NZ572200A - Method of inhibiting c-kit kinase - Google Patents

Info

Publication number

NZ572200A

NZ572200A NZ572200A NZ57220007A NZ572200A NZ 572200 A NZ572200 A NZ 572200A NZ 572200 A NZ572200 A NZ 572200A NZ 57220007 A NZ57220007 A NZ 57220007A NZ 572200 A NZ572200 A NZ 572200A

Authority

NZ

New Zealand

Prior art keywords

carboxylic acid

phenyl

cyano

mmol

enyl

Prior art date

2006-04-20

Links

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• Global Dossier
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• 238000000034 method Methods 0.000 title claims description 94
• 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 title description 14
• 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 title description 14
• 230000002401 inhibitory effect Effects 0.000 title description 8
• 150000001875 compounds Chemical class 0.000 claims abstract description 323
• 239000003795 chemical substances by application Substances 0.000 claims abstract description 24
• 230000008685 targeting Effects 0.000 claims abstract description 17
• 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims abstract description 10
• 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims abstract description 10
• 208000008585 mastocytosis Diseases 0.000 claims abstract description 6
• 150000003839 salts Chemical class 0.000 claims description 27
• 239000012453 solvate Substances 0.000 claims description 23
• 238000002360 preparation method Methods 0.000 claims description 16
• 239000003814 drug Substances 0.000 claims description 11
• 239000002246 antineoplastic agent Substances 0.000 claims description 9
• 229940127089 cytotoxic agent Drugs 0.000 claims description 9
• 238000001959 radiotherapy Methods 0.000 claims description 6
• GUBJNPWVIUFSTR-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1h-imidazole-2-carboxamide Chemical compound C1CN(C(=O)CN(C)C)CCC1C(C=C1C=2CCCCC=2)=CC=C1NC(=O)C1=NC(C#N)=CN1 GUBJNPWVIUFSTR-UHFFFAOYSA-N 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 285
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 190
• 239000000203 mixture Substances 0.000 description 148
• 239000000243 solution Substances 0.000 description 122
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 105
• -1 2,2,4-trimethylpentyl Chemical group 0.000 description 98
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 97
• 238000001819 mass spectrum Methods 0.000 description 97
• 235000019439 ethyl acetate Nutrition 0.000 description 92
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 89
• XTDRPNJABDWQFI-UHFFFAOYSA-N 5-cyano-1h-imidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC(C#N)=CN1 XTDRPNJABDWQFI-UHFFFAOYSA-N 0.000 description 88
• 239000007787 solid Substances 0.000 description 83
• 238000006243 chemical reaction Methods 0.000 description 78
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 76
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 71
• 229910001868 water Inorganic materials 0.000 description 67
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 58
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
• 238000005481 NMR spectroscopy Methods 0.000 description 54
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 50
• 229910052739 hydrogen Inorganic materials 0.000 description 49
• 239000001257 hydrogen Substances 0.000 description 47
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
• 210000004027 cell Anatomy 0.000 description 41
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
• 208000035475 disorder Diseases 0.000 description 39
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
• 239000002904 solvent Substances 0.000 description 38
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
• 238000005160 1H NMR spectroscopy Methods 0.000 description 34
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 34
• 239000000741 silica gel Substances 0.000 description 34
• 229910002027 silica gel Inorganic materials 0.000 description 34
• 239000012267 brine Substances 0.000 description 33
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
• BPMBNLJJRKCCRT-UHFFFAOYSA-N 4-phenylbenzonitrile Chemical compound C1=CC(C#N)=CC=C1C1=CC=CC=C1 BPMBNLJJRKCCRT-UHFFFAOYSA-N 0.000 description 32
• 239000012044 organic layer Substances 0.000 description 32
• 239000000377 silicon dioxide Substances 0.000 description 32
• 125000003277 amino group Chemical group 0.000 description 31
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 29
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 29
• 229910052757 nitrogen Inorganic materials 0.000 description 29
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 28
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
• 125000003118 aryl group Chemical group 0.000 description 26
• 239000011541 reaction mixture Substances 0.000 description 26
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 25
• MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 25
• 230000002829 reductive effect Effects 0.000 description 25
• 235000002639 sodium chloride Nutrition 0.000 description 25
• 238000011282 treatment Methods 0.000 description 25
• 125000000217 alkyl group Chemical group 0.000 description 24
• 206010028980 Neoplasm Diseases 0.000 description 23
• 101150041968 CDC13 gene Proteins 0.000 description 21
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 21
• 125000003545 alkoxy group Chemical group 0.000 description 20
• 229920006395 saturated elastomer Polymers 0.000 description 20
• 125000002768 hydroxyalkyl group Chemical group 0.000 description 19
• 229910052760 oxygen Inorganic materials 0.000 description 19
• 238000000746 purification Methods 0.000 description 19
• 238000006467 substitution reaction Methods 0.000 description 19
• 239000000725 suspension Substances 0.000 description 19
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 18
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 18
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 18
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 18
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 17
• 238000003756 stirring Methods 0.000 description 17
• 108091000080 Phosphotransferase Proteins 0.000 description 16
• 150000002431 hydrogen Chemical class 0.000 description 16
• 102000020233 phosphotransferase Human genes 0.000 description 16
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
• 238000004007 reversed phase HPLC Methods 0.000 description 16
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 15
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 238000006069 Suzuki reaction reaction Methods 0.000 description 15
• 125000003282 alkyl amino group Chemical group 0.000 description 15
• 229910052799 carbon Inorganic materials 0.000 description 15
• 125000004093 cyano group Chemical group *C#N 0.000 description 15
• 125000004122 cyclic group Chemical group 0.000 description 15
• 125000000753 cycloalkyl group Chemical group 0.000 description 15
• 238000003818 flash chromatography Methods 0.000 description 15
• 238000002414 normal-phase solid-phase extraction Methods 0.000 description 15
• 239000003921 oil Substances 0.000 description 15
• 235000019198 oils Nutrition 0.000 description 15
• 238000003786 synthesis reaction Methods 0.000 description 15
• 230000000694 effects Effects 0.000 description 14
• 125000002541 furyl group Chemical group 0.000 description 14
• 125000004076 pyridyl group Chemical group 0.000 description 14
• 150000001412 amines Chemical class 0.000 description 13
• 230000015572 biosynthetic process Effects 0.000 description 13
• 125000002883 imidazolyl group Chemical group 0.000 description 13
• 230000035755 proliferation Effects 0.000 description 13
• 239000003826 tablet Substances 0.000 description 13
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
• 239000002253 acid Substances 0.000 description 12
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 12
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 12
• 238000004587 chromatography analysis Methods 0.000 description 12
• 239000012230 colorless oil Substances 0.000 description 12
• 235000019441 ethanol Nutrition 0.000 description 12
• 229910052736 halogen Inorganic materials 0.000 description 12
• 150000002367 halogens Chemical group 0.000 description 12
• 239000010410 layer Substances 0.000 description 12
• 239000001301 oxygen Substances 0.000 description 12
• XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 12
• 239000000047 product Substances 0.000 description 12
• 230000002062 proliferating effect Effects 0.000 description 12
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 11
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
• 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 11
• 201000010099 disease Diseases 0.000 description 11
• 125000001072 heteroaryl group Chemical group 0.000 description 11
• 150000004677 hydrates Chemical class 0.000 description 11
• SVVAEQDRNMUYKO-UHFFFAOYSA-N 2-(cyclohexen-1-yl)-4-piperidin-4-ylaniline 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.NC1=CC=C(C2CCNCC2)C=C1C1=CCCCC1 SVVAEQDRNMUYKO-UHFFFAOYSA-N 0.000 description 10
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
• 125000001309 chloro group Chemical group Cl* 0.000 description 10
• 238000005859 coupling reaction Methods 0.000 description 10
• 238000002875 fluorescence polarization Methods 0.000 description 10
• 239000007858 starting material Substances 0.000 description 10
• 125000005942 tetrahydropyridyl group Chemical group 0.000 description 10
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 9
• 208000031261 Acute myeloid leukaemia Diseases 0.000 description 9
• 125000003710 aryl alkyl group Chemical group 0.000 description 9
• 125000004663 dialkyl amino group Chemical group 0.000 description 9
• 150000002148 esters Chemical class 0.000 description 9
• 125000001153 fluoro group Chemical group F* 0.000 description 9
• 125000000842 isoxazolyl group Chemical group 0.000 description 9
• 125000002971 oxazolyl group Chemical group 0.000 description 9
• 239000008194 pharmaceutical composition Substances 0.000 description 9
• 229910000027 potassium carbonate Inorganic materials 0.000 description 9
• 125000000168 pyrrolyl group Chemical group 0.000 description 9
• 229910000029 sodium carbonate Inorganic materials 0.000 description 9
• 238000002560 therapeutic procedure Methods 0.000 description 9
• 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 8
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
• HHHCADSYQQJUGV-UHFFFAOYSA-N 5-cyanofuran-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(C#N)O1 HHHCADSYQQJUGV-UHFFFAOYSA-N 0.000 description 8
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
• 125000004103 aminoalkyl group Chemical group 0.000 description 8
• 239000002775 capsule Substances 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• XZWQKJXJNKYMAP-UHFFFAOYSA-N cyclohexen-1-ylboronic acid Chemical compound OB(O)C1=CCCCC1 XZWQKJXJNKYMAP-UHFFFAOYSA-N 0.000 description 8
• 125000001188 haloalkyl group Chemical group 0.000 description 8
• 125000004475 heteroaralkyl group Chemical group 0.000 description 8
• 125000005842 heteroatom Chemical group 0.000 description 8
• 125000005191 hydroxyalkylamino group Chemical group 0.000 description 8
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 8
• 230000005764 inhibitory process Effects 0.000 description 8
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
• 238000012746 preparative thin layer chromatography Methods 0.000 description 8
• 108090000623 proteins and genes Proteins 0.000 description 8
• 238000012552 review Methods 0.000 description 8
• 238000010898 silica gel chromatography Methods 0.000 description 8
• 239000002002 slurry Substances 0.000 description 8
• 229910052717 sulfur Inorganic materials 0.000 description 8
• GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 7
• 230000037396 body weight Effects 0.000 description 7
• 150000001721 carbon Chemical group 0.000 description 7
• 230000008878 coupling Effects 0.000 description 7
• 238000010168 coupling process Methods 0.000 description 7
• 125000004990 dihydroxyalkyl group Chemical group 0.000 description 7
• 239000003937 drug carrier Substances 0.000 description 7
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
• 230000009467 reduction Effects 0.000 description 7
• 229910052701 rubidium Inorganic materials 0.000 description 7
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
• WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
• 239000004480 active ingredient Substances 0.000 description 6
• 239000011230 binding agent Substances 0.000 description 6
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 6
• 125000004432 carbon atom Chemical group C* 0.000 description 6
• 125000005518 carboxamido group Chemical group 0.000 description 6
• 239000000969 carrier Substances 0.000 description 6
• 230000014509 gene expression Effects 0.000 description 6
• 239000007788 liquid Substances 0.000 description 6
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
• 238000007254 oxidation reaction Methods 0.000 description 6
• 235000015320 potassium carbonate Nutrition 0.000 description 6
• BNQGKHUEVQWESM-UHFFFAOYSA-M potassium;4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylate Chemical compound [K+].C[Si](C)(C)CCOCN1C=C(C#N)N=C1C([O-])=O BNQGKHUEVQWESM-UHFFFAOYSA-M 0.000 description 6
• 229940002612 prodrug Drugs 0.000 description 6
• 239000000651 prodrug Substances 0.000 description 6
• 125000001424 substituent group Chemical group 0.000 description 6
• 125000001544 thienyl group Chemical group 0.000 description 6
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
• SQMINWFWFXVWHK-UHFFFAOYSA-N 4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylic acid Chemical compound C[Si](C)(C)CCOCN1C=C(C#N)N=C1C(O)=O SQMINWFWFXVWHK-UHFFFAOYSA-N 0.000 description 5
• AYFFPEOVSJSGAT-UHFFFAOYSA-N 5-cyano-n-[2-(cyclohexen-1-yl)-4-piperidin-4-ylphenyl]-1h-imidazole-2-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.N=1C(C#N)=CNC=1C(=O)NC1=CC=C(C2CCNCC2)C=C1C1=CCCCC1 AYFFPEOVSJSGAT-UHFFFAOYSA-N 0.000 description 5
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
• 201000003793 Myelodysplastic syndrome Diseases 0.000 description 5
• 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 5
• 238000006619 Stille reaction Methods 0.000 description 5
• RSWGJHLUYNHPMX-ONCXSQPRSA-N abietic acid Chemical compound C([C@@H]12)CC(C(C)C)=CC1=CC[C@@H]1[C@]2(C)CCC[C@@]1(C)C(O)=O RSWGJHLUYNHPMX-ONCXSQPRSA-N 0.000 description 5
• 230000004913 activation Effects 0.000 description 5
• 150000001408 amides Chemical class 0.000 description 5
• 229910021529 ammonia Inorganic materials 0.000 description 5
• 239000002585 base Substances 0.000 description 5
• 125000005620 boronic acid group Chemical class 0.000 description 5
• 125000001246 bromo group Chemical group Br* 0.000 description 5
• 239000011203 carbon fibre reinforced carbon Substances 0.000 description 5
• 239000012043 crude product Substances 0.000 description 5
• 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 5
• 229940079593 drug Drugs 0.000 description 5
• 125000000623 heterocyclic group Chemical group 0.000 description 5
• 239000003112 inhibitor Substances 0.000 description 5
• 239000000543 intermediate Substances 0.000 description 5
• 208000032839 leukemia Diseases 0.000 description 5
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
• 230000036210 malignancy Effects 0.000 description 5
• 239000000463 material Substances 0.000 description 5
• 125000000896 monocarboxylic acid group Chemical group 0.000 description 5
• 230000035772 mutation Effects 0.000 description 5
• 230000001613 neoplastic effect Effects 0.000 description 5
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
• 230000003647 oxidation Effects 0.000 description 5
• 239000006187 pill Substances 0.000 description 5
• 239000000843 powder Substances 0.000 description 5
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
• 239000000523 sample Substances 0.000 description 5
• UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 description 5
• 210000004881 tumor cell Anatomy 0.000 description 5
• HBDRPHJEILPZNR-UHFFFAOYSA-N 2-(cyclohexen-1-yl)-4-(1-methoxypiperidin-4-yl)aniline 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CN(OC)CCC1C1=CC=C(N)C(C=2CCCCC=2)=C1 HBDRPHJEILPZNR-UHFFFAOYSA-N 0.000 description 4
• PNUYPUHKYGQCQF-UHFFFAOYSA-N 2-(cyclohexen-1-yl)-4-(4-methylpiperazin-1-yl)aniline Chemical compound C1CN(C)CCN1C1=CC=C(N)C(C=2CCCCC=2)=C1 PNUYPUHKYGQCQF-UHFFFAOYSA-N 0.000 description 4
• KMVOPBQPFUYFHA-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)-2-(4-methylthiophen-3-yl)aniline Chemical compound C1CN(C)CCN1C1=CC=C(N)C(C=2C(=CSC=2)C)=C1 KMVOPBQPFUYFHA-UHFFFAOYSA-N 0.000 description 4
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