JP5583698B2 - プロテインキナーゼａｂｌおよびｓｒｃの阻害剤としてのアザインドール誘導体 - Google Patents
プロテインキナーゼａｂｌおよびｓｒｃの阻害剤としてのアザインドール誘導体 Download PDFInfo
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- JP5583698B2 JP5583698B2 JP2011549698A JP2011549698A JP5583698B2 JP 5583698 B2 JP5583698 B2 JP 5583698B2 JP 2011549698 A JP2011549698 A JP 2011549698A JP 2011549698 A JP2011549698 A JP 2011549698A JP 5583698 B2 JP5583698 B2 JP 5583698B2
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- cancer
- pyrrolo
- compound
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- 239000003112 inhibitor Substances 0.000 title claims description 47
- 125000005334 azaindolyl group Chemical class N1N=C(C2=CC=CC=C12)* 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 211
- -1 pyrrolo [2,3-b] pyridyl group Chemical group 0.000 claims description 71
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- 238000002360 preparation method Methods 0.000 claims description 58
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 48
- 125000001072 heteroaryl group Chemical group 0.000 claims description 43
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 33
- 125000005843 halogen group Chemical group 0.000 claims description 32
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 30
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 102000001253 Protein Kinase Human genes 0.000 claims description 23
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 108060006633 protein kinase Proteins 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 22
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 21
- KBOWEPWOSHLMGE-UHFFFAOYSA-N methyl 5-amino-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound NC1=CN=C2NC(C(=O)OC)=CC2=C1 KBOWEPWOSHLMGE-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 125000004076 pyridyl group Chemical group 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- 150000001408 amides Chemical class 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- WWCIKRATXUMSLS-UHFFFAOYSA-N methyl 5-nitro-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound [O-][N+](=O)C1=CN=C2NC(C(=O)OC)=CC2=C1 WWCIKRATXUMSLS-UHFFFAOYSA-N 0.000 claims description 14
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 238000000746 purification Methods 0.000 claims description 12
- 150000001263 acyl chlorides Chemical class 0.000 claims description 11
- 238000012512 characterization method Methods 0.000 claims description 11
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- 229910052763 palladium Inorganic materials 0.000 claims description 11
- 125000003107 substituted aryl group Chemical group 0.000 claims description 11
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 10
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
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- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 9
- 206010033128 Ovarian cancer Diseases 0.000 claims description 9
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 201000005202 lung cancer Diseases 0.000 claims description 9
- 208000020816 lung neoplasm Diseases 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 208000011580 syndromic disease Diseases 0.000 claims description 9
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 8
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 8
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 8
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 8
- 230000001154 acute effect Effects 0.000 claims description 8
- 201000004101 esophageal cancer Diseases 0.000 claims description 8
- 206010017758 gastric cancer Diseases 0.000 claims description 8
- 201000007270 liver cancer Diseases 0.000 claims description 8
- 208000014018 liver neoplasm Diseases 0.000 claims description 8
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 8
- OEYPDGZCSFPTBF-UHFFFAOYSA-N methyl 5-[(2-bromobenzoyl)amino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC(=O)C1=CC=CC=C1Br OEYPDGZCSFPTBF-UHFFFAOYSA-N 0.000 claims description 8
- 230000002071 myeloproliferative effect Effects 0.000 claims description 8
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 8
- 201000011549 stomach cancer Diseases 0.000 claims description 8
- 230000003197 catalytic effect Effects 0.000 claims description 7
- 230000001684 chronic effect Effects 0.000 claims description 7
- 201000002528 pancreatic cancer Diseases 0.000 claims description 7
