JP4740878B2 - キナーゼインヒビターとしてのピロロトリアジン化合物 - Google Patents
キナーゼインヒビターとしてのピロロトリアジン化合物 Download PDFInfo
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- JP4740878B2 JP4740878B2 JP2006547328A JP2006547328A JP4740878B2 JP 4740878 B2 JP4740878 B2 JP 4740878B2 JP 2006547328 A JP2006547328 A JP 2006547328A JP 2006547328 A JP2006547328 A JP 2006547328A JP 4740878 B2 JP4740878 B2 JP 4740878B2
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- Prior art keywords
- amino
- methyl
- pyrrolo
- compound
- triazin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 150000001875 compounds Chemical class 0.000 title claims description 493
- 229940043355 kinase inhibitor Drugs 0.000 title description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 471
- -1 cyano, carboxy Chemical group 0.000 claims description 258
- 229910052739 hydrogen Inorganic materials 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
- 150000001412 amines Chemical class 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000004104 aryloxy group Chemical group 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 9
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 9
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- BVOCPVIXARZNQN-UHFFFAOYSA-N nipecotamide Chemical compound NC(=O)C1CCCNC1 BVOCPVIXARZNQN-UHFFFAOYSA-N 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 125000001589 carboacyl group Chemical group 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical class 0.000 claims description 7
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- LKLQWOKKPWCIAW-UHFFFAOYSA-N piperidin-3-yl carbamate Chemical compound NC(=O)OC1CCCNC1 LKLQWOKKPWCIAW-UHFFFAOYSA-N 0.000 claims description 6
- GMCGYLIRFCDMPS-UHFFFAOYSA-N piperidin-3-ylcarbamic acid Chemical compound OC(=O)NC1CCCNC1 GMCGYLIRFCDMPS-UHFFFAOYSA-N 0.000 claims description 6
- 229940124530 sulfonamide Drugs 0.000 claims description 6
- 150000003456 sulfonamides Chemical class 0.000 claims description 6
- NRJLIXYRMUTXLB-HZPDHXFCSA-N (3r,4r)-4-amino-1-[[4-(3-chloro-4-fluoroanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound C1[C@@H](O)[C@H](N)CCN1CC1=C2C(NC=3C=C(Cl)C(F)=CC=3)=NC=NN2C=C1 NRJLIXYRMUTXLB-HZPDHXFCSA-N 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000001769 aryl amino group Chemical group 0.000 claims description 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- QCQKTGJRAPFKRX-UHFFFAOYSA-N piperidine-3,5-diol Chemical compound OC1CNCC(O)C1 QCQKTGJRAPFKRX-UHFFFAOYSA-N 0.000 claims description 5
- BOUIZPWBFIVJPD-UHFFFAOYSA-N 3h-1,2,4-triazin-4-amine Chemical compound NN1CN=NC=C1 BOUIZPWBFIVJPD-UHFFFAOYSA-N 0.000 claims description 4
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- FKCHPOABUFANIL-QZTJIDSGSA-N n-[(3r,4r)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-yl]methanesulfonamide Chemical compound COC1=CC=CC(NC=2C3=C(CN4C[C@H]([C@H](N)CC4)NS(C)(=O)=O)C=CN3N=CN=2)=C1 FKCHPOABUFANIL-QZTJIDSGSA-N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- CSBLWLJGGLNGJK-RTBURBONSA-N (3r,4r)-4-amino-1-[[4-(3-ethynylanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]-n-methylpiperidine-3-carboxamide Chemical compound C1C[C@@H](N)[C@H](C(=O)NC)CN1CC1=C2C(NC=3C=C(C=CC=3)C#C)=NC=NN2C=C1 CSBLWLJGGLNGJK-RTBURBONSA-N 0.000 claims description 3
- JUVHFLNLYRNFBF-QZTJIDSGSA-N (3r,4r)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]-n-methylpiperidine-3-carboxamide Chemical compound C1C[C@@H](N)[C@H](C(=O)NC)CN1CC1=C2C(NC=3C=C(OC)C=CC=3)=NC=NN2C=C1 JUVHFLNLYRNFBF-QZTJIDSGSA-N 0.000 claims description 3
- CSGQVNMSRKWUSH-IAGOWNOFSA-N (3r,4r)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound COC1=CC=CC(NC=2C3=C(CN4C[C@@H](O)[C@H](N)CC4)C=CN3N=CN=2)=C1 CSGQVNMSRKWUSH-IAGOWNOFSA-N 0.000 claims description 3
- YWRLNUHRICTSGM-HZPDHXFCSA-N (3r,4r)-4-amino-1-[[4-(4-fluoro-3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound C1=C(F)C(OC)=CC(NC=2C3=C(CN4C[C@@H](O)[C@H](N)CC4)C=CN3N=CN=2)=C1 YWRLNUHRICTSGM-HZPDHXFCSA-N 0.000 claims description 3
- CSGQVNMSRKWUSH-DLBZAZTESA-N (3r,4s)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound COC1=CC=CC(NC=2C3=C(CN4C[C@@H](O)[C@@H](N)CC4)C=CN3N=CN=2)=C1 CSGQVNMSRKWUSH-DLBZAZTESA-N 0.000 claims description 3
- CSGQVNMSRKWUSH-SJORKVTESA-N (3s,4r)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound COC1=CC=CC(NC=2C3=C(CN4C[C@H](O)[C@H](N)CC4)C=CN3N=CN=2)=C1 CSGQVNMSRKWUSH-SJORKVTESA-N 0.000 claims description 3
- CGRLNCABNBKKKW-UHFFFAOYSA-N 5-[(4-aminopiperidin-1-yl)methyl]-n-(3-chloro-4-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound C1CC(N)CCN1CC1=C2C(NC=3C=C(Cl)C(F)=CC=3)=NC=NN2C=C1 CGRLNCABNBKKKW-UHFFFAOYSA-N 0.000 claims description 3
- ISZKKKYCKGVQSB-QZTJIDSGSA-N 5-[[(3r,4r)-4-amino-3-methoxypiperidin-1-yl]methyl]-n-(3-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound C1C[C@@H](N)[C@H](OC)CN1CC1=C2C(NC=3C=C(OC)C=CC=3)=NC=NN2C=C1 ISZKKKYCKGVQSB-QZTJIDSGSA-N 0.000 claims description 3
- DQRNCWQTRZSQMO-IAGOWNOFSA-N [(3r,4r)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-yl]urea Chemical compound COC1=CC=CC(NC=2C3=C(CN4C[C@H]([C@H](N)CC4)NC(N)=O)C=CN3N=CN=2)=C1 DQRNCWQTRZSQMO-IAGOWNOFSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- FKCHPOABUFANIL-MSOLQXFVSA-N n-[(3s,4r)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-yl]methanesulfonamide Chemical compound COC1=CC=CC(NC=2C3=C(CN4C[C@@H]([C@H](N)CC4)NS(C)(=O)=O)C=CN3N=CN=2)=C1 FKCHPOABUFANIL-MSOLQXFVSA-N 0.000 claims description 3
- 150000002916 oxazoles Chemical class 0.000 claims description 3
- 150000003557 thiazoles Chemical class 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- LQNVONXQKXUJDE-HZPDHXFCSA-N (3r,4r)-4-amino-1-[[4-(3-bromoanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound C1[C@@H](O)[C@H](N)CCN1CC1=C2C(NC=3C=C(Br)C=CC=3)=NC=NN2C=C1 LQNVONXQKXUJDE-HZPDHXFCSA-N 0.000 claims description 2
- HOUKWZNKSYHXTQ-QZTJIDSGSA-N (3r,4r)-4-amino-1-[[4-(3-ethoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound CCOC1=CC=CC(NC=2C3=C(CN4C[C@@H](O)[C@H](N)CC4)C=CN3N=CN=2)=C1 HOUKWZNKSYHXTQ-QZTJIDSGSA-N 0.000 claims description 2
- BSPRDLDPJJSYSN-QZTJIDSGSA-N (3r,4r)-4-amino-1-[[4-(3-ethynylanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound C1[C@@H](O)[C@H](N)CCN1CC1=C2C(NC=3C=C(C=CC=3)C#C)=NC=NN2C=C1 BSPRDLDPJJSYSN-QZTJIDSGSA-N 0.000 claims description 2
- JRXMZGIAVYPICG-IAGOWNOFSA-N (3r,4r)-4-amino-1-[[4-(3-fluoro-5-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound COC1=CC(F)=CC(NC=2C3=C(CN4C[C@@H](O)[C@H](N)CC4)C=CN3N=CN=2)=C1 JRXMZGIAVYPICG-IAGOWNOFSA-N 0.000 claims description 2
- YIDARPMZWLLAGQ-IAGOWNOFSA-N (3r,4r)-4-amino-1-[[4-(3-methoxy-4-methylanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound C1=C(C)C(OC)=CC(NC=2C3=C(CN4C[C@@H](O)[C@H](N)CC4)C=CN3N=CN=2)=C1 YIDARPMZWLLAGQ-IAGOWNOFSA-N 0.000 claims description 2
- CHZZCBXUKKCCMZ-JKSUJKDBSA-N (3r,4s)-4-amino-1-[[4-(3-chloroanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound C1[C@@H](O)[C@@H](N)CCN1CC1=C2C(NC=3C=C(Cl)C=CC=3)=NC=NN2C=C1 CHZZCBXUKKCCMZ-JKSUJKDBSA-N 0.000 claims description 2
- BSPRDLDPJJSYSN-ZWKOTPCHSA-N (3r,4s)-4-amino-1-[[4-(3-ethynylanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound C1[C@@H](O)[C@@H](N)CCN1CC1=C2C(NC=3C=C(C=CC=3)C#C)=NC=NN2C=C1 BSPRDLDPJJSYSN-ZWKOTPCHSA-N 0.000 claims description 2
- OELOITYVKLJQKK-IAGOWNOFSA-N (3r,5r)-4-amino-1-[[4-(3-ethynylanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidine-3,5-diol Chemical compound C1[C@@H](O)C(N)[C@H](O)CN1CC1=C2C(NC=3C=C(C=CC=3)C#C)=NC=NN2C=C1 OELOITYVKLJQKK-IAGOWNOFSA-N 0.000 claims description 2
- NRJLIXYRMUTXLB-CVEARBPZSA-N (3s,4r)-4-amino-1-[[4-(3-chloro-4-fluoroanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound C1[C@H](O)[C@H](N)CCN1CC1=C2C(NC=3C=C(Cl)C(F)=CC=3)=NC=NN2C=C1 NRJLIXYRMUTXLB-CVEARBPZSA-N 0.000 claims description 2
- CHZZCBXUKKCCMZ-CVEARBPZSA-N (3s,4r)-4-amino-1-[[4-(3-chloroanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound C1[C@H](O)[C@H](N)CCN1CC1=C2C(NC=3C=C(Cl)C=CC=3)=NC=NN2C=C1 CHZZCBXUKKCCMZ-CVEARBPZSA-N 0.000 claims description 2
- BSPRDLDPJJSYSN-MSOLQXFVSA-N (3s,4r)-4-amino-1-[[4-(3-ethynylanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound C1[C@H](O)[C@H](N)CCN1CC1=C2C(NC=3C=C(C=CC=3)C#C)=NC=NN2C=C1 BSPRDLDPJJSYSN-MSOLQXFVSA-N 0.000 claims description 2
- NRJLIXYRMUTXLB-HOTGVXAUSA-N (3s,4s)-4-amino-1-[[4-(3-chloro-4-fluoroanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound C1[C@H](O)[C@@H](N)CCN1CC1=C2C(NC=3C=C(Cl)C(F)=CC=3)=NC=NN2C=C1 NRJLIXYRMUTXLB-HOTGVXAUSA-N 0.000 claims description 2
- CSGQVNMSRKWUSH-IRXDYDNUSA-N (3s,4s)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound COC1=CC=CC(NC=2C3=C(CN4C[C@H](O)[C@@H](N)CC4)C=CN3N=CN=2)=C1 CSGQVNMSRKWUSH-IRXDYDNUSA-N 0.000 claims description 2
- HLXBYPFCHOFLKX-GJZGRUSLSA-N (3s,5s)-4-amino-1-[[4-(4-fluoro-3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidine-3,5-diol Chemical compound C1=C(F)C(OC)=CC(NC=2C3=C(CN4C[C@H](O)C(N)[C@@H](O)C4)C=CN3N=CN=2)=C1 HLXBYPFCHOFLKX-GJZGRUSLSA-N 0.000 claims description 2
- RKUHGVDFHLNNLT-UHFFFAOYSA-N 5-[(4-aminopiperidin-1-yl)methyl]-n-(3-ethynylphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound C1CC(N)CCN1CC1=C2C(NC=3C=C(C=CC=3)C#C)=NC=NN2C=C1 RKUHGVDFHLNNLT-UHFFFAOYSA-N 0.000 claims description 2
- WJZSIGPQTIPBIK-UHFFFAOYSA-N 5-[(4-aminopiperidin-1-yl)methyl]-n-(3-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound COC1=CC=CC(NC=2C3=C(CN4CCC(N)CC4)C=CN3N=CN=2)=C1 WJZSIGPQTIPBIK-UHFFFAOYSA-N 0.000 claims description 2
- SSUUQWPXLWNCND-UHFFFAOYSA-N 5-[(4-aminopiperidin-1-yl)methyl]-n-(4-fluoro-3-methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound C1=C(F)C(OC)=CC(NC=2C3=C(CN4CCC(N)CC4)C=CN3N=CN=2)=C1 SSUUQWPXLWNCND-UHFFFAOYSA-N 0.000 claims description 2
- FTXFFNBSNBDXNA-UHFFFAOYSA-N 5-[(4-aminopiperidin-1-yl)methyl]-n-naphthalen-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound C1CC(N)CCN1CC1=C2C(NC=3C=C4C=CC=CC4=CC=3)=NC=NN2C=C1 FTXFFNBSNBDXNA-UHFFFAOYSA-N 0.000 claims description 2
- JPKXJWBKGYESKN-UHFFFAOYSA-N 5-[(4-aminopiperidin-1-yl)methyl]-n-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound C1CC(N)CCN1CC1=C2C(NC=3C=CC=CC=3)=NC=NN2C=C1 JPKXJWBKGYESKN-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical class C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 125000005239 aroylamino group Chemical group 0.000 claims description 2
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 2
- SISDRHXFWXSTMQ-UHFFFAOYSA-N 5-[(4-aminopiperidin-1-yl)methyl]-n-(2-chloropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound C1CC(N)CCN1CC1=C2C(NC=3C=C(Cl)N=CC=3)=NC=NN2C=C1 SISDRHXFWXSTMQ-UHFFFAOYSA-N 0.000 claims 1
- SKUKNQIXDIJXOV-UHFFFAOYSA-N 5-[(4-aminopiperidin-1-yl)methyl]-n-(4-methoxy-6-methylpyrimidin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound COC1=CC(C)=NC(NC=2C3=C(CN4CCC(N)CC4)C=CN3N=CN=2)=N1 SKUKNQIXDIJXOV-UHFFFAOYSA-N 0.000 claims 1
- ZBPFRVZUBJEOLK-UHFFFAOYSA-N 5-[(4-aminopiperidin-1-yl)methyl]-n-(5-bromopyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound C1CC(N)CCN1CC1=C2C(NC=3N=CC(Br)=CC=3)=NC=NN2C=C1 ZBPFRVZUBJEOLK-UHFFFAOYSA-N 0.000 claims 1
- NRBIPIHGEPKDPX-UHFFFAOYSA-N 5-[(4-aminopiperidin-1-yl)methyl]-n-(5-chloropyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound C1CC(N)CCN1CC1=C2C(NC=3N=CC(Cl)=CC=3)=NC=NN2C=C1 NRBIPIHGEPKDPX-UHFFFAOYSA-N 0.000 claims 1
- MRXWBAZOLGAZSQ-UHFFFAOYSA-N 5-[(4-aminopiperidin-1-yl)methyl]-n-(6-bromopyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound C1CC(N)CCN1CC1=C2C(NC=3N=C(Br)C=CC=3)=NC=NN2C=C1 MRXWBAZOLGAZSQ-UHFFFAOYSA-N 0.000 claims 1
- UMMOOCNQPNYYEF-UHFFFAOYSA-N 5-[(4-aminopiperidin-1-yl)methyl]-n-(6-chloropyridazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound C1CC(N)CCN1CC1=C2C(NC=3N=NC(Cl)=CC=3)=NC=NN2C=C1 UMMOOCNQPNYYEF-UHFFFAOYSA-N 0.000 claims 1
- QYIVMGKLAPQSPI-UHFFFAOYSA-N 5-[(4-aminopiperidin-1-yl)methyl]-n-(6-chloropyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine Chemical compound C1CC(N)CCN1CC1=C2C(NC=3C=NC(Cl)=CC=3)=NC=NN2C=C1 QYIVMGKLAPQSPI-UHFFFAOYSA-N 0.000 claims 1
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- 238000007631 vascular surgery Methods 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
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- 239000003643 water by type Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
本発明は、成長因子受容体(例えば、HER1、HER2、およびHER4)のチロシンキナーゼ活性を阻害し、それによって、抗癌剤として有用である、化合物に関する。該化合物はまた、成長因子受容体(例えば、HER1、HER2、およびHER4)を通じて作動するシグナル伝達経路と関係する、癌以外の疾患の処置において有用でもある。
受容体チロシンキナーゼ(RTKs)は、細胞の原形質膜を横切る生化学シグナルの伝達において重要である。これらの膜貫通分子は、原形質膜中のセグメントによって、細胞内チロシンキナーゼドメインと連結する細胞外リガンド結合ドメインから特徴的に構成される。
(1)S. K. HanksおよびT. Hunterによる, Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9 (1995), 頁576-596。
(2)PDB ID: 1M14
Stamos, J., Sliwkowski, M. X., Eigenbrot, C.による: Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor. J. Biol. Chem. 277, 頁46265 (2002)。
(3)H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, H. Weissig, I. N. Shindyalov, P. E. Bourneによる. The Protein Data Bank. Nucleic Acids Research, 28, 頁235-242 (2000): website: http://www.pdb.org/。
(4)PDB ID: 1HCK
Schulze-Gahmen, U., De Bondt, H. L., Kim, S. H.による: High-resolution crystal structures of human cyclin-dependent kinase 2 with and without ATP: bound waters and natural ligand as guides for inhibitor design. J. Med. Chem. 39, 頁4540 (1996)。
記号は以下の意味を有し、そして各々は独立して以下から選ばれる:
R1は、シクロアルキルもしくは置換シクロアルキル、アリールもしくは置換アリール、またはヘテロサイクリルもしくは置換ヘテロサイクリルであり;
R2は、アリール、置換アリール、ヘテロアリールもしくは置換ヘテロアリール、またはヘテロサイクリルもしくは置換ヘテロサイクリルであり;
R3は、水素、アルキル、または置換アルキルであり;
Xは、直結、−NR3−、または−O−であり;
Yは、直結、アルキルもしくは置換アルキル、アルケニルもしくは置換アルケニル、またはアルキニルもしくは置換アルキニルであり;
但し、R2は、インダゾリルまたは置換インダゾリルではない]
で示される化合物、またはその医薬的に許容し得る塩もしくは立体異性体、を開示する。
R1は、ヘテロサイクリルまたは置換ヘテロサイクリルであり;
R2は、アリール、置換アリール、ヘテロアリール、または置換ヘテロアリールであり;
R3は、水素であり;
Xは、−NR3−または−O−であり;
Yは、アルキルまたは置換アルキルである。
Xは、直結、−NR3−、または−O−であり;
Zは、
R2は、アリールもしくは置換アリール、またはヘテロアリールもしくは置換ヘテロアリールであり;
R3、R4およびR5は独立して、水素、アルキル、または置換アルキルから選ばれ;
R6、R6aおよびR6bは独立して、1個以上の水素、ハロゲン、アルキル、アルコキシ、アリールオキシ、−CN、−NH2、−OH、−COOH、−CH2OR5、−CONHSO2R5、−CONR4R5、−NHアルキル、−NHCOアルキル、−NR4SO2アルキル、−NR4SO2NR4R5、−OCONR4R5、−CF3、および−OCF3からなる群から選ばれ、ここで、得られる化合物が化学的に安定であるという条件で、これらの2つは同じ環内炭素原子と結合し得て;
R7は、水素、アルキル、または−NH2であり;そして、
nは、0、1、2、または3である。
Xは、直結、−NR3−、または−O−であり;
R2は、アリールもしくは置換アリール、またはヘテロアリールもしくは置換ヘテロアリールであり;
R3、R4およびR5は独立して、水素、アルキル、または置換アルキルから選ばれ;
R6、R6aおよびR6bは独立して、1つ以上の水素、ハロゲン、アルキル、アルコキシ、アリールオキシ、−CN、−NH2、−OH、−COOH、−CH2OR5、−CONHSO2R5、−CONR4R5、−NHアルキル、−NHCOアルキル、−NR4SO2アルキル、−NR4SO2NR4R5、−OCONR4R5、−CF3、および−OCF3からなる群から選ばれ、ここで、得られる化合物が化学的に安定であるという条件で、これらの2つは同じ環内炭素原子と結合し得て;そして、
nは、0、1、2、または3である。
R2は、フェニル、置換フェニル、ピリジニル、置換ピリジニル、ピリミジニル、置換ピリミジニル、オキサゾール、置換オキサゾール、チアゾール、置換チアゾール、ピラジニル、または置換ピラジニルであり;
R6、R6aおよびR6bは独立して、1つ以上の水素、−NH2、−OH、アルコキシ、−CONR4R5、−NR4SO2アルキル、−NR4SO2NR4R5、−OCONR4R5、−NHアルキル、および−NHCOアルキルからなる群から選ばれ;
Xは、−NH−であり;そして、
nは、1または2である。
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(3−クロロ−4−フルオロフェニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−2−ナフタレニルピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−フェニルピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(3−メトキシフェニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(3−エチニルフェニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノピペリジン−1−イル)メチル]−N−(4−フルオロ−3−メトキシフェニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
(3R,4R)−4−アミノ−1−[[4−[(3−クロロ−4−フルオロフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]ピペリジン−3−オール;
(3S,4S)−4−アミノ−1−[[4−[(3−クロロ−4−フルオロフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−[[4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]ピペリジン−3−オール;
(3S,4S)−4−アミノ−1−[[4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]ピペリジン-3−オール;
(3R,4R)−4−アミノ−1−[[4−[(3−メトキシ−4−フルオロフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−({4−[(3−エチニルフェニル)−アミノ]ピロロ[2,1−f][1,2,4]−トリアジン−5−イル}−メチル)ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−({4−[(3−エトキシフェニル)−アミノ]−ピロロ[2,1−f][1,2,4]トリアジン−5−イル}−メチル)ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−{[4−(2−ナフチルアミノ)−ピロロ[2,1−f][1,2,4]−トリアジン−5−イル]メチル}ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−({4−[(3−メトキシ−4−メチル−フェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}−メチル)ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−({4−[(3−ブロモフェニル)アミノ]ピロロ[2,1−f][1,2,4]−トリアジン−5−イル}メチル)−ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−({4−[(3−フルオロ−5−メトキシ−フェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}−メチル)ピペリジン−3−オール;
(3S,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−オール;
(3R,4S)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−オール;
(3S,4R)−4−アミノ−1−({4−[(3−クロロフェニル)アミノ]−ピロロ[2,1−f][1,2,4]−トリアジン−5−イル}メチル)−ピペリジン−3−オール;
(3S,4R)−4−アミノ−1−({4−[(3−クロロ−4−フルオロ−フェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}−メチル)ピペリジン−3−オール;
(3S,4R)−4−アミノ−1−({4−[(3−エチニルフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−オール;
(3R,4S)−4−アミノ−1−({4−[(3−エチニルフェニル)−アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−オール;
(3R,4S)−4−アミノ−1−({4−[(3−クロロフェニル)アミノ]ピロロ[2,1−f][1,2,4]−トリアジン−5−イル}メチル)ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イルカルバメート;
(3R,4R)−4−アミノ−1−({4−[(3−エチニルフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イルカルバメート;
(3R,4R)−4−アミノ−1−({4−[(3−クロロ−4−フルオロ−フェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イルカルバメート;
(3S,4R)−4−アミノ−1−({4−[(3−クロロ−4−フルオロ−フェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イルカルバメート;
(3S,4R)−4−アミノ−1−({4−[(3−エチニルフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イルカルバメート;
(3S,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−3−メチルピペリジン−3−オール;
(3R/S,5R/S)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3,5−ジオール;
(3S,5S)−4−アミノ−1−({4−[(4−フルオロ−3−メトキシ−フェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3,5−ジオール;
(3R,5R)−4−アミノ−1−({4−[(3−エチニルフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3,5−ジオール;
5−{[(3R,4R)−4−アミノ−3−メトキシピペリジン−1−イル]メチル}−N−(3−メトキシフェニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−(((4aR,8aR)−rel−ヘキサヒドロ−1H−ピリド[3,4−b][1,4]オキサジン−6(7H)−イル)メチル)−N−(3−メトキシフェニル)ピロロ[1,2−f][1,2,4]トリアジン−4−アミン;
(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−N−(メチルスルホニル)ピペリジン−3−カルボキサミド;
(3R,4R)−4−アミノ−1−({4−[(3−エチニルフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−N−メチルピペリジン−3−カルボキサミド;
(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−N−メチルピペリジン−3−カルボキサミド;
(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−カルボキサミド;
((3R,4R)−1−((4−(3−メトキシフェニルアミノ)ピロロ[1,2−f][1,2,4]−トリアジン−5−イル)メチル)−4−((R)−1−フェニルエチルアミノ)ピペリジン−3−イル)メタノール;
N−[(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イル]ウレア;
N−[(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イル]メタンスルホンアミド;および、
N−[(3S,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イル]メタンスルホンアミド
または、その医薬的に許容し得る塩。
a)Design of Prodrugs, H. Bundgaardによる編, (Elsevier, 1985)、およびMethods in Enzymology, 42巻, 頁309-396, K. Widderらによる編 (Acamedic Press, 1985);
b)A Textbook of Drug Design and Development, Krosgaard-LarsenおよびH. Bundgaardによる編, 5章, 「Design and Application of Prodrugs」, H. Bundgardによる, 頁113-191 (1991);および、
c)H. Bundgaardによる, Advanced Drug Delivery Reviews, 8, 1-38 (1992)。
本発明は、あるピロロトリアジンがプロテインキナーゼのインヒビターであるとの発見に基づく。より具体的には、ピロロトリアジン(例えば、本明細書中に記載するもの)が、HERファミリー受容体の要素のプロテインチロシンキナーゼ活性を阻害する。これらのインヒビターは、1つ以上のこれらの受容体によるシグナル伝達に依存する増殖性疾患の処置において有用である。該疾患としては、乾癬、関節リウマチ、並びに肺、頭頸部、乳、腸、卵巣、および前立腺の固形腫瘍を含む。本発明は、哺乳動物における異常増殖性疾患の処置における、式Iで示される化合物、その医薬的に許容し得る塩もしくは水和物、および医薬的に許容し得る担体の医薬組成物に関する。特に、該医薬組成物は、HER1(EGF受容体)およびHER2と関係する、原発性および再発性の固形腫瘍、特にそれらの増殖および伝播についてHER1またはHER2に有意に依存する腫瘍(例えば、膀胱、扁平細胞、頭部、結腸直腸、食道、婦人科学(例えば、卵巣)、膵臓、乳、前立腺、外陰部、皮膚、脳、尿生殖器系菅、リンパ系(例えば、甲状腺)、胃、喉頭、および肺の癌を含む)の増殖を阻害すると予想される。別の実施態様において、本発明の化合物はまた、非癌性疾患(例えば、乾癬、および関節リウマチ)の処置においても有用である。
(i)本明細書中に上で定義するものとは異なる機構によって作用する抗血管新生薬(例えば、リノミド(linomide)、インテグリンαvβ3機能のインヒビター、アンジオスタチン、ラゾキサン(razoxane));
(ii)細胞分裂停止薬(例えば、抗エストロゲン薬(例えば、タモキシフェン、トレミフェン、ラロキシフェン、ドロロキシフェン(droloxifene)、ヨードキシフェン(iodoxyfene));プロゲストーゲン(例えば、酢酸メゲストロール)、アロマターゼインヒビター(例えば、アナストロゾール、レトロゾール(letrozole)、ボラゾール(borazole)、エキセメスタン)、抗ホルモン薬、抗プロゲストーゲン薬、抗アンドロゲン薬(例えば、フルタミド、ニルタミド、ビカルタミド、酢酸シプロテロン)、LHRH作動薬および拮抗薬(例えば、酢酸ゴセレリン、ロイプロリド(leuprolide))、テストステロン5α−ジヒドロレダクターゼのインヒビター(例えば、フィナステリド)、ファルネシルトランスフェラーゼインヒビター、抗侵襲薬(例えば、マリマスタット(marimastat)などのメタロプロテイナーゼインヒビター、およびウロキナーゼプラスミノーゲンアクチベーター受容体機能のインヒビター)、および他の成長因子機能のインヒビター(該成長因子としては例えば、EGF、FGF、血小板由来成長因子、および肝細胞成長因子を含み;該インヒビターは、成長因子抗体、成長因子受容体抗体(アバスチン(登録商標)(ベバシズマブ)およびエルビタックス(登録商標)(セツキシマブ)、チロシンキナーゼインヒビター、およびセリン/トレオニンキナーゼインヒビターを含む));および、
(iii)医学的な腫瘍学において使用される抗増殖薬/抗新生物薬およびその組み合わせ(例えば、代謝拮抗薬(例えば、メトトレキセート等の葉酸代謝拮抗薬、5−フルオロウラシル等のフルオロピリミジン、プリンおよびアデノシンアナログ、シトシンアラビノシド);介在性(Intercalating)抗腫瘍抗生物質(例えば、ドキソルビシン、ダウノマイシン、エピルビシンおよびイダルビシン、マイトマイシン−C、ダクチノマイシン、ミトラマイシン(mithramycin)などのアントラサイクリン);白金誘導体(例えば、シスプラチン、カルボプラチン);アルキル化薬(例えば、ナイトロジェンマスタード、メルファラン、クロランブシル、ブスルファン、シクロホスファミド、イホスファミド、ニトロソ尿素、チオテファン(thiotephan));有糸分裂阻害薬(例えば、ビンカアルカロイド(例えば、ビンクリスチン、ビノレルビン、ビンブラスチン、およびビンフルニン(vinflunine))およびタキソイド(例えば、タキソール(登録商標)およびタキソテール)(登録商標))、および新規な微小管(microbtubule)薬(例えば、エポシロンアナログ、ジスコデルモリド(discodermolide)アナログ、およびエレウテロビン(eleutherobin)アナログ);トポイソメラーゼインヒビター(例えば、エピポドフィロトキシン(epipodophyllotoxin)(例えば、エトポシド、テニポシド(teniposide)、アムサクリン、トポテカン、イリノテカン));細胞周期インヒビター(例えば、フラボピリドール(flavopyridol));並びに、生物学的応答調節物質、およびプロテアソームインヒビター(例えば、ベルカデ(Vercade)(登録商標)(ボルテゾミブ))。
癌腫(膀胱、乳、大腸、腎臓、肝臓、肺(例えば、小細胞肺癌を含む)、食道、胆のう、卵巣、膵臓、胃、頚部、甲状腺、前立腺、および皮膚(例えば、扁平上皮細胞癌腫を含む)の癌腫を含む);
間葉起源の腫瘍(例えば、線維肉腫および横紋筋肉腫を含む);
中枢および末梢の神経系の腫瘍(例えば、星細胞腫、神経芽細胞腫、神経こう腫およびシュワン腫を含む);および
他の腫瘍(例えば、メラノーマ、精上皮腫、奇形癌腫、骨肉腫を含む)。
HER1、HER2、またはHER4キナーゼアッセイ
関心ある化合物を、キナーゼ緩衝液(このものは、20mMのトリス・HCl、pH7.5、10mM MnCl2、0.5mM ジチオトレイトール、0.1mg/mL ウシ血清アルブミン、0.1mg/mL ポリ(glu/tyr)、1μM ATP、4μCi/mLの[ガンマ−33P]ATPを含む)中でアッセイした。ポリ(glu/tyr、4:1)は、ホスホリルアクセプターとして機能する合成高分子であって、このものはシグマ化学社(Sigma Chemicals)から購入する。該キナーゼ反応は、酵素を加えることによって開始し、そして該反応混合物を26℃で1時間インキュベートした。該反応は、EDTAを50mMまで加えることによって停止させ、そしてトリクロロ酢酸を5%まで加えることによって、タンパク質を沈降させた。該沈降したタンパク質をパッカード・ユニフィルタープレート上でのろ過によって回収し、そして取り込まれた放射能の量をトップカウントシンチレーションカウンター中で測定する。
式Iで示される化合物は通常、以下の反応式および当該分野の通常の知識に従って、製造し得る。補足的な製造の情報はまた、同時出願米国特許出願番号09/573,829(2000年5月18日出願)、および国際公開番号WO 00/71129(共に、本明細書中の一部を構成する)中でも知ることができる。
反応式1の第1工程は、不活性雰囲気(例えば、N2)下、無水溶媒(例えば、THF)中で、化合物i(Ref. WO 03/042172 A2)をチオール(例えば、メタンチオールまたはブタンチオール)を用いて処理することによって達成されて、化合物iiを得る。
化合物iiの5−メチル基のハロゲン化は、ハロゲン化試薬(例えば、N−ブロモスクシンイミド)を用いる処理によって有効となる。該反応は、不活性雰囲気(例えば、Ar)下、触媒(例えば、ジベンゾイルペルオキシド、または2,2'−アゾビスイソブチロニトリル)の存在下で行なって、5−ハロメチル−ピロロトリアジン化合物iiiを得る。
化合物iiiを、溶媒(例えば、アセトニトリル、またはN,N−ジメチルホルムアミド)中、塩基(例えば、NaHCO3、トリエチルアミン、またはジイソプロピルエチルアミン)の存在下で、第1級または第2級のアミンまたはアルコールを用いて処理することにより、中間体の化合物ivを得る。
中間体化合物ivを、溶媒(例えば、トルエン)中、HgCl2の存在下でアニリンを用いて処理することにより、4−置換ピロロトリアジン化合物vを得る。
別法として、式ivの化合物は、溶媒(例えば、CH2Cl2)中、適当な酸化剤(例えば、m−クロロ過安息香酸)を用いて処理して、スルホンviを得ることができる。
スルホンviは、不活性溶媒(例えば、CH2Cl2)中、第1級または第2級のアミンまたはアルコールを用いて処理することによって、化合物vに変換し得る。
反応式2の第1工程は、不活性雰囲気(例えば、Ar)下、化合物i(Ref. WO 03/042172 A2)をハロゲン化試薬(例えば、N−ブロモスクシンイミド)を用いて処理することによって達成される。該反応は、適当な溶媒(例えば、CCl4)中、触媒(例えば、ジベンゾイルペルオキシド、2,2'−アゾビスイソブチロニトリル)の存在下で行なって、ジハロピロロトリアジン化合物viiを得る。
化合物viiは、無水溶媒(例えば、THF)中、第3級塩基(例えば、トリエチルアミン)を用いる処理によって、アンモニウム塩化合物viiiに変換し得る。
無水溶媒(例えば、アセトニトリル、クロロホルム、またはTHF)中、化合物viiiをアミンまたはそのアニオンを用いて処理することにより、アンモニウム塩の化合物ixを得る。
化合物ixのピロロトリアジン化合物vへの変換は、溶媒(例えば、アセトニトリル)中、塩基(例えば、ジイソプロピルエチルアミン)の存在下で、第1級または第2級のアミンまたはアルコールを用いて処理することによって達成し得る。
化合物iは、高温で溶媒(例えば、CCl4)中、2当量の臭素化試薬(例えば、N−ブロモスクシンイミド)を用いて処理し得る。得られる5−ジブロモピロロトリアジンは、塩基(例えば、NaHCO3)の存在下、メタノールを用いて対応するジメチルアセタールに変換し、次いで水の存在下、中間体アセタールを酸(例えば、トリフルオロ酢酸)を用いて処理することによって、該アルデヒド化合物xivに変換し得る。
アルデヒド化合物xivを、無水溶媒(例えば、THF)中、有機金属試薬(例えば、グリニャール試薬)を用いて処理することにより、アルコールxvを得る。
アルコールxvは、適当な溶媒(例えば、アセトニトリル)中、塩基(例えば、NaHCO3)の存在下、第1級または第2級のアミンまたはアルコールを用いて処理して、式xviの化合物を得ることができる。
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(3−クロロ−4−フルオロフェニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン
トルエン(2mL)中の1B(30mg、0.08mmol)、3−クロロ−4−フルオロフェニルアミン(11mg、0.08mmol)の混合物を、8時間加熱還流した。rtまで冷却し、EtOAc(5mL)を用いて希釈し、そしてろ過した。該ろ液を濃縮し、そして該残渣をプレパHPLCによって精製して、油状物の1Fを得た。
70℃のCH3CN(55mL)中のピペリジン−4−イル−カルバミン酸tert−ブチルエステル(4.1g、20.3mmol)の懸濁液に、CH3CN(40mL)中の1E(9.1g、18.4mmol)およびDIPEA(3.2mL、18.4mmol)の混合物を40分間かけて滴下した。該反応混合物を70℃で1時間撹拌し、次いでこのものをrtまで冷却し、その後に、H2O(155mL)をゆっくりと加えた。該固体をろ過し、そして15% CH3CN/H2O、次いでH2Oを用いてすすぎ、そして真空下で乾燥して1F(7.84g、90%)を得た。そのものは、分析用HPLCの保持時間が2.73分を有した(Chromolith SpeedROD 4.6×50mm、0.1%TFAを含有する10〜90%水性メタノールを4分間使用、4mL/分、220nmで追跡する)。LC/MS M++1=475。
化合物1F(方法1由来)を、0℃で20% TFA/CH2Cl2(3mL)を用いて処理して、次いでrtで2時間撹拌した。該反応混合物を濃縮し、そしてプレパHPLCによって精製してTFA塩の生成物を得て、このものを飽和NaHCO3を用いて処理して、遊離塩基1G(4mg、2工程で13%)を得た。そのものは、分析用HPLCの保持時間が1.49分を有した(Chromolith SpeedROD 4.6×50mm、0.1%TFAを含有する10〜90%水性メタノールを4分間使用、4mL/分、220nmで追跡する)。LC/MS M++1=375。
5−[(4−アミノ−1−ピペリジニル)メチル]−N−4−ピリジニルピロロ[2,1−f][1,2,4]トリアジン−4−アミン
化合物(HPLCの注意書き(b)を有する)は、以下の標準的な方法によって製造した。
(a)(YMC S5 ODSカラム 4.6×50mm、0.2% H3PO4を含有する10〜90%水性メタノールを4分間使用、3mL/分、220nmで追跡する);
(b)(Chromolith SpeedROD 4.6×50mm、0.1%TFAを含有する10〜90%水性メタノールを4分間使用、4mL/分、220nmで追跡する)。
注意:実施例97〜99、101、および104は、重複するもの(duplicate)として、表から削除した。
5−[(4−アミノ−1−ピペラジニル)メチル]−N−(3−クロロ−4−フルオロフェニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン
(3−クロロ−4−フルオロフェニル)−[5−(モルホリン−2−イルメトキシメチル)ピロロ[2,1−f][1,2,4]トリアジン−4−イル]−アミン
4−アミノ−1−[[4−[(3−クロロ−4−フルオロフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]−(3R,4R)−rel−3−ピペリジノール
化合物135D:1H-NMR (CDCl3): 7.20-7.35 (m, 5H), 5.06 (s, 2H), 4.25および4.10 (部分的なm, 1H), 3.99 (d, J = 13.44, 1H), 3.50 (m, 1H), 3.22 (m, 1H), 2.85 (t, J = 2.69, 1H), 2.73 (m, 1H), 2.40 (m, 1H), 1.90 (m, 1H), 1.45 (m, 1H)。
化合物135Jの製造:
3−アミノ−1−[[4−[(3−クロロ−4−フルオロフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]−(3R,4R)−rel−4−ピペリジノール
4−アミノ−1−[[4−[(3−クロロ−4−フルオロフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]−(3R,4R)−(+)−rel−3−ピペリジノール
4−アミノ−1−[[4−[(3−クロロ−4−フルオロフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]−(3R,4R)−(−)−rel−3−ピペリジノール
N−(3−クロロ−4−フルオロフェニル)−5−[[4−[(2,2−ジメチルプロピル)アミノ]−1−ピペリジニル]メチル]ピロロ[2,1−f][1,2,4]トリアジン−4−アミン
N−(3−クロロ−4−フルオロフェニル)−5−[[4−(プロピルアミノ)−1−ピペリジニル]メチル]−ピロロ[2,1−f][1,2,4]トリアジン−4−アミン
1−[[4−[(3−クロロ−4−フルオロフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]−4−ピペリジノール
トランス−4−[4−(3−クロロ−4−フルオロ−フェニルアミノ)−ピロロ[2,1−f][1,2,4]トリアジン−5−イルメチル]−シクロヘキサノール
耐圧フラスコ中、N2下でTFA(8mL)中の[4−(3−クロロ−4−フルオロ−フェニルアミノ)−ピロロ[2,1−f][1,2,4]トリアジン−5−イル]−[4−(1−メチル−1−トリメチルシラニル−エトキシ)−シクロヘキシル]−メタノール(448mg、0.887mmol)、トリエチルシラン(1.03g、8.87mmol)の混合物を、75℃で終夜加熱した。該溶媒を除去し、そして該残渣をCH3OH(10mL)中に溶解し、そして固体のNa2CO3(2.0g)を加えた。1時間激しく撹拌後に、該溶媒を除去し、そして該残渣をDCM(200mL)およびH2O(50mL)との間で分配した。該有機相を分離し、Na2SO4を用いて乾燥し、そして該溶媒を除去した。円形クロマトグラフィー精製(2mmシリカゲルプレート、DCM中のMeOH(2N)中の0〜4% NH3の勾配溶出を使用)により、固体の標題化合物(209mg、63%)を得た。MS:375 (M+H)+;HPLC保持時間:1.49分(Xterra 3.0×50mm S7カラム、2分の勾配、5mL/分)。
シス−4−[4−(3−クロロ−4−フルオロ−フェニルアミノ)−ピロロ[2,1−f][1,2,4]トリアジン−5−イルメチル]−シクロヘキサノール
4−[4−(3−クロロ−4−フルオロ−フェニルアミノ)−ピロロ[2,1−f][1,2,4]トリアジン−5−イルメチル]−シクロヘキサノン
4−アミノ−1−[4−(3−クロロ−4−フルオロ−フェニルアミノ)−ピロロ[2,1−f][1,2,4]トリアジン−5−イルメチル]−シクロヘキサノール
(3R,4R)−4−アミノ−1−[[4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]ピペリジン−3−オール
(3R,4R)−4−アジド−3−ヒドロキシ−ピペリジン−1−カルボン酸tert−ブチルエステル(146A):
化合物146Fの製造:
(3S,4S)−4−アミノ−1−[[4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]3−ピペリジン−3−オール
(3R,4R)−4−アミノ−1−[[4−[(3−メトキシ−4−フルオロフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]ピペリジン−3−オール
(3S,4S)−4−アミノ−1−[[4−[(3−メトキシ−4−フルオロフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]−ピペリジン−3−オール
rac−(3S,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−オール
(3S,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−オール
(エナンチオマーA、キラル)
(3R,4S)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−オール
(エナンチオマーB、キラル)
(3S,4R)−4−アミノ−1−({4−[(3−メチルフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−オール
(キラル)
(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イルカルバメート
(3R,4S)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イルカルバメート
(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−3−メチルピペリジン−3−オール
(キラル、エナンチオマーA)
(3S,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−3−メチルピペリジン−3−オール
(キラル、エナンチオマーB)
(3R,4r,5S)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3,5−ジオール
(3R/S,5R/S)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3,5−ジオール
(3S,5S)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3,5−ジオール
(エナンチオマーA、キラル)
(3R,5R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3,5−ジオール
(エナンチオマーB、キラル)
rac−5−{[(3R,4R)−4−アミノ−3−メトキシピペリジン−1−イル]メチル}−N−(3−メトキシフェニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン
化合物247C(ラセミ)は、146について記載するのと同様な方法で、247Bから製造した。化合物247Cは、SCXカートリッジ(1g)を通すことによって精製した(MeOH(16mL)、続いて2M NH3/MeOH(16mL)を用いて溶出する)。該溶出液を真空下で濃縮し、そして更にプレパHPLCによって精製して、固体の247C(26mg、収率:42%)を得た。そのものは、分析用HPLCの保持時間が1.51分を有した(Phenomenox S5 C18-HC 4.6×50mmカラム、0.1%TFAを含有する10〜90%水性メタノールを4分間使用、4mL/分、220nmで追跡する)。LC/MS M++1=383。
rac−5−{[(3R,4R)−4−アミノ−3−メトキシピペリジン−1−イル]メチル}−N−(4−フルオロ−3−メトキシフェニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン
(4aR,8aR)−rel−6−((4−(3−メトキシフェニルアミノ)ピロロ[1,2−f][1,2,4]トリアジン−5−イル)メチル)−ヘキサヒドロ−1H−ピリド[3,4−b][1,4]オキサジン−2(3H)−オン
5−(((4aR,8aR)−rel−ヘキサヒドロ−1H−ピリド[3,4−b][1,4]オキサジン−6(7H)−イル)メチル)−N−(3−メトキシフェニル)ピロロ[1,2−f][1,2,4]トリアジン−4−アミン
N−(4−フルオロ-3−メトキシフェニル)−5−(((4aR,8aR)−rel−ヘキサヒドロ−1H−ピリド[3,4−b][1,4]オキサジン−6(7H)−イル)メチル)ピロロ[1,2−f][1,2,4]トリアジン−4−アミン
(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−N−(メチルスルホニル)ピペリジン−3−カルボキサミド
(3R,4R)−4−アミノ−1−({4−[(3−エチニルフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−N−メチルピペリジン−3−カルボキサミド
(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−N−メチルピペリジン−3−カルボキサミド
(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−カルボン酸
(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−カルボキサミド
(3S,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−N−(メチルスルホニル)ピペリジン−3−カルボキサミド
(3R,4S)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−N−(メチルスルホニル)ピペリジン−3−カルボキサミド
(3S,4R)−4−アミノ−1−({4−[(3−エチニルフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−N−メチルピペリジン−3−カルボキサミド
(3S,4S)−4−アミノ−1−((4−(3−メトキシフェニルアミノ)ピロロ[1,2−f][1,2,4]トリアジン−5−イル)メチル)−N−メチルピペリジン−3−カルボキサミド
を得た。
((3R,4R)−1−((4−(3−メトキシフェニルアミノ)ピロロ[1,2−f][1,2,4]−トリアジン−5−イル)メチル)−4−((R)−1−フェニルエチルアミノ)ピペリジン−3−イル)メタノール
rac−(3R,4R)−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3,4−ジアミン
rac−N−[(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イル]ウレア
rac−N−[(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イル]メタンスルホンアミド
N−[(3S,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イル]メタンスルホンアミド
N−[(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イル]メタンスルホンアミド
(エナンチオマーA)
N−[(3S,4S)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イル]メタンスルホンアミド
(エナンチオマーB)
Claims (5)
- 式:
Xは、直結、−NR3−、または−O−であり;
R2は、フェニル、置換フェニル、ピリジニル、置換ピリジニル、ピリミジニル、置換ピリミジニル、オキサゾール、置換オキサゾール、チアゾール、置換チアゾール、ピラジニル、置換ピラジニル、ピリダジニル、または置換ピリダジニルであり;ここで、用語「置換フェニル」における置換基とは、アルキル、アルケニル、アルキニル、アリール、アラルキル、ハロ、トリフルオロメトキシ、トリフルオロメチル、ヒドロキシ、アルコキシ、アルカノイル、アルカノイルオキシ、アリールオキシ、アラルキルオキシ、アミノ、アルキルアミノ、アリールアミノ、アラルキルアミノ、ジアルキルアミノ、アルカノイルアミノ、チオール、アルキルチオ、ウレイド、ニトロ、シアノ、カルボキシ、カルボキシアルキル、カルバミル、アルコキシカルボニル、アルキルチオノ、アリールチオノ、アリールスルホニルアミン、スルホン酸、アルキルスルホニル、スルホンアミド、またはアリールオキシから選択される1〜4個の基であって、該基は、ヒドロキシ、ハロ、アルキル、アルコキシ、アルケニル、アルキニル、アリール、またはアラルキルでさらに置換されてもよく;ここで、用語「置換ピリジニル」、「置換ピリミジニル」、「置換オキサゾール」、「置換チアゾール」、「置換ピラジニル」、および「置換ピリダジニル」における置換基とは、アルキルまたはアラルキルから選択される1個以上の基であり;
R3、R4およびR5は独立して、水素、アルキル、または置換アルキルから選ばれ;ここで、用語「置換アルキル」における置換基とは、ハロ、ヒドロキシ、アルコキシ、オキソ、アルカノイル、アリールオキシ、アルカノイルオキシ、アミノ、アルキルアミノ、アリールアミノ、アラルキルアミノ、ジ置換アミン(ここで、該2個のアミノ置換基は、アルキル、アリール、またはアラルキルから選ばれる)、アルカノイルアミノ、アロイルアミノ、アルアルカノイルアミノ、チオール、アルキルチオ、アリールチオ、アラルキルチオ、アルキルチオノ、アリールチオノ、アラルキルチオノ、アルキルスルホニル、アリールスルホニル、アラルキニルスルホニル、スルホンアミド、ニトロ、シアノ、カルボキシ、カルバミル、CONHアルキル、CONHアリール、CONHアラルキル、CON(アルキル)2、CON(アリール)2、CON(アラルキル)2、アルコキシカルボニル、アリール、グアジニノ、およびヘテロサイクリルから選択される1〜4個の基であって、該基は、アルキル、アルコキシ、アリール、またはアラルキルでさらに置換されてもよく;
R6、R6aおよびR6bは独立して、1つ以上の水素、ハロゲン、アルキル、アルコキシ、アリールオキシ、−CN、−NH2、−OH、−COOH、−CH2OR5、−CONHSO2R5、−CONR4R5、−NHアルキル、−NHCOアルキル、−NR4SO2アルキル、−NR4SO2NR4R5、−OCONR4R5、−CF3、および−OCF3からなる群から選ばれ、ここで、これらの2つは同じ環内炭素原子と結合し得て;そして、
nは、0、1、2、または3である]
で示される化合物、またはその医薬的に許容し得る塩もしくは立体異性体。 - R6、R6aおよびR6bが独立して、1つ以上の水素、−NH2、−OH、アルコキシ、−CONR4R5、−NR4SO2アルキル、−NR4SO2NR4R5、−OCONR4R5、−NHアルキル、および−NHCOアルキルからなる群から選ばれ;
Xが、−NH−であり;そして、
nが、1または2である、
請求項1記載の化合物。 - 5−[(4−アミノ−1−ピペリジニル)メチル]−N−(3−クロロ−4−フルオロフェニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−2−ナフタレニルピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−フェニルピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(3−メトキシフェニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(3−エチニルフェニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノピペリジン−1−イル)メチル]−N−(4−フルオロ−3−メトキシフェニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
(3R,4R)−4−アミノ−1−[[4−[(3−クロロ−4−フルオロフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]ピペリジン−3−オール;
(3S,4S)−4−アミノ−1−[[4−[(3−クロロ−4−フルオロフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−[[4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]ピペリジン−3−オール;
(3S,4S)−4−アミノ−1−[[4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]ピペリジン-3−オール;
(3R,4R)−4−アミノ−1−[[4−[(3−メトキシ−4−フルオロフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル]メチル]ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−({4−[(3−エチニルフェニル)−アミノ]ピロロ[2,1−f][1,2,4]−トリアジン−5−イル}−メチル)ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−({4−[(3−エトキシフェニル)−アミノ]−ピロロ[2,1−f][1,2,4]トリアジン−5−イル}−メチル)ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−{[4−(2−ナフチルアミノ)−ピロロ[2,1−f][1,2,4]−トリアジン−5−イル]メチル}ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−({4−[(3−メトキシ−4−メチル−フェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}−メチル)ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−({4−[(3−ブロモフェニル)アミノ]ピロロ[2,1−f][1,2,4]−トリアジン−5−イル}メチル)−ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−({4−[(3−フルオロ−5−メトキシ−フェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}−メチル)ピペリジン−3−オール;
(3S,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−オール;
(3R,4S)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−オール;
(3S,4R)−4−アミノ−1−({4−[(3−クロロフェニル)アミノ]−ピロロ[2,1−f][1,2,4]−トリアジン−5−イル}メチル)−ピペリジン−3−オール;
(3S,4R)−4−アミノ−1−({4−[(3−クロロ−4−フルオロ−フェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}−メチル)ピペリジン−3−オール;
(3S,4R)−4−アミノ−1−({4−[(3−エチニルフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−オール;
(3R,4S)−4−アミノ−1−({4−[(3−エチニルフェニル)−アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−オール;
(3R,4S)−4−アミノ−1−({4−[(3−クロロフェニル)アミノ]ピロロ[2,1−f][1,2,4]−トリアジン−5−イル}メチル)ピペリジン−3−オール;
(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イルカルバメート;
(3R,4R)−4−アミノ−1−({4−[(3−エチニルフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イルカルバメート;
(3R,4R)−4−アミノ−1−({4−[(3−クロロ−4−フルオロ−フェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イルカルバメート;
(3S,4R)−4−アミノ−1−({4−[(3−クロロ−4−フルオロ−フェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イルカルバメート;
(3S,4R)−4−アミノ−1−({4−[(3−エチニルフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イルカルバメート;
(3S,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−3−メチルピペリジン−3−オール;
(3R/S,5R/S)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3,5−ジオール;
(3S,5S)−4−アミノ−1−({4−[(4−フルオロ−3−メトキシ−フェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3,5−ジオール;
(3R,5R)−4−アミノ−1−({4−[(3−エチニルフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3,5−ジオール;
5−{[(3R,4R)−4−アミノ−3−メトキシピペリジン−1−イル]メチル}−N−(3−メトキシフェニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−(((4aR,8aR)−rel−ヘキサヒドロ−1H−ピリド[3,4−b][1,4]オキサジン−6(7H)−イル)メチル)−N−(3−メトキシフェニル)ピロロ[1,2−f][1,2,4]トリアジン−4−アミン;
(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−N−(メチルスルホニル)ピペリジン−3−カルボキサミド;
(3R,4R)−4−アミノ−1−({4−[(3−エチニルフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−N−メチルピペリジン−3−カルボキサミド;
(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)−N−メチルピペリジン−3−カルボキサミド;
(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−カルボキサミド;
((3R,4R)−1−((4−(3−メトキシフェニルアミノ)ピロロ[1,2−f][1,2,4]−トリアジン−5−イル)メチル)−4−((R)−1−フェニルエチルアミノ)ピペリジン−3−イル)メタノール;
N−[(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イル]ウレア;
N−[(3R,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イル]メタンスルホンアミド;および、
N−[(3S,4R)−4−アミノ−1−({4−[(3−メトキシフェニル)アミノ]ピロロ[2,1−f][1,2,4]トリアジン−5−イル}メチル)ピペリジン−3−イル]メタンスルホンアミド
からなる群から選ばれる化合物、またはその医薬的に許容し得る塩。 - 5−[(4−アミノ−1−ピペリジニル)メチル]−N−(6-クロロ-3-ピリジニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(6−メトキシ−3−ピリジニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(5−ブロモ−2−ピリジニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(5−クロロ−2−ピリジニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(4−メトキシ−6−メチル−2−ピリミジニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(6−メトキシ−4−ピリミジニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(6−ブロモ−2−ピリジニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(6−クロロ−3−ピリダジニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(2−クロロ−4−ピリジニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン;および、
5−[(4−アミノ−1−ピペリジニル)メチル]−N−(6−フルオロ−5−メチル−3−ピリジニル)ピロロ[2,1−f][1,2,4]トリアジン−4−アミン
からなる群から選ばれる化合物、またはその医薬的に許容し得る塩。
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