WO2021063346A1 - Kras g12c抑制剂及其应用 - Google Patents
Kras g12c抑制剂及其应用 Download PDFInfo
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- WO2021063346A1 WO2021063346A1 PCT/CN2020/118772 CN2020118772W WO2021063346A1 WO 2021063346 A1 WO2021063346 A1 WO 2021063346A1 CN 2020118772 W CN2020118772 W CN 2020118772W WO 2021063346 A1 WO2021063346 A1 WO 2021063346A1
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- Prior art keywords
- alkyl
- alkoxy
- group
- amino
- cycloalkyl
- Prior art date
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- 229940125399 kras g12c inhibitor Drugs 0.000 title claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 262
- 150000003839 salts Chemical class 0.000 claims abstract description 59
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 30
- 201000011510 cancer Diseases 0.000 claims abstract description 28
- 102200006538 rs121913530 Human genes 0.000 claims abstract description 21
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 348
- -1 cyano, amino Chemical group 0.000 claims description 123
- 125000003545 alkoxy group Chemical group 0.000 claims description 97
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 76
- 229910052736 halogen Inorganic materials 0.000 claims description 60
- 150000002367 halogens Chemical class 0.000 claims description 60
- 229910052757 nitrogen Inorganic materials 0.000 claims description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims description 57
- 239000001257 hydrogen Substances 0.000 claims description 51
- 125000003118 aryl group Chemical group 0.000 claims description 48
- 125000001424 substituent group Chemical group 0.000 claims description 39
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 38
- 150000002431 hydrogen Chemical class 0.000 claims description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 33
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 30
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 26
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 24
- 239000000460 chlorine Chemical group 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 125000004043 oxo group Chemical group O=* 0.000 claims description 17
- 125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 14
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 229910052720 vanadium Inorganic materials 0.000 claims description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 229910052805 deuterium Inorganic materials 0.000 claims description 10
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 9
- 125000002947 alkylene group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 229940124597 therapeutic agent Drugs 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 5
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 4
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 4
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 4
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000006721 (C5-C10) heteroaryl (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000006719 (C6-C10) aryl (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000005955 1H-indazolyl group Chemical group 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- MDQRDWAGHRLBPA-UHFFFAOYSA-N fluoroamine Chemical group FN MDQRDWAGHRLBPA-UHFFFAOYSA-N 0.000 claims 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 68
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 359
- 239000000543 intermediate Substances 0.000 description 303
- 239000000243 solution Substances 0.000 description 261
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 116
- 238000003818 flash chromatography Methods 0.000 description 91
- 239000012074 organic phase Substances 0.000 description 91
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 82
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 72
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 68
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- 230000015572 biosynthetic process Effects 0.000 description 51
- 238000003786 synthesis reaction Methods 0.000 description 51
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 34
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 20
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- 238000001308 synthesis method Methods 0.000 description 17
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- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 15
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- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000004262 preparative liquid chromatography Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- LMWFKCYJTRUATP-UHFFFAOYSA-N pyridin-1-ium-4-carbonitrile;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.N#CC1=CC=[NH+]C=C1 LMWFKCYJTRUATP-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- ROEMZCLHRRRKGF-SFYZADRCSA-N tert-butyl (2s,4r)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1CO ROEMZCLHRRRKGF-SFYZADRCSA-N 0.000 description 1
- NUZXPHIQZUYMOR-IUCAKERBSA-N tert-butyl (3s,5s)-3,5-dimethylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1 NUZXPHIQZUYMOR-IUCAKERBSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 201000006134 tongue cancer Diseases 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
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- 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
- C07D498/02—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 two hetero rings
- C07D498/04—Ortho-condensed systems
-
- 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
- C07D498/02—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 two hetero rings
- C07D498/06—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to a novel compound that inhibits the activity of KRAS G12C.
- the present invention relates to a compound that irreversibly inhibits the activity of KRAS G12C, including its pharmaceutical composition and its application as a cancer therapeutic agent.
- the RAS gene family mainly includes three genes, KRAS, NRAS and HRAS.
- the RAS gene is a proto-oncogene, which becomes an oncogene with carcinogenic activity after being activated.
- RAS encodes a group of monomeric globular proteins (21kD) composed of 188-189 amino acids, called p21 protein or RAS protein.
- the RAS protein is a GDP/GTP binding protein, which can cycle between the inactive GDP binding state and the active GTP binding state, acting as a "molecular switch".
- the GDP/GTP cycle of RAS is activated by guanine nucleotide exchange factors (such as SOS or RASGRP) and inactivated by GTPase initiating proteins (GAPs, such as p120GAP or neurofibroma protein).
- GAPs GTPase initiating proteins
- the interaction between GAPs and RAS can greatly accelerate the conversion of GTP to GDP. Turn off the switch to inactivate RAS. Any mutation that affects the interaction between RAS and GAP or the ability to convert GTP back to GDP will cause RAS to continue to activate, and thus cause damage to the cell. Extended signal.
- RAS can regulate cell proliferation, differentiation and senescence through a variety of important signal pathways, the prolonged activation of downstream signal pathways (for example: PI3K-AKT-mTOR, RAF-MEK-ERK, RALGDS-RAL) will eventually lead to the occurrence of cancer .
- downstream signal pathways for example: PI3K-AKT-mTOR, RAF-MEK-ERK, RALGDS-RAL
- the RAS protein includes a highly conserved N-terminal G-binding domain, which also contains a nucleotide-binding p-loop and switch I (residues 30-40) and switch II (residues 60-76).
- the p-loop is the rigid part of the binding domain with conserved amino acid residues (glycine 12, threonine 26, and lysine 16), which is necessary for amino acid binding and hydrolysis.
- Threonine-35 and glycine-60 in Switch I and Switch II can form hydrogen bonds with the ⁇ -phosphate/ester of GTP to maintain the active conformation of Switch I and II regions, respectively. After GTP hydrolysis and phosphate/ester release, both can relax into the inactive GDP conformation.
- the RAS protein also includes a C-terminal extension called the CAAX box, which can be post-translationally modified and is responsible for targeting the protein to the cell membrane (Jonathan et al. Nature Reviews, 2016, 15: 771-785).
- the RAS gene can be continuously activated through point mutation, overexpression, gene insertion and translocation.
- the most common one is point mutation. About 30% of human malignancies have RAS gene point mutations.
- the most common is the point mutation of KRAS.
- the common mutation sites are codons 12, 13, and 61, among which codon 12 is the most common mutation.
- G12C mutation is one of the most frequently occurring mutations, and this mutation is found in about 13% of malignant tumors. Among them, the incidence of G12C mutation in non-small cell lung cancer is about 11%, and the incidence of G12C mutation in colorectal cancer, pancreatic cancer and endometrial cancer is about 1%-4% (Hobbs et al. J Cell Sci, 2016, 129: 1287-1292; Prior et al. Cancer Res, 2012, 72: 2457-67).
- KRAS especially mutants including KRAS G12C
- KRAS G12C KRAS mutant inhibitors
- the technical problem to be solved by the present invention is to provide a novel compound that inhibits the activity of KRAS G12C, which can effectively treat various diseases related to KRAS G12C, such as cancer.
- the present invention provides a compound represented by formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts;
- the ⁇ and ⁇ bonds are single bonds or double bonds, respectively;
- X is N or CR 2 ;
- Y is C(O) and Z is NR 3 ; when the ⁇ bond is a double bond, Y and Z are independently N or CR 2 respectively ;
- W When the ⁇ bond is a single bond, W is N and V is CH 2 or C(O); when the ⁇ bond is a double bond, W is C and V is CR 4 or N;
- U and M are each independently N, C or CH;
- the A ring is a phenyl group, a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group or a 4-8 membered heterocycloalkyl group; the A ring is unsubstituted or optionally substituted by 1 to 3 R 5 The group is substituted at any position;
- the B ring is a 5-10 membered heterocycloalkyl; the B ring is unsubstituted or optionally substituted by 1 to 3 R 6 groups at any position;
- R is C 6-10 aryl, 5-10 membered heteroaryl or 9-14 membered fused heterocycloalkyl; said R is unsubstituted or optionally substituted by one or more R 7 groups in any position;
- R 1 is C 2-4 alkenyl, C 2-4 alkynyl or partially unsaturated C 4-6 cycloalkyl; said R 1 is unsubstituted or optionally substituted by 1 to 3 R 8 groups Anywhere
- R 2 is hydrogen, hydroxy, halo, cyano, amino, -R A, -NR A R B , -OR A , or -SR A;
- R 3 is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3 8-membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl or 5-10 heteroaryl-C 1-4 alkyl; said R 3 is unsubstituted Alternatively, one to three selected from halogen, hydroxyl, cyano, amino, oxo, halogenated C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3- The substituents of 6 cycloalkyl-C 1-4 alkyl, 4-6 membered heterocycloalkyl or 4-6 membered heterocycloalkyl-C 1-4 alkyl are substituted at any position;
- R 4 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl or C 3-8 cycloalkyl;
- R 5 is hydrogen, hydroxyl, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, acyl, C 3-8 membered cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocyclic ring Alkyl-C 1-4 alkyl or -B(OR”) 2 ;
- R 6 is hydrogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -C (O)OR' or -C(O)NR' 2 ; in R 6 , the C 1-6 alkyl group is unsubstituted or optionally selected from 1 to 3 halogen, hydroxyl, amino, carboxyl, cyano groups , Substituents of C 1-4 alkoxy, halogenated C 1-4 alkoxy and C 1-6 alkylamino are substituted at any position;
- R 7 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl- C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-4 alkyl , -NH-C 3-6 cycloalkyl, -(CH 2 ) n OR',
- R 8 is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy-C 1 -4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1-4 alkyl, 5-10 membered heteroaryl , 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C 1-4 alkyl or 3-10 heterocycloalkyl-C 1-4 alkyl; wherein, the C 1-6 alkylamino- C 1-4 alkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or heteroarylalkyl is unsubstituted, or optionally one to three selected from halogen, hydroxy, amino, cyano , Substituents of C 1-4 alkoxy, oxo and C 1-4 al
- R A is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3 -10 membered heterocycloalkyl, C 3-10 cycloalkyl-C 1-6 alkyl, 3-10 membered heterocycloalkyl-C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl group or a 5-10 membered heteroaryl -C 1-6 alkyl; the R a is unsubstituted or optionally substituted with one or more R c substituents at any position;
- R B is hydrogen, cyano, hydroxyl or C 1-6 alkyl
- R A and R B each other to form 4-8 heterocycloalkyl; said heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from hydroxy, cyano, amino, oxo, halo, C 1-4 alkyl, acyl, C 1-4 alkoxy, C 1-6 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-4 alkane Group, C 1-4 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1-4 alkyl, C 3-8 membered cycloalkyl, 3 -8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-
- R c is hydroxy, cyano, amino, oxo, halogen, C 1-4 alkyl, C 1-4 alkylene, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1 -4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1 -6 alkylamino-C 1-6 alkyl, C 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 ring Alkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1 -4 alkyl, -(CH 2 ) n -N(CN)R', -(CH
- R' is hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, amino-C 1- 4- alkyl, C 1-6 alkylamino-C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl, 6-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl or 6-10 membered hetero Aryl-C 1-4 alkyl;
- R" is hydrogen or C 1-6 alkyl
- n is an integer from 0 to 4.
- the definition of certain groups in the compound represented by formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts may be as follows, and those not described The group can be as described in any of the above schemes:
- the ⁇ and ⁇ bonds are single bonds or double bonds, respectively;
- X is N or CH
- ⁇ bond is a single bond
- Y is C(O) and Z is NR 3
- Y and Z are N or CR 2 respectively;
- W When the ⁇ bond is a single bond, W is N and V is CH 2 or C(O); when the ⁇ bond is a double bond, W is C and V is CR 4 or N;
- U and M are each independently N, C or CH;
- the A ring is a phenyl group, a 3-8 membered cycloalkyl group, a 5-6 membered heteroaryl group or a 4-8 membered heterocycloalkyl group; the A ring is unsubstituted or optionally substituted by 1 to 3 R 5 The group is substituted at any position;
- the B ring is a 5-10 membered heterocycloalkyl; the B ring is unsubstituted or optionally substituted by 1 to 3 R 6 groups at any position;
- R is C 6-10 aryl, 5-10 membered heteroaryl or 9-14 membered fused heterocycloalkyl; said R is unsubstituted or optionally substituted by one or more R 7 groups in any position;
- R 1 is C 2-4 alkenyl, C 2-4 alkynyl or partially unsaturated C 4-6 cycloalkyl; said R 1 is unsubstituted or optionally substituted by 1 to 3 R 8 groups Anywhere
- R 2 is -R A , -NR A R B , -OR A or -SR A ;
- R 3 is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3 8-membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl or 5-10 heteroaryl-C 1-4 alkyl; said R 3 is unsubstituted Alternatively, one to three selected from halogen, hydroxyl, cyano, amino, oxo, halogenated C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, C 3- The substituents of 6 cycloalkyl-C 1-4 alkyl, 4-6 membered heterocycloalkyl or 4-6 membered heterocycloalkyl-C 1-4 alkyl are substituted at any position;
- R 4 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl or C 3-8 cycloalkyl;
- R 5 is hydrogen, hydroxyl, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, acyl, C 3-8 membered cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocyclic ring Alkyl-C 1-4 alkyl or -B(OR”) 2 ;
- R 6 is hydrogen, oxo, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, halogenated C 1-6 alkoxy, -C (O)OR' or -C(O)NR' 2 ; in R 6 , the C 1-6 alkyl group is unsubstituted or optionally selected from 1 to 3 halogen, hydroxyl, amino, carboxyl, cyano groups , Substituents of C 1-4 alkoxy, halogenated C 1-4 alkoxy and C 1-6 alkylamino are substituted at any position;
- R 7 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl- C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-4 alkyl , -NH-C 3-6 cycloalkyl, -(CH 2 ) n OR',
- R 8 is hydrogen, deuterium, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy-C 1 -4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1-4 alkyl, 5-10 membered heteroaryl , 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C 1-4 alkyl or 3-10 heterocycloalkyl-C 1-4 alkyl; wherein, the C 1-6 alkylamino- C 1-4 alkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or heteroarylalkyl is unsubstituted, or optionally one to three selected from halogen, hydroxy, amino, cyano , Substituents of C 1-4 alkoxy, oxo and C 1-4 al
- R A is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 Member heterocycloalkyl, C 3-10 cycloalkyl-C 1-6 alkyl, 3-10 heterocycloalkyl-C 1-6 alkyl, C 6-10 aryl-C 1-6 alkyl or 5-10 membered heteroaryl -C 1-6 alkyl; the R a is unsubstituted or optionally substituted with one or more R c substituents at any position;
- R B is hydrogen, cyano, hydroxyl or C 1-6 alkyl
- R A and R B each other to form 4-8 heterocycloalkyl; said heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from hydroxy, cyano, amino, oxo, halo, C 1-4 alkyl, acyl, C 1-4 alkoxy, C 1-6 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-4 alkane Group, C 1-4 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1-4 alkyl, C 3-8 membered cycloalkyl, 3 -8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-
- R c is hydroxy, cyano, amino, oxo, halogen, C 1-4 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkylamino-C 1- 6 alkyl, C 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkane Group, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, -(CH 2 ) n -N(CN)R', -(CH 2 ) n -C
- R' is hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, amino-C 1- 4- alkyl, C 1-6 alkylamino-C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl, 6-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl or 6-10 membered hetero Aryl-C 1-4 alkyl;
- R" is hydrogen or C 1-6 alkyl
- n is an integer from 0 to 4.
- the definition of certain groups in the compound represented by formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts may be as follows, and those not described The group can be as described in any of the above schemes:
- the ⁇ and ⁇ bonds are double bonds respectively;
- U and M are respectively N and C independently;
- Ring A is 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl
- Ring B is The ring B is unsubstituted or optionally substituted by 1 to 3 R 6 groups at any position;
- R is a C 6-10 aryl group or a 5-10 membered heteroaryl group; said R is unsubstituted or optionally substituted by 1 to 4 R 7 groups in any position;
- R 1 is a C 2-4 alkenyl group; said R 1 is unsubstituted or optionally substituted by 1 to 3 R 8 groups at any position;
- R 2 is -OR A ;
- R 6 is hydrogen, a C 1-6 alkyl group or a C 1-6 alkoxy group; in R 6 , the C 1-6 alkyl group is unsubstituted or optionally selected from 1 to 3 halogen, hydroxyl, and cyano groups. The substituents of the C 1-4 alkoxy group and the C 1-4 alkoxy group are substituted at any position;
- R 7 is hydrogen, hydroxy, halogen, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 3 -8 cycloalkyl or 3-8 membered heterocycloalkyl;
- R 8 is hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino- C 1-4 alkyl or C 1-6 alkylamino-C 1-4 alkyl;
- R A is C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 3-10 cycloalkyl or -C 1-6 alkyl heterocycloalkyl 3-10 - C 1-6 alkyl; the R a is unsubstituted or optionally substituted with one or more R c at an arbitrary position;
- R c is hydroxy, cyano, amino, oxo, halogen, C 1-4 alkyl, C 1-4 alkylene, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1 -4 alkyl or halogenated C 1-4 alkoxy.
- the definition of certain groups in the compound represented by formula (I), its isomers, stable isotope derivatives or pharmaceutically acceptable salts may be as follows, and those not described The group can be as described in any of the above schemes:
- R 3 is C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 heteroaryl, C 3-8 cycloalkyl-C 1-4 alkyl , 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl or 5-10 heteroaryl-C 1-4 alkyl; said R 3 is Unsubstituted or optionally substituted by 1 to 3 substituents selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl or C 3-6 cycloalkyl at any position;
- R 7 is hydrogen, hydroxy, halogen, C 2-6 alkenyl, C 2-6 alkynyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkane Group, halogenated C 1-6 alkoxy, hydroxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkane Amino-C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkyl, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl- C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl, 5-10 membered heteroaryl-C 1-4 alkyl , -NH-C 3-6 cycloalkyl, -(CH 2 ) n OR',
- R c is hydroxy, cyano, amino, oxo, halogen, C 1-4 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy-C 1-6 alkyl, C 1-4 alkoxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkylamino-C 1- 6 alkyl, C 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-8 cycloalkyl-C 1-4 alkane Group, 3-8 membered heterocycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, -(CH 2 ) n -N(CN)R', -(CH 2 ) n -C
- the alpha bond is a double bond; the beta bond is a single bond or a double bond.
- the ⁇ and ⁇ bonds are respectively double bonds; X is N; W is C, V is CR 4 or N; Y is CR 2 ; Z is N.
- the ⁇ bond is a double bond; the ⁇ bond is a single bond; X is N; W is C and V is CR 4 or N; Y is C(O) and Z is NR 3 ;
- the A ring is 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl.
- the A ring is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazole Group, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl Or tetrazolyl.
- the A ring is furyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxa Diazolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl or tetrazolyl.
- the A ring is 2,3-dihydrofuranyl.
- the A ring has any of the following structures:
- the A ring is unsubstituted or optionally substituted by 1 to 3 R 5 at any position, and R 5 is defined as described above.
- the A ring has any of the following structures:
- the A ring is unsubstituted or optionally substituted by 1 to 3 R 5 at any position, and R 5 is defined as described above.
- the B ring has any of the following structures:
- the ring B is unsubstituted or optionally substituted by 1 to 3 R 6 at any position, and R 6 is defined as described above.
- the R 6 is H, -CH 3 , -CF 3 , -CHF 2 , -CH 2 CN, -CH 2 OH, -CH 2 CH 2 OH , -CH 2 CH 2 OCH 3 or -CH 2 OCH 3 .
- the B ring is
- the B ring is
- the 9-14 membered fused heterocycloalkyl is obtained by condensing a monocyclic heterocycloalkyl with a phenyl, naphthyl, pyridyl, pyrimidinyl, or pyrazinyl group Group, preferably 9-membered or 13-membered condensed heterocycloalkyl, for example: indolinyl, 2,3-dihydrobenzofuranyl, 1,3-dihydrobenzo[c][1,2 ]Oxaborolanyl, 1,3-dihydronaphtho[2,1-c][1,2]oxaborolanyl, 1,3-dihydronaphtho[2,3-c] [1,2] Oxaboranyl and the like.
- the R is phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 1H-benzo[d]imidazole-2( 3H)-keto, 1H-indazolyl, phthalazinyl, 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolanyl, 3-hydroxy-1,3 -Dihydronaphtho[2,1-c][1,2]oxaborolanyl or 1-hydroxy-1,3-dihydronaphtho[2,3-c][1,2]oxa Boronpentyl; the R is unsubstituted or optionally substituted by 1 to 5, 1 to 4 or 1 to 3 R 7 at any position, and R 7 is defined as described above.
- the R 7 is hydrogen, halogen, hydroxy, amino, cyano, C 1-4 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1 -3 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or -B(OH) 2 .
- the R 7, C 3-6 cycloalkyl or a 3-6 membered heterocycloalkyl is unsubstituted or optionally substituted with 1 to 3 substituents selected from hydroxy, amino, fluoro, chloro
- the substituents of, methyl, trifluoromethyl and trifluoromethoxy are substituted at any position.
- the R is any of the following structures:
- the R is any of the following structures:
- the R is any of the following structures:
- the R 1 is wherein, R 8a is H, D, halogen or C 1-3 alkoxy-C 1-4 alkyl; R 8b and R 8c are independently H, D, halogen, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy-C 1-4 alkyl, C 1-3 alkoxy-C 1-4 alkyl, amino-C 1-4 alkyl, C 1-6 alkylamino-C 1- 4- alkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C 1-4 alkyl or 3-10 heterocycloalkyl-C 1-4 alkyl; Wherein, the C 1-6 alkylamino-C 1-4 alkyl group, 5-10 membered heteroaryl group, 3-10 membered heterocycloalkyl group, 5-10 heteroaryl-C 1-4 alkyl group or 3 -10 Heterocycloalkyl-C 1-4 alkyl is unsubstituted,
- the R 1 is Wherein, R 8a is H, D or halogen; R 8b and R 8c are as defined above.
- the R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- R A is a C 1-6 alkyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, aryl, 5-6 membered heteroaryl -C 1-4 alkyl, C 3-8 cycloalkyl -C 1-4 alkyl or -C 1-4 3-8 membered heterocycloalkyl group; the R A is unsubstituted or is selectively 1 to 5 R c are substituted at any position; the definition of R c is as described above.
- the R 2 is -OR A; R A is as previously defined.
- the R 2 is any of the following structures:
- the R 2 is any of the following structures:
- the R 2 is -NR A R B ; the definitions of R A and R B are as described above.
- the R 2 is any of the following structures:
- the R 2 is a 5-10 membered heteroaryl group or a 3-10 membered heterocycloalkyl group; the 5-10 membered heteroaryl group or a 3-10 membered heterocycloalkyl group is unsubstituted or Optionally substituted by one or more R c at any position.
- the R 2 is a 5-6 membered heteroaryl group or a 4-8 membered heterocycloalkyl group; the 5-10 membered heteroaryl group or a 3-10 membered heterocycloalkyl group is unsubstituted or Optionally substituted by one or more R c at any position.
- the R 2 is any of the following structures:
- the R 2 is H or CN.
- the R 3 is cyclohexyl, cyclopropylmethyl, phenyl, pyridyl, pyrimidinyl, thiazole or 1H-pyrazolyl; the R 3 is unsubstituted or is optionally substituted by 1 to Three substituents selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 3-6 cycloalkyl are substituted at any position.
- the R 3 is any of the following structures:
- the R 4 is hydrogen, halogen, C 2-4 alkenyl, C 1-4 alkyl, C 1-3 alkoxy, halo C 1-3 alkyl, halo C 1 -3 alkoxy or C 3-6 cycloalkyl.
- the compound represented by formula (I), its isomer, stable isotope derivative or pharmaceutically acceptable salt is the compound represented by formula (II), its isomer, stable Isotope derivatives or pharmaceutically acceptable salts:
- ring A, ring B, X, U, M, R, R 1 , R 2 and R 4 are as defined above.
- the compound represented by formula (I), its isomer, stable isotope derivative or pharmaceutically acceptable salt is of formula (IIA), (IIB), (IIC) or (IID )
- Ring B, R, R A, R 1 and R 5 are as previously described.
- the present invention also provides a method for preparing the compound represented by formula (I), which is any of the following methods:
- Method 1 In the solvent, the compound represented by formula II-1 and R-L are coupled to obtain the compound represented by formula II,
- Suzuki coupling reaction Lev is Cl, Br or I, L is boronic acid or boronic acid ester group; or Lev is boronic acid or boronic acid ester group, L is Cl, Br or I; Suzuki coupling reaction conditions are Common reaction conditions in the art, the solvent is preferably 1,4-dioxane, and the catalytic system is preferably [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride/sodium carbonate aqueous solution system or For the tetratriphenylphosphine palladium/sodium carbonate aqueous system, the reaction temperature is preferably 80-120°C, and the reaction time is preferably 0.5-16 hours.
- Stille coupling reaction where Lev is Cl, Br or I, L is -Sn(CH 3 ) 3 or -Sn(n-Bu) 3 ; or Lev is -Sn(CH 3 ) 3 or -Sn( n-Bu) 3 , L is Cl, Br or I; Stille coupling reaction conditions are common reaction conditions in the field, the solvent is preferably 1,4-dioxane, and the catalytic system is preferably tetrakistriphenylphosphine palladium/iodine Copper chloride, tetrakistriphenylphosphine palladium/tris(2-furyl)phosphorus or bistriphenylphosphine palladium dichloride/tris(2-furyl)phosphorus, the reaction conditions are preferably microwave or sealing at 80 ⁇ 160°C React in the tube for 0.5 to 4 hours.
- Method 2 In a solvent, the compound represented by formula II-2 is reacted with R 1 (CO)Cl or (R 1 (CO)) 2 O under basic conditions to obtain the compound represented by formula II,
- the solvent shown is preferably dichloromethane; the base is preferably triethylamine or N,N-diisopropylethylamine; the reaction temperature is preferably 0 to 35° C.; and the reaction time is preferably 0.5 to 6 hours.
- Method 3 In the solvent, the compound represented by formula II-2 and R 1 (CO)OH are condensed to obtain the compound represented by formula II,
- the solvent shown is preferably dichloromethane and/or ethyl acetate; the base is preferably triethylamine or N,N-diisopropylethylamine; the reaction temperature is preferably 0 to 35°C; the condensing agent is preferably HATU or 1-Propyl phosphoric anhydride; the reaction time is preferably 0.5-6 hours.
- the pharmaceutically acceptable salt of the compound represented by formula (I) can be synthesized by general chemical methods.
- the salt can be prepared by reacting a free base or acid with an equivalent or excess acid (inorganic acid or organic acid) or base (inorganic base or organic base) in a suitable solvent or solvent composition.
- the present invention also provides a pharmaceutical composition, which includes a therapeutically effective amount of active components and pharmaceutically acceptable excipients; the active components include the compound represented by formula (I), its isomers and pharmaceutically acceptable One or more of acceptable salts.
- the active ingredient may also include other therapeutic agents for cancer.
- the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent and/or excipient.
- the pharmaceutical composition can be made into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc. , Preferably liquids, suspensions, emulsions, suppositories and injections (solutions and suspensions) and the like.
- any excipient known and widely used in the art can be used.
- carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.
- disintegrant such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Fatty acid esters of calcium, polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch and lactose, etc.
- disintegration inhibitors such as white sugar, glyceryl tristearate, coconut oil and hydrogenated Oil
- adsorption promoters such as quaternaryl, sodium glyceryl tristearate, coconut
- any known and widely used excipients in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.; binders , Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol; disintegrants such as agar and kelp powder.
- carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc.
- binders Such as gum arabic powder, gum tragacanth powder, gelatin and ethanol
- disintegrants such as agar and kelp powder.
- any excipients known and widely used in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. .
- the solution or suspension can be sterilized (preferably by adding an appropriate amount of sodium chloride, glucose or glycerin, etc.) to prepare an injection that is isotonic with blood.
- any carriers commonly used in the art can also be used.
- usual dissolving agents, buffers and analgesics can also be added.
- the content of the composition in the pharmaceutical composition is not particularly limited, and can be selected in a wide range, usually 5-95% by mass, preferably 30-80% by mass. %.
- the method of administration of the pharmaceutical composition is not particularly limited.
- various dosage forms can be selected for administration.
- tablets, pills, solutions, suspensions, emulsions, granules or capsules can be administered orally; injections can be administered alone or mixed with delivery fluids for injection (such as glucose solution and amino acid solution) for intravenous injection; suppositories are for administration
- delivery fluids for injection such as glucose solution and amino acid solution
- suppositories are for administration The medicine reaches the rectum.
- the present invention also provides the application of the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of KRAS G12C inhibitors.
- the present invention also provides the compound represented by formula (I), its isomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of a medicine for the treatment of KRAS G12C-mediated related diseases application.
- the related disease is cancer.
- the cancer is a cancer that contains the G12C mutant KRAS gene in the tumor cell DNA.
- the present invention also provides the application of the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of drugs for treating and/or alleviating cancer.
- the present invention also provides the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition for preparing treatment and/or alleviation of non-small cell lung cancer, pancreatic cancer and/ Or the application of colorectal cancer drugs.
- the present invention also provides the application of the compound represented by formula (I), its isomer or pharmaceutically acceptable salt, or the pharmaceutical composition in the treatment of cancer.
- the present invention also provides the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the treatment and/or alleviation of non-small cell lung cancer, pancreatic cancer, intrauterine Application in membrane cancer and/or colorectal cancer.
- the present invention still further provides a method for treating cancer with the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition, which comprises: administering to a mammal a dose required for treatment
- the compound as described in formula (I), its isomer or pharmaceutically acceptable salt, or a pharmaceutical composition comprises: administering to a mammal a dose required for treatment
- the compound as described in formula (I), its isomer or pharmaceutically acceptable salt, or a pharmaceutical composition
- the mammal is preferably a human.
- the present invention further provides the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition can also be combined with one or more other types of therapeutic agents and/ Or the treatment method is used in combination to treat and/or alleviate related diseases mediated by KRAS G12C.
- the KRAS G12C-mediated related disease is cancer.
- the cancer is a cancer that contains the G12C mutant KRAS gene in the tumor cell DNA.
- the present invention preferably uses the compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition can also be combined with one or more other types of therapeutic agents and/or treatments.
- the method is used in combination to treat and/or alleviate cancers mediated by KRAS G12C.
- the KRAS G12C-mediated cancer is a cancer that contains the G12C mutant KRAS gene in the tumor cell DNA.
- the other types of therapeutic agents can be combined with the compound represented by formula (I) into a single-administration therapeutic dosage form, or a treatment that is administered separately and sequentially Dosage form.
- the present invention further provides a combined preparation, comprising a compound represented by formula (I), its isomers or pharmaceutically acceptable salts, or the pharmaceutical composition and other types of therapeutic agents for the treatment of cancer and / Or combination of treatment methods.
- the cancer includes metastatic and non-metastatic cancers, as well as family hereditary and sporadic cancers, as well as solid tumors and non-solid tumors.
- the cancer may include, but are not limited to: eye cancer, bone cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer), stomach cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer (including malignant glioma) , Medulloblastoma), ovarian cancer, bladder cancer, cervical cancer, endometrial cancer, fallopian tube cancer, peritoneal cancer, testicular cancer, kidney cancer (including adenocarcinoma and Wilms cancer), oral cancer (including squamous cell carcinoma) Cell carcinoma), tongue cancer, laryngeal cancer, nasopharyngeal cancer, head and neck cancer, colon cancer, small bowel cancer, rectal cancer, parathyroid cancer, thyroid cancer, esophageal cancer, gallbladder cancer, cholangiocarcinoma, liver cancer, sarcoma, skin cancer , Lymphatic leukemia (including acute lymphocytic leukemia, lymphoma, myeloma, chronic lymphoc
- C tq refers to the range from the start point to the end point, where t and q and each point in the range are integers, representing the number of carbon atoms, for example, C 1-4 means that the number of carbon atoms is 1, 2, 3 Or 4; C 1-6 means that the number of carbon atoms is 1, 2, 3, 4, 5 or 6; C 3-8 means that the number of carbon atoms is 3, 4, 5, 6, 7 or 8; C tq can follow any Groups containing carbon atoms are used in combination to limit the number of carbon atoms, such as C 1-6 alkyl, C 1-4 alkylene, C 3-8 cycloalkyl, C 6-10 aryl, C 1 -4 alkoxy, C 3-8 cycloalkyl C 1-4 alkyl and the like.
- alkyl refers to a saturated linear or branched hydrocarbon group containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8, 1-6, 1-4 or 1-3 carbons Atom
- representative examples of alkyl include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, N-heptyl, octyl, nonyl, decyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1, 2-dimethylbutyl, 2,2-dimethylbutyl,
- cycloalkyl refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) monocyclic or polycyclic group containing 3-20 carbon atoms.
- Cycloalkyl is preferably 3-10 membered monocyclic alkyl or partially unsaturated 4-6 membered cycloalkyl, more preferably 3-8 or 3-6 membered monocyclic alkyl, for example: cyclopropyl, cyclobutyl Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclobutenyl, cyclopentenyl, cyclohexenyl.
- Polycyclic cycloalkyl includes “bridged cyclic group”, “fused cycloalkyl” and “spirocycloalkyl”.
- the monocyclic cycloalkyl or polycyclic cycloalkyl can be linked to the parent molecule through any carbon atom on the ring.
- heterocycloalkyl refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) non-aromatic cyclic group composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur or boron.
- the shaped group can be monocyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic group.
- the number of heteroatoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and heterocycloalkyl Nitrogen, carbon, sulfur or boron atoms in can optionally be oxidized.
- the nitrogen atom may optionally be further substituted with other groups to form a tertiary amine or a quaternary ammonium salt.
- the "monocyclic heterocycloalkyl” is preferably a 3-10 membered monocyclic heterocycloalkyl, more preferably a 3-8 or 4-8 membered monocyclic heterocycloalkyl.
- Representative examples include but are not limited to: aziridinyl, tetrahydrofuran-2-yl, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide-4-yl, piperidinyl, pyrrolidinyl , Piperazinyl, homopiperazinyl, 1,4-dioxanyl, pyranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, 2,3-dihydrofuranyl, 2 ,5-Dihydrofuryl, dihydropyrazolyl, 2,3-dihydro-1H-pyrrolidinyl, 2,5-dihydro-1H-pyrrolidinyl, 1,
- Polycyclic heterocycloalkyl includes “fused heterocycloalkyl”, “spiroheterocyclic group” and “bridged heterocyclyl”, “fused heterocycloalkyl” includes fused to aryl, cycloalkyl , Heterocycloalkyl or heteroaryl monocyclic heterocycloalkyl ring, condensed heterocycloalkyl includes but not limited to: indolinyl, 2,3-dihydrobenzofuranyl, 1,3-dihydrobenzofuranyl Hydroisobenzofuranyl, 2,3-dihydrobenzo[b]thienyl, dihydrobenzopiperanyl, 1,2,3,4-tetrahydroquinolinyl, benzo[d][1 ,3]dioxolanyl, 1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolanyl 3-hydroxy-1,3-dihydronaphtho[2,1-
- Spiroheterocyclic group refers to a bicyclic group formed by two heterocycloalkyl groups or one cycloalkyl group and one heterocycloalkyl group sharing one carbon atom. Spiro heterocyclic group includes but is not limited to: Wait.
- Bridged heterocyclic group means that any two unlinked ring atoms of a monocyclic heterocycloalkyl group are connected by a straight chain group formed by 1 to 3 additional carbon atoms or heteroatoms (the straight chain group The group is selected from but not limited to: -CH 2 -, -O-, -NH-, -S-, -CH 2 CH 2 -, -CH 2 O-, -CH 2 S-, -CH 2 NH-,- CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 CH 2 O-, -CH 2 CH 2 NH-, -CH 2 NHCH 2 -), bridged heterocyclic groups include but are not limited to:
- the bicyclic heterocycloalkyl group is preferably a 7 to 12-membered bicyclic heterocycloalkyl group.
- the monocyclic heterocycloalkyl and bicyclic heterocycloalkyl can be linked to the parent molecule through any ring atom on the ring.
- the aforementioned ring atoms specifically refer to carbon atoms and/or nitrogen atoms constituting the ring skeleton.
- cycloalkylalkyl refers to the connection between a cycloalkyl group and the core structure through an alkyl group.
- cycloalkylalkyl encompasses the definitions of alkyl and cycloalkyl described above.
- heterocycloalkylalkyl refers to the connection between the heterocycloalkyl group and the core structure through an alkyl group.
- heterocycloalkylalkyl encompasses the definitions of alkyl and heterocycloalkyl as described above.
- alkenyl refers to a linear, branched or cyclic non-aromatic hydrocarbon group containing at least one carbon-carbon double bond. There may be 1-3 carbon-carbon double bonds, preferably one carbon-carbon double bond.
- C 2-4 alkenyl refers to an alkenyl group having 2-4 carbon atoms
- C 2-6 alkenyl refers to an alkenyl group having 2-6 carbon atoms, including vinyl and propenyl. , Butenyl, 2-methylbutenyl and cyclohexenyl. The alkenyl group may be substituted.
- alkynyl refers to a straight chain, branched chain or cyclic hydrocarbon group containing at least one carbon-carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond.
- C 2-6 alkynyl refers to an alkynyl group having 2-6 carbon atoms, including ethynyl, propynyl, butynyl, and 3-methylbutynyl.
- alkoxy refers to a cyclic or acyclic alkyl group having the stated number of carbon atoms connected through an oxygen bridge, including alkyloxy, cycloalkyloxy and heterocycloalkyloxy.
- alkoxy encompasses the definitions of alkyl, heterocycloalkyl, and cycloalkyl described above.
- aryl refers to any stable 6-14 membered all-carbon monocyclic or fused bicyclic aromatic group with a conjugated ⁇ -electron system, in which at least one ring of the fused bicyclic aromatic group is an aromatic ring
- the aryl group is preferably 6-10 members, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl or biphenyl.
- heteroaryl refers to an aromatic ring group formed by replacing at least one carbon atom on the ring with a heteroatom selected from nitrogen, oxygen or sulfur, which can be a 5-6 membered monocyclic structure or 7-12
- the membered bicyclic structure is preferably a 5-10 membered heteroaryl group.
- the number of heteroatoms is preferably 1, 2 or 3, including: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridazine-3(2H)-keto, 1H-benzo[d] Imidazole-2(3H)-keto, furyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxa Azolyl, 1,2,4-oxadiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, 1H-indazolyl, isoindazole Group, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinolinyl, is
- arylalkyl refers to the connection between the aryl group and the core structure through an alkyl group.
- arylalkyl encompasses the definitions of alkyl and aryl as described above.
- heteroarylalkyl refers to the connection between the heterocycloalkyl group and the core structure through an alkyl group.
- heteroarylalkyl encompasses the above definitions of alkyl and heteroaryl.
- halogen means fluorine, chlorine, bromine or iodine.
- haloalkyl refers to an alkyl group optionally substituted by halogen.
- haloalkyl encompasses the definitions of halogen and alkyl above.
- haloalkoxy refers to an alkoxy group optionally substituted by halogen.
- haloalkoxy encompasses the definitions of halogen and alkoxy above.
- amino refers to -NH 2 .
- alkylamino means that at least one hydrogen atom on an amino group is replaced by an alkyl group, including “monoalkylamino” and "dialkylamino". Examples include but are not limited to: -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 3 )(CH 2 CH 2 CH 3 ).
- aminoalkyl means that any hydrogen atom on the alkyl group is replaced by an amino group, and examples include but are not limited to: -CH 2 NH 2 , -CH 2 CH 2 NH 2 . Therefore, “aminoalkyl” and “alkylamino” encompass the definitions of alkyl and amino as described above.
- alkylaminoalkyl means that any hydrogen atom on the alkyl group is replaced by an alkylamino group. Examples include but are not limited to: -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , -CH 2 NHCH 3 .
- alkylaminoalkyl encompasses the definitions of alkylamino and alkyl as described above.
- hydroxy refers to -OH.
- hydroxyalkyl means that any hydrogen atom on the alkyl group is replaced by a hydroxyl group. Examples include but are not limited to: -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 C(CH 3 ) 2 OH , -CH(CH 3 ) 2 OH.
- hydroxyalkyl encompasses the above definitions of hydroxyl and alkyl.
- alkoxyalkyl means that any hydrogen atom on the alkyl group is replaced by an alkoxy group, and examples include but are not limited to: -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 .
- alkoxyalkyl encompasses the definitions of alkoxy and alkyl as described above.
- acyl refers to -C(O)R.
- cyano refers to -CN.
- room temperature in the present invention refers to 15-30°C.
- the term "optionally substituted by 1-3 groups at any position" refers to any 1, 2, or 3 of the 1, 2, or 3 atoms specified on the group.
- any combination of variables is allowed only if the combination will produce a stable compound.
- each variable when any variable occurs more than once in the composition or structure of a compound, its definition in each case is independent.
- each R 5 substituent is an independent substituent, which may be the same or different.
- the compound represented by formula (I) in any of the embodiments described in the present invention includes isotopic derivatives thereof.
- the isotopically substituted derivatives include: any hydrogen atom (1 to 5) in formula (I) is substituted by 1 to 5 deuterium atoms; any carbon atom (1 to 5) in formula (I) 3) Isotope substituted derivatives obtained by substituting 1 to 3 C 14 atoms or isotopic substituted derivatives obtained by substituting any oxygen atom in formula (I) with 1 to 3 O 18 atoms.
- the "pharmaceutically acceptable salt” of the present invention is discussed in Berge, et al., "Pharmaceutically acceptable salts", J. Pharm. Sci., 66, 1-19 (1977), and has been discussed by medicinal chemists. It is obvious that the salt is basically non-toxic and can provide the required pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion.
- the compound of the present invention may have an acidic group, a basic group or an amphoteric group.
- Typical pharmaceutically acceptable salts include salts prepared by reacting the compound of the present invention with an acid, such as: hydrochloride, hydrobromic acid Salt, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, caprate, caprylate, formate, acrylate, isobutyrate, caproate, enanthate, oxalate, malonate, succinate, suberate, Benzoate, methyl benzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, (D,L)-tartaric acid, citric acid, maleic acid, (D,L)-malic acid, fumaric acid, succinic acid, succinate, lactate, triflate, naphthalene-1-
- its pharmaceutically acceptable salts may also include: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic alkali salts, such as ammonia and alkane. Salts formed from base aminos, hydroxyalkyl aminos, amino acids (lysine, arginine), N-methylglucamine, etc.
- the “isomer” in the present invention means that the compound of formula (I) of the present invention may have asymmetric centers and racemates, racemic mixtures and single diastereomers, and all these isomers, including Both stereoisomers and geometric isomers are included in the present invention.
- the compound of formula (I) or its salt exists in a stereoisomeric form (for example, it contains one or more asymmetric carbon atoms)
- the individual stereoisomers (enantiomers and non- Enantiomers) and their mixtures are included in the scope of the present invention.
- the present invention also includes individual isomers of the compound or salt represented by formula (I), and mixtures with isomers in which one or more chiral centers are inverted.
- the scope of the present invention includes: mixtures of stereoisomers, and purified enantiomers or enantiomer/diastereomer enriched mixtures.
- the present invention includes mixtures of stereoisomers in all possible different combinations of all enantiomers and diastereomers.
- the present invention includes all combinations and subsets of stereoisomers of all specific groups as defined above.
- the reagents and raw materials used in the present invention are all commercially available.
- the structures of all the compounds of the present invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
- Liquid mass spectrometry is determined by Agilent 1200HPLC/6120 mass spectrometer, using chromatographic column: Xtimate C18, 3.0 ⁇ 50mm, 3 ⁇ m, column temperature 40°C; or by Thermo UltiMate 3000HPLC/MSQ PLUS mass spectrometer, using column XBridge C18, 3.0 ⁇ 50mm, 3.5 ⁇ m, column temperature 30°C.
- Agilent gradient elution condition 1 95-5% solvent A 1 and 5-95% solvent B 1 (0-2.0 minutes), then 95% solvent B 1 and 5% solvent A 1 (hold for 1.1 minutes), the percentage is a certain The volume percentage of a solvent in the total solvent volume.
- Solvent A 1 0.01% trifluoroacetic acid (TFA) in water; solvent B 1 : 0.01% trifluoroacetic acid in acetonitrile; the percentage is the volume percentage of the solute in the solution.
- Thermo gradient elution condition 2 95-5% solvent A 2 and 5-95% solvent B 2 (0-2 minutes), then 95% solvent B 2 and 5% solvent A 2 (hold for 1.8 minutes), the percentage is a certain The volume percentage of a solvent in the total solvent volume.
- Solvent A 2 10 mM ammonium bicarbonate aqueous solution; Solvent B 2 : Acetonitrile.
- All the compounds of the present invention can be separated by preparative high performance liquid chromatograph or fast column chromatography.
- the preparative high performance liquid chromatograph uses Shimadzu LC-20 for preparative liquid chromatography, and the column is: Xtimate 21.2*250mm, 10 ⁇ m.
- Mobile phase A 10mmol/L ammonium bicarbonate aqueous solution
- mobile phase B acetonitrile
- gradient elution condition 1 mobile phase B from 10% to 30%, elution time 5 minutes; mobile phase B from 30% to 60%, Elution time 15 minutes
- Condition 2 Mobile phase B from 15% to 25%, Elution time: 5 minutes, Elution mobile phase B from 25% to 55%, Elution time 15 minutes
- Condition 3 Mobile phase B From 15% to 30%, elution time: 5 minutes, elution mobile phase B from 30% to 65%, elution time 15 minutes
- condition 4 mobile phase B from 0% to 35%, elution time: 5 Minutes, elution mobile phase B from 35% to 60%, elution time 15 minutes
- condition 5 mobile phase B from 10% to 40%, elution
- Mobile phase A 0.1% trifluoroacetic acid aqueous solution
- mobile phase B acetonitrile
- gradient elution condition 6 mobile phase B from 15% to 25%, elution time 5 minutes, 25% to 55%, elution time 15 minutes
- Condition 7 mobile phase B from 15% to 30%, elution time 5 minutes, 30% to 60%, elution time 15 minutes
- Condition 8 mobile phase B from 15% to 45%, elution time 5 minutes , 45% to 80%, elution time 15 minutes.
- Detection wavelength 214nm&254nm
- flow rate 15.0mL/min.
- Flash column chromatography uses Agela Technologies MP200, and the matched normal phase separation column is Flash column Silica-CS (25g, 40g, 80g, 120g, or 330g), Tianjin Bonaageer, the elution system is ethyl acetate/petroleum ether, or dichloromethane/methanol; the reverse-phase separation column is a C18 reverse-phase column (12g, 20g, or 40g), Changzhou Santai Technology, the elution system It is acetonitrile/0.1% trifluoroacetic acid aqueous solution or acetonitrile/10mmol/L ammonium bicarbonate aqueous solution.
- Thin layer silica gel plate is Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
- the microwave reaction used in the embodiment of the present invention Initiator+Microwave System EU (356006) type microwave reactor. Unless otherwise specified in the present invention, the reactions in all the examples were carried out under a nitrogen atmosphere or an argon atmosphere.
- the hydrogen atmosphere refers to the reaction system connected to a hydrogen balloon with a volume of about 1L.
- Step 2 Combine 1-Benzylmethyl-N-(2-fluoroethyl)azetidin-3-amine (4g, 14.1mmol), iodoethane (3.3g, 21.1mmol) and potassium carbonate (5.8 g, 42.2 mmol) of acetonitrile (50 mL) mixture was stirred at 40°C for 20 hours in a sealed tube.
- Step 3 Combine 1-Benzylmethyl-N-ethyl-N-(2-fluoroethyl)azetidin-3-amine (1g, 3.19mmol), ammonium formate (4g, 63.8mmol), hydrogen Palladium oxide on carbon (1 g) was added to methanol (20 mL), and the reaction system was replaced with nitrogen three times, and then stirred at 60°C for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain N-ethyl-N-(2-fluoroethyl)azetidin-3-amine (466 mg) as a yellow oil. m/z: [M+H] + 147.2.
- Step 1 Combine 1-chloro-2,6-dibromo-4-fluorobenzene (1.0g, 3.47mmol), benzophenone imine (754mg, 4.16mmol), t-BuONa (500mg, 5.21mmol), An anhydrous toluene (30 mL) solution of BINAP (324 mg, 0.52 mmol) and Pd 2 (dba) 3 (156 mg, 0.17 mmol) was replaced with nitrogen and stirred at 80° C. for 16 hours.
- Step 2 Under the protection of nitrogen, the isopropenyl borate pinacol ester (293mg, 1.74mmol), 3-bromo-5-fluoro-4-iodoaniline (500mg, 1.58mmol), potassium phosphate (1.01g, 4.75mmol) ) And PdCl 2 dppf . CH 2 Cl 2 (130 mg, 0.16 mmol) in 1,4-dioxane (25 mL) was stirred at 80°C for 16 hours.
- Step 3 Add 3-bromo-5-fluoro-4-(prop-1-en-2-yl)aniline (272mg, 1.18mmol) and platinum carbon (30mg) to ethyl acetate (20mL) and methanol (25mL ), stirring at room temperature under a hydrogen atmosphere for 16 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain 3-bromo-5-fluoro-4-isopropylaniline (250 mg) as a yellow oil. m/z: [M+H] + 232.0.
- Step 1 Under ice bath conditions, add sodium hydrogen (60%, 3.74g, 93.5mmol) to a solution of 6-chloro-5-iodopyrazine-2-amine (9.56g, 37.4mmol) in DMF (58mL), The reaction mixture was stirred for 40 minutes, and p-methoxybenzyl chloride (14.6 g, 93.5 mmol) was slowly added to the above reaction solution and stirring was continued for 2 hours.
- Step 2 Add 6-chloro-5-iodo-N,N-bis(4-methoxybenzyl)pyrazine-2-amine (2.5g, 5.10mmol), 2,2-difluoro-2-( Methyl fluorosulfonyl)acetate (2.9g, 15.0mmol) and cuprous iodide (2.86g, 15.0mmol) were suspended in anhydrous DMF (70mL) solution, and the reaction solution was stirred at 100°C for 4 hours under the protection of nitrogen.
- Step 2 Combine 2-(bis(4-methoxybenzyl)amino)-6-chloroisonicotinonitrile (8.7g, 37.4mmol), N-iodosuccinimide (5.73g, 25.5mmol) Dissolved in anhydrous DMF (70mL), the reaction mixture was stirred at 100°C overnight, diluted with ethyl acetate (500mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
- Step 3 Add 6-(bis(4-methoxybenzyl)amino)-2-chloro-3-iodoisonicotinonitrile (8.0g, 15.4mmol), 2,2-difluoro-2- (Fluorosulfonyl) methyl acetate (8.9g, 46.2mmol) and cuprous iodide (8.8g, 46.2mmol) were suspended in anhydrous DMF (120mL) solution, and the reaction system was stirred at 100°C for 4 hours under nitrogen protection .
- Step 2 Under nitrogen protection at -10°C, slowly add n-butyllithium (2.5M tetrahydrofuran solution, 1.2mL, 2.8mmol) to 3-methoxy-1-(2-methoxyethoxy)
- naphthalene 0.5 g, 2.34 mmol
- tetramethylethylenediamine 0.35 mL, 3.0 mmol
- hexachloroethane solid (0.87 g, 3.66 mmol
- reaction solution was warmed to room temperature, quenched by adding water, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- Step 3 Combine 2-chloro-3-methoxy-1-(2-methoxyethoxy)naphthalene (0.5g, 1.98mmol) and hydrogen chloride (4.0M 1,4-dioxane solution, 4.0mL) in dichloromethane (10mL) solution was stirred at room temperature for 1.5 hours, then, saturated aqueous sodium bicarbonate was added to adjust the pH to 7.0, the organic phase was separated and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-Chloro-3-methoxynaphthalen-1-ol (0.41 g) is a yellow solid. m/z: [M+H] + 209.0.
- Step 4 Under ice bath conditions, add trifluoromethanesulfonic anhydride (0.7g, 2.5mmol) to 2-chloro-3-methoxynaphthalene-1-ol (0.4g, 1.92mmol) and triethylamine (0.8 mL, 5.76 mmol) in dichloromethane (5 mL). The reaction solution was stirred at 0°C for 2 hours. The reaction was quenched by adding water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate) to obtain the corresponding borate.
- Step 1 Under ice bath conditions, to 2,4-dichloro-5-fluoroaniline (2.62g, 14.6mmol) and sodium carbonate (2.65g, 25mmol) in methyl tert-butyl ether (60mL) solution was added three Fluoroacetic anhydride (3.78g, 18mmol), the reaction solution was stirred at room temperature for 12 hours, diluted with n-hexane and filtered, and the filtrate was concentrated under reduced pressure.
- Step 1 Add 4-bromo-2,6-difluorobenzonitrile (25g, 0.11mol), ammonia water (100mL) and isopropanol (60mL) into the sealed tube, and stir the reaction system at 90°C for 16 hours. After the reaction solution was cooled to room temperature, it was poured into water, a large amount of solids were precipitated out, filtered with suction, and the filter cake was vacuum dried to obtain Intermediate 1-1 (23.2g) as a gray solid. m/z: [M+H] + 215.0.
- Step 2 Under ice bath conditions, add sodium hydrogen (60%, 1.1g, 27.9mmol) to a solution of 2,2-diethoxyethanol (3.7g, 27.9mmol) in DMF (60mL) in batches to obtain The mixture was stirred at 0°C for 1 hour. Next, Intermediate 1-1 (5 g, 23.3 mmol) was added to the above reaction solution, and stirred at 50°C for 1 hour.
- Step 4 A mixed solution of intermediate 1-3 (0.33 g, 1.39 mmol) in formic acid (12 mL) and concentrated sulfuric acid (0.3 mL) was stirred at 100° C. for 0.5 hours. The reaction solution was cooled to room temperature and poured into water. A large amount of solids precipitated out, filtered off with suction, and the filter cake was vacuum dried to obtain Intermediate 1-4 (0.21 g) as a yellow solid. m/z: [M+H] + 264.8.
- Step 5 To the 1,4-dioxane (16mL) solution of Intermediate 1-4 (350mg, 1.32mmol) and N,N-dimethylaniline (1.78g, 14.7mmol) was added phosphorus oxychloride (1.6 mL), the reaction solution was stirred at 110°C for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure to obtain Intermediate 1-5 (crude product) as a yellow solid. m/z: [M+H] + 282.8.
- Step 3 Add phosphorus oxychloride (2mL) to the solution of Intermediate 2-2 (100mg, 0.36mmol) and N,N-dimethylaniline (0.2mL) in 1,4-dioxane (5mL) The reaction solution was stirred at 110°C for 2 hours. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure to obtain Intermediate 2-3 (crude) as a yellow solid. m/z: [M+H] + 316.8.
- Step 2 To a solution of chloral hydrate (3.9g, 23.6mmol), concentrated hydrochloric acid (5mL), anhydrous sodium sulfate (13.4g, 94.3mmol) in water (50mL) was added Intermediate 3-1 (2.5g, 11.8) mmol) in DMF (25 mL). After the resulting mixture was stirred at 90°C for 30 minutes, hydroxylamine hydrochloride (4.9 g, 70.7 mmol) was added, and stirring was continued at 90°C overnight. The reaction was quenched by adding ice water, the resulting mixture was stirred for 15 minutes, filtered, and the filter cake was washed with water and dried in vacuo to obtain Intermediate 3-2 (2.9 g) as a yellow solid. m/z: [M+H] + 284.5.
- Step 3 A solution of Intermediate 3-2 (2.9g, 10.2mmol) in concentrated sulfuric acid (20mL) was stirred at 60°C for 1.5 hours, then carefully added to ice water, the reaction mixture was filtered, the filter cake was washed with water and dried in vacuo The intermediate 3-3 (2.7g) was obtained as a brown solid. m/z: [M+H] + 267.8.
- Step 5 Under ice bath conditions, add HATU to a solution of Intermediate 3-4 (1.6g, 6.3mmol), ammonium chloride (3.3g, 62.5mmol), DIPEA (2.4g, 18.8mmol) in DMF (50mL) (1.6g, 6.3mmol), the resulting mixture was stirred at room temperature for 2 days, and water (10mL) was added to quench the reaction.
- the reaction solution was purified by Flash column chromatography (30% acetonitrile in ammonium bicarbonate aqueous solution) to obtain Intermediate 3-5 (630mg) is a pale yellow solid. m/z: [M+H] + 256.8.
- Step 6 Intermediate 3-5 (300mg, 1.2mmol) and urea (3.5g, 58.8mmol) were melted at 180°C and stirred for 2 hours, then cooled to 80°C, water (15mL) was added and stirred for 5 minutes, and the reaction mixture was filtered The filter cake was washed with water and dried in vacuo to obtain Intermediate 3-6 (330 mg) as a pale yellow solid. m/z: [M+H] + 280.8.
- Step 1 To a solution of Intermediate 2-3 (1.1g, 3.56mmol) and DIPEA (14.1g, 109mmol) in 1,4-dioxane (60mL) was added (S)-2-(piperazine-2 -Base) acetonitrile dihydrochloride (0.86 g, 4.43 mmol) in acetonitrile (10 mL). The reaction solution was stirred at 50° C. for 2 hours, and the reaction was quenched with water. The aqueous phase was extracted with dichloromethane, and the organic phase was separated and concentrated under reduced pressure to obtain Intermediate 4-1 (crude) as a yellow oil. m/z: [M+H] + 406.0.
- Step 4 A mixed solution of Intermediate 4-3 (110 mg, 0.19 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 3 hours, and then concentrated under reduced pressure to obtain Intermediate 4-4 ( Crude product) is yellow oil. m/z: [M+H] + 485.2.
- Step 5 Under ice bath conditions, add acrylic anhydride (39mg, 0.31mmol) in anhydrous dichloromethane to the solution of Intermediate 4-4 (crude) and DIPEA (0.5mL) in anhydrous dichloromethane (6mL) dropwise (1mL) solution.
- the reaction solution was stirred at room temperature for 6 hours, and the reaction was quenched with water.
- Intermediate 4-5 (70 mg) is a yellow oil. m/z: [M+H] + 539.2.
- Steps 2 to 4 Using the synthesis method of Steps 3 to 5 of Intermediate 4-5, react with Intermediate 4-6 to obtain 4-7 as a yellow oil. m/z: [M+H] + 514.2.
- Step 2&3 Using the synthesis method of Steps 4 to 5 of Intermediate 4-5, react with Intermediate 5-1 to obtain 5-3 as a brown oil. m/z: [M+H] + 552.2.
- Step 1&2 Same as Intermediate 4-5 Step 3&4.
- Step 3 Under ice bath conditions, to a solution of Intermediate 4-4 (100mg, 0.2mmol) in anhydrous ethyl acetate (3mL) were added triethylamine (0.23mL, 1.6mmol) and 2-fluoroacrylic acid (36mg , 0.4 mmol) and 1-propyl phosphoric anhydride (50% ethyl acetate solution, 0.6 mmol).
- Step 1 To (E)-4-bromobut-2-enoic acid (170mg, 1.03mmol) in dichloromethane (5mL) was added oxalyl chloride (1.5mL), the reaction solution was stirred at 70°C for 3 hours Concentrate directly under reduced pressure.
- Step 1 Using the synthesis method of Intermediate 5-1, Intermediate 4-2 is reacted with N-ethyl-N-(2-fluoroethyl)azetidin-3-amine to obtain Intermediate 7-1. m/z: [M+H] + 616.2.
- Step 2 Under ice bath conditions, add hydrogen chloride (4M 1,4-dioxane (4 mL) to the anhydrous 1,4-dioxane (4 mL) solution of Intermediate 7-1 (150 mg, 0.24 mmol) Solution, 2mL), after the addition, the reaction solution was stirred at room temperature for 2 hours. The reaction solution was directly concentrated under reduced pressure to obtain Intermediate 7-2 (crude product) as a pale yellow solid. m/z: [M+H] + 516.2.
- Step 3 Under an ice-water bath, add 2-fluoroacrylic acid (97.7 mg, 1.1 mmol) to a solution of Intermediate 7-2 (crude) and triethylamine (0.7 mL, 5.43 mmol) in anhydrous ethyl acetate (10 mL) And 1-propyl phosphoric anhydride (50% ethyl acetate solution, 1.63 mmol), after the addition, the reaction system was raised to room temperature, and stirring was continued for 3 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by prep-TLC (100% ethyl acetate) to obtain Intermediate 7-3 (80 mg) as a pale yellow solid. m/z: [M+H] + 588.2.
- Step 1&2 Intermediate 3-7 (350mg, 1.09mmol), DIPEA (427mg, 3.3mmol), (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (261mg, 1.32mmol)
- DMSO 15.0 mL
- Boc 478 mg, 2.19 mmol
- the reaction system was stirred at room temperature for 30 minutes and then water (50 mL) was added to quench the reaction.
- the phases were extracted with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure.
- m/z [M+H] + 606.2.
- Step 3 Mix Intermediate 8-2 (180mg, 297 ⁇ mol), N-methyl-L-prolinol (171mg, 1.48mmol), DIPEA (192mg, 1.48mmol) and cesium carbonate (557mg, 1.48mmol) in 1
- the 4 dioxane (5 mL) mixture was stirred at 165°C for 3 hours in a sealed tube.
- Step 4 To a solution of Intermediate 8-3 (230 mg, 393 ⁇ mol) in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was slowly added dropwise. The reaction solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain Intermediate 8-4 (crude product) as a brown solid. m/z: [M+H] + 487.2.
- Step 1 Under ice bath conditions, sodium hydrogen (60%, 2.23 g, 93 mmol) was added to a solution of allyl alcohol (6.36 mL, 93 mmol) in anhydrous DMF (15 mL), and the reaction solution was raised to room temperature and stirred for 1.5 hours. A solution of 2-amino-4-bromo-6-fluorobenzonitrile (10g, 46.5mmol) in anhydrous DMF (5mL) was added dropwise to the above reaction solution, and the resulting mixture was stirred at room temperature for 10 hours, and quenched by adding water (500mL) Reaction, filtration, and vacuum drying of the filter cake gave Intermediate 9-1 (11.7 g) as a yellow solid. m/z: [M+H] + 253.0.
- Step 4 At -78°C, pass ozone in the mixed solution of intermediate 9-3 (10g, 23.7mmol) in dichloromethane (50mL) and methanol (50mL) for 15 minutes, and then discharge the remaining ozone in the reaction solution Then sodium borohydride (13.5 g, 356 mmol) was added, and the reaction solution was warmed to room temperature and stirred for 30 minutes. The reaction was quenched by adding water (100 mL), the organic phase was separated, washed with dilute hydrochloric acid (1M, 20 mL), and concentrated under reduced pressure to obtain Intermediate 9-4 (8.0 g) as a yellow solid. m/z: [M+H] + 343.0.
- Step 5 Under ice bath conditions, slowly add DIAD (5.54 mL, 28.1 mmol) to a solution of Intermediate 9-4 (8.0 g, 23.4 mmol), triphenylphosphine (7.4 g, 28.1 mmol) in tetrahydrofuran (150 mL) .
- Step 7 Heat Intermediate 9-6 (300mg, 1.17mmol) and urea (3.5g, 58.5mmol) to 180°C, stir for 2 hours in a molten state, then cool to 100°C, add water (15mL) and stir for 1 hour. The temperature was lowered to 0°C and filtered. The filter cake was washed with water and dried in vacuo to obtain Intermediate 9-7 (330 mg) as a pale yellow solid. m/z: [M+H] + 283.0.
- Step 8 Intermediate 9-7 (330 mg, 1.17 mmol) and N,N dimethylaniline (0.5 mL) were added to phosphorus oxychloride (10 mL), and the reaction system was stirred at 110° C. for 2 hours. Then it was directly concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with ice water, the organic phase was separated and concentrated under reduced pressure to obtain Intermediate 9-8 (crude) as a yellow solid. m/z: [M+H] + 319.0.
- Steps 9-13 Using the synthesis method of Intermediate 4-5, react with Intermediate 9-8 to obtain Intermediate 9-13 as a yellow solid. m/z: [M+H] + 541.0.
- Step 3 Intermediate 10-2 (1.2 g, 4.5 mmol) and potassium hydroxide aqueous solution (2M, 22 mL) were added to ethanol (30 mL), and the reaction solution was refluxed and stirred at 90° C. for 12 hours.
- Intermediate 10-3 (1.1 g) was purified as a white solid. m/z: [M+H] + 287.0.
- Step 4 Intermediate 10-3 (800mg, 2.8mmol) and urea (8.4g, 140mmol) were mixed uniformly and heated to 180°C and stirred for 1.5 hours.
- the reaction solution was cooled to room temperature, water (15mL) was added, then stirred at 100°C for 1 hour, filtered under reduced pressure, the filtrate was extracted with ethyl acetate/tetrahydrofuran mixed solvent (10/1), the organic phase was separated and concentrated under reduced pressure.
- Step 6&7 Intermediate 10-5 (310 mg, 0.87 mmol) and phosphorus oxychloride (10 mL) in N,N-xylidine (0.5 mL) were stirred at 110°C for 2 hours. Concentrate under reduced pressure. Under ice bath conditions, ethyl acetate (50 mL) was added to the residue, then washed with ice water, the organic phase was separated and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 10-6.
- Steps 10&11 Under ice bath conditions, disperse sodium hydrogen (26mg, 0.65mmol) in anhydrous DMF (5mL) solution, and add ((2S,4R)-4-fluoro-1-methylpyrrolidine dropwise under the protection of nitrogen -2-yl) methanol in DMF solution (87 mg, 0.65 mmol, 0.5 mL), the reaction solution was stirred at this temperature for 0.5 hours, and then the DMF solution of intermediate 10-9 (80 mg, 0.13 mmol, 0.5 mL) was added dropwise To the above reaction solution, after the addition, continue to stir for 0.5 hours in an ice bath to obtain a reaction solution containing intermediate 10-10.
- Steps 12 & 13 To intermediate 10-11 (83 mg, 0.13 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL) dropwise. The reaction solution was stirred for 2 hours and then concentrated under reduced pressure to obtain Intermediate 10-12. Under ice bath conditions, to a solution of Intermediate 10-12 and DIPEA (0.2 mL) in anhydrous dichloromethane (2 mL) was slowly added a dichloromethane solution (0.5 M, 0.3 mL) of acrylic anhydride. The reaction solution was continuously stirred at this temperature for 10 minutes.
- Step 1&2 Same as Step 3&4 of Intermediate 4-7.
- Step 1 To a solution of 2-amino-4-bromo-6-fluorobenzonitrile (23.6g, 110mmol) in anhydrous acetonitrile (370mL) was added N-iodosuccinimide (27.2g, 121mmol) and Trifluoroacetic acid (25g, 220mmol), the reaction system was stirred at room temperature for 1.5 hours in the dark and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with saturated sodium bisulfite aqueous solution, saturated sodium bicarbonate aqueous solution and saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. It was slurried with dichloromethane at °C, filtered, and the filter cake was vacuum dried to obtain Intermediate 13-1 (22.3g) as an off-white solid. m/z: [M+H] + 340.8.
- Step 2 Add bistriphenylphosphorus palladium dichloride (4.59g, 6.54mmol) to Intermediate 13-1 (22.3g, 65.4mmol), (E)-styrylboronic acid (14.5g, 98.1mmol)
- a mixed solution of potassium carbonate (18.1 g, 131 mmol) in toluene (200 mL) and ethanol (50 mL) the reaction system was replaced with nitrogen three times and stirred overnight at 80° C., cooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and then washed with water and saturated brine. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- Step 3 Add hydrogen peroxide (30%, 9mL) dropwise to intermediate 13-2 (6.92g, 21.8mmol) and potassium carbonate (6.03g, 43.6mmol) in DMSO (90mL) solution, and the reaction system is stirred at room temperature for 1.5 hours . Then the reaction solution was poured into ice water, a large amount of solids precipitated out, filtered with suction, and the filter cake was vacuum dried to obtain Intermediate 13-3 (7.03 g) as a yellow solid. m/z: [M+H] + 335.0.
- Step 4 To a solution of Intermediate 13-3 (7.03 g, 21 mmol) in tetrahydrofuran (212 mL) was added triphosgene (6.22 g, 21 mmol), and the reaction system was stirred at room temperature overnight. After concentration under reduced pressure, it was poured into ice water, adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, filtered with suction, the filter cake was washed with petroleum ether and dried in vacuo to obtain Intermediate 13-4 (7.1 g) as a yellow solid. m/z: [M+H] + 361.0.
- Step 5 Intermediate 13-4 (10.7g, 29.5mmol) was added to phosphorus oxychloride (106mL), and then N,N-dimethylaniline (10.6mL) was added, and the reaction system was stirred at 110°C for 2 hours . Phosphorus oxychloride was removed by concentration under reduced pressure, the residue was poured into ice water, and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution.
- Step 6 Under ice bath conditions, mix (S)-2-(piperazin-2-yl)acetonitrile dihydrochloride (5.88g, 29.7mmol) and DIPEA (10.5g, 80.9mmol) in DMF (60mL) Replace with nitrogen, add a solution of intermediate 13-5 (10.7g, 27.0mmol) in DMF (100mL) dropwise to the above reaction solution, and then add (Boc) 2 O (29.4g, 135mmol) and DIPEA (25.6g, 198mmol), and the reaction system was stirred overnight at room temperature.
- Step 8 To the mixed solution of Intermediate 13-7 (2.63g, 3.95mmol) in dichloromethane (36mL) and water (6mL) was added N-methyl-N-morpholine oxide (0.93g, 7.9mmol) and Potassium osmate dihydrate (0.15 g, 0.4 mmol), and the reaction system was stirred at room temperature overnight.
- Step 10 Under ice bath conditions, add sodium carbonate (0.37 g, 3.5 mmol) and hydroxylamine hydrochloride (0.49 g, 7.0 mmol) in ethanol (20 mL) and water (10 mL) to a mixed solution of intermediate 13-9 (2.07 g, 3.5 mmol) and hydroxylamine hydrochloride (0.49 g, 7.0 mmol). g, 3.5 mmol) in water (10 mL), and the reaction system was stirred overnight at room temperature.
- Step 11 Under ice bath conditions, add potassium tert-butoxide (0.56g, 5.0mmol) to a solution of Intermediate 13-10 (2.02g, 3.3mmol) in tetrahydrofuran (100mL), and stir the reaction system at 0°C for 15 minutes Then, it was raised to room temperature and stirred for 1.5 hours. The reaction was quenched by adding ice water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- Step 12 Under ice bath conditions, add 1,4-dioxane solution (4M, 2.5 mL) of hydrogen chloride dropwise to the solution of Intermediate 13-11 (170 mg, 290 ⁇ mol) in dichloromethane (5 mL), and the reaction system Stir at 0°C for 1 hour. The reaction was quenched by adding ice water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 13-12 (200 mg) as an off-white solid. m/z: [M+H] + 486.2.
- Step 13 DIPEA (0.5 mL), 2-fluoroacrylic acid (99 mg, 0.6 mmol) and HATU (171 mg, 0.45 mmol) were added to the solution of Intermediate 13-12 (200 mg, crude product) in anhydrous DMF (5 mL), respectively.
- the reaction mixture was stirred overnight at room temperature, and saturated aqueous sodium bicarbonate solution was added to quench the reaction.
- the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
- Step 1 Under ice bath conditions, add sodium hydrogen (60%, 0.88g, 0.022mol) to 2,2-ethoxyethanol (2.8g, 0.021mmol) in anhydrous tetrahydrofuran (50mL) solution in batches, and react The mixture was stirred at 10°C for 1 hour. Then a tetrahydrofuran solution (10 mL) of methyl 4-bromo-2,6-difluorobenzoate (5 g, 0.02 mol) was slowly added dropwise to the above reaction mixture.
- Step 2 A toluene (80 mL) suspension of polyphosphoric acid (11.4 g, 33.7 mmol) was stirred at 60° C. for 30 minutes. Then, a toluene solution (20 mL) of Intermediate 15-1 (4.1 g, 11.2 mmol) was added to the above suspension, the reaction system was stirred at 60°C for 1 hour and then concentrated under reduced pressure.
- Step 4 Add oxalyl chloride (372 mg, 2.93 mmol) dropwise to the solution of Intermediate 15-3 (630 mg, 2.44 mmol) in anhydrous 1,2-dichloroethane (20 mL), and the reaction solution was stirred at 80°C for 2 hour. Then the reaction solution was cooled with an ice-water bath, and a solution of 2-isopropylaniline (660 mg, 4.88 mmol) in anhydrous 1,2-dichloroethane (5 mL) was slowly added dropwise to the above reaction solution.
- Step 5 At -20°C, slowly add LiHMDS (1M tetrahydrofuran solution, 4.3 mL) to the intermediate 15-4 (0.82 g, 1.96 mmol) in anhydrous tetrahydrofuran (30 mL) solution, and the resulting mixture slowly rises
- LiHMDS Li tetrahydrofuran solution
- anhydrous tetrahydrofuran (30 mL) solution anhydrous tetrahydrofuran (30 mL) solution
- the resulting mixture slowly rises
- the reaction with saturated aqueous ammonium chloride solution (20 mL)
- extract the aqueous phase with ethyl acetate separate the organic phase, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use petroleum
- the ether/ethyl acetate mixed solvent (1/1, 30 mL) was slurried, filtered, and the filter cake was vacuum dried to obtain Intermediate 15-5 (680 mg) as
- Step 6 To a solution of Intermediate 15-5 (0.3 g, 0.75 mmol) in anhydrous acetonitrile (30 mL) were sequentially added triethylamine (455 mg, 4.5 mmol) and phosphorus oxychloride (691 mg, 4.5 mmol). The reaction mixture was stirred at 80°C for 2 hours, and then directly concentrated under reduced pressure to obtain Intermediate 15-6 (crude product) as a yellow solid.
- Step 1 Intermediate 1-6 (120mg, 0.28mmol), (5-methyl-1H-indazol-4-yl)boronic acid (80mg, 0.45mmol), cesium carbonate (92mg, 0.28mmol) and PdCl 2 dppf .
- CH 2 Cl 2 (15 mg, 0.02 mmol)
- 1,4-dioxane (12 mL) and water (1 mL) was replaced with nitrogen three times, and the reaction system was stirred at 90° C. for 12 hours.
- Step 2 A mixture of compound 1A (110 mg, 0.23 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain compound 1B (crude) as a yellow oil. m/z: [M+H] + 385.0.
- Step 3 To the dichloromethane (20 mL) solution of compound 1B (crude) and DIPEA (1 mL) was added dropwise a dichloromethane solution (1M, 25 mg, 0.28 mL) of acryloyl chloride, and the reaction solution was stirred at room temperature for 30 minutes. The reaction was quenched with water and concentrated under reduced pressure. The residue was purified by prep-HPLC (condition 1) to obtain compound 1-1-1 (33.1 mg, two-step yield: 32%) as a yellow solid.
- Step 1 To the solution of Intermediate 1-5 (425mg, 1.5mmol) and triethylamine (0.62ml, 4.5mmol) in dichloromethane (10mL) was added (S)-2-(1-acryloylpiperazine- 2-yl)acetonitrile hydrochloride (480 mg, 2.7 mmol), and the reaction solution was stirred at room temperature for 16 hours. The reaction was quenched by adding water, the aqueous phase was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated.
- Step 2 Under the protection of nitrogen, compound 3A (0.11g, 0.26mmol), Intermediate 2 (0.11g, 0.38mmol), PdCl 2 dppf . CH 2 Cl 2 (32mg, 0.04mmol) and sodium carbonate (1.0M, A mixed solution of 0.78 mL) of water (0.8 mL) and 1,4-dioxane (7 mL) was reacted at 100°C under microwave conditions for 1 hour, then the reaction system was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was decompressed After concentration, it was purified by prep-HPLC (condition 2) to obtain compound 1-1-2 (36 mg, yield: 28%) as an off-white solid.
- Step 1 Under ice bath conditions, add sodium hydrogen (60%, 56mg, 1.38mmol) to a solution of N-methyl-L-prolinol (159mg, 1.38mmol) in DMF (12mL) in batches. After stirring at 0°C for 1 hour, Intermediate 2-4 (63.5 mg, 0.13 mmol) was added to the above reaction solution, and the resulting mixture was stirred at room temperature for 2 hours.
- Step 2 Combine compound 4A (29mg, 53.1 ⁇ mol), (5-methyl-1H-indazol-4-yl)boronic acid (19mg, 106 ⁇ mol), sodium carbonate aqueous solution (0.26mL, 1M) and PdCl 2 dppf .
- Step 3 A solution of compound 4B (17 mg, 28.5 ⁇ mol) in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain compound 4C (crude) as a yellow oil. m/z: [M+H] + 497.8.
- Step 4 Add acryloyl chloride (2.8 mg, 31.3 ⁇ mol) in dichloromethane (5 mL) dropwise to the dichloromethane (5 mL) solution of compound 4C (crude) and DIPEA (0.5 mL), and the reaction solution is stirred at room temperature for 10 minute. After quenching the reaction with water, it was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 4) to obtain compound 1-2-1 (3.56 mg, two-step yield: 23%) as a white solid.
- Step 1 The intermediate 2-6 (100mg, 0.18mmol), N-methyl-L-prolinol (238mg, 2.06mmol), cesium carbonate (268mg, 0.82mmol) and DIPEA (505mg, 3.91mmol)
- the 1,4-dioxane (15 mL) mixture was placed in a sealed tube, replaced with nitrogen, and stirred at 150°C for 3 hours.
- the reaction solution was cooled to room temperature and diluted with ethyl acetate.
- the organic phase was washed with water.
- the organic phase was separated and concentrated under reduced pressure.
- Step 2 Compound 6A (40mg, 64.6 ⁇ mol), (5-methyl-1H-indazol-4-yl)boronic acid (57mg, 323 ⁇ mol), sodium carbonate aqueous solution (0.30mL, 1M) and PdCl 2 dppf .
- Step 3 A mixture of compound 6B (45 mg, 67.1 ⁇ mol) and 10% palladium-carbon (45 mg) in methanol (20 mL) was replaced with hydrogen and stirred at room temperature under a hydrogen atmosphere for 2.5 hours. The reaction solution was filtered with Celite, and the filtrate was concentrated under reduced pressure to obtain compound 6C (crude) as a yellow solid. m/z: [M+H] + 537.4.
- Step 4 To the dichloromethane (8mL) solution of compound 6C (crude) and DIPEA (0.5mL) was added dropwise a dichloromethane solution (2mL) of acrylic acid chloride (6.1mg, 67.1 ⁇ mol), and the reaction mixture was stirred at room temperature for 3 hour. The reaction was quenched with water and concentrated under reduced pressure. The residue was purified by prep-HPLC (condition 2) to obtain compound 1-2-2 (6 mg, two-step yield: 13%) as a white solid.
- Step 1 Combine Intermediate 4-3 (100mg, 0.17mmol), Intermediate 3 (57mg, 0.19mmol), aqueous sodium carbonate (0.85mL, 0.85mmol) and PdCl 2 dppf.CH 2 Cl 2 (14mg, 0.017mmol) The mixture of 1,4-dioxane (5 mL) in) was replaced with nitrogen three times, and the reaction system was microwaved at 110° C. for 1 hour.
- Step 2 A mixed solution of compound 9A (crude product) in dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 2 hours and then directly concentrated under reduced pressure to obtain compound 9B (crude product) as a yellow oil. m/z: [M+H] + 575.4.
- Step 3 To the dichloromethane (3mL) solution of compound 9B (crude) and DIPEA (0.5mL) was added dropwise a dichloromethane solution (0.1mL, 0.25M) of acrylic anhydride, and the reaction solution was stirred at room temperature for 2 hours. The reaction was quenched with water, the resulting mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 6) to obtain compound 1-2-3 (1.65 mg, three-step yield: 13%) as a yellow solid.
- Step 2 At -40°C, slowly add boron tribromide (0.2 mL) dropwise to a solution of compound 12A (5 mg, 7.2 ⁇ mol) in tetrahydrofuran (2 mL), and the reaction solution was slowly warmed to room temperature and stirred for 1 hour.
- the reaction solution was reduced to 0°C, water was added to quench the reaction, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 12B (crude) as a yellow solid.
- Step 3 Under ice bath conditions, add a dichloromethane solution (0.85M, 0.016mL) of acryloyl chloride to compound 12B (crude) and triethylamine (0.05mL, 0.36mmol) in dichloromethane (1mL), The reaction system was stirred at room temperature for 0.5 hours, concentrated under reduced pressure to remove the solvent, the residue was dissolved in acetonitrile (2 mL), ammonia water (1 mL) was added, and the resulting mixture was stirred at room temperature for 0.5 hours. The mixture was directly purified by prep-HPLC (condition 2) to obtain compound 1-2-4 (0.42 mg, two-step yield: 9%) as a white solid. m/z: [M+H] + 637.3.
- Example 8 2-((2S)-1-acryloyl-4-(4-(2,3-dichloro-5-hydroxyphenyl)-7-(((S)-1-methylpyrrolidine) 2-yl)methoxy)furo[2,3-f]quinazolin-9-yl)piperazin-2-yl)acetonitrile trifluoroacetate (compound 1-2-6)
- Step 2 To the 1,4-dioxane (2mL) solution of compound 8A (30mg, 46.4 ⁇ mol) was added the 1,4-dioxane solution (0.2mL, 4M) of hydrogen chloride, and the reaction solution was stirred at room temperature for 1 After hours, it was concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 3) to obtain compound 1-3-1 (12.0 mg, yield: 43%) as a yellow solid.
- intermediate 2 (3-fluoro-5-hydroxyphenyl)boronic acid, intermediate 4, 5-amino-2-methylphenylboronic acid Pinacol ester, intermediates 5, 10, 6, 7, 11, 5-amino-2-fluorophenylboronic acid pinacol ester, 4-amino-2-chlorophenylboronic acid pinacol ester, intermediates 8, 9 , (2-fluoro-4-hydroxyphenyl)boronic acid, (2-chloro-5-hydroxyphenyl)boronic acid, 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)aniline, (2,3-difluoro-4-hydroxyphenyl)boronic acid, (3-chloro-4-hydroxyphenyl)boronic acid, (2 -Chloro-4-hydroxyphenyl)boronic acid, intermediate 12, (5-amino-2,3-difluorophenyl)boronic acid,
- Trifluoroacetic acid (1 mL) was added to a dichloromethane (3 mL) solution of compound 13A (40 mg, 0.05 mmol), and the reaction solution was stirred at room temperature for 1 hour. Then it was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 8) to obtain compound 1-5-1 (5.95 mg, yield: 14%) as a pale yellow solid. m/z: [M+H] + 587.2.
- Step 2 Trifluoroacetic acid (1 mL) was added to the dichloromethane (1 mL) solution of compound 16C (15 mg, 0.02 mmol), and the reaction solution was stirred at room temperature for 1 hour. Then it was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 2) to obtain compound 1-5-2 (0.72 mg, yield: 6%) as a pale yellow solid. m/z: [M+H] + 626.2.
- Example 17 1-(7-(4-(5-methyl-1H-indazol-4-yl)-7-(((S)-1-methylpyrrolidin-2-yl)methoxy )Furo[2,3-f]quinazolin-9-yl)-2,7-diazaspiro[3.5]nonane-2-yl)prop-2-en-1-one (compound 1- 6-1) Synthesis
- Step 1 Mix Intermediate 4-2 (200mg, 0.39mmol), Intermediate 1 (118mg, 0.37mmol), sodium carbonate aqueous solution (1.95mL, 1M) and Pd(PPh 3 ) 4 (45mg, 0.04mmol) in 1
- the mixture of ,4-dioxane (20 mL) was placed in a microwave tube, the reaction system was replaced with nitrogen, and the reaction was performed in a microwave at 90°C for 5 hours. Then the reaction solution was cooled to room temperature and quenched with water. The aqueous phase was extracted with ethyl acetate, the organic phases were combined and concentrated under reduced pressure.
- Step 2 Combine compound 17A (220mg, 0.36mmol), (6-methylpyridin-3-yl)boronic acid (128mg, 0.93mmol), aqueous sodium carbonate (1.8mL, 1M) and Pd(PPh 3 ) 4 (86mg , 0.09mmol) of 1,4-dioxane (20mL) mixture was placed in a microwave tube, the reaction system was replaced with nitrogen and then microwaved at 90°C for 5 hours. Then the reaction solution was cooled to room temperature and quenched with water. The aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure.
- Step 3 A mixture of compound 17B (120mg, 0.18mmol) in methanol (10mL) and hydrochloric acid (1mL, 1M) was stirred at 50°C for 3 hours and then directly concentrated under reduced pressure to obtain compound 17C (75mg, yield: 79%) as Yellow solid. m/z: [M+H] + 527.2.
- Step 4 To compound 17C (75mg, 0.14mmol) and DIPEA (0.5mL) in dichloromethane (5mL) solution was added dropwise acryloyl anhydride (0.6mL, 0.5M dichloromethane solution), and the reaction mixture was stirred at room temperature 3 hours. The reaction was quenched with ammonia water (5 mL), the resulting mixture was stirred at room temperature for 2 hours, and then directly concentrated under reduced pressure. The residue was purified by prep-HPLC (condition 5) to obtain compound 1-7-1 (7.12 mg, yield: 9%) is a white solid.
- Step 1 Under the protection of nitrogen, the intermediate 6-1 (130mg, 0.23mmol), pinacol diborate (120mg, 0.47mmol), PdCl 2 dppf . CH 2 Cl 2 (38mg, 0.05mmol) and potassium acetate
- 1,4-dioxane 5 mL
- ethyl acetate 50 mL
- saturated brine saturated brine
- the organic phase was separated and concentrated under reduced pressure to obtain compound 18A (crude) as a yellow solid.
- Step 2 Add 6-chloro-4-methyl-5-(trifluoromethyl)pyridin-2-amine (70mg, 0.33 mmol), Pd(PPh 3 ) 4 (53 mg, 0.046 mmol) and aqueous sodium carbonate (1.0 M, 0.7 mL). The reaction system was blown with nitrogen for 2 minutes, and reacted in a microwave at 120°C for 0.5 hours. The reaction system was cooled to room temperature and diluted with ethyl acetate (50 mL), washed with saturated brine, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 6) to obtain compound 1-8-1 (4.3 mg, Yield: 3%) is a white solid.
- Example 21 1-(4-(4-(5-methyl-1H-indazol-4-yl)-7-(((S)-1-methylpyrrolidin-2-yl)methoxy )-1H-pyrazolo[3,4-f]quinazolin-9-yl)piperazin-1-yl)prop-2-en-1-one (Compound 2-1-1)
- Step 1 The intermediate 3-9 (106mg, 0.2mmol), N-methyl-L-prolinol (111mg, 0.8mmol), DIPEA (250mg, 0.4mmol) and cesium carbonate (188mg, 0.5mmol)
- the 1,4 dioxane (2.5 mL) solution was stirred at 170°C for 3 hours in a sealed tube.
- Step 2 The compound 7A (46.8mg, 74.2 ⁇ mol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxoboran-2-yl)-1H-indazole (30.5mg, 89.1 ⁇ mol), PdCl 2 dppf .
- CH 2 Cl 2 (6mg, 7.3 ⁇ mol), sodium carbonate aqueous solution (1M, 222 ⁇ mol) ) 1,4 dioxane (25 mL) mixture was replaced with nitrogen 3 times.
- Step 3 Add trifluoroacetic acid (1 mL) dropwise to a solution of compound 7B (40.3 mg, 52.6 ⁇ mol) in dichloromethane (5 mL). The reaction solution was stirred at room temperature for 5 hours and then concentrated under reduced pressure to obtain compound 7C (crude product) as a brown solid. m/z: [M+H] + 498.3.
- Step 4 Under an ice water bath, DIPEA (17.1 mg, 133 ⁇ mol) and acrylic anhydride (5.6 mg, 44.2 ⁇ mol) were added to the dichloromethane (3 mL) solution of compound 7C (crude product), respectively. The reaction solution was stirred at room temperature for 5 minutes, and 1 drop of ammonia was added to quench the reaction. The resulting mixture was concentrated under reduced pressure and purified by prep-HPLC (condition 2) to obtain compound 2-1-1 (3.01 mg, two-step yield: 12%) It is a white solid.
- Step 2 Under ice bath conditions, dissolve compound 20A (40 mg, 0.06 mmol) in acetonitrile (5 mL), add aqueous lithium hydroxide solution (1M, 0.6 mL), and stir the reaction system at this temperature for 1 hour. Then it was extracted with ethyl acetate/tetrahydrofuran mixed solvent (10/1), the organic phase was separated and concentrated, and the residue was purified by prep-HPLC (condition 5) to obtain compound 3-2-1 (3.9 mg, yield: 11%) It is a white solid.
- Example 26 2-((S)-4-(4-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-7-(((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3-dihydrofuro[2,3-f]quinazolin-9-yl)-1-(2- Synthesis of fluoroacryloyl)piperazin-2-yl)acetonitrile trifluoroacetate (compound 3-3-1)
- Example 27 6-Amino-2-(9-((S)-3-(cyanomethyl)-4-(2-fluoroacryloyl)piperazin-1-yl)-7-(((S )-1-Methylpyrrolidin-2-yl)methoxy)-2,3-dihydrofuro[2,3-f]quinazolin-4-yl)-3-(trifluoromethyl) Synthesis of isonicotinonitrile trifluoroacetate (compound 3-3-2)
- Step 1 Under the protection of nitrogen, 6-(bis(4-methoxybenzyl)amino)-2-chloro-3-(trifluoromethyl)isonicotinonitrile (130mg, 0.28mmol), 12-2( 120mg, 0.19mmol), PdCl 2 dppf . CH 2 Cl 2 (30mg, 0.04mmol) and potassium fluoride (120mg, 2.07mmol) in 1,4-dioxane and water (6.6mL/3.0mL) mixed solution Microwave reaction at 120°C for 0.5 hour.
- Step 3 Under ice bath conditions, add compound 19B (70 mg, 0.12 mmol), 1-propyl phosphoric anhydride (50% ethyl acetate solution, 2.40 mmol) and DIPEA (774 mg, 6.0 mmol) in anhydrous ethyl acetate/ 2-Fluoroacrylic acid (53 mg, 0.59 mmol) was added to the dichloromethane (10.0 mL/2.0 mL) solution, and the reaction solution was stirred at room temperature for 1 hour.
- Example 29 1-((S)-4-(4-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-7-(((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-2,3-dihydrofuro[2,3-f]quinazolin-9-yl)-3-methylpiper Synthesis of azin-1-yl)prop-2-en-1-one (compound 3-3-10)
- Step 1 To a solution of Intermediate 15-7 (95mg, 0.16mmol) in 1,4-dioxane (5mL) was added (5-methyl-1H-indazol-4-yl)boronic acid (58mg, 0.33 mmol), Pd(PPh 3 ) 4 (19 mg, 0.016 mmol) and aqueous sodium carbonate (0.48 mL, 0.48 mmol). After bubbling the reaction mixture with nitrogen for 1-2 minutes, it was reacted at 160°C for 0.5 hours under microwave conditions, and then the reaction solution was cooled to room temperature and concentrated under reduced pressure. 4) Purified compound 10A (79 mg, yield: 76%) as a pale yellow solid. m/z: [M+H] + 633.3.
- Step 2 A mixed solution of compound 10A (79 mg, 0.12 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 2 hours and then directly concentrated under reduced pressure to obtain compound 10B (crude product) as a yellow solid.
- Step 3 Under an ice-water bath, add DIPEA (78mg, 0.60mmol) and acrylic anhydride in dichloromethane (0.25M, 0.59mL, 0.15mmol) to a solution of compound 10B (crude) in anhydrous dichloromethane (10mL). ). After the reaction mixture was stirred at this temperature for 1 hour, ammonia water (0.05 mL) was added to quench the reaction, the resulting mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 2) to obtain compound 4-1-1 (24.3 mg , Yield: 34%) is a white solid.
- Step 1 Using the synthetic method of compound 10A, intermediate 15-8 is reacted with (5-methyl-1H-indazol-4-yl)boronic acid to obtain compound 11A as a white solid. m/z: [M+H] + 692.2.
- Step 2 To a methanol (30 mL) solution of compound 11A (100 mg, 0.14 mmol) was added palladium on carbon (10%, 60 mg), the reaction system was replaced with hydrogen 3 times, and then stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain compound 11B (75 mg, yield: 92%) as a white solid. m/z: [M+H] + 558.3.
- Step 3 Under ice bath conditions, add DIPEA (50mg, 0.39mmol) and acrylic anhydride in dichloromethane (0.3M, 0.54 mL, 0.16 mmol). After the reaction mixture was stirred at this temperature for 5 hours, ammonia water (0.05 mL) was added to quench the reaction, the resulting mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (, condition 7) to obtain compound 4-1-2 (4.1 mg, yield: 5%) is a white solid.
- Step 1 Using the synthetic method of compound 10A, the intermediate 15-7 is reacted with 4-fluoro-6-methoxyphenylboronic acid to obtain compound 15A as a pale yellow solid. m/z: [M+H] + 627.4.
- Step 3 Under ice bath conditions, add DIPEA (260 mg, 2.10 mmol) and acrylic anhydride in dichloromethane (0.30M, 0.85) to a solution of compound 15B (130 mg, 0.21 mmol) in anhydrous dichloromethane (10 mL). mL, 0.26 mmol). After the reaction mixture was stirred at this temperature for 1 hour, ammonia water (2.5 mL) was added to quench the reaction, and then the stirring was continued for 2 hours. The resulting mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 5) to obtain compound 4- 1-3 (30.9 mg, yield: 26%) is a white solid.
- Step 1 A mixture of compound 15-9 (350 mg, 0.59 mmol) in dichloromethane (16 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain compound 14A (crude product) as a yellow oil. m/z: [M+H] + 497.2.
- Step 3 Compound 14B (55mg, 0.10mmol), Intermediate 2 (54mg, 0.20mmol), sodium carbonate aqueous solution (1M, 0.30mL) and Pd(PPh 3 ) 4 (12mg, 0.01mmol) 1,4-bis
- the oxane (2 mL) mixture was added to the microwave tube, and after nitrogen bubbling for 1-2 minutes, the reaction system was reacted in a microwave at 130° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 7) to obtain compound 4-1-4 (16.6 mg, yield: 27%) as a white solid.
- the Phospho-ERK1/2 (THR202/TYR 204) (Cisibo, 64ERKPEH) kit was used to detect the phosphorylation level of ERK1/2 in human pancreatic cancer cells Mia Paca-2, and the phosphorylation level of ERK1/2 was used to study The inhibitory effect of the compound on KRAS.
- the experiment was carried out according to the manufacturer's experimental protocol.
- On the first day adjust the density of the MIA PaCa-2 cell (ATCC) suspension to 2.1 ⁇ 10 5 cells/mL, and spread it in a 96-well plate at 95ul/well, then the number of cells per well will be 2 ⁇ 10 4.
- the culture plate was placed in an incubator at 37°C and 5% CO 2 for overnight culture.
- the compound was diluted with 100% DMSO gradient, and then further diluted with complete medium (DMDM+10%FBS+1%P/S) to become the compound working solution, and 5ul/well was added to 96-well cell culture plate at 37 Incubate in a 5% CO 2 incubator for 4 hours.
- Compound number IC 50 ( ⁇ M) Compound number IC 50 ( ⁇ M) 1-1-1 11.930 1-4-66 0.0069 1-1-2 0.5201 1-4-67 0.0045 1-2-1 0.6361 1-4-68 0.0004 1-2-2 0.0665 1-4-69 0.1030 1-2-3 0.1229 1-4-70 0.0019
- the method of cell proliferation experiment is used to evaluate the biological activity of the compound.
- 3000 Miapaca-2 human pancreatic cancer cells (Nanjing Kebai) were planted in 96-well plates, and the cells were cultured in Dulbecco's Modified Eagle's matrix and 10% fetal bovine serum. The culture environment was 37°C and 5% CO 2 . On the second day, the stock solution of the test compound is dissolved in DMSO and added to the medium of the indicated concentration, and incubated for 72 hours. The concentration of the test compound ranges from 1.5 nM to 100 ⁇ M. Negative control cells were treated with vehicle only. Use the Cell Titer-Glo test kit (Cell Titer-glo, Promega) to evaluate cell viability under the instructions of the product manual. Use Graphpad software to analyze the data, and obtain IC 50 values and compound fitting curves (see Table 18 for the results).
Abstract
Description
化合物编号 | IC 50(μM) | 化合物编号 | IC 50(μM) |
1-1-1 | 11.930 | 1-4-66 | 0.0069 |
1-1-2 | 0.5201 | 1-4-67 | 0.0045 |
1-2-1 | 0.6361 | 1-4-68 | 0.0004 |
1-2-2 | 0.0665 | 1-4-69 | 0.1030 |
1-2-3 | 0.1229 | 1-4-70 | 0.0019 |
1-2-4 | 0.0090 | 1-4-71 | >1 |
1-2-5 | 0.6005 | 1-4-72 | 0.0097 |
1-2-6 | 0.0069 | 1-4-73 | 0.0064 |
1-3-1 | 0.0017 | 1-4-74 | 0.0012 |
1-3-2 | 0.0163 | 1-4-75 | 0.0057 |
1-4-1 | 0.0894 | 1-4-76 | 0.0040 |
1-4-2 | 0.0225 | 1-4-77 | 0.0106 |
1-4-3 | 0.0022 | 1-4-78 | 0.0048 |
1-4-4 | 0.4296 | 1-4-79 | 0.0084 |
1-4-5 | 1.414 | 1-4-80 | 0.0012 |
1-4-6 | 0.0247 | 1-4-81 | 0.0005 |
1-4-7 | 0.0894 | 1-4-82 | 0.1351 |
1-4-8 | 0.0198 | 1-4-83 | 0.0033 |
1-4-9 | 0.0043 | 1-4-84 | 0.0207 |
1-4-10 | 0.0180 | 1-4-85 | 0.0069 |
1-4-11 | >1 | 1-4-86 | 0.0016 |
1-4-12 | 2.031 | 1-4-87 | 0.0005 |
1-4-13 | 0.5713 | 1-4-88 | 0.0007 |
1-4-14 | 0.0018 | 1-4-89 | 0.0020 |
1-4-15 | 0.0919 | 1-4-90 | 0.0918 |
1-4-16 | 5.771 | 1-5-1 | 0.1908 |
1-4-17 | 0.0038 | 1-5-2 | 0.0287 |
1-4-18 | 0.0459 | 1-5-3 | 0.0232 |
1-4-19 | 2.605 | 1-5-4 | 0.0071 |
1-4-20 | 1.612 | 1-6-1 | 0.8770 |
1-4-21 | 0.0747 | 1-7-1 | >1 |
1-4-22 | 0.0101 | 1-8-1 | 0.0123 |
1-4-23 | 2.663 | 1-8-2 | 0.0131 |
1-4-24 | 0.0017 | 1-8-3 | 0.0877 |
1-4-25 | 1.367 | 1-8-4 | 0.0621 |
1-4-26 | 0.6894 | 1-8-5 | 0.0103 |
1-4-27 | 0.0054 | 2-1-1 | 1.291 |
1-4-28 | 0.0009 | 2-1-2 | 0.0060 |
1-4-29 | 0.0312 | 3-1-1 | 0.0047 |
1-4-30 | 0.5480 | 3-1-2 | 0.0886 |
1-4-31 | 0.0551 | 3-1-3 | 0.0191 |
1-4-32 | 0.1725 | 3-1-4 | 0.0057 |
1-4-33 | 0.0008 | 3-1-5 | 0.1332 |
1-4-34 | 0.3837 | 3-1-6 | 0.0537 |
1-4-35 | 0.1638 | 3-1-7 | 0.0029 |
1-4-36 | 0.0104 | 3-1-8 | 0.0013 |
1-4-37 | 0.0122 | 3-1-9 | 0.0285 |
1-4-38 | 0.0150 | 3-1-10 | 0.1360 |
1-4-39 | 0.0005 | 3-1-11 | 0.0864 |
1-4-40 | 0.0091 | 3-1-12 | 0.0050 |
1-4-41 | 0.0006 | 3-1-13 | 0.0085 |
1-4-42 | >1 | 3-1-14 | 0.0244 |
1-4-43 | 0.0030 | 3-1-15 | 0.0020 |
1-4-44 | 0.0139 | 3-1-16 | 0.0120 |
1-4-45 | >1 | 3-2-1 | 0.0620 |
1-4-46 | 0.0999 | 3-3-1 | 0.0204 |
1-4-47 | 0.0727 | 3-3-2 | 0.1937 |
1-4-48 | 0.0128 | 3-3-3 | 0.0786 |
1-4-49 | 0.0422 | 3-3-6 | 0.0313 |
1-4-50 | 0.5278 | 3-3-7 | 0.3754 |
1-4-51 | 0.3169 | 3-3-8 | 0.0013 |
1-4-52 | >1 | 3-3-9 | 0.0700 |
1-4-53 | 0.1050 | 3-3-10 | 0.1619 |
1-4-54 | 1.535 | 4-1-1 | 0.1692 |
1-4-55 | 0.0586 | 4-1-2 | 0.3782 |
1-4-56 | 0.0227 | 4-1-3 | 0.4701 |
1-4-57 | 0.0089 | 4-1-4 | 1.005 |
1-4-58 | 0.0019 | 4-1-5 | 0.4480 |
1-4-59 | 0.1684 | 4-1-6 | 1.209 |
1-4-60 | 0.0202 | 4-1-7 | 1.046 |
1-4-61 | 0.0256 | 4-1-8 | 1.869 |
1-4-62 | 0.1196 | 4-1-9 | 0.7137 |
1-4-63 | 0.1645 | 4-1-10 | 0.5252 |
1-4-64 | 0.0460 | 4-1-11 | >1 |
1-4-65 | 0.0096 | 4-1-12 | >1 |
化合物编号 | IC 50(μM) | 化合物编号 | IC 50(μM) |
1-2-1 | 0.569 | 1-4-60 | 0.101 |
1-2-2 | 0.177 | 1-4-61 | 0.355 |
1-2-3 | 0.505 | 1-4-63 | 0.199 |
1-2-4 | 0.090 | 1-4-65 | 0.238 |
1-2-5 | 0.294 | 1-4-66 | 0.061 |
1-2-6 | 0.019 | 1-4-67 | 0.086 |
1-3-1 | 0.011 | 1-4-68 | 0.039 |
1-3-2 | 0.053 | 1-4-70 | 0.026 |
1-4-1 | 0.438 | 1-4-72 | 0.020 |
1-4-2 | 0.396 | 1-4-73 | 0.240 |
1-4-3 | 0.031 | 1-4-74 | 0.041 |
1-4-6 | 0.356 | 1-4-75 | 0.079 |
1-4-7 | 0.252 | 1-4-76 | 0.014 |
1-4-8 | 0.037 | 1-4-77 | 0.043 |
1-4-9 | 0.005 | 1-4-78 | 0.008 |
1-4-10 | 0.156 | 1-4-79 | 0.116 |
1-4-14 | 0.018 | 1-4-80 | 0.182 |
1-4-17 | 0.065 | 1-4-81 | 0.005 |
1-4-18 | 0.365 | 1-4-83 | 0.129 |
1-4-22 | 0.394 | 1-4-84 | 0.029 |
1-4-24 | 0.029 | 1-4-85 | 0.107 |
1-4-29 | 0.124 | 1-4-86 | 0.008 |
1-4-30 | 0.484 | 1-4-87 | 0.013 |
1-4-31 | 0.191 | 1-4-88 | 0.037 |
1-4-32 | 0.418 | 1-4-89 | 0.014 |
1-4-33 | 0.001 | 1-8-1 | 0.260 |
1-4-35 | 0.125 | 1-8-2 | 0.328 |
1-4-36 | 0.503 | 1-8-5 | 0.171 |
1-4-37 | 0.198 | 2-1-2 | 0.037 |
1-4-38 | 0.266 | 3-1-1 | 0.035 |
1-4-39 | 0.031 | 3-1-2 | 0.373 |
1-4-40 | 0.319 | 3-1-3 | 0.048 |
1-4-41 | 0.016 | 3-1-4 | 0.007 |
1-4-43 | 0.019 | 3-1-7 | 0.019 |
1-4-44 | 0.372 | 3-1-8 | 0.018 |
1-4-48 | 0.141 | 3-1-9 | 0.094 |
1-4-49 | 0.193 | 3-1-12 | 0.120 |
1-4-53 | 0.458 | 3-1-13 | 0.089 |
1-4-55 | 0.246 | 3-1-14 | 0.251 |
1-4-56 | 0.191 | 3-1-15 | 0.061 |
1-4-57 | 0.125 | 3-3-6 | 0.195 |
1-4-58 | 0.027 | 4-1-1 | 0.158 |
Claims (22)
- 一种如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐;其中,α和β键分别为单键或双键;X为N或CR 2;β键为单键时,Y为C(O),Z为NR 3;β键为双键时,Y和Z分别独立地为N或CR 2;α键为单键时,W为N,V为CH 2或C(O);α键为双键时,W为C,V为CR 4或N;U和M分别独立地为N、C或CH;A环为苯基、3-8元环烷基、5-6元杂芳基或4-8元杂环烷基;所述A环为未取代,或者选择性地被1~3个R 5基团取代在任意位置;B环为5-10元杂环烷基;所述B环为未取代,或者选择性被1~3个R 6基团取代在任意位置;R为C 6-10芳基、5-10元杂芳基或9-14元稠合杂环烷基;所述R为未取代或者选择性被1个或多个R 7基团取代在任意位置;R 1为C 2-4烯基、C 2-4炔基或部分不饱和的C 4-6环烷基;所述R 1为未取代或者选择性被1~3个R 8基团取代在任意位置;R 2为氢、羟基、卤素、氰基、氨基、-R A、-NR AR B、-OR A或-SR A;R 3为C 3-8环烷基、3-8元杂环烷基、C 6-10芳基、5-10杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基或5-10杂芳基-C 1-4烷基;所述R 3为未取代或者选择性被1~3个选自卤素、羟基、氰基、氨基、氧代基、卤代C 1-6烷基、C 1-6烷基、C 3-6环烷基、C 3-6环烷基-C 1-4烷基、4-6元杂环烷基或4-6元杂环烷基-C 1-4烷基的取代基 取代在任意位置;R 4为氢、羟基、卤素、C 2-6烯基、C 2-6炔基、氰基、氨基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基-C 1-6烷基、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基或C 3-8环烷基;R 5为氢、羟基、卤素、C 2-6烯基、C 2-6炔基、氰基、氨基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基-C 1-6烷基、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、酰基、C 3-8元环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基、3-8元杂环烷基-C 1-4烷基或-B(OR”) 2;R 6为氢、氧代基、羟基、氰基、氨基、C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、卤代C 1-6烷氧基、-C(O)OR’或-C(O)NR’ 2;R 6中,所述C 1-6烷基为未取代或者选择性被1~3个选自卤素、羟基、氨基、羧基、氰基、C 1-4烷氧基、卤代C 1-4烷氧基和C 1-6烷氨基的取代基取代在任意位置;R 7为氢、羟基、卤素、C 2-6烯基、C 2-6炔基、氰基、氨基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、羟基-C 1-4烷基、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、C 3-8环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基、C 6-10芳基-C 1-4烷基、5-10元杂芳基、5-10元杂芳基-C 1-4烷基、-NH-C 3-6环烷基、-(CH 2) nOR’、-NHC(O)R”、-C(O)R”、-C(O)N(R”) 2、-OC(O)R”、-OC(O)N(R”) 2或-B(OR”) 2;R 7中,所述C 3-8环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基、C 6-10芳基-C 1-4烷基、5-10元杂芳基或5-10元杂芳基-C 1-4烷基为未取代或者选择性被1~3个选自卤素、羟基、氨基、羧基、氰基、C 1-4烷基、卤代C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷氧基和C 1-6烷氨基的取代基取代在任意位置;R 8为氢、氘、卤素、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、羟基-C 1-4烷基、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、5-10元杂芳基、3-10元杂环烷基、5-10杂芳基-C 1-4烷基或3-10杂环烷基-C 1-4烷基;其中,所述C 1-6烷氨基-C 1-4烷基、杂芳基、杂环烷基、杂环烷基烷基或杂芳基烷基为未取代,或者选择性被1~3个选自卤素、羟基、氨基、氰基、C 1-4烷氧基、氧代基和C 1-4烷基的取代基取代在任意位置;R A为氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 6-10芳基、5-10元杂芳基、C 3-10环烷基、3-10元杂环烷基、C 3-10环烷基-C 1-6烷基、3-10元杂环烷基-C 1-6烷基、C 6-10芳基-C 1-6烷基或5-10元杂芳基-C 1-6烷基;所述R A为未取代或者选择性被一个或多个R c取代在任意位置;R B为氢、氰基、羟基或C 1-6烷基;或者,R A和R B相互连接形成4-8杂环烷基;所述杂环烷基为未取代或者选择性被 1~3个选自羟基、氰基、氨基、氧代基、卤素、C 1-4烷基、酰基、C 1-4烷氧基、C 1-6烷氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基-C 1-4烷基、C 1-4烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、C 3-8元环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基和5-10元杂芳基-C 1-4烷基的取代基取代在任意位置;R c为羟基、氰基、氨基、氧代基、卤素、C 1-4烷基、C 1-4亚烷基、C 1-6烷氧基、C 1-6烷氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基-C 1-6烷基、C 1-4烷氧基-C 1-6烷基、氨基-C 1-6烷基、C 1-6烷氨基-C 1-6烷基、C 3-8元环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基、5-10元杂芳基-C 1-4烷基、-(CH 2) n-N(CN)R’、-(CH 2) n-C(O)R’、-(CH 2) n-C(O)N(R’) 2、-(CH 2) n-S(O) 2N(R’) 2、-(CH 2) n-NR”C(O)R’、-(CH 2) n-NR”S(O) 2R’或-(CH 2) n-B(OR”) 2;R c中,所述C 1-4亚烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8元环烷基、3-8元杂环烷基、C 6-10芳基、5-10元杂芳基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基-C 1-4烷基、5-10元杂芳基-C 1-4烷基为未取代或者选择性被1-3个选自卤素、羟基、氨基、氰基、C 1-4烷氧基、C 1-4烷氨基和C 1-4烷基的取代基取代在任意位置;R’为氢、C 1-4烷基、卤代C 1-4烷基、羟基-C 1-4烷基、C 1-4烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、C 3-8环烷基、3-8元杂环烷基、C 3-8环烷基-C 1-4烷基、3-8元杂环烷基-C 1-4烷基、C 6-10芳基、6-10元杂芳基、C 6-10芳基-C 1-4烷基或6-10元杂芳基-C 1-4烷基;R”为氢或C 1-6烷基;n为0到4的整数;并且,排除以下情况:A环为苯基或1,3-二氧杂环戊烯基时,R 2为氢。
- 如权利要求2所述的如式(I)所示的化合物,其异构体、稳定的同位素衍生物或药学上可接受的盐,其特征在于,R 5为H或-CH 2OH;和/或,R 6为H、-CH 3、-CF 3、-CHF 2、-CH 2CN、-CH 2OH、-CH 2CH 2OH 、-CH 2CH 2OCH 3或-CH 2OCH 3。
- 如权利要求1所述的如式(I)所示的化合物,其异构体、稳定的同位素衍生物或药学上可接受的盐,其特征在于,R为苯基、萘基、吡啶基、吡嗪基、哒嗪基、喹啉基、 异喹啉基、2,3-二氢苯并呋喃基、1H-苯并[d]咪唑-2(3H)-酮基、1H-吲唑基、酞嗪基、1-羟基-1,3-二氢苯并[c][1,2]氧杂硼戊环基、3-羟基-1,3-二氢萘并[2,1-c][1,2]氧杂硼戊环基或1-羟基-1,3-二氢萘并[2,3-c][1,2]氧杂硼戊环基;所述R为未取代或者选择性被1~5个R 7取代在任意位置;和/或,R 7为氢、卤素、羟基、氨基、氰基、C 1-4烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-6烷氨基、C 3-6环烷基、3-6元杂环烷基或-B(OH) 2;所述C 3-6环烷基或3-6元杂环烷基为未取代或者选择性被1~3个选自羟基、氨基、氟、氯、甲基、三氟甲基和三氟甲氧基的取代基取代在任意位置。
- 如权利要求1所述的如式(I)所示的化合物,其异构体、稳定的同位素衍生物或 药学上可接受的盐,其特征在于,R 1为 其中,R 8a为H、D、卤素或C 1-3烷氧基-C 1-4烷基;R 8b和R 8c分别独立地为H、D、卤素、C 1-6烷基、卤代C 1-6烷基、羟基-C 1-4烷基、C 1-3烷氧基-C 1-4烷基、氨基-C 1-4烷基、C 1-6烷氨基-C 1-4烷基、5-10元杂芳基、3-10元杂环烷基、5-10杂芳基-C 1-4烷基或3-10杂环烷基-C 1-4烷基;其中,所述C 1-6烷氨基-C 1-4烷基、杂芳基、杂环烷基、杂环烷基烷基或杂芳基烷基为未取代,或者选择性被1~3个选自卤素、羟基、氨基、氰基、C 1-4烷氧基、氧代基和C 1-4烷基的取代基取代在任意位置;
- 如权利要求1~7任一项所述的如式(I)所示的化合物,其异构体、稳定的同位素衍生物或药学上可接受的盐,其特征在于,α和β键分别为双键;X为N;W为C,V为CR 4或N;Y为CR 2;Z为N。
- 如权利要求1所述的如式(I)所示的化合物,其异构体、稳定的同位素衍生物或药学上可接受的盐,其特征在于,R 2为-OR A、-NR AR B、5-10元杂芳基或3-10元杂环烷基;所述5-10元杂芳基或3-10元杂环烷基为未取代或者选择性被一个或多个R c取代在任意位置;和/或,R 4为氢、卤素、C 2-4烯基、C 1-4烷基、C 1-3烷氧基、卤代C 1-3烷基、卤代C 1-3烷氧基或C 3-6环烷基。
- 如权利要求11所述的如式(I)所示的化合物,其异构体、稳定的同位素衍生物或药学上可接受的盐,其特征在于,X为N;U和M分别独立地为N、C;A环为5-6元杂芳基或5-6元杂环烷基;R为C 6-10芳基或5-10元杂芳基;所述R为未取代或者选择性被1~4个R 7基团取代在任意位置;R 1为C 2-4烯基;所述R 1为未取代或者选择性被1~3个R 8基团取代在任意位置;R 2为-OR A;R 4为H;R 6为氢、C 1-6烷基或C 1-6烷氧基;R 6中,所述C 1-6烷基为未取代或者选择性被1~3个选自卤素、羟基、氰基和C 1-4烷氧基的取代基取代在任意位置;R 7为氢、羟基、卤素、氰基、氨基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 3-8环烷基或3-8元杂环烷基;R 8为氢、氘、卤素、C 1-6烷基、C 1-6烷氧基、羟基-C 1-4烷基、C 1-6烷氧基-C 1-4烷基、氨基-C 1-4烷基或C 1-6烷氨基-C 1-4烷基;R A为C 1-6烷基、C 3-10环烷基、3-10元杂环烷基、C 3-10环烷基-C 1-6烷基或3-10杂环烷基-C 1-6烷基;所述R A为未取代或者选择性被一个或多个R c取代在任意位置;R c为羟基、氰基、氨基、氧代基、卤素、C 1-4烷基、C 1-4亚烷基、C 1-6烷氧基、C 1-6烷氨基、卤代C 1-4烷基或卤代C 1-4烷氧基。
- 如权利要求1~7任一项所述的如式(I)所示的化合物,其异构体、稳定的同位素衍生物或药学上可接受的盐,其特征在于,α键为双键;β键为单键;X为N;W为C,V为CR 4或N;Y为C(O),Z为NR 3;和/或,R 3为环己基、环丙基甲基、苯基、吡啶基、嘧啶基、噻唑或1H-吡唑基;所述R 3为未取代或者选择性被1~3个选自卤素、羟基、氰基、氨基、C 1-6烷基或C 3-6环烷基的取代基取代在任意位置;和/或,R 4为氢。
- 一种药物组合物,其包括治疗有效量的活性组分以及药学上可接受的辅料;所述活性组分包括如权利要求1~16任一项所述的如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐。
- 一种如权利要求1~16任一项所述的如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐,或如权利要求17所述药物组合物在制备KRAS G12C抑制剂药物中的应用。
- 一种如权利要求1~16任一项所述的如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐,或如权利要求17所述药物组合物在制备治疗和/或缓解与KRAS G12C相关疾病的药物中的应用。
- 如权利要求19所述的应用,其特征在于:所述的KRAS G12C相关疾病为癌症。
- 一种如权利要求1~16任一项所述的如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐,或如权利要求17所述药物组合物在制备治疗癌症的药物中的应用。
- 一种联合制剂,包括如权利要求1~16任一项所述如式(I)所示化合物、其异构体、稳定的同位素衍生物或药学上可接受的盐,或如权利要求17所述所述药物组合物和其它种类的用于治疗癌症的治疗剂合用。
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Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022105859A1 (en) * | 2020-11-20 | 2022-05-27 | Jacobio Pharmaceuticals Co., Ltd. | Kras g12d inhibitors |
WO2022152233A1 (en) * | 2021-01-15 | 2022-07-21 | Beigene, Ltd. | Kras g12c inhibitors |
US11453683B1 (en) | 2019-08-29 | 2022-09-27 | Mirati Therapeutics, Inc. | KRas G12D inhibitors |
WO2022266206A1 (en) | 2021-06-16 | 2022-12-22 | Erasca, Inc. | Kras inhibitor conjugates |
US11548888B2 (en) | 2019-01-10 | 2023-01-10 | Mirati Therapeutics, Inc. | KRas G12C inhibitors |
WO2023056421A1 (en) * | 2021-10-01 | 2023-04-06 | Incyte Corporation | Pyrazoloquinoline kras inhibitors |
US11697657B2 (en) | 2019-10-28 | 2023-07-11 | Merck Sharp & Dohme Llc | Small molecule inhibitors of KRAS G12C mutant |
US11702418B2 (en) | 2019-12-20 | 2023-07-18 | Mirati Therapeutics, Inc. | SOS1 inhibitors |
US11890285B2 (en) | 2019-09-24 | 2024-02-06 | Mirati Therapeutics, Inc. | Combination therapies |
US11932633B2 (en) | 2018-05-07 | 2024-03-19 | Mirati Therapeutics, Inc. | KRas G12C inhibitors |
US11939328B2 (en) | 2021-10-14 | 2024-03-26 | Incyte Corporation | Quinoline compounds as inhibitors of KRAS |
US11964989B2 (en) | 2022-07-20 | 2024-04-23 | Mirati Therapeutics, Inc. | KRas G12D inhibitors |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109988135B (zh) * | 2019-04-04 | 2022-10-28 | 宜昌市第一人民医院(三峡大学人民医院) | 一种小分子抑制剂azin19及其在制药中的应用 |
CN114621244B (zh) * | 2020-12-14 | 2023-08-18 | 成都百裕制药股份有限公司 | 吡啶衍生物及其在医药上的应用 |
WO2022184178A1 (en) * | 2021-03-05 | 2022-09-09 | Jacobio Pharmaceuticals Co., Ltd. | Kras g12d inhibitors |
CN115181106B (zh) * | 2021-04-07 | 2024-04-05 | 药雅科技(上海)有限公司 | 喹唑啉类krasg12d突变蛋白抑制剂的制备及其应用 |
TW202304934A (zh) * | 2021-04-08 | 2023-02-01 | 美商建南德克公司 | 非環氧氮呯化合物及其用途 |
EP4349828A1 (en) * | 2021-05-24 | 2024-04-10 | Shanghai Yingli Pharmaceutical Co. Ltd. | Nitrogen-containing heterocyclic compound, preparation method therefor and application thereof |
WO2024032702A1 (en) * | 2022-08-11 | 2024-02-15 | Beigene, Ltd. | Heterocyclic compounds, compositions thereof, and methods of treatment therewith |
CN116120315B (zh) * | 2023-04-19 | 2023-06-09 | 山东绿叶制药有限公司 | 一种kras g12c抑制剂及其应用 |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106488910A (zh) * | 2013-10-10 | 2017-03-08 | 亚瑞克西斯制药公司 | Kras g12c的抑制剂 |
CN107849022A (zh) * | 2015-04-10 | 2018-03-27 | 亚瑞克西斯制药公司 | 取代的喹唑啉化合物和其使用方法 |
CN108779097A (zh) * | 2015-11-16 | 2018-11-09 | 亚瑞克西斯制药公司 | 包含取代的杂环基的2-取代的喹唑啉化合物及其使用方法 |
WO2018206539A1 (en) * | 2017-05-11 | 2018-11-15 | Astrazeneca Ab | Heteroaryl compounds that inhibit g12c mutant ras proteins |
WO2018218070A2 (en) * | 2017-05-25 | 2018-11-29 | Araxes Pharma Llc | Covalent inhibitors of kras |
US20190177338A1 (en) * | 2017-12-08 | 2019-06-13 | Astrazeneca Ab | Chemical compounds |
CN110036010A (zh) * | 2016-09-29 | 2019-07-19 | 亚瑞克西斯制药公司 | Kras g12c突变蛋白的抑制剂 |
CN110256421A (zh) * | 2019-06-26 | 2019-09-20 | 微境生物医药科技(上海)有限公司 | Kras-g12c抑制剂 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2473054B1 (en) * | 2009-09-04 | 2017-06-14 | The Regents of the University of Michigan | Compositions and methods for treatment of leukemia |
WO2017172979A1 (en) * | 2016-03-30 | 2017-10-05 | Araxes Pharma Llc | Substituted quinazoline compounds and methods of use |
WO2018218069A1 (en) * | 2017-05-25 | 2018-11-29 | Araxes Pharma Llc | Quinazoline derivatives as modulators of mutant kras, hras or nras |
-
2020
- 2020-09-29 WO PCT/CN2020/118772 patent/WO2021063346A1/zh active Application Filing
- 2020-09-29 CN CN202011050829.4A patent/CN112574224A/zh active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106488910A (zh) * | 2013-10-10 | 2017-03-08 | 亚瑞克西斯制药公司 | Kras g12c的抑制剂 |
CN107849022A (zh) * | 2015-04-10 | 2018-03-27 | 亚瑞克西斯制药公司 | 取代的喹唑啉化合物和其使用方法 |
CN108779097A (zh) * | 2015-11-16 | 2018-11-09 | 亚瑞克西斯制药公司 | 包含取代的杂环基的2-取代的喹唑啉化合物及其使用方法 |
CN110036010A (zh) * | 2016-09-29 | 2019-07-19 | 亚瑞克西斯制药公司 | Kras g12c突变蛋白的抑制剂 |
WO2018206539A1 (en) * | 2017-05-11 | 2018-11-15 | Astrazeneca Ab | Heteroaryl compounds that inhibit g12c mutant ras proteins |
WO2018218070A2 (en) * | 2017-05-25 | 2018-11-29 | Araxes Pharma Llc | Covalent inhibitors of kras |
US20190177338A1 (en) * | 2017-12-08 | 2019-06-13 | Astrazeneca Ab | Chemical compounds |
CN110256421A (zh) * | 2019-06-26 | 2019-09-20 | 微境生物医药科技(上海)有限公司 | Kras-g12c抑制剂 |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11932633B2 (en) | 2018-05-07 | 2024-03-19 | Mirati Therapeutics, Inc. | KRas G12C inhibitors |
US11548888B2 (en) | 2019-01-10 | 2023-01-10 | Mirati Therapeutics, Inc. | KRas G12C inhibitors |
US11453683B1 (en) | 2019-08-29 | 2022-09-27 | Mirati Therapeutics, Inc. | KRas G12D inhibitors |
US11890285B2 (en) | 2019-09-24 | 2024-02-06 | Mirati Therapeutics, Inc. | Combination therapies |
US11697657B2 (en) | 2019-10-28 | 2023-07-11 | Merck Sharp & Dohme Llc | Small molecule inhibitors of KRAS G12C mutant |
US11702418B2 (en) | 2019-12-20 | 2023-07-18 | Mirati Therapeutics, Inc. | SOS1 inhibitors |
WO2022105859A1 (en) * | 2020-11-20 | 2022-05-27 | Jacobio Pharmaceuticals Co., Ltd. | Kras g12d inhibitors |
WO2022152233A1 (en) * | 2021-01-15 | 2022-07-21 | Beigene, Ltd. | Kras g12c inhibitors |
WO2022266206A1 (en) | 2021-06-16 | 2022-12-22 | Erasca, Inc. | Kras inhibitor conjugates |
WO2023056421A1 (en) * | 2021-10-01 | 2023-04-06 | Incyte Corporation | Pyrazoloquinoline kras inhibitors |
US11939328B2 (en) | 2021-10-14 | 2024-03-26 | Incyte Corporation | Quinoline compounds as inhibitors of KRAS |
US11964989B2 (en) | 2022-07-20 | 2024-04-23 | Mirati Therapeutics, Inc. | KRas G12D inhibitors |
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