CN115403575A - 杂芳环类衍生物及其制备方法和用途 - Google Patents
杂芳环类衍生物及其制备方法和用途 Download PDFInfo
- Publication number
- CN115403575A CN115403575A CN202210100843.3A CN202210100843A CN115403575A CN 115403575 A CN115403575 A CN 115403575A CN 202210100843 A CN202210100843 A CN 202210100843A CN 115403575 A CN115403575 A CN 115403575A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- group
- heteroaryl
- cancer
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 125000001072 heteroaryl group Chemical group 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 125000001424 substituent group Chemical group 0.000 claims abstract description 47
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 239000003814 drug Substances 0.000 claims abstract description 10
- 101710113436 GTPase KRas Proteins 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 93
- 150000001875 compounds Chemical class 0.000 claims description 92
- 125000000623 heterocyclic group Chemical group 0.000 claims description 66
- 125000003118 aryl group Chemical group 0.000 claims description 63
- -1 nitro, amino Chemical group 0.000 claims description 59
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 57
- 229910052736 halogen Inorganic materials 0.000 claims description 51
- 150000002367 halogens Chemical class 0.000 claims description 51
- 125000003545 alkoxy group Chemical group 0.000 claims description 46
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 40
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 39
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 31
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 201000005202 lung cancer Diseases 0.000 claims description 14
- 208000020816 lung neoplasm Diseases 0.000 claims description 14
- 206010069755 K-ras gene mutation Diseases 0.000 claims description 13
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 102200006538 rs121913530 Human genes 0.000 claims description 12
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- 230000035772 mutation Effects 0.000 claims description 11
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 10
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 10
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 10
- 206010009944 Colon cancer Diseases 0.000 claims description 9
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 9
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 8
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 201000002528 pancreatic cancer Diseases 0.000 claims description 8
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 claims description 5
- 208000034578 Multiple myelomas Diseases 0.000 claims description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 5
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 5
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 4
- 206010004593 Bile duct cancer Diseases 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 229940122242 GTPase inhibitor Drugs 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 201000000331 Testicular germ cell cancer Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 208000026900 bile duct neoplasm Diseases 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 150000007942 carboxylates Chemical group 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000010106 skin squamous cell carcinoma Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- 206010046766 uterine cancer Diseases 0.000 claims description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 229940125399 kras g12c inhibitor Drugs 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims 2
- 208000037845 Cutaneous squamous cell carcinoma Diseases 0.000 claims 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 2
- 201000010881 cervical cancer Diseases 0.000 claims 2
- 229940125532 enzyme inhibitor Drugs 0.000 abstract description 3
- 239000002532 enzyme inhibitor Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 18
- 102000016914 ras Proteins Human genes 0.000 description 16
- 239000000203 mixture Substances 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 125000002619 bicyclic group Chemical group 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 102000004169 proteins and genes Human genes 0.000 description 9
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 125000003367 polycyclic group Chemical group 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 229940124785 KRAS inhibitor Drugs 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 125000006413 ring segment Chemical group 0.000 description 6
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 6
- 239000012980 RPMI-1640 medium Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- QVLMARHBOOFWIO-UHFFFAOYSA-N (3-fluoro-2-methoxyphenyl)thiourea Chemical compound COC1=C(F)C=CC=C1NC(N)=S QVLMARHBOOFWIO-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000011535 reaction buffer Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- SYXIINHHRQQNGK-UHFFFAOYSA-N 1,3-thiazol-4-ol Chemical compound [O-]C1=CSC=[NH+]1 SYXIINHHRQQNGK-UHFFFAOYSA-N 0.000 description 3
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 3
- 102000018898 GTPase-Activating Proteins Human genes 0.000 description 3
- 108091006094 GTPase-accelerating proteins Proteins 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 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 3
- 229930006000 Sucrose Natural products 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 229920001615 Tragacanth Polymers 0.000 description 3
- 235000010419 agar Nutrition 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 3
- 235000012216 bentonite Nutrition 0.000 description 3
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 102000049555 human KRAS Human genes 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 108010014186 ras Proteins Proteins 0.000 description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 2
- ZOPJSIWUOKNVON-UHFFFAOYSA-N 1,3-thiazol-4-yl trifluoromethanesulfonate Chemical compound S1C=NC(=C1)OS(=O)(=O)C(F)(F)F ZOPJSIWUOKNVON-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 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 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 102100030708 GTPase KRas Human genes 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- KVVMXWRFYAGASO-UHFFFAOYSA-N azetidine-1-carboxylic acid Chemical compound OC(=O)N1CCC1 KVVMXWRFYAGASO-UHFFFAOYSA-N 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 201000006612 cervical squamous cell carcinoma Diseases 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000003906 humectant Substances 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 231100000590 oncogenic Toxicity 0.000 description 2
- 230000002246 oncogenic effect Effects 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 238000000611 regression analysis Methods 0.000 description 2
- 102200006531 rs121913529 Human genes 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 229940054269 sodium pyruvate Drugs 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- PEMUGDMSUDYLHU-ZEQRLZLVSA-N 2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile Chemical compound ClC=1C=CC=C2C=CC=C(C=12)N1CC=2N=C(N=C(C=2CC1)N1C[C@@H](N(CC1)C(C(=C)F)=O)CC#N)OC[C@H]1N(CCC1)C PEMUGDMSUDYLHU-ZEQRLZLVSA-N 0.000 description 1
- YRYQLVCTQFBRLD-UIOOFZCWSA-N 2-[(2S)-4-[7-(8-methylnaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoylpiperazin-2-yl]acetonitrile Chemical compound C(C=C)(=O)N1[C@H](CN(CC1)C=1C2=C(N=C(N=1)OC[C@H]1N(CCC1)C)CN(CC2)C1=CC=CC2=CC=CC(=C12)C)CC#N YRYQLVCTQFBRLD-UIOOFZCWSA-N 0.000 description 1
- 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 1
- GKOCMECQJXRXIB-UHFFFAOYSA-N 2-amino-5-fluoro-1,3-benzothiazol-4-ol Chemical compound NC1=NC(C(O)=C(C=C2)F)=C2S1 GKOCMECQJXRXIB-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- JNODDICFTDYODH-UHFFFAOYSA-N 2-hydroxytetrahydrofuran Chemical compound OC1CCCO1 JNODDICFTDYODH-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- RCYMPYMITUEHOJ-UHFFFAOYSA-N 3-fluoro-2-methoxyaniline Chemical compound COC1=C(N)C=CC=C1F RCYMPYMITUEHOJ-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- DPXCDPQFBWIJIX-UHFFFAOYSA-N 5-fluoro-4-methoxy-1,3-benzothiazol-2-amine Chemical compound COC(C1=C(C=C2)SC(N)=N1)=C2F DPXCDPQFBWIJIX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- QSYNBTOEZUZLCI-UHFFFAOYSA-N BrC1=C(C=C2C(=C(C=NC2=C1F)[N+](=O)[O-])Cl)Cl Chemical compound BrC1=C(C=C2C(=C(C=NC2=C1F)[N+](=O)[O-])Cl)Cl QSYNBTOEZUZLCI-UHFFFAOYSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- HFWJRBSBEKBPKU-UHFFFAOYSA-N CC(C)(C)OC(NC1=NC(C(OS(C(F)(F)F)(=O)=O)=C(C=C2)F)=C2S1)=O Chemical compound CC(C)(C)OC(NC1=NC(C(OS(C(F)(F)F)(=O)=O)=C(C=C2)F)=C2S1)=O HFWJRBSBEKBPKU-UHFFFAOYSA-N 0.000 description 1
- NJTZSWLQBQJUHK-UHFFFAOYSA-N CCCP(=O)=O Chemical compound CCCP(=O)=O NJTZSWLQBQJUHK-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 244000239659 Eucalyptus pulverulenta Species 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 102100029974 GTPase HRas Human genes 0.000 description 1
- 102100039788 GTPase NRas Human genes 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101150012162 H-RAS gene Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000779641 Homo sapiens ALK tyrosine kinase receptor Proteins 0.000 description 1
- 101000584633 Homo sapiens GTPase HRas Proteins 0.000 description 1
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 1
- 101000686031 Homo sapiens Proto-oncogene tyrosine-protein kinase ROS Proteins 0.000 description 1
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 description 1
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 1
- 101000628562 Homo sapiens Serine/threonine-protein kinase STK11 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000004034 Kelch-Like ECH-Associated Protein 1 Human genes 0.000 description 1
- 108090000484 Kelch-Like ECH-Associated Protein 1 Proteins 0.000 description 1
- 101100193693 Kirsten murine sarcoma virus K-RAS gene Proteins 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 102000006335 Phosphate-Binding Proteins Human genes 0.000 description 1
- 108010058514 Phosphate-Binding Proteins Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 description 1
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 1
- 102100026715 Serine/threonine-protein kinase STK11 Human genes 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 206010041834 Squamous cell carcinoma of skin Diseases 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 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
- 102000015098 Tumor Suppressor Protein p53 Human genes 0.000 description 1
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- UJQAHAANAPEYLR-UHFFFAOYSA-N [2-chloro-6-[2,4,6-tri(propan-2-yl)phenyl]phenyl]-dicyclohexylphosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(Cl)=C1P(C1CCCCC1)C1CCCCC1 UJQAHAANAPEYLR-UHFFFAOYSA-N 0.000 description 1
- DPOVEZGQWNNGBG-UHFFFAOYSA-N [5-fluoro-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-benzothiazol-4-yl]boronic acid Chemical compound CC(C)(C)OC(NC1=NC(C(B(O)O)=C(C=C2)F)=C2S1)=O DPOVEZGQWNNGBG-UHFFFAOYSA-N 0.000 description 1
- AQMHNCQZLQUNJI-UHFFFAOYSA-N [CH2]CCCCCC Chemical compound [CH2]CCCCCC AQMHNCQZLQUNJI-UHFFFAOYSA-N 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229940124988 adagrasib Drugs 0.000 description 1
- 208000037844 advanced solid tumor Diseases 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- VXAUWWUXCIMFIM-UHFFFAOYSA-M aluminum;oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Al+3] VXAUWWUXCIMFIM-UHFFFAOYSA-M 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- CPEKAXYCDKETEN-UHFFFAOYSA-N benzoyl isothiocyanate Chemical compound S=C=NC(=O)C1=CC=CC=C1 CPEKAXYCDKETEN-UHFFFAOYSA-N 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000001602 bicycloalkyls Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000012200 cell viability kit Methods 0.000 description 1
- 238000012054 celltiter-glo Methods 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000005827 chlorofluoro hydrocarbons Chemical class 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000005366 cycloalkylthio group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 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
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 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
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 150000002013 dioxins Chemical class 0.000 description 1
- 125000000597 dioxinyl group Chemical group 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 102000034238 globular proteins Human genes 0.000 description 1
- 108091005896 globular proteins Proteins 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([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
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 108700042226 ras Genes Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 102200006539 rs121913529 Human genes 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 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
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229940100996 sodium bisulfate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- NXQKSXLFSAEQCZ-SFHVURJKSA-N sotorasib Chemical compound FC1=CC2=C(N(C(N=C2N2[C@H](CN(CC2)C(C=C)=O)C)=O)C=2C(=NC=CC=2C)C(C)C)N=C1C1=C(C=CC=C1O)F NXQKSXLFSAEQCZ-SFHVURJKSA-N 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- JSURSCDQTBSUPP-UHFFFAOYSA-N tert-butyl 3-(1-aminoethyl)azetidine-1-carboxylate Chemical compound CC(N)C1CN(C(=O)OC(C)(C)C)C1 JSURSCDQTBSUPP-UHFFFAOYSA-N 0.000 description 1
- ZDKPIWKXNAQJRX-UHFFFAOYSA-N tert-butyl N-(5-fluoro-4-hydroxy-1,3-benzothiazol-2-yl)carbamate Chemical compound CC(C)(C)OC(NC1=NC(C(O)=C(C=C2)F)=C2S1)=O ZDKPIWKXNAQJRX-UHFFFAOYSA-N 0.000 description 1
- PUWGYOUDDSFZLF-UHFFFAOYSA-N tert-butyl [5-fluoro-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-benzothiazol-4-yl] carbonate Chemical compound CC(C)(C)OC(NC1=NC(C(OC(OC(C)(C)C)=O)=C(C=C2)F)=C2S1)=O PUWGYOUDDSFZLF-UHFFFAOYSA-N 0.000 description 1
- QUERMGFVJPRMJL-UHFFFAOYSA-N tert-butyl azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC1 QUERMGFVJPRMJL-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
本发明涉及杂芳环类衍生物、其制备方法及其在医药上的应用。具体而言,本发明涉及一种通式(I)所示的杂芳环类衍生物、其制备方法及其可药用的盐,以及它们作为治疗剂,特别是作为K‑Ras GTP酶抑制剂的用途,其中通式(I)中的各取代基的定义与说明书中的定义相同。
Description
技术领域
本发明涉及一种杂芳环类衍生物、其制备方法及含有该衍生物的药物组合物以及其作为治疗剂特别是作为K-Ras GTP酶抑制剂的用途。
背景技术
RAS代表一组紧密相关的单体球状蛋白质(21kDa分子量),其具有189个氨基酸且与质膜相连并且结合GDP或GTP。在正常发育或生理条件下,RAS接收生长因子和各种其它细胞外信号而被激活,负责调节细胞生长、存活、迁移和分化等功能。RAS起分子开关作用,RAS蛋白的开/关状态通过核苷酸结合确定,活性信号传导构象结合GTP,非活性构象结合GDP。当RAS包含结合的GDP时,其处于休眠或静止或关闭状态,并且是“非活化的”。当细胞暴露于某些生长促进刺激物进行响应时,RAS被诱导将结合的GDP转换为GTP。随着GTP被结合,RAS是“开启的”,并且能够与其它蛋白相互作用且活化其它蛋白(其“下游靶标”)。RAS蛋白本身具有极低的将GTP水解回到GDP并由此将自身变为关闭状态的固有能力。将RAS转换为关闭需要称作GTP酶激活蛋白(GAPs)的外源性蛋白,其与RAS相互作用并且能大大促进GTP向GDP的转化。任何在RAS中的影响其与GAP相互作用或将GTP转化回到GDP的能力的突变,将会导致所述蛋白的延长的活化,并且因此产生到细胞的延长的信号,该信号告知其继续生长和***。因此这些信号会使得细胞生长和***,过度活化的RAS信号转导可能最终导致癌症。
在结构上,RAS蛋白包含负责RAS的酶促活性-----鸟嘌呤核苷酸结合和水解(GTP酶反应)的G结构域。其还包括含称为CAAX盒的C端延伸区,其可被转译后修饰并且使该蛋白靶向膜。G结构域在尺寸上大约为21-25kDa并含有磷酸结合环(P-环)。P-环表示蛋白中结合核苷酸的囊袋,并且这是具有保守氨基酸残基的结构域的刚性部分,所述保守氨基酸残基为核苷酸结合和水解所必需的(甘氨酸12、苏氨酸26和赖氨酸16)。G结构域还含有所谓的开关I区(残基30-40)和开关II区(残基60-76),其均为蛋白的动态部分,由于该动态部分在静止和负载状态之间进行转换的能力而常常被表示为“弹簧加载”机制。主要相互作用为由苏氨酸-35和甘氨酸-60与GTP的γ-磷酸所形成的氢键,其使开关I区和开关II区分别维持它们的活性构象。在水解GTP和释放磷酸盐之后,此两者松弛成无活性的GDP构象。
在RAS家族成员中,致癌突变最常见于KRAS(85%),而NRAS(12%)和HRAS(3%)则较为少见。KRAS突变在美国三大致命癌症类型中普遍存在:胰腺癌(95%)、结肠直肠癌(45%)和肺癌(25%),在包括多发性骨髓瘤、子宫癌、胆管癌、胃癌、膀胱癌、弥漫性大B细胞淋巴瘤、横纹肌肉瘤、皮肤鳞状细胞癌、***、睾丸生殖细胞癌等在内的其他癌症类型中也发现KRAS突变,而在乳腺癌、卵巢癌和脑癌中很少发现(<2%)。在非小细胞肺癌(NSCLC)中,KRAS G12C是最常见的突变,占所有KRAS突变的近一半,其次是G12V和G12D。在非小细胞肺癌中,特定等位基因突变频率的增加多来自经典的由吸烟诱导的典型突变(G:C至T:A置换),从而导致了KRAS G12C(GGT至TGT)和G12V(GGT至GTT)突变。
大型基因组学研究表明,肺癌KRAS突变,包括G12C,与NSCLC中其它已知的驱动致癌突变相互排斥,包括EGFR、ALK、ROS1、RET和BRAF,表明KRAS突变在肺癌中的独特性。而同时,KRAS突变经常与某些共突变同时发生,例如STK11、KEAP1和TP53,它们与突变的RAS合作将细胞转化为高度恶性和侵袭性的肿瘤细胞。
三种RAS癌基因构成了人类癌症中突变最频繁的基因家族。令人失望的是,尽管经过三十多年的研究努力,临床上仍然没有有效的抗RAS疗法,使用小分子靶向该基因是项挑战。因此,本领域迫切需要用于靶向RAS(例如,K-RAS,H-RAS和/或N-RAS)的小分子并且利用其治疗多种疾病,例如癌症。
目前,国内外对于KRAS抑制剂的临床开发竞争激烈,其中Mirati TherapeuticsInc公司研发的KRAS酶抑制剂MRTX-849已经进入临床二期,用于预防和治疗晚期实体瘤、转移性结直肠癌和转移性非小细胞肺癌等疾病。同时还有其他在研的KRAS抑制剂,包括AMG-510(Amgen Inc,phase 2)和MRTX1257(Mirati Therapeutics Inc,发现)。早期的临床研究表明,KRAS抑制剂显著控制和缓解非小细胞肺癌患者疾病进展,并且显著降低了晚期肺癌和大肠癌患者的肿瘤大小。目前已经公开了一系列的KRAS抑制剂专利申请,其中包括WO2020047192、WO2019099524和WO2018217651等,KRAS抑制剂的研究和应用已取得一定的进展,但是提高的空间仍然巨大,仍有必要继续研究和开发新的KRAS抑制剂。
发明内容
本发明的目的在于提供一种通式(I)所示的杂芳环类衍生物,或其立体异构体、互变异构体或其可药用的盐:
其中:
环B选自5~6元杂芳基或5-6元杂环基;
X和Y各自独立地选自N或CR4;
L选自C1-C6亚烷基,其中所述的亚烷基任选进一步被一个或多个选自烷基、环烷基、杂环基、芳基、杂芳基、卤素、氰基、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5的取代基所取代;
G选自一个含有1-2个氮原子的4~12元的杂环基,其中所述杂环基任选进一步被一个或多个Rc所取代;
Ra选自氢原子或氟;
Rb选自氢原子、-CH2F、-CHF2或-CH2-NR6R7;
Rc相同或不同,各自独立地选自氢原子、烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5的取代基所取代;
R1选自氢原子、卤素、烷基或烷氧基;其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代;R1优选为氢原子;
R2选自芳基或杂芳基,其中所述的芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5的取代基所取代;其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5-NHC(O)OR5、-NR6R7、-C(O)NR6R7、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5的取代基所取代;
R3选自不存在、氢原子、卤素、烷基、烷氧基、氰基、卤代烷基或卤代烷氧基,优选为不存在或氢原子;
R4相同或不同,各自独立地选自氢原子、卤素、烷基或烷氧基;其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代;R4优选为卤素,更优选为氟或氯;
R5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
R6和R7各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
或者,R6和R7与它们相连接的原子一起形成一个4~8元杂环基,其中4~8元杂环基内含有一个或多个N、O或S(O)r,并且所述的4~8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
R8、R9和R10各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代;
n选自0、1或2;
r为0、1或2。
本发明提供一种通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其为通式(II)所示的化合物或其立体异构体、互变异构体或其可药用的盐:
其中:
环B、R1~R4、L、G、E和n的定义如通式(I)中所述。
本发明提供一种通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
-G-E选自:
Rc相同或不同,各自独立地选自氢原子、卤素、烷基或烷氧基,优选烷基,更优选为甲基;
m选自0、1、2、3或4;
E的定义如通式(I)中所述。
本发明的优选方案,本发明提供一种通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
-G-E选自:
Rc相同或不同,各自独立地选自氢原子、卤素、烷基或烷氧基,优选烷基,更优选为甲基;m选自0、1、2、3或4;
E选自:
本发明的优选方案,本发明提供一种通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R1选自氢原子、卤素、烷基、烷氧基、卤代烷基或卤代烷氧基,R1优选为氢原子。
本发明的优选方案,本发明提供一种通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
R2选自苯基、萘基、吡啶基、苯并噻唑基或苯并吡唑基,其中所述的苯基、萘基、吡啶基、苯并噻唑基或苯并吡唑基任选进一步被一个或多个选自卤素、羟基、烷基、烷氧基、环烷基或-NR6R7的取代基所取代,其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素或-NR6R7的取代基所取代;其中所述的卤素优选为氟;
R6和R7各自独立地选自氢原子或烷基,其中所述烷基优选为甲基。
本发明的优选方案,本发明提供一种通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
R2选自:
本发明的优选方案,本发明提供一种通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R3选自不存在或氢原子。
本发明的优选方案,本发明提供一种通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中环B选自:
R3的定义如通式(I)中所述。
本发明的优选方案,本发明提供一种通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R4选自氢原子、卤素、烷基、烷氧基、卤代烷基或卤代烷氧基,R4优选为卤素,更优选为氟或氯。
本发明的优选方案,本发明提供一种通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中L选自-CH2-、-CH2CH2-或-CH(CH3)-。
本发明的典型化合物包括,但不限于:
或其立体异构体、互变异构体或其可药用的盐。
注:如果在画出的结构和给出的该结构的名称之间有差异,则画出的结构将给予更大的权重。
进一步,本发明提供通式(I)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法,所述方法为:
通式(IA)化合物与通式(IB)化合物在碱性条件下反应,任选进一步脱去保护基,得到通式(I)化合物;
其中:
X1为离去基团,优选为氯;
环B、R1~R3、X、Y、L、G、E和n的定义如通式(I)中所述。
在另一方面,本发明提供一种药物组合物,所述的药物组合物含有有效剂量的通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合。
在另一方面,本发明提供一种抑制K-Ras GTP酶方法,其中所述的方法包括,给予病人一种药物组合物,所述的药物组合物含有有效剂量的通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合,其中K-Ras GTP酶优选为KRAS G12C。
本发明还提供了一种通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗由KRAS突变介导的疾病的药物中的用途,其中所述的由KRAS突变介导的疾病选自癌症,其中所述的癌症选自胰腺癌、结肠直肠癌、肺癌、多发性骨髓瘤、子宫癌、胆管癌、胃癌、膀胱癌、弥漫性大B细胞淋巴瘤、横纹肌肉瘤、皮肤鳞状细胞癌、***、睾丸生殖细胞癌,优选为胰腺癌、结肠直肠癌和肺癌;其中所述的肺癌优选为非小细胞肺癌。
在另一方面,本发明提供一种通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备K-Ras GTP酶抑制剂中的用途,其中K-RasGTP酶抑制剂优选为KRAS G12C抑制剂。
本发明的另一方面涉及一种预防和/或治疗KRAS突变介导的疾病的方法,其包括向患者施用治疗有效剂量的通式(I)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式或其可药用盐或包含其的药物组合物,其中所述的KRAS突变优选为KRAS G12C突变。
本发明还提供了一种通式(I)或(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐,或其药物组合物在制备治疗癌症的药物中的用途,其中所述的癌症选自胰腺癌、结肠直肠癌、肺癌、多发性骨髓瘤、子宫癌、胆管癌、胃癌、膀胱癌、弥漫性大B细胞淋巴瘤、横纹肌肉瘤、皮肤鳞状细胞癌、***、睾丸生殖细胞癌,优选为胰腺癌、结肠直肠癌和肺癌;其中所述的肺癌优选为非小细胞肺癌。
本发明的药物制剂可以经局部、口服、经皮、经直肠、经***、非经肠、鼻内、肺内、眼内、静脉内、肌肉内、动脉内、鞘内、囊内、皮内、腹膜内、皮下、角质层下或者通过吸入进行给药。含活性成分的药物组合物可以是适用于口服的形式,例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊,或糖浆剂或酏剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。
本发明的制剂适合以单位计量的形式存在,并且所述制剂可借由在制药技术中所众所周知的任何方法进行制备。能够通过与载体物质进行组合,从而产生单一剂型的活性成分的量可以依据所治疗的宿主及特定给药模式而变化。能够通过与载体物质进行组合从而产生单一剂型的活性成分的量通常指的是能够产生治疗效果的化合物的量。
用于本发明化合物的局部或者透皮给药的剂型可包括粉末、喷雾剂、软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液、贴片及吸入剂。活性化合物可在无菌条件下与药学上可接受的载剂进行混合,并且其可与可能需要的任何防腐剂、缓冲剂或者推进剂进行混合。
当本发明的化合物以药物的形式对人类及动物进行给药时,所述化合物可进行单独提供或者以药物组合物的形式提供,所述药物组合物含有与药学上可接受的载剂进行组合的活性成分,例如0.1%至99.5%(更优选地,0.5%至90%)的活性成分。
药学上可接受的载剂的实例包括但不限于:(1)糖,例如乳糖、葡萄糖及蔗糖;(2)淀粉,例如玉米淀粉及马铃薯淀粉;(3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素及乙酸纤维素;(4)粉末状黄蓍胶;(5)麦芽;(6)明胶;(7)滑石;(8)赋形剂,例如可可脂及栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨糖醇、甘露糖醇及聚乙二醇;(12)酯,例如油酸乙酯及月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁及氢氧化铝;(15)海藻酸;(16)无热原水;(17)等渗盐水;(18)林格氏溶液(Ringer's solution);(19)乙醇;(20)磷酸盐缓冲溶液;(21)环糊精,例如连接于纳米粒子的靶向配体,例如AccurinsTM;及(22)用于药物制剂中的其它无毒兼容物质,例如聚合物基组合物。
药学上可接受的抗氧化剂的实例包括但不限于:(1)水溶性抗氧化剂,例如抗坏血酸、半胱胺酸盐酸盐、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠及其类似物;(2)油溶性抗氧化剂,例如抗坏血酸棕榈酸酯、丁基化羟基苯甲醚(BHA)、丁基化羟基甲苯(BHT)、卵磷脂、五倍子酸丙酯、α-生育酚及其类似物;及(3)金属螯合剂,例如柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸及其类似物。固体剂型(例如胶囊、锭剂丸剂、糖衣锭、粉末、颗粒剂及其类似物)可包括一种或者多种药学上可接受的载剂,例如柠檬酸钠或者磷酸二钙,和/或以下任意其中之一:(1)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇及/或者硅酸;(2)黏合剂,例如羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯啶酮、蔗糖和/或***胶;(3)保湿剂,例如甘油;(4)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐及碳酸钠;(5)溶解阻滞剂,例如石蜡;(6)吸收加速剂,例如四级铵化合物;(7)湿润剂,例如十六醇及甘油单硬脂酸酯;(8)吸收剂,例如高岭土及膨润土;(9)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物;和(10)着色剂。液体剂型可包括药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆及酏剂。除活性成分之外,液体剂型可含有通常用于本技术领域中的惰性稀释剂,例如水或其它溶剂;增溶剂及乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙脂、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油、及芝麻油)、甘油、四氢呋喃甲醇、聚乙二醇以及脱水山梨醇的脂肪酸酯、及其混合物。
除活性化合物之外,悬浮液也可含有悬浮剂,例如乙氧基化异硬脂醇、聚氧化乙烯山梨糖醇及脱水山梨醇酯、微晶纤维素、氢氧化铝氧化物、膨润土、琼脂及黄蓍胶及其混合物。
除活性化合物之外,软膏剂、糊剂、乳膏剂以及凝胶剂也可含有赋形剂,例如动物脂肪及植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、聚硅氧、膨润土、硅酸、滑石及氧化锌或者其混合物。
除活性化合物之外,粉末及喷雾剂也可以含有赋形剂,例如乳糖、滑石、硅酸、氢氧化铝、硅酸钙及聚酰胺粉末或者上述这些物质的混合物。所述喷雾剂可以含有其它的常用推进剂,例如氯氟烃、以及挥发性的未被取代的烃,例如丁烷及丙烷。
发明的详细说明
除非有相反陈述,否则本发明在说明书和权利要求书中所使用的部分术语定义如下:
“烷基”当作一基团或一基团的一部分时是指包括C1-C20直链或者带有支链的脂肪烃基团。优选为C1-C10烷基,更优选为C1-C6烷基。烷基基团的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上定义的烷基,代表性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-,2-或3-丁烯基等。烯基可以是任选取代的或未取代的。
“炔基”是指含有一个碳碳三键的脂肪烃基团,可为直链也可以带有支链。优先选择的是C2-C10的炔基,更优选C2-C6炔基,最优选C2-C4炔基。炔基基团的实施例包括,但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。炔基可以是取代或未取代的。
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环。优选为C3-C12环烷基,更优选为C3-C8环烷基,最优选为C3-C6环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等,优选环丙基、环己烯基。环烷基可以是任选取代的或未取代的。
“螺环烷基”指5至18元,两个或两个以上环状结构,且单环之间彼此共用一个碳原子(称螺原子)的多环基团,环内含有1个或多个双键,但没有一个环具有完全共轭的π电子的芳香***。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺、双螺或多螺环烷基,优选为单螺和双螺环烷基,优选为4元/5元、4元/6元、5元/5元或5元/6元。“螺环烷基”的非限制性实施例包括但不限于:螺[4.5]癸基、螺[4.4]壬基、螺[3.5]壬基、螺[2.4]庚基。
“稠环烷基”指5至18元,含有两个或两个以上环状结构彼此共用一对碳原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,优选为6至12元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环烷基。“稠环烷基”的非限制性实施例包括但不限于:二环[3.1.0]己基、二环[3.2.0]庚-1-烯基、二环[3.2.0]庚基、十氢化萘基或十四氢菲基。
“桥环烷基”指5至18元,含有两个或两个以上环状结构,彼此共用两个不直接相连接碳原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,优选为6至12元,更优选为7至10元。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,优选为双环、三环或四环,更有选为双环或三环。“桥环烷基”的非限制性实施例包括但不限于:(1s,4s)-二环[2.2.1]庚基、二环[3.2.1]辛基、(1s,5s)-二环[3.3.1]壬基、二环[2.2.2]辛基、(1r,5r)-二环[3.3.2]癸基。
“杂环基”、“杂环”或“杂环的”在本申请中可交换使用,都是指非芳香性杂环基,其中一个或多个成环的原子是杂原子,如氧、氮、硫原子等,包括单环、稠环、桥环和螺环。优选具有5至7元单环或7至10元双或三环,其可以包含1,2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于吗啉基,氧杂环丁烷基,硫代吗啉基,四氢吡喃基,1,1-二氧代硫代吗啉基,哌啶基,2-氧代哌啶基,吡咯烷基,2-氧代吡咯烷基,哌嗪-2-酮,8-氧杂-3-氮杂-双环[3.2.1]辛基和哌嗪基。杂环基可以是取代或未取代的。
“螺杂环基”指5至18元,两个或两个以上环状结构,且单环之间彼此共用一个原子的多环基团,环内含有1个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,其中一个或多个环原子选自氮、氧或S(O)r(其中r选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。“螺杂环基”的非限制性实施例包括但不限于:1,7-二氧杂螺[4.5]癸基、2-氧杂-7-氮杂螺[4.4]壬基、7-氧杂螺[3.5]壬基和5-氧杂螺[2.4]庚基。
“稠杂环基”指含有两个或两个以上环状结构彼此共用一对原子的全碳多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,其中一个或多个环原子选自氮、氧或S(O)r(其中r选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基,优选为双环或三环,更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环基”的非限制性实施例包括但不限于:八氢吡咯并[3,4-c]吡咯基、八氢-1H-异吲哚基,3-氮杂二环[3.1.0]己基,八氢苯并[b][1,4]二噁英(dioxine)。
“桥杂环基”指5至14元,5至18元,含有两个或两个以上环状结构,彼此共用两个不直接相连接的原子的多环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子的芳香***,其中一个或多个环原子选自氮、氧或S(O)r(其中r选自0、1或2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基,优选为双环、三环或四环,更有选为双环或三环。“桥杂环基”的非限制性实施例包括但不限于:2-氮杂二环[2.2.1]庚基,2-氮杂二环[2.2.2]辛基和2-氮杂二环[3.3.2]癸基。
“芳基”是指含有一个或者两个环的碳环芳香***,其中所述环可以以稠合的方式连接在一起。术语“芳基”包括单环或双环的芳基,比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C6-C10芳基,更优选芳基为苯基和萘基。芳基可以是取代或未取代的。
“杂芳基”是指芳香族5至6元单环或8至10元双环,其可以包含1至4个选自氮、氧和/或硫中的原子。优选为双环杂芳基,“杂芳基”的实施例包括但不限于呋喃基,吡啶基,2-氧代-1,2-二氢吡啶基,哒嗪基,嘧啶基,吡嗪基,噻吩基,异噁唑基,噁唑基,噁二唑基,咪唑基,吡咯基,吡唑基,***基,四氮唑基,噻唑基,异噻唑基,1,2,3-噻二唑基,苯并间二氧杂环戊烯基,苯并噻吩基、苯并咪唑基,吲哚基,异吲哚基,1,3-二氧代-异吲哚基,喹啉基,吲唑基,苯并异噻唑基,苯并噁唑基、苯并异噁唑基、
杂芳基可以是取代或未取代的。
“烷氧基”是指(烷基-O-)的基团。其中,烷基见本文有关定义。C1-C6的烷氧基为优先选择。其实例包括,但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“卤代烷基”是指烷基任选进一步被一个或多个卤素所取代的基团,其中烷基见本文有关定义。
“羟烷基”是指烷基任选进一步被一个或多个羟基所取代的基团,其中烷基见本文有关定义。
“卤代烷氧基”是指(烷基-O-)的烷基任选进一步被一个或多个卤素所取代的基团,其中烷氧基见本文有关定义。
“羟基”指-OH基团。
“卤素”是指氟、氯、溴和碘。
“氨基”指-NH2。
“氰基”指-CN。
“硝基”指-NO2。
“苄基”指-CH2-苯基。
“羧基”指-C(O)OH。
“羧酸酯基”指-C(O)O-烷基或-C(O)O-环烷基,其中烷基、环烷基的定义如上所述。
“DMSO”指二甲基亚砜。
“BOC”指叔丁氧基羰基。
“Ts”指对甲苯磺酰基。
“T3P”指丙基磷酸酐。
“DPPA”指叠氮磷酸二苯酯。
“DEA”指二乙胺。
“X-PHOS Pd G2”氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯(II)。
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”,如无特别指出,均是指基团可被一个或多个选自以下的基团取代:烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基、羧基、羧酸酯基、=O、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5的取代基所取代;
R5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
R6和R7各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
或者,R6和R7与它们相连接的原子一起形成一个4~8元杂环基,其中4~8元杂环基内含有一个或多个N、O或S(O)r,并且所述的4~8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
R8、R9和R10各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代;
r为0、1或2。
本发明化合物可以含有不对称中心或手性中心,因此以不同的立体异构体形式存在。所预期的是,本发明化合物的所有立体异构体形式,包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)和几何(构象)异构体及它们的混合物,如外消旋体混合物,均在本发明的范围内。
除非另外指出,本发明描述的结构还包括此结构的所有异构体(如,非对映异构体、对映异构体和阻转异构体和几何(构象)异构体形式;例如,各不对称中心的R和S构型,(Z)和(E)双键异构体,以及(Z)和(E)构象异构体。因此本发明化合物的单个立体异构体以及对映体混合物、非对映异构体混合物和几何(构象)异构体混合物均在本发明范围内。
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。式(I)所表示的化合物的可药用的盐可以为金属盐、与合适的酸形成的胺盐。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。
本发明化合物的合成方法
为了完成本发明的目的,本发明采用如下技术方案:
本发明通式(I)所述的化合物或其立体异构体、互变异构体或其可药用的盐的制备方法,包括以下步骤:
通式(IA)化合物与通式(IB)化合物在碱性条件下反应,任选进一步脱去保护基,得到通式(I)化合物;
其中:
X1为离去基团,优选为氯;
环B、R1~R3、X、Y、L、G、E和n的定义如通式(I)中所述。
具体实施方式
以下结合实施例用于进一步描述本发明,但这些实施例并非限制着本发明的范围。
实施例
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明,下述实施例是用于说明本发明而不是对本发明的限制。1HNMR图谱是用Bruker仪器(400MHz)测定而得,化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。1HNMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用LC/MS仪测定得到,离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
在下列实例中,除非另有指明,所有温度为摄氏温度,除非另有指明,各种起始原料和试剂来自市售或者是根据已知的方法合成,市售原料和试剂均不经进一步纯化直接使用,除非另有指明,市售厂家包括但不限于上海皓鸿生物医药科技有限公司,上海韶远试剂有限公司,上海毕得医药科技有限公司,萨恩化学技术(上海)有限公司和上海凌凯医药科技有限公司等。
CD3OD:氘代甲醇。
CDCl3:氘代氯仿。
DMSO-d6:氘代二甲基亚砜。
实施例中无特殊说明,反应中的溶液是指水溶液。
对化合物进行纯化,采用柱层析和薄层色谱法的洗脱剂体系,其中该体系选自:A:石油醚和乙酸乙酯体系;B:二氯甲烷和甲醇体系;C:二氯甲烷和乙酸乙酯体系,D:二氯甲烷和乙醇体系,E:乙酸乙酯和四氢呋喃体系,其中溶剂的体积比根据化合物的极性不同而不同,也可以加入少量的酸性或碱性试剂进行条件,如醋酸或三乙胺等。
室温:20℃~30℃。
实施例1
1-(3-(1-(7-(2-amino-5-fluorobenzo[d]thiazol-4-yl)-8-chloro-6-fluoro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)ethyl)azetidin-1-yl)prop-2-en-1-one
1-(3-(1-(7-(2-氨基-5-氟苯并[d]噻唑-4-基)-8-氯-6-氟-1H-[1,2,3]***并[4,5-c]喹啉-1-基)乙基)氮杂环丁烷-1-基)丙-2-烯-1-酮
第一步
1-(3-fluoro-2-methoxyphenyl)thiourea
1-(3-氟-2-甲氧基苯基)硫脲
将3-氟-2-甲氧基苯胺1a(20g,141.70mmol)加入四氢呋喃(500mL)中,缓慢滴加苯甲酰基异硫氰酸酯1b(23.13g,141.70mmol)的四氢呋喃溶液(100mL),滴加完毕,继续室温反应3小时,LCMS监测原料都转化成中间体,加入水(80mL)、氢氧化钠(6.80g,170.04mmol),加热至80℃反应过夜。冷却至室温,乙酸乙酯萃取(100mL×1),有机相用饱和食盐水洗(100mL×1),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:A体系)分离纯化,得到产物1-(3-氟-2-甲氧基苯基)硫脲1c(22g,109.87mmol),产率:77.55%。MS m/z(ESI):201.1[M+1]+
第二步
5-fluoro-4-methoxybenzo[d]thiazol-2-amine
5-氟-4-甲氧基苯并[d]噻唑-2-胺
将1-(3-氟-2-甲氧基苯基)硫脲1c(7.09g,35.41mmol)加入乙酸(200mL)中,加入溴化锂(4.61g,53.11mmol),缓慢滴加液溴(5.77g,36.12mmol),保持温度低于30℃。滴加完毕后,反应液升温至40℃反应过夜。反应液冷却,倒入水(500mL)中,用饱和碳酸钠溶液调至碱性,乙酸乙酯萃取(300mL×1),有机相用饱和食盐水洗(100mL×1),无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:A体系)分离纯化,得到产物5-氟-4-甲氧基苯并[d]噻唑-2-胺1d(7g,35.31mmol),产率:99.73%。
MS m/z(ESI):199.1[M+1]+
第三步
2-amino-5-fluorobenzo[d]thiazol-4-ol
2-氨基-5-氟苯并[d]噻唑-4-醇
将5-氟-4-甲氧基苯并[d]噻唑-2-胺1d(7g,35.31mmol)加入二氯甲烷(70mL)中,冷却至0℃,滴加三溴化硼(22.12g,88.29mmol,8.51mL),滴加完毕后转至室温反应过夜。反应液倒入冰水(300mL)中,用饱和碳酸钠溶液调至碱性,乙酸乙酯萃取(500mL×1),有机相用饱和食盐水洗(100mL×1),无水硫酸钠干燥,过滤,减压浓缩,得到粗品产物2-氨基-5-氟苯并[d]噻唑-4-醇1e(5.2g,28.23mmol),产率:79.94%。
MS m/z(ESI):185.1[M+1]+
第四步
tert-butyl(4-((tert-butoxycarbonyl)oxy)-5-fluorobenzo[d]thiazol-2-yl)carbamate
(4-((叔丁氧羰基)氧基)-5-氟苯并[d]噻唑-2-基)氨基甲酸叔丁酯
将2-氨基-5-氟苯并[d]噻唑-4-醇1e(10g,54.29mmol)、二甲基氨基吡啶(1.33g,10.86mmol)、三乙胺(10.99g,108.58mmol,15.13mL)、二碳酸二叔丁酯(23.70g,108.58mmol)加入二氯甲烷(80mL)中,室温反应4小时。反应液减压浓缩,加入乙酸乙酯(100mL)和水(50mL),分液,有机相用无水硫酸钠干燥,过滤,减压浓缩,得到粗品产物(4-((叔丁氧羰基)氧基)-5-氟苯并[d]噻唑-2-基)氨基甲酸叔丁酯1f(20g,52.03mmol),产率:95.83%。
MS m/z(ESI):385.1[M+1]+
第五步
tert-butyl(5-fluoro-4-hydroxybenzo[d]thiazol-2-yl)carbamate
(5-氟-4-羟基苯并[d]噻唑-2-基)氨基甲酸叔丁酯
将(4-((叔丁氧羰基)氧基)-5-氟苯并[d]噻唑-2-基)氨基甲酸叔丁酯1f(20g,52.03mmol)加入四氢呋喃(80mL)和水(20mL)的混合溶剂中,冷却至0℃,加入氢氧化锂一水合物(10.92g,260.13mmol),转至室温反应过夜。反应液加入乙酸乙酯(100mL)和水(50mL),乙酸乙酯萃取(100mL×2),合并有机相,无水硫酸钠干燥,过滤,减压浓缩,得到粗品产物(5-氟-4-羟基苯并[d]噻唑-2-基)氨基甲酸叔丁酯1g(14.45g,50.83mmol),产率:97.69%。
MS m/z(ESI):228.9[M+1-56]+
第六步
2-((tert-butoxycarbonyl)amino)-5-fluorobenzo[d]thiazol-4-yltrifluoromethanesulfonate
2-((叔丁氧羰基)氨基)-5-氟苯并[d]噻唑-4-基三氟甲磺酸酯
冰浴下,将(5-氟-4-羟基苯并[d]噻唑-2-基)氨基甲酸叔丁酯1g(20g,70.35mmol)溶于二氯甲烷(80mL)中,依次加入吡啶(11.13g,140.69mmol,11.36mL),三氟甲磺酸酐(23.82g,84.42mmol,14.26mL),搅拌30分钟。反应液加入水(150mL),二氯甲烷萃取(150mL×3),合并有机相,依次用一水合柠檬酸水溶液(50mL),饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:A体系)分离纯化,得到产物2-((叔丁氧羰基)氨基)-5-氟苯并[d]噻唑-4-基三氟甲磺酸酯1h(13.6g,32.66mmol),产率:46.43%。MS m/z(ESI):361.0[M+1-56]+
第七步
(2-((tert-butoxycarbonyl)amino)-5-fluorobenzo[d]thiazol-4-yl)boronicacid
(2-((叔丁氧羰基)氨基)-5-氟苯并[d]噻唑-4-基)硼酸
将2-((叔丁氧羰基)氨基)-5-氟苯并[d]噻唑-4-基三氟甲磺酸酯1h(5g,12.01mmol),联硼酸频那醇酯(24.40g,96.07mmol)混合于1,4-二氧六环(80mL)中,加入乙酸钾(3.54g,36.03mmol),氩气置换,搅拌10分钟,加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(2.64g,3.60mmol),氩气保护,100℃下搅拌8小时。补加联硼酸频那醇酯(24.40g,96.07mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(2.64g,3.60mmol),氩气保护,100℃下继续搅拌8小时。反应液减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:A体系)分离纯化,得到产物(2-((叔丁氧羰基)氨基)-5-氟苯并[d]噻唑-4-基)硼酸1i(2g,6.41mmol),产率:53.36%。
MS m/z(ESI):312.9[M+1]+
第八步
tert-butyl
3-(1-((7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4-yl)amino)ethyl)azetidine-1-carboxylate3-(1-((7-溴-6-氯-8-氟-3-硝基喹啉-4-基)氨基)乙基)氮杂环丁烷-1-羧酸叔丁酯
将7-溴-4,6-二氯-8-氟-3-硝基喹啉1j(527.47mg,1.55mmol,根据公开专利WO2019110751制备)和3-(1-氨基乙基)氮杂环丁烷-1-羧酸叔丁酯1k(404mg,2.02mmol)溶于乙腈(15mL)中,冷却至0℃,滴加N,N-二异丙基乙胺(601.62mg,4.66mmol),转至室温,继续反应6小时。减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:A体系)分离纯化,得到3-(1-((7-溴-6-氯-8-氟-3-硝基喹啉-4-基)氨基)乙基)氮杂环丁烷-1-羧酸叔丁酯1m(650mg,1.29mmol),产率:83.16%。
MS m/z(ESI):504.8[M+1]+
第九步
tert-butyl
3-(1-((3-amino-7-bromo-6-chloro-8-fluoroquinolin-4-yl)amino)ethyl)azetidine-1-carboxylate
3-(1-((3-氨基-7-溴-6-氯-8-氟喹啉-4-基)氨基)乙基)氮杂环丁烷-1-羧酸叔丁酯
将3-(1-((7-溴-6-氯-8-氟-3-硝基喹啉-4-基)氨基)乙基)氮杂环丁烷-1-羧酸叔丁酯1m(650mg,1.29mmol)、氯化铵(344.84mg,6.45mmol)和铁粉(360.32mg,6.45mmol)溶于甲醇(20mL)和水(5mL)的混合溶剂中,加热至90℃反应5小时。反应结束后,趁热过滤,将滤液减压浓缩,除去甲醇。体系用乙酸乙酯萃取(100mL×2),合并有机相,以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:A体系)分离纯化,得到产品3-(1-((3-氨基-7-溴-6-氯-8-氟喹啉-4-基)氨基)乙基)氮杂环丁烷-1-羧酸叔丁酯1n(500mg,1.06mmol),产率:81.79%。
MS m/z(ESI):474.8[M+1]+
第十步
tert-butyl3-(1-(7-bromo-8-chloro-6-fluoro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)ethyl)azetidine-1-carboxyla
te
3-(1-(7-溴-8-氯-6-氟-1H-[1,2,3]***并[4,5-c]喹啉-1-基)乙基)氮杂环丁烷-1-羧酸叔丁酯
将3-(1-((3-氨基-7-溴-6-氯-8-氟喹啉-4-基)氨基)乙基)氮杂环丁烷-1-羧酸叔丁酯1n(320mg,675.44μmol)溶于乙酸(6mL)和水(2mL)的混合溶剂中,冷却至0℃,加入亚硝酸钠(69.91mg,1.01mmol),0℃下继续反应0.5小时,升温至室温反应2小时。反应结束后,体系用饱和碳酸钠溶液调至碱性,以乙酸乙酯萃取(100mL×2),合并有机相,以饱和食盐水(100mL×3)洗涤,以无水硫酸钠干燥,过滤,减压浓缩,得到的残留物用硅胶柱层析法(洗脱剂:A体系)分离纯化,得到3-(1-(7-溴-8-氯-6-氟-1H-[1,2,3]***并[4,5-c]喹啉-1-基)乙基)氮杂环丁烷-1-羧酸叔丁酯1p(300mg,618.88μmol),产率:91.63%。
MS m/z(ESI):484.1[M+1]+
第十一步
tert-butyl3-(1-(7-(2-((tert-butoxycarbonyl)amino)-5-fluorobenzo[d]thiazol-4-yl)-8-chloro-6-fluoro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)ethyl)azetidine-1-carboxylate
3-(1-(7-(2-((叔丁氧羰基)氨基)-5-氟苯并[d]噻唑-4-基)-8-氯-6-氟-1H-[1,2,3]***并[4,5-c]喹啉-1-基)乙基)氮杂环丁烷-1-羧酸叔丁酯
将3-(1-(7-溴-8-氯-6-氟-1H-[1,2,3]***并[4,5-c]喹啉-1-基)乙基)氮杂环丁烷-1-羧酸叔丁酯1p(200mg,412.58μmol)、(2-((叔丁氧羰基)氨基)-5-氟苯并[d]噻唑-4-基)硼酸1i(154.53mg,495.10μmol)、磷酸钾(175.15mg,825.17μmol)和X-PHOS Pd G2(64.84mg,82.52μmol)溶于四氢呋喃(5mL)中,氩气保护,加热至50℃,反应过夜。反应结束后,过滤,将滤液减压浓缩,得到的残留物用制备HPLC分离纯化(分离柱:AKZONOBELKromasil;250×21.2mm I.D.;5μm;流动相A:0.05%TFA+H2O,流动相B:乙腈;流速:20mL/min)得到3-(1-(7-(2-((叔丁氧羰基)氨基)-5-氟苯并[d]噻唑-4-基)-8-氯-6-氟-1H-[1,2,3]***并[4,5-c]喹啉-1-基)乙基)氮杂环丁烷-1-羧酸叔丁酯1q(50mg,74.39μmol),产率:18.03%。
MS m/z(ESI):671.8[M+1]+
第十二步
4-(1-(1-(azetidin-3-yl)ethyl)-8-chloro-6-fluoro-1H-[1,2,3]triazolo[4,5-c]quinolin-7-yl)-5-fluorobenzo[d]thiazol-2-amine
4-(1-(1-(氮杂环丁烷-3-基)乙基)-8-氯-6-氟-1H-[1,2,3]***并[4,5-c]喹啉-7-基)-5-氟苯并[d]噻唑-2-胺
将3-(1-(7-(2-((叔丁氧羰基)氨基)-5-氟苯并[d]噻唑-4-基)-8-氯-6-氟-1H-[1,2,3]***并[4,5-c]喹啉-1-基)乙基)氮杂环丁烷-1-羧酸叔丁酯1q(49.12mg,73.08μmol)溶于二氯甲烷(3mL)中,加入盐酸的1,4-二氧六环溶液(4M,2mL),室温反应2小时。反应结束后,减压浓缩,得到粗品4-(1-(1-(氮杂环丁烷-3-基)乙基)-8-氯-6-氟-1H-[1,2,3]***并[4,5-c]喹啉-7-基)-5-氟苯并[d]噻唑-2-胺1r(34.49mg,73.08μmol),产率:100%。
MS m/z(ESI):471.8[M+1]+
第十三步
1-(3-(1-(7-(2-amino-5-fluorobenzo[d]thiazol-4-yl)-8-chloro-6-fluoro-1H-[1,2,3]triazolo[4,5-c]quinolin-1-yl)ethyl)azetidin-1-yl)prop-2-en-1-one
1-(3-(1-(7-(2-氨基-5-氟苯并[d]噻唑-4-基)-8-氯-6-氟-1H-[1,2,3]***并[4,5-c]喹啉-1-基)乙基)氮杂环丁烷-1-基)丙-2-烯-1-酮
将4-(1-(1-(氮杂环丁烷-3-基)乙基)-8-氯-6-氟-1H-[1,2,3]***并[4,5-c]喹啉-7-基)-5-氟苯并[d]噻唑-2-胺1r(34.13mg,72.33μmol)溶于二氯甲烷(3mL)中,加入三乙胺(21.96mg,216.98μmol),冷却至0℃,滴加丙烯酰氯(7.86mg,86.79μmol)的二氯甲烷(1mL)溶液,0℃下继续反应1小时。将反应液减压浓缩,得到的残留物用制备HPLC分离纯化(分离柱:AKZONOBEL Kromasil;250×21.2mm I.D.;5μm;流动相A:0.05%TFA+H2O,流动相B:乙腈;流速:20mL/min)得到1-(3-(1-(7-(2-氨基-5-氟苯并[d]噻唑-4-基)-8-氯-6-氟-1H-[1,2,3]***并[4,5-c]喹啉-1-基)乙基)氮杂环丁烷-1-基)丙-2-烯-1-酮1(5mg,3.43μmol),产率:11.86%。
MS m/z(ESI):526.1[M+1]+
1H NMR(400MHz,Methanol-d4)δ9.55(s,1H),8.67(t,J=2.2Hz,1H),7.79(dd,J=8.7,5.1Hz,1H),7.09(t,J=9.1Hz,1H),6.41(dd,J=17.0,10.3Hz,1H),6.29–6.20(m,1H),5.90(t,J=7.5Hz,1H),5.72(ddd,J=30.2,9.9,2.4Hz,1H),4.44(dt,J=35.2,9.4Hz,2H),4.28–4.05(m,2H),3.97–3.87(m,1H),1.77(dd,J=6.5,2.4Hz,3H).
生物学评价
测试例1、本发明化合物与KRAS G12C蛋白共价结合能力测定
以下方法用于测定本发明化合物在体外条件下与重组人源KRAS G12C蛋白的共价结合能力。
将实验流程简述如下:使用反应缓冲液(20mM HEPES,150mM NaCl,1mM MgCl2,1mMDTT)配置重组人源KRAS G12C蛋白(aa1-169),浓度为4uM备用。受试化合物溶解于DMSO中制备为10mM贮存液,随后使用反应缓冲液进行稀释备用。首先向孔中加入1.5uL使用反应缓冲液稀释的受试化合物(反应体系终浓度为3μM或10μM),随后加入23.5uL反应缓冲液混匀,随后加入25μL 4uM的重组人源KRAS G12C蛋白,室温条件下孵育5或15分钟后,加入5uL乙酸终止反应,并将样品转移至进样瓶中。使用Agilent 1290/6530仪器检测受试化合物与KRASG12C蛋白发生共价结合的比率,样品在液相色谱柱(XBridge Protein BEH C4,3.5μm,2.1mm×50mm)中分析,检测过程中流动相A是0.1%甲酸水溶液,流动相B是乙腈,流动相洗脱程序为:0~0.5分钟,保持流动相A:95%,2.5分钟时,流动相A变为30%,并保持0.5分钟,3.1分钟,流动相A变为95%,并保持1.9分钟;流速:0.5ml/min;最后使用MassHunterWorkstation Software Bioconfirm Version B.08.00软件分析数据,获得受试化合物浓度在3μM,孵育5min条件与KRAS G12C蛋白共价结合率(Binding Rate)。
化合物编号 | 蛋白共价结合率(%) |
1 | 47.6 |
结论:本发明化合物1与KRAS G12C蛋白有较好的共价结合率。
测试例2、本发明化合物对NCI-H358细胞增殖抑制测定
以下方法用于测定本发明化合物对NCI-H358细胞增殖的影响。NCI-H358细胞(含有KRAS G12C突变)购于中国科学院上海生命科学研究院细胞资源中心,培养于含10%胎牛血清、100U青霉素,100μg/mL链霉素和1mM Sodium Pyruvate的RPMI 1640培养基中。细胞活力通过 Luminescent Cell Viability Assay试剂盒(Promega,货号G7573)进行测定。
实验方法按照试剂盒说明书的步骤操作,简述如下:受试化合物首先溶解于DMSO中制备为10mM贮存液,随后以培养基进行稀释,配制成测试样品,化合物的终浓度范围在1000nM-0.015nM。将处于对数生长期的细胞以800个细胞每孔的密度接种至96孔细胞培养板中,在37℃,5%CO2培养箱中培养过夜,随后加入受试化合物后继续培养120小时。培养结束后,向每孔加入50μL体积的CellTiter-Glo检测液,震荡5分钟后静置10分钟,随后在酶标仪上使用Luminescence模式读取样品各孔发光值。通过与对照组(0.3%DMSO)的数值进行比较计算化合物在各浓度点的百分比抑制率,之后在GraphPad Prism 5软件中以化合物浓度对数-抑制率进行非线性回归分析,获得化合物抑制细胞增殖的IC50值。
化合物编号 | IC<sub>50</sub>(nM) |
1 | 41 |
结论:本发明的化合物1对NCI-H358(人非小细胞肺癌)细胞具有较好的增殖抑制作用。
测试例3、本发明化合物对NCI-H358细胞中p-ERK1/2抑制活性的测定
以下方法用于测定本发明化合物对NCI-H358细胞中p-ERK1/2抑制活性。本方法使用Cisbio公司的Advanced phospho-ERK1/2(Thr202/tyr204)试剂盒(货号64AERPEH),详细实验操作可参考试剂盒说明书。NCI-H358细胞(含有KRAS G12C突变)购于中国科学院上海生命科学研究院细胞资源中心。
将实验流程简述如下:NCI-H358细胞培养于含10%胎牛血清、100U青霉素,100μg/mL链霉素和1mM Sodium Pyruvate的RPMI 1640完全培养基中。NCI-H358细胞按每孔30000个铺于96孔板中,培养基为完全培养基,在37℃,5%CO2培养箱内培养过夜。将受试化合物溶解于DMSO中制备为10mM贮存液,随后使用RPMI 1640基础培养基进行稀释,每孔加入90μL含对应浓度受试化合物的RPMI 1640基础培养基,受试化合物在反应体系中的终浓度范围为1000nM-0.015nM,置于细胞培养箱培养3小时40分钟。随后加入10μL用RPMI 1640基础培养基配制的hEGF(购自Roche,货号11376454001),使其终浓度为5nM,置于培养箱培养20分钟。弃去细胞上清,使用冰浴的PBS清洗细胞,之后每孔加入45μL的1×cell phospho/totalprotein lysis buffer(Advanced phospho-ERK1/2试剂盒组分)进行裂解,96孔板置于冰上裂解半小时,随后参照Advanced phospho-ERK1/2(Thr202/tyr204)试剂盒说明书检测裂解液。最后在酶标仪以TF-FRET模式上测定在304nM的激发波长下,各孔发射波长为620nM和665nM的荧光强度,并计算各孔665/620的荧光强度比值。通过与对照组(0.1%DMSO)的荧光强度比值进行比较,计算受试化合物在各浓度下的百分比抑制率,并通过GraphPad Prism5软件以受试化合物浓度对数值-抑制率进行非线性回归分析,获得化合物的IC50值。
结论:本发明化合物对NCI-H358细胞中p-ERK1/2具有较好的增殖抑制作用,优选化合物的IC50<500nM,更优选化合物的IC50<200nM。
Claims (17)
1.一种通式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐:
其中:
环B选自5~6元杂芳基或5-6元杂环基;
X和Y各自独立地选自N或CR4;
L选自C1-C6亚烷基,其中所述的亚烷基任选进一步被一个或多个选自烷基、环烷基、杂环基、芳基、杂芳基、卤素、氰基、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5的取代基所取代;
G选自一个含有1-2个氮原子的4~12元的杂环基,其中所述杂环基任选进一步被一个或多个Rc所取代;
Ra选自氢原子或氟;
Rb选自氢原子、-CH2F、-CHF2或-CH2-NR6R7;
Rc相同或不同,各自独立地选自氢原子、烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5的取代基所取代;
R1选自氢原子、卤素、烷基或烷氧基;其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代;R1优选为氢原子;
R2选自芳基或杂芳基,其中所述的芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5、-NHC(O)OR5、-NR6R7、-C(O)NR6R7、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5的取代基所取代;其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自烷基、卤素、硝基、氰基、环烷基、杂环基、芳基、杂芳基、=O、-OR5、-C(O)R5、-C(O)OR5、-NHC(O)R5-NHC(O)OR5、-NR6R7、-C(O)NR6R7、-CH2NHC(O)OR5、-CH2NR6R7或-S(O)rR5的取代基所取代;
R3选自不存在、氢原子、卤素、烷基、烷氧基、氰基、卤代烷基或卤代烷氧基,优选为不存在或氢原子;
R4相同或不同,各自独立地选自氢原子、卤素、烷基或烷氧基;其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代;R4优选为卤素,更优选为氟或氯;
R5选自氢原子、烷基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
R6和R7各自独立地选自氢原子、羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
或者,R6和R7与它们相连接的原子一起形成一个4~8元杂环基,其中4~8元杂环基内含有一个或多个N、O或S(O)r,并且所述的4~8元杂环基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、=O、-C(O)R8、-C(O)OR8、-OC(O)R8、-NR9R10、-C(O)NR9R10、-SO2NR9R10或-NR9C(O)R10的取代基所取代;
R8、R9和R10各自独立地选自氢原子、烷基、氨基、环烷基、杂环基、芳基或杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基任选进一步被一个或多个选自羟基、卤素、硝基、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基或羧酸酯基的取代基所取代;
n选自0、1或2;
r为0、1或2。
5.根据权利要求1或2所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R1选自氢原子、卤素、烷基、烷氧基、卤代烷基或卤代烷氧基,R1优选为氢原子。
6.根据权利要求1或2所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中:
R2选自苯基、萘基、吡啶基、苯并噻唑基或苯并吡唑基,其中所述的苯基、萘基、吡啶基、苯并噻唑基或苯并吡唑基任选进一步被一个或多个选自卤素、羟基、烷基、烷氧基、环烷基或-NR6R7的取代基所取代,其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素或-NR6R7的取代基所取代;其中所述的卤素优选为氟;
R6和R7各自独立地选自氢原子或烷基,其中所述烷基优选为甲基。
8.根据权利要求1或2所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R3选自不存在或氢原子。
10.根据权利要求1或2所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中R4选自氢原子、卤素、烷基、烷氧基、卤代烷基或卤代烷氧基,R4优选为卤素,更优选为氟或氯。
11.根据权利要求1或2所述的化合物或其立体异构体、互变异构体或其可药用的盐,其中L选自-CH2-、-CH2CH2-或-CH(CH3)-。
14.一种药物组合物,所述的药物组合物含有有效剂量的根据权利要求1~12中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,及可药用的载体、赋形剂或它们的组合。
15.根据权利要求1~12中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求14所述的药物组合物在制备K-Ras GTP酶抑制剂中的用途,其中K-Ras GTP酶抑制剂优选为KRAS G12C抑制剂。
16.根据权利要求1~12中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求14所述的药物组合物在制备治疗由KRAS突变介导的疾病的药物中的用途,其中所述的由KRAS突变介导的疾病选自癌症,其中所述的癌症选自胰腺癌、结肠直肠癌、肺癌、多发性骨髓瘤、子宫癌、胆管癌、胃癌、膀胱癌、弥漫性大B细胞淋巴瘤、横纹肌肉瘤、皮肤鳞状细胞癌、***、睾丸生殖细胞癌,优选为胰腺癌、结肠直肠癌和肺癌,其中所述的KRAS突变优选为KRAS G12C突变。
17.根据权利要求1~12中任何一项所述的化合物或其立体异构体、互变异构体或其可药用的盐,或根据权利要求14所述的药物组合物在制备治疗癌症的药物中的用途,其中所述的癌症选自胰腺癌、结肠直肠癌、肺癌、多发性骨髓瘤、子宫癌、胆管癌、胃癌、膀胱癌、弥漫性大B细胞淋巴瘤、横纹肌肉瘤、皮肤鳞状细胞癌、***、睾丸生殖细胞癌,优选为胰腺癌、结肠直肠癌和肺癌;其中所述的肺癌优选为非小细胞肺癌。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2021105870082 | 2021-05-27 | ||
CN202110587008 | 2021-05-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115403575A true CN115403575A (zh) | 2022-11-29 |
Family
ID=84157790
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210100843.3A Pending CN115403575A (zh) | 2021-05-27 | 2022-01-27 | 杂芳环类衍生物及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115403575A (zh) |
-
2022
- 2022-01-27 CN CN202210100843.3A patent/CN115403575A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
RU2726115C1 (ru) | Пиридопиримидиновые ингибиторы cdk2/4/6 | |
CN113286794A (zh) | Kras突变蛋白抑制剂 | |
WO2022206723A1 (zh) | 杂环类衍生物、其制备方法及其医药上的用途 | |
CN112552295A (zh) | Kras突变蛋白抑制剂 | |
WO2015077193A1 (en) | Inhibitors of lysine methyl transferase | |
CN112300153B (zh) | 一种杂环化合物、药物组合物和用途 | |
TW201607930A (zh) | 作為t790m/wt-egfr的選擇性和不可逆的激酶抑制劑的5-氨基-4-氨甲醯基-吡唑化合物及其用途 | |
CN116249683A (zh) | 氘甲基取代吡嗪并吡嗪并喹啉酮类衍生物、其制备方法及其在医药上的应用 | |
CN113939518A (zh) | 作为激酶抑制剂的稠合三环化合物 | |
WO2023025116A1 (zh) | 杂环类衍生物、其制备方法及其医药上的用途 | |
CN112839944B (zh) | 用于治疗狂犬病的化合物及其方法 | |
WO2023001229A1 (zh) | 嘧啶并环类衍生物及其制备方法和用途 | |
WO2022037630A1 (zh) | 四环类衍生物、其制备方法及其医药上的用途 | |
CN113929681A (zh) | 四环类衍生物及其制备方法和用途 | |
CN113929676A (zh) | 吡啶并杂环类衍生物及其制备方法和用途 | |
CN116162099A (zh) | 杂环类衍生物及其制备方法和用途 | |
CN116390923A (zh) | 杂环类衍生物及其制备方法和用途 | |
WO2022037631A1 (zh) | 杂环类衍生物及其制备方法和用途 | |
CN116514846A (zh) | 杂环类衍生物、其制备方法及其医药上的用途 | |
CN115403575A (zh) | 杂芳环类衍生物及其制备方法和用途 | |
CN113166148B (zh) | 作为cdk-hdac双通路抑制剂的杂环化合物 | |
WO2022198904A1 (zh) | 一种kras抑制剂关键中间体及其制备方法 | |
CN106349180B (zh) | 4,5-二苯基异噁唑衍生物及其制备方法和应用 | |
CN115557949A (zh) | 四环类衍生物、其制备方法及其在医药上的应用 | |
CN115611898A (zh) | 四环类衍生物、其制备方法及其在医药上的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication |