ES2540962T3 - Derivados de azaindoles como inhibidores de las proteína cinasas Abl y Src - Google Patents
Derivados de azaindoles como inhibidores de las proteína cinasas Abl y Src Download PDFInfo
- Publication number
- ES2540962T3 ES2540962T3 ES10710439.0T ES10710439T ES2540962T3 ES 2540962 T3 ES2540962 T3 ES 2540962T3 ES 10710439 T ES10710439 T ES 10710439T ES 2540962 T3 ES2540962 T3 ES 2540962T3
- Authority
- ES
- Spain
- Prior art keywords
- group
- polysubstituted
- methyl
- optionally mono
- pyrrolo
- 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.)
- Active
Links
- 102000001253 Protein Kinase Human genes 0.000 title claims description 19
- 108060006633 protein kinase Proteins 0.000 title claims description 19
- 239000003112 inhibitor Substances 0.000 title description 61
- 125000005334 azaindolyl group Chemical class N1N=C(C2=CC=CC=C12)* 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 224
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 60
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 53
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 47
- 125000005843 halogen group Chemical group 0.000 claims abstract description 41
- 125000003118 aryl group Chemical group 0.000 claims abstract description 40
- 125000000565 sulfonamide group Chemical group 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 22
- 125000004950 trifluoroalkyl group Chemical group 0.000 claims abstract description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 14
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 7
- 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 7
- 125000003368 amide group Chemical group 0.000 claims abstract description 5
- 125000004185 ester group Chemical group 0.000 claims abstract description 5
- -1 imidazyl group Chemical group 0.000 claims description 113
- 102000020233 phosphotransferase Human genes 0.000 claims description 80
- 108091000080 Phosphotransferase Proteins 0.000 claims description 79
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- 101100268648 Mus musculus Abl1 gene Proteins 0.000 claims description 58
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 22
- 125000004076 pyridyl group Chemical group 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 239000000460 chlorine Substances 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 19
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- 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 17
- NMMIHXMBOZYNET-UHFFFAOYSA-N Methyl picolinate Chemical compound COC(=O)C1=CC=CC=N1 NMMIHXMBOZYNET-UHFFFAOYSA-N 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- 238000000746 purification Methods 0.000 claims description 14
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 13
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical group CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 12
- 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
- 239000000741 silica gel Substances 0.000 claims description 12
- 229910002027 silica gel Inorganic materials 0.000 claims description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 11
- 150000001263 acyl chlorides Chemical class 0.000 claims description 11
- 125000005412 pyrazyl group Chemical group 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 238000005897 peptide coupling reaction Methods 0.000 claims description 9
- 125000001544 thienyl 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
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 8
- 230000001684 chronic effect Effects 0.000 claims description 8
- 208000020816 lung neoplasm Diseases 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
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 7
- 208000014767 Myeloproliferative disease Diseases 0.000 claims description 7
- 230000001154 acute effect Effects 0.000 claims description 7
- 230000003831 deregulation Effects 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 102000001332 SRC Human genes 0.000 claims description 6
- 108060006706 SRC Proteins 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- 230000003197 catalytic effect Effects 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
- 239000003909 protein kinase inhibitor Substances 0.000 claims description 6
- 150000003335 secondary amines Chemical class 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 5
- 239000012298 atmosphere Substances 0.000 claims description 5
- 125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 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 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000003396 thiol group Chemical group [H]S* 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 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 229910052763 palladium Inorganic materials 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
- DHIHZLGSYHTLMS-UHFFFAOYSA-N 3-methoxy-1h-indazole Chemical compound C1=CC=C2C(OC)=NNC2=C1 DHIHZLGSYHTLMS-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 229940043355 kinase inhibitor Drugs 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
- 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
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 3
- 201000004101 esophageal cancer Diseases 0.000 claims 3
- 206010017758 gastric cancer Diseases 0.000 claims 3
- 201000007270 liver cancer Diseases 0.000 claims 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 3
- 201000002528 pancreatic cancer Diseases 0.000 claims 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 3
- 201000011549 stomach cancer Diseases 0.000 claims 3
- 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
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 201000005296 lung carcinoma Diseases 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 183
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 120
- 238000004949 mass spectrometry Methods 0.000 description 81
- 238000004128 high performance liquid chromatography Methods 0.000 description 79
- 239000007787 solid Substances 0.000 description 72
- 238000005160 1H NMR spectroscopy Methods 0.000 description 67
- 230000002829 reductive effect Effects 0.000 description 59
- 238000002360 preparation method Methods 0.000 description 50
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 47
- 230000000694 effects Effects 0.000 description 44
- 239000000047 product Substances 0.000 description 44
- 239000000243 solution Substances 0.000 description 41
- 230000015572 biosynthetic process Effects 0.000 description 34
- 238000003786 synthesis reaction Methods 0.000 description 32
- 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 230000005764 inhibitory process Effects 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- 210000004027 cell Anatomy 0.000 description 25
- 229910052938 sodium sulfate Inorganic materials 0.000 description 25
- 235000011152 sodium sulphate Nutrition 0.000 description 25
- 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 24
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 24
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 24
- 229910052794 bromium Inorganic materials 0.000 description 24
- 239000003153 chemical reaction reagent Substances 0.000 description 24
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 23
- 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
- 239000008346 aqueous phase Substances 0.000 description 22
- 229960002411 imatinib Drugs 0.000 description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 22
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 206010028980 Neoplasm Diseases 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 102000009076 src-Family Kinases Human genes 0.000 description 11
- 108010087686 src-Family Kinases Proteins 0.000 description 11
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- JNPZKGOLYSCSEL-UHFFFAOYSA-N methyl 5-amino-2-methylbenzoate Chemical compound COC(=O)C1=CC(N)=CC=C1C JNPZKGOLYSCSEL-UHFFFAOYSA-N 0.000 description 10
- 150000004702 methyl esters Chemical class 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- 238000006268 reductive amination reaction Methods 0.000 description 10
- 150000001299 aldehydes Chemical class 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 208000032839 leukemia Diseases 0.000 description 9
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 230000002496 gastric effect Effects 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 238000000021 kinase assay Methods 0.000 description 8
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 7
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 7
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 7
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 150000002148 esters Chemical group 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
- 125000002098 pyridazinyl group Chemical group 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KCGKYAORRXGWMN-UHFFFAOYSA-N CNS(=O)=O Chemical compound CNS(=O)=O KCGKYAORRXGWMN-UHFFFAOYSA-N 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- 150000004982 aromatic amines Chemical class 0.000 description 6
- 150000003857 carboxamides Chemical class 0.000 description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 125000003884 phenylalkyl group Chemical group 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 238000002953 preparative HPLC Methods 0.000 description 6
- 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
- PBIXGSYVMDNMKP-UHFFFAOYSA-N 2-(methoxymethyl)-1h-pyrrolo[2,3-b]pyridin-5-amine Chemical compound NC1=CN=C2NC(COC)=CC2=C1 PBIXGSYVMDNMKP-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 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 5
- 241000238631 Hexapoda Species 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- ZAHXYMFVNNUHCP-UHFFFAOYSA-N Naphazoline nitrate Chemical group O[N+]([O-])=O.C=1C=CC2=CC=CC=C2C=1CC1=NCCN1 ZAHXYMFVNNUHCP-UHFFFAOYSA-N 0.000 description 5
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 5
- 230000007170 pathology Effects 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 5
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- YDTDKKULPWTHRV-UHFFFAOYSA-N 1H-indazol-3-amine Chemical compound C1=CC=C2C(N)=NNC2=C1 YDTDKKULPWTHRV-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- CAPKAYDTKWGFQB-UHFFFAOYSA-N 4-methyl-3-(trifluoromethyl)benzoic acid Chemical compound CC1=CC=C(C(O)=O)C=C1C(F)(F)F CAPKAYDTKWGFQB-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 4
- 108091008606 PDGF receptors Proteins 0.000 description 4
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- 229960002448 dasatinib Drugs 0.000 description 4
- 238000000099 in vitro assay Methods 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 3
- XMFAFBGIXMWQPR-UHFFFAOYSA-N 2-bromo-n-[2-(bromomethyl)-1h-pyrrolo[2,3-b]pyridin-5-yl]benzamide Chemical compound C=1N=C2NC(CBr)=CC2=CC=1NC(=O)C1=CC=CC=C1Br XMFAFBGIXMWQPR-UHFFFAOYSA-N 0.000 description 3
- RRHZXEQDWRUHNB-UHFFFAOYSA-N 2-methyl-5-[[4-[(4-methylpiperazin-1-yl)methyl]benzoyl]amino]benzoic acid Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(C(C)=CC=2)C(O)=O)C=C1 RRHZXEQDWRUHNB-UHFFFAOYSA-N 0.000 description 3
- ZQOCDOFDUXPNGM-UHFFFAOYSA-N 3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)benzoic acid Chemical compound C1=NC(C)=CN1C1=CC(C(O)=O)=CC(C(F)(F)F)=C1 ZQOCDOFDUXPNGM-UHFFFAOYSA-N 0.000 description 3
- MRCOGEIHIZHMFO-UHFFFAOYSA-N 5-[(3-fluorobenzoyl)amino]-n-(2-morpholin-4-ylethyl)-1h-pyrrolo[2,3-b]pyridine-2-carboxamide Chemical compound FC1=CC=CC(C(=O)NC=2C=C3C=C(NC3=NC=2)C(=O)NCCN2CCOCC2)=C1 MRCOGEIHIZHMFO-UHFFFAOYSA-N 0.000 description 3
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 3
- 239000012448 Lithium borohydride Substances 0.000 description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 3
- 102000001393 Platelet-Derived Growth Factor alpha Receptor Human genes 0.000 description 3
- 108010068588 Platelet-Derived Growth Factor alpha Receptor Proteins 0.000 description 3
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 3
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 3
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 3
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- KFBZGRLLFITJKG-UHFFFAOYSA-N methyl 5-benzamido-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC(=O)C1=CC=CC=C1 KFBZGRLLFITJKG-UHFFFAOYSA-N 0.000 description 3
- KXAVAWJHCAUBBY-UHFFFAOYSA-N n-[2-[3-(dimethylamino)propylcarbamoyl]-1h-pyrrolo[2,3-b]pyridin-5-yl]quinoxaline-6-carboxamide Chemical compound N1=CC=NC2=CC(C(=O)NC=3C=C4C=C(NC4=NC=3)C(=O)NCCCN(C)C)=CC=C21 KXAVAWJHCAUBBY-UHFFFAOYSA-N 0.000 description 3
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 3
- 229960001346 nilotinib Drugs 0.000 description 3
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
- OUJBZEYKOMREBA-UHFFFAOYSA-N (4-methoxyphenyl) pyridine-2-carboxylate Chemical compound C1=CC(OC)=CC=C1OC(=O)C1=CC=CC=N1 OUJBZEYKOMREBA-UHFFFAOYSA-N 0.000 description 2
- PFFUVBDNNZUUCW-UHFFFAOYSA-N (5-amino-1h-pyrrolo[2,3-b]pyridin-2-yl)-morpholin-4-ylmethanone Chemical compound C=1C2=CC(N)=CN=C2NC=1C(=O)N1CCOCC1 PFFUVBDNNZUUCW-UHFFFAOYSA-N 0.000 description 2
- DXMRZBGFYBCTLR-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine-2-carboxylic acid Chemical compound C1=CN=C2NC(C(=O)O)=CC2=C1 DXMRZBGFYBCTLR-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- GNGMKJGQYROQBT-UHFFFAOYSA-N 2-fluoro-n-[2-(morpholine-4-carbonyl)-1h-pyrrolo[2,3-b]pyridin-5-yl]-5-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=C(F)C(C(=O)NC=2C=C3C=C(NC3=NC=2)C(=O)N2CCOCC2)=C1 GNGMKJGQYROQBT-UHFFFAOYSA-N 0.000 description 2
- SYVNVEGIRVXRQH-UHFFFAOYSA-N 3-fluorobenzoyl chloride Chemical compound FC1=CC=CC(C(Cl)=O)=C1 SYVNVEGIRVXRQH-UHFFFAOYSA-N 0.000 description 2
- TZEVCJIZADBEMY-UHFFFAOYSA-N 4-[[3-(dimethylamino)pyrrolidin-1-yl]methyl]-n-[3-[[[2-(methoxymethyl)-1h-pyrrolo[2,3-b]pyridin-5-yl]amino]methyl]-4-methylphenyl]-3-(trifluoromethyl)benzamide Chemical compound C=1N=C2NC(COC)=CC2=CC=1NCC(C(=CC=1)C)=CC=1NC(=O)C(C=C1C(F)(F)F)=CC=C1CN1CCC(N(C)C)C1 TZEVCJIZADBEMY-UHFFFAOYSA-N 0.000 description 2
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- WYVYATUJBANZIN-UHFFFAOYSA-N 5-nitro-1h-pyrrolo[2,3-b]pyridine-2-carboxylic acid Chemical compound [O-][N+](=O)C1=CN=C2NC(C(=O)O)=CC2=C1 WYVYATUJBANZIN-UHFFFAOYSA-N 0.000 description 2
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 108090000461 Aurora Kinase A Proteins 0.000 description 2
- 102100032311 Aurora kinase A Human genes 0.000 description 2
- 101150049556 Bcr gene Proteins 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 2
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000007080 aromatic substitution reaction Methods 0.000 description 2
- 108010056708 bcr-abl Fusion Proteins Proteins 0.000 description 2
- 102000004441 bcr-abl Fusion Proteins Human genes 0.000 description 2
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 2
- 229960003736 bosutinib Drugs 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- JPFAEMAZJNUMME-UHFFFAOYSA-N methyl 2-methyl-5-[[4-[(4-methylpiperazin-1-yl)methyl]benzoyl]amino]benzoate Chemical group C1=C(C)C(C(=O)OC)=CC(NC(=O)C=2C=CC(CN3CCN(C)CC3)=CC=2)=C1 JPFAEMAZJNUMME-UHFFFAOYSA-N 0.000 description 2
- UKKQILPRRXWYFY-UHFFFAOYSA-N methyl 5-(4-iodoanilino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC1=CC=C(I)C=C1 UKKQILPRRXWYFY-UHFFFAOYSA-N 0.000 description 2
- BRZBUTILYDDOIZ-UHFFFAOYSA-N methyl 5-(quinoxaline-6-carbonylamino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound N1=CC=NC2=CC(C(=O)NC=3C=C4C=C(NC4=NC=3)C(=O)OC)=CC=C21 BRZBUTILYDDOIZ-UHFFFAOYSA-N 0.000 description 2
- ZOVLDGHFLOZXCR-UHFFFAOYSA-N methyl 5-[(3-fluorobenzoyl)amino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC(=O)C1=CC=CC(F)=C1 ZOVLDGHFLOZXCR-UHFFFAOYSA-N 0.000 description 2
- VFIDNKBEBGLRQT-UHFFFAOYSA-N methyl 5-[[2-(trifluoromethoxy)benzoyl]amino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC(=O)C1=CC=CC=C1OC(F)(F)F VFIDNKBEBGLRQT-UHFFFAOYSA-N 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- SNHPRBGZISTEER-UHFFFAOYSA-N morpholin-4-yl-(5-nitro-1h-pyrrolo[2,3-b]pyridin-2-yl)methanone Chemical compound C=1C2=CC([N+](=O)[O-])=CN=C2NC=1C(=O)N1CCOCC1 SNHPRBGZISTEER-UHFFFAOYSA-N 0.000 description 2
- ZPHVCXQPVIQNAF-UHFFFAOYSA-N n-(3-formyl-4-methylphenyl)-3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)benzamide Chemical compound C1=NC(C)=CN1C1=CC(C(=O)NC=2C=C(C=O)C(C)=CC=2)=CC(C(F)(F)F)=C1 ZPHVCXQPVIQNAF-UHFFFAOYSA-N 0.000 description 2
- AWXYGPZHSNSOHC-UHFFFAOYSA-N n-(3-formyl-4-methylphenyl)-4-[(4-methylpiperazin-1-yl)methyl]benzamide Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(C=O)C(C)=CC=2)C=C1 AWXYGPZHSNSOHC-UHFFFAOYSA-N 0.000 description 2
- DMAYKFYSNSGKHA-UHFFFAOYSA-N n-[3-[[[2-(methoxymethyl)-1h-pyrrolo[2,3-b]pyridin-5-yl]amino]methyl]-4-methylphenyl]-3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)benzamide Chemical compound C=1N=C2NC(COC)=CC2=CC=1NCC(C(=CC=1)C)=CC=1NC(=O)C(C=C(C=1)C(F)(F)F)=CC=1N1C=NC(C)=C1 DMAYKFYSNSGKHA-UHFFFAOYSA-N 0.000 description 2
- 230000001613 neoplastic effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 150000003138 primary alcohols Chemical class 0.000 description 2
- 150000003141 primary amines Chemical group 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 125000005495 pyridazyl group Chemical group 0.000 description 2
- UTEQROVYZDJSOO-UHFFFAOYSA-N quinoxaline-6-carbonyl chloride Chemical compound N1=CC=NC2=CC(C(=O)Cl)=CC=C21 UTEQROVYZDJSOO-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- FRDZGSBXKJXGNR-HTQZYQBOSA-N (1r,2r)-2-n,2-n-dimethylcyclohexane-1,2-diamine Chemical compound CN(C)[C@@H]1CCCC[C@H]1N FRDZGSBXKJXGNR-HTQZYQBOSA-N 0.000 description 1
- WBVDUENDEGLBDO-UHFFFAOYSA-N (4-methoxyphenyl) 5-benzamido-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C1=CC(OC)=CC=C1OC(=O)C1=CC2=CC(NC(=O)C=3C=CC=CC=3)=CN=C2N1 WBVDUENDEGLBDO-UHFFFAOYSA-N 0.000 description 1
- PXHHIBMOFPCBJQ-UHFFFAOYSA-N 1,2-dimethylpyrrolidine Chemical compound CC1CCCN1C PXHHIBMOFPCBJQ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- CZXPBOPRQAPKGX-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine-2-carboxamide Chemical compound C1=CN=C2NC(C(=O)N)=CC2=C1 CZXPBOPRQAPKGX-UHFFFAOYSA-N 0.000 description 1
- YEIPDMVCOQKQHV-UHFFFAOYSA-N 2-(2,5-diphenyltetrazol-1-ium-1-yl)-4,5-dimethyl-1,3-thiazole Chemical compound S1C(C)=C(C)N=C1[N+]1=C(C=2C=CC=CC=2)N=NN1C1=CC=CC=C1 YEIPDMVCOQKQHV-UHFFFAOYSA-N 0.000 description 1
- IUVCFHHAEHNCFT-INIZCTEOSA-N 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one Chemical compound C1=C(F)C(OC(C)C)=CC=C1C(C1=C(N)N=CN=C11)=NN1[C@@H](C)C1=C(C=2C=C(F)C=CC=2)C(=O)C2=CC(F)=CC=C2O1 IUVCFHHAEHNCFT-INIZCTEOSA-N 0.000 description 1
- KRQUFUKTQHISJB-YYADALCUSA-N 2-[(E)-N-[2-(4-chlorophenoxy)propoxy]-C-propylcarbonimidoyl]-3-hydroxy-5-(thian-3-yl)cyclohex-2-en-1-one Chemical compound CCC\C(=N/OCC(C)OC1=CC=C(Cl)C=C1)C1=C(O)CC(CC1=O)C1CCCSC1 KRQUFUKTQHISJB-YYADALCUSA-N 0.000 description 1
- HLCPWBZNUKCSBN-UHFFFAOYSA-N 2-aminobenzonitrile Chemical compound NC1=CC=CC=C1C#N HLCPWBZNUKCSBN-UHFFFAOYSA-N 0.000 description 1
- ZXMISUUIYPFORW-UHFFFAOYSA-N 2-bromo-5-methylbenzoic acid Chemical compound CC1=CC=C(Br)C(C(O)=O)=C1 ZXMISUUIYPFORW-UHFFFAOYSA-N 0.000 description 1
- SSOCQEDPOBCFAW-UHFFFAOYSA-N 2-bromo-n-[2-(imidazol-1-ylmethyl)-1h-pyrrolo[2,3-b]pyridin-5-yl]benzamide Chemical compound BrC1=CC=CC=C1C(=O)NC1=CN=C(NC(CN2C=NC=C2)=C2)C2=C1 SSOCQEDPOBCFAW-UHFFFAOYSA-N 0.000 description 1
- NAHTXKMFJBJLCV-UHFFFAOYSA-N 2-bromo-n-[2-[(2-cyanoanilino)methyl]-1h-pyrrolo[2,3-b]pyridin-5-yl]benzamide Chemical compound BrC1=CC=CC=C1C(=O)NC1=CN=C(NC(CNC=2C(=CC=CC=2)C#N)=C2)C2=C1 NAHTXKMFJBJLCV-UHFFFAOYSA-N 0.000 description 1
- KMNQRIQDMIFHEJ-UHFFFAOYSA-N 2-bromo-n-[2-[(3-bromoanilino)methyl]-1h-pyrrolo[2,3-b]pyridin-5-yl]benzamide Chemical compound BrC1=CC=CC(NCC=2NC3=NC=C(NC(=O)C=4C(=CC=CC=4)Br)C=C3C=2)=C1 KMNQRIQDMIFHEJ-UHFFFAOYSA-N 0.000 description 1
- AKYZFIHDZNFGCA-UHFFFAOYSA-N 2-bromo-n-[2-[(3-methoxyanilino)methyl]-1h-pyrrolo[2,3-b]pyridin-5-yl]benzamide Chemical compound COC1=CC=CC(NCC=2NC3=NC=C(NC(=O)C=4C(=CC=CC=4)Br)C=C3C=2)=C1 AKYZFIHDZNFGCA-UHFFFAOYSA-N 0.000 description 1
- AHNNKDGAXZGGNU-UHFFFAOYSA-N 2-bromo-n-[2-[(4-cyanoanilino)methyl]-1h-pyrrolo[2,3-b]pyridin-5-yl]benzamide Chemical compound BrC1=CC=CC=C1C(=O)NC1=CN=C(NC(CNC=2C=CC(=CC=2)C#N)=C2)C2=C1 AHNNKDGAXZGGNU-UHFFFAOYSA-N 0.000 description 1
- VKNWFBJIODHKRU-UHFFFAOYSA-N 2-bromo-n-[2-[(pyridin-4-ylamino)methyl]-1h-pyrrolo[2,3-b]pyridin-5-yl]benzamide Chemical compound BrC1=CC=CC=C1C(=O)NC1=CN=C(NC(CNC=2C=CN=CC=2)=C2)C2=C1 VKNWFBJIODHKRU-UHFFFAOYSA-N 0.000 description 1
- DKOWWMJCQMXPGQ-UHFFFAOYSA-N 2-bromo-n-[2-[(tert-butylamino)methyl]-1h-pyrrolo[2,3-b]pyridin-5-yl]benzamide Chemical compound C=1N=C2NC(CNC(C)(C)C)=CC2=CC=1NC(=O)C1=CC=CC=C1Br DKOWWMJCQMXPGQ-UHFFFAOYSA-N 0.000 description 1
