JP2013529619A - タンパク質キナーゼ阻害剤としてのヘテロアリール化合物および組成物 - Google Patents
タンパク質キナーゼ阻害剤としてのヘテロアリール化合物および組成物 Download PDFInfo
- Publication number
- JP2013529619A JP2013529619A JP2013515902A JP2013515902A JP2013529619A JP 2013529619 A JP2013529619 A JP 2013529619A JP 2013515902 A JP2013515902 A JP 2013515902A JP 2013515902 A JP2013515902 A JP 2013515902A JP 2013529619 A JP2013529619 A JP 2013529619A
- Authority
- JP
- Japan
- Prior art keywords
- pyrimidin
- chloro
- mmol
- cancer
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 125000001072 heteroaryl group Chemical group 0.000 title claims description 12
- 239000000203 mixture Substances 0.000 title description 50
- 239000003909 protein kinase inhibitor Substances 0.000 title description 2
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 129
- 238000011282 treatment Methods 0.000 claims abstract description 26
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
- 201000011510 cancer Diseases 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims description 99
- -1 2 -substituted phenyl Chemical group 0.000 claims description 61
- 150000003839 salts Chemical class 0.000 claims description 36
- 239000003814 drug Substances 0.000 claims description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 25
- 229940124597 therapeutic agent Drugs 0.000 claims description 21
- 108091000080 Phosphotransferase Proteins 0.000 claims description 20
- 102000020233 phosphotransferase Human genes 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000003112 inhibitor Substances 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 102000009929 raf Kinases Human genes 0.000 claims description 11
- 108010077182 raf Kinases Proteins 0.000 claims description 11
- 239000000654 additive Substances 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 206010009944 Colon cancer Diseases 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 7
- 230000000996 additive effect Effects 0.000 claims description 7
- 201000005202 lung cancer Diseases 0.000 claims description 7
- 208000020816 lung neoplasm Diseases 0.000 claims description 7
- 201000001441 melanoma Diseases 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 208000003200 Adenoma Diseases 0.000 claims description 6
- 206010001233 Adenoma benign Diseases 0.000 claims description 6
- 206010005003 Bladder cancer Diseases 0.000 claims description 6
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 6
- 239000000730 antalgic agent Substances 0.000 claims description 6
- 230000003474 anti-emetic effect Effects 0.000 claims description 6
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 6
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 6
- 239000000935 antidepressant agent Substances 0.000 claims description 6
- 229940005513 antidepressants Drugs 0.000 claims description 6
- 239000002111 antiemetic agent Substances 0.000 claims description 6
- 208000015322 bone marrow disease Diseases 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 230000001404 mediated effect Effects 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 6
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 claims description 5
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 102000043136 MAP kinase family Human genes 0.000 claims description 4
- 108091054455 MAP kinase family Proteins 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 229940123690 Raf kinase inhibitor Drugs 0.000 claims description 4
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 4
- 229940035676 analgesics Drugs 0.000 claims description 4
- 229940125683 antiemetic agent Drugs 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 102000051624 phosphatidylethanolamine binding protein Human genes 0.000 claims description 4
- 108700021017 phosphatidylethanolamine binding protein Proteins 0.000 claims description 4
- 201000002510 thyroid cancer Diseases 0.000 claims description 4
- 101100181041 Arabidopsis thaliana KINUA gene Proteins 0.000 claims description 3
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 claims description 3
- 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 claims description 3
- 108091007960 PI3Ks Proteins 0.000 claims description 3
- 102000038030 PI3Ks Human genes 0.000 claims description 3
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 claims description 3
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 claims description 3
- 230000001093 anti-cancer Effects 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- MGHMLSOIEGSRJJ-UHFFFAOYSA-N n-[2,5-dichloro-3-[2-cyclopropyl-5-[2-(methylamino)pyrimidin-4-yl]-1,3-thiazol-4-yl]phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C2=C(SC(=N2)C2CC2)C=2N=C(NC)N=CC=2)=C1Cl MGHMLSOIEGSRJJ-UHFFFAOYSA-N 0.000 claims description 2
- VQYUTZHTANREQN-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-[2-(methylamino)pyrimidin-4-yl]-1,3-thiazol-4-yl]-5-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(F)=CC(C2=C(SC(=N2)C2CC2)C=2N=C(NC)N=CC=2)=C1Cl VQYUTZHTANREQN-UHFFFAOYSA-N 0.000 claims description 2
- DDUWRZARRSESMJ-UHFFFAOYSA-N n-[3-[5-(2-aminopyrimidin-4-yl)-2-cyclopropyl-1,3-oxazol-4-yl]-2,5-dichlorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C2=C(OC(=N2)C2CC2)C=2N=C(N)N=CC=2)=C1Cl DDUWRZARRSESMJ-UHFFFAOYSA-N 0.000 claims description 2
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 claims 2
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 claims 2
- 102000003923 Protein Kinase C Human genes 0.000 claims 2
- 108090000315 Protein Kinase C Proteins 0.000 claims 2
- 230000000202 analgesic effect Effects 0.000 claims 2
- 230000001430 anti-depressive effect Effects 0.000 claims 2
- RIRVVFAHOYCHPH-UHFFFAOYSA-N n-[3-[5-(2-aminopyrimidin-4-yl)-2-cyclopropyl-1,3-oxazol-4-yl]-5-chloro-2-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C2=C(OC(=N2)C2CC2)C=2N=C(N)N=CC=2)=C1F RIRVVFAHOYCHPH-UHFFFAOYSA-N 0.000 claims 1
- 101100381978 Mus musculus Braf gene Proteins 0.000 abstract description 17
- 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 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 15
- 201000010099 disease Diseases 0.000 abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 138
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 128
- 239000000543 intermediate Substances 0.000 description 99
- 238000006243 chemical reaction Methods 0.000 description 92
- 238000002360 preparation method Methods 0.000 description 89
- 239000011541 reaction mixture Substances 0.000 description 72
- 235000019439 ethyl acetate Nutrition 0.000 description 68
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
- 239000011734 sodium Substances 0.000 description 57
- 239000007858 starting material Substances 0.000 description 55
- 239000012267 brine Substances 0.000 description 54
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 53
- 239000000243 solution Substances 0.000 description 48
- 238000005481 NMR spectroscopy Methods 0.000 description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 229920006395 saturated elastomer Polymers 0.000 description 32
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 239000007787 solid Substances 0.000 description 29
- 239000000463 material Substances 0.000 description 28
- 238000004519 manufacturing process Methods 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 239000010410 layer Substances 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 18
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 238000007792 addition Methods 0.000 description 17
- 239000012071 phase Substances 0.000 description 16
- 238000000746 purification Methods 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- 238000010828 elution Methods 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000460 chlorine Substances 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 239000000284 extract Substances 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 239000008346 aqueous phase Substances 0.000 description 10
- 230000002051 biphasic effect Effects 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000006260 foam Substances 0.000 description 10
- 230000006698 induction Effects 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 description 10
- KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 9
- 210000003050 axon Anatomy 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- ZHWWPRBSUHITHG-UHFFFAOYSA-N 1-aminopropan-2-ylcarbamic acid Chemical compound NCC(C)NC(O)=O ZHWWPRBSUHITHG-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 229940043355 kinase inhibitor Drugs 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 229930194542 Keto Natural products 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 125000000468 ketone group Chemical group 0.000 description 7
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 7
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 7
- 108010014186 ras Proteins Proteins 0.000 description 7
- 102000016914 ras Proteins Human genes 0.000 description 7
- 230000011664 signaling Effects 0.000 description 7
- 239000012064 sodium phosphate buffer Substances 0.000 description 7
- 229940124647 MEK inhibitor Drugs 0.000 description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 150000002085 enols Chemical group 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 6
- YKLQJWZIYVPXQL-UHFFFAOYSA-N n-[3-[2-bromo-2-(2-methylsulfanylpyrimidin-4-yl)acetyl]-2-chloro-5-fluorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C(Br)C(=O)C=2C(=C(NC(=O)C(C)(C)C)C=C(F)C=2)Cl)=N1 YKLQJWZIYVPXQL-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 229940124530 sulfonamide Drugs 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 102000001253 Protein Kinase Human genes 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-GUEYOVJQSA-N acetic acid-d4 Chemical compound [2H]OC(=O)C([2H])([2H])[2H] QTBSBXVTEAMEQO-GUEYOVJQSA-N 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 239000011324 bead Substances 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 239000013058 crude material Substances 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- MHMMVAMMASEGOB-UHFFFAOYSA-N ethyl 3-amino-2,5-dichlorobenzoate Chemical compound CCOC(=O)C1=CC(Cl)=CC(N)=C1Cl MHMMVAMMASEGOB-UHFFFAOYSA-N 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- 108060006633 protein kinase Proteins 0.000 description 5
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 150000003456 sulfonamides Chemical class 0.000 description 5
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 5
- KNTZCGBYFGEMFR-UHFFFAOYSA-N (propan-2-ylazaniumyl)formate Chemical compound CC(C)NC(O)=O KNTZCGBYFGEMFR-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- BHAKRVSCGILCEW-UHFFFAOYSA-N 2-chloro-4-methylpyrimidine Chemical compound CC1=CC=NC(Cl)=N1 BHAKRVSCGILCEW-UHFFFAOYSA-N 0.000 description 4
- UCERVHYBSTYCQS-UHFFFAOYSA-N 4-methyl-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC(C)=N1 UCERVHYBSTYCQS-UHFFFAOYSA-N 0.000 description 4
- AIPRBUGPVUCEOB-UHFFFAOYSA-N 5-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-oxazol-4-yl]-2-fluoroaniline Chemical compound CSC1=NC=CC(C2=C(N=C(O2)C2CC2)C=2C(=C(N)C=C(Cl)C=2)F)=N1 AIPRBUGPVUCEOB-UHFFFAOYSA-N 0.000 description 4
- XKDXKIAPLXNONX-UHFFFAOYSA-N 5-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-fluoroaniline Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C2CC2)C=2C(=C(N)C=C(Cl)C=2)F)=N1 XKDXKIAPLXNONX-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 101710113436 GTPase KRas Proteins 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 150000002576 ketones Chemical class 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
- VEKYKLDXYNUERO-UHFFFAOYSA-N methyl 2-fluoro-3-nitrobenzoate Chemical compound COC(=O)C1=CC=CC([N+]([O-])=O)=C1F VEKYKLDXYNUERO-UHFFFAOYSA-N 0.000 description 4
- BJUVQYJSEWHMGS-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-oxazol-4-yl]-5-fluorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(O2)C2CC2)C=2C(=C(NC(=O)C(C)(C)C)C=C(F)C=2)Cl)=N1 BJUVQYJSEWHMGS-UHFFFAOYSA-N 0.000 description 4
- DWEFRJKQXMDLOV-UHFFFAOYSA-N n-[3-[2-bromo-2-(2-methylsulfanylpyrimidin-4-yl)acetyl]-5-chloro-2-fluorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C(Br)C(=O)C=2C(=C(NC(=O)C(C)(C)C)C=C(Cl)C=2)F)=N1 DWEFRJKQXMDLOV-UHFFFAOYSA-N 0.000 description 4
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 4
- DROIHSMGGKKIJT-UHFFFAOYSA-N propane-1-sulfonamide Chemical compound CCCS(N)(=O)=O DROIHSMGGKKIJT-UHFFFAOYSA-N 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 150000003462 sulfoxides Chemical class 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical class 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 3
- KMPIZDXJQPBACJ-UHFFFAOYSA-N 2-(2-chloropyrimidin-4-yl)-1-(2-fluoro-3-nitrophenyl)ethanone Chemical compound [O-][N+](=O)C1=CC=CC(C(=O)CC=2N=C(Cl)N=CC=2)=C1F KMPIZDXJQPBACJ-UHFFFAOYSA-N 0.000 description 3
- IQISDKYMIPPETH-UHFFFAOYSA-N 2-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-5-fluoroaniline Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C2CC2)C=2C(=C(N)C=C(F)C=2)Cl)=N1 IQISDKYMIPPETH-UHFFFAOYSA-N 0.000 description 3
- KZZUNYMUGZESHY-UHFFFAOYSA-N 2-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]aniline Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C2CC2)C=2C(=C(N)C=CC=2)Cl)=N1 KZZUNYMUGZESHY-UHFFFAOYSA-N 0.000 description 3
- XHYXSIFQGLTLTM-UHFFFAOYSA-N 3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-1,3-thiazol-4-yl]-2-fluoroaniline Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(N)C=CC=2)F)=C1C1=CC=NC(Cl)=N1 XHYXSIFQGLTLTM-UHFFFAOYSA-N 0.000 description 3
- DKZJHQLTFDITTJ-UHFFFAOYSA-N 3-[2-tert-butyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-chloro-5-fluoroaniline Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C(C)(C)C)C=2C(=C(N)C=C(F)C=2)Cl)=N1 DKZJHQLTFDITTJ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 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 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- SZBPJZXGRXWNGF-UHFFFAOYSA-N OC(=O)NC(C)CNC1=NC=CC(C2=C(N=C(O2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 Chemical compound OC(=O)NC(C)CNC1=NC=CC(C2=C(N=C(O2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 SZBPJZXGRXWNGF-UHFFFAOYSA-N 0.000 description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 3
- 102100033479 RAF proto-oncogene serine/threonine-protein kinase Human genes 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 229940098773 bovine serum albumin Drugs 0.000 description 3
- JHRWWRDRBPCWTF-OLQVQODUSA-N captafol Chemical compound C1C=CC[C@H]2C(=O)N(SC(Cl)(Cl)C(Cl)Cl)C(=O)[C@H]21 JHRWWRDRBPCWTF-OLQVQODUSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 230000005595 deprotonation Effects 0.000 description 3
- 238000010537 deprotonation reaction Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 3
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000012636 effector Substances 0.000 description 3
- ZILJXERRDURVKD-UHFFFAOYSA-N ethyl 2-chloro-3-(methanesulfonamido)benzoate Chemical compound CCOC(=O)C1=CC=CC(NS(C)(=O)=O)=C1Cl ZILJXERRDURVKD-UHFFFAOYSA-N 0.000 description 3
- RFKXQGCBYQQWNX-UHFFFAOYSA-N ethyl 2-chloro-3-nitrobenzoate Chemical compound CCOC(=O)C1=CC=CC([N+]([O-])=O)=C1Cl RFKXQGCBYQQWNX-UHFFFAOYSA-N 0.000 description 3
