CA2803055A1 - Heteroaryl compounds and compositions as protein kinase inhibitors - Google Patents

Info

Publication number

CA2803055A1

CA2803055A1 CA2803055A CA2803055A CA2803055A1 CA 2803055 A1 CA2803055 A1 CA 2803055A1 CA 2803055 A CA2803055 A CA 2803055A CA 2803055 A CA2803055 A CA 2803055A CA 2803055 A1 CA2803055 A1 CA 2803055A1

Authority

CA

Canada

Prior art keywords

pyrimidin

chloro

compound

mmol

phenyl

Prior art date

2010-06-25

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

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• CIPO
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• 125000001072 heteroaryl group Chemical group 0.000 title claims description 13
• 239000000203 mixture Substances 0.000 title description 52
• 239000003909 protein kinase inhibitor Substances 0.000 title description 3
• 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 137
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 21
• 238000011282 treatment Methods 0.000 claims abstract description 20
• 201000011510 cancer Diseases 0.000 claims abstract description 16
• 238000000034 method Methods 0.000 claims description 100
• -1 P13K Proteins 0.000 claims description 39
• 150000003839 salts Chemical class 0.000 claims description 34
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
• 239000003814 drug Substances 0.000 claims description 30
• 229940124597 therapeutic agent Drugs 0.000 claims description 23
• 125000000217 alkyl group Chemical group 0.000 claims description 22
• 108091000080 Phosphotransferase Proteins 0.000 claims description 21
• 102000020233 phosphotransferase Human genes 0.000 claims description 21
• 229910052736 halogen Inorganic materials 0.000 claims description 18
• 239000003112 inhibitor Substances 0.000 claims description 17
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
• 229910052801 chlorine Inorganic materials 0.000 claims description 12
• 229910052731 fluorine Inorganic materials 0.000 claims description 12
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
• 229910052717 sulfur Inorganic materials 0.000 claims description 12
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
• 208000035475 disorder Diseases 0.000 claims description 11
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
• 108010077182 raf Kinases Proteins 0.000 claims description 11
• 102000009929 raf Kinases Human genes 0.000 claims description 11
• 229910052760 oxygen Inorganic materials 0.000 claims description 10
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
• 125000005843 halogen group Chemical group 0.000 claims description 9
• 229910052739 hydrogen Inorganic materials 0.000 claims description 9
• 108091054455 MAP kinase family Proteins 0.000 claims description 8
• 102000043136 MAP kinase family Human genes 0.000 claims description 8
• 239000003085 diluting agent Substances 0.000 claims description 8
• 206010009944 Colon cancer Diseases 0.000 claims description 7
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
• 230000001404 mediated effect Effects 0.000 claims description 7
• 201000001441 melanoma Diseases 0.000 claims description 7
• 208000003200 Adenoma Diseases 0.000 claims description 6
• 206010005003 Bladder cancer Diseases 0.000 claims description 6
• 230000001430 anti-depressive effect Effects 0.000 claims description 6
• 230000003474 anti-emetic effect Effects 0.000 claims description 6
• 239000002260 anti-inflammatory agent Substances 0.000 claims description 6
• 229940121363 anti-inflammatory agent Drugs 0.000 claims description 6
• 239000000935 antidepressant agent Substances 0.000 claims description 6
• 229940005513 antidepressants Drugs 0.000 claims description 6
• 239000002111 antiemetic agent Substances 0.000 claims description 6
• 201000001531 bladder carcinoma Diseases 0.000 claims description 6
• 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 6
• 201000005296 lung carcinoma Diseases 0.000 claims description 6
• 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
• 208000010570 urinary bladder carcinoma Diseases 0.000 claims description 6
• 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 claims description 5
• 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 claims description 5
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
• 206010060862 Prostate cancer Diseases 0.000 claims description 4
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
• 229940123690 Raf kinase inhibitor Drugs 0.000 claims description 4
• 208000024770 Thyroid neoplasm Diseases 0.000 claims description 4
• 239000002246 antineoplastic agent Substances 0.000 claims description 4
• 229940041181 antineoplastic drug Drugs 0.000 claims description 4
• 229910052794 bromium Inorganic materials 0.000 claims description 4
• 125000000623 heterocyclic group Chemical group 0.000 claims description 4
• 102000051624 phosphatidylethanolamine binding protein Human genes 0.000 claims description 4
• 108700021017 phosphatidylethanolamine binding protein Proteins 0.000 claims description 4
• 201000002510 thyroid cancer Diseases 0.000 claims description 4
• 101100181041 Arabidopsis thaliana KINUA gene Proteins 0.000 claims description 3
• 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 claims description 3
• 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 claims description 3
• 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 claims description 3
• 108090000315 Protein Kinase C Proteins 0.000 claims description 3
• 102000003923 Protein Kinase C Human genes 0.000 claims description 3
• 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 claims description 3
• 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 claims description 3
• 230000000202 analgesic effect Effects 0.000 claims description 3
• 230000001093 anti-cancer Effects 0.000 claims description 3
• 229940124583 pain medication Drugs 0.000 claims description 3
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
• XNEMSTQPJZUPKE-ZDUSSCGKSA-N methyl n-[(2s)-1-[[4-[4-[2-chloro-5-fluoro-3-(propylsulfonylamino)phenyl]-2-cyclopropyl-1,3-thiazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound CCCS(=O)(=O)NC1=CC(F)=CC(C2=C(SC(=N2)C2CC2)C=2N=C(NC[C@H](C)NC(=O)OC)N=CC=2)=C1Cl XNEMSTQPJZUPKE-ZDUSSCGKSA-N 0.000 claims description 2
• KIXAITHSFCNXHT-ZDUSSCGKSA-N methyl n-[(2s)-1-[[4-[4-[5-chloro-2-fluoro-3-(propylsulfonylamino)phenyl]-2-cyclopropyl-1,3-thiazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C2=C(SC(=N2)C2CC2)C=2N=C(NC[C@H](C)NC(=O)OC)N=CC=2)=C1F KIXAITHSFCNXHT-ZDUSSCGKSA-N 0.000 claims description 2
• VQYUTZHTANREQN-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-[2-(methylamino)pyrimidin-4-yl]-1,3-thiazol-4-yl]-5-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(F)=CC(C2=C(SC(=N2)C2CC2)C=2N=C(NC)N=CC=2)=C1Cl VQYUTZHTANREQN-UHFFFAOYSA-N 0.000 claims description 2
• DDUWRZARRSESMJ-UHFFFAOYSA-N n-[3-[5-(2-aminopyrimidin-4-yl)-2-cyclopropyl-1,3-oxazol-4-yl]-2,5-dichlorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C2=C(OC(=N2)C2CC2)C=2N=C(N)N=CC=2)=C1Cl DDUWRZARRSESMJ-UHFFFAOYSA-N 0.000 claims description 2
• RIRVVFAHOYCHPH-UHFFFAOYSA-N n-[3-[5-(2-aminopyrimidin-4-yl)-2-cyclopropyl-1,3-oxazol-4-yl]-5-chloro-2-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C2=C(OC(=N2)C2CC2)C=2N=C(N)N=CC=2)=C1F RIRVVFAHOYCHPH-UHFFFAOYSA-N 0.000 claims description 2
• MZPIULGDCVMOOW-UHFFFAOYSA-N n-[3-[5-(2-aminopyrimidin-4-yl)-2-cyclopropyl-1,3-thiazol-4-yl]-2,5-dichlorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C2=C(SC(=N2)C2CC2)C=2N=C(N)N=CC=2)=C1Cl MZPIULGDCVMOOW-UHFFFAOYSA-N 0.000 claims description 2
• DSKDWKRQSKYILI-UHFFFAOYSA-N n-[3-[5-(2-aminopyrimidin-4-yl)-2-cyclopropyl-1,3-thiazol-4-yl]-5-chloro-2-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C2=C(SC(=N2)C2CC2)C=2N=C(N)N=CC=2)=C1F DSKDWKRQSKYILI-UHFFFAOYSA-N 0.000 claims description 2
• 125000003107 substituted aryl group Chemical group 0.000 claims description 2
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
• DROIHSMGGKKIJT-UHFFFAOYSA-N propane-1-sulfonamide Chemical compound CCCS(N)(=O)=O DROIHSMGGKKIJT-UHFFFAOYSA-N 0.000 claims 1
• 201000010099 disease Diseases 0.000 abstract description 10
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 138
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 129
• 238000002360 preparation method Methods 0.000 description 119
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 118
• 239000000543 intermediate Substances 0.000 description 98
• 239000000243 solution Substances 0.000 description 94
• 238000006243 chemical reaction Methods 0.000 description 91
• 239000011541 reaction mixture Substances 0.000 description 72
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 70
• 235000019439 ethyl acetate Nutrition 0.000 description 68
• 239000012267 brine Substances 0.000 description 56
• 239000007858 starting material Substances 0.000 description 55
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 54
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 53
• 238000005160 1H NMR spectroscopy Methods 0.000 description 46
• 238000005481 NMR spectroscopy Methods 0.000 description 46
• 101150041968 CDC13 gene Proteins 0.000 description 43
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 43
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 43
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 41
• 239000000741 silica gel Substances 0.000 description 34
• 229910002027 silica gel Inorganic materials 0.000 description 34
• 239000000460 chlorine Substances 0.000 description 29
• 239000000463 material Substances 0.000 description 29
• 239000007787 solid Substances 0.000 description 29
• 229920006395 saturated elastomer Polymers 0.000 description 28
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
• 238000003818 flash chromatography Methods 0.000 description 24
• 239000010410 layer Substances 0.000 description 23
• 238000007792 addition Methods 0.000 description 22
• 238000003756 stirring Methods 0.000 description 22
• 238000000746 purification Methods 0.000 description 20
• 235000017557 sodium bicarbonate Nutrition 0.000 description 20
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
• 239000012071 phase Substances 0.000 description 19
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
• DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 18
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
• 101100381978 Mus musculus Braf gene Proteins 0.000 description 15
• KKVYYGGCHJGEFJ-UHFFFAOYSA-N 1-n-(4-chlorophenyl)-6-methyl-5-n-[3-(7h-purin-6-yl)pyridin-2-yl]isoquinoline-1,5-diamine Chemical compound N=1C=CC2=C(NC=3C(=CC=CN=3)C=3C=4N=CNC=4N=CN=3)C(C)=CC=C2C=1NC1=CC=C(Cl)C=C1 KKVYYGGCHJGEFJ-UHFFFAOYSA-N 0.000 description 14
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
• 239000002904 solvent Substances 0.000 description 14
• 238000010828 elution Methods 0.000 description 13
• 229910052757 nitrogen Inorganic materials 0.000 description 13
• 239000000047 product Substances 0.000 description 13
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
• 239000000725 suspension Substances 0.000 description 12
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 11
• SECXISVLQFMRJM-UHFFFAOYSA-N N-methyl-pyrrolidinone Natural products CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 11
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 11
• 239000000284 extract Substances 0.000 description 11
• 239000006260 foam Substances 0.000 description 11
• 229940124530 sulfonamide Drugs 0.000 description 11
• 210000003050 axon Anatomy 0.000 description 10
• 230000002051 biphasic effect Effects 0.000 description 10
• 239000000706 filtrate Substances 0.000 description 10
• 150000002367 halogens Chemical group 0.000 description 10
• 230000006698 induction Effects 0.000 description 10
• KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 description 10
• 230000000694 effects Effects 0.000 description 9
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
• 238000003556 assay Methods 0.000 description 8
• 210000004027 cell Anatomy 0.000 description 8
• 239000003795 chemical substances by application Substances 0.000 description 8
• 229940043355 kinase inhibitor Drugs 0.000 description 8
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 8
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
• 239000012044 organic layer Substances 0.000 description 8
• 239000012074 organic phase Substances 0.000 description 8
• XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 description 8
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
• 229930194542 Keto Natural products 0.000 description 7
• 239000002253 acid Substances 0.000 description 7
• 239000004480 active ingredient Substances 0.000 description 7
• 239000003153 chemical reaction reagent Substances 0.000 description 7
• 125000000468 ketone group Chemical group 0.000 description 7
• 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 7
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
• 239000003757 phosphotransferase inhibitor Substances 0.000 description 7
• 108010014186 ras Proteins Proteins 0.000 description 7
• 102000016914 ras Proteins Human genes 0.000 description 7
• 230000011664 signaling Effects 0.000 description 7
• 235000017550 sodium carbonate Nutrition 0.000 description 7
• 229910000029 sodium carbonate Inorganic materials 0.000 description 7
• 239000012064 sodium phosphate buffer Substances 0.000 description 7
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
• 229940124647 MEK inhibitor Drugs 0.000 description 6
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 6
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
• 239000008346 aqueous phase Substances 0.000 description 6
• 239000000872 buffer Substances 0.000 description 6
• QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 6
• 125000000753 cycloalkyl group Chemical group 0.000 description 6
• 150000002085 enols Chemical group 0.000 description 6
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
• HNQIVZYLYMDVSB-NJFSPNSNSA-N methanesulfonamide Chemical compound [14CH3]S(N)(=O)=O HNQIVZYLYMDVSB-NJFSPNSNSA-N 0.000 description 6
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
• RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 6
• XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 6
• YKLQJWZIYVPXQL-UHFFFAOYSA-N n-[3-[2-bromo-2-(2-methylsulfanylpyrimidin-4-yl)acetyl]-2-chloro-5-fluorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C(Br)C(=O)C=2C(=C(NC(=O)C(C)(C)C)C=C(F)C=2)Cl)=N1 YKLQJWZIYVPXQL-UHFFFAOYSA-N 0.000 description 6
• 150000003456 sulfonamides Chemical class 0.000 description 6
• UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
• 125000003118 aryl group Chemical group 0.000 description 5
• 239000011324 bead Substances 0.000 description 5
• 230000004663 cell proliferation Effects 0.000 description 5
• 125000001309 chloro group Chemical group Cl* 0.000 description 5
• 239000013058 crude material Substances 0.000 description 5
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
• 150000002576 ketones Chemical class 0.000 description 5
• DWEFRJKQXMDLOV-UHFFFAOYSA-N n-[3-[2-bromo-2-(2-methylsulfanylpyrimidin-4-yl)acetyl]-5-chloro-2-fluorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C(Br)C(=O)C=2C(=C(NC(=O)C(C)(C)C)C=C(Cl)C=2)F)=N1 DWEFRJKQXMDLOV-UHFFFAOYSA-N 0.000 description 5
• 230000037361 pathway Effects 0.000 description 5
• 239000008177 pharmaceutical agent Substances 0.000 description 5
• 238000002953 preparative HPLC Methods 0.000 description 5
• 230000002441 reversible effect Effects 0.000 description 5
• 239000012453 solvate Substances 0.000 description 5
• 235000011149 sulphuric acid Nutrition 0.000 description 5
• JQXZBJAAOLPTKP-LURJTMIESA-N tert-butyl n-[(2s)-1-aminopropan-2-yl]carbamate Chemical compound NC[C@H](C)NC(=O)OC(C)(C)C JQXZBJAAOLPTKP-LURJTMIESA-N 0.000 description 5
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
• JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 4
• IQISDKYMIPPETH-UHFFFAOYSA-N 2-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-5-fluoroaniline Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C2CC2)C=2C(=C(N)C=C(F)C=2)Cl)=N1 IQISDKYMIPPETH-UHFFFAOYSA-N 0.000 description 4
• BHAKRVSCGILCEW-UHFFFAOYSA-N 2-chloro-4-methylpyrimidine Chemical compound CC1=CC=NC(Cl)=N1 BHAKRVSCGILCEW-UHFFFAOYSA-N 0.000 description 4
• UCERVHYBSTYCQS-UHFFFAOYSA-N 4-methyl-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC(C)=N1 UCERVHYBSTYCQS-UHFFFAOYSA-N 0.000 description 4
• AIPRBUGPVUCEOB-UHFFFAOYSA-N 5-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-oxazol-4-yl]-2-fluoroaniline Chemical compound CSC1=NC=CC(C2=C(N=C(O2)C2CC2)C=2C(=C(N)C=C(Cl)C=2)F)=N1 AIPRBUGPVUCEOB-UHFFFAOYSA-N 0.000 description 4
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