CA2751478A1 - Derivatives of azaindoles as inhibitors of protein kinases abl and src - Google Patents
Derivatives of azaindoles as inhibitors of protein kinases abl and src Download PDFInfo
- Publication number
- CA2751478A1 CA2751478A1 CA2751478A CA2751478A CA2751478A1 CA 2751478 A1 CA2751478 A1 CA 2751478A1 CA 2751478 A CA2751478 A CA 2751478A CA 2751478 A CA2751478 A CA 2751478A CA 2751478 A1 CA2751478 A1 CA 2751478A1
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- CA
- Canada
- Prior art keywords
- group
- methyl
- pyrrolo
- optionally mono
- polysubstituted
- 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.)
- Abandoned
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 58
- 102000001253 Protein Kinase Human genes 0.000 title claims abstract description 31
- 108060006633 protein kinase Proteins 0.000 title claims abstract description 31
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 227
- 238000000034 method Methods 0.000 claims abstract description 40
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 229940126601 medicinal product Drugs 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 113
- 108091000080 Phosphotransferase Proteins 0.000 claims description 95
- 102000020233 phosphotransferase Human genes 0.000 claims description 95
- -1 phenyloxy Chemical group 0.000 claims description 86
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 81
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 70
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 64
- 238000002360 preparation method Methods 0.000 claims description 58
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 45
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 44
- 125000003545 alkoxy group Chemical group 0.000 claims description 43
- 125000001072 heteroaryl group Chemical group 0.000 claims description 43
- 125000005843 halogen group Chemical group 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 125000003118 aryl group Chemical group 0.000 claims description 35
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 32
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 31
- 229910052794 bromium Inorganic materials 0.000 claims description 31
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 29
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 27
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 25
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 25
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- 239000000460 chlorine Substances 0.000 claims description 24
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 23
- 229910052801 chlorine Inorganic materials 0.000 claims description 23
- 125000000565 sulfonamide group Chemical group 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 150000002148 esters Chemical group 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 22
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 20
- 125000004076 pyridyl group Chemical group 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 229910052740 iodine Inorganic materials 0.000 claims description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 17
- 150000001412 amines Chemical class 0.000 claims description 16
- 238000000746 purification Methods 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 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 15
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 14
- 150000001408 amides Chemical class 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 14
- 125000004950 trifluoroalkyl group Chemical group 0.000 claims description 14
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 14
- 125000005412 pyrazyl group Chemical group 0.000 claims description 13
- 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 12
- 150000001263 acyl chlorides Chemical class 0.000 claims description 11
- 238000012512 characterization method Methods 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000001544 thienyl group Chemical group 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 9
- 206010006187 Breast cancer Diseases 0.000 claims description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 8
- 230000001684 chronic effect Effects 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 208000020816 lung neoplasm Diseases 0.000 claims description 8
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 8
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical class C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 claims description 7
- KCGKYAORRXGWMN-UHFFFAOYSA-N CNS(=O)=O Chemical compound CNS(=O)=O KCGKYAORRXGWMN-UHFFFAOYSA-N 0.000 claims description 7
- 208000014767 Myeloproliferative disease Diseases 0.000 claims description 7
- 102000001332 SRC Human genes 0.000 claims description 7
- 108060006706 SRC Proteins 0.000 claims description 7
- 230000001154 acute effect Effects 0.000 claims description 7
- 230000003197 catalytic effect Effects 0.000 claims description 7
- 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 7
- 230000003831 deregulation Effects 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 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 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
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- ZAHXYMFVNNUHCP-UHFFFAOYSA-N Naphazoline nitrate Chemical group O[N+]([O-])=O.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 ZAHXYMFVNNUHCP-UHFFFAOYSA-N 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical group CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 6
- 150000003335 secondary amines Chemical class 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 5
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 5
- 239000012298 atmosphere Substances 0.000 claims description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 5
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 5
- 238000005984 hydrogenation reaction Methods 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000003368 amide group Chemical group 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- DHIHZLGSYHTLMS-UHFFFAOYSA-N 3-methoxy-1h-indazole Chemical compound C1=CC=C2C(OC)=NNC2=C1 DHIHZLGSYHTLMS-UHFFFAOYSA-N 0.000 claims description 3
- 150000001298 alcohols Chemical class 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
- 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 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 238000005897 peptide coupling reaction Methods 0.000 claims description 3
- 150000003140 primary amides Chemical class 0.000 claims description 3
- 125000005495 pyridazyl group Chemical group 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
- 238000004090 dissolution Methods 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 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 1
- CYOZJGAFKCEXBD-UHFFFAOYSA-N 5-[(2-bromobenzoyl)amino]-n-[3-(dimethylamino)propyl]-1h-pyrrolo[2,3-b]pyridine-2-carboxamide Chemical compound C=1N=C2NC(C(=O)NCCCN(C)C)=CC2=CC=1NC(=O)C1=CC=CC=C1Br CYOZJGAFKCEXBD-UHFFFAOYSA-N 0.000 claims 1
- 229910020667 PBr3 Inorganic materials 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 181
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- 238000004128 high performance liquid chromatography Methods 0.000 description 78
- 239000007787 solid Substances 0.000 description 71
- 238000004949 mass spectrometry Methods 0.000 description 69
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 68
- 230000002829 reductive effect Effects 0.000 description 60
- 239000000047 product Substances 0.000 description 55
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 50
- 238000005481 NMR spectroscopy Methods 0.000 description 49
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 25
- 235000011152 sodium sulphate Nutrition 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
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- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 239000008346 aqueous phase Substances 0.000 description 22
- 229960002411 imatinib Drugs 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 238000012360 testing method Methods 0.000 description 16
- 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 14
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 14
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 13
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- 238000006268 reductive amination reaction Methods 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 9
- 150000001299 aldehydes Chemical class 0.000 description 9
- 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 9
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- 229910052757 nitrogen Inorganic materials 0.000 description 9
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- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 7
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 7
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- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 150000004982 aromatic amines Chemical class 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 235000011167 hydrochloric acid Nutrition 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
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- 238000002953 preparative HPLC Methods 0.000 description 6
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- PNEJDIFQKCQXPM-UHFFFAOYSA-N n-[2-[[bis(2-methoxyethyl)amino]methyl]-1h-pyrrolo[2,3-b]pyridin-5-yl]-2-bromobenzamide Chemical compound C=1N=C2NC(CN(CCOC)CCOC)=CC2=CC=1NC(=O)C1=CC=CC=C1Br PNEJDIFQKCQXPM-UHFFFAOYSA-N 0.000 description 1
- VSSWZOOAQIXYDI-UHFFFAOYSA-N n-[3-(hydroxymethyl)-4-methylphenyl]-4-[(4-methylpiperazin-1-yl)methyl]benzamide Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(CO)C(C)=CC=2)C=C1 VSSWZOOAQIXYDI-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- JCSQXEINQFERDM-UHFFFAOYSA-N n-benzyl-1h-indazol-3-amine Chemical compound N=1NC2=CC=CC=C2C=1NCC1=CC=CC=C1 JCSQXEINQFERDM-UHFFFAOYSA-N 0.000 description 1
- ILCQYORZHHFLNL-UHFFFAOYSA-N n-bromoaniline Chemical compound BrNC1=CC=CC=C1 ILCQYORZHHFLNL-UHFFFAOYSA-N 0.000 description 1
- VBEGHXKAFSLLGE-UHFFFAOYSA-N n-phenylnitramide Chemical compound [O-][N+](=O)NC1=CC=CC=C1 VBEGHXKAFSLLGE-UHFFFAOYSA-N 0.000 description 1
- XGXNTJHZPBRBHJ-UHFFFAOYSA-N n-phenylpyrimidin-2-amine Chemical compound N=1C=CC=NC=1NC1=CC=CC=C1 XGXNTJHZPBRBHJ-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 201000004931 neurofibromatosis Diseases 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 210000004214 philadelphia chromosome Anatomy 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 208000015768 polyposis Diseases 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 159000000018 pyrido[2,3-d]pyrimidines Chemical class 0.000 description 1
- 229910052761 rare earth metal Inorganic materials 0.000 description 1
- 150000002910 rare earth metals Chemical class 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 238000002821 scintillation proximity assay Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 150000003668 tyrosines Chemical class 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US20227909P | 2009-02-12 | 2009-02-12 | |
| FR0900631 | 2009-02-12 | ||
| US61/202,279 | 2009-02-12 | ||
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2751478A1 true CA2751478A1 (en) | 2010-08-19 |
Family
ID=40886859
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2751478A Abandoned CA2751478A1 (en) | 2009-02-12 | 2010-02-12 | Derivatives of azaindoles as inhibitors of protein kinases abl and src |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US8580815B2 (https=) |
| EP (1) | EP2396325B1 (https=) |
| JP (1) | JP5583698B2 (https=) |
| AU (1) | AU2010212560B2 (https=) |
| CA (1) | CA2751478A1 (https=) |
| DK (1) | DK2396325T3 (https=) |
| ES (1) | ES2540962T3 (https=) |
| FR (1) | FR2941948B1 (https=) |
| HR (1) | HRP20150697T8 (https=) |
| HU (1) | HUE024989T2 (https=) |
| PL (1) | PL2396325T3 (https=) |
| PT (1) | PT2396325E (https=) |
| SI (1) | SI2396325T1 (https=) |
| SM (1) | SMT201500175B (https=) |
| WO (1) | WO2010092489A1 (https=) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2935248B1 (en) * | 2012-12-21 | 2018-02-28 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
| FR3000492B1 (fr) * | 2012-12-28 | 2015-09-11 | Oribase Pharma | Nouveaux derives azaindole en tant qu'inhibiteurs multikinases |
| FR3000494B1 (fr) * | 2012-12-28 | 2015-08-21 | Oribase Pharma | Nouveaux derives d'azaindoles en tant qu'inhibiteurs de proteines kinases |
| FR3000493A1 (fr) * | 2012-12-28 | 2014-07-04 | Oribase Pharma | Nouveaux inhibiteurs de proteines kinases |
| US10722484B2 (en) | 2016-03-09 | 2020-07-28 | K-Gen, Inc. | Methods of cancer treatment |
| AU2018238138A1 (en) | 2017-03-21 | 2019-10-17 | Arbutus Biopharma Corporation | Substituted dihydroindene-4-carboxamides and analogs thereof, and methods using same |
| CN115605460A (zh) | 2020-04-29 | 2023-01-13 | 普莱希科公司（Us） | 杂环化合物的合成 |
| 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 |
| AU2021358123A1 (en) | 2020-10-05 | 2023-06-08 | Enliven Inc. | 5- and 6-azaindole compounds for inhibition of bcr-abl tyrosine kinases |
| EP4225741A4 (en) * | 2020-10-05 | 2024-10-30 | Enliven Inc. | 7-AZAINDOLE COMPOUNDS FOR INHIBITION OF BCR-ABL TYROSINE KINASES |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CA2570817A1 (en) * | 2004-06-17 | 2006-01-26 | Plexxikon, Inc. | Azaindoles modulating c-kit activity and uses therefor |
| EP1781654A1 (en) | 2004-07-27 | 2007-05-09 | SGX Pharmaceuticals, Inc. | Pyrrolo-pyridine kinase modulators |
| US7361764B2 (en) | 2004-07-27 | 2008-04-22 | Sgx Pharmaceuticals, Inc. | Pyrrolo-pyridine kinase modulators |
| US7709645B2 (en) | 2004-07-27 | 2010-05-04 | Sgx Pharmaceuticals, Inc. | Pyrrolo-pyridine kinase modulators |
| ATE421510T1 (de) * | 2005-03-28 | 2009-02-15 | Bristol Myers Squibb Co | Kompetitive atp-kinasehemmer |
| JP2010502660A (ja) | 2006-09-06 | 2010-01-28 | エフ．ホフマン−ラ ロシュ アーゲー | プロテインキナーゼインヒビターとしてのヘテロアリール誘導体 |
| WO2008060907A2 (en) * | 2006-11-10 | 2008-05-22 | Bristol-Myers Squibb Company | Pyrrolo-pyridine kinase inhibitors |
| WO2008144253A1 (en) * | 2007-05-14 | 2008-11-27 | Irm Llc | Protein kinase inhibitors and methods for using thereof |
| PE20091561A1 (es) * | 2008-02-29 | 2009-10-30 | Array Biopharma Inc | Compuestos inhibidores de raf y metodos para su uso |
| AU2009320481C1 (en) * | 2008-11-03 | 2016-12-08 | Syntarga B.V. | Novel CC-1065 analogs and their conjugates |
-
2009
- 2009-02-12 FR FR0900631A patent/FR2941948B1/fr not_active Expired - Fee Related
-
2010
- 2010-02-12 HR HRP20150697TT patent/HRP20150697T8/hr unknown
- 2010-02-12 WO PCT/IB2010/000593 patent/WO2010092489A1/en not_active Ceased
- 2010-02-12 CA CA2751478A patent/CA2751478A1/en not_active Abandoned
- 2010-02-12 AU AU2010212560A patent/AU2010212560B2/en not_active Ceased
- 2010-02-12 SI SI201030964T patent/SI2396325T1/sl unknown
- 2010-02-12 DK DK10710439.0T patent/DK2396325T3/en active
- 2010-02-12 HU HUE10710439A patent/HUE024989T2/en unknown
- 2010-02-12 PL PL10710439T patent/PL2396325T3/pl unknown
- 2010-02-12 US US13/148,988 patent/US8580815B2/en not_active Expired - Fee Related
- 2010-02-12 JP JP2011549698A patent/JP5583698B2/ja not_active Expired - Fee Related
- 2010-02-12 ES ES10710439.0T patent/ES2540962T3/es active Active
- 2010-02-12 PT PT107104390T patent/PT2396325E/pt unknown
- 2010-02-12 EP EP10710439.0A patent/EP2396325B1/en not_active Not-in-force
-
2015
- 2015-07-22 SM SM201500175T patent/SMT201500175B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SMT201500175B (it) | 2015-09-07 |
| US8580815B2 (en) | 2013-11-12 |
| EP2396325B1 (en) | 2015-04-01 |
| EP2396325A1 (en) | 2011-12-21 |
| AU2010212560A1 (en) | 2011-08-11 |
| PL2396325T3 (pl) | 2015-10-30 |
| HRP20150697T8 (xx) | 2015-11-06 |
| HRP20150697T1 (hr) | 2015-08-14 |
| FR2941948A1 (fr) | 2010-08-13 |
| US20110312959A1 (en) | 2011-12-22 |
| JP2012517465A (ja) | 2012-08-02 |
| FR2941948B1 (fr) | 2013-04-05 |
| PT2396325E (pt) | 2015-08-21 |
| JP5583698B2 (ja) | 2014-09-03 |
| AU2010212560B2 (en) | 2016-01-21 |
| WO2010092489A1 (en) | 2010-08-19 |
| ES2540962T3 (es) | 2015-07-15 |
| HUE024989T2 (en) | 2016-01-28 |
| DK2396325T3 (en) | 2015-06-29 |
| SI2396325T1 (sl) | 2015-08-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20150112 |
|
| FZDE | Discontinued |
Effective date: 20181227 |