CN111278815A - 戊二酰亚胺 - Google Patents
戊二酰亚胺 Download PDFInfo
- Publication number
- CN111278815A CN111278815A CN201880069719.7A CN201880069719A CN111278815A CN 111278815 A CN111278815 A CN 111278815A CN 201880069719 A CN201880069719 A CN 201880069719A CN 111278815 A CN111278815 A CN 111278815A
- Authority
- CN
- China
- Prior art keywords
- carboxamide
- dioxo
- dioxopiperidin
- piperidyl
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 177
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 25
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 25
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- -1 2, 6-dioxopiperidin-3-yl Chemical group 0.000 claims description 165
- 150000003839 salts Chemical class 0.000 claims description 70
- 125000000217 alkyl group Chemical group 0.000 claims description 68
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 62
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 53
- 238000006467 substitution reaction Methods 0.000 claims description 26
- 235000005152 nicotinamide Nutrition 0.000 claims description 25
- 239000011570 nicotinamide Substances 0.000 claims description 25
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 19
- CTVJOMHYRHQHLU-KFJBMODSSA-N N-[(3S)-2,6-dioxopiperidin-3-yl]-1,2,3,4-tetrahydroquinoline-4-carboxamide Chemical compound O=C(N[C@H]1CCC(=O)NC1=O)C1CCNC2=C1C=CC=C2 CTVJOMHYRHQHLU-KFJBMODSSA-N 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 16
- HQDMUGFDSMUBCS-LSLKUGRBSA-N (1S)-N-(1-methyl-2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide Chemical compound CN1C(=O)CCC(NC(=O)[C@H]2CCCC3=C2C=CC=C3)C1=O HQDMUGFDSMUBCS-LSLKUGRBSA-N 0.000 claims description 13
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 12
- 239000013543 active substance Substances 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 10
- QDCDITVKCKBZTO-UHFFFAOYSA-N n-(2,6-dioxopiperidin-3-yl)benzamide Chemical compound C=1C=CC=CC=1C(=O)NC1CCC(=O)NC1=O QDCDITVKCKBZTO-UHFFFAOYSA-N 0.000 claims description 10
- 238000011321 prophylaxis Methods 0.000 claims description 10
- 230000001225 therapeutic effect Effects 0.000 claims description 10
- 102100029895 Bromodomain-containing protein 4 Human genes 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- HJIUSPUWMFCKIL-PZORYLMUSA-N (1R)-N-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide Chemical compound O=C1NC(CCC1NC(=O)[C@@H]1CCCC2=CC=CC=C12)=O HJIUSPUWMFCKIL-PZORYLMUSA-N 0.000 claims description 8
- CTVJOMHYRHQHLU-CMPLNLGQSA-N (4S)-N-[(3R)-2,6-dioxopiperidin-3-yl]-1,2,3,4-tetrahydroquinoline-4-carboxamide Chemical compound O=C(N[C@@H]1CCC(=O)NC1=O)[C@H]1CCNC2=C1C=CC=C2 CTVJOMHYRHQHLU-CMPLNLGQSA-N 0.000 claims description 8
- LPCQBTAOTIZGAE-UHFFFAOYSA-N 2h-pyrimidine-1-carboxamide Chemical compound NC(=O)N1CN=CC=C1 LPCQBTAOTIZGAE-UHFFFAOYSA-N 0.000 claims description 8
- 108091005625 BRD4 Proteins 0.000 claims description 8
- HJIUSPUWMFCKIL-UEWDXFNNSA-N (1S)-N-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide Chemical compound O=C(NC1CCC(=O)NC1=O)[C@H]1CCCC2=CC=CC=C12 HJIUSPUWMFCKIL-UEWDXFNNSA-N 0.000 claims description 7
- HJIUSPUWMFCKIL-QWHCGFSZSA-N (1S)-N-[(3R)-2,6-dioxopiperidin-3-yl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide Chemical compound O=C(N[C@@H]1CCC(=O)NC1=O)[C@H]1CCCc2ccccc12 HJIUSPUWMFCKIL-QWHCGFSZSA-N 0.000 claims description 7
- HJIUSPUWMFCKIL-STQMWFEESA-N (1S)-N-[(3S)-2,6-dioxopiperidin-3-yl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide Chemical compound O=C(N[C@H]1CCC(=O)NC1=O)[C@H]1CCCc2ccccc12 HJIUSPUWMFCKIL-STQMWFEESA-N 0.000 claims description 7
- DVZDBGSLWMRUKV-SNVBAGLBSA-N N-[(3R)-2,6-dioxopiperidin-3-yl]-1-benzothiophene-3-carboxamide Chemical compound O=C(N[C@@H]1CCC(=O)NC1=O)c1csc2ccccc12 DVZDBGSLWMRUKV-SNVBAGLBSA-N 0.000 claims description 7
- DLQXJRQBPBIMKG-JTQLQIEISA-N N-[(3S)-2,6-dioxopiperidin-3-yl]-1-benzofuran-3-carboxamide Chemical compound O=C1NC(CC[C@@H]1NC(=O)C1=COC2=C1C=CC=C2)=O DLQXJRQBPBIMKG-JTQLQIEISA-N 0.000 claims description 7
- DVZDBGSLWMRUKV-JTQLQIEISA-N N-[(3S)-2,6-dioxopiperidin-3-yl]-1-benzothiophene-3-carboxamide Chemical compound O=C(N[C@H]1CCC(=O)NC1=O)C1=CSC2=CC=CC=C12 DVZDBGSLWMRUKV-JTQLQIEISA-N 0.000 claims description 7
- GSAMMNQBAJVRMF-VIFPVBQESA-N N-[(3S)-2,6-dioxopiperidin-3-yl]-2,3-dihydropyrrolo[2,3-b]pyridine-1-carboxamide Chemical compound O=C(N[C@H]1CCC(=O)NC1=O)N1CCC2=CC=CN=C12 GSAMMNQBAJVRMF-VIFPVBQESA-N 0.000 claims description 7
- HJIUSPUWMFCKIL-CHWSQXEVSA-N (1R)-N-[(3R)-2,6-dioxopiperidin-3-yl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide Chemical compound O=C(N[C@@H]1CCC(=O)NC1=O)[C@@H]1CCCC2=C1C=CC=C2 HJIUSPUWMFCKIL-CHWSQXEVSA-N 0.000 claims description 6
- HJIUSPUWMFCKIL-OLZOCXBDSA-N (1R)-N-[(3S)-2,6-dioxopiperidin-3-yl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide Chemical compound O=C(N[C@H]1CCC(=O)NC1=O)[C@@H]1CCCC2=C1C=CC=C2 HJIUSPUWMFCKIL-OLZOCXBDSA-N 0.000 claims description 6
- ZWCMOFGBHZHJPY-QVDQXJPCSA-N N-[(3R)-2,6-dioxopiperidin-3-yl]-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxamide Chemical compound O=C(N[C@@H]1CCC(=O)NC1=O)C1CCc2cccnc12 ZWCMOFGBHZHJPY-QVDQXJPCSA-N 0.000 claims description 6
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 6
- CTVJOMHYRHQHLU-ZYHUDNBSSA-N (4R)-N-[(3R)-2,6-dioxopiperidin-3-yl]-1,2,3,4-tetrahydroquinoline-4-carboxamide Chemical compound O=C(N[C@@H]1CCC(=O)NC1=O)[C@@H]1CCNC2=C1C=CC=C2 CTVJOMHYRHQHLU-ZYHUDNBSSA-N 0.000 claims description 5
- QNKWDLBTSYDRHK-GFCCVEGCSA-N N-[(3R)-2,6-dioxopiperidin-3-yl]-N-methyl-2,3-dihydroindole-1-carboxamide Chemical compound O=C1NC(CC[C@H]1N(C(=O)N1CCC2=CC=CC=C12)C)=O QNKWDLBTSYDRHK-GFCCVEGCSA-N 0.000 claims description 5
- QNKWDLBTSYDRHK-LBPRGKRZSA-N N-[(3S)-2,6-dioxopiperidin-3-yl]-N-methyl-2,3-dihydroindole-1-carboxamide Chemical compound CN([C@H]1CCC(=O)NC1=O)C(=O)N1CCC2=CC=CC=C12 QNKWDLBTSYDRHK-LBPRGKRZSA-N 0.000 claims description 5
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- DLQXJRQBPBIMKG-SNVBAGLBSA-N N-[(3R)-2,6-dioxopiperidin-3-yl]-1-benzofuran-3-carboxamide Chemical compound O=C(N[C@@H]1CCC(=O)NC1=O)c1coc2ccccc12 DLQXJRQBPBIMKG-SNVBAGLBSA-N 0.000 claims description 4
- ZUISDMVKTDAPMR-SECBINFHSA-N N-[(3R)-2,6-dioxopiperidin-3-yl]-1H-indazole-3-carboxamide Chemical compound O=C(N[C@@H]1CCC(=O)NC1=O)c1n[nH]c2ccccc12 ZUISDMVKTDAPMR-SECBINFHSA-N 0.000 claims description 4
- ZCTRHIPLIVOKIE-LLVKDONJSA-N N-[(3R)-2,6-dioxopiperidin-3-yl]-1H-indole-3-carboxamide Chemical compound O=C(N[C@@H]1CCC(=O)NC1=O)c1c[nH]c2ccccc12 ZCTRHIPLIVOKIE-LLVKDONJSA-N 0.000 claims description 4
- GSAMMNQBAJVRMF-SECBINFHSA-N N-[(3R)-2,6-dioxopiperidin-3-yl]-2,3-dihydropyrrolo[2,3-b]pyridine-1-carboxamide Chemical compound O=C(N[C@@H]1CCC(=O)NC1=O)N1CCc2cccnc12 GSAMMNQBAJVRMF-SECBINFHSA-N 0.000 claims description 4
- JXYQVGYLWZVTER-SNVBAGLBSA-N N-[(3R)-2,6-dioxopiperidin-3-yl]indolizine-3-carboxamide Chemical compound O=C(N[C@@H]1CCC(=O)NC1=O)c1ccc2ccccn12 JXYQVGYLWZVTER-SNVBAGLBSA-N 0.000 claims description 4
- HBTFWBKPBZUTOJ-QMMMGPOBSA-N N-[(3S)-2,6-dioxopiperidin-3-yl]-1-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxamide Chemical compound O=C1NC(CC[C@@H]1NC(=O)C1=NN(C2=C1CNCC2)C)=O HBTFWBKPBZUTOJ-QMMMGPOBSA-N 0.000 claims description 4
- ZCTRHIPLIVOKIE-NSHDSACASA-N N-[(3S)-2,6-dioxopiperidin-3-yl]-1H-indole-3-carboxamide Chemical compound O=C1NC(CC[C@@H]1NC(=O)C1=CNC2=CC=CC=C12)=O ZCTRHIPLIVOKIE-NSHDSACASA-N 0.000 claims description 4
- JXYQVGYLWZVTER-JTQLQIEISA-N N-[(3S)-2,6-dioxopiperidin-3-yl]indolizine-3-carboxamide Chemical compound O=C(N[C@H]1CCC(=O)NC1=O)C1=CC=C2C=CC=CN12 JXYQVGYLWZVTER-JTQLQIEISA-N 0.000 claims description 4
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 125000005647 linker group Chemical group 0.000 claims description 4
- FNCUEVKJDKUOIQ-NSHDSACASA-N methyl 3-[[(3S)-2,6-dioxopiperidin-3-yl]carbamoyl]-1H-indole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C(NC=C2C(=O)N[C@H]2CCC(=O)NC2=O)=C1 FNCUEVKJDKUOIQ-NSHDSACASA-N 0.000 claims description 4
- DLQXJRQBPBIMKG-UHFFFAOYSA-N n-(2,6-dioxopiperidin-3-yl)-1-benzofuran-3-carboxamide Chemical compound C=1OC2=CC=CC=C2C=1C(=O)NC1CCC(=O)NC1=O DLQXJRQBPBIMKG-UHFFFAOYSA-N 0.000 claims description 4
- DVZDBGSLWMRUKV-UHFFFAOYSA-N n-(2,6-dioxopiperidin-3-yl)-1-benzothiophene-3-carboxamide Chemical compound C=1SC2=CC=CC=C2C=1C(=O)NC1CCC(=O)NC1=O DVZDBGSLWMRUKV-UHFFFAOYSA-N 0.000 claims description 4
- RKPBOLOTHPHQOI-UHFFFAOYSA-N n-(2,6-dioxopiperidin-3-yl)-1-methylindole-3-carboxamide Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)NC1CCC(=O)NC1=O RKPBOLOTHPHQOI-UHFFFAOYSA-N 0.000 claims description 4
- ZCTRHIPLIVOKIE-UHFFFAOYSA-N n-(2,6-dioxopiperidin-3-yl)-1h-indole-3-carboxamide Chemical compound C=1NC2=CC=CC=C2C=1C(=O)NC1CCC(=O)NC1=O ZCTRHIPLIVOKIE-UHFFFAOYSA-N 0.000 claims description 4
- GVVMLDZDEDVDJM-UHFFFAOYSA-N n-(2,6-dioxopiperidin-3-yl)cyclopentanecarboxamide Chemical compound C1CCCC1C(=O)NC1CCC(=O)NC1=O GVVMLDZDEDVDJM-UHFFFAOYSA-N 0.000 claims description 4
- JROFNEPHRJSWLC-NSHDSACASA-N tert-butyl 3-[[(3S)-2,6-dioxopiperidin-3-yl]carbamoyl]-1-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate Chemical compound CN1N=C(C(=O)N[C@H]2CCC(=O)NC2=O)C2=C1CCN(C2)C(=O)OC(C)(C)C JROFNEPHRJSWLC-NSHDSACASA-N 0.000 claims description 4
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 3
- OQGRFQCUGLKSAV-JTQLQIEISA-N n-[(3s)-2,6-dioxopiperidin-3-yl]-2-phenylacetamide Chemical compound N([C@@H]1C(NC(=O)CC1)=O)C(=O)CC1=CC=CC=C1 OQGRFQCUGLKSAV-JTQLQIEISA-N 0.000 claims description 3
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- NVQNTNNKVVVBRQ-GCJDJSOWSA-N (1R,2R)-N-(2,6-dioxopiperidin-3-yl)-2-ethylcyclopropane-1-carboxamide Chemical compound O=C1NC(CCC1NC(=O)[C@H]1[C@@H](C1)CC)=O NVQNTNNKVVVBRQ-GCJDJSOWSA-N 0.000 claims description 2
- ICTRTBSHSCRHHB-WPZUCAASSA-N (3R,4R)-N-(2,6-dioxopiperidin-3-yl)-4-methylpyrrolidine-3-carboxamide Chemical compound O=C1NC(CCC1NC(=O)[C@H]1CNC[C@@H]1C)=O ICTRTBSHSCRHHB-WPZUCAASSA-N 0.000 claims description 2
- CZGVDMWXQRDIBT-PKPIPKONSA-N (3S)-N-(2,6-dioxopiperidin-3-yl)pyrrolidine-3-carboxamide Chemical compound O=C1NC(CCC1NC(=O)[C@@H]1CNCC1)=O CZGVDMWXQRDIBT-PKPIPKONSA-N 0.000 claims description 2
- PCXQMOLQXOVQSR-UHFFFAOYSA-N 2-(3,4-dihydro-2H-chromen-4-yl)-N-(2,6-dioxopiperidin-3-yl)acetamide Chemical compound O=C(CC1CCOc2ccccc12)NC1CCC(=O)NC1=O PCXQMOLQXOVQSR-UHFFFAOYSA-N 0.000 claims description 2
- LUGVSDYOYNQPDW-UHFFFAOYSA-N 2-(azetidin-3-yl)-n-(2,6-dioxopiperidin-3-yl)acetamide Chemical compound C1CC(=O)NC(=O)C1NC(=O)CC1CNC1 LUGVSDYOYNQPDW-UHFFFAOYSA-N 0.000 claims description 2
- YNNUSGIPVFPVBX-UHFFFAOYSA-N 2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine Chemical compound CN1CCCC1CCOC(C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-UHFFFAOYSA-N 0.000 claims description 2
- LETARFCIZBLOMT-UHFFFAOYSA-N 2-cyclopentyl-n-(2,6-dioxopiperidin-3-yl)acetamide Chemical compound C1CC(=O)NC(=O)C1NC(=O)CC1CCCC1 LETARFCIZBLOMT-UHFFFAOYSA-N 0.000 claims description 2
- PCMGHJOQBNLEDY-UHFFFAOYSA-N 2-ethyl-N-methyl-1-(2-oxo-1,3-dihydrobenzimidazol-5-yl)benzimidazole-5-carboxamide Chemical compound CCC1=NC2=CC(=CC=C2N1C1=CC2=C(NC(=O)N2)C=C1)C(=O)NC PCMGHJOQBNLEDY-UHFFFAOYSA-N 0.000 claims description 2
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 2
- XTIWISLWWFVRIF-UHFFFAOYSA-N 3-piperidin-1-ylpiperidine-2,6-dione Chemical compound O=C1NC(CCC1N1CCCCC1)=O XTIWISLWWFVRIF-UHFFFAOYSA-N 0.000 claims description 2
- HPKJSLIAXLUJIS-UHFFFAOYSA-N 4-butyl-n-(2,6-dioxopiperidin-3-yl)cyclohexane-1-carboxamide Chemical compound C1CC(CCCC)CCC1C(=O)NC1C(=O)NC(=O)CC1 HPKJSLIAXLUJIS-UHFFFAOYSA-N 0.000 claims description 2
- WXWMKAXAGZAKMA-UHFFFAOYSA-N 5-(2-quinolin-4-ylbenzimidazol-1-yl)-1,3-dihydrobenzimidazol-2-one Chemical compound O=C1NC2=C(N1)C=C(C=C2)N1C2=CC=CC=C2N=C1C1=CC=NC2=CC=CC=C12 WXWMKAXAGZAKMA-UHFFFAOYSA-N 0.000 claims description 2
- ZGOUQTYKAQUKOV-UHFFFAOYSA-N 5-[2-[2-(3-methylimidazol-4-yl)quinolin-4-yl]benzimidazol-1-yl]-1,3-dihydrobenzimidazol-2-one Chemical compound CN1C=NC=C1C1=NC2=CC=CC=C2C(=C1)C1=NC2=CC=CC=C2N1C1=CC2=C(NC(=O)N2)C=C1 ZGOUQTYKAQUKOV-UHFFFAOYSA-N 0.000 claims description 2
- VCFJPBFJLDUJHL-UHFFFAOYSA-N C1=C(C)C(C)=CC=C1C(=O)NC1C(=O)NC(=O)CC1 Chemical compound C1=C(C)C(C)=CC=C1C(=O)NC1C(=O)NC(=O)CC1 VCFJPBFJLDUJHL-UHFFFAOYSA-N 0.000 claims description 2
- QVKZOPDZWIRRMK-UHFFFAOYSA-N C1CC(=O)NC(=O)C1NC(=O)CC1CC1 Chemical compound C1CC(=O)NC(=O)C1NC(=O)CC1CC1 QVKZOPDZWIRRMK-UHFFFAOYSA-N 0.000 claims description 2
- HJIUSPUWMFCKIL-UHFFFAOYSA-N C1CCC2=CC=CC=C2C1C(=O)NC1CCC(=O)NC1=O Chemical compound C1CCC2=CC=CC=C2C1C(=O)NC1CCC(=O)NC1=O HJIUSPUWMFCKIL-UHFFFAOYSA-N 0.000 claims description 2
- TYZIHOIJSJPKLV-UHFFFAOYSA-N C1CCCCCCC1C(=O)NC1CCC(=O)NC1=O Chemical compound C1CCCCCCC1C(=O)NC1CCC(=O)NC1=O TYZIHOIJSJPKLV-UHFFFAOYSA-N 0.000 claims description 2
- LHEKYGRRSUYZEM-UHFFFAOYSA-N C1COCC1C(=O)NC1CCC(=O)NC1=O Chemical compound C1COCC1C(=O)NC1CCC(=O)NC1=O LHEKYGRRSUYZEM-UHFFFAOYSA-N 0.000 claims description 2
- IGKKZTUZVGGKCY-UHFFFAOYSA-N C1CSCC1C(=O)NC1CCC(=O)NC1=O Chemical compound C1CSCC1C(=O)NC1CCC(=O)NC1=O IGKKZTUZVGGKCY-UHFFFAOYSA-N 0.000 claims description 2
- JBSTVVKYVUJZRG-UHFFFAOYSA-N CC1=CC=CC=C1CC(=O)NC1C(=O)NC(=O)CC1 Chemical compound CC1=CC=CC=C1CC(=O)NC1C(=O)NC(=O)CC1 JBSTVVKYVUJZRG-UHFFFAOYSA-N 0.000 claims description 2
- ZRUWFPSTZFFMRJ-UHFFFAOYSA-N N,2-dimethyl-1-(2-oxo-1,3-dihydrobenzimidazol-5-yl)benzimidazole-5-carboxamide Chemical compound CNC(=O)C1=CC=C2N(C(C)=NC2=C1)C1=CC2=C(NC(=O)N2)C=C1 ZRUWFPSTZFFMRJ-UHFFFAOYSA-N 0.000 claims description 2
- OFFGBFXKSRUGIQ-UHFFFAOYSA-N N-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide Chemical compound O=C(NC1CCC(=O)NC1=O)C1CCc2ccccc2C1 OFFGBFXKSRUGIQ-UHFFFAOYSA-N 0.000 claims description 2
- CTVJOMHYRHQHLU-UHFFFAOYSA-N N-(2,6-dioxopiperidin-3-yl)-1,2,3,4-tetrahydroquinoline-4-carboxamide Chemical compound C1CNC2=CC=CC=C2C1C(=O)NC1CCC(=O)NC1=O CTVJOMHYRHQHLU-UHFFFAOYSA-N 0.000 claims description 2
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- 239000004408 titanium dioxide Substances 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
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Abstract
本发明提供了化合物,其与泛表达的E3连接酶蛋白cereblon(CRBN)结合并改变CRBN E3泛素蛋白连接酶复合体的底物特异性,从而导致固有的下游蛋白的分解。因此,本发明化合物可用于治疗各种癌症。
Description
技术领域
本发明提供了化合物,其与泛表达的E3连接酶蛋白cereblon(CRBN)结合并改变CRBN E3泛素蛋白连接酶复合体的底物特异性,从而导致固有的下游蛋白的分解。因此,本发明化合物可用于治疗各种癌症。
背景技术
近年来,由小分子促进的靶蛋白质降解领域得到了深入的研究1。
蛋白质降解在各种细胞功能中起作用,即通过降解成小肽来调整调节蛋白的浓度,以维持细胞的健康和生产力。
Cereblon是一种形成E3泛素连接酶复合体的蛋白质,该复合体泛素化其他各种蛋白质。已知Cereblon为抗癌药物沙利度胺类似物的主要靶标。Cereblon的较高表达与沙利度胺类似物在癌症治疗中的功效有关。
近年来,已经记载了一些双功能化合物作为靶向泛素化的有用的调节剂,例如WO20130205572、WO20130635603、WO 20131066434、WO20151608455、WO20160119066、WO20161055187、WO20170076128、WO20170243189和WO201711747310。
US455805711、CN169612712、Buckner等13、Huang等14、Xu等15、Hendry等16、WO200800797917、CAS No.1491860-78-618、CAS No.1480842-08-719、CAS No.1466257-08-820、CAS No.1465134-13-721、CAS No.1462991-23-622、WO201719705123、CAS No.1487722-61-124、CAS No.1925250-20-925、CAS No.1512181-14-426、CAS No.1466882-97-227、CASNo.1468435-76-828、CAS No.1467495-41-529、CAS No.1480018-59-430、CAS No.1496032-76-831、CAS No.1993422-50-632、CAS No.1869440-20-933、CAS No.1495663-98-334、CASNo.1491860-78-635、CAS No.1485498-58-536、CAS No.1702002-20-737、CAS No.1490092-2738、CAS No.1540138-47-339、CAS No.1998850-87-540、CAS No.1966549-05-241、CASNo.1957941-94-442、CAS No.1948185-02-143、CAS No.1925097-89-744、CAS No.1922676-64-945、CAS No.1923778-80-646、CAS No.1560748-55-147、CAS No.1559709-03-348、CASNo.1543949-70-749、CAS No.1541076-23-650、CAS No.1522124-94-251、CAS No.1519516-43-852、CAS No.1492524-17-053、CAS No.1491481-66-354、CAS No.1486311-15-255、CASNo.1467658-22-556、CAS No.1462942-69-357、CAS No.1464846-46-558和CAS No.1466763-16-559描述了一些结构类似的化合物。
但是,持续存在对有效治疗癌症的需求。
发明内容
本发明提供式I的戊二酰亚胺,或其药学上可接受的盐,
其中取代基和变量如以下和权利要求中所述,或其药学上可接受的盐。
本发明化合物可用于癌症的治疗性和/或预防性治疗。
本发明的化合物可以进一步用作包含本发明的化合物作为E3泛素连接酶部分的双功能化合物的一部分,该E3泛素连接酶部分连接至与靶蛋白结合的部分,其中靶蛋白接近泛素连接酶以实现所述蛋白质的降解。
具体实施方式
本发明提供了式I的化合物及其药学上可接受的盐,上述化合物的制备,包含它们的药物及其制备以及上述化合物在癌症的治疗性和/或预防性治疗中的用途。
不管所讨论的术语是单独出现还是与其他基团组合出现,本说明书中通用术语的以下定义都适用。
除非另有说明,否则本申请中使用的以下术语(包括说明书和权利要求书)具有以下给出的定义。必须注意,在说明书和所附权利要求书中使用的单数形式“一(a)”,“一个(an)”和“所述(the)”包括复数个提及物,除非上下文另有明确说明。
单独的或与其他基团组合的术语“C1-6-烷基”代表可以是直链或支链的(具有单个或多个支链的)烃基,其中烷基通常包含1至6个碳原子,例如甲基(Me)、乙基(Et)、丙基、异丙基(异丙基)、正丁基、异丁基(异丁基)、2-丁基(仲丁基)、叔丁基(叔丁基)、异戊基、2-乙基-丙基(2-甲基-丙基)、1,2-二甲基-丙基等。具体的基团是甲基。
单独的或与其他基团组合的术语“卤素-C1-6-烷基”是指如本文所定义的C1-6-烷基,其被一个或多个卤素,特别是1-5个卤素,更特别是1-3个卤素取代。具体的卤素是氟。具体的“卤素-C1-6-烷基”是氟代-C1-6-烷基,并且具体的“卤素-C1-3-烷基”是氟代-C1-3-烷基。实例是三氟甲基、二氟甲基、氟代甲基等。
单独的或与其他基团组合的术语“羟基-C1-6-烷基”是指如本文所定义的C1-6-烷基,其被一个或多个羟基,特别是1个羟基取代。实例是-CH2OH,-CH2CH2OH等。
单独的或与其他基团组合的术语“羟基”是指OH。
单独的或与其他基团组合的术语“卤素”表示氯(Cl),碘(I),氟(F)和溴(Br)。具体的基团是F。
术语“杂芳基”表示具有5至12个环原子的单价杂环的单环或双环环系,其包含1,2,3或4个选自N,O和S的杂原子,其余的环原子为碳,并且其中至少一个环是芳族的。杂芳基基团的实例包括吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、三唑基、噁二唑基、噻二唑基、四唑基、吡啶基、吡嗪基、吡唑基、哒嗪基、嘧啶基、三嗪基、氮杂基(azepinyl)、二氮杂基(diazepinyl)、异噁唑基、苯并呋喃基、异噻唑基、苯并噻吩基、吲哚啉基、吲哚基、异吲哚、异苯并呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并噁二唑基、苯并噻二唑基、苯并三唑基、嘌呤基、喹啉基、异喹啉基、二氢喹啉基、二氢吡咯并吡啶基、二氢萘啶基、色满基、四氢喹啉基、二氢环戊二烯并吡啶基、喹唑啉基或喹喔啉基。
术语“杂环烷基”表示具有4至9个环原子的单价饱和的或部分不饱和的单环或双环环系,其包含1,2或3个选自N,O和S的环杂原子,其余的环原子为碳。单环饱和杂环烷基的实例是氮杂环丁烷基、吡咯烷基、四氢呋喃基、四氢噻吩基、吡唑烷基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、哌啶基、四氢吡喃基、四氢硫代吡喃基、哌嗪基、吗啉基、硫代吗啉基、l,l-二氧代-硫代吗啉-4-基、氮杂环庚烷基(azepanyl)、二氮杂环庚烷基(diazepanyl)、高哌嗪基或氧杂氮杂环庚烷基(oxazepanyl)。双环饱和杂环烷基的实例是8-氮杂-双环[3.2.1]辛基、奎宁环基、8-氧杂-3-氮杂-双环[3.2.1]辛基、9-氮杂-双环[3.3.1]壬基、3-氧杂-9-氮杂-双环[3.3.1]壬基或3-硫杂9-氮杂-双环[3.3.1]壬基。部分不饱和杂环烷基的实例是二氢呋喃基、咪唑啉基、二氢-噁唑基、四氢-吡啶基或二氢吡喃基。
单独的或与其他基团组合的术语“C1-6-烷氧基”代表可以是直链或支链的(具有单个或多个支链的)-O-C1-6-烷基,其中烷基通常包括1-6个碳原子,例如甲氧基(OMe、MeO)、乙氧基(OEt)、丙氧基、异丙氧基(异丙氧基)、正丁氧基、异丁氧基(异丁氧基)、2-丁氧基(仲丁氧基)、叔丁氧基(叔丁氧基)、异戊氧基(异戊氧基)等。具体的“C1-6烷氧基”是具有1-4个碳原子的基团。具体的基团是甲氧基。
术语“芳基”表示包含6至10个碳环原子并且其中至少一个环为芳族的单价芳族碳环单环或双环环系。芳基基团的实例包括苯基(Ph)、茚满基、萘满基和萘基。具体的“芳基”是苯基。
类似“被R取代的a-b-x”的术语是指该基团的“x”部分被R取代。
术语“药学上可接受的”表示可用于制备药物组合物的材料的属性,该材料通常是安全的、无毒的、在生物学上或其他方面都不是不期望的并且对于兽用和人的药用而言都是可接受的。
术语“药学上可接受的盐”是指适用于与人和动物的组织接触的盐。与无机酸和有机酸形成的合适盐的实例是但不限于:乙酸、柠檬酸、甲酸、富马酸、盐酸、乳酸、马来酸、苹果酸、甲烷-磺酸、硝酸、磷酸、对甲苯磺酸、琥珀酸、硫酸(硫酸)、酒石酸、三氟乙酸等。具体的酸是甲酸、三氟乙酸和盐酸。具体的酸是盐酸、三氟乙酸和富马酸。
术语“药学上可接受的辅助物质”是指与制剂的其他成分相容的载体和辅助物质,例如稀释剂或赋形剂。
术语“药物组合物”涵盖包含预定量或比例的特定成分的产品,以及通过合并特定量的特定成分而直接或间接产生的任何产品。特别地,它涵盖包含一种或多种活性成分以及任选的载体(包括惰性成分)的产品,以及通过以下而直接或间接产生的任何产品:通过使任意两种或更多种成分合并、络合或聚集,或者通过一种或多种成分的解离,或者通过一种或多种成分的其他类型的反应或相互作用。
“治疗有效量”是指当施用于个体以治疗疾病状态时足以对所述疾病状态进行治疗的化合物的量。“治疗有效量”将根据化合物、所治疗的疾病状态、所治疗的疾病的严重程度、个体的年龄和相对健康状况、给药途径和形式、主治医师或兽医的判断以及其他因素而变化。
当涉及变量时,术语“如本文所定义的”和“如本文所述的”通过引用并入该变量的广义定义以及具体地,更具体的,最具体的定义(如果有的话)。
当涉及化学反应时,术语“处理”、“接触”和“反应”是指在适当条件下添加或混合两种或更多种试剂以产生所示和/或所需的产物。应当理解,产生所示的和/或所需的产物的反应可能不一定直接由最初加入的两种试剂的组合产生,即,可能存在一种或多种中间体,所述中间体在最终导致所示的和/或所需的产物的形成的混合物中产生。
术语“芳族的”表示如文献中所定义的芳香性的常规概念,特别是在IUPAC-Compendium of Chemical Terminology,2nd Edition,A.D.McNaught&A.Wilkinson(Eds).Blackwell Scientific Publications,Oxford(1997)中。
术语“药学上可接受的赋形剂”表示用于配制药物产品的、没有治疗活性且无毒的任何成分,例如崩解剂、粘合剂、填充剂、溶剂、缓冲剂、张度剂、稳定剂、抗氧化剂、表面活性剂或润滑剂。
每当在化学结构中存在手性碳时,旨在将与该手性碳相关的所有立体异构体以纯的立体异构体及其混合物的形式涵盖在该结构中。
本发明还提供了药物组合物,其使用方法和制备上述化合物的方法。
所有单独的实施例可以组合。
E1本发明的一个实施方案提供式I的化合物或其药学上可接受的盐,
其中
R1选自由以下组成的组:
i)芳基,任选地被一个或多个R3取代,
ii)杂环烷基,任选地被一个或多个R4取代,
iii)环烷基,任选地被一个或多个R5取代,
iv)杂芳基,任选地被一个或多个R6取代,
R2为H,C1-6烷基或-NC(=O)-C1-6烷基,
R3为H或C1-6烷基,
R4为H或C1-6烷基,
R5为H或C1-6烷基,
R6为H,C1-6烷基,-C(=O)O-C1-6烷基或氧代,
n为0或l;
用作治疗活性物质。
E2本发明的某个实施方案涉及用作治疗活性物质的式I的化合物或其药学上可接受的盐,其中R1是碳环。
E3本发明的某个实施方案涉及用作治疗活性物质的式I的化合物或其药学上可接受的盐,其中R1是杂环。
E4本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,其中
R1选自由以下组成的组:
i)芳基,任选地被一个或多个R3取代,
ii)杂环烷基,任选地被一个或多个R4取代,
iii)环烷基,任选地被一个或多个R5取代,
iv)杂芳基,任选地被一个或多个R6取代,
R2为H或C1-6烷基,
R3为H或C1-6烷基,
R4为H或C1-6烷基,
R5为H或C1-6烷基,
R6为H或C1-6烷基,
n为0或l;
用作治疗活性物质。
E5本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,其中R3选自由以下组成的组:
i)H,
ii)-C(=O)C1-6烷基
iii)-C(=O)-N(R7,R8),
iv)-C(=O)OC1-6烷基,
v)-C1-6烷氧基,
vi)-C1-6烷基,
vii)-C1-6烷基-N(R9)-C(=O)-R10
viii)-卤素,
ix)-卤素-C1-6烷基,
x)-羟基-C1-6烷基,
xi)-N(R7,R8),和
xii)-NH-C(=O)C1-6烷基,
其中R7,R8,R9和R10各自独立地选自H和C1-6烷基。
E6本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,其中R4选自由以下组成的组:
i)H,
ii)-C(=O)C1-6烷基
iii)-C(=O)-N(R7,R8),
iv)-C(=O)OC1-6烷基,
v)-C1-6烷氧基,
vi)-C1-6烷基,
vii)-C1-6烷基-N(R9)-C(=O)-R10
viii)-卤素,
ix)-卤素-C1-6烷基,
x)-羟基-C1-6烷基,
xi)-N(R7,R8),和
xii)-NH-C(=O)C1-6烷基,
其中R7,R8,R9和R10各自独立地选自H和C1-6烷基。
E7本发明的某些实施方案涉及式I的化合物或其药学上可接受的盐,其中R5选自由以下组成的组:
i)H,
ii)-C(=O)C1-6烷基
iii)-C(=O)-N(R7,R8),
iv)-C(=O)OC1-6烷基,
v)-C1-6烷氧基,
vi)-C1-6烷基,
vii)-C1-6烷基-N(R9)-C(=O)-R10
viii)-卤素,
ix)-卤素-C1-6烷基,
x)-羟基-C1-6烷基,
xi)-N(R7,R8),和
xii)-NH-C(=O)C1-6烷基,
其中R7,R8,R9和R10各自独立地选自H和C1-6烷基。
E8本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,其中R6选自由以下组成的组:
i)H,
ii)-C(=O)C1-6烷基
iii)-C(=O)-N(R7,R8),
iv)-C(=O)OC1-6烷基,
v)-C1-6烷氧基,
vi)-C1-6烷基,
vii)-C1-6烷基-N(R9)-C(=O)-R10
viii)-卤素,
ix)-卤素-C1-6烷基,
x)-羟基-C1-6烷基,
xi)-N(R7,R8),和
xii)-NH-C(=O)C1-6烷基,
其中R7,R8,R9和R10各自独立地选自H和C1-6烷基。
E9本发明的某个实施方案涉及用作治疗活性物质的式I的化合物或其药学上可接受的盐,选自由以下组成的组:
(-)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
(+)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
(lR)-N-(2,6-二氧代-3-哌啶基)萘满-1-甲酰胺,
(1S)-N-(2,6-二氧代-3-哌啶基)萘满-1-甲酰胺,
(N-((R)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺,
(S)-N-((R)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(S)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢-1,8-萘啶-l(2H)-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢喹啉-l(2H)-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)苯并呋喃-3-甲酰胺,
N-((R)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酰胺,
N-((S)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酰胺,
N-((S)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-lH-吲哚-3-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-1-甲基-吲哚-3-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-2-丙基-异吲哚啉-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)苯甲酰胺,
N-(2,6-二氧代-3-哌啶基)苯并呋喃-3-甲酰胺,
N-(2,6-二氧代-3-哌啶基)苯并噻吩-3-甲酰胺,
N-(2,6-二氧代-3-哌啶基)环戊烷甲酰胺,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,异构体A,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,异构体B,
N-(2,6-二氧代-3-哌啶基)吲哚啉-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-N-甲基-lH-吲哚-3-甲酰胺,
N-[(3R)-2,6-二氧代-3-哌啶基]-lH-吲哚-3-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]-lH-吲哚-3-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]-2-苯基-乙酰胺,和
N-[(3S)-2,6-二氧代-3-哌啶基]色满-4-甲酰胺。
E10本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,其中
R1选自由以下组成的组:
i)芳基,任选地被一个或多个R3取代,
ii)杂环烷基,任选地被一个或多个R4取代,
iii)环烷基,任选地被一个或多个R5取代,和
iv)杂芳基,任选地被一个或多个R6取代,
R2为H或C1-6烷基,
R3为H或C1-6烷基,
R4为H或C1-6烷基,
R5为H或C1-6烷基,
R6为H或C1-6烷基,
n为0或l;
条件是将以下物质排除在外:(lR,2R)-rel-N-(2,6-二氧代-3-哌啶基)-2-乙基-环丙烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-1,2,3,4-四氢-2-萘甲酰胺、N-(2,6-二氧代-3-哌啶基)-1-乙基-环丙烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-2,2-二甲基-环丙烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-2,2,3,3-四甲基-环丙烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-1-甲基-环戊烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-环庚烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-环丙烷乙酰胺、N-(2,6-二氧代-3-哌啶基)-环戊烷乙酰胺、N-(2,6-二氧代-3-哌啶基)-1,2,3,4-四氢-1-萘甲酰胺、N-(2,6-二氧代-3-哌啶基)-2-甲基-苯乙酰胺、N-(2,6-二氧代-3-哌啶基)-环丁烷甲酰胺、4-丁基-N-(2,6-二氧代-3-哌啶基)-环己烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-3,4-二甲基-苯甲酰胺、N-(2,6-二氧代-3-哌啶基)-环辛烷甲酰胺、4-(l,l-二甲基乙基)-N-(2,6-二氧代-3-哌啶基)-苯甲酰胺、2,6-二氧代-3-哌啶基)-环己烷乙酰胺、N-(2,6-二氧代-3-哌啶基)-2,4,6-三甲基-苯甲酰胺、N-(2,6-二氧代-3-哌啶基)-2,5-二甲基-苯甲酰胺、(3S)-N-(2,6-二氧代-3-哌啶基)-3-吡咯烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-2-甲基-4-哌啶甲酰胺、N-(2,6-二氧代-3-哌啶基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺、N-(2,6-二氧代-3-哌啶基)-3,4-二氢-2H-1-苯并吡喃-4-乙酰胺、N-(2,6-二氧代-3-哌啶基)-2-乙基四氢-3-呋喃甲酰胺、(3R,4R)-rel-N-(2,6-二氧代-3-哌啶基)-4-甲基-3-吡咯烷甲酰胺、N-(2,6-二氧代-3-哌啶基)四氢-3-甲基-2H-吡喃-4-甲酰胺、N-(2,6-二氧代-3-哌啶基)-4-甲基-3-吡咯烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-2-甲基-3-吡咯烷甲酰胺、N-(2,6-二氧代-3-哌啶基)四氢-2H-硫代吡喃-4-乙酰胺、N-(2,6-二氧代-3-哌啶基)-1,2,3,4-四氢-4-喹啉甲酰胺、N-(2,6-二氧代-3-哌啶基)-4-甲基-1-哌啶甲酰胺、N-(2,6-二氧代-3-哌啶基)-3-甲基-1-哌啶甲酰胺、N-(2,6-二氧代-3-哌啶基)-3-吡咯烷乙酰胺、N-(2,6-二氧代-3-哌啶基)-3-氮杂环丁烷乙酰胺、N-(2,6-二氧代-3-哌啶基)-3-氮杂环丁烷甲酰胺、N-(2,6-二氧代-3-哌啶基)四氢-2H-吡喃-4-甲酰胺、N-(2,6-二氧代-3-哌啶基)四氢-3-呋喃甲酰胺、N-(2,6-二氧代-3-哌啶基)四氢-3-噻吩甲酰胺、N-(2,6-二氧代-3-哌啶基)-3,4-二氢-2H-1-苯并吡喃-4-甲酰胺、N-[(3S)-2,6-二氧代-3-哌啶基]-4-甲基-苯甲酰胺、N-(2,6-二氧代-3-哌啶基)-4-甲基-苯乙酰胺、N-(2,6-二氧代-3-哌啶基)-4-甲基-苯甲酰胺、(S)-N-(2,6-二氧代-3-哌啶基)-1-萘乙酰胺、N-[(3S)-2,6-二氧代-3-哌啶基]-苯甲酰胺、N-[(3R)-2,6-二氧代-3-哌啶基]-苯乙酰胺、N-[(3S)-2,6-二氧代-3-哌啶基]-苯乙酰胺、N-[(3S)-2,6-二氧代-3-哌啶基]-2-苯基-乙酰胺、N-(2,6-二氧代-3-哌啶基)-lH-吲哚-3-甲酰胺、N-(2,6-二氧代-3-哌啶基)-1-甲基-吲哚-3-甲酰胺、N-(2,6-二氧代-3-哌啶基)苯甲酰胺、N-(2,6-二氧代-3-哌啶基)环戊烷甲酰胺、N-(2,6-二氧代-3-哌啶基)苯并呋喃-3-甲酰胺、N-(2,6-二氧代-3-哌啶基)苯并噻吩-3-甲酰胺、(lR)-N-(2,6-二氧代-3-哌啶基)萘满-1-甲酰胺、(lS)-N-(2,6-二氧代-3-哌啶基)萘满-1-甲酰胺、N-[(3S)-2,6-二氧代-3-哌啶基]-lH-吲哚-3-甲酰胺和N-[(3R)-2,6-二氧代-3-哌啶基]-lH-吲哚-3-甲酰胺。
E11本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,
R1选自由以下组成的组:
i)杂环烷基,任选地被一个或多个R4取代,
ii)环烷基,任选地被一个或多个R5取代,和
iii)杂芳基,任选地被一个或多个R6取代,
R2为H或C1-6烷基,
R3为H或C1-6烷基,
R4为H或C1-6烷基,
R5为H或C1-6烷基,
R6为H或C1-6烷基,
n为0或l;
条件是将以下物质排除在外:N-[(3S)-2,6-二氧代-3-哌啶基]-2-苯基-乙酰胺、N-(2,6-二氧代-3-哌啶基)-lH-吲哚-3-甲酰胺、N-(2,6-二氧代-3-哌啶基)-1-甲基-吲哚-3-甲酰胺、N-(2,6-二氧代-3-哌啶基)苯甲酰胺、N-(2,6-二氧代-3-哌啶基)环戊烷甲酰胺、N-(2,6-二氧代-3-哌啶基)苯并呋喃-3-甲酰胺、N-(2,6-二氧代-3-哌啶基)苯并噻吩-3-甲酰胺、(lR)-N-(2,6-二氧代-3-哌啶基)萘满-1-甲酰胺、(1S)-N-(2,6-二氧代-3-哌啶基)萘满-1-甲酰胺、N-[(3S)-2,6-二氧代-3-哌啶基]-lH-吲哚-3-甲酰胺和N-[(3R)-2,6-二氧代-3-哌啶基]-lH-吲哚-3-甲酰胺。
E12本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,其中R1是碳环。
E13本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,其中R1是杂环。
E14本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,其中
n为0,
R1选自由以下组成的组:
i)杂环烷基,
ii)环烷基,和
iii)杂芳基。
R2为H或C1-6烷基。
E15本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,其中,R1选自由以下组成的组:
i)杂环烷基,
ii)环烷基,和
iii)杂芳基。
E16本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,其中,R1选自由以下组成的组:
i)1,2,3,4-四氢萘基,
ii)1,2,3,4-四氢喹啉基,
iii)lH-吲哚基,
iv)1-甲基-吲哚基,
v)2,3-二氢-lH-吡咯并[2,3-b]吡啶基,
vi)3,4-二氢-1,8-萘啶基,
vii)3,4-二氢喹啉基,
viii)6,7-二氢-5H-环戊二烯并[b]吡啶基,
ix)苯并[b]噻吩基,
x)苯并呋喃基,
xi)苯并噻吩基,
xii)色满基,
xiii)环戊基,
xiv)茚满基,
xv)吲哚啉基,
xvi)异吲哚啉基,和
xvii)萘满基。
E17本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,其中R2为H。
E18本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,其中R6为C1-6烷基。
E19本发明的某个实施方案涉及式I化合物或其药学上可接受的盐,其中R6是Me或丙基。
E20本发明的某个实施方案涉及式I化合物或其药学上可接受的盐,其选自由以下组成的组:
(S)-N-((R)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(S)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(-)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
(+)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]-1,2,3,4-四氢喹啉-4-甲酰胺,
N-[(3R)-2,6-二氧代-3-哌啶基]-1,2,3,4-四氢喹啉-4-甲酰胺,
(S)-N-((R)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
(4R)-N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺,
(R)-N-((R)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(R)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(1S)-N-(1-甲基-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(1S)-N-(1-甲基-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(1S)-N-(1-甲基-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-1-甲基-4,5,6,7-四氢-lH-吡唑并[4,3-c]吡啶-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,2-a]吡啶-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,2-a]吡啶-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺,
N-(2,6-二氧代哌啶-3-基)-N-甲基-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]-1-甲基-3,4-二氢-2H-喹啉-4-甲酰胺,
