JP2010521458A5 - - Google Patents
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- JP2010521458A5 JP2010521458A5 JP2009553600A JP2009553600A JP2010521458A5 JP 2010521458 A5 JP2010521458 A5 JP 2010521458A5 JP 2009553600 A JP2009553600 A JP 2009553600A JP 2009553600 A JP2009553600 A JP 2009553600A JP 2010521458 A5 JP2010521458 A5 JP 2010521458A5
- Authority
- JP
- Japan
- Prior art keywords
- group
- trifluoromethyl
- ylamino
- pyridin
- compound
- 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.)
- Granted
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- 150000001875 compounds Chemical class 0.000 claims description 251
- 238000000034 method Methods 0.000 claims description 210
- -1 cyano, thio, nitro Chemical group 0.000 claims description 200
- 239000000203 mixture Substances 0.000 claims description 97
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 91
- 125000000217 alkyl group Chemical group 0.000 claims description 57
- 125000003118 aryl group Chemical group 0.000 claims description 42
- 125000001072 heteroaryl group Chemical group 0.000 claims description 37
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 34
- 125000005842 heteroatom Chemical group 0.000 claims description 33
- 229910052799 carbon Inorganic materials 0.000 claims description 31
- 125000005843 halogen group Chemical group 0.000 claims description 29
- 229910052717 sulfur Inorganic materials 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 125000000623 heterocyclic group Chemical group 0.000 claims description 26
- 102000001253 Protein Kinase Human genes 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 108060006633 protein kinase Proteins 0.000 claims description 21
- 125000002950 monocyclic group Chemical group 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 18
- 229910052763 palladium Inorganic materials 0.000 claims description 18
- 241000124008 Mammalia Species 0.000 claims description 17
- 108091000080 Phosphotransferase Proteins 0.000 claims description 17
- 102000020233 phosphotransferase Human genes 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 125000004122 cyclic group Chemical group 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 16
- 201000011510 cancer Diseases 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- 230000002401 inhibitory effect Effects 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 210000001650 focal adhesion Anatomy 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 11
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 11
- 201000010099 disease Diseases 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 11
- 230000003211 malignant effect Effects 0.000 claims description 11
- 239000000651 prodrug Substances 0.000 claims description 11
- 229940002612 prodrug Drugs 0.000 claims description 11
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
- 239000003446 ligand Substances 0.000 claims description 9
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 230000002159 abnormal effect Effects 0.000 claims description 7
- 125000002619 bicyclic group Chemical group 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000004043 oxo group Chemical group O=* 0.000 claims description 7
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 7
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 6
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 6
- 230000009286 beneficial effect Effects 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 229910052723 transition metal Inorganic materials 0.000 claims description 6
- 150000003624 transition metals Chemical class 0.000 claims description 6
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 5
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 5
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- 238000000338 in vitro Methods 0.000 claims description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 5
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical compound C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 claims description 5
- 150000003852 triazoles Chemical class 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 3
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 108010067715 Focal Adhesion Protein-Tyrosine Kinases Proteins 0.000 claims description 2
