WO2023025320A1 - 含氮杂环类衍生物抑制剂、其制备方法和应用 - Google Patents
含氮杂环类衍生物抑制剂、其制备方法和应用 Download PDFInfo
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- WO2023025320A1 WO2023025320A1 PCT/CN2022/115479 CN2022115479W WO2023025320A1 WO 2023025320 A1 WO2023025320 A1 WO 2023025320A1 CN 2022115479 W CN2022115479 W CN 2022115479W WO 2023025320 A1 WO2023025320 A1 WO 2023025320A1
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- Prior art keywords
- alkyl
- alkoxy
- amino
- hydroxyalkyl
- group
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- 238000002360 preparation method Methods 0.000 title claims abstract description 185
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 201000011510 cancer Diseases 0.000 claims abstract description 8
- 229940121647 egfr inhibitor Drugs 0.000 claims abstract description 8
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 367
- -1 amino, hydroxy Chemical group 0.000 claims description 349
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 210
- 125000003118 aryl group Chemical group 0.000 claims description 183
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- 239000001257 hydrogen Substances 0.000 claims description 175
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 170
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- 229910052805 deuterium Inorganic materials 0.000 claims description 158
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 157
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 140
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- 125000003342 alkenyl group Chemical group 0.000 claims description 131
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- 125000004043 oxo group Chemical group O=* 0.000 claims description 115
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- 229910004845 P(O) Inorganic materials 0.000 claims description 64
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 63
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 62
- 238000006467 substitution reaction Methods 0.000 claims description 56
- 125000006708 (C5-C14) heteroaryl group Chemical group 0.000 claims description 53
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 49
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 39
- 102200048955 rs121434569 Human genes 0.000 claims description 37
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 35
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
- 102200048928 rs121434568 Human genes 0.000 claims description 24
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 21
- 230000035772 mutation Effects 0.000 claims description 20
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
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- 125000004429 atom Chemical group 0.000 claims description 18
- 239000011737 fluorine Substances 0.000 claims description 18
- 229910052731 fluorine Inorganic materials 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 16
- 239000000460 chlorine Substances 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 16
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims description 15
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- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
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- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
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- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 11
- 150000001345 alkine derivatives Chemical class 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 9
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 9
- 229910052698 phosphorus Inorganic materials 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 150000001336 alkenes Chemical class 0.000 claims description 7
- 239000011593 sulfur Substances 0.000 claims description 7
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 6
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 239000011574 phosphorus Substances 0.000 claims description 6
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- 125000004970 halomethyl group Chemical group 0.000 claims description 4
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- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims 3
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims 3
- VYCKDIRCVDCQAE-UHFFFAOYSA-N isoquinolin-3-amine Chemical compound C1=CC=C2C=NC(N)=CC2=C1 VYCKDIRCVDCQAE-UHFFFAOYSA-N 0.000 description 94
- 239000000243 solution Substances 0.000 description 85
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 73
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- 238000005481 NMR spectroscopy Methods 0.000 description 59
- 238000006243 chemical reaction Methods 0.000 description 59
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 49
- 230000002829 reductive effect Effects 0.000 description 48
- 102000001301 EGF receptor Human genes 0.000 description 42
- 108060006698 EGF receptor Proteins 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- 238000003786 synthesis reaction Methods 0.000 description 37
- 230000015572 biosynthetic process Effects 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
- 238000004440 column chromatography Methods 0.000 description 27
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- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 25
- 125000004432 carbon atom Chemical group C* 0.000 description 22
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- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 description 17
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- 125000006413 ring segment Chemical group 0.000 description 13
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- 210000004027 cell Anatomy 0.000 description 11
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical group C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 108091000080 Phosphotransferase Proteins 0.000 description 9
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- 238000012360 testing method Methods 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 206010059866 Drug resistance Diseases 0.000 description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
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- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
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- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
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- HNYWLFBFDMEHNC-PHDIDXHHSA-N (2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidine Chemical compound C[C@H]1NC[C@@H]1CS(=O)(=O)C HNYWLFBFDMEHNC-PHDIDXHHSA-N 0.000 description 4
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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 3
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- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- 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
- C07D471/22—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 systems contains four or more hetero rings
-
- 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
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- 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
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- 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
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- 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
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- 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
- C07D498/22—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 four or more hetero rings
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- 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
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Definitions
- the invention belongs to the field of biomedicine, and specifically relates to a nitrogen-containing heterocyclic derivative inhibitor, a preparation method and application thereof.
- EGFR Epidermal Growth Factor Receptor
- EGF epidermal growth factor
- TGF ⁇ transforming growth factor ⁇
- Activated EGFR forms homodimers on the cell membrane or heterodimers with other receptors in the family (such as ErbB-2, ErbB-3, or ErbB-4), causing critical intracellular tyrosine release of EGFR Phosphorylation of acid residues, thereby activating intracellular downstream signaling pathways, plays an important role in cell proliferation, survival and anti-apoptosis.
- Activating mutations, overexpression or gene amplification of EGFR can lead to excessive activation of EGFR, promote the transformation of cells into tumor cells, and play an important role in the proliferation, invasion, metastasis and angiogenesis of tumor cells. An important target for lung cancer drug development.
- the first-generation EGFR small molecule inhibitors including gefitinib (Iressa) and erlotinib (Tarceva) have shown good efficacy in the treatment of lung cancer and have been used as first-line drugs for the treatment of patients with EGFR activating mutations ( Non-small cell lung cancer (NSCLC) including L858R and delE746_A750).
- NSCLC Non-small cell lung cancer
- a secondary mutation of residue T790M results in.
- Osimertinib (Osimertinib or AZD9291) is a third-generation EGFR TKI inhibitor, which has a high response rate and good therapeutic effect against drug resistance caused by the EGFR T790M mutation, and was approved for marketing by the US FDA in November 2015. Clinically, it can effectively treat patients with advanced non-small cell lung cancer with EGFR T790M drug resistance mutation. Although osimertinib has achieved great success in the clinical treatment of EGFR T790M-mutated non-small cell lung cancer, patients still inevitably develop drug resistance after 9 to 14 months of treatment. Studies have shown that up to 20-40% of drug-resistant patients are resistant to EGFR C797S mutations.
- the EGFR C797S mutation changes the cysteine at position 797 to serine, resulting in the inability of osimertinib to form a covalent binding bond with the EGFR protein, thereby causing drug resistance.
- EGFR C797S drug resistance mutation there is no effective inhibitor against EGFR C797S drug resistance mutation. Therefore, it is urgent to develop new highly active EGFR inhibitors to solve the problem of drug resistance caused by EGFR C797S mutation.
- Lung cancer is a major disease that threatens human health, and the mortality rate of lung cancer ranks first among all malignant tumors.
- the incidence of lung cancer is increasing year by year, with about 700,000 new cases each year.
- the cases of lung cancer with EGFR activating mutations in my country account for about 35% of all NSCLC.
- the use of first-generation or third-generation EGFR inhibitors can achieve good therapeutic effects, but new drug-resistant mutations will occur later, so the development of new A generation of anti-drug-resistant EGFR inhibitors has great clinical and market value.
- the object of the present invention is to provide a compound represented by general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound structure represented by general formula (I) is as follows:
- Ring A, Ring B, Ring C and Ring D are each independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
- L 1 , L 2 and L 3 are each independently selected from a bond, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -(CH 2 ) n -, -(CH 2 ) n C(O)( CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR aa (CH 2 ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 -, -(CR aa R bb ) n O(CH 2 ) n1 -, -(CH 2 ) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n3 S(CH 2 ) n4 -, -(CH 2 ) n S(CR aa R bb ) n3 -,
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, hetero Cyclic group, aryl group, heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , the amino, alkyl , alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted; Or, wherein two R 1 are connected with atoms between them to form cycloalkyl, heterocyclyl, aryl and heteroaryl, described cycloalky
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, hetero Cyclic group, aryl group, heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , the amino, alkyl , alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, hetero Cyclic group, aryl group, heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , wherein the amino, alkyl Base, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, hetero Cyclic group, aryl group, heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , wherein the amino, alkyl
- the radical, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl can optionally be further substituted;
- one R2 and one R4 are connected with atoms between them to form cycloalkyl, heterocyclyl, aryl or heteroaryl, and said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally can be further replaced;
- R is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl
- the amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups can optionally be further substituted;
- R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally can be further replaced;
- x 0, 1, 2, 3, 4, 5 or 6;
- y is 0, 1, 2, 3, 4, 5 or 6;
- z 0, 1, 2, 3, 4, 5 or 6;
- w 0, 1, 2, 3, 4, 5 or 6;
- p, m, n, n1, n2, n3, n4 and n5 are each independently 0, 1, 2 or 3.
- the compound of formula (I) is further shown in general formula (I-1):
- M1 is N, CH;
- M 1-1 is N, CH;
- M3 is N, CH;
- M5 is N, CH;
- Ring D is selected from heteroaryl
- Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, hetero Cyclic group, aryl group, heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , the amino, alkyl , alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally can be further substituted; or, wherein two R 1 and between them The atoms are connected to form cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl can optionally be further
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, hetero Cyclic group, aryl group, heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , the amino, alkyl , alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
- R is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, haloalkyl, deuterated alkyl, alkenyl, alkynyl, alkoxy, deuterated alkoxy, haloalkane Oxygen or hydroxyalkyl; preferably hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, halogenated C 1-3 alkyl, deuterated C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, deuterated C 1-3 alkoxy, halogenated C 1-3 alkoxy or C 1-3 hydroxyalkyl;
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, hetero Cyclic group, aryl group, heteroaryl group, -OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , wherein the amino, alkyl Base, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally may be further substituted;
- R a is each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl Or heteroaryl, said amino, alkyl, alkenyl, alkynyl, alkoxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally can be further substituted;
- x 0, 1, 2, 3, 4, 5 or 6;
- y is 0, 1, 2, 3, 4, 5 or 6;
- z 0, 1, 2 or 3;
- w 0, 1, 2, 3, 4, 5 or 6;
- p, m and n5 are each independently 0, 1, 2 or 3.
- said compound of formula (I) is further such as general formula (II-A), (II-B), (II-C), (II-D), (II-E ) or (II-F):
- M1 is C, N, CH;
- M 2 is N, NH, CH, CH 2 , O or S;
- M3 is N, CH;
- M 4 is N, NH, CH, CH 2 , O or S;
- M5 is N, CH;
- M9 is N, CH;
- M 10 is N, CH;
- n1 0, 1, 2, 3 or 4.
- ring A is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl, wherein, 3-12
- the heteroatoms in the membered heterocyclic group and the 5-14 membered heteroaryl group are independently selected from nitrogen, oxygen, sulfur and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; or, ring A does not exist , L 1 and R 1 are directly connected;
- ring A is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl; wherein, 3-12 membered heterocyclic group and 5-
- the heteroatoms in the 14-membered heteroaryl are independently selected from nitrogen, oxygen, sulfur and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; preferably 4-10 membered heterocyclic groups; more preferably 4- 6-membered monocyclic heterocyclic group, 7-9 membered spirocyclic heterocyclic group or 8-10 membered condensed ring heterocyclic group;
- ring A is
- ring B is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; wherein, 3-12 The heteroatoms in the membered heterocyclic group and the 5-14 membered heteroaryl are independently selected from nitrogen, oxygen, sulfur and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; preferably 5-14 membered heteroaryl Aryl, the heteroaryl is a single ring or condensed ring; preferably 8-14 membered heteroaryl;
- Ring B 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
- ring B is
- Ring B is
- ring C is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; wherein, 3-12 The heteroatoms in the membered heterocyclic group and the 5-14 membered heteroaryl are independently selected from nitrogen, oxygen, sulfur and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; preferably 5-6 membered heteroatoms Aryl;
- ring C is
- ring C is
- ring D is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl or 5-14 membered heteroaryl; wherein, 3-12 The heteroatoms in the membered heterocyclic group and the 5-14 membered heteroaryl group are independently selected from nitrogen, oxygen, sulfur and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; preferably C 3-6 ring Alkyl, 5-8 membered heterocyclic group, 5-8 membered heteroaryl group;
- 5-membered heteroaryl 6-membered heteroaryl, 5-6-membered monocyclic heterocyclyl, 7-8-membered spirocyclic heterocyclyl or 7-8-membered fused-ring heterocyclyl;
- ring D is
- ring D is
- said compound of formula (I) is further such as general formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X):
- M1 is C, N, CH;
- M 2 is N, NH, CH, CH 2 , O or S;
- M3 is N, CH;
- M 4 is N, NH, CH, CH 2 , O or S;
- M5 is N, CH;
- M 7 is a bond, N, NH, CH;
- M 8 is NH, CH 2 , O or S
- M9 is N, CH;
- M 10 is N, CH;
- Ring E is a 4-10 membered heterocyclic group; preferably a 4-10 membered heterocyclic group containing 1-4 N, O, S or P;
- n1 0, 1, 2, 3 or 4;
- n2 is 1, 2 or 3;
- n3 is 1, 2, 3, 4, 5 or 6.
- R 1 is not substituted or unsubstituted -CH 2 S(O) 2 R a .
- R 1 is not -CH 2 S(O) 2 R a .
- R 1 is not -CH 2 S(O) 2 CH 3 , -CHCH 3 S (O) 2 CH 3 , —CH 2 S(O) 2 CH 2 CH 3 .
- ring E is selected from 4-6 membered monocyclic heterocyclyl, 7-9 membered spirocyclic heterocyclyl or 8-10 membered fused ring heterocyclyl; preferably
- the compound is further shown in general formula (VII-1) or (VIII-1):
- R 5 , R 6 , R 7 and R 8 are independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl; preferably, R 5 , R 6 , R 7 and R 8 independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkane Oxygen, C 1-3 haloalkoxy, C 1-6 hydroxyalkyl;
- n6 0, 1 or 2.
- R5 and R7 are independently methyl, ethyl, n-propyl or isopropyl, preferably isopropyl.
- R 8 is -OCH 2 CF 3 , -OCH 2 CHF 2 , -OCH 2 CH 2 F, -OCHFCF 3 , -OCF 2 CF 3 , preferably -OCH 2 CF 3 .
- n6 is zero.
- L 1 is selected from a bond, a substituted or unsubstituted C 2-6 alkenyl, a substituted or unsubstituted C 2-6 alkynyl, -(CH 2 ) n -, -( CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR aa (CH 2 ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 - , -(CR aa R bb ) n O(CH 2 ) n1 -, -(CH 2 ) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n3 S(CH 2 ) n4 -, - (CH 2 ) n S(CR aa R bbb
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkene Base, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5- 14-membered heteroaryl, -OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , the amino, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6- 14 aryl and 5-14 membered heteroaryl can optionally be further
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Base, C 1-6 alkoxyl group, C 1-6 hydroxyalkyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclic group, C 6-14 aryl group, 5-14 membered heteroaryl group, - OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , the amino, C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-
- the 14-membered heteroaryl can optional
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkyne Base, C 1-3 alkoxyl group, C 1-3 hydroxyalkyl group, C 3-8 cycloalkyl group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-12 membered heteroaryl group, - OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , the amino, C 1-3 alkyl, C 2-3 alkenyl , C 2-3 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-12
- the heteroaryl group optionally can be further replaced by hydrogen,
- C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl said C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further replaced by hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl , cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl .
- two R 1 are connected with atoms between them to form C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-12 aryl or 5-12 membered heteroaryl, said C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl can optionally be further replaced by hydrogen, deuterium, oxo, thio, halogen, amino, One or more of hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl replace.
- R 1 is independently selected from -NHS(O) 2 CH 3 , -NCH 3 S(O) 2 CH 3 , -CH 2 S(O) 2 N(CH 3 ) 2 , -CH 2 Se(O) 2 CH 3 , -CH 2 S(O) 2 CH 3 , -CH 2 SOCH 3 , -CH 2 NO 2 , methyl, hydrogen, Methoxy, cyano, -CH 2 OCH 3 , -CH 2 CN, -CH(CN) 2 , -S(O) 2 CH 3 , oxo, hydroxyl, -CH 2 COCH 3 , -COCH 3 , - CH 2 P(O)(CH 3 ) 2 ,
- R 1 is independently -CH 2 S(O) 2 N(CH 3 ) 2 , -CH 2 Se(O) 2 CH 3 , -CH 2 S(O) 2 CH 3 , methyl, hydrogen, Methoxy, cyano, -CH 2 OCH 3 , -CH 2 CN, -CH(CN) 2 , -S(O) 2 CH 3 , oxo, hydroxyl, -CH 2 COCH 3 , -COCH 3 , - CH 2 P(O)(CH 3 ) 2 ; or, wherein two R 1 are connected with atoms between them to form a 3-12 membered heterocyclic group, preferably
- R 1 is independently -CH 2 S(O) 2 CH 3 , methyl, hydrogen, Methoxy, cyano, -CH 2 OCH 3 , -CH 2 CN, -S(O) 2 CH 3 , oxo, hydroxyl, -CH 2 COCH 3 , -COCH 3 , -CH 2 P(O)( CH 3 ) 2 ; or, wherein two R 1 are connected with atoms between them to form a 3-12 membered heterocyclic group, preferably
- R 1 is independently -CH 2 S(O) 2 CH 3 , methyl, hydrogen, or _ _ _ _ _ _ _ _ _ , wherein two R 1 are connected with atoms between them to form a 3-12 membered heterocyclic group, preferably
- L 2 is selected from a bond, a substituted or unsubstituted C 2-6 alkenyl, a substituted or unsubstituted C 2-6 alkynyl, -(CH 2 ) n -, -( CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR aa (CH 2 ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 - , -(CR aa R bb ) n O(CH 2 ) n1 -, -(CH 2 ) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n3 S(CH 2 ) n4 -, - (CH 2 ) n S(CR aa R bbb
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C alkyl , C alkene Base, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5- 14-membered heteroaryl, -OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , the amino, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12
- R2 is independently oxo, fluoro, isopropyl, cyano, trifluoromethyl, -NHCH(CH) 3 , -OCH2CF3 .
- L 3 is selected from a bond, a substituted or unsubstituted C 2-6 alkenyl, a substituted or unsubstituted C 2-6 alkynyl, -(CH 2 ) n -, -( CH 2 ) n C(O)(CR aa R bb ) n1 -, -(CH 2 ) n C(O)NR aa (CH 2 ) n1 -, -(CH 2 ) n (CR aa R bb ) n2 - , -(CR aa R bb ) n O(CH 2 ) n1 -, -(CH 2 ) n O(CR aa R bb ) n1 -, -(CR aa R bb ) n3 S(CH 2 ) n4 -, - (CH 2 ) n S(CR aa R bbb )
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkene Base, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5- 14-membered heteroaryl, -OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , the amino, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalky
- R 3 is independently selected from hydrogen, methoxy, methoxy, fluoro, chloro, bromo, trifluoromethyl, cyano, cyclopropyl or -COCH 3 .
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkene Base, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5- 14-membered heteroaryl, -OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , the amino, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6- 14 aryl and 5-14 membered heteroaryl optionally can be
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkene Base, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl, 5- 12-membered heteroaryl, -OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , the amino, C 1-3 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy , C 1-3 hydroxyalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6- 12 aryl and 5-12 membered heteroaryl optionally can be further
- R 4 is independently fluoro, methyl, hydroxyl, methoxy, -OCD 3 , -CH 2 F, -CHF 2 , CH 2 CF 3 , -CH 2 CH 2 F , hydrogen, -CH 2 OCH 3 , -CF 3 , amino, oxo, -COCH 3 ,
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkene Base, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5- 14-membered heteroaryl, -OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , the amino, C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalky
- R is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkyne Base, C 1-3 alkoxyl group, C 1-3 hydroxyalkyl group, C 3-10 cycloalkyl group, 3-10 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group, - OR a , -P(O) p (R a ) n5 , -S(O) m R a or -C(O)R a , the amino, C 1-3 alkyl, C 2-3 alkenyl , C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-10 cycloalkyl , 3-10 membered heterocyclyl, C 6-12 aryl and 5-12
- the heteroaryl group optionally can be further replaced by hydrogen
- R4 is independently selected from fluoro, chloro, cyano, trifluoromethyl, methyl, ethyl, nitro, hydroxyl, methoxy, -OCD3 , hydrogen, Cyclopropyl, Difluoromethyl,
- the C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl and 5-14 membered heteroaryl can optionally be further substituted by hydrogen, deuterium, oxo , Thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-12 aromatic One or more substitutions in radicals, 5-12 membered heteroaryl groups;
- R a is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl,
- the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5-14 membered heteroaryl can optionally be further replaced by hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl
- R a is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 Alkoxy, C 1-3 hydroxyalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-12 aryl, 5-12 membered heteroaryl, the amino, C 1 -3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group , C 6-12 aryl, 5-12 membered heteroaryl can optionally be further replaced by hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 deuterated alky
- R aa , R bb and R cc are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-14 aryl, 5 -14-membered heteroaryl, the amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl, 5-14 membered heteroaryl can optionally be further replaced by hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl , cyano, nitro, C 1-6 alkyl,
- R aa , R bb are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-12 aryl, 5-12 membered heteroaryl, the described Amino, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl , C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-10 cycloalkyl, 3-10 Member heterocyclic group, C 6-12 aryl, 5-12 member heteroaryl can optionally be further replaced by hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1- 3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C C 1-3 alk
- the compound is further shown in general formula (VII-2):
- M 11 is CH or N
- R 1-1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halomethyl, haloethyl;
- R 1-2 is selected from amino, hydroxyl, cyano, C 1-3 alkoxy, C 1-3 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, the amino, C 1-3 alkoxy, C 1-3 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group can optionally be further replaced by hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl , cyano, nitro, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1 -3 hydroxyalkyl, -C(O)R ee , -OR ee , -P(O) p (R ee ) n5 , -S(O) m R ee , -S(O) 2 N(R ee ) 2 and one or
- R is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, halomethyl, haloethyl;
- R 2-1 is selected from amino, C 1-3 alkyl, halogenated C 1-3 alkyl or deuterated C 1-3 alkyl, the amino, C 1-3 alkyl, halogenated C 1- 3 Alkyl and deuterated C 1-3 alkyl optionally can be further deuterium, halogen, cyano, hydroxyl, nitro, C 1-3 alkyl, halogenated C 1-3 alkyl or deuterated C 1 One or more substitutions in -3 alkyl groups;
- R is selected from halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -S(O) m R d or -C(O) R d , the amino, C 1-3 alkyl, C 1 -3 alkoxyl group, C 1-3 hydroxyalkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 3-6 cycloalkyl group and 3-8 membered heterocyclic group can optionally be further replaced by one or multiple R 4-1 substitutions;
- R 4-1 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl , 3-8 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
- R 4-1 is replaced by hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano Base, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, Halogenated C 1-3 alkoxy, C 1-3
- R 6-1 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 deuterated alkyl , C 1-3 alkoxy, C 1-3 hydroxyalkyl;
- R6-2 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -S(O) m Re or -C(O) Re , the amino, C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl can optionally be further replaced by deuterium, halogen, amino, hydroxyl, cyano, nitro and C 1- One or more substitutions in 3 alkyl groups;
- R d is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl , 3-6 membered heterocyclic group, C 1-3 haloalkyl or C 1-3 deuterated alkyl;
- R is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl , 3-6 membered heterocyclic group, C 1-3 haloalkyl or C 1-3 deuterated alkyl;
- R ee is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl , 3-6 membered heterocyclic group, C 1-3 haloalkyl or C 1-3 deuterated alkyl;
- n 0, 1 or 2;
- p 0, 1 or 2;
- n5 is 0, 1 or 2;
- y is 0, 1, 2, 3 or 4.
- the compound is further shown in general formula (VII-3):
- M 12 is selected from bond, NR 9 or CR 10 R 11 ;
- R is selected from hydrogen, deuterium, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl;
- R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl;
- R is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl;
- R 1-1 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl;
- R is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, monofluoromethyl, difluoromethyl or trifluoromethyl;
- R 2-1 is selected from amino, C 1-3 alkyl, halogenated C 1-3 alkyl or deuterated C 1-3 alkyl, the amino, C 1-3 alkyl, halogenated C 1- 3 alkyl or deuterated C 1-3 alkyl optionally can be further deuterium, halogen, cyano, hydroxyl, nitro, C 1-3 alkyl, halogenated C 1-3 alkyl and deuterated C 1 One or more substitutions in -3 alkyl groups;
- R 2-1 is selected from isopropyl, -CH(Me)OMe, or -N(Me) 2 ;
- R is selected from halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -S(O) m R d or -C(O) R d , the amino, C 1-3 alkyl, C 1 -3 alkoxyl group, C 1-3 hydroxyalkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 3-6 cycloalkyl group and 3-8 membered heterocyclic group can optionally be further replaced by one or multiple R 4-1 substitutions;
- R 4-1 is independently selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl , 3-8 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
- R 4-1 is replaced by hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano Base, nitro, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, Halogenated C 1-3 alkoxy, C 1-3
- R 6-1 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl ;
- R 6-2 is selected from hydrogen, deuterium, oxo, thio, halogen, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl , C 3-6 cycloalkyl, 3-6 membered heterocyclic group, -S(O) m Re or -C(O) Re , the amino, C 1-3 alkyl, C 1-3 Alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl and 3-8 membered heterocyclyl can optionally be further replaced by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- One or more substitutions in 3 alkyl groups;
- R d is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl , 3-6 membered heterocyclic group, C 1-3 haloalkyl, C 1-3 deuterated alkyl;
- R is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl , 3-6 membered heterocyclic group, C 1-3 haloalkyl, C 1-3 deuterated alkyl;
- n 0, 1 or 2;
- y is 0, 1, 2, 3 or 4.
- the present invention further relates to the application of the above-mentioned compounds of the general formulas, their stereoisomers or pharmaceutically acceptable salts thereof in the preparation of EGFR inhibitor drugs.
- the present invention further relates to the use of the compounds of the above general formulas, their stereoisomers or pharmaceutically acceptable salts thereof in the preparation of medicines for treating cancer; wherein the cancer is non-small cell lung cancer.
- the present invention also relates to a method for the prevention and/or treatment of EGFR-related diseases, which comprises administering therapeutically effective doses of the compounds of the general formula, their stereoisomers or pharmaceutically acceptable salts thereof to patients.
- the EGFR-related disease is non-small cell lung cancer.
- the EGFR is a mutated EGFR, preferably one or more mutations in Del19, L858R, T790M or C797S, more preferably Del19, L858R, L858R/T790M, Del19/T790M, Del19 /C797S, L858R/C797S, Del19/T790M/C797S, or L858R/T790M/C797S mutated EGFR.
- the cancer is EGFR Del19, L858R, L858R/T790M, Del19/T790M, Del19/C797S, L858R/C797S, Del19/T790M/C797S or L858R/T790M/C797S mutated cancer .
- alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms An alkyl group, most preferably an alkyl group of 1 to 3 carbon atoms.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
- lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl group, 2,3-dimethylbutyl group, etc.
- Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl in the present invention , deuterated alkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.
- alkylene means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene” means -CH 2 -, "ethylene” means -(CH 2 ) 2 -, “propylene” refers to -(CH 2 ) 3 -, “butylene” refers to -(CH 2 ) 4 -, and the like.
- alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- -butenyl etc.
- Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
- cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, preferably containing 3 to 8 Carbon atoms, more preferably contain 3 to 6 carbon atoms.
- Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene group, cyclooctyl group, etc.; polycyclic cycloalkyl group includes spiro ring, fused ring and bridged ring cycloalkyl group, preferably cyclopropyl group, cyclobutyl group, cyclohexyl group, cyclopentyl group and cycloheptyl group.
- spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
- spirocycloalkyl groups include:
- spirocycloalkyls in which a single spirocycloalkyl shares a spiro atom with a heterocycloalkyl, non-limiting examples include:
- fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
- it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
- fused cycloalkyl groups include:
- bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
- bridged cycloalkyl groups include:
- the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
- Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
- heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, P(O) pp or S (O) mm (where pp, mm are integers 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon.
- Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazolyl, Hydrogen pyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azeptyl, 1,4-diazepanyl, pyranyl, etc., preferably pyrrolidine morpholinyl, piperidinyl, azepanyl, 1,4-diazepanyl and piperazinyl.
- Polycyclic heterocyclic groups include spiro rings, fused rings and bridged ring heterocyclic groups; the spiro rings, condensed rings and bridged ring heterocyclic groups involved are optionally connected to other groups through single bonds, or through rings Any two or more atoms on the ring are further linked with other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.
- spiroheterocyclic group refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen, P(O ) pp or S(O) mm (where pp, mm are integers from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclic group.
- spiroheterocyclyls include:
- fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated ⁇ -electron system, where one or more ring atoms are selected from nitrogen, oxygen, P(O) pp or S(O) mm (where pp, mm are integers from 0 to 2), the remaining ring atoms are carbon.
- it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
- fused heterocyclic groups include:
- bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond.
- the ⁇ -electron system of the yoke wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, P(O) pp or S(O) mm (where pp, mm are integers from 0 to 2), and the remaining ring atoms are carbon.
- it is 6 to 14 yuan, more preferably 7 to 10 yuan.
- bridged heterocyclyl groups include:
- the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
- Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
- aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 12 membered, having a conjugated pi-electron system, such as benzene base and naphthyl. Phenyl is more preferred.
- the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered Heteroalkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclic group contains 1-3 nitrogen atoms, oxygen atoms, A heterocyclic group with a sulfur atom; or a three-membered nitrogen-containing condensed ring containing a benzene ring.
- ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
- Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
- heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
- Heteroaryl is preferably 5 to 12, more preferably 8 to 11, 5 or 6, for example imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazole Base, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidyl or thiazolyl; more preferably Pyrazolyl, pyrrolyl and oxazolyl.
- the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where
- Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
- alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as above, preferably alkyl containing 1 to 8 carbon atoms, more preferably An alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms.
- alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
- Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
- the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
- Haloalkyl means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
- Haloalkoxy means an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
- Hydroalkyl means an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
- Alkenyl means an alkenyl group, also known as an alkenyl group, preferably an alkyl group containing 2 to 8 carbon atoms, more preferably an alkyl group containing 2 to 6 carbon atoms, and most preferably an alkyl group containing 2 to 3 carbon atoms .
- alkenyl mentioned therein can be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
- other related groups for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
- Alkynyl refers to (CH ⁇ C-), preferably an alkyl group containing 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, most preferably 2 to 3 carbon atoms.
- the alkynyl mentioned therein can be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
- alkenylcarbonyl refers to -C(O)-(alkenyl), wherein alkenyl is as defined above.
- alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl.
- Alkenylcarbonyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
- Haldroxy means an -OH group.
- Halogen means fluorine, chlorine, bromine or iodine.
- Amino refers to -NH2 .
- Cyano refers to -CN.
- Niro refers to -NO2 .
- Carbonyl refers to -C(O)-.
- Carboxy refers to -C(O)OH.
- THF tetrahydrofuran
- EtOAc means ethyl acetate
- MeOH means methanol
- DMF N,N-dimethylformamide
- DIPEA diisopropylethylamine
- TFA trifluoroacetic acid
- MeCN refers to acetonitrile
- DMA refers to N,N-dimethylacetamide.
- Et2O means diethyl ether
- DCE 1,2 dichloroethane
- DIPEA N,N-diisopropylethylamine
- NBS N-bromosuccinimide
- NIS N-iodosuccinimide
- Cbz-Cl refers to benzyl chloroformate
- Pd 2 (dba) 3 refers to tris(dibenzylideneacetone)dipalladium.
- Dppf refers to 1,1'-bisdiphenylphosphinoferrocene.
- HATU refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
- KHMDS refers to potassium hexamethyldisilazide
- LiHMDS refers to lithium bistrimethylsilylamide.
- MeLi means methyllithium
- n-BuLi refers to n-butyllithium
- NaBH(OAc) 3 refers to sodium triacetoxyborohydride.
- X is selected from A, B, or C
- X is selected from A, B, and C
- X is A, B, or C
- X is A, B, and C
- the hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by a deuterium atom.
- Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
- a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
- Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
- Multiple in “replaced by...one or more” can mean 2, 3, 4, 5, 6 or more than 6.
- linking substituents are described.
- the Markush variables recited for that group are to be understood as linking groups.
- the Markush group definition for that variable recites “alkyl” or “aryl,” it is understood that “alkyl” or “aryl” respectively represents the linking group.
- “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
- the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
- the determination of NMR is to use Bruker AVANCE-400 nuclear magnetic apparatus, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard is four Methylsilane (TMS).
- Agilent 1200 Infinity Series mass spectrometer was used for liquid chromatography-mass chromatography LC-MS determination.
- the determination of HPLC uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150 ⁇ 4.6mm chromatographic column).
- Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates.
- the specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin-layer chromatography separation and purification products are 0.4mm-0.5mm.
- Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
- the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or following methods known in the art.
- tert-Butyl 3-(iodomethyl)azetidine-1-carboxylate (2 g, 6.73 mmol) and sodium methylthiolate (970 mg, 13.50 mmol) were dissolved in ACN (15 mL) and H 2 O (5 mL) , raised to 60°C for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure and separated by column chromatography to obtain the target compound tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate (1.30 g, 88.9%).
- the second step is the synthesis of tert-butyl 3-((methylsulfonyl)methyl)azetidine-1-carboxylate
- the third step is the synthesis of 3-((methylsulfonyl)methyl)azetidine trifluoroacetate
- the second step is the synthesis of methyl (R)-2-((2S,3R)-1-benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl) acetate
- reaction solution was cooled to room temperature, quenched with saturated ammonium chloride solution, ethyl acetate and water solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the target compound methyl (R)-2- ((2S,3R)-1-Benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate (12 g, 79.0%).
- the third step is the synthesis of (2S,3R)-1-benzhydryl-2-methyl-3-((methylsulfonyl)methyl)azetidine
- the second step is the synthesis of tert-butyl 3-fluoro-3-methyl-4-carbonylpiperidine-1-carboxylate
- the third step is the synthesis of tert-butyl 3-fluoro-4-hydroxyl-3-methylpiperidine-1-carboxylate
- the fourth step is the synthesis of 3-fluoro-3-methylpiperidin-4-ol
- the purified product 1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol was purified by a reverse phase column to obtain two fractions, respectively Concentrated and freeze-dried to obtain cis racemate (3S, 4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (2.20 g) and trans racemate (3R,4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (1.40g) .
- the second step is the synthesis of methyl (S)-2-((2R,3S)-1-benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate
- reaction solution was cooled to room temperature, quenched with saturated ammonium chloride solution, ethyl acetate and water solution, the organic phase was dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to obtain the target compound methyl (S)-2-(( 2R,3S)-1-Benzhydryl-2-methylazetidin-3-yl)-2-(methylsulfonyl)acetate (11.60 g, 77.5%).
- the third step is the synthesis of (2R,3S)-1-benzhydryl-2-methyl-3-((methylsulfonyl)methyl)azetidine
- 1,3-Dichloro-6-fluoroisoquinoline (7.50g, 34.72mmol) was dissolved in glacial acetic acid (40mL) and hydroiodic acid (20mL, 45% aqueous solution), heated to 100°C for 4 hours. Cool the reaction solution to room temperature, concentrate the reaction solution, add dichloromethane (100mL) to dilute, wash with saturated aqueous sodium carbonate solution, separate the organic phase and dry it with anhydrous sodium sulfate, filter, concentrate the organic solvent under reduced pressure, and separate by column chromatography to obtain The target compound 3-chloro-6-fluoroisoquinoline (4.90 g, 77.8%).
- the second step is the synthesis of 5-bromo-3-chloro-6-fluoroisoquinoline
- the third step is the synthesis of 3-chloro-6-fluoro-5-(prop-1-en-2-yl)isoquinoline
- reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound 3-chloro-6-fluoro-5-(prop-1-en-2-yl)isoquinoline (3.0g, 88.1% ).
- the second step is the synthesis of 8-bromo-3-chloro-5-(prop-1-en-2-yl)isoquinoline
- reaction solution was cooled to room temperature, the reaction solution was concentrated, dichloromethane and water solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the target compound 8-bromo-3-chloro-5-(propane- 1-en-2-yl)isoquinoline (2.90 g, 61.7%).
- the third step is the synthesis of 8-bromo-3-chloro-5-isopropylisoquinoline
- the fourth step is the synthesis of 3-chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline
- reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, dichloromethane and water solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the target compound 3-chloro-5-isopropyl-8 -(3-((Methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (286 mg, 46.0%).
- the second step is the synthesis of 2-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-amine
- the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and dichloromethane and water solution were used, and the organic phase was dried with anhydrous sodium sulfate. After the organic solvent was concentrated under reduced pressure, the target compound 2-(1-(cyclo Propylsulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-amine (500 mg, 75.7%).
- reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, dichloromethane and water solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by column chromatography to obtain the target compound N-(2-(1-(cyclopropane Sulfonyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)iso Quinolin-3-amine (31.2 mg, 19.2%).
- Cyclopropyl(4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl) Refer to Reference Example 1 for the preparation method of isoquinolin-3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)methanone.
- the third step is the synthesis of 2-(3-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-amine
- the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, dichloromethane and water solution were used, the organic phase was dried with anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the target compound N-(2-(3 -Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-( (2R,3S)-2-Methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (81 mg, 45.7%).
- reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, dichloromethane and water solution were used, the organic phase was dried with anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the target compound N-(2-(3 -Chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl) Azetidin-1-yl)isoquinolin-3-amine (31 mg, 49.1%).
- N-(2-(3-chloro-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-(( Methanesulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine (57.9mg, 0.11mmol) was dissolved in DMF (2mL), cesium carbonate (107.5mg, 0.33mmol) was added, and the temperature was raised to 40 °C for 12 hours.
- the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, dichloromethane and water solution were used, the organic phase was dried with anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the target compound 2-(3-chloro- 4-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline- 3-yl)amino)pyrimidin-2-yl)-1H-pyrazol-1-yl)ethanol (21.1 mg, 33.6%).
- reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, dichloromethane and water solution, the organic phase was dried with anhydrous sodium sulfate, and the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the target compound 3-chloro-5-isopropyl yl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (318 mg, 49.2%).
- the second step is the synthesis of 2-(1-cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-amine
- 2-Chloropyrimidin-4-amine (1.29g, 10mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- base)-1H-pyrazole (2.58g, 11mmol) and potassium carbonate (3.46g, 25mmol) were mixed in dioxane (20mL) and water (2mL), and bistriphenylphosphine palladium dichloride (702mg , 1 mmol), heated to 100°C and stirred for 12 hours.
- reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and dichloromethane and water solution were used, the organic phase was dried with anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the target compound 2-(1-cyclopropane yl-1H-pyrazol-4-yl)pyrimidin-4-amine (1.05 g, 52.2%).
- the reaction solution was cooled to room temperature, the reaction solution was concentrated under reduced pressure, dichloromethane and water solution were used, the organic phase was dried with anhydrous sodium sulfate, the organic solvent was concentrated under reduced pressure and separated by column chromatography to obtain the target compound N-(2-(1 -Cyclopropyl-1H-pyrazol-4-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl yl)azetidin-1-yl)isoquinolin-3-amine (31 mg, 21.6%).
- the preparation method of sulfinyl>)methyl)azetidin-1-yl)isoquinolin-3-amine refers to Example 15.
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Abstract
Description
Claims (16)
- 一种如通式(II-A)所示的化合物、其立体异构体或其药学上可接受盐:其中:M 1为N、CH;M 3为N、CH;环D选自杂芳基;环A选自环烷基、杂环基、芳基或杂芳基;R 1独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR a、-P(O) p(R a) n5、-S(O) mR a或-C(O)R a,所述的氨基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;或者,其中两个R 1与他们之间的原子相连形成环烷基、杂环基、芳基或杂芳基,所述的环烷基、杂环基、芳基和杂芳基任选地可以进一步被取代;R 2独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR a、-P(O) p(R a) n5、-S(O) mR a或-C(O)R a,所述的氨基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;R 4独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR a、-P(O) p(R a) n5、-S(O) mR a或-C(O)R a,其中所述的氨基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;R a各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基,所述的氨基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;x为0、1、2、3、4、5或6;y为0、1、2、3、4、5或6;w为0、1、2、3、4、5或6;p、m和n5各自独立地为0、1、2或3。
- 一种如通式(VII)化合物、其立体异构体或其药学上可接受盐:其中,M 3为N、CH;M 5为N、CH;环E为4-10元杂环基;优选含1-4个N、O、S或P的4-10元杂环基;R 1独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR a、-P(O) p(R a) n5、-S(O) mR a或-C(O)R a,所述的氨基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;或者,其中两个R 1与他们之间的原子相连形成环烷基、杂环基、芳基或杂芳基,所述的环烷基、杂环基、芳基和杂芳基任选地可以进一步被取代;R 2独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR a、-P(O) p(R a) n5、-S(O) mR a或-C(O)R a,所述的氨基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;R 4独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、烷 基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR a、-P(O) p(R a) n5、-S(O) mR a或-C(O)R a,其中所述的氨基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;R a各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基或杂芳基,所述的氨基、烷基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基,任选地可以进一步被取代;x为0、1、2、3、4、5或6;y为0、1、2、3、4、5或6;w为0、1、2、3、4、5或6;p、m和n5各自独立地为0、1、2或3。
- 根据权利要求4所述的化合物、其立体异构体或其药学上可接受盐,其特征在于,进一步如通式(VII-1)所示:其中,R 5选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基或C 1-6羟烷基;优选地,R 5选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3卤代烷氧基或C 1-6羟烷基;R 6独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基或C 1-6羟烷基;优选地,R 6独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3卤代烷氧基或C 1-6羟烷基;n6为0、1或2。
- 根据权利要求1~6任一项所述的各通式化合物、其立体异构体或其药学上可接受盐,其特征在于,R 1独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-OR a、-P(O) p(R a) n5、-S(O) mR a或-C(O)R a,所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基、-OR aa、-P(O) p(R aa) n5、-S(O) mR aa、 -Se(O) mR aa或-C(O)R aa中的一个或多个取代;或者,其中两个R 1与他们之间的原子相连形成C 3-12环烷基、3-12元杂环基、C 6-14芳基或5-14元杂芳基,所述的C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基中的一个或多个取代;优选地,R 1独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-OR a、-P(O) p(R a) n5、-S(O) mR a或-C(O)R a,所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基、-OR aa、-P(O) p(R aa) n5、-S(O) mR aa或-C(O)R aa中的一个或多个取代;或者,其中两个R 1与他们之间的原子相连形成C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,所述的C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基,任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基中的一个或多个取代;更优选地,R 1独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-8环烷基、3-10元杂环基、C 6-10芳基、5-12元杂芳基、-OR a、-P(O) p(R a) n5、-S(O) mR a或-C(O)R a,所述的氨基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-8环烷基、3-10元杂环基、C 6-10芳基和5-12元杂芳基,任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基、5-10元杂芳基、-OR aa、-P(O) p(R aa) n5、-S(O) mR aa或-C(O)R aa中的一个或多个取代;更进一步优选地,R 1独立地选自-NHS(O) 2CH 3、-NCH 3S(O) 2CH 3、-CH 2S(O) 2N(CH 3) 2、-CH 2Se(O) 2CH 3、-CH 2S(O) 2CH 3、-CH 2SOCH 3、-CH 2NO 2、甲基、氢、 甲氧基、氰基、-CH 2OCH 3、-CH 2CN、-CH(CN) 2、-S(O) 2CH 3、氧代、羟基、-CH 2COCH 3、-COCH 3、-CH 2P(O)(CH 3) 2、R aa各自独立的选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基,所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基,任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基中的一个或多个取代;优选地,R aa各自独立的选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-10环烷基、3-8元杂环基、C 6-12芳基、5-12元杂芳基,所述的氨基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-8环烷基、3-10元杂环基、C 6-12芳基、5-12元杂芳基,任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基、5-10元杂芳基中的一个或多个取代。
- 根据权利要求1~7任一项所述的各通式化合物、其立体异构体或其药学上可接受盐,其特征在于,R 2独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-OR a、-P(O) p(R a) n5、-S(O) mR a或-C(O)R a,所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基、-OR aa、-P(O) p(R aa) n5、-S(O) mR aa或-C(O)R aa中的一个或多个取代;优选地,R 2独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-10环烷基、3-10元杂环基、C 6-12芳基、5-12元杂芳基、-OR a、-P(O) p(R a) n5、-S(O) mR a或-C(O)R a,所述的氨基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-10环烷基、3-10元杂环基、C 6-12芳基和5-12元杂芳基任选地可以进一步被氢、氘、 氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-2烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-10元杂芳基、-OR aa、-P(O) p(R aa) n5、-S(O) mR aa或-C(O)R aa中的一个或多个取代;R aa各自独立的选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基,所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基中的一个或多个取代;优选地,R aa各自独立的选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-8环烷基、3-8元杂环基、C 6-12芳基、5-12元杂芳基,所述的氨基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-8环烷基、3-8元杂环基、C 6-12芳基、5-12元杂芳基任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基、5-10元杂芳基中的一个或多个取代。
- 根据权利要求1~8任一项所述的各通式化合物、其立体异构体或其药学上可接受盐,其特征在于,R 4独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-OR a、-P(O) p(R a) n5、-S(O) mR a或-C(O)R a,所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基任选地可以进一步被一个或多个R 4-1取代;R 4-1各自独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基、-OR aa、-P(O) p(R aa) n5、-S(O) mR aa或-C(O)R aa;任选地,R 4-1被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基中的一个或多个取代,其中, 氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基,任选地被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基中的一个或多个取代;优选地,R 4独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-4烯基、C 2-4炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-10环烷基、3-10元杂环基、C 6-12芳基、5-12元杂芳基、-OR a、-P(O) p(R a) n5、-S(O) mR a或-C(O)R a,所述的氨基、C 1-3烷基、C 2-4烯基、C 2-4炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-10环烷基、3-10元杂环基、C 6-12芳基和5-12元杂芳基任选地可以进一步被一个或多个R 4-1取代;R 4-1各自独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-4烯基、C 2-4炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-10环烷基、3-10元杂环基、C 6-12芳基、5-12元杂芳基、-OR aa、-P(O) p(R aa) n5、-S(O) mR aa或-C(O)R aa;任选地,R 4-1被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-4烯基、C 2-4炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-10环烷基、3-10元杂环基、C 6-12芳基、5-12元杂芳基中的一个或多个取代,其中,氨基、C 1-3烷基、C 2-4烯基、C 2-4炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基,任选地被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-4烯基、C 2-4炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基中的一个或多个取代;或者,R 4独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基、-OR a、-P(O) p(R a) n5、-S(O) mR a或-C(O)R a,所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基和5-14元杂芳基任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基、-OR aa、-P(O) p(R aa) n5、-S(O) mR aa或-C(O)R aa中的一个或多个取代;R aa各自独立的选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基,所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6 烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基中的一个或多个取代;优选地,R aa各自独立的选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-8环烷基、3-8元杂环基、C 6-12芳基、5-12元杂芳基,所述的氨基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-8环烷基、3-8元杂环基、C 6-12芳基、5-12元杂芳基任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-8环烷基、3-8元杂环基、C 6-10芳基、5-10元杂芳基中的一个或多个取代;
- 根据权利要求1~9任一项所述的各通式化合物、其立体异构体或其药学上可接受盐,其特征在于,R a各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基,所述的氨基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-14芳基、5-14元杂芳基任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6烷氧基、卤代C 1-6烷氧基、 C 1-6羟烷基、C 3-12环烷基、3-12元杂环基、C 6-12芳基、5-12元杂芳基中的一个或多个取代取代;优选地,R a各自独立地选自氢、氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-10环烷基、3-10元杂环基、C 6-12芳基、5-12元杂芳基,所述的氨基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-10环烷基、3-10元杂环基、C 6-12芳基、5-12元杂芳基任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-3烯基、C 2-3炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-10元杂芳基中的一个或多个取代。
- 根据权利要求1所述的化合物、其立体异构体或其药学上可接受盐,其特征在于,进一步如通式(VII-2)所示:其中,M 11为CH或N;R 1-1选自氢、氘、氟、氯、溴、甲基、乙基、卤代甲基、卤代乙基;R 1-2选自氨基、羟基、氰基、C 1-3烷氧基、C 1-3烷基、C 3-6环烷基、3-8元杂环基,所述的氨基、C 1-3烷氧基、C 1-3烷基、C 3-6环烷基、3-8元杂环基任选地可以进一步被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、-C(O)R ee、-OR ee、-P(O) p(R ee) n5、-S(O) mR ee、-S(O) 2N(R ee) 2和-S(=O)(=NCN)R ee中的一个或多个取代;优选地,R 1-2选自-NHS(O) 2CH 3、-NCH 3S(O) 2CH 3、-CH 2S(O) 2N(CH 3) 2、-CH 2S(O) 2CH 3、-CH 2SOCH 3、-CH 2NO 2、甲基、氢、 甲氧基、氰基、-CH 2OCH 3、-CH 2CN、-CH(CN) 2、羟基、-CH 2COCH 3、R 2独立地选自氢、氘、氟、氯、溴、甲基、乙基、卤代甲基、卤代乙基;R 2-1选自氨基、C 1-3烷基、卤代C 1-3烷基或氘代C 1-3烷基,所述的氨基、C 1-3烷基、卤代C 1-3烷基和氘代C 1-3烷基任选地可以进一步被氘、卤素、氰基、羟基、硝基、C 1-3烷基、卤代C 1-3烷基或氘代C 1-3烷基中的一个或多个取代;R 4选自卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3烷氧基、C 1-3羟烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-8元杂环基、-S(O) mR d或-C(O)R d,所述的氨基、C 1-3烷基、C 1-3烷氧基、C 1-3羟烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基和3-8元杂环基任选地可以进一步被一个或多个R 4-1取代;R 4-1独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-4烯基、C 2-4炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、3-8元杂环基、C 6-12芳基或5-12元杂芳基;任选地,R 4-1被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-4烯基、C 2-4炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、3-8元杂环基、C 6-12芳基、5-12元杂芳基中的一个或多个取代,其中,氨基、C 1-3烷基、C 2-4烯基、C 2-4炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基,任选地被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-4烯基、C 2-4炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基中的一个或多个取代;优选地,R 4选自氟、氯、氰基、三氟甲基、甲基、乙基、硝基、羟基、甲氧基、-OCD 3、氢、 环丙基、 二氟甲基、R 6-1选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、 C 1-3卤代烷基、C 1-3氘代烷基、C 1-3烷氧基、C 1-3羟烷基;R 6-2选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、3-6元杂环基、-S(O) mR e或-C(O)R e,所述的氨基、C 1-3烷基、C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基和3-6元杂环基任选地可以进一步被氘、卤素、氨基、羟基、氰基、硝基和C 1-3烷基中的一个或多个取代;R d独立地选自氢、氘、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、3-6元杂环基、C 1-3卤代烷基或C 1-3氘代烷基;R e独立地选自氢、氘、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、3-6元杂环基、C 1-3卤代烷基或C 1-3氘代烷基;R ee独立地选自氢、氘、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、3-6元杂环基、C 1-3卤代烷基或C 1-3氘代烷基;m为0、1或2;p为0、1或2;n5为0、1或2;y为0、1、2、3或4。
- 根据权利要求11所述的各通式化合物、其立体异构体或其药学上可接受盐,其特征在于,进一步如通式(VII-3)所示:其中,M 12选自键、NR 9或CR 10R 11;R 9选自氢、氘、甲基、乙基、一氟甲基、二氟甲基或三氟甲基;R 10选自氢、氘、氟、氯、溴、甲基、乙基、一氟甲基、二氟甲基或三氟甲基;R 11选自氢、氘、氟、氯、溴、甲基、乙基、一氟甲基、二氟甲基或三氟甲基;R 1-1选自氢、氘、氟、氯、溴、甲基、乙基、一氟甲基、二氟甲基或三氟甲基;R 2独立地选自氢、氘、氟、氯、溴、甲基、乙基、一氟甲基、二氟甲基或 三氟甲基;R 2-1选自氨基、C 1-3烷基、卤代C 1-3烷基或氘代C 1-3烷基,所述的氨基、C 1-3烷基、卤代C 1-3烷基或氘代C 1-3烷基任选地可以进一步被氘、卤素、氰基、羟基、硝基、C 1-3烷基、卤代C 1-3烷基和氘代C 1-3烷基中的一个或多个取代;优选地,R 2-1选自异丙基、-CH(Me)OMe、或-N(Me) 2;R 4选自卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3烷氧基、C 1-3羟烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、3-8元杂环基、-S(O) mR d或-C(O)R d,所述的氨基、C 1-3烷基、C 1-3烷氧基、C 1-3羟烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基和3-8元杂环基任选地可以进一步被一个或多个R 4-1取代;R 4-1独立地选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-4烯基、C 2-4炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、3-8元杂环基、C 6-12芳基或5-12元杂芳基;任选地,R 4-1被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-4烯基、C 2-4炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、3-8元杂环基、C 6-12芳基、5-12元杂芳基中的一个或多个取代,其中,氨基、C 1-3烷基、C 2-4烯基、C 2-4炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基,任选地被氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 2-4烯基、C 2-4炔基、C 1-3氘代烷基、C 1-3卤代烷基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基中的一个或多个取代;优选地,R 4独立地选自氟、氯、氰基、三氟甲基、甲基、乙基、硝基、羟基、甲氧基、-OCD 3、氢、 环丙基、 二氟甲基、R 6-1选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3烷氧基、C 1-3羟烷基;R 6-2选自氢、氘、氧代、硫代、卤素、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、3-6元杂环基、-S(O) mR e或-C(O)R e,所述的氨基、C 1-3烷基、C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基和3-8元杂环基任选地可以进一步被氘、卤素、氨基、羟基、氰基、硝基、C 1-3烷基中的一个或多个取代;R d独立地选自氢、氘、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、3-6元杂环基、C 1-3卤代烷基、C 1-3氘代烷基;R e独立地选自氢、氘、氨基、羟基、氰基、硝基、C 1-3烷基、C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、3-6元杂环基、C 1-3卤代烷基、C 1-3氘代烷基;m为0、1或2;y为0、1、2、3或4。
- 根据权利要求1~13任一项所述的化合物、其立体异构体或其药学上可接受的盐在制备EGFR抑制剂药物中的应用。
- 根据权利要求14所述的应用,所述的EGFR为突变的EGFR,优选Del19、L858R、T790M或C797S中的一个或多个突变,更优选L858R/T790M、Del19/T790M、Del19/C797S、L858R/C797S、Del19/T790M/C797S或L858R/T790M/C797S突变的EGFR。
- 根据权利要求1~13任一项所述的化合物、其立体异构体或其药学上可接受的盐在制备治疗癌症的药物中的应用;优选地,所述癌症是非小细胞肺癌。
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CN115650958A (zh) * | 2022-10-14 | 2023-01-31 | 中国药科大学 | 2-氨基嘧啶类化合物及其制备方法、用途和药物组合物 |
CN115650958B (zh) * | 2022-10-14 | 2024-05-17 | 中国药科大学 | 2-氨基嘧啶类化合物及其制备方法、用途和药物组合物 |
WO2024152986A1 (zh) * | 2023-01-18 | 2024-07-25 | 北京鞍石生物科技有限责任公司 | 杂芳基氨基化合物及其制备方法和应用 |
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AU2022334647A1 (en) | 2024-02-15 |
CN115724827A (zh) | 2023-03-03 |
JP2024532835A (ja) | 2024-09-10 |
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TW202328100A (zh) | 2023-07-16 |
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