CN108699057B - 5-取代的2-(吗啉-4-基)-1,7-萘啶 - Google Patents
5-取代的2-(吗啉-4-基)-1,7-萘啶 Download PDFInfo
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- CN108699057B CN108699057B CN201780014935.7A CN201780014935A CN108699057B CN 108699057 B CN108699057 B CN 108699057B CN 201780014935 A CN201780014935 A CN 201780014935A CN 108699057 B CN108699057 B CN 108699057B
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- Prior art keywords
- methyl
- pyrazol
- methylmorpholin
- leu
- naphthyridine
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- -1 5-substituted 2- (morpholin-4-yl) -1, 7-naphthyridines Chemical class 0.000 title claims abstract description 220
- 150000001875 compounds Chemical class 0.000 claims abstract description 265
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 42
- 238000011282 treatment Methods 0.000 claims abstract description 36
- 201000010099 disease Diseases 0.000 claims abstract description 34
- 239000004480 active ingredient Substances 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims description 125
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 66
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
- 150000003839 salts Chemical class 0.000 claims description 45
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 32
- 239000003814 drug Substances 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000000824 cytostatic agent Substances 0.000 claims description 5
- 230000001085 cytostatic effect Effects 0.000 claims description 5
- 231100000433 cytotoxic Toxicity 0.000 claims description 5
- 230000001472 cytotoxic effect Effects 0.000 claims description 5
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 5
- 229910005948 SO2Cl Inorganic materials 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- TXLSLFAMHPYNKD-CYBMUJFWSA-N (3R)-3-methyl-4-[5-methyl-4-(2-methyl-1,3-thiazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound C[C@@H]1COCCN1C1=CC(C2=CN=C(C)S2)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 TXLSLFAMHPYNKD-CYBMUJFWSA-N 0.000 claims description 2
- OXRXVUFXWUHKFH-OAHLLOKOSA-N (3R)-3-methyl-4-[5-methyl-4-(2-methyl-6-methylsulfonylpyridin-3-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound C[C@@H]1COCCN1C1=CC(C2=CC=C(N=C2C)S(C)(=O)=O)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 OXRXVUFXWUHKFH-OAHLLOKOSA-N 0.000 claims description 2
- NEDVPBWGQIFKMF-CQSZACIVSA-N (3R)-3-methyl-4-[5-methyl-4-(2-methylpyrazol-3-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound CC1=C2C(=CC(=NC2=C(N=C1)C1=CC=NN1)N1[C@@H](COCC1)C)C1=CC=NN1C NEDVPBWGQIFKMF-CQSZACIVSA-N 0.000 claims description 2
- ORCLMIDYEJMJAU-CQSZACIVSA-N (3R)-3-methyl-4-[5-methyl-4-(3-methylimidazol-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound CC1=C2C(=CC(=NC2=C(N=C1)C1=CC=NN1)N1[C@@H](COCC1)C)C1=CN=CN1C ORCLMIDYEJMJAU-CQSZACIVSA-N 0.000 claims description 2
- RDHKKZKPLZVGRF-MRXNPFEDSA-N (3R)-3-methyl-4-[5-methyl-4-(4-methylsulfonylpiperazin-1-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound C[C@@H]1COCCN1C1=CC(N2CCN(CC2)S(C)(=O)=O)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 RDHKKZKPLZVGRF-MRXNPFEDSA-N 0.000 claims description 2
- ZMSOXGOCLSWZJT-ZYRTVQBDSA-N (3R)-3-methyl-4-[5-methyl-4-[methyl(2-methylpropoxy)phosphoryl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound CC(C)COP(C)(=O)C1=C2C(C)=CN=C(C3=CC=NN3)C2=NC(=C1)N1CCOC[C@H]1C ZMSOXGOCLSWZJT-ZYRTVQBDSA-N 0.000 claims description 2
- QQAJWYGKLULJTC-CQSZACIVSA-N (3R)-3-methyl-4-[5-methyl-4-propan-2-yloxy-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound CC(C)OC1=C2C(C)=CN=C(C3=CC=NN3)C2=NC(=C1)N1CCOC[C@H]1C QQAJWYGKLULJTC-CQSZACIVSA-N 0.000 claims description 2
- BOJWUFJLJWGSJF-CQSZACIVSA-N (3R)-4-[4-(2,3-difluorophenyl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound C[C@@H]1COCCN1C1=CC(C2=C(F)C(F)=CC=C2)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 BOJWUFJLJWGSJF-CQSZACIVSA-N 0.000 claims description 2
- VMANOFJCAXUHCN-CYBMUJFWSA-N (3R)-4-[4-(2-chloro-3-methylimidazol-4-yl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound C[C@@H]1COCCN1C1=CC(C2=CN=C(Cl)N2C)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 VMANOFJCAXUHCN-CYBMUJFWSA-N 0.000 claims description 2
- OEQSHZAKOGOMFO-GOSISDBHSA-N (3R)-4-[4-(2-fluoro-4-piperazin-1-ylphenyl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound C[C@@H]1COCCN1C1=CC(C2=C(F)C=C(C=C2)N2CCNCC2)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 OEQSHZAKOGOMFO-GOSISDBHSA-N 0.000 claims description 2
- QGOAOXQTSNIWRO-CQSZACIVSA-N (3R)-4-[4-(2-fluoropyridin-3-yl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound C[C@@H]1COCCN1C1=CC(C2=CC=CN=C2F)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 QGOAOXQTSNIWRO-CQSZACIVSA-N 0.000 claims description 2
- PEFRLTGYMAIBOE-AIGSFVTNSA-N (3R)-4-[4-[ethoxy(methyl)phosphoryl]-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound CCOP(C)(=O)c1cc(nc2c(ncc(C)c12)-c1ccn[nH]1)N1CCOC[C@H]1C PEFRLTGYMAIBOE-AIGSFVTNSA-N 0.000 claims description 2
- YGKAXRXFRVLWOS-CYBMUJFWSA-N (3R)-4-[4-dimethylphosphoryl-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound C[C@@H]1COCCN1C1=CC(=C2C(C)=CN=C(C3=CC=NN3)C2=N1)P(C)(C)=O YGKAXRXFRVLWOS-CYBMUJFWSA-N 0.000 claims description 2
- VZDIJHHZQJEPIA-MRXNPFEDSA-N N-(2,2-dimethylpropyl)-N,5-dimethyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-amine Chemical compound C[C@@H]1COCCN1C1=CC(N(C)CC(C)(C)C)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 VZDIJHHZQJEPIA-MRXNPFEDSA-N 0.000 claims description 2
- ZKHUNSZQDLJQTM-MRXNPFEDSA-N [1-[5-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl]piperidin-4-yl]methanol Chemical compound C[C@@H]1COCCN1C1=CC(N2CCC(CO)CC2)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 ZKHUNSZQDLJQTM-MRXNPFEDSA-N 0.000 claims description 2
- ICRLFNNZXAVRSM-GFCCVEGCSA-N methyl 5-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-naphthyridine-4-carboxylate Chemical compound COC(=O)C1=C2C(C)=CN=C(C3=CC=NN3)C2=NC(=C1)N1CCOC[C@H]1C ICRLFNNZXAVRSM-GFCCVEGCSA-N 0.000 claims description 2
- HMAFHVDVWJJOGN-QGZVFWFLSA-N (3R)-3-methyl-4-[5-methyl-4-(1-methylindol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound CC1=C2C(=CC(=NC2=C(N=C1)C1=CC=NN1)N1[C@@H](COCC1)C)C=1C=C2C=CN(C2=CC=1)C HMAFHVDVWJJOGN-QGZVFWFLSA-N 0.000 claims 1
- SIXNUKIYYDCJRY-MRXNPFEDSA-N (3R)-3-methyl-4-[5-methyl-4-(2-methylsulfonylphenyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound CC1=C2C(=CC(=NC2=C(N=C1)C1=CC=NN1)N1[C@@H](COCC1)C)C1=C(C=CC=C1)S(=O)(=O)C SIXNUKIYYDCJRY-MRXNPFEDSA-N 0.000 claims 1
- VJVZSITYFXZVII-GOSISDBHSA-N (3R)-3-methyl-4-[5-methyl-4-(2-propan-2-ylphenyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound CC(C)C1=C(C=CC=C1)C1=C2C(C)=CN=C(C3=CC=NN3)C2=NC(=C1)N1CCOC[C@H]1C VJVZSITYFXZVII-GOSISDBHSA-N 0.000 claims 1
- LTJXKSQYXOIWOH-MRXNPFEDSA-N (3R)-3-methyl-4-[5-methyl-4-(3-methylpyridin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound C[C@@H]1COCCN1C1=CC(C2=C(C)C=NC=C2)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 LTJXKSQYXOIWOH-MRXNPFEDSA-N 0.000 claims 1
- PIWGUHNETFHILR-MRXNPFEDSA-N (3R)-3-methyl-4-[5-methyl-4-(3-methylsulfonylphenyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound CC1=C2C(=CC(=NC2=C(N=C1)C1=CC=NN1)N1[C@@H](COCC1)C)C1=CC(=CC=C1)S(=O)(=O)C PIWGUHNETFHILR-MRXNPFEDSA-N 0.000 claims 1
- KMSAQFOAARJFDX-GOSISDBHSA-N (3R)-3-methyl-4-[5-methyl-4-(3-propan-2-yloxyphenyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound CC1=C2C(=CC(=NC2=C(N=C1)C1=CC=NN1)N1[C@@H](COCC1)C)C1=CC(=CC=C1)OC(C)C KMSAQFOAARJFDX-GOSISDBHSA-N 0.000 claims 1
- RZWQIEYYAQJGEI-MRXNPFEDSA-N (3R)-3-methyl-4-[5-methyl-4-(4-methylpyridin-3-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound C[C@@H]1COCCN1c1cc(-c2cnccc2C)c2c(C)cnc(-c3ccn[nH]3)c2n1 RZWQIEYYAQJGEI-MRXNPFEDSA-N 0.000 claims 1
- PNTDYSYBERUSEH-MRXNPFEDSA-N (3R)-3-methyl-4-[5-methyl-4-(4-methylsulfanylphenyl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound CC1=C2C(=CC(=NC2=C(N=C1)C1=CC=NN1)N1[C@@H](COCC1)C)C1=CC=C(C=C1)SC PNTDYSYBERUSEH-MRXNPFEDSA-N 0.000 claims 1
- DNJICMSXIXKLEU-MRXNPFEDSA-N (3R)-3-methyl-4-[5-methyl-4-phenyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]morpholine Chemical compound C[C@@H]1COCCN1C1=CC(C2=CC=CC=C2)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 DNJICMSXIXKLEU-MRXNPFEDSA-N 0.000 claims 1
- MDNYGAMEFDKZMA-CYBMUJFWSA-N (3R)-3-methyl-4-[5-methyl-8-(1H-pyrazol-5-yl)-4-(2,3,5-trifluorophenyl)-1,7-naphthyridin-2-yl]morpholine Chemical compound C[C@@H]1COCCN1c1cc(-c2cc(F)cc(F)c2F)c2c(C)cnc(-c3ccn[nH]3)c2n1 MDNYGAMEFDKZMA-CYBMUJFWSA-N 0.000 claims 1
- AJZWIDOHFZREJY-QGZVFWFLSA-N (3R)-3-methyl-4-[5-methyl-8-(1H-pyrazol-5-yl)-4-quinolin-3-yl-1,7-naphthyridin-2-yl]morpholine Chemical compound C[C@@H]1COCCN1C1=CC(C2=CC3=CC=CC=C3N=C2)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 AJZWIDOHFZREJY-QGZVFWFLSA-N 0.000 claims 1
- RIYIKEFCTXFBQU-QGZVFWFLSA-N (3R)-3-methyl-4-[5-methyl-8-(1H-pyrazol-5-yl)-4-quinolin-4-yl-1,7-naphthyridin-2-yl]morpholine Chemical compound C[C@@H]1COCCN1C1=CC(C2=CC=NC3=CC=CC=C23)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 RIYIKEFCTXFBQU-QGZVFWFLSA-N 0.000 claims 1
- MATBIODSLGTTFH-MRXNPFEDSA-N (3R)-4-[4-(1H-indol-4-yl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound C[C@@H]1COCCN1C1=CC(C2=C3C=CNC3=CC=C2)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 MATBIODSLGTTFH-MRXNPFEDSA-N 0.000 claims 1
- HCDJCBNVDORPMG-MRXNPFEDSA-N (3R)-4-[4-(1H-indol-6-yl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound C[C@@H]1COCCN1C1=CC(C2=CC=C3C=CNC3=C2)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 HCDJCBNVDORPMG-MRXNPFEDSA-N 0.000 claims 1
- HDOGZHYLNGEBMS-MRXNPFEDSA-N (3R)-4-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound C[C@@H]1COCCN1c1cc(-c2ccc3OCCOc3c2)c2c(C)cnc(-c3ccn[nH]3)c2n1 HDOGZHYLNGEBMS-MRXNPFEDSA-N 0.000 claims 1
- ASYCMQYSMZIZID-MRXNPFEDSA-N (3R)-4-[4-(2,3-dimethoxyphenyl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound COC1=CC=CC(=C1OC)C1=C2C(C)=CN=C(C3=CC=NN3)C2=NC(=C1)N1CCOC[C@H]1C ASYCMQYSMZIZID-MRXNPFEDSA-N 0.000 claims 1
- FNUCQSOPJSQQDJ-CQSZACIVSA-N (3R)-4-[4-(2,4-dichlorophenyl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound C[C@@H]1COCCN1C1=CC(C2=C(Cl)C=C(Cl)C=C2)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 FNUCQSOPJSQQDJ-CQSZACIVSA-N 0.000 claims 1
- DDDXGGGAUPXKHR-OAHLLOKOSA-N (3R)-4-[4-(2-fluoro-3-methoxyphenyl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound FC1=C(C=CC=C1OC)C1=CC(=NC2=C(N=CC(=C12)C)C1=CC=NN1)N1[C@@H](COCC1)C DDDXGGGAUPXKHR-OAHLLOKOSA-N 0.000 claims 1
- GSTOHAFBYYDDSU-OAHLLOKOSA-N (3R)-4-[4-(2-methoxypyridin-3-yl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound COC1=NC=CC=C1C1=C2C(C)=CN=C(C3=CC=NN3)C2=NC(=C1)N1CCOC[C@H]1C GSTOHAFBYYDDSU-OAHLLOKOSA-N 0.000 claims 1
- QQKLRXCROWFVIK-MRXNPFEDSA-N (3R)-4-[4-(3,5-dimethoxyphenyl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound COc1cc(OC)cc(c1)-c1cc(nc2c(ncc(C)c12)-c1ccn[nH]1)N1CCOC[C@H]1C QQKLRXCROWFVIK-MRXNPFEDSA-N 0.000 claims 1
- WRLCDHHQXZABLT-OAHLLOKOSA-N (3R)-4-[4-(4-chloro-2-methoxyphenyl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound ClC1=CC(=C(C=C1)C1=CC(=NC2=C(N=CC(=C12)C)C1=CC=NN1)N1[C@@H](COCC1)C)OC WRLCDHHQXZABLT-OAHLLOKOSA-N 0.000 claims 1
- FCMUOPFTRWJYMB-MRXNPFEDSA-N (3R)-4-[4-(4-chloro-3-methylphenyl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound ClC1=C(C=C(C=C1)C1=CC(=NC2=C(N=CC(=C12)C)C1=CC=NN1)N1[C@@H](COCC1)C)C FCMUOPFTRWJYMB-MRXNPFEDSA-N 0.000 claims 1
- ZNYDAKXSZVCCQZ-OAHLLOKOSA-N (3R)-4-[4-(4-fluorophenyl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound C[C@@H]1COCCN1C1=CC(C2=CC=C(F)C=C2)=C2C(C)=CN=C(C3=CC=NN3)C2=N1 ZNYDAKXSZVCCQZ-OAHLLOKOSA-N 0.000 claims 1
- HWHCOEQBLYPBBA-MRXNPFEDSA-N (3R)-4-[4-(4-methoxyphenyl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound COC1=CC=C(C=C1)C1=CC(=NC2=C(N=CC(=C12)C)C1=CC=NN1)N1[C@@H](COCC1)C HWHCOEQBLYPBBA-MRXNPFEDSA-N 0.000 claims 1
- MROBSVMBBZKBPA-OAHLLOKOSA-N (3R)-4-[4-(5-methoxypyridin-3-yl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound COc1cncc(c1)-c1cc(nc2c(ncc(C)c12)-c1ccn[nH]1)N1CCOC[C@H]1C MROBSVMBBZKBPA-OAHLLOKOSA-N 0.000 claims 1
- BNZBJVDXFSUINY-CQSZACIVSA-N (3R)-4-[4-(6-fluoropyridin-3-yl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound FC1=CC=C(C=N1)C1=CC(=NC2=C(N=CC(=C12)C)C1=CC=NN1)N1[C@@H](COCC1)C BNZBJVDXFSUINY-CQSZACIVSA-N 0.000 claims 1
- DPFYJOWCUIVMQN-OAHLLOKOSA-N (3R)-4-[4-(6-methoxypyridin-3-yl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound COC1=CC=C(C=N1)C1=C2C(C)=CN=C(C3=CC=NN3)C2=NC(=C1)N1CCOC[C@H]1C DPFYJOWCUIVMQN-OAHLLOKOSA-N 0.000 claims 1
- VRQLVUIFYRVTIQ-OAHLLOKOSA-N (3R)-4-[4-(cyclopenten-1-yl)-5-methyl-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-2-yl]-3-methylmorpholine Chemical compound C1(=CCCC1)C1=CC(=NC2=C(N=CC(=C12)C)C1=CC=NN1)N1[C@@H](COCC1)C VRQLVUIFYRVTIQ-OAHLLOKOSA-N 0.000 claims 1
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Classifications
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- 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
- A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Abstract
本发明涉及通式(I)或(Ib)的5‑取代的2‑(吗啉‑4‑基)‑1,7‑萘啶化合物、制备所述化合物的方法、用于制备所述化合物的中间体化合物、包含所述化合物的药物组合物和组合以及所述化合物在制备用于治疗或预防疾病的药物组合物中的用途,特别是所述化合物作为唯一药剂或与其他活性成分组合用于制备治疗或预防过度增殖性疾病的药物组合物中的用途。
Description
技术领域
本发明涉及取代的5-烷基-或5-烷氧基-2-(吗啉-4-基)-1,7-萘啶化合物,其制备方法及其用途。
背景技术
真核细胞基因组的完整性由称为DNA损伤应答(DDR)的复杂的信号传导通路和多个DNA修复机制保护。意识到DNA损伤后,DDR通路的激活导致细胞周期阻滞、总的翻译的抑制、DNA修复的诱导、并且最终导致细胞存活或细胞死亡。直接识别异常DNA结构的蛋白质,例如通过与双链DNA末端结合识别DNA双链断裂的MRE11-Rad50-Nbs1复合物或者与单链DNA结合的RPA(复制蛋白A),募集并激活DDR通路最上游的激酶、ATM(共济失调毛细血管扩张突变)、ATR(ATM-和Rad3-相关的,UniProtKB/Swiss-Prot Q13535)和DNA-PKcs(DNA-依赖性蛋白激酶)。而ATM主要由DNA双链断裂活化,并且DNA-PKcs主要涉及DNA修复的非同源末端连接过程,ATR响应广泛的DNA损伤,包括双链断裂和损伤,其源自DNA复制的干扰。ATM下游信号传导的主要组分包括Chk2和p53,而ATR信号传导涉及Chk1和cdc25。在小鼠中敲除ATR基因是胚胎致命的并且ATR敲除细胞出现染色体断裂并经历细胞凋亡[E.J.Brown,D.Baltimore:ATR disruption leads to chromosomal fragmentation and earlyembryonic lethality.Genes Dev.14,397-402,2000]。相反,ATM对于细胞存活不是必须的,但ATM敲除细胞对于导致DNA双链断裂的电离辐射和药剂高度敏感。
与ATRIP(ATR-相互作用蛋白,UniProtKB/Swiss-Prot Q8WXE1)形成复合物的ATR要由停顿复制时螺旋酶的连续DNA解链活动产生的长段单链DNA活化。这种由停顿复制叉(stalled replication fork)加强的复制应激可以由下列诱导:紫外光、某些化疗药物、羟基脲或异常致癌信号传导,其导致增加的复制启动或最初放电(origin firing)。ATR的活化通过Chk1-cdc25通路导致阻止细胞周期在S或G2期并且导致对最近的最初放电的抑制。细胞得到时间来解决复制应激并且最终在已经除去应激源之后重新开始复制。由于ATR通路确保在复制应激后细胞存活,其可能有助于抵抗化疗。因此,ATR激酶活性的抑制可能可用于癌症治疗。
在致癌基因驱动的肿瘤细胞(例如Ras突变/上调、Myc上调、CyclinE过表达)中观察到与健康正常细胞相比增加的复制应激。已报道在Ras致癌基因驱动的细胞中的ATR抑制导致大量肿瘤细胞杀死[O.Gilad,BY Nabet等人:Combining ATR suppression withoncogenic Ras synergistically increases genomic instability,causing syntheticlethality or tumorigenesis in a dosage-dependent manner.Cancer Res.70,9693-9702,2010]。
虽然ATM和ATR主要由不同类型的DNA损伤活化,但其信号传导包括一些交叉,由此它们可以至少部分替换彼此的功能。这一发现表明药物抑制ATR的一些肿瘤细胞选择性。具有平行的ATM和ATR通路的健康正常细胞在诱导DNA损伤时甚至在ATR抑制剂存在的情况下阻止细胞周期在G1期。相反,在ATR抑制剂的存在下,最通常缺乏ATM和/或p53信号传导的肿瘤细胞依赖ATR通路并且经历细胞死亡。这表明ATR抑制剂可用于治疗缺乏ATM信号传导和/或p53功能的肿瘤。
DDR信号传导和ATM和ATR的功能作用的细节最近综述于:E.Fokas,R.Prevo等人:Targeting ATR in DNA damage response and cancer therapeutics.Cancer TreatmentRev 40,109-117,2014.J.M.Wagner&S.H.Kaufmann:Prospects for the use of ATRinhibitors to treat cancer。Pharmaceuticals 3,1311-1334,2010.D.Woods&J.J.Tuchi:Chemotherapy induced DNA damage response.Cancer Biol.Thera.14,379-389,2013.A.Marechal&L.Zou:DNA damage sensing by the ATM and ATR kinases.ColdSpring Harb.Perspect.Biol.5,a012716,2013.M.K.Zeman&K.A.Cimprich:Causes andconsequences of replication stress.Nat.Cell Biol.16,2-9,2014.S.Llona-Minguez,A.et al.:Chemical strategies for development of ATRinhibitors.Exp.Rev.Mol.Med.16,e10,2014。
已知ATR激酶的一些抑制剂(J.Med.Chem.2013,56,2125-2138;Exp.Rev.Mol.Med.16,e10,2014;WO2010054398A1;WO2010071837A1;WO2010073034A1;WO2011143399A1;WO2011143419A1;WO2011143422A1;WO2011143423A2;WO2011143425A2;WO2011143426A1;WO2011154737A1;WO2011163527A1;WO2012138938A1;WO2012178123A1;WO2012178124A1;WO2012178125A1;WO2013049719A1;WO2013049720A1;WO2013049722A1;WO2013049859A1;WO2013071085A1;WO2013071088A1;WO2013071090A1;WO2013071093A1;WO2013071094A1;WO2013152298A1;WO2014062604A1;WO2014089379A1;WO2014143240)。
WO 0058307描述了作为NK3受体配体的芳基稠合的2,4-二取代的吡啶。但是,没有例示1,7-萘啶化合物。
WO 2006039718描述了用于预防和治疗蛋白激酶介导的疾病的芳基含氮双环化合物。但是,没有例示1,7-萘啶化合物。
WO 2008017461和the Journal of Medicinal Chemistry 2011,54(22),7899-7910描述了作为p38MAP激酶抑制剂的1,7-萘啶衍生物。所述1,7-萘啶衍生物的8位被苯环取代。没有例示1,7-萘啶化合物,其在所述1,7-萘啶的8位被杂芳基取代。
需要开发用于治疗疾病,特别是过度增殖性疾病的ATR抑制剂。本发明所要解决的问题是提供抑制ATR的其他化合物。令人惊讶地发现通式(I)或(Ib)的5-烷基-和5-烷氧基-2-(吗啉-4-基)-1,7-萘啶抑制ATR。
根据第一方面,本发明包括通式(I)化合物
其中:
R1代表选自以下的基团:
其中*表示所述基团与分子剩余部分的连接点;
R2代表氢、卤素、-NR7R8、CN、C1-C6-烷基、C1-C6-烷氧基、3-至10-元杂环烷氧基、C2-C6-烯基、C3-C6-环烷基、C4-C6-环烯基、3-至10-元杂环烷基、4-至10-元杂环烯基、苯基、杂芳基、-(CO)OR7、-(CO)NR7R8、-(SO2)R9、-(SO)R9、-SR9、-(SO2)NR7R8、-NR7(SO2)R9、-((SO)=NR11)R10、-N=(SO)R9R10、-SiR10R11R12、–(PO)(OR7)2、–(PO)(OR7)R10或–(PO)(R10)2,
其中各C1-C6-烷基、C1-C6-烷氧基、3-至10-元杂环烷氧基、C2-C6-烯基、C3-C6-环烷基、3-至10-元杂环烷基、苯基或杂芳基彼此独立地任选被下列基团取代一次或多次:卤素、OH、-CN、-NR7R8、C1-C6-烷基、C1-C6-卤代烷基、C1-C4-羟基烷基、苯基-C1-C4-烷基、(C1-C4-烷氧基)-(C1-C4-烷基)-、C1-C6-烷氧基、C3-C6-环烷基、3-至6-元杂环烷基、苯基、-(CO)OR7、-(CO)NR7R8、-NR7(CO)R10、-NR8(CO)OR7、-NR8(CO)NR7R8、-(SO2)R9、-(SO)R9、-SR9、-(SO2)NR7R8、-NR7(SO2)R9、-((SO)=NR11)R10、-N=(SO)R9R10、-(PO)(OR7)2、–(PO)(OR7)R10、–(PO)(R10)2或任选被C1-C4-烷基取代一次或多次的杂芳基,或
其中与苯环两个相邻原子相连的所述苯基的两个取代基彼此连接以形成亚甲基二氧基、亚乙基二氧基、亚乙基氧基或三亚甲基氧基基团;
其中各4-至10-元杂环烯基彼此独立地任选被C1-C4-烷基取代一次或多次;
R3、R4彼此独立地代表氢或甲基;
R5代表C1-C6-烷基、C1-C6-卤代烷基或C1-C6-烷氧基;
R7、R8彼此独立地代表氢、C1-C6-烷基、C3-C6-环烷基、苯基或苯基-CH2-,所述苯基任选被卤素取代一次或多次;或
R7和R8一起代表4-、5-、6-或7-元环胺基团,其彼此独立地任选被下列基团取代一次或多次:C1-C6-烷基、C1-C6-卤代烷基,所述4-、5-、6-或7-元环胺基团任选含有一个另外的选自O、N和S的杂原子;
R9代表C1-C4-烷基或苯基,其中各C1-C4-烷基或苯基彼此独立地任选被下列基团取代一次或多次:R13;
R10代表C1-C4-烷基;或
R9和R10一起,在-N=(SO)R9R10基团的情况下,代表5-至8-元杂环烷基;
R11代表氢、C1-C4-烷基、-(CO)OR7、-(CO)NR7R8或CN;
R12代表氢或C1-C4-烷基;
R13代表卤素、OH、-NR7R8、CN、NO2、C1-C6-烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基、C2-C6-烯基、C3-C6-环烷基、-(CO)OR7或-(CO)NR7R8;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
本文中提及的术语具有下列含义:
术语“卤素原子”、“卤代-”或“卤-”应被理解为是指氟、氯、溴或碘原子。
术语“C1-C6-烷基”应被理解为是指具有1、2、3、4、5或6个碳原子的直链或支链的饱和单价烃基团,例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基,或其异构体。具体地,所述基团具有1、2、3或4个碳原子(“C1-C4-烷基”),例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基,更具体地具有1、2或3碳原子(“C1-C3-烷基”),例如甲基、乙基、正丙基或异丙基。
术语“C1-C6-卤代烷基”应被理解为是指直链或支链饱和单价烃基,其中术语“C1-C6-烷基”如上文所定义,和其中一个或多个氢原子被相同或不同的卤素原子替换,即一个卤素原子独立于另一个卤素原子。具体地,所述卤素原子为F。所述C1-C6-卤代烷基是,例如,–CF3、-CHF2、-CH2F、-CF2CF3或–CH2CF3。
术语“C1-C4-羟基烷基”应被理解为是指直链或支链饱和单价烃基,其中术语“C1-C4-烷基”如上文所定义,和其中一个或多个氢原子被羟基替换,例如羟基甲基、1-羟基乙基、2-羟基乙基、1,2-二羟基乙基、3-羟基丙基、2-羟基丙基、2,3-二羟基丙基、1,3-二羟基丙-2-基、3-羟基-2-甲基-丙基、2-羟基-2-甲基-丙基、1-羟基-2-甲基-丙基。
术语“C1-C6-烷氧基”应被理解为是指式–O-烷基的直链或支链饱和单价烃基,其中术语“烷基”如上文所定义,例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、戊氧基、异戊氧基、或正己氧基或其异构体。具体地,所述“C1-C6-烷氧基”可含有1、2、3、4或5个碳原子,(“C1-C5-烷氧基”),优选1、2、3或4碳原子(“C1-C4-烷氧基”)。
术语“C1-C6-卤代烷氧基”应被理解为是指直链或支链饱和单价的上文所定义的C1-C6-烷氧基,其中一个或多个氢原子被相同或不同的卤素原子替换。具体地,所述卤素原子为F。所述C1-C6-卤代烷氧基是,例如,–OCF3、-OCHF2、-OCH2F、-OCF2CF3或-OCH2CF3。
术语“C2-C6-烯基”应被理解为是指直链或支链单价烃基,其含有一个或多个双键,且其具有2、3、4、5或6个碳原子或2、3或4个碳原子(“C2-C4-烯基),具体地2或3个碳原子(“C2-C3-烯基”),应当理解在所述烯基含有一个以上双键的情况下,所述双键可以彼此分离或彼此共轭。所述烯基为,例如,乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、高烯丙基(homoallyl)、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基、4-甲基戊-4-烯基、3-甲基戊-4-烯基、2-甲基戊-4-烯基、1-甲基戊-4-烯基、4-甲基戊-3-烯基、(E)-3-甲基戊-3-烯基、(Z)-3-甲基戊-3-烯基、(E)-2-甲基戊-3-烯基、(Z)-2-甲基戊-3-烯基、(E)-1-甲基戊-3-烯基、(Z)-1-甲基戊-3-烯基、(E)-4-甲基戊-2-烯基、(Z)-4-甲基戊-2-烯基、(E)-3-甲基戊-2-烯基、(Z)-3-甲基戊-2-烯基、(E)-2-甲基戊-2-烯基、(Z)-2-甲基戊-2-烯基、(E)-1-甲基戊-2-烯基、(Z)-1-甲基戊-2-烯基、(E)-4-甲基戊-1-烯基、(Z)-4-甲基戊-1-烯基、(E)-3-甲基戊-1-烯基、(Z)-3-甲基戊-1-烯基、(E)-2-甲基戊-1-烯基、(Z)-2-甲基戊-1-烯基、(E)-1-甲基戊-1-烯基、(Z)-1-甲基戊-1-烯基、3-乙基丁-3-烯基、2-乙基丁-3-烯基、1-乙基丁-3-烯基、(E)-3-乙基丁-2-烯基、(Z)-3-乙基丁-2-烯基、(E)-2-乙基丁-2-烯基、(Z)-2-乙基丁-2-烯基、(E)-1-乙基丁-2-烯基、(Z)-1-乙基丁-2-烯基、(E)-3-乙基丁-1-烯基、(Z)-3-乙基丁-1-烯基、2-乙基丁-1-烯基、(E)-1-乙基丁-1-烯基、(Z)-1-乙基丁-1-烯基、2-丙基丙-2-烯基、1-丙基丙-2-烯基、2-异丙基丙-2-烯基、1-异丙基丙-2-烯基、(E)-2-丙基丙-1-烯基、(Z)-2-丙基丙-1-烯基、(E)-1-丙基丙-1-烯基、(Z)-1-丙基丙-1-烯基、(E)-2-异丙基丙-1-烯基、(Z)-2-异丙基丙-1-烯基、(E)-1-异丙基丙-1-烯基、(Z)-1-异丙基丙-1-烯基、(E)-3,3-二甲基丙-1-烯基、(Z)-3,3-二甲基丙-1-烯基、1-(1,1-二甲基乙基)乙烯基、丁-1,3-二烯基、戊-1,4-二烯基、己-1,5-二烯基或甲基己二烯基。具体地,所述基团为乙烯基或烯丙基。
术语“C3-C10-环烷基”应被理解为是指含有3、4、5、6、7、8、9或10个碳原子的饱和单价单-或双环烃环(“C3-C10-环烷基”)。所述C3-C10-环烷基是例如,单环烃环,例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基或双环烃环,例如全氢并环萜烯或十氢化萘环。具体地,所述环含有3、4、5或6个碳原子(“C3-C6-环烷基”),优选环丙基。
术语“C4-C6-环烯基”应被理解为是指单价,单环烃环,其含有4、5或6个碳原子。所述C4-C6-环烯基是例如,环丁烯基、环戊烯基或环己烯基。
术语“3-至10-元杂环烷基”应被理解为是指饱和单价单-或双环烃环,其含有2、3、4、5、6、7、8或9个碳原子,和一个或多个选自C(=O)、O、S、S(=O)、S(=O)2、NRa的含有杂原子的基团,其中Ra代表氢原子,或C1-C6-烷基或C1-C6-卤代烷基;所述杂环烷基可以通过任何一个碳原子,或,如果存在的话,通过氮原子与分子的其余部分相连接。
具体地,所述3-至10-元杂环烷基可以含有2、3、4、或5个碳原子,和一个或多个上述含有杂原子的基团(“3-至6-元杂环烷基”),更具体地所述杂环烷基可含有4或5个碳原子,和一个或多个上述含有杂原子的基团(“5-至6-元杂环烷基”)。
具体地,并不限于此,所述杂环烷基可以是4-元环,例如氮杂环丁烷基、氧杂环丁烷基,或5-元环,例如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基,或6-元环,例如四氢吡喃基、哌啶基、吗啉基、二硫杂环己烷基、硫吗啉基、哌嗪基或三噻烷基,或7-元环,例如二氮杂环庚烷基环。任选地,所述杂环烷基可以是苯并稠合的。优选地,所述3-至6-元杂环烷基是四氢呋喃基、四氢吡喃基或哌嗪基。
所述杂环烷基可以是双环的,例如但不限于,5,5-元环,例如六氢环戊二烯[c]吡咯-2(1H)-基环,或5,6-元双环,例如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。
如上所述,所述含氮原子的环可以是部分不饱和的,即其可含有一个或多个双键,例如但不限于,2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基,或4H-[1,4]噻嗪基环,或者,其可以是苯并稠合的,例如但不限于,二氢异喹啉基环。
式–O-杂环烷基的术语“3-至10-元杂环烷氧基”理解为是指饱和单价单-或双环烃环,其中术语“杂环烷基”如上文所定义,其含有2、3、4、5、6、7、8或9碳原子,和一个或多个选自C(=O)、O、S、S(=O)、S(=O)2、NRa的含有杂原子的基团,其中Ra代表氢原子、C1-C6-烷基或C1-C6-卤代烷基,并且其通过氧原子与分子的剩余部分连接,例如吡咯烷氧基、四氢呋喃氧基或四氢吡喃氧基。
术语“4-至10-元杂环烯基”应理解为是指不饱和单价单-或双环烃环,其含有3、4、5、6、7、8或9个碳原子,和一个或多个选自C(=O)、O、S、S(=O)、S(=O)2、NRa的含有杂原子的基团,其中Ra代表氢原子,或C1-C6-烷基或C1-C6-卤代烷基;所述杂环烯基可以通过任何一个碳原子,或如果存在的话,通过氮原子与分子的剩余部分相连。所述杂环烯基的实例可含有一个或多个双键,例如4H-吡喃基、2H-吡喃基、3,6-二氢-2H-吡喃-4-基、3,6-二氢-2H-噻喃-4-基、1,2,3,6-四氢吡啶-4-基、3H-二氮杂环丙烯基、2,5-二氢-1H-吡咯基、[1,3]间二氧杂环戊烯基、4H-[1,3,4]噻二嗪基、2,5-二氢呋喃基、2,3-二氢呋喃基、2,5-二氢噻吩基、2,3-二氢噻吩基、4,5-二氢噁唑基、4H-[1,4]噻嗪基或5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基或其可以是苯并稠合的。
术语“杂芳基”应理解为是指单价的单环-、双环-或三环的芳香环系统,其具有5、6、7、8、9、10、11、12、13或14个环原子(“5-至14-元杂芳基”)、5或6或9或10个环原子(“5-至10-元杂芳基”)或具体地为5或6个环原子(“5-至6-元杂芳基”),且其含有至少一个可以相同或不同的杂原子,所述杂原子是例如氧、氮或硫,另外,在每种情况下,可以是苯并稠合的(benzo condensed)。具体地,杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、硫杂-4H-吡唑基等,及它们的苯并衍生物,例如,苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等,以及它们的苯并衍生物,例如,例如,喹啉基、喹唑啉基、异喹啉基等;或氮杂环辛烷基、吲嗪基、嘌呤基等,基它们的苯并衍生物;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、喋啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基、呫吨基、氧杂环庚三烯基或1H-吡咯并[2,3-b]吡啶-4-基等。
通常并且除非另作说明,否则杂芳基或亚杂芳基包括其所有可能的异构形式,例如其位置异构体。由此,对于一些说明性的非限制性实例,术语吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基;或术语噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基。
贯穿本文使用的术语“C1-C6”,例如在“C1-C6-烷基”、“C1-C6-卤代烷基”、“C1-C6-烷氧基”、或“C1-C6-卤代烷氧基”的定义的背景下,应被理解为是指具有1至6个有限数量的碳原子的烷基,即1、2、3、4、5、或6个碳原子。进一步理解,所述术语“C1-C6”应解释为其中包括的任何子范围,例如C1-C6、C2-C5、C3-C4、C1-C2、C1-C3、C1-C4、C1-C5;具体地C1-C2、C1-C3、C1-C4、C1-C5、C1-C6;更具体地为C1-C4;在“C1-C6-卤代烷基”或“C1-C6-卤代烷氧基”的情况下,更具体地是C1-C2。
类似地,如本文所用,贯穿本文使用的术语“C2-C6”,例如在“C2-C6-烯基”和“C2-C6-炔基”的定义的背景下,应理解为是指具有2至6个有限数量的碳原子的烯基或炔基,即2、3、4、5、或6个碳原子。进一步理解,所述术语“C2-C6”应解释为其中包括的任何子范围,例如C2-C6、C3-C5、C3-C4、C2-C3、C2-C4、C2-C5;具体地为C2-C3。
进一步地,如本文所用的,贯穿本文使用的术语“C3-C6”,例如在“C3-C6-环烷基”的定义的背景下,应理解为是指具有3-6个有限数量的碳原子的环烷基,即3、4、5或6个碳原子。进一步理解,所述术语“C3-C6”应解释为其中包括的任何子范围,例如C3-C6、C4-C5、C3-C5、C3-C4、C4-C6、C5-C6;具体地是C3-C6。
此外,如本文所用,贯穿本文使用的术语“C2-C4”,例如在“C2-C4–烯基”的定义的背景下,应被理解为是指具有2-4个有限数量的碳原子的烯基,即2、3或4个碳原子。进一步理解,所述术语“C2-C4”应解释为其中包括的任何子范围,例如C2-C4、C2-C3、C3-C4。
术语“取代的”是指在指定原子上的一个或多个氢被选自指定组的基团替换,条件是:不超过所指定原子的现有情况下的正常价,并且该取代产生稳定化合物。取代基和/或变量可以组合,只要该组合可以产生稳定化合物即可。
术语“任选取代的”是指被具体基团、原子团或部分任选取代。
环系取代是指与芳香族或非芳香族环系连接的取代基,其例如,替换环系上的可用氢。
本文使用的术语“一个或多个”,例如在本发明通式化合物的取代基的定义中,是指“一个、两个、三个、四个或五个,尤其是一个、两个、三个或四个,更尤其是一个、两个或三个,更尤其是一个或两个”。
本发明还包括本发明化合物的所有合适的同位素变体。本发明化合物的同位素变体定义为:其中至少一个原子被原子序数相同但原子量不同于自然界中通常或主要发现的原子量的原子替代的本发明化合物。可以结合到本发明化合物中的同位素的例子分别包括下列的同位素:氢、碳、氮、氧、磷、硫、氟、氯、溴和碘,例如2H(氘)、3H(氚)、11C、13C、14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I和131I。本发明化合物的一些同位素变体,例如,引入一个或多个放射性同位素(例如3H或14C)的那些变体,用于药物和/或底物组织分配研究。尤其优选氚和碳-14(即,14C)同位素,这是由于它们容易制备和检测。此外,用同位素(例如,氘)取代,由于代谢稳定性更大(例如,体内半衰期增加)或剂量要求降低,所以,可以提供某些治疗优势,并由此在一些情况下可以优选。通常可以利用本领域技术人员已知的常规方法来制备本发明化合物的同位素变体,例如,利用下文实施例所描述的说明性方法或制备例,使用合适试剂的适当同位素变体。
在本文使用的化合物、盐、多晶型物、水合物、溶剂合物既包括复数形式也包括单数形式。
“稳定化合物”或“稳定结构”是指充分稳固的化合物,能够经得住从反应混合物中分离至有效纯度,并且可以配制成为有效的治疗剂。
根据所期望的各种取代基的位置和性质,本发明化合物可以包含一个或多个非对称中心。不对称碳原子可以存在(R)或(S)构型,在单一非对称中心的情况下,形成外消旋混合物,和在多个非对称中心的情况下,形成非对映体的混合物。在一些情况下,由于围绕所给定的键的旋转受阻,例如,连接具体化合物的两个取代的芳香环的中心键,也可以存在不对称性。
本发明化合物可以包含非对称的硫原子,例如下列结构的非对称亚砜或亚砜亚胺(sulphoximine)基团:
其中*表示可以与分子的其他部分键合的原子。
环上的取代基也可以以顺式或反式存在。意味着所有这种构型(包括对映异构体和非对映异构体)包括在本发明范围内。
优选的化合物是得到更合乎需要的生物活性的那些化合物。本发明化合物的分离的、纯化或部分纯化的异构体和立体异构体或外消旋的或非对映体的混合物也包括在本发明范围内。这种材料的纯化和分离可以通过本领域已知的标准技术实现。
按照常规方法拆分外消旋混合物,可以获得光学异构体,例如,使用光学活性的酸或碱形成非对映异构体的盐,或形成共价非对映异构体。合适的酸的例子是酒石酸、二乙酰基酒石酸、二甲苯酰酒石酸和樟脑磺酸。利用本领域技术人员熟知的方法,例如,色谱或分级结晶,基于它们的物理和/或化学差异,可以将非对映异构体的混合物分离为它们的单一非对映异构体。然后,从分离的非对映体的盐中释放出光学活性的酸或碱。分离旋光异构体的不同方法包括:在进行或不进行常规衍生化的条件下,使用手性色谱(例如,手性HPLC柱),最好选择使对映异构体的分离最大化的方法。Daicel生产的合适的手性HPLC柱,例如,Chiracel OD和Chiracel OJ,还有许多其他的手性HPLC柱,都是通常可选择的柱。在进行或不进行衍生化的条件下,也使用酶分离。同样地,使用光学活性的起始原料,通过手性合成,也可以获得本发明的光学活性的化合物。
为了限制彼此类型不同的异构体,参考IUPAC Rules Section E(Pure Appl Chem45,11-30,1976)。
本发明包括本发明化合物的所有可能的立体异构体,可以是单一立体异构体,或任何比例的所述立体异构体(例如R-或S-异构体,或E-或Z-异构体)的任意混合物。利用任何合适的本领域的方法,例如,色谱飞,尤其是手性色谱法,可以实现本发明化合物的单一立体异构体(例如单一对映异构体或单一非对映异构体)的分离。
此外,本发明化合物可以以互变异构体形态存在。例如,包含吡唑部分作为杂芳基的任何本发明化合物,可以以1H互变异构体或2H互变异构体或任何量的两种互变异构体的混合物的形态存在,或包含三唑部分的化合物可以以1H互变异构体、2H互变异构体或4H互变异构体或甚至任何量的所述1H、2H和4H互变异构体的混合物的形态存在,即:
本发明包括所有可能的本发明化合物的互变异构体,作为单一互变异构体,或所述互变异构体的任何比例的任何混合物。
此外,本发明化合物可以以N-氧化物形式存在,其定义为:本发明化合物的至少一个氮被氧化。本发明包括所有这种可能的N-氧化物。
本发明还涉及本文公开的化合物的可用形式,例如代谢物、水合物、溶剂合物、前药、盐尤其是药学上可接受的盐,和共沉淀物。
本发明化合物可以以水合物或溶剂合物形式存在,其中本发明化合物含有极性溶剂,尤其是例如水、甲醇或乙醇,作为化合物的晶格的结构要素。极性溶剂尤其是水的量,可以以化学计量或非化学计量的比例存在。在化学计量的溶剂合物,例如水合物的情况下,可以分别是半-(hemi-)、(半-)(semi-)、一-\一又二分之一-、二-、三-、四-、五-溶剂合物或水合物等等。本发明包括所有这种水合物或溶剂合物。
此外,本发明化合物可以游离形式存在,例如作为游离碱,或游离酸,或两性离子,或可以以盐形式存在。所述盐可以是药学通常使用的任何盐,有机或无机加成盐,具体是任何药学上可接受的有机或无机加成盐。
术语“药学上可接受的盐”是指本发明化合物的相对无毒的无机或有机酸加成盐。例如,参见S.M.Berge,等人“Pharmaceutical Salts,”J.Pharm.Sci.1977,66,1-19。
本发明化合物的合适的药学上可接受的盐可以是,例如,链或环中携带氮原子的本发明化合物的酸加成盐,例如,对于足够碱性的本发明化合物为酸加成盐,例如与无机酸形成的酸加成盐,例如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、磷酸盐或硝酸盐,或与有机酸形成的酸加成盐,例如甲酸盐、乙酸盐、乙酰乙酸盐、丙酮酸盐、三氟乙酸盐、丙酸盐、丁酸盐、己酸盐、庚酸盐、十一烷酸盐、月桂酸盐、苯甲酸盐、水杨酸盐、2-(4-羟基苯甲酰基)-苯甲酸盐、樟脑酸盐、肉桂酸盐、环戊丙酸盐、二葡糖酸盐、3-羟基-2-萘酸盐、烟酸盐、双羟萘酸盐、果胶质酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、2-羟基乙磺酸盐、衣康酸盐、氨基磺酸盐、三氟甲磺酸盐、十二烷基硫酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、甲磺酸盐、2-萘磺酸盐、萘二磺酸盐、樟脑磺酸盐、柠檬酸盐、酒石酸盐、硬脂酸盐、乳酸盐、草酸盐、丙二酸盐、琥珀酸盐、苹果酸盐、己二酸盐、海藻酸盐、马来酸盐、富马酸盐、D-葡糖酸盐、扁桃酸盐、抗坏血酸盐、葡庚糖酸盐、甘油磷酸盐、天冬氨酸盐、磺基水杨酸盐、半硫酸盐或硫氰酸盐。
此外,足够酸性的本发明化合物的其它合适的药学上可接受的盐是碱金属盐例如钠或钾盐,碱土金属盐例如钙或镁盐,铵盐或与提供生理学可接受的阳离子的有机碱形成的盐,例如与下列形成的盐:N-甲基-葡糖胺、二甲基-葡糖胺、乙基-葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、氨基葡萄糖、肌氨酸、丝氨醇、三-羟基-甲基-氨基甲烷、氨基丙二醇、sovak-碱、1-氨基-2,3,4-丁三醇。此外,碱性含氮基团可以用试剂季胺化,所述试剂例如低级烷基卤化物,例如甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物;硫酸二烷基酯,如硫酸二甲酯、硫酸二乙酯和硫酸二丁酯;和硫酸二戊酯,长链卤化物例如癸基、月桂基、肉豆蔻基和硬脂基的氯化物、溴化物和碘化物,芳烷基卤化物,如苄基和苯乙基的溴化物等。
本领域技术人员将会进一步认识到,请求保护的化合物的酸加成盐,可以通过许多已知的方法中的任何方法,通过所述化合物与合适的无机或有机酸的反应来制备。或者,通过各种已知的方法,通过本发明的化合物与合适的碱的反应,制备本发明酸性化合物的碱金属或碱土金属盐。
本发明包括所有可能的本发明化合物的盐,作为单一盐,或所有盐的任何比例的任何混合物。
此外,本发明包括本发明化合物的所有可能的结晶形式或多晶型物,作为单一多晶型物,或多于一种的多晶型物的任何比例的混合物。
当本发明化合物中的基团被取代时,基团可以为单-或多取代的,除非另外说明。在本发明的背景下,彼此独立地定义出现多于一次的所有基团。优选被一个、两个或三个相同或不同的取代基取代。
在本发明的背景下,术语“治疗(treatment或treating)”包括抑制、延迟、检查、缓解、减弱、限制、减少、压制、抵制或治愈疾病(术语“疾病”包括但不限于病症、障碍、损伤或健康问题),或这种病症和/或这种病症的症状的发展、进程或进展。术语“疗法”在本文理解为与术语“治疗”同义。
术语“防止(prevention)”、“预防(prophylaxis)”或“阻止(preclusion)”在本发明的背景下是同义使用的,并且是指避免或减少感染、经历、患有或具有疾病的风险或者这种病症和/或这种病症的症状的发展或进展。
疾病的治疗或预防可以是部分或完全的。
在另一实施方案中,本发明包括通式(I)化合物
其中:
R1代表下列基团:
其中*表示所述基团与分子剩余部分的连接点;
R2代表氢、卤素、-NR7R8、CN、C1-C4-烷基、C1-C4-烷氧基、3-至6-元杂环烷氧基、C3-C6-环烷基、C4-C6-环烯基、3-至6-元杂环烷基、苯基、杂芳基、-(CO)OR7、-(CO)NR7R8、-(SO2)R9、-(SO)R9、-SR9,-(SO2)NR7R8、-NR7(SO2)R9、-((SO)=NR11)R10、-N=(SO)R9R10、–(PO)(OR7)2、–(PO)(OR7)R10或–(PO)(R10)2,
其中各C1-C4-烷基、C1-C4-烷氧基、3-至6-元杂环烷氧基、C3-C6-环烷基、3-至6-元杂环烷基、苯基或杂芳基彼此独立地任选被下列基团取代一次或多次:卤素、OH、-CN、-NR7R8、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-羟基烷基、苯基-C1-C2-烷基、(C1-C4-烷氧基)-(C1-C4-烷基)-、C1-C4-烷氧基、C3-C6-环烷基、3-至6-元杂环烷基、苯基、-(CO)OR7、-(CO)NR7R8、-NR7(CO)R10、-NR8(CO)OR7、-NR8(CO)NR7R8、-(SO2)R9、-(SO)R9、-SR9、-(SO2)NR7R8、-NR7(SO2)R9、-((SO)=NR11)R10、-N=(SO)R9R10或任选被C1-C4-烷基取代一次或多次的杂芳基,或
其中与苯环两个相邻原子相连的所述苯基的两个取代基彼此连接以形成亚甲基二氧基、亚乙基二氧基、亚乙基氧基或三亚甲基氧基;
R3,R4彼此独立地代表氢或甲基;
R5代表C1-C4-烷基;
R7,R8彼此独立地代表氢、C1-C6-烷基、C3-C6-环烷基、苯基或苯基-CH2-,所述苯基任选被卤素取代一次或多次;或
R7和R8一起代表5-或6-元环胺基团,其彼此独立地任选被选自下列的取代基取代一次或多次:C1-C4-烷基、C1-C4-卤代烷基,所述5-或6-元环胺基团任选含有一个另外的选自O、N和S的杂原子;
R9代表C1-C4-烷基;
R10代表C1-C4-烷基;或
R9和R10一起,在-N=(SO)R9R10基团的情况下,代表5-至6-元杂环烷基;
R11代表氢或C1-C4-烷基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明包括通式(I)化合物
其中:
R1代表选自下列的基团:
其中*表示所述基团与分子剩余部分的连接点;
R2代表氢、卤素、-NR7R8、CN、C1-C6-烷基、C1-C6-烷氧基、3-至10-元杂环烷氧基、C2-C6-烯基、C3-C6-环烷基、C4-C6-环烯基、3-至10-元杂环烷基、4-至10-元杂环烯基、苯基、杂芳基、-(CO)OR7、-(CO)NR7R8、-(SO2)R9、-(SO)R9、-SR9、-(SO2)NR7R8、-NR7(SO2)R9、-((SO)=NR11)R10、-N=(SO)R9R10、-SiR10R11R12、–(PO)(OR7)2、–(PO)(OR7)R10或–(PO)(R10)2,
其中各个C1-C6-烷基、C1-C6-烷氧基、3-至10-元杂环烷氧基、C2-C6-烯基、C3-C6-环烷基、3-至10-元杂环烷基、苯基或杂芳基彼此独立地任选被下列基团取代一次或多次:卤素、OH、-CN、-NR7R8、C1-C6-烷基、C1-C6-卤代烷基、C1-C4-羟基烷基、苯基-C1-C4-烷基、(C1-C4-烷氧基)-(C1-C4-烷基)-、C1-C6-烷氧基、C3-C6-环烷基、3-至6-元杂环烷基、苯基、-(CO)OR7、-(CO)NR7R8、-NR7(CO)R10、-NR8(CO)OR7、-NR8(CO)NR7R8、-(SO2)R9、-(SO)R9、-SR9、-(SO2)NR7R8、-NR7(SO2)R9、-((SO)=NR11)R10、-N=(SO)R9R10、-(PO)(OR7)2、–(PO)(OR7)R10、–(PO)(R10)2或任选被C1-C4-烷基取代一次或多次的杂芳基,或
其中与苯环两个相邻原子相连的所述苯基的两个取代基彼此连接以形成亚甲基二氧基、亚乙基二氧基、亚乙基氧基或三亚甲基氧基;
其中各4-至10-元杂环烯基彼此独立地任选被C1-C4-烷基取代;
R3,R4彼此独立地代表氢或甲基;
R5代表氢、C1-C6-烷基、C1-C6-卤代烷基或C1-C6-烷氧基;
R7,R8彼此独立地代表氢、C1-C6-烷基、C3-C6-环烷基、苯基或苯基-CH2-,所述苯基任选被卤素取代一次或多次;或
R7和R8一起代表4-、5-、6-或7-元环胺基团,其彼此独立地任选被选自下列的基团取代一次或多次:C1-C6-烷基、C1-C6-卤代烷基,所述4-、5-、6-或7-元环胺基团任选含有一个另外的选自O、N和S的杂原子;
R9代表C1-C4-烷基或苯基,其中各个C1-C4-烷基或苯基彼此独立地任选被下列基团取代一次或多次:R13;
R10代表C1-C4-烷基;或
R9和R10一起,在-N=(SO)R9R10基团的情况下,代表5-至8-元杂环烷基;
R11代表氢、C1-C4-烷基、-(CO)OR7、-(CO)NR7R8或CN;
R12代表氢或C1-C4-烷基;
R13代表卤素、OH、-NR7R8、CN、NO2、C1-C6-烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基、C2-C6-烯基、C3-C6-环烷基、-(CO)OR7或-(CO)NR7R8;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明包括通式(Ib)化合物
其中R1、R2、R4、R5、R7、R8、R9、R10、R11、R12和R13如上文或下文针对通式(I)的化合物所定义。
在另一实施方案中,本发明包括通式(Ib)化合物
其中:
R1代表下列基团:
其中*表示所述基团与分子剩余部分的连接点;
R2代表-NR7R8、C1-C4-烷氧基、C4-C6-环烯基、6-元杂环烷基、苯基、杂芳基、-(CO)OR7、-N=(SO)R9R10、–(PO)(OR7)R10或–(PO)(R10)2,
其中各个C1-C4-烷氧基、6-元杂环烷基、苯基或杂芳基彼此独立地任选被下列基团取代一次或多次:卤素、OH、-CN、-NR7R8、C1-C4-烷基、羟基甲基、苯基-CH2-、甲氧基甲基、C1-C4-烷氧基、6-元杂环烷基、-(CO)OR7、-(CO)NR7R8、-(SO2)R9、-(SO)R9、-SR9、-NR7(SO2)R9,或
其中与苯环两个相邻原子相连的所述苯基的两个取代基彼此连接以形成亚乙基二氧基;
R4代表甲基;
R5代表甲基;
R7,R8彼此独立地代表氢、C1-C6-烷基、环丙基、苯基或苯基-CH2-,所述苯基任选被卤素取代一次或多次;或
R7和R8一起代表5-元环胺基团;
R9代表甲基或乙基;
R10代表甲基或乙基;或
R9和R10一起,在-N=(SO)R9R10基团的情况下,代表5-元杂环烷基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明包括通式(Ib)化合物,其中
R1代表下列基团:
其中*表示所述基团与分子剩余部分的连接点;
R2代表–N-甲基-(2,2-二甲基丙基)、丙-2-基氧基、环戊-1-烯-1-基、6-元杂环烷基、苯基、杂芳基、-(CO)O-甲基、-N=(SO)二乙基、-N=(SO)(CH2)4、–(PO)(O-乙基)甲基、–(PO)(O-(2-甲基丙基))甲基或–(PO)(甲基)2,
其中各6-元杂环烷基、苯基或杂芳基彼此独立地任选被下列基团取代一次或多次:卤素、OH、-CN、-NR7R8、C1-C4-烷基、羟基甲基、苯基-CH2-、甲氧基甲基、C1-C4-烷氧基、6-元杂环烷基、-(CO)OR7、-(CO)NR7R8、-(SO2)R9、-(SO)R9、-SR9、-NR7(SO2)R9,或
其中与苯环两个相邻原子相连的所述苯基的两个取代基彼此连接以形成亚乙基二氧基;
R4代表甲基;
R5代表甲基;
R7,R8彼此独立地代表氢、C1-C5-烷基、环丙基、苯基或未取代的苯基-CH2-,所述苯基任选被卤素取代一次或多次;或
R7和R8一起代表5-元环胺基团
R9代表甲基或乙基;
R10代表甲基或乙基;或
R9和R10一起,在-N=(SO)R9R10基团的情况下,代表四亚甲基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明包括通式(Ib)化合物,其中
R1代表下列基团:
其中*表示所述基团与分子剩余部分的连接点;
R2代表丙-2-基氧基、-N=(SO)二乙基、–(PO)(O-乙基)甲基、1-甲基-1H-吡唑-5-基、吗啉-4-基、4-(羟基甲基)哌啶-1-基、4-(甲基磺酰基)哌嗪-1-基、1-甲基-1H-咪唑-5-基或2-甲基-1,3-噻唑-5-基;
R4代表甲基;
R5代表甲基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明包括通式(Ib)化合物,其中
R1代表选自下列的基团:
其中*表示所述基团与分子剩余部分的连接点;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明包括通式(Ib)化合物,其中
R1代表:
其中*表示所述基团与分子剩余部分的连接点;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R1代表选自下列的基团:
其中*表示所述基团与分子剩余部分的连接点;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R1代表选自下列的基团:
其中*表示所述基团与分子剩余部分的连接点;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R1代表
其中*表示所述基团与分子剩余部分的连接点;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中
R2代表氢、卤素、-NR7R8、CN、C1-C6-烷基、C1-C6-烷氧基、3-至10-元杂环烷氧基、C2-C6-烯基、C3-C6-环烷基、C4-C6-环烯基、3-至10-元杂环烷基、4-至10-元杂环烯基、苯基、杂芳基、-(CO)OR7、-(CO)NR7R8、-(SO2)R9、-(SO)R9、-SR9、-(SO2)NR7R8、-NR7(SO2)R9、-((SO)=NR11)R10、-N=(SO)R9R10、-SiR10R11R12、–(PO)(OR7)2、–(PO)(OR7)R10或–(PO)(R10)2,
其中各C1-C6-烷基、C1-C6-烷氧基、3-至10-元杂环烷氧基、C2-C6-烯基、C3-C6-环烷基、3-至10-元杂环烷基、苯基或杂芳基彼此独立地任选被下列基团取代一次或多次:卤素、OH、-CN、-NR7R8、C1-C6-烷基、C1-C6-卤代烷基、C1-C4-羟基烷基、苯基-C1-C4-烷基、(C1-C4-烷氧基)-(C1-C4-烷基)-、C1-C6-烷氧基、C3-C6-环烷基、3-至6-元杂环烷基、苯基、-(CO)OR7、-(CO)NR7R8、-NR7(CO)R10、-NR8(CO)OR7、-NR8(CO)NR7R8、-(SO2)R9、-(SO)R9、-SR9、-(SO2)NR7R8、-NR7(SO2)R9、-((SO)=NR11)R10、-N=(SO)R9R10、-(PO)(OR7)2、–(PO)(OR7)R10、–(PO)(R10)2或任选被C1-C4-烷基取代一次或多次的杂芳基,或
其中与苯环两个相邻原子相连的所述苯基的两个取代基彼此连接以形成亚甲基二氧基、亚乙基二氧基、亚乙基氧基或三亚甲基氧基;
其中各4-至10-元杂环烯基彼此独立地任选被C1-C4-烷基取代一次或多次;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中
R2代表氢、卤素、-NR7R8、CN、C1-C4-烷基、C1-C4-烷氧基、3-至6-元杂环烷氧基、C3-C6-环烷基、C4-C6-环烯基、3-至6-元杂环烷基、苯基、杂芳基、-(CO)OR7、-(CO)NR7R8、-(SO2)R9、-(SO)R9、-SR9、-(SO2)NR7R8、-NR7(SO2)R9、-((SO)=NR11)R10、-N=(SO)R9R10、–(PO)(OR7)2、–(PO)(OR7)R10或–(PO)(R10)2,
其中各C1-C4-烷基、C1-C4-烷氧基、3-至6-元杂环烷氧基、C3-C6-环烷基、3-至6-元杂环烷基、苯基或杂芳基彼此独立地任选被下列基团取代一次或多次:卤素、OH、-CN、-NR7R8、C1-C4-烷基、C1-C4-卤代烷基、C1-C4-羟基烷基、苯基-C1-C2-烷基、(C1-C4-烷氧基)-(C1-C4-烷基)-、C1-C4-烷氧基、C3-C6-环烷基、3-至6-元杂环烷基、苯基、-(CO)OR7、-(CO)NR7R8、-NR7(CO)R10、-NR8(CO)OR7、-NR8(CO)NR7R8、-(SO2)R9、-(SO)R9、-SR9、-(SO2)NR7R8、-NR7(SO2)R9、-((SO)=NR11)R10、-N=(SO)R9R10或任选被C1-C4-烷基取代一次或多次的杂芳基,或
其中与苯环两个相邻原子相连的所述苯基的两个取代基彼此连接以形成亚甲基二氧基、亚乙基二氧基、亚乙基氧基或三亚甲基氧基;
其中当与相邻的环原子连接时,所述苯基的两个取代基任选地以这样的方式相互连接,即它们共同形成亚甲基二氧基、亚乙基二氧基、亚乙基氧基或三亚甲基氧基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中
R2代表-NR7R8、C1-C4-烷氧基、C4-C6-环烯基、6-元杂环烷基、苯基、杂芳基、-(CO)OR7、-N=(SO)R9R10、–(PO)(OR7)R10或–(PO)(R10)2,
其中各个C1-C4-烷氧基、6-元杂环烷基、苯基或杂芳基彼此独立地任选被下列基团取代一次或多次:卤素、OH、-CN、-NR7R8、C1-C4-烷基、羟基甲基、苯基-CH2-、甲氧基甲基、C1-C4-烷氧基、6-元杂环烷基、-(CO)OR7、-(CO)NR7R8、-(SO2)R9、-(SO)R9、-SR9、-NR7(SO2)R9,或
其中与苯环两个相邻原子相连的所述苯基的两个取代基彼此连接以形成亚乙基二氧基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中
R2代表–N-甲基-(2,2-二甲基丙基)、丙-2-基氧基、环戊-1-烯-1-基、6-元杂环烷基、苯基、杂芳基、-(CO)O-甲基、-N=(SO)二乙基、-N=(SO)(CH2)4、–(PO)(O-乙基)甲基、–(PO)(O-(2-甲基丙基))甲基或–(PO)(甲基)2,
其中各个6-元杂环烷基、苯基或杂芳基彼此独立地任选被下列基团取代一次或多次:卤素、OH、-CN、-NR7R8、C1-C4-烷基、羟基甲基、苯基-CH2-、甲氧基甲基、C1-C4-烷氧基、6-元杂环烷基、-(CO)OR7、-(CO)NR7R8、-(SO2)R9、-(SO)R9、-SR9、-NR7(SO2)R9,或
其中与苯环两个相邻原子相连的所述苯基的两个取代基彼此连接以形成亚乙基二氧基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中
R2代表丙-2-基氧基、-N=(SO)二乙基、–(PO)(O-乙基)甲基、1-甲基-1H-吡唑-5-基、吗啉-4-基、4-(羟基甲基)哌啶-1-基、4-(甲基磺酰基)哌嗪-1-基、1-甲基-1H-咪唑-5-基或2-甲基-1,3-噻唑-5-基;
或其立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或盐,或它们的混合物。
在另一实施方案中,本发明涉及式(I)化合物,其中R3代表甲基和R4代表H。
在另一实施方案中,本发明涉及式(I)化合物,其中R3代表H和R4代表甲基。
在另一实施方案中,本发明涉及式(I)化合物,其中R3代表H和R4代表H。
在另一实施方案中,本发明涉及式(I)化合物,其中R3代表甲基和R4代表甲基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R4代表H或甲基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R4代表H。
在优选实施方案中,本发明涉及式(I)或(Ib)化合物,其中R4代表甲基。
在另一优选实施方案中,本发明涉及式(I)或(Ib)化合物,其中R4代表绝对构型为R的甲基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R5代表C1-C6-烷基、C1-C6-卤代烷基或C1-C6-烷氧基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R5代表C1-C4-烷基、C1-C4-卤代烷基或C1-C4-烷氧基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R5代表C1-C4-烷基或C1-C4-卤代烷基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R5代表C1-C4-烷基或C1-C4-烷氧基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R5代表甲基、乙基、丙基、甲氧基、乙氧基或丙氧基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R5代表C1-C4-烷基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R5代表甲基、乙基或丙基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R5代表甲基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R5代表氢。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R7、R8彼此独立地代表氢、C1-C6-烷基、C3-C6-环烷基、苯基或苯基-CH2-,所述苯基任选被卤素取代一次或多次;或
R7和R8一起代表4-、5-、6-或7-元环胺基团,其彼此独立地任选被选自下列的基团取代一次或多次:C1-C6-烷基、C1-C6-卤代烷基,所述4-、5-、6-或7-元环胺基团任选含有一个另外的选自O、N和S的杂原子;
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R7、R8彼此独立地代表氢、C1-C6-烷基、C3-C6-环烷基、苯基或苯基-CH2-,所述苯基任选被卤素取代一次或多次;或
R7和R8一起代表5-或6-元环胺基团,其彼此独立地任选被选自下列的基团取代一次或多次:C1-C4-烷基、C1-C4-卤代烷基,所述5-或6-元环胺基团任选含有一个另外的选自O、N和S的杂原子;
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R7,R8彼此独立地代表氢、C1-C5-烷基、环丙基、苯基或未取代的苯基-CH2-,所述苯基任选被卤素取代一次或多次;或
R7和R8一起代表5-元环胺基团;
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R7代表氢和R8代表氢。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R7代表氢和R8代表C1-C4-烷基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R7代表氢和R8代表C1-C5-烷基、环丙基或未取代的苯基-CH2-。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R7代表C1-C4-烷基和R8代表C1-C4-烷基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R9代表甲基、乙基、丙基或苯基,其任选取代有R13。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R9代表甲基、乙基或丙基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R9代表甲基或乙基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R10代表甲基、乙基或丙基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R10代表甲基或乙基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R10代表甲基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R10代表乙基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R9和R10一起,在-N=(SO)R9R10基团的情况下,代表5-元杂环烷基。
在另一实施方案中,本发明涉及式(I)或(Ib)化合物,其中R9和R10一起,在-N=(SO)R9R10基团的情况下,代表四亚甲基。
在其他实施方案中,本发明涉及根据任一上述实施方案的式(I)或(Ib)化合物,其为立体异构体、互变异构体、N-氧化物、水合物、溶剂合物或其盐,或它们的混合物的形式。
应理解,本发明涉及上述通式(I)或(Ib)化合物在本发明任一实施方案或方面中的亚组合。
更具体地,本发明包括通式(I)或(Ib)的标题化合物,其公开于下文的实施例部分。
根据另一方面,本发明包括制备本发明化合物的方法,所述方法包括如下述反应式1-6和/或实验部分中所述的步骤。
具体地,本发明包括制备通式5化合物的方法,
其特征在于使用碱(优选强碱)使通式4的化合物(其中R3、R4和R5具有与通式(I)或(Ib)化合物相同的定义),在溶剂中优选在-20℃至溶剂沸点的温度下(优选-5℃至30℃)反应,以获得通式(5)的化合物。优选地,通式5的化合物的制备可以在非质子有机溶剂中进行,优选在四氢呋喃或N,N-二甲基甲酰胺中进行。
可用于制备通式5化合物的优选强碱为LiHMDS、KHMDS、NaHMDS或LDA。
具体地,本发明包括制备通式8化合物的方法,
其特征在于使用碱(优选强碱)使通式7的化合物(其中R1、R3、R4和R5具有与通式(I)或(Ib)化合物相同的定义),优选在-20℃至溶剂沸点的温度下(优选-5℃至30℃)反应,以获得通式(8)的化合物。
优选地,通式8的化合物的制备可以在非质子有机溶剂中进行,优选在四氢呋喃或N,N-二甲基甲酰胺中进行。
可用于制备通式8的化合物的优选强碱为LiHMDS、KHMDS、NaHMDS或LDA。
根据另一方面,本发明包括中间体化合物,其可用于制备本发明通式(I)或(Ib)化合物,尤其是在本文所述的方法中。具体地,本发明包括通式5化合物,
其中R3、R4和R5如上文通式(I)或(Ib)的化合物所定义。
根据另一方面,本发明包括中间体化合物,其可用于制备本发明通式(I)或(Ib)化合物,尤其是在本文所述的方法中。具体地,本发明包括通式8化合物,
其中R1、R3、R4和R5如上文通式(I)或(Ib)的化合物所定义。
根据另一方面,本发明包括中间体化合物,其可用于制备本发明通式(I)或(Ib)的化合物,尤其是在本文所述的方法中。具体地,本发明包括通式9的化合物,
其中R3、R4和R5如上文通式(I)或(Ib)的化合物所定义。
根据另一方面,本发明包括中间体化合物,其可用于制备本发明通式(I)或(Ib)的化合物,尤其是在本文所述的方法中。具体地,本发明包括通式11化合物,
其中R1、R3、R4和R5如上文通式(I)或(Ib)的化合物所定义。
根据另一方面,本发明包括中间体化合物,其可用于制备本发明通式(I)或(Ib)化合物,尤其是在本文所述的方法中。具体地,本发明包括通式12化合物,
其中R1、R3、R4和R5如上文通式(I)或(Ib)的化合物所定义,和X为氯、溴或碘。
根据另一方面,本发明包括中间体化合物,其可用于制备本发明通式(I)或(Ib)的化合物,尤其是在本文所述的方法中。具体地,本发明包括通式15的化合物,
其中R1、R3、R4和R5如上文通式(I)或(Ib)的化合物所定义的。
根据另一方面,本发明包括中间体化合物,其可用于制备本发明通式(I)或(Ib)的化合物,尤其是在本文所述的方法中。具体地,本发明包括通式16化合物,
其中R1、R3、R4和R5如上文通式(I)或(Ib)的化合物所定义的。
根据另一方面,本发明包括中间体化合物,其可用于制备本发明通式(Ib)化合物,尤其是在本文所述的方法中。具体地,本发明包括通式39化合物,
其中Y代表OH、-O-SO2-CF3、Cl、Br、I、SH或–SO2Cl,优选OH、-O-SO2-CF3或Cl和R5如上述通式(I)或(Ib)化合物所定义。
还根据另一方面,本发明包括通式5的中间体化合物的用途,
其中R3、R4和R5如上文通式(I)或(Ib)的化合物所定义的,其用于制备上文定义的通式(I)或(Ib)的化合物。
还根据另一方面,本发明包括通式8的中间体化合物,
其中R1、R3、R4和R5如上文通式(I)或(Ib)的化合物所定义的,其用于制备上文定义的通式(I)或(Ib)的化合物。
还根据另一方面,本发明包括通式9的中间体化合物的用途,
其中R3、R4和R5如上文通式(I)或(Ib)的化合物所定义的,其用于制备上文定义的通式(I)或(Ib)的化合物。
还根据另一方面本发明包括通式11的中间体化合物的用途,
其中R1、R3、R4和R5如上文通式(I)或(Ib)的化合物所定义的,其用于制备上文定义的通式(I)或(Ib)的化合物。
还根据另一方面本发明包括通式12的中间体化合物的用途,
其中R1、R3、R4和R5如上文通式(I)或(Ib)的化合物所定义的,和X为氯、溴或碘,其用于制备上文定义的通式(I)或(Ib)的化合物。
还根据另一方面,本发明包括通式15的中间体化合物的用途,
其中R1、R3、R4和R5如上文通式(I)或(Ib)的化合物所定义的,其用于制备上文定义的通式(I)或(Ib)的化合物。
还根据另一方面,本发明包括通式16的中间体化合物的用途,
其中R1、R3、R4和R5如上文通式(I)或(Ib)的化合物所定义的,其用于制备上文定义的通式(I)或(Ib)的化合物。
还根据另一方面,本发明包括通式39的中间体化合物用于制备上文定义的通式(I)或(Ib)的化合物的用途,
其中Y代表OH、-O-SO2-CF3、Cl、Br、I、SH或–SO2Cl,优选OH、-O-SO2-CF3或Cl和R5如上述通式(I)或(Ib)化合物所定义,优选R5为甲基。
本发明的通式(I)或(Ib)化合物显示之前尚未被预测的有价值的作用谱。因此,它们适合用作治疗和/或预防人和动物中的疾病的药物。
特别地,已经惊人地发现所述本发明化合物有效抑制ATR激酶并且因此可用于治疗或预防由ATR激酶介导的疾病,尤其是过度增殖性疾病。
本发明涉及本发明的通式(I)或(Ib)化合物,其用于治疗或预防疾病,尤其是过度增殖性疾病。
本发明涉及使用本发明化合物和/或药物组合物来治疗疾病,尤其是过度增殖性疾病的方法。可以使用化合物,使细胞增殖和/或细胞分裂得到抑制、阻碍、减少、降低等等,和/或导致细胞凋亡。该方法包括:向有此需要的哺乳动物,尤其是人给药有效治疗疾病的量的本发明化合物。过度增殖性疾病包括但不限于,例如,牛皮癣、瘢痕疙瘩和影响皮肤的其他增生、良性前列腺增生(BPH)、实体瘤,例如乳腺、呼吸道、脑、生殖器官、消化道、泌尿道、眼睛、肝、皮肤、头及颈、甲状腺、甲状旁腺的癌症,以及它们的远端转移。那些疾病还包括淋巴瘤、肉瘤和白血病。
乳腺癌的实例包括,但不限于侵入性导管癌、侵入性小叶癌、原位导管癌和原位小叶癌。
呼吸道癌症的实例包括,但不限于小细胞和非小细胞肺癌,以及支气管腺癌和胸膜肺母细胞瘤。
脑癌的实例包括,但不限于脑干和下丘脑(hypophtalmic)胶质瘤、小脑和大脑的星形细胞瘤、成神经管细胞瘤、室管膜瘤以及神经外胚层和松果体肿瘤。
雄性生殖器官的肿瘤包括,但不限于前列腺和睾丸癌。雌性生殖器官的肿瘤包括,但不限于子宫内膜癌、子宫颈癌、卵巢癌、阴道癌和外阴癌,以及子宫肉瘤。
消化道的肿瘤包括,但不限于肛门癌、结肠癌、结肠直肠癌、食道癌、胆囊癌、胃癌、胰腺癌、直肠癌、小肠癌和唾液腺癌。
泌尿道的肿瘤包括,但不限于膀胱癌、阴茎癌、肾脏癌、肾盂癌、输尿管癌、尿道癌和人乳头状肾癌。
眼癌包括,但不限于眼内黑素瘤和视网膜母细胞瘤。
肝癌的实例包括,但不限于肝细胞癌(有或没有纤维板层变体的肝细胞癌)、胆管癌(肝内胆管癌)和混合型肝细胞胆管癌。
皮肤癌包括,但不限于鳞状细胞癌、卡波西肉瘤、恶性黑素瘤、Merkel细胞皮肤癌和非黑素瘤性皮肤癌。
头颈癌包括,但不限于喉癌、下咽癌、鼻咽癌、口咽癌、唇癌和口腔癌和鳞状细胞癌。淋巴瘤包括,但不限于AIDS-相关的淋巴瘤、非霍奇金淋巴瘤、皮肤T细胞淋巴瘤、伯基特淋巴瘤、霍奇金病和中枢神经系统的淋巴瘤。
肉瘤包括,但不限于软组织的肉瘤、骨肉瘤、恶性纤维组织细胞瘤、淋巴肉瘤和横纹肌肉瘤。
白血病包括,但不限于急性骨髓性白血病、急性淋巴母细胞性白血病、慢性淋巴细胞性白血病、慢性骨髓性白血病和毛细胞白血病。
这些疾病已经在人类中进行了很好的表征,但在其它哺乳动物中也存在类似的病因,并且可以通过给予本发明的化合物或药物组合物来治疗。
本发明涉及治疗具有缺陷ATM信号传导和/或p53功能的过度增殖性疾病,尤其是肺癌,特别是小细胞肺癌,结直肠癌、膀胱癌、淋巴瘤、胶质瘤和卵巢癌。
特别地,本发明涉及治疗肺癌,特别是小细胞肺癌,结直肠癌、膀胱癌、淋巴瘤,特别是弥漫性大B细胞淋巴瘤(DLBC)和套细胞淋巴瘤(MCL),前列腺癌,特别是去势抗性前列腺癌,胶质瘤和卵巢癌。
本发明还提供了本发明的通式(I)或(Ib)的化合物和/或药物组合物用于生产治疗和/或预防疾病的药物的用途,尤其是上述疾病,特别是过度增殖性疾病。
本发明的进一步的主题是本发明的通式(I)或(Ib)的化合物和/或药物组合物在制备治疗和/或预防病症的药物中的用途,尤其是上述病症。
此外,本发明涉及通式(I)或(Ib)的化合物,其用在治疗和/或预防疾病的方法中,特别是过度增殖性疾病。
本发明还提供了使用有效量的本发明的通式(I)或(Ib)的化合物和/或药物组合物治疗和/或预防疾病的方法,尤其是上述疾病,特别是过度增殖性疾病。
本发明还提供了本发明的通式(I)或(Ib)的化合物和/或药物组合物,其用于治疗和/或预防疾病,尤其是上述疾病,特别是过度增殖性疾病。本发明还提供了本发明的通式(I)或(Ib)的化合物和/或药物组合物,其用在治疗和/或预防上述疾病的方法中,特别是过度增殖性疾病。
本发明还提供了药物组合物,其包含通式(I)或(Ib)的化合物,或其立体异构体、互变异构体、N-氧化物、水合物、溶剂化物或盐,特别是其药学上可接受的盐,或它们的混合物,以及一种或多种赋形剂,特别是药学上可接受的赋形剂,其是惰性和无毒的。可以使用将这种药物组合物制备成合适剂型的常规程序。
此外,本发明涉及药物组合物,特别是药物,其包含至少一种本发明的化合物,常规上还包含一种或多种药学上合适的赋形剂,以及涉及其用于上述目的的用途。
药学上可接受的赋形剂包括:
·软膏基质(例如凡士林、石蜡、甘油三酯、蜡、羊毛蜡、羊毛蜡醇、羊毛脂、亲水性软膏、聚乙二醇),
·栓剂基质(例如聚乙二醇、可可脂、硬脂)
·溶剂(例如水、乙醇、异丙醇、甘油、丙二醇、中链长度甘油三酯脂肪油、液体聚乙二醇、石蜡),
·表面活性剂、乳化剂、分散剂或润湿剂(例如,十二烷基硫酸钠、卵磷脂、磷脂、脂肪醇例如,去水山梨糖醇脂肪酸酯例如,聚氧乙烯去水山梨糖醇脂肪酸酯例如,聚氧乙烯脂肪酸甘油酯例如,聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、甘油脂肪酸酯、泊洛沙姆例如,);
·缓冲剂以及酸和碱(例如,磷酸盐、碳酸盐、柠檬酸、乙酸、盐酸、氢氧化钠溶液、碳酸铵、氨丁三醇、三乙醇胺);
·等渗剂(例如,葡萄糖、氯化钠);
·吸附剂(例如,高分散二氧化硅);
·包衣物质(例如,糖、虫胶)和用于以快速或以改性方式溶解的薄膜或扩散膜的成膜剂(例如,聚乙烯吡咯烷酮例如,聚乙烯醇、羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、醋酸纤维素、醋酸纤维素邻苯二甲酸酯、聚丙烯酸酯、聚甲基丙烯酸酯例如,);
·胶囊物质(例如,明胶、羟丙基甲基纤维素);
·增塑剂(例如,聚乙二醇、丙二醇、甘油、三醋酸甘油酯、柠檬酸三乙酯、邻苯二甲酸二丁酯);
·渗透增强剂;
·稳定剂(例如,抗氧化剂例如抗坏血酸、抗坏血酸棕榈酸酯、抗坏血酸钠、丁基羟基苯甲醚、丁基羟基甲苯、没食子酸丙酯);
·防腐剂(例如,对羟基苯甲酸酯、山梨酸、硫柳汞、苯扎氯铵、醋酸氯己定、苯甲酸钠);
·着色剂(例如,无机颜料,例如氧化铁、二氧化钛);
·调味剂、甜味剂、味道和/或气味遮蔽剂。
下列文献中描述了其他赋形剂和操作,其各自通过引用并入本文:Powell,M.F.等人,"Compendium of Excipients for Parenteral Formulations"PDA Journal ofPharmaceutical Science&Technology 1998,52(5),238-311;Strickley,R.G"ParenteralFormulations of Small Molecule Therapeutics Marketed in the United States(1999)-Part-1"PDA Journal of Pharmaceutical Science&Technology 1999,53(6),324-349;和Nema,S.等人,"Excipients and Their Use in Injectable Products"PDAJournal of Pharmaceutical Science&Technology 1997,51(4),166-171。
此外,本发明涉及药物组合,尤其是药物,其包含至少一种本发明的化合物和至少一种或多种其他活性成分,特别是用于治疗和/或预防上述疾病。
本发明还提供药物组合产品,其包含:
一种或多种选自通式(I)或(Ib)的化合物的活性成分,和
一种或多种活性成分,其选自用于治疗癌症的抗过度增殖、抑制细胞生长或细胞毒性物质。
在本发明中,术语“组合”如本领域技术人员已知的使用,并且可以固定组合、非固定组合或试剂盒的形式存在。
在本发明中,“固定组合”如本领域技术人员已知的使用,并且定义为:其中例如第一活性成分和第二活性成分一起存在于一个单位剂量或单一实体中的组合。“固定组合”的一个例子是药物组合物,其中,第一活性成分和第二活性成分存在于同时给药的混合物中,例如,存在于一个制剂中。“固定组合”的另一个例子是药物组合产品,其中,第一活性成分和第二活性成分存在于一个单元中,但不是混合物。
在本发明中,非固定组合或“套装试剂盒”如本领域技术人员已知的使用,并且定义为:其中第一活性成分和第二活性成分存在于多于一个的单元中的组合。非固定组合或套装试剂盒的一个例子是其中第一活性成分和第二活性成分单独存在的组合。可以单独、顺序、同时、并行或按时间顺序交错给予非固定组合或套装试剂盒的组分。
本发明的化合物可以以单一药剂形式给予,或在组合不会引起无法接受的副作用的情况下,与一或多种其它药物活性成分组合给予。本发明还涉及这种药物组合。例如,本发明的化合物可以与已知的化疗剂和/或抗癌剂联用,例如,抗过度增殖或其它适应症的药剂,等等,以及与其混合物和组合联用。其它适应症药剂包括但不局限于:抗血管生成剂、有丝分裂抑制剂、烷化剂、抗代谢剂、DNA-嵌入抗生素、生长因子抑制剂、细胞周期抑制剂、酶抑制剂、拓扑异构酶抑制剂、生物反应调节剂或抗激素。
例如,本发明的化合物可以与已知的用于治疗癌症的抗过度增殖、抑制细胞生长或细胞毒性物质组合。
合适的抗过度增殖、抑制细胞生长或细胞毒性组合活性成分的实例包括:
131I-chTNT、阿倍瑞克(abarelix)、阿比特龙、阿柔比星、曲妥珠单抗-美坦新偶联物(ado-trastuzumabemtansine)、阿法替尼、阿柏西普、阿地白介素、阿仑单抗(alemtuzumab)、阿仑棒酸、阿利维A酸(alitretinoin)、六甲蜜胺、氨磷汀、氨鲁米特、氨基乙酰丙酸己酯、氨柔比星、安吖啶、阿那曲唑、安西司亭、茴三硫(anetholeditholethione)、血管紧张素II、抗凝血酶III、阿瑞吡坦、阿西莫单抗、arglabin、三氧化二砷、门冬酰胺酶、阿西替尼、阿扎胞苷、巴利昔单抗(basiliximab)、贝洛替康(belotecan)、苯达莫司汀、贝利司他、贝伐单抗(bevacizumab)、贝沙罗汀(bexarotene)、比卡鲁胺、比生群、博来霉素、硼替佐米、布舍瑞林、博舒替尼、乙酸阿比特龙酯(brentuximab vedotin)、白消安、卡巴他赛(cabazitaxel)、卡博替尼、甲酰四氢叶酸钙(calcium folinate)、左亚叶酸钙、卡培他滨、卡罗单抗、卡铂、卡菲偌米布、卡莫氟、卡莫司汀、卡妥索单抗(catumaxomab)、西乐葆、西莫白介素、色瑞替尼、西妥昔单抗、苯丁酸氮芥、氯地孕酮、氮芥、西多福韦、西那卡塞、顺铂、克拉屈滨、氯膦酸、氯法拉滨(clofarabine)、copanlisib、克立他酶(crisantaspase)、环磷酰胺、环丙孕酮、阿糖胞苷、达卡巴嗪、放线菌素、达贝泊汀α(darbepoetin alfa)、达拉非尼、达沙替尼、柔红霉素、地西他滨、地加瑞克、地尼白介素-毒素连接物(denileukin diftitox)、地诺塞麦(denosumab)、地普奥肽、地洛瑞林、右雷佐生、二溴螺氯铵、二去水卫矛醇、双氯芬酸、多西他赛、多拉司琼、去氧氟尿苷、多柔比星、多柔比星+雌酮、屈大麻酚、依库丽珠单抗(eculizumab)、依决洛单抗、依利醋铵、伊屈泼帕(eltrombopag)、血管内皮抑素、依诺他滨、恩扎鲁胺、表柔比星、环硫雄醇、依泊汀α、依泊汀β、依泊汀ζ、依他铂、艾日布林(eribulin)、埃洛替尼、埃索美拉唑、雌二醇、雌莫司汀、依托泊苷、依维莫司、依西美坦、法屈唑、芬太尼、非格司亭、氟羚甲基睾丸素、氟尿苷、氟达拉滨、氟尿嘧啶、氟他胺、亚叶酸、福美坦、福沙吡坦、福莫司汀、氟维司群、钆布醇、加多利道、钆特酸葡胺、钆弗塞胺、钆塞酸、硝酸镓、加尼瑞克、吉非替尼、吉西他滨、吉妥单抗(gemtuzumab)、羧肽酶、谷胱甘肽(glutoxim)、GM-CSF、戈舍瑞林、格兰西龙、粒细胞集落刺激因子、二盐酸组胺、组氨瑞林(histrelin)、羟基脲、I-125粒子、兰索拉唑、依班膦酸、替伊莫单抗(ibritumomab tiuxetan)、依鲁替尼、伊达比星、异环磷酰胺、伊马替尼、咪喹莫特、英丙舒凡(improsulfan)、吲地司琼、英卡膦酸、巨大戟醇甲基丁烯酸酯、干扰素α、干扰素β、干扰素γ、碘比醇、碘苄胍(123I)、碘美普尔、易普利姆玛(ipilimumab)、伊立替康、伊曲康唑、伊沙匹隆(ixabepilone)、兰瑞肽、拉帕替尼(lapatinib)、Iasocholine、来那度胺(lenalidomide)、来格司亭、蘑菇多糖、来曲唑、亮丙瑞林、左旋四咪唑、左炔诺孕酮、左甲状腺素钠、麦角乙脲、乐铂、洛莫斯汀、氯尼达明、马索罗酚、甲羟孕酮、甲地孕酮、美拉胂醇、美法仑、美雄烷、巯基嘌呤、美司钠、美沙酮、氨甲喋呤、甲氧呋豆素、甲基氨基酮戊酸盐、甲基泼尼松龙、甲基睾甾酮、甲酪氨酸、米伐木肽(mifamurtide)、米特福辛、米铂(miriplatin)、二溴甘露醇、丙脒腙、二溴卫矛醇、丝裂霉素、米托坦、米托蒽醌、mogamulizumab、莫拉司亭、莫哌达醇、盐酸吗啡、硫酸吗啡、大麻隆、nabiximols、那法瑞林、纳洛酮+戊唑辛、纳曲酮、那托司亭、奈达铂、奈拉滨(nelarabine)、奈立膦酸、nivolumabpentetreotide、尼洛替尼(nilotinib)、尼鲁米特、尼莫唑、尼妥珠单抗(nimotuzumab)、嘧啶亚硝脲、二胺硝吖啶(nitraerine)、纳武单抗、阿托珠单抗、奥曲肽、奥法木单抗(ofatumumab)、高三尖杉酯碱、奥美拉唑、奥坦西隆、奥普瑞白介素(oprelvekin)、奥古蛋白、orilotimod、奥沙利铂、羟考酮、羟甲烯龙、ozogamicine、p53基因治疗、紫杉醇、palifermin、钯-103粒子、帕洛诺司琼、帕米膦酸、帕尼单抗(panitumumab)、泮托拉唑、帕唑帕尼(pazopanib)、培加帕酶、PEG-倍他依泊汀(甲氧基PEG-倍他依泊汀)、帕母单抗、聚乙二醇非格司亭(pegfilgrastim)、聚乙二醇干扰素α-2b、培美曲唑、喷他佐辛、喷司他丁、培洛霉素、全氟丁烷、培磷酰胺、帕妥株单抗、溶链菌制剂(picibanil)、毛果芸香碱、吡柔比星、匹克生琼、普乐沙福(plerixafor)、普卡霉素、聚氨葡糖(poliglusam)、磷酸聚雌二醇、聚乙烯吡咯烷酮+透明质酸钠、多糖-K、泊马度胺、帕纳替尼、卟吩姆钠、普拉曲沙(pralatrexate)、泼尼莫司汀、泼尼松、甲基苄肼、丙考达唑、普萘洛尔、喹高利特(quinagolide)、雷贝拉唑、racotumomab、氯化镭223、拉多替尼、雷诺昔酚、雷替曲塞(raltitrexed)、雷莫司琼、雷莫芦单抗、雷莫司汀(ranimustine)、拉布立酶、雷佐生、refametinib、瑞戈非尼(regorafenib)、利塞膦酸、铼-186依替膦酸盐、利妥昔单抗(rituximab)、罗米地辛(romidepsin)、罗米司亭(romiplostim)、罗莫肽、roniciclib、来昔决南钐(153Sm)、沙莫司亭、沙妥莫单抗、分泌素、sipuleucel-T、西佐喃、索布佐生、甘氨双唑钠(sodium glycididazole)、索拉非尼(sorafenib)、司坦唑醇、链脲霉素、舒尼替尼、他拉泊芬(talaporfin)、他米巴罗汀(tamibarotene)、他莫昔芬、他喷他多、他索纳明(tasonermin)、替西白介素(teceleukin)、锝[99mTc]巯诺莫单抗、99mTc-HYNIC-[Tyr3]-奥曲肽、替加氟、替加氟+吉美嘧啶(gimeracil)+奥替拉西(oteracil)、替莫卟吩、替莫唑胺、西罗莫司(temsirolimus)、替尼泊苷、睾酮、替曲膦(tetrofosmin)、沙利度胺、硫替派、胸腺法新(thymalfasin)、促甲状腺素α、硫鸟嘌呤(tioguanine)、托珠单抗(tocilizumab)、托泊替康、托瑞米芬、托西莫单抗(tositumomab)、曲贝替定(trabectedin)、曲马多、曲妥珠单抗、曲妥珠单抗美坦辛偶联物、曲奥舒凡(treosulfan)、维甲酸、曲氟尿苷+tipiracil、曲洛司坦、曲普瑞林、曲美替尼、曲磷胺、促血小板生成素、色氨酸、乌苯美司、瓦他拉尼、戊柔比星(valrubicin)、凡德他尼(vandetanib)、伐普肽、维罗非尼(vemurafenib)、长春碱、长春新碱、长春地辛、长春氟宁、长春瑞宾、维莫德吉、伏立诺他(vorinostat)、伏氯唑、钇-90玻璃微球、净司他丁、净司他丁斯酯、唑来膦酸、佐柔比星。
在优选实施方案中,本发明的药物组合包含:
通式(I)或(Ib)的化合物,和
一种或多种活性成分,其选自卡铂和顺铂。
通常,与本发明的化合物或药物组合物组合使用抗过度增殖、抑制细胞生长或细胞毒性组合活性成分,用于:
(1)与给予任一单独药剂相比较,在降低肿瘤生长或甚至消除肿瘤方面得到更好效力,
(2)使得所给予的化疗剂的给药量更少,
(3)提供化疗治疗,与单一药剂化疗和某些其它联合治疗所观察到的相比,这种化疗治疗能够使患者的耐受性良好,同时,不利的药理学并发症更少,
(4)为哺乳动物尤其人的更宽谱的不同癌症类型提供治疗,
(5)在所治疗的患者中产生更高的响应率,
(6)相比于标准化疗治疗,使所治疗的患者的存活时间更长,
(7)提供更长的肿瘤进展时间,和/或
(8)相比于其它癌症药剂组合产生拮抗效应的已知案例,效力和耐受性结果至少与单独使用的药剂的效力和耐受性同样好。
此外,通式(I)的化合物还可以与放射疗法和/或外科手术干预组合使用。
在本发明的其他实施方案中,本发明的化合物可用于使细胞对于辐射敏感。也就是说,相比于没有使用本发明的化合物进行任何处理的细胞,在辐射处理细胞之前,用本发明的化合物处理细胞,使细胞对DNA损伤和细胞死亡更敏感。在一方面,用至少一种本发明的化合物处理细胞。
由此,本发明还提供了杀死细胞的方法,在这种方法中,给予细胞一或多种本发明的化合物与常规放射治疗的组合。
本发明还提供了使细胞对细胞死亡更敏感的方法,在这种方法中,在处理细胞之前,用一或多种本发明的化合物处理细胞,导致或诱导细胞死亡。在一方面,用一或多种本发明的化合物处理细胞之后,用至少一种化合物或至少一种方法或其组合来处理细胞,以便导致DNA损伤达到抑制正常细胞的功能或杀死细胞的目的。
在本发明的另一个实施方案中,通过用至少一种DNA损伤剂来处理细胞,从而杀死细胞。也就是说,用一或多种本发明的化合物处理细胞使细胞对于细胞死亡敏感之后,用至少一种DNA损伤剂来处理细胞,从而杀死细胞。在本发明中使用的DNA损伤剂包括但不局限于:化疗剂(例如,顺铂)、电离辐射(X射线、紫外辐射)、致癌剂和诱变剂。
在另一个实施方案中,通过用至少一种方法处理细胞导致或诱导DNA损伤,从而杀死细胞。这种方法包括但不局限于:活化细胞信号传导途径,当所述途径被活化时引起DNA损伤,抑制细胞信号传导途径,当所述途径受到抑制时引起DNA损伤,以及诱导细胞的生物化学变化,其中,这种变化导致DNA损伤。作为非限制性实例,可以抑制细胞中的DNA修复途径,由此防止DNA损伤的修复,并导致细胞中的DNA损伤的异常积累。
在本发明的一方面,在辐射或其它诱导细胞DNA损伤之前,给予细胞本发明的化合物。在本发明的另一个方面,给予细胞本发明的化合物,同时伴随辐射或其它诱导细胞DNA损伤。在本发明的又一个方面,在辐射或其它诱导细胞DNA损伤开始之后,立即给予细胞本发明的化合物。
在另一个方面,细胞在体外。在另一个实施方案中,细胞在体内。
通式(I)或(Ib)的化合物可以全身和/或局部起作用。为了该目的,他们可以合适方式给予,例如通过口服、肠胃外、肺、鼻、舌下、舌、含服、直肠、皮肤、透皮、结膜、耳途径,或者作为植入物或支架。
通式(I)或(Ib)的化合物可以适合这些给药途径的给药形式给予。
口服给药的合适给药形式是以快速和/或改性方式释放通式(I)或(Ib)的化合物、根据现有技术工作且包含结晶和/或无定形和/或溶解形式的通式(I)或(Ib)的化合物的那些,例如,片剂(未包衣或包衣片剂,例如具有控制通式(I)或(Ib)的化合物的释放的肠或延迟-溶解或不溶性包衣)、片剂或薄膜/薄片,其在口腔中迅速崩解,薄膜/冻干剂、胶囊(例如,硬或软明胶胶囊)、糖包衣片剂、颗粒剂、小丸、粉剂、乳剂、悬浮剂、气雾剂或溶液剂。
肠胃外给药可以通过避免吸收步骤(例如,通过静脉内、动脉内、心内、脊柱内或腰椎内途径)或通过加入吸收(例如,通过肌内、皮下、皮内、经皮或腹膜内途径)来完成。肠胃外给药的合适给药形式包括溶液剂、悬浮液、乳剂、冻干剂或无菌粉剂形式的注射和输注制剂。
对于其他给药途径,合适的实例是用于吸入的药物形式或吸入药物(包括粉末吸入剂、喷雾剂)、滴鼻剂、溶液剂或喷雾;片剂、薄膜/薄片或胶囊,其用于舌、舌下或含服给药;薄膜/薄片或胶囊、栓剂、耳或眼用制剂(例如,洗眼器、眼用插入物、滴耳剂、耳用粉剂、洗耳剂(ear-rinse)、耳塞)、阴道胶囊、水性悬浮液(洗剂、摇动混合物)、亲脂性悬浮液、软膏、乳膏、透皮治疗系统(例如,贴剂)、乳剂、糊剂、泡沫剂、扑粉、植入物、子宫内线圈、阴道环或支架。
通式(I)或(Ib)的化合物可以转化为提及的给药形式。这可以本身已知的方式,通过与药学上合适的赋形剂混合进行。
基于评价用于治疗过度增殖性疾病的化合物的已知的标准实验室技术,通过确定上面确定的哺乳动物病症的治疗的标准毒性检验和标准药理学试验,并且将这些结果与用于治疗这些病症的已知活性成分或药物的结果相比较,可以容易地确定本发明化合物的治疗各个目标适应症的有效剂量。根据诸如所使用的具体化合物和剂量单位、给药模式、疗程、所治疗患者的年龄和性别以及所治疗病症的性质和程度的考虑因素,可以在很大程度上改变在治疗这些病症的一种中要给予的活性成分的量。
所给予的活性成分的总量通常在每天大约0.001mg/kg至大约200mg/kg体重的范围内,优选每天大约0.01mg/kg至大约20mg/kg体重。临床上使用的给药计划在每天给药一至三次至每四周给药一次的范围内。另外,其中不给患者药物达某一时段的“休药期”,可以有益于药理学效果和耐受性之间的综合平衡。单位剂量可以含有大约0.5mg至大约1500mg活性成分,并且可以每天给药一或多次,或每天少于一次。注射给药(包括静脉内、肌内、皮下和肠胃外注射以及使用输注技术)的平均日剂量,优选为0.01至200mg/kg总体重。优选,平均每天直肠给药方案为0.01至200mg/kg总体重。优选,平均每天阴道给药方案为0.01至200mg/kg总体重。优选,平均每天局部给药方案为0.1至200mg,每天给药一至四次。优选,透皮浓度要求保持0.01至200mg/kg的日剂量。优选,平均每天吸入剂量方案为0.01至100mg/kg总体重。
当然,对于每个患者来说,具体的初始和连续剂量方案根据诊断医生所确定的病症的性质和严重程度、使用的具体化合物的活性、患者的年龄和常规状况、给药时间、给药途径、药物的排泄率、药物组合等等而变化。治疗的目标模式和本发明化合物或其药学上可接受的盐或酯或组合物的剂量数,可以由本领域技术人员使用常规治疗试验来确定。
尽管如此,偏离规定量可能是必须的,具体地依赖于体重、给药途径、对活性成分的个人行为、制剂类型和给药时间或间隔。例如,在某些情况下,小于上述最小量可能是足够的,而在其他情况下不得不超过提及的上限。在给予更大量的情况下,在一天内将其分为若干单个剂量是可取的。
除非另外规定,在后面的实验和实施例中的百分比是重量百分比;份是重量份。在每种情况下,液体/液体溶液的溶剂比、稀释比和浓度数据是基于体积的。
化合物的合成(概述):
本发明的化合物可以如以下部分所述制备。下述反应式和程序例示本发明的通式(I)的化合物的一般合成途径并且不旨在限制。本领域技术人员明白可以多种方式改变方案例示的转化顺序。因此,方案例示的转化顺序不旨在限制。另外,可以在例示的转化之前和/或之后实现任何取代基的互换。这些改变可以是例如引入保护基、除去保护基、交换、还原或氧化官能团、卤代、金属化、取代或本领域技术人员已知的其他反应。这些转化包括引入官能团的那些,其允许进一步取代基互换。合适的保护基及其引入和除去是本领域技术人员公知的(参见,例如P.G.M.Wuts和T.W.Greene,“Protective Groups inOrganicSynthesis”,第四版,Wiley 2006)。具体实例描述在随后的段落中。进一步地,可以进行两个或更多个连续步骤而不在所述步骤之间进行后处理,例如,“一锅”反应,这对本领域技术人员来说是公知的。
优选根据一般合成顺序进行本发明的2-(吗啉-4-基)-1,7-萘啶衍生物的合成,如反应式1-6所示。
反应式1:制备通式8化合物的路线,其中R1、R3、R4和R5具有上文针对通式(I)给出的含义。此外,取代基R1可以具有保护基并且可以在例示的转化之前和/或之后实现任何取代基R1的互换。这些修饰可以是例如引入保护基或除去保护基。合适的保护基及其引入和除去是本领域技术人员公知的(参见例如,T.W.Greene和P.G.M.Wuts,ProtectiveGroupsin Organic Synthesis,第三版,Wiley 1999)。具体实例在随后的段落中描述。
式3的起始材料为可商购的或可以根据文献制备。
步骤1→2(反应式1)
酰胺形成
在第一步骤中(反应式1),使用乙酰化剂可将吗啉衍生物1(其是可商购的或者描述在文献中)转化为相应的乙酰胺2。起始的吗啉可以盐(例如HCl盐)的形式或以游离胺的形式使用。
例如,可使用乙酰氯在有机溶剂例如二氯甲烷中在碱例如K2CO3的存在下将吗啉1乙酰化。乙酰化也可以使用乙酸酐在吡啶中进行。或者,在有机溶剂中的乙酸、碱和原位产生活性酯的活化剂可用于转化。综述参见:C.A.G.N.Montalbetti和V.Falque Tetrahedron2005,61,10827–10852和其中的参考文献)。
步骤3→4(反应式1)
脒形成
在脒形成反应中使式3化合物与式2的吗啉酰胺反应以得到通式4的化合物。通常用纯的或在有机溶剂中的POCl3在0℃至所选溶剂沸点的温度范围下进行反应。优选地,卤化溶剂例如氯仿、DCE或DCM用于反应。
步骤4→5(反应式1)
萘啶形成
式4的脒可以转化为式5的相应化合物。通常反应在有机溶剂中在-20℃至所选溶剂沸点的温度下使用强碱进行。优选地,LiHMDS、KHMDS、NaHMDS或LDA用作碱。
步骤5→8(反应式1)
与硼酸的钯催化反应
式5的氯萘啶可与硼酸衍生物R1-B(OR)2反应以得到式8化合物。硼酸衍生物可以为硼酸(R=–H)或硼酸的酯,例如其异丙基酯(R=–CH(CH3)2),优选为衍生自频哪醇的酯,其中硼酸中间体形成2-芳基-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(R-R=–C(CH3)2-C(CH3)2–)。硼酸衍生物的杂环R1的NH基团可以通过任何合适的保护基掩盖(参见Green,Wuts,“Protective groups in organic synthesis”1999,John Wiley&Sons和其中引用的参考文献)。相应的保护基可以在合成的任何合适步骤除去。优选地,在合成期间,THP(四氢吡喃基)、BOC(叔丁氧基羰基)或PMB(对甲氧基苄基)用作保护基。
偶联反应通过钯催化剂催化,例如通过Pd(0)催化剂,如四(三苯基膦)钯(0)[Pd(PPh3)4]、三(二亚苄基丙酮)二-钯(0)[Pd2(dba)3],或通过Pd(II)催化剂,如二氯双(三苯基膦)-钯(II)[Pd(PPh3)2Cl2]、乙酸钯(II)和三苯基膦,或通过[1,1'-双(二苯基膦基)二茂铁]二氯化钯催化。
反应优选在溶剂如1,2-二甲氧基乙烷、二噁烷、DMF、DME、THF或异丙醇与水的混合物中并且在碱如碳酸钾、碳酸氢钠或磷酸钾的存在下进行。
(综述:D.G.Hall,Boronic Acids,2005WILEY-VCH Verlag GmbH&Co.KGaA,Weinheim,ISBN 3-527-30991-8和其中引用的参考文献)。
反应在室温(即,约20℃)至各个溶剂沸点的温度下进行。更进一步地,反应可在高于沸点的温度下使用压力管和微波炉进行。反应优选在1-36小时的反应时间之后完成。
反应式2:制备通式11化合物的路线,其中R1、R3,R4和R5具有上文针对通式(I)给出的含义。此外,取代基R1可以具有保护基并且可以在例示的转化之前和/或之后实现任何取代基R1的互换。这些修饰可以是例如引入保护基或除去保护基。合适的保护基及其引入和除去是本领域技术人员公知的(参见例如T.W.Greene和P.G.M.Wuts in ProtectiveGroups in Organic Synthesis,3rd edition,Wiley 1999)。具体实例在随后的段落中描述。
步骤8→11(反应式2)
三氟甲磺酸酯形成
通式8的羟基-萘啶可以转化为相应的式11的三氟甲磺酸酯。通常,使羟基-萘啶8与三氟甲磺酸酯试剂例如N-苯基双(三氟甲磺酰亚胺)在有或没有碱的情况下在有机溶剂例如二氯甲烷中反应。
反应式3:制备通式12和13化合物的路线,其中R1、R3、R4和R5具有上文针对通式(I)给出的含义和R”具有C1-C6-烷基或3-至10-元杂环烷基的含义。R1可以具有保护基并且可以在例示的转化之前和/或之后实现任何取代基R1的互换。这些修饰可以是例如引入保护基或除去保护基。合适的保护基及其引入和除去是本领域技术人员公知的(参见例如T.W.Greene和P.G.M.Wuts in Protective Groups in Organic Synthesis,3rd edition,Wiley 1999)。具体实例在随后的段落中描述。
步骤5→12(反应式3)
羟基转化成醚
式5的羟基-萘啶可以转化为相应的通式13的醚,其中R″为C1-C6-烷基或3-至10-元杂环烷基。使用卤化物(优选Cl、Br或I)、甲苯磺酸酯、甲磺酸酯或三氟甲磺酸酯进行反应。在溶剂例如乙腈、DMF或甲醇和水的1:1混合物中进行该反应。在碱例如CsCO3或K2CO3的存在下进行反应。在室温至各个溶剂沸点的温度下进行反应。此外,反应在高于沸点的温度下在压力下进行。反应优选在1-16小时之后完成。
或者,通式12的醚可以在膦(例如,三苯基膦)和偶氮二甲酸酯(例如,偶氮二甲酸二异丙酯)的存在下在溶剂例如THF中通过Mitsunobu反应从醇合成。
步骤12→13(反应式3)
钯催化的与硼酸的反应
式12的氯萘啶可以与硼酸衍生物R1-B(OR)2反应,得到式13的化合物。硼酸衍生物可以是硼酸(R=–H)或硼酸的酯,例如其异丙酯(R=–CH(CH3)2),优选衍生自频哪醇的酯,其中硼酸中间体形成2-芳基-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(R-R=–C(CH3)2-C(CH3)2–)。硼酸衍生物的杂环R1的NH基团可被任何合适的保护基团掩蔽(参见Green,Wuts,“Protective groups in organic synthesis”1999,John Wiley&Sons和其中引用的参考文献)。可以在合成的任何合适步骤中除去相应的保护基团。优选THP(四氢吡喃基)、BOC(叔丁氧基羰基)或PMB(对甲氧基苄基)在合成过程中用作保护基团。
偶联反应由钯催化剂催化,例如用Pd(0)催化剂如四(三苯基膦)钯(0)[Pd(PPh3)4]、三(二亚苄基丙酮)二钯(0)[Pd2(dba)3],或Pd(II)催化剂如二氯双(三苯基膦)-钯(II)[Pd(PPh3)2Cl2],乙酸钯(II)和三苯基膦或[1,1'-双(二苯基膦基)二茂铁]二氯化钯。
该反应优选在溶剂如1,2-二甲氧基乙烷、二噁烷、DMF、DME、THF或异丙醇与水的混合物中和在碱如碳酸钾、碳酸氢钠或磷酸钾的存在下进行。
(综述:D.G.Hall,Boronic Acids,2005WILEY-VCH Verlag GmbH&Co。KGaA,Weinheim,ISBN 3-527-30991-8和其中引用的参考文献)。
反应在室温(即约20℃)至各溶剂沸点的温度下进行。此外,可以使用压力管和微波炉在高于沸点的温度下进行反应。反应优选在反应时间为1至36小时后完成。
反应式3:制备通式12、13、18、19和20化合物的路线,其中R1、R3、R4、R5、R7、R8和R9具有上文针对通式(I)给出的含义和R”具有C1-C6-烷基或3-至10-元杂环烷基的含义。此外,取代基R1可以具有保护基并且可以在例示的转化之前和/或之后实现任何取代基R1的互换。这些修饰可以是例如引入保护基或除去保护基。合适的保护基及其引入和除去是本领域技术人员公知的(参见例如T.W.Greene和P.G.M.Wuts in Protective Groups in OrganicSynthesis,3rd edition,Wiley 1999)。具体实例在随后的段落中描述。
步骤8→12(反应式3)
羟基转化为卤素(F、Br、Cl、I)
可以例如使用氯化试剂例如三氯磷酸盐,在有或没有有机溶剂的情况下,进行羟基-萘啶8到式12的卤素化合物的转化(卤素=Cl)。通常,反应在升高的温度下进行。可以使用卤素=Br的试剂,例如三溴化磷或氧溴化磷。对于卤素=F参见例如J.of Org.Chem.,2013,78,4184–4189。对于卤素=I参见例如Journal of Organic Chemistry,2009,74,5111–5114及其中的参考文献。
步骤8→13(反应式3)
羟基转化成醚
式8的羟基-萘啶可以转化为相应的通式13的醚,其中R″为C1-C6-烷基或3-至10-元杂环烷基。使用卤化物(优选Cl、Br或I)、甲苯磺酸酯、甲磺酸酯或三氟甲磺酸酯进行反应。在溶剂例如乙腈、DMF或甲醇和水的1:1混合物中进行该反应。在碱例如CsCO3或K2CO3的存在下进行反应。在室温至各个溶剂沸点的温度下进行反应。此外,反应在高于沸点的温度下在压力下进行。反应优选在1-16小时之后完成。
或者,通式13的醚可以在膦(例如,三苯基膦)和偶氮二甲酸酯(例如,偶氮二甲酸二异丙酯)的存在下在溶剂例如THF中通过Mitsunobu反应从醇合成。
步骤8→15(反应式3)
羟基转化为硫醇
为了将式8的羟基-萘啶衍生物转化为式15的硫醇,例如可以在有机溶剂中使用Lawesson试剂或五硫化二磷。通常,这些反应在升高的温度下进行。
步骤15→20(反应式3)
硫醇转化为磺酰胺
与文献方法类似,通式15的硫醇可通过式16的中间体磺酰氯转化为相应的磺酰胺20。例如,参见European J.of Medicinal Chemistry 2013,60,42-50及其中的参考文献。
步骤15→17(反应式3)
硫醇转化为硫醚
式15的硫醇可以烷基化成相应的硫醚17。使用烷基卤化物(优选Cl、Br或I)、甲苯磺酸酯、甲磺酸酯或三氟甲磺酸酯进行反应。该反应在溶剂例如乙腈、DMF或甲醇和水的1:1混合物中进行。该反应在碱例如CsCO3或K2CO3存在下进行。反应在室温至各溶剂沸点的温度范围内进行。此外,反应可在高于沸点的温度下在压力下进行。反应优选在1至16小时后完成。
步骤17→18(反应式3)
硫醚转化为亚砜
式17的硫醚可被氧化成相应的亚砜18。通常使用在有机溶剂中的氧化剂(例如在二氯甲烷中的3-氯-过氧苯甲酸)。
步骤17→19(反应式3)
硫醚转化为砜
通式17的硫醚可以被氧化成相应的亚砜19。通常使用有机溶剂中的氧化剂(例如在二氯甲烷中的3-氯-过氧苯甲酸)。
反应式4:制备通式17、19、21、23、24、26和27化合物的路线,其中R1、R3、R4、R5、R7、R8和R9具有上文针对通式(I)给出的含义。基团A代表C2-C6-烯基、C5-C6-环烯基、4-至10-元杂环烯基、芳基或杂芳基和基团D代表C2-C6-烷基、C5-C6-环烷基或4-至10-元杂环烷基。此外,取代基R1可以具有保护基并且可以在例示的转化之前和/或之后实现任何取代基R1的互换。这些修饰可以是例如引入保护基或除去保护基。合适的保护基及其引入和除去是本领域技术人员公知的(参见例如T.W.Greene和P.G.M.Wuts in Protective Groups in OrganicSynthesis,3rd edition,Wiley 1999)。具体实例在随后的段落中描述。
步骤12→17(反应式4)
转化为硫醚
通式12的卤素化合物可通过硫醇的亲核取代转化为通式17的相应硫醚。通常使用碱(例如KOtBu、NaH、碳酸铯、碳酸钾),在有机溶剂(例如叔丁醇、DMSO或DMF)中。通常,反应在升高的温度下进行。参见例如:Journal of Medicinal Chemistry,2008,51,3466-3479及其中的参考文献。
步骤11或12→21(反应式4)
C-N交叉偶联反应或亲核取代
通式11的三氟甲磺酸酯可以通过C-N交叉偶联反应转化为相应的胺21。通常使用在有机溶剂中的金属催化剂、配体和碱。对于最近的综述参见例如:Chem.Soc.Rev.,2013,42,9283或“Metal-Catalyzed Cross-Coupling Reactions(2 Volume Set)”,2004byArmin de Meijere(Editor),Diederich(Editor)及其中的参考文献。
或者,通式12的卤素化合物可以通过亲核取代反应转化为相应的胺21。通常在有机溶剂(例如iPrOH、DCM、DMSO、DMF)中使用亲核胺和碱(例如三乙胺、Hünig碱、碳酸钾)的组合。参见例如:Bioorganic和Medicinal Chemistry Letters,2011,21,5502–5505及其中的参考文献。
步骤11或12→22(反应式4)
烃化
通式11的三氟甲磺酸酯可以通过金属催化的羰基化反应转化为相应的酯22。通常使用一氧化碳和具有或不具有配体的钯催化剂(例如:乙酸钯/1,3-双-(二苯基膦基)丙烷;双-三苯基膦-氯化钯(II)/三苯基膦)、作为亲核试剂的醇(例如,使用在有机溶剂(例如:DMF、甲醇、乙醇)中的甲醇,乙醇)。参见例如:Journal of Medicinal Chemistry,2008,51,1649–1667或Synthesis,2001,7,1098–1109及其中的参考文献。
步骤22→23(反应式4)
酰胺形成
通式22的酯可以转化为相应的通式23的酰胺。通常,胺与碱(例如氢氧化钠或甲醇镁)在溶剂(例如甲醇、异丙醇、水)中反应。或者,酯22可以在有机溶剂(例如THF、甲苯)中与胺和正丁基锂或三甲基铝反应,形成式23的酰胺。参见例如Chem.Commun.,2008,1100-1102及其中的参考文献。
或者,可将通式22的酯水解成相应的羧酸(使用例如KOH、水、甲醇作为酯水解条件),并在经典的酰胺偶联条件下进一步与相应的酰胺23反应。关于使用游离羧酸和胺与活化剂组合的酰胺偶联条件的综述,参见例如Chem.SOC.Rev.,2009,38,606-631及其中的参考文献。
步骤11或12→24(反应式4)
腈形成
通式12的卤素化合物或通式11的三氟甲磺酸酯可以转化成相应的腈24。通常在溶剂(例如N,N-二甲基乙酰胺/水)中使用钯催化剂和配体(例如1,1'-双-(二苯基膦基)二茂铁/三-(二亚苄基丙酮))二氧化钯(0))、氰化锌(II)。参见例如Tetrahedron Letters,2006,47,3303–3305及其中的参考文献。
步骤11或12→25(反应式4)
C-C交叉偶联反应
通式11的三氟甲磺酸酯可以与硼酸衍生物A-B(OR)2反应,得到式25的化合物。基团A代表C1-C6-烷基、C2-C6-烯基、C3-C6-环烷基、3-至10-元杂环烷基、4-至10-元杂环烯基、苯基、杂芳基。硼酸衍生物可以是硼酸(R=–H)或硼酸的酯,例如其异丙酯(R=–CH(CH3)2),优选衍生自频哪醇的酯,其中硼酸中间体形成2-芳基-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(R-R=–C(CH3)2-C(CH3)2–)。硼酸衍生物的基团A可以被任何合适的保护基团掩蔽(参见Green,Wuts,“Protective groups in organic synthesis”1999,John Wiley&Sons)。可以在合成的任何合适步骤中除去相应的保护基团。
偶联反应通过钯催化剂催化,例如通过Pd(0)催化剂,如四(三苯基膦)钯(0)[Pd(PPh3)4]、三(二亚苄基丙酮)二-钯(0)[Pd2(dba)3],或通过Pd(II)催化剂,如二氯双(三苯基膦)-钯(II)[Pd(PPh3)2Cl2]、乙酸钯(II)和三苯基膦,或通过[1,1'-双(二苯基膦基)二茂铁]二氯化钯催化。
反应优选在溶剂如1,2-二甲氧基乙烷、二噁烷、DMF、DME、THF或异丙醇与水的混合物中并且在碱如碳酸钾、碳酸氢钠或磷酸钾的存在下进行。
(综述:D.G.Hall,Boronic Acids,2005WILEY-VCH Verlag GmbH&Co.KGaA,Weinheim,ISBN 3-527-30991-8和其中引用的参考文献)。
反应在室温至各个溶剂沸点的温度下进行。更进一步地,反应可在高于沸点的温度下使用压力进行。反应优选在1-36小时的反应时间之后完成。
步骤25→26(反应式4)
双键氢化
式25的不饱和衍生物(其中基团A代表C2-C6-烯基、C5-C6-环烯基、4-至10-元杂环烯基)可以被氢化成相应的通式26的饱和衍生物(其中基团D代表C2-C6-烷基、C5-C6-环烷基、4-至10-元杂环烷基)。通常,氢气(在大气压或高压下)与非均相或均相催化剂组合使用,例如在有机溶剂如乙酸乙酯,甲醇或乙酸中的钯/炭。
步骤12→27(反应式4)
脱卤反应
通式12的卤化物可以脱卤,例如通过氢化反应得到通式27的萘啶。通常使用的是氢气(在大气压或高压下),碱(如三乙胺)和非均相金属催化剂(如钯活性炭),在有机溶剂中(例如乙醇、乙酸乙酯、乙酸)。
步骤11或12→19(反应式4)
磺酰化反应
通式12的卤化物或通式11的三氟甲磺酸酯可通过与烷基亚磺酸钠盐或芳基亚磺酸钠盐与碱例如4-(N,N-二甲基氨基)吡啶或吡啶在有机溶剂(例如N,N-二甲基-甲酰胺)中反应而转化为相应的通式19的砜。通常,反应在升高的温度下进行。该反应也可以由铜介导(参见例如European Journal of Medicinal Chemistry,2004,vol。39,735–744)。
反应式5:制备通式38化合物的路线,其中R1、R3、R4、R5、R9和R11具有上文针对通式(I)给出的含义。此外,取代基R1可以具有保护基并且可以在例示的转化之前和/或之后实现任何取代基R1的互换。这些修饰可以是例如引入保护基或除去保护基。合适的保护基及其引入和除去是本领域技术人员公知的(参见例如T.W.Greene和P.G.M.Wuts inProtective Groups in Organic Synthesis,3rd edition,Wiley 1999)。具体实例在随后的段落中描述。
步骤18→31(反应式5)
磺胺亚胺的形成
通过两步法将亚砜18转化为相应的亚砜亚胺31。通常,使用所述方法(Org.Lett.,2004,6,1305-1307及其中的参考文献)将亚砜18转化为受保护的亚砜亚胺中间体。使用碱例如K2CO3在甲醇中将亚砜亚胺脱保护形成31。将亚砜18转化为未保护的亚砜亚胺31的其他选择是使用原位制备的叠氮酸(例如ChemMedChem,2013,8,1021)或使用O-(均三甲苯磺酰基)羟胺(MSH)(例如J.Org.Chem.,1973,38,1239。
步骤31→38(反应式5)
亚砜亚胺氮的官能化
通式31的亚砜亚胺的氮的官能化可以使用前述方法进行:式31的N-未保护的亚砜亚胺可以反应得到式38的N-官能化的衍生物。制备N-官能化的亚砜亚胺有多种方法,其通过亚砜亚胺基团的氮的官能化:
-烷基化:参见例如:a)U.Lücking等人,US 2007/0232632;b)C.R.Johnson,J.Org.Chem.1993,58,1922;c)C.Bolm等人,Synthesis 2009,10,1601。
-与异氰酸酯反应:参见例如:a)V.J.Bauer等人,J.Org.Chem.1966,31,3440;b)C.R.Johnson等人,J.Am.Chem.Soc.1970,92,6594;c)S.Allenmark等人,ActaChem.Scand.Ser.B 1983,325;d)U.Lücking等人,US2007/0191393。
-与氯甲酸酯的反应:参见例如:a)P.B.Kirby等人,DE2129678;b)D.J.Cram等人,J.Am.Chem.Soc.1974,96,2183;c)P.Stoss等人,Chem.Ber.1978,111,1453;d)U.Lücking等人,WO2005/37800。
-与溴化氰(bromocyane)反应:参见例如:a)D.T.Sauer等人,InorganicChemistry 1972,11,238;b)C.Bolm等人,Org.Lett.2007,9,2951;c)U.Lücking等人,WO2011/29537。
反应式6:制备通式32、33、34、35、36和37化合物的路线,其中R1、R3、R4、R5、R7、R8、R9、R10、R11和R12具有上文针对通式(I)给出的含义。此外,取代基R1可以具有保护基并且可以在例示的转化之前和/或之后实现任何取代基R1的互换。这些修饰可以是例如引入保护基或除去保护基。合适的保护基及其引入和除去是本领域技术人员公知的(参见例如T.W.Greene和P.G.M.Wuts in Protective Groups in Organic Synthesis,3rd edition,Wiley 1999)。具体实例在随后的段落中描述。
步骤11→32(反应式6)
类似于文献方法在钯催化下,通式11的三氟甲磺酸酯可以转化成相应的磺酰胺32。例如参见J.Am.Chem.Soc.,2009,131,16720–16734及其中的参考文献。
步骤11→33(反应式6)
类似于文献方法在钯催化下,通式11的三氟甲磺酸酯可以转化成相应的亚砜亚胺33。例如,参见US2001/144345。
步骤11→34(反应式6)
类似于文献方法在钯催化下,通式11的三氟甲磺酸酯可以转化成相应的硅烷化化合物34。例如参见Org.Lett.2007,9,3785-3788及其中的参考文献。
步骤11→35(反应式6)
与文献方法类似,可以在钯催化下将通式11的三氟甲磺酸酯转化为膦酸酯35。例如,参见US2008/9465
步骤11→36(反应式6)
与文献方法类似,可以在钯催化下将通式11的三氟甲磺酸酯转化为次膦酸酯36。例如参见Adv.Synth.Cat.,2013,355,1361–1373及其中的参考文献。
步骤11→37(反应式6)
与文献方法类似,可以在钯催化下将通式11的三氟甲磺酸酯转化为氧化膦37。例如,参见US2007/4648
实验部分
下表列出了该段和实施例部分使用的缩写。
Boc 叔丁基氧基羰基
BuLi 丁基锂
conc. 浓的
DCE 二氯乙烷
DCM 二氯甲烷
DMAP N,N-二甲基氨基吡啶
DME 二甲氧基乙烷
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
EA 乙酸乙酯
EtOAc 乙酸乙酯
EtOH 乙醇
HPLC,LC 高效液相色谱
h 小时
LiHMDS 双(三甲基甲硅烷基)氨基锂
KHMDS 双(三甲基甲硅烷基)氨基钾
KOtBU 叔丁醇钾
min 分钟
LCMS,LC-MS,LC/MS 液相色谱–质谱
LDA 二异丙基氨基锂
MS 质谱
NMR 核磁共振
NMO N-甲基吗啉-N-氧化物
NaHMDS 双(三甲基甲硅烷基)氨基钠
PE 石油醚
Pd(dppf)Cl2 [1,1'-双-二苯基膦基-二茂铁]二氯化钯(II)
Rac 外消旋体
Rf 阻滞因数
Rt 保留时间
sat. 饱和的
rt,RT 室温
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层色谱
使用ACD/Name Batch Version 12.01或Autonom 2000生成化学名称。
实验部分未描述其合成的所有试剂是可商购的或者如参考文献所述合成。
分析方法
LC-MS方法1:
梯度:
LC-MS方法2:
MS仪器类型:Micromass Quatro Micro;HPLC仪器类型:Agilent 1100系列;UVDAD;柱:Chromolith Flash RP-18E 25-2mm;流动相A:0.0375%TFA于水中,流动相B:0.01875%TFA在乙腈中;梯度:0.0min 100%A→1.0min 95%A→3.0min 95%A→3.5min5%A→3.51min 5%A→4.0min95%A;流速:0.8ml/min;柱温:50℃;UV检测:220nm&254nm。
LC-MS方法3:
LC-MS方法4:
仪器MS:Waters ZQ;仪器HPLC:Waters UPLC Acquity;柱:Acquity BEH C18(Waters),50mm x 2.1mm,1.7μm;洗脱剂A:水+0.1体积%甲酸,洗脱剂B:乙腈(LichrosolvMerck);梯度:0.0min 99%A-1.6min 1%A-1.8min 1%A-1.81min 99%A-2.0min 99%A;温度:60℃;流速:0.8mL/min;UV-检测PDA 210-400nmnm–加固定波长254nm;MS ESI(+),扫描范围170-800m/z
LC-MS方法5:
系统:UPLC Acquity(Waters)具有PDA检测器和Waters ZQ mass光谱仪;柱:Acquity BEH C18 1.7μm 2.1x50mm;温度:60℃;溶剂A:水+0.1%甲酸;溶剂B:乙腈;梯度:99%A至1%A(1.6min)至1%A(0.4min);流速:0.8mL/min;进样量:1.0μl(0.1mg-1mg/mL样品浓度);检测:PDA扫描范围210-400nm–加固定波长254nm;MS ESI(+),扫描范围170-800m/z
制备型HPLC
自动纯化器:酸性条件
自动纯化器:碱性条件
中间体的制备
中间体-1
步骤a:
3-[(叔丁氧基羰基)氨基]-2-氯-5-甲基吡啶-4-甲酸甲酯
在0℃,将三甲基硅烷基重氮甲烷在乙醚中的溶液(2M;0.35mL;0.7mmol)滴加至3-[(叔丁氧基羰基)氨基]-2-氯-5-甲基吡啶-4-甲酸(100mg;0.35mmol)在THF(1.30mL)和MeOH(0.14mL)中的搅拌溶液中。将该混合物搅拌过夜,缓慢达到室温。将该混合物用EE稀释,用氯化钠水溶液洗涤,使用Whatman过滤器过滤并浓缩,达到粗产物(106mg),将其使用而不用进一步纯化。
1H NMR(400MHz,DMSO):δ[ppm]=1.42(9H),2.28(3H),3.83(3H),8.27(1H),9.21(1H).
步骤b:
3-氨基-2-氯-5-甲基吡啶-4-甲酸甲酯盐酸盐
将HCl在二噁烷中的溶液(4N;56.5mL;226mmol)加至粗制的3-[(叔丁氧基羰基)氨基]-2-氯-5-甲基吡啶-4-甲酸甲酯(5.10g)在DCM(172mL)和MeOH(17mL)中的溶液中。将该混合物在室温搅拌90分钟并浓缩。用DCM(3x)共蒸发,得到粗产物(3.56g),将其使用而不用进一步纯化。
1H NMR(400MHz,DMSO):δ[ppm]=2.22(3H),3.88(3H),5.99(2H),7.50-7.57(1H).
步骤c:
1-[(3R)-3-甲基吗啉-4-基]乙酮
在室温,将乙酸酐(14.0mL;148mmol)滴加至(3R)-3-甲基吗啉(1.50g;14.8mmol)在吡啶(36mL)中的搅拌溶液中。将该反应在室温搅拌72小时并浓缩。用甲苯(3x)共蒸发,得到所需粗制产物(2.27g),将其使用而不用进一步纯化。
步骤d:
2-氯-5-甲基-3-[(E)-{1-[(3R)-3-甲基吗啉-4-基]亚乙基}氨基]吡啶-4-甲酸甲酯
在0℃,在氩气下,将三氯氧磷(7.60g;49.6mmol)滴加至1-[(3R)-3-甲基吗啉-4-基]乙酮(4.95g;34.5mmol)在DCE(22mL)中的搅拌溶液中。将该混合物在室温搅拌30分钟,然后加入粗制的3-氨基-2-氯-5-甲基吡啶-4-甲酸甲酯盐酸盐(3.56g;15.0mmol)。将该混合物在80℃搅拌2小时。将该混合物在搅拌下加至冰水和碳酸氢钠水溶液的混合物中。将该混合物搅拌直至温度达到室温。将该混合物用DCM萃取,使用Whatman过滤器过滤并浓缩。将该残余物用硅胶柱色谱纯化(己烷至己烷/乙酸乙酯60%),得到所需产物(3.15g;9.7mmol)。
1H NMR(400MHz,DMSO):δ[ppm]=1H-NMR(400MHz,DMSO-d6):位移[ppm]=1.18(3H),1.74(3H),2.18(3H),3.06-3.22(1H),3.37-3.44(1H),3.50-3.59(1H),3.63-3.80(m,5H),3.86(1H),4.15–4.35(1H),7.91(s,1H).
步骤e:
8-氯-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-1,7-萘啶-4-醇
在0℃在氩气下,将双(三甲基甲硅烷基)氨基锂在THF中的溶液(1M;29.0mL,29.0mmol)滴加至2-氯-5-甲基-3-[(E)-{1-[(3R)-3-甲基吗啉-4-基]亚乙基}氨基]吡啶-4-甲酸甲酯(3.15g;9.7mmol)在THF(120mL)中的搅拌溶液中。将该混合物搅拌过夜,缓慢温热至室温。将该混合物冷却至0℃并在搅拌下加入冰水。所述pH通过添加HCl(2N)调节至5.5。加入固体NaCl,然后将混合物用EE/THF(1:1)萃取。将有机相用Whatman过滤器过滤并浓缩。将该残余物用硅胶柱色谱纯化(己烷/乙酸乙酯30%至50%),得到所需产物(1.20g;4.1mmol)。
1H NMR(400MHz,DMSO):δ[ppm]=1.20(3H),2.63(3H),3.11-3.30(1H),3.39-3.54(1H),3.65(1H),3.77(1H),3.98(1H),4.11(1H),4.34(1H),6.54(1H),7.72(1H).
中间体-2
8-氯-4-异丙氧基-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-1,7-萘啶
将碳酸钾(141mg;1.02mmol)加至8-氯-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-1,7-萘啶-4-醇(200mg;0.68mmol)在MeCN(11mL)中的搅拌溶液中然后加入2-碘丙烷(289mg;1.70mmol)。将该混合物在60℃搅拌过夜。冷却后,将该混合物用EE稀释,用氯化钠水溶液洗涤,使用Whatman过滤器过滤并浓缩,达到粗产物(247mg),将其使用而不用进一步纯化。
1H NMR(400MHz,DMSO):δ[ppm]=1.21(3H),1.40(6H),2.60(3H),3.13-3.23(1H),3.36-3.55(1H),3.66(1H),3.78(1H),3.95-4.04(1H),4.23-4.31(1H),4.60(1H),5.03(1H),6.70(1H),7.74(1H).
中间体-3
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-醇
在氩气下,将8-氯-4-异丙氧基-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-1,7-萘啶(300mg;1.02mmol)、1-(四氢-2H-吡喃-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(426mg;1.53mmol)、[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)·二氯甲烷络合物(83mg;0.10mmol)和碳酸铯(525mg;1.61mmol)在二噁烷(2.7mL)中的混合物在80℃搅拌150min。冷却后,将该混合物用DCM稀释。加入饱和氯化铵水溶液并将该混合物搅拌10min。将该有机相使用Whatman过滤器过滤并浓缩。将该残余物用硅胶柱色谱纯化(乙酸乙酯),得到所需产物(369mg;0.90mmol)。
1H-NMR(400MHz,DMSO):δ[ppm]=1.17(5H),1.39-1.61(2H),2.30-2.40(1H),2.71(3H),3.04-3.15(1H),3.19-3.31(1H),3.38-3.50(1H),3.60(1H),3.67-3.77(2H),3.83-4.06(3H),4.14–4.30(1H),5.89-5.99(1H),6.54(1H),6.77(1H),7.57(1H),8.07(1H),11.38(1H).
中间体-4
三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯
在氩气下,将N,N-二异丙基乙胺(0.17mL;0.98mmol)加至5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-醇(200mg;0.49mmol)和1,1,1-三氟-N-苯基-N-[(三氟甲基)磺酰基]甲磺酰胺(195mg;0.55mmol)在DCM(2.8mL)中的搅拌混合物中。将该混合物在室温搅拌2h,然后将其浓缩。将该残余物用硅胶柱色谱纯化(己烷至己烷/乙酸乙酯50%),得到所需产物(228mg;0.42mmol)。
1H-NMR(400MHz,DMSO):δ[ppm]=1.16-1.26(3H),1.40-1.63(3H),1.90-2.02(2H),2.30-2.41(1H),2.70(3H),3.18-3.30(2H),3.38-3.52(1H),3.59-3.80(3H),3.94-4.09(2H),4.40(1H),5.91-5.98(1H),6.84(1H),7.42(1H),7.62(1H),8.32(1H).
中间体-5
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-甲酸甲酯
在室温,在高压釜中,将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(1000mg;1.85mmol)、1,3-双(二苯基膦基)丙烷(79mg;0.19mmol)、乙酸钯(II)(41mg;0.19mmol)和三乙胺(0.5mL)在DMF(13mL)和甲醇(7mL)中的混合物用一氧化碳吹扫。将该高压釜用一氧化碳加压至13.8bar并将该混合物在室温搅拌30分钟。将该高压釜降压,然后用一氧化碳加压至15.5bar。将该混合物在80℃搅拌21小时。将该高压釜降压并冷却后,将该混合物用氯化钠水溶液稀释并用乙酸乙酯(2x)萃取。将合并的有机相干燥(Na2SO4),过滤并浓缩。将该残余物用柱色谱纯化(梯度从Hex/EtOAc 505至100%EtOAc),得到所需产物(350mg;0.78mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.13-1.30(4H),1.38-1.63(3H),1.89-2.01(2H),2.32-2.46(4H),3.14-3.31(2H),3.35-3.50(1H),3.57-3.78(3H),3.92-4.16(5H),4.46(1H),5.87-5.98(1H),6.80(1H),7.61(1H),8.27(1H).
实施例1
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-(丙-2-基氧基)-8-(1H-吡唑-5-基)-1,7-萘啶
在氩气下,将双(三苯基膦)二氯化钯(II)(21mg;0.03mmol)加至8-氯-4-异丙氧基-5-甲基-2-(3-甲基吗啉-4-基)-1,7-萘啶(100mg;0.30mmol)、1-(四氢-2H-吡喃-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(248mg;0.89mmol)和碳酸钾(123mg;0.89mmol)在DME(0.8mL)和水(0.4mL)中的混合物中。将该混合物在微波炉中在130℃搅拌10分钟。冷却后,将该反应混合物用EE稀释并使用Whatman过滤器过滤并浓缩。
将该残余物溶于MeOH(3.2mL)中并加入氯化氢水溶液(2N;0.8mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化。加入氯化钠水溶液并将该混合物用乙酸乙酯/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:碱性条件),得到所需产物(9mg;0.02mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.25(3H),1.42(6H),2.69(3H),3.15-3.31(1H),3.56(1H),3.71(1H),3.82(1H),4.04(1H),4.11(1H),4.56(1H),5.04(1H),6.74(1H),7.27(1H),7.57(1H),8.07(1H),13.29(1H).
实施例2
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-(1-甲基-1H-吡唑-5-基)-8-(1H-吡唑-5-基)-1,7-萘啶
将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(110mg;0.20mmol)、1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(42mg;0.20mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)与二氯甲烷络合(1:1,Pd(dppf)Cl2;17mg;0.02mmol))和碳酸钾(70mg;0.51mmol)在MeCN(4.2mL)和水(1.4mL)中的混悬液用氩气脱气。在氩气下,将该反应混合物在130℃微波反应器中搅拌10分钟。冷却后,将该反应混合物用EE稀释并用饱和氯化钠水溶液洗涤。将该有机相使用Whatman过滤器过滤,然后浓缩。
将该残余物溶于MeOH(1.5mL)并加入氯化氢水溶液(2N;0.4mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化。加入氯化钠水溶液并将混合物用乙酸乙酯/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:碱性条件),得到所需产物(10mg;0.03mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.24-1.33(3H),1.80(3H),3.48-3.62(4H),3.64-3.75(1H),3.81(1H),4.03(1H),4.19(1H),4.60(1H),6.48(1H),7.34(1H),7.42(1H),7.59(1H),7.62(1H),8.16(1H),13.36(1H).
实施例3
4-(2-氟吡啶-3-基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(110mg;0.20mmol)、(2-氟吡啶-3-基)硼酸(29mg;0.20mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)·二氯甲烷络合物(1:1,Pd(dppf)Cl2;17mg;0.02mmol))和碳酸钾(70mg;0.51mmol)在MeCN(4.2mL)和水(1.4mL)中的混悬液用氩气脱气。在氩气下,将该反应混合物在微波反应器中在130℃搅拌10分钟。冷却后,将该反应混合物用EE稀释并用饱和氯化钠水溶液洗涤。将该有机相使用Whatman过滤器过滤和然后浓缩。
将该残余物溶于MeOH(1.5mL)并加入氯化氢水溶液(2N;0.4mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化。加入氯化钠水溶液并将混合物用乙酸乙酯/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:碱性条件),得到所需产物(30mg;0.07mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.29(3H),1.86(3H),3.29-3.40(1H),3.55(1H),3.70(1H),3.81(1H),4.03(1H),4.18(1H),4.60(1H),7.34(1H),7.45(1H),7.54-7.59(1H),7.62(1H),8.00-8.23(2H),8.38-8.45(1H),13.36(1H).
实施例4
5-甲基-4-[2-甲基-6-(甲基磺酰基)吡啶-3-基]-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(190mg;0.35mmol)、2-甲基-6-(甲基磺酰基)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶(104mg;0.35mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)·二氯甲烷络合物(1:1,Pd(dppf)Cl2;29mg;0.04mmol))和碳酸钾(121mg;0.88mmol)在MeCN(7.4mL)和水(2.5mL)中的混悬液用氩气脱气。在氩气下,将该反应混合物在130℃微波反应器中搅拌10分钟。冷却后,将该反应混合物用EE稀释并用饱和氯化钠水溶液洗涤。将该有机相使用Whatman过滤器过滤和然后浓缩。
将该残余物溶于MeOH(1.6mL)并加入氯化氢水溶液(2N;0.4mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化。加入氯化钠水溶液并将该混合物用乙酸乙酯/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:碱性条件),得到所需产物(68mg;0.14mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.23-1.31(3H),1.74(3H),2.33(3H),3.35-3.37(3H),3.56(1H),3.66-3.85(2H),4.03(1H),4.12-4.22(1H),4.56(1H),7.36(1H),7.39(1H),7.53-7.67(1H),8.02(1H),8.08(2H),13.31-13.40(1H).
实施例5
4-(2-氯-1-甲基-1H-咪唑-5-基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(190mg;0.35mmol)、2-氯-1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-咪唑(85mg;0.35mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)·二氯甲烷络合物(1:1,Pd(dppf)Cl2;29mg;0.04mmol))和碳酸钾(121mg;0.88mmol)在MeCN(7.4mL)和水(2.5mL)中的混悬液用氩气脱气。在氩气下,将该反应混合物在130℃微波反应器中搅拌10分钟。冷却后,将该反应混合物用EE稀释并用饱和氯化钠水溶液洗涤。将该有机相使用Whatman过滤器过滤和然后浓缩。
将该残余物溶于MeOH(1.6mL)并加入氯化氢水溶液(2N;0.4mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化。加入氯化钠水溶液并将该混合物用乙酸乙酯/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:碱性条件),得到所需产物(22mg;0.05mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.23-1.32(3H),1.92(3H),3.29(3H),3.35-3.41(1H),3.46-3.63(1H),3.66-3.74(1H),3.81(1H),4.03(1H),4.17(1H),4.57(1H),7.07(1H),7.33(1H),7.47(1H),7.61(1H),8.14-8.18(1H),13.35(1H).
实施例6
4-[2-氟-4-(哌嗪-1-基)苯基]-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(190mg;0.35mmol)、[2-氟-4-(哌嗪-1-基)苯基]硼酸(79mg;0.35mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)·二氯甲烷络合物(1:1,Pd(dppf)Cl2;29mg;0.04mmol))和碳酸钾(121mg;0.88mmol)在MeCN(7.4mL)和水(2.5mL)中的混悬液用氩气脱气。在氩气下,将该反应混合物在微波反应器中在130℃搅拌10分钟。冷却后,将该反应混合物用EE稀释并用饱和氯化钠水溶液洗涤。将该有机相使用Whatman过滤器过滤和然后浓缩。
将该残余物溶于MeOH(1.6mL)并加入氯化氢水溶液(2N;0.4mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化。加入氯化钠水溶液并将该混合物用乙酸乙酯/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:碱性条件),得到所需产物(16mg;0.03mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.22-1.32(3H),1.96(3H),2.82-2.89(4H),3.11-3.24(4H),3.29(1H),3.54(1H),3.69(1H),3.79(1H),4.01(1H),4.15(1H),4.57(1H),6.82-6.93(2H),7.21-7.35(3H),7.61(1H),8.10(1H),13.32(1H).
实施例7
4-(2,3-二氟苯基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(190mg;0.35mmol)、(2,3-二氟苯基)硼酸(55mg;0.35mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)·二氯甲烷络合物(1:1,Pd(dppf)Cl2;29mg;0.04mmol))和碳酸钾(121mg;0.88mmol)在MeCN(7.4mL)和水(2.5mL)中的混悬液用氩气脱气。在氩气下,将该反应混合物在130℃微波反应器中搅拌10分钟。冷却后,将该反应混合物用EE稀释并用饱和氯化钠水溶液洗涤。将该有机相使用Whatman过滤器过滤和然后浓缩。
将该残余物溶于MeOH(1.6mL)并加入氯化氢水溶液(2N;0.4mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化。加入氯化钠水溶液并将该混合物用乙酸乙酯/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:碱性条件),得到所需产物(56mg;0.13mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.28(3H),1.89(3H),3.44-3.61(1H),3.69(1H),3.80(1H),4.02(1H),4.17(1H),4.58(1H),7.30-7.43(4H),7.56-7.67(2H),8.13(1H),13.35(1H).
实施例8
N-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基四氢-1H-1λ4-噻吩-1-亚胺1-氧化物
在氮气下,将4,5-双(二苯基膦基)-9,9-二甲基呫吨(11mg;0.018mmol)和三(二亚苄基丙酮)二钯(0)(8mg;0.009mmol)加至三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(100mg;0.185mmol)、四氢-1H-1λ4-噻吩-1-亚胺1-氧化物(29mg;0.24mmol)和碳酸铯(90mg;0.277mmol)在甲苯(1mL)中的混合物中。将该混合物在110℃搅拌8小时。冷却后,将该反应混合物用乙酸乙酯稀释并用水洗涤。将有机相使用Whatman过滤器过滤并浓缩,达到粗产物,将其使用而不用进一步纯化。
将该残余物溶于MeOH(4mL)并加入氯化氢水溶液(2N;0.2mL)。将该反应混合物在室温搅拌2小时。将该混合物通过加入碳酸氢钠水溶液碱化并用乙酸乙酯(2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:酸性条件),得到所需产物(24mg;0.06mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.24(3H),2.10-2.35(4H),2.77(3H),3.05-3.33(2H),3.36-3.63(4H),3.71(1H),3.81(1H),3.89-3.99(1H),4.04(1H),4.28-4.41(1H),6.60(s,1H),7.24(1H),7.56(1H),8.03(1H).
实施例9
4-[二乙基(氧化)-λ6-亚硫烷基]氨基-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
在氮气下,将4,5-双(二苯基膦基)-9,9-二甲基呫吨(11mg;0.018mmol)和三(二亚苄基丙酮)二钯(0)(8mg;0.009mmol)加至三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(100mg;0.185mmol)、(S-乙基亚氨基代磺酰基)乙烷(29mg;0.24mmol)和碳酸铯(90mg;0.277mmol)在甲苯(1mL)中的混合物中。将该混合物在110℃搅拌7小时。冷却后,将该反应混合物用乙酸乙酯稀释并用水洗涤。将该有机相使用Whatman过滤器过滤并浓缩,达到粗产物,将其使用而不用进一步纯化。
将该残余物溶于MeOH(4mL)并加入氯化氢水溶液(2N;0.2mL)。将该反应混合物在室温搅拌2小时。将该混合物通过加入碳酸氢钠水溶液碱化并用乙酸乙酯(2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:酸性条件),得到所需产物(29mg;0.07mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.23(3H),1.31(6H),2.77(3H),3.24(1H),3.55(5H),3.70(1H),3.76-3.86(1H),3.88-3.98(1H),4.03(1H),4.18-4.40(1H),6.81(1H),7.23(1H),7.56(1H),8.02(1H).
实施例10
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-(吗啉-4-基)-8-(1H-吡唑-5-基)-1,7-萘啶
将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(150mg;0.28mmol)和吗啉(82mg;0.94mmol)在MeCN(0.4mL)中的混合物在70℃搅拌10小时。冷却后,将该混合物用EE和THF稀释并用饱和氯化钠水溶液洗涤。将该有机相使用Whatman过滤器过滤并浓缩,达到粗产物,将其使用而不用进一步纯化。
将该残余物溶于MeOH(1.3mL)并加入氯化氢水溶液(2N;0.3mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化并用EE/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:碱性条件),得到所需产物(17mg;0.04mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.26(3H),2.76-2.93(5H),3.10-3.17(2H),3.21-3.33(1H),3.53(1H),3.66-3.91(6H),3.98-4.12(2H),4.51-4.58(1H),6.80(1H),7.24(1H),7.57(1H),8.07(1H),13.26(1H).
实施例11
(1-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}哌啶-4-基)甲醇
将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(150mg;0.28mmol)和哌啶-4-基甲醇(108mg;0.94mmol)在MeCN(0.4mL)中的混合物在70℃搅拌3小时。冷却后,将该混合物用EE和THF稀释并用饱和氯化钠水溶液洗涤。将该有机相使用Whatman过滤器过滤并浓缩,达到粗产物,将其使用而不用进一步纯化。
将该残余物溶于MeOH(1.3mL)并加入氯化氢水溶液(2N;0.3mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化并用EE/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:碱性条件),得到所需产物(19mg;0.04mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.25(3H),1.38-1.56(2H),1.69-1.85(2H),2.52-2.69(2H),2.76(3H),3.24-3.39(6H),3.52(1H),3.68(1H),3.80(1H),3.98-4.10(2H),4.48-4.58(2H),6.78(1H),7.23(1H),7.56(1H),8.06(1H),13.26(1H).
实施例12
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-[4-(甲基磺酰基)哌嗪-1-基]-8-(1H-吡唑-5-基)-1,7-萘啶
将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(150mg;0.28mmol)和1-(甲基磺酰基)哌嗪(155mg;0.94mmol)在MeCN(0.4mL)中的混合物在70℃搅拌10小时。加入额外的1-(甲基磺酰基)哌嗪(155mg;0.94mmol)并将该混合物在70℃搅拌72小时。冷却后,将该混合物用EE和THF稀释并用饱和氯化钠水溶液洗涤。将该有机相使用Whatman过滤器过滤并浓缩,达到粗产物,将其使用而不用进一步纯化。
将该残余物溶于MeOH(1.3mL)并加入氯化氢水溶液(2N;0.3mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化并用EE/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:碱性条件),得到所需产物(34mg;0.07mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.26(3H),2.78(3H),2.86(3H),2.99(3H),3.08-3.20(3H),3.24-3.32(1H),3.49-3.62(3H),3.68(1H),3.81(1H),3.99-4.06(1H),4.10(1H),4.55(1H),6.88(1H),7.24(1H),7.57(1H),8.09(1H),13.26(1H).
实施例13
N-(2,2-二甲基丙基)-N,5-二甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-胺
将5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基-三氟甲磺酸酯(150mg;0.28mmol)和N,2,2-三甲基丙-1-胺(95mg;0.94mmol)在MeCN(0.4mL)中的混合物在70℃搅拌72小时。冷却后,将该混合物用EE和THF稀释并用饱和氯化钠水溶液洗涤。将该有机相使用Whatman过滤器过滤并浓缩,达到粗产物,将其使用而不用进一步纯化。
将该残余物溶于MeOH(1.3mL)并加入氯化氢水溶液(2N;0.3mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化并用EE/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:碱性条件),得到所需产物(9mg;0.02mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.88-0.95(9H),1.23(3H),2.66-2.82(7H),3.22-3.31(1H),3.50-3.73(3H),3.77-3.84(1H),4.01–4.15(2H),4.53(1H),6.99(1H),7.24(1H),7.56(1H),8.07(1H),13.26(1H).
实施例14
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-甲酸甲酯
将5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-甲酸甲酯(50mg;0.11mmol)溶于MeOH(0.5mL)并加入氯化氢水溶液(2N;0.1mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化。加入氯化钠水溶液并将该混合物用乙酸乙酯/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩,得到所需产物(30mg;0.08mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.15-1.32(3H),2.39(3H),3.47-3.61(1H),3.69(1H),3.75-3.87(1H),3.95-4.05(4H),4.14(1H),4.57(1H),7.31(1H),7.60(1H),7.66(1H),8.23(1H),13.35(1H).
实施例15
5-甲基-4-(1-甲基-1H-咪唑-5-基)-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(150mg;0.28mmol)、1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-咪唑(115mg;0.55mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)·二氯甲烷络合物(1:1,Pd(dppf)Cl2;23mg;0.03mmol))和碳酸钾(96mg;0.70mmol)在MeCN(2.9mL)和水(1.5mL)中的混悬液用氩气脱气。在氩气下,将该反应混合物在130℃微波反应器中搅拌10分钟。冷却后,将该反应混合物用EE稀释并用饱和氯化钠水溶液洗涤。将该有机相使用Whatman过滤器过滤和然后浓缩。
将该残余物溶于MeOH(2.4mL)并加入氯化氢水溶液(2N;0.3mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化。加入氯化钠水溶液并将该混合物用乙酸乙酯/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:碱性条件),得到所需产物(17mg;0.04mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.28(3H),1.83(3H),3.34(3H),3.55(1H),3.69(1H),3.75-3.85(1H),3.97-4.07(1H),4.12-4.23(1H),4.59(1H),7.04(1H),7.28-7.42(2H),7.61(1H),7.82(1H),8.14(1H),13.34(1H)。
实施例16
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-(2-甲基-1,3-噻唑-5-基)-8-(1H-吡唑-5-基)-1,7-萘啶
将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(150mg;0.28mmol)、2-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3-噻唑(125mg;0.55mmol)、[1,1’-双(二苯基膦基)二茂铁]二氯化钯(II)·二氯甲烷络合物(1:1,Pd(dppf)Cl2;23mg;0.03mmol))和碳酸钾(96mg;0.70mmol)在MeCN(2.9mL)和水(1.5mL)中的混悬液用氩气脱气。在氩气下,将该反应混合物在130℃微波反应器搅拌10分钟。冷却后,将该反应混合物用EE稀释并用饱和氯化钠水溶液洗涤。将该有机相使用Whatman过滤器过滤和然后浓缩。
将该残余物溶于MeOH(2.4mL)并加入氯化氢水溶液(2N;0.3mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化。加入氯化钠水溶液并将该混合物用乙酸乙酯/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:碱性条件),得到所需产物(5mg;0.01mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.27(3H),2.08(3H),2.76(3H),3.54(1H),3.68(1H),3.80(1H),4.02(1H),4.15(1H),4.58(1H),7.32(1H),7.42(1H),7.61(2H),7.71(1H),8.14(1H),13.34(1H).
实施例17
甲基{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}次膦酸乙酯
将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(150mg;0.28mmol)、甲基次膦酸乙酯(30mg;0.28mmol)、乙酸钯(II)(1mg;0.006mmol)、1,1′-双(二苯基膦基)二茂铁(3mg;0.006mmol)和乙基二异丙胺(47mg;0.36mmol)在DMF(1.2ml)和1,2-二甲氧基乙烷(0.1ml)中的混合物用氩气脱气。在氩气下,将该反应混合物在室温搅拌10分钟,然后在110℃搅拌过夜。冷却后,将该反应混合物用乙酸乙酯稀释并用饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤。将有机相使用Whatman过滤器过滤,然后浓缩,得到粗产物,将其在下一步中使用而不用进一步纯化。
将该残余物溶于MeOH(1.2mL)并加入氯化氢水溶液(2N;0.3mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化。加入氯化钠水溶液并将该混合物用乙酸乙酯/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:碱性条件),得到所需产物(3mg;0.01mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.10-1.34(6H),2.01-2.10(3H),2.89(3H),3.39-3.45(1H),3.46-3.61(1H),3.69(1H),3.75-3.89(1H),3.96-4.19(4H),4.53-4.63(1H),7.24(1H),7.60(1H),7.75(1H),8.25(1H),13.31(1H).
实施例18
4-(二甲基磷酰基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(150mg;0.28mmol)、二甲基膦氧化物(22mg;0.28mmol)、乙酸钯(II)(1mg;0.006mmol)、1,1′-双(二苯基膦基)二茂铁(3mg;0.006mmol)和乙基二异丙胺(47mg;0.36mmol)在DMF(1.2ml)和1,2-二甲氧基乙烷(0.1ml)中的混合物用氩气脱气。在氩气下,将该反应混合物在室温搅拌10分钟,然后在110℃过夜。冷却后,将该反应混合物用乙酸乙酯稀释并用饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤。将该有机相使用Whatman过滤器过滤,然后浓缩,得到粗产物,将其在下一步中使用而不用进一步纯化。
将该残余物溶于MeOH(1.3mL)中,加入氯化氢的水溶液(2N;0.3mL)。将该反应混合物在室温搅拌1小时。将混合物通过加入碳酸氢钠水溶液碱化。加入氯化钠水溶液并将混合物用乙酸乙酯/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC(Autopurifier:酸性条件)纯化,得到所需产物(9mg;0.02mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=1.30(3H),1.95(6H),2.99(3H),3.35-3.40(1H),3.54(1H),3.69(1H),3.83(1H),4.02-4.07(1H),4.14-4.20(1H),4.61(1H),7.24(1H),7.55-7.61(2H),8.24(1H),13.31(1H).
实施例19
甲基{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}次膦酸2-甲基丙基酯
将三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(150mg;0.28mmol)、甲基次膦酸异丁基酯(38mg;0.28mmol)、乙酸钯(II)(1mg;0.006mmol)、1,1′-双(二苯基膦基)二茂铁(3mg;0.006mmol)和乙基二异丙胺(47mg;0.36mmol)在DMF(1.2ml)和1,2-二甲氧基乙烷(0.1ml)中的混合物用氩气脱气。在氩气下,将该反应混合物在室温搅拌10分钟,然后在110℃搅拌过夜。冷却后,将该反应混合物用乙酸乙酯稀释并用饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤。将有机相使用Whatman过滤器过滤和然后浓缩得到粗制产物,将其在下一步中使用而不用进一步纯化。
将该残余物溶于MeOH(1.2mL)并加入氯化氢水溶液(2N;0.3mL)。将该反应混合物在室温搅拌1小时。将该混合物通过加入碳酸氢钠水溶液碱化。加入氯化钠水溶液并将该混合物用乙酸乙酯/THF(1:1;2x)萃取。将合并的有机相使用Whatman过滤器过滤并浓缩。将该残余物用制备型HPLC纯化(Autopurifier:酸性条件),得到所需产物(10mg;0.02mmol)。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=0.72-0.96(6H),1.31(3H),1.84-2.00(1H),2.06(3H),2.90(3H),3.37-3.44(1H),3.48-3.64(1H),3.65-3.86(3H),4.05(1H),4.09-4.25(2H),4.58(1H),7.24(1H),7.60(1H),7.75(1H),8.24(1H),13.30(1H).
以下实例是使用Automated Medicinal Chemistry方法,通过以下步骤制备的:
向0.2mmol三氟甲磺酸5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-{1-[(2R)-四氢-2H-吡喃-2-基]-1H-吡唑-5-基}-1,7-萘啶-4-基酯(0.25M于NMP中,800μL)中添加2当量的硼酸衍生物(0.4mmol,800μL,0.5M在NMP中)、40μmol1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(0.04M在NMP中,1000μL)和0.6mmol碳酸钾(1M在水中,600μL)并将该混合物在110℃加热块上加热过夜。冷却后,加入1.2mmol HCl(2M在水中,600μL)并将该混合物在50℃加热块上加热10小时。冷却后,将该混合物过滤,用NMP洗涤并进行制备型HPLC,得到目标产物。
在上表中的实施例具有下表中给出的名称:
在所选的生物实验中测试实施例部分中描述的标题化合物一或多次。当测试多于一次时,数据报道为平均值或中值,其中
·平均值,还称为算术平均值,代表获得的值的和除以测试次数,和
·中值,代表当以升序或降序排列时一组值的中间数。如果数据组中的值的数为奇数,中值为中间的值。如果数据组中的值的数为偶数,中值是两个中间值的算术平均值。
一或多次合成实施例。当合成多于一次时,来自生物试验的数据代表使用由测试一个或多个合成批次获得的数据组计算的平均值或中值。
HEK 293-6E细胞中ATR/ATRIP的表达:
对编码具有N末端融合Flag标签的全长人ATR序列(Q13535)和全长人ATRIP(Q8WXEl)的蛋白序列的cDNA进行优化以用于在真核细胞中表达并由GeneArt Technology在LifeTechnologies合成。两种cDNA还在5′和3′端编码att-site序列以使用GatewayTechnology亚克隆到下列目标载体中:pD-MamA(来自EdgeBioSystems的载体pEAK的内部衍生物,但是具有人CMV启动子),其提供GST-标签与目标整合基因的N-末端融合;pD-MamB(来自NRCC,Y.Durocher的pTT5的内部衍生物),其提供STREP II-标签与整合基因的N-末端融合。将ATR和ATR-DN的cDNA克隆到pD-MamA中并将ATRIP-FL克隆为pD-MamB。
包括GST标签的密码子优化的ATR的cDNA序列描述于所附序列表的SEQ ID No.1,其相应的蛋白序列描述于SEQ IDNo.3。包括STREP II标签的密码子优化的ATRIP的cDNA序列描述于SEQ ID No.2,其相应的蛋白序列描述于SEQ ID No.4。
HEK293-6E细胞中通过瞬时转染进行的ATR和ATRIP的共表达:
对于HEK293-6E悬浮细胞的瞬时转染,使用具有20L培养袋中的5L培养体积(起始体积)的Biostat Cultibag生物反应器。在F17培养基(Gibco,Invitrogen,Cat#05-0092DK)中培养细胞,所述F17培养基具有下列补充物:Pluronic F68(10mL/L的10%溶液,Gibco#24040)、Gluta-Max(20ml的100x溶液/L)、L-丙氨酰-谷氨酰胺(200mM,Invitrogen#25030)、G418(终浓度25μg/ml,PAA#P02-012)。应用的培养条件为37℃,摇摆速率18rpm,pH 7.0,pO255%。在转染日,细胞培养物达到1.6x106细胞/mL的细胞密度和99%的存活率。转染溶液制备如下:向500mL F17培养基(无补充物)中按顺序加入4mg ATR编码质粒、1mg ATRIP编码质粒和10mg PEI(聚乙烯亚胺,线性,Polysciences#23966,作为1mg/mL原液),小心混合并在室温下孵育15min。然后向培养袋中的5L细胞培养物中加入该转染溶液。孵育该细胞培养物5h,然后加入5L具有所述补充物的F17培养基,并将摇摆速率增加至19rpm。转染后48h,通过离心(30min.,1000g,15℃)收获细胞,并将细胞团沉淀物储存在-80℃。
纯化:
通过亲和色谱使用抗-FLAG-树脂(Sigma,#A220)实现ATR(Flag-Tag)/ATRIP(Strep-Tag)复合物的纯化。
通过离心(4000xg)收获细胞并在4℃下在缓冲液A(50mM Tris-HCl pH 7.5;150mMNaCl,5%甘油,1mM Na3VO4,1mM NaF,10mMβ-甘油磷酸,1%Tween 20;0.1%NP40;用EDTA补齐)中裂解1h。然后将上清液(20.000xg)与Flag-琼脂糖结合,并在若干洗涤步骤后用缓冲液B(50mM Tris-HCl pH7.4;150mM NaCl;10%甘油,来自Sigma的200μg/ml Flag肽,#F3290)洗脱。将洗脱级分等分并使用液氮休克冷冻(shock frozen)。最终制剂中ATR的终浓度为250μg/ml,使用BSA作为标准在Coomassie染色凝胶中以密度计计算。共纯化的ATRIP的产率远低于1:1比例,与ATR相比,但是对于ATR活性是必须的。
示踪剂A:3',6'-双(二甲基氨基)-N-(4-{[2-(1H-吲哚-4-基)-6-(吗啉-4-基)嘧啶-4-基]氨基}丁基)-3-氧代-3H-螺[2-苯并呋喃-1,9'-呫吨]-5-甲酰胺
步骤a:
(4-{[2-(1H-吲哚-4-基)-6-(吗啉-4-基)嘧啶-4-基]氨基}丁基)氨基甲酸叔丁酯
根据文献(WO2008/125833)合成起始物质4-[4-氯-6-(吗啉-4-基)嘧啶-2-基]-1H-吲哚。将4-[4-氯-6-(吗啉-4-基)嘧啶-2-基]-1H-吲哚(980mg,3.11mmol)、二异丙基乙胺(805mg,1.09ml,6.23mmol)和N-BOC-1,4-二氨基丁烷(879mg,4.67mmol)在1-甲基-2-吡咯烷酮(24.5ml)中的溶液在150℃搅拌过夜。将该混合物冷却至环境温度。加入乙酸乙酯(50ml)和盐水(50ml),分离层并将有机层用盐水(3x 50ml)洗涤。将有机层用硫酸钠干燥并将溶剂减压除去。获得标题化合物,其为粗制混合物(纯度40%,2.37g)并将其用于下一步而不进行进一步纯化。
步骤b:
N-[2-(1H-吲哚-4-基)-6-(吗啉-4-基)嘧啶-4-基]丁烷-1,4-二胺
将(4-{[2-(1H-吲哚-4-基)-6-(吗啉-4-基)嘧啶-4-基]氨基}丁基)氨基甲酸叔丁酯(2.37g,2.03mmol)溶于HCl/二噁烷(4M,20ml)中并在室温搅拌10分钟。加入乙酸乙酯(50ml)和水(50ml)并分离相。通过加入NaOH水溶液(2N,50ml)将水层的pH碱化并用乙酸乙酯(2x 50ml)萃取。将合并的有机层用硫酸钠干燥并将溶剂减压除去。获得标题化合物,产率77%(770mg)并将其用于下一步而不进行进一步纯化。
步骤c:
3',6'-双(二甲基氨基)-N-(4-{[2-(1H-吲哚-4-基)-6-(吗啉-4-基)嘧啶-4-基]氨基}丁基)-3-氧代-3H-螺[2-苯并呋喃-1,9'-呫吨]-6-甲酰胺,和
3',6'-双(二甲基氨基)-N-(4-{[2-(1H-吲哚-4-基)-6-(吗啉-4-基)嘧啶-4-基]氨基}丁基)-3-氧代-3H-螺[2-苯并呋喃-1,9'-呫吨]-5-甲酰胺
将N-[2-(1H-吲哚-4-基)-6-(吗啉-4-基)嘧啶-4-基]丁烷-1,4-二胺(70mg,0.14mmol)溶于DMF(3mL)。相继加入DIPEA(74μl,0.43mmol,3当量)和可商购的5-羧基四甲基罗丹明N-琥珀酰亚胺酯和6-羧基四甲基罗丹明N-琥珀酰亚胺酯的混合物(75mg,0.14mmol,1当量)。将该混合物在环境温度搅拌15分钟并减压浓缩。通过制备型HPLC(H2O(NH4OH)/CH3CN:85:15至45:55)分离两个标题化合物。
获得异构体1,产率为22%(25mg)。1H-NMR(300MHz,DMSO-d6):δ[ppm]:1.56(4H),2.92(12H),3.49(4H),3.69(4H),5.53(1H),6.48(6H),6.74(1H),7.06(1H),7.33(2H),7.43(1H),7.63(1H),8.03(2H),8.15(1H),8.71(1H),11.11(1H)。
获得异构体2,产率为34%(31mg)。1H-NMR(400MHz,DMSO-d6):δ[ppm]:1.67(4H),2.93(12H),3.38(4H),3.52(4H),3.71(4H),5.58(1H),6.47(6H),6.80(1H),7.09(1H),7.28(1H),7.36(2H),7.44(1H),8.02(1H),8.22(1H),8.44(1H),8.83(1H)。
异构体2用作下述ATR结合试验的配体。
1.结合试验ATR
为了测定测试化合物的结合活性,与ATRIP一起表达和纯化全长人ATR蛋白,如上所述。此外,将荧光标记化合物(上述示踪剂A或B)用作示踪分子。通过时间分辨荧光能量转移(TR-FRET)实现示踪剂结合活动的检测。我们使用抗-GST-铽抗体(CisBio),其在ATR-激酶的N-末端与GST-标签结合。用337nm光激发铽导致发射545nm荧光。在形成四聚体复合物的情况下(抗GST-Tb+GST-ATR+Strp2-ATRIP+示踪剂),部分能量将从铽转移至本身发射570nm光的荧光团。测试化合物代替荧光示踪剂导致TR-FRET-信号减少。
为了试验,用移液管将50nl测试化合物在DMSO中的100倍浓缩溶液移至黑色低容量384孔微量滴定板(MTP,Greiner Bio-One,Frickenhausen,Germany)。为了制备ATR-工作溶液,在试验缓冲液[50mM HEPES(pH 7.0),10mM MgCl2,1mM DTT,0.01%(w/v)Igepal,0.01%(w/v)BSA]中将ATR/ATRIP原液稀释至4.2nM蛋白浓度(浓度可以随蛋白制剂不同而有所不同)。将抗GST-Tb抗体稀释至4.2nM。在22℃孵育ATR-工作溶液30min,然后分配以预形成抗GST-Tb+GST-ATR+ATRIP的复合物。然后,向测试化合物中加入3μl ATR-工作溶液并在22℃孵育混合物10min以允许测试化合物与ATR/ATRIP的预结合。然后,向ATR-工作溶液中加入2μl示踪剂A或B在试验缓冲液中的100nM溶液。在22℃孵育所得混合物30min。在标准HTRF-兼容MTP读数器(例如BMG Pherastar)中通过记录在337-350nm激发后在545nm和570nm的荧光发射进行TR-FRET信号的测量。计算在570nm的发射除以在545nm的发射的比例以得到恰当的比例。通过下列方式标准化试验数据(恰当的比例):阳性对照含有ATR-工作溶液+示踪剂A或B溶液(=0%抑制),阴性对照含有所有组分,除了GST-ATR/ATRIP(=100%抑制)。通常,在相同MTP上以11个不同浓度测试化合物,所述浓度范围为20μM至0.1nM(20μM、5.9μM、1.7μM、0.51μM、0.15μM、44nM、13nM、3.8nM、1.1nM、0.33nM和0.1nM)。在试验前分别制备稀释系列,其在DMSO中的100倍浓缩溶液水平上以连续1:3.4稀释且每个浓度一式两份值进行。通过4参数拟合使用标准软件(GraphPad prism或对等物)计算IC50值。
ATR结合:
1.ATR活性实验
ATR激酶磷酸化衍生自Rad17的生物素化的肽(序列:生物素-PEG2-ASELPASQPQPFS-酰胺,产自Biosyntan GmbH,Berlin)。该试验通过时间分辨荧光(TR-FRET)测量磷酸化肽的量。使用Streptavidin-XL665(Cisbio,参考#610SAXLB)、抗-Rad17-膦酸-丝氨酸645特异性抗体(可得自Imgenex/Biomol,参考#IMG-6386A或Lifespan,参考#LS-C43028)和抗兔-IgG-铕(PerkinElmer,参考#AD0083)来特异性检测磷酸化生物素-肽,而不是非磷酸化肽。用337nm光激发铕导致发射620nm荧光。在形成四聚体检测复合物的情况下,部分能量将转移至本身发射665nm光的Streptavidin-XL665荧光体。未磷酸化的肽不会导致在665nm发射光,因为不能形成FRET-充足的检测复合物。
为了试验,用移液管将50nl测试化合物在DMSO中的100倍浓缩溶液移至黑色低容量384孔微量滴定板(MTP,Greiner Bio-One,Frickenhausen,Germany)。为了制备ATR-工作溶液,在试验缓冲液[50mM HEPES(pH 7.0),10mM MgCl2,1mM二硫苏糖醇(DTT),0.01%(w(v)Igepal,0.2%(w/v)牛丙种球蛋白(BGG)]中将ATR/ATRIP原液(表达和纯化:参见上文)稀释至10nM蛋白浓度(浓度可以随蛋白制剂批次不同而有所不同)。通过在试验缓冲液中将生物素化Rad17肽稀释至0.5μM以及将ATP稀释至20μM制备底物工作溶液。制备停止/检测工作溶液,其含有50mM Hepes pH 7.0,0.15%(w/v)牛血清白蛋白(BSA)、150mM EDTA、200nMStreptavidin-XL665、2.5nM抗磷酸Rad17-pS645(IMG-6386A)和1.5nM抗-兔-IgG-Eu。抗体的量依赖于所用的批次并且通过改变批次的活性优化。所有溶液保持在20℃。首先,将2.5μl ATR-工作溶液分配至含有测试化合物的MTP孔中。在预孵育10分钟以允许化合物与ATR结合后,将2.5μl底物工作溶液分配至所述孔。180分钟后,将5μl停止/检测溶液分配至所述孔。在20℃下孵育所得混合物60min。在标准HTRF-兼容MTP读数器(例如BMG Pherastar或Perkin Elmer ViewLux)中通过记录在337-350nm激发后在620nm和665nm的荧光发射进行TR-FRET信号的测量。计算在665nm的发射除以在620nm的发射的比例以得到恰当的比例。通过下列方式标准化试验数据(恰当的比例):阳性对照含有ATR-工作溶液+底物溶液(=0%抑制),阴性对照含有相同试剂,除了用试验缓冲液替换ATR-工作溶液(=100%抑制)。通常,在相同MTP上以11个不同浓度测试化合物,所述浓度范围为20μM至0.1nM(20μM、5.9μM、1.7μM、0.51μM、0.15μM、44nM、13nM、3.8nM、1.1nM、0.33nM和0.1nM)。在试验前分别制备稀释系列,其在DMSO中的100倍浓缩溶液水平上以连续1:3.4稀释且每个浓度一式两份值进行。通过4参数拟合使用标准软件(GraphPad prism或对等物)计算IC50值。
2.增殖试验
最初从美国典型培养物保藏中心(American Type Culture Collection,ATCC)、德国微生物和细胞培养物保藏中心(Deutsche Sammlung von MikroorganismenundZellkulturen,DSMZ,German Collection ofMicroorganisms and Cell Cultures)或EpoGmbH Berlin获得人肿瘤细胞。
以1500-4000细胞/检测点的密度(取决于细胞系生长速率)将贴壁生长细胞(HeLa、HeLa-MaTu-ADR、HT-144、Lovo、HT-29、NCI-H460、DU145、Caco2、B16F10)铺板于200μl生长培养基(DMEM/HAMS F12,2mM L-谷氨酰胺,10%胎牛血清)中的96-孔微量滴定板中。24小时后,用结晶紫(参见下文)将一个板(零板)的细胞染色,而其他板的培养基用其中加入了各种浓度测试底物(0μM以及在0.001-10μM的范围内;溶剂二甲基亚砜的终浓度为0.1或0.5%)的新鲜培养基(200μl)替换。在测试底物的存在下孵育细胞4天。通过用结晶紫染色细胞测定细胞增殖:通过加入20μl/检测点的11%浓度戊二醛溶液在室温下固定细胞15min。用水洗涤固定细胞三次后,在室温下干燥板。通过加入100μl/检测点的0.1%浓度结晶紫溶液将细胞染色(通过加入乙酸调节pH至pH 3)。用水洗涤细胞三次后,在室温下干燥板。通过加入100μl/检测点的10%浓度乙酸溶液溶解染料。在595nm的波长下用光度计测定吸光度。通过将检测值标准化为零板的吸光度值(=0%)和未处理(0μM)细胞的吸光度(=100%)计算细胞生长变化百分比。通过四参数拟合确定IC50值。
以2000-4000细胞/检测点的细胞密度(取决于细胞系生长速率)将悬浮生长的细胞(GRANTA-519,Jeko-1)铺板于100μl生长培养基(DMEM/HAMS F12,2mM L-谷氨酰胺,10%胎牛血清)中的黑壁透明底96-孔微量滴定板中。24小时后,通过如下操作测定在一个板(零板)中的细胞密度:加入60μl/检测点的CTG溶液(Promega Cell Titer-Glo溶液(目录号G755B和G756B)),随后孵育2min,然后摇动10min(在黑暗中),并检测发光(VICTOR V,Perkin Elmer)在一个板(零板)。
对于测试板,以各种浓度制备测试物(0μM,以及范围为0.001-10μM;溶剂二甲基亚砜的终浓度为0.1或0.5%),其为于新鲜生长培养基中的3x浓缩溶液。向细胞悬浮液中加入每个50μl的等分试样,并在测试底物的存在下孵育细胞4天。然后,如上所述,使用CTG溶液测定细胞密度并通过四参数拟合计算IC50值。
在下列细胞系中研究所述物质,其例如代表特定的适应症。
增殖试验中研究的细胞系清单。
肿瘤适应症 | 细胞系 | 来源 |
子宫颈癌 | HeLa | DSMZ ACC-57 |
增殖试验结果证明了测试化合物在所研究的人肿瘤细胞中的效力。这些数据表明测试化合物可用于所研究的肿瘤类型。
通过本发明的化合物抑制HeLa细胞的增殖,如上所述测定。所有IC50(在50%最大效力下的抑制浓度)值表示为M,“n.t.”是指未在各个试验中测试的化合物。
实施例 | HeLa细胞增殖的抑制 |
01 | 4.98E-7 |
02 | 6.34E-8 |
03 | 1.54E-7 |
04 | 3.33E-7 |
05 | 8.51E-8 |
06 | 2.96E-7 |
07 | 4.99E-7 |
08 | 4.73E-7 |
09 | 1.17E-7 |
10 | 1.09E-7 |
11 | 3.32E-8 |
12 | 4.40E-7 |
13 | 7.45E-7 |
14 | 4.40E-7 |
15 | 1.45E-7 |
16 | 3.39E-8 |
17 | 1.12-7 |
3.磷酸-H2AX测试
磷酸-Ser139组蛋白H2AX(还称为H2AX,UniProtKB/Swiss-Prot P16104)代表DNA损伤应答的细胞早期标志物。特别地,在DNA复制应激下ATR将H2AX磷酸化。以12000细胞/检测点的密度将最初获自DSMZ的HT-29人结直肠腺癌细胞铺板于100μl生长培养基(DMEM/HAMS F12,2mM L-谷氨酰胺,10%胎牛血清)中的黑壁透明底96-孔微量滴定板中。24小时后,以各种浓度(0μM以及范围为0.001-10μM,一式四份;溶剂二甲基亚砜的终浓度为0.1%)加入测试底物,然后加入羟基脲溶液以实现2.5mM的终浓度和200μL的最终试验体积。留下一个对照板不处理并进一步平行继续试验。在37℃孵育细胞30min。然后,小心蒸发生长培养基并用50μL/孔的冰冷甲醇固定细胞15min。用100μL/孔的PBS洗涤细胞一次,然后在室温下用50μL/孔的封闭缓冲液(Liqor,927-40000)孵育1h。然后,在室温下用在封闭缓冲液中的以1∶500稀释的50μL/孔的抗-磷酸-H2AX(Ser 139)抗体(Merck Millipore,克隆JBW301,05-636)孵育细胞1h(或在4℃下孵育过夜)。用100μL/孔的PBS洗涤细胞三次,然后在室温下用50μL/孔在TBST中的1∶500稀释的Alexa Fluor 488共轭的驴抗小鼠IgG抗体溶液(LifeTechnologies,A-21202)孵育1h并避光。用100μL/孔PBS洗涤细胞三次后,用100μLPBS填充孔并使用Acumen激光扫描细胞仪(TTP Labtech)测定荧光。通过将测量值标准化为未处理对照孔的荧光值(=0%)和无测试化合物的羟基脲对照孔的荧光值(0μM,=100%)计算羟基脲诱导的磷酸-H2AX含量的变化百分比。通过四参数拟合测定IC50值。
2.Caco-2渗透试验
以4.5x 104细胞/孔的密度将Caco-2细胞(购自DSMZ Braunschweig,Germany)接种于24孔插入板(0.4μm孔径),并在补充有10%胎牛血清、1%GlutaMAX(100x,GIBCO)、100U/ml青霉素、100μg/ml链霉素(GIBCO)和1%非必需氨基酸(100x)的DMEM培养基中生长15天。将细胞保持在37℃,潮湿的5%CO2气氛中。每2-3天更换培养基。在进行渗透试验之前,用无FCS的hepes-碳酸盐运输缓冲液(FCS-free hepes-carbonate transport puffer)(pH 7.2)替换培养基。为了评价单层完整性,检测跨膜电阻(TEER)。将测试化合物预先溶解于DMSO并以2μM的终浓度将其加入至基顶室或基底室。在37℃孵育2h之前和之后,从两个室提取样品。在用甲醇沉淀后通过LC/MS/MS分析来分析化合物含量。在基顶至基底(A→B)和基底至基顶(B→A)方向计算渗透率(Papp)。使用下列方程计算表观渗透率:
Papp=(Vr/Po)(1/S)(P2/t)
其中Vr是接受室中的培养基体积,Po是t=o时供体室中测试药物的检测峰面积,S是单层表面积,P2是孵育2h后受体室中测试药物的检测峰面积,以及t是孵育时间。通过Papp B-A除以Papp A-B计算基底(B)与基顶(A)的流出比。另外计算化合物回收率。作为试验对照,并行分析参照化合物。
序列表
<110> 拜耳医药股份公司(Bayer Pharma AG)
<120> 5-取代的2-(吗啉-4-基)-1,7-萘啶
<130> BHC143030
<160> 4
<170> BiSSAP 1.3
<210> 1
<211> 8697
<212> DNA
<213> 合成有机体
<220>
<223> 包括GST标签的密码子优化的ATR
<400> 1
atggcctccc ctatactagg ttattggaaa attaagggcc ttgtgcaacc cactcgactt 60
cttttggaat atcttgaaga aaaatatgaa gagcatttgt atgagcgcga tgaaggtgat 120
aaatggcgaa acaaaaagtt tgaattgggt ttggagtttc ccaatcttcc ttattatatt 180
gatggtgatg ttaaattaac acagtctatg gccatcatac gttatatagc tgacaagcac 240
aacatgttgg gtggttgtcc aaaagagcgt gcagagattt caatgcttga aggagcggtt 300
ttggatatta gatacggtgt ttcgagaatt gcatatagta aagactttga aactctcaaa 360
gttgattttc ttagcaagct acctgaaatg ctgaaaatgt tcgaagatcg tttatgtcat 420
aaaacatatt taaatggtga tcatgtaacc catcctgact tcatgttgta tgacgctctt 480
gatgttgttt tatacatgga cccaatgtgc ctggatgcgt tcccaaaatt agtttgtttt 540
aaaaaacgta ttgaagctat cccacaaatt gataagtact tgaaatccag caagtatata 600
gcatggcctt tgcagggctg gcaagccacg tttggtggtg gcgaccatcc tccaaaatcg 660
gatcagatca caagtttgta caaaaaagca ggctccgact atgacattcc aactacggag 720
aatttgtact tccaaggcga ctacaaggac gacgatgata agatgggtga acatggtttg 780
gagctcgcat ccatgattcc agccctgcgt gaactgggct ccgcaactcc agaggagtac 840
aacacggtgg tgcaaaaacc gcgtcagata ctgtgccagt tcatcgacag aatcctgacg 900
gatgtgaacg tggtggctgt cgagctcgtc aaaaagaccg attctcaacc aacgtccgtc 960
atgctgttgg actttatcca acacatcatg aaatcctccc cgctgatgtt cgttaacgtt 1020
tctggatccc acgaggctaa aggctcctgc atcgagttct caaactggat tatcaccaga 1080
ctgttgcgta ttgctgccac gcctagctgt cacttgctcc acaagaagat ctgcgaagta 1140
atatgctccc tgctgtttct gttcaagtcc aaatcacccg ctatatttgg agttctgaca 1200
aaggaattgt tgcagctgtt tgaggacctg gtatacttgc ataggcgtaa cgtgatgggt 1260
catgccgtcg agtggcctgt cgtcatgtct cgcttcctgt ctcagctcga cgaacatatg 1320
ggttatctcc agtccgcacc actccagttg atgtccatgc aaaacctgga gttcatagaa 1380
gtgacgttgc tcatggtgct gactagaatc attgctattg tgttcttccg ccgtcaagag 1440
ttgttgttgt ggcaaatcgg ctgcgtgttg ctggagtatg gctccccaaa gattaagagc 1500
ttggctatat cctttctgac agaactgttc cagctcggcg gtctgccggc ccagccggct 1560
tccacattct tctcctcatt cctggaactg ctgaagcacc tcgttgagat ggacacggac 1620
caactcaagc tgtacgaaga gcccttgtcc aaattgatta agacactgtt cccctttgag 1680
gcagaggcgt acaggaacat cgagcccgta tatctgaaca tgctgctgga gaagctctgc 1740
gtgatgtttg aagatggagt actgatgcgc ctgaagtccg atctgctgaa ggctgctctg 1800
tgtcatctcc tgcaatactt cttgaaattc gttcctgccg gttacgagtc cgctttgcaa 1860
gtacgcaagg tgtacgtacg taatatctgc aaggctctgc tggacgtgct cggtattgag 1920
gtagacgccg aatatctgtt gggcccattg tacgctgcgc tgaaaatgga gtcaatggaa 1980
atcattgagg aaatccagtg ccagacccag caagaaaatc tgagctccaa ctccgacgga 2040
atttctccaa agaggcgccg cttgagcagc tccctgaacc cttcaaagcg tgcaccaaag 2100
cagactgagg aaatcaagca cgtggacatg aaccaaaaga gcatactgtg gtccgcattg 2160
aagcagaaag ccgagtcttt gcagatttcc ctcgaatatt ccggcctgaa aaatcccgta 2220
attgaaatgc tcgagggcat cgccgtagtt ttgcaactga ccgctctgtg tactgtgcac 2280
tgctctcatc agaacatgaa ctgcaggaca ttcaaggact gccagcataa gtctaaaaag 2340
aagccctcag tcgtcatcac ttggatgtct ttggatttct ataccaaggt cctgaagtcc 2400
tgtcgtagcc tgctggagtc agtgcaaaag ttggatctgg aagccaccat cgataaagta 2460
gttaagattt acgacgccct catctacatg caagtcaact ccagcttcga ggaccatatc 2520
ctcgaagatc tgtgcggtat gctgagcctc ccttggatct acagccactc cgatgacgga 2580
tgtctgaagc tcaccacttt tgccgcaaat ttgttgaccc tgtcttgccg catatccgac 2640
tcatattcac ctcaagccca atcccgttgt gtattcctgc tcaccctgtt cccacgtcgt 2700
atttttctgg aatggagaac cgccgtatac aactgggctc tgcagtcctc ccacgaagtg 2760
ataagagcct catgtgtctc cggcttcttc atcttgctgc agcaacaaaa ctcttgtaat 2820
cgcgtcccga agatcctgat cgataaggtc aaggacgact ccgacattgt gaagaaagaa 2880
tttgccagca tcttgggcca gctggtctgc acactccacg gtatgttcta cctcacttcc 2940
agcttgacag aacccttctc cgagcatgga cacgtcgatc tgttttgtag gaatctgaaa 3000
gcaacttcac agcacgaatg ctcctcctcc cagctcaaag cctctgtctg caagcccttt 3060
ctgtttctgc tgaaaaagaa aatcccatca ccggttaaac tcgctttcat cgacaatctc 3120
caccacctgt gcaagcatct ggatttcagg gaggatgaga cagatgtgaa ggccgttctg 3180
ggtactctgc tcaacctgat ggaggaccca gacaaggacg tgagagtggc tttctccggt 3240
aacattaagc atatcctgga aagcctcgat agcgaggacg gatttatcaa agaattgttc 3300
gtcctgcgca tgaaggaagc ttacacgcat gcgcagatct ctcgtaataa cgagctgaag 3360
gacaccctga tattgacaac tggtgatatc ggaagagctg ccaagggcga tttggtgccg 3420
ttcgcgctgc tgcatttgct gcactgcctg ctgtctaagt ccgcttctgt ctctggcgct 3480
gcatacaccg aaattagggc gctggtggct gctaagtccg ttaaactcca gtctttcttc 3540
tcccagtaca aaaaacctat ttgccaattc ttggttgagt ccctgcactc ctcccagatg 3600
accgctctgc ccaacacacc ctgtcagaac gcagatgttc gcaaacagga cgttgcccac 3660
cagagggaga tggcactgaa tacactgtcc gagattgcta atgtgttcga ctttcccgat 3720
ctgaacaggt tcctgactcg tactctccag gtactgctgc ctgacctcgc cgctaaagcc 3780
tctccagctg cttcagccct gatccgtacc ctgggtaaac agctgaatgt caataggaga 3840
gaaatattga tcaacaactt caaatacatc ttttcacacc tggtatgctc ctgctctaag 3900
gacgagctgg agcgtgctct gcattatctg aagaacgaaa ccgaaataga actgggttcc 3960
ttgctccgcc aagatttcca aggtctgcat aacgagctgc tgctcaggat cggcgagcat 4020
taccagcaag tgttcaatgg tttgtcaatt ttggcgtcct tcgcctcctc cgacgaccca 4080
tatcagggcc ctagagacat catcagccca gaactgatgg ctgattatct gcaacctaag 4140
ttgctcggaa tcctcgcatt tttcaacatg caactgttgt caagctcagt cggcattgaa 4200
gataaaaaga tggcgctcaa ctcactgatg agcctcatga agctgatggg cccaaagcat 4260
gtctcctccg tgagggttaa gatgatgacc actctgagga ctggcctgag gtttaaggac 4320
gatttccctg aactgtgctg ccgtgcctgg gattgtttcg tccgttgcct cgatcacgcc 4380
tgtctcggtt ccctgctgtc ccacgtcatc gtggcactct tgccactgat tcacatacag 4440
cccaaggaaa cggccgcgat atttcactac ctcatcatcg aaaaccgtga cgcggtccag 4500
gatttcctgc atgagatcta cttcctgccc gaccacccgg aactgaagaa gatcaaggcc 4560
gttctgcagg aatatcgtaa agaaacctcc gagtccaccg atctgcagac caccctgcag 4620
ttgtcaatga aggcaatcca acatgagaac gtcgacgtca gaatacacgc actgacctct 4680
ctgaaggaaa cactgtacaa gaaccaagag aagttgatca aatacgctac tgactcagag 4740
acagtagaac ccatcatctc acagctcgtg accgttctcc tcaagggttg ccaggacgct 4800
aactctcagg cgagattgct gtgtggcgag tgcctgggag aattgggcgc cattgacccc 4860
ggtcgcctgg acttcagcac aaccgagact caaggtaaag actttacctt cgtgaccgga 4920
gtcgaggatt cctccttcgc ttacggactg ctcatggaac tcactagagc ctacctggcc 4980
tatgctgaca actctcgcgc acaagattca gccgcttacg caatccaaga gctcctgtca 5040
atttacgact gccgtgagat ggaaacgaat ggtcccggtc accagctgtg gcgccgcttt 5100
ccagaacacg ttcgcgaaat cctggaaccc cacttgaaca ccagatacaa atccagccaa 5160
aagtctactg actggtccgg tgtgaagaag cctatttacc tgtccaaact gggcagcaat 5220
ttcgcagagt ggtccgctag ctgggcgggc tacctgatca ctaaagtgcg ccacgatctc 5280
gcaagcaaaa tcttcacttg ctgctccatt atgatgaagc atgacttcaa ggtgacaatt 5340
tatctgctcc cacacatcct ggtatacgtc ctgctgggct gtaaccagga agaccagcag 5400
gaggtatacg ctgagataat ggcagttttg aagcacgacg atcagcacac cattaacaca 5460
caggacattg cgtctgacct gtgtcaactg tccactcaaa ccgttttctc catgttggac 5520
catttgaccc agtgggcaag gcacaagttc caagccctca aagcagagaa atgccctcac 5580
agcaagagca atcgcaacaa ggttgactcc atggtttcta cagttgatta tgaggactat 5640
caatcagtta cacgctttct ggatctgatt ccacaagaca ctctggctgt ggcatctttc 5700
cgctctaagg cttacactag ggccgtgatg cacttcgaat cctttatcac cgagaaaaaa 5760
cagaacatcc aggagcactt gggtttcctc caaaagctgt acgccgccat gcacgagccg 5820
gacggcgtcg cgggtgtttc cgcaattcgc aaagctgagc cctccctgaa ggaacagatt 5880
ctggagcacg agtcactggg tctgctccgc gatgccacgg cgtgttacga tcgcgcgatt 5940
cagttggagc cagaccaaat catccactat catggtgtag taaagtccat gctgggactg 6000
ggtcagctct ctacggttat cactcaggta aacggagtgc atgcgaaccg ctccgaatgg 6060
accgatgagc tcaatactta cagggtggag gcagcgtgga agctcagcca gtgggacttg 6120
gtcgaaaatt acctggctgc ggatggcaag tccacaacgt ggtccgtgcg cctcggccag 6180
ctgctgctgt cagctaaaaa gagggatatt acggctttct acgactctct gaaactcgtc 6240
cgcgccgaac aaattgttcc gctgagcgcc gcgtctttcg aacgcggaag ctaccagaga 6300
ggatatgagt acatcgttcg cctgcacatg ttgtgcgagc tggagcactc tatcaaaccc 6360
ttgttccaac actccccggg tgattcatcc caagaggact ctctgaattg ggtcgctcgt 6420
ttggaaatga cccagaactc ctaccgcgcg aaggaaccta ttctggccct caggcgtgct 6480
ctgctgtcac tcaacaaacg cccggactac aatgagatgg tcggagaatg ttggctgcaa 6540
tcagctcgcg tggcgcgtaa agccggtcat catcaaactg cgtacaacgc tctgctgaac 6600
gccggcgaat cacgcttggc agaactctac gtagagcgcg caaaatggct gtggtccaag 6660
ggtgatgtgc accaggcgct catcgtcctg cagaagggag tggagctgtg tttccccgag 6720
aacgagacac caccggaagg aaagaacatg ctgatacatg gaagggctat gttgctggtg 6780
ggacgcttca tggaggaaac agcgaacttc gagtccaatg ctataatgaa gaagtacaaa 6840
gatgttacag cttgtctgcc cgaatgggag gacggtcact tctacttggc gaagtactat 6900
gataaattga tgcctatggt aaccgacaac aagatggaga agcaaggtga tctgatccgc 6960
tatatcgtgc tgcatttcgg tcgctcactg caatacggaa accagtttat ctaccaatcc 7020
atgccacgta tgttgaccct gtggctggat tacggtacca aagcttacga gtgggaaaaa 7080
gcgggcagga gcgacagagt gcagatgaga aatgacctgg gtaaaatcaa caaagtcata 7140
actgaacata ccaactacct cgcgccgtat cagtttctga ctgctttcag ccaactcatc 7200
tcacgcatct gtcacagcca cgacgaggtt ttcgtggtcc tgatggaaat catcgcaaaa 7260
gtgttcctgg cctatcctca acaggccatg tggatgatga cggctgtgtc caagtcttca 7320
taccccatgc gcgttaaccg ttgtaaggaa atcctgaaca aggctatcca catgaagaaa 7380
agcctggaga agtttgtcgg tgacgctacg agactgaccg acaagttgct ggaattgtgc 7440
aacaagcctg tggatggaag ctccagcact ctgtctatga gcacgcactt caagatgctg 7500
aagaagctgg tagaagaggc cacgttttcc gaaatcctga tacccctgca gtccgtgatg 7560
atccctacct tgccttccat cctgggaacc cacgctaacc acgcctctca tgaacccttc 7620
cccggacact gggcctatat cgctggattt gacgatatgg tcgaaattct ggcatccctg 7680
cagaagccca aaaagatctc actgaagggt tccgacggta agttctacat aatgatgtgc 7740
aagcctaagg atgacctcag aaaggactgc cgtctgatgg agttcaactc cctgattaac 7800
aaatgtctca gaaaggacgc tgagagccgt cgcagggagc tgcacattcg tacatacgca 7860
gtgatccctc tgaacgatga gtgtggcatc atagagtggg tcaataacac tgcgggactc 7920
cgcccgattc tgacaaaact ctacaaagag aagggtgtct atatgacagg taaagagttg 7980
cgccaatgta tgctccctaa atccgctgcc ctctccgaga agttgaaggt tttcagagaa 8040
ttcctcctgc caaggcaccc accaattttc cacgaatggt ttctgcgcac attccccgac 8100
cctacgtcct ggtattcttc ccgctccgcc tactgtcgtt caactgcagt aatgagcatg 8160
gttggttaca tcctcggtct gggcgaccgc cacggagaga acatcctgtt cgactccctg 8220
accggcgagt gcgtgcacgt ggatttcaat tgcttgttca ataagggtga aactttcgaa 8280
gtacctgaaa tagtgccttt ccgcctgaca cataacatgg tcaatggcat gggaccaatg 8340
ggcacggaag gactgttcag aagagcctgc gaggtcacca tgcgcctgat gcgcgatcag 8400
cgcgagccgc tgatgtcagt actcaagacg tttctgcatg accctctcgt ggagtggtcc 8460
aagcccgtca aaggccatag caaagcgcct ctgaacgaga ctggagaggt agtgaacgag 8520
aaggctaaaa cgcacgtcct cgatatagaa cagaggctgc aaggtgtgat caagacaaga 8580
aatcgtgtca cgggtctgcc tctgtccatt gaaggccacg tccactacct gatccaggag 8640
gccacagacg aaaatctgct ctgccaaatg tacctgggat ggacaccata catgtaa 8697
<210> 2
<211> 2493
<212> DNA
<213> 合成有机体
<220>
<223> 包括STREP标签的密码子优化的ATRIP
<400> 2
atggccagct ggagccaccc tcagttcgaa aagagcgcgg gcctcgagac aagtttgtac 60
aaaaaagcag gctccgatta tgacattcca acgaccgaaa atctgtactt tcagggcatg 120
gctggtacct ctgccccagg tagcaagagg agatcagaac ctcctgcacc aaggcccggt 180
ccacctcccg gtactggaca tccaccctct aagcgcgcca gaggctttag cgctgccgcg 240
gcacctgatc ctgatgaccc ttttggtgct cacggtgact ttacagcaga cgatctggag 300
gagctcgaca ctttggcgtc ccaggcactg tcacaatgcc ccgcagccgc tcgcgacgtt 360
tcatccgacc acaaagtgca ccgtttgctc gacggaatgt ctaagaaccc ctccggaaaa 420
aacagggaaa ccgtccctat caaagacaac ttcgagctgg aggtgttgca agcccagtac 480
aaagagctga aggagaagat gaaggtgatg gaggaagagg tcctgatcaa gaacggcgag 540
atcaagattc tgcgcgattc cctgcaccag acggaaagcg tcctggaaga gcagaggcgt 600
tcccactttc tgctggagca ggaaaaaacg caggctctgt ccgacaagga gaaggagttc 660
agcaagaagc tgcaaagctt gcaaagcgaa ctccagttca aagatgctga aatgaatgaa 720
ctccgtacaa agctgcagac cagcgagaga gctaataagc tcgctgcacc gagtgtgtca 780
cacgtatccc cgcgcaagaa tccgagtgta gttatcaagc ctgaagcctg ttctccacaa 840
ttcggcaaaa catccttccc gacaaaggag tccttctccg ccaacatgtc tctgcctcac 900
ccttgtcaga ccgagtcagg ctacaaaccg ctggtcggta gagaggatag taagccccac 960
tctctgcgcg gagattccat aaagcaggag gaagcccaga agtccttcgt cgattcttgg 1020
cgtcaaagga gcaataccca gggttctatc ctcattaact tgctcctgaa gcaacctttg 1080
atccccggct cttccctctc cctgtgtcat ctgctgtcca gctcttccga gtccccagct 1140
ggcacaccgc tgcaacctcc cggcttcggc tccactctcg cgggcatgtc aggactgagg 1200
acgaccggca gctatgacgg ttccttctct ctctccgcct tgcgcgaagc gcagaacttg 1260
gcattcacgg gattgaacct ggttgctagg aacgagtgct cacgtgacgg agatccagcc 1320
gaaggtggac gcagagcctt tcctttgtgc caactgcccg gtgctgttca cttcttgcca 1380
ctggtgcagt tcttcatcgg tttgcactgt caagctctgc aggatctggc ggccgctaaa 1440
agatccggtg ctccgggtga ctcacccact catagctcat gcgtctcttc cggtgtggaa 1500
acgaatccgg aggatagtgt atgcattctg gagggtttct cagttaccgc gctctccatt 1560
ctgcagcacc tggtgtgcca ttcaggcgcc gttgtcagtc tcctgctgtc tggagtcgga 1620
gcggactcag ccgcgggtga gggtaaccgc tccctcgtcc atcgcctgtc tgacggcgac 1680
atgaccagcg ctttgcgtgg agtcgcagat gaccaaggtc agcatcccct cttgaagatg 1740
ctgctgcatc tgttggcatt ttcctccgca gctactggtc acctccaagc cagcgtgttg 1800
acccagtgtc tcaaagtgct ggtcaaactg gcggagaaca caagttgcga cttcttgcct 1860
cgcttccaat gcgtgttcca agtactccct aagtgcttgt caccagaaac accgctgcca 1920
agtgtgctcc tggccgttga actgctgagt ctgctggctg accacgacca actggctccc 1980
cagctgtgca gtcacagtga aggttgtctg ctgctcctgc tctacatgta catcacgtca 2040
cgtcccgacc gtgtggcctt ggagactcaa tggttgcagc tggaacagga ggtcgtgtgg 2100
ctcctggcga aactgggagt gcagagtcca ctgccaccag ttacaggaag caactgtcag 2160
tgcaacgtag aggtggtgag agctctgaca gtcatgttgc atcgccaatg gctcactgta 2220
cgcagggcag gcggtccacc ccgtaccgat caacagcgcc gcaccgtaag atgtctgcgc 2280
gacactgttc tgctgctgca tggactgagc caaaaggaca aactgttcat gatgcactgc 2340
gtggaagtgc tgcaccagtt cgaccaagtc atgcccggcg tatccatgct catacgtgga 2400
ctgcccgatg taactgactg cgaggaagct gccctggacg atctgtgtgc tgcggaaact 2460
gacgtcgaag atcctgaggt tgaatgcggc taa 2493
<210> 3
<211> 2898
<212> PRT
<213> 合成有机体
<400> 3
Met Ala Ser Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln
1 5 10 15
Pro Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His
20 25 30
Leu Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu
35 40 45
Leu Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val
50 55 60
Lys Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His
65 70 75 80
Asn Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu
85 90 95
Glu Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr
100 105 110
Ser Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro
115 120 125
Glu Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu
130 135 140
Asn Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu
145 150 155 160
Asp Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys
165 170 175
Leu Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys
180 185 190
Tyr Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln
195 200 205
Ala Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Gln Ile Thr
210 215 220
Ser Leu Tyr Lys Lys Ala Gly Ser Asp Tyr Asp Ile Pro Thr Thr Glu
225 230 235 240
Asn Leu Tyr Phe Gln Gly Asp Tyr Lys Asp Asp Asp Asp Lys Met Gly
245 250 255
Glu His Gly Leu Glu Leu Ala Ser Met Ile Pro Ala Leu Arg Glu Leu
260 265 270
Gly Ser Ala Thr Pro Glu Glu Tyr Asn Thr Val Val Gln Lys Pro Arg
275 280 285
Gln Ile Leu Cys Gln Phe Ile Asp Arg Ile Leu Thr Asp Val Asn Val
290 295 300
Val Ala Val Glu Leu Val Lys Lys Thr Asp Ser Gln Pro Thr Ser Val
305 310 315 320
Met Leu Leu Asp Phe Ile Gln His Ile Met Lys Ser Ser Pro Leu Met
325 330 335
Phe Val Asn Val Ser Gly Ser His Glu Ala Lys Gly Ser Cys Ile Glu
340 345 350
Phe Ser Asn Trp Ile Ile Thr Arg Leu Leu Arg Ile Ala Ala Thr Pro
355 360 365
Ser Cys His Leu Leu His Lys Lys Ile Cys Glu Val Ile Cys Ser Leu
370 375 380
Leu Phe Leu Phe Lys Ser Lys Ser Pro Ala Ile Phe Gly Val Leu Thr
385 390 395 400
Lys Glu Leu Leu Gln Leu Phe Glu Asp Leu Val Tyr Leu His Arg Arg
405 410 415
Asn Val Met Gly His Ala Val Glu Trp Pro Val Val Met Ser Arg Phe
420 425 430
Leu Ser Gln Leu Asp Glu His Met Gly Tyr Leu Gln Ser Ala Pro Leu
435 440 445
Gln Leu Met Ser Met Gln Asn Leu Glu Phe Ile Glu Val Thr Leu Leu
450 455 460
Met Val Leu Thr Arg Ile Ile Ala Ile Val Phe Phe Arg Arg Gln Glu
465 470 475 480
Leu Leu Leu Trp Gln Ile Gly Cys Val Leu Leu Glu Tyr Gly Ser Pro
485 490 495
Lys Ile Lys Ser Leu Ala Ile Ser Phe Leu Thr Glu Leu Phe Gln Leu
500 505 510
Gly Gly Leu Pro Ala Gln Pro Ala Ser Thr Phe Phe Ser Ser Phe Leu
515 520 525
Glu Leu Leu Lys His Leu Val Glu Met Asp Thr Asp Gln Leu Lys Leu
530 535 540
Tyr Glu Glu Pro Leu Ser Lys Leu Ile Lys Thr Leu Phe Pro Phe Glu
545 550 555 560
Ala Glu Ala Tyr Arg Asn Ile Glu Pro Val Tyr Leu Asn Met Leu Leu
565 570 575
Glu Lys Leu Cys Val Met Phe Glu Asp Gly Val Leu Met Arg Leu Lys
580 585 590
Ser Asp Leu Leu Lys Ala Ala Leu Cys His Leu Leu Gln Tyr Phe Leu
595 600 605
Lys Phe Val Pro Ala Gly Tyr Glu Ser Ala Leu Gln Val Arg Lys Val
610 615 620
Tyr Val Arg Asn Ile Cys Lys Ala Leu Leu Asp Val Leu Gly Ile Glu
625 630 635 640
Val Asp Ala Glu Tyr Leu Leu Gly Pro Leu Tyr Ala Ala Leu Lys Met
645 650 655
Glu Ser Met Glu Ile Ile Glu Glu Ile Gln Cys Gln Thr Gln Gln Glu
660 665 670
Asn Leu Ser Ser Asn Ser Asp Gly Ile Ser Pro Lys Arg Arg Arg Leu
675 680 685
Ser Ser Ser Leu Asn Pro Ser Lys Arg Ala Pro Lys Gln Thr Glu Glu
690 695 700
Ile Lys His Val Asp Met Asn Gln Lys Ser Ile Leu Trp Ser Ala Leu
705 710 715 720
Lys Gln Lys Ala Glu Ser Leu Gln Ile Ser Leu Glu Tyr Ser Gly Leu
725 730 735
Lys Asn Pro Val Ile Glu Met Leu Glu Gly Ile Ala Val Val Leu Gln
740 745 750
Leu Thr Ala Leu Cys Thr Val His Cys Ser His Gln Asn Met Asn Cys
755 760 765
Arg Thr Phe Lys Asp Cys Gln His Lys Ser Lys Lys Lys Pro Ser Val
770 775 780
Val Ile Thr Trp Met Ser Leu Asp Phe Tyr Thr Lys Val Leu Lys Ser
785 790 795 800
Cys Arg Ser Leu Leu Glu Ser Val Gln Lys Leu Asp Leu Glu Ala Thr
805 810 815
Ile Asp Lys Val Val Lys Ile Tyr Asp Ala Leu Ile Tyr Met Gln Val
820 825 830
Asn Ser Ser Phe Glu Asp His Ile Leu Glu Asp Leu Cys Gly Met Leu
835 840 845
Ser Leu Pro Trp Ile Tyr Ser His Ser Asp Asp Gly Cys Leu Lys Leu
850 855 860
Thr Thr Phe Ala Ala Asn Leu Leu Thr Leu Ser Cys Arg Ile Ser Asp
865 870 875 880
Ser Tyr Ser Pro Gln Ala Gln Ser Arg Cys Val Phe Leu Leu Thr Leu
885 890 895
Phe Pro Arg Arg Ile Phe Leu Glu Trp Arg Thr Ala Val Tyr Asn Trp
900 905 910
Ala Leu Gln Ser Ser His Glu Val Ile Arg Ala Ser Cys Val Ser Gly
915 920 925
Phe Phe Ile Leu Leu Gln Gln Gln Asn Ser Cys Asn Arg Val Pro Lys
930 935 940
Ile Leu Ile Asp Lys Val Lys Asp Asp Ser Asp Ile Val Lys Lys Glu
945 950 955 960
Phe Ala Ser Ile Leu Gly Gln Leu Val Cys Thr Leu His Gly Met Phe
965 970 975
Tyr Leu Thr Ser Ser Leu Thr Glu Pro Phe Ser Glu His Gly His Val
980 985 990
Asp Leu Phe Cys Arg Asn Leu Lys Ala Thr Ser Gln His Glu Cys Ser
995 1000 1005
Ser Ser Gln Leu Lys Ala Ser Val Cys Lys Pro Phe Leu Phe Leu Leu
1010 1015 1020
Lys Lys Lys Ile Pro Ser Pro Val Lys Leu Ala Phe Ile Asp Asn Leu
1025 1030 1035 1040
His His Leu Cys Lys His Leu Asp Phe Arg Glu Asp Glu Thr Asp Val
1045 1050 1055
Lys Ala Val Leu Gly Thr Leu Leu Asn Leu Met Glu Asp Pro Asp Lys
1060 1065 1070
Asp Val Arg Val Ala Phe Ser Gly Asn Ile Lys His Ile Leu Glu Ser
1075 1080 1085
Leu Asp Ser Glu Asp Gly Phe Ile Lys Glu Leu Phe Val Leu Arg Met
1090 1095 1100
Lys Glu Ala Tyr Thr His Ala Gln Ile Ser Arg Asn Asn Glu Leu Lys
1105 1110 1115 1120
Asp Thr Leu Ile Leu Thr Thr Gly Asp Ile Gly Arg Ala Ala Lys Gly
1125 1130 1135
Asp Leu Val Pro Phe Ala Leu Leu His Leu Leu His Cys Leu Leu Ser
1140 1145 1150
Lys Ser Ala Ser Val Ser Gly Ala Ala Tyr Thr Glu Ile Arg Ala Leu
1155 1160 1165
Val Ala Ala Lys Ser Val Lys Leu Gln Ser Phe Phe Ser Gln Tyr Lys
1170 1175 1180
Lys Pro Ile Cys Gln Phe Leu Val Glu Ser Leu His Ser Ser Gln Met
1185 1190 1195 1200
Thr Ala Leu Pro Asn Thr Pro Cys Gln Asn Ala Asp Val Arg Lys Gln
1205 1210 1215
Asp Val Ala His Gln Arg Glu Met Ala Leu Asn Thr Leu Ser Glu Ile
1220 1225 1230
Ala Asn Val Phe Asp Phe Pro Asp Leu Asn Arg Phe Leu Thr Arg Thr
1235 1240 1245
Leu Gln Val Leu Leu Pro Asp Leu Ala Ala Lys Ala Ser Pro Ala Ala
1250 1255 1260
Ser Ala Leu Ile Arg Thr Leu Gly Lys Gln Leu Asn Val Asn Arg Arg
1265 1270 1275 1280
Glu Ile Leu Ile Asn Asn Phe Lys Tyr Ile Phe Ser His Leu Val Cys
1285 1290 1295
Ser Cys Ser Lys Asp Glu Leu Glu Arg Ala Leu His Tyr Leu Lys Asn
1300 1305 1310
Glu Thr Glu Ile Glu Leu Gly Ser Leu Leu Arg Gln Asp Phe Gln Gly
1315 1320 1325
Leu His Asn Glu Leu Leu Leu Arg Ile Gly Glu His Tyr Gln Gln Val
1330 1335 1340
Phe Asn Gly Leu Ser Ile Leu Ala Ser Phe Ala Ser Ser Asp Asp Pro
1345 1350 1355 1360
Tyr Gln Gly Pro Arg Asp Ile Ile Ser Pro Glu Leu Met Ala Asp Tyr
1365 1370 1375
Leu Gln Pro Lys Leu Leu Gly Ile Leu Ala Phe Phe Asn Met Gln Leu
1380 1385 1390
Leu Ser Ser Ser Val Gly Ile Glu Asp Lys Lys Met Ala Leu Asn Ser
1395 1400 1405
Leu Met Ser Leu Met Lys Leu Met Gly Pro Lys His Val Ser Ser Val
1410 1415 1420
Arg Val Lys Met Met Thr Thr Leu Arg Thr Gly Leu Arg Phe Lys Asp
1425 1430 1435 1440
Asp Phe Pro Glu Leu Cys Cys Arg Ala Trp Asp Cys Phe Val Arg Cys
1445 1450 1455
Leu Asp His Ala Cys Leu Gly Ser Leu Leu Ser His Val Ile Val Ala
1460 1465 1470
Leu Leu Pro Leu Ile His Ile Gln Pro Lys Glu Thr Ala Ala Ile Phe
1475 1480 1485
His Tyr Leu Ile Ile Glu Asn Arg Asp Ala Val Gln Asp Phe Leu His
1490 1495 1500
Glu Ile Tyr Phe Leu Pro Asp His Pro Glu Leu Lys Lys Ile Lys Ala
1505 1510 1515 1520
Val Leu Gln Glu Tyr Arg Lys Glu Thr Ser Glu Ser Thr Asp Leu Gln
1525 1530 1535
Thr Thr Leu Gln Leu Ser Met Lys Ala Ile Gln His Glu Asn Val Asp
1540 1545 1550
Val Arg Ile His Ala Leu Thr Ser Leu Lys Glu Thr Leu Tyr Lys Asn
1555 1560 1565
Gln Glu Lys Leu Ile Lys Tyr Ala Thr Asp Ser Glu Thr Val Glu Pro
1570 1575 1580
Ile Ile Ser Gln Leu Val Thr Val Leu Leu Lys Gly Cys Gln Asp Ala
1585 1590 1595 1600
Asn Ser Gln Ala Arg Leu Leu Cys Gly Glu Cys Leu Gly Glu Leu Gly
1605 1610 1615
Ala Ile Asp Pro Gly Arg Leu Asp Phe Ser Thr Thr Glu Thr Gln Gly
1620 1625 1630
Lys Asp Phe Thr Phe Val Thr Gly Val Glu Asp Ser Ser Phe Ala Tyr
1635 1640 1645
Gly Leu Leu Met Glu Leu Thr Arg Ala Tyr Leu Ala Tyr Ala Asp Asn
1650 1655 1660
Ser Arg Ala Gln Asp Ser Ala Ala Tyr Ala Ile Gln Glu Leu Leu Ser
1665 1670 1675 1680
Ile Tyr Asp Cys Arg Glu Met Glu Thr Asn Gly Pro Gly His Gln Leu
1685 1690 1695
Trp Arg Arg Phe Pro Glu His Val Arg Glu Ile Leu Glu Pro His Leu
1700 1705 1710
Asn Thr Arg Tyr Lys Ser Ser Gln Lys Ser Thr Asp Trp Ser Gly Val
1715 1720 1725
Lys Lys Pro Ile Tyr Leu Ser Lys Leu Gly Ser Asn Phe Ala Glu Trp
1730 1735 1740
Ser Ala Ser Trp Ala Gly Tyr Leu Ile Thr Lys Val Arg His Asp Leu
1745 1750 1755 1760
Ala Ser Lys Ile Phe Thr Cys Cys Ser Ile Met Met Lys His Asp Phe
1765 1770 1775
Lys Val Thr Ile Tyr Leu Leu Pro His Ile Leu Val Tyr Val Leu Leu
1780 1785 1790
Gly Cys Asn Gln Glu Asp Gln Gln Glu Val Tyr Ala Glu Ile Met Ala
1795 1800 1805
Val Leu Lys His Asp Asp Gln His Thr Ile Asn Thr Gln Asp Ile Ala
1810 1815 1820
Ser Asp Leu Cys Gln Leu Ser Thr Gln Thr Val Phe Ser Met Leu Asp
1825 1830 1835 1840
His Leu Thr Gln Trp Ala Arg His Lys Phe Gln Ala Leu Lys Ala Glu
1845 1850 1855
Lys Cys Pro His Ser Lys Ser Asn Arg Asn Lys Val Asp Ser Met Val
1860 1865 1870
Ser Thr Val Asp Tyr Glu Asp Tyr Gln Ser Val Thr Arg Phe Leu Asp
1875 1880 1885
Leu Ile Pro Gln Asp Thr Leu Ala Val Ala Ser Phe Arg Ser Lys Ala
1890 1895 1900
Tyr Thr Arg Ala Val Met His Phe Glu Ser Phe Ile Thr Glu Lys Lys
1905 1910 1915 1920
Gln Asn Ile Gln Glu His Leu Gly Phe Leu Gln Lys Leu Tyr Ala Ala
1925 1930 1935
Met His Glu Pro Asp Gly Val Ala Gly Val Ser Ala Ile Arg Lys Ala
1940 1945 1950
Glu Pro Ser Leu Lys Glu Gln Ile Leu Glu His Glu Ser Leu Gly Leu
1955 1960 1965
Leu Arg Asp Ala Thr Ala Cys Tyr Asp Arg Ala Ile Gln Leu Glu Pro
1970 1975 1980
Asp Gln Ile Ile His Tyr His Gly Val Val Lys Ser Met Leu Gly Leu
1985 1990 1995 2000
Gly Gln Leu Ser Thr Val Ile Thr Gln Val Asn Gly Val His Ala Asn
2005 2010 2015
Arg Ser Glu Trp Thr Asp Glu Leu Asn Thr Tyr Arg Val Glu Ala Ala
2020 2025 2030
Trp Lys Leu Ser Gln Trp Asp Leu Val Glu Asn Tyr Leu Ala Ala Asp
2035 2040 2045
Gly Lys Ser Thr Thr Trp Ser Val Arg Leu Gly Gln Leu Leu Leu Ser
2050 2055 2060
Ala Lys Lys Arg Asp Ile Thr Ala Phe Tyr Asp Ser Leu Lys Leu Val
2065 2070 2075 2080
Arg Ala Glu Gln Ile Val Pro Leu Ser Ala Ala Ser Phe Glu Arg Gly
2085 2090 2095
Ser Tyr Gln Arg Gly Tyr Glu Tyr Ile Val Arg Leu His Met Leu Cys
2100 2105 2110
Glu Leu Glu His Ser Ile Lys Pro Leu Phe Gln His Ser Pro Gly Asp
2115 2120 2125
Ser Ser Gln Glu Asp Ser Leu Asn Trp Val Ala Arg Leu Glu Met Thr
2130 2135 2140
Gln Asn Ser Tyr Arg Ala Lys Glu Pro Ile Leu Ala Leu Arg Arg Ala
2145 2150 2155 2160
Leu Leu Ser Leu Asn Lys Arg Pro Asp Tyr Asn Glu Met Val Gly Glu
2165 2170 2175
Cys Trp Leu Gln Ser Ala Arg Val Ala Arg Lys Ala Gly His His Gln
2180 2185 2190
Thr Ala Tyr Asn Ala Leu Leu Asn Ala Gly Glu Ser Arg Leu Ala Glu
2195 2200 2205
Leu Tyr Val Glu Arg Ala Lys Trp Leu Trp Ser Lys Gly Asp Val His
2210 2215 2220
Gln Ala Leu Ile Val Leu Gln Lys Gly Val Glu Leu Cys Phe Pro Glu
2225 2230 2235 2240
Asn Glu Thr Pro Pro Glu Gly Lys Asn Met Leu Ile His Gly Arg Ala
2245 2250 2255
Met Leu Leu Val Gly Arg Phe Met Glu Glu Thr Ala Asn Phe Glu Ser
2260 2265 2270
Asn Ala Ile Met Lys Lys Tyr Lys Asp Val Thr Ala Cys Leu Pro Glu
2275 2280 2285
Trp Glu Asp Gly His Phe Tyr Leu Ala Lys Tyr Tyr Asp Lys Leu Met
2290 2295 2300
Pro Met Val Thr Asp Asn Lys Met Glu Lys Gln Gly Asp Leu Ile Arg
2305 2310 2315 2320
Tyr Ile Val Leu His Phe Gly Arg Ser Leu Gln Tyr Gly Asn Gln Phe
2325 2330 2335
Ile Tyr Gln Ser Met Pro Arg Met Leu Thr Leu Trp Leu Asp Tyr Gly
2340 2345 2350
Thr Lys Ala Tyr Glu Trp Glu Lys Ala Gly Arg Ser Asp Arg Val Gln
2355 2360 2365
Met Arg Asn Asp Leu Gly Lys Ile Asn Lys Val Ile Thr Glu His Thr
2370 2375 2380
Asn Tyr Leu Ala Pro Tyr Gln Phe Leu Thr Ala Phe Ser Gln Leu Ile
2385 2390 2395 2400
Ser Arg Ile Cys His Ser His Asp Glu Val Phe Val Val Leu Met Glu
2405 2410 2415
Ile Ile Ala Lys Val Phe Leu Ala Tyr Pro Gln Gln Ala Met Trp Met
2420 2425 2430
Met Thr Ala Val Ser Lys Ser Ser Tyr Pro Met Arg Val Asn Arg Cys
2435 2440 2445
Lys Glu Ile Leu Asn Lys Ala Ile His Met Lys Lys Ser Leu Glu Lys
2450 2455 2460
Phe Val Gly Asp Ala Thr Arg Leu Thr Asp Lys Leu Leu Glu Leu Cys
2465 2470 2475 2480
Asn Lys Pro Val Asp Gly Ser Ser Ser Thr Leu Ser Met Ser Thr His
2485 2490 2495
Phe Lys Met Leu Lys Lys Leu Val Glu Glu Ala Thr Phe Ser Glu Ile
2500 2505 2510
Leu Ile Pro Leu Gln Ser Val Met Ile Pro Thr Leu Pro Ser Ile Leu
2515 2520 2525
Gly Thr His Ala Asn His Ala Ser His Glu Pro Phe Pro Gly His Trp
2530 2535 2540
Ala Tyr Ile Ala Gly Phe Asp Asp Met Val Glu Ile Leu Ala Ser Leu
2545 2550 2555 2560
Gln Lys Pro Lys Lys Ile Ser Leu Lys Gly Ser Asp Gly Lys Phe Tyr
2565 2570 2575
Ile Met Met Cys Lys Pro Lys Asp Asp Leu Arg Lys Asp Cys Arg Leu
2580 2585 2590
Met Glu Phe Asn Ser Leu Ile Asn Lys Cys Leu Arg Lys Asp Ala Glu
2595 2600 2605
Ser Arg Arg Arg Glu Leu His Ile Arg Thr Tyr Ala Val Ile Pro Leu
2610 2615 2620
Asn Asp Glu Cys Gly Ile Ile Glu Trp Val Asn Asn Thr Ala Gly Leu
2625 2630 2635 2640
Arg Pro Ile Leu Thr Lys Leu Tyr Lys Glu Lys Gly Val Tyr Met Thr
2645 2650 2655
Gly Lys Glu Leu Arg Gln Cys Met Leu Pro Lys Ser Ala Ala Leu Ser
2660 2665 2670
Glu Lys Leu Lys Val Phe Arg Glu Phe Leu Leu Pro Arg His Pro Pro
2675 2680 2685
Ile Phe His Glu Trp Phe Leu Arg Thr Phe Pro Asp Pro Thr Ser Trp
2690 2695 2700
Tyr Ser Ser Arg Ser Ala Tyr Cys Arg Ser Thr Ala Val Met Ser Met
2705 2710 2715 2720
Val Gly Tyr Ile Leu Gly Leu Gly Asp Arg His Gly Glu Asn Ile Leu
2725 2730 2735
Phe Asp Ser Leu Thr Gly Glu Cys Val His Val Asp Phe Asn Cys Leu
2740 2745 2750
Phe Asn Lys Gly Glu Thr Phe Glu Val Pro Glu Ile Val Pro Phe Arg
2755 2760 2765
Leu Thr His Asn Met Val Asn Gly Met Gly Pro Met Gly Thr Glu Gly
2770 2775 2780
Leu Phe Arg Arg Ala Cys Glu Val Thr Met Arg Leu Met Arg Asp Gln
2785 2790 2795 2800
Arg Glu Pro Leu Met Ser Val Leu Lys Thr Phe Leu His Asp Pro Leu
2805 2810 2815
Val Glu Trp Ser Lys Pro Val Lys Gly His Ser Lys Ala Pro Leu Asn
2820 2825 2830
Glu Thr Gly Glu Val Val Asn Glu Lys Ala Lys Thr His Val Leu Asp
2835 2840 2845
Ile Glu Gln Arg Leu Gln Gly Val Ile Lys Thr Arg Asn Arg Val Thr
2850 2855 2860
Gly Leu Pro Leu Ser Ile Glu Gly His Val His Tyr Leu Ile Gln Glu
2865 2870 2875 2880
Ala Thr Asp Glu Asn Leu Leu Cys Gln Met Tyr Leu Gly Trp Thr Pro
2885 2890 2895
Tyr Met
<210> 4
<211> 830
<212> PRT
<213> 合成有机体
<400> 4
Met Ala Ser Trp Ser His Pro Gln Phe Glu Lys Ser Ala Gly Leu Glu
1 5 10 15
Thr Ser Leu Tyr Lys Lys Ala Gly Ser Asp Tyr Asp Ile Pro Thr Thr
20 25 30
Glu Asn Leu Tyr Phe Gln Gly Met Ala Gly Thr Ser Ala Pro Gly Ser
35 40 45
Lys Arg Arg Ser Glu Pro Pro Ala Pro Arg Pro Gly Pro Pro Pro Gly
50 55 60
Thr Gly His Pro Pro Ser Lys Arg Ala Arg Gly Phe Ser Ala Ala Ala
65 70 75 80
Ala Pro Asp Pro Asp Asp Pro Phe Gly Ala His Gly Asp Phe Thr Ala
85 90 95
Asp Asp Leu Glu Glu Leu Asp Thr Leu Ala Ser Gln Ala Leu Ser Gln
100 105 110
Cys Pro Ala Ala Ala Arg Asp Val Ser Ser Asp His Lys Val His Arg
115 120 125
Leu Leu Asp Gly Met Ser Lys Asn Pro Ser Gly Lys Asn Arg Glu Thr
130 135 140
Val Pro Ile Lys Asp Asn Phe Glu Leu Glu Val Leu Gln Ala Gln Tyr
145 150 155 160
Lys Glu Leu Lys Glu Lys Met Lys Val Met Glu Glu Glu Val Leu Ile
165 170 175
Lys Asn Gly Glu Ile Lys Ile Leu Arg Asp Ser Leu His Gln Thr Glu
180 185 190
Ser Val Leu Glu Glu Gln Arg Arg Ser His Phe Leu Leu Glu Gln Glu
195 200 205
Lys Thr Gln Ala Leu Ser Asp Lys Glu Lys Glu Phe Ser Lys Lys Leu
210 215 220
Gln Ser Leu Gln Ser Glu Leu Gln Phe Lys Asp Ala Glu Met Asn Glu
225 230 235 240
Leu Arg Thr Lys Leu Gln Thr Ser Glu Arg Ala Asn Lys Leu Ala Ala
245 250 255
Pro Ser Val Ser His Val Ser Pro Arg Lys Asn Pro Ser Val Val Ile
260 265 270
Lys Pro Glu Ala Cys Ser Pro Gln Phe Gly Lys Thr Ser Phe Pro Thr
275 280 285
Lys Glu Ser Phe Ser Ala Asn Met Ser Leu Pro His Pro Cys Gln Thr
290 295 300
Glu Ser Gly Tyr Lys Pro Leu Val Gly Arg Glu Asp Ser Lys Pro His
305 310 315 320
Ser Leu Arg Gly Asp Ser Ile Lys Gln Glu Glu Ala Gln Lys Ser Phe
325 330 335
Val Asp Ser Trp Arg Gln Arg Ser Asn Thr Gln Gly Ser Ile Leu Ile
340 345 350
Asn Leu Leu Leu Lys Gln Pro Leu Ile Pro Gly Ser Ser Leu Ser Leu
355 360 365
Cys His Leu Leu Ser Ser Ser Ser Glu Ser Pro Ala Gly Thr Pro Leu
370 375 380
Gln Pro Pro Gly Phe Gly Ser Thr Leu Ala Gly Met Ser Gly Leu Arg
385 390 395 400
Thr Thr Gly Ser Tyr Asp Gly Ser Phe Ser Leu Ser Ala Leu Arg Glu
405 410 415
Ala Gln Asn Leu Ala Phe Thr Gly Leu Asn Leu Val Ala Arg Asn Glu
420 425 430
Cys Ser Arg Asp Gly Asp Pro Ala Glu Gly Gly Arg Arg Ala Phe Pro
435 440 445
Leu Cys Gln Leu Pro Gly Ala Val His Phe Leu Pro Leu Val Gln Phe
450 455 460
Phe Ile Gly Leu His Cys Gln Ala Leu Gln Asp Leu Ala Ala Ala Lys
465 470 475 480
Arg Ser Gly Ala Pro Gly Asp Ser Pro Thr His Ser Ser Cys Val Ser
485 490 495
Ser Gly Val Glu Thr Asn Pro Glu Asp Ser Val Cys Ile Leu Glu Gly
500 505 510
Phe Ser Val Thr Ala Leu Ser Ile Leu Gln His Leu Val Cys His Ser
515 520 525
Gly Ala Val Val Ser Leu Leu Leu Ser Gly Val Gly Ala Asp Ser Ala
530 535 540
Ala Gly Glu Gly Asn Arg Ser Leu Val His Arg Leu Ser Asp Gly Asp
545 550 555 560
Met Thr Ser Ala Leu Arg Gly Val Ala Asp Asp Gln Gly Gln His Pro
565 570 575
Leu Leu Lys Met Leu Leu His Leu Leu Ala Phe Ser Ser Ala Ala Thr
580 585 590
Gly His Leu Gln Ala Ser Val Leu Thr Gln Cys Leu Lys Val Leu Val
595 600 605
Lys Leu Ala Glu Asn Thr Ser Cys Asp Phe Leu Pro Arg Phe Gln Cys
610 615 620
Val Phe Gln Val Leu Pro Lys Cys Leu Ser Pro Glu Thr Pro Leu Pro
625 630 635 640
Ser Val Leu Leu Ala Val Glu Leu Leu Ser Leu Leu Ala Asp His Asp
645 650 655
Gln Leu Ala Pro Gln Leu Cys Ser His Ser Glu Gly Cys Leu Leu Leu
660 665 670
Leu Leu Tyr Met Tyr Ile Thr Ser Arg Pro Asp Arg Val Ala Leu Glu
675 680 685
Thr Gln Trp Leu Gln Leu Glu Gln Glu Val Val Trp Leu Leu Ala Lys
690 695 700
Leu Gly Val Gln Ser Pro Leu Pro Pro Val Thr Gly Ser Asn Cys Gln
705 710 715 720
Cys Asn Val Glu Val Val Arg Ala Leu Thr Val Met Leu His Arg Gln
725 730 735
Trp Leu Thr Val Arg Arg Ala Gly Gly Pro Pro Arg Thr Asp Gln Gln
740 745 750
Arg Arg Thr Val Arg Cys Leu Arg Asp Thr Val Leu Leu Leu His Gly
755 760 765
Leu Ser Gln Lys Asp Lys Leu Phe Met Met His Cys Val Glu Val Leu
770 775 780
His Gln Phe Asp Gln Val Met Pro Gly Val Ser Met Leu Ile Arg Gly
785 790 795 800
Leu Pro Asp Val Thr Asp Cys Glu Glu Ala Ala Leu Asp Asp Leu Cys
805 810 815
Ala Ala Glu Thr Asp Val Glu Asp Pro Glu Val Glu Cys Gly
820 825 830
Claims (8)
2.化合物,其选自:
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-(丙-2-基氧基)-8-(1H-吡唑-5-基)-1,7-萘啶
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-(1-甲基-1H-吡唑-5-基)-8-(1H-吡唑-5-基)-1,7-萘啶
4-(2-氟吡啶-3-基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
5-甲基-4-[2-甲基-6-(甲基磺酰基)吡啶-3-基]-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
4-(2-氯-1-甲基-1H-咪唑-5-基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
4-[2-氟-4-(哌嗪-1-基)苯基]-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
4-(2,3-二氟苯基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
N-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基四氢-1H-1λ4-噻吩-1-亚胺1-氧化物
4-[二乙基(氧化)-λ6-亚硫烷基]氨基-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-(吗啉-4-基)-8-(1H-吡唑-5-基)-1,7-萘啶
(1-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}哌啶-4-基)甲醇
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-[4-(甲基磺酰基)哌嗪-1-基]-8-(1H-吡唑-5-基)-1,7-萘啶
N-(2,2-二甲基丙基)-N,5-二甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-胺
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-甲酸甲酯5-甲基-4-(1-甲基-1H-咪唑-5-基)-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-(2-甲基-1,3-噻唑-5-基)-8-(1H-吡唑-5-基)-1,7-萘啶
甲基{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}次膦酸乙酯
4-(二甲基磷酰基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
甲基{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}次膦酸2-甲基丙基酯
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-苯基-8-(1H-吡唑-5-基)-1,7-萘啶
4-(2,3-二氢-1,4-苯并二氧杂环己二烯-6-基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
4-(2,4-二氯苯基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
(3-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}苯基)甲醇
4-(4-氟苯基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
4-(4-甲氧基苯基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-4-(2,3,5-三氟苯基)-1,7-萘啶
4-(6-甲氧基吡啶-3-基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
3-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}苯甲酸甲酯
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-[4-(甲基亚磺酰基)苯基]-8-(1H-吡唑-5-基)-1,7-萘啶
4-(2-氟-3-甲氧基苯基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-[2-(甲基磺酰基)苯基]-8-(1H-吡唑-5-基)-1,7-萘啶
N-(4-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}苯基)甲磺酰胺
4-(环戊-1-烯-1-基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-4-(喹啉-3-基)-1,7-萘啶
N,N-二甲基-4-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}苯甲酰胺
4-(4-氯-3-甲基苯基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
4-(2,3-二甲氧基苯基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
4-(4-氯-2-甲氧基苯基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-[4-(甲基硫烷基)苯基]-8-(1H-吡唑-5-基)-1,7-萘啶
N,N-二甲基-3-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}苯胺
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-[3-(甲基磺酰基)苯基]-8-(1H-吡唑-5-基)-1,7-萘啶
4-(3,5-二甲氧基苯基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-4-(喹啉-4-基)-1,7-萘啶
4-(1H-吲哚-4-基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
4-(1H-吲哚-6-基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-(3-甲基吡啶-4-基)-8-(1H-吡唑-5-基)-1,7-萘啶
(5-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}噻吩-2-基)甲醇
2-氟-4-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}苄腈
4-(6-氟吡啶-3-基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
4-(2-甲氧基吡啶-3-基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-[2-(丙-2-基)苯基]-8-(1H-吡唑-5-基)-1,7-萘啶
4-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}苯甲酰胺
(4-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}苯基)(吡咯烷-1-基)甲酮
N-苄基-4-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}苯甲酰胺
N,N-二甲基-3-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}苯甲酰胺
4-[3-(甲氧基甲基)苯基]-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
5-甲基-4-(1-甲基-1H-吲哚-5-基)-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
4-(异喹啉-4-基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
4-(5-甲氧基吡啶-3-基)-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-[3-(丙-2-基氧基)苯基]-8-(1H-吡唑-5-基)-1,7-萘啶
5-甲基-2-[(3R)-3-甲基吗啉-4-基]-4-(4-甲基吡啶-3-基)-8-(1H-吡唑-5-基)-1,7-萘啶
N-叔丁基-4-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}苯甲酰胺
N-环丙基-4-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}苯甲酰胺
3-甲基-4-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}苯酚
4-[4-(甲氧基甲基)苯基]-5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶
N-甲基-4-{5-甲基-2-[(3R)-3-甲基吗啉-4-基]-8-(1H-吡唑-5-基)-1,7-萘啶-4-基}苯甲酰胺。
3.根据权利要求1-2中任一项的化合物在制备用于治疗或预防过度增殖性疾病的药物中的用途。
4.药物组合物,其包含权利要求1-2中任一项的化合物和一种或多种药学上可接受的赋形剂。
5.根据权利要求4的药物组合物在制备用于治疗或预防过度增殖性疾病的药物中的用途。
6.药物组合物,其包含:
-一种或多种活性成分,其选自权利要求1-2中任一项的化合物,和
-一种或多种活性成分,其选自用于治疗癌症的抗过度增殖物质、抑制细胞生长物质或细胞毒性物质。
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TWI700283B (zh) | 2014-08-04 | 2020-08-01 | 德商拜耳製藥公司 | 2-(嗎啉-4-基)-1,7-萘啶 |
WO2018153972A1 (en) | 2017-02-24 | 2018-08-30 | Bayer Pharma Aktiengesellschaft | Combination of atr kinase inhibitors and antiandrogens |
WO2018153971A1 (en) | 2017-02-24 | 2018-08-30 | Bayer Pharma Aktiengesellschaft | Combination of atr kinase inhibitors |
AR110995A1 (es) | 2017-02-24 | 2019-05-22 | Bayer Ag | Combinación de inhibidores de quinasa atr con sal de radio-223 |
WO2018153970A1 (en) | 2017-02-24 | 2018-08-30 | Bayer Pharma Aktiengesellschaft | Solid forms of 2-[(3r)-3-methylmorpholin-4-yl]-4-(1-methyl-1h-pyrazol-5-yl)-8-(1h-pyrazol-5-yl)-1,7-naphthyridine |
WO2018206547A1 (en) | 2017-05-12 | 2018-11-15 | Bayer Pharma Aktiengesellschaft | Combination of bub1 and atr inhibitors |
CA3071760A1 (en) | 2017-08-04 | 2019-02-07 | Bayer Pharma Aktiengesellschaft | Combination of atr kinase inhibitors and pd-1/pd-l1 inhibitors |
WO2019057852A1 (en) | 2017-09-22 | 2019-03-28 | Bayer Aktiengesellschaft | USE OF KAP1 AS A BIOMARKER FOR DETECTION OR MONITORING ATR INHIBITION IN A SUBJECT |
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WO2017121684A1 (en) | 2017-07-20 |
CN108699057A (zh) | 2018-10-23 |
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EP3402795B1 (en) | 2019-10-30 |
JP2019508384A (ja) | 2019-03-28 |
EP3402795A1 (en) | 2018-11-21 |
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