- 102000016621 Focal Adhesion Protein-Tyrosine Kinases Human genes 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 230000036210 malignancy Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 125
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 110
- 238000005481 NMR spectroscopy Methods 0.000 description 97
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 77
- 239000007787 solid Substances 0.000 description 71
- 238000005160 1H NMR spectroscopy Methods 0.000 description 61
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 239000002904 solvent Substances 0.000 description 37
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 36
- 239000012043 crude product Substances 0.000 description 35
- 239000000243 solution Substances 0.000 description 35
- 235000019439 ethyl acetate Nutrition 0.000 description 34
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 33
- 229910000024 caesium carbonate Inorganic materials 0.000 description 33
- 238000010898 silica gel chromatography Methods 0.000 description 32
- 239000000047 product Substances 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 30
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 29
- 102100037813 Focal adhesion kinase 1 Human genes 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- YNNUSGIPVFPVBX-UHFFFAOYSA-N 2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine Chemical compound CN1CCCC1CCOC(C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-UHFFFAOYSA-N 0.000 description 22
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 22
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 22
- 229910052786 argon Inorganic materials 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- 150000003840 hydrochlorides Chemical class 0.000 description 16
- 238000002953 preparative HPLC Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 125000003277 amino group Chemical group 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 13
- BLDAPDVJFOJWMZ-UHFFFAOYSA-N 2-[[2-chloro-5-(trifluoromethyl)pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=CC(Cl)=NC=C1C(F)(F)F BLDAPDVJFOJWMZ-UHFFFAOYSA-N 0.000 description 12
- 238000003556 assay Methods 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- XEEQBBXEZSNIQV-UHFFFAOYSA-N 2-chloro-4-iodo-5-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CN=C(Cl)C=C1I XEEQBBXEZSNIQV-UHFFFAOYSA-N 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 10
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 9
- 239000003039 volatile agent Substances 0.000 description 9
- 239000003085 diluting agent Substances 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- OEBXWWBYZJNKRK-UHFFFAOYSA-N 1-methyl-2,3,4,6,7,8-hexahydropyrimido[1,2-a]pyrimidine Chemical compound C1CCN=C2N(C)CCCN21 OEBXWWBYZJNKRK-UHFFFAOYSA-N 0.000 description 7
- BQTMHUUWYHEPNQ-UHFFFAOYSA-N 2-methoxy-4-morpholin-4-ylaniline Chemical compound C1=C(N)C(OC)=CC(N2CCOCC2)=C1 BQTMHUUWYHEPNQ-UHFFFAOYSA-N 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 235000014113 dietary fatty acids Nutrition 0.000 description 7
- 239000000194 fatty acid Substances 0.000 description 7
- 229930195729 fatty acid Natural products 0.000 description 7
- 239000003999 initiator Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 125000004149 thio group Chemical group *S* 0.000 description 7
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001502 aryl halides Chemical class 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 description 6
- 125000001041 indolyl group Chemical group 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
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- 0 **Nc1cc(N*)ncc1* Chemical compound **Nc1cc(N*)ncc1* 0.000 description 5
- FBBFBZJZXFGFCK-UHFFFAOYSA-N 2-[[2-chloro-5-(trifluoromethyl)pyridin-4-yl]amino]-n-methylbenzenesulfonamide Chemical compound CNS(=O)(=O)C1=CC=CC=C1NC1=CC(Cl)=NC=C1C(F)(F)F FBBFBZJZXFGFCK-UHFFFAOYSA-N 0.000 description 5
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 150000001721 carbon Chemical class 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 102000006495 integrins Human genes 0.000 description 5
- 108010044426 integrins Proteins 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000001394 metastastic effect Effects 0.000 description 5
- 206010061289 metastatic neoplasm Diseases 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000011593 sulfur Substances 0.000 description 5
- 125000000335 thiazolyl group Chemical group 0.000 description 5
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 4
- HMYXHQDSYJOVBG-UHFFFAOYSA-N 2-chloro-n-(2-pyrimidin-2-ylphenyl)-5-(trifluoromethyl)pyridin-4-amine Chemical compound FC(F)(F)C1=CN=C(Cl)C=C1NC1=CC=CC=C1C1=NC=CC=N1 HMYXHQDSYJOVBG-UHFFFAOYSA-N 0.000 description 4
- CCFGTKQIRWHYTB-UHFFFAOYSA-N 2-methyl-3-nitropyridine Chemical compound CC1=NC=CC=C1[N+]([O-])=O CCFGTKQIRWHYTB-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 4
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
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- 229910052740 iodine Inorganic materials 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- IQEKCKQBCMCLQF-UHFFFAOYSA-N n,n-dimethyl-2-(5-nitro-1h-indol-3-yl)-2-oxoacetamide Chemical compound C1=C([N+]([O-])=O)C=C2C(C(=O)C(=O)N(C)C)=CNC2=C1 IQEKCKQBCMCLQF-UHFFFAOYSA-N 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000002971 oxazolyl group Chemical group 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- 125000003226 pyrazolyl group Chemical group 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- 125000003107 substituted aryl group Chemical group 0.000 description 4
- 125000001425 triazolyl group Chemical group 0.000 description 4
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 3
- WQYDASORCSDVNY-UHFFFAOYSA-N 2-[[5-bromo-2-(2-methoxy-4-morpholin-4-ylanilino)pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=CC(NC=2C(=CC(=CC=2)N2CCOCC2)OC)=NC=C1Br WQYDASORCSDVNY-UHFFFAOYSA-N 0.000 description 3
- SVIILPGBQTUQPJ-UHFFFAOYSA-N 2-[[5-chloro-2-(2-methoxy-4-morpholin-4-ylanilino)pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=CC(NC=2C(=CC(=CC=2)N2CCOCC2)OC)=NC=C1Cl SVIILPGBQTUQPJ-UHFFFAOYSA-N 0.000 description 3
- JMHVADDHAXZSPT-UHFFFAOYSA-N 2-[[5-cyano-2-(2-methoxy-4-morpholin-4-ylanilino)pyridin-4-yl]amino]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC=C1NC1=CC(NC=2C(=CC(=CC=2)N2CCOCC2)OC)=NC=C1C#N JMHVADDHAXZSPT-UHFFFAOYSA-N 0.000 description 3
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| GB0719644D0 (en) | 2007-10-05 | 2007-11-14 | Cancer Rec Tech Ltd | Therapeutic compounds and their use |
| GB0803018D0 (en) | 2008-02-19 | 2008-03-26 | Cancer Rec Tech Ltd | Therapeutic compounds and their use |
| JP2011512413A (ja) * | 2008-02-19 | 2011-04-21 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | Ｆａｋの阻害剤としてのアニリノピリジン |
| JP5551689B2 (ja) * | 2008-06-17 | 2014-07-16 | アストラゼネカ アクチボラグ | ピリジン化合物 |
| JO3067B1 (ar) * | 2008-10-27 | 2017-03-15 | Glaxosmithkline Llc | بيرميدينات بيرازولو امينو كمثبطات ل fak |
| JP2012511567A (ja) * | 2008-12-10 | 2012-05-24 | ドン ファ ファーム カンパニー リミテッド | 新規の２，６−置換−３−ニトロピリジン誘導体、その製造方法及びこれを含む薬学組成物 |
| US20120196858A1 (en) * | 2009-08-12 | 2012-08-02 | Poniard Pharmaceuticals ,Inc. | Method of promoting apoptosis and inhibiting metastasis |
| AU2011254550B2 (en) | 2010-05-21 | 2013-11-07 | Noviga Research Ab | Novel pyrimidine derivatives |
| MX340819B (es) * | 2010-06-29 | 2016-07-26 | Poniard Pharmaceuticals Inc * | Formulacion oral de inhibidores de quinasa. |
| CN103168037A (zh) * | 2010-06-30 | 2013-06-19 | 博尼亚德医药品股份有限公司 | 激酶抑制剂的合成和用途 |
| DE102010034699A1 (de) | 2010-08-18 | 2012-02-23 | Merck Patent Gmbh | Pyrimidinderivate |
| US20120244141A1 (en) | 2010-09-28 | 2012-09-27 | Boehringer Ingelheim International Gmbh | Stratification of cancer patients for susceptibility to therapy with PTK2 inhibitors |
| CA2825790A1 (en) * | 2011-01-26 | 2012-08-02 | Board Of Regents The University Of Texas System | Combinations |
| AU2012216893B2 (en) | 2011-02-17 | 2016-08-11 | Cancer Therapeutics Crc Pty Limited | FAK inhibitors |
| CN103534240B (zh) | 2011-02-17 | 2015-12-09 | 癌症疗法Crc私人有限公司 | 选择性fak抑制剂 |
| EP2688883B1 (en) | 2011-03-24 | 2016-05-18 | Noviga Research AB | Pyrimidine derivatives |
| DE102011111400A1 (de) | 2011-08-23 | 2013-02-28 | Merck Patent Gmbh | Bicyclische heteroaromatische Verbindungen |
