1
- 229960001777 castor oil Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 201000005667 central retinal vein occlusion Diseases 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229940081733 cetearyl alcohol Drugs 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- NFCRBQADEGXVDL-UHFFFAOYSA-M cetylpyridinium chloride monohydrate Chemical compound O.[Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 NFCRBQADEGXVDL-UHFFFAOYSA-M 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229960002242 chlorocresol Drugs 0.000 description 1
- DOZZESQBLWOEBQ-UHFFFAOYSA-N chlorohydrazine Chemical compound NNCl DOZZESQBLWOEBQ-UHFFFAOYSA-N 0.000 description 1
- XENVCRGQTABGKY-ZHACJKMWSA-N chlorohydrin Chemical compound CC#CC#CC#CC#C\C=C\C(Cl)CO XENVCRGQTABGKY-ZHACJKMWSA-N 0.000 description 1
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 1
- RSLSVURFMXHEEU-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[3-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;2-phenylaniline Chemical compound [Pd+]Cl.NC1=CC=CC=C1C1=CC=CC=[C-]1.CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(P(C2CCCCC2)C2CCCCC2)=C1 RSLSVURFMXHEEU-UHFFFAOYSA-M 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 210000004240 ciliary body Anatomy 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 235000004634 cranberry Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 229940013361 cresol Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002150 cyclohexa-1,4-dienyl group Chemical group [H]C1=C([H])C([H])(*)C([H])=C([H])C1([H])[H] 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229940086555 cyclomethicone Drugs 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- WSDPCCDUJXMLAX-UHFFFAOYSA-N cyclopropyl-(2-methyl-3,4-dihydro-2h-quinolin-1-yl)methanone Chemical compound CC1CCC2=CC=CC=C2N1C(=O)C1CC1 WSDPCCDUJXMLAX-UHFFFAOYSA-N 0.000 description 1
- ZFGPVOPEPHKOLL-IBGZPJMESA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(4-piperazin-1-ylpyrazol-1-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)N1N=CC(=C1)N1CCNCC1)OC1=CC=CC=C1)C ZFGPVOPEPHKOLL-IBGZPJMESA-N 0.000 description 1
- UJSNYIXIDZMVMO-HNNXBMFYSA-N cyclopropyl-[(2S)-2-methyl-5-phenoxy-6-(triazol-2-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)N1N=CC=N1)OC1=CC=CC=C1)C UJSNYIXIDZMVMO-HNNXBMFYSA-N 0.000 description 1
- LZRAONNKSBDXGD-IBGZPJMESA-N cyclopropyl-[(2S)-2-methyl-6-(4-morpholin-4-ylpyrazol-1-yl)-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)N1N=CC(=C1)N1CCOCC1)OC1=CC=CC=C1)C LZRAONNKSBDXGD-IBGZPJMESA-N 0.000 description 1
- VJWOQAXZXHCCOT-IBGZPJMESA-N cyclopropyl-[(2S)-5-(3-methoxyphenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C=1C=NN(C1)C1CCNCC1)OC1=CC(=CC=C1)OC)C VJWOQAXZXHCCOT-IBGZPJMESA-N 0.000 description 1
- MQODKXWHJDFRDL-HNNXBMFYSA-N cyclopropyl-[(2S)-6-cyclopropyl-2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C1CC1)OC1=CC=CC=C1)C MQODKXWHJDFRDL-HNNXBMFYSA-N 0.000 description 1
- QEAFUMSIOGSHSS-HNNXBMFYSA-N cyclopropyl-[(2S)-6-ethynyl-2-methyl-5-phenoxy-3,4-dihydro-2H-quinolin-1-yl]methanone Chemical compound C1(CC1)C(=O)N1[C@H](CCC2=C(C(=CC=C12)C#C)OC1=CC=CC=C1)C QEAFUMSIOGSHSS-HNNXBMFYSA-N 0.000 description 1
- 201000010206 cystoid macular edema Diseases 0.000 description 1
- 230000020335 dealkylation Effects 0.000 description 1
- 238000006900 dealkylation reaction Methods 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 125000004652 decahydroisoquinolinyl group Chemical group C1(NCCC2CCCCC12)* 0.000 description 1
- 239000013530 defoamer Substances 0.000 description 1
- 235000019258 dehydroacetic acid Nutrition 0.000 description 1
- 229940061632 dehydroacetic acid Drugs 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 229960001610 denatonium benzoate Drugs 0.000 description 1
- 230000027832 depurination Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 201000011190 diabetic macular edema Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-O diazenium Chemical compound [NH2+]=N RAABOESOVLLHRU-UHFFFAOYSA-O 0.000 description 1
- LMEDOLJKVASKTP-UHFFFAOYSA-N dibutyl sulfate Chemical compound CCCCOS(=O)(=O)OCCCC LMEDOLJKVASKTP-UHFFFAOYSA-N 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- CVKBMWWNKUWISK-UHFFFAOYSA-L dichloromethane;dichloropalladium Chemical compound ClCCl.Cl[Pd]Cl CVKBMWWNKUWISK-UHFFFAOYSA-L 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- BIPUHAHGLJKIPK-UHFFFAOYSA-N dicyclopropylmethanone Chemical compound C1CC1C(=O)C1CC1 BIPUHAHGLJKIPK-UHFFFAOYSA-N 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- UYAAVKFHBMJOJZ-UHFFFAOYSA-N diimidazo[1,3-b:1',3'-e]pyrazine-5,10-dione Chemical compound O=C1C2=CN=CN2C(=O)C2=CN=CN12 UYAAVKFHBMJOJZ-UHFFFAOYSA-N 0.000 description 1
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 1
- 229940043276 diisopropanolamine Drugs 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 229940008099 dimethicone Drugs 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- DXPIZCZNFUTPEI-UHFFFAOYSA-O diphenylphosphanium;azide Chemical compound [N-]=[N+]=[N-].C=1C=CC=CC=1[PH2+]C1=CC=CC=C1 DXPIZCZNFUTPEI-UHFFFAOYSA-O 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960000878 docusate sodium Drugs 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229940124274 edetate disodium Drugs 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000010102 embolization Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 229940073505 ethyl vanillin Drugs 0.000 description 1
- 125000005469 ethylenyl group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229950004696 flusalan Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 229940044170 formate Drugs 0.000 description 1
- VEPYXRRTOARCQD-IGPDFVGCSA-N formycin Chemical compound N1=N[C]2C(N)=NC=NC2=C1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O VEPYXRRTOARCQD-IGPDFVGCSA-N 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000004615 furo[2,3-b]pyridinyl group Chemical group O1C(=CC=2C1=NC=CC2)* 0.000 description 1
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000003209 gene knockout Methods 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 125000005946 imidazo[1,2-a]pyridyl group Chemical group 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- 239000001282 iso-butane Substances 0.000 description 1
- 229940035415 isobutane Drugs 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 229940075495 isopropyl palmitate Drugs 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 201000010666 keratoconjunctivitis Diseases 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229940059904 light mineral oil Drugs 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000002960 lipid emulsion Substances 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 231100000515 lung injury Toxicity 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- OIIUPEGQEISCCZ-SFHVURJKSA-N methyl (2S)-2-methyl-5-(6-methylpyridin-2-yl)oxy-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C[C@@H]1N(C2=CC=C(C(=C2CC1)OC1=NC(=CC=C1)C)C=1C=NN(C1)C1CCNCC1)C(=O)OC OIIUPEGQEISCCZ-SFHVURJKSA-N 0.000 description 1
- YCRGOGKEZSKOMU-IRXDYDNUSA-N methyl (2S)-2-methyl-6-[1-(2-methylsulfonylethyl)pyrazol-4-yl]-5-[[(3S)-pyrrolidin-3-yl]methoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound CS(=O)(=O)CCN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC[C@@H]1CNCC1 YCRGOGKEZSKOMU-IRXDYDNUSA-N 0.000 description 1
- RTEFLPVJOWNVJJ-INIZCTEOSA-N methyl (2S)-5-(3-chloro-4-fluorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC=1C=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=CC1F RTEFLPVJOWNVJJ-INIZCTEOSA-N 0.000 description 1
- JGVUJYJCSXZKJT-KRWDZBQOSA-N methyl (2S)-5-(4-chlorophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound ClC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=C1 JGVUJYJCSXZKJT-KRWDZBQOSA-N 0.000 description 1
- UHYUGSKLLATOIM-SFHVURJKSA-N methyl (2S)-5-(4-cyanophenoxy)-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C(#N)C1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CCNCC2)C(=O)OC)C)C=C1 UHYUGSKLLATOIM-SFHVURJKSA-N 0.000 description 1
- UXUUIAWEWZVOJO-INIZCTEOSA-N methyl (2S)-5-(4-fluorophenoxy)-2-methyl-6-[1-(1-methylazetidin-3-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)C2CN(C2)C)C(=O)OC)C)C=C1 UXUUIAWEWZVOJO-INIZCTEOSA-N 0.000 description 1
- AXLJVHWCUNJUHM-XTZPKPCCSA-N methyl (2S)-5-(4-fluorophenoxy)-6-[1-[(3R,4R)-3-fluoropiperidin-4-yl]pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound FC1=CC=C(OC2=C3CC[C@@H](N(C3=CC=C2C=2C=NN(C2)[C@H]2[C@@H](CNCC2)F)C(=O)OC)C)C=C1 AXLJVHWCUNJUHM-XTZPKPCCSA-N 0.000 description 1
- COWFTWBCAALKLH-KRWDZBQOSA-N methyl (2S)-5-(cyclopentylmethoxy)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCCC1)COC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CC(C)(C)O)C(=O)OC)C COWFTWBCAALKLH-KRWDZBQOSA-N 0.000 description 1
- JRABXTMGSKWHOL-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-[1-(1-methylazetidin-3-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CN(C1)C)C(=O)OC)C JRABXTMGSKWHOL-HNNXBMFYSA-N 0.000 description 1
- IXZDHAJIGPSGHY-KRWDZBQOSA-N methyl (2S)-5-cyclobutyloxy-2-methyl-6-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCN(CC1)C)C(=O)OC)C IXZDHAJIGPSGHY-KRWDZBQOSA-N 0.000 description 1
- IMHQXKIZOLOLFU-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)CC(C)(C)O)C(=O)OC)C IMHQXKIZOLOLFU-HNNXBMFYSA-N 0.000 description 1
- DBMGIUFETYDSPO-ZDUSSCGKSA-N methyl (2S)-5-cyclobutyloxy-6-[2-(3-fluoroazetidin-3-yl)-1,3-thiazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(SC1)C1(CNC1)F)C(=O)OC)C DBMGIUFETYDSPO-ZDUSSCGKSA-N 0.000 description 1
- SWHIXTNQWFMWBE-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-6-[2-(4-fluoropiperidin-4-yl)-1,3-thiazol-4-yl]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1N=C(SC1)C1(CCNCC1)F)C(=O)OC)C SWHIXTNQWFMWBE-HNNXBMFYSA-N 0.000 description 1
- QBRZZPGDGJGWSO-HNNXBMFYSA-N methyl (2S)-5-cyclobutyloxy-8-fluoro-2-methyl-6-(1-piperidin-4-ylpyrazol-4-yl)-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=C(C=C1C=1C=NN(C1)C1CCNCC1)F)C(=O)OC)C QBRZZPGDGJGWSO-HNNXBMFYSA-N 0.000 description 1
- HNQSPAFOBFAXKB-ZDUSSCGKSA-N methyl (2S)-6-(1-cyclopropylpyrazol-4-yl)-5-(3,3-difluorocyclobutyl)oxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CC1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1CC(C1)(F)F HNQSPAFOBFAXKB-ZDUSSCGKSA-N 0.000 description 1
- VHLGNPHDUZAMKP-FUSSNKQKSA-N methyl (2S)-6-[1-(1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl)pyrazol-4-yl]-5-cyclobutyloxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CC2C(CNC2)C1)C(=O)OC)C VHLGNPHDUZAMKP-FUSSNKQKSA-N 0.000 description 1
- UKWJPEZRUGBRAK-IRXDYDNUSA-N methyl (2S)-6-[1-(2-hydroxy-2-methylpropyl)pyrazol-4-yl]-2-methyl-5-[[(3S)-pyrrolidin-3-yl]methoxy]-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound OC(CN1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC[C@@H]1CNCC1)(C)C UKWJPEZRUGBRAK-IRXDYDNUSA-N 0.000 description 1
- WKJJIVYOBYMZEA-AWEZNQCLSA-N methyl (2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-5-(3,4-difluorophenoxy)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=CC(=C(C=C1)F)F WKJJIVYOBYMZEA-AWEZNQCLSA-N 0.000 description 1
- ZDKSTNFLHSILLM-AWEZNQCLSA-N methyl (2S)-6-[1-(azetidin-3-yl)pyrazol-4-yl]-5-(3,5-difluorophenoxy)-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylate Chemical compound N1CC(C1)N1N=CC(=C1)C=1C(=C2CC[C@@H](N(C2=CC1)C(=O)OC)C)OC1=CC(=CC(=C1)F)F ZDKSTNFLHSILLM-AWEZNQCLSA-N 0.000 description 1
- KRCMKUNIILUXPF-UHFFFAOYSA-N methyl 4-hydroxybenzoate;sodium Chemical compound [Na].COC(=O)C1=CC=C(O)C=C1 KRCMKUNIILUXPF-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N methyl undecanoic acid Natural products CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000013081 microcrystal Substances 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 229940114937 microcrystalline wax Drugs 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- LPUQAYUQRXPFSQ-DFWYDOINSA-M monosodium L-glutamate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CCC(O)=O LPUQAYUQRXPFSQ-DFWYDOINSA-M 0.000 description 1
- 239000004223 monosodium glutamate Substances 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 208000001725 mucocutaneous lymph node syndrome Diseases 0.000 description 1
- 230000008383 multiple organ dysfunction Effects 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 208000010805 mumps infectious disease Diseases 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- VNBZEVWCBPVJKK-UHFFFAOYSA-N n-(4-bromo-1,3-thiazol-2-yl)acetamide Chemical compound CC(=O)NC1=NC(Br)=CS1 VNBZEVWCBPVJKK-UHFFFAOYSA-N 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 201000002165 neuroretinitis Diseases 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229940073555 nonoxynol-10 Drugs 0.000 description 1
- 229920004918 nonoxynol-9 Polymers 0.000 description 1
- 229940087419 nonoxynol-9 Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- JFNLZVQOOSMTJK-KNVOCYPGSA-N norbornene Chemical compound C1[C@@H]2CC[C@H]1C=C2 JFNLZVQOOSMTJK-KNVOCYPGSA-N 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 230000005937 nuclear translocation Effects 0.000 description 1
- YZNWXXJZEDHRKB-UHFFFAOYSA-N octadecyl 2-hydroxypropanoate;sodium Chemical compound [Na].CCCCCCCCCCCCCCCCCCOC(=O)C(C)O YZNWXXJZEDHRKB-UHFFFAOYSA-N 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 229920002114 octoxynol-9 Polymers 0.000 description 1
- 229940098514 octoxynol-9 Drugs 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 229940012843 omega-3 fatty acid Drugs 0.000 description 1
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007243 oxidative cyclization reaction Methods 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000007407 panuveitis Diseases 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 208000008494 pericarditis Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 229940096826 phenylmercuric acetate Drugs 0.000 description 1
- PDTFCHSETJBPTR-UHFFFAOYSA-N phenylmercuric nitrate Chemical compound [O-][N+](=O)O[Hg]C1=CC=CC=C1 PDTFCHSETJBPTR-UHFFFAOYSA-N 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229940081066 picolinic acid Drugs 0.000 description 1
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229960000540 polacrilin potassium Drugs 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000004848 polyfunctional curative Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 108010073734 polymyxin D Proteins 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 235000010235 potassium benzoate Nutrition 0.000 description 1
- 239000004300 potassium benzoate Substances 0.000 description 1
- 229940103091 potassium benzoate Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- OQZCJRJRGMMSGK-UHFFFAOYSA-M potassium metaphosphate Chemical compound [K+].[O-]P(=O)=O OQZCJRJRGMMSGK-UHFFFAOYSA-M 0.000 description 1
- 229940099402 potassium metaphosphate Drugs 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- QZWHWHNCPFEXLL-UHFFFAOYSA-N propan-2-yl n-[2-(1,3-thiazol-4-yl)-3h-benzimidazol-5-yl]carbamate Chemical compound N1C2=CC(NC(=O)OC(C)C)=CC=C2N=C1C1=CSC=N1 QZWHWHNCPFEXLL-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 description 1
- 239000000770 propane-1,2-diol alginate Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- FOWDZVNRQHPXDO-UHFFFAOYSA-N propyl hydrogen carbonate Chemical compound CCCOC(O)=O FOWDZVNRQHPXDO-UHFFFAOYSA-N 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229940116423 propylene glycol diacetate Drugs 0.000 description 1
- 229940093625 propylene glycol monostearate Drugs 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical class O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 239000005871 repellent Substances 0.000 description 1
- 230000002940 repellent Effects 0.000 description 1
- 230000004264 retinal detachment Effects 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 235000019719 rose oil Nutrition 0.000 description 1
- 239000010666 rose oil Substances 0.000 description 1
- 239000008132 rose water Substances 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 150000003902 salicylic acid esters Chemical class 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229940080237 sodium caseinate Drugs 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 235000019259 sodium dehydroacetate Nutrition 0.000 description 1
- 229940079839 sodium dehydroacetate Drugs 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000010268 sodium methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004290 sodium methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 1
- 235000010334 sodium propionate Nutrition 0.000 description 1
- 239000004324 sodium propionate Substances 0.000 description 1
- 229960003212 sodium propionate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- HUAUNKAZQWMVFY-UHFFFAOYSA-M sodium;oxocalcium;hydroxide Chemical compound [OH-].[Na+].[Ca]=O HUAUNKAZQWMVFY-UHFFFAOYSA-M 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- LMUMMJCCZMWLEN-UHFFFAOYSA-N spiro[3.3]heptyl Chemical group [CH]1CCC11CCC1 LMUMMJCCZMWLEN-UHFFFAOYSA-N 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 229940013883 sucrose octaacetate Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229940044609 sulfur dioxide Drugs 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 235000010269 sulphur dioxide Nutrition 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000008718 systemic inflammatory response Effects 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 208000009056 telangiectasis Diseases 0.000 description 1
- FBWNMEQMRUMQSO-UHFFFAOYSA-N tergitol NP-9 Chemical compound CCCCCCCCCC1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1 FBWNMEQMRUMQSO-UHFFFAOYSA-N 0.000 description 1
- XPDIKRMPZNLBAC-UHFFFAOYSA-N tert-butyl 3-iodoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(I)C1 XPDIKRMPZNLBAC-UHFFFAOYSA-N 0.000 description 1
- WLAZHMYDLUILKR-UHFFFAOYSA-N tert-butyl 3-methylsulfonyloxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1 WLAZHMYDLUILKR-UHFFFAOYSA-N 0.000 description 1
- HZVCWGMCTPAYAC-UHFFFAOYSA-N tert-butyl 4-(3-bromopyrazol-1-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1N=C(Br)C=C1 HZVCWGMCTPAYAC-UHFFFAOYSA-N 0.000 description 1
- VVDCRJGWILREQH-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(B2OC(C)(C)C(C)(C)O2)=C1 VVDCRJGWILREQH-UHFFFAOYSA-N 0.000 description 1
- ZKPJADAFPCXLBO-UHFFFAOYSA-N tert-butyl 4-(4,5-dibromotriazol-2-yl)piperidine-1-carboxylate Chemical compound BrC1=NN(N=C1Br)C1CCN(CC1)C(=O)OC(C)(C)C ZKPJADAFPCXLBO-UHFFFAOYSA-N 0.000 description 1
- PESUHIVCJNQHMI-UHFFFAOYSA-N tert-butyl 4-(4-bromo-1-methylimidazol-2-yl)piperidine-1-carboxylate Chemical compound BrC=1N=C(N(C1)C)C1CCN(CC1)C(=O)OC(C)(C)C PESUHIVCJNQHMI-UHFFFAOYSA-N 0.000 description 1
- LPYRUIDRWMZJHX-UHFFFAOYSA-N tert-butyl 4-(4-bromotriazol-2-yl)piperidine-1-carboxylate Chemical compound BrC1=NN(N=C1)C1CCN(CC1)C(=O)OC(C)(C)C LPYRUIDRWMZJHX-UHFFFAOYSA-N 0.000 description 1
- YDOFQQJWIHQHIX-UHFFFAOYSA-N tert-butyl 4-(5-bromo-1h-imidazol-2-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC=C(Br)N1 YDOFQQJWIHQHIX-UHFFFAOYSA-N 0.000 description 1
- ORPJARXRVYEZJQ-UHFFFAOYSA-N tert-butyl 4-(5-bromopyrazol-1-yl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1N1C(Br)=CC=N1 ORPJARXRVYEZJQ-UHFFFAOYSA-N 0.000 description 1
- IMFCKWVSCKLRLJ-FQEVSTJZSA-N tert-butyl 4-[4-[(2S)-5-cyclobutyloxy-1-(cyclopropanecarbonyl)-2-methyl-3,4-dihydro-2H-quinolin-6-yl]pyrazol-1-yl]piperidine-1-carboxylate Chemical compound C1(CCC1)OC1=C2CC[C@@H](N(C2=CC=C1C=1C=NN(C1)C1CCN(CC1)C(=O)OC(C)(C)C)C(=O)C1CC1)C IMFCKWVSCKLRLJ-FQEVSTJZSA-N 0.000 description 1
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
- UHOLSENWUXJOTP-UHFFFAOYSA-N tert-butyl N-(5-cyclobutyloxy-2,3-difluorophenyl)carbamate Chemical compound C1(CCC1)OC=1C=C(C(=C(C1)NC(OC(C)(C)C)=O)F)F UHOLSENWUXJOTP-UHFFFAOYSA-N 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 150000003530 tetrahydroquinolines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- VJYJJHQEVLEOFL-UHFFFAOYSA-N thieno[3,2-b]thiophene Chemical compound S1C=CC2=C1C=CS2 VJYJJHQEVLEOFL-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- FCFMKFHUNDYKEG-UHFFFAOYSA-N thietane 1,1-dioxide Chemical compound O=S1(=O)CCC1 FCFMKFHUNDYKEG-UHFFFAOYSA-N 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229960005196 titanium dioxide Drugs 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
- 229960004224 tyloxapol Drugs 0.000 description 1
- 229920001664 tyloxapol Polymers 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- DEXZEPDUSNRVTN-UHFFFAOYSA-K yttrium(3+);trihydroxide Chemical compound [OH-].[OH-].[OH-].[Y+3] DEXZEPDUSNRVTN-UHFFFAOYSA-K 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/16—Masculine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/28—Oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Rheumatology (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Immunology (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Quinoline Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本發明關於適用於治療癌症、發炎性疾病、糖尿病及肥胖症之溴(bromo)及外端(BET)溴域之抑制劑,其具有式I:
□其中W、X、Y、Z、R1、R2、R5及R8係如本文所述。
Description
本申請案主張2013年11月18日申請之美國臨時專利申請案第61/905,639號及2014年9月24日申請之美國臨時專利申請案第62/054,811號之權益及優先權。該等案之全部內容藉此以全文引用的方式併入。
本發明針對溴域之溴及外端(BET)家族之抑制劑,其適用於治療與調節溴域之溴及外端(BET)家族相關之疾病或病症。特定而言,本發明涉及用於抑制溴域之溴及外端(BET)家族之化合物及組成物,治療、預防或改善與抑制溴域之溴及外端(BET)家族相關之疾病或病症之方法,及合成此等化合物之方法。
哺乳動物中之溴及外端(BET)家族蛋白質含有四個成員,BRD2、BRD3、BRD4及BRDT,其中此等成員中之每一者含有兩個溴域(BRD):保守N端溴域(溴域1[BD1])及C端溴域(溴域2[BD2])。BET家族蛋白質已顯示在細胞增殖及細胞週期進程中具有關鍵作用。
已知含溴域蛋白質參與轉錄調控。一般而言,溴域見於調控染色質結構及基因表現之蛋白質中。此等蛋白質之存在為各種生長及抗凋亡基因之全身表現所需。另外,此等蛋白質在普遍存在之細胞週期
進程中起作用,此係因為許多核蛋白具有與染色質相互作用之溴域,諸如組蛋白乙醯轉移酶。含溴域蛋白質之功能不良與許多疾病之發展、尤其與癌症之發展相關聯(Muller,S.Filippakopoulos,P.Knapp,S.(2011),Bromodomains as therapeutic targets.Expert Rev.Mol.Med.13:e29)。溴域亦已牽涉於發炎過程中(Nicodeme等人,Nature,2010,第468卷,第1119頁)。
作為基因產物之BRD4蛋白含有1362個胺基酸。BRD4 BD1為約75-147;BRD4 BD2為約368-440;由此各者之長度為73個殘基。出於生物化學篩選、生物物理學或X射線結晶學之目的,表現並使用具有經添加用於兩個溴域之其他N端及C端殘基之各種蛋白質構築體。另外,亦已使用具有表現於相同蛋白質內之兩個溴域之蛋白質構築體(總共約400aa殘基)。
蛋白質包含四個α螺旋,全部左旋定向,此與蛋白質之高度多樣化之序列性質成鮮明對比。螺旋(αZ、αA、αC及αB)以Z與A螺旋相互作用形成長「ZA環」且C與B螺旋相互作用形成短「BC環」之方式排列(Dhalluin C.,Carlson J.E.,Zeng L.,He C.,Aggarwal A.K.,Zhou M.M.(1999),Structure and ligand of a histone acetyltransferase bromodomain.Nature.399,491-6)。此等環形成蛋白質中之疏水袋,在此處蛋白質與乙醯化離胺酸殘基相互作用。突變誘發研究表明,兩個螺旋間環之間的疏水及芳族殘基當中之三級接觸直接促成蛋白質之結構穩定性(Dhalluin C.,Carlson J.E.,Zeng L.,He C.,Aggarwal A.K.,Zhou M.M.(1999),Structure and ligand of a histone acetyltransferase bromodomain.Nature.399,491-6)。
長久以來已表明,溴域在染色質重塑中起重要作用。近年來,雙溴域家族之某些蛋白質,包括BRD2、BRD3、BRD4及BRDT已經鑒別為人類癌症中之主要表觀遺傳調控子。因而,此等雙溴域似乎在人
類癌症增生及分化中起到尤其重要之作用。舉例而言,BRD4影響乳癌微環境及存活率(Crawford,N.P,Alsarraj,J.,Lukes,L.,Walker,R.C.,Officewala,J.S.,Yang,H.H.,Lee,M.P.,Ozato,K.,Hunter,K.W.(2008),Bromodomain 4 Activation Predicts Breast Cancer Survival.Proc.Natl.Acad.Sci.USA.105(17):6380-6385)。BRD4亦在卡波西氏肉瘤(Kaposi's sarcoma)中起作用且BRD2為一些混合譜系白血病中之因子(Guo,N.,Faller,D.V.,Denis,G.V.,Activation-Induced Nuclear Translocation of RING3(2001),J.Cell Sci.113(17):3085-3091)。另外,由RNAi進行基因敲除或細胞暴露於BET抑制劑已引起MYC(許多癌症中所見之突變型式)之顯著轉錄下調(Delmore J.E.,Issa G.C.,Lemieux M.E.,Rahl,P.B.,Shi J.,Jacobs H.M.(2011),BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc.Cell.146:904-17)。因此,抑制此等相互作用及細胞暴露於BET抑制劑引起顯著轉錄下調。此繼而為醫療團體提供用於治療癌症之新穎藥理學策略。
溴域之高度分化之序列性質已成為發現強力且有效之溴域抑制劑之嚴重阻礙(Dawson,M.A,Prinjha,R.K.,Dittman,A.Giotopoulos,G.Bantcheff,M.,Chan,W-I.,Robson,S.C.,Chung,C.,Hopf,C.,Savitski,M.M.,Hutmacher,C.,Gudgin,E.,Lugo,D.,Beinke,S.,Chapman.T.D.,Roberts,E.J.,Soden.P.E,Auger,K.R.,Mirguet,O.,Doehner,K.,Delwel,R.,Burnett,A.K.,Jeffrey,P.,Drewes,G.,Lee,K.,Huntly,B.J.P.及Kouzarides,T.(2011),Inhibition of BET recruitment of chromatin as an effective treatment of MLL-fusion leukemia.Nature.0:1-5;Picaud,S.,Da Costa,D.Thanasopoulou,A.,Filippakopoulos,P.,Fish,P.,Philpott,M.,Federov,O.Brennan,P.,Bunnage,M.E.,Owen,D.R.,Bradner,J.E.,Taniere,P.,O'Sullivan,B.,Muller,S,Schwaller,
J.,Stankovic,T.,Knapp,S.,PFI-1-A highly Selective Protein Interaction Inhibitor Targeting BET Bromodomains,Cancer Res.,73(11),2013,3336-3346)。因此,當前不存在可用於市面上之經批準之溴域抑制劑,儘管其具有作為抗癌治療劑之公認潛力。出於此等原因,對BET溴域之新穎且強力之小分子調節劑仍有相當大的需要。
本發明之一個態樣關於式I化合物:
及其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物及互變異構物,其中:W為O、S、C(O)或CHR3;X為N或CR4;Y為N或CR6;Z為N或CR7;R1為氫、C1-C6烷基或C1-C6鹵代烷基;R2為氫或NRaRb;R3為氫、鹵素、羥基、C1-C6烷基或C1-C6鹵代烷基;R4為氫、-(CH2)nRd、-O(CH2)nRd、-N(CH2)nRd、-O(CH2)nC(O)Rd或-O(CH2)nS(O)2Rd;R5及R6各自獨立地為氫、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6鹵代烷基、C3-C8環烷基、雜環烷基、環烯基、雜環烯基、芳基、雜芳基、-(C1-C6)-伸烷基-芳基、-(C1-C6)-伸烷基-雜芳基、-
(C1-C6)-伸烷基-雜環烷基、-(CRaRb)nORc、-(CRaRb)nRc、-O(CRaRb)nNRaRb、-NRaRb、-NRaC(O)Rb、-NRaS(O)2Rb或Rc,其中該等烷基、烯基、炔基、環烷基、雜環烷基、環烯基、雜環烯基、芳基及雜芳基視情況經一或多個獨立地選自Ra、Rb及Rc之取代基取代;R7為氫或鹵素;R8為Ra、-ORa、-NRa或雜環烷基;Ra及Rb各自獨立地為氫、鹵素、C1-C6烷基、環烷基或雜環烷基;Rc為-NH2、-NH(C1-C6烷基)、-NH(C1-C6烷氧基)、-(CH2)nRa、-(CH2)nORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-(CH2)nS(O)2CH3、-S(O)2Ra、-S(O)2NRaRb、-NHC(O)Ra、C1-C6烷基、C1-C6鹵代烷基、C1-C6鹵代烷氧基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、芳基、雜芳基、環烷基、雜環烷基、鹵基、氰基或側氧基,或兩個相鄰Rc可與其所連接之碳組合以形成碳環或雜環;Rd為氫、NH(C1-C6烷基)、N(C1-C6烷基)2、C1-C6烷基、環烷基、雜環烷基、芳基或雜芳基,其中該等烷基、環烷基、雜環烷基、芳基及雜芳基視情況經一或多個獨立地選自Ra、Rb及Rc之取代基取代;且n為0、1或2。
本發明之另一態樣關於一種醫藥組成物,其包含式I化合物,或其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物或互變異構物,及醫藥學上可接受之載劑。
在另一態樣中,本發明關於一種調節BET家族溴域中之一或多者之方法。該方法包括向有需要之患者投予治療有效量之式I化合物,或其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物或互變異構物。
本發明之另一態樣關於一種抑制BET家族溴域中之一或多者之方
法。該方法包括向有需要之患者投予治療有效量之式I化合物,或其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物或互變異構物。
在另一態樣中,本發明關於一種抑制BET家族溴域中之一或多者之方法。該方法包括向有需要之患者投予治療有效量之式I之醫藥組成物。
本發明之另一態樣關於一種治療、預防、抑制或消除患者之與抑制BET家族溴域中之一或多者相關之疾病或病症之方法。該方法包括向有需要之患者投予治療有效量之本文所述之式I化合物,其中該疾病或病症係選自由以下組成之群組:癌症、發炎性病症、大腸激躁症候群、發炎性腸病、類風濕性關節炎、肥胖症及糖尿病。
在另一態樣中,本發明關於一種男性避孕藥,其包含治療有效量之本文所述之式I化合物。
本發明提供BET域之抑制劑,其為治療諸如癌症、發炎、代謝及神經病症及感染性疾病之治療劑。
本發明關於能夠調節BET家族溴域,例如BRD2、BRD3、BRD4及BRDT溴域之活性之化合物及組成物。本發明特徵在於治療、預防或改善與BET溴域相關之疾病或病症之方法,此係藉由向有需要之患者投予治療有效量之式(I)、(II)、(III)或(IV)之化合物,或其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物或互變異構物來達成。本發明之方法可用於藉由抑制BET溴域之活性來治療多種BET溴域依賴性疾病及病症。BET溴域之抑制提供一種用以治療、預防或改善包括(但不限於)癌症、發炎性疾病、糖尿病及肥胖症
之疾病的新穎方法,及研發男性避孕藥。
本發明之一個態樣關於式I化合物
及其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物或互變異構物,其中W、X、Y、Z、R1、R2、R3、R4、R5、R6、R7、R8、Ra、Rb、Rc、Rd及n係如上文所述。
本發明之細節闡述於下文之隨附描述中。儘管類似或等效於本文所述者之方法及材料可用於實施或測試本發明,但現描述說明性方法及材料。本發明之其他特徵、目的及優點將自描述及自申請專利範圍顯而易知。在說明書及所附申請專利範圍中,除非本文另有明確指示,否則單數形式亦包括複數。除非另有規定,否則本文所用之所有技術及科學術語具有與一般熟習本發明所屬技術者通常所理解之含義相同的含義。本說明書中所引用之所有專利及公開案以全文引用的方式併入本文中。
定義
如上文所用且在本發明通篇中,除非另有指示,否則以下術語應理解為具有以下含義。若缺少定義,則以如熟習此項技術者已知之習知定義為準。
如本文所用之術語「包括」、「含有」及「包含」以其開放式、非限制性含義使用。
冠詞「一(a及an)」在本發明中用於指物品之一個或一個以上(亦即至少一個)文法物件。舉例而言,「一個要素」意謂一個要素或一個以上要素。
除非另有指示,否則術語「及/或」在本發明中用於意謂「及」或「或」。
為提供更簡明之描述,本文所給出之一些定量表述不用術語「約」修飾。應瞭解,無論術語「約」明確使用與否,本文所給出之每個量欲指實際給定值,且亦欲指將基於一般技術合理推斷之對該給定值之近似,包括由於實驗及/或量測條件而對該給定值之等效及近似。在產率以百分比給出之任何情況下,該產率係指給出產率之實體之質量相對於在特定化學計量條件下可獲得之相同實體之最大量。除非有不同指示,否則以百分比給出之濃度係指質量比。
「患者」為哺乳動物,例如,人類、小鼠、大鼠、天竺鼠、犬、貓、馬、乳牛、豬,或非人類靈長類動物,諸如猴、黑猩猩、狒狒或恆河猴。「患者」包括人類與動物二者。
術語「抑制劑」係指阻斷或以其他方式干擾特定生物活性之分子,諸如化合物、藥物、酶或激素。
術語「溴域抑制劑」表示抑制溴域與其同源乙醯化蛋白質結合之化合物。在一個實施例中,溴域抑制劑為抑制溴域中之任一者或其組合與乙醯化離胺酸殘基結合之化合物。在另一實施例中,溴域抑制劑為抑制溴域與組蛋白、尤其組蛋白H3及H4上之乙醯化離胺酸殘基結合之化合物。
術語「BET家族溴域抑制劑」或「BET家族蛋白質之溴域之抑制劑」意謂抑制BET(溴及外端)溴域BRD2 BD1、BRD2 BD2、BRD3 BD1、BRD3 BD2、BRD4 BD1、BRD4 BD2、BRDT BD1或BRDT BD2之結合的化合物。在一個實施例中,BET家族溴域抑制劑為式I-IV之化合物。根據另一實施例,BET家族溴域抑制劑為選自表1之化合物。
術語「有效量」或「治療有效量」當與化合物聯合使用時係指
足以提供所需生物結果之化合物之量。結果可為疾病之徵象、症狀或病因之減少及/或減輕,或生物系統之任何其他所需改變。舉例而言,用於治療用途之「有效量」為提供疾病之臨床顯著減退所需之包含如本文所揭示之化合物之組成物的量。在任何個別情況下之適當「有效量」可由一般技術者使用常規實驗來確定。因此,表述「有效量」一般係指活性物質具有治療效果之量。在本發明情況下,活性物質為BET蛋白質之溴域之抑制劑。
如本文所用之術語「治療(treat/treatment)」與術語「預防」同義,且欲指示延緩疾病之發展,預防疾病之發展,及/或降低將會發展或預期會發展之該等症狀之嚴重性。因此,此等術語包括改善現有疾病症狀,預防其他症狀,改善或預防症狀之潛在病因,抑制病症或疾病,例如遏止病症或疾病之發展,減輕病症或疾病,引起病症或疾病之衰退,減輕由疾病或病症引起之病狀,或終止或減輕疾病或病症之症狀。
除非另有指示,否則術語「病症」在本發明中用於意謂術語疾病、病狀或疾患,且可與該等術語互換使用。
使用術語「醫藥學上可接受」或「藥理學上可接受」欲意謂生物學上或其他方面合乎需要之物質-可將該物質投予個體而不引起任何實質上不合需要之生物作用或以有害方式與含有其之組成物之任何組分相互作用。
如本發明中所用之術語「載劑」涵蓋載劑、賦形劑及稀釋劑且意謂物質、組成物或媒劑,諸如液體或固體填充劑、稀釋劑、賦形劑、溶劑或囊封物質,其涉及於將醫藥劑自身體之一個器官或部分載運或轉運至個體之身體之另一器官或部分。賦形劑應基於所需劑型之相容性及釋放型態特性來選擇。例示性載劑物質包括例如黏合劑、懸浮劑、崩解劑、填充劑、界面活性劑、增溶劑、穩定劑、潤滑劑、濕
潤劑、稀釋劑及其類似物。
「醫藥學上相容之載劑物質」可包含例如阿拉伯膠、明膠、膠態二氧化矽、甘油磷酸鈣、乳酸鈣、麥芽糊精、甘油、矽酸鎂、酪蛋白酸鈉、大豆卵磷脂、氯化鈉、磷酸三鈣、磷酸二鉀、硬脂醯乳酸鈉、角叉菜膠、單酸甘油酯、二酸甘油酯、預膠凝化澱粉及其類似物。參見例如Hoover,John E.,Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pa.1975。
如本文所用之術語「個體」涵蓋哺乳動物及非哺乳動物。哺乳動物之實例包括(但不限於)哺乳綱之任何成員:人類、非人類靈長類動物,諸如黑猩猩,及其他猿及猴種類;農畜,諸如牛、馬、綿羊、山羊、豬;家畜,諸如兔、犬及貓;實驗動物,包括齧齒動物,諸如大鼠、小鼠及天竺鼠,及其類似物。非哺乳動物之實例包括(但不限於)鳥、魚及其類似物。在本發明之一個實施例中,哺乳動物為人類。
本發明亦包括本發明化合物之「前藥」。術語「前藥」意謂在活體內由代謝方式(例如藉由水解)可轉化成所揭示之化合物或活性成分之化合物。前藥可藉由熟習此項技術者已知之技術來製備。此等技術一般修飾給定化合物中之適當官能基,例如羥基、胺基、羧基等基團。然而,此等經修飾之官能基藉由常規操作或在活體內再生原始官能基。前藥之實例包括(但不限於)本發明化合物中之羥基或胺基官能基之酯(例如乙酸酯、甲酸酯及苯甲酸酯衍生物)、胺基甲酸酯(例如N,N-二甲基胺基羰基)、醯胺(例如三氟乙醯胺基、乙醯胺基及其類似基團),及其類似物。由於已知前藥增強醫藥品之眾多所需質量(例如溶解度、生物可用性、製造、運輸、藥效學等),故本發明化合物可依前藥形式傳遞。前藥例如可藉由經口投予而具生物可用性,甚至在母體藥物不可如此時。因此,本發明欲涵蓋本發明所主張之化合物之
前藥、傳遞其之方法及含有其之組成物。一般而言,前藥為在投予之後經歷轉化或代謝成生理活性物質之藥物本身之衍生物。轉化可為自發的,諸如在生理環境中水解,或可經酶催化。前藥包括可經氧化、還原、胺化、脫胺化、羥基化、脫羥基化、水解、酯化、烷基化、脫烷基化、醯化、脫醯化、磷酸化及/或脫磷酸化以產生活性化合物之化合物。
如本文所用之術語「IC 50 」係指諸如腫瘤細胞之細胞之可量測活性、表型或反應,例如生長或增殖受50%抑制之濃度。IC50值可自適當劑量反應曲線估算,例如用眼睛或藉由使用適當曲線擬合或統計軟體。更確切而言,IC50值可使用非線性回歸分析來確定。
如本發明中所用之術語「投予(administered,administration或administering)」係指將所揭示之化合物或所揭示之化合物之醫藥學上可接受之鹽或組成物直接投予個體,或將化合物或化合物之醫藥學上可接受之鹽之前藥衍生物或類似物或組成物投予個體,此可藉由使該個體與該化合物接觸或以其他方式使該個體暴露於該化合物而在需要治療之個體(包括動物)體內形成等效量之活性化合物。
如本文所用之「烷基」意謂具有1至10個碳原子之直鏈或分支飽和鏈。代表性飽和烷基包括(但不限於)甲基、乙基、正丙基、異丙基、2-甲基-1-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、丁基、異丁基、第三丁基、正戊基、異戊基、新戊基、正己基及其類似基團,及更長烷基,諸如庚基及辛基及其類似基團。烷基可未經取代或經取代。含有三個或三個以上碳原子之烷基可為直鏈或分支鏈。如本文所用之「低碳烷基」意謂具有1至6個碳原子之烷基。
如本文所用之「烯基」包括含有2-12個碳原子之未分支或分支烴鏈。「烯基」基團含有至少一個雙鍵。烯基之雙鍵可未共軛或與另一不飽和基團共軛。烯基之實例包括(但不限於)乙烯基(ethylenyl、vinyl)、烯丙基、丁烯基、戊烯基、己烯基、丁二烯基、戊二烯基、己二烯基、2-乙基己烯基、2-丙基-2-丁烯基、4-(2-甲基-3-丁烯)-戊烯基及其類似基團。烯基可未經取代或經取代。如本文所定義之烯基亦可為分支鏈或直鏈。
如本文所用之「炔基」包括含有2-12個碳原子之未分支或分支不飽和烴鏈。「炔基」基團含有至少一個參鍵。炔基之參鍵可未共軛或與另一不飽和基團共軛。炔基之實例包括(但不限於)乙炔基、丙炔基、丁炔基、戊炔基、己炔基、甲基丙炔基、4-甲基-1-丁炔基、4-丙基-2-戊炔基、4-丁基-2-己炔基及其類似基團。炔基可未經取代或經取代。
術語「伸烷基(alkylene或alkylenyl)」係指二價烷基。上文所提及之單價烷基中之任一者可藉由自烷基除去第二氫原子而成為伸烷基。如本文所定義之伸烷基亦可為C1-C6伸烷基。伸烷基可進一步為C1-C4伸烷基。典型伸烷基包括(但不限於)-CH2-、-CH(CH3)-、-C(CH3)2-、-CH2CH2-、-CH2CH(CH3)-、-CH2C(CH3)2-、-CH2CH2CH2-、-CH2CH2CH2CH2-及其類似基團。
術語「三氟甲基」、「磺醯基」及「羧基」分別係指CF3、S(O)2及C(O)OH。
術語「羥基(hydroxyl或hydroxy)」意謂OH基團。
術語「羥烷基」意謂如上文所定義之烷基,其中該烷基經一或多個OH基團取代。羥烷基之實例包括HO-CH2-、HO-CH2-CH2-及CH3-CH(OH)-。
如本文所用之術語「烷氧基」係指含有1-12個碳原子且在鏈中含
有末端「O」之直鏈或分支鏈飽和烴,亦即-O(烷基)。烷氧基之實例包括(但不限於)甲氧基、乙氧基、丙氧基、丁氧基、第三丁氧基或戊氧基。
「芳烷基」或「芳基烷基」意謂經每個環含有3至24個環原子之芳基環取代之如上文所定義之C1-C6烷基。舉例而言,本文所述之芳
基烷基可具有下式:,其中n為1至6之整數。適合芳烷基之
非限制性實例包括苯甲基、2-苯乙基及萘基甲基。與母體部分之鍵結係經由烷基。
「環烷基烷基」意謂含有3-18個碳原子且進一步經C1-C6烷基取代之單環飽和碳環。一般而言,本文所述之環烷基烷基展示下式:
,其中m為1至6之整數且n為1至16之整數。
「雜環烷基-烷基」意謂經每個環含有3至24個環原子之雜環烷基環取代之如上文所定義之C1-C6烷基。舉例而言,雜環烷基-烷基可具
有以下結構:,其中n為1至6之整數。與母體部分之鍵結係
經由烷基。
「雜芳基烷基」意謂經每個環含有5至24個環原子之雜芳基環取代之如上文所定義之C1-C6烷基。舉例而言,雜芳基烷基可具有以下
結構:,其中n為1至6之整數。與母體部分之鍵結係經由烷
基。
亦應注意,假定在本文中之正文、流程、實例及表格中具有不飽和價數之任何碳以及雜原子具有足以使價數飽和之數目的氫原子。
如本文所用,必要時,提及氫亦可指氘取代。如本文所用之術
語「氘」意謂具有奇數數目之質子及中子之穩定氫同位素。
術語「鹵基」或「鹵素」係指氟、氯、溴或碘。
如本文所用之術語「鹵代烷基」係指經一或多個鹵素取代之如本文所定義之烷基。鹵代烷基之實例包括(但不限於)三氟甲基、二氟甲基、五氟乙基、三氯甲基等。
如本文所用之術語「鹵代烷氧基」係指經一或多個鹵素取代之如本文所定義之烷氧基。鹵代烷基之實例包括(但不限於)三氟甲氧基、二氟甲氧基、五氟乙氧基、三氯甲氧基等。
如本文所用之術語「氰基」意謂具有經參鍵連接至氮原子之碳原子之取代基,亦即。
如本文所用之術語「胺」係指一級(R-NH2,R≠H)、二級(R2-NH,R2≠H)及三級(R3-N,R≠H)胺。經取代之胺欲意謂至少一個氫原子已經取代基置換之胺。
如本文所用之術語「胺基」意謂含有至少一個氮原子之取代基。特定而言,NH2、-NH(烷基)或烷基胺基、-N(烷基)2或二烷基胺基、醯胺、碳醯胺、脲及硫醯胺取代基包括於術語「胺基」中。
如本文所用之術語「(胺基)烷氧基」或「胺基烷氧基」意謂如上文所定義之烷氧基,其中該烷氧基之直鏈或分支鏈飽和烴經一或多個胺基取代。
如本文所用之術語「胺基烷基」或「胺基(烷基)」係指經一或多個胺基一或多次取代之如本文所定義之烷基。
如本文所用之術語「烷基胺基」係指一個氫已經如上文所定義之烷基置換之胺基或NH2基團,亦即-NH-烷基。烷基胺基之實例包括(但不限於)甲基胺基(亦即-NHCH3)、乙基胺基、丙基胺基、異丙基胺基、正丁基胺基、第二丁基胺基及第三丁基胺基。
如本文所用之術語「二烷基胺基」係指兩個氫已經如上文所定
義之烷基置換之胺基或NH2基團,亦即-N(烷基)2。胺基上之烷基可為相同或不同烷基。烷基胺基之實例包括(但不限於)二甲基胺基(亦即-N(CH3)2)、二乙基胺基、二丙基胺基、二異丙基胺基、二正丁基胺基、二第二丁基胺基、二第三丁基胺基、甲基(乙基)胺基、甲基(丁基胺基)等。
術語「芳氧基」係指含有末端「O」之如本文所定義之芳基環,亦即Ar-O-,其中Ar為芳基。芳氧基之實例包括(但不限於)苯氧基、聯苯氧基及萘氧基。
如本文所用之術語「亞甲二氧基」意謂具有結構式-O-CH2-O-之官能基,其經由氧以兩個化學鍵連接至分子。
如本文所用之「烷氧基烷基」意謂進一步經一或多個如本文所定義之烷氧基取代之如本文所定義之烷基,亦即烷基-O-烷基-。
如本文所用之術語「(烷氧基烷基)胺基」意謂具有至少一個如上文所定義之烷氧基烷基及至少一個如上文所定義之胺基之胺基取代基。
除非另有特別規定,否則術語「芳基」係指具有1至3個芳族環之環狀、芳族烴基,包括單環或雙環基團,諸如苯基、聯苯基或萘基。在含有兩個芳族環(雙環等)之情況下,芳基之芳族環可在單一點處連接(例如聯苯基),或稠合(例如萘基)。芳基可在任何連接點處視情況經一或多個取代基,例如1至5個取代基取代。取代基可本身視情況經取代。此外,當含有兩個稠合環時,本文所定義之芳基可具有與完全飽和環稠合之不飽和或部分飽和環。此等芳基之例示性環系統包括(但不限於)苯基、聯苯基、萘基、蒽基、萉基、菲基、二氫茚基、茚基、四氫萘基、四氫苯并輪烯基及其類似基團。
除非另有特別規定,否則「雜芳基」意謂5至18個環原子之單價單環芳族基團、或多環芳族基團,其含有一或多個選自N、O或S之環
雜原子,其餘環原子為C。如本文所定義之雜芳基亦意謂雙環雜芳族基團,其中雜原子選自N、O或S。芳族基團視情況獨立地經一或多個本文所述之取代基取代。取代基可本身視情況經取代。實例包括(但不限於)苯并噻吩、呋喃基、噻吩基、吡咯基、吡啶基、吡嗪基、吡唑基、嗒嗪基、嘧啶基、咪唑基、異噁唑基、噁唑基、噁二唑基、吡嗪基、吲哚基、噻吩-2-基、喹啉基、苯并哌喃基、異噻唑基、噻唑基、噻二唑基、噻吩并[3,2-b]噻吩、三唑基、三嗪基、咪唑并[1,2-b]吡唑基、呋喃并[2,3-c]吡啶基、咪唑并[1,2-a]吡啶基、吲唑基、吡咯并[2,3-c]吡啶基、吡咯并[3,2-c]吡啶基、吡唑并[3,4-c]吡啶基、苯并咪唑基、噻吩并[3,2-c]吡啶基、噻吩并[2,3-c]吡啶基、噻吩并[2,3-b]吡啶基、苯并噻唑基、吲哚基、吲哚啉基、吲哚啉酮基、二氫苯并噻吩基、二氫苯并呋喃基、苯并呋喃、色滿基、硫代色滿基、四氫喹啉基、二氫苯并噻嗪、二氫苯并噁烷基、喹啉基、異喹啉基、1,6-萘啶基、苯并[de]異喹啉基、吡啶并[4,3-b][1,6]萘啶基、噻吩并[2,3-b]吡嗪基、喹唑啉基、四唑并[1,5-a]吡啶基、[1,2,4]三唑并[4,3-a]吡啶基、異吲哚基、吡咯并[2,3-b]吡啶基、吡咯并[3,4-b]吡啶基、吡咯并[3,2-b]吡啶基、咪唑并[5,4-b]吡啶基、吡咯并[1,2-a]嘧啶基、四氫吡咯并[1,2-a]嘧啶基、3,4-二氫-2H-1λ2-吡咯并[2,1-b]嘧啶、二苯并[b,d]噻吩、吡啶-2-酮、呋喃并[3,2-c]吡啶基、呋喃并[2,3-c]吡啶基、1H-吡啶并[3,4-b][1,4]噻嗪基、苯并噁唑基、苯并異噁唑基、呋喃并[2,3-b]吡啶基、苯并噻吩基、1,5-萘啶基、呋喃并[3,2-b]吡啶、[1,2,4]三唑并[1,5-a]吡啶基、苯并[1,2,3]三唑基、咪唑并[1,2-a]嘧啶基、[1,2,4]三唑并[4,3-b]嗒嗪基、苯并[c][1,2,5]噻二唑基、苯并[c][1,2,5]噁二唑、1,3-二氫-2H-苯并[d]咪唑-2-酮、3,4-二氫-2H-吡唑并[1,5-b][1,2]噁嗪基、4,5,6,7-四氫吡唑并[1,5-a]吡啶基、噻唑并[5,4-d]噻唑基、咪唑并[2,1-b][1,3,4]噻二唑基、噻吩并[2,3-b]吡咯基、3H-吲哚基及其衍
生物。此外,當含有兩個稠合環時,本文所定義之雜芳基可具有與完全飽和環稠合之不飽和或部分飽和環。
如本文所用之術語「環烷基」係指每個環具有3至18個碳原子之飽和或部分飽和、單環、稠合或螺式多環碳環。環烷基環或碳環可在任何連接點處視情況經一或多個取代基,例如1至5個取代基取代。取代基可本身視情況經取代。環烷基之實例包括(但不限於)環丙基、環丁基、環戊基、環己基、環庚基、環辛基、降冰片基、降冰片烯基、雙環[2.2.2]辛基、雙環[2.2.2]辛烯基、十氫萘基、八氫-1H-茚基、環戊烯基、環己烯基、環己-1,4-二烯基、環己-1,3-二烯基、1,2,3,4-四氫萘基、八氫并環戊二烯基、3a,4,5,6,7,7a-六氫-1H-茚基、1,2,3,3a-四氫并環戊二烯基、雙環[3.1.0]己基、雙環[2.1.0]戊基、螺[3.3]庚基、雙環[2.2.1]庚基、雙環[2.2.1]庚-2-烯基、雙環[2.2.2]辛基、6-甲基雙環[3.1.1]庚基、2,6,6-三甲基雙環[3.1.1]庚基及其衍生物。
如本文所用之術語「雜環烷基」係指飽和或部分飽和單環或稠合或螺式多環環結構,其含有碳及獲自氧、氮或硫之雜原子且其中不存在環碳或雜原子之間共用之非定域π電子(芳族性)。雜環烷基環結構可經一或多個取代基取代。取代基可本身視情況經取代。雜環基環之實例包括(但不限於)氧雜環丁烷基、氮雜環丁烷基、四氫呋喃基、吡咯啶基、噁唑啉基、噁唑啶基、噻唑啉基、四氫噻唑基、哌喃基、硫代哌喃基、四氫哌喃基、二氧雜環戊烷基、哌啶基、嗎啉基、硫代嗎啉基、硫代嗎啉基S-氧化物、硫代嗎啉基S-二氧化物、哌嗪基、氮呯基、氧呯基、二氮呯基、托烷基、高托烷基、二氫噻吩-2(3H)-酮基、四氫噻吩1,1-二氧化物、2,5-二氫-1H-吡咯基、咪唑啶-2-酮、吡咯啶-2-酮、二氫呋喃-2(3H)-酮、1,3-二氧雜環戊烷-2-酮、異四氫噻唑1,1-二氧化物、4,5-二氫-1H-咪唑基、4,5-二氫噁唑基、環氧乙烷基、吡唑啶基、4H-1,4-噻嗪基、硫代嗎啉基、1,2,3,4-四氫吡啶基、
1,2,3,4-四氫吡嗪基、1,3-噁嗪烷-2-酮、四氫-2H-硫代哌喃1,1-二氧化物、7-氧雜雙環[2.2.1]庚基、1,2-硫氮雜環庚烷1,1-二氧化物、八氫-2H-喹嗪基、1,3-二氮雜雙環[2.2.2]辛基、2,3-二氫苯并[b][1,4]二氧雜環己烷、3-氮雜雙環[3.2.1]辛基、8-氮雜螺[4.5]癸烷、8-氧雜-3-氮雜雙環[3.2.1]辛基、2-氮雜雙環[2.2.1]庚烷、2,8-二氮雜螺[5.5]十一烷基、2-氮雜螺[5.5]十一烷基、3-氮雜螺[5.5]十一烷基、十氫異喹啉基、1-氧雜-8-氮雜螺[4.5]癸基、8-氮雜雙環[3.2.1]辛基、1,4'-聯哌啶基、氮雜環庚烷基、8-氧雜-3-氮雜雙環[3.2.1]辛基、3,4-二氫-2H-苯并[b][1,4]噁嗪基、5,6,7,8-四氫咪唑并[1,2-a]吡啶基、1,4-二氮雜環庚烷基、啡噁噻基、苯并[d][1,3]二氧雜環戊烯基、2,3-二氫苯并呋喃基、2,3-二氫苯并[b][1,4]二氧雜環己烷基、4-(哌啶-4-基)嗎啉基、3-氮雜螺[5.5]十一烷基、十氫喹啉基、哌嗪-2-酮、1-(吡咯啶-2-基甲基)吡咯啶基、1,3'-聯吡咯啶基及6,7,8,9-四氫-1H,5H-吡唑并[1,2-a][1,2]二氮呯基。
如本文所用之數值範圍欲包括順序之整數。舉例而言,表示為「0至4」之範圍將包括0、1、2、3及4。
如本文所用之術語「經取代」意謂指定基團或部分帶有一或多個適合之取代基,其中該等取代基可在一或多個位置處連接至指定基團或部分。舉例而言,經環烷基取代之芳基可指示環烷基以一鍵或藉由與芳基稠合且共用兩個或兩個以上共有原子而連接至芳基之一個原子。
如本文所用之術語「未經取代」意謂指定基團不帶有取代基。
術語「視情況經取代」應理解為意謂給定化學部分(例如烷基)可能(但不需要)鍵結其他取代基(例如雜原子)。舉例而言,視情況經取代之烷基可為完全飽和之烷基鏈(亦即純烴)。或者,上述視情況經取代之烷基可具有不同於氫之取代基。舉例而言,其可在沿著鏈之任何
點處結合至鹵素原子、羥基或本文所述之任何其他取代基。因此,術語「視情況經取代」意謂給定化學部分具有含其他官能基之潛力,但不一定具有任何其他官能基。在視情況取代所述基團中所用之適合取代基包括(但不限於)側氧基、鹵素、C1-C6烷基、C1-C6烷氧基、C1-C6鹵代烷基、C1-C6鹵代烷氧基、-OC1-C6烯基、-OC1-C6炔基、-C1-C6烯基、-C1-C6炔基、-OH、CN(氰基)、-CH2CN、-OP(O)(OH)2、-C(O)OH、-OC(O)C1-C6烷基、-C(O)C1-C6烷基、-C(O)-C0-C6伸烷基-環烷基、-C(O)-C0-C6伸烷基-雜環烷基、-C(O)-C0-C6伸烷基-芳基、-C(O)-C0-C6伸烷基-雜芳基、-OC(O)OC1-C6烷基、NH2、NH(C1-C6烷基)、N(C1-C6烷基)2、-C(O)NH2、-C(O)NH(C1-C6烷基)、-C(O)N(C1-C6烷基)2、-C(O)NH環烷基、-C(O)N(C1-C6烷基)環烷基、-C(O)NH雜環烷基、-C(O)N(C1-C6烷基)雜環烷基、-C(O)NH芳基、-C(O)N(C1-C6烷基)芳基、-C(O)NH雜芳基、-C(O)N(C1-C6烷基)雜芳基、-S(O)2-C1-C6烷基、-S(O)2-C1-C6鹵代烷基、-S(O)2-環烷基、-S(O)2-雜環烷基、-S(O)2-芳基、-S(O)2-雜芳基、-C0-C6伸烷基-S(O)2NH2、-S(O)2NHC1-C6烷基、-S(O)2N(C1-C6烷基)2、-S(O)2NH環烷基、-S(O)2NH雜環烷基、-S(O)2NH芳基、-S(O)2NH雜芳基、-NHS(O)2C1-C6烷基、-N(C1-C6烷基)S(O)2(C1-C6烷基)、-NHS(O)2芳基、-N(C1-C6烷基)S(O)2芳基、-NHS(O)2雜芳基、-N(C1-C6烷基)S(O)2雜芳基、-NHS(O)2環烷基、-N(C1-C6烷基)S(O)2環烷基、-NHS(O)2雜環烷基、-N(C1-C6烷基)S(O)2雜環烷基、-N(C1-C6烷基)S(O)2芳基、-C0-C6伸烷基-芳基、-C0-C6伸烷基-雜芳基、-C0-C6伸烷基-環烷基、-C0-C6伸烷基-雜環烷基、-O-芳基、-NH-芳基及N(C1-C6烷基)芳基。取代基可本身視情況經取代。當展示多官能部分時,與核心之連接點由線指示,例如,(環烷氧基)烷基-係指烷基為與核心之連接點,而環烷基經由氧基連接至烷基。「視情況經取代」亦指「經取代」或「未經取代」,其含義描述於上文。
如本文所用之術語「氧基」係指「-O-」基團。
如本文所用之術語「側氧基」係指「=O」基團。
術語「溶劑合物」係指由溶質及溶劑形成之可變化學計量之複合物。用於本發明目的之該等溶劑可能不干擾溶質之生物活性。適合溶劑之實例包括(但不限於)水、MeOH、EtOH及AcOH。水為溶劑分子之溶劑合物典型地稱作水合物。水合物包括含有化學計算量之水之組成物,以及含有可變量之水之組成物。
術語「異構物」係指具有相同組成及分子量,但物理及/或化學特性不同之化合物。結構差異可在構造方面(幾何異構物)或在使偏振光之平面旋轉之能力方面(立體異構物)。關於立體異構物,式(I)、(II)、(III)或(IV)之化合物可具有一或多個不對稱碳原子且可依外消旋體、外消旋混合物形式及個別鏡像異構物或非鏡像異構物形式出現。
如本文所用之術語「鹽」表示與無機及/或有機酸形成之酸性鹽,以及與無機及/或有機鹼形成之鹼性鹽。另外,當式之化合物含有諸如(但不限於)吡啶或咪唑之鹼性部分與諸如(但不限於)羧酸之酸性部分時,可形成兩性離子(「內鹽」)且其包括於如本文所用之術語「鹽」內。醫藥學上可接受(亦即無毒、生理學上可接受)之鹽較佳,不過其他鹽亦適用。式之化合物之鹽可例如藉由使式之化合物與一定量(諸如當量)之酸或鹼在諸如鹽於其中沈澱之介質中或在水性介質中反應繼而凍乾來形成。
在本發明之另一實施例中,式(I)-(IV)之化合物為鏡像異構物。
在一些實施例中,化合物為(S)-鏡像異構物。在其他實施例中,化合物為(R)-鏡像異構物。在其他實施例中,式(I)、(II)、(III)或(IV)之化合物可為(+)或(-)鏡像異構物。
應瞭解,所有異構形式均包括於本發明內,包括其混合物。若化合物含有雙鍵,則取代基可呈E或Z構型。若化合物含有經二取代
之環烷基,則環烷基取代基可具有順式或反式構型。所有互變異構形式亦欲包括在內。
各種式之化合物及其鹽、溶劑合物、酯及前藥可依其互變異構形式(例如醯胺或亞胺基醚形式)存在。所用該等互變異構形式作為本發明之一部分涵蓋於本文中。
各種式之化合物可含有不對稱或對掌性中心,且因此以不同立體異構形式存在。各種式之化合物之所有立體異構形式以及其混合物(包括外消旋混合物)欲構成本發明之一部分。另外,本發明包含所有幾何及位置異構物。舉例而言,若各種式之化合物併有雙鍵或稠合環,則順式與反式形式以及混合物包含於本發明之範疇內。本文所揭示之各化合物包括符合化合物之通式結構之所有鏡像異構物。化合物可呈外消旋或鏡像異構純之形式,或依據立體化學之任何其他形式。
分析結果可反映外消旋形式、鏡像異構純之形式或依據立體化學之任何其他形式所收集之資料。
非鏡像異構物混合物可基於其物理化學差異藉由熟習此項技術者熟知之方法,諸如藉由層析及/或分步結晶而分離成其個別非鏡像異構物。鏡像異構物可藉由使鏡像異構物混合物經由與適當光學活性化合物(例如對掌性助劑,諸如對掌性醇或莫舍氏酸氯化物(Mosher's acid chloride))反應而轉化成非鏡像異構物混合物,分離非鏡像異構物且使個別非鏡像異構物轉化(例如水解)成相應純鏡像異構物來分離。
此外,各種式之化合物中之一些化合物可為滯轉異構物(例如經取代之聯芳基化物)且視為本發明之一部分。鏡像異構物亦可藉由使用對掌性HPLC管柱來分離。
各種式之化合物亦可能以不同互變異構形式存在,且所有該等形式均包含於本發明之範疇內。此外,舉例而言,化合物之所有酮-烯醇及亞胺-烯胺形式包括於本發明中。
本發明化合物(包括化合物之鹽、溶劑合物、酯及前藥以及前藥之鹽、溶劑合物及酯)之所有立體異構物(例如幾何異構物、光學異構物及其類似物),諸如由於各種取代基上之不對稱碳而可存在之立體異構物,包括鏡像異構形式(其甚至在不存在不對稱碳之情況下亦可存在)、旋轉異構形式、滯轉異構物及非鏡像異構形式,涵蓋於本發明之範疇內,位置異構物(諸如4-吡啶基及3-吡啶基)同樣如此。(舉例而言,若各種式之化合物併有雙鍵或稠合環,則順式與反式形式以及混合物包涵於本發明之範疇內。此外,舉例而言,化合物之所有酮-烯醇及亞胺-烯胺形式包括於本發明中。)本發明化合物之個別立體異構物可例如實質上無其他異構物,或可例如以外消旋體形式混合,或與所有其他或其他所選立體異構物混合。本發明之對掌性中心可具有如由IUPAC 1974 Recommendations定義之S或R構型。術語「鹽」、「溶劑合物」、「酯」、「前藥」及其類似術語之使用欲同等地適用於本發明化合物之鏡像異構物、立體異構物、旋轉異構物、互變異構物、位置異構物、外消旋體或前藥之鹽、溶劑合物、酯及前藥。
本發明亦包含經同位素標記之本發明化合物,其與本文所述之化合物相同,但一或多個原子經原子質量或質量數不同於自然界中通常所見之原子質量或質量數之原子置換。可併入本發明化合物中之同位素之實例包括氫、碳、氮、氧、磷、氟及氯之同位素,分別為諸如2H(或D)、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F及36Cl。
某些經同位素標記之各種式之化合物(例如經3H及14C標記之化合物)適用於化合物及/或基質組織分佈分析。氚化(亦即3H)及碳-14(亦即14C)同位素因其製備簡易性及可偵測性而尤其較佳。此外,經諸如氘(亦即2H)之較重同位素取代可得到由較高代謝穩定性而產生之某些治療優勢(例如增加之活體內半衰期或降低之劑量需求)且因此在一些
情況下可能較佳。經同位素標記之各種式之化合物一般可藉由遵循與下文之流程中及/或實例中所揭示之程序類似之程序,藉由用適當經同位素標記之試劑取代未經同位素標記之試劑來製備。
式I至IV之化合物可形成鹽,該等鹽亦處於本發明之範疇內。除非另有指示,否則在本文中提及式之化合物應理解為包括提及其鹽。
本發明關於作為BET家族之一或多個溴域之調節劑的化合物。在一個實施例中,本發明化合物為BET家族之一或多個溴域之抑制劑。
本發明針對如本文所述之化合物及其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物或互變異構物,及包含如本文所述之一或多種化合物或其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物或互變異構物之醫藥組成物。
本發明化合物
本發明關於能夠調節BET家族溴域,包括BRD2、BRD3、BRD4及BRDT之化合物或其醫藥學上可接受之鹽或異構物,其適用於治療與調節BET家族溴域相關之疾病及病症。本發明進一步關於適用於抑制BET家族溴域之化合物或其醫藥學上可接受之鹽或異構物。
本發明之另一態樣提供醫藥組成物,其包含治療有效量之至少一種具有式I、II、III或IV之化合物。
本發明之一個態樣關於式I化合物
及其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物及互變異構物,其中W、X、Y、Z、R1、R2、R3、R4、R5、R6、R7、R8、Ra、Rb、Rc、Rd及n係如上文所述。
本發明之一個實施例關於式II化合物
及其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物及互變異構物,其中:W為O、C(O)或CHR3;Ar為芳基或雜芳基;R2為氫或NRaRb;R3為氫、羥基或鹵基;R4為氫、-O(CH2)nRd、-O(CH2)nC(O)Rd、-O(CH2)nS(O)2Rd或-N(CH2)nRd;R7為氫或鹵基;R8為Ra、-ORa或雜環烷基;Ra及Rb各自獨立地為氫、C1-C6烷基、環烷基或雜環烷基;Rc為Ra、-(CH2)nORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-S(O)2Ra、鹵基或側氧基;且n為0、1或2;Rd為氫、NH(C1-C6烷基)、N(C1-C6烷基)2、C1-C6烷基、環烷基、雜環烷基、芳基或雜芳基,其中該等烷基、環烷基、雜環烷基、芳基及雜芳基視情況經一或多個獨立地選自Ra、Rb及Rc之取代基取代;且n為0、1或2。
本發明之另一實施例關於式III化合物
及其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物及互變異構物,其中:Ar為吡唑基或苯基;R4為氫、-O(CH2)nRd、-O(CH2)nC(O)Rd或-O(CH2)nS(O)2Rd;R8為甲基、甲氧基或環丙基;Ra及Rb各自獨立地為氫或C1-C6烷基;Rc為-(CH2)nRa、-(CH2)nORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-(CH2)nS(O)2CH3、-S(O)2Ra、-S(O)2NRaRb、C1-C6鹵代烷基、C1-C6鹵代烷氧基、環烷基、雜環烷基、鹵基、氰基或側氧基;Rd為氫、NH(C1-C6烷基)、N(C1-C6烷基)2、C1-C6烷基、環烷基、雜環烷基、芳基或雜芳基,其中該等烷基、環烷基、雜環烷基、芳基及雜芳基視情況經一或多個獨立地選自Ra、Rb及Rc之取代基取代;且n為0、1或2。
本發明之另一實施例關於式IV化合物
及其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、
前藥、異構物及互變異構物,其中:R4為-O(CH2)nRd、-O(CH2)nC(O)Rd或-O(CH2)nS(O)2Rd;R8為烷基、環烷基、O-烷基或O-環烷基;Ra及Rb各自獨立地為氫或C1-C6烷基;Rc為-(CH2)nRa、-(CH2)nORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-S(O)2Ra、-S(O)2NRaRb、C1-C6鹵代烷基、C1-C6鹵代烷氧基、芳基、雜芳基、環烷基、雜環烷基、鹵基、氰基或側氧基;Rd為氫、NH(C1-C6烷基)、N(C1-C6烷基)2、C1-C6烷基、環烷基、雜環烷基、芳基或雜芳基,其中該等烷基、環烷基、雜環烷基、芳基及雜芳基視情況經一或多個獨立地選自Ra、Rb及Rc之取代基取代;且n為0、1或2。
本發明之一態樣涉及作為或可為BET家族之一或多個溴域之抑制劑的化合物。
本發明之一態樣涉及BET家族溴域之抑制劑用於製備用以治療、預防、抑制或消除腫瘤之藥劑的用途。
本發明之一態樣涉及BET家族溴域之抑制劑用於製備用以治療、預防、抑制或消除癌症之藥劑的用途。
本發明之一態樣涉及BET家族溴域之抑制劑用於製備用以治療、預防、抑制或消除與慢性自體免疫及發炎性病狀相關之疾病之藥劑的用途。
本發明之一態樣涉及BET家族溴域之抑制劑用於製備用以治療、預防、抑制或消除與急性發炎性病狀相關之疾病之藥劑的用途。
本發明之一態樣涉及BET家族溴域之抑制劑用於製備用以治療、預防、抑制或消除與全身發炎反應症候群相關之疾病之藥劑的用途。
本發明之一態樣涉及BET家族溴域之抑制劑用於製備用以治療、
預防、抑制或消除與病毒、細菌或真菌感染相關之疾病或病症之藥劑的用途。
本發明之一態樣涉及BET家族溴域之抑制劑用於製備用以治療、預防、抑制或消除糖尿病或肥胖症之藥劑的用途。
本發明之一態樣涉及BET家族溴域之抑制劑用於製備男性避孕藥之用途。
本發明之一個實施例關於式I化合物,其中X為CR4且Y及Z為CH。
本發明之另一實施例關於式I化合物,其中W為CHR3。
本發明之另一實施例關於式II化合物,其中W為CHR3。
本發明之另一實施例關於式II化合物,其中Ar為吡唑或苯基。
本發明之另一實施例關於式III化合物,其中Ar為吡唑且Rc為環烷基。
本發明之另一態樣關於式III化合物,其中Rc為環丙基。
本發明之又一實施例針對式III化合物,其中Ar為苯基,Rc為-(CH2)nS(O)2CH3。
本發明之另一實施例針對式IV化合物,其中Rc為環烷基或雜環烷基。
本發明之另一實施例針對式IV化合物,其中R4為-O(CH2)nRc。
本發明之另一實施例針對式IV化合物,其中Rc為芳基、雜芳基或環烷基。
在本發明之一些實施例中,W為CH。在另一實施例中,W為CH。在又一實施例中,W為CH且X為CR4。在另一實施例中,W為CH,X為CR4且Y為CH。在又一實施例中,W為CH,X為CR4,Y為CH,且Z為CR7。在另一實施例中,W為CH,X為CR4,Y為CH,Z為CR7,且R1為C1-C6烷基。在另一實施例中,W為CH,X為CR4,Y為
CH,Z為CR7,R1為C1-C6烷基且R2為H。在又一實施例中,W為CH,X為CR4,Y為CH,Z為CR7,R1為C1-C6烷基,R2為H,且R8為Ra或ORa。在另一實施例中,W為CH,X為CR4,Y為CH,Z為CR7,R1為C1-C6烷基,R2為H,R8為Ra或ORa,且Ra為C1-C6烷基或環烷基。在又一實施例中,W為CH,X為CR4,Y為CH,Z為CR7,R1為C1-C6烷基,R2為H,R8為Ra或ORa,Ra為C1-C6烷基或環烷基,且R4為ORd。
在另一實施例中,W為CH,X為CR4,Y為CH,Z為CR7,R1為C1-C6烷基,R2為H,R8為Ra或ORa,Ra為C1-C6烷基或環烷基,R4為ORd,且Rd為視情況經一或多個較佳取代基取代之C1-C6烷基、C1-C6鹵代烷基、環烷基、芳基或雜芳基。在又一實施例中,W為CH,X為CR4,Y為CH,Z為CR7,R1為C1-C6烷基,R2為H,R8為Ra或ORa,Ra為C1-C6烷基或環烷基,R4為ORd,Rd為視情況經一或多個較佳取代基取代之C1-C6烷基、C1-C6鹵代烷基、環烷基、芳基或雜芳基,且R5為視情況經一或多個較佳取代基取代之雜芳基。
在本發明之一些實施例中,W為CH。在另一實施例中,W為CH。在又一實施例中,W為CH且X為CR4。在另一實施例中,W為CH,X為CR4且Y為CH。在又一實施例中,W為CH,X為CR4,Y為CH,且Z為CH或CF。在另一實施例中,W為CH,X為CR4,Y為CH,Z為CH或CF,且R1為甲基。在另一實施例中,W為CH,X為CR4,Y為CH,Z為CH或CF,R1為甲基且R2為H。在又一實施例中,W為CH,X為CR4,Y為CH,Z為CH或CF,R1為甲基,R2為H,且R8為Ra或ORa。在另一實施例中,W為CH,X為CR4,Y為CH,Z為CH或CF,R1為甲基,R2為H,R8為Ra或ORa,且Ra為C1-C6烷基或環烷基。在又一實施例中,W為CH,X為CR4,Y為CH,Z為CH或CF,R1為甲基,R2為H,R8為Ra或ORa,Ra為C1-C6烷基或環烷基,且R4為ORd。在另一實施例中,W為CH,X為CR4,Y為CH,Z為CH或CF,R1為甲
基,R2為H,R8為Ra或ORa,Ra為C1-C6烷基或環烷基,R4為ORd,且Rd為視情況經一或多個較佳取代基取代之C1-C6烷基、C1-C6鹵代烷基、環烷基、芳基或雜芳基。在又一實施例中,W為CH,X為CR4,Y為CH,Z為CH或CF,R1為甲基,R2為H,R8為Ra或ORa,Ra為C1-C6烷基或環烷基,R4為ORd,Rd為視情況經一或多個較佳取代基取代之C1-C6烷基、C1-C6鹵代烷基、環烷基、芳基或雜芳基,且R5為視情況經一或多個較佳取代基取代之雜芳基。
本發明之另一態樣為一種包含式I化合物及醫藥學上可接受之載劑之醫藥組成物。
本發明之另一態樣為一種包含式I化合物及醫藥學上可接受之載劑之醫藥組成物,其包含治療有效量之一或多種其他治療劑。
在某一實施例中,本發明關於一種包含式I化合物及醫藥學上可接受之載劑之醫藥組成物,其包含治療有效量之一或多種其他治療劑,其中該等其他治療劑係選自由以下組成之群組:細胞毒性劑、順鉑(cisplatin)、小紅莓(doxorubicin)、剋癌易(taxotere)、紫杉醇(taxol)、依託泊苷(etoposide)、伊立替康(irinotecan)、開普拓(camptostar)、拓撲替康(topotecan)、太平洋紫杉醇(paclitaxel)、多烯紫杉醇(docetaxel)、埃博黴素(epothilone)、他莫昔芬(tamoxifen)、5-氟尿嘧啶、胺甲喋呤(methotrexate)、替莫唑胺(temozolomide)、環磷醯胺、SCH 66336、替吡法尼(tipifarnib)、R115777、L778,123、BMS 214662、C225、GLEEVEC®、intron®、Peg-Intron®、芳香酶組合、ara-C、阿黴素(adriamycin)、癌得星(cytoxan)、吉西他濱(gemcitabine)、尿嘧啶氮芥(Uracil mustard)、雙(氯乙基)甲胺(Chlormethine)、異環磷醯胺(Ifosfamide)、美法侖(Melphalan)、苯丁酸氮芥(Chlorambucil)、哌泊溴烷(Pipobroman)、三伸乙基三聚氰胺(Triethylenemelamine)、三伸乙基硫代磷醯胺
(Triethylenethiophosphoramine)、白消安(Busulfan)、卡莫司汀(Carmustine)、洛莫司汀(Lomustine)、鏈脲菌素(Streptozocin)、達卡巴嗪(Dacarbazine)、氟尿苷(Floxuridine)、阿糖胞苷(Cytarabine)、6-巰基嘌呤、6-硫鳥嘌呤、磷酸氟達拉濱(Fludarabine phosphate)、甲醯四氫葉酸(leucovirin)、奧沙利鉑(oxaliplatin;ELOXATIN®)、噴司他丁(Pentostatine)、長春鹼(Vinblastine)、長春新鹼(Vincristine)、長春地辛(Vindesine)、博萊黴素(Bleomycin)、放線菌素D(Dactinomycin)、道諾黴素(Daunorubicin)、表柔比星(Epirubicin)、伊達比星(Idarubicin)、MithramycinTM、去氧助間型黴素(Deoxycoformycin)、絲裂黴素C(Mitomycin-C)、L-天冬醯胺酶、替尼泊苷(Teniposide)、17α-乙炔雌二醇(17α-Ethinylestradiol)、己烯雌酚(Diethylstilbestrol)、睪固酮(Testosterone)、潑尼松(Prednisone)、氟甲睪固酮(Fluoxymesterone)、丙酸屈他雄酮(Dromostanolone propionate)、睪內酯(Testolactone)、乙酸甲地孕酮(Megestrol acetate)、甲基潑尼松龍(Methylprednisolone)、甲基睪固酮(Methyltestosterone)、潑尼松龍(Prednisolone)、曲安西龍(Triamcinolone)、氯烯雌醚(Chlorotrianisene)、羥孕酮(Hydroxyprogesterone)、胺魯米特(Aminoglutethimide)、雌莫司汀(Estramustine)、乙酸甲羥孕酮(Medroxyprogesteroneacetate)、亮丙瑞林(Leuprolide)、氟他胺(Flutamide)、托瑞米芬(Toremifene)、戈舍瑞林(goserelin)、卡鉑(Carboplatin)、羥基脲、安吖啶(Amsacrine)、丙卡巴肼(Procarbazine)、米托坦(Mitotane)、米托蒽醌(Mitoxantrone)、左旋咪唑(Levamisole)、諾維本(Navelbene)、阿那曲唑(Anastrazole)、利妥唑(Letrazole)、卡培他濱(Capecitabine)、雷洛昔芬(Reloxafine)、屈洛昔芬(Droloxafine)、六甲三聚氰胺(Hexamethylmelamine)、癌思停(Avastin)、賀癌平(herceptin)、百克沙(Bexxar)、萬珂(Velcade)、澤瓦
靈(Zevalin)、三氧化二砷(Trisenox)、截瘤达(Xeloda)、長春瑞濱(Vinorelbine)、卟吩姆(Porfimer)、爾必得舒(Erbitux)、微脂體(Liposomal)、沙奧特帕(Thiotepa)、六甲蜜胺(Altretamine)、美法侖、曲妥珠單抗(Trastuzumab)、利妥唑(Lerozole)、氟維司群(Fulvestrant)、依西美坦(Exemestane)、利妥昔單抗(Rituximab)、C225、坎帕斯(Campath)、甲醯四氫葉酸、地塞米松(dexamethasone)、比卡魯胺(bicalutamide)、卡鉑、苯丁酸氮芥、順鉑、利妥唑、甲地孕酮(megestrol)及戊柔比星(valrubicin)。
本發明之另一態樣針對一種抑制患者之BET家族溴域中之一或多者之方法,其包括向有需要之患者投予有效量之式I化合物。
本發明之另一態樣針對一種抑制患者之BET家族溴域中之一或多者之方法,其包括向有需要之患者投予有效量之包含式I化合物及醫藥學上可接受之載劑之醫藥組成物。
本發明之另一態樣針對一種治療、預防、抑制或消除患者之與一或多個BET家族溴域之活性相關之疾病或病症之方法,其包括向該有需要之患者投予治療有效量之式I化合物。
本發明之一個實施例關於一種治療、預防、抑制或消除患者之與一或多個BET家族溴域之活性相關之疾病或病症之方法,其包括向該有需要之患者投予治療有效量之式I化合物,且進一步包括向該有需要之患者投予治療有效量之另一治療劑。
本發明之另一實施例關於一種治療、預防、抑制或消除患者之與一或多個BET家族溴域之活性相關之疾病或病症之方法,其包括向該有需要之患者投予治療有效量之式I化合物,其中該疾病或病症係選自由以下組成之群組:癌症、發炎性病症、大腸激躁症候群、發炎性腸病、類風濕性關節炎、肥胖症及糖尿病。
本發明之另一態樣為一種男性避孕藥,其包含治療有效量之至
少一種式I化合物。
本發明之另一態樣為一種男性避孕藥,其包含治療有效量之至少一種表1之化合物。
本發明係由表1中所示之化合物與該等化合物之IUPAC命名及結構來進一步說明。該表亦提供對用以製造如下文實例中所述之各化合物之方法的參考。
在另一實施例中,本發明之說明性化合物包括:(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-{[3-(羥甲基)氧雜環丁烷-3-基]甲氧基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-{八氫環戊并[c]吡咯-5-基}-1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(3,3-二氟環丁氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-(1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-5-(氮雜環丁烷-3-基甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(2,2,2-三氟乙氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(3-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2,2-二氟乙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-
1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2,2-二氟丙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(4-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(1,3-二氟丙-2-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(3,4-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(3-羥基-2,2-二甲基丙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-2-甲基丙醯胺;(2S)-1-環丙烷羰基-5-(2-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(3,3,3-三氟丙氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-1-環丙烷羰基-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;1-(2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙基)吡咯啶-2-酮;(2S)-1-環丙烷羰基-5-(4-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四
氫喹啉-5-基]氧基}-1-(嗎啉-4-基)乙-1-酮;(2S)-5-(2-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;2-(2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙基)-1λ6,2-四氫噻唑-1,1-二酮;(2S)-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}甲烷磺醯胺;(2S)-5-(4-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基甲烷磺醯胺;(2S)-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[2-(氧雜環丁烷-3-基)乙氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(2,2-二氟環丙基)甲氧基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;3-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-{[3-(羥甲基)氧雜環丁烷-3-基]甲氧基}-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡啶-2-基氧
基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(3-氟氧雜環丁烷-3-基)甲氧基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(3,3-二氟環丁氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(氮雜環丁烷-3-基甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1H-吡唑-5-基)-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-咪唑-4-基)-1,2,3,4-四氫喹啉;(2S)-5-({1-[(第三丁氧基)羰基]氮雜環丁烷-3-基}氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(氮雜環丁烷-3-基氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-5-(氮雜環丁烷-3-基氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-6-[1-(1,1-二側氧基-1λ6-硫雜環丁烷-3-基)-1H-吡
唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[1-(1,1-二側氧基-1λ6-硫雜環己烷-3-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2R)-2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-2-氟乙醯胺;(2S)-2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-2-氟乙醯胺;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(3-氟氧雜環丁烷-3-基)甲氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-2,2-二氟乙醯胺;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟-2-甲基丙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-2-甲基-6-[1-(氧雜環己烷-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;(2S)-5-[(二甲基胺甲醯基)甲氧基]-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N-乙基乙醯胺;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟乙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四
