TWI527815B - 吡唑并喹啉酮衍生物、其製備及其治療用途 - Google Patents
吡唑并喹啉酮衍生物、其製備及其治療用途 Download PDFInfo
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- TWI527815B TWI527815B TW101135394A TW101135394A TWI527815B TW I527815 B TWI527815 B TW I527815B TW 101135394 A TW101135394 A TW 101135394A TW 101135394 A TW101135394 A TW 101135394A TW I527815 B TWI527815 B TW I527815B
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- Prior art keywords
- compound
- dihydro
- pyrazolo
- trifluoroethyl
- quinoline
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 13
- 230000001225 therapeutic effect Effects 0.000 title description 3
- QKQGPTWJARHPJQ-UHFFFAOYSA-N pyrazolo[3,4-h]quinolin-2-one Chemical class C1=C2N=NC=C2C2=NC(=O)C=CC2=C1 QKQGPTWJARHPJQ-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 334
- HETSDWRDICBRSQ-UHFFFAOYSA-N 3h-quinolin-4-one Chemical compound C1=CC=C2C(=O)CC=NC2=C1 HETSDWRDICBRSQ-UHFFFAOYSA-N 0.000 claims description 231
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 134
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 86
- PMZDQRJGMBOQBF-UHFFFAOYSA-N 1H-quinolin-4-one Natural products C1=CC=C2C(O)=CC=NC2=C1 PMZDQRJGMBOQBF-UHFFFAOYSA-N 0.000 claims description 50
- -1 Quinoline-7-yl Chemical group 0.000 claims description 35
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 35
- 239000002253 acid Substances 0.000 claims description 32
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 31
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 25
- 229910003827 NRaRb Inorganic materials 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- VLCMRTMCMQJSKM-UHFFFAOYSA-N phenyl-[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone Chemical compound C=1C=CC=CC=1C(=O)C1=CN=C2C(C(F)(F)F)=CC=CC2=C1C1=CC=CC=C1 VLCMRTMCMQJSKM-UHFFFAOYSA-N 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 15
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 14
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 13
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- FFNVQNRYTPFDDP-UHFFFAOYSA-N 2-cyanopyridine Chemical compound N#CC1=CC=CC=N1 FFNVQNRYTPFDDP-UHFFFAOYSA-N 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 7
- 229940125904 compound 1 Drugs 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940126179 compound 72 Drugs 0.000 claims description 6
- 201000007270 liver cancer Diseases 0.000 claims description 6
- 208000014018 liver neoplasm Diseases 0.000 claims description 6
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 claims description 6
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims description 5
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- YRRCTZOLPNGWQY-UHFFFAOYSA-N 5-cyclopropyl-7-pyridin-4-yl-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C12=CC(C=3C=CN=CC=3)=CC=C2C=2NN=CC=2C(=O)N1C1CC1 YRRCTZOLPNGWQY-UHFFFAOYSA-N 0.000 claims description 4
- ZYBJLMUDXFIHRS-UHFFFAOYSA-N 5-propan-2-yl-7-pyridin-4-yl-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C=3NN=CC=3C(=O)N(C(C)C)C2=CC=1C1=CC=NC=C1 ZYBJLMUDXFIHRS-UHFFFAOYSA-N 0.000 claims description 4
- DFBCTHRFQFEYOJ-UHFFFAOYSA-N 7-pyridin-2-yl-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C=3NN=CC=3C(=O)N(CC(F)(F)F)C2=CC=1C1=CC=CC=N1 DFBCTHRFQFEYOJ-UHFFFAOYSA-N 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 208000002780 macular degeneration Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 4
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
- ZBATVTZGYKVYKF-UHFFFAOYSA-N 4H-pyrazolo[4,3-c]quinoline-8-carbonitrile Chemical compound N1=NC=C2CN=C3C=CC(=CC3=C21)C#N ZBATVTZGYKVYKF-UHFFFAOYSA-N 0.000 claims description 3
- VFLYEIXGKQSVIK-UHFFFAOYSA-N 5-(2-fluoroethyl)-7-pyridin-4-yl-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C=3NN=CC=3C(=O)N(CCF)C2=CC=1C1=CC=NC=C1 VFLYEIXGKQSVIK-UHFFFAOYSA-N 0.000 claims description 3
- IRULQWBVWCFRSD-UHFFFAOYSA-N 5-ethyl-7-[2-(morpholin-4-ylmethyl)phenyl]-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C=3NN=CC=3C(=O)N(CC)C2=CC=1C1=CC=CC=C1CN1CCOCC1 IRULQWBVWCFRSD-UHFFFAOYSA-N 0.000 claims description 3
- AUMILJVKVTWIOX-UHFFFAOYSA-N 5-ethyl-7-pyridin-3-yloxy-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C3=NNC=C3C(=O)N(CC)C2=CC=1OC1=CC=CN=C1 AUMILJVKVTWIOX-UHFFFAOYSA-N 0.000 claims description 3
- BPLNZOQGPAGRTJ-UHFFFAOYSA-N 5-propyl-7-pyridin-4-yl-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C=3NN=CC=3C(=O)N(CCC)C2=CC=1C1=CC=NC=C1 BPLNZOQGPAGRTJ-UHFFFAOYSA-N 0.000 claims description 3
- QRIZIGNSNQSURC-UHFFFAOYSA-N 7-(2-aminopyridin-3-yl)-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound NC1=NC=CC=C1C1=CC=C(C2=C(C=NN2)C(=O)N2CC(F)(F)F)C2=C1 QRIZIGNSNQSURC-UHFFFAOYSA-N 0.000 claims description 3
- QFSGIAOTXDDUEB-UHFFFAOYSA-N 7-(3-chloro-2-hydroxyphenyl)-5-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]quinolin-4-one Chemical compound OC1=C(Cl)C=CC=C1C1=CC=C(C2=C(C=NN2)C(=O)N2CC(F)(F)F)C2=C1 QFSGIAOTXDDUEB-UHFFFAOYSA-N 0.000 claims description 3
- OJBJDYSHRFHMKF-UHFFFAOYSA-N 7-(4-cyclopentylpyrimidin-5-yl)-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C=3NN=CC=3C(=O)N(CC(F)(F)F)C2=CC=1C1=CN=CN=C1C1CCCC1 OJBJDYSHRFHMKF-UHFFFAOYSA-N 0.000 claims description 3
- OONDBQRXNZDPTK-UHFFFAOYSA-N 7-(4-propylpyrimidin-5-yl)-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound CCCC1=NC=NC=C1C1=CC=C(C2=C(C=NN2)C(=O)N2CC(F)(F)F)C2=C1 OONDBQRXNZDPTK-UHFFFAOYSA-N 0.000 claims description 3
- ATRNPBPVHWXSTC-UHFFFAOYSA-N 7-(5-fluoropyridin-2-yl)-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound N1=CC(F)=CC=C1C1=CC=C(C2=C(C=NN2)C(=O)N2CC(F)(F)F)C2=C1 ATRNPBPVHWXSTC-UHFFFAOYSA-N 0.000 claims description 3
- OYUSLAVQMOQZPJ-UHFFFAOYSA-N 7-(6-amino-2-methylpyridin-3-yl)-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound CC1=NC(N)=CC=C1C1=CC=C(C2=C(C=NN2)C(=O)N2CC(F)(F)F)C2=C1 OYUSLAVQMOQZPJ-UHFFFAOYSA-N 0.000 claims description 3
- BZIDBJUSOCQJBZ-UHFFFAOYSA-N 7-(pyridin-3-ylamino)-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C3=NNC=C3C(=O)N(CC(F)(F)F)C2=CC=1NC1=CC=CN=C1 BZIDBJUSOCQJBZ-UHFFFAOYSA-N 0.000 claims description 3
- QWFRPPGNFUITAQ-UHFFFAOYSA-N 7-[2-(cyclopentylamino)pyridin-3-yl]-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C3=NNC=C3C(=O)N(CC(F)(F)F)C2=CC=1C1=CC=CN=C1NC1CCCC1 QWFRPPGNFUITAQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- 229940126657 Compound 17 Drugs 0.000 claims description 3
- 229940126639 Compound 33 Drugs 0.000 claims description 3
- 229940127007 Compound 39 Drugs 0.000 claims description 3
- 206010027476 Metastases Diseases 0.000 claims description 3
- 230000033115 angiogenesis Effects 0.000 claims description 3
- 206010003246 arthritis Diseases 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N benzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000002512 chemotherapy Methods 0.000 claims description 3
- 229940125773 compound 10 Drugs 0.000 claims description 3
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- 229940127113 compound 57 Drugs 0.000 claims description 3
- 229940125900 compound 59 Drugs 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 230000009401 metastasis Effects 0.000 claims description 3
- LPOIGVZLNWEGJG-UHFFFAOYSA-N n-benzyl-5-(4-methylpiperazin-1-yl)-2-nitroaniline Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C(NCC=2C=CC=CC=2)=C1 LPOIGVZLNWEGJG-UHFFFAOYSA-N 0.000 claims description 3
- WIRTYVGMQVIVDM-UHFFFAOYSA-N pyridine-3-carbonitrile Chemical compound N#CC1=C=NC=C[CH]1 WIRTYVGMQVIVDM-UHFFFAOYSA-N 0.000 claims description 3
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 3
- HPQRQAOVNXWEEQ-UHFFFAOYSA-N quinoline-8-carboxamide Chemical compound C1=CN=C2C(C(=O)N)=CC=CC2=C1 HPQRQAOVNXWEEQ-UHFFFAOYSA-N 0.000 claims description 3
- 230000007420 reactivation Effects 0.000 claims description 3
- 229910052701 rubidium Inorganic materials 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- MPMKMQHJHDHPBE-RUZDIDTESA-N 4-[[(2r)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid Chemical compound O=C([C@@]1(N(CC1)C(=O)C=1C2=CC=CC=C2SC=1)C)N(CCCC(O)=O)CC1=CC=CC(Cl)=C1 MPMKMQHJHDHPBE-RUZDIDTESA-N 0.000 claims description 2
- SVCLSMRYYZRTBF-UHFFFAOYSA-N 4H-pyrazolo[4,3-c]quinoline-8-carboxylic acid Chemical compound N1=NC=C2CN=C3C=CC(=CC3=C21)C(=O)O SVCLSMRYYZRTBF-UHFFFAOYSA-N 0.000 claims description 2
- XDSXIJYRSOHJHJ-UHFFFAOYSA-N 5-(2,2,2-trifluoroethyl)-7-[2-(trifluoromethyl)pyridin-3-yl]-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C=3NN=CC=3C(=O)N(CC(F)(F)F)C2=CC=1C1=CC=CN=C1C(F)(F)F XDSXIJYRSOHJHJ-UHFFFAOYSA-N 0.000 claims description 2
- CABNJKZVGJLQEQ-UHFFFAOYSA-N 5-(2,2,2-trifluoroethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C=3NN=CC=3C(=O)N(CC(F)(F)F)C2=CC=1C1=NC=CC=C1C(F)(F)F CABNJKZVGJLQEQ-UHFFFAOYSA-N 0.000 claims description 2
- AZIADLAMYVSFIX-UHFFFAOYSA-N 5-(2,2-difluoroethyl)-7-pyridin-4-yl-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C=3NN=CC=3C(=O)N(CC(F)F)C2=CC=1C1=CC=NC=C1 AZIADLAMYVSFIX-UHFFFAOYSA-N 0.000 claims description 2
- IXOHJAJRAOXJRR-UHFFFAOYSA-N 5-ethyl-7-(2-piperazin-1-ylpyridin-4-yl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C=3NN=CC=3C(=O)N(CC)C2=CC=1C(C=1)=CC=NC=1N1CCNCC1 IXOHJAJRAOXJRR-UHFFFAOYSA-N 0.000 claims description 2
- AVTROAWJOKEDPE-UHFFFAOYSA-N 5-ethyl-7-[4-(1-pyrrolidin-1-ylethyl)phenyl]-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C=3NN=CC=3C(=O)N(CC)C2=CC=1C(C=C1)=CC=C1C(C)N1CCCC1 AVTROAWJOKEDPE-UHFFFAOYSA-N 0.000 claims description 2
- HRQDQQHDKSPWNL-UHFFFAOYSA-N 7-(2-amino-5-fluoropyridin-3-yl)-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound NC1=NC=C(F)C=C1C1=CC=C(C2=C(C=NN2)C(=O)N2CC(F)(F)F)C2=C1 HRQDQQHDKSPWNL-UHFFFAOYSA-N 0.000 claims description 2
- UNSXVWDBLGGKAU-UHFFFAOYSA-N 7-(2-chloro-6-methylpyridin-3-yl)-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound ClC1=NC(C)=CC=C1C1=CC=C(C2=C(C=NN2)C(=O)N2CC(F)(F)F)C2=C1 UNSXVWDBLGGKAU-UHFFFAOYSA-N 0.000 claims description 2
- CNNMFDXNOFOMKU-UHFFFAOYSA-N 7-(2-methoxypyridin-4-yl)-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C1=NC(OC)=CC(C=2C=C3N(CC(F)(F)F)C(=O)C=4C=NNC=4C3=CC=2)=C1 CNNMFDXNOFOMKU-UHFFFAOYSA-N 0.000 claims description 2
- SITQYXHEMXRNGJ-UHFFFAOYSA-N 7-(2-methylpyridin-3-yl)-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound CC1=NC=CC=C1C1=CC=C(C2=C(C=NN2)C(=O)N2CC(F)(F)F)C2=C1 SITQYXHEMXRNGJ-UHFFFAOYSA-N 0.000 claims description 2
- IULAFOOANWGYSP-UHFFFAOYSA-N 7-(2-methylpyridin-4-yl)-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C1=NC(C)=CC(C=2C=C3N(CC(F)(F)F)C(=O)C=4C=NNC=4C3=CC=2)=C1 IULAFOOANWGYSP-UHFFFAOYSA-N 0.000 claims description 2
- NRVRNLFKYSLYRJ-UHFFFAOYSA-N 7-(2-piperazin-1-ylphenyl)-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C3=NNC=C3C(=O)N(CC(F)(F)F)C2=CC=1C1=CC=CC=C1N1CCNCC1 NRVRNLFKYSLYRJ-UHFFFAOYSA-N 0.000 claims description 2
- OLPZOSSDIKGRBX-UHFFFAOYSA-N 7-(2-piperidin-1-ylpyridin-3-yl)-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C3=NNC=C3C(=O)N(CC(F)(F)F)C2=CC=1C1=CC=CN=C1N1CCCCC1 OLPZOSSDIKGRBX-UHFFFAOYSA-N 0.000 claims description 2
- BSVHOQXLMHDKHC-UHFFFAOYSA-N 7-(2-pyrrolidin-1-ylpyridin-3-yl)-5-(2,2,2-trifluoroethyl)-1h-pyrazolo[4,3-c]quinolin-4-one Chemical compound C=1C=C2C=3NN=CC=3C(=O)N(CC(F)(F)F)C2=CC=1C1=CC=CN=C1N1CCCC1 BSVHOQXLMHDKHC-UHFFFAOYSA-N 0.000 claims description 2
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- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims 1
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- GYUURHMITDQTRU-UHFFFAOYSA-N tributyl(pyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=N1 GYUURHMITDQTRU-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
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- A61P37/00—Drugs for immunological or allergic disorders
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/62—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino groups and at least two carboxyl groups bound to carbon atoms of the same six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
-
- 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
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- 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
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
-
- C—CHEMISTRY; METALLURGY
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Description
本發明係關於吡唑并喹啉酮衍生物、其製備及其治療用途。
本發明化合物為2型甲硫胺酸胺基肽酶(MetAP2)之可逆性及選擇性抑制劑。
MetAP2為多肽分解代謝中涉及之普遍存在的基於胞溶質之金屬蛋白酶。
MetAP2催化位於由細胞新合成之蛋白質之N末端處的甲硫胺酸殘基之裂解(Bradshaw R.A.等人,TIBS,1998,23,263-267)。N端甲硫胺酸殘基之裂解為許多蛋白質及多肽之成熟中的重要步驟。其使細胞能夠繼續進行通常的轉譯後修飾(肉豆蔻醯基化、軟脂醯基化等),接著降解此等相同蛋白質。然而,MetAP2僅可在第二殘基具有較小尺寸且不帶電之情況下裂解此殘基。
當活性位點含有兩個二價金屬原子(諸如Co(II)或Mn(II))時,MetAP2具有活性(Li X.,Chang Y.H.,Biochem.Biophys.Res.Commun.227,1996,152-159)。此外,研究已證實人類MetAP2相當可能使用錳作為生理學金屬離子(Wang J.等人,Biochemistry 2003,42,5035-5042)。
MetAP2之另一功能為與蛋白質轉譯因子eIF2(真核起始因子2)組合,由此防止其磷酸化(Datta等人,1988;Li及Chang,1996)。已顯示eIF2之磷酸化使得真核細胞中之整
體蛋白質合成得到抑制。藉由結合於eIF2,MetAP2保護磷酸化位點(Datta,2000;Kimball,1999;Pestova等人,2001)。然而,MetAP2活性之抑制劑不會影響MetAP2阻斷eIF2磷酸化之能力(Griffith,1997),表明該兩種功能為獨立的。
存在MetAP2同功異型物:MetAP1。此兩種同功異型物區別於在MetAP2之C端結構域內存在約60個殘基之另一螺旋結構域。真核細胞具有兩種形式。兩種形式之突變對真核細胞係致死的。此結果強調識別對MetAP2具有選擇性之抑制劑的關注。另一方面,當僅一種同功異型物突變時,觀察到生長減少(Li X.及Chang Y.H.,Proc.Natl.Acad.Sci.1995,92,12357-12361)。此等結果證實甲硫胺酸胺基肽酶(MAP)功能對於細胞生長為必需的且此活性不能由與MetAP無關之途徑中繼。
亦存在兩種類型MetAP2抑制劑:可逆性抑制劑及不可逆性抑制劑。某些已知不可逆性抑制劑為煙黴素(fumagillin)、TNP-470及卵假散囊菌素(ovalicin)。在分子層面,TNP-470正如煙黴素及卵假散囊菌素一樣共價及不可逆地結合於MetAP2(Griffith E.C.等人,Chem.Biol.1997,4,461-471)。
MetAP2已被識別為源自描述為強大不可逆性MetAP2抑制劑之煙黴素之抗血管生成劑家族的目標。已明確建立MetAP2抑制與內皮細胞增殖及新血管生成之由此引起的抑制之間的因果聯繫(Griffith E.C.等人,Chem.Biol.1998,95,15183-15188)。
在細胞層面,目前仍極少知曉MetAP2之目標蛋白質。其中一者為甘油醛-3-磷酸去氫酶。已在用TNP-470治療內皮細胞期間觀察到此酶之合成中的缺陷。近期研究支持TNP-470之抗MetAP2活性為其抗血管生成活性之來源的假設。
已顯示,不可逆性MetAP2抑制劑在治療肺纖維化及肝纖維化中起作用。纖維化為繼組織病變後之疤痕組織的異常形成且使得受累及器官慢性及進行性損傷,由此會導致受累及器官之嚴重功能障礙。纖維化可能存在許多病因,但在大多數情況下,病痛原因仍然未知且難以偵測到病變。產生活化纖維母細胞及肌纖維母細胞之聚集體,其構成眾多纖維變性病灶之開始。當形成病變時,其為不可逆的且不能消除。治療因此針對減緩疾患進展及改善症狀。在此背景下,不可逆性MetAP2抑制劑已在活體內模型上顯示減少肺纖維化及肝纖維化。然而,已證明此等不可逆性抑制劑之實質毒性(Kruger E.A.,Exp.Opinion Invest.Drugs,2000;Satchi-Fainaro R.等人,Nature Medicine,2004)。
本發明之一個標的為對應於式(I)之化合物:
其中:R1表示:
˙-(C1-C4)烷基
˙-(C1-C4)鹵烷基
R2表示:
˙基團:
˙基團:
˙基團:-A-X
R3表示:
˙-H
˙鹵素
˙-(C1-C6)烷基
˙氰基
˙-CO2H
˙-CONH2
A表示:
˙芳基或雜芳基
X不存在或表示:
˙鹵素
˙氰基
˙側氧基
˙-(CH2)nOH
˙-(C1-C6)鹵烷基
˙-(C1-C6)烷基
˙-(C1-C6)烷氧基,
˙-CHOH-芳基
˙雜環
˙雜芳基
˙-(C1-C6)烷基-雜環
˙-(C1-C6)烷基-雜芳基
˙-(C1-C6)烷基-COORa
˙-(C1-C6)烷基-NRaRb
˙-雜芳基-(CH2)n-NRaRb
˙-(CH2)n-NRa-C(O)-Rb
˙-NRaRb
˙-NRa-(CH2)n-O-Rb
˙-NRa-雜環
˙-NRa-芳基
˙-NRa-C(O)-(CH2)n-NRaRb
˙-NRaC(O)-(C1-C6)烷基
˙-NRa-C(O)-(C1-C6)烷基-芳基
˙-NRa-C(O)-(CH2)n-O-Rb
˙-NRa-SO2-(CH2)n-芳基
˙-NRa-SO2-(CH2)n-NRaRb
˙-NRa-SO2-Rb
˙-NRa-SO2-芳基-O-芳基
˙-NRa-SO2-芳基-(CH2)n-NRb-C(O)-Rb
˙-COORa
˙-CONRaRb
˙-C(O)-NRa-(CH2)n-O-Rb
˙-C(O)-NRa-芳基-C(O)-NRaRb
˙-C(O)-NRa-(CH2)n-NRaRb
˙-C(O)-NRa-(CH2)n-雜芳基
˙-O-(CH2)n-NRaRb
˙-O-雜環
˙-CO-雜環
˙-CO-雜芳基
˙-SO2NRaRb
˙-SO2-雜環
Ra及Rb獨立地表示:
˙-H
˙-(C1-C6)烷基
n表示0、1、2或3。
式(I)化合物可包含一或多個不對稱碳原子。其可因此以對映異構體或非對映異構體形式存在。此等對映異構體及非對映異構體,以及其混合物(包括外消旋混合物)形成本
發明之部分。
式(I)化合物可以互變異構體形式存在。此等互變異構形式形成本發明之部分。
式(I)化合物可以鹼形式存在或與酸或鹼(尤其是醫藥學上可接受之酸或鹼)成鹽。此等加成鹽形成本發明之部分。
此等鹽宜用醫藥學上可接受之酸製備,但適用於例如純化或分離式(I)化合物之其他酸的鹽亦形成本發明之部分。
式(I)化合物亦可以水合物形式存在,亦即以與一或多個水分子締合或組合之形式存在。此等水合物亦形成本發明之部分。
在本發明之上下文中,且除非在本文另有提及,否則以下定義適用:- 鹵素原子:氟、氯、溴或碘;- 烷基:直鏈、分支鏈或環狀飽和脂族基。烷基可經一或多個烷氧基取代。可提及之實例包括甲基、乙基、丙基、異丙基、環丙基、環丁基、環戊基、環己基等基團;- 烷氧基:基團-O-烷基,其中烷基如先前所定義;提及之一個實例為甲氧基;- 鹵烷基:如上所定義之烷基經1至5個如先前所定義之鹵素原子取代。提及之實例為三氟甲基、三氟乙基等基團;- 氰基:基團CN;- 側氧基:呈形式=O之含有雙鍵結氧原子之基團;此基
團可取代芳基、雜芳基或雜環基
如以下實例中:
- 芳基:包含5個至10個碳原子的環狀芳族基團,此基團可能與諸如嗎啉之雜環稠合(化合物56)。可提及之芳基之實例為苯基;芳基可經一或多個鹵素原子或(C1-C6)烷基、(C1-C6)烷氧基、NRaRb、OH、C(O)-(C1-C6)烷基或側氧基取代;- 雜芳基:包含5個至10個碳原子且包含1個至5個雜原子(諸如氮、氧或硫)的環狀芳族基團。雜芳基可包含N-氧化物基團。可提及之雜芳基之實例包括吡啶、2-吡啶基、4-吡啶基、3-吡啶基、吡唑基、噻吩基、吲哚基、嘧啶基、咪唑基、呋喃基、吲唑基、四唑基、苯并噁嗪基、噁唑基、喹啉基、三唑基及噁二唑基;雜芳基可經一或多個鹵素原子或(C1-C6)烷基、(C1-C6)烷氧基、NRaRb、OH、C(O)-(C1-C6)烷基或側氧基取代;- 雜環:包含4至9個形成此環之原子(其中1或2個為雜原子,諸如氧、氮或硫)的視情況橋連之環狀烷基。可尤其提及吡咯啶基、哌嗪基、哌啶基、嗎啉基、氧氮雜環庚烷基、二氮雜環庚烷基及氮雜環丁烷基;雜環基可經一或多個鹵素原子或(C1-C6)烷基、(C1-C6)烷氧基、NRaRb、OH、C(O)-(C1-C6)烷基或側氧基取代。
在作為本發明之標的之化合物中,可提及第一組式(I)化
合物,其中R3表示H或鹵素原子,更尤其表示氯,其他取代基之定義保持不變。
另一組作為本發明之標的之化合物係由式(I)化合物形成,其中R1表示(C1-C4)烷基(更尤其為乙基)或(C1-C4)鹵烷基(更尤其為三氟乙基),其他取代基之定義保持不變。
另一組作為本發明之標的之化合物係由式(I)化合物形成,其中R2表示基團-A-X,其中A表示芳基或雜芳基且X不存在或表示雜環、NRaRb、(C1-C6)烷基、鹵素(更尤其為氯或氟)、氰基、NRa-SO2-Rb或CO-雜環基;其他取代基之定義保持不變。
本發明化合物之上述組之組合亦形成本發明之部分作為本發明之實施例。
另一組作為本發明之標的之化合物係由式(I)化合物形成,以下化合物除外:- 化合物2:7-(2-胺基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物12:7-[2-(嗎啉-4-基羰基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物14:7-(2-嗎啉-4-基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物16:7-(2-嗎啉-4-基甲基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物19:7-[4-(4-甲基哌嗪-1-基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物23:7-(4-二乙胺基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物30:7-[4-(哌嗪-1-基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物32:7-(4-二甲胺基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物42:7-(2-{5-[(丙-2-基胺基)甲基]呋喃-2-基}苯基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物66:7-[6-(哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物68:7-[2-(4-甲基哌嗪-1-基)吡啶-4-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物70:7-[2-(哌嗪-1-基)吡啶-4-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物83:7-[6-(嗎啉-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物95:7-(6-胺基吡啶-3-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物113:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸異丙酯;- 化合物114:環丙烷甲酸{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}醯胺;- 化合物115:7-[2-(1-甲基-1H-咪唑-2-羰基)苯基]-5-
(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物116:7-(4-環戊基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物117:7-(4-環己基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物118:7-(2-丙基胺基甲基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物119:2-甲氧基-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}乙醯胺;- 化合物120:N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}異丁醯胺;- 化合物121:N-{4-甲基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}丙醯胺;- 化合物123:7-[4-甲基-2-(哌啶-4-基氧基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物124:7-[2-(1,4-二氮雜環庚烷-1-基甲基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物125:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸乙酯;- 化合物126:7-(2-胺基苯基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物127:7-(2-哌嗪-1-基苯基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物172:7-[2-(嗎啉-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物174:7-(2-環丙基胺基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物178:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]菸鹼酸甲酯;- 化合物181:7-[2-(4-氟苯基胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物196:8-氯-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物204:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸;- 化合物209:7-{2-[(4-甲基-1,4-二氮雜環庚烷-1-基)羰基]苯基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物210:7-{2-[(4-甲基哌嗪-1-基)羰基]苯基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物212:N-(3-二甲胺基丙基)-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲醯胺;- 化合物214:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]-N-[2-(吡啶-4-基)乙基]苯甲醯胺;
- 化合物218:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]-N-(吡啶-3-基甲基)苯甲醯胺;- 化合物219:N-乙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]-N-(吡啶-4-基甲基)苯甲醯胺;- 化合物223:N-{3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺;- 化合物224:3-二甲胺基-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-2H,4H-吡唑并[4,3-c]喹啉-7-基]苯基}丙醯胺;- 化合物225:4-(二甲胺基)-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}丁醯胺;- 化合物230:2-(3-氯苯基)-N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}乙醯胺;- 化合物231:2-(2,4-二氯苯基)-N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}乙醯胺;- 化合物232:N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-2H-吡唑并[4,3-c]喹啉-7-基]苯基}甲烷磺醯胺;- 化合物233:2-(二甲胺基)-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}乙烷
磺醯胺;- 化合物234:N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}-1-苯基甲烷磺醯胺;- 化合物235:3-氯-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}苯磺醯胺;- 化合物236:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}甲烷磺醯胺;- 化合物237:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}-1-苯基甲烷磺醯胺;- 化合物238:3-氯-N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}苯磺醯胺;- 化合物240:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}-2-苯氧基苯磺醯胺。
在作為本發明之標的之式(I)化合物中,尤其可提及以下化合物:- 化合物1:7-(吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物2:7-(2-胺基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物3:7-(2-氟苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-
4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物4:5-乙基-7-吡啶-2-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物5:5-乙基-7-(4-氟苯基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物6:7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物7:5-乙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物8:7-(2-二甲胺基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物9:N-(3-二甲胺基丙基)-4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;- 化合物10:5-乙基-7-(4-哌嗪-1-基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物11:5-乙基-7-[4-(4-甲基哌嗪-1-基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物12:7-[2-(嗎啉-4-基羰基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物13:N-(2-二甲胺基乙基)-4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;- 化合物14:7-(2-嗎啉-4-基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物15:7-[4-(1-二甲胺基乙基)苯基]-5-乙基-1,5-二
氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物16:7-(2-嗎啉-4-基甲基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物17:5-乙基-7-(2-嗎啉-4-基甲基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物18:5-乙基-7-[4-(哌嗪-1-羰基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物19:7-[4-(4-甲基哌嗪-1-基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物20:5-乙基-7-(2-哌嗪-1-基嘧啶-5-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物21:5-乙基-7-[4-(4-甲基哌嗪-1-羰基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物22:5-乙基-7-[4-(1-吡咯啶-1-基-乙基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物23:7-(4-二乙胺基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物24:7-(4-胺基-2-甲基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物25:7-(4-嗎啉-4-基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物26:5-乙基-7-(4-嗎啉-4-基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物27:5-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并
[4,3-c]喹啉-7-基)-2-氟-N-甲基苯甲醯胺;- 化合物28:5-乙基-7-(2-氟-5-甲氧苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物29:7-[3-氯-4-(嗎啉-4-羰基)苯基]-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物30:7-[4-(哌嗪-1-基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物31:5-乙基-7-[2-(4-甲基哌嗪-1-基)嘧啶-5-基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物32:7-(4-二甲胺基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物33:2-氯-4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;- 化合物34:5-乙基-7-(1H-吲唑-5-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物35:N-乙基-3-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;- 化合物36:5-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)-2-氟-苯甲醯胺;- 化合物37:N-(2-二甲胺基乙基)-3-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;- 化合物38:N-[4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲基]乙醯胺;- 化合物39:3-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并
[4,3-c]喹啉-7-基)-N-(2-甲氧基乙基)苯甲醯胺;- 化合物40:7-(3-羥苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物41:7-(2-氯-3-氟吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物42:7-(2-{5-[(丙-2-基胺基)甲基]呋喃-2-基}苯基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物43:N-[2-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯基]甲烷磺醯胺;- 化合物44:7-(2-胺基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物45:5-乙基-7-(3-嗎啉-4-基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物46:N-[2-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯基]乙醯胺;- 化合物47:5-乙基-7-(2-羥苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物48:5-乙基-7-[4-(嗎啉-4-磺醯基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物49:7-(2-羥甲基-4-甲氧苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物50:5-乙基-7-(3-吡唑-1-基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物51:5-乙基-7-(1H-吲哚-5-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物52:5-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)-噻吩-2-甲腈;- 化合物53:7-(3-氯-2-羥苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物54:5-乙基-7-(2-羥基-3-甲氧苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物55:3-胺基-4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸甲酯;- 化合物56:5-乙基-7-(4-甲基-3,4-二氫-2H-苯并[1,4]噁嗪-7-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物57:7-(2,5-二氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物58:7-(2-氯-5-甲氧苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物59:N-(3-二甲胺基丙基)-3-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;- 化合物60:5-乙基-7-(4-氟-2-羥苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物61:5-乙基-7-(2-氟-4-甲氧苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物62:7-(4-胺基甲基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物63:5-乙基-7-(2-氟-3-甲氧苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物64:7-(2-二甲胺基甲基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物65:4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲酸;- 化合物66:7-[6-(哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物67:5-乙基-7-[6-(哌嗪-1-基)吡啶-3-基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物68:7-[2-(4-甲基哌嗪-1-基)吡啶-4-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物69:5-乙基-7-[2-(4-甲基哌嗪-1-基)吡啶-4-基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物70:7-[2-(哌嗪-1-基)吡啶-4-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物71:5-乙基-7-(2-哌嗪-1-基吡啶-4-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物72:7-(2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物73:5-乙基-7-(2-甲基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物74:7-(2-氯-6-甲基吡啶-3-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物75:7-(2-氯-6-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物76:7-(2-氯吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物77:7-(2-氟吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物78:5-乙基-7-(2-氟吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物79:7-(6-氯-2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物80:7-(2-甲氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物81:5-乙基-7-(2-甲氧基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物82:7-(6-氯-4-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物83:7-[6-(嗎啉-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物84:7-[6-(3-二甲胺基丙氧基)吡啶-3-基]-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物85:5-乙基-7-喹啉-8-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物86:7-(6-氯吡啶-2-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物87:5-乙基-7-喹啉-6-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物88:7-(6-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物89:7-(6-氯-5-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物90:5-乙基-7-(3-氟吡啶-4-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物91:7-(3-氯吡啶-4-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物92:5-乙基-7-(6-氟-5-甲基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物93:7-(2-乙氧基吡啶-3-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物94:5-乙基-7-(5-甲氧基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物95:7-(6-胺基吡啶-3-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物96:5-乙基-7-吡啶-3-基-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物97:7-(2-氯-6-異丙基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物98:7-(5-氯-2-甲氧基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物99:7-(吡啶-3-基氧基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物100:5-乙基-7-(吡啶-3-基氧基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物101:7-(吡啶-3-基胺基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物102:5-(2,2-二氟乙基)-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物103:5-環丙基甲基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物104:5-丙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物105:5-(2,2-二氟環丙基甲基)-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物106:5-(2-氟乙基)-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物107:5-異丙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物108:5-環丙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物109:8-氟-7-吡啶-2-基-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物110:7-(2-氯吡啶-3-基)-8-甲基-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物111:7-(2-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物112:7-[2-(二甲胺基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物113:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸異丙酯;- 化合物114:環丙烷甲酸{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}醯胺;- 化合物115:7-[2-(1-甲基-1H-咪唑-2-羰基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物116:7-(4-環戊基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物117:7-(4-環己基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物118:7-(2-丙基胺基甲基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物119:2-甲氧基-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}乙醯胺;- 化合物120:N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}異丁醯胺;- 化合物121:N-{4-甲基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}丙醯胺;- 化合物122:N-異丙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-
4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲醯胺;- 化合物123:7-[4-甲基-2-(哌啶-4-基氧基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物124:7-[2-(1,4-二氮雜環庚烷-1-基甲基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物125:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸乙酯;- 化合物126:7-(2-胺基苯基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物127:7-(2-哌嗪-1-基苯基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物128:7-(6-甲氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物129:7-(5-氯-2-氟吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物130:N-{5-甲基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺;- 化合物131:7-[2-(2-羥基-乙基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物132:7-(2-胺基-5-氟吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物133:7-[2-(吡咯啶-1-磺醯基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物134:N-異丙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯磺醯胺;- 化合物135:7-(2-氟-5-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物136:N,N-二乙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯磺醯胺;- 化合物137:7-(6-胺基-4-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物138:7-(6-甲氧基-2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物139:7-(5-甲基-6-[1,2,4]三唑-4-基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物140:7-(4-甲基-6-[1,2,4]三唑-4-基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物141:7-[6-(嗎啉-4-羰基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物142:7-(6-胺基-2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物143:7-(4-乙基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物144:{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}乙酸甲酯;- 化合物145:7-(4-甲氧基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物146:7-(4-丙基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物147:N-{6-甲基-5-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}丙醯胺;- 化合物148:7-(2-噁唑-5-基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物149:7-(4-二甲胺基-2-甲氧基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物150:7-[2-(5-乙基-[1,2,4]]噁二唑-3-基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物151:N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲基}乙醯胺;- 化合物152:7-[5-(羥苯基甲基)吡啶-2-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物153:6-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲腈;- 化合物154:7-(6-羥甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物155:7-[3-(2-二甲胺基乙氧基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物156:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸甲酯;- 化合物157:7-(5-羥甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-
1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物158:7-(2-甲氧基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物159:7-(2-[1,2,4]三唑-1-基甲基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物160:7-(4-苯基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物161:7-(6-甲氧基-4-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物162:7-(4-異丙基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物163:7-(6-氟吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物164:6-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲酸甲酯;- 化合物165:7-(5-氟吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物166:7-[2-(4-甲基哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物167:7-(3-胺基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物168:7-(2,6-二甲基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物169:7-(3-氯吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-
二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物170:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲酸甲酯;- 化合物171:7-(6-甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物172:7-[2-(嗎啉-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物173:5-(2,2,2-三氟乙基)-7-(2-三氟甲基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物174:7-(2-環丙基胺基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物175:5-(2,2,2-三氟乙基)-7-(3-三氟甲基吡啶-2-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物176:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲腈;- 化合物177:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-甲腈;- 化合物178:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]菸鹼酸甲酯;- 化合物179:7-(2-丙氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物180:7-(3-羥基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物181:7-[2-(4-氟苯基胺基)吡啶-3-基]-5-(2,2,2-三
氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物182:7-(2-甲胺基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物183:7-(2-乙氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物184:7-(2-異丙氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物185:7-(5-氯-2-甲氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物186:7-(2-甲基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物187:7-(4-甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物188:7-(6-嗎啉-4-基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物189:7-(4-甲胺基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物190:5-(2,2,2-三氟乙基)-7-(6-三氟甲基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物191:7-(6-甲氧基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物192:7-[4-(2H-四唑-5-基)苯基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物193:7-(3,5-二氯吡啶-2-基)-5-(2,2,2-三氟乙基)-
1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物194:8-氯-7-(吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物195:8-溴-7-吡啶-2-基-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物196:8-氯-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物197:8-溴-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物198:8-氯-5-乙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物199:8-氯-7-(2-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物200:8-甲基-7-吡啶-2-基-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物201:4-側氧基-7-吡啶-4-基-5-(2,2,2-三氟乙基)-4,5-二氫-2H,4H-吡唑并[4,3-c]喹啉-8-甲腈;- 化合物202:4-側氧基-7-吡啶-4-基-5-(2,2,2-三氟乙基)-4,5-二氫-2H,4H-吡唑并[4,3-c]喹啉-8-甲酸;- 化合物203:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲酸;- 化合物204:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸;- 化合物205:4-側氧基-7-(吡啶-4-基)-5-(2,2,2-三氟乙
基)-4,5-二氫-2H-吡唑并[4,3-c]喹啉-8-甲醯胺;- 化合物206:7-[2-(嗎啉-4-基羰基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物207:N-[2-(二甲胺基)乙基]-N-甲基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲醯胺;- 化合物208:N-(2-二甲胺基乙基)-N-乙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲醯胺;- 化合物209:7-{2-[(4-甲基-1,4-二氮雜環庚烷-1-基)羰基]苯基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物210:7-{2-[(4-甲基哌嗪-1-基)羰基]苯基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物211:N-(3-胺甲醯基苯基)-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲醯胺;- 化合物212:N-(3-二甲胺基丙基)-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲醯胺;- 化合物213:N,N-二甲基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲醯胺;
- 化合物214:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]-N-[2-(吡啶-4-基)乙基]苯甲醯胺;- 化合物215:N-[2-(二甲胺基)乙基]-N-甲基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲醯胺;- 化合物216:7-[2-(1,4-氧氮雜環庚烷-4-基羰基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物217:N-甲基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲醯胺;- 化合物218:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]-N-(吡啶-3-基甲基)苯甲醯胺;- 化合物219:N-乙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]-N-(吡啶-4-基甲基)苯甲醯胺;- 化合物220:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲醯胺;- 化合物221:N-[2-(二甲胺基)乙基]-N-乙基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲醯胺;- 化合物222:7-[2-((2S,6R)-2,6-二甲基嗎啉-4-羰基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹
啉-4-酮;- 化合物223:N-{3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺;- 化合物224:3-二甲胺基-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-2H,4H-吡唑并[4,3-c]喹啉-7-基]苯基}丙醯胺;- 化合物225:4-(二甲胺基)-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}丁醯胺;- 化合物226:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}乙醯胺;- 化合物227:N-{3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}環丙烷甲醯胺;- 化合物228:2-甲氧基-N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}-2-苯基乙醯胺;- 化合物229:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}-2-苯基丙醯胺;- 化合物230:2-(3-氯苯基)-N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}乙醯胺;- 化合物231:2-(2,4-二氯苯基)-N-{4-[4-側氧基-5-(2,2,2-
三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}乙醯胺;- 化合物232:N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-2H-吡唑并[4,3-c]喹啉-7-基]苯基}甲烷磺醯胺;- 化合物233:2-(二甲胺基)-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}乙烷磺醯胺;- 化合物234:N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}-1-苯基甲烷磺醯胺;- 化合物235:3-氯-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}苯磺醯胺;- 化合物236:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}甲烷磺醯胺;- 化合物237:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}-1-苯基甲烷磺醯胺;- 化合物238:3-氯-N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}苯磺醯胺;- 化合物239:N-(4-甲氧基-3-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基胺磺醯基}苯甲基)乙醯胺;- 化合物240:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二
氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}-2-苯氧基苯磺醯胺;- 化合物241:N-甲基-N-{3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺;- 化合物242:N-甲基-N-{3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}環丙烷甲醯胺;- 化合物243:7-[2-(甲胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物244:7-[2-(1,4-二氮雜環庚烷-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物245:7-(3,4,5,6-四氫-2H-[1,2']聯吡啶-3'-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物246:7-[2-(3-羥基吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物247:7-[2-(3,4-二羥基吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物248:7-[2-(二甲胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物249:7-{2-[乙基(甲基)胺基]吡啶-3-基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物250:7-{2-[(2-羥乙基)(甲基)胺基]吡啶-3-基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物251:7-[2-(吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物252:7-[2-(1,4-氧氮雜環庚烷-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物253:7-[2-(3-側氧基哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物254:7-[2-(氮雜環丁烷-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物255:7-{2-[(2-甲氧基乙基)甲胺基]吡啶-3-基}-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物256:7-[2-(4-乙醯基哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物257:7-[2-(二乙胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物258:7-[2-(環丁胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物259:7-[2-(2,6-二甲基嗎啉-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物260:7-[2-(4-環丙基哌嗪-1-基)吡啶-4-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物261:7-(2-環己胺基吡啶-3-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物262:7-[2-(異丙基甲基胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物263:7-(2-環戊胺基吡啶-3-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物264:7-(6-吡咯啶-1-基吡啶-2-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物265:7-[6-(2,6-二甲基嗎啉-4-基)吡啶-2-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物266:7-{2-[環己基(甲基)胺基]吡啶-3-基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物267:7-[2-(4-環丙基哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物268:7-[3-(4-環丙基哌嗪-1-基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物269:7-[2-(4-乙醯基-1,4-二氮雜環庚烷-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物270:7-[2-(4-甲基-1,4-二氮雜環庚烷-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物271:7-[2-(4-環丙基-[1,4]二氮雜環庚烷-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物272:7-[2-(3-氟吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物273:7-[2-(4-氟哌啶-1-基)吡啶-3-基]-5-(2,2,2-三
氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物274:7-(2-羥基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物275:7-(1-氧基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物276:7-(1-氧基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;呈鹼或酸加成鹽之形式,且亦可呈水合物形式。
在作為本發明之標的之式(I)化合物中,尤其可提及以下化合物:- 化合物1:7-(吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物3:7-(2-氟苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物4:5-乙基-7-吡啶-2-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物5:5-乙基-7-(4-氟苯基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物6:7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物7:5-乙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物8:7-(2-二甲胺基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物9:N-(3-二甲胺基丙基)-4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;- 化合物10:5-乙基-7-(4-哌嗪-1-基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物11:5-乙基-7-[4-(4-甲基哌嗪-1-基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物13:N-(2-二甲胺基乙基)-4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;- 化合物15:7-[4-(1-二甲胺基乙基)苯基]-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物17:5-乙基-7-(2-嗎啉-4-基甲基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物18:5-乙基-7-[4-(哌嗪-1-羰基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物20:5-乙基-7-(2-哌嗪-1-基嘧啶-5-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物21:5-乙基-7-[4-(4-甲基哌嗪-1-羰基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物22:5-乙基-7-[4-(1-吡咯啶-1-基-乙基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物24:7-(4-胺基-2-甲基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物25:7-(4-嗎啉-4-基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物26:5-乙基-7-(4-嗎啉-4-基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物27:5-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)-2-氟-N-甲基苯甲醯胺;- 化合物28:5-乙基-7-(2-氟-5-甲氧苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物29:7-[3-氯-4-(嗎啉-4-羰基)苯基]-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物31:5-乙基-7-[2-(4-甲基哌嗪-1-基)嘧啶-5-基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物33:2-氯-4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;- 化合物34:5-乙基-7-(1H-吲唑-5-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物35:N-乙基-3-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;- 化合物36:5-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)-2-氟-苯甲醯胺;- 化合物37:N-(2-二甲胺基乙基)-3-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;- 化合物38:N-[4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲基]乙醯胺;- 化合物39:3-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)-N-(2-甲氧基乙基)苯甲醯胺;
- 化合物40:7-(3-羥苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物41:7-(2-氯-3-氟吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物43:N-[2-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯基]甲烷磺醯胺;- 化合物44:7-(2-胺基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物45:5-乙基-7-(3-嗎啉-4-基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物46:N-[2-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯基]乙醯胺;- 化合物47:5-乙基-7-(2-羥苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物48:5-乙基-7-[4-(嗎啉-4-磺醯基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物49:7-(2-羥甲基-4-甲氧苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物50:5-乙基-7-(3-吡唑-1-基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物51:5-乙基-7-(1H-吲哚-5-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物52:5-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)-噻吩-2-甲腈;
- 化合物53:7-(3-氯-2-羥苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物54:5-乙基-7-(2-羥基-3-甲氧苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物55:3-胺基-4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸甲酯;- 化合物56:5-乙基-7-(4-甲基-3,4-二氫-2H-苯并[1,4]噁嗪-7-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物57:7-(2,5-二氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物58:7-(2-氯-5-甲氧苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物59:N-(3-二甲胺基丙基)-3-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;- 化合物60:5-乙基-7-(4-氟-2-羥苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物61:5-乙基-7-(2-氟-4-甲氧苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物62:7-(4-胺基甲基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物63:5-乙基-7-(2-氟-3-甲氧苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物64:7-(2-二甲胺基甲基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物65:4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲酸;- 化合物67:5-乙基-7-[6-(哌嗪-1-基)吡啶-3-基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物69:5-乙基-7-[2-(4-甲基哌嗪-1-基)吡啶-4-基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物71:5-乙基-7-(2-哌嗪-1-基吡啶-4-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物72:7-(2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物73:5-乙基-7-(2-甲基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物74:7-(2-氯-6-甲基吡啶-3-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物75:7-(2-氯-6-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物76:7-(2-氯吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物77:7-(2-氟吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物78:5-乙基-7-(2-氟吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物79:7-(6-氯-2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物80:7-(2-甲氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物81:5-乙基-7-(2-甲氧基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物82:7-(6-氯-4-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物84:7-[6-(3-二甲胺基丙氧基)吡啶-3-基]-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物85:5-乙基-7-喹啉-8-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物86:7-(6-氯吡啶-2-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物87:5-乙基-7-喹啉-6-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物88:7-(6-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物89:7-(6-氯-5-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物90:5-乙基-7-(3-氟吡啶-4-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物91:7-(3-氯吡啶-4-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物92:5-乙基-7-(6-氟-5-甲基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物93:7-(2-乙氧基吡啶-3-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物94:5-乙基-7-(5-甲氧基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物96:5-乙基-7-吡啶-3-基-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物97:7-(2-氯-6-異丙基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物98:7-(5-氯-2-甲氧基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物99:7-(吡啶-3-基氧基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物100:5-乙基-7-(吡啶-3-基氧基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物101:7-(吡啶-3-基胺基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物102:5-(2,2-二氟乙基)-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物103:5-環丙基甲基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物104:5-丙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物105:5-(2,2-二氟環丙基甲基)-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物106:5-(2-氟乙基)-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物107:5-異丙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物108:5-環丙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物109:8-氟-7-吡啶-2-基-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物110:7-(2-氯吡啶-3-基)-8-甲基-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物111:7-(2-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物112:7-[2-(二甲胺基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物122:N-異丙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲醯胺;- 化合物128:7-(6-甲氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物129:7-(5-氯-2-氟吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物130:N-{5-甲基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺;- 化合物131:7-[2-(2-羥基-乙基)苯基]-5-(2,2,2-三氟乙