- FTYCWUMDMDTTJH-UHFFFAOYSA-N 2-bromo-n-[2-[[(2-methylcyclohexyl)amino]methyl]-1h-pyrrolo[2,3-b]pyridin-5-yl]benzamide Chemical compound CC1CCCCC1NCC1=CC2=CC(NC(=O)C=3C(=CC=CC=3)Br)=CN=C2N1 FTYCWUMDMDTTJH-UHFFFAOYSA-N 0.000 description 1
- SXJNRYPVXFTJOU-UHFFFAOYSA-N 2-fluoro-5-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(F)C(C(Cl)=O)=C1 SXJNRYPVXFTJOU-UHFFFAOYSA-N 0.000 description 1
- YZWKSOYWTHKNLX-UHFFFAOYSA-N 2-fluoro-6-methoxybenzoyl chloride Chemical compound COC1=CC=CC(F)=C1C(Cl)=O YZWKSOYWTHKNLX-UHFFFAOYSA-N 0.000 description 1
- IBZKBSXREAQDTO-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)ethanamine Chemical compound COCCNCCOC IBZKBSXREAQDTO-UHFFFAOYSA-N 0.000 description 1
- FEUISMYEFPANSS-UHFFFAOYSA-N 2-methylcyclohexan-1-amine Chemical compound CC1CCCCC1N FEUISMYEFPANSS-UHFFFAOYSA-N 0.000 description 1
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 1
- KCHXSJOOCZQXND-UHFFFAOYSA-N 3-(4-methylimidazol-1-yl)-N-[4-methyl-3-[(1H-pyrrolo[2,3-b]pyridin-5-ylamino)methyl]phenyl]-5-(trifluoromethyl)benzamide Chemical compound FC(C=1C=C(C(=O)NC=2C=CC(=C(CNC=3C=C4C(=NC=3)NC=C4)C=2)C)C=C(C=1)N1C=NC(=C1)C)(F)F KCHXSJOOCZQXND-UHFFFAOYSA-N 0.000 description 1
- JPVKCHIPRSQDKL-UHFFFAOYSA-N 3-aminobenzenesulfonamide Chemical compound NC1=CC=CC(S(N)(=O)=O)=C1 JPVKCHIPRSQDKL-UHFFFAOYSA-N 0.000 description 1
- DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 1
- OWIRCRREDNEXTA-UHFFFAOYSA-N 3-nitro-1h-indazole Chemical compound C1=CC=C2C([N+](=O)[O-])=NNC2=C1 OWIRCRREDNEXTA-UHFFFAOYSA-N 0.000 description 1
- WJQGMUPBMHWAEX-UHFFFAOYSA-N 4-(2-methyl-1,3-thiazol-4-yl)benzoyl chloride Chemical compound S1C(C)=NC(C=2C=CC(=CC=2)C(Cl)=O)=C1 WJQGMUPBMHWAEX-UHFFFAOYSA-N 0.000 description 1
- RCOVTJVRTZGSBP-UHFFFAOYSA-N 4-(chloromethyl)benzoyl chloride Chemical compound ClCC1=CC=C(C(Cl)=O)C=C1 RCOVTJVRTZGSBP-UHFFFAOYSA-N 0.000 description 1
- JQQBMLYOMLPPHQ-UHFFFAOYSA-N 4-[[3-(dimethylamino)pyrrolidin-1-yl]methyl]-3-(trifluoromethyl)benzoic acid Chemical group C1C(N(C)C)CCN1CC1=CC=C(C(O)=O)C=C1C(F)(F)F JQQBMLYOMLPPHQ-UHFFFAOYSA-N 0.000 description 1
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 1
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 1
- JTLNJMZZPORPHX-UHFFFAOYSA-N 5-[(3-fluorobenzoyl)amino]-1h-pyrrolo[2,3-b]pyridine-2-carboxamide Chemical compound C=1N=C2NC(C(=O)N)=CC2=CC=1NC(=O)C1=CC=CC(F)=C1 JTLNJMZZPORPHX-UHFFFAOYSA-N 0.000 description 1
- KYCLECLLHVULPH-UHFFFAOYSA-N 5-amino-1h-pyrrolo[2,3-b]pyridine-2-carboxamide Chemical compound NC1=CN=C2NC(C(=O)N)=CC2=C1 KYCLECLLHVULPH-UHFFFAOYSA-N 0.000 description 1
- NOWRIRSAASGKRU-UHFFFAOYSA-N 5-nitro-1h-pyrrolo[2,3-b]pyridine-2-carboxamide Chemical compound [O-][N+](=O)C1=CN=C2NC(C(=O)N)=CC2=C1 NOWRIRSAASGKRU-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 102000004000 Aurora Kinase A Human genes 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- VIFCSOHSTIPPOS-UHFFFAOYSA-N BrC1=C(C(=O)NC=2C=C3C(=NC=2)NC(=C3)C(=O)O)C=CC=C1 Chemical compound BrC1=C(C(=O)NC=2C=C3C(=NC=2)NC(=C3)C(=O)O)C=CC=C1 VIFCSOHSTIPPOS-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 229940124204 C-kit inhibitor Drugs 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- CSOXYYDEGWQZHV-UHFFFAOYSA-N COC(=O)c1cc2cc(NCc3cccc(c3)S(N)(=O)=O)cnc2[nH]1 Chemical compound COC(=O)c1cc2cc(NCc3cccc(c3)S(N)(=O)=O)cnc2[nH]1 CSOXYYDEGWQZHV-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000008334 Dermatofibrosarcoma Diseases 0.000 description 1
- 206010057070 Dermatofibrosarcoma protuberans Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 101000798300 Homo sapiens Aurora kinase A Proteins 0.000 description 1
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000033833 Myelomonocytic Chronic Leukemia Diseases 0.000 description 1
- 208000009905 Neurofibromatoses Diseases 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 102100030485 Platelet-derived growth factor receptor alpha Human genes 0.000 description 1
- 101710148465 Platelet-derived growth factor receptor alpha Proteins 0.000 description 1
- 208000002151 Pleural effusion Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- YNOGYQAEJGADFJ-RXMQYKEDSA-N [(2r)-oxolan-2-yl]methanamine Chemical compound NC[C@H]1CCCO1 YNOGYQAEJGADFJ-RXMQYKEDSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 239000003719 aurora kinase inhibitor Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- KQNZLOUWXSAZGD-UHFFFAOYSA-N benzylperoxymethylbenzene Chemical compound C=1C=CC=CC=1COOCC1=CC=CC=C1 KQNZLOUWXSAZGD-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 229910010277 boron hydride Inorganic materials 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- JINWVMKLXKAPRV-UHFFFAOYSA-N carbonic acid;3-(ethyliminomethylideneamino)-n,n-dimethylpropan-1-amine Chemical compound OC(O)=O.CCN=C=NCCCN(C)C JINWVMKLXKAPRV-UHFFFAOYSA-N 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 201000010902 chronic myelomonocytic leukemia Diseases 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 238000012866 crystallographic experiment Methods 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- IZCSREAMZDZVFW-UHFFFAOYSA-N ethyl 5-amino-1,3-thiazole-2-carboxylate Chemical compound CCOC(=O)C1=NC=C(N)S1 IZCSREAMZDZVFW-UHFFFAOYSA-N 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229960004979 fampridine Drugs 0.000 description 1
