JP5190062B2 - Ｉａｐ阻害剤としてのピロリジン誘導体 - Google Patents
Ｉａｐ阻害剤としてのピロリジン誘導体 Download PDFInfo
- Publication number
- JP5190062B2 JP5190062B2 JP2009532544A JP2009532544A JP5190062B2 JP 5190062 B2 JP5190062 B2 JP 5190062B2 JP 2009532544 A JP2009532544 A JP 2009532544A JP 2009532544 A JP2009532544 A JP 2009532544A JP 5190062 B2 JP5190062 B2 JP 5190062B2
- Authority
- JP
- Japan
- Prior art keywords
- pyrrolidin
- ethyl
- cyclohexyl
- pyridin
- oxo
- 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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- 239000003112 inhibitor Substances 0.000 title 1
- 150000003235 pyrrolidines Chemical class 0.000 title 1
- -1 methoxy Indolyl Chemical group 0.000 claims description 80
- 150000001875 compounds Chemical class 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- 125000001424 substituent group Chemical group 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 229940080818 propionamide Drugs 0.000 claims description 21
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000001041 indolyl group Chemical group 0.000 claims description 8
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 7
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 4
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical group N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- PDQRQJVPEFGVRK-UHFFFAOYSA-N 2,1,3-benzothiadiazole Chemical compound C1=CC=CC2=NSN=C21 PDQRQJVPEFGVRK-UHFFFAOYSA-N 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- FUQJVCQDMIKMLZ-UHFFFAOYSA-N n-[1-[2-[2-(benzimidazol-1-yl)pyridin-4-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]-2-(methylamino)propanamide Chemical compound CNC(C)C(=O)NC(C(C)C)C(=O)N1CCCC1C1=CC=NC(N2C3=CC=CC=C3N=C2)=C1 FUQJVCQDMIKMLZ-UHFFFAOYSA-N 0.000 claims 1
- XGAQLJAHEOQJEK-UHFFFAOYSA-N n-[1-cyclohexyl-2-[2-(5-indazol-1-ylpyridin-3-yl)pyrrolidin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1CCC(C=2C=C(C=NC=2)N2C3=CC=CC=C3C=N2)N1C(=O)C(NC(=O)C(C)NC)C1CCCCC1 XGAQLJAHEOQJEK-UHFFFAOYSA-N 0.000 claims 1
- NPQDDJGXKMNGIB-UHFFFAOYSA-N n-[1-cyclohexyl-2-[2-(5-naphthalen-2-ylpyridin-3-yl)pyrrolidin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1CCC(C=2C=C(C=NC=2)C=2C=C3C=CC=CC3=CC=2)N1C(=O)C(NC(=O)C(C)NC)C1CCCCC1 NPQDDJGXKMNGIB-UHFFFAOYSA-N 0.000 claims 1
- CMBQZNRFGUADIY-UHFFFAOYSA-N n-[1-cyclohexyl-2-[2-[2-(2,3-dihydroindol-1-yl)pyridin-4-yl]pyrrolidin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1CCC(C=2C=C(N=CC=2)N2C3=CC=CC=C3CC2)N1C(=O)C(NC(=O)C(C)NC)C1CCCCC1 CMBQZNRFGUADIY-UHFFFAOYSA-N 0.000 claims 1
- GAPYLLQYZGTWHG-UHFFFAOYSA-N n-[1-cyclohexyl-2-[2-[2-(5-fluoroindol-1-yl)pyridin-4-yl]pyrrolidin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1CCC(C=2C=C(N=CC=2)N2C3=CC=C(F)C=C3C=C2)N1C(=O)C(NC(=O)C(C)NC)C1CCCCC1 GAPYLLQYZGTWHG-UHFFFAOYSA-N 0.000 claims 1
- HZJHWCJCYNSURC-UHFFFAOYSA-N n-[1-cyclohexyl-2-[2-[5-(3,5-dimethylphenyl)pyridin-3-yl]pyrrolidin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1CCC(C=2C=C(C=NC=2)C=2C=C(C)C=C(C)C=2)N1C(=O)C(NC(=O)C(C)NC)C1CCCCC1 HZJHWCJCYNSURC-UHFFFAOYSA-N 0.000 claims 1
- ACQFZFNGNCKJHL-UHFFFAOYSA-N n-[2-[2-[5-(1,3-benzodioxol-5-yl)pyridin-3-yl]pyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1CCC(C=2C=C(C=NC=2)C=2C=C3OCOC3=CC=2)N1C(=O)C(NC(=O)C(C)NC)C1CCCCC1 ACQFZFNGNCKJHL-UHFFFAOYSA-N 0.000 claims 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 67
- 125000000217 alkyl group Chemical group 0.000 description 57
- 239000000243 solution Substances 0.000 description 44
- 125000003118 aryl group Chemical group 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
- 235000019439 ethyl acetate Nutrition 0.000 description 33
- 238000003756 stirring Methods 0.000 description 32
- 125000000753 cycloalkyl group Chemical group 0.000 description 29
- 239000011541 reaction mixture Substances 0.000 description 29
- 239000000460 chlorine Substances 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 25
- 239000012043 crude product Substances 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- 229910052799 carbon Inorganic materials 0.000 description 17
- 239000011734 sodium Substances 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- 238000000746 purification Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- MXFMJGFYNDWNGX-UHFFFAOYSA-N 1-(5-bromopyridin-3-yl)-4-hydroxybutan-1-one Chemical compound OCCCC(=O)C1=CN=CC(Br)=C1 MXFMJGFYNDWNGX-UHFFFAOYSA-N 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- 229910052717 sulfur Inorganic materials 0.000 description 13
- PHOAACHMLQQNDX-ACJLOTCBSA-N 3-bromo-5-[(2s)-1-[(1r)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-yl]pyridine Chemical compound C1=CC(OC)=CC=C1[C@@H](C)N1[C@H](C=2C=C(Br)C=NC=2)CCC1 PHOAACHMLQQNDX-ACJLOTCBSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 125000003342 alkenyl group Chemical group 0.000 description 11
- 125000000304 alkynyl group Chemical group 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 229910052760 oxygen Inorganic materials 0.000 description 11
- CMBQZNRFGUADIY-OICBGKIFSA-N (2s)-n-[(1s)-1-cyclohexyl-2-[(2s)-2-[2-(2,3-dihydroindol-1-yl)pyridin-4-yl]pyrrolidin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2C=C(N=CC=2)N2C3=CC=CC=C3CC2)CCCCC1 CMBQZNRFGUADIY-OICBGKIFSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 102100033189 Diablo IAP-binding mitochondrial protein Human genes 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- QGRFJDVIGRRNRD-HSQYWUDLSA-N tert-butyl n-[(2s)-1-[[(1s)-2-[(2s)-2-(5-bromopyridin-3-yl)pyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl]amino]-1-oxopropan-2-yl]-n-methylcarbamate Chemical compound C1([C@H](NC(=O)[C@@H](N(C)C(=O)OC(C)(C)C)C)C(=O)N2[C@@H](CCC2)C=2C=C(Br)C=NC=2)CCCCC1 QGRFJDVIGRRNRD-HSQYWUDLSA-N 0.000 description 9
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 9
- VOIKGSQXCABASX-UHFFFAOYSA-N 1-(2-bromopyridin-4-yl)-4,4-dimethoxybutan-1-one Chemical compound COC(OC)CCC(=O)C1=CC=NC(Br)=C1 VOIKGSQXCABASX-UHFFFAOYSA-N 0.000 description 8
- 101710101225 Diablo IAP-binding mitochondrial protein Proteins 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- GAPYLLQYZGTWHG-SZJUTTIESA-N (2s)-n-[(1s)-1-cyclohexyl-2-[(2s)-2-[2-(5-fluoroindol-1-yl)pyridin-4-yl]pyrrolidin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2C=C(N=CC=2)N2C3=CC=C(F)C=C3C=C2)CCCCC1 GAPYLLQYZGTWHG-SZJUTTIESA-N 0.000 description 7
- 125000004562 2,3-dihydroindol-1-yl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 7
- 125000001072 heteroaryl group Chemical group 0.000 description 7
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
- UKPQLGJCONUWCH-VFXRXZKFSA-N tert-butyl n-[(2s)-1-[[(1s)-2-[(2s)-2-[5-(1,3-benzodioxol-5-yl)pyridin-3-yl]pyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl]amino]-1-oxopropan-2-yl]-n-methylcarbamate Chemical compound C1([C@H](NC(=O)[C@@H](N(C)C(=O)OC(C)(C)C)C)C(=O)N2[C@@H](CCC2)C=2C=C(C=NC=2)C=2C=C3OCOC3=CC=2)CCCCC1 UKPQLGJCONUWCH-VFXRXZKFSA-N 0.000 description 7
- OPEHGMFUUJOWFW-DOYMOWJKSA-N (2s)-n-[(1s)-1-cyclohexyl-2-[(2s)-2-[5-(1h-indol-3-yl)pyridin-3-yl]pyrrolidin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2C=C(C=NC=2)C=2C3=CC=CC=C3NC=2)CCCCC1 OPEHGMFUUJOWFW-DOYMOWJKSA-N 0.000 description 6
- ACQFZFNGNCKJHL-WMDMVVLCSA-N (2s)-n-[(1s)-2-[(2s)-2-[5-(1,3-benzodioxol-5-yl)pyridin-3-yl]pyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2C=C(C=NC=2)C=2C=C3OCOC3=CC=2)CCCCC1 ACQFZFNGNCKJHL-WMDMVVLCSA-N 0.000 description 6
- SCTLVYBPRSXTHY-INIZCTEOSA-N 3-[5-[(2s)-pyrrolidin-2-yl]pyridin-3-yl]-1h-indole Chemical compound C1CCN[C@@H]1C1=CN=CC(C=2C3=CC=CC=C3NC=2)=C1 SCTLVYBPRSXTHY-INIZCTEOSA-N 0.000 description 6
- ITBASFJZHKONHG-UHFFFAOYSA-N 4-(5-bromopyridin-3-yl)-4-oxobutanal Chemical compound BrC1=CN=CC(C(=O)CCC=O)=C1 ITBASFJZHKONHG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 6
- GEJTZUDPYQYVQV-DYYNRBQXSA-N benzyl n-[(2s)-1-[[(1s)-1-cyclohexyl-2-[(2s)-2-[2-(5-fluoroindol-1-yl)pyridin-4-yl]pyrrolidin-1-yl]-2-oxoethyl]amino]-1-oxopropan-2-yl]-n-methylcarbamate Chemical compound CN([C@@H](C)C(=O)N[C@@H](C1CCCCC1)C(=O)N1[C@@H](CCC1)C=1C=C(N=CC=1)N1C2=CC=C(F)C=C2C=C1)C(=O)OCC1=CC=CC=C1 GEJTZUDPYQYVQV-DYYNRBQXSA-N 0.000 description 6
- 125000001589 carboacyl group Chemical group 0.000 description 6
- 239000013058 crude material Substances 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 102000050257 X-Linked Inhibitor of Apoptosis Human genes 0.000 description 5
- 108700031544 X-Linked Inhibitor of Apoptosis Proteins 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- NVPATEJVELYCCI-AXRGIPJOSA-N tert-butyl n-[(2s)-1-[[(1s)-1-cyclohexyl-2-[(2s)-2-[5-(1h-indol-3-yl)pyridin-3-yl]pyrrolidin-1-yl]-2-oxoethyl]amino]-1-oxopropan-2-yl]-n-methylcarbamate Chemical compound C1([C@H](NC(=O)[C@@H](N(C)C(=O)OC(C)(C)C)C)C(=O)N2[C@@H](CCC2)C=2C=C(C=NC=2)C=2C3=CC=CC=C3NC=2)CCCCC1 NVPATEJVELYCCI-AXRGIPJOSA-N 0.000 description 5
- MQJAFAOTJXJINO-ZDUSSCGKSA-N 1-[4-[(2s)-pyrrolidin-2-yl]pyridin-2-yl]benzimidazole Chemical compound C1CCN[C@@H]1C1=CC=NC(N2C3=CC=CC=C3N=C2)=C1 MQJAFAOTJXJINO-ZDUSSCGKSA-N 0.000 description 4
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 4
- 125000000335 thiazolyl group Chemical group 0.000 description 4
- QSUXZIPXYDQFCX-JTQLQIEISA-N (2s)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)C1CCCCC1 QSUXZIPXYDQFCX-JTQLQIEISA-N 0.000 description 3
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 3
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 3
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 3
- VQIHFIHZAPEOHA-DYVFJYSZSA-N 2-bromo-4-[(2s)-1-[(1r)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-yl]pyridine Chemical compound C1=CC(OC)=CC=C1[C@@H](C)N1[C@H](C=2C=C(Br)N=CC=2)CCC1 VQIHFIHZAPEOHA-DYVFJYSZSA-N 0.000 description 3
- OOGALSDKTFQSKW-UHFFFAOYSA-N 2-bromo-n-methoxy-n-methylpyridine-4-carboxamide Chemical compound CON(C)C(=O)C1=CC=NC(Br)=C1 OOGALSDKTFQSKW-UHFFFAOYSA-N 0.000 description 3
- SSCZEPSQBZQLPI-HNNXBMFYSA-N 3-[4-[(2s)-pyrrolidin-2-yl]pyridin-2-yl]-1h-indole Chemical compound C1CCN[C@@H]1C1=CC=NC(C=2C3=CC=CC=C3NC=2)=C1 SSCZEPSQBZQLPI-HNNXBMFYSA-N 0.000 description 3
- 0 BC(C=C(C**C)[C@](CCC1)N1C(C)c1ccc(C)cc1)=CC Chemical compound BC(C=C(C**C)[C@](CCC1)N1C(C)c1ccc(C)cc1)=CC 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Veterinary Medicine (AREA)
- Genetics & Genomics (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Applications Claiming Priority (3)
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| US82923406P | 2006-10-12 | 2006-10-12 | |
| US60/829,234 | 2006-10-12 | ||
| PCT/US2007/080875 WO2008045905A1 (en) | 2006-10-12 | 2007-10-10 | Pyrrolydine derivatives as iap inhibitors |
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| JP2010506847A JP2010506847A (ja) | 2010-03-04 |
| JP2010506847A5 JP2010506847A5 (enExample) | 2010-12-16 |
| JP5190062B2 true JP5190062B2 (ja) | 2013-04-24 |
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| JP (1) | JP5190062B2 (enExample) |
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| CN (1) | CN101595121A (enExample) |
| AU (1) | AU2007307763A1 (enExample) |
| BR (1) | BRPI0719221A2 (enExample) |
| CA (1) | CA2666112A1 (enExample) |
| MX (1) | MX2009003834A (enExample) |
| RU (1) | RU2009117701A (enExample) |
| WO (1) | WO2008045905A1 (enExample) |
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| MX2007007195A (es) | 2004-12-20 | 2007-10-08 | Genentech Inc | Inhibidores de pirrolidina de iap. |
| WO2006122408A1 (en) | 2005-05-18 | 2006-11-23 | Aegera Therapeutics Inc. | Bir domain binding compounds |
| AU2006308453B9 (en) | 2005-10-25 | 2011-12-01 | Pharmascience Inc. | IAP BIR domain binding compounds |
| WO2007106192A2 (en) | 2005-12-19 | 2007-09-20 | Genentech, Inc. | Inhibitors of iap |
| TWI504597B (zh) | 2006-03-16 | 2015-10-21 | Pharmascience Inc | 結合於細胞凋亡抑制蛋白（ｉａｐ）之桿狀病毒ｉａｐ重複序列（ｂｉｒ）區域之化合物 |
| US8110681B2 (en) | 2006-03-17 | 2012-02-07 | The United States Of America As Represented By The Secretary, Department Of Health And Human Services | Compounds for the treatment of spinal muscular atrophy and other uses |
| BRPI0711591A2 (pt) | 2006-05-16 | 2011-11-16 | Aegera Therapeutics, Inc. | composto de ligação de domìnio bir da iap |
| PE20110217A1 (es) * | 2006-08-02 | 2011-04-01 | Novartis Ag | DERIVADOS DE 2-OXO-ETIL-AMINO-PROPIONAMIDA-PIRROLIDIN-2-IL-SUSTITUIDOS COMO INHIBIDORES DEL ENLACE DE LA PROTEINA Smac AL INHIBIDOR DE LA PROTEINA DE APOPTOSIS |
| CN101605786A (zh) * | 2006-12-19 | 2009-12-16 | 健泰科生物技术公司 | 细胞凋亡抑制剂的咪唑并吡啶抑制剂 |
| NZ598890A (en) * | 2007-04-30 | 2013-10-25 | Genentech Inc | Inhibitors of iap |
| EP2296650B1 (en) | 2008-05-16 | 2020-05-06 | Novartis AG | Immunomodulation by iap inhibitors |
| US8835393B2 (en) | 2008-08-02 | 2014-09-16 | Genentech, Inc. | Inhibitors of IAP |
| BRPI0916576A2 (pt) | 2008-08-04 | 2017-06-27 | Chdi Inc | pelo menos uma entidade química, composição farmacêutica, e, método para tratar uma condição ou distúrbio. |
| JP2012500272A (ja) * | 2008-08-16 | 2012-01-05 | ジェネンテック， インコーポレイテッド | Ｉａｐのアザインドールインヒビター |
| US9643922B2 (en) | 2008-08-18 | 2017-05-09 | Yale University | MIF modulators |
| MX2011001872A (es) * | 2008-08-18 | 2011-05-23 | Univ Yale | Moduladores de mif. |
| US9540322B2 (en) | 2008-08-18 | 2017-01-10 | Yale University | MIF modulators |
| US20100317593A1 (en) * | 2009-06-12 | 2010-12-16 | Astrazeneca Ab | 2,3-dihydro-1h-indene compounds |
| UY32826A (es) | 2009-08-04 | 2011-02-28 | Takeda Pharmaceutical | Compuestos heterocíclicos |
| MY159958A (en) | 2009-12-18 | 2017-02-15 | Idenix Pharmaceuticals Inc | 5,5-fused arylene or heteroarylene hepatitis c virus inhibitors |
| NZ602368A (en) | 2010-02-12 | 2014-10-31 | Pharmascience Inc | Iap bir domain binding compounds |
| US8835458B2 (en) * | 2010-08-31 | 2014-09-16 | Hanmi Science Co., Ltd | Quinoline or quinazoline derivatives with apoptosis inducing activity on cells |
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| TWI773657B (zh) | 2015-12-18 | 2022-08-11 | 美商亞德利克斯公司 | 作爲非全身ｔｇｒ５促效劑之經取代之4-苯基吡啶化合物 |
| US12084472B2 (en) | 2015-12-18 | 2024-09-10 | Ardelyx, Inc. | Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists |
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| WO2020027225A1 (ja) | 2018-07-31 | 2020-02-06 | ファイメクス株式会社 | 複素環化合物 |
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| WO2020228642A1 (zh) * | 2019-05-10 | 2020-11-19 | 正大天晴药业集团股份有限公司 | 一种用作iap抑制剂的smac模拟物的结晶及其制备方法 |
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| CN112521372B (zh) * | 2019-09-18 | 2022-07-08 | 南京华威医药科技集团有限公司 | 一种细胞凋亡蛋白抑制剂及其制备方法和用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ516918A (en) | 2000-05-23 | 2004-06-25 | Vertex Pharma | Caspase inhibitors and uses thereof |
| WO2004007529A2 (en) * | 2002-07-15 | 2004-01-22 | The Trustees Of Princeton University | Iap binding compounds |
| CA2491041A1 (en) | 2002-07-02 | 2004-01-15 | Novartis Ag | Peptide inhibitors of smac protein binding to inhibitor of apoptosis proteins (iap) |
| PL2253614T3 (pl) | 2004-04-07 | 2013-03-29 | Novartis Ag | Inhibitory IAP |
| KR100926203B1 (ko) * | 2004-07-02 | 2009-11-09 | 제넨테크, 인크. | Ｉａｐ의 억제제 |
| MX2007007195A (es) * | 2004-12-20 | 2007-10-08 | Genentech Inc | Inhibidores de pirrolidina de iap. |
| WO2007106192A2 (en) * | 2005-12-19 | 2007-09-20 | Genentech, Inc. | Inhibitors of iap |
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2007
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- 2007-10-10 RU RU2009117701/04A patent/RU2009117701A/ru not_active Application Discontinuation
- 2007-10-10 WO PCT/US2007/080875 patent/WO2008045905A1/en not_active Ceased
- 2007-10-10 BR BRPI0719221-5A patent/BRPI0719221A2/pt not_active Application Discontinuation
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- 2007-10-10 CA CA002666112A patent/CA2666112A1/en not_active Abandoned
- 2007-10-10 KR KR1020097009617A patent/KR20090065548A/ko not_active Withdrawn
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| US20110015232A1 (en) | 2011-01-20 |
| EP2102229A1 (en) | 2009-09-23 |
| RU2009117701A (ru) | 2010-11-20 |
| US8044209B2 (en) | 2011-10-25 |
| CN101595121A (zh) | 2009-12-02 |
| BRPI0719221A2 (pt) | 2014-03-18 |
| CA2666112A1 (en) | 2008-04-17 |
| JP2010506847A (ja) | 2010-03-04 |
| AU2007307763A1 (en) | 2008-04-17 |
| WO2008045905A1 (en) | 2008-04-17 |
| MX2009003834A (es) | 2009-04-22 |
| EP2102229B1 (en) | 2014-03-26 |
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