氫喹啉-5-基]氧基}-N-環丙基-N-甲基乙醯胺;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-1-(氮雜環丁烷-1-基)乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-1-(哌啶-1-基)乙-1-酮;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(2,2,2-三氟乙氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2,2-二氟乙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟乙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2,2-二氟丙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(3,3,3-三氟丙氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(胺甲醯基二氟甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(1,3-二氟丙-2-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟-2-甲基丙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(3-羥基-2,2-二甲基丙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(1-胺甲醯基-1-甲基乙氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(R)-胺甲醯基(氟)甲氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-
甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(S)-胺甲醯基(氟)甲氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(乙基胺甲醯基)甲氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-{[環丙基(甲基)胺甲醯基]甲氧基}-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[2-(氮雜環丁烷-1-基)-2-側氧基乙氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[2-側氧基-2-(哌啶-1-基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[2-(2-側氧基吡咯啶-1-基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[2-(嗎啉-4-基)-2-側氧基乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[2-(1,1-二側氧基-1λ6,2-四氫噻唑-2-基)乙氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(胺磺醯基甲氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(二甲基胺磺醯基)甲氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[2-(氧雜環丁烷-3-基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(2,2-二氟環丙基)甲氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(喹唑啉-2-基氧基)-
1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(1,3-苯并噁唑-2-基氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(1,3-苯并噁唑-2-基氧基)-2-甲基-6-[1-(氧雜環丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-(嘧啶-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}吡啶-3-甲醯胺;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{1H-吡唑并[3,4-d]嘧啶-6-基氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(1,3-噻唑-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}吡啶-3-甲腈;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[4-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(3-氯吡啶-2-基)氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(吡啶-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(4,6-二甲基嘧啶-2-基)氧
基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;6-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}嗒嗪-3-甲腈;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[2-(三氟甲基)嘧啶-4-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-丙氧基-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-丙氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(吡咯啶-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-(1-{八氫環戊并[c]吡咯-5-基}-1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[6-(4-甲烷磺醯基苯基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-(2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-基)乙-1-酮;
1-[(2S)-5-環丙氧基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(5-甲烷磺醯基吡啶-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;N-{6-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]吡啶-3-基}甲烷磺醯胺;2-{[(2S)-1-乙醯基-6-(5-甲烷磺醯基吡啶-2-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-6-(1,3-苯并噁唑-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-丙氧基-6-{吡唑并[1,5-a]吡啶-2-基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-{咪唑并[1,2-a]吡啶-2-基}-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1,3-苯并噻唑-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1H-1,3-苯并二唑-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(5-甲基-1,3,4-噻二唑-2-基)-1,2,3,4-四氫喹啉;5-[(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-6-基]-1,3,4-噻二唑-2-胺;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;
(2S)-5-(2-氰基-4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(2-氯-4-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氰基-2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-5-(2-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(2-氰基苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(2-氰基-3-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;4-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(3-氯吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}吡啶-3-甲腈;1-[(2S)-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡嗪-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;
(2S)-5-(4-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(3-氰基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(2-氰基-3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氯-2-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;2-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;2-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}-6-氟苯甲腈;4-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}-3-氟苯甲腈;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(3-氯-4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;4-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲醯胺;1-[(2S)-5-(2-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;
(2S)-5-(2-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-胺甲醯基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氰基-4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氯-4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-(2-氯苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-(4-氯苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;4-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-(3-氯-4-氟苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;
(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(3-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(3,4-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(3-氯苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(3-氯苯氧基)-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉;(2S)-5-(3-氯苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(3,5-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(3,5-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-5-(3,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(3,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;5-[(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6-基]-1,3,4-噻二唑-2-胺;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(吡咯啶-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;
4-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}苯甲醯胺;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-(1H-吡唑-5-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-(5-甲基-1,3,4-噻二唑-2-基)-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-咪唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-6-[1-(1,1-二側氧基-1λ6-硫雜環己烷-3-基)-1H-吡唑-4-基]-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(1,1-二側氧基-1λ6-硫雜環丁烷-3-基)-1H-吡唑-4-基]-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-吡唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(4-氯苯氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉;
3-{4-[(2S)-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環丁烷-1,1-二酮;3-{4-[(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環丁烷-1,1-二酮;1-[(2S)-5-(2-氯苯氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氰基苯氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氯苯氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(2-氯苯氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-胺甲醯基苯氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;4-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[1-(丙-2-基)氮雜環丁烷-3-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-5-環丁氧基-2-甲基-6-[1-(1-甲基吡咯啶-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;
(2S)-5-環丁氧基-2-甲基-6-(1-{2-甲基-八氫環戊并[c]吡咯-5-基}-1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(1-甲基吡咯啶-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-{2-甲基-八氫環戊并[c]吡咯-5-基}-1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(1-乙基氮雜環丁烷-3-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[1-(丙-2-基)氮雜環丁烷-3-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(1-乙基氮雜環丁烷-3-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(4-甲基吡啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(異喹啉-1-基氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;
(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(2,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(2,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(2,4-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(2,4-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(2,3-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(2,3-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-5-(2,3-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(2,3-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(2,5-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(2,5-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-5-(2,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(2,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;
1-[(2S)-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(2,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮1-[(2S)-5-{[(E)-2-氯乙烯基]氧基}-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-{1H,2H,3H-吡唑并[1,5-a]咪唑-7-基}-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-6-{1-甲烷磺醯基-1H,2H,3H-吡唑并[1,5-a]咪唑-7-基}-2-甲基-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-6-[2-(4-羥基哌啶-4-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[2-(4-氟哌啶-4-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(1-甲基氮雜環丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(1-甲基氮雜環丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(3-甲基吡啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(5-甲基吡啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-氯吡啶-2-基)氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(7H-嘌呤-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-6-[1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-6-[1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[1-(3-甲氧基-1-甲基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-6-[1-(3-甲氧基-1-甲基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;3-{4-[(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環己烷-1,1-二酮;3-{4-[(2S)-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環己烷-1,1-二酮;(2S)-5-環丁氧基-2-甲基-6-[1-(2-側氧基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(2-側氧基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-{1-[(2S)-2-甲基氮雜環丁烷-3-基]-1H-吡唑-4-基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-{1-[(2S)-2-甲基氮雜環丁烷-3-基]-1H-吡唑-4-基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;N-{4-[(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-6-基]-1-環丙基-1H-吡唑-5-基}甲烷磺醯胺;
N-{4-[(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-6-基]-1-環丙基-1H-吡唑-5-基}乙醯胺;(2S)-5-環丁氧基-6-[1-(3-羥基環丁基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[2-(哌啶-4-基)-1H-咪唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-甲基-2-(哌啶-4-基)-1H-咪唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(氧雜環丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}-N-甲基乙醯胺;1-[(2S)-2-甲基-5-(1,2-噁唑-5-基甲氧基)-6-[1-(氧雜環丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;N-(2-{[(2S)-1-乙醯基-2-甲基-6-[1-(氧雜環丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}乙基)甲烷磺醯胺;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(1,2-噁唑-5-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;N-(2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙基)甲烷磺醯胺;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N-甲基乙醯胺;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(氧雜環丁烷-3-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(環戊基甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[2-(二甲基胺基)乙氧基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(丙-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(環丙基甲氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙醯胺;1-[(2S)-5-(環丁基甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(苯甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(3-甲基氧雜環丁烷-3-基)甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(環戊氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙腈;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-甲氧基乙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(吡啶-3-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;
1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(氧雜環己烷-4-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-5-(環己基甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(吡啶-2-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(1-甲基-1H-吡唑-3-基)甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(1,3-噻唑-5-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;
1-[(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-(氧雜環己烷-4-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(氧雜環己烷-4-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-(氧雜環己烷-4-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-(氧雜環己烷-4-基甲氧基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;2-{[(2S)-1-乙醯基-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-(2-甲基丙氧基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(環戊基甲氧基)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(環戊基甲氧基)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;
1-[(2S)-5-(環戊基甲氧基)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(環戊基甲氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-1-(吡咯啶-1-基)乙-1-酮;2-{[(2S)-1-乙醯基-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-1-(吡咯啶-1-基)乙-1-酮;2-{[(2S)-1-乙醯基-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-1-(吡咯啶-1-基)乙-1-酮;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}-1-(吡咯啶-1-基)乙-1-酮;(5R)-5-({[(2S)-1-乙醯基-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}甲基)吡咯啶-2-酮;(5R)-5-({[(2S)-1-乙醯基-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}甲基)吡咯啶-2-酮;(5R)-5-({[(2S)-1-乙醯基-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}甲基)吡咯啶-2-酮;(5R)-5-({[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}甲基)吡咯啶-2-酮;N-(2-{[(2S)-1-乙醯基-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙基)-N-甲基甲烷磺醯胺;N-(2-{[(2S)-1-乙醯基-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙基)-N-甲基甲烷磺醯胺;N-(2-{[(2S)-1-乙醯基-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙基)-N-甲基甲烷磺醯胺;
N-(2-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}乙基)-N-甲基甲烷磺醯胺;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-(氧雜環己烷-4-基甲氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(氧雜環己烷-4-基甲氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-(氧雜環己烷-4-基甲氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-(氧雜環己烷-4-基甲氧基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;
(2S)-5-[(二甲基胺甲醯基)甲氧基]-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(二甲基胺甲醯基)甲氧基]-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(二甲基胺甲醯基)甲氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-(2-甲基丙氧基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(環戊基甲氧基)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(環戊基甲氧基)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(環戊基甲氧基)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(環戊基甲氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-[2-側氧基-2-(吡咯啶-1-基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[2-側氧基-2-(吡咯啶-1-基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-[2-側氧基-2-(吡咯啶-1-基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-[2-側氧基-2-(吡咯啶-1-基)乙氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-{[(2R)-5-側氧基吡咯啶-2-基]甲氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-{[(2R)-5-側氧基吡咯啶-2-基]甲氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-{[(2R)-5-側氧基吡咯啶-2-基]甲氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-{[(2R)-5-側氧基吡咯啶-2-基]甲氧基}-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-[2-(N-甲基甲烷磺醯胺基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[2-(N-甲基甲烷磺醯胺基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-[2-(N-甲基甲烷磺醯胺基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-[2-(N-甲基甲烷磺醯胺基)乙氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;
(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(5-甲基-1,3-噁唑-2-基)甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(吡啶-4-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(1,3-苯并噁唑-2-基甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(4-甲烷磺醯基苯基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(4-甲烷磺醯基苯基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-6-[4-(乙烷磺醯基)苯基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-[4-(乙烷磺醯基)苯基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-6-{4-[2-(二甲基胺基)乙氧基]苯基}-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-{4-[2-(二甲基胺基)乙氧基]苯基}-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-2-甲基-6-[3-(嗎啉-4-羰基)苯基]-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-2-甲基-6-[3-(嗎啉-4-羰基)苯基]-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;N-{3-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]苯基}甲烷磺醯胺;
2-{[(2S)-1-乙醯基-6-(3-甲烷磺醯胺基苯基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-6-(3-甲烷磺醯基苯基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(3-甲烷磺醯基苯基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;N-{4-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]苯基}甲烷磺醯胺;2-{[(2S)-1-乙醯基-6-(4-甲烷磺醯胺基苯基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-2-甲基-6-[4-(嗎啉-4-羰基)苯基]-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-2-甲基-6-[4-(嗎啉-4-羰基)苯基]-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;2-{4-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]苯基}-1λ6,2-四氫噻唑-1,1-二酮;2-{[(2S)-1-乙醯基-6-[4-(1,1-二側氧基-1λ6,2-四氫噻唑-2-基)苯基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-6-(1-甲烷磺醯基-2,3-二氫-1H-吲哚-5-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-甲烷磺醯基-2,3-二氫-1H-吲哚-5-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;N-{4-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]苯基}-N-甲基甲烷磺醯胺;2-{[(2S)-1-乙醯基-2-甲基-6-[4-(N-甲基甲烷磺醯胺基)苯基]-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;
1-[(2S)-6-(1-苯并呋喃-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1H-吲哚-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-環丁氧基-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[1-(氧雜環己烷-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;3-{4-[(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環己烷-1,1-二酮;3-{4-[(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環丁烷-1,1-二酮;1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(嘧啶-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[4-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[2-(三氟甲基)嘧啶-4-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-{[6-(嗎啉-4-基)嘧啶-4-基]氧基}-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(6-環丙基嘧啶-4-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-環丙基嘧啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}吡啶-3-甲醯胺;1-[(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;6-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}吡啶-3-甲酸甲酯;6-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}吡啶-3-甲醯胺;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(嘧啶-2-基氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡嗪-2-基氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[4-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[2-(三氟甲基)嘧啶-4-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;
(2S)-2-甲基-5-{[6-(嗎啉-4-基)嘧啶-4-基]氧基}-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(6-環丙基嘧啶-4-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-環丙基嘧啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-氟嘧啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-{[5-(甲氧基羰基)吡啶-2-基]氧基}-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-胺甲醯基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉;2-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}吡啶-3-甲腈;(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(4,6-二甲基嘧啶-2-基)氧基]-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(丙-2-基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-5-[(5-甲氧基嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-環丙基嘧啶-2-基)氧基]-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-(1-甲烷磺醯基-2,3-二氫-1H-吲哚-5-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-(4-甲烷磺醯基苯基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(1-羥基-2-甲基丙-2-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{4-[(2S)-1-乙醯基-5-[(5-氟嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-6-基]苯基}-1λ6,2-四氫噻唑-1,1-二酮;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(3-氰基吡啶-2-基)氧基]-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(3-氰基吡啶-2-基)氧基]-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(3-氰基吡啶-2-基)氧基]-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;
(2S)-5-[(3-氰基吡啶-2-基)氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-環丙基嘧啶-2-基)氧基]-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-環丙基嘧啶-2-基)氧基]-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-環丙基嘧啶-2-基)氧基]-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(5-環丙基嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(5-氟嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;
(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(3-胺甲醯基吡啶-2-基)氧基]-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(3-胺甲醯基吡啶-2-基)氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(氧雜環己烷-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;
4-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基苯甲醯胺;(2S)-5-(3-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-環丙烷羰基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉;6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-2-甲基-6-[1-(氧雜環丁烷-3-基)-1H-吡唑-4-基]-5-[(3R)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(氧雜環丁烷-3-基)-1H-吡唑-4-基]-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(3R)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-5-(環戊基甲氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-({1-[(1E)-丙-1-烯-1-
基]-1H-1,3-苯并二唑-2-基}氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-({1-[(1Z)-丙-1-烯-1-基]-1H-1,3-苯并二唑-2-基}氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-2-甲基-6-[1-甲基-2-(哌嗪-1-基)-1H-咪唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[2-(哌嗪-1-基)-1,3-噻唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[2-(3-羥基氮雜環丁烷-1-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1,2-噁唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-(1,2-噁唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-6-(1-環丙基-1H-吡唑-4-基)-8-氟-2-甲基-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-8-氟-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-(1-環丙基-1H-吡唑-4-基)-8-氟-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-8-氟-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-5-環丁氧基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-
1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-6-(1-環丙基-1H-吡唑-4-基)-8-氟-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-8-氟-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-1-環丙烷羰基-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-6-(1-環丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉;(2S)-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-7,8-二氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-6-(1-環丙基-1H-吡唑-4-基)-7,8-二氟-2-甲基-
1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1H-吡唑-1-基)-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(2H-1,2,3-三唑-2-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-(1H-吡唑-1-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-(2H-1,2,3-三唑-2-基)-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-3-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-5-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[2-(哌啶-4-基)-2H-1,2,3-三唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-1,2,3-三唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[5-(哌啶-4-基)-1H-咪唑-2-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-3-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-5-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[2-(哌啶-4-基)-2H-1,2,3-三唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-1,2,3-
三唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[5-(哌啶-4-基)-1H-咪唑-2-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-5-環丁氧基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-1-環丙烷羰基-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-[(2,6-二甲基吡啶-3-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-[(2,6-二甲基吡啶-4-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-[(6-氯吡啶-2-基)氧基]-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡啶-2-基氧基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-[(6-氟吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-
基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡啶-2-基氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-1-環丙烷羰基-2-甲基-6-[4-(嗎啉-4-基)-1H-吡唑-1-基]-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[4-(哌嗪-1-基)-1H-吡唑-1-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[4-(哌啶-4-基)-1H-吡唑-1-基]-1,2,3,4-四氫喹啉;(2S)-2-甲基-6-[4-(嗎啉-4-基)-1H-吡唑-1-基]-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-苯氧基-6-[4-(哌嗪-1-基)-1H-吡唑-1-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6-甲腈;(2S)-1-環丙烷羰基-6-乙炔基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-(丙-1-炔-1-基)-1,2,3,4-四氫喹啉;(2S)-6-氰基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-乙炔基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[2-(氮雜環丁烷-3-基)-1,3-噻唑-4-基]-5-環丁氧基-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;
(2S)-5-環丁氧基-6-[2-(3-氟氮雜環丁烷-3-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[2-(3-羥基氮雜環丁烷-3-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[2-(3-甲氧基氮雜環丁烷-3-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(2-胺甲醯基-1,3-噻唑-4-基)-5-環丁氧基-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[2-(甲基胺甲醯基)-1,3-噻唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-(2-乙醯胺基-1,3-噻唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-6-環丙基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-6-環丙基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-8-氟-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-1-環丙烷羰基-5-(3-甲氧基苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(2,5-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(3,4-二氟苯氧基)-2-甲基-6-(1-甲基-1H-
1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;2-{[(2S)-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-1-環丙烷羰基-5-(3-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(2-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-[(6-甲氧基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-[(6-甲氧基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-5-[(6-甲氧基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-6-[1-(1,1-二側氧基-1λ6-硫雜環己烷-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;4-{4-[(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環己烷-1,1-二酮;1-[(2S)-6-(1-乙醯基哌啶-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-甲烷磺醯基哌啶-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;4-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]-1,2,3,6-四氫吡啶-1-甲酸第三丁酯;1-[(2S)-2-甲基-6-(哌啶-4-基)-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-
1-酮;4-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]-N-乙基哌啶-1-甲醯胺;4-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]哌啶-1-甲酸甲酯;1-[(2S)-6-(1-乙基哌啶-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-(苯基胺基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-{1-[(3R,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-{1-[(3S,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-6-{1-[(3S,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-6-{1-[(3R,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-{1-[(3R,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-6-{1-[(3R,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(2-甲基哌啶-4-基)-1H-吡唑-4-基]-
1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(2-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-1-環丙烷羰基-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-6-[5-氟-1-(哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-{1-[(3R*,4S*)-4-氟吡咯啶-3-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;及(2S)-5-環丁氧基-1-環丙烷羰基-6-{1-[(3R*,4S*)-4-氟哌啶-3-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉。在另一實施例中,本發明之適合化合物包括:(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-丙氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟-2-甲基丙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;1-[(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(4-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;
1-[(2S)-5-(2-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(4-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(2-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡喹-4-基)-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;1-[(2S)-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;
1-[(2S)-5-[(5-氯吡啶-2-基)氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(2-氰基-3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氯-4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(氧雜環己烷-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(4-氯苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;4-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;2-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-6-[1-(1,1-二側氧基-1l6-硫雜環丁烷-3-基)-1H-吡唑-4-基]-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氯-4-氟苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;
(2S)-1-環丙烷羰基-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-(2-氯苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(2,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-咪唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-5-(3-氯苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(2,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-(3,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(3,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;
(2S)-1-環丙烷羰基-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(2-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;3-{4-[(2S)-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1l6-硫雜環丁烷-1,1-二酮;3-{4-[(2S)-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1l6-硫雜環己烷-1,1-二酮;(2S)-1-環丙烷羰基-5-(4-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;及1-[(2S)-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮。
合成化合物之方法
本發明化合物可藉由包括標準化學法之多種方法製得。適合之合成途徑描繪於下文所給出之流程中。
本發明化合物,亦即式(I)-(IV)之化合物,或其醫藥學上可接受
之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物或互變異構物,可藉由如部分地由以下合成流程所闡述之在有機合成技術中已知之方法來製備。在下文所述之流程中,應充分瞭解,根據一般原則或化學在必要時採用敏感性或反應性基團之保護基。根據有機合成之標準方法操作保護基(T.W.Greene及P.G.M.Wuts,「Protective Groups in Organic Synthesis」,第三版,Wiley,New York 1999)。在化合物合成之適宜階段使用熟習此項技術者顯而易知之方法移除此等基團。選擇過程以及反應條件及其執行次序應與式(I)-(IV)之化合物的製備一致。
熟習此項技術者將識別立體中心是否存在於式(I)-(IV)之化合物中。因此,本發明包括可能之立體異構物(除非合成中有規定),且不僅包括外消旋化合物,而且同樣包括個別鏡像異構物及/或非鏡像異構物。當化合物需要為單一鏡像異構物或非鏡像異構物時,其可藉由立體特異性合成或藉由解析最終產物或任何適宜中間物來獲得。最終產物、中間物或起始物質之解析可藉由此項技術中已知之任何適合方法來實現。參見例如E.L.Eliel,S.H.Wilen及L.N.Mander之「Stereochemistry of Organic Compounds」(Wiley-lnterscience,1994)。
本文所述之化合物可自市售起始物質製得或使用已知之有機、無機及/或酶促過程來合成。
化合物之製備
本發明化合物可依熟習有機合成技術者熟知之許多方式來製備。舉例而言,本發明化合物可使用下文所述之方法,連同合成有機化學技術中已知之合成方法,或如熟習此項技術者所瞭解之對其作出之變化來合成。說明性方法包括(但不限於)下文所述之彼等方法。本發明化合物可藉由遵循一般流程1及2中所概述之步驟來合成,該等流
程包含裝配中間物之不同順序。起始物質可購得或藉由所報導之文獻中之已知程序或如說說明來製得。
其中R5及R8如上文所定義。
本文所述之經取代之四氫喹啉(10)可根據流程1中所概述之一般程序來製備。使用氯醌作為氧化劑對2-氯-5-甲氧基苯胺及丁烯醛進行氧化環化,得到呈其鹽酸鹽形式之甲氧基喹啉2。在鹼存在下催化氫化以還原方式移除氯,得到良好產率之3。在高壓下用對掌性釕(II)複合物對3進行催化不對稱氫化,得到極佳產率之所需四氫喹啉4。或者,可經由使用對掌性銠(II)複合物對3進行不對稱轉移氫化來獲得四氫喹啉4。可經由兩種途徑之一使4轉化成酚7。用酸氯化物或氯甲酸酯使4醯化且用三溴化硼脫甲基,得到7。亦可經由用氫溴酸脫甲基,繼而用酸氯化物或氯甲酸酯醯化來獲得酚7。用N-溴代丁二醯亞胺對7進行區域選擇性溴化,得到作為主要產物之8。分別用適當芳基或烷基鹵化物進行親核芳族取代或烷基化,得到9。可經由使用適當硼酸或酯進行鈀催化之鈴木(Suzuki)交叉偶合使芳基溴化物9轉化成所需四氫喹啉10。或者,可經由用雙(頻哪醇根基)二硼進行鈀催化之交叉偶合使芳基溴化物9轉化成硼酸酯11。隨後用適當芳基鹵化物進行鈀催化之鈴木交叉偶合,得到所需四氫喹啉10。
流程2
其中R5及R8如上文所定義。
或者,四氫喹啉(10)可根據流程2中所概述之程序來製備。可經由在硫酸存在下用硝酸鈉對2-胺基-3-硝基苯酚(12)進行重氮化,繼而添加碘化鉀來獲得碘苯酚13。用甲氧基甲基氯保護苯酚,得到中間物14,其可與(R)-丁-3-炔-2-醇經歷鈀催化之薗頭(Sonagashira)偶合,得到16。對16中之參鍵進行鈀催化之氫化,得到17,其可用適當酸氯化物、酸酐或氯甲酸酯醯化,得到18。用甲烷磺醯氯處理18,繼而與氫化鈉反應引起分子內環化,得到四氫喹啉20。移除甲氧基甲基得到酚7,其可經由用N-溴代丁二醯亞胺進行區域選擇性溴化而轉化成中間物8。分別用適當芳基或烷基鹵化物進行親核芳族取代或烷基化,得到9。可經由使用適當硼酸或酯進行鈀催化之鈴木交叉偶合使芳基溴化物9轉化成所需四氫喹啉10。或者,可經由用雙(頻哪醇根基)二
硼進行鈀催化之交叉偶合使芳基溴化物9轉化成硼酸酯11。隨後用適當芳基鹵化物進行鈀催化之鈴木交叉偶合,得到所需四氫喹啉10。
使用所揭示之化合物之方法
本發明之一個態樣關於一種調節BET家族溴域中之一或多者之方法,其包括向有需要之患者投予治療有效量之式(I)、(II)、(III)或(IV)之化合物。
本發明之另一態樣關於一種抑制BET家族溴域中之一或多者之方法,其包括向有需要之患者投予治療有效量之式(I)、(II)、(III)或(IV)之化合物。
在另一態樣中,本發明關於一種抑制BET家族溴域中之一或多者之方法,其包括向有需要之患者投予治療有效量之式(I)、(II)、(III)或(IV)之醫藥組成物。
本發明之另一態樣關於一種治療、預防、抑制或消除患者之與抑制BET家族溴域中之一或多者相關之疾病或病症之方法,該方法包括投予治療有效量之式(I)、(II)、(III)或(IV)之化合物。在一個實施例中,疾病或病症係選自由以下組成之群組:癌症、發炎性病症、大腸激躁症候群、發炎性腸病、類風濕性關節炎、肥胖症及糖尿病。
本發明亦關於BET家族溴域之抑制劑用於製備用以治療、預防、抑制或消除由BET家族溴域介導之疾病或病症之藥劑的用途,其中該藥劑包含式(I)、(II)、(III)或(IV)之化合物。
在另一態樣中,本發明關於一種製造用以治療、預防、抑制或消除由BET家族溴域介導之疾病或病症之藥劑的方法,其中該藥劑包含式(I)、(II)、(III)或(IV)之化合物。
本發明之另一態樣關於一種用於治療由BET家族溴域介導之疾病或病症之方法中之醫藥組成物,其中該醫藥組成物包含式(I)、(II)、(III)或(IV)之化合物。
在又一態樣中,本發明關於一種用於治療由BET家族溴域介導之疾病或病症之方法中之化合物,其中該化合物包含式(I)、(II)、(III)或(IV)之化合物。
本發明亦關於BET家族溴域之抑制劑用於製備用以治療、預防、抑制或消除腫瘤之藥劑的用途,其中該藥劑包含式(I)、(II)、(III)或(IV)之化合物。
本發明進一步關於BET家族溴域之抑制劑用於製備用以治療、預防、抑制或消除癌症之藥劑的用途,其中該藥劑包含式(I)、(II)、(III)或(IV)之化合物。
在一個實施例中,本發明關於BET家族溴域之抑制劑用於製備用以治療、預防、抑制或消除與慢性自體免疫發炎性病狀、急性發炎性病狀、全身發炎反應症候群、病毒、細菌或真菌感染、糖尿病及/或肥胖症相關之疾病之藥劑的用途。在一個實施例中,所製備之藥劑包含式(I)、(II)、(III)或(IV)之化合物,或其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物或互變異構物。在另一實施例中,本發明關於BET家族溴域之抑制劑用於製備男性避孕藥之用途,其中該抑制劑包含式(I)、(II)、(III)或(IV)之化合物。
本發明之另一實施例關於式(I)、(II)、(III)或(IV)之化合物,或其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物或互變異構物,或包含本發明化合物或其醫藥學上可接受之鹽、鏡像異構物、水合物、溶劑合物、前藥、異構物或互變異構物及醫藥學上可接受之載劑之醫藥組成物,其在投予人類後提供腫瘤負荷及/或轉移之減少。醫藥組成物可由經口方式或其他適合方式投予。
在另一實施例中,本發明關於式(I)、(II)、(III)或(IV)之化合物或包含本發明化合物及醫藥學上可接受之載劑之醫藥組成物,其用於治療癌症,包括(但不限於)子宮頸癌、結腸癌、乳癌、肺癌及胃癌;
血液癌,諸如(但不限於)白血病、淋巴瘤及多發性骨髓瘤;中線癌、間葉腫瘤、肝腫瘤、腎腫瘤及神經腫瘤;及黑素瘤、鱗狀細胞癌及皮膚T細胞淋巴瘤。
在另一實施例中,本發明關於式(I)、(II)、(III)或(IV)之化合物或包含本發明化合物及醫藥學上可接受之載劑之醫藥組成物,其用於治療與全身或組織發炎、對感染或低氧之發炎反應、細胞活化及增殖、脂質代謝、纖維化有關之多種疾病或病症,及預防及治療病毒感染。在一個實施例中,使用醫藥組成物。
本發明之另一實施例關於式(I)、(II)、(III)或(IV)之化合物或包含本發明化合物及醫藥學上可接受之載劑之醫藥組成物,其用於治療多種慢性及發炎性病狀,包括(但不限於)類風濕性關節炎、骨關節炎、急性痛風、牛皮癬、全身性紅斑狼瘡、多發性硬化、克羅恩氏病(Crohn's disease)、潰瘍性結腸炎、氣喘、慢性阻塞性氣道疾病、肺炎、心肌炎、心包炎、肌炎、濕疹、皮炎、禿頭症、白癜風、大皰性皮膚病、腎炎、血管炎、動脈粥樣硬化、阿茲海默氏病(Alzheimer's disease)、抑鬱症、修格連氏症候群(Sjogren's syndrome)、涎腺炎、視網膜中央靜脈阻塞、視網膜分支靜脈阻塞、伊爾文-蓋斯症候群(Irvine-Gass syndrome)、旁中心凹毛細血管擴張症、色素性視網膜炎、睫狀體平坦部炎、鳥槍彈丸樣視網膜脈絡膜病變、視網膜前膜、囊樣黃斑水腫、黃斑病變、玻璃體黃斑牽引症候群、視網膜脫離、神經視網膜炎、特發性黃斑水腫、視網膜炎、乾眼病、春季角膜結膜炎、異位性角膜結膜炎、前葡萄膜炎、全葡萄膜炎、後葡萄膜炎、葡萄膜炎相關之黃斑水腫、鞏膜炎、糖尿病性視網膜病變、糖尿病性黃斑水腫、年齡相關之黃斑營養不良、肝炎、胰腺炎、原發性膽汁性肝硬化、硬化性膽管炎、艾迪森氏病(Addison's disease)、垂體炎、甲狀腺炎、I型糖尿病及移植生物體之急性排斥反應。
在另一實施例中,本發明關於式(I)、(II)、(III)或(IV)之化合物或包含本發明化合物及醫藥學上可接受之載劑之醫藥組成物,其用於治療多種急性發炎性病狀,諸如急性痛風、巨細胞動脈炎、包括狼瘡腎炎之腎炎、伴有器官累及之血管炎(諸如腎小球腎炎)、包括巨細胞動脈炎之血管炎、韋格納氏肉芽腫病(Wegner's granulomatosis)、結節性多動脈炎、白塞氏病(Becet's disease)、川崎病(Kawasaki disease)、高安氏動脈炎(Takayasu's arteritis)、壞疽性膿皮病、伴有器官累及之血管炎及移植器官之急性排斥反應。
本發明之另一實施例關於式(I)、(II)、(III)或(IV)之化合物或包含本發明化合物及醫藥學上可接受之載劑之醫藥組成物,其用於治療涉及對細菌、病毒、真菌、寄生蟲或其毒素感染之發炎反應的多種疾病或病症,諸如(但不限於)敗血症、敗血症候群、敗血性休克、內毒素血症、全身發炎反應症候群、多器官功能障礙症候群、中毒性休克症候群、急性肺損傷、急性呼吸窘迫症候群、急性腎衰竭、暴發型肝炎、灼傷、急性胰腺炎、術後症候群、肉狀瘤病、赫氏反應(Herxheimer reaction)、腦炎、脊髓炎、腦膜炎、瘧疾、與諸如(但不限於)流感、帶狀皰疹、單純瘡疹及冠狀病毒之病毒感染相關之全身發炎反應。
在另一實施例中,本發明關於式(I)、(II)、(III)或(IV)之化合物或包含本發明化合物及醫藥學上可接受之載劑之醫藥組成物,其用於治療與缺血再灌注損傷相關之多種病狀,諸如心肌梗塞、腦血管缺血、急性冠狀動脈症候群、腎再灌注損傷、器官移植、冠狀動脈繞道手術、心、肺及繞道手術、肺、腎、肝、胃腸或外周肢栓塞。
本發明之另一實施例關於式(I)、(II)、(III)或(IV)之化合物或包含本發明化合物及醫藥學上可接受之載劑之醫藥組成物,其用於治療多種脂質代謝病症,諸如高膽固醇血症、動脈粥樣硬化及阿茲海默氏
病。
在另一實施例中,本發明關於式(I)、(II)、(III)或(IV)之化合物或包含本發明化合物及醫藥學上可接受之載劑之醫藥組成物,其用於治療多種纖維化病狀,諸如(但不限於)特發性肺纖維化、腎纖維化、術後結構、瘢瘤性疤痕形成、硬結病及心纖維化。
本發明之另一實施例關於式(I)、(II)、(III)或(IV)之化合物或包含本發明化合物之醫藥組成物,其用於治療多種病毒感染,一般而言,諸如(但不限於)皰疹病毒、人乳頭狀瘤病毒、腺病毒、痘病毒及DNA病毒。
在另一實施例中,本發明關於式(I)、(II)、(III)或(IV)之化合物或包含本發明化合物及醫藥學上可接受之載劑之醫藥組成物,其用於治療多種病狀,諸如非惡性黑素瘤、光化性角化病、基底細胞黑素瘤、原位黑素瘤、鱗狀細胞癌及皮膚T細胞淋巴瘤。
本發明之另一實施例關於式(I)、(II)、(III)或(IV)之化合物或包含本發明化合物及醫藥學上可接受之載劑之醫藥組成物,其用於治療肥胖症。
在另一實施例中,本發明關於式(I)、(II)、(III)或(IV)之化合物或包含醫藥學上可接受之本發明化合物及醫藥學上可接受之載劑之醫藥組成物,其用於男性避孕藥。
本發明之另一實施例關於一種治療與全身發炎反應症候群相關之疾病之方法,該疾病諸如(但不限於)敗血症、灼傷、胰腺炎、嚴重創傷、出血及缺血,該方法包括投予式(I)、(II)、(III)或(IV)之化合物。
在另一實施例中,本發明關於一種在診斷時藉由投予式(I)、(II)、(III)或(IV)之化合物來降低SIRS、休克發作、多器官功能障礙症候群、急性肺損傷、急性腎、肝、心及胃腸損傷之發病率之方法。
本發明之另一實施例關於一種在具有高敗血症風險之手術或任何程序之前降低敗血症、出血、組織損傷及多器官功能障礙之發病率之方法,該方法包括投予式(I)、(II)、(III)或(IV)之化合物。
所揭示之本發明化合物可按有效量投予以治療或預防個體之病症及/或防止其發展。
本發明亦關於一種醫藥組成物,其包含式(I)、(II)、(III)或(IV)之化合物及醫藥學上可接受之載劑。醫藥學上可接受之載劑可進一步包括賦形劑、稀釋劑、添加劑或界面活性劑。
本發明之化合物或醫藥組成物可經由用於治療劑之任何投予模式來投予。此等模式包括全身或局部投予,諸如經口、經鼻、非經腸、經皮、皮下、經陰道、經頰、經直腸或表面投予模式。
視預期投予模式而定,所揭示之化合物或組成物可呈固體、半固體或液體劑型,諸如可注射劑、錠劑、栓劑、丸劑、定時釋放膠囊、酏劑、酊劑、乳液、糖漿、散劑、液體、懸浮液或其類似物,有時呈單位劑量且與習知醫藥慣例一致。同樣地,其亦可依靜脈內(推注與輸注)、腹膜內、皮下或肌肉內形式及熟習醫藥技術者熟知之所有使用形式來投予。
組成物可分別根據習知混合、粒化或包衣方法製備,且本發明醫藥組成物可含有以重量或體積計約0.1%至約99%、約5%至約90%或約1%至約20%之所揭示化合物。
在一個實施例中,本發明關於一種製備本發明之醫藥組成物之方法,此係藉由混合至少一種醫藥學上可接受之本發明化合物,及視情況一或多種醫藥學上可接受之載劑、添加劑或賦形劑來達成。
在另一實施例中,本發明關於一種製備本發明之醫藥組成物之方法,此係藉由混合至少一種醫藥學上可接受之本發明化合物及一或多種其他治療劑來達成。
根據本發明之一個實施例,其他治療劑可選自由以下組成之群組:細胞毒性劑、順鉑、小紅莓、剋癌易、紫杉醇、依託泊苷、伊立替康、開普拓、拓撲替康、太平洋紫杉醇、多烯紫杉醇、埃博黴素、他莫昔芬、5-氟尿嘧啶、胺甲喋呤、替莫唑胺、環磷醯胺、SCH 66336、替吡法尼(Zarnestra®)、R115777、L778,123、BMS 214662、Iressa®、Tarceva®、C225、GLEEVEC®、intron®、Peg-Intron®、芳香酶組合、ara-C、阿黴素、癌得星、吉西他濱、尿嘧啶氮芥、雙(氯乙基)甲胺、異環磷醯胺、美法侖、苯丁酸氮芥、哌泊溴烷、三伸乙基三聚氰胺、三伸乙基硫代磷醯胺、白消安、卡莫司汀、洛莫司汀、鏈脲菌素、達卡巴嗪、氟尿苷、阿糖胞苷、6-巰基嘌呤、6-硫鳥嘌呤、磷酸氟達拉濱、甲醯四氫葉酸、奧沙利鉑(ELOXATIN®)、噴司他丁、長春鹼、長春新鹼、長春地辛、博萊黴素、放線菌素D、道諾黴素、表柔比星、伊達比星、MithramycinTM、去氧助間型黴素、絲裂黴素C、L-天冬醯胺酶、替尼泊苷、17α-乙炔雌二醇、己烯雌酚、睪固酮、潑尼松、氟甲睪固酮、丙酸屈他雄酮、睪內酯、乙酸甲地孕酮、甲基潑尼松龍、甲基睪固酮、潑尼松龍、曲安西龍、氯烯雌醚、羥孕酮、胺魯米特、雌莫司汀、乙酸甲羥孕酮、亮丙瑞林、氟他胺、托瑞米芬、戈舍瑞林、卡鉑、羥基脲、安吖啶、丙卡巴肼、米托坦、米托蒽醌、左旋咪唑、諾維本、阿那曲唑、利妥唑、卡培他濱、雷洛昔芬、屈洛昔芬、六甲三聚氰胺、癌思停、賀癌平、百克沙、萬珂、澤瓦靈、三氧化二砷、截瘤达、長春瑞濱、卟吩姆、爾必得舒、微脂體、沙奧特帕、六甲蜜胺、美法侖、曲妥珠單抗、利妥唑、氟維司群、依西美坦、利妥昔單抗、C225、坎帕斯、甲醯四氫葉酸、地塞米松、比卡魯胺、卡鉑、利妥唑、甲地孕酮及戊柔比星。
本發明之劑型可含有一或多種本發明化合物之混合物,且可包括熟習此項技術者已知作為醫藥賦形劑之其他物質。穩定添加劑可併
入傳遞劑溶液中。關於一些藥物,該等添加劑之存在促進溶液中藥劑之穩定劑及可分散性。穩定添加劑可按約0.1%及5%(W/V)範圍內之濃度採用,較佳為約0.5%(W/V)。穩定添加劑之適合但非限制性實例包括阿拉伯膠、明膠、甲基纖維素、聚乙二醇、羧酸及其鹽,及聚離胺酸。在一個實施例中,穩定添加劑為阿拉伯膠、明膠及甲基纖維素。
醫藥賦形劑及添加劑之實例包括(但不限於):酸化劑(乙酸、冰乙酸、檸檬酸、反丁烯二酸、鹽酸、稀鹽酸、蘋果酸、硝酸、磷酸、稀磷酸、硫酸、酒石酸);氣霧劑推進劑(丁烷、二氯二氟-甲烷、二氯四氟乙烷、異丁烷、丙烷、三氯單氟甲烷);空氣置換物(二氧化碳、氮氣);乙醇變性劑(苯甲地那銨(denatonium benzoate)、甲基異丁基酮、蔗糖八乙酸酯);鹼化劑(濃氨溶液、碳酸銨、二乙醇胺、二異丙醇胺、氫氧化鉀、碳酸氫鈉、硼酸鈉、碳酸鈉、氫氧化鈉、三乙醇胺(trolamine));防結塊劑(參見助流劑);消泡劑(二甲矽油(dimethicone)、西甲矽油(simethicone));抗微生物防腐劑(氯化苯甲烴銨(benzalkonium chloride)、氯化苯甲烴銨溶液、氯化苯銨松寧(benzethonium chloride)、苯甲酸、苯甲醇、對羥基苯甲酸丁酯、氯化鯨蠟基吡啶嗡、氯丁醇、氯甲酚、甲酚、脫氫乙酸、對羥基苯甲酸乙酯、對羥基苯甲酸甲酯、對羥基苯甲酸甲酯鈉、苯酚、苯基乙醇、乙酸苯汞、硝酸苯汞、苯甲酸鉀、山梨酸鉀、對羥基苯甲酸丙酯、對羥基苯甲酸丙酯鈉、苯甲酸鈉、脫氫乙酸鈉、丙酸鈉、山梨酸、硫柳汞(thimerosal)、百里酚);抗氧化劑(抗壞血酸、抗壞血酸棕櫚酸酯、丁基化羥基苯甲醚、丁基化羥基甲苯、次磷酸、單硫代甘油、沒食子酸丙酯、甲醛次硫酸鈉、焦亞硫酸鈉、硫代硫酸鈉、二氧化硫、生育酚、生育酚賦形劑);緩衝劑(乙酸、碳酸銨、磷酸銨、硼酸、檸檬酸、乳酸、磷酸、檸檬酸鉀、偏磷酸鉀、磷酸二氫鉀、乙酸鈉、檸檬
酸鈉、乳酸鈉溶液、磷酸氫二鈉、磷酸二氫鈉);膠囊潤滑劑(參見錠劑及膠囊潤滑劑);螯合劑(依地酸二鈉(edetate disodium)、乙二胺四乙酸及鹽、依地酸(edetic acid));包衣劑(羧甲基纖維素鈉、乙酸纖維素、鄰苯二甲酸乙酸纖維素、乙基纖維素、明膠、藥用釉料、羥丙基纖維素、羥丙基甲基纖維素、鄰苯二甲酸羥丙基甲基纖維素、甲基丙烯酸共聚物、甲基纖維素、聚乙二醇、鄰苯二甲酸聚乙酸乙烯酯、蟲膠、蔗糖、二氧化鈦、巴西棕櫚蠟、微晶蠟、玉米蛋白);著色劑(糖色、紅色、黃色、黑色或摻合物、氧化鐵);錯合劑(乙二胺四乙酸及鹽(EDTA)、依地酸、龍膽酸乙醇醯胺、硫酸羥喹啉);乾燥劑(氯化鈣、硫酸鈣、二氧化矽);乳化劑及/或增溶劑(阿拉伯膠、膽固醇、二乙醇胺(佐劑)、單硬脂酸甘油酯、羊毛脂醇、卵磷脂、單酸甘油酯及二酸甘油酯、單乙醇胺(佐劑)、油酸(佐劑)、油醇(穩定劑)、泊洛沙姆(poloxamer)、聚氧乙烯50硬脂酸酯、聚氧乙烯35蓖麻油、聚氧乙烯40氫化蓖麻油、聚氧乙烯10油醚、聚氧乙烯20鯨蠟硬脂醚、聚氧乙烯40硬脂酸酯、聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、丙二醇二乙酸酯、丙二醇單硬脂酸酯、月桂基硫酸鈉、硬脂酸鈉、脫水山梨糖醇單月桂酸酯、脫水山梨糖醇單油酸酯、脫水山梨糖醇單棕櫚酸酯、脫水山梨糖醇單硬脂酸酯、硬脂酸、三乙醇胺、乳化蠟);助濾劑(粉狀纖維素、純化矽藻土);調味劑及香料(茴香腦、苯甲醛、乙基香草醛、薄荷醇、水楊酸甲酯、麩胺酸單鈉、橙花油、薄荷、薄荷油、歐薄荷醑、玫瑰油、濃玫瑰水、百里酚、吐魯香脂酊、香草、香草酊、香草醛);助流劑及/或防結塊劑(矽酸鈣、矽酸鎂、膠態二氧化矽、滑石);保濕劑(甘油、己二醇、丙二醇、山梨糖醇);增塑劑(蓖麻油、二乙醯化單酸甘油酯、鄰苯二甲酸二乙酯、甘油、單乙醯化及二乙醯化單酸甘油酯、聚乙二醇、丙二醇、三醋精、檸檬酸三乙酯);聚合物(例如乙酸纖維素、烷基纖維素、羥烷基纖維
素、丙烯酸聚合物及共聚物);溶劑(丙酮、乙醇、稀乙醇、水合戊烯、苯甲酸苯甲酯、丁醇、四氯化碳、氯仿、玉米油、棉籽油、乙酸乙酯、甘油、己二醇、異丙醇、甲醇、亞甲基氯、甲基異丁基酮、礦物油、花生油、聚乙二醇、碳酸伸丙酯、丙二醇、芝麻油、注射用水、無菌注射用水、無菌沖洗用水、純化水);吸附劑(粉狀纖維素、木炭、純化矽藻土);二氧化碳吸附劑(氫氧化鋇石灰、鹼石灰);硬化劑(氫化蓖麻油、鯨蠟硬脂醇、鯨蠟醇、鯨蠟酯蠟、硬脂、石蠟、聚乙烯賦形劑、硬脂醇、乳化蠟、白蠟、黃蠟);懸浮劑及/或增黏劑(阿拉伯膠、瓊脂、海藻酸、單硬脂酸鋁、膨潤土、純化膨潤土、岩漿膨潤土、卡波姆934p(carbomer 934p)、羧甲基纖維素鈣、羧甲基纖維素鈉、羧甲基纖維素鈉12、角叉菜膠、微晶及羧甲基纖維素鈉纖維素、糊精、明膠、瓜爾膠、羥乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素、矽酸鎂鋁、甲基纖維素、果膠、聚氧化乙烯、聚乙烯醇、聚維酮(povidone)、丙二醇海藻酸酯、二氧化矽、膠態二氧化矽、海藻酸鈉、黃蓍膠、三仙膠);甜味劑(阿斯巴甜糖、葡萄糖結合劑(dextrate)、右旋糖、右旋糖賦形劑、果糖、甘露糖醇、糖精、糖精鈣、糖精鈉、山梨糖醇、山梨糖醇溶液、蔗糖、可壓縮糖、糖粉、糖漿);錠劑黏合劑(阿拉伯膠、海藻酸、羧甲基纖維素鈉、微晶纖維素、糊精、乙基纖維素、明膠、液體葡萄糖、瓜爾膠、羥丙基甲基纖維素、甲基纖維素、聚氧化乙烯、聚維酮、預膠凝化澱粉、糖漿);錠劑及/或膠囊稀釋劑(碳酸鈣、磷酸氫鈣、磷酸三鈣、硫酸鈣、微晶纖維素、粉狀纖維素、葡萄糖結合劑、糊精、右旋糖賦形劑、果糖、高嶺土、乳糖、甘露糖醇、山梨糖醇、澱粉、預膠凝化澱粉、蔗糖、可壓縮糖、糖粉);錠劑崩解劑(海藻酸、微晶纖維素、交聯羧甲基纖維素鈉(croscarmellose sodium)、交聯聚維酮(crospovidone)、波拉克林鉀(polacrilin potassium)、羧基乙酸澱粉鈉、預膠凝化澱粉);錠劑
及/或膠囊潤滑劑(硬脂酸鈣、山崳酸甘油酯、硬脂酸鎂、輕質礦物油、聚乙二醇、硬脂醯反丁烯二酸鈉、硬脂酸、純化硬脂酸、滑石、氫化植物油、硬脂酸鋅);張力劑(右旋糖、甘油、甘露糖醇、氯化鉀、氯化鈉);媒劑:調味及/或加甜(芳香酏、複方苯甲醛酏、等醇酏、薄荷水、山梨糖醇溶液、糖漿、吐魯香脂糖漿);媒劑:油性(杏仁油、玉米油、棉籽油、油酸乙酯、肉豆蔻酸異丙酯、棕櫚酸異丙酯、礦物油、輕質礦物油、肉豆寇醇、辛基十二烷醇、橄欖油、花生油、桃仁油、芝麻油、大豆油、角鯊烷);媒劑:固體載劑(糖丸);媒劑:無菌(抑菌注射用水、抑菌氯化鈉注射劑);增黏劑(參見懸浮劑);拒水劑(環甲矽油(cyclomethicone)、二甲矽油、西甲矽油);及濕潤劑及/或增溶劑(氯化苯甲烴銨、氯化苯銨松寧、氯化鯨蠟基吡啶嗡、多庫酯鈉(docusate sodium)、壬苯聚醇9(nonoxynol 9)、壬苯聚醇10(nonoxynol 10)、辛苯聚醇9(octoxynol 9)、泊洛沙姆、聚氧乙烯35蓖麻油、聚氧乙烯40、氫化蓖麻油、聚氧乙烯50硬脂酸酯、聚氧乙烯10油醚、聚氧乙烯20、鯨蠟硬脂醚、聚氧乙烯40硬脂酸酯、聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、月桂基硫酸鈉、脫水山梨糖醇單月桂酸酯、脫水山梨糖醇單油酸酯、脫水山梨糖醇單棕櫚酸酯、脫水山梨糖醇單硬脂酸酯、泰洛沙泊(tyloxapol))可用作賦形劑。此清單不欲為排他性的,而是僅代表可用於本發明之劑型中之賦形劑種類及特定賦形劑。
說明性醫藥組成物為錠劑及明膠膠囊,其包含本發明化合物及醫藥學上可接受之載劑,諸如a)稀釋劑,例如純化水、三酸甘油酯油(諸如氫化或部分氫化植物油,或其混合物)、玉米油、橄欖油、向日葵油、紅花油、魚油(諸如EPA或DHA,或其酯或三酸甘油酯或其混合物)、ω-3脂肪酸或其衍生物、乳糖、右旋糖、蔗糖、甘露糖醇、山梨糖醇、纖維素、鈉、糖精、葡萄糖及/或甘胺酸;b)潤滑劑,例如
二氧化矽、滑石、硬脂酸、其鎂或鈣鹽、油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、乙酸鈉、氯化鈉及/或聚乙二醇;對於錠劑而言,亦存在c)黏合劑,例如矽酸鎂鋁、澱粉糊、明膠、黃蓍膠、甲基纖維素、羧甲基纖維素鈉、碳酸鎂、天然糖(諸如葡萄糖或β-乳糖)、玉米甜味劑、天然及合成膠(諸如阿拉伯膠、黃蓍膠或海藻酸鈉)、蠟及/或聚乙烯吡咯啶酮(必要時);d)崩解劑,例如澱粉、瓊脂、甲基纖維素、膨潤土、三仙膠、海藻酸或其鈉鹽,或泡騰混合物;e)吸收劑、著色劑、調味劑及甜味劑;f)乳化劑或分散劑,諸如吐溫80(Tween 80)、辛酸癸酸聚乙二醇甘油酯(Labrasol)、HPMC、DOSS、丙二醇單辛酸酯909(caproyl 909)、丙二醇雙癸酸酯(labrafac)、油酸聚乙二醇甘油酯(labrafil)、單油酸甘油酯(peceol)、二乙二醇單乙基醚(transcutol)、中鏈脂肪酸甘油酯MCM(capmul MCM)、中鏈脂肪酸甘油酯PG-12(capmul PG-12)、中鏈三酸甘油酯355(captex 355)、單硬脂酸甘油酯(gelucire)、維生素E TGPS或其他可接受之乳化劑;及/或g)增強化合物吸收之試劑,諸如環糊精、羥丙基-環糊精、PEG400、PEG200。
對於自本發明所述之化合物製備醫藥組成物,醫藥學上可接受之惰性載劑可為固體或液體。固體形式製劑包括散劑、錠劑、可分散顆粒、膠囊、扁囊劑及栓劑。散劑及錠劑可包含約5%至約95%之活性成分。適合之固體載劑在此項技術中為已知的,例如碳酸鎂、硬脂酸鎂、滑石、糖或乳糖。錠劑、散劑、扁囊劑及膠囊可用作適合於經口投予之固體劑型。醫藥學上可接受之載劑之實例及製造各種組成物之方法可見於A.Gennaro(編),Remington's Pharmaceutical Sciences,第18版,(1990),Mack Publishing Co.,Easton,Pa中。
液體形式製劑包括溶液、懸浮液及乳液。舉例而言,水或水-丙二醇溶液用於非經腸注射或添加甜味劑及遮光劑用於口服溶液、懸浮
液及乳液。液體形式製劑亦可包括供鼻內投予之溶液。
液體、尤其可注射組成物可例如藉由溶解、分散等來製備。舉例而言,將所揭示之化合物溶解於醫藥學上可接受之溶劑中或與醫藥學上可接受之溶劑混合,該溶劑為諸如水、鹽水、右旋糖水溶液、甘油、乙醇及其類似物,以藉此形成可注射等滲溶液或懸浮液。諸如白蛋白、乳糜微粒粒子或血清蛋白之蛋白質可用於溶解所揭示之化合物。
非經腸可注射劑投予一般用於皮下、肌肉內或靜脈內注射及輸注。可注射劑可依習知形式,作為液體溶液或懸浮液或適合於在注射前溶解於液體中之固體形式製備。
適合於吸入之氣霧劑製劑可包括溶液及呈粉末形式之固體,其可與醫藥學上可接受之載劑,諸如惰性壓縮氣體,例如氮氣組合。
亦包括固體形式製劑,其欲在即將使用前轉變成液體形式製劑以供經口或非經腸投予。該等液體形式包括溶液、懸浮液及乳液。
本發明化合物亦可經皮傳遞。經皮組成物可採用乳膏、洗劑、氣霧劑及/或乳液之形式,且可包括於如此項技術中習知用於此目的之基質或儲集型經皮貼片中。
所揭示之化合物亦可調配成栓劑,其可自脂肪乳液或懸浮液製備;使用聚烷二醇(諸如丙二醇)作為載劑。
所揭示之化合物亦可依脂質體傳遞系統之形式投予,諸如小單層囊泡、大單層囊泡及多層囊泡。脂質體可自多種磷脂形成,其含有膽固醇、硬脂胺或磷脂醯膽鹼。在一些實施例中,液體組分之膜與藥物之水溶液水合以形成囊封藥物之脂質層,如美國專利第5,262,564號中所述。
所揭示之化合物亦可藉由使用單株抗體作為所揭示之化合物偶合之個別載體來傳遞。所揭示之化合物亦可與作為可靶向藥物載體之
可溶性聚合物偶合。該等聚合物可包括聚乙烯吡咯啶酮、哌喃共聚物、聚羥丙基甲基丙烯醯胺-苯酚、聚羥乙基天冬醯胺苯酚,或經棕櫚醯基殘基取代之聚氧化乙烯聚離胺酸。此外,所揭示之化合物可偶合至一類適用於達成藥物之控制釋放之可生物降解聚合物,例如聚乳酸、聚ε己內酯、聚羥基丁酸、聚原酸酯、聚縮醛、聚二氫哌喃、聚氰基丙烯酸酯,及水凝膠之交聯或兩親性嵌段共聚物。在一個實施例中,所揭示之化合物並不共價結合至聚合物,例如聚羧酸聚合物或聚丙烯酸酯。
若調配成固定劑量,該等組合產品採用在本文所述或如熟習此項技術者已知之劑量範圍內之本發明化合物。
由於本發明化合物欲用於醫藥組成物中,故熟習此項技術者應瞭解,其可依實質上純之形式提供,例如至少60%純、更適宜至少75%純、較佳至少85%純且最佳至少98%純(w/w)。
醫藥製劑可呈單位劑型。在該形式中,製劑細分成適當大小之單位劑量,其含有適量(例如有效量)之活性組分以達成所需目的。
製劑之單位劑量中活性化合物之量可根據特定應用在約1mg至約1000mg、約1mg至約500mg、約1mg至約250mg或約1mg至約25mg之間變化或調整。
利用所揭示之化合物之給藥方案根據多種因素來選擇,包括患者之類型、物種、年齡、體重、性別及醫學狀況;所治療病狀之嚴重性;投予途徑;患者之腎或肝功能;及所採用之特定揭示之化合物。
一般熟習此項技術之醫師或獸醫可容易地確定及開立預防、對抗或遏止病狀進展所需之藥物的有效量。
所採用之實際劑量可視患者之需求及所治療病狀之嚴重性而變化。針對特定情況之適當給藥方案的確定處於此項技術之技能範圍內。為方便起見,需要時,可分割總日劑量且在一天當中分數份投
予。
本發明化合物及/或其醫藥學上可接受之鹽之投予量及頻率將根據主治臨床醫師之判斷考慮以下因素來調節:諸如患者之年齡、狀況及體型以及所治療症狀之嚴重性。所揭示之化合物之有效劑量當用於指定作用時在如治療病狀所需之約0.5mg至約5000mg所揭示之化合物之範圍內。供活體內或試管內使用之組成物可含有約0.5、5、20、50、75、100、150、250、500、750、1000、1250、2500、3500或5000mg所揭示之化合物,或在劑量清單中之一個量至另一個量之範圍內。供經口投予之典型推薦日劑量方案可在約1毫克/天至約500毫克/天或1毫克/天至200毫克/天之範圍內,分兩個至四個分次劑量。
式I至IV之化合物可形成鹽,其亦處於本發明之範疇內。除非另有指示,否則在本文中提及式之化合物應理解為包括提及其鹽。
例示性酸加成鹽包括乙酸鹽、抗壞血酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、檸檬酸鹽、樟腦酸鹽、樟腦磺酸鹽、反丁烯二酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、乳酸鹽、順丁烯二酸鹽、甲烷磺酸鹽、萘磺酸鹽、硝酸鹽、草酸鹽、磷酸鹽、丙酸鹽、水楊酸鹽、丁二酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽(toluenesulfonate)(亦稱為甲苯磺酸鹽(tosylate))及其類似物。另外,一般視為適合於自鹼性醫藥化合物形成醫藥學上適用之鹽的酸例如由以下論述:P.Stahl等人,Camille G.(編)Handbook of Pharmaceutical Salts.Properties,Selection and Use.(2002)Zurich:Wiley-VCH;S.Berge等人,Journal of Pharmaceutical Sciences(1977)66(1)1-19;P.Gould,International J.of Pharmaceutics(1986)33 201-217;Anderson等人,The Practice of Medicinal Chemistry(1996),Academic Press,New York;及The Orange Book(Food & Drug Administration,Washington,D.C.在其網站上)。此等揭示案以引用的
方式併入本文中。
例示性鹼性鹽包括銨鹽;鹼金屬鹽,諸如鈉、鋰及鉀鹽;鹼土金屬鹽,諸如鈣及鎂鹽;與有機鹼(例如有機胺)之鹽,該等有機鹼為諸如二環己胺、第三丁胺;及與胺基酸之鹽,該等胺基酸為諸如精胺酸、離胺酸及其類似物。鹼性含氮基團可用以下試劑進行四級銨化:諸如低碳烷基鹵化物(例如甲基、乙基及丁基氯化物、溴化物及碘化物)、硫酸二烷酯(例如硫酸二甲酯、硫酸二乙酯及硫酸二丁酯)、長鏈鹵化物(例如癸基、月桂基及硬脂基氯化物、溴化物及碘化物)、芳烷基鹵化物(例如苯甲基溴及苯乙基溴),及其他。
出於本發明之目的,所有該等酸鹽及鹼鹽欲為處於本發明範疇內之醫藥學上可接受之鹽且所有酸及鹼鹽視為等效於相應化合物之游離形式。
本發明由以下實例及合成流程進一步說明,其不應解釋為將本發明之範疇或精神限於本文所述之特定程序。應瞭解,提供實例以說明某些實施例且藉此不欲對本發明之範疇作限制。應進一步瞭解,在不脫離本發明之精神及/或所附申請專利範圍之範疇的情況下可採用本身可為熟習此項技術者所想到的各種其他實施例、修改及其等效物。
呈現用於合成本文所揭示之某些化合物之合成流程。亦描述測試BET家族溴域抑制及對癌細胞系增殖之影響的分析之過程及結果。
以下流程及本文別處所用之定義為:
Xphos 2-二環己基膦基-2',4',6'-三異丙基聯苯
材料
除非另有注釋,否則所有材料均獲自商業供應商且未經進一步純化即使用。無水溶劑獲自Sigma-Aldrich(Milwaukee,WI)且直接使用。涉及空氣或水分敏感性試劑之所有反應均在氮氣氛圍下進行。
除非另有注釋,否則質量觸發式HPLC純化及/或純度及低解析度質譜資料係使用以下量測:(1)使用220nm下之UV偵測及低共振電噴霧正離子模式(ESI)之Waters Acquity超高效液相層析(UPLC)系統(具有樣品組織器及Waters Micromass ZQ質譜儀之Waters Acquity UPLC)(管柱:Acquity UPLC BEH C18 1.7μm 2.1×50mm;梯度:含5-100%溶劑B(95/5/0.09%:乙腈/水/甲酸)之溶劑A(95/5/0.1%:10mM甲酸銨/乙腈/甲酸)維持2.2分鐘,接著含100-5%溶劑B之溶劑A維持0.01分鐘,接著保持含5%溶劑B之溶劑A維持0.29分鐘);或(2)使用220nm及254nm下之UV偵測及低共振電噴霧電離(正/負)模式(ESI)之Waters HT2790 Alliance高效液相層析(HPLC)系統(Waters 996 PDA及Waters ZQ單四極桿質譜儀)(管柱:XBridge Phenyl或C18,5μm 4.6×50mm;梯度:含5-95%溶劑B(95%甲醇/5%水,含0.1%甲酸)之溶劑A(95%水/5%甲醇,含0.1%甲酸)維持2.5分鐘,接著保持含95%溶劑B之溶劑A維持1分鐘)(僅純度及低解析度MS)。
向1000-mL 3頸圓底燒瓶中饋入2-氯-5-甲氧基苯胺(50g,317
mmol)、正丁醇(120mL)、濃鹽酸(37%,90mL)及氯醌(四氯-1,4-苯醌)(78g,317mmol)。在100℃下於油浴中攪拌所得溶液1小時。經1小時逐滴添加(E)-丁烯醛(28.9mL,349mmol)於正丁醇(50mL)中之溶液。在100℃下於油浴中攪拌所得溶液1小時,接著冷卻至70℃。添加四氫呋喃(650mL),且在70℃下攪拌反應混合物1小時,接著冷卻至0℃。使所得沈澱物在0-5℃下保持1小時。過濾混合物,用冷(約0℃)THF(2×350mL)洗滌固體,接著在烘箱中乾燥,得到呈黃色固體狀之8-氯-5-甲氧基-2-甲基喹啉鹽酸鹽(83.0g,74%)。MS(ES,m/z):208[M+H]+
向1000-mL圓底燒瓶中饋入8-氯-5-甲氧基-2-甲基喹啉鹽酸鹽(50.0g,204.8mmol)、甲醇(300mL)、氫氧化鈉水溶液(3M,205mL)及10%鈀/活性碳(25g)。用氫氣淨化系統,且在室溫下於氫氣氛圍下攪拌所得混合物3小時。經矽藻土襯墊過濾反應混合物,且在真空下濃縮以移除大部分甲醇。用乙酸乙酯(2×2000mL)萃取所得溶液。合併有機層,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以0-20%乙酸乙酯/石油醚進行梯度洗提)純化殘餘物,得到呈黃色固體狀之5-甲氧基-2-甲基喹啉(36g,63%)。MS(ES,m/z):174[M+H]+
向具有磁性攪拌棒之30-mL玻璃襯裏不銹鋼反應器中饋入5-甲氧基-2-甲基喹啉(4.0g,23.1mmol)、Ru(OTf)(η6-六甲基苯)((S,S)-TsDPEN)([N-[(1S,2S)-2-(胺基-κN)-1,2-二苯基乙基]-4-甲基苯磺醯胺根合-κN][(1,2,3,4,5,6-η)-1,2,3,4,5,6-六甲基苯](1,1,1-三氟甲烷磺酸根合-κO)-釕,根據J.Am.Chem.Soc. 2011,133,9878-9891中之程序製備)(0.100g,0.13mmol)及甲醇(10mL)。將反應器封閉,且最初在50
atm之壓力下引入氫氣,隨後降至1atm。重複此程序三次之後,用氫氣將反應器加壓至50atm。在室溫下於此氫氣壓力下攪拌所得混合物24小時。小心釋放氫氣之後,在真空下濃縮反應混合物。經由矽膠管柱層析(以0-20%乙酸乙酯/石油醚進行梯度洗提)純化殘餘物,得到呈黃色油狀之(2S)-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉(4.0g,98%,>99% ee)。MS(ES,m/z):178[M+H]+
向配備有頂置式攪拌器、熱電偶及氮氣入口之三頸2-L圓底燒瓶中饋入甲醇(1350mL)及甲酸(51.8mL,1350mmol)。使燒瓶下降至冰-水浴中,且當內部溫度達到13℃時,緩慢添加三乙胺(75mL,540mmol),使得內部溫度升至21℃。接著,一次性添加5-甲氧基-2-甲基喹啉(58.47g,338mmol),且冷卻所得溶液至0℃。最後,一次性添加Cp*RhCl[(S,S)-TsDPEN]([N-[(1S,2S)-2-(胺基-κN)-1,2-二苯基乙基]-4-甲基苯磺醯胺根合-κN]氯[(1,2,3,4,5-η)-1,2,3,4,5-五甲基-2,4-環戊二烯-1-基]銠,根據Org.Lett. 1999,1,841中之程序製備)(2.157g,3.38mmol)。將冰浴保留於原處且緩慢終止。22小時(內部溫度=17℃)後,再添加甲酸(12.95mL,338mmol)至反應混合物中。在室溫下攪拌深色溶液4天。總共5天後,在減壓下濃縮溶液。將經濃縮之反應混合物再溶解於乙酸乙酯(約750mL)中,且用飽和碳酸氫鈉水溶液(250mL、接著100mL)洗滌兩次,且最後用5%氯化鈉水溶液(100mL)洗
滌。接著在減壓下濃縮乙酸乙酯萃取物,得到64.7g深色糊漿。對掌性HPLC分析顯示物質具有97.2:2.8 e.r.之鏡像體純度(94.4% ee)。(對掌性HPLC方法:管柱:ODH;方法:ODH 98%己烷/2% IPA;UV:254,流量:0.5mL/min)。粗(S)-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉(59.8g,338mmol,100%產率)未經進一步純化即用於鹽形成(假定100%產率)。MS(ES,m/z):178[M+H]+
向配備有磁性攪拌棒及熱電偶之三頸500-mL圓底燒瓶中饋入乙醇(160mL),且冷卻溶液至0℃。經45分鐘緩慢添加乙醯氯(26.4mL,372mmol),同時維持內部溫度低於8℃。移除冰浴,且使HCl溶液(約2M)升溫約30分鐘(內部溫度=15℃)。
向配備有頂置式攪拌器、熱電偶及氮氣入口之三頸1-L圓底燒瓶中饋入粗(S)-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉(59.9g,338mmol)於乙酸乙酯(600mL)中之溶液。接著,在17℃下向此溶液中添加新鮮製備之HCl溶液(約2M,於乙醇中,86mL,372mmol)。在添加HCl溶液時,混合物最初變混濁,但接著在完全添加後變成澄清溶液。內部溫度升至26℃。在周圍溫度下攪拌澄清溶液,且在10-15分鐘後,形成粒狀沈澱物。在周圍溫度下攪拌漿液4.5小時,接著在600-mL玻璃布氏漏斗(Buchner funnel)上過濾。用新鮮乙酸乙酯沖洗燒瓶及固體,過濾,且在抽吸及氮氣正壓下於篩檢程序上乾燥,得到呈奶黃色、自由流動、粒狀固體狀之(S)-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉鹽酸鹽(64.43g,89%)。對掌性HPLC分析顯示鹽具有98.9:1.1 e.r.之鏡像體純度(97.8% ee)。(對掌性HPLC方法:管柱:ODH;方法:ODH 98%己烷/2% IPA;UV:254,流量:0.5mL/min)。MS(ES,m/z):178[M+H]+
向1000-mL 3頸圓底燒瓶中饋入(2S)-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉(47.41g,267.5mmol)、二氯甲烷(500mL)及吡啶(38mL)。在0℃下於攪拌下逐滴添加環丙烷羰基氯(28.4g,271.7mmol),且在0℃下攪拌所得溶液3小時。將反應混合物傾倒至400mL水/冰中,接著用2N鹽酸(1×100mL)及鹽水(3×300mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以0-15%乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色固體狀之(2S)-1-環丙烷羰基-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉(64.6g,98%)。MS(ES,m/z):246[M+H]+
向1000-mL圓底燒瓶中饋入(2S)-1-環丙烷羰基-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉(15.0g,61.2mmol)及二氯甲烷(300mL)。在0℃下逐滴添加三溴化硼溶液(1M,於二氯甲烷中,308mL,308mmol),且在0℃下攪拌所得溶液1小時。接著將反應混合物傾倒至500mL水/冰中,且用二氯甲烷(2×500mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由矽膠管柱層析(以0-80%乙酸乙
酯/石油醚洗提)純化殘餘物,得到呈灰白色固體狀之(2S)-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-5-醇(9.4g,66%)。MS(ES,m/z):232[M+H]+
向配備有加熱罩及頂置式攪拌器之500-mL圓底燒瓶中饋入(S)-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉鹽酸鹽(20g,94mmol),繼而饋入氫溴酸(48%,154mL,1361mmol)。加熱混合物至100℃,且反應容易地進行,同時損失之溴甲烷通過未冷卻之回流冷凝器。1小時後,固體自溶液中沈澱。在100℃下10小時後反應完成,且使其冷卻至周圍溫度,同時攪拌隔夜。將反應混合物置於冰浴中,且在0-5℃下攪拌2小時。過濾所得白色漿液,且用20mL冰冷水洗滌罐及固體。在氮氣覆蓋層下於布氏漏斗上乾燥濾餅,得到呈白色粉末狀之(S)-2-甲基-1,2,3,4-四氫喹啉-5-醇氫溴酸鹽(21.71g,95%)。MS(ES,m/z):164[M+H]+
向配備有氮氣入口、頂置式攪拌器、加料漏斗及熱電偶之1000-mL圓底燒瓶中饋入(S)-2-甲基-1,2,3,4-四氫喹啉-5-醇氫溴酸鹽(20g,82mmol),繼而饋入無水DMF(109mL)及吡啶(19.8mL,246mmol)。經30分鐘逐滴添加環丙烷羰基氯(7.43mL,82mmol),同時用冷水浴保持溫度低於20℃。添加完成之後,在周圍溫度下攪拌反應混合物1.5小時。將罐在冰浴中冷卻至0℃,且經15分鐘逐滴添加0.29M HCl水溶液(315mL)。在冰浴中攪拌漿液90分鐘,隨後過濾。用25mL冰水洗滌罐及濾餅。在氮氣下於布氏漏斗上乾燥濾餅,得到呈灰白色粉末狀之(2S)-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-5-醇
(17.16g,91%)。MS(ES,m/z):232[M+H]+
向用惰性氮氣氛圍淨化並維持之1000-mL 3頸圓底燒瓶中置放含(2S)-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-5-醇(4.0g,17.3mmol)之乙腈(600mL)及二氯甲烷(150mL)。冷卻溶液至-10℃,且經3小時逐滴添加N-溴代丁二醯亞胺(3.08g,17.3mmol)於乙腈(50mL)中之溶液。在-10℃下攪拌所得溶液30分鐘,接著在真空下濃縮。經由矽膠管柱層析(以0-20%乙酸乙酯/石油醚洗提)純化殘餘物,得到呈淡黃色固體狀之(2S)-6-溴-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-5-醇(3.6g,68%)。MS:(ES,m/z):310,312[M+H]+
向配備有頂置式攪拌器、熱電偶及氮氣入口之1-L三頸圓底燒瓶中饋入2-胺基-3-硝基苯酚(17.5g,114mmol)、DMSO(280mL)及30%硫酸(280mL,1575mmol)。加熱深紅色-橙色溶液至50℃。45分鐘後,停止加熱,且冷卻溶液至3℃(一旦溶液達到13℃,即形成沈澱物)。接著,將亞硝酸鈉(10.97g,159mmol)於水(35mL)中之溶液緩
慢添加至漿液中,同時維持內部溫度低於5℃;添加耗時約5-7分鐘。在0℃下攪拌溶液。1小時後,經5分鐘之時段緩慢添加碘化鉀(52.8g,318mmol)於水(105mL)中之溶液。1小時後,移除冰浴,且使反應混合物升溫至室溫且攪拌20小時。接著用甲基第三丁基醚(1×800mL及1×400mL)萃取反應混合物。用20%硫代硫酸鈉水溶液(2×200mL)、繼而用5%氯化鈉水溶液(2×200mL)洗滌經合併之甲基第三丁基醚萃取物。在減壓下濃縮有機萃取物。添加甲苯(200mL),接著在減壓下移除,得到呈棕色粉末狀之2-碘-3-硝基苯酚(30.2g,100%)。1H NMR(400MHz,CDCl3):δ 7.44(dd,J=8.0,1.5Hz,1 H),7.37(t,J=8.0Hz,1 H),7.24(dd,J=8.0,1.5Hz,1 H),5.97(br,1 H)ppm。
向配備有磁性攪拌棒之200-mL圓底燒瓶中饋入乙酸乙酯(37mL)、二甲氧基甲烷(12.25mL,137mmol)及乙酸鋅(2.51mg,0.014mmol)。接著,經20分鐘之時段緩慢添加乙醯氯(9.73mL,137mmol)。在室溫下攪拌溶液2小時。接著將此氯甲基甲基醚溶液添加至2-碘-3-硝基苯酚(30.2g,114mmol)於N,N-二甲基甲醯胺(170mL)中之溶液中。冷卻所得溶液至0℃,且經20分鐘之時段用二異丙基乙胺(49.8mL,285mmol)緩慢處理。將冰浴保留於原處,且在冰浴緩慢終止時攪拌反應混合物隔夜。接著用乙酸乙酯稀釋反應混合物,且分配於水(340mL)與乙酸乙酯(500mL)之間。分離有機層,且用半飽和碳酸氫鈉水溶液(1×340mL)及5%氯化鈉水溶液(1×340mL、接著1×200mL)洗滌。接著在減壓下濃縮有機層,得到深棕色糊漿(33.6g),其在靜置時結晶。將粗產物溶解於少量二氯甲烷中,且藉由經矽膠襯墊(14cm(d)×6cm(h),以3:2己烷-二氯甲烷洗提)過濾來純化,得到呈淺黃色固體狀之2-碘-1-(甲氧基甲氧基)-3-硝基苯(30.2g,86%)。1H NMR(400MHz,CDCl3):δ 7.39(t,J=8.1Hz,1 H),7.34
(dd,J=8.0,1.6Hz,1 H),7.25(dd,J=8.1,1.6Hz,1 H),5.30(s,2 H),3.52(s,3 H)ppm。
向配備有磁性攪拌棒之兩頸100-mL圓底燒瓶中饋入2-碘-1-(甲氧基甲氧基)-3-硝基苯(5.0g,16.18mmol)、碘化銅(I)(0.154g,0.809mmol)、氯化雙(三苯基膦)鈀(II)(0.284g,0.404mmol)、N,N-二甲基乙醯胺(25mL)及三乙胺(9.02mL,64.7mmol)。使氮氣鼓泡通過深橙色溶液持續數分鐘,接著添加(R)-丁-3-炔-2-醇(1.33mL,17.0mmol),此使得溶液顏色明顯變淡。接著加熱溶液至70℃維持10小時,屆時停止加熱且使反應混合物冷卻至室溫。在室溫下攪拌10小時後,用乙酸異丙酯稀釋反應混合物,且用水(50mL)、飽和氯化銨水溶液(50mL)及5%氯化鈉水溶液(2×50mL)洗滌。在減壓下濃縮有機層,得到深棕色糊漿(4.7g)。藉由矽膠急驟層析(以2:1己烷-乙酸乙酯、接著3:2己烷-乙酸乙酯及最後1:1己烷-乙酸乙酯洗提)純化粗產物,得到(R)-4-(2-(甲氧基甲氧基)-6-硝基苯基)丁-3-炔-2-醇(2.1g,52%)。MS(ESI,正離子)m/z 274[M+23]+。
將裝有(R)-4-(2-(甲氧基甲氧基)-6-硝基苯基)丁-3-炔-2-醇(2.9g,11.54mmol)、甲醇(58mL)及10%鈀/碳(50%水,1.228g,0.577mmol)之400-mL帕爾瓶(Parr bottle)用氫氣加壓至39psig,接著震盪。快速消耗氫氣,且在15分鐘內,壓力已降至0psig。將瓶再加壓至39psig,且繼續震盪。壓力經下一個15分鐘降至約20psig且穩定。將瓶再加壓至34psig,且在繼續震盪下保持2小時。用氮氣吹洗混合物,接著經矽藻土襯墊過濾。用甲醇沖洗瓶及催化劑,且在減壓下濃縮濾液。添加甲苯且濃縮混合物,得到呈深黃色糊漿狀之(R)-4-(2-胺基-6-(甲氧基甲氧基)苯基)丁-2-醇(2.60g,100%),其未經進一步純化即使
用。MS(ESI,正離子)m/z 248[M+23]+。
將粗(R)-4-(2-胺基-6-(甲氧基甲氧基)苯基)丁-2-醇(2.60g,11.54mmol)及吡啶(2.80mL,34.6mmol)於二氯甲烷(52mL)中之溶液冷卻至0℃,且用乙酸酐(1.14mL,12.1mmol)處理。移除冰浴,且在室溫下攪拌反應混合物。45分鐘後,用5%氯化鈉水溶液(2×20mL)洗滌溶液,接著在減壓下濃縮。添加甲苯(約100mL)且濃縮混合物。藉由矽膠管柱層析(以25-100%乙酸乙酯-己烷進行梯度洗提)純化殘餘物,得到呈淺黃色糊漿狀之(R)-N-(2-(3-羥丁基)-3-(甲氧基甲氧基)苯基)乙醯胺(2.7g,88%)。MS(ESI,正離子)m/z 290[M+23]+。
用三乙胺(3.13mL,22.44mmol)處理(R)-N-(2-(3-羥丁基)-3-(甲氧基甲氧基)苯基)乙醯胺(4.0g,14.96mmol)於乙腈(40mL)中之溶液,且冷卻至0℃。緩慢添加甲烷磺醯氯(1.46mL,18.7mmol),且立即形成沈澱物。在0℃下攪拌漿液。3小時後,用乙酸乙酯稀釋反應混合物,且傾倒至5%氯化鈉水溶液(50mL)中。分離各層,且再用5%氯化鈉水溶液(40mL)洗滌有機層。用乙酸乙酯萃取經合併之水層,且在減壓下濃縮經合併之有機層。將殘餘物溶解於甲苯(50-75mL)中,接著在減壓下移除,得到呈琥珀色糊漿狀之甲烷磺酸(R)-4-(2-乙醯胺基-6-(甲氧基甲氧基)苯基)丁-2-基酯(5.17g,100%)。粗物質未經進一步純化即使用。MS(ESI,正離子)m/z 250[M-95].+。
將甲烷磺酸(R)-4-(2-乙醯胺基-6-(甲氧基甲氧基)苯基)丁-2-基酯(3.39g,9.8mmol)溶解於N,N-二甲基甲醯胺(34mL)中。冷卻溶液至0
℃,且一次性添加氫化鈉(60%,於礦物油中,0.510g,12.74mmol)。移除冰浴,且在室溫下攪拌反應混合物。2小時後,用冰浴冷卻反應混合物至0℃,且用水(40mL)緩慢稀釋。用乙酸乙酯萃取混合物。分離有機層,且用5%氯化鈉水溶液(2×40mL)洗滌。用乙酸乙酯萃取經合併之水層,且在減壓下濃縮經合併之有機萃取物,得到深琥珀色糊漿(3.9g)。經由矽膠管柱層析(以2:1己烷-乙酸乙酯、繼而3:2己烷-乙酸乙酯洗提)純化粗產物,得到呈深黃色-橙色糊漿狀之(S)-1-(5-(甲氧基甲氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(1.74g,71%)。MS(ESI,正離子)m/z 250[M+1]+。
在室溫下,用濃鹽酸(1.0mL,12.8mmol)處理(S)-1-(5-(甲氧基甲氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(1.6g,6.42mmol)於甲醇(16mL)中之溶液。加熱溶液至50℃維持90分鐘。停止加熱,且使溶液緩慢冷卻至室溫隔夜。在減壓下移除甲醇,且將殘餘物分配於二氯甲烷與水之間。分離水層,且用二氯甲烷萃取。在減壓下濃縮經合併之有機萃取物。將殘餘物溶解於乙腈(約20-30mL)中,接著在減壓下濃縮,得到呈灰白色至褐色固體狀之(S)-1-(5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(1.23g,93%)。MS(ESI,正離子)m/z 206[M+1]+。
將(S)-1-(5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(1.2g,5.85mmol)於乙腈(24mL)中之溶液冷卻至0℃,且用N-溴代丁二醯亞胺(1.041g,5.85mmol)一次性處理。溶液最初顏色變成深黃色-橙色,接著經下一個10-15分鐘變淡至淺橙色。30分鐘後,在減壓下濃縮溶液。藉由矽膠管柱層析(以8:1二氯甲烷-乙酸乙酯、繼而7:1二氯甲烷-
乙酸乙酯洗提)純化粗產物,得到(S)-1-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(1.37g,82%)。MS(ESI,正離子)m/z 284,286[M+1]+。
亦可遵循用於合成(2S)-6-溴-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-5-醇之程序,用乙醯氯替代環丙烷羰基氯,自(2S)-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉合成中間物3。MS:(ES,m/z):284,286[M+H]+
(S)-6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯係遵循用於(S)-1-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮之程序,用氯甲酸甲酯替代步驟5中之乙醯氯合成,或遵循用於合成(2S)-6-溴-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-5-醇之程序,用氯甲酸甲酯替代環丙烷羰基氯,自(2S)-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉合成。MS:(ES,m/z):300,302[M+H]+
向配備有磁性攪拌棒之100-mL圓底燒瓶中饋入4-氯-3-硝基苯酚(6.0g,34.6mmol)及乙酸(60mL)。添加鐵粉(325目)(19.31g,346mmol),且在100℃下加熱混合物30分鐘。冷卻混合物至室溫,且用水(40mL)稀釋。接著經矽藻土襯墊過濾混合物,且用水沖洗。接著用乙酸乙酯萃取濾液,且在減壓下濃縮經合併之萃取物。將庚烷(約100mL)添加至濾液中,接著在減壓下移除以移除殘餘乙酸及水。重複此過程。將殘餘物溶解於乙腈中,且在減壓下濃縮。使所得固體懸浮於庚烷中且在減壓下濃縮,得到呈淺紫色/琥珀色固體狀之3-胺基-4-氯苯酚(4.38g,88%)。MS(ESI,正離子)m/z 144[M+1]。
向配備有磁性攪拌棒之經加熱槍乾燥之100-mL圓底燒瓶中饋入磷酸鉀(5.91g,27.9mmol)、吡啶甲酸(0.171g,1.393mmol)、碘化銅(I)(0.133g,0.697mmol)、3-胺基-4-氯苯酚(2.0g,13.93mmol)、二甲亞碸(27.9mL)及碘苯(3.41g,16.72mmol)。加熱所得混合物至80℃。15小時後,對反應混合物進行水性處理,得到粗產物,接著藉由急驟層析來純化,得到純2-氯-5-苯氧基苯胺(2.61g,85%)。MS(ESI,正離子)m/z 220[M+1]。
向配備有磁性攪拌棒之50-mL圓底燒瓶中饋入2-氯-5-苯氧基苯胺(1.25g,5.69mmol)、氯醌(1.399g,5.69mmol)、正丁醇(5mL)及濃鹽酸(1.61mL,19.3mmol)。加熱混合物至100℃,接著經5分鐘緩慢添加(E)-丁-2-烯醛(0.566mL,6.83mmol)於正丁醇(2mL)中之溶液。混合物變成深琥珀色/棕色溶液。45分鐘後,停止加熱。冷卻後,用THF(30mL)稀釋溶液。接著在減壓下濃縮溶液以移除THF。添加乙酸乙酯且形成沈澱物。攪拌漿液15分鐘,接著過濾。用乙酸乙酯沖洗
固體且乾燥,得到1.9g深黃色-棕色固體。使此物質懸浮於25mL 1N氫氧化鈉水溶液中,且快速攪拌漿液30分鐘,接著過濾。用水徹底沖洗固體且乾燥,得到呈灰白色固體狀之8-氯-2-甲基-5-苯氧基喹啉(0.95g,62%)。MS(ESI,正離子)m/z 270[M+1]。
向帕爾瓶中饋入8-氯-2-甲基-5-苯氧基喹啉(0.93g,3.45mmol)、甲醇(20mL)及3M氫氧化鈉水溶液(3.79mL,11.38mmol)。用氮氣吹洗該瓶,且添加10%鈀/碳(0.5g,0.470mmol)。接著在氫氣氛圍(30psig)下震盪混合物。4.5小時後,經矽藻土襯墊過濾混合物。用甲醇沖洗瓶及過濾襯墊。在減壓下濃縮濾液。接著將殘餘物分配於乙酸乙酯與5%氯化鈉水溶液(25mL)之間。分離各層,且再次用5%氯化鈉水溶液(25mL)洗滌有機層。用乙酸乙酯萃取水性洗滌物一次,且濃縮經合併之萃取物,得到呈淺黃色-橙色糊漿狀之粗2-甲基-5-苯氧基喹啉(0.82g,101%),其未經進一步純化即使用。MS(ESI,正離子)m/z 236[M+1]。
向配備有磁性攪拌棒之玻璃螺旋蓋小瓶中饋入2-甲基-5-苯氧基喹啉(0.05g,0.213mmol)、甲醇(1mL)及氯化鎳(II)(4.96mg,0.038mmol)。在室溫下經30秒逐份添加硼氫化鈉(0.032g,0.850mmol)。反應混合物變成深紫色(接近黑色),且觀測到放熱。10分鐘後,在氮氣流下濃縮反應混合物。接著用1N氫氧化鈉水溶液(1mL)及二氯甲烷(2-3mL)處理殘餘物。經矽藻土襯墊過濾所得乳液,且用乙酸乙酯洗滌。濃縮濾液,得到呈淺黃色糊漿狀之外消旋-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉(0.051g)。粗產物未經進一步純化即繼續使用。MS(ESI,正離子)m/z 240[M+1]。
向配備有磁性攪拌棒及熱電偶之50-mL圓底燒瓶中饋入外消旋-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉(0.574g,2.399mmol)及乙腈(11.5mL)。冷卻溶液至0℃,且一次性添加N-溴代丁二醯亞胺(0.427g,2.399mmol)。溶液變成黃色,且內部溫度升至5℃,隨後下降返回至0℃。10分鐘後,再添加N-溴代丁二醯亞胺(0.021g,0.120mmol)。再經10分鐘後,自冰浴移除反應混合物且在減壓下濃縮。接著將殘餘物分配於乙酸乙酯與10%碳酸鈉水溶液之間。分離各層,且用5%氯化鈉水溶液(10mL)洗滌乙酸乙酯層且濃縮成黃色油狀物(0.81g)。藉由矽膠管柱層析(以12:1己烷-乙酸乙酯、繼而10:1己烷-乙酸乙酯洗提)純化粗產物,得到呈無色糊漿狀之外消旋-6-溴-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉(0.60,79%)。MS(ESI,正離子)m/z 318,320[M+1]。
向100-mL圓底燒瓶中饋入4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑(0.942g,4.85mmol)、N,N-二甲基甲醯胺(20mL)及碳酸銫(3.16g,9.71mmol)。添加3-溴硫雜環丁烷1,1-二氧化物(0.925g,5.00mmol),且在60℃下攪拌反應物隔夜。冷卻反應混合物至室溫,接著分配於乙酸乙酯與水之間。分離水相,且用乙酸乙酯萃取。用水及鹽水洗滌經合併之有機相且濃縮,得到油狀物。經由矽膠管柱層析(以1:5乙酸乙酯-己烷洗提)純化此物質,得到呈白色固體狀之3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)硫雜環丁烷1,1-二氧化物(0.172g,12%產率)。MS(ESI,正離子)m/z 299[M+H]+。
根據上文針對3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)硫雜環丁烷1,1-二氧化物(中間物7)所概述之程序,自4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑及4-溴四氫-2H-硫代哌喃1,1-二氧化物合成3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)四氫-2H-硫代哌喃1,1-二氧化物。13C NMR(400MHz,CDCl3)δ ppm 20.85(s,1 C),24.75(s,1 C),24.77(s,4 C),31.38(s,1 C),50.50(s,1 C),56.62(s,1 C),57.33(s,1 C),83.50(s,2 C),134.95(s,1 C),146.21(s,1 C)。MS(ESI,正離子)m/z 327[M+H]+。
根據上文針對8-氯-5-甲氧基-2-甲基喹啉鹽酸鹽(中間物1,步驟1)所述之程序,自2-氟-5-甲氧基苯胺(30.0g,213mmol)合成8-氟-5-甲氧基-2-甲基喹啉,作出以下改變:將鹽酸鹽溶解於二氯甲烷(400mL)中,且用飽和碳酸鉀水溶液將所得溶液之pH值調整至8-9。用二氯甲烷萃取所得混合物,且經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由矽膠管柱層析(以20%乙酸乙酯-石油醚洗提)純化殘餘物,得到呈黃色固體狀之8-氟-5-甲氧基-2-甲基喹啉(25.2g,62%)。MS(ESI,正離子)m/z 192[M+H]+。
根據上文針對(2S)-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉(中間物1)所
述之程序,自8-氟-5-甲氧基-2-甲基喹啉合成(S)-8-氟-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉。MS(ESI,正離子)m/z 196[M+H]+。
根據上文針對(2S)-6-溴-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-5-醇(中間物2,步驟1a、2a及3)所述之程序,自(S)-8-氟-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉合成(S)-(6-溴-8-氟-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮。MS(ESI,正離子)m/z 328,330[M+H]+。
根據上文針對中間物11所述之程序製備以下中間物:
MS(ESI,正離子)m/z 302,304[M+H]+。
MS(ESI,正離子)m/z 318,320[M+H]+。
將氯化三異丙基矽烷(166mL,961.5mmol)緩慢添加至3,4-二氟苯酚(125g,961.5mmol)及咪唑(65.4g,961.5mmol)於N,N-二甲基甲醯胺(500mL)中之混合物中,且在室溫下攪拌所得溶液隔夜。用水(1500mL)稀釋反應混合物,且用二氯甲烷(3×300mL)萃取。用水(3×200mL)及鹽水(2×200mL)洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以石油醚洗提)純化殘餘物,得到呈無色油狀之(3,4-二氟苯氧基)三異丙基矽烷(220g,80%)。
將N,N,N',N",N"-五甲基二伸乙基三胺(60.4g,349.1mmol)於四氫呋喃(480mL)中之溶液冷卻至-70℃,且經10分鐘添加第二丁基鋰(1.25M,於環己烷中,335mL,419mmol)。經1小時逐滴添加(3,4-二氟苯氧基)三異丙基矽烷(99.85g,349.1mmol),且在-70℃下攪拌所得混合物2小時。將二氧化碳鼓入溶液中,且在-70℃下攪拌所得混合物5小時,接著在室溫下攪拌2小時。接著將反應混合物傾倒至水(200mL)中,且用2N鹽酸將pH值調整至5。用乙酸乙酯(3×500mL)
萃取所得混合物,且用鹽水(200mL)洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾且濃縮,得到呈淡黃色固體狀之2,3-二氟-5-(三異丙基矽烷氧基)苯甲酸(99.1g,86%)。MS(ESI,負陰離子)m/z 329[M-H]-。
將三水合氟化四丁基銨(191g,731.8mmol)分數份添加至2,3-二氟-5-(三異丙基矽烷氧基)苯甲酸(99.13g,300.0mmol)於四氫呋喃(500mL)中之溶液中,且在室溫下攪拌所得混合物隔夜。將反應混合物傾倒至水(1000mL)中,且用乙酸乙酯(2×500mL)萃取。用鹽水(2×500mL)洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾,且在真空下濃縮,得到呈淡黃色固體狀之2,3-二氟-5-羥基苯甲酸(50g,95%)。MS(ESI,負陰離子)m/z 173[M-H]-。
將溴環丁烷(150g,1.12mol)添加至2,3-二氟-5-羥基苯甲酸(50g,287mmol)及碳酸鉀(230g,1.67mol)於乙腈(1500mL)中之混合物中,且在90℃下攪拌所得混合物隔夜。冷卻反應混合物至室溫,過濾,且在真空下濃縮。經由矽膠管柱層析(以石油醚洗提)純化殘餘物,得到呈黃綠色固體狀之5-環丁氧基-2,3-二氟苯甲酸環丁酯(49g,60%)。MS(ESI,正離子)m/z 283[M+H]+。
將5-環丁氧基-2,3-二氟苯甲酸環丁酯(49g,174mmol)、乙醇(300mL)、氫氧化鈉(20g,500mmol)及水(300mL)之混合物在60℃下攪拌隔夜。冷卻混合物至室溫,且用石油醚(2×100mL)萃取。用6M鹽酸將水層之pH值調整至5,接著將其用乙酸乙酯(3×300mL)萃取。用鹽水洗滌經合併之乙酸乙酯層,經無水硫酸鈉乾燥,過濾且濃縮,得到呈白色固體狀之5-環丁氧基-2,3-二氟苯甲酸(38g,96%)。
MS(ESI,負陰離子)m/z 227[M-H]-。
將5-環丁氧基-2,3-二氟苯甲酸(38g,148mmol)、第三丁醇(280mL)、三乙胺(21.4mL,154mmol)及二苯基磷醯基疊氮化物(33.2mL,154mmol)之溶液在90℃下攪拌隔夜。冷卻反應混合物至室溫且濃縮。將殘餘物溶解於二氯甲烷(200mL)中,用1M氫氧化鈉(2×100mL)及鹽水(2×50mL)洗滌,經無水硫酸鈉乾燥,過濾且濃縮。經由矽膠管柱層析(以5%乙酸乙酯/石油醚洗提)純化殘餘物,得到呈白色固體狀之5-環丁氧基-2,3-二氟苯基胺基甲酸第三丁酯(32g,76%)。MS(ESI,正離子)m/z 230[M+H]+。
將三氟乙酸(70mL)添加至5-環丁氧基-2,3-二氟苯基胺基甲酸第三丁酯(32g,107mmol)於二氯甲烷(320mL)中之溶液中,且在室溫下攪拌所得溶液隔夜。濃縮反應溶液,且將殘餘物溶解於二氯甲烷(500mL)中。在攪拌下緩慢添加HCl溶液(4M,於1,4-二噁烷中,120mL)。濃縮所得混合物,且傾倒至乙醚(480mL)中。過濾所得沈澱物,且在減壓下乾燥濾餅,得到呈淡黃色固體狀之5-環丁氧基-2,3-二氟苯胺鹽酸鹽(21g,89%)。MS(ESI,正離子)m/z 200[M+H]+。
將5-環丁氧基-2,3-二氟苯胺鹽酸鹽(9.9g,42.1mmol)、濃鹽酸(36mL)、氯醌(12.32g,49.8mmol)於正丁醇(60mL)中之混合物在100℃下攪拌1小時。逐滴添加(E)-丁烯醛(19.8mL,239mmol),且在100℃下攪拌所得溶液1小時,接著冷卻至70℃。添加四氫呋喃(600mL),且在70℃下再攪拌混合物30分鐘。冷卻反應混合物至室溫,且在真空下濃縮。將殘餘物傾倒至水(300mL)中,且用飽和碳酸鉀水溶液將混合物之pH值調整至7-8。用乙酸乙酯(3×300mL)萃取所得混合
物,且經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由矽膠管柱層析(以25%乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色固體狀之5-環丁氧基-7,8-二氟-2-甲基喹啉鹽酸鹽(6g,57%)。MS(ESI,正離子)m/z 250[M+H]+。
向30-mL玻璃襯裏不銹鋼反應器中饋入5-環丁氧基-7,8-二氟-2-甲基喹啉(4.2g,16.9mmol)、Cp*Ru(OTf)[(S,S)-TsDPEN](0.100g,0.13mmol)及甲醇(10mL)。將反應器封閉,且在50atm之壓力下引入氫氣,隨後降至1atm。重複此程序三次之後,用氫氣將反應器加壓至50atm。在室溫下於此氫氣壓力下攪拌所得混合物24小時。小心釋放氫氣之後,在真空下濃縮反應混合物。經由矽膠管柱層析(以25%乙酸乙酯/石油醚洗提)純化殘餘物,得到呈無色油狀之(S)-5-環丁氧基-7,8-二氟-2-甲基-1,2,3,4-四氫喹啉(1.4g,33%,87% ee)。
MS(ESI,正離子)m/z 254[M+H]+。
將N-溴代丁二醯亞胺(0.703g,3.95mmol)於乙腈(10mL)中之溶液逐滴添加至(S)-5-環丁氧基-7,8-二氟-2-甲基-1,2,3,4-四氫喹啉(1.0g,3.95mmol)於乙腈(80mL)及二氯甲烷(15mL)中之-5℃溶液中,且在-5℃下攪拌所得溶液4小時。在真空下濃縮反應混合物。經由矽膠管柱層析(以50%乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色固體狀之(S)-6-溴-5-環丁氧基-7,8-二氟-2-甲基-1,2,3,4-四氫喹啉(1.05g,81%)。MS(ESI,正離子)m/z 332,334[M+H]+。
將乙醯氯(0.21mL,3.02mmol)逐滴添加至(S)-6-溴-5-環丁氧基-7,8-二氟-2-甲基-1,2,3,4-四氫喹啉(1.0g,3.02mmol)於二氯甲烷(20
mL)及吡啶(0.6mL)中之0℃溶液中,且攪拌所得溶液且升溫至室溫隔夜。用二氯甲烷(40mL)稀釋反應混合物,用1N鹽酸(40mL)及鹽水(40mL)洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到呈黃色油狀之(S)-1-(6-溴-5-環丁氧基-7,8-二氟-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(1.19g,99%)。MS(ESI,正離子)m/z 374,376[M+H]+。
將2-溴-1H-咪唑(1.2g,8.16mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-5,6-二氫吡啶-1(2H)-甲酸第三丁酯(3.0g,9.70mmol)、碳酸鈉(2.1g,19.8mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.120g,0.16mmol)於1,4-二噁烷(30mL)及水(10mL)中之混合物在100℃下攪拌隔夜。冷卻反應混合物至室溫,傾倒至乙酸乙酯(100mL)中,用水(30mL)及鹽水(30mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以25%乙酸乙酯-石油醚洗提)純化殘餘物,得到呈淡黃色固體狀之4-(1H-咪唑-2-基)-5,6-二氫吡啶-1(2H)-甲酸第三丁酯(0.300g,15%)。MS(ESI,正離子)m/z 250[M+H]+。
將鈀/碳(10wt%,0.100g)添加至4-(1H-咪唑-2-基)-5,6-二氫吡啶-1(2H)-甲酸第三丁酯(0.300g,1.20mmol)於乙醇(20mL)中之溶液中,且在室溫下於氫氣氛圍下攪拌混合物2小時。過濾反應混合物,且在真空下濃縮濾液,得到呈灰白色固體狀之4-(1H-咪唑-2-基)哌啶-
1-甲酸第三丁酯(0.300g,99%)。MS(ESI,正離子)m/z 252[M+H]+。
向100-mL圓底燒瓶中饋入4-(1H-咪唑-2-基)哌啶-1-甲酸第三丁酯(0.300g,1.19mmol)及四氫呋喃(10mL),且冷卻溶液至-78。添加N-溴代丁二醯亞胺(0.185g,1.04mmol),且在-78℃下攪拌所得溶液2小時。將反應混合物傾倒至水(10mL)中,且用乙酸乙酯(3×20mL)萃取。用鹽水(10mL)洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以2:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈白色固體狀之4-(4-溴-1H-咪唑-2-基)哌啶-1-甲酸第三丁酯(0.26g,66%)。MS(ESI,正離子)m/z 330,332[M+H]+。
根據上文針對4-(1H-咪唑-2-基)哌啶-1-甲酸第三丁酯(中間物15)所述之程序,用2-溴-1-甲基-1H-咪唑替代步驟1中之2-溴-1H-咪唑來合成4-(4-溴-1-甲基-1H-咪唑-2-基)哌啶-1-甲酸第三丁酯。MS(ESI,正離子)m/z 264[M+H]+。
將甲烷磺醯氯(2.90mL,37.6mmol)添加至4-羥基哌啶-1-甲酸第三丁酯(5.00g,24.8mmol)及三乙胺(10.4mL,74.65mmol)於二氯甲烷(50mL)中之0℃溶液中,且在室溫下攪拌所得溶液1小時。用二氯甲烷(200mL)稀釋反應混合物,用水(2×50mL)洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到呈黃色固體狀之4-(甲基磺醯氧基)哌啶-1-甲酸第三丁酯(7.00g,99%)。MS(ESI,正離子)m/z 280[M+H]+。
將4-(甲基磺醯氧基)哌啶-1-甲酸第三丁酯(0.837g,3.00mmol)、3-溴-1H-吡唑(0.441g,3.02mmol)及碳酸銫(2.94g,9.02mmol)於DMF(10mL)中之混合物在100℃下攪拌5小時。冷卻反應混合物至室溫,且傾倒至乙酸乙酯(50mL)中。用水(3×10mL)洗滌混合物,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以10%二氯甲烷/甲醇洗提)純化殘餘物,得到呈白色固體狀之4-(3-溴-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(0.25g,25%)。MS(ESI,正離子)m/z 330,332[M+H]+。
亦獲得呈白色固體狀之4-(5-溴-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(0.150g,15%)。MS(ESI,正離子)m/z 330,332[M+H]+。
將溴(11.59g,73.35mmol)逐滴添加至2H-1,2,3-三唑(5.00g,72.46mmol)於水(50mL)中之0℃溶液中,且使所得溶液升溫至室溫且攪拌隔夜。藉由過濾收集沈澱物且乾燥,得到呈白色固體狀之4,5-二溴-2H-1,2,3-三唑(8.00g,49%)。MS(ESI,正離子)m/z 228,226,230[M+H]+。
將4,5-二溴-2H-1,2,3-三唑(2.27g,10.08mmol)、4-(甲基磺醯氧基)哌啶-1-甲酸第三丁酯(2.79g,10.00mmol)及碳酸銫(9.75g,29.91mmol)於N,N-二甲基甲醯胺(50mL)中之混合物在100℃下攪拌隔夜。冷卻反應混合物至室溫,傾倒至水(100mL)中,且用乙酸乙酯(2×100mL)萃取。用鹽水(100mL)洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾且濃縮,得到呈黃色油狀之4-(4,5-二溴-2H-1,2,3-三唑-2-基)哌啶-1-甲酸第三丁酯與4-(4,5-二溴-1H-1,2,3-三唑-1-基)哌啶-1-甲酸第三丁酯之混合物(4.00g,97%)。MS(ESI,正離子)m/z 411,409,413[M+H]+。
將正丁基鋰(2.5M,於己烷中,2.92mL,7.30mmol)逐滴添加至含有4-(4,5-二溴-2H-1,2,3-三唑-2-基)哌啶-1-甲酸第三丁酯與4-(4,5-二溴-1H-1,2,3-三唑-1-基)哌啶-1-甲酸第三丁酯之混合物(3.00g,7.35mmol)於四氫呋喃(20mL)中之-78℃溶液中。在-78℃下攪拌所得溶液1小時,接著將反應混合物傾倒至飽和氯化銨水溶液(20mL)中。分離水相且用乙酸乙酯(3×20mL)萃取,且經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由矽膠管柱層析(以2:1乙酸乙酯/石
油醚洗提)純化殘餘物,得到呈無色油狀之4-(4-溴-2H-1,2,3-三唑-2-基)哌啶-1-甲酸第三丁酯(0.800g,33%)。MS(ESI,正離子)m/z 331,333[M+H]+。
亦獲得呈無色油狀之4-(4-溴-1H-1,2,3-三唑-1-基)哌啶-1-甲酸第三丁酯(0.500g,20%)。MS(ESI,正離子)m/z 331,333[M+H]+。
將1,2-二溴乙烷(0.084mL,0.97mmol)添加至鋅粉(0.520g,8.13mmol)於四氫呋喃(2mL)中之混合物中,且在80℃下攪拌所得混合物10分鐘,接著冷卻至室溫。在攪拌下逐滴添加氯三甲基矽烷(0.115mL,1.22mmol)於四氫呋喃(1mL)中之溶液,且在室溫下攪拌所得混合物45分鐘。添加3-碘氮雜環丁烷-1-甲酸第三丁酯(1.74g,6.15mmol)於四氫呋喃(2mL)中之溶液,且在室溫下攪拌所得混合物2小時。添加2,4-二溴噻唑(0.744g,3.09mmol)於四氫呋喃(1mL)中之溶液及肆(三苯基膦)鈀(0)(0.354g,0.31mmol),且在室溫下攪拌所得混合物隔夜。將反應混合物傾倒至水(10mL)中,且用乙酸乙酯(3×10mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由矽膠管柱層析(以1:2乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之3-(4-溴噻唑-2-基)氮雜環丁烷-1-甲酸第三丁酯(0.151g,8%)。MS(ESI,正離子)m/z 319,321[M+H]+。
將正丁基鋰(1.6M,於THF中,6.3mL,10.1mmol)逐滴添加至2,4-二溴噻唑(2.00g,8.30mmol)於四氫呋喃(50mL)中之-78℃溶液中,且在-78℃下攪拌混合物1小時。添加3-側氧基氮雜環丁烷-1-甲酸第三丁酯(2.83g,16.55mmol)於四氫呋喃(5mL)中之溶液,且在室溫下攪拌所得混合物1小時。將反應混合物傾倒至飽和氯化銨水溶液(50mL)中,且用二氯甲烷(3×50mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由矽膠管柱層析(以20%乙酸乙酯/石油醚洗提)純化殘餘物,得到呈白色固體狀之3-(4-溴噻唑-2-基)-3-羥基氮雜環丁烷-1-甲酸第三丁酯(0.890g,32%)。MS(ESI,正離子)m/z 335,337[M+H]+。
使4-溴噻唑-2-胺(0.500g,2.81mmol)、乙酸酐(0.43mL,4.50mmol)及乙酸(5mL)之溶液回流2小時。冷卻反應混合物至室溫,且在真空下濃縮。經由矽膠管柱層析(以25%乙酸乙酯-石油醚洗提)純化殘餘物,得到呈白色固體狀之N-(4-溴噻唑-2-基)乙醯胺(0.300g,49%)。MS(ESI,正離子)m/z 221,223[M+H]+。
向100-mL圓底燒瓶中置放4-溴噻唑-2-甲酸(800mg,3.86mmol,1.00當量)、DIEA(1.03g,7.92mmol,2.00當量)、四氫呋喃(50mL)、NH4Cl(424mg,8.00mmol,2.07當量)及HATU(1.82g,4.80
mmol,1.24當量)。在25℃下攪拌所得混合物24小時。在真空下濃縮反應混合物,溶解於25mL乙酸乙酯中,用3×5mL水、5mL鹽水洗滌,經無水硫酸鈉乾燥,且在真空下濃縮。將殘餘物施加至具有乙酸乙酯/石油醚(1/1)之矽膠管柱上。此得到500mg(63%)呈白色固體狀之4-溴噻唑-2-甲醯胺。MS(ESI,正離子)m/z 207,209[M+H]+。
根據上文針對N-(4-溴噻唑-2-基)乙醯胺(中間物24)所述之程序,用甲胺替代氯化銨來合成4-溴-N-甲基噻唑-2-甲醯胺。MS(ESI,正離子)m/z 221,223[M+H]+。
在80℃下加熱(S)-1-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(0.150g,0.528mmol)、1-溴丙烷(0.24mL,2.64mmol)及第三丁醇鉀(0.296g,2.64mmol)於N,N-二甲基甲醯胺(3.0mL)中之混合物。24小時後,添加第二份1-溴丙烷(0.24mL,2.64mmol)及第三丁醇鉀(0.296g,2.64mmol),且在100℃下加熱混合物24小時。冷卻反應混合物至室溫,且添加水。用二氯甲烷萃取混合物,且用水及鹽水洗滌經合併之有機相,經無水硫酸鈉乾燥,過濾且濃縮,得到黃色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以50-100%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈無色油狀之(S)-1-(6-溴-2-甲基-5-
丙氧基-3,4-二氫喹啉-1(2H)-基)乙酮(0.100g,58%)。MS(ESI,正離子)m/z 326,328[M+H]+。
將(S)-1-(6-溴-2-甲基-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙酮(0.050g,0.153mmol)、2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)乙醇(0.055g,0.230mmol)、氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)(XPhos第2代預催化劑)(0.012g,0.015mmol)及碳酸銫(0.150g,0.460mmol)於1,4-二噁烷(2.0mL)及水(0.40mL)中之混合物在100℃下於微波中加熱2.5小時。經矽藻土過濾反應混合物且濃縮,得到橙色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以50-100%乙酸乙酯-己烷、繼而10%甲醇-乙酸乙酯進行梯度洗提)純化此物質,得到呈灰白色固體狀之(S)-1-(6-(1-(2-羥乙基)-1H-吡唑-4-基)-2-甲基-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙酮(0.047g,86%)。1H NMR(300MHz,DMSO-d 6)δ ppm 0.97(t,J=7.48Hz,3 H),1.03(d,J=6.45Hz,3 H),1.23(m,1 H),1.64-1.80(m,2 H),2.07(s,3 H),2.18-2.38(m,2 H),2.75-2.90(m,1 H),3.50-3.65(m,2 H),3.68-3.80(m,2 H),4.17(t,J=5.57Hz,2 H),4.62(m,1 H),4.84-4.94(m,1 H),7.12(br d,J=8.21Hz,1 H),7.38(d,J=8.50Hz,1 H),7.85(s,1 H),8.09(s,1 H)。MS(ESI,正離子)m/z 358[M+H]+。
根據針對實例24所概述之程序製得以下實例:
1H NMR(300MHz,DMSO-d 6)δ ppm 0.98-1.09(m,3 H),1.29(m,1 H),2.08(s,3 H),2.18-2.40(m,1 H),2.75-2.90(m,2 H),2.81(s,3 H),2.84(s,3 H),3.63-3.78(m,2 H),4.05-4.18(m,2 H),4.22-4.48(m,2 H),4.61(m,1 H),4.82-4.95(m,1 H),7.15(br d,J=8.50Hz,1 H),7.43(d,J=8.50Hz,1 H),7.93(s,1 H),8.21(s,1 H)。MS(ESI,正離子)m/z 401[M+H]+。
1H NMR(300MHz,DMSO-d 6)δ ppm 1.03-1.12(m,3 H),1.48(td,J=13.12,6.89Hz,1 H),2.09(td,J=13.63,5.28Hz,1 H),2.70-2.82(m,2 H),2.80(s,3 H),2.84(s,3 H),3.67(s,3 H),3.72(q,J=5.77Hz,2 H),4.11(t,J=5.57Hz,2 H),4.35(q,J=13.88Hz,2 H),4.42-4.56(m,1 H),4.88(t,J=5.28Hz,1 H),7.23-7.34(m,1 H),7.35-7.45(m,1 H),7.90(s,1 H),8.18(s,1 H)。MS(ESI,正離子)m/z 417[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.15(m,7 H),1.22(t,J=7.20Hz,3 H),1.29-1.42(m,1 H),2.17(s,3 H),2.31-2.45(m,2 H),2.91-3.01(m,1 H),3.35-3.43(m,3 H),3.65-3.72(m,1 H),4.07(d,J=14.40Hz,1 H),4.15(d,J=14.40Hz,1 H),4.71-4.81(m,1 H),7.08-7.15(m,1 H),7.43(d,J=8.40Hz,1 H),7.89(s,1 H),8.12(s,1 H)。MS(ESI,正離子)m/z 397[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.15(m,7 H),1.21-1.39(m,1 H),2.15(s,3 H),2.22-2.43(m,2 H),2.95-2.07(m,1 H),3.63-3.71(m,1 H),3.81-4.01(m,2 H),4.50-4.62(m,1 H),4.67-4.78(m,2 H),7.02-7.13(m,1 H),7.45(d,J=8.40Hz,1 H),7.89(s,1 H),8.12(s,1 H)。MS(ESI,正離子)m/z 358[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.55-0.65(m,2 H),0.72-0.78(m,2 H),1.05-1.15(m,7 H),1.23-1.41(m,1 H),2.19(s,3 H),2.30-2.42(m,2 H),2.51-2.59(m,1 H),2.98(s,3 H),2.95-3.08(m,1 H),3.65-3.72(m,1 H),4.55(d,J=14.80Hz,1 H),4.64(d,J=14.80Hz,1 H),4.71-4.83(m,1 H),7.05-7.20(m,1 H),7.47(d,J=8.40Hz,1 H),
7.91(s,1 H),8.21(s,1 H)。MS(ESI,正離子)m/z 423[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.02-1.15(m,7 H),1.24-1.43(m,1 H),2.16(s,3 H),2.24-2.43(m,4 H),2.90-3.05(m,1 H),3.65-3.75(m,1 H),4.01-4.25(m,6 H),4.65-4.82(m,1 H),7.05-7.15(m,1 H),7.45(d,J=8.10Hz,1 H),7.89(s,1 H),8.19(s,1 H)。MS(ESI,正離子)m/z 409[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.18(m,7 H),1.21-1.53(m,3H),1.55-1.73(m,4 H),2.18(s,3 H),2.30-2.47(m,2 H),2.94-3.05(m,1 H),3.21-3.38(m,2 H),3.58-3.65(m,2 H),3.66-3.74(m,1 H),4.39(d,J=14.10Hz,1 H),4.50(d,J=14.10Hz,1 H),4.73-4.85(m,1 H),7.09-7.17(m,1 H),7.48(d,J=8.40Hz,1 H),7.92(s,1 H),8.21(s,1 H)。MS(ESI,正離子)m/z 437[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.19(m,7 H),1.49-1.68(m,1 H),2.14-2.28(m,1 H),2.50-2.63(m,1 H),2.87-3.01(m,1 H),3.65-3.78(m,1 H),3.78(s,3 H),4.01-4.18(m,2 H),4.55-4.68(m,1 H),7.37(q,d=8.70Hz,2 H),7.83(s,1 H),8.02(s,1 H)。MS(ESI,正離子)m/z 410[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.01-1.20(m,7 H),1.50-1.62(m,1 H),2.20-2.28(m,1 H),2.49-2.59(m,1 H),2.91-3.01(m,1 H),3.67-3.72(m,1 H),3.79(s,3 H),3.79-3.91(m,2 H),4.55-4.62(m,1 H),6.10(tt,J=54.80,3.60Hz,1 H),7.37(s,2 H),7.86(s,1 H),8.04(s,1 H)。MS(ESI,正離子)m/z 392[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.01-1.15(m,4 H),1.18(d,J=6.80Hz,3 H),1.47-1.58(m,1 H),2.18-2.25(m,1 H),2.48-2.58(m,1 H),2.90-2.99(m,1 H),3.63-3.71(m,1 H),3.78(s,3 H),3.81-3.87(m,1 H),3.90-3.94(m,1 H 0),4.51-4.62(m,2 H),4.68-4.73(m,1 H),7.33
(d,J=8.40Hz,1 H),7.38(d,J=8.80Hz,1 H),7.88(s,1 H),8.11(s,1 H)。MS(ESI,正離子)m/z 374[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.02-1.19(m,7 H),1.51-1.62(m,1 H),1.77(t,J=18.90Hz,3 H),2.15-2.25(m,1 H),2.51-2.68(m,1 H),2.89-3.01(m,1 H),3.65-3.71(m,1 H),3.75-3.85(m,5 H),4.55-4.65(m,1 H),7.36-7.37(m,2 H),7.86(s,1 H),8.06(s,1 H)。MS(ESI,正離子)m/z 406[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.19(m,7 H),1.48-1.61(m,1 H),2.15-2.27(m,1 H),2.48-2.72(m,3 H),2.85-2.95(m,1 H),3.65-3.72(m,1 H),3.72-3.83(m,5 H),4.58-4.62(m,1 H),7.28-7.34(m,2 H),7.82(s,1 H),8.01(s,1 H)。MS(ESI,正離子)m/z 424[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.98-1.21(m,7 H),1.25-1.39(m,1 H),2.21-2.45(m,2 H),2.91-3.04(m,1 H),3.61-3.68(m,1 H),3.77(s,3 H),4.41-4.52(m,1 H),7.37-7.41(m,2 H),7.79(s,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 421[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.98-1.15(m,4 H),1.18(d,J=6.60Hz,3 H),1.35-1.45(m,1 H),2.20-2.31(m,1 H),2.35-2.47(m,1 H),2.95-3.03(m,1 H),3.62-3.69(m,1 H),3.69(s,3 H),4.05-4.25(m,1 H),4.29-4.33(m,1 H),4.45-4.52(m,3 H),4.61-4.63(m,1 H),7.31(s,2 H),7.78(s,1 H),7.99(s,1 H)。MS(ESI,正離子)m/z 406[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.98-1.18(m,7 H),1.37-1.62(m,7 H),2.11-2.23(m,1 H),2.48-2.59(m,1 H),2.87-2.99(m,1 H),
3.57(s,1 H),3.58-3.71(m,2 H),3.77(s,3 H),4.52-4.62(m,1 H),7.28-7.29(m,2 H),7.86(s,1 H),8.09(s,1 H)。MS(ESI,正離子)m/z 402[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.99(s,6 H),1.01-1.18(m,7 H),1.45-1.61(m,1 H),2.17-2.23(m,1 H),2.47-2.57(m,1 H),2.91-3.01(m,1 H),3.30-3.45(m,4 H),3.60-3.71(m,1 H),3.77(s,3 H),4.51-4.62(m,1 H),7.19-7.30(m,2 H),7.76(s,1 H),7.98(s,1 H)。MS(ESI,正離子)m/z 414[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.98-1.38(m,14 H),2.20-2.39(m,2 H),2.92-3.03(m,1 H),3.63-3.72(m,1 H),3.77(s,3 H),4.38-4.52(m,1 H),7.18-7.28(m,2 H),7.72(s,1 H),7.96(s,1 H)。MS(ESI,正離子)m/z 413[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.34(m,7 H),1.42-1.58(m,1 H),2.15-2.29(m,1 H),2.48-2.62(m,1 H),2.95-3.09(m,1 H),3.59-3.71(m,1 H),3.79(s,3 H),4.52-4.63(m,1 H),5.41(d,J=61.20Hz,1 H),7.38(d,J=8.70Hz,1 H),7.45(d,J=8.70Hz,1 H),7.83(s,1 H),8.08(s,1 H)。MS(ESI,正離子)m/z 403[M+H]+。氟之立體化學試驗性地指定。
1H NMR(300MHz,CD3OD)δ ppm 1.03-1.1.35(m,7 H),1.45-1.55(m,1 H),2.17-2.24(m,1 H),2.49-2.72(m,1 H),3.01-3.12(m,1 H),3.68-3.73(m,1 H),3.80(s,3 H),4.55-4.65(m,1 H),5.49(d,J=61.50Hz,1 H),7.41(d,J=8.40Hz,1 H),7.47(d,J=8.70Hz,1 H),7.84(s,1 H),8.09(s,1 H)。MS(ESI,正離子)m/z 403[M+H]+。氟之立體化學試驗性地指定。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.27(m,10 H),1.55-1.65(m,1 H),2.15-2.23(m,1 H),2.58-2.68(m,1 H),2.83-2.93(m,1 H),3.29-3.38(m,2 H),3.65-3.71(m,1 H),3.78(s,3 H),4.08(s,2 H),4.55-4.65(m,1 H),7.35-7.42(m,2 H),7.86(s,1 H),8.09(s,1 H)。MS(ESI,正離子)m/z 413[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.48-0.62(m,2 H),0.65-0.83(m,2 H),1.01-1.09(m,4 H),1.17(d,J=6.30Hz,3 H),1.48-1.62(m,1 H),2.15-2.25(m,1 H),2.28-2.63(m,2 H),2.78-3.01(m,4 H),3.65-3.72(m,1 H),3.77(s,3 H),4.049-4.63(m,3 H),7.31-7.41(m,2 H),7.87(s,1 H),8.12(s,1 H)。MS(ESI,正離子)m/z 439[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.99-1.19(m,7 H),1.49-1.62(m,1 H),2.15-2.35(m,3 H),2.49-2.63(m,1 H),2.87-2.98(m,1 H),3.76-3.82(m,1 H),3.76(s,3 H),4.01-4.20(m,6 H),4.58-4.65(m,1 H),7.36(s,2 H),7.86(s,1 H),8.12(s,1 H)。MS(ESI,正離子)m/z 425[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.99-1.12(m,4 H),1.17(d,J=6.60Hz,3 H),1.38-1.72(m,7 H),2.10-2.23(m,1 H),2.49-2.62(m,1 H),2.85-2.99(m,1 H),3.17-3.21(m,2 H),3.55-3.60(m,2 H),3.61-3.68(m,1 H),3.76(s,3 H),4.38(q,J=14.10Hz,2 H),4.51-4.62(m,1 H),7.36(s,2 H),7.86(s,1 H),8.12(s,1 H)。MS(ESI,正離子)m/z 453[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.19(m,7 H),1.48-1.62(m,1 H),2.03-2.25(m,3 H),2.40-2.58(m,3 H),2.80-2.91(m,1 H),3.50-3.61(m,4 H),3.68-3.79(m,6 H),4.55-4.65(m,1 H),7.25-7.32(m,2 H),7.80(s,1 H),8.03(s,1 H)。MS(ESI,正離子)m/z 439[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.12(m,4 H),1.18(d,J=6.40Hz,3 H),1.52-1.63(m,1 H),2.17-2.23(m,1 H),2.50-2.65(m,1 H),2.89-3.01(m,1 H),3.53-3.73(m,7 H),3.78(s,3 H),4.31-4.45(m,2 H),4.58-4.63(m,1 H),7.30-7.38(m,2 H),7.88(s,1 H),8.15(s,1 H)。MS(ESI,正離子)m/z 455[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.19(m,7 H),1.48-1.49(m,1 H),2.15-2.23(m,1 H),2.30-2.41(m,2 H),2.48-2.58(m,1 H),2.89-3.01(m,1 H),3.18-3.22(m,2 H),3.35-3.41(m,4 H),3.63-3.79(m,6 H),4.52-4.62(m,1 H),7.32(s,2 H),7.87(s,1 H),8.09(s,1 H)。MS(ESI,正離子)m/z 475[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.99-1.09(m,2 H),1.11-1.19(m,5 H),1.49-1.62(m,1 H),2.15-2.25(m,1 H),2.52-2.68(m,1 H),
2.99-2.3.12(m,1 H),3.61-3.70(m,1 H),3.78(s,3 H),4.50-4.63(m,3 H),7.39(s,2 H),7.89(s,1 H),8.20(s,1 H)。MS(ESI,正離子)m/z 421[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.98-1.19(m,7 H),1.52-1.63(m,1 H),2.15-2.25(m,1 H),2.55-2.73(m,1 H),2.88-3.02(m,7 H),3.60-3.72(m,1 H),3.77(s,3 H),4.50-4.67(m,3 H),7.34(d,J=8.70Hz,1 H),7.41(d,J=8.70Hz,1 H),7.85(s,1 H),8.12(s,1 H)。MS(ESI,正離子)m/z 449[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.19(m,7 H),1.45-1.69(m,1 H),2.03-2.21(m,3 H),2.38-2.53(m,1 H),2.75-2.89(m,1 H),3.15-3.20(m,1 H),3.47-3.58(m,2 H),3.65-3.73(m,1 H),3.76(s,3 H),4.40-4.48(m,2 H),4.49-4.62(m,1 H),4.78-4.83(m,2 H),7.21-7.31(m,2 H),7.80(s,1 H),7.99(s,1 H)。MS(ESI,正離子)m/z 412[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.19(m,8 H),1.45-1.58(m,2 H),1.90-2.05(m,1 H),2.18-2.25(m,1 H),2.45-2.55(m,1 H),2.88-2.99(m,1 H),3.57-3.71(m,2 H),3.77(s,3 H),3.78-3.83(m,1 H),4.50-4.61(m,1 H),7.32(s,2 H),7.84(s,1 H),8.02(s,1 H)。MS(ESI,正離子)m/z 418[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.17(m,7 H),1.45-1.55(m,1 H),2.15-2.25(m,1 H),2.48-2.62(m,1 H),2.88-2.99(m,1 H),3.67-3.72(m,1 H),3.75-3.85(m,7 H),4.45-4.63(m,5 H),7.25(d,J=8.40Hz,1 H),7.33(d,J=8.70Hz,1 H),7.73(s,1 H),7.93(s,1 H)。MS(ESI,正離子)m/z 428[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.02-1.19(m,7 H),1.38-1.48(m,1 H),2.25-2.31(m,1 H),2.39-2.48(m,1 H),2.53-2.82(m,4 H),2.89-2.95(m,1 H),3.68-3.73(m,1 H),3.78(s,3 H),4.21-4.30(m,1
H),4.48-4.58(m,1 H),7.30(s,2 H),7.79(s,1 H),7.99(s,1 H)。MS(ESI,正離子)m/z 418[M+H]+。
1H NMR(300MHz,DMSO-d6)δ ppm 0.94(t,3 H),1.00(d,3 H),1.20-1.30(m,2 H),1.40(s,9 H),1.59-1.69(m,2 H),2.05(s,3 H),2.16-2.32(m,2 H),2.36-2.44(m,2 H),2.70-2.81(m,1 H),3.49(d,2 H),3.53-3.67(m,2 H),3.94(t,2 H),5.82(m,1 H),6.98(d,1 H),7.07(d,1 H)。MS(ESI,正離子)m/z 429[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.18(m,7 H),1.21-1.42(m,1 H),2.16(s,3 H),2.28-2.32(m,2 H),2.95-3.05(m,1 H),3.65-3.75(m,1 H),4.01-4.21(m,2 H),4.68-4.83(m,1 H),7.10-7.20(m,1 H),7.43(d,J=8.10Hz,1 H),7.85(s,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 394[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.20(m,7 H),1.28-1.43(m,1 H),2.18(s,3 H),2.28-2.35(m,2 H),2.95-3.05(m,1 H),3.65-3.75(m,1 H),3.85-4.01(m,2 H),4.61(s,1 H),4.69-4.82(m,1 H),6.13(tt,J=54.60,3.30Hz,1 H),7.05-7.15(m,1 H),7.46(d,J=8.40Hz,1 H),7.90(s,1 H),8.11(s,1 H)。MS(ESI,正離子)m/z 376[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.01-1.18(m,7 H),1.25-1.40(m,1 H),1.77(t,J=18.80Hz,3 H),2.18(s,3 H),2.30-2.42(m,2 H),2.95-3.05(m,1 H),3.68-3.89(m,3 H),4.70-4.82(m,1 H),7.05-7.18(m,1 H),7.44(d,J=8.40Hz,1 H),7.88(s,1 H),8.10(s,1 H)。MS(ESI,正離子)m/z 390[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.98-1.30(m,8 H),2.15(s,3 H),2.25-2.49(m,2 H),3.05-3.12(m,1 H),3.65-3.72(m,1 H),4.10-
4.32(m,2 H),4.47-4.54(m,2 H),4.65-4.80(m,2 H),7.05-7.15(m,1 H),7.40(d,J=8.10Hz,1 H),7.92(s,1 H),8.02(s,1 H)。MS(ESI,正離子)m/z 390[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.99(s,6 H),1.05-1.25(m,7 H),1.23-1.35(m,1 H),2.17(s,3 H),2.23-2.38(m,2 H),3.01-3.13(m,1 H),3.40-3.48(m,4 H),3.65-3.75(m,1 H),4.70-4.83(m,1 H),7.01-7.09(m,1 H),7.35(d,J=8.00Hz,1 H),7.81(s,1 H),8.04(s,1 H)。MS(ESI,正離子)m/z 398[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.98-1.20(m,11 H),1.30(s,3 H),2.05-2.30(m,4 H),2.33-2.45(m,1 H),3.01-3.12(m,1 H),3.65-3.72(m,1 H),4.60-4.72(m,1 H),7.05-7.12(m,1 H),7.33(d,J=8.10Hz,1 H),7.77(s,1 H),8.02(s,1 H)。MS(ESI,正離子)m/z 397[M+H]+。
1H NMR(400MHz,CDCl3)δ ppm 1.07-1.18(m,7 H),1.31-1.37(m,1 H),2.18(s,2 H),2.38-2.41(m,2 H),2.61-2.72(m,2 H),2.97-3.02(m,1 H),3.69-3.75(m,1 H),3.82-3.92(m,2 H),4.78(s,1 H),7.14(s,1 H),7.41(d,J=8.00Hz,1 H),7.87(s,1 H),8.10(s,1 H)。MS(ESI,正離子)m/z 408[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.19(m,7 H),1.25-1.39(m,1 H),2.01-2.19(m,5 H),2.27-2.48(m,4 H),2.85-2.95(m,1 H),3.55-3.68(m,4 H),3.59-3.84(m,3 H),4.65-4.78(m,1 H),7.01-7.12(m,1 H),7.37(d,J=8.40Hz,1 H),7.83(s,1 H),8.09(s,1 H)。MS(ESI,正離子)m/z 423[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.15(m,7 H),1.15-1.45(m,1 H),2.16(s,3 H),2.30-2.43(m,2 H),2.90-3.05(m,1 H),3.50-3.80(m,7 H),4.35-4.55(m,2 H),4.68-4.84(m,1 H),7.05-7.15(m,1
H),7.46(d,J=8.40Hz,1 H),7.90(s,1 H),8.19(s,1 H)。MS(ESI,正離子)m/z 439[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.19(m,7 H),1.25-1.35(m,1 H),2.16(s,3 H),2.28-2.45(m,4 H),2.98-3.05(m,1 H),3.22(t,J=7.80Hz,2 H),3.28-3.42(m,4 H),3.68-3.86(m,3 H),4.70-4.83(m,1 H),7.05-7.12(m,1 H),7.41(d,J=8.40Hz,1 H),7.91(s,1 H),8.12(s,1 H)。MS(ESI,正離子)m/z 459[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.01-1.25(m,7 H),1.30-1.45(m,1 H),2.18(s,3 H),2.30-2.45(m,2 H),3.10-3.20(m,1 H),3.68-3.72(m,1 H),4.58-4.68(m,2 H),4.70-4.85(m,1 H),7.10-7.20(m,1 H),7.47(d,J=8.40Hz,1 H),7.93(s,1 H),8.21(s,1 H)。MS(ESI,正離子)m/z 405[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.03-1.23(m,7 H),1.34-1.52(m,1 H),2.18(s,3 H),2.30-2.52(m,2 H),3.00(s,6 H),3.05-3.15(m,1 H),3.68-3.74(m,1 H),4.67(d,J=10.80Hz,1 H),4.72-4.79(m,2 H),7.10-7.20(m,1 H),7.45(d,J=8.40Hz,1 H),7.91(s,1 H),8.22(s,1 H)。MS(ESI,正離子)m/z 433[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.05-1.15(m,7 H),1.21-1.37(m,1 H),2.05-2.15(m,5 H),2.25-2.42(m,2 H),2.82-2.95(m,1 H),3.18-3.30(m,1 H),3.55-3.78(m,3 H),4.46(t,J=6.30Hz,2 H),4.65-4.83(m,2 H),4.83-4.89(m,1 H),7.01-7.11(m,1 H),7.37(d,J=8.40Hz,1 H),7.84(s,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 396[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.01-1.15(m,8 H),1.21-1.35(m,1 H),1.45-1.55(m,1 H),1.90-2.05(m,1 H),2.16(s,3 H),2.25-2.45(m,2 H),2.95-3.05(m,1 H),3.58-3.75(m,2 H),3.85-3.99(m,1 H),4.67-4.82(m,1 H),7.05-7.12(m,1 H),7.42(d,J=8.40Hz,1 H),7.89(s,1 H),8.10(s,1 H)。MS(ESI,正離子)m/z 402[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.19(m,7 H),1.15-1.42(m,1 H),2.17(s,3 H),2.28-2.45(m,2 H),2.95-3.05(m,1 H),3.68-3.75(m,1 H),3.79-3.95(m,4 H),4.45-4.57(m,4 H),4.68-4.82(m,1 H),7.05-7.12(m,1 H),7.35(d,J=8.40Hz,1 H),7.77(s,1 H),7.99(s,1 H)。MS(ESI,正離子)m/z 412[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.99-1.15(m,7 H),1.25-1.41(m,1 H),2.16(s,3 H),2.28-2.45(m,2 H),2.95-3.05(m,1 H),3.65-3.75(m,1 H),3.99-4.25(m,2 H),4.55-4.85(m,5 H),7.05-7.15(m,1 H),7.41(d,J=8.70Hz,1 H),7.84(s,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 400[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.15(m,7 H),1.15-1.25
(m,1 H),2.15(s,3 H),2.20-2.48(m,2 H),2.55-2.89(m,4 H),2.91-3.01(m,1 H),3.68-3.75(m,1 H),4.25-4.35(m,1 H),4.65-4.80(m,1 H),7.05-7.11(m,1 H),7.38(d,J=8.40Hz,1 H),7.82(s,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 402[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.00-1.15(m,7 H),1.21-1.39(m,1 H),2.16(s,3 H),2.25-2.45(m,2 H),2.75-3.10(m,3 H),3.48-3.65(m,2 H),3.70-3.95(m,4 H),4.69-4.85(m,1 H),7.05-7.11(m,1 H),7.37(d,J=8.40Hz,1 H),7.82(s,1 H),8.03(s,1 H)。MS(ESI,正離子)m/z 381[M+H]+。
1H NMR(300MHz,CDCl3)δ ppm 065-0.67(m,1 H),0.81-0.92(m,1 H),0.93-1.03(m,1 H),1.13(d,J=660Hz,3 H),1.23-1.32(m,1 H),1.33-1.42(m,1 H),1.60-1.70(m,1 H),1.83-1.87(m,2 H),2.03-2.26(m,4 H),2.27-2.44(m,2 H),2.91-3.07(m,1 H),4.05-4.28(m,4 H),4.68-4.82(m,1 H),7.15-7.28(m,1 H),7.92-8.08(m,2H)。MS(ESI,正離子)m/z 367[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.55-0.65(m,1 H),0.72-0.89(m,2 H),1.13(d,J=6.60Hz,4 H),1.13-1.40(m,2 H),1.41-1.70(m,1 H),1.71-1.90(m,1 H),1.90-1.93(m,4 H),2.14-2.39(m,2 H),2.90-3.02(m,1 H),3.99-4.16(m,1 H),4.55-4.65(m,1 H),7.05(d,J=8.10Hz,1 H),7.31(d,J=8.10Hz,1 H),7.88(s,1 H)。MS(ESI,正離子)m/z 352[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.65-0.79(m,1 H),0.85-1.01(m,2 H),1.13(d,J=6.60Hz,4 H),1.25-1.51(m,2 H),1.51-1.76(m,1 H),1.85-2.01(m,1 H),2.01-2.57(m,6 H),2.99-3.15(m,1 H),3.85-3.04(m,3 H),4.12-4.31(m,1 H),4.61-4.79(m,1 H),7.15(d,J=8.10Hz,1 H),7.39(d,J=8.10Hz,1 H),7.86(s,1 H),7.99(s,1 H)。MS(ESI,正離子)m/z 367[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.61-0.85(m,1 H),0.85-1.03(m,2 H),1.15(d,J=6.60Hz,4 H),1.25-1.51(m,2 H),1.51-1.80(m,1 H),1.81-2.28(m,5 H),2.29-2.60(m,2 H),2.99-3.20(m,1 H),4.06-4.29(m,1 H),4.68-4.82(m,1 H),7.15(br s,1 H),7.04-7.32(m,1 H),7.61(br s,2 H)。MS(ESI,正離子)m/z 352[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.63-0.78(m,1 H),0.87-0.98(m,2 H),1.29(d,J=13.20Hz,4 H),1.25-1.36(m,1 H),1.37-1.51(m,1 H),1.61-1.77(m,1 H),1.84-1.96(m,1 H),2.05-2.49(m,6 H),2.99-3.13(m,1 H),3.81(s,3 H),4.13-4.35(m,1 H),4.62-4.77(m,1 H),7.17(d,J=8.40Hz,1 H),7.70(s,1 H),7.64-7.76(m,2 H)。MS(ESI,正離子)m/z 366[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.05-1.21(m,7 H),1.39-1.55(m,10 H),2.18-2.28(m,1 H),2.40-2.53(m,1 H),2.85-2.95(m,1 H),3.68-3.75(m,1 H),3.79(s,3 H),3.78-4.05(m,4 H),4.50-4.65(m,2 H),7.28-7.30(m,2 H),7.80(s,1 H),8.03(s,1 H)。MS(ESI,正離子)
m/z 483[M+H]+。
根據實例5-1步驟3中所概述之程序,藉由用三氟乙酸處理(S)-5-(1-(第三丁氧基羰基)氮雜環丁烷-3-基氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯於二氯甲烷中之溶液來製備(S)-5-(氮雜環丁烷-3-基氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(300MHz,CD3OD)δ ppm 1.01-1.15(m,7 H),1.40-1.58(m,1 H),2.15-2.25(m,1 H),2.35-2.50(m,1 H),2.80-2.92(m,1 H),3.40-3.59(m,2 H),3.60-3.81(m,6 H),4.43-4.62(m,2 H),7.21-7.32(m,2 H),7.75(s,1 H),7.95(s,1 H)。MS(ESI,正離子)m/z 383[M+H]+。
如上文針對實例1-58及1-59所概述,自(S)-3-((1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基)氧基)氮雜環丁烷-1-甲酸第三丁酯製備(S)-1-(5-(氮雜環丁烷-3-基氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮。1H NMR(400MHz,CD3OD)δ ppm 0.85-1.05(m,7 H),1.10-1.25(m,1 H),2.04(s,3 H),2.05-2.35(m,2 H),2.78-2.88(m,1 H),3.34-3.48(m,2 H),3.55-3.75
(m,3 H),4.35-4.45(m,1 H),4.55-4.65(m,1 H),6.85-7.05(m,1 H),7.25(d,J=8.40Hz,1 H),7.69(s,1 H),7.97(s,1 H)。MS(ESI,正離子)m/z 367[M+H]+。
MS(ESI,正離子)m/z 446[M+H]+。
MS(ESI,正離子)m/z 474[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.03-1.30(m,7 H),1.32-1.38(m,2 H),2.17(s,3 H),2.35-2.42(m,2 H),3.08-3.17(m,1 H),3.65-3.72(m,1 H),4.75-4.77(m,1 H),5.42-5.63(m,1 H),7.22-7.24(m,1 H),7.47-7.50(m,1 H),7.86(s,1 H),8.15(s,1 H)。MS(ESI,正離子)m/z 387[M+H]+。立體化學任意地指定。
1H NMR(300MHz,CD3OD)δ ppm 1.00-1.21(m,7 H),1.21-1.40(m,2 H),2.17(s,3 H),2.25-2.45(m,2 H),3.03-3.19(m,1 H),3.65-3.72(m,1 H),4.68-4.84(m,1 H),5.53(d,J=61.20Hz,1 H),7.15-7.25(m,1 H),7.49(d,J=8.40Hz,1 H),7.86(s,1 H),8.11(s,1 H)。MS(ESI,正離子)m/z 387[M+H]+。立體化學任意地指定。
1H NMR(300MHz,CD3OD)δ ppm 1.05-1.23(m,7 H),1.41-1.71(m,1 H),2.12-2.38(m,1 H),2.47-2.70(m,1 H),2.81-3.05(m,1 H),3.65-3.73(m,1 H),3.78(s,3 H),3.96-4.19(m,2 H),4.55-4.83(m,5 H),7.28-7.41(m,2 H),7.82(s,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 416[M+H]+。
1H NMR(400MHz,CDCl3)δ ppm 0.93-1.19(m,8 H),2.06(s,3 H),2.16-2.22(m,1 H),2.30-2.37(m,1 H),2.95-2.98(m,1 H),3.55-
3.61(m,1 H),4.61-4.77(m,1 H),7.18(s,1 H),7.41(d,J=8.00Hz,1 H),7.74(s,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 405[M+H]+。
1H NMR(300MHz,CDCl3)δ ppm 1.04-1.17(m,7 H),1.24-1.53(m,7 H),2.17(s,3 H),2.21-2.35(m,2 H),2.96-3.01(m,1 H),3.57-3.64(m,3 H),4.75-4.85(m,1 H),6.91-6.98(m,1 H),7.30-7.33(m,1 H),7.81(s,1 H),7.99(s,1 H)。MS(ESI,正離子)m/z 386[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.17(d,J=6.30Hz,3 H),1.25-1.50(m,2 H),1.55-1.67(m,1 H),2.05-2.21(m,8 H),2.22-2.29(m,1 H),2.35-2.49(m,1 H),2.91-3.01(m,1 H),3.52-3.66(m,2 H),3.77(s,3 H),4.05-4.21(m,3 H),4.42-4.61(m,2 H),7.25-7.36(m,2 H),7.84(s,1 H),8.07(s,1 H)。MS(ESI,正離子)m/z 426[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.62-0.71(m,1 H),0.85-1.03
(m,3 H),1.08-1.20(m,8 H),1.37-1.48(m,1 H),1.59-1.71(m,2 H),2.10-2.31(m,5 H),2.41-2.51(m,1 H),3.07-3.13(m,1 H),3.69-3.78(m,1 H),4.10-4.22(m,1 H),4.68-4.75(m,1 H),7.28(d,J=10.80Hz,1 H),7.90(s,1 H),8.12(s,1 H)。MS(ESI,正離子)m/z 410[M+H]+。
1H NMR(400MHz,DMSO-d 6 )δ ppm 0.55-0.89(m,4 H),0.99-1.18(m,4 H),1.26-1.35(m,1 H),1.48-1.61(m,2 H),1.99-2.41(m,6 H),2.90-3.01(m,1 H),4.09-4.13(m,1 H),4.55-4.65(m,1 H),7.43(d,J=10.80Hz,1 H),7.92-8.21(m,2 H)。MS(ESI,正離子)m/z 370[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.08-1.20(m,7 H),1.22-1.41(m,2 H),1.60-1.71(m,1 H),2.05-2.20(m,4 H),2.25-2.42(m,2 H),2.96-3.05(m,1 H),3.67-3.80(m,4 H),4.11-4.19(m,1 H),4.38-4.49(m,1 H),7.14(d,J=11.20Hz,1 H),7.85(s,1 H),8.06(s,1 H)。MS(ESI,正離子)m/z 400[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.17(d,J=6.30Hz,3 H),1.25-1.35(m,2 H),1.55-1.65(m,1 H),2.01-2.18(m,4 H),2.23-2.41(m,2 H),2.95-3.07(m,1 H),3.74(s,3 H),4.07-4.15(m,1 H),4.39-4.45(m,1 H),7.15(d,J=14.40Hz,1 H),8.00(s,2 H)。MS(ESI,正離子)m/z 360[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.10-1.18(m,8 H),1.35-1.45(m,1 H),1.59-1.70(m,1 H),1.95-2.25(m,8 H),2.42-2.51(m,1 H),3.05-3.11(m,1 H),3.70-3.78(m,1 H),4.15-4.20(m,1 H),4.70-4.80(m,1 H),7.29(d,J=11.20Hz,1 H),7.90(s,1 H),8.12(s,1 H)。MS(ESI,正離子)m/z 384[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.10-1.18(m,4 H),1.35-1.45(m,1 H),1.59-1.70(m,1 H),2.05-2.25(m,8 H),2.42-2.51(m,1 H),3.05-3.11(m,1 H),4.15-4.20(m,1 H),4.70-4.80(m,1 H),7.31(d,J=11.20Hz,1 H),8.05(br s,2 H)。MS(ESI,正離子)m/z 344
[M+H]+。
根據上文合成(S)-1-(6-(1-(2-羥乙基)-1H-吡唑-4-基)-2-甲基-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙酮(實例24)之步驟2中所述之程序,自(S)-1-(6-溴-5-環丁氧基-7,8-二氟-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮合成(S)-1-(5-環丁氧基-6-(1-環丙基-1H-吡唑-4-基)-7,8-二氟-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮。1H NMR(300MHz,CD3OD)δ ppm 1.11-1.18(m,9 H),1.56-1.68(m,1 H),1.98-2.47(m,9 H),2.94-3.08(m,1 H),3.70-3.81(m,1 H),4.09-4.20(m,1 H),4.73-4.81(m,1 H),7.86(s,1 H),8.12(s,1 H)。MS(ESI,正離子)m/z 402[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.21(m,6 H),1.48-1.68(m,1 H),2.18-2.28(m,1 H),2.48-2.63(m,1 H),2.83-2.99(m,1 H),3.65-3.99(m,9 H),4.55-4.68(m,1 H),7.25-7.35(m,2 H),7.81(s,1 H),8.01(s,1 H)。MS(ESI,正離子)m/z 397[M+H]+。
將(S)-1-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(0.025g,0.088mmol)、2-氯喹唑啉(0.017g,0.106mmol)及碳酸鉀(0.024g,0.176mmol)於N,N-二甲基甲醯胺(1.0mL)中之混合物在100℃下於微波中攪拌4小時。冷卻反應混合物至室溫,且添加水。用二氯甲烷萃取混合物,且用水及鹽水洗滌經合併之有機相,經無水硫酸鈉乾燥,過濾且濃縮,得到黃色油狀物。經由矽膠管柱層析(Biotage 10g管柱,以50-100%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到(S)-1-(6-溴-2-甲基-5-(喹唑啉-2-基氧基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.023g,63%)。MS(ESI,正離子)m/z 412,414[M+H]+。
將(S)-1-(6-溴-2-甲基-5-(喹唑啉-2-基氧基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.025g,0.061mmol)、1-環丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑(0.017g,0.073mmol)、氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)(XPhos第2代預催化劑)(2.4mg,0.003mmol)及碳酸銫(0.059g,0.182mmol)於1,4-二噁烷(2.0mL)及水(0.40mL)中之混合物在100℃下加熱2小時。經矽藻土過濾反應混合物且濃縮,得到橙色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以25-100%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈白色固體狀之(S)-1-(6-(1-環丙基-1H-吡唑-4-基)-2-甲基-
5-(喹唑啉-2-基氧基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.012g,45%)。MS(ESI,正離子)m/z 440。1H NMR(300MHz,DMSO-d 6)δ ppm 0.81-0.91(m,5 H),1.07(d,J=6.74Hz,3 H),1.47(m,1 H),2.03(br dd,J=13.34,6.89Hz,1 H),2.18(s,3 H),2.44(m,1 H),3.55-3.67(m,1 H),4.63(m,1 H),7.41(br s,1 H),7.51-7.70(m,3 H),7.72(s,1 H),7.91(ddd,J=8.50,7.04,1.47Hz,1 H),8.06(s,1 H),8.10(d,J=8.21Hz,1 H),9.54(s,1 H)。MS(ESI,正離子)m/z 440[M+H]+。
根據上文針對實例25所述之程序製得以下實例:
MS(ESI,正離子)m/z 429[M+H]+。
MS(ESI,正離子)m/z 445[M+H]+。
1H NMR(300MHz,DMSO-d 6)δ ppm 1.04(d,J=6.45Hz,3 H),1.42(m,1 H),1.93-2.10(m,1 H),2.16(s,3 H),2.28(m,1 H),2.40(br t,J=7.18Hz,1 H),3.64(q,J=5.47Hz,2 H),4.05(t,J=5.72Hz,2 H),4.64(m,1 H),4.83(t,J=5.28Hz,1 H),7.21(t,J=4.84Hz,1 H),7.38(br s,1 H),7.52(d,J=8.50Hz,1 H),7.70(s,1 H),7.94(s,1 H),8.60(d,J=4.69Hz,2 H)。MS(ESI,正離子)m/z 394[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.91-1.01(m,4 H),1.16(d,J=6.40Hz,3 H),1.35-1.55(m,1 H),2.05-2.35(m,4 H),2.37-2.55(m,1 H),2.70-2.85(m,1 H),3.51-3.59(m,1 H),4.70-4.85(m,1 H),7.11-7.18(m,1 H),7.20-7.35(m,1 H),7.53(d,J=8.40Hz,1 H),7.32(s,1 H),7.96(s,1 H),8.01-8.09(m,1 H),8.35-8.39(m,1 H)。MS(ESI,正離子)m/z 432[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.90-1.01(m,4 H),1.18(d,J=6.40Hz,3 H),1.35-1.52(m,1 H),2.15-2.45(m,5 H),2.60-2.72(m,1 H),3.52-3.59(m,1 H),4.73-4.85(m,1 H),7.25-7.35(m,1 H),7.57(d,
J=8.40Hz,1 H),7.78(s,1 H),7.99(s,1 H),8.19(s,1 H),9.05(s,1 H)。MS(ESI,正離子)m/z 430[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.98-1.05(m,4 H),1.15(d,J=6.60Hz,3 H),1.39-1.53(m,1 H),2.15-2.45(m,5 H),2.70-2.82(m,1 H),3.58-3.65(m,1 H),4.70-4.85(m,1 H),6.95(d,J=4.20Hz,1 H),7.18(d,J=4.20Hz,1 H),7.30-7.45(m,1 H),7.60(d,J=8.40Hz,1 H),7.79(s,1 H),7.99(s,1 H)。MS(ESI,正離子)m/z 395[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.95-1.02(m,4 H),1.15(d,J=6.60Hz,3 H),1.35-1.52(m,1 H),2.15-2.38(m,5 H),2.51-2.63(m,1 H),3.53-3.63(m,1 H),4.70-4.85(m,1 H),7.15-7.19(m,1 H),7.25-7.35(m,1 H),7.51(d,J=8.40Hz,1 H),7.70(s,1 H),7.92(s,1 H),8.15-8.25(m,2 H)。MS(ESI,正離子)m/z 414[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.95-1.05(m,4 H),1.16(d,J=6.60Hz,3 H),1.40-1.58(m,1 H),2.15-2.45(m,5 H),2.55-2.65(m,1 H),3.55-3.65(m,1 H),4.70-4.85(m,1 H),7.25-7.35(m,1 H),7.53-7.60(m,2 H),7.76(s,1 H),7.99(s,1 H),8.85(d,J=5.10Hz,1 H)。MS(ESI,正離子)m/z 458[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.89-1.01(m,4 H),1.05-1.15(m,3 H),1.20-1.45(m,1 H),1.95-2.25(m,5 H),2.75-2.89(m,1 H),3.49-3.60(m,1 H),4.70-4.85(m,1 H),7.11-7.19(m,1 H),7.20-7.35(m,1 H),7.54(d,J=8.40Hz,1 H),7.68(s,1 H),7.84(s,1 H),8.09-8.19(m,2 H)。MS(ESI,正離子)m/z 457[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.95-1.05(m,4 H),1.16(d,J=6.60Hz,3 H),1.35-1.60(m,1 H),2.10-2.30(m,5 H),2.50-2.63(m,1 H),3.55-3.60(m,1 H),4.70-4.89(m,1 H),6.95-7.09(m,1 H),7.25-
7.35(m,1 H),7.54(d,J=8.40Hz,1 H),7.78(s,1 H),7.82-7.89(m,1 H),7.91-7.99(m,2 H)。MS(ESI,正離子)m/z 423[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.95-1.01(m,4 H),1.14(d,J=5.40Hz,3 H),1.30-1.48(m,1 H),2.10-2.40(m,5 H),2.55-2.68(m,1 H),3.50-3.65(m,1 H),4.68-4.85(m,1 H),7.20-7.35(m,1 H),7.52(d,J=8.40Hz,1 H),7.69(s,1 H),7.92(s,1 H),7.99-8.03(m,1 H),8.22(d,J=2.70Hz,1 H),8.50(d,J=1.20Hz,1 H)。MS(ESI,正離子)m/z 390[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.95-1.05(m,4 H),1.16(d,J=6.60Hz,3 H),1.32-1.50(m,1 H),2.10-2.32(m,5 H),2.55-2.72(m,1 H),3.55-3.65(m,1 H),4.72-4.90(m,1 H),6.94(d,J=8.10Hz,1 H),7.02-7.10(m,1 H),7.32(br s,1 H),7.58(d,J=8.40Hz,1 H),7.74(s,1 H),7.75-7.85(m,1 H),7.93(s,1 H),8.05-8.09(m,1 H)。MS(ESI,正離子)m/z 389[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.95-1.01(m,4 H),1.14(d,J=6.30Hz,3 H),1.30-1.49(m,1 H),2.10-2.35(m,11 H),2.52-2.65(m,1 H),3.55-3.65(m,1 H),4.70-4.85(m,1 H),6.93(s,1 H),7.20-7.35(m,1 H),7.54(d,J=8.10Hz,1 H),7.75(s,1 H),7.96(s,1 H)。MS(ESI,正離子)m/z 418[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.95-1.01(m,4 H),1.15(d,J=6.60Hz,3 H),1.45(br s,1 H),2.15-2.32(m,5 H),2.55-2.72(m,1 H),3.52-3.69(m,1 H),4.75-4.90(m,1 H),7.39(br s,1 H),7.54(d,J=8.10Hz,1 H),7.62-7.69(m,2 H),7.92(s,1 H),8.12(d,J=9.30Hz,1 H)。MS(ESI,正離子)m/z 415[M+H]+。
1H NMR(400MHz,CDCl3)δ ppm 0.90-0.92(m,4 H),1.04(d,J=6.40Hz,3 H),1.35(m,1 H),2.07-2.14(m,8 H),2.49-2.55(m,1 H),
3.45-3.51(m,1 H),4.68(m,1 H),7.19(m,1 H),7.44(d,J=8.40Hz,1 H),7.64(s,1 H),7.84(s,1 H),8.27(d,J=4.80Hz,2 H)。MS(ESI,正離子)m/z 404[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.02(s,4 H),1.15(s,3 H),1.49(s,1 H),2.19-2.38(m,5 H),2.52-2.63(m,1 H),3.55-3.63(m,1 H),4.76-4.82(m,1 H),7.29-7.49(m,2 H),7.56(d,J=8.40Hz,1 H),7.70(s,1 H),7.94(s,1 H),8.78(s,1 H)。MS(ESI,正離子)m/z 458[M+H]+。
根據上文針對實例25所述之程序製得以下實例,作出以下改變:(1)在步驟2中,使用4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯替代1-環丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑;(2)根據下文實例27之步驟3中所述之程序移除Boc基團。
1H NMR(300MHz,CD3OD)δ ppm 0.73-0.82(m,1 H),0.91-1.02(m,2 H),1.12-1.21(m,4 H),1.45-1.53(m,1 H),1.85-2.00(m,2 H),2.00(s,3 H),2.22-2.41(m,2 H),2.63-2.71(m,1 H),2.72-2.82(m,2
H),3.16-3.24(m,2 H),4.22-4.31(m,1 H),4.71-4.85(m,1 H),6.87(d,J=8.10Hz,1 H),7.07(d,J=7.50Hz,1 H),7.39(d,J=8.40Hz,1 H),7.57(d,J=8.40Hz,1 H),7.73-7.77(m,2 H),7.96(s,1 H)。MS(ESI,正離子)m/z 492[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.73-0.82(m,1 H),0.89-1.01(m,2 H),1.12-1.24(m,4 H),1.41-1.51(m,1 H),2.05-2.37(m,7 H),2.62-2.71(m,1 H),3.14-3.22(m,2 H),3.50-3.64(m,2 H),4.45-4.55(m,1 H),4.78-4.85(m,1 H),6.92(d,J=8.40Hz,1 H),7.04-7.09(m,1 H),7.39(d,J=8.40Hz,1 H),7.59(d,J=8.40Hz,1 H),7.77-7.81(m,2 H),7.96(s,1 H),8.05(t,J=3.60Hz,1 H)。MS(ESI,正離子)m/z 458[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.16(d,J=6.90Hz,3 H),1.25-1.33(m,1 H),1.54-1.64(m,1 H),1.73-1.90(m,2 H),1.95-2.15(m,3 H),2.40-2.50(m,1 H),2.53-2.76(m,3 H),3.09-3.16(m,2 H),3.81(s,3 H),4.15-4.24(m,1 H),4.60-4.71(m,1 H),6.83(d,J=8.40Hz,1 H),7.01-7.09(m,1 H),7.47-7.61(m,2 H),7.70-7.80(m,2 H),7.89(s,1
H),8.06(m,1 H)。MS(ESI,正離子)m/z 448[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.67-0.74(m,1 H),0.81-0.92(m,2 H),1.02-1.08(m,4 H),1.42-1.49(m,1 H),1.62-1.71(m,2 H),1.82-1.95(m,3 H),2.05-2.16(m,1 H),2.05-2.16(m,1 H),2.27-2.34(m,1 H),2.46-2.58(m,3 H),2.95-3.05(m,2 H),4.05-4.16(m,1 H),4.66-4.74(m,1 H),6.78-6.81(m,1 H),6.95-7.00(m,1 H),7.33-7.37(m,1 H),7.66(s,1 H),7.96-8.05(m,2 H)。MS(ESI,正離子)m/z 476[M+H]+。
將(S)-環丙基(5-(6-氟吡啶-2-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.024g,0.05mmol)及甲醇鈉(0.015g,0.28mmol)於N,N-二甲基甲醯胺(1mL)中之混合物在80℃下攪拌隔夜。冷卻反應混合物至室溫,用乙酸乙酯(15mL)稀釋,用鹽水(2×5mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。藉由製備型HPLC使用以下條件(Waters I)純化殘餘物:管柱,SunFirePrep C18,5μm,19×100mm;移動相,水(0.05%碳酸氫銨)
及乙腈(在10分鐘內16%至34%乙腈,流動速率:20mL/min);偵測器,UV 220及254nm。此得到呈白色固體狀之(S)-環丙基(5-(6-甲氧基吡啶-2-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.0033g,13%)。1H NMR(400MHz,CD3OD)δ ppm 0.79-0.87(m,1 H),0.91-1.00(m,2 H),1.10-1.18(m,4 H),1.39-1.49(m,1 H),1.79-1.84(m,2 H),1.97-2.09(m,3 H),2.18-2.41(m,2 H),2.62-2.79(m,3 H),3.12-3.19(m,2 H),3.62(s,3 H),4.15-4.27(m,1 H),4.72-4.89(m,1 H),6.41(t,J=8.00Hz,2 H),7.36(d,J=8.40Hz,1 H),7.55-7.65(m,2 H),7.79(s,1 H),7.96(s,1 H)。MS(ESI,正離子)m/z 488[M+H]+。
向250-mL圓底燒瓶中饋入(2S)-6-溴-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-5-醇(2.00g,6.45mmol)、溴環丁烷(1.81mL,2.60g,19.3mmol)、碳酸銫(6.3g,19.34mmol)及乙腈(100mL)。在80℃
下攪拌所得混合物6小時。經矽藻土襯墊過濾反應混合物,且在真空下濃縮。經由矽膠管柱層析(以0-10%乙酸乙酯-石油醚進行梯度洗提)純化殘餘物,得到呈無色油狀之(2S)-6-溴-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉(2.00g,85%)。MS(ES,m/z):364,366[M+H]+。
用惰性氮氣氛圍淨化並維持250-mL圓底燒瓶,且饋入(2S)-6-溴-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉(2.0g,5.5mmol)、4-[4-(四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基]哌啶-1-甲酸第三丁酯(2.5g,6.63mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.45g,0.55mmol)、碳酸鉀(2.3g,16.64mmol)、1,4-二噁烷(50mL)及水(5mL)。在100℃下攪拌所得混合物隔夜。冷卻反應混合物至室溫,接著經矽藻土襯墊過濾。濃縮濾液,且經由矽膠管柱層析(以0-30%乙酸乙酯-石油醚進行梯度洗提)純化殘餘物,得到呈淡黃色固體狀之(S)-4-(4-(5-環丁氧基-1-(環丙烷羰基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(2.2g,75%)。MS(ES,m/z):535[M+H]+
將三氟乙酸(0.5mL,6.49mmol)添加至(S)-4-(4-(5-環丁氧基-1-(環丙烷羰基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌哌-1-甲酸第三丁酯(0.032g,0.060mmol)於二氯甲烷(2.0mL)中之0℃溶液中。移除冰浴,且在室溫下攪拌混合物1.5小時。濃縮反應混合物,且將殘餘物分配於二氯甲烷與飽和碳酸氫鈉水溶液之間。分離各層,且用鹽水洗滌有機相,經無水硫酸鈉乾燥,過濾且濃縮,得到呈灰白
色固體狀之(S)-(5-環丁氧基-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.022g,85%)。1H NMR(300MHz,氯仿-d)δ ppm 0.57-0.71(m,1 H),0.78-0.91(m,1 H),0.92-1.04(m,1 H),1.13(d,J=6.45Hz,3 H),1.19-1.45(m,3 H),1.53-1.71(m,2 H),1.79-2.42(m,11 H),2.74-2.92(m,2 H),2.94-3.09(m,1 H),3.30(br d,J=12.61Hz,2 H),4.04-4.21(m,1 H),4.28(ddt,J=11.43,7.62,3.96,3.96Hz,1 H),4.66-4.84(m,1 H),7.12(d,J=8.21Hz,1 H),7.28(d,J=8.21Hz,1 H),7.81(s,1 H),7.88(s,1 H)。MS(ESI,正離子)m/z 435[M+H]+。
根據針對實例27所概述之程序製得以下實例:
1H NMR(300MHz,CD3OD)δ ppm 0.65-0.778(m,1 H),0.85-0.99(m,2 H),1.01-1.19(m,7 H),1.25-1.42(m,1 H),1.70-1.82(m,2 H),1.85-2.05(m,3 H),2.10-2.21(m,2 H),2.30-2.49(m,2 H),2.75-2.89(m,2 H),2.95-3.07(m,1 H),3.17-3.20(m,2 H),3.58-3.72(m,2 H),4.28-4.42(m,1 H),4.70-4.83(m,1 H),7.19(d,J=8.10Hz,1 H),7.44(d,J=8.10Hz,1 H),7.93(s,1 H),8.12(s,1 H)。MS(ESI,正離子)m/z 423[M+H]+
1H NMR(300MHz,CD3OD)0.65-0.75(m,1 H),0.85-0.95(m,2 H),1.05-1.15(m,4 H),1.20-1.40(m,2 H),1.50-1.70(m,1 H),1.80-1.95(m,1 H),2.01-2.45(m,6 H),2.95-3.05(m,1 H),3.92-4.01(m,2 H),4.10-4.25(m,3 H),4.65-4.75(m,1 H),5.25-5.40(m,1 H),7.15(d,J=8.10Hz,1 H),7.40(d,J=8.70Hz,1 H),7.96(s,1 H),8.14(s,1 H)。MS(ESI,正離子)m/z 407[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.60-0.75(m,1 H),0.85-0.95(m,2 H),1.00-1.08(m,3 H),1.10-1.18(m,4 H),1.25-1.38(m,1 H),1.70-1.80(m,2 H),1.85-1.95(m,1 H),2.30-2.45(m,2 H),2.90-3.05(m,1 H),3.55-2.75(m,2 H),3.95-4.05(m,2 H),4.15-4.25(m,2 H),4.65-4.75(m,1 H),5.28-5.38(m,1 H),7.17(d,J=8.40Hz,1 H),7.43(d,J=8.40Hz,1 H),8.00(s,1 H),8.15(s,1 H)。MS(ESI,正離子)m/z 395[M+H]+。
1H NMR(400MHz,DMSO-d6)δ ppm 0.56-0.90(m,4 H),0.99-1.17(m,4 H),1.25-1.34(m,1 H),1.47-1.59(m,2 H),1.74-1.81(m,2 H),1.95-2.28(m,7 H),2.31-2.41(m,1 H),2.55-2.61(m,2 H),2.85-2.93(m,1 H),3.02-3.09(m,2 H),4.05-4.24(m,2 H),4.56-4.67(m,1 H),7.42(d,J=10.0Hz,1 H),7.90(s,1 H),8.18(s,1 H)。MS(ESI,正離子)m/z 453[M+H]+。
在80℃下加熱(S)-1-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(0.150g,0.528mmol)、1-溴丙烷(0.240mL,2.64mmol)及第三丁醇鉀(0.296g,2.64mmol)於DMF(3.0mL)中之混合物。24小時後,再添加1-溴丙烷(0.240mL,2.64mmol),且在70℃下攪拌混合物16小時。反應未完成,因此添加1-溴丙烷(0.240mL,2.64mmol)及第三丁醇鉀(0.296g,2.64mmol),且在100℃下攪拌混合物。24小時後,冷
卻反應混合物至室溫,且添加水。用二氯甲烷萃取混合物,且用水及鹽水洗滌經合併之有機相,經無水硫酸鈉乾燥,過濾且濃縮,得到黃色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以50-100%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈無色油狀之(S)-1-(6-溴-2-甲基-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙酮(0.100g,58%)。MS(ESI,正離子)m/z 326,328[M+H]+
將(S)-1-(6-溴-2-甲基-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙酮(0.050g,0.153mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(0.058g,0.153mmol)、氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)(XPhos第2代預催化劑)(0.012g,0.015mmol)及碳酸銫(0.150g,0.460mmol)於1,4-二噁烷(2.0mL)及水(0.40mL)中之混合物在100℃下於微波中加熱2.5小時。經矽藻土過濾反應混合物且濃縮,得到橙色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以50-100%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈灰白色固體狀之(S)-4-(4-(1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(0.063g,83%)。MS(ESI,正離子)m/z 497[M+H]+
將三氟乙酸(0.5mL,6.49mmol)添加至(S)-4-(4-(1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(0.063g,0.127mmol)於二氯甲烷(2.0mL)中之溶液中,且在室溫下攪拌反應混合物1.5小時。濃縮反應混合物,且將殘餘物分配於二氯甲烷與飽和碳酸氫鈉水溶液之間。分離有機相,經無水硫酸鈉乾
燥,過濾且濃縮,得到呈褐色固體狀之(S)-1-(2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙酮(0.045g,89%)。1H NMR(300MHz,DMSO-d 6)δ ppm 0.91-1.12(m,6 H),1.18-1.37(m,1 H),1.57-1.88(m,5 H),1.97(br d,J=10.26Hz,2 H),2.07(s,3 H),2.16-2.40(m,2 H),2.53-2.66(m,2 H),2.73-2.89(m,1 H),3.03(br d,J=12.61Hz,2 H),3.46-3.65(m,2 H),4.09-4.30(m,1 H),4.62(br d,J=5.86Hz,1 H),7.11(br d,J=8.21Hz,1 H),7.38(d,J=8.21Hz,1 H),7.84(s,1 H),8.09(s,1 H)。MS(ESI,正離子)m/z 397[M+H]+。
根據針對實例28所概述之程序製得以下實例:
1H NMR(400MHz,CD3OD)δ ppm 0.93-1.17(m,4 H),1.27-1.41(m,1 H),1.55-1.68(m,1 H),1.92-2.48(m,13 H),2.70-2.83(m,2 H),3.02-3.10(m,1 H),3.10-3.22(m,2 H),4.05-4.18(m,1 H),4.25-4.43(m,1 H),4.70-4.88(m,1 H),7.15-7.35(m,1 H),7.90(s,1 H),8.13(s,1 H)。MS(ESI,正離子)m/z 427[M+H]+。
根據上文合成(S)-1-(2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-丙
氧基-3,4-二氫喹啉-1(2H)-基)乙酮(實例4-1)之步驟2及3中所述之程序,自(S)-1-(6-溴-5-環丁氧基-7,8-二氟-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮合成(S)-1-(5-環丁氧基-7,8-二氟-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-基)乙酮。1H NMR(300MHz,CD3OD)δ ppm 1.12-1.28(m,4 H),1.30-1.41(m,1 H),1.56-1.68(m,1 H),1.98-2.20(m,11 H),2.32-2.49(m,2 H),2.75-2.88(m,2 H),2.99-3.10(m,1 H),3.21-3.25(m,2 H),4.17-4.20(m,1 H),4.35-4.45(m,1 H),4.75-4.82(m,1 H),7.91(s,1 H),8.12(s,1 H)。MS(ESI,正離子)m/z 445[M+H]+。
在100℃下於密封管中加熱(S)-6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.110g,0.366mmol)、1-溴丙烷(0.166mL,1.832mmol)及第三丁醇鉀(0.103g,0.916mmol)於DMF(3.0mL)中之混合物。24小時後,再添加1-溴丙烷(0.166mL,1.832mmol)及第三丁醇鉀(0.103g,0.916mmol),且在100℃下於密封管中加熱混合物24小時。冷卻反應混合物至室溫,且添加水。用二氯甲烷萃取混合物,且用水及鹽水洗滌經合併之有機相,經無水硫酸鈉乾燥,過濾且濃縮,
得到黃色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以0-25%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈無色油狀之(S)-6-溴-2-甲基-5-丙氧基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.120g,96%)。MS(ESI,正離子)m/z 342,344[M+H]+。
將(S)-6-溴-2-甲基-5-丙氧基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.060g,0.175mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(0.066g,0.175mmol)、氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)(XPhos第2代預催化劑)(0.014g,0.018mmol)及碳酸銫(0.171g,0.526mmol)於1,4-二噁烷(2.0mL)及水(0.40mL)中之混合物在100℃下於微波中加熱5小時。經矽藻土過濾反應混合物且濃縮,得到橙色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以0-50%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈無色油狀之(S)-6-(1-(1-(第三丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)-2-甲基-5-丙氧基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.090g,100%)。MS(ESI,正離子)m/z 513[M+H]+。
將三氟乙酸(0.5mL,6.49mmol)添加至(S)-6-(1-(1-(第三丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)-2-甲基-5-丙氧基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.090g,0.176mmol)於二氯甲烷(2.0mL)中之溶液中,且在室溫下攪拌反應混合物1小時。濃縮反應混合物,且將殘餘物分配於二氯甲烷與飽和碳酸氫鈉水溶液之間。分離有機相,經無水硫酸鈉乾燥,過濾且濃縮,得到呈灰白色固體狀之(S)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-5-丙氧基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.070g,
97%)。1H NMR(300MHz,DMSO-d 6)δ ppm 0.97(t,J=7.48Hz,3 H),1.05-1.13(m,3 H),1.48(dq,J=13.05,6.50Hz,1 H),1.63-1.87(m,5 H),1.88-2.03(m,2 H),2.05-2.19(m,2 H),2.53-2.66(m,2 H),2.72-2.90(m,1 H),3.04(br d,J=12.61Hz,2 H),3.54(br t,J=6.60Hz,2 H),3.67(s,3 H),4.11-4.32(m,1 H),4.37-4.57(m,1 H),7.21-7.31(m,1 H),7.31-7.40(m,1 H),7.81(s,1 H),8.06(s,1 H)。MS(ESI,正離子)m/z 413[M+H]+。MS(ESI,正離子)m/z 413[M+H]+。
向100-mL圓底燒瓶中饋入(2S)-6-溴-5-羥基-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(600mg,2.00mmol)、溴環丁烷(807mg,5.98mmo1)、乙腈(30mL)及碳酸銫(1.96g,6.00mmol)。在80℃下於油浴中攪拌混合物6小時。冷卻至室溫後,將反應混合物傾倒至10mL水中,且分離各層。用乙酸乙酯(3×15mL)萃取水層。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由矽膠管柱層析(以8:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈無色油狀之(S)-6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.67g,95%)。MS(ESI,正離子)m/z 354,356[M+H]+。
根據上文實例29之步驟2及3中所概述之程序,自(S)-6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸酯及3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)吡咯啶-1-甲酸第三丁酯合成(2S)-5-環丁氧基-2-甲基-6-(1-(吡咯啶-3-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(400MHz,CD3OD)δ ppm 1.17(d,J=6.40Hz,3 H),1.25-1.65(m,3 H),1.98-2.30(m,6 H),2.31-2.45(m,2 H),2.85-3.08(m,2 H),3.20-3.35(m,3 H),3.79(s,3 H),4.10-4.15(m,1 H),4.49-4.55(m,1 H),4.90-5.05(m,1 H),7.20-7.32(m,2 H),7.86(s,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 411[M+H]+。
根據針對實例30所概述之程序製得以下實例:
1H NMR(300MHz,CD3OD)δ ppm 1.17(d,J=6.30Hz,3 H),1.20-1.52(m,2 H),1.55-1.75(m,1 H),1.95-2.30(m,7 H),2.35-2.50(m,3 H),2.85-3.00(m,1 H),3.05-3.20(m,4 H),3.50-3.62(m,2 H),3.77(s,1 H),4.05-4.15(m,1 H),4.45-4.55(m,1 H),4.85-5.00(m,1 H),7.20-7.30(m,2 H),7.85(s,1 H),8.01(s,1 H)。MS(ESI,正離子)m/z 451[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.14(d,J=6.60Hz,3 H),1.21-1.38(m,2 H),1.55-1.61(m,1 H),1.90-2.16(m,8 H),2.35-2.40(m,2 H),2.71-2.79(m,2 H),2.95-3.15(m,1 H),3.15-3.22(m,2 H),3.71(s,3 H),4.05-4.16(m,1 H),4.25-4.43(m,2 H),7.11(d,J=11.40Hz,1 H),7.83(s,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 443[M+H]+。
將外消旋-6-溴-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉(0.022g,0.069mmol)於二氯甲烷(1mL)及吡啶(0.017mL,0.207mmol)中之溶液冷卻至0℃,且用乙醯氯(5.41μL,0.076mmol)處理。接著在室溫下攪拌反應混合物。10分鐘後,再添加乙醯氯(3.93μL,0.055mmol),且在室溫下繼續攪拌。75分鐘後,用二氯甲烷稀釋反應混合物,且用1N鹽酸水溶液(2×0.5mL)及5%氯化鈉水溶液(0.5mL)洗滌。濃縮二氯甲烷層,得到呈幾乎無色膠狀之粗外消旋-1-(6-溴-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)乙酮(0.024g,96%),其在靜置時凝固。粗產物未經進一步純化即使用。MS(ESI,正離子)m/z 360,362[M+H]+。
向配備有磁性攪拌棒之螺旋蓋小瓶中饋入外消旋-1-(6-溴-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)乙酮(0.024g,0.067mmol)、4-(甲
基磺醯基)苯基硼酸(0.020g,0.100mmol)、1,4-二噁烷(0.67mL)、1.0M碳酸氫鈉水溶液(0.200mL,0.200mmol)及氯化雙(三苯基膦)鈀(II)(4.7mg,6.7μmol)。用氮氣吹洗小瓶,接著封蓋。接著加熱反應混合物至80℃維持3小時,接著冷卻至室溫。用5%氯化鈉水溶液(0.5mL)及乙酸乙酯稀釋反應混合物。分離各層,且用乙酸乙酯萃取水層。在減壓下濃縮經合併之萃取物,得到深棕色殘餘物,接著藉由製備型薄層層析(1×1000微米板;以3:2乙酸乙酯-己烷洗提)純化。分離主要色帶(26mg)且藉由製備型HPLC進一步純化,得到外消旋-1-(2-甲基-6-(4-(甲基磺醯基)苯基)-5-苯氧基-3,4-二氫喹啉-1(2H)-基)乙酮。1H NMR(400MHz,CDCl3)δ ppm 1.17(d,J=6.60Hz,3 H),1.45(br s,1 H),2.07-2.24(m,1 H),2.27(s,3 H),2.29-2.37(m,1 H),2.71(dt,J=16.13,6.42Hz,1 H),3.01(s,3 H),4.79(br s,1 H),6.59-6.69(m,2 H),6.82-6.95(m,1 H),7.15(t,J=7.70Hz,2 H),7.32(br d,J=7.33Hz,2 H),7.65(d,J=8.43Hz,2 H),7.84(d,J=8.43Hz,2 H)。MS(ESI,正離子)m/z 436[M+H]+。
向配備有磁性攪拌棒之玻璃螺旋蓋小瓶中饋入外消旋-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉(0.050g,0.21mmol)於二氯甲烷(1mL)及吡啶(0.051mL,0.630mmol)中之溶液。冷卻溶液至0℃,且添加乙醯氯(0.015mL,0.210mmol)。移除冰浴,且在室溫下攪拌反應混合物。10分鐘後,用二氯甲烷稀釋反應混合物,且用1N鹽酸水溶液(2×1
mL)、繼而用5%氯化鈉水溶液(1mL)洗滌。將有機層濃縮成黃色油狀物,其在靜置時結晶。藉由製備型薄層層析(1×1000微米板,以2:1己烷-乙酸乙酯洗提)純化粗產物,得到呈幾乎無色油狀之1-(2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)乙酮(0.0189g,32%)。1H NMR(400MHz,CDCl3)δ ppm 1.13(d,J=6.60Hz,3 H),1.36-1.55(m,1 H),2.11-2.27(m,4 H),2.36(br s,1 H),2.85(dt,J=16.04,6.09Hz,1 H),4.88(br s,1 H),6.76(d,J=8.80Hz,1 H),6.89-6.96(m,2 H),6.96-7.04(m,1 H),7.04-7.11(m,1 H),7.12-7.19(m,1 H),7.29-7.37(m,2 H)。MS(ESI,正離子)m/z 282[M+H]+。
將(S)-1-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(17.05mg,0.06mmol)於DMP(500μL)中之溶液添加至配備有磁性攪拌棒之微波反應小瓶中。接著添加溴環丙烷(150μL,1.87mmol)、碘化鈉(8.99mg,0.060mmol)及碳酸銫(98mg,0.300mmol),且密封反應物。在180℃下於微波中加熱反應物6小時。用乙酸乙酯稀釋混合物,且用鹽水洗滌。經無水硫酸鈉乾燥有機層,過濾且濃縮,得到(S)-1-(6-溴-5-環丙氧基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(0.019g,100%),其未經進一步純化即使用。MS(ESI,正離子)m/z 324,326[M+H]+。
向1.5mL反應小瓶中饋入(S)-1-(6-溴-5-環丙氧基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(0.019g,0.06mmol)及1,4-二噁烷(50μL)。添加1-環丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑(0.2M溶液,於1,4-二噁烷中,540μL,0.108mmol)及碳酸鉀(1M溶液,於水中,180μL,0.18mmol),且用氮氣淨化反應混合物。添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.02M溶液,於1,2-二氯乙烷中,300μL,0.006mmol),且用氮氣淨化反應物,且在加熱震盪器上加熱至80℃隔夜。用乙酸乙酯稀釋反應物,且用1N氫氧化鈉水溶液洗滌。分離水層且用乙酸乙酯洗滌,且在氮氣流下濃縮經合併之有機層。藉由質量觸發式製備型HPLC純化粗產物。合併含產物之洗提份且在Genevac中濃縮,得到(S)-1-(5-環丙氧基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(0.0039g,19%)。MS(ESI,正離子)m/z 352[M+H]+。
在80℃下加熱(S)-1-(6-溴-2-甲基-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙酮(0.127g,0.389mmol)、雙(頻哪醇根基)二硼(0.109g,0.428mmol)、乙酸鉀(0.096g,0.973mmol)及[1,1'-雙(二苯基膦基)二茂鐵]
二氯鈀(II)與二氯甲烷之複合物(0.028g,0.039mmol)於1,4-二噁烷(3.0mL)中之混合物。24小時後,添加更多份[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(0.028g,0.039mmol)、雙(頻哪醇根基)二硼(0.109g,0.428mmol)及乙酸鉀(0.096g,0.973mmol),且在100℃下加熱混合物4小時。冷卻反應混合物至室溫且經矽藻土過濾,得到深棕色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以25-50%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈無色油狀之(S)-1-(2-甲基-5-丙氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.110g,76%)。MS(ESI,正離子)m/z 374[M+H]+。
將(S)-1-(2-甲基-5-丙氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.055g,0.147mmol)、2-溴-5-(甲基磺醯基)吡啶(0.037g,0.155mmol)、XPhos第2代預催化劑(0.012g,0.015mmol)及碳酸銫(0.144g,0.442mmol)於1,4-二噁烷(2.0mL)及水(0.40mL)中之混合物在100℃下於微波中加熱1.5小時。經矽藻土過濾反應混合物且濃縮,得到橙色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以25-100%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈褐色固體狀之(S)-1-(2-甲基-6-(5-(甲基磺醯基)吡啶-2-基)-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙酮(0.016g,27%)。1H NMR(300MHz,DMSO-d 6)δ ppm 0.85(t,J=7.33Hz,3 H),1.07(d,J=6.45Hz,3 H),1.32-1.50(m,2 H),1.56(dt,J=14.07,7.04Hz,2 H),2.14(s,3 H),2.19-2.33(m,1 H),2.79-2.94(m,1 H),3.37(s,3 H),3.50(td,J=6.30,2.64Hz,2 H),4.51-4.75(m,1 H),7.33(br d,J=8.50Hz,1 H),7.64(d,J=8.50Hz,1 H),8.08-8.21(m,1 H),8.36(dd,J=8.50,2.35
Hz,1 H),9.14(d,J=2.05Hz,1 H)。MS(ESI,正離子)m/z 403[M+H]+。
將N,N-二異丙基乙胺(0.992mL,5.68mmol)添加至6-碘吡啶-3-胺(0.500g,2.273mmol)及甲烷磺醯氯(0.186mL,2.386mmol)於1,2-二氯乙烷(10.0mL)中之溶液中,且在50℃下攪拌混合物2.5小時。濃縮反應混合物,得到棕色油狀物,將其溶解於1,4-二噁烷(5.0mL)及水(1.0mL)中。添加氫氧化鉀(0.128g,2.273mmol),且在80℃下攪拌混合物4小時。冷卻反應混合物至室溫,接著分配於二氯甲烷與水之間。分離水相,且用二氯甲烷萃取。用鹽水洗滌經合併之有機相,經無水硫酸鈉乾燥,過濾且濃縮,得到棕色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以0-50%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈褐色固體狀之N-(6-碘吡啶-3-基)甲烷磺醯胺(0.537g,79%)。MS(ESI,正離子)m/z 299[M+H]+。
將(S)-1-(2-甲基-5-丙氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.055g,0.147mmol)、N-(6-碘吡啶-3-基)甲烷磺醯胺(0.046g,0.155mmol)、XPhos第2代預催化劑(0.012
g,0.015mmol)及碳酸銫(0.144g,0.442mmol)於1,4-二噁烷(2.0mL)及水(0.40mL)中之混合物在100℃下於微波中加熱1.5小時。經矽藻土過濾反應混合物且濃縮,得到橙色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以25-100%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈灰白色固體狀之(S)-N-(6-(1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基)吡啶-3-基)甲烷磺醯胺(0.007g,11%)。1H NMR(300MHz,CDCl3)δ ppm 0.79-0.85(m,3 H),1.08(d,J=6.45Hz,3 H),1.17-1.55(m,3 H),2.12(s,3 H),2.20-2.41(m,2 H),2.82-3.01(m,1 H),3.04(s,3 H),3.28-3.59(m,2 H),4.76(br s,1 H),6.64-6.86(m,1 H),6.98(br s,1 H),7.52(d,J=8.21Hz,1 H),7.68(dd,J=8.79,2.64Hz,1 H),7.87(d,J=8.50Hz,1 H),8.47(d,J=2.64Hz,1 H)。MS(ESI,正離子)m/z 418[M+H]+。
根據針對實例34所概述之程序製得以下實例:
1H NMR(300MHz,CDCl3)δ ppm 1.09(d,J=6.74Hz,3 H),2.07-2.20(m,3 H),2.20-2.42(m,2 H),2.73(s,3 H),2.83-2.94(m,3 H),2.94-3.07(m,1 H),3.11(s,3 H),4.03(dt,J=19.35,6.89Hz,1 H),4.20-4.30(m,2 H),4.61-4.82(m,1 H),7.00-7.17(m,1 H),7.63(d,J=8.50Hz,1 H),8.15-8.20(m,2 H),9.06-9.22(m,1 H)。MS(ESI,正離子)m/z 446[M+H]+。
1H NMR(300MHz,DMSO-d 6)δ ppm 1.01(t,J=7.48Hz,3 H),1.08(d,J=6.45Hz,3 H),1.38-1.58(m,2 H),1.79(dq,J=14.14,7.01Hz,2 H),2.17(s,3 H),2.20-2.32(m,1 H),2.77-3.01(m,1 H),3.84(t,J=6.30Hz,2 H),4.52-4.74(m,1 H),7.36-7.45(m,3 H),7.71-7.85(m,2 H),7.92(d,J=8.50Hz,1 H)。MS(ESI,正離子)m/z 365[M+H]+。
1H NMR(300MHz,DMSO-d 6)δ ppm 0.73(t,J=7.33Hz,3 H),1.03-1.10(m,6 H),1.32-1.51(m,3 H),2.12(s,3 H),2.20-2.45(m,2 H),2.89(dt,J=15.32,5.09Hz,1 H),3.36-3.43(m,1 H),3.94(s,1 H),4.55-4.72(m,1 H),6.93(t,J=6.89Hz,1 H),7.18-7.30(m,2 H),7.33(d,J=8.21Hz,1 H),7.73(d,J=8.79Hz,1 H),8.24(s,1 H),8.71(dd,J=7.04,0.88Hz,1 H)。MS(ESI,正離子)m/z 364[M+H]+。
1H NMR(300MHz,DMSO-d 6)δ ppm 0.98-1.08(m,6 H),1.21-
1.56(m,1 H),1.78-1.96(m,2 H),2.10(s,3 H),2.21-2.44(m,2 H),2.79-3.00(m,1 H),3.60-3.78(m,2 H),4.44-4.76(m,1 H),6.88(t,J=6.74Hz,1 H),7.16-7.30(m,2 H),7.56(d,J=9.09Hz,1 H),8.04(d,J=8.50Hz,1 H),8.35(s,1 H),8.65(d,J=6.74Hz,1 H)。MS(ESI,正離子)m/z 364[M+H]+。
1H NMR(300MHz,DMSO-d 6)δ ppm 1.01-1.15(m,6 H),1.43(m,2 H),1.82-2.04(m,2 H),2.15(s,3 H),2.29(br dd,J=12.46,6.01Hz,1 H),2.82-2.98(m,1 H),3.84(br t,J=6.45Hz,2 H),4.53-4.70(m,1 H),7.31-7.49(m,2 H),7.49-7.61(m,1 H),8.05(d,J=7.92Hz,1 H),8.16(t,J=9.09Hz,2 H)。MS(ESI,正離子)m/z 381[M+H]+。
1H NMR(300MHz,DMSO-d 6)δ ppm 0.88(t,J=7.33Hz,3 H),1.07(d,J=6.45Hz,3 H),1.36-1.52(m,2 H),1.57-1.79(m,2 H),2.15(s,3 H),2.22-2.38(m,1 H),2.90(dt,J=15.83,5.86Hz,1 H),3.50-3.72(m,2 H),4.52-4.78(m,1 H),7.10-7.25(m,2 H),7.33(br d,J=8.21Hz,1 H),7.51-7.60(m,1 H),7.61-7.70(m,1 H),7.83(d,J=8.50Hz,1 H),12.30(s,1 H)。MS(ESI,正離子)m/z 364[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.65-0.83(m,1 H),0.85-1.06(m,2 H),1.11-1.22(m,4 H),1.23-1.38(m,1 H),1.41-1.53(m,1 H),1.53-1.69(m,1 H),1.81-1.94(m,1 H),2.15-2.51(m,6 H),2.84(s,3 H),2.95-2.13(m,1 H),4.32-4.51(m,1 H),4.60-4.79(m,1 H),7.33(d,J=8.40Hz,1 H),7.85-8.12(m,1 H)。MS(ESI,正離子)m/z 384[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.66-0.72(m,1 H),0.76-0.71(m,2 H),0.98-1.08(m,4 H),1.15-1.33(m,2 H),1.50-1.58(m,1 H),1.74-1.81(m,1 H),1.96-2.03(m,2 H),2.03-2.14(m,2 H),2.14-2.33(m,2 H),2.89-2.94(m,1 H),4.10-4.16(m,1 H),4.52-4.63(m,1 H),7.11(d,J=8.40Hz,1 H),7.35(d,J=8.40Hz,1 H),8.73(s,1 H),8.96(s,1 H)。MS(ESI,正離子)m/z 353[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.76-0.85(m,1 H),0.91-1.03(m,3 H),1.04-1.30(m,4 H),1.35-1.47(m,1 H),1.61-1.72(m,2 H),2.13-2.36(m,5 H),2.46-2.55(m,1 H),3.05-3.13(m,2 H),4.20-4.27(m,4 H),4.69-4.78(m,1 H),7.69(d,J=8.40Hz,1 H),8.38(s,1 H)。MS(ESI,正離子)m/z 385[M+H]+。
1H NMR(400MHz,CDCl3)δ ppm 1.21-1.25(m,3 H),1.25-1.34(m,4 H),1.60-1.70(m,1 H),2.05-2.20(m,4 H),2.26-2.41(m,1 H),3.79(s,3 H),4.13-4.14(m,1 H),4.17(s,3 H),4.42-4.53(m,1 H),7.8(s,1 H),8.0(s,1 H)。MS(ESI,正離子)m/z 375[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.11-1.25(m,4 H),1.31-1.45(m,1 H),1.55-1.71(m,1 H),1.98-2.55(m,9 H),2.97-3.10(m,1 H),4.20-4.37(m,4 H),4.71-4.83(m,1 H),7.69(d,J=11.10Hz,1 H),8.37(s,1 H)。MS(ESI,正離子)m/z 359[M+H]+。
對於(S)-(6-(5-胺基-1,3,4-噻二唑-2-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮,使用(5-溴-1,3,4-噻二唑-2-基)胺基甲酸第三丁酯作為芳基溴化物來源。如實例29步驟3中所概述移除Boc基團。1H NMR(400MHz,CD3OD)δ ppm 0.65-0.80(m,1 H),0.87-1.01(m,2 H),1.09-1.19(m,4 H),1.21-1.39(m,1 H),1.42-1.59(m,1 H),1.68-1.79(m,1 H),1.82-1.96(m,1 H),2.15-2.53(m,6 H),2.97-3.10(m,1 H),4.32-4.54(m,1 H),4.60-4.75(m,1 H),7.27(d,J=8.40Hz,1 H),7.82-7.94(m,1 H)。MS(ESI,正離子)m/z 385[M+H]+。
對於(S)-(5-環丁氧基-2-甲基-6-(1H-1,2,3-三唑-4-基)-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮,使用1-苯甲基-4-溴-1H-1,2,3-三唑作為芳基溴化物來源。使用上文針對中間物1步驟2所概述之氫化條件移除苯甲基。1H NMR(300MHz,CD3OD)δ ppm 0.65-0.80(m,1 H),0.87-0.99(m,2 H),1.13(d,J=6.60Hz,4 H),1.27-1.39(m,2 H),1.53-1.73(m,1 H),1.82-1.97(m,1 H),2.01-2.23(m,4 H),2.27-2.44(m,2 H),2.99-3.16(m,1 H),4.05-4.28(m,4 H),4.65-4.81(m,1 H),7.24(d,J=7.80Hz,1 H),7.72(d,J=8.40Hz,1 H),8.15(s,1 H)。MS(ESI,正離子)
m/z 353[M+H]+。
1H NMR(300MHz,CDCl3)δ ppm 1.19(d,J=6.60Hz,3 H),1.21-1.32(m,2 H),1.46-1.56(m,1 H),2.01-2.16(m,4 H),2.18-2.27(m,1 H),2.86-3.00(m,1 H),3.80(s,3 H),4.05-4.13(m,1 H),4.55-4.63(m,1 H),5.58-5.63(m,1 H),7.41(d,J=8.70Hz,1 H),7.74(d,J=8.70Hz,1 H),8.03(s,1 H)。MS(ESI,正離子)m/z 402[M+H]+。
1H NMR(300MHz,CDCl3)δ ppm 1.16-1.31(m,5 H),1.45-1.59(m,2 H),1.98-2.11(m,4 H),2.15-2.28(m,1 H),2.45-2.55(m,1 H),2.90-2.99(m,1 H),3.06(d,J=5.40Hz,3 H),3.80(s,3 H),4.05-4.14(m,1 H),4.55-4.65(m,1 H),7.41(d,J=8.70Hz,1 H),7.72(d,J=8.70Hz,1 H),7.96(s,1 H)。MS(ESI,正離子)m/z 416[M+H]+。
1H NMR(400MHz,CDCl3)δ ppm 1.17(d,J=6.40Hz,3 H),1.25-
1.36(m,1 H),1.45-1.66(m,1 H),1.67-1.75(m,1 H),1.92-1.95(m 3 H),1.97-2.13(m,4 H),2.16-2.26(m,1 H),2.45-2.51(m,1 H),2.90-3.00(m,1 H),3.79(s,3 H),4.13-4.15(m,1 H),4.55-4.62(m,1 H),7.31-7.37(m,2 H),7.54-7.57(m,1 H),11.6(br s,1 H)。MS(ESI,正離子)m/z 416[M+H]+。
將(S)-6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.050g,0.167mmol)、5-氯-2-氟苯甲腈(0.065g,0.416mmol)及碳酸銫(0.136g,0.416mmol)於DMF(2.0mL)中之混合物在100℃下加熱16小時。冷卻反應混合物至室溫,且添加水。將混合物分配於乙酸乙酯與水之間。分離水相,且用乙酸乙酯萃取。用鹽水洗滌經合併之有機相,經無水硫酸鈉乾燥,過濾且濃縮,得到棕色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以0-25%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈灰白色固體狀之(S)-6-溴-5-(4-氯-2-氰基苯氧基)-2-甲
基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.068g,94%)。MS(ESI,正離子)m/z 435,437[M+H]+。
將(S)-6-溴-5-(4-氯-2-氰基苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.068g,0.156mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(0.065g,0.172mmol)、XPhos第2代預催化劑(0.012g,0.016mmol)及碳酸銫(0.153g,0.468mmol)於二噁烷(2.0mL)及水(0.400mL)中之混合物在100℃下於微波中加熱2小時。經矽藻土過濾反應混合物且濃縮,得到橙色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以25-50%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈灰白色固體狀之(S)-6-(1-(1-(第三丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)-5-(4-氯-2-氰基苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.057g,60%)。MS(ESI,正離子)m/z 606[M+H]+。
將三氟乙酸(0.5mL,6.49mmol)添加至(S)-6-(1-(1-(第三丁氧基羰基)哌啶-4-基)-1H-吡唑-4-基)-5-(4-氯-2-氰基苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.057g,0.094mmol)於二氯甲烷(2.0mL)中之溶液中,且在室溫下攪拌反應混合物1.5小時。濃縮反應混合物,且將殘餘物分配於二氯甲烷與飽和碳酸氫鈉水溶液之間。分離有機相,經無水硫酸鈉乾燥,過濾且濃縮,得到呈灰白色固體狀之(S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.041g,86%)。1H NMR(300MHz,DMSO-d 6)δ ppm 1.01-1.09(m,4 H),1.49-1.79(m,4 H),1.80-2.07(m,4 H),
2.52-2.63(m,2 H),2.99(br d,J=12.31Hz,2 H),3.72(s,3 H),4.03-4.23(m,1 H),4.45-4.70(m,1 H),6.44(br d,J=9.09Hz,1 H),7.47-7.64(m,3 H),7.67(s,1 H),7.95(s,1 H),8.10(d,J=2.35Hz,1 H)。MS(ESI,正離子)m/z 506[M+H]+。
根據針對實例36所概述之程序製得以下實例:
1H NMR(300MHz,DMSO-d 6)δ ppm 1.00-1.12(m,4 H),1.48-1.79(m,4 H),1.79-2.05(m,4 H),2.51-2.61(m,2 H),2.98(br d,J=12.31Hz,2 H),3.72(s,3 H),3.99-4.23(m,1 H),4.38-4.67(m,1 H),6.43(br d,J=5.28Hz,1 H),7.37(td,J=8.79,3.22Hz,1 H),7.54-7.70(m,3 H),7.89-7.98(m,2 H)。MS(ESI,正離子)m/z 490[M+H]+。
1H NMR(300MHz,DMSO-d 6)δ ppm 1.06(br d,J=1.76Hz,4 H),1.43-1.75(m,4 H),1.77-2.08(m,4 H),2.52-2.68(m,2 H),2.98(br d,J=12.02Hz,2 H),3.72(s,3 H),4.09(br t,J=12.02Hz,1 H),4.44-4.73(m,1 H),6.27-6.66(m,1 H),7.50-7.65(m,3 H),7.67(s,1 H),
7.95(s,1 H),8.22(s,1 H)。MS(ESI,正離子)m/z 506[M+H]+。
1H NMR(300MHz,DMSO-d 6)δ ppm 1.00-1.12(m,4 H),1.50-1.76(m,4 H),1.79-2.09(m,4 H),2.47-2.64(m,2 H),2.99(br d,J=12.61Hz,2 H),3.72(s,3 H),4.01-4.21(m,1 H),4.44-4.70(m,1 H),6.52(br t,J=8.65Hz,1 H),7.37-7.71(m,4 H),7.94(s,1 H),8.05(br d,J=11.14Hz,1 H)。MS(ESI,正離子)m/z 490[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.16(d,J=6.60Hz,3 H),1.47(br s,1 H),1.78-1.93(m,2 H),2.01-2.09(m,2 H),2.15-2.35(m,5 H),2.55-2.83(m,3 H),3.10-3.21(m,2 H),4.18-4.32(m,1 H),4.78(br s,1 H),6.50(d,J=8.10Hz,1 H),7.11(t,J=7.80Hz,1 H),7.35-7.50(m,2 H),7.61(d,J=8.40Hz,1 H),7.71-7.79(m,2 H),7.99(s,1 H)。MS(ESI,正離子)m/z 456[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.06(d,J=6.40Hz,3 H),1.48-1.55(m,1 H),1.65-1.74(m,1 H),1.85-2.05(m,3 H),2.20-2.85(m,4 H),2.95-3.05(m,2 H),3.72(s,3 H),4.05-4.15(m,1 H),4.50-4.60(m,1 H),6.30-6.40(m,1 H),6.93-6.99(m,1 H),7.23-7.30(m,1 H),7.43(d,J=8.80Hz,1 H),7.50-7.60(m,1 H),7.59-7.65(m,2 H),7.79(s,1 H)。MS(ESI,正離子)m/z 472[M+H]+。
1H NMR(300MHz,DMSO-d 6)δ ppm 1.00(br d,J=6.45Hz,3 H),1.39-1.62(m,2 H),1.83-2.00(m,2 H),3.29-3.51(m,2 H),3.55-3.63(m,1 H),3.66(s,3 H),3.70-3.82(m,1 H),4.52(m,1 H),4.80(br d,J=7.04Hz,1 H),4.95-5.16(m,1 H),6.37(br d,J=8.50Hz,1 H),6.94-7.20(m,1 H),7.42(q,J=7.52Hz,1 H),7.55(m,2 H),7.65-7.75(m,1 H),7.75-7.90(m,1 H),7.93-8.12(m,1 H)。MS(ESI,正離子)m/z 444[M+H]+。
1H NMR(300MHz,DMSO-d 6)δ ppm 1.00(br d,J=5.86Hz,3 H),1.45-1.67(m,2 H),1.81-1.99(m,2 H),3.29-3.51(m,2 H),3.66(s,3 H),3.73-4.02(m,2 H),4.40-4.65(m,1 H),4.82(m,1 H),4.98-5.27(m,1 H),6.25(br d,J=7.33Hz,1 H),7.08(br t,J=8.79Hz,1 H),7.38-7.64(m,3 H),7.72(br d,J=6.16Hz,1 H),7.89-8.10(m,1 H)。MS(ESI,正離子)m/z 462[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.15(d,J=6.60Hz,3 H),1.20-1.45(m,1 H),1.80-1.95(m,2 H),1.97-2.05(m,2 H),2.10-2.25(m,5 H),2.52-2.69(m,1 H),2.72-2.82(m,2 H),3.20(d,J=12.90Hz,2 H),4.15-4.25(m,1 H),4.65-4.82(m,1 H),6.93(d,J=8.70Hz,2 H),7.38(br s,1 H),7.62(t,J=9.00Hz,3 H),7.75(s,1 H),7.93(s,1 H)。MS(ESI,正離子)m/z 456[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.15(s,3 H),1.20-1.50(m,1 H),1.72-1.87(m,2 H),1.95-2.05(m,2 H),2.07-2.45(m,6 H),2.65-2.75(m,2 H),3.05-3.15(m,2 H),4.10-4.22(m,1 H),4.79(br s,1 H),7.15-7.37(m,2 H),7.56(d,J=8.40Hz,1 H),7.71(s,1 H),7.86(s,1 H),8.12-8.19(m,2 H)。MS(ESI,正離子)m/z 500[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.16(d,J=6.60Hz,3 H),1.45(br s,1 H),1.75-1.92(m,2 H),1.97-2.10(m,2 H),2.15-2.32(m,5 H),2.50-2.70(m,1 H),2.69-2.78(m,2 H),3.08-3.15(m,2 H),4.08-4.21(m,1 H),4.72-4.91(m,1 H),6.95-7.05(m,1 H),7.25-7.35(m,1 H),7.55(d,J=8.10Hz,1 H),7.77(s,1 H),7.85-7.95(m,2 H),7,96(s,1 H)。MS(ESI,正離子)m/z 466[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.17(d,J=6.80Hz,3 H),1.38-1.55(m,1 H),1.79-1.92(m,2 H),1.98-2.09(m,2 H),2.15-2.41(m,5 H),2.82-2.70(m,1 H),2.70-2.79(m,2 H),3.10-3.18(m,2 H),4.18-4.28(m,1 H),4.70-4.85(m,1 H),7.12-7.18(m,1 H),7.20-7.39(m,1 H),7.53(d,J=8.40Hz,1 H),7.74(s,1 H),7.95(s,1 H),8.11-8.22(m,2
H)。MS(ESI,正離子)m/z 457[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.02(d,J=6.80Hz,3 H),1.25-1.35(m,1 H),1.65-1.78(m,2 H),1.85-95(m,2 H),2.01-2.21(m,8 H),2.45-2.65(m,3 H),2.98-3.059(m,2 H),4.05-4.12(m,1 H),4.58-4.75(m,1 H),7.05-7.20(m,1 H),7.43(d,J=8.40Hz,1 H),7.66(s,1 H),7.87(s,1 H),8.27(s,2 H)。MS(ESI,正離子)m/z 447[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.05(d,J=6.40Hz,3 H),1.20-1.45(m,1 H),1.65-1.80(m,2 H),1.82-1.89(m,2 H),2.05-2.25(m,5 H),2.48-2.65(m,3 H),2.95-3.05(m,2 H),4.05-4.15(m,1 H),4.60-4.78(m,1 H),7.10-7.25(m,1 H),7.43(d,J=8.40Hz,1 H),7.61(s,1 H),7.84(s,1 H),7.92(s,1H),8.10(d,J=2.80Hz,1 H),8.38(s,1 H)。MS(ESI,正離子)m/z 433[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.17(d,J=6.30Hz,3 H),1.52-1.65(m,1 H),1.75-1.95(m,2 H),1.97-2.15(m,3 H),2.38-2.48(m,1 H),2.55-2.78(m,3 H),3.08-3.15(m,2 H),3.83(s,1 H),4.15-4.29(m,1 H),4.65-4.72(m,1 H),6.89-6.99(m,2 H),7.53-7.70(m,5 H),7.92(s,1 H)。MS(ESI,正離子)m/z 472[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.18(d,J=6.80Hz,3 H),1.59-1.68(m,1 H),1.80-1.95(m,2 H),1.99-2.15(m,3 H),2.30-2.70(br m,2 H),2.70-2.80(m,2 H),3.10-3.19(m,2 H),3.83(s,3 H),4.15-4.25(m,1 H),4.65-4.71(m,1 H),7.11-7.15(m,1 H),7.45(d,J=8.80Hz,1 H),7.61(d,J=8.80Hz,1 H),7.71(s,1 H),7.91(s,1 H),8.12-8.21(m,2 H)。MS(ESI,正離子)m/z 473[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.19(d,J=6.60Hz,3 H),1.58-
1.72(m,1 H),1.78-1.99(m,2 H),1.98-2.15(m,3 H),2.68-2.82(m,2 H),3.07-3.19(m,2 H),4.20-4.30(m,1 H),4.60-4.75(m,1 H),6.25-6.35(m,1 H),6.96(t,J=8.40Hz,1H),7.39-7.55(m,2 H),7.65-7.71(m,1 H),7.76(s,1 H),7.95(s,1 H)。MS(ESI,正離子)m/z 490[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.05-1.20(m,3 H),1.58-1.72(m,1 H),1.79-1.95(m,2 H),1.98-2.15(m,3 H),2.20-2.70(br s,1 H),2.65-2.80(m,3 H),3.05-3.15(m,2 H),3.82(s,3 H),4.15-4.25(m,1 H),4.60-4.75(m,1 H),6.30-6.50(m,1 H),7.20(d,J=8.10Hz,1 H),7.38(t,J=8.40Hz,1 H),7.52(d,J=8.70Hz,1 H),7.60-7.75(m,2 H),7.93(s,1 H)。MS(ESI,正離子)m/z 506[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.75-0.90(m,1 H),0.95-1.05(m,2 H),1.15-1.30(m,4 H),1.45-1.65(m,1 H),1.81-1.99(m,2 H),2.01-2.13(m,3 H),2.20-2.60(m,2 H),2.65-2.82(m,3 H),3.10-3.21(m,2 H),4.20-4.35(m,1 H),4.80-4.95(m,1 H),6.50-6.64(m,1 H),7.18(t,J=7.50Hz,1 H),7.45-7.55(m,2 H),7.67(d,J=8.40Hz,1 H),
7.78-7.82(m,2 H),8.03(s,1 H)。MS(ESI,正離子)m/z 483[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.75-0.82(m,1 H),0.85-1.01(m,2 H),1.10-1.21(m,4 H),1.45-1.60(m,1 H),1.79-1.92(m,2 H),1.95-2.10(m,3 H),2.15-2.30(m,1 H),2.30-2.50(m,1 H),2.65-2.79(m,3 H),3.08-3.19(m,2 H),4.15-4.30(m,1 H),4.78-4.90(m,1 H),6.30-6.40(m,1 H),6.90-7.00(m,1 H),7.40-7.50(m,2 H),7.62(d,J=8.40Hz,1 H),7.78(s,1 H),7.98(s,1 H)。MS(ESI,正離子)m/z 500[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.65-0.70(m,1 H),0.78-0.92(m,2 H),0.99-1.11(m,4 H),1.30-1.42(m,1 H),1.65-1.80(m,2 H),1.85-1.95(m,3 H),2.08-2.19(m,1 H),2.20-2.30(m,1 H),2.50-2.65(m,3 H),2.95-3.05(m,2 H),4.05-4.15(m,1 H),4.65-4.75(m,1 H),6.51(t,J=8.40Hz,1 H),7.24(d,J=8.80Hz,1 H),7.36(d,J=8.40Hz,1 H),7.51(d,J=8.40Hz,1 H),7.60-7.70(m,2 H),7.80(s,1 H)。MS
(ESI,正離子)m/z 500[M+H]+。
根據上文針對實例36所述之程序合成(S)-2-(1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基氧基)苯甲腈,作出以下改變:(1)在步驟2中,使用1-環丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑替代4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯;(3)去除步驟3(移除Boc保護基)。1H NMR(300MHz,CD3OD)δ ppm 0.92-1.05(m,4 H),1.16(d,J=6.30Hz,3 H),1.35-1.52(m,1 H),2.10-2.40(m,5 H),2.58-2.80(m,1 H),3.55-3.65(m,1 H),4.68-4.89(m,1 H),6.40-6.55(m,1 H),7.05-7.15(m,1 H),7.30-7.52(m,2 H),7.55-7.65(m,1 H),7.70-7.80(m,2 H),7.96(s,1 H)。MS(ESI,正離子)m/z 413[M+H]+。
將(S)-2-(6-溴-1-(環丙烷羰基)-2-甲基-1,2,3,4-四氫喹啉-5-基氧基)
苯甲腈(0.70g,0.17mmol,1.00當量)、雙(頻哪醇根基)二硼(0.216g,0.85mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.015g,0.02mmol)、乙酸鉀(0.042g,0.43mmol)於1,4-二噁烷(10mL)中之混合物在90℃下攪拌隔夜。冷卻混合物至室溫,用乙酸乙酯(50mL)稀釋,用水(20mL)及鹽水(20mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以25%乙酸乙酯-石油醚洗提)純化殘餘物,得到呈黃色油狀之(S)-2-(1-(環丙烷羰基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1,2,3,4-四氫喹啉-5-基氧基)苯甲腈(0.050g,64%)。MS(ESI,正離子)m/z 459[M+H]+。
將(S)-2-(1-(環丙烷羰基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1,2,3,4-四氫喹啉-5-基氧基)苯甲腈(0.050g,0.11mmol)、4-溴-1-甲基-1H-1,2,3-三唑(0.025g,0.15mmol)、碳酸銫(0.110g,0.34mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.10g,0.01mmol)於1,4-二噁烷(10mL)及水(3mL)中之混合物在80℃下攪拌隔夜。冷卻反應混合物至室溫,且經短矽藻土襯墊過濾。濃縮濾液,且經由製備型薄層層析(以25%乙酸乙酯-石油醚洗提)純化,得到呈白色固體狀之(S)-2-(1-(環丙烷羰基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉-5-基氧基)苯甲腈(0.006g,13%)。
MS(ESI,正離子)m/z 414[M+H]+。1H NMR(400MHz,CD3OD)δ ppm 0.75-0.82(m,1H),0.88-1.05(m,2H),1.15-1.25(m,3H),1.28-1.35(m,1H),1.45-1.55(m,1H),1.97-2.05(m,1H),2.15-2.25(m,1H),2.27-2.45(m,1H),2.60-2.75(m,1H),4.09(s,3H),4.75-4.85(m,1H),6.58(d,J=8.40Hz,1H),7.17(t,J=8.00Hz,1H),7.45-7.51(m,1H),7.57(d,J=8.40Hz,1H),7.78(d,J=1.20Hz,1H),8.03-8.07(m,2H)。MS(ESI,
正離子)m/z 414[M+H]+。
向配備有經空氣填充之氣球之100-mL圓底燒瓶中饋入1-[(2S)-6-溴-5-羥基-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮(0.300g,1.06mmol)、(4-胺甲醯基苯基)硼酸(0.437g,2.65mmol)、乙酸銅(0.386g,2.12mmol)、吡啶(1mL)、二氯甲烷(40mL)及4Å分子篩(4.0g)。在室溫下攪拌所得混合物3天。經矽藻土襯墊過濾反應混合物,且在真空下濃縮濾液。藉由製備型薄層層析(以20-25%乙酸乙酯-石油醚洗提)純化殘餘物,得到呈黃色油狀之4-[[(2S)-1-乙醯基-6-溴-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基]苯甲醯胺(0.148g,35%)。MS(ESI,正離子)m/z 403,405[M+H]+。
將4-[[(2S)-1-乙醯基-6-溴-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基]苯甲醯胺(0.080g,0.20mmol)、4-[4-(四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基]哌啶-1-甲酸第三丁酯(0.090g,0.24mmol)、碳酸鉀
(0.082g,0.59mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.016g,0.02mmol)於1,4-二噁烷(20mL)及水(2mL)中之混合物在100℃下攪拌隔夜。冷卻反應混合物至室溫,經矽藻土襯墊過濾,且在真空下濃縮。經由製備型薄層層析(以50%乙酸乙酯-石油醚洗提)純化殘餘物,得到呈黃色油狀之4-[4-[(2S)-1-乙醯基-5-(4-胺甲醯基苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基]哌啶-1-甲酸第三丁酯(0.080g,70%)。MS(ESI,正離子)m/z 574[M+H]+。
將三氟乙酸(3.5mL)添加至4-[4-[(2S)-1-乙醯基-5-(4-胺甲醯基苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基]哌啶-1-甲酸第三丁酯(0.080g,0.14mmol)於二氯甲烷(30mL)中之溶液中。在室溫下攪拌反應混合物2小時,接著在真空下濃縮。將殘餘物溶解於二氯甲烷(50mL)中,用飽和碳酸鉀水溶液(3×20mL)及鹽水(20mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。藉由製備型HPLC使用以下條件(製備型HPLC-12)純化殘餘物:管柱,XBridge Prep C18 OBD管柱,19×150mm 5μm 13nm;移動相:水(0.05%碳酸氫銨)及乙腈(在18分鐘內20%至95%乙腈,流動速率:20mL/min);偵測器,UV 254/220nm。此得到呈灰白色固體狀之4-[[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基]苯甲醯胺(0.033g,50%)。1H NMR(300MHz,CD3OD)δ ppm 1.15(d,J=6.60Hz,3H),1.25-1.45(m,1H),1.72-1.92(m,2H),1.95-2.05(m,2H),2.15-2.40(m,5H),2.60-2.80(m,3H),3.05-3.15(m,2H),4.15-4.25(m,1H),4.79(br s,1H),6.87(d,J=8.70Hz,2H),7.38(br s,1H),7.64(d,J=8.70Hz,1H),7.75-7.89(m,3H),7.96(s,1H)。MS(ESI,正離子)m/z 474[M+H]+。
根據針對實例38所概述之程序製得以下實例:
1H NMR(300MHz,CD3OD)δ ppm 1.11(d,J=6.60Hz,3 H),1.22-1.42(m,1 H),1.75-1.89(m,2 H),1.98-2.08(m,2 H),2.23(s,3 H),2.14-2.35(m,2 H),2.64-2.79(m,3 H),3.09-3.18(m,2 H),3.72(s,3 H),4.15-4.25(m,1 H),4.68-4.83(m,1 H),6.28-35(m,2 H),6.52-6.57(m,1 H),7.14(t,J=8.10Hz,1 H),7.20-7.35(m,1 H),7.61(d,J=8.40Hz,1 H),7.80(s,1 H),7.96(s,1 H)。MS(ESI,正離子)m/z 461[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.16(d,J=6.80Hz,3 H),1.30-1.45(m,1 H),1.75-1.89(m,2 H),1.95-2.05(m,2 H),2.15-2.35(m,5 H),2.55-2.79(m,3 H),3.09-3.15(m,2 H),4.12-4.22(m,1 H),4.78(br s,1 H),6.30-6.35(m,1 H),6.89-6.97(m,1 H),6.99-7.05(m,1 H),7.37(br s,1 H),7.42-7.49(m,1 H),7.64(d,J=8.40Hz,1 H),7.83(s,1 H),8.01(s,1 H)。MS(ESI,正離子)m/z 465[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.14(d,J=6.60Hz,3 H),1.48-1.62(m,1 H),1.75-1.91(m,2 H),1.95-2.15(m,3 H),2.35-2.45(m,1 H),2.55-2.78(m,3 H),3.09-3.18(m,2 H),4.15-4.25(m,1 H),4.55-4.68(m,1 H),6.68-6.78(m,2 H),6.91-7.02(m,2 H),7.49-7.52(m,2 H),7.76(s,1 H),7.92(s,1 H)。MS(ESI,正離子)m/z 465[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.15(d,J=6.60Hz,3 H),1.50-1.62(m,1 H),1.75-1.92(m,2 H),1.97-2.15(m,3 H),2.35-2.48(m,1 H),2.52-2.82(m,3 H),3.09-3.18(m,2 H),4.15-4.25(m,1 H),4.55-4.72(m,1 H),6.77(d,J=8.70Hz,2 H),7.24(d,J=9.00Hz,2 H),7.45-7.55(m,2 H),7.77(s,1 H),7.92(s,1 H)。MS(ESI,正離子)m/z 481[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.15(d,J=6.60Hz,3 H),1.52-1.68(m,1 H),1.72-1.92(m,2 H),1.95-2.15(m,4 H),2.65-2.80(m,3
H),3.05-3.18(m,2 H),3.81(s,3 H),4.12-4.25(m,1 H),4.55-4.75(m,1 H),6.28-6.35(m,1 H),6.85-6.95(m,1 H),6.95-7.05(m,1 H),7.42-7.65(m,3 H),7.79(s,1 H),7.96(s,1 H)。MS(ESI,正離子)m/z 481[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.16(d,J=6.40Hz,3 H),1.52-1.62(m,1 H),1.83-1.95(m,2 H),1.99-2.13(m,3 H),2.42-2.49(m,1 H),2.55-2.65(m,1 H),2.78-2.85(m,2 H),3.15-3.22(m,2 H),3.83(s,3 H),4.19-4.25(m,1 H),4.62-4.65(m,1 H),6.84(d,J=8.80Hz,2 H),7.50-7.60(m,2 H),7.75-7.82(m,3 H),7.91(s,1 H)。MS(ESI,正離子)m/z 490[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.16(d,J=6.80Hz,3 H),1.55-1.65(m,1 H),1.80-1.98(m,2 H),1.99-2.12(m,3 H),2.39-2.48(m,1 H),2.60-2.80(m,3 H),3.10-3.20(m,2 H),3.82(s,3 H),4.19-4.30(m,1 H),4.60-4.70(m,1 H),7.05-7.22(m,3 H),7.50-7.62(m,2 H),7.75(s,1 H),7.94(s,1 H)。MS(ESI,正離子)m/z 490[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.17(d,J=6.60Hz,3 H),1.52-1.65(m,1 H),1.78-1.95(m,2 H),1.97-2.15(m,3 H),2.38-2.45(m,1 H),2.58-2.79(m,3 H),3.09-3.15(m,2 H),3.83(s,3 H),4.15-4.30(m,1 H),4.60-4.72(m,1 H),6.68-6.72(m,1 H),6.85-6.89(m,1 H),7.13(t,J=9.00Hz,1 H),7.52-7.63(m,2 H),7.76(s,1 H),7.95(s,1 H)。MS(ESI,正離子)m/z 499[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.65-0.82(m,1 H),0.85-1.01(m,2 H),1.01-1.19(m,4 H),1.30-1.45(m,1 H),1.75-1.90(m,2 H),1.90-2.05(m,3 H),2.09-2.35(m,2 H),2.60-2.80(m,3 H),3.05-3.20(m,2 H),4.11-4.28(m,1 H),4.70-4.82(m,1 H),6.79(s,1 H),6.90-7.03(m,2 H),7.39(d,J=8.00Hz,1 H),7.62(d,J=8.00Hz,1 H),7.79(s,1 H),7.96(s,1 H)。MS(ESI,正離子)m/z 475[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.72-0.82(m,1 H),0.90-1.05(m,2 H),1.10-1.25(m,4 H),1.40-1.50(m,1 H),1.78-1.95(m,2 H),1.95-2.10(m,3 H),2.20-2.40(m,2 H),2.70-2.90(m,3 H),3.10-3.18(m,2 H),4.15-4.25(m,1 H),4.75-4.85(m,1 H),6.35-6.42(m,1 H),6.90-6.98(m,1 H),7.01-7.09(m,1 H),7.40-7.50(m,2 H),7.65(d,J=8.40Hz,1 H),7.84(s,1 H),8.01(s,1 H)。MS(ESI,正離子)m/z 491[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.72-0.80(m,1 H),0.85-1.05(m,2 H),1.10-1.19(m,4 H),1.35-1.45(m,1 H),1.75-1.90(m,2 H),1.95-2.05(m,3 H),2.15-2.35(m,2 H),2.65-2.79(m,3 H),3.10-3.20(m,2 H),4.15-4.30(m,1 H),4.75-4.85(m,1 H),6.80(dd,J=10.80,2.00Hz,2 H),7.26(dd,J=10.80,2.00Hz,2 H),7.40(d,J=8.40Hz,1 H),7.63(d,J=8.40Hz,1 H),7.79(s,1 H),7.96(s,1 H)。MS(ESI,正離子)m/z 491[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.69-0.80(m,1 H),0.83-1.01(m,2 H),1.09-1.22(m,4 H),1.30-1.50(m,1 H),1.70-1.90(m,2 H),1.90-2.01(m,3 H),2.11-2.35(m,2 H),2.60-2.75(m,3 H),3.03-3.12(m,2 H),4.10-4.25(m,1 H),4.70-4.85(m,1 H),6.95(d,J=8.70Hz,2 H),7.41(d,J=8.40Hz,2 H),7.55-7.68(m,3 H),7.73(s,1 H),7.92(s,1 H)。MS(ESI,正離子)m/z 491[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.75-0.80(m,1 H),0.90-1.01(m,2 H),1.10-1.20(m,4 H),1.32-1.45(m,1 H),1.75-1.92(m,2 H),1.95-2.05(m,3 H),2.15-2.35(m,2 H),2.65-2.75(m,3 H),3.05-3.15(m,2 H),4.10-4.25(m,1 H),4.70-4.82(m,1 H),6.80(d,J=8.00Hz,2 H),6.98(t,J=7.20Hz,1 H),7.28(t,J=8.00Hz,2 H),7.39(d,J=8.40Hz,1 H),7.80(s,1 H),7.98(s,1 H)。MS(ESI,正離子)m/z 457[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.62-0.72(m,1 H),0.78-0.90(m,2 H),0.98-1.10(m,4 H),1.25-1.35(m,1 H),1.68-1.80(m,2 H),1.85-1.95(m,3 H),2.09-2.25(m,2 H),2.55-2.70(m,3 H),2.95-3.05(m,2 H),4.05-4.15(m,1 H),4.65-4.75(m,1 H),6.55-6.65(m,1 H),6.75-6.85(m,1 H),7.03(t,J=8.80Hz,1 H),7.31(d,J=8.40Hz,1 H),7.51(d,J=8.40Hz,1 H),7.67(s,1 H),7.83(s,1 H)。MS(ESI,正離子)m/z 509[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.58-0.70(m,1 H),0.78-0.92(m,2 H),0.95-1.10(m,4 H),1.20-1.30(m,1 H),1.80-1.90(m,1 H),2.05-2.18(m,2 H),2.55-2.65(m,1 H),3.75-3.85(m,2 H),3.88-3.95(m,2 H),4.60-4.70(m,1 H),5.01-5.12(m,1 H),6.65-6.70(m,2 H),6.85-6.90(m,2 H),7.28(d,J=8.40Hz,1 H),7.51(d,J=8.40Hz,1 H),7.77(s,1 H),7.93(s,1 H)。MS(ESI,正離子)m/z 447[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.62-0.72(m,1 H),0.78-0.90(m,2 H),0.95-1.10(m,4 H),1.20-1.35(m,1 H),1.68-1.80(m,2 H),1.85-1.95(m,3 H),2.05-2.25(m,2 H),2.55-2.70(m,3 H),2.95-3.10(m,2 H),4.05-4.15(m,1 H),4.65-4.70(m,1 H),6.40-6.52(m,2 H),6.55-6.65(m,1 H),7.10-7.15(m,1 H),7.30(d,J=8.40Hz,1 H),7.52(d,J=8.40Hz,1 H),7.69(s,1 H),7.85(s,1 H)。MS(ESI,正離子)m/z 475[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.65-0.70(m,1 H),0.75-0.90(m,2 H),0.95-1.10(m,4 H),1.25-1.35(m,1 H),1.65-1.80(m,2 H),1.85-1.95(m,3 H),2.05-2.25(m,2 H),2.55-2.65(m,3 H),2.95-3.05(m,2 H),4.05-4.18(m,1 H),4.65-4.75(m,1 H),6.40-6.50(m,1 H),6.55-6.70(m,1 H),6.95-7.10(m,1 H),7.30(d,J=8.40Hz,1 H),7.51(d,J=8.40Hz,1 H),7.68(s,1 H),7.86(s,1 H)。MS(ESI,正離子)m/z 493[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.65-0.72(m,1 H),0.75-0.90(m,2 H),0.95-1.10(m,4 H),1.20-1.35(m,1 H),1.85-1.95(m,1 H),2.05-2.25(m,2 H),2.55-2.65(m,1 H),3.55-3.70(m,1 H),3.75-3.85(m,1 H),3.90-3.98(m,1 H),4.65-4.72(m,1 H),5.05-5.12(m,1 H),6.40-6.50(m,2 H),6.55-6.70(m,1 H),7.05-7.15(m,1 H),7.25-7.30(m,1 H),7.53(d,J=8.40Hz,1 H),7.70-7.79(m,1 H),7.90-8.00(m,1 H)。MS(ESI,正離子)m/z 447[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.60-0.70(m,1 H),0.75-0.90(m,2 H),0.95-1.10(m,4 H),1.20-1.35(m,1 H),1.85-1.90(m,1 H),2.05-2.22(m,2 H),2.55-2.62(m,1 H),3.75-3.85(m,2 H),3.92-3.98(m,2 H),4.65-4.70(m,1 H),5.05-5.15(m,1 H),6.40-6.50(m,1 H),6.60-6.68(m,1 H),6.95-7.05(m,1 H),7.30(d,J=8.40Hz,1 H),7.52(d,J=8.00Hz,1 H),7.77(s,1 H),7.93(s,1 H)。MS(ESI,正離子)m/z 465[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.75-0.80(m,1 H),0.85-1.02(m,2 H),1.10-1.20(m,4 H),1.30-1.40(m,1 H),1.92-2.02(m,1 H),2.12-2.32(m,2 H),2.65-2.75(m,1 H),4.48(d,J=7.60,4 H),4.75-4.81(m,1 H),5.30-41(m,1 H),6.75-6.82(m,2 H),6.95-7.01(m,1 H),7.23-7.29(m,2 H),7.40(d,J=8.40Hz,1 H),7.64(d,J=8.40Hz,1 H),7.98(s,1 H),8.03(s,1 H)。MS(ESI,正離子)m/z 429[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.04(d,J=6.40Hz,3 H),1.45-1.52(m,1 H),1.68-1.82(m,2 H),1.87-2.02(m,3 H),2.25-2.35(m,1 H),2.45-2.70(m,3 H),3.00-3.10(m,2 H),3.70(s,3 H),4.05-4.15(m,1 H),4.48-4.55(m,1 H),6.35-6.42(m,1 H),6.55-6.65(m,1 H),6.95-7.05(m,1 H),7.45-7.55(m,2 H),7.65(s,1 H),7.80(s,1 H)。MS(ESI,正離子)m/z 483[M+H]+。
1H NMR(300MHz,DMSO-d6)δ ppm 1.06(d,J=6.60Hz,3 H),1.46-1.67(m,1 H),1.89-2.09(m,1 H),2.37-2.48(m,2 H),3.60-3.90(m,7 H),4.45-4.70(m,1 H),5.03-5.20(m,1 H),6.59-6.64(m,1 H),6.86(s,1 H),6.95-7.11(m,1 H),7.21-7.33(m,1 H),7.58(s,2 H),7.78(s,1 H),8.14(s,1 H)。MS(ESI,正離子)m/z 453[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.59-0.75(m,1 H),0.76-0.99(m,2 H),0.99-1.14(m,4 H),1.14-1.41(m,1 H),1.80-1.99(m,1 H),2.02-2.31(m,2 H),2.58-2.69(m,1 H),3.48-3.71(m,1 H),3.77-3.98(m,1 H),3.98-4.07(m,1 H),4.58-4.71(m,1 H),4.82-4.90(m,1 H),5.00-5.22(m,1 H),6.55-6.67(m,1 H),6.67-6.80(m,1 H),6.80-6.97(m,1 H),7.13-7.22(m,1 H),7.23-7.39(m,1 H),7.42-7.49(m,1 H),7.53-7.62(m,1 H),7.62-7.80(m,1 H),7.85-8.08(m,1 H)。MS(ESI,正離子)m/z 463[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.69-0.84(m,1 H),0.90-1.09(m,2 H),1.10-1.26(m,4 H),1.37-1.52(m,1 H),1.80-1.95(m,2 H),
1.98-2.11(m,3 H),2.18-2.39(m,1 H),2.39-2.43(m,1 H),2.68-2.84(m,3 H),3.17-3.22(m,2 H),4.14-4.34(m,1 H),4.70-4.89(m,1 H),6.62-6.78(m,1 H),6.80-6.85(m,1 H),6.93-7.07(m,1 H),7.14-7.30(m,1 H),7.34-7.46(m,1 H),7.55-7.66(m,1 H),7.79(s,1 H),8.00(s,1 H)。MS(ESI,正離子)m/z 491[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.16(d,J=6.30Hz,3 H),1.55-1.69(m,1 H),2.06-2.18(m,1 H),2.41-2.55(m,1 H),2.62-2.75(m,1 H),3.82(s,3 H),3.90-4.01(m,2 H),4.01-4.15(m,1 H),4.64-4.75(m,1 H),5.21-5.31(m,1 H),6.39(d,J=8.40Hz,2 H),6.54-6.63(m,1 H),7.55-7.65(m,2 H),7.86(s,1 H),8.04(s,1 H)。MS(ESI,正離子)m/z 455[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.78-0.81(m,1 H),0.95-1.00(m,2 H),1.13-1.20(m,4 H),1.40-1.53(m,1 H),2.01-2.08(m,1 H),2.22-2.27(m,1 H),2.29-2.38(m,1 H),2.69-2.74(m,1 H),3.85-3.94(m,2 H),4.04-4.08(m,2 H),4.75-4.84(m,1 H),5.22-5.28(m,1 H),
6.41-6.48(m,2 H),6.53-6.63(m,1 H),7.44(d,J=8.40Hz,1 H),7.63(d,J=8.40Hz,1 H),7.88(s,1 H),8.07(s,1 H)。MS(ESI,正離子)m/z 465[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.17(m,3 H),1.56-1.67(m,1 H),185-1.97(m,2 H),2.01-2.11(m,2 H),2.11-2.18(m,1 H),2.43-2.52(m,1 H),2.62-2.69(m,1 H),2.71-2.82(m,2 H),3.14-3.12(m,2 H),3.83(s,3 H),4.22-4.33(m,1 H),4.75-4.84(m,1 H),6.41-6.48(m,2 H),6.53-6.63(m,1 H),7.54-7.57(m,1 H),7.63-7.65(m,1 H),7.77(s,1 H),7.96(s,1 H)。MS(ESI,正離子)m/z 483[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.76-7.84(m,1 H),0.91-1.03(m,2 H),1.11-1.21(m,4 H),1.41-1.52(m,1H),1.87-2.11(m,5 H),2.22-2.41(m,2 H),320-3.28(m,2 H),6.39-6.46(m,2 H),6.53-6.63(m,1 H),7.43(d,J=8.40Hz,1 H),7.63(d,J=8.70Hz,1 H),7.80(s,1 H),8.00(s,1 H)。MS(ESI,正離子)m/z 493[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.79-0.88(m,1 H),0.92-1.09(m,2 H),1.11-1.25(m,4 H),1.38-1.49(m,1 H),1.96-2.08(m,1 H),2.14-2.24(m,1 H),2.24-2.35(m,1 H),2.62-2.73(m,1 H),4.73-4.82(m,1 H),6.75-6.89(m,2 H),6.97-7.12(m,1 H),7.20-7.37(m,2 H),7.42-7.53(m,1 H),8.08-8.19(m,1 H)。MS(ESI,正離子)m/z 407[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.15(d,J=6.40Hz,3 H),1.48-1.52(m,1 H),2.01-2.11(m,2 H),2.20-2.30(m,1 H),2.38-2.45(m,1 H),2.55-2.70(m,1 H),2.90-3.01(m,1 H),3.02-3.25(m,3 H),3.82(s,3 H),4.60-4.70(m,1 H),4.80-4.95(m,1 H),6.68-6.75(m,2 H),6.91-7.00(m,2 H),7.50-7.58(m,2 H),7.78(s,1 H),7.92(s,1 H)。MS(ESI,正離子)m/z 451[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.14(d,J=6.60Hz,3 H),1.48-1.62(m,1 H),1.79-1.90(m,2 H),1.98-2.10(m,1 H),2.15-2.25(m,2 H),2.35-2.45(m,1 H),2.58-2.70(m,5 H),2.95-3.05(m,2 H),3.80(s,3 H),4.58-4.80(m,2 H),6.68-6.72(m,2 H),6.93-7.02(m,2 H),7.50-7.60(m,2 H),7.76(s,1 H),7.89(s,1 H)。MS(ESI,正離子)m/z 491[M+H]+。
對於(S)-環丙基(2-甲基-5-苯氧基-6-(1H-1,2,3-三唑-4-基)-3,4-二氫喹啉-1(2H)-基)甲酮,使用1-苯甲基-4-溴-1H-1,2,3-三唑作為芳基溴化物來源。使用上文針對中間物1步驟2所概述之氫化條件移除苯甲基。1H NMR(400MHz,CD3OD)δ ppm 0.75-0.87(m,1 H),0.91-1.03(m,2 H),1.11-1.22(m,4 H),1.39-1.52(m,1 H),1.95-2.08(m,1 H),2.17-2.29(m,1 H),2.29-2.38(m,1 H),2.66-2.82(m,1 H),4.73-4.88(m,1 H),6.71-6.89(m,2 H),6.96-7.22(m,1 H),7.21-7.38(m,2 H),7.44-7.53(m,1 H),8.03(s,1 H),8.03-8.14(m,1 H)。MS(ESI,正離子)m/z 375[M+H]+。
MS(ESI,正離子)m/z 465[M+H]+。
MS(ESI,正離子)m/z 481[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.10-1.15(m,3 H),1.30-1.43(m,1 H),1.76-1.86(m,2 H),1.94-2.10(m,2 H),2.20-2.35(m,5 H),2.63-2.76(m,3 H),3.06-3.18(m,2 H),4.15-4.26(m,1 H),4.69-4.81(m,1 H),6.70-6.78(m,2 H),6.97-7.03(m,2 H),7.30(br s,1 H),7.61(d,J=8.40Hz,1 H),7.78(s,1 H),7.95(s,1 H)。MS(ESI,正離子)m/z 449[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.13(d,J=6.30Hz,3 H),1.35-1.51(m,1 H),1.75-1.90(m,2 H),1.95-2.10(m,2 H),2.15-2.33(m,5 H),2.63-2.77(m,3 H),3.08-3.15(m,2 H),4.15-4.27(m,1 H),4.68-4.81(m,1 H),6.73-6.80(m,2 H),7.20-7.39(m,3 H),7.59-7.63(m,1 H),7.78(s,1 H),7.95(s,1 H)。MS(ESI,正離子)m/z 465[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.04(d,J=6.80Hz,3 H),1.41-1.48(m,1 H),1.93-2.02(m,1 H),2.29-2.36(m,1 H),2.51-2.57(m,1 H),3.70(s,3 H),3.77-3.82(m,2 H),3.93-3 99(m,2 H),14.50-4.60(m,1 H),5.08-5.16(m,1 H),6.40-6.45(m,1 H),6.55-6.64(m,1 H),6.95-7.07(m,1 H),7.40-7.51(m,2 H),7.74(s,1 H),7.91(s,1 H)。MS(ESI,正離子)m/z 455[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.03(d,J=6.80Hz,3 H),1.38-1.48(m,1 H),1.91-2.01(m,1 H),2.35-2.48(m,1 H),2.49-2.58(m,1 H),3.70(s,3 H),3.73-3.82(m,2 H),2.85-2.95(m,2 H),4.43-4.53(m,1 H),5.05-5.13(m,1 H),6.65(d,J=8.80Hz,2 H),6.84-6.89(m,1 H),
7.12-7.18(m,2 H),7.47(s,1 H),7.91(s,1 H),7.74(s,1 H)。MS(ESI,正離子)m/z 419[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.75-0.81(m,1 H),0.92-1.02(m,2 H),1.14-1.22(m,4 H),1.39-1.49(m,1 H),1.77-1.88(m,2 H),2.01-2.09(m,3 H),2.21-2.35(m,2 H),2.69-2.79(m,3 H),3.14-3.19(m,2 H),4.02(s,3 H),4.15-4.25(m,1 H),4.75-4.84(m,1 H),6.30(d,J=3.60Hz,1 H),6.69-6.73(m,1 H),6.94-6.98(m,1 H),7.11-7.15(m,1 H),7.38(d,J=6.30Hz,1 H),7.65(d,J=6.30Hz,1 H),7.86(s,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 487[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.78-0.85(m,1 H),0.83-1.01(m,2 H),1.12-1.21(m,4 H),1.38-1.46(m,1 H),1.85-1.95(m,2 H),1.97-2.09(m,3 H),2.20-2.47(m,2 H),2.69-2.81(m,3 H),3.15-3.20(m,2 H),3.74(s,3 H),4.21-4.31(m,1 H),4.75-4.85(m,1 H),6.33-6.38(m,2 H),6.55-6.58(m,1 H),7.15-7.19(m,1 H),7.37-7.41(m,1 H),7.64-7.68(m,1 H),7.81(s,1 H),7.96(s,1 H)。MS(ESI,正離子)
m/z 487[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.63-0.71(m,1 H),0.83-0.91(m,2 H),0.96-1.11(m,4 H),1.25-1.31(m,1 H),1.66-1.78(m,2 H),1.85-1.95(m,3 H),2.10-2.21(m,2 H),2.57-2.69(m,3 H),3.02-3.08(m,2 H),3.61(s,3 H),4.09-4.19(m,1 H),4.63-4.69(m,1 H),6.57-6.61(m,2 H),6.70-6.73(m,2 H),7.24(d,J=8.40Hz,1 H),7.51(d,J=8.40Hz,1 H),7.69(s,1 H),7.81(s,1 H)。MS(ESI,正離子)m/z 487[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.04(d,J=6.40Hz,3 H),1.42-1.49(m,1 H),1.69-1.78(m,2 H),1.90-1.99(m,3 H),2.31-2.39(m,1 H),2.52-2.59(m,1 H),2.61-2.68(m,2 H),3.05-3.11(m,2 H),3.70(s,3 H),3.89(s,3 H),4.05-4.15(m,1 H),4.46-4.58(m,1 H),6.15-6.17(m,1 H),6.52-6.58(m,1 H),6.75-6.81(m,1 H),6.96-9.99(m,1 H),7.44(s,1 H),7.71(s,1 H),7.90(s,1 H)。MS(ESI,正離子)m/z 477[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.15(d,J=6.40Hz,3 H),1.42-1.49(m,1 H),1.78-1.91(m,2 H),2.01-2.13(m,3 H),2.41-2.48(m,1 H),7.26-2.78(m,3 H),3.12-3.20(m,2 H),3.72(s,3 H),3.82(s,3 H),4.18-4.28(m,1 H),4.63-4.72(m,1 H),6.29-6.36(m,1 H),6.53-6.58(m,1 H),7.10-7.17(m,1 H),7.55(s,1 H),7.77(s,1 H),7.91(s,1 H)。MS(ESI,正離子)m/z 477[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.15(d,J=6.40Hz,3 H),1.42-1.49(m,1 H),1.80-1.91(m,2 H),2.01-2.13(m,3 H),2.41-2.48(m,1 H),2.63-2.79(m,3 H),3.12-3.20(m,2 H),3.72(s,3 H),3.81(s,3 H),4.18-4.28(m,1 H),4.63-4.69(m,1 H),6.68-6.70(m,2 H),6.80-6.80(m,2 H),7.53(s,2 H),7.53(s,1 H),7.95(s,1 H)。MS(ESI,正離子)m/z 477[M+H]+。
1H NMR(300MHz,CDCl3)δ ppm 1.10-1.15(m,3 H),1.48-1.59(m,1 H),1.75-1.95(m,2 H),1.96-2.12(m,3 H),2.40-2.50(m,1 H),2.56-2.81(m,3 H),3.16-3.37(m,2 H),3.81(s,3 H),4.08-4.20(m,1 H),4.61-4.72(m,1 H),6.71-6.79(m,2 H),6.89-6.95(m,1 H),7.21-7.26(m,2 H),7.45-7.48(m,1 H),7.63-7.68(m,2 H),7.72(s,1 H)。MS(ESI,正離子)m/z 447[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.14(d,J=6.60Hz,3 H),1.30-1.43(m,1 H),1.76-1.90(m,2 H),1.97-2.11(m,2 H),2.21-2.32((m,5 H),2.65-2.80(m,3 H),3.10-3.21(m,2 H),4.15-4.29(m,1 H),4.71-4.84(m,1 H),6.75-6.81(m,2 H),6.98(d,J=7.20Hz,1 H),7.25-7.34(m,3 H),7.62(d,J=6.60Hz,1 H),7.80(s,1 H),7.95(s,1 H)。MS(ESI,正離子)m/z 431[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.76-0.83(m,1 H),1.13-1.22
(m,4 H),1.29-1.38(m,1 H),1.81-1.94(m,2 H),1.96-2.10(m,3 H),2.22-2.38(m,2 H),2.36-2.78(m,3 H),3.15-3.21(m,2 H),4.24-4.31(m,1 H),4.80-4.85(m,1 H),7.78(s,1 H),7.89(s,1 H)。MS(ESI,正離子)m/z 482[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.11(d,J=6.60Hz,3 H),1.29-1.49(m,1 H),1.75-1.90(m,2 H),1.92-2.01(m,2 H),2.18(s,5 H),2.59-2.69(m,1 H),2.70-2.80(m,2 H),4.15-4.26(m,1 H),4.68-4.81(m,1 H),6.85-6.91(m,1 H),6.95-7.04(m,1 H),7.21-7.33(m,1 H),7.55-7.58(m,1 H),7.71-7.79(m,2 H),7.89(s,1 H),7.97-8.04(m,1 H)。MS(ESI,正離子)m/z 432[M+H]+。
1H NMR(400MHz,DMSO-d 6 )δ ppm 0.63-0.95(m,4 H),1.04-1.31(m,4 H),1.60-1.71(m,3 H),1.82-1.91(m,2 H),2.11-2.23(m,2 H),2.54-2.57(m,2 H),2.95-3.05(m,1 H),3.27-3.40(m,1 H),4.60-4.71(m,1 H),6.81(d,J=8.00Hz,2 H),6.95-7.01(m,1 H),7.25-7.32(m,2 H),7.64-7.70(m,1 H),7.80(s,1 H),8.10(s,1 H)。MS(ESI,正
離子)m/z 475[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.18(d,J=6.40Hz,3 H),1.35-1.46(m 1 H),1.76-1.84(m,2 H),1.96-2.05(m,2 H),2.20-2.32(m,2 H),2.68-2.73(m,3 H),3.15-3.20(m,2 H),3.79(s,3 H),4.17-4.22(m,1 H),4.43-4.53(m,1 H),6.75-6.78(m,2 H),6.95-7.00(m,1 H),7.25-7.31(m,2 H),7.45-7.52(m,1 H),7.79(s,1 H),7.97(s,1 H)。MS(ESI,正離子)m/z 465[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.10-1.25(m,4 H),1.78-1.91(m,2 H),1.96-2.07(m,2 H),2.10-2.20(m,3 H),2.25-2.37(m,2 H),2.67-2.79(m,3 H),3.10-3.18(m,2 H),4.18-4.18(m 1 H),4.77-4.83(m,1 H),6.79-6.82(m,2 H),6.95-7.03(m,1 H),7.25-7.30(m,2 H),7.55-7.59(m,1 H),7.83(s,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 449[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.61-0.85(m,4 H),1.02-1.11(m,4 H),1.60(m,1 H),2.04-2.20(m,6 H),2.62-2.66(m,1 H),3.03-3.10(m,2 H),3.39-3.42(m,2 H),3.63(s,3 H),4.37-4.42(m,1 H),4.60-4.67(m,1 H),6.23-6.28(m,2 H),6.46-6.48(m,1 H),7.03-7.08(m,1 H),7.40-7.42(m,1 H),7.78(s,1 H),7.90(s,1 H)。MS(ESI,正離子)m/z 505[M+H]+。
1H NMR(300MHz,DMSO-d 6)δ ppm 0.99(d,J=6.45Hz,3 H),1.33-1.56(m,2 H),1.80-2.02(m,2 H),2.22-2.40(m,2 H),3.34-3.48(m,1 H),3.55-3.64(m,1 H),3.65(s,3 H),3.69-3.84(m,1 H),4.36-4.61(m,1 H),4.70-4.93(m,1 H),6.52-6.70(m,1 H),6.87-7.04(m,1 H),7.12-7.31(m,1 H),7.52(s,2 H),7.69-7.79(m,1 H),8.06(br d,J=13.49Hz,1 H)。MS(ESI,正離子)m/z 471[M+H]+。
向配備有經空氣填充之氣球之100-mL圓底燒瓶中饋入(S)-1-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(0.300g,1.06mmol)、4-胺甲醯基苯基硼酸(0.437g,2.65mmol)、吡啶(1mL)、二氯甲烷(40mL)、乙酸銅(II)(0.580g,3.20mmol)及4Å分子篩(4.0g)。在室溫下攪拌所得混合物3天。過濾反應混合物,且在真空下濃縮濾液。藉由製備型薄層層析(以3:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之(S)-4-(1-乙醯基-6-溴-2-甲基-1,2,3,4-四氫喹啉-5-基氧基)苯甲醯胺(0.148g,35%)。MS(ESI,正離子)m/z 403,405[M+H]+。
向50-mL圓底燒瓶中饋入(S)-4-(1-乙醯基-6-溴-2-甲基-1,2,3,4-四氫喹啉-5-基氧基)苯甲醯胺(0.068g,0.17mmol)、1-環丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑(0.059g,0.25mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(0.014g,0.02mmol)、碳酸鉀(0.070g,0.50mmol)、1,4-二噁烷(20mL)及水(2mL)。在100℃下攪拌所得混合物隔夜。冷卻至室溫後,使反應混合物通過短矽藻土襯墊,且在真空下濃縮濾液。藉由製備型薄層層析(以1:1乙酸乙酯/石油醚洗提)純化殘餘物。藉由製備型HPLC使用以下條件(Waters I)進一步純化產物:管柱,XBridge Prep C18 OBD管柱,19×150mm 5μm 13nm;移動相,水(0.05%碳酸氫銨)及乙腈
(在12分鐘內15.0%至95%乙腈;流動速率:20mL/min);偵測器,UV 254/220nm。此得到呈灰白色固體狀之(S)-4-(1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基氧基)苯甲醯胺(0.029g,40%)。1H NMR(300MHz,CD3OD)δ ppm 0.93-1.03(m,4 H),1.15(d,J=6.60Hz,3 H,1.19-1.42(m,1 H),2.18-2.27(m,5 H),2.67-2.75(m,1 H),3.56-3.63(m,1 H),4.77-4.79(m,1 H),6.85-6.88(m,2 H),7.37(m,1 H),7.63(d,J=8.40Hz,1 H),7.77(s,1 H),7.81-7.85(m,2 H),7.94(s,1 H)。MS(ESI,正離子)m/z 431[M+H]+。
根據上文針對實例39所概述之程序合成以下化合物:
1H NMR(300MHz,CD3OD)δ ppm 0.95-1.02(m,4 H),1.16(d,J=6.60Hz,3 H),1.30-1.48(m,1 H),2.15-2.40(m,5 H),2.65-2.80(m,1 H),3.55-3.65(m,1 H),4.70-4.89(m,1 H),6.35-6.45(m,1 H),6.95-7.00(m,2 H),7.15-7.25(m,1 H),7.29-7.38(m,1 H),7.61(d,J=8.40Hz,1 H),7.79(s,1 H),7.97(s,1 H)。MS(ESI,正離子)m/z 406[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.89-1.01(m,4 H),1.15(d,
J=6.80Hz,3 H),1.30-1.45(m,1 H),2.05-2.34(m,5 H),2.55-2.78(m,1 H),3.55-3.65(m,1 H),4.68-4.88(m,1 H),6.31-6.38(m,1 H),6.97(t,J=7.20Hz,1 H),7.07(t,J=7.20Hz,1 H),7.25-7.40(m,1 H),7.45-7.50(m,1 H),7.58-7.65(m,1 H),7.81(s,1 H),7.98(s,1 H)。MS(ESI,正離子)m/z 422[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.95-1.01(m,4 H),1.13(d,J=6.80Hz,3 H),1.51-1.65(m,1 H),2.01-2.10(m,1 H),2.35-2.45(m,1 H),2.58-2.71(m,1 H),3.55-3.60(m,1 H),3.81(s,3 H),4.58-4.62(m,1 H),6.69-6.75(m,2 H),6.91-7.01(m,2 H),7.49-7.59(m,2 H),7.74(s,1 H),7.89(s,1 H)。MS(ESI,正離子)m/z 422[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.97-1.01(m,4 H),1.15(d,J=6.60Hz,3 H),1.55-1.65(m,1 H),1.98-2.15(m,1 H),2.35-2.45(m,1 H),2.55-2.68(m,1 H),3.50-3.60(m,1 H),3.83(s,3 H),4.61-4.72(m,1 H),6.90-6.98(m,2 H),7.51-7.71(m,5 H),7.89(s,1 H)。MS(ESI,正離子)m/z 429[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.97-1.01(m,4 H),1.16(d,J=6.60Hz,3 H),1.50-1.68(m,1 H),1.99-2.15(m,1 H),2.35-2.48(m,1 H),2.55-2.75(m,1 H),3.52-3.62(m,1 H),3.82(s,3 H),4.58-4.70(m,1 H),6.75-6.81(m,2 H),7.20-7.28(m,2 H),7.48-7.60(m,2 H),7.73(s,1 H),7.89(s,1 H)。MS(ESI,正離子)m/z 438[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.90-1.01(m,4 H),1.15(d,J=6.60Hz,3 H),1.52-1.65(m,1 H),1.99-2.10(m,1 H),2.10-2.90(br m,2 H),3.50-3.60(m,1 H),3.81(s,3 H),4.61-4.71(m,1 H),6.29-6.38(m,1 H),6.85-6.95(m,1 H),6.98-7.05(m,1 H),7.45-7.62(m,3 H),7.76(s,1 H),7.92(s,1 H)。MS(ESI,正離子)m/z 438[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.89-1.05(m,4 H),1.16(d,
J=6.60Hz,3 H),1.55-1.65(m,1 H),1.98-2.15(m,1 H),2.38-2.48(m,1 H),2.55-2.75(m,1 H),3.50-3.60(m,1 H),3.83(s,3 H),4.60-4.75(m,1 H),6.85(d,J=8.70Hz,2 H),7.50-7.62(m,2 H),7.70-7.92(m,4 H)。
MS(ESI,正離子)m/z 447[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.93-0.99(m,4 H),1.12(d,J=6.60Hz,3 H),1.30-1.45(m,1 H),2.10-2.30(m,5 H),2.55-2.70(m,1 H),3.50-3.60(m,1 H),4.65-4.83(m,1 H),6.93(d,J=9.00Hz,2 H),7.28-7.35(m,1 H),7.55-7.68(m,3 H),7.71(s,1 H),7.90(s,1 H)。MS(ESI,正離子)m/z 413[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.72-0.87(m,1 H),0.95-1.08(m,2 H),1.11-1.22(m,4 H),1.35-1.51(m,1 H),1.95-2.08(m,1 H),2.18-2.28(m,1 H),2.29-2.39(m,1 H),2.69-2.79(m,1 H),4.72-4.84(m,1 H),6.51-6.69(m,2 H),6.71-6.82(m,2 H),6.89-7.02(m,1 H),7.12-7.37(m,2 H),7.39-8.00(m,3 H)。MS(ESI,正離子)m/z 374[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.63-99(m,3 H),1.03(d,J=9.90Hz,4 H),1.30-1.50(m,1 H),1.88-2.01(m,1 H),2.01-2.18(m,1 H),2.20-2.39(m,1 H),2.53-2.62(m,1 H),4.00(s,3 H),4.58-4.79(m,1 H),6.74-6.89(m,2 H),6.90-7.09(m,1 H),7.19-7.37(m,2 H),7.42-7.54(m,1 H),8.03-8.15(m,2 H)。MS(ESI,正離子)m/z 389[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.72-0.89(m,1 H),0.92-1.09(m,2 H),1.11-1.29(m,4 H),1.35-1.52(m,1 H),1.88-2.07(m,1 H),2.08-2.27(m,1 H),2.27-2.46(m,1 H),2.62-2.81(m,4 H),4.74-4.83(m,1 H),6.71-6.98(m,2 H),6.89-7.19(m,1 H),7.28-7.39(m,2 H),7.39-7.69(m,1 H),8.21-8.39(m,1 H)。MS(ESI,正離子)m/z 406[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.72-0.84(m,1 H),0.91-1.03(m,2 H),1.08-1.19(m,4 H),1.29-1.44(m,1 H),1.88-2.07(m,1 H),2.13-2.33(m,2 H),2.62-2.76(m,1 H),3.64(s,3 H),4.76-4.83(m,1 H),6.74-6.79(m,2 H),6.86-7.06(m,1 H),7.20-7.37(m,3 H),7.38-7.47(m,1 H),7.61(s,1 H),7.76-8.02(m,1 H)。MS(ESI,正離子)m/z 388[M+H]+。
MS(ESI,正離子)m/z 514[M+H]+。
MS(ESI,正離子)m/z 486[M+H]+。
1H NMR(400MHz,CDCl3)δ ppm 0.75-0.88(m,1 H),0.93-1.04(m,2 H),1.11-1.23(m,4 H),1.38-1.52(m,1 H),1.95-2.08(m,1 H),2.17-2.29(m,1 H),2.29-2.38(m,1 H),2.66-2.81(m,1 H),4.72-4.86(m,1 H),6.69-6.89(m,2 H),6.96-7.12(m,1 H),7.22-7.37(m,2 H),7.45-7.54(m,1 H),8.03(s,1 H),8.00-8.14(m,1 H)。MS(ESI,正離子)m/z 388[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.00-1.03(m,4 H),1.14(d,J=6.30Hz,3 H),1.36-1.38(m,1 H),2.19-2.24(m,5 H),2.66-2.76(m,1 H),3.57-3.64(m,1 H),4.77(m,1 H),6.75-6.81(m,2 H),6.97-7.04(m,2 H),7.32(m,1 H),7.61(d,J=8.40Hz,1 H),7.75(s,1 H),7.91(s,1 H)。MS(ESI,正離子)m/z 406[M+H]+。
1H NMR(300MHz,CD3OD)δ 0.89-0.94(m,4 H),1.15(d,J=6.60Hz,3 H),1.34-1.44(m,1 H),2.26-2.34(m,5 H),2.60-2.65(m,1 H),
4.70(m,1 H),6.75(d,J=8.40Hz,2 H),7.35(m,1 H),7.60(d,J=8.40Hz,1 H),7.75(s,1 H),7.91(s,1 H)。MS(ESI,正離子)m/z 422[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.73-0.82(m,1H),0.90-1.01(m,2H),1.11-1.21(m,4H),1.25-1.31(m,1H),1.31-1.44(m,1H),1.93-2.09(m,1H),213-2.45(m,2H),2.68-2.77(m,1H),4.73-4.81(m,1H),6.79(d,J=7.80Hz,2H),6.95-7.02(m,1H),7.28-7.33(m,2H),7.39(d,J=8.40Hz,1H),7.66(d,J=8.40Hz,1H),7.91(s,2H)。MS(ESI,正離子)m/z 374[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.92-1.01(m,2H),1.12-1.23(m,4H),1.37-1.46(m,1H),1.96-2.05(m,1H),2.11-2.36(m,2H),2.65-2.78(m,1H),4.56-4.79(m,4H),4.73-4.83(m,1H),5.22-5.34(m,1H),6.75-6.81(m,2H),6.95-7.06(m,2H),7.40(d,J=8.40Hz,1H),7.63(d,J=8.80Hz,1H),7.92(s,1H),8.12(s,1H)。MS(ESI,正離子)m/z 524[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.64-0.81(m,1H),0.89-1.02(m,2H),1.12-1.22(m,4H),1.33-1.45(m,1H),1.92-2.05(m,1H),2.15-4.41(m,2H),2.63-2.77(m,1H),4.54-4.63(m,4H),4.75-4.79(m,1H),5.25-5.34(m,1H),6.79(d,J=7.80Hz,2H),6.95-7.04(m,1H),7.25-7.29(m,2H),7.35-7.42(m,1H),7.63(d,J=8.40Hz,1H),7.90(s,1H),8.11(s,1H)。MS(ESI,正離子)m/z 478[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.75-0.82(m,1 H),0.85-1.14(m,2 H),1.11-1.25(m,4 H),1.40-1.49(m,1 H),1.95-2.08(m,1 H),2.15-2.34(m,2H),2.67-2.76(m,1 H),4.77-4.85(m,1 H),6.78-6.81(m,2 H),6.99-7.04(m,1H),7.25-7.35(m,2H),7.45-7.53(m,1 H),7.66-7.71(m,1 H),8.78(s,1H),8.88(s,1 H)。MS(ESI,正離子)m/z 375[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.04(d,J=6.40Hz,3 H),1.39-1.43(m,1 H),1.81-2.02(m,1 H),2.25-2.42(m,1 H),2.45-2.62(m,1 H),3.71(s,1 H),3.92(s,2 H),4.42-4.65(m,1 H),6.68(d,J=8.00Hz,2 H),6.88(t,J=7.20Hz,1 H),7.16-7.13(m,2 H),7.55(d,J=8.80Hz,1 H),7.88(t,J=6.40Hz,2 H)。MS(ESI,正離子)m/z 379[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.16(d,J=6.60Hz,3 H),1.30-1.40(m,1H),2.15-2.26(m,5 H),2.64-2.74(m,1 H),4.04(s,3 H),4.76-4.80(m,1 H),6.80-6.83(m,2 H),6.99-7.02(m,1 H),7.24-7.30(m,2 H),7.41-7.43(m,1 H),8.01(s,1 H),8.08(d,J=8.40Hz,1 H)。MS(ESI,正離子)m/z 363[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.70-0.80(m,1 H),0.89-1.02(m,2 H),1.13-1.20(m,4 H),1.30-1.45(m,1 H),1.98-2.05(m,1H),2.15-2.35(m,2H),2.70-2.75(m,1 H),3.75(s,3H),4.06(s,3 H),4.79-
4.83(m,1 H),6.33-6.37(m,1 H),6.41-6.43(m,1 H),6.57-6.61(m,1 H),7.14-7.19(m,1 H),7.48(d,J=8.40Hz,1 H),8.00(s,1 H),8.07(d,J=8.40Hz,1 H)。MS(ESI,正離子)m/z 419[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.75-0.83(m,1 H),0.89-1.05(m,2 H),1.10-1.25(m,4 H),1.35-1.45(m,1 H),1.95-2.05(m,1 H),2.15-2.48(m,2 H),2.65-2.75(m,1 H),4.06(s,3 H)4.75-4.85(m,1 H),6.55-6.67(m,2 H),6.69-6.77(m,1 H),7.09-7.27(m,1 H),7.51(d,J=8.70Hz,1 H),8.04(s,1 H),8.07(d,J=8.40Hz,1 H)。MS(ESI,正離子)m/z 407[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.72-0.82(m,1 H),0.87-1.02(m,2 H),1.08-1.21(m,4 H),1.37-1.48(m,1 H),1.95-2.05(m,1 H),2.15-2.36(m,2 H),2.65-2.78(m,1 H),4.71-4.85(m,1 H),6.75-6.83(m,2 H),6.95-7.05(m,2 H),7.48(d,J=8.40Hz,1 H),8.03(s,1 H),8.07(d,J=8.70Hz,1 H)。MS(ESI,正離子)m/z 407[M+H]+。
1H NMR(300MHz,DMSO-d 6 )δ ppm 0.63-0.72(m,1 H),0.83-0.99(m,5 H),1.04-1.31(m,4 H),1.60-1.71(m,3 H),2.11-2.33(m,2 H),2.68-2.77(m,1 H),3.52-3.59(m,1 H),4.71-4.78(m,1 H),6.73-6.78(m,2 H),6.95-7.01(m,1 H),7.25-7.32(m,2 H),7.45-7.55(m,1 H),7.75(s,1 H),7.92(s,1 H)。MS(ESI,正離子)m/z 432[M+H]+。
1H NMR(300MHz,DMSO-d 6 )δ ppm 0.69-0.80(m,1 H),0.91-1.08(m,3 H),1.10-1.36(m,4 H),1.70-1.80(m,1 H),2.11-2.33(m,2 H),2.71-2.79(m,1 H),4.73-4.80(m,1 H),6.76-6.82(m,2 H),6.95-7.03(m,1 H),7.25-7.32(m,2 H),7.51-7.62(m,1 H),7.93(s,1 H)。MS(ESI,正離子)m/z 392[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.95-1.01(m,4 H),1.18(d,
J=6.40Hz,3 H),1.35-1.46(m 1 H),2.20-2.32(m,2 H),2.68-2.73(m,1 H),3.55-3.62(m,1 H),3.79(s,3 H),4.43-4.53(m,1 H),6.75-6.78(m,2 H),6.95-7.02(m,1 H),7.25-7.29(m,2 H),7.41-7.45(m,1 H),7.77(s,1 H),7.93(s,1 H)。MS(ESI,正離子)m/z 422[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.19(d,J=6.40Hz,3 H),1.35-1.46(m 1 H),2.20-2.32(m,2 H),2.68-2.73(m,1 H),3.79(s,3 H),4.46-4.53(m,1 H),6.77-6.79(m,2 H),6.95-7.02(m,1 H),7.25-7.29(m,2 H),7.42-7.45(m,1 H),7.91(br s,2 H)。MS(ESI,正離子)m/z 382[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.95-1.02(m,4 H),1.10-1.23(m,4 H),2.16-2.15(m,3 H),2.24-2.37(m,2 H),2.68-2.80(m,1H),3.55-3.64(m,1H),4.76-4.85(m,1 H),6.77-6.82(m,2H),6.95-7.03(m,1 H),7.25-7.33(m,2H),7.49-7.54(m,1 H),7.81(s,1H),7.98(s,1 H)。MS(ESI,正離子)m/z 406[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.09-1.30(m,4 H),2.11-2.37(m,5 H),2.71-2.81(m,1 H),4.75-4.85(m,1 H),6.81(d,J=7.80Hz,2 H),7.00(t,J=7.20Hz,1 H),7.29(t,J=8.10Hz,2 H),7.57(d,J=10.80Hz,2 H),7.95(s,2 H)。MS(ESI,正離子)m/z 366[M+H]+。
1H NMR(300MHz,CDCl3)δ ppm 0.57-0.72(m,3 H),0.79-0.91(m,3 H),1.91-2.03(m,1 H),1.09(d,J=6.60Hz,3 H),1.25-1.31(m,1 H),1.32-1.34(m,1 H),1.84-1.91(m,2 H),2.13-2.21(m,1 H),2.25-2.37(m,1 H),2.66-2.75(m,1 H),4.78-4.65(m,1 H),6.73-6.81(m,3 H),6.95-7.04(m,1 H),7.19(d,J=7.80Hz,1 H),7.26-7.33(m,2 H)。MS(ESI,正離子)m/z 348[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.55-0.60(m,2 H),0.62-0.77(m,2 H),1.11(d,J=6.60Hz,3 H),1.49-1.59(m,1 H),1.82-1.88(m,1 H),2.00-2.07(m,1 H),2.39-2.49(m,1 H),2.58-2.67(m,1 H),3.79(s,
3 H),4.62-4.68(m,1 H),6.73-6.80(m,3 H),6.95-7.00(m,1 H),7.23-7.26(m,1 H),7.25-7.27(m,1 H),7.43(d,J=8.70Hz,1 H)。MS(ESI,正離子)m/z 338[M+H]+。
將甲醛(37%水溶液,0.015mL,0.198mmol)添加至(S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.010g,0.020mmol)於甲醇(1.0mL)中之溶液中,且攪拌反應混合物2小時。冷卻混合物至0℃,且添加三乙醯氧基硼氫化鈉(8.4mg,0.040mmol)。在0℃下攪拌反應混合物,且使其升溫至室溫隔夜。將反應混合物分配於乙酸乙酯與水之間。用乙酸乙酯萃取水相,且用鹽水洗滌經合併之有機相,經無水硫酸鈉乾燥,過濾且濃縮,得到呈白色固體狀之(S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.0095g,92%)。1H NMR(300MHz,DMSO-d 6)δ ppm 1.06(br d,J=6.74Hz,3 H),1.47-1.69(m,4 H),1.71-2.13(m,4 H),2.19(s,3 H),2.71-2.90(m,2 H),3.72(s,3 H),3.93-4.13(m,1 H),4.32-4.45(m,1 H),4.50-4.65(m,1 H),6.35-6.54(m,1 H),7.45-7.65(m,4 H),7.65-7.72(m,1 H),7.97(s,1 H),8.11(d,J=2.64Hz,1 H)。MS(ESI,正離子)m/z 521[M+H]+。
將(S)-2-((1-乙醯基-6-溴-2-甲基-1,2,3,4-四氫喹啉-5-基)氧基)苯甲腈(0.017g,0.044mmol)、1-甲基-4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)哌啶(0.030g,0.101mmol)、XPhos第2代預催化劑(3.47.mg,4.41μmol)及碳酸銫(0.058g,0.177mmol)於二噁烷(2.0mL)及水(0.400mL)中之混合物在100℃下加熱16小時。經矽藻土過濾反應混合物且濃縮,得到橙色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以0-50%(90:10:1二氯甲烷/甲醇/氫氧化銨)-二氯甲烷進行梯度洗提)純化此物質,得到呈白色固體狀之(S)-2-((1-乙醯基-2-甲基-6-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-1,2,3,4-四氫喹啉-5-基)氧基)苯甲腈(0.017g,82%)。1H NMR(300MHz,DMSO-d 6)δ ppm 1.04(d,J=7.04Hz,3 H),1.27-1.58(m,2 H),1.77-1.97(m,4 H),1.97-2.14(m,4 H),2.17(s,3 H),2.19(s,3 H),2.81(br d,J=11.43Hz,2 H),3.90-4.17(m,1 H),4.62(br s,1 H),6.48(br s,1 H),7.14(t,J=7.62Hz,1 H),7.39-7.56(m,2 H),7.61(d,J=8.50Hz,1 H),7.72(s,1 H),7.89(dd,J=7.77,1.61Hz,1 H),8.01(s,1 H)。MS(ESI,正離子)m/z 470[M+H]+。
根據上文針對實例40所概述之程序,自(2S)-5-環丁氧基-2-甲基-
6-(1-(吡咯啶-3-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯合成(2S)-5-環丁氧基-2-甲基-6-(1-(1-甲基吡咯啶-3-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(400MHz,CD3OD)δ ppm 1.17(d,J=6.40Hz,3 H),1.25-1.48(m,2 H),1.55-1.65(m,1 H),1.99-2.20(m,4 H),2.21-2.28(m,1 H),2.30-2.50(m,2 H),2.75-2.99(m,2 H),3.01-3.20(m,3 H),3.30-3.40(m,1 H),3.55-3.72(m,1 H),3.78(s,3 H),3.90-4.05(m,2 H),4.10-4.25(m,1 H),4.48-4.60(m,1 H),7.20-7.30(m,2 H),7.95(s,1 H),8.09(s,1 H)。MS(ESI,正離子)m/z 425[M+H]+。
根據上文針對實例40所概述之程序,自(2S)-5-環丁氧基-2-甲基-6-(1-(八氫環戊并[c]吡咯-5-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯合成(2S)-5-環丁氧基-2-甲基-6-(1-(2-甲基-八氫環戊并[c]吡咯-5-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(400MHz,CD3OD)1.17(d,J=6.40Hz,3 H),1.28-1.48(m,2H),1.55-1.70(m,1 H),1.99-2.20(m,6 H),2.21-2.50(m,9H),2.79-2.98(m,5 H),3.78(s,3H),4.05-4.15(m,1 H),4.45-4.55(m,1 H),4.85-4.95(m,1 H),7.20-7.30(m,2 H),7.83(s,1 H),8.01(s,1 H)。MS(ESI,正離子)m/z 465[M+H]+。
根據上文針對實例40所概述之程序,自(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(吡咯啶-3-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯合成(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(1-甲基吡咯啶-3-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(400MHz,CD3OD)δ ppm 1.15(d,J=6.40Hz,3 H),1.48-1.65(m,1 H),2.01-2.10(m,1 H),2.12-2.23(m,1 H),2.38-2.45(m,1 H),2.55-2.85(m,2 H),2.92-3.05(m,3 H),3.20-3.30(m,1 H),3.40-4.60(m,1 H),3.82(s,3 H),3.89-3.95(m,2 H),4.58-4.65(m,1 H),5.15-5.25(m,1 H),6.68-6.74(m,2 H),6.95-7.02(m,2 H),7.48-6.60(m,2 H),7.89(s,1 H),7.99(s,1 H)。MS(ESI,正離子)m/z 465[M+H]+。
根據上文針對實例40所概述之程序,自(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(八氫環戊并[c]吡咯-5-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯合成(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(2-甲基-八氫環戊并[c]吡咯-5-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(300MHz,CD3OD)δ ppm 1.14(d,J=6.60Hz,3 H),1.50-1.62(m,1 H),1.85-1.99(m,2 H),2.01-2.20(m,3 H),2.25-2.45(m,6 H),2.55-2.75(m,5 H),4.55-4.70(m,1 H),4.70-4.82(m,1 H),6.65-6.75(m,2 H),
6.90-7.02(m,2 H),7.48-7.52(m,2 H),7.75(s,1 H),7.89(s,1 H)。MS(ESI,正離子)m/z 505[M+H]+。
根據上文針對實例40所概述之程序,自(S)-5-(氮雜環丁烷-3-基氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯及乙醛合成(S)-6-(1-環丙基-1H-吡唑-4-基)-5-(1-乙基氮雜環丁烷-3-基氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(400MHz,CD3OD)δ ppm 0.96(t,J=7.20Hz,3 H),1.05-1.20(m,7 H),1.42-1.55(m,1 H),2.15-2.25(m,1 H),2.40-2.52(m,3 H),2.81-2.95(m,1 H),3.01-3.15(m,2 H),3.41-3.52(m,2 H),3.68-3.71(m,1 H),3.78(s,3 H),4.21-4.28(m,1 H),4.51-4.61(m,1 H),7.20-7.32(m,2 H),7.76(s,1 H),7.99(s,1 H)。MS(ESI,正離子)m/z 411[M+H]+。
根據上文針對實例40所概述之程序,自(S)-5-(氮雜環丁烷-3-基氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯及丙酮合成(S)-6-(1-環丙基-1H-吡唑-4-基)-5-(1-異丙基氮雜環丁烷-3-基氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(400MHz,CD3OD)δ ppm 0.85-0.95(m,6 H),1.05-1.15(m,7 H),1.45-1.55(m,1
H),2.15-2.52(m,3 H),2.80-2.90(m,1 H),3.01-3.11(m,2 H),3.40-3.50(m,2 H),3.67-3.71(m,1 H),3.78(s,3 H),4.15-4.25(m,1 H),4.51-4.62(m,1 H),7.20-7.35(m,2 H),7.76(s,1 H),7.97(s,1 H)。MS(ESI,正離子)m/z 425[M+H]+。
根據上文針對實例40所概述之程序,自(S)-1-(5-(氮雜環丁烷-3-基氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮及乙醛合成(S)-1-(6-(1-環丙基-1H-吡唑-4-基)-5-(1-乙基氮雜環丁烷-3-基氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮。1H NMR(400MHz,CD3OD)δ ppm 0.97(t,J=7.20Hz,3 H),1.05-1.18(m,7 H),1.10-1.35(m,1 H),2.16(s,3 H),2.20-2.40(m,2 H),2.51(q,J=7.20Hz,2 H),2.88-2.98(m,1 H),3.07(t,J=7.20Hz,1 H),3.15(t,J=7.20Hz,1 H),3.41-3.55(m,2 H),3.68-3.75(m,1 H),4.25-4.32(m,1 H),4.65-4.80(m,1 H),7.01-7.12(m,1 H),7.37(d,J=8.00Hz,1 H),7.81(s,1 H),8.02(s,1 H)。MS(ESI,正離子)m/z 395[M+H]+。
根據上文針對實例40所概述之程序,自(S)-1-(5-(氮雜環丁烷-3-基氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-基)乙
酮及丙酮合成(S)-1-(6-(1-環丙基-1H-吡唑-4-基)-5-(1-異丙基氮雜環丁烷-3-基氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮。1H NMR(400MHz,CD3OD)δ ppm 0.89-1.01(m,6 H),1.01-1.15(m,7 H),1.21-1.35(m,1 H),2.16(s,3 H),2.25-2.45(m,3 H),2.85-2.95(m,1 H),3.06(t,J=7.20Hz,1 H),3.15(t,J=7.20Hz,1 H),3.41-3.55(m,2 H),3.68-3.73(m,1 H),4.21-4.29(m,1 H),4.65-4.81(m,1 H),7.01-7.12(m,1 H),7.36(d,J=8.00Hz,1 H),7.81(s,1 H),8.03(s,1 H)。MS(ESI,正離子)m/z 409[M+H]+。
向20-mL微波管中饋入1-[(2S)-6-溴-5-羥基-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮(200mg,0.70mmol)、2-氯-4-甲基吡啶(180mg,1.41mmol)、N,N-二甲基甲醯胺(15mL)、碘化銅(I)(133mg,0.70mmol)及碳酸銫(700mg,2.10mmol)。在120℃下於微波輻射下加熱反應混合物8小時。冷卻至室溫後,用乙酸乙酯(50mL)稀釋所得混合物,用水(3×15mL)及鹽水(15mL)洗滌,經無水硫酸鈉乾燥,過濾且濃縮。經由矽膠管柱層析(以2:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈淡黃色固體狀之1-[(2S)-6-溴-2-甲基-5-[(4-甲基吡啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮(111mg,42%)。MS(ESI,正離子)m/z 375,377[M+H]+。
用惰性氮氣氛圍淨化並維持50-mL圓底燒瓶,且饋入1-[(2S)-6-溴-2-甲基-5-[(4-甲基吡啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮(111mg,0.30mmol)、1,4-二噁烷(15mL)、1-環丙基-4-(四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑(139mg,0.59mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)(30mg,0.04mmol)、碳酸鉀(124mg,0.90mmol)及水(5mL)。在100℃下攪拌所得混合物隔夜。冷卻至室溫後,用乙酸乙酯(10mL)稀釋溶液。分離水層,且用乙酸乙酯(2×20mL)萃取。用鹽水洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以1:1乙酸乙酯/石油醚洗提)純化殘餘物。合併所收集之洗提份,且在真空下濃縮。藉由製備型HPLC使用以下條件(Waters I)進一步純化粗產物:管柱,SunFire Prep C18,5μm,19×100mm;移動相,水(0.05%碳酸氫銨)及乙腈(在7分鐘內65%至85%乙腈,流動速率20mL/min);偵測器,UV 220及254nm。此得到呈灰白色固體狀之1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(4-甲基吡啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮(63.6mg,53%)。1H NMR(300MHz,CD3OD)δ ppm 0.95-1.01(m,4H),1.14(d,J=6.30Hz,3H),1.30-1.45(m,1H),2.10-2.30(m,5H),2.34(s,3H),2.55-2.70(m,1H),3.55-3.65(m,1H),4.68-4.85(m,1H),6.75(s,1H),6.85-6.95(m,1H),7.20-7.32(m,1H),7.55-7.58(m,1H),7.72(s,1H),7.89-7.93(m,2H)。MS(ESI,正離子)m/z 403[M+H]+。
根據針對實例50所概述之程序製得以下實例:
1H NMR(300MHz,CD3OD)δ ppm 0.91-0.99(m,4 H),1.12(d,J=6.60Hz,3 H),1.25-1.45(m,1 H),2.10-2.30(m,5 H),2.37(s,3 H),2.55-2.68(m,1 H),3.55-3.62(m,1 H),4.65-4.83(m,1 H),6.45(d,J=8.40Hz,1 H),6.89(d,J=7.50Hz,1 H),7.20-7.35(m,1 H),7.50-7.62(m,2 H),7.73(s,1 H),7.93(s,1 H)。MS(ESI,正離子)m/z 403[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.68-0.71(m,2 H),0.83-0.90(m,2 H),1.19(d,J=6.60Hz,3 H),1.46(m,1 H),2.18-2.31(m,5 H),2.67(m,1 H),3.43-3.48(m,1 H),4.75-4.80(m,1 H),7.36-7.44(m,1 H),7.57(d,J=4.80Hz,1 H),7.60-7.67(m,1 H),7.74(s,1 H),7.76-7.79(m,1 H),7.89(m,3 H),7.91-7.98(m,1 H),8.61(d,J=8.10Hz,1 H)。MS(ESI,正離子)m/z 439[M+H]+。
用惰性氮氣氛圍淨化並維持50-mL圓底燒瓶,且饋入1-[(2S)-6-溴-5-羥基-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮(350mg,1.23mmol)、N,N-二甲基甲醯胺(10mL)、1,2-二氟-4-硝基苯(415mg,2.61mmol)及碳酸銫(1.3g,3.99mmol)。在110℃下攪拌所得混合物3小時。冷卻至室溫後,將反應混合物傾倒至二氯甲烷(50mL)中,用水(10mL)及鹽水(10mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以5:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之1-[(2S)-6-溴-5-(2-氟-4-硝基苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮(450mg,86%)。MS(ESI,負離子)m/z 421,423[M-H]。
用惰性氮氣氛圍淨化並維持100-mL圓底燒瓶,且饋入1-[(2S)-6-溴-5-(2-氟-4-硝基苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮(500mg,1.18mmol)、鐵粉(331mg,5.91mmol)、氯化銨(128mg,2.37mmol)、四氫呋喃(9mL)、乙醇(3mL)及水(9mL)。在80℃下攪拌所得混合物12小時,接著過濾。濃縮濾液,且用乙酸乙酯稀釋殘餘物,
用水洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到呈淡棕色固體狀之1-[(2S)-5-(4-胺基-2-氟苯氧基)-6-溴-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮(370mg,80%)。MS(ESI,正離子)m/z 393,395[M+H]+。
向100-mL圓底燒瓶中饋入1-[(2S)-5-(4-胺基-2-氟苯氧基)-6-溴-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮(370mg,0.92mmol)及乙酸(5mL)。分數份添加亞硝酸鈉(1.3g,18.8mmol),且在室溫下攪拌混合物30分鐘。添加亞硫酸氫鈉(2.0g,18.8mmol)及乙醇(5mL),且在室溫下攪拌所得混合物12小時。在真空下濃縮反應混合物,用二氯甲烷稀釋,用水及鹽水洗滌,經無水硫酸鈉乾燥,過濾且濃縮。經由矽膠管柱層析(以5:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之1-[(2S)-6-溴-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮(300mg,86%)。MS(ESI,正離子)m/z 378,380[M+H]+。
用惰性氮氣氛圍淨化並維持100-mL圓底燒瓶,且饋入1-[(2S)-6-溴-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮(300mg,0.79mmol)、1,4-二噁烷(18mL)、水(3mL)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)(65mg,0.08mmol)、碳酸銫(776mg,2.37mmol)及4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(378mg,1.00mmol)。在80℃下攪拌所得混合物12小時。冷卻至室溫後,使反應混合物通過短矽藻土襯墊,且在真空下濃縮。經由矽膠管柱層析(以5:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之(S)-4-(4-(1-乙醯基-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(370mg,85%)。MS
(ESI,正離子)m/z 549[M+H]+。
向100-mL圓底燒瓶中饋入(S)-4-(4-(1-乙醯基-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(370mg,0.67mmol)、二氯甲烷(10mL)及三氟乙酸(4mL)。在室溫下攪拌所得溶液2小時。用飽和碳酸鉀水溶液將溶液之pH值調整至8。用乙酸乙酯萃取所得混合物。合併有機層,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以5:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈白色固體狀之(S)-1-(5-(2-氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-基)乙酮(141mg,47%)。1H NMR(300MHz,CD3OD)δ ppm 1.15(d,J=6.60Hz,3 H),1.25-1.45(m,1 H),1.75-1.95(m,2 H),1.97-2.08(m,2 H),2.15-2.35(m,5 H),2.65-2.89(m,3 H),3.09-3.20(m,2 H),4.15-4.29(m,1 H),4.65-4.85(m,1 H),6.35-6.48(m,1 H),6.85-6.98(m,2 H),7.13-7.22(m,1 H),7.27-7.42(m,1 H),7.61(d,J=8.40Hz,1 H),7.81(s,1 H),7.99(s,1 H)。MS(ESI,正離子)m/z 449[M+H]+。
根據針對實例51所概述之程序製得以下實例:
1H NMR(400MHz,CD3OD)δ ppm 1.17(d,J=6.80Hz,3 H),1.55-1.68(m,1 H),1.78-1.92(m,2 H),1.97-2.13(m,3 H),2.45-2.55(m,1 H),2.60-2.79(m,3 H),3.11-3.18(m,2 H),4.18-4.25(m,1 H),4.62-
4.70(m,1 H),6.38-6.42(m,1 H),6.85-6.95(m,2 H),7.15-7.25(m,1 H),7.50-7.62(m,2 H),7.78(s,1 H),7.93(s,1 H)。MS(ESI,正離子)m/z 465[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.75-0.85(m,1 H),8.87-1.01(m,2 H),1.10-1.20(m,4 H),1.39-1.50(m,1 H),1.78-1.90(m,2 H),1.95-2.09(m,3 H),2.15-2.38(m,2 H),2.65-2.80(m,3 H),3.11-3.19(m,2 H),4.18-4.28(m,1 H),4.75-4.85(m,1 H),6.41-6.48(m,1 H),6.85-6.99(m,2 H),7.18-7.28(m,1 H),7.42(d,J=8.40Hz,1 H),7.63(d,J=8.80Hz,1 H),7.81(s,1 H),8.01(s,1 H)。MS(ESI,正離子)m/z 475[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.16(d,J=6.40Hz,3H),1.55-1.64(m,1 H),2.05-2.14(m,1 H),2.45-2.52(m,1 H),2.63-2.72(m,1 H),3.82(s,3 H),3.90-3.98(m,2 H),4.03-4.11(m,2 H),4.63-4.73(m,1 H),5.19-5.29(m,1 H),6.35-6.42(m,1 H),6.83-6.95(m,2 H),7.17-7.25(m,1 H),7.20-7.25(m,1 H),7.53-7.62(m,2 H),7.65-7.70(m,1
H),8.03(s,1 H)。MS(ESI,正離子)m/z 437[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.60-0.70(m,1 H),0.75-0.90(m,2 H),1.00-1.10(m,4 H),1.20-1.30(m,1 H),1.80-1.92(m,1 H),2.05-2.25(m,2 H),2.55-2.65(m,1 H),3.72-3.80(m,2 H),3.85-3.95(m,2 H),4.65-4.75(m,1 H),5.05-5.15(m,1 H),6.25-6.35(m,1 H),6.70-6.90(m,2 H),7.05-7.15(m,1 H),7.30(d,J=8.40Hz,1 H),7.51(d,J=8.40Hz,1 H),7.78(s,1 H),7.95(s,1 H)。MS(ESI,正離子)m/z 447[M+H]+。
根據上文針對實例51所概述之程序製得以下實例,對步驟1作出以下改變:(1)使用1,2,5-三氟-3-硝基苯替代1,2-二氟-4-硝基苯;(2)使用第三丁醇鉀替代碳酸銫;(3)使用四氫呋喃作為溶劑替代DMF;(4)反應在0℃下進行1小時,與在110℃下3小時相對比。
1H NMR(400MHz,CDCl3)δ ppm 1.15(d,J=6.80Hz,3 H),1.55-1.65(m,1 H),1.80-1.95(m,2 H),2.01-2.15(m,3 H),2.35-2.45(m,1 H),2.60-2.80(m,3 H),3.20-3.30(m,2 H),4.08-4.20(m,1 H),4.60-
4.70(m,1 H),6.30-6.40(m,1 H),6.50-6.60(m,1 H),6.85-6.95(m,1 H),7.41(d,J=8.80Hz,1 H),7.60(d,J=8.40Hz,1 H),7.69-7.62(m,2H)。MS(ESI,正離子)m/z 483[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.70-0.80(m,1 H),0.89-1.03(m,2 H),1.09-1.20(m,4 H),1.35-1.45(m,1 H),1.80-2.10(m,5 H),2.15-2.40(m,2 H),2.68-2.80(m,3 H),3.10-3.20(m,2 H),4.20-4.30(m,1 H),4.75-4.85(m,1 H),6.40-6.50(m,1 H),6.70-6.80(m,1 H),7.05-7.12(m,1 H),7.42(d,J=8.40Hz,1 H),7.61(d,J=8.80Hz,1 H),7.80(s,1 H),8.01(s,1 H)。MS(ESI,正離子)m/z 493[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.70-0.82(m,1 H),0.89-1.02(m,2 H),1.10-1.22(m,3 H),1.40-1.52(m,1 H),1.95-2.05(m,1 H),2.15-2.42(m,2 H),2.68-2.80(m,1 H),3.65-3.85(m,2 H),4.10-4.30(m,2 H),4.75-4.88(m,1 H),4.90-5.05(m,1 H),6.40-6.50(m,1 H),6.65-6.75(m,1 H),7.05-7.15(m,1 H),7.43(d,J=8.40Hz,1 H),7.55-7.65(m,1 H),7.80-8.10(m,2 H)。MS(ESI,正離子)m/z 465
[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.17(d,J=6.40Hz,3 H),1.56-1.66(m,1 H),2.07-2.15(m,1 H),2.45-2.51(m,1 H),2.63-2.71(m,1 H),3.82(s,3 H),3.92-3.97(m,2 H),4.06-4.12(m,2 H),4.65-4.71(m,1 H),7.51-7.56(m,1 H),7.57-7.64(m,1 H),7.85(m,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 455[M+H]+。
根據上文針對實例51所概述之程序製得以下實例,對步驟1作出以下改變:(1)使用1,2,3-三氟-4-硝基苯替代1,2-二氟-4-硝基苯;(2)使用第三丁醇鉀替代碳酸銫;(3)使用四氫呋喃作為溶劑替代DMF;(4)反應在0℃下進行1小時,與在110℃下3小時相對比。
1H NMR(400MHz,CD3OD)δ ppm 0.75-0.80(m,1 H),0.85-1.01(m,2 H),1.10-1.21(m,4 H),1.40-1.50(m,1 H),1.80-2.10(m,5 H),2.15-2.40(m,2 H),2.68-2.82(m,3 H),3.10-3.25(m,2H),4.20-4.34(m,1 H),4.75-4.85(m,1 H),6.20-6.30(m,1 H),6.80-6.95(m,2H),7.44(d,J=8.40Hz,1H),7.62(d,J=8.40Hz,1 H),7.79(s,1 H),7.99(s,1 H)。
MS(ESI,正離子)m/z 493[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.72-0.80(m,1 H),0.85-1.01(m,2 H),1.10-1.20(m,4 H),1.40-1.52(m,1 H),1.95-2.05(m,1 H),2.15-2.45(m,2 H),2.65-2.80(m,1 H),3.60-3.82(m,1 H),3.85-4.12(m,3 H),4.75-4.85(m,1 H),5.15-5.30(m,1 H),6.20-6.30(m,1 H),6.82-6.95(m,2 H),7.44(d,J=8.80Hz,1 H),7.62(d,J=8.40Hz,1 H),7.80-7.90(m,1 H),8.02-8.12(m,1 H)。MS(ESI,正離子)m/z 465[M+H]+。
1H NMR(400MHz,CD3OD)1.05(d,J=6.80Hz,3 H),1.55-1.65(m,1 H),1.65-1.80(m,2 H),1.85-2.05(m,3 H),2.30-2.42(m,1 H),2.50-2.65(m,3 H),3.01-3.10(m,2 H),3.71(s,1 H),4.05-4.15(m,1 H),4.52-4.62(m,1 H),6.05-6.15(M,1 H),6.68-6.78(m,2 H),7.41(d,J=8.80Hz,1 H),7.51(d,J=8.80Hz,1 H),7.64(s,1 H),7.83(s,1 H)。MS(ESI,正離子)m/z 483[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.09(d,J=6.40Hz,3 H),1.60-1.66(m,1 H),2.08-2.13(m,1 H),2.46-2.52(m,1 H),2.63-2.71(m,1 H),3.82(s,3 H),3.92-3.98(m,2 H),4.06-4.13(m,2 H),4.64-4.71(m,1 H),5.21-5.28(m,1 H),6.21-6.28(m,1 H),6.84-6.91(m,2 H),7.54(d,J=8.80Hz,1H),7.63(d,J=8.40Hz,1 H),7.85(s,1 H),8.02(s,1 H)。MS(ESI,正離子)m/z 455[M+H]+。
根據上文針對實例51所概述之程序製得以下實例,對步驟1作出以下改變:(1)使用1,2,4-三氟-5-硝基苯替代1,2-二氟-4-硝基苯;(2)使用第三丁醇鉀替代碳酸銫;(3)使用四氫呋喃作為溶劑替代DMF;(4)反應在0℃下進行1小時,與在110℃下3小時相對比。
1H NMR(300MHz,DMSO-d6)δ ppm 0.98-1.16(m,3 H),1.49-1.55(m,1 H),1.95-2.06(m,1 H),2.36-2.44(m,2 H),3.61-3.68(m,2 H),3.69-3.75(m 3 H),3.77-3.85(m,2 H),4.46(m,1 H),5.02-5.20(m,1 H),6.35-6.61(m,1 H),6.85-7.11(m,1 H),7.18-7.43(m,1 H),7.58(s,2 H),7.79(s,1 H),8.13(s,1 H)。MS(ESI,正離子)m/z 455
[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.59-0.72(m,1 H),0.82-0.93(m,2 H),1.02-1.09(m,4 H),1.30-1.43(m,1 H),1.88-1.95(m,1 H),2.13-2.23(m,1 H),2.60-2.70(m,1H),3.53-3.69(m,1 H),3.82-4.05(m,3 H),4.69-4.74(m,1 H),5.13-5.19(m,1 H),6.03-6.11(m,1 H),7.08-7.19(m,1 H),7.34-7.38(m,1 H),7.50-7.55(m,1 H),7.73-7.77(m,1 H),7.93-7.99(m,1 H)。MS(ESI,正離子)m/z 465[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.18(d,J=6.80Hz,3 H),1.50-1.59(m,1 H),2.11-2.22(m,5 H),2.45-2.54(m,1 H),2.63-2.72(m,1 H),3.04-3.11(m,2 H),3.39-3.46(m,2 H),3.83(m,3 H),4.49-4.59(m,1 H),4.66-4.71(m,1 H),6.08-6.16(m,1 H),6.62-6.74(m,1 H),7.18-7.27(m,1 H),7.56(d,J=8.40Hz,1 H),7.65(d,J=8.40Hz,1 H),7.82(s,1H),7.96(s,1 H),8.57(br s,1 H)。MS(ESI,正離子)m/z 483[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 0.75-0.82(m,1 H),0.91-1.02(m,2 H),1.11-1.22(m,4 H),1.41-1.52(m,1 H),1.80-1.91(m,2 H),1.98-2.07(m,3 H),2.21-2.32(m,1 H),2.33-2.41(m,1 H),2.64-2.79(m,3 H),3.11-3.15(m,2 H),4.18-4.29(m,1 H),4.71-4.83(m,1 H),6.12-6.21(m,1 H),6.63-6.74(m,1 H),7.22-7.29(m,1 H),7.45(d,J=8.40Hz,1 H),7.63(d,J=8.40Hz,1H),7.80(m,1 H)。MS(ESI,正離子)m/z 493[M+H]+。
向100-mL 3頸圓底燒瓶中饋入(S)-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(2.00g,6.45mmol)於四氫呋喃(20mL)中之溶液。在0℃下分數份添加第三丁醇鉀(0.797g,7.10mmol),且攪拌混合物5分鐘。接著添加1,2,4-三氟-5-硝基苯(1.72g,9.71mmol),且在0℃下攪拌所得混合物3小時。添加鹽酸(1N水溶液,10mL),且分離水相,且用乙酸乙酯(2×15mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由矽膠管柱層析(以1:10乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之(S)-(6-溴-5-(2,5-二氟-4-硝基苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮與(S)-(6-溴-5-(4,5-二氟-2-硝基苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮之混合物(2.1g,70%)。MS(ESI,正離子)m/z 467,469[M+H]+。
向100-mL圓底燒瓶中饋入(S)-(6-溴-5-(2,5-二氟-4-硝基苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮與(S)-(6-溴-5-(4,5-二氟-2-硝基苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮之混合物(2.1g,4.49mmol)、鐵粉(1.26g,22.5mmol)、氯化銨(0.476g,8.90mmol)、四氫呋喃(10mL)、乙醇(10mL)及水(3mL)。在80℃下攪拌所得混合物隔夜。冷卻至室溫後,過濾反應混合物,且用乙酸乙酯(2×15mL)萃取濾液。在真空下濃縮經合併之有機層,得到呈棕色油狀之(S)-(5-(4-胺基-2,5-二氟苯氧基)-6-溴-2-甲基-3,4-二氫喹啉-1(2H)-
基)(環丙基)甲酮與(S)-(5-(2-胺基-4,5-二氟苯氧基)-6-溴-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮之混合物(1.8g,96%),其未經進一步純化即直接用於下一步驟中。MS(ESI,正離子)m/z 437,439[M+H]+。
向100-mL圓底燒瓶中饋入(S)-(5-(2-胺基-4,5-二氟苯氧基)-6-溴-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮與(S)-(5-(4-胺基-2,5-二氟苯氧基)-6-溴-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮之混合物(1.8g,4.12mmol)及N,N-二甲基甲醯胺(10mL)。逐滴添加亞硝酸第三丁酯(1.2g,11.64mmol)於N,N-二甲基甲醯胺(10mL)中之溶液,且在50℃下攪拌所得溶液4小時。冷卻至室溫後,用乙酸乙酯(100mL)稀釋反應混合物。用水(3×20mL)及鹽水(20mL)洗滌有機層,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以1:10乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之(S)-(6-溴-5-(3,4-二氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮與(S)-(6-溴-5-(2,5-二氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮之混合物(0.600g,35%)。MS(ESI,正離子)m/z 422,424[M+H]+。
向100-mL圓底燒瓶中饋入(S)-1-(6-溴-5-(3,4-二氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮與(S)-1-(6-溴-5-(2,5-二氟苯氧基)-2-甲基-
3,4-二氫喹啉-1(2H)-基)乙酮之混合物(0.130g,0.33mmol)、4-[3-(四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基]哌啶-1-甲酸第三丁酯(0.149mg,0.39mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.027g,0.03mmol)、碳酸鉀(0.137mg,0.99mmol)、1,4-二噁烷(15mL)及水(3mL)。在100℃下攪拌所得混合物隔夜。冷卻至室溫後,使反應混合物通過短矽藻土襯墊,且在真空下濃縮濾液。經由製備型薄層層析(以1:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之4-[4-[(2S)-1-乙醯基-5-(3,4-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基]哌啶-1-甲酸第三丁酯與4-[4-[(2S)-1-乙醯基-5-(2,5-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基]哌啶-1-甲酸第三丁酯之混合物(0.160g,86%)。MS(ESI,正離子)m/z 567[M+H]+。
向100-mL圓底燒瓶中饋入(S)-4-(4-(1-乙醯基-5-(3,4-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯與(S)-4-(4-(1-乙醯基-5-(2,5-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯之混合物(0.160g,0.28mmol)、二氯甲烷(9mL)及三氟乙酸(3mL)。在室溫下攪拌所得溶液2小時。用飽和碳酸鉀水溶液將溶液之pH值調整至7-8。分離水層,且用二氯甲烷(3×10mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。藉由製備型HPLC使用以下條件(Waters I)純化殘餘物:管柱:XBridge RP C18,19×150mm,5μm;移動相:水(0.05%碳酸氫銨)及乙腈(在7.0分鐘內5%至60%乙腈,流動速率:20mL/min);偵測器,UV 254及220nm。此得到:
呈淡黃色固體狀之(S)-1-(5-(3,4-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.031g,24%)。1H NMR(300MHz,CD3OD)δ ppm 1.10(d,J=6.60Hz,3H),1.18-1.41(m,1 H),1.72-1.89(m,2 H),1.92-2.01(m,2 H),2.10-2.31(m,2 H),2.16(s,3 H),2.58-2.74(m,3 H),3.08-3.12(m,2 H),4.10-4.23(m,1 H),4.63-4.83(m,1 H),6.45-6.52(m,1 H),6.60-6.73(m,1 H),7.11(q,J=9.30Hz,1 H),7.20-7.33(m,1 H),7.57(d,J=8.40Hz,1 H),7.74(s,1 H),7.92(s,1 H)。MS(ESI,正離子)m/z 467[M+H]+。
及
呈淡黃色固體狀之(S)-1-(5-(2,5-二氟苯氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.006g,5%)。1H NMR(300MHz,CD3OD)δ ppm 1.11(d,J=6.60Hz,3H),1.25-1.49(m,1 H),1.71-1.87(m,2 H),1.92-2.05(m,2 H),2.19(s,3 H),2.15-2.38(m,2 H),2.59-2.73(m,3 H),3.11(d,J=12.60Hz,2 H),4.10-4.22(m,1 H),4.65-4.85(m,1 H),6.05-6.15(m,1 H),6.57-6.71(m,1 H),7.13-7.21(m,1 H),7.22-7.39(m,1 H),7.58(d,J=8.40Hz,1 H),7.75(s,1 H),7.93(s,1 H)。MS(ESI,正離子)m/z 467[M+H]+。
向40-mL可再密封管中饋入1-[(2S)-6-溴-5-羥基-2-甲基-1,2,3,4-四
氫喹啉-1-基]乙-1-酮(90mg,0.32mmol)、甲烷磺酸2,2-二氯乙酯(82mg,0.42mmol)、碳酸鉀(135mg,0.96mmol)及N,N-二甲基甲醯胺(10mL)。在110℃下攪拌所得混合物48小時。冷卻至室溫後,過濾反應混合物且在減壓下濃縮。藉由製備型薄層層析(以石油醚/乙酸乙酯洗提,10:1、接著1:2)純化殘餘物,得到呈淡黃色油狀之1-[(2S)-6-溴-5-(2,2-二氯乙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮(56mg,46%)。MS(ESI,正離子)m/z 31,383[M+H]+。
用惰性氮氣氛圍淨化並維持50-mL圓底燒瓶,且饋入1-[(2S)-6-溴-5-(2,2-二氯乙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮(43mg,0.11mmol)、1-環丙基-4-(四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑(40mg,0.17mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)(8mg,0.01mmol)、碳酸鉀(31mg,0.22mmol)、1,4-二噁烷(24mL)及水(4mL)。在100℃下於油浴中攪拌所得混合物15小時。冷卻至室溫後,使反應混合物通過短矽藻土襯墊,且在真空下濃縮。藉由製備型薄層層析(以二氯甲烷/甲醇洗提,50:1、接著20:1)純化殘餘物,得到呈白色固體狀之(S,E)-1-(5-(2-氯乙烯氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(12mg,26%)。1H NMR(300MHz,CD3OD)δ ppm 1.05-1.15(m,7 H),1.35-1.58(m,1 H),2.21(s,3 H),2.25-2.50(m,2 H),2.80-2.93(m,1 H),3.65-3.75(m,1 H),4.61(s,1 H),4.70-4.85(m,1 H),5.52(d,J=4.20Hz,1 H),6.52(d,J=4.20Hz,1 H),7.15-7.25(m,1 H),7.54(d,J=8.40Hz,1 H),7.89(s,1 H),8.07(s,1 H)。MS(ESI,正離子)m/z 372[M+H]+。
向100-mL圓底燒瓶中饋入2-(乙氧基亞甲基)丙二腈(4.88g,39.96mmol)、乙醇(50mL)及2-肼基乙-1-醇(4.4g,57.82mmol)。在95℃下攪拌所得溶液10小時。冷卻至室溫後,在真空下濃縮反應混合物。羥由矽膠管柱層析(以9:1二氯甲烷/甲醇洗提)純化殘餘物,得到呈黃色固體狀之5-胺基-1-(2-羥乙基)-1H-吡唑-4-甲腈(3.9g,63%)。MS(ESI,正離子)m/z 153[M+H]+。
向250-mL 3頸圓底燒瓶中饋入5-胺基-1-(2-羥乙基)-1H-吡唑-4-甲腈(6.00g,39.4mmol)及濃硫酸(80mL)。在170℃下攪拌所得溶液隔夜。用冰/水浴冷卻至0℃之後,用氫氧化鈉將溶液之pH值調整至8。用氯仿(4×500mL)萃取所得溶液。合併有機層,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以1:4乙酸乙酯/石油醚洗提)純化殘餘物。藉由用乙醚再結晶進一步純化粗產物,得到呈黃色固體狀之2,3-二氫-1H-咪唑并[1,2-b]吡唑(2.0g,46%)。MS(ESI,正離子)m/z 110[M+H]+。
向100-mL圓底燒瓶中饋入2,3-二氫-1H-咪唑并[1,2-b]吡唑(1.7g,15.6mmol)及乙酸(5mL)。接著緩慢添加溴(7.39g,46.2mmol)於乙酸(47mL)中之溶液。在室溫下攪拌所得溶液3小時。過濾反應混合物
且在真空下濃縮濾液,得到呈黃色固體狀之7-溴-2,3-二氫-1H-咪唑并[1,2-b]吡唑氫溴酸鹽(3.0g,72%)。MS(ESI,正離子)m/z 188,190[M+H]+。
向50-mL圓底燒瓶中饋入7-溴-2,3-二氫-1H-咪唑并[1,2-b]吡唑氫溴酸鹽(100mg,0.53mmol)於二氯甲烷(5mL)中之溶液。添加氫化鈉(30mg,1.20mmol),且在室溫下攪拌反應混合物15分鐘。添加二碳酸二第三丁酯(232mg,1.06mmol)及4-二甲基胺基吡啶(6.5mg,0.05mmol),且在室溫下攪拌所得混合物3.5小時。將反應混合物傾倒至10mL水中,且分離各層。用乙酸乙酯(3×50mL)萃取水層。合併有機層,用鹽水(3×20mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以35%乙酸乙酯-石油醚洗提)純化殘餘物,得到呈白色固體狀之7-溴-2,3-二氫-1H-咪唑并[1,2-b]吡唑-1-甲酸第三丁酯(100mg,65%)。MS(ESI,正離子)m/z 288,290[M+H]+。
向100-mL圓底燒瓶中饋入(2S)-6-溴-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉(1.54g,4.25mmol)、雙(頻哪醇根基)二硼(3.22g,12.68mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(347mg,0.04mmol)、乙酸鉀(1.04g,10.60mmol)及1,4-二噁烷(15mL)。在80℃下攪拌所得混合物隔夜。冷卻至室溫後,將反應混合物傾倒至50mL水中,且分離各層。用乙酸乙酯(3×100mL)萃取水層。合併有機層,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以9%乙酸乙酯-石油醚洗提)純化殘餘物,得到呈黃色油狀之(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(四甲基-1,3,2-二氧硼戊環-2-基)-1,2,3,4-四氫喹啉(0.9g,55%)。MS(ESI,正離子)m/z 386
[M+H]+。
向8-mL可再密封管中饋入(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(四甲基-1,3,2-二氧硼戊環-2-基)-1,2,3,4-四氫喹啉(60mg,0.15mmol)、7-溴-2,3-二氫-1H-咪唑并[1,2-b]吡唑-1-甲酸第三丁酯(45mg,0.16mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(11mg,0.02mmol)、碳酸鈉(30mg,0.28mmol)、1,4-二噁烷(1.5mL)及水(0.5mL)。在80℃下攪拌所得混合物隔夜。冷卻至室溫後,將反應混合物傾倒至20mL乙酸乙酯中。分離有機層,且用水及鹽水洗滌,經無水硫酸鈉乾燥,過濾且在真空下濃縮。經由矽膠管柱層析(以40%乙酸乙酯-石油醚洗提)純化殘餘物,得到呈黑色固體狀之7-((2S)-5-環丁氧基-1-(環丙烷羰基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-2,3-二氫咪唑并[1,2-b]吡唑-1-甲酸第三丁酯(50mg,69%)。MS(ESI,正離子)m/z 493[M+H]+。
向8-mL小瓶中饋入7-((2S)-5-環丁氧基-1-(環丙烷羰基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-2,3-二氫咪唑并[1,2-b]吡唑-1-甲酸第三丁酯(50mg,0.10mmol)、二氯甲烷(3mL)及三氟乙酸(1mL)。在室溫下攪拌所得溶液4小時。在真空下濃縮反應混合物。經由製備型薄層層析(以30%乙酸乙酯-石油醚洗提)純化殘餘物,得到呈白色固體狀之((2S)-5-環丁氧基-6-(2,3-二氫-1H-咪唑并[1,2-b]吡唑-7-基)-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(11.7mg,20%)。1H NMR(400MHz,CD3OD)δ ppm 0.65-0.75(m,1 H),0.85-0.95(m,2 H),1.05-1.15(m,4 H),1.20-1.45(m,2 H),1.58-1.72(m,1 H),1.85-1.95(m,1 H),
1.98-2.45(m,6 H),3.01-3.09(m,1 H),3.99-4.09(m,2 H),4.10-4.22(m,3 H),4.65-4.75(m,1 H),7.14(d,J=8.00Hz,1 H),7.30(d,J=8.00Hz,1 H),7.65(s,1 H)。MS(ESI,正離子)m/z 393[M+H]+。
根據上文針對(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(四甲基-1,3,2-二氧硼戊環-2-基)-1,2,3,4-四氫喹啉(實例54)所概述之程序製備((2S)-5-環丁氧基-2-甲基-6-(1-(甲基磺醯基)-2,3-二氫-1H-吡唑并[1,5-a]咪唑-7-基)-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮,作出以下改變:(1)在步驟4中,使用三乙胺作為鹼以替代氫化鈉,甲烷磺醯氯替代二碳酸二第三丁酯,且不添加DMAP;(2)去除步驟7(Boc脫保護)。1H NMR(400MHz,CD3OD)δ ppm 0.72(d,J=7.60Hz,1 H),0.85-0.96(m,2 H),1.14(d,J=7.60Hz,4 H),1.28-1.46(m,2 H),1.55-1.60(m,1 H),1.88-2.21(m,5 H),2.21-2.33(m,2 H),2.95-3.05(m,1 H),3.08(s,3 H),4.05-4.18(m,1 H),4.26-4.51(m,2 H),4.51-4.69(m,2 H),4.70-4.80(m,1 H),7.13(d,J=8.40Hz,1 H),7.24(d,J=8.00Hz,1 H),7.59(s,1 H)。MS(ESI,正離子)m/z 471[M+H]+。
將正丁基鋰(1.6M,於己烷中,1.48mL,2.37mmol)逐滴添加至2,4-二溴噻唑(0.524g,2.16mmol)於二氯甲烷(11mL)中之-78℃溶液中。在-78℃下攪拌混合物20分鐘,接著分8份添加4-側氧基哌啶-1-甲酸第三丁酯(0.516g,2.59mmol)。在-78℃下攪拌反應混合物10分鐘。移除冷卻浴,且經1小時使反應物升溫至室溫。冷卻反應混合物至-30℃,接著藉由添加飽和氯化銨水溶液淬滅。分離水相且用二氯甲烷萃取,且經無水硫酸鈉乾燥經合併之有機相,過濾且濃縮。經由矽膠管柱層析(Biotage 50g管柱,以5-60%乙酸乙酯-己烷進行梯度洗提)純化殘餘物,得到4-(4-溴噻唑-2-基)-4-羥基哌啶-1-甲酸第三丁酯(0.744g,95%)。MS(ESI,正離子)m/z 363,365[M+H]+。
將(S)-6-溴-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.534g,1.51mmol)、雙(頻哪醇根基)二硼(0.421g,1.66mmol)、乙酸鉀(0.370g,3.77mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二
氯甲烷加合物(0.123g,0.151mmol)於1,4-二噁烷(5.0mL)中之混合物在80℃下加熱隔夜。冷卻反應混合物至室溫,經矽藻土襯墊過濾,且濃縮。經由矽膠管柱層析(Biotage 25g管柱,以5-10%乙酸乙酯-己烷進行梯度洗提)純化殘餘物,得到呈無色油狀之(S)-5-環丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.217g,36%)。MS(ESI,正離子)m/z 402[M+H]+。
將(S)-5-環丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.109g,0.273mmol)、4-(4-溴噻唑-2-基)-4-羥基哌啶-1-甲酸第三丁酯(0.090g,0.248mmol)、XPhos第2代預催化劑(0.019g,0.025mmol)及碳酸銫(0.242g,0.743mmol)於1,4-二噁烷(1.0mL)及水(0.2mL)中之混合物在100℃下加熱2.5小時。冷卻反應混合物至室溫,經矽藻土襯墊過濾,且濃縮。經由矽膠管柱層析(Biotage 25g管柱,以5-50%乙酸乙酯-己烷進行梯度洗提)純化殘餘物,得到(S)-6-(2-(1-(第三丁氧基羰基)-4-羥基哌啶-4-基)噻唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.128g,93%)。MS(ESI,正離子)m/z 558[M+H]+。
將HCl(4M,於1,4-二噁烷中,0.58mL,2.30mmol)添加至(S)-6-(2-(1-(第三丁氧基羰基)-4-羥基哌啶-4-基)噻唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.128g,0.230mmol)於1,4-二噁烷(1.0mL)中之溶液中,且在室溫下攪拌反應混合物1小時。濃縮反應混合物,且將殘餘物分配於乙酸乙酯與飽和碳酸氫鈉水溶液之間。分離水相,且用乙酸乙酯萃取。經無水硫酸鈉乾燥經合併之有機相,過
濾且濃縮。將殘餘物溶解於二氯甲烷中,接著經矽膠栓塞(以10%乙醇-乙酸乙酯洗提)過濾。濃縮濾液,得到(S)-5-環丁氧基-6-(2-(4-羥基哌啶-4-基)噻唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(62mg,59%)。1H NMR(300MHz,DMSO-d6)δ ppm 1.11(d,J=6.45Hz,3 H),1.22-1.72(m,6 H),1.93-2.24(m,7 H),2.39-2.49(m,2 H),2.71-2.96(m,4 H),3.69(s,3 H),4.05-4.20(m,1 H),4.47(dq,J=13.05,6.50Hz,1 H),5.88(s,1 H),7.33(d,J=8.79Hz,1 H),7.69(d,J=8.50Hz,1 H),7.77(s,1 H)。MS(ESI,正離子)m/z 458[M+H]+。
將三氟化二乙基胺基硫(DAST)(0.083mL,0.627mmol)添加至4-(4-溴噻唑-2-基)-4-羥基哌啶-1-甲酸第三丁酯(0.207g,0.570mmol)於二氯甲烷(2.8mL)中之0℃溶液中。5分鐘後,移除冷卻浴,且在室溫下攪拌反應混合物隔夜。添加飽和碳酸氫鈉水溶液,且分離水相,且用二氯甲烷萃取。經無水硫酸鈉乾燥經合併之有機相,過濾且濃縮。經由矽膠管柱層析(Biotage 25g管柱,以5-50%乙酸乙酯-己烷進行梯度洗提)純化殘餘物,得到呈無色蠟狀固體狀之4-(4-溴噻唑-2-基)-4-
氟哌啶-1-甲酸第三丁酯(0.163g,78%)。MS(ESI,正離子)m/z 387,389[M+Na]+。
將(S)-5-環丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.099g,0.247mmol)、4-(4-溴噻唑-2-基)-4-氟哌啶-1-甲酸第三丁酯(0.082g,0.224mmol)、XPhos第2代預催化劑(0.018g,0.022mmol)及碳酸銫(0.219g,0.673mmol)於1,4-二噁烷(1.0mL)及水(0.2mL)中之混合物在100℃下加熱2小時。冷卻反應混合物至室溫,經矽藻土襯墊過濾,且濃縮。經由矽膠管柱層析(Biotage 25g管柱,以25-50%乙酸乙酯-己烷進行梯度洗提)純化殘餘物,得到(S)-6-(2-(1-(第三丁氧基羰基)-4-氟哌啶-4-基)噻唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.072g,57%)。MS(ESI,正離子)m/z 558[M+H]+。
將HCl(4M,於1,4-二噁烷中,0.32mL,1.28mmol)添加至(S)-6-(2-(1-(第三丁氧基羰基)-4-氟哌啶-4-基)噻唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.072g,0.128mmol)於1,4-二噁烷(0.5mL)中之溶液中,且在室溫下攪拌反應混合物1小時。濃縮反應混合物,且藉由質量觸發式製備型HPLC純化殘餘物。合併含產物之洗提份且在Genevac中濃縮,得到(S)-5-環丁氧基-6-(2-(4-羥基哌啶-4-基)噻唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯。MS(ESI,正離子)m/z 460[M+H]+。
將(S)-6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(2.00g,6.66mmol)、(4-氟苯基)硼酸(1.865g,13.33mmol)、乙酸銅(II)(1.33g,7.33mmol)、4Å分子篩(1g)、三乙胺(0.93mL,6.66mmol)及吡啶(1.08mL,13.33mmol)於二氯甲烷(30mL)中之混合物在室溫下在對空氣敞開下攪拌兩天。經矽藻土過濾反應混合物且濃縮濾液,得到棕色油狀物。經由矽膠管柱層析(Biotage 25g管柱,以0-10%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈無色膜狀之(S)-6-溴-5-(4-氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(1.81g,69%)。MS(ESI,正離子)m/z 394,396[M+H]+。
將(S)-6-溴-5-(4-氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.100g,0.254mmol)、3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)氮雜環丁烷-1-甲酸第三丁酯(0.106g,0.304mmol)、XPhos第2代預催化劑(0.004g,0.005mmol)及碳酸銫(0.246g,0.761
mmol)於1,4-二噁烷(2.0mL)及水(0.40mL)中之混合物在100℃下加熱16小時。經矽藻土過濾反應混合物且濃縮,得到綠色油狀物。經由矽膠管柱層析(Biotage 10g管柱,以25-50%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈無色油狀之(S)-6-(1-(1-(第三丁氧基羰基)氮雜環丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.098g,72%)。MS(ESI,正離子)m/z 537[M+H]+。
將三氟乙酸(1.0mL,6.49mmol)添加至(S)-6-(1-(1-(第三丁氧基羰基)氮雜環丁烷-3-基)-1H-吡唑-4-基)-5-(3-氯-4-氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.098g,0.033mmol)於二氯甲烷(1.0mL)中之溶液中,且在室溫下攪拌反應混合物2小時。接著濃縮混合物,且將殘餘物分配於二氯甲烷與飽和碳酸氫鈉水溶液之間。分離有機相,經無水硫酸鈉乾燥,過濾且濃縮,得到呈灰白色固體狀之(S)-6-(1-(1-(第三丁氧基羰基)氮雜環丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.105g,100%)。MS(ESI,正離子)m/z 437[M+H]+。
將(S)-6-(1-(氮雜環丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(105mg,0.241mmol)溶解於甲醇中,且添加甲醛(179μL,2.41mmol)。在周圍溫度下攪拌反應物4小時,接著冷卻至0℃。添加三乙醯氧基硼氫化鈉(0.102g,0.481mmol),且使反應物緩慢升溫至周圍溫度。16小時後,反應完成,且將反應混合物分配於乙酸乙酯與水之間。分離水相且用乙酸乙酯萃取,且用鹽水洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾且濃
縮,得到呈淺橙色油狀之(S)-5-(4-氟苯氧基)-2-甲基-6-(1-(1-甲基氮雜環丁烷-3-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.086g,79%)。1H NMR(300MHz,CDCl3)δ ppm 1.13(d,J=6.45Hz,3 H)1.18-1.20(m,1 H)1.20-1.33(m,1 H)1.55(br dd,J=13.34,5.42Hz,1 H)1.94-2.18(m,4 H)2.22-2.49(m,1 H)2.49-2.69(m,1 H)3.81(s,3 H)4.26(br s,1 H)4.61-4.89(m,2 H)5.13-5.32(m,1 H)6.63-6.82(m,2 H)6.83-7.01(m,2 H)7.40(d,J=8.79Hz,1 H)7.54-7.67(m,2 H)7.79-8.02(m,1 H)。MS(ESI,正離子)m/z 451[M+H]+。
根據上文針對實例58所概述之程序,自(S)-6-溴-5-(4-氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯及4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯合成(S)-5-(4-氟苯氧基)-2-甲基-6-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(300MHz,CDCl3)δ ppm 0.74-1.01(m,1 H),1.14(d,J=6.74Hz,3 H),1.47-1.82(m,2 H),1.99-2.07(m,1 H),2.31(br s,1 H),2.44(dt,J=17.00,5.72Hz,1 H),2.52-2.72(m,1 H),2.77(s,3 H),3.16(br s,1 H),3.27-3.62(m,2 H),3.82(s,3 H),4.43(br s,1H),4.57-4.84(m,2 H),4.85-5.10(m,1 H),6.68-6.75(m,2 H),6.86-6.98(m,2 H),7.27(s,1 H),7.41(d,J=8.50Hz,1 H),7.57-7.78(m,2 H)。MS(ESI,正離子)m/z 479[M+H]+。
用氮氣淨化(S)-6-溴-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.096g,0.254mmol)、3-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)氮雜環丁烷-1-甲酸第三丁酯(0.113g,0.325mmol)及碳酸銫(0.264g,0.811mmol)於二噁烷(2.0mL)及水(0.40mL)中之混合物以移除任何氧氣。添加XPhos第2代預催化劑(0.020g,0.027mmol),且用氮氣淨化反應物,接著在100℃下加熱16小時。濃縮反應混合物,且將殘餘物分配於乙酸乙酯與飽和碳酸氫鈉水溶液之間。分離水相且用乙酸乙酯萃取,且濃縮經合併之有機相,得到油狀物。經由矽膠管柱層析(Biotage 10g管柱,以25-50%乙酸乙酯-己烷進行梯度洗提)純化此物質,得到呈無色油狀之(S)-6-(1-(1-(第三丁氧基羰基)氮雜環丁烷-3-基)-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.132g,98%)。MS(ESI,正離子)m/z 497[M+H]+。
將三氟乙酸(1.0mL,6.49mmol)添加至(S)-6-(1-(1-(第三丁氧基羰基)氮雜環丁烷-3-基)-1H-吡唑-4-基)-5-(3-氯-4-氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.132g,0.265mmol)於二氯甲烷(1.0mL)中之溶液中,且在室溫下攪拌反應混合物2小時。濃縮反應混合物,且將殘餘物分配於二氯甲烷與飽和碳酸氫鈉水溶液之間。分離有機相,經無水硫酸鈉乾燥,過濾且濃縮,得到呈灰白色固體狀之(S)-6-(1-(氮雜環丁烷-3-基)-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.115g,88%)。MS(ESI,正離子)m/z 396[M+H]+。
將(S)-6-(1-(氮雜環丁烷-3-基)-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸酯(0.115g,0.290mmol)溶解於甲醇(3.6mL)中,且添加甲醛(216μL,2.90mmol)。在周圍溫度下攪拌反應物4小時且冷卻至0℃。添加三乙醯氧基硼氫化鈉(0.123g,0.58mmol),且使反應物緩慢升溫至周圍溫度。16小時後,將反應物分配於乙酸乙酯與水之間。分離水相且用乙酸乙酯萃取,且用鹽水洗滌經合併之有機相,且經無水硫酸鈉乾燥,過濾且濃縮,得到呈淺橙色油狀之(S)-5-環丁氧基-2-甲基-6-(1-(1-甲基氮雜環丁烷-3-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.115g,97%)。1H NMR(300MHz,CDCl3)δ ppm 1.16-1.33(m,4 H),1.33-1.41(m,1 H),1.41-1.54(m,1 H),1.55-1.68(m,1 H),1.95-2.30(m,4 H),2.34-2.67(m,1 H),2.92(dt,J=15.68,6.08Hz,1 H),3.06(s,2 H),3.22(br d,J=15.54Hz,1 H),3.33-3.64(m,2 H),3.69-3.89(m,3 H),4.33(br s,2 H),4.54(dq,J=13.34,6.69Hz,1 H),4.78-4.97(m,1 H),5.32(五重峰,J=7.40Hz,1 H),7.08-7.43(m,2 H),7.68-7.87(m,1 H),7.96(s,1 H)。MS(ESI,正離子)
m/z 411[M+H]+。
根據上文針對實例60所概述之程序,自(S)-6-溴-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯及4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯合成(S)-5-環丁氧基-2-甲基-6-(1-(1-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(300MHz,CDCl3)δ ppm 0.64-0.99(m,1 H),1.12-1.26(m,4 H),1.39-1.52(m,1 H),1.55-1.67(m,1 H),1.97-2.14(m,5 H),2.14-2.27(m,1 H),2.30-2.58(m,2 H),2.63(br s,1 H),2.73-2.78(m,1 H),2.79(s,3 H),2.84-3.09(m,1 H),3.15(br s,1 H),3.37-3.63(m,4 H),3.64-3.92(m,3 H),4.54(s,1 H),7.14-7.39(m,2 H),7.81(d,J=8.21Hz,2 H)。MS(ESI,正離子)m/z 439[M+H]+。
向100-mL 3頸圓底燒瓶中饋入2-溴-3-甲基吡啶(1.00g,5.81mmol)及乙醚(30mL)。在0℃下於攪拌下逐滴添加氯化異丙基鎂溶液(2M,於THF中,8.0mL,16.0mmol),且在0℃下攪拌所得溶液3小
時。添加硼酸三異丙酯(2.6g,13.8mmol),且在室溫下攪拌溶液1小時。接著藉由添加飽和氯化銨水溶液(10mL)淬滅反應物。分離水層,且用乙酸乙酯(2×10mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮,得到呈淡黃色油狀之3-甲基吡啶-2-基硼酸(0.730g,92%)。MS(ESI,正離子)m/z 138[M+H]+。
向配備有經空氣填充之氣球之100-mL圓底燒瓶中饋入(S)-1-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(0.200g,0.70mmol)、吡啶(1mL)、乙酸銅(II)(0.382g,2.10mmol)、3-甲基吡啶-2-基硼酸(0.190g,1.39mmol)及N,N-二甲基甲醯胺(8mL)。在90℃下攪拌所得混合物隔夜。冷卻至室溫後,過濾反應混合物,且在真空下濃縮濾液。藉由矽膠管柱層析(以1:8乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之(S)-1-(6-溴-2-甲基-5-(3-甲基吡啶-2-基氧基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.129g,49%)。MS(ESI,正離子)m/z 375,377[M+H]+。
向100-mL圓底燒瓶中饋入(S)-1-(6-溴-2-甲基-5-(3-甲基吡啶-2-基氧基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.129g,0.34mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)(0.025g,0.03mmol)、碳酸鉀(0.142g,1.03mmol)、1-環丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑(0.243g,1.04mmol)、1.4-二噁烷(10mL)及水(2mL)。在100℃下攪拌所得混合物隔夜。冷卻至室溫後,使反應混合物通過短矽藻土襯墊,且在真空下濃縮濾液。藉由製備型薄層層析(以50%乙酸乙酯-石油醚洗提)純化殘餘物。藉由製備型HPLC使用以下條件(Waters I)進
一步純化產物:管柱,SunFire Prep C18,19×150mm;移動相,水(0.05%碳酸氫銨)及乙腈(在10分鐘內54%至80%乙腈,流動速率:20mL/min);偵測器,UV 220及254nm。此得到呈灰白色固體狀之(S)-1-(6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(3-甲基吡啶-2-基氧基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.0285g,21%)。1H NMR(300MHz,CD3OD)δ ppm 1.00-1.03(m,4 H),1.16(d,J=6.60Hz,3 H),1.32-1.42(m,1 H),2.20-2.28(m,5 H),2.48(s,3 H),2.54-2.59(m,1 H),3.57-3.64(m,1 H),4.75-4.80(m,1 H),6.95-7.00(m,1 H),7.22-7.27(m,1 H),7.54(d,J=8.40Hz,1 H),7.63(s,1 H),7.72-7.77(m,2 H),7.80(s,1 H)。MS(ESI,正離子)m/z 403[M+H]+。
根據針對實例62所概述之程序製得以下實例:
1H NMR(300MHz,CD3OD)δ ppm 1.01-1.04(m,4 H),1.16(d,J=6.60Hz,3 H),1.30-1.40(m,1 H),2.06-2.27(m,8 H),2.63-2.68(m,1 H),3.57-3.62(m,1 H),4.80(m,1 H),6.80(d,J=8.40Hz,1 H),7.31-7.32(m,1 H),7.56-7.66(m,2 H),7.74(s,1 H),7.88-7.92(m,2 H)。MS(ESI,正離子)m/z 403[M+H]+。
1H NMR(300MHz,CD3OD)0.90-1.02(m,4H),1.14(d,J=6.30Hz,3H),1.42(br s,1H),2.10-2.32(m,5H),2.55-2.69(m,1H),3.52-3.69(m,1H),4.65-4.90(m,1H),7.00(d,J=8.70Hz,1H),7.30(br s,1H),7.53(d,J=8.70Hz,1H),7.70(s,1H),7.75-7.85(m,1H),7.90(s,1H),8.00(d,J=2.70Hz,1H)。MS(ESI,正離子)m/z 423[M+H]+。
向100-mL圓底燒瓶中饋入2-氯-7H-嘌呤(0.200g,1.29mmol)、甲苯(20mL)、對甲苯磺酸(0.011g,0.06mmol)、3,4-二氫-2H-哌喃(0.328g,3.90mmol),且在80℃下攪拌所得溶液2小時。冷卻至室溫後,在真空下濃縮反應混合物。藉由矽膠管柱層析(以1:5乙酸乙酯/石油醚洗提)純化殘餘物,得到呈棕色油狀之2-氯-7-(四氫-2H-哌喃-2-基)-7H-嘌呤(0.245g,79%)。MS(ESI,正離子)m/z 239[M+H]+。
向100-mL圓底燒瓶中饋入(S)-1-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(0.170g,0.60mmol)、2-氯-7-(四氫-2H-哌喃-2-基)-
7H-嘌呤(0.200g,0.84mmol)、碳酸鉀(0.247g,1.79mmol)及N,N-二甲基甲醯胺(6mL)。在110℃下攪拌所得混合物隔夜。冷卻至室溫後,過濾反應混合物,且在真空下濃縮濾液。藉由製備型薄層層析(以1:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之1-((S)-6-溴-2-甲基-5-(7-(四氫-2H-哌喃-2-基)-7H-嘌呤-2-基氧基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.200g,69%)。MS(ESI,正離子)m/z 486,488[M+H]+。
向100-mL圓底燒瓶中饋入1-((S)-6-溴-2-甲基-5-(7-(四氫-2H-哌喃-2-基)-7H-嘌呤-2-基氧基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.200g,0.41mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)(0.030g,0.04mmol)、碳酸鉀(0.170g,1.23mmol)、1-環丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑(0.288g,1.23mmol)、1,4-二噁烷(20mL)及水(2mL)。在100℃下攪拌所得混合物隔夜。冷卻至室溫後,使反應混合物通過短矽藻土襯墊,且在真空下濃縮濾液。藉由製備型薄層層析(以1:2乙酸乙酯/石油醚洗提)純化殘餘物,得到呈淡黃色油狀之1-((S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(7-(四氫-2H-哌喃-2-基)-7H-嘌呤-2-基氧基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.150g,71%)。MS(ESI,正離子)m/z 514[M+H]+。
向100-mL圓底燒瓶中饋入1-((S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(7-(四氫-2H-哌喃-2-基)-7H-嘌呤-2-基氧基)-3,4-二氫喹啉-1(2H)-基)乙酮(0.150g,0.29mmol)、HCl(6M水溶液,3mL)及甲醇(20mL)。在40℃下攪拌所得溶液隔夜。冷卻至室溫後,用飽和碳酸鈉水
溶液將反應混合物之pH值調整至7-8。濃縮所得混合物以移除甲醇,且添加乙酸乙酯。分離水層,且用乙酸乙酯(3×20mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾且濃縮。藉由製備型HPLC使用以下條件(Waters I)純化殘餘物:管柱,SunFire Prep C18,19×150mm;移動相,水(0.05%碳酸氫銨)及乙腈(在10分鐘內37%至58%乙腈,流動速率:20mL/min);偵測器,UV 220及254nm。此得到呈黃色固體狀之(S)-1-(5-(7H-嘌呤-2-基氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(0.030g,24%)。1H NMR(300MHz,CD3OD)δ ppm 0.86-1.00(m,4 H),1.16(d,J=6.30Hz,3 H),1.21-1.49(m,1 H),2.18-2.47(m,5 H),2.63-2.72(m,1 H),3.52-3.59(m,1 H),4.72-4.80(m,1 H),7.19-7.30(m,1 H),7.56(d,J=8.40Hz,1 H),7.60(s,1 H),7.99(s,1 H),8.41(s,1 H),8.79(s,1 H)。MS(ESI,正離子)m/z 430[M+H]+。
向100-mL圓底燒瓶中饋入4-(四甲基-1,3,2-二氧硼戊環-2-基)-1H-
吡唑-1-甲酸第三丁酯(250mg,0.85mmol)、(S)-6-溴-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(317mg,0.89mmol)、碳酸鈉(150mg,1.42mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)(58mg,0.18mmol)、1,4-二噁烷(10mL)及水(2mL)。在100℃下於油浴中攪拌所得混合物隔夜。冷卻至室溫後,將反應混合物傾倒至10mL水中,且分離各層。用乙酸乙酯(3×10mL)萃取水層。合併有機層,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以5:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之(S)-5-環丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(200mg,52%)。MS(ESI,正離子)m/z 342[M+H]+。
向100-mL圓底燒瓶中饋入(S)-5-環丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(200mg,0.59mmol)及N,N-二甲基甲醯胺(10mL)。添加氫化鈉(47mg,1.96mmol),且在室溫下攪拌混合物30分鐘。添加7-氧雜-3-氮雜雙環[4.1.0]庚烷-3-甲酸第三丁酯(995mg,4.99mmol),且在80℃下於油浴中攪拌所得溶液隔夜。冷卻至室溫後,將反應混合物傾倒至乙酸乙酯(50mL)中,用水(3×10mL)及鹽水(10mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以10:1二氯甲烷/甲醇洗提)純化殘餘物,得到呈黃色油狀之(2S)-6-(1-[1-[(第三丁氧基)羰基]-3-羥基哌啶-4-基]-1H-吡唑-4-基)-5-環丁氧基-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(250mg,78%)。MS(ESI,正離子)m/z 541[M+H]+。
向50-mL圓底燒瓶中饋入(2S)-6-(1-[1-[(第三丁氧基)羰基]-3-羥基
哌啶-4-基]-1H-吡唑-4-基)-5-環丁氧基-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(250mg,0.46mmol)及N,N-二甲基甲醯胺(5mL)。添加氫化鈉(78mg,3.25mmol),且在室溫下攪拌混合物30分鐘。添加碘甲烷(0.079mL,1.28mmol),且在室溫下攪拌所得溶液4小時。接著將反應混合物傾倒至20mL水中,且用乙酸乙酯(3×20mL)萃取。合併有機層,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以1:5乙酸乙酯/石油醚洗提)純化殘餘物,得到呈無色油狀之(2S)-6-(1-(1-(第三丁氧基羰基)-3-甲氧基哌啶-4-基)-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(80mg,31%)。MS(ESI,正離子)m/z 555[M+H]+。
向25-mL圓底燒瓶中饋入(2S)-6-(1-(1-(第三丁氧基羰基)-3-甲氧基哌啶-4-基)-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(40mg,0.07mmol)、二氯甲烷(3mL)及三氟乙酸(1mL)。在室溫下攪拌所得溶液1小時。在真空下濃縮反應混合物。藉由製備型HPLC使用以下條件純化殘餘物:管柱:Xbridge RP C18,19×150mm,5μm;移動相:水(0.05%三氟乙酸)、乙腈(在9分鐘內15%至43%乙腈,流動速率:20mL/min);偵測器,254/220nm。合併洗提份且在真空下濃縮,且經由逆相層析(乙腈/水(0.05%碳酸氫銨)=5/95-95/5)進一純化殘餘物。合併洗提份,濃縮且凍乾,得到呈灰白色固體狀之(2S)-5-環丁氧基-6-[1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(14mg,43%)。1H NMR(300MHz,CD3OD)δ ppm 1.10-1.20(m,3 H),1.25-1.50(m,2 H),1.50-1.70(m,1 H),1.95-2.52(m,8 H),2.80-3.10(m,2 H),3.10-3.35(m,4 H),3.55-3.90(m,6 H),4.05-3.15(m,1 H),4.40-4.65(m,2 H),7.18-7.35
(m,2 H),7.93(s,1 H),8.01-8.12(m,2 H)。MS(ESI,正離子)m/z 455[M+H]+。
根據針對實例52所概述之程序,自(S)-6-溴-5-(4-氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯合成(2S)-5-(4-氟苯氧基)-6-(1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(400MHz,CD3OD)δ ppm 1.16(d,J=6.40Hz,3H),1.55-1.65(m,1 H),2.01-2.12(m,1 H),2.20-2.50(m,3 H),2.60-2.72(m,1 H),2.90-3.01(m,3 H),3.08-3.15(m,2 H),3.45-3.75(m,3 H),3.82(s,3 H),4.25-4.35(m,1 H),4.60-4.70(m,1 H),6.65-4.75(m,2 H),6.90-7.00(m,2 H),7.50-7.60(m,2 H),7.82-8.01(m,2 H)。MS(ESI,正離子)m/z 495[M+H]+。
根據上文針對實例40所概述之程序,自(2S)-6-(1-(1-(第三丁氧基羰基)-3-甲氧基哌啶-4-基)-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯及甲醛合成(2S)-5-環丁氧基-6-(1-(3-甲氧基-1-甲基哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(300MHz,CD3OD)δ ppm 1.19(d,J=6.00Hz,3 H),1.20-1.50
(m,2 H),1.55-1.85(m,1 H),2.01-2.22(m,4 H),2.22-2.68(m,4 H),2.88-3.08(m,5 H),3.10-3.22(m,2 H),3.50-3.60(m,1 H),3.80(s,3 H),3.81-4.01(m,1 H),4.05-4.25(m,1 H),4.30-4.45(m,1 H),4.48-4.70(m,1 H),7.20-7.40(m,2 H),7.85-8.10(m,2 H)。MS(ESI,正離子)m/z 469[M+H]+。
根據上文針對實例40所概述之程序,自(2S)-5-(4-氟苯氧基)-6-(1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯及甲醛合成(2S)-5-(4-氟苯氧基)-6-(1-(3-甲氧基-1-甲基哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(400MHz,CD3OD)δ ppm 1.16(d,J=6.80Hz,3 H),1.50-1.65(m,1 H),1.98-2.11(m,1 H),2.15-2.22(m,1 H),2.40-2.70(m,3 H),2.78-3.01(m,5 H),3.02-3.18(m,1 H),3.42-3.85(m,8 H),4.15-4.25(m,1 H),4.55-4.72(m,1 H),6.72-6.80(m,2 H),6.90-7.01(m,2 H),7.50-7.62(m,2 H),7.80-8.10(m,2 H)。MS(ESI,正離子)m/z 509[M+H]+。
向配備有經空氣填充之氣球之100-mL圓底燒瓶中饋入(S)-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.800g,2.58mmol)、苯基硼酸(0.937g,7.68mmol)、吡啶(0.83mL,10.30mmol)、二氯甲烷(50mL)及乙酸銅(II)(0.934g,5.14mmol)。在40℃下攪拌所得混合物1天。冷卻混合物至室溫且過濾。在真空下濃縮濾液,且經由矽膠管柱層析(以5-10%乙酸乙酯/石油醚進行梯度洗提)純化殘餘物,得到呈白色固體狀之(S)-(6-溴-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.700g,70%)。MS(ESI,正離子)m/z 386,388[M+H]+。
向100-mL圓底燒瓶中饋入(S)-(6-溴-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.400g,1.04mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.083g,0.10mmol)、碳酸銫(0.985g,3.02mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-甲酸第三丁酯(0.343g,1.17mmol)、1,4-二噁烷(10mL)及水(3mL)。在100℃下攪拌所得混合物隔夜且冷卻至室溫。使反應混合物通過短矽藻土襯墊,且在真空下濃縮濾液。經由矽膠管柱層析(以10-25%乙酸乙酯/石油醚進行梯度洗提)純化殘餘物,得到呈淡黃色固體狀之(S)-環丙基(2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.200g,52%)。MS(ESI,正離子)m/z 374[M+H]+。
向100-mL圓底燒瓶中饋入(S)-環丙基(2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.200g,0.56mmol)、碳酸銫
(0.114g,0.35mmol)、N,N-二甲基甲醯胺(5mL)及4-溴-1λ6-硫雜環己烷-1,1-二酮(0.114g,0.53mmol)。在100℃下攪拌所得混合物4小時,接著冷卻至室溫。用乙酸乙酯(50mL)稀釋反應混合物且用水(3×10mL)洗滌。經無水硫酸鈉乾燥有機相,過濾,且在真空下濃縮。經由矽膠管柱層析(以25-50%乙酸乙酯/石油進行梯度洗提)純化殘餘物。
藉由製備型HPLC使用以下條件(Waters I)進一步純化產物:管柱,SunFire Prep C18,5μm,19×100mm;移動相,水及乙腈(在7分鐘內55%至75%乙腈,流動速率:20mL/min);偵測器,UV 220及254nm。此得到呈白色固體狀之3-{4-[(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環己烷-1,1-二酮(0.122g,43%)。1H NMR(400MHz,CD3OD)δ ppm 0.76-0.82(m,1 H),0.92-1.02(m,2 H),1.13-1.22(m,4 H),1.42-1.50(m,1 H),1.95-2.08(m,3 H),2.08-2.13(m,1 H),2.14-2.37(m,3 H),2.68-2.77(m,1 H),3.11-3.19(m,2 H),3.37(s,1 H),3.53-3.60(m,1 H),4.66-4.72(m,1 H),4.74-4.81(m,1 H),6.79(d,J=8.00Hz,2 H),6.98(t,J=7.60Hz,1 H),7.23(t,J=7.60Hz,2 H),7.62(d,J=8.40Hz,1 H),7.83(s,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 506[M+H]+。
根據針對實例71所概述之程序製得以下實例:
1H NMR(300MHz,CD3OD)δ ppm 0.73-0.81(m,1 H),0.91-1.01(m,2 H),1.13(d,J=6.30Hz,4 H),1.32-147(m,1 H),1.94-2.15(m,5
H),2.16-2.34(m,3 H),2.78-2.87(m,1 H),3.13-3.19(m,2 H),3.53-3.62(m,1 H),4.65-4.79(m,2 H),6.74-6.79(m,2 H),6.93-7.02(m,2 H),7.38(d,J=8.70Hz,1 H),7.60(d,J=8.40Hz,1 H),8.02(s,1 H)。
MS(ESI,正離子)m/z 524[M+H]+。
向100-mL圓底燒瓶中饋入4-羥基-2-側氧基哌啶-1-甲酸第三丁酯(1.00g,4.65mmol)於二氯甲烷(30mL)中之溶液。添加三乙胺(1.03mL,7.42mmol)及4-二甲基胺基吡啶(0.057g,0.47mmol),且冷卻混合物至0℃。逐滴添加甲烷磺醯氯(0.47mL,6.05mmol),且在室溫下攪拌所得溶液1小時。用水(2×10mL)及0.1M HCl水溶液(2×10mL)洗滌反應混合物,經無水硫酸鈉乾燥,過濾,且在真空下濃縮,得到呈棕色固體狀之4-(甲基磺醯氧基)-2-側氧基哌啶-1-甲酸第三丁酯(0.900g,66%)。MS(ESI,正離子)m/z 294[M+H]+。
向100-mL圓底燒瓶中饋入4-(四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-甲酸第三丁酯(0.250g,0.85mmol)、(S)-6-溴-5-環丁氧基-2-
甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.317g,0.89mmol)、碳酸鈉(0.150g,1.42mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.070g,0.085mmol)、1,4-二噁烷(10mL)及水(2mL)。在100℃下攪拌所得混合物隔夜,冷卻至室溫,且添加水(10mL)。分離水層,且用乙酸乙酯(3×10mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由矽膠管柱層析(以5:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之(S)-5-環丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.200g,52%)。MS(ESI,正離子)m/z 342[M+H]+。
向8-mL可再密封管中饋入(S)-5-環丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.050g,0.15mmol)及N,N-二甲基甲醯胺(2mL)。添加氫化鈉(60%分散液,於礦物油中,0.012g,0.50mmol),且在室溫下攪拌所得混合物15分鐘。添加4-(甲基磺醯氧基)-2-側氧基哌啶-1-甲酸第三丁酯(0.141g,0.48mmol),且在50℃下攪拌所得混合物隔夜。冷卻反應混合物至室溫,且添加水(10mL)。分離水相,且用乙酸乙酯(3×10mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。藉由製備型HPLC使用以下條件(Waters I)純化殘餘物:管柱,Xbridge RPC18,19×150mm,5μm;移動相,水(0.05%碳酸氫銨)及乙腈(在8分鐘內13%至60%乙腈;流動速率:20mL/min);偵測器,UV254及220。此得到呈白色固體狀之(2S)-5-環丁氧基-2-甲基-6-(1-(2-側氧基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.0091mg,14%)。1H NMR(400MHz,CD3OD)δ ppm 1.17-1.20(m,3 H),1.29-1.40(m,1 H),1.40-1.51(m,1 H),1.58-1.68(m,1 H),2.03-2.19(m,4 H),2.22-2.35(m,3 H),2.41-
2.49(m,1 H),2.92-2.99(m,1 H),3.32-3.48(m,2 H),3.78(s,3 H),4.12-4.22(m,1 H),4.50-4.60(m,1 H),4.78-4.88(m,1 H),7.25-7.33(m,2 H),7.87(s,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 439[M+H]+。
根據針對實例72所概述之程序製得以下實例:
1H NMR(400MHz,CD3OD)δ ppm 1.17-1.20(m,3 H),1.54-1.62(m,1 H),2.13-2.20(m,3 H),2.41-2.50(m,1 H),2.60-2.71(m,1 H),2.75-2.81(m,2 H),6.72-6.79(m,2 H),2.92-2.99(m,1 H),3.32-3.48(m,2 H),3.78(s,3 H),4.62-4.75(m,1 H),6.72-6.79(m,2 H),6.95-7.02(m,2 H),7.52-7.61(m,2 H),7.81(s,1 H),7.94(s,1 H)。MS(ESI,正離子)m/z 479[M+H]+。
向2000-mL圓底燒瓶中饋入(E)-1-溴丁-2-烯(50.0g,370.4mmol)及二氯甲烷(1000mL)。經1.5小時分數份添加3-氯過氧苯甲酸(75wt%,94g,407mmol),且在室溫下攪拌所得混合物隔夜。用飽和碳酸氫鈉水溶液(3×200mL)及鹽水(2×200mL)洗滌反應混合物,經無水硫酸鈉乾燥,過濾且濃縮,得到呈淡黃色油狀之2-(溴甲基)-3-甲基環氧乙烷(42.4g,84%)。MS(ESI,正離子)m/z 192,194[M+H+MeCN]+。
向500-mL圓底燒瓶中饋入2-(溴甲基)-3-甲基環氧乙烷(42.4g,280mmol)、甲醇(120mL)及二苯基甲胺(44mL,260mmol),且在80℃下攪拌所得溶液隔夜。冷卻反應混合物至室溫且濃縮。經由矽膠管柱層析(以50:1二氯甲烷/甲醇洗提)純化殘餘物,得到呈白色固體狀之1-二苯甲基-2-甲基氮雜環丁烷-3-醇(25g,35%)。MS(ESI,正離子)m/z 254[M+H]+。
向500-mL圓底燒瓶中饋入1-二苯甲基-2-甲基氮雜環丁烷-3-醇(15.0g,59.2mmol)、二氯甲烷(30mL)及N,N-二異丙胺(21mL,160mmol),且冷卻溶液至0℃。添加甲烷磺醯氯(6.2mL,77mmol)於二氯甲烷(10mL)中之溶液,且在室溫下攪拌所得溶液隔夜。將反應混合物傾倒至200mL水中,且分離水相,且用二氯甲烷(2×100mL)萃取。用鹽水(2×100mL)洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以20:1二氯甲烷/乙酸乙酯洗提)純化殘餘物。藉由自己烷中再結晶進一步純化產物,得到呈白色固體狀之甲烷磺酸1-二苯甲基-2-甲基氮雜環丁烷-3-基酯(5.6g,29%)。MS(ESI,正離子)m/z 332[M+H]+。
向100-mL圓底燒瓶中饋入(S)-5-(4-氟苯氧基)-2-甲基-6-(1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.300g,0.79mmol)及N,N-二甲基甲醯胺(10mL),且冷卻溶液至0℃。添加氫化鈉(60%分散液,於礦物油中,0.047g,1.17mmol),且在室溫下攪拌所得混合物30分鐘。添加甲烷磺酸1-二苯甲基-2-甲基氮雜環丁烷-3-基酯(0.286g,0.86mmol),且在50℃下攪拌所得混合物隔夜。冷卻反應混合物至室溫,且傾倒至水(30mL)中。分離水相,且用乙酸乙酯(3×20mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由矽膠管柱層析(以25%乙酸乙酯-石油醚洗提)純化殘餘物,得到呈黃色油狀之(2S)-6-(1-(1-二苯甲基-2-甲基氮雜環丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.100g,21%)。MS(ESI,正離子)m/z 617[M+H]+。
向50-mL圓底燒瓶中饋入(2S)-6-(1-(1-二苯甲基-2-甲基氮雜環丁烷-3-基)-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.020g,0.03mmol)、1,2-二氯乙烷(5mL)及氯甲酸1-氯乙酯(1mL),且在80℃下攪拌所得溶液3小時。冷卻反應混合物至室溫,接著用乙酸乙酯(20mL)稀釋。分離有機相且用水(10mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以25%乙酸乙酯-石油醚洗提)純化殘餘物。藉由製備型HPLC使用以下條件(Waters I)進一步純化產物:管柱,Xbridge RP C18,19×150mm,5μm;移動相,水(0.05%碳酸氫銨)及乙腈(在10分鐘內20%至80%乙腈;流動速率:20mL/min);偵測器,UV254及220。此得到呈白色固體狀之(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-(2-甲基氮雜環丁烷-3-基)-
1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.0021g,14%)。1H NMR(300MHz,CD3OD)δ ppm 0.75(d,J=6.40Hz,3 H),0.85-0.97(m,1 H),1.10-1.18(m,3 H),1.29-1.39(m,3 H),1.52-1.65(m,1 H),1.99-2.25(m,2 H),2.41-2.75(m,2 H),3.82(s,3 H),4.05-4.17(m,2 H),4.26-4.35(m,1 H),4.62-4.73(m,1 H),5.16-5.23(m,1 H),6.73-6.81(m,2 H),6.93-6.99(m,2 H),7.51-7.62(m,2 H),7.85(s,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 451[M+H]+。
根據針對實例73所概述之程序製得以下實例:
1H NMR(300MHz,CD3OD)δ ppm 0.85-0.92(m,1 H),1.17-1.19(m,6 H),1.25-1.51(m,11 H),1.52-1.70(m,2 H),1.99-2.32(m,7 H),2.38-2.48(m,1 H),2.90-3.01(m,1 H),3.77(s,1 H),4.14-4.19(m,1 H),4.49-4.68(m,2 H),4.72-4.82(m,1 H),4.92-5.10(m,1 H),5.31-5.45(m,1 H),7.26-7.33(m,2 H),8.03(s,2 H)。MS(ESI,正離子)m/z 411[M+H]+。
向100-mL圓底燒瓶中饋入3,3-二乙氧基丙腈(0.600g,4.19mmol)、環丙基肼二鹽酸鹽(0.610g,4.21mmol)及乙醇(20mL),且在80℃下攪拌所得溶液18小時。冷卻反應混合物至室溫,且在真空下濃縮。經由矽膠管柱層析(以10:1二氯甲烷/甲醇洗提)純化殘餘物,得到呈淡黃色油狀之1-環丙基-1H-吡唑-5-胺(0.206g,36%)。MS(ESI,正離子)m/z 124[M+H]+。
向100-mL圓底燒瓶中饋入1-環丙基-1H-吡唑-5-胺(0.410g,3.33mmol)及N,N-二甲基甲醯胺(10mL)。添加N-碘代丁二醯亞胺(0.820g,3.64mmol),且在室溫下攪拌所得溶液18小時。將反應混合物傾倒至飽和亞硫酸氫鈉水溶液(50mL)中,且用乙酸乙酯(3×20mL)萃取。用鹽水(10mL)洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以1:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈淡黃色油狀之1-環丙基-4-碘-1H-吡唑-5-胺(0.440g,48%)。MS(ESI,正離子)m/z 250[M+H]+。
向50-mL圓底燒瓶中饋入(S)-(5-環丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.140g,0.34mmol)、1-環丙基-4-碘-1H-吡唑-5-胺(0.071g,0.29mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(23.2mg,0.03mmol,0.10當量)、碳酸鈉(0.061g,0.58mmol)、1,4-二噁烷(10mL)及水(3mL)。在80℃下攪拌所得混合物18小時,接著冷卻至室溫。經短矽藻土襯墊過濾反應混合物,且在真空下濃縮濾液。經由矽膠管柱層析(以1:5乙酸乙酯/石油醚洗提)純化殘餘物,得到呈淡黃色油狀之((2S)-6-(5-胺基-1-環丙基-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.025g,20%)。MS(ESI,正離子)m/z 407[M+H]+。
向8-mL圓底燒瓶中饋入((2S)-6-(5-胺基-1-環丙基-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.020g,0.05mmol)、1,4-二噁烷(1mL)及4M氫氧化鈉水溶液(1mL)。添加甲烷磺醯氯(0.028g,0.019mL,0.24mmol),且在室溫下攪拌所得溶液隔夜。用1N HCl水溶液將反應混合物之pH值調整至7,且用乙酸乙酯(3×5mL)萃取混合物。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。藉由製備型HPLC使用以下條件(Waters I)純化殘餘物:管柱,SunFire Prep C18,5μm,19×100mm;移動相,水(0.05%碳酸氫銨)及乙腈(在10分鐘內20%至80%乙腈,流動速率:20mL/min);偵測器,UV 220及254nm。此得到呈黃色油狀之N-(4-((2S)-5-環丁氧基-1-(環丙烷羰基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1-環丙基-1H-吡唑-5-基)甲烷磺醯胺(0.010g,42%)。1H NMR(300MHz,
CD3OD)δ ppm 0.63-0.75(m,1 H),0.80-1.00(m,2 H),1.00-1.18(m,8 H),1.25-1.34(m,2 H),1.51-1.68(m,1 H),1.85-2.11(m,5 H),2.25-2.42(m,2 H),2.99-3.08(m,1 H),3.13(s,3 H),3.65-3.75(m,1 H),3.96-4.17(m,1 H),4.66-4.74(m,1 H),7.15(d,J=8.10Hz,1 H),7.38(d,J=8.40Hz,1 H),7.82(s,1 H)。MS(ESI,正離子)m/z 485[M+H]+。
向100-mL圓底燒瓶中饋入1-環丙基-4-碘-1H-吡唑-5-胺(0.250g,1.00mmol)、N,N-二異丙胺(0.52mL,2.99mmol)及二氯甲烷(8mL),且冷卻溶液至0℃。逐滴添加乙醯氯(0.085mL,1.19mmol)於二氯甲烷(2mL)中之溶液,且在0℃下攪拌所得溶液1小時。在真空下濃縮反應混合物,且經由矽膠管柱層析(以0.5-50%乙酸乙酯/石油醚進行梯度洗提)純化殘餘物,得到呈黃色油狀之N-(1-環丙基-4-碘-1H-吡唑-5-基)乙醯胺(0.300g,92%)。MS(ESI,正離子)m/z 292[M+H]+。
向25-mL圓底燒瓶中饋入N-(1-環丙基-4-碘-1H-吡唑-5-基)乙醯胺(0.067g,0.23mmol)、(S)-(5-環丁氧基-2-甲基-6-(4,4,5,5-四甲基-
1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.103g,0.25mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.019mg,0.02mmol)、碳酸鈉(0.048g,0.45mmol)、1,4-二噁烷(10mL)及水(3mL)。在80℃下攪拌所得混合物18小時且冷卻至室溫。經短矽藻土襯墊過濾反應混合物,且在真空下濃縮濾液。經由矽膠管柱層析(以0.5-50%乙酸乙酯/石油醚進行梯度洗提)純化殘餘物。
藉由製備型HPLC使用以下條件(Waters I)進一步純化產物:管柱,XBridge RP C18 OBD管柱,5μm,19×150mm;移動相,水(0.03%氨水)及乙腈(在10分鐘內16%至34%乙腈,流動速率:20mL/min);偵測器,UV254及220nm。此得到23mg(22%)呈白色固體狀之N-(4-((2S)-5-環丁氧基-1-(環丙烷羰基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1-環丙基-1H-吡唑-5-基)乙醯胺。1H NMR(400MHz,CD3OD)δ ppm 0.68-0.80(m,1 H),0.91-0.99(m,2 H),1.06-1.19(m,8 H),1 .28-1.45(m,3 H),1.55-1.68(m,1 H),1.90-2.11(m,8 H),2.29-2.48(m,2 H),2.94-3.15(m,1 H),3.62-3.78(m,1 H),4.00-4.20(m,1 H),4.67-4.83(m,1 H),7.14(d,J=8.00Hz,1 H),7.21(d,J=8.40Hz,1 H),7.83(s,1 H)。
MS(ESI,正離子)m/z 449[M+H]+。
向100-mL圓底燒瓶中饋入3-(苯甲氧基)環丁酮(2.00g,11.4mmol)、四氫呋喃(20mL)及甲醇(1mL),且冷卻溶液至0℃。逐份添加硼氫化鈉(0.475g,12.5mmol),且在室溫下攪拌所得混合物30分鐘。將反應混合物傾倒至水(30mL)中,且用乙酸乙酯(2×30mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾且濃縮,得到呈黃色油狀之3-(苯甲氧基)環丁醇(1.83g,90%)。MS(ESI,正離子)m/z 179[M+H]+。
向100-mL圓底燒瓶中饋入3-(苯甲氧基)環丁醇(1.83g,10.3mmol)、二氯甲烷(20mL)及三乙胺(2.15mL,15.4mmol),且冷卻溶液至0℃。逐滴添加甲烷磺醯氯(1.20mL,1.77g,15.4mmol),且在0℃下攪拌所得溶液30分鐘。將反應混合物傾倒至水(30mL)中,且用二氯甲烷(2×30mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾且濃縮,得到呈淡黃色固體狀之甲烷磺酸3-(苯甲氧基)環丁酯(2.60g,99%)。MS(ESI,正離子)m/z 257[M+H]+。
向250-mL圓底燒瓶中饋入4-碘-1H-吡唑(1.97g,10.2mmol)、N,N-二甲基甲醯胺(20mL)、甲烷磺酸3-(苯甲氧基)環丁酯(2.60g,10.2mmol)及碳酸銫(9.75g,29.9mmol),且在80℃下攪拌所得混合物隔夜。冷卻反應混合物至室溫,傾倒至水(50mL)中,且用乙酸乙酯(3×50mL)萃取。用鹽水(50mL)洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾且濃縮,得到呈黃色油狀之1-(3-(苯甲氧基)環丁基)-4-碘-1H-吡唑(3.00g,83%)。MS(ESI,正離子)m/z 355[M+H]+。
向25-mL圓底燒瓶中饋入(S)-5-環丁氧基-2-甲基-6-(4,4,5,5-四甲
基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.100g,0.25mmol)、1-(3-(苯甲氧基)環丁基)-4-碘-1H-吡唑(0.106g,0.30mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.020g,0.02mmol)、碳酸鈉(0.053g,0.50mmol)、1,4-二噁烷(10mL)及水(3mL)。在80℃下攪拌所得混合物隔夜,接著冷卻至室溫。用乙酸乙酯(20mL)稀釋反應混合物,用水(10mL)及鹽水(10mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以1-10%乙酸乙酯/石油醚進行梯度洗提)純化殘餘物,得到呈黃色固體狀之(S)-6-(1-(3-(苯甲氧基)環丁基)-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.060g,48%)。MS(ESI,正離子)m/z 502[M+H]+。
將鈀/碳(10wt%,0.060g)添加至(S)-6-(1-(3-(苯甲氧基)環丁基)-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.060g,0.12mmol)於甲醇(10mL)中之溶液中,且在室溫下於氫氣氛圍下攪拌所得混合物16小時。過濾反應混合物,且在真空下濃縮濾液。藉由製備型HPLC使用以下條件(Waters I)純化殘餘物:管柱,XBridge Prep Shield RP18 OBD管柱,19×150mm,5μm;移動相,水(0.05%碳酸氫銨)及乙腈(在10分鐘內30%至50%乙腈,流動速率:20mL/min);偵測器,UV254及220nm。此得到呈白色固體狀之(S)-5-環丁氧基-6-(1-(3-羥基環丁基)-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.031g,63%)。1H NMR(300MHz,CD3OD)δ ppm 1.16(d,J=6.30Hz,3 H),1.32-1.51(m,2 H),1.55-1.68(m,1 H),2.00-2.33(m,5 H),2.33-2.58(m,3 H),2.76-2.84(m,2 H),2.93-3.01(m,1 H),3.77(s,3 H),4.12-4.19(m,1 H),4.51-4.64(m,2 H),4.99-5.08(m,
1 H),7.24-7.35(m,2 H),7.86(s,1 H),8.04(s,1 H)。MS(ESI,正離子)m/z 412[M+H]+。
將(S)-5-環丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.080g,0.20mmol)、4-(4-溴-1H-咪唑-2-基)哌啶-1-甲酸第三丁酯(0.200g,0.61mmol)、碳酸鈉(0.45g,0.42mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.010g,0.01mmol)於1,4-二噁烷(10mL)及水(3mL)中之混合物在90℃下攪拌隔夜。冷卻反應混合物至室溫,經短矽藻土襯墊過濾,且在真空下濃縮。經由製備型薄層層析(以1:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈淡黃色固體狀之(S)-6-(2-(1-(第三丁氧基羰基)哌啶-4-基)-1H-咪唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.050g,48%)。MS(ESI,正離子)m/z 525[M+H]+。
步驟2. (S)-5-環丁氧基-2-甲基-6-(2-(哌啶-4-基)-1H-咪唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯 將三氟乙酸(3mL)添加至(S)-6-(2-(1-(第三丁氧基羰基)哌啶-4-基)-1H-咪唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.050g,0.09mmol)於二氯甲烷(6mL)中之溶液中,且在室溫下攪拌反應混合物3小時。在真空下濃縮反應混合物,且經由製備型HPLC(Waters I)純化殘餘物:管柱:Waters HSS C18,2.1×50mm,1.8μm;移動相:水(0.05%碳酸氫銨)及乙腈(在10
分鐘內5%至95%乙腈,流動速率:20mL/min);偵測器:UV254及220nm。此得到呈灰白色固體狀之(S)-5-環丁氧基-2-甲基-6-(2-(哌啶-4-基)-1H-咪唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.0039g,10%)。
1H NMR(300MHz,CD3OD)δ ppm 1.15-1.26(m,2 H),1.32-1.68(m,3 H),1.95-2.55(m,8 H),2.97-3.19(m,3 H),3.40-3.47(m,2 H),3.77-3.82(m,2 H),4.13-4.25(m,1 H),4.51-4.71(m,3 H),7.28-7.47(m,2 H),8.55-8.61(m,1 H)。MS(ESI,正離子)m/z 425[M+H]+。
根據上文針對實例77所概述之程序製得以下實例:
1H NMR(300MHz,CD3OD)δ ppm 1.17(d,J=6.30Hz,3 H),1.25-1.33(m,1 H),1.85-1.99(m,8 H),2.18-2.27(m,1 H),2.50-2.61(m,1 H),2.81-2.95(m,3 H),3.01-3.15(m,1 H),3.21-3.26(m,2 H),3.47(s,3 H),3.79(s,3 H),3.93-3.99(m,1 H),6.86(s,1 H),7.08(d,J=8.70Hz,1 H),7.37(d,J=8.70Hz,1 H)。MS(ESI,正離子)m/z 439[M+H]+。
1H NMR(400MHz,DMSO-d 6 )δ ppm 0.63-0.68(m,1 H),0.75-0.80(m,1 H),0.80-0.85(m,1 H),0.95-1.01(m,1 H),1.05(d,J=6.40
Hz,3 H),1.22-1.35(m,2 H),1.52-1.61(m,1 H),1.75-1.87(m,3 H),1.93-2.12(m,5 H),2.27-2.33(m,2 H),2.55-2.61(m,2 H),2.89-2.95(m,1 H),3.01-3.07(m,2 H),4.15-4.28(m,2 H),4.59-4.68(m,1 H),6.64(s,1 H),7.13(d,J=8.40Hz,1 H),7.64(d,J=8.40Hz,1 H),7.79(s,1 H)。MS(ESI,正離子)m/z 435[M+H]+。
1H NMR(400MHz,DMSO-d 6 )δ ppm 0.67-0.75(m,1H),0.75-0.85(m,1 H),0.85-0.89(m,1 H),0.99-1.05(m,1 H),1.07(d,J=6.40Hz,3 H),1.17-1.23(m,1 H),1.41-1.51(m,2 H),1.67-1.78(m,3 H),1.78-1.99(m,6 H),2.22-2.29(m,1 H),2.31-2.49(m,3 H),2.83-2.91(m,1 H),2.92-3.01(m,2 H),3.85-3.96(m,2 H),4.86-4.78(m,1 H),6.24(s,1 H),7.11(d,J=8.40Hz,1 H),7.23(d,J=8.40Hz,1 H),7.53(s,1 H)。MS(ESI,正離子)m/z 435[M+H]+。
1H NMR(400MHz,DMSO-d 6 )δ ppm 0.68-0.75(m,1 H),0.81-0.89(m,1 H),0.90-0.97(m,1 H),1.01-1.08(m,4 H),1.31-1.42(m,1 H),1.69-1.79(m,2 H),1.81-1.98(m,3 H),2.05-2.15(m,1 H),2.21-
2.32(m,1 H),2.51-2.60(m,3 H),2.99-3.05(m,2 H),4.11-4.19(m,1 H),4.65-4.77(m,1 H),6.42(s,1 H),6.76-6.82(m,2 H),6.96-7.01(m,1 H),7.28-7.33(m,2 H),7.36-7.41(m,1 H),7.66(s,1 H),7.93(m,1 H)。MS(ESI,正離子)m/z 457[M+H]+。
1H NMR(400MHz,DMSO-d 6 )δ ppm 0.72-0.88(m,2 H),0.90-0.97(m,1 H),1.01-1.08(m,4 H),1.45-1.51(m,2 H),1.55-1.62(m,1 H),1.77-1.95(m,2 H),1.97-2.03(m,1 H),2.05-2.14(m,1 H),2.32-2.41(m,3 H),2.53-2.59(m,1 H),2.91-2.99(m,2 H),3.89-3.95(m,1 H),4.73-4.81(m,1 H),6.08(s,1 H),6.62-6.67(m,2 H),6.91-6.96(m,1 H),7.20-7.40(m,3 H),7.36(s,1 H),7.47(m,1 H)。MS(ESI,正離子)m/z 457[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.68-0.77(m,1 H),0.89-0.99(m,2 H),1.13(d,J=6.60Hz,4 H),1.25-1.42(m,2 H),1.61-1.72(m,1 H),1.85-1.96(m,1 H),2.05-2.26(m,9 H),2.29-2.56(m,2 H),2.75-2.88(m,2 H),3.02-3.11(m,1 H),3.19-3.28(m,2 H),4.17-4.19(m,
1H),4.63-4.74(m,2 H),7.22(d,J=8.40Hz,1 H),7.72(d,J=8.40Hz,1 H),8.05(s,1 H)。MS(ESI,正離子)m/z 436[M+H]+。三唑區位化學試驗性地指定。
1H NMR(300MHz,CD3OD)δ ppm 0.68-0.77(m,1 H),0.89-0.99(m,2 H),1.13(d,J=6.60Hz,4 H),1.25-1.47(m,2 H),1.61-1.69(m,1 H),1.85-1.96(m,1 H),2.05-2.48(m,10 H),2.82-3.11(m,3 H),3.23-3.28(m,2 H),4.17-4.26(m,1 H),4.70-4.81(m,2 H),7.25(d,J=8.40Hz,1 H),7.82(d,J=8.40Hz,1 H),8.35(s,1 H)。MS(ESI,正離子)m/z 436[M+H]+。三唑區位化學試驗性地指定。
1H NMR(300MHz,CD3OD)δ ppm 0.75-0.87(m,1 H),0.90-1.07(m,2 H),1.12-1.23(m,4 H),1.31-1.49(m,1 H),1.95-2.40(m,7 H),2.69-2.83(m,3 H),3.11-3.19(m,2 H),3.34(s,1 H),4.53-4.66(m,1 H),4.80-4.85(m,1 H),6.78-6.83(m,2 H),6.95-7.03(m,1 H),7.24-7.30(m,2 H),7.43-7.59(m,1 H),7.78(s,1 H),7.98(d,J=8.40Hz,1 H)。MS(ESI,正離子)m/z 458[M+H]+。三唑區位化學試驗性地指定。
1H NMR(300MHz,CD3OD)δ ppm 0.73-0.83(m,1 H),0.90-1.05(m,2 H),1.11-1.22(m,4 H),1.35-1.47(m,1 H),1.83-2.10(m,5 H),2.17-2.41(m,2 H),2.69-2.80(m,3 H),3.10-3.20(m,2 H),4.51-4.62(m,1 H),4.75-4.83(m,1 H),6.78-6.82(m,2 H),6.93-7.01(m,1 H),7.23-7.30(m,2 H),7.45-7.51(m,1 H),8.04-8.09(m,2 H)。MS(ESI,正離子)m/z 458[M+H]+。三唑區位化學試驗性地指定。
1H NMR(300MHz,CD3OD)δ ppm 1.13-1.21(m,3 H),1.23-1.41(m,1 H),1.45-1.64(m,2 H),1.95-2.14(m,4 H),2.18-2.31(m,1 H),2.45-4.53(m,1 H),2.91-3.02(m,1 H),3.78(s,3 H),4.01-4.19(m,5 H),4.33-4.48(m,1 H),4.51-4.65(m,1 H),7.34(d,J=8.70Hz,1 H),7.69(d,J=8.40Hz,1 H),7.76(s,1 H)。MS(ESI,正離子)m/z 414[M+H]+。
1H NMR(400MHz,CD3OD)δ ppm 1.08(d,J=6.40Hz,3H),1.16-1.25(m,1 H),1.33-1.45(m,1 H),1.46-1.52(m,1 H),1.90-2.09(m,4 H),2.12-2.21(m,1 H),2.35-2.42(m,1H),2.83-2.92(m,1 H),3.68(s,3H),3.76-3.78(m,2 H),3.80-3.86(m,1 H),4.03-4.12(m,3 H),4.45-4.51(m,1 H),7.24-7.27(m,1 H),7.67-7.73(m,2 H)。MS(ESI,正離子)m/z 430[M+H]+。
向20-mL可再密封管中饋入2,4-二溴-1-甲基-1H-咪唑(0.480g,2.00mmol)及哌嗪(3.4g,39.5mmol),且在130℃下攪拌所得混合物3小時。冷卻反應混合物至室溫,用二氯甲烷(20mL)稀釋,用水(2×10mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以10:1二氯甲烷/甲醇洗提)純化殘餘物,得到呈淡黃色固體狀之1-(4-溴-1-甲基-1H-咪唑-2-基)哌嗪(0.300g,61%)。MS(ESI,正離子)m/z 245,247[M+H]+。
向100-mL圓底燒瓶中饋入(S)-5-環丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.580g,1.47mmol)、1-(4-溴-1-甲基-1H-咪唑-2-基)哌嗪(0.300g,1.22mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.100g,0.12mmol)、碳酸鈉(0.260g,2.45mmol)、1,4-二噁烷(9mL)及水(3mL)。在80℃下攪拌所得混合物18小時。冷卻反應混合物至室溫,經短矽藻土襯墊過濾,且在真空下濃縮濾液。經由矽膠管柱層析(以10:1二氯甲烷/甲醇洗提)純化殘餘物。藉由製備型HPLC使用以下條件(Waters I)進一步純化產物:管柱,XBridge Prep C18 OBD管柱,5μm,19×150mm;移動相,水(0.03%氨水)及乙腈(在10分鐘內16.0%至34.0%乙腈,流動速率:20mL/min);偵測器,UV 220及254nm。此得到呈淡黃色固體狀之(S)-5-環丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.015g,6%)。1H NMR(400MHz,CD3OD)δ ppm 1.17(d,J=4.80Hz,3 H),1.25-1.33(m,1 H),1.34-1.49(m,2 H),1.57-1.68(m,1 H),2.03-2.28(m,5 H),2.39-2.49(m,1 H),2.93-2.99(m,1 H),2.99-3.02(m,4 H),3.09-3.13(m,4 H),3.59(s,3 H),3.77(s,3 H),4.18-4.23(m,1 H),4.51-4.53(m,1 H),7.18-7.29(m,2 H),7.53-7.57(m,1 H)。MS(ESI,正離子)m/z 440[M+H]+。
向100-mL圓底燒瓶中饋入2,4-二溴噻唑(1.00g,4.12mmol)、哌嗪-1-甲酸第三丁酯(0.918g,4.93mmol)、三乙胺(1.72mL,12.35mmol)及N,N-二甲基甲醯胺(20mL)。在120℃下攪拌所得溶液18小時。冷卻反應混合物至室溫,傾倒至水(50mL)中,且用乙酸乙酯(3×20mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由矽膠管柱層析(以10:1二氯甲烷/甲醇洗提)純化殘餘物,得到呈棕色油狀之4-(4-溴噻唑-2-基)哌嗪-1-甲酸第三丁酯(0.350g,23%)。MS(ESI,正離子)m/z 348,350[M+H]+。
向50-mL圓底燒瓶中饋入(S)-5-環丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.080g,0.20mmol)、4-(4-溴噻唑-2-基)哌嗪-1-甲酸第三丁酯(0.083g,0.24mmol)、碳酸鈉(0.042g,0.40mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.081g,0.10mmol)、1,4-二噁烷(10mL)及水(3mL)。在80℃下攪拌所得混合物4小時。冷卻反應混合物至室溫,經短矽藻土襯墊過濾,且在真空下濃縮濾液。經由製備型薄層層析(以10:1二氯甲烷/甲醇洗提)純化殘餘物,得到呈淡黃色固體狀之(S)-6-(2-(4-(第三丁氧基羰基)哌嗪-1-基)噻唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.070g,64%)。MS(ESI,正離子)m/z 543[M+H]+。
將三氟乙酸(1mL)添加至(S)-5-環丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.070g,0.13mmol)於二氯甲烷(3mL)中之溶液中,且在室溫下攪拌所得溶液2
小時。在真空下濃縮反應溶液,且藉由製備型HPLC使用以下條件(Waters 1)純化殘餘物:管柱,SunFire Prep C18,5μm,19×100mm;移動相,水(0.05%碳酸氫銨)及乙腈(在7分鐘內55%至75%乙腈,流動速率:20mL/min);偵測器,UV 220及254nm。此得到呈白色固體狀之(S)-5-環丁氧基-2-甲基-6-(2-(哌嗪-1-基)噻唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.010mg,9%)。1H NMR(300MHz,DMSO-d 6 )δ ppm 1.19(d,J=6.30Hz,3 H),1.20-1.45(m,3 H),1.45-1.52(m,1 H),2.03-2.21(m,5 H),2.80-2.86(m,4 H),3.33-3.42(m,5 H),3.68(s,3 H),4.15-4.22(m,1 H),4.40-4.50(m,1 H),7.15(s,1 H),7.27(d,J=8.70Hz,1 H),7.67(d,J=8.70Hz,1 H)。MS(ESI,正離子)m/z 443[M+H]+。
將2,4-二溴噻唑(1.00g,4.12mmol)、氮雜環丁烷-3-醇鹽酸鹽(0.543g,4.96mmol)及碳酸銫(4.03g,12.37mmol)於乙腈(30mL)中之混合物在70℃下攪拌18小時。冷卻反應混合物至室溫且過濾。在真空下濃縮濾液,且經由矽膠管柱層析(以10:1二氯甲烷/甲醇洗提)純化殘餘物,得到呈淡黃色固體狀之1-(4-溴噻唑-2-基)氮雜環丁烷-3-醇(0.535g,53%)。MS(ESI,正離子)m/z 235,237[M+H]+。
將(S)-5-環丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.080g,0.20mmol)、1-(4-溴噻唑-2-基)氮雜環丁烷-3-醇(0.056g,0.24mmol)、碳酸鈉(0.042g,0.40mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.081g,0.10mmol)於1,4-二噁烷(10mL)及水(3mL)中之混合物在80℃下攪拌4小時。冷卻反應混合物至室溫,且經短矽藻土襯墊過濾。在真空下濃縮濾液,且經由矽膠管柱層析(以2:1乙酸乙酯/石油醚洗提)純化殘餘物。藉由製備型HPLC使用以下條件(Waters I)進一步純化產物:管柱,XBridge Prep C18 OBD管柱,5μm,19×150mm;移動相,水(0.03%氨水)及乙腈(在10分鐘內16.0%至34.0%乙腈,流動速率:20mL/min);偵測器:UV 254及220nm。此得到呈白色固體狀之(S)-5-環丁氧基-6-(2-(3-羥基氮雜環丁烷-1-基)噻唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.030g,34%)。1H NMR(400MHz,CD3OD)δ ppm 1.17(d,J=6.40Hz,3 H),1.32-1.41(m,1 H),1.42-1.54(m,1 H),1.55-1.67(m,1 H),2.04-2.18(m,4 H),2.21-2.29(m,1 H),2.45-2.55(m,1 H),2.91-3.00(m,1 H),3.78(s,3 H),3.90-3.96(m,2 H),4.15-4.21(m,1 H),4.32-4.39(m,2 H),4.53-4.59(m,1 H),4.73-4.80(m,1 H),6.99(s,1 H),7.28-7.30(m,1 H),7.53-7.55(m,1 H)。MS(ESI,正離子)m/z 430[M+H]+。
根據上文針對(S)-(6-溴-5-(3,4-二氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮及(S)-(6-溴-5-(2,5-二氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(實例52,步驟1-3)所述之程序,自(S)-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮及1,2,4-三氟-5-硝基苯製備(S)-(6-溴-5-(3,4-二氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮及(S)-(6-溴-5-(2,5-二氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮。MS(ESI,正離子)m/z 422,424[M+H]+。
將含(S)-(6-溴-5-(3,4-二氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮與(S)-(6-溴-5-(2,5-二氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮之混合物(0.100g,0.24mmol)、雙(頻哪醇根
基)二硼(0.600g,2.37mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.019g,0.02mmol)及乙酸鉀(0.046mg,0.47mmol)之1,4-二噁烷(10mL)在80℃下攪拌隔夜。冷卻反應混合物至室溫,用乙酸乙酯(50mL)稀釋,用水(20mL)及鹽水(20mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。藉由製備型薄層層析(以1:5乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之(S)-環丙基(5-(3,4-二氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-基)甲酮與(S)-環丙基(5-(2,5-二氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-基)甲酮之混合物(0.080g,72%)。MS(ESI,正離子)m/z 470[M+H]+。
將含(S)-環丙基(5-(3,4-二氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-基)甲酮與(S)-環丙基(5-(2,5-二氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-基)甲酮之混合物(0.080g,0.09mmol)、4-溴-1-甲基-1H-1,2,3-三唑(0.062g,0.38mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.021g,0.03mmol)及碳酸銫(0.167g,0.51mmol)之1,4-二噁烷(10mL)及水(3mL)在90℃下攪拌隔夜。冷卻反應混合物至室溫,用乙酸乙酯(50mL)稀釋,用水(20mL)及鹽水(20mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以1:5乙酸乙酯/石油醚洗提)純化殘餘物。藉由製備型HPLC使用以下條件(Waters I)進一步純化產物:管柱,Xbridge Prep C18 OBD管柱,5μm,19×150mm;移動相,水(0.03%氫氧化銨)及
乙腈(在10分鐘內16%至34%乙腈,流動速率:20mL/min);偵測器,UV 220及254nm。此得到:呈白色固體狀之(S)-環丙基(5-(2,5-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.0083g,23%)(I-318)。1H NMR(300MHz,CD3OD)δ ppm 0.75-0.82(m,1 H),0.85-1.05(m,2 H),1.10-1.23(m,4 H),1.38-1.52(m,1 H),1.95-2.05(m,1 H),2.17-2.42(m,2 H),2.65-2.79(m,1 H),4.08(s,3 H),4.75-4.88(m,1 H),6.18-6.28(m,1 H),6.67-6.78(m,1 H),7.23-7.31(m,1 H),7.54(d,J=8.40Hz,1 H),8.01-8.10(m,2 H)。MS(ESI,正離子)m/z 425[M+H]+。
及
呈白色固體狀之(S)-環丙基(5-(3,4-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.0053g,15%)(I-319)。1H NMR(300MHz,CD3OD)δ ppm 0.72-0.83(m,1 H),0.89-1.02(m,2 H),1.11-1.22(m,4 H),1.35-1.49(m,1 H),1.96-2.05(m,1 H),2.18-2.39(m,2 H),2.67-2.75(m,1 H),4.07(s,3 H),4.75-4.88(m,1 H),6.51-6.62(m,1 H),6.78-6.89(m,1 H),7.13(d,J=9.00Hz,1 H),7.20(d,J=9.00Hz,1 H),7.51(d,J=8.40Hz,1 H),8.03-8.09(m,2 H)。MS(ESI,正離子)m/z 425[M+H]+。
將(S)-(6-溴-5-(2-氟苯氧基)-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(根據針對1-[(2S)-6-溴-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮(實例51,步驟1-3)所述之程序製備,0.270g,0.67mmol)、雙(頻哪醇根基)二硼(3.30g,13.00mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(50mg,0.07mmol)及乙酸鉀(0.170g,1.73mmol)於1,4-二噁烷(10mL)中之混合物在80℃下攪拌隔夜。冷卻反應混合物至室溫,用乙酸乙酯(920mL)稀釋,用水(2×10mL)及鹽水(10mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以5-10%乙酸乙酯-石油醚洗提)純化殘餘物,得到呈淡黃色固體狀之(S)-環丙基(5-(2-氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.140g,46%)。MS(ESI,正離子)m/z 452[M+H]+。
將(S)-環丙基(5-(2-氟苯氧基)-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.140g,0.31mmol)、4-溴-1-甲基-1H-1,2,3-三唑(0.050g,0.31mmol)、碳酸鈉(0.090g,0.85mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.010g,0.01mmol)於1,4-二噁烷(10mL)及水(3mL)中之混合物在80℃下攪拌隔夜。冷卻反應混合物至室溫,經短矽藻土襯墊過濾,且在真空下濃縮。經由製備型薄層層析(以2:1石油醚-乙酸乙酯洗提)純化殘餘物。藉由製備型HPLC使用以下條件(Waters I)進一步純化產物:管柱,XBridge C18,19×150mm,5μm;移動相,水(0.05%碳酸氫銨)及乙腈(在10分鐘內35%至65%乙腈,流動速率:20mL/min);偵測
器:UV254及220nm。此得到呈白色固體狀之(S)-環丙基(5-(2-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.033g,26%)。1H NMR(400MHz,CD3OD)δ ppm 0.74-0.81(m,1 H),0.89-1.03(m,2 H),1.11-1.21(m,4 H),1.35-1.47(m,1 H),1.95-2.05(m,1 H),2.17-2.40(m,2 H),2.65-2.78(m,1 H),4.07(s,3 H),4.75-4.81(m,1 H),6.40-6.49(m,1 H),6.89-6.97(m,2 H),7.21-7.27(m,1 H),7.51(d,J=8.40Hz,1 H),8.03(s,1 H),8.08(d,J=8.40Hz,1 H)。MS(ESI,正離子)m/z 407[M+H]+。
根據上文針對實例82所述之程序製得以下實例:
1H NMR(400MHz,CD3OD)δ ppm 0.64-0.87(m,1 H),0.92-1.10(m,3 H),1.10-1.35(m,4 H),1.65-1.80(m,1 H),2.10-2.41(m,2 H),2.68-2.79(m,1 H),4.05(s,3 H),4.70-4.89(m,1 H),6.85(d,J=8.00Hz,2 H),7.03(t,J=7.60Hz,1 H),7.31(t,J=8.00Hz,2 H),7.93-7.97(m,1 H),8.06(s,1 H)。MS(ESI,正離子)m/z 407[M+H]+。
1H NMR(300MHz,DMSO-d 6)δ ppm 1.11(d,J=6.60,3 H),1.21-1.36(m,2 H),2.05-2.15(m,1 H),2.17-2.30(m,1 H),3.70(s,3 H),
4.40(d,J=6.60Hz,3 H),4.35-4.45(m,1 H),6.81(d,J=7.80Hz,2 H),7.01(t,J=7.50Hz,1 H),7.28-7.34(m,2 H),7.84(d,J=11.4Hz,1 H),8.11(s,1 H)。MS(ESI,正離子)m/z 397[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.05-1.31(m,4 H),2.10-2.44(m,5 H),2.61-2.80(m,1 H),4.05(s,3 H),4.70-4.90(m,1 H),6.78-6.90(m,2 H),6.95-7.10(m,1 H),7.25-7.40(m,2 H),7.90-8.10(m,2 H)。MS(ESI,正離子)m/z 381[M+H]+。
將(S)-(6-溴-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.182g,0.50mmol)、1H-吡唑(0.340g,5.00mmol)、碘化銅(I)(0.038g,0.20mmol)、(1R,2R)-N1,N2-二甲基環己-1,2-二胺(0.57g,0.40mmol)及碳酸鉀(0.276g,2.00mmol)於1,4-二噁烷(10mL)中之混合物在120℃下攪拌18小時。冷卻反應混合物至室溫,且傾倒至乙酸乙酯(50mL)中。用水(3×10mL)洗滌混合物,經無水硫酸鈉乾燥,
過濾,且在真空下濃縮。藉由製備型薄層層析(以1:2乙酸乙酯/石油醚洗提)純化殘餘物,得到呈白色固體狀之(S)-(5-環丁氧基-2-甲基-6-(1H-吡唑-1-基)-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.023g,13%)。1H NMR(300MHz,DMSO-d 6 )δ ppm 0.63-0.72(m,1 H),0.77-0.91(m,2 H),0.99-1.10(m,4 H),1.15-1.19(m,1 H),1.30-1.53(m,2 H),1.72-1.95(m,5 H),2.22-2.43(m,2 H),2.95-2.96(m,1 H),3.88-3.95(m,1 H),4.63-4.71(m,1 H),6.51(s,1 H),7.24(d,J=8.70Hz,1 H),7.41(d,J=8.70Hz,1 H),7.73(s,1 H),8.08(s,1 H)。MS(ESI,正離子)m/z 352[M+H]+。
根據上文針對實例83所述之程序製備以下實例:
1H NMR(300MHz,DMSO-d 6 )δ ppm 0.65-0.99(m,3 H),0.95-1.11(m,4 H),1.35-1.50(m,1 H),1.85-2.00(m,1 H),2.02-2.15(m,1 H),2.23-2.42(m,1 H),2.50-2.65(m,1 H),4.65-4.75(m,1 H),6.31-6.35(m,1 H),6.71-6.78(m,2 H),6.90-7.01(m,1 H),7.18-7.30(m,2 H),7.45-7.50(m,1 H),7.58-7.68(m,2 H),8.02(s,1 H)。MS(ESI,正離子)m/z 374[M+H]+。
將(S)-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(1.20g,3.87mmol)、2H-1,2,3-三唑(0.258g,3.74mmol)、碘化銅(I)(0.030g,0.16mmol)、(1R,2R)-N1,N2-二甲基環己-1,2-二胺(0.044g,0.31mmol)及碳酸鉀(1.60g,11.61mmol)於N,N-二甲基甲醯胺(20mL)中之混合物在120℃下攪拌24小時。冷卻反應混合物至室溫,且傾倒至乙酸乙酯(100mL)中。用水(3×20mL)洗滌混合物,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。藉由矽膠管柱層析(以1:3乙酸乙酯/石油醚洗提)純化殘餘物,得到呈淡黃色油狀之(S)-環丙基(5-羥基-2-甲基-6-(2H-1,2,3-三唑-2-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.150g,13%)。MS(ESI,正離子)m/z 299[M+H]+。
將(S)-環丙基(5-羥基-2-甲基-6-(2H-1,2,3-三唑-2-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.055g,0.18mmol)、溴環丁烷(0.050g,0.37mmol)及碳酸銫(0.150g,0.46mmol)於乙腈(5mL)中之混合物在80℃下攪拌18小時。冷卻反應混合物至室溫且過濾,且在真空下濃縮濾液。藉由製備型HPLC使用以下條件(Waters 1)純化殘餘物:管柱,XBridge Prep C18 OBD管柱,5μm,19×150mm;移動相,水(0.03%氨水)及乙腈(在10分鐘內16%至34%乙腈,流動速率:20
mL/min);偵測器:UV 220及254nm。此得到呈白色固體狀之(S)-(5-環丁氧基-2-甲基-6-(2H-1,2,3-三唑-2-基)-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.030g,45%)。1H NMR(300MHz,CD3OD)δ ppm 0.67-0.75(m,1H),0.85-0.95(m,2H),1.11-1.17(m,4H),1.22-1.55(m,3H),1.74-2.01(m,5H),2.31-2.46(m,2H),2.95-3.07(m,1H),3.88-3.94(m,1H),4.72-4.82(m,1H),7.28(d,J=8.40Hz,1H),7.37(d,J=8.40Hz,1H),7.99(s,2H)。MS(ESI,正離子)m/z 353[M+H]+。
向配備有空氣氣球之50-mL圓底燒瓶中饋入(S)-環丙基(5-羥基-2-甲基-6-(2H-1,2,3-三唑-2-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.150g,0.50mmol)、苯基硼酸(0.185g,1.52mmol)、乙酸銅(II)(0.228g,1.26mmol)、吡啶(0.12mL,1.49mmol)、三乙胺(0.10mL,0.75mmol)及二氯甲烷(4mL),且在40℃下攪拌所得混合物18小時。冷卻反應混合物至室溫且過濾,且在真空下濃縮濾液。經由矽膠管柱層析(以5%二氯甲烷/甲醇洗提)純化殘餘物。藉由製備型HPLC使用以下條件(Waters I)進一步純化產物:管柱,SunFire Prep C18,5μm,19×100mm;移動相,水(0.05%碳酸氫銨)及乙腈(在7分鐘內55%至75%乙腈,流動速率:20mL/min);偵測器,UV 220及254nm。此得到呈白色固體狀之(S)-環丙基(2-甲基-5-苯氧基-6-(2H-1,2,3-三唑-2-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.025g,14%)。1H NMR(300MHz,CD3OD)δ ppm 0.76-0.84(m,1 H),0.91-1.06(m,2 H),1.15-1.23(m,4 H),1.43-
1.52(m,1 H),1.94-2.04(m,1 H),2.21-2.49(m,2 H),2.75-2.88(m,1 H),4.75-4.83(m,1 H),6.65-6.74(m,2 H),6.92(d,J=7.20Hz,1 H),7.17(t,J=7.50Hz,2 H),7.52(d,J=8.70Hz,1 H),7.62(d,J=8.70Hz,1 H),7.75(s,2 H)。MS(ESI,正離子)m/z 375[M+H]+。
將氫化鈉(60%分散液,於礦物油中,0.212g,5.30mmol)分數份添加至2,5-二溴-1H-咪唑(0.600g,2.67mmol)於N,N-二甲基甲醯胺(4mL)中之0℃溶液中,且在0℃下攪拌所得混合物30分鐘。在0℃下添加2-(三甲基矽烷基)乙氧基甲基氯(0.665g,4.01mmol)於N,N-二甲基甲醯胺(0.5mL)中之溶液,且在室溫下再攪拌所得溶液2.5小時。將反應混合物傾倒至乙酸乙酯(20mL)中,用鹽水(3×5mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以10:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈淡黃色油狀之2,5-二溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑(0.390g,41%)。MS(ESI,正離子)m/z 357,355,359[M+H]+。
將(S)-(5-環丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.200g,0.49mmol)、2,5-二溴-1-[[2-(三甲基矽烷基)乙氧基]甲基]-1H-咪唑(0.178g,0.50mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.046g,0.06mmol)及碳酸銫(0.549g,1.68mmol)於水(3mL)及1,4-二噁烷(10mL)中之混合物在80℃下攪拌隔夜。冷卻反應混合物至室溫且經短矽藻土襯墊過濾,且在真空下濃縮濾液。藉由製備型薄層層析(以50%乙酸乙酯/石油醚洗提)純化殘餘物,得到呈白色固體狀之((S)-6-(5-溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.091g,32%)。MS(ESI,正離子)m/z 560,562[M+H]+。
將((S)-6-(5-溴-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-2-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.091g,0.16mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-5,6-二氫吡啶-1(2H)-甲酸第三丁酯(0.050g,0.16mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.013g,0.02mmol)及碳酸銫(0.159g,0.49mmol)於水(3mL)及1,4-二噁烷(10mL)中之混合物在80℃下攪拌隔夜。冷卻反應混合物至室溫且經短矽藻土襯墊過濾,且在真空下濃縮濾液。藉由製備型薄層層析(以1:2乙酸乙酯/石油醚洗提)純化殘餘物,得到呈淡黃色固體狀之4-(2-((S)-5-環丁氧基-1-(環丙烷羰基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-5-基)-5,6-二氫吡啶-1(2H)-甲酸第三丁酯(0.094g,
87%)。MS(ESI,正離子)m/z 663[M+H]+。
將4-[2-[(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-6-基]-1-[[2-(三甲基矽烷基)乙氧基]甲基]-1H-咪唑-5-基]-1,2,3,6-四氫吡啶-1-甲酸第三丁酯(0.094g,0.14mmol)及鈀/碳(10wt%,0.047g)於甲醇(4mL)中之混合物在室溫下於氫氣氛圍下攪拌30分鐘。過濾反應混合物,且在真空下濃縮濾液,得到呈淡黃色固體狀之4-(2-((S)-5-環丁氧基-1-(環丙烷羰基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-5-基)哌啶-1-甲酸第三丁酯(0.094g,100%)。MS(ESI,正離子)m/z 665[M+H]+。
將氯化氫(氣體)鼓入4-(2-((S)-5-環丁氧基-1-(環丙烷羰基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-咪唑-5-基)哌啶-1-甲酸第三丁酯(0.094g,0.14mmol)於二氯甲烷(4mL)及四氫呋喃(1mL)中之溶液中,且在室溫下攪拌所得溶液1.5小時。在真空下濃縮反應混合物,且將殘餘物溶解於甲醇(5mL)中。用飽和碳酸鈉水溶液將溶液之pH值調整至8,且用乙酸乙酯(3×10mL)萃取所得溶液。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。藉由製備型HPLC使用以下條件(Waters I)純化殘餘物:管柱,SunFire Prep C18,5μm,19×100mm;移動相,水(0.05%碳酸氫銨)及乙腈(在7分鐘內55%至75%乙腈,流動速率:20mL/min);偵測器,UV 220及254nm。此得到呈白色固體狀之(S)-(5-環丁氧基-2-甲基-6-(5-(哌啶-4-基)-1H-咪唑-2-基)-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮
(0.0018g,3%)。1H NMR(400MHz,CD3OD)δ ppm 0.71-0.78(m,1 H),0.82-0.99(m,2 H),1.13-1.18(m,4 H),1.21-1.41(m,5 H),1.55-1.65(m,1 H),1.75-2.21(m,9 H),2.32-2.48(m,2 H),2.89-3.11(m,4 H),3.31-3.34(m,1 H),4.16-4.21(m,1 H),4.70-4.81(m,1 H),6.97(s,1 H),7.26(d,J=8.40Hz,1 H),7.65(d,J=8.40Hz,1 H)。MS(ESI,正離子)m/z 435[M+H]+。
根據上文針對實例86所述之程序製備以下實例:
1H NMR(400MHz,CD3OD)δ ppm 0.75-0.83(m,1 H),0.85-1.01(m,4 H),1.14-1.18(m,3 H),1.18-1.21(m,1 H),1.25-1.40(m,2 H),1.42-1.51(m,1 H),1.52-1.77(m,3 H),1.93-2.14(m,4 H),2.18-2.22(m,2 H),2.31-2.42(m,2 H),2.72-2.89(m,2 H),2.89-2.99(m,2 H),3.20-3.31(m,2 H),4.75(s,1 H),4.81-4.86(m,1 H),6.72-6.82(m,3 H),6.92-6.99(m,1 H),7.20-7.25(m,2 H),7.48(d,J=8.40Hz,1 H),7.83(d,J=8.40Hz,1 H)。MS(ESI,正離子)m/z 457[M+H]+。
將(S)-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(1.00g,3.24mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(2.40g,6.37mmol)、碳酸鈉(0.686g,6.47mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.263g,0.32mmol)、1,4-二噁烷(15mL)及水(5mL)之混合物在80℃下攪拌隔夜。冷卻反應混合物至室溫,傾倒至水(20mL)中,且用乙酸乙酯(3×20mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由矽膠管柱層析(以70%乙酸乙酯/石油醚洗提)純化殘餘物,得到呈深紅色固體狀之(S)-4-(4-(1-(環丙烷羰基)-5-羥基-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(0.400g,26%)。MS(ESI,正離子)m/z 481[M+H]+。
將(S)-4-(4-(1-(環丙烷羰基)-5-羥基-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(0.100g,0.21mmol)、4-溴-2,6-二甲基吡啶(0.077g,0.42mmol)、碘化銅(I)(0.004g,0.02
mmol)、吡啶甲酸(0.013g,0.10mmol)及磷酸鉀(0.133g,0.63mmol)於DMSO(2mL)中之混合物在90℃下攪拌隔夜。冷卻反應混合物至室溫,傾倒至水(5mL)中,且用乙酸乙酯(3×5mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由矽膠管柱層析(以1:2乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之(S)-4-(4-(1-(環丙烷羰基)-5-(2,6-二甲基吡啶-4-基氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(0.030g,25%)。MS(ESI,正離子)m/z 586[M+H]+。
將三氟乙酸(1mL)添加至(S)-4-(4-(1-(環丙烷羰基)-5-(2,6-二甲基吡啶-4-基氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(0.030g,0.05mmol)於二氯甲烷(3mL)中之溶液中,且在室溫下攪拌所得溶液1小時。在真空下濃縮反應混合物,且經由矽膠管柱層析(以1:2乙酸乙酯/石油醚洗提)純化殘餘物。藉由製備型HPLC使用以下條件(Waters I)進一步純化粗產物:管柱,SunFire Prep C18,5μm,19×100mm;移動相,水(0.05%碳酸氫銨)及乙腈(在7分鐘內65%至85%乙腈,流動速率:20mL/min);偵測器,UV 220/254nm。此得到呈白色粉末狀之(S)-環丙基(5-(2,6-二甲基吡啶-4-基氧基)-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.003g,12%)。1H NMR(400MHz,CD3OD)δ ppm 0.73-0.84(m,1 H),0.92-1.03(m,2 H),1.12-1.21(m,4 H),1.42-1.51(m,1 H),1.99-2.20(m,5 H),2.20-2.29(m,2 H),2.29-2.41(m,6 H),2.63-2.72(m,1 H),2.95-3.04(m,2 H),3.31-3.41(m,2 H),4.35-4.45(m,1 H),4.79-4.90(m,1 H),6.53(s,2 H),7.45(d,J=8.40Hz,1 H),7.63(d,J=8.80Hz,1 H),7.79(s,1 H),7.96(s,1 H)。MS(ESI,正離子)m/z
486[M+H]+。
根據上文針對實例87所述之程序製得以下實例:
1H NMR(400MHz,CD3OD)δ ppm 0.62-0.71(m,1 H),0.80-0.90(m,2 H),1.03-1.10(m,4 H),1.31-1.38(m,1 H),1.70-1.81(m,2 H),1.89-1.97(m,3 H),2.11-2.27(m,2 H),2.26(s,3 H),2.55-2.69(m,3 H),3.03-3.09(m,2 H),4.05-4.16(m,1 H),4.68-4.73(m,1 H),6.39(d,J=8.40Hz,1 H),6.80(d,J=8.40Hz,1 H),7.28(d,J=8.40Hz,1 H),7.46-7.51(m,2 H),7.67(s,1 H),7.86(s,1 H)。MS(ESI,正離子)m/z 472[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 0.73-0.84(m,1H),0.88-1.01(m,2 H),1.11-1.23(m,4 H),1.25-1.33(m,1 H),1.36-1.43(m,1 H),1.91-2.11(m,5 H),2.19-2.37(m,2 H),2.40(s,3 H),2.53-2.71((m,4 H),2.80-2.92(m,2 H),3.22-3.27(m,1 H),4.28-4.37(m,1 H),4.76-4.85(m,1 H),6.58(d,J=8.40Hz,1 H),6.88(d,J=8.40Hz,1 H),7.38-7.41(m,1 H),7.55-7.61(m,1 H),7.71(s,1 H),7.86(s,1 H)。MS
(ESI,正離子)m/z 486[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.13-1.19(m,3 H),1.54-1.64(m,1 H),1.88-1.99(m,2 H),2.00-2.14(m,3 H),2.41(s,4 H),2.54-2.67(m,1 H),2.69-2.79(m,2 H),3.14-3.22(m,2 H),3.82(s,3 H),4.18-4.41(m,1 H),4.65-4.73(m,1 H),6.41(d,J=8.10Hz,1 H),6.91(d,J=7.50Hz,1 H),7.50-7.62(m,3 H),7.76(s,1 H),7.94(s,1 H)。MS(ESI,正離子)m/z 462[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.09-1.21(m,3 H),1.35-1.51(m,1 H),1.81-1.95(m,2 H),1.96-2.10(m,2 H),2.16-2.31(m,5 H),2.38(s,3 H),2.61-2.81(m,3 H),3.13-3.21(m,2 H),4.19-4.29(m,1 H),4.72-4.83(m,1 H),6.49(d,J=8.70Hz,1 H),6.90(d,J=7.20Hz,1 H),7.32(br s,1 H),7.55-7.63(m,2 H),7.78(s,1 H),7.96(s,1 H)。MS(ESI,正離子)m/z 446[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.15(d,J=6.60Hz,3 H),1.55-1.69(m,1 H),1.75-1.91(m,2 H),1.95-2.15(m,3 H),2.40-2.79(m,4 H),3.07-3.18(m,2 H),3.66(s,3 H),3.80(s,3 H),4.15-4.22(m,1 H),4.60-4.75(m,1 H),6.30(d,J=7.80Hz,1 H),6.38(d,J=7.80Hz,1 H),7.48-7.61(m,3 H),7.74(s,1 H)。7.92(s,1 H)。MS(ESI,正離子)m/z 478[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.11(d,J=6.60Hz,3 H),1.31-1.48(m,1 H),1.78-1.94(m,2 H),1.95-2.08(m,2 H),2.18-2.39(m,2 H),2.22(s,3 H),2.60-2.82(m,3 H),3.09-3.18(m,2 H),3.60(s,3 H),4.15-4.28(m,1 H),4.70-4.88(m,1 H),6.36-6.42(m,2 H),7.18-7.34(m,1 H),7.55-7.65(m,2 H),7.77(s,1 H),7.20(s,1 H)。MS(ESI,正離子)m/z 462[M+H]+。
向配備有經空氣填充之氣球之100-mL圓底燒瓶中饋入(S)-環丙基(2-甲基-5-苯氧基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.240g,0.55mmol)、4-硝基-1H-吡唑(0.188g,1.66mmol)、乙酸銅(II)(0.301g,1.66mmol)、吡啶(0.2mL)及N,N-二甲基甲醯胺(5mL),且在90℃下攪拌所得混合物隔夜。冷卻反應混合物至室溫,且經矽藻土襯墊過濾。濃縮濾液,且藉由製備型薄層層析(以1:3乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之(S)-環丙基(2-甲基-6-(4-硝基-1H-吡唑-1-基)-5-苯氧基-3,4-二氫喹啉-1(2H)-基)甲酮(0.060g,26%)。MS(ESI,正離子)m/z 419[M+H]+。
將(S)-環丙基(2-甲基-6-(4-硝基-1H-吡唑-1-基)-5-苯氧基-3,4-二氫喹啉-1(2H)-基)甲酮(0.060g,0.15mmol)、鐵粉(0.040g,0.72mmol)、氯化銨(0.023g,0.43mmol)、四氫呋喃(4mL)、乙醇(4mL)及水(1mL)之混合物在80℃下攪拌隔夜。冷卻反應混合物至室溫且過濾。在真空下濃縮濾液,且藉由製備型薄層層析(以1:1乙酸乙酯/石油醚洗提)純化殘餘物,得到呈棕色固體狀之(S)-(6-(4-胺基-1H-吡唑-1-基)-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.045g,81%)。MS(ESI,正離子)m/z 389[M+H]+。
將(S)-(6-(4-胺基-1H-吡唑-1-基)-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.020g,0.05mmol)、雙(2-溴乙基)胺(0.020g,0.09mmol)、碘化鈉(0.003g,0.02mmol)及碳酸銫(0.084g,0.26mmol)於乙腈(2mL)中之混合物在85℃下攪拌隔夜。冷卻反應混合物
至室溫且過濾。在真空下濃縮濾液,且藉由製備型薄層層析(以10%甲醇/二氯甲烷洗提)純化殘餘物。藉由製備型HPLC使用以下條件進一步純化產物:管柱:XBridge RP C18,19×150mm,5μm;移動相:水(0.05%碳酸氫銨)及乙腈(在7.0分鐘內5%至60%乙腈,流動速率:20mL/min);偵測器:UV220及254nm。此得到呈淡黃色固體狀之(S)-環丙基(2-甲基-5-苯氧基-6-(4-(哌嗪-1-基)-1H-吡唑-1-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.0011g,5%)。1H NMR(300MHz,CD3OD)δ ppm 0.96-0.82(m,1 H),0.91-1.06(m,2 H),1.15-1.22(m,3 H),1.31-1.38(m,2 H),1.42-1.51(m,1 H),1.95-2.07(m,1 H),2.21-2.32(m,1 H),2.33-2.45(m,1 H),2.73-2.92(m,9 H),4.55-4.65(m,1 H),6.71-6.79(m,2 H),6.93-7.01(m,1 H),7.19-7.26(m,2 H),7.40(s,1 H),7.45-7.50(m,1 H),7.54-7.63(m,2 H)。MS(ESI,正離子)m/z 458[M+H]+。
根據上文針對實例88所述之程序製得以下實例:
1H NMR(300MHz,CD3OD)δ ppm 0.74-0.86(m,1 H),0.89-1.03(m,2 H),1.13-1.24(m,4 H),1.42-1.51(m,1 H),1.93-2.07(m,1 H),2.21-2.33(m,1 H),2.33-2.47(m,1 H),2.78-2.88(m,5 H),3.70-3.80(m,4 H),4.78-4.81(m,1 H),6.74-6.78(m,2 H),6.93-7.01(m,1 H),7.18-7.24(m,2 H),7.40-7.51(m,2 H),7.55-7.63(m,2 H)。MS(ESI,正離子)m/z 459[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.17(d,J=6.60Hz,3 H),1.55-1.64(m,1 H),2.05-2.18(m,1 H),2.49-2.58(m,1 H),2.67-2.80(m,1 H),2.80-2.86(m,4 H),3.72-3.80(m,4 H),3.84(s,3 H),4.65-4.74(m,1 H),6.68-6.73(m,2 H),6.93-7.01(m,1 H),7.16-7.23(m,2 H),7.37(s,1 H),7.49-7.55(m,2 H),7.65-7.71(m,1 H)。MS(ESI,正離子)m/z 449[M+H]+。
1H NMR(300MHz,CD3OD)δ ppm 1.17(d,J=6.30Hz,3 H),1.29-1.34(m,1 H),1.56-1.65(m,1 H),2.05-2.13(m,1 H),2.50-2.59(m,1 H),2.65-2.78(m,1 H),2.82-2.91(m,4 H),2.92-2.97(m,4 H),3.82(s,3 H),4.64-4.72(m,1 H),6.68-6.74(m,2 H),6.91-6.99(m,1 H),7.15-7.24(m,2 H),7.39(s,1 H),7.50-7.54(m,2 H),7.64-7.70(m,1 H)。MS(ESI,正離子)m/z 448[M+H]+。
將三乙胺(7.80mL,55.9mmol)添加至4-羥基四氫-2H-硫代哌喃1,1-二氧化物(3.5g,23.3mmol)於二氯甲烷(35.0mL)中之溶液中。冷卻反應溶液至0℃,且添加甲烷磺醯氯(3.25ml,41.9mmol)。10分鐘後,使反應溶液升溫至室溫且攪拌3小時。經由添加飽和氯化銨水溶液(15mL)淬滅反應物。分離有機層,且用飽和碳酸氫鈉水溶液(15mL)及鹽水(15mL)洗滌,經無水硫酸鈉乾燥,過濾且在真空中濃縮,得到灰白色固體。使固體殘餘物懸浮於乙酸乙酯(20mL)中且過濾。接著收集經過濾之固體且在真空中乾燥,得到呈白色固體狀之甲烷磺酸1,1-二氧離子基四氫-2H-硫代哌喃-4-基酯(5.1g,95%)。1H NMR(400MHz,CDCl3)δ ppm 2.38-2.56(m,4 H)2.94-3.06(m,2 H)3.10(s,3 H)3.23-3.39(m,2 H)5.03(tt,J=4.74,2.49Hz,1 H)。
將(S)-5-環丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.160g,0.47mmol)、甲烷磺酸1,1-二氧離子基四氫-2H-硫代哌喃-4-基酯(0.320g,1.40mmol)及碳酸銫(0.457g,1.40mmol)於N,N-二甲基甲醯胺(5mL)中之混合物在110℃下攪拌隔夜。冷卻反應混合物至室溫,用水(20mL)稀釋,且用乙酸乙酯(3×10mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。藉由製備型薄層層析(以50%乙酸乙酯/石油醚洗提)純化殘餘物。藉由製備型
HPLC使用以下條件(Waters I)進一步純化產物:管柱,Xbridge RP18 5μm,19×150mm;移動相,水(0.05%碳酸氫銨)及乙腈(在10分鐘內40%至80%乙腈;流動速率:20mL/min);偵測器,UV 220及254nm。此得到呈白色固體狀之(2S)-5-環丁氧基-6-[1-(1,1-二側氧基-1λ6-硫雜環己烷-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯(0.040g,18%)。1H NMR(400MHz,CD3OD)δ ppm 1.18(d,J=6.40Hz,3 H),1.29-1.31(m,1 H),1.47-1.49(m,1 H),1.60-1.62(m,1 H),2.01-2.08(m,4 H),2.11-2.24(m,1 H),2.45-2.47(m,1 H),2.63-2.68(m,4 H),2.90-2.94(m,1 H),3.10-3.17(m,2 H),3.45-3.47(m,2 H),3.78(s,3 H),4.06-1.10(m,1 H),4.45-4.58(m,2 H),7.22(d,J=8.40Hz,1 H),7.31(d,J=8.40Hz,1 H),7.81(s,2 H)。MS(ESI,正離子)m/z 474[M+H]+。
根據上文針對實例89所述之程序製得以下實例:
1H NMR(400MHz,CD3OD)δ ppm 0.64-0.66(m,1 H),0.83-0.85(m,1 H),0.98-0.99(m,1 H),1.13(d,J=6.40Hz,3 H),1.24-1.37(m,3 H),1.58-1.65(m,1 H),1.82-1.85(m,1 H),2.05-2.17(m,4 H),2.32-2.36(m,2 H),2.65-2.68(m,4 H),2.92-2.99(m,1 H),3.01-3.17(m,2 H),3.45-3.46(m,2 H),4.11-4.15(m,1 H),4.50-4.58(m,1 H),4.75-4.77(m,1 H),7.14(d,J=8.00Hz,1 H),7.26(d,J=8.00Hz,1 H),7.85(s,1 H),7.96(s,1 H)。MS(ESI,正離子)m/z 484[M+H]+。
將(S)-(6-溴-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.100g,0.26mmol)、肆(三苯基膦)鈀(0)(0.30g,0.03mmol)及氰化鋅(0.036g,0.31mmol)於N,N-二甲基甲醯胺(2mL)中之混合物在160℃下於微波照射下加熱30分鐘。冷卻反應混合物至室溫,傾倒至乙酸乙酯(10mL)中,用水(3×2mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由矽膠管柱層析(以1:8乙酸乙酯/石油醚洗提)純化殘餘物,得到呈無色油狀之(S)-1-(環丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6-甲腈(0.27g,32%)。1H NMR(300MHz,CDCl3)δ ppm 0.74-0.82(m,1 H),0.90-1.10(m,2 H),1.10-1.18(m,3 H),1.28-1.39(m,1 H),1.49-1.61(m,1 H),1.80-1.91(m,1 H),2.10-2.22(m,1 H),2.39-2.51(m,1 H),2.67-2.80(m,1 H),4.71-4.89(m,1 H),6.85(d,J=8.10Hz,2 H),7.08(t,J=7.50Hz,1 H),7.28-7.38(m,2 H),7.40-7.47(m,1 H),7.49-7.55(m,1 H)。MS(ESI,正離子)m/z 333[M+H]+。
根據上文針對(S)-1-(環丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6-甲腈(實例90)所概述之程序合成(S)-6-氰基-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(300MHz,CD3Cl)δ ppm 1.12
(d,J=6.60Hz,3 H),1.52-1.70(m,1 H),1.88-2.10(m,1 H),2.42-2.72(m,2 H),3.84(s,3 H),4.62-4.80(m,1 H),6.82(d,J=8.10Hz,2 H),7.06(t,J=7.50Hz,1 H),7.20-7.35(m,2 H),7.48(d,J=8.70Hz,1 H),7.75(d,J=8.70Hz,1 H)。MS(ESI,正離子)m/z 323[M+H]+。
將(S)-(6-溴-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.030g,0.08mmol)、三丁基(乙炔基)錫烷(0.030g,0.09mmol)及肆(三苯基膦)鈀(0)(0.037g,0.03mmol)於N,N-二甲基甲醯胺(1.5mL)中之混合物在120℃下攪拌隔夜。冷卻反應混合物至室溫,傾倒至乙酸乙酯(15mL)中,用水(2×5mL)及鹽水(5mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由製備型薄層層析(以1:5乙酸乙酯/石油醚洗提)純化殘餘物。藉由製備型HPLC使用以下條件(Waters III)進一步純化產物:管柱,Xbridge RP C18,19×150mm,5μm;移動相,水(0.05%碳酸氫銨)及乙腈(在10分鐘內50%至100%乙腈,流動速率:20mL/min);偵測器,UV 220及254nm。此得到呈棕色半固體狀之(S)-環丙基(6-乙炔基-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)甲酮(0.004g,16%)。1H NMR(300MHz,CD3OD)δ ppm 0.65-0.85(m,1 H),0.87-1.04(m,2 H),1.05-1.25(m,4 H),1.38-1.52(m,1 H),1.85-2.02(m,1 H),2.11-2.47(m,2 H),2.62-2.85(m,1 H),3.47(m,1 H),4.75-4.82(m,1 H),6.79(d,J=8.10Hz,2 H),6.95-7.05(m,1 H),7.19-7.39(m,3 H),7.45(d,J=8.40Hz,1 H)。MS(ESI,正離子)m/z 332
[M+H]+。
根據上文針對(S)-環丙基(6-乙炔基-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)甲酮(實例91)所概述之程序合成(S)-6-乙炔基-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-甲酸甲酯。1H NMR(300MHz,CD3OD)δ ppm 1.06(d,J=6.60Hz,3 H),1.49-1.71(m,1 H),1.85-2.06(m,1 H),2.33-2.49(m,2 H),3.73(s,3 H),4.07(s,1 H),4.54-4.60(m,1 H),6.76(d,J=7.80Hz,2 H),7.01(t,J=7.50Hz,1 H),7.45-7.21(m,3 H),7.57(d,J=8.70Hz,1 H)。MS(ESI,正離子)m/z 322[M+H]+。
將(S)-(6-溴-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.050g,0.13mmol)、RuPhos第3代預催化劑(甲烷磺酸(2-二環己基膦基-2',6'-二異丙氧基-1,1'-聯苯)[2-(2'-胺基-1,1'-聯苯)]鈀(II))(0.011g,0.01mmol)、氟化銫(0.099g,0.65mmol)及三丁基(丙-1-炔基)錫烷(0.107g,0.32mmol)於1,4-二噁烷(4mL)中之混合物在160℃下於微波照射下加熱1小時。冷卻反應混合物至室溫,通過短矽藻土襯墊,且在真空下濃縮。經由製備型薄層層析(以1:5乙酸乙酯/石油醚
洗提)純化殘餘物。藉由製備型HPLC使用以下條件(Waters I)進一步純化產物:管柱,SunFire Prep C18,5μm,19×100mm;移動相,水(0.05%碳酸氫銨)及乙腈(在10分鐘內50%至100%乙腈,流動速率:20mL/min);偵測器:UV 220及254nm。此得到呈淡棕色半固體狀之(S)-環丙基(2-甲基-5-苯氧基-6-(丙-1-炔基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.011g,26%)。1H NMR(400MHz,CD3OD)δ ppm 0.65-0.85(m,1H),1.02-0.87(m,2 H),1.03-1.22(m,4 H),1.37-1.51(m,1 H),1.82(s,3 H),1.88-2.03(m,1 H),2.07-2.42(m,2 H),2.58-2.82(m,1 H),4.85-4.72(m,1 H),6.78(d,J=7.80Hz,2 H)7.00(t,J=7.50Hz,1 H),7.25-7.31(m,4 H)。MS(ESI,正離子)m/z 346[M+H]+。
將(S)-(6-溴-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.300g,0.78mmol)、1H-吡唑(0.053g,0.78mmol)、氧化銅(I)
(0.056g,0.39mmol)、碳酸銫(0.508g,1.56mmol)於N,N-二甲基甲醯胺(5mL)中之混合物在100℃下攪拌18小時。冷卻所得混合物至室溫,用水(20mL)稀釋,且用乙酸乙酯(3×20mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由製備型薄層層析(以1:10乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色固體狀之(S)-環丙基(2-甲基-5-苯氧基-6-(1H-吡唑-1-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.050g,17%)。MS(ESI,正離子)m/z 374[M+H]+。
將N-溴代丁二醯亞胺(0.025g,0.15mmol)添加至(S)-環丙基(2-甲基-5-苯氧基-6-(1H-吡唑-1-基)-3,4-二氫喹啉-1(2H)-基)甲酮(0.050g,0.13mmol)於N,N-二甲基甲醯胺(2mL)中之溶液中,且在室溫下攪拌所得溶液隔夜。用水(5mL)稀釋反應混合物,且用乙酸乙酯(3×10mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由製備型薄層層析(以1:10乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之(S)-(6-(4-溴-1H-吡唑-1-基)-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.055g,91%)。MS(ESI,正離子)m/z 452,454[M+H]+。
將(S)-(6-(4-溴-1H-吡唑-1-基)-2-甲基-5-苯氧基-3,4-二氫喹啉-1(2H)-基)(環丙基)甲酮(0.060g,0.14mmol)、4-(四甲基-1,3,2-二氧硼戊環-2-基)-1,2,3,6-四氫吡啶-1-甲酸第三丁酯(0.049g,0.16mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.011g,0.01mmol)及碳酸銫(0.085g,0.26mmol)於1,4-二噁烷(8mL)及水(2mL)中之混合物在80℃下攪拌隔夜。冷卻反應混合物至室溫,通過短矽藻土
襯墊,且在真空下濃縮。經由製備型薄層層析(以50%乙酸乙酯/石油醚洗提)純化殘餘物,得到呈白色固體狀之(S)-4-(1-(1-(環丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-4-基)-5,6-二氫吡啶-1(2H)-甲酸第三丁酯(0.050g,68%)。MS(ESI,正離子)m/z 555[M+H]+。
將(S)-4-(1-(1-(環丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-4-基)-5,6-二氫吡啶-1(2H)-甲酸第三丁酯(0.050g,0.09mmol)及鈀/木炭(10% wt%,0.040g)於甲醇(15mL)中之混合物在室溫下於氫氣氛圍下攪拌20分鐘。過濾反應混合物且在真空下濃縮,得到呈白色固體狀之(S)-4-(1-(1-(環丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-4-基)哌啶-1-甲酸第三丁酯(0.048g,99%)。MS(ESI,正離子)m/z 557[M+H]+。
將三氟乙酸(3mL)添加至(S)-4-(1-(1-(環丙烷羰基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-4-基)哌啶-1-甲酸第三丁酯(0.048g,0.09mmol)於二氯甲烷(10mL)中之溶液中,且在室溫下攪拌所得溶液20分鐘。用飽和碳酸鉀水溶液將溶液之pH值調整至8,且用二氯甲烷(2×10mL)萃取所得溶液。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。藉由製備型HPLC使用以下條件(Waters I)純化殘餘物:管柱,SunFire Prep C18,5μm,19×100mm;移動相,水(0.05%碳酸氫銨)及乙腈(在10分鐘內20%至50%乙腈,流動速率:20mL/min);偵測器,UV 220及254nm。此得到呈淡黃色固體狀之(S)-環丙基(2-甲基-5-苯氧基-6-(4-(哌啶-4-基)-1H-吡唑-1-基)-3,4-二氫
喹啉-1(2H)-基)甲酮(0.0095g,24%)。1H NMR(400MHz,CDCl3)δ ppm 0.65-0.78(m,1H),0.89-0.99(m,2 H),1.03-1.16(m,4 H),1.28-1.45(m,3 H),1.61-1.82(m,2 H),1.83-2.02(m,1 H),2.18-2.22(m,1 H),2.24-2.38(m,1 H),2.45-2.62(m,3 H),2.68-2.82(m,1 H),2.88-3.01(m,2 H),4.69-4.78(m,1 H),6.64(d,J=8.80Hz,2 H),6.84(t,J=7.60Hz,1 H),7.08-7.11(m,2 H),7.42-7.28(m,2 H),7.38(d,J=8.80Hz,1 H),7.48(s,1 H)。MS(ESI,正離子)m/z 457[M+H]+。
將(S)-5-環丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.400g,1.00mmol)、3-(4-溴噻唑-2-基)-3-羥基氮雜環丁烷-1-甲酸第三丁酯(0.367g,1.10mmol)、碳酸鈉(0.212g,2.00mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.082g,0.10mmol)於1,4-二噁烷(10mL)及水(3mL)中之溶液在80℃下攪拌隔夜。冷卻反應混合物至室溫,經矽藻土襯墊過濾,且在真空下濃縮。經由矽膠管柱層析(以30%乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色固體狀之(S)-6-(2-(1-(第三丁氧基羰基)-
3-羥基氮雜環丁烷-3-基)噻唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.366g,69%)。MS(ESI,正離子)m/z 530[M+H]+。
將三氟化(二乙基胺基)硫(DAST)(0.152g,0.94mmol)添加至(S)-6-(2-(1-(第三丁氧基羰基)-3-羥基氮雜環丁烷-3-基)噻唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.100g,0.19mmol)於二氯甲烷(4mL)中之-78℃溶液中,且在-78℃下攪拌所得溶液2小時。將反應混合物傾倒至飽和碳酸氫鈉水溶液(20mL)中,且用二氯甲烷(3×20mL)萃取。經無水硫酸鈉乾燥經合併之有機層,過濾,且在真空下濃縮。經由製備型薄層層析(以30%乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色固體狀之(S)-6-(2-(1-(第三丁氧基羰基)-3-氟氮雜環丁烷-3-基)噻唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.059g,59%)。MS(ESI,正離子)m/z 532[M+H]+。
將三氟乙酸(1mL)添加至(S)-6-(2-(1-(第三丁氧基羰基)-3-氟氮雜環丁烷-3-基)噻唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.059g,0.11mmol)於二氯甲烷(3mL)中之溶液中,且在室溫下攪拌所得溶液2小時,接著在真空下濃縮。藉由製備型HPLC使用以下條件(Waters I)純化殘餘物:管柱,XBridge C18,19×150mm,5μm;移動相:水(0.05%碳酸氫銨)及乙腈(在8分鐘內5%至95%乙腈;流動速率:20mL/min);偵測器,UV 220及254nm。此得到呈白色固體狀之(S)-5-環丁氧基-6-(2-(3-氟氮雜環丁烷-3-基)噻唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.025g,53%)。1H NMR(400MHz,CD3OD)δ ppm 1.20(d,J=6.40Hz,3 H),1.31-1.40(m,1 H),1.45-1.55
(m,1 H),1.55-1.66(m,1 H),2.02-2.18(m,4 H),2.22-2.31(m,1 H),2.49-2.55(m,1 H),2.95-3.06(m,1 H),3.80(s,3 H),4.08-4.20(m,3 H),4.28-4.36(m,2 H),4.56-4.64(m,1 H),7.24-7.27(m,1 H),7.67-7.73(m,2 H)。MS(ESI,正離子)m/z 432[M+H]+。
將氫化鈉(60%分散液,於礦物油中,0.012g,0.30mmol)添加至(S)-6-(2-(1-(第三丁氧基羰基)-3-羥基氮雜環丁烷-3-基)噻唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.100g,0.19mmol)於N,N-二甲基甲醯胺(2mL)中之溶液中,且在室溫下攪拌所得混合物30分鐘。添加碘甲烷(0.014mL,0.23mmol),且在室溫下攪拌所得混合物隔夜。將反應混合物傾倒至10mL水中,用3×10mL乙酸乙酯萃取。合併有機層,經無水硫酸鈉乾燥,且在真空下濃縮。藉由製備型TLC使用乙酸乙酯/石油醚(1/3)純化殘餘物。此得到70mg(68%)呈無色油狀之(S)-6-(2-(1-(第三丁氧基羰基)-3-甲氧基氮雜環丁烷-3-基)噻唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯。MS(ESI,正離子)m/z 544[M+H]+。
將三氟乙酸(1mL)添加至(S)-6-(2-(1-(第三丁氧基羰基)-3-甲氧基氮雜環丁烷-3-基)噻唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-
甲酸甲酯(0.070g,0.13mmol)於二氯甲烷(3mL)中之溶液中,且在室溫下攪拌所得溶液2小時。在真空下濃縮反應混合物,且藉由製備型HPLC使用以下條件(Waters I)純化殘餘物:管柱,Xbridge C18,5μm,19×150nm;移動相,水(0.05%碳酸氫銨)及乙腈(在10分鐘內25%至65%乙腈;流動速率:20mL/min);偵測器,220及254nm。此得到呈灰白色固體狀之(S)-5-環丁氧基-6-(2-(3-甲氧基氮雜環丁烷-3-基)噻唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(0.037g,65%)。1H NMR(400MHz,CD3OD)1.20(d,J=6.80Hz,3 H),1.25-65(m,3 H),1.95-2.20(m,4 H),2.20-2.31(m,1 H),2.45-2.55(m,1 H),2.90-3.01(m,1 H),3.30(s,3 H),3.80(s,3 H),3.92-3.98(m,2 H),4.10-4.22(m,3 H),4.55-4.62(m,1 H),7.36(d,J=8.40Hz,1 H),7.82(d,J=8.40Hz,1 H),7.95(s,1 H)。MS(ESI,正離子)m/z 444[M+H]+。
將2-溴-1H-苯并[d]咪唑(0.400g,2.04mmol)、烯丙基溴(0.35mL,4.08mmol)、1,4-二噁烷(15mL)及2M氫氧化鈉水溶液(15mL,3.00mmol)之混合物在100℃下攪拌2小時。冷卻反應混合物至室溫,且用乙酸乙酯(50mL)稀釋。分離有機相,且用鹽水(30mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空下濃縮。經由製備型薄層層析(以20%乙酸乙酯/石油醚洗提)純化殘餘物,得到呈黃色油狀之1-烯丙基-2-溴-1H-苯并[d]咪唑(0.251g,52%)。MS(ESI,正離子)m/z 237,239[M+H]+。
將(S)-1-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(0.200g,0.71mmol)、1-烯丙基-2-溴-1H-苯并[d]咪唑(0.340g,1.44mmol)及碳酸鉀(0.293g,2.12mmol)於N,N-二甲基乙醯胺(10mL)中之混合物在200℃下於微波中加熱2小時。冷卻反應混合物至室溫,過濾,且
在真空下濃縮。經由製備型薄層層析(以20%乙酸乙酯/石油醚洗提)純化殘餘物,得到呈淡黃色固體狀之(S)-5-(1-烯丙基-1H-苯并[d]咪唑-2-基氧基)-6-溴-2-甲基-1,2,3,4-四氫喹啉(0.115g,41%)。MS(ESI,正離子)m/z 398,400[M+H]+。
將(S)-5-(1-烯丙基-1H-苯并[d]咪唑-2-基氧基)-6-溴-2-甲基-1,2,3,4-四氫喹啉(0.115g,0.29mmol)、1-環丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑(0.269g,1.15mmol)、碳酸鉀(0.118g,0.85mmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.023g,0.03mmol)於1,4-二噁烷(10mL)及水(3mL)中之混合物在100℃下攪拌3小時。冷卻反應混合物至室溫,經短矽藻土襯墊過濾,且在真空下濃縮。經由製備型薄層層析(以1:2乙酸乙酯/石油醚洗提)純化殘餘物,得到呈紅色油狀之(S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-((1-(丙-1-烯-1-基)-1H-苯并[d]咪唑-2-基)氧基)-1,2,3,4-四氫喹啉(0.106g,86%),其為E與Z異構物之混合物。MS(ESI,正離子)m/z 426[M+H]+。
將乙醯氯(0.035mL,0.49mmol)逐滴添加至E-及Z-(S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(1-(丙-1-烯基)-1H-苯并[d]咪唑-2-基氧基)-1,2,3,4-四氫喹啉(0.070g,0.16mmol)及吡啶(0.029mL,0.36mmol)於二氯甲烷(20mL)中之0℃溶液中。在室溫下使所得溶液保持2小時,接著在真空下濃縮。藉由製備型HPLC使用以下條件(Waters I)純化殘餘物:管柱,Xbridge Prep C18,19×150mm;移動相,水(0.05%碳酸氫銨)及乙腈(在10分鐘內37%至56%乙腈,流動速率:20
mL/min);偵測器,UV220及254nm。此得到呈淡黃色固體狀之(S,E)-1-(6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(1-(丙-1-烯基)-1H-苯并[d]咪唑-2-基氧基)-3,4-二氫喹啉-1(2H)-基)乙酮(2.6mg,3%)。(I-351)1H NMR(300MHz,CD3OD)δ ppm 0.92-1.00(m,4 H),1.19(d,J=6.60Hz,3 H),1.51(br s,1 H),1.71-1.80(m,3 H),2.15-2.30(m,4 H),2.31-2.45(m,1 H),2.67-2.81(m,1 H),3.51-3.65(m,1 H),4.70-4.92(m,1 H),6.11-6.25(m,1 H),6.70-6.79(m,1 H),7.10-7.25(m,3 H),7.29-7.45(m,2 H),7.54(d,J=8.40Hz,1 H),7.66(s,1 H),7.86(s,1 H)。MS(ESI,正離子)m/z 468[M+H]+。E-丙烯立體化學試驗性地指定。
亦獲得呈淡黃色固體狀之(S,Z)-1-(6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(1-(丙-1-烯基)-1H-苯并[d]咪唑-2-基氧基)-3,4-二氫喹啉-1(2H)-基)乙酮(2.4mg,3%)。(I-352)1H NMR(300MHz,CD3OD)δ ppm 0.88-1.00(m,4 H),1.18(d,J=6.60Hz,3 H),1.50(br s,1 H),2.01-2.05(m,3 H),2.15-2.30(m,4 H),2.31-2.45(m,1 H),2.65-2.82(m,1 H),3.48-3.62(m,1 H),4.72-4.92(m,1 H),6.25-6.42(m,1 H),7.05-7.35(m,4 H),7.36-7.45(m,1 H),7.48-7.58(m,2 H),7.65(s,1 H),7.84(s,1H)。MS(ESI,正離子)m/z 468[M+H]+。Z-丙烯立體化學試驗性地指定。
將經氫氣加壓之氣球饋入含有(S)-4-(1-乙醯基-2-甲基-5-丙氧基-
1,2,3,4-四氫喹啉-6-基)-5,6-二氫吡啶-1(2H)-甲酸第三丁酯(500mg,1.17mmol)及20%氫氧化鈀/碳(30mg,0.21mmol)於甲醇(10mL)中之懸浮液的圓底燒瓶中。在氣球壓力下攪拌反應物2小時。使反應物與氮氣相通,且經矽藻土襯墊過濾。在真空中濃縮經過濾之溶液,且經由矽膠管柱層析(Biotage 25g管柱,以20-40%乙酸乙酯-己烷進行梯度洗提)純化,得到呈無色油狀之(S)-4-(1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基)哌啶-1-甲酸第三丁酯(500mg,100%)。MS(ESI,正離子)m/z 432[M+H]+。
將氯化氫溶液(4.0N,於1,4-二噁烷中,1.4mL,5.6mmol)添加至(S)-4-(1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基)哌啶-1-甲酸第三丁酯(480mg,1.1mmol)於1,4-二噁烷(3mL)中之溶液中。攪拌反應物3小時,產生白色沈澱物。用乙醚(10mL)稀釋反應溶液,且藉由過濾收集沈澱物。再用乙醚(10mL)洗滌濾液,收集且在真空中乾燥,得到呈白色粉末狀之標題化合物之鹽酸鹽。經由在乙酸乙酯中用飽和碳酸鈉水溶液中和直至達到pH=7.5使鹽呈游離鹼形式。經無水硫酸鈉乾燥有機層,過濾且在真空中濃縮,得到呈無色固體狀之(S)-1-(2-甲基-6-(哌啶-4-基)-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙-1-酮(356mg,97%)。1H NMR(300MHz,DMSO-d 6 )δ ppm 0.96-1.06(m,6 H),1.11-1.26(m,1 H),1.38-1.61(m,4 H),1.66-1.89(m,2 H),2.20(s,3 H),2.16-2.28(m,2 H),2.52(m,2 H),2.67-2.80(m,2 H),2.83-2.94(m,1 H),2.99(br d,J=12.02Hz,2 H),3.58-3.72(m,2 H),4.40-4.63(br d,J=6.75Hz,1H),7.03(br s,2 H)。MS(ESI,正離子)m/z 331[M+H]+。
將乙醯氯(6μL,0.08mmol)添加至(S)-1-(2-甲基-6-(哌啶-4-基)-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙酮(26.1mg,0.07mmol)及三乙胺(0.03mL,0.21mmol)於二氯甲烷(1.0mL)中之溶液中,且在室溫下攪拌反應物隔夜。經由矽膠管柱層析(Biotage 10g管柱,以含10-20%甲醇之乙酸乙酯進行梯度洗提)直接純化反應溶液,得到呈灰白色固體狀之(S)-1-(4-(1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基)哌啶-1-基)乙-1-酮(19mg,71%)。1H NMR(300MHz,DMSO-d 6 )δ ppm 0.98-1.05(m,6 H),1.17-1.29(m,1 H),1.38-1.47(m,1 H),1.54-1.59(m,1 H),1.65-1.81(m,5 H),2.01(s,6 H),2.16-2.35(m,2 H),2.48-2.59(m,1 H),2.71-2.78(m,1 H),3.01-3.03(m,2 H),3.55-3.76(m,2 H),3.90(br d,J=14.66Hz,1 H),4.52(br d,J=13.20Hz,1 H),7.04(br s,2 H)。MS(ESI,正離子)m/z 373[M+H]+。
將甲烷磺醯氯(4μL,0.05mmol)添加至(S)-1-(2-甲基-6-(哌啶-4-基)-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙酮(17.0mg,0.05mmol)及三乙胺(0.02mL,0.14mmol)於二氯甲烷(1.0mL)中之溶液中,且在室溫下攪拌反應物隔夜。經由矽膠管柱層析(Biotage 10g管柱,以含10-0%己烷之乙酸乙酯進行梯度洗提)直接純化反應溶液,得到呈白色固
體狀之(S)-1-(2-甲基-6-(1-(甲基磺醯基)哌啶-4-基)-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙-1-酮(14mg,72%)。1H NMR(300MHz,DMSO-d 6 )δ ppm 0.98-1.04(m,6 H),1.19-1.26(m,1 H),1.58-1.81(m,6 H),2.02(s,3 H),2.17-2.30(m,2 H),2.68-2.85(m,3 H),2.89(s,3 H),2.89-2.99(m,1 H),3.60-3.76(m,4 H),4.57(br d,J=6.45Hz,1 H),7.09(br s,2H)。MS(ESI,正離子)m/z 409[M+H]+。
將三乙胺(0.05mL,0.35mmol)添加至(S)-1-(2-甲基-6-(哌啶-4-基)-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙酮(20.0mg,0.06mmol)於二氯甲烷(5mL)中之溶液中。冷卻反應物至0℃,且添加溶解於二氯甲烷(3mL)中之三光氣(6.3mg,0.02mmol)。使反應混合物升溫至室溫且攪拌3小時。接著按順序添加吡啶(3μL,0.03mmol)及乙胺(2.7mg,0.06mmol),且攪拌溶液隔夜。經由添加水(5mL)及1M檸檬酸(1mL)淬滅反應物。收集有機層且再用水(5mL)及鹽水(5mL)洗滌。經無水硫酸鈉乾燥有機層,過濾且在真空中濃縮。經由矽膠管柱層析(Biotage 10g管柱,以含0-5%甲醇之乙酸乙酯進行梯度洗提)純化殘餘物,得到呈無色油狀之(S)-4-(1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基)-N-乙基哌啶-1-甲醯胺(15mg,61%)。1H NMR(300MHz,DMSO-d 6 )δ ppm 0.97-1.05(m,6 H),1.15(t,J=7.04Hz,3 H),1.18-1.27(m,1 H),1.37-1.53(m,2 H),1.63(br d,J=11.73Hz,2 H),1.69-1.78(m,2 H),2.02(s,3 H),2.15-2.30(m,2 H),2.63-2.79(m,3 H),
2.90-3.07(m,3 H),3.60-3.75(m,2 H),4.07(br d,J=16.12Hz,2 H),4.50-4.62(m,1 H),6.45(br t,J=5.42Hz,1H),7.03(br s,2 H)。
MS(ESI,正離子)m/z 402[M+H]+。
將氯甲酸甲酯(5μL,0.06mmol)添加至(S)-1-(2-甲基-6-(哌啶-4-基)-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙酮(20mg,0.05mmol)及三乙胺(0.04mL,0.27mmol)於二氯甲烷(0.5mL)中之溶液中,且在室溫下攪拌反應物隔夜。經由添加水(5mL)淬滅反應物。收集有機層且再用水(5mL)及鹽水(5mL)洗滌。經無水硫酸鈉乾燥有機層,過濾且在真空中濃縮。經由矽膠管柱層析(Biotage 10g管柱,以含10-20%甲醇之乙酸乙酯進行梯度洗提)純化殘餘物,得到呈無色油狀之(S)-4-(1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基)哌啶-1-甲酸甲酯(19mg,89%)。1H NMR(300MHz,DMSO-d 6 )δ ppm 0.94-1.07(m,6 H),1.17-1.26(m,1 H),1.43-1.57(m,2 H),1.60-1.79(m,4 H),2.01(s,3 H),2.16-2.31(m,2 H),2.68-2.91(m,3 H),2.95-3.03(m,1 H),3.58(s,3 H),3.61-3.73(m,2 H),4.04-4.15(m,2 H),4.56(br d,J=6.45Hz,1 H),7.05(br s,2 H)。MS(ESI,正離子)m/z 389[M+H]+。
將碘乙烷(5μl,0.06mmol)添加至(S)-1-(2-甲基-6-(哌啶-4-基)-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙酮(20mg,0.06mmol)及碳酸鉀(38mg,0.27mmol)於DMF(1.0mL)中之溶液中,且在室溫下攪拌反應物隔夜。經由添加水(5mL)淬滅反應物,且用乙酸乙酯(2×10mL)萃取。收集有機層且再用水(5mL)及鹽水(5mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空中濃縮。經由矽膠管柱層析(Biotage 10g管柱,以含50-80%甲醇之乙酸乙酯進行梯度洗提)純化殘餘物,得到呈淡黃色油狀之(S)-1-(6-(1-乙基哌啶-4-基)-2-甲基-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙-1-酮(10mg,51%)。1H NMR(300MHz,DMSO-d 6 )δ ppm 0.96-1.06(m,6 H),1.15(t,J=7.04Hz,3 H),1.15-1.26(m,1 H),1.38-1.61(m,4 H),1.66-1.89(m,2 H),2.20(s,3 H),2.16-2.28(m,2 H),2.52(m,2 H),2.67-2.80(m,2 H),2.83-2.94(m,1 H),2.92-3.07(m,3 H),3.58-3.72(m,2 H),4.40-4.63(br d,J=6.75Hz,1H),7.03(br s,2 H)。MS(ESI,正離子)m/z 359[M+H]+。
將XPhos第2代預催化劑(0.186g,0.24mmol)添加至(S)-1-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(0.672g,2.36mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(0.892g,2.36mmol)及磷酸鉀(2.51g,11.8mmol)於1,4-二噁烷(4.0mL)及水(0.8mL)中之經氮氣淨化溶液中,且在100℃下加熱反應混合物隔夜。經由矽膠管柱層析(Biotage 25g管柱,以含30-10%己烷之乙酸乙酯進行梯度洗提)直接純化粗反應混合物,得到呈白色鬆散粉末狀之(S)-4-(4-(1-乙醯基-5-羥基-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(225mg,21%)。MS(ESI,正離子)m/z 455[M+H]+。
將三乙胺(0.07mL,0.54mmol)及N,N-二甲基吡啶-4-胺(6.1mg,0.049mmol)添加至(S)-4-(4-(1-乙醯基-5-羥基-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(225mg,0.495mmol)於二氯甲烷(4.5mL)中之溶液中。冷卻反應溶液至0℃,且逐滴添加N-(5-氯吡啶-2-基)-1,1,1-三氟-N-((三氟甲基)磺醯基)甲烷磺醯胺(214mg,0.544mmol)(澄清溶液變成淡黃橙色)。接著使反應混合物緩慢升溫返回至室溫,且攪拌2小時。經由矽膠管柱層析(Biotage 25g管柱,以含0-4% MeOH之二氯甲烷進行梯度洗提)直接純化反應溶液,得到呈白色固體狀之(S)-4-(4-(1-乙醯基-2-甲基-5-(((三氟甲基)磺醯基)氧基)-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(290mg,100%)。MS(ESI,正離子)m/z 587[M+H]+。
將XPhos第2代預催化劑(10.7mg,0.014mmol)添加至(S)-4-(4-(1-乙醯基-2-甲基-5-(((三氟甲基)磺醯基)氧基)-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(40mg,0.068mmol)、苯胺(7μL,0.075mmol)及磷酸鉀(43.4mg,0.20mmol)於1,4-二噁烷(0.5mL)中之經氮氣淨化溶液中,且在100℃下加熱反應混合物隔夜。經由矽膠管柱層析(Biotage 25g管柱,以含25-40%乙酸乙酯之己烷進行梯度洗提)直接純化粗反應混合物,得到呈淡黃色油狀之(S)-4-(4-(1-乙醯基-2-甲基-5-(苯基胺基)-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯與(S)-4-(4-(1-乙醯基-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯之混合物(31mg)。MS(ESI,正離子)m/z 530[M+H]+及438[M+H]+。
將二碳酸二第三丁酯(0.02mL,0.088mmol)添加至含有(S)-4-(4-(1-乙醯基-2-甲基-5-(苯基胺基)-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯與(S)-4-(4-(1-乙醯基-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯之混合物(31mg,0.059mmol)及DMAP(7.2mg,0.059mmol)於THF(1.0mL)中之0℃溶液中。使反應混合物升溫至室溫且攪拌3小時。在真空中濃縮反應溶液,且經由矽膠管柱層析(Biotage 25g管柱,以含40-50%乙酸乙酯之己烷進行梯度洗提)直接純化粗產物,得到呈白色固體狀之(S)-4-(4-(1-乙醯基-5-((第三丁氧基羰基)(苯基)胺基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(29.5mg,80%)。MS(ESI,正離子)m/z 630[M+H]+。
將氯化氫(4N,於1,4-二噁烷中,0.024mL,0.095mmol)添加至(S)-4-(4-(1-乙醯基-5-((第三丁氧基羰基)(苯基)胺基)-2-甲基-1,2,3,4-四氫喹啉-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(12mg,0.019mmol)於二噁烷(1.0mL)中之溶液中。在室溫下攪拌反應溶液1小時,產生白色沈澱物。在氮氣流下濃縮反應溶液,添加乙醚(1mL),且經由添加飽和碳酸氫鈉水溶液(1mL)中和產物。收集有機層,經無水硫酸鈉乾燥,過濾,且在真空中濃縮,得到呈淡黃色蠟狀固體狀之(S)-1-(6-(1-乙基哌啶-4-基)-2-甲基-5-丙氧基-3,4-二氫喹啉-1(2H)-基)乙-1-酮(5.1mg,62%)。1H NMR(300MHz,DMSO-d 6 )δ ppm 1.03(d,J=6.74Hz,3 H),1.11-1.25(m,2 H),1.35-1.52(m,1H),1.61-1.69(m,1 H),1.76-1.90(m,2 H),1.97-2.10(m,2 H),2.15(s,3 H),2.19-2.30(m,1 H),2.36-2.44(m,1 H),2.91-3.01(m,2 H),3.98-4.16(m,1 H),4.53-4.68(m,1 H),6.84-7.04(m,2 H),7.04-7.11(m,1 H),7.12-7.19(m,1 H),7.29-7.37(m,3 H),7.83(s,1 H),8.11(s,1 H),10.02(br s,1 H)。MS(ESI,正離子)m/z 430[M+H]+。
將苯甲基溴(0.42mL,3.56mmol)及碳酸鉀(670mg,4.85mmol)添加至4-(4-溴-1H-吡唑-1-基)哌啶(743.7mg,3.23mmol)於DMF(10mL)中之溶液中,且在室溫下攪拌反應物隔夜。藉由添加水(50mL)淬滅反應物,且用乙酸乙酯(3×50mL)萃取。合併有機萃取物,且用水(2×50mL)及鹽水(30mL)洗滌,經無水硫酸鈉乾燥,過濾且在真空中濃縮。經由矽膠管柱層析(Biotage 25g管柱,以含20-30%乙酸乙酯之己烷進行梯度洗提)直接純化粗產物,得到呈淡黃色油狀之1-苯甲基-4-(4-溴-1H-吡唑-1-基)哌啶(673mg,65%)。MS(ESI,正離子)m/z 321[M+H]+。
將二異丙基胺化鋰溶液(1.0M,於THF/己烷中)(1.25mL,1.25mmol)緩慢添加至1-苯甲基-4-(4-溴-1H-吡唑-1-基)哌啶(200mg,0.625mmol)於THF(2.0mL)中之-78℃溶液中,且在-78℃下攪拌反應物1小時。添加N-氟-N-(苯基磺醯基)苯磺醯胺(295mg,0.937mmol),且在-78℃下再攪拌反應物1小時。經由添加飽和氯化銨水溶液(5mL)淬滅反應物。使反應物升溫至室溫,且在真空中濃縮。添加乙酸乙酯(25mL),且用水(2×10mL)及鹽水(10mL)洗滌有機溶液。經無水硫酸鈉乾燥有機層,過濾,且在真空中濃縮。經由矽膠管柱層析(Biotage 25g管柱,以含20-30%乙酸乙酯之己烷進行梯度洗提)直接純化粗產物,得到呈淡黃色油狀之1-苯甲基-4-(4-溴-5-氟-1H-吡唑-1-基)哌啶(53mg,25%)。MS(ESI,正離子)m/z 339[M+H]+。
將XPhos第2代預催化劑(6.0mg,0.008mmol)添加至(S)-5-環丁氧基-2-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3,4-二氫喹啉-
1(2H)-甲酸甲酯(30.8mg,0.077mmol)、1-苯甲基-4-(4-溴-5-氟-1H-吡唑-1-基)哌啶(26.0mg,0.077mmol)及磷酸鉀(81mg,0.384mmol)於1,4-二噁烷(1.00mL)及水(0.20mL)中之經氮氣淨化溶液中,且在100℃下加熱反應混合物隔夜。經由矽膠管柱層析(Biotage 25g管柱,以含10-20%乙酸乙酯之己烷進行梯度洗提)直接純化粗反應混合物,得到呈白色固體狀之(S)-6-(1-(1-苯甲基哌啶-4-基)-5-氟-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(16mg,39%)。MS(ESI,正離子)m/z 533[M+H]+。
將填充氫氣之氣球饋入(S)-6-(1-(1-苯甲基哌啶-4-基)-5-氟-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(15.0mg,0.028mmol)及20%氫氧化鈀/碳(40mg,0.285mmol)於甲醇(10mL)中之經氮氣淨化懸浮液中。用氫氣回填反應燒瓶3次。接著在氫氣氛圍下攪拌反應溶液2小時。用氮氣淨化燒瓶,且經矽藻土過濾反應混合物,且用乙酸乙酯(10mL)洗滌矽藻土床。接著在真空中濃縮經過濾之溶劑。將粗產物直接添加至矽膠栓塞中且用含30%乙酸乙酯之甲醇洗提,得到呈灰白色固體狀之(S)-5-環丁氧基-6-(5-氟-1-(哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(7.2mg,58%)。
1H NMR(300MHz,DMSO-d 6 )δ ppm 1.09(d,J=6.45Hz,3 H),1.21-1.30(m,2 H),1.42-1.57(m,1 H),1.76-1.88(m,3 H),1.89-2.01(m,5 H),2.34-2.43(m,2 H),2.53-2.61(m,1 H),2.71-2.85(m,2 H),3.03(br d,J=12.31Hz,1 H),3.13-3.21(m,1 H),3.68(s,3 H),3.95-4.05(m,1 H),4.15-4.30(m,1 H),4.41-4.52(m,1 H),7.14(d,J=8.15Hz,1 H),7.29(d,J=8.79Hz,1 H),7.61(s,1 H)。MS(ESI,正離子)m/z 443[M+H]+。
將三乙胺(0.95mL,6.8mmol)添加至(3S,4S)-3-氟-4-羥基哌啶-1-甲酸第三丁酯(500.0mg,2.28mmol)及甲烷磺醯氯(0.27mL,3.4mmol)於二氯甲烷(9mL)中之0℃溶液中,且使所得混合物升溫至室溫且攪拌隔夜。用飽和碳酸氫鈉水溶液(10mL)淬滅反應物。再添加二氯甲烷(10mL),且分離各層。用1M檸檬酸水溶液(10mL)及鹽水(10mL)洗滌有機層,經無水硫酸鈉乾燥,過濾且在真空中濃縮。經由矽膠管柱層析(Biotage 50g管柱,以含20-30%乙酸乙酯之己烷進行梯度洗提)直接純化粗產物,得到呈無色油狀之(3S,4S)-3-氟-4-((甲基磺醯基)氧基)哌啶-1-甲酸第三丁酯(629mg,93%),其在靜置時凝固成白色固體。1H NMR(300MHz,CDCl3)δ ppm 1.46(s,9 H),1.73-1.87(m,1 H),2.15-2.25(m,1 H),2.97-3.12(m,2 H),3.08(s,3 H),3.85-3.95(m,1 H),4.39-4.46(m,1 H),4.55-4.62(m,1 H),4.65-4.78(m,1 H)。
步驟2.
(S)-6-(1-((3S,4R)-1-(第三丁氧基羰基)-3-氟哌啶-4-基)-1H-
吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯
將(3S,4S)-3-氟-4-((甲基磺醯基)氧基)哌啶-1-甲酸第三丁酯(96mg,0.322mmol)添加至(S)-5-環丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(100mg,0.293mmol)及碳酸銫(153mg,0.469mmol)於DMF(1.0mL)中之溶液中,且在100℃下加熱反應混合物1小時。冷卻反應溶液至室溫,用水稀釋,且用乙酸乙酯(3×50mL)萃取。用水(2×25mL)及鹽水(25mL)洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾,且在真空中濃縮。經由矽膠管柱層析(Biotage 25g管柱,以含20-30%乙酸乙酯之己烷進行梯度洗提)純化粗產物,得到呈無色油狀之(S)-6-(1-((3S,4R)-1-(第三丁氧基羰基)-3-氟哌啶-4-基)-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(89mg,56%)。MS(ESI,正離子)m/z 543[M+H]+。
將氯化氫(4.0N,於1,4-二噁烷中,0.23mL,0.931mmol)添加至(S)-6-(1-((3S,4R)-1-(第三丁氧基羰基)-3-氟哌啶-4-基)-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(101mg,0.186mmol)於1,4-二噁烷(1.0mL)中之溶液中,且在室溫下攪拌反應混合物3小時。在氮氣流下濃縮反應溶液,用飽和碳酸氫鈉水溶液(1mL)稀釋,且用乙酸乙酯(3×1mL)萃取。將經合併之有機層直接添加至矽膠栓塞中且用含30%乙酸乙酯之甲醇洗提,得到呈白色固體狀之(S)-5-環丁氧基-6-(1-((3S,4R)-3-氟哌啶-4-基)-1H-吡唑-4-基)-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯(38mg,47%)。1H NMR(300MHz,DMSO-d 6 )δ ppm 1.07(d,J=6.45Hz,3 H),1.19-1.39(m,2 H),1.47-1.58(m,1 H),1.96-2.18(m,8 H),2.34-2.43(m,2 H),2.55-2.72(m,1 H),2.77-2.89(m,2 H),3.00-3.13(m,1 H),3.14(br d,J=4.98Hz,1 H),
3.65(s,3 H),4.02-4.12(m,1 H),4.37-4.49(m,1 H),4.78-4.94(m,1 H),7.21(d,J=8.50Hz,1 H),7.32(d,J=8.79Hz,1 H),7.83(s,1 H),8.02(s,1 H)。MS(ESI,正離子)m/z 443[M+H]+。
根據上文針對實例106所述之程序製得以下實例:
1H NMR(300MHz,DMSO-d 6 )δ ppm 1.07(d,J=6.45Hz,3 H),1.19-1.39(m,2 H),1.47-1.58(m,1 H),1.96-2.18(m,8 H),2.34-2.43(m,2 H),2.55-2.72(m,1 H),2.77-2.89(m,2 H),3.00-3.13(m,1 H),3.14(br d,J=4.98Hz,1 H),3.65(s,3 H),4.02-4.12(m,1 H),4.31-4.49(m,1 H),4.72-4.94(m,1 H),7.21(d,J=8.50Hz,1 H),7.32(d,J=8.79Hz,1 H),7.83(s,1 H),8.00(s,1 H)。MS(ESI,正離子)m/z 443[M+H]+。
1H NMR(300MHz,DMSO-d 6 )δ ppm 1.06(d,J=6.45Hz,3 H),1.19-1.39(m,2 H),1.47-1.58(m,1 H),1.89-2.18(m,8 H),2.34-2.43(m,2 H),2.55-2.72(m,1 H),2.77-2.87(m,2 H),2.88-2.95(m,1 H),3.65(s,3 H),4.01-4.11(m,1 H),4.31-4.45(m,1 H),4.60-4.84(m,1 H),7.21(d,J=8.50Hz,1 H),7.28(d,J=8.79Hz,1 H),7.82
(s,1 H),8.08(s,1 H)。MS(ESI,正離子)m/z 443[M+H]+。
1H NMR(300MHz,DMSO-d 6 )δ ppm 1.04(d,J=6.74Hz,3 H),1.51(dd,J=13.34,5.72Hz,1 H),1.79-1.98(m,4 H),2.34-2.46(m,4 H),2.87(br d,J=9.09,1 H),3.19-3.29(m,1 H),3.70(s,3 H),4.17-4.35(m,1 H),4.50-4.77(m,2 H),6.73-6.77(m,2 H),7.06-7.12(m,2 H),7.54(d,J=2.93Hz,2 H),7.76(s,1 H),8.02(s,1 H)。MS(ESI,正離子)m/z 483[M+H]+。
1H NMR(300MHz,DMSO-d 6 )δ ppm 1.04(d,J=6.74Hz,3 H),1.51(dd,J=13.92,4.84Hz,1 H),1.71-1.80(m,1 H),1.90-2.04(m,3 H),2.34-2.46(m,4 H),2.93-3.10(m,1 H),3.11-3.19(m,1 H),3.70(s,3 H),4.27-4.42(m,1H),4.48-4.57(m,1 H),4.65-4.84(m,1 H),6.72-6.76(m,2 H),7.06-7.12(m,2 H),7.51-7.61(m,2 H),7.76(s,1 H),7.94(s,1 H)。MS(ESI,正離子)m/z 483[M+H]+。
1H NMR(300MHz,DMSO-d 6 )δ ppm 1.04(d,J=6.74Hz,3 H),1.51(dd,J=13.92,4.84Hz,1 H),1.71-1.80(m,1 H),1.90-2.04(m,3 H),2.34-2.46(m,4 H),2.93-3.10(m,1 H),3.11-3.19(m,1 H),3.70(s,3 H),4.27-4.42(m,1H),4.48-4.57(m,1 H),4.63-4.85(m,1 H),6.72-6.76(m,2 H),7.06-7.12(m,2 H),7.51-7.61(m,2 H),7.76(s,1 H),7.94(s,1 H)。MS(ESI,正離子)m/z 483[M+H]+。
1H NMR(300MHz,DMSO-d 6 )δ ppm 1.06(d,J=6.45Hz,3 H),1.17-1.28(m,1 H),1.29-1.42(m,1H),1.47-1.56(m,1 H),1.86-2.17(m,8 H),2.34-2.43(m,2 H),2.55-2.72(m,1 H),2.77-2.87(m,2 H),2.88-2.95(m,1 H),3.65(s,3 H),4.01-4.11(m,1 H),4.31-4.45(m,1 H),4.60-4.84(m,1 H),7.21(d,J=8.50Hz,1 H),7.28(d,J=8.79Hz,1 H),7.82(s,1 H),8.08(s,1 H)。MS(ESI,正離子)m/z 443[M+H]+。
1H NMR(300MHz,DMSO-d 6 )δ ppm 1.04(d,J=6.74Hz,3 H),1.51(dd,J=13.92,4.84Hz,1 H),1.71-1.84(m,2 H),1.90-2.04(m,3 H),2.67-2.73(m,1 H),2.81-2.93(m,2 H),3.11-3.19(m,1 H),3.70(s,3 H),4.23-4.36(m,1H),4.50-4.60(m,1 H),4.63-4.83(m,1 H),6.72-6.76(m,2 H),7.06-7.12(m,2 H),7.54(d,J=2.93Hz,2 H),7.76(s,1 H),8.02(s,1 H)。MS(ESI,正離子)m/z 483[M+H]+。
1H NMR(300MHz,DMSO-d 6 )δ ppm 0.59-0.68(m,1 H),0.73-0.87(m,2 H),0.91-0.98(m,1 H),1.01(d,J=6.45Hz,3 H),1.17-1.31(m,2 H),1.49-1.59(m,1 H),1.73-1.93(m,2 H),1.96-2.17(m,6 H),2.23-2.33(m,2 H),2.60-2.77(m,1 H),2.86-2.95(m,2 H),4.05-4.18(m,1 H),4.29-4.39(m,1 H),4.43-4.62(m,2 H),4.74-4.97(m,1 H),7.08(d,J=8.50Hz,1 H),7.42(d,J=8.50Hz,1 H),7.87(s,1 H),8.07(s,1 H)。MS(ESI,正離子)m/z 453[M+H]+。
異構物之2:1混合物。主要異構物:1H NMR(300MHz,DMSO-
d 6 )δ ppm 1.09(d,J=6.45Hz,3 H),1.19-1.43(m,2 H),1.49-1.60(m,1 H),1.99-2.22(m,4 H),2.35-2.43(m,1 H),2.79-3.11(m,4 H),3.68(s,3 H),4.07-4.15(m,1 H),4.40-4.47(m,1 H),4.69-4.85(m,1 H),5.01-5.18(m,2 H),5.26-5.37(m,1 H),7.23(d,J=8.50Hz,1 H),7.33(d,J=8.79Hz,1 H),7.84(s,1 H),8.10(s,1 H)。MS(ESI,正離子)m/z 429[M+H]+。
異構物之1:1混合物。1H NMR(300MHz,CDCl3)δ ppm 0.51-0.62(m,1 H),0.73-0.83(m,2 H),0.87-0.95(m,1 H),1.06(d,J=6.45Hz,3 H),1.12-1.30(m,4 H),1.50-1.63(m,1 H),1.73-1.82(m,1 H),1.90-2.15(m,7 H),2.23-2.33(m,2 H),2.88-2.98(m,1 H),3.05-3.32(m,1 H),3.41-3.62(m,1 H),4.00-4.11(m,1 H),4.60-4.73(m,1 H),4.96-5.29(m,1 H),7.06(d,J=8.21Hz,1 H),7.19(m,1 H),7.78(s,1 H),7.89(s,1 H)。MS(ESI,正離子)m/z 453[M+H]+。
將二碳酸二第三丁酯(1.09g,5.01mmol)添加至2-甲基哌啶-4-酮鹽酸鹽(異構物之1:1混合物,0.500g,3.34mmol)及DMAP(0.817g,6.68mmol)於無水THF(10mL)中之0℃溶液中,且在0℃下攪拌所得混合物2小時。藉由添加飽和氯化銨水溶液(50mL)淬滅反應物,且添加乙酸乙酯(70mL)。分離水相,且用乙酸乙酯(2×50mL)萃取。用鹽水(50mL)洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾,且在真空中濃縮。經由矽膠管柱層析(Biotage 50g管柱,以含25-35%乙酸乙酯之己烷進行梯度洗提)純化殘餘物,得到呈白色固體狀之2-甲基-4-側氧基哌啶-1-甲酸第三丁酯(0.660g,93%)。1H NMR(300MHz,DMSO-d 6 )δ ppm 1.06(d,J=6.74Hz,3 H),1.40(s,9 H),2.11-2.25(m,2 H),2.36-2.45(m,1 H),2.68(dd,J=14.51,6.6Hz,1 H),3.25-3.36(m,1 H),3.93-4.06(m,1 H),4.42-4.48(m,1 H)。
遵循見於Plettenburg,Oliver等人(PCT國際申請案2007012421)中之程序,將硼氫化鈉(213mg,5.6mmol)逐份添加至2-甲基-4-側氧基
哌啶-1-甲酸第三丁酯(1.0g,4.7mmol)於乙醇(10mL)中之溶液中。
在室溫下攪拌混合物2小時。在真空中濃縮溶液,接著分配於水(40mL)與乙酸乙酯(40mL)之間。用乙酸乙酯(40mL)萃取水層兩次。用鹽水(20mL)洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾,且在真空中濃縮。經由矽膠管柱層析(Biotage 50g管柱,以含40-50%乙酸乙酯之己烷進行梯度洗提)純化殘餘物,得到呈白色固體狀之(外消旋)-(順)-4-羥基-2-甲基哌啶-1-甲酸第三丁酯(367mg,36%)及(外消旋)-(反)-4-羥基-2-甲基哌啶-1-甲酸第三丁酯(205mg,20%)。
將三乙胺(0.49mL,3.49mmol)添加至(外消旋)-(順)-4-羥基-2-甲基哌啶-1-甲酸第三丁酯(250mg,1.16mmol)及甲烷磺醯氯(0.14mL,1.74mmol)於二氯甲烷(4.5mL)中之0℃溶液中。使所得混合物升溫至室溫且攪拌隔夜。藉由添加飽和碳酸氫鈉水溶液(10mL)淬滅反應物,且添加二氯甲烷(10mL)。分離有機層,且用1M檸檬酸水溶液(10mL)及鹽水(10mL)洗滌,經無水硫酸鈉乾燥,過濾,且在真空中濃縮。經由矽膠管柱層析(Biotage 50g管柱,以含20-30%乙酸乙酯之己烷進行梯度洗提)純化殘餘物,得到呈無色油狀之(外消旋)-(順)-2-甲基-4-((甲基磺醯基)氧基)哌啶-1-甲酸第三丁酯(315mg,92%),其在靜置時緩慢凝固成白色固體。1H NMR(300MHz,DMSO-d 6 )δ ppm 1.17(d,J=7.04Hz,3 H),1.38(s,9 H),1.63-1.76(m,1 H),1.85-1.90(m,3 H),2.96-3.06(m,1 H),3.18(s,3 H),3.72-3.78(m,1 H),4.16-4.24(m,1 H),4.93-4.98(m,1 H)。
將(外消旋)-(順)-4-羥基-2-甲基哌啶-1-甲酸第三丁酯(55.9mg,0.190mmol)添加至(S)-5-環丁氧基-2-甲基-6-(1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯(50.0mg,0.146mmol)及碳酸銫(76mg,0.234mmol)於DMF(1.0mL)中之溶液中,且加熱反應混合物至100℃,且攪拌隔夜。冷卻混合物至室溫,用水稀釋,且用乙酸乙酯(3×50mL)萃取。用水(2×25mL)及鹽水(25mL)洗滌經合併之有機層,經無水硫酸鈉乾燥,過濾,且在真空中濃縮。經由矽膠管柱層析(Biotage 25g管柱,以含20-30%乙酸乙酯之己烷進行梯度洗提)純化殘餘物,得到呈無色油狀之(S)-6-(1-((2S,4R)-1-(第三丁氧基羰基)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯與(S)-6-(1-((2R,4S)-1-(第三丁氧基羰基)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯之1:1混合物(54.2mg,69%)。MS(ESI,正離子)m/z 539[M+H]+。
將氯化氫(4.0N,於1,4-二噁烷中,0.126mL,0.503mmol)添加至含有(S)-6-(1-((2S,4R)-1-(第三丁氧基羰基)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯與(S)-6-(1-((2R,4S)-1-(第三丁氧基羰基)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-5-環丁氧基-2-甲基-3,4-二氫喹啉-1(2H)-甲酸甲酯之1:1混合物(54.2mg,0.101mmol)於1,4-二噁烷(1.0mL)中之溶液中,且在室溫下攪拌反應混合物3小時。在氮氣流下濃縮溶液,用飽和碳酸氫鈉水溶液(1.0mL)稀釋,且用乙酸乙酯(3×1.0mL)萃取。將經合併之有機層直接添加
至矽膠栓塞中,且用含30%乙酸乙酯之甲醇洗提產物,得到呈白色固體狀之(S)-5-環丁氧基-2-甲基-6-(1-((2S,4R)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯與(S)-5-環丁氧基-2-甲基-6-(1-((2R,4S)-2-甲基哌啶-4-基)-1H-吡唑-4-基)-3,4-二氫喹啉-1(2H)-甲酸甲酯之1:1混合物(18.1mg,41%)。1H NMR(300MHz,DMSO-d 6 )δ ppm 0.81(d,J=6.74Hz,3 H),1.05(d,J=6.74Hz,3 H),1.22-1.43(m,3 H),1.48-1.65(m,2 H),1.81-2.22(m,8 H),2.34-2.43(m,1 H),2.72-2.87(m,2 H),2.90-3.00(m,1 H),3.10-3.17(m,1 H),3.66(s,3 H),4.05-4.12(m,1 H),4.40-4.52(m,1 H),7.21(d,J=8.79Hz,1 H),7.30(d,J=9.38Hz,1 H),7.78(s,1 H),8.08(s,1 H)。MS(ESI,正離子)m/z 439[M+H]+。
根據上文針對實例107所述之程序製得以下實例:
1H NMR(300MHz,DMSO-d6)δ ppm 0.80(d,J=6.45Hz,3 H),1.05(d,J=6.74Hz,3 H),1.22-1.43(m,3 H),1.48-1.75(m,2 H),1.90-2.13(m,8 H),2.34-2.45(m,1 H),2.58-2.70(m,2 H),2.76-2.86(m,1 H),2.99-3.05(m,1 H),3.66(s,3 H),4.02-4.12(m,1 H),4.15-4.26 4.36-4.48(m,1 H),7.20(d,J=8.79Hz,1 H),7.29(d,J=9.38Hz,1 H),7.76(s,1 H),8.01(s,1 H)。MS(ESI,正離子)m/z 439[M+H]+。
向半打蘭小瓶中饋入(S)-6-溴-2-甲基-1,2,3,4-四氫喹啉-5-醇A(0.2M,於N,N-二甲基乙醯胺中,150μL,30μmol)及第三丁醇鉀(1M,於THF中,36μL,36μmol),且震盪混合物5秒。添加烷基鹵化物B(0.2M,於N,N-二甲基乙醯胺中,180μL,36μmol),且密封系統,且在80℃下震盪14小時。添加乙酸乙酯(0.7mL)及含1N氫氧化鈉之鹽水(0.5mL),且震盪混合物。分離有機層,且用乙酸乙酯(1.0mL)萃取水相。濃縮經合併之有機相,且將殘餘物溶解於無水1,4-二噁烷(100μL)中。添加芳基硼酸酯C(0.2M,於1,4-二噁烷中,270μL,54μmol)、碳酸鉀(1M水溶液,90μL,90μmol)及[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.02M,於1,2-二氯乙烷中,150μL,3μmol),且密封混合物,且在80℃下震盪14小時。添加乙酸乙酯(0.5mL)及含1N氫氧化鈉之鹽水(0.4mL),且震盪混合物。分離有機層,且用乙酸乙酯(1.0mL)萃取水相。濃縮經合併之有機相,得到粗產物。藉由質量觸發式製備型HPLC純化此物質。合併含產物之洗提份且在Genevac中濃縮,得到所需產物。
根據上述方案合成表1中之下列化合物:
向半打蘭小瓶中饋入(S)-6-溴-2-甲基-1,2,3,4-四氫喹啉-5-醇A(0.2M,於乙腈中,200μL,40μmol)及芳基鹵化物B(0.4M,於乙腈中,200μL,80μmol)。添加碳酸銫(66mg,200μmol),且密封系統,且在80℃下震盪14小時。添加乙酸乙酯(0.7mL)及含1N氫氧化鈉之鹽水(0.5mL),且震盪混合物。分離有機層,且用乙酸乙酯(1.0mL)萃取水相。濃縮經合併之有機相,且將殘餘物溶解於無水1,4-二噁烷(100μL)中。添加吡唑硼酸酯C(0.2M,於1,4-二噁烷中,360μL,72μmol)及碳酸鉀(1M水溶液,120μL,120μmol),且將反應物移至手套箱中。在氮氣氛圍下添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.02M,於1,2-二氯乙烷中,200μL,4μmol),且密封混合物,且在80℃下震盪14小時。添加乙酸乙酯(0.5mL)及含1N氫氧化鈉之鹽水(0.4mL),且震盪混合物。分離有機層,且用乙酸乙酯(1.0mL)萃取水相。濃縮經合併之有機相,且將殘餘物溶解於無水1,4-二噁烷(200μL)中。添加HCl(4M,於1,4-二噁烷中,100μL),且密封系統,且在50℃下震盪2小時。濃縮混合物,且溶解
於乙酸乙酯(500μL)中。將溶液轉移至基於二氧化矽之陽離子交換管柱(SCX 0.5g),且用乙酸乙酯/甲醇(3:1,3mL)(以洗提廢物)、繼而用氨(2M,於甲醇中,3mL)(以洗提產物)洗滌。濃縮氨溶液,得到粗產物。藉由質量觸發式製備型HPLC純化此物質。合併含產物之洗提份且在Genevac中濃縮,得到所需產物。
根據上述方案合成表2中之下列化合物:
向半打蘭小瓶中饋入(S)-6-溴-2-甲基-1,2,3,4-四氫喹啉-5-醇A(0.2M,於乙腈中,150μL,30μmol)及芳基鹵化物B(0.4M,於乙腈中,150μL,60μmol)。添加碳酸銫(50mg,150μmol),且密封系統,且在80℃下震盪14小時。添加乙酸乙酯(0.7mL)及含1N氫氧化鈉之鹽水(0.5mL),且震盪混合物。分離有機層,且用乙酸乙酯(1.0mL)萃取水相。濃縮經合併之有機相,且將殘餘物溶解於無水1,4-二噁烷(100μL)中。添加芳基硼酸酯C(0.2M,於1,4-二噁烷中,270μL,54μmol)及碳酸鉀(1M水溶液,90μL,90μmol),且將反應物轉
移至手套箱中。接著在氮氣氛圍下添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.02M,於1,2-二氯乙烷中,150μL,3μmol),且密封混合物,且在80℃下震盪14小時。添加乙酸乙酯(0.5mL)及鹽水(0.5mL),且震盪混合物。分離有機層,且用乙酸乙酯(1.0mL)萃取水相。濃縮經合併之有機相,且藉由質量觸發式製備型HPLC純化殘餘物。合併含產物之洗提份且在Genevac中濃縮,得到所需產物。
根據上述方案合成表3中之下列化合物:
向半打蘭小瓶中饋入芳基硼酸B(0.2M,於1,4-二噁烷中,500μL,100μmol)及乙酸銅(II)(0.2M,於水中,260μL,52μmol)。濃縮混合物,且添加分子篩(50mg)。添加(S)-6-溴-2-甲基-1,2,3,4-四氫喹啉-5-醇A(0.2M,於1,2-二氯乙烷中,200μL,40μmol)及吡啶(0.5M,於1,2-二氯乙烷中,400μL,200μmol),且密封系統,且在80℃下震盪14小時。添加乙酸乙酯(0.7mL)及飽和氯化銨水溶液(0.5mL),且震盪混合物。分離有機層,且用乙酸乙酯(1.0mL)萃取水相。濃縮經合併之有機相,且將殘餘物溶解於無水1,4-二噁烷(100μL)中。添加吡唑硼酸酯C(0.2M,於1,4-二噁烷中,400μL,80μmol)及碳酸鉀(1M水溶液,120μL,120μmol),且將反應物轉移至手套箱中。接著在氮氣氛圍下添加[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.02M,於1,2-二氯乙烷中,200μL,4μmol),且密封混合物,且在80℃下震盪14小時。添加乙酸乙酯(0.5mL)及含1N氫氧化鈉之鹽水(0.4mL),且震盪混合物。分離有機層,且用乙酸乙酯(1.0mL)萃取水相。濃縮經合併之有機相,且將殘餘物溶解於無水1,4-二噁烷(200μL)中。(注意:對於缺乏經Boc保護之中間物之實例,省略以下酸水解步驟及SCX純化)。添加HCl(4M,於1,4-二噁烷中,100μL),且密封系統,且在50℃下震盪2小時。濃縮混合物,且溶解於乙酸乙酯(500μL)中。將溶液轉移至基於二氧化矽之陽離子交換管柱(SCX 0.5g),且用乙酸乙酯/甲醇(3:1,3mL)(以洗提廢物)、繼而用氨(2M,於甲醇中,3mL)(以洗提產物)洗滌。濃縮氨溶液,得到粗產物。藉由質量觸發式製備型HPLC純化此物質。合併含產物
之洗提份且在Genevac中濃縮,得到所需產物。
根據上述方案合成表4中之下列化合物:
向反應小瓶中饋入6-溴-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉(0.2M,於1,2-二氯乙烷中,0.10mL,0.02mmol)、N,N-二異丙基乙胺(10.5μL,0.06mmol)及酸氯化物或氯甲酸酯(A)(0.5M,於1,2-二氯乙烷中,0.05mL,0.025mmol),且在50℃下震盪混合物2小時。添加乙酸乙酯及水,且震盪混合物。分離有機層,且用乙酸乙酯萃取水
相。濃縮經合併之有機相,且將殘餘物溶解於無水1,4-二噁烷(100μL)中。添加1-環丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吡唑(0.2M,於1,4-二噁烷中,0.10mL,0.02mmol)及碳酸氫鈉(1M水溶液,0.06mL,0.06mmol),且將反應物轉移至手套箱中。接著在氮氣氛圍下添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.02M,於1,2-二氯乙烷中,0.05mL,0.001mmol),且密封混合物,且在80℃下震盪18小時。添加乙酸乙酯及水,且震盪混合物。分離有機層,且用乙酸乙酯萃取水相。濃縮經合併之有機相,得到粗產物。藉由質量觸發式製備型HPLC純化此物質。合併含產物之洗提份且在Genevac中濃縮,得到所需產物。
根據上述方案合成表5中之下列化合物:
向反應小瓶中饋入(S)-1-(6-溴-5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(0.2M,於N,N-二甲基乙醯胺中,0.100mL,0.02mmol)及(R)-或(S)-3-(溴甲基)吡咯啶-1-甲酸第三丁酯A(0.2M,於N,N-二甲基乙醯胺中,0.12mL,0.024mmol)。添加第三丁醇鉀(1M,於THF中,0.024mL,0.024mmol),且密封系統,且在80℃下震盪隔夜。添加乙酸乙酯及含1N氫氧化鈉之鹽水,且震盪混合物。分離有機層,且用乙酸乙酯萃取水相。濃縮經合併之有機相,且將殘餘物溶解於無水1,4-二噁烷(100μL)中。添加吡唑硼酸酯B(0.2M,於1,4-二噁烷中,0.15mL,0.030mmol)及碳酸鉀(1M水溶液,0.060mL,0.060mmol),且將反應物轉移至手套箱中。接著在氮氣氛圍下添加[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)二氯甲烷加合物(0.02M,於1,2-二氯乙烷中,0.10mL,2.0μmol),且密封混合物,且在80℃下震盪4小時。添加乙酸乙酯及含1N氫氧化鈉之鹽水,且震盪混合物。
分離有機層,且用乙酸乙酯(1.0mL)萃取水相。濃縮經合併之有機相,得到粗產物。將殘餘物溶解於1,2-二氯乙烷(0.1mL)中,添加三氟乙酸(0.1mL,1.3mmol),且在室溫下攪拌混合物2小時。濃縮反應混合物,且將殘餘物分配於乙酸乙酯與飽和碳酸氫鈉水溶液之間。分離水層且用乙酸乙酯萃取,且在氮氣流及真空下濃縮經合併之有機層。藉由質量觸發式製備型HPLC純化粗產物。合併含產物之洗提份且在Genevac中濃縮,得到所需產物。
根據上述方案合成表6中之下列化合物:
向1.5-mL反應小瓶中饋入(S)-1-(5-羥基-2-甲基-3,4-二氫喹啉-1(2H)-基)乙酮(0.2M溶液,於N,N-二甲基乙醯胺中,0.1mL,0.02mmol)及第三丁醇鉀(1M,於THF中,0.024mL,0.024mmol)。接著添加芳基鹵化物(A)(0.2M溶液,於N,N-二甲基乙醯胺中,0.12mL,0.024mmol),且在加熱震盪器上加熱反應物至80℃隔夜。用乙酸乙酯稀釋反應物,且用1N氫氧化鈉水溶液洗滌。分離水層且用乙酸乙酯洗滌,且在氮氣流及真空下濃縮經合併之有機層。藉由質量觸發式製備型HPLC純化粗產物。合併含產物之洗提份且在Genevac中濃縮,得到所需產物。
根據上述方案製得表7中之下列實例:
使用384孔AlphaScreen分析技術評估實例化合物與BRD4溴域1及BRD4溴域2之結合。將經His抗原決定基標記之BRD4 BD144-168及BRD4 BD2333-460選殖,表現,且純化至均質。藉由使用AlphaScreen技術(PerkinElmer)監測經生物素標記之組蛋白H4(1-21)K5/8/12/16四乙醯基化肽與標靶之接合來評估BRD4 BD1及BRD4 BD2結合及抑制。特定而言,在384孔黑色或白色平底盤中,在50mM HEPES(pH 7.3)、100mM NaCl、0.1%(w/v)BSA及0.01%(w/v)Triton X-100中於DMSO(最終1.25% DMSO)或含化合物稀釋系列之DMSO存在下將BRD4 BD1(最終50nM)或BRD4 BD2(最終100nM)與肽(對於BD1最終50nM或對於BD2最終100nM)組合。添加α抗生蛋白鏈菌素供體珠粒及鎳螯合物接受體珠粒,各自達到10μg/ml之最終濃度。最少平衡1小時之後,在BMG PHERAstar FS多標記讀取器(BMG LabTech)上讀取盤。使用具有四參數邏輯曲線擬合之IDBS Activity Base軟體由等式y=A+((B-A)/(1+((C/x)^D)))計算半最大抑制濃度(IC50)值,其中A表示曲線之底部平臺,B表示曲線之頂部平臺,C表示曲線中間之x值,D表示斜率因子,x表示原始已知x值,且y表示原始已知y值。使用萊文貝格-馬誇特演算法(Levenburg Marquardt algorithm)對資料進行擬合。
下表8根據BRD4 BD1之抑制提供代表性化合物之活性。化合物分組為四個類別:在<0.1μM之濃度下抑制;在介於0.1μM與1μM之間的濃度下抑制;在介於1μM與10μM之間的濃度下抑制;在>10μM之濃度下抑制。
表9 提供根據BRD4 BD2之抑制排列之化合物。
化合物分組為三個組:IC50<0.05μM;0.05IC50 0.5μM;及IC50>0.5μM。
在3天增殖分析中使用急性髓細胞白血病(AML)細胞系MV4-11(ATCC)確定實例化合物對癌細胞增殖之影響。在37℃及5% CO2氛圍下將MV4-11細胞維持於補充有10% FBS之RPMI 1640培養基中。對於化合物測試,在384孔白色平底盤中於DMSO中經由自2mM至0.001mM之3倍連續稀釋來製備化合物稀釋系列。孔中之最終化合物濃度為10、3.3、1.1、0.37、0.12、0.041、0.013及0.0045μM。將MV4-11細胞以3000個細胞/孔之密度塗鋪於50μl最終體積之培養基中,且培育72小時。根據製造商建議之方案使用CellTiter-Glo發光細胞存活力分
析套組(Promega)測定活細胞之量。在EnVision多標記盤讀取器(PerkinElmer)上讀取來自CellTiter-Glo分析之發光信號。使用具有四參數邏輯曲線擬合之IDBS Activity Base軟體由等式y=A+((B-A)/(1+((C/x)^D)))確定在DMSO對照與背景對照(無細胞)之間使細胞生長抑制50%之值(gIC50),其中A表示曲線之底部平臺,B表示曲線之頂部平臺,C表示曲線中間之x值,D表示斜率因子,x表示原始已知x值,且y表示原始已知y值。使用萊文貝格-馬誇特演算法對資料進行擬合。
表10提供根據MV411細胞系增殖之抑制排列之化合物。化合物分組為三個組:IC50<0.5μM;0.5μM>IC50 1.0μM;及IC50>1.0μM。
在文獻中預期且指示,所有BET家族抑制劑對所有BET溴域均具有某種活性。
儘管已結合上文所闡述之特定實施例描述本發明,但其許多替代、修改及其他變化將為業內普通技術者顯而易知。所有該等替代、修改及變化欲處於本發明之精神及範疇內。
Claims (27)
- 一種式I化合物,
- 如請求項1之化合物,其中X為CR4且Y及Z為CH。
- 請求項2之化合物,其中W為CHR3。
- 如請求項1之化合物,其具有式II
- 如請求項4之化合物,其中W為CHR3。
- 如請求項4之化合物,其中Ar為吡唑或苯基。
- 如請求項1之化合物,其具有式III
- 如請求項7之化合物,其中Ar為吡唑且Rc為環烷基。
- 如請求項8之化合物,其中Rc為環丙基。
- 如請求項7之化合物,其中Ar為苯基,Rc為-(CH2)nS(O)2CH3。
- 如請求項1之化合物,其具有式IV
- 如請求項11之化合物,其中Rc為環烷基或雜環烷基。
- 如請求項12之化合物,其中R4為-O(CH2)nRd。
- 如請求項13之化合物,其中Rd為芳基、雜芳基或環烷基。
- 如請求項1之化合物,其選自由以下組成之群組:(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-{[3-(羥甲基)氧雜環丁烷-3-基]甲氧基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-{八氫環戊并[c]吡咯-5-基}-1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(3,3-二氟環丁氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-(1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-5-(氮雜環丁烷-3-基甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(2,2,2-三氟乙氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(3-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯; 1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2,2-二氟乙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2,2-二氟丙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(4-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(1,3-二氟丙-2-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(3,4-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(3-羥基-2,2-二甲基丙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-2-甲基丙醯胺;(2S)-1-環丙烷羰基-5-(2-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(3,3,3-三氟丙氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-1-環丙烷羰基-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;1-(2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙基)吡咯啶-2-酮; (2S)-1-環丙烷羰基-5-(4-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-1-(嗎啉-4-基)乙-1-酮;(2S)-5-(2-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;2-(2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙基)-1λ6,2-四氫噻唑-1,1-二酮;(2S)-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}甲烷磺醯胺;(2S)-5-(4-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基甲烷磺醯胺;(2S)-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[2-(氧雜環丁烷-3-基)乙氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(2,2-二氟環丙基)甲氧基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;3-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈; 1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-{[3-(羥甲基)氧雜環丁烷-3-基]甲氧基}-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡啶-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(3-氟氧雜環丁烷-3-基)甲氧基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(3,3-二氟環丁氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(氮雜環丁烷-3-基甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-吡唑-4-基)-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1H-吡唑-5-基)-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-咪唑-4-基)-1,2,3,4-四氫喹啉;(2S)-5-({1-[(第三丁氧基)羰基]氮雜環丁烷-3-基}氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(氮雜環丁烷-3-基氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯; 1-[(2S)-5-(氮雜環丁烷-3-基氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-6-[1-(1,1-二側氧基-1λ6-硫雜環丁烷-3-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[1-(1,1-二側氧基-1λ6-硫雜環己烷-3-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2R)-2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-2-氟乙醯胺;(2S)-2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-2-氟乙醯胺;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(3-氟氧雜環丁烷-3-基)甲氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-2,2-二氟乙醯胺;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟-2-甲基丙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-2-甲基-6-[1-(氧雜環己烷-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;(2S)-5-[(二甲基胺甲醯基)甲氧基]-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N-乙基乙醯胺; 1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟乙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N-環丙基-N-甲基乙醯胺;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-1-(氮雜環丁烷-1-基)乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-1-(哌啶-1-基)乙-1-酮;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(2,2,2-三氟乙氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2,2-二氟乙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟乙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2,2-二氟丙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(3,3,3-三氟丙氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(胺甲醯基二氟甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(1,3-二氟丙-2-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟-2-甲基丙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(3-羥基-2,2-二甲基丙氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯; (2S)-5-(1-胺甲醯基-1-甲基乙氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(R)-胺甲醯基(氟)甲氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(S)-胺甲醯基(氟)甲氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(乙基胺甲醯基)甲氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-{[環丙基(甲基)胺甲醯基]甲氧基}-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[2-(氮雜環丁烷-1-基)-2-側氧基乙氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[2-側氧基-2-(哌啶-1-基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[2-(2-側氧基吡咯啶-1-基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[2-(嗎啉-4-基)-2-側氧基乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[2-(1,1-二側氧基-1λ6,2-四氫噻唑-2-基)乙氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(胺磺醯基甲氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(二甲基胺磺醯基)甲氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[2-(氧雜環丁烷-3-基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯; (2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(2,2-二氟環丙基)甲氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(喹唑啉-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(1,3-苯并噁唑-2-基氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(1,3-苯并噁唑-2-基氧基)-2-甲基-6-[1-(氧雜環丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-(嘧啶-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}吡啶-3-甲醯胺;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{1H-吡唑并[3,4-d]嘧啶-6-基氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(1,3-噻唑-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}吡啶-3-甲腈;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[4-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(3-氯吡啶-2-基)氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮; 1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(吡啶-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(4,6-二甲基嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;6-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}嗒嗪-3-甲腈;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[2-(三氟甲基)嘧啶-4-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-丙氧基-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-丙氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(吡咯啶-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-(1-{八氫環戊并[c]吡咯-5-基}-1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-甲酸甲酯; 1-[6-(4-甲烷磺醯基苯基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-(2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-基)乙-1-酮;1-[(2S)-5-環丙氧基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(5-甲烷磺醯基吡啶-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;N-{6-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]吡啶-3-基}甲烷磺醯胺;2-{[(2S)-1-乙醯基-6-(5-甲烷磺醯基吡啶-2-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-6-(1,3-苯并噁唑-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-丙氧基-6-{吡唑并[1,5-a]吡啶-2-基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-{咪唑并[1,2-a]吡啶-2-基}-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1,3-苯并噻唑-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1H-1,3-苯并二唑-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(5-甲基-1,3,4-噻二唑-2-基)-1,2,3,4-四氫喹啉;5-[(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-6-基]-1,3,4-噻二唑-2-胺;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1H-1,2,3-三唑-4-基)- 1,2,3,4-四氫喹啉;(2S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(2-氰基-4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(2-氯-4-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氰基-2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-5-(2-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(2-氰基苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(2-氰基-3-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;4-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(3-氯吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}吡啶-3-甲腈;1-[(2S)-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-6-[1-(哌啶-4-基)- 1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡嗪-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(4-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(3-氰基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(2-氰基-3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氯-2-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;2-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;2-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}-6-氟苯甲腈;4-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}-3-氟苯甲腈;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(3-氯-4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;4-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲醯胺;1-[(2S)-5-(2-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]- 1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(2-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-胺甲醯基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氰基-4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氯-4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-(2-氯苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-(4-氯苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;4-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-(3-氯-4-氟苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)- 1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(3-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(3,4-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(3-氯苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(3-氯苯氧基)-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉;(2S)-5-(3-氯苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(3,5-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(3,5-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-5-(3,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(3,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;5-[(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6- 基]-1,3,4-噻二唑-2-胺;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(吡咯啶-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;4-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}苯甲醯胺;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-(1H-吡唑-5-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-(5-甲基-1,3,4-噻二唑-2-基)-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-咪唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-6-[1-(1,1-二側氧基-1λ6-硫雜環己烷-3-基)-1H-吡唑-4-基]-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(1,1-二側氧基-1λ6-硫雜環丁烷-3-基)-1H-吡唑-4-基]-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-吡唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(4-氯苯氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟苯氧基)-2-甲基- 1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉;3-{4-[(2S)-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環丁烷-1,1-二酮;3-{4-[(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環丁烷-1,1-二酮;1-[(2S)-5-(2-氯苯氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氰基苯氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氯苯氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(2-氯苯氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-胺甲醯基苯氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;4-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-5-(4-氯-2-氰基苯氧基)-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[1-(丙-2-基)氮雜環丁烷-3-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4- 基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-5-環丁氧基-2-甲基-6-[1-(1-甲基吡咯啶-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-(1-{2-甲基-八氫環戊并[c]吡咯-5-基}-1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(1-甲基吡咯啶-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-(1-{2-甲基-八氫環戊并[c]吡咯-5-基}-1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(1-乙基氮雜環丁烷-3-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[1-(丙-2-基)氮雜環丁烷-3-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(1-乙基氮雜環丁烷-3-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(4-甲基吡啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(異喹啉-1-基氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)- 1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(2-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(2,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(2,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(2,4-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(2,4-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(2,3-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(2,3-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-5-(2,3-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(2,3-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(2,5-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(2,5-二氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-5-(2,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4- 基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(2,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;1-[(2S)-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(2,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-{[(E)-2-氯乙烯基]氧基}-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-{1H,2H,3H-吡唑并[1,5-a]咪唑-7-基}-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-6-{1-甲烷磺醯基-1H,2H,3H-吡唑并[1,5-a]咪唑-7-基}-2-甲基-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-6-[2-(4-羥基哌啶-4-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[2-(4-氟哌啶-4-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(1-甲基氮雜環丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(1-甲基氮雜環丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(3-甲基吡啶-2- 基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(5-甲基吡啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-氯吡啶-2-基)氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(7H-嘌呤-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-6-[1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-6-[1-(3-甲氧基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[1-(3-甲氧基-1-甲基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-6-[1-(3-甲氧基-1-甲基哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;3-{4-[(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環己烷-1,1-二酮;3-{4-[(2S)-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環己烷-1,1-二酮;(2S)-5-環丁氧基-2-甲基-6-[1-(2-側氧基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(2-側氧基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-{1-[(2S)-2-甲基氮雜環丁烷-3-基]-1H-吡唑-4-基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-{1-[(2S)-2-甲基氮雜環丁烷-3-基]- 1H-吡唑-4-基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;N-{4-[(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-6-基]-1-環丙基-1H-吡唑-5-基}甲烷磺醯胺;N-{4-[(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-6-基]-1-環丙基-1H-吡唑-5-基}乙醯胺;(2S)-5-環丁氧基-6-[1-(3-羥基環丁基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[2-(哌啶-4-基)-1H-咪唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-甲基-2-(哌啶-4-基)-1H-咪唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(氧雜環丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}-N-甲基乙醯胺;1-[(2S)-2-甲基-5-(1,2-噁唑-5-基甲氧基)-6-[1-(氧雜環丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;N-(2-{[(2S)-1-乙醯基-2-甲基-6-[1-(氧雜環丁烷-3-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}乙基)甲烷磺醯胺;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(1,2-噁唑-5-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;N-(2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙基)甲烷磺醯胺;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N-甲基乙醯胺;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(氧雜環丁烷-3-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(環戊基甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基- 1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[2-(二甲基胺基)乙氧基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(丙-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(環丙基甲氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙醯胺;1-[(2S)-5-(環丁基甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(苯甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(3-甲基氧雜環丁烷-3-基)甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(環戊氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙腈;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-甲氧基乙氧基)-2-甲基 -1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(吡啶-3-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(氧雜環己烷-4-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-5-(環己基甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(吡啶-2-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-甲氧基-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(1-甲基-1H-吡唑-3-基)甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(1,3-噻唑-5-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基- 1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-(氧雜環己烷-4-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(氧雜環己烷-4-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-(氧雜環己烷-4-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-(氧雜環己烷-4-基甲氧基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;2-{[(2S)-1-乙醯基-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-(2-甲基丙氧基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(環戊基甲氧基)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑- 4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(環戊基甲氧基)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(環戊基甲氧基)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(環戊基甲氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-1-(吡咯啶-1-基)乙-1-酮;2-{[(2S)-1-乙醯基-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-1-(吡咯啶-1-基)乙-1-酮;2-{[(2S)-1-乙醯基-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-1-(吡咯啶-1-基)乙-1-酮;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}-1-(吡咯啶-1-基)乙-1-酮;(5R)-5-({[(2S)-1-乙醯基-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}甲基)吡咯啶-2-酮;(5R)-5-({[(2S)-1-乙醯基-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}甲基)吡咯啶-2-酮;(5R)-5-({[(2S)-1-乙醯基-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}甲基)吡咯啶-2-酮;(5R)-5-({[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}甲基)吡咯啶-2-酮;N-(2-{[(2S)-1-乙醯基-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙基)-N-甲基甲烷磺醯胺;N-(2-{[(2S)-1-乙醯基-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4- 基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙基)-N-甲基甲烷磺醯胺;N-(2-{[(2S)-1-乙醯基-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}乙基)-N-甲基甲烷磺醯胺;N-(2-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}乙基)-N-甲基甲烷磺醯胺;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-(氧雜環己烷-4-基甲氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(氧雜環己烷-4-基甲氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯; (2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-(氧雜環己烷-4-基甲氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-(氧雜環己烷-4-基甲氧基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(二甲基胺甲醯基)甲氧基]-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(二甲基胺甲醯基)甲氧基]-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(二甲基胺甲醯基)甲氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-(2-甲基丙氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-(2-甲基丙氧基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(環戊基甲氧基)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(環戊基甲氧基)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(環戊基甲氧基)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(環戊基甲氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯; (2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-[2-側氧基-2-(吡咯啶-1-基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[2-側氧基-2-(吡咯啶-1-基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-[2-側氧基-2-(吡咯啶-1-基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-[2-側氧基-2-(吡咯啶-1-基)乙氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-{[(2R)-5-側氧基吡咯啶-2-基]甲氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-{[(2R)-5-側氧基吡咯啶-2-基]甲氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-{[(2R)-5-側氧基吡咯啶-2-基]甲氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-{[(2R)-5-側氧基吡咯啶-2-基]甲氧基}-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-[2-(N-甲基甲烷磺醯胺基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[2-(N-甲基甲烷磺醯胺基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-[2-(N-甲基甲烷磺醯胺基)乙氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-[2-(N-甲基甲烷磺醯胺基)乙氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯; (2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(5-甲基-1,3-噁唑-2-基)甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(吡啶-4-基甲氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(1,3-苯并噁唑-2-基甲氧基)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(4-甲烷磺醯基苯基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(4-甲烷磺醯基苯基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-6-[4-(乙烷磺醯基)苯基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-[4-(乙烷磺醯基)苯基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-6-{4-[2-(二甲基胺基)乙氧基]苯基}-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-{4-[2-(二甲基胺基)乙氧基]苯基}-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-2-甲基-6-[3-(嗎啉-4-羰基)苯基]-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮; 2-{[(2S)-1-乙醯基-2-甲基-6-[3-(嗎啉-4-羰基)苯基]-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;N-{3-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]苯基}甲烷磺醯胺;2-{[(2S)-1-乙醯基-6-(3-甲烷磺醯胺基苯基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-6-(3-甲烷磺醯基苯基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(3-甲烷磺醯基苯基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;N-{4-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]苯基}甲烷磺醯胺;2-{[(2S)-1-乙醯基-6-(4-甲烷磺醯胺基苯基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-2-甲基-6-[4-(嗎啉-4-羰基)苯基]-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-2-甲基-6-[4-(嗎啉-4-羰基)苯基]-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;2-{4-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]苯基}-1λ6,2-四氫噻唑-1,1-二酮;2-{[(2S)-1-乙醯基-6-[4-(1,1-二側氧基-1λ6,2-四氫噻唑-2-基)苯基]-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-6-(1-甲烷磺醯基-2,3-二氫-1H-吲哚-5-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-甲烷磺醯基-2,3-二氫-1H-吲哚-5-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺; N-{4-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]苯基}-N-甲基甲烷磺醯胺;2-{[(2S)-1-乙醯基-2-甲基-6-[4-(N-甲基甲烷磺醯胺基)苯基]-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基乙醯胺;1-[(2S)-6-(1-苯并呋喃-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1H-吲哚-2-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-環丁氧基-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[1-(氧雜環己烷-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;3-{4-[(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環己烷-1,1-二酮;3-{4-[(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環丁烷-1,1-二酮;1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(嘧啶-2-基氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[4-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮; 1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[2-(三氟甲基)嘧啶-4-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-{[6-(嗎啉-4-基)嘧啶-4-基]氧基}-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(6-環丙基嘧啶-4-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-環丙基嘧啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}吡啶-3-甲醯胺;1-[(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;6-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}吡啶-3-甲酸甲酯;6-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}吡啶-3-甲醯胺;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(嘧啶-2-基氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡嗪-2-基氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯; (2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[4-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[2-(三氟甲基)嘧啶-4-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-{[6-(嗎啉-4-基)嘧啶-4-基]氧基}-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(6-環丙基嘧啶-4-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-環丙基嘧啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-氟嘧啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-{[5-(甲氧基羰基)吡啶-2-基]氧基}-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-胺甲醯基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉;2-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}吡啶-3-甲腈; (2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(4,6-二甲基嘧啶-2-基)氧基]-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(丙-2-基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-5-[(5-甲氧基嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-環丙基嘧啶-2-基)氧基]-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-(1-甲烷磺醯基-2,3-二氫-1H-吲哚-5-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-(4-甲烷磺醯基苯基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(1-羥基-2-甲基丙-2-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{4-[(2S)-1-乙醯基-5-[(5-氟嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-6-基]苯基}-1λ6,2-四氫噻唑-1,1-二酮; (2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[5-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-(吡嗪-2-基氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[3-(三氟甲基)吡啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(3-氰基吡啶-2-基)氧基]-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯; (2S)-5-[(3-氰基吡啶-2-基)氧基]-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(3-氰基吡啶-2-基)氧基]-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(3-氰基吡啶-2-基)氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-環丙基嘧啶-2-基)氧基]-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-環丙基嘧啶-2-基)氧基]-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-環丙基嘧啶-2-基)氧基]-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(5-環丙基嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(5-氟嘧啶-2-基)氧基]-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-[(5-氟嘧啶-2-基)氧基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯; (2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-{[5-(三氟甲基)嘧啶-2-基]氧基}-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(5-甲基嘧啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(3-胺甲醯基吡啶-2-基)氧基]-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-[(3-胺甲醯基吡啶-2-基)氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-6-[1-(2-甲烷磺醯基乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-6-[1-(2-羥乙基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-{[3-氟-5-(三氟甲基)吡啶-2-基]氧基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(氧雜環己烷-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯; (2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;4-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二甲基苯甲醯胺;(2S)-5-(3-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-環丙烷羰基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉;6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-2-甲基-6-[1-(氧雜環丁烷-3-基)-1H-吡唑-4-基]-5-[(3R)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-6-[1-(氧雜環丁烷-3-基)-1H-吡唑-4-基]-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(3R)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-[1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基]-2-甲基-5-[(3S)-吡咯啶-3-基甲氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}-N,N-二 甲基乙醯胺;1-[(2S)-5-(環戊基甲氧基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-({1-[(1E)-丙-1-烯-1-基]-1H-1,3-苯并二唑-2-基}氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-({1-[(1Z)-丙-1-烯-1-基]-1H-1,3-苯并二唑-2-基}氧基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-2-甲基-6-[1-甲基-2-(哌嗪-1-基)-1H-咪唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[2-(哌嗪-1-基)-1,3-噻唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[2-(3-羥基氮雜環丁烷-1-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1,2-噁唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-(1,2-噁唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-6-(1-環丙基-1H-吡唑-4-基)-8-氟-2-甲基-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-8-氟-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]- 1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-(1-環丙基-1H-吡唑-4-基)-8-氟-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-8-氟-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-5-環丁氧基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-6-(1-環丙基-1H-吡唑-4-基)-8-氟-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-8-氟-2-甲基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-1-環丙烷羰基-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-6-(1-環丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉;(2S)-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(1-環丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-8-氟-2-甲基-5-苯氧基- 1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-8-氟-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-7,8-二氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-環丁氧基-6-(1-環丙基-1H-吡唑-4-基)-7,8-二氟-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(1H-吡唑-1-基)-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-(2H-1,2,3-三唑-2-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-(1H-吡唑-1-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-(2H-1,2,3-三唑-2-基)-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-3-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-5-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[2-(哌啶-4-基)-2H-1,2,3-三唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-1,2,3-三唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[5-(哌啶-4-基)-1H-咪唑-2-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑 -3-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-5-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[2-(哌啶-4-基)-2H-1,2,3-三唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-1,2,3-三唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[5-(哌啶-4-基)-1H-咪唑-2-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-5-環丁氧基-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-8-氟-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-1-環丙烷羰基-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-[(2,6-二甲基吡啶-3-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-[(2,6-二甲基吡啶-4-基)氧基]-2-甲基-6- [1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-[(6-氯吡啶-2-基)氧基]-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡啶-2-基氧基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-[(6-氟吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-(吡啶-2-基氧基)-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-1-環丙烷羰基-2-甲基-6-[4-(嗎啉-4-基)-1H-吡唑-1-基]-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[4-(哌嗪-1-基)-1H-吡唑-1-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[4-(哌啶-4-基)-1H-吡唑-1-基]-1,2,3,4-四氫喹啉;(2S)-2-甲基-6-[4-(嗎啉-4-基)-1H-吡唑-1-基]-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-苯氧基-6-[4-(哌嗪-1-基)-1H-吡唑-1-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-6-甲腈;(2S)-1-環丙烷羰基-6-乙炔基-2-甲基-5-苯氧基-1,2,3,4-四氫喹 啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-(丙-1-炔-1-基)-1,2,3,4-四氫喹啉;(2S)-6-氰基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-乙炔基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-[2-(氮雜環丁烷-3-基)-1,3-噻唑-4-基]-5-環丁氧基-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[2-(3-氟氮雜環丁烷-3-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[2-(3-羥基氮雜環丁烷-3-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-[2-(3-甲氧基氮雜環丁烷-3-基)-1,3-噻唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-6-(2-胺甲醯基-1,3-噻唑-4-基)-5-環丁氧基-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[2-(甲基胺甲醯基)-1,3-噻唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-(2-乙醯胺基-1,3-噻唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-6-環丙基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-6-環丙基-2-甲基-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-8-氟-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉; (2S)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-1-環丙烷羰基-5-(3-甲氧基苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(2,5-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(3,4-二氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;2-{[(2S)-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-1-環丙烷羰基-5-(3-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(2-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-[(6-甲氧基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-[(6-甲氧基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-5-[(6-甲氧基吡啶-2-基)氧基]-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-6-[1-(1,1-二側氧基-1λ6-硫雜環己烷-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯; 4-{4-[(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1λ6-硫雜環己烷-1,1-二酮;1-[(2S)-6-(1-乙醯基哌啶-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-6-(1-甲烷磺醯基哌啶-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;4-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]-1,2,3,6-四氫吡啶-1-甲酸第三丁酯;1-[(2S)-2-甲基-6-(哌啶-4-基)-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;4-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]-N-乙基哌啶-1-甲醯胺;4-[(2S)-1-乙醯基-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-6-基]哌啶-1-甲酸甲酯;1-[(2S)-6-(1-乙基哌啶-4-基)-2-甲基-5-丙氧基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-(苯基胺基)-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-環丁氧基-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-{1-[(3R,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-{1-[(3S,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-6-{1-[(3S,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯; (2S)-5-(4-氟苯氧基)-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-6-{1-[(3R,4S)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-{1-[(3R,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(4-氟苯氧基)-6-{1-[(3R,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(2-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(2-甲基哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-1-環丙烷羰基-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-6-[5-氟-1-(哌啶-4-基)-1H-吡唑-4-基]-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-{1-[(3R*,4S*)-4-氟吡咯啶-3-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;及(2S)-5-環丁氧基-1-環丙烷羰基-6-{1-[(3R*,4S*)-4-氟哌啶-3-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉。
- 如請求項15之化合物,其選自由以下組成之群組:(2S)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-5-丙氧基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟-2-甲基丙氧基)-2- 甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;2-{[(2S)-1-乙醯基-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;2-{[(2S)-1-乙醯基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;1-[(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(4-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-(2-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(4-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(2-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氯苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氰基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-5-(2-氟苯氧基)-2-甲基- 1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;1-[(2S)-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;1-[(2S)-5-[(5-氯吡啶-2-基)氧基]-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(2-氰基-3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氯-4-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-2-甲基-6-[1-(氧雜環己烷-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-環丁氧基-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;1-[(2S)-6-(1-環丙基-1H-吡唑-4-基)-2-甲基-5-[(6-甲基吡啶-2-基)氧基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮;(2S)-5-(4-氯苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;4-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑 -4-基]-1,2,3,4-四氫喹啉;2-{[(2S)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-5-基]氧基}苯甲腈;(2S)-6-[1-(1,1-二側氧基-1l6-硫雜環丁烷-3-基)-1H-吡唑-4-基]-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-5-(3-氯-4-氟苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-6-[1-(氮雜環丁烷-3-基)-1H-吡唑-4-基]-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(2-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-(2-氯苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(3-氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-(3,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(2,4-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-4-基)-5-苯氧基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-5-苯氧基-6-(1H-吡唑-4-基)-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-2-甲基-6-(1-甲基-1H-咪唑-4-基)-5-苯氧基- 1,2,3,4-四氫喹啉;(2S)-5-(3-氯苯氧基)-1-環丙烷羰基-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(2,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-(3,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-1-環丙烷羰基-5-(3,5-二氟苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-1-環丙烷羰基-6-{1-[(3S,4R)-3-氟哌啶-4-基]-1H-吡唑-4-基}-2-甲基-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-5-(2-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-(3-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;3-{4-[(2S)-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1l6-硫雜環丁烷-1,1-二酮;3-{4-[(2S)-1-環丙烷羰基-5-(4-氟苯氧基)-2-甲基-1,2,3,4-四氫喹啉-6-基]-1H-吡唑-1-基}-1l6-硫雜環己烷-1,1-二酮;(2S)-1-環丙烷羰基-5-(4-甲氧基苯氧基)-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-1-環丙烷羰基-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉;(2S)-5-環丁氧基-8-氟-2-甲基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]- 1,2,3,4-四氫喹啉-1-甲酸甲酯;(2S)-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-甲酸甲酯;及1-[(2S)-8-氟-2-甲基-5-苯氧基-6-[1-(哌啶-4-基)-1H-吡唑-4-基]-1,2,3,4-四氫喹啉-1-基]乙-1-酮。
- 一種醫藥組成物,其包含如請求項1之化合物及醫藥學上可接受之載劑。
- 如請求項17之醫藥組成物,其進一步包含治療有效量之一或多種其他治療劑。
- 如請求項18之醫藥組成物,其中該等其他治療劑係選自由以下組成之群組:細胞毒性劑、順鉑(cisplatin)、小紅莓(doxorubicin)、剋癌易(taxotere)、紫杉醇(taxol)、依託泊苷(etoposide)、伊立替康(irinotecan)、開普拓(camptostar)、拓撲替康(topotecan)、太平洋紫杉醇(paclitaxel)、多烯紫杉醇(docetaxel)、埃博黴素(epothilone)、他莫昔芬(tamoxifen)、5-氟尿嘧啶、胺甲喋呤(methotrexate)、替莫唑胺(temozolomide)、環磷醯胺、SCH 66336、替吡法尼(tipifarnib)、R115777、L778,123、BMS 214662、C225、GLEEVEC®、intron®、Peg-Intron®、芳香酶組合、ara-C、阿黴素(adriamycin)、癌得星(cytoxan)、吉西他濱(gemcitabine)、尿嘧啶氮芥(Uracil mustard)、雙(氯乙基)甲胺(Chlormethine)、異環磷醯胺(Ifosfamide)、美法侖(Melphalan)、苯丁酸氮芥(Chlorambucil)、哌泊溴烷(Pipobroman)、三伸乙基三聚氰胺(Triethylenemelamine)、三伸乙基硫代磷醯胺(Triethylenethiophosphoramine)、白消安(Busulfan)、卡莫司汀(Carmustine)、洛莫司汀(Lomustine)、鏈脲菌素(Streptozocin)、 達卡巴嗪(Dacarbazine)、氟尿苷(Floxuridine)、阿糖胞苷(Cytarabine)、6-巰基嘌呤、6-硫鳥嘌呤、磷酸氟達拉濱(Fludarabine phosphate)、甲醯四氫葉酸(leucovirin)、奧沙利鉑(oxaliplatin;ELOXATIN®)、噴司他丁(Pentostatine)、長春鹼(Vinblastine)、長春新鹼(Vincristine)、長春地辛(Vindesine)、博萊黴素(Bleomycin)、放線菌素D(Dactinomycin)、道諾黴素(Daunorubicin)、表柔比星(Epirubicin)、伊達比星(Idarubicin)、MithramycinTM、去氧助間型黴素(Deoxycoformycin)、絲裂黴素C(Mitomycin-C)、L-天冬醯胺酶、替尼泊苷(Teniposide)、17α-乙炔雌二醇(17α-Ethinylestradiol)、己烯雌酚(Diethylstilbestrol)、睪固酮(Testosterone)、潑尼松(Prednisone)、氟甲睪固酮(Fluoxymesterone)、丙酸屈他雄酮(Dromostanolone propionate)、睪內酯(Testolactone)、乙酸甲地孕酮(Megestrol acetate)、甲基潑尼松龍(Methylprednisolone)、甲基睪固酮(Methyltestosterone)、潑尼松龍(Prednisolone)、曲安西龍(Triamcinolone)、氯烯雌醚(Chlorotrianisene)、羥孕酮(Hydroxyprogesterone)、胺魯米特(Aminoglutethimide)、雌莫司汀(Estramustine)、乙酸甲羥孕酮(Medroxyprogesteroneacetate)、亮丙瑞林(Leuprolide)、氟他胺(Flutamide)、托瑞米芬(Toremifene)、戈舍瑞林(goserelin)、卡鉑(Carboplatin)、羥基脲、安吖啶(Amsacrine)、丙卡巴肼(Procarbazine)、米托坦(Mitotane)、米托蒽醌(Mitoxantrone)、左旋咪唑(Levamisole)、諾維本(Navelbene)、阿那曲唑(Anastrazole)、利妥唑(Letrazole)、卡培他濱(Capecitabine)、雷洛昔芬(Reloxafine)、屈洛昔芬(Droloxafine)、六甲三聚氰胺(Hexamethylmelamine)、癌思停(Avastin)、賀癌平(herceptin)、百克沙(Bexxar)、萬珂(Velcade)、澤瓦靈(Zevalin)、三氧化二砷 (Trisenox)、截瘤达(Xeloda)、長春瑞濱(Vinorelbine)、卟吩姆(Porfimer)、爾必得舒(Erbitux)、微脂體(Liposomal)、沙奧特帕(Thiotepa)、六甲蜜胺(Altretamine)、美法侖、曲妥珠單抗(Trastuzumab)、利妥唑(Lerozole)、氟維司群(Fulvestrant)、依西美坦(Exemestane)、利妥昔單抗(Rituximab)、C225、坎帕斯(Campath)、甲醯四氫葉酸、地塞米松(dexamethasone)、比卡魯胺(bicalutamide)、卡鉑、苯丁酸氮芥、順鉑、利妥唑、甲地孕酮(megestrol)及戊柔比星(valrubicin)。
- 一種抑制患者之BET家族溴域(bromodomain)中之一或多者之方法,其包括向該有需要之患者投予有效量之如請求項1之化合物。
- 一種抑制患者之BET家族溴域中之一或多者之方法,其包括向該有需要之患者投予有效量之如請求項17之醫藥組成物。
- 一種治療、預防、抑制或消除患者之與一或多個BET家族溴域之活性相關之疾病或病症之方法,其包括向該有需要之患者投予治療有效量之如請求項1之化合物。
- 如請求項22之方法,其中該疾病或病症係選自由以下組成之群組:癌症、發炎性病症、大腸激躁症候群、發炎性腸病、類風濕性關節炎、肥胖症及糖尿病。
- 一種男性避孕藥,其包含治療有效量之至少一種如請求項1之化合物。
- 一種男性避孕藥,其包含治療有效量之至少一種如請求項15之化合物。
- 如請求項1至16中任一項之化合物,其用於製造用以治療與抑制BET家族溴域中之一或多者相關之疾病的藥劑。
- 一種如請求項1至16中任一項之化合物之用途,其用於治療與抑制BET家族溴域中之一或多者相關之疾病。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361905639P | 2013-11-18 | 2013-11-18 | |
US61/905,639 | 2013-11-18 | ||
US201462054811P | 2014-09-24 | 2014-09-24 | |
US62/054,811 | 2014-09-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201609657A true TW201609657A (zh) | 2016-03-16 |
TWI684588B TWI684588B (zh) | 2020-02-11 |
Family
ID=53058297
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW103139976A TWI684588B (zh) | 2013-11-18 | 2014-11-18 | 作為bet溴域抑制劑之四氫喹啉組成物 |
TW109101151A TWI742513B (zh) | 2013-11-18 | 2014-11-18 | 作為bet溴域抑制劑之四氫喹啉組成物 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW109101151A TWI742513B (zh) | 2013-11-18 | 2014-11-18 | 作為bet溴域抑制劑之四氫喹啉組成物 |
Country Status (25)
Country | Link |
---|---|
US (6) | US9388161B2 (zh) |
EP (2) | EP3799872A1 (zh) |
JP (2) | JP6553632B2 (zh) |
KR (1) | KR102007796B1 (zh) |
CN (2) | CN105934246B (zh) |
AU (1) | AU2014348191B2 (zh) |
BR (3) | BR122019007990B1 (zh) |
CA (1) | CA2930414C (zh) |
CY (1) | CY1124394T1 (zh) |
DK (1) | DK3071203T3 (zh) |
ES (1) | ES2860695T3 (zh) |
HR (1) | HRP20210431T1 (zh) |
HU (1) | HUE053645T2 (zh) |
IL (2) | IL245582B (zh) |
LT (1) | LT3071203T (zh) |
MX (2) | MX370535B (zh) |
NZ (1) | NZ720004A (zh) |
PL (1) | PL3071203T3 (zh) |
PT (1) | PT3071203T (zh) |
RS (1) | RS61519B1 (zh) |
RU (1) | RU2727169C2 (zh) |
SI (1) | SI3071203T1 (zh) |
TW (2) | TWI684588B (zh) |
WO (1) | WO2015074064A2 (zh) |
ZA (1) | ZA201603278B (zh) |
Families Citing this family (59)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102204989B1 (ko) | 2012-01-12 | 2021-01-20 | 예일 유니버시티 | E3 유비퀴틴 리가아제에 의한 표적 단백질 및 다른 폴리펩티드의 증진된 분해를 위한 화합물 및 방법 |
MX2015007921A (es) | 2012-12-21 | 2016-03-03 | Zenith Epigenetics Corp | Compuestos heterociclicos novedosos como inhibidores de bromodominio. |
WO2015004533A2 (en) | 2013-06-21 | 2015-01-15 | Zenith Epigenetics Corp. | Novel substituted bicyclic compounds as bromodomain inhibitors |
CA2915838C (en) | 2013-06-21 | 2023-04-18 | Zenith Epigenetics Corp. | Bicyclic bromodomain inhibitors |
GB201311891D0 (en) | 2013-07-03 | 2013-08-14 | Glaxosmithkline Ip Dev Ltd | Novel compound |
GB201311888D0 (en) | 2013-07-03 | 2013-08-14 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
WO2015015318A2 (en) | 2013-07-31 | 2015-02-05 | Zenith Epigenetics Corp. | Novel quinazolinones as bromodomain inhibitors |
TWI684588B (zh) * | 2013-11-18 | 2020-02-11 | 美商弗瑪治療公司 | 作為bet溴域抑制劑之四氫喹啉組成物 |
US9422281B2 (en) | 2013-11-18 | 2016-08-23 | Forma Therapeutics, Inc. | Benzopiperazine compositions as BET bromodomain inhibitors |
US20160256448A1 (en) * | 2013-11-18 | 2016-09-08 | Forma Therapeutics, Inc. | Tetrahydroquinoline compositions as bet bromodomain inhibitors |
CA2966303A1 (en) | 2014-12-01 | 2016-06-09 | Zenith Epigenetics Ltd. | Substituted pyridines as bromodomain inhibitors |
CA2966298A1 (en) | 2014-12-01 | 2016-06-09 | Zenith Epigenetics Ltd. | Substituted pyridinones as bromodomain inhibitors |
CA2966449A1 (en) | 2014-12-11 | 2016-06-16 | Zenith Epigenetics Ltd. | Substituted heterocycles as bromodomain inhibitors |
JP2017538721A (ja) | 2014-12-17 | 2017-12-28 | ゼニス・エピジェネティクス・リミテッドZenith Epigenetics Ltd. | ブロモドメインの阻害剤 |
KR102616762B1 (ko) | 2015-03-18 | 2023-12-20 | 아비나스 오퍼레이션스, 인코포레이티드 | 타겟화된 단백질들의 향상된 분해를 위한 화합물들 및 방법들 |
CA2995036A1 (en) | 2015-08-06 | 2017-02-09 | Dana-Farber Cancer Institute, Inc. | Tunable endogenous protein degradation |
US10772962B2 (en) | 2015-08-19 | 2020-09-15 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of bromodomain-containing proteins |
EP3455218A4 (en) | 2016-05-10 | 2019-12-18 | C4 Therapeutics, Inc. | C3 CARBON-BASED GLUTARIMIDE DEGRONIMERS FOR TARGET PROTEIN REDUCTION |
CN109562107A (zh) | 2016-05-10 | 2019-04-02 | C4医药公司 | 用于靶蛋白降解的杂环降解决定子体 |
CN109562113A (zh) | 2016-05-10 | 2019-04-02 | C4医药公司 | 用于靶蛋白降解的螺环降解决定子体 |
TWI794171B (zh) | 2016-05-11 | 2023-03-01 | 美商滬亞生物國際有限公司 | Hdac抑制劑與pd-l1抑制劑之組合治療 |
TWI808055B (zh) | 2016-05-11 | 2023-07-11 | 美商滬亞生物國際有限公司 | Hdac 抑制劑與 pd-1 抑制劑之組合治療 |
MX2019002937A (es) * | 2016-09-14 | 2019-06-06 | Bayer Cropscience Ag | Metodo para producir compuestos biciclicos halogenados. |
AU2018219289A1 (en) | 2017-02-08 | 2019-09-05 | Dana-Farber Cancer Institute, Inc. | Regulating chimeric antigen receptors |
WO2018207882A1 (ja) * | 2017-05-12 | 2018-11-15 | 武田薬品工業株式会社 | 複素環化合物 |
CN107216331B (zh) * | 2017-07-07 | 2019-06-18 | 华南理工大学 | 一种四氢萘啶并四氢喹唑啉衍生物及其合成方法和应用 |
WO2019018584A1 (en) | 2017-07-18 | 2019-01-24 | GiraFpharma LLC | HETEROCYCLIC COMPOUNDS AS ADENOSINE ANTAGONISTS |
JP2020527593A (ja) | 2017-07-18 | 2020-09-10 | ニューベイション・バイオ・インコーポレイテッドNuvation Bio Inc. | 1,8−ナフチリジノン化合物およびその使用 |
TWI795440B (zh) | 2017-09-15 | 2023-03-11 | 美商佛瑪治療公司 | 作為CBP/p300抑制劑之四氫─咪唑並喹啉化合物 |
US20210179607A1 (en) | 2017-11-01 | 2021-06-17 | Merck Sharp & Dohme Corp. | Novel substituted tetrahydroquinolin compounds as indoleamine 2,3-dioxygenase (ido) inhibitors |
US11220515B2 (en) | 2018-01-26 | 2022-01-11 | Yale University | Imide-based modulators of proteolysis and associated methods of use |
CN112236172A (zh) | 2018-01-30 | 2021-01-15 | 福宏治疗公司 | 用于治疗病症的方法和化合物 |
CA3095912A1 (en) | 2018-04-13 | 2019-10-17 | Arvinas Operations, Inc. | Cereblon ligands and bifunctional compounds comprising the same |
WO2020006329A1 (en) * | 2018-06-29 | 2020-01-02 | Forma Therapeutics, Inc. | Salts of (s)-(5-cyclobutoxy-2-methyl-6-(1-(piperidin-4-yl)-1h-pyrazol-4-yl)-3,4-dihydroquinolin-1(2h)-yl)(cyclopropyl)methanone and solid forms thereof |
US10870648B2 (en) | 2018-06-29 | 2020-12-22 | Forma Therapeutics, Inc. | Inhibiting CREB binding protein (CBP) |
TWI841598B (zh) * | 2018-09-13 | 2024-05-11 | 大陸商恒翼生物醫藥(上海)股份有限公司 | 用於治療雌激素受體陽性乳癌之組合療法 |
EP3873474A4 (en) | 2018-10-30 | 2022-07-13 | Nuvation Bio Inc. | HETEROCYCLIC COMPOUNDS AS BET Inhibitors |
WO2020132561A1 (en) | 2018-12-20 | 2020-06-25 | C4 Therapeutics, Inc. | Targeted protein degradation |
KR20210116550A (ko) | 2019-01-18 | 2021-09-27 | 누베이션 바이오 인크. | 아데노신 길항제로서의 헤테로시클릭 화합물 |
AU2020207951A1 (en) | 2019-01-18 | 2021-08-26 | Nuvation Bio Inc. | 1,8-naphthyridinone compounds and uses thereof |
US20230065463A1 (en) * | 2019-01-29 | 2023-03-02 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
EP3917529A4 (en) * | 2019-01-29 | 2022-11-02 | Foghorn Therapeutics Inc. | CONNECTIONS AND USES THEREOF |
JP2022523073A (ja) * | 2019-01-29 | 2022-04-21 | フォグホーン セラピューティクス インコーポレイテッド | 化合物及びその使用 |
CA3132995A1 (en) * | 2019-03-15 | 2020-09-24 | Forma Therapeutics, Inc. | Compositions and methods for treating androgen receptor positive forms of cancer |
WO2021003163A1 (en) | 2019-07-01 | 2021-01-07 | Forma Therapeutics, Inc. | Treating cancer with a bromodomain and extra-terminal (bet) family inhibitor |
JP7465945B2 (ja) | 2019-07-02 | 2024-04-11 | ニューベイション・バイオ・インコーポレイテッド | Bet阻害剤としてのヘテロ環式化合物 |
TW202126638A (zh) | 2019-09-30 | 2021-07-16 | 日商協和麒麟股份有限公司 | Bet分解劑 |
IL293213A (en) | 2019-11-28 | 2022-07-01 | Bayer Ag | Transmuted aminoquinolones as dgkalpha inhibitors for immune activation |
BR112022012110A2 (pt) | 2019-12-19 | 2022-12-13 | Arvinas Operations Inc | Compostos e métodos para a degradação direcionada de receptor androgênico |
US11851445B2 (en) | 2020-01-29 | 2023-12-26 | Foghorn Therapeutics Inc. | Compounds and uses thereof |
CN111617305B (zh) * | 2020-04-23 | 2021-05-11 | 杭州千芝雅卫生用品有限公司 | 一种亲肤性吸液材料的制备方法 |
WO2021226208A2 (en) | 2020-05-05 | 2021-11-11 | Nuvalent, Inc. | Heteroaromatic macrocyclic ether chemotherapeutic agents |
US11787800B2 (en) | 2020-07-29 | 2023-10-17 | Foghorn Therapeutics Inc. | BRD9 degraders and uses thereof |
US11795168B2 (en) | 2020-09-23 | 2023-10-24 | Forma Therapeutics, Inc. | Inhibiting cyclic amp-responsive element-binding protein (CREB) binding protein (CBP) |
US11801243B2 (en) | 2020-09-23 | 2023-10-31 | Forma Therapeutics, Inc. | Bromodomain inhibitors for androgen receptor-driven cancers |
AU2022299172A1 (en) * | 2021-06-23 | 2024-01-18 | Blueprint Medicines Corporation | Process for preparing egfr inhibitors |
US11767330B2 (en) | 2021-07-06 | 2023-09-26 | Foghorn Therapeutics Inc. | Citrate salt, pharmaceutical compositions, and methods of making and using the same |
KR20240087788A (ko) | 2021-10-01 | 2024-06-19 | 뉴베일런트, 아이엔씨. | 헤테로방향족 매크로사이클릭 에테르 화합물의 고체 형태, 약학 조성물 및 제조 |
TW202339721A (zh) * | 2022-03-31 | 2023-10-16 | 英屬開曼群島商百濟神州有限公司 | Bcl-xL抑制劑 |
Family Cites Families (169)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0028765B1 (de) | 1979-11-09 | 1983-05-04 | Bayer Ag | Alkylharnstoffderivate zur Behandlung von Erkrankungen des Fettstoffwechsels; Verfahren zu deren Herstellung, deren Verwendung in Arzneimitteln zur Behandlung von Fettstoffwechselstörungen, diese enthaltende Arzneimittel, Verfahren zur Herstellung der Arzneimittel sowie einige Alkylharnstoffverbindungen |
FR2541680B1 (fr) | 1983-02-24 | 1985-06-14 | Rhone Poulenc Sante | Nouveaux derives de l'amino-5 dithiole-1,2 one-3, leur preparation et les compositions medicinales qui les contiennent |
EP0190105A3 (de) | 1985-01-31 | 1988-10-26 | Ciba-Geigy Ag | Herbizides Mittel |
JPS61227506A (ja) | 1985-04-01 | 1986-10-09 | Nippon Tokushu Noyaku Seizo Kk | カルバモイルイミダゾ−ル類、その中間体、それらの製法並びに除草剤又は農園芸用殺菌剤 |
DE3600288A1 (de) | 1986-01-08 | 1987-07-16 | Bayer Ag | Verwendung von amiden zur verbesserung der kulturpflanzen-vertraeglichkeit von herbizid wirksamen sulfonylharnstoff-derivaten |
DE3618004A1 (de) | 1986-05-28 | 1987-12-03 | Bayer Ag | Verwendung von amiden zur verbesserung der kulturpflanzen-vertraeglichkeit von herbizid wirksamen sulfonyliso(thio)-harnstoff-derivaten |
JPS6434982A (en) | 1987-07-30 | 1989-02-06 | Nissan Chemical Ind Ltd | Condensed heterocyclic derivative, production thereof and herbicide containing said derivative as active ingredient |
US5256625A (en) | 1987-08-13 | 1993-10-26 | Monsanto Company | Safening imidazolinone herbicides |
US5502025A (en) | 1987-08-13 | 1996-03-26 | Monsanto Company | Safening herbicidal pyrazolylsulfonylureas |
US5041454A (en) | 1987-09-25 | 1991-08-20 | Janssen Pharmaceutica N.V. | Novel substituted N-(1-alkyl-3-hydroxy-4-piperidinyl)benzamides |
US5201933A (en) | 1988-08-01 | 1993-04-13 | Monsanto Company | Safening herbicidal benzoic acid derivatives |
US5063230A (en) | 1988-11-29 | 1991-11-05 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Substituted saturated and unsaturated indole quinoline and benzazepine carboxamides and their use as pharmacological agents |
JP2955634B2 (ja) | 1990-04-12 | 1999-10-04 | 株式会社リコー | 電子写真感光体 |
KR900016822A (ko) | 1990-04-20 | 1990-11-14 | 하라 레이노스께 | 슬라이드 프로젝터 |
US5462965A (en) | 1990-08-13 | 1995-10-31 | Gd Searle & Co. | Use of heterocyclic amino-alcohol compounds for treatment of CNS diseases |
IL100643A (en) | 1991-01-25 | 1996-10-31 | Nippon Kayaku Kk | History of hydrazine and pesticides containing these histories as an active ingredient |
CA2066104C (en) | 1991-04-19 | 2003-05-27 | Hidenori Ogawa | Benzazepine derivatives as vasopressin antagonists |
US5194571A (en) | 1991-08-19 | 1993-03-16 | Eastman Kodak Company | Colored polyester compositions |
TW222276B (zh) | 1992-01-27 | 1994-04-11 | Fujisawa Pharmaceutical Co | |
EP0555183A1 (de) * | 1992-02-07 | 1993-08-11 | Ciba-Geigy Ag | Schädlingsbekämpfungsmittel |
US5262564A (en) | 1992-10-30 | 1993-11-16 | Octamer, Inc. | Sulfinic acid adducts of organo nitroso compounds useful as retroviral inactivating agents anti-retroviral agents and anti-tumor agents |
GB9307527D0 (en) | 1993-04-13 | 1993-06-02 | Fujisawa Pharmaceutical Co | New venzamide derivatives,processes for the preparation thereof and pharmaceutical composition comprising the same |
GB9307833D0 (en) | 1993-04-15 | 1993-06-02 | Glaxo Inc | Modulators of cholecystokinin and gastrin |
CZ39396A3 (en) | 1993-08-19 | 1996-05-15 | Janssen Pharmaceutica Nv | The use of substituted aryloxyalkyldiamines, the compounds per se, process of their preparation, pharmaceutical compositions based thereon and process of their preparation |
JPH09506885A (ja) | 1993-12-21 | 1997-07-08 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | 5ht▲下1d▼(抗うつ作用)活性を有するインドール、インドリンおよびキノリン誘導体 |
US5739129A (en) | 1994-04-14 | 1998-04-14 | Glaxo Wellcome Inc. | CCK or gastrin modulating 5-heterocyclic-1, 5 benzodiazepines |
EP0758330A1 (en) | 1994-05-06 | 1997-02-19 | Smithkline Beecham Plc | Biphenylcarboxamides useful as 5-ht1d antagonists |
GB9416972D0 (en) | 1994-08-23 | 1994-10-12 | Smithkline Beecham Plc | Carbon side chain/indole/indolene |
EP0702004A2 (de) | 1994-09-15 | 1996-03-20 | Ciba-Geigy Ag | 2,9-Diamino- und 2-amino-8-carbamoyl-4-hydroxy-alkansäureamid-derivative |
US5910495A (en) | 1994-10-14 | 1999-06-08 | Glaxo Wellcome Inc. | Use of 1,5-benzo b!1,4-diazepines to control gastric emptying |
US5780464A (en) | 1994-10-14 | 1998-07-14 | Glaxo Wellcome Inc. | Enteric coated compositions of 1,5-benzodiazepine derivatives having CCK antagonistic or agonistic activity |
GB9420763D0 (en) | 1994-10-14 | 1994-11-30 | Glaxo Inc | Acetamide derivatives |
US5693647A (en) | 1994-12-22 | 1997-12-02 | Ligand Pharmaceuticals Incorporated | Steroid receptor modulator compounds and methods |
GB9508637D0 (en) | 1995-04-28 | 1995-06-14 | Fujisawa Pharmaceutical Co | New use |
US5654316A (en) | 1995-06-06 | 1997-08-05 | Schering Corporation | Piperidine derivatives as neurokinin antagonists |
US5767129A (en) | 1995-08-24 | 1998-06-16 | Warner-Lambert Company | Substituted quinolines and isoquinolines as calcium channel blockers, their preparation and the use thereof |
US6696448B2 (en) | 1996-06-05 | 2004-02-24 | Sugen, Inc. | 3-(piperazinylbenzylidenyl)-2-indolinone compounds and derivatives as protein tyrosine kinase inhibitors |
CA2264020A1 (en) | 1996-08-26 | 1998-03-05 | Jean Bemis | Inhibitors of phospholipase enzymes |
DE19638484A1 (de) | 1996-09-20 | 1998-03-26 | Basf Ag | Hetaroylderivate |
DE19638486A1 (de) | 1996-09-20 | 1998-03-26 | Basf Ag | Hetaroylderivate |
WO1998035939A1 (fr) | 1997-02-18 | 1998-08-20 | Sanwa Kagaku Kenkyusho Co., Ltd. | Derives de diamide malonique et utilisation de ces derniers |
WO1998050346A2 (en) | 1997-04-18 | 1998-11-12 | Smithkline Beecham Plc | Acetamide and urea derivatives, process for their preparation and their use in the treatment of cns disorders |
US6011031A (en) | 1997-05-30 | 2000-01-04 | Dr. Reddy's Research Foundation | Azolidinediones useful for the treatment of diabetes, dyslipidemia and hypertension: process for their preparation and pharmaceutical compositions containing them |
DE19727117A1 (de) | 1997-06-26 | 1999-01-07 | Boehringer Ingelheim Pharma | Phenylalkylderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
AU735366B2 (en) | 1997-09-29 | 2001-07-05 | Bristol-Myers Squibb Company | Inhibitors of farnesyl protein transferase |
HUP0101110A3 (en) | 1997-10-27 | 2002-06-28 | Reddys Lab Ltd Dr | Bicyclic compounds, process for their preparation and pharmaceutical compositions containing them |
AU1687699A (en) | 1997-12-25 | 1999-07-19 | Yamanouchi Pharmaceutical Co., Ltd. | Nitrogenous heterocyclic derivatives |
US5994379A (en) | 1998-02-13 | 1999-11-30 | Merck Frosst Canada, Inc. | Bisaryl COX-2 inhibiting compounds, compositions and methods of use |
EE200000522A (et) | 1998-02-25 | 2002-02-15 | Genetics Institute, Inc. | Fosfolipaas A2 ensüümi inhibiitor, seda sisaldav farmatseutiline kompositsioon ning meetod fosfolipaasensüümi toime pärssimiseks |
EP1068193A1 (en) | 1998-02-26 | 2001-01-17 | Neurogen Corporation | Benzylpiperazinyl- and benzylpiperidinyl ethanone derivatives, their preparation and their use as dopamine d 4? receptor antagonists |
US6084098A (en) | 1999-02-26 | 2000-07-04 | Neurogen Corporation | Benzylpiperazinyl and piperidinyl ethanone derivatives: dopamine receptor subtype specific ligands |
CA2327695A1 (en) | 1998-04-08 | 1999-10-21 | Takeda Chemical Industries, Ltd. | Amine compounds, their production and their use as somatostatin receptor antagonists or agonists |
DE59901242D1 (de) | 1998-06-19 | 2002-05-23 | Rodenstock Optik G | Photochrome naphthopyrane |
DE19827855A1 (de) | 1998-06-23 | 1999-12-30 | Hoechst Schering Agrevo Gmbh | Kombinationen aus Herbiziden und Safenern |
DE19838011C2 (de) | 1998-08-21 | 2000-01-13 | Christoph Syldatk | Verfahren zur biotechnischen Herstellung von Fettsäuremethylestern ("Biodiesel") auf Molkebasis |
CA2344169C (en) | 1998-09-29 | 2011-07-19 | American Cyanamid Company | Substituted 3-cyanoquinolines as protein tyrosine kinases inhibitors |
US6048873A (en) | 1998-10-01 | 2000-04-11 | Allergan Sales, Inc. | Tetrahdroquinolin-2-one 6 or 7-yl, tetrahdroquinilin-2-thione 6 or 7-yl pentadienoic acid and related derivatives having retinoid-like biological activity |
ES2297943T3 (es) | 1998-12-23 | 2008-05-01 | Aventis Pharma Limited | Dihidro-benzo(1,4)oxacinas y tetrahidroquinoxalinas. |
US6642228B1 (en) | 1999-06-24 | 2003-11-04 | Toray Industries, Inc. | α1b-adrenergic receptor antagonists |
DE50000137D1 (en) | 1999-07-02 | 2002-05-16 | Rodenstock Optik G | Spirofluorenopyrane |
AU7961200A (en) | 1999-10-29 | 2001-05-14 | Kaken Pharmaceutical Co., Ltd. | Urea derivative, process for producing the same, and medicine containing the urea derivative |
US7101869B2 (en) | 1999-11-30 | 2006-09-05 | Pfizer Inc. | 2,4-diaminopyrimidine compounds useful as immunosuppressants |
TWI245761B (en) | 2001-03-01 | 2005-12-21 | Telik Inc | Antagonists of MCP-1 function and methods of use thereof |
US20030216398A1 (en) | 2001-04-05 | 2003-11-20 | Mitsuru Kakihana | Soluble beta amyloid precursor protein secretion promoters |
WO2002080895A2 (en) | 2001-04-06 | 2002-10-17 | Schering Corporation | Treatment of malaria with farsenyl protein transferase inhibitors |
EP1382598A4 (en) | 2001-04-26 | 2005-03-23 | Takeda Pharmaceutical | NEW HETEROCYCLIC DERIVATIVES |
US6720420B2 (en) | 2001-12-21 | 2004-04-13 | Johnson & Johnson Vision Care, Inc. | Photochromic oxazine compounds and methods for their manufacture |
TW200301698A (en) | 2001-12-21 | 2003-07-16 | Bristol Myers Squibb Co | Acridone inhibitors of IMPDH enzyme |
WO2004014388A1 (en) | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | 6,6-fused heteroaryl derivatives as matrix metalloproteinase inhibitors |
GB0224557D0 (en) | 2002-10-22 | 2002-11-27 | Glaxo Group Ltd | Novel compounds |
WO2004056820A1 (en) | 2002-12-20 | 2004-07-08 | Warner-Lambert Company Llc | Benzoxazines and derivatives thereof as inhibitors of pi3ks |
TWI322012B (en) | 2002-12-20 | 2010-03-21 | Organon Nv | Tetrahydroquinoline derivatives |
WO2004072041A1 (en) | 2003-02-12 | 2004-08-26 | Care X S.A. | Tetrahydroquinolines as agonists of liver- x receptors |
US20040204450A1 (en) | 2003-03-28 | 2004-10-14 | Pfizer Inc | Quinoline and quinoxaline compounds |
EP1622872A1 (en) | 2003-03-28 | 2006-02-08 | Pfizer Products Inc. | 1,2,4-substituerte 1,2,3,4-tetrahydro-and 1,2 dihydro-quinoline and 1,2,3,4-tetrahydro-quinoxaline derivatives as cetp inhibitors for the treatment of atherosclerosis and obesity |
MXPA06001510A (es) | 2003-08-06 | 2006-09-04 | Senomyx Inc | Receptores de degustacion hetero-oligomericos t1r, lineas celulares que expresan tales receptores y compuestos de degustacion. |
CA2535260A1 (en) | 2003-08-07 | 2005-02-17 | Allergan, Inc. | Method for treating cachexia with retinoid ligands |
EP1515192B1 (en) | 2003-09-11 | 2015-07-15 | Ricoh Company, Ltd. | Electrophotographic photoconductor, electrophotographic process, electrophotographic apparatus, and process cartridge |
DE10343098A1 (de) | 2003-09-18 | 2005-04-14 | Bayer Healthcare Ag | Tetrahydrochinoxaline und ihre Verwendung |
AU2004286836A1 (en) | 2003-10-28 | 2005-05-19 | Amgen Inc. | Triazole compounds and uses related thereto |
ES2315727T3 (es) | 2003-12-20 | 2009-04-01 | Merck Patent Gmbh | Derivados de tetrahidroquinolina 2-(hetero-)aril-substituidos. |
BRPI0418255A (pt) | 2003-12-31 | 2007-04-17 | Warner Lambert Co | derivados de piperazina e piperidina n-substituìdos |
US8519158B2 (en) | 2004-03-12 | 2013-08-27 | Ligand Pharmaceuticals Incorporated | Androgen receptor modulator compounds and methods |
EP2522670A1 (en) | 2004-04-07 | 2012-11-14 | Takeda Pharmaceutical Company Limited | Heterocyclic CRF receptor antagonists |
US7846959B2 (en) | 2004-05-07 | 2010-12-07 | Exelixis, Inc. | Raf modulators and methods of use |
US7442693B2 (en) | 2004-05-28 | 2008-10-28 | Smithkline Beecham Corporation | Diazepine compounds as ligands of the melanocortin 1 and/or 4 receptors |
WO2006009819A1 (en) | 2004-06-18 | 2006-01-26 | Array Biopharma Inc. | Inhibitors of cholesteryl ester transfer protien |
US20090036484A1 (en) | 2004-10-29 | 2009-02-05 | Astrazeneca Ab | Use of Unsaturated Quionoline or Naphtalene Derivatives as Medicaments |
AU2005302519A1 (en) | 2004-11-01 | 2006-05-11 | Nuada, Llc | Compounds and methods of use thereof |
WO2007134169A2 (en) | 2006-05-10 | 2007-11-22 | Nuada, Llc | Indole, benzimidazole, and benzolactam boronic acid compounds, analogs thereof and methods of use thereof |
US20080319044A1 (en) | 2004-11-01 | 2008-12-25 | Nuada, Llc | Compounds and Methods of Use Thereof |
US20090264384A1 (en) | 2004-11-01 | 2009-10-22 | Nuada, Inc. | Indole, benzimidazole, and benzolactam boronic acid compounds, analogs thereof and methods of use thereof |
AR051780A1 (es) | 2004-11-29 | 2007-02-07 | Japan Tobacco Inc | Compuestos en anillo fusionados que contienen nitrogeno y utilizacion de los mismos |
US7951950B2 (en) | 2005-02-24 | 2011-05-31 | Millennium Pharmaceuticals, Inc. | PGD2 receptor antagonists for the treatment of inflammatory diseases |
BRPI0520097A2 (pt) | 2005-02-25 | 2009-08-25 | Lilly Co Eli | composto ou estereoisÈmeros únicos, misturas de estereoisÈmeros, ou sais farmaceuticamente aceitáveis dos mesmos, composição farmacêutica, e, uso de um composto ou um sal farmaceuticamente aceitável do mesmo |
WO2006094210A2 (en) | 2005-03-03 | 2006-09-08 | Sirtris Pharmaceuticals, Inc. | Tetrahydroquinoxalinone sirtuin modulators |
AU2006244074B2 (en) | 2005-05-09 | 2012-12-13 | Hydra Biosciences, Inc. | Compounds for modulating TRPV3 function |
NZ563200A (en) | 2005-05-11 | 2011-04-29 | Abbott Lab | Antagonists of the vanilloid receptor subtype 1 (VR1) and uses thereof |
CA2610759A1 (en) | 2005-06-14 | 2006-12-21 | Nippon Kayaku Kabushiki Kaisha | Dye-sensitized photoelectric conversion device |
CA2611688A1 (en) | 2005-06-30 | 2007-01-11 | Amgen Inc. | Bis-aryl kinase inhibitors and their use in the treatment of inflammation, angiogenesis and cancer |
CA2615577C (en) | 2005-07-26 | 2014-09-09 | Sanofi-Aventis | Piperidinyl-substituted isoquinolone derivatives as rho-kinase inhibitors |
EP1937244B1 (en) | 2005-09-30 | 2018-07-25 | Io Therapeutics, LLC | Treatment of cancer with specific rxr agonists |
US7741317B2 (en) | 2005-10-21 | 2010-06-22 | Bristol-Myers Squibb Company | LXR modulators |
DE602006014022D1 (de) | 2005-11-30 | 2010-06-10 | Hoffmann La Roche | 5-substituierte indol-2-carbonsäureamidderivate |
BRPI0619268A2 (pt) | 2005-11-30 | 2011-09-20 | Hoffmann La Roche | compostos, processo para a sua manufatura, composições farmacêuticas, método para o tratamento e/ou prevenção de enfermidades que estão associadas com a modulação de receptores de h3, uso dos compostos e método para o tratamento ou prevenção de obesidade e de diabetes do tipo ii em um ser humano ou animal |
US7713987B2 (en) | 2005-12-06 | 2010-05-11 | Rigel Pharmaceuticals, Inc. | Pyrimidine-2,4-diamines and their uses |
EP1981849A1 (en) | 2005-12-29 | 2008-10-22 | LEK Pharmaceuticals D.D. | Heterocyclic compounds |
TWI385161B (zh) | 2006-02-02 | 2013-02-11 | Mitsubishi Tanabe Pharma Corp | 含氮雜雙環化合物 |
US20070185055A1 (en) | 2006-02-06 | 2007-08-09 | Guang Liang Jiang | Method for treating cachexia with retinoid ligands |
KR20080093123A (ko) | 2006-02-13 | 2008-10-20 | 에프. 호프만-라 로슈 아게 | 당뇨병 치료용 헤테로바이사이클릭 설폰아마이드 유도체 |
CN101415674A (zh) | 2006-02-16 | 2009-04-22 | 先灵公司 | 作为erk抑制剂的吡咯烷衍生物 |
JPWO2007129745A1 (ja) | 2006-05-09 | 2009-09-17 | 第一三共株式会社 | ヘテロアリールアミド低級カルボン酸誘導体 |
WO2008079427A1 (en) | 2006-05-11 | 2008-07-03 | Janssen Pharmaceutica N.V. | 1,2,3,4-tetrahydro-quinoline derivatives as cetp inhibitors |
AU2007267184A1 (en) | 2006-05-30 | 2007-12-06 | F. Hoffmann-La Roche Ag | Piperidinyl pyrimidine derivatives |
FR2901794A1 (fr) | 2006-06-01 | 2007-12-07 | Oreal | Composition pour la coloration des fibres keratiniques comprenant un colorant direct diazoique a motif 2-imidazolium |
WO2007146230A2 (en) | 2006-06-14 | 2007-12-21 | Merck & Co., Inc. | Non-nucleoside reverse transcriptase inhibitors |
TW200811158A (en) | 2006-06-27 | 2008-03-01 | Sanofi Aventis | Piperidine or pyrrolidine urea derivatives, their preparation and their therapeutic application |
TW200811170A (en) | 2006-06-27 | 2008-03-01 | Sanofi Aventis | Urea derivatives of tropane, their preparation and their therapeutic application |
PT2041156E (pt) | 2006-07-13 | 2014-02-21 | Achillion Pharmaceuticals Inc | Péptidos 4-amino-4-oxobutanoil como inibidores da replicação viral |
GB0618168D0 (en) | 2006-09-15 | 2006-10-25 | Babraham Inst | Compounds |
US20080186971A1 (en) | 2007-02-02 | 2008-08-07 | Tarari, Inc. | Systems and methods for processing access control lists (acls) in network switches using regular expression matching logic |
KR100999592B1 (ko) | 2007-02-15 | 2010-12-08 | 주식회사 엘지화학 | 새로운 시클로펜타디에닐 리간드를 갖는 4족 전이금속화합물, 이의 제조방법 및 이를 이용한 올레핀계 중합체의제조방법 |
TW200848021A (en) | 2007-03-06 | 2008-12-16 | Wyeth Corp | Sulfonylated heterocycles useful for modulation of the progesterone receptor |
GB0706072D0 (en) | 2007-03-28 | 2007-05-09 | Sterix Ltd | Compound |
US20090012045A1 (en) | 2007-06-26 | 2009-01-08 | Rigel Pharmaceuticals, Inc. | Methods of Treating Cell Proliferative Disorders |
WO2009001817A1 (ja) | 2007-06-27 | 2008-12-31 | Taisho Pharmaceutical Co., Ltd. | 11β-HSD1阻害活性を有する化合物 |
WO2009020140A1 (ja) | 2007-08-06 | 2009-02-12 | Dainippon Sumitomo Pharma Co., Ltd. | アダマンチルウレア誘導体 |
CN101778833A (zh) | 2007-08-10 | 2010-07-14 | 日本曹达株式会社 | 含氮杂环化合物和有害生物防除剂 |
US9493419B2 (en) | 2007-08-21 | 2016-11-15 | The Hong Kong Polytechnic University | Quinoline derivatives as anti-cancer agents |
WO2009029682A1 (en) | 2007-08-28 | 2009-03-05 | Rigel Pharmaceuticals, Inc. | Combination therapy with syk kinase inhibitor |
JP5438008B2 (ja) | 2007-09-21 | 2014-03-12 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | MDM2とp53の間の相互作用の阻害剤 |
US20100280024A1 (en) | 2007-10-15 | 2010-11-04 | Jigar Desai | Renin inhibitors |
JP2009114107A (ja) | 2007-11-06 | 2009-05-28 | Daiichi Sankyo Co Ltd | ヘテロアリールアミド低級カルボン酸誘導体を含有する医薬組成物 |
US8119656B2 (en) | 2007-12-07 | 2012-02-21 | The Board Of Regents Of The University Of Texas System | Inhibitors of the influenza virus non-structural 1 protein |
CA2713519A1 (en) | 2008-02-07 | 2009-08-13 | Abbott Laboratories | Amide derivatives as positive allosteric modulators and methods of use thereof |
JP2011528369A (ja) | 2008-07-16 | 2011-11-17 | シェーリング コーポレイション | 二環式ヘテロ環誘導体およびそれらの使用方法 |
PE20110574A1 (es) | 2008-10-29 | 2011-08-11 | Hoffmann La Roche | Derivados de fenilamida y de piridilamida como agonistas de gpbar1 |
TW201030007A (en) | 2009-02-06 | 2010-08-16 | Gruenenthal Gmbh | Substituted spiro-amides as b1r modulators |
WO2010107768A1 (en) | 2009-03-18 | 2010-09-23 | Schering Corporation | Bicyclic compounds as inhibitors of diacylglycerol acyltransferase |
EP2415764A4 (en) | 2009-03-31 | 2012-08-08 | Kowa Co | PROPHYLACTIC AND / OR THERAPEUTIC AGENT AGAINST ANEMIA WITH A TETRAHYDROCHINOLINE COMPOUND AS AN ACTIVE SUBSTANCE |
BRPI1014574A2 (pt) | 2009-04-15 | 2015-08-25 | Jw Pharmaceutical Corp | Compostos inéditos de imitadores de ligação revesa, método para fabricar os mesmos e uso destes |
GB0909672D0 (en) | 2009-06-04 | 2009-07-22 | Xention Discovery Ltd | Compounds |
US9360482B2 (en) * | 2009-11-05 | 2016-06-07 | Glaxosmithkline Llc | Process for the identification of a compound which inhibits the binding of the second bromodomain of each of human BRD-2, BRD-3, and BRD-4 |
GB0919434D0 (en) * | 2009-11-05 | 2009-12-23 | Glaxosmithkline Llc | Novel compounds |
GB0919432D0 (en) * | 2009-11-05 | 2009-12-23 | Glaxosmithkline Llc | Use |
US8420647B2 (en) | 2010-01-21 | 2013-04-16 | Hoffmann-La Roche Inc. | 4-phenoxy-nicotinamide or 4-phenoxy-pyrimidine-5-carboxamide compounds |
ES2822130T3 (es) | 2010-02-11 | 2021-04-29 | Bristol Myers Squibb Co | Macrociclos como inhibidores del factor XIa |
US8299117B2 (en) | 2010-06-16 | 2012-10-30 | Metabolex Inc. | GPR120 receptor agonists and uses thereof |
US9512111B2 (en) | 2010-11-08 | 2016-12-06 | Lycera Corporation | N-sulfonylated tetrahydroquinolines and related bicyclic compounds for inhibition of RORγ activity and the treatment of disease |
WO2012137224A1 (en) | 2011-04-05 | 2012-10-11 | University Of Delhi | Coumarin compounds for the treatment of mycobacterial infections |
AU2012241426A1 (en) | 2011-04-14 | 2013-10-31 | Novartis Ag | Glycoside derivatives and uses thereof |
GB201106750D0 (en) * | 2011-04-21 | 2011-06-01 | Glaxosmithkline Llc | Novel compounds |
EP2702042A1 (en) | 2011-04-28 | 2014-03-05 | Bristol-Myers Squibb Company | Novel bicyclic nitrogen containing heteroaryl tgr5 receptor modulators |
GB201107325D0 (en) * | 2011-05-04 | 2011-06-15 | Glaxosmithkline Llc | Novel compounds |
CN102816175B (zh) | 2011-06-09 | 2015-12-16 | 上海汇伦生命科技有限公司 | 一种杂环并吡啶酮类化合物,其中间体、制备方法和用途 |
US8962810B2 (en) | 2011-06-16 | 2015-02-24 | AB Pharma Ltd. | Macrocyclic heterocyclic compound for inhibiting hepatitis C virus and preparation and use thereof |
CN102827170A (zh) | 2011-06-17 | 2012-12-19 | 安吉奥斯医药品有限公司 | 治疗活性组合物和它们的使用方法 |
JP2014520858A (ja) | 2011-07-13 | 2014-08-25 | ノバルティス アーゲー | タンキラーゼ阻害剤として用いるための新規な2−ピペリジン−1−イル−アセトアミド化合物 |
EP2753176A4 (en) | 2011-09-06 | 2015-10-21 | New York Blood Ct Inc | HIV INHIBITORS |
US9403800B2 (en) | 2012-01-24 | 2016-08-02 | Chemregen, Inc. | Compounds for inhibition of cancer cell proliferation |
WO2013152687A1 (zh) | 2012-04-11 | 2013-10-17 | 中国科学院理化技术研究所 | 一种近红外荧光染料的制备及应用 |
CA2871514C (en) | 2012-05-08 | 2020-08-25 | Merck Sharp & Dohme Corp. | Tetrahydronaphthyridine and related bicyclic compounds for inhibition of ror.gamma.activity and the treatment of disease |
WO2013184755A2 (en) | 2012-06-07 | 2013-12-12 | Georgia State University Research Foundation, Inc. | Seca inhibitors and methods of making and using thereof |
JP6465803B2 (ja) | 2012-10-22 | 2019-02-06 | シティ・オブ・ホープCity of Hope | Etp誘導体 |
WO2014080290A2 (en) | 2012-11-21 | 2014-05-30 | Rvx Therapeutics Inc. | Cyclic amines as bromodomain inhibitors |
US20160256448A1 (en) | 2013-11-18 | 2016-09-08 | Forma Therapeutics, Inc. | Tetrahydroquinoline compositions as bet bromodomain inhibitors |
US9422281B2 (en) | 2013-11-18 | 2016-08-23 | Forma Therapeutics, Inc. | Benzopiperazine compositions as BET bromodomain inhibitors |
US20160256458A1 (en) | 2013-11-18 | 2016-09-08 | Forma Therapeutics, Inc. | Benzopiperazine compositions as bet bromodomain inhibitors |
TWI684588B (zh) | 2013-11-18 | 2020-02-11 | 美商弗瑪治療公司 | 作為bet溴域抑制劑之四氫喹啉組成物 |
-
2014
- 2014-11-18 TW TW103139976A patent/TWI684588B/zh not_active IP Right Cessation
- 2014-11-18 EP EP20203216.5A patent/EP3799872A1/en not_active Withdrawn
- 2014-11-18 RU RU2016124176A patent/RU2727169C2/ru active
- 2014-11-18 EP EP14862604.7A patent/EP3071203B1/en active Active
- 2014-11-18 CN CN201480073069.5A patent/CN105934246B/zh active Active
- 2014-11-18 DK DK14862604.7T patent/DK3071203T3/da active
- 2014-11-18 TW TW109101151A patent/TWI742513B/zh not_active IP Right Cessation
- 2014-11-18 SI SI201431797T patent/SI3071203T1/sl unknown
- 2014-11-18 PL PL14862604T patent/PL3071203T3/pl unknown
- 2014-11-18 MX MX2016006438A patent/MX370535B/es active IP Right Grant
- 2014-11-18 RS RS20210279A patent/RS61519B1/sr unknown
- 2014-11-18 LT LTEP14862604.7T patent/LT3071203T/lt unknown
- 2014-11-18 JP JP2016554547A patent/JP6553632B2/ja not_active Expired - Fee Related
- 2014-11-18 BR BR122019007990-0A patent/BR122019007990B1/pt not_active IP Right Cessation
- 2014-11-18 BR BR112016011024-2A patent/BR112016011024B1/pt not_active IP Right Cessation
- 2014-11-18 AU AU2014348191A patent/AU2014348191B2/en not_active Ceased
- 2014-11-18 WO PCT/US2014/066198 patent/WO2015074064A2/en active Application Filing
- 2014-11-18 ES ES14862604T patent/ES2860695T3/es active Active
- 2014-11-18 NZ NZ720004A patent/NZ720004A/en not_active IP Right Cessation
- 2014-11-18 CN CN201910939773.9A patent/CN110627770A/zh active Pending
- 2014-11-18 US US14/546,775 patent/US9388161B2/en not_active Expired - Fee Related
- 2014-11-18 PT PT148626047T patent/PT3071203T/pt unknown
- 2014-11-18 KR KR1020167016331A patent/KR102007796B1/ko active IP Right Grant
- 2014-11-18 CA CA2930414A patent/CA2930414C/en active Active
- 2014-11-18 BR BR122020006707-1A patent/BR122020006707B1/pt not_active IP Right Cessation
- 2014-11-18 HU HUE14862604A patent/HUE053645T2/hu unknown
-
2016
- 2016-05-10 IL IL245582A patent/IL245582B/en active IP Right Grant
- 2016-05-12 US US15/153,692 patent/US20160257692A1/en not_active Abandoned
- 2016-05-13 ZA ZA2016/03278A patent/ZA201603278B/en unknown
- 2016-05-17 MX MX2019015068A patent/MX2019015068A/es unknown
-
2018
- 2018-03-27 US US15/937,271 patent/US10336722B2/en not_active Expired - Fee Related
- 2018-12-19 US US16/225,484 patent/US10611750B2/en not_active Expired - Fee Related
-
2019
- 2019-07-04 JP JP2019125297A patent/JP6845897B2/ja active Active
-
2020
- 2020-01-28 US US16/774,515 patent/US11111229B2/en active Active
- 2020-08-03 IL IL276456A patent/IL276456B/en active IP Right Grant
-
2021
- 2021-03-09 CY CY20211100203T patent/CY1124394T1/el unknown
- 2021-03-16 HR HRP20210431TT patent/HRP20210431T1/hr unknown
- 2021-07-23 US US17/383,610 patent/US20230061891A1/en not_active Abandoned
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6845897B2 (ja) | Betブロモドメイン阻害剤としてのテトラヒドロキノリン組成物 | |
US11084831B1 (en) | Benzopiperazine compositions as BET bromodomain inhibitors | |
KR101712576B1 (ko) | Atr 키나제의 억제제로서 유용한 화합물 | |
JP2017510641A (ja) | 置換インドールmcl−1阻害剤 | |
US20160256448A1 (en) | Tetrahydroquinoline compositions as bet bromodomain inhibitors | |
US20160256458A1 (en) | Benzopiperazine compositions as bet bromodomain inhibitors | |
TW202304917A (zh) | Tead抑制劑及其用途 | |
WO2024054956A1 (en) | Heterobifunctional compounds and methods of treating disease | |
WO2024092115A2 (en) | Mk2 inhibitors and uses thereof | |
US20240150365A1 (en) | Pyridinylsulfonamide compounds and their use in therapy |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |