JP5726190B2 - 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 - Google Patents

Info

Publication number

JP5726190B2

JP5726190B2 JP2012526067A JP2012526067A JP5726190B2 JP 5726190 B2 JP5726190 B2 JP 5726190B2 JP 2012526067 A JP2012526067 A JP 2012526067A JP 2012526067 A JP2012526067 A JP 2012526067A JP 5726190 B2 JP5726190 B2 JP 5726190B2

Authority

JP

Japan

Prior art keywords

methyl

imidazol

alkyl

cyclopropyl

pyrimidin

Prior art date

2009-08-28

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.)

Active

Links

• Espacenet
• Global Dossier
• Discuss

• 150000001875 compounds Chemical class 0.000 title claims description 141
• 239000000203 mixture Substances 0.000 title description 114
• 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 2
• 239000003909 protein kinase inhibitor Substances 0.000 title description 2
• -1 methoxy, methyl Chemical group 0.000 claims description 131
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 74
• 150000003839 salts Chemical class 0.000 claims description 72
• 125000000217 alkyl group Chemical group 0.000 claims description 55
• 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims description 51
• 229910052736 halogen Inorganic materials 0.000 claims description 44
• 150000002367 halogens Chemical class 0.000 claims description 44
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 41
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 39
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
• 239000002253 acid Substances 0.000 claims description 34
• 239000003814 drug Substances 0.000 claims description 28
• 229910052731 fluorine Inorganic materials 0.000 claims description 28
• 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 claims description 27
• 125000002947 alkylene group Chemical group 0.000 claims description 23
• 229910052739 hydrogen Inorganic materials 0.000 claims description 22
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
• 239000008194 pharmaceutical composition Substances 0.000 claims description 21
• 229940124597 therapeutic agent Drugs 0.000 claims description 21
• 125000006536 (C1-C2)alkoxy group Chemical group 0.000 claims description 20
• 238000011282 treatment Methods 0.000 claims description 20
• 229910052801 chlorine Inorganic materials 0.000 claims description 18
• 206010028980 Neoplasm Diseases 0.000 claims description 17
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 17
• 201000011510 cancer Diseases 0.000 claims description 12
• 239000003795 chemical substances by application Substances 0.000 claims description 12
• 239000000654 additive Substances 0.000 claims description 10
• 239000004480 active ingredient Substances 0.000 claims description 9
• 239000003085 diluting agent Substances 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 7
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
• 206010009944 Colon cancer Diseases 0.000 claims description 6
• 230000000996 additive 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
• 201000001441 melanoma Diseases 0.000 claims description 6
• 125000001424 substituent group Chemical group 0.000 claims description 6
• 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 claims description 5
• 239000000730 antalgic agent Substances 0.000 claims description 5
• 230000003474 anti-emetic effect Effects 0.000 claims description 5
• XJNXDPBTZPNVPO-UHFFFAOYSA-N n-[2-chloro-3-(2-cyclopropyl-5-pyrimidin-4-yl-1h-imidazol-4-yl)-5-fluorophenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC(F)=CC(C2=C(NC(=N2)C2CC2)C=2N=CN=CC=2)=C1Cl XJNXDPBTZPNVPO-UHFFFAOYSA-N 0.000 claims description 5
• DMNKAFXXZZAQNF-UHFFFAOYSA-N n-[2-chloro-3-(2-cyclopropyl-5-pyrimidin-4-yl-1h-imidazol-4-yl)-5-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(F)=CC(C2=C(NC(=N2)C2CC2)C=2N=CN=CC=2)=C1Cl DMNKAFXXZZAQNF-UHFFFAOYSA-N 0.000 claims description 5
• 208000003200 Adenoma Diseases 0.000 claims description 4
• 206010001233 Adenoma benign Diseases 0.000 claims description 4
• 206010005003 Bladder cancer Diseases 0.000 claims description 4
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
• 239000002246 antineoplastic agent Substances 0.000 claims description 4
• 208000015322 bone marrow disease Diseases 0.000 claims description 4
• 208000029742 colonic neoplasm Diseases 0.000 claims description 4
• 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 4
• 201000005202 lung cancer Diseases 0.000 claims description 4
• 208000020816 lung neoplasm Diseases 0.000 claims description 4
• VDVHEBQEJCHLCN-UHFFFAOYSA-N n-[2-chloro-3-(2-cyclopropyl-5-pyrimidin-4-yl-1h-imidazol-4-yl)-5-fluorophenyl]-2,6-difluorobenzenesulfonamide Chemical compound ClC=1C(C2=C(NC(=N2)C2CC2)C=2N=CN=CC=2)=CC(F)=CC=1NS(=O)(=O)C1=C(F)C=CC=C1F VDVHEBQEJCHLCN-UHFFFAOYSA-N 0.000 claims description 4
• 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
• 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
• JVFZRJGWWKMSNF-UHFFFAOYSA-N 1-[[4-[4-[2-chloro-5-fluoro-3-(methanesulfonamido)phenyl]-2-cyclopropyl-1H-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-ylcarbamic acid Chemical compound OC(=O)NC(C)CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(F)C=2)Cl)=N1 JVFZRJGWWKMSNF-UHFFFAOYSA-N 0.000 claims description 3
• 230000001093 anti-cancer Effects 0.000 claims description 3
• 230000001430 anti-depressive effect Effects 0.000 claims description 3
• 206010060862 Prostate cancer Diseases 0.000 claims description 2
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
• 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
• 201000002510 thyroid cancer Diseases 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 6
• 230000000202 analgesic effect Effects 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 282
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 226
• 238000006243 chemical reaction Methods 0.000 description 167
• 235000019439 ethyl acetate Nutrition 0.000 description 136
• 239000000243 solution Substances 0.000 description 112
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 107
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 102
• 230000014759 maintenance of location Effects 0.000 description 98
• 238000002360 preparation method Methods 0.000 description 95
• 239000011541 reaction mixture Substances 0.000 description 85
• 239000007787 solid Substances 0.000 description 81
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 80
• 239000011734 sodium Substances 0.000 description 80
• 239000010410 layer Substances 0.000 description 75
• 239000012267 brine Substances 0.000 description 65
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 65
• 238000000034 method Methods 0.000 description 63
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
• 239000012044 organic layer Substances 0.000 description 56
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 51
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
• 238000003818 flash chromatography Methods 0.000 description 42
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
• 238000004519 manufacturing process Methods 0.000 description 37
• 229910004298 SiO 2 Inorganic materials 0.000 description 36
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 36
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 36
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 36
• 239000003921 oil Substances 0.000 description 36
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 35
• 125000005843 halogen group Chemical group 0.000 description 35
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 34
• 238000000746 purification Methods 0.000 description 34
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
• 239000000543 intermediate Substances 0.000 description 28
• 239000000706 filtrate Substances 0.000 description 27
• 239000000047 product Substances 0.000 description 27
• 239000007858 starting material Substances 0.000 description 26
• 239000000463 material Substances 0.000 description 25
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
• 238000007792 addition Methods 0.000 description 22
• 239000000460 chlorine Substances 0.000 description 22
• 229920006395 saturated elastomer Polymers 0.000 description 22
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 19
• 229910052757 nitrogen Inorganic materials 0.000 description 17
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
• 108091000080 Phosphotransferase Proteins 0.000 description 16
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 16
• 102000020233 phosphotransferase Human genes 0.000 description 16
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
• 239000002904 solvent Substances 0.000 description 14
• 238000003756 stirring Methods 0.000 description 14
• 101100381978 Mus musculus Braf gene Proteins 0.000 description 13
• 239000000725 suspension Substances 0.000 description 13
• ZHWWPRBSUHITHG-UHFFFAOYSA-N 1-aminopropan-2-ylcarbamic acid Chemical compound NCC(C)NC(O)=O ZHWWPRBSUHITHG-UHFFFAOYSA-N 0.000 description 12
• KKVYYGGCHJGEFJ-UHFFFAOYSA-N 1-n-(4-chlorophenyl)-6-methyl-5-n-[3-(7h-purin-6-yl)pyridin-2-yl]isoquinoline-1,5-diamine Chemical compound N=1C=CC2=C(NC=3C(=CC=CN=3)C=3C=4N=CNC=4N=CN=3)C(C)=CC=C2C=1NC1=CC=C(Cl)C=C1 KKVYYGGCHJGEFJ-UHFFFAOYSA-N 0.000 description 12
• 229910052786 argon Inorganic materials 0.000 description 12
• 238000001816 cooling Methods 0.000 description 12
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 12
• 238000010992 reflux Methods 0.000 description 12
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
• 210000003050 axon Anatomy 0.000 description 11
• 238000004128 high performance liquid chromatography Methods 0.000 description 11
• DJQVTWXPVHCLSW-UHFFFAOYSA-N n-(3-bromo-2-chloro-5-fluorophenyl)-1,1-diphenylmethanimine Chemical compound FC1=CC(Br)=C(Cl)C(N=C(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 DJQVTWXPVHCLSW-UHFFFAOYSA-N 0.000 description 11
• 239000012074 organic phase Substances 0.000 description 11
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
• 239000007864 aqueous solution Substances 0.000 description 10
• 201000010099 disease Diseases 0.000 description 10
• LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 10
• XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 10
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
• BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 9
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 9
• 150000001408 amides Chemical class 0.000 description 9
• 238000003556 assay Methods 0.000 description 9
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
• 239000013058 crude material Substances 0.000 description 9
• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
• 230000000694 effects Effects 0.000 description 9
• 239000012458 free base Substances 0.000 description 9
• 102000009929 raf Kinases Human genes 0.000 description 9
• 108010077182 raf Kinases Proteins 0.000 description 9
• 239000000741 silica gel Substances 0.000 description 9
• 229910002027 silica gel Inorganic materials 0.000 description 9
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 8
• KNTZCGBYFGEMFR-UHFFFAOYSA-N (propan-2-ylazaniumyl)formate Chemical compound CC(C)NC(O)=O KNTZCGBYFGEMFR-UHFFFAOYSA-N 0.000 description 8
• BHRDAUOXWKBEKC-UHFFFAOYSA-N 2-[[4-bromo-5-(2-chloropyrimidin-4-yl)-2-cyclopropylimidazol-1-yl]methoxy]ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCN1C(C2CC2)=NC(Br)=C1C1=CC=NC(Cl)=N1 BHRDAUOXWKBEKC-UHFFFAOYSA-N 0.000 description 8
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 8
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
• 210000004027 cell Anatomy 0.000 description 8
• 125000004093 cyano group Chemical group *C#N 0.000 description 8
• 239000012065 filter cake Substances 0.000 description 8
• 150000003840 hydrochlorides Chemical class 0.000 description 8
• BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 8
• MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 8
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
• 238000009472 formulation Methods 0.000 description 7
• 238000010438 heat treatment Methods 0.000 description 7
• 229910000104 sodium hydride Inorganic materials 0.000 description 7
• UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 6
• WFFDTMNHOINATE-UHFFFAOYSA-N 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(Cl)=CC(N)=C1F WFFDTMNHOINATE-UHFFFAOYSA-N 0.000 description 6
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
• DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
• 239000000908 ammonium hydroxide Substances 0.000 description 6
• ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 6
• 239000000872 buffer Substances 0.000 description 6
• 150000002148 esters Chemical class 0.000 description 6
• 239000006260 foam Substances 0.000 description 6
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
• 229940043355 kinase inhibitor Drugs 0.000 description 6
• 239000003757 phosphotransferase inhibitor Substances 0.000 description 6
• 235000011056 potassium acetate Nutrition 0.000 description 6
• 229940124530 sulfonamide Drugs 0.000 description 6
• LXMXPKGROLGLJT-UHFFFAOYSA-N 2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(F)=CC(N)=C1Cl LXMXPKGROLGLJT-UHFFFAOYSA-N 0.000 description 5
• JQYPICYMRVGSCU-UHFFFAOYSA-N 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC(N)=C1F JQYPICYMRVGSCU-UHFFFAOYSA-N 0.000 description 5
• HIZADWSSPWORHH-UHFFFAOYSA-N 3-bromo-2,6-difluoroaniline Chemical compound NC1=C(F)C=CC(Br)=C1F HIZADWSSPWORHH-UHFFFAOYSA-N 0.000 description 5
• UPVPOYFTFVALDZ-UHFFFAOYSA-N 5-chloro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound CC1=C(N)C=C(Cl)C=C1B1OC(C)(C)C(C)(C)O1 UPVPOYFTFVALDZ-UHFFFAOYSA-N 0.000 description 5
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
• 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 5
• 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 5
• 125000003118 aryl group Chemical group 0.000 description 5
• 239000011324 bead Substances 0.000 description 5
• 230000015572 biosynthetic process Effects 0.000 description 5
• IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 5
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
• 229910052794 bromium Inorganic materials 0.000 description 5
• 208000035475 disorder Diseases 0.000 description 5
• 229940079593 drug Drugs 0.000 description 5
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 5
• 239000011521 glass Substances 0.000 description 5
• 229940015043 glyoxal Drugs 0.000 description 5
• 239000001257 hydrogen Substances 0.000 description 5
• 239000005457 ice water Substances 0.000 description 5
• JYQATCYYNADNJV-UHFFFAOYSA-N n-[2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=C(F)C=CC(B2OC(C)(C)C(C)(C)O2)=C1F JYQATCYYNADNJV-UHFFFAOYSA-N 0.000 description 5
• YMDVIBUFSLKPDX-UHFFFAOYSA-N n-[2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(B2OC(C)(C)C(C)(C)O2)=C1Cl YMDVIBUFSLKPDX-UHFFFAOYSA-N 0.000 description 5
• 238000004007 reversed phase HPLC Methods 0.000 description 5
• 239000000377 silicon dioxide Substances 0.000 description 5
• 239000002002 slurry Substances 0.000 description 5
• 239000012453 solvate Substances 0.000 description 5
• 238000003786 synthesis reaction Methods 0.000 description 5
• PNEKDOVULYEEER-QMMMGPOBSA-N (2s)-1-n-[4-(5-bromo-2-cyclobutyl-1h-imidazol-4-yl)pyrimidin-2-yl]propane-1,2-diamine Chemical compound C[C@H](N)CNC1=NC=CC(C2=C(N=C(N2)C2CCC2)Br)=N1 PNEKDOVULYEEER-QMMMGPOBSA-N 0.000 description 4
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 4
• GNTAGGBBCNMHOL-UHFFFAOYSA-N 2-[[4-bromo-5-(2-chloropyrimidin-4-yl)-2-(1-methylcyclopropyl)imidazol-1-yl]methoxy]ethyl-trimethylsilane Chemical compound N=1C(Br)=C(C=2N=C(Cl)N=CC=2)N(COCC[Si](C)(C)C)C=1C1(C)CC1 GNTAGGBBCNMHOL-UHFFFAOYSA-N 0.000 description 4
• GDIMNXJSMJSDSB-UHFFFAOYSA-N 3-amino-2-methylpropanenitrile Chemical compound NCC(C)C#N GDIMNXJSMJSDSB-UHFFFAOYSA-N 0.000 description 4
• YZGMWJRUAGKYER-UHFFFAOYSA-N 3-bromo-2-chloro-5-fluoroaniline Chemical compound NC1=CC(F)=CC(Br)=C1Cl YZGMWJRUAGKYER-UHFFFAOYSA-N 0.000 description 4
• HKNLHCGTRMCOLV-UHFFFAOYSA-N 3-bromo-2-chloroaniline Chemical compound NC1=CC=CC(Br)=C1Cl HKNLHCGTRMCOLV-UHFFFAOYSA-N 0.000 description 4
• CSHMFIIPOVGVDN-UHFFFAOYSA-N 3-bromo-5-chloro-2-fluoroaniline Chemical compound NC1=CC(Cl)=CC(Br)=C1F CSHMFIIPOVGVDN-UHFFFAOYSA-N 0.000 description 4
• YNDHZVOCDIYUNS-UHFFFAOYSA-N 3-methoxy-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound NC1=C(C)C(OC)=CC(B2OC(C)(C)C(C)(C)O2)=C1 YNDHZVOCDIYUNS-UHFFFAOYSA-N 0.000 description 4
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
• DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 4
• 239000007983 Tris buffer Substances 0.000 description 4
• SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 4
• 229940125683 antiemetic agent Drugs 0.000 description 4
• 239000002585 base Substances 0.000 description 4
• 239000001569 carbon dioxide Substances 0.000 description 4
• 229910002092 carbon dioxide Inorganic materials 0.000 description 4
• 239000012043 crude product Substances 0.000 description 4
• 125000000753 cycloalkyl group Chemical group 0.000 description 4
• SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 4
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 4
• DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 4
• 238000001914 filtration Methods 0.000 description 4
• 150000004677 hydrates Chemical class 0.000 description 4
• IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 4
• 239000003112 inhibitor Substances 0.000 description 4
• DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 4
• 238000004020 luminiscence type Methods 0.000 description 4
• UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(II) oxide Inorganic materials [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 4
• OTOUMEDPEMHRQN-UHFFFAOYSA-N n-(3-bromo-2,6-difluorophenyl)propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=C(F)C=CC(Br)=C1F OTOUMEDPEMHRQN-UHFFFAOYSA-N 0.000 description 4
• WDAKVRIFOFZSFK-UHFFFAOYSA-N n-[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(B2OC(C)(C)C(C)(C)O2)=C1F WDAKVRIFOFZSFK-UHFFFAOYSA-N 0.000 description 4
• 229910052763 palladium Inorganic materials 0.000 description 4
• 239000012071 phase Substances 0.000 description 4
• LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
• 239000002516 radical scavenger Substances 0.000 description 4
• 239000000376 reactant Substances 0.000 description 4
• 230000002829 reductive effect Effects 0.000 description 4
• 238000006467 substitution reaction Methods 0.000 description 4