- PQYZWIXJWWAFSD-UHFFFAOYSA-N ethyl 3-amino-2-chlorobenzoate Chemical compound CCOC(=O)C1=CC=CC(N)=C1Cl PQYZWIXJWWAFSD-UHFFFAOYSA-N 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 3
- HUPACJRNVMYQIE-UHFFFAOYSA-N methyl 3-[bis(propylsulfonyl)amino]-2-fluorobenzoate Chemical compound CCCS(=O)(=O)N(S(=O)(=O)CCC)C1=CC=CC(C(=O)OC)=C1F HUPACJRNVMYQIE-UHFFFAOYSA-N 0.000 description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- GCNVINNLQABHBI-UHFFFAOYSA-N n-(3-bromo-2-chloro-5-fluorophenyl)-2,2-dimethylpropanamide Chemical compound CC(C)(C)C(=O)NC1=CC(F)=CC(Br)=C1Cl GCNVINNLQABHBI-UHFFFAOYSA-N 0.000 description 3
- LDAIPPVCPATMEA-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-5-fluorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C2CC2)C=2C(=C(NC(=O)C(C)(C)C)C=C(F)C=2)Cl)=N1 LDAIPPVCPATMEA-UHFFFAOYSA-N 0.000 description 3
- JWJQAQITFPETCG-UHFFFAOYSA-N n-[2-chloro-5-fluoro-3-[2-(2-methylsulfanylpyrimidin-4-yl)acetyl]phenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(CC(=O)C=2C(=C(NC(=O)C(C)(C)C)C=C(F)C=2)Cl)=N1 JWJQAQITFPETCG-UHFFFAOYSA-N 0.000 description 3
- HJUYWKVLSRWEPW-UHFFFAOYSA-N n-[3-[2-bromo-2-(2-methylsulfanylpyrimidin-4-yl)acetyl]-2,5-dichlorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C(Br)C(=O)C=2C(=C(NC(=O)C(C)(C)C)C=C(Cl)C=2)Cl)=N1 HJUYWKVLSRWEPW-UHFFFAOYSA-N 0.000 description 3
- OWCFBBLCHRWTQH-UHFFFAOYSA-N n-[3-[2-bromo-2-(2-methylsulfanylpyrimidin-4-yl)acetyl]-2,5-dichlorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C(=O)C(Br)C=2N=C(SC)N=CC=2)=C1Cl OWCFBBLCHRWTQH-UHFFFAOYSA-N 0.000 description 3
- GKKVQAYZMRUUJZ-UHFFFAOYSA-N n-[3-[2-bromo-2-(2-methylsulfanylpyrimidin-4-yl)acetyl]-2-chlorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C(Br)C(=O)C=2C(=C(NC(=O)C(C)(C)C)C=CC=2)Cl)=N1 GKKVQAYZMRUUJZ-UHFFFAOYSA-N 0.000 description 3
- BVHQRAZWTTVMOH-UHFFFAOYSA-N n-[3-[2-bromo-2-(2-methylsulfanylpyrimidin-4-yl)acetyl]-2-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C(=O)C(Br)C=2N=C(SC)N=CC=2)=C1F BVHQRAZWTTVMOH-UHFFFAOYSA-N 0.000 description 3
- NMTBAGJSGQCVAC-UHFFFAOYSA-N n-[3-[2-bromo-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-chloro-5-fluorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(Br)S2)C=2C(=C(NC(=O)C(C)(C)C)C=C(F)C=2)Cl)=N1 NMTBAGJSGQCVAC-UHFFFAOYSA-N 0.000 description 3
- PFRJYJSPWLELPX-UHFFFAOYSA-N n-[3-[2-cyclopropyl-5-(2-methylsulfonylpyrimidin-4-yl)-1,3-oxazol-4-yl]-2-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(OC(=N2)C2CC2)C=2N=C(N=CC=2)S(C)(=O)=O)=C1F PFRJYJSPWLELPX-UHFFFAOYSA-N 0.000 description 3
- NVJUSTMMXRPYRD-UHFFFAOYSA-N n-[3-[2-cyclopropyl-5-(2-methylsulfonylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(SC(=N2)C2CC2)C=2N=C(N=CC=2)S(C)(=O)=O)=C1F NVJUSTMMXRPYRD-UHFFFAOYSA-N 0.000 description 3
- DOCDXNFECZAJJV-UHFFFAOYSA-N n-[3-[2-tert-butyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-chloro-5-fluorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C(C)(C)C)C=2C(=C(NC(=O)C(C)(C)C)C=C(F)C=2)Cl)=N1 DOCDXNFECZAJJV-UHFFFAOYSA-N 0.000 description 3
- DVSDRCVUUFQPPZ-UHFFFAOYSA-N n-[5-chloro-2-fluoro-3-[2-(2-methylsulfanylpyrimidin-4-yl)acetyl]phenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(CC(=O)C=2C(=C(NC(=O)C(C)(C)C)C=C(Cl)C=2)F)=N1 DVSDRCVUUFQPPZ-UHFFFAOYSA-N 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 150000003457 sulfones Chemical class 0.000 description 3
- 230000006103 sulfonylation Effects 0.000 description 3
- 238000005694 sulfonylation reaction Methods 0.000 description 3
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 150000003556 thioamides Chemical class 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical class 0.000 description 2
- JLOXTZFYJNCPIS-FYWRMAATSA-N (z)-3-amino-3-(4-aminophenyl)sulfanyl-2-[2-(trifluoromethyl)phenyl]prop-2-enenitrile Chemical compound C=1C=CC=C(C(F)(F)F)C=1C(\C#N)=C(/N)SC1=CC=C(N)C=C1 JLOXTZFYJNCPIS-FYWRMAATSA-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
- ZTPSKJBIWDDKJF-UHFFFAOYSA-N 2,5-dichloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-oxazol-4-yl]aniline Chemical compound CSC1=NC=CC(C2=C(N=C(O2)C2CC2)C=2C(=C(N)C=C(Cl)C=2)Cl)=N1 ZTPSKJBIWDDKJF-UHFFFAOYSA-N 0.000 description 2
- DYHHTYPOOLRANB-UHFFFAOYSA-N 2,5-dichloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]aniline Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C2CC2)C=2C(=C(N)C=C(Cl)C=2)Cl)=N1 DYHHTYPOOLRANB-UHFFFAOYSA-N 0.000 description 2
- WTLJAGXEHUOYNG-UHFFFAOYSA-N 2-bromo-2-(2-chloropyrimidin-4-yl)-1-(2-fluoro-3-nitrophenyl)ethanone Chemical compound [O-][N+](=O)C1=CC=CC(C(=O)C(Br)C=2N=C(Cl)N=CC=2)=C1F WTLJAGXEHUOYNG-UHFFFAOYSA-N 0.000 description 2
- YMLHJJZOCAEPQI-UHFFFAOYSA-N 2-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-oxazol-4-yl]-5-fluoroaniline Chemical compound CSC1=NC=CC(C2=C(N=C(O2)C2CC2)C=2C(=C(N)C=C(F)C=2)Cl)=N1 YMLHJJZOCAEPQI-UHFFFAOYSA-N 0.000 description 2
- FRLWSNFNNSPQKA-UHFFFAOYSA-N 2-tert-butyl-5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3-nitrophenyl)-1,3-thiazole Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(C=CC=2)[N+]([O-])=O)F)=C1C1=CC=NC(Cl)=N1 FRLWSNFNNSPQKA-UHFFFAOYSA-N 0.000 description 2
- FIMYFEGKMOCQKT-UHFFFAOYSA-N 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-n-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide Chemical compound FC=1C(F)=C(NC=2C(=CC(I)=CC=2)F)C(C(=O)NOCCO)=CC=1CN1OCCCC1=O FIMYFEGKMOCQKT-UHFFFAOYSA-N 0.000 description 2
- UMIJIQMJEJLAFG-UHFFFAOYSA-N 3-[2-tert-butyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-5-chloro-2-fluoroaniline Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C(C)(C)C)C=2C(=C(N)C=C(Cl)C=2)F)=N1 UMIJIQMJEJLAFG-UHFFFAOYSA-N 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- BUROJSBIWGDYCN-GAUTUEMISA-N AP 23573 Chemical compound C1C[C@@H](OP(C)(C)=O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 BUROJSBIWGDYCN-GAUTUEMISA-N 0.000 description 2
- 108700028369 Alleles Proteins 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 2
- 102100039788 GTPase NRas Human genes 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 2
- 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 2
- 229910004373 HOAc Inorganic materials 0.000 description 2
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 108091008606 PDGF receptors Proteins 0.000 description 2
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108010029869 Proto-Oncogene Proteins c-raf Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 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 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group 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 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000010307 cell transformation Effects 0.000 description 2
- 230000033077 cellular process Effects 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 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 description 2
- 229960002271 cobimetinib Drugs 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 230000002074 deregulated effect Effects 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 238000006471 dimerization reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- FNXDGXTVFSONFD-UHFFFAOYSA-N methyl 3-bromo-5-chloro-2-fluorobenzoate Chemical compound COC(=O)C1=CC(Cl)=CC(Br)=C1F FNXDGXTVFSONFD-UHFFFAOYSA-N 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- CRXYNKQVEOKFNI-UHFFFAOYSA-N n-[2,5-dichloro-3-[2-(2-methylsulfanylpyrimidin-4-yl)acetyl]phenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(CC(=O)C=2C(=C(NC(=O)C(C)(C)C)C=C(Cl)C=2)Cl)=N1 CRXYNKQVEOKFNI-UHFFFAOYSA-N 0.000 description 2
- FAZYOIRDBZXZAL-UHFFFAOYSA-N n-[2,5-dichloro-3-[2-(2-methylsulfanylpyrimidin-4-yl)acetyl]phenyl]methanesulfonamide Chemical compound CSC1=NC=CC(CC(=O)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)Cl)=N1 FAZYOIRDBZXZAL-UHFFFAOYSA-N 0.000 description 2
- FYOKNHQARMXYLD-UHFFFAOYSA-N n-[2,5-dichloro-3-[2-(2-methylsulfanylpyrimidin-4-yl)acetyl]phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C(=O)CC=2N=C(SC)N=CC=2)=C1Cl FYOKNHQARMXYLD-UHFFFAOYSA-N 0.000 description 2
- DGEMOTABBZUUHY-UHFFFAOYSA-N n-[2,5-dichloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-oxazol-4-yl]phenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(O2)C2CC2)C=2C(=C(NC(=O)C(C)(C)C)C=C(Cl)C=2)Cl)=N1 DGEMOTABBZUUHY-UHFFFAOYSA-N 0.000 description 2
- KORPZNDHTRKDEA-UHFFFAOYSA-N n-[2,5-dichloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-oxazol-4-yl]phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C2=C(OC(=N2)C2CC2)C=2N=C(SC)N=CC=2)=C1Cl KORPZNDHTRKDEA-UHFFFAOYSA-N 0.000 description 2
- BTIDQNQIJCTPDU-UHFFFAOYSA-N n-[2,5-dichloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]phenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C2CC2)C=2C(=C(NC(=O)C(C)(C)C)C=C(Cl)C=2)Cl)=N1 BTIDQNQIJCTPDU-UHFFFAOYSA-N 0.000 description 2
- XUMYCALTFDDJTH-UHFFFAOYSA-N n-[2,5-dichloro-3-[2-cyclopropyl-5-(2-methylsulfonylpyrimidin-4-yl)-1,3-oxazol-4-yl]phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C2=C(OC(=N2)C2CC2)C=2N=C(N=CC=2)S(C)(=O)=O)=C1Cl XUMYCALTFDDJTH-UHFFFAOYSA-N 0.000 description 2
- PSVGOVPQWXHSHC-UHFFFAOYSA-N n-[2,5-dichloro-3-[2-cyclopropyl-5-(2-methylsulfonylpyrimidin-4-yl)-1,3-thiazol-4-yl]phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C2=C(SC(=N2)C2CC2)C=2N=C(N=CC=2)S(C)(=O)=O)=C1Cl PSVGOVPQWXHSHC-UHFFFAOYSA-N 0.000 description 2
- MJLRDFCEJHOQMN-UHFFFAOYSA-N n-[2-chloro-3-[2-(2-chloropyrimidin-4-yl)acetyl]phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C(=O)CC=2N=C(Cl)N=CC=2)=C1Cl MJLRDFCEJHOQMN-UHFFFAOYSA-N 0.000 description 2
- CZLGYFOQMUPYGR-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-oxazol-4-yl]phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(OC(=N2)C2CC2)C=2N=C(SC)N=CC=2)=C1Cl CZLGYFOQMUPYGR-UHFFFAOYSA-N 0.000 description 2
- LLIGCSYWFIEQJJ-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(SC(=N2)C2CC2)C=2N=C(SC)N=CC=2)=C1Cl LLIGCSYWFIEQJJ-UHFFFAOYSA-N 0.000 description 2
- UYIBBIHIJCDKPZ-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-(2-methylsulfonylpyrimidin-4-yl)-1,3-oxazol-4-yl]phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(OC(=N2)C2CC2)C=2N=C(N=CC=2)S(C)(=O)=O)=C1Cl UYIBBIHIJCDKPZ-UHFFFAOYSA-N 0.000 description 2
- MOXYNSDSKSPXKM-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-(2-methylsulfonylpyrimidin-4-yl)-1,3-thiazol-4-yl]phenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=CC(C2=C(SC(=N2)C2CC2)C=2N=C(N=CC=2)S(C)(=O)=O)=C1Cl MOXYNSDSKSPXKM-UHFFFAOYSA-N 0.000 description 2
- GNOGICDOBHGMSQ-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-(2-methylsulfonylpyrimidin-4-yl)-1,3-thiazol-4-yl]phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(SC(=N2)C2CC2)C=2N=C(N=CC=2)S(C)(=O)=O)=C1Cl GNOGICDOBHGMSQ-UHFFFAOYSA-N 0.000 description 2
- MNPIJRGVULFFMZ-UHFFFAOYSA-N n-[2-fluoro-3-[2-(2-methylsulfanylpyrimidin-4-yl)acetyl]phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C(=O)CC=2N=C(SC)N=CC=2)=C1F MNPIJRGVULFFMZ-UHFFFAOYSA-N 0.000 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 description 2
- DMWZVGCMNAQAPU-UHFFFAOYSA-N n-[3-[2-amino-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2,5-dichlorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(N)S2)C=2C(=C(NC(=O)C(C)(C)C)C=C(Cl)C=2)Cl)=N1 DMWZVGCMNAQAPU-UHFFFAOYSA-N 0.000 description 2
- WODOGYBWTKROAN-UHFFFAOYSA-N n-[3-[2-amino-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-chloro-5-fluorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(N)S2)C=2C(=C(NC(=O)C(C)(C)C)C=C(F)C=2)Cl)=N1 WODOGYBWTKROAN-UHFFFAOYSA-N 0.000 description 2
- YDRWPFMJOMYXIX-UHFFFAOYSA-N n-[3-[2-amino-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-5-chloro-2-fluorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(N)S2)C=2C(=C(NC(=O)C(C)(C)C)C=C(Cl)C=2)F)=N1 YDRWPFMJOMYXIX-UHFFFAOYSA-N 0.000 description 2
- KCMUGDNNBORXBY-UHFFFAOYSA-N n-[3-[2-bromo-2-(2-chloropyrimidin-4-yl)acetyl]-2-chlorophenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=CC(C(=O)C(Br)C=2N=C(Cl)N=CC=2)=C1Cl KCMUGDNNBORXBY-UHFFFAOYSA-N 0.000 description 2
- SZQDKJLPKPLVJL-UHFFFAOYSA-N n-[3-[2-bromo-2-(2-chloropyrimidin-4-yl)acetyl]-2-chlorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C(=O)C(Br)C=2N=C(Cl)N=CC=2)=C1Cl SZQDKJLPKPLVJL-UHFFFAOYSA-N 0.000 description 2
- GGEPSDCIPSNQFZ-UHFFFAOYSA-N n-[3-[2-bromo-2-(2-methylsulfanylpyrimidin-4-yl)acetyl]-2,5-dichlorophenyl]methanesulfonamide Chemical compound CSC1=NC=CC(C(Br)C(=O)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)Cl)=N1 GGEPSDCIPSNQFZ-UHFFFAOYSA-N 0.000 description 2
- KHZLVNJPTRTQBP-UHFFFAOYSA-N n-[3-[2-bromo-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2,5-dichlorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(Br)S2)C=2C(=C(NC(=O)C(C)(C)C)C=C(Cl)C=2)Cl)=N1 KHZLVNJPTRTQBP-UHFFFAOYSA-N 0.000 description 2
- AVZFSAQDLAEUMT-UHFFFAOYSA-N n-[3-[2-bromo-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-5-chloro-2-fluorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(Br)S2)C=2C(=C(NC(=O)C(C)(C)C)C=C(Cl)C=2)F)=N1 AVZFSAQDLAEUMT-UHFFFAOYSA-N 0.000 description 2
- GUOYLJSOCCKUSS-UHFFFAOYSA-N n-[3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-oxazol-4-yl]-2-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(OC(=N2)C2CC2)C=2N=C(SC)N=CC=2)=C1F GUOYLJSOCCKUSS-UHFFFAOYSA-N 0.000 description 2
- CJMBKKXSEAAQHG-UHFFFAOYSA-N n-[3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(SC(=N2)C2CC2)C=2N=C(SC)N=CC=2)=C1F CJMBKKXSEAAQHG-UHFFFAOYSA-N 0.000 description 2
- QARKIOCCDIZOBO-UHFFFAOYSA-N n-[3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(SC(=N2)C(C)(C)C)C=2N=C(Cl)N=CC=2)=C1Cl QARKIOCCDIZOBO-UHFFFAOYSA-N 0.000 description 2
- NDJDJAPJBPWWIV-UHFFFAOYSA-N n-[3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl]methanesulfonamide Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(C)(=O)=O)C=CC=2)F)=C1C1=CC=NC(Cl)=N1 NDJDJAPJBPWWIV-UHFFFAOYSA-N 0.000 description 2
- CLIPRTOKRYYIEX-UHFFFAOYSA-N n-[3-[2-tert-butyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-chloro-5-fluorophenyl]methanesulfonamide Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C(C)(C)C)C=2C(=C(NS(C)(=O)=O)C=C(F)C=2)Cl)=N1 CLIPRTOKRYYIEX-UHFFFAOYSA-N 0.000 description 2
- WBHPUXVDSRILAJ-UHFFFAOYSA-N n-[3-[2-tert-butyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-5-chloro-2-fluorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C(C)(C)C)C=2C(=C(NC(=O)C(C)(C)C)C=C(Cl)C=2)F)=N1 WBHPUXVDSRILAJ-UHFFFAOYSA-N 0.000 description 2
- JSUCCVJYBPEEAX-UHFFFAOYSA-N n-[5-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-oxazol-4-yl]-2-fluorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(O2)C2CC2)C=2C(=C(NC(=O)C(C)(C)C)C=C(Cl)C=2)F)=N1 JSUCCVJYBPEEAX-UHFFFAOYSA-N 0.000 description 2
- DJDKFKJQKAUZIZ-UHFFFAOYSA-N n-[5-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-oxazol-4-yl]-2-fluorophenyl]methanesulfonamide Chemical compound CSC1=NC=CC(C2=C(N=C(O2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 DJDKFKJQKAUZIZ-UHFFFAOYSA-N 0.000 description 2
- QPSDDYKOLPVHKJ-UHFFFAOYSA-N n-[5-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C2CC2)C=2C(=C(NC(=O)C(C)(C)C)C=C(Cl)C=2)F)=N1 QPSDDYKOLPVHKJ-UHFFFAOYSA-N 0.000 description 2
- MPWPOADUEFLYJJ-UHFFFAOYSA-N n-[5-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl]methanesulfonamide Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 MPWPOADUEFLYJJ-UHFFFAOYSA-N 0.000 description 2
- GFDDLOPSFOAWNN-UHFFFAOYSA-N n-[5-chloro-3-[2-cyclopropyl-5-(2-methylsulfinylpyrimidin-4-yl)-1,3-oxazol-4-yl]-2-fluorophenyl]methanesulfonamide Chemical compound CS(=O)C1=NC=CC(C2=C(N=C(O2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 GFDDLOPSFOAWNN-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 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
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 125000003145 oxazol-4-yl group Chemical group O1C=NC(=C1)* 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 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 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229960001302 ridaforolimus Drugs 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 125000005463 sulfonylimide group Chemical group 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 2
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 2
- 229960000575 trastuzumab Drugs 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 2
- RNEACARJKXYVND-KQGZCTBQSA-N (2r)-2-[[(5z)-5-[(5-ethylfuran-2-yl)methylidene]-4-oxo-1,3-thiazol-2-yl]amino]-2-(4-fluorophenyl)acetic acid Chemical compound O1C(CC)=CC=C1\C=C/1C(=O)N=C(N[C@@H](C(O)=O)C=2C=CC(F)=CC=2)S\1 RNEACARJKXYVND-KQGZCTBQSA-N 0.000 description 1
- 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 description 1
- OYYVWNDMOQPMGE-SDQBBNPISA-N (5z)-5-[[5-(4-fluoro-2-hydroxyphenyl)furan-2-yl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound OC1=CC(F)=CC=C1C(O1)=CC=C1\C=C/1C(=O)NC(=O)S\1 OYYVWNDMOQPMGE-SDQBBNPISA-N 0.000 description 1
- 125000006573 (C1-C10) heteroaryl group Chemical group 0.000 description 1
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-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
- ACTKAGSPIFDCMF-UHFFFAOYSA-N 1,3-oxazol-2-amine Chemical compound NC1=NC=CO1 ACTKAGSPIFDCMF-UHFFFAOYSA-N 0.000 description 1
- HKDFRDIIELOLTJ-UHFFFAOYSA-N 1,4-dithianyl Chemical group [CH]1CSCCS1 HKDFRDIIELOLTJ-UHFFFAOYSA-N 0.000 description 1
- CTYUQEUZFSWMJE-UHFFFAOYSA-N 1-(2-chloro-3-nitrophenyl)-2-(2-methylsulfanylpyrimidin-4-yl)ethanone Chemical compound CSC1=NC=CC(CC(=O)C=2C(=C(C=CC=2)[N+]([O-])=O)Cl)=N1 CTYUQEUZFSWMJE-UHFFFAOYSA-N 0.000 description 1
- DWZAEMINVBZMHQ-UHFFFAOYSA-N 1-[4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl]-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea Chemical compound C1CC(N(C)C)CCN1C(=O)C(C=C1)=CC=C1NC(=O)NC1=CC=C(C=2N=C(N=C(N=2)N2CCOCC2)N2CCOCC2)C=C1 DWZAEMINVBZMHQ-UHFFFAOYSA-N 0.000 description 1
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 description 1
- XLJORQYAOTYVQS-OGCOKEDGSA-N 17-hydroxywortmannin Chemical class C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O XLJORQYAOTYVQS-OGCOKEDGSA-N 0.000 description 1
- DCYGAPKNVCQNOE-UHFFFAOYSA-N 2,2,2-triphenylacetic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)O)C1=CC=CC=C1 DCYGAPKNVCQNOE-UHFFFAOYSA-N 0.000 description 1
- FJZJUSOFGBXHCV-UHFFFAOYSA-N 2,2-dimethylpropanethioamide Chemical compound CC(C)(C)C(N)=S FJZJUSOFGBXHCV-UHFFFAOYSA-N 0.000 description 1
- GFMMXOIFOQCCGU-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=C(F)C(F)=CC=C1C(=O)NOCC1CC1 GFMMXOIFOQCCGU-UHFFFAOYSA-N 0.000 description 1
- RWEVIPRMPFNTLO-UHFFFAOYSA-N 2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-3-pyridinecarboxamide Chemical compound CN1C(=O)C(C)=CC(C(=O)NOCCO)=C1NC1=CC=C(I)C=C1F RWEVIPRMPFNTLO-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- QINPEPAQOBZPOF-UHFFFAOYSA-N 2-amino-n-[3-[[3-(2-chloro-5-methoxyanilino)quinoxalin-2-yl]sulfamoyl]phenyl]-2-methylpropanamide Chemical compound COC1=CC=C(Cl)C(NC=2C(=NC3=CC=CC=C3N=2)NS(=O)(=O)C=2C=C(NC(=O)C(C)(C)N)C=CC=2)=C1 QINPEPAQOBZPOF-UHFFFAOYSA-N 0.000 description 1
- YFFUYGSLQXVHMB-UHFFFAOYSA-N 2-bromo-4-chloro-1-fluorobenzene Chemical compound FC1=CC=C(Cl)C=C1Br YFFUYGSLQXVHMB-UHFFFAOYSA-N 0.000 description 1
- ALLRFFYKIHXDKB-UHFFFAOYSA-N 2-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-oxazol-4-yl]aniline Chemical compound CSC1=NC=CC(C2=C(N=C(O2)C2CC2)C=2C(=C(N)C=CC=2)Cl)=N1 ALLRFFYKIHXDKB-UHFFFAOYSA-N 0.000 description 1
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical group ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 1
- WLGUSLGYTNJJFV-UHFFFAOYSA-N 2-fluoro-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1F WLGUSLGYTNJJFV-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- WBJWXIQDBDZMAW-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carbonyl chloride Chemical compound C1=CC=CC2=C(C(Cl)=O)C(O)=CC=C21 WBJWXIQDBDZMAW-UHFFFAOYSA-N 0.000 description 1
- FOEMIZSFFWGXHX-UHFFFAOYSA-N 2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC=N1 FOEMIZSFFWGXHX-UHFFFAOYSA-N 0.000 description 1
- OIGXNHYFKZCTCH-UHFFFAOYSA-N 2-methylsulfonylpyrimidine Chemical compound CS(=O)(=O)C1=NC=CC=N1 OIGXNHYFKZCTCH-UHFFFAOYSA-N 0.000 description 1
- XSQMYBFFYPTMFE-UHFFFAOYSA-N 3-(4-morpholin-4-ylpyrido[2,3]furo[2,4-b]pyrimidin-2-yl)phenol;hydrochloride Chemical compound Cl.OC1=CC=CC(C=2N=C3C4=CC=CN=C4OC3=C(N3CCOCC3)N=2)=C1 XSQMYBFFYPTMFE-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical class C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- NRFJSFXSRKRVLO-UHFFFAOYSA-N 3-[2-tert-butyl-5-(2-methylsulfonylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-chloro-5-fluoroaniline Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(N)C=C(F)C=2)Cl)=C1C1=CC=NC(S(C)(=O)=O)=N1 NRFJSFXSRKRVLO-UHFFFAOYSA-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
- IQMIVFNEHPKEAI-UHFFFAOYSA-N 3-amino-2-chlorobenzoic acid Chemical compound NC1=CC=CC(C(O)=O)=C1Cl IQMIVFNEHPKEAI-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- JRQDVRIQJJPHEQ-UHFFFAOYSA-N 3970-35-2 Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1Cl JRQDVRIQJJPHEQ-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
- SWUAYTHFOCGUNR-UHFFFAOYSA-N 4-(4-bromo-2-fluoroanilino)-n-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridazine-3-carboxamide Chemical compound OCCONC(=O)C1=NN(C)C(=O)C(C)=C1NC1=CC=C(Br)C=C1F SWUAYTHFOCGUNR-UHFFFAOYSA-N 0.000 description 1
- GVKWJWXRSWROJM-UHFFFAOYSA-N 4-[2-(1h-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[2,3-d]pyrimidin-4-yl]morpholine Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=CC2=C(N3CCOCC3)N=C(C=3C=4C=NNC=4C=CC=3)N=C2S1 GVKWJWXRSWROJM-UHFFFAOYSA-N 0.000 description 1
- RFRIKACSFOTIMU-UHFFFAOYSA-N 4-[2-(1h-indazol-4-yl)-6-[(4-methylsulfonylpiperazin-1-yl)methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine;methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.C1CN(S(=O)(=O)C)CCN1CC1=CC2=NC(C=3C=4C=NNC=4C=CC=3)=NC(N3CCOCC3)=C2S1 RFRIKACSFOTIMU-UHFFFAOYSA-N 0.000 description 1
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- DLQOCRQNPSGPSR-UHFFFAOYSA-N 4-methyl-2-methylsulfanylpyridine Chemical compound CSC1=CC(C)=CC=N1 DLQOCRQNPSGPSR-UHFFFAOYSA-N 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CPRAGQJXBLMUEL-UHFFFAOYSA-N 9-(1-anilinoethyl)-7-methyl-2-(4-morpholinyl)-4-pyrido[1,2-a]pyrimidinone Chemical compound C=1C(C)=CN(C(C=C(N=2)N3CCOCC3)=O)C=2C=1C(C)NC1=CC=CC=C1 CPRAGQJXBLMUEL-UHFFFAOYSA-N 0.000 description 1
- 101150019464 ARAF gene Proteins 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 229920001817 Agar Polymers 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
- 241000416162 Astragalus gummifer Species 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- CWHUFRVAEUJCEF-UHFFFAOYSA-N BKM120 Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=CC(N2CCOCC2)=NC(N2CCOCC2)=N1 CWHUFRVAEUJCEF-UHFFFAOYSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OPBBZQXWEXBQGX-UHFFFAOYSA-N CSC1=NC=CC(=N1)C2=CN=C(S2)C3CC3 Chemical compound CSC1=NC=CC(=N1)C2=CN=C(S2)C3CC3 OPBBZQXWEXBQGX-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-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
