CA2803055A1

CA2803055A1 - Heteroaryl compounds and compositions as protein kinase inhibitors

Heteroaryl compounds and compositions as protein kinase inhibitors Download PDF

Info

Publication number: CA2803055A1
Authority: CA; Canada
Prior art keywords: pyrimidin; chloro; compound; mmol; phenyl
Prior art date: 2010-06-25
Legal status : Abandoned

Application number

CA2803055A

Other languages

English (en)

French (fr)

Inventor

Ann Marie Madera

Daniel Poon

Aaron Smith

Current Assignee

Novartis AG

Original Assignee

Novartis AG

Priority date

2010-06-25

Filing date

2011-06-23

Publication date

2011-12-29

2011-06-23 Application filed by Novartis AG filed Critical Novartis AG

2011-12-29 Publication of CA2803055A1 publication Critical patent/CA2803055A1/en

Status Abandoned legal-status Critical Current

Links

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
XKDXKIAPLXNONX-UHFFFAOYSA-N 5-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-fluoroaniline Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C2CC2)C=2C(=C(N)C=C(Cl)C=2)F)=N1 XKDXKIAPLXNONX-UHFFFAOYSA-N 0.000 description 4
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
101710113436 GTPase KRas Proteins 0.000 description 4
JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 4
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