CN114685532A - Macrocyclic compound and medical application thereof - Google Patents
Macrocyclic compound and medical application thereof Download PDFInfo
- Publication number
- CN114685532A CN114685532A CN202111661404.1A CN202111661404A CN114685532A CN 114685532 A CN114685532 A CN 114685532A CN 202111661404 A CN202111661404 A CN 202111661404A CN 114685532 A CN114685532 A CN 114685532A
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- CN
- China
- Prior art keywords
- alkyl
- radical
- formula
- alkylamino
- halo
- 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.)
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- 150000002678 macrocyclic compounds Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 150000003254 radicals Chemical class 0.000 claims description 78
- -1 C2-6Alkenyl radical Chemical class 0.000 claims description 49
- 125000005843 halogen group Chemical group 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 33
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 18
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 16
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 8
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 5
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000004306 triazinyl group Chemical group 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical group C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims 10
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 5
- 206010028980 Neoplasm Diseases 0.000 abstract description 7
- 201000011510 cancer Diseases 0.000 abstract description 5
- 239000003112 inhibitor Substances 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 118
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
- 239000000243 solution Substances 0.000 description 43
- 239000012043 crude product Substances 0.000 description 38
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 33
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 230000002829 reductive effect Effects 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 229910052731 fluorine Inorganic materials 0.000 description 24
- 239000000460 chlorine Substances 0.000 description 23
- 238000002156 mixing Methods 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 229910052801 chlorine Inorganic materials 0.000 description 22
- 125000004429 atom Chemical group 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 238000010898 silica gel chromatography Methods 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 229910052786 argon Inorganic materials 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 13
- 229910052794 bromium Inorganic materials 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 101150105104 Kras gene Proteins 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000000758 substrate Substances 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 125000005842 heteroatom Chemical group 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- 239000002671 adjuvant Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 125000003003 spiro group Chemical group 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 229910052805 deuterium Inorganic materials 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 239000013642 negative control Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 239000007640 basal medium Substances 0.000 description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 125000002757 morpholinyl group Chemical group 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 125000004193 piperazinyl group Chemical group 0.000 description 4
- 125000003386 piperidinyl group Chemical group 0.000 description 4
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 102000016914 ras Proteins Human genes 0.000 description 4
- 108010014186 ras Proteins Proteins 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000012224 working solution Substances 0.000 description 4
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 101150040459 RAS gene Proteins 0.000 description 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 3
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 231100000590 oncogenic Toxicity 0.000 description 3
- 230000002246 oncogenic effect Effects 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 229940116357 potassium thiocyanate Drugs 0.000 description 3
- 108700042226 ras Genes Proteins 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 101100404726 Arabidopsis thaliana NHX7 gene Proteins 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 2
- 239000005751 Copper oxide Substances 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 206010069755 K-ras gene mutation Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 102000057028 SOS1 Human genes 0.000 description 2
- 108700022176 SOS1 Proteins 0.000 description 2
- 101100197320 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) RPL35A gene Proteins 0.000 description 2
- 101150100839 Sos1 gene Proteins 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 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
- 239000002775 capsule Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229910000431 copper oxide Inorganic materials 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 125000004663 dialkyl amino group Chemical group 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
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- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 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
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 108010001062 polysaccharide-K Proteins 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000002441 reversible effect Effects 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
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000012321 sodium triacetoxyborohydride 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
- 230000003595 spectral effect Effects 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 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
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 238000005533 tritiation Methods 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged 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
The application relates to a macrocyclic compound and medical application thereof, and the structure is shown as a formula (I). The application also relates to a preparation method of the compound, a pharmaceutical composition and application of the compound as KRasG12CUse of an inhibitor in the treatment of cancer.
Description
Technical Field
The present application relates to macrocyclic compounds, processes for their preparation, pharmaceutical compositions containing them, and their use as Kras G12C inhibitors in the treatment of cancer.
Background
The Ras gene is an important protooncogene, named after being found in rat sarcoma virus, and its encoded Ras protein is located inside the cell membrane, can bind to GTP/GDP and can hydrolyze GTP with the aid of Gtpase Activator Protein (GAP). Ras proteins control "on" and "off" in the signaling process of growth factors and cytokines through interconversion between active (GTP-bound) and inactive (GDP-bound) conformations, playing an important role in the life processes of Cell proliferation, differentiation, senescence and apoptosis (Bos J L et al, Cell,2007,129(5): 865-. There are three members of the human Ras gene family: harvey rat sarcoma oncogenic homolog (Hras), neuroblastoma rat sarcoma oncogenic homolog (Nras), and Krestin rat sarcoma oncogenic homolog (Kras), wherein Kras is expressed predominantly in intestine, lung, and thymus (Rajalingam K et al, Biochim Biophys Acta,2007,1773(8): 1177. sup. 1195).
Studies have shown that Ras gene mutations occur in more than 30% of human tumors, with Kras mutations accounting for approximately 86% (Riely G J et al, Proc Am Thorac Soc,2009,6(2): 201-. For the Kras mutation, the mutation at glycine position 12 (G12) accounted for approximately 80%, while the G12C mutation (glycine at position 12 mutated to cysteine) accounted for approximately 14% of all the mutations at G12 (Prior I A et al, Cancer Res,2012,72(10): 2457-. The G12 mutation can reduce the catalytic activity of GAP, and finally promote the continuous activation of Ras, so that Ras cannot effectively regulate and control cell signal transduction, thereby promoting the occurrence and development of tumors.
In recent years, Kras has been utilizedG12CThe mutant allosteric site has made progress in drug development. At present, Kras has entered clinical trialsG12CThe inhibitor comprises AMG-510, MRTX-849, GDC-6036, BI-1701963 and ARS-3248, and part of the structure is as follows.
Detailed Description
The present application relates to compounds of formula (I), stereoisomers thereof, tautomers thereof, or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
x is selected from N or CRX;
Y is selected from N or CRY;
Z is selected from N or CRZ;
Provided that at least one of X, Y, Z is not selected from N;
RX、RY、RZeach independently selected from H, halogen, -CN, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, vinyl, or ethynyl;
each R1Independently selected from halogen, oxo, -OH, -NH2、-CN、C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl radical, C1-6Alkoxy radical, C1-4Alkoxy radical C1-3Alkyl radical, C1-6Alkylamino, or di-C1-6An alkylamino group;
m is selected from 0, 1,2,3, or 4;
R2selected from the group consisting of-C (O) C ≡ CR2b、-SO2C≡CR2b、-C(O)C(R2a)=C(R2b)2or-SO2C(R2a)=C(R2b)2;
R2aSelected from H, halogen, -CN, C1-4Alkyl radical, C1-4Alkoxy, hydroxy C1-4Alkyl, or halo C1-4An alkyl group;
each R2bIndependently selected from H, halogen, -CN, or optionally substituted with 1,2 or 3R2cSubstituted with the following groups: c1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino, di-C1-6Alkylamino radical, C1-4Alkoxy radical C1-3Alkyl radical, C1-4Alkylamino radical C1-3Alkyl, di-C1-4Alkylamino radical C1-3Alkyl, 3-7 membered cycloalkyl C1-3Alkyl, or 4-7 membered heterocycloalkyl C1-3An alkyl group;
each R2cIndependently selected from halogen, oxo, -OH, -NH2or-CN;
w is selected from O, S, or NRW1;
RW1Is selected from H or C1-4An alkyl group;
R3a、R3beach independently selected from H or C1-3An alkyl group; or, R3a、R3bTaken together to form ═ O;
R4selected from H, C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy radical, C1-4Alkylamino radical C1-3Alkyl, di-C1-4Alkylamino radical C1-3Alkyl, di-C1-4Alkylaminoacyl radical C1-3Alkyl, halo C1-6Alkyl, halo C1-6Alkoxy, halo C1-4Alkylamino radical C1-3Alkyl, di (halo C)1-4Alkyl) amino C1-3Alkyl, or optionally substituted by 1,2,3 or 4R4aSubstituted with the following groups: 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 3-7 membered cycloalkylC1-3Alkyl, or 4-7 membered heterocycloalkyl C1-3An alkyl group;
each R4aIndependently selected from halogen, -OH, oxo, -NH2、-CN、C1-4Alkyl, hydroxy C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy radical, C1-2Alkyl carbonyl, C1-4Alkylamino, di-C1-4Alkylamino, 3-7 membered cycloalkyl, or 4-7 membered heterocycloalkyl;
ring B is selected from phenyl, naphthyl, 5-10 membered heteroaryl, benzo 5-6 membered cycloalkenyl, benzo 5-6 membered heterocyclyl, 5-6 membered heteroaryland 5-6 membered cycloalkenyl, or 5-6 membered heteroaryland 5-6 membered heterocyclyl, the 5-6 membered cycloalkenyl or 5-6 membered heterocyclyl moiety being optionally substituted with one or two ═ O;
each R5Independently selected from halogen, -CN, -OH, -NH2、-C(O)NH2、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, hydroxy C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkylthio, halo C1-6Alkylthio radical, C1-6Alkylamino, halogeno C1-6Alkylamino, di-C1-6Alkylamino, di (halo C)1-6Alkyl) amino, or optionally substituted with 1,2 or 3R5aSubstituted with the following groups: 3-7 membered cycloalkyl, 3-7 membered cycloalkyl C1-3Alkyl, 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C1-3An alkyl group;
each R5aIndependently selected from oxo, halogen, -CN, -OH, -NH2、C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy radical, C1-4Alkylamino, or di-C1-4An alkylamino group;
n is selected from 0, 1,2,3,4, 5, or 6.
In some embodiments, X is selected from CRX(ii) a Y is selected from N; z is selected from N. In some embodiments, X is selected from N; y is selected from CRY(ii) a Z is selected from N. In some embodiments, X is selected from N; y is selected from N; z is selected from CRZ。
In some embodiments, X is selected from N; y is selected from CRY(ii) a Z is selected from CRZ. In some embodiments, X is selected from CRX(ii) a Y is selected from N; z is selected from CRZ. In some embodiments, X is selected from CRX(ii) a Y is selected from CRY(ii) a Z is selected from N.
In some embodiments, X is selected from CRX(ii) a Y is selected from CRY(ii) a Z is selected from CRZ。
In some embodiments, RX、RY、RZEach independently selected from H, F, Cl, Br, -CN, C1-4Alkyl radical, C1-4Alkoxy, fluoro C1-4Alkyl, fluoro C1-4Alkoxy, or ethynyl. In some embodiments, RX、RY、RZEach independently selected from H, F, Cl, Br, -CN, methyl, ethyl, methoxy, trifluoromethyl, or ethynyl. In some embodiments, RX、RY、RZEach independently selected from H, F, Cl, or Br.
In some embodiments, RXSelected from H, F, Cl, Br, -CN, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Fluoroalkyl, C1-4Fluoroalkoxy, or ethynyl; rY、RZEach independently selected from H, F, Cl, Br, C1-4Alkyl radical, C1-4An alkoxy group. In some embodiments, RXSelected from H, F, Cl, Br, -CN, methyl, ethyl, methoxy, trifluoromethyl, or ethynyl; rY、RZEach independently selected from H, F, Cl, Br, -CN, methyl, or methoxy. In some embodiments, RYIs selected from H; rX、RZEach independently selected from H, F, Cl, or Br.
In some embodiments of the present invention, the substrate is,selected from 4-10 membered heterocycloalkyl containing two N's. In some embodiments of the present invention, the substrate is,selected from 4-9 membered heterocycloalkyl containing two N's. In some embodiments of the present invention, the substrate is,selected from 4-7 membered heterocycloalkyl containing two N's. In some embodiments, the heterocycloalkyl is selected from monocyclic heterocycloalkyl or spirocyclic heterocycloalkyl. In some embodiments, the heterocycloalkyl group is selected from monocyclic heterocycloalkyl groups.
In some embodiments of the present invention, the substrate is,is selected fromIn some embodiments of the present invention, the substrate is,is selected from
In some embodiments, R1Independently selected from F, Cl, Br, oxo, -OH, -NH2、-CN、C1-4Alkyl, fluoro C1-4Alkyl, cyano C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino, or di-C1-4An alkylamino group. In some embodiments, R1Independently selected from F, Cl, oxo, -OH, -NH2-CN, methyl, ethyl, difluoromethyl, trifluoromethyl, cyanomethyl, methoxy, or dimethylamino. In some embodiments, R1Selected from methyl.
In some embodiments, m is selected from 0, 1,2, or 3. In some embodiments, m is selected from 0, 1, or 2.
In some embodiments, R2Selected from the group consisting of-C (O) C ≡ CR2b、-C(O)C(R2a)=C(R2b)2or-SO2C(R2a)=C(R2b)2. In some embodiments, R2Selected from the group consisting of-C (O) C ≡ CR2b、-C(O)C(R2a)=CHR2bor-SO2C(R2a)=CHR2b. In some embodiments, R2Selected from the group consisting of-C (O) C (R)2a)=CH(R2b)。
In some embodiments, R2aSelected from H, F, Cl, methyl, or ethyl. In some embodiments, R2aSelected from H or F. In some embodiments, R2aIs selected from H.
In some embodiments, R2bIndependently selected from H or optionally substituted with 1,2 or 3R2cSubstituted with the following groups: c1-4Alkyl, di-C1-3Alkylamino radical C1-2Alkyl, or 4-6 membered heterocycloalkyl C1-2 alkyl. In some embodiments. In some embodiments, R2bIndependently selected from H or optionally substituted with 1,2 or 3R2cSubstituted with the following groups: methyl, dimethylaminomethyl, morpholinylmethyl, piperidinylmethyl, tetrahydropyrrolylmethyl, or azetidinylmethyl. In some embodiments, R2bIndependent of each otherIs selected from H, or dimethylaminomethyl. In some embodiments, R2bIs selected from H.
In some embodiments, R2cIndependently selected from F, Cl, oxo, -OH, -NH2or-CN. In some embodiments, R2cIndependently selected from F, or Cl.
In some embodiments, R2Selected from the group consisting of: in some embodiments, R2Selected from the group consisting of:in some embodiments, R2Selected from the group consisting of:
in some embodiments, W is selected from O or NRW1. In some embodiments, W is selected from O.
In some embodiments, RW1Selected from H, methyl, or ethyl. In some embodiments, RW1Selected from methyl.
In some embodiments, R3a、R3bEach independently selected from H or methyl.
In some embodiments, when W is selected from NRW1When R is3a、R3bTogether form ═ O.
In some embodiments, R4Selected from H, C1-6Alkyl radical, C1-4Alkylamino radical C1-3Alkyl, di-C1-4Alkylamino radical C1-3Alkyl, di-C1-4Alkylaminoacyl radical C1-3Alkyl, halo C1-6Alkyl, halo C1-4Alkylamino radical C1-3Alkyl, di (halo C)1-4Alkyl) amino C1-3An alkyl group,Or optionally substituted with 1,2,3 or 4R4aSubstituted groups as follows: 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C1-3An alkyl group. In some embodiments, R4Selected from H, C1-6Alkyl radical, C1-4Alkylamino radical C1-3Alkyl, di-C1-4Alkylamino radical C1-3Alkyl, di-C1-4Alkylaminoacyl radical C1-3Alkyl, halo C1-6Alkyl, halo C1-4Alkylamino radical C1-3Alkyl, di (halo C)1-4Alkyl) amino C1-3Alkyl, or optionally substituted by 1,2,3 or 4R4aSubstituted groups as follows: azetidinyl, azetidinylmethyl, azetidinylethyl, tetrahydropyrrolyl, tetrahydropyrrolylmethyl, tetrahydropyrrolethyl, morpholinyl, morpholinylmethyl, morpholinylethyl, piperazinyl, piperidinyl, piperidinylmethyl, piperidinylethyl, piperazinylethyl, and mixtures thereof,In some embodiments, R4Selected from H, or optionally substituted with 1,2,3 or 4R4aSubstituted tetrahydropyrrolemethyl.
In some embodiments, R4aIndependently selected from F, Cl, Br, -OH, oxo, -NH2、-CN、C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino, or di-C1-4An alkylamino group. In some embodiments, R4aIndependently selected from F, Cl, -OH, oxo, -NH2Methyl, ethyl, isopropyl, trifluoromethyl, methoxy, methylamino, ethylamino, dimethylamino, or diethylamino. In some embodiments, R4aIndependently selected from F, Cl, -OH, oxo, -NH2Methyl, ethyl, isopropyl, trifluoromethyl, methoxy, methylamino, ethylamino, dimethylamino, or diethylamino. In some embodiments, R4aIndependently selected from F, methyl, ethyl, methoxy, dimethylamino, or diethylamino.
In some embodiments, R4Selected from H, In some embodiments, R4Selected from H, In some embodiments, R4Is selected from H. In some embodiments, R4Is selected from
In some embodiments, the B ring is selected from the group consisting of phenyl, indenyl, 2, 3-indanyl, naphthyl, 1,2,3, 4-tetrahydronaphthalene, pyrrolyl, furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, benzopyrazolyl, pyrazolyl, naphthyl, phenanthrenyl, and the like,Benzimidazolyl, benzotriazolyl, benzothiazolyl, benzisothiazolyl, indolyl, indolinyl, benzimidazolyl, benzothiazolyl, benzimidazolyl, and benzothiazolyl,Benzoxazolyl group,Benzisoxazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, quinoxalinyl, or
In some embodiments, the B ring is selected from phenyl, pyridyl, naphthyl, benzopyrazolyl,Benzimidazolyl, benzotriazolyl, benzothiazolyl, benzisothiazolyl, indolyl,Benzisoxazolyl, isoquinolinyl, or
In some embodiments, the B ring is selected from phenyl, pyridyl, benzothiazolyl, benzopyrazolyl, or isoquinolyl.
In some embodiments, R5Independently selected from F, Cl, Br, -CN, -OH and-NH2、-C(O)NH2、C1-4Alkyl radical, C2-4Alkynyl, hydroxy C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy radical, C1-4Alkylamino, halogeno C1-4Alkylamino, di-C1-4Alkylamino, di (halo C)1-4Alkyl) amino, or optionally substituted with 1,2 or 3R5aSubstituted groups as follows: 3-6 membered cycloalkyl, or 4-6 membered heterocycloalkyl. In some embodiments, R5Independently selected from F, Cl, -OH, -NH2、-C(O)NH2Methyl, ethyl, ethynyl, difluoromethyl, trifluoromethyl, methoxy, methylamino, dimethylamino, or optionally substituted with 1,2 or 3R5aSubstituted with the following groups: cyclopropane, cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl. In some embodiments, R5Independently selected from F, Cl, -OH, -NH2Methyl, trifluoromethyl, methoxy, or methylamino.
In some embodiments, each R is5aIndependently selected from oxo, F, Cl、Br、-CN、-OH、-NH2、C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino, or di-C1-4An alkylamino group. In some embodiments, each R is5aIndependently selected from oxo, F, Cl, Br, -CN, -OH, -NH2Methyl, ethyl, trifluoromethyl, methoxy, methylamino, or dimethylamino.
In some embodiments, n is selected from 0, 1,2,3, or 4. In some embodiments, n is selected from 1,2,3, or 4.
In some embodiments, n is selected from 0.
In some embodiments, said C1-6The alkyl group being selected from C1-4An alkyl group. In some embodiments, said C1-4Alkyl is selected from C1-3Alkyl or C1-2An alkyl group.
In some embodiments, the halo is selected from fluoro, chloro, bromo, or iodo. In some embodiments, the halo is selected from fluoro or chloro.
In some embodiments, the heterocycloalkyl contains 1 or 2 heteroatoms selected from N or O.
In some embodiments, the heterocycloalkyl group contains 1N atom.
In some embodiments, the heterocycloalkyl group contains 2N atoms.
In some embodiments, the heterocycloalkyl group contains 1O atom.
In some embodiments, the heterocycloalkyl group contains 1N atom and 1O atom.
In some embodiments, the heterocyclyl contains 1 or 2 heteroatoms selected from N or O.
In some embodiments, the heterocyclyl contains 1N atom.
In some embodiments, the heterocyclyl contains 2N atoms.
In some embodiments, the heterocyclyl contains 1N atom and 1O atom.
In some embodiments, the heteroaryl contains 1,2, or 3 heteroatoms selected from S, N or O.
In some embodiments, the heteroaryl group contains 3N atoms.
In some embodiments, the heteroaryl contains 1 or 2 heteroatoms selected from S, N.
In some embodiments, the heteroaryl group contains 1 or 2N atoms.
In some embodiments, the heteroaryl group contains 1N atom and 1S atom.
In some embodiments, the heteroaryl group contains 1N atom and 1O atom.
In some embodiments, the heterocycloalkyl group comprises a monocyclic ring, a spiro ring, or a bridged ring. In some embodiments, the heterocycloalkyl group comprises a monocyclic ring or a spiro ring. In some embodiments, the heterocycloalkyl group comprises a single ring or a bridged ring.
The present application relates to compounds of formula (II) or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、R3a、R3b、R4、R5The moieties W, X, Y, Z, m, n, A, and B are as defined above.
The present application relates to compounds of formula (Ia) or formula (Ib) or formula (Ic) or formula (Id) or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、R3a、R3b、R4、R5、RWX, Y, Z, m, n, A, and B moieties are as defined above.
The present application relates to compounds of formula (IIa) or formula (IIb) or formula (IIc) or formula (IId) or pharmaceutically acceptable salts thereof,
wherein R is1、R2、R3a、R3b、R4、R5、RWX, Y, Z, m, n, A, and B moieties are as defined above.
The present application relates to compounds of formula (III) or formula (IV) or formula (IVa) or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、R5、RX、RZM, n, A, and B are as defined above.
The present application also relates to the following compounds or pharmaceutically acceptable salts thereof:
the present application also relates to the following compounds or pharmaceutically acceptable salts thereof:
the present application also relates to the following compounds or pharmaceutically acceptable salts thereof:
in another aspect, the present application relates to pharmaceutical compositions comprising a compound of formula (I) or formula (Ia) or formula (Ib) or formula (Ic) or formula (Id) or formula (II) or formula (IIa) or formula (IIb) or formula (IIc) or formula (IId) or formula (III) or formula (IV) or formula (IVa), stereoisomers thereof, tautomers thereof, or pharmaceutically acceptable salts thereof, of the present application. In some embodiments, the pharmaceutical compositions of the present application further comprise a pharmaceutically acceptable excipient.
In another aspect, the application relates to the treatment of Kras in mammalsG12CA method of treating a related disorder comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) or formula (Ia) or formula (Ib) or formula (Ic) or formula (Id) or formula (II) or formula (IIa) or formula (IIb) or formula (IIc) or formula (IId) or formula (III) or formula (IV) or formula (IVa), stereoisomers thereof, tautomers thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.
In another aspect, the present application relates to formula (I) or formula (Ia) or formula (Ib) or formula (Ic) or formula (Id) or formula (II) or formula (IIa) or formula(IIb) or formula (IIc) or formula (IId) or formula (III) or formula (IV) or formula (IVa), stereoisomers thereof, tautomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of a medicament for treating KrasG12CThe use in the preparation of medicaments for treating related diseases.
In another aspect, the present application relates to a compound of formula (I) or formula (Ia) or formula (Ib) or formula (Ic) or formula (Id) or formula (II) or formula (IIa) or formula (IIb) or formula (IIc) or formula (IId) or formula (III) or formula (IV) or formula (IVa), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of KrasG12CThe use in the associated diseases.
In another aspect, the application relates to the treatment of KrasG12CA compound of formula (I) or formula (Ia) or formula (Ib) or formula (Ic) or formula (Id) or formula (II) or formula (IIa) or formula (IIb) or formula (IIc) or formula (IId) or formula (III) or formula (IV) or formula (IVa), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a related disease.
In some embodiments of the present application, the KrasG12CThe associated disease is preferably cancer.
In some embodiments of the present application, the cancer comprises lung cancer, preferably non-small cell lung cancer.
Definition of
The following terms used in the present application have the following meanings, unless otherwise specified. A particular term should not be considered as ambiguous or unclear without special definition, but rather construed according to ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., ═ O), meaning that two hydrogen atoms are substituted, oxo does not occur on the aryl.
The term "optional" or "optionally" means that the subsequently described event or circumstance may occur or beNot occurring, the description includes both occurring and not occurring the event or circumstance. For example, ethyl is "optionally" substituted with halo, meaning that ethyl may be unsubstituted (CH)2CH3) Monosubstituted (e.g. CH)2CH2F) Polysubstituted (e.g. CHFCH)2F、CH2CHF2Etc.) or completely substituted (CF)2CF3). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.
Herein Cm-nIt is the moiety that has an integer number of carbon atoms in the given range. For example "C1-6By "is meant that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 2R, then there are separate options for each R.
When the number of one linking group is 0, e.g. - (CH)2)0-, indicates that the linking group is a covalent bond.
When one of the variables is selected from a covalent bond, it means that the two groups to which it is attached are directly linked, for example, where L represents a covalent bond in A-L-Z, it means that the structure is actually A-Z.
When the linking group is listed without indicating its direction of attachment, its direction of attachment is arbitrary, such as in A-L-Z, where the linking group L is-M-W-which indicates that the structure may be A-M-W-Z or A-W-M-Z.
When a substituent bond is cross-linked to two atoms on a ring, such substituent may be bonded to any atom on the ring. For example, a structural unitMeaning that it may be substituted at any position on the cyclohexyl or cyclohexadiene.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "hydroxy" refers to an-OH group.
The term "cyano" refers to the group — CN.
The term "mercapto" refers to the-SH group.
The term "amino" refers to the group-NH2A group.
The term "nitro" means-NO2A group.
The term "alkyl" refers to a group of formula CnH2n+1A hydrocarbon group of (1). The alkyl group may be linear or branched. For example, the term "C1-6Alkyl "means an alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio groups have the same definitions as above.
The term "alkoxy" refers to-O-alkyl.
The term "alkylamino" refers to-NH-alkyl.
The term "dialkylamino" refers to-N (alkyl)2。
The term "alkylsulfonyl" refers to-SO2-an alkyl group.
The term "alkylthio" refers to-S-alkyl.
The term "alkylaminoacylalkyl" refers to an alkyl NHC (O) alkyl group.
The term "dialkylaminoalkyl" refers to (alkyl)2NC (O) alkyl-.
The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond, consisting of carbon atoms and hydrogen atoms. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like.
The term "alkynyl" refers to a straight or branched chain composed of carbon and hydrogen atomsAn unsaturated aliphatic hydrocarbon group having at least one triple bond. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C ≡ CH), 1-propynyl (-C ≡ C-CH)3) 2-propynyl (-CH)2-C.ident.CH), 1, 3-butadiynyl (-C.ident.C-C.ident.CH), and the like.
The term "cycloalkyl" refers to a carbon ring that is fully saturated and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the carbocycle is typically a 3 to 10 membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, and the like.
The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and may exist as a single ring, bridged ring, or spiro ring. Unless otherwise indicated, the carbocycle is typically a 5 to 8 membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.
The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the heterocyclic ring is generally a 3 to 7-membered ring, preferably a 5 to 6-membered ring, containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Non-limiting examples of heterocyclyl groups include, but are not limited to, oxiranyl, tetrahydrofuryl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, and the like.
The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a single ring, a bridged ring, or a spiro ring. Unless otherwise indicated, the heterocyclic ring is typically a 3 to 12 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Examples of 3-membered heterocycloalkyl include, but are not limited to, oxiranyl, thietanyl, cycloazenyl, non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thiabutinyl, examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, examples of tetrahydropyrazolyl, 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, 4-thialkyl, 1, 4-dioxanyl, thiomorpholinyl, 1, 3-dithianyl, 1, 4-dithianyl, and examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, thiepanyl.
The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system. For example, the aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.
The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic heterocyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C. Preferred heteroaryls have a single 4-to 8-membered ring, especially a 5-to 8-membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like.
The term "treating" means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease condition, but has not yet been diagnosed as having the disease condition;
(ii) inhibiting the disease or disease state, i.e., arresting its development;
(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition.
The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art with their own knowledge and this disclosure.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As the pharmaceutically acceptable salt, for example, a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like can be mentioned.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
The term "pharmaceutically acceptable adjuvants" refers to those adjuvants which do not have a significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable adjuvants are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
The words "comprise" or "comprise" and variations thereof such as "comprises" or "comprising," are to be understood in an open, non-exclusive sense, i.e., "including but not limited to.
The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, wherein the proton can migrate between two ring nitrogens. Valence tautomers include interconversion by recombination of some of the bonding electrons.
The present application also includes isotopically-labeled compounds of the present application, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as respectively2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I and36cl, and the like.
Certain isotopically-labelled compounds of the present application (e.g. with3H and14c-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation)3H) And carbon-14 (i.e.14C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as15O、13N、11C and18f can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
In addition, heavier isotopes are used (such as deuterium (i.e., deuterium)2H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium.
The compounds of the present application may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:
the compounds of the present application may have one or more atropisomers, which, unless otherwise indicated, refers to the optically active isomer resulting from the hindrance of free rotation between single bonds. The compounds of the present application containing a chiral axis can be isolated in racemic form. When the energy barrier for free rotation of a single bond of a compound containing a chiral axis is sufficiently high, its atropisomer can be isolated in an optically active pure form. Non-limiting examples of atropisomers include, but are not limited to:
the pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Typical routes of administration of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The pharmaceutical compositions of the present application can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These adjuvants enable the compounds of the present application to be formulated as tablets, pills, lozenges, dragees, capsules, gels, slurries, suspensions and the like, for oral administration to a patient.
Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid adjuvants, optionally the mixture obtained is milled, if desired with further suitable adjuvants, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents and the like.
The pharmaceutical compositions may also be adapted for parenteral administration, as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
In all methods of administration of the compounds of formula I described herein, the daily dose administered is from 0.01 to 200mg/kg body weight, and the compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, the examples herein.
The chemical reactions of the embodiments herein are carried out in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select a synthesis procedure or a reaction scheme based on the existing embodiments.
In some embodiments, when R4When selected from H, the compounds of formula (Ia) herein can be prepared by one skilled in the art of organic synthesis via scheme 1, wherein PG1Selected from N atom protecting groups, PG2Selected from O atom protecting groups, R1、R2、R3a、R3b、R4、R5M, n, W, X, Y, Z, A and B moieties are as defined above.
Route 1
Under appropriate conditions, reacting compound 1 with compound 2 to obtain intermediate 3, halogenating intermediate 3 to obtain intermediate 4, performing substitution reaction with compound 5 to obtain intermediate 6, and removing PG from intermediate 62The protecting group affords intermediate 7. Oxidation of intermediate 7 to give intermediate 8, subsequent cyclisation to give intermediate 9, coupling of intermediate 9 with the corresponding compound 10 to give intermediate 11, followed by removal of PG1The protecting group gives intermediate 12 which is finally reacted with the corresponding acid halide compound to give the compound of formula (Ia).
Each of the products of the reactions in the above routes may be obtained by conventional separation techniques including, but not limited to, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials may be synthesized by themselves or purchased from commercial establishments (such as, but not limited to, Adrich or Sigma). These materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described herein can be synthesized as a single isomer or as a mixture of isomers.
The following abbreviations are used in this application:
boc represents tert-butyloxycarbonyl; bn represents a benzyl group; TBS represents tert-butyldimethyl; KSCN represents potassium thiocyanate; (BPin)2 represents pinacol diboron; DMAP for 4-dimethylaminopyridine; DIPEA stands for N, N-diisopropylethylamine; boc2O represents di-tert-butyl dicarbonate; m-CPBA stands for m-chloroperoxybenzoic acid. PMBCl represents 4-methoxy benzyl chloride; PMB represents 4-methoxybenzyl; pd2(dba)3Represents tris (dibenzylideneacetone) dipalladium; PCy3Represents tricyclohexylphosphine.
The compound is artificially synthesized orThe software names, and the commercial compounds are under the supplier catalog name.
For clarity, the invention is further illustrated by examples, which do not limit the scope of the application. Having described the present application in detail and disclosed specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the embodiments of the present application without departing from the spirit and scope of the application.
All reagents used herein were commercially available and used without further purification.
Examples
Preparation Z1
Step 1:
at room temperature, mixingZ1a(6g) Dissolved in methylene chloride (120mL), benzaldehyde (7.4g) was added to the reaction system, and the mixture was stirred at room temperature for 30 min. Adding sodium triacetoxyborohydride (11.8g) into the reaction system at 0-5 ℃, and after the addition is finished, moving to room temperature for reaction for 24 hours. After the reaction is finished, slowly adding saturated sodium bicarbonate solution (80mL) into the reaction system, layering, collecting an organic phase, concentrating under reduced pressure to obtain a crude product, and purifying the crude product by silica gel column chromatography (petroleum)Ether/ethyl acetate 150:1 to 1:1) to obtainZ1b(5.1g)。
LC-MS:m/z 307(M+H)+。
Step 2:
at room temperature, mixingZ1b(2g) (2-Bromoethoxy) -dimethyl-t-butylsilane (9.9g) and tetrabutylammonium hydrogensulfate (0.5g) were dissolved in toluene (30mL), and a 50% sodium hydroxide solution (17.5mL) was added dropwise to the reaction system to conduct a reaction at room temperature for 45 hours. After the reaction is finished, adding water (40mL) into the reaction system, extracting with ethyl acetate (100mL), collecting an organic phase, washing with water (50mL) and saturated saline solution (50mL) once respectively, collecting the organic phase, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate is 40: 1-10: 1) to obtain the productZ1c(1.1g)。
LC-MS:m/z 465(M+H)+。
And step 3:
at room temperature, mixingZ1c(1g) 10% Palladium on carbon (0.1g) was dissolved in methanol (10mL) and hydrogenated at room temperature for 24 hours. After the reaction, filtering, and concentrating the filtrate under reduced pressure until no liquid flows out to obtain the title compoundZ1(660mg)。
LC-MS:m/z 375(M+H)+。
Preparation Z2
Step 1:
at room temperature, mixingZ2a(10g) Dissolving in toluene (50mL), adding thionyl chloride (19g) into the reaction system, and heating to 65-70 ℃ for reaction for 5 h. After the reaction is finished, concentrating the reaction liquid under reduced pressure until no liquid flows out to obtain a crude productZ2b(11g) In that respect The product is used for the next reaction without purification.
And 2, step:
potassium thiocyanate (4.2g) was dissolved in acetone (50mL) under ice-bath conditions, and the solution was added dropwise to the reaction systemZ2b(6g) After the acetone (30mL) solution is added, the temperature is raised to 50-55 ℃ for reaction for 0.5 h. Cooling the reaction system to 0-5 ℃,dropwise adding an acetone (20mL) solution of 2-bromo-5-fluoroaniline (7.6g), and after the addition, heating to 50-55 ℃ for reaction for 2 h. After the reaction is finished, adding the reaction solution into water (600mL), precipitating a solid, filtering, adding the solid into a sodium hydroxide solution (2.5mol/L,145mL), heating to 80 ℃, stirring for 30min, then cooling to room temperature, adjusting the pH to 9-10 with concentrated hydrochloric acid, extracting with ethyl acetate (2X 200mL), collecting an organic phase, washing with saturated saline (2X 100mL), collecting the organic phase, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude productZ2d(9.8 g). The product is used for the next reaction without purification.
LC-MS:m/z 249(M+H)+。
And 3, step 3:
under ice-bath condition, mixingZ2d(5g) Dissolving in methane sulfonic acid (100mL), adding N-bromosuccinimide (3.6g) into the reaction system, and heating to 60 ℃ for reaction for 4h after the addition is finished. After the reaction is finished, pouring the reaction liquid into ice water (1L), adjusting the pH value to 10-11 by using ammonia water, separating out solids, filtering, adding the solids into methanol (20mL), heating to 50 ℃, stirring for 1h, cooling to room temperature, and filtering to obtain the productZ2e(3.6g)。LC-MS:m/z 247(M+H)+。
And 4, step 4:
at room temperature, mixingZ2e(2g) Pinacol diboron (10g) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (584mg) and potassium acetate (2.4g) were dissolved in dioxane (200mL), replaced with argon 5 times, and the reaction was stirred at 100 ℃ for 40 hours under argon protection. After the reaction is finished, filtering, concentrating under reduced pressure to obtain a crude product, and purifying the crude product by silica gel column chromatography (dichloromethane/methanol is 100: 1-10: 1) to obtain a title compoundZ2(1.1g)。
LC-MS:m/z 213(M+H)+。
Preparation Z3
The title CompoundZ3Synthesis of (2) Synthesis of reference preparation Z1Z3aInstead of the formerZ1aTo obtainZ3(500mg)。
LC-MS:m/z 375(M+H)+。
Preparation Z4
Step 1:
potassium thiocyanate (12.4g) was dissolved in acetone (200mL) under ice-bath conditions, and the solution was added dropwise to the reaction systemZ2b(17.8g) in 100mL of acetone, and heating to 50-55 ℃ for 0.5 h. Cooling the reaction system to 0-5 ℃, dropwise adding an acetone (100mL) solution of 2-bromo-3, 5-difluoroaniline (25g), and heating to 50-55 ℃ for reaction for 2h after the addition is finished. After the reaction is finished, adding the reaction solution into water (2.5L), separating out solids, filtering, adding the solids into a sodium hydroxide solution (2.5mol/L,400mL), heating to 80 ℃, stirring for 30min, then cooling to room temperature, adjusting the pH to 9-10 by using concentrated hydrochloric acid, decompressing, filtering, washing with water, and drying to obtain a crude productZ4a(24.2 g). The product is used for the next reaction without purification.
LC-MS:m/z 267(M+H)+。
Step 2:
under ice-bath condition, mixingZ4a(24.2g) was dissolved in methanesulfonic acid (200mL), and N-bromosuccinimide (16.1g) was added to the reaction system, and after the addition, the temperature was raised to 80 ℃ to react for 4 hours. After the reaction is finished, pouring the reaction solution into ice water (2L), adjusting the pH to 10-11 by using ammonia water, separating out solids, performing reduced pressure suction filtration, washing with water, and drying to obtain the productZ4b(22.9 g). The product is used for the next reaction without purification.
LC-MS:m/z 265(M+H)+。
And 4, step 4:
at room temperature, mixingZ4b(5.0g), DMAP (50mg), DIPEA (3.2g) in tetrahydrofuran (100mL) and Boc was slowly added dropwise2O (5.3g) was stirred further for 12 h. After the reaction is finished, adding 5mL of methanol and 5mL of saturated sodium bicarbonate to quench the reaction, concentrating under reduced pressure to obtain a crude product, and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate: 100: 1-10: 1) to obtain the compoundZ4c(4.9g)。
LC-MS:m/z 365(M+H)+。
And 5:
will be provided withZ4c(3.0g) and triisopropyl borate (4.6g) were dissolved in 60mL of anhydrous tetrahydrofuran, and the mixture was replaced with argon 5 times, and stirred at-78 ℃ under the protection of argon. 2.4M butyl lithium (10.3mL) was slowly added dropwise, and after the addition was complete, the temperature was slowly raised to-35 ℃ and the reaction was stirred for 30 min. The reaction was quenched by adding 30mL of saturated ammonium chloride solution to the reaction at-35 ℃. To the reaction was added 200mL of water at room temperature, and extracted with 200mL of ethyl acetate 2. Combining organic phases, concentrating to obtain a crude product, and purifying by silica gel column chromatography (petroleum ether/ethyl acetate: 30: 1-3: 1) to obtain the productZ4(850mg)。
Preparation Z5
Step 1:
1-bromo-2-aminoisoquinoline (500mg), hexa-n-butylditin (1.2mL), tris (dibenzylideneacetone) dipalladium (205mg), tricyclohexylphosphine (122mg), and lithium chloride (460mg) were dissolved in 10mL of dioxane, and nitrogen was replaced 5 times. The temperature is increased to 115 ℃ for reaction for 18 h. To the reaction system, 50mL of water was added and 100mL of ethyl acetate was extracted 2. Combining organic phases, concentrating under reduced pressure, and performing silica gel column chromatography (dichloromethane: methanol: 100: 1-30: 1) on a crude product to obtain the compoundZ5(200mg)。
LC-MS:m/z 435(M+H)+。
Preparation Z6
Step 1:
at room temperature, mixing the raw materialsZ6a(4g) And S-methylisothiourea sulfate (3.4g) is dissolved in N, N-dimethylformamide (40mL), then N, N-diisopropylethylamine (10g) and 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (9.2g) are sequentially added into the reaction system, and the reaction system is reacted for 2 hours at room temperature and then heated to 100 ℃ for 12 hours. After the reaction, the reaction mixture was slowly added to water (500mL) to precipitate a solid, which was then filtered to obtainStirring the solid with mixed solution of methyl tert-butyl ether/methanol (volume ratio: 4:3,35mL) at 60 deg.C for 0.5h, cooling to room temperature, and filtering to obtainZ6b(2.1g)。
LC-MS:m/z 304.9(M+H)+。
Step 2:
at 0 ℃ ofZ6b(2.0g) is dissolved in toluene (50mL), phosphorus oxychloride (10g) is added dropwise into the reaction system, after the addition is finished, the reaction system is stirred for 10min at 0 ℃, then N, N-diisopropylethylamine (3.8g) is added into the reaction system, the reaction system is stirred for 0.5h at 0 ℃, and the reaction system is heated to 110 ℃ for reaction for 6 h. After the reaction, the reaction solution was cooled to room temperature, slowly added to potassium dihydrogen phosphate solution (1000mL, 2mol/L), extracted with ethyl acetate (3 × 200mL), the organic phases were combined and washed with saturated sodium bicarbonate solution (2 × 200mL) and saturated brine (1 × 200), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude productZ6c(1.9 g). The product is used for the next reaction without purification.
LC-MS:m/z 322.9(M+H)+。
And step 3:
at room temperature, mixingZ6c(550mg) was dissolved in N, N-dimethylformamide (6mL), and the solution was added dropwise to the reaction systemZ1A solution of (660mg) in N, N-dimethylformamide (5mL) was stirred at room temperature for 0.5h, and then N, N-diisopropylethylamine (1.1g) was added dropwise to the reaction system to conduct a reaction at room temperature for 15 h. After the reaction is finished, adding the reaction solution into 100mL of water, extracting with ethyl acetate (100mL), collecting an organic phase, washing with water (50mL) and saturated saline solution (50mL) respectively, collecting the organic phase, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate is 100: 1-10: 1) to obtain the productZ6d(760mg)。
LC-MS:m/z 661.3(M+H)+。
And 4, step 4:
at 0 ℃ ofZ6d(640mg) was dissolved in tetrahydrofuran (20mL), a tetrahydrofuran (10mL) solution of tetrabutylammonium fluoride (370mg) was added dropwise to the reaction system, and after the addition, the reaction was maintained at 0-5 ℃ for 1 hour, and then the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction mixture was added to water (300mL) and the mixture was usedExtracting with ethyl acetate (150mL), collecting organic phase, washing with saturated ammonium chloride solution (100mL) and saturated saline (100mL), respectively, collecting organic phase, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain crude productZ6e(580 mg). The product is used for the next reaction without purification.
LC-MS:m/z 547.2(M+H)+。
And 5:
at 0 ℃ ofZ6e(580mg) was dissolved in methylene chloride (20mL), and a solution of m-chloroperoxybenzoic acid (415mg) in methylene chloride (10mL) was added dropwise to the reaction system, after which it was allowed to stand at room temperature for 6 hours. After the reaction is finished, slowly adding the reaction solution into a saturated sodium carbonate solution/a saturated sodium thiosulfate solution/a saturated sodium chloride solution (volume ratio: 1:1:1,90mL), stirring, layering, collecting an organic phase, drying through anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude productZ6f(520 mg). The product is used for the next reaction without purification.
LC-MS:m/z 579.1(M+H)+。
Step 6:
at-10 ℃ to-5 ℃, the temperature is controlled byZ6f(520mg) is dissolved in tetrahydrofuran (30mL), and bis (trimethylsilyl) aminolithium (1.4mL, 1M/tetrahydrofuran) is added dropwise into the reaction system, and after the addition is finished, the reaction is carried out for 2h at 0-5 ℃. After the reaction is finished, adding the reaction solution into ice water (200mL), extracting with ethyl acetate (100mL), collecting an organic phase, washing with saturated saline solution (100mL) once, collecting the organic phase, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, and purifying the crude product by silica gel column chromatography (petroleum ether/ethyl acetate is 50: 1-1: 1) to obtain the productZ6(224mg)。LC-MS:m/z 499.2(M+H)+。
Preparation Z7
Step 1:
at room temperature, mixingZ7a(50g) N-chlorosuccinimide (35g) was dissolved in acetonitrile (400ml), and the reaction was carried out at 80 ℃ for 2 hours. After the reaction is finished, the heating is closed, the temperature is reduced to the room temperature, and the mixture is filtered to obtainZ7b(54g)。
LC-MS:m/z 268.0(M+H)+。
Step 2:
at room temperature, mixingZ7b(54g) Urea (64g) was dissolved in diphenyl ether (300ml), and the reaction was carried out at 180 ℃ for 5 hours. Cooling to 40 deg.C after reaction, filtering, pulping the obtained solid with mixed solution of methyl tert-butyl ether/methanol (volume ratio: 5: 1; 300ml), and filtering to obtain the final productZ7c(55g)。
LC-MS:m/z 293.0(M+H)+。
And step 3:
at room temperature, mixingZ7c(55g) Dissolved in POCl3To (350ml) was added N, N-dimethylformamide (5ml), followed by heating to 110 ℃ and reacting for 12 hours. After the reaction, slowly adding the reaction solution into ice water (5L), extracting with ethyl acetate (5L), collecting organic phase, washing with saturated saline (2X 2.5L), mixing organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain the final productZ7d(25g)。
LC-MS:m/z 328.9(M+H)+。
And 4, step 4:
will be provided withZ7d(12g) Dissolving in N, N-dimethylformamide (70ml), stirring at 0 deg.C for 10min, and adding dropwise into the reaction systemZ1After addition of a solution of (9.6g) in N, N-dimethylformamide (30ml), N-diisopropylethylamine (17g) was added dropwise to the reaction system, and the reaction was carried out at 0 ℃ for 2 hours. After the reaction, the reaction solution was poured into water (1000ml), extracted with ethyl acetate (3 x 500ml), the organic phases were combined, washed with saturated brine (2 x 500ml), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, and purified by silica gel column chromatography to give a crude productZ7e(15g)。
LC-MS:m/z 667.1(M+H)+。
And 5:
will be provided withZ7e(11g) Dissolved in tetrahydrofuran (60ml), stirred at 0 ℃ for 15min, and a solution of tetrabutylammonium fluoride trihydrate (5.2g) in tetrahydrofuran (20ml) was added dropwise to the reaction system, followed by reaction at 0 ℃ for 3 h. After the reaction, the reaction mixture was poured into water (800ml), extracted with ethyl acetate (3 × 300ml), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressureObtaining a crude product, purifying by silica gel column chromatography to obtainZ7f(7.3g)。
LC-MS:m/z 553.0(M+H)+。
Step 6:
dissolving sodium bis (trimethylsilyl) amide (2M/THF) (NaHMDS; 12.6ml) in tetrahydrofuran (200ml), stirring at 0 ℃ under the protection of nitrogen, and dropwise adding the mixture into the reaction systemZ7f(7g) Then, the reaction was continued for 2 hours after the addition of tetrahydrofuran (200 ml). After the reaction, adding the reaction solution into saturated ammonium chloride solution (2L), extracting with ethyl acetate (2X 500L), collecting organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain crude product, and purifying with silica gel column chromatography to obtain the title compoundZ7(2.9g)。
LC-MS:m/z 517.1(M+H)+。
Preparation Z8
Step 1:
at room temperature, mixingZ8a(25g) Dissolving in DMF (400mL), replacing with argon, stirring in ice bath for 15min under the protection of argon, then adding sodium hydrogen in batches, removing the ice bath after adding, returning to room temperature, and stirring for reaction for 1 h. PMBCl (47g) was slowly added dropwise to the system, and the reaction was continued with stirring for 4 h. The reaction was quenched by addition of 500mL of saturated aqueous ammonium chloride. Extracting the reaction solution with 2.5L ethyl acetate, combining the organic phases, washing the organic phase with 500mL of 5 saline, drying the organic phase with anhydrous sodium sulfate, and concentrating the mixture under reduced pressure to obtain a crude product. Purifying with silica gel column chromatography (petroleum ether: dichloromethane: 3: 1-1: 1) to obtainZ8b(47g)。
LC-MS:m/z 427.3(M+H)+。
Step 2:
will be provided withZ8b(5.0g), lithium chloride (2.6g), Pd2(dba)3(1.1g)、PCy3(0.68g) and hexa-n-butylditin (21g) were dissolved in 32mL of 1, 4-dioxane, and then replaced with argon for 5 times, and the mixture was heated to 80 ℃ under the protection of argon and stirred for reaction for 6 hours. Concentrating under reduced pressure to obtain crude product, and purifying with silica gel column chromatography (dichloromethane: methanol: 80: 1-10: 1) to obtain the title compoundZ8(5.8g)。
LC-MS:m/z 639.36(M+H)+。
Example 1
Step 1:
at room temperature, mixingZ6(100mg)、Z2(125mg), palladium acetate (3mg), potassium phosphate (125mg), 2-dicyclohexyl-phosphorus-2 ',6' -dimethoxy-biphenyl (SPhos,9.5mg) were dissolved in 1, 4-dioxane/water (4:1,12.5mL), replaced with argon 5 times, heated to 90 ℃ under argon protection, and stirred for reaction for 10 h. After the reaction, the reaction solution was poured into ice water (150mL), extracted with ethyl acetate (3 × 50mL), the organic phases were combined, concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 10: 1-pure ethyl acetate) to give a crude product1a(30mg)。
LC-MS:m/z 587.3(M+H)+。
And step 8:
at 0 ℃ of1a(30mg) was dissolved in ethyl acetate (10mL), and a HCl/methanol (0.8mL) solution was added dropwise to the reaction system, after which the reaction system was allowed to react at room temperature for 15 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure until no liquid flowed out, water (30mL) was added to the residue, and the mixture was extracted with dichloromethane (15mL), and the aqueous phase was collected, adjusted to Ph 8 to 9 with a saturated sodium bicarbonate solution, and extracted with dichloromethane (15mL)
Extracting, collecting organic phase, concentrating under reduced pressure to obtain crude product1b(25 mg). The product is used for the next reaction without purification.
LC-MS:m/z 487.2(M+H)+。
And step 9:
at 0 ℃ of1b(25mg) and potassium carbonate (30mg) were dissolved in 2-methyltetrahydrofuran/water (1:1,5mL), and acryloyl chloride (5.2mg) was added dropwise to the reaction system, followed by reaction at 0-5 ℃ for 10 min. The reaction mixture was added to ice water (50mL), extracted with ethyl acetate (20mL), and the organic phase was collected, washed with saturated brine (2 × 20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. Preparative reverse color for crude productPurifying with chromatographic column (column type: Luna C185 um 21.5.5 × 250 mm; mobile phase A0.05% formic acid B acetonitrile; flow rate 10 mL/min; elution gradient 10-50%, time 60 min; detection wavelength 254nm) to obtain the title compound1(10mg)。LC-MS:m/z 541.1(M+H)+。
1H NMR(500MHz,Chloroform-d)δ7.89(d,J=93.8Hz,2H),6.94(s,1H),6.80–6.21(m,3H),6.20–5.59(m,3H),4.67–4.39(m,4H),4.07(d,J=102.6Hz,6H),3.54–3.15(m,3H).
Example 2
Synthesis of example 2 reference example 1 was madeZ3Instead of the formerZ1Purification by preparative reverse phase chromatography to give the title compound2(12mg)。LC-MS:m/z 541.1(M+H)+。
Example 3 (Compound 3)
Synthesis of example 3 reference example 1 with (1H-indazol-4-yl) boronic acidZ2Purification by preparative reverse phase chromatography to give the title compound3(2.2mg)。
LC-MS:m/z 509.3(M+H)+。
Example 4, example 5 and example 6
Synthesis of example 4 reference example 1 was madeZ7Substitute forZ6By 2-fluoro-6-hydroxyphenylboronic acid instead ofZ2To obtain the title compound4。
Example 4 the Compound was isolated and purified by preparative column to give atropisomers5(7.6mg) and atropisomers6(4.2mg)。
Atropisomer 5: when reservedTime 36min, LC-MS: M/z 503.2(M + H)+。
And (3) purification conditions:
atropisomer 6: retention time 38min, LC-MS: M/z 503.2(M + H)+。
And (3) purification conditions:
example 7, example 8 and example 9
Synthesis of example 7 reference example 1 toZ7Instead of the formerZ6By replacing (5-methyl-1H-indazol-4-yl) boronic acidZ2To obtain the title compound7。
The compound of example 7 was isolated and purified by preparative column under the following conditions:
to obtain atropisomers8(2mg) and atropisomers9(2.2mg)。
Atropisomer 8: retention time 45min, LC-MS: M/z 523.2(M + H)+. Atropisomer 9: retention time 42min, LC-MS: M/z 523.2(M + H)+。
Example 10, example 11 and example 12
Synthesis of example 10 reference example 1 was made toZ7Substitute forZ6By usingZ4Instead of the formerZ2To obtain the title compound10。
The compound of example 10 was isolated and purified by preparative column under the following conditions:
to obtain atropisomers11(2.4mg) and atropisomers12(4.9mg)。
Atropisomer 11: retention time 35min, LC-MS: M/z 577.13(M + H)+. Atropisomer 12: retention time 32min, LC-MS: M/z 577.13(M + H)+。
Example 13
Step 1:
at room temperature, mixingZ7(300mg)、Z5(756mg), methanesulfonic acid (2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl) (2 '-methylamino-1, 1' -biphenyl-2-yl) palladium (II) (101mg), copper oxide (139mg) and cesium fluoride (176mg) were dissolved in DMF (15mL), replaced with argon for 5 times, and the reaction was stirred at 80 ℃ for 15 hours under argon protection. After the reaction, the reaction solution was poured into ice water (100ml), extracted with ethyl acetate (3 × 30ml), the organic phases were combined, concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give a crude product2a(125mg)。
Step 2
Reference example 1 Steps 2 and 3, to give the title compound13。
Example 14 and example 15
Example 13 isolation and purification of the Compound on a preparative column to give atropisomers14And atropisomers15。
Example 16
Step 1:
at room temperature, mixingZ7(1g)、Z8(3.8g), methanesulfonic acid (2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl) (2 '-methylamino-1, 1' -biphenyl-2-yl) palladium (II) (200mg), copper oxide (500mg) and cesium fluoride (500mg) were dissolved in DMF (100ml), replaced with argon for 5 times, and the temperature was raised to 80 ℃ under the protection of argon, and the reaction was stirred for 15 hours. After the reaction, the reaction solution was poured into ice water (1000ml), extracted with ethyl acetate (3 x 200ml), the organic phases were combined, concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give a crude product3a(525mg)。
Step 2:
at room temperature, mixing3a(500mg), N-iodosuccinimide (NIS, 720mg) was dissolved in acetonitrile (50ml) and reacted at 50 ℃ for 5 hours. After the reaction, the reaction solution was added to a saturated sodium thiosulfate solution (500ml), extracted with ethyl acetate (3 x 150ml), the organic phase was collected, concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography to give a crude product3b(496mg)。
And 3, step 3:
at room temperature, mixing3b(490mg), methyl fluorosulfonyl difluoroacetate (2.6g), and cuprous iodide (1.2g) were dissolved in N, N-dimethylacetamide (15ml), and the mixture was heated to 90 ℃ under argon protection to react for 18 hours. After the reaction, the reaction mixture was added to water (150ml), extracted with ethyl acetate (3 × 50ml), the organic phase was collected, washed with saturated brine (2 × 50ml), the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. Purifying the crude product by silica gel column chromatography to obtain3c(376mg)。
Step 4
The title compound was prepared by referring to steps 2 and 3 in example 116。
Example 17 and example 18
Synthesis of example 16 reference example 1Z6Instead of the formerZ2To obtain the title compound16。
Example 16 the Compound was isolated and purified using a preparative column to give atropisomers17And atropisomers18。
Test example 1 in vitro guanine nucleotide exchange inhibitory Activity test
1. Reagent:His-KRASG12C(1-169);SOS1cat(564-1049); anti-6HIS-Cryptate (from Cisbio); EDA-GTP-DY-647P1 (available from Jena Bioscience).
2. Preparing buffer solution:
1) Assay buffer: HEPES pH 7.4, NaCl, MgCl2、DTT、BSA、Igepal
2)KRASG12CWorking fluid: assay buffer was used to prepare a reagent containing 100nM His-KRASG12CAnd 2nM KRAS of Anti-6HIS-CryptateG12CWorking fluid
3)SOS1catWorking fluid: assay buffer was prepared containing 20nM SOS1catAnd SOS1 of 200nM EDA-GTP-DY-647P1catWorking fluid
4) Blank control working solution: a blank control solution containing 2nM of Anti-6HIS-Cryptate was prepared in assay buffer.
3. The testing process comprises the following steps:
the whole experimental process is completed under the condition of room temperature. 5 μ LKRAS was added to each well of the experimental and negative groups using a black bottom-penetrating 384-well plateG12CWorking solution, simultaneously, 5 μ L of blank control working solution was added to each well of the blank group, and incubated at room temperature for 10 min. Then, compounds were added to the experimental group at an initial concentration of 20. mu.M in 11 concentration gradients diluted 1:4 in succession using a super-microsyringe and incubated at room temperature for 30 min. Finally, 5. mu.L of SOS1 was added to each wellcatWorking solution, incubated at room temperature for 10min and read using Perkinelmer Envision HTS multiple tagsThe device detects 665nm/620nm signal values. The inhibition rate was calculated as (average of negative control group-average of experimental group)/(average of negative control group-average of blank group) × 100%. The logarithmic concentration of the compound is used as the abscissa, the inhibition rate is used as the ordinate, a four-parameter logical model is used for fitting a curve, and the IC is calculated50The value is obtained.
The results of the relevant tests on some of the example compounds of the present application are shown in table 1.
Test example 2NCI-H358 (Kras)G12CMutation) cell proliferation inhibitory Activity test
Taking NCI-H358 cells (Kras) in exponential growth phaseG12CMutation), collecting cells into a centrifuge tube, centrifuging for 5min at 1000 rpm by a low-speed bench centrifuge, discarding supernatant, and adding 5mL of complete medium (RPMI basal medium + 10% Fetal Bovine Serum (FBS)) by a pipette to resuspend the cells. Counting with a cell counter, diluting the complete medium, and adjusting the cell density to 6X 104each/mL, the FBS concentration was adjusted to 5% and the cell density was adjusted to 3X 10 in the same amount of RPMI basal medium4seed/mL. Inoculating to a 96-well plate using a multi-channel pipette at 100. mu.L/well, at 37 ℃ with 5% CO2Culturing in a cell culture box with saturated humidity. After 24 hours of incubation, compound loading was carried out using an ultramicrotome to a final compound concentration of 5000nM to 0.31nM, 2 wells were provided for each concentration, cells without compound were used as negative controls, CCK-8 (beijing homorph chemical, CK04) was added 72 hours later, 10 μ L/well was measured at 450nM for 1 hour later using an Envision microplate reader, the inhibition rate was calculated, the inhibition rate (%) was (negative control mean-experimental mean)/(negative control mean-blank mean) × 100%, the logarithm of compound concentration was used as abscissa, the inhibition rate was used as ordinate, four-parameter analysis was carried out, a dose-effect curve was fitted, and IC calculation was carried out50。
The results of the relevant activity tests for some of the example compounds of the present application are shown in table 1.
Experimental example 3NCI-H358 cells (Kras)G12CMutation) ERK protein phosphorylation inhibition activity assay
Is taken at an indexNCI-H358 cells (Kras) in good growth phaseG12CMutation), collecting cells to a centrifuge tube, a low-speed desk centrifuge, 1000 rpm, centrifuging for 5min, discarding supernatant, and adding 5mL of complete medium (RPMI basal medium + 10% FBS) by using a pipette to perform cell resuspension. Counting with a cell counter, diluting the complete medium, and adjusting the cell density to 3X 105each/mL, the concentration of FBS was adjusted to 5% and the cell density was adjusted to 1.5X 10 in the same amount of RPMI basal medium5seed/mL. Using a multi-channel pipette, the cells were seeded in 384 well plates at 40. mu.L/well and placed at 37 ℃ in 5% CO2Culturing in a cell culture box with saturated humidity. After 24 hours of incubation, the compounds were loaded using an ultramicrotome to a final concentration of 5000nM to 0.32nM, 2 duplicate wells per concentration, and controls. . After 1 hour, the medium was discarded, 40. mu.L of 4% paraformaldehyde was added to each well, and after incubation at room temperature for 20min, 40. mu.L of methanol was added to each well, followed by incubation at room temperature for 10min and PBST washing. Adding 20 μ L of 5% BSA blocking buffer into each well, blocking at room temperature for 1 hr, removing the blocking solution, and adding 20 μ L of pERK antibody (CST, 9101) and GAPDH antibody (R) into each well&D, MAB5718), incubated overnight at 4 ℃, and PBST washed. mu.L of a mixture of 800nm fluorescent secondary antibody (CST, 5151) and 680nm fluorescent secondary antibody (CST, 5470) was added to each well, incubated at room temperature in the dark for 45min, and washed with PBST. Scanning with a multispectral laser imager, taking the logarithm of the concentration of the compound as an abscissa and the inhibition rate as an ordinate, analyzing four parameters, fitting a dose-effect curve, and calculating EC50。
Table 1: results of Compound Activity test
Note: a represents IC50≤50nM;
B represents 50nM < IC50(EC50)≤150nM;
C represents 150nM < IC50≤500nM;
D represents 500nM < IC50≤999nM;
-represents not detected.
Claims (10)
1. A compound of formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
x is selected from N or CRX;
Y is selected from N or CRY;
Z is selected from N or CRZ;
Provided that at least one of X, Y, Z is not selected from N;
RX、RY、RZeach independently selected from H, halogen, -CN, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, vinyl, or ethynyl;
each R1Independently selected from halogen, oxo, -OH, -NH2、-CN、C1-6Alkyl, halo C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl radical, C1-6Alkoxy radical, C1-4Alkoxy radical C1-3Alkyl radical, C1-6Alkylamino, or di-C1-6An alkylamino group;
m is selected from 0, 1,2,3, or 4;
R2selected from the group consisting of-C (O) C ≡ CR2b、-SO2C≡CR2b、-C(O)C(R2a)=C(R2b)2or-SO2C(R2a)=C(R2b)2;
R2aSelected from H, halogen, -CN, C1-4Alkyl radical, C1-4Alkoxy, hydroxy C1-4Alkyl, or haloC1-4An alkyl group;
each R2bIndependently selected from H, halogen, -CN, or optionally substituted with 1,2 or 3R2cSubstituted groups as follows: c1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino, di-C1-6Alkylamino radical, C1-4Alkoxy radical C1-3Alkyl radical, C1-4Alkylamino radical C1-3Alkyl, di-C1-4Alkylamino radical C1-3Alkyl, 3-7 membered cycloalkyl C1-3Alkyl, or 4-7 membered heterocycloalkyl C1-3An alkyl group;
each R2cIndependently selected from halogen, oxo, -OH, -NH2or-CN;
w is selected from O, S, or NRW1;
RW1Is selected from H or C1-4An alkyl group;
R3a、R3beach independently selected from H or C1-3An alkyl group; or, R3a、R3bTogether form ═ O;
R4selected from H, C1-6Alkyl, hydroxy C1-6Alkyl radical, C1-6Alkoxy radical, C1-4Alkylamino radical C1-3Alkyl, di-C1-4Alkylamino radical C1-3Alkyl, di-C1-4Alkylaminoacyl radical C1-3Alkyl, halo C1-6Alkyl, halo C1-6Alkoxy, halo C1-4Alkylamino radical C1-3Alkyl, di (halo C)1-4Alkyl) amino C1-3Alkyl, or optionally substituted by 1,2,3 or 4R4aSubstituted with the following groups: 3-7 membered cycloalkyl, 4-7 membered heterocycloalkyl, 3-7 membered cycloalkyl C1-3Alkyl, or 4-7 membered heterocycloalkyl C1-3An alkyl group;
each R4aIndependently selected from halogen, -OH, oxo, -NH2、-CN、C1-4Alkyl, hydroxy C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy radical, C1-2Alkylcarbonyl group, C1-4Alkylamino, di-C1-4Alkylamino, 3-7 membered cycloalkyl, or 4-7 membered heterocycloalkyl;
ring B is selected from phenyl, naphthyl, 5-10 membered heteroaryl, benzo 5-6 membered cycloalkenyl, benzo 5-6 membered heterocyclyl, 5-6 membered heteroaryland 5-6 membered cycloalkenyl, or 5-6 membered heteroaryland 5-6 membered heterocyclyl, the 5-6 membered cycloalkenyl or 5-6 membered heterocyclyl moiety being optionally substituted with one or two ═ O;
each R5Independently selected from halogen, -CN, -OH, -NH2、-C(O)NH2、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, hydroxy C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkylthio, halogeno C1-6Alkylthio radical, C1-6Alkylamino, halogeno C1-6Alkylamino, di-C1-6Alkylamino, di (halo C)1-6Alkyl) amino, or optionally substituted with 1,2 or 3R5aSubstituted with the following groups: 3-7 membered cycloalkyl, 3-7 membered cycloalkyl C1-3Alkyl, 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C1-3An alkyl group;
each R5aIndependently selected from oxo, halogen, -CN, -OH, -NH2、C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy radical, C1-4Alkylamino, or di-C1-4An alkylamino group;
n is selected from 0, 1,2,3,4, 5, or 6.
2. A compound of formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein X is selected from CRX(ii) a Y is selected from CRY(ii) a Z is selected from CRZ。
4. A compound of formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-3, wherein R2Selected from the group consisting of-C (O) C ≡ CR2b、-C(O)C(R2a)=C(R2b)2or-SO2C(R2a)=C(R2b)2。
5. A compound of formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-4, wherein R4Selected from H, C1-6Alkyl radical, C1-4Alkylamino radical C1-3Alkyl, di-C1-4Alkylamino radical C1-3Alkyl, di-C1-4Alkylaminoacyl radical C1-3Alkyl, halo C1-6Alkyl, halo C1-4Alkylamino radical C1-3Alkyl, di (halo C)1-4Alkyl) amino C1-3Alkyl, or optionally substituted by 1,2,3 or 4R4aSubstituted with the following groups: 4-7 membered heterocycloalkyl, or 4-7 membered heterocycloalkyl C1-3An alkyl group.
6. A compound of formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, wherein ring B is selected from phenyl, indenyl, 2, 3-indanyl, naphthyl, 1,2,3, 4-tetrahydronaphthalene, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, benzopyrazolyl, pyrazolyl, and pharmaceutically acceptable salts thereof,Benzimidazolyl, benzotriazolyl, benzothiazolyl, benzisothiazolyl, indolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzimidazolyl, benzoxazolyl, benzimidazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, benzoxazolyl, benzimidazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzimidazolyl, indolinyl, benzimidazolyl, benzoxazolyl, benzimidazolyl, benzoxazolyl, benzimidazolyl, indolinyl, benzoxazolyl, and the like,Benzoxazolyl group,Benzisoxazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, quinoxalinyl, or
7. A compound of formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, selected from a compound of formula (Ia) or formula (Ib) or formula (Ic) or formula (Id) or formula (II) or formula (IIa) or formula (IIb) or formula (IIc) or formula (IId) or formula (III) or formula (IV) or formula (IVa), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、R3a、R3b、R4、R5、W、RW、X、Y、Z、RX、RZM, n, A, and B are as defined in any one of claims 1 to 6.
9. a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-8.
10. Use of a compound of formula (I), a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, or a pharmaceutical composition according to claim 9, for the preparation of a medicament for the treatment of KrasG12CThe use in the preparation of medicaments for treating related diseases.
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