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 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
- 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 description 1
- 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 description 1
- 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 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 1
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 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
- 102100023401 Dual specificity mitogen-activated protein kinase kinase 6 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
- 239000001116 FEMA 4028 Substances 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
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-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
- 101000624426 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 6 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical group Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- CZQHHVNHHHRRDU-UHFFFAOYSA-N LY294002 Chemical compound C1=CC=C2C(=O)C=C(N3CCOCC3)OC2=C1C1=CC=CC=C1 CZQHHVNHHHRRDU-UHFFFAOYSA-N 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
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 101150003567 Mapk12 gene Proteins 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- 108700027649 Mitogen-Activated Protein Kinase 3 Proteins 0.000 description 1
- 102100024193 Mitogen-activated protein kinase 1 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
- 102100024192 Mitogen-activated protein kinase 3 Human genes 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- FCKJZIRDZMVDEM-UHFFFAOYSA-N N-(7,8-dimethoxy-2,3-dihydro-1H-imidazo[1,2-c]quinazolin-5-ylidene)pyridine-3-carboxamide Chemical compound COC1=C(C2=NC(=NC(=O)C3=CN=CC=C3)N4CCNC4=C2C=C1)OC FCKJZIRDZMVDEM-UHFFFAOYSA-N 0.000 description 1
- YDVVGBYZYRLTBZ-UHFFFAOYSA-N N-[3-(2-tert-butyl-5-pyrimidin-4-yl-1,3-thiazol-4-yl)-2-chloro-5-fluorophenyl]methanesulfonamide Chemical compound C(C)(C)(C)C=1SC(=C(N=1)C1=C(C(=CC(=C1)F)NS(=O)(=O)C)Cl)C1=NC=NC=C1 YDVVGBYZYRLTBZ-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 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
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 208000012868 Overgrowth Diseases 0.000 description 1
- SUDAHWBOROXANE-SECBINFHSA-N PD 0325901 Chemical compound OC[C@@H](O)CONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F SUDAHWBOROXANE-SECBINFHSA-N 0.000 description 1
- SUDAHWBOROXANE-VIFPVBQESA-N PD 0325901-Cl Chemical compound OC[C@H](O)CONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F SUDAHWBOROXANE-VIFPVBQESA-N 0.000 description 1
- 239000012828 PI3K inhibitor Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 101710141955 RAF proto-oncogene serine/threonine-protein kinase 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
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- PYHXGXCGESYPCW-UHFFFAOYSA-N alpha-phenylbenzeneacetic acid Natural products C=1C=CC=CC=1C(C(=O)O)C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 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
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 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
- 150000003939 benzylamines Chemical class 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 150000005347 biaryls Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 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 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229950003628 buparlisib Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical compound BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- XDLYKKIQACFMJG-WKILWMFISA-N chembl1234354 Chemical compound C1=NC(OC)=CC=C1C(C1=O)=CC2=C(C)N=C(N)N=C2N1[C@@H]1CC[C@@H](OCCO)CC1 XDLYKKIQACFMJG-WKILWMFISA-N 0.000 description 1
- JROFGZPOBKIAEW-HAQNSBGRSA-N chembl3120215 Chemical compound N1C=2C(OC)=CC=CC=2C=C1C(=C1C(N)=NC=NN11)N=C1[C@H]1CC[C@H](C(O)=O)CC1 JROFGZPOBKIAEW-HAQNSBGRSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 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
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([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
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- JOGKUKXHTYWRGZ-UHFFFAOYSA-N dactolisib Chemical compound O=C1N(C)C2=CN=C3C=CC(C=4C=C5C=CC=CC5=NC=4)=CC3=C2N1C1=CC=C(C(C)(C)C#N)C=C1 JOGKUKXHTYWRGZ-UHFFFAOYSA-N 0.000 description 1
- 229950006418 dactolisib Drugs 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000006001 difluoroethyl group Chemical group 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- HTXVBGDRUBBSBH-UHFFFAOYSA-N ethyl 2,5-dichloro-3-nitrobenzoate Chemical compound CCOC(=O)C1=CC(Cl)=CC([N+]([O-])=O)=C1Cl HTXVBGDRUBBSBH-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000005843 halogen 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
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- ZXRCAYWYTOIRQS-UHFFFAOYSA-N hydron;phenol;chloride Chemical compound Cl.OC1=CC=CC=C1 ZXRCAYWYTOIRQS-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- UOYDNSRSUSNCKS-UHFFFAOYSA-N methyl 3-amino-2-fluorobenzoate Chemical compound COC(=O)C1=CC=CC(N)=C1F UOYDNSRSUSNCKS-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 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
- 230000001483 mobilizing effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- QTHCAAFKVUWAFI-DJKKODMXSA-N n-[(e)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylideneamino]-n,2-dimethyl-5-nitrobenzenesulfonamide Chemical compound C=1N=C2C=CC(Br)=CN2C=1/C=N/N(C)S(=O)(=O)C1=CC([N+]([O-])=O)=CC=C1C QTHCAAFKVUWAFI-DJKKODMXSA-N 0.000 description 1
- HKEZUDZJFWZUAY-UHFFFAOYSA-N n-[2,5-dichloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C2=C(SC(=N2)C2CC2)C=2N=C(SC)N=CC=2)=C1Cl HKEZUDZJFWZUAY-UHFFFAOYSA-N 0.000 description 1
- CTBNBGHNDYDLMJ-UHFFFAOYSA-N n-[2-chloro-3-[2-(2-methylsulfanylpyrimidin-4-yl)acetyl]phenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(CC(=O)C=2C(=C(NC(=O)C(C)(C)C)C=CC=2)Cl)=N1 CTBNBGHNDYDLMJ-UHFFFAOYSA-N 0.000 description 1
- RRMFPNCGOKFPPO-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-oxazol-4-yl]phenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(O2)C2CC2)C=2C(=C(NC(=O)C(C)(C)C)C=CC=2)Cl)=N1 RRMFPNCGOKFPPO-UHFFFAOYSA-N 0.000 description 1
- KUSGTBDCUPQOHF-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-5-fluorophenyl]methanesulfonamide Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(F)C=2)Cl)=N1 KUSGTBDCUPQOHF-UHFFFAOYSA-N 0.000 description 1
- OOLAEIBRZQUTOB-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]phenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C2CC2)C=2C(=C(NC(=O)C(C)(C)C)C=CC=2)Cl)=N1 OOLAEIBRZQUTOB-UHFFFAOYSA-N 0.000 description 1
- IBIFTEYUMPUZPG-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]phenyl]methanesulfonamide Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=CC=2)Cl)=N1 IBIFTEYUMPUZPG-UHFFFAOYSA-N 0.000 description 1
- YDTMZPBWPADRIS-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-(2-methylsulfonylpyrimidin-4-yl)-1,3-thiazol-4-yl]-5-fluorophenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC(F)=CC(C2=C(SC(=N2)C2CC2)C=2N=C(N=CC=2)S(C)(=O)=O)=C1Cl YDTMZPBWPADRIS-UHFFFAOYSA-N 0.000 description 1
- ULSXYFCGKFNLLR-UHFFFAOYSA-N n-[3-(2-tert-butyl-5-pyrimidin-4-yl-1,3-thiazol-4-yl)-2-chloro-5-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(F)=CC(C2=C(SC(=N2)C(C)(C)C)C=2N=CN=CC=2)=C1Cl ULSXYFCGKFNLLR-UHFFFAOYSA-N 0.000 description 1
- TUBDZILGJNSZST-UHFFFAOYSA-N n-[3-[2-amino-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(N)S2)C=2C(=C(NC(=O)C(C)(C)C)C=CC=2)Cl)=N1 TUBDZILGJNSZST-UHFFFAOYSA-N 0.000 description 1
- DBBXKEDXJZKWPO-UHFFFAOYSA-N n-[3-[2-amino-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(SC(N)=N2)C=2N=C(SC)N=CC=2)=C1F DBBXKEDXJZKWPO-UHFFFAOYSA-N 0.000 description 1
- VJHCEURLVSOBRW-UHFFFAOYSA-N n-[3-[2-bromo-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl]-2,2-dimethylpropanamide Chemical compound CSC1=NC=CC(C2=C(N=C(Br)S2)C=2C(=C(NC(=O)C(C)(C)C)C=CC=2)Cl)=N1 VJHCEURLVSOBRW-UHFFFAOYSA-N 0.000 description 1
- VYEDRNBHVGQWPX-UHFFFAOYSA-N n-[3-[2-bromo-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(SC(Br)=N2)C=2N=C(SC)N=CC=2)=C1F VYEDRNBHVGQWPX-UHFFFAOYSA-N 0.000 description 1
- MUHRJMGGJPOWRC-UHFFFAOYSA-N n-[3-[2-cyclopropyl-5-[2-(methylamino)pyrimidin-4-yl]-1,3-oxazol-4-yl]-2-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(OC(=N2)C2CC2)C=2N=C(NC)N=CC=2)=C1F MUHRJMGGJPOWRC-UHFFFAOYSA-N 0.000 description 1
- FGRMHGHAVLLNGZ-UHFFFAOYSA-N n-[3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-1,3-thiazol-4-yl]-2-chlorophenyl]methanesulfonamide Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(C)(=O)=O)C=CC=2)Cl)=C1C1=CC=NC(Cl)=N1 FGRMHGHAVLLNGZ-UHFFFAOYSA-N 0.000 description 1
- KXBRBQNRMAJOFZ-UHFFFAOYSA-N n-[3-[2-tert-butyl-5-(2-chloropyrimidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(SC(=N2)C(C)(C)C)C=2N=C(Cl)N=CC=2)=C1F KXBRBQNRMAJOFZ-UHFFFAOYSA-N 0.000 description 1
- WBEURMWKHBNAMD-UHFFFAOYSA-N n-[3-[2-tert-butyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2,5-dichlorophenyl]methanesulfonamide Chemical compound CSC1=NC=CC(C2=C(N=C(S2)C(C)(C)C)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)Cl)=N1 WBEURMWKHBNAMD-UHFFFAOYSA-N 0.000 description 1
- NGPYHOQUKYKNCX-UHFFFAOYSA-N n-[3-[2-tert-butyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2,5-dichlorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(C2=C(SC(=N2)C(C)(C)C)C=2N=C(SC)N=CC=2)=C1Cl NGPYHOQUKYKNCX-UHFFFAOYSA-N 0.000 description 1
- GNNQKUHNUFXTEG-UHFFFAOYSA-N n-[3-[2-tert-butyl-5-(2-methylsulfanylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-chloro-5-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(F)=CC(C2=C(SC(=N2)C(C)(C)C)C=2N=C(SC)N=CC=2)=C1Cl GNNQKUHNUFXTEG-UHFFFAOYSA-N 0.000 description 1
- QTXRGDFGWJOCOM-UHFFFAOYSA-N n-[3-[2-tert-butyl-5-(2-methylsulfonylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-chloro-5-fluorophenyl]methanesulfonamide Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(C)(=O)=O)C=C(F)C=2)Cl)=C1C1=CC=NC(S(C)(=O)=O)=N1 QTXRGDFGWJOCOM-UHFFFAOYSA-N 0.000 description 1
- GQXBMFMKMPULRW-UHFFFAOYSA-N n-[3-[2-tert-butyl-5-(2-methylsulfonylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-chloro-5-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(F)=CC(C2=C(SC(=N2)C(C)(C)C)C=2N=C(N=CC=2)S(C)(=O)=O)=C1Cl GQXBMFMKMPULRW-UHFFFAOYSA-N 0.000 description 1
- QXLSYMUZKQAQGN-AWEZNQCLSA-N n-[3-[5-[2-[[(2s)-2-aminopropyl]amino]pyrimidin-4-yl]-2-tert-butyl-1,3-thiazol-4-yl]-2-chlorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(SC(=N2)C(C)(C)C)C=2N=C(NC[C@H](C)N)N=CC=2)=C1Cl QXLSYMUZKQAQGN-AWEZNQCLSA-N 0.000 description 1
- DOFMINHAJHEQEP-UHFFFAOYSA-N n-[5-chloro-3-[2-cyclopropyl-5-(2-methylsulfinylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl]methanesulfonamide Chemical compound CS(=O)C1=NC=CC(C2=C(N=C(S2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 DOFMINHAJHEQEP-UHFFFAOYSA-N 0.000 description 1
- GZNXIJBLIVIMFQ-UHFFFAOYSA-N n-[5-chloro-3-[2-cyclopropyl-5-(2-methylsulfonylpyrimidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC(Cl)=CC(C2=C(SC(=N2)C2CC2)C=2N=C(N=CC=2)S(C)(=O)=O)=C1F GZNXIJBLIVIMFQ-UHFFFAOYSA-N 0.000 description 1
- ILCQYORZHHFLNL-UHFFFAOYSA-N n-bromoaniline Chemical compound BrNC1=CC=CC=C1 ILCQYORZHHFLNL-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000005338 nitrobenzoic acids Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 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
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- CGBJSGAELGCMKE-UHFFFAOYSA-N omipalisib Chemical compound COC1=NC=C(C=2C=C3C(C=4C=NN=CC=4)=CC=NC3=CC=2)C=C1NS(=O)(=O)C1=CC=C(F)C=C1F CGBJSGAELGCMKE-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 229960002087 pertuzumab Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 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
- 235000019260 propionic acid Nutrition 0.000 description 1
- JAQOMSTTXPGKTN-UHFFFAOYSA-N propylboronic acid Chemical compound CCCB(O)O JAQOMSTTXPGKTN-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 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
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 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 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000008137 solubility enhancer Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-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
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- 210000001519 tissue Anatomy 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
- 229940100411 torisel Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229960004066 trametinib Drugs 0.000 description 1
- OQUFJVRYDFIQBW-UHFFFAOYSA-N trametinib dimethyl sulfoxide Chemical compound CS(C)=O.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 OQUFJVRYDFIQBW-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 1
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US35860310P | 2010-06-25 | 2010-06-25 | |
| US61/358,603 | 2010-06-25 | ||
| US36853410P | 2010-07-28 | 2010-07-28 | |
| US61/368,534 | 2010-07-28 | ||
| PCT/EP2011/060561 WO2011161216A1 (en) | 2010-06-25 | 2011-06-23 | Heteroaryl compounds and compositions as protein kinase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2013529619A true JP2013529619A (ja) | 2013-07-22 |
| JP2013529619A5 JP2013529619A5 (enExample) | 2014-07-24 |
Family
ID=44280749
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2013515902A Pending JP2013529619A (ja) | 2010-06-25 | 2011-06-23 | タンパク質キナーゼ阻害剤としてのヘテロアリール化合物および組成物 |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20130096149A1 (enExample) |
| EP (1) | EP2585454A1 (enExample) |
| JP (1) | JP2013529619A (enExample) |
| KR (2) | KR20130048293A (enExample) |
| CN (1) | CN103080107A (enExample) |
| AU (1) | AU2011268906A1 (enExample) |
| BR (1) | BR112012032884A2 (enExample) |
| CA (1) | CA2803055A1 (enExample) |
| EA (1) | EA201201676A1 (enExample) |
| MX (1) | MX2012015100A (enExample) |
| WO (1) | WO2011161216A1 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014506585A (ja) * | 2011-02-24 | 2014-03-17 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | キナーゼ阻害剤としてのチアゾリルフェニル−ベンゼンスルホンアミド誘導体 |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9242969B2 (en) | 2013-03-14 | 2016-01-26 | Novartis Ag | Biaryl amide compounds as kinase inhibitors |
| WO2014172639A1 (en) * | 2013-04-19 | 2014-10-23 | Ruga Corporation | Raf kinase inhibitors |
| UY36294A (es) | 2014-09-12 | 2016-04-29 | Novartis Ag | Compuestos y composiciones como inhibidores de quinasa |
| CN109715163B (zh) | 2016-09-19 | 2022-11-22 | 诺华股份有限公司 | 包含raf抑制剂和erk抑制剂的治疗组合 |
| EP3515909A1 (en) | 2016-09-23 | 2019-07-31 | Cellipse | Lim kinase inhibitors, pharmaceutical composition and method of use in limk-mediated diseases |
| WO2018203219A1 (en) | 2017-05-02 | 2018-11-08 | Novartis Ag | Combination therapy |
| WO2020124397A1 (en) * | 2018-12-19 | 2020-06-25 | Inventisbio Shanghai Ltd. | C-terminal src kinase inhibitors |
| EP4563150A3 (en) | 2019-05-13 | 2025-07-23 | Novartis AG | New crystalline forms of n-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methvlphenyl)-2(trifluoromethyl) isonicotinamide as raf inhibitors for the treatment of cancer |
| CN114746419B (zh) * | 2019-12-05 | 2023-10-24 | 国家医疗保健研究所 | N-(3-(5-(嘧啶-4-基)噻唑-4-基)苯基)磺酰胺化合物及其用作braf抑制剂的用途 |
| CN111320548B (zh) * | 2020-04-24 | 2022-10-18 | 浦拉司科技（上海）有限责任公司 | 抗癌药物中间体2-氟-3-氨基苯甲酸甲酯的合成方法 |
| EP4281436A1 (en) * | 2021-01-20 | 2023-11-29 | Basf Se | Synthesis of polyfluorinated aryl and heteroaryl carboxamides |
| KR20240167846A (ko) | 2022-03-28 | 2024-11-28 | 니캉 테라퓨틱스 인코포레이티드 | 사이클린 의존적 키나제 2 억제제로서의 설폰아미도 유도체 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003063993A (ja) * | 2001-06-11 | 2003-03-05 | Takeda Chem Ind Ltd | 医薬組成物 |
| WO2009012283A1 (en) * | 2007-07-17 | 2009-01-22 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
| WO2009076140A1 (en) * | 2007-12-13 | 2009-06-18 | Smithkline Beecham Corporation | Thiazole and oxazole kinase inhibitors |
| WO2009137391A2 (en) * | 2008-05-06 | 2009-11-12 | Smithkline Beecham Corporation | Benzene sulfonamide thiazole and oxazole compounds |
Family Cites Families (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6358932B1 (en) | 1994-05-31 | 2002-03-19 | Isis Pharmaceticals, Inc. | Antisense oligonucleotide inhibition of raf gene expression |
| US6391636B1 (en) | 1994-05-31 | 2002-05-21 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide modulation of raf gene expression |
| US6037136A (en) | 1994-10-24 | 2000-03-14 | Cold Spring Harbor Laboratory | Interactions between RaF proto-oncogenes and CDC25 phosphatases, and uses related thereto |
| US5717100A (en) | 1995-10-06 | 1998-02-10 | Merck & Co., Inc. | Substituted imidazoles having anti-cancer and cytokine inhibitory activity |
| IL127210A0 (en) | 1996-05-23 | 1999-09-22 | Applied Research Systems | Compounds inhibiting the binding of raf-1 or 13-3-3 proteins to the beta-chain of il-2 pharmaceutical compositions containing them and their use |
| AR012634A1 (es) | 1997-05-02 | 2000-11-08 | Sugen Inc | Compuesto basado en quinazolina, composicion famaceutica que lo comprende, metodo para sintetizarlo, su uso, metodos de modulacion de la funcion deserina/treonina proteinaquinasa con dicho compuesto y metodo in vitro para identificar compuestos que modulan dicha funcion |
| US6187799B1 (en) | 1997-05-23 | 2001-02-13 | Onyx Pharmaceuticals | Inhibition of raf kinase activity using aryl ureas |
| GB9716557D0 (en) | 1997-08-06 | 1997-10-08 | Glaxo Group Ltd | Benzylidene-1,3-dihydro-indol-2-one derivatives having anti-cancer activity |
| US6022884A (en) | 1997-11-07 | 2000-02-08 | Amgen Inc. | Substituted pyridine compounds and methods of use |
| US6204467B1 (en) | 1998-03-24 | 2001-03-20 | Ford Global Technologies, Inc. | Method and apparatus for resistive welding |
| US7351834B1 (en) | 1999-01-13 | 2008-04-01 | Bayer Pharmaceuticals Corporation | ω-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
| US6756410B2 (en) | 2000-08-30 | 2004-06-29 | Kamal D. Mehta | Induction of LDL receptor expression by extracellular-signal regulated kinase, ERK-1/2 |
| SG2013013339A (en) | 2002-03-13 | 2014-12-30 | Array Biopharma Inc | N3 alkylated benzimidazole derivatives as mek inhibitors |
| TW200626610A (en) | 2004-10-13 | 2006-08-01 | Wyeth Corp | Analogs of 17-hydroxywortmannin as PI3K inhibitors |
| MX2007010401A (es) | 2005-02-25 | 2008-02-19 | Kudos Pharm Ltd | Derivados de 2,4-diamino-piridopirimidina y su uso como inhbidores de mtor. |
| EP1877388A2 (en) | 2005-02-25 | 2008-01-16 | Kudos Pharmaceuticals Ltd | Hydrazinomethyl, hydrazonomethyl and 5-membered heterocylic compounds which act as mtor inhibitors and their use as anti cancer agents |
| KR101464384B1 (ko) | 2005-11-22 | 2014-11-21 | 쿠도스 파마슈티칼스 리미티드 | ｍＴＯＲ 억제제로서 피리도피리미딘, 피라조피리미딘 및피리미도피리미딘 유도체 |
| KR20080083188A (ko) | 2006-01-11 | 2008-09-16 | 아스트라제네카 아베 | 모르폴리노 피리미딘 유도체 및 요법에서의 그 유도체의용도 |
| JP5227321B2 (ja) | 2006-08-23 | 2013-07-03 | クドス ファーマシューティカルズ リミテッド | Ｍｔｏｒ阻害剤としての２−メチルモルホリンピリド−、ピラゾ−及びピリミド−ピリミジン誘導体 |
| EP2324008B1 (en) * | 2008-07-24 | 2012-05-09 | Nerviano Medical Sciences S.R.L. | 3,4-diarylpyrazoles as protein kinase inhibitors |
| EP2498608A4 (en) * | 2009-11-10 | 2013-04-24 | Glaxosmithkline Llc | BENZOLSULFONAMIDE THIAZOL AND OXAZOLE COMPOUNDS |
-
2011
- 2011-06-23 BR BR112012032884A patent/BR112012032884A2/pt not_active IP Right Cessation
- 2011-06-23 CN CN201180040746XA patent/CN103080107A/zh active Pending
- 2011-06-23 US US13/805,793 patent/US20130096149A1/en not_active Abandoned
- 2011-06-23 KR KR1020137001935A patent/KR20130048293A/ko not_active Abandoned
- 2011-06-23 KR KR1020147024689A patent/KR20140117684A/ko not_active Withdrawn
- 2011-06-23 MX MX2012015100A patent/MX2012015100A/es not_active Application Discontinuation
- 2011-06-23 WO PCT/EP2011/060561 patent/WO2011161216A1/en not_active Ceased
- 2011-06-23 CA CA2803055A patent/CA2803055A1/en not_active Abandoned
- 2011-06-23 EA EA201201676A patent/EA201201676A1/ru unknown
- 2011-06-23 EP EP11728247.5A patent/EP2585454A1/en not_active Withdrawn
- 2011-06-23 AU AU2011268906A patent/AU2011268906A1/en not_active Abandoned
- 2011-06-23 JP JP2013515902A patent/JP2013529619A/ja active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003063993A (ja) * | 2001-06-11 | 2003-03-05 | Takeda Chem Ind Ltd | 医薬組成物 |
| WO2009012283A1 (en) * | 2007-07-17 | 2009-01-22 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
| WO2009076140A1 (en) * | 2007-12-13 | 2009-06-18 | Smithkline Beecham Corporation | Thiazole and oxazole kinase inhibitors |
| WO2009137391A2 (en) * | 2008-05-06 | 2009-11-12 | Smithkline Beecham Corporation | Benzene sulfonamide thiazole and oxazole compounds |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014506585A (ja) * | 2011-02-24 | 2014-03-17 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | キナーゼ阻害剤としてのチアゾリルフェニル−ベンゼンスルホンアミド誘導体 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20130048293A (ko) | 2013-05-09 |
| MX2012015100A (es) | 2013-05-01 |
| BR112012032884A2 (pt) | 2016-11-08 |
| EP2585454A1 (en) | 2013-05-01 |
| WO2011161216A1 (en) | 2011-12-29 |
| CN103080107A (zh) | 2013-05-01 |
| CA2803055A1 (en) | 2011-12-29 |
| EA201201676A1 (ru) | 2013-06-28 |
| AU2011268906A1 (en) | 2013-01-31 |
| US20130096149A1 (en) | 2013-04-18 |
| KR20140117684A (ko) | 2014-10-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US20130096149A1 (en) | Heteroaryl compounds and compositions as protein kinase inhibitors | |
| JP5726190B2 (ja) | タンパク質キナーゼ阻害剤としての化合物および組成物 | |
| JP6736559B2 (ja) | トリアゾロピリミジン化合物およびその使用 | |
| CN102725283B (zh) | 作为蛋白激酶抑制剂的化合物和组合物 | |
| CN108430993A (zh) | Tank-结合激酶抑制剂化合物 | |
| KR20100089082A (ko) | 조합 059 | |
| US20090042928A1 (en) | Modulators of muscarinic receptors | |
| CA2904797A1 (en) | Combination of an egfr t790m inhibitor and an egfr inhibitor for the treatment of non-small cell lung cancer | |
| WO2018019222A1 (zh) | 作为jak抑制剂杂环化合物，该化合物的盐类及其治疗用途 | |
| US20220265669A1 (en) | Compounds useful for inhibiting raf dimers | |
| JP7856666B2 (ja) | 三環式化合物およびその使用 | |
| TWI480276B (zh) | 作為蛋白質激酶抑制劑之化合物及組合物 | |
| HK1167390B (en) | Compounds and compositions as protein kinase inhibitors | |
| HK1191936B (en) | Compounds and compositions as protein kinase inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140603 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20140603 |
|
| RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7423 Effective date: 20140821 |
|
| RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20140902 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20150416 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150421 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20151006 |