| JP6073910B2 (ja) | 2011-11-09 | 2017-02-01 | キャンサー・リサーチ・テクノロジー・リミテッド | ５−（ピリジン−２−イル−アミノ）−ピラジン−２−カルボニトリル化合物及びその治療使用 |
| KR102341637B1 (ko) | 2012-05-15 | 2021-12-21 | 캔써 리서치 테크놀로지 리미티드 | 5-[[4-[[모르폴린-2-일]메틸아미노]-5-(트리플루오로메틸)-2-피리딜]아미노]피라진-2-카보니트릴 및 그의 치료적 용도 |
| HK1209742A1 (en) | 2012-11-20 | 2016-04-08 | 沃泰克斯药物股份有限公司 | Compounds useful as inhibitors of indoleamine 2,3-dioxygenase |
| CN105164114B (zh) * | 2013-05-01 | 2018-03-23 | 豪夫迈·罗氏有限公司 | C‑连接的杂环烷基取代的嘧啶类和它们的用途 |
| WO2015035199A1 (en) * | 2013-09-06 | 2015-03-12 | Mayo Foundation For Medical Education And Research | Neem compositions used for the treatment of cancer |
| WO2015054477A1 (en) | 2013-10-09 | 2015-04-16 | The General Hospital Corporation | Methods of diagnosing and treating b cell acute lymphoblastic leukemia |
| TWI713455B (zh) | 2014-06-25 | 2020-12-21 | 美商伊凡克特治療公司 | ＭｎＫ抑制劑及其相關方法 |
| AU2016286091B2 (en) | 2015-06-29 | 2021-02-04 | Verastem, Inc. | Therapeutic compositions, combinations, and methods of use |
| SG11201803242TA (en) | 2015-10-29 | 2018-05-30 | Effector Therapeutics Inc | Isoindoline, azaisoindoline, dihydroindenone and dihydroazaindenone inhibitors of mnk1 and mnk2 |
| CN108602814A (zh) | 2015-10-29 | 2018-09-28 | 效应治疗股份有限公司 | 抑制mnk1和mnk2的吡咯并-、吡唑并-、咪唑并-嘧啶和吡啶化合物 |
| WO2017087808A1 (en) | 2015-11-20 | 2017-05-26 | Effector Therapeutics, Inc. | Heterocyclic compounds that inhibit the kinase activity of mnk useful for treating various cancers |
| ES2829052T3 (es) | 2015-11-26 | 2021-05-28 | Novartis Ag | Derivados de diaminopiridina |
| JOP20190024A1 (ar) | 2016-08-26 | 2019-02-19 | Gilead Sciences Inc | مركبات بيروليزين بها استبدال واستخداماتها |
| JP2020507588A (ja) | 2017-02-14 | 2020-03-12 | イーフェクター セラピューティクス， インコーポレイテッド | ピぺリジン置換ＭｎＫ阻害剤およびそれに関連する方法 |
| KR102526964B1 (ko) | 2018-02-26 | 2023-04-28 | 길리애드 사이언시즈, 인코포레이티드 | Hbv 복제 억제제로서의 치환된 피롤리진 화합물 |
| AU2019236402A1 (en) | 2018-03-12 | 2020-10-01 | Assistance Publique-Hôpitaux De Paris (Aphp) | Use of caloric restriction mimetics for potentiating chemo-immunotherapy for the treatment of cancers |
| US20220040317A1 (en) * | 2018-09-27 | 2022-02-10 | Dana-Farber Cancer Institute, Inc. | Degradation of fak or fak and alk by conjugation of fak and alk inhibitors with e3 ligase ligands and methods of use |
| BR112021007745A2 (pt) | 2018-10-24 | 2021-07-27 | Effector Therapeutics, Inc. | formas cristalinas de inibidores de mnk |
| CN110724137B (zh) * | 2019-11-13 | 2021-03-30 | 广东工业大学 | 一种噻吩类衍生物及其制备方法与应用 |
| CN111233834B (zh) * | 2020-03-09 | 2021-08-31 | 北京师范大学 | 一类靶向fak的化合物和其标记物、及它们的制备方法和应用 |
| WO2021237121A1 (en) * | 2020-05-21 | 2021-11-25 | Gossamer Bio Services, Inc. | Substituted pyridines |
| CN114181257B (zh) * | 2020-09-14 | 2025-02-14 | 四川科伦博泰生物医药股份有限公司 | 吡啶类化合物，包含其的药物组合物，其制备方法及其用途 |
| EP4263523A2 (en) * | 2020-12-16 | 2023-10-25 | IFM Due, Inc. | Compounds and compositions for treating conditions associated with sting activity |
| GB202113079D0 (en) * | 2021-09-14 | 2021-10-27 | Ucl Business Ltd | New therapy |
| WO2023218245A1 (en) * | 2022-05-13 | 2023-11-16 | Voronoi Inc. | Heteroaryl derivative compounds, and pharmaceutical composition comprising thereof |
| WO2024251270A1 (zh) * | 2023-06-08 | 2024-12-12 | 希格生科（深圳）有限公司 | 含氮芳环化合物及其医药用途 |
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| GB0004888D0 (en) * | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
| GB0004887D0 (en) * | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
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| TW200409629A (en) * | 2002-06-27 | 2004-06-16 | Bristol Myers Squibb Co | 2,4-disubstituted-pyridine N-oxides useful as HIV reverse transcriptase inhibitors |
| US7585866B2 (en) * | 2002-07-31 | 2009-09-08 | Critical Outcome Technologies, Inc. | Protein tyrosine kinase inhibitors |
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| CN103641816A (zh) | 2006-12-08 | 2014-03-19 | Irm责任有限公司 | 作为蛋白激酶抑制剂的化合物和组合物 |
| CN101616895A (zh) | 2006-12-08 | 2009-12-30 | Irm责任有限公司 | 作为蛋白激酶抑制剂的化合物和组合物 |
| US8501763B2 (en) | 2007-03-16 | 2013-08-06 | The Scripps Research Institute | Inhibitors of focal adhesion kinase |
| JP2011512413A (ja) | 2008-02-19 | 2011-04-21 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | Ｆａｋの阻害剤としてのアニリノピリジン |
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