- 125000006332 fluoro benzoyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 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 description 1
- 238000012188 high-throughput screening assay Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.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 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- ZNXYRIHRAXFGNU-UHFFFAOYSA-N methyl 1-aminopyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound COC(=O)C1=CC=2C(=NC=CC2)N1N ZNXYRIHRAXFGNU-UHFFFAOYSA-N 0.000 description 1
- IHGOYDMXENEUOO-UHFFFAOYSA-N methyl 2-aminopyrimidine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(N)=N1 IHGOYDMXENEUOO-UHFFFAOYSA-N 0.000 description 1
- LXXRFFAIWGWJMA-UHFFFAOYSA-N methyl 4-(bromomethyl)-3-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC=C(CBr)C(C(F)(F)F)=C1 LXXRFFAIWGWJMA-UHFFFAOYSA-N 0.000 description 1
- SXGSDQKSQXVGCY-UHFFFAOYSA-N methyl 4-[[3-(dimethylamino)pyrrolidin-1-yl]methyl]-3-(trifluoromethyl)benzoate Chemical compound FC(F)(F)C1=CC(C(=O)OC)=CC=C1CN1CC(N(C)C)CC1 SXGSDQKSQXVGCY-UHFFFAOYSA-N 0.000 description 1
- PYQRUDYLXHRTQU-UHFFFAOYSA-N methyl 4-aminopyrimidine-2-carboxylate Chemical compound COC(=O)C1=NC=CC(N)=N1 PYQRUDYLXHRTQU-UHFFFAOYSA-N 0.000 description 1
- LXUTXZRWQVCTTR-UHFFFAOYSA-N methyl 4-methyl-3-(trifluoromethyl)benzoate Chemical compound COC(=O)C1=CC=C(C)C(C(F)(F)F)=C1 LXUTXZRWQVCTTR-UHFFFAOYSA-N 0.000 description 1
- LSMUHQOCLGFXEW-UHFFFAOYSA-N methyl 5-(1,3-thiazol-2-ylmethylamino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NCC1=NC=CS1 LSMUHQOCLGFXEW-UHFFFAOYSA-N 0.000 description 1
- HJPUOGSIQDMJDB-UHFFFAOYSA-N methyl 5-(1h-imidazol-2-ylmethylamino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NCC1=NC=CN1 HJPUOGSIQDMJDB-UHFFFAOYSA-N 0.000 description 1
- CSGDMICHMNNVRM-UHFFFAOYSA-N methyl 5-(1h-indol-5-ylmethylamino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C1=C2NC=CC2=CC(CNC=2C=C3C=C(NC3=NC=2)C(=O)OC)=C1 CSGDMICHMNNVRM-UHFFFAOYSA-N 0.000 description 1
- KAXCHEJKCNRZCL-UHFFFAOYSA-N methyl 5-(1h-indol-6-ylmethylamino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C1=C2C=CNC2=CC(CNC=2C=C3C=C(NC3=NC=2)C(=O)OC)=C1 KAXCHEJKCNRZCL-UHFFFAOYSA-N 0.000 description 1
- KXJQXFXXPCNCQU-UHFFFAOYSA-N methyl 5-(1h-indole-5-carbonylamino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C1=C2NC=CC2=CC(C(=O)NC=2C=C3C=C(NC3=NC=2)C(=O)OC)=C1 KXJQXFXXPCNCQU-UHFFFAOYSA-N 0.000 description 1
- YABPBMZTKLWFAM-UHFFFAOYSA-N methyl 5-(1h-pyrazol-5-ylmethylamino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NCC=1C=CNN=1 YABPBMZTKLWFAM-UHFFFAOYSA-N 0.000 description 1
- GIKOLBWSCQNXAE-UHFFFAOYSA-N methyl 5-(1h-pyrrolo[2,3-b]pyridin-5-ylmethylamino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound N1=C2NC=CC2=CC(CNC=2C=C3C=C(NC3=NC=2)C(=O)OC)=C1 GIKOLBWSCQNXAE-UHFFFAOYSA-N 0.000 description 1
- XBIUTPGDPILUHH-UHFFFAOYSA-N methyl 5-(3-bromoanilino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC1=CC=CC(Br)=C1 XBIUTPGDPILUHH-UHFFFAOYSA-N 0.000 description 1
- XURCVDQJWBLPMU-UHFFFAOYSA-N methyl 5-(3-iodoanilino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC1=CC=CC(I)=C1 XURCVDQJWBLPMU-UHFFFAOYSA-N 0.000 description 1
- MMNVTXMHJPCDLZ-UHFFFAOYSA-N methyl 5-(3-methoxyanilino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC1=CC=CC(OC)=C1 MMNVTXMHJPCDLZ-UHFFFAOYSA-N 0.000 description 1
- GXDKEOXBKFYQBY-UHFFFAOYSA-N methyl 5-(4-methoxyanilino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC1=CC=C(OC)C=C1 GXDKEOXBKFYQBY-UHFFFAOYSA-N 0.000 description 1
- VYMBFNQPILFZQT-UHFFFAOYSA-N methyl 5-(cyclopropanecarbonylamino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC(=O)C1CC1 VYMBFNQPILFZQT-UHFFFAOYSA-N 0.000 description 1
- MUEAFINVGVSIJM-UHFFFAOYSA-N methyl 5-(propanoylamino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound CCC(=O)NC1=CN=C2NC(C(=O)OC)=CC2=C1 MUEAFINVGVSIJM-UHFFFAOYSA-N 0.000 description 1
- KVVSEHVSCHEWNZ-UHFFFAOYSA-N methyl 5-(pyridin-4-ylamino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC1=CC=NC=C1 KVVSEHVSCHEWNZ-UHFFFAOYSA-N 0.000 description 1
- CVNGIJDNTWLTPR-UHFFFAOYSA-N methyl 5-(thiophen-2-ylmethylamino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NCC1=CC=CS1 CVNGIJDNTWLTPR-UHFFFAOYSA-N 0.000 description 1
- CMUUMIKNQANVSF-UHFFFAOYSA-N methyl 5-(thiophene-2-carbonylamino)-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC(=O)C1=CC=CS1 CMUUMIKNQANVSF-UHFFFAOYSA-N 0.000 description 1
- INHKTKGJEIKALZ-UHFFFAOYSA-N methyl 5-[(2,6-dichlorobenzoyl)amino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC(=O)C1=C(Cl)C=CC=C1Cl INHKTKGJEIKALZ-UHFFFAOYSA-N 0.000 description 1
- DJCLBOJZORFUMR-UHFFFAOYSA-N methyl 5-[(2,6-dichlorophenyl)methylamino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NCC1=C(Cl)C=CC=C1Cl DJCLBOJZORFUMR-UHFFFAOYSA-N 0.000 description 1
- MOEQLLUONDJIIJ-UHFFFAOYSA-N methyl 5-[(2-bromophenyl)methylamino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NCC1=CC=CC=C1Br MOEQLLUONDJIIJ-UHFFFAOYSA-N 0.000 description 1
- UVFLAWMNLLGDNC-UHFFFAOYSA-N methyl 5-[(2-chloro-6-methylbenzoyl)amino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC(=O)C1=C(C)C=CC=C1Cl UVFLAWMNLLGDNC-UHFFFAOYSA-N 0.000 description 1