- 230000009467 reduction Effects 0.000 claims description 7
- 238000007127 saponification reaction Methods 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 6
- 125000005412 pyrazyl group Chemical class 0.000 claims description 6
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 6
- DFTQETXFGOIVPQ-UHFFFAOYSA-N 2-(ethyliminomethylideneamino)-n,n-dimethyl-1h-pyrrol-3-amine Chemical compound CCN=C=NC=1NC=CC=1N(C)C DFTQETXFGOIVPQ-UHFFFAOYSA-N 0.000 claims description 5
- ZWXCSTVTBKAEAD-UHFFFAOYSA-N 2-bromo-n-[2-(methoxymethyl)-1h-pyrrolo[2,3-b]pyridin-5-yl]benzamide Chemical compound C=1N=C2NC(COC)=CC2=CC=1NC(=O)C1=CC=CC=C1Br ZWXCSTVTBKAEAD-UHFFFAOYSA-N 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 239000012298 atmosphere Substances 0.000 claims description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- 230000003831 deregulation Effects 0.000 claims description 5
- 238000005984 hydrogenation reaction Methods 0.000 claims description 5
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 125000000524 functional group Chemical group 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical group CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 150000003335 secondary amines Chemical class 0.000 claims description 4
- DHIHZLGSYHTLMS-UHFFFAOYSA-N 3-methoxy-1h-indazole Chemical compound C1=CC=C2C(OC)=NNC2=C1 DHIHZLGSYHTLMS-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 150000003140 primary amides Chemical class 0.000 claims description 3
- 150000003141 primary amines Chemical class 0.000 claims description 3
- DZJWVPHWQSPJDD-UHFFFAOYSA-N 2-bromo-n-[2-(1h-pyrrol-2-ylmethyl)-1h-pyrrolo[2,3-b]pyridin-5-yl]benzamide Chemical compound BrC1=CC=CC=C1C(=O)NC1=CN=C(NC(CC=2NC=CC=2)=C2)C2=C1 DZJWVPHWQSPJDD-UHFFFAOYSA-N 0.000 claims description 2
- OPMOBCCZILYPTP-UHFFFAOYSA-N 2-bromo-n-[2-[(4-hydroxyanilino)methyl]-1h-pyrrolo[2,3-b]pyridin-5-yl]benzamide Chemical compound C1=CC(O)=CC=C1NCC1=CC2=CC(NC(=O)C=3C(=CC=CC=3)Br)=CN=C2N1 OPMOBCCZILYPTP-UHFFFAOYSA-N 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- FCDMJPPRJSFFRX-UHFFFAOYSA-N methyl 5-[(2-fluoro-6-methoxybenzoyl)amino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC(=O)C1=C(F)C=CC=C1OC FCDMJPPRJSFFRX-UHFFFAOYSA-N 0.000 claims description 2
- 125000004950 trifluoroalkyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- 150000004703 alkoxides Chemical class 0.000 claims 3
- TUFZUIHQACRNON-UHFFFAOYSA-N CN(C)CCCN1C=CC2=CC(=CN=C21)NC(=O)C3=CC=CC=C3Br Chemical compound CN(C)CCCN1C=CC2=CC(=CN=C21)NC(=O)C3=CC=CC=C3Br TUFZUIHQACRNON-UHFFFAOYSA-N 0.000 claims 1
- 125000005549 heteroarylene group Chemical class 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 229940127557 pharmaceutical product Drugs 0.000 claims 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- 108091000080 Phosphotransferase Proteins 0.000 description 75
- 102000020233 phosphotransferase Human genes 0.000 description 75
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 59
- 230000002829 reductive effect Effects 0.000 description 59
- 238000000034 method Methods 0.000 description 48
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 42
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- 239000007787 solid Substances 0.000 description 39
- 230000000694 effects Effects 0.000 description 38
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 36
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
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- 235000011152 sodium sulphate Nutrition 0.000 description 25
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 23
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- 239000008346 aqueous phase Substances 0.000 description 22
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 18
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- JNPZKGOLYSCSEL-UHFFFAOYSA-N methyl 5-amino-2-methylbenzoate Chemical compound COC(=O)C1=CC(N)=CC=C1C JNPZKGOLYSCSEL-UHFFFAOYSA-N 0.000 description 11
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- AHDMPEPNBHGIGD-UHFFFAOYSA-N 2-bromo-n-[2-(hydroxymethyl)-1h-pyrrolo[2,3-b]pyridin-5-yl]benzamide Chemical compound C=1N=C2NC(CO)=CC2=CC=1NC(=O)C1=CC=CC=C1Br AHDMPEPNBHGIGD-UHFFFAOYSA-N 0.000 description 7
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 7
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
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- YDTDKKULPWTHRV-UHFFFAOYSA-N 1H-indazol-3-amine Chemical compound C1=CC=C2C(N)=NNC2=C1 YDTDKKULPWTHRV-UHFFFAOYSA-N 0.000 description 4
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- 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
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| FR0900631A FR2941948B1 (fr) | 2009-02-12 | 2009-02-12 | Derives d'azaindoles en tant qu'inhibiteur des proteines kinases abl et src |
| PCT/IB2010/000593 WO2010092489A1 (en) | 2009-02-12 | 2010-02-12 | Derivatives of azaindoles as inhibitors of protein kinases abl and src |
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| FR3000493A1 (fr) * | 2012-12-28 | 2014-07-04 | Oribase Pharma | Nouveaux inhibiteurs de proteines kinases |
| FR3000494B1 (fr) * | 2012-12-28 | 2015-08-21 | Oribase Pharma | Nouveaux derives d'azaindoles en tant qu'inhibiteurs de proteines kinases |
| FR3000492B1 (fr) * | 2012-12-28 | 2015-09-11 | Oribase Pharma | Nouveaux derives azaindole en tant qu'inhibiteurs multikinases |
| US10722484B2 (en) | 2016-03-09 | 2020-07-28 | K-Gen, Inc. | Methods of cancer treatment |
| MA49014A (fr) * | 2017-03-21 | 2020-02-05 | Arbutus Biopharma Corp | Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant |
| AU2021263383A1 (en) | 2020-04-29 | 2022-11-24 | Plexxikon Inc. | Synthesis of heterocyclic compounds |
| CN111943947B (zh) * | 2020-07-24 | 2021-04-30 | 重庆文理学院 | 1H-吡咯[2,3-b]吡啶衍生物及其合成方法与应用 |
| CA3196620A1 (en) | 2020-10-05 | 2022-04-14 | Enliven Therapeutics, Inc. | 5- and 6-azaindole compounds for inhibition of bcr-abl tyrosine kinases |
| WO2022076973A1 (en) * | 2020-10-05 | 2022-04-14 | Enliven Therapeutics, Inc. | 7-azaindole compounds for inhibition of bcr-abl tyrosine kinases |
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| GB0330043D0 (en) * | 2003-12-24 | 2004-01-28 | Pharmacia Italia Spa | Pyrrolo [2,3-b] pyridine derivatives active as kinase inhibitors process for their preparation and pharmaceutical compositions comprising them |
| GB0330042D0 (en) | 2003-12-24 | 2004-01-28 | Pharmacia Italia Spa | Pyrrolo [2,3-b] pyridine derivatives active as kinase inhibitors process for their preparation and pharmaceutical compositions them |
| TW200616632A (en) * | 2004-06-17 | 2006-06-01 | Plexxikon Inc | Compounds modulating c-kit activity and uses therefor |
| US7361764B2 (en) | 2004-07-27 | 2008-04-22 | Sgx Pharmaceuticals, Inc. | Pyrrolo-pyridine kinase modulators |
| NZ553267A (en) | 2004-07-27 | 2010-09-30 | Sgx Pharmaceuticals Inc | Pyrrolo-pyridine kinase modulators |
| US7709645B2 (en) | 2004-07-27 | 2010-05-04 | Sgx Pharmaceuticals, Inc. | Pyrrolo-pyridine kinase modulators |
| WO2006104971A1 (en) * | 2005-03-28 | 2006-10-05 | Bristol-Myers Squibb Company | Atp competitive kinase inhibitors |
| BRPI0716477A2 (pt) | 2006-09-06 | 2014-03-18 | Hoffmann La Roche | Derivados heteroarila como inibidores de quinase protéica |
| JP5244118B2 (ja) * | 2006-11-10 | 2013-07-24 | ブリストル−マイヤーズ スクイブ カンパニー | 新規キナーゼ阻害剤 |
| WO2008144253A1 (en) * | 2007-05-14 | 2008-11-27 | Irm Llc | Protein kinase inhibitors and methods for using thereof |
| WO2009111278A2 (en) * | 2008-02-29 | 2009-09-11 | Array Biopharma Inc. | Raf inhibitor compounds and methods of use thereof |
| HUE035798T2 (en) * | 2008-11-03 | 2018-05-28 | Syntarga Bv | CC-1065 analogues and conjugates |
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- 2010-02-12 PT PT107104390T patent/PT2396325E/pt unknown
- 2010-02-12 JP JP2011549698A patent/JP5583698B2/ja not_active Expired - Fee Related
- 2010-02-12 US US13/148,988 patent/US8580815B2/en not_active Expired - Fee Related
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| US8580815B2 (en) | 2013-11-12 |
| ES2540962T3 (es) | 2015-07-15 |
| DK2396325T3 (en) | 2015-06-29 |
| EP2396325B1 (en) | 2015-04-01 |
| SI2396325T1 (sl) | 2015-08-31 |
| FR2941948A1 (fr) | 2010-08-13 |
| US20110312959A1 (en) | 2011-12-22 |
| PT2396325E (pt) | 2015-08-21 |
| AU2010212560B2 (en) | 2016-01-21 |
| FR2941948B1 (fr) | 2013-04-05 |
| HRP20150697T8 (xx) | 2015-11-06 |
| WO2010092489A1 (en) | 2010-08-19 |
| HRP20150697T1 (hr) | 2015-08-14 |
| AU2010212560A1 (en) | 2011-08-11 |
| JP2012517465A (ja) | 2012-08-02 |
| SMT201500175B (it) | 2015-09-07 |
| EP2396325A1 (en) | 2011-12-21 |
| CA2751478A1 (en) | 2010-08-19 |
| PL2396325T3 (pl) | 2015-10-30 |
| HUE024989T2 (en) | 2016-01-28 |
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