N-[(3R)-2,6-二氧代-3-哌啶基]-1-甲基-3,4-二氢-2H-喹啉-4-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢喹啉-l(2H)-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢喹啉-l(2H)-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]吡啶-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]吡啶-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,5-a]吡啶-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,5-a]吡啶-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]嘧啶-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]嘧啶-3-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]-2-苯基-乙酰胺,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-2-丙基-异吲哚啉-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,异构体A,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,异构体B,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-lH-吲哚-3-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-1-甲基-吲哚-3-甲酰胺,
N-(2,6-二氧代-3-哌啶基)吲哚啉-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)苯甲酰胺,
N-(2,6-二氧代-3-哌啶基)环戊烷甲酰胺,
N-(2,6-二氧代-3-哌啶基)苯并呋喃-3-甲酰胺,
N-(2,6-二氧代-3-哌啶基)苯并噻吩-3-甲酰胺,
(lR)-N-(2,6-二氧代-3-哌啶基)萘满-1-甲酰胺,
(1S)-N-(2,6-二氧代-3-哌啶基)萘满-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-N-甲基-lH-吲哚-3-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]-lH-吲哚-3-甲酰胺,
N-[(3R)-2,6-二氧代-3-哌啶基]-lH-吲哚-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)苯并呋喃-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]色满-4-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)苯并呋喃-3-甲酰胺,
N-[(3R)-2,6-二氧代-3-哌啶基]色满-4-甲酰胺,
(S)-3-((2,6-二氧代哌啶-3-基)氨甲酰基)-lH-吲哚-6甲酸甲酯,
(R)-N-(2,6-二氧代哌啶-3-基)-lH-吲唑-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)中氮茚-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)中氮茚-3-甲酰胺,
N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-2-(吡啶-3-基)乙酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-2-(吡啶-3-基)乙酰胺,
(S)-2-(4-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺,
(R)-2-(4-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺,
(R)-2-(3-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺,
(S)-2-(3-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-2-(2-氧代吲哚啉-5-基)乙酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-2-(2-氧代吲哚啉-5-基)乙酰胺,
(S)-3-((2,6-二氧代哌啶-3-基)氨基甲酰基)-1-甲基-1,4,6,7-四氢-5H-吡唑并[4,3-c]吡啶-5甲酸叔丁酯,
N-((S)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酰胺,
N-((R)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酰胺,
(N-((R)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺,
N-((S)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢-1,8-萘啶-l(2H)-甲酰胺,和
(R)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢-1,8-萘啶-l(2H)-甲酰胺。
E21本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,选自由以下组成的组:
(S)-N-((R)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(S)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(-)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
(+)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]-1,2,3,4-四氢喹啉-4-甲酰胺,
N-[(3R)-2,6-二氧代-3-哌啶基]-1,2,3,4-四氢喹啉-4-甲酰胺,
(S)-N-((R)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
(4R)-N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺,
(R)-N-((R)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(R)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-1-甲基-4,5,6,7-四氢-lH-吡唑并[4,3-c]吡啶-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,2-a]吡啶-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,2-a]吡啶-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺,
N-(2,6-二氧代哌啶-3-基)-N-甲基-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]-1-甲基-3,4-二氢-2H-喹啉-4-甲酰胺,
N-[(3R)-2,6-二氧代-3-哌啶基]-1-甲基-3,4-二氢-2H-喹啉-4-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢喹啉-l(2H)-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢喹啉-l(2H)-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]吡啶-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]吡啶-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,5-a]吡啶-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,5-a]吡啶-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]嘧啶-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]嘧啶-3-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]-2-苯基-乙酰胺,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-2-丙基-异吲哚啉-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,异构体A,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,异构体B,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-lH-吲哚-3-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-1-甲基-吲哚-3-甲酰胺,
N-(2,6-二氧代-3-哌啶基)吲哚啉-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)苯甲酰胺,
N-(2,6-二氧代-3-哌啶基)环戊烷甲酰胺,
N-(2,6-二氧代-3-哌啶基)苯并呋喃-3-甲酰胺,
N-(2,6-二氧代-3-哌啶基)苯并噻吩-3-甲酰胺,
(lR)-N-(2,6-二氧代-3-哌啶基)萘满-1-甲酰胺,
(1S)-N-(2,6-二氧代-3-哌啶基)萘满-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-N-甲基-lH-吲哚-3-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]-lH-吲哚-3-甲酰胺,
N-[(3R)-2,6-二氧代-3-哌啶基]-lH-吲哚-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)苯并呋喃-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]色满-4-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)苯并呋喃-3-甲酰胺,
N-[(3R)-2,6-二氧代-3-哌啶基]色满-4-甲酰胺,
(S)-3-((2,6-二氧代哌啶-3-基)氨基甲酰基)-lH-吲哚-6甲酸甲酯,
(R)-N-(2,6-二氧代哌啶-3-基)-lH-吲唑-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)中氮茚-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)中氮茚-3-甲酰胺,
N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-2-(吡啶-3-基)乙酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-2-(吡啶-3-基)乙酰胺,
(S)-2-(4-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺,
(R)-2-(4-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺,
(R)-2-(3-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺,
(S)-2-(3-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-2-(2-氧代吲哚啉-5-基)乙酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-2-(2-氧代吲哚啉-5-基)乙酰胺,
(S)-3-((2,6-二氧代哌啶-3-基)氨基甲酰基)-1-甲基-1,4,6,7-四氢-5H-吡唑并[4,3-c]吡啶-5甲酸叔丁酯,
N-((S)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酰胺,
N-((R)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酰胺,
(N-((R)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺,
N-((S)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢-1,8-萘啶-l(2H)-甲酰胺,和
(R)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢-1,8-萘啶-l(2H)-甲酰胺。
E22本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,选自由以下组成的组:
(-)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
(+)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
(N-((R)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺,
(S)-N-((R)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(S)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢-1,8-萘啶-l(2H)-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢喹啉-l(2H)-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)苯并呋喃-3-甲酰胺,
N-((R)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酰胺,
N-((S)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酰胺,
N-((S)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]色满-4-甲酰胺,
3-氨基-N-甲基-4-[(2-氧代-1,3-二氢苯并咪唑-5-基)氨基]苯甲酰胺,
N-甲基-2-[2-(3-甲基咪唑-4-基)-4-喹啉基]-1-(2-氧代-1,3-二氢苯并咪唑-5-基)苯并咪唑-5-甲酰胺,
N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)-2-(4-喹啉基)苯并咪唑-5-甲酰胺,
2-乙基-N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)苯并咪唑-5-甲酰胺,
N,2-二甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)苯并咪唑-5-甲酰胺,
5-[2-(4-喹啉基)苯并咪唑-1-基]-1,3-二氢苯并咪唑-2-酮,
5-[2-[2-(3-甲基咪唑-4-基)-4-喹啉基]苯并咪唑-1-基]-1,3-二氢苯并咪唑-2-酮,
3-氨基-4-[(2-氧代-1,3-二氢苯并咪唑-5-基)氨基]苯甲酸甲酯,
N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)-2-苯基-苯并咪唑-5-甲酰胺,
N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)-2-(4-吡啶基)苯并咪唑-5-甲酰胺,
N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)-2-(三氟甲基)苯并咪唑-5-甲酰胺,
N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)-2-丙基-苯并咪唑-5-甲酰胺,
2-(lH-咪唑-5-基)-N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)苯并咪唑-5-甲酰胺,
2-异丙基-N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)苯并咪唑-5-甲酰胺,
1-(l,3-二甲基-2-氧代-苯并咪唑-5-基)-N-甲基-2-[2-(3-甲基咪唑-4-基)-4-喹啉基]苯并咪唑-5-甲酰胺,
N,N-二甲基-2-[2-(3-甲基咪唑-4-基)-4-喹啉基]-1-(2-氧代-1,3-二氢苯并咪唑基)苯并咪唑-5-甲酰胺,
2-(3-甲氧基苄基)-N-甲基-2'-氧代-2',3'-二氢-1'H-[l,5'-联苯并[d]咪唑]-5-甲酰胺,和
2-异丙基-N-甲基-2'-氧代-2',3'-二氢-1'H-[l,5'-联苯并[d]咪唑]-6-甲酰胺。
E23本发明的某个实施方案涉及式I的化合物或其药学上可接受的盐,其具有包含以下的化学结构:
P-L-C
其中
L为连接基团;
C为任一实施方案的式I的化合物,
其中L与C化学连接;并且
P为与靶蛋白或靶多肽结合的蛋白靶部分、
其中L与P化学连接。
E24本发明的某个实施方案涉及式P-L-C的化合物或其药学上可接受的盐,其中L选自由以下组成的组:
i)-NHCH2-(CH2)1-30-CH2NH-和
ii)-NH-(CH2CH2O)1-25-CH2CH2-NH-。
E25本发明的某个实施方案涉及式P-L-C的化合物或其药学上可接受的盐,其中L选自由以下组成的组:
i)-NHCH2-(CH2)1-10-CH2NH-和
ii)-NH-(CH2CH2O)1-5-CH2CH2-NH-。
E26本发明的某个实施方案涉及式P-L-C的化合物或其药学上可接受的盐,其中P为BRD4抑制剂,尤其是其中P为
E27本发明的某个实施方案涉及式P-L-C的化合物或其药学上可接受的盐,选自由以下组成的组:
(4S)-1-[6-[[2-[(9S)-7-(4-氯代苯基)-4,5,13-三甲基-3-硫杂-1,8,11,12-四氮杂三环[8.3.0.02,6]十三-2(6),4,7,10,12-五烯-9-基]乙酰基]氨基]己酰基]-N-[(3R)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺,
(4R)-1-[2-[2-[2-[2-[[2-[(9S)-7-(4-氯代苯基)-4,5,13-三甲基-3-硫杂-1,8,11,12-四氮杂三环[8.3.0.02,6]十三-2(6),4,7,10,12-五烯-9-基]乙酰基]氨基]乙氧基]乙氧基]乙氧基]乙酰基]-N-[(3S)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺,和
(4S)-1-[6-[[2-[(9S)-7-(4-氯代苯基)-4,5,13-三甲基-3-硫杂-1,8,11,12-四氮杂三环[8.3.0.02,6]十三-2(6),4,7,10,12-五烯-9-基]乙酰基]氨基]己酰基]-N-[(3S)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺。
E28本发明的某个实施方案涉及本文所述的式I的化合物或其药学上可接受的盐,其用作治疗活性物质。
E29本发明的某个实施方案涉及本文所述的式I的化合物或其药学上可接受的盐,其用于癌症的治疗性和/或预防性治疗。
E30本发明的某个实施方案涉及本文所述的式I的化合物或其药学上可接受的盐,其用于制备用于癌症的治疗性和/或预防性治疗的药物。
E31本发明的某个实施方案涉及药物组合物,其包含如本文所述的式I的化合物或其药学上可接受的盐,以及药学上可接受的辅助物质。
E32本发明的某个实施方案涉及通过将如本文所述的式I的化合物或其药学上可接受的盐施用于患者来治疗性和/或预防性治疗癌症的方法。
E33本发明的某个实施方案涉及本文所述的P-L-C化合物或其药学上可接受的盐,其用作治疗活性物质。
E34本发明的某个实施方案涉及本文所述的P-L-C的化合物或其药学上可接受的盐,其用于癌症的治疗性和/或预防性治疗。
E35本发明的某个实施方案涉及如本文所述的P-L-C的化合物或其药学上可接受的盐,其用于制备用于癌症的治疗性和/或预防性治疗的药物。
E36本发明的某个实施方案涉及药物组合物,其包含本文所述的P-L-C化合物或其药学上可接受的盐,以及药学上可接受的辅助物质,特别是惰性载体。
E37本发明的某个实施方案涉及通过将如本文所述的P-L-C化合物或其药学上可接受的盐施用于患者来治疗性和/或预防性治疗癌症的方法。
此外,本发明包括式I的化合物的所有光学异构体,即非对映异构体、非对映异构体混合物、外消旋混合物、所有它们相应的对映异构体和/或互变异构体以及它们的溶剂化物。
式I或式P-L-C的化合物可以包含一个或多个不对称中心,因此可以以外消旋体、外消旋混合物、单一对映异构体、非对映体混合物和单独的非对映异构体的形式存在。取决于分子上各种取代基的性质,可以存在另外的不对称中心。每个这样的不对称中心将独立地产生两种光学异构体,并且本发明旨在包含混合物形式或纯的或部分纯的化合物形式的所有可能的光学异构体和非对映异构体。本发明意在涵盖这些化合物的所有此类异构形式。如本领域已知的,这些非对映异构体的独立合成或其色谱分离可通过适当改进本文公开的方法来实现。它们的绝对立体化学可以通过结晶产物或结晶中间体的X射线晶体学测定,如果需要,可以用具有已知绝对构型的不对称中心的试剂将它们衍生化。如果需要,可以分离化合物的外消旋混合物,从而分离出各对映异构体。分离可以通过本领域熟知的方法进行,例如将化合物的外消旋混合物与对映体纯的化合物偶联以形成非对映异构体混合物,然后通过标准方法,例如分级结晶或色谱法,分离各非对映异构体。
在提供光学纯对映异构体的实施方案中,光学纯对映异构体是指化合物包含按重量计>90%的所需异构体,特别是按重量计>95%的所需异构体,或更特别是按重量计>99%的所需异构体,所述重量百分比基于化合物中一种或多种异构体的总重量。手性纯的或手性富集的化合物可通过手性选择性合成或对映异构体的分离来制备。对映异构体的分离可以用最终产物或合适的中间体进行。
式I或式P-L-C的化合物可以根据实施例中所述的方案制备。起始原料是可商购的,或者可以根据已知方法制备。
式I或式P-L-C的化合物的制备在以下方案中进一步详细描述。
方案1
取代基和n如本文所定义。
步骤A:酰胺键的形成可以在室温或升高的温度下在偶联剂(如DCC、EDC、TBTU或HATU)和有机碱(如三乙胺、N,N-二异丙基乙胺或N-甲基吗啉)的存在下在卤化溶剂(如二氯甲烷或1,2-二氯乙烷)或醚溶剂(如乙醚、二噁烷、THF、DME或TBME)或极性非质子有机溶剂(如N,N-二甲基甲酰胺)中通过羧酸2与合适的氨基-酰亚胺1之间偶联反应2-18小时来完成。
合适的氨基-酰亚胺1的实例包括但不限于3-氨基哌啶-2,6-二酮60,(3S)-3-氨基哌啶-2,6-二酮61,(3S)-3-氨基哌啶-2,6-二酮盐酸盐62,(3R)-3-氨基哌啶-2,6-二酮63,(3R)-3-氨基哌啶-2,6-二酮盐酸盐64或3-(甲基氨基)哌啶-2,6-二酮65。
优选的条件是HATU与N,N-二异丙基乙胺在N,N-二甲基甲酰胺中,在室温下,进行18小时。
在氨基-酰亚胺1的外消旋混合物与非手性羧酸2偶联的情况下,偶联反应得到作为外消旋混合物的酰胺3,可以使用手性HPLC将其分离成对映异构体组分。在羧酸2包含一个或多个立体异构中心的情况下,偶联反应提供为非对映异构体混合物的酰胺3,其可以使用手性HPLC分离。
方案2
R,R'=H,杂环烷基,杂芳基或与它们所连接的氮一起形成杂环烷基或杂芳基
R2=如本文所定义
步骤A:脲的形成可以通过合适的氨基-酰亚胺1、三光气4和伯胺或仲胺6之间的偶联反应来完成。该反应以逐步的方式进行,包括氨基-酰亚胺1和一当量的三光气4的初始反应以提供中间体三氯乙酰胺5,然后使其与伯胺或仲胺6原位反应以提供脲7。该反应在有机碱如三乙胺、N,N-二异丙基乙胺或N-甲基吗啉的存在下,在卤化溶剂(如二氯甲烷或1,2-二氯乙烷)或醚溶剂(如乙醚、二噁烷、THF、DME或TBME)中进行。
优选的条件是在1,2-二氯乙烷中的三乙胺。形成中间体5的第一步优选在0℃和室温之间的温度下进行1-2小时,而形成脲7的第二步优选在室温下进行18小时。
合适的氨基-酰亚胺1的实例包括但不限于3-氨基哌啶-2,6-二酮60,(3S)-3-氨基哌啶-2,6-二酮61,(3S)-3-氨基哌啶-2,6-二酮盐酸盐62,(3R)-3-氨基哌啶-2,6-二酮63,(3R)-3-氨基哌啶-2,6-二酮盐酸盐64或3-(甲基氨基)哌啶-2,6-二酮65。
在氨基-酰亚胺1的外消旋混合物与非手性胺6偶联的情况下,偶联反应得到作为外消旋混合物的脲7,可以使用手性HPLC将其分离成对映异构体组分。在胺6包含一个或多个立体异构中心的情况下,偶联反应提供为非对映异构体混合物的脲7,其可以使用手性HPLC分离。
方案3
R,R'=H,杂环烷基,杂芳基或与它们所连接的氮一起形成杂环烷基或杂芳基
R2=如本文所定义
步骤A:脲的形成还可以通过合适的氨基-酰亚胺1、l,l'-羰基-二-(lH-咪唑)4和伯胺或仲胺6之间的偶联反应来完成。该反应以逐步的方式进行,包括氨基-酰亚胺1和l,l'-羰基-二-(lH-咪唑)4的初始反应以提供中间体咪唑-1-甲酰胺9,然后使其与伯胺或仲胺6原位反应以提供脲7。该反应在极性非质子有机溶剂如N-甲基-2-吡咯烷酮或N,N-二甲基甲酰胺,优选N,N-二甲基甲酰胺中进行。形成中间体9的第一步优选在室温下进行1-2小时,而形成脲7的第二步优选在80℃下进行3小时。
合适的氨基-酰亚胺1的实例包括但不限于3-氨基哌啶-2,6-二酮60,(3S)-3-氨基哌啶-2,6-二酮61,(3S)-3-氨基哌啶-2,6-二酮盐酸盐62,(3R)-3-氨基哌啶-2,6-二酮63,(3R)-3-氨基哌啶-2,6-二酮盐酸盐64或3-(甲基氨基)哌啶-2,6-二酮65。
在氨基-酰亚胺1的外消旋混合物与非手性胺6偶联的情况下,偶联反应得到作为外消旋混合物的脲7,可以使用手性HPLC将其分离成对映异构体组分。在胺6包含一个或多个立体异构中心的情况下,偶联反应提供为非对映异构体混合物的脲7,其可以使用手性HPLC分离。
方案4
作为说明性实例,可以基于已知的BRD4配体JQ166(Filippakopoulos67)制备靶向BET溴结构域BRD4的降解剂化合物。该合成采用相应的羧酸衍生物1568。
步骤A:酰胺键的形成可以通过胺10与带有末端羧酸官能团和末端BOC-保护的胺官能团的含连接基的化合物11之间的偶联反应来完成。该偶联反应在偶联剂如DCC、EDC、TBTU或HATU的存在下,在有机碱如三乙胺、N,N-二异丙基乙胺、N-甲基吗啉或4-(N,N-二甲基氨基)吡啶的存在下,在卤化溶剂(如二氯甲烷或1,2-二氯乙烷)或醚溶剂(如乙醚、二噁烷、THF、DME或TBME)或极性非质子有机溶剂(如N,N-二甲基甲酰胺)中,在室温或升高的温度下进行2-18小时。
优选的条件是HATU与N,N-二异丙基乙胺在N,N-二甲基甲酰胺中,在室温下,进行18小时。
或者,酰胺键的形成可以通过胺10与酰氯化合物12之间的偶联反应来完成,该酰氯化合物12由具有末端羧酸官能团和末端BOC-保护的胺官能团的含连接基的化合物11原位形成。酰氯化合物12可以根据Ghosez和同事的方法70,在0℃至室温的温度下,通过在卤代溶剂(如二氯乙烷或1,2-二氯乙烷)中用1-氯代-N,N,2-三甲基丙烯胺69处理,由相应的羧酸11原位制备。然后可以通过酰氯化合物12与胺10在卤化溶剂如二氯甲烷或1,2-二氯乙烷中的反应来完成酰胺键的形成。优选的条件是二氯甲烷,在室温下进行2小时。
步骤B:可以在0至回流温度下,在诸如CH2Cl2、CHCl3、THF、EtOAc、二噁烷、MeOH、EtOH或H2O的溶剂中,用无机酸如HCl、H2SO4或H3PO4或有机酸如CF3COOH、CHCl2COOH、HOAc或对甲苯磺酸除去13中的Boc N-保护基。
优选的条件是在二噁烷和二氯甲烷中的4M HCl水溶液,在室温下,进行2小时。
步骤C:酰胺键的形成可以在室温或升高的温度下,在偶联剂如DCC、EDC、TBTU或HATU的存在下,在有机碱如三乙胺、N,N-二异丙基乙胺或N-甲基吗啉的存在下,在卤代溶剂(如二氯甲烷或1,2-二氯乙烷)或醚溶剂(如乙醚、二噁烷、THF、DME或TBME)或极性非质子有机溶剂(如N,N-二甲基甲酰胺)中,通过羧酸15与胺14之间偶联反应2-18小时来完成。
优选的条件是HATU与N,N-二异丙基乙胺在N,N-二甲基甲酰胺中,在室温下进行2小时。
化合物的分离和纯化
如果需要,本文所述的化合物和中间体的分离和纯化可以通过任何合适的分离或纯化方法进行,例如过滤,萃取,结晶,柱色谱法,薄层色谱法,厚层色谱法,制备型低压或高压液相色谱法或这些方法的组合。合适的分开和分离步骤的具体说明可参考下文的制备方法和实施例。但是,当然也可以使用其他等效的分开或分离方法。可以使用手性HPLC分离式I的手性化合物的外消旋混合物。手性合成中间体的外消旋混合物也可以使用手性HPLC分离。
式I的化合物的盐
在式I化合物为碱性的情况下,它们可以转化为相应的酸加成盐。转化可以通过用至少化学计量的量的合适的酸和有机酸进行处理来完成,酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等,有机酸例如乙酸、丙酸、乙醇酸、丙酮酸、草酸、苹果酸、丙二酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。通常,将游离碱溶于惰性有机溶剂(如乙醚、乙酸乙酯、氯仿、乙醇或甲醇等)中,并将酸加入类似的溶剂中。温度保持在0℃至50℃之间。生成的盐会自发沉淀,或者可以用极性较小的溶剂从溶液中带出。
在实施例中并没有描述它们的制备的情况下,式I或式P-L-C的化合物以及所有中间产物可以根据类似的方法或根据本文阐述的方法来制备。起始原料是可商购的,本领域已知的或可以通过本领域已知的方法或与其类似的方法制备。
应当理解,本发明中的通式I或通式P-L-C的化合物可以在官能团上衍生化以提供能够在体内转化回母体化合物的衍生物。
药理学测试
式I或式P-L-C的化合物及其药学上可接受的盐具有有价值的药理学性质。根据下文给出的测试研究化合物。
双荧光报告基因测试
为了以中等通量测量哺乳动物细胞系统中的BRD4蛋白丰度,基于1中所述的原理开发了双荧光报告基因系统。设计了瞬时表达载体,该载体包含与荧光标签融合的BRD4编码序列(NM_058243.2)。使用pD2610 CMV骨架在ATUM(Newark,CA,USA)合成了载体,该载体按以下构建:c-末端版本BRD4_eGFP-IRES-FresnoRFP_NLS,n末端版本eGFP_BRD4-IRES-FresnoRFP NLS,空载体对照eGFP-IRES-FresnoRFP NLS。C末端版本用于报告基因测试,因为它具有最佳的测试窗口。将HEK293A细胞(Invitrogen,目录号R705-07)在Dulbecco改良Eagle培养基(DMEM),10%胎牛血清,2mM L-谷氨酰胺,1%青霉素/链霉素中培养。根据制造商的方案(Invitrogen,Carlsbad,CA,USA),用Lipofectamine 2000进行质粒的转染。转染后40小时,将细胞以40’000/100ul/96孔平底的密度接种,8小时后用化合物(DMSO中10mM储备液)以0-25μM的10点稀释度处理。处理16小时后,将细胞用PBS洗涤,重悬于Accumax溶液(Sigma-Aldrich,目录号A7089)中,并通过流式细胞仪(CytoFlex S,BeckmanCoulter)进行分析。根据单细胞的前向和侧向散射曲线对单个细胞进行门控,并使用脉冲宽度排除双峰。每个样品至少采集20’000个细胞。使用Flow Jo V10.1程序对BRD4-eGFP低/中细胞(<106FL1-A平均荧光强度(MFI))进行分析。得出一个因子以将BRD4-eGFP值归一化至RFP蛋白丰度对照(20xFL1A-GFP/FL11A-RFP),然后计算中位值和众数值并将其用于处理条件之间的比较。
基于毛细管的免疫测试以测量内源性BRD4水平
在允许定量内源性BRD4水平的另一种测试中证实了所选化合物的生物活性(截止值为BRD4-eGFP水平降低>20%)。为此,将HEK293A细胞(来源和培养条件参见上文)以400’000/300ul/48孔接种,并在6小时后用所示的化合物浓度处理。处理后16小时,将细胞用PBS洗涤,并在50ul尿素裂解缓冲液(10mM Tris-HCl pH 8,2%CHAPS,7M尿素,0.4%DTT)中裂解,该缓冲液补充有1x蛋白酶抑制剂混合物(Complete Mini,Roche)和1x磷酸酶抑制剂混合物(PhosSTOP,Sigma-Aldrich)。然后根据制造商的方案(Protein Simple/Bio-Techne,San Jose,California,,95134USA),通过基于Peggy Sue或WES毛细管的免疫分析系统对样品进行分析。使用的抗体是抗BRD4抗体(Cell signaling,CST 13440 1:50)和抗黏着斑蛋白抗体(Sigma,V9131,1:4000)。为了量化BRD4蛋白水平,将峰信号面积归一化至黏着斑蛋白负载对照和DMSO条件。
此外,请参见Yen等71。
荧光直接结合方案
原理
可以通过监测直接模式下的荧光发射来测定化合物对含有一个或多个色氨酸的蛋白质的亲和力。取决于蛋白质可利用量的测量是在ISS-PC1光子计数荧光光谱仪上的比色杯中手动进行的,或者是在荧光板读取器设备上的孔板上自动进行的。通过使用相对于配体浓度变化而定义的恒定的蛋白质浓度,在选定的结合测定缓冲液中于20℃进行荧光滴定。加入溶于DMSO中的、已知配体浓度的小等分试样,并在340nm处记录在280nm处激发的荧光。将荧光强度针对蛋白稀释度和滤波器效应进行校正(Birdsall et al.72)。将校正后的荧光强度相对于配体浓度作图,使用四参数Sigmoidal函数拟合,使用质量作用定律(假定1:1蛋白质-配体复合物)从中计算平衡解离常数Kd(Eftink,199773)。
方法
1)优化测量参数以最大程度地减少蛋白质消耗并最大程度地减少稀释效应和DMSO含量
2)通过至少12个滴定步骤进行蛋白质对配体的滴定测量以获得良好的s-曲线拟合
3)仅用配体重复相同的滴定测量以进行校正
4)单独用DMSO进行滴定检查蛋白质的稳定性,进行一次
5)借助紫外分光光度计测定配体在280和340nm处的摩尔消光系数
6)使用Excel模板校正测量的原始数据
7)使用GraphPad Prism软件进行二次结合拟合和KD评估。
实验细节
表1:蛋白-缓冲液,参考化合物:沙利度胺,Contergan,Softenon
设备 | ISS-PC1 |
激发波长[nm] | 280 |
发射波长[nm] | 340 |
比色杯 | Hellma 115F-QS |
体积[μL] | 500 |
表2:设置
蛋白制剂:
体积蛋白[μL] | 体积缓冲液[μL] | 蛋白浓度[M] |
1.8@2.5mg/ml | 498.2 | 5.0E-8 |
表3:蛋白制剂
表4:滴定步骤
表5.实施例对蛋白的亲和力
药物组合物
式I或式P-L-C的化合物和药学上可接受的盐可以用作治疗活性物质,例如,以药物制剂的形式。药物制剂可以口服给药,例如,以片剂、包衣片剂、糖衣丸、硬和软明胶胶囊剂、溶液剂、乳剂或混悬剂的形式。但是,给药也可以例如通过直肠进行,以栓剂的形式,或者通过胃肠外形式进行,例如以注射溶液的形式。
式I或式P-L-C的化合物及其药学上可接受的盐可以与药学上惰性的无机或有机载体一起加工以制备药物制剂。乳糖、玉米淀粉或其衍生物、滑石粉、硬脂酸或其盐等可以用作例如片剂、包衣片剂、糖衣丸和硬明胶胶囊的载体。用于软明胶胶囊的合适载体是例如植物油、蜡、脂肪、半固体和液体多元醇等。然而,取决于活性物质的性质,在软明胶胶囊的情况下,通常不需要载体。用于生产溶液剂和糖浆剂的合适载体是例如水、多元醇、甘油、植物油等。用于栓剂的合适载体是例如天然或硬化油、蜡、脂肪、半液体或液体多元醇等。
此外,药物制剂可以包含药学上可接受的辅助物质,例如防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、调味剂、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们还可以包含其他治疗上有价值的物质。
本发明还提供了包含式I或式P-L-C的化合物或其药学上可接受的盐以及治疗惰性载体的药物,以及其制备方法,所述制备方法包括使一种或多种式I的化合物和/或将其药学上可接受的盐,以及如果需要的话,一种或多种其他治疗上有价值的物质,与一种或多种治疗惰性载体一起制成盖伦施用形式。
剂量可以在很宽的范围内变化,当然,在每个具体案例中必须根据个人需要进行调整。在口服给药的情况下,成人用剂量可以为每天约0.01mg至约1000mg通式I的化合物或相应量的其药学上可接受的盐。日剂量可以以单剂量施用或分剂量施用,此外,当发现有需要时,也可以超过上限。
以下实施例举例说明本发明而不是限制本发明,仅作为本发明的代表。药物制剂方便地包含约1-500mg,特别是1-100mg的式I或式P-L-C的化合物。根据本发明的组合物的实例是:
实施例A
按常规方式制备具有以下组成的片剂:
表6.可能的片剂组成
制造工艺
1.混合成分1、2、3和4,然后用纯净水制粒。
2.在50℃下干燥颗粒。
3.使颗粒通过合适的研磨设备。
4.加入成分5,混合三分钟;以合适的压力压制。
实施例B-1
制备具有以下组成的胶囊:
表7:可能的胶囊成分组成
制备工艺
1.在合适的混合器中将成分1、2和3混合30分钟。
2.添加成分4和5并混合3分钟。
3.装入合适的胶囊中。
首先在混合机中混合式I或式P-L-C的化合物、乳糖和玉米淀粉,然后在粉碎机中混合。将混合物返回至混合器;向其中加入滑石粉并充分混合。通过机器将混合物填充到合适的胶囊中,例如硬明胶胶囊。
实施例B-2
制备具有以下组成的软明胶胶囊
成分 | mg/胶囊 |
式I或式P-L-C的化合物 | 5 |
黄蜡 | 8 |
氢化的大豆油 | 8 |
部分氢化的植物油 | 34 |
大豆油 | 110 |
总计 | 165 |
表8.可能的软明胶胶囊成分组成
成分 | mg/胶囊 |
明胶 | 75 |
甘油85% | 32 |
Karion 83 | 8(干物质) |
二氧化钛 | 0.4 |
氧化铁黄 | 1.1 |
总计 | 116.5 |
表9:可能的软明胶胶囊组成
制造工艺
将式I式P-L-C的化合物溶解在其他成分的热熔物中,并将混合物填充至适当大小的软明胶胶囊中。经填充的软明胶胶囊按照常规工艺进行处理。
实施例C
制备具有以下组成的栓剂:
成分 | mg/栓剂 |
式I或式P-L-C的化合物 | 15 |
栓剂基质 | 1285 |
总计 | 1300 |
表10:可能的栓剂组成
制造工艺
将栓剂基质在玻璃或钢制容器中融化,充分混合并冷却至45℃。然后,向其中加入细粉化的式I或式P-L-C的化合物并搅拌直至其完全分散。将混合物倒入适当大小的栓剂模具中,静置冷却。然后将栓剂从模具中取出并单独包装在蜡纸或金属箔中。
实施例D
制备具有以下组成的注射液:
成分 | mg/注射溶液 |
式I或式P-L-C的化合物 | 3 |
聚乙二醇400 | 150 |
乙酸 | 适量,调节至pH5.0 |
注射液用水 | 调节至1.0ml |
表11:可能的注射液组成
制造工艺
将式I或式P-L-C的化合物溶解在聚乙二醇400和注射用水(部分)的混合物中。通过添加乙酸将pH调节至5.0。通过添加剩余量的水将体积调节至1.0ml。过滤溶液,适当过量地将其装入小瓶中并灭菌。
实施例E
制备具有以下组成的小袋:
表12:可能的小袋组成
制造工艺
将式I或式P-L-C的化合物与乳糖、微晶纤维素和羧甲基纤维素钠混合,并用聚乙烯吡咯烷酮在水中的混合物制粒。将颗粒与硬脂酸镁和调味添加剂混合,并装入小袋中。
实验部分
提供以下实施例以说明本发明。它们不应被视为限制本发明的范围,而仅是本发明的代表。
实施例l74
(S)-N-(2,6-二氧代-3-哌啶基)苯乙酰胺
可购买该标题化合物。
实施例2
N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-茚-1-甲酰胺(所有非对映异构体的外消旋混合物)
向2,3-二氢-1H-茚-1-甲酸75(100mg),N,N-二异丙基乙胺(323μl)和3-氨基哌啶-2,6-二酮60(86.9mg)在DMF(1.5ml)中的经搅拌的悬浮液中加入HATU(352mg)。将反应混合物在室温搅拌18小时。将所得黄色溶液直接通过反相HPLC纯化,冻干后得到N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-茚-1-甲酰胺(所有非对映异构体的外消旋混合物),为白色固体(168mg,66%)。MS(ISP):273.5([M+H]+)。
实施例3
N-(2,6-二氧代哌啶-3-基)-2-丙基异吲哚啉-1-甲酰胺(所有非对映异构体的外消旋混合物)
a)l-((2,6-二氧代哌啶-3-基)氨基甲酰基)异吲哚啉-2-甲酸叔丁酯
以类似于实施例2的方式,使用(RS)-BOC-1,3-二氢-2H-异吲哚甲酸76替换2,3-二氢-lH-茚-1-甲酸75得到标题化合物。白色固体。MS(ISP):372.4([M-H]-)。
b)N-(2,6-二氧代哌啶-3-基)异吲哚啉-1-甲酰胺盐酸盐.
向l-((2,6-二氧代哌啶-3-基)氨基甲酰基)异吲哚啉-2甲酸叔丁酯(88mg)在二氯甲烷(2ml)中的经搅拌的溶液中加入4M HCl的二噁烷溶液(884μl)。搅拌3小时后,将溶剂蒸发至干,并将乙醚加入到残余物中。将悬浮液超声处理,在0℃下搅拌15分钟,然后过滤,得到N-(2,6-二氧代哌啶-3-基)异吲哚啉-1-甲酰胺盐酸盐,为灰白色固体(72mg,99%)。MS(ISP):274.1([M+H]+)。
c)N-(2,6-二氧代哌啶-3-基)-2-丙基异吲哚啉-1-甲酰胺
向N-(2,6-二氧代哌啶-3-基)异吲哚啉-1-甲酰胺盐酸盐(63mg),丙醛77(22.2μl),乙酸钠(16.7mg)和氯化锌(111mg)在MeOH(1.2ml)中的经搅拌的溶液中加入氰基硼氢化钠(38.3mg)。将反应混合物在室温搅拌5小时。直接通过反相HPLC纯化反应混合物,得到N-(2,6-二氧代哌啶-3-基)-2-丙基异吲哚啉-1-甲酰胺,为白色固体(31mg,48%)。MS(ISP):316.0([M+H]+)。
实施例4
(-)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-茚-1-甲酰胺(差向异构体1)
使用手性HPLC(柱:Reprosil手性-R,洗脱液:庚烷/乙醇+NH4OAc(70:30),压力:18bar;流速:35ml/min)从实施例2(95mg)分离N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-茚-1-甲酰胺的非对映异构体,得到(-)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-茚-1-甲酰胺(差向异构体1)(17mg,白色固体),保留时间=36.1min。MS(ISP):273.1([M+H]+)。
实施例5
(+)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-茚-1-甲酰胺(差向异构体2)
使用手性HPLC(柱:Reprosil手性-NR,洗脱液:庚烷/乙醇+NH4OAc(70:30),压力:18bar;流速:35ml/min)从实施例2(95mg)分离N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-茚-1-甲酰胺的非对映异构体,得到(+)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-茚-1-甲酰胺(差向异构体2)(15mg,白色固体),保留时间=45min。MS(ISP):273.1([M+H]+)。
实施例6
N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-茚-1-甲酰胺(差向异构体3&4)
使用手性HPLC(柱:Reprosil手性-NR,洗脱液:庚烷/乙醇+NH4OAc(70:30),压力:18bar;流速:35ml/min)从实施例2(95mg)分离N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-茚-1-甲酰胺的非对映异构体,得到N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-茚-1-甲酰胺的两种差向异构体的混合物(差向异构体3&4)(28mg,白色固体),保留时间=63.3min。MS(ISP):273.1([M+H]+)。
实施例778
N-(2,6-二氧代哌啶-3-基)-lH-吲哚-3-甲酰胺
可购买该标题化合物。
实施例879
N-(2,6-二氧代哌啶-3-基)-1-甲基-lH-吲哚-3-甲酰胺
可购买该标题化合物。
实施例9
N-(2,6-二氧代哌啶-3-基)吲哚啉-1-甲酰胺
在0-5℃下向密封管中的3-氨基哌啶-2,6-二酮60(199mg)和三乙胺(433μl)在二氯乙烷(12ml)中的经搅拌的悬浮液中加入三光气(170mg)。在室温下搅拌1小时后,加入吲哚啉80(185mg)。将反应混合物在室温搅拌18小时。加入几滴水以淬灭反应,然后将溶剂蒸发至干,并将残余物通过反相HPLC(Gemini NX C18,12nm,5μ,100x 30mm,40ml/min,CH3CN/H2O+甲酸)纯化,冻干后得到为黄色固体的N-(2,6-二氧代哌啶-3-基)吲哚啉-1-甲酰胺(24mg,6%)。MS(ISP):274.2([M+H]+)。
实施例1081
N-(2,6-二氧代哌啶-3-基)苯甲酰胺
可购买该标题化合物。
实施例1182
N-(2,6-二氧代哌啶-3-基)环戊烷甲酰胺
可购买该标题化合物。
实施例1283
N-(2,6-二氧代哌啶-3-基)苯并呋喃-3-甲酰胺
可购买该标题化合物。
实施例1384
N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺
可购买该标题化合物。
实施例14
(lR)-N-(2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺
(2种差向异构体的混合物)
以类似于实施例2的方式,使用(R)-1,2,3,4-四氢萘甲酸85替代2,3-二氢-lH-茚-1-甲酸75,得到标题化合物。白色固体。MS(ISP):287([M+H]+)。
实施例15
(1S)-N-(2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺
(2种差向异构体的混合物)
以类似于实施例2的方式,使用(S)-1,2,3,4-四氢萘甲酸86替代2,3-二氢-lH-茚-1-甲酸75,得到标题化合物。白色固体。MS(ISP):287([M+H]+)。
实施例16
N-(2,6-二氧代哌啶-3-基)-N-甲基-lH-吲哚-3-甲酰胺
以类似于实施例2的方式,使用lH-吲哚-3-甲酸87替代2,3-二氢-lH-茚-1-甲酸75,使用3-(甲基氨基)哌啶-2,6-二酮65替代3-氨基哌啶-2,6-二酮60,得到标题化合物。浅蓝色固体。MS(ISP):286.2([M+H]+)。
实施例17
(S)-N-(2,6-二氧代哌啶-3-基)-lH-吲哚-3-甲酰胺
以类似于实施例2的方式,使用lH-吲哚-3-甲酸87替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):272.2([M+H]+)。
实施例18
(R)-N-(2,6-二氧代哌啶-3-基)-lH-吲哚-3-甲酰胺
以类似于实施例2的方式,使用lH-吲哚-3-甲酸87替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):272.2([M+H]+).
实施例19
N-((S)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酰胺
(2种差向异构体的混合物)
以类似于实施例2的方式,使用(RS)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酸88替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):274.3([M+H]+)。
实施例20
N-((R)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酰胺
(2种差向异构体的混合物)
以类似于实施例2的方式,使用(RS)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酸88替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):274.3([M+H]+)。
实施例21
(S)-N-(2,6-二氧代哌啶-3-基)苯并呋喃-3-甲酰胺
以类似于实施例2的方式,使用苯并呋喃-3-甲酸替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):273.2([M+H]+)。
实施例22
(N-((R)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺
(2种差向异构体的混合物)
以类似于实施例2的方式,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):274.2([M+H]+)。
实施例23
N-((S)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺
(2种差向异构体的混合物)
以类似于实施例2的方式,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):274.2([M+H]+)。
实施例24
(R)-N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺
以类似于实施例2的方式,使用苯并噻吩-3-甲酸89替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):289.1([M+H]+)。
实施例25
(S)-N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺
以类似于实施例2的方式,使用苯并噻吩-3-甲酸89替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):289.1([M+H]+)。
实施例26
(S)-N-((R)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺
以类似于实施例2的方式,使用(S)-1,2,3,4-四氢萘甲酸86替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):287.1([M+H]+)。
实施例27
(S)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺
以类似于实施例2的方式,使用(S)-1,2,3,4-四氢萘甲酸替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):287.1([M+H]+)。
实施例28
(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢喹啉-l(2H)-甲酰胺
向(S)-3-氨基哌啶-2,6-二酮盐酸盐62(100mg)在N,N-二甲基甲酰胺(1.5ml)中的经搅拌的悬浮液中添加1,1'-羰基-二-(1H-咪唑)(128mg),将反应混合物在室温搅拌2小时。一次性加入1,2,3,4-四氢喹啉90(125mg)。将反应混合物在80℃加热3小时,然后在乙酸乙酯和水之间分配。分离各层,水层用乙酸乙酯(3×25ml)萃取。合并的有机层用盐水洗涤,经无水硫酸钠干燥,并真空浓缩。所得残余物通过反相HPLC纯化,得到为白色固体的(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢喹啉-l(2H)-甲酰胺(68mg,39%)。MS(ISP):288([M+H]+)。
实施例29
(S)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺
以类似于实施例28的方式,使用2,3-二氢-lH-吡咯并[2,3-b]吡啶91替代1,2,3,4-四氢喹啉90,得到标题化合物。黄色固体。MS(ISP):275([M+H]+)。
实施例30
(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢-1,8-萘啶-1(2H)-甲酰胺
以类似于实施例28的方式,使用1,2,3,4-四氢-1,8-萘啶92替代1,2,3,4-四氢喹啉90,得到标题化合物。白色固体。MS(ISP):289.1([M+H]+)。
实施例31
N-[(3S)-2,6-二氧代-3-哌啶基]色满-4-甲酰胺(2种差向异构体的混合物)
以类似于实施例2的方式,使用(RS)-色满-4-甲酸93替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):289.2([M+H]+)。
实施例32
(4S)-N-[(3S)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺
a)N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺(2种差向异构体的混合物)
以类似于实施例2的方式,使用(RS)-1,2,3,4-四氢喹啉-4-甲酸94替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):288.3([M+H]+)。
b)(4S)-N-[(3S)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺
使用手性HPLC(柱:Reprosil手性-NR,洗脱液:庚烷/乙醇+NH4OAc(60:40),压力:18bar;流速:35ml/min)分离N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺(160mg)的差向异构体,得到(4S)-N-[(3S)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺(57mg,白色固体),保留时间=49min。MS(ISP):288.1([M+H]+)。
实施例33
(4R)-N-[(3S)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺
使用手性HPLC(柱:Reprosil手性-NR,洗脱液:庚烷/乙醇+NH4OAc(60:40),压力:18bar;流速:35ml/min)分离N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺(160mg)的差向异构体,得到(4R)-N-[(3S)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺(35mg,白色固体),保留时间=58min。MS(ISP):288.1([M+H]+)。
实施例34
(R)-N-(2,6-二氧代哌啶-3-基)苯并呋喃-3-甲酰胺
以类似于实施例2的方式,使用苯并呋喃-3-甲酸95替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):273.1([M+H]+)。
实施例35
(R)-N-(2,6-二氧代哌啶-3-基-3,4-二氢喹啉-l(2H)-甲酰胺
以类似于实施例28的方式,使用(R)-3-氨基哌啶-2,6-二酮盐酸盐64替代(S)-3-氨基哌啶-2,6-二酮盐酸盐62,得到标题化合物。白色固体。MS(ISP):288.1([M+H]+)。
实施例36
(R)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺
以类似于实施例28的方式,使用2,3-二氢-lH-吡咯并[2,3-b]吡啶91替代1,2,3,4-四氢喹啉90,使用(R)-3-氨基哌啶-2,6-二酮盐酸盐64替代(S)-3-氨基哌啶-2,6-二酮盐酸盐62,得到标题化合物。白色固体。MS(ISP):275.1([M+H]+)。
实施例37
N-[(3S)-2,6-二氧代-3-哌啶基]-1,2,3,4-四氢喹啉-4-甲酰胺(差向异构体的1:1混合物)
以类似于实施例2的方式,使用(RS)-1,2,3,4-四氢喹啉-4-甲酸94替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):288.3([M+H]+)。
实施例38
N-[(3S)-2,6-二氧代-3-哌啶基]-1-甲基-3,4-二氢-2H-喹啉-4-甲酰胺(差向异构体的1:1混合物)
以类似于实施例2的方式,使用(RS)-1-甲基-1,2,3,4-四氢喹啉-4-甲酸96替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):302.2([M+H]+)。
实施例39
N-[(3R)-2,6-二氧代-3-哌啶基]-1,2,3,4-四氢喹啉-4-甲酰胺(差向异构体的1:1混合物)
以类似于实施例2的方式,使用(RS)-1,2,3,4-四氢喹啉-4-甲酸94替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):288.3([M+H]+)。
实施例40
N-[(3R)-2,6-二氧代-3-哌啶基]-1-甲基-3,4-二氢-2H-喹啉-4-甲酰胺(差向异构体的1:1混合物)
以类似于实施例2的方式,使用(RS)-1-甲基-1,2,3,4-四氢喹啉-4-甲酸96替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。浅红色固体。MS(ISP):302.3([M+H]+)。
实施例41
N-[(3R)-2,6-二氧代-3-哌啶基]色满-4-甲酰胺(差向异构体的1:1混合物)
以类似于实施例2的方式,使用(RS)-色满-4-甲酸97替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。浅红色固体。MS(ISP):289.2([M+H]+)。
实施例42
(S)-3-((2,6-二氧代哌啶-3-基)氨基甲酰基)-lH-吲哚-6甲酸甲酯
以类似于实施例2的方式,使用6-甲氧基羰基-lH-吲哚-3-甲酸98替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):330.1([M+H]+)。
实施例43
(4S)-N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺
a)N-[(3R)-2,6-二氧代-3-哌啶基]-1,2,3,4-四氢喹啉-4-甲酰胺(2种差向异构体的混合物)
以类似于实施例2的方式,使用(RS)-1,2,3,4-四氢喹啉-4-甲酸94替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):288.3([M+H]+)。
b)(4S)-N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺
使用手性HPLC(柱:Reprosil手性-NR,洗脱液:庚烷/乙醇+NH4OAc(60:40),压力:18bar;流速:35ml/min)分离N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺(110mg)的差向异构体,得到(4S)-N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺(32mg,白色固体),保留时间=39min。MS(ISP):288.1([M+H]+)。
实施例44
(4R)-N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺
使用手性HPLC(柱:Reprosil手性-NR,洗脱液:庚烷/乙醇+NH4OAc(60:40),压力:18bar;流速:35ml/min)分离N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺的差向异构体(110mg),得到(4R)-N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺(37mg,白色固体),保留时间=53min。MS(ISP):288.1([M+H]+)。
实施例45
(1R)-N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢萘-1-甲酰胺
a)N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢萘-1-甲酰胺(2种差向异构体的混合物)
以类似于实施例2的方式,使用(RS)-1,2,3,4-四氢萘-1-甲酸99替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):287.1([M+H]+)。
b)(1R)-N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢萘-1-甲酰胺
使用手性HPLC(柱:Reprosil手性-NR,洗脱液:庚烷/乙醇+NH4OAc(60:40),压力:18bar;流速:35ml/min)分离N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢萘-1-甲酰胺的差向异构体(48mg),得到(lR)-N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢萘-1-甲酰胺(48mg,白色固体),保留时间=43min。MS(ISP):287.1([M+H]+)。
实施例46
(1R)-N-[(3S)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢萘-1-甲酰胺
a)N-[(3S)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢萘-1-甲酰胺(2种差向异构体的混合物)
以类似于实施例2的方式,使用(RS)-1,2,3,4-四氢萘-1-甲酸99替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):287.2([M+H]+)。
b)(lR)-N-[(3S)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢萘-1-甲酰胺
使用手性HPLC(柱:Reprosil手性-NR,洗脱液:庚烷/乙醇+NH4OAc(60:40),压力:18bar;流速:35ml/min)分离N-[(3S)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢萘-1-甲酰胺的差向异构体(210mg),得到(lR)-N-[(3S)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢萘-1-甲酰胺(39mg,白色固体),保留时间=44min。MS(ISP):287.1([M+H]+)。
实施例47
(S)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]吡啶-3-甲酰胺
以类似于实施例2的方式,使用吡唑并[l,5-a]吡啶-3-甲酸100替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):273.1([M+H]+)。
实施例48
(R)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]吡啶-3-甲酰胺
以类似于实施例2的方式,使用吡唑并[l,5-a]吡啶-3-甲酸100替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):273.1([M+H]+)。
实施例49
(R)-N-(2,6-二氧代哌啶-3-基)-lH-吲唑-3-甲酰胺
以类似于实施例2的方式,使用lH-吲唑-3-甲酸101替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):273.1([M+H]+)。
实施例50
(S)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,5-a]吡啶-3-甲酰胺
以类似于实施例2的方式,使用咪唑并[l,5-a]吡啶-3-甲酸102替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):273.1([M+H]+)。
实施例51
(R)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,5-a]吡啶-3-甲酰胺
以类似于实施例2的方式,使用咪唑并[l,5-a]吡啶-3-甲酸102替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。MS(ISP):273.1([M+H]+)。
实施例52
(S)-N-(2,6-二氧代哌啶-3-基)中氮茚-3-甲酰胺
以类似于实施例2的方式,使用中氮茚-3-甲酸103替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):272.1([M+H]+)。
实施例53
(R)-N-(2,6-二氧代哌啶-3-基)中氮茚-3-甲酰胺
以类似于实施例2的方式,使用中氮茚-3-甲酸103替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):272.1([M+H]+)。
实施例54
(S)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,2-a]吡啶-3-甲酰胺
以类似于实施例2的方式,使用咪唑并[l,2-a]吡啶-3-甲酸104替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):273.1([M+H]+)。
实施例55
(R)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,2-a]吡啶-3-甲酰胺
以类似于实施例2的方式,使用咪唑并[l,2-a]吡啶-3-甲酸104替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):273.1([M+H]+)。
实施例56
(S)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]嘧啶-3-甲酰胺
以类似于实施例2的方式,使用吡唑并[l,5-a]嘧啶-3-甲酸105替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮盐酸盐62替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):274.1([M+H]+)。
实施例57
(R)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]嘧啶-3-甲酰胺
以类似于实施例2的方式,使用吡唑并[l,5-a]嘧啶-3-甲酸105替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):274.1([M+H]+)。
实施例58
N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺
以类似于实施例9的方式,使用3-(甲基氨基)哌啶-2,6-二酮65替代3-氨基哌啶-2,6-二酮60,得到标题化合物。灰白色固体。MS(ISP):288.1([M+H]+)。
实施例59
(S)-N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺
使用手性HPLC(柱:Reprosil手性-NR,洗脱液:庚烷/乙醇+NH4OAc(60:40),压力:18bar;流速:35ml/min)分离N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺的差向异构体(120mg),得到(S)-N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺(56mg,灰白色固体),保留时间=12.4min。MS(ISP):288.1([M+H]+)。
实施例60
(R)-N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺
使用手性HPLC(柱:Reprosil手性-NR,洗脱液:庚烷/乙醇+NH4OAc(60:40),压力:18bar;流速:35ml/min)分离N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺的差向异构体(120mg),得到(R)-N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺(52mg,灰白色固体),保留时间=15.4min。MS(ISP):288.1([M+H]+)。
实施例61
(S)-N-(2,6-二氧代哌啶-3-基)-2-(吡啶-3-基)乙酰胺
以类似于实施例2的方式,使用2-(吡啶-3-基)乙酸106替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮61替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):248.1([M+H]+)。
实施例62
N-(2,6-二氧代哌啶-3-基)-N-甲基-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺
以类似于实施例9的方式,使用2,3-二氢-lH-吡咯并[2,3-b]吡啶91替代吲哚啉,使用3-(甲基氨基)哌啶-2,6-二酮65替代3-氨基哌啶-2,6-二酮60,得到标题化合物。黄色固体。MS(ISP):289.1([M+H]+)。
实施例63
(R)-N-(2,6-二氧代哌啶-3-基)-2-(吡啶-3-基)乙酰胺
以类似于实施例2的方式,使用2-(吡啶-3-基)乙酸106替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮63替代3-氨基哌啶-2,6-二酮60,得到标题化合物。灰白色固体。MS(ISP):248.1([M+H]+)。
实施例64
(R)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢-1,8-萘啶-l(2H)-甲酰胺
以类似于实施例9的方式,使用1,2,3,4-四氢-1,8-萘啶92替代吲哚啉,使用(R)-3-氨基哌啶-2,6-二酮63替代3-氨基哌啶-2,6-二酮60得到标题化合物。白色固体。MS(ISP):289.1([M+H]+)。
实施例65
(S)-2-(4-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺
以类似于实施例2的方式,使用2-(4-乙酰胺基苯基)乙酸107替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮61替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):304.1([M+H]+)。
实施例66
(R)-2-(4-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺
以类似于实施例2的方式,使用2-(4-乙酰胺基苯基)乙酸107替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮63替代3-氨基哌啶-2,6-二酮60,得到标题化合物。灰白色固体。MS(ISP):304.1([M+H]+)。
实施例67
(R)-2-(3-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺
以类似于实施例2的方式,使用2-(3-乙酰胺基苯基)乙酸108替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮63替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):304.2([M+H]+)。
实施例68
(S)-2-(3-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺
以类似于实施例2的方式,使用2-(3-乙酰胺基苯基)乙酸108替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮61替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):304.1([M+H]+)。
实施例69
(S)-N-(2,6-二氧代哌啶-3-基)-2-(2-氧代吲哚啉-5-基)乙酰胺
以类似于实施例2的方式,使用2-(2-氧代吲哚啉-6-基)乙酸109替代2,3-二氢-lH-茚-1-甲酸75,使用(3S)-3-氨基哌啶-2,6-二酮61替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):302.1([M+H]+)。
实施例70
(R)-N-(2,6-二氧代哌啶-3-基)-2-(2-氧代吲哚啉-5-基)乙酰胺
以类似于实施例2的方式,使用2-(2-氧代吲哚啉-6-基)乙酸109替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮63替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):302.1([M+H]+)。
实施例71
(S)-3-((2,6-二氧代哌啶-3-基)氨基甲酰基)-1-甲基-1,4,6,7-四氢-5H-吡唑并[4,3-c]吡啶-5甲酸叔丁酯
向(S)-3-氨基哌啶-2,6-二酮盐酸盐62(54mg)和5-(叔丁氧基羰基)-1-甲基-4,5,6,7-四氢-lH-吡唑并[4,3-c]吡啶-3-甲酸110(102mg)的混合物加入HATU的N,N-二甲基甲酰胺溶液(1.1ml,0.358M)和N,N-二异丙基乙胺(170mg)。将反应混合物在25℃下摇动4小时。然后将反应混合物在水与乙酸乙酯/THF1:1混合物之间分配。有机层用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。粗物质经制备型HPLC纯化,然后冻干,得到(S)-3-((2,6-二氧代哌啶-3-基)氨基甲酰基)-1-甲基-1,4,6,7-四氢-5H-吡唑并[4,3-c]吡啶-5甲酸叔丁酯(116mg,90.3%),为白色固体。MS(ISP):392.4([M+H]+)。
实施例72
(S)-N-(2,6-二氧代哌啶-3-基)-1-甲基-4,5,6,7-四氢-lH-吡唑并[4,3-c]吡啶-3-甲酰胺
向(S)-3-((2,6-二氧代哌啶-3-基)氨基甲酰基)-1-甲基-1,4,6,7-四氢-5H-吡唑并[4,3-c]吡啶-5甲酸叔丁酯(110mg)在乙酸乙酯(1ml)中的经搅拌的溶液中加入4M HCl的二噁烷溶液(0.5ml)。将反应混合物在0℃搅拌2小时。然后通过过滤收集产物,将其用乙酸乙酯洗涤,干燥,得到(S)-N-(2,6-二氧代哌啶-3-基)-1-甲基-4,5,6,7-四氢-lH-吡唑并[4,3-c]吡啶-3-甲酰胺(51mg,62.3%),为白色固体。MS(ISP):292.3([M+H]+)。
实施例73
(1S)-N-(l-甲基-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺
(差向异构体的1:1混合物)
以类似于实施例2的方式,使用(S)-1,2,3,4-四氢萘甲酸替代2,3-二氢-lH-茚-1-甲酸75,使用3-氨基-1-甲基哌啶-2,6-二酮盐酸盐111替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(EI):300.1([M+H]+)。
实施例74
(1S)-N-(l-甲基-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺
(差向异构体1)
使用手性HPLC(柱:Reprosil手性-NR,洗脱液:庚烷/乙醇+NH4OAc(70:30),压力:18bar;流速:35ml/min)分离(1S)-N-(l-甲基-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺的差向异构体(118mg),得到(1S)-N-(1-甲基-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺(差向异构体1)(29mg,白色固体),保留时间=37min。MS(EI):300.1([M+H]+)。
实施例-75
(1S)-N-(l-甲基-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺
(差向异构体2)
使用手性HPLC(柱:Reprosil手性-NR,洗脱液:庚烷/乙醇+NH4OAc(70:30),压力:18bar;流速:35ml/min)分离(1S)-N-(l-甲基-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺的差向异构体(118mg),得到(1S)-N-(1-甲基-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺(差向异构体1)(29mg,白色固体),保留时间=41min。MS(EI):300.1([M+H]+)。
实施例A
(4S)-1-[6-[[2-[(9S)-7-(4-氯代苯基)-4,5,13-三甲基-3-硫杂-1,8,11,12-四氮杂三环[8.3.0.02,6]十三-2(6),4,7,10,12-五烯-9-基]乙酰基]氨基]己酰基]-N-[(3S)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺
a)N-[6-[(4S)-4-[[(3S)-2,6-二氧代哌啶-3-基]氨基甲酰基]-3,4-二氢喹啉-1
(2H)-基]-6-氧代己基]氨基甲酸叔丁酯
在0℃下向6-(叔丁氧基羰基氨基)己酸112(19.5mg)在二氯甲烷(0.4ml)中的经搅拌的溶液中添加1-氯-N,N,2-三甲基丙烯胺(12.2μl)。在室温下搅拌20分钟后,滴加(4S)-N-[(3S)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺(22mg,实施例32)在二氯甲烷(0.2ml)中的溶液,然后滴加N,N-二异丙基乙胺(33.4μl)。将该溶液在室温搅拌2小时。将反应混合物在水和乙酸乙酯与THF的1:1混合物之间分配。有机层用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩。粗物质通过快速色谱法纯化(硅胶,4g,洗脱液:0至5%甲醇的二氯甲烷溶液),得到N-[6-[(4S)-4-[[(3S)-2,6-二氧代哌啶-3-基]氨基甲酰基]-3,4-二氢喹啉-1(2H)-基]-6-氧代己基]氨基甲酸叔丁酯(36mg,94%),为无定型无色固体。MS(ISP):499.3([M+H]+)。
b)(4S)-1-(6-氨基己酰基)-N-[(3S)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹
啉-4-甲酰胺盐酸盐
向N-[6-[(4S)-4-[[(3S)-2,6-二氧代哌啶-3-基]氨基甲酰基]-3,4-二氢喹啉-1(2H)-基]-6-氧代己基]氨基甲酸叔丁酯(33mg)在二氯甲烷(1ml)中的经搅拌的溶液中加入4M HCl的二噁烷溶液(412μl)。将反应混合物在室温搅拌2小时,然后蒸发至干。将残余物悬浮在乙醚中,超声处理并过滤,得到(4S)-1-(6-氨基己酰基)-N-[(3S)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺盐酸盐(13mg,45%),其无需进一步纯化即可用于下一步。MS(ISP):401.3([M+H]+)。
c)(4S)-1-[6-[[2-[(9S)-7-(4-氯代苯基)-4,5,13-三甲基-3-硫杂-1,8,11,12-
四氮杂三环[8.3.0.02,6]十三-2(6),4,7,10,12-五烯-9-基]乙酰基]氨基]己酰基]-N-
[(3S)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺
向(S)-2-(4-(4-氯代苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑并[4,3-a][l,4]二氮杂-6-基)乙酸68(13.1mg),(4S)-1-(6-氨基己酰基)-N-[(3S)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺盐酸盐(13.0mg)和N,N-二异丙基乙胺(20.8μl)在DMF(0.5ml)中的经搅拌的溶液中加入HATU(17mg)。将该溶液在室温搅拌2小时。将反应混合物倒入乙酸乙酯/THF的1:1混合物中,并依次用水和盐水洗涤。有机层经Na2SO4干燥,过滤,并真空浓缩。通过快速色谱法(硅胶,4g,洗脱液:0至10%甲醇的二氯甲烷溶液)纯化粗物质,得到(4S)-1-[6-[[2-[(9S)-7-(4-氯代苯基)-4,5,13-三甲基-3-硫杂-1,8,11,12-四氮杂三环[8.3.0.02,6]十三-2(6),4,7,10,12-五烯-9-基]乙酰基]氨基]己酰基]-N-[(3S)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺(15mg,64%),为白色固体。MS(ISP):783.3([M+H]+)。
实施例B
(4S)-1-[6-[[2-[(9S)-7-(4-氯代苯基)-4,5,13-三甲基-3-硫杂-1,8,11,12-四氮杂三环[8.3.0.02,6]十三-2(6),4,7,10,12-五烯-9-基]乙酰基]氨基]己酰基]-N-[(3R)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺
a)N-[(3R)-2,6-二氧代-3-哌啶基]-1,2,3,4-四氢喹啉-4-甲酰胺(2种差向异构体的混合物)
以类似于实施例2的方式,使用(RS)-1,2,3,4-四氢喹啉-4-甲酸94替代2,3-二氢-lH-茚-1-甲酸75,使用(3R)-3-氨基哌啶-2,6-二酮盐酸盐64替代3-氨基哌啶-2,6-二酮60,得到标题化合物。白色固体。MS(ISP):288.3([M+H]+)。
b)(4S)-N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺
使用手性HPLC(柱:Reprosil手性-NR,洗脱液:庚烷/乙醇+NH4OAc(60:40),压力:18bar;流速:35ml/min)分离N-[(3R)-2,6-二氧代-3-哌啶基]-1,2,3,4-四氢喹啉-4-甲酰胺的差向异构体(110mg),得到(4S)-N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺(32mg,白色固体),保留时间=39min。MS(ISP):288.1([M+H]+)。
c)N-[6-[(4S)-4-[[(3R)-2,6-二氧代哌啶-3-基]氨基甲酰基]-3,4-二氢喹啉-1(2Η)-基]-6-氧代己基]氨基甲酸叔丁酯
以类似于实施例A的方式,在步骤a中使用(4S)-N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺替代(4S)-N-[(3S)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺,得到标题化合物。无定型无色固体。MS(ISP):501.3([M+H]+)。
d)(4S)-1-(6-氨基己酰基)-N-[(3R)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹
啉-4-甲酰胺盐酸盐
以类似于实施例A的方式,在步骤b中使用N-[6-[(4S)-4-[[(3R)-2,6-二氧代哌啶-3-基]氨基甲酰基]-3,4-二氢喹啉-l(2H)-基]-6-氧代己基]氨基甲酸叔丁酯替代N-[6-[(4S)-4-[[(3S)-2,6-二氧代哌啶-3-基]氨基甲酰基]-3,4-二氢喹啉-l(2H)-基]-6-氧代己基]氨基甲酸叔丁酯,得到标题化合物。白色固体。MS(ISP):401.2([M+H]+)。
e)(4S)-1-[6-[[2-[(9S)-7-(4-氯代苯基-4,5,13-三甲基-3-硫杂-1,8,11,12-四
氮杂三环[8.3.0.02,6]十三-2(6),4,7,10,12-五烯-9-基]乙酰基]氨基]己酰基]-N-
[(3R)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺
以类似于实施例A的方式,在步骤c中使用(4S)-1-(6-氨基己酰基)-N-[(3R)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺盐酸盐替代(4S)-1-(6-氨基己酰基)-N-[(3S)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺盐酸盐,得到标题化合物。白色固体。MS(ISP):781.4([M+H]+)。
实施例C
(4R)-1-[2-[2-[2-[2-[[2-[(9S)-7-(4-氯代苯基)-4,5,13-三甲基-3-硫杂-1,8,11,12-四氮杂三环[8.3.0.02,6]十三-2(6),4,7,10,12-五烯-9-基]乙酰基]氨基]乙氧基]乙氧基]乙氧基]乙酰基]-N-[(3S)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺
a)N-[2-[2-[2-[2-[(4R)-4-[[(3S)-2,6-二氧代哌啶-3-基]氨基甲酰基]-3,4-二
氢喹啉-1(2H)-基]-2-氧代乙氧基]乙氧基]乙氧基]乙基]氨基甲酸叔丁酯
以类似于实施例A的方式,在步骤a中使用(4R)-N-[(3S)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺(实施例33)替代(4S)-N-[(3S)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺,使用2,2-二甲基-4-氧代-3,8,11,14-四氧杂-5-氮杂十六-16-烷酸113替代6-(叔丁氧基羰基氨基)己酸,得到标题化合物。浅黄色泡沫。MS(ISP):577.5([M+H]+)。
b)(4R)-1-[2-[2-[2-(2-氨基乙氧基)乙氧基]乙氧基]乙酰基]-N-[(3S)-2,6-二
氧代哌啶-3-基]-3,4-二氢-2H-喹啉-4-甲酰胺盐酸盐
以类似于实施例A的方式,在步骤b中使用N-[2-[2-[2-[2-[(4R)-4-[[(3S)-2,6-二氧代哌啶-3-基]氨基甲酰基]-3,4-二氢喹啉-1(2H)-基]-2-氧代乙氧基]乙氧基]乙氧基]乙基]氨基甲酸叔丁酯替代N-[6-[(4S)-4-[[(3S)-2,6-二氧代哌啶-3-基]氨基甲酰基]-3,4-二氢喹啉-1(2H)-基]-6-氧代己基]氨基甲酸叔丁酯,得到标题化合物。浅黄色固体。MS(ISP):477.4([M+H]+)。
c)(4R)-1-[2-[2-[2-[2-[[2-[(9S)-7-(4-氯代苯基)-4,5,13-三甲基-3-硫杂-1,
8,11,12-四氮杂三环[8.3.0.02,6]十三-2(6),4,7,10,12-五烯-9-基]乙酰基]氨基]乙氧
基]乙氧基]乙氧基]乙酰基]-N-[(3S)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰
胺
以类似于实施例A的方式,在步骤c中使用(4R)-1-[2-[2-[2-(2-氨基乙氧基)乙氧基]乙氧基]乙酰基]-N-[(3S)-2,6-二氧代哌啶-3-基]-3,4-二氢-2H-喹啉-4-甲酰胺盐酸盐替代(4S)-1-(6-氨基己酰基)-N-[(3S)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺盐酸盐,得到标题化合物。白色固体。MS(ISP):859.4([M+H]+)。
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Claims (15)
2.式I的化合物,或其药学上可接受的盐,其中R1选自由以下组成的组:
i)芳基,任选地被一个或多个R3取代,
ii)杂环烷基,任选地被一个或多个R4取代,
iii)环烷基,任选地被一个或多个R5取代,和
iv)杂芳基,任选地被一个或多个R6取代,
R2为H或C1-6烷基,
R3为H或C1-6烷基,
R4为H或C1-6烷基,
R5为H或C1-6烷基,
R6为H或C1-6烷基,
n为0或l;
用作治疗活性物质。
3.根据权利要求1所述的式I的化合物,或其药学上可接受的盐,选自由以下组成的组:
(S)-N-((R)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(S)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(-)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
(+)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]-1,2,3,4-四氢喹啉-4-甲酰胺,
N-[(3R)-2,6-二氧代-3-哌啶基]-1,2,3,4-四氢喹啉-4-甲酰胺,
(S)-N-((R)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
(4R)-N-[(3R)-2,6-二氧代哌啶-3-基]-1,2,3,4-四氢喹啉-4-甲酰胺,
(R)-N-((R)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(R)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(1S)-N-(1-甲基-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(1S)-N-(1-甲基-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(1S)-N-(1-甲基-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-1-甲基-4,5,6,7-四氢-lH-吡唑并[4,3-c]吡啶-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,2-a]吡啶-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,2-a]吡啶-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺,
N-(2,6-二氧代哌啶-3-基)-N-甲基-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]-1-甲基-3,4-二氢-2H-喹啉-4-甲酰胺,
N-[(3R)-2,6-二氧代-3-哌啶基]-1-甲基-3,4-二氢-2H-喹啉-4-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢喹啉-l(2H)-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢喹啉-l(2H)-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]吡啶-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]吡啶-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,5-a]吡啶-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)咪唑并[l,5-a]吡啶-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]嘧啶-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)吡唑并[l,5-a]嘧啶-3-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]-2-苯基-乙酰胺,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-2-丙基-异吲哚啉-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,异构体A,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,异构体B,
N-(2,6-二氧代-3-哌啶基)茚满-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-lH-吲哚-3-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-1-甲基-吲哚-3-甲酰胺,
N-(2,6-二氧代-3-哌啶基)吲哚啉-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)苯甲酰胺,
N-(2,6-二氧代-3-哌啶基)环戊烷甲酰胺,
N-(2,6-二氧代-3-哌啶基)苯并呋喃-3-甲酰胺,
N-(2,6-二氧代-3-哌啶基)苯并噻吩-3-甲酰胺,
(lR)-N-(2,6-二氧代-3-哌啶基)萘满-1-甲酰胺,
(1S)-N-(2,6-二氧代-3-哌啶基)萘满-1-甲酰胺,
N-(2,6-二氧代-3-哌啶基)-N-甲基-lH-吲哚-3-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]-lH-吲哚-3-甲酰胺,
N-[(3R)-2,6-二氧代-3-哌啶基]-lH-吲哚-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)苯并呋喃-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]色满-4-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)苯并呋喃-3-甲酰胺,
N-[(3R)-2,6-二氧代-3-哌啶基]色满-4-甲酰胺,
(S)-3-((2,6-二氧代哌啶-3-基)氨基甲酰基)-lH-吲哚-6甲酸甲酯,
(R)-N-(2,6-二氧代哌啶-3-基)-lH-吲唑-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)中氮茚-3-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)中氮茚-3-甲酰胺,
N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-N-甲基吲哚啉-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-2-(吡啶-3-基)乙酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-2-(吡啶-3-基)乙酰胺,
(S)-2-(4-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺,
(R)-2-(4-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺,
(R)-2-(3-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺,
(S)-2-(3-乙酰胺基苯基)-N-(2,6-二氧代哌啶-3-基)乙酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-2-(2-氧代吲哚啉-5-基)乙酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)-2-(2-氧代吲哚啉-5-基)乙酰胺,
(S)-3-((2,6-二氧代哌啶-3-基)氨基甲酰基)-1-甲基-1,4,6,7-四氢-5H-吡唑并[4,3-c]吡啶-5甲酸叔丁酯,
N-((S)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酰胺,
N-((R)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酰胺,
N-((R)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺,
N-((S)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢-1,8-萘啶-l(2H)-甲酰胺,和
(R)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢-1,8-萘啶-l(2H)-甲酰胺。
4.式I的化合物,或其药学上可接受的盐,
R1选自由以下组成的组
i)芳基,任选地被一个或多个R3取代,
ii)杂环烷基,任选地被一个或多个R4取代,
iii)环烷基,任选地被一个或多个R5取代,和
iv)杂芳基,任选地被一个或多个R6取代,
R2为H或C1-6烷基,
R3为H或C1-6烷基,
R4为H或C1-6烷基,
R5为H或C1-6烷基,
R6为H或C1-6烷基,
n为0或l;
条件是将以下物质排除在外:(lR,2R)-rel-N-(2,6-二氧代-3-哌啶基)-2-乙基-环丙烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-1,2,3,4-四氢-2-萘甲酰胺、N-(2,6-二氧代-3-哌啶基)-1-乙基-环丙烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-2,2-二甲基-环丙烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-2,2,3,3-四甲基-环丙烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-1-甲基-环戊烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-环庚烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-环丙烷乙酰胺、N-(2,6-二氧代-3-哌啶基)-环戊烷乙酰胺、N-(2,6-二氧代-3-哌啶基)-1,2,3,4-四氢-1-萘甲酰胺、N-(2,6-二氧代-3-哌啶基)-2-甲基-苯乙酰胺、N-(2,6-二氧代-3-哌啶基)-环丁烷甲酰胺、4-丁基-N-(2,6-二氧代-3-哌啶基)-环己烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-3,4-二甲基-苯甲酰胺、N-(2,6-二氧代-3-哌啶基)-环辛烷甲酰胺、4-(l,l-二甲基乙基)-N-(2,6-二氧代-3-哌啶基)-苯甲酰胺、2,6-二氧代-3-哌啶基)-环己烷乙酰胺、N-(2,6-二氧代-3-哌啶基)-2,4,6-三甲基-苯甲酰胺、N-(2,6-二氧代-3-哌啶基)-2,5-二甲基-苯甲酰胺、(3S)-N-(2,6-二氧代-3-哌啶基)-3-吡咯烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-2-甲基-4-哌啶甲酰胺、N-(2,6-二氧代-3-哌啶基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺、N-(2,6-二氧代-3-哌啶基)-3,4-二氢-2H-1-苯并吡喃-4-乙酰胺、N-(2,6-二氧代-3-哌啶基)-2-乙基四氢-3-呋喃甲酰胺、(3R,4R)-rel-N-(2,6-二氧代-3-哌啶基)-4-甲基-3-吡咯烷甲酰胺、N-(2,6-二氧代-3-哌啶基)四氢-3-甲基-2H-吡喃-4-甲酰胺、N-(2,6-二氧代-3-哌啶基)-4-甲基-3-吡咯烷甲酰胺、N-(2,6-二氧代-3-哌啶基)-2-甲基-3-吡咯烷甲酰胺、N-(2,6-二氧代-3-哌啶基)四氢-2H-硫代吡喃-4-乙酰胺、N-(2,6-二氧代-3-哌啶基)-1,2,3,4-四氢-4-喹啉甲酰胺、N-(2,6-二氧代-3-哌啶基)-4-甲基-1-哌啶甲酰胺、N-(2,6-二氧代-3-哌啶基)-3-甲基-1-哌啶甲酰胺、N-(2,6-二氧代-3-哌啶基)-3-吡咯烷乙酰胺、N-(2,6-二氧代-3-哌啶基)-3-氮杂环丁烷乙酰胺、N-(2,6-二氧代-3-哌啶基)-3-氮杂环丁烷甲酰胺、N-(2,6-二氧代-3-哌啶基)四氢-2H-吡喃-4-甲酰胺、N-(2,6-二氧代-3-哌啶基)四氢-3-呋喃甲酰胺、N-(2,6-二氧代-3-哌啶基)四氢-3-噻吩甲酰胺、N-(2,6-二氧代-3-哌啶基)-3,4-二氢-2H-1-苯并吡喃-4-甲酰胺、N-[(3S)-2,6-二氧代-3-哌啶基]-4-甲基-苯甲酰胺、N-(2,6-二氧代-3-哌啶基)-4-甲基-苯乙酰胺、N-(2,6-二氧代-3-哌啶基)-4-甲基-苯甲酰胺、(S)-N-(2,6-二氧代-3-哌啶基)-1-萘乙酰胺、N-[(3S)-2,6-二氧代-3-哌啶基]-苯甲酰胺、N-[(3R)-2,6-二氧代-3-哌啶基]-苯乙酰胺、N-[(3S)-2,6-二氧代-3-哌啶基]-苯乙酰胺、N-[(3S)-2,6-二氧代-3-哌啶基]-2-苯基-乙酰胺、N-(2,6-二氧代-3-哌啶基)-lH-吲哚-3-甲酰胺、N-(2,6-二氧代-3-哌啶基)-1-甲基-吲哚-3-甲酰胺、N-(2,6-二氧代-3-哌啶基)苯甲酰胺、N-(2,6-二氧代-3-哌啶基)环戊烷甲酰胺、N-(2,6-二氧代-3-哌啶基)苯并呋喃-3-甲酰胺、N-(2,6-二氧代-3-哌啶基)苯并噻吩-3-甲酰胺、(lR)-N-(2,6-二氧代-3-哌啶基)萘满-1-甲酰胺、(1S)-N-(2,6-二氧代-3-哌啶基)萘满-1-甲酰胺、N-[(3S)-2,6-二氧代-3-哌啶基]-lH-吲哚-3-甲酰胺和N-[(3R)-2,6-二氧代-3-哌啶基]-lH-吲哚-3-甲酰胺。
5.根据权利要求1或4中任一项所述的式I的化合物,或其药学上可接受的盐,
其中
n为0,
R1选自由以下的组:
i)杂环烷基,任选地被一个或多个R4取代,
ii)环烷基,任选地被一个或多个R5取代,和
iii)杂芳基,任选地被一个或多个R6取代,
R2为H或C1-6烷基。
6.根据权利要求1或4-5中任一项所述的化合物,其中R1选自由以下组成的组:
i)1,2,3,4-四氢萘基,
ii)1,2,3,4-四氢喹啉基,
iii)lH-吲哚基,
iv)1-甲基-吲哚基,
v)2,3-二氢-lH-吡咯并[2,3-b]吡啶基,
vi)3,4-二氢-1,8-萘啶基,
vii)3,4-二氢喹啉基,
viii)6,7-二氢-5H-环戊二烯并[b]吡啶基,
ix)苯并[b]噻吩基,
x)苯并呋喃基,
xi)苯并噻吩基,
xii)色满基,
xiii)环戊基,
xiv)茚满基,
xv)吲哚啉基,
xvi)异吲哚啉基,和
xvii)萘满基。
7.根据权利要求1或4-6中任一项所述的化合物,其中R2为H。
8.根据权利要求1或4-7中任一项所述的化合物,其中R6为C1-6烷基,特别是甲基或丙基。
9.根据权利要求1-8中任一项所述的式I的化合物,或其药学上可接受的盐,选自由以下组成的组:
(-)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
(+)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢喹啉-4-甲酰胺,
(N-((R)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺,
(R)-N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺,
(S)-N-((R)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(S)-N-((S)-2,6-二氧代哌啶-3-基)-1,2,3,4-四氢萘-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-2,3-二氢-lH-吡咯并[2,3-b]吡啶-1-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢-1,8-萘啶-l(2H)-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)-3,4-二氢喹啉-l(2H)-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)苯并[b]噻吩-3-甲酰胺,
(S)-N-(2,6-二氧代哌啶-3-基)苯并呋喃-3-甲酰胺,
N-((R)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酰胺,
N-((S)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-5-甲酰胺,
N-((S)-2,6-二氧代哌啶-3-基)-6,7-二氢-5H-环戊二烯并[b]吡啶-7-甲酰胺,
N-[(3S)-2,6-二氧代-3-哌啶基]色满-4-甲酰胺,
3-氨基-N-甲基-4-[(2-氧代-1,3-二氢苯并咪唑-5-基)氨基]苯甲酰胺,
N-甲基-2-[2-(3-甲基咪唑-4-基)-4-喹啉基]-1-(2-氧代-1,3-二氢苯并咪唑-5-基)苯并咪唑-5-甲酰胺,
N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)-2-(4-喹啉基)苯并咪唑-5-甲酰胺,
2-乙基-N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)苯并咪唑-5-甲酰胺,
N,2-二甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)苯并咪唑-5-甲酰胺,
5-[2-(4-喹啉基)苯并咪唑-1-基]-1,3-二氢苯并咪唑-2-酮,
5-[2-[2-(3-甲基咪唑-4-基)-4-喹啉基]苯并咪唑-1-基]-1,3-二氢苯并咪唑-2-酮,
3-氨基-4-[(2-氧代-1,3-二氢苯并咪唑-5-基)氨基]苯甲酸甲酯,
N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)-2-苯基-苯并咪唑-5-甲酰胺,
N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)-2-(4-吡啶基)苯并咪唑-5-甲酰胺,
N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)-2-(三氟甲基)苯并咪唑-5-甲酰胺,
N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)-2-丙基-苯并咪唑-5-甲酰胺,
2-(lH-咪唑-5-基)-N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)苯并咪唑-5-甲酰胺,
2-异丙基-N-甲基-1-(2-氧代-1,3-二氢苯并咪唑-5-基)苯并咪唑-5-甲酰胺,
1-(l,3-二甲基-2-氧代-苯并咪唑-5-基)-N-甲基-2-[2-(3-甲基咪唑-4-基)-4-喹啉基]苯并咪唑-5-甲酰胺,
N,N-二甲基-2-[2-(3-甲基咪唑-4-基)-4-喹啉基]-1-(2-氧代-1,3-二氢苯并咪唑-5-基)苯并咪唑-5-甲酰胺,
2-(3-甲氧基苄基)-N-甲基-2'-氧代-2',3'-二氢-1'H-[l,5'-联苯并[d]咪唑]-5-甲酰胺,和
2-异丙基-N-甲基-2'-氧代-2',3'-二氢-1'H-[l,5'-联苯并[d]咪唑]-6-甲酰胺。
10.具有包含以下的化学结构的化合物,或其药学上可接受的盐:
P-L-C
其中
L为连接基团;
C为根据权利要求1至8中任一项所述的化合物,
其中L与C化学连接;并且
P为与靶蛋白或靶多肽结合的蛋白靶部分,
其中L与P化学连接。
12.根据权利要求10-11中任一项所述的化合物,或其药学上可接受的盐,选自由以下组成的组:
(4S)-1-[6-[[2-[(9S)-7-(4-氯代苯基)-4,5,13-三甲基-3-硫杂-1,8,11,12-四氮杂三环[8.3.0.02,6]十三-2(6),4,7,10,12-五烯-9-基]乙酰基]氨基]己酰基]-N-[(3R)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺,
(4R)-1-[2-[2-[2-[2-[[2-[(9S)-7-(4-氯代苯基)-4,5,13-三甲基-3-硫杂-1,8,11,12-四氮杂三环[8.3.0.02,6]十三-2(6),4,7,10,12-五烯-9-基]乙酰基]氨基]乙氧基]乙氧基]乙氧基]乙酰基]-N-[(3S)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺,和
(4S)-1-[6-[[2-[(9S)-7-(4-氯代苯基)-4,5,13-三甲基-3-硫杂-1,8,11,12-四氮杂三环[8.3.0.02,6]十三-2(6),4,7,10,12-五烯-9-基]乙酰基]氨基]己酰基]-N-[(3S)-2,6-二氧代-3-哌啶基]-3,4-二氢-2H-喹啉-4-甲酰胺。
13.根据权利要求10-12中任一项所述的化合物,或其药学上可接受的盐,用于癌症的治疗性和/或预防性治疗。
14.根据权利要求1-13中任一项所述的化合物,或其药学上可接受的盐用于癌症的治疗性和/或预防性治疗的用途。
15.药物组合物,其包含根据权利要求1-13中任一项所述的化合物,和治疗上惰性的载体。
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US20200207783A1 (en) | 2020-07-02 |
US11802131B2 (en) | 2023-10-31 |
WO2019043214A1 (en) | 2019-03-07 |
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