AU2020288706A1 - Benzo[h][1,6] naphthyridin-2(1H)-ones as BMX inhibitors, for use against cancer - Google Patents

Info

Publication number

AU2020288706A1

AU2020288706A1 AU2020288706A AU2020288706A AU2020288706A1 AU 2020288706 A1 AU2020288706 A1 AU 2020288706A1 AU 2020288706 A AU2020288706 A AU 2020288706A AU 2020288706 A AU2020288706 A AU 2020288706A AU 2020288706 A1 AU2020288706 A1 AU 2020288706A1

Authority

AU

Australia

Prior art keywords

compound

group

formula

covalent bond

bmx

Prior art date

2019-06-07

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

Abandoned

Links

• Espacenet
• Global Dossier
• Discuss

• 206010028980 Neoplasm Diseases 0.000 title claims abstract description 39
• 201000011510 cancer Diseases 0.000 title claims abstract description 34
• 239000003112 inhibitor Substances 0.000 title claims description 47
• MIXZGJHGSYDMRA-UHFFFAOYSA-N 1H-benzo[h][1,6]naphthyridin-2-one Chemical class C1=CC=CC2=C(NC(=O)C=C3)C3=CN=C21 MIXZGJHGSYDMRA-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 352
• 238000000034 method Methods 0.000 claims abstract description 146
• 238000011282 treatment Methods 0.000 claims abstract description 33
• 125000000623 heterocyclic group Chemical group 0.000 claims description 82
• 125000003118 aryl group Chemical group 0.000 claims description 80
• 125000001424 substituent group Chemical group 0.000 claims description 59
• 125000000217 alkyl group Chemical group 0.000 claims description 47
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 46
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 38
• 125000004122 cyclic group Chemical group 0.000 claims description 37
• 125000000304 alkynyl group Chemical group 0.000 claims description 32
• 125000003342 alkenyl group Chemical group 0.000 claims description 30
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
• 125000002947 alkylene group Chemical group 0.000 claims description 20
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 20
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 19
• 150000003839 salts Chemical class 0.000 claims description 18
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 229910052799 carbon Inorganic materials 0.000 claims description 16
• 239000008194 pharmaceutical composition Substances 0.000 claims description 15
• 239000012453 solvate Substances 0.000 claims description 15
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 14
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
• 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 11
• 125000000732 arylene group Chemical group 0.000 claims description 11
• 125000002993 cycloalkylene group Chemical group 0.000 claims description 11
• 150000003573 thiols Chemical class 0.000 claims description 10
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
• 125000005551 pyridylene group Chemical group 0.000 claims description 9
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 9
• 125000006591 (C2-C6) alkynylene group Chemical group 0.000 claims description 8
• 125000004474 heteroalkylene group Chemical group 0.000 claims description 8
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
• 125000004432 carbon atom Chemical group C* 0.000 claims description 6
• 125000005750 substituted cyclic group Chemical group 0.000 claims description 6
• 208000023275 Autoimmune disease Diseases 0.000 claims description 4
• 125000003107 substituted aryl group Chemical group 0.000 claims description 4
• 125000001475 halogen functional group Chemical group 0.000 claims 3
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
• 210000004027 cell Anatomy 0.000 description 107
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 104
• 239000007787 solid Substances 0.000 description 104
• 101000935548 Homo sapiens Cytoplasmic tyrosine-protein kinase BMX Proteins 0.000 description 101
• 102100027907 Cytoplasmic tyrosine-protein kinase BMX Human genes 0.000 description 100
• 238000004896 high resolution mass spectrometry Methods 0.000 description 94
• 238000005160 1H NMR spectroscopy Methods 0.000 description 91
• 239000000203 mixture Substances 0.000 description 62
• 108091000080 Phosphotransferase Proteins 0.000 description 46
• 102000020233 phosphotransferase Human genes 0.000 description 46
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
• SFMJNHNUOVADRW-UHFFFAOYSA-N n-[5-[9-[4-(methanesulfonamido)phenyl]-2-oxobenzo[h][1,6]naphthyridin-1-yl]-2-methylphenyl]prop-2-enamide Chemical compound C1=C(NC(=O)C=C)C(C)=CC=C1N1C(=O)C=CC2=C1C1=CC(C=3C=CC(NS(C)(=O)=O)=CC=3)=CC=C1N=C2 SFMJNHNUOVADRW-UHFFFAOYSA-N 0.000 description 42
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 40
• 230000000694 effects Effects 0.000 description 37
• 108090000765 processed proteins & peptides Proteins 0.000 description 33
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 31
• 239000000543 intermediate Substances 0.000 description 30
• 102000004196 processed proteins & peptides Human genes 0.000 description 30
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 30
• 229920001184 polypeptide Polymers 0.000 description 29
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
• 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 28
• 239000003814 drug Substances 0.000 description 28
• 238000009472 formulation Methods 0.000 description 27
• 102000004169 proteins and genes Human genes 0.000 description 27
• 108090000623 proteins and genes Proteins 0.000 description 27
• 108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 description 26
• 235000018102 proteins Nutrition 0.000 description 26
• 238000004128 high performance liquid chromatography Methods 0.000 description 25
• 229910052757 nitrogen Inorganic materials 0.000 description 25
• 229910001868 water Inorganic materials 0.000 description 25
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 24
• 229920006395 saturated elastomer Polymers 0.000 description 24
• 230000003993 interaction Effects 0.000 description 23
• 238000006243 chemical reaction Methods 0.000 description 22
• 229940079593 drug Drugs 0.000 description 22
• 235000019439 ethyl acetate Nutrition 0.000 description 21
• 239000002243 precursor Substances 0.000 description 21
• -1 PLCy Proteins 0.000 description 20
• 239000003795 chemical substances by application Substances 0.000 description 20
• 230000035699 permeability Effects 0.000 description 19
• 208000000236 Prostatic Neoplasms Diseases 0.000 description 18
• 230000005764 inhibitory process Effects 0.000 description 18
• 239000000243 solution Substances 0.000 description 18
• 206010060862 Prostate cancer Diseases 0.000 description 17
• 238000004458 analytical method Methods 0.000 description 17
• 125000005842 heteroatom Chemical group 0.000 description 17
• 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
• 241000282414 Homo sapiens Species 0.000 description 15
• 239000002904 solvent Substances 0.000 description 15
• 238000003556 assay Methods 0.000 description 14
• 239000000872 buffer Substances 0.000 description 14
• 239000007788 liquid Substances 0.000 description 14
• 125000002950 monocyclic group Chemical group 0.000 description 14
• 230000001028 anti-proliverative effect Effects 0.000 description 13
• RWGYILAQPCSTMT-UHFFFAOYSA-N 9-bromo-1-(4-methyl-3-nitrophenyl)benzo[h][1,6]naphthyridin-2-one Chemical compound Cc1ccc(cc1[N+]([O-])=O)-n1c2c(ccc1=O)cnc1ccc(Br)cc21 RWGYILAQPCSTMT-UHFFFAOYSA-N 0.000 description 12
• 239000013078 crystal Substances 0.000 description 12
• NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 12
• 201000010099 disease Diseases 0.000 description 12
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
• 125000001072 heteroaryl group Chemical group 0.000 description 12
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
• 239000003921 oil Substances 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
• 101000889732 Homo sapiens Tyrosine-protein kinase Tec Proteins 0.000 description 11
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
• 102100040177 Tyrosine-protein kinase Tec Human genes 0.000 description 11
• 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 11
• 108010034265 Vascular Endothelial Growth Factor Receptors Proteins 0.000 description 11
• 150000001721 carbon Chemical group 0.000 description 11
• MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 11
• 239000003446 ligand Substances 0.000 description 11
• 125000004433 nitrogen atom Chemical group N* 0.000 description 11
• 239000012071 phase Substances 0.000 description 11
• UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 11
• MFYSUUPKMDJYPF-UHFFFAOYSA-N 2-[(4-methyl-2-nitrophenyl)diazenyl]-3-oxo-n-phenylbutanamide Chemical compound C=1C=CC=CC=1NC(=O)C(C(=O)C)N=NC1=CC=C(C)C=C1[N+]([O-])=O MFYSUUPKMDJYPF-UHFFFAOYSA-N 0.000 description 10
• QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 10
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
• 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 10
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
• 125000003275 alpha amino acid group Chemical group 0.000 description 10
• 235000001014 amino acid Nutrition 0.000 description 10
• 239000008346 aqueous phase Substances 0.000 description 10
• 229940125846 compound 25 Drugs 0.000 description 10
• 230000009467 reduction Effects 0.000 description 10
• 238000004809 thin layer chromatography Methods 0.000 description 10
• 101000779418 Homo sapiens RAC-alpha serine/threonine-protein kinase Proteins 0.000 description 9
• 150000001412 amines Chemical class 0.000 description 9
• 125000005488 carboaryl group Chemical group 0.000 description 9
• 238000002474 experimental method Methods 0.000 description 9
• 239000004615 ingredient Substances 0.000 description 9
• 238000013149 parallel artificial membrane permeability assay Methods 0.000 description 9
• 238000002360 preparation method Methods 0.000 description 9
• 230000004044 response Effects 0.000 description 9
• 229940124530 sulfonamide Drugs 0.000 description 9
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 9
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
• 150000001413 amino acids Chemical class 0.000 description 8
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 8
• 125000004956 cyclohexylene group Chemical group 0.000 description 8
• 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
• 229960002074 flutamide Drugs 0.000 description 8
• 229910052739 hydrogen Inorganic materials 0.000 description 8
• 230000002401 inhibitory effect Effects 0.000 description 8
• 230000004048 modification Effects 0.000 description 8
• 238000012986 modification Methods 0.000 description 8
• 235000019198 oils Nutrition 0.000 description 8
• 125000004193 piperazinyl group Chemical group 0.000 description 8
• 125000003386 piperidinyl group Chemical group 0.000 description 8
• 238000006467 substitution reaction Methods 0.000 description 8
• 239000000725 suspension Substances 0.000 description 8
• 102100032187 Androgen receptor Human genes 0.000 description 7
• 239000004215 Carbon black (E152) Substances 0.000 description 7
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 7
• 102000042834 TEC family Human genes 0.000 description 7
• 108091082333 TEC family Proteins 0.000 description 7
• 108010009978 Tec protein-tyrosine kinase Proteins 0.000 description 7
• 102100023345 Tyrosine-protein kinase ITK/TSK Human genes 0.000 description 7
• 239000013543 active substance Substances 0.000 description 7
• 230000002776 aggregation Effects 0.000 description 7
• 238000004220 aggregation Methods 0.000 description 7
• 108010080146 androgen receptors Proteins 0.000 description 7
• 239000012267 brine Substances 0.000 description 7
• 239000000969 carrier Substances 0.000 description 7
• 230000003833 cell viability Effects 0.000 description 7
• 238000002022 differential scanning fluorescence spectroscopy Methods 0.000 description 7
• 150000002148 esters Chemical class 0.000 description 7
• 125000005843 halogen group Chemical group 0.000 description 7
• 229930195733 hydrocarbon Natural products 0.000 description 7
• 239000007924 injection Substances 0.000 description 7
• 238000002347 injection Methods 0.000 description 7
• 125000002757 morpholinyl group Chemical group 0.000 description 7
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
• 229910052760 oxygen Inorganic materials 0.000 description 7
• 230000003389 potentiating effect Effects 0.000 description 7
• 230000002062 proliferating effect Effects 0.000 description 7
• 230000035755 proliferation Effects 0.000 description 7
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
• 238000010992 reflux Methods 0.000 description 7
• 239000000523 sample Substances 0.000 description 7
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
• 239000003826 tablet Substances 0.000 description 7
• 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 6
• 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 6
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
• 239000012828 PI3K inhibitor Substances 0.000 description 6
• 108091007960 PI3Ks Proteins 0.000 description 6
• 101150001535 SRC gene Proteins 0.000 description 6
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
• 102100039079 Tyrosine-protein kinase TXK Human genes 0.000 description 6
• 125000004429 atom Chemical group 0.000 description 6
• 230000010261 cell growth Effects 0.000 description 6
• 230000001413 cellular effect Effects 0.000 description 6
• 238000011278 co-treatment Methods 0.000 description 6
• 235000019253 formic acid Nutrition 0.000 description 6
• 238000011534 incubation Methods 0.000 description 6
• 229940043355 kinase inhibitor Drugs 0.000 description 6
• 125000005647 linker group Chemical group 0.000 description 6
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
• 239000003757 phosphotransferase inhibitor Substances 0.000 description 6
• 229910000027 potassium carbonate Inorganic materials 0.000 description 6
• 239000000843 powder Substances 0.000 description 6
• 210000002307 prostate Anatomy 0.000 description 6
• 150000005299 pyridinones Chemical group 0.000 description 6
• 125000006413 ring segment Chemical group 0.000 description 6
• 230000019491 signal transduction Effects 0.000 description 6
• 239000007858 starting material Substances 0.000 description 6
• 150000003456 sulfonamides Chemical group 0.000 description 6
• 229910052717 sulfur Inorganic materials 0.000 description 6
• 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 6
• 238000002560 therapeutic procedure Methods 0.000 description 6
• 229940124291 BTK inhibitor Drugs 0.000 description 5
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 5
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
• 102000001253 Protein Kinase Human genes 0.000 description 5
• 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 5
• 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 5
• LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 5
• HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 5
• 239000000853 adhesive Substances 0.000 description 5
• 230000001070 adhesive effect Effects 0.000 description 5
• 239000000443 aerosol Substances 0.000 description 5
• 230000006907 apoptotic process Effects 0.000 description 5
• XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 5
• 210000000481 breast Anatomy 0.000 description 5
• 239000011203 carbon fibre reinforced carbon Substances 0.000 description 5
• 229940125961 compound 24 Drugs 0.000 description 5
• 229940127204 compound 29 Drugs 0.000 description 5
• 239000000356 contaminant Substances 0.000 description 5
• 239000006071 cream Substances 0.000 description 5
• XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 5
• 235000018417 cysteine Nutrition 0.000 description 5
• 230000007423 decrease Effects 0.000 description 5
• 230000001419 dependent effect Effects 0.000 description 5
• 238000011161 development Methods 0.000 description 5
• 230000018109 developmental process Effects 0.000 description 5
• 238000002296 dynamic light scattering Methods 0.000 description 5
• 239000003995 emulsifying agent Substances 0.000 description 5
• 239000000839 emulsion Substances 0.000 description 5
• YGMLKBFPHVLHGT-UHFFFAOYSA-N ethyl 6-bromo-4-chloroquinoline-3-carboxylate Chemical compound C1=CC(Br)=CC2=C(Cl)C(C(=O)OCC)=CN=C21 YGMLKBFPHVLHGT-UHFFFAOYSA-N 0.000 description 5
• 239000003925 fat Substances 0.000 description 5
• 235000019197 fats Nutrition 0.000 description 5
• 125000005549 heteroarylene group Chemical group 0.000 description 5
• 239000001257 hydrogen Substances 0.000 description 5
• 230000006872 improvement Effects 0.000 description 5
• 230000003834 intracellular effect Effects 0.000 description 5
• 230000002427 irreversible effect Effects 0.000 description 5
• 210000004072 lung Anatomy 0.000 description 5
• 230000007246 mechanism Effects 0.000 description 5
• 238000002844 melting Methods 0.000 description 5
• 230000008018 melting Effects 0.000 description 5
• 235000010603 pastilles Nutrition 0.000 description 5
• 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 5
• 108060006633 protein kinase Proteins 0.000 description 5
• 239000003197 protein kinase B inhibitor Substances 0.000 description 5
• 238000000746 purification Methods 0.000 description 5
• 125000004076 pyridyl group Chemical group 0.000 description 5
• 125000005756 tetralinylene group Chemical group 0.000 description 5
• 125000004568 thiomorpholinyl group Chemical group 0.000 description 5
• 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 5
• UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 4
• 102100037263 3-phosphoinositide-dependent protein kinase 1 Human genes 0.000 description 4
• GIUZUAUCCUFVKW-UHFFFAOYSA-N 6-bromo-4-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=C(Br)C=C2C(=O)C(C(=O)O)=CNC2=C1 GIUZUAUCCUFVKW-UHFFFAOYSA-N 0.000 description 4
• 229940126638 Akt inhibitor Drugs 0.000 description 4
• RFXPTYOCUAASDB-UHFFFAOYSA-N C(C=C)(=O)NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NC(OC)=O)=O Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NC(OC)=O)=O RFXPTYOCUAASDB-UHFFFAOYSA-N 0.000 description 4
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
• WPVJPKXENBARHX-UHFFFAOYSA-N CC=1C=C(C=C(C=1)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)NC(C=C)=O Chemical compound CC=1C=C(C=C(C=1)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)NC(C=C)=O WPVJPKXENBARHX-UHFFFAOYSA-N 0.000 description 4
• 101000600756 Homo sapiens 3-phosphoinositide-dependent protein kinase 1 Proteins 0.000 description 4
• 101000598921 Homo sapiens Orexin Proteins 0.000 description 4
• 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 4
• 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 description 4
• 241001465754 Metazoa Species 0.000 description 4
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
• 241000283984 Rodentia Species 0.000 description 4
• 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 4
• ZKYSAKOTKXUGEO-UHFFFAOYSA-N [N+](=O)([O-])C=1C=C(C=CC=1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O Chemical compound [N+](=O)([O-])C=1C=C(C=CC=1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O ZKYSAKOTKXUGEO-UHFFFAOYSA-N 0.000 description 4
• ZSEUEKCXNXRIKT-UHFFFAOYSA-N [N].O=C1C=CC=CN1 Chemical group [N].O=C1C=CC=CN1 ZSEUEKCXNXRIKT-UHFFFAOYSA-N 0.000 description 4
• 230000010933 acylation Effects 0.000 description 4
• 238000005917 acylation reaction Methods 0.000 description 4
• 150000001299 aldehydes Chemical class 0.000 description 4
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 4
• 125000000539 amino acid group Chemical group 0.000 description 4
• 230000008901 benefit Effects 0.000 description 4
• 239000011230 binding agent Substances 0.000 description 4
• 230000015572 biosynthetic process Effects 0.000 description 4
• 238000012054 celltiter-glo Methods 0.000 description 4
• 238000002425 crystallisation Methods 0.000 description 4
• 230000008025 crystallization Effects 0.000 description 4
• 125000004979 cyclopentylene group Chemical group 0.000 description 4
• 230000003013 cytotoxicity Effects 0.000 description 4
• 231100000135 cytotoxicity Toxicity 0.000 description 4
• 125000005754 decalinylene group Chemical group 0.000 description 4
• 239000003085 diluting agent Substances 0.000 description 4
• 238000007876 drug discovery Methods 0.000 description 4
• 238000007824 enzymatic assay Methods 0.000 description 4
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 4
• 239000000499 gel Substances 0.000 description 4
• 239000001963 growth medium Substances 0.000 description 4
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
• 150000002500 ions Chemical class 0.000 description 4
• 239000000463 material Substances 0.000 description 4
• 239000011159 matrix material Substances 0.000 description 4
• LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
• 239000002324 mouth wash Substances 0.000 description 4
• 239000002674 ointment Substances 0.000 description 4
• 125000002971 oxazolyl group Chemical group 0.000 description 4
• 230000003647 oxidation Effects 0.000 description 4
• 238000007254 oxidation reaction Methods 0.000 description 4
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
• 239000002245 particle Substances 0.000 description 4
• 239000006072 paste Substances 0.000 description 4
• 230000037361 pathway Effects 0.000 description 4
• 239000013610 patient sample Substances 0.000 description 4
• 235000015320 potassium carbonate Nutrition 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
• LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical group C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 4
• 230000035484 reaction time Effects 0.000 description 4
• 238000012216 screening Methods 0.000 description 4
• 239000007921 spray Substances 0.000 description 4
• 239000003381 stabilizer Substances 0.000 description 4
• 238000005556 structure-activity relationship Methods 0.000 description 4
• 239000000126 substance Substances 0.000 description 4
• 239000000829 suppository Substances 0.000 description 4
• 230000004083 survival effect Effects 0.000 description 4
• 238000004885 tandem mass spectrometry Methods 0.000 description 4
• 238000012360 testing method Methods 0.000 description 4
• 230000001225 therapeutic effect Effects 0.000 description 4
• 210000001519 tissue Anatomy 0.000 description 4
• GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 4
• 239000003981 vehicle Substances 0.000 description 4
• HPJGEESDHAUUQR-SKGSPYGFSA-N (2s)-2-[[(2s)-5-(diaminomethylideneamino)-2-[[(2s)-1-[(2s)-5-(diaminomethylideneamino)-2-[[(2s)-2-[[(2s)-3-naphthalen-2-yl-2-(3-pyridin-3-ylpropanoylamino)propanoyl]amino]-3-phenylpropanoyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]buta Chemical compound NC(=O)C[C@@H](C(N)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=C2C=CC=CC2=CC=1)NC(=O)CCC=1C=NC=CC=1)CC1=CC=CC=C1 HPJGEESDHAUUQR-SKGSPYGFSA-N 0.000 description 3
• 125000006656 (C2-C4) alkenyl group Chemical group 0.000 description 3
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 3
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 3
• 125000006713 (C5-C10) cycloalkyl group Chemical group 0.000 description 3
• WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 3
• ZZAKLGGGMWORRT-UHFFFAOYSA-N 1-methylsulfonylpiperazine Chemical compound CS(=O)(=O)N1CCNCC1 ZZAKLGGGMWORRT-UHFFFAOYSA-N 0.000 description 3
• TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 3
• JXNDRJOKVJEQMU-UHFFFAOYSA-N 6-bromo-4-(4-methyl-3-nitroanilino)quinoline-3-carbaldehyde Chemical compound C1=C([N+]([O-])=O)C(C)=CC=C1NC1=C(C=O)C=NC2=CC=C(Br)C=C12 JXNDRJOKVJEQMU-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
• RTNNYKCMUGQKQC-UHFFFAOYSA-N 9-bromo-1-(3-nitrophenyl)benzo[h][1,6]naphthyridin-2-one Chemical compound BrC1=CC=2C(=NC=C3C=CC(N(C=23)C2=CC(=CC=C2)[N+](=O)[O-])=O)C=C1 RTNNYKCMUGQKQC-UHFFFAOYSA-N 0.000 description 3
• HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 3
• 229940123407 Androgen receptor antagonist Drugs 0.000 description 3
• FNVNEQXNFJYWKF-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC=1)C(=O)OCC)NC1=C(C=CC(=C1)[N+](=O)[O-])C Chemical compound BrC=1C=C2C(=C(C=NC2=CC=1)C(=O)OCC)NC1=C(C=CC(=C1)[N+](=O)[O-])C FNVNEQXNFJYWKF-UHFFFAOYSA-N 0.000 description 3
• CGEXTBHYDHMSIN-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC=1)C(=O)OCC)NC1=CC(=C(C=C1)OC)[N+](=O)[O-] Chemical compound BrC=1C=C2C(=C(C=NC2=CC=1)C(=O)OCC)NC1=CC(=C(C=C1)OC)[N+](=O)[O-] CGEXTBHYDHMSIN-UHFFFAOYSA-N 0.000 description 3
• 206010006187 Breast cancer Diseases 0.000 description 3
• 208000026310 Breast neoplasm Diseases 0.000 description 3
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 3
• KSJFMGNMWAVDBQ-UHFFFAOYSA-N CC(=CC(=O)NC1=C(C=CC(=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)C)C Chemical compound CC(=CC(=O)NC1=C(C=CC(=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)C)C KSJFMGNMWAVDBQ-UHFFFAOYSA-N 0.000 description 3
• HINYJQMODRRGRL-UHFFFAOYSA-N CN(C1CCN(CC1)C1=CC=2C(=NC=C3C=CC(N(C=23)C=2C=CC(=C(C=2)NC(C=C)=O)C)=O)C=C1)C Chemical compound CN(C1CCN(CC1)C1=CC=2C(=NC=C3C=CC(N(C=23)C=2C=CC(=C(C=2)NC(C=C)=O)C)=O)C=C1)C HINYJQMODRRGRL-UHFFFAOYSA-N 0.000 description 3
• MJAVOJRRICMORF-UHFFFAOYSA-N COC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)NC(C=C)=O Chemical compound COC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)NC(C=C)=O MJAVOJRRICMORF-UHFFFAOYSA-N 0.000 description 3
• BBPCMUWBZJCOKJ-UHFFFAOYSA-N CS(=O)(=O)NC1=CC=C(C=C1)C1=CC=2C(=NC=C3C=CC(N(C=23)C=2C=C(C=CC=2)NC(C=C)=O)=O)C=C1 Chemical compound CS(=O)(=O)NC1=CC=C(C=C1)C1=CC=2C(=NC=C3C=CC(N(C=23)C=2C=C(C=CC=2)NC(C=C)=O)=O)C=C1 BBPCMUWBZJCOKJ-UHFFFAOYSA-N 0.000 description 3
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
• 102000004190 Enzymes Human genes 0.000 description 3
• 108090000790 Enzymes Proteins 0.000 description 3
• 239000005977 Ethylene Substances 0.000 description 3
• 102100037813 Focal adhesion kinase 1 Human genes 0.000 description 3
• 101000878536 Homo sapiens Focal adhesion kinase 1 Proteins 0.000 description 3
• 101000628562 Homo sapiens Serine/threonine-protein kinase STK11 Proteins 0.000 description 3
• 101000984551 Homo sapiens Tyrosine-protein kinase Blk Proteins 0.000 description 3
• 102000042838 JAK family Human genes 0.000 description 3
• 108091082332 JAK family Proteins 0.000 description 3
• 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 3
• PUWJBNVCXXCOKJ-UHFFFAOYSA-N N-[4-[1-(4-methyl-3-nitrophenyl)-2-oxobenzo[h][1,6]naphthyridin-9-yl]phenyl]methanesulfonamide Chemical compound Cc1ccc(cc1[N+]([O-])=O)-n1c2c(ccc1=O)cnc1ccc(cc21)-c1ccc(NS(C)(=O)=O)cc1 PUWJBNVCXXCOKJ-UHFFFAOYSA-N 0.000 description 3
• VABXRGWQBXTUOA-UHFFFAOYSA-N NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)N1CCN(CC1)S(=O)(=O)C)=O Chemical compound NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)N1CCN(CC1)S(=O)(=O)C)=O VABXRGWQBXTUOA-UHFFFAOYSA-N 0.000 description 3
• 108700020796 Oncogene Proteins 0.000 description 3
• YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 3
• 102000001708 Protein Isoforms Human genes 0.000 description 3
• 108010029485 Protein Isoforms Proteins 0.000 description 3
• 102100026715 Serine/threonine-protein kinase STK11 Human genes 0.000 description 3
• 238000006069 Suzuki reaction reaction Methods 0.000 description 3
• 102100027053 Tyrosine-protein kinase Blk Human genes 0.000 description 3
• 239000002253 acid Substances 0.000 description 3
• 150000001263 acyl chlorides Chemical class 0.000 description 3
• 150000001408 amides Chemical class 0.000 description 3
• 239000003936 androgen receptor antagonist Substances 0.000 description 3
• 230000000840 anti-viral effect Effects 0.000 description 3
• 239000002246 antineoplastic agent Substances 0.000 description 3
• 238000013459 approach Methods 0.000 description 3
• 229910052786 argon Inorganic materials 0.000 description 3
• 230000004071 biological effect Effects 0.000 description 3
• 210000004369 blood Anatomy 0.000 description 3
• 239000008280 blood Substances 0.000 description 3
• 238000006664 bond formation reaction Methods 0.000 description 3
• 210000001185 bone marrow Anatomy 0.000 description 3
• ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 3
• 210000004556 brain Anatomy 0.000 description 3
• 238000004422 calculation algorithm Methods 0.000 description 3
• 239000002775 capsule Substances 0.000 description 3
• 230000030833 cell death Effects 0.000 description 3
• 210000000170 cell membrane Anatomy 0.000 description 3
• 229960003677 chloroquine Drugs 0.000 description 3
• WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 3
• 210000001072 colon Anatomy 0.000 description 3
• 238000011284 combination treatment Methods 0.000 description 3
• 229940125851 compound 27 Drugs 0.000 description 3
• 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 3
• 238000010790 dilution Methods 0.000 description 3
• 239000012895 dilution Substances 0.000 description 3
• 238000006073 displacement reaction Methods 0.000 description 3
• 238000010494 dissociation reaction Methods 0.000 description 3
• 230000005593 dissociations Effects 0.000 description 3
• 239000006196 drop Substances 0.000 description 3
• 239000003937 drug carrier Substances 0.000 description 3
• 230000009977 dual effect Effects 0.000 description 3
• 239000000975 dye Substances 0.000 description 3
• 238000005516 engineering process Methods 0.000 description 3
• DTZJZEWVCXUFAZ-UHFFFAOYSA-N ethyl 6-bromo-4-(4-methyl-3-nitroanilino)quinoline-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2C=CC(Br)=CC2=C1NC1=CC=C(C)C([N+]([O-])=O)=C1 DTZJZEWVCXUFAZ-UHFFFAOYSA-N 0.000 description 3
• 125000001153 fluoro group Chemical group F* 0.000 description 3
• 239000008187 granular material Substances 0.000 description 3
• 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 3
• 230000002209 hydrophobic effect Effects 0.000 description 3
• 238000000126 in silico method Methods 0.000 description 3
• 238000000338 in vitro Methods 0.000 description 3
• 238000001727 in vivo Methods 0.000 description 3
• 230000000155 isotopic effect Effects 0.000 description 3
• 238000000021 kinase assay Methods 0.000 description 3
• 150000002634 lipophilic molecules Chemical class 0.000 description 3
• 239000006210 lotion Substances 0.000 description 3
• 238000004949 mass spectrometry Methods 0.000 description 3
• 230000001404 mediated effect Effects 0.000 description 3
• 239000012528 membrane Substances 0.000 description 3
• 238000003032 molecular docking Methods 0.000 description 3
• HBEDNENASUYMPO-LJQANCHMSA-N n-hydroxy-4-[[(2r)-3-oxo-2-(thiophen-2-ylmethyl)-2,4-dihydroquinoxalin-1-yl]methyl]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1CN1C2=CC=CC=C2NC(=O)[C@H]1CC1=CC=CS1 HBEDNENASUYMPO-LJQANCHMSA-N 0.000 description 3
• 125000001624 naphthyl group Chemical group 0.000 description 3
• 230000009826 neoplastic cell growth Effects 0.000 description 3
• 239000006187 pill Substances 0.000 description 3
• 239000011505 plaster Substances 0.000 description 3
• 238000012746 preparative thin layer chromatography Methods 0.000 description 3
• 230000008569 process Effects 0.000 description 3
• 239000000651 prodrug Substances 0.000 description 3
• 229940002612 prodrug Drugs 0.000 description 3
• 239000000047 product Substances 0.000 description 3
• 230000002685 pulmonary effect Effects 0.000 description 3
• 125000003226 pyrazolyl group Chemical group 0.000 description 3
• 125000000168 pyrrolyl group Chemical group 0.000 description 3
• 238000011160 research Methods 0.000 description 3
• 206010039073 rheumatoid arthritis Diseases 0.000 description 3
• 238000007363 ring formation reaction Methods 0.000 description 3
• 230000011664 signaling Effects 0.000 description 3
• 239000000741 silica gel Substances 0.000 description 3
• 229910002027 silica gel Inorganic materials 0.000 description 3
• 229960001866 silicon dioxide Drugs 0.000 description 3
• 239000000377 silicon dioxide Substances 0.000 description 3
• 229910000033 sodium borohydride Inorganic materials 0.000 description 3
• 239000012279 sodium borohydride Substances 0.000 description 3
• 125000000565 sulfonamide group Chemical group 0.000 description 3
• 229940124597 therapeutic agent Drugs 0.000 description 3
• 125000001544 thienyl group Chemical group 0.000 description 3
• 238000011144 upstream manufacturing Methods 0.000 description 3
• SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
• KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 2
• PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 description 2
• FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 2
• UXKLQDCALAWFIU-VKNDCNMPSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-tetradecoxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCCCC)C1=CC=CC=C1 UXKLQDCALAWFIU-VKNDCNMPSA-N 0.000 description 2
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
• UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
• LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
• HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
• QLVGHFBUSGYCCG-UHFFFAOYSA-N 2-amino-n-(1-cyano-2-phenylethyl)acetamide Chemical compound NCC(=O)NC(C#N)CC1=CC=CC=C1 QLVGHFBUSGYCCG-UHFFFAOYSA-N 0.000 description 2
• QKJAZPHKNWSXDF-UHFFFAOYSA-N 2-bromoquinoline Chemical compound C1=CC=CC2=NC(Br)=CC=C21 QKJAZPHKNWSXDF-UHFFFAOYSA-N 0.000 description 2
• DZIJEXQVMORGQX-UHFFFAOYSA-N 3-methyl-5-nitroaniline Chemical compound CC1=CC(N)=CC([N+]([O-])=O)=C1 DZIJEXQVMORGQX-UHFFFAOYSA-N 0.000 description 2
• XJCVRTZCHMZPBD-UHFFFAOYSA-N 3-nitroaniline Chemical compound NC1=CC=CC([N+]([O-])=O)=C1 XJCVRTZCHMZPBD-UHFFFAOYSA-N 0.000 description 2
• GDIIPKWHAQGCJF-UHFFFAOYSA-N 4-Amino-2-nitrotoluene Chemical compound CC1=CC=C(N)C=C1[N+]([O-])=O GDIIPKWHAQGCJF-UHFFFAOYSA-N 0.000 description 2
• WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 2
• SMJAOUCQUQYLOP-UHFFFAOYSA-N 9-bromo-1-(2-methyl-5-nitrophenyl)benzo[h][1,6]naphthyridin-2-one Chemical compound BrC1=CC=2C(=NC=C3C=CC(N(C=23)C2=C(C=CC(=C2)[N+](=O)[O-])C)=O)C=C1 SMJAOUCQUQYLOP-UHFFFAOYSA-N 0.000 description 2
• CEXJZGSMBSPAEL-UHFFFAOYSA-N 9-bromo-1-(3-methyl-5-nitrophenyl)benzo[h][1,6]naphthyridin-2-one Chemical compound BrC1=CC=2C(=NC=C3C=CC(N(C=23)C2=CC(=CC(=C2)[N+](=O)[O-])C)=O)C=C1 CEXJZGSMBSPAEL-UHFFFAOYSA-N 0.000 description 2
• UEVJPKGDEQQFLO-UHFFFAOYSA-N 9-bromo-1-(4-methoxy-3-nitrophenyl)benzo[h][1,6]naphthyridin-2-one Chemical compound BrC1=CC=2C(=NC=C3C=CC(N(C=23)C2=CC(=C(C=C2)OC)[N+](=O)[O-])=O)C=C1 UEVJPKGDEQQFLO-UHFFFAOYSA-N 0.000 description 2
• 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 2
• 241000283690 Bos taurus Species 0.000 description 2
• UIASHVHHFRTXLB-UHFFFAOYSA-N BrC1=CC=2C(=NC=C3C=CC(N(C=23)C=2C=CC(=C(C=2)NC(C=C)=O)C)=O)C=C1 Chemical compound BrC1=CC=2C(=NC=C3C=CC(N(C=23)C=2C=CC(=C(C=2)NC(C=C)=O)C)=O)C=C1 UIASHVHHFRTXLB-UHFFFAOYSA-N 0.000 description 2
• AYRAUPKNSXZMFB-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC=1)C(=O)OCC)NC1=CC(=CC(=C1)[N+](=O)[O-])C Chemical compound BrC=1C=C2C(=C(C=NC2=CC=1)C(=O)OCC)NC1=CC(=CC(=C1)[N+](=O)[O-])C AYRAUPKNSXZMFB-UHFFFAOYSA-N 0.000 description 2
• XJYOKJPPNHASSD-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC=1)C=O)NC1=C(C=CC(=C1)[N+](=O)[O-])C Chemical compound BrC=1C=C2C(=C(C=NC2=CC=1)C=O)NC1=C(C=CC(=C1)[N+](=O)[O-])C XJYOKJPPNHASSD-UHFFFAOYSA-N 0.000 description 2
• YVKUGKROARIGES-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC=1)C=O)NC1=CC(=C(C=C1)OC)[N+](=O)[O-] Chemical compound BrC=1C=C2C(=C(C=NC2=CC=1)C=O)NC1=CC(=C(C=C1)OC)[N+](=O)[O-] YVKUGKROARIGES-UHFFFAOYSA-N 0.000 description 2
• JYLGAEMBWADJCH-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC=1)C=O)NC1=CC(=CC(=C1)[N+](=O)[O-])C Chemical compound BrC=1C=C2C(=C(C=NC2=CC=1)C=O)NC1=CC(=CC(=C1)[N+](=O)[O-])C JYLGAEMBWADJCH-UHFFFAOYSA-N 0.000 description 2
• FYYUKABZUYYYDD-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC=1)C=O)NC1=CC(=CC=C1)[N+](=O)[O-] Chemical compound BrC=1C=C2C(=C(C=NC2=CC=1)C=O)NC1=CC(=CC=C1)[N+](=O)[O-] FYYUKABZUYYYDD-UHFFFAOYSA-N 0.000 description 2
• DGGWNBGYZKPRBR-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC=1)CO)NC1=C(C=CC(=C1)[N+](=O)[O-])C Chemical compound BrC=1C=C2C(=C(C=NC2=CC=1)CO)NC1=C(C=CC(=C1)[N+](=O)[O-])C DGGWNBGYZKPRBR-UHFFFAOYSA-N 0.000 description 2
• NPEMKWFJVIDNSA-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC=1)CO)NC1=CC(=C(C=C1)OC)[N+](=O)[O-] Chemical compound BrC=1C=C2C(=C(C=NC2=CC=1)CO)NC1=CC(=C(C=C1)OC)[N+](=O)[O-] NPEMKWFJVIDNSA-UHFFFAOYSA-N 0.000 description 2
• FUCOIMHOPWFZPA-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC=1)CO)NC1=CC(=CC(=C1)[N+](=O)[O-])C Chemical compound BrC=1C=C2C(=C(C=NC2=CC=1)CO)NC1=CC(=CC(=C1)[N+](=O)[O-])C FUCOIMHOPWFZPA-UHFFFAOYSA-N 0.000 description 2
• UMHLIZGDDOSWMA-UHFFFAOYSA-N BrC=1C=C2C(=C(C=NC2=CC=1)CO)NC1=CC(=CC=C1)[N+](=O)[O-] Chemical compound BrC=1C=C2C(=C(C=NC2=CC=1)CO)NC1=CC(=CC=C1)[N+](=O)[O-] UMHLIZGDDOSWMA-UHFFFAOYSA-N 0.000 description 2
• 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 2
• CWCZFOMTFDHPSI-UHFFFAOYSA-N C(#N)C1=CC=C(C=N1)C1=CC=2C(=NC=C3C=CC(N(C=23)C=2C=CC(=C(C=2)NC(C=C)=O)C)=O)C=C1 Chemical compound C(#N)C1=CC=C(C=N1)C1=CC=2C(=NC=C3C=CC(N(C=23)C=2C=CC(=C(C=2)NC(C=C)=O)C)=O)C=C1 CWCZFOMTFDHPSI-UHFFFAOYSA-N 0.000 description 2
• HLACTDPSFOXFNB-UHFFFAOYSA-N C(C=C)(=O)NC=1C=C(C=CC=1C)NC1=C(C=NC2=CC=C(C=C12)C1=CC=C(C=C1)NS(=O)(=O)C)C(=O)OCC Chemical compound C(C=C)(=O)NC=1C=C(C=CC=1C)NC1=C(C=NC2=CC=C(C=C12)C1=CC=C(C=C1)NS(=O)(=O)C)C(=O)OCC HLACTDPSFOXFNB-UHFFFAOYSA-N 0.000 description 2
• HGBFITWKAOFFRL-UHFFFAOYSA-N C(CCC)S(=O)(=O)NC1=CC=C(C=C1)C1=CC=2C(=NC=C3C=CC(N(C=23)C=2C=CC(=C(C=2)NC(C=C)=O)C)=O)C=C1 Chemical compound C(CCC)S(=O)(=O)NC1=CC=C(C=C1)C1=CC=2C(=NC=C3C=CC(N(C=23)C=2C=CC(=C(C=2)NC(C=C)=O)C)=O)C=C1 HGBFITWKAOFFRL-UHFFFAOYSA-N 0.000 description 2
• TYABBKIYDGDGBH-UHFFFAOYSA-N CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC(=CC=C1)NS(=O)(=O)C)=O)NC(C=C)=O Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC(=CC=C1)NS(=O)(=O)C)=O)NC(C=C)=O TYABBKIYDGDGBH-UHFFFAOYSA-N 0.000 description 2
• BFPJXQKXCPNDJD-UHFFFAOYSA-N CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C=1C=NC(=CC=1)C(F)(F)F)=O)NC(C=C)=O Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C=1C=NC(=CC=1)C(F)(F)F)=O)NC(C=C)=O BFPJXQKXCPNDJD-UHFFFAOYSA-N 0.000 description 2
• ZXAZBZOJJUTDCT-UHFFFAOYSA-N CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)N1CCN(CC1)S(=O)(=O)C)=O)NC(C=C)=O Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)N1CCN(CC1)S(=O)(=O)C)=O)NC(C=C)=O ZXAZBZOJJUTDCT-UHFFFAOYSA-N 0.000 description 2
• HMANUVXQDISNEN-UHFFFAOYSA-N CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)NC(C=C)=O Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)NC(C=C)=O HMANUVXQDISNEN-UHFFFAOYSA-N 0.000 description 2
• RPMADVRTXSLERW-UHFFFAOYSA-N CC1=C(C=C(C=C1)NC(C=C)=O)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O Chemical compound CC1=C(C=C(C=C1)NC(C=C)=O)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O RPMADVRTXSLERW-UHFFFAOYSA-N 0.000 description 2
• HCTPGYJEMSKQKB-UHFFFAOYSA-N CC1=C(C=C(C=C1)[N+](=O)[O-])N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O Chemical compound CC1=C(C=C(C=C1)[N+](=O)[O-])N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O HCTPGYJEMSKQKB-UHFFFAOYSA-N 0.000 description 2
• AOMANNMQWBHHJS-UHFFFAOYSA-N CC=1C=C(C=C(C=1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)NC(C=C)=O Chemical compound CC=1C=C(C=C(C=1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)NC(C=C)=O AOMANNMQWBHHJS-UHFFFAOYSA-N 0.000 description 2
• CBMMZYMIUHNOKI-UHFFFAOYSA-N CC=1C=C(C=C(C=1)[N+](=O)[O-])N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O Chemical compound CC=1C=C(C=C(C=1)[N+](=O)[O-])N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O CBMMZYMIUHNOKI-UHFFFAOYSA-N 0.000 description 2
• FGISVCWODHCHDN-UHFFFAOYSA-N COC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)[N+](=O)[O-] Chemical compound COC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)[N+](=O)[O-] FGISVCWODHCHDN-UHFFFAOYSA-N 0.000 description 2
• VKNNSLCHRXECPH-UHFFFAOYSA-N CS(=O)(=O)N1CCN(CC1)C=1C=CC=2C(=NC=C3C=CC(N(C=23)C=2C=C(C=CC=2)NC(C=C)=O)=O)C=1 Chemical compound CS(=O)(=O)N1CCN(CC1)C=1C=CC=2C(=NC=C3C=CC(N(C=23)C=2C=C(C=CC=2)NC(C=C)=O)=O)C=1 VKNNSLCHRXECPH-UHFFFAOYSA-N 0.000 description 2
• VUCJXAVLLNQNRN-UHFFFAOYSA-N CS(=O)(=O)NC1=CC=C(C=C1)C=1C=CC=2C(=NC=C3C=CC(N(C=23)C=2C=C(C=CC=2)NC(C=C)=O)=O)C=1 Chemical compound CS(=O)(=O)NC1=CC=C(C=C1)C=1C=CC=2C(=NC=C3C=CC(N(C=23)C=2C=C(C=CC=2)NC(C=C)=O)=O)C=1 VUCJXAVLLNQNRN-UHFFFAOYSA-N 0.000 description 2
• 241000282693 Cercopithecidae Species 0.000 description 2
• 206010008342 Cervix carcinoma Diseases 0.000 description 2
• 206010009944 Colon cancer Diseases 0.000 description 2
• XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
• ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 2
• 102100023332 Dual specificity mitogen-activated protein kinase kinase 7 Human genes 0.000 description 2
• 241000792859 Enema Species 0.000 description 2
• 241000283073 Equus caballus Species 0.000 description 2
• 102100028043 Fibroblast growth factor 3 Human genes 0.000 description 2
• 239000007995 HEPES buffer Substances 0.000 description 2
• 229940125497 HER2 kinase inhibitor Drugs 0.000 description 2
• 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 2
• 108050002021 Integrator complex subunit 2 Proteins 0.000 description 2
• 101710092886 Integrator complex subunit 3 Proteins 0.000 description 2
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
• 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
• 239000002067 L01XE06 - Dasatinib Substances 0.000 description 2
• 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
• 240000007472 Leucaena leucocephala Species 0.000 description 2
• 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
• 206010025323 Lymphomas Diseases 0.000 description 2
• 241000699666 Mus <mouse, genus> Species 0.000 description 2
• RLXHAMNOGNRZLD-UHFFFAOYSA-N N-[4-[1-(3-amino-4-methylphenyl)-2-oxobenzo[h][1,6]naphthyridin-9-yl]phenyl]methanesulfonamide Chemical compound Cc1ccc(cc1N)-n1c2c(ccc1=O)cnc1ccc(cc21)-c1ccc(NS(C)(=O)=O)cc1 RLXHAMNOGNRZLD-UHFFFAOYSA-N 0.000 description 2
• MWRYEVZCHYQCRO-UHFFFAOYSA-N N-[5-[9-[4-(methanesulfonamido)phenyl]-2-oxobenzo[h][1,6]naphthyridin-1-yl]-2-methylphenyl]but-2-enamide Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)NC(C=CC)=O MWRYEVZCHYQCRO-UHFFFAOYSA-N 0.000 description 2
• TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 2
• TZCCKCLHNUSAMQ-DUGSHLAESA-N NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N Chemical compound NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N TZCCKCLHNUSAMQ-DUGSHLAESA-N 0.000 description 2
• AWUHKEQCXFMJHR-UHFFFAOYSA-N NC=1C=C(C=C(C=1)C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O Chemical compound NC=1C=C(C=C(C=1)C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O AWUHKEQCXFMJHR-UHFFFAOYSA-N 0.000 description 2
• UUVYAWQJYHNVFI-UHFFFAOYSA-N NC=1C=C(C=CC=1OC)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O Chemical compound NC=1C=C(C=CC=1OC)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O UUVYAWQJYHNVFI-UHFFFAOYSA-N 0.000 description 2
• VSTFGNAYFUAJRJ-UHFFFAOYSA-N NC=1C=CC(=C(C=1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)C Chemical compound NC=1C=CC(=C(C=1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)C VSTFGNAYFUAJRJ-UHFFFAOYSA-N 0.000 description 2
• 102100025254 Neurogenic locus notch homolog protein 4 Human genes 0.000 description 2
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
• 241000920340 Pion Species 0.000 description 2
• 108091008611 Protein Kinase B Proteins 0.000 description 2
• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
• 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
• 241000700159 Rattus Species 0.000 description 2
• VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
• 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 2
• 229930006000 Sucrose Natural products 0.000 description 2
• 101710086214 Tyrosine-protein kinase BTK Proteins 0.000 description 2
• 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
• 238000002441 X-ray diffraction Methods 0.000 description 2
• UDIDKECKYFSPQJ-UHFFFAOYSA-N [6-bromo-4-(4-methyl-3-nitroanilino)quinolin-3-yl]methanol Chemical compound C1=C([N+]([O-])=O)C(C)=CC=C1NC1=C(CO)C=NC2=CC=C(Br)C=C12 UDIDKECKYFSPQJ-UHFFFAOYSA-N 0.000 description 2
• CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 2
• 150000007513 acids Chemical class 0.000 description 2
• 230000004913 activation Effects 0.000 description 2
• 150000001298 alcohols Chemical class 0.000 description 2
• 150000001336 alkenes Chemical class 0.000 description 2
• 230000029936 alkylation Effects 0.000 description 2
• 238000005804 alkylation reaction Methods 0.000 description 2
• 125000003277 amino group Chemical group 0.000 description 2
• 239000003963 antioxidant agent Substances 0.000 description 2
• 235000006708 antioxidants Nutrition 0.000 description 2
• 239000003125 aqueous solvent Substances 0.000 description 2
• 239000000823 artificial membrane Substances 0.000 description 2
• 125000002619 bicyclic group Chemical group 0.000 description 2
• 125000001246 bromo group Chemical group Br* 0.000 description 2
• 244000309464 bull Species 0.000 description 2
• OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
• 229910002092 carbon dioxide Inorganic materials 0.000 description 2
• 201000010881 cervical cancer Diseases 0.000 description 2
• 125000001309 chloro group Chemical group Cl* 0.000 description 2
• 210000000349 chromosome Anatomy 0.000 description 2
• 208000029742 colonic neoplasm Diseases 0.000 description 2
• 238000004440 column chromatography Methods 0.000 description 2
• 238000002648 combination therapy Methods 0.000 description 2
• 230000000052 comparative effect Effects 0.000 description 2
• 230000001447 compensatory effect Effects 0.000 description 2
• 229940125773 compound 10 Drugs 0.000 description 2
• 229940126543 compound 14 Drugs 0.000 description 2
• 229940125796 compound 3d Drugs 0.000 description 2
• 229940125872 compound 4d Drugs 0.000 description 2
• 230000021615 conjugation Effects 0.000 description 2
• 230000008878 coupling Effects 0.000 description 2
• 238000010168 coupling process Methods 0.000 description 2
• 238000005859 coupling reaction Methods 0.000 description 2
• 230000007402 cytotoxic response Effects 0.000 description 2
• 229960002448 dasatinib Drugs 0.000 description 2
• 230000003247 decreasing effect Effects 0.000 description 2
• 238000001514 detection method Methods 0.000 description 2
• USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
• 239000002552 dosage form Substances 0.000 description 2
• 231100000673 dose–response relationship Toxicity 0.000 description 2
• 239000003480 eluent Substances 0.000 description 2
• 239000007920 enema Substances 0.000 description 2
• 229940095399 enema 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
• MSIRNYGKTHRHLC-UHFFFAOYSA-N ethyl 6-bromo-4-(3-nitroanilino)quinoline-3-carboxylate Chemical compound CCOC(=O)C1=CN=C2C=CC(Br)=CC2=C1NC1=CC=CC([N+]([O-])=O)=C1 MSIRNYGKTHRHLC-UHFFFAOYSA-N 0.000 description 2
• 239000003889 eye drop Substances 0.000 description 2
• 229940012356 eye drops Drugs 0.000 description 2
• 238000001914 filtration Methods 0.000 description 2
• 239000006260 foam Substances 0.000 description 2
• 230000037406 food intake Effects 0.000 description 2
• 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 2
• 235000011187 glycerol Nutrition 0.000 description 2
• 125000002883 imidazolyl group Chemical group 0.000 description 2
• 230000002779 inactivation Effects 0.000 description 2
• 238000001802 infusion Methods 0.000 description 2
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
• ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
• 239000002502 liposome Substances 0.000 description 2
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
• 201000005202 lung cancer Diseases 0.000 description 2
• 208000020816 lung neoplasm Diseases 0.000 description 2
• 206010025135 lupus erythematosus Diseases 0.000 description 2
• 230000014759 maintenance of location Effects 0.000 description 2
• 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 2
• 239000003550 marker Substances 0.000 description 2
• RWIKCBHOVNDESJ-NSCUHMNNSA-N methyl (e)-4-bromobut-2-enoate Chemical compound COC(=O)\C=C\CBr RWIKCBHOVNDESJ-NSCUHMNNSA-N 0.000 description 2
• RDYGYMWZIAXVOR-UHFFFAOYSA-N methyl 4-[5-[9-[4-(methanesulfonamido)phenyl]-2-oxobenzo[h][1,6]naphthyridin-1-yl]-2-methylanilino]but-2-enoate Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)NCC=CC(=O)OC RDYGYMWZIAXVOR-UHFFFAOYSA-N 0.000 description 2
• 230000004899 motility Effects 0.000 description 2
• PHVXTQIROLEEDB-UHFFFAOYSA-N n-[2-(2-chlorophenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-n-pyrrolidin-3-ylbenzamide Chemical compound CC1=CC=CC=C1C1CN(CC=2C=CC(=CC=2)C(=O)N(CCC=2C(=CC=CC=2)Cl)C2CNCC2)CCC1 PHVXTQIROLEEDB-UHFFFAOYSA-N 0.000 description 2
• NPSPNWPZDXQYAC-UHFFFAOYSA-N n-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(NS(C)(=O)=O)C=C1 NPSPNWPZDXQYAC-UHFFFAOYSA-N 0.000 description 2
• 108700043045 nanoluc Proteins 0.000 description 2
• 229940097496 nasal spray Drugs 0.000 description 2
• 239000007922 nasal spray Substances 0.000 description 2
• 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 2
• 230000000269 nucleophilic effect Effects 0.000 description 2
• 239000003883 ointment base Substances 0.000 description 2
• 230000003287 optical effect Effects 0.000 description 2
• 238000005457 optimization Methods 0.000 description 2
• 210000001672 ovary Anatomy 0.000 description 2
• 238000002888 pairwise sequence alignment Methods 0.000 description 2
• 230000007170 pathology Effects 0.000 description 2
• 238000005191 phase separation Methods 0.000 description 2
• 230000026731 phosphorylation Effects 0.000 description 2
• 238000006366 phosphorylation reaction Methods 0.000 description 2
• 239000004033 plastic Substances 0.000 description 2
• 229920005862 polyol Polymers 0.000 description 2
• 150000003077 polyols Chemical class 0.000 description 2
• 239000002244 precipitate Substances 0.000 description 2
• 239000003755 preservative agent Substances 0.000 description 2
• 230000000069 prophylactic effect Effects 0.000 description 2
• 238000011321 prophylaxis Methods 0.000 description 2
• XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 2
• 238000012342 propidium iodide staining Methods 0.000 description 2
• 239000002516 radical scavenger Substances 0.000 description 2
• 230000002829 reductive effect Effects 0.000 description 2
• 230000008844 regulatory mechanism Effects 0.000 description 2
• RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 2
• 238000012552 review Methods 0.000 description 2
• 238000002864 sequence alignment Methods 0.000 description 2
• 150000003384 small molecules Chemical class 0.000 description 2
• 239000011734 sodium Substances 0.000 description 2
• 229910000029 sodium carbonate Inorganic materials 0.000 description 2
• 125000005017 substituted alkenyl group Chemical group 0.000 description 2
• 239000005720 sucrose Substances 0.000 description 2
• 230000002195 synergetic effect Effects 0.000 description 2
• 238000003786 synthesis reaction Methods 0.000 description 2
• 235000020357 syrup Nutrition 0.000 description 2
• 239000006188 syrup Substances 0.000 description 2
• 230000009897 systematic effect Effects 0.000 description 2
• 230000008685 targeting Effects 0.000 description 2
• 125000000335 thiazolyl group Chemical group 0.000 description 2
• 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 2
• 230000035899 viability Effects 0.000 description 2
• 239000001993 wax Substances 0.000 description 2
• AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
• GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
• SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
• GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
• DIXMBHMNEHPFCX-MCMMXHMISA-N (2r)-2-[5-[6-amino-5-[(1r)-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethoxy]pyridin-3-yl]-4-methyl-1,3-thiazol-2-yl]propane-1,2-diol Chemical compound O([C@H](C)C=1C(=CC=C(F)C=1)N1N=CC=N1)C(C(=NC=1)N)=CC=1C=1SC([C@](C)(O)CO)=NC=1C DIXMBHMNEHPFCX-MCMMXHMISA-N 0.000 description 1
• WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
• LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 1
• QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
• IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
• DMQYDVBIPXAAJA-VHXPQNKSSA-N (3z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)-(5-methyl-1h-imidazol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1CN(CC)CCC1NC1=CC=C(NC(=O)\C2=C(/C=3NC=C(C)N=3)C=3C=C(F)C=CC=3)C2=C1 DMQYDVBIPXAAJA-VHXPQNKSSA-N 0.000 description 1
• FOLCUFKJHSQMEL-BIXPGCQOSA-N (4-butylcyclohexyl) N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CCCCC1CCC(CC1)OC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@@H]2CCNC2=O)C=O FOLCUFKJHSQMEL-BIXPGCQOSA-N 0.000 description 1
• VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 1
• VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 1
• MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 1
• QOLHWXNSCZGWHK-BWBORTOCSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecylcarbamoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)NCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QOLHWXNSCZGWHK-BWBORTOCSA-N 0.000 description 1
• VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 1
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
• 125000006586 (C3-C10) cycloalkylene group Chemical group 0.000 description 1
• LVHOHZHTZXRVRJ-CMDGGOBGSA-N (e)-3-(3-methoxyphenyl)-n-(3,4,5-trimethoxyphenyl)prop-2-enamide Chemical compound COC1=CC=CC(\C=C\C(=O)NC=2C=C(OC)C(OC)=C(OC)C=2)=C1 LVHOHZHTZXRVRJ-CMDGGOBGSA-N 0.000 description 1
• IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 1
• HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 1
• LKTBIAWKYBOSJY-UHFFFAOYSA-N 1-(3-amino-4-methylphenyl)-9-[4-(dimethylamino)piperidin-1-yl]benzo[h][1,6]naphthyridin-2-one Chemical compound NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)N1CCC(CC1)N(C)C)=O LKTBIAWKYBOSJY-UHFFFAOYSA-N 0.000 description 1
• YHUFJZHEXMWCOS-UHFFFAOYSA-N 1-(3-amino-4-methylphenyl)-9-[6-(trifluoromethyl)pyridin-3-yl]benzo[h][1,6]naphthyridin-2-one Chemical compound NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C=1C=NC(=CC=1)C(F)(F)F)=O YHUFJZHEXMWCOS-UHFFFAOYSA-N 0.000 description 1
• SDOFRPNJOYYHNA-UHFFFAOYSA-N 1-(3-amino-4-methylphenyl)-9-bromobenzo[h][1,6]naphthyridin-2-one Chemical compound C1=C(N)C(C)=CC=C1N1C(=O)C=CC2=C1C1=CC(Br)=CC=C1N=C2 SDOFRPNJOYYHNA-UHFFFAOYSA-N 0.000 description 1
• SVAVRRBWGIVRMW-UHFFFAOYSA-N 1-(3-amino-4-methylphenyl)-9-morpholin-4-ylbenzo[h][1,6]naphthyridin-2-one Chemical compound NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)N1CCOCC1)=O SVAVRRBWGIVRMW-UHFFFAOYSA-N 0.000 description 1
• RDAMANMQARPQEU-UHFFFAOYSA-N 1-(3-amino-4-methylphenyl)-9-piperidin-1-ylbenzo[h][1,6]naphthyridin-2-one Chemical compound NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)N1CCCCC1)=O RDAMANMQARPQEU-UHFFFAOYSA-N 0.000 description 1
• JFJYCJFURULRCR-UHFFFAOYSA-N 1-(3-amino-4-methylphenyl)-9-pyridin-4-ylbenzo[h][1,6]naphthyridin-2-one Chemical compound NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=NC=C1)=O JFJYCJFURULRCR-UHFFFAOYSA-N 0.000 description 1
• OFMGWVVGOZXYFG-UHFFFAOYSA-N 1-(4-methyl-3-nitrophenyl)-9-(4-methylsulfonylpiperazin-1-yl)benzo[h][1,6]naphthyridin-2-one Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)N1CCN(CC1)S(=O)(=O)C)=O)[N+](=O)[O-] OFMGWVVGOZXYFG-UHFFFAOYSA-N 0.000 description 1
• NMQGVWZJBQMZSW-UHFFFAOYSA-N 1-(4-methyl-3-nitrophenyl)-9-[6-(trifluoromethyl)pyridin-3-yl]benzo[h][1,6]naphthyridin-2-one Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C=1C=NC(=CC=1)C(F)(F)F)=O)[N+](=O)[O-] NMQGVWZJBQMZSW-UHFFFAOYSA-N 0.000 description 1
• LDBKUSPTZRJUNG-UHFFFAOYSA-N 1-(4-methyl-3-nitrophenyl)-9-morpholin-4-ylbenzo[h][1,6]naphthyridin-2-one Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)N1CCOCC1)=O)[N+](=O)[O-] LDBKUSPTZRJUNG-UHFFFAOYSA-N 0.000 description 1
• VELQJJQVINHABA-UHFFFAOYSA-N 1-(4-methyl-3-nitrophenyl)-9-piperidin-1-ylbenzo[h][1,6]naphthyridin-2-one Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)N1CCCCC1)=O)[N+](=O)[O-] VELQJJQVINHABA-UHFFFAOYSA-N 0.000 description 1
• FJCXJKCSFGMIEX-UHFFFAOYSA-N 1-(4-methyl-3-nitrophenyl)-9-pyridin-4-ylbenzo[h][1,6]naphthyridin-2-one Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=NC=C1)=O)[N+](=O)[O-] FJCXJKCSFGMIEX-UHFFFAOYSA-N 0.000 description 1
• ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
• JGMXNNSYEFOBHQ-OWOJBTEDSA-N 2-[(e)-4-morpholin-4-ylbut-2-enyl]-1,1-dioxothieno[3,2-e]thiazine-6-sulfonamide Chemical compound O=S1(=O)C=2SC(S(=O)(=O)N)=CC=2C=CN1C\C=C\CN1CCOCC1 JGMXNNSYEFOBHQ-OWOJBTEDSA-N 0.000 description 1
• KKKJYDOHVKIIQP-UHFFFAOYSA-N 2-[4-(3-chlorobenzoyl)phenoxy]-N-pyridin-3-ylacetamide Chemical compound ClC=1C=C(C(=O)C2=CC=C(OCC(=O)NC=3C=NC=CC=3)C=C2)C=CC=1 KKKJYDOHVKIIQP-UHFFFAOYSA-N 0.000 description 1
• LHASZEBEQGPCFM-CJFMBICVSA-N 2-amino-4-[(1r)-1-[[(6r)-6-[(5-chloro-2-methoxyphenyl)methyl]-7-oxo-3-(phenoxyamino)-5,6-dihydro-2h-1,4-diazepine-1-carbonyl]amino]propyl]benzoic acid Chemical compound C([C@@H]1CNC(CN(C1=O)C(=O)N[C@H](CC)C=1C=C(N)C(C(O)=O)=CC=1)=NOC=1C=CC=CC=1)C1=CC(Cl)=CC=C1OC LHASZEBEQGPCFM-CJFMBICVSA-N 0.000 description 1
• YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
• AALIIUIRMKPDPI-UHFFFAOYSA-N 2-hydroxy-3-(1H-imidazol-2-yl)butanedioic acid Chemical compound OC(=O)C(O)C(C(O)=O)C1=NC=CN1 AALIIUIRMKPDPI-UHFFFAOYSA-N 0.000 description 1
• AGARPHPERRYPRP-UHFFFAOYSA-N 3-bromo-1h-quinolin-2-one Chemical compound C1=CC=C2C=C(Br)C(O)=NC2=C1 AGARPHPERRYPRP-UHFFFAOYSA-N 0.000 description 1
• DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 1
• MWDVCHRYCKXEBY-LBPRGKRZSA-N 3-chloro-n-[2-oxo-2-[[(1s)-1-phenylethyl]amino]ethyl]benzamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(=O)CNC(=O)C1=CC=CC(Cl)=C1 MWDVCHRYCKXEBY-LBPRGKRZSA-N 0.000 description 1
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
• OVDGUTHABMXVMI-UHFFFAOYSA-N 3-nitro-4-(propylamino)benzoic acid Chemical compound CCCNC1=CC=C(C(O)=O)C=C1[N+]([O-])=O OVDGUTHABMXVMI-UHFFFAOYSA-N 0.000 description 1
• RUFOHZDEBFYQSV-UHFFFAOYSA-N 4-methoxy-3-nitroaniline Chemical compound COC1=CC=C(N)C=C1[N+]([O-])=O RUFOHZDEBFYQSV-UHFFFAOYSA-N 0.000 description 1
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
• DSBIJCMXAIKKKI-UHFFFAOYSA-N 5-nitro-o-toluidine Chemical compound CC1=CC=C([N+]([O-])=O)C=C1N DSBIJCMXAIKKKI-UHFFFAOYSA-N 0.000 description 1
• RRELDGDKULRRDM-UHFFFAOYSA-N 6-[2-chloro-4-nitro-5-(oxan-4-yloxy)anilino]-3,4-dihydro-1H-quinolin-2-one Chemical compound [O-][N+](=O)c1cc(Cl)c(Nc2ccc3NC(=O)CCc3c2)cc1OC1CCOCC1 RRELDGDKULRRDM-UHFFFAOYSA-N 0.000 description 1
• WXZUFTMQNUNOOP-UHFFFAOYSA-N 8-(4-methylsulfonylpiperazin-1-yl)-1-(3-nitrophenyl)benzo[h][1,6]naphthyridin-2-one Chemical compound CS(=O)(=O)N1CCN(CC1)C=1C=CC=2C(=NC=C3C=CC(N(C=23)C2=CC(=CC=C2)[N+](=O)[O-])=O)C=1 WXZUFTMQNUNOOP-UHFFFAOYSA-N 0.000 description 1
• KAUZGRWHHLKSAH-UHFFFAOYSA-N 8-bromo-1-(3-methyl-5-nitrophenyl)benzo[h][1,6]naphthyridin-2-one Chemical compound BrC=1C=CC=2C(=NC=C3C=CC(N(C=23)C2=CC(=CC(=C2)[N+](=O)[O-])C)=O)C=1 KAUZGRWHHLKSAH-UHFFFAOYSA-N 0.000 description 1
• WVXUXICSJZUTLQ-UHFFFAOYSA-N 8-bromo-1-(3-nitrophenyl)benzo[h][1,6]naphthyridin-2-one Chemical compound BrC=1C=CC=2C(=NC=C3C=CC(N(C=23)C2=CC(=CC=C2)[N+](=O)[O-])=O)C=1 WVXUXICSJZUTLQ-UHFFFAOYSA-N 0.000 description 1
• HWPCHBDJUOXLPV-UHFFFAOYSA-N 8-bromo-1-(4-methyl-3-nitrophenyl)benzo[h][1,6]naphthyridin-2-one Chemical compound BrC=1C=CC=2C(=NC=C3C=CC(N(C=23)C2=CC(=C(C=C2)C)[N+](=O)[O-])=O)C=1 HWPCHBDJUOXLPV-UHFFFAOYSA-N 0.000 description 1
• WNLMAZNKPQIOPI-UHFFFAOYSA-N 9-[4-(dimethylamino)piperidin-1-yl]-1-(4-methyl-3-nitrophenyl)benzo[h][1,6]naphthyridin-2-one Chemical compound CN(C1CCN(CC1)C1=CC=2C(=NC=C3C=CC(N(C=23)C2=CC(=C(C=C2)C)[N+](=O)[O-])=O)C=C1)C WNLMAZNKPQIOPI-UHFFFAOYSA-N 0.000 description 1
• HPLNQCPCUACXLM-PGUFJCEWSA-N ABT-737 Chemical compound C([C@@H](CCN(C)C)NC=1C(=CC(=CC=1)S(=O)(=O)NC(=O)C=1C=CC(=CC=1)N1CCN(CC=2C(=CC=CC=2)C=2C=CC(Cl)=CC=2)CC1)[N+]([O-])=O)SC1=CC=CC=C1 HPLNQCPCUACXLM-PGUFJCEWSA-N 0.000 description 1
• 102000007469 Actins Human genes 0.000 description 1
• 108010085238 Actins Proteins 0.000 description 1
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
• 239000005695 Ammonium acetate Substances 0.000 description 1
• 102100022014 Angiopoietin-1 receptor Human genes 0.000 description 1
• 101710131689 Angiopoietin-1 receptor Proteins 0.000 description 1
• 102000006306 Antigen Receptors Human genes 0.000 description 1
• 108010083359 Antigen Receptors Proteins 0.000 description 1
• 101100181122 Arabidopsis thaliana KIN14C gene Proteins 0.000 description 1
• 101100234530 Arabidopsis thaliana KIN14M gene Proteins 0.000 description 1
• 101100234532 Arabidopsis thaliana KIN14N gene Proteins 0.000 description 1
• 101100288145 Arabidopsis thaliana KNAT2 gene Proteins 0.000 description 1
• 241000416162 Astragalus gummifer Species 0.000 description 1
• 241000271566 Aves Species 0.000 description 1
• 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
• 208000003950 B-cell lymphoma Diseases 0.000 description 1
• 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 1
• 102000004506 Blood Proteins Human genes 0.000 description 1
• 108010017384 Blood Proteins Proteins 0.000 description 1
• FSZBRDAJQCMPDT-UHFFFAOYSA-N BrC1=CC=C2C(=C(C=NC2=C1)C(=O)OCC)NC1=CC(=C(C=C1)C)[N+](=O)[O-] Chemical compound BrC1=CC=C2C(=C(C=NC2=C1)C(=O)OCC)NC1=CC(=C(C=C1)C)[N+](=O)[O-] FSZBRDAJQCMPDT-UHFFFAOYSA-N 0.000 description 1
• ACAXQFKOLOYXBZ-UHFFFAOYSA-N BrC1=CC=C2C(=C(C=NC2=C1)C(=O)OCC)NC1=CC(=CC(=C1)[N+](=O)[O-])C Chemical compound BrC1=CC=C2C(=C(C=NC2=C1)C(=O)OCC)NC1=CC(=CC(=C1)[N+](=O)[O-])C ACAXQFKOLOYXBZ-UHFFFAOYSA-N 0.000 description 1
• YYXGAYCMXCMWQB-UHFFFAOYSA-N BrC1=CC=C2C(=C(C=NC2=C1)C(=O)OCC)NC1=CC(=CC=C1)[N+](=O)[O-] Chemical compound BrC1=CC=C2C(=C(C=NC2=C1)C(=O)OCC)NC1=CC(=CC=C1)[N+](=O)[O-] YYXGAYCMXCMWQB-UHFFFAOYSA-N 0.000 description 1
• BUPZBULQHHZFJH-UHFFFAOYSA-N BrC1=CC=C2C(=C(C=NC2=C1)C=O)NC1=CC(=C(C=C1)C)[N+](=O)[O-] Chemical compound BrC1=CC=C2C(=C(C=NC2=C1)C=O)NC1=CC(=C(C=C1)C)[N+](=O)[O-] BUPZBULQHHZFJH-UHFFFAOYSA-N 0.000 description 1
• JPGHTVAKOZHCFG-UHFFFAOYSA-N BrC1=CC=C2C(=C(C=NC2=C1)C=O)NC1=CC(=CC(=C1)[N+](=O)[O-])C Chemical compound BrC1=CC=C2C(=C(C=NC2=C1)C=O)NC1=CC(=CC(=C1)[N+](=O)[O-])C JPGHTVAKOZHCFG-UHFFFAOYSA-N 0.000 description 1
• PNCULXZHOOXKOZ-UHFFFAOYSA-N BrC1=CC=C2C(=C(C=NC2=C1)C=O)NC1=CC(=CC=C1)[N+](=O)[O-] Chemical compound BrC1=CC=C2C(=C(C=NC2=C1)C=O)NC1=CC(=CC=C1)[N+](=O)[O-] PNCULXZHOOXKOZ-UHFFFAOYSA-N 0.000 description 1
• RDZNQQPKFFZLPP-UHFFFAOYSA-N BrC1=CC=C2C(=C(C=NC2=C1)CO)NC1=CC(=C(C=C1)C)[N+](=O)[O-] Chemical compound BrC1=CC=C2C(=C(C=NC2=C1)CO)NC1=CC(=C(C=C1)C)[N+](=O)[O-] RDZNQQPKFFZLPP-UHFFFAOYSA-N 0.000 description 1
• SIWQOQPAGKJVPX-UHFFFAOYSA-N BrC1=CC=C2C(=C(C=NC2=C1)CO)NC1=CC(=CC(=C1)[N+](=O)[O-])C Chemical compound BrC1=CC=C2C(=C(C=NC2=C1)CO)NC1=CC(=CC(=C1)[N+](=O)[O-])C SIWQOQPAGKJVPX-UHFFFAOYSA-N 0.000 description 1
• QHMSUYQQQIVSJN-UHFFFAOYSA-N BrC1=CC=C2C(=C(C=NC2=C1)CO)NC1=CC(=CC=C1)[N+](=O)[O-] Chemical compound BrC1=CC=C2C(=C(C=NC2=C1)CO)NC1=CC(=CC=C1)[N+](=O)[O-] QHMSUYQQQIVSJN-UHFFFAOYSA-N 0.000 description 1
• 208000003174 Brain Neoplasms Diseases 0.000 description 1
• QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 1
• AMLDPBCHMKHQTB-UHFFFAOYSA-N CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NC(OC)=O)=O)[N+](=O)[O-] Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NC(OC)=O)=O)[N+](=O)[O-] AMLDPBCHMKHQTB-UHFFFAOYSA-N 0.000 description 1
• GIGMZQLWVBVVJY-UHFFFAOYSA-N CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)CCCC)=O)[N+](=O)[O-] Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)CCCC)=O)[N+](=O)[O-] GIGMZQLWVBVVJY-UHFFFAOYSA-N 0.000 description 1
• RIVCAZOYFJUSPP-UHFFFAOYSA-N CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=NC=C1)=O)NC(C=C)=O Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=NC=C1)=O)NC(C=C)=O RIVCAZOYFJUSPP-UHFFFAOYSA-N 0.000 description 1
• LJOWFCDRAGIBOK-UHFFFAOYSA-N CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C=1C=C(C=CC=1)NS(=O)(=O)C)=O)[N+](=O)[O-] Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C=1C=C(C=CC=1)NS(=O)(=O)C)=O)[N+](=O)[O-] LJOWFCDRAGIBOK-UHFFFAOYSA-N 0.000 description 1
• GREABCGOXWGQHA-UHFFFAOYSA-N CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C=1C=CC(=NC=1)C#N)=O)[N+](=O)[O-] Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C=1C=CC(=NC=1)C#N)=O)[N+](=O)[O-] GREABCGOXWGQHA-UHFFFAOYSA-N 0.000 description 1
• WUJPGCNDTSTSMW-UHFFFAOYSA-N CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)N1CCCCC1)=O)NC(C=C)=O Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)N1CCCCC1)=O)NC(C=C)=O WUJPGCNDTSTSMW-UHFFFAOYSA-N 0.000 description 1
• MMZCNVQXXYVQRE-UHFFFAOYSA-N CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)[N+](=O)[O-] Chemical compound CC1=C(C=C(C=C1)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O)[N+](=O)[O-] MMZCNVQXXYVQRE-UHFFFAOYSA-N 0.000 description 1
• BBDDOYLIBALWBA-UHFFFAOYSA-N CC1=C(C=C(C=C1)NC1=C(C=NC2=CC=C(C=C12)C1=CC=C(C=C1)NS(=O)(=O)C)C(=O)OCC)[N+](=O)[O-] Chemical compound CC1=C(C=C(C=C1)NC1=C(C=NC2=CC=C(C=C12)C1=CC=C(C=C1)NS(=O)(=O)C)C(=O)OCC)[N+](=O)[O-] BBDDOYLIBALWBA-UHFFFAOYSA-N 0.000 description 1
• KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 1
• OSEBINWXHGTHJY-UHFFFAOYSA-N CC=1C=C(C=C(C=1)[N+](=O)[O-])N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O Chemical compound CC=1C=C(C=C(C=1)[N+](=O)[O-])N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O OSEBINWXHGTHJY-UHFFFAOYSA-N 0.000 description 1
• 101100268645 Caenorhabditis elegans abl-1 gene Proteins 0.000 description 1
• 241000282465 Canis Species 0.000 description 1
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
• KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
• 241000700198 Cavia Species 0.000 description 1
• 241000700199 Cavia porcellus Species 0.000 description 1
• 102000000844 Cell Surface Receptors Human genes 0.000 description 1
• 108010001857 Cell Surface Receptors Proteins 0.000 description 1
• 241000700114 Chinchillidae Species 0.000 description 1
• 241000251556 Chordata Species 0.000 description 1
• 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
• 229940126657 Compound 17 Drugs 0.000 description 1
• 229940126650 Compound 3f Drugs 0.000 description 1
• 229940126559 Compound 4e Drugs 0.000 description 1
• 241000699800 Cricetinae Species 0.000 description 1
• 108090000695 Cytokines Proteins 0.000 description 1
• 102000004127 Cytokines Human genes 0.000 description 1
• 101710190589 Cytoplasmic tyrosine-protein kinase BMX Proteins 0.000 description 1
• 102100025698 Cytosolic carboxypeptidase 4 Human genes 0.000 description 1
• 239000012623 DNA damaging agent Substances 0.000 description 1
• 102000009058 Death Domain Receptors Human genes 0.000 description 1
• 108010049207 Death Domain Receptors Proteins 0.000 description 1
• 206010012310 Dengue fever Diseases 0.000 description 1
• 241000725619 Dengue virus Species 0.000 description 1
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
• 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
• 241000255925 Diptera Species 0.000 description 1
• 101710146522 Dual specificity mitogen-activated protein kinase kinase 7 Proteins 0.000 description 1
• 102100040862 Dual specificity protein kinase CLK1 Human genes 0.000 description 1
• 101150029707 ERBB2 gene Proteins 0.000 description 1
• 239000004150 EU approved colour Substances 0.000 description 1
• VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
• 241000289695 Eutheria Species 0.000 description 1
• 102100027286 Fanconi anemia group C protein Human genes 0.000 description 1
• 241000282324 Felis Species 0.000 description 1
• 241000282326 Felis catus Species 0.000 description 1
• 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
• 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
• 230000005526 G1 to G0 transition Effects 0.000 description 1
• 108010010803 Gelatin Proteins 0.000 description 1
• 241000282575 Gorilla Species 0.000 description 1
• 102000009465 Growth Factor Receptors Human genes 0.000 description 1
• 108010009202 Growth Factor Receptors Proteins 0.000 description 1
• 241000238631 Hexapoda Species 0.000 description 1
• 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 1
• 101000749294 Homo sapiens Dual specificity protein kinase CLK1 Proteins 0.000 description 1
• 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 description 1
• 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 description 1
• 101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 description 1
• 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
• 101001050476 Homo sapiens Tyrosine-protein kinase ITK/TSK Proteins 0.000 description 1
• 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 1
• 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 1
• 101000606067 Homo sapiens Tyrosine-protein kinase TXK Proteins 0.000 description 1
• 101000820294 Homo sapiens Tyrosine-protein kinase Yes Proteins 0.000 description 1
• 101001117146 Homo sapiens [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Proteins 0.000 description 1
• 241000282620 Hylobates sp. Species 0.000 description 1
• 101710092857 Integrator complex subunit 1 Proteins 0.000 description 1
• 102100024061 Integrator complex subunit 1 Human genes 0.000 description 1
• 238000003749 KINOMEscan Methods 0.000 description 1
• 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
• 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
• 241000283953 Lagomorpha Species 0.000 description 1
• 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 description 1
• 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
• 108010068339 MAP Kinase Kinase 7 Proteins 0.000 description 1
• 241000289581 Macropus sp. Species 0.000 description 1
• OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
• 241000124008 Mammalia Species 0.000 description 1
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
• 241001529936 Murinae Species 0.000 description 1
• 241000699670 Mus sp. Species 0.000 description 1
• NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
• CLYMYGKVOUOPCQ-UHFFFAOYSA-N N-[2-methyl-5-(9-morpholin-4-yl-2-oxobenzo[h][1,6]naphthyridin-1-yl)phenyl]prop-2-enamide Chemical compound Cc1ccc(cc1NC(=O)C=C)N2C(=O)C=Cc3cnc4ccc(cc4c23)N5CCOCC5 CLYMYGKVOUOPCQ-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
• OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
• RJJGVCREJDOWAJ-UHFFFAOYSA-N NC=1C=C(C=C(C=1)C)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O Chemical compound NC=1C=C(C=C(C=1)C)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O RJJGVCREJDOWAJ-UHFFFAOYSA-N 0.000 description 1
• GQNTXLYQHAXEBD-UHFFFAOYSA-N NC=1C=C(C=CC=1)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O Chemical compound NC=1C=C(C=CC=1)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O GQNTXLYQHAXEBD-UHFFFAOYSA-N 0.000 description 1
• LFSXNQPILICIRD-UHFFFAOYSA-N NC=1C=C(C=CC=1)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)N1CCN(CC1)S(=O)(=O)C)=O Chemical compound NC=1C=C(C=CC=1)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)N1CCN(CC1)S(=O)(=O)C)=O LFSXNQPILICIRD-UHFFFAOYSA-N 0.000 description 1
• XEKJOONJGCUVTO-UHFFFAOYSA-N NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NC(OC)=O)=O Chemical compound NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NC(OC)=O)=O XEKJOONJGCUVTO-UHFFFAOYSA-N 0.000 description 1
• QJOOVRLXBUUZFK-UHFFFAOYSA-N NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)CCCC)=O Chemical compound NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C1=CC=C(C=C1)NS(=O)(=O)CCCC)=O QJOOVRLXBUUZFK-UHFFFAOYSA-N 0.000 description 1
• QQXLRLQMOKTEET-UHFFFAOYSA-N NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C=1C=CC(=NC=1)C#N)=O Chemical compound NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=C(C=C3)C=1C=CC(=NC=1)C#N)=O QQXLRLQMOKTEET-UHFFFAOYSA-N 0.000 description 1
• OKCNKNLALWBEQM-UHFFFAOYSA-N NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O Chemical compound NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O OKCNKNLALWBEQM-UHFFFAOYSA-N 0.000 description 1
• BOLHJKKSMSIXFX-UHFFFAOYSA-N NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C=1C=C(C=CC=1)NS(=O)(=O)C)=O Chemical compound NC=1C=C(C=CC=1C)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C=1C=C(C=CC=1)NS(=O)(=O)C)=O BOLHJKKSMSIXFX-UHFFFAOYSA-N 0.000 description 1
• NJPZTIHSAZFFNC-UHFFFAOYSA-N NC=1C=C(C=CC=1C)NC1=C(C=NC2=CC=C(C=C12)C1=CC=C(C=C1)NS(=O)(=O)C)C(=O)OCC Chemical compound NC=1C=C(C=CC=1C)NC1=C(C=NC2=CC=C(C=C12)C1=CC=C(C=C1)NS(=O)(=O)C)C(=O)OCC NJPZTIHSAZFFNC-UHFFFAOYSA-N 0.000 description 1
• 238000005481 NMR spectroscopy Methods 0.000 description 1
• 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
• 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 1
• 102100028448 Nuclear receptor subfamily 2 group C member 2 Human genes 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
• 229930012538 Paclitaxel Natural products 0.000 description 1
• 241000282577 Pan troglodytes Species 0.000 description 1
• 241001504519 Papio ursinus Species 0.000 description 1
• 229910002666 PdCl2 Inorganic materials 0.000 description 1
• 241001494479 Pecora Species 0.000 description 1
• 241001406852 Perola Species 0.000 description 1
• 102100038332 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Human genes 0.000 description 1
• 206010035226 Plasma cell myeloma Diseases 0.000 description 1
• 229920002582 Polyethylene Glycol 600 Polymers 0.000 description 1
• 229920001213 Polysorbate 20 Polymers 0.000 description 1
• 241000282405 Pongo abelii Species 0.000 description 1
• 241000288906 Primates Species 0.000 description 1
• 108010076504 Protein Sorting Signals Proteins 0.000 description 1
• 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
• 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 1
• 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 1
• 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 1
• 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
• 239000008156 Ringer's lactate solution Substances 0.000 description 1
• 102000038012 SFKs Human genes 0.000 description 1
• 108091008118 SFKs Proteins 0.000 description 1
• 229940125907 SJ995973 Drugs 0.000 description 1
• 102000001332 SRC Human genes 0.000 description 1
• 108060006706 SRC Proteins 0.000 description 1
• 108010017324 STAT3 Transcription Factor Proteins 0.000 description 1
• 101150040067 STK11 gene Proteins 0.000 description 1
• 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 description 1
• 201000010001 Silicosis Diseases 0.000 description 1
• 229940122924 Src inhibitor Drugs 0.000 description 1
• 241000718541 Tetragastris balsamifera Species 0.000 description 1
• AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
• 239000004473 Threonine Substances 0.000 description 1
• 229920001615 Tragacanth Polymers 0.000 description 1
• DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
• 101710083606 Tyrosine-protein kinase ABL Proteins 0.000 description 1
• 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 1
• 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 1
• 102100022356 Tyrosine-protein kinase Mer Human genes 0.000 description 1
• 101710101516 Tyrosine-protein kinase TXK Proteins 0.000 description 1
• 102100021788 Tyrosine-protein kinase Yes Human genes 0.000 description 1
• 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
• 108010067390 Viral Proteins Proteins 0.000 description 1
• 241000289674 Vombatidae Species 0.000 description 1
• LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
• GFVQWMXOLYHARX-UHFFFAOYSA-N [4-(butylsulfonylamino)phenyl]boronic acid Chemical compound CCCCS(=O)(=O)NC1=CC=C(B(O)O)C=C1 GFVQWMXOLYHARX-UHFFFAOYSA-N 0.000 description 1
• ROAKVYQVTMOEGR-UHFFFAOYSA-N [4-(methoxycarbonylamino)phenyl]boronic acid Chemical compound COC(=O)NC1=CC=C(B(O)O)C=C1 ROAKVYQVTMOEGR-UHFFFAOYSA-N 0.000 description 1
• BNTIPMNMTIAWIW-UHFFFAOYSA-N [6-(trifluoromethyl)pyridin-3-yl]boronic acid Chemical compound OB(O)C1=CC=C(C(F)(F)F)N=C1 BNTIPMNMTIAWIW-UHFFFAOYSA-N 0.000 description 1
• KNWBNJAJZBHIPP-UHFFFAOYSA-N [N+](=O)([O-])C=1C=C(C=CC=1)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O Chemical compound [N+](=O)([O-])C=1C=C(C=CC=1)N1C(C=CC2=CN=C3C(=C12)C=CC(=C3)C1=CC=C(C=C1)NS(=O)(=O)C)=O KNWBNJAJZBHIPP-UHFFFAOYSA-N 0.000 description 1
• 238000010521 absorption reaction Methods 0.000 description 1
• WDENQIQQYWYTPO-IBGZPJMESA-N acalabrutinib Chemical compound CC#CC(=O)N1CCC[C@H]1C1=NC(C=2C=CC(=CC=2)C(=O)NC=2N=CC=CC=2)=C2N1C=CN=C2N WDENQIQQYWYTPO-IBGZPJMESA-N 0.000 description 1
• 229950009821 acalabrutinib Drugs 0.000 description 1
• 238000009825 accumulation Methods 0.000 description 1
• 150000001242 acetic acid derivatives Chemical class 0.000 description 1
• CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
• 230000009471 action Effects 0.000 description 1
• 239000002671 adjuvant Substances 0.000 description 1
• 229960001686 afatinib Drugs 0.000 description 1
• ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
• 125000001931 aliphatic group Chemical group 0.000 description 1
• 125000004450 alkenylene group Chemical group 0.000 description 1
• 150000001350 alkyl halides Chemical class 0.000 description 1
• 208000026935 allergic disease Diseases 0.000 description 1
• 239000004411 aluminium Substances 0.000 description 1
• XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
• 229910052782 aluminium Inorganic materials 0.000 description 1
• 238000005576 amination reaction Methods 0.000 description 1
• 235000019257 ammonium acetate Nutrition 0.000 description 1
• 229940043376 ammonium acetate Drugs 0.000 description 1
• 239000012491 analyte Substances 0.000 description 1
• 230000033115 angiogenesis Effects 0.000 description 1
• 150000001448 anilines Chemical class 0.000 description 1
• 230000002424 anti-apoptotic effect Effects 0.000 description 1
• 230000003466 anti-cipated effect Effects 0.000 description 1
• 229940041181 antineoplastic drug Drugs 0.000 description 1
• 239000012062 aqueous buffer Substances 0.000 description 1
• 239000007864 aqueous solution Substances 0.000 description 1
• 239000012300 argon atmosphere Substances 0.000 description 1
• 206010003246 arthritis Diseases 0.000 description 1
• 238000011914 asymmetric synthesis Methods 0.000 description 1
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
• 239000012822 autophagy inhibitor Substances 0.000 description 1
• 125000004069 aziridinyl group Chemical group 0.000 description 1
• 210000003719 b-lymphocyte Anatomy 0.000 description 1
• MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
• 238000010256 biochemical assay Methods 0.000 description 1
• 230000033228 biological regulation Effects 0.000 description 1
• 230000000903 blocking effect Effects 0.000 description 1
• 230000017531 blood circulation Effects 0.000 description 1
• 210000001124 body fluid Anatomy 0.000 description 1
• 238000009835 boiling Methods 0.000 description 1
• 239000007853 buffer solution Substances 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
• 239000006227 byproduct Substances 0.000 description 1
• 108010018804 c-Mer Tyrosine Kinase Proteins 0.000 description 1
• BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
• 238000004364 calculation method Methods 0.000 description 1
• 230000009702 cancer cell proliferation Effects 0.000 description 1
• 239000001569 carbon dioxide Substances 0.000 description 1
• 230000003197 catalytic effect Effects 0.000 description 1
• 238000006555 catalytic reaction Methods 0.000 description 1
• 238000002701 cell growth assay Methods 0.000 description 1
• 230000004663 cell proliferation Effects 0.000 description 1
• 208000019065 cervical carcinoma Diseases 0.000 description 1
• 230000008859 change Effects 0.000 description 1
• 239000003153 chemical reaction reagent Substances 0.000 description 1
• 238000002512 chemotherapy Methods 0.000 description 1
• 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
• 238000010367 cloning Methods 0.000 description 1
• 229940110456 cocoa butter Drugs 0.000 description 1
• 235000019868 cocoa butter Nutrition 0.000 description 1
• 238000002288 cocrystallisation Methods 0.000 description 1
• 238000001360 collision-induced dissociation Methods 0.000 description 1
• 201000010989 colorectal carcinoma Diseases 0.000 description 1
• 239000002131 composite material Substances 0.000 description 1
• 229940125797 compound 12 Drugs 0.000 description 1
• 229940125758 compound 15 Drugs 0.000 description 1
• 229940126142 compound 16 Drugs 0.000 description 1
• 229940125810 compound 20 Drugs 0.000 description 1
• 229940126086 compound 21 Drugs 0.000 description 1
• 229940126208 compound 22 Drugs 0.000 description 1
• 229940125833 compound 23 Drugs 0.000 description 1
• 229940125801 compound 7f Drugs 0.000 description 1
• 238000007906 compression Methods 0.000 description 1
• 230000006835 compression Effects 0.000 description 1
• 238000010276 construction Methods 0.000 description 1
• 238000001816 cooling Methods 0.000 description 1
• 238000012937 correction Methods 0.000 description 1
• 238000002447 crystallographic data Methods 0.000 description 1
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
• 150000001945 cysteines Chemical group 0.000 description 1
• 102000003675 cytokine receptors Human genes 0.000 description 1
• 108010057085 cytokine receptors Proteins 0.000 description 1
• 230000001086 cytosolic effect Effects 0.000 description 1
• 229940127089 cytotoxic agent Drugs 0.000 description 1
• 230000003297 denaturating effect Effects 0.000 description 1
• 208000025729 dengue disease Diseases 0.000 description 1
• 238000001212 derivatisation Methods 0.000 description 1
• 229910052805 deuterium Inorganic materials 0.000 description 1
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
• 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
• ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
• LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 description 1
• 230000004069 differentiation Effects 0.000 description 1
• 238000002050 diffraction method Methods 0.000 description 1
• 238000009792 diffusion process Methods 0.000 description 1
• IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
• 238000007865 diluting Methods 0.000 description 1
• 125000005716 dioxanylene group Chemical group 0.000 description 1
• 230000008034 disappearance Effects 0.000 description 1
• 238000011037 discontinuous sequential dilution Methods 0.000 description 1
• SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C SACNIGZYDTUHKB-UHFFFAOYSA-N 0.000 description 1
• 229960003668 docetaxel Drugs 0.000 description 1
• 239000000890 drug combination Substances 0.000 description 1
• 229940112141 dry powder inhaler Drugs 0.000 description 1
• 239000012636 effector Substances 0.000 description 1
• 229940121647 egfr inhibitor Drugs 0.000 description 1
• 239000012039 electrophile Substances 0.000 description 1
• 230000001804 emulsifying effect Effects 0.000 description 1
• 239000008387 emulsifying waxe Substances 0.000 description 1
• RDYMFSUJUZBWLH-UHFFFAOYSA-N endosulfan Chemical compound C12COS(=O)OCC2C2(Cl)C(Cl)=C(Cl)C1(Cl)C2(Cl)Cl RDYMFSUJUZBWLH-UHFFFAOYSA-N 0.000 description 1
• 230000003511 endothelial effect Effects 0.000 description 1
• 239000003623 enhancer Substances 0.000 description 1
• 125000002587 enol group Chemical group 0.000 description 1
• HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 1
• 229960001433 erlotinib Drugs 0.000 description 1
• DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
• 238000011156 evaluation Methods 0.000 description 1
• 230000005284 excitation Effects 0.000 description 1
• 230000007717 exclusion Effects 0.000 description 1
• 230000001747 exhibiting effect Effects 0.000 description 1
• 239000000945 filler Substances 0.000 description 1
• 239000000796 flavoring agent Substances 0.000 description 1
• 238000000684 flow cytometry Methods 0.000 description 1
• 239000007850 fluorescent dye Substances 0.000 description 1
• 239000003269 fluorescent indicator Substances 0.000 description 1
• 235000013355 food flavoring agent Nutrition 0.000 description 1
• 235000003599 food sweetener Nutrition 0.000 description 1
• 238000001640 fractional crystallisation Methods 0.000 description 1
• 238000013467 fragmentation Methods 0.000 description 1
• 238000006062 fragmentation reaction Methods 0.000 description 1
• 125000000524 functional group Chemical group 0.000 description 1
• 125000002541 furyl group Chemical group 0.000 description 1
• 230000004927 fusion Effects 0.000 description 1
• 239000007789 gas Substances 0.000 description 1
• 229960002584 gefitinib Drugs 0.000 description 1
• 239000008273 gelatin Substances 0.000 description 1
• 229920000159 gelatin Polymers 0.000 description 1
• 239000007903 gelatin capsule Substances 0.000 description 1
• 235000019322 gelatine Nutrition 0.000 description 1
• 235000011852 gelatine desserts Nutrition 0.000 description 1
• 230000014509 gene expression Effects 0.000 description 1
• 102000034356 gene-regulatory proteins Human genes 0.000 description 1
• 108091006104 gene-regulatory proteins Proteins 0.000 description 1
• 238000007429 general method Methods 0.000 description 1
• 239000011521 glass Substances 0.000 description 1
• PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
• 239000010931 gold Substances 0.000 description 1
• 229910052737 gold Inorganic materials 0.000 description 1
• 210000003714 granulocyte Anatomy 0.000 description 1
• 230000012010 growth Effects 0.000 description 1
• 239000003102 growth factor Substances 0.000 description 1
• 230000009036 growth inhibition Effects 0.000 description 1
• JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
• 210000002216 heart Anatomy 0.000 description 1
• 238000010438 heat treatment Methods 0.000 description 1
• 201000005787 hematologic cancer Diseases 0.000 description 1
• 230000002489 hematologic effect Effects 0.000 description 1
• 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
• 102000047287 human BMX Human genes 0.000 description 1
• 210000005260 human cell Anatomy 0.000 description 1
• 150000004677 hydrates Chemical class 0.000 description 1
• 150000002430 hydrocarbons Chemical group 0.000 description 1
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
• XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
• 229960001507 ibrutinib Drugs 0.000 description 1
• 150000003949 imides Chemical class 0.000 description 1
• 230000001771 impaired effect Effects 0.000 description 1
• 239000007943 implant Substances 0.000 description 1
• 208000015181 infectious disease Diseases 0.000 description 1
• 230000028709 inflammatory response Effects 0.000 description 1
• 229910052500 inorganic mineral Inorganic materials 0.000 description 1
• 238000009434 installation Methods 0.000 description 1
• 230000010354 integration Effects 0.000 description 1
• 102000006495 integrins Human genes 0.000 description 1
• 108010044426 integrins Proteins 0.000 description 1
• 230000009878 intermolecular interaction Effects 0.000 description 1
• 238000001361 intraarterial administration Methods 0.000 description 1
• 230000008863 intramolecular interaction Effects 0.000 description 1
• 238000007918 intramuscular administration Methods 0.000 description 1
• 238000007912 intraperitoneal administration Methods 0.000 description 1
• 238000007913 intrathecal administration Methods 0.000 description 1
• 238000001990 intravenous administration Methods 0.000 description 1
• 125000002346 iodo group Chemical group I* 0.000 description 1
• 238000005040 ion trap Methods 0.000 description 1
• 229940084651 iressa Drugs 0.000 description 1
• 230000007794 irritation Effects 0.000 description 1
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
• 238000012933 kinetic analysis Methods 0.000 description 1
• 238000011813 knockout mouse model Methods 0.000 description 1
• 208000032839 leukemia Diseases 0.000 description 1
• 150000002632 lipids Chemical class 0.000 description 1
• 239000000314 lubricant Substances 0.000 description 1
• 238000004519 manufacturing process Methods 0.000 description 1
• 241001515942 marmosets Species 0.000 description 1
• 230000000873 masking effect Effects 0.000 description 1
• 238000001819 mass spectrum Methods 0.000 description 1
• 239000002609 medium Substances 0.000 description 1
• HNQIVZYLYMDVSB-NJFSPNSNSA-N methanesulfonamide Chemical compound [14CH3]S(N)(=O)=O HNQIVZYLYMDVSB-NJFSPNSNSA-N 0.000 description 1
• KQNYTTDHCMFOME-UHFFFAOYSA-N methyl n-[[3-[(4-tert-butylpiperazin-1-yl)methyl]-8-fluoro-2-phenylquinoline-4-carbonyl]amino]-n-phenylcarbamate Chemical compound C=1C=CC=CC=1N(C(=O)OC)NC(=O)C(C1=CC=CC(F)=C1N=C1C=2C=CC=CC=2)=C1CN1CCN(C(C)(C)C)CC1 KQNYTTDHCMFOME-UHFFFAOYSA-N 0.000 description 1
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
• 230000000813 microbial effect Effects 0.000 description 1
• 230000005012 migration Effects 0.000 description 1
• 238000013508 migration Methods 0.000 description 1
• 239000011707 mineral Substances 0.000 description 1
• 235000010755 mineral Nutrition 0.000 description 1
• 238000002156 mixing Methods 0.000 description 1
• 210000001616 monocyte Anatomy 0.000 description 1
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
• 238000000465 moulding Methods 0.000 description 1
• 201000000050 myeloid neoplasm Diseases 0.000 description 1
• MLACQEBQGUBHKX-UHFFFAOYSA-N n,n-dimethylpiperidin-1-amine Chemical compound CN(C)N1CCCCC1 MLACQEBQGUBHKX-UHFFFAOYSA-N 0.000 description 1
• YFJAIURZMRJPDB-UHFFFAOYSA-N n,n-dimethylpiperidin-4-amine Chemical compound CN(C)C1CCNCC1 YFJAIURZMRJPDB-UHFFFAOYSA-N 0.000 description 1
• PSBGROLQRNSAMY-UHFFFAOYSA-N n-(3-chlorophenyl)-4-methyl-3-(2-pyrazolo[1,5-a]pyrimidin-6-ylethynyl)benzamide Chemical compound C1=C(C#CC2=CN3N=CC=C3N=C2)C(C)=CC=C1C(=O)NC1=CC=CC(Cl)=C1 PSBGROLQRNSAMY-UHFFFAOYSA-N 0.000 description 1
• PHHRKRGXWSEXFZ-UHFFFAOYSA-N n-(pyridin-3-ylmethyl)-3-[[2-[(2,3,4-trifluorophenoxy)methyl]-1,3-benzoxazol-4-yl]oxy]propan-1-amine Chemical compound FC1=C(F)C(F)=CC=C1OCC(OC1=CC=C2)=NC1=C2OCCCNCC1=CC=CN=C1 PHHRKRGXWSEXFZ-UHFFFAOYSA-N 0.000 description 1
• LBTPCAAJDFFVTA-UHFFFAOYSA-N n-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanesulfonamide Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC(NS(C)(=O)=O)=C1 LBTPCAAJDFFVTA-UHFFFAOYSA-N 0.000 description 1
• RCSBCWXPGSPJNF-UHFFFAOYSA-N n-[4-[5-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl]butyl]-4-(1,8-naphthyridin-2-yl)butanamide Chemical compound C1=C(Cl)C(OC(F)(F)F)=CC=C1C(O1)=NN=C1CCCCNC(=O)CCCC1=CC=C(C=CC=N2)C2=N1 RCSBCWXPGSPJNF-UHFFFAOYSA-N 0.000 description 1
• XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
• VQVCFYIDCWPSNE-UHFFFAOYSA-N n-methyl-3-[(2-naphthalen-2-ylacetyl)amino]benzamide Chemical compound CNC(=O)C1=CC=CC(NC(=O)CC=2C=C3C=CC=CC3=CC=2)=C1 VQVCFYIDCWPSNE-UHFFFAOYSA-N 0.000 description 1
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
• 125000004957 naphthylene group Chemical group 0.000 description 1
• 239000007923 nasal drop Substances 0.000 description 1
• 229940100662 nasal drops Drugs 0.000 description 1
• 230000001338 necrotic effect Effects 0.000 description 1
• JWNPDZNEKVCWMY-VQHVLOKHSA-N neratinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 JWNPDZNEKVCWMY-VQHVLOKHSA-N 0.000 description 1
• 229950008835 neratinib Drugs 0.000 description 1
• FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
• 150000002825 nitriles Chemical class 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
• 239000012038 nucleophile Substances 0.000 description 1
• 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
• 230000009437 off-target effect Effects 0.000 description 1
• 238000011275 oncology therapy Methods 0.000 description 1
• 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
• 150000007524 organic acids Chemical class 0.000 description 1
• 235000005985 organic acids Nutrition 0.000 description 1
• 239000003960 organic solvent Substances 0.000 description 1
• 229960003278 osimertinib Drugs 0.000 description 1
• DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 1
• PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 1
• 125000000466 oxiranyl group Chemical group 0.000 description 1
• 239000001301 oxygen Substances 0.000 description 1
• 108010058266 p21-Activated Kinases Proteins 0.000 description 1
• 102000006271 p21-Activated Kinases Human genes 0.000 description 1
• 238000004806 packaging method and process Methods 0.000 description 1
• 229960001592 paclitaxel Drugs 0.000 description 1
• 229910052763 palladium Inorganic materials 0.000 description 1
• PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
• RUVINXPYWBROJD-UHFFFAOYSA-N para-methoxyphenyl Natural products COC1=CC=C(C=CC)C=C1 RUVINXPYWBROJD-UHFFFAOYSA-N 0.000 description 1
• 238000007911 parenteral administration Methods 0.000 description 1
• 230000035515 penetration Effects 0.000 description 1
• 239000012466 permeate Substances 0.000 description 1
• 229940124531 pharmaceutical excipient Drugs 0.000 description 1
• 150000003003 phosphines Chemical class 0.000 description 1
• 150000003904 phospholipids Chemical class 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
• 150000004885 piperazines Chemical class 0.000 description 1
• 150000003053 piperidines Chemical class 0.000 description 1
• 239000013612 plasmid Substances 0.000 description 1
• 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
• 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
• 239000011148 porous material Substances 0.000 description 1
• 238000011533 pre-incubation Methods 0.000 description 1
• 238000001556 precipitation Methods 0.000 description 1
• 238000002953 preparative HPLC Methods 0.000 description 1
• 230000002035 prolonged effect Effects 0.000 description 1
• 239000003380 propellant Substances 0.000 description 1
• 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
• 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
• 238000000159 protein binding assay Methods 0.000 description 1
• 230000002797 proteolythic effect Effects 0.000 description 1
• WYRIWHXERKODLJ-UHFFFAOYSA-N pyridin-4-ylboronic acid;hydrate Chemical compound O.OB(O)C1=CC=NC=C1 WYRIWHXERKODLJ-UHFFFAOYSA-N 0.000 description 1
• 150000003222 pyridines Chemical class 0.000 description 1
• 125000001422 pyrrolinyl group Chemical group 0.000 description 1
• 230000005855 radiation Effects 0.000 description 1
• 238000004725 rapid separation liquid chromatography Methods 0.000 description 1
• 238000013102 re-test Methods 0.000 description 1
• 239000011541 reaction mixture Substances 0.000 description 1
• 230000009257 reactivity Effects 0.000 description 1
• 238000003753 real-time PCR Methods 0.000 description 1
• 238000003259 recombinant expression Methods 0.000 description 1
• 239000012088 reference solution Substances 0.000 description 1
• 230000014493 regulation of gene expression Effects 0.000 description 1
• 230000001105 regulatory effect Effects 0.000 description 1
• 230000003014 reinforcing effect Effects 0.000 description 1
• 230000027425 release of sequestered calcium ion into cytosol Effects 0.000 description 1
• 230000008521 reorganization Effects 0.000 description 1
• 230000002441 reversible effect Effects 0.000 description 1
• 239000012146 running buffer Substances 0.000 description 1
• YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
• 229960001860 salicylate Drugs 0.000 description 1
• 238000007423 screening assay Methods 0.000 description 1
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
• 230000028327 secretion Effects 0.000 description 1
• 238000000926 separation method Methods 0.000 description 1
• 238000007493 shaping process Methods 0.000 description 1
• 230000007727 signaling mechanism Effects 0.000 description 1
• 206010041232 sneezing Diseases 0.000 description 1
• 239000001632 sodium acetate Substances 0.000 description 1
• 235000017281 sodium acetate Nutrition 0.000 description 1
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
• 239000008354 sodium chloride injection Substances 0.000 description 1
• 230000003381 solubilizing effect Effects 0.000 description 1
• 238000001179 sorption measurement Methods 0.000 description 1
• 238000004611 spectroscopical analysis Methods 0.000 description 1
• 238000001228 spectrum Methods 0.000 description 1
• 230000006641 stabilisation Effects 0.000 description 1
• 238000011105 stabilization Methods 0.000 description 1
• 238000010186 staining Methods 0.000 description 1
• HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
• CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
• 210000000130 stem cell Anatomy 0.000 description 1
• 230000023895 stem cell maintenance Effects 0.000 description 1
• 239000011550 stock solution Substances 0.000 description 1
• 238000007920 subcutaneous administration Methods 0.000 description 1
• 125000004426 substituted alkynyl group Chemical group 0.000 description 1
• 239000000758 substrate Substances 0.000 description 1
• 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
• 239000004094 surface-active agent Substances 0.000 description 1
• 239000000375 suspending agent Substances 0.000 description 1
• 239000003765 sweetening agent Substances 0.000 description 1
• 208000024891 symptom Diseases 0.000 description 1
• 230000005469 synchrotron radiation Effects 0.000 description 1
• 229940120982 tarceva Drugs 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
• WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 1
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• 108091008743 testicular receptors 4 Proteins 0.000 description 1
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
• 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
• 125000005710 tetrahydropyranylene group Chemical group 0.000 description 1
• 238000002849 thermal shift Methods 0.000 description 1
• 239000002562 thickening agent Substances 0.000 description 1
• 125000001730 thiiranyl group Chemical group 0.000 description 1
• 125000000341 threoninyl group Chemical class [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
• 231100000419 toxicity Toxicity 0.000 description 1
• 230000001988 toxicity Effects 0.000 description 1
• 239000000196 tragacanth Substances 0.000 description 1
• 235000010487 tragacanth Nutrition 0.000 description 1
• 229940116362 tragacanth Drugs 0.000 description 1
• 230000007704 transition Effects 0.000 description 1
• 238000011269 treatment regimen Methods 0.000 description 1
• 229940066528 trichloroacetate Drugs 0.000 description 1
• YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
• 229940029284 trichlorofluoromethane Drugs 0.000 description 1
• 238000007039 two-step reaction Methods 0.000 description 1
• 238000002211 ultraviolet spectrum Methods 0.000 description 1
• 230000003827 upregulation Effects 0.000 description 1
• 238000010200 validation analysis Methods 0.000 description 1
• 235000015112 vegetable and seed oil Nutrition 0.000 description 1
• 239000008158 vegetable oil Substances 0.000 description 1
• 230000003612 virological effect Effects 0.000 description 1
• 239000011534 wash buffer Substances 0.000 description 1
• 239000003643 water by type Substances 0.000 description 1
• 239000008215 water for injection Substances 0.000 description 1
• 239000000080 wetting agent Substances 0.000 description 1
• UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1