基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物132:7-(2-胺基-5-氟吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物133:7-[2-(吡咯啶-1-磺醯基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物134:N-異丙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯磺醯胺;- 化合物135:7-(2-氟-5-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物136:N,N-二乙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯磺醯胺;- 化合物137:7-(6-胺基-4-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物138:7-(6-甲氧基-2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物139:7-(5-甲基-6-[1,2,4]三唑-4-基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物140:7-(4-甲基-6-[1,2,4]三唑-4-基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物141:7-[6-(嗎啉-4-羰基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物142:7-(6-胺基-2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物143:7-(4-乙基嘧啶-5-基)-5-(2,2,2-三氟乙基)-
1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物144:{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}乙酸甲酯;- 化合物145:7-(4-甲氧基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物146:7-(4-丙基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物147:N-{6-甲基-5-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}丙醯胺;- 化合物148:7-(2-噁唑-5-基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物149:7-(4-二甲胺基-2-甲氧基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物150:7-[2-(5-乙基-[1,2,4]噁二唑-3-基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物151:N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲基}乙醯胺;- 化合物152:7-[5-(羥苯基甲基)吡啶-2-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物153:6-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲腈;- 化合物154:7-(6-羥甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物155:7-[3-(2-二甲胺基乙氧基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物156:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸甲酯;- 化合物157:7-(5-羥甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物158:7-(2-甲氧基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物159:7-(2-[1,2,4]三唑-1-基甲基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物160:7-(4-苯基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物161:7-(6-甲氧基-4-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物162:7-(4-異丙基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物163:7-(6-氟吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物164:6-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲酸甲酯;- 化合物165:7-(5-氟吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物166:7-[2-(4-甲基哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物167:7-(3-胺基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物168:7-(2,6-二甲基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物169:7-(3-氯吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物170:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲酸甲酯;- 化合物171:7-(6-甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物173:5-(2,2,2-三氟乙基)-7-(2-三氟甲基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物175:5-(2,2,2-三氟乙基)-7-(3-三氟甲基吡啶-2-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物176:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲腈;- 化合物177:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-甲腈;- 化合物179:7-(2-丙氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物180:7-(3-羥基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物182:7-(2-甲胺基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物183:7-(2-乙氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物184:7-(2-異丙氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物185:7-(5-氯-2-甲氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物186:7-(2-甲基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物187:7-(4-甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物188:7-(6-嗎啉-4-基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物189:7-(4-甲胺基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物190:5-(2,2,2-三氟乙基)-7-(6-三氟甲基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物191:7-(6-甲氧基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物192:7-[4-(2H-四唑-5-基)苯基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物193:7-(3,5-二氯吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物194:8-氯-7-(吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
- 化合物195:8-溴-7-吡啶-2-基-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物197:8-溴-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物198:8-氯-5-乙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物199:8-氯-7-(2-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物200:8-甲基-7-吡啶-2-基-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物201:4-側氧基-7-吡啶-4-基-5-(2,2,2-三氟乙基)-4,5-二氫-2H,4H-吡唑并[4,3-c]喹啉-8-甲腈;- 化合物202:4-側氧基-7-吡啶-4-基-5-(2,2,2-三氟乙基)-4,5-二氫-2H,4H-吡唑并[4,3-c]喹啉-8-甲酸;- 化合物203:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲酸;- 化合物204:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸;- 化合物205:4-側氧基-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-4,5-二氫-2H-吡唑并[4,3-c]喹啉-8-甲醯胺;- 化合物206:7-[2-(嗎啉-4-基羰基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物207:N-[2-(二甲胺基)乙基]-N-甲基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-
基]苯甲醯胺;- 化合物208:N-(2-二甲胺基乙基)-N-乙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲醯胺;- 化合物211:N-(3-胺甲醯基苯基)-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲醯胺;- 化合物213:N,N-二甲基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲醯胺;- 化合物215:N-[2-(二甲胺基)乙基]-N-甲基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲醯胺;- 化合物216:7-[2-(1,4-氧氮雜環庚烷-4-基羰基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物217:N-甲基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲醯胺;- 化合物220:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲醯胺;- 化合物221:N-[2-(二甲胺基)乙基]-N-乙基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲醯胺;- 化合物222:7-[2-((2S,6R)-2,6-二甲基嗎啉-4-羰基)吡啶-
3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物226:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}乙醯胺;- 化合物227:N-{3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}環丙烷甲醯胺;- 化合物228:2-甲氧基-N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}-2-苯基乙醯胺;- 化合物229:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}-2-苯基丙醯胺;- 化合物238:3-氯-N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}苯磺醯胺;- 化合物239:N-(4-甲氧基-3-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基胺磺醯基}苯甲基)乙醯胺;- 化合物241:N-甲基-N-{3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺;- 化合物242:N-甲基-N-{3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}環
丙烷甲醯胺;- 化合物243:7-[2-(甲胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物244:7-[2-(1,4-二氮雜環庚烷-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物245:7-(3,4,5,6-四氫-2H-[1,2']聯吡啶-3'-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物246:7-[2-(3-羥基吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物247:7-[2-(3,4-二羥基吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物248:7-[2-(二甲胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物249:7-{2-[乙基(甲基)胺基]吡啶-3-基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物250:7-{2-[(2-羥乙基)(甲基)胺基]吡啶-3-基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物251:7-[2-(吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物252:7-[2-(1,4-氧氮雜環庚烷-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物253:7-[2-(3-側氧基哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物254:7-[2-(氮雜環丁烷-1-基)吡啶-3-基]-5-(2,2,2-
三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物255:7-{2-[(2-甲氧基乙基)甲胺基]吡啶-3-基}-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物256:7-[2-(4-乙醯基哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物257:7-[2-(二乙胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物258:7-[2-(環丁胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物259:7-[2-(2,6-二甲基嗎啉-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物260:7-[2-(4-環丙基哌嗪-1-基)吡啶-4-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物261:7-(2-環己胺基吡啶-3-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物262:7-[2-(異丙基甲基胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物263:7-(2-環戊胺基吡啶-3-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物264:7-(6-吡咯啶-1-基吡啶-2-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物265:7-[6-(2,6-二甲基嗎啉-4-基)吡啶-2-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物266:7-{2-[環己基(甲基)胺基]吡啶-3-基}-5-
(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物267:7-[2-(4-環丙基哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物268:7-[3-(4-環丙基哌嗪-1-基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物269:7-[2-(4-乙醯基-1,4-二氮雜環庚烷-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物270:7-[2-(4-甲基-1,4-二氮雜環庚烷-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物271:7-[2-(4-環丙基-[1,4]二氮雜環庚烷-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物272:7-[2-(3-氟吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物273:7-[2-(4-氟哌啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物274:7-(2-羥基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物275:7-(1-氧基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物276:7-(1-氧基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;
呈鹼或酸加成鹽之形式,且亦可呈水合物形式。
在作為本發明之標的之式(I)化合物中,尤其可提及以下化合物:- 化合物1:7-(吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物2:7-(2-胺基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物6:7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物19:7-[4-(4-甲基哌嗪-1-基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物67:5-乙基-7-[6-(哌嗪-1-基)吡啶-3-基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物68:7-[2-(4-甲基哌嗪-1-基)吡啶-4-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物69:5-乙基-7-[2-(4-甲基哌嗪-1-基)吡啶-4-基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物72:7-(2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物74:7-(2-氯-6-甲基吡啶-3-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物75:7-(2-氯-6-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物76:7-(2-氯吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二
氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物77:7-(2-氟吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物79:7-(6-氯-2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物83:7-[6-(嗎啉-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物88:7-(6-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物111:7-(2-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物168:7-(2,6-二甲基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物169:7-(3-氯吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物171:7-(6-甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物172:7-[2-(嗎啉-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物176:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲腈;- 化合物186:7-(2-甲基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物196:8-氯-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-
二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物199:8-氯-7-(2-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物209:7-{2-[(4-甲基-1,4-二氮雜環庚烷-1-基)羰基]苯基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物232:N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-2H-吡唑并[4,3-c]喹啉-7-基]苯基}甲烷磺醯胺;- 化合物248:7-[2-(二甲胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物251:7-[2-(吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物257:7-[2-(二乙胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物273:7-[2-(4-氟哌啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;呈鹼或酸加成鹽之形式,且亦可呈水合物形式。
在作為本發明之標的之式(I)化合物中,尤其可提及以下化合物:- 化合物1:7-(吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物6:7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物67:5-乙基-7-[6-(哌嗪-1-基)吡啶-3-基]-1,5-二
氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物69:5-乙基-7-[2-(4-甲基哌嗪-1-基)吡啶-4-基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物72:7-(2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物74:7-(2-氯-6-甲基吡啶-3-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物75:7-(2-氯-6-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物76:7-(2-氯吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物77:7-(2-氟吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物79:7-(6-氯-2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物88:7-(6-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物111:7-(2-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物168:7-(2,6-二甲基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物169:7-(3-氯吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物171:7-(6-甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-
1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物176:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲腈;- 化合物186:7-(2-甲基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物199:8-氯-7-(2-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物248:7-[2-(二甲胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物251:7-[2-(吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物257:7-[2-(二乙胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;- 化合物273:7-[2-(4-氟哌啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;呈鹼或酸加成鹽之形式,且亦可呈水合物形式。
在下文中,術語「保護基PG」意謂以下基團:其首先可在合成期間保護反應性官能基,諸如側接羥基或胺,且其次在合成結束時再生完整的反應性官能基。保護基及保護方法與脫除保護基方法之實例係於「Protective Groups in Organic Synthesis」,Greene等人,第3版(John Wiley & Sons,Inc.,New York)中給出。
在下文中,術語「脫離基LG」意謂可藉由失去電子對斷開異質鍵而輕易自分子裂解之基團。此基團因此可輕易
地在例如取代反應期間由另一基團置換。此等脫離基為例如鹵素或活化羥基,諸如甲磺醯基、甲苯磺醯基、三氟甲磺酸酯、乙醯基等。脫離基之實例及其製備之參考文獻係在「Advanced Organic Chemistry」,J.March,第3版,Wiley Interscience,第310-316頁中給出。
根據本發明,通式(I)化合物可根據以下方法來製備。
除非另有提及,否則R1、R2及R3如先前所定義。
除非另有提及,否則基團Hal表示溴原子、碘原子或氯原子,更特定言之表示溴原子或碘原子。
流程1說明式(VI)之關鍵中間物的合成。式(II)之4-羥基喹啉-2(1H)-酮衍生物[根據Bioorganic & Medicinal Chemistry,2005,13(4),1069-1081中所述之方法或其修改版後獲得]與N,N-二甲基甲醯胺二甲基縮醛(DMFDMA)之反應得到式(III)之烯胺[根據Tetrahedron,2004,60(39),8633-
8644中所述之方法的修改版]。在室溫下在諸如DMF之惰性溶劑中以POCl3處理化合物(III),在水性處理後得到式(IV)之衍生物4-氯-2-側氧基-1,2-二氫喹啉-3-甲醛。術語「室溫」意謂介於5℃與25℃之間的溫度。在諸如DMF、THF或乙醇之溶劑中,在室溫與100℃之間的溫度下操作且較佳藉由加熱至80℃使肼與式(IV)之氯-醛縮合產生式(V)之1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮。可用在諸如SEM或THP之鹼性介質中穩定之保護基選擇性保護吡唑,得到式(VI)之中間物。
如流程2中所示,式(I)化合物(其中基團R2為-O-吡啶或-NH-吡啶或先前所定義之-A-X,且R3表示-CO2H之情況除外)可根據以下途徑獲得:-途徑A:式(VI)之1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮可在鹼(諸如氫化鈉、第三丁醇鉀或碳酸鈉、碳酸鉀或碳酸銫)存在下,在惰性溶劑(諸如DMF或THF)中,在室溫下或
藉由加熱至80℃,用親電子劑R1-E進行烷基化,其中E為良好脫離基,諸如鹵素或三氟甲磺酸酯。以式(VII)之N-烷基化合物為主且視所用親電子劑及鹼而定,其O-烷基異構體係以至多30%之量獲得。
式(VII)之鹵化衍生物可參與如下反應:- 在於溶劑(諸如DMF)中之膦配位體及/或弱鹼存在或不存在下,藉由加熱至介於80℃與150℃之間,用鈀(例如PdCl2(dppf))或用酸或酸酯或用錫衍生物催化之有機金屬偶合反應,得到R2為基團-A-X-之式(VIII)化合物;- 或在配位體及/或弱鹼存在或不存在下,用銅催化之與羥基吡啶或胺基吡啶衍生物之偶合反應,得到R2為基團-O-吡啶或-NH-吡啶之式(VIII)化合物。
最終,在式(VIII)化合物之吡唑在根據保護基PG之適合條件下脫除保護基後獲得式(I)化合物。舉例而言,當式(VIII)化合物中之PG表示SEM或THP時,在酸性介質中處理,例如用TFA或無水稀鹽酸處理可能獲得式(I)化合物。- 途徑B:式(VI)之鹵化衍生物可參與分別與酸或酸酯或錫衍生物或與羥基吡啶或胺基吡啶衍生物(其中R2為基團-A-X或-O-吡啶或-NH-吡啶)進行的有機金屬偶合反應,得到式(IX)化合物,其可接著如上文途徑A中所述在鹼存在下用親電子劑R1-E進行烷基化。
流程3(途徑C):製備式(XIV)之中間物1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及製造式(I)化合物
藉由用親電子劑R1-E將式(VI)或式(IX)之中間物N-烷基化來引入取代基R1(參見上述途徑A及B)之替代方案係在於經由取代式(X)化合物(以下情況除外:其中R3表示氟原子)之氟原子,經由胺R1-NH2,如J.Med.Chem.,2008,51(6),1925-1944中所述,或藉由用式(XI)之苯胺之醛R1-CHO進行還原性胺化(如流程3中所示)來引入基團R1。根據對於製備式(II)化合物所述之方法將所得式(XII)化合物轉化為式(XIII)化合物。將式(II)化合物轉化為式(V)化合物之方法係用於將式(XIII)化合物轉化為式(XIV)化合物。自式(XIV)化合物經由以下程序直接獲得式(I)化合物:
- 在於溶劑(諸如DMF)中之膦配位體及/或弱鹼存在下,藉由加熱至介於80℃與150℃之間,用鈀,例如用PdCl2(dppf),用酸或酸酯或用錫衍生物催化之有機金屬偶合反應。由此獲得R2為基團-A-X之式(I)化合物。
- 或在配位體及/或弱鹼存在下,用銅催化之與羥基吡啶
或胺基吡啶衍生物之偶合反應,得到R2為基團-O-吡啶或-NH-吡啶之式(I)化合物。
流程4說明合成式(VII)化合物之替代性途徑,其中間物可如流程2中關於製備式(I)化合物所述來使用。使式(XV)之苯胺與包含在諸如SEM或THP之鹼性介質中穩定之保護基的式(XVI)之酸氯化物在諸如tBuOK或NaH之鹼存在下在諸如THF或DMF之溶劑中在室溫下反應,得到式(XVII)之醯胺。式(XVII)之醯胺可在鹼(諸如氫化鈉、第三丁醇鉀或碳酸鈉、碳酸鉀或碳酸銫)存在下,在諸如DMF或THF之惰性溶劑中,在室溫下或藉由加熱至80℃用親電子基團R1-E進行烷基化,其中E為良好脫離基,諸如鹵素或三氟甲磺酸酯。接著使相對於其O-烷基異構體主要獲得之式(XVIII)之N-烷基化合物參與以下反應:在諸如三乙胺或乙酸鉀之弱鹼存在下,在諸如DMF之溶劑中,同時加熱至介於60℃與120℃之間,以鈀,例如以Pd(PPh3)4催化之分子內赫克反應,得到經保護之式(VII)之1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮。
根據流程2、3及4中所述之方法獲得的式(VII)或式(XIV)之鹵化衍生物可經由與二硼烷衍生物(例如四甲基乙二醇二硼烷)之鈀催化偶合反應分別轉化為式(XIX)或式(XX)之酸或酸酯。R表示氫原子或兩個基團R為鍵接在一起且視情況經一或多個(C1-C4)烷基取代之碳原子的式(XIX)或式(XX)之酸或酸酯可參與與具有脫離基E(諸如鹵素,例如氯、溴或碘;或三氟甲磺酸酯基)之芳族化合物R2-E進行的鈀催化之鈴木偶合反應(Suzuki coupling reaction),分別得到式(VIII)化合物,其允許如先前所述製備式(I)化合物,或直接得到式(I)化合物。
如流程6中所示,將鹵素原子區位選擇性引入式(V)或(VI)或(VII)或(VIII)或(IX)或(XIV)或(I)(當R3為氫時)之
1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮化合物之位置8中可如下進行:在催化劑(諸如鈀,例如Pd(OAc)2)存在或不存在下,在酸(諸如無水乙酸)存在或不存在下,同時自60℃加熱至120℃,用諸如NBS或NCS之試劑進行芳族親電取代反應。
當R3為氯或溴原子時,式(VIII)或(IX)或(I)之鹵化衍生物可參與與四甲基錫之鈀催化偶合反應,得到R3為甲基之式(VIII)或(IX)或(I)之化合物,或者可參與與氰化鋅之鈀催化偶合反應,得到R3為腈基之式(VIII)或(IX)或(I)之化合物。
當X及/或R3含有或表示氰基時,根據熟習此項技術者熟知之方法(途徑H),其可水解為基團-COORa,其中Ra為H或一級醯胺。
當X含有或表示基團-COORa(其中Ra不為H)時,其可藉由皂化轉化為基團-COORa(其中Ra為H)(途徑I)。
當X及/或R3含有或表示基團-COORa(其中Ra為H)時,其可在活化後與胺或碳酸氫銨或雜環或包含-NH官能基之雜
芳基偶合,得到基團-CONRaRb(對於R3,Ra=Rb=H)及/或基團-CONRaRb、-C(O)-NRa-(CH2)n-O-Rb、-C(O)-NRa-芳基-C(O)-NRaRb、-C(O)-NRa-(CH2)n-NRaRb、-C(O)-NRa-(CH2)n-雜芳基、-CO-雜環或-CO-雜芳基(對於X)(途徑J)。
當X含有或表示基團-NRaRb(其中Rb為H)時,其可在弱鹼存在下與活化羧酸衍生物偶合,得到基團-NRaC(O)-(C1-C6)烷基、-NRa-C(O)-(CH2)n-NRaRb、-NRa-C(O)-芳基、-NRa-C(O)-(C1-C6)烷基-芳基或-NRa-C(O)-(CH2)n-O-Rb(途徑K)。
當X含有或表示基團-NRaRb(其中Rb為H)時,其可在弱鹼存在下與磺醯氯反應,得到基團-NRa-SO2-(CH2)n-芳基、-NRa-SO2-(CH2)n-NRaRb、-NRa-SO2-Rb、-NRa-SO2-芳基-O-芳基或-NRa-SO2-芳基-(CH2)n-NRa-C(O)-Rb(途徑L)。
當X含有或表示基團-NRaC(O)-(C1-C6)烷基、-NRa-C(O)-(CH2)n-NRaRb、-NRa-C(O)-芳基、-NRa-C(O)-(C1-C6)烷基-芳基、-NRa-C(O)-(CH2)n-O-Rb、-NRa-SO2-(CH2)n-芳基、-NRa-SO2-(CH2)n-NRaRb、-NRa-SO2-Rb、-NRa-SO2-芳基-O-芳基或-NRa-SO2-芳基-(CH2)n-NRb-C(O)-Rb(其中Ra為H)時,其可在鹼存在下與式(C1-C6)烷基-LG(LG為脫離基)之親電子劑反應,得到基團-NRaC(O)-(C1-C6)烷基、-NRa-C(O)-(CH2)n-NRaRb、-NRa-C(O)-芳基、-NRa-C(O)-(C1-C6)烷基-芳基、-NRa-C(O)-(CH2)n-O-Rb、-NRa-SO2-(CH2)n-芳基、-NRa-SO2-(CH2)n-
NRaRb、-NRa-SO2-Rb、-NRa-SO2-芳基-O-芳基或-NRa-SO2-芳基-(CH2)n-NRb-C(O)-Rb(其中Ra表示-(C1-C6)烷基)(途徑M)。
當X為鹵素時,其可在鈀(0)或銅(I)催化劑存在或不存在下,在鹼存在下或不存在下經胺取代,得到X表示以下基團之化合物:-NRaRb、-NRa-(CH2)n-O-Rb、-NRa-雜環或-NRa-芳基(途徑N)。
當X含有一級胺或二級胺官能基時,其可參與在氫化物型還原劑存在下與醛之還原性胺化反應,得到相應胺(途徑O)。
當X含有羥基官能基時,其可參與氟化反應(途徑P)。
當X表示基團-(C1-C6)烷氧基時,其可參與水解反應,得到基團-O-Ra(其中Ra為H)(途徑Q)。
當A表示雜芳基(例如吡啶)時,其可被氧化,得到雜芳基之N-氧化物類似物(途徑R)。
在流程1-7中,起始化合物及試劑當其製備方法未經描述時為市售或描述於文獻中,否則可根據文獻中所述或熟習此項技術者已知之方法製備。
根據其另一態樣,本發明之標的亦為式(II)至式(XX)之化合物。此等化合物適用作合成式(I)化合物之中間物,且更特定言之中間物(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)、(XIII)、(XIV)、(XVII)、(XVIII)、(XIX)及(XX)。
以下實例描述本發明之某些化合物的製備。實例不具有
限制性,而僅用以說明本發明。下表說明許多本發明化合物之化學結構及物理性質。
使用以下縮寫及經驗公式:
在下文中:- 如下所述之質磁共振光譜(1H NMR)係在400 MHz或500 MHz下在DMSO-d6中,使用峰DMSO-d6作為參考來記錄。化學位移δ以百萬分之份數(ppm)表示。如下表示觀察到之信號:s=單峰;d=雙重峰;t=三重峰;m=多重峰或br.s.=寬單峰;
- 如下所述之LCMS特徵依次指示下文使用及詳述之高效液相層析分析法(A至J)、由質譜分析識別之MH+峰及化合物之滯留時間(以分鐘表示)。
*
方法A
儀器:1100(Agilent)或Alliance(Waters)型HPLC管線;MSD(Agilent)或ZQ(Waters)型簡單四極質譜計
管柱:Symmetry C18 3.5 μm(2.1×50 mm)Waters
溶劑A:H2O+0.005% TFA;溶劑B:CH3CN+0.005% TFA
流動速率:0.4 mL/min
梯度A/B:100/0(t0分鐘)至0/100(t10分鐘)至0/100(t15分鐘)
偵測:UV 220 nm
電離:電噴霧正模式ESI+
* 方法B:梯度A/B具有變化之方法A
梯度A/B:100/0(t0分鐘)至0/100(t30分鐘)至0/100(t35分鐘)
*
方法C
儀器:1100(Agilent)或Alliance(Waters)型HPLC管線;MSD(Agilent)或ZQ(Waters)型簡單四極質譜計
管柱:X Terra C18 3.5 μm(2.1×50 mm)Waters
溶劑A:H2O+NH4OAc 10 mM pH 7;溶劑B:CH3CN
流動速率:0.4 mL/min
梯度A/B:100/0(t0分鐘)至10/90(t10分鐘)至10/90(t15分鐘)
偵測:UV 220 nm
電離:電噴霧正模式ESI+
*
方法D
儀器:UPLC Acquity管線(Waters);SQD質譜儀(Waters)
管柱:BEH-C18(2.1×50 mm)1.7 μm(Waters);管柱溫度:55℃
溶劑A:H2O+0.02% HCOOH;溶劑B:CH3CN+0.02% HCOOH
流動速率:1 mL/min
梯度A/B:98/2(t0分鐘)至2/98(t4分鐘)至2/98(t4.5分鐘)
偵測:UV 220 nm
電離:電噴霧正模式ESI+
*
方法E
儀器:1100(Agilent)或Alliance(Waters)型HPLC管線;MSD(Agilent)或ZQ(Waters)型簡單四極質譜計
管柱:Luna C18(2)-HST Phenomenex(30×2 mm)2.5 μm;管柱溫度:50℃
溶劑A:H2O+0.05% TFA;溶劑B:CH3CN+0.035% TFA
流動速率:1 mL/min
梯度A/B:100/0(t0分鐘)至0/100(t2.5分鐘)至0/100(t3.5分鐘)
偵測:UV 220 nm
電離:電噴霧正模式ESI+
*
方法F
儀器:1100(Agilent)或Alliance(Waters)型HPLC管線;MSD(Agilent)或ZQ(Waters)型簡單四極質譜計
管柱:Symmetry C18(50×2.1 mm)3.5 μm(Waters);管柱
溫度:40℃
溶劑A:H2O+0.05% TFA;溶劑B:CH3CN+0.035% TFA
流動速率:0.5 mL/min
梯度A/B:100/0(t0分鐘)至0/100(t7分鐘)
偵測:UV 220 nm
電離:電噴霧正模式ESI+
*
方法G
儀器:UPLC Acquity管線(Waters)、SQD質譜儀(Waters)
管柱:BEH C18(50×2.1 mm)1.7 μm(Waters);管柱溫度:55℃
溶劑A:H2O+0.05% TFA;溶劑B:CH3CN+0.035% TFA
流動速率:0.8 mL/min
梯度A/B:98/2(t0分鐘)至0/100(t2.4分鐘)至0/100(t3分鐘)
偵測:UV 220 nm
電離:電噴霧正模式ESI+
*
方法H
儀器:Waters UPLC
管柱:BEH C18(2.1×50 mm)1.7 μm
溶劑A:H2O+0.05% HCO2H;溶劑B:CH3CN+0.035% HCO2H
流動速率:0.9 mL/min
梯度A/B:95/5(t0分鐘)至5/95(t1.1分鐘)至5/95(t1.7分鐘)
偵測:220 nM
電離:電噴霧正模式ESI+
* 方法H':溶離劑有變化之方法H
溶劑A:H2O+0.1% HCO2H;溶劑B:CH3CN+0.08% HCO2H
梯度A/B:95/5(t0分鐘)至5/95(t1.1分鐘)至5/95(t1.7分鐘)
*
方法I
儀器:Waters UPLC
管柱:Waters XBridge C18(4.6×50 mm)2.5 μm
溶劑A:H2O+0.1% HCO2H;溶劑B:CH3CN+0.08% HCO2H
梯度A/B:97/3(t0分鐘)至40/60(t3.5分鐘)至2/98(t4分鐘)至2/98(t5分鐘)
偵測:220 nM
電離:電噴霧正模式ESI+
* 方法I':溶離劑有變化之方法H
溶劑A:H2O+0.05% TFA;溶劑B:CH3CN+0.05% TFA
梯度A/B:95/5(t0分鐘)至95/5(t0.3分鐘)至5/95(t3.5分鐘)至5/95(t4分鐘)
*
方法J
儀器:Waters UPLC
管柱:Jsphere(33×2.1 mm)4 μm
溶劑A:H2O+0.05% TFA;溶劑B:CH3CN+0.05% TFA
梯度A/B:98/2(t0分鐘)至98/2(t1分鐘)至5/95(t5分鐘)至5/95(t6.25分鐘)
偵測:220 nM
電離:電噴霧正模式ESI+
在三頸燒瓶中,將N,N-二甲基甲醯胺二甲基縮醛(103 mL,0.77 mol)添加至7-溴-4-羥基喹啉-2(1H)-酮(12.3 g,51.2 mmol)於250 mL甲苯中之懸浮液中。在80℃下攪拌反應混合物24小時,接著冷卻至室溫且過濾。以甲苯洗滌所得固體且在真空下乾燥,得到13.5 g呈米色固體形式之(3E,Z)-7-溴-3-[(二甲胺基)亞甲基]喹啉-2,4(1H,3H)-二酮(產率:89%)。
LCMS(方法C):MH+=295.0,RT=5.86分鐘
在0℃下將磷醯氯(1.9 mL,20.3 mmol)逐滴添加至(3E,Z)-7-溴-3-[(二甲胺基)亞甲基]喹啉-2,4(1H,3H)-二酮(5 g,16.9 mmol)於50 mL DMF中之懸浮液中。在室溫下攪拌
反應混合物4小時,接著傾入冰水中。濾出所形成之沈澱物且在真空下乾燥,得到4.6 g呈黃色固體形式之7-溴-4-氯-2-側氧基-1,2-二氫喹啉-3-甲醛(產率:81%)。
LCMS(方法A):MH+=288.0,RT=6.38分鐘
在80℃之7-溴-4-氯-2-側氧基-1,2-二氫喹啉-3-甲醛(8.0 g,27.9 mmol)之150 mL DMF溶液中添加80℃之水合肼(2 mL,33.5 mmol)。在80℃下攪拌反應介質24小時,接著冷卻至室溫且過濾。以二異丙醚洗滌所得固體且乾燥,得到5.3 g呈淺黃色粉末形式之7-溴-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(產率:72%)。
LCMS(方法A):MH+=264.1,RT=5.27分鐘
在室溫下向7-溴-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(17.95 g,67.97 mmol)之1 L DMF溶液中添加3,4-二氫-2H-哌喃(18.6 mL,204 mmol)及對甲苯磺酸(1.29 g,6.80 mmol)。在室溫下攪拌反應介質72小時,接著傾入飽和NaHCO3中且以EtOAc萃取。以飽和NaCl溶液洗滌有機相且經Na2SO4乾燥,過濾且濃縮至乾燥,得到褐色固體。將固體溶解於二異丙醚中且在濾出後獲得18.8 g橙色粉末(產率:71%)。
LCMS(方法A):MH+=350.1,RT=5.28分鐘
在70℃下向7-溴-1-(四氫-2H-哌喃-2-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-溴-2-(四氫-2H-哌喃-2-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(17.3 g,49.7 mmol)於170 mL無水MeTHF中之懸浮液中逐份添加t-BuOK(11.2 g,99.4 mmol)。在70℃下攪拌15分鐘後,逐滴添加三氟甲磺酸2,2,2-三氟乙酯(14.4 mL,99.4 mmol)。在添加180 mL無水MeTHF後在70℃下攪拌反應介質2小時。2小時之後,在70℃下添加另一份t-BuOK(11.14 g,49.7 mmol)及三氟甲磺酸2,2,2-三氟乙酯(7.2 mL,49.7 mmol)。在70℃下攪拌反應介質2小時30分鐘。濃縮反應介質且將殘餘物溶解於DCM中。依次以水及飽和NaCl溶液洗滌溶液,經Na2SO4乾燥,過濾且濃縮至乾燥,得到褐色固體,將其溶解於二異丙醚/丙酮混合物(2/1)中且攪拌16小時,得到12.1 g白色粉末(產率:57%)。
LCMS(方法E):MH+=347.9,RT=5.27分鐘
在氮氣下向微波反應器中所含之7-溴-1-(四氫-2H-哌喃-
2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-溴-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(1.0 g,2.32 mmol)於20 mL無水DMF中之懸浮液中添加2-吡啶基三-正丁基錫烷(1.21 mL,3.02 mmol)及催化劑Pd(t-Bu3P)2(356 mg,0.7 mmol)。密封反應器且在120℃下在微波輻射下攪拌反應介質10分鐘。將混合物濃縮至乾燥且溶解於EtOAc中。以飽和NaHCO3溶液、飽和NaCl水溶液洗滌溶液,經Na2SO4乾燥,過濾且濃縮至乾燥,得到米色固體。在藉由矽膠急驟層析(DCM/EtOH:95/5至85/15)純化後,獲得0.38 g白色粉末(產率:38%)。
LCMS(方法A):MH+=429.2,RT=8.14分鐘
向7-(吡啶-2-基)-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-(吡啶-2-基)-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(60 mg,0.14 mmol)於1 mL DCM中之溶液中添加4 M無水氯化氫之二噁烷(350 μL,1.40 mmol)溶液。在室溫下攪拌1小時後,過濾懸浮液且在真空下乾燥固體,得到59 mg呈米色粉末形式之7-(吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(鹽酸鹽,0.88 H2O;定量產率)。
LCMS(方法A):MH+=345.0,RT=6.63分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 8.79(dd,1H)8.47(br.s.,1H)8.39(s,1H)8.35(d,1H)8.26(d,1H)8.14(dd,1H)8.10(t,1H)7.51-7.58(m,1H)5.47(d,1H)5.42(d,1H)
在氬氣下將7-溴-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-溴-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(9.7 g,19.4 mmol)、碳酸鉀(5.3 g,38.4 mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶-2-胺(4.82 g,21.9 mmol)、14 mL無水DMF、1.8 mL脫氣水及催化劑PdCl2(dppf)(0.79 g,0.96 mmol)依次引入微波反應器中。密封反應器且在130℃下在微波輻射下攪拌混合物10分鐘。以EtOAc稀釋混合物,傾入飽和NaHCO3水溶液中且攪拌30分鐘。濾出沈澱物且以水洗滌,接著溶解於異丙醇中。在濾出及乾燥之後,獲得7.58 g灰色粉末(產率:88%)。
LCMS(方法D):MH+=444.2,RT=0.87分鐘
根據步驟1.7.中所述程序,藉由以無水HCl之二噁烷溶
液(4 M)處理7-(3-胺基吡啶-4-基)-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮,獲得呈米色粉末形式之產物(鹽酸鹽,2 H2O;產率89%)。
LCMS(方法A):MH+=360.1,RT=4.83分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 14.22(br.s.,1H)8.20-8.60(m,2H)8.11(dd,1H)7.95(dd,1H)7.87(s,1H)7.80(br.s.,2H)7.50(d,1H)7.06(dd,1H)5.35(d,1H)5.31(d,1H)
向7-溴-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮[步驟1.3.中所述](1.49 g,5.64 mmol)於30 mL無水DMF中之懸浮液中逐滴添加碳酸銫(2.0 g,6.21 mmol)及[2-(氯甲氧基)乙基](三甲基)矽烷(10 mL,56.4 mmol)。在室溫下在氮氣下攪拌反應混合物16小時,接著傾入水中且以THF/EtOAc混合物(50/50)萃取。以飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥,過濾且濃縮至乾燥。藉由矽膠急驟層析(DCM/MeOH:100/0至98/2)純化所得殘餘物,得到1.45 g黃色固體(產率:61%)。
LCMS(方法A):MH+=396.1,RT=8.77分鐘
向7-溴-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮、7-溴-2-{[2-(三甲基矽烷基)乙氧基]甲基}-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(10.0 g,25.4 mmol)及碳酸銫(24.8 g,76.1 mmol)於130 mL MeTHF中之加熱至60℃之懸浮液中逐滴添加三氟甲磺酸2,2,2-三氟乙酯(5.5 mL,38.0 mmol)。在60℃下攪拌混合物3小時。冷卻反應介質且濃縮至乾燥。將所得殘餘物溶解於水中,過濾且乾燥。在藉由急驟層析(環己烯/EtOAc:90/10至50/50)純化後,獲得6.67 g白色粉末(產率:55%)。
LCMS(方法A):MH+=476.3,RT=10.64分鐘
在氬氣下將7-溴-1-[2-(三甲基矽烷基)乙氧基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-溴-2-[2-(三甲基矽烷基)乙氧基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(0.2 g,0.42 mmol)、3-羥基吡啶(0.12 g,1.26 mmol)、催化劑CuI(80 mg,0.42 mmol)、配位體1,1,1-參(羥甲基)乙烷(50 mg,0.42 mmol)、碳酸銫(0.55 g,1.68 mmol)、0.4 mL無水
DMF及1.5 mL二噁烷依次引入反應器中。密封反應器且在110℃下劇烈攪拌混合物17小時。冷卻後,經由矽藻土濾出混合物且以EtOAc洗滌。以水及飽和NaCl水溶液洗滌溶液,經Na2SO4乾燥且濃縮至乾燥,得到195 mg褐色膠狀物,其用於下一步驟。
LCMS(方法E):MH+=491.4,RT=2.36分鐘
在室溫下攪拌7-(吡啶-3-基氧基)-5-(2,2,2-三氟乙基)-1-{[2-(三甲基矽烷基)乙氧基]-甲基}-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-(吡啶-3-基氧基)-5-(2,2,2-三氟乙基)-2-{[2-(三甲基矽烷基)乙氧基]甲基}-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(0.19 g,0.39 mmol)於10 mL溶解於二噁烷中之無水氯化氫(4 M)中之懸浮液持續18小時。過濾懸浮液且以DCM洗滌固體,接著藉由C18逆相急驟層析(H2O/MeCN:100/0至0/100)純化。將所得膠狀物溶解於莫耳(molar)鹽酸溶液中,接著濃縮至乾燥,得到78 mg白色粉末(1.2鹽酸鹽,1.15 H2O;產率:58%)。
LCMS(方法A):MH+=361.2,RT=6.65分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 8.66(d,1H)8.56(d,1H)8.41(s,1H)8.30(d,1H)7.84(d,1H)7.73(dd,1H)7.62(s,1H)7.19(dd,1H)5.27(d,1H)5.23(d,1H)
在氮氣下向置於微波反應器中之7-溴-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-溴-2-{[2-(三甲基矽烷基)乙氧基]甲基}-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮[步驟3.1.中所述](18.2 g,46.2 mmol)於150 mL DMF中之溶液中依次添加4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶(11.4 g,55.4 mmol)、2 M K3PO4水溶液(47 mL,92.4 mmol)及催化劑PdCl2(dppf)(1.88 g,2.31 mmol)。密封反應器且在150℃下在微波輻射下攪拌反應混合物20分鐘。在濃縮反應混合物後,藉由矽膠急驟層析(DCM/MeOH:0/100至95/5)純化,得到12.4 g呈白色固體形式之7-(吡啶-4-基)-1-[2-(三甲基矽烷基)乙氧基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-(吡啶-4-基)-2-[2-(三甲基矽烷基)乙氧基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(產率:54%)。
LCMS(方法A)MH+=393.2,RT=6.60及6.74分鐘(以SEM基團保護之吡唑的異構體)
向7-(吡啶-4-基)-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-(吡啶-4-基)-2-{[2-(三甲基矽烷基)乙氧基]甲基}-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(0.40 g,1.0 mmol)於8 mL DMF中之溶液中添加碳酸銫(0.66 g,2.04 mmol)及三氟甲磺酸2,2-二氟乙酯(0.33 mL,2.55 mmol)。在室溫下攪拌混合物24小時,接著傾入水中且以EtOAc萃取。以飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥,過濾且濃縮至乾燥。在二氧化矽上藉由急驟層析(DCM/EtOH:100/0至95/5)純化後,獲得108 mg橙色固體(產率:23%)。
LCMS(方法A)MH+=457.3,RT=6.94分鐘
在室溫下向5-(2,2-二氟乙基)-7-(吡啶-4-基)-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及5-(2,2-二氟乙基)-7-(吡啶-4-基)-2-{[2-(三甲基矽烷基)乙氧基]甲基}-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(100 mg,0.22 mmol)於2 mL DCM中之溶液中添加4 M無水氯化氫之二噁烷(1.10 mL,4.38 mmol)溶液。在室溫下攪拌24小時之後,過濾混合物。將所得固體溶解於異丙醇中,濾出且在真空下乾燥,得到74 mg白色粉末(鹽酸鹽,產率:94%)。
LCMS(方法A):MH+=327.0,RT=4.86分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 8.96-9.03(m,2H)
8.37-8.56(m,4H)8.19(s,1H)7.98(d,1H)6.43(tt,1H)5.04(td,2H)
在微波反應器中將逐份添加之異丙胺(134.9 g,2.28 mol)、10 mL第三丁醇及4-溴-2-氟苯甲酸(10 g,45.7 mmol)混合在一起。密封反應器且在150℃下在微波輻射下攪拌混合物45分鐘。冷卻無色溶液且傾入冰水中,接著添加冰乙酸。濾出所形成之白色沈澱物,以水洗滌且在真空下乾燥。獲得7.9 g白色固體(產率:67%)。
LCMS(方法A)MH+=257.1,RT=8.11分鐘
向4-溴-2-(丙-2-基胺基)苯甲酸(6.8 g,26.64 mmol)於260 mL DCM中之溶液中添加添加三乙胺(4 mL,31.6 mmol),接著逐滴添加丙二酸乙酯氯化物(4.0 mL,31.mmol)。在室溫下攪拌混合物2小時,接著傾入莫耳鹽酸溶液中且以EtOAc萃取。以水及飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥且濃縮至乾燥。獲得7.15 g淺黃色固體(產率:72%)。
LCMS(方法A):MH+=372.1,RT=7.42分鐘
在0℃下向4-溴-2-[(3-乙氧基-3-側氧基丙醯基)(丙-2-基)胺基]苯甲酸(6.2 g,16.7 mmol)於170 mL DCE中之溶液中添加三乙胺(3.5 mL,25.1 mmol),接著添加亞硫醯氯(1.45 mL,20.6 mmol)。在室溫下攪拌3小時後,以DCM稀釋反應介質且以HCl水溶液(1 M)洗滌。以飽和NaHCO3水溶液及飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥,且濃縮至乾燥。藉由急驟層析(甲苯/EtOAc:100/0至90/10)純化所得油狀物,得到2.23 g白色固體(產率:52%)。
LCMS(方法A)MH+=354.2,RT=9.58分鐘
將7-溴-2,4-二側氧基-1-(丙-2-基)-1,2,3,4-四氫喹啉-3-甲酸乙酯(1.5 g,4.23 mmol)於氫氧化鈉中之懸浮液(2 M溶液,32 mL,64 mmol)加熱至回流。反應介質變得均質且在3小時後再次觀察到懸浮液。添加6 mL NMP以均質化,接著回流所得混合物12小時。將冷卻至室溫之溶液傾入6 M鹽酸溶液中,得到白色沈澱物,將其濾出。在以水沖洗且在真空下乾燥沈澱物後,獲得1.1 g白色固體(產率:91%)。
LCMS(方法A)MH+=284.1 RT=6.99分鐘
如步驟1.1.中所述,向7-溴-4-羥基-1-(丙-2-基)喹啉-2(1H)-酮(1.2 g,4.25 mmol)於43 mL甲苯中之溶液中添加N,N-二甲基甲醯胺二甲基縮醛(8.8 mL,63.8 mmol)。在
80℃下加熱溶液8小時。將所得混合物濃縮至乾燥,得到淺黃色固體,將其溶解於二異丙醚中。濾出之後,獲得321 mg白色固體(產率:92%)。
LCMS(方法A)MH+=338.1,RT=8.39分鐘
如步驟1.2.中所述,在0℃下向(3E,Z)-7-溴-3-[(二甲胺基)亞甲基]-1-(丙-2-基)喹啉-2,4(1H,3H)-二酮(1.32 g,3.9 mmol)於10 mL DMF中之溶液中逐滴添加POCl3(0.44 mL,4.70 mmol)。在室溫下攪拌溶液3小時,接著傾入冰水中得到沈澱物。在濾出及在真空下乾燥沈澱物後,獲得1.2 g黃色固體(產率:93%)。
LCMS(方法A)MH+=327.1,RT=7.29分鐘
如步驟1.3.中所述,在0℃下向7-溴-4-氯-2-側氧基-1-(丙-2-基)-1,2-二氫喹啉-3-甲醛(1.0 g,3.08 mmol)於30 mL DMF中之溶液中添加水合肼(0.19 mL,3.70 mmol)。在室溫下攪拌8小時之後,將反應混合物傾入水中。濾出所形成之橙色沈澱物且以水洗滌,接著在真空下乾燥,得到859 mg橙色固體(產率:73%)。
LCMS(方法A)MH+=306.1,RT=6.88分鐘
向置於微波反應器中之7-溴-5-(丙-2-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(0.25 g,0.82 mmol)於8 mL DMF中之溶液中添加碳酸銫(0.8 g 2.5 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶(0.25 g 1.22 mmol)及催化劑PdCl2(dppf)(60 mg,0.08 mmol)。密封反應器且在150℃下在微波輻射下攪拌混合物20分鐘。以EtOAc/THF混合物(50/50)稀釋反應介質且依次以水及飽和NaCl水溶液洗滌。經Na2SO4乾燥有機相且濃縮至乾燥。藉由急驟層析(DCM/MeOH:100/0至90/10)純化後,獲得45 mg白色固體(產率:19%)。
LCMS(方法A):MH+=305.2,RT=4.98分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 8.92(d,2H)8.23-8.44(m,4H)8.11(s,1H)7.90(d,1H)5.48(br.s.,1H)1.64(d,6H)
向1H-吡唑-4-甲酸(50 g,446 mmol)於500 mL DMF中之懸浮液中添加對甲苯磺酸(8.48 g,44 mmol)及DHP(132 mL,1561 mmol)。反應介質變黃,接著在室溫下攪拌20小時後變黑。將反應混合物傾入飽和NaHCO3水溶液中且以EtOAc萃取。藉由添加6 M鹽酸溶液將水相酸化至pH 3。濾出所形成之沈澱物且以水洗滌,接著在真空下在50℃下乾燥,得到61.2 g白色粉末(產率:70%)。
LCMS(方法D):MH+=197.1,RT=0.60分鐘
在0℃下向1-(四氫-2H-哌喃-2-基)-1H-吡唑-4-甲酸(31.7 g,61 mmol)於650 mL DCM中之溶液中逐滴添加吡啶(77 mL,0.97 mol)及氟化氰(41 mL,0.48 mmol)。在室溫下攪拌反應介質4小時,傾入飽和NaHCO3水溶液中且以DCM萃取。依次以水及飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥,過濾且濃縮至乾燥,得到29.1 g褐色油狀物(產率:91%)。
LCMS(方法D):[M+NH4]+=216.6,RT=0.95分鐘
在氮氣下在室溫下將第三丁醇鉀(12.52 g,111.6 mmol)添加至5-氯-4-氟-2-碘苯胺(5.0 g,22.3 mmol)於250 mL無水THF中之溶液中。攪拌15分鐘後,逐滴添加1-(四氫-2H-哌喃-2-基)-1H-吡唑-4-甲酸氟化物(5.67 g,24.6 mmol)於30 mL無水THF中之溶液。在室溫下攪拌反應混合物4小時,接著傾入飽和NaHCO3水溶液中且以EtOAc萃取。以飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥且濃縮至乾燥。在藉由矽膠急驟層析(環己烯/EtOAc:95/5至80/20)純化後,獲得紅色固體,其藉由胺相(DCM)急驟層析純化,得到2.84 g白色固體(產率:31%)。
LCMS(方法E):MH+=404.0,RT=2.29分鐘
向N-(5-氯-4-氟-2-碘苯基)-1-(四氫-2H-哌喃-2-基)-1H-吡唑-4-甲醯胺(1.26 g,3.13 mmol)於55 mL無水MeTHF中加熱至65℃之溶液中添加第三丁醇鉀(421 mg,3.76 mmol)及三氟甲磺酸2,2,2-三氟乙酯(0.54 mL,3.76 mmol)。在65℃下攪拌反應混合物2小時,接著冷卻,傾入飽和NaHCO3水溶液中且以EtOAc萃取。以飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥且濃縮至乾燥。在藉由矽膠急驟層析(DCM/EtOAc:100/0至95/5)純化後,獲得2.32 g橙色固體(產率:73%)。
LCMS(方法G):MH+=404.0,RT=1.82分鐘
在氮氣下將催化劑Pd(PPh3)4(630 mg,0.55 mmol)及乙酸鉀(890 mg,9.0 mmol)添加至置於微波反應器中之N-(5-氯-4-氟-2-碘苯基)-1-(四氫-2H-哌喃-2-基)-N-(2,2,2-三氟乙基)-1H-吡唑-4-甲醯胺(2.2 g,4.5 mmol)於10 mL無水DMF中之溶液中。密封反應器且在90℃下在微波輻射下攪拌反應混合物15分鐘。將其他量之催化劑Pd(PPh3)4(630 mg,0.55 mmol)及乙酸鉀(890 mg,9.0 mmol)添加至反應介質中,在110℃下在微波輻射下攪拌15分鐘。冷卻混合物,傾入水中且以EtOAc萃取。以飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥且濃縮至乾燥。藉由矽膠急驟層析(依次為(DCM/EtOAc:100/0至95/5)及(環己烯/EA:90/10)及
DCM(100%))純化後,獲得260 mg白色固體(產率:57%)。
LCMS(方法G):MH+=403.9,RT=2.59分鐘
根據步驟1.6.中所述之方法,在氮氣下將2-吡啶基三-正丁基錫烷(4.40 mL,11.5 mmol)及催化劑Pd(tBu3P)2(199 mg,0.39 mmol)添加至置於微波反應器中之7-氯-8-氟-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(526 mg,1.30 mmol)於10 mL無水DMF中之溶液中。密封反應器且在130℃下在微波輻射下攪拌反應混合物20分鐘。將混合物傾入飽和NaHCO3水溶液中且以EtOAc萃取。以水、飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥且濃縮至乾燥。在藉由矽膠急驟層析(依次為環己烯/EtOAc:90/10至70/30及DCM/丙酮:98/2至90/10)純化後,獲得72 mg白色粉末(產率:12%)。
LCMS(方法E):MH+=447.0,RT=2.44分鐘
根據步驟1.7.中所述程序,藉由以HCl之二噁烷溶液(4 M)處理8-氟-7-(吡啶-2-基)-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮,獲得產物。其呈白色粉末形式(鹽酸鹽;產率75%)。
LCMS(方法D):MH+=363.1,RT=1.69分鐘
1H NMR(500 MHz,DMSO-d6):δ ppm 8.81-8.83(m,1H)8.52(br.s.,1H)8.21(d,1H)8.13(d,1H)8.03(td,1H)7.90-7.93(m,1H)7.52(ddd,1H)5.35(d,1H)5.32(d,1H)
向7-溴-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-溴-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮[步驟1.5.中所述](8.0 g,18.6 mmol)於200 mL DMF中之懸浮液中添加四甲基乙二醇二硼烷(18.9 g,74.4 mmol)。在氮氣下將混合物加熱至60℃,接著添加乙酸鉀(4.6 g,46.5 mmol)及催化劑PdCl2(dppf)(3.04 g,3.72 mmol)。在60℃下加熱溶液3小時,接著冷卻至室溫且傾入飽和NaHCO3水溶液中。在以EtOAc萃取後,以飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥且濃縮至乾燥。獲得黑色油狀物,向此添加二異丙醚,使得形成黑色固體。在過濾及濃縮濾液後,獲得黃色油狀物,將其溶解於石油醚(40-65℃)/二異丙醚混合物中,沈澱出淺黃色固體。在濾出及在真空下乾燥沈澱物後,獲得5.10 g淺黃色固體(第一
批)。
濃縮濾液。將飽和NaHCO3水溶液及10% THF添加至所得黃色油狀物中。在室溫下劇烈攪拌混合物持續12小時,接著以莫耳鹽酸溶液酸化,且以EtOAc萃取。以飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥且濃縮至乾燥,得到黃色固體,將其溶解於石油醚中。在濾出及在真空下乾燥後,獲得1.44 g白色固體(第二批)。
合併該兩批且溶解於二異丙醚中。在濾出及乾燥之後,獲得6.54 g白色粉末(產率:74%)。
LCMS(方法F):MH+=478.0,RT=2.80分鐘
在氮氣下在95℃下向1-(四氫-2H-哌喃-2-基)-7-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及2-(四氫-2H-哌喃-2-基)-7-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(100 mg,0.1 mmol)於3 mL DMF中之溶液中添加催化劑PdCl2(dppf)(17 mg,0.02 mmol)、碳酸銫(136 mg,0.42 mmol)、0.5 mL脫氣水及3-溴-2-氯吡啶(40 mg,0.21 mmol)。在氮氣下在95℃下攪拌反應混合物1.5小時,冷卻至室溫,濃縮且溶解於EtOAc中。依次以水及飽和NaCl水溶液洗滌溶液,經
Na2SO4乾燥,過濾且濃縮至乾燥,得到黑色蠟狀物。在藉由矽膠急驟層析(DCM/EtOH:100/0至95/5)純化後,獲得38 mg黃色固體(產率=79%)。
LCMS(方法G):MH+=463.3,RT=1.66分鐘
向7-(2-氯吡啶-3-基)-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-(2-氯吡啶-3-基)-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(1.6 g,3.46 mmol)於34 mL DCM中之溶液中添加4 M氯化氫之二噁烷(8.5 mL,34.6 mmol)溶液。在室溫下攪拌混合物3小時且濃縮至乾燥。藉由胺相急驟層析(DCM/EtOH:100/0至90/10)純化後,獲得189 mg白色固體(產率=15%)。
LCMS(方法A):MH+=379.2,RT=6.91分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 8.51(dd,1H)8.47(br.s.,1H)8.29(d,1H)7.95(dd,1H)7.90(s,1H)7.61(dd,1H)7.53(d,1H)5.36(d,1H)5.31(dd,1H)
向7-(吡啶-2-基)-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-(吡啶-2-基)-
2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮[步驟1.5.中所述](1.6 g,3.73 mmol)於32 mL乙酸中之懸浮液中添加N-氯丁二醯亞胺(2.49 g,18.67 mmol)。在80℃下攪拌反應混合物3小時,冷卻至室溫且濃縮至乾燥,得到黃色固體,將其溶解於DCM中。依次以飽和NaHCO3水溶液及飽和NaCl水溶液洗滌溶液,經Na2SO4乾燥,過濾且濃縮,得到黃色固體。將固體溶解於DCM中。在濾出及乾燥之後,獲得542 mg白色固體(產率:35%)。
LCMS(方法A):MH+=379.2,RT=6.93分鐘
向8-氯-7-(吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(532 mg,1.40 mmol)於DCM/MeOH混合物(50/50)中之溶液中添加4 M氯化氫之二噁烷(3.5 mL,14.1 mmol)溶液。在室溫下攪拌懸浮液,接著過濾且在真空下乾燥,得到420 mg白色粉末(鹽酸鹽,0.06 H2O;產率:72%)。
LCMS(方法A):MH+=379.2,RT=6.91分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 8.77-8.83(m,1H)8.52(br.s.,1H)8.40(s,1H)8.06(td,1H)7.96(s,1H)7.77(d,1H)7.54-7.59(m,1H)5.35(d,1H)5.30(d,1H)
在氮氣下向置於微波反應器中之7-(吡啶-2-基)-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-(吡啶-2-基)-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮[步驟1.5.中所述](100 mg,0.23 mmol)於2 mL乙腈中之溶液中添加N-溴丁二醯亞胺(50 mg,0.28 mmol)及催化劑Pd(OAc)2(2.6 mg,0.01 mmol)。密封反應器且在100℃下在微波輻射下在氮氣下攪拌反應混合物15分鐘。因為反應不完全,所以再將N-溴丁二醯亞胺(17 mg,0.1 mmol)及催化劑Pd(OAc)2(2.6 mg,0.01 mmol)添加至反應混合物中,在100℃下在微波輻射下再攪拌10分鐘。在EtOAc中稀釋混合物,且依次以水及飽和NaCl水溶液洗滌溶液,經Na2SO4乾燥,過濾且濃縮至乾燥。在藉由矽膠急驟層析(DCM/EtOAc:90/10至80/20)純化後,獲得72 mg黃色固體(產率:43%)。
LCMS(方法A):MH+=507.0,RT=8,88分鐘
根據步驟1.7.中所述程序,藉由以4 M HCl之二噁烷溶液處理8-溴-7-(吡啶-2-基)-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三
氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及8-溴-7-(吡啶-2-基)-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮來獲得呈白色粉末形式之產物(鹽酸鹽,0.4 H2O;產率94%)。
LCMS(方法A):MH+=425.2,RT=7.00分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 8.77-8.84(m,1H)8.58(s,1H)8.51(br.s.,1H)8.04-8.17(m,1H)7.93(s,1H)7.75(dd,1H)7.56-7.65(m,1H)5.33(d,1H)5.29(d,1H)
在氮氣下將8-溴-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-2-{[2-(三甲基矽烷基)乙氧基]甲基}-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮[根據步驟4.2.(用三氟甲磺酸2,2,2-三氟乙酯)及步驟9.1.中所述之方案獲得](1.0 g,1.88 mmol)、氰化鋅(0.66 g,5.64 mmol)、催化劑Pd(PPh3)4(390 mg,0.34 mmol)及16 mL無水DMF依次引入微波反應器中。密封反應器且在180℃下在微波輻射下劇烈攪拌混合物10分鐘。冷卻後,將混合物傾入飽和NaHCO3水溶液中。在以EtOAc萃取後,以飽和NaCl水溶液洗滌有機相,經Na2SO4
乾燥且濃縮至乾燥。在藉由矽膠急驟層析(依次為二異丙醚/EtOAc:90/10至20/80及二異丙醚/EtOAc:50/50)純化後,獲得342 mg白色粉末(產率:36%)。
LCMS(方法A):MH+=500.0,RT=8.59分鐘
根據步驟4.3.中所述程序,以4-側氧基-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-1-{[2-(三甲基矽烷基)乙氧基]甲基}-4,5-二氫-2H-吡唑并[4,3-c]喹啉-8-甲腈及4-側氧基-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-2-{[2-(三甲基矽烷基)乙氧基]甲基}-4,5-二氫-2H-吡唑并[4,3-c]喹啉-8-甲腈為起始物,獲得呈白色粉末形式之產物(1.8鹽酸鹽;產率15%)。
LCMS(方法C):MH+=369.9,RT=6.82分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 8.92(d,2H)8.80(s,1H)8.61(br.s,1H)8.08(s,1H)7.90(d,2H)5.47(d,1H)5.43(d,1H)
在160℃下攪拌4-側氧基-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-1-{[2-(三甲基矽烷基)乙氧基]-甲基}-4,5-二氫-2H-吡唑并[4,3-c]喹啉-8-甲腈及4-側氧基-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-2-{[2-(三甲基矽烷基)乙氧基]甲基}-4,5-二氫-2H-吡唑并[4,3-c]喹啉-8-甲腈[步驟10.1中所述](0.23 g,0.46 mmol)於5 mL乙酸與5 mL濃鹽酸之混合物中之溶液持續80
分鐘。將混合物濃縮至乾燥。將所得褐色殘餘物溶解於MeOH中且使其自乙醚沈澱。在濾出及在真空下乾燥後,獲得182 mg米色粉末(鹽酸鹽,2.8 H2O;產率:93%)。
LCMS(方法A):MH+=389.0,RT=4.37分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 13.33(br.s.,1H)8.88-8.97(m,3 H)8.55(br.s.,1H)7.96(d,2H)7.81(s,1H)5.40(d,1H)5.36(d,1H)
在40℃下將氫氧化鈉(1 M)(3.1 mL,3.1 mmol)添加至3-[4-側氧基-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲酸甲酯[經由步驟7.2.中所述方法獲得](1.0 g,2.06 mmol)於15 mL DMSO中之溶液中。在40℃下攪拌反應混合物15分鐘,接著傾入水中,且用30 mL 0.1 M鹽酸溶液酸化以達成pH=3-4。在以EtOAc萃取後,以飽和NaCl溶液洗滌有機相,經Na2SO4乾燥且濃縮至乾燥,得到890 mg白色固體(產率:92%)。
LCMS(方法A):MH+=473.1,RT=6.73分鐘
向3-[4-側氧基-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲酸及3-[4-側氧基-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲酸(50 mg,0.11 mmol)於1 mL DCM中之溶液中添加4 M氯化氫之二噁烷(0.26 mL,1.06 mmol)溶液。在室溫下攪拌1小時之後,過濾反應混合物。以DCM洗滌固體且在真空下乾燥,得到42 mg白色粉末(鹽酸鹽;產率:93%)。
LCMS(方法E):MH+=389.0,RT=1.58分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 8.68(dd,1H)8.46(s,1H)8.26(d,1H)7.99(dd,1H)7.81(s,1H)7.70(dd,1H)7.42(dd,1H)5.35(d,1H)5.30(d,1H)
在室溫下在氮氣下攪拌4-側氧基-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-4,5-二氫-2H-吡唑并[4,3-c]喹啉-8-甲酸[實例11](38 mg,0.10 mmol)、碳酸氫銨(46 mg,0.59 mmol)及二碳酸二第三丁酯(47 mg,0.22 mmol)於1 mL吡啶/EtOAc(1/1)中之混合物持續16小時,接著濃縮至乾燥。在藉由製備型C18逆相HPLC[溶離劑A:H2O/0.1 M CH3COONH4(90/10);溶離劑B:CH3CN/0.1 M CH3COONH4(90/10);梯度A/B:95/5至50/50]純化後,獲得3 mg白色粉末(8%)。
LCMS(方法C):MH+=388.0,RT=5.78分鐘
1H NMR(500 MHz,DMSO-d6):δ ppm 14.37(br.s.,1H)
8.65-8.68(m,2H)8.47(br.s.,1H)8.36(s,1H)7.99(s,1H)7.77(s,1H)7.53(br.s.,1H)7.48-7.50(m,2H)5.43(d,1H)5.39(d,1H)
在室溫下在氮氣下向3-[4-側氧基-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲酸及3-[4-側氧基-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲酸[步驟12.1.中所述](100 mg,0.21 mmol)於5 mL無水THF中之溶液中依次添加三乙胺(60 μL,0.53 mmol)、PyBOP®(132 mg,0.25 mmol)且在攪拌10分鐘後添加嗎啉(22 μL,22 mg,0.25 mmol)。攪拌溶液3小時,傾入飽和NaHCO3水溶液中且以EtOAc萃取。以飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥且濃縮至乾燥。在藉由急驟層析(DCM/EtOH:100/0至95/5)純化後,獲得46 mg白色固體(產率:36%)。
LCMS(方法A):MH+=542.1,RT=7.18分鐘
根據步驟1.7.中所述程序,以7-[2-(嗎啉-4-基羰基)吡啶-3-基]-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-[2-(嗎啉-4-基羰基)吡啶-3-基]-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮為起始物,獲得呈白色粉末形式之產物(鹽酸鹽,0.7 H2O;產率78%)。
LCMS(方法A):MH+=458.1,RT=5.95分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 8.68(dd,1H)8.49(br.s.,1H)8.28(d,1H)8.03(dd,1H)7.81(s,1H)7.66(dd,1H)7.46(dd,1H)5.33(d,1H)5.29(d,1H)3.45-3.52(m,2H)3.33-3.41(m,2H)3.05-3.11(m,2H)2.98-3.04(m,2H)
將乙酸酐(1.28 mL,13.5 mmol)添加至7-(2-胺基吡啶-3-基)-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-
4H-吡唑并[4,3-c]喹啉-4-酮及7-(2-胺基吡啶-3-基)-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮[步驟2.1.中所述](3.0 g,6.77 mmol)於34 mL吡啶中之加熱至80℃之溶液中。在80℃下攪拌2.5小時後,冷卻反應介質且濃縮至乾燥。在藉由矽膠急驟層析(DCM/EtOAc:100/0至70/30)純化後,獲得2.1白色粉末(產率63%)。
LCMS(方法A):MH+=486.2,RT=6.69分鐘
根據步驟3.4.中所述程序,以N-{3-[4-側氧基-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺及N-{3-[4-側氧基-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺為起始物,獲得呈白色粉末形式之產物(鹽酸鹽,1.5 H2O;產率66%)。
LCMS(方法A):MH+=402.0,RT=5.56分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 10.34(s,1H)8.52(dd,1H)8.44(s,1H)8.28(d,1H)8.05(dd,1H)7.82(s,1H)7.54(dd,1H)7.48(dd,1H)5.33(d,1H)5.29(d,1H)1.91(s,3 H)
在室溫下將甲烷磺醯氯(33 μL,0.41 mmol)添加至7-(2-胺基苯基)-5-(2,2,2-三氟乙基)-1-{[2-(三甲基矽烷基)乙氧基]甲基}-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-(2-胺基苯基)-5-(2,2,2-三氟乙基)-2-{[2-(三甲基矽烷基)-乙氧基]-甲基}-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮[根據步驟7.2.所述方法,以如下為起始物獲得:根據步驟7.1.中所述方法,以如下為起始物獲得之2-氯苯胺及7-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-5-(2,2,2-三氟乙基)-2-{[2-(三甲基矽烷基)-乙氧基]甲基}-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮:步驟3.1.中所述之7-溴-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-溴-2-{[2-(三甲基矽烷基)乙氧基]甲基}-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮](0.20 g,0.41 mmol)於2 mL吡啶中之溶液中。攪拌1小時後,將反應介質傾入莫耳鹽酸溶液中且以EtOAc萃取。以水洗滌有機相,經Na2SO4乾燥且濃縮至乾燥。在藉由矽膠急驟層析(環己烯/EtOAc:100/0至50/50)純化後,獲得195 mg白色粉末(產率:84%)。
LCMS(方法A):MH+=567.0,RT=9.70分鐘
根據步驟4.3.中所述程序,以N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-1-{[2-(三甲基矽烷基)乙氧基]甲基}-4,5-二氫-2H-吡唑并[4,3-c]喹啉-7-基]苯基}甲烷磺醯胺及N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-2-{[2-(三甲基矽烷基)乙氧基]甲基}-4,5-二氫-2H-吡唑并[4,3-c]喹啉-7-基]苯基}甲烷磺醯胺為起始物,獲得呈白色粉末形式之產物(產率74%)。
LCMS(方法B):MH+=437.1,RT=13.31分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 14.29(br.s.,1H)9.08(br.s.,1H)8.39(br.s,1H)8.24(d,1H)7.79(s,1H)7.37-7.56(m,5H)5.35(d,1H)5.33(d,1H)2.74(s,3 H)
在氮氣下在室溫下將N-{3-[4-側氧基-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺及N-{3-[4-側氧基-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺[步驟15.1中所述](0.69 g,1.43 mmol)及甲基碘(0.27 mL,4.33 mmol)依次添加至氫化鈉
(油中之60%懸浮液,0.17 g,4.33 mmol)之16 mL無水DMF溶液中。在攪拌15分鐘後,將反應混合物傾入莫耳硫酸氫鉀溶液中且以EtOAc萃取。以水及飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥且濃縮至乾燥。在藉由矽膠急驟層析(DCM/EtOAc:100/0至50/50)純化後,獲得0.57 g白色粉末(產率:80%)。
LCMS(方法A):MH+=500.3,RT=1.16分鐘
根據步驟1.7.中所述程序,以N-甲基-N-{3-[4-側氧基-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺及N-甲基-N-{3-[4-側氧基-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺為起始物,獲得呈白色粉末形式之產物(鹽酸鹽,1 H2O;產率58%)。
LCMS(方法A):MH+=416.1,RT=6.15分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 8.62(d,1H)8.46(br.s.,1H)8.26(d,1H)8.03(d,1H)7.82(s,1H)7.63(dd,1H)7.38(d,1H)5.27-5.41(m,2H)2.97(s,3 H)1.70(s,3 H)
在密封反應器中在180℃下在微波輻射下加熱7-(2-氟吡啶-3-基)-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-(2-氟吡啶-3-基)-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(1.0 g,2.16 mmol)於11 mL高哌嗪中之溶液4小時。將溶液冷卻至室溫且傾入水中。濾出所形成之白色沈澱物且藉由矽膠急驟層析(DCM/EtOH:100/0至70/30)純化。獲得745 mg白色固體(產率:66%)。
LCMS(方法A):MH+=527.4,RT=5.90分鐘
根據步驟1.7.中所述程序,以7-[2-(1,4-二氮雜環庚烷-1-基)吡啶-3-基]-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-[2-(1,4-二氮雜環庚烷-1-基)吡啶-3-基]-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮為起始物,獲得呈白色粉末形式之產物(鹽酸鹽,1 H2O;產率75%)。
LCMS(方法A):MH+=443.2,RT=5.13分鐘
1H NMR(400 MHz,DMSO-d6):δ ppm 8.90(br.s.,2H)8.44
(br.s.,1H)8.28(d,1H)8.24(dd,1H)7.80(s,1H)7.68(d,1H)7.47(dd,1H)7.05(dd,1H)5.35(d,1H)5.31(d,1H)3.58-3.62(m,2H)3.13-3.24(m,4H)2.98-3.06(m,2H)1.80-1.89(m,2H)
在密封反應器中在185℃下在微波輻射下加熱7-(2-氟吡啶-3-基)-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-(2-氟吡啶-3-基)-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(0.4 g,0.896 mmol)及環己胺(0.76 g,8.96 mmol)於5 mL NMP中之溶液2小時。將反應混合物傾入水中且以EtOAc萃取。以飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥且濃縮至乾燥。在藉由矽膠急驟層析(DCM/EtOH:100/0至90/10)純化後,獲得232 mg呈固體形式之產物(產率:51%)。
LCMS(方法E):MH+=512.1,RT=2.01分鐘
根據步驟1.7.中所述程序,以7-[2-(哌啶-1-基)吡啶-3-
基]-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-[2-(哌啶-1-基)吡啶-3-基]-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮為起始物,獲得呈白色粉末形式之產物(鹽酸鹽,1.3 H2O;產率86%)。
LCMS(方法A):MH+=428.2,RT=6.13分鐘
1H NMR(250 MHz,DMSO-d6):δ ppm 8.46(s,1H)8.31(d,1H)8.23(dd,1H)7.83-7.98(m,2H)7.62(d,1H)7.23(dd,1H)5.35(d,1H)5.30(d,1H)3.15(br.s.,4H)1.46(br.s.,6H)
在氬氣下將7-(2-氯吡啶-3-基)-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-(2-氯吡啶-3-基)-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮[步驟7.2.中所述](0.4 g,0.86 mmol)、第三丁醇鈉(0.83 g,8.64 mmol)、1-環丙基哌嗪(0.69 g,3.46 mmol)、9 mL無水DMF及催化劑[Pd(μ-Br)(tBu3P)]2(0.14 g,0.18 mmol)依次
引入微波反應器中。密封反應器且在100℃下在微波輻射下攪拌混合物30分鐘。冷卻混合物且使其吸附於二氧化矽上。在藉由矽膠急驟層析(DCM/EtOAc:100/0至50/50)純化後,獲得75 mg黃色粉末(產率:16%)。
LCMS(方法E):MH+=553.0,RT=1.92分鐘
根據步驟1.7.中所述程序,以7-[2-(4-環丙基哌嗪-1-基)吡啶-3-基]-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-[2-(4-環丙基-哌嗪-1-基)吡啶-3-基]-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮為起始物,獲得呈白色粉末形式之產物(3鹽酸鹽,3 H2O;產率70%)。
LCMS(方法A):MH+=469.2,RT=5.32分鐘
1H NMR(250 MHz,DMSO-d6):δ ppm 10.57(br.s.,1H)8.46(br.s.,1H)8.28-8.33(m,2H)7.88(s,1H)7.71-7.75(m,2H)7.19(dd,1H)5.38(d,1H)5.34(d,1H)3.53(d,2H)3.38(d,2H)3.03-3.24(m,4H)2.85(br.s.,1H)1.04(br.s.,2H)0.70-0.78(m,2H)
向7-[2-(1,4-二氮雜環庚烷-1-基)吡啶-3-基]-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-[2-(1,4-二氮雜環庚烷-1-基)吡啶-3-基]-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮[步驟18.1中所述](0.2 g,0.38 mmol)於17 mL MeOH中之溶液中添加甲醛(0.356 mL,3.80 mmol)且在室溫下攪拌溶液1小時。在0℃下逐份添加NaBH4(72 mg,1.90 mmol)且觀察到放出氣體。在室溫下攪拌反應混合物3小時,接著傾入水中且以EtOAc萃取。以飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥且濃縮至乾燥。將所得白色固體溶解於二異丙醚中且在濾出後,獲得142 mg呈白色粉末形式之產物(產率:70%)。
LCMS(方法C):MH+=541.2,RT=7.68分鐘
根據步驟1.7.中所述程序,以7-[2-(4-甲基-1,4-二氮雜環庚烷-1-基)吡啶-3-基]-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-[2-(4-甲基-1,4-二氮雜環庚烷-1-基)吡啶-3-基]-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮為起始物,獲得呈白色粉末形式之產物(2鹽酸鹽,5.5 H2O;產率28%)。
LCMS(方法A):MH+=457.2,RT=5.21分鐘
1H NMR(250 MHz,DMSO-d6):δ ppm 9.61(br.s.,1H)8.40(br.s.,1H)8.18-8.29(m,2H)7.76(s,1H)7.64(dd,1H)7.45(d,1H)7.01(dd,1H)5.26-5.42(m,2H)2.91-4.04(m,8H)2.73-2.80(m,3 H)1.90(br.s.,2H)
向7-[2-(1,4-二氮雜環庚烷-1-基)吡啶-3-基]-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-[2-(1,4-二氮雜環庚烷-1-基)吡啶-3-基]-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮[步驟18.1中所述](0.1 g,0.19 mmol)溶解於8 mL MeOH中之溶液中添加(1-甲氧基環丙氧基)三甲基矽烷(36.5 mg,0.23 mmol)。在室溫下攪拌混合物30分鐘,接著添加NaBH3CN(24 mg,0.38 mmol)。觀察到氣體放出,且攪拌混合物72小時。將所得混合物傾入水溶液中,以EtOAc萃取,以飽和NaCl水溶液洗滌,經無水Na2SO4乾燥,過濾且濃縮至乾燥。獲得85 mg白色固體(產率:78%)。
LCMS(方法A):MH+=567.1,RT=6.11分鐘
根據步驟1.7.中所述程序,以7-[2-(4-環丙基-1,4-二氮雜環庚烷-1-基)吡啶-3-基]-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-[2-(4-環丙基-1,4-二氮雜環庚烷-1-基)吡啶-3-基]-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮為起始物,獲得呈白色粉末形式之產物(鹽酸鹽,3.6 H2O;產率57%)。
LCMS(方法A):MH+=483.2,RT=5.36分鐘
1H NMR(250 MHz,DMSO-d6):δ ppm 9.95(br.s.,1H)8.44(br.s.,1H)8.19-8.29(m,2H)7.77(s,1H)7.66(dd,1H)7.46(d,1H)7.02(dd,1H)5.33(q,2H)3.54(br.s.,2H)3.12-3.47(m,4H)3.06(br.s.,2H)2.88(br.s.,1H)1.96(br.s.,2H)1.00-1.06(m,2H)0.72-0.84(m,2H)
