TW202304884A - 經取代之吡咯甲醯胺、其製備方法及其作為激酶抑制劑之用途 - Google Patents
經取代之吡咯甲醯胺、其製備方法及其作為激酶抑制劑之用途 Download PDFInfo
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- TW202304884A TW202304884A TW111112350A TW111112350A TW202304884A TW 202304884 A TW202304884 A TW 202304884A TW 111112350 A TW111112350 A TW 111112350A TW 111112350 A TW111112350 A TW 111112350A TW 202304884 A TW202304884 A TW 202304884A
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- pyrrole
- pyridin
- pyrrolo
- carboxamide
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- 238000000034 method Methods 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims description 11
- 230000008569 process Effects 0.000 title description 6
- RLOQBKJCOAXOLR-UHFFFAOYSA-N 1h-pyrrole-2-carboxamide Chemical class NC(=O)C1=CC=CN1 RLOQBKJCOAXOLR-UHFFFAOYSA-N 0.000 title description 4
- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
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- 201000010099 disease Diseases 0.000 claims abstract description 21
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- 238000006243 chemical reaction Methods 0.000 claims description 47
- 239000001257 hydrogen Substances 0.000 claims description 46
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 26
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- 150000003839 salts Chemical class 0.000 claims description 25
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
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- 150000002431 hydrogen Chemical class 0.000 claims description 15
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 14
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
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- 125000001424 substituent group Chemical group 0.000 claims description 9
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- 230000026030 halogenation Effects 0.000 claims description 8
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- UFEXQRMNIXMBRE-UHFFFAOYSA-N NC(C1=C(C(C=CC=C2Cl)=C2Cl)NC(C2=C(C=CN3)C3=NC=C2)=C1)=O Chemical compound NC(C1=C(C(C=CC=C2Cl)=C2Cl)NC(C2=C(C=CN3)C3=NC=C2)=C1)=O UFEXQRMNIXMBRE-UHFFFAOYSA-N 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
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- 125000003107 substituted aryl group Chemical group 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
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- CZOTYSXWRSEXEB-UHFFFAOYSA-N CC1=NNC=C1C1=CC(C(N)=O)=C(C(C=CC(C)=C2)=C2F)N1 Chemical compound CC1=NNC=C1C1=CC(C(N)=O)=C(C(C=CC(C)=C2)=C2F)N1 CZOTYSXWRSEXEB-UHFFFAOYSA-N 0.000 claims description 6
- SKFGHECPXPZXPO-UHFFFAOYSA-N CN(C(C1=C(C=CN2)C2=NC=C1)=C1)C(C(C=CC(Cl)=C2)=C2Cl)=C1C(N)=O Chemical compound CN(C(C1=C(C=CN2)C2=NC=C1)=C1)C(C(C=CC(Cl)=C2)=C2Cl)=C1C(N)=O SKFGHECPXPZXPO-UHFFFAOYSA-N 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 210000004027 cell Anatomy 0.000 claims description 6
- 229940127089 cytotoxic agent Drugs 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 6
- 102000004169 proteins and genes Human genes 0.000 claims description 6
- 108090000623 proteins and genes Proteins 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
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- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 4
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- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 claims description 4
- 238000000844 transformation Methods 0.000 claims description 4
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- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 3
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- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 3
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 claims description 3
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 claims description 3
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 3
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- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 3
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 claims description 3
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 claims description 3
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 claims description 3
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 claims description 3
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 3
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 3
- 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 description 3
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 claims description 3
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 claims description 3
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 claims description 3
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 3
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- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- IJAPPYDYQCXOEF-UHFFFAOYSA-N phthalazin-1(2H)-one Chemical compound C1=CC=C2C(=O)NN=CC2=C1 IJAPPYDYQCXOEF-UHFFFAOYSA-N 0.000 description 1
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- 238000010837 poor prognosis Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229940093956 potassium carbonate Drugs 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
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- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
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- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Chemical compound OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 239000000661 sodium alginate Substances 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical group [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
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- 239000003277 telomerase inhibitor Substances 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 description 1
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 description 1
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- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 1
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- JUDXOKKZTISQDJ-UHFFFAOYSA-N triphenylphosphane;hydrochloride Chemical compound Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 JUDXOKKZTISQDJ-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
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- 229960005080 warfarin Drugs 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyrrole Compounds (AREA)
Abstract
本發明係關於某些經取代之吡咯化合物,其等調節週期7相關蛋白激酶(Cdc7)之活性。因此,本發明之化合物適用於治療與失調之激酶活性相關之疾病,例如癌症、細胞增殖性疾病、病毒感染、免疫失調、神經退化性疾病、心血管疾病及骨相關疾病。
本發明亦提供此等化合物之製備方法,包含此等化合物之醫藥組合物,及利用包含此等化合物之醫藥組合物治療疾病之方法。
Description
本發明係關於某些經取代之吡咯化合物,其等調節蛋白激酶之活性。因此,本發明之化合物適用於治療與失調之激酶活性相關之疾病,例如癌症、細胞增殖性疾患、病毒感染、免疫失調、神經退化性疾病、心血管疾病及骨相關疾病。
本發明亦提供此等化合物之製備方法;包含此等化合物之醫藥組合物;及利用包含此等化合物之醫藥組合物治療疾病之方法。
蛋白激酶(PK)之功能失效係許多疾病之特徵。人類癌症中涉及之大部分致癌基因及原致癌基因編碼PK。PK之經增強活性亦與許多非惡性疾病相關。關於PK功能失效或失調之一般參考,參見例如Current Opinion in Chemical Biology 1999, 3, 459 - 465。
此項技術中已知與癌細胞生長有關之數種蛋白激酶中的一種係細胞分裂週期7相關蛋白激酶(Cdc7),其係一種藉由在DNA複製起點催化MCM解旋酶活化進行複製DNA所需的關鍵細胞週期蛋白。Cdc7激酶及其調節次單元Dbf4於許多腫瘤中過表現且過表現與不良預後及晚期腫瘤分級相關。Cdc7亦涉及解決複製應激或損傷後介導停滯複製叉之處理且涉及跨損傷區DNA修復(參見Montagnoli A.等人,EMBO Journal,2002,第21卷,第12期,3171;Montagnoli A.等人,Cancer Research 2004,第64卷,October 1, 7110;Hou Y.等人,Mol Oncol 2012,第29卷,3498;Day TA等人,2010,J Cell Biol,第191卷,953)。
吡咯甲醯胺衍生物在此項技術中稱為蛋白激酶抑制劑。在其等之中,例如,WO2009/040399報導適用於與失調之蛋白激酶活性,特別Polo樣激酶(PLK)家族相關聯之疾病之療法中之嘧啶基-吡咯衍生物;WO2013/014039及WO2014/019908揭示具有詹納斯激酶(Janus Kinase,JAK)及Src抑制活性之嘧啶基-吡咯衍生物,而WO2007/110344主張針對Cdc7蛋白酶活性具有抑制活性之嘧啶基-吡咯化合物。
藥物代謝及藥物動力學(DMPK)主要與藥物發現及藥物開發過程中之安全性評估相關聯。除針對靶蛋白具有足夠效價外,亦需可接受之安全性概況以增加候選藥物成為成功療法之機率。
考慮到上文因素,迫切需開發用於治療癌症及其他疾病之Cdc7抑制劑。本發明人現已鑑別針對Cdc7蛋白激酶具有抑制活性之新穎吡咯甲醯胺化合物。本發明之化合物為該Cdc7激酶之強效抑制劑且其相較於先前技術中揭示之相同化學類別之化合物出乎意料地顯示經增加之代謝穩定性性質。下文章節「實驗部分」中將更詳細討論此等經改良之性質。
由於PK (特定言之Cdc7)在調節細胞增殖中之關鍵作用,因此此等吡咯甲醯胺衍生物特別適用於治療癌症及治療細胞增殖性疾患及免疫相關疾患。
因此,本發明之第一目標係提供一種由式(I)表示之經取代之吡咯甲醯胺化合物,
其中:
R1係選自由以下組成之群之雜芳基:
、
、
、
及
其中:
Ra、Rb及Rc獨立地係氫、視需要經取代之直鏈或分支鏈(C
1-C
6)烷基或視需要經取代之直鏈或分支鏈(C
2-C
6)烯基;
R2係經取代之芳基或經取代之雜芳基環,其攜載一至三個選自以下之取代基:鹵素、硝基、胺基、(C
1-C
6)烷基胺基、胺基羰基、視需要經取代之直鏈或分支鏈(C
1-C
6)烷基、視需要經取代之直鏈或分支鏈(C
1-C
6)烷氧基、視需要經取代之直鏈或分支鏈多氟化(C
1-C
6)烷基及視需要經取代之直鏈或分支鏈多氟化(C
1-C
6)烷氧基;
前提條件係排除2,5-雙取代之苯基;
R3係氫、視需要經取代之直鏈或分支鏈(C
1-C
4)烷基、視需要經取代之(C
3-C
6)環烷基或視需要經取代之(C
5-C
6)雜環基;
R4係氫、視需要經取代之直鏈或分支鏈(C
1-C
6)烷基或視需要經取代之直鏈或分支鏈(C
2-C
6)烯基;及
R5係氫、鹵素或視需要經取代之直鏈或分支鏈(C
1-C
3)烷基;
或其醫藥上可接受之鹽。
較佳之式(I)化合物係以下化合物,其中:
R1係選自(A)、(B)、(C)、(D)及(E)之群之視需要經取代之雜芳基;
其中:
Ra、Rb及Rc獨立地係氫或視需要經取代之直鏈或分支鏈(C1-C6)烷基;
R2係2,4-雙取代之苯基、4,6-雙取代之吡啶-3-基、2,6-雙取代之吡啶-3-基或3,5-雙取代之吡啶-2-基;及
R3、R4及R5係如上文定義。
更佳之式(I)化合物係以下化合物,其中:
R2係2,4-雙取代之苯基;
R3係氫或視需要經取代之直鏈或分支鏈(C
1-C
4)烷基鏈;
R5係氫;及
R1及R4係如上文定義。
甚至更佳之式(I)化合物係以下化合物,其中:
R4係氫;及
R1、R2、R3及R5係如上文定義。
較佳之特定式(I)化合物或其醫藥上可接受之鹽係下文列舉之化合物:
2-(3-氯-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物1);
2-(4-氯-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物2);
2-(2-氯-4-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物3);
2-(2,4-二氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物4);
2-[2-氯-4-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物5);
2-(2,3-二氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物6);
2-(2,3-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物7);
2-[4-甲基-2-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物8);
2-(2-氯-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物9);
2-(2,3-二氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物10);
2-[2-甲基-4-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物11);
2-(2-氟-3-甲氧基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物12);
2-(2-氯-3-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物13);
2-(2-氟-3-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物14);
2-[2-甲基-3-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物15);
2-[4-甲氧基-2-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物16);
2-[2-氯-4-(二氟甲氧基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物17);
2-(3,4-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物18);
2-(3,4-二氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物19);
2-(3-乙氧基-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物20);
2-(4-甲基-3-硝基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物21);
2-(3-胺甲醯基-4-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物22);
2-(2-氟-4-甲基苯基)-N-[2-(吡咯啶-1-基)乙基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物23);
N-[2-(二甲基胺基)乙基]-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物24);
2-(2-氟-4-甲基苯基)-N-[2-(嗎啉-4-基)乙基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物25);
N-[(1S,2R)-2-胺基環己基]-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物26);
2-(2-氟-4-甲基苯基)-N-(呋喃-2-基甲基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物27);
N-(氟乙基)-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物28);
2-(2-氟-4-甲基苯基)-N-[2-(甲基胺基)乙基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物29);
2-(2-氟-4-甲基苯基)-N-(1-甲基哌啶-4-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物30);
2-(二苯并[b,d]噻吩-4-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物31);
2-(4-甲基萘-1-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物32);
2-(3-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物33);
5-(1H-吡咯并[2,3-b]吡啶-4-基)-2-[4-(三氟甲氧基)苯基]-1H-吡咯-3-甲醯胺(化合物34);
2-(1-苯并噻吩-3-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物35);
2-(2,3-二氫-1,4-苯并戴奧辛(benzodioxin)-6-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物36);
2-(4-氟-2-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物37);
2-(2-氟-4-甲基苯基)-4-碘-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物38);
4-溴-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物39);
4-乙基-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物40);
2-(2-氟-4-甲基苯基)-4-(丙-2-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物41);
5-(6-胺基嘧啶-4-基)-2-(2,4-二氯苯基)-1H-吡咯-3-甲醯胺(化合物42)
2-(2,4-二氯苯基)-5-(1H-吡唑-4-基)-1H-吡咯-3-甲醯胺(化合物43);
2-(2,4-二氯苯基)-5-(3-甲基-1H-吡唑-4-基)-1H-吡咯-3-甲醯胺(化合物44);
5-(2-胺基-1,3-噻唑-4-基)-2-(2,4-二氯苯基)-1H-吡咯-3-甲醯胺(化合物45);
2-(2,4-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物46);
2-(2,4-二氯苯基)-5-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物47);
2-(2,4-二氯苯基)-5-[3-(三氟甲基)-1H-吡唑-4-基]-1H-吡咯-3-甲醯胺(化合物48);
2-(2-氟-4-甲基苯基)-5-(1H-吡唑-4-基)-1H-吡咯-3-甲醯胺(化合物49);
5-(3,5-二甲基-1H-吡唑-4-基)-2-(2-氟-4-甲基苯基)-1H-吡咯-3-甲醯胺(化合物50);
2-(2-氟-4-甲基苯基)-5-(1-甲基-1H-吡唑-4-基)-1H-吡咯-3-甲醯胺(化合物51);
2-(2-氟-4-甲基苯基)-5-(3-甲基-1H-吡唑-4-基)-1H-吡咯-3-甲醯胺(化合物52);
2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物53);
2-(2,4-二氯苯基)-1-(2-羥乙基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物54);
2-(2,4-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-(3,3,3-三氟丙基)-1H-吡咯-3-甲醯胺(化合物55);
2-(2,4-二氯苯基)-1-甲基-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物56);及
2-(2,4-二氯苯基)-1-乙基-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物57)。
若本發明之化合物中存在立體中心或另一種形式之非對稱中心,則本文意欲涵蓋此等光學異構體或異構體之所有形式,包括對映體及非對映體。含有立體中心之化合物可以外消旋混合物、對映體富集之混合物的形式使用或可使用眾所周知的技術分離外消旋混合物且可使用個別對映體。此等程序包括標準層析技術,包括使用對掌性固定相之層析術或結晶化。用於分離含有一或多個非對稱中心之化合物之一般方法係報導(例如)於Jacques, Jean;Collet, André;Wilen, Samuel H.,Enantiomers, Racemates, and Resolutions, John Wiley & Sons Inc., New York (NY), 1981中。
在化合物具有不飽和碳碳雙鍵之情況下,順式(Z)及反式(E)異構體兩者均於本發明之範圍內。
在其中化合物可以互變異構形式(諸如酮-烯醇互變異構體)存在之情況下,各互變異構形式係經審慎考慮為包括於本發明內,無論是以平衡形式還是主要以一種形式存在。
式(I)化合物之醫藥上可接受之鹽包括與無機或有機酸(例如硝酸、鹽酸、氫溴酸、硫酸、過氯酸、磷酸、乙酸、三氟乙酸、丙酸、乙醇酸、乳酸、草酸、延胡索酸、丙二酸、蘋果酸、順丁烯二酸、酒石酸、檸檬酸、苯甲酸、桂皮酸、苦杏仁酸、甲烷磺酸、羥乙磺酸及水楊酸)形成之鹽。
式(I)化合物之醫藥上可接受之鹽亦包括與無機或有機鹼(例如鹼金屬或鹼土金屬,尤其鈉、鉀、鈣、銨或鎂的氫氧化物、碳酸鹽或碳酸氫鹽、無環或環胺)形成之鹽。
本發明之另一目標係式(I)化合物,其中一或多個氫係經一或多個氘原子置換。
術語「(C
1-C
6)烷基」意謂僅含有碳碳單鍵的脂族(C
1-C
6)烴鏈,其可為直鏈或分支鏈的。代表性實例包括(但不限於)甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、正己基,及類似物。
除非另有規定,否則術語「(C
3-C
6)環烷基」意謂3至6員全碳單環,其可含有一或多個雙鍵,但不具有完全共軛之π電子系統。
(C
3-C
6)環烷基之實例(不限於)係環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基及環己二烯基。
術語「(C
5-C
6)雜環基」意謂5至6員、飽和或部分不飽和碳環,其中一或多個碳原子係經雜原子(諸如氮、氧及硫)置換。雜環基之非限制性實例係例如哌喃基、四氫哌喃基、吡咯啶基、吡咯啉基、咪唑啉基、咪唑啶基、吡唑啶基、吡唑啉基、噻唑啉基、噻唑啶基、二氫呋喃基、四氫呋喃基、四氫吡啶基、1,3-二氧雜環戊烷基、哌啶基、哌嗪基、嗎啉基及類似物。該雜環基環可視需要進一步稠合或連接至芳族及非芳族碳環或雜環。
術語「(C
2-C
6)烯基」意謂含有至少一個碳碳雙鍵之脂族直鏈或分支鏈(C
2-C
6)烴鏈。代表性實例包括(但不限於)乙烯基、1-丙烯基、2-丙烯基、1-或2-丁烯基,及類似物。
術語「芳基」係指具有1至4個環系統之單、雙或多碳環烴,視需要由單鍵彼此進一步稠合或連接,其中該等碳環中之至少一者係「芳族」的,其中該術語「芳族」係指完全共軛之π電子鍵系統。此等芳基之非限制性實例係苯基、α-或β-萘基、α-或β-四氫萘基、聯苯及二氫茚基。
術語「雜芳基」係指芳族雜環,通常具有1至3個選自N、O或S之雜原子之5至6員雜環;該雜芳基環可視需要進一步稠合或連接至芳族及非芳族碳環及雜環。此等雜芳基之非限制性實例係(例如)吡啶基、吡嗪基、嘧啶基、噠嗪基、吲哚基、咪唑基、噻唑基、異噻唑基、吡咯基、呋喃基、噁唑基、異噁唑基、吡唑基、噻吩基、噻二唑基、異噁唑基、異噻唑基、噁二唑基、吲唑基、噌啉基、苯并[1,3]二氧雜環戊烯基、苯并[1,4]戴奧辛基、苯并噻唑基、苯并噻吩基、苯并呋喃基、異吲哚啉基、苯并咪唑基、苯并噁唑基、喹啉基、異喹啉基、1,2,3-三唑基、1-苯基-1,2,3-三唑基、2,3-二氫吲哚基、2,3-二氫苯并呋喃基、2,3-二氫苯并噻吩基、苯并哌喃基、2,3-二氫苯并噁嗪基、2,3-二氫喹喔啉基及類似物。
術語「鹵素」意謂氟、氯、溴或碘。
術語「多氟化(C
1-C
6)烷基」或「多氟化(C
1-C
6)烷氧基」意謂經多於一個氟原子取代的上文定義之(C
1-C
6)烷基或(C
1-C
6)烷氧基中之任一者,諸如,舉例而言,三氟甲基、三氟乙基、1,1,1,3,3,3-六氟丙基、三氟甲氧基及類似物。
術語「羥基(C
1-C
6)烷基」意謂攜載羥基的上文定義之(C
1-C
6)烷基中之任一者,諸如,舉例而言,羥基甲基、2-羥乙基、3-羥基丙基及類似物。
根據本發明且除非另有規定,否則R1、R2、R3、R4、R5、Ra、Rb及Rc可視需要於其等任意位置之任一者中經獨立地選自以下的一或多個基團(例如1至6個基團)取代:羥基、(C
1-C
6)烷氧基羥基(C
1-C
6)烷基、鹵素、硝基、側氧基(=O)、氰基、(C
1-C
6)烷基、多氟化(C
1-C
6)烷基、多氟化(C
1-C
6)烷氧基、(C
2-C
6)烯基、(C
2-C
6)炔基、芳基、芳基(C
1-C
6)烷基、(C
1-C
6)烷基芳基、芳基(C
1-C
6)烷氧基、雜芳基、雜芳基(C
1-C
6)烷基、(C
1-C
6)烷基雜芳基、雜環基、雜環基(C
1-C
6)烷基、(C
1-C
6)烷基雜環基、(C
1-C
6)烷基雜環基(C
1-C
6)烷基、三(C
1-C
6)烷基矽基、(C
3-C
7)環烷基、芳氧基、雜環氧基、亞甲二氧基、(C
1-C
6)烷基羰氧基、芳基羰氧基、二(C
1-C
6)烷基胺基雜環基(C
1-C
6)烷基、(C
3-C
7)環烯氧基、雜環基羰氧基、(C
1-C
6)伸烷基胺氧基、羧基、(C
1-C
6)烷氧基羰基、芳氧基羰基、(C
3-C
7)環烷氧基羰基、硝基、胺基、雜環基(C
1-C
6)烷氧基羰基胺基、脲基、(C
1-C
6)烷基胺基、胺基(C
1-C
6)烷基、二(C
1-C
6)烷基胺基、芳基胺基、二芳基胺基、雜環基胺基、甲醯基胺基、(C
1-C
6)烷基羰基胺基、芳基羰基胺基、雜環基羰基胺基、胺基羰基、(C
1-C
6)烷基胺基羰基、二(C
1-C
6)烷基胺基羰基、芳基胺基羰基、雜芳基胺基羰基、芳基胺基羰基(C
1-C
6)烷基、(C
3-C
7)環烷基胺基羰基、雜環基胺基羰基、(C
1-C
6)烷氧基羰基胺基、羥基胺基羰基、(C
1-C
6)烷氧基亞胺基、(C
1-C
6)烷基磺醯基胺基、芳基磺醯基胺基、雜環基磺醯基胺基、甲醯基、(C
1-C
6)烷基羰基、芳基羰基、(C
3-C
7)環烷基羰基、雜環基羰基、雜環基羰基(C
1-C
6)烷基、(C
1-C
6)烷基磺醯基、多氟化(C
1-C
6)烷基磺醯基、芳基磺醯基、胺基磺醯基、(C
1-C
6)烷基胺基磺醯基、二(C
1-C
6)烷基胺基磺醯基、芳基胺基磺醯基、雜環基胺基磺醯基、芳基硫基、(C
1-C
6)烷基硫基;進一步,每當適當時,上文取代基中之各者可經前述基團中之一或多者進一步取代。
綜上所述,熟悉此項技術者清楚名稱係複合名稱之任何基團,諸如,舉例而言,「芳基胺基」必須按照其衍生部分之習知解釋,例如由經芳基取代之胺基,其中芳基係如上文定義。
同樣,該等術語諸如,舉例而言,(C
1-C
6)烷基硫基、(C
1-C
6)烷基胺基、二(C
1-C
6)烷基胺基、(C
1-C
6)烷氧基羰基、(C
1-C
6)烷氧基羰基胺基、雜環基羰基、雜環基羰基胺基、(C
3-C
7)環烷氧基羰基及類似物中之任一者包括其中(C
1-C
6)烷基、(C
1-C
6)烷氧基、芳基、(C
3-C
7)環烷基及雜環基部分係如上文定義之基團。
本發明亦提供用於製備如上文定義之通式(I)化合物之方法,其藉由使用下文描述之反應途徑及合成方案,採用此項技術中可用之技術及可容易獲得之起始材料。本發明之某些實施例之製備係描述於下列實例中,但一般技術者將認知本發明描述之製備可容易適用以製備本發明之其他實施例。例如,根據本發明之非例示性化合物之合成可藉由熟習此項技術者顯而易見之修飾進行,例如藉由適當保護干擾基團、藉由用此項技術中已知的其他試劑適當地替換試劑,或藉由對反應條件作出例行性修飾來進行。或者,本文提及或此項技術中已知的其他反應將識別為具有用於製備本發明之其他化合物之適應性。
本發明之化合物可使用下列一般方法及程序自容易獲得之起始材料製備。除非另有指示,否則該等起始材料係已知化合物或可根據眾所周知的程序自已知化合物製備。將認知除非另有說明,否則在描述典型或較佳方法條件(即,反應溫度、時間、反應物之莫耳比率、溶劑、壓力)之情況下,亦可使用不同之方法條件。最佳反應條件可隨使用之反應物或溶劑而變化,但此等條件可由熟習此項技術者藉由例行性最佳化程序確定。
如上文定義的通式(I)化合物可根據此後於方案A、B及C中描述之一般合成方法製備。
式(I)化合物之製備,其中R1係選自式(A)、(B)、(C)、(D)及(E)之群之雜芳基;R2係經取代之芳基或經取代之雜芳基環,其攜載一至三個選自以下之取代基:鹵素、硝基、胺基、(C
1-C
6)烷基胺基、胺基羰基、視需要經取代之直鏈或分支鏈(C
1-C
6)烷基、視需要經取代之直鏈或分支鏈(C
1-C
6)烷氧基、視需要經取代之直鏈或分支鏈多氟化(C
1-C
6)烷基及視需要經取代之直鏈或分支鏈多氟化(C
1-C
6)烷氧基;R3係H、視需要經取代之直鏈或分支鏈(C
1-C
4)烷基鏈、視需要經取代之(C
3-C
6)環烷基或視需要經取代之(C
5-C
6)雜環基;R4係氫及R5係氫、鹵素或視需要經取代之直鏈或分支鏈(C
1-C
3)烷基,可遵循下文方案A獲得:
方案A
因此,該方法預見下列步驟:
步驟1)式(II)化合物與合適之式(III)有機硼酸衍生物之金屬催化之偶合反應:
式(II)為
其中R5係氫或視需要經取代之直鏈或分支鏈(C
1-C
3)烷基及X係鹵素,
式(III)為
其中R1係式(A)、(B)、(C)、(D)或(E)雜芳基;
步驟2)如此獲得之式(IV)化合物之鹵化:
其中R1及R5係如上文於步驟1中定義,因此以獲得式(V)化合物:
其中R1及R5係如上文於步驟1中定義且X係鹵素;
步驟3)式(V)化合物與合適之式(VI)有機硼酸衍生物之金屬催化之偶合反應:
其中R2係經取代之芳基或經取代之雜芳基環,其攜載一至三個選自以下之取代基:鹵素、硝基、胺基、(C
1-C
6)烷基胺基、胺基羰基、視需要經取代之直鏈或分支鏈(C
1-C
6)烷基、視需要經取代之直鏈或分支鏈(C
1-C
6)烷氧基、視需要經取代之直鏈或分支鏈多氟化(C
1-C
6)烷基及視需要經取代之直鏈或分支鏈多氟化(C
1-C
6)烷氧基,因此以獲得式(VII)化合物:
其中R1及R5係如上文於步驟1中定義及R2係如步驟3中定義;
轉化1) 自步驟3獲得之其中R5為氫的式(VII)化合物可遵循於上文步驟2中已報導之條件轉化為R5為鹵素(X)的式(VII)化合物;
步驟4)自步驟3或轉化1獲得之式(VII)化合物之保護:
其中R1及R2係如上文分別於步驟1中及於步驟3中定義,及R5係氫、鹵素或視需要經取代之直鏈或分支鏈(C
1-C
3)烷基,藉由與合適之保護基之反應,因此以獲得式(VIII)羧酸酯:
其中R1、R2及R5係如上文定義及PG係保護基諸如三甲基矽基乙氧基甲基(SEM)、第三丁氧基羰基(BOC)或苯磺醯基;
步驟5)該式(VIII)羧酸酯在鹼性條件下水解,因此以產生式(IX)羧酸:
其中R1、R2、R5及PG係如上文於步驟4中定義;
步驟6)式(IX)中間物藉由與式(X)胺衍生物反應之醯胺化:
其中R3係氫、視需要經取代之直鏈或分支鏈(C
1-C
4)烷基鏈、視需要經取代之(C
3-C
6)環烷基或視需要經取代之(C
5-C
6)雜環基;
步驟7)所得式(XI)化合物之去保護:
其中R1、R2、R5及PG係如上文在步驟5下定義及R3係如在步驟6下定義,以產生式(I)化合物:
其中R1、R2、R3及R5係如上文定義及R4係氫;或
其中R5為鹵素的式(VIII)中間化合物可遵循下文方案A1轉化為式(XI)中間物,其中R5係直鏈或分支鏈C
1-C
3烷基鏈:
方案A1
因此,該方法預見下列步驟:
轉化2) 遵循已報導於方案A之步驟3中的此項技術中已知用於鈀催化之反應之條件,將式(VIII)化合物(其中R1及R2係如上文在步驟1下定義)轉化為式(VIII)化合物(其中R5係視需要經取代之直鏈或分支鏈(C
1-C
3)烯基鏈):
;
然後使該化合物(VIII)在該方案A之步驟5及6中報導之條件下反應,因此以獲得化合物(XIa),其中R1、R2及R5係如上文定義;
轉化3) 遵循此項技術中已知用於還原雙鍵/氫化之條件,將如此獲得之式(XIa)化合物轉化為式(XI)化合物:
式(XIa)中的R5係如上文定義,式(XI)中的R5係視需要經取代之直鏈或分支鏈(C
1-C
3)烷基。
或者,可遵循下文方案B製備式(I)化合物,其中R1係視需要經取代之式(A)、(B)、(C)、(D)或(E)雜芳基;R2係經取代之芳基或經取代之雜芳基環,其攜載一至三個取代基;R3及R4係氫及R5係氫或視需要經取代之直鏈或分支鏈(C
1-C
3)烷基:
方案B
因此,該方法預見下列步驟:
步驟8)式(XII)化合物之保護:
其中R2係經取代之芳基或經取代之雜芳基環,其攜載一至三個取代基,及R5係氫或視需要經取代之直鏈或分支鏈(C
1-C
3)烷基;
步驟9)如此獲得之式(XIII)化合物之鹵化:
其中R2及R5係如上文在步驟8下定義及PG係保護基諸如SEM、BOC或苯磺醯基;
步驟10)所得式(XIV)化合物與合適之式(III)有機硼酸衍生物之金屬催化之偶合反應:
式(XIV)為
其中R2、R5及PG係如上文於步驟9中定義及X係鹵素,
式(III)為
其中R1係式(A)、(B)、(C)、(D)或(E)雜芳基;
步驟11)如此獲得之式(XV)化合物之水解:
其中R1、R2、R5及PG係如上文於步驟10中定義,因此以產生相應之式(XVI)醯胺中間物;
步驟12)式(XVI)化合物之去保護以產生式(I)化合物:
其中R1、R2及R5係如上文定義及R3及R4係氫。
或者,可遵循下文方案C製備式(I)化合物,其中R1係式(A)、(B)、(C)、(D)或(E)雜芳基;R2係經取代之芳基或經取代之雜芳基環,其攜載一至三個取代基;R3係氫,R4係氫、視需要經取代之直鏈或分支鏈(C
1-C
6)烷基或視需要經取代之直鏈或分支鏈(C
2-C
6)烯基,及R5係氫或視需要經取代之直鏈或分支鏈(C
1-C
4)烷基鏈:
方案C
因此,該方法預見下列步驟:
步驟13)在鹼之存在下或藉由添加金屬觸媒使式(XII)衍生物與式(XVII)鹵基衍生物反應:
式(XII)為
其中R2係經取代之芳基或經取代之雜芳基環,其攜載一至三個取代基,及R5係氫或視需要經取代之直鏈或分支鏈(C
1-C
3)烷基,
式(XVII)為
其中R4係視需要經取代之直鏈或分支鏈C
1-C
6烷基或視需要經取代之直鏈或分支鏈C
2-C
6烯基及X係鹵素;
步驟14)如此獲得之式(XVIII)化合物之鹵化:
其中R2、R4及R5係如上文於步驟13中定義;
步驟15)所得式(XIX)化合物與合適之式(III)有機硼酸衍生物之金屬催化之偶合反應:
式(XIX)為
其中X係鹵素及R2、R3及R4係如上文定義,
式(III)為
其中R1係雜芳基(A)、(B)、(C)、(D)或(E);
步驟16)如此獲得之式(XX)中間物之水解:
以產生式(I)化合物:
其中R1、R2、R4及R5係如上文定義及R3係氫。
根據方案A之步驟1,式(II)化合物與通式(III)有機硼衍生物之金屬催化之偶合反應以產生式(IV)化合物可以各種方式進行。較佳地,式(IV)化合物可由式(II)中間物藉由Pd催化之鈴木-宮浦偶合製備。 (雜)芳基鹵化物與(雜)芳基硼酸或硼酸酯之過渡金屬催化之偶合為熟習此項技術者熟知,參見參考文獻:a) Miyaura, Norio;Suzuki, Akira (1979). 「Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds」. Chemical Reviews 95 (7): 2457-2483;b) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions, Diederich, F.及Stang, P. J.編;Wiley-VCH: New York, 1998,第49至97頁。在所謂之鈴木-宮浦反應中,(雜)芳基硼酸或硼酸酯與(雜)芳基鹵化物之偶合反應通常由鈀錯合物觸發。膦-鈀錯合物諸如[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)用於此反應,但亦可採用雙(三苯基膦)氯化鈀(II)、肆(三苯基膦)鈀(0)。添加鹼,諸如磷酸鉀、碳酸鈉、碳酸銫、碳酸鉀、第三丁醇鉀、四乙基氫氧化銨、三乙胺,且可使用四氫呋喃、二噁烷、N,N-二甲基甲醯胺、乙醇、甲苯、水或其混合物作為反應介質。通常,溫度在室溫至150℃之範圍內。可採用習知加熱連同微波輻射。反應持續時間在約30 min至約96小時之範圍內。各種Pd觸媒/鹼/溶劑組合已描述於參考文獻中,其容許微調反應條件以在兩個偶合搭配物上容許廣泛之另外官能基組。
根據方案A之步驟2,式(V)化合物可藉由以各種方式及此項技術中已知的實驗條件使式(IV)化合物鹵化而獲得。較佳地,此反應係在N-溴琥珀醯亞胺、N-碘琥珀醯亞胺、N-氯琥珀醯亞胺、溴、碘、氫溴酸/過氧化氫之存在下,於合適之溶劑(諸如乙腈、甲醇、四氫呋喃、N,N-二甲基甲醯胺、二噁烷、二甲基亞碸、乙酸、水或其混合物)中在約0℃至回流範圍內之溫度下進行在約1小時至約96小時範圍內之時段。
根據方案A之步驟3,產生式(VII)化合物之式(V)化合物與通式(VI)有機硼衍生物之金屬催化之偶合反應可以方案A之步驟1已描述之各種方式進行。
根據方案A之步驟4,可以此項技術中廣泛已知用於保護二級胺基之各種方式及實驗條件將式(VII)化合物轉化為式(VIII)化合物。較佳地,該反應係藉由用過量之(三甲基矽基)乙氧基甲基氯於合適之溶劑(諸如四氫呋喃、二氯甲烷)中在鹼(諸如,舉例而言,氫化鈉)之存在下處理進行。通常,該反應係在自0℃至回流之範圍內之溫度下進行在自約30分鐘至約96小時之範圍內之時間。苯磺醯基可藉由與苯磺醯氯,於溶劑(諸如二氯甲烷、乙腈)中在質子清除劑(諸如,舉例而言,三乙胺、N,N-二異丙基乙基胺)之存在下在自室溫至回流之範圍內之溫度下反應而引入。第三丁氧基羰基(Boc)可藉由用過量之二碳酸二-第三丁酯在鹼(諸如碳酸氫鈉、三乙胺、N,N-二異丙基乙基胺)之存在下,於溶劑(諸如四氫呋喃、二噁烷、二氯甲烷)中在自室溫至回流之範圍內之溫度下處理而引入。
根據方案A之步驟5,式(VIII)羧酸酯水解為式(IX)羧酸可以各種方式進行。較佳地,此反應係於合適之溶劑(諸如,舉例而言,甲醇、乙醇、1,4-二噁烷、四氫呋喃)中在合適之鹼(諸如,舉例而言,氫氧化鈉、氫氧化鉀或氫氧化鋰.H
2O於四氫呋喃中)之存在下進行。通常,該反應係在室溫至150℃之範圍內之溫度下進行在自約1小時至約96小時之範圍內之時間。可採用習知加熱連同微波輻射。
根據方案A之步驟6,式(IX)羧酸轉化為式(XI)甲醯胺可以此項技術中廣泛已知用於製備甲醯胺之各種方式及實驗條件進行。作為一實例,式(IX)化合物可與1-羥基苯并三唑之銨鹽或與胺NH
2R
3(X)在O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲四氟硼酸、羥基苯并三唑、二環己基碳二亞胺、二異丙基碳二亞胺、1-乙基-3-(3’-二甲基胺基)碳二亞胺鹽酸鹽之存在下反應。較佳地,此反應係於合適之溶劑(諸如,舉例而言,四氫呋喃、二氯甲烷、甲苯、二噁烷、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺中)及在質子清除劑(諸如,舉例而言,三乙胺、N,N-二異丙基乙基胺)之存在下,在自0℃至回流之範圍內之溫度下,進行在自約30 min至約96小時之範圍內之時間。或者,式(IX)化合物可在亞硫醯氯或草醯氯之存在下,於合適之溶劑(諸如甲苯、二氯甲烷、氯仿、乙醚、四氫呋喃、二噁烷中,在自約-10℃至回流之範圍內之溫度下及歷時在自約1小時至約96小時之範圍內之時段,轉化為其相應之醯基氯。該醯基氯可藉由將該溶劑蒸發並與33%氫氧化銨溶液或與胺NH
2R
3(X)於合適之溶劑(諸如甲苯、二氯甲烷、氯仿、乙醚、四氫呋喃、二噁烷)中在自約-10℃至回流之範圍內之溫度下及歷時在自約1小時至約96小時之範圍內之時段進一步反應而經分離。
根據方案A之步驟7,式(XI)化合物之吡咯環上之保護基PG之移除可遵循此項技術中熟知的程序進行。取決於選擇之保護基,可採用下列條件:2-(三甲基矽基)乙氧基甲基(SEM)可用四正丁基氟化銨、氟化氫吡啶或三氟乙酸於溶劑(諸如四氫呋喃、二氯甲烷)中在室溫下或以下移除;苯磺醯基(Bs)可用氫氧化鉀、氫氧化鈉、碳酸鉀、氫氧化鋰,於溶劑(諸如甲醇、四氫呋喃、二噁烷)中在自室溫至回流之範圍內之溫度下移除;第三丁氧基羰基(Boc)可在三氟乙酸之存在下於二氯甲烷中或由碳酸鈉於二甲氧基乙烷、N,N-二甲基甲醯胺中在自室溫至130℃之範圍內之溫度下移除。
根據方案B之步驟8,通式(XII)化合物轉化為式(XIII)化合物可藉由方案A之步驟4中已描述之反應進行。
根據方案B之步驟9,鹵化式(XIII)化合物以獲得式(XIV)化合物可如上文於方案A之步驟2中之描述進行。
根據方案B之步驟10,式(XIV)化合物與通式(III)有機硼衍生物之金屬催化之偶合反應以產生式(XV)化合物可以方案A之步驟1中已描述之各種方式進行。
根據方案B之步驟11,式(XV)化合物水解為式(XVI)化合物可以各種方式,根據用於將氰基轉化為醯胺之習知方式進行。較佳地,此反應係於合適之溶劑(諸如,舉例而言,甲醇、乙醇、正丁醇、1,4-二噁烷、甲苯、水,或其混合物)中,在合適之酸或鹼(諸如,舉例而言,硫酸、鹽酸、甲磺酸、氯化銦、氫氧化鈉或氫氧化鉀、碳酸鈉或碳酸鉀)或合適試劑(諸如過氧化氫、過硼酸鈉或乙醛肟)之存在下進行。通常,該反應係在自室溫至回流之範圍內之溫度下進行在自約1小時至約96小時之範圍內之時間。
根據方案B之步驟12,移除式(XVI)化合物之吡咯環上之保護基PG以獲得式(I)化合物可如上文於方案A之步驟7中之描述進行。
根據方案C之步驟13,式(XII)化合物與通式(XVII)鹵基衍生物反應以產生式(XVIII)化合物可在鹼(諸如氫化鈉及四氫呋喃)之存在下進行或可使用二噁烷作為反應介質。通常,溫度在自5℃至回流之範圍內。反應持續時間在自約30 min至約24小時之範圍內。或者,式(XIV)化合物與通式(V)鹵基衍生物之金屬催化之偶合反應以產生式(Ic)化合物可在參(二亞苯甲基丙酮)二鈀及三-第三丁基膦之存在下進行。添加鹼(諸如碳酸鈉、碳酸銫、碳酸鉀)且可使用四氫呋喃、二噁烷、N,N-二甲基甲醯胺及甲苯作為反應介質。通常,溫度在自室溫至150℃之範圍內。可採用習知加熱連同微波輻射。反應持續時間在自約30 min至約24小時之範圍內。
根據方案C之步驟14,鹵化式(XVIII)化合物以獲得式(XIX)化合物可如上文於方案A之步驟2中之描述進行。
根據方案C之步驟15,式(XIX)化合物與通式(III)有機硼衍生物之金屬催化之偶合反應以產生式(XX)化合物可以方案A之步驟1中已描述之各種方式進行。
根據方案C之步驟16,式(XX)化合物水解為式(I)化合物可如上文於方案B之步驟11中之描述進行。
根據在轉化1)下描述之轉化,式(VII)化合物轉化為式(VII)化合物可以不同之方式及實驗條件進行。較佳地,其係以與針對方案A之步驟2報導之方式類似之方式進行。
根據在轉化2)下描述之轉化,式(VIII)化合物衍生為式(VIII)化合物可以方案A之步驟3中已描述之各種方式進行。
根據在轉化3)下描述之轉化,式(XIa)化合物轉化為式(XI)化合物可以此項技術中廣泛已知用於還原雙鍵之各種方式及實驗條件進行。較佳地,此反應係於合適之溶劑(諸如,舉例而言,甲醇、乙醇、甲苯、四氫呋喃)中在合適之觸媒(諸如,舉例而言,碳載鈀(10%)、乙酸鈀、銠觸媒)之存在下進行。通常,該反應係在自室溫至150℃之範圍內之溫度下進行在自約1小時至約96小時之範圍內之時間。
綜上所述,熟悉此項技術者清楚攜載之官能基可藉由根據此項技術中熟知的方法處理而進一步衍生為另一官能基,因此導致其他式(I)化合物之任何式(I)化合物意欲包含於本發明之範圍內。
當根據上文方法變體中之任一者製備通式(I)化合物時,起始材料、試劑或其中間物內,且可產生非所需之副反應之任選官能基需根據習知技術進行適當保護(參見例如,Green, Theodora W.及Wuts, Peter G.M. - Protective Groups in Organic Synthesis,第三版,John Wiley & Sons Inc., New York (NY), 1999)。同樣地,此等後者轉化為游離之脫保護化合物可根據已知程序進行。
如實驗部分中報導,每個通式之化合物可根據文獻中熟知的方法進一步轉化為具有相同通式之其他化合物。
根據用於製備式(I)化合物之方法之任何變體,起始材料及任何其他反應物係已知的或根據已知方法容易製備。
式(XII)化合物可如WO2009133170A1中描述製備。
式(II)、(III)、(VI)、(X)及(XVII)化合物可購買獲得。
最終化合物可使用習知程序(例如層析術及/或結晶化及成鹽)分離及純化。
如上文定義之通式(I)化合物可轉化為醫藥上可接受之鹽。如上文定義之通式(I)化合物或其醫藥上可接受之鹽可後續用醫藥上可接受之載劑或稀釋劑調配以提供醫藥組合物。
通式(I)化合物根據上文描述之合成方法之合成可以以逐步方式進行,藉此各中間物視需要藉由標準純化技術(諸如,舉例而言,管柱層析術)分離並純化,然後進行後續反應。或者,合成序列之兩個或更多個步驟可以所謂之「一鍋」程序進行,如此項技術中已知,藉此僅由該等兩個或更多個步驟產生之化合物係經分離並純化。
本發明亦提供一種治療由失調之Cdc7激酶活性引起及/或與其相關聯之疾病之方法,其包括對有需要哺乳動物(較佳人類)投與有效量之如上文定義之式(I)化合物。
此外,本發明提供一種如上文定義的式(I)化合物或其醫藥上可接受之鹽,其用於治療由失調之Cdk7激酶活性引起及/或與其相關聯之疾病之方法中,該方法包括對有需要哺乳動物(較佳人類)投與有效量之如上文定義之式(I)化合物。
另外,本發明提供如上文定義的式(I)化合物或其醫藥上可接受之鹽之用途,其用以製造用於治療由失調之Cdc7激酶活性引起及/或與其相關聯之疾病之藥劑。
較佳地,該疾病係選自由以下組成之群:癌症、細胞增殖性疾患、免疫相關疾患。更佳地,該疾病係癌症。
根據本發明之一最佳實施例,該癌症係選自由以下組成之群:癌,諸如膀胱、乳房、腎、肝、結腸、肺(包括小細胞肺癌)、食道、膽囊、卵巢、胰臟、胃、宮頸、前列腺、頭頸及皮膚(包括鱗狀細胞癌);淋巴譜系之造血腫瘤,其包括白血病、急性淋巴細胞性白血病、急性淋巴胚細胞性白血病、B細胞淋巴瘤、血管免疫母細胞性T細胞淋巴瘤、霍奇金氏淋巴瘤(Hodgkin's lymphoma)、非霍奇金氏淋巴瘤、毛細胞淋巴瘤外套細胞淋巴瘤及勃兒基特氏淋巴瘤(Burkitt's lymphoma);骨髓譜系之造血腫瘤,包括急性及慢性骨髓性白血病、骨髓增生異常症候群及前髓細胞白血病;間葉源性腫瘤,包括纖維肉瘤及橫紋肌肉瘤;中樞及周圍神經系統之腫瘤,包括神經膠質瘤、神經膠質母細胞瘤、多形性神經膠質母細胞瘤、星細胞瘤、寡樹突神經膠質瘤、副神經膠質瘤、神經胚細胞瘤及神經鞘瘤;及其他腫瘤,包括黑色素瘤、精原細胞瘤、畸胎上皮癌、骨肉瘤、著色性乾皮症、角化黃瘤、甲狀腺癌諸如乳突甲狀腺癌及甲狀腺髓質癌、卡波西肉瘤(Kaposi's sarcoma)、軟骨肉瘤、膽管癌、頭頸部腫瘤。
由失調之Cdc7激酶活性引起及/或與其相關聯之其他較佳疾病係細胞增殖疾患,諸如,舉例而言,良性前列腺增生、家族性腺瘤病、息肉病、神經纖維瘤病、牛皮廯、與動脈粥樣硬化相關聯之血管平滑肌細胞增殖、肺纖維化、關節炎、腎小球腎炎及術後狹窄及再狹窄。
由失調之Cdc7激酶活性引起及/或與其相關聯之其他較佳疾病係免疫相關疾患,其等包括(但不限於):移植排斥、皮膚疾患(諸如牛皮廯)、過敏、哮喘及自體免疫介導之疾病,諸如類風濕性關節炎(RA)、全身性紅斑狼瘡(SLE)、克羅恩病(Crohn’s disease)及肌萎縮側索硬化症。
此外,本發明提供一種如上文定義的式(I)化合物或其醫藥上可接受之鹽,其與放射療法組合或與化療、標靶療法或免疫療法方案組合用於治療有需要哺乳動物之方法中。
在一項實施例中,化療方案及/或標靶療法方案包含至少一種細胞抑制劑或細胞毒性劑。
細胞抑制劑或細胞毒性劑包括(但不限於)抗生物素型劑、烷化劑、抗代謝劑、荷爾蒙劑、免疫學劑、干擾素型劑、環氧合酶抑制劑(例如COX-2抑制劑)、基質金屬蛋白酶抑制劑、端粒酶抑制劑、酪胺酸激酶抑制劑、抗生長因子受體劑、抗HER2劑、抗EGFR劑、抗血管生成劑(例如血管生成抑制劑)、法尼基轉移酶抑制劑、ras-raf信號轉導途徑抑制劑、細胞週期抑制劑、cdks抑制劑、微管蛋白結合劑、拓撲異構酶I抑制劑、拓撲異構酶II抑制劑、芳香酶抑制劑、驅動蛋白之抑制劑、治療性單株抗體、mTOR之抑制劑、組蛋白脫乙醯酶抑制劑、鉑、缺氧反應之抑制劑。免疫療法劑包括PD-1拮抗劑、特異性結合至PD-1或PD-L1之抗體。
若調配成固定劑量,則此組合產品在下文描述之劑量範圍內採用本發明之化合物及在批准之劑量範圍內採用其他醫藥活性劑。
當組合調配物不適合時,式(I)化合物可與已知抗癌劑循序使用。
適用於對哺乳動物(例如對人類)投與之本發明之式(I)化合物可由一般途徑及劑量根據病患之年齡、重量及病症及投與途徑投與。
例如,適用於經口投與式(I)化合物之合適劑量可在自約10至約1000 mg每劑量,每天1至5次之範圍內。本發明之化合物可以多種劑型投與,例如經口,以錠劑、膠囊、糖或膜包衣錠、液體溶液或懸浮液之形式;直腸內以栓劑之形式;非經腸,例如肌內,或通過靜脈內及/或鞘內及/或椎管內注射或輸注。
含有本發明之化合物之醫藥組合物通常遵循習知方法製備並以合適之醫藥形式投與。
例如,固體經口形式可含有活性化合物連同稀釋劑,例如乳糖、右旋糖、甘蔗糖、蔗糖、纖維素、玉米澱粉或馬鈴薯澱粉;潤滑劑,例如二氧化矽、滑石、硬脂酸、硬脂酸鎂或硬脂酸鈣,及/或聚乙二醇;結合劑,例如澱粉、阿拉伯樹膠、明膠甲基纖維素、羧基甲基纖維素或聚乙烯吡咯啶酮;崩解劑,例如澱粉、海藻酸、海藻酸鹽或乙醇酸澱粉鈉;泡騰混合物;染料;甜味劑;潤濕劑,諸如卵磷脂、聚山梨酯、十二烷基硫酸酯;及一般而言,用於醫藥調配物中之無毒且藥理學滅活物質。此等醫藥製劑可以已知方式製造,例如,藉助於混合、造粒、壓片、包糖衣或包膜衣方法。
用於經口投與之液體分散液可為(例如)糖漿、乳液及懸浮液。
作為實例,糖漿可含有作為載劑之甘蔗糖或甘蔗糖及甘油及/或甘露醇及山梨醇。
懸浮液及乳劑可含有(例如)載劑、天然樹膠、瓊脂、海藻酸鈉、果膠、甲基纖維素、羧基甲基纖維素或聚乙烯醇。
用於肌內注射之懸浮液或溶液可含有活性化合物連同醫藥上可接受之載劑,例如無菌水、橄欖油、油酸乙酯、二醇(例如丙二醇),及視需要,合適量之鹽酸利多卡因。
用於靜脈內注射或輸注之溶液可含有作為載劑之無菌水或較佳其等可呈無菌、水性、等滲、鹽溶液之形式或其等可含有作為載劑之丙二醇。
栓劑可含有活性化合物連同醫藥上可接受之載劑,例如可可脂、聚乙二醇、聚氧乙烯山梨醇酐脂肪酸酯表面活性劑或卵磷脂。
本發明亦提供一種醫藥組合物,其包含治療有效量之如上文定義的式(I)化合物或其醫藥上可接受之鹽,及至少一種醫藥上可接受之賦形劑、載劑或稀釋劑。
本發明進一步提供一種式(I)化合物之醫藥組合物,其進一步包含一或多種化學治療劑。
此外,本發明提供一種用於抑制Cdc7蛋白質活性之活體外方法,其包括使該蛋白質與有效量之如上文定義之式(I)化合物接觸。
另外,本發明提供一種產品,其包含如上文定義的式(I)化合物或其醫藥上可接受之鹽,及一或多種化學治療劑,作為同時、單獨或循序用於抗癌療法中之組合製劑。
最後,本發明提供一種如上文定義的式(I)化合物或其醫藥上可接受之鹽,其用作藥劑。
實驗部分
本文使用之縮寫形式及縮寫具有下列含義:
g公克 mg毫克
mL毫升 μL微升
mM毫莫耳 mmol毫莫耳
μM (微莫耳) MHz (兆赫)
h小時 Hz (赫茲)
mm (毫米) min (分鐘)
μm (微米) M (莫耳)
BSA牛血清白蛋白 DTT二硫蘇糖醇
NADPH煙鹼醯胺腺嘌呤二核苷酸磷酸鹽 Rt滯留時間
2-HG 2-羥基戊二酸 KOtBu (第三丁醇鉀)
rt (室溫) TEA (三乙胺)
DMAP (4-二甲基胺基吡啶) DME (1,2-二甲氧基乙烷)
TFA (三氟乙酸) Na
2SO
4(硫酸鈉)
AcOH (乙酸) ESI (電噴霧電離)
Na
2CO
3(碳酸鈉) K
2CO
3(碳酸鉀)
Cs
2CO
3(碳酸銫) K
3PO
4(磷酸鉀)
LiOH (氫氧化鋰) NaOH (氫氧化鈉)
KOH (氫氧化鉀) p-TsOH (對甲苯磺酸)
EtOAc (乙酸乙酯) LiHMDS (雙(三甲基矽基)醯胺鋰)
NMP (N-甲基-2-吡咯啶酮) NaH (氫化鈉)
DMA (N,N-二甲基乙醯胺) KH (氫化鉀)
DMF (N,N-二甲基甲醯胺) DCM (二氯甲烷)
DIPEA (N,N-二異丙基-N-乙基胺) hex (己烷)
THF (四氫呋喃) DMSO (二甲基亞碸)
MeOH (甲醇) ACN (乙腈)
EtOH (乙醇) Bn (苯甲基)
-OMs (甲磺酸根) -OTs (甲苯磺酸根)
HOBT (N-羥基-苯并三唑) DCC (1,3-二環己基碳二亞胺)
NMR核磁共振 MS質譜法
m/z質荷比 LC液相層析術
MgCl
2氯化鎂
EDCI (1-乙基-3-(3-二甲基胺基丙基)碳二亞胺鹽酸鹽)
TBTU (N,N,N’,N’-四甲基-O-(苯并三唑-1-基)四氟硼酸脲)
RP-HPLC (反相高效液相層析術)
生物化學分析
假定Cdc7抑制劑之抑制活性及選定化合物之效價係透過下文報導之方法測定。
ADPGlo 分析形式。藉由用特異性酶及受質培養,接著定量ADP產物來測定化合物之生物活性。化合物自10至0.0006 uM連續稀釋4倍;在預培養步驟之情況下,將該酶添加至抑制劑溶液並將該混合物在室溫(r.t.)下培養30分鐘。當該酶已存在於預培養步驟中時,該反應以添加該受質及該ATP開始,或當該預培養步驟不存在時,添加受質、ATP及酶。上文描述ATP、受質及反應緩衝液之濃度。於384孔盤上以機器人化形式運行該等分析。各384孔盤含有一些參考孔(總酶活性相比於由特異性抑制劑完全抑制之酶),其等係用於Z’及信號與背景評估。在培養時間結束時,添加等體積ADPGlo試劑1 (Promega)以使該反應停止並移除所有未反應之ATP。60分鐘後,添加等體積ADPGlo試劑2 (Promega)以轉化ATP中之ADP及然後藉由螢光素酶反應轉化光中之ATP。15分鐘後,在室溫下,發光信號用讀盤器讀取。
以兩種分析形式獲得之資料藉由SW軟體包「分析瀏覽器」之內部訂製版分析,該軟體包使用4參數邏輯方程為IC
50測定提供八稀釋曲線之S形擬合之:
y =底部+ (頂部-底部)/(1+10^((logIC
50-x)*斜率))
其中x係抑制劑濃度之對數,y係反應;y於底部開始並以S形到達頂部。
有關盤稀釋、分佈、分析類型、標靶及抑制之原始資料之所有資訊均經由條形碼讀取進行追蹤並儲存於Oracle DB中。
以上文報導之方法獲得之本發明之化合物的生物化學活性總結於下表1中。
表1
*以氯酸鹽的形式測試之化合物
**以TFA鹽的形式測試之化合物
ND:未測定
化合物編號 | CDC7 IC 50µM ADPGlo |
1 | 0.004 |
2 | 0.003 |
3 | 0.001 |
4* | 0.004 |
5 | 0.001 |
6* | 0.005 |
7 | 0.001 |
8 | 0.003 |
9 | 0.001 |
10 | 0.003 |
11 | 0.007 |
12 | 0.004 |
13 | 0.001 |
14 | 0.010 |
15* | 0.006 |
16 | 0.006 |
17 | 0.001 |
18 | 0.031 |
19 | 0.015 |
20 | 0.005 |
21 | 0.034 |
22 | 0.027 |
24** | 0.741 |
26** | 0.012 |
27 | 0.061 |
28 | 0.067 |
30 | 3.134 |
31 | 0.759 |
32 | 0.017 |
33 | 0.014 |
34 | 0.042 |
35 | 0.007 |
36 | 0.010 |
37 | 0.002 |
38 | 0.101 |
39 | 0.159 |
40 | 0.717 |
42 | 0.090 |
43 | 0.013 |
44 | 0.048 |
46 | 0.001 |
47 | 0.004 |
48 | 0.188 |
49 | 0.018 |
54 | 0.418 |
55 | 0.996 |
56 | 0.014 |
57 | 0.017 |
如表1中總結,本發明之化合物對細胞分裂週期7相關蛋白激酶(Cdc7)顯示顯著活性。
代謝穩定性分析
藉由在存在及缺乏醛氧化酶抑制劑聯胺肼鹽酸鹽下比較內在清除率值來測定參與測試品代謝之醛氧化酶。本研究目的係評估活體外內在清除率、對醛氧化酶(AO)活性之代謝穩定性,及該測試品於人類肝胞質液中之代謝。該內在清除率係使用半衰期方法,藉由量測受質用人類肝胞質液培養60分鐘之消失測定。培養係在1 μM濃度下進行。假定1 μM起始濃度<< Km。使用HPLC-MS/MS偵測該培養期間留下之化合物。為測定內在清除率,藉由高效液相層析術(HPLC)連線質譜(MS)設備分析樣本。為測定胞質液之醛氧化酶活性(即陽性對照),在存在及缺乏醛氧化酶抑制劑下用人類肝胞質液培養酞嗪。在培養當天,以10 mM濃度該化合物溶解於DMSO中。將此溶液之等分試樣添加至測試系統至最終濃度1。最終培養物中DMSO之百分比係0.1%。在37℃將測試品之等分試樣添加至杜爾貝科緩衝液(pH 7.4)中的人類肝胞質液(1 mg/mL蛋白質含量)中,以達成1 μM之最終濃度。於48孔盤中在振盪下進行培養。於培養0、5、10、20、30及60分鐘時,對該培養物之50 μL等分試樣取樣,倒入80 μL冰冷乙腈中及20 μL於乙腈中之1 μM華法林中(注射對照)並在2500 rpm離心20分鐘。藉由LC-MS/MS立即分析上清液。
測試品以1 μM濃度於杜爾貝科緩衝液(pH 7.4)中在37℃在存在10 µM聯胺肼鹽酸鹽(醛氧化酶抑制劑)下平行、一式兩份培養60 min。
藉由測試品單獨以1 μM濃度於杜爾貝科緩衝液(pH 7.4)中在37℃培養60分鐘(陰性對照)平行檢查該測試品之化學穩定性。
使用半衰期方法計算內在清除率(CLint)。使用LC-MS/MS方法,自不同採樣點殘餘之濃度(面積計數)測定半衰期及CLint。藉由繪製殘餘化合物之自然對數面積相對於時間的圖,藉由線性回歸分析計算斜率並根據下式將其轉化為半衰期(t1/2)及Clint,以μL/min/mg蛋白質表示:
使用HPLC-MS/MS方法,自不同採樣點之濃度確定酞嗪代謝物酞嗪酮之形成。藉由繪製該代謝物之濃度相對於時間的圖,計算斜率,並將其最大值轉化為以pmol/min/mg表示之代謝物形成速率。
參考化合物A及參考化合物B分別對應於國際PCT申請案WO2007/110344之化合物(53)及(55)。
表2
HLC:人類肝胞質液
IntCl:內在清除率
*以氯酸鹽的形式測試之化合物
**以TFA鹽的形式測試之化合物
化合物編號 | 醛氧化酶測試 | |||
殘餘HLC% (培養1 h) | HLC T1/2 min | IntCl | ||
參考化合物A | 42 | 14.8 | 46.7 | |
參考化合物B | 70 | 154 | 4.5 | |
1* | 100 | 239 | 2.9 | |
2 | 98 | 239 | 2.9 | |
3 | 97 | 239 | 2.9 | |
4* | 100 | 239 | 2.9 | |
5* | 100 | 239 | 2.9 | |
6* | 100 | 239 | 2.9 | |
7* | 95 | 239 | 2.9 | |
8* | 85 | 239 | 2.9 | |
9* | 100 | 239 | 2.9 | |
10* | 95 | 239 | 2.9 | |
11* | 100 | 239 | 2.9 | |
12 | 97 | 239 | 2.9 | |
13 | 100 | 239 | 2.9 | |
14 | 100 | 239 | 2.9 | |
15 | 100 | 239 | 2.9 | |
42* | 100 | 239 | 2.9 | |
43 | 100 | 239 | 2.9 | |
44 | 100 | 239 | 2.9 | |
45** | 98 | 239 | 2.9 | |
46 | 100 | 239 | 2.9 | |
48 | 100 | 239 | 2.9 | |
49 | 100 | 239 | 2.9 | |
52 | 100 | 239 | 2.9 | |
53 | 100 | 239 | 2.9 |
如表2中顯示,當於人類肝胞質液中培養時,參考化合物A相比於參考化合物B均顯示較差之代謝穩定性,其顯示低半衰期(T1/1 =分別14.8 min及154 min)及培養60 min後殘餘化合物之低百分比(分別40%及70%)。令人驚訝地,發現本發明之化合物在相同實驗條件下顯示比現有技術化合物明顯更佳之代謝穩定性。
特定言之,新穎化合物顯示增加之半衰期(225 min)、更高之殘餘化合物百分比(在最壞情況下85%)及降低之內在清除率值,因此在DMPK性質方面優於參考現有技術化合物,因此增加成為候選藥物之機率。
式(I)化合物之製備
關於針對本發明之任何特定式(I)化合物,視需要以醫藥上可接受之鹽之形式之參考,參見實驗部分及申請專利範圍。參考下列實例,本發明之化合物係使用本文描述之方法,或此項技術中熟知的其他方法合成。
為更好地闡述本發明,而不對其構成任何限制,給定下列實例。
如本文使用,方法、方案及實例中使用之符號及慣例與彼等當代科學文獻(例如,美國化學化學雜誌(the Journal of the American Chemical Society)或生物化學雜誌(the Journal of Biological Chemistry))中使用者一致。
化合物名稱係IUPAC名稱,藉由使用ACD名稱(由Advanced Chemistry Development, Inc.提供)產生。除非另有說明,否則所有材料(包括無水溶劑,諸如DMF、THF、DCM)均獲自商業供應商,該等材料為最佳等級,且無需進一步純化即可使用。涉及空氣或水分敏感之化合物之所有反應均在氮或氬氣氛下進行。
一般純化及分析方法
急驟層析術係於矽膠(Merck等級9395, 60A)上進行。
HPLC設備由Waters Alliance
TMHT 2795系統構成,該系統配備Waters 996 PDA偵測器及Waters mod. ZQ 2000單四級質譜儀,該質譜儀配備電噴霧(ESI)離子源。儀器控制、資料獲取及資料處理由Empower 2及MassLynx 4.1軟體提供。HPLC係在25℃下以1.2 mL/min之流動速率使用YMC-Triart C18 (4.6 x 50 mm,3 μm)管柱進行。流動相B係具有乙腈(95:5)之乙酸銨5 mM pH=5.2緩衝液,及流動相C係H
2O/乙腈(5:95);梯度係於5分鐘內自10至90% C,然後於0.1分鐘內升至100% C。注射體積係10 µL。質譜儀以正離子及以負離子模式操作,毛細管電壓設定為3.5 kV (ES
+)及2.8 kV (ES
-);錐電壓係14 V (ES
+)及28 V (ES
-);源溫度係120℃;全掃描,質量範圍設定為100至800 amu。
製備型HPLC設備由Shimadzu HPLC系統構成,該系統配備SCL-8A系統控制器、兩個LC-8A泵、SPD-6A UV分光光度偵測器及手動流變儀注射系統。資料獲取(模擬信號)及資料處理由Empower 2軟體提供。純化係在25℃下以15mL/min之流動速率使用Waters X-Terra MS RP18 (150 x 30 mm,10 µm)管柱進行。流動相A係於水/乙腈(95:5)中之0.1% TFA,或者,流動相A係於水/乙腈(95:5)中之0.05% NH
3及流動相B係H
2O/乙腈(5:95);梯度係於15分鐘內自10至90% B,然後於0.1分鐘內升至100% B。最大注射體積500 µL。
在400.5 MHz下操作且配備5 mm
1H{
15N-
31P} z軸PFG間接偵測探針之Varian INOVA 400光譜儀上及在499.7 MHz下操作且配備5 mm
1H{
13C-
15N}三重共振間接偵測探針之Varian INOVA 500光譜儀上在28℃之恆定溫度下記錄
1H-NMR譜。參考關於殘餘溶劑信號之化學位移(針對
1H,DMSO-d
6: 2.50 ppm)。如下報導資料:化學位移(δ),多重性(s =單重峰、d =雙重鋒、t =三重峰、q =四重峰、br. s =寬單重峰、dd =雙重峰之雙重峰、ddd =雙重峰之雙重峰之雙重峰、m =多重峰),偶合常數(J, Hz)及質子數。
如先前報導(M. Colombo、F. R. Sirtori、V. Rizzo,Rapid Commun Mass Spectrom 2004, 18(4), 511-517),在與Agilent 1100微HPLC系統(Palo Alto, US)直接連接之Q-Tof Ultima (Waters, Manchester, UK)質譜儀上獲得ESI(+)高解析度質譜(HRMS)。
在反應器中,在氬氣氛下,添加5-溴-1H-吡咯-3-羧酸甲酯(1當量,5 g,24.51 mmol)、1-(苯基磺醯基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)-1H-吡咯并[2,3-b]吡啶(1當量,9.41 g,24.51 mmol)、Na
2CO
3(3當量,7.79 g,73.53 mmol)、經脫氣之1,4-二噁烷(25 ml)及經脫氣之蒸餾水(6.25 ml)。在三次真空/氬週期後,添加觸媒[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II),其與二氯甲烷(0,1當量,2 g,2.45 mmol)錯合。在三次真空/氬週期後,在T = 100℃下將該反應混合物加熱30分鐘。添加蒸餾水及產物用AcOEt萃取(3次)。有機層用蒸餾水及鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(DCM/丙酮95/5 - 9/1)純化以提供標題化合物(固體,4.58 g,Y=49%)。
1H NMR (500 MHz, DMSO-d
6) d ppm 3.75 (s, 3 H) 7.14 (s, 1 H) 7.16 (d, J=4.12 Hz, 1 H) 7.52 (d, J=5.19 Hz, 1 H) 7.60 - 7.65 (m, 2 H) 7.70 (s, 1 H) 7.71 - 7.75 (m, 1 H) 7.97 (d, J=4.27 Hz, 1 H) 8.09 - 8.16 (m, 2 H) 8.35 (d, J=5.19 Hz, 1 H) 12.30 (br. s., 1 H)。LCMS:m/z 382 [M+H]
+。針對C
19H
15N
3O
4S [M + H]
+之HRMS (ESI)計算值382.0856,實測值382.0855;
在T = 0℃下向5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸甲酯(1當量,4 g,10.499 mmol)於MeOH (410 ml)及THF (205 ml)中之溶液添加0.33當量之N-溴琥珀醯亞胺(566.3 mg,3.18 mmol)。在T = 0℃下將該反應混合物攪拌30分鐘及然後添加0.33當量之N-溴琥珀醯亞胺(566.3 mg,3.18 mmol)。在T = 0℃下將該反應混合物攪拌30分鐘及然後添加最後一部分之N-溴琥珀醯亞胺(0.33當量,566.3 mg,3.18 mmol)。在T = 0℃下將該反應攪拌1小時及30分鐘。添加蒸餾水及產物用AcOEt萃取3次。有機層用鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(DCM/丙酮99/1 - 9/1)純化以提供標題化合物(白色固體,3.62 g,Y=75%)。
1H NMR (500 MHz, DMSO-d6) d ppm 3.76 (s, 3 H) 7.10 (d, J=4.12 Hz, 1 H) 7.15 (s, 1 H) 7.53 (d, J=5.19 Hz, 1 H) 7.60 - 7.66 (m, 2 H) 7.70 - 7.75 (m, 1 H) 7.97 (d, J=4.12 Hz, 1 H) 8.11 - 8.15 (m, 2 H) 8.36 (d, J=5.19 Hz, 1 H) 12.93 (s, 1 H)。LCMS:m/z 459 [M+H]
+。針對C
19H
14BrN
3O
4S [M + H]
+之HRMS (ESI)計算值459.9961,實測值459.996;
在反應器中,在氬氣氛下,添加2-溴-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸甲酯(1當量,150 mg,0.33 mmol)、(3-氯-2-氟苯基)硼酸(1.2當量,68 mg,0.39 mmol)、Na
2CO
3(3當量,103.7 mg,0.978 mmol)、經脫氣之1,4-二噁烷(4 ml)及經脫氣之蒸餾水(1 ml)。在三次真空/氬週期後,添加觸媒[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II),其與二氯甲烷(0.1當量,26.6 mg,0.033 mmol)錯合。在三個真空/氬週期後,在T = 100℃下將該反應混合物加熱2小時及30分鐘。添加蒸餾水及產物用AcOEt萃取(3次)。有機層用蒸餾水及鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(DCM/丙酮98/2)純化以提供標題化合物(固體,115 mg,Y=69%)。
1H NMR (500 MHz, DMSO-d
6) d ppm 3.66 (s, 3 H) 7.17 (d, J=4.27 Hz, 1 H) 7.23 (s, 1 H) 7.34 (t, J=7.85 Hz, 1 H) 7.53 - 7.60 (m, 2 H) 7.61 - 7.66 (m, 2 H) 7.67 - 7.71 (m, 1 H) 7.71 - 7.76 (m, 1 H) 8.00 (d, J=4.12 Hz, 1 H) 8.12 - 8.15 (m, 2 H) 8.37 (d, J=5.19 Hz, 1 H) 12.49 (s, 1 H)。LCMS:m/z 510 [M+H]
+。針對C
25H
17ClFN
3O
4S [M + H]
+之HRMS (ESI)計算值510.0685,實測值510.0681;
以類似方式操作,但採用合適之經取代之起始材料,獲得下列化合物:
甲基-2-(2-氟-4-甲基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 2.39 (s, 3 H) 3.63 (s, 3 H) 7.08 - 7.17 (m, 3 H) 7.20 (d, J=1.37 Hz, 1 H) 7.44 (t, J=7.78 Hz, 1 H) 7.58 (d, J=5.19 Hz, 1 H) 7.63 (t, J=1.00 Hz, 2 H) 7.73 (t, J=1.00 Hz, 1 H) 7.98 (d, J=4.12 Hz, 1 H) 8.11 - 8.17 (m, 2 H) 8.35 (d, J=5.19 Hz, 1 H) 12.32 (br. s., 1 H)。LCMS:m/z 490 [M+H]
+。針對C
26H
20FN
3O
4S [M + H]
+之HRMS (ESI)計算值490.1232,實測值490.1209;
甲基-2-(4-氯-2-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.65 (s, 3 H) 7.16 (d, J=4.12 Hz, 1 H) 7.22 (d, J=2.59 Hz, 1 H) 7.42 (dd, J=8.31, 2.06 Hz, 1 H) 7.55 - 7.59 (m, 2 H) 7.61 - 7.67 (m, 3 H) 7.72 (d, J=7.47 Hz, 1 H) 7.99 (d, J=4.12 Hz, 1 H) 8.14 (dd, J=8.46, 1.14 Hz, 2 H) 8.37 (d, J=5.19 Hz, 1 H) 12.43 (d, J=1.52 Hz, 1 H)。LCMS:m/z 510 [M+H]
+。針對C
25H
17ClFN
3O
4S [M + H]
+之HRMS (ESI)計算值510.0685,實測值510.067;
甲基-2-(2-氯-4-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.61 (s, 3 H) 7.16 - 7.19 (m, 1 H) 7.22 (d, J=2.75 Hz, 1 H) 7.33 (td, J=8.54, 2.59 Hz, 1 H) 7.56 (d, J=5.19 Hz, 1 H) 7.58 - 7.67 (m, 4 H) 7.71 - 7.75 (m, 1 H) 7.99 (d, J=4.12 Hz, 1 H) 8.10 - 8.16 (m, 2 H) 8.35 (d, J=5.18 Hz, 1 H) 12.42 (d, J=1.98 Hz, 1 H)。LCMS:m/z 510 [M+H]
+。針對C
25H
17ClFN
3O
4S [M + H]
+之HRMS (ESI)計算值510.0685,實測值510.0689;
甲基-2-(2,4-二氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.65 (s, 3 H) 7.17 (d, J=4.12 Hz, 1 H) 7.19 - 7.25 (m, 2 H) 7.39 (td, J=9.84, 2.29 Hz, 1 H) 7.58 (d, J=5.19 Hz, 1 H) 7.61 - 7.67 (m, 3 H) 7.71 - 7.75 (m, 1 H) 7.99 (d, J=4.12 Hz, 1 H) 8.14 (d, J=7.47 Hz, 2 H) 8.37 (d, J=5.19 Hz, 1 H) 12.41 (br. s., 1 H)。LCMS:m/z 494 [M+H]
+。針對C
25H
17F
2N
3O
4S [M + H]
+之HRMS (ESI)計算值494.0981,實測值494.0977;
甲基-2-[2-氯-4-(三氟甲基)苯基]-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.62 (s, 3 H) 7.19 (d, J=3.78 Hz, 1 H) 7.24 (s, 1 H) 7.55 (d, J=5.25 Hz, 1 H) 7.60 - 7.67 (m, 2 H) 7.71 - 7.75 (m, 1 H) 7.77 - 7.85 (m, 2 H) 7.99 (d, J=3.78 Hz, 1 H) 8.01 (s, 1 H) 8.13 (d, J=7.69 Hz, 2 H) 8.36 (d, J=5.13 Hz, 1 H) 12.48 (br. s., 1 H)。LCMS:m/z 560 [M+H]
+。針對C
26H
17ClF
3N
3O
4S [M + H]
+之HRMS (ESI)計算值560.0653,實測值560.0656;
甲基-2-(2,3-二氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.66 (s, 3 H) 7.17 (d, J=4.12 Hz, 1 H) 7.23 (d, J=1.22 Hz, 1 H) 7.33 (dd, J=7.78, 5.03 Hz, 1 H) 7.39 - 7.44 (m, 1 H) 7.51 - 7.57 (m, 1 H) 7.59 (d, J=5.34 Hz, 1 H) 7.61 - 7.67 (m, 2 H) 7.71 - 7.76 (m, 1 H) 8.00 (d, J=4.12 Hz, 1 H) 8.14 (dd, J=8.46, 1.14 Hz, 2 H) 8.38 (d, J=5.19 Hz, 1 H) 12.49 (s, 1 H)。LCMS:m/z 494 [M+H]
+。針對C
25H
17F
2N
3O
4S [M + H]
+之HRMS (ESI)計算值494.0981,實測值494.0981;
甲基-2-(2,3-二氯苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.62 (s, 3 H) 7.18 (d, J=4.27 Hz, 1 H) 7.22 (s, 1 H) 7.43 - 7.48 (m, 1 H) 7.50 - 7.53 (m, 1 H) 7.55 (d, J=5.19 Hz, 1 H) 7.60 - 7.67 (m, 2 H) 7.70 - 7.78 (m, 2 H) 7.99 (d, J=4.12 Hz, 1 H) 8.11 - 8.16 (m, 2 H) 8.36 (d, J=5.19 Hz, 1 H) 12.47 (s, 1 H)。LCMS:m/z 526 [M+H]
+。針對C
25H
17Cl
2N
3O
4S [M + H]
+之HRMS (ESI)計算值526.039,實測值526.0383;
甲基-2-[4-甲基-2-(三氟甲基)苯基]-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 2.47 (s, 3 H) 3.54 (s, 3 H) 7.16 (d, J=4.12 Hz, 1 H) 7.19 (d, J=2.75 Hz, 1 H) 7.44 (d, J=7.78 Hz, 1 H) 7.52 (d, J=5.34 Hz, 1 H) 7.55 (d, J=7.63 Hz, 1 H) 7.60 - 7.65 (m, 2 H) 7.68 (s, 1 H) 7.70 - 7.75 (m, 1 H) 7.98 (d, J=4.12 Hz, 1 H) 8.10 - 8.14 (m, 2 H) 8.33 (d, J=5.19 Hz, 1 H) 12.39 (d, J=2.14 Hz, 1 H)。LCMS:m/z 540 [M+H]
+。針對C
27H
20F
3N
3O
4S [M + H]
+之HRMS (ESI)計算值540.1199,實測值540.1193;
甲基-2-(2-氯-4-甲基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 2.38 (s, 3 H) 3.60 (s, 3 H) 7.16 (d, J=4.12 Hz, 1 H) 7.20 (d, J=2.90 Hz, 1 H) 7.24 (dd, J=7.78, 0.76 Hz, 1 H) 7.39 (s, 2 H) 7.56 (d, J=5.19 Hz, 1 H) 7.61 - 7.66 (m, 2 H) 7.71 - 7.76 (m, 1 H) 7.98 (d, J=4.12 Hz, 1 H) 8.10 - 8.16 (m, 2 H) 8.34 (d, J=5.34 Hz, 1 H) 12.34 (d, J=2.29 Hz, 1 H)。LCMS:m/z 506 [M+H]
+。針對C
26H
20ClN
3O
4S [M + H]
+之HRMS (ESI)計算值506.0936,實測值506.0938;
甲基-2-(2,3-二氟-4-甲基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 2.36 (d, J=1.53 Hz, 3 H) 3.66 (s, 3 H) 7.16 (d, J=4.12 Hz, 1 H) 7.18 - 7.21 (m, 1 H) 7.22 (d, J=2.75 Hz, 1 H) 7.27 - 7.32 (m, 1 H) 7.59 (d, J=5.34 Hz, 1 H) 7.62 - 7.67 (m, 2 H) 7.70 - 7.76 (m, 1 H) 7.99 (d, J=4.12 Hz, 1 H) 8.14 (dd, J=8.46, 1.14 Hz, 2 H) 8.37 (d, J=5.18 Hz, 1 H) 12.43 (d, J=2.14 Hz, 1 H)。LCMS:m/z 508 [M+H]
+。針對C
26H
19F
2N
3O
4S [M + H]
+之HRMS (ESI)計算值508.1137,實測值508.1132;
甲基-2-[2-甲基-4-(三氟甲基)苯基]-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 2.25 (s, 3 H) 3.62 (s, 3 H) 7.18 (d, J=4.27 Hz, 1 H) 7.25 (s, 1 H) 7.52 - 7.58 (m, 2 H) 7.63 (t, J=7.93 Hz, 3 H) 7.69 - 7.76 (m, 2 H) 7.99 (d, J=4.12 Hz, 1 H) 8.13 (dd, J=8.54, 1.07 Hz, 2 H) 8.34 (d, J=5.19 Hz, 1 H) 12.36 (s, 1 H)。LCMS:m/z 540 [M+H]
+。針對C
27H
20F
3N
3O
4S [M + H]
+之HRMS (ESI)計算值540.12,實測值540.1207;
甲基-2-(2-氟-3-甲氧基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.64 (s, 3 H) 3.88 (s, 3 H) 7.10 (td, J=6.83, 1.75 Hz, 1 H) 7.16 (d, J=4.12 Hz, 1 H) 7.18 - 7.30 (m, 3 H) 7.59 (d, J=5.19 Hz, 1 H) 7.60 - 7.67 (m, 2 H) 7.71 - 7.77 (m, 1 H) 7.98 (d, J=4.12 Hz, 1 H) 8.13 (dd, J=8.46, 0.99 Hz, 2 H) 8.36 (d, J=5.19 Hz, 1 H) 12.39 (br. s., 1 H)。LCMS:m/z 506 [M+H]
+。針對C
26H
20FN
3O
5S [M + H]
+之HRMS (ESI)計算值506.1181,實測值506.1177;
甲基-2-(2-氯-3-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.61 (s, 3 H) 7.17 (d, J=4.12 Hz, 1 H) 7.22 (s, 1 H) 7.39 (d, J=7.02 Hz, 1 H) 7.44 - 7.50 (m, 1 H) 7.50 - 7.54 (m, 1 H) 7.55 (d, J=5.19 Hz, 1 H) 7.60 - 7.66 (m, 2 H) 7.70 - 7.75 (m, 1 H) 7.99 (d, J=4.12 Hz, 1 H) 8.12 (dd, J=8.46, 1.14 Hz, 2 H) 8.35 (d, J=5.34 Hz, 1 H) 12.48 (br. s., 1 H)。LCMS:m/z 510 [M+H]
+。針對C
25H
17ClFN
3O
4S [M + H]
+之HRMS (ESI)計算值510.0685,實測值510.0686;
甲基-2-(2-氟-3-甲基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 2.30 (d, J=1.59 Hz, 3 H) 3.64 (s, 3 H) 7.09 - 7.24 (m, 3 H) 7.37 (t, J=7.26 Hz, 2 H) 7.59 (d, J=5.25 Hz, 1 H) 7.61 - 7.66 (m, 2 H) 7.70 - 7.76 (m, 1 H) 7.98 (d, J=4.15 Hz, 1 H) 8.11 - 8.16 (m, 2 H) 8.35 (d, J=5.13 Hz, 1 H) 12.34 (br. s., 1 H)。LCMS:m/z 490 [M+H]
+。針對C
26H
20FN
3O
4S [M + H]
+之HRMS (ESI)計算值490.1232,實測值490.1225;
甲基-2-[2-甲基-3-(三氟甲基)苯基]-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 2.25 (s, 3 H) 3.61 (s, 3 H) 7.17 - 7.20 (m, 1 H) 7.24 - 7.26 (m, 1 H) 7.44 - 7.51 (m, 1 H) 7.55 - 7.58 (m, 1 H) 7.60 - 7.67 (m, 3 H) 7.70 - 7.75 (m, 1 H) 7.78 - 7.82 (m, 1 H) 7.98 - 8.00 (m, 1 H) 8.10 - 8.15 (m, 2 H) 8.31 - 8.36 (m, 1 H) 12.38 (d, J=2.29 Hz, 1 H)。LCMS:m/z 540 [M+H]
+。針對C
27H
20F
3N
3O
4S [M + H]
+之HRMS (ESI)計算值540.11994,實測值540.1203;
甲基-2-[4-甲氧基-2-(三氟甲基)苯基]-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.55 (s, 3 H) 3.90 (s, 3 H) 7.15 (d, J=4.12 Hz, 1 H) 7.19 (d, J=2.75 Hz, 1 H) 7.30 (dd, J=8.46, 2.52 Hz, 1 H) 7.33 (d, J=2.59 Hz, 1 H) 7.47 - 7.50 (m, 1 H) 7.52 (d, J=5.19 Hz, 1 H) 7.61 - 7.66 (m, 2 H) 7.71 - 7.75 (m, 1 H) 7.98 (d, J=4.12 Hz, 1 H) 8.09 - 8.14 (m, 2 H) 8.33 (d, J=5.34 Hz, 1 H) 12.37 (d, J=2.29 Hz, 1 H)。LCMS:m/z 556 [M+H]
+。針對C
27H
20F
3N
3O
5S [M + H]
+之HRMS (ESI)計算值556.1149,實測值556.1144;
甲基-2-[2-氯-4-(二氟甲氧基)苯基]-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.94 (s, 3 H) 7.18 (d, J=4.12 Hz, 1 H) 7.22 (d, J=2.75 Hz, 1 H) 7.27 (dd, J=8.35, 2.52 Hz, 1 H) 7.48 (d, J=2.59 Hz, 1 H) 7.55 - 7.56 (m, 1 H) 7.63 - 7.65 (m, 2 H) 7.71 - 7.74 (m, 1 H) 7.98 (d, J=4.10 Hz, 1 H) 8.12 - 8.14 (m, 2 H) 8.35 (d, J=5.31 Hz, 1 H) 12.42 (d, J=2.24 Hz, 1 H)。LCMS:m/z 558 [M+H]
+。針對C
26H
18ClF
2N
3O
5S [M + H]
+之HRMS (ESI)計算值558.0697,實測值558.0714;
甲基-2-(3,4-二氯苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.71 (s, 3 H) 7.15 (d, J=4.12 Hz, 1 H) 7.21 (d, J=2.59 Hz, 1 H) 7.61 - 7.66 (m, 3 H) 7.66 - 7.70 (m, 1 H) 7.71 - 7.76 (m, 2 H) 7.94 - 8.02 (m, 2 H) 8.14 (dd, J=8.39, 1.07 Hz, 2 H) 8.39 (d, J=5.19 Hz, 1 H) 12.32 (d, J=1.98 Hz, 1 H)。LCMS:m/z 526 [M+H]
+。針對C
25H
17Cl
2N
3O
4S [M + H]
+之HRMS (ESI)計算值526.039,實測值526.0387;
甲基-2-(3,4-二氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.70 (s, 3 H) 7.15 (d, J=4.12 Hz, 1 H) 7.20 (s, 1 H) 7.53 - 7.57 (m, 1 H) 7.62 - 7.67 (m, 3 H) 7.70 - 7.76 (m, 1 H) 7.77 - 7.84 (m, 1 H) 7.99 (d, J=4.12 Hz, 1 H) 8.12 - 8.16 (m, 2 H) 8.38 (d, J=5.19 Hz, 1 H) 12.27 (s, 1 H)。LCMS:m/z 494 [M+H]
+。針對C
25H
17F
2N
3O
4S [M + H]
+之HRMS (ESI)計算值494.0981,實測值494.0982;
甲基-2-(3-乙氧基-2-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 1.37 (t, J=6.94 Hz, 1 H) 3.65 (s, 3 H) 4.15 (q, J=6.91 Hz, 1 H) 7.08 (td, J=6.90, 1.60 Hz, 1 H) 7.16 (d, J=4.27 Hz, 1 H) 7.17 - 7.22 (m, 2 H) 7.22 - 7.27 (m, 1 H) 7.59 (d, J=5.19 Hz, 1 H) 7.61 - 7.67 (m, 2 H) 7.70 - 7.76 (m, 1 H) 7.99 (d, J=4.12 Hz, 1 H) 8.13 (dd, J=8.39, 1.07 Hz, 2 H) 8.36 (d, J=5.19 Hz, 1 H) 12.38 (d, J=2.14 Hz, 1 H)。LCMS:m/z 520 [M+H]
+。針對C
27H
22FN
3O
5S [M + H]
+之HRMS (ESI)計算值520.1337,實測值520.1335;
甲基-2-(4-甲基-3-硝基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 2.58 (s, 3 H) 3.69 - 3.72 (m, 3 H) 7.16 (d, J=4.12 Hz, 1 H) 7.23 (s, 1 H) 7.57 - 7.68 (m, 4 H) 7.70 - 7.77 (m, 1 H) 7.94 (dd, J=7.93, 1.83 Hz, 1 H) 8.00 (d, J=4.12 Hz, 1 H) 8.12 - 8.18 (m, 2 H) 8.32 (d, J=1.68 Hz, 1 H) 8.39 (d, J=5.18 Hz, 1 H) 12.36 (s, 1 H)。LCMS:m/z 517 [M+H]
+。針對C
26H
20N
4O
6S [M + H]
+之HRMS (ESI)計算值517.1177,實測值517.118;
甲基-2-(4-氰基-3-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.70 (s, 3 H) 7.17 (d, J=4.12 Hz, 1 H) 7.21 (d, J=2.75 Hz, 1 H) 7.61 - 7.69 (m, 4 H) 7.72 - 7.77 (m, 1 H) 8.00 (d, J=4.12 Hz, 1 H) 8.06 - 8.18 (m, 3 H) 8.27 (dd, J=6.18, 2.36 Hz, 1 H) 8.39 (d, J=5.19 Hz, 1 H) 12.35 (d, J=2.14 Hz, 1 H)。LCMS:m/z 501 [M+H]
+。針對C
26H
17FN
4O
4S [M + H]
+之HRMS (ESI)計算值501.1028,實測值501.102;
甲基-2-(二苯并[b,d]噻吩-4-基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.51 - 3.60 (m, 3 H) 7.23 (d, J=4.27 Hz, 1 H) 7.31 (d, J=2.59 Hz, 1 H) 7.51 - 7.56 (m, 2 H) 7.59 - 7.68 (m, 5 H) 7.69 - 7.77 (m, 1 H) 7.94 - 8.05 (m, 2 H) 8.09 - 8.17 (m, 2 H) 8.37 (d, J=5.19 Hz, 1 H) 8.40 - 8.51 (m, 2 H) 12.60 (d, J=2.14 Hz, 1 H)。LCMS:m/z 564 [M+H]
+。針對C
31H
21N
3O
4S
2[M + H]
+之HRMS (ESI)計算值564.1046,實測值564.1054;
甲基-2-(4-甲基萘-1-基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 2.74 (s, 3 H) 3.49 (s, 3 H) 7.21 (d, J=4.27 Hz, 1 H) 7.32 (d, J=2.90 Hz, 1 H) 7.42 - 7.52 (m, 3 H) 7.55 - 7.68 (m, 5 H) 7.71 - 7.78 (m, 1 H) 7.99 (d, J=4.12 Hz, 1 H) 8.07 - 8.17 (m, 3H) 8.33 (d, J=5.19 Hz, 1 H) 12.44 (d, J=2.14 Hz, 1 H)。LCMS:m/z 522 [M+H]
+。針對C
30H
23N
3O
4S [M + H]
+之HRMS (ESI)計算值522.1482,實測值522.1477;
2-(3-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸甲酯(VII)
1H NMR (500 MHz, DMSO-d6) d ppm 3.70 (s, 3 H) 7.15 (d, J=4.27 Hz, 1 H) 7.21 (d, J=2.75 Hz, 1 H) 7.23 - 7.30 (m, 1 H) 7.44 - 7.56 (m, 3 H) 7.60 - 7.68 (m, 3 H) 7.73 (d, J=7.47 Hz, 1 H) 7.99 (d, J=4.27 Hz, 1 H) 8.04 - 8.17 (m, 2 H) 8.37 (d, J=5.34 Hz, 1 H) 12.26 (d, J=2.14 Hz, 1 H)。LCMS:m/z 476 [M+H]
+。針對C
25H
18FN
3O
4S [M + H]
+之HRMS (ESI)計算值476.1075,實測值476.1072;
5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-2-[4-(三氟甲氧基)苯基]-1H-吡咯-3-羧酸甲酯(VII)
1H NMR (500 MHz, DMSO-d6) d ppm 3.69 (s, 3 H) 7.16 (d, J=4.12 Hz, 1 H) 7.21 (d, J=2.75 Hz, 1 H) 7.47 (d, J=8.08 Hz, 2 H) 7.57 - 7.67 (m, 3 H) 7.70 - 7.76 (m, 1 H) 7.77 - 7.84 (m, 2 H) 7.99 (s, 1 H) 8.07 - 8.18 (m, 2 H) 8.37 (d, J=5.19 Hz, 1 H) 12.28 (d, J=2.29 Hz, 1 H)。LCMS:m/z 542 [M+H]
+。針對C
26H
18F
3N
3O
5S [M + H]
+之HRMS (ESI)計算值542.0992,實測值542.0999;
2-(1-苯并噻吩-3-基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸甲酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 3.57 (s, 3 H) 7.20 (d, J=4.12 Hz, 1 H) 7.29 (d, J=2.59 Hz, 1 H) 7.37 - 7.45 (m, 2 H) 7.57 (m, J=1.98 Hz, 1 H) 7.64 (m, J=5.19 Hz, 3 H) 7.73 (tt, J=7.50, 1.40 Hz, 1 H) 8.00 (m, J=4.12 Hz, 2 H) 8.07 (m, J=1.83 Hz, 1 H) 8.14 (m, J=8.46, 1.14 Hz, 2 H) 8.36 (d, J=5.34 Hz, 1 H) 12.45 (d, J=1.83 Hz, 1 H)。LCMS:m/z 514 [M+H]
+。針對C
27H
19N
3O
4S
2[M + H]
+514.089之HRMS (ESI)計算值,實測值514.0878;
2-(2,3-二氫-1,4-苯并戴奧辛-6-基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸甲酯(VII)
1H NMR (500 MHz, DMSO-d6) d ppm 3.68 (s, 3 H) 4.22 - 4.35 (m, 4 H) 6.93 (d, J=8.39 Hz, 1 H) 7.12 (d, J=4.12 Hz, 1 H) 7.13 - 7.18 (m, 2 H) 7.20 (d, J=2.14 Hz, 1 H) 7.58 - 7.68 (m, 3 H) 7.69 - 7.76 (m, 1 H) 7.97 (d, J=4.12 Hz, 1 H) 8.13 (dd, J=8.46, 0.99 Hz, 2 H) 8.34 (d, J=5.19 Hz, 1 H) 12.06 (s, 1 H)。LCMS:m/z 516 [M+H]
+。針對C
27H
21N
3O
6S [M + H]
+之HRMS (ESI)計算值516.1224,實測值516.1206;
2-(4-氟-2-甲基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸甲酯(VII)
1H NMR (500 MHz, DMSO-d
6) d ppm 2.16 (s, 1 H) 3.61 (s, 3 H) 7.10 (td, J=8.50, 2.67 Hz, 1 H) 7.16 (d, J=4.12 Hz, 1 H) 7.18 - 7.22 (m, 2 H) 7.36 (dd, J=8.39, 6.10 Hz, 1 H) 7.57 (d, J=5.19 Hz, 1 H) 7.61 - 7.65 (m, 2 H) 7.70 - 7.75 (m, 1 H) 7.97 (d, J=4.12 Hz, 1 H) 8.11 - 8.13 (m, 2 H) 8.33 (d, J=5.19 Hz, 1 H) 12.26 (br. s., 1 H)。LCMS:m/z 490 [M+H]
+。針對C
26H
20FN
3O
4S [M + H]
+之HRMS (ESI)計算值490.1232,實測值490.1224;
向甲基-2-(2-氟-4-甲基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(1當量,200 mg,0.40 mmol)於DMF (2 ml)中之溶液添加N-碘琥珀醯亞胺(1.15當量,106 mg,0.47 mmol)。在室溫下將該反應混合物攪拌15 h。添加冰及蒸餾水且觀測到形成沈澱。將該固體過濾並用蒸餾水清洗三次(及用Et
2O清洗三次以達成標題化合物(米色固體,960 mg,Y=數量%)。
1H NMR (500 MHz, DMSO-d
6) d ppm 2.36 (s, 3 H) 3.58 (s, 3 H) 6.84 (d, J=3.81 Hz, 1 H) 7.05 - 7.16 (m, 2 H) 7.45 (t, J=8.01 Hz, 1 H) 7.48 - 7.53 (m, 1 H) 7.60 - 7.69 (m, 2 H) 7.70 - 7.77 (m, 1 H) 8.00 (d, J=4.12 Hz, 1 H) 8.10 - 8.21 (m, 2 H) 8.46 (d, J=4.88 Hz, 1 H) 12.49 (br. s., 1 H)。LCMS:m/z 616 [M+H]
+。針對C
26H
19FIN
3O
4S [M + H]
+之HRMS (ESI)計算值616.0198,實測值616.0182;
2-(2-氟-4-甲基苯基)-4-溴-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸甲酯(VII)
在T = 0℃下向甲基-2-(2-氟-4-甲基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸酯(1當量,300 mg,0.61 mmol)於MeOH (24.4 ml)及THF (6.1 ml)中之溶液添加0.33當量之N-溴琥珀醯亞胺(36 mg,0.3 mmol)。在T = 0℃下將該反應混合物攪拌30分鐘及然後添加0.33當量之N-溴琥珀醯亞胺(36 mg,0.3 mmol)。在T = 0℃下將該反應混合物攪拌30分鐘及然後添加最後一部分之N-溴琥珀醯亞胺(0.33當量,36 mg,0.3 mmol)。在T = 0℃下將該反應攪拌1小時及30分鐘。添加蒸餾水及產物用AcOEt萃取3次。有機層用鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(己烷/AcOEt 6/4)純化以提供標題化合物(白色固體,188 mg,Y=54%)。LCMS:m/z 568 [M+H]
+。針對C
26H
19BrFN
3O
4S [M + H]
+之HRMS (ESI)計算值568.0336,實測值568.0331;
步驟 4甲基-2-(3-氯-2-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
在T = 0℃下向2-(3-氯-2-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1H-吡咯-3-羧酸甲酯(1當量,100 mg,0.196 mmol)於無水THF (1 ml)中之溶液添加於礦物油中之NaH 60% (1.7當量,13.4 mg,0.33 mmol)。在T = 0℃下將該反應混合物攪拌20分鐘並添加SEMCl (1.8當量,63 μl,0.35 mmol)。10分鐘後在T = 0℃下在室溫下使該反應升溫並攪拌3小時。添加蒸餾水及產物用AcOEt萃取。有機層用蒸餾水及鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(Hex/AcOEt 85/15 - 7/3)純化以提供標題化合物(固體,118 mg,Y=94%)。
1H NMR (500 MHz, DMSO-d
6) d ppm -0.34 - -0.21 (m, 9 H) 0.40 - 0.59 (m, 2 H) 2.89 - 2.98 (m, 2 H) 3.62 (s, 3 H) 4.96 - 5.21 (m, 2 H) 6.90 (d, J=4.12 Hz, 1 H) 6.92 (s, 1 H) 7.36 (t, J=7.93 Hz, 1 H) 7.50 (d, J=5.03 Hz, 1 H) 7.52 - 7.56 (m, 1 H) 7.62 - 7.68 (m, 2 H) 7.71 - 7.77 (m, 2 H) 8.01 (d, J=3.97 Hz, 1 H) 8.17 (dd, J=8.46, 1.14 Hz, 2 H) 8.45 (d, J=5.03 Hz, 1 H)。LCMS:m/z 640 [M+H]
+。針對C
31H
31ClFN
3O
5SSi [M + H]
+之HRMS (ESI)計算值640.1499,實測值640.149;
以類似方式操作,但採用合適之經取代之起始材料,獲得下列化合物:
甲基-2-(2-氟-4-甲基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.33 - -0.26 (m, 9 H) 0.47 (t, J=8.31 Hz, 1 H) 2.40 (s, 3 H) 2.93 (q, J=8.29 Hz, 1 H) 3.60 (s, 3 H) 4.98 - 5.18 (m, 2 H) 6.87 - 6.94 (m, 2 H) 7.11 - 7.19 (m, 2 H) 7.36 - 7.41 (m, 1 H) 7.51 (d, J=5.19 Hz, 1 H) 7.62 - 7.68 (m, 2 H) 7.71 - 7.79 (m, 1 H) 8.00 (d, J=4.12 Hz, 1 H) 8.13 - 8.22 (m, 2 H) 8.44 (d, J=5.03 Hz, 1 H)。LCMS:m/z 620 [M+H]
+。針對C
31H
31ClFN
3O
5SSi [M + H]
+之HRMS (ESI)計算值620.2045,實測值620.2047;
甲基-2-(4-氯-2-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.30 - -0.28 (m, 9 H) 0.44 - 0.50 (m, 2 H) 2.91 - 2.97 (m, 2 H) 3.59 - 3.64 (m, 3 H) 5.00 - 5.18 (m, 2 H) 6.89 (d, J=4.12 Hz, 1 H) 6.91 (s, 1 H) 7.44 (dd, J=8.24, 1.98 Hz, 1 H) 7.47 - 7.51 (m, 1 H) 7.57 - 7.62 (m, 2 H) 7.63 - 7.67 (m, 2 H) 7.73 - 7.77 (m, 1 H) 8.01 (d, J=3.97 Hz, 1 H) 8.17 (dd, J=8.46, 1.14 Hz, 2 H) 8.45 (d, J=5.19 Hz, 1 H)。LCMS:m/z 640 [M+H]
+。針對C
31H
31ClFN
3O
5SSi [M + H]
+之HRMS (ESI)計算值640.1499,實測值640.1;
甲基-2-(2-氯-4-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.31 - -0.27 (m, 9 H) 0.47 (dd, J=9.38, 6.94 Hz, 2 H) 2.93 (dd, J=9.23, 7.55 Hz, 2 H) 3.59 (s, 3 H) 4.93 (d, J=11.13 Hz, 1 H) 5.10 (d, J=11.13 Hz, 1 H) 6.86 (d, J=4.12 Hz, 1 H) 6.89 (s, 1 H) 7.36 (td, J=8.46, 2.59 Hz, 1 H) 7.48 (d, J=5.19 Hz, 1 H) 7.60 (dd, J=8.62, 6.18 Hz, 1 H) 7.62 - 7.68 (m, 3 H) 7.71 - 7.77 (m, 1 H) 8.01 (d, J=4.12 Hz, 1 H) 8.16 (dd, J=8.46, 1.14 Hz, 2 H) 8.44 (d, J=5.03 Hz, 1 H)。LCMS:m/z 640 [M+H]
+。針對C
31H
31ClFN
3O
5SSi [M + H]
+之HRMS (ESI)計算值640.1499,實測值640.1491;
甲基-2-(2,4-二氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
LCMS:m/z 624 [M+H]
+。針對C
31H
31F
2N
3O
5SSi [M + H]
+之HRMS (ESI)計算值624.1795,實測值624.1788;
甲基-2-[2-氯-4-(三氟甲基)苯基]-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.32 - -0.30 (m, 8 H) 0.40 - 0.48 (m, 2 H) 2.87 - 2.95 (m, 2 H) 3.57 - 3.62 (m, 3 H) 4.93 - 5.14 (m, 2 H) 6.87 (d, J=4.12 Hz, 1 H) 6.92 (s, 1 H) 7.45 - 7.51 (m, 1 H) 7.62 - 7.68 (m, 2 H) 7.72 - 7.77 (m, 1 H) 7.79 - 7.82 (m, 1 H) 7.84 - 7.88 (m, 1 H) 8.02 (d, J=4.12 Hz, 1 H) 8.05 (d, J=0.76 Hz, 1 H) 8.17 (dd, J=8.54, 1.07 Hz, 2 H) 8.46 (d, J=5.19 Hz, 1 H)。LCMS:m/z 690 [M+H]
+。針對C
32H
31ClF
3N
3O
5SSi [M + H]
+之HRMS (ESI)計算值690.1467,實測值690.1469;
甲基-2-(2,3-二氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
LCMS:m/z 624 [M+H]
+。針對C
31H
31F
2N
3O
5SSi [M + H]
+之HRMS (ESI)計算值624.1795,實測值624.1791;
甲基-2-(2,3-二氯苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
LCMS:m/z 656 [M+H]
+。針對C
31H
31Cl
2N
3O
5SSi [M + H]
+之HRMS (ESI)計算值656.1204,實測值656.1207;
甲基-2-[4-甲基-2-(三氟甲基)苯基]-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.33 - -0.29 (m, 9 H) 0.45 (dd, J=9.23, 7.55 Hz, 2 H) 2.48 (s, 3 H) 2.90 (dd, J=9.30, 7.47 Hz, 2 H) 3.51 - 3.53 (m, 3 H) 4.75 (d, J=10.98 Hz, 1 H) 5.07 (d, J=10.98 Hz, 1 H) 6.77 (d, J=4.12 Hz, 1 H) 6.85 (s, 1 H) 7.39 - 7.45 (m, 2 H) 7.58 (d, J=7.93 Hz, 1 H) 7.62 - 7.67 (m, 2 H) 7.70 (s, 1 H) 7.72 - 7.76 (m, 1 H) 8.01 (d, J=3.97 Hz, 1 H) 8.16 (dd, J=8.62, 1.14 Hz, 2 H) 8.44 (d, J=5.03 Hz, 1 H)。LCMS:m/z 670 [M+H]
+。針對C
33H
34F
3N
3O
5SSi [M + H]
+之HRMS (ESI)計算值670.2014,實測值670.2007;
甲基-2-(2-氯-4-甲基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
LCMS:m/z 636 [M+H]
+。針對C
32H
34ClN
3O
5SSi [M + H]
+之HRMS (ESI)計算值636.1750,實測值636.1753;
甲基-2-(2,3-二氟-4-甲基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
LCMS:m/z 638 [M+H]
+。針對C
32H
33F
2N
3O
5SSi [M + H]
+之HRMS (ESI)計算值638.1951,實測值638.1956;
甲基-2-[2-甲基-4-(三氟甲基)苯基]-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
LCMS:m/z 670 [M+H]
+。針對C
33H
34F
3N
3O
5SSi [M + H]
+之HRMS (ESI)計算值670.2013,實測值670.2017;
甲基-2-(2-氟-3-甲氧基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
LCMS:m/z 636 [M+H]
+。針對C
32H
34FN
3O
6SSi [M + H]
+之HRMS (ESI)計算值636.1994,實測值636.1993;
甲基-2-(2-氯-3-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
LCMS:m/z 640 [M+H]
+。針對C
31H
31ClFN
3O
5SSi [M + H]
+之HRMS (ESI)計算值640.1499,實測值640.1495;
甲基-2-(2-氟-3-甲基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
LCMS:m/z 620 [M+H]
+。針對C
32H
34FN
3O
5SSi [M + H]
+之HRMS (ESI)計算值620.2045,實測值620.2039;
甲基-2-[2-甲基-3-(三氟甲基)苯基]-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
LCMS:m/z 670 [M+H]
+。針對C
33H
34F
3N
3O
5SSi [M + H]
+之HRMS (ESI)計算值670.2013,實測值670.2008;
甲基-2-[4-甲氧基-2-(三氟甲基)苯基]-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
LCMS:m/z 686 [M+H]
+。針對C
33H
34F
3N
3O
6SSi [M + H]
+之HRMS (ESI)計算值686.1963,實測值686.1961;
甲基-2-[2-氯-4-(二氟甲氧基)苯基]-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.31 - -0.28 (m, 9 H) 0.44 - 0.49 (m, 2 H) 2.91 - 2.95 (m, 2 H) 3.59 (s, 3 H) 4.42- 5.12 (m, 2 H) 6.85 (d, J=3.85 Hz, 1 H) 6.89 (s, 1 H) 7.59 (d, J=3.88 Hz, 1 H) 7.63 - 7.66 (m, 2 H) 7.73 - 7.76 (m, 1 H) 8.01 (d, J=4.22 Hz, 1 H) 8.15 - 8.17 (m, 2 H) 8.45 (d, J=5.22 Hz, 1 H)。LCMS:m/z 688 [M+H]
+。針對C
32H
32ClF
2N
3O
6SSi [M + H]
+之HRMS (ESI)計算值688.1511,實測值688.1508;
甲基-2-(3,4-二氯苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.27 - -0.24 (m, 8 H) 0.47 - 0.57 (m, 2 H) 2.97 - 3.04 (m, 2 H) 3.62 (s, 3 H) 5.05 (s, 2 H) 6.89 (s, 1 H) 6.93 (d, J=3.97 Hz, 1 H) 7.45 - 7.54 (m, 2 H) 7.62 - 7.69 (m, 2 H) 7.71 - 7.78 (m, 2 H) 7.81 (d, J=1.98 Hz, 1 H) 8.01 (d, J=4.12 Hz, 1 H) 8.13 - 8.21 (m, 2 H) 8.45 (d, J=5.19 Hz, 1 H)。LCMS:m/z 656 [M+H]
+。針對C
31H
31Cl
2N
3O
5SSi [M + H]
+之HRMS (ESI)計算值656.1204,實測值656.1215;
甲基-2-(3,4-二氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.28 - -0.26 (m, 8 H) 0.48 - 0.56 (m, 2 H) 2.96 - 3.03 (m, 2 H) 3.61 (s, 3 H) 5.06 (s, 2 H) 6.88 (s, 1 H) 6.92 (d, J=4.12 Hz, 1 H) 7.34 - 7.39 (m, 1 H) 7.47 - 7.51 (m, 1 H) 7.53 - 7.67 (m, 4 H) 7.72 - 7.78 (m, 1 H) 8.01 (d, J=3.97 Hz, 1 H) 8.14 - 8.21 (m, 2 H) 8.45 (d, J=5.03 Hz, 1 H)。LCMS:m/z 624 [M+H]
+。針對C
31H
31F
2N
3O
5SSi [M + H]
+之HRMS (ESI)計算值624.1795,實測值624.1816;
甲基-2-(3-乙氧基-2-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.31 - -0.26 (m, 9 H) 0.47 (t, J=8.31 Hz, 2 H) 1.37 (t, J=7.02 Hz, 1 H) 2.87 - 3.02 (m, 2 H) 3.61 (s, 3 H) 4.04 - 4.22 (m, 1 H) 4.98 - 5.18 (m, 2 H) 6.84 - 6.94 (m, 1 H) 6.97 - 7.09 (m, 2 H) 7.19 - 7.25 (m, 1 H) 7.26 - 7.32 (m, 1 H) 7.52 (d, J=5.03 Hz, 1 H) 7.62 - 7.68 (m, 2 H) 7.72 - 7.77 (m, 1 H) 8.00 (d, J=4.12 Hz, 1 H) 8.17 (dd, J=8.46, 1.14 Hz, 2 H) 8.44 (d, J=5.19 Hz, 1 H)。LCMS:m/z 650 [M+H]
+。針對C
33H
36FN
3O
6SSi [M + H]
+之HRMS (ESI)計算值650.2151,實測值650.2164;
甲基-2-(4-甲基-3-硝基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.28 - -0.25 (m, 8 H) 0.52 - 0.58 (m, 2 H) 2.60 (s, 3 H) 2.98 - 3.05 (m, 2 H) 3.62 (s, 3 H) 5.04 (s, 2 H) 6.91 (s, 1 H) 6.93 (d, J=4.12 Hz, 1 H) 7.51 (d, J=5.03 Hz, 1 H) 7.59 - 7.69 (m, 3 H) 7.71 - 7.78 (m, 2 H) 8.01 (d, J=4.12 Hz, 1 H) 8.14 - 8.24 (m, 3 H) 8.45 (d, J=5.03 Hz, 1 H)。LCMS:m/z 647 [M+H]
+。針對C
32H
34N
4O
7SSi [M + H]
+之HRMS (ESI)計算值647.1990,實測值647.2003;
甲基-2-(4-氰基-3-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.28 - -0.24 (m, 9 H) 0.46 - 0.57 (m, 2 H) 2.92 - 3.04 (m, 2 H) 3.62 (s, 3 H) 5.05 (s, 2 H) 6.90 (s, 1 H) 6.92 (d, J=4.12 Hz, 1 H) 7.47 (d, J=5.03 Hz, 1 H) 7.62 - 7.71 (m, 3 H) 7.72 - 7.77 (m, 1 H) 7.87 - 7.97 (m, 1 H) 8.02 (d, J=4.12 Hz, 1 H) 8.12 (dd, J=6.25, 2.14 Hz, 1 H) 8.15 - 8.20 (m, 2 H) 8.46 (d, J=5.03 Hz, 1 H)。LCMS:m/z 631 [M+H]
+。針對C
32H
31FN
4O
5SSi [M + H]
+之HRMS (ESI)計算值631.1841,實測值631.1846;
甲基-2-(二苯并[b,d]噻吩-4-基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
LCMS:m/z 694 [M+H]
+。針對C
37H
35N
3O
5S
2Si [M + H]
+之HRMS (ESI)計算值694.1860,實測值694.1863;
甲基-2-(4-甲基萘-1-基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.40 - -0.35 (m, 9 H) 0.19 - 0.32 (m, 2H) 2.67 - 2.81 (m, 5 H) 3.44 (s, 3 H) 4.74 - 5.08 (m, 2 H) 6.91 - 7.01 (m, 2 H) 7.43 - 7.51 (m, 4 H) 7.53 - 7.61 (m, 2 H) 7.62 - 7.71 (m, 2 H) 7.73 - 7.78 (m, 1 H) 8.02 (d, J=4.12 Hz, 1 H) 8.10 (d, J=8.39 Hz, 1 H) 8.17 (dd, J=8.46, 0.99 Hz, 1 H) 8.44 (d, J=5.03 Hz, 1 H)。LCMS:m/z 652 [M+H]
+。針對C
36H
37N
3O
5SSi [M + H]
+之HRMS (ESI)計算值652.2296,實測值652.2303;
2-(3-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸甲酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.29 - -0.24 (m, 9 H) 0.49 - 0.56 (m, 2 H) 2.94 - 3.02 (m, 2 H) 3.60 (s, 3 H) 5.05 (s, 2 H) 6.89 (s, 1 H) 6.92 (d, J=3.97 Hz, 1 H) 7.29 - 7.40 (m, 3 H) 7.47 - 7.56 (m, 2 H) 7.60 - 7.68 (m, 2 H) 7.70 - 7.77 (m, 1 H) 8.01 (d, J=4.12 Hz, 1 H) 8.17 (dd, J=8.46, 1.14 Hz, 2 H) 8.45 (d, J=5.03 Hz, 1 H)。LCMS:m/z 606 [M+H]
+。針對C
31H
32FN
3O
5SSi [M + H]
+之HRMS (ESI)計算值606.1889,實測值606.1885;
5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-2-[4-(三氟甲氧基)苯基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸甲酯(VIII)
1H NMR (500 MHz, DMSO-d6) d ppm -0.30 - -0.26 (m, 9 H) 0.46 - 0.55 (m, 2 H) 2.94 - 3.01 (m, 2 H) 3.60 (s, 3 H) 5.04 (s, 2 H) 6.90 (s, 1 H) 6.92 (d, J=4.12 Hz, 1 H) 7.44 - 7.53 (m, 3 H) 7.61 - 7.68 (m, 4 H) 7.71 - 7.78 (m, 1 H) 8.01 (d, J=4.12 Hz, 1 H) 8.17 (dd, J=8.46, 1.14 Hz, 2 H) 8.45 (d, J=5.03 Hz, 1 H)。LCMS:m/z 672 [M+H]
+。針對C
32H
32F
3N
3O
6SSi [M + H]
+之HRMS (ESI)計算值672.1806,實測值672.1808;
2-(1-苯并噻吩-3-基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸甲酯(VIII)
1H NMR (500 MHz, DMSO-d6) d ppm -0.39 - -0.33 (m, 9 H) 0.31 - 0.43 (m, 2 H) 2.78 - 2.89 (m, 2 H) 3.49 (s, 3 H) 4.97 (d, J=10.98 Hz, 1 H) 5.21 (d, J=10.98 Hz, 1 H) 6.93 (d, J=4.12 Hz, 1 H) 6.99 (s, 1 H) 7.33 - 7.45 (m, 3 H) 7.56 (d, J=5.03 Hz, 1 H) 7.62 - 7.69 (m, 2 H) 7.71 - 7.78 (m, 1 H) 7.99 (s, 1 H) 8.02 (d, J=4.12 Hz, 1 H) 8.04 - 8.12 (m, 1 H) 8.14 - 8.22 (m, 2 H) 8.45 (d, J=5.19 Hz, 1 H)。LCMS:m/z 644 [M+H]
+。針對C
33H
33N
3O
5S
2Si [M + H]
+之HRMS (ESI)計算值644.1704,實測值644.17;
2-(2,3-二氫-1,4-苯并戴奧辛-6-基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸甲酯(VIII)
1H NMR (500 MHz, DMSO-d6) d ppm -0.25 (s, 9 H) 0.50 - 0.59 (m, 2 H) 2.98 - 3.07 (m, 2 H) 3.61 (s, 3 H) 4.29 (q, J=4.98 Hz, 4 H) 5.04 (s, 2 H) 6.86 (s, 1 H) 6.91 (d, J=4.12 Hz, 1 H) 6.92 - 6.96 (m, 2 H) 7.00 (m, J=1.22 Hz, 1 H) 7.52 (d, J=5.19 Hz, 1 H) 7.61 - 7.67 (m, 2 H) 7.74 (m, J=7.47 Hz, 1 H) 7.99 (d, J=4.12 Hz, 1 H) 8.17 (dd, J=8.39, 1.07 Hz, 2 H) 8.43 (d, J=5.19 Hz, 1 H)。LCMS:m/z 646 [M+H]
+。針對C
33H
35N
3O
7SSi [M + H]
+之HRMS (ESI)計算值646.2038,實測值646.2045;
2-(4-氟-2-甲基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸甲酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.32 - -0.28 (m, 9 H) 0.40 - 0.50 (m, 2 H) 2.08 (s, 3 H) 2.82 - 3.04 (m, 2 H) 3.57 (s, 3 H) 4.79 - 5.05 (m, 2 H) 6.84 - 6.92 (m, 2 H) 7.12 (d, J=2.59 Hz, 1 H) 7.21 (dd, J=10.07, 2.59 Hz, 1 H) 7.33 (dd, J=8.46, 6.02 Hz, 1 H) 7.47 - 7.52 (m, 1 H) 7.58 - 7.68 (m, 2 H) 7.70 - 7.77 (m, 1 H) 8.00 (d, J=3.97 Hz, 1 H) 8.16 (dd, J=8.46, 1.14 Hz, 2 H) 8.43 (d, J=5.19 Hz, 1 H)。LCMS:m/z 620 [M+H]
+。針對C
32H
34FN
3O
5SSi [M + H]
+之HRMS (ESI)計算值620.2045,實測值620.2034;
甲基-2-(2-氟-3-甲基苯基)-4-碘-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.30 (s, 9 H) 0.32 (m, J=9.65, 9.65, 6.63 Hz, 2 H) 2.38 (s, 3 H) 2.67 - 2.86 (m, 2 H) 3.53 (s, 3 H) 4.58 - 5.07 (m, 2 H) 6.37 - 6.81 (m, 1 H) 7.09 - 7.19 (m, 2 H) 7.39 (d, J=5.03 Hz, 2 H) 7.61 - 7.71 (m, 2 H) 7.73 - 7.79 (m, 1 H) 8.02 (d, J=3.97 Hz, 1 H) 8.19 (d, J=7.47 Hz, 2 H) 8.51 (d, J=5.03 Hz, 1 H)。LCMS:m/z 746 [M+H]
+。針對C
33H
33FIN
3O
5S [M + H]
+之HRMS (ESI)計算值746.1012,實測值746.1024;
甲基-2-(2-氟-3-甲基苯基)-4-溴-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸酯(VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.34 - -0.27 (m, 9 H) 0.26 - 0.41 (m, 2 H) 2.39 (s, 3 H) 2.80 (m, J=11.13, 11.13, 6.56 Hz, 2 H) 3.55 (s, 3 H) 4.68 - 5.18 (m, 2 H) 6.47 - 6.85 (m, 1 H) 7.08 - 7.22 (m, 2 H) 7.30 - 7.48 (m, 2 H) 7.59 - 7.70 (m, 2 H) 7.70 - 7.82 (m, 1 H) 8.03 (d, J=3.97 Hz, 1 H) 8.18 - 8.22 (m, 2 H) 8.51 (d, J=5.03 Hz, 1 H)。LCMS:m/z 698 [M+H]
+。針對C
33H
33BrFN
3O
5S [M + H]
+之HRMS (ESI)計算值698.1151,實測值698.1159;
在反應器中,在氬氣氛下,添加2-(2-氟-4-甲基苯基)-4-碘-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸甲酯(1當量,50 mg,0.06 mmol)、乙烯基硼酸(2當量,23 µl,0.13 mmol)、Na
2CO
3(3當量,21.3 mg,0.2 mmol)、經脫氣之1,4-二噁烷(1 ml)及經脫氣之蒸餾水(0.25 ml)。在三次真空/氬週期後,添加觸媒肆(三苯基膦)-鈀(0) (0.1當量,7.7 mg,0.006 mmol)。在三次真空/氬週期後,在T = 100℃將該反應混合物加熱2小時。添加蒸餾水及產物用AcOEt萃取(3次)。有機層用蒸餾水及鹽水洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(己烷/乙酸乙酯8/2)純化提供標題化合物(白色固體,28 mg,Y=72%)。
1H NMR (500 MHz, DMSO-d
6) d ppm -0.32 - -0.28 (m, 9 H) 0.27 - 0.37 (m, 2 H) 2.36 - 2.40 (m, 3 H) 2.77 (td, J=10.29, 6.41 Hz, 2 H) 3.50 - 3.54 (m, 3 H) 4.64 (d, J=17.54 Hz, 1 H) 4.84 (dd, J=11.44, 1.68 Hz, 1 H) 4.86 - 5.02 (m, 2 H) 6.79 (br. s., 2 H) 7.08 - 7.18 (m, 2 H) 7.28 - 7.47 (m, 2 H) 7.60 - 7.69 (m, 2 H) 7.74 (t, J=7.40 Hz, 1 H) 7.93 - 8.04 (m, 1 H) 8.11 - 8.22 (m, 2 H) 8.45 - 8.53 (m, 1 H)。LCMS:m/z 645 [M+ H]
+。針對C
34H
36FN
3O
5SSi [M + H]
+之HRMS (ESI)計算值646.2202,實測值646.2194;
以類似方式操作,但採用合適之經取代之起始材料,獲得下列化合物:
2-(2-氟-4-甲基苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-4-(丙-1-烯-2-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸甲酯12 (VIII)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.34 - -0.23 (m, 9 H) 0.27 - 0.39 (m, 2 H) 1.88 (s, 3 H) 2.38 (s, 3 H) 2.74 - 2.81 (m, 2 H) 3.49 (s, 3 H) 4.44 (d, J=1.37 Hz, 1 H) 4.76 (s, 3 H) 6.39 - 6.76 (m, 1 H) 7.07 - 7.17 (m, 3 H) 7.32 (d, J=4.88 Hz, 1 H) 7.62 - 7.68 (m, 2 H) 7.70 - 7.80 (m, 1 H) 7.95 (d, J=4.12 Hz, 1 H) 8.17 (d, J=7.47 Hz, 2 H) 8.42 (d, J=5.03 Hz, 1 H)。LCMS:m/z 659 [M+H]
+。針對C
35H
38FN
3O
5SSi [M + H]
+之HRMS (ESI)計算值660.2358,實測值660.2358;
向2-(3-氯-2-氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸甲酯(1當量,100 mg,0.156 mmol)於二噁烷(0.5 ml)中之溶液添加NaOH 4M之溶液(0.5 ml)。在T = 100℃將該反應混合物攪拌4小時。在室溫下冷卻後,添加乙酸以達成pH = 6。添加蒸餾水及產物用AcOEt萃取3次。有機層用鹽水洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物無需進一步純化即用於下一步驟中(白色固體,70 mg,Y=92%)。
1H NMR (500 MHz, DMSO-d
6) d ppm -0.24 - -0.18 (m, 9 H) 0.46 - 0.58 (m, 2 H) 2.90 - 3.02 (m, 2 H) 5.04 - 5.21 (m, 2 H) 6.53 (dd, J=3.43, 1.91 Hz, 1 H) 6.86 (s, 1 H) 7.23 (d, J=5.03 Hz, 1 H) 7.35 (t, J=7.85 Hz, 1 H) 7.53 - 7.61 (m, 2 H) 7.67 - 7.73 (m, 1 H) 8.29 (d, J=4.88 Hz, 1 H) 11.86 (br. s., 1 H) 12.04 (br. s., 1 H)。LCMS:m/z 486 [M+H]
+。針對C
24H
25ClFN
3O
3Si [M + H]
+之HRMS (ESI)計算值486.1411,實測值486.1397;
以類似方式操作,但採用合適之經取代之起始材料,獲得下列化合物:
2-(4-氯-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.23 - -0.18 (m, 9 H) 0.48 - 0.56 (m, 2 H) 2.94 - 3.00 (m, 2 H) 5.04 - 5.22 (m, 2 H) 6.52 (dd, J=3.43, 1.91 Hz, 1 H) 6.85 (s, 1 H) 7.22 (d, J=4.88 Hz, 1 H) 7.42 (dd, J=8.31, 2.06 Hz, 1 H) 7.53 - 7.58 (m, 2 H) 7.61 (t, J=8.08 Hz, 1 H) 8.28 (d, J=5.03 Hz, 1 H) 11.85 (br. s., 1 H) 12.08 (br. s., 1 H)。LCMS:m/z 486 [M+H]
+。針對C
24H
25ClFN
3O
3Si [M + H]
+之HRMS (ESI)計算值486.1411,實測值486.1417;
2-(2-氯-4-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 486 [M+H]
+。針對C
24H
25ClFN
3O
3Si [M + H]
+之HRMS (ESI)計算值486.1411,實測值486.1408;
2-(2,4-二氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 470 [M+H]
+。針對C
24H
25F
2N
3O
3Si [M + H]
+之HRMS (ESI)計算值470.1706,實測值470.1711;
2-[2-氯-4-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.24 - -0.22 (m, 7 H) 0.42 - 0.52 (m, 2 H) 2.89 - 2.98 (m, 2 H) 4.96 - 5.18 (m, 2 H) 6.49 (dd, J=3.36, 1.83 Hz, 1 H) 6.85 (s, 1 H) 7.20 (d, J=4.88 Hz, 1 H) 7.56 - 7.59 (m, 1 H) 7.80 - 7.87 (m, 2 H) 8.03 (s, 1 H) 8.29 (d, J=4.88 Hz, 1 H) 11.87 (br. s., 1 H)。LCMS:m/z 536 [M+H]
+。針對C
25H
25ClF
3N
3O
3Si [M + H]
+之HRMS (ESI)計算值536.1379,實測值536.1384;
2-(2,3-二氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 470 [M+H]
+。針對C
24H
25F
2N
3O
3Si [M + H]
+之HRMS (ESI)計算值470.1706,實測值470.1701;
2-(2,3-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 502 [M+H]
+。針對C
24H
25Cl
2N
3O
3Si [M + H]
+之HRMS (ESI)計算值502.1112,實測值502.1119;
2-[4-甲基-2-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.25 - -0.19 (m, 9 H) 0.49 (ddd, J=9.76, 7.02, 2.29 Hz, 2 H) 2.47 (s, 3 H) 2.86 - 2.99 (m, 2 H) 4.76 (d, J=10.98 Hz, 1 H) 5.11 (d, J=10.98 Hz, 1 H) 6.39 (dd, J=3.36, 1.83 Hz, 1 H) 6.79 (s, 1 H) 7.16 (d, J=5.03 Hz, 1 H) 7.43 (d, J=7.78 Hz, 1 H) 7.52 - 7.60 (m, 2 H) 7.68 (s, 1 H) 8.28 (d, J=4.88 Hz, 1 H) 11.85 (br. s., 1 H)。LCMS:m/z 516 [M+H]
+。針對C
26H
28F
3N
3O
3Si [M + H]
+之HRMS (ESI)計算值516.1925,實測值516.1931;
2-(2-氯-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 482 [M+H]
+。針對C
25H
28ClN
3O
3Si [M + H]
+之HRMS (ESI)計算值482.1661,實測值482.1664;
2-(2,3-二氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 484 [M+H]
+。針對C
25H
27F
2N
3O
3Si [M + H]
+之HRMS (ESI)計算值484.1863,實測值484.1866;
2-[2-甲基-4-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 516 [M+H]
+。針對C
26H
28F
3N
3O
3Si [M + H]
+之HRMS (ESI)計算值516.1925,實測值516.1927;
2-(2-氟-3-甲氧基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 482 [M+H]
+。針對C
25H
28FN
3O
4Si [M + H]
+之HRMS (ESI)計算值482.1906,實測值482.1904;
2-(2-氯-3-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 486 [M+H]
+。針對C
24H
25ClFN
3O
3Si [M + H]
+之HRMS (ESI)計算值486.1411,實測值486.1409;
2-(2-氟-3-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 466 [M+H]
+。針對C
25H
28FN
3O
3Si [M + H]
+之HRMS (ESI)計算值466.1957,實測值466.1951;
2-[2-甲基-3-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 516 [M+H]
+。針對C
26H
28F
3N
3O
3Si [M + H]
+之HRMS (ESI)計算值516.1925,實測值516.1919;
2-[4-甲氧基-2-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 532 [M+H]
+。針對C
26H
28F
3N
3O
4Si [M + H]
+之HRMS (ESI)計算值532.1874,實測值532.1871;
2-[2-氯-4-(二氟甲氧基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 534 [M+H]
+。針對C
25H
26ClF
2N
3O
4Si [M + H]
+之HRMS (ESI)計算值534.1422,實測值534.1423;
2-(3,4-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 502 [M+H]
+。針對C
24H
25Cl
2N
3O
3Si [M + H]
+之HRMS (ESI)計算值502.1115,實測值502.1121;
2-(3,4-二氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 470 [M+H]
+。針對C
24H
25F
2N
3O
3Si [M + H]
+之HRMS (ESI)計算值470.1706,實測值470.1715;
2-(3-乙氧基-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.24 - -0.16 (m, 9 H) 0.48 - 0.58 (m, 2 H) 1.38 (t, J=6.94 Hz, 1 H) 2.87 - 3.08 (m, 2 H) 4.04 - 4.25 (m, 1 H) 4.95 - 5.23 (m, 2 H) 6.52 (dd, J=3.43, 1.91 Hz, 1 H) 6.81 - 6.91 (m, 1 H) 7.02 - 7.11 (m, 1 H) 7.18 - 7.32 (m, 3 H) 7.55 - 7.61 (m, 1 H) 8.28 (d, J=4.88 Hz, 1 H) 11.85 (br. s., 1 H) 11.95 (br. s., 1 H)。LCMS:m/z 496 [M+H]
+。針對C
26H
30FN
3O
4Si [M + H]
+之HRMS (ESI)計算值496.2063,實測值496.2069;
2-(4-甲基-3-硝基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.20 - -0.14 (m, 2 H) 0.57 - 0.67 (m, 1 H) 2.61 (s, 1 H) 2.99 - 3.11 (m, 1 H) 5.09 (s, 1 H) 6.57 (dd, J=3.36, 1.98 Hz, 1 H) 6.88 (s, 1 H) 7.26 (d, J=5.03 Hz, 1 H) 7.55 - 7.65 (m, 1 H) 7.80 (dd, J=7.85, 1.75 Hz, 1 H) 8.18 (d, J=1.68 Hz, 1 H) 8.30 (d, J=4.88 Hz, 1 H) 11.60 - 12.24 (m, 1 H)。LCMS:m/z 493 [M+H]
+。針對C
25H
28N
4O
5Si [M + H]
+之HRMS (ESI)計算值493.1902,實測值493.1903;
2-(3-羧基-4-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 496 [M+H]
+。針對C
25H
26FN
3O
5Si [M + H]
+之HRMS (ESI)計算值496.1699,實測值496.1701;
2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 466 [M+H]
+。針對C
25H
28FN
3O
3Si [M + H]
+之HRMS (ESI)計算值466.1957,實測值466.1959;
2-(二苯并[b,d]噻吩-4-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 540 [M+H]
+。針對C
30H
29N
3O
3SSi [M + H]
+之HRMS (ESI)計算值540.1772,實測值540.1775;
2-(4-甲基萘-1-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 498 [M+H]
+。針對C
29H
31N
3O
3Si [M + H]
+之HRMS (ESI)計算值498.2207,實測值498.2209;
2-(3-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 452 [M+H]
+。針對C
24H
26FN
3O
3Si [M + H]
+之HRMS (ESI)計算值452.1800,實測值452.1811;
5-(1H-吡咯并[2,3-b]吡啶-4-基)-2-[4-(三氟甲氧基)苯基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 518 [M+H]
+。針對C
25H
26F
3N
3O
4Si [M + H]
+之HRMS (ESI)計算值518.1718,實測值518.1725;
2-(1-苯并噻吩-3-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 490 [M+H]
+。針對C
26H
27N
3O
3SSi [M + H]
+之HRMS (ESI)計算值490.1615,實測值490.1624;
2-(2,3-二氫-1,4-苯并戴奧辛-6-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 492 [M+H]
+。針對C
26H
29N
3O
5Si [M + H]
+之HRMS (ESI)計算值492.1949,實測值492.1952;
2-(4-氟-2-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 466 [M+H]
+。針對C
25H
28N
3O
3Si [M + H]
+之HRMS (ESI)計算值466.1957,實測值466.1959;
2-(2-氟-4-甲基苯基)-4-碘-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 592 [M+H]
+。針對C
25H
27FIN
3O
3Si [M + H]
+之HRMS (ESI)計算值592.0923,實測值592.0929;
2-(2-氟-4-甲基苯基)-4-溴-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 544 [M+H]
+。針對C
25H
27BrFN
3O
3Si [M + H]
+之HRMS (ESI)計算值544.1062,實測值544.1067;
4-乙烯基-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 492 [M+H]
+。針對C
27H
30FN
3O
3Si [M + H]
+之HRMS (ESI)計算值492.2113,實測值492.2114;
2-(2-氟-4-甲基苯基)-4-(丙-1-烯-2-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(IX)
LCMS:m/z 506 [M+H]
+。針對C
28H
32FN
3O
3Si [M + H]
+之HRMS (ESI)計算值506.2270,實測值506.2271;
向2-(3-氯-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸甲酯(1當量,70 mg,0.144 mmol)於DMA (1 ml)中之溶液添加DIPEA (6當量,143 μl,0.87 mmol)、TBTU (2當量,93 mg,0.289 mmol)、HOBt NH
3(2當量,44 mg,0.289 mmol)。在室溫下將該反應混合物攪拌整夜。添加蒸餾水,及產物用AcOEt萃取3次。有機層用NaOH 0.5 M及鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(DCM/丙酮7/3)純化以提供標題化合物(具有固體,67 mg,Y=96%)。
1H NMR (500 MHz, DMSO-d
6) d ppm -0.21 - -0.18 (m, 9 H) 0.52 - 0.58 (m, 2 H) 2.95 - 3.02 (m, 2 H) 5.01 - 5.19 (m, 2 H) 6.67 (dd, J=3.43, 1.91 Hz, 1 H) 6.87 (br. s., 1 H) 7.08 (s, 1 H) 7.23 (d, J=4.88 Hz, 1 H) 7.30 (t, J=7.93 Hz, 1 H) 7.46 - 7.51 (m, 1 H) 7.54 (br. s., 1 H) 7.56 - 7.58 (m, 1 H) 7.62 - 7.68 (m, 1 H) 8.28 (d, J=5.03 Hz, 1 H) 11.82 (br. s., 1 H)。LCMS:m/z 485 [M+H]
+。針對C
24H
26ClFN
4O
2Si [M + H]
+之HRMS (ESI)計算值485.1571,實測值485.1555;
以類似方式操作,但採用合適之經取代之起始材料,獲得下列化合物:
2-(4-氯-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.23 - -0.16 (m, 9 H) 0.50 - 0.59 (m, 2 H) 2.94 - 3.04 (m, 2 H) 4.96 - 5.17 (m, 2 H) 6.65 (dd, J=3.43, 1.91 Hz, 1 H) 6.86 (br. s., 1 H) 7.06 (s, 1 H) 7.22 (d, J=4.88 Hz, 1 H) 7.38 (dd, J=8.24, 1.83 Hz, 1 H) 7.46 - 7.60 (m, 4 H) 8.27 (d, J=5.03 Hz, 1 H) 11.82 (br. s., 1 H)。LCMS:m/z 485 [M+H]
+。針對C
24H
26ClFN
4O
2Si [M + H]
+之HRMS (ESI)計算值485.1571,實測值485.1567;
2-(2-氯-4-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
LCMS:m/z 485 [M+H]
+。針對C
24H
26ClFN
4O
2Si [M + H]
+之HRMS (ESI)計算值485.1571,實測值485.1566;
2-(2,4-二氟苯基)-5-[1-(苯基磺醯基)-1H-吡咯并[2,3-b]吡啶-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
LCMS:m/z 469 [M+H]
+。針對C
24H
26F
2N
4O
2Si [M + H]
+之HRMS (ESI)計算值469.1866,實測值469.1861;
2-[2-氯-4-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.24 - -0.20 (m, 9 H) 0.45 - 0.55 (m, 0 H) 2.90 - 2.96 (m, 2 H) 4.87 - 5.20 (m, 2 H) 6.62 (dd, J=3.43, 1.91 Hz, 1 H) 6.87 (br. s., 1 H) 7.08 (s, 1 H) 7.20 (d, J=4.88 Hz, 1 H) 7.54 (br. s., 1 H) 7.57 - 7.60 (m, 1 H) 7.71 - 7.76 (m, 1 H) 7.77 - 7.82 (m, 1 H) 7.97 (d, J=0.92 Hz, 1 H) 8.28 (d, J=4.88 Hz, 1 H) 11.84 (s, 1 H)。LCMS:m/z 535 [M+H]
+。針對C
25H
26ClF
3N
4O
2Si [M + H]
+之HRMS (ESI)計算值535.1539,實測值535.1536;
2-(2,3-二氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
LCMS:m/z 469 [M+H]
+。針對C
24H
26F
2N
4O
2Si [M + H]
+之HRMS (ESI)計算值469.1866,實測值469.1862;
2-(2,3-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
LCMS:m/z 501 [M+H]
+。針對C
24H
26Cl
2N
4O
2Si [M + H]
+之HRMS (ESI)計算值501.1275,實測值501.1278;
2-[4-甲基-2-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.23 - -0.19 (m, 9 H) 0.46 - 0.57 (m, 2 H) 2.46 (s, 3 H) 2.83 - 3.02 (m, 2 H) 4.71 (d, J=10.83 Hz, 1 H) 5.09 (d, J=10.98 Hz, 1 H) 6.52 (dd, J=3.43, 1.91 Hz, 1 H) 6.73 (br. s., 1 H) 7.00 (s, 1 H) 7.16 (d, J=4.88 Hz, 1 H) 7.24 (br. s., 1 H) 7.38 (d, J=7.93 Hz, 1 H) 7.53 (d, J=7.93 Hz, 1 H) 7.55 - 7.57 (m, 1 H) 7.64 (s, 1 H) 8.26 (d, J=4.88 Hz, 1 H) 11.81 (br. s., 1 H)。LCMS:m/z 515 [M+H]
+。針對C
26H
29F
3N
4O
2Si [M + H]
+之HRMS (ESI)計算值515.2085,實測值515.2093;
2-(2-氯-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
LCMS:m/z 481 [M+H]
+。針對C
25H
29ClN
4O
2Si [M + H]
+之HRMS (ESI)計算值481.1821,實測值481.1825;
2-(2,3-二氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
LCMS:m/z 483 [M+H]
+。針對C
25H
28F
2N
4O
2Si [M + H]
+之HRMS (ESI)計算值483.2022,實測值483.2025;
2-[2-甲基-4-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.25 - -0.19 (m, 9 H) 0.46 - 0.54 (m, 2 H) 2.20 (s, 3 H) 2.82 - 2.98 (m, 2 H) 4.89 (d, J=10.83 Hz, 1 H) 5.01 (d, J=10.83 Hz, 1 H) 6.65 (dd, J=3.43, 1.91 Hz, 1 H) 6.83 (br. s., 1 H) 7.08 (s, 1 H) 7.21 (d, J=5.03 Hz, 1 H) 7.41 (br. s., 1 H) 7.51 (d, J=7.78 Hz, 1 H) 7.55 - 7.57 (m, 1 H) 7.60 (d, J=7.78 Hz, 1 H) 7.67 (s, 1 H) 8.27 (d, J=4.88 Hz, 1 H) 11.81 (br. s., 1 H)。LCMS:m/z 515 [M+H]
+。針對C
26H
29F
3N
4O
2Si [M + H]
+之HRMS (ESI)計算值515.2085,實測值515.2084;
2-(2-氟-3-甲氧基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.22 - -0.17 (m, 9 H) 0.54 (t, J=8.39 Hz, 2 H) 2.92 - 3.04 (m, 2 H) 3.87 (s, 3 H) 4.99 - 5.05 (m, 1 H) 5.12 - 5.17 (m, 1 H) 6.66 (dd, J=3.43, 1.91 Hz, 1 H) 6.81 (br. s., 1 H) 6.98 - 7.03 (m, 1 H) 7.04 (s, 1 H) 7.17 - 7.21 (m, 1 H) 7.21 - 7.27 (m, 1 H) 7.38 (br. s., 1 H) 7.53 - 7.57 (m, 1 H) 8.26 (d, J=4.88 Hz, 1 H) 11.80 (s, 1 H)。LCMS:m/z 481 [M+H]
+。針對C
25H
29FN
4O
3Si [M + H]
+之HRMS (ESI)計算值481.2066,實測值481.2061;
2-(2-氯-3-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.24 - -0.17 (m, 9 H) 0.48 - 0.56 (m, 2 H) 2.90 - 3.00 (m, 2 H) 4.96 (d, J=11.13 Hz, 1 H) 5.13 (d, J=11.13 Hz, 1 H) 6.62 (dd, J=3.43, 1.91 Hz, 1 H) 6.83 (br. s., 1 H) 7.07 (s, 1 H) 7.21 (d, J=4.88 Hz, 1 H) 7.35 (dd, J=7.47, 1.22 Hz, 1 H) 7.42 - 7.53 (m, 3 H) 7.55 - 7.59 (m, 1 H) 8.27 (d, J=5.03 Hz, 1 H) 11.82 (br. s., 1 H)。LCMS:m/z 485 [M+H]
+。針對C
24H
26ClFN
4O
2Si [M + H]
+之HRMS (ESI)計算值485.1571,實測值485.1562;
2-(2-氟-3-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.21 - -0.17 (m, 9 H) 0.55 (t, J=8.39 Hz, 2 H) 2.27 (s, 3 H) 2.95 - 3.04 (m, 2 H) 4.97 - 5.04 (m, 1 H) 5.12 - 5.17 (m, 1 H) 6.66 (dd, J=3.43, 1.91 Hz, 1 H) 6.79 (br. s., 1 H) 7.04 (s, 1 H) 7.14 - 7.18 (m, 1 H) 7.25 (d, J=5.03 Hz, 1 H) 7.28 - 7.32 (m, 1 H) 7.33 - 7.41 (m, 2 H) 7.55 - 7.57 (m, 1 H) 8.26 (d, J=5.03 Hz, 1 H) 11.80 (br. s., 1 H)。LCMS:m/z 465 [M+H]
+。針對C
25H
29FN
4O
2Si [M + H]
+之HRMS (ESI)計算值465.2117,實測值465.2108;
2-[2-甲基-3-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
LCMS:m/z 515 [M+H]
+。針對C
26H
29F
3N
4O
2Si [M + H]
+之HRMS (ESI)計算值515.2085,實測值515.2081;
2-[4-甲氧基-2-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
LCMS:m/z 531 [M+H]
+。針對C
26H
29F
3N
4O
3Si [M + H]
+之HRMS (ESI)計算值531.2034,實測值531.2029;
2-[2-氯-4-(二氟甲氧基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.22 - -0.19 (m, 9 H) 0.48 - 0.55 (m, 2 H) 2.91 - 3.00 (m, 2 H) 4.91 (d, J=10.98 Hz, 1 H) 5.14 (d, J=11.13 Hz, 1 H) 6.61 (dd, J=3.36, 1.98 Hz, 1 H) 6.81 (br. s., 1 H) 7.05 (s, 1 H) 7.16 - 7.28 (m, 3 H) 7.37 - 7.45 (m, 3 H) 7.52 - 7.59 (m, 3 H) 8.25 - 8.29 (m, 1 H) 11.82 (br. s., 1 H)。LCMS:m/z 533 [M+H]
+。針對C
25H
27ClF
2N
4O
3Si [M + H]
+之HRMS (ESI)計算值533.1582,實測值533.1585;
2-(3,4-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.17 -0.13 (m, 8 H) 0.61 - 0.68 (m, 1 H) 1.95 (s, 1 H) 2.78 (s, 1 H) 2.94 (s, 1 H) 3.05 - 3.12 (m, 1 H) 5.06 (s, 1 H) 6.71 (dd, J=3.36, 1.98 Hz, 1 H) 6.93 (br. s., 1 H) 7.02 (s, 1 H) 7.25 (d, J=5.03 Hz, 1 H) 7.46 - 7.50 (m, 1 H) 7.51 - 7.54 (m, 1 H) 7.56 - 7.58 (m, 1 H) 7.70 (d, J=8.24 Hz, 1 H) 7.76 (d, J=1.98 Hz, 1 H) 8.27 (d, J=5.03 Hz, 1 H) 11.82 (br. s., 1 H)。LCMS:m/z 501 [M+H]
+。針對C
24H
26Cl
2N
4O
2Si [M + H]
+之HRMS (ESI)計算值501.1275,實測值501.1282;
2-(3,4-二氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.18 - -0.13 (m, 8 H) 0.58 - 0.66 (m, 2 H) 3.03 - 3.11 (m, 2 H) 5.07 (s, 2 H) 6.69 (dd, J=3.43, 1.91 Hz, 1 H) 6.89 (br. s., 1 H) 7.00 (s, 1 H) 7.25 (d, J=4.88 Hz, 1 H) 7.31 - 7.38 (m, 1 H) 7.44 (br. s., 1 H) 7.48 - 7.60 (m, 3 H) 8.27 (d, J=4.88 Hz, 1 H) 11.81 (br. s., 1 H)。LCMS:m/z 469 [M+H]
+。針對C
24H
26F
2N
4O
2Si [M + H]
+之HRMS (ESI)計算值469.1866,實測值469.1864;
2-(3-乙氧基-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.22 - -0.18 (m, 8 H) 0.55 (t, J=8.39 Hz, 2 H) 1.34 - 1.40 (m, 3 H) 4.12 (五重峰,J=7.40 Hz, 2 H) 4.98 - 5.19 (m, 2 H) 6.66 (dd, J=3.36, 1.98 Hz, 1 H) 6.81 (br. s., 1 H) 6.96 - 7.02 (m, 1 H) 7.04 (s, 1 H) 7.13 - 7.29 (m, 3 H) 7.37 (br. s., 1 H) 7.53 - 7.59 (m, 1 H) 8.26 (d, J=5.03 Hz, 1 H) 11.80 (br. s., 1 H)。LCMS:m/z 495 [M+H]
+。針對C
26H
31FN
4O
3Si [M + H]
+之HRMS (ESI)計算值495.2222,實測值495.2216;
2-(4-甲基-3-硝基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.22 - -0.09 (m, 1 H) 0.57 - 0.73 (m, 1 H) 2.59 (s, 1 H) 3.06 - 3.14 (m, 1 H) 5.05 (s, 1 H) 6.72 (dd, J=3.36, 1.98 Hz, 1 H) 6.93 (br. s., 1 H) 7.05 (s, 1 H) 7.27 (d, J=5.03 Hz, 1 H) 7.52 - 7.60 (m, 1 H) 7.74 (dd, J=7.85, 1.75 Hz, 1 H) 8.15 (d, J=1.68 Hz, 1 H) 8.28 (d, J=5.03 Hz, 1 H) 11.82 (br. s., 1 H)。LCMS:m/z 492 [M+H]
+。針對C
25H
29N
5O
4Si [M + H]
+之HRMS (ESI)計算值492.2062,實測值492.2056;
2-(3-胺甲醯基-4-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.13 (s, 9 H) 0.63 - 0.75 (m, 2 H) 3.03 - 3.16 (m, 2 H) 5.00 - 5.07 (m, 2 H) 6.67 - 6.77 (m, 1 H) 6.85 - 6.93 (m, 1 H) 6.99 - 7.07 (m, 1 H) 7.27 - 7.33 (m, 1 H) 7.33 - 7.40 (m, 1 H) 7.41 - 7.48 (m, 1 H) 7.56 - 7.60 (m, 1 H) 7.61 - 7.66 (m, 1 H) 7.68 - 7.73 (m, 1 H) 7.74 - 7.79 (m, 1 H) 7.82 - 7.87 (m, 1 H) 8.26 - 8.31 (m, 1 H) 11.66 - 11.98 (m, 1 H)。LCMS:m/z 494 [M+H]
+。針對C
25H
28FN
5O
3Si [M + H]
+之HRMS (ESI)計算值494.2018,實測值494.2011;
2-(2-氟-4-甲基苯基)-N-[2-(嗎啉-4-基)乙基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
向2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-羧酸(1當量,90 mg,0.19 mmol)於DMA (1.5 ml)中之溶液添加DIPEA (3當量,131 μl,07.6 mmol)、TBTU (2當量,118.5 mg,0.38 mmol)、2-(嗎啉-1-基)乙胺(1.5當量,38 μl,0.28 mmol)。在室溫下將該反應混合物攪拌整夜。添加蒸餾水,及產物用AcOEt萃取3次。有機層用NaOH 0.5 M及鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(DCM/MeOH 9/1)純化以提供標題化合物(米色固體,92 mg,Y=84%)。
1H NMR (500 MHz, DMSO-d
6) d ppm -0.24 - -0.17 (m, 2 H) 0.54 (t, J=8.39 Hz, 1 H) 2.27 - 2.41 (m, 2 H) 2.90 - 3.04 (m, 1 H) 3.19 - 3.28 (m, 1 H) 3.52 (t, J=4.50 Hz, 1 H) 4.92 - 5.27 (m, 1 H) 6.64 (dd, J=3.43, 1.91 Hz, 1 H) 6.99 (s, 1 H) 7.07 - 7.15 (m, 1 H) 7.24 (d, J=4.88 Hz, 1 H) 7.38 (t, J=7.85 Hz, 1 H) 7.55 - 7.60 (m, 1 H) 7.65 (t, J=5.57 Hz, 1 H) 8.26 (d, J=5.03 Hz, 1 H) 11.81 (s, 1 H)。LCMS:m/z 578 [M+H]
+。針對C
31H
40FN
5O
3Si [M + H]
+之HRMS (ESI)計算值578.2957,實測值578.2952;
以類似方式操作,但採用合適之經取代之起始材料,獲得下列化合物:
N-[2-(二甲基胺基)乙基]-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.23 - -0.16 (m, 9 H) 0.54 (t, J=8.39 Hz, 1 H) 2.10 (s, 6 H) 2.27 (t, J=6.79 Hz, 2 H) 2.39 (s, 3 H) 2.90 - 3.04 (m, 2 H) 3.13 - 3.24 (m, 2 H) 4.94 - 5.23 (m, 2 H) 6.64 (dd, J=3.35, 1.98 Hz, 1 H) 7.00 (s, 1 H) 7.04 - 7.15 (m, 2 H) 7.24 (d, J=5.03 Hz, 1 H) 7.36 (t, J=7.85 Hz, 1 H) 7.57 (t, J=2.97 Hz, 1 H) 7.65 (t, J=5.49 Hz, 1 H) 8.26 (d, J=4.88 Hz, 1 H) 11.81 (br. s., 1 H)。LCMS:m/z 536 [M+H]
+。針對C
29H
38FN
5O
2Si [M + H]
+之HRMS (ESI)計算值536.2852,實測值536.2849;
2-(2-氟-4-甲基苯基)-N-[2-(吡咯啶-1-基)乙基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
LCMS:m/z 562 [M+H]
+。針對C
31H
40FN
5O
2Si [M + H]
+之HRMS (ESI)計算值562.3008,實測值562.3012;
第三丁基-[(1R,2S)-2-({[2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-基]羰基}胺基)環己基]胺基甲酸酯(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.21 (s, 9 H) 0.52 (t, J=8.39 Hz, 2 H) 1.16 - 1.67 (m, 15 H) 2.38 (s, 3 H) 2.92 - 3.01 (m, 2 H) 3.52 - 3.66 (m, 1 H) 3.89 (br. s., 1 H) 4.92 - 5.26 (m, 2 H) 6.47 - 6.64 (m, 2 H) 6.91 (br. s., 1 H) 7.11 (d, J=10.22 Hz, 3 H) 7.23 (d, J=4.88 Hz, 1 H) 7.35 - 7.48 (m, 1 H) 7.56 (t, J=2.97 Hz, 1 H) 8.27 (d, J=4.88 Hz, 1 H) 11.82 (br. s., 1 H)。LCMS:m/z 662 [M+H]
+。針對C
36H
48FN
5O
4Si [M + H]
+之HRMS (ESI)計算值662.3533,實測值662.3553;
2-(2-氟-4-甲基苯基)-N-(呋喃-2-基甲基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.25 - -0.16 (m, 9 H) 0.55 (t, J=8.31 Hz, 2 H) 2.37 - 2.41 (m, 3 H) 2.95 - 3.05 (m, 2H) 4.27 - 4.39 (m, 2 H) 4.95 - 5.26 (m, 2 H) 6.18 (dd, J=3.13, 0.69 Hz, 1 H) 6.37 (dd, J=3.20, 1.83 Hz, 1 H) 6.68 (dd, J=3.36, 1.98 Hz, 1 H) 7.04 - 7.14 (m, 3 H) 7.25 (d, J=5.03 Hz, 1 H) 7.36 (t, J=7.70 Hz, 1 H) 7.52 - 7.59 (m, 2 H) 8.26 (d, J=4.88 Hz, 1 H) 8.42 (t, J=5.87 Hz, 1 H) 11.81 (br. s., 1 H)。LCMS:m/z 545 [M+H]
+。針對C
30H
33FN
4O
3Si [M + H]
+之HRMS (ESI)計算值545.2379,實測值545.2383;
第三丁基-[2-({[2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-基]羰基}胺基)乙基]甲基胺基甲酸酯(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.24 - -0.18 (m, 9 H) 0.54 (t, J=8.39 Hz, 2 H) 1.27 - 1.41 (m, 9 H) 2.36 - 2.42 (m, 3 H) 2.77 (d, J=10.37 Hz, 2 H) 2.89 - 3.05 (m, 2 H) 3.14 - 3.29 (m, 2 H) 4.87 - 5.31 (m, 2 H) 6.64 (d, J=8.69 Hz, 1 H) 6.97 - 7.12 (m, 3 H) 7.24 (d, J=4.88 Hz, 1 H) 7.34 (br. s., 1 H) 7.57 (t, J=2.82 Hz, 1 H) 7.99 (br. s., 1 H) 8.26 (d, J=5.03 Hz, 1 H) 11.81 (br. s., 1 H)。LCMS:m/z 622 [M+H]
+。針對C
33H
44FN
5O
4Si [M + H]
+之HRMS (ESI)計算值622.322,實測值622.3234;
N-(2-氟乙基)-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.21 - -0.17 (m, 9 H) 0.55 (t, J=8.39 Hz, 2 H) 2.36 - 2.41 (m, 3 H) 2.95 - 3.05 (m, 2 H) 3.38 - 3.47 (m, 1 H) 4.39 (t, J=5.19 Hz, 1 H) 4.48 (t, J=5.19 Hz, 1 H) 4.89 - 5.28 (m, 2 H) 6.68 (dd, J=3.43, 1.91 Hz, 1 H) 7.05 - 7.13 (m, 3 H) 7.26 (d, J=4.88 Hz, 1 H) 7.36 (t, J=7.63 Hz, 1 H) 7.52 - 7.62 (m, 1 H) 8.16 (t, J=5.57 Hz, 1 H) 8.26 (d, J=5.03 Hz, 1 H) 11.81 (br. s., 1 H)。LCMS:m/z 511 [M+H]
+。針對C
27H
32F
2N
4O
2Si [M + H]
+之HRMS (ESI)計算值511.2336,實測值511.2336;
2-(2-氟-4-甲基苯基)-N-(1-甲基哌啶-4-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.28 - -0.14 (m, 9 H) 0.54 (t, J=8.39 Hz, 2 H) 1.53 (d, J=9.15 Hz, 2 H) 1.74 (br. s., 2 H) 2.15 - 2.35 (m, 2 H) 2.38 (s, 3H) 2.74 - 3.05 (m, 4 H) 3.65 (br. s., 1 H) 4.91 - 5.29 (m, 2 H) 6.65 (dd, J=3.36, 1.98 Hz, 1 H) 7.05 (s, 1 H) 7.07 - 7.12 (m, 2 H) 7.24 (d, J=4.88 Hz, 1 H) 7.37 (t, J=7.78 Hz, 1 H) 7.53 - 7.59 (m, 1 H) 7.63 (br. s., 1 H) 8.26 (d, J=4.88 Hz, 1 H) 11.81 (br. s., 1 H)。LCMS:m/z 562 [M+H]
+。針對C
31H
40FN
5O
2Si [M + H]
+之HRMS (ESI)計算值562.3008,實測值562.2991;
2-(二苯并[b,d]噻吩-4-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
LCMS:m/z 539 [M+H]
+。針對C
30H
30N
4O
2SSi [M + H]
+之HRMS (ESI)計算值539.1932,實測值539.1938;
2-(4-甲基萘-1-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.32 - -0.26 (m, 9 H) 0.26 - 0.36 (m, 2 H) 2.68 - 2.83 (m, 5 H) 4.73 - 5.08 (m, 2 H) 6.65 - 6.77 (m, 2 H) 6.86 - 6.99 (m, 1 H) 7.12 (s, 1 H) 7.28 (d, J=5.03 Hz, 1 H) 7.43 - 7.54 (m, 4 H) 7.55 - 7.61 (m, 2 H) 8.09 (d, J=8.39 Hz, 1 H) 8.26 (d, J=5.03 Hz, 1 H) 11.81 (br. s., 1 H)。LCMS:m/z 497 [M+H]
+。針對C
29H
32N
4O
2Si [M + H]
+之HRMS (ESI)計算值497.2368,實測值497.2369;
2-(3-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d6) d ppm -0.20 - -0.12 (m, 9 H) 0.57 - 0.67 (m, 2 H) 3.01 - 3.10 (m, 2 H) 5.06 (s, 2 H) 6.70 (dd, J=3.43, 1.91 Hz, 1 H) 6.88 (br. s., 1 H) 6.99 (s, 1 H) 7.22 - 7.30 (m, 2 H) 7.30 - 7.36 (m, 2 H) 7.39 (br. s., 1 H) 7.44 - 7.52 (m, 1 H) 7.52 - 7.60 (m, 1 H) 8.27 (d, J=4.88 Hz, 1 H) 11.80 (br. s., 1 H)。LCMS:m/z 451 [M+H]
+。針對C
24H
27FN
4O
2Si [M + H]
+之HRMS (ESI)計算值451.196,實測值451.1948;
5-(1H-吡咯并[2,3-b]吡啶-4-基)-2-[4-(三氟甲氧基)苯基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d6) d ppm -0.22 - -0.14 (m, 9 H) 0.52 - 0.67 (m, 2 H) 2.92 - 3.11 (m, 2 H) 5.05 (s, 2 H) 6.70 (dd, J=3.36, 1.98 Hz, 1 H) 6.82 - 6.91 (m, 1 H) 7.01 (s, 1 H) 7.26 (d, J=5.03 Hz, 1 H) 7.43 (m, 3 H) 7.53 - 7.58 (m, 1 H) 7.59 - 7.66 (m, 2 H) 8.27 (d, J=4.88 Hz, 1 H) 11.80 (br. s., 1 H)。LCMS:m/z 517 [M+H]
+。針對C
25H
27F
3N
4O
3Si [M + H]
+之HRMS (ESI)計算值517.1878,實測值517.1857;
2-(1-苯并噻吩-3-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.28 - -0.25 (m, 9 H) 0.39 - 0.49 (m, 2 H) 2.88 (dd, J=9.00, 7.78 Hz, 2 H) 4.97 (d, J=10.83 Hz, 1 H) 5.22 (d, J=10.83 Hz, 1 H) 6.70 (dd, J=3.43, 1.91 Hz, 1 H) 6.78 - 6.86 (m, 1 H) 7.10 (s, 1 H) 7.24 (br. s., 1 H) 7.29 (d, J=5.03 Hz, 1 H) 7.34 - 7.42 (m, 2 H) 7.43 - 7.47 (m, 1 H) 7.57 (t, J=1.00 Hz, 1 H) 7.93 (s, 1 H) 8.04 (m, J=7.09, 1.14 Hz, 1 H) 8.27 (d, J=5.03 Hz, 1 H) 11.81 (br. s., 1 H)。LCMS:m/z 489 [M+H]
+。針對C
26H
28N
4O
2SSi [M + H]
+之HRMS (ESI)計算值489.1775,實測值489.1761;
2-(2,3-二氫-1,4-苯并戴奧辛-6-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.17 - -0.12 (m, 9 H) 0.61 - 0.70 (m, 2 H) 3.03 - 3.13 (m, 2 H) 4.21 - 4.34 (m, 4 H) 5.04 (s, 2 H) 6.68 (dd, J=3.43, 1.91 Hz, 1 H) 6.84 (br. s., 1 H) 6.89 - 6.98 (m, 3 H) 7.01 (d, J=1.98 Hz, 1 H) 7.06 (br. s., 1 H) 7.27 (d, J=5.03 Hz, 1 H) 7.54 (t, J=1.00 Hz, 1 H) 8.25 (d, J=5.03 Hz, 1 H) 11.77 (br. s., 1 H)。LCMS:m/z 491 [M+H]
+。針對C
26H
30N
4O
4Si [M + H]
+之HRMS (ESI)計算值491.2109,實測值491.2094;
2-(4-氟-2-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.22 - -0.19 (m, 9 H) 0.54 (t, J=8.39 Hz, 2 H) 2.12 (s, 3 H) 2.86 - 3.01 (m, 2 H) 4.88 (d, J=10.83 Hz, 1 H) 5.01 (d, J=10.68 Hz, 1 H) 6.63 (dd, J=3.36, 1.98 Hz, 1 H) 6.79 (br. s., 1 H) 7.03 (s, 1 H) 7.09 (td, J=8.58, 2.82 Hz, 1 H) 7.12 - 7.19 (m, 2 H) 7.22 (d, J=5.03 Hz, 1 H) 7.32 (dd, J=8.39, 6.10 Hz, 1 H) 7.53 - 7.57 (m, 1 H) 8.25 (d, J=5.03 Hz, 1 H) 11.79 (br. s., 1 H)。LCMS:m/z 465 [M+H]
+。針對C
25H
29FN
4O
2Si [M + H]
+之HRMS (ESI)計算值465.2117,實測值465.2126;
2-(2-氟-4-甲基苯基)-4-碘-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.27 - -0.23 (m, 9 H) 0.36 (t, J=7.70 Hz, 2 H) 2.36 - 2.40 (m, 3 H) 2.74 - 2.89 (m, 2 H) 4.93 (br. s., 1 H) 6.04 - 6.40 (m, 1 H) 6.99 (d, J=4.88 Hz, 2 H) 7.07 - 7.21 (m, 3 H) 7.43 (br. s., 1 H) 7.54 - 7.61 (m, 1 H) 8.28 - 8.38 (m, 1 H) 11.87 (br. s., 1 H)。LCMS:m/z 591 [M+H]
+。針對C
25H
28FIN
4O
2Si [M + H]
+之HRMS (ESI)計算值591.1083,實測值591.1073;
2-(2-氟-4-甲基苯基)-4-溴-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.35 - -0.19 (m, 9 H) 0.37 (t, J=7.78 Hz, 2 H) 2.38 (s, 3 H) 2.76 - 2.92 (m, 2 H) 4.90 - 5.23 (m, 2 H) 6.32 (br. s., 1 H) 6.84 - 7.25 (m, 4 H) 7.43 (br. s., 1 H) 7.59 (t, J=2.97 Hz, 1 H) 8.33 (d, J=4.88 Hz, 1 H) 11.88 (br. s., 1 H)。LCMS:m/z 543 [M+H]
+。針對C
25H
28BrFN
4O
2Si [M + H]
+之HRMS (ESI)計算值543.1222,實測值543.1221;
4-乙烯基-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XIa)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.32 - -0.18 (m, 9 H) 0.38 (br. s., 2 H) 2.33 - 2.42 (m, 3 H) 2.72 - 2.91 (m, 2 H) 4.90 (d, J=12.81 Hz, 3 H) 5.28 (d, J=17.69 Hz, 1 H) 6.22 (br. s., 1 H) 6.44 (dd, J=17.77, 11.67 Hz, 1 H) 7.01 - 7.29 (m, 5 H) 7.44 (t, J=7.85 Hz, 1 H) 7.56 (br. s., 1 H) 8.26 - 8.39 (m, 1 H) 11.84 (br. s., 1 H)。LCMS:m/z 491 [M+H]
+。針對C
27H
31FN
4O
2Si [M + H]
+之HRMS (ESI)計算值491.2273,實測值491.2267;
2-(2-氟-4-甲基苯基)-4-(丙-1-烯-2-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XIa)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.23 (s, 9 H) 0.38 (t, J=8.31 Hz, 2 H) 1.76 (s, 3 H) 2.36 - 2.39 (m, 3 H) 2.71 - 2.89 (m, 2 H) 4.75 (d, J=1.68 Hz, 1 H) 4.86 (br. s., 3 H) 6.22 (br. s., 1 H) 6.75 (br. s., 1 H) 6.93 - 7.06 (m, 2 H) 7.07 - 7.17 (m, 2 H) 7.37 - 7.66 (m, 2 H) 8.25 (d, J=4.88 Hz, 1 H) 11.77 (br. s., 1 H)。LCMS:m/z 505 [M+H]
+。針對C
28H
33FN
4O
2Si [M + H]
+之HRMS (ESI)計算值505.243,實測值505.2415;
在60℃之溫度,1 ml/min之流動速率及60 bar之壓力下將2-(2-氟-4-甲基苯基)-4-(丙-1-烯-2-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(1當量,50 mg,0.1 mmol)於DCM/MeOH 1/1 (2 ml)中之溶液倒入H-Cube
®裝置內。使用之觸媒係包裝於CatCart
®內之Pd/C 10%。產物係自25 ml產物溶液分離並藉由HPLC分析。將溶劑蒸發且該粗產物藉由急驟層析術(DCM/MeOH 85/15)純化以提供標題化合物(白色固體,48 mg,Y=97%)。
1H NMR (500 MHz, DMSO-d
6) d ppm -0.23 (s, 9 H) 0.29 - 0.40 (m, 2 H) 1.12 - 1.22 (m, 6 H) 2.36 (s, 3 H) 2.75 (br. s., 2 H) 2.84 (五重峰,J=7.02 Hz, 1 H) 4.64 - 5.02 (m, 2 H) 6.19 (br. s., 1 H) 6.54 - 6.86 (m, 1 H) 6.92 (br. s., 1 H) 6.99 (d, J=4.88 Hz, 1 H) 7.07 - 7.16 (m, 2 H) 7.39 (br. s., 1 H) 7.51 - 7.57 (m, 1 H) 8.29 (d, J=4.73 Hz, 1 H) 11.81 (br. s., 1 H)。LCMS:m/z 507[M+H]
+。針對C
28H
35FN
4O
2Si [M + H]
+之HRMS (ESI)計算值507.2586,實測值507.2566;
以類似方式操作,但採用合適之經取代之起始材料,獲得下列化合物:
4-乙基-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XI)
1H NMR (500 MHz, DMSO-d
6) d ppm -0.24 (s, 9 H) 0.37 (br. s., 2 H) 0.92 (t, J=7.40 Hz, 3 H) 2.37 (s, 4 H) 2.70 - 2.91 (m, 2 H) 4.87 (br. s., 2 H) 6.25 (br. s., 1 H) 6.64 (br. s., 1 H) 6.92 (br. s., 1 H) 7.03 (d, J=4.12 Hz, 1 H) 7.08 - 7.19 (m, 2 H) 7.43 (t, J=7.85 Hz, 1 H) 7.53 (t, J=2.90 Hz, 1 H) 8.29 (d, J=4.88 Hz, 1 H) 11.80 (br. s., 1 H)。LCMS:m/z 493 [M+H]
+。針對C
27H
33FN
4O
2Si [M + H]
+之HRMS (ESI)計算值493.243,實測值493.2415;
步驟 72-(3-氯-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1= 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 3-氯-2-氟苯基,R3 = R4 = R5 = H]化合物1
向2-(3-氯-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(1當量,60 mg,0.12 mmol)於DCM (2.6 ml)中之溶液添加TFA (75當量,9.3 mmol,711 μl)。在室溫下將該反應混合物攪拌5小時。在減壓下移除溶劑且粗產物用甲苯處理三次。在相同反應器中,將2-(3-氯-2-氟苯基)-1-(羥基甲基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺溶解於EtOH 95% (0.6 ml)中並添加氫氧化銨溶液30至32% (0.3 ml)。在室溫下將該反應混合物攪拌2小時,觀測到形成沈澱。將該固體過濾並用蒸餾水清洗三次(以移除CF
3COO
-NH
4 +)及用DCM/Et
2O 1/1清洗三次以達成標題化合物(淺黃色固體,36 mg,Y=82%)。
1H NMR (500 MHz, DMSO-d
6) d ppm 1H NMR (500 MHz, DMSO-d6) d ppm 6.84 (br. s., 1 H) 7.01 (dd, J=3.5, 2.0 Hz, 1 H) 7.28 (t, J=7.9 Hz, 1 H) 7.39 (d, J=5.2 Hz, 1 H) 7.43 (d, J=2.7 Hz, 1 H) 7.50 - 7.53 (m, 1 H) 7.55 - 7.57 (m, 1 H) 7.58 - 7.62 (m, 1 H) 7.63 (br. s., 1 H) 8.20 (d, J=5.0 Hz, 1 H) 11.71 (br. s., 1 H) 12.03 (d, J=1.8 Hz, 1 H)。LCMS:m/z 355 [M+H]
+。針對C
18H
12ClFN
4O [M + H]
+之HRMS (ESI)計算值355.0757,實測值355.0758;
以類似方式操作,但採用合適之經取代之起始材料,獲得下列化合物:
2-(4-氯-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 4-氯-2-氟苯基,R3 = R4 = R5 = H]化合物2
1H NMR (500 MHz, DMSO-d
6) d ppm 6.83 (br. s., 1 H) 7.00 (dd, J=3.5, 1.8 Hz, 1 H) 7.35 (dd, J=8.2, 2.0 Hz, 1 H) 7.38 (d, J=5.2 Hz, 1 H) 7.42 (d, J=2.6 Hz, 1 H) 7.46 - 7.51 (m, 1 H) 7.52 - 7.56 (m, 1 H) 7.57 - 7.59 (m, 1 H) 7.60 (br. s., 1 H) 8.20 (d, J=5.0 Hz, 1 H) 11.71 (br. s., 1 H) 11.98 (d, J=2.0 Hz, 1 H)。LCMS:m/z 355 [M+H]
+。針對C
18H
12ClFN
4O [M + H]
+之HRMS (ESI)計算值355.0757,實測值355.0757;
2-(2-氯-4-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氯-4-氟苯基,R3 = R4 = R5 = H]化合物3
1H NMR (500 MHz, DMSO-d
6) d ppm 6.76 (br. s., 1 H) 7.02 (dd, J=3.4, 1.9 Hz, 1 H) 7.28 (td, J=8.5, 2.7 Hz, 1 H) 7.37 (d, J=5.2 Hz, 1 H) 7.44 (d, J=2.7 Hz, 1 H) 7.49 - 7.57 (m, 4 H) 8.17 (d, J=5.0 Hz, 1 H) 11.69 (br. s., 1 H) 11.96 (d, J=2.1 Hz, 1 H)。LCMS:m/z 355 [M+H]
+。針對C
18H
12ClFN
4O [M + H]
+之HRMS (ESI)計算值355.0757,實測值355.0756;
2-(2,4-二氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2,4-二氟苯基,R3 = R4 = R5 = H]化合物4
1H NMR (500 MHz, DMSO-d
6) d ppm 6.80 (br. s., 1 H) 7.01 (dd, J=3.6, 1.9 Hz, 1 H) 7.15 (td, J=8.5, 2.3 Hz, 1 H) 7.30 (td, J=9.8, 2.6 Hz, 1 H) 7.39 (d, J=5.2 Hz, 1 H) 7.42 (d, J=2.7 Hz, 1 H) 7.53 - 7.56 (m, 1 H) 7.56 - 7.62 (m, 2 H) 8.19 (d, J=5.0 Hz, 1 H) 11.70 (br. s., 1 H) 11.96 (d, J=1.8 Hz, 1 H)。LCMS:m/z 339 [M+H]
+。針對C
18H
12F
2N
4O [M + H]
+之HRMS (ESI)計算值339.1052,實測值339.1048;
2-[2-氯-4-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氯-4-(三氟甲基)苯基,R3 = R4 = R5 = H]化合物5
1H NMR (500 MHz, DMSO-d
6) d ppm 6.80 (br. s., 1 H) 7.03 (dd, J=3.4, 1.8 Hz, 1 H) 7.36 (d, J=5.1 Hz, 1 H) 7.48 (d, J=2.4 Hz, 1 H) 7.54 - 7.57 (m, 1 H) 7.61 (br. s., 1 H) 7.70 - 7.79 (m, 2 H) 7.94 (s, 1 H) 8.19 (d, J=5.0 Hz, 1 H) 11.69 (br. s., 1 H) 12.04 (br. s., 1 H)。LCMS:m/z 405 [M+H]
+。針對C
19H
12ClF
3N
4O [M + H]
+之HRMS (ESI)計算值405.0725,實測值405.0724;
2-(2,3-二氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2,3-二氟苯基,R3 = R4 = R5 = H]化合物6
1H NMR (500 MHz, DMSO-d
6) d ppm 6.81 (br. s., 1 H) 7.01 (dd, J=3.5, 1.8 Hz, 1 H) 7.21 - 7.30 (m, 1 H) 7.33 - 7.49 (m, 4 H) 7.55 (t, J=3.1 Hz, 1 H) 7.60 (br. s., 1 H) 8.20 (d, J=5.0 Hz, 1 H) 11.69 (br. s., 1 H) 12.01 (br. s., 1 H)。LCMS:m/z 339 [M+H]
+。針對C
18H
12F
2N
4O [M + H]
+之HRMS (ESI)計算值339.1052,實測值339.1046;
2-(2,3-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2,3-二氯苯基,R3 = R4 = R5 = H]化合物7
1H NMR (500 MHz, DMSO-d
6) d ppm 6.78 (br. s., 1 H) 7.02 (dd, J=3.5, 2.0 Hz, 1 H) 7.36 (d, J=5.2 Hz, 1 H) 7.39 - 7.43 (m, 1 H) 7.44 - 7.47 (m, 2 H) 7.54 - 7.56 (m, 1 H) 7.57 (br. s., 1 H) 7.68 (dd, J=7.9, 1.8 Hz, 1 H) 8.18 (d, J=5.2 Hz, 1 H) 11.70 (br. s., 1 H) 12.01 (d, J=1.8 Hz, 1 H)。LCMS:m/z 371 [M+H]
+。針對C
18H
12Cl
2N
4O [M + H]
+之HRMS (ESI)計算值371.0461,實測值371.0463;
2-[4-甲基-2-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 4-甲基-2-(三氟甲基)苯基,R3 = R4 = R5 = H]化合物8
1H NMR (500 MHz, DMSO-d
6) d ppm 2.46 (s, 3 H) 6.66 (br. s., 1 H) 7.01 (dd, J=3.51, 1.83 Hz, 1 H) 7.33 (d, J=5.19 Hz, 1 H) 7.39 (d, J=7.78 Hz, 2 H) 7.42 (d, J=2.75 Hz, 1 H) 7.48 - 7.51 (m, 1 H) 7.53 - 7.54 (m, 1 H) 7.62 (s, 1 H) 8.15 (d, J=5.19 Hz, 1 H) 11.67 (br. s., 1 H) 11.91 (d, J=1.98 Hz, 1 H)。LCMS:m/z 385 [M+H]
+。針對C
20H
15F
3N
4O [M + H]
+之HRMS (ESI)計算值385.1271,實測值385.1270;
2-(2-氯-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氯-4-甲基苯基,R3 = R4 = R5 = H]化合物9
1H NMR (500 MHz, DMSO-d6) d ppm 2.35 - 2.40 (m, 3 H) 6.68 - 6.78 (m, 1 H) 7.01 (dd, J=3.5, 1.8 Hz, 1 H) 7.20 (dd, J=7.9, 0.8 Hz, 1 H) 7.33 - 7.38 (m, 3 H) 7.39 - 7.43 (m, 2 H) 7.52 - 7.55 (m, 1 H) 8.16 (d, J=5.2 Hz, 1 H) 11.67 (br. s., 1 H) 11.88 (d, J=1.8 Hz, 1 H)。LCMS:m/z 351 [M+H]
+。針對C
19H
15ClN
4O [M + H]
+之HRMS (ESI)計算值351.1007,實測值351.1008;
2-(2,3-二氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2,3-二氟-4-甲基苯基,R3 = R4 = R5 = H]化合物10
1H NMR (500 MHz, DMSO-d6) d ppm 2.32 - 2.36 (m, 3 H) 6.82 (br. s., 1 H) 7.00 (dd, J=3.4, 1.9 Hz, 1 H) 7.12 - 7.16 (m, 1 H) 7.22 - 7.26 (m, 1 H) 7.39 (d, J=5.2 Hz, 1 H) 7.41 (d, J=2.6 Hz, 1 H) 7.53 - 7.56 (m, 1 H) 7.59 (br. s., 1 H) 8.20 (d, J=5.2 Hz, 1 H) 11.70 (br. s., 1 H) 11.97 (br. s., 1 H)。LCMS:m/z 353 [M+H]
+。針對C
19H
14F
2N
4O [M + H]
+之HRMS (ESI)計算值353.1209,實測值353.121;
2-[2-甲基-4-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-甲基-4-(三氟甲基)苯基,R3 = R4 = R5 = H]化合物11
1H NMR (500 MHz, DMSO-d6) d ppm 2.28 (s, 3 H) 6.80 (br. s., 1 H) 7.03 (dd, J=3.5, 2.0 Hz, 1 H) 7.38 (d, J=5.2 Hz, 1 H) 7.47 - 7.49 (m, 1 H) 7.50 - 7.53 (m, 1 H) 7.53 - 7.60 (m, 3 H) 7.66 (s, 1 H) 8.17 (d, J=5.2 Hz, 1 H) 11.68 (br. s., 1 H) 11.90 (d, J=2.1 Hz, 1 H)。LCMS:m/z 385 [M+H]
+。針對C
20H
15F
3N
4O [M + H]
+之HRMS (ESI)計算值385.1271,實測值385.127;
2-(2-氟-3-甲氧基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氟-3-甲氧基苯基,R3 = R4 = R5 = H]化合物12
1H NMR (500 MHz, DMSO-d6) d ppm 3.87 (s, 3 H) 6.77 (br. s., 1 H) 7.00 (dd, J=3.5, 1.8 Hz, 1 H) 7.03 - 7.08 (m, 1 H) 7.13 - 7.21 (m, 2 H) 7.37 - 7.41 (m, 2 H) 7.51 (br. s., 1 H) 7.53 - 7.55 (m, 1 H) 8.18 (d, J=5.0 Hz, 1 H) 11.68 (br. s., 1 H) 11.93 (d, J=2.0 Hz, 1 H)。LCMS:m/z 351 [M+H]
+。針對C
19H
15FN
4O
2[M + H]
+之HRMS (ESI)計算值351.1252,實測值351.1252;
2-(2-氯-3-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氯-3-氟苯基,R3 = R4 = R5 = H]化合物13
1H NMR (500 MHz, DMSO-d6) d ppm 6.79 (br. s., 1 H) 7.03 (dd, J=3.4, 1.9 Hz, 1 H) 7.32 - 7.36 (m, 1 H) 7.38 (d, J=5.2 Hz, 1 H) 7.41 - 7.48 (m, 3 H) 7.53 - 7.62 (m, 2 H) 8.18 (d, J=5.2 Hz, 1 H) 11.72 (br. s., 1 H) 12.02 (br. s., 1 H)。LCMS:m/z 355 [M+H]
+。針對C
18H
12ClFN
4O [M + H]
+之HRMS (ESI)計算值355.0757,實測值355.0755;
2-(2-氟-3-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氟-3-甲基苯基,R3 = R4 = R5 = H]化合物14
1H NMR (500 MHz, DMSO-d6) d ppm 2.28 (d, J=0.9 Hz, 3 H) 6.76 (br. s., 1 H) 7.00 (dd, J=3.4, 1.9 Hz, 1 H) 7.11 - 7.16 (m, 1 H) 7.32 (dt, J=19.9, 7.2 Hz, 2 H) 7.38 - 7.42 (m, 2 H) 7.50 (br. s., 0 H) 7.53 - 7.56 (m, 1 H) 8.18 (d, J=5.0 Hz, 1 H) 11.68 (br. s., 1 H) 11.90 (br. s., 1 H)。LCMS:m/z 335 [M+H]
+。針對C
19H
15FN
4O [M + H]
+之HRMS (ESI)計算值335.1303,實測值335.1299;
2-[2-甲基-3-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-甲基-3-(三氟甲基)苯基,R3 = R4 = R5 = H]化合物15
1H NMR (500 MHz, DMSO-d6) ppm 2.27 (s, 3 H) 6.90 (br. s., 1 H) 7.33 (br. s., 1 H) 7.44 - 7.50 (m, 1 H) 7.61 (d, J=7.47 Hz, 1 H) 7.69 (d, J=5.80 Hz, 2 H) 7.74 - 7.86 (m, 3 H) 8.37 (d, J=6.10 Hz, 1 H) 12.34 (br. s., 1 H) 12.56 (br. s., 1 H)。LCMS:m/z 385 [M+H]
+。針對C
20H
15F
3N
4O [M + H]
+之HRMS (ESI)計算值385.1271,實測值385.1276;
2-[4-甲氧基-2-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 4-甲氧基-2-(三氟甲基)苯基,R3 = R4 = R5 = H]化合物16
1H NMR (500 MHz, DMSO-d6) d ppm 3.89 (s, 3 H) 6.65 (br. s., 1 H) 7.01 (dd, J=3.43, 1.91 Hz, 1 H) 7.24 - 7.30 (m, 2 H) 7.33 (d, J=5.03 Hz, 2 H) 7.40 - 7.45 (m, 2 H) 7.52 - 7.55 (m, 1 H) 8.15 (d, J=5.03 Hz, 1 H) 11.66 (br. s., 1 H) 11.89 (d, J=2.29 Hz, 1 H)。LCMS:m/z 401 [M+H]
+。針對C
20H
15F
3N
4O
2[M + H]
+之HRMS (ESI)計算值401.122,實測值401.1208;
2-[2-氯-4-(二氟甲氧基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氯-4-(二氟甲氧基)苯基,R3 = R4 = R5 = H]化合物17
1H NMR (500 MHz, DMSO-d6) d ppm 3.89 (s, 3 H) 6.65 (br. s., 1 H) 7.01 (dd, J=3.43, 1.91 Hz, 1 H) 7.24 - 7.30 (m, 2 H) 7.33 (d, J=5.03 Hz, 2 H) 7.40 - 7.45 (m, 2 H) 7.52 - 7.55 (m, 3 H) 8.15 (d, J=5.03 Hz, 1 H) 11.66 (br. s., 1 H) 11.89 (d, J=2.29 Hz, 1 H)。LCMS:m/z 403 [M+H]
+。針對C
19H
13ClF
2N
4O
2[M + H]
+之HRMS (ESI)計算值403.07679,實測值403.0769;
2-(3,4-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 3,4-二氯苯基,R3 = R4 = R5 = H]化合物18
1H NMR (500 MHz, DMSO-d6) d ppm 6.92 - 7.04 (m, 2 H) 7.36 (d, J=2.59 Hz, 1 H) 7.47 (d, J=5.03 Hz, 1 H) 7.52 - 7.57 (m, 1 H) 7.64 - 7.75 (m, 3 H) 8.00 (d, J=1.98 Hz, 1 H) 8.22 (d, J=5.03 Hz, 1 H) 11.71 (br. s., 1 H) 11.88 (d, J=1.83 Hz, 1 H)。LCMS:m/z 371 [M+H]
+。針對C
18H
12Cl
2N
4O [M + H]
+之HRMS (ESI)計算值371.0461,實測值371.0458;
2-(3,4-二氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 3,4-二氟苯基,R3 = R4 = R5 = H]化合物19
1H NMR (500 MHz, DMSO-d6) d ppm 6.88 - 7.03 (m, 2 H) 7.35 (d, J=2.59 Hz, 1 H) 7.43 - 7.61 (m, 4 H) 7.66 (br. s., 1 H) 7.83 (ddd, J=12.32, 8.12, 1.98 Hz, 1 H) 8.21 (d, J=5.03 Hz, 1 H) 11.46 - 11.96 (m, 2 H)。LCMS:m/z 339 [M+H]
+。針對C
18H
12F
2N
4O [M + H]
+之HRMS (ESI)計算值339.1052,實測值339.1049;
2-(3-乙氧基-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 3-乙氧基-2-氟苯基,R3 = R4 = R5 = H]化合物20
1H NMR (500 MHz, DMSO-d6) d ppm 1.38 (t, J=7.02 Hz, 3 H) 4.13 (q, J=7.02 Hz, 2 H) 6.77 (br. s., 1 H) 7.00 (dd, J=3.51, 1.98 Hz, 1 H) 7.03 - 7.09 (m, 1 H) 7.11 - 7.20 (m, 2 H) 7.36 - 7.44 (m, 2 H) 7.46 - 7.58 (m, 2 H) 8.18 (d, J=5.03 Hz, 1 H) 11.36 - 12.12 (m, 2 H)。LCMS:m/z 365 [M+H]
+。針對C
20H
17FN
4O
2[M + H]
+之HRMS (ESI)計算值365.1409,實測值365.141;
2-(4-甲基-3-硝基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 4-甲基-3-硝基苯基,R3 = R4 = R5 = H]化合物21
1H NMR (500 MHz, DMSO-d6) d ppm 2.57 (s, 3 H) 6.96 (br. s., 1 H) 7.00 (br. s., 1 H) 7.39 (d, J=2.59 Hz, 1 H) 7.47 (d, J=5.19 Hz, 1 H) 7.50 - 7.57 (m, 2 H) 7.72 (br. s., 1 H) 7.97 (dd, J=7.85, 1.75 Hz, 1 H) 8.22 (d, J=5.19 Hz, 1 H) 8.37 (d, J=1.83 Hz, 1 H) 11.43 - 12.13 (m, 2 H)。LCMS:m/z 362 [M+H]
+。針對C
19H
15N
5O
3[M + H]
+之HRMS (ESI)計算值362.1248,實測值362.1241;
2-(3-胺甲醯基-4-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 3-胺甲醯基-4-氟苯基,R3 = R4 = R5 = H]化合物22
1H NMR (500 MHz, DMSO-d6) d ppm 6.87 (br. s., 1 H) 7.01 (dd, J=3.36, 1.83 Hz, 1 H) 7.31 (dd, J=10.37, 8.69 Hz, 1 H) 7.37 (d, J=2.44 Hz, 1 H) 7.41 - 7.51 (m, 1 H) 7.52 - 7.57 (m, 1 H) 7.59 - 7.78 (m, 1 H) 7.85 (ddd, J=8.46, 4.88, 2.36 Hz, 1 H) 7.96 (dd, J=7.02, 2.29 Hz, 1 H) 8.21 (d, J=5.19 Hz, 1 H) 11.71 (br. s., 1 H) 11.84 (br. s., 1 H)。LCMS:m/z 364 [M+H]
+。針對C
19H
14FN
5O
2[M + H]
+之HRMS (ESI)計算值364.1205,實測值364.1204;
2-(2-氟-4-甲基苯基)-N-[2-(吡咯啶-1-基)乙基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氟-4-甲基苯基,R3 = N-2-(吡咯啶-1-基)乙基,R4 = R5 = H]化合物23
將化合物分離為TFA鹽。
1H NMR (500 MHz, DMSO-d6) d ppm 1.78 - 1.91 (m, 2 H) 1.93 - 2.06 (m, 2 H) 2.37 - 2.40 (m, 3H) 2.97 - 3.10 (m, 2 H) 3.23 - 3.31 (m, 2 H) 3.47 - 3.55 (m, 1 H) 3.56 - 3.65 (m, 2 H) 6.94 - 6.98 (m, 1 H) 7.04 - 7.11 (m, 2 H) 7.38 - 7.47 (m, 3 H) 7.57 - 7.60 (m, 1 H) 8.17 - 8.23 (m, 1 H) 8.24 - 8.31 (m, 1 H) 9.25 - 9.63 (m, 1 H) 11.67 - 11.83 (m, 1 H) 11.99 - 12.09 (m, 1 H)。LCMS:m/z 432 [M+H]
+。針對C
25H
26FN
5O [M + H]
+之HRMS (ESI)計算值432.2194,實測值432.2197;
N-[2-(二甲基胺基)乙基]-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氟-4-甲基苯基,R3 = N-2-(二甲基胺基)乙基,R4 = R5 = H]化合物24
將化合物分離為TFA鹽。
1H NMR (500 MHz, DMSO-d6) d ppm 2.37 - 2.41 (m, 3 H) 2.78 - 2.88 (m, 6 H) 3.17 - 3.24 (m, 2 H) 3.46 - 3.56 (m, 2 H) 6.92 - 6.98 (m, 1 H) 7.05 - 7.13 (m, 2 H) 7.38 - 7.46 (m, 3 H) 7.55 - 7.61 (m, 1 H) 8.13 - 8.24 (m, 1 H) 8.25 - 8.32 (m, 1 H) 11.59 - 11.85 (m, 1 H) 11.95 - 12.12 (m, 1 H)。LCMS:m/z 406 [M+H]
+。針對C
23H
24FN
5O [M + H]
+之HRMS (ESI)計算值406.2038,實測值406.2036;
2-(2-氟-4-甲基苯基)-N-[2-(嗎啉-4-基)乙基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氟-4-甲基苯基,R3 = N-2-(嗎啉-4-基)乙基,R4 = R5 = H]化合物25
1H NMR (500 MHz, DMSO-d6) d ppm 2.37 - 2.39 (m, 3 H) 2.9 - 4.02 (m, 12 H) 6.95 (dd, J=3.43, 1.91 Hz, 1 H) 7.04 - 7.12 (m, 2 H) 7.32 - 7.47 (m, 2 H) 7.57 (t, J=2.82 Hz, 1 H) 8.20 (d, J=5.03 Hz, 1 H) 11.47 - 12.21 (m, 2 H)。LCMS:m/z 448 [M+H]
+。針對C
25H
26FN
5O
2[M + H]
+之HRMS (ESI)計算值448.2144,實測值448.2132;
N-[(1S,2R)-2-胺基環己基]-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氟-4-甲基苯基,R3 = N-(1S,2R)-2-胺基環己基,R4 = R5 = H]化合物26
將化合物分離為TFA鹽。
1H NMR (500 MHz, DMSO-d6) d ppm 1.30 - 1.45 (m, 2 H) 1.48 - 1.78 (m, 6 H) 2.38 (s, 3 H) 4.23 (br. s., 1 H) 6.98 (dd, J=3.43, 1.91 Hz, 1 H) 7.06 - 7.15 (m, 2 H) 7.40 (d, J=5.19 Hz, 1 H) 7.42 - 7.49 (m, 3 H) 7.55 - 7.62 (m, 1 H) 7.71 (br. s., 2 H) 8.21 (d, J=5.19 Hz, 1 H) 11.74 (br. s., 1 H) 11.98 (d, J=2.14 Hz, 1 H)。LCMS:m/z 432 [M+H]
+。針對C
25H
26FN
5O [M + H]
+之HRMS (ESI)計算值432.2194,實測值432.2189;
2-(2-氟-4-甲基苯基)-N-(呋喃-2-基甲基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氟-4-甲基苯基,R3 = N-(呋喃-2-基甲基),R4 = R5 = H]化合物27
1H NMR (500 MHz, DMSO-d6) d ppm 2.38 (s, 1 H) 4.38 (d, J=5.80 Hz, 1 H) 6.20 - 6.25 (m, 1 H) 6.39 (dd, J=3.13, 1.91 Hz, 1 H) 7.03 - 7.11 (m, 1 H) 7.37 - 7.47 (m, 1 H) 7.55 - 7.60 (m, 1 H) 8.22 (d, J=5.34 Hz, 1 H) 8.50 (t, J=5.87 Hz, 1 H) 11.64 - 12.14 (m, 1 H)。LCMS:m/z 415 [M+H]
+。針對C
24H
19FN
4O
2[M + H]
+之HRMS (ESI)計算值415.1565,實測值415.1569;
N-(氟乙基)-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氟-4-甲基苯基,R3 = N-(氟乙基),R4 = R5 = H]化合物28
1H NMR (500 MHz, DMSO-d6) d ppm 2.36 - 2.40 (m, 3 H) 3.41 - 3.54 (m, 2 H) 4.38 - 4.58 (m, 2 H) 7.00 (dd, J=3.51, 1.83 Hz, 1 H) 7.04 - 7.10 (m, 2 H) 7.38 - 7.44 (m, 3 H) 7.54 - 7.56 (m, 1 H) 8.19 (d, J=5.19 Hz, 1 H) 8.24 (t, J=5.64 Hz, 1 H) 11.53 - 12.04 (m, 2 H)。LCMS:m/z 381 [M+H]
+。針對C
21H
18F
2N
4O [M + H]
+之HRMS (ESI)計算值381.1522,實測值381.1518;
2-(2-氟-4-甲基苯基)-N-[2-(甲基胺基)乙基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氟-4-甲基苯基,R3 = N-(2-(甲基胺基)乙基,R4 = R5 = H]化合物29
1H NMR (500 MHz, DMSO-d6) d ppm 2.37 - 2.40 (m, 3 H) 2.58 (s, 3 H) 3.04 (t, J=5.95 Hz, 2 H) 3.45 (q, J=6.00 Hz, 2 H) 6.96 (dd, J=3.43, 1.91 Hz, 1 H) 7.04 - 7.11 (m, 2 H) 7.37 - 7.46 (m, 3 H) 7.55 - 7.60 (m, 1 H) 8.20 (d, J=5.03 Hz, 1 H) 8.26 (t, J=5.64 Hz, 1 H) 8.33 (br. s., 1 H) 11.51 - 12.14 (m, 2 H)。LCMS:m/z 392 [M+H]
+。針對C
22H
22FN
5O [M + H]
+之HRMS (ESI)計算值392.1881,實測值392.1878;
2-(2-氟-4-甲基苯基)-N-(1-甲基哌啶-4-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氟-4-甲基苯基,R3 = N-(1-甲基哌啶-4-基),R4 = R5 = H]化合物30
1H NMR (500 MHz, DMSO-d6) d ppm 1.45 - 1.59 (m, 2 H) 1.72 (d, J=10.37 Hz, 2 H) 1.90 (t, J=11.21 Hz, 2 H) 2.15 (s, 3 H) 2.35 - 2.39 (m, 3 H) 2.74 (d, J=11.13 Hz, 2 H) 3.56 - 3.68 (m, 1 H) 7.00 (dd, J=3.51, 1.98 Hz, 1 H) 7.04 - 7.10 (m, 2 H) 7.31 - 7.43 (m, 3 H) 7.52 - 7.58 (m, 1 H) 7.70 (d, J=7.93 Hz, 1 H) 8.18 (d, J=5.03 Hz, 1 H) 11.53 - 12.01 (m, 2 H)。LCMS:m/z 432 [M+H]
+。針對C
25H
26FN
5O [M + H]
+之HRMS (ESI)計算值432.2194,實測值432.2186;
2-(二苯并[b,d]噻吩-4-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 =二苯并[b,d]噻吩-4-基,R3 = R4 = R5 = H]化合物31
1H NMR (500 MHz, DMSO-d6) d ppm 6.81 (br. s., 1 H) 7.07 (dd, J=3.51, 1.83 Hz, 1 H) 7.43 (d, J=5.19 Hz, 1 H) 7.46 - 7.55 (m, 3 H) 7.56 - 7.58 (m, 1 H) 7.59 - 7.64 (m, 1 H) 7.96 - 8.02 (m, 1 H) 8.19 (d, J=5.19 Hz, 1 H) 8.36 - 8.46 (m, 2 H) 11.71 (br. s., 1 H) 12.13 (d, J=1.83 Hz, 1 H)。LCMS:m/z 409 [M+H]
+。針對C
24H
16N
4OS [M + H]
+之HRMS (ESI)計算值409.1118,實測值409.1119;
2-(4-甲基萘-1-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 4-甲基萘-1-基,R3 = R4 = R5 = H]化合物32
1H NMR (500 MHz, DMSO-d6) d ppm 2.73 (s, 3 H) 6.68 (br. s., 1 H) 7.05 (dd, J=3.43, 1.91 Hz, 1 H) 7.23 (br. s., 1 H) 7.40 (d, J=5.19 Hz, 1 H) 7.43 - 7.48 (m, 3 H) 7.51 (d, J=2.75 Hz, 1 H) 7.54 - 7.61 (m, 2 H) 7.66 (d, J=8.24 Hz, 1 H) 8.09 (d, J=8.39 Hz, 1 H) 8.14 (d, J=5.03 Hz, 1 H) 11.68 (br. s., 1 H) 11.98 (br. s., 1 H)。LCMS:m/z 367 [M+H]
+。針對C
23H
18N
4O [M + H]
+之HRMS (ESI)計算值367.1554,實測值367.1545;
2-(3-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 3-氟苯基,R3 = R4 = R5 = H]化合物33
1H NMR (500 MHz, DMSO-d6) d ppm 6.92 (br. s., 1 H) 7.00 (dd, J=3.51, 1.83 Hz, 1 H) 7.14 - 7.23 (m, 1 H) 7.34 (d, J=2.59 Hz, 1 H) 7.41 - 7.50 (m, 1 H) 7.52 - 7.61 (m, 3 H) 7.62 - 7.66 (m, 1 H) 8.21 (d, J=5.19 Hz, 1 H) 11.70 (br. s., 1 H) 11.81 (br. s., 1 H)。LCMS:m/z 321 [M+H]
+。針對C
18H
13FN
4O [M + H]
+之HRMS (ESI)計算值321.1146,實測值321.1143;
5-(1H-吡咯并[2,3-b]吡啶-4-基)-2-[4-(三氟甲氧基)苯基]-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 4-(三氟甲氧基)苯基,R3 = R4 = R5 = H]化合物34
1H NMR (500 MHz, DMSO-d6) d ppm 6.89 (br. s., 1 H) 7.01 (dd, J=3.51, 1.83 Hz, 1 H) 7.37 (d, J=2.59 Hz, 1 H) 7.41 (d, J=8.24 Hz, 1 H) 7.46 (d, J=5.19 Hz, 1 H) 7.51 - 7.57 (m, 1 H) 7.64 (br. s., 1 H) 7.77 - 7.85 (m, 1 H) 8.20 (d, J=5.03 Hz, 1 H) 11.69 (br. s., 1 H) 11.83 (d, J=1.98 Hz, 1 H)。LCMS:m/z 387 [M+H]
+。針對C
19H
13F
3N
4O
2[M + H]
+之HRMS (ESI)計算值387.1064,實測值387.106;
2-(1-苯并噻吩-3-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 1-苯并噻吩-3-基,R3 = R4 = R5 = H]化合物35
1H NMR (500 MHz, DMSO-d6) d ppm 6.79 - 6.82 (m, 1 H) 7.03 - 7.05 (m, 1 H) 7.37 - 7.41 (m, 1 H) 7.43 - 7.45 (m, 1 H) 7.47 - 7.49 (m, 1 H) 7.54 - 7.57 (m, 1 H) 7.58 - 7.61 (m, 1 H) 7.90 - 7.92 (m, 1 H) 8.03 - 8.06 (m, 1 H) 8.16 - 8.20 (m, 1 H) 11.66 - 11.71 (m, 1 H) 11.97 - 12.02 (m, 1 H)。LCMS:m/z 359 [M+H]
+。針對C
20H
14N
4OS [M + H]
+之HRMS (ESI)計算值359.0961,實測值359.0962;
2-(2,3-二氫-1,4-苯并戴奧辛-6-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2,3-二氫-1,4-苯并戴奧辛-6-基,R3 = R4 = R5 = H]化合物36
1H NMR (500 MHz, DMSO-d6) d ppm 4.28 (s, 4 H) 6.81 (br. s., 1 H) 6.88 (d, J=8.39 Hz, 1 H) 6.97 (dd, J=3.51, 1.83 Hz, 1 H) 7.18 (dd, J=8.39, 2.14 Hz, 1 H) 7.24 (d, J=2.14 Hz, 1 H) 7.27 (d, J=2.74 Hz, 1 H) 7.46 (d, J=5.19 Hz, 1 H) 7.51 - 7.52 (m, 1 H) 8.18 (d, J=5.03 Hz, 1 H) 11.58 - 11.67 (m, 2 H)。LCMS:m/z 361 [M+H]
+。針對C
20H
16N
4O
3[M + H]
+之HRMS (ESI)計算值361.1295,實測值361.1295;
2-(4-氟-2-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 4-氟-2-甲基苯基,R3 = R4 = R5 = H]化合物37
1H NMR (500 MHz, DMSO-d6) d ppm 2.20 (s, 3 H) 6.73 (br. s., 1 H) 7.01 (dd, J=3.51, 1.98 Hz, 1 H) 7.06 (d, J=2.75 Hz, 1 H) 7.15 (dd, J=10.22, 2.75 Hz, 1 H) 7.33 (dd, J=8.46, 6.18 Hz, 1 H) 7.36 - 7.40 (m, 1 H) 7.43 (d, J=2.59 Hz, 1 H) 7.52 - 7.54 (m, 1 H) 8.15 (d, J=5.19 Hz, 1 H) 11.66 (br. s., 1 H) 11.81 (d, J=1.98 Hz, 1 H)。LCMS:m/z 335 [M+H]
+。針對C
19H
15FN
4O [M + H]
+之HRMS (ESI)計算值335.1303,實測值335.13;
2-(2-氟-4-甲基苯基)-4-碘-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(I) [R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氟-4-甲基苯基,R3 = R4 = H,R5 =碘]化合物38
1H NMR (500 MHz, DMSO-d6) d ppm 2.35 (s, 3 H) 6.54 (dd, J=3.43, 1.91 Hz, 1 H) 7.07 (d, J=7.78 Hz, 1 H) 7.11 (d, J=11.44 Hz, 1 H) 7.17 (br. s., 1 H) 7.23 (br. s., 1 H) 7.26 (d, J=5.03 Hz, 1 H) 7.42 (t, J=7.85 Hz, 1 H) 7.51 - 7.60 (m, 1 H) 8.29 (d, J=5.03 Hz, 1 H) 11.78 (br. s., 1 H) 11.99 (s, 1 H)。LCMS:m/z 461 [M+H]
+。針對C
19H
14FIN
4O [M + H]
+之HRMS (ESI)計算值461.0269,實測值461.0263;
2-(2-氟-4-甲基苯基)-4-溴-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2-氟-4-甲基苯基,R3 = R4 = H,R5 =溴]化合物39
1H NMR (500 MHz, DMSO-d6) d ppm 2.36 (s, 3 H) 6.58 (dd, J=3.43, 1.91 Hz, 1 H) 7.08 (d, J=7.78 Hz, 1 H) 7.12 (d, J=11.44 Hz, 1 H) 7.23 (br. s., 1 H) 7.25 (d, J=4.88 Hz, 1 H) 7.28 (br. s., 1 H) 7.44 (t, J=7.85 Hz, 1 H) 7.53 - 7.58 (m, 1 H) 8.28 (d, J=5.03 Hz, 1 H) 11.79 (br. s., 1 H) 12.00 (s, 1 H)。LCMS:m/z 413 [M+H]
+。針對C
19H
14FBrN
4O [M + H]
+之HRMS (ESI)計算值413.0408,實測值413.0407;
4-乙基-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 4-氟-2-甲基苯基,R3 = R4 = R5 =乙基]化合物40
1H NMR (500 MHz, DMSO-d
6) d ppm 1.05 (t, J=7.40 Hz, 3 H) 2.35 (s, 3 H) 2.71 (q, J=7.37 Hz, 2 H) 6.51 (dd, J=3.43, 1.91 Hz, 1 H) 6.95 (s, 2 H) 7.02 - 7.11 (m, 3 H) 7.44 (t, J=7.93 Hz, 1 H) 7.50 (t, J=1.00 Hz, 1 H) 8.24 (d, J=4.88 Hz, 1 H) 11.28 (s, 1 H) 11.70 (br. s., 1 H)。LCMS:m/z 363 [M+H]
+。針對C
21H
19FN
4O [M + H]
+之HRMS (ESI)計算值363.1616,實測值363.1601;
2-(2-氟-4-甲基苯基)-4-(丙-2-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 4-氟-2-甲基苯基,R3 = R4 = H,R5 =丙-2-基]化合物41
1H NMR (500 MHz, DMSO-d
6) d ppm 1.31 (d, J=7.02 Hz, 6 H) 2.34 (s, 3 H) 3.10 (spt, J=7.00 Hz, 1 H) 6.51 (dd, J=3.36, 1.98 Hz, 1 H) 6.89 - 7.14 (m, 5 H) 7.39 (t, J=7.93 Hz, 1 H) 7.51 (t, J=2.90 Hz, 1 H) 8.24 (d, J=4.88 Hz, 1 H) 11.18 (s, 1 H) 11.71 (br. s., 1 H)。LCMS:m/z 377 [M+H]
+。針對C
22H
21FN
4O [M + H]
+之HRMS (ESI)計算值377.1772,實測值377.1767;
在T = 0℃下向2-(2,4-二氯苯基)-1H-吡咯-3-甲腈(1當量,1.0 g,4.22 mmol)於無水THF (20 ml)中之溶液添加於礦物油中之NaH 60% (1.7當量,287 mg,7.17 mmol)。在T = 0℃下將該反應混合物攪拌20分鐘並添加SEMCl (1.8當量,1.35 ml,7.59 mmol)。10分鐘後在T = 0℃下在室溫下使該反應升溫並攪拌3小時。添加蒸餾水,且產物用DCM萃取。有機層用蒸餾水及鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(Hex/AcOEt 9/1)純化以提供標題化合物(淡黃色油,1.45 g,Y=94%)。
1H NMR (500 MHz, DMSO-d
6) d ppm -0.13 - -0.06 (m, 9 H) 0.65 - 0.75 (m, 2 H) 3.19 - 3.31 (m, 2 H) 5.01 - 5.07 (m, 1 H) 5.19 - 5.22 (m, 1 H) 6.64 - 6.69 (m, 1 H) 7.24 - 7.29 (m, 1 H) 7.54 - 7.57 (m, 1 H) 7.59 - 7.62 (m, 1 H) 7.87 - 7.90 (m, 1 H)。LCMS:m/z 367 [M+H]
+。針對C
17H
21Cl
2N
2OSi [M + H]
+之HRMS (ESI)計算值367.0795,實測值367.08;
以類似方式操作,但採用2-(2-氟-4-甲基苯基)-1H-吡咯-3-甲腈作為起始材料,獲得下列化合物:
2-(2-氟-4-甲基苯基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(XIII)
1H NMR (500 MHz, DMSO-d6) d ppm -0.15 - -0.07 (m, 9 H) 0.66 - 0.72 (m, 2 H) 2.40 (s, 3 H) 3.18 - 3.32 (m, 2 H) 5.17 (s, 2 H) 6.65 (d, J=3.20 Hz, 1 H) 7.17 - 7.21 (m, 1 H) 7.23 - 7.27 (m, 2 H) 7.40 (t, J=7.78 Hz, 1 H)。LCMS:m/z 331 [M+H]
+。針對C
18H
24FN
2OSi [M + H]
+之HRMS (ESI)計算值331.1637,實測值331.1628;
2-(2,4-二氯苯基)-1-(苯基磺醯基)-1H-吡咯-3-甲腈(XIII)
在T = 0℃下向2-(2,4-二氯苯基)-1H-吡咯-3-甲腈(1當量,1.0 g,4.22 mmol)於無水DMF (10 ml)中之溶液添加於礦物油中之NaH 60% (1.3當量,219 mg,5.49 mmol)。在T = 0℃下將該反應混合物攪拌20分鐘並添加苯磺醯氯(1.2當量,0.64 ml,5.06 mmol)。在T=0℃下將該反應攪拌2.5小時。在T=0℃下添加蒸餾水及產物用AcOEt萃取。有機層用蒸餾水及鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(Hex/AcOEt 9/1-Hex/AcOEt 8/2)純化以提供標題化合物(白色固體,1.32 g,Y=83%)。
1H NMR (500 MHz, DMSO-d6) d ppm 6.96 (d, J=3.51 Hz, 1 H) 7.37 (d, J=8.24 Hz, 1 H) 7.58 (dd, J=8.24, 2.14 Hz, 1 H) 7.60 - 7.66 (m, 4 H) 7.78 (d, J=2.13 Hz, 1 H) 7.81 (tt, J=5.85, 2.76 Hz, 1 H) 7.85 (d, J=3.51 Hz, 1 H)。LCMS:m/z 378 [M+H]
+。針對C
17H
11Cl
2N
2O
2S [M + H]
+之HRMS (ESI)計算值378.9732,實測值378.9744;
在T = 0℃下向2-(2,4-二氯苯基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(1當量,1.44 g,3.93 mmol)於MeOH (20 ml)及THF (10 ml)中之溶液添加0,5當量之N-溴琥珀醯亞胺(349.5 mg,1.96 mmol)。在T = 0℃下將該反應混合物攪拌30分鐘及然後添加0.5當量之N-溴琥珀醯亞胺(349.5 mg,1.96 mmol)。在T = 0℃下將該反應攪拌1小時及30分鐘。添加蒸餾水及產物用AcOEt萃取3次。有機層用鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(Hex/AcOEt 95/5)純化以提供標題化合物(透明-淺黃色油,1.44 g,Y=82%)。
1H NMR (500 MHz, DMSO-d6) d ppm -0.15 - -0.06 (m, 9 H) 0.69 (t, J=8.16 Hz, 2 H) 3.17 - 3.32 (m, 2 H) 5.06 (d, J=11.44 Hz, 1 H) 5.21 (d, J=11.44 Hz, 1 H) 6.96 (s, 1 H) 7.59 - 7.67 (m, 2 H) 7.92 (d, J=1.98 Hz, 1 H)。LCMS:m/z 444 [M+H]
+。針對C
17H
20BrCl
2N
2OSi [M + H]
+之HRMS (ESI)計算值444.99,實測值444.9915;
以類似方式操作,但採用2-(2-氟-4-甲基苯基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈作為起始材料,獲得下列化合物:
5-溴-2-(2-氟-4-甲基苯基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(XIV)
1H NMR (500 MHz, DMSO-d6) d ppm -0.13 - -0.09 (m, 9 H) 0.63 - 0.71 (m, 2 H) 2.41 (s, 3 H) 3.17 - 3.27 (m, 2 H) 5.18 (br. s., 2 H) 6.89 - 6.97 (m, 1 H) 7.16 - 7.23 (m, 1 H) 7.25 - 7.32 (m, 1 H) 7.39 - 7.45 (m, 1 H)。LCMS:m/z 409 [M+H]
+。針對C
18H
23BrFN
2OSi [M + H]
+之HRMS (ESI)計算值409.0742,實測值409.0743;
5-溴-2-(2,4-二氯苯基)-1-(苯基磺醯基)-1H-吡咯-3-甲腈(XIV)
LCMS:m/z 454 [M+H]
+。針對C
17H
10BrCl
2N
2O
2S [M + H]
+之HRMS (ESI)計算值454.9018,實測值454.9125;
在反應器中,在氬氣氛下,添加5-溴-2-(2,4-二氯苯基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(1當量,100 mg,0.22 mmol)、4-(4,4,5,5-四甲基-[1,3,2]二氧雜環戊硼烷-2-基)-1H-吡唑(1.5當量,99 mg,0.34 mmol)、Na
2CO
3(3當量,71 mg,0.67 mmol)、經脫氣之1,4-二噁烷(4 ml)及經脫氣之蒸餾水(1 ml)。在三次真空/氬週期後,觸媒[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II) (1:1) (0.1當量,18 mg,0.022 mmol)。在三個真空/氬週期後,在T = 100℃下將該反應混合物加熱2小時。添加蒸餾水及產物用AcOEt萃取(3次)。有機層用蒸餾水及鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(DCM/MeOH 98/2)純化以提供標題化合物(黃色固體,43 mg,Y=45%)。
1H NMR (401 MHz, DMSO-d6) d ppm -0.12 (s, 9 H) 0.65 (t, J=8.30 Hz, 2 H) 1.28 - 1.28 (m, 1 H) 3.10 - 3.21 (m, 2 H) 4.99 (d, J=11.35 Hz, 1 H) 5.21 (d, J=11.35 Hz, 1 H) 6.78 (s, 1 H) 7.59 - 7.63 (m, 1 H) 7.63 - 7.67 (m, 1 H) 7.78 (s, 1 H) 7.91 (d, J=1.71 Hz, 1 H) 8.02 (s, 1 H)。LCMS:m/z 433 [M+H]
+。針對C
20H
23Cl
2N
4OSi [M + H]
+之HRMS (ESI)計算值433.1013,實測值433.1014;
以類似方式操作,但採用合適之經取代之起始材料,獲得下列化合物:
2-(2,4-二氯苯基)-5-(3-甲基-1H-吡唑-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(XV)
1H NMR (500 MHz, DMSO-d6) d ppm -0.13 (s, 9 H) 0.61 (t, J=8.31 Hz, 2 H) 2.15 - 2.29 (m, 3 H) 3.07 (q, J=7.83 Hz, 2 H) 4.91 (d, J=11.29 Hz, 1 H) 5.09 (d, J=10.98 Hz, 1 H) 6.61 - 6.72 (m, 1 H) 7.57 - 7.68 (m, 3 H) 7.84 - 7.96 (m, 2 H) 12.72 - 12.97 (m, 1 H)。LCMS:m/z 447 [M+H]
+。針對C
21H
25Cl
2N
4OSi [M + H]
+之HRMS (ESI)計算值447.1169,實測值447.1173;
5-(2-胺基-1,3-噻唑-4-基)-2-(2,4-二氯苯基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(XV)
LCMS:m/z 465 [M+H]
+。針對C
20H
23Cl
2N
4OSSi [M + H]
+之HRMS (ESI)計算值465.0733,實測值465.0764;
2-(2,4-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(XV)
LCMS:m/z 483 [M+H]
+。針對C
24H
25Cl
2N
4OSi [M + H]
+之HRMS (ESI)計算值483.1169,實測值483.1185;
2-(2,4-二氯苯基)-5-(1H-吡唑并[3,4-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(XV)
LCMS:m/z 484 [M+H]
+。針對C
23H
24Cl
2N
5OSi [M + H]
+之HRMS (ESI)計算值484.1122,實測值484.1157;
2-(2,4-二氯苯基)-5-[3-(三氟甲基)-1H-吡唑-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(XV)
LCMS:m/z 501 [M+H]
+。針對C
21H
22Cl
2F
3N
4OSi [M + H]
+之HRMS (ESI)計算值501.0887,實測值501.0894;
以類似方式操作,但採用5-溴-2-(2,4-二氯苯基)-1-(苯基磺醯基)-1H-吡咯-3-甲腈作為起始材料,獲得下列化合物:
5-(6-胺基嘧啶-4-基)-2-(2,4-二氯苯基)-1-(苯基磺醯基)-1H-吡咯-3-甲腈(XV)
1H NMR (500 MHz, DMSO-d6) d ppm 6.60 (d, J=0.91 Hz, 1 H) 7.12 (s, 1 H) 7.14 (br. s., 1 H) 7.41 (d, J=8.24 Hz, 1 H) 7.56 (dd, J=8.31, 2.06 Hz, 1 H) 7.58 - 7.63 (m, 2 H) 7.76 (dd, J=8.46, 0.99 Hz, 2 H) 7.78 (d, J=1.98 Hz, 1 H) 7.80 (t, J=7.50 Hz, 0 H) 8.40 (d, J=0.92 Hz, 1 H)。LCMS:m/z 470 [M+H]
+。針對C
21H
14Cl
2N
5O
2S [M + H]
+之HRMS (ESI)計算值470.0240,實測值470.0256;
以類似方式操作,但採用5-溴-2-(2-氟-4-甲基苯基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈作為起始材料,獲得下列化合物:
2-(2-氟-4-甲基苯基)-5-(1H-吡唑-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(XV)
1H NMR (500 MHz, DMSO-d6) d ppm -0.15 - -0.12 (m, 9 H) 0.59 - 0.69 (m, 2 H) 2.41 (s, 3 H) 3.09 - 3.19 (m, 2 H) 5.14 (br. s., 2 H) 6.76 (s, 1 H) 7.22 (d, J=8.24 Hz, 1 H) 7.29 (d, J=10.83 Hz, 1 H) 7.43 (t, J=7.85 Hz, 1 H) 7.77 (s, 1 H) 8.01 (s, 1 H) 13.14 (br. s., 1 H)。LCMS:m/z 397 [M+H]
+。針對C
21H
26FN
4OSi [M + H]
+之HRMS (ESI)計算值397.1855,實測值397.1857;
5-(3,5-二甲基-1H-吡唑-4-基)-2-(2-氟-4-甲基苯基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(XV)
1H NMR (500 MHz, DMSO-d6) d ppm -0.16 (s, 9 H) 0.46 - 0.58 (m, 2 H) 2.02 (s, 3 H) 2.10 (s, 3 H) 2.41 (s, 3 H) 2.86 - 3.00 (m, 2 H) 4.93 (s, 2 H) 6.56 (s, 1 H) 7.20 (d, J=7.63 Hz, 1 H) 7.26 (d, J=10.98 Hz, 1 H) 7.46 (t, J=7.78 Hz, 1 H) 12.50 (s, 1 H)。LCMS:m/z 425 [M+H]
+。針對C
23H
30FN
4OSi [M + H]
+之HRMS (ESI)計算值425.2168,實測值425.2172;
2-(2-氟-4-甲基苯基)-5-(1-甲基-1H-吡唑-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(XV)
1H NMR (500 MHz, DMSO-d6) d ppm -0.13 (s, 9 H) 0.65 (dd, J=9.00, 7.63 Hz, 2 H) 2.41 (s, 3 H) 3.08 - 3.19 (m, 2 H) 3.88 (s, 3 H) 5.14 (br. s., 2 H) 6.74 (s, 1 H) 7.22 (dsxt, J=7.78, 0.80, 0.80, 0.80, 0.80, 0.80 Hz, 1 H) 7.29 (d, J=10.98 Hz, 1 H) 7.43 (t, J=7.85 Hz, 1 H) 7.71 (d, J=0.61 Hz, 1 H) 7.96 (s, 1 H)。LCMS:m/z 411 [M+H]
+。針對C
22H
28FN
4OSi [M + H]
+之HRMS (ESI)計算值411.2011,實測值411.2011;
2-(2-氟-4-甲基苯基)-5-(3-甲基-1H-吡唑-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(XV)
LCMS:m/z 411 [M+H]
+。針對C
22H
28FN
4OSi [M + H]
+之HRMS (ESI)計算值411.2011,實測值411.2035;
2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(XV)
1H NMR (500 MHz, DMSO-d6) d ppm -0.27 - -0.19 (m, 9 H) 0.40 - 0.55 (m, 2 H) 2.43 (s, 3 H) 2.91 - 3.01 (m, 2 H) 5.23 (br. s., 2 H) 6.53 (dd, J=3.43, 1.91 Hz, 1 H) 7.01 (s, 1 H) 7.21 - 7.28 (m, 2 H) 7.32 (d, J=10.83 Hz, 1 H) 7.54 - 7.62 (m, 2 H) 8.30 (d, J=4.88 Hz, 1 H) 11.90 (br. s., 1 H)。LCMS:m/z 447 [M+H]
+。針對C
25H
28FN
4OSi [M + H]
+之HRMS (ESI)計算值447.2011,實測值447.2020;
向2-(2,4-二氯苯基)-5-(1H-吡唑-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(1當量,220 mg,0.51 mmol)於甲苯(7 ml)中之溶液添加乙醛肟(20當量,0.62 ml,10.16 mmol)及InCl
3(0.1當量,11 mg,0.051 mmol)。在T = 100℃下將該反應混合物加熱4小時。添加蒸餾水及產物用AcOEt萃取(3次)。有機層用蒸餾水及鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(DCM/MeOH 95/5)純化以提供標題化合物(白色固體,106 g,Y=47%)。
1H NMR (500 MHz, DMSO-d6) d ppm -0.14 - -0.10 (m, 8 H) 0.59 - 0.69 (m, 2 H) 3.05 - 3.17 (m, 2 H) 4.81 (d, J=11.13 Hz, 1 H) 5.06 (d, J=11.29 Hz, 1 H) 6.71 - 6.76 (m, 2 H) 7.18 (br. s., 1 H) 7.38 - 7.42 (m, 1 H) 7.47 - 7.50 (m, 2 H) 7.70 (d, J=2.14 Hz, 1 H) 7.92 (d, J=4.27 Hz, 1 H) 13.05 (br. s., 1 H)。LCMS:m/z 451 [M+H]
+。針對C
20H
25Cl
2N
4O
2Si [M + H]
+之HRMS (ESI)計算值451.1119,實測值451.1119;
以類似方式操作,但採用合適之經取代之起始材料,獲得下列化合物:
2-(2,4-二氯苯基)-5-(3-甲基-1H-吡唑-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XVI)
1H NMR (500 MHz, DMSO-d6) d ppm -0.22 - -0.04 (m, 9 H) 0.61 (t, J=8.39 Hz, 2 H) 2.26 (br. s., 3 H) 2.89 - 3.13 (m, 2 H) 4.73 (d, J=10.98 Hz, 1 H) 4.95 (d, J=10.98 Hz, 1 H) 6.48 - 6.69 (m, 1 H) 6.73 (br. s., 1 H) 7.22 (br. s., 1 H) 7.40 (d, J=8.20 Hz, 1 H) 7.47 (dd, J=8.20, 2.10 Hz, 1 H) 7.68 (d, J=2.14 Hz, 1 H) 12.46 - 13.03 (m, 1 H)。LCMS:m/z 465 [M+H]
+。針對C
21H
27Cl
2N
4O
2Si [M + H]
+之HRMS (ESI)計算值465.1275,實測值465.1289;
5-(2-胺基-1,3-噻唑-4-基)-2-(2,4-二氯苯基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲腈(XVI)
LCMS:m/z 483 [M+H]
+。針對C
20H
24Cl
2N
4O
2SSi [M + H]
+之HRMS (ESI)計算值483.0839,實測值483.0852;
2-(2,4-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XVI)
LCMS:m/z 501 [M+H]
+。針對C
24H
27Cl
2N
4O
2Si [M + H]
+之HRMS (ESI)計算值501.1275,實測值501.1268;
2-(2,4-二氯苯基)-5-(1H-吡唑并[3,4-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XVI)
LCMS:m/z 502 [M+H]
+。針對C
23H
26Cl
2N
5O
2Si [M + H]
+之HRMS (ESI)計算值502.1227,實測值502.1236;
2-(2,4-二氯苯基)-5-[3-(三氟甲基)-1H-吡唑-4-基]-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XVI)
LCMS:m/z 519 [M+H]
+。針對C
21H
24Cl
2F
3N
4O
2Si [M + H]
+之HRMS (ESI)計算值519.0992,實測值519.0996;
5-(6-胺基嘧啶-4-基)-2-(2,4-二氯苯基)-1-(苯基磺醯基)-1H-吡咯-3-甲醯胺(XVI)
LCMS:m/z 488 [M+H]
+。針對C
21H
16Cl
2N
5O
3S [M + H]
+之HRMS (ESI)計算值488.0345,實測值488.0352;
2-(2-氟-4-甲基苯基)-5-(1H-吡唑-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XVI)
LCMS:m/z 415 [M+H]
+。針對C
21H
28FN
4O
2Si [M + H]
+之HRMS (ESI)計算值415.1960,實測值415.1975;
5-(3,5-二甲基-1H-吡唑-4-基)-2-(2-氟-4-甲基苯基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XVI)
1H NMR (500 MHz, DMSO-d6) d ppm -0.15 (s, 9 H) 0.42 - 0.60 (m, 2 H) 2.05 (br. s., 6 H) 2.36 (s, 3 H) 2.89 (q, J=8.80 Hz, 2 H) 4.56 - 4.95 (m, 2 H) 6.48 (s, 1 H) 6.69 (br. s., 1 H) 7.02 (br. s., 1 H) 7.03 - 7.08 (m, 2 H) 7.26 (t, J=7.85 Hz, 1 H) 12.38 (br. s., 1 H)。LCMS:m/z 443 [M+H]
+。針對C
23H
32FN
4O
2Si [M + H]
+之HRMS (ESI)計算值443.2273,實測值443.2272;
2-(2-氟-4-甲基苯基)-5-(1-甲基-1H-吡唑-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XVI)
1H NMR (500 MHz, DMSO-d6) d ppm -0.12 (s, 9 H) 0.64 (t, J=8.31 Hz, 2 H) 2.37 (s, 3 H) 2.97 - 3.09 (m, 1 H) 3.12 (t, J=8.24 Hz, 1 H) 3.88 (s, 3 H) 4.80 - 4.98 (m, 1 H) 4.98 - 5.18 (m, 1 H) 6.68 (s, 1 H) 6.70 (br. s., 1 H) 7.04 (br. s., 1 H) 7.05 - 7.11 (m, 2 H) 7.23 (t, J=7.85 Hz, 1 H) 7.61 (d, J=0.61 Hz, 1 H) 7.86 (s, 1 H)。LCMS:m/z 429 [M+H]
+。針對C
22H
30FN
4O
2Si [M + H]
+之HRMS (ESI)計算值429.2117,實測值429.2116;
2-(2-氟-4-甲基苯基)-5-(3-甲基-1H-吡唑-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XVI)
LCMS:m/z 429 [M+H]
+。針對C
22H
30FN
4O
2Si [M + H]
+之HRMS (ESI)計算值429.2117,實測值429.2116;
2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(XVI)
1H NMR (500 MHz, DMSO-d6) d ppm -0.21 - -0.17 (m, 9 H) 0.55 (t, J=8.39 Hz, 2 H) 2.38 (s, 3 H) 2.87 - 3.10 (m, 2 H) 4.95 - 5.22 (m, 2 H) 6.66 (br. s., 0 H) 6.80 (br. s., 1 H) 7.09 (d, J=9.15 Hz, 2 H) 7.24 (d, J=5.03 Hz, 1 H) 7.31 - 7.41 (m, 2 H) 7.54 - 7.58 (m, 1 H) 8.26 (d, J=4.88 Hz, 1 H) 11.80 (br. s., 1 H)。LCMS:m/z 465 [M+H]
+。針對C
25H
30FN
4O
2Si [M + H]
+之HRMS (ESI)計算值465.2117,實測值465.2132;
向5-(6-胺基嘧啶-4-基)-2-(2,4-二氯苯基)-1-(苯基磺醯基)-1H-吡咯-3-甲醯胺(1當量,100 mg,0.20 mmol)於THF (2.3 ml)及H
2O (1.8 ml)中之溶液添加LiOH (4當量,0.8 mmol,33.5 mg)。在回流下將該反應混合物攪拌4小時。在減壓下將溶劑部分移除並將HCl 2N添加至該混合物。在室溫下將該反應攪拌30分鐘並藉由過濾收集標題化合物(白色固體,67 mg,Y=95%)。
1H NMR (500 MHz, DMSO-d6) d ppm 6.65 (s, 1 H) 6.76 (br. s., 1 H) 6.91 (br. s., 2 H) 7.29 (s, 1 H) 7.35 (br. s., 1 H) 7.40 - 7.47 (m, 2 H) 7.65 (d, J=1.68 Hz, 1 H) 8.34 (s, 1 H) 12.09 (br. s., 1 H)。LCMS:m/z 348 [M+H]
+。針對C
15H
12Cl
2N
5O [M + H]
+之HRMS (ESI)計算值348.0414,實測值348.0424;
2-(2,4-二氯苯基)-5-(1H-吡唑-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡唑-4-基,R2 = 2,4-二氯苯基,R3 = R4 = R5 = H]化合物43
向2-(2,4-二氯苯基)-5-(1H-吡唑-4-基)-1-{[2-(三甲基矽基)乙氧基]甲基}-1H-吡咯-3-甲醯胺(1當量,100 mg,0.22 mmol)於DCM (4.9 ml)中之溶液添加TFA (75當量,16.5 mmol,1.26 ml)。在室溫下將該反應混合物攪拌5小時。在減壓下移除溶劑且粗產物用甲苯處理三次。在相同反應器中,將2-(2,4-二氯苯基)-1-(羥基甲基)-5-(1H-吡唑-4-基)-1H-吡咯-3-甲醯胺溶解於EtOH 95% (8.5 ml)中並添加氫氧化銨溶液30至32% (1.2 ml)。在室溫下將該反應混合物攪拌2小時。在減壓下移除溶劑且固體用蒸餾水清洗五次(以移除CF
3COO
-NH
4 +)及用DCM/Et
2O 1/1清洗三次以達成標題化合物(淺黃色固體,31 mg,Y=44%)。
1H NMR (500 MHz, DMSO-d6) d ppm 6.65 (br. s., 1 H) 6.67 (d, J=2.6 Hz, 1 H) 7.09 (br. s., 1 H) 7.40 - 7.48 (m, 2 H) 7.66 (dd, J=1.4, 0.8 Hz, 1 H) 7.73 (br. s., 1 H) 7.93 (br. s., 1 H) 11.46 (s, 1 H) 12.84 (br. s., 1 H)。LCMS:m/z 321 [M+H]
+。針對C
14H
11Cl
2N
4O [M + H]
+之HRMS (ESI)計算值321.0305,實測值321.0305;
以類似方式操作,但採用合適之經取代之起始材料,獲得下列化合物:
2-(2,4-二氯苯基)-5-(3-甲基-1H-吡唑-4-基)-1H-吡咯-3-甲醯胺[R1 = 3-甲基-1H-吡唑-4-基,R2 = 2,4-二氯苯基,R3 = R4 = R5 = H]化合物44
1H NMR (500 MHz, DMSO-d6) d ppm 6.61 (br. s., 1 H) 6.64 (br. s., 2 H) 7.20 (br. s., 1 H) 7.44 (d, J=1.2 Hz, 2 H) 7.65 (s, 1 H) 11.15 - 11.47 (m, 1 H) 12.30 - 12.76 (m, 1 H)。LCMS:m/z 335 [M+H]
+。針對C
15H
13Cl
2N
4O [M + H]
+之HRMS (ESI)計算值335.0461,實測值335.0464;
5-(2-胺基-1,3-噻唑-4-基)-2-(2,4-二氯苯基)-1H-吡咯-3-甲醯胺[R1 = 2-胺基-1,3-噻唑-4-基,R2 = 2,4-二氯苯基,R3 = R4 = R5 = H]化合物45
1H NMR (500 MHz, DMSO-d6) d ppm 6.70 (br. s., 1 H) 6.75 (s, 1 H) 6.83 (d, J=2.59 Hz, 1 H) 7.19 (br. s., 1 H) 7.42 - 7.45 (m, 1 H) 7.45 - 7.47 (m, 1 H) 7.67 (d, J=1.98 Hz, 1 H) 11.70 (br. s., 1 H)。LCMS:m/z 353 [M+H]
+。針對C
14H
11Cl
2N
4OS [M + H]
+之HRMS (ESI)計算值353.0025,實測值353.0023;
2-(2,4-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基,R2 = 2,4-二氯苯基,R3 = R4 = R5 = H]化合物46
1H NMR (500 MHz, DMSO-d6) d ppm 6.78 (br. s., 1 H) 7.02 (dd, J=3.5, 1.8 Hz, 1 H) 7.36 (d, J=5.2 Hz, 1 H) 7.43 - 7.52 (m, 3 H) 7.53 - 7.59 (m, 2 H) 7.70 (d, J=2.0 Hz, 1 H) 8.18 (d, J=5.0 Hz, 1 H) 9.50 - 9.51 (m, 1 H) 11.69 (br. s., 1 H) 11.98 (d, J=1.7 Hz, 1 H)。LCMS:m/z 371 [M+H]
+。針對C
18H
12Cl
2N
4O [M + H]
+之HRMS (ESI)計算值371.0461,實測值371.0462;
2-(2,4-二氯苯基)-5-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡唑并[3,4-b]吡啶-4-基,R2 = 2,4-二氯苯基,R3 = R4 = R5 = H]化合物47
1H NMR (500 MHz, DMSO-d6) d ppm 6.88 (br. s., 1 H) 7.46 (d, J=4.9 Hz, 1 H) 7.48 - 7.51 (m, 1 H) 7.51 - 7.54 (m, 1 H) 7.59 (br. s., 1 H) 7.67 (d, J=2.6 Hz, 1 H) 7.72 (d, J=2.0 Hz, 1 H) 8.46 (d, J=4.9 Hz, 1 H) 8.67 (d, J=1.1 Hz, 1 H) 12.23 (br. s., 1 H) 13.68 (s, 1 H)。LCMS:m/z 372 [M+H]
+。針對C
17H
12Cl
2N
5O [M + H]
+之HRMS (ESI)計算值372.0414,實測值372.0417;
2-(2,4-二氯苯基)-5-[3-(三氟甲基)-1H-吡唑-4-基]-1H-吡咯-3-甲醯胺[R1 = 3-(三氟甲基)-1H-吡唑-4-基,R2 = 2,4-二氯苯基,R3 = R4 = R5 = H]化合物48
1H NMR (500 MHz, DMSO-d6) d ppm 6.68 (d, J=1.7 Hz, 2 H) 7.22 (br. s., 1 H) 7.41 - 7.50 (m, 2 H) 7.67 (dd, J=1.7, 0.6 Hz, 1 H) 8.15 (s, 1 H) 11.53 (br. s., 1 H) 13.61 (br. s., 1 H)。LCMS:m/z 389 [M+H]
+。針對C
15H
10Cl
2F
3N
4O [M + H]
+之HRMS (ESI)計算值389.0178,實測值389.0184;
2-(2-氟-4-甲基苯基)-5-(1H-吡唑-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡唑-4-基,R2 = 2-氟-4-甲基苯基,R3 = R4 = R5 = H]化合物49
1H NMR (500 MHz, DMSO-d6) d ppm 2.39 (s, 3 H) 6.65 (br. s, 1 H) 6.66 (d, J=2.6 Hz, 1 H) 7.04 (br. s., 1 H) 7.05 - 7.12 (m, 2 H) 7.37 (t, J=7.9 Hz, 1 H) 7.78 (s, 1 H) 7.98 (s, 1 H) 11.38 (br. s., 1 H) 12.86 (br. s., 1 H)。LCMS:m/z 285 [M+H]
+。針對C
15H
14FN
4O [M + H]
+之HRMS (ESI)計算值285.1146,實測值285.1147;
5-(3,5-二甲基-1H-吡唑-4-基)-2-(2-氟-4-甲基苯基)-1H-吡咯-3-甲醯胺[R1 = 3,5-二甲基-1H-吡唑-4-基,R2 = 2-氟-4-甲基苯基,R3 = R4 = R5 = H]化合物50
1H NMR (500 MHz, DMSO-d6) d ppm 2.20 (br. s., 3 H) 2.25 (br. s., 3 H) 2.34 (s, 3 H) 6.43 (d, J=2.7 Hz, 1 H) 6.62 (br. s., 1 H) 6.98 - 7.04 (m, 2 H) 7.07 (br. s., 1 H) 7.35 (t, J=8.0 Hz, 1 H) 10.97 (d, J=2.0 Hz, 1 H) 12.24 (s, 1 H)。LCMS:m/z 313 [M+H]
+。針對C
17H
18FN
4O [M + H]
+之HRMS (ESI)計算值313.1459,實測值313.1456;
2-(2-氟-4-甲基苯基)-5-(1-甲基-1H-吡唑-4-基)-1H-吡咯-3-甲醯胺[R1 = 1-甲基-1H-吡唑-4-基,R2 = 2-氟-4-甲基苯基,R3 = R4 = R5 = H]化合物51
1H NMR (500 MHz, DMSO-d6) d ppm 2.35 (s, 3 H) 3.84 (s, 3 H) 6.60 (d, J=2.7 Hz, 1 H) 6.63 (br. s., 1 H) 7.01 (br. s., 1 H) 7.03 (d, J=7.0 Hz, 1 H) 7.05 (d, J=10.4 Hz, 1 H) 7.33 (t, J=7.9 Hz, 1 H) 7.68 (d, J=0.6 Hz, 1 H) 7.88 (s, 1 H) 11.37 (br. s., 1 H)。LCMS:m/z 299 [M+H]
+。針對C
16H
16FN
4O [M + H]
+之HRMS (ESI)計算值299.1303,實測值299.1299;
2-(2-氟-4-甲基苯基)-5-(3-甲基-1H-吡唑-4-基)-1H-吡咯-3-甲醯胺[R1 = 3-甲基-1H-吡唑-4-基,R2 = 2-氟-4-甲基苯基,R3 = R4 = R5 = H]化合物52
1H NMR (500 MHz, DMSO-d6) d ppm 2.35 (s, 6 H) 6.51 - 6.68 (m, 2 H) 7.00 - 7.07 (m, 2 H) 7.10 (br. s., 1 H) 7.33 (t, J=7.9 Hz, 1 H) 7.75 (br. s., 1 H) 11.23 (br. s., 1 H) 12.18 - 12.82 (m, 1 H)。LCMS:m/z 299 [M+H]
+。針對C
16H
16FN
4O [M + H]
+之HRMS (ESI)計算值299.1303,實測值299.1299;
2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基),R2 = 2-氟-4-甲基苯基,R3 = R4 = R5 = H]化合物53
1H
NMR (500 MHz, DMSO-d
6) d ppm 2.38 (s, 3 H) 6.81 (br. s., 1 H) 7.02 - 7.15 (m, 3 H) 7.38 - 7.44 (m, 1 H) 7.47 - 7.57 (m, 3 H) 7.63 (t, J=2.90 Hz, 1 H) 8.26 (d, J=5.49 Hz, 1 H) 11.89 - 12.15 (m, 2 H)。LCMS:m/z 335 [M+H]
+。針對C
19H
16FN
4O [M + H]
+之HRMS (ESI)計算值335.1303,實測值335.1302;
在T = 0℃下向2-(2,4-二氯苯基)-1H-吡咯-3-甲腈(1當量,300 mg,1.27 mmol)於無水THF (6 ml)中之溶液添加於礦物油中之NaH 60% (1.8當量,92 mg,2.29 mmol)。在T = 0℃下將該反應混合物攪拌20分鐘並添加(2-溴-乙氧基)-第三丁基-二甲基-矽烷(XVII) (1.8當量,0.49 ml,2.29 mmol)。10分鐘後在T = 0℃下在室溫下使該反應升溫並攪拌6小時。添加蒸餾水且產物用DCM萃取。有機層用蒸餾水及鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(Hex/AcOEt 9/1)純化以提供標題化合物(淡黃色油,336 mg,Y=67%)。
1H NMR (500 MHz, DMSO-d6) d ppm -0.14 - -0.08 (m, 6 H) 0.73 - 0.80 (m, 9 H) 3.54 - 3.78 (m, 3 H) 3.89 - 3.97 (m, 1 H) 6.63 (d, J=3.05 Hz, 1 H) 7.14 (d, J=3.05 Hz, 1 H) 7.52 (d, J=8.39 Hz, 1 H) 7.63 (dd, J=8.24, 2.14 Hz, 1 H) 7.89 (d, J=2.14 Hz, 1 H)。 LCMS:m/z 395 [M+H]
+。針對C
19H
25Cl
2N
2OSi [M + H]
+之HRMS (ESI)計算值395.1108,實測值395.1110;
以類似方式操作,但採用合適之經取代之起始材料作為中間物(XVII),獲得下列化合物:
2-(2,4-二氯苯基)-1-(3,3,3-三氟丙基)-1H-吡咯-3-甲腈(XVIII)
LCMS:m/z 333 [M+H]
+。針對C
14H
9Cl
2F
3N
2[M + H]
+之HRMS (ESI)計算值333.0168 ,實測值333.0172;
2-(2,4-二氯苯基)-1-甲基-1H-吡咯-3-甲腈(XVIII)
LCMS:m/z 251 [M+H]
+。針對C
12H
8Cl
2N
2[M + H]
+之HRMS (ESI)計算值251.0137,實測值251.0139;
2-(2,4-二氯苯基)-1-乙基-1H-吡咯-3-甲腈(XVIII)
LCMS:m/z 265 [M+H]
+。針對C
13H
10Cl
2N
2[M + H]
+之HRMS (ESI)計算值265.0294,實測值265.0297;
在T = 0℃下向1-(2-{[第三丁基(二甲基)矽基]氧基}乙基)-2-(2,4-二氯苯基)-1H-吡咯-3-甲腈(1當量,330 mg,0.84 mmol)於MeOH (4 ml)及THF (2 ml)中之溶液添加0.5當量之N-溴琥珀醯亞胺(74.5 mg,0.42 mmol)。在T = 0℃下將該反應混合物攪拌30分鐘及然後添加0.5當量之N-溴琥珀醯亞胺(74.5 mg,0.42 mmol)。在T = 0℃下將該反應攪拌1小時及30分鐘。添加蒸餾水及產物用AcOEt萃取3次。有機層用鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(Hex/AcOEt 95/5)純化以提供標題化合物(透明-淺黃色油,360 mg,Y=48%)。
LCMS:m/z 358 [M+H]
+。針對C
13H
10BrCl
2N
2O [M + H]
+之HRMS (ESI)計算值358.9348,實測值358.9352;
以類似方式操作,但採用合適之經取代之起始材料,獲得下列化合物:
5-溴-2-(2,4-二氯苯基)-1-(3,3,3-三氟丙基)-1H-吡咯-3-甲腈(XIX)
LCMS:m/z 410 [M+H]
+。針對C
14H
9BrCl
2F
3N
2[M + H]
+之HRMS (ESI)計算值410.9273,實測值410.9274;
5-溴-2-(2,4-二氯苯基)-1-甲基-1H-吡咯-3-甲腈(XIX)
LCMS:m/z 328 [M+H]
+。針對C
12H
7BrCl
2N
2[M + H]
+之HRMS (ESI)計算值328.9242,實測值328.9240;
5-溴-2-(2,4-二氯苯基)-1-乙基-1H-吡咯-3-甲腈(XIX)
LCMS:m/z 342 [M+H]
+。針對C
13H
9BrCl
2N
2[M + H]
+之HRMS (ESI)計算值342.9399,實測值342.9398;
在反應器中,在氬氣氛下,添加5-溴-2-(2,4-二氯苯基)-1-(2-羥乙基)-1H-吡咯-3-甲腈(1當量,140 mg,0.39 mmol)、4-(4,4,5,5-四甲基-[1,3,2]二氧雜環戊硼烷-2-基)-1H-吡咯并[2,3-b]吡啶(1.5當量,142 mg,0.58 mmol)、Na
2CO
3(3當量,124 mg,1.17 mmol)、經脫氣之1,4-二噁烷(4 ml)及經脫氣之蒸餾水(1 ml)。在三次真空/氬週期後,添加觸媒[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II) (1:1) (0.1當量,32 mg,0.039 mmol)。在三個真空/氬週期後,在T = 100℃下將該反應混合物加熱3小時。添加蒸餾水,及產物用AcOEt萃取(3次)。有機層用蒸餾水及鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(AcOEt)純化以提供標題化合物(黃色固體,110 mg,Y=71%)。
1H NMR (500 MHz, DMSO-d6) d ppm 3.01 (五重峰,J=11.74, 11.74, 11.74, 11.74, 6.10 Hz, 2 H) 3.77 (dt, J=14.03, 6.86 Hz, 1 H) 3.99 - 4.07 (m, 1 H) 4.63 (t, J=5.57 Hz, 1 H) 6.42 - 6.44 (m, 1 H) 6.89 (s, 1 H) 7.18 (d, J=5.0 Hz, 1 H) 7.59 - 7.61 (m, 1 H) 7.67 - 7.69 (m, 1 H) 7.74 - 7.72 (m, 1 H) 7.94 (d, J=2.0 Hz, 1 H) 8.30 (d, J=5.0 Hz, 1 H) 11.91 (br. s., 1 H)。LCMS:m/z 397 [M+H]
+。針對C
20H
15Cl
2N
4O [M + H]
+之HRMS (ESI)計算值397.0618,實測值397.0623;
以類似方式操作,但採用合適之經取代之起始材料,獲得下列化合物:
2-(2,4-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-(3,3,3-三氟丙基)-1H-吡咯-3-甲腈(XX)
LCMS:m/z 449 [M+H]
+。針對C
21H
14Cl
2F
3N
4[M + H]
+之HRMS (ESI)計算值449.0542,實測值449.0541;
2-(2,4-二氯苯基)-1-甲基-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲腈(XX)
LCMS:m/z 367 [M+H]
+。針對C
19H
12Cl
2N
4[M + H]
+之HRMS (ESI)計算值367.0512,實測值367.0513;
2-(2,4-二氯苯基)-1-乙基-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲腈(XX)
LCMS:m/z 381 [M+H]
+。針對C
20H
14Cl
2N
4[M + H]
+之HRMS (ESI)計算值381.0668,實測值381.0670;
步驟 152-(2,4-二氯苯基)-1-(2-羥乙基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基),R2 = 2,4-二氯苯基,R3 = R5 = H,R4 = 2-羥乙基]化合物54
向2 2-(2,4-二氯苯基)-1-(2-羥乙基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲腈(1當量,100 mg,0.25 mmol)於甲苯(3.6 ml)中之溶液添加乙醛肟(20當量,0.307 ml,5.05 mmol)及InCl
3(0.1當量,5.6 mg,0.025 mmol)。在T = 100℃下將該反應混合物加熱1小時。添加蒸餾水及產物用AcOEt萃取(3次)。有機層用蒸餾水及鹽水清洗,經無水Na
2SO
4乾燥並蒸發至乾燥。該粗產物藉由急驟層析術(DCM/EtOH 95/5)純化以提供標題化合物(白色固體,21 mg,Y=20%)。
1H NMR (500 MHz, DMSO-d6) d ppm 2.94 - 3.07 (m, 2 H) 3.68 (dt, J=14.2, 7.1 Hz, 1 H) 3.88 - 3.97 (m, 1 H) 6.53 (dd, J=3.4, 1.8 Hz, 1 H) 6.74 (br. s., 1 H) 6.93 (s, 1 H) 7.18 (d, J=5.0 Hz, 1 H) 7.33 (br. s., 1 H) 7.50 - 7.52 (m, 1 H) 7.53 - 7.55 (m, 1 H) 7.57 - 7.60 (m, 1 H) 7.75 (d, J=2.0 Hz, 1 H) 8.30 (d, J=5.0 Hz, 1 H) 11.91 (br. s., 1 H)。LCMS:m/z 415 [M+H]
+。針對C
20H
17Cl
2N
4O
2[M + H]
+之HRMS (ESI)計算值415.0723,實測值415.0722;
以類似方式操作,但採用合適之經取代之起始材料,獲得下列化合物:
2-(2,4-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-(3,3,3-三氟丙基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基),R2 = 2,4-二氯苯基,R3 = R5 = H,R4 = 3,3,3-三氟丙基]化合物55
1H NMR (500 MHz, DMSO-d6) d ppm 1.99 - 2.17 (m, 2 H) 3.88 - 3.97 (m, 1 H) 4.11 - 4.20 (m, 1 H) 6.51 (dd, J=3.4, 1.9 Hz, 1 H) 6.80 (br. s., 1 H) 6.97 (s, 1 H) 7.14 (d, J=4.9 Hz, 1 H) 7.39 (br. s., 1 H) 7.53 - 7.56 (m, 1 H) 7.57 - 7.61 (m, 2 H) 7.79 (d, J=2.0 Hz, 1 H) 8.30 (d, J=4.9 Hz, 1 H) 11.86 (br. s., 1 H)。LCMS:m/z 467 [M+H]
+。針對C
21H
16Cl
2F
3N
4O [M + H]
+之HRMS (ESI)計算值467.0648,實測值467.0656;
2-(2,4-二氯苯基)-1-甲基-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基),R2 = 2,4-二氯苯基,R3 = R5 = H,R4 =甲基]化合物56
1H NMR (500 MHz, DMSO-d
6) d ppm 3.30 (s, 1 H) 6.60 (dd, J=3.43, 1.91 Hz, 1 H) 6.74 (br. s., 1 H) 7.02 (s, 1 H) 7.11 (d, J=4.88 Hz, 1 H) 7.38 (br. s., 1 H) 7.50 - 7.52 (m, 2 H) 7.56 (t, J=1.00 Hz, 1 H) 7.76 (s, 1 H) 8.27 (d, J=4.88 Hz, 1 H) 11.81 (br. s., 1 H)。LCMS:m/z 385 [M+H]
+。針對C
19H
14Cl
2N
4O [M + H]
+之HRMS (ESI)計算值385.0618,實測值385.0616;
2-(2,4-二氯苯基)-1-乙基-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺[R1 = 1H-吡咯并[2,3-b]吡啶-4-基),R2 = 2,4-二氯苯基,R3 = R5 = H,R4 =乙基]化合物57
1H NMR (500 MHz, DMSO-d
6) d ppm 0.73 (t, J=7.17 Hz, 3 H) 3.61 - 3.90 (m, 2 H) 6.51 (dd, J=3.36, 1.83 Hz, 1 H) 6.72 (br. s., 1 H) 6.93 (s, 1 H) 7.10 (d, J=4.88 Hz, 1 H) 7.32 (br. s., 1 H) 7.48 - 7.59 (m, 3 H) 7.75 (d, J=1.83 Hz, 1 H) 8.28 (d, J=5.03 Hz, 1 H) 11.83 (br. s., 1 H)。LCMS:m/z 399 [M+H]
+。針對C
20H
16Cl
2N
4O [M + H]
+之HRMS (ESI)計算值399.0774,實測值399.0767。
Claims (15)
- 一種式(I)化合物, 其中: R1係選自由以下組成之群之雜芳基: 、 、 、 及 其中: Ra、Rb及Rc獨立地係氫、視需要經取代之直鏈或分支鏈(C 1-C 6)烷基或視需要經取代之直鏈或分支鏈(C 2-C 6)烯基; R2係經取代之芳基或經取代之雜芳基環,其攜載一至三個選自以下之取代基:鹵素、硝基、胺基、(C 1-C 6)烷基胺基、胺基羰基、視需要經取代之直鏈或分支鏈(C 1-C 6)烷基、視需要經取代之直鏈或分支鏈(C 1-C 6)烷氧基、視需要經取代之直鏈或分支鏈多氟化(C 1-C 6)烷基及視需要經取代之直鏈或分支鏈多氟化(C 1-C 6)烷氧基; 前提條件係排除2,5-雙取代之苯基; R3係氫、視需要經取代之直鏈或分支鏈(C 1-C 4)烷基、視需要經取代之(C 3-C 6)環烷基或視需要經取代之(C 5-C 6)雜環基; R4係氫、視需要經取代之直鏈或分支鏈(C 1-C 6)烷基或視需要經取代之直鏈或分支鏈(C 2-C 6)烯基;及 R5係氫、鹵素或視需要經取代之直鏈或分支鏈(C 1-C 3)烷基; 或其醫藥上可接受之鹽。
- 如請求項1之式(I)化合物或其醫藥上可接受之鹽,其中: Ra、Rb及Rc獨立地係氫或視需要經取代之直鏈或分支鏈(C1-C6)烷基;及 R2係2,4-雙取代之苯基、4,6-雙取代之吡啶-3-基、2,6-雙取代之吡啶-3-基或3,5-雙取代之吡啶-2-基。
- 如請求項2之式(I)化合物或其醫藥上可接受之鹽,其中: R2係2,4-雙取代之苯基; R3係氫或視需要經取代之直鏈或分支鏈(C 1-C 4)烷基鏈;及 R5係氫。
- 如請求項3之式(I)化合物或其醫藥上可接受之鹽,其中: R4係氫。
- 如請求項1之式(I)化合物(cpd)或其醫藥上可接受之鹽,其選自由以下組成之群: 2-(3-氯-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物1); 2-(4-氯-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物2); 2-(2-氯-4-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物3); 2-(2,4-二氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物4); 2-[2-氯-4-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物5); 2-(2,3-二氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物6); 2-(2,3-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物7); 2-[4-甲基-2-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物8); 2-(2-氯-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物9); 2-(2,3-二氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物10); 2-[2-甲基-4-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物11); 2-(2-氟-3-甲氧基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物12); 2-(2-氯-3-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物13); 2-(2-氟-3-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物14); 2-[2-甲基-3-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物15); 2-[4-甲氧基-2-(三氟甲基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物16); 2-[2-氯-4-(二氟甲氧基)苯基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物17); 2-(3,4-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物18); 2-(3,4-二氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物19); 2-(3-乙氧基-2-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物20); 2-(4-甲基-3-硝基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物21); 2-(3-胺甲醯基-4-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物22); 2-(2-氟-4-甲基苯基)-N-[2-(吡咯啶-1-基)乙基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物23); N-[2-(二甲基胺基)乙基]-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物24); 2-(2-氟-4-甲基苯基)-N-[2-(嗎啉-4-基)乙基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物25); N-[(1S,2R)-2-胺基環己基]-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物26); 2-(2-氟-4-甲基苯基)-N-(呋喃-2-基甲基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物27); N-(氟乙基)-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物28); 2-(2-氟-4-甲基苯基)-N-[2-(甲基胺基)乙基]-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物29); 化合物2-(2-氟-4-甲基苯基)-N-(1-甲基哌啶-4-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物30); 2-(二苯并[b,d]噻吩-4-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物31); 2-(4-甲基萘-1-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物32); 2-(3-氟苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物33); 5-(1H-吡咯并[2,3-b]吡啶-4-基)-2-[4-(三氟甲氧基)苯基]-1H-吡咯-3-甲醯胺(化合物34); 2-(2,3-二氫-1,4-苯并戴奧辛(benzodioxin)-6-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物36); 2-(4-氟-2-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物37); 2-(2-氟-4-甲基苯基)-4-碘-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物38); 4-溴-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物39); 4-乙基-2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物40); 2-(2-氟-4-甲基苯基)-4-(丙-2-基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物41); 5-(6-胺基嘧啶-4-基)-2-(2,4-二氯苯基)-1H-吡咯-3-甲醯胺(化合物42) 2-(2,4-二氯苯基)-5-(1H-吡唑-4-基)-1H-吡咯-3-甲醯胺(化合物43); 2-(2,4-二氯苯基)-5-(3-甲基-1H-吡唑-4-基)-1H-吡咯-3-甲醯胺(化合物44); 5-(2-胺基-1,3-噻唑-4-基)-2-(2,4-二氯苯基)-1H-吡咯-3-甲醯胺(化合物45); 2-(2,4-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物46); 2-(2,4-二氯苯基)-5-(1H-吡唑并[3,4-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物47); 2-(2,4-二氯苯基)-5-[3-(三氟甲基)-1H-吡唑-4-基]-1H-吡咯-3-甲醯胺(化合物48); 2-(2-氟-4-甲基苯基)-5-(1H-吡唑-4-基)-1H-吡咯-3-甲醯胺(化合物49); 5-(3,5-二甲基-1H-吡唑-4-基)-2-(2-氟-4-甲基苯基)-1H-吡咯-3-甲醯胺(化合物50); 2-(2-氟-4-甲基苯基)-5-(1-甲基-1H-吡唑-4-基)-1H-吡咯-3-甲醯胺(化合物51); 2-(2-氟-4-甲基苯基)-5-(3-甲基-1H-吡唑-4-基)-1H-吡咯-3-甲醯胺(化合物52); 2-(2-氟-4-甲基苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物53); 2-(2,4-二氯苯基)-1-(2-羥乙基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物54); 2-(2,4-二氯苯基)-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1-(3,3,3-三氟丙基)-1H-吡咯-3-甲醯胺(化合物55); 2-(2,4-二氯苯基)-1-甲基-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物56);及 2-(2,4-二氯苯基)-1-乙基-5-(1H-吡咯并[2,3-b]吡啶-4-基)-1H-吡咯-3-甲醯胺(化合物57)。
- 一種用於製備如請求項1之式(I)化合物或其醫藥上可接受之鹽之方法,該方法包括下列步驟: 步驟1)式(II)化合物: 其中R5係氫或視需要經取代之直鏈或分支鏈(C 1-C 3)烷基且X係鹵素,與合適之式(III)有機硼酸衍生物之金屬催化偶合反應 其中R1係如請求項1中定義; 步驟2)如此獲得之式(IV)化合物之鹵化: 其中R1及R5係如上文步驟1中定義,因此獲得式(V)化合物: 其中R1及R5係如上文步驟1中定義且X係鹵素; 步驟3)式(V)化合物與合適之式(VI)有機硼酸衍生物之金屬催化偶合反應: 其中R2係如請求項1中定義,因此獲得式(VII)化合物: 其中R1及R5係如上文步驟1中定義且R2係如步驟3中定義; 自步驟3獲得之R5為氫的式(VII)化合物可遵循於上文步驟2中已報導之條件根據下文轉化1轉化為R5為鹵素(X)的另一式(VII)化合物: 轉化1) ; 步驟4)自步驟3或轉化1獲得之式(VII)化合物之保護: 其中R1及R2係分別如上文步驟1及步驟3中定義,及R5係氫、鹵素或視需要經取代之直鏈或分支鏈(C 1-C 3)烷基,藉由與合適保護基反應,因此獲得式(VIII)之羧酸酯: 其中R1、R2及R5係如上文定義及PG係保護基,諸如三甲基矽基乙氧基甲基(SEM)、第三丁氧基羰基(BOC)或苯磺醯基; 步驟5)式(VIII)羧酸酯在鹼性條件下水解,因此產生式(IX)之羧酸: 其中R1、R2、R5及PG係如上文步驟4中定義; 步驟6)式(IX)中間物藉由與式(X)胺衍生物反應之醯胺化: 其中R3係如請求項1中定義; 步驟7)所得式(XI)化合物之去保護: 其中R1、R2、R5及PG係如上文步驟5下定義及R3係如步驟6下定義,產生式(I)化合物: 其中R1、R2、R3係如請求項1中定義及R4係氫;或 其中R5為鹵素的式(VIII)中間化合物可遵循包括下列轉化之方法轉化為式(XI)中間物: 轉化2) 遵循已報導於步驟3中的此項技術中已知用於鈀催化反應之條件,將式(VIII)化合物(其中R1及R2係如請求項1中定義)轉化為式(VIII)化合物(其中R5係視需要經取代之直鏈或分支鏈(C 1-C 3)烯基鏈): ; 使如此獲得之(VIII)化合物在步驟5及6中報導之條件下反應: , 因此獲得化合物(XIa),其中R1、R2及R5係如上文定義; 轉化3) 遵循此項技術中已知用於還原雙鍵/氫化之條件,將如此獲得之式(XIa)化合物轉化為式(XI)化合物: 其中R1、R2及R3係如請求項1中定義及R5係視需要經取代之直鏈或分支鏈(C 1-C 3)烷基;或 或者,可根據包括下列步驟之方法製備式(I)化合物,其中R1及R2係如請求項1中定義,R3及R4係氫及R5係氫或視需要經取代之直鏈或分支鏈(C 1-C 3)烷基: 步驟8)式(XII)化合物之保護: 其中R2係如請求項1中定義及R5係氫或視需要經取代之直鏈或分支鏈(C 1-C 3)烷基; 步驟9)如此獲得之式(XIII)化合物之鹵化: 其中R2及R5係如上文步驟8下定義及PG係保護基,諸如SEM、BOC或苯磺醯基; 步驟10)所得式(XIV)化合物: 其中R2、R5及PG係如上文步驟9中定義及X係鹵素,與合適之式(III)有機硼酸衍生物之金屬催化偶合反應: 其中R1係如請求項1中定義; 步驟11)如此獲得之式(XV)化合物之水解: 其中R1、R2、R5及PG係如上文步驟10中定義,因此產生相應之式(XVI)醯胺中間物; 步驟12)式(XVI)化合物之去保護,產生式(I)化合物: 其中R1及R2係如請求項1中定義,R3及R4係氫及R5係如上文步驟8下定義;或 或者,可遵循包括下列步驟之方法製備式(I)化合物,其中R1、R2及R4係如請求項1中定義,R3係氫及R5係氫或視需要經取代之直鏈或分支鏈(C 1-C 4)烷基鏈: 步驟13)使式(XII)衍生物: 其中R2係如請求項1中定義及R5係氫或視需要經取代之直鏈或分支鏈(C 1-C 4)烷基,與式(XVII)之鹵基衍生物: 其中R4係視需要經取代之直鏈或分支鏈C 1-C 6烷基或視需要經取代之直鏈或分支鏈C 2-C 6烯基及X係鹵素,在鹼存在下或藉由添加金屬觸媒反應; 步驟14)如此獲得之式(XVIII)化合物之鹵化: 其中R2、R4及R5係如上文步驟13中定義; 步驟15)所得式(XIX)化合物: 其中X係鹵素及R2、R3及R4係如上文步驟13中定義,與合適之式(III)有機硼酸衍生物之金屬催化偶合反應 其中R1係如請求項1中定義; 步驟16)如此獲得之式(XX)中間物之水解: 產生式(I)化合物: 其中R1及R2係如請求項1中定義,R3係氫,R4係如步驟13中定義及R5係氫或視需要經取代之直鏈或分支鏈(C 1-C 4)烷基鏈。
- 一種醫藥組合物,其包含如請求項1之式(I)化合物或其醫藥上可接受之鹽,及至少一種醫藥上可接受之賦形劑、載劑或稀釋劑。
- 如請求項7之醫藥組合物,其進一步包含一或多種化學治療劑。
- 一種用於抑制Cdc7激酶活性之活體外方法,其包括使該蛋白質與有效量之如請求項1之式(I)化合物接觸。
- 一種產品或套組,其包含如請求項1之式(I)化合物或其醫藥上可接受之鹽,及一或多種化學治療劑,作為組合製劑用於同時、分開或循序用於抗癌療法中。
- 如請求項1之式(I)化合物或其醫藥上可接受之鹽,其用作藥劑。
- 一種如請求項1之式(I)化合物或其醫藥上可接受之鹽之用途,其用以製造用於治療失調之Cdc7激酶活性所引起及/或相關聯之疾病之藥劑。
- 如請求項12之用途,其中該疾病係選自由以下組成之群:癌症及細胞增殖性疾病。
- 如請求項13之用途,其中該癌症係選自由以下組成之群:癌,諸如膀胱、乳房、腎、肝、結腸、肺,包括小細胞肺癌、食道、膽囊、卵巢、胰臟、胃、子宮頸、前列腺、頭頸及皮膚,包括鱗狀細胞癌;淋巴譜系之造血腫瘤,包括白血病、急性淋巴細胞性白血病、急性淋巴胚細胞性白血病、B細胞淋巴瘤、血管免疫母細胞性T細胞淋巴瘤、霍奇金氏淋巴瘤(Hodgkin's lymphoma)、非霍奇金氏淋巴瘤、毛細胞淋巴瘤,外套細胞淋巴瘤及勃兒基特氏淋巴瘤(Burkitt's lymphoma);骨髓譜系之造血腫瘤,包括急性及慢性骨髓性白血病、骨髓增生異常(myelodysplastic)症候群及前髓細胞白血病;間葉源性腫瘤,包括纖維肉瘤及橫紋肌肉瘤;中樞及周圍神經系統之腫瘤,包括神經膠質瘤、神經膠質母細胞瘤、多形性神經膠質母細胞瘤、星細胞瘤、寡樹突神經膠質瘤、副神經膠質瘤、神經胚細胞瘤及神經鞘瘤;及其他腫瘤,包括黑色素瘤、精原細胞瘤、畸胎上皮癌(teratocarcinoma)、骨肉瘤、著色性乾皮症(pigmentosum)、角化黃瘤(keratoxanthoma)、甲狀腺癌,諸如乳突甲狀腺癌及甲狀腺髓質癌、卡波西肉瘤(Kaposi's sarcoma)、軟骨肉瘤、膽管癌、頭頸部腫瘤。
- 如請求項12之用途,其與放射療法、標靶療法、免疫療法或化療方案組合。
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WO2007110344A1 (en) | 2006-03-27 | 2007-10-04 | Nerviano Medical Sciences S.R.L. | Pyridyl- and pyrimidinyl-substituted pyrrole-, thiophene- and furane-derivatives as kinase inhibitors |
EP2203442B1 (en) | 2007-09-28 | 2012-06-20 | Nerviano Medical Sciences S.r.l. | Substituted pyrrolo-pyrimidine derivatives, process for their preparation and their use as kinase inhibitors |
TWI426074B (zh) | 2008-04-30 | 2014-02-11 | Nerviano Medical Sciences Srl | 5-(2-胺基-嘧啶-4-基)-2-芳基-1h-吡咯-3-羧醯胺之製造方法 |
WO2013014039A1 (en) | 2011-07-28 | 2013-01-31 | Nerviano Medical Sciences S.R.L. | Alkynyl substituted pyrimidinyl-pyrroles active as kinases inhibitors |
CN104507923B (zh) | 2012-08-02 | 2018-02-09 | 内尔维阿诺医学科学有限公司 | 作为激酶抑制剂的取代的吡咯类活性剂 |
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WO2022207404A1 (en) | 2022-10-06 |
IL307251A (en) | 2023-11-01 |
AU2022251756A1 (en) | 2023-11-16 |
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