• 150000003456 sulfonamides Chemical class 0.000 description 4
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
• WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 4
• 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
• 239000003039 volatile agent Substances 0.000 description 4
• SMOPNWBXNKPLRS-ZETCQYMHSA-N (2s)-1-n-[4-(5-bromo-2-cyclopropyl-1h-imidazol-4-yl)pyrimidin-2-yl]propane-1,2-diamine Chemical compound C[C@H](N)CNC1=NC=CC(C2=C(N=C(N2)C2CC2)Br)=N1 SMOPNWBXNKPLRS-ZETCQYMHSA-N 0.000 description 3
• WEODDWWPFPDSJS-QMMMGPOBSA-N (2s)-1-n-[4-[5-bromo-2-(1-methylcyclopropyl)-1h-imidazol-4-yl]pyrimidin-2-yl]propane-1,2-diamine Chemical compound C[C@H](N)CNC1=NC=CC(C2=C(N=C(N2)C2(C)CC2)Br)=N1 WEODDWWPFPDSJS-QMMMGPOBSA-N 0.000 description 3
• WICRKCABAQJKSY-UHFFFAOYSA-N 1-(aminomethyl)cyclopropane-1-carbonitrile Chemical compound NCC1(C#N)CC1 WICRKCABAQJKSY-UHFFFAOYSA-N 0.000 description 3
• QMCQBAJOOAMKBX-UHFFFAOYSA-N 1-(hydroxymethyl)cyclopropane-1-carbonitrile Chemical compound OCC1(C#N)CC1 QMCQBAJOOAMKBX-UHFFFAOYSA-N 0.000 description 3
• XTCIFWCZYRHDOF-UHFFFAOYSA-N 1-[(1,3-dioxoisoindol-2-yl)methyl]cyclopropane-1-carbonitrile Chemical compound O=C1C2=CC=CC=C2C(=O)N1CC1(C#N)CC1 XTCIFWCZYRHDOF-UHFFFAOYSA-N 0.000 description 3
• XTTZFLRDPMATAY-UHFFFAOYSA-N 1-bromo-2,5-dichloro-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(Br)=C1Cl XTTZFLRDPMATAY-UHFFFAOYSA-N 0.000 description 3
• JNIDAGAFFKAPRV-UHFFFAOYSA-N 1-bromo-2-chloro-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(Br)=C1Cl JNIDAGAFFKAPRV-UHFFFAOYSA-N 0.000 description 3
• AUAXYMOBWXOEQD-UHFFFAOYSA-N 2,5-dichloro-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC([N+]([O-])=O)=C1Cl AUAXYMOBWXOEQD-UHFFFAOYSA-N 0.000 description 3
• QKWVGDAAZHJCLH-UHFFFAOYSA-N 2,5-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(F)=CC(N)=C1F QKWVGDAAZHJCLH-UHFFFAOYSA-N 0.000 description 3
• FPHVYHZZNGSDSS-UHFFFAOYSA-N 2-[(4,5-dibromo-2-tert-butylimidazol-1-yl)methoxy]ethyl-trimethylsilane Chemical compound CC(C)(C)C1=NC(Br)=C(Br)N1COCC[Si](C)(C)C FPHVYHZZNGSDSS-UHFFFAOYSA-N 0.000 description 3
• MKRNXWHYXVOUPM-UHFFFAOYSA-N 2-[[4-bromo-2-tert-butyl-5-(2-chloropyrimidin-4-yl)imidazol-1-yl]methoxy]ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCN1C(C(C)(C)C)=NC(Br)=C1C1=CC=NC(Cl)=N1 MKRNXWHYXVOUPM-UHFFFAOYSA-N 0.000 description 3
• ZKHDXHJANRHECA-UHFFFAOYSA-N 2-[[4-bromo-5-(2-chloro-4,5-dihydropyrimidin-4-yl)-2-cyclopropylimidazol-1-yl]methoxy]ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCN1C(C2CC2)=NC(Br)=C1C1CC=NC(Cl)=N1 ZKHDXHJANRHECA-UHFFFAOYSA-N 0.000 description 3
• AXHRGVJWDJDYPO-UHFFFAOYSA-N 2-bromo-1h-imidazole Chemical compound BrC1=NC=CN1 AXHRGVJWDJDYPO-UHFFFAOYSA-N 0.000 description 3
• JWWBQCGHXVOJNW-UHFFFAOYSA-N 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC(N)=C1Cl JWWBQCGHXVOJNW-UHFFFAOYSA-N 0.000 description 3
• UTHYAAGLSHVKBB-UHFFFAOYSA-N 2-chloro-4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=C(F)C=CC(N)=C1Cl UTHYAAGLSHVKBB-UHFFFAOYSA-N 0.000 description 3
• WKXWDJPPGNDPCR-UHFFFAOYSA-N 2-chloro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound CC1=CC(N)=C(Cl)C(B2OC(C)(C)C(C)(C)O2)=C1 WKXWDJPPGNDPCR-UHFFFAOYSA-N 0.000 description 3
• MBQKTXUCJWIHQQ-UHFFFAOYSA-N 2-cyclopropyl-1h-imidazole Chemical compound C1CC1C1=NC=CN1 MBQKTXUCJWIHQQ-UHFFFAOYSA-N 0.000 description 3
• JBGGFYZUDGDHMN-UHFFFAOYSA-N 3-bromo-2,5-difluoroaniline Chemical compound NC1=CC(F)=CC(Br)=C1F JBGGFYZUDGDHMN-UHFFFAOYSA-N 0.000 description 3
• WEBVJSPIUIPJKV-UHFFFAOYSA-N 3-bromo-2,6-difluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC(Br)=C1F WEBVJSPIUIPJKV-UHFFFAOYSA-N 0.000 description 3
• JFAQBRSYTNDGBL-UHFFFAOYSA-N 3-bromo-2-fluoro-5-methylbenzoic acid Chemical compound CC1=CC(Br)=C(F)C(C(O)=O)=C1 JFAQBRSYTNDGBL-UHFFFAOYSA-N 0.000 description 3
• HYPQOSVTIONWSN-UHFFFAOYSA-N 3-bromo-2-fluoroaniline Chemical compound NC1=CC=CC(Br)=C1F HYPQOSVTIONWSN-UHFFFAOYSA-N 0.000 description 3
• WEUJKWDULBTKPA-UHFFFAOYSA-N 4,5-dibromo-2-(1-methylcyclopropyl)-1h-imidazole Chemical compound N=1C(Br)=C(Br)NC=1C1(C)CC1 WEUJKWDULBTKPA-UHFFFAOYSA-N 0.000 description 3
• VSYNJLZSZQQECA-UHFFFAOYSA-N 4,5-dibromo-2-cyclobutyl-1h-imidazole Chemical compound N1C(Br)=C(Br)N=C1C1CCC1 VSYNJLZSZQQECA-UHFFFAOYSA-N 0.000 description 3
• JGSDZPADLJZJGP-UHFFFAOYSA-N 4,5-dibromo-2-cyclopropyl-1h-imidazole Chemical compound N1C(Br)=C(Br)N=C1C1CC1 JGSDZPADLJZJGP-UHFFFAOYSA-N 0.000 description 3
• MQWXUMPGBOMYOC-UHFFFAOYSA-N 4,5-dibromo-2-tert-butyl-1h-imidazole Chemical compound CC(C)(C)C1=NC(Br)=C(Br)N1 MQWXUMPGBOMYOC-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
• 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
• 108091054455 MAP kinase family Proteins 0.000 description 3
• 102000043136 MAP kinase family Human genes 0.000 description 3
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-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
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
• 230000002159 abnormal effect Effects 0.000 description 3
• 230000002378 acidificating effect Effects 0.000 description 3
• 230000004913 activation Effects 0.000 description 3
• PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
• 150000001412 amines Chemical class 0.000 description 3
• 229940035676 analgesics Drugs 0.000 description 3
• 239000006286 aqueous extract Substances 0.000 description 3
• 239000008346 aqueous phase Substances 0.000 description 3
• 239000012131 assay buffer Substances 0.000 description 3
• 229940098773 bovine serum albumin Drugs 0.000 description 3
• 230000005587 bubbling Effects 0.000 description 3
• 235000015165 citric acid Nutrition 0.000 description 3
• 239000012230 colorless oil Substances 0.000 description 3
• 230000001276 controlling effect Effects 0.000 description 3
• 238000010511 deprotection reaction Methods 0.000 description 3
• 238000001514 detection method Methods 0.000 description 3
• 229940043279 diisopropylamine Drugs 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
• 239000003937 drug carrier Substances 0.000 description 3
• 238000001035 drying Methods 0.000 description 3
• 239000000284 extract Substances 0.000 description 3
• 239000007789 gas Substances 0.000 description 3
• 150000002460 imidazoles Chemical class 0.000 description 3
• 125000002883 imidazolyl group Chemical group 0.000 description 3
• 230000005764 inhibitory process Effects 0.000 description 3
• 238000006138 lithiation reaction Methods 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
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
• 238000002156 mixing Methods 0.000 description 3
• 230000035772 mutation Effects 0.000 description 3
• ACGHDZFEHJCPBC-UHFFFAOYSA-N n-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propane-2-sulfonamide Chemical compound CC(C)S(=O)(=O)NC1=CC(C)=CC(B2OC(C)(C)C(C)(C)O2)=C1 ACGHDZFEHJCPBC-UHFFFAOYSA-N 0.000 description 3
• MCDWGZVFUBGZDF-UHFFFAOYSA-N n-[5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(B2OC(C)(C)C(C)(C)O2)=C1F MCDWGZVFUBGZDF-UHFFFAOYSA-N 0.000 description 3
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
• 239000002244 precipitate Substances 0.000 description 3
• 230000002265 prevention Effects 0.000 description 3
• 239000000651 prodrug Substances 0.000 description 3
• 229940002612 prodrug Drugs 0.000 description 3
• FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 3
• 150000003230 pyrimidines Chemical class 0.000 description 3
• 229910000029 sodium carbonate Inorganic materials 0.000 description 3
• 235000019698 starch Nutrition 0.000 description 3
• 239000000126 substance Substances 0.000 description 3
• YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
• 230000001225 therapeutic effect Effects 0.000 description 3
• PWLROCHXTREGKR-UHFFFAOYSA-N trimethyl-[2-[(2,4,5-tribromoimidazol-1-yl)methoxy]ethyl]silane Chemical compound C[Si](C)(C)CCOCN1C(Br)=NC(Br)=C1Br PWLROCHXTREGKR-UHFFFAOYSA-N 0.000 description 3
• 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
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
• 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 2
• PBHLHGCJRAGCFI-UHFFFAOYSA-N 1-[[2-[5-bromo-2-[4-(trifluoromethyl)phenyl]-1H-imidazol-4-yl]pyrimidin-4-yl]amino]propan-2-ylcarbamic acid Chemical compound BrC=1N=C(NC1C1=NC=CC(=N1)NCC(C)NC(O)=O)C1=CC=C(C=C1)C(F)(F)F PBHLHGCJRAGCFI-UHFFFAOYSA-N 0.000 description 2
• PNAGBLLJUBUYPT-UHFFFAOYSA-N 1-[[4-[5-bromo-2-cyclobutyl-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]pyrimidin-2-yl]amino]propan-2-ylcarbamic acid Chemical compound OC(=O)NC(C)CNC1=NC=CC(C=2N(C(C3CCC3)=NC=2Br)COCC[Si](C)(C)C)=N1 PNAGBLLJUBUYPT-UHFFFAOYSA-N 0.000 description 2
• OOWPZKIOAPIRQZ-UHFFFAOYSA-N 1-bromo-3-(difluoromethoxy)-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(Br)=CC(OC(F)F)=C1 OOWPZKIOAPIRQZ-UHFFFAOYSA-N 0.000 description 2
• CZZCIUKNDIAFKX-UHFFFAOYSA-N 1-hydroxypropan-2-ylcarbamic acid Chemical compound OCC(C)NC(O)=O CZZCIUKNDIAFKX-UHFFFAOYSA-N 0.000 description 2
• FJJYHTVHBVXEEQ-UHFFFAOYSA-N 2,2-dimethylpropanal Chemical compound CC(C)(C)C=O FJJYHTVHBVXEEQ-UHFFFAOYSA-N 0.000 description 2
• JCGGPCDDFXIVQB-UHFFFAOYSA-N 2,4,5-tribromo-1h-imidazole Chemical compound BrC1=NC(Br)=C(Br)N1 JCGGPCDDFXIVQB-UHFFFAOYSA-N 0.000 description 2
• ZBGAPLDNRPQMAM-UHFFFAOYSA-N 2,5-dichloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(Cl)=CC(N)=C1Cl ZBGAPLDNRPQMAM-UHFFFAOYSA-N 0.000 description 2
• GUXIRHGZIZSWFC-UHFFFAOYSA-N 2-(1-methylcyclopropyl)-1h-imidazole Chemical compound N=1C=CNC=1C1(C)CC1 GUXIRHGZIZSWFC-UHFFFAOYSA-N 0.000 description 2
• YWTYEZRWZCWTPU-UHFFFAOYSA-N 2-[(2-cyclopropyl-4-pyrimidin-4-ylimidazol-1-yl)methoxy]ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCN1C=C(C=2N=CN=CC=2)N=C1C1CC1 YWTYEZRWZCWTPU-UHFFFAOYSA-N 0.000 description 2
• PWCZPJXBQQJUTN-UHFFFAOYSA-N 2-[(4,5-dibromo-2-cyclobutylimidazol-1-yl)methoxy]ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCN1C(Br)=C(Br)N=C1C1CCC1 PWCZPJXBQQJUTN-UHFFFAOYSA-N 0.000 description 2
• MTTWJIFPIPIPPE-UHFFFAOYSA-N 2-[(4,5-dibromo-2-cyclopropylimidazol-1-yl)methoxy]ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCN1C(Br)=C(Br)N=C1C1CC1 MTTWJIFPIPIPPE-UHFFFAOYSA-N 0.000 description 2
• HVCLPTBEVOQNRQ-UHFFFAOYSA-N 2-[[4,5-dibromo-2-(1-methylcyclopropyl)imidazol-1-yl]methoxy]ethyl-trimethylsilane Chemical compound N=1C(Br)=C(Br)N(COCC[Si](C)(C)C)C=1C1(C)CC1 HVCLPTBEVOQNRQ-UHFFFAOYSA-N 0.000 description 2
• YGTPQTKVWLDMGS-UHFFFAOYSA-N 2-[[4,5-dibromo-2-[4-(trifluoromethyl)phenyl]imidazol-1-yl]methoxy]ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCN1C(Br)=C(Br)N=C1C1=CC=C(C(F)(F)F)C=C1 YGTPQTKVWLDMGS-UHFFFAOYSA-N 0.000 description 2
• HHIBBOJFLHQKHT-UHFFFAOYSA-N 2-[[4-bromo-5-(2-chloropyrimidin-4-yl)-2-[4-(trifluoromethyl)phenyl]imidazol-1-yl]methoxy]ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCN1C(C=2C=CC(=CC=2)C(F)(F)F)=NC(Br)=C1C1=CC=NC(Cl)=N1 HHIBBOJFLHQKHT-UHFFFAOYSA-N 0.000 description 2
• MCLFKUDGXPUVSJ-UHFFFAOYSA-N 2-[[4-bromo-5-(2-chloropyrimidin-4-yl)-2-cyclobutylimidazol-1-yl]methoxy]ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCN1C(C2CCC2)=NC(Br)=C1C1=CC=NC(Cl)=N1 MCLFKUDGXPUVSJ-UHFFFAOYSA-N 0.000 description 2
• CNOAXNNBTQYBCJ-UHFFFAOYSA-N 2-cyclobutyl-1h-imidazole Chemical compound C1CCC1C1=NC=CN1 CNOAXNNBTQYBCJ-UHFFFAOYSA-N 0.000 description 2
• DYGVGOKYPMMXMI-UHFFFAOYSA-N 2-fluoro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound CC1=CC(N)=C(F)C(B2OC(C)(C)C(C)(C)O2)=C1 DYGVGOKYPMMXMI-UHFFFAOYSA-N 0.000 description 2
• CTUNHIMNHSKDBN-UHFFFAOYSA-N 2-tert-butyl-1h-imidazole Chemical compound CC(C)(C)C1=NC=CN1 CTUNHIMNHSKDBN-UHFFFAOYSA-N 0.000 description 2
• PCALPXHVQPTOER-UHFFFAOYSA-N 3,6-dichloro-2-nitrobenzoic acid Chemical compound OC(=O)C1=C(Cl)C=CC(Cl)=C1[N+]([O-])=O PCALPXHVQPTOER-UHFFFAOYSA-N 0.000 description 2
• PAHTYRXPKLMBCR-UHFFFAOYSA-N 3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(N)=CC(OC(F)F)=C1 PAHTYRXPKLMBCR-UHFFFAOYSA-N 0.000 description 2
• BYBFHPHMWZWZJD-UHFFFAOYSA-N 3-[5-(2-chloropyrimidin-4-yl)-1h-imidazol-4-yl]aniline Chemical compound NC1=CC=CC(C2=C(NC=N2)C=2N=C(Cl)N=CC=2)=C1 BYBFHPHMWZWZJD-UHFFFAOYSA-N 0.000 description 2
• IWKQEVUXEGNWJD-UHFFFAOYSA-N 3-[5-(2-chloropyrimidin-4-yl)-2-cyclopropyl-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-2-fluoroaniline Chemical compound C[Si](C)(C)CCOCN1C(C2CC2)=NC(C=2C(=C(N)C=CC=2)F)=C1C1=CC=NC(Cl)=N1 IWKQEVUXEGNWJD-UHFFFAOYSA-N 0.000 description 2
• TYUPDZWQCZZQPF-UHFFFAOYSA-N 3-[[4-[5-bromo-2-(1-methylcyclopropyl)-1h-imidazol-4-yl]pyrimidin-2-yl]amino]propanenitrile Chemical compound N=1C(Br)=C(C=2N=C(NCCC#N)N=CC=2)NC=1C1(C)CC1 TYUPDZWQCZZQPF-UHFFFAOYSA-N 0.000 description 2
• OCUTXSQERDXKMC-UHFFFAOYSA-N 3-[[4-[5-bromo-2-(1-methylcyclopropyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]pyrimidin-2-yl]amino]propanenitrile Chemical compound N=1C(Br)=C(C=2N=C(NCCC#N)N=CC=2)N(COCC[Si](C)(C)C)C=1C1(C)CC1 OCUTXSQERDXKMC-UHFFFAOYSA-N 0.000 description 2
• FHEFXECHHOBHIQ-UHFFFAOYSA-N 3-[[4-[5-bromo-2-cyclopropyl-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]pyrimidin-2-yl]amino]propanenitrile Chemical compound C[Si](C)(C)CCOCN1C(C2CC2)=NC(Br)=C1C1=CC=NC(NCCC#N)=N1 FHEFXECHHOBHIQ-UHFFFAOYSA-N 0.000 description 2
• ZEQKZRGDHYMUHS-UHFFFAOYSA-N 3-bromo-2,5-dichloroaniline Chemical compound NC1=CC(Cl)=CC(Br)=C1Cl ZEQKZRGDHYMUHS-UHFFFAOYSA-N 0.000 description 2
• SMWXBKRWRZKILZ-UHFFFAOYSA-N 3-bromo-2-chloro-5-fluoroaniline;hydron;chloride Chemical compound Cl.NC1=CC(F)=CC(Br)=C1Cl SMWXBKRWRZKILZ-UHFFFAOYSA-N 0.000 description 2
• RXLNTBOIPLOOEA-UHFFFAOYSA-N 3-bromo-2-chloro-5-methylaniline Chemical compound CC1=CC(N)=C(Cl)C(Br)=C1 RXLNTBOIPLOOEA-UHFFFAOYSA-N 0.000 description 2
• BSJSHGSLFVAXAK-UHFFFAOYSA-N 3-bromo-5-(difluoromethoxy)aniline Chemical compound NC1=CC(Br)=CC(OC(F)F)=C1 BSJSHGSLFVAXAK-UHFFFAOYSA-N 0.000 description 2
• 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 2
• MYYYOBVDIRECDX-UHFFFAOYSA-N 4,5-dibromo-1h-imidazole Chemical compound BrC=1N=CNC=1Br MYYYOBVDIRECDX-UHFFFAOYSA-N 0.000 description 2
• ZEYILTNFNNUSBW-UHFFFAOYSA-N 4-[5-bromo-2-cyclopropyl-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]pyrimidin-2-amine Chemical compound C[Si](C)(C)CCOCN1C(C2CC2)=NC(Br)=C1C1=CC=NC(N)=N1 ZEYILTNFNNUSBW-UHFFFAOYSA-N 0.000 description 2
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 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
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
• 101100181041 Arabidopsis thaliana KINUA gene Proteins 0.000 description 2
• 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 2
• FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
• 0 CCS(Nc1cc(Cl)cc(-c2c(-c3ccnc(NC[C@](C)NC(*C)=O)n3)[n]c(C(C)(C)C)n2)c1)(=O)=O Chemical compound CCS(Nc1cc(Cl)cc(-c2c(-c3ccnc(NC[C@](C)NC(*C)=O)n3)[n]c(C(C)(C)C)n2)c1)(=O)=O 0.000 description 2
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
• 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
• 102100024457 Cyclin-dependent kinase 9 Human genes 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
• 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 2
• 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 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
• 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 description 2
• 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 2
• 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
• 239000005511 L01XE05 - Sorafenib 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
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
• JIUUIQQQPSBGOG-UHFFFAOYSA-N NC1=NC=CC(=N1)C1(NC=C(N1)C1(CC=C(C(=C1)C=1C(=C(C(=CC1)F)S(=O)(=O)N)F)Cl)F)C(C)(C)C Chemical compound NC1=NC=CC(=N1)C1(NC=C(N1)C1(CC=C(C(=C1)C=1C(=C(C(=CC1)F)S(=O)(=O)N)F)Cl)F)C(C)(C)C JIUUIQQQPSBGOG-UHFFFAOYSA-N 0.000 description 2
• ABJYRWWGHPVOQG-UHFFFAOYSA-N NC1=NC=CC(=N1)C1(NC=C(N1)C1(CC=C(C(=C1)C=1C(=C(C(=CC1)F)S(=O)(=O)N)F)F)Cl)C(C)(C)C Chemical compound NC1=NC=CC(=N1)C1(NC=C(N1)C1(CC=C(C(=C1)C=1C(=C(C(=CC1)F)S(=O)(=O)N)F)F)Cl)C(C)(C)C ABJYRWWGHPVOQG-UHFFFAOYSA-N 0.000 description 2
• MLQFKWPELKGMQV-UHFFFAOYSA-N NC1=NC=CC(=N1)C1(NC=C(N1)C=1C=CC(=C(C1)C=1C(=C(C(=CC1)F)S(=O)(=O)N)F)Cl)C(C)(C)C Chemical compound NC1=NC=CC(=N1)C1(NC=C(N1)C=1C=CC(=C(C1)C=1C(=C(C(=CC1)F)S(=O)(=O)N)F)Cl)C(C)(C)C MLQFKWPELKGMQV-UHFFFAOYSA-N 0.000 description 2
• UVNLBDGOLZCCCN-UHFFFAOYSA-N NC1=NC=CC(=N1)C1(NC=C(N1)C=1C=CC(=C(C1)C=1C(=C(C(=CC1)F)S(=O)(=O)N)F)Cl)C1CC1 Chemical compound NC1=NC=CC(=N1)C1(NC=C(N1)C=1C=CC(=C(C1)C=1C(=C(C(=CC1)F)S(=O)(=O)N)F)Cl)C1CC1 UVNLBDGOLZCCCN-UHFFFAOYSA-N 0.000 description 2
• GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
• 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 2
• 108091008606 PDGF receptors Proteins 0.000 description 2
• 108091007960 PI3Ks Proteins 0.000 description 2
• 102000038030 PI3Ks Human genes 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
• 239000004743 Polypropylene Substances 0.000 description 2
• 102000001253 Protein Kinase Human genes 0.000 description 2
• 108010029869 Proto-Oncogene Proteins c-raf Proteins 0.000 description 2
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
• 229940123690 Raf kinase inhibitor Drugs 0.000 description 2
• 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 2
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
• 238000006069 Suzuki reaction reaction Methods 0.000 description 2
• 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
• 102000013530 TOR Serine-Threonine Kinases Human genes 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
• 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
• 125000004429 atom Chemical group 0.000 description 2
• HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 2
• 230000004888 barrier function Effects 0.000 description 2
• 230000008901 benefit Effects 0.000 description 2
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
• RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 2
• 239000012965 benzophenone Substances 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
• AGSPXMVUFBBBMO-UHFFFAOYSA-N beta-aminopropionitrile Chemical compound NCCC#N AGSPXMVUFBBBMO-UHFFFAOYSA-N 0.000 description 2
• 125000002619 bicyclic group Chemical group 0.000 description 2
• MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
• 159000000007 calcium salts Chemical class 0.000 description 2
• 125000004432 carbon atom Chemical group C* 0.000 description 2
• RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 2
• 239000001768 carboxy methyl cellulose Substances 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
• 239000012141 concentrate Substances 0.000 description 2
• 239000006071 cream Substances 0.000 description 2
• 238000006880 cross-coupling reaction Methods 0.000 description 2
• 230000002074 deregulated effect Effects 0.000 description 2
• 239000008121 dextrose Substances 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
• 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
• 229960005167 everolimus Drugs 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
• 239000003102 growth factor Substances 0.000 description 2
• 125000001188 haloalkyl group Chemical group 0.000 description 2
• 239000012535 impurity Substances 0.000 description 2
• 238000001727 in vivo Methods 0.000 description 2
• 238000010348 incorporation Methods 0.000 description 2
• 238000002347 injection Methods 0.000 description 2
• 239000007924 injection Substances 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
• 238000012417 linear regression 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
• NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
• 239000011159 matrix material Substances 0.000 description 2
• 230000001404 mediated effect Effects 0.000 description 2
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-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
• 230000004048 modification Effects 0.000 description 2
• 238000012986 modification Methods 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
• KJUFNBQYBZTFRU-UHFFFAOYSA-N n-(3-bromo-2-chlorophenyl)propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(Br)=C1Cl KJUFNBQYBZTFRU-UHFFFAOYSA-N 0.000 description 2
• XNPLKJNMBAWPTC-UHFFFAOYSA-N n-(3-bromo-2-fluorophenyl)propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(Br)=C1F XNPLKJNMBAWPTC-UHFFFAOYSA-N 0.000 description 2
• RYQGTYVUUPMJQF-UHFFFAOYSA-N n-(3-bromo-5-chloro-2-fluorophenyl)propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC(Cl)=CC(Br)=C1F RYQGTYVUUPMJQF-UHFFFAOYSA-N 0.000 description 2
• TYVZMDXOAAZCMM-UHFFFAOYSA-N n-(3-bromo-5-methylphenyl)propane-2-sulfonamide Chemical compound CC(C)S(=O)(=O)NC1=CC(C)=CC(Br)=C1 TYVZMDXOAAZCMM-UHFFFAOYSA-N 0.000 description 2
• ZROPISXBHMLTRK-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-[2-(methylamino)pyrimidin-4-yl]-1h-imidazol-4-yl]-5-fluorophenyl]-2,6-difluorobenzenesulfonamide Chemical compound CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=C(F)C=2)Cl)=N1 ZROPISXBHMLTRK-UHFFFAOYSA-N 0.000 description 2
• HBFGDBZADKPXLP-UHFFFAOYSA-N n-[2-chloro-3-[5-[2-(2-cyanoethylamino)pyrimidin-4-yl]-2-(1-methylcyclopropyl)-1h-imidazol-4-yl]-5-fluorophenyl]methanesulfonamide Chemical compound N=1C(C=2C(=C(NS(C)(=O)=O)C=C(F)C=2)Cl)=C(C=2N=C(NCCC#N)N=CC=2)NC=1C1(C)CC1 HBFGDBZADKPXLP-UHFFFAOYSA-N 0.000 description 2
• WUCQBMDFNJXQJF-UHFFFAOYSA-N n-[2-chloro-3-[5-[2-(2-cyanopropylamino)pyrimidin-4-yl]-2-cyclopropyl-1h-imidazol-4-yl]phenyl]methanesulfonamide Chemical compound N#CC(C)CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=CC=2)Cl)=N1 WUCQBMDFNJXQJF-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
• OLGBVGGMHKVNCX-UHFFFAOYSA-N n-[3-[2-cyclopropyl-5-[2-(methylamino)pyrimidin-4-yl]-1h-imidazol-4-yl]-2-fluorophenyl]methanesulfonamide Chemical compound CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=CC=2)F)=N1 OLGBVGGMHKVNCX-UHFFFAOYSA-N 0.000 description 2
• DKTRDLWKMZIANJ-UHFFFAOYSA-N n-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1h-imidazol-4-yl]-5-chloro-2-fluorophenyl]methanesulfonamide Chemical compound N1C(C(C)(C)C)=NC(C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=C1C1=CC=NC(N)=N1 DKTRDLWKMZIANJ-UHFFFAOYSA-N 0.000 description 2
• XDCDWWUTQYLHIN-UHFFFAOYSA-N n-[3-[5-[2-(2-cyanoethylamino)pyrimidin-4-yl]-2-(1-methylcyclopropyl)-1h-imidazol-4-yl]-2-fluoro-5-methylphenyl]methanesulfonamide Chemical compound CC1=CC(NS(C)(=O)=O)=C(F)C(C2=C(NC(=N2)C2(C)CC2)C=2N=C(NCCC#N)N=CC=2)=C1 XDCDWWUTQYLHIN-UHFFFAOYSA-N 0.000 description 2
• HEOKTLLFGNGUMD-UHFFFAOYSA-N n-[3-[5-[2-(2-cyanoethylamino)pyrimidin-4-yl]-2-cyclopropyl-1h-imidazol-4-yl]-2-fluorophenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=CC(C2=C(NC(=N2)C2CC2)C=2N=C(NCCC#N)N=CC=2)=C1F HEOKTLLFGNGUMD-UHFFFAOYSA-N 0.000 description 2
• DIPMNTOKWOPMSO-UHFFFAOYSA-N n-[3-[5-[2-(2-cyanoethylamino)pyrimidin-4-yl]-2-cyclopropyl-1h-imidazol-4-yl]-2-fluorophenyl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=CC=CC(C2=C(NC(=N2)C2CC2)C=2N=C(NCCC#N)N=CC=2)=C1F DIPMNTOKWOPMSO-UHFFFAOYSA-N 0.000 description 2
• JXUVQKLLPWLOHV-UHFFFAOYSA-N n-[5-chloro-3-[5-[2-(2-cyanoethylamino)pyrimidin-4-yl]-2-(1-methylcyclopropyl)-1h-imidazol-4-yl]-2-fluorophenyl]methanesulfonamide Chemical compound N=1C(C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=C(C=2N=C(NCCC#N)N=CC=2)NC=1C1(C)CC1 JXUVQKLLPWLOHV-UHFFFAOYSA-N 0.000 description 2
• 230000007935 neutral effect Effects 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
• 230000037361 pathway Effects 0.000 description 2
• 239000003208 petroleum Substances 0.000 description 2
• HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
• 102000051624 phosphatidylethanolamine binding protein Human genes 0.000 description 2
• 108700021017 phosphatidylethanolamine binding protein Proteins 0.000 description 2
• XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
• 239000004033 plastic Substances 0.000 description 2
• 229920003023 plastic Polymers 0.000 description 2
• 229920001155 polypropylene Polymers 0.000 description 2
• 229920000136 polysorbate Polymers 0.000 description 2
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
• 239000003755 preservative agent Substances 0.000 description 2
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
• KPBSJEBFALFJTO-UHFFFAOYSA-N propane-1-sulfonyl chloride Chemical compound CCCS(Cl)(=O)=O KPBSJEBFALFJTO-UHFFFAOYSA-N 0.000 description 2
• 125000006239 protecting group Chemical group 0.000 description 2
• 108060006633 protein kinase Proteins 0.000 description 2
• 102000004169 proteins and genes Human genes 0.000 description 2
• 108090000623 proteins and genes Proteins 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
• 230000019491 signal transduction Effects 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
• 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
• 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
• 239000011780 sodium chloride Substances 0.000 description 2
• 239000012312 sodium hydride Substances 0.000 description 2
• 229960003787 sorafenib Drugs 0.000 description 2
• 239000003381 stabilizer Substances 0.000 description 2
• 239000008107 starch Substances 0.000 description 2
• FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 2
• 239000000829 suppository Substances 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
• GFFALKCIACMPPO-UHFFFAOYSA-N tert-butyl n-(3-bromo-2,6-difluorophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=C(F)C=CC(Br)=C1F GFFALKCIACMPPO-UHFFFAOYSA-N 0.000 description 2
• ROQBTCYBYFOFJH-UHFFFAOYSA-N tert-butyl n-(3-bromo-5-chloro-2-fluorophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC(Cl)=CC(Br)=C1F ROQBTCYBYFOFJH-UHFFFAOYSA-N 0.000 description 2
• 238000012360 testing method Methods 0.000 description 2
• 238000002560 therapeutic procedure Methods 0.000 description 2
• 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 2
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
• 229960000575 trastuzumab Drugs 0.000 description 2
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
• PIZQWRXTMGASCZ-UHFFFAOYSA-N (1-methylcyclopropyl)methanol Chemical compound OCC1(C)CC1 PIZQWRXTMGASCZ-UHFFFAOYSA-N 0.000 description 1
• 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
• LMIDQXVWQHUHCR-VIFPVBQESA-N (2s)-1-n-[2-[5-bromo-2-[4-(trifluoromethyl)phenyl]-1h-imidazol-4-yl]pyrimidin-4-yl]propane-1,2-diamine Chemical compound C[C@H](N)CNC1=CC=NC(C2=C(N=C(N2)C=2C=CC(=CC=2)C(F)(F)F)Br)=N1 LMIDQXVWQHUHCR-VIFPVBQESA-N 0.000 description 1
• BRJWACBOVUYPNS-VIFPVBQESA-N (2s)-1-n-[4-[5-bromo-2-[4-(trifluoromethyl)phenyl]-1h-imidazol-4-yl]pyrimidin-2-yl]propane-1,2-diamine Chemical compound C[C@H](N)CNC1=NC=CC(C2=C(N=C(N2)C=2C=CC(=CC=2)C(F)(F)F)Br)=N1 BRJWACBOVUYPNS-VIFPVBQESA-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
• WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical compound C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 description 1
• FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
• QTZSKHCRRPXONC-UHFFFAOYSA-N 1,3-dibromo-2,5-difluorobenzene Chemical compound FC1=CC(Br)=C(F)C(Br)=C1 QTZSKHCRRPXONC-UHFFFAOYSA-N 0.000 description 1
• HVPWZGWQKWAJMQ-UHFFFAOYSA-N 1,3-dibromo-2-chloro-5-methylbenzene Chemical compound CC1=CC(Br)=C(Cl)C(Br)=C1 HVPWZGWQKWAJMQ-UHFFFAOYSA-N 0.000 description 1
• HKDFRDIIELOLTJ-UHFFFAOYSA-N 1,4-dithianyl Chemical group [CH]1CSCCS1 HKDFRDIIELOLTJ-UHFFFAOYSA-N 0.000 description 1
• QCLCDUXYRKMILY-UHFFFAOYSA-N 1-[[4-[4-[3-chloro-5-(methanesulfonamido)phenyl]-2-cyclopropyl-1H-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-ylcarbamic acid Chemical compound OC(=O)NC(C)CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C=C(NS(C)(=O)=O)C=C(Cl)C=2)=N1 QCLCDUXYRKMILY-UHFFFAOYSA-N 0.000 description 1
• VOMPXNIJPCNUJI-UHFFFAOYSA-N 1-[[4-[5-bromo-2-(1-methylcyclopropyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]pyrimidin-2-yl]amino]propan-2-ylcarbamic acid Chemical compound OC(=O)NC(C)CNC1=NC=CC(C=2N(C(=NC=2Br)C2(C)CC2)COCC[Si](C)(C)C)=N1 VOMPXNIJPCNUJI-UHFFFAOYSA-N 0.000 description 1
• ATATVWZFASNLJL-UHFFFAOYSA-N 1-[[4-[5-bromo-2-cyclopropyl-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]pyrimidin-2-yl]amino]propan-2-ylcarbamic acid Chemical compound OC(=O)NC(C)CNC1=NC=CC(C=2N(C(C3CC3)=NC=2Br)COCC[Si](C)(C)C)=N1 ATATVWZFASNLJL-UHFFFAOYSA-N 0.000 description 1
• RDDZQMFGHYSKJZ-UHFFFAOYSA-N 1-[[[4-[5-bromo-2-cyclopropyl-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]pyrimidin-2-yl]amino]methyl]cyclopropane-1-carbonitrile Chemical compound C[Si](C)(C)CCOCN1C(C2CC2)=NC(Br)=C1C(N=1)=CC=NC=1NCC1(C#N)CC1 RDDZQMFGHYSKJZ-UHFFFAOYSA-N 0.000 description 1
• MGHBDQZXPCTTIH-UHFFFAOYSA-N 1-bromo-2,4-difluorobenzene Chemical compound FC1=CC=C(Br)C(F)=C1 MGHBDQZXPCTTIH-UHFFFAOYSA-N 0.000 description 1
• MWYFDHRLYOKUMH-UHFFFAOYSA-N 1-bromo-2-fluoro-3-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC(Br)=C1F MWYFDHRLYOKUMH-UHFFFAOYSA-N 0.000 description 1
• PONMYPMRWXBYEV-UHFFFAOYSA-N 1-bromo-5-chloro-2-methyl-3-nitrobenzene Chemical compound CC1=C(Br)C=C(Cl)C=C1[N+]([O-])=O PONMYPMRWXBYEV-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
• QVTQYSFCFOGITD-UHFFFAOYSA-N 2,5-dichlorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1Cl QVTQYSFCFOGITD-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
• BIYKLEZTCUPOQM-UHFFFAOYSA-N 2-[(4-bromo-2-cyclopropyl-5-pyrimidin-4-ylimidazol-1-yl)methoxy]ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCN1C(C2CC2)=NC(Br)=C1C1=CC=NC=N1 BIYKLEZTCUPOQM-UHFFFAOYSA-N 0.000 description 1
• VWDVKFOLZQSGRM-UHFFFAOYSA-N 2-[(5-bromo-2-cyclopropyl-4-pyrimidin-4-ylimidazol-1-yl)methoxy]ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCN1C(Br)=C(C=2N=CN=CC=2)N=C1C1CC1 VWDVKFOLZQSGRM-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
• IGBXAWVFNNXCEG-UHFFFAOYSA-N 2-[[4-bromo-5-(2-chloro-1,4-dihydropyrimidin-4-yl)-2-[4-(trifluoromethyl)phenyl]imidazol-1-yl]methoxy]ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCN1C(C=2C=CC(=CC=2)C(F)(F)F)=NC(Br)=C1C1NC(Cl)=NC=C1 IGBXAWVFNNXCEG-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
• GBESIUPWXGQOFP-UHFFFAOYSA-N 2-bromo-1-chloro-3-fluorobenzene Chemical compound FC1=CC=CC(Cl)=C1Br GBESIUPWXGQOFP-UHFFFAOYSA-N 0.000 description 1
• QLRKALMVPCQTMU-UHFFFAOYSA-N 2-bromo-1-fluoro-4-methylbenzene Chemical compound CC1=CC=C(F)C(Br)=C1 QLRKALMVPCQTMU-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
• FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 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
• 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
• 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
• QOXAHAQUPCQGTF-UHFFFAOYSA-N 3-[[4-[4-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-1h-imidazol-5-yl]pyrimidin-2-yl]amino]propanenitrile Chemical compound NC1=CC(Cl)=CC(C2=C(NC(=N2)C2CC2)C=2N=C(NCCC#N)N=CC=2)=C1F QOXAHAQUPCQGTF-UHFFFAOYSA-N 0.000 description 1
• YHSRGCNBSMCVBR-UHFFFAOYSA-N 3-[[4-[5-(3-amino-5-chloro-2-fluorophenyl)-2-cyclopropyl-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]pyrimidin-2-yl]amino]propanenitrile Chemical compound C[Si](C)(C)CCOCN1C(C2CC2)=NC(C=2C(=C(N)C=C(Cl)C=2)F)=C1C1=CC=NC(NCCC#N)=N1 YHSRGCNBSMCVBR-UHFFFAOYSA-N 0.000 description 1
• QDUDKSFHEOOHAS-UHFFFAOYSA-N 3-[[4-[5-bromo-2-cyclopropyl-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]pyrimidin-2-yl]amino]-2-methylpropanenitrile Chemical compound N#CC(C)CNC1=NC=CC(C=2N(C(C3CC3)=NC=2Br)COCC[Si](C)(C)C)=N1 QDUDKSFHEOOHAS-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
• BWAYZLJQQXIODW-UHFFFAOYSA-N 3-bromo-2-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Br)=C1Cl BWAYZLJQQXIODW-UHFFFAOYSA-N 0.000 description 1
• KNPUHWXDXJQPOD-UHFFFAOYSA-N 3-bromo-2-fluoro-5-methylaniline Chemical compound CC1=CC(N)=C(F)C(Br)=C1 KNPUHWXDXJQPOD-UHFFFAOYSA-N 0.000 description 1
• BGECTFQDFFAMKV-UHFFFAOYSA-N 3-bromo-5-chloro-2-methylaniline Chemical compound CC1=C(N)C=C(Cl)C=C1Br BGECTFQDFFAMKV-UHFFFAOYSA-N 0.000 description 1
• YYBRLVWWPRAQDX-UHFFFAOYSA-N 3-bromo-5-chloroaniline Chemical compound NC1=CC(Cl)=CC(Br)=C1 YYBRLVWWPRAQDX-UHFFFAOYSA-N 0.000 description 1
• YIZRPAWCIFTHNA-UHFFFAOYSA-N 3-bromo-5-methylaniline Chemical compound CC1=CC(N)=CC(Br)=C1 YIZRPAWCIFTHNA-UHFFFAOYSA-N 0.000 description 1
• VJQGLUHOAIZTNK-UHFFFAOYSA-N 3-bromo-5-nitrophenol Chemical compound OC1=CC(Br)=CC([N+]([O-])=O)=C1 VJQGLUHOAIZTNK-UHFFFAOYSA-N 0.000 description 1
• RLQGPOJAVFWHPC-UHFFFAOYSA-N 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC(N)=CC(Cl)=C1 RLQGPOJAVFWHPC-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
• SYNFTGCUTKKUJI-UHFFFAOYSA-N 4-(5-bromo-1h-imidazol-4-yl)-2-chloropyrimidine Chemical compound ClC1=NC=CC(C2=C(N=CN2)Br)=N1 SYNFTGCUTKKUJI-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
• NCRVMROGAYDZFS-UHFFFAOYSA-N 4-[5-bromo-2-(1-methylcyclopropyl)-1H-imidazol-4-yl]pyrimidine Chemical compound BrC=1N=C(NC=1C1=NC=NC=C1)C1(CC1)C NCRVMROGAYDZFS-UHFFFAOYSA-N 0.000 description 1
• XMFXNVQDKUPCJE-UHFFFAOYSA-N 4-[5-bromo-2-cyclopropyl-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-N-(cyclopropylmethyl)pyrimidin-2-amine Chemical compound BrC=1N=C(N(C=1C1=NC(=NC=C1)NCC1CC1)COCC[Si](C)(C)C)C1CC1 XMFXNVQDKUPCJE-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
• 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
• OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 1
• XTZNLELDRXUAOX-UHFFFAOYSA-N 5-bromo-1-methoxy-2-methyl-3-nitrobenzene Chemical compound COC1=CC(Br)=CC([N+]([O-])=O)=C1C XTZNLELDRXUAOX-UHFFFAOYSA-N 0.000 description 1
• CSQIETQHZSHSIA-UHFFFAOYSA-N 5-bromo-3-methoxy-2-methylaniline Chemical compound COC1=CC(Br)=CC(N)=C1C CSQIETQHZSHSIA-UHFFFAOYSA-N 0.000 description 1
• 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
• 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
• 239000005711 Benzoic acid Substances 0.000 description 1
• MUXZUVZRSXHZKB-UHFFFAOYSA-N BrC=1C(=C(C=C(C1)C)NC(OC(C)(C)C)=O)F.C(C)(C)(C)NC1=C(C(=CC(=C1)C)Br)F Chemical compound BrC=1C(=C(C=C(C1)C)NC(OC(C)(C)C)=O)F.C(C)(C)(C)NC1=C(C(=CC(=C1)C)Br)F MUXZUVZRSXHZKB-UHFFFAOYSA-N 0.000 description 1
• IHXLVVYIXQVHHR-UHFFFAOYSA-N BrC=1N=C(N(C1C1=NC(=NC=C1)CCC#N)CCOCC[Si](C)(C)C)C1CC1 Chemical compound BrC=1N=C(N(C1C1=NC(=NC=C1)CCC#N)CCOCC[Si](C)(C)C)C1CC1 IHXLVVYIXQVHHR-UHFFFAOYSA-N 0.000 description 1
• MZNZWPIMLPVSPV-UHFFFAOYSA-N BrC=1N=C(N(C1C1=NC(=NC=C1)NC(C#N)C)COCC[Si](C)(C)C)C1(CC1)C Chemical compound BrC=1N=C(N(C1C1=NC(=NC=C1)NC(C#N)C)COCC[Si](C)(C)C)C1(CC1)C MZNZWPIMLPVSPV-UHFFFAOYSA-N 0.000 description 1
• WNUQPPLACJHKQT-UHFFFAOYSA-N BrC=1N=C(N(C1C1=NC(=NC=C1)NCC(C)C)COCC[Si](C)(C)C)C1CC1 Chemical compound BrC=1N=C(N(C1C1=NC(=NC=C1)NCC(C)C)COCC[Si](C)(C)C)C1CC1 WNUQPPLACJHKQT-UHFFFAOYSA-N 0.000 description 1
• MMAKCDYFLNBOCK-UHFFFAOYSA-N BrC=1N=C(NC1C1=NC(=NC=C1)NCCC)C1CCC1 Chemical compound BrC=1N=C(NC1C1=NC(=NC=C1)NCCC)C1CCC1 MMAKCDYFLNBOCK-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
• JDEISRSRLNPTST-JPMBUGEZSA-N CC(C)/C(/N(C)C[C@H](C)I)=C\[C@@H]([C@]1(C)NC(NCC(C)N)=NC=C1)N Chemical compound CC(C)/C(/N(C)C[C@H](C)I)=C\[C@@H]([C@]1(C)NC(NCC(C)N)=NC=C1)N JDEISRSRLNPTST-JPMBUGEZSA-N 0.000 description 1
• YBJMUURMDZTJAG-UHFFFAOYSA-N CC(CNC1=NC=CC(C2=C(C(C=C(C=C3N)F)=C3Cl)NC(C3CC3)=N2)=N1)NC(O)=O Chemical compound CC(CNC1=NC=CC(C2=C(C(C=C(C=C3N)F)=C3Cl)NC(C3CC3)=N2)=N1)NC(O)=O YBJMUURMDZTJAG-UHFFFAOYSA-N 0.000 description 1
• YEYHITPYMZLEJV-LBPRGKRZSA-N C[C@@H](CNc1nc(-c2c(-c3cc(Cl)cc(NS(C(F)(F)F)(=O)=O)c3)nc(C(C)(C)C)[nH]2)ccn1)NC(OC)=O Chemical compound C[C@@H](CNc1nc(-c2c(-c3cc(Cl)cc(NS(C(F)(F)F)(=O)=O)c3)nc(C(C)(C)C)[nH]2)ccn1)NC(OC)=O YEYHITPYMZLEJV-LBPRGKRZSA-N 0.000 description 1
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
• 102000000844 Cell Surface Receptors Human genes 0.000 description 1
• 108010001857 Cell Surface Receptors Proteins 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
• ZDNRBLLCZBAXHE-UHFFFAOYSA-N ClC1=C(C=C(C=C1NS(=O)(=O)C)F)C=1N=C(NC1)C1CC1 Chemical compound ClC1=C(C=C(C=C1NS(=O)(=O)C)F)C=1N=C(NC1)C1CC1 ZDNRBLLCZBAXHE-UHFFFAOYSA-N 0.000 description 1
• VLOKQQFTAOUDGD-UHFFFAOYSA-N ClC1=C(C=CC=C1CCC)C=1N=C(N(C1C1=NC(=NC=C1)NCC(C)NC(O)=O)COCC[Si](C)(C)C)C1CC1 Chemical compound ClC1=C(C=CC=C1CCC)C=1N=C(N(C1C1=NC(=NC=C1)NCC(C)NC(O)=O)COCC[Si](C)(C)C)C1CC1 VLOKQQFTAOUDGD-UHFFFAOYSA-N 0.000 description 1
• 229920000858 Cyclodextrin Polymers 0.000 description 1
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 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
• 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
• 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
• 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
• 229920003119 EUDRAGIT E PO Polymers 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
• 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 1
• 244000166102 Eucalyptus leucoxylon Species 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
• 229910004373 HOAc Inorganic materials 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
• LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 1
• 229920002153 Hydroxypropyl cellulose Polymers 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
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
• 229920003083 Kollidon® VA64 Polymers 0.000 description 1
• 239000005411 L01XE02 - Gefitinib 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
• 108060001084 Luciferase Proteins 0.000 description 1
• 239000005089 Luciferase Substances 0.000 description 1
• 229940124647 MEK inhibitor Drugs 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
• GYCMBHHDWRMZGG-UHFFFAOYSA-N Methylacrylonitrile Chemical compound CC(=C)C#N GYCMBHHDWRMZGG-UHFFFAOYSA-N 0.000 description 1
• 102000056243 Mitogen-activated protein kinase 12 Human genes 0.000 description 1
• 108700015929 Mitogen-activated protein kinase 12 Proteins 0.000 description 1
• HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-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
• 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
• OOXCXAONCHLBPY-UHFFFAOYSA-N Nc1nc(-c2c(-c(cc(cc3NS(c(c(F)ccc4)c4F)(=O)=O)F)c3Cl)nc(C3CC3)[nH]2)ccn1 Chemical compound Nc1nc(-c2c(-c(cc(cc3NS(c(c(F)ccc4)c4F)(=O)=O)F)c3Cl)nc(C3CC3)[nH]2)ccn1 OOXCXAONCHLBPY-UHFFFAOYSA-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
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 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
• 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
• 239000012828 PI3K inhibitor Substances 0.000 description 1
• 229930012538 Paclitaxel Natural products 0.000 description 1
• 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 1
• 101150003085 Pdcl gene Proteins 0.000 description 1
• YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 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
• 229920002685 Polyoxyl 35CastorOil Polymers 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
• 108090000315 Protein Kinase C Proteins 0.000 description 1
• 102000003923 Protein Kinase C Human genes 0.000 description 1
• 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 1
• PVNHTBMOMSJQTQ-UHFFFAOYSA-N S(C)(=O)(=O)O.S(C)(=O)(=O)O.N1=CN=CC2=C1C=CS2 Chemical compound S(C)(=O)(=O)O.S(C)(=O)(=O)O.N1=CN=CC2=C1C=CS2 PVNHTBMOMSJQTQ-UHFFFAOYSA-N 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
• 101150082971 Sgk1 gene Proteins 0.000 description 1
• 235000021355 Stearic acid Nutrition 0.000 description 1
• 229910000831 Steel Inorganic materials 0.000 description 1
• 238000006619 Stille reaction Methods 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
• 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
• DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
• ALMFIOZYDASRRC-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]boronic acid Chemical compound OB(O)C1=CC=C(C(F)(F)F)C=C1 ALMFIOZYDASRRC-UHFFFAOYSA-N 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
• HUXCSBSKSYIRDN-UHFFFAOYSA-N [O-][N+](=O)C1=CC=C(F)C(Br)=C1Cl Chemical compound [O-][N+](=O)C1=CC=C(F)C(Br)=C1Cl HUXCSBSKSYIRDN-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
• PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
• 150000007513 acids Chemical class 0.000 description 1
• 239000008186 active pharmaceutical agent Substances 0.000 description 1
• 239000002671 adjuvant Substances 0.000 description 1
• 238000005273 aeration Methods 0.000 description 1
• 239000008272 agar Substances 0.000 description 1
• 235000010419 agar Nutrition 0.000 description 1
• 238000013019 agitation Methods 0.000 description 1
• 150000001299 aldehydes Chemical class 0.000 description 1
• 235000010443 alginic acid Nutrition 0.000 description 1
• 239000000783 alginic acid Substances 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
• 229910052783 alkali metal Inorganic materials 0.000 description 1
• 150000001340 alkali metals Chemical class 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
• 230000004075 alteration Effects 0.000 description 1
• 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
• 229910021529 ammonia Inorganic materials 0.000 description 1
• VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 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
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
• 239000003242 anti bacterial agent Substances 0.000 description 1
• 230000002280 anti-androgenic 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
• 239000013059 antihormonal agent Substances 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
• 150000001555 benzenes Chemical class 0.000 description 1
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
• 235000010233 benzoic acid Nutrition 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
• 230000002051 biphasic effect Effects 0.000 description 1
• 230000000903 blocking effect Effects 0.000 description 1
• 230000037396 body weight Effects 0.000 description 1
• 230000031709 bromination Effects 0.000 description 1
• 238000005893 bromination reaction Methods 0.000 description 1
• 125000001246 bromo group Chemical group Br* 0.000 description 1
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
• 229910052799 carbon Inorganic materials 0.000 description 1
• 235000011089 carbon dioxide Nutrition 0.000 description 1
• KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
• 229960004562 carboplatin Drugs 0.000 description 1
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
• 239000003054 catalyst Substances 0.000 description 1
• 230000003915 cell function Effects 0.000 description 1
• 230000010261 cell growth Effects 0.000 description 1
• 238000001516 cell proliferation assay Methods 0.000 description 1
• 238000005119 centrifugation Methods 0.000 description 1
• 229960005395 cetuximab Drugs 0.000 description 1
• 238000012512 characterization method Methods 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
• 239000003153 chemical reaction reagent Substances 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
• 238000011260 co-administration Methods 0.000 description 1
• 238000000576 coating method Methods 0.000 description 1
• 239000003086 colorant Substances 0.000 description 1
• 238000002648 combination therapy Methods 0.000 description 1
• 239000008139 complexing agent Substances 0.000 description 1
• 238000007796 conventional method Methods 0.000 description 1
• 238000002425 crystallisation Methods 0.000 description 1
• 230000008025 crystallization Effects 0.000 description 1
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• WPOPOPFNZYPKAV-UHFFFAOYSA-N cyclobutylmethanol Chemical compound OCC1CCC1 WPOPOPFNZYPKAV-UHFFFAOYSA-N 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
• SNRCKKQHDUIRIY-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloromethane;dichloropalladium;iron(2+) Chemical compound [Fe+2].ClCCl.Cl[Pd]Cl.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.C1=C[CH-]C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 SNRCKKQHDUIRIY-UHFFFAOYSA-L 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
• JMYVMOUINOAAPA-UHFFFAOYSA-N cyclopropanecarbaldehyde Chemical compound O=CC1CC1 JMYVMOUINOAAPA-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
• 230000003111 delayed effect Effects 0.000 description 1
• 230000005595 deprotonation Effects 0.000 description 1
• 238000010537 deprotonation reaction 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
• 125000003963 dichloro group Chemical group Cl* 0.000 description 1
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 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
• 238000010790 dilution Methods 0.000 description 1
• 239000012895 dilution Substances 0.000 description 1
• 229910001873 dinitrogen Inorganic materials 0.000 description 1
• 150000002016 disaccharides Chemical class 0.000 description 1
• 230000008034 disappearance Effects 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
• 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
• 239000012636 effector 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
• HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 1
• 150000002169 ethanolamines Chemical class 0.000 description 1
• FDZLCIITHLSEQK-UHFFFAOYSA-N ethyl 1-cyanocyclopropane-1-carboxylate Chemical compound CCOC(=O)C1(C#N)CC1 FDZLCIITHLSEQK-UHFFFAOYSA-N 0.000 description 1
• 239000002038 ethyl acetate fraction Substances 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
• 125000001207 fluorophenyl group Chemical group 0.000 description 1
• 235000019253 formic acid Nutrition 0.000 description 1
• 238000001640 fractional crystallisation Methods 0.000 description 1
• 238000004108 freeze drying 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
• 230000036541 health Effects 0.000 description 1
• 125000001072 heteroaryl group Chemical group 0.000 description 1
• 125000005842 heteroatom Chemical group 0.000 description 1
• 125000000623 heterocyclic group Chemical group 0.000 description 1
• 125000000592 heterocycloalkyl group Chemical group 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
• 230000007062 hydrolysis Effects 0.000 description 1
• 238000006460 hydrolysis reaction Methods 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
• 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
• 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
• 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
• 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
• 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
• 238000005286 illumination Methods 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
• 125000001041 indolyl group Chemical group 0.000 description 1
• 230000002401 inhibitory effect Effects 0.000 description 1
• 239000003999 initiator Substances 0.000 description 1
• 239000007972 injectable composition 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
• 238000006317 isomerization reaction Methods 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
• 230000000670 limiting effect Effects 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
• 235000019359 magnesium stearate Nutrition 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
• 125000006431 methyl cyclopropyl group Chemical group 0.000 description 1
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
• 239000002480 mineral oil Substances 0.000 description 1
• 235000010446 mineral oil Nutrition 0.000 description 1
• 150000007522 mineralic acids Chemical class 0.000 description 1
• 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
• 230000000394 mitotic effect Effects 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
• 239000012452 mother liquor Substances 0.000 description 1
• YUYHJXUXHNZDTL-UHFFFAOYSA-N n-(3-bromo-2-fluorophenyl)-3,3,3-trifluoropropane-1-sulfonamide Chemical compound FC1=C(Br)C=CC=C1NS(=O)(=O)CCC(F)(F)F YUYHJXUXHNZDTL-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
• FTQOCABQYQGKRJ-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-[2-(2-methylpropylamino)pyrimidin-4-yl]-1h-imidazol-4-yl]-5-fluorophenyl]methanesulfonamide Chemical compound CC(C)CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(F)C=2)Cl)=N1 FTQOCABQYQGKRJ-UHFFFAOYSA-N 0.000 description 1
• UJKHYWAOJNKUFU-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-[2-(ethylamino)pyrimidin-4-yl]-1h-imidazol-4-yl]-5-fluorophenyl]methanesulfonamide Chemical compound CCNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(F)C=2)Cl)=N1 UJKHYWAOJNKUFU-UHFFFAOYSA-N 0.000 description 1
• OBXWGHIIUPFBTP-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-[2-(methylamino)pyrimidin-4-yl]-1h-imidazol-4-yl]-5-fluorophenyl]methanesulfonamide Chemical compound CNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(F)C=2)Cl)=N1 OBXWGHIIUPFBTP-UHFFFAOYSA-N 0.000 description 1
• GSLKVJWUTOOFHO-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-[2-(propan-2-ylamino)pyrimidin-4-yl]-1h-imidazol-4-yl]-5-fluorophenyl]methanesulfonamide Chemical compound CC(C)NC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(F)C=2)Cl)=N1 GSLKVJWUTOOFHO-UHFFFAOYSA-N 0.000 description 1
• WHWSNJNEODHCAR-UHFFFAOYSA-N n-[2-chloro-3-[2-cyclopropyl-5-[2-(propylamino)pyrimidin-4-yl]-1h-imidazol-4-yl]-5-fluorophenyl]methanesulfonamide Chemical compound CCCNC1=NC=CC(C2=C(N=C(N2)C2CC2)C=2C(=C(NS(C)(=O)=O)C=C(F)C=2)Cl)=N1 WHWSNJNEODHCAR-UHFFFAOYSA-N 0.000 description 1
• RPYSRXCKVSZCBM-UHFFFAOYSA-N n-[3-[2-cyclopropyl-5-[2-(methylamino)pyrimidin-4-yl]-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-2-fluorophenyl]methanesulfonamide Chemical compound CNC1=NC=CC(C=2N(C(C3CC3)=NC=2C=2C(=C(NS(C)(=O)=O)C=CC=2)F)COCC[Si](C)(C)C)=N1 RPYSRXCKVSZCBM-UHFFFAOYSA-N 0.000 description 1
• SLOWBIWRFDGYFV-UHFFFAOYSA-N n-[5-chloro-3-[5-[2-(2-cyanoethylamino)pyrimidin-4-yl]-2-cyclopropyl-1h-imidazol-4-yl]-2-fluorophenyl]methanesulfonamide Chemical compound CS(=O)(=O)NC1=CC(Cl)=CC(C2=C(NC(=N2)C2CC2)C=2N=C(NCCC#N)N=CC=2)=C1F SLOWBIWRFDGYFV-UHFFFAOYSA-N 0.000 description 1
• 125000001624 naphthyl group Chemical group 0.000 description 1
• 210000000653 nervous system Anatomy 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
• 150000002825 nitriles Chemical class 0.000 description 1
• 239000012299 nitrogen atmosphere Substances 0.000 description 1
• 238000004172 nitrogen cycle Methods 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
• 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
• 230000003647 oxidation Effects 0.000 description 1
• 238000007254 oxidation reaction Methods 0.000 description 1
• QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
• 239000001301 oxygen Substances 0.000 description 1
• 229910052760 oxygen Inorganic materials 0.000 description 1
• 238000012856 packing Methods 0.000 description 1
• 229960001592 paclitaxel Drugs 0.000 description 1
• 229960001972 panitumumab Drugs 0.000 description 1
• 239000002245 particle Substances 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
• 229960002087 pertuzumab Drugs 0.000 description 1
• 230000000144 pharmacologic effect Effects 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
• 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 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
• 229920001993 poloxamer 188 Polymers 0.000 description 1
• 125000003367 polycyclic group Chemical group 0.000 description 1
• 239000008389 polyethoxylated castor oil Substances 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
• 235000015497 potassium bicarbonate Nutrition 0.000 description 1
• 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
• 239000011736 potassium bicarbonate Substances 0.000 description 1
• 229910000027 potassium carbonate Inorganic materials 0.000 description 1
• 235000011181 potassium carbonates Nutrition 0.000 description 1
• TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
• 239000000843 powder Substances 0.000 description 1
• 238000011533 pre-incubation Methods 0.000 description 1
• 238000001556 precipitation Methods 0.000 description 1
• 150000003141 primary amines Chemical group 0.000 description 1
• 238000012545 processing Methods 0.000 description 1
• 230000002062 proliferating effect Effects 0.000 description 1
• 230000002035 prolonged effect Effects 0.000 description 1
• DROIHSMGGKKIJT-UHFFFAOYSA-N propane-1-sulfonamide Chemical compound CCCS(N)(=O)=O DROIHSMGGKKIJT-UHFFFAOYSA-N 0.000 description 1
• DRINJBFRTLBHNF-UHFFFAOYSA-N propane-2-sulfonyl chloride Chemical compound CC(C)S(Cl)(=O)=O DRINJBFRTLBHNF-UHFFFAOYSA-N 0.000 description 1
• 235000019260 propionic acid Nutrition 0.000 description 1
• 239000003586 protic polar solvent Substances 0.000 description 1
• 239000012521 purified sample Substances 0.000 description 1
• 125000003226 pyrazolyl group Chemical group 0.000 description 1
• ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 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
• 125000000714 pyrimidinyl group Chemical group 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
• 239000013557 residual solvent Substances 0.000 description 1
• 230000002441 reversible effect Effects 0.000 description 1
• 125000006413 ring segment Chemical group 0.000 description 1
• 238000002390 rotary evaporation Methods 0.000 description 1
• 239000000523 sample Substances 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
• 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
• 229910052708 sodium Inorganic materials 0.000 description 1
• 239000012064 sodium phosphate buffer Substances 0.000 description 1
• 159000000000 sodium salts Chemical class 0.000 description 1
• MRTAVLDNYYEJHK-UHFFFAOYSA-M sodium;2-chloro-2,2-difluoroacetate Chemical compound [Na+].[O-]C(=O)C(F)(F)Cl MRTAVLDNYYEJHK-UHFFFAOYSA-M 0.000 description 1
• XZPVPNZTYPUODG-UHFFFAOYSA-M sodium;chloride;dihydrate Chemical compound O.O.[Na+].[Cl-] XZPVPNZTYPUODG-UHFFFAOYSA-M 0.000 description 1
• 239000008137 solubility enhancer Substances 0.000 description 1
• 239000000600 sorbitol Substances 0.000 description 1
• KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
• 229910000080 stannane Inorganic materials 0.000 description 1
• 239000008117 stearic acid Substances 0.000 description 1
• 239000010959 steel Substances 0.000 description 1
• 239000005720 sucrose Substances 0.000 description 1
• 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
• 150000003460 sulfonic acids Chemical class 0.000 description 1
• 229910052717 sulfur Inorganic materials 0.000 description 1
• 239000011593 sulfur Substances 0.000 description 1
• 239000006228 supernatant Substances 0.000 description 1
• 230000004083 survival effect Effects 0.000 description 1
• 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
• BSBUYMURKFVOJK-UHFFFAOYSA-N tert-butyl n-(3-bromo-2-fluoro-5-methylphenyl)carbamate Chemical compound CC1=CC(Br)=C(F)C(NC(=O)OC(C)(C)C)=C1 BSBUYMURKFVOJK-UHFFFAOYSA-N 0.000 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
• KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 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
• 235000010487 tragacanth Nutrition 0.000 description 1
• 239000000196 tragacanth Substances 0.000 description 1
• 229940116362 tragacanth Drugs 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
• 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
• GFQTXMBEFAATTO-UHFFFAOYSA-N trimethyl-[2-[[2-[4-(trifluoromethyl)phenyl]imidazol-1-yl]methoxy]ethyl]silane Chemical compound FC(C1=CC=C(C=C1)C=1N(C=CN1)COCC[Si](C)(C)C)(F)F GFQTXMBEFAATTO-UHFFFAOYSA-N 0.000 description 1
• 238000001665 trituration Methods 0.000 description 1
• 230000004565 tumor cell growth Effects 0.000 description 1
• 238000009423 ventilation Methods 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