- KNTPBVJWLVSQOV-UHFFFAOYSA-N methyl 5-[(2-chloro-6-methylphenyl)methylamino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NCC1=C(C)C=CC=C1Cl KNTPBVJWLVSQOV-UHFFFAOYSA-N 0.000 description 1
- KENHMYXWDPBTAU-UHFFFAOYSA-N methyl 5-[(2-ethylpyrazol-3-yl)methylamino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound CCN1N=CC=C1CNC1=CN=C(NC(=C2)C(=O)OC)C2=C1 KENHMYXWDPBTAU-UHFFFAOYSA-N 0.000 description 1
- MDMLHBBPUVVDII-UHFFFAOYSA-N methyl 5-[(2-methoxybenzoyl)amino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC(=O)C1=CC=CC=C1OC MDMLHBBPUVVDII-UHFFFAOYSA-N 0.000 description 1
- XHNJVFQIMAESOO-UHFFFAOYSA-N methyl 5-[(2-methoxyphenyl)methylamino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NCC1=CC=CC=C1OC XHNJVFQIMAESOO-UHFFFAOYSA-N 0.000 description 1
- NSRFIEYUXOOISZ-UHFFFAOYSA-N methyl 5-[(2-methylbenzoyl)amino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC(=O)C1=CC=CC=C1C NSRFIEYUXOOISZ-UHFFFAOYSA-N 0.000 description 1
- ONXVBFWIQSGWAH-UHFFFAOYSA-N methyl 5-[(2-methylphenyl)methylamino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NCC1=CC=CC=C1C ONXVBFWIQSGWAH-UHFFFAOYSA-N 0.000 description 1
- VVHXNKYRTPCMBO-UHFFFAOYSA-N methyl 5-[(3-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(Br)=C1 VVHXNKYRTPCMBO-UHFFFAOYSA-N 0.000 description 1
- SSAOJTZTWPNCBO-UHFFFAOYSA-N methyl 5-[(3-cyanobenzoyl)amino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC(=O)C1=CC=CC(C#N)=C1 SSAOJTZTWPNCBO-UHFFFAOYSA-N 0.000 description 1
- QSLXNAZCAJSVIR-UHFFFAOYSA-N methyl 5-[(6-methyl-1h-indol-5-yl)methylamino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NCC(C(=C1)C)=CC2=C1NC=C2 QSLXNAZCAJSVIR-UHFFFAOYSA-N 0.000 description 1
- PRGAKQWPQRXYMK-UHFFFAOYSA-N methyl 5-[4-(methylcarbamoyl)anilino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C1=CC(C(=O)NC)=CC=C1NC1=CN=C(NC(=C2)C(=O)OC)C2=C1 PRGAKQWPQRXYMK-UHFFFAOYSA-N 0.000 description 1
- SIUOVOCGMYQPIB-UHFFFAOYSA-N methyl 5-[[2-(trifluoromethyl)benzoyl]amino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NC(=O)C1=CC=CC=C1C(F)(F)F SIUOVOCGMYQPIB-UHFFFAOYSA-N 0.000 description 1
- MFAPLYWBOUSVJJ-UHFFFAOYSA-N methyl 5-[[2-(trifluoromethyl)phenyl]methylamino]-1h-pyrrolo[2,3-b]pyridine-2-carboxylate Chemical compound C=1N=C2NC(C(=O)OC)=CC2=CC=1NCC1=CC=CC=C1C(F)(F)F MFAPLYWBOUSVJJ-UHFFFAOYSA-N 0.000 description 1
- OBWMULCASPZKTP-UHFFFAOYSA-N methyl 5-[[4-(chloromethyl)benzoyl]amino]-2-methylbenzoate Chemical compound C1=C(C)C(C(=O)OC)=CC(NC(=O)C=2C=CC(CCl)=CC=2)=C1 OBWMULCASPZKTP-UHFFFAOYSA-N 0.000 description 1
- OHIHEJTUXNQOPM-UHFFFAOYSA-N methyl 6-aminopyridine-2-carboxylate Chemical compound COC(=O)C1=CC=CC(N)=N1 OHIHEJTUXNQOPM-UHFFFAOYSA-N 0.000 description 1
- 230000004001 molecular interaction Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- YRWYLPAVVWDGGS-UHFFFAOYSA-N n,n-dimethoxypropan-1-amine Chemical compound CCCN(OC)OC YRWYLPAVVWDGGS-UHFFFAOYSA-N 0.000 description 1
- ZUHZZVMEUAUWHY-UHFFFAOYSA-N n,n-dimethylpropan-1-amine Chemical compound CCCN(C)C ZUHZZVMEUAUWHY-UHFFFAOYSA-N 0.000 description 1
- AVAWMINJNRAQFS-UHFFFAOYSA-N n,n-dimethylpyrrolidin-3-amine Chemical compound CN(C)C1CCNC1 AVAWMINJNRAQFS-UHFFFAOYSA-N 0.000 description 1
- 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
- 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
- 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
- 239000013642 negative control Substances 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 230000010309 neoplastic transformation Effects 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
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 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
- 230000037361 pathway Effects 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 208000015768 polyposis Diseases 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 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
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000011160 research Methods 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
- 208000037803 restenosis Diseases 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000002821 scintillation proximity assay Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 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
- 229930192474 thiophene Natural products 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
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 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 | |
| US202279P | 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 |
| FR0900631 | 2009-02-12 | ||
| 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 |
|---|---|
| ES2540962T3 true ES2540962T3 (es) | 2015-07-15 |
Family
ID=40886859
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES10710439.0T Active ES2540962T3 (es) | 2009-02-12 | 2010-02-12 | Derivados de azaindoles como inhibidores de las proteína cinasas Abl y 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 |
|---|---|---|---|---|
| MX365640B (es) | 2012-12-21 | 2019-06-10 | Plexxikon Inc | Compuestos y metodos para la modulacion de quinasas y sus indicaciones. |
