SG178351A1 - Compounds and compositions as protein kinase inhibitors - Google Patents

Info

Publication number

SG178351A1

SG178351A1 SG2012009304A SG2012009304A SG178351A1 SG 178351 A1 SG178351 A1 SG 178351A1 SG 2012009304 A SG2012009304 A SG 2012009304A SG 2012009304 A SG2012009304 A SG 2012009304A SG 178351 A1 SG178351 A1 SG 178351A1

Authority

SG

Singapore

Prior art keywords

propan

pyrazol

pyrimidin

methyl

chloro

Prior art date

2009-08-28

Links

• Espacenet
• Global Dossier
• Discuss

• 150000001875 compounds Chemical class 0.000 title claims abstract description 305
• 239000000203 mixture Substances 0.000 title description 182
• 239000003909 protein kinase inhibitor Substances 0.000 title description 3
• 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 2
• 238000000034 method Methods 0.000 claims abstract description 40
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 30
• 108091000080 Phosphotransferase Proteins 0.000 claims abstract description 23
• 102000020233 phosphotransferase Human genes 0.000 claims abstract description 23
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
• 208000035475 disorder Diseases 0.000 claims abstract description 10
• -1 cyano, hydroxyl Chemical group 0.000 claims description 45
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
• 229910052739 hydrogen Inorganic materials 0.000 claims description 37
• 239000001257 hydrogen Substances 0.000 claims description 35
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 31
• 150000003839 salts Chemical class 0.000 claims description 31
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 26
• 238000011282 treatment Methods 0.000 claims description 25
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 24
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
• 206010028980 Neoplasm Diseases 0.000 claims description 23
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 21
• 239000003112 inhibitor Substances 0.000 claims description 21
• 125000000217 alkyl group Chemical group 0.000 claims description 20
• 125000001153 fluoro group Chemical group F* 0.000 claims description 18
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 17
• 229910000029 sodium carbonate Inorganic materials 0.000 claims description 16
• 150000002431 hydrogen Chemical class 0.000 claims description 15
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 14
• 125000005843 halogen group Chemical group 0.000 claims description 14
• 235000017550 sodium carbonate Nutrition 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 12
• 229940124597 therapeutic agent Drugs 0.000 claims description 12
• 125000003118 aryl group Chemical group 0.000 claims description 11
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
• 229940124647 MEK inhibitor Drugs 0.000 claims description 10
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
• 125000001072 heteroaryl group Chemical group 0.000 claims description 10
• 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 claims description 10
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 9
• 102000043136 MAP kinase family Human genes 0.000 claims description 8
• 108091054455 MAP kinase family Proteins 0.000 claims description 8
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
• 201000011510 cancer Diseases 0.000 claims description 7
• VWEMYHDJVJQLKH-JTQLQIEISA-N methyl n-[(2s)-1-[[4-(3-iodo-1-propan-2-ylpyrazol-4-yl)pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)I)=N1 VWEMYHDJVJQLKH-JTQLQIEISA-N 0.000 claims description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
• 229940002612 prodrug Drugs 0.000 claims description 7
• 239000000651 prodrug Substances 0.000 claims description 7
• ZSCAXCZFFCKFAE-UHFFFAOYSA-N 3-bromo-5-chloro-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC(Br)=C1F ZSCAXCZFFCKFAE-UHFFFAOYSA-N 0.000 claims description 6
• 201000009030 Carcinoma Diseases 0.000 claims description 6
• 229920002472 Starch Polymers 0.000 claims description 6
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
• 108010077182 raf Kinases Proteins 0.000 claims description 6
• 102000009929 raf Kinases Human genes 0.000 claims description 6
• 235000019698 starch Nutrition 0.000 claims description 6
• ROQBTCYBYFOFJH-UHFFFAOYSA-N tert-butyl n-(3-bromo-5-chloro-2-fluorophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(Cl)=CC(Br)=C1F ROQBTCYBYFOFJH-UHFFFAOYSA-N 0.000 claims description 6
• SOUCBWOXSGFWMF-AATRIKPKSA-N (e)-3-(dimethylamino)-1-(3-iodo-1-propan-2-ylpyrazol-4-yl)prop-2-en-1-one Chemical compound CC(C)N1C=C(C(=O)\C=C\N(C)C)C(I)=N1 SOUCBWOXSGFWMF-AATRIKPKSA-N 0.000 claims description 5
• NVQXUVPDZGMTOH-UHFFFAOYSA-N 2-chloro-4-(3-iodo-1-propan-2-ylpyrazol-4-yl)pyrimidine Chemical compound IC1=NN(C(C)C)C=C1C1=CC=NC(Cl)=N1 NVQXUVPDZGMTOH-UHFFFAOYSA-N 0.000 claims description 5
• LNIAYEZWZUPIGS-UHFFFAOYSA-N 4-(2-methylsulfanylpyrimidin-4-yl)-1-propan-2-ylpyrazol-3-amine Chemical compound CSC1=NC=CC(C=2C(=NN(C=2)C(C)C)N)=N1 LNIAYEZWZUPIGS-UHFFFAOYSA-N 0.000 claims description 5
• CLKDOEFITZFAQG-UHFFFAOYSA-N 6-(3-iodo-1-propan-2-ylpyrazol-4-yl)-1h-pyrimidin-2-one Chemical compound IC1=NN(C(C)C)C=C1C1=CC=NC(O)=N1 CLKDOEFITZFAQG-UHFFFAOYSA-N 0.000 claims description 5
• 206010009944 Colon cancer Diseases 0.000 claims description 5
• FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 5
• FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
• FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 5
• 229930195725 Mannitol Natural products 0.000 claims description 5
• 206010060862 Prostate cancer Diseases 0.000 claims description 5
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
• DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 5
• 239000001913 cellulose Substances 0.000 claims description 5
• 235000010355 mannitol Nutrition 0.000 claims description 5
• 239000000594 mannitol Substances 0.000 claims description 5
• 201000001441 melanoma Diseases 0.000 claims description 5
• BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 claims description 5
• 239000000600 sorbitol Substances 0.000 claims description 5
• 235000010356 sorbitol Nutrition 0.000 claims description 5
• 229940032147 starch Drugs 0.000 claims description 5
• 239000008107 starch Substances 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
• YFDOOBMHAJTEEL-UHFFFAOYSA-N 2,4-dibromo-3,6-dichloroaniline Chemical compound NC1=C(Cl)C=C(Br)C(Cl)=C1Br YFDOOBMHAJTEEL-UHFFFAOYSA-N 0.000 claims description 4
• ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims description 4
• LXMXPKGROLGLJT-UHFFFAOYSA-N 2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(F)=CC(N)=C1Cl LXMXPKGROLGLJT-UHFFFAOYSA-N 0.000 claims description 4
• KWNDFHCAHOPJIT-UHFFFAOYSA-N 4-(3-iodo-1-propan-2-ylpyrazol-4-yl)pyrimidin-2-amine Chemical compound IC1=NN(C(C)C)C=C1C1=CC=NC(N)=N1 KWNDFHCAHOPJIT-UHFFFAOYSA-N 0.000 claims description 4
• VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
• VIUAUNHCRHHYNE-JTQLQIEISA-N N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide Chemical compound OC[C@@H](O)CNC(=O)C1=CC=NC=C1NC1=CC=C(I)C=C1F VIUAUNHCRHHYNE-JTQLQIEISA-N 0.000 claims description 4
• BSMCAPRUBJMWDF-KRWDZBQOSA-N cobimetinib Chemical compound C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F BSMCAPRUBJMWDF-KRWDZBQOSA-N 0.000 claims description 4
• 229960002271 cobimetinib Drugs 0.000 claims description 4
• 210000001508 eye Anatomy 0.000 claims description 4
• CMJCXYNUCSMDBY-ZDUSSCGKSA-N lgx818 Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 CMJCXYNUCSMDBY-ZDUSSCGKSA-N 0.000 claims description 4
• 210000004185 liver Anatomy 0.000 claims description 4
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
• 210000000653 nervous system Anatomy 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• WAJWXGIIQOTWJW-UHFFFAOYSA-N tert-butyl 2-cyano-2-(2-methylsulfanylpyrimidin-4-yl)acetate Chemical compound CSC1=NC=CC(C(C#N)C(=O)OC(C)(C)C)=N1 WAJWXGIIQOTWJW-UHFFFAOYSA-N 0.000 claims description 4
• WDHVFZPKWBEOCL-UHFFFAOYSA-N 1-(3-iodo-1-methylpyrazol-4-yl)ethanone Chemical compound CC(=O)C1=CN(C)N=C1I WDHVFZPKWBEOCL-UHFFFAOYSA-N 0.000 claims description 3
• UCOLLSRIDVGQAA-UHFFFAOYSA-N 2,3,6-trifluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(F)=C(F)C(N)=C1F UCOLLSRIDVGQAA-UHFFFAOYSA-N 0.000 claims description 3
• ZBGAPLDNRPQMAM-UHFFFAOYSA-N 2,5-dichloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(Cl)=CC(N)=C1Cl ZBGAPLDNRPQMAM-UHFFFAOYSA-N 0.000 claims description 3
• FTUCLOKSCWKQOJ-UHFFFAOYSA-N 2-[[(benzylideneamino)-ethylamino]methylidene]propanedinitrile Chemical compound N#CC(C#N)=CN(CC)N=CC1=CC=CC=C1 FTUCLOKSCWKQOJ-UHFFFAOYSA-N 0.000 claims description 3
• JJHQDSMGGUVBJP-UHFFFAOYSA-N 3-(dimethylamino)-1-(1-ethyl-3-iodopyrazol-4-yl)prop-2-en-1-one Chemical compound CCN1C=C(C(=O)C=CN(C)C)C(I)=N1 JJHQDSMGGUVBJP-UHFFFAOYSA-N 0.000 claims description 3
• YQWCMZNQBZRUHQ-UHFFFAOYSA-N 3-(dimethylamino)-1-(3-iodo-1-methylpyrazol-4-yl)prop-2-en-1-one Chemical compound CN(C)C=CC(=O)C1=CN(C)N=C1I YQWCMZNQBZRUHQ-UHFFFAOYSA-N 0.000 claims description 3
• QDMBSUYYBOHAMQ-UHFFFAOYSA-N 3-[[4-(3-iodo-1-propan-2-ylpyrazol-4-yl)pyrimidin-2-yl]amino]propanenitrile Chemical compound IC1=NN(C(C)C)C=C1C1=CC=NC(NCCC#N)=N1 QDMBSUYYBOHAMQ-UHFFFAOYSA-N 0.000 claims description 3
• ZAOKQCUBWKXHMH-UHFFFAOYSA-N 3-bromo-2,5,6-trifluoroaniline Chemical compound NC1=C(F)C(F)=CC(Br)=C1F ZAOKQCUBWKXHMH-UHFFFAOYSA-N 0.000 claims description 3
• JBGGFYZUDGDHMN-UHFFFAOYSA-N 3-bromo-2,5-difluoroaniline Chemical compound NC1=CC(F)=CC(Br)=C1F JBGGFYZUDGDHMN-UHFFFAOYSA-N 0.000 claims description 3
• GTTQRVGVEIXEHQ-UHFFFAOYSA-N 3-chloro-4-iodopyridin-2-amine Chemical compound NC1=NC=CC(I)=C1Cl GTTQRVGVEIXEHQ-UHFFFAOYSA-N 0.000 claims description 3
• RNDRHBMMPKFNLJ-UHFFFAOYSA-N 3-fluoro-4-iodopyridin-2-amine Chemical compound NC1=NC=CC(I)=C1F RNDRHBMMPKFNLJ-UHFFFAOYSA-N 0.000 claims description 3
• YNDHZVOCDIYUNS-UHFFFAOYSA-N 3-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound NC1=C(C)C(OC)=CC(B2OC(C)(C)C(C)(C)O2)=C1 YNDHZVOCDIYUNS-UHFFFAOYSA-N 0.000 claims description 3
• BQXPYWFJZDVNAO-UHFFFAOYSA-N 4-(3-iodo-1-methylpyrazol-4-yl)pyrimidin-2-amine Chemical compound IC1=NN(C)C=C1C1=CC=NC(N)=N1 BQXPYWFJZDVNAO-UHFFFAOYSA-N 0.000 claims description 3
• JMPHCCDMHBHXNN-UHFFFAOYSA-N 4-(3-iodo-1-propan-2-ylpyrazol-4-yl)-n-methylpyrimidin-2-amine Chemical compound CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)I)=N1 JMPHCCDMHBHXNN-UHFFFAOYSA-N 0.000 claims description 3
• 208000003200 Adenoma Diseases 0.000 claims description 3
• 229920001817 Agar Polymers 0.000 claims description 3
• 241000416162 Astragalus gummifer Species 0.000 claims description 3
• 206010005003 Bladder cancer Diseases 0.000 claims description 3
• 108010010803 Gelatin Proteins 0.000 claims description 3
• 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 claims description 3
• 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 claims description 3
• 239000002202 Polyethylene glycol Substances 0.000 claims description 3
• 235000021355 Stearic acid Nutrition 0.000 claims description 3
• 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
• 229920001615 Tragacanth Polymers 0.000 claims description 3
• 235000010419 agar Nutrition 0.000 claims description 3
• 235000010443 alginic acid Nutrition 0.000 claims description 3
• 239000000783 alginic acid Substances 0.000 claims description 3
• 229920000615 alginic acid Polymers 0.000 claims description 3
• 229960001126 alginic acid Drugs 0.000 claims description 3
• 150000004781 alginic acids Chemical class 0.000 claims description 3
• SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 3
• 230000001430 anti-depressive effect Effects 0.000 claims description 3
• 230000003474 anti-emetic effect Effects 0.000 claims description 3
• 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
• 229940121363 anti-inflammatory agent Drugs 0.000 claims description 3
• 239000000935 antidepressant agent Substances 0.000 claims description 3
• 229940005513 antidepressants Drugs 0.000 claims description 3
• 239000002111 antiemetic agent Substances 0.000 claims description 3
• 239000002246 antineoplastic agent Substances 0.000 claims description 3
• 229940041181 antineoplastic drug Drugs 0.000 claims description 3
• 210000003445 biliary tract Anatomy 0.000 claims description 3
• 201000001531 bladder carcinoma Diseases 0.000 claims description 3
• 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
• 235000010980 cellulose Nutrition 0.000 claims description 3
• 229920002678 cellulose Polymers 0.000 claims description 3
• 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 3
• 239000008273 gelatin Substances 0.000 claims description 3
• 229920000159 gelatin Polymers 0.000 claims description 3
• 235000019322 gelatine Nutrition 0.000 claims description 3
• 235000011852 gelatine desserts Nutrition 0.000 claims description 3
• 201000005296 lung carcinoma Diseases 0.000 claims description 3
• 229920000609 methyl cellulose Polymers 0.000 claims description 3
• VWEMYHDJVJQLKH-SNVBAGLBSA-N methyl n-[(2r)-1-[[4-(3-iodo-1-propan-2-ylpyrazol-4-yl)pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)I)=N1 VWEMYHDJVJQLKH-SNVBAGLBSA-N 0.000 claims description 3
• BEPGTMTXHVYWRS-HNNXBMFYSA-N methyl n-[(2s)-1-[[4-[3-[2,6-difluoro-3-(propylsulfonylamino)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C=2C(=CN(N=2)C(C)C)C=2N=C(NC[C@H](C)NC(=O)OC)N=CC=2)=C1F BEPGTMTXHVYWRS-HNNXBMFYSA-N 0.000 claims description 3
• ZKZGAMDUVHYNPH-ZDUSSCGKSA-N methyl n-[(2s)-1-[[4-[3-[2-chloro-5-fluoro-3-(methanesulfonamido)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(F)C=2)Cl)=N1 ZKZGAMDUVHYNPH-ZDUSSCGKSA-N 0.000 claims description 3
• 235000010981 methylcellulose Nutrition 0.000 claims description 3
• 239000001923 methylcellulose Substances 0.000 claims description 3
• WENAYZOQQUHJBN-UHFFFAOYSA-N n-(3-bromo-2,4-difluorophenyl)propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(Br)=C1F WENAYZOQQUHJBN-UHFFFAOYSA-N 0.000 claims description 3
• QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
• OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
• 210000001672 ovary Anatomy 0.000 claims description 3
• 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
• 229920001223 polyethylene glycol Polymers 0.000 claims description 3
• 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
• 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
• 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
• 239000000377 silicon dioxide Substances 0.000 claims description 3
• 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
• 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 3
• 239000008117 stearic acid Substances 0.000 claims description 3
• 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 3
• 239000000454 talc Substances 0.000 claims description 3
• 235000012222 talc Nutrition 0.000 claims description 3
• 229910052623 talc Inorganic materials 0.000 claims description 3
• BSBUYMURKFVOJK-UHFFFAOYSA-N tert-butyl n-(3-bromo-2-fluoro-5-methylphenyl)carbamate Chemical compound CC1=CC(Br)=C(F)C(NC(=O)OC(C)(C)C)=C1 BSBUYMURKFVOJK-UHFFFAOYSA-N 0.000 claims description 3
• SVJJHDWAMYIVMD-LBPRGKRZSA-N tert-butyl n-[(2s)-1-[[4-(3-iodo-1-propan-2-ylpyrazol-4-yl)pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)I)=N1 SVJJHDWAMYIVMD-LBPRGKRZSA-N 0.000 claims description 3
• MJCQNRAYNOMAIU-UHFFFAOYSA-N tert-butyl n-[2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=C(F)C=CC(B2OC(C)(C)C(C)(C)O2)=C1F MJCQNRAYNOMAIU-UHFFFAOYSA-N 0.000 claims description 3
• PIPHWNAVJFOPAO-UHFFFAOYSA-N tert-butyl n-[2-fluoro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate Chemical compound CC1=CC(NC(=O)OC(C)(C)C)=C(F)C(B2OC(C)(C)C(C)(C)O2)=C1 PIPHWNAVJFOPAO-UHFFFAOYSA-N 0.000 claims description 3
• 201000002510 thyroid cancer Diseases 0.000 claims description 3
• 235000010487 tragacanth Nutrition 0.000 claims description 3
• 239000000196 tragacanth Substances 0.000 claims description 3
• 229940116362 tragacanth Drugs 0.000 claims description 3
• 208000010570 urinary bladder carcinoma Diseases 0.000 claims description 3
• LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
• KDWQLICBSFIDRM-UHFFFAOYSA-N 1,1,1-trifluoropropane Chemical compound CCC(F)(F)F KDWQLICBSFIDRM-UHFFFAOYSA-N 0.000 claims description 2
• VRXSOTRSWXUNKA-UHFFFAOYSA-N 1-(1-ethyl-3-iodopyrazol-4-yl)ethanone Chemical compound CCN1C=C(C(C)=O)C(I)=N1 VRXSOTRSWXUNKA-UHFFFAOYSA-N 0.000 claims description 2
• IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
• QKWVGDAAZHJCLH-UHFFFAOYSA-N 2,5-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(F)=CC(N)=C1F QKWVGDAAZHJCLH-UHFFFAOYSA-N 0.000 claims description 2
• RNRPIYYFOPOLSL-UHFFFAOYSA-N 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC([N+]([O-])=O)=C1F RNRPIYYFOPOLSL-UHFFFAOYSA-N 0.000 claims description 2
• WKXWDJPPGNDPCR-UHFFFAOYSA-N 2-chloro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound CC1=CC(N)=C(Cl)C(B2OC(C)(C)C(C)(C)O2)=C1 WKXWDJPPGNDPCR-UHFFFAOYSA-N 0.000 claims description 2
• RCLQNICOARASSR-SECBINFHSA-N 3-[(2r)-2,3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione Chemical compound FC=1C(=O)N(C)C=2N=CN(C[C@@H](O)CO)C(=O)C=2C=1NC1=CC=C(I)C=C1F RCLQNICOARASSR-SECBINFHSA-N 0.000 claims description 2
• RXLNTBOIPLOOEA-UHFFFAOYSA-N 3-bromo-2-chloro-5-methylaniline Chemical compound CC1=CC(N)=C(Cl)C(Br)=C1 RXLNTBOIPLOOEA-UHFFFAOYSA-N 0.000 claims description 2
• CSHMFIIPOVGVDN-UHFFFAOYSA-N 3-bromo-5-chloro-2-fluoroaniline Chemical compound NC1=CC(Cl)=CC(Br)=C1F CSHMFIIPOVGVDN-UHFFFAOYSA-N 0.000 claims description 2
• WVUOJGNYULRIOH-UHFFFAOYSA-N 4-(1-ethyl-3-iodopyrazol-4-yl)pyrimidin-2-amine Chemical compound IC1=NN(CC)C=C1C1=CC=NC(N)=N1 WVUOJGNYULRIOH-UHFFFAOYSA-N 0.000 claims description 2
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 2
• 239000005995 Aluminium silicate Substances 0.000 claims description 2
• 101100181041 Arabidopsis thaliana KINUA gene Proteins 0.000 claims description 2
• 229920002261 Corn starch Polymers 0.000 claims description 2
• 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
• 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 claims description 2
• LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 2
• 239000001856 Ethyl cellulose Substances 0.000 claims description 2
• ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
• 241000206672 Gelidium Species 0.000 claims description 2
• 229920002907 Guar gum Polymers 0.000 claims description 2
• 101710113864 Heat shock protein 90 Proteins 0.000 claims description 2
• 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 claims description 2
• 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 claims description 2
• 240000003183 Manihot esculenta Species 0.000 claims description 2
• 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 claims description 2
• 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
• 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 claims description 2
• 229920000881 Modified starch Polymers 0.000 claims description 2
• WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
• 108091007960 PI3Ks Proteins 0.000 claims description 2
• 102000038030 PI3Ks Human genes 0.000 claims description 2
• 235000019483 Peanut oil Nutrition 0.000 claims description 2
• 108091008611 Protein Kinase B Proteins 0.000 claims description 2
• 108090000315 Protein Kinase C Proteins 0.000 claims description 2
• 102000003923 Protein Kinase C Human genes 0.000 claims description 2
• 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 claims description 2
• 229940123690 Raf kinase inhibitor Drugs 0.000 claims description 2
• DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
• BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 claims description 2
• 235000019486 Sunflower oil Nutrition 0.000 claims description 2
• 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 claims description 2
• 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 claims description 2
• 235000012211 aluminium silicate Nutrition 0.000 claims description 2
• ACWZRVQXLIRSDF-UHFFFAOYSA-N binimetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1F ACWZRVQXLIRSDF-UHFFFAOYSA-N 0.000 claims description 2
• 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
• 235000010216 calcium carbonate Nutrition 0.000 claims description 2
• CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
• 235000013539 calcium stearate Nutrition 0.000 claims description 2
• 239000008116 calcium stearate Substances 0.000 claims description 2
• 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 2
• 229920002301 cellulose acetate Polymers 0.000 claims description 2
• 235000005687 corn oil Nutrition 0.000 claims description 2
• 239000002285 corn oil Substances 0.000 claims description 2
• 239000008120 corn starch Substances 0.000 claims description 2
• 235000012343 cottonseed oil Nutrition 0.000 claims description 2
• 239000002385 cottonseed oil Substances 0.000 claims description 2
• 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
• 229960000913 crospovidone Drugs 0.000 claims description 2
• 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
• 229940096516 dextrates Drugs 0.000 claims description 2
• 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
• 229920001249 ethyl cellulose Polymers 0.000 claims description 2
• LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 2
• 229940093471 ethyl oleate Drugs 0.000 claims description 2
• 235000011187 glycerol Nutrition 0.000 claims description 2
• 150000002334 glycols Chemical class 0.000 claims description 2
• 235000010417 guar gum Nutrition 0.000 claims description 2
• 239000000665 guar gum Substances 0.000 claims description 2
• 229960002154 guar gum Drugs 0.000 claims description 2
• 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 2
• 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
• 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
• 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
• NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 2
• 229940059904 light mineral oil Drugs 0.000 claims description 2
• 235000019359 magnesium stearate Nutrition 0.000 claims description 2
• 230000001404 mediated effect Effects 0.000 claims description 2
• GTVBBDKLBUVTKF-HNNXBMFYSA-N methyl n-[(2s)-1-[[4-[3-[2,4-difluoro-3-(propylsulfonylamino)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound CCCS(=O)(=O)NC1=C(F)C=CC(C=2C(=CN(N=2)C(C)C)C=2N=C(NC[C@H](C)NC(=O)OC)N=CC=2)=C1F GTVBBDKLBUVTKF-HNNXBMFYSA-N 0.000 claims description 2
• FIMRNHGGRIJTEX-ZDUSSCGKSA-N methyl n-[(2s)-1-[[4-[3-[2-chloro-3-(ethylsulfonylamino)-4,5-difluorophenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound CCS(=O)(=O)NC1=C(F)C(F)=CC(C=2C(=CN(N=2)C(C)C)C=2N=C(NC[C@H](C)NC(=O)OC)N=CC=2)=C1Cl FIMRNHGGRIJTEX-ZDUSSCGKSA-N 0.000 claims description 2
• FOKYULGGOAAGRF-HNNXBMFYSA-N methyl n-[(2s)-1-[[4-[3-[2-fluoro-3-(methanesulfonamido)-5-methylphenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(C)C=2)F)=N1 FOKYULGGOAAGRF-HNNXBMFYSA-N 0.000 claims description 2
• MFQUQRONWUFERA-HNNXBMFYSA-N methyl n-[(2s)-1-[[4-[3-[3-(methanesulfonamido)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C=C(NS(C)(=O)=O)C=CC=2)=N1 MFQUQRONWUFERA-HNNXBMFYSA-N 0.000 claims description 2
• AZFXVYSHIJAZOU-AWEZNQCLSA-N methyl n-[(2s)-1-[[4-[3-[3-chloro-5-(methanesulfonamido)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C=C(NS(C)(=O)=O)C=C(Cl)C=2)=N1 AZFXVYSHIJAZOU-AWEZNQCLSA-N 0.000 claims description 2
• GVJFWGLLYQAPCL-AWEZNQCLSA-N methyl n-[(2s)-1-[[4-[3-[5-chloro-3-(cyclopropylsulfonylamino)-2-fluorophenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(=O)(=O)C3CC3)C=C(Cl)C=2)F)=N1 GVJFWGLLYQAPCL-AWEZNQCLSA-N 0.000 claims description 2
• HKXKEELLDFNXRA-ZDUSSCGKSA-N methyl n-[(2s)-2-[[4-[3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propyl]carbamate Chemical compound COC(=O)NC[C@H](C)NC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 HKXKEELLDFNXRA-ZDUSSCGKSA-N 0.000 claims description 2
• 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
• 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
• 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
• 239000002480 mineral oil Substances 0.000 claims description 2
• 235000010446 mineral oil Nutrition 0.000 claims description 2
• JKPZNQBOXNCTMJ-UHFFFAOYSA-N n-[2,4-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(B2OC(C)(C)C(C)(C)O2)=C1F JKPZNQBOXNCTMJ-UHFFFAOYSA-N 0.000 claims description 2
• RDSACQWTXKSHJT-NSHDSACASA-N n-[3,4-difluoro-2-(2-fluoro-4-iodoanilino)-6-methoxyphenyl]-1-[(2s)-2,3-dihydroxypropyl]cyclopropane-1-sulfonamide Chemical compound C1CC1(C[C@H](O)CO)S(=O)(=O)NC=1C(OC)=CC(F)=C(F)C=1NC1=CC=C(I)C=C1F RDSACQWTXKSHJT-NSHDSACASA-N 0.000 claims description 2
• LDNRMMCYKPMHQR-UHFFFAOYSA-N n-[5-chloro-2-fluoro-3-[4-[2-(methylamino)pyrimidin-4-yl]-1-propan-2-ylpyrazol-3-yl]phenyl]methanesulfonamide Chemical compound CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 LDNRMMCYKPMHQR-UHFFFAOYSA-N 0.000 claims description 2
• MYBONFQSJQUEQD-UHFFFAOYSA-N n-[5-chloro-3-[4-[2-(2-cyanoethylamino)pyrimidin-4-yl]-1-propan-2-ylpyrazol-3-yl]-2-fluorophenyl]methanesulfonamide Chemical compound N=1N(C(C)C)C=C(C=2N=C(NCCC#N)N=CC=2)C=1C1=CC(Cl)=CC(NS(C)(=O)=O)=C1F MYBONFQSJQUEQD-UHFFFAOYSA-N 0.000 claims description 2
• 229920001206 natural gum Polymers 0.000 claims description 2
• 239000004006 olive oil Substances 0.000 claims description 2
• 235000008390 olive oil Nutrition 0.000 claims description 2
• 229940124583 pain medication Drugs 0.000 claims description 2
• 239000000312 peanut oil Substances 0.000 claims description 2
• 102000051624 phosphatidylethanolamine binding protein Human genes 0.000 claims description 2
• 108700021017 phosphatidylethanolamine binding protein Proteins 0.000 claims description 2
• LHNIIDJUOCFXAP-UHFFFAOYSA-N pictrelisib Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=CC2=NC(C=3C=4C=NNC=4C=CC=3)=NC(N3CCOCC3)=C2S1 LHNIIDJUOCFXAP-UHFFFAOYSA-N 0.000 claims description 2
• 229960000540 polacrilin potassium Drugs 0.000 claims description 2
• 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
• 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
• WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 claims description 2
• 229920001592 potato starch Polymers 0.000 claims description 2
• 229920003124 powdered cellulose Polymers 0.000 claims description 2
• 235000019814 powdered cellulose Nutrition 0.000 claims description 2
• CYOHGALHFOKKQC-UHFFFAOYSA-N selumetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CYOHGALHFOKKQC-UHFFFAOYSA-N 0.000 claims description 2
• 239000008159 sesame oil Substances 0.000 claims description 2
• 235000011803 sesame oil Nutrition 0.000 claims description 2
• RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 2
• 235000012239 silicon dioxide Nutrition 0.000 claims description 2
• 235000010413 sodium alginate Nutrition 0.000 claims description 2
• 239000000661 sodium alginate Substances 0.000 claims description 2
• 229940005550 sodium alginate Drugs 0.000 claims description 2
• 229940001593 sodium carbonate Drugs 0.000 claims description 2
• 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 2
• RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 claims description 2
• 229920003109 sodium starch glycolate Polymers 0.000 claims description 2
• 239000008109 sodium starch glycolate Substances 0.000 claims description 2
• 229940079832 sodium starch glycolate Drugs 0.000 claims description 2
• 239000003549 soybean oil Substances 0.000 claims description 2
• 235000012424 soybean oil Nutrition 0.000 claims description 2
• 235000000346 sugar Nutrition 0.000 claims description 2
• 150000008163 sugars Chemical class 0.000 claims description 2
• 239000002600 sunflower oil Substances 0.000 claims description 2
• 229960004066 trametinib Drugs 0.000 claims description 2
• LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 claims description 2
• XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 2
• 230000000202 analgesic effect Effects 0.000 claims 1
• 230000001093 anti-cancer Effects 0.000 claims 1
• UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 1
• CMJCXYNUCSMDBY-CYBMUJFWSA-N methyl n-[(2r)-1-[[4-[3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 CMJCXYNUCSMDBY-CYBMUJFWSA-N 0.000 claims 1
• LCWPXLBWVNEYIW-LBPRGKRZSA-N methyl n-[(2s)-1-[[4-[1-propan-2-yl-3-[2,4,5-trifluoro-3-(methanesulfonamido)phenyl]pyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C(F)=C(F)C=2)F)=N1 LCWPXLBWVNEYIW-LBPRGKRZSA-N 0.000 claims 1
• SJTRSVMDXLVDFY-ZDUSSCGKSA-N methyl n-[(2s)-1-[[4-[3-[2,4-difluoro-3-(methanesulfonamido)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C(F)=CC=2)F)=N1 SJTRSVMDXLVDFY-ZDUSSCGKSA-N 0.000 claims 1
• APHFVSFDSHEMLK-ZDUSSCGKSA-N methyl n-[(2s)-1-[[4-[3-[2,5-dichloro-3-(methanesulfonamido)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)Cl)=N1 APHFVSFDSHEMLK-ZDUSSCGKSA-N 0.000 claims 1
• IDDGSCPILQDMST-ZDUSSCGKSA-N methyl n-[(2s)-1-[[4-[3-[2,5-difluoro-3-(methanesulfonamido)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(F)C=2)F)=N1 IDDGSCPILQDMST-ZDUSSCGKSA-N 0.000 claims 1
• FCSQNBKYSFKSHZ-AWEZNQCLSA-N methyl n-[(2s)-1-[[4-[3-[2-fluoro-3-(methanesulfonamido)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=CC=2)F)=N1 FCSQNBKYSFKSHZ-AWEZNQCLSA-N 0.000 claims 1
• MISNBEQFUJYEAG-AWEZNQCLSA-N methyl n-[(2s)-1-[[4-[3-[3-(ethylsulfonylamino)-2,4-difluorophenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound CCS(=O)(=O)NC1=C(F)C=CC(C=2C(=CN(N=2)C(C)C)C=2N=C(NC[C@H](C)NC(=O)OC)N=CC=2)=C1F MISNBEQFUJYEAG-AWEZNQCLSA-N 0.000 claims 1
• IFUNYGIIWVIYAY-HNNXBMFYSA-N methyl n-[(2s)-1-[[4-[3-[5-chloro-2-fluoro-3-(propylsulfonylamino)phenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C=2C(=CN(N=2)C(C)C)C=2N=C(NC[C@H](C)NC(=O)OC)N=CC=2)=C1F IFUNYGIIWVIYAY-HNNXBMFYSA-N 0.000 claims 1
• 101100381978 Mus musculus Braf gene Proteins 0.000 abstract description 28
• 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 abstract description 27
• 201000010099 disease Diseases 0.000 abstract description 20
• 230000000694 effects Effects 0.000 abstract description 18
• 230000004913 activation Effects 0.000 abstract description 5
• 230000002159 abnormal effect Effects 0.000 abstract description 4
• 230000002074 deregulated effect Effects 0.000 abstract description 3
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 198
• 239000000243 solution Substances 0.000 description 112
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 102
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 96
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 78
• 238000006243 chemical reaction Methods 0.000 description 74
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 73
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
• 235000019439 ethyl acetate Nutrition 0.000 description 66
• 239000000543 intermediate Substances 0.000 description 65
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 51
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
• 239000007787 solid Substances 0.000 description 47
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 43
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
• 238000007792 addition Methods 0.000 description 36
• 239000010410 layer Substances 0.000 description 35
• 210000004027 cell Anatomy 0.000 description 34
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 31
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 31
• 239000012044 organic layer Substances 0.000 description 31
• 229910052938 sodium sulfate Inorganic materials 0.000 description 31
• 235000011152 sodium sulphate Nutrition 0.000 description 31
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
• 239000012267 brine Substances 0.000 description 30
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
• 239000000725 suspension Substances 0.000 description 30
• 239000000460 chlorine Substances 0.000 description 27
• 239000011541 reaction mixture Substances 0.000 description 26
• HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 26
• 230000004663 cell proliferation Effects 0.000 description 25
• 235000017557 sodium bicarbonate Nutrition 0.000 description 25
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 25
• 239000002904 solvent Substances 0.000 description 25
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
• 239000002585 base Substances 0.000 description 21
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
• 239000003153 chemical reaction reagent Substances 0.000 description 20
• 238000010898 silica gel chromatography Methods 0.000 description 20
• 238000004128 high performance liquid chromatography Methods 0.000 description 16
• 229910052757 nitrogen Inorganic materials 0.000 description 16
• NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 16
• 238000003756 stirring Methods 0.000 description 16
• 239000012043 crude product Substances 0.000 description 15
• 238000012360 testing method Methods 0.000 description 14
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
• 239000000706 filtrate Substances 0.000 description 13
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 13
• 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 12
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
• 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 12
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
• 239000002253 acid Substances 0.000 description 12
• 125000006239 protecting group Chemical group 0.000 description 12
• 229920006395 saturated elastomer Polymers 0.000 description 12
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 12
• 239000000126 substance Substances 0.000 description 12
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 11
• 230000006698 induction Effects 0.000 description 11
• 239000012074 organic phase Substances 0.000 description 11
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 11
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
• 239000003795 chemical substances by application Substances 0.000 description 10
• 239000000047 product Substances 0.000 description 10
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 9
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
• 238000003556 assay Methods 0.000 description 9
• 239000000284 extract Substances 0.000 description 9
• 238000010926 purge Methods 0.000 description 9
• 230000011664 signaling Effects 0.000 description 9
• 239000000741 silica gel Substances 0.000 description 9
• 229910002027 silica gel Inorganic materials 0.000 description 9
• 239000002002 slurry Substances 0.000 description 9
• 230000037396 body weight Effects 0.000 description 8
• 229940043355 kinase inhibitor Drugs 0.000 description 8
• 239000003921 oil Substances 0.000 description 8
• 235000019198 oils Nutrition 0.000 description 8
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
• 239000004480 active ingredient Substances 0.000 description 7
• 239000012065 filter cake Substances 0.000 description 7
• 239000012442 inert solvent Substances 0.000 description 7
• 230000005764 inhibitory process Effects 0.000 description 7
• 230000002503 metabolic effect Effects 0.000 description 7
• 239000003757 phosphotransferase inhibitor Substances 0.000 description 7
• TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 7
• 150000003254 radicals Chemical class 0.000 description 7
• 108010014186 ras Proteins Proteins 0.000 description 7
• 102000016914 ras Proteins Human genes 0.000 description 7
• NNFRECPXCDWHEX-LICLKQGHSA-N 2-[[[(e)-benzylideneamino]-propan-2-ylamino]methylidene]propanedinitrile Chemical compound N#CC(C#N)=CN(C(C)C)\N=C\C1=CC=CC=C1 NNFRECPXCDWHEX-LICLKQGHSA-N 0.000 description 6
• 241000282414 Homo sapiens Species 0.000 description 6
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 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
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
• HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
• 125000001246 bromo group Chemical group Br* 0.000 description 6
• 239000003054 catalyst Substances 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• 238000001914 filtration Methods 0.000 description 6
• 238000000338 in vitro Methods 0.000 description 6
• 125000002346 iodo group Chemical group I* 0.000 description 6
• GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 6
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
• 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 6
• 230000036961 partial effect Effects 0.000 description 6
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
• 229910000027 potassium carbonate Inorganic materials 0.000 description 6
• 230000008569 process Effects 0.000 description 6
• 238000010992 reflux Methods 0.000 description 6
• 239000011780 sodium chloride Substances 0.000 description 6
• 235000010288 sodium nitrite Nutrition 0.000 description 6
• 230000009466 transformation Effects 0.000 description 6
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 5
• JJGDYVYAZMFKEY-UHFFFAOYSA-N 3-amino-1-propan-2-ylpyrazole-4-carbonitrile Chemical compound CC(C)N1C=C(C#N)C(N)=N1 JJGDYVYAZMFKEY-UHFFFAOYSA-N 0.000 description 5
• 241001465754 Metazoa Species 0.000 description 5
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
• 241000699670 Mus sp. Species 0.000 description 5
• 150000001204 N-oxides Chemical class 0.000 description 5
• 101150003085 Pdcl gene Proteins 0.000 description 5
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
• 230000015572 biosynthetic process Effects 0.000 description 5
• 230000007423 decrease Effects 0.000 description 5
• 238000009472 formulation Methods 0.000 description 5
• 239000012458 free base Substances 0.000 description 5
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
• 238000001727 in vivo Methods 0.000 description 5
• OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 5
• JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 5
• 229940011051 isopropyl acetate Drugs 0.000 description 5
• 230000000155 isotopic effect Effects 0.000 description 5
• 238000004020 luminiscence type Methods 0.000 description 5
• XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 5
• SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 5
• 230000037361 pathway Effects 0.000 description 5
• 238000000746 purification Methods 0.000 description 5
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
• 239000012258 stirred mixture Substances 0.000 description 5
• 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 5
• ALVXXWPPAVGXHP-UHFFFAOYSA-N 1-(3-iodo-1-propan-2-ylpyrazol-4-yl)ethanone Chemical compound CC(C)N1C=C(C(C)=O)C(I)=N1 ALVXXWPPAVGXHP-UHFFFAOYSA-N 0.000 description 4
• MWDMUSJKDGYJIQ-UHFFFAOYSA-N 4-(2-methylsulfanylpyrimidin-4-yl)-1h-pyrazol-5-amine Chemical compound CSC1=NC=CC(C2=C(NN=C2)N)=N1 MWDMUSJKDGYJIQ-UHFFFAOYSA-N 0.000 description 4
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
• 208000031261 Acute myeloid leukaemia Diseases 0.000 description 4
• 229920000936 Agarose Polymers 0.000 description 4
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
• 101710113436 GTPase KRas Proteins 0.000 description 4
• 241000699666 Mus <mouse, genus> Species 0.000 description 4
• 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 4
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
• VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
• 239000000908 ammonium hydroxide Substances 0.000 description 4
• 239000011324 bead Substances 0.000 description 4
• 239000008280 blood Substances 0.000 description 4
• 210000004369 blood Anatomy 0.000 description 4
• BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 4
• 235000011089 carbon dioxide Nutrition 0.000 description 4
• 229910002091 carbon monoxide Inorganic materials 0.000 description 4
• 230000010261 cell growth Effects 0.000 description 4
• 239000006184 cosolvent Substances 0.000 description 4
• 238000001514 detection method Methods 0.000 description 4
• 238000006193 diazotization reaction Methods 0.000 description 4
• 238000003818 flash chromatography Methods 0.000 description 4
• 239000007789 gas Substances 0.000 description 4
• 208000005017 glioblastoma Diseases 0.000 description 4
• 229910052736 halogen Inorganic materials 0.000 description 4
• 150000002367 halogens Chemical class 0.000 description 4
• 230000002440 hepatic effect Effects 0.000 description 4
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
• 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 4
• RAQGRRSIZXWJDN-LBPRGKRZSA-N methyl n-[(2s)-1-[[4-[3-(3-amino-5-chloro-2-fluorophenyl)-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(N)C=C(Cl)C=2)F)=N1 RAQGRRSIZXWJDN-LBPRGKRZSA-N 0.000 description 4
• 230000035772 mutation Effects 0.000 description 4
• REPVNSJSTLRQEQ-UHFFFAOYSA-N n,n-dimethylacetamide;n,n-dimethylformamide Chemical compound CN(C)C=O.CN(C)C(C)=O REPVNSJSTLRQEQ-UHFFFAOYSA-N 0.000 description 4
• BOBFBVDQVKTCJH-DHZHZOJOSA-N n-[(e)-benzylideneamino]propan-2-amine Chemical compound CC(C)N\N=C\C1=CC=CC=C1 BOBFBVDQVKTCJH-DHZHZOJOSA-N 0.000 description 4
• 229910052760 oxygen Inorganic materials 0.000 description 4
• 239000002244 precipitate Substances 0.000 description 4
• 238000002360 preparation method Methods 0.000 description 4
• 150000003384 small molecules Chemical class 0.000 description 4
• 238000006467 substitution reaction Methods 0.000 description 4
• 210000001519 tissue Anatomy 0.000 description 4
• QZRHAYWDKWCREZ-UHFFFAOYSA-N 1-(3-amino-1-propan-2-ylpyrazol-4-yl)ethanone Chemical compound CC(C)N1C=C(C(C)=O)C(N)=N1 QZRHAYWDKWCREZ-UHFFFAOYSA-N 0.000 description 3
• 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 3
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
• ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 3
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
• 208000001333 Colorectal Neoplasms Diseases 0.000 description 3
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
• ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 3
• IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 3
• 206010033701 Papillary thyroid cancer Diseases 0.000 description 3
• 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 3
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
• 239000003637 basic solution Substances 0.000 description 3
• 230000008901 benefit Effects 0.000 description 3
• 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
• IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 3
• 229910052796 boron Inorganic materials 0.000 description 3
• 239000000872 buffer Substances 0.000 description 3
• 125000004744 butyloxycarbonyl group Chemical group 0.000 description 3
• 238000001516 cell proliferation assay Methods 0.000 description 3
• 238000010511 deprotection reaction Methods 0.000 description 3
• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
• 229940079593 drug Drugs 0.000 description 3
• 239000012636 effector Substances 0.000 description 3
• 239000003102 growth factor Substances 0.000 description 3
• 238000010438 heat treatment Methods 0.000 description 3
• 150000004677 hydrates Chemical class 0.000 description 3
• 150000002466 imines Chemical class 0.000 description 3
• 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 3
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
• 235000019341 magnesium sulphate Nutrition 0.000 description 3
• 238000004519 manufacturing process Methods 0.000 description 3
• VAYYLOQTRPJVAQ-BYPYZUCNSA-N methyl n-[(2s)-1-aminopropan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CN VAYYLOQTRPJVAQ-BYPYZUCNSA-N 0.000 description 3
• JSLYKJSBKICCAQ-BYPYZUCNSA-N methyl n-[(2s)-1-azidopropan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CN=[N+]=[N-] JSLYKJSBKICCAQ-BYPYZUCNSA-N 0.000 description 3
• DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 3
• HXRAMSFGUAOAJR-UHFFFAOYSA-N n,n,n',n'-tetramethyl-1-[(2-methylpropan-2-yl)oxy]methanediamine Chemical compound CN(C)C(N(C)C)OC(C)(C)C HXRAMSFGUAOAJR-UHFFFAOYSA-N 0.000 description 3
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
• 230000002611 ovarian Effects 0.000 description 3
• 229910052763 palladium Inorganic materials 0.000 description 3
• QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
• 230000007170 pathology Effects 0.000 description 3
• 230000000144 pharmacologic effect Effects 0.000 description 3
• 239000012071 phase Substances 0.000 description 3
• 230000026731 phosphorylation Effects 0.000 description 3
• 238000006366 phosphorylation reaction Methods 0.000 description 3
• 235000011056 potassium acetate Nutrition 0.000 description 3
• 230000019491 signal transduction Effects 0.000 description 3
• 235000015424 sodium Nutrition 0.000 description 3
• 239000001632 sodium acetate Substances 0.000 description 3
• 235000017281 sodium acetate Nutrition 0.000 description 3
• 239000012312 sodium hydride Substances 0.000 description 3
• 229910000104 sodium hydride Inorganic materials 0.000 description 3
• 239000012265 solid product Substances 0.000 description 3
• 238000000527 sonication Methods 0.000 description 3
• 239000007858 starting material Substances 0.000 description 3
• 239000003826 tablet Substances 0.000 description 3
• KYNFNBQBRPGRND-HNNXBMFYSA-N tert-butyl n-[5-chloro-2-fluoro-3-[4-[2-[[(2s)-2-(methoxycarbonylamino)propyl]amino]pyrimidin-4-yl]-1-propan-2-ylpyrazol-3-yl]phenyl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NC(=O)OC(C)(C)C)C=C(Cl)C=2)F)=N1 KYNFNBQBRPGRND-HNNXBMFYSA-N 0.000 description 3
• XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 3
• 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 3
• 238000011269 treatment regimen Methods 0.000 description 3
• 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 3
• LOZWAPSEEHRYPG-UHFFFAOYSA-N 1,4-dithiane Chemical compound C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 2
• RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 2
• UNJFVPAZNQVRLN-UHFFFAOYSA-N 2-(2-methylsulfanylpyrimidin-4-yl)acetonitrile Chemical compound CSC1=NC=CC(CC#N)=N1 UNJFVPAZNQVRLN-UHFFFAOYSA-N 0.000 description 2
• OEICGMPRFOJHKO-UHFFFAOYSA-N 2-(ethoxymethylidene)propanedinitrile Chemical compound CCOC=C(C#N)C#N OEICGMPRFOJHKO-UHFFFAOYSA-N 0.000 description 2
• ZNOVTXRBGFNYRX-UHFFFAOYSA-N 2-[[4-[(2-amino-5-methyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-UHFFFAOYSA-N 0.000 description 2
• YFFUYGSLQXVHMB-UHFFFAOYSA-N 2-bromo-4-chloro-1-fluorobenzene Chemical compound FC1=CC=C(Cl)C=C1Br YFFUYGSLQXVHMB-UHFFFAOYSA-N 0.000 description 2
• JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
• BWAKGWVPZRHAQG-UHFFFAOYSA-N 3-(dimethylamino)-2-(2-methylsulfanylpyrimidin-4-yl)prop-2-enenitrile Chemical compound CSC1=NC=CC(C(=CN(C)C)C#N)=N1 BWAKGWVPZRHAQG-UHFFFAOYSA-N 0.000 description 2
• YZGMWJRUAGKYER-UHFFFAOYSA-N 3-bromo-2-chloro-5-fluoroaniline Chemical compound NC1=CC(F)=CC(Br)=C1Cl YZGMWJRUAGKYER-UHFFFAOYSA-N 0.000 description 2
• WYDFJQCDJMWXQR-UHFFFAOYSA-N 3-bromo-5-chloro-2-fluorobenzaldehyde Chemical compound FC1=C(Br)C=C(Cl)C=C1C=O WYDFJQCDJMWXQR-UHFFFAOYSA-N 0.000 description 2
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
• VWJAKSYFRFNDAH-UHFFFAOYSA-N 4-(3-iodo-1-propan-2-ylpyrazol-4-yl)-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC(C=2C(=NN(C=2)C(C)C)I)=N1 VWJAKSYFRFNDAH-UHFFFAOYSA-N 0.000 description 2
• BAFRLLPPAVQAMN-UHFFFAOYSA-N 4-(3-iodo-1-propan-2-ylpyrazol-4-yl)-2-methylsulfonylpyrimidine Chemical compound IC1=NN(C(C)C)C=C1C1=CC=NC(S(C)(=O)=O)=N1 BAFRLLPPAVQAMN-UHFFFAOYSA-N 0.000 description 2
• XBRURAHDFBJPMJ-UHFFFAOYSA-N 4-(5-iodo-1h-pyrazol-4-yl)-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC(C2=C(NN=C2)I)=N1 XBRURAHDFBJPMJ-UHFFFAOYSA-N 0.000 description 2
• YQUDMSXPNNZXAJ-UHFFFAOYSA-N 4-[3-iodo-1-(oxan-2-yl)pyrazol-4-yl]-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC(C=2C(=NN(C=2)C2OCCCC2)I)=N1 YQUDMSXPNNZXAJ-UHFFFAOYSA-N 0.000 description 2
• DFOHHQRGDOQMKG-UHFFFAOYSA-N 4-chloro-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC(Cl)=N1 DFOHHQRGDOQMKG-UHFFFAOYSA-N 0.000 description 2
• IIPZJSKSBHUQRN-UHFFFAOYSA-N 5-chloro-2-fluoro-3-[4-(2-methylsulfanylpyrimidin-4-yl)-1-(oxan-2-yl)pyrazol-3-yl]aniline Chemical compound CSC1=NC=CC(C=2C(=NN(C=2)C2OCCCC2)C=2C(=C(N)C=C(Cl)C=2)F)=N1 IIPZJSKSBHUQRN-UHFFFAOYSA-N 0.000 description 2
• ADHFMENDOUEJRK-UHFFFAOYSA-N 9-[(4-fluorophenyl)methyl]-n-hydroxypyrido[3,4-b]indole-3-carboxamide Chemical compound C1=NC(C(=O)NO)=CC(C2=CC=CC=C22)=C1N2CC1=CC=C(F)C=C1 ADHFMENDOUEJRK-UHFFFAOYSA-N 0.000 description 2
• 108700028369 Alleles Proteins 0.000 description 2
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
• 208000003174 Brain Neoplasms Diseases 0.000 description 2
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
• 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 2
• 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 description 2
• 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
• KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
• 102100039788 GTPase NRas Human genes 0.000 description 2
• ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
• 239000012981 Hank's balanced salt solution Substances 0.000 description 2
• 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 2
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
• 125000000769 L-threonyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](O[H])(C([H])([H])[H])[H] 0.000 description 2
• 108060001084 Luciferase Proteins 0.000 description 2
• 239000005089 Luciferase Substances 0.000 description 2
• 206010027480 Metastatic malignant melanoma Diseases 0.000 description 2
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
• JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
• 108091008606 PDGF receptors Proteins 0.000 description 2
• XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
• 241001482237 Pica Species 0.000 description 2
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
• 229920001213 Polysorbate 20 Polymers 0.000 description 2
• 102000001253 Protein Kinase Human genes 0.000 description 2
• 241000700159 Rattus Species 0.000 description 2
• 241000700157 Rattus norvegicus Species 0.000 description 2
• 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
• DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
• 208000005718 Stomach Neoplasms Diseases 0.000 description 2
• RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
• 238000006069 Suzuki reaction reaction Methods 0.000 description 2
• 239000007983 Tris buffer Substances 0.000 description 2
• 230000003213 activating effect Effects 0.000 description 2
• 238000007083 alkoxycarbonylation reaction Methods 0.000 description 2
• 239000002168 alkylating agent Substances 0.000 description 2
• 229940100198 alkylating agent Drugs 0.000 description 2
• 239000007864 aqueous solution Substances 0.000 description 2
• 239000012300 argon atmosphere Substances 0.000 description 2
• 239000012131 assay buffer Substances 0.000 description 2
• 125000004429 atom Chemical group 0.000 description 2
• HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
• FIKPNNGOJITHLO-JTQLQIEISA-N benzyl n-[(2s)-2-(methoxycarbonylamino)propyl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC(=O)OCC1=CC=CC=C1 FIKPNNGOJITHLO-JTQLQIEISA-N 0.000 description 2
• 125000002619 bicyclic group Chemical group 0.000 description 2
• 230000033228 biological regulation Effects 0.000 description 2
• 230000002051 biphasic effect Effects 0.000 description 2
• 238000009835 boiling Methods 0.000 description 2
• STIAPHVBRDNOAJ-UHFFFAOYSA-N carbamimidoylazanium;carbonate Chemical compound NC(N)=N.NC(N)=N.OC(O)=O STIAPHVBRDNOAJ-UHFFFAOYSA-N 0.000 description 2
• 229960004424 carbon dioxide Drugs 0.000 description 2
• 230000010307 cell transformation Effects 0.000 description 2
• 238000012054 celltiter-glo Methods 0.000 description 2
• 230000033077 cellular process Effects 0.000 description 2
• FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 2
• 239000012230 colorless oil Substances 0.000 description 2
• 238000001816 cooling Methods 0.000 description 2
• 239000006071 cream Substances 0.000 description 2
• NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
• NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 2
• 239000003085 diluting agent Substances 0.000 description 2
• 238000010790 dilution Methods 0.000 description 2
• 239000012895 dilution Substances 0.000 description 2
• 238000006471 dimerization reaction Methods 0.000 description 2
• MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 2
• 238000006073 displacement reaction Methods 0.000 description 2
• 231100000371 dose-limiting toxicity Toxicity 0.000 description 2
• 238000000605 extraction Methods 0.000 description 2
• 206010017758 gastric cancer Diseases 0.000 description 2
• 238000003304 gavage Methods 0.000 description 2
• 239000000499 gel Substances 0.000 description 2
• 230000012010 growth Effects 0.000 description 2
• 239000001963 growth medium Substances 0.000 description 2
• IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
• 238000005984 hydrogenation reaction Methods 0.000 description 2
• 238000003018 immunoassay Methods 0.000 description 2
• 239000007943 implant Substances 0.000 description 2
• 230000001965 increasing effect Effects 0.000 description 2
• 230000002401 inhibitory effect Effects 0.000 description 2
• 230000003993 interaction Effects 0.000 description 2
• PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
• 229910052740 iodine Inorganic materials 0.000 description 2
• 238000012417 linear regression Methods 0.000 description 2
• AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
• DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
• 230000007246 mechanism Effects 0.000 description 2
• 230000004060 metabolic process Effects 0.000 description 2
• 208000021039 metastatic melanoma Diseases 0.000 description 2
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
• CFQBGCTYPNYOHG-AWEZNQCLSA-N methyl N-[(2S)-1-[[4-[3-[3-[bis(methylsulfonyl)amino]-5-chloro-2-fluorophenyl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound ClC=1C=C(C(=C(C1)C1=NN(C=C1C1=NC(=NC=C1)NC[C@H](C)NC(OC)=O)C(C)C)F)N(S(=O)(=O)C)S(=O)(=O)C CFQBGCTYPNYOHG-AWEZNQCLSA-N 0.000 description 2
• DTVBZYSSZUCODC-WCCKRBBISA-N methyl n-[(2s)-1-aminopropan-2-yl]carbamate;hydrochloride Chemical compound Cl.COC(=O)N[C@@H](C)CN DTVBZYSSZUCODC-WCCKRBBISA-N 0.000 description 2
• RXFVDPLFYFUMOV-BYPYZUCNSA-N methyl n-[(2s)-1-hydroxypropan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CO RXFVDPLFYFUMOV-BYPYZUCNSA-N 0.000 description 2
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
• 230000003228 microsomal effect Effects 0.000 description 2
• 238000002156 mixing Methods 0.000 description 2
• 125000002950 monocyclic group Chemical group 0.000 description 2
• DJQVTWXPVHCLSW-UHFFFAOYSA-N n-(3-bromo-2-chloro-5-fluorophenyl)-1,1-diphenylmethanimine Chemical compound FC1=CC(Br)=C(Cl)C(N=C(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 DJQVTWXPVHCLSW-UHFFFAOYSA-N 0.000 description 2
• LFAHREIPGOASFZ-UHFFFAOYSA-N n-(benzylideneamino)ethanamine Chemical compound CCNN=CC1=CC=CC=C1 LFAHREIPGOASFZ-UHFFFAOYSA-N 0.000 description 2
• XRCYSJXOEWSFPE-UHFFFAOYSA-N n-[3-[4-(2-aminopyrimidin-4-yl)-1-propan-2-ylpyrazol-3-yl]-5-chloro-2-fluorophenyl]methanesulfonamide Chemical compound N=1N(C(C)C)C=C(C=2N=C(N)N=CC=2)C=1C1=CC(Cl)=CC(NS(C)(=O)=O)=C1F XRCYSJXOEWSFPE-UHFFFAOYSA-N 0.000 description 2
• 239000012299 nitrogen atmosphere Substances 0.000 description 2
• 239000002674 ointment Substances 0.000 description 2
• 231100000590 oncogenic Toxicity 0.000 description 2
• 230000002246 oncogenic effect Effects 0.000 description 2
• 239000003960 organic solvent Substances 0.000 description 2
• 125000002524 organometallic group Chemical group 0.000 description 2
• KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
• 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 2
• 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 2
• 239000006072 paste Substances 0.000 description 2
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
• 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
• 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
• 239000000843 powder Substances 0.000 description 2
• 239000003755 preservative agent Substances 0.000 description 2
• OVPLZYJGTGDFNB-UHFFFAOYSA-N propan-2-yl carbamate Chemical compound CC(C)OC(N)=O OVPLZYJGTGDFNB-UHFFFAOYSA-N 0.000 description 2
• UCQHWQIQCCNKTE-UHFFFAOYSA-N propane-1-sulfonamide Chemical compound [CH2]CCS(N)(=O)=O UCQHWQIQCCNKTE-UHFFFAOYSA-N 0.000 description 2
• KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 description 2
• 108060006633 protein kinase Proteins 0.000 description 2
• 239000003586 protic polar solvent Substances 0.000 description 2
• LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 2
• 230000004044 response Effects 0.000 description 2
• 230000002441 reversible effect Effects 0.000 description 2
• 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
• MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
• AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
• 235000019345 sodium thiosulphate Nutrition 0.000 description 2
• 239000012453 solvate Substances 0.000 description 2
• 241000894007 species Species 0.000 description 2
• 239000003381 stabilizer Substances 0.000 description 2
• 230000000638 stimulation Effects 0.000 description 2
• 201000011549 stomach cancer Diseases 0.000 description 2
• 229940124530 sulfonamide Drugs 0.000 description 2
• 238000005694 sulfonylation reaction Methods 0.000 description 2
• 239000000829 suppository Substances 0.000 description 2
• 238000003786 synthesis reaction Methods 0.000 description 2
• BFNYNEMRWHFIMR-UHFFFAOYSA-N tert-butyl 2-cyanoacetate Chemical compound CC(C)(C)OC(=O)CC#N BFNYNEMRWHFIMR-UHFFFAOYSA-N 0.000 description 2
• 230000001225 therapeutic effect Effects 0.000 description 2
• 238000002560 therapeutic procedure Methods 0.000 description 2
• 238000004809 thin layer chromatography Methods 0.000 description 2
• 238000000844 transformation Methods 0.000 description 2
• 229910052723 transition metal Inorganic materials 0.000 description 2
• 150000003624 transition metals Chemical class 0.000 description 2
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
• 230000004614 tumor growth Effects 0.000 description 2
• 239000003981 vehicle Substances 0.000 description 2
• 210000003462 vein Anatomy 0.000 description 2
• 239000003039 volatile agent Substances 0.000 description 2
• 238000010792 warming Methods 0.000 description 2
• 230000003442 weekly effect Effects 0.000 description 2
• 238000010626 work up procedure Methods 0.000 description 2
• 229910052727 yttrium Inorganic materials 0.000 description 2
• GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
• AEIAMRMQKCPGJR-QTNFYWBSSA-N (2s)-propane-1,2-diamine;dihydrochloride Chemical compound Cl.Cl.C[C@H](N)CN AEIAMRMQKCPGJR-QTNFYWBSSA-N 0.000 description 1
• WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
• BKMMTJMQCTUHRP-VKHMYHEASA-N (S)-2-aminopropan-1-ol Chemical compound C[C@H](N)CO BKMMTJMQCTUHRP-VKHMYHEASA-N 0.000 description 1
• LORRLQMLLQLPSJ-UHFFFAOYSA-N 1,3,5-Trithiane, Natural products C1SCSCS1 LORRLQMLLQLPSJ-UHFFFAOYSA-N 0.000 description 1
• FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
• HKKSDHKJUSSWAI-UHFFFAOYSA-N 1,3-dibromo-2,5-dichlorobenzene Chemical compound ClC1=CC(Br)=C(Cl)C(Br)=C1 HKKSDHKJUSSWAI-UHFFFAOYSA-N 0.000 description 1
• PZKDJJMHRYNBOR-UHFFFAOYSA-N 1,3-dibromo-2-chloro-5-fluorobenzene Chemical compound FC1=CC(Br)=C(Cl)C(Br)=C1 PZKDJJMHRYNBOR-UHFFFAOYSA-N 0.000 description 1
• RAZYWQMDQSSKND-UHFFFAOYSA-N 1-(3-amino-1-ethylpyrazol-4-yl)ethanone Chemical compound CCN1C=C(C(C)=O)C(N)=N1 RAZYWQMDQSSKND-UHFFFAOYSA-N 0.000 description 1
• DFQZBFYXDVHWQJ-UHFFFAOYSA-N 1-(3-amino-1-methylpyrazol-4-yl)ethanone Chemical compound CC(=O)C1=CN(C)N=C1N DFQZBFYXDVHWQJ-UHFFFAOYSA-N 0.000 description 1
• KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
• WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
• ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
• BUYSIDPAOVWMQX-UHFFFAOYSA-N 1-bromo-2,3,4,5-tetrafluorobenzene Chemical compound FC1=CC(Br)=C(F)C(F)=C1F BUYSIDPAOVWMQX-UHFFFAOYSA-N 0.000 description 1
• OBHOTAOWJPXUBN-UHFFFAOYSA-N 1-ethyl-4-(2-methylsulfanylpyrimidin-4-yl)pyrazol-3-amine Chemical compound NC1=NN(CC)C=C1C1=CC=NC(SC)=N1 OBHOTAOWJPXUBN-UHFFFAOYSA-N 0.000 description 1
• XEHFIEBYUHCURF-UHFFFAOYSA-N 1-methyl-4-(2-methylsulfanylpyrimidin-4-yl)pyrazol-3-amine Chemical compound CSC1=NC=CC(C=2C(=NN(C)C=2)N)=N1 XEHFIEBYUHCURF-UHFFFAOYSA-N 0.000 description 1
• HKCFTGZESMCKJA-UHFFFAOYSA-N 1-pyridin-4-ylimidazolidin-2-one Chemical compound O=C1NCCN1C1=CC=NC=C1 HKCFTGZESMCKJA-UHFFFAOYSA-N 0.000 description 1
• NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 1
• HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 description 1
• AVYGCQXNNJPXSS-UHFFFAOYSA-N 2,5-dichloroaniline Chemical compound NC1=CC(Cl)=CC=C1Cl AVYGCQXNNJPXSS-UHFFFAOYSA-N 0.000 description 1
• HLJYTZZSJLJDOG-UHFFFAOYSA-N 2-[[(benzylideneamino)-methylamino]methylidene]propanedinitrile Chemical compound N#CC(C#N)=CN(C)N=CC1=CC=CC=C1 HLJYTZZSJLJDOG-UHFFFAOYSA-N 0.000 description 1
• METIWNNPHPBEHP-UHFFFAOYSA-N 2-[[4-[4-(4-methyl-n-(4-methylphenyl)anilino)phenyl]-2,1,3-benzothiadiazol-7-yl]methylidene]propanedinitrile Chemical compound C1=CC(C)=CC=C1N(C=1C=CC(=CC=1)C=1C2=NSN=C2C(C=C(C#N)C#N)=CC=1)C1=CC=C(C)C=C1 METIWNNPHPBEHP-UHFFFAOYSA-N 0.000 description 1
• MCXDUQNYDSDTFX-UHFFFAOYSA-N 2-chloro-4-(3-iodo-1-methylpyrazol-4-yl)pyrimidine Chemical compound IC1=NN(C)C=C1C1=CC=NC(Cl)=N1 MCXDUQNYDSDTFX-UHFFFAOYSA-N 0.000 description 1
• JQYPICYMRVGSCU-UHFFFAOYSA-N 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC(N)=C1F JQYPICYMRVGSCU-UHFFFAOYSA-N 0.000 description 1
• NSTREUWFTAOOKS-UHFFFAOYSA-N 2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1F NSTREUWFTAOOKS-UHFFFAOYSA-N 0.000 description 1
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
• LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
• MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
• HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
• WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
• WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
• OALFQLAIPMSUAW-UHFFFAOYSA-N 3-amino-1-ethylpyrazole-4-carbonitrile Chemical compound CCN1C=C(C#N)C(N)=N1 OALFQLAIPMSUAW-UHFFFAOYSA-N 0.000 description 1
• FBQOIRKIQMQJNS-UHFFFAOYSA-N 3-amino-1-methylpyrazole-4-carbonitrile Chemical compound CN1C=C(C#N)C(N)=N1 FBQOIRKIQMQJNS-UHFFFAOYSA-N 0.000 description 1
• NUDDKKLQNVWKRU-UHFFFAOYSA-N 3-bromo-2,4-difluoroaniline Chemical compound NC1=CC=C(F)C(Br)=C1F NUDDKKLQNVWKRU-UHFFFAOYSA-N 0.000 description 1
• ZEQKZRGDHYMUHS-UHFFFAOYSA-N 3-bromo-2,5-dichloroaniline Chemical compound NC1=CC(Cl)=CC(Br)=C1Cl ZEQKZRGDHYMUHS-UHFFFAOYSA-N 0.000 description 1
• WEBVJSPIUIPJKV-UHFFFAOYSA-N 3-bromo-2,6-difluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC(Br)=C1F WEBVJSPIUIPJKV-UHFFFAOYSA-N 0.000 description 1
• JFAQBRSYTNDGBL-UHFFFAOYSA-N 3-bromo-2-fluoro-5-methylbenzoic acid Chemical compound CC1=CC(Br)=C(F)C(C(O)=O)=C1 JFAQBRSYTNDGBL-UHFFFAOYSA-N 0.000 description 1
• DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical class NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 1
• JPWYOWDXUZEYHM-UHFFFAOYSA-N 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=NC(N)=C1Cl JPWYOWDXUZEYHM-UHFFFAOYSA-N 0.000 description 1
• HTGJERCZXARQNR-UHFFFAOYSA-N 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=NC(N)=C1F HTGJERCZXARQNR-UHFFFAOYSA-N 0.000 description 1
• WWEINXQNCAWBPD-UHFFFAOYSA-N 3-fluoropyridin-2-amine Chemical compound NC1=NC=CC=C1F WWEINXQNCAWBPD-UHFFFAOYSA-N 0.000 description 1
• RVTXGWQLJJPADR-UHFFFAOYSA-N 4-(3-iodo-1-methylpyrazol-4-yl)-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC(C=2C(=NN(C)C=2)I)=N1 RVTXGWQLJJPADR-UHFFFAOYSA-N 0.000 description 1
• UXDLMTSUHUBUSL-UHFFFAOYSA-N 4-(3-iodo-1-methylpyrazol-4-yl)-2-methylsulfonylpyrimidine Chemical compound IC1=NN(C)C=C1C1=CC=NC(S(C)(=O)=O)=N1 UXDLMTSUHUBUSL-UHFFFAOYSA-N 0.000 description 1
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
• MRUWJENAYHTDQG-UHFFFAOYSA-N 4H-pyran Chemical compound C1C=COC=C1 MRUWJENAYHTDQG-UHFFFAOYSA-N 0.000 description 1
• XTZNLELDRXUAOX-UHFFFAOYSA-N 5-bromo-1-methoxy-2-methyl-3-nitrobenzene Chemical compound COC1=CC(Br)=CC([N+]([O-])=O)=C1C XTZNLELDRXUAOX-UHFFFAOYSA-N 0.000 description 1
• CSQIETQHZSHSIA-UHFFFAOYSA-N 5-bromo-3-methoxy-2-methylaniline Chemical compound COC1=CC(Br)=CC(N)=C1C CSQIETQHZSHSIA-UHFFFAOYSA-N 0.000 description 1
• WFFDTMNHOINATE-UHFFFAOYSA-N 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(Cl)=CC(N)=C1F WFFDTMNHOINATE-UHFFFAOYSA-N 0.000 description 1
• UYYOAZXXHWPNHY-UHFFFAOYSA-N 6-(3-iodo-1-methylpyrazol-4-yl)-1h-pyrimidin-2-one Chemical compound IC1=NN(C)C=C1C1=CC=NC(O)=N1 UYYOAZXXHWPNHY-UHFFFAOYSA-N 0.000 description 1
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
• QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
• 101150019464 ARAF gene Proteins 0.000 description 1
• RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
• 241001415342 Ardea Species 0.000 description 1
• IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
• 206010006187 Breast cancer Diseases 0.000 description 1
• 208000026310 Breast neoplasm Diseases 0.000 description 1
• BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
• 108010001857 Cell Surface Receptors Proteins 0.000 description 1
• 102000000844 Cell Surface Receptors Human genes 0.000 description 1
• 229940123587 Cell cycle inhibitor Drugs 0.000 description 1
• 241000282693 Cercopithecidae Species 0.000 description 1
• 229940126639 Compound 33 Drugs 0.000 description 1
• 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
• 108090000695 Cytokines Proteins 0.000 description 1
• 102000004127 Cytokines Human genes 0.000 description 1
• 102000010831 Cytoskeletal Proteins Human genes 0.000 description 1
• 108010037414 Cytoskeletal Proteins Proteins 0.000 description 1
• BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
• 101100291385 Drosophila melanogaster p38a gene Proteins 0.000 description 1
• 102100023266 Dual specificity mitogen-activated protein kinase kinase 2 Human genes 0.000 description 1
• 101710146529 Dual specificity mitogen-activated protein kinase kinase 2 Proteins 0.000 description 1
• 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 description 1
• 102000004190 Enzymes Human genes 0.000 description 1
• 108090000790 Enzymes Proteins 0.000 description 1
• 101100127166 Escherichia coli (strain K12) kefB gene Proteins 0.000 description 1
• 108091008794 FGF receptors Proteins 0.000 description 1
• 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 1
• 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 1
• 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 1
• 102000020897 Formins Human genes 0.000 description 1
• 108091022623 Formins Proteins 0.000 description 1
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
• 102000009465 Growth Factor Receptors Human genes 0.000 description 1
• 108010009202 Growth Factor Receptors Proteins 0.000 description 1
• 241000282412 Homo Species 0.000 description 1
• 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 description 1
• 101100457333 Homo sapiens MAPK11 gene Proteins 0.000 description 1
• 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
• 102000003777 Interleukin-1 beta Human genes 0.000 description 1
• 108090000193 Interleukin-1 beta Proteins 0.000 description 1
• 108090001007 Interleukin-8 Proteins 0.000 description 1
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
• 239000012448 Lithium borohydride Substances 0.000 description 1
• 108700012928 MAPK14 Proteins 0.000 description 1
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
• 241000124008 Mammalia Species 0.000 description 1
• 101150003567 Mapk12 gene Proteins 0.000 description 1
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
• 108700036166 Mitogen-Activated Protein Kinase 11 Proteins 0.000 description 1
• 108700027649 Mitogen-Activated Protein Kinase 3 Proteins 0.000 description 1
• 102100026929 Mitogen-activated protein kinase 11 Human genes 0.000 description 1
• 108700015929 Mitogen-activated protein kinase 12 Proteins 0.000 description 1
• 102000056243 Mitogen-activated protein kinase 12 Human genes 0.000 description 1
• 108700015928 Mitogen-activated protein kinase 13 Proteins 0.000 description 1
• 102000054819 Mitogen-activated protein kinase 14 Human genes 0.000 description 1
• 102100024192 Mitogen-activated protein kinase 3 Human genes 0.000 description 1
• HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
• CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
• AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
• 125000000815 N-oxide group Chemical group 0.000 description 1
• 238000006411 Negishi coupling reaction Methods 0.000 description 1
• 102000007339 Nerve Growth Factor Receptors Human genes 0.000 description 1
• 108010032605 Nerve Growth Factor Receptors Proteins 0.000 description 1
• 239000005642 Oleic acid Substances 0.000 description 1
• ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
• 235000019502 Orange oil Nutrition 0.000 description 1
• 241000283973 Oryctolagus cuniculus Species 0.000 description 1
• 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
• 241000009328 Perro Species 0.000 description 1
• 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
• 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
• 108010089430 Phosphoproteins Proteins 0.000 description 1
• 102000007982 Phosphoproteins Human genes 0.000 description 1
• 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
• 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
• 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
• 108010029485 Protein Isoforms Proteins 0.000 description 1
• 102000001708 Protein Isoforms Human genes 0.000 description 1
• 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 1
• 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 1
• 239000012980 RPMI-1640 medium Substances 0.000 description 1
• PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 1
• 235000014548 Rubus moluccanus Nutrition 0.000 description 1
• 101150046814 SAPK2 gene Proteins 0.000 description 1
• 101150105578 SAPK3 gene Proteins 0.000 description 1
• 108060006706 SRC Proteins 0.000 description 1
• 102000001332 SRC Human genes 0.000 description 1
• 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
• 101150082971 Sgk1 gene Proteins 0.000 description 1
• PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
• 108020004459 Small interfering RNA Proteins 0.000 description 1
• 238000006619 Stille reaction Methods 0.000 description 1
• 229930006000 Sucrose Natural products 0.000 description 1
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
• ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
• 108091023040 Transcription factor Proteins 0.000 description 1
• 102000040945 Transcription factor Human genes 0.000 description 1
• 102000004142 Trypsin Human genes 0.000 description 1
• 108090000631 Trypsin Proteins 0.000 description 1
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
• XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
• 230000001594 aberrant effect Effects 0.000 description 1
• 238000002835 absorbance Methods 0.000 description 1
• 239000002250 absorbent Substances 0.000 description 1
• 230000002745 absorbent Effects 0.000 description 1
• GPWHDDKQSYOYBF-UHFFFAOYSA-N ac1l2u0q Chemical compound Br[Br-]Br GPWHDDKQSYOYBF-UHFFFAOYSA-N 0.000 description 1
• SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
• 239000000654 additive Substances 0.000 description 1
• 230000000996 additive effect Effects 0.000 description 1
• 239000002671 adjuvant Substances 0.000 description 1
• 239000008272 agar Substances 0.000 description 1
• 125000003545 alkoxy group Chemical group 0.000 description 1
• VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
• 239000004037 angiogenesis inhibitor Substances 0.000 description 1
• 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
• 230000002280 anti-androgenic effect Effects 0.000 description 1
• 230000003388 anti-hormonal effect Effects 0.000 description 1
• 230000000340 anti-metabolite Effects 0.000 description 1
• 230000001028 anti-proliverative effect Effects 0.000 description 1
• 230000000259 anti-tumor effect Effects 0.000 description 1
• 239000000051 antiandrogen Substances 0.000 description 1
• 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
• 229940100197 antimetabolite Drugs 0.000 description 1
• 239000002256 antimetabolite Substances 0.000 description 1
• 239000012446 aqueous acidic reagent Substances 0.000 description 1
• 239000003125 aqueous solvent Substances 0.000 description 1
• 125000000732 arylene group Chemical group 0.000 description 1
• 239000012298 atmosphere Substances 0.000 description 1
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
• 150000001540 azides Chemical class 0.000 description 1
• 125000005604 azodicarboxylate group Chemical group 0.000 description 1
• 230000004888 barrier function Effects 0.000 description 1
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
• RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
• 239000012965 benzophenone Substances 0.000 description 1
• 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
• 125000004600 benzothiopyranyl group Chemical group S1C(C=CC2=C1C=CC=C2)* 0.000 description 1
• WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
• MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
• 239000011230 binding agent Substances 0.000 description 1
• 238000010256 biochemical assay Methods 0.000 description 1
• 230000000903 blocking effect Effects 0.000 description 1
• 230000017531 blood circulation Effects 0.000 description 1
• 229940045348 brown mixture Drugs 0.000 description 1
• 159000000007 calcium salts Chemical class 0.000 description 1
• 239000002775 capsule Substances 0.000 description 1
• 229910052799 carbon Inorganic materials 0.000 description 1
• 125000004432 carbon atom Chemical group C* 0.000 description 1
• OEERIBPGRSLGEK-UHFFFAOYSA-N carbon dioxide;methanol Chemical compound OC.O=C=O OEERIBPGRSLGEK-UHFFFAOYSA-N 0.000 description 1
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
• 239000000969 carrier Substances 0.000 description 1
• 230000024245 cell differentiation Effects 0.000 description 1
• 230000003915 cell function Effects 0.000 description 1
• 210000000170 cell membrane Anatomy 0.000 description 1
• 230000003833 cell viability Effects 0.000 description 1
• 238000003570 cell viability assay Methods 0.000 description 1
• 230000005754 cellular signaling Effects 0.000 description 1
• 230000006364 cellular survival Effects 0.000 description 1
• 239000003638 chemical reducing agent Substances 0.000 description 1
• 239000012320 chlorinating reagent Substances 0.000 description 1
• 229910052801 chlorine Inorganic materials 0.000 description 1
• 239000002026 chloroform extract Substances 0.000 description 1
• 238000004587 chromatography analysis Methods 0.000 description 1
• 238000010549 co-Evaporation Methods 0.000 description 1
• 238000011260 co-administration Methods 0.000 description 1
• 229940126523 co-drug Drugs 0.000 description 1
• 238000000576 coating method Methods 0.000 description 1
• 239000003086 colorant Substances 0.000 description 1
• 229940125904 compound 1 Drugs 0.000 description 1
• 229940125758 compound 15 Drugs 0.000 description 1
• 229940125877 compound 31 Drugs 0.000 description 1
• 239000012141 concentrate Substances 0.000 description 1
• 230000001276 controlling effect Effects 0.000 description 1
• LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
• 238000005859 coupling reaction Methods 0.000 description 1
• 238000002425 crystallisation Methods 0.000 description 1
• 230000008025 crystallization Effects 0.000 description 1
• 239000012228 culture supernatant Substances 0.000 description 1
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• UVJHQYIOXKWHFD-UHFFFAOYSA-N cyclohexa-1,4-diene Chemical compound C1C=CCC=C1 UVJHQYIOXKWHFD-UHFFFAOYSA-N 0.000 description 1
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
• 231100000433 cytotoxic Toxicity 0.000 description 1
• 230000001472 cytotoxic effect Effects 0.000 description 1
• 230000034994 death Effects 0.000 description 1
• 239000008367 deionised water Substances 0.000 description 1
• 229910021641 deionized water Inorganic materials 0.000 description 1
• 238000013461 design Methods 0.000 description 1
• 238000011161 development Methods 0.000 description 1
• 230000018109 developmental process Effects 0.000 description 1
• 239000008121 dextrose Substances 0.000 description 1
• 239000012954 diazonium Substances 0.000 description 1
• IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
• FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
• 125000006001 difluoroethyl group Chemical group 0.000 description 1
• 229940043279 diisopropylamine Drugs 0.000 description 1
• FAMGJMYDHOESPR-UHFFFAOYSA-M dilithium;carbanide;bromide Chemical compound [Li+].[Li+].[CH3-].[Br-] FAMGJMYDHOESPR-UHFFFAOYSA-M 0.000 description 1
• 239000000539 dimer Substances 0.000 description 1
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
• SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
• 229910001873 dinitrogen Inorganic materials 0.000 description 1
• SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 1
• 230000008034 disappearance Effects 0.000 description 1
• 239000007884 disintegrant Substances 0.000 description 1
• 238000009826 distribution Methods 0.000 description 1
• 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
• 239000002552 dosage form Substances 0.000 description 1
• 230000007783 downstream signaling Effects 0.000 description 1
• 239000003937 drug carrier Substances 0.000 description 1
• 239000003995 emulsifying agent Substances 0.000 description 1
• 239000000839 emulsion Substances 0.000 description 1
• 229940088598 enzyme Drugs 0.000 description 1
• FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
• 230000001747 exhibiting effect Effects 0.000 description 1
• 238000002474 experimental method Methods 0.000 description 1
• 210000002950 fibroblast Anatomy 0.000 description 1
• 239000012467 final product Substances 0.000 description 1
• 239000000796 flavoring agent Substances 0.000 description 1
• 235000019634 flavors Nutrition 0.000 description 1
• 235000003599 food sweetener Nutrition 0.000 description 1
• 235000019253 formic acid Nutrition 0.000 description 1
• 230000006870 function Effects 0.000 description 1
• 125000000524 functional group Chemical group 0.000 description 1
• 125000002541 furyl group Chemical group 0.000 description 1
• 230000004927 fusion Effects 0.000 description 1
• 239000007903 gelatin capsule Substances 0.000 description 1
• 230000002068 genetic effect Effects 0.000 description 1
• 230000005484 gravity Effects 0.000 description 1
• 229960004198 guanidine Drugs 0.000 description 1
• 229960000789 guanidine hydrochloride Drugs 0.000 description 1
• 150000002357 guanidines Chemical class 0.000 description 1
• PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
• 125000001188 haloalkyl group Chemical group 0.000 description 1
• 230000036541 health Effects 0.000 description 1
• 125000005842 heteroatom Chemical group 0.000 description 1
• 229940088597 hormone Drugs 0.000 description 1
• 239000005556 hormone Substances 0.000 description 1
• 150000002429 hydrazines Chemical class 0.000 description 1
• JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
• 239000000852 hydrogen donor Substances 0.000 description 1
• ILULYDJFTJKQAP-UHFFFAOYSA-N hydron;propan-2-ylhydrazine;chloride Chemical compound [Cl-].CC(C)N[NH3+] ILULYDJFTJKQAP-UHFFFAOYSA-N 0.000 description 1
• 239000005457 ice water Substances 0.000 description 1
• YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
• 125000002883 imidazolyl group Chemical group 0.000 description 1
• 210000000987 immune system Anatomy 0.000 description 1
• 239000000367 immunologic factor Substances 0.000 description 1
• 238000000099 in vitro assay Methods 0.000 description 1
• 238000005462 in vivo assay Methods 0.000 description 1
• 238000011065 in-situ storage Methods 0.000 description 1
• 238000011534 incubation Methods 0.000 description 1
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
• 125000001041 indolyl group Chemical group 0.000 description 1
• 230000001939 inductive effect Effects 0.000 description 1
• 239000007972 injectable composition Substances 0.000 description 1
• 150000007529 inorganic bases Chemical class 0.000 description 1
• 239000012444 intercalating antibiotic Substances 0.000 description 1
• 239000011630 iodine Substances 0.000 description 1
• 229910052742 iron Inorganic materials 0.000 description 1
• QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
• FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
• 239000000644 isotonic solution Substances 0.000 description 1
• 125000000842 isoxazolyl group Chemical group 0.000 description 1
• 239000008101 lactose Substances 0.000 description 1
• 208000032839 leukemia Diseases 0.000 description 1
• 230000000670 limiting effect Effects 0.000 description 1
• 239000007788 liquid Substances 0.000 description 1
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
• 210000001853 liver microsome Anatomy 0.000 description 1
• 239000006210 lotion Substances 0.000 description 1
• 239000000314 lubricant Substances 0.000 description 1
• 201000005202 lung cancer Diseases 0.000 description 1
• 208000020816 lung neoplasm Diseases 0.000 description 1
• 239000006166 lysate Substances 0.000 description 1
• 239000012139 lysis buffer Substances 0.000 description 1
• 239000011777 magnesium Substances 0.000 description 1
• 229910052749 magnesium Inorganic materials 0.000 description 1
• NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
• 230000003211 malignant effect Effects 0.000 description 1
• CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
• 210000004962 mammalian cell Anatomy 0.000 description 1
• 238000004949 mass spectrometry Methods 0.000 description 1
• 108010082117 matrigel Proteins 0.000 description 1
• 239000011159 matrix material Substances 0.000 description 1
• 238000002844 melting Methods 0.000 description 1
• 230000008018 melting Effects 0.000 description 1
• 229940087646 methanolamine Drugs 0.000 description 1
• SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
• ZUVAACFIEPYYOP-UHFFFAOYSA-N methoxycyclopropane Chemical compound COC1CC1 ZUVAACFIEPYYOP-UHFFFAOYSA-N 0.000 description 1
• VAYYLOQTRPJVAQ-SCSAIBSYSA-N methyl N-[(2R)-1-aminopropan-2-yl]carbamate Chemical compound COC(=O)N[C@H](C)CN VAYYLOQTRPJVAQ-SCSAIBSYSA-N 0.000 description 1
• JSLYKJSBKICCAQ-SCSAIBSYSA-N methyl N-[(2R)-1-azidopropan-2-yl]carbamate Chemical compound COC(=O)N[C@H](C)CN=[N+]=[N-] JSLYKJSBKICCAQ-SCSAIBSYSA-N 0.000 description 1
• IBHCDFNFRRCVQI-LBPRGKRZSA-N methyl N-[(2S)-1-[[4-[3-(3-amino-2-chloro-5-fluorophenyl)-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(N)C=C(F)C=2)Cl)=N1 IBHCDFNFRRCVQI-LBPRGKRZSA-N 0.000 description 1
• RXFVDPLFYFUMOV-SCSAIBSYSA-N methyl n-[(2r)-1-hydroxypropan-2-yl]carbamate Chemical compound COC(=O)N[C@H](C)CO RXFVDPLFYFUMOV-SCSAIBSYSA-N 0.000 description 1
• SDCZJIUXNFJUCH-NSHDSACASA-N methyl n-[(2s)-1-[[4-(1-propan-2-ylpyrazol-4-yl)pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C2=CN(N=C2)C(C)C)=N1 SDCZJIUXNFJUCH-NSHDSACASA-N 0.000 description 1
• OYJJSQKATCWOOM-ZDUSSCGKSA-N methyl n-[(2s)-1-[[4-[3-[3-chloro-2-(methanesulfonamido)pyridin-4-yl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)N=CC=2)Cl)=N1 OYJJSQKATCWOOM-ZDUSSCGKSA-N 0.000 description 1
• BEJNUMRZYPYGDM-ZDUSSCGKSA-N methyl n-[(2s)-1-[[4-[3-[3-fluoro-2-(methanesulfonamido)pyridin-4-yl]-1-propan-2-ylpyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)N=CC=2)F)=N1 BEJNUMRZYPYGDM-ZDUSSCGKSA-N 0.000 description 1
• RPKHXXHDQCZMJE-PVCZSOGJSA-N methyl n-[(2s)-1-[[4-[3-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1-(oxan-2-yl)pyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C2OCCCC2)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 RPKHXXHDQCZMJE-PVCZSOGJSA-N 0.000 description 1
• WOXRHSRZAMPSON-JTQLQIEISA-N methyl n-[(2s)-1-[[4-[5-[5-chloro-2-fluoro-3-(methanesulfonamido)phenyl]-1h-pyrazol-4-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NNC=2)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 WOXRHSRZAMPSON-JTQLQIEISA-N 0.000 description 1
• 239000004530 micro-emulsion Substances 0.000 description 1
• 230000005012 migration Effects 0.000 description 1
• 238000013508 migration Methods 0.000 description 1
• 150000007522 mineralic acids Chemical class 0.000 description 1
• 230000002297 mitogenic effect Effects 0.000 description 1
• 230000000394 mitotic effect Effects 0.000 description 1
• 230000004048 modification Effects 0.000 description 1
• 238000012986 modification Methods 0.000 description 1
• HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
• 239000012452 mother liquor Substances 0.000 description 1
• PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
• XXCMGYNVDSOFHV-UHFFFAOYSA-N n-(benzylideneamino)methanamine Chemical compound CNN=CC1=CC=CC=C1 XXCMGYNVDSOFHV-UHFFFAOYSA-N 0.000 description 1
• JBNKSLCTVLKCIV-UHFFFAOYSA-N n-[4-methyl-3-[[1-[6-[(4-methylpiperazin-1-yl)amino]pyrimidin-4-yl]imidazol-2-yl]amino]phenyl]-3-(trifluoromethyl)benzamide Chemical compound C1CN(C)CCN1NC1=CC(N2C(=NC=C2)NC=2C(=CC=C(NC(=O)C=3C=C(C=CC=3)C(F)(F)F)C=2)C)=NC=N1 JBNKSLCTVLKCIV-UHFFFAOYSA-N 0.000 description 1
• PSFBQFCJTLSRGW-UHFFFAOYSA-N n-[5-chloro-2-fluoro-3-[4-(2-methylsulfanylpyrimidin-4-yl)-1-(oxan-2-yl)pyrazol-3-yl]phenyl]methanesulfonamide Chemical compound CSC1=NC=CC(C=2C(=NN(C=2)C2OCCCC2)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 PSFBQFCJTLSRGW-UHFFFAOYSA-N 0.000 description 1
• LEEMSSRUGRAKDG-UHFFFAOYSA-N n-bromo-5-chloro-2-fluoroaniline Chemical compound FC1=CC=C(Cl)C=C1NBr LEEMSSRUGRAKDG-UHFFFAOYSA-N 0.000 description 1
• 125000001624 naphthyl group Chemical group 0.000 description 1
• 230000007935 neutral effect Effects 0.000 description 1
• 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
• ZHCAAFJSYLFLPX-UHFFFAOYSA-N nitrocyclohexatriene Chemical group [O-][N+](=O)C1=CC=C=C[CH]1 ZHCAAFJSYLFLPX-UHFFFAOYSA-N 0.000 description 1
• 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
• 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
• ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
• 238000010915 one-step procedure Methods 0.000 description 1
• 239000010502 orange oil Substances 0.000 description 1
• 150000007524 organic acids Chemical class 0.000 description 1
• 150000007530 organic bases Chemical class 0.000 description 1
• 239000003791 organic solvent mixture Substances 0.000 description 1
• 230000003204 osmotic effect Effects 0.000 description 1
• 150000003891 oxalate salts Chemical class 0.000 description 1
• 125000002971 oxazolyl group Chemical group 0.000 description 1
• 230000001590 oxidative effect Effects 0.000 description 1
• QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
• 239000001301 oxygen Substances 0.000 description 1
• 238000010979 pH adjustment Methods 0.000 description 1
• UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
• JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
• 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
• 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
• 150000002978 peroxides Chemical class 0.000 description 1
• 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
• IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
• FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
• 230000000704 physical effect Effects 0.000 description 1
• XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
• 125000003367 polycyclic group Chemical group 0.000 description 1
• 239000008389 polyethoxylated castor oil Substances 0.000 description 1
• 235000011181 potassium carbonates Nutrition 0.000 description 1
• 235000011118 potassium hydroxide Nutrition 0.000 description 1
• 239000012286 potassium permanganate Substances 0.000 description 1
• 239000008057 potassium phosphate buffer Substances 0.000 description 1
• 230000002062 proliferating effect Effects 0.000 description 1
• 230000035755 proliferation Effects 0.000 description 1
• 230000002035 prolonged effect Effects 0.000 description 1
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
• 102000004169 proteins and genes Human genes 0.000 description 1
• 108090000623 proteins and genes Proteins 0.000 description 1
• 125000003226 pyrazolyl group Chemical group 0.000 description 1
• 239000005297 pyrex Substances 0.000 description 1
• 125000004076 pyridyl group Chemical group 0.000 description 1
• VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
• 125000000714 pyrimidinyl group Chemical group 0.000 description 1
• 238000010791 quenching Methods 0.000 description 1
• 230000000171 quenching effect Effects 0.000 description 1
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
• 230000006340 racemization Effects 0.000 description 1
• 230000002285 radioactive effect Effects 0.000 description 1
• 230000035484 reaction time Effects 0.000 description 1
• 230000009257 reactivity Effects 0.000 description 1
• 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
• 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
• 238000001953 recrystallisation Methods 0.000 description 1
• 230000002829 reductive effect Effects 0.000 description 1
• 238000000611 regression analysis Methods 0.000 description 1
• 230000001105 regulatory effect Effects 0.000 description 1
• 238000003571 reporter gene assay Methods 0.000 description 1
• 239000011347 resin Substances 0.000 description 1
• 229920005989 resin Polymers 0.000 description 1
• 238000007363 ring formation reaction Methods 0.000 description 1
• 125000006413 ring segment Chemical group 0.000 description 1
• 238000000926 separation method Methods 0.000 description 1
• 238000013207 serial dilution Methods 0.000 description 1
• 239000012279 sodium borohydride Substances 0.000 description 1
• 229910000033 sodium borohydride Inorganic materials 0.000 description 1
• 159000000000 sodium salts Chemical class 0.000 description 1
• GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
• 230000000087 stabilizing effect Effects 0.000 description 1
• 239000000758 substrate Substances 0.000 description 1
• 239000005720 sucrose Substances 0.000 description 1
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
• 230000006103 sulfonylation Effects 0.000 description 1
• 229910052717 sulfur Inorganic materials 0.000 description 1
• 239000011593 sulfur Substances 0.000 description 1
• 239000006228 supernatant Substances 0.000 description 1
• 230000004083 survival effect Effects 0.000 description 1
• 239000003765 sweetening agent Substances 0.000 description 1
• 208000024891 symptom Diseases 0.000 description 1
• 230000002195 synergetic effect Effects 0.000 description 1
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
• GFFALKCIACMPPO-UHFFFAOYSA-N tert-butyl n-(3-bromo-2,6-difluorophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=C(F)C=CC(Br)=C1F GFFALKCIACMPPO-UHFFFAOYSA-N 0.000 description 1
• QNBSOZHFBNUGCB-LURJTMIESA-N tert-butyl n-[(2s)-1-azidopropan-2-yl]carbamate Chemical compound [N-]=[N+]=NC[C@H](C)NC(=O)OC(C)(C)C QNBSOZHFBNUGCB-LURJTMIESA-N 0.000 description 1
• PDAFIZPRSXHMCO-LURJTMIESA-N tert-butyl n-[(2s)-1-hydroxypropan-2-yl]carbamate Chemical compound OC[C@H](C)NC(=O)OC(C)(C)C PDAFIZPRSXHMCO-LURJTMIESA-N 0.000 description 1
• CVZYUPSHMKRFAB-UHFFFAOYSA-N tert-butyl n-[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(Cl)=CC(B2OC(C)(C)C(C)(C)O2)=C1F CVZYUPSHMKRFAB-UHFFFAOYSA-N 0.000 description 1
• IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
• 239000012414 tert-butyl nitrite Substances 0.000 description 1
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• 239000012085 test solution Substances 0.000 description 1
• 125000003831 tetrazolyl group Chemical group 0.000 description 1
• 125000001544 thienyl group Chemical group 0.000 description 1
• 125000005505 thiomorpholino group Chemical group 0.000 description 1
• 239000012443 tonicity enhancing agent Substances 0.000 description 1
• 230000000699 topical effect Effects 0.000 description 1
• 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
• 231100000419 toxicity Toxicity 0.000 description 1
• 230000001988 toxicity Effects 0.000 description 1
• 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
• 125000001425 triazolyl group Chemical group 0.000 description 1
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
• FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
• 239000012588 trypsin Substances 0.000 description 1
• 210000004881 tumor cell Anatomy 0.000 description 1
• 238000003260 vortexing Methods 0.000 description 1
• 238000009736 wetting Methods 0.000 description 1
• 239000000080 wetting agent Substances 0.000 description 1
• 238000012447 xenograft mouse model Methods 0.000 description 1
• 229910052725 zinc Inorganic materials 0.000 description 1
• 239000011701 zinc Substances 0.000 description 1