向三氟化二乙基胺基硫(32 mg,0.20 mmol)於4 mL DCM
中之冷卻至-70℃之溶液中添加7-[2-(3-羥基吡咯啶-1-基)吡啶-3-基]-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-[2-(3-羥基吡咯啶-1-基)吡啶-3-基]-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮[根據步驟18.1.中所述方法,以吡咯啶-3-醇為起始物來獲得](85 mg,0.17 mmol)溶解於3 mL DCM中之溶液。在室溫下攪拌混合物2小時,接著添加飽和NaHCO3水溶液且以DCM萃取所得混合物。以飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥且濃縮至乾燥。在藉由矽膠急驟層析(DCM/EtOH:100/0至90/10)純化後,獲得38 mg白色固體(產率:43%)。
LCMS(方法E):MH+=516.1,RT=1.89分鐘
根據步驟1.7.中所述程序,以7-[2-(3-氟吡咯啶-1-基)吡啶-3-基]-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-[2-(3-氟吡咯啶-1-基)吡啶-3-基]-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮為起始物,獲得呈白色粉末形式之產物(鹽酸鹽,H2O;產率47%)。
LCMS(方法A):MH+=432.1,RT=5.50分鐘
1H NMR(250 MHz,DMSO-d6):δ ppm 8.45(br.s.,1H)8.26(d,1H)8.17(dd,1H)7.82(s,1H)7.76(br.s.,1H)7.41(d,1H)7.02(br.s.,1H)5.15-5.39(m,3H)3.18-3.48(m,4H)1.83-2.22(m,2H)
向置於微波反應器中之7-溴-1-(四氫-2H-哌喃-2-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-溴-3-(四氫-2H-哌喃-2-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮[步驟1.4.中所述](0.40 g,0.93 mmol)溶解於10 mL DMF中之溶液中添加2-甲氧基-3-吡啶酸(0.284 g,1.86 mmol)、Cs2CO3(1.2 g,3.72 mmol)、1 mL脫氣水及催化劑PdCl2(dppf)(0.159 mg,0.2 mmol)。密封反應器且在110℃下在微波輻射下在氮氣下攪拌混合物10分鐘。冷卻反應混合物,傾入水中且以EtOAc萃取。以飽和NaCl水溶液洗滌有機相,經Na2SO4乾燥且濃縮至乾燥。在藉由矽膠急驟層析(DCM/EtOH:100/0至90/10)純化後,獲得103 mg黃色固體(產率:24%)。
LCMS(方法A):MH+=459.2,RT=9.04分鐘
向7-(2-甲氧基吡啶-3-基)-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-(2-甲氧基吡啶-3-基)-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(90 mg,0.20
mmol)於DCM/MeOH混合物(50/50)中之溶液中添加4 M氯化氫之無水二噁烷(2 mL,2.45 mmol)溶液。在室溫下攪拌溶液10日,接著傾入二異丙醚中。濾出所形成之沈澱物且以EtOH洗滌。獲得52 mg白色固體(產率:65%)。
LCMS(方法A):MH+=361.0,RT=5.91分鐘
1H NMR(250 MHz,DMSO-d6):δ ppm 14.30(br.s.,1H)11.92(br.s.,1H)8.20-8.80(m,1H)8.17(d,1H)8.08(br.s.,1H)7.85(d,2H)7.48(d,1H)6.38(t,1H)5.31(q,2H)
在0℃下將間氯過苯甲酸(585 mg,2.62 mmol)添加至7-(吡啶-2-基)-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-(吡啶-2-基)-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮(280 mg,0.65 mmol)於5 mL DCM中之懸浮液中。在室溫下攪拌混合物3小時。在藉由胺相急驟層析(依次為DCM/EtOAc:95/5至80/20及DCM/EtOH:95/5)純化後,獲得120 mg白色粉末(產率:43%)。
LCMS(方法A):MH+=445.2,RT=6.69分鐘
根據步驟1.7.中所述程序,藉由以4 M HCl之二噁烷溶液處理7-(1-氧離子基吡啶-2-基)-1-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮及7-(1-氧離子基吡啶-2-基)-2-(四氫-2H-哌喃-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮來獲得呈白色粉末形式之產物(鹽酸鹽,1 H2O;產率99%)。
LCMS(方法A):MH+=361.2,RT=5.53分鐘
1H NMR(250 MHz,DMSO-d6):δ ppm 8.48(br.s.,1H)8.39-8.43(m,1H)8.27(d,1H)8.15(s,1H)7.92(d,1H)7.70-7.76(m,1H)7.46-7.52(m,2H)5.36(d,1H)5.31(d,1H)
下表說明許多本發明化合物之化學結構及物理性質。在此表中:- Me、Et、Pr、c-Pr及i-Pr分別表示甲基、乙基、丙基、環丙基及異丙基;- 在「鹽」之行中,「/」表示呈游離鹼形式之化合物,而「HCl」表示呈鹽酸鹽形式之化合物且「TFA」表示呈三氟乙酸鹽形式之化合物。
對本發明化合物進行生物化學研究,以測定其抑制酵素甲硫胺酸-胺基肽酶2之能力(對分離之酶的酶促測試)。接著於細胞測試(用FGF-2(纖維母細胞生長因子2)誘導之HUVEC細胞之活體外增殖測試)中驗證化合物之抑制活性。
為進行酶促測試,自感染MetAP2重組體桿狀病毒之昆蟲細胞(sf9)之培養物上清液中獲得人類MetAP2蛋白質。
在進行實驗之前,在4℃下,在緩衝液(10 mM Hepes、100 mM KCl、10%甘油,pH 7.4)中,前12小時在EDTA(1 mM)存在下透析MetAP2上清液歷經24小時。
回收透析上清液,且將用作輔因子之錳添加至300 μM之最終濃度。
酶促測試為兩步驟測試。
第一步驟,將以下物質與本發明化合物接觸:透析之MetAP2蛋白質及受質(由Neosystem合成之Met-Pro-Arg-
pNa肽),其N端甲硫胺酸可使用MetAP2裂解且其C端具有對硝基苯胺(pNa)發色團,僅當N端甲硫胺酸已事先裂解時,其本身才可被另一種肽酶釋放。
因此,第二步驟,使前述步驟中裂解之肽與第二肽酶反應,以釋放發色團。此第二步驟中所用之肽酶為組織蛋白酶(cathepsin),其來自TagZyme「DAPase」套組(Quiagen,34366)。
MetAP2活性與對硝基苯胺之釋放量成比例,可由405 nm之吸光率量測。
本發明化合物之IC50值一般小於550 nM,更特定言之在1 nM與550 nM之間,且甚至更特定言之在1 nM與100 nM之間,及/或在100 nM下顯示大於或等於34%之抑制性,如下表所示:
為測定本發明化合物對蛋白質MetAP1之選擇性,對分離之酶進行酶促測試。在大腸桿菌(Escherichia coli)中產生MetAP1重組體蛋白質。
MetAP1酶促測試係基於與MetAP2測試相同之原理。
MetAP1活性與由在405 nm下之吸光率量測的釋放之對硝基苯胺之量成比例。
本發明化合物在10 μM下不顯示活性。
已證明血管生成抑制劑煙黴素能夠選擇性抑制內皮細胞之增殖(Wang J.等人,J.Cell.Bioch.2000,第77卷,465-473)。因此,在用FGF-2誘導之HUVEC細胞的活體外增殖測試中評估在MetAP2酶促測試中顯示良好活性之本發明化合物。
在96孔板(Biocoat collagen I cellware,Becton Dickinson 354650)中,在含2% FCS(胎牛血清)及hEGF(人類表皮生長因子)(10 μg/ml)之200 μl EBM培養基(Clonetics C3121)中,以5000個細胞/孔之比率接種人類靜脈內皮細胞HUVEC(promocell,C-12200),接著在37℃下在CO2存在下培育24小時。接著抽吸培養基且經補充有0.5% FCS、2 mM麩醯胺酸、2 mM丙酮酸鈉1×(Invitrogen,11360-039)及
NEAA(非必需胺基酸)1×(Invitrogen,11140-035)之200 μl剝奪培養基RPMI1640(Invitrogen,31872-025)置換。接著以1 ng/ml(R&D System,133-FB-025)之比例將細胞與本發明化合物及FGF-2接觸。培育48小時之後,抽吸培養基且經先前提及之剝奪培養基RPMI1640置換。接著進行第二次刺激。在37℃下在CO2存在下再培育細胞。培育72小時之後,再次抽吸培養基且歷經10分鐘添加100 μl Cell Titer-GLOTM發光細胞生存力分析(Cell Titer-GLOTM Luminescent Cell Viability Assay)(Promega,G7571)。使用光度計量測之細胞中存在之ATP量與對應於細胞增殖之每孔細胞數目成比例。
本發明化合物之IC50值一般小於900 nM,更特定言之在150 nM與900 nM之間且甚至更特定言之在100 nM與350 nM之間,例如下文對化合物所示:
因此,本發明化合物似乎對MetAP2具有抑制活性。
本發明化合物因此可用於製備藥物,尤其用於製備預防或治療涉及MetAP2之任何病狀的藥物,更特定言之下文所示者。
本發明化合物亦可用於預防或治療涉及MetAP2之任何病狀,更特定言之下文所示者。
因此,根據其另一態樣,本發明之標的為藥物,其包含式(I)化合物,或其與醫藥學上可接受之酸所形成之加成鹽,或者式(I)化合物之水合物。
因此,可將本發明化合物用於治療或預防人類或動物中的肺纖維化及肝纖維化。
本發明化合物亦可用於治療或預防涉及血管生成再活化之病狀,諸如糖尿病性視網膜病、年齡相關之黃斑部變性
(ARMD)及牛皮癬。
本發明化合物亦可用於治療或預防具有實質性血管化程度之任何癌瘤,諸如肺癌、乳癌、前列腺癌、食道癌、胰腺癌、肝癌、結腸癌或腎癌,或誘發轉移之癌瘤,諸如結腸癌、乳癌、肝癌及胃癌,及黑色素瘤。此等化合物可用於單方療法中或與放射線療法或化學療法組合。
本發明化合物亦可單獨或與化學療法組合用於實體腫瘤(諸如胰腺腫瘤、乳房腫瘤、前列腺腫瘤、結腸腫瘤或腎腫瘤、神經母細胞瘤及卡波西氏肉瘤(Kaposi's sarcoma))之抗腫瘤治療。
本發明化合物亦可用於治療或預防肝癌、膽管癌以及惡性間皮瘤、胰腺癌、血管瘤、子宮內膜異位、關節炎且尤其用於治療或預防類風濕性關節炎、自體免疫疾病、肥胖症及微孢子蟲病(microsporidiosis)。
根據其另一態樣,本發明係關於醫藥組合物,其包含本發明化合物作為活性成分。此等醫藥組合物含有有效劑量之至少一種本發明化合物或該化合物之醫藥學上可接受之鹽,及至少一種醫藥學上可接受之賦形劑。
根據醫藥形式及所需投藥模式,該等賦形劑係選自熟習此項技術者已知的常見賦形劑。
在用於經口、舌下、皮下、肌肉內、靜脈內、表面、局部、氣管內、鼻內、經皮或經直腸投藥之本發明之醫藥組合物中,上述式(I)之活性成分或其鹽可與標準醫藥賦形劑形成混合物,呈單位投藥形式投與人類及動物,以便預防
或治療上述病症或疾病。
適當之單位投藥形式包括經口途徑形式(諸如錠劑、軟式或硬式膠囊、散劑、粒劑及口服溶液或懸浮液)、舌下、頰內、氣管內、眼內、鼻內或吸入投藥形式、表面、非經腸(諸如經皮、皮下、肌肉內或靜脈內投藥形式)、經直腸投藥形式及植入物。經表面施用時,本發明化合物可呈乳膏、凝膠、軟膏或洗劑使用。
舉例而言,呈錠劑形式之本發明化合物的單位投藥形式可包含以下組分:
每日投與之活性成分之劑量可在0.01 mg/kg至100 mg/kg之範圍內且較佳在0.02 mg/kg至50 mg/kg之範圍內,分一或多次劑量攝入。一般而言,本發明化合物之日劑量將為能夠產生治療作用的化合物之最低有效劑量。
可能存在較高或較低劑量較為適當的特殊情況;此等劑量不脫離本發明之範疇。根據慣例,適於各患者之劑量係由醫師根據投藥模式及該患者之體重及反應來確定。
根據其另一態樣,本發明亦係關於一種治療上文所示之病狀的方法,其包含向患者投與有效劑量之本發明化合物或其醫藥學上可接受之鹽。
Claims (19)
- 一種對應於式(I)之化合物,
- 如請求項1之式(I)化合物,其中R3表示H或鹵素;該化合物呈鹼或酸加成鹽之形式,且亦可呈水合物形式。
- 如請求項2之式(I)化合物,其中R3表示氯。
- 如請求項1及2中任一項之式(I)化合物,其中R1表示乙基或三氟乙基;該化合物呈鹼或酸加成鹽之形式,且亦可呈水合物形式。
- 如請求項1或2之式(I)化合物,其中R2表示基團-A-X,其中A表示芳基或雜芳基且X不存在或表示雜環、NRaRb、(C1-C6)烷基、鹵素、氰基、NRa-SO2-Rb、CO-雜環;該化合物呈鹼或酸加成鹽之形式,且亦可呈水合物形式。
- 如請求項5之式(I)化合物,其中X表示氯或氟。
- 如請求項1或2之式(I)化合物,其選自以下化合物:化合物1:7-(吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物2:7-(2-胺基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物3:7-(2-氟苯基)-5-(2,2,2-三氟乙基)-1,5-二氫- 4H-吡唑并[4,3-c]喹啉-4-酮;化合物4:5-乙基-7-吡啶-2-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物5:5-乙基-7-(4-氟苯基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物6:7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物7:5-乙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物8:7-(2-二甲胺基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物9:N-(3-二甲胺基丙基)-4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;化合物10:5-乙基-7-(4-哌嗪-1-基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物11:5-乙基-7-[4-(4-甲基哌嗪-1-基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物12:7-[2-(嗎啉-4-基羰基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物13:N-(2-二甲胺基乙基)-4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;化合物14:7-(2-嗎啉-4-基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物15:7-[4-(1-二甲胺基乙基)苯基]-5-乙基-1,5-二 氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物16:7-(2-嗎啉-4-基甲基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物17:5-乙基-7-(2-嗎啉-4-基甲基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物18:5-乙基-7-[4-(哌嗪-1-羰基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物19:7-[4-(4-甲基哌嗪-1-基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物20:5-乙基-7-(2-哌嗪-1-基嘧啶-5-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物21:5-乙基-7-[4-(4-甲基哌嗪-1-羰基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物22:5-乙基-7-[4-(1-吡咯啶-1-基-乙基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物23:7-(4-二乙胺基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物24:7-(4-胺基-2-甲基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物25:7-(4-嗎啉-4-基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物26:5-乙基-7-(4-嗎啉-4-基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物27:5-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并 [4,3-c]喹啉-7-基)-2-氟-N-甲基苯甲醯胺;化合物28:5-乙基-7-(2-氟-5-甲氧苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物29:7-[3-氯-4-(嗎啉-4-羰基)苯基]-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物30:7-[4-(哌嗪-1-基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物31:5-乙基-7-[2-(4-甲基哌嗪-1-基)嘧啶-5-基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物32:7-(4-二甲胺基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物33:2-氯-4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;化合物34:5-乙基-7-(1H-吲唑-5-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物35:N-乙基-3-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;化合物36:5-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)-2-氟-苯甲醯胺;化合物37:N-(2-二甲胺基乙基)-3-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;化合物38:N-[4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲基]乙醯胺;化合物39:3-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并 [4,3-c]喹啉-7-基)-N-(2-甲氧基乙基)苯甲醯胺;化合物40:7-(3-羥苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物41:7-(2-氯-3-氟吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物42:7-(2-{5-[(丙-2-基胺基)甲基]呋喃-2-基}苯基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物43:N-[2-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯基]甲烷磺醯胺;化合物44:7-(2-胺基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物45:5-乙基-7-(3-嗎啉-4-基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物46:N-[2-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯基]乙醯胺;化合物47:5-乙基-7-(2-羥苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物48:5-乙基-7-[4-(嗎啉-4-磺醯基)苯基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物49:7-(2-羥甲基-4-甲氧苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物50:5-乙基-7-(3-吡唑-1-基苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮; 化合物51:5-乙基-7-(1H-吲哚-5-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物52:5-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)-噻吩-2-甲腈;化合物53:7-(3-氯-2-羥苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物54:5-乙基-7-(2-羥基-3-甲氧苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物55:3-胺基-4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸甲酯;化合物56:5-乙基-7-(4-甲基-3,4-二氫-2H-苯并[1,4]噁嗪-7-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物57:7-(2,5-二氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物58:7-(2-氯-5-甲氧苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物59:N-(3-二甲胺基丙基)-3-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲醯胺;化合物60:5-乙基-7-(4-氟-2-羥苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物61:5-乙基-7-(2-氟-4-甲氧苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物62:7-(4-胺基甲基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮; 化合物63:5-乙基-7-(2-氟-3-甲氧苯基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物64:7-(2-二甲胺基甲基苯基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物65:4-(5-乙基-4-側氧基-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基)苯甲酸;化合物66:7-[6-(哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物67:5-乙基-7-[6-(哌嗪-1-基)吡啶-3-基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物68:7-[2-(4-甲基哌嗪-1-基)吡啶-4-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物69:5-乙基-7-[2-(4-甲基哌嗪-1-基)吡啶-4-基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物70:7-[2-(哌嗪-1-基)吡啶-4-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物71:5-乙基-7-(2-哌嗪-1-基吡啶-4-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物72:7-(2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物73:5-乙基-7-(2-甲基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物74:7-(2-氯-6-甲基吡啶-3-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮; 化合物75:7-(2-氯-6-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物76:7-(2-氯吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物77:7-(2-氟吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物78:5-乙基-7-(2-氟吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物79:7-(6-氯-2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物80:7-(2-甲氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物81:5-乙基-7-(2-甲氧基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物82:7-(6-氯-4-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物83:7-[6-(嗎啉-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物84:7-[6-(3-二甲胺基丙氧基)吡啶-3-基]-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物85:5-乙基-7-喹啉-8-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物86:7-(6-氯吡啶-2-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮; 化合物87:5-乙基-7-喹啉-6-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物88:7-(6-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物89:7-(6-氯-5-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物90:5-乙基-7-(3-氟吡啶-4-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物91:7-(3-氯吡啶-4-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物92:5-乙基-7-(6-氟-5-甲基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物93:7-(2-乙氧基吡啶-3-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物94:5-乙基-7-(5-甲氧基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物95:7-(6-胺基吡啶-3-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物96:5-乙基-7-吡啶-3-基-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物97:7-(2-氯-6-異丙基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物98:7-(5-氯-2-甲氧基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮; 化合物99:7-(吡啶-3-基氧基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物100:5-乙基-7-(吡啶-3-基氧基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物101:7-(吡啶-3-基胺基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物102:5-(2,2-二氟乙基)-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物103:5-環丙基甲基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物104:5-丙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物105:5-(2,2-二氟環丙基甲基)-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物106:5-(2-氟乙基)-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物107:5-異丙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物108:5-環丙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物109:8-氟-7-吡啶-2-基-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物110:7-(2-氯吡啶-3-基)-8-甲基-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮; 化合物111:7-(2-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物112:7-[2-(二甲胺基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物113:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸異丙酯;化合物114:環丙烷甲酸{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}醯胺;化合物115:7-[2-(1-甲基-1H-咪唑-2-羰基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物116:7-(4-環戊基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物117:7-(4-環己基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物118:7-(2-丙基胺基甲基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物119:2-甲氧基-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}乙醯胺;化合物120:N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}異丁醯胺;化合物121:N-{4-甲基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}丙醯胺;化合物122:N-異丙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲醯胺; 化合物123:7-[4-甲基-2-(哌啶-4-基氧基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物124:7-[2-(1,4-二氮雜環庚烷-1-基甲基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物125:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸乙酯;化合物126:7-(2-胺基苯基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物127:7-(2-哌嗪-1-基苯基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物128:7-(6-甲氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物129:7-(5-氯-2-氟吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物130:N-{5-甲基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺;化合物131:7-[2-(2-羥基-乙基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物132:7-(2-胺基-5-氟吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物133:7-[2-(吡咯啶-1-磺醯基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮; 化合物134:N-異丙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯磺醯胺;化合物135:7-(2-氟-5-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物136:N,N-二乙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯磺醯胺;化合物137:7-(6-胺基-4-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物138:7-(6-甲氧基-2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物139:7-(5-甲基-6-[1,2,4]三唑-4-基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物140:7-(4-甲基-6-[1,2,4]三唑-4-基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物141:7-[6-(嗎啉-4-羰基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物142:7-(6-胺基-2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物143:7-(4-乙基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物144:{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}乙酸甲酯; 化合物145:7-(4-甲氧基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物146:7-(4-丙基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物147:N-{6-甲基-5-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}丙醯胺;化合物148:7-(2-噁唑-5-基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物149:7-(4-二甲胺基-2-甲氧基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物150:7-[2-(5-乙基-[1,2,4]噁二唑-3-基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物151:N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲基}乙醯胺;化合物152:7-[5-(羥苯基甲基)吡啶-2-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物153:6-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲腈;化合物154:7-(6-羥甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物155:7-[3-(2-二甲胺基乙氧基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮; 化合物156:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸甲酯;化合物157:7-(5-羥甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物158:7-(2-甲氧基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物159:7-(2-[1,2,4]三唑-1-基甲基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物160:7-(4-苯基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物161:7-(6-甲氧基-4-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物162:7-(4-異丙基嘧啶-5-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物163:7-(6-氟吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物164:6-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲酸甲酯;化合物165:7-(5-氟吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物166:7-[2-(4-甲基哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物167:7-(3-胺基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮; 化合物168:7-(2,6-二甲基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物169:7-(3-氯吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物170:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲酸甲酯;化合物171:7-(6-甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物172:7-[2-(嗎啉-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物173:5-(2,2,2-三氟乙基)-7-(2-三氟甲基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物174:7-(2-環丙基胺基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物175:5-(2,2,2-三氟乙基)-7-(3-三氟甲基吡啶-2-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物176:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲腈;化合物177:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-甲腈;化合物178:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]菸鹼酸甲酯;化合物179:7-(2-丙氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮; 化合物180:7-(3-羥基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物181:7-[2-(4-氟苯基胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物182:7-(2-甲胺基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物183:7-(2-乙氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物184:7-(2-異丙氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物185:7-(5-氯-2-甲氧基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物186:7-(2-甲基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物187:7-(4-甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物188:7-(6-嗎啉-4-基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物189:7-(4-甲胺基苯基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物190:5-(2,2,2-三氟乙基)-7-(6-三氟甲基吡啶-3-基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物191:7-(6-甲氧基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮; 化合物192:7-[4-(2H-四唑-5-基)苯基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物193:7-(3,5-二氯吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物194:8-氯-7-(吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物195:8-溴-7-吡啶-2-基-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物196:8-氯-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物197:8-溴-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物198:8-氯-5-乙基-7-吡啶-4-基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物199:8-氯-7-(2-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物200:8-甲基-7-吡啶-2-基-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物201:4-側氧基-7-吡啶-4-基-5-(2,2,2-三氟乙基)-4,5-二氫-2H,4H-吡唑并[4,3-c]喹啉-8-甲腈;化合物202:4-側氧基-7-吡啶-4-基-5-(2,2,2-三氟乙基)-4,5-二氫-2H,4H-吡唑并[4,3-c]喹啉-8-甲酸;化合物203:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲酸; 化合物204:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲酸;化合物205:4-側氧基-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-4,5-二氫-2H-吡唑并[4,3-c]喹啉-8-甲醯胺;化合物206:7-[2-(嗎啉-4-基羰基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物207:N-[2-(二甲胺基)乙基]-N-甲基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲醯胺;化合物208:N-(2-二甲胺基乙基)-N-乙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲醯胺;化合物209:7-{2-[(4-甲基-1,4-二氮雜環庚烷-1-基)羰基]苯基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物210:7-{2-[(4-甲基哌嗪-1-基)羰基]苯基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-4H-吡唑并[4,3-c]喹啉-4-酮;化合物211:N-(3-胺甲醯基苯基)-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲醯胺;化合物212:N-(3-二甲胺基丙基)-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯甲醯胺; 化合物213:N,N-二甲基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲醯胺;化合物214:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]-N-[2-(吡啶-4-基)乙基]苯甲醯胺;化合物215:N-[2-(二甲胺基)乙基]-N-甲基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲醯胺;化合物216:7-[2-(1,4-氧氮雜環庚烷-4-基羰基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物217:N-甲基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲醯胺;化合物218:2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]-N-(吡啶-3-基甲基)苯甲醯胺;化合物219:N-乙基-2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]-N-(吡啶-4-基甲基)苯甲醯胺;化合物220:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲醯胺;化合物221:N-[2-(二甲胺基)乙基]-N-乙基-3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉- 7-基]吡啶-2-甲醯胺;化合物222:7-[2-((2S,6R)-2,6-二甲基嗎啉-4-羰基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物223:N-{3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺;化合物224:3-二甲胺基-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-2H,4H-吡唑并[4,3-c]喹啉-7-基]苯基}丙醯胺;化合物225:4-(二甲胺基)-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}丁醯胺;化合物226:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}乙醯胺;化合物227:N-{3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}環丙烷甲醯胺;化合物228:2-甲氧基-N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}-2-苯基乙醯胺;化合物229:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}-2-苯基丙醯胺;化合物230:2-(3-氯苯基)-N-{4-[4-側氧基-5-(2,2,2-三 氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}乙醯胺;化合物231:2-(2,4-二氯苯基)-N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}乙醯胺;化合物232:N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-2H-吡唑并[4,3-c]喹啉-7-基]苯基}甲烷磺醯胺;化合物233:2-(二甲胺基)-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}乙烷磺醯胺;化合物234:N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}-1-苯基甲烷磺醯胺;化合物235:3-氯-N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]苯基}苯磺醯胺;化合物236:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}甲烷磺醯胺;化合物237:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}-1-苯基甲烷磺醯胺;化合物238:3-氯-N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}苯磺醯胺; 化合物239:N-(4-甲氧基-3-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基胺磺醯基}苯甲基)乙醯胺;化合物240:N-{4-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-3-基}-2-苯氧基苯磺醯胺;化合物241:N-甲基-N-{3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}乙醯胺;化合物242:N-甲基-N-{3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-基}環丙烷甲醯胺;化合物243:7-[2-(甲胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物244:7-[2-(1,4-二氮雜環庚烷-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物245:7-(3,4,5,6-四氫-2H-[1,2']聯吡啶-3'-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物246:7-[2-(3-羥基吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物247:7-[2-(3,4-二羥基吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮; 化合物248:7-[2-(二甲胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物249:7-{2-[乙基(甲基)胺基]吡啶-3-基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物250:7-{2-[(2-羥乙基)(甲基)胺基]吡啶-3-基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物251:7-[2-(吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物252:7-[2-(1,4-氧氮雜環庚烷-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物253:7-[2-(3-側氧基哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物254:7-[2-(氮雜環丁烷-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物255:7-{2-[(2-甲氧基乙基)甲胺基]吡啶-3-基}-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物256:7-[2-(4-乙醯基哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物257:7-[2-(二乙胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物258:7-[2-(環丁胺基)吡啶-3-基]-5-(2,2,2-三氟 乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物259:7-[2-(2,6-二甲基嗎啉-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物260:7-[2-(4-環丙基哌嗪-1-基)吡啶-4-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物261:7-(2-環己胺基吡啶-3-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物262:7-[2-(異丙基甲基胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物263:7-(2-環戊胺基吡啶-3-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物264:7-(6-吡咯啶-1-基吡啶-2-基)-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物265:7-[6-(2,6-二甲基嗎啉-4-基)吡啶-2-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物266:7-{2-[環己基(甲基)胺基]吡啶-3-基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物267:7-[2-(4-環丙基哌嗪-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物268:7-[3-(4-環丙基哌嗪-1-基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物269:7-[2-(4-乙醯基-1,4-二氮雜環庚烷-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮; 化合物270:7-[2-(4-甲基-1,4-二氮雜環庚烷-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物271:7-[2-(4-環丙基-[1,4]二氮雜環庚烷-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物272:7-[2-(3-氟吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-2,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物273:7-[2-(4-氟哌啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物274:7-(2-羥基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物275:7-(1-氧基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物276:7-(1-氧基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;該化合物呈鹼或酸加成鹽之形式,且亦可呈水合物形式。
- 如請求項1或2之式(I)化合物,其選自以下化合物:化合物1:7-(吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物2:7-(2-胺基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物6:7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫- 4H-吡唑并[4,3-c]喹啉-4-酮;化合物19:7-[4-(4-甲基哌嗪-1-基)苯基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物67:5-乙基-7-[6-(哌嗪-1-基)吡啶-3-基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物68:7-[2-(4-甲基哌嗪-1-基)吡啶-4-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物69:5-乙基-7-[2-(4-甲基哌嗪-1-基)吡啶-4-基]-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物72:7-(2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物74:7-(2-氯-6-甲基吡啶-3-基)-5-乙基-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物75:7-(2-氯-6-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物76:7-(2-氯吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物77:7-(2-氟吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物79:7-(6-氯-2-甲基吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物83:7-[6-(嗎啉-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物88:7-(6-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5- 二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物111:7-(2-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物168:7-(2,6-二甲基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物169:7-(3-氯吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物171:7-(6-甲基吡啶-2-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物172:7-[2-(嗎啉-4-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物176:3-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-1H-吡唑并[4,3-c]喹啉-7-基]吡啶-2-甲腈;化合物186:7-(2-甲基吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物196:8-氯-7-(吡啶-4-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物199:8-氯-7-(2-氯吡啶-3-基)-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物209:7-{2-[(4-甲基-1,4-二氮雜環庚烷-1-基)羰基]苯基}-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物232:N-{2-[4-側氧基-5-(2,2,2-三氟乙基)-4,5-二氫-2H-吡唑并[4,3-c]喹啉-7-基]苯基}甲烷磺醯胺; 化合物248:7-[2-(二甲胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物251:7-[2-(吡咯啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物257:7-[2-(二乙胺基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;化合物273:7-[2-(4-氟哌啶-1-基)吡啶-3-基]-5-(2,2,2-三氟乙基)-1,5-二氫-4H-吡唑并[4,3-c]喹啉-4-酮;該化合物呈鹼或酸加成鹽之形式,且亦可呈水合物形式。
- 一種式(VIII)化合物,
- 一種式(XIV)化合物,
- 一種藥物,其特徵在於其包含如請求項1至8中任一項之式(I)化合物,或此化合物與醫藥學上可接受之酸的加成鹽。
- 一種醫藥組合物,其特徵在於其包含如請求項1至8中任一項之式(I)化合物,或此化合物之醫藥學上可接受之鹽,以及至少一種醫藥學上可接受之賦形劑。
- 一種如請求項1至8中任一項之式(I)化合物的用途,其用於製備供治療以下疾病用之藥物:肺纖維化及肝纖維化;涉及血管生成再活化之病理;具有實質性血管化程度之任何癌瘤;實體腫瘤;肝癌;膽管癌;惡性間皮瘤;胰腺癌;血管瘤;子宮內膜異位;關節炎;肥胖症;自體免疫疾病;微孢子蟲病。
- 如請求項13之用途,其中該涉及血管生成再活化之病理為糖尿病性視網膜病、年齡相關之黃斑部變性(ARMD)或牛皮癬。
- 如請求項13之用途,其中該具有實質性血管化程度之任何癌瘤為肺癌、乳癌、前列腺癌、食道癌、胰腺癌、肝癌、結腸癌或腎癌,或任何癌瘤誘發性轉移。
- 如請求項15之用途,其中該癌瘤誘發性轉移為結腸癌、乳癌、肝癌或胃癌,或黑色素瘤。
- 如請求項13之用途,其中該實體腫瘤為胰腺腫瘤、乳房腫瘤、前列腺腫瘤、結腸腫瘤或腎腫瘤、神經母細胞瘤 或卡波西氏肉瘤,
- 如請求項13之用途,其中該關節炎為類風濕性關節炎。
- 如請求項13至18中任一項之用途,其中該藥物用於單方療法中或與放射線療法或化學療法組合使用。
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ES2308272T3 (es) * | 2003-11-21 | 2008-12-01 | Novartis Ag | Derivados de 1h-imidazoquinolina como inhibidores de la proteina quinasa. |
WO2006063167A1 (en) * | 2004-12-08 | 2006-06-15 | Smithkline Beecham Corporation | 1h-pyrrolo[2,3-b]pyridines |
CA2594091A1 (en) * | 2005-01-07 | 2006-07-13 | Arpida Ag | Selected benzofuran derivatives |
FR2921657A1 (fr) * | 2007-09-28 | 2009-04-03 | Sanofi Aventis Sa | Derives de nicotinamide, leur preparation et leur application en therapeutique |
DE102008027574A1 (de) * | 2008-06-10 | 2009-12-17 | Merck Patent Gmbh | Neue Pyrrolidinderivate als MetAP-2 Inhibitoren |
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DE102010048374A1 (de) * | 2010-10-13 | 2012-04-19 | Merck Patent Gmbh | Pyrrolidinone als MetAP-2 Inhibitoren |
JP6042060B2 (ja) * | 2011-09-26 | 2016-12-14 | サノフイ | ピラゾロキノリノン誘導体、その調製および治療上の使用 |
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PL2573073T3 (pl) | 2015-04-30 |
KR20140082743A (ko) | 2014-07-02 |
EP2760841A1 (en) | 2014-08-06 |
DK2573073T3 (en) | 2015-01-19 |
RU2621037C2 (ru) | 2017-05-31 |
BR112014007193A2 (pt) | 2017-04-04 |
AU2012314620B2 (en) | 2017-06-29 |
CY1115945T1 (el) | 2017-01-25 |
EP2573073B1 (en) | 2014-10-22 |
SI2573073T1 (sl) | 2015-02-27 |
SG11201400403SA (en) | 2014-08-28 |
ES2527188T3 (es) | 2015-01-21 |
HK1181763A1 (zh) | 2013-11-15 |
CN103958479B (zh) | 2017-06-13 |
CA2847921A1 (en) | 2013-04-04 |
UY34350A (es) | 2013-04-30 |
IL231386A0 (en) | 2014-04-30 |
EP2760841B1 (en) | 2016-08-24 |
AU2012314620A1 (en) | 2014-03-27 |
WO2013045400A1 (en) | 2013-04-04 |
JP6073328B2 (ja) | 2017-02-01 |
PT2573073E (pt) | 2015-02-05 |
MX2014003675A (es) | 2014-08-21 |
EP2573073A1 (en) | 2013-03-27 |
ES2605152T3 (es) | 2017-03-13 |
IL231386A (en) | 2016-04-21 |
JP2014526545A (ja) | 2014-10-06 |
HRP20150024T1 (hr) | 2015-02-13 |
TW201313719A (zh) | 2013-04-01 |
CN103958479A (zh) | 2014-07-30 |
AR088000A1 (es) | 2014-04-30 |
RU2014117035A (ru) | 2015-11-10 |
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