| 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 |
| WO2017156350A1 (en) | 2016-03-09 | 2017-09-14 | 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 |
| WO2021222442A1 (en) | 2020-04-29 | 2021-11-04 | 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 |
| KR20230104781A (ko) | 2020-10-05 | 2023-07-10 | 인라이븐 테라퓨틱스, 인크. | Bcr-abl 티로신 키나아제의 억제를 위한 5- 및 6-아자인돌 화합물 |
| MX2023003996A (es) * | 2020-10-05 | 2023-06-15 | Enliven Inc | Compuestos de 7-azaindol para la inhibicion de tirosina cinasas bcr-abl. |
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 |
| JP2008503473A (ja) * | 2004-06-17 | 2008-02-07 | プレキシコン，インコーポレーテッド | Ｃ−ｋｉｔ活性を調節する化合物 |
| US7709645B2 (en) | 2004-07-27 | 2010-05-04 | Sgx Pharmaceuticals, Inc. | Pyrrolo-pyridine kinase modulators |
| WO2006015123A1 (en) | 2004-07-27 | 2006-02-09 | Sgx Pharmaceuticals, Inc. | Pyrrolo-pyridine kinase modulators |
| US7361764B2 (en) | 2004-07-27 | 2008-04-22 | Sgx Pharmaceuticals, Inc. | Pyrrolo-pyridine kinase modulators |
| WO2006104971A1 (en) * | 2005-03-28 | 2006-10-05 | Bristol-Myers Squibb Company | Atp competitive kinase inhibitors |
| KR101104666B1 (ko) * | 2006-09-06 | 2012-01-13 | 에프. 호프만-라 로슈 아게 | 단백질 키나제 억제제로서의 헤테로아릴 유도체 |
| US8148361B2 (en) * | 2006-11-10 | 2012-04-03 | Bristol-Myers Squibb Company | Kinase inhibitors |
| WO2008144253A1 (en) * | 2007-05-14 | 2008-11-27 | Irm Llc | Protein kinase inhibitors and methods for using thereof |
| KR20100122505A (ko) * | 2008-02-29 | 2010-11-22 | 어레이 바이오파마 인크. | Ｒａｆ 저해물질 화합물 및 이들의 이용 방법 |
| ES2647317T3 (es) * | 2008-11-03 | 2017-12-20 | Syntarga B.V. | Análogos de CC-1065 y sus conjugados |
-
2009
- 2009-02-12 FR FR0900631A patent/FR2941948B1/fr not_active Expired - Fee Related
-
2010
- 2010-02-12 PT PT107104390T patent/PT2396325E/pt unknown
- 2010-02-12 ES ES10710439.0T patent/ES2540962T3/es active Active
- 2010-02-12 WO PCT/IB2010/000593 patent/WO2010092489A1/en not_active Ceased
- 2010-02-12 US US13/148,988 patent/US8580815B2/en not_active Expired - Fee Related
- 2010-02-12 AU AU2010212560A patent/AU2010212560B2/en not_active Ceased
- 2010-02-12 CA CA2751478A patent/CA2751478A1/en not_active Abandoned
- 2010-02-12 PL PL10710439T patent/PL2396325T3/pl unknown
- 2010-02-12 DK DK10710439.0T patent/DK2396325T3/en active
- 2010-02-12 HR HRP20150697TT patent/HRP20150697T8/hr unknown
- 2010-02-12 HU HUE10710439A patent/HUE024989T2/en unknown
- 2010-02-12 SI SI201030964T patent/SI2396325T1/sl unknown
- 2010-02-12 EP EP10710439.0A patent/EP2396325B1/en not_active Not-in-force
- 2010-02-12 JP JP2011549698A patent/JP5583698B2/ja not_active Expired - Fee Related
-
2015
- 2015-07-22 SM SM201500175T patent/SMT201500175B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HUE024989T2 (en) | 2016-01-28 |
| HRP20150697T1 (hr) | 2015-08-14 |
| AU2010212560B2 (en) | 2016-01-21 |
| HRP20150697T8 (xx) | 2015-11-06 |
| SI2396325T1 (sl) | 2015-08-31 |
| US20110312959A1 (en) | 2011-12-22 |
| PT2396325E (pt) | 2015-08-21 |
| PL2396325T3 (pl) | 2015-10-30 |
| DK2396325T3 (en) | 2015-06-29 |
| EP2396325B1 (en) | 2015-04-01 |
| SMT201500175B (it) | 2015-09-07 |
| WO2010092489A1 (en) | 2010-08-19 |
| JP2012517465A (ja) | 2012-08-02 |
| FR2941948B1 (fr) | 2013-04-05 |
| FR2941948A1 (fr) | 2010-08-13 |
| AU2010212560A1 (en) | 2011-08-11 |
| EP2396325A1 (en) | 2011-12-21 |
| JP5583698B2 (ja) | 2014-09-03 |
| CA2751478A1 (en) | 2010-08-19 |
| US8580815B2 (en) | 2013-11-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2540962T3 (es) | Derivados de azaindoles como inhibidores de las proteína cinasas Abl y Src | |
| ES2955132T3 (es) | Compuestos heterocíclicos sustituidos con amina como inhibidores de EHMT2 y métodos de uso de los mismos | |
| CN107428690B (zh) | 可用于治疗癌症的突变idh1抑制剂 | |
| CN113061132B (zh) | 一类稠环内酰胺类化合物、制备方法和用途 | |
| WO2013134298A1 (en) | Raf inhibitor compounds | |
| HK1223100A1 (zh) | 杂环化合物 | |
| ES2903528T3 (es) | Compuestos de heteroarilo y su uso como inhibidores de MER | |
| KR20110105792A (ko) | 페닐피리미돈을 함유하는 화합물, 그 약물 조성물 및 그 제조방법과 용도 | |
| CN116157128B (zh) | 吡唑并哒嗪酮化合物、其药物组合物及其用途 | |
| BR112015017963A2 (pt) | composto de fenil amino pirimidina deuterado, método para preparar a composição farmacêutica, composição farmacêutica e uso do composto | |
| WO2023224998A1 (en) | Inhibitors of parg | |
| CN109721600B (zh) | 一类含氮稠环化合物及其制备方法和用途 | |
| AU2023271807A1 (en) | Inhibitors of parg | |
| CN117295734A (zh) | 甲硫氨酸腺苷转移酶抑制剂、其制备方法及应用 | |
| EP3154547A1 (en) | Pyrimidine compounds and methods using the same | |
| CA3069602A1 (en) | Formylpyridine derivative having fgfr4 inhibitory activity, preparation method therefor and use thereof | |
| Modica et al. | Design, synthesis and binding properties of novel and selective 5-HT3 and 5-HT4 receptor ligands | |
| ES2303758B1 (es) | Nuevos derivados de piridin-3-amina. | |
| CN114437113B (zh) | 一种噻唑并吡啶环联三氮唑类化合物及其制备方法和应用 | |
| CA3243368A1 (en) | COMPOUND FOR REGULATING AND CONTROLLING THE ACTIVITY OF 15-PGDH AND ITS PREPARATION PROCESS | |
| CN109942544A (zh) | 一类新型吲唑类衍生物激酶抑制剂 | |
| WO2014125410A1 (en) | N-substituted heterocyclic derivatives as kinase inhibitors | |
| WO2020004518A1 (ja) | 新規ｐｄｅ４阻害剤 | |
| CN103228656B (zh) | 3-取代基-6-(吡啶基甲氧基)-吡咯并吡啶化合物 | |
| CN119431402A (zh) | 噻唑并